Surgery of the Brainstem 2019027144, 9781626232914, 9781626232921, 7118931421

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Surgery of the Brainstem

Robert F. Spetzler, MD Emeritus President and CEO Barrow Neurological Institute Phoenix, Arizona M. Yashar S. Kalani, MD, PhD Vice Chair and Associate Professor Director of Skull Base and Neurovascular Surgery Departments of Neurosurgery and Neuroscience University of Virginia School of Medicine Charlottesville, Virginia Michael T. Lawton, MD President and CEO Department of Neurosurgery Chair Barrow Neurological Institute Phoenix, Arizona

Thieme New York • Stuttgart • Delhi • Rio de Janeiro

Library of Congress Cataloging-in-Publication Data Names: Spetzler, Robert F. (Robert Friedrich), 1944- editor. | Kalani,   Yashar, editor. | Lawton, Michael T, editor. Title: Surgery of the brainstem / [edited by] Robert F. Spetzler,   M. Yashar S. Kalani, Michael T. Lawton. Description: New York : Thieme, [2020] | Includes bibliographical­   references and index. Identifiers: LCCN 2019027144 | ISBN 9781626232914 | ISBN   9781626232921 eISBN Subjects: MESH: Brain Stem—surgery | Thalamus—surgery | Pineal   Gland–surgery | Brain Neoplasms—surgery | Cerebrovascular —  Disorders—surgery Classification: LCC RD594 | NLM WL 310 | DDC 617.4/81—dc23   LC record available at https://lccn.loc.gov/2019027144

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To my patients, always my greatest inspiration. Robert F. Spetzler To Kristin, Kayhan, and Layla. M. Yahar S. Kalani To Suzanne—my rock, my warrior, my inspiration. Michael T. Lawton

 

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Contents Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xii

I History of Brainstem Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

01

1

History of Brainstem Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

03

II Anatomy, Development, and Pathology of the Brainstem, Thalamus, and Pineal Region. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

19



2

3

Nikolay L. Martirosyan, Alessandro Carotenuto, Arpan A. Patel, and Mark C. Preul

Anatomy of the Brainstem, Thalamus, Pineal Region, and Cranial Nerves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Kaan Yağmurlu, M. Yashar S. Kalani, and Albert L. Rhoton Jr.

Development of the Human Brainstem and Its Vasculature. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41



Nicholas T. Gamboa, Bornali Kundu, and M. Yashar S. Kalani

4

Pathology of the Brainstem. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53



Hannes Vogel

III Examination, Imaging, and Monitoring for Brainstem Surgery. . . . . . . . . . . . . . . . . .  5

6

7

Imaging Anatomy and Pathology of the Brainstem, Thalamus, and Pineal Region. . . . . . . . . . . . . . . . . . . . . . . 73

Jeremy N. Hughes and John P. Karis

Neuromonitoring for Brainstem Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

Christian Musahl and Nikolai J. Hopf

Neurologic Examination of the Brainstem and Thalamus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

Yazan J. Alderazi and Mohamed S. Teleb

IV Surgical Approaches to the Brainstem, Thalamus, and Pineal Region . . . . . . .  8

9

10

11

12

71

109

Surgical Approaches to the Ventral Brainstem and Thalamus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

Jayson Sack, Siviero Agazzi, and Harry R. van Loveren

Approaches to the Dorsal Brainstem, Thalamus, and Pineal Region. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118

M. Yashar S. Kalani, Nikolay L. Martirosyan, and Robert F. Spetzler

Skull Base Approaches to the Lateral Brainstem and Cranial Nerves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138

Takanori Fukushima

Endoscopic Approaches to the Brainstem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158

Alaa S. Montaser, André Beer-Furlan, Ricardo L. Carrau, Bradley A. Otto, and Daniel M. Prevedello

Safe Entry Zones to the Brainstem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

Daniel D. Cavalcanti

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Contents

V Comprehensive Management of Tumors of the Brainstem, Thalamus, and Pineal Region. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  13

14

15

185

Adult Brainstem Gliomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187

Helmut Bertalanffy, Yoshihito Tsuji, Rouzbeh Banan, and Souvik Kar

Pediatric Brainstem Tumors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210

Roberta Rehder and Alan R. Cohen

Tumors of the Thalamus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219



Ziev B. Moses, Gabriel N. Friedman, Muhammad M. Abd-El-Barr, and E. Antonio Chiocca

16

Tumors of the Third Ventricle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226



17

18

19

20



21

22

Srikant S. Chakravarthi, Melanie B. Fukui, Alejandro Monroy-Sosa, Juanita M. Celix, Jonathan Jennings, George Bobustuc, Ken Bastin, Richard Rovin, and Amin B. Kassam

Tumors of the Fourth Ventricle. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255

Semra Isik, Saira Alli, and James T. Rutka

Tumors of the Cerebellopontine Angle. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276

Omar Arnaout and Ossama Al-Mefty

Pineal Region Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

Stephen G. Bowden, Adam M. Sonabend, and Jeffrey N. Bruce

Stereotactic Radiosurgery for Tumors of the Brainstem, Thalamus, and Pineal Region. . . . . . . . . . . . . . . . . 298

Amparo Wolf and Douglas Kondziolka

Radiotherapy for Pineal, Thalamic, and Brainstem Tumors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308

Susan G. R. McDuff, Shannon M. MacDonald, and Kevin S. Oh

Neuro-Oncologic Considerations for Pineal, Thalamic, and Brainstem Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . 319

Abdulrazag Ajlan and Lawrence Recht

VI Comprehensive Management of Vascular Pathology of the Brainstem and Thalamus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  23

24

25

329

Brainstem Ischemia, Stroke, and Endovascular Revascularization of the Posterior Circulation. . . . . . . . 331

Stephan A. Munich, Jason Davies, Hussain Shallwani, and Elad I. Levy

Microsurgical Embolectomy for Emergency Revascularization of the Brainstem. . . . . . . . . . . . . . . . . . . . . . . . . 340

Felix Goehre and Rokuya Tanikawa

Brainstem and Thalamic Intraparenchymal Hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349



B. McGrath and Michael R. Levitt

26

Surgical Management of Posterior Circulation Aneurysms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354



27

28

29

30

Behnam Rezai Jahromi, Tarik F. Ibrahim, Ferzat Hijazy, Danil A. Kozyrev, Felix Goehre, Hugo Andrade-Barazante, Hanna Lehto, and Juha Hernesniemi

Endovascular Management of Aneurysms of the Posterior Circulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383

Pervinder Bhogal, Marta Aguilar Pérez, Elina Henkes, Hansjörg Bäzner, Oliver Ganslandt, and Hans Henkes

Surgical Management of Thalamic and Brainstem Arteriovenous Malformations. . . . . . . . . . . . . . . . . . . . . . . . 397

Caleb Rutledge and Michael T. Lawton

Endovascular Management of Brainstem and Thalamic Arteriovenous Malformations. . . . . . . . . . . . . . . . . 404

Fadi Al-Saiegh and Pascal M. Jabbour

Surgery for Thalamic and Brainstem Cavernous Malformations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412

Da Li, Zhen Wu, and Jun-Ting Zhang

Contents

31

ix

Revascularization of the Brainstem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423

Anoop Patel, Harley Brito da Silva, and Laligam N. Sekhar

32 Stereotactic Radiosurgery for Arteriovenous Malformations of the Basal Ganglia, Thalamus, and Brainstem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437

Or Cohen-Inbar and Jason P. Sheehan

VII Implants and Cranial Nerve Repair. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  33

449

Auditory Brainstem Implants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451

Ksenia A. Aaron, Elina Kari, and Rick A. Friedman

Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461

x

Preface The brainstem has long been fabled to be unsurmountable territory, with surgery in and around it considered to be a fool’s errand. However, recent advances in imaging, anesthesia, monitoring, surgical technique and instrumentation, postoperative care, and rehabilitation have made it possible to approach lesions in the brainstem with more surety and better outcomes. Nonetheless, the decision to proceed with the treatment of a patient with brainstem pathology is not trivial, and many factors influence this decision. The physician must have an honest and frank discussion with the patient and counsel toward treatment only if the therapy can likely improve upon the natural history of the pathology. Then and only then should treatment be recommended, after weighing such factors as the nature of the ailment; the patient’s wishes, age, and medical condition; the surgeon’s experience; and the expected outcomes.

Operations in and around the brainstem are often fraught with transient, and sometimes permanent, morbidity. Counseling patients about the nature and duration of expected morbidity is one of the most important responsibilities of the physician. Not all pathology within or adjacent to the brainstem requires surgery. Selecting patients cautiously, developing technical skill, and building experience are keys to success.

Robert F. Spetzler, MD M. Yashar S. Kalani, MD, PhD Michael T. Lawton, MD

 

xi

Acknowledgments The editors would like to acknowledge the expertise provided by the master surgeons and physicians who took time from their busy practices to share their knowledge and experience in the chapters they have contributed that made this work a possibility. We would also like to acknowledge the Neuroscience Publications staff, editors, and illustrators at Barrow Neurological Institute for their immense effort and dedication to editorial, graphic, and artistic excellence in bringing this project to pass. Specifically, we would like to thank medical illustrators Kristen Larson Keil, Peter M. Lawrence (who also prepared the cover illustration), and

Mark Schornak; medical editors Mary Ann Clifft, Paula ­Higginson, Joseph Mills, Dawn Mutchler, and Lynda Orescanin; editorial coordinators Rogena Lake and Samantha Soto; and production editor Cassandra Todd and production assistant Cindy Giljames. Our thanks also go to the staff at Thieme Medical Publishers with whom we have worked, including Tim Hiscock, who saw the potential in this book from the beginning, and Sarah Landis, who oversaw its production. Finally, and most importantly, we would like to thank our patients and their families for entrusting us with their lives and for giving us the honor of caring for them.

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Contributors Ksenia A. Aaron, MD T32 Neurotology Fellow Department of Otolaryngology-Head and Neck Surgery Stanford University Stanford, California

Omar Arnaout, MD Member of the Faculty, Harvard Medical School Department of Neurological Surgery Brigham and Women’s Hospital Boston, Massachusetts

Muhammad M. Abd-El-Barr, MD, PhD Assistant Professor Department of Neurosurgery Duke University Medical Center Durham, North Carolina

Rouzbeh Banan, MD Resident of Neuropathology Department of Neuropathology Institute of Pathology Hanover Medical School Hanover, Germany

Siviero Agazzi, MD, MBA, FACS Professor and Director Division of Cranial Surgery Department of Neurosurgery University of South Florida Tampa, Florida Abdulrazag M. Ajlan, MD, MSc, FRCSC, UCNS(D) Assistant Professor & Neurosurgery Consultant Surgery Department King Saud University Riyadh, Kingdom of Saudi Arabia Adjunct Assistant Professor, Neurosurgery Department Stanford University Palo Alto, California Ossama Al-Mefty, MD, FACS Director of Skull Base Surgery Department of Neurosurgery Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts Yazan J. Alderazi, MD Assistant Professor Director of Neurointerventional Service Department of Neurology Texas Tech University Health Sciences Center,   School of Medicine Lubbock, Texas Saira Alli, MBBS, MRCS, MRCP Neurosurgery Resident Division of Neurosurgery, Department of Surgery University of Toronto Toronto, Ontario, Canada Hugo Andrade-Barazarte, MD, PhD Department of Neurosurgery Helsinki University Hospital & University of Helsinki Helsinki, Finland

Kenneth Bastin, MD, MBA Director of Radiosurgery St. Luke’s Medical Center, Aurora Health Care Milwaukee, Wisconsin Hansjörg Bäzner, MD, Prof. Dr. med. Neurological Clinic Neurozentrum, Klinikum Stuttgart Stuttgart, Germany Andre Beer-Furlan, MD Clinical Instructor Department of Neurological Surgery The Ohio State University Columbus, Ohio Helmut Bertalanffy, MD, PhD Professor of Neurosurgery Director of Vascular Neurosurgery International Neuroscience Institute Hannover, Germany Pervinder Bhogal, BSc (Hons), MBBS, MRCS, FRCR Consultant Interventional Neuroradiologist Neuroradiological Clinic Neurocenter Klinikum Stuttgart Stuttgart, Germany Department of Interventional Neuroradiology The Royal London Hospital London, United Kingdom George Bobustuc, MD Neuro-Oncology Department Aurora Neuroscience Innovation Institute Aurora Cancer Care Milwaukee, Wisconsin Stephen G. Bowden, MD Department of Neurological Surgery Columbia University Irving Medical Center Neurological Institute of New York New York, New York

 Contributors Harley Brito da Silva, MD Visiting Professor Department of Neurological Surgery University of Washington Seattle, Washington Jeffrey N. Bruce, MD Edgar M. Housepian Professor Department of Neurological Surgery Columbia University College of Physicians and Surgeons New York, New York Alessandro Carotenuto, BA Medical Student College of Medicine-Phoenix University of Arizona Phoenix, Arizona Daniel D. Cavalcanti, MD, PhD Director of Cerebrovascular Surgery Department of Neurosurgery Paulo Niemeyer State Brain Institute Rio de Janeiro, Brazil Ricardo L. Carrau, MD Professor and Lynne Shepard Jones Chair in   Head & Neck Oncology Department of Otolaryngology-Head & Neck Surgery Department of Neurological Surgery Director of the Comprehensive Skull Base Surgery Program The Ohio State University Wexner Medical Center Columbus, Ohio Juanita M. Celix, MD, MPH Neurosurgeon Aurora Neuroscience Innovation Institute Aurora St. Luke’s Medical Center Milwaukee, Wisconsin Srikant S. Chakravarthi, MD, MSc Neurosurgery Research Fellow Department of Neurosurgery Aurora Neuroscience Innovation Institute Aurora St. Luke’s Medical Center Milwaukee, Wisconsin E. Antonio Chiocca, MD, PhD, FAANS Harvey W. Cushing Professor of Neurosurgery,   Harvard Medical School Established by the Daniel E. Ponton Fund Neurosurgeon-in-Chief and Chairman,   Department of Neurosurgery Brigham and Women’s Hospital Boston, Massachusetts Alan R. Cohen, MD, FACS, FAAP Professor of Neurosurgery, Oncology and Pediatrics Chief of Pediatric Neurosurgery The Johns Hopkins University School of Medicine Baltimore, Maryland

xiii

Or Cohen-Inbar, MD, PhD Assistant Professor Department of Neurological Surgery, Rambam Maimonides Health Care Center Technion Israel Institute of Technology Haifa, Israel Assistant Professor Department of Neurological Surgery and Gamma Knife Center University of Virginia Health Care Campus Charlottesville Virginia Jason Davies, MD, PhD Cerebrovascular and Skullbase Neurosurgery Departments of Neurosurgery and Biomedical Informatics Director of Cerebrovascular Microsurgery Director of Endoscopy, Kaleida Health Research Director, Jacobs Institute State University of New York, Buffalo Buffalo, New York Gabriel N. Friedman, MD Resident Department of Neurosurgery Massachusetts General Hospital Boston, Massachusetts Rick A. Friedman, MD, PhD Professor of Otolaryngology and Neurosurgery Director of the Acoustic Neuroma Center UC San Diego Health La Jolla, California Melanie Brown Fukui, MD Director of Neuroradiology Aurora Neuroscience Innovation Institute Aurora St. Luke’s Medical Center Milwaukee, Wisconsin Takanori Fukushima, MD, DMSc Consulting Professor Department of Neurosurgery Duke University Medical Center Durham, North Carolina Nicholas T. Gamboa, MD Resident Department of Neurosurgery University of Utah School of Medicine Salt Lake City, Utah Oliver Ganslandt, MD, PhD Professor of Neurosurgery Department of Neurosurgery Klinikum Stuttgart Stuttgart, Germany Felix Goehre, MD, PhD Adjunct Professor of Neurosurgery Department of Neurosurgery Bergmannstrost Hospital Halle Halle, Germany

xiv

Contributors

Elina Henkes, MD Neuroradiological Clinic Neurozentrum, Klinikum Stuttgart Stuttgart, Germany Hans Henkes, MD, Prof. Dr. med. Dr. h.c. Neuroradiological Clinic Neurozentrum, Klinikum Stuttgart Stuttgart, Germany Juha Hernesniemi, MD, PhD Department of Neurosurgery Helsinki University Hospital & University of Helsinki Helsinki, Finland Ferzat Hijazy, MD Neurovascular Fellow Department of Neurosurgery Helsinki University Hospital Helsinki, Finland Nikolai J. Hopf, MD, PhD Director NeuroChirurgicum Center for Endoscopic & Minimally Invasive Neurosurgery Stuttgart, Germany Jeremy N. Hughes, MD Assistant Professor, Department of Neuroradiology Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, Arizona Tarik F. Ibrahim, MD† Department of Neurosurgery Loyola University Medical Center Maywood, Illinois Semra Isik, MD Assistant Professor Department of Neurosurgery Baskent University Istanbul, Turkey Pascal Jabbour, MD Professor of Neurological Surgery Chief, Division of Neurovascular Surgery and Endovascular  Neurosurgery Thomas Jefferson University Hospital Philadelphia, Pennsylvania Behnam Rezai Jahromi, MD Department of Neurosurgery Helsinki University Hospital & University of Helsinki Helsinki, Finland Jonathan E. Jennings, MD Chief of Neuroradiology Aurora St. Luke’s Medical Center Milwaukee, Wisconsin

M. Yashar S. Kalani, MD, PhD Vice Chair and Associate Professor Director of Skull Base and Neurovascular Surgery Departments of Neurosurgery and Neuroscience University of Virginia School of Medicine Charlottesville, Virginia Souvik Kar, PhD Postdoctoral Research Fellow Department of Neurosurgery International Neuroscience Institute Hannover, Germany Elina Kari, MD Assistant Professor Otolaryngology - Otology & Neurotology University of California, San Diego La Jolla, California John P. Karis, MD Director, MRI and Brain Imaging Professor, Department of Neuroradiology Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, Arizona Amin B. Kassam, MD Vice President, Department of Neurosciences Chairman, Department of Neurological Surgery Aurora Neuroscience Innovation Institute Aurora St. Luke’s Medical Center Milwaukee, Wisconsin Douglas Kondziolka, MD, MSc, FRCSC, FACS Gray Family Professor of Neurosurgery Vice-Chair, Clinical Research (Neurosurgery) Professor of Radiation Oncology Director, Center for Advanced Radiosurgery NYU Langone Medical Center New York, New York Danil A. Kozyrev, MD Junior Researcher Department of Pediatric Neurology and  Neurosurgery North-Western State Medical University St. Petersburg, Russia Bornali Kundu, MD, PhD Resident Department of Neurosurgery University of Utah Salt Lake City, Utah Michael T. Lawton, MD President and CEO Department of Neurosurgery Chair Barrow Neurological Institute Phoenix, Arizona

Contributors Hanna Lehto, MD, PhD Associate Professor Department of Neurosurgery Helsinki University Hospital Helsinki, Finland Michael R. Levitt, MD Assistant Professor Departments of Neurological Surgery, Radiology,   and Mechanical Engineering University of Washington Seattle, Washington Elad I. Levy, MD, MBA, FACS, FAHA Professor and Chair and L. Nelson Hopkins MD   Professor Endowed Chair Department of Neurosurgery Professor Department of Radiology Jacobs School of Medicine and Biomedical Sciences   at the University at Buffalo Medical Director, Department of Neuroendovascular Services Co-Director, Gates Stroke Center Kaleida Health Buffalo, New York Da Li, MD Lecturer Department of Neurosurgery Beijing Tiantan Hospital, Capital Medical University Beijing, China Shannon M. MacDonald, MD Associate Professor Harvard Medical School Massachusetts General Hospital Boston, Massachusetts Nikolay L. Martirosyan, MD, PhD Resident Department of Neurosurgery University of Arizona Phoenix, Arizona Susan G. R. McDuff, MD, PhD Harvard Radiation Oncology Program Department of Radiation Oncology The Massachusetts General Hospital Boston, Massachusetts Lynn B. McGrath Jr, MD Resident Department of Neurological Surgery University of Washington Seattle, Washington

Alaa S. Montaser, MD Assistant Lecturer Neurosurgery Department Ain Shams University Cairo, Egypt Research Fellow Neurosurgery Department The Ohio State University Wexner Medical Center Columbus, Ohio Ziev B. Moses, MD Resident Department of Neurosurgery Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts Stephan A. Munich, MD Neuroendovascular Fellow Department of Neurosurgery SUNY at Buffalo Buffalo, New York Christian Musahl, MD Vice Chairman Department of Neurosurgery Helios Dr. Horst Schmidt Klinik Wiesbaden, Germany Kevin S. Oh, MD Assistant Professor Department of Radiation Oncology The Massachusetts General Hospital Harvard Medical School Boston, Massachusetts Bradley A. Otto, MD Assistant Professor Department of Otolaryngology - Head and Neck Surgery The Ohio State University Wexner Medical Center Columbus, Ohio Anoop P. Patel, MD Assistant Professor Department of Neurosurgery University of Washington Seattle, Washington Arpan A. Patel, BS Medical Student College of Medicine - Phoenix University of Arizona Phoenix, Arizona Marta Aguilar Pérez, MD Senior Consultant Department of Neuroradiology Klinikum Stuttgart Stuttgart, Germany

xv

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Contributors

Mark C. Preul, MD Newsome Chair of Neurosurgery Research Director of Neurosurgery Research and the Neurosurgery   Research Laboratory Professor of Neurosurgery and Neuroscience Department of Neurosurgery Barrow Neurological Institute Dignity Health St. Joseph’s Hospital and Medical Center Phoenix, Arizona Clinical Professor of Neuroscience Interdisciplinary Graduate Program in Neuroscience Arizona State University Tempe, Arizona Daniel M. Prevedello, MD Professor Department of Neurosurgery The Ohio State University Columbus, Ohio Lawrence D. Recht, MD Professor Department of Neurology & Clinical Neurosciences Stanford University School of Medicine Palo Alto, California Roberta Rehder, MD, PhD Research Associate Department of Neurosurgery The Johns Hopkins University School of Medicine Baltimore, Maryland Albert L. Rhoton Jr, MD† Professor Department of Neurological Surgery University of Florida Gainesville, Florida Richard A. Rovin, MD Department of Neurosurgery Aurora Neuroscience Innovation Institute Aurora St. Luke’s Medical Center Milwaukee, Wisconsin James T. Rutka, MD, PhD, FRCSC Professor and RS McLaughlin Chair Division of Neurosurgery Department of Surgery University of Toronto Toronto, Canada Caleb Rutledge, MD Resident Department of Neurological Surgery University of California San Francisco San Francisco, California Jayson Sack, MD Assistant Professor Department of Neurosurgery and Brain Repair University of South Florida Tampa, Florida

Fadi Al-Saiegh, MD Resident Physician Department of Neurological Surgery Thomas Jefferson University Hospital Philadelphia, Pennsylvania Laligam N. Sekhar, MD, FACS, FAANS Professor and Vice Chairman Director of Cerebrovascular and Skull Base Surgery Department of Neurological Surgery University of Washington Seattle, Washington Hussain Shallwani, MBBS Endovascular Research Fellow Department of Neurosurgery State University of New York at Buffalo Buffalo, New York Jason P. Sheehan, MD, PhD Professor of Neurological Surgery Department of Neurosurgery University of Virginia Charlottesville, Virginia Robert F. Spetzler, MD Emeritus President and CEO Barrow Neurological Institute Phoenix, Arizona Adam M. Sonabend, MD Assistant Professor Department of Neurosurgery Northwestern University Feinberg School of Medicine Chicago, Illinois Rokuya Tanikawa, MD Director Department of Neurosurgery Stroke Center Sapporo Teishinkai Hospital Sapporo, Japan Mohamed S. Teleb, MD Medical Director of Neurosciences, Banner Desert Medical Center Department of Neuroscience Banner Health Phoenix, Arizona Yoshihito Tsuji, MD, PhD Guest Doctor Director of Vascular Neurosurgery International Neuroscience Institute Hannover, Germany Harry van Loveren, MD David W. Cahill Professor and Chair Department of Neurosurgery and Brain Repair Institution Morsani College of Medicine University of South Florida Tampa, Florida

Contributors Hannes Vogel, MD Professor Department of Pathology Stanford University Palo Alto, California Amparo Wolf, MD, PhD Department of Clinical Neurological Sciences University of Western Ontario London, Canada Zhen Wu, MD, PhD Professor Dapartment of Neurosurgery Beijing Tiantan Hospital, Capital Medical University Beijing, China

Kaan Yağmurlu, MD Neurosurgery Research Fellow Department of Neurosurgery Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, Arizona Jun-Ting Zhang, MD Professor Dapartment of Neurosurgery Beijing Tiantan Hospital, Capital Medical University Beijing, China †

Deceased

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Section I

1 History of Brainstem Surgery01

History of Brainstem Surgery

I

1

History of Brainstem Surgery

Nikolay L. Martirosyan, Alessandro Carotenuto, Arpan A. Patel, and Mark C. Preul

Abstract

The history of brainstem surgery had been a seemingly unexplored locus in the history neurosurgery, as it pertains to neuroanatomy, until Andreas Vesalius’s Fabrica and Thomas Willis’s Cerebri Anatome. However, neuroanatomists dating back to Galen in the 2nd century AD had identified structures of the brainstem but had associated them with the betterknown parts of the brain. The history of brainstem surgery can be understood most clearly by placing it into three distinct phases: premodern (before 1879), gestational (1879–1919), and modern (after 1919). The premodern phase consists entirely of the world’s first neuroanatomists, from Galen to Franz Joseph Gall, who developed new perspectives with which to dissect the brain and view its structures. Groundbreaking techniques in tissue preservation and dissection ushered in a new era of microscopic neuroanatomy. These innovations, in combination with newly developed surgical techniques, became the basis on which neurosurgery was created. Even after the beginning of the gestational period, marked by the onset of general surgeons operating within the brain, surgery within the posterior fossa and particularly on brainstem lesions lagged behind operations within other regions of the brain. By the end of the early 1900s, leaders such as Fedor Krause, Harvey Cushing, and Walter Dandy had revolutionized surgery within the posterior fossa, successfully completing operations on the brainstem that were previously considered impossible. Throughout the 20th century, significant advances were made in the field of brainstem surgery, fueled by the introduction of computed tomography and magnetic resonance imaging, and by progress in surgical technology development. Keywords:  brainstem, Leonardo da Vinci, history of neurosurgery, neuroanatomy, neurosurgery, Andreas Vesalius, Thomas Willis

■■ Introduction In textbooks and articles that narrate the history of neurosurgery, there seems to be a blank space between the cerebellum and the spinal cord. Even leading historians of neuroanatomy appear to have forgotten a chapter about the brainstem. On closer observation, it is not so much that scholars have forgotten to chronicle the discovery of the brainstem and its components, but rather that these components are hidden between the lines in chapters devoted to other regions of the brain. However, deeper consideration of the medical history of the seemingly forgotten brainstem makes it clear why authors might exclude a chapter explicitly on the brainstem; it was because the brainstem was once regarded as part of its surrounding structures—the

c­ erebellum, diencephalon, and spinal cord. In Cerebri Anatome, Thomas Willis (1621–1675) described the gross structures of the midbrain, pons, and medulla, although he identified these structures collectively as the “cerebellum.” Willis is credited with being the first to accurately describe the general functions of the brainstem and to recognize the individual areas of this brain structure, although he did so under the impression that they were part of the cerebellum. For this reason, Willis is considered to be the first to identify the brainstem. The purpose of this chapter is to serve as a guide to the history of brainstem surgery in what we believe to be the first dedicated history of the brainstem itself. In this chapter, we will chronicle the history of the brainstem as the earliest pioneers of neuroanatomy saw it. After we stretch a canvas across the centuries, from Galen to modern-day surgery, we will paint a picture of the evolving identity of the brainstem as it unfolded in accordance with associated techniques and technology. In this way, we will compartmentalize the epochs of neuroscience, starting with macroanatomy in the 2nd century AD and concluding with microanatomy leading into the 21st century. In a similar manner, this chapter will discuss the development of brainstem surgery. The history of brainstem surgery can be understood most clearly by placing it within the historical context of neuroanatomy and surgery as a whole, which can be divided into three distinct phases: premodern (before 1879), gestational (1879–1919), and modern (after 1919). The transition from premodern to gestational was marked by the introduction of clinical cerebral localization, the antiseptic or aseptic technique, and the use of anesthesia. The pioneers and the driving force behind the birth of neurosurgery include the famous surgeons William Macewen (1848–1924) and Joseph Lister (1827–1912).1 When operating within the brain parenchyma became more common, leaders such as Victor Horsley (1857–1916), Fedor Krause (1857–1937), Harvey Cushing (1869–1939), Charles Elsberg  (1871–1948), Wilder Penfield  (1891–1976), Walter Dandy (1886–1946), Ernest Sachs (1879–1958), and Charles Frazier (1870–1936), foremost among others, worked tirelessly to establish neurosurgery as its own specialty.2 After Cushing’s presentation at the 1919 meeting of the American College of Surgeons, William J. Mayo declared, “Gentleman, we have this day witnessed the birth of a new specialty—neurosurgery.”3 This momentous occasion marks the transition from the gestational period into the modern era of neurosurgery. Several pivotal discoveries during the development of modern neurosurgery have revolutionized its practice, including the introduction of computed tomography (CT), magnetic resonance imaging (MRI), and the surgical microscope.4 The scope of this chapter will focus on the birth and progression of brainstem surgery until the introduction of the surgical microscope in the 1970s.

3

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I  History of Brainstem Surgery

■■ From Galen to Gall To properly analyze the discoveries pertaining to neuroanatomy, and specifically the brainstem, we must extend the scope of our subject to events that subsequently advanced the development of neuroanatomy. Such landmark events range from huge societal events such as the lifting of the ban on dissection in the 15th century,5 to the simple 16th-century suggestion to flip the brain upside down. Although the earliest “neurosurgical” procedures took place in ancient Egypt during the second millennium BC, one might argue that these practices were merely a means of embalming rather than a curative or diagnostic form of medicine.6 It was not until Herophilus (c. 335–280 BC) entered Alexandria in 300 BC that the development of neuroanatomical medicine truly took flight. Described by Elhadi et al6 as “fully equipped to support medical education,” Alexandria was the birthplace of anatomical study, with Herophilus and Erasistratus (c. 310–250 BC) as two of its most significant contributors. The Egyptian pharaohs Ptolemy I (c. 366–282 BC) and Ptolemy II (c. 308–246 BC) decreed that vivisection of sentenced criminals was allowed, and Herophilus apparently did so publicly, in large numbers. Although Herophilus and Erasistratus had amassed considerable knowledge of cerebral and cerebellar anatomy, and they had discussed the importance of the ventricular system, the history of the brainstem begins with the macroanatomical studies of Galen of Pergamum (c. 129–216) in the 2nd century AD, as he was the first to write about explorations around the brainstem.7,​8,​9,​10 Galen lived in Alexandria during a time when human dissection was no longer allowed, and he was therefore forced to explore the neuroanatomy of animals.8 According to early texts, Galen, and many others until the 1600s, believed that the brain was the seat of the human soul and that the ventricles were the conduit of the animal spirit. Galen supported this claim through experiments showing that compression of the fourth ventricle caused marked depression of animal behavior.11 For the purposes of this chapter, it is important to understand this point: How these early anatomists approached the brain reveals what they considered important and how they used it to construct their theories. To understand why Galen was so fascinated with the ventricles, one must know how he viewed the brain, which was from a top-down approach. In the translation of his personal account, titled Anatomical Procedures, he explained that his dissection starts by separating the brain into its natural divisions, the two cerebral hemispheres and the cerebellum.12 Naturally, one can infer from a dissection of this nature that the first structures he came across were the septum pellucidum and the ventricular system. Notably, this approach allowed Galen to explore other parts of the brain, such as the corpora quadrigemina, the cerebellar vermis, and the cerebellar peduncles.11,​12,​13 As part of Galen’s quest to prove his theory of a ventricular conduit, he postulated that animal spirits could be made within the linings of the ventricles and stored within the ventricles until called into action in the brain.8,​14 Galen used his dissection methods to reveal other deep structures of the brain beyond the ventricular system, including the basal ganglia.11 Notable scholars such as Avicenna (980–1037) and Mondino de Luzzi (1275–1326) worked diligently to preserve and uphold the status of Galen’s work until the Renaissance.13 Thus, Galen’s findings lasted 1500 years until 1664 when Thomas Willis eventually penned the most accurate reasoning on the function of the ventricular system.13

After Galen’s death, developments in neuroanatomy remained largely dormant throughout the Dark Ages when the church still forbade human dissection. However, Pope Sixtus IV  (1414–1484) lifted the ban on human dissection in 1482, allowing the bodies of executed prisoners to be dissected.5 One of the first to take advantage of the Pope’s decree was Leonardo da Vinci  (1452–1519), who had previously been dissecting corpses in secrecy.9 It is believed that Leonardo was among the first persons since Galen to perform his own dissections, as anatomists at the time hired untrained barber surgeons or butchers. Leonardo diverged from Galenic teachings, albeit not immediately nor in all aspects.15 He maintained the belief that the ventricular system carried the vital spirits of “humanness,” and he relied on Galen’s texts for much of his work.15,​16 However, because Leonardo did not know that Galen’s work was based on animals, some of his earlier illustrations were inaccurate because Galen’s work depicted animals rather than humans.15,​16 It was not until Leonardo began illustrating what he learned through firsthand experience with cadaver dissections, and not by reference, that his work more accurately portrayed human subjects. His abiding interests in physics and mechanics helped him to illustrate cranial sinuses. Yet even more impressive was his use of molten wax injections to create a cast of the ventricular system, for the first accurate depiction of these structures in humans.15,​16 Although much of Leonardo’s work was not realized because of the untimely death of his partner and probable publisher, it did pave the way for the beginning of the “Renaissance of Anatomy,” which began with the work of the Flemish anatomist and physician Andreas Vesalius (1514–1564). In this era, it was common for men and women to be obsessed with their bodies, even journaling about the appearance of the body and various bodily functions.17 It was also the beginning of the search for improved artistic means to truly represent the human body. Explorations of nature were aimed at understanding reality, and the introduction and demonstrations of linear perspective and the communication of its mathematical basis significantly impacted renderings of anatomy, especially the brain.17 Vesalius, while adhering to old doctrine, reinvented neuroanatomy (Fig. 1.1). As described in Brain Renaissance, a biography of Vesalius: Vesalius laid down a new paradigm in medical knowledge: a revolutionary inductive approach that seeks direct evidence to explain the wonders of the human form. Vesalius was not prepared to take for granted what had not been clearly demonstrated for the human body at the dissection table. His anatomy was based only on knowledge derived from direct observation, which led him to identify significant differences between animals and humans.18 Although the texts of Vesalius’s works are not recognized for being groundbreaking expressions, his illustrations were immediately held to be revolutionary.11 His 1543 compilation of drawings in De humani corporis fabrica [On the fabric of the human body] is considered to be one of the most influential graphic works of its time and of all of science, and the drawings remain very close to modern brain illustrations.19 In fact, the folio publication of the Fabrica (i.e., Epitome), which contained brief text and concentrated on the illustrations, became even more popular among students. Like Galen, Vesalius devoted much of his work on the brain to the ventricular system,9,​13,​16 but that is where the similarities end. In fact, Vesalius was arguably Galen’s first dissenter. While a senior lecturer in surgery at the University of Bologna, Vesalius came to realize Galen’s shortcomings as an

1  History of Brainstem Surgery

5

Fig. 1.1  Andreas Vesalius’ Fabrica, published in 1543, was the first masterpiece of human anatomy. Although his work lacked exposure of the undersurface of the brain, it presented new perspectives of the brain and skull that had never been seen before. (a) After sawing off the top of the cranium, he removed both the dura mater and the arachnoid membrane and separated the cerebral hemispheres. (b) He then removed the posterior half of the cortex and retracted the cerebellum anteriorly to view the inferior lobes of the

cerebellum and the posterior brainstem. (c) He separated the posterior dorsal cord with the peduncles and the cavity of the fourth ventricle. (d) After he had removed the cerebral cortex and cerebellum, he kept a small quantity of the brain and dorsal cord intact to show the cranial nerves. (e) Vesalius published few illustrations of the undersurface of the brain, as shown here. He also labeled very little of the brainstem on his illustrations, presumably because of his lack of understanding of its anatomy and function. 

anatomist.8,​9 Perplexed about how such error-filled texts carried such weight for 1300 years, Vesalius finally realized that Galen had not been referring to humans.8,​10 This realization is what sparked his effort to create the first human-based neuroanatomical masterpiece, Fabrica.8,​11 The singular importance of Fabrica was that for the first time, science (anatomical examination method and technology) and art were brought together to produce a cohesive, illustrated anatomical publication. For this innovation, Vesalius is recognized as the greatest of the Renaissance anatomists. Vesalius observed the brain from a top-down perspective, just as Galen had. However, it was the change in Vesalius’ dissection technique that enabled him to better understand the ventricular system and to even better visualize deep structures such as the basal ganglia. For the most part, Vesalius’ technique involved horizontal sectioning from top to bottom with the brain still attached in the cranium.18 This attitude allowed him to realistically portray the brain as it had never been—to draw the deeper layers of the brain, specifically the lateral ventricles and basal ganglia, in greater detail than Galen. On the downside, however,

this technique limited his ability to understand relationships among various structures.13 Vesalius was not the illustrator of his texts, and identification of the artists remains controversial.20 He had close association with the Titian’s bottega, and specifically with Jan Stefan van Calcar, a student and nephew of Titian. In keeping with Vesalius’ ground-breaking approach, he combined the intricate approach to science with the very best illustration capability he could find so as to have artists intimately involved with the dissections.17 Overall, the extent of anatomy that Vesalius was able to illustrate in his texts was vastly greater than what he could label or describe.11 In Fabrica, he did mention the brainstem, which he called the “dorsal cord,” and he described its attachments to the cerebellum via the peduncles and the sharing of the fourth ventricle with the cerebellum.21 Vesalius is credited with showing a radically different detailed illustration of the posterior fossae with the cerebellum and the posterior brainstem by lifting and tilting the brain forward and labeling the fourth ventricle, cerebellar peduncles, and three pairs of cranial nerves (CNs).7,​18 He even provided instructions for properly visualizing the area.18

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I  History of Brainstem Surgery

After removing the cerebellum, he described in some detail the corpora quadrigemina (on the basis of their resemblance to male genitalia) and the cerebellar peduncles.18 Anteriorly he described less, leaving the dorsal cord without labels, aside from the optic nerve. Further description in Fabrica leads the reader to believe that Vesalius considered the cerebellum and dorsal cord to be two separate brain structures, which is an idea that was contradicted by Thomas Willis in the following century.18 It took another 30 years before Costanzo Varolio (1543–1575), a contemporary of Vesalius, further elucidated the brainstem. The name Costanzo Varolio, better known as Constantius Varolius, should be familiar when discussing the pons varolii. Varolio identified the first brainstem segment when he decided

upon a simple change in view: flipping the brain upside down to examine it from its base upward instead of from the top downward.13,​22,​23 In his short life, Varolio accomplished much; as a student of anatomist Giulio Cesare Aranzio (1529–1589), who was himself a student of Vesalius, he became a professor of surgical anatomy at the University of Bologna and Sapienza University of Rome, and he later became the personal physician to the Pope.23 Believing that the important parts of the brain resided at its base (Fig. 1.2a), Varolio decided to remove the brain to examine it using a bottom-up approach. Although doing so would allow for a greater appreciation of the anterior brainstem and the origins of the CNs, Vesalius did not achieve this feat.24

Fig. 1.2  (a) Costanzo Varolio was the first surgeon to champion the technique of disconnecting the brain from the cranium via the dorsal cord and illustrating it from the bottom up. This 1573 woodcut illustration from De nervis opticis nonnullisque aliis, praeter communem opinionem in humano capite observatis, epistolae, is one of his earliest illustrations. (b) The circle

of Willis was not actually discovered by Thomas Willis, but its correct function was identified by him and published in Cerebri Anatome in 1664. This detailed illustration depicts the vasculature encircling the brainstem. (c) A 1664 depiction by Willis of the cerebellar connections to the brainstem via the peduncles published in Cerebri Anatome.

1  History of Brainstem Surgery In his 1573 text, De nervis opticis nonnullisque aliis, praeter communem opinionem in humano capite observatis, epistolae, Varolio states, “When the membrane has been removed, it will be seen at once that the spinal marrow [brainstem] does not take origin thence where it was first attached, but ascends further upwards and anteriorly. . . .”25 The “origin thence where it was first attached” most likely refers to the site that Vesalius illustrated, which is at the base of the occipital lobe where the cerebral and cerebellar peduncles meet the brainstem. Varolio may also have included the inferior-most surfaces of the hypothalamus since he noted that the infundibulum and pituitary are attached to the same membrane as the brainstem, or “spinal marrow,” as he called it. Upon removing the vessels and membrane overlaying the spinal marrow, Varolio described it as “a series of swelling transverse fibers,” which is part of the marrow he called the bridge from which the auditory nerve originates.25 Given this new anatomical description, Varolio accurately stated that the cerebellum must play some role in movement, as Galen once suggested 1300 years earlier.18 Varolio then explained the ease with which the optic nerves and the other CNs can be traced into the brainstem.25 Lastly, Varolio presented one of the first attempts to describe tracts running through the brainstem as two anterior tracts for sensation and two posterior tracts for cerebellar function.25 These tracts would be corrected and further detailed 300 years later, but Varolio’s idea set the stage for descriptions by Willis in the 1600s and by the German “Naturphilosophen” in the early 1800s. Between Varolio and Willis, there were relatively few developments made regarding the brainstem or the cerebellum. The career of Willis marks the first in “medical physiology,” for those who were more interested in clinical experiences than in referencing old texts.8 Willis believed that a correlation existed between location and the evolutionary status of the brain, such that the superior regions of the brain were the most recently evolved and the most “human,” and the inferior structures were those governing primitive or instinctual functions.8,​13,​26,​27 Such was the explanation behind his somewhat accurate claim that the cerebellum governs involuntary function. However, today his claim would be considered more incorrect than correct without the context of his understanding of the cerebellum. In his texts, Willis showed that he understood the cerebellum to include the midbrain and pons because of their connection via the cerebellar peduncles.9,​18,​28 The medulla or “oblong marrow” was a different structure than the rest of the brainstem, and Willis recognized it to be a continuation of the spinal cord, which traveled under the pons and terminated in the deep cerebrum.28,​29 Willis also considered the medulla to be a part of the involuntary function control center.27 Willis was not actually the first to discover the circle of Willis, but he was the first to correctly document the nature of its redundancies and its purpose of providing auxiliary flow in the event of obstruction.18,​30 Willis is regarded as the “father of neurology” and was the first to present a systematic approach to the functional anatomy of the brain with his Cerebri Anatome. He advanced brain anatomy exploration with a carefully engineered approach to assembling personnel with exquisite specialty training, in fact establishing the model for a medical research and teaching institute at the University of Oxford. The illustrations, done largely by Christopher Wren (1632–1723), especially of the sheep and human brainstems, are incomparable for their accuracy, perspective, line, and objectivity. For Willis to have his friend and partner Wren, an expert in architecture, physiology, and anatomy, render the images of the brain was ingenious.17

7

Both Willis (Fig. 1.2b, c) and his contemporary, Raymond de Vieussens (1641–1715), studied the medulla (Fig. 1.3a). Vieussens labeled the pyramids and olivary nuclei of the medulla,29 and his Neurographia universalis contains a detailed compilation of his illustrations of brainstem tracts.31 At the end of the 17th century, Domenico Mistichelli (1675–1715) was the first to accurately describe the decussation of the brainstem (Fig. 1.3b).22,​32,​33 In his words, the medulla is like a woman’s plaited tresses because the woven nature of the pyramidal decussation is like a braid of hair.32 However, one might question how many times Mistichelli thought these fibers were crossed, for unlike a braided hair, which may cross several times over, the pyramids cross only once. Thus, it could be inferred that his analogy was not to be taken literally, but rather as a way to understand the concept of crossing sides in the anterior medulla. At the start of the 18th century a few years later, François Pourfour du Petit (1664–1741) presented a clinical correlate to complement Mistichelli’s untested theory. Having noted contralateral motor paralysis in French soldiers with brain abscesses, Pourfour du Petit validated the idea of decussating pyramids traveling underneath the pons on their way from the cerebrum to the rest of the body (Fig. 1.3c).22,​33,​34 The 18th century would prove to be an uneventful time in the history of brainstem discoveries, aside from the ideas of the two aforementioned scientists. This stagnant period occurred because fresh brain and spinal tissue was simply too difficult to analyze at the level at which these anatomists were attempting to view it.13 In the mid 1600s, Willis came up with one of the first methods of fixation, using alcoholic spirits and india ink.13,​17,​19,​35 It may have been his illustrator, Christopher Wren, who introduced Willis and Richard Lower  (1631–1691) to both the fixative and the intravenous method, respectively, which they used to preserve brain tissue.17,​35 It was with this innovation that Willis could propose the redundant and circular nature of the cerebral vasculature.1 Marcello Marpighi (1628–1694) boiled his specimens in water, whereas Vieussens boiled his in oil.13,​19,​29 However, none of these techniques was adequate enough to visualize the brainstem at the level of tracts and fibers, which was the direction in which neuroanatomy was heading in the late 17th century. More than 100 years passed before the next landmark development occurred that would launch neuroanatomy into microscopic proportions.

■■ The Neurosciences of the 1800s In the 1700s, after the work of Willis and his contemporaries, the rate of discovery in neuroanatomy of the brainstem outpaced the rate of technological development. Thus, anatomists like Pourfour du Petit and Mistichelli could only speculate with their theories, which were later proven to be true. The following century would bring a flood of technical, technological, and theoretical developments, making the 19th century a fertile era for neurologic study. The 19th century marks the shift of neuroanatomical expertise from Italy to Germany, where a group of scientists called the Naturphilosophen pioneered neuroanatomical research. This group included Franz Joseph Gall (1758–1828) and Johann Gaspar Spurzheim (1776–1832) (Fig. 1.4), Johann Christian Reil (1759–1813), and Karl Friedrich Burdach (1776–1847).8,​11,​13 Using the technique of fine dissection, these anatomists collectively made great strides in understanding the role of the brainstem by analyzing the fibers that traveled within it. During the 1600s, Marpighi and Vieussens initially pointed out that white matter was made of fibers traceable from the brainstem to the

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I  History of Brainstem Surgery

Fig. 1.3 (a) Raymond de Vieussens illustrated his understanding of the undersurface of the brain in Neurographia universalis (published in 1716). (b) Domenico Mistichelli depicted the decussating pyramids in 1709.

(c) François Pourfour du Petit depicted the contents of the brainstem, including the cranial nerves, the pons, medulla, and olivary nuclei, in 1710. 

Fig. 1.4  Franz Joseph Gall and Johann Spurzheim detailed (a, b) the convolutions of the cortical surface in their illustrations, and they delineated (c) the structures of the brainstem and cerebellum in The Anatomy of the

Brain with a General View of the Nervous System, published in 1826. (Reproduced with permission from Spurzheim, Johann Gaspar. The anatomy of the brain: with a general view of the nervous system. S. Highley, 1826.)

1  History of Brainstem Surgery cortex.7,​29 This idea was certainly ahead of its time, as it would not be until the 1800s when the same idea would be summoned again and elucidated. In 1809, Reil developed the first consistent method of fixation, which marked the beginning of the reinvigoration of neuroanatomy. Reil found that serial washes of alcohol, potash, and ammonia made tissue far more suitable for fine dissection and for analysis of the tracts within the structures.7,​36,​37 Anatomists of this time were aware of Pourfour du Petit’s theories of decussation and wanted to further clarify the pathways in the brainstem. In 1809, Gall and Spurzheim became best known for the development of what came to be called phrenology, which was a detailed account of the locality of character and mental abilities within the brain.7,​11,​13 Furthermore, they contributed a great deal to the collection of information regarding the origin of CNs.38 They were among the first to begin fine dissection by teasing out tracts and CNs from parenchyma, and they were pioneers in finding a pathway from the olivary nucleus to the midbrain. Yet it was Reil who, in the same year, presented the first realistic idea of this pathway.11,​38,​39 Having already described the pes pedunculi and tegmentum divisions of the brainstem, Reil recognized the olivary tracts as a continuation of the gray spinal cord.36 He traced the pathways from the olivary nuclei to the thalamus in two divisions: one traveling over the external sources of the inferior corpora quadrigemina and below the corpus geniculatum into the thalamus, and probably into the corona radiata; the other bending medially to form the roof of the aqueduct, crossing to its contralateral partner, and possibly also contributing to the posterior commissures. This newly classified Reil’s ribbon most likely contained fibers from what is known today as the medial and lateral lemniscus pathway36; thus, Reil is credited with the original discovery of the pathway. In 1812, Burdach endorsed Reil’s work and emphasized that this pathway was a continuation of the gray spinal cord, as myelinated tracts were not yet delineated. Between 1819 and 1826, Burdach traced the tractus [fasciculus] cuneatus from the spinal cord into the medulla and pons.40,​41 He also recognized a portion of the pyramidal tracts that went uncrossed, thus anticipating the pathway of the lateral corticospinal tract. It would be another 60 years before further improvements were made on these pathways, when Theodor Meynert (1833–1892) revamped Reil’s idea by naming a “superior” and an “inferior” lemniscus, only to be outdone by Wladimir von Bechterew (1857–1927). Bechterew is credited with the correct tracing of the lemnisci, which he properly labeled medial and lateral, respective to Meynert’s nomenclature.42,​43 Meynert and Auguste Forel (1848– 1931) believed that the lateral lemniscus could not be traced superior to the corpora quadrigemina. However, Bechterew insisted that tracing was not necessary. He suggested instead that the inferior colliculi could be traced myelinogenetically down to the superior olivary complex, the trapezoidal body, and thus the vestibulocochlear nerve (CN VIII), via the lateral lemniscus, which would then propagate the idea that the lateral lemniscus pathway carries cochlear signals to the inferior colliculus, which may lead into the cortex by way of the thalamus.43 An analysis of this era of discovery raises a significant question. What caused such a vast discrepancy between the perspectives of anatomists of the first half of the 19th century and those of the latter half? Furthermore, what led the anatomists of the latter half to posit opposing ideas? The answer lies in the context of parallel developments during this time. Although the early 1800s marked the dawn of tract-based neuroanatomy, it was still 20 to 30 years before the beginning of microscopic

9

­ euroanatomy. Although the Naturphilosophen were limited in n what they could examine, they nevertheless came up with brilliant ideas that were not far from the truth. With the revamping of the compound microscope in the 1820s, followed by Benedict Stilling’s (1810–1879) invention of the serial microtome 20 years later, we see the shift from macroscopic anatomy, with Burdach as its last disciple, to the advent of microscopic neuroanatomy.8,​11,​13 The epoch of microneuroanatomy was layered with technological advancements that were followed by new techniques. During the 1840s, Stilling’s microtome allowed anatomists to analyze the brainstem both inside and out with serial sectioning.44 Also in the 1840s, Reil’s alcohol-and-potash fixative was dethroned by Adolph Hannover’s (1814–1894) chromic acid, which was subsequently supplanted by Ferdinand Blum’s (1865–1959) use of formaldehyde in 1895 (Hannover 1840,45 Blum 189346). Vladimir Betz (1834–1894) recognized that the earlier methods of fixation did not penetrate the deepest parts of the brain. He devised a solution of iodine in alcohol, followed by potassium bichromate, that allowed him to better examine the white matter tracts of the brain and to cut sections thinner than those of any of his predecessors.47,​48 His technique also led him to the discovery of pyramidal cells in the deep cortex and initiated the nexus of histology, brain function, and cerebral localization.48 Despite these improvements, anatomists remained uncertain about the validity of many of their observations. In 1877, Forel brilliantly stated: It must be frankly admitted that almost nothing is known of origin and termination of these fibres. The general direction of these fibres is best studied in serial sagittal sections…but no certain information is obtainable on the real course of individual fibre bundles…since the direct connection with nerve cells can be traced for only short distances.11 Forel also described how fibers in the brainstem rarely travel in straight longitudinal paths, such that they “seem to join each other in acute angles, forming a network…, they appear to be mainly continuations of the anterior and lateral [spinal] tracts, which become loosened through interposition of grey matter.” The framework had been laid, but the canvas could not be painted, quite literally, until the development of histologic staining. Histologic staining began in the 1850s with Joseph von Gerlach (1820–1896), who used carmine dye that stained cerebellar gray matter red while sparing white matter. However, it did not allow microscopists to see axons and dendrites.49 In 1873, Camillo Golgi (1843–1926) developed the silver nitrate stain, which made beautifully contrasted pictures of neuron structures.50 At the turn of the 20th century, Santiago Ramón y Cajal (1852–1934) perfected Golgi’s stain, which would garner them both a Nobel prize for Cajal’s neuron theory.13 Tract-tracing techniques were also developing during the latter half of the 19th century. Using Vittorio Marchi’s  (1851–1908) degenerating myelin stain, Ludwig Türck (1810–1868) and Bernhard von Gudden (1824–1886) were able to trace the spinal tract and the intracerebral tract, respectively, by inducing degeneration and observing the stained footprint.51,​52,​53 Paul Flechsig (1847–1929) performed a similar feat, but developed a method to study staining in myelogenesis instead of degeneration.18,​54 If one were to superimpose the timeline of these developments in histology onto the timeline of the neuroanatomical discoveries in the 1800s, one could see why it took until 1885 for Bechterew to correctly map the lemnisci. Furthermore, from this perspective a strong correlation emerges between these histologic developments and Bechterew’s experimental findings of other brainstem

10

I  History of Brainstem Surgery

tracts and nuclei. In fact, Bechterew and Flechsig were corresponding during their major discoveries of the 1880s.11 The work of Türck and Flechsig applied not only to the lemnisci, but also to the pyramids and the other tracts. In the 1850s, Türck was the first to examine and confirm the crossed and uncrossed pyramidal tracts on a microscopic level after Burdach macroscopically speculated their existence in the 1820s.52 In his 1877 work, Flechsig described his elucidation of the pyramidal tracts from cortex to medulla, but only after stating, “Until now, there has existed no absolutely exact reports as into how large a segment of the pons seen cross section, or of the cerebral peduncle, or of the internal capsule, etc., the pyramidal tracts extend.”55 He described the struggle that every anatomist had prior to his technique, leading up to Bechterew’s finding. For this work, Flechsig is credited with providing the first accurate depiction of the pyramidal tracts.55 His techniques sparked a gold rush in fiber identification, including the cerebellar peduncles and the trigeminal lemniscus.11 The turn of the 20th century led to even greater advancements in fiber-tracing techniques. One contributor to this era of development was Josef Klingler (1888–1963), who developed methods of preservation, dissection, and three-dimensional modeling that would become the basis for future stereotactic neurosurgery56 (Fig. 1.5). Although his work included brainstem fiber tracing, the vast majority of it pertained to the limbic system, insula, thalamus, and basal ganglia. His method of fixation included 5% formalin for 2 to 3 months, followed by freezing at –10°C for 8 to 10 days, and then thawing at room temperature in 5% formalin. He modeled his dissections in wax and plaster casts, and his meticulous tracing techniques received national attention. In 1949, Klingler began to teach M. Gazi Yaşargil (1925-), who went on to become a prominent neurosurgeon.

■■ Surgery of the Brainstem Surgery of the brainstem began long before anatomists fully appreciated the functions of the brainstem and their localizations. Few surgeries were performed in this region because of the lack

Fig. 1.5  Josef Klingler was known for his incredibly well-preserved tissue samples. His technique allowed for gross fiber tracing. Klingler’s advanced preservation techniques are depicted in both (a) his gross tissue sample displaying a sagittal section and (b) the subsequent illustration. Klingler

of knowledge regarding the brainstem’s functions and its physical inaccessibility. Investigation into and surgery of the brainstem were plagued by a high rate of morbidity and thus lagged behind the rapid growth and burst of knowledge that occurred in other areas of neurosurgery.22 To appreciate how surgical skill and knowledge evolved with regard to the brainstem, one must first examine the development of neurosurgery in general. The first phase of neurosurgery, the premodern era  (before 1879), is important for advancements in anesthesia, antiseptic and aseptic techniques, and cerebral localization.1 The first of these three landmark discoveries was the use of anesthesia. Although dentist William T. G. Morton (1819–1868) was not the first to use ether anesthesia, he convinced chief of surgery, John Collins Warren (1778–1856), to allow him to introduce its use into clinical practice at Massachusetts General Hospital in 1846. Morton and Warren worked to spread the knowledge of its use, which led to a dramatic increase in the number of surgeries that were performed.57 However, this success was short-lived, as surgeons quickly realized that even with the use of anesthesia their patients remained at high risk for postoperative infection.58 It was not until Joseph Lister (1827–1912) proposed sterile techniques in the 1860s that germ theory and antiseptic technique reached the operating room. Having learned of Louis Pasteur’s (1822–1895) work regarding atmospheric bacteria, Lister applied Pasteur’s theories to surgical wounds. Although Lister was able to prove to himself the efficacy of his method of “Listerian dressing” (i.e., gauze permeated with carbolic acid), surgeons who used his methods did not experience the same success. Lister continued to work on his antiseptic technique and expanded it to his hands, instruments, and patients. He even sprayed carbolic acid to disinfect the air before his operations. Despite Lister’s efforts, other surgeons were reluctant to accept his techniques and continued to practice in their own way until the 1870s.57,​58 In 1875, Johann Nussbaum (1829–1890), an eminent professor at the University of Munich, reported a decrease in overall postoperative mortality due to a significant decrease in the rate of postoperative infections after adopting Listerian surgery and wound management techniques.58 Over the next few years, countless discoveries were made in the field of microbiology that supported

published these findings in Atlas Cerebri Humani in 1956. (Reproduced with permission from Ludwig e, Klinger J. Atlas Cerebri Humani - The Inner Structure of the Brain. Little, Brown, 1956.)

1  History of Brainstem Surgery Lister’s approach to antisepsis. Among these was the work of Robert Koch (1843–1910), who studied the pathogenesis of anthrax in 1876. Koch investigated the life cycle of the Bacillus anthracis spore and presented evidence implicating it as the pathogen causing anthrax, also known as splenic fever. In the following years, Koch made strides in bacteriology and medicine, including identifying Streptococcus and Staphylococcus as the most common causes of wound infections.59 Even with rapid developments in the use of anesthesia and infection control, the last ingredient that was needed before the birth of neurosurgery was the study of cerebral localization. Surgery of the nervous system was primarily limited to trauma cases because surgeons lacked knowledge of the brain’s localized functions. However, during the 1860s, major advances were made in the field of cerebral localization. Pioneers such as Pierre Paul Broca (1824–1880), David Ferrier (1843–1928), Eduard Hitzig (1838–1907), and Gustav Fritsch (1838–1927) investigated cerebral functions and the specific locations responsible for them.57 They conducted studies using a range of techniques, including ablation and electrical stimulation procedures, to assign functions to the various regions of the cerebrum. However, the lack of localization studies done in the posterior fossa is worth noting. Although the work of anatomists such as Gall and Félix Vicq-d’Azyr (1748–1794) revealed some of the generalized functions of the brainstem, knowledge of the brainstem was still severely limited. Investigation and discovery of the brainstem continued to be overshadowed by the rapid advancements being made regarding the cerebrum. It was not until the 1880s that great strides were made in the discovery of the anatomical structures of the brainstem and that localization studies of that region were conducted. Progress in this field is credited both to surgeons and to anatomists alike; among these were Vladimir von Bekhterev (Wladimer von Bechterew; 1857–1927), Robert Henry Clarke (1850–1926), Victor Horsley (1857–1916), Ludwig Pick (1868–1944), and Adolf Wallenberg (1862–1949).22,​57 In 1879, William Macewen (1848–1924) applied the available knowledge of antiseptic technique, anesthesia, and cerebral localization to a pediatric brain tumor case in which he successfully removed a periosteal tumor above the patient’s right eye. With the help of neurologists and the presence of focal motor seizures, Macewen was able to accurately predict the location of the tumor.60 He used an antiseptic trephining technique to successfully remove the growth. The 14-year-old patient survived for 8 years after the operation until succumbing to Bright’s disease, which is now known as acute or chronic glomerulonephritis.57 The year 1879 marked the transition from the premodern era to the gestational period of neurosurgery (1879–1919), as the birth of neurosurgery took place during the 1880s. For the first time in history, general surgeons, with the guidance of neurologists, were frequently operating on the brain to remove tumors and abscesses. Pioneers in neurosurgery during this era include Macewen, Horsley, Krause and Rickman Godlee (1849–1925).57,​60 Macewen and Horsley are particularly famous for having been the first to remove a brain tumor and the first to remove a spinal tumor, respectively.61 Although Macewen was one of the first surgeons to practice neurosurgery, his professional interests and energy lay elsewhere. Thus, he is not regarded as the first “modern” neurosurgeon. That honor belongs to Horsley, who was appointed in 1886 as Surgeon to the National Hospital for the Paralysed and Epileptic in London, and termed by Cushing as the father of neurosurgery. Horsley was unique in that he was the first surgeon to dedicate his entire practice to the nervous system.1

11

During the 1880s, various surgeons compiled reports summarizing their successes with brain surgery. In 1888, Macewen reported his success in neurosurgical operations to the British Medical Association: he had operated on 21 patients with only 3 deaths.62 These astounding numbers provided evidence that the use of the antiseptic technique and cerebral localization could lead to great success. In 1890, Horsley reported that he had operated on 43 brain tumors resulting in only 10 deaths, a rate that was widely considered incredibly successful for that time period.1 Despite the success in cerebral surgery during the 19th century, the brainstem continued to remain uncharted territory largely because of its inaccessible location and delicate nature.22 Like the surgical history of the cerebrum, the history of brainstem surgery begins with the discovery of, and experimentation with, surgical approach. Typically, the first experience of a surgeon with the area was limited to trauma, and it then advanced to the removal of abnormal brain masses, such as abscesses and tumors. As expected, the most complicated procedures were developed later in the timeline.

■■ Accessing the Posterior Fossa The earliest reports of a successful surgery within the posterior fossa were those made by Hermann Schwartze (1837–1910) in 1887. Schwartze used trephination in the posterior fossa to drain a cerebellar abscess.63 In 1893, Charles McBurney (1845–1913), best known for McBurney’s point and McBurney’s sign, used to diagnose appendicitis, became the first surgeon to successfully remove a cerebellar tumor.22 Surgeons had mixed preferences when approaching the posterior fossa. Both Horsley and Krause, who preferred to be known as general surgeons, but were perhaps the most technically skilled neurosurgeons of their time, preferred to keep the patient in the lateral position, although surgeons such as Cushing and Frazier opted to approach the fossa with the patient prone.57 However, by 1913 most surgeons preferred to keep the patient in the sitting position due to the invention of Thierry de Martel’s (1876–1940) surgical chair (Fig. 1.6).22 Surgeons differed on their preferences for patient positions and on the type of craniotomy they chose to perform. Krause was a pioneer in posterior fossa surgery (Fig. 1.7) who described and had illustrated highly complex operations including osteoplastic craniotomy for tumors around the brainstem in his foundational surgical text. This method of approaching the posterior fossa was not popular among other surgeons because of its difficulty, and perhaps the only other surgeon to the use this procedure was the

Fig. 1.6 Thierry de Martel invented the surgical chair and was an early advocate for the sitting position in posterior fossa surgery, having first introduced it in 1913. 

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I  History of Brainstem Surgery

Fig. 1.7 (a) Fedor Krause’s neurosurgical monograph, Surgery of the Brain and Spinal Cord, was published in 1910. (b) In this text, he described

techniques for unilateral and bilateral osteoplastic craniotomy and (c) techniques to approach cerebellopontine angle tumors.

French surgeon Antony Chipault (1866–1920). Other surgeons preferred the suboccipital craniectomy but differed on the type of skin incision to use. Horsley used the mastoid-to-mastoid skin incision, whereas Frazier opted to use his own method, known as the midline “bloodless” incision. Cushing was unique in his approach, using an original method that he called the “crossbow” incision.22,​57 Despite the variety of techniques available to surgically approach the posterior fossa, most efforts were limited to the cerebellum, as even a suboccipital approach leaves the brainstem largely out of reach.

surgeon. Charles Bell described one of the earliest accounts of a cerebellopontine angle tumor, detailing the clinical history of a patient who developed a burning sensation in her tongue that eventually progressed to hearing loss. Fearing the futility of intervention, the patient was treated non-surgically. Upon autopsy, he noted how the seventh nerve “was completely involved and lost in the tumor” (Fig. 1.8). However, even more dangerous than cerebellopontine angle tumors and cerebellum tumors were lesions associated with the brainstem parenchyma. One of the earliest accounts of a confirmed brainstem lesion was reported by Richard Bright (1789–1858) in Volume II, Part I, of his series Reports of Medical Cases, Selected with a View of Illustrating the Symptoms and Cure of Diseases by a Reference to Morbid Anatomy. Bright described the case of a young girl (6 ½ years old) who came to his service on

■■ Brainstem Tumors Surgery into the posterior fossa was considered one of the greatest, yet one of the most dangerous, challenges for the

1  History of Brainstem Surgery

13

Fig. 1.8  Charles Bell’s detailed illustrations depicted (a) a cerebellopontine angle tumor and (b) the brainstem and cranial nerves. He published these

findings in 1830 in The nervous system of the human body. Embracing the papers delivered to the Royal Society on the subject of the nerves.

December 10, 1828, with numerous neurologic symptoms, including whole-body paralysis but intact consciousness and intelligence. He suspected a tumor near the base of the brain and “feared the impossibility of affording any effectual aid” and, indeed, the girl died two months later. Upon autopsy, Bright illustrated and described in detail what appeared to be a “tumour of the pons Varolii” that had caused the trochlear  (CN IV), trigeminal (CN V), abducens (CN VI), and facial (CN VII) CNs to become “implicated in the mischief.”64 As the 19th century progressed and a better understanding of cerebral anatomy evolved, physicians became more skilled at recognizing the presence of brainstem gliomas. By the 1890s, surgeons were commonly able to identify a brainstem glioma on autopsy, although these reports were limited to postmortem analyses. By the turn of the 19th century, surgeons had become familiar with operating around the brainstem, although reports of surgeons intentionally entering the brainstem parenchyma are incredibly rare. Krause was often cited as proving such formidable operations could be undertaken by using new technology. He was one of the first surgeons to adopt the use of radiographs for diagnostic localization (obtaining an X-ray unit within 2 months of the initial description of X-rays in late 1895), and he was certainly the first neurosurgeon to use it routinely. In 1909, Theodore Weisenburg (1876–1934) provided the earliest account of surgical intervention in the treatment of a brainstem tumor suspected to be of cerebellar origin, although the tumor was later found to have infiltrated several structures of the brainstem. The patient was a 46-year-old man who had

a history of headaches, nausea, vomiting, general weakness, insomnia, and nervousness. After undergoing decompressive surgery over the cerebellar region, the patient exhibited slight improvement but died six months later. Autopsy revealed that the tumor was not isolated to the cerebellar region but rather that it had significant involvement with the medulla, pons, and cerebral peduncles.65 In 1910, Cushing reported the case of a 15-year-old girl who presented with a complicated past medical history that included paralysis, nystagmus, and Babinski reflex. Cushing suspected a cerebellar tumor that had some medullary involvement and thus decided to perform suboccipital exploration and decompressive surgery. When he was unable to locate a tumor, Cushing stated, “It is probable that the tumor is actually a Pontial tumor, cerebellar symptoms due to involvement of the superior cerebellar peduncles.” The day after the operation, the patient became comatose, and two days after the operation, she died from “respiratory failure.” The autopsy revealed that the tumor had infiltrated a significant portion of the pons and the substantia nigra. Such cases were incredibly rare, with only a single case of pediatric brainstem glioma reported at Johns Hopkins Hospital from 1896 to 1912.66 Cushing became a champion of palliative suboccipital surgery, having first introduced it in 1908. For most complicated tumors of the posterior fossa, including cerebellopontine angle tumors, medulloblastomas, and ependymomas, Cushing and his associate, Percival Bailey (1892–1973), recommended a decompressive suboccipital craniectomy. Together Cushing and Bailey

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I  History of Brainstem Surgery

became p ­ ioneers in the study of neuropathology and posterior fossa tumors, working to classify different types of gliomas and their clinical manifestations. In 1925, they provided the first detailed description of a medulloblastoma and posited that surgical removal of the tumor was highly dangerous.67,​68 In 1926, they published a comprehensive guide to the histology of nervous system gliomas, A Classification of the Tumors of the Glioma Group on a Histogenetic Basis with a Correlated Study of Prognosis.69 The pair also worked together to classify hemangioblastomas, a term they coined.70 A few short years after his pioneering work on tumors of the posterior fossa, Cushing retired in 1932. Having completed over 2000 brain tumor surgeries, Cushing compiled his knowledge and recommendations in his book, Intracranial Tumours: Notes Upon a Series of Two Thousand Verified Cases with Surgical-mortality Percentages Pertaining Thereto.71 Cushing’s efforts were followed by those of his former student, Walter Dandy of Johns Hopkins.57 Perhaps Dandy’s most influential contribution to the early efforts in posterior fossa surgery was the discovery of ventriculography or pneumoencephalography in 1919. Dandy created a method of imaging that involved draining cerebrospinal fluid from the ventricles, replacing the volume with air, and taking a roentgenogram (i.e., radiograph) of the skull.72 These modalities served as the earliest and only method for imaging the brain, and they helped Dandy’s contemporaries revolutionize their diagnostic capabilities. Information gathered from pneumoencephalographies led to the standardization of the posterior fossa and the characterization of various lesions, including ependymomas, brainstem gliomas, and syringobulbia.22 The year 1919 was important for another reason: it marked the transition from neurosurgery’s gestational period to the modern era. This transition occurred on a single day during the American College of Surgeons meeting in 1919, when William J. Mayo (1861–1939) declared neurosurgery to be a surgical specialty. The following year, neurosurgery was officially recognized as a surgical specialty, and the Society of Neurological Surgeons was founded.1 Dandy worked extensively in the posterior fossa and was a much more aggressive surgeon than Cushing. For example, Dandy described a procedure that involved splitting the vermis to access the fourth ventricle, suggesting that this procedure could be done safely as long as the surgeon did not damage the dentate nucleus. Dandy, like Krause, believed that technology could improve surgery. He had a headlight fashioned with a powerful bare bulb to illuminate what were otherwise dark avenues and recesses around the brainstem, much to the chagrin of his assistants who were nearly blinded in the meantime by the “Boss” (their respectful and affectionate name for Dandy). Differences in surgical technique and approach led to bitterness and animosity between Dandy and Cushing.57 The Dandy-Cushing feud became a matter of public knowledge and created a political divide within the neurosurgery community. Both men had loyal followers who dismissed the other’s work, regardless of medical advantages.73 At the conclusion of Dandy’s career, he had completed more than 2000 surgeries on the posterior fossa alone, a number that matched the total number of surgeries Cushing had performed on the brain.57 Dandy is regarded as one of the most technically gifted neurosurgeons. With improvements in radiation therapy and surgical approach came a slight increase in the long-term survival of patients with brainstem lesions, but the prognosis was still rather pessimistic.22 In 1947, Gerard Guiot (1912–1998) reported a new and innovative approach to the brainstem. He revealed that a

subtemporal approach provides the best access to the brainstem, and he used it extensively in patients for mesencephalic tractotomy.74 Although various surgical centers had not used this approach for tumors, they adopted the technique for the treatment of lesions in the midbrain and pons.57 In 1960, Charles Drake (1920–1998), a prominent neurosurgeon from Canada, used this approach to surgically correct basilar aneurysms.75 The invention of MRI in the 1980s made it possible for surgeons to visualize tumors and potentially identify pathologic processes before surgery. Before the use of highly detailed imaging modalities, surgeons tended to categorize all brainstem gliomas into a single group.76 During the early 1980s, Fred Epstein (1937–2006), a pioneer in the field of brainstem glioma surgery, reported some of the first positive outcomes using surgical intervention. He was one of the earliest surgeons to report the heterogeneous nature of brainstem gliomas, which he categorized as diffuse, focal, cystic, and cervicomedullary. From 1980 to 1986, Epstein operated on patients with 66 brainstem tumors, demonstrating to the neurosurgery community that brainstem gliomas were no longer inoperable lesions.76

■■ Mesencephalic Spinothalamic Tractotomy In 1942, Arthur Earl Walker (1907–1995), perhaps best known for identification of the Dandy-Walker syndrome, reported his use of a mesencephalic spinothalamic tractotomy to treat complicated pain syndromes.77 He argued that this procedure was not safe when performed in the rostral cervical segments because of the risk of respiratory failure and that it was better suited for the midbrain. Walker first practiced this procedure on animals before using it on two patients described in his 1942 report. The first patient underwent a left mesencephalic tractotomy to cure right-sided body and face pain. Walker performed a left temporal occipital bone flap craniotomy and placed an incision 2 mm in depth from the “lateral sulcus to the lower margin of the inferior colliculus.” The day after surgery, the patient entered a coma and died from cerebral edema within 26 hours of the operation. The second patient had right-sided pain in the neck and face. Walker performed a posterior temporal flap craniotomy and placed a 6-mm incision from the brachium to the rostral margin of the inferior colliculus. The patient awoke from the surgery with complete relief of the right-sided pain but died a month later due to bronchopneumonia. Although the surgery accomplished its intended goal, the rate of complications was high. Walker also agreed with surgeon Achille Mario Dogliotti (1897–1966), who suggested that resection of the lateral lemniscus at the rostral pons level was ideal for patients with arm, neck, and face pain. Dogliotti had performed this procedure on four patients but never published the case reports.77

■■ Medullary Spinothalamic Tractotomy In 1940, Henry G. Schwartz (1909–1998) and James L. O’Leary (1904–1975) were the first neurosurgeons to perform a medullary spinothalamic tractotomy. They presented their findings at the Society of Neurological Surgeons meeting in April of that same year.78 Schwartz and O’Leary had performed this operation on two patients; the first patient had an advanced malignant

1  History of Brainstem Surgery disease, and the second had breast cancer.78,​79 The operation performed on the patient with breast cancer began with a suboccipital craniotomy and proceeded with retraction of the cerebellar lobe upward to expose the lateral wall of the medulla. An incision 5 mm in depth was made between the root of the vagus nerve (CN X) and the inferior olive. Neurologic examination revealed that the patient had loss of pain but intact touch and position sensation. The patient was discharged 10 days after the operation and lived a pain-free life until her death a month later.79 Schwartz and O’Leary saw similar success in their other patient, although that patient died a few days after the operation because of advanced disease.80 This surgical procedure was not common, and it was performed only by a few surgeons because of its associated risks. In 1941, James C. White (1895– 1981) reported performing a similar procedure on a 29-year-old woman who had chronic pain and Raynaud disease. White performed an occipital craniectomy and proceeded to create a lesion 4 mm in depth from a position just caudal to the vagus root to the inferior olive—replicating almost exactly what Schwartz and O’Leary had done.78,​79 The patient, who was conscious during the procedure, immediately felt relief from her right arm pain. The immediate postoperative recovery was uneventful, and the patient was relieved of her initial symptoms. White, Schwartz, and O’Leary spoke confidently of this procedure and worked to improve their technique while being especially careful of the risks involved with lesions in the medulla.78,​79,​80

■■ Brainstem Hematomas and Vascular Malformations In 1905, Rudolph Finkelnburg  (1870–1950) published the first detailed account of surgical intervention for a brainstem hematoma. The patient was a 14-year-old boy with a history of headaches and vertigo.81 Almost three decades later, Dandy was the first neurosurgeon to make an accurate diagnosis and successfully remove a hematoma surgically.82 In 1988, John R. Mangiardi (1950-) and Fred Epstein published a comprehensive review of all documented cases of brainstem hematomas. They found that since Finkelnberg’s first surgical attempt in 1905, there had been a total of 55 new cases. Since Dandy’s case in 1932, only five patients had negative outcomes; four died, and one had severe deficits. These outcomes shed a positive light on surgical intervention. Their study showed that 85% of patients with surgical intervention had normal or mild postoperative symptoms, and only 30% of patients with conservative management had normal symptomology, although this difference was not statistically significant.83 In 1851, Rudolf Virchow  (1821–1902) published the first report of hemangioma of the pons.84 Although many hemangiomas have been reported since then, it was not until 1934 that the first successful operation on a cavernous malformation of the brainstem was performed by Dandy. A prolific vascular surgeon, Dandy is credited with achieving many “firsts” in vascular neurosurgery.85,​86 In 1953, Karl Teilmann (1915–1956) conducted a thorough literature review of hemangiomas of the pons that had been reported since Virchow’s account in 1851. He documented a total of 45 cases of hemangiomas in the pons; more than onehalf were telangiectasias and one-third were cavernous hemangiomas. Surgery was performed on four of the 45 cases because of a diagnostic error, which usually occurred when the hemangioma was misdiagnosed as a cerebellar tumor. Three of the four patients

15

who underwent surgery died shortly after the operation, suggesting that surgical intervention for vascular malformations was still in an early stage of development in the 1920s.87 By 1975, surgeons appeared to be more comfortable with operations on arteriovenous malformations of the brainstem. Drake described four successful cases of arteriovenous malformation removal using a combination of subtemporal and suboccipital approaches.88

■■ Vascular Surgery of the Brainstem The 1950s marked the beginning of surgical management of the vasculature of the brainstem. After Dandy published his work in 1944 on intracranial hemorrhages, Drake provided an account in 1960 of four cases of surgical management of basilar aneurysms. Using a subtemporal approach, Drake retracted the temporal lobe and exposed a passage through to the interpeduncular space that exposed the basilar artery. Local circulation was temporarily interrupted in 5-minute intervals while the clot was removed and the aneurysm was reinforced with muscle.75 Drake used imaging techniques, such as vertebrobasilar angiography, to improve diagnostic accuracy and visualization of the region. The advent of these imaging modalities reduced the complexity of the surgery and improved outcomes.89 In addition to surgically repairing aneurysms, vascular neurosurgeons also performed vessel bypass surgery. Yaşargil was the first to popularize this surgery with the publication of his technique for a superficial temporal artery anastomosis to the middle cerebral artery.90 This development made way for other neurosurgeons, particularly Robert Spetzler (1944-), who began devising techniques for various other brainstem anastomoses.91 One specific report was of an occipital artery–to–posterior inferior cerebellar artery bypass for vertebrobasilar ischemia.92 In this procedure, conducted with the patient prone and fixed in a Mayfield head holder, a hockey stick incision is made from the midline of the cervical neck, curving laterally toward the site of anastomosis. Success in 12 of 14 reported cases suggested that anastomotic surgery was an effective way to correct ischemia in the brainstem.92

■■ Stereotactic Surgery of the Brainstem Stereotactic neurosurgery combines minimally invasive techniques with three-dimensional brain mapping and functional localization. Before stereotactic surgery could be practiced as it is today, neurologists had to compile information regarding cerebral function and localization. Hence, functional neurosurgery gave rise to stereotactic neurosurgery. Functional neurosurgery was first practiced in the late 1800s by the Swiss psychiatrist Gottlieb Burckhardt (1836–1907). His interest in the surgical treatment of psychological conditions led him to remove small portions of the cortex in an attempt to interrupt transcortical connections. Burckhardt meticulously planned his surgeries to strategically remove portions of the brain to obtain a desired result. His work is regarded as the first attempt at psychosurgery, which brought about the birth of functional neurosurgery.93 The combination of surgery and localization technique evolved into the modern concept of stereotactic surgery with the advent of the stereotactic frame. Modern stereotactic surgery first began in 1908, when Horsley and Clarke invented the Horsley-Clarke stereotactic frame (Fig. 1.9). They had built the frame for experimental

16

I  History of Brainstem Surgery

Fig. 1.9 (a) Victor Horsley and Robert Henry Clarke invented the stereotactic frame in 1908. (b) The frame was subsequently adapted for neurosurgery by Ernest A. Spiegel and Henry T. Wycis in 1947. (Fig. 1.9a is reproduced with permission from Horsley VAH, Clarke RH. The structure

and functions of the cerebellum examined by a new method. Brain 1908;31:45–124. Fig. 1.9b is reproduced with permission from Spiegel EA, Wycis HT, Marks M, et al. Stereotaxic apparatus for operations on the human brain. Science 1947;106:349–350.)

studies of the cerebellum, and later the cerebrum, in primates but never used it in humans.57 Almost five decades later, in 1947, Ernest Spiegel (1895–1985) and Henry Wycis (1911– 1972) were the first neurosurgeons to use the stereotactic frame in human neurosurgery. Their landmark publication illustrated the stereotactic frame and described its use in various surgeries, including spinothalamic tractotomy.56,​94 The use of the stereotactic needle was popular in lesion-creating procedures that involved the injection of fluids or thermocoagulation.22,​94 As the years passed, surgeons began creating stereotactic atlases of the human brain. These atlases are comprehensive guides that involve the intersection of mathematics and anatomy. In 1977, Georges Schaltenbrand (1897–1979) and Waldemar Wahren published a comprehensive guide to stereotaxic surgery that is still in use today. Their Atlas for Stereotaxy of the Human Brain is regarded as one of the most important textbooks on stereotaxy.95 In 1978, Farhad Afshar published a detailed stereotactic atlas of the brainstem and other posterior fossa structures.96 Neurosurgery, and stereotactic surgery of the brainstem in particular, was revolutionized by the advent of the surgical microscope, and more importantly by the invention of MRI. Combined with stereotactic surgery, MRI significantly improved the surgeon’s ability to biopsy brainstem lesions. In 1989, Chad Abernathey published a report detailing 26 cases in which he used a transcerebellar stereotactic approach, informed by MRIs and CTs, to biopsy pontine lesions. Despite having passed through the middle cerebellar peduncle, Abernathey reported no complications or deaths using this procedure.97 Access to the brainstem and the study and assessment of surgical techniques applied to anatomy remain of paramount

i­mportance to neurosurgeons and trainees. In no other region of the brain are operations carried out with such precision and regard for the slightest movement. Trainees must be confident in their ability to tackle vascular lesions, tumors, and other pathology around and within the midbrain to the medulla. In an era of minimally invasive access, technology is joined to anatomical knowledge ever more closely. Trainees must become intimately familiar with the gateway region of the brain, the outlet-inlet that encompasses the functions we rely on to be alive. Such neuroanatomical knowledge, experience, and practice has come for decades from the hands-on major neurosurgical neuroanatomical laboratories of Albert Rhoton (1932–2016) “the father of microscopic neurosurgery” and his disciple Mark Preul (1958-). Under their tutelage, neurosurgeons from around the world have explored the brain, studied and described anatomical details, attempted new avenues to brainstem regions, assessed and challenged established operative theory, and produced hundreds of studies.

■■ Conclusion To understand and appreciate the surgical history of the brainstem, one must first explore the history of its anatomical discovery. This chapter has provided an overview of the major milestones and developments in neuroanatomy and surgical history that occurred from 200 AD to the 1970s. After the 1970s, the advent of CT, MRI, and the high-powered surgical microscope revolutionized the practice of neurosurgery, giving rise to what is now known as microneurosurgery. Yet even with these technological advances, surgery of the brainstem remains a challenging frontier and a personal challenge for neurosurgeons.

1  History of Brainstem Surgery References 1. Greenblatt SH. The historiography of neurosurgery: Organizing themes and methodological issues. A History of Neurosurgery. In its scientific and professional context. Park Ridge (Illinois): The American Association of Neurological Surgeons; 1997:1–26 2. Alexander E, Jr. A perspective of the 1940s. Surg Neurol 1987; 28(4):319–320 3. Sachs E. Fifty Years of Neurosurgery: A Personal Story. New York: Vintage Press; 1958 4. Afifi A, Bergman R. Functional Neuroanatomy. New York: McGraw-Hill; 1998 5. Gomes MdaM, Moscovici M, Engelhardt E. Andreas Vesalius as a renaissance innovative neuroanatomist: his 5th centenary of birth. Arq Neuropsiquiatr 2015;73(2):155–158 6. Elhadi AM, Kalb S, Perez-Orribo L, Little AS, Spetzler RF, Preul MC. The journey of discovering skull base anatomy in ancient Egypt and the special influence of Alexandria. Neurosurg Focus 2012;33(2):E2 7. Preul MC. A history of neuroscience from Galen to Gall. Park Ridge: AANS Publications Committee; 1997 8. Finger S. Minds Behind the Brain: A History of the Pioneers and Their Discoveries. Oxford University Press; 2000 9. Finger S. Origins of Neuroscience: A History of Explorations into Brain Function. Oxford University Press; 2001 10. Pearce JM. Fragments of Neurological History. World Scientific; 2003 11. Meyer A. Historical Aspects of Cerebral Anatomy. Oxford University Press; 1971 12. Causey G, Singer C. Galen on Anatomical Procedures. Oxford University Press; 1957 13. Clarke E, O’Malley CD. The Human Brain and Spinal Cord: A Historical Study Illustrated by Writings from Antiquity to the Twentieth Century. Norman Publishing; 1996 14. Rocca J. Galen and 1997;6(3):227–239

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28. Willis T. The Anatomy of the Brain and the Nerves. Montreal: McGill Univ; 1965 29. Vergani F, Morris CM, Mitchell P, Duffau H. Raymond de Vieussens and his contribution to the study of white matter anatomy: historical vignette. J Neurosurg 2012;117(6):1070–1075 30. Hughes J. Eponymists in medicine: Thomas Willis 1621–1675, His Life and Work. Royal Society of Medicine Press Ltd; 1991 31. Vieussens R. Neurographia universalis: 30 Tab. Fol. Lugduni; 1716 32. Mistichelli D. A treatment of apoplexy in which with new anatomical observations, and physical reflections, all the causes and spices of that evil are sought, and a new, effective remedy is revealed among the others. Roma: A spese di Antonio de’ Rossi; 1709 33. Pearce JM. Burdach’s column. Eur Neurol 2006;55(3):179–180 34. Pourfour du Petit F, Albert CG. Letters from a doctor of the hospitals of the king, to another doctor of his friends. The first letter contains a new brain system. The second letter contains a dissertation on sentiment, and several experiments of chemistry contrary to the system of acids and alkalis. The third letter contains a review of the three chrysosplenium species of M. tournois institutes, three new kinds of plants and some new species. A Namur, chez Charles Gerard Albert, Imprimeur du Roy. 1710 35. Feindel W, Willis T. The Anatomy of the Brain and Nerves: Introduction to the Anatomy of the Brain and Nerves with a Note on Pordage’s English Translation and a Bibliographic Survey of Cerebri Anatome Vol. 1. Vol 1. Montreal: McGill University Press; 1965 36. Reil JC. Investigations on the construction of the big brain in humans... fourth continuation. Arch Physiol 1809;9:136–146 37. York GK. Brain-cutting conferences in the Napoleonic era. Neurol Today 2004;4(9):59 38. Rawlings CE, III, Rossitch E, Jr. Franz Josef Gall and his contribution to neuroanatomy with emphasis on the brain stem. Surg Neurol 1994; 42(3):272–275 39. Spurzheim JG, Chenevix R. Examination of the Objections Made in Britain Against the Doctrines of Gall and Spurzheim. Marsh, Capen & Lyon; 1833 40. Meyer A. Karl Friedrich Burdach and his place in the history of neuroanatomy. J Neurol Neurosurg Psychiatry 1970;33(5):553–561 41. Burdach KF. Karl Friedrich Burdach of the construction and life of the brain. Leipzig: Dyk; 1819 42. Meynert T. Vom gehirne der säugethiere. From brains of mammals. Manual of the doctrine of the tissues of man and animals 1872;2:694–808 43. Bechterew W. About a previously unknown connection of the big olives with the cerebrum. Neurol Centralblatt 1885;4:194–196 44. Stilling B. Untersuchungen über die functionen des rückenmarks und der nerven. mit specieller beziehung auf die abhandlungen J. van deen's, zur physiologie des rüekenmarks... mit abbildungen. O. Wigand; 1842 45. Hannover A. Die chromsäure, ein vorzügliches mittel bei mikroskopischen untersuchungen. Arch Anat Physiol Wiss 1840;1

20. Cushing H, Fulton JF. A Bio-Bibliography of Andreas Vesalius. New York: Schuman’s; 1943

46. Blum F. Der formaldehyd als hartungsmittel. Z Wiss Mikrosk 1893; 10:314–315

21. Vesalius A, Singer C. Vesalius on the Human Brain [Being a Translation of a Section of His Fabrica of 1543]. London; New York: Published for the Wellcome Historical Medical Museum by Oxford University Press; 1952

47. Betz W. Memoirs: methods of investigating the central nervous system in man. J Cell Sci 1873;2(52):343–350

22. Morcos JJ, Haines SJ. History of brain stem surgery. Neurosurg Clin N Am 1993;4(3):357–365 23. Tubbs RS, Loukas M, Shoja MM, et al. Costanzo Varolio (Constantius Varolius 1543–1575) and the Pons Varolli. Neurosurgery 2008;62 ­ (3):734–737, discussion 734–737 24. O’Malley CD. Costanzo Varolio. In: Gillispie CC, ed. Dictionary of Scientific Biography. Vol 13. New York: Charles Scribner’s Sons; 1980: 587–588 25. Varolio C. Varolii of Constantius, of Bologna, the philosophers, and physicians, the anatomy of the human or of the dissolution of the body of the book 4: With copious list. Francofurti: Wechel [u.a.]. 1591 26. Grand W. The anatomy of the brain, by Thomas Willis. Neurosurgery 1999;45(5):1234–1236, 1236–1237 27. Molnár Z. Thomas Willis (1621–1675), the founder of clinical neuroscience. Nat Rev Neurosci 2004;5(4):329–335

48. Kushchayev SV, Moskalenko VF, Wiener PC, et al. The discovery of the pyramidal neurons: Vladimir Betz and a new era of neuroscience. Brain 2012;135(Pt 1):285–300 49. von Gerlach J. Microscopic studies from the field of human morphology. Enke; 1858 50. Golgi C. On the fine structure of olfactory teeth. Reggio-Emilia: Tipografia di Stefano Calderini; 1875 51. Marchi V, Algeri G. On consecutive descending degenerations to experimental lesions in different areas of the cerebral cortex. Experimental Journal of Phrenology and Forensic Medicine Related to Anthropology and Legal and Social Sciences 1886;12 52. Türck L. About secondary disease of individual spinal cords and their sequelae to the brains. Fortsetzung. 1853 53. Gudden B. Experimental studies on the peripheral and central nervous system. Archive for Psychiatry Archive for Psychiatry and Nervous Diseases 1870;2(3):693–7233

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54. Flechsig P. The pathways in the human brain and spinal cord, on the basis of developmental studies. Leipzig: Engelmann; 1876

74. Guiot G, Forjaz S. Subtemporal mesencephalic tractotomy. Rev Neurol 1947;79(10):733–740

55. Flechsig PE. About “systemic diseases” in the spinal cord (4th article). Leipzig: Druck von W. Wigand; 1878

75. Drake CG. Bleeding aneurysms of the basilar artery. Direct surgical management in four cases. J Neurosurg 1961;18:230–238

56. Agrawal A, Kapfhammer JP, Kress A, et al. Josef Klingler’s models of white matter tracts: influences on neuroanatomy, neurosurgery, and neuroimaging. Neurosurgery 2011;69(2):238–252, discussion 252–254

76. Epstein F, Wisoff JH. Intrinsic brainstem tumors in childhood: surgical indications. J Neurooncol 1988;6(4):309–317

57. Goodrich JT. History of posterior fossa tumor surgery. Posterior fossa tumors in children. Springer; 2015:3–60

78. White JC. Spinothalamic tractotomy in the medulla oblongata: an operation for the relief of intractable neuralgias of the occiput, neck and shoulder. Arch Surg 1941;43(1):113–127

58. Smith DC. The evolution of modern surgery: A brief overview. In: Greenblatt SH, ed. A History of Neurosurgery. The American Association of Neurological Surgeons. Park Ridge; 1997:11–26 59. Sakula A. Robert Koch (1843–1910): founder of the science of bacteriology and discoverer of the tubercle bacillus. A study of his life and work. Br J Dis Chest 1979;73(4):389–394 60. Finger S, Boller F, Tyler K. A history of seizures and epilepsies: From the falling disease to dysrhythmias of the brain. 2009 61. Eadie MJ. Victor Horsley’s contribution to Jacksonian epileptology. Epilepsia 2005;46(11):1836–1840 62. Goodrich J. Landmarks in the history of neurosurgery. Principles of ­Neurosurgery. London: Wolfe; 1994 63. Braun E. Successes of trepanation at otitic brain abscess. Eur Arch Otorhinolaryngol 1890;29(3):161–200 64. Bright R. Reports of medical cases selected with a view of illustrating the symptoms and cure of diseases by a reference to morbid anatomy. Vol 2. London: Longman; 1827 65. Weisenburg T. Extensive gliomatous tumor involving the cerebellum and the posterior portions of the medulla, pons and cerebral peduncle and the posterior limb of one internal capsule. J Am Med Assoc 1909; 53(25):2086–2091 66. Dmetrichuk JM, Pendleton C, Jallo GI, Quiñones-Hinojosa A. Father of neurosurgery: Harvey Cushing’s early experience with a pediatric brainstem glioma at the Johns Hopkins Hospital. J Neurosurg Pediatr 2011; 8(4):337–341 67. Bailey P, Cushing H. Medulloblastoma cerebelli: a common type of midcerebellar glioma of childhood. Arch Neurol Psychiatry 1925; 14(2):192–224 68. Ingraham FD, Bailey OT, Barker WF. Medulloblastoma cerebelli; diagnosis, treatment and survivals, with a report of 56 cases. N Engl J Med 1948;238(6):171–174 69. Bailey P, Cushing H. A Classification of the Tumors of the Glioma Group on a Histogenetic Basis With a Correlated Study of Prognosis. ­Philadelphia: Lippincott; 1926 70. Cushing H, Bailey P. Hemangiomas of cerebellum and retina (Lindau’s disease): with the report of a case. Trans Am Ophthalmol Soc 1928; 26:182–202 71. Cushing H. Intracranial Tumours: Notes upon a Series of Two Thousand Verified Cases with Surgical-mortality Percentages Pertaining Thereto. CC Thomas; 1932 72. Dandy WE. Rontgenography of the brain after the injection of air into the spinal canal. Ann Surg 1919;70(4):397–403 73. Pinkus RL. Innovation in neurosurgery: Walter Dandy in his day. Neurosurgery 1984;14(5):623–631

77. Walker AE. Mesencephalic tractotomy: a method for the relief of unilateral intractable pain. Arch Surg 1942;44(5):953–962

79. Schwartz HG, O’Leary JL. Section of the spinothalamic tract at the level of the inferior olive. Arch Neurol Psychiatry 1942;47(2):293–304 80. Schwartz HG, O’Leary JL. Section of the spinothalamic tract in the medulla with observations on the pathway for pain. Surgery 1941;9(2):183–193 81. Finkelnburg R. Differential diagnosis between cerebellum tumors and chronic hydrocephalus (also contributing to the knowledge of angiomas of the central nervous system). J Neurol 1905;29(1):135–151 82. Dandy W. Surgery of the brain: Lewis’ practice of surgery. Hagerstown: WF Prior; 1945 83. Mangiardi JR, Epstein FJ. Brainstem haematomas: review of the literature and presentation of five new cases. J Neurol Neurosurg Psychiatry 1988;51(7):966–976 84. Virchow R. About the extension of smaller vessels. Virchows Arch. 1851; 3(3):427–462 85. Haque R, Kellner CP, Solomon RA. Cavernous malformations of the brainstem. Clin Neurosurg 2008;55:88–96 86. Kretzer RM, Coon AL, Tamargo RJ. Walter E. Dandy’s contributions to vascular neurosurgery. J Neurosurg 2010;112(6):1182–1191 87. Teilmann K. Hemangiomas of the pons. AMA Arch Neurol Psychiatry 1953;69(2):208–223 88. Drake CG. Surgical removal at arteriovenous malformations from the brain stem and cerebellopontine angle. J Neurosurg 1975;43(6):661–670 89. Drake CG. Surgical treatment of ruptured aneurysms of the basilar artery. Experience with 14 cases. J Neurosurg 1965;23(5):457–473 90. Yasargil MG, Krayenbuhl HA, Jacobson JH, II. Microneurosurgical arterial reconstruction. Surgery 1970;67(1):221–233 91. Kalani MY, Rangel-Castilla L, Ramey W, et al. Indications and results of direct cerebral revascularization in the modern era. World Neurosurg 2015;83(3):345–350 92. Roski RA, Spetzler RF, Hopkins LN. Occipital artery to posterior inferior cerebellar artery bypass for vertebrobasilar ischemia. Neurosurgery 1982;10(1):44–49 93. Reis CV, Sankar T, Crusius M, et al. Comparative study of cranial topographic procedures: Broca’s legacy toward practical brain surgery. Neurosurgery 2008;62(2):294–310, discussion 310 94. Spiegel EA, Wycis HT, Marks M, Lee AJ. Stereotaxic apparatus for operations on the human brain. Science 1947;106(2754):349–350 95. Schaltenbrand G, Wahren W. Atlas for Stereotaxy of the Human Brain: With an Accompanying Guide. Thieme; 1977 96. Afshar F, Watkins ES, Yap JC. Stereotaxic Atlas of the Human Brainstem and Cerebellar Nuclei: A Variability Study. Raven Press; 1978 97. Abernathey CD, Camacho A, Kelly PJ. Stereotaxic suboccipital transcerebellar biopsy of pontine mass lesions. J Neurosurg 1989;70(2):195–200

Section II Anatomy, Development, and Pathology of the Brainstem, Thalamus, and Pineal Region

2 Anatomy of the Brainstem, Thalamus,  Pineal Region, and Cranial Nerves

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3  D  evelopment of the Human Brainstem  and Its Vasculature

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4 Pathology of the Brainstem

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Anatomy of the Brainstem, Thalamus, Pineal Region, and Cranial Nerves Kaan Yağmurlu, M. Yashar S. Kalani, and Albert L. Rhoton Jr.

Abstract

The anatomy of the brainstem, thalamus, pineal region, and cranial nerves should be familiar to neurosurgeons treating lesions in these areas because lesions in this region are difficult to reach and remove. The pineal region and thalamus are located deep in the calvaria and are surrounded by critical neurologic structures. Removal of brainstem lesions is cumbersome due to the dense packing of nuclei into a structure that is roughly the size of the human thumb. Approach selection is often based on the shortest distance to reach the lesion. However, because of the need to traverse an area with a high density of critical neurologic structures, safe entry zones into this region have been described, including the perioculomotor, interpeduncular, lateral mesencephalic sulcus, and supra-, infra-, and intracollicular areas in the midbrain; the peritrigeminal zone, supratrigeminal zone, middle cerebellar peduncle, suprafacial and infrafacial approaches, and superior fovea triangle in the pons; and the anterolateral, postolivary, and dorsal medullary sulci. A better neuroanatomical understanding of these areas provides a better surgical strategy and surgical outcomes. Keywords:  brainstem, brainstem surgery, cranial nerves, microsurgical anatomy, pineal region, thalamus The best image guidance that you can have is the knowledge of microsurgical anatomy. Albert L. Rhoton Jr.

■■ Introduction The pineal region and thalamus are challenging to access because of their central location within the calvaria near important surrounding neurovascular structures. Likewise, lesions in the brainstem are challenging because of the many pathways and nuclei packed into a small area and the risks of exposing intra-axial brainstem pathology. However, improved imaging techniques, electrophysiological monitoring, and more precise microsurgical and endoscopic techniques have decreased morbidity and mortality rates related to surgery for brainstem, thalamus, and pineal region lesions (e.g., cavernous malformations and gliomas). As a result, there has been an increase in the number of surgeries performed for lesions in this region. These surgeries have also been facilitated by the definition of several safe entry zones1,​2,​3,​4,​5,​6,​7,​8 and surgical approaches that can be tailored to the morphology of the target lesion.

■■ Thalamus and Pineal Region Microsurgical Anatomy of the Thalamus The thalamus is located in the center of the lateral ventricle at the upper end of the brainstem. It is positioned deep to the posterior half of the insula and the lower part of the pre- and postcentral gyri, and deep to the adjacent part of the superior temporal gyrus (Fig. 2.1a-e).9 The anterior thalamic tubercle, the prominence overlying the anterior thalamic nucleus, forms the posterior edge of the foramen of Monro. The thalamus reaches the level of the posterior commissure posteriorly and the hypothalamus sulcus inferiorly. Its upper margin forms the floor of the lateral ventricle. The stria terminalis and thalamostriate veins run along the striothalamic sulcus, at the junction of the thalamus and caudate nucleus, and the choroid plexus attaches along the choroidal fissure, which is the cleft between the thalamus and fornix. Each lateral ventricle wraps around the superior, inferior, and posterior surfaces of the thalamus.10 The prominent posterior part, the pulvinar, presents in the wall of three different supratentorial compartments: the posterolateral part of the pulvinar forms the lateral half of the anterior wall of the atrium; the posteromedial part of the pulvinar is covered by the crus of the fornix and the part medial to the fornix forms part of the anterior wall of the quadrigeminal cistern; and the inferolateral part of the pulvinar in the region of the geniculate bodies forms part of the roof of the ambient cistern. The medial part of the thalamus forms the upper part of the lateral wall of the third ventricle.10 Blood is supplied to the thalamus through anterolateral, lateral, posterolateral, medial, and dorsal arteries (Fig. 2.1f, g).11 The anterolateral arteries of the thalamus arise from the premammillary branch of the posterior communicating artery; the lateral arteries arise from the anterior choroidal artery; the posterolateral arteries arise from the thalamogeniculate artery; and the medial arteries arise from the thalamoperforating artery. The thalamogeniculate and the thalamoperforating arteries are two of the larger perforating branches of the posterior cerebral artery.9 The thalamoperforating arteries enter the brain through the posterior perforated substance to supply structures in the floor and lateral walls of the third ventricle, including the anterior two-thirds of the thalamus in the area below the floor of the body of the lateral ventricle. They also supply the cerebral peduncle, hypothalamus, midbrain, and internal capsule. The thalamogeniculate arteries arise in the ambient cistern, enter the brain in the region of the geniculate bodies, and send branches into the

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II  Anatomy, Development, and Pathology of the Brainstem, Thalamus, and Pineal Region

Fig. 2.1  Thalamus. (a) Medial view. The thalamus forms the superior part of the lateral wall of the third ventricle. The hypothalamic sulcus is the border between the thalamus above and hypothalamus below. (b) Superolateral view of the position of the thalamus in the lateral ventricle. The thalamus is located in the center of the lateral ventricle at the upper end of the brainstem. The anterior thalamic nucleus (tubercle) forms the posterior edge of the foramen of Monro. (c) Superior view. The upper margin of the

thalamus forms the lateral parts of the floor of the lateral ventricle. The stria terminalis and thalamostriate vein run along the striathalamic sulcus. (d) The fornix wraps around the medial edge of the thalamus, and the caudate nucleus wraps around the lateral edge of the thalamus. (e) Posterolateral view. The left thalamus was removed to expose the subthalamic nucleus and red nucleus. The pulvinar is the posterolateral part of the thalamus.

2 

Anatomy of the Brainstem, Thalamus, Pineal Region, and Cranial Nerves

23

Fig. 2.1 (Continued) (f,g) Superior and lateral views of the arterial supply of the thalamus. (Continued)

posterolateral part of the thalamus, including the geniculate bodies and the adjacent part of the internal capsule. The thalamic veins are divided into superficial and deep veins (Fig. 2.1h, i). Some of the thalamic veins course on the ventricular surface and some course in the basal cisterns.12,​13 Anterior and superior superficial thalamic veins cross the surface of the thalamus and drain into the internal cerebral vein.14 The superficial thalamic veins course along the ventricular surface of the thalamus in a subependymal location and drain into the adjacent veins in the ventricle, velum interpositum, or basal cisterns.14 The deep thalamic veins are divided into anterior, superior, inferior, and posterior thalamic veins.14 The anterior thalamic vein drains the anterosuperior part of the thalamus and terminates in the adjacent part of the internal cerebral, anterior septal, thalamostriate, or anterior caudate vein, or other smaller veins in the region. The superior thalamic vein is the largest of the thalamic veins. It arises in the central superior

part of the thalamus, runs medially to emerge from the medial surface of the thalamus near the striae medullaris thalami, runs posteriorly below the internal cerebral vein in the velum interpositum, and ends in the internal cerebral or great cerebral vein. The inferior thalamic veins arise in the anteroinferior part of the thalamus and traverse the posterior perforated substance to drain into the posterior communicating or peduncular vein. The posterior thalamic veins drain the posterior inferolateral portion of the thalamus and empty into the posterior part of the basal vein or into the veins coursing on the posterolateral surface of the midbrain.

Microsurgical Anatomy of the Pineal Region The pineal gland is an extra-axial structure that is surrounded superiorly by the splenium of the corpus callosum and the vein of Galen and anteriorly by the habenular commissure and

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II  Anatomy, Development, and Pathology of the Brainstem, Thalamus, and Pineal Region Fig. 2.1  (Continued) (h,i) Superior and lateral views of the venous anatomy of the thalamus. The ventricular veins are divided into medial and lateral groups. The ventricular veins drain into the internal cerebral and basal veins and the vein of Galen. The lateral group consists of the anterior caudate vein in the frontal horn; the thalamostriate, posterior caudate, and thalamocaudate veins in the body; the lateral atrial veins in the atrium and occipital horn; and the inferior ventricular and amygdalar veins in the temporal horn. The medial group is formed by the anterior septal vein in the frontal horn, the posterior septal veins in the body, the medial atrial veins in the atrium, and the transverse hippocampal veins (not shown) in the temporal horn. The transverse hippocampal veins drain into the anterior and posterior longitudinal hippocampal veins. The superior choroidal veins drain into the thalamostriate and internal cerebral veins, and the inferior choroidal vein drains into the inferior ventricular vein. The vein of Galen drains into the straight sinus. Abbreviations: Ant. thal. nucl., anterior thalamic nucleus; call., callosum; Caud., caudate; Chor., choroid; Collat., collateral; Corp., corpus; fiss., fissure; For., foramen; Front., frontal; gl., gland; Hypothal., hypothalamic; Lat. vent., lateral ventricular; nucl., nucleus; pell., pellucidum; plex., plexus; Quad., quadrigeminal; Sept., Septum; STN., subthalamic nucleus; Str., stria; Str. thal. sulc., striathalamic sulcus; sulc., sulcus; term., terminalis; vent., ventricle. (Fig. 2.1a-e dissections were prepared by Kaan Yağmurlu, MD. Reproduced with permission from the Rhoton Collection (http://rhoton.ineurodb.org), CC BY-NC-SA 4.0 (http://creativecommons.org/licenses/ by-nc-sa/4.0). Fig. 2.1f-i are used with permission from Barrow Neurological Institute, Phoenix, Arizona.)

posterior commissure (Fig. 2.2). The pineal gland extends ­posteriorly into the quadrigeminal cistern from its stalk. The internal cerebral vein, basal vein of Rosenthal, anterior calcarine vein, and superior vermian vein converge on the vein of Galen before it drains into the straight sinus above the pineal gland. The blood supply to the pineal gland is from branches of the medial and lateral choroidal arteries through anastomoses to the pericallosal, posterior cerebral, superior cerebellar, and quadrigeminal arteries.15 The inferior margin of the posterior part of the falx cerebri slopes toward the splenium to meet the tentorium in the midline.

The straight sinus originates below the splenium of the corpus callosum and travels on the superior surface of the tentorium to where both sides of the tentorium come together at an angle to meet the falx cerebri.16

Surgical Approaches Depending on the location of the lesion in the thalamus, the approach may be the anterior interhemispheric transcallosal approach (including the transventricular, transforaminal, and transchoroidal or transforniceal variations), or the posterior

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Fig. 2.2  Anatomical relationship of the pineal region to surrounding structures. (a) Right hemisphere showing the relationship between the tentorium and falx cerebri and the straight sinus, which lies between them. (b) Medial view showing exposure of the pineal region and surrounding structures. (c) Enlarged view of Fig. 2.2b. The pineal gland is positioned inferior to the vein of Galen. The internal cerebral veins running through the velum interpositum and the basal veins of Rosenthal come together to form the vein of Galen in the subsplenial area. (d) Superior view. The body of the fornix and the hippocampal commissure have been split to expose the internal cere-

bral vein and medial posterior choroidal artery in the velum interpositum. (e) Posterior view. The pineal gland and its relationship to deep venous structures. Abbreviations: A., artery; Cer., cerebral; Chor., choroidal; Gl., gland; Int., internal; Lat., lateral; Med., medial; Post., posterior; S., Sinus; Sag., sagittal; Sup., superior; Occ., occipital; V., vein; Vent., ventricle; Verm., vermian. (Dissections prepared by Kaan Yağmurlu, MD. Reproduced with permission from the Rhoton Collection (http://rhoton.ineurodb.org), CC BYNC-SA 4.0 (http://creativecommons.org/licenses/by-nc-sa/4.0).)

interhemispheric transcallosal, parieto-occipital t­ranscortical transventricular, or infratentorial supracerebellar approach (Fig. 2.3).3,​17 A number of different types of tumors can occupy the pineal region, including tumors originating in the pineal body (pinealoblastomas/pineocytomas, teratomas, and germinomas), in the splenium of the corpus callosum (intrinsic glial tumors), in the velum interpositum (meningiomas), or in the fornix.16 The surgical approaches used to access lesions in the pineal region are dependent on the complex anatomical relationship of the

surgical target to surrounding structures, the location of the arteries feeding the lesion, anatomical variations, and the extent of resection goals. A wide variety of approaches to this region have been described, which can be tailored to the morphology of the target lesion. These approaches include the infratentorial supracerebellar approach, the posterior-interhemispheric transtentorial approach, the occipital interhemispheric approach, the parieto-occipital interhemispheric transcallosal approach, the posterior transcortical approach via the angular gyrus and lateral ventricle, the posterior subtemporal approach, and

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II  Anatomy, Development, and Pathology of the Brainstem, Thalamus, and Pineal Region

Fig. 2.3  Surgical approaches to the pineal region and thalamus. The surgical routes to the pineal region (yellow lines) or thalamus (dashed green arrows) can be classified as from above, from below, and from lateral (transcortical). Insets indicate patient or head positioning and craniotomy options for the four indicated surgical approaches. (Dissection prepared by

Kaan Yağmurlu, MD. Reproduced with permission from the Rhoton Collection (http://rhoton.ineurodb.org), CC BY-NC-SA 4.0 (http://creativecommons. org/licenses/by-nc-sa/4.0). Insets are used with permission from Barrow Neurological Institute, Phoenix, Arizona.)

the combined supra- and infratentorial transsinus approaches (Fig. 2.3).18,​19,​20,​21,​22,​23,​24,​25,​26,​27,​28

Fig. 2.5).29,​30 The upper complex includes the SCA, midbrain, cerebellomesencephalic fissure, superior cerebellar peduncle, tentorial surface of the cerebellum, and the oculomotor, trochlear, and trigeminal cranial nerves ([CNs] III-V).29 The SCA arises anterior to the midbrain, passes inferior to the oculomotor and trochlear nerves and superior to the trigeminal nerve to reach the cerebellomesencephalic fissure, where it runs on the superior cerebellar peduncle and terminates by supplying the tentorial surface of the cerebellum.29 The middle complex includes the AICA, pons, middle cerebellar peduncle, cerebellopontine fissure, petrosal surface of the cerebellum, and the abducens, facial, and vestibulocochlear nerves (CNs VI-VIII).29 The AICA arises at the level of the pons, courses alongside the abducens, facial, and vestibulocochlear nerves to reach the surface of the middle cerebellar peduncle, where it courses along the cerebellopontine fissure and

■■ Brainstem Vascularization of the Brainstem The brainstem is supplied by the posterior circulation arising from the vertebral arteries. The two vertebral arteries come together in the midline to form the basilar artery, most c­ ommonly at the level of the pontomedullary sulcus. Three neurovascular complexes can be defined: an upper complex related to the superior cerebellar artery (SCA); a middle complex related to the anterior inferior cerebellar artery (AICA); and a lower complex related to the posteroinferior cerebellar artery (PICA) (Fig. 2.4 and

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Fig. 2.4 Cranial nerves. (a) Superolateral view. The course of the cranial nerves (CNs) through the skull base was exposed, showing the locations where CNs III through XII arise in or exit from the brainstem. (b) Anterior view of the brainstem showing the origins of CNs II through

XII (CN IV not shown). (Dissections prepared by Kaan Yağmurlu, MD. Reproduced with permission from the Rhoton Collection (http://rhoton.ineurodb.org), CC BY-NC-SA 4.0 (http://creativecommons.org/licenses/ by-nc-sa/4.0).)

terminates by supplying the petrosal surface of the cerebellum.29 The lower complex includes the PICA, medulla, inferior cerebellar peduncle, cerebellomedullary fissure, suboccipital surface of the cerebellum, and the glossopharyngeal, vagus, spinal accessory, and hypoglossal nerves. The PICA arises at the level of the

medulla, encircles the medulla, and courses past the glossopharyngeal, vagus, spinal accessory, and hypoglossal nerves to reach the surface of the inferior cerebellar peduncle, where it dips into the cerebellomedullary fissure and terminates by supplying the suboccipital surface of the cerebellum.29

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Fig. 2.5  Blood supply of the brainstem. (a) Anterior view of the brainstem without vessels. (b) Anterior view. The posterior inferior cerebellar arteries (PICAs) arise from the vertebral arteries (VAs) at the medullary level and course alongside the glossopharyngeal (cranial nerve [CN] IX), vagus (CN X), spinal accessory (CN XI), and hypoglossal (CN XII) nerves. The two VAs come together to form the basilar artery (BA), frequently at the level of the pontomedullary junction. The BA gives off the basilar perforators that supply the ventral pons, and it gives off the anterior inferior cerebellar artery (AICA) in close proximity to the abducens (CN VI), facial (CN VII), and vestibulocochlear (CN VIII) nerves. (c) The superior cerebellar artery (SCA) arises at the midbrain level and encircles the brainstem near the pontomesencephalic junction. The SCA courses inferior to the oculomotor (CN III) and trochlear (CN IV) nerves and superior to the trigeminal (CN V) nerve. The SCA courses along the midbrain, cerebellomesencephalic fissure, superior

cerebellar peduncle, and tentorial surface of the cerebellum. The AICA lies in close proximity to the pons, middle cerebellar peduncle, cerebellopontine fissure, and petrosal surface of the cerebellum. The PICA lies in close proximity to the medulla, inferior cerebellar peduncle, cerebellomedullary fissure, and suboccipital surface of the cerebellum. (d) Medial view. The SCA courses along the superior half of the roof of the fourth ventricle; the PICA courses along the inferior half of the roof; and the AICA is intimately related to the lateral recess and the foramen of Luschka. Abbreviations: Cerebellomed., cerebellomedullary; Cerebellomes., cerebellomesencephalic; ICP, inferior cerebellar peduncle; MCP, middle cerebellar peduncle; PCA, posterior cerebral artery; Pontomed., pontomedullary; Pontomes., pontomesencephalic; Sulc., sulcus; Tr., tract. (Dissections prepared by Kaan Yağmurlu, MD. Reproduced with permission from the Rhoton Collection (http://rhoton.ineurodb. org), CC BY-NC-SA 4.0 (http://creativecommons.org/licenses/by-nc-sa/4.0).)

Long Tracts of the Brainstem

tracts lie in the middle part, and the temporoparieto-occipitopontine tract lies in the lateral part of the cerebral peduncle.1,​5,​32,​33,​34,​35 In the pons, the corticospinal tract courses anteromedially. The corticobulbar tract descends immediately dorsal to the corticospinal tract to connect with the related CN nuclei. The corticopontine fibers end at the pontine nuclei that are scattered anterior and posterior to the corticospinal and corticobulbar tracts.1,​36

The brainstem is divided into ventral and dorsal parts by the medial lemniscus (ML) (Fig. 2.6a).1,​31

Medial Lemniscus The ML arises in the gracile and cuneate tubercles and ascends to divide the brainstem into ventral and dorsal parts and to terminate in the thalamus (Fig. 2.6a).1 In the pons, the ML is concave ventrally in the lateral view. In the midbrain, it ascends dorsal to the cerebral peduncle where its fibers intermingle with the substantia nigra.1

Ventral Fiber Tracts The ventral midbrain and pons contain the corticospinal, corticobulbar, and corticopontine tracts (Fig. 2.6b).1 The caudal medulla contains only the corticospinal tract. In the midbrain, the frontopontine fibers lie in the medial part, the corticospinal and corticobulbar

Dorsal Fiber Tracts The dorsal tracts examined include the medial longitudinal fasciculus (MLF), the central tegmental tract (CTT), the trigeminal mesencephalic tract (TMT), and the trigeminal spinal tract (TST).1 The MLF extends from the midbrain to the upper thoracic spinal cord and connects the visual and vestibular centers to the nuclei controlling the movement of the eyes, head, and neck at the level of the midbrain.1 The MLF ends in the interstitial nucleus rostral to the cerebral aqueduct in the midbrain (Fig. 2.6a, c, d).35 The MLF travels near the floor of the fourth ventricle, adjacent to the midline

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Anatomy of the Brainstem, Thalamus, Pineal Region, and Cranial Nerves

Fig. 2.6  The long tracts of the brainstem. (a) Lateral view. The medial lemniscus (ML) and medial longitudinal fasciculus (MLF) were exposed. The ML ascends from the gracile and cuneate tubercles to the thalamus. In the midbrain, it ascends dorsal to the cerebral peduncle and substantia nigra, ventrolateral to the red nucleus, and lateral to the subthalamic nucleus, to terminate in the thalamus. In the medulla, the MLF is located just behind the pyramids formed by the corticospinal tracts that descend in the ventral medulla. The MLF curves ventrally at the lower edge of the facial colliculus and passes ventral to the hypoglossal triangle. It crosses the ML at the level of the gracile and cuneate tubercles and descends in the ventral funiculus of the spinal cord. The olive is located lateral to the ML. (b) Anterior view demonstrating the relationships between the cerebral peduncle, ML, and corticospinal tract in the pons. The ventral fiber tracts in the left half of the pons have been removed to expose the ML. (c) Posterior view of the dorsal pontine tracts: the MLF, trigeminal mesencephalic tract (TMT), and trigeminal spinal tract (TST). The MLF courses adjacent to the midline near the floor of the fourth ventricle and passes medial to the abducens nucleus and intrapontine

29

segment of the facial nerve. The trigeminal nerve divides into the rostrally directed TMT and the caudally directed TST. (d) Posterior view. The parts of the dorsal pons and midbrain have been removed, leaving the right central tegmental tract (CTT), which connects the red nucleus and the olive. In the midbrain, the CTT originates from the dorsomedial part of the red nucleus and descends ipsilaterally between the superior cerebellar peduncle laterally, the MLF medially, and the ML ventrally. At the level of the facial colliculus, the CTT courses medial to the intrapontine segments of the facial nerve and courses lateral to the intrapontine segment of the abducens nerve to terminate in the olive. Abbreviations: CN, cranial nerve; Corticospin., corticospinal; Frontopon., frontopontine; Hypogl., hypoglossal; Lemn., lemniscus; Med., medial; Nucl., nucleus; Pontomed., pontomedullary; SCP, superior cerebellar peduncle; Spin., spinal; Subst., substantia; Sup., superior; TPO Pon., temporoparieto-occipitopontine; Tr., tract; Tub., tubercle.(Dissections prepared by Kaan Yağmurlu, MD. Reproduced with permission from the Rhoton Collection (http:// rhoton.ineurodb.org), CC BY-NC-SA 4.0 (http://creativecommons.org/licenses/ by-nc-sa/4.0).)

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Fig. 2.7 Surface, internal anatomy, safe entry zones, and surgical exposures of the midbrain. (a) Left lateral view. The upper and lower limits of the midbrain have been exposed. (b) The ventral and dorsal parts of the midbrain, medial lemniscus (ML) and lateral mesencephalic sulcus (LMS, thick yellow line) have been exposed. The LMS extends along the lateral edge of the ML. (c) Midbrain axial section. Entry into the LMS at a right

angle (dashed green arrow) to the tectal surface (dashed white lines) reaches the dorsal midbrain. Angling 45° forward (dashed blue arrow) will reach the ML. The substantia nigra is located along the anterior surface of the ML. (d) The subtemporal exposure of the LMS. Inset shows location of the craniotomy (yellow rectangle). (e) The lateral infratentorial supracerebellar exposure of the LMS. Inset shows location of craniotomy (yellow circle).

of the pons.1 It curves ventrally at the lower edge of the facial colliculus, approaches the ML, and passes ventral to the hypoglossal triangle. It then crosses the ML at the level of the gracile and cuneate tubercles and continues in the ventral funiculus of the spinal cord (Fig. 2.6a). The trigeminal nerve enters the brainstem at the level of the midpons. It courses through the middle cerebellar peduncle toward the fourth ventricle to reach the trigeminal motor and main sensory nuclei, where it divides into the TMT and TST (Fig. 2.6c). The TMT ascends deep to the superior half of the floor of the fourth ventricle between the superior cerebellar peduncle laterally, the sulcus limitans medially, and the CTT ventrally. The TST turns caudally at the level of the trigeminal motor and sensory nuclei and descends between the intrapontine segment of the vestibulocochlear nerve dorsally and the intrapontine segments of the facial, glossopharyngeal, vagus, spinal accessory, and hypoglossal nerves ventrally to reach the spinal cord (Fig. 2.6c).1 The CTT, which is a part of the extrapyramidal system, connects the red nucleus and the inferior olivary nucleus

(Fig. 2.6d).1 At the level of the midbrain, the CTT originates from the dorsomedial part of the red nucleus and descends ipsilaterally, passing dorsally through the decussation of the superior cerebellar peduncle and laterally to the MLF.31 The CTT courses deep to the superior half of the floor of the fourth ventricle between the sulcus limitans laterally and the superior cerebellar peduncle medially. The CTT is located deep to the TMT and dorsal to the ML.1 At the level of the facial colliculus, the CTT courses between the intrapontine segments of the facial nerve laterally and the intrapontine segment of the abducens nerve medially to end in the dorsomedial part of the inferior olivary nucleus.1

Midbrain Surface and Internal Anatomy The midbrain is separated from the diencephalon above by the sulcus between the optic tracts and the cerebral peduncles, and from the pons below by the pontomesencephalic sulcus

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Fig. 2.7 (Continued) (f) Posterior view of the tectal plate and the supracollicular, infracollicular, and intercollicular safe entry zones (yellow lines). (g) Posterior view. Further dissection of the tectal plate. The superior and inferior colliculi have been removed on the right side to expose the aqueduct, an important landmark at the ventral limit of the supracollicular, infracollicular, and intercollicular approaches. The nuclei of the superior and inferior colliculi have been exposed on the right side. (h) Posterior view after removal of the thalami. In the midbrain, the ML ascends ventrolateral to

the red nucleus and lateral to the subthalamic nucleus to enter the thalamus. The red nucleus extends from midlevel of the inferior colliculus to the lateral wall of the third ventricle. The subthalamic nucleus is located just ventral to the red nucleus and dorsomedial to the internal capsule. (i) Paramedian infratentorial supracerebellar approach to the dorsal midbrain and collicular safe entry zones. Yellow lines indicate the supracollicular, infracollicular, and intercollicular safe entry zones. Inset shows location of craniotomy with dura exposed. (Continued)

(Fig. 2.7a).1 The paired cerebral peduncles sit at the ventral surface of the midbrain. The interpeduncular fossa, a wedgeshaped depression between the cerebral peduncles, contains the posterior perforated substance in its floor.1,​37 The quadrigeminal plate, which consists of the superior and inferior colliculi, is situated at the dorsal surface of the midbrain. The ML divides the midbrain into ventral and dorsal parts.1 The tegmentum (which includes the oculomotor, trochlear, and red nuclei) and the tectum (which includes the quadrigeminal plate) are situated in the dorsal midbrain, and the cerebral peduncle is situated in the ventral midbrain. The tegmentum is situated ventral to the cerebral aqueduct, and the tectum is situated dorsal to the cerebral aqueduct. The decussation of the superior cerebellar peduncle and MLF also travel in the tegmentum (Fig. 2.7b, c). The midbrain contains the intramesencephalic segments of the oculomotor and trochlear nerves and their nuclei. The oculomotor nucleus is located next to the

midline at the level of the lower half of the superior colliculus and the upper half of the inferior colliculus, and between the cerebral aqueduct dorsally and the decussation of the superior cerebellar peduncle ventrally. The intramesencephalic segment of the oculomotor nerve arises from its nuclei and passes medial to and inside the red nucleus to exit the brainstem at the interpeduncular fossa. The trochlear nucleus is located adjacent to the midline in the midbrain at the level of the lower half of the inferior colliculi (Fig. 2.7b). Like the oculomotor nuclei, it is positioned between the cerebral aqueduct dorsally and the decussation of the superior cerebellar peduncle ventrally.1

Safe Entry Zones and Surgical Approaches The proposed safe entry zones of the midbrain are along the lateral mesencephalic sulcus (LMS), the supracollicular, infracol-

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II  Anatomy, Development, and Pathology of the Brainstem, Thalamus, and Pineal Region

Fig. 2.7  (Continued) (j) Anterior view of the midbrain. The perioculomotor and interpeduncular fossa safe entry zones (yellow ovals) have been exposed. (k) The perioculomotor zone is bordered superiorly by the posterior cerebral artery (PCA), and inferiorly by the superior cerebellar artery (SCA). (l) Superior view. The contralateral orbitozygomatic trajectory (dashed green arrow) to the lesion (red square) located in the centromedian midbrain and the ipsilateral orbitozygomatic route (dashed yellow arrow) for reaching the perioculomotor zone are shown. (m) The orbitozygomatic or mini-orbitozygomatic exposure of the perioculomotor zone (yellow oval). Inset indicates head position. (n) The contralateral trajectory for reaching the interpeduncular zone passes through the opticocarotid triangle (inset indicates head position) (o) After passing through

the opticocarotid triangle, the interpeduncular fossa is reached between the basilar tip and mammillary body. Abbreviations: A., artery; Cer., cerebri; CN, cranial nerve; Coll., colliculus; Contralat., contralateral; Corticospin., corticospinal; Gen., geniculate; Gl., gland; ICA, internal cerebral artery; Inf., inferior; Interped., interpeduncular; Ipsilat., ipsilateral; Lat., lateral; Lemn., lemniscus; Mamm., mammillary; Med., medial; Mes., mesencephalic; Nucl., nucleus; Periocc., perioculomotor; Pontomes., pontomesencephalic; Post. Perf. Subs., posterior perforated substance; Sulc., sulcus; Sup., superior; STN, subthalamic nucleus; Temp., temporal; Tr., tract; V., vein. (Dissections prepared by Kaan Yağmurlu, MD. Reproduced with permission from the Rhoton Collection (http://rhoton.ineurodb.org), CC BY-NC-SA 4.0 (http://creativecommons.org/licenses/by-nc-sa/4.0).)

licular, and intercollicular areas, and the perioculomotor and interpeduncular zones.1,​4,​37

the border between the ventral and dorsal midbrain.1 Angling an incision into the LMS 45° forward will reach the ML at the border between the ventral and dorsal midbrain (Fig. 2.7c).1 Angling the incision through the sulcus farther forward will reach the cerebral peduncle. An incision entering at a right angle to the tectal surface will be directed further posterior to enter the dorsal midbrain (Fig. 2.7c). Depending on the level of the entry point, these structures may be encountered via this incision, in order from lateral to medial: the TMT and CTT located dorsal to the decussation of the superior cerebellar peduncle, the red nucleus located at the

Lateral Mesencephalic Sulcus The LMS runs on the surface of the midbrain between the cerebral peduncle and the lateral lemniscus and extends from the pontomesencephalic sulcus inferiorly to the medial geniculate body superiorly (Fig. 2.7a-e).1,​32 It is positioned immediately lateral to the ventral surfaces of the ML and the substantia nigra at

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level of the upper half of the inferior colliculus near the midline and extending upward along the lateral wall of the third ventricle, the decussation of the superior cerebellar peduncle located just caudal to the red nucleus at the level of the inferior colliculus, the oculomotor nucleus at the level of the lower half of the superior colliculus and upper half of the inferior colliculus, and the trochlear nucleus at the level of the lower half of the inferior colliculus.1 The LMS can be reached by a lateral infratentorial supracerebellar approach or a subtemporal approach (Fig. 2.7d, e).

nucleus is located dorsal to the ML and the exit point of the oculomotor nerve from the midbrain. Care must be taken to avoid the red nucleus, the intramesencephalic segment of the oculomotor nerve, and the corticospinal and corticobulbar tracts in the middle third of the cerebral peduncle.1 This zone can be approached using an orbitozygomatic, a mini-orbitozygomatic, or a pretemporal approach (Fig. 2.7l, m).

Supracollicular and Infracollicular Areas

The interpeduncular fossa is incised to resect centromedially located lesions that are medial to the third nerve.37 This safe entry zone utilizes the space between the mammillary bodies and the top of the basilar artery to gain access to the centromedian midbrain (Fig. 2.7l, n, o). It is is best approached using a contralateral mini-orbitozygomatic craniotomy. The opening into the brainstem should be vertical.

The supracollicular and infracollicular areas are the proposed safe entry zones for lesions in the tectum (quadrigeminal plate), dorsal to the aqueduct (Fig. 2.7f-i).5 The aqueduct is an important midline landmark for determining the depth of the approach.1 For the supracollicular approach, a transverse incision is made just above the upper edge of the superior colliculus (Fig. 2.7f).1 An incision deeper than the aqueduct will damage the intramesencephalic segment of the oculomotor nerve and the MLF, both of which sit ventral to the aqueduct next to the midline. As the supracollicular incision extends laterally from the midline, it will reach, in order, the habenula, TMT, CTT, and red nucleus (Fig. 2.7f-i). For the infracollicular approach, a transverse incision is made between the trochlear nerve and the lower edge of the inferior colliculus.1 An incision deeper than the aqueduct will encounter, from superficial to deep, the trochlear nucleus, MLF, and decussation of the superior cerebellar peduncle (Fig. 2.7f-i).

Intercollicular Area The intercollicular area is an entry zone that can be used with relatively minimal morbidity instead of the supracollicular and infracollicular safe entry zones. Although the colliculi are involved in visual and auditory stimulus processing, the intercollicular region is sparse in fibers (Fig. 2.7g). The colliculi can be readily identified intraoperatively as round eminences on the dorsal midbrain surface (Fig. 2.7i). A median or paramedian infratentorial supracerebellar approach can be used to reach the dorsal midbrain (Fig. 2.7l).

Perioculomotor Zone Ventromedian lesions of the midbrain can be reached via the perioculomotor zone that is directed through the cerebral peduncle between the exit point of the oculomotor nerve medially and the corticospinal and corticobulbar tracts laterally (Fig. 2.6b and Fig. 2.7j-o).1,​5,​33,​35 This zone is also bordered superiorly by the posterior cerebral artery and inferiorly by the SCA (Fig. 2.7k). The width of the perioculomotor zone is the distance between the exit point of the oculomotor nerve medially and the medial edge of the corticospinal and corticobulbar tracts laterally, making it a narrow zone that is adjacent to the oculomotor nerve and is approximately the medial one-third to one-fourth of the cerebral peduncle.1,​5,​32,​33,​34,​35 However, it is best to restrict the approach to the medial one-fourth of the peduncle. The fibers in the cerebral peduncle immediately lateral to the oculomotor nerve are frontopontine fibers (Fig. 2.6b).1 The first structures to be encountered in the dorsal midbrain are the red nucleus and the intramesencephalic segment of the oculomotor nerve passing through it. The red

Interpeduncular Fossa Approach

Pons Surface and Internal Anatomy The pons is located between the pontomesencephalic sulcus superiorly and the pontomedullary sulcus inferiorly.1 It is divided into ventral (basilar) and dorsal (tegmentum) parts by the ML (Fig. 2.8a). The pons contains the intrapontine segments of the trigeminal, abducens, facial, and vestibulocochlear nerves and their individual nuclei. The trigeminal motor and main sensory nuclei are located at the level of the midpons and deep to the lateral edge of the floor of the fourth ventricle (Fig. 2.8b). These nuclei sit deep to the superolateral edge of the superior fovea triangle and the medial edge of the superior cerebellar peduncle (Fig. 2.8m).1 The trigeminal nerve has three sensory nuclei: (1) the main sensory nucleus, which is located immediately lateral to the motor nucleus, (2) the trigeminal mesencephalic nucleus, which ascends to the midbrain with its tract, and (3) the trigeminal spinal nucleus, which descends with its tract to the upper spinal cord (Fig. 2.8n). The abducens nucleus is located in a paramedian location immediately ventral to the floor of the fourth ventricle. The MLF and intrapontine segment of the facial nerve course between the median sulcus and the abducens nucleus (Fig. 2.8k). The intrapontine segment of the abducens nerve originates from the ventral face of the abducens nucleus and proceeds ventrally through the ML lateral to the corticospinal tract to exit the pons at the lateral edge of the corticospinal tract. The facial nucleus is located at the level of the pontomedullary junction, dorsal to the ML, rostral to the nucleus ambiguus, ventrolateral to the abducens nucleus, ventromedial to the TST, and immediately dorsomedial to the uppermost edge of the inferior olivary nucleus. The intrapontine segment of the facial nerve originates from the facial nucleus and passes dorsomedially toward the floor of the fourth ventricle. It courses around, in order, the lower, medial, and upper edge of the abducens nucleus, just lateral to the MLF. After passing medial to the TST, it exits the pons in the cerebellopontine angle (Fig. 2.8l). The vestibulocochlear nerve enters the brainstem at the lateral end of the pontomedullary sulcus. The vestibular component of this nerve is located anterosuperiorly and the cochlear component is located posteroinferiorly. The dorsal cochlear nucleus sits on the dorsal surface of the inferior cerebellar peduncle in

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Fig.   2.8  Surface, internal anatomy, safe entry zones, and surgical exposures of the pons. (a) Lateral surface of the pons. The supratrigeminal entry zone (blue oval), peritrigeminal entry zone (yellow oval), and middle cerebellar peduncle entry zone (green oval) are shown. (b) Critical structures at the peritrigeminal and supratrigeminal safe entry zones are exposed by further dissection of the left ventral pons. (c) Axial section of the pons. The middle cerebellar peduncle zone can be

easily reached by splitting the petrosal fissure of the cerebellum (green arrow) to remove the central pontine lesion (yellow circle). The red arrow indicates the route to the central pons without splitting the petrosal fissure that requires more cerebellar retraction. (d) Right retrosigmoid view as seen when the patient is in a sitting position. Inset shows head position with vertical line marking skin incision. (e) The technique for splitting the petrosal fissure to expose the middle cerebellar peduncle (green oval) is shown.

the lateral recess where it forms a smooth prominence called the auditory tubercle (Fig. 2.8n). The ventral cochlear nucleus is located on the lateral surface of the inferior cerebellar peduncle.1

of the pontine and medullary parts of the floor of the fourth ventricle. The floor is divided into three parts: the superior part in the pons, the intermediate part in the pontomedullary junction, and the inferior part in the medulla. The superior part has a triangular shape: its apex is at the aqueduct and its base is created by a line crossing the rostral edges of the lateral recesses. The intermediate part is formed by the strip between the upper and lower edges of the lateral recesses. The caudal part has a triangular shape limited laterally by the inferolateral margin of the floor, along which the tela choroidea is attached, and caudally by the obex. The floor from rostral apex to caudal tip is divided into two symmetric halves

Floor of the Fourth Ventricle The floor of the fourth ventricle has a rhomboid shape (Fig. 2.8j).1 The rostral two-thirds of the floor are on the posterior surface of the pons and the caudal one-third is on the posterior surface of the medulla.1,​38 The cerebral aqueduct opens into the apex and the caudal end is at the obex.1 A line connecting the rostral edges of the lateral recesses marks the j­unction

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Anatomy of the Brainstem, Thalamus, Pineal Region, and Cranial Nerves

35

Fig. 2.8  (Continued) (f) Left retrosigmoid approach to the peritrigeminal zone, as seen when the patient is in a sitting position. Inset shows head position with skin incision marked for the craniotomy. (g) The left presigmoid approach can be used to expose the peritrigeminal zone (yellow oval). Inset shows head position with craniotomy marked (yellow rectangle). (h) Left subtemporal transtentorial approach for exposure of the supratrigeminal

(green oval) and peritrigeminal (yellow oval) zones. Inset shows head position with craniotomy marked (yellow rectangle). (i) Left anterior petrosectomy (Kawase approach) for exposure of the supratrigeminal (green oval) and peritrigeminal (yellow oval) zones. Inset shows head position with craniotomy marked (yellow rectangle). (Continued)

by the median sulcus. The sulcus limitans, another longitudinal sulcus, extends along the ventricular floor lateral to the median sulcus. The median eminence is the longitudinal prominence between the median sulcus and the sulcus limitans. It is the site of the facial colliculus, prominences overlying the hypoglossal and vagal nuclei, and the area postrema. These three paired triangular areas overlying the hypoglossal and vagal nuclei and area postrema in the medullary part of the floor give this area a pen nib-shaped appearance, and consequently, the name calamus scriptorius. The sulcus limitans deepens at two points to form dimples called fovea. The superior fovea is lateral to the facial colliculus, and the inferior fovea is lateral to the hypoglossal triangle. The inferior fovea is located in the medullary part of the floor immediately lateral to the hypoglossal triangle between the vestibular area superiorly and the upper edge of the vagal triangle inferiorly. The striae medullaris cross the ventricular floor at the level of the lateral recess.1

Superior Fovea The superior fovea has a triangle shape and is located lateral to the facial colliculus (Fig. 2.8m).1 The superolateral edge of the triangle is formed by the superior cerebellar peduncle, the inferolateral edge by the vestibular area, and the medial base by the sulcus limitans. The apex of the triangle is located at the most lateral point of the rostral part of the fourth ventricle. The superior fovea is an important landmark for estimating the position of the facial colliculus and the deep location of the motor and main sensory nuclei of the trigeminal nerve. The apex of the superior fovea triangle is located laterally at the same transverse level as the upper edge of the facial colliculus. The superolateral edge of the triangle is a landmark for estimating the deep position of the trigeminal motor and main sensory nuclei. If the prominence of the facial colliculus is not well defined, the level of the apex of the superior fovea triangle can be used as the transverse level of the upper edge of the facial colliculus.

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Fig. 2.8  (Continued) (j) Dorsal pons and floor of the fourth ventricle. White dashed circle indicates extent of lateral recess. White dashed V shape indicates the border of the medullary part of the fourth ventricle. (k) Posterior view of the facial colliculi. (l) Posterolateral view of the facial colliculi. The facial colliculus overlies the abducens nucleus and the intrapontine segments of the facial nerve. (m) The superior fovea triangle. The superolateral edge of the superior fovea triangle is a landmark for the deep location of the trigeminal

motor and main sensory nuclei (yellow circle). The apex of the superior fovea triangle (green dashed triangle) is located at the same transverse level as the rostral edge of the facial colliculus (blue dashed line). The lower half of the superior fovea triangle may be incised to remove a lesion located at the level of the facial colliculus. (n) The superior fovea triangle (yellow oval) and the suprafacial and infrafacial approaches (green areas) and their position in relation to the facial colliculus are shown.

Facial Colliculus

ment of the facial nerve, located at the same transverse level as the lateral apex of the superior fovea triangle. Its caudal edge is formed by the inferior intrapontine segment of the facial nerve, located at the level of a transverse line crossing the upper edges of the lateral recess.

The facial colliculus is positioned near the midline between the MLF and the sulcus limitans (Fig. 2.8k, l).1 The rostral edge of the facial colliculus is formed by the superior intrapontine seg-

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37

Fig. 2.8 (Continued) (o) The median suboccipital approach is used to reach the floor of the fourth ventricle. (p) The telovelar incision (green dashed line) is performed to expose the floor of the fourth ventricle. (q) The facial colliculus frequently makes a prominence on the floor. (o-q) Insets show patient positioning and craniotomy location. Abbreviations: AICA, anterior inferior cerebellar artery; Aud., auditory; Cerebellopont., cerebellopontine; CN, cranial nerve; coll., colliculus; Corticospin., corticospinal; CTT, central tegmental tract; Ext. external; Fiss., fissure; Flocc., flocculus; Hypogl., hypoglossal; Inf., inferior; Intermed., intermediate; Junct., junction; Lat., lateral; Lemn., lemniscus; limit., limitans; MCP, middle

cerebellar peduncle; Med., medial, median; MLF, medial longitudinal fasciculus; Nucl., nucleus; Pontomed., pontomedullary; Pontomes., pontomesencephalic; rec., recess; SCP, superior cerebellar peduncle; Sulc., sulcus; Sup., superior; TMT, trigeminal mesencephalic tract; Tr., tract; TST, trigeminal spinal tract; V. of CPF, vein of cerebellopontine fissure; Vest., vestibular. (Dissections prepared by Kaan Yağmurlu, MD. Reproduced with permission from the Rhoton Collection (http://rhoton.ineurodb.org), CC BYNC-SA 4.0 (http://creativecommons.org/licenses/by-nc-sa/4.0). Fig. 2.8d,f,o-q insets are used with permission from Barrow Neurological Institute, Phoenix, Arizona.)

Safe Entry Zones and Surgical Approaches

Supratrigeminal Zone

Middle Cerebellar Peduncle Zone

The supratrigeminal entry zone is used to manage lesions that are located just above the level of the exit zone of the trigeminal nerve from the pons. An oblique incision is made parallel to the course of the transverse pontine fibers (Fig. 2.8a, b). In addition to the supratrigeminal zone, other safe entry zones in the ventral pons are the middle cerebellar peduncle and peritrigeminal zones. The anterior petrosectomy (Kawase), subtemporal transtentorial, retrosigmoid, or presigmoid approaches are the options for reaching these safe entry zones (Fig. 2.8f-i). The proposed safe entry zones in the dorsal pons are the superior fovea triangle and the suprafacial and infrafacial approaches via the midline suboccipital craniotomy (Fig. 2.8m-q).

The middle cerebellar peduncle is a connection between the pons and cerebellum that is composed of the transverse pontine fibers, where the fibers pass posterior to the level of the exit point of the trigeminal nerve from the brainstem (Fig. 2.8a-e).39 This entry zone is used for deep central and lateral pontine or exophytic lesions. After a retrosigmoid approach, splitting the petrosal fissure (horizontal fissure) of the cerebellum provides greater exposure for the middle cerebellar peduncle zone and decreases the requirement for cerebellar retraction (Fig. 2.8d, e).39,​40

Peritrigeminal Zone The approach through the peritrigeminal entry zone for lesions in the ventral pons is usually directed through a ­longitudinal incision between the trigeminal and facial nerves (Fig. 2.8a).2,​41,​42 The critical neurologic structures at this zone are the intrapontine segments of the abducens and facial nerves inferiorly; the intrapontine segment of the trigeminal nerve superiorly; the corticospinal tract anteromedially; and the trigeminal motor nucleus and TST posteromedially (Fig. 2.8b).2,​42

Superior Fovea Triangle Approach In the superior fovea triangle approach, the lower half of the superior fovea triangle may be used to remove lesions located at the level of the facial colliculus (Fig. 2.8m).43

Suprafacial Collicular Approach The suprafacial safe entry zone is limited rostrally by the frenulum veli through which the trochlear nerve passes, caudally by

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Fig. 2.9 Surface, internal anatomy, safe entry zones, and surgical exposures of the medulla. (a) The anterolateral sulcus safe entry zone makes use of the decussation of the corticospinal tract between the rootlets of the hypoglossal nerve and the C1 nerve as a point of entry. Similarly, at the level of the olives (yellow oval) on the anterolateral surface of the medulla, a safe entry zone limited medially by the anterolateral sulcus (yellow dashed line) and the pyramids and posteriorly by the posterolateral sulcus can be used to enter the medulla for deep lesions that do not reach a pial surface. The lateral medullary zone (LMZ; yellow rectangle) through the inferior cerebel-

lar peduncle can also be used as a safe entry zone. (b) The left far lateral view to the ventral medullary entry zones. (c) The dorsal medullary sulci and the LMZ (light red areas) have been used as entry zones. Abbreviations: CN, cranial nerve; ICP, inferior cerebellar peduncle; inter., intermediate; lat., lateral; med., median; PICA, posterior inferior cerebellar artery; Post., posterior; Sulc., sulcus; VA, vertebral artery.(Dissections prepared by Kaan Yağmurlu, MD. Reproduced with permission from the Rhoton Collection (http:// rhoton.ineurodb.org), CC BY-NC-SA 4.0 (http://creativecommons.org/licenses/ by-nc-sa/4.0).)

the superior intrapontine segment of the facial nerve at the upper margin of the facial colliculus, medially by the MLF, and laterally by the sulcus limitans (Fig. 2.8n).7 The incision for this approach should not extend medially into the MLF or laterally to the sulcus limitans to avoid damaging the TMT and CTT located deep to the locus coeruleus, or the trigeminal motor and main sensory nuclei deep to the superolateral edge of the superior fovea triangle.1

of the tela choroidea along the lower margin of the lateral recess.1

Infrafacial Collicular Approach The inferior intrapontine segment of the facial nerve that forms the lower edge of the facial colliculus also forms the rostral border of the infrafacial approach located at the level of a transverse line passing through the upper edges of the lateral recess1,​7 (Fig. 2.8n). The caudal border is positioned at the upper edge of the hypoglossal triangle located at the level of the attachment of the tela choroidea to the lower edges of the lateral recess.1 The rostrocaudal length of the infrafacial safe entry zone is the same as the distance between the upper and lower borders of the lateral recess or the intermediate part of the floor of the fourth ventricle.1 The MLF forms the medial border, and the facial nucleus and nucleus ambiguus located in order from rostral to caudal deep to the floor form the lateral border. The facial nucleus and nucleus ambiguus are found deep and just lateral to the most medial point of attachment

Medulla Surface and Internal Anatomy The ventral surface of the medulla is formed by the medullary pyramids (Fig. 2.9).1,​38 The anteromedian sulcus divides the upper medulla in the anterior midline between the pyramids and disappears on the lower medulla at the level of the decussation of the pyramids, but it reappears below the decussation and is continuous caudally with the anteromedian fissure of the spinal cord.38 The lateral surface of the medulla is formed predominantly by the inferior olives, which are situated lateral to and separated from the pyramids by the anterolateral (preolivary) sulcus. The rootlets of the hypoglossal nerves arise in the anterolateral sulcus. The lateral surface is demarcated posteriorly by the exits of the rootlets of the glossopharyngeal, vagus, and spinal accessory nerves just dorsal to the posterolateral (postolivary) sulcus, which courses along the dorsal margin of the olive and is continuous below with the posterolateral sulcus of the spinal cord. The dorsal surface of the medulla is divided into superior and inferior parts. The superior part is composed in the midline of the inferior half of the floor of the fourth ventricle and laterally by the inferior cerebellar pedun-

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Anatomy of the Brainstem, Thalamus, Pineal Region, and Cranial Nerves

cles. The inferior part of the posterior surface is divided into two halves in the midline by the posteromedian sulcus, and each half is composed of the gracile fasciculus and tubercle medially and by the cuneate fasciculus and tubercle laterally. The posteromedian sulcus of the medulla, which separates the paired gracile fasciculi in the midline, ends superiorly at the obex of the fourth ventricle and is continuous inferiorly with the posteromedian sulcus of the spinal cord. The posterior intermediate sulcus, which separates the gracile and cuneate fasciculi, is continuous inferiorly with the posterior intermediate sulcus of the spinal cord. The lower medulla blends indistinguishably into the upper spinal cord at the level of the C1 nerve roots.38

Medial Lemniscus Divides Medulla into Ventral and Dorsal Parts The ventral medulla is formed by the pyramids overlying the corticospinal tracts (Fig. 2.9a).1 The olive is located lateral to the ML. The preolivary sulcus extends longitudinally between the pyramid and the olive. The intramedullary segment of the hypoglossal nerve arises in the hypoglossal nucleus underlying the hypoglossal triangle and extends ventrally between the MLF medially and the olive laterally to exit the medulla along the caudal two-thirds of the preolivary sulcus. The supraolivary fossette, a depressed area rostral to the olive, is where the facial and vestibulocochlear nerves join the brainstem. The postolivary sulcus, the groove between the olive ventrally and the inferior cerebellar peduncle dorsally, is located just ventral to where the glossopharyngeal, vagus, and accessory nerves exit the medulla. The TST descends ventromedial and the cuneate fasciculus ascends medial to the inferior cerebellar peduncle. The nucleus ambiguus is located ventrolateral to the vagal triangle, ventromedial to the TST, dorsal to the olive, and caudal to the facial nucleus.1 The glossopharyngeal, vagus, and spinal accessory nerves pass laterally from the nucleus ambiguus and ventrally to the TST to exit the medulla just dorsal to the postolivary sulcus. The glossopharyngeal and vagus nerves exit just dorsal to the upper part of the retro-olivary sulcus, and the accessory rootlets exit along the caudal part of the retro-olivary sulcus.1

Safe Entry Zones and Surgical Approaches The proposed medullary safe entry zones are along the anterolatera l (preolivary), postolivary, posterior medullary zone, and the posterior median, posterior intermediate, and posterior lateral sulci (Fig. 2.9b, c).1,​44

Anterolateral (Preolivary) Sulcus The anterolateral (preolivary) sulcus entry zone is located along the preolivary sulcus between the caudal hypoglossal rootlets and the rostral C1 rootlets. Because it is very close to the pyramidal tract and its decussation, this entry is preferred only for exophytic lesions (Fig. 2.9a). The far lateral or retrosigmoid approach is used to reach the preolivary sulcus.6

Postolivary Sulcus The postolivary sulcus zone is entered through the postolivary sulcus located between the olive and inferior cerebellar peduncle and ventral to the glossopharyngeal and vagus rootlets.45 The glossopharyngeal and vagal rootlets join the brainstem just dorsal to the upper part of this sulcus. As the incision deepens, the nucleus ambiguus located an average of 4 mm deep to the

39

s­ urface of the sulcus is encountered. The far lateral or retrosigmoid approach is used to reach the postolivary sulcus.1

Lateral Medullary Zone The lateral medullary zone is directed through the inferior cerebellar peduncle (Fig. 2.9b, c).4 The inferior cerebellar peduncle is approached between the lower CNs and the facial nerve/ vestibulocochlear nerve complex. Direct ventral approaches to the medulla are challenging and pose significant risks to the patient, and our preference is to approach ventral and ventrolateral lesions from the side using either a retrosigmoid or far lateral craniotomy.

Dorsal Medullary Sulci Three entry zones for dorsal medullary lesions have been defined1 (Fig. 2.9c). These are the posterior median sulcus located inferior to the obex in the midline, the posterior intermediate sulcus located between the gracile and cuneate fasciculi, and the posterior lateral sulcus located lateral to the cuneate fasciculus. This region is reached via the suboccipital median approach.1,​5

■■ Conclusion The central nervous system is a remarkably beautiful, intricate, and delicate structure. The goal of understanding microsurgical anatomy is to perform gentle, precise, and accurate ­neurosurgery and to be able to navigate safely around and through the central nervous system and intracranial space.

Note on the Text Portions of the anatomical descriptions have been previously published in and are reproduced with permission from Yağmurlu K, Rhoton AL Jr, Tanriover N, et al. Three-dimensional microsurgical anatomy and the safe entry zones of the brainstem. Neurosurgery 2014;10(Suppl 4):602–619; discussion 619–620. References 1. Y ağmurlu K, Rhoton AL Jr, Tanriover N, Bennett JA. Three-dimensional microsurgical anatomy and the safe entry zones of the brainstem. Neurosurgery 2014;10 Suppl 4:602–619, discussion 619–620 2. C avalheiro S, Yağmurlu K, da Costa MD, et al. Surgical approaches for brainstem tumors in pediatric patients. Childs Nerv Syst 2015; 31(10):1815–1840 3. R angel-Castilla L, Spetzler RF. The 6 thalamic regions: surgical approaches to thalamic cavernous malformations, operative results, and clinical outcomes. J Neurosurg 2015;123(3):676–685 4. Cavalcanti DD, Preul MC, Kalani MY, Spetzler RF. Microsurgical anatomy of safe entry zones to the brainstem. J Neurosurg 2016; 124(5):1359–1376 5. Bricolo A. Surgical management of intrinsic brain stem gliomas. Oper Tech Neurosurg 2000;3(2):137–154 6. Cantore G, Missori P, Santoro A. Cavernous angiomas of the brain stem. Intra-axial anatomical pitfalls and surgical strategies. Surg Neurol 1999; 52(1):84–93, discussion 93–94 7. Kyoshima K, Kobayashi S, Gibo H, Kuroyanagi T. A study of safe entry zones via the floor of the fourth ventricle for brain-stem lesions: report of three cases. J Neurosurg 1993;78(6):987–993 8. Bertalanffy H, Benes L, Miyazawa T, Alberti O, Siegel AM, Sure U. Cerebral cavernomas in the adult: review of the literature and analysis of 72 surgically treated patients. Neurosurg Rev 2002;25(1–2):1–53, discussion 54–55

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9. Rhoton AL Jr. The lateral and third ventricles. Neurosurgery 2002;51(4) Suppl:S207–S271 10. Yağmurlu K, Rhoton AL Jr. Lateral and third ventricle. In: Torres-Corzo JG, Rangel-Castilla L, Nakaji P, eds. Neuroendoscopic Surgery. New York, NY: Thieme Medical Publishers; 2016:33–51 11. Yaşargil MG. Microneurosurgery. Vol 4A. Stuttgart, Germany: Thieme Medical Publishers; 1994 12. Ono M, Rhoton AL Jr, Peace D, Rodriguez RJ. Microsurgical anatomy of the deep venous system of the brain. Neurosurgery 1984;15(5):621–657 13. Mitsos AP. Endovascular Neurosurgery Through Clinical Cases. Milan, Italy: Springer-Verlag Italia; 2015

29. Rhoton AL Jr. The cerebellar arteries. Neurosurgery 2000; 47(3) Suppl:S29–S68 30. Matsushima T, Rhoton AL Jr, Lenkey C. Microsurgery of the fourth ventricle: Part 1. Microsurgical anatomy. Neurosurgery 1982;11(5): 631–667 31. Nieuwenhuys R, Voogd J, Huijzen CV. The Human Central Nervous System: A Synopsis and Atlas. 4th ed. New York, NY: Springer-Verlag; 2008 32. Giliberto G, Lanzino DJ, Diehn FE, Factor D, Flemming KD, Lanzino G. Brainstem cavernous malformations: anatomical, clinical, and surgical considerations. Neurosurg Focus 2010;29(3):E9 33. Bricolo A, Turazzi S. Surgery for gliomas and other mass lesions of the brainstem. Adv Tech Stand Neurosurg 1995;22:261–341

14. Rhoton AL Jr. The cerebral veins. Neurosurgery 2002;51(4, Suppl): S159–S205

34. Prats-Galino A, Soria G, de Notaris M, Puig J, Pedraza S. Functional anatomy of subcortical circuits issuing from or integrating at the human brainstem. Clin Neurophysiol 2012;123(1):4–12

15. Bruce JN. Pineal tumors. In: Winn HR, ed. Youmans neurological surgery. 6th ed. Philadelphia, PA: Saunders; 2011:1359–1372

35. Hendelman W. Atlas of Functional Neuroanatomy. 2nd ed. Boca Raton, FL: CRC Press; 2006

16. Yağmurlu K, Zaidi HA, Kalani MYS, Rhoton AL Jr, Preul MC, Spetzler RF. Anterior interhemispheric transsplenial approach to pineal region tumors: anatomical study and illustrative case. J Neurosurg 2018; 128(1):182–192

36. Williams PL, Warwick R. Gray’s Anatomy. 36th ed. Edinburgh, Scotland: Churchill Livingstone; 1980

17. Ozek MM, Türe U. Surgical approach to thalamic tumors. Childs Nerv Syst 2002;18(8):450–456 18. Araki C. Removal of the pineal tumor. Gekashinryo 1960;2:517–524 19. Dandy W. An operation for the removal of pineal tumors. Surg Gynecol Obstet 1921;33:113–119 20. Horrax G. Extirpation of a huge pinealoma from a patient with pubertas praecox: a new operative approach. Arch Neurol Psychiatry 1937; 37(2):385–397

37. Kalani MYS, Yağmurlu K, Spetzler RF. The interpeduncular fossa approach for resection of ventromedial midbrain lesions. J Neurosurg 2018;128(3)):834–839 38. Rhoton AL Jr. Cerebellum and fourth ventricle. Neurosurgery 2000;47(3) Suppl:S7–S27 39. Russin J, Fusco DJ, Spetzler RF. Left retrosigmoid craniotomy for cavernous malformation of the middle cerebellar peduncle. Neurosurg Focus 2014;36(1, Suppl):1

21. Jamieson KG. Excision of pineal tumors. J Neurosurg 1971;35(5):550–553

40. Kalani MY, Yağmurlu K, Martirosyan NL, Spetzler RF. The retrosigmoid petrosal fissure transpeduncular approach to central pontine lesions. World Neurosurg 2016;87:235–241

22. Kunicki A. Operative experiences in 8 cases of pineal tumor. J Neurosurg 1960;17:815–823

41. Baghai P, Vries JK, Bechtel PC. Retromastoid approach for biopsy of brain stem tumors. Neurosurgery 1982;10(5):574–579

23. Lazar ML, Clark K. Direct surgical management of masses in the region of the vein of Galen. Surg Neurol 1974;2(1):17–21

42. Hebb MO, Spetzler RF. Lateral transpeduncular approach to intrinsic lesions of the rostral pons. Neurosurgery 2010;66(3) Suppl Operative: 26–29, discussion 29

24. Little KM, Friedman AH, Fukushima T. Surgical approaches to pineal region tumors. J Neurooncol 2001;54(3):287–299 25. Poppen JL. The right occipital approach to a pinealoma. J Neurosurg 1966;25(6):706–710 26. Sekhar LN, Goel A. Combined supratentorial and infratentorial approach to large pineal-region meningioma. Surg Neurol 1992;37(3):197–201 27. Stein BM. The infratentorial supracerebellar approach to pineal lesions. J Neurosurg 1971;35(2):197–202 28. Van Wagenen WP. A surgical approach for the removal of certain pineal tumors: report of a case. Surg Gynecol Obstet 1931;53:216–220

43. Yağmurlu K, Kalani MYS, Preul MC, Spetzler RF. The superior fovea triangle approach: a novel safe entry zone to the brainstem. J Neurosurg 2017;127(5):1134–1138 44. Kalani MY, Yağmurlu K, Martirosyan NL, Cavalcanti DD, Spetzler RF. Approach selection for intrinsic brainstem pathologies. J Neurosurg 2016; 125(6):1596–1607 45. Recalde RJ, Figueiredo EG, de Oliveira E. Microsurgical anatomy of the safe entry zones on the anterolateral brainstem related to surgical approaches to cavernous malformations. Neurosurgery 2008;62(3) Suppl 1:9–15, discussion 15–17

3

Development of the Human Brainstem and Its Vasculature Nicholas T. Gamboa, Bornali Kundu, and M. Yashar S. Kalani

Abstract

Safe and efficient surgery in and around the brainstem depends on a thorough understanding of the development of the human brainstem and its vasculature. This chapter reviews the development of the human brainstem, including embryonic and postnatal developmental milestones, with an emphasis on the developmental mechanisms of tracts and nuclei. The work also highlights both the vasculogenesis and the angiogenesis of the human brain that lead to formation of blood vessels in this part of the brain. Surgery in and around the brainstem requires a thorough understanding of developmental anatomy. An indepth understanding of this anatomy can be used to safely traverse tracts and nuclei to remove pathology while minimizing the disruption of surrounding structures.

Keywords:  angiogenesis, brainstem, development, diencephalon, embryology, medulla, midbrain, neurosurgery, pons, vasculogenesis

■■ Introduction The cerebral hemispheres (cerebrum) are adjoined to the cerebellum and spinal cord by the most primordial portion of the central nervous system (CNS), the brainstem and the diencephalon (Fig. 3.1).1,2 These structures control the flow of motor and sensory information between the brain and the rest of the body while also controlling breathing and modulating heart rate and blood pressure, in addition to wakefulness and numerous other Fig. 3.1 Medial surface of cerebrum and brainstem depicting regional neuroanatomy. (a) Illustration shows a midsagittal cut of the brainstem, which consists of the midbrain, pons, and medulla, and the diencephalon, which consists of the thalamus and hypothalamus. (b) Sagittal T1-weighted magnetic resonance image demonstrating midline structures of the cerebrum and brainstem. The brainstem, comprising the midbrain (Mi), pons (Po), and medulla (Me), is continuous caudally with the spinal cord (SC). The corpus callosum (CC) is located superiorly. The pituitary (P) rests in the sella turcica and connects to the hypothalamus (Hy) via the infundibulum. The mammillary bodies (Ma) are located anterior to the brainstem. The lateral ventricles (LV) are bordered inferiorly by the thalamus (Th). The third ventricle (3) is connected to the fourth ventricle (4) via the cerebral aqueduct of Sylvius (AS), which is bordered by the cerebellum (Ce) posteriorly and the brainstem anteriorly. (Fig. 3.1a is reproduced with permission from Bear et al 2016.1 Fig.3.1b is modified with permission from Herring 2016.2)

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II  Anatomy, Development, and Pathology of the Brainstem, Thalamus, and Pineal Region

essential bodily functions. The brainstem lies in the anterior portion of the posterior cranial fossa with its ventral surface abutting the clivus, the basilar part of the occipital bone. It is continuous with the forebrain at the level of the tentorial notch and with the spinal cord at the foramen magnum. The brainstem comprises an ectodermally derived nexus of neuronal cell bodies  (gray matter) that form nuclei and axon fibers  (white matter) grouped into tracts (i.e., fasciculi, pedunculi, and lemnisci). These internal structures give rise to the characteristic surface anatomy and surgical landmarks of the human brainstem. Clinical neurosurgery requires an understanding of the art of neurology (the “méthode anatomo-clinique” of Jean-Martin Charcot) and the principles of the neurosciences, as well as an appreciation for embryology begetting regional and functional neuroanatomy. Thus, a thorough understanding of the embryology and anatomy of the brainstem, and of the development of its nearby structures, is essential in the diagnosis, operative planning, and treatment of numerous pathologic conditions of the CNS, especially those involving the brainstem and its vasculature. In this chapter, we explore the embryologic principles guiding the development of the human CNS, with special emphasis on the brainstem and the formation of its network of vessels through vasculogenesis.

■■ Early Embryogenesis From Zygote to Blastocyst After spermatozoon–oocyte fusion, a single-celled zygote undergoes a series of mitotic divisions to give rise to a 16-cell morula (Latin mōrus for “mulberry”). At this stage, the 16-cell morula consists of compressed blastomeres, which undergo the process of blastulation (Fig. 3.2).4 Through compaction and rearrangement, this early blastula forms the inner cell mass (embryoblast) that differentiates into epiblast and hypoblast layers (i.e., the bilaminar [or two-layered] germ disc), the outer trophoblast layer of cytotrophoblasts and syncytiotrophoblasts, and the discrete blastocele cavity.3 The inner cell mass gives rise to the

tissues of the developing embryo, whereas the trophoblasts are responsible for the formation of the embryonic placenta. Subsequent divisions, continued differentiation, protease digestion, and hatching from the surrounding zona pellucida allow the blastocyst to successfully implant into the richly vascularized endometrium of the uterus approximately 10 to 11 days after fertilization.

Gastrulation At the beginning of the third week of embryonic development, the cells begin to organize into distinct germ layers through gastrulation. Gastrulation is the process by which the bilaminar embryonic disc reorganizes into a trilaminar structure called the gastrula. The primitive streak is formed at the beginning of gastrulation  (days 15–16), and it appears as a narrow groove of pluripotent cells flanked by protruding regions at the caudal midline of the embryo (Fig. 3.3a).3,​5 The primitive streak is restricted caudally by the cloacal membrane (future site of the anus) but progressively increases in length and forms a thickening at its cranial-most end called the primitive node (Hensen node).6,​7 The primitive node is also aptly called the organizer by embryologists because it regulates several important processes such as laterality and notochord formation, thereby making it the primary initiator of the developing CNS. Cells of the epiblast migrate toward the primitive streak and, upon arrival, detach from the epiblast to form an intermediate layer (the mesoderm) between the epiblast and hypoblast layers (Fig. 3.3b).8 In addition, some of these migrating cells displace the existing hypoblast to create the embryonic endoderm, while others remain in the epiblast layer, forming the overlying ectoderm.8 This inward movement (i.e., invagination) represents the earliest stage of the trilaminar embryo. Later in gastrulation, epiblast cells migrating more posteriorly form the paraxial mesoderm, lateral plate mesoderm, and extraembryonic mesoderm sequentially.3,​8 As more cells migrate from the epiblast layer to the hypoblast layer, they begin to increasingly spread in the cranial and lateral directions of the developing embryo, thereby contributing to subsequent stages of embryogenesis. Fig. 3.2 Sequential photomicrographs of the development of an in vitro fertilized human embryo. (a) Two-cell stage with prominent surrounding zona pellucida (arrow). (b) ­Twelve-cell morula with actively dividing blastomeres (arrow). (c) Morula in late stage of compaction with indistinct cell outlines. (d) Morula with ­dividing blastomeres showing the beginning of cavitation. (e) Blastocysts showing embryoblasts as a well-defined inner cell mass  (arrow) and prominent blastocele cavity (asterisk). (f) ­Hatching of blastocyst through opening in surrounding zona pellucida. (Reproduced with permission from Veeck et al 2003.4)

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Fig. 3.3 Diagrammatic representation of the embryonic disc during gastrulation. (a) Dorsal view of the embryonic disc at 16 days, indicating the movement of surface epiblast cells  (solid black lines) through the primitive streak and node. Note the migration of prenotochordal cells cranially toward the prechordal plate (oropharyngeal membrane) in preparation for notochord formation. (b) Cross-section through the cranial region of the embryonic disc at 15 days showing invagination of epiblast cells at the primitive streak. Note the migration of epiblastic cells forming the endoderm, mesoderm, and ectoderm. (Reproduced with permission from Sadler 2015.3)

■■ Early Development of the CNS Formation of the Notochord The notochord is the defining structure formed in all chordate embryos that is required for the patterning of surrounding tissues. Its formation begins with the ingression of a population of epiblastic cells into the primitive streak during gastrulation, where they become prenotochordal cells at the primitive node and continue to move cranially toward the prechordal plate (oropharyngeal membrane, the future site of the mouth) (Fig. 3.3a).3,​9 As the hypoblast is replaced by endoderm cells, the cells of the notochordal plate separate from the surrounding endoderm and proliferate.3 Ultimately, this proliferation results in the formation of a solid, but flexible, cord-like cellular structure termed the definitive notochord. The notochord serves phylogenetically and ontogenetically as the original support along the longitudinal axis of the developing embryo, and it serves a central role in the transformation of undifferentiated embryonic cells into definitive tissues and organs. Specifically, through inductive signaling, the notochord stimulates conversion of the overlying surface ectoderm into neural tissue  (i.e., neural plate), it specifies floor plate cells within the developing CNS, and it transforms certain somitic mesodermal cells into vertebral bodies, thereby contributing to the formation of the axial skeleton.10,​11,​12 Although the notochord is an embryonic anatomical structure critical for the development of the human CNS, it is largely transient, being lost in the adult human, with the exception of its contribution to the nucleus pulposus of the intervertebral disc.13

Neurulation The human brain begins modestly as a flat sheet of ectodermally derived cells at the dorsal midline of the embryo. In response to inductive notochord signals (i.e., relief of bone morphogenetic protein-4 [BMP-4] inhibition by chordin, noggin, and follistatin), this sheet of cells thickens to form a large placode called the neural plate around day 17 of embryonic development.14,​15,​16,​17

The neural plate undergoes a phase of rapid growth, leading to the formation of a neural groove with neural folds on each side along the longitudinal axis of the developing embryo. Through continued cellular proliferation, the neural folds move closer together and ultimately fuse at the dorsal midline, thus forming the neural tube (Fig. 3.4).18 This process by which the neural tube initially forms is called neurulation. Moreover, neural tube fusion begins at the midcervical level and proceeds in both cranial and caudal directions.3,​19 The cells forming the walls of the neural tube constitute the neuroepithelium, which will give rise to the entire CNS. At this point in embryonic development, the neural tube has two temporary openings, the cranial and caudal neuropores, which communicate with the amniotic cavity (Fig. 3.5).3 With the exception of notable pathologic conditions (e.g., anencephaly and spina bifida), the cranial neuropore closes by the middle of the fourth week, and the caudal neuropore closes by the end of the fourth week.20,​21 The final position of the cranial neuropore is represented by the lamina terminalis in the adult brain.22

Neural Crest As the neural folds combine to form the incipient neural tube, cells located along the lateral margins of the neural plate break free to form the neural crest, which is a grouping of cells between the neural tube and the overlying ectoderm (Fig. 3.4).18 These bilaterally paired neural crest cells arise through induction from adjacent nonneural ectoderm and mesoderm, causing them to change their shape and properties compared with other neighboring ectodermally derived tissues.18 In particular, these cells lose their cell-to-cell adhesiveness through decreased expression of cell adhesion molecules, thereby permitting a migratory phenotype.8,​23 As the CNS continues to develop, some populations of neural crest cells remain posterolateral to the neural tube, giving rise to sensory ganglia of the spinal nerves (dorsal root ganglia) and the cranial nerves (CNs) and to the ganglia of the autonomic nervous system.24 Other populations of neural crest cells migrate along well-defined pathways to differentiate into several elements: neural (e.g., Schwann and satellite cells of

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II  Anatomy, Development, and Pathology of the Brainstem, Thalamus, and Pineal Region three primary brain vesicles: the cranial-most prosencephalon, or forebrain; the mesencephalon, or midbrain; and the caudal-most rhombencephalon, or hindbrain (Fig. 3.6, Table 3.1).24,​29 During the fifth week, the secondary vesicles develop from the prosencephalon and rhombencephalon, creating a total of five secondary vesicles: the cranial-most telencephalon, the diencephalon, the mesencephalon, the metencephalon, and the caudal-most myelencephalon (Fig. 3.6, Table 3.1).24,​29 Each of these secondary vesicles undergoes distinct developmental changes as brain development progresses, thus driving further structural and functional specialization. Coinciding with the rapid shape changes of the developing brain, the lumen of the neural tube develops into the ventricular system of the mature brain and the central canal of the spinal cord (Fig. 3.6).22,​29 In the adult brain, the lateral ventricles of the cerebral hemispheres communicate with the third ventricle of the diencephalon via the interventricular foramen (foramen of Monro). The rhombencephalon contains the fourth ventricle and is situated between the cerebellum posteriorly and the brainstem anteriorly. The fourth ventricle communicates with the superior third ventricle via the cerebral aqueduct (aqueduct of Sylvius) of the mesencephalon. By the fifth month of development, openings in the roof plate  (the two lateral foramina of Luschka and the foramen of Magendie) establish communication of cerebrospinal fluid between the ventricular system and the subarachnoid space.29

Formation of the Flexures

Fig. 3.4  Diagrammatic representation of neurulation. Notochord induces neural plate formation by releasing inhibitors of bone morphogenetic protein-4 (i.e., chordin, noggin, and follistatin). Cellular proliferation of the neural plate leads to the formation of neural folds. Continued proliferation leads to fusion of the neural folds at the dorsal midline and formation of the neural tube. The remaining overlying ectoderm differentiates into epidermis. A population of flanking neuroectodermal cells, termed the neural crest, detaches from nearby ectoderm to migrate along welldefined pathways and forms various neural crest derivatives throughout the body. (Reproduced with permission from Wolpert 2015.18)

the peripheral nervous system, meninges of the spinal cord, and enteric nerve plexus), neuroendocrine  (e.g., chromaffin cells of the adrenal medulla and parafollicular cells of the thyroid), and nonneural (e.g., melanocytes and craniofacial bones).25,​26,​27,​28

Development of the Primitive Brain Even before neural fold closure, the neural plate is noticeably larger at the cranial end of the developing embryo. At this stage of development, the major divisions of the developing brain become increasingly evident. As previously mentioned in the section on neurulation, the brain begins as a flat sheet of cells, but through the processes of neurulation and differentiation, the human CNS becomes increasingly complex and functionally specialized. By the end of the fourth week, the cranial end of the neural tube has three distinct swellings that correspond to the

In addition to the rapid neuronal growth giving rise to the swellings of the nascent CNS, the developing CNS concurrently undergoes a series of three characteristic bends. These distinctive bends are termed flexures and are thought to be due to differential rates of neuronal cell growth between opposite sides of the developing brain.3,​30 At the end of the third week, a bend at the level of the mesencephalon, termed the cephalic flexure, gives the early brain a characteristic C shape facing ventrally (Fig. 3.6d).29 By the start of the fifth week, a cervical flexure appears at the boundary of the myelencephalon and the spinal cord, with its concavity also facing ventrally (Fig. 3.6d).29 Around the sixth week of development, a third and final flexure called the pontine flexure forms at the level of the rhombencephalon, with its concavity facing dorsally (Fig. 3.6e, f).24,​29 This pontine flexure divides the developing rhombencephalon into the metencephalon and more caudal myelencephalon.

Development of the Spinal Cord The spinal cord is the least differentiated portion of the CNS, as it remains segmentally organized throughout its development and consists of 31 segments when it is fully developed.31 The spinal cord is derived from the caudal-most end of the developing neural tube.32 The wall of the neural tube is composed of a layer of pseudostratified neuroepithelial cells characterized by a rapid rate of division during neurulation; however, soon after neural tube closure, the neuroepithelium begins to generate primitive nerve cells known as neuroblasts, which accumulate and form a mantle layer  (mantle zone), coating the existing neural tube.19 This mantle layer later differentiates to form the gray matter of the spinal cord (Fig. 3.7).3 As the mantle layer of neuroblasts further develops and arborizes with neighboring neural tissue, the neuroblasts extend numerous dendritic and axonal projections. The myelination of these many nerve processes gives rise to the outer marginal

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Fig. 3.5  Illustration of a dorsal view of an embryo sequentially throughout neurulation. (a) Around 17 days postfertilization, the notochord induces the formation of a slipper-shaped thickening of overlying ectoderm, called the neural plate. With the amnion removed, the neural plate is clearly visible, as are the primitive streak and the primitive node located at the caudal end of the developing embryo. (b) At 20 days, the neural plate undergoes a phase of rapid growth to form the neural folds

flanking a midline neural groove. (c) At day 22, the rapid proliferation of neural cells leads to the formation of the neural tube, which seals in both cranial and caudal directions. (d) At day 23, the neural tube is completely formed. The cranial and caudal neuropores remain patent (in communication with the amniotic cavity) until the middle and end of the fourth week, respectively. (Reproduced with permission from Sadler 2015.3)

Fig. 3.6  Diagrammatic representation depicting the sequence of brain development from three primary vesicles to five secondary vesicles with coinciding development of the ventricular system. (a-c) Dorsal views temporally correlate with (d-f) lateral views. (a,d) By the end of week four, three primary vesicles are apparent: the cranial-most prosencephalon (forebrain), the mesencephalon (midbrain), and the caudal-most rhombencephalon (hindbrain). Note the formation of the cephalic and cervical flexures with their concavity facing ventrally (d, red dashed lines). (b,c) At the beginning of week five, further growth and differentiation give rise to five secondary vesicles: the cranial-most

telencephalon, the diencephalon, the mesencephalon, the metencephalon, and the caudal-most myelencephalon. Note the formation of the pontine flexure with its concavity facing dorsally (e, red dashed line). (c,f) By the middle of week eight, there is rapid enlargement of the forebrain, particularly the telencephalon. Note the deepening of the pontine flexure with its concavity facing dorsally (f, red dashed line). Following the rapid shape changes of the developing brain, the components of the ventricular system begin to assume their characteristic architecture. (Reproduced with permission from Haines 2013.29)

layer  (marginal zone) and eventual white matter of the developed spinal cord.3,​19 Concurrently, a longitudinal furrow arises bilaterally on the inner aspect of the neural tube’s walls. This groove, termed the sulcus limitans, serves as a delineation of the dorsally located alar plates (or laminae) from the ventrally located basal

plates (Fig. 3.7).33 In response to inductive signals from the notochord, a thin cellular floor plate further divides the basal plates into left and right halves.34 Similarly, the alar plate is divided by a cellular roof plate. The alar plate differentiates to form the dorsal horn gray matter  (sensory neurons), which is connected by a thin intermediate zone  (interneurons) with the alar plate,

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II  Anatomy, Development, and Pathology of the Brainstem, Thalamus, and Pineal Region

Table 3.1  Adult derivatives of the three primary brain vesicles and five secondary brain vesicles

Primary Vesicles

Secondary Vesicles

Adult Derivatives Walls

Cavities

Prosencephalon (forebrain)

Telencephalon

• Cerebral hemispheres (cortex,white matter) • Basal ganglia • Olfactory bulb

Lateral ventricles

Diencephalon

• Retina and optic nerves • Thalamus • Epithalamus • Hypothalamus • Subthalamus • Mammillary bodies

Third ventricle

Mesencephalon (midbrain)

Mesencephalon

• Midbrain (tectum and tegmentum) • Cerebral peduncles

Cerebral aqueduct (of Sylvius)

Rhombencephalon (hindbrain)

Metencephalon

• Pons • Cerebellum • Middle cerebellar peduncles • Superior cerebellar peduncles

Fourth ventricle (cranial aspect)

Myelencephalon

• Medulla oblongata • Inferior cerebellar peduncles

Fourth ventricle (caudal aspect)

Fig. 3.7  Illustration of spinal cord development. (a) Early depiction of the developing spinal cord with the dorsal alar plate (sensory neurons) divided from the ventral basal plate (motor neurons) by the sulcus limitans. Note the division of alar and basal plates into left and right halves by the thin cellular floor plate. (b) Later depiction of the developed spinal cord with its characteristic appearance of ventral and dorsal horn gray matter surrounded by white matter (myelinated axon fibers). (Reproduced with permission from Sadler 2015.3)

which will form the ventral horn gray matter (motor neurons). The mature spinal cord retains a similar organization but with further subdivision into somatic and visceral components. Finally, as neuroblasts of the basal plate mature into multipolar neurons, their axonal processes pierce through the marginal layer to group with other efferent axon fibers, thereby forming ventral rootlets that coalesce distally to form the ventral root of a spinal nerve.

■■ Differentiation of the Brainstem Development of the Medulla The myelencephalon is the caudal-most portion of the rhombencephalon (hindbrain), and it gives rise to the medulla oblongata of the human brainstem. The medulla represents a transitional structure between the brain and spinal cord; much of its early formation and functional organization parallel that of the spinal cord. During the sixth week of development, the pontine flexure appears and begins to stretch the roof plate of the myelencephalon into a thin cellular layer while simultaneously widening and giving the central cavity a rhomboidal shape (Fig. 3.8a, b).29,30 This rhomboid-shaped cavity of the myelencephalon will form

the fourth ventricle of the ventricular system, with contributions cranially from the metencephalon.3 Furthermore, the roof plate is composed of a single layer of ependymal cells covered by vascular mesenchymal tissue (collectively referred to as tela choroidea), from which both the pia mater of the myelencephalon and the choroid plexus of the fourth ventricle are later derived.24 Similar to the developing spinal cord, the sensory nuclei– containing alar plate of the myelencephalon and the motor nuclei–containing basal plate of the metencephalon are separated by the sulcus limitans.22 The alar and basal plates are also further subdivided into somatic and visceral components arranged in interrupted columns spanning the brainstem.31 Furthermore, branchial arch derivatives developing around this region also require a special branchial column in the brainstem, which arises between somatic and visceral columns of both alar and basal plates (Fig. 3.8b, c).3 The basal plates of the myelencephalon form nuclei divided into three separate columns (from medial to lateral): the somatic efferent (SE) column, the special visceral efferent (SVE) column, and the general visceral efferent (GVE) column (Fig. 3.8b).3,​24 The medial-most column (the SE) gives rise to the somatic motor fibers of the hypoglossal nerve (CN XII) to supply innervation of the tongue musculature. SVE nuclei form the nucleus ambiguus

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Fig. 3.8 Illustrations of cross-sections through the brainstem (medulla, pons, and midbrain) at various developmental stages. Cranial nerves (CN) are noted: oculomotor (CN III), trochlear (CN IV), trigeminal (CN V), abducens (CN VI), facial (CN VII), glossopharyngeal (CN IX), vagus (CN X), spinal accessory (CN XI), and hypoglossal (CN XII) nerves. (a,b) Position and differentiation of the basal and alar plates of the myelencephalon (medulla) at subsequent stages of development. Note the formation of the nuclear groups in the basal and alar plates. Arrows represent the migratory path followed by cells of the alar plate to the olivary nuclear complex. The roof plate associates with overlying vascular mesenchyme to form the choroid plexus,

which produces cerebrospinal fluid. (c) The position and differentiation of the basal and alar plates in the caudal metencephalon (pons). Note the dorsolateral position of the rhombic lips, which undergo rapid growth to form the cerebral hemispheres. Arrows represent the direction of the migration of the pontine nuclei. (d,e) The position and differentiation of the basal and alar plates in the mesencephalon (midbrain) at subsequent stages of development. The nucleus ruber (red nucleus) and substantia nigra. Arrows (a-d) indicate migratory path of cells that form the red nucleus and the substantia nigra. Note the motor nuclei surrounding the future cerebral aqueduct of Sylvius. (Reproduced with permission from Sadler 2015.3)

and thereby contribute branchiomotor fibers to the glossopharyngeal (CN IX), vagus (CN X), and spinal accessory (CN XI) nerves to supply musculature derived from the third, fourth, and sixth branchial arches, respectively. The GVE column contributes to the dorsal vagal and inferior salivatory nuclei, whose fibers supply widespread preganglionic parasympathetic innervation to the body (CN X and CN IX, respectively). The alar plates of the myelencephalon form sensory nuclei divided into four distinct columns (medial to lateral): the general visceral afferent  (GVA) column, the special visceral afferent  (SVA) column, the general somatic afferent column, and the special somatic afferent (SSA) column (Fig. 3.8b).3,​24 The

GVA and SVA columns contribute to the solitary nuclei (nucleus tractus solitarius), which convey sensory information from the facial nerve (CN VII), CN IX, and CN X. Interestingly, some populations of cells that are also derived from the alar plate migrate either ventrally to form the inferior olivary complex or dorsally to form the dorsal column nuclei of the medulla  (gracile and cuneate nuclei).24 The gracile and cuneate nuclei will contribute contralaterally ascending axonal fibers to form the medial lemnisci of the brainstem. The SSA column gives rise to the auditory and vestibular nuclei, and the general somatic afferent column contributes to the caudal trigeminal complex. Fibers descending from the cerebral cortex form the

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II  Anatomy, Development, and Pathology of the Brainstem, Thalamus, and Pineal Region

characteristic ventromedially located medullary pyramids, which contain descending corticospinal axons that decussate around the spinomedullary junction.

Development of the Pons and Cerebellum The metencephalon is the cranial-most portion of the rhombencephalon (hindbrain), and it gives rise to the pons and the cerebellum. The pons (Latin for “bridge”) comprises two parts: the dorsal pontine tegmentum, which shares features with the rest of the brainstem (i.e., ascending and descending tracts and CN nuclei), and the ventral basal pons, which functions to provide extensive connections between the cerebral and cerebellar cortices and spinal cord. Once fully developed, dorsally extending cerebellar peduncles attach the cerebellum to the pons (via the pair of middle cerebellar peduncles) and to the midbrain (via the pair of superior cerebellar peduncles). Analogous to the myelencephalon, the metencephalon contains basal plate–derived motor nuclei separated into three distinct columns (Fig. 3.8c).3,​29 The medial-most SE column gives rise to the nucleus of the abducens nerve (CN VI). The SVE column contributes to the motor nuclei of the trigeminal (CN V) and facial nerves, which ultimately supply musculature derived from the first and second branchial arches, respectively. Finally, the GVE column gives rise to the superior salivatory nucleus, whose fibers will supply parasympathetic innervation to the lacrimal, submandibular, and sublingual glands via the facial nerve. Of note, the cells of the basal plate also contribute to the reticular formation of the pons.35 The alar plates of the metencephalon contain sensory nuclei that are also divided into separate columns: the GVA column, the SVA column, and the somatic afferent column (Fig. 3.8c).3,​29 The somatic afferent columns contribute to sensory neurons of the trigeminal and vestibulocochlear (CN VIII) nerves. Like the myelencephalon, the SVA column of the metencephalon contributes to the solitary nuclei. In addition, the alar plates of the myelencephalon and metencephalon contribute to the development of the pontine nuclei.29 These pontine nuclei ultimately give rise to axons that relay information from the ipsilateral primary motor cortex to the contralateral cerebellar hemisphere via the middle cerebellar peduncle. Finally, the cranial portion of the dorsal sensory nucleus of the CN X nerve derives from the GVA group of the metencephalon. Around week five of development, the dorsolateral alar plate undergoes a phase of rapid mitotic division that gives rise to the laterally paired rhombic lips.8 Through continued cellular proliferation and extension dorsomedially, the rhombic lips approach one another at the dorsal midline. Further deepening of the pontine flexure causes the rhombic lips to compress to form the left and right cerebellar plates.8 These cerebellar plates ultimately fuse at the dorsal midline of the developing nervous system, with each half forming the left and right cerebellar hemisphere.30 As the cerebellum continues to differentiate, neuroepithelial cells migrate through the mantle layer to the marginal layer to form the cerebellar cortex (i.e., external granular layer).3 Neuroblasts remaining in the mantle layer of the developing cerebellum will differentiate and form the bilateral deep cerebellar nuclei  (i.e., dentate, emboliform, globose, and fastigial nuclei).24,​29

Development of the Midbrain The mesencephalon is situated cranial to the metencephalon, and it gives rise to the most morphologically primitive of the brain vesicles, the midbrain. The midbrain is the shortest segment of

the brainstem, and it traverses the tentorial hiatus to connect the pons and cerebellum with the forebrain. Once fully formed, the midbrain can be divided into a portion dorsal to the aqueduct of Sylvius, called the midbrain tectum, and a portion ventral to the aqueduct of Sylvius, called the cerebral peduncles (crus cerebri).31 These left and right cerebral peduncles serve as pathways for nerve fibers descending from the cerebral cortex to the pons and spinal cord. As the mesencephalon differentiates, its walls thicken because of rapid neuronal division. As this differentiation occurs, the relatively patent lumen of the early neural tube becomes the narrow cleft known as the aqueduct of Sylvius.19 Similar to the myelencephalon and metencephalon, the mesencephalon contains basal and alar plates separated by a welldefined sulcus limitans. The basal plates of the mesencephalon form the motor nuclei and are divided into two groups  (from medial to lateral): the SE and GVE groups (Fig. 3.6d, e).3,24 The SE group contributes to the nuclei of the oculomotor (CN III) and the trochlear (CN IV) nerves, which provide motor innervation to musculature of the eye. In addition, the GVE group forms the EdingerWestphal nucleus, which will ultimately provide preganglionic, parasympathetic innervation to the pupillary sphincter muscles of the eyes. Of note, the cerebral peduncles are derived from the marginal layer of the basal plates and initially form as thickenings at the ventral aspect of the mesencephalon.3,​30 Once fully developed, the cerebral peduncles can be further divided into the ventral crus cerebri and dorsal tegmentum. Finally, the exact origin of the neuroblasts that form the red nucleus (nucleus ruber) and the substantia nigra of the tegmentum are not well understood, as there is mixed evidence pointing to both basal and alar plate origins.36 The alar plates of the mesencephalon form the tectum, which is composed of the superior and inferior colliculi that collectively represent the SSA column of nuclei.37 The inferior colliculus is formed through the proliferation of neuroepithelium, which results in a central homogeneous collection of cells with a thin outer cortical rim.24 However, the superior colliculus is formed by successional waves of migrating neuroepithelial cells in an inside-out sequence (i.e., cells of deeper layers are formed earlier), which ultimately forms its characteristic stratified structure.24 The alar plate–derived nuclei of the inferior and superior colliculi serve as synaptic relay points for auditory and visual reflexes, respectively.

■■ Differentiation of the Forebrain At the beginning of the fifth week of embryonic development, the prosencephalon (forebrain) is divided into two secondary vesicles: the diencephalon and the telencephalon. The telencephalon goes on to form the cerebral hemispheres and the olfactory bulbs and tracts, whereas the diencephalon develops into the retina, thalamus, hypothalamus, epithalamus, and pituitary gland.

Development of the Diencephalon Early in the fourth week of embryonic development, the primary prosencephalic vesicle gives rise to the bilateral protrusions of the optic vesicles.8 The optic vesicles extend laterally toward surface ectoderm and, upon arrival, induce the formation of the ectodermal lens placode, which will later form the lens of the eye.30 The optic vesicle subsequently invaginates to form the optic cup, from which the neuroepithelium and pigmented epithelium of the mature retina will be derived.29 As retinal neurons continue to proliferate and extend axons

3  Development of the Human Brainstem and Its Vasculature toward the developing diencephalon, the optic vesicles become the primordial optic nerves. The diencephalon, which develops from the median portion of the prosencephalon, consists of a roof plate and two dorsally located alar plates. The developing prosencephalon conspicuously lacks paired basal and floor plates.29 However, some studies have demonstrated the presence of sonic hedgehog, a ventral midline marker, in the floor of the early diencephalon, which suggests the presence of floor plate cells—albeit diminished or transient.38,​39 Nevertheless, the roof plate of the developing diencephalon consists of a thin ependymal layer covered with vascular mesenchyme. Similar to other regions of the brainstem, the ependymal layer and vascular mesenchyme will invaginate and contribute to the formation of the choroid plexus of the third ventricle.19 In addition, during the seventh week of development, the caudal-most portion of the roof plate undergoes a phase of rapid proliferation leading to midline thickening.24 This grouping of cells subsequently forms a midline protrusion that becomes the endocrine pineal gland (epiphysis), and it will also contribute to the medial and lateral habenular nuclei.30 Once developed, the pineal gland secretes melatonin, which contributes to maintenance of the circadian rhythm. By the end of the fifth week of embryonic development, the thalamus and underlying hypothalamus are visible as swellings on the inner surface of the diencephalic neural canal, separated by a transverse groove called the hypothalamic sulcus (sulcus of Monro).40 Both the thalamus and the hypothalamus are derived from the dorsally located alar plates of the diencephalon. Moreover, the nuclei of the hypothalamus originate ventral to the hypothalamic sulcus, they send axonal projections down into the developing neurohypophysis, and they serve important roles in several hemostatic mechanisms of the body.18 By the seventh week, the paired thalami undergo a phase of rapid growth to become the largest component of the developing diencephalon. Through continued growth and differentiation, the thalami expand into the third ventricle, thereby decreasing its size.3,​29 Continued growth can also lead to a midline fusion between the lateral thalami, termed the interthalamic adhesions (mass intermedia), that bridge the third ventricle.31,​40 When the thalamus is fully developed, it is composed of a nexus of diverse nuclei and serves as a critical sensory relay system. The pituitary gland  (hypophysis) develops from two distinct ectodermal origins. A ventral outgrowth of the developing diencephalon leads to the formation of the median eminence and infundibulum (pituitary stalk), which later connects the hypothalamus to the pituitary gland inferiorly.24,​30 This ventral extension of diencephalon contributes to the formation of the posterior pituitary (neurohypophysis). An outpocketing of ectodermal tissue destined to differentiate into the roof of the mouth, termed the Rathke pouch, elongates toward the diencephalic floor around the fourth week of embryonic development.30 Cells derived from this oral ectoderm separate from their origin and form the anterior pituitary (adenohypophysis). The anterior pituitary will further differentiate into the pars distalis, pars tuberalis, and pars intermedia layers.24

Development of the Telencephalon Around the fifth week of development, the lateral telencephalic vesicles arise from the cranial-most end of the developing prosencephalon.3 Over the ensuing weeks, the telencephalon undergoes a phase of rapid growth, dominated largely by the

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development of the cerebral hemispheres.8,​24 By the sixteenth week, the cerebral hemispheres have overgrown the underlying diencephalon and mesencephalon and have assumed a more oval shape.30 The roof plate and lateral walls of each hemisphere contribute to the formation of the cerebral cortex (pallium). Moreover, the floor plate in this region thickens and contributes to neuronal aggregations called the ganglionic eminences. Through further growth and differentiation, these ganglionic eminences (subpallium) derive the bilateral basal ganglia (i.e., corpus striatum and globus pallidus) of the mature brain. As the cerebral hemispheres continue to expand, they exert direct pressure on the walls of the diencephalon. The meningeal layers separating these two distinct neural structures ultimately disband, thereby making the cerebral hemispheres continuous with the paired thalami. As the cerebral hemispheres continue to develop, a large bundle of axons traverses this telencephalic–diencephalic fusion to form the internal capsule of the mature brain.30 As the cerebral hemispheres expand in ventral, dorsal, and caudal directions, their initially smooth surface becomes an increasingly complex pattern of gyri and sulci.30,​40 Furthermore, continued growth results in the formation of the bilateral frontal, parietal, temporal, and occipital lobes. The convolutions of gyri, sulci, and fissures delineating the lobes of the cerebrum allow for the massive expansion of the developing cerebral cortex (pallium). Despite the rapid division of neural tissue in the forebrain region, the lumina of the telencephalic vesicles remains relatively large. As previously noted, each cerebral hemisphere will form a lateral ventricle that will communicate inferiorly with the third ventricle via the foramen of Monro. Finally, a region between the telencephalon and diencephalon contains a thin layer of ependymal cells covered by vascular mesenchyme that, like the brainstem, contributes to the formation of the choroid plexus of the lateral ventricles.3

■■ Development of the CNS Vasculature Vasculogenesis The human vascular system first appears in the middle of the third week of embryonic development, when the developing embryo’s metabolic demands exceed what can be provided through diffusion.3 Vasculogenesis begins with the differentiation of vascular progenitor cells (angioblasts) of intraembryonic splanchnic mesodermal origin into endothelial cells that migrate and coalesce to form primitive vascular cords on day 19 of embryonic development.30 These mesenchymally derived cords subsequently form a lumen through tubulogenesis and then further differentiate into arterial or venous vessels from which the central axial vessels are derived: the dorsal aortae and the cardinal veins, respectively.8,​30 The bilaterally paired dorsal aortae later connect with the developing aortic arches and with the heart to form the primordial circulatory system. After vasculogenesis, much of the remaining vascular system of the embryo is derived through the process of angiogenesis. Specifically, vasculogenesis refers to de novo formation of blood vessels, and angiogenesis denotes the formation of new vessels from preexisting vasculature. Nevertheless, the induction, patterning, and maturation of both processes are largely regulated by growth factors such as vascular endothelial growth factor-A, platelet-derived growth factor, and transforming growth factor-β.41

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Overview of Cardiac and Aortic Arch Formation Early in embryonic development, the central region of the cardiac crescent (primary and secondary heart fields), which contains cardiogenic progenitor cells, lies in a precephalic position anterior to both the oropharyngeal membrane and the neural plate. After neural tube closure, formation of the brain vesicles and subsequent craniocaudal and lateral body folding cause the primitive nervous system to extend cranially over this cardiogenic region.3,​ 30 That is, as the developing brain moves to a more cranial position, the future heart and pericardial cavity are brought through the cervical region to their final position in the ventral thorax. At the beginning of the fourth week, two endocardial tubes fuse at the midline to form a linear heart tube.8 Soon afterward, the myocytes of the heart tube begin to contract in a synchronized fashion.3 The primitive heart further differentiates through thickening of the myocardium, secretion of cardiac jelly, and formation of a distinct pericardium.30 Through dextral cardiac looping, the arterial (truncus arteriosus and aortic sac) and venous (sinus venosus) elements move closer to one another through the process of convergence.3 By the end of the fourth week, cardiac looping is completed, leading to formation of the medial conus cordis and truncus arteriosus.3,​19 The conus cordis goes on to form the ventricular outflow tracts, whereas the truncus arteriosus makes contributions to the proximal aorta and pulmonary trunk.30 Around day 22 of embryonic development, the paired pharyngeal (branchial) arches begin to appear.3,​30 The cranial-most portion of the truncus arteriosus, termed the aortic sac, gives rise to aortic arches, which parallel the development of the CNs as they embed in the mesenchyme of the pharyngeal arches (Fig. 3.9).8,​30 The aortic arches also anastomose dorsally with the right and left dorsal aortae on their respective sides. Although the dorsal aortae remain

separated in the region of the aortic arches, during the fourth week the right and left dorsal aortae fuse at the fourth thoracic through fourth lumbar levels.30 Development of the aortic arches does not occur concurrently; rather, their formation proceeds in discontiguous craniocaudal succession such that all aortic arches are not present simultaneously. With each pharyngeal arch, the aortic sac contributes to the formation of the respective developing aortic arch.30 Neural crest cells concurrently migrate into the developing pharyngeal arches to assist with vascular patterning and contribute to the formation of vascular smooth muscle and connective tissue.18 A total of five pairs of aortic arch arteries (numbered I, II, III, IV, and VI) form throughout embryonic development. The conspicuous absence of a fifth aortic arch is the result of it either not forming or forming incompletely and then immediately regressing.30 As the primordial vasculature continues to develop, this labyrinth of vessels becomes modified, with some of the vasculature regressing completely. By the end of week four, the first aortic arch has disappeared almost completely, with the exception of the small contribution it makes to the formation of the maxillary arteries.30 In a similar fashion, the second aortic arch regresses soon thereafter, with remnants contributing to the formation of the hyoid and stapedial arteries.3 The third aortic arch subsequently becomes increasingly prominent while the fourth and six aortic arches are forming.30 As the primitive vasculature continues to develop and mature, aortic arches III, IV, and VI increase in size. By the beginning of the fifth week, the dorsal aortae connecting aortic arches III and IV disappear bilaterally, which results in the cranial region of the developing embryo receiving perfusion solely via the third aortic arches.8 These paired third aortic arches give rise to the formation of the right and left common carotid arteries and Fig. 3.9 Diagrammatic representation of dorsal aortae and aortic arches from which is derived the embryonic vascular system. (a) Aortic arches I (1), II (2), III (3), IV (4), and VI (6) arise from the aortic sac to form connections with the bilateral dorsal aortae. Of note, aortic arches do not form simultaneously as diagrammed, but rather form discontiguously (as described in the text). (b) Later steps in the development of the embryonic vasculature. The third aortic arch (3) gives rise to the left and right common carotid and internal carotid arteries. The external carotid artery forms through sprouting angiogenesis from the internal carotid artery. The relative locations of the recurrent laryngeal nerves to the developing vasculature are depicted. (c) The left fourth aortic arch (IV) goes on to form the ascending and descending portions of the adult aortic arch, which is continuous with the fused dorsal aorta and forms the adult descending aorta.  (Reproduced with permission from Carlson 2009.8)

3  Development of the Human Brainstem and Its Vasculature

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Fig. 3.10 Diagrammatic representation of stages of development of the cerebrovasculature. (Reproduced with permission from Carlson 2009.8)

the proximal portions of the internal carotid arteries (ICAs).3 However, the distal aspects of the ICAs are derived from the cranial extensions of the dorsal aortae.30 The right and left common carotid arteries give rise to the external carotid arteries through sprouting angiogenesis.8 Around week seven of development, the connections among the right dorsal aorta, the right sixth aortic arch, and the fused midline dorsal aorta degenerate, while they remain connected to the right fourth aortic arch (Fig. 3.9b).8 With contribution from the right seventh intersegmental artery of the right limb bud region, the right dorsal aorta and its ipsilateral fourth aortic arch coalesce to form the definitive right subclavian artery.3,​30 Moreover, modification of the origin of the right fourth aortic arch at the aortic sac gives rise to the brachiocephalic artery.8 The left fourth aortic arch receives contribution from the aortic sac to form the mature aortic arch (ascending and proximal descending aorta) and remains connected with the fused dorsal aorta to form the descending aorta.3,​ 8 Similar to the right seventh segmental artery, the left seventh segmental artery is derived from the ipsilateral limb and contributes to the formation of the left subclavian artery.3

Also during the seventh week of embryonic development, regression occurs in the distal connection of the right sixth aortic arch and the ipsilateral dorsal aorta.30 However, the left sixth aortic arch remains connected to the dorsal aorta, forming the ductus arteriosus of the developing embryo.8,​19 This connection allows blood to shunt from the pulmonary trunk to the descending aorta in utero, but the connection closes soon after birth, resulting in the remnant ligamentum arteriosum.8

Development of the Brainstem and Cerebral Vasculature At the beginning of the fifth week of embryonic development, the primordial anterior and posterior circulations of the brain begin to take shape. As discussed, the common carotid arteries and ICAs are derived from the paired third aortic arches. The external carotid arteries, which sprout from the common carotid arteries, go on to supply the face, whereas the ICAs supply the anterior circulation of the brain via the paired anterior cerebral arteries (Fig. 3.10).8 Also, the middle

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cerebral arteries and posterior cerebral arteries form through sprouting angiogenesis of the bilateral ICAs to supply their respective territories of the brain. The vertebral arteries are formed through the longitudinal anastomoses of the first through seventh cervical intersegmental arteries.24,​30 The vertebral arteries grow toward the brain, where they merge at the level of the pontomedullary junction to form a single midline basilar artery. The basilar artery runs along the ventral surface of the developing brainstem and supplies it with a series of paired arterial branches. From the cranial to the caudal direction, these paired branches include the superior cerebellar arteries, pontine arteries, anterior inferior cerebellar arteries, and posterior inferior cerebellar arteries (Fig. 3.10). Around the seventh week of embryonic development, the ICAs form the posterior communicating arteries with contributions from the basilar artery, ultimately leading to the formation of the circle of Willis. References 1. Bear MF, Connors BW, Paradiso MA. Neuroscience: Exploring the Brain. 4th ed. Philadelphia, PA: Wolters Kluwer; 2016 2. Herring W. Learning Radiology: Recognizing the Basics. 3rd ed. Philadelphia, PA: Elsevier; 2016 3. Sadler TW. Langman’s Essential Medical Embryology. 13th ed. Philadelphia, PA: Wolters Kluwer Health; 2015 4. Veeck LL, Zaninović N. An Atlas of Human Blastocysts. New York, NY: Parthenon Publishing Group; 2003 5. Müller F, O’Rahilly R. The primitive streak, the caudal eminence and related structures in staged human embryos. Cells Tissues Organs 2004; 177(1):2–20 6. Robb L, Tam PP. Gastrula organiser and embryonic patterning in the mouse. Semin Cell Dev Biol 2004;15(5):543–554 7. Spemann H, Mangold H. Uber induktion von embryonalanlagen durch implatation artfremder organisatoren. Roux Arch EntwMmech Org 1924;100(3–4):599–638

18. Wolpert L, Tickle C, Martinez AM. Principles of Development. 5th ed. New York, NY: Oxford University Press; 2015 19. Moore KL, Persaud TVN, Torchia MG. The Developing Human: Clinically Oriented Embryology. 10th ed. Philadelphia, PA: Elsevier; 2016 20. Detrait ER, George TM, Etchevers HC, Gilbert JR, Vekemans M, Speer MC. Human neural tube defects: developmental biology, epidemiology, and genetics. Neurotoxicol Teratol 2005;27(3):515–524 21. Purves D, Lichtman JW. Principles of Neural Development. Philadelphia, PA: Sinauer Associates; 1985 22. Vanderah TW, Gould DJ. Nolte’s the Human Brain: An Introduction to Its Functional Anatomy. 7th ed. Philadelphia, PA: Elsevier; 2016 23. Hatta K, Takagi S, Fujisawa H, Takeichi M. Spatial and temporal expression pattern of N-cadherin cell adhesion molecules correlated with morphogenetic processes of chicken embryos. Dev Biol 1987; 120(1):215–227 24. Patestas MA, Gartner LP. A Textbook of Neuroanatomy. 2nd ed. Hoboken, NJ: John Wiley & Sons; 2016 25. Le Douarin NM, Teillet MA. Experimental analysis of the migration and differentiation of neuroblasts of the autonomic nervous system and of neurectodermal mesenchymal derivatives, using a biological cell marking technique. Dev Biol 1974;41(1):162–184 26. Reedy MV, Faraco CD, Erickson CA. The delayed entry of thoracic neural crest cells into the dorsolateral path is a consequence of the late emigration of melanogenic neural crest cells from the neural tube. Dev Biol 1998;200(2):234–246 27. Teillet MA, Kalcheim C, Le Douarin NM. Formation of the dorsal root ganglia in the avian embryo: segmental origin and migratory behavior of neural crest progenitor cells. Dev Biol 1987;120(2):329–347 28. Weston JA. A radioautographic analysis of the migration and localization of trunk neural crest cells in the chick. Dev Biol 1963;6:279–310 29. Haines DE. Fundamental Neuroscience for Basic and Clinical Applications. 4th ed. Philadelphia, PA: Elsevier/Saunders; 2013 30. Schoenwolf GC, Bleyl SB, Brauer PR, Francis-West PH. Larsen’s Human Embryology. 5th ed. Philadelphia, PA: Elsevier/Churchill Livingstone; 2015 31. Mancall EL, Brock DG. Gray’s Clinical Neuroanatomy: The Anatomic Basis for Clinical Neuroscience. Philadelphia, PA: Saunders/Elsevier; 2011

8. Carlson BM. Human Embryology and Developmental Biology. 4th ed. Philadelphia, PA: Elsevier/Mosby; 2009

32. Tanabe Y, Jessell TM. Diversity and pattern in the developing spinal cord. Science 1996;274(5290):1115–1123

9. Müller F, O’Rahilly R. The prechordal plate, the rostral end of the notochord and nearby median features in staged human embryos. Cells Tissues Organs 2003;173(1):1–20

33. Singh V. Textbook of Clinical Embryology. New Delhi, India: Elsevier; 2012

10. Fan CM, Tessier-Lavigne M. Patterning of mammalian somites by surface ectoderm and notochord: evidence for sclerotome induction by a hedgehog homolog. Cell 1994;79(7):1175–1186

34. van Straaten HW, Hekking JW, Wiertz-Hoessels EJ, Thors F, Drukker J. Effect of the notochord on the differentiation of a floor plate area in the neural tube of the chick embryo. Anat Embryol  (Berl) 1988; 177(4):317–324

11. Muñoz-Sanjuán I, Brivanlou AH. Neural induction, the default model and embryonic stem cells. Nat Rev Neurosci 2002;3(4):271–280

35. Kiernan JA, Rajakumar N. Barr’s The Human Nervous System: An Anatomical Viewpoint. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014

12. Wilson SI, Edlund T. Neural induction: toward a unifying mechanism. Nat Neurosci 2001;4(Suppl):1161–1168

36. Pansky B. Review of Medical Embryology. New York, NY: Macmillan USA; 1982

13. Young PA, Young PH, Tolbert DH. Basic Clinical Neuroscience. Vol 1. 3rd ed. Philadelphia, PA: Wolters Kluwer; 2015

37. Waxman SG. Clinical Neuroanatomy. 28th ed. New York, NY: McGrawHill Education; 2017

14. Hemmati-Brivanlou A, Kelly OG, Melton DA. Follistatin, an antagonist of activin, is expressed in the Spemann organizer and displays direct neuralizing activity. Cell 1994;77(2):283–295

38. Dale JK, Vesque C, Lints TJ, et al. Cooperation of BMP7 and SHH in the induction of forebrain ventral midline cells by prechordal mesoderm. Cell 1997;90(2):257–269

15. Lamb TM, Knecht AK, Smith WC, et al. Neural induction by the secreted polypeptide noggin. Science 1993;262(5134):713–718

39. Ericson J, Muhr J, Placzek M, Lints T, Jessell TM, Edlund T. Sonic hedgehog induces the differentiation of ventral forebrain neurons: a common signal for ventral patterning within the neural tube Cell 1995;81(5):747–756

16. Sasai Y, De Robertis EM. Ectodermal patterning in vertebrate embryos. Dev Biol 1997;182(1):5–20 17. Sasai Y, Lu B, Steinbeisser H, Geissert D, Gont LK, De Robertis EM. Xenopus chordin: a novel dorsalizing factor activated by organizer-specific homeobox genes. Cell 1994;79(5):779–790

40. Dockery P, Gruener G, Mtui E. Fitzgerald’s Clinical Neuroanatomy and Neuroscience. 7th ed. Philadelphia, PA: Elsevier; 2016 41. Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell 2011;146(6):873–887

4 

Pathology of the Brainstem Hannes Vogel

Abstract

The brainstem contains all cell types of the central nervous system. Consequently, the brainstem may be involved in infectious, oncologic, neurodegenerative, and vascular disease processes. This chapter highlights the common pathological processes affecting the brainstem. Keywords:  central pontine myelinolysis, cerebral aqueduct of Sylvius, diffuse midline glioma, fourth ventricle, H3K27 mutant, medulla, midbrain, pons

■■ Introduction The brainstem is an anatomical and functional hub of the central nervous system (CNS) that not only serves as a conduit for nearly all the information between the brain and the spinal cord and elsewhere, but also performs numerous vital functions by the presence of cranial nerve nuclei and centers of control for many essential functions. Even the smallest lesion may have profound effects on brainstem function. From a histological standpoint, the brainstem contains all the cellular elements found throughout the CNS, including neurons, glia, leptomeninges, ventricular surfaces, and a rich vascular supply. Thus, almost all pathological processes found elsewhere in the CNS may be represented in the brainstem, sometimes in isolation or in conjunction with diffuse or multifocal CNS diseases. For obvious reasons, much of the abnormal pathology of the brainstem cannot be easily assessed by large biopsies or resections and is therefore elucidated by neuroradiological studies and autopsy-based examinations.

■■ Developmental and Acquired Malformations Midbrain Aqueductal Abnormalities The cerebral aqueduct of Sylvius is the most common site of obstruction in noncommunicating hydrocephalus. In normal fetal development, the aqueduct is comparatively more distended than in the adult form. The normal adult aqueduct at its narrowest point, usually at the level of the middle of the superior colliculus, ranges between 0.4 and 1.5 mm2 in cross-sectional area1 and is subject to anatomical variation in length and contour (Fig. 4.1). The normal aqueduct may display forking, depending on the level and angle of the section. Consequently, this finding should not necessarily be considered pathological if seen in the setting of hydrocephalus. The cerebral aqueduct may be considered abnormally narrow if it is less than 0.15 mm2 in cross-sectional area. Complete obliteration has been referred to as atresia, whereas incomplete

obstruction is considered stenosis. Stenosis may be sporadic, X-linked, or, rarely, autosomal recessive. Traditionally, aqueductal narrowings are divided between malformations lacking gliosis and acquired causes with gliosis; however, some forms of experimental viral infection in mice have resulted in aqueductal stenosis without gliosis. Thus, some stenotic conditions without gliosis may be acquired. It has been proposed that aqueductal stenosis may be the result of compression by the expanding hydrocephalic hemispheres in utero on the midbrain tectal plate and the normally developing aqueduct.2 A particular form of aqueductal stenosis is X-linked recessive in inheritance.3 This inherited form of aqueductal stenosis accounts for 2% of congenital hydrocephalus.4 The degree of hydrocephalus may vary widely. Adduction-flexion deformity of the thumbs was reported in 25% of cases.5 X-linked recessive aqueductal stenosis is associated with congenital absence of the pyramids and is attributed to mutations in the L1CAM gene. Stenosis of the aqueduct is severe in some cases and relatively normal in others.6 Atresia of the aqueduct may result in an abnormally complex forked configuration.7 Other forms of atresia result in the lack of a recognizable aqueduct, which is represented by small tubules and other ependymal-lined canals without associated gliosis. This lack of a recognizable aqueduct has been associated with Arnold-Chiari malformation, hydranencephaly, craniosynostosis,8 or arhinencephalic syndromes,9 or seen in isolation. Gliotic obliteration of the aqueduct is marked by the coexistence of widespread ependymitis involving other ventricular walls, commonly associated with meningitis with ventriculitis.10 Gliotic obliteration of the aqueduct may also occur as a gradual process with a diversity of occlusive causes. Intraventricular hemorrhage in the premature brain or occlusion by necrotic tissue, such as in hydranencephaly, may also be responsible for gliotic obliteration. This type of cerebrospinal fluid (CSF) obstruction tends to result in the gradual onset and worsening of obstructive hydrocephalus in childhood or even adulthood. Microscopy reveals residual nests of ependyma indicating the profile of the aqueduct, whereby the lumen is occluded by an invasive glial reaction. The presence of a thin translucent septum resulting in hydrocephalus is a rare cause of aqueductal obstruction and may be a variant of gliotic stenosis.11

Pons Pontocerebellar Hypoplasia Pontocerebellar hypoplasia (PCH) is group of rare inherited progressive neurodegenerative disorders with prenatal onset that affect growth and function of the brainstem and cerebellum, resulting in little or no normal development. Ten different subtypes have been reported. They are classified based on the

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Fig. 4.1 Cerebral aqueduct and characteristic abnormalities. (a) Normal appearance of the aqueduct in cross section at the level of the superior colliculus. (b) The caudal third of the aqueduct may show a deep median slit in its floor extending into the midline raphe. The slit walls may fuse dorsally forming a pouch that extends in the midline below the main lumen of the aqueduct, which should not be misinterpreted as pathological forking of the aqueduct in conditions such as hydrocephalus of infancy. (c) Aqueduct stenosis, in which there is no pathological abnormality such as gliosis in the adjacent neuropil. A cross-sectional area of less than 0.15 mm2 should

be considered abnormal. (d) Aqueductal atresia features the absence of a stenotic channel, replaced in its expected position by small tubules and tiny ependymal canals or “aqueductules,” as with stenosis, without accompanying gliosis. (e) Aqueductal gliosis shows the contours of the original normalsized aqueduct, identified by an interrupted ring of ependymal cells, rosettes, and tubules, surrounded and filled by dense fibrillary gliosis. (f) Aqueductal septum, a rare occurrence caused by a glial plug giving rise to an obstructive membrane. The ring of aqueductules suggest a common origin with that of aqueductal gliosis. Small hatching marks signify gliosis in (e) and (f).

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is very shallow, with few transverse fibers, and often with significant gliosis (Fig. 4.2). Hypoplasia or dysplasia of the inferior olives may also be present.

Medulla Inferior Olivary Abnormalities Several types of abnormalities occur in the inferior olive (Fig. 4.3). Olivary heterotopia may be single or multiple and assume a number of sizes and conformations whereby there is variable folding and surrounding by neuropil, much like normal inferior olives (Fig. 4.3a). Most occur laterally near the inferior cerebellar peduncle (Fig. 4.3b). The normal migration of inferior olivary neurons occurs before the end of the third month of gestation.13 Therefore, cerebral agyria or pachygyria may coexist with inferior olivary heterotopia. Other conditions associated with olivary heterotopia include the Dandy-Walker syndrome, pyruvate dehydrogenase deficiency, megalencephaly, and trisomy 13.6 The inferior olives may also show a number of other dysplastic abnormalities with certain known associations  (Fig. 4.3c-f). They are neither known to occur in isolation nor associated with any symptoms. These include Joubert syndrome, Dandy-Walker malformation, Miller-Dieker syndrome, Zellweger syndrome, dentate-olivary dysplasia with intractable seizures in infancy, trisomies 13 and 18, pachygyria, thanatophoric dysplasia, and others. Importantly, the inferior olives and dentate nuclei of the cerebellum have a common ancestry in the rhombic lip; therefore, dysplasias of the dentate nuclei may frequently coexist with those of the inferior olives.

Inferior Olivary Hypertrophy Fig. 4.2 Pontocerebellar hypoplasia. (a) Low-power view of hypoplastic pons and neocerebellum in a case of PCH6, stained for glial fibrillary acidic protein (GFAP). Note the shallow pons with few transverse tracts. (b) High-power photomicrograph of the area bounded by the rectangle in (a), showing marked astrogliosis.

clinical presentation, genetic characteristics, and the spectrum of pathologic changes.12 PCH type 1 (PCH1) is characterized by central and peripheral motor dysfunction associated with cell degeneration in the anterior horn. This condition resembles infantile spinal muscular atrophy and results in early death. In PCH2, there is progressive microcephaly from birth combined with extrapyramidal dyskinesias. PCH3 is characterized by hypotonia, hyperreflexia, microcephaly, optic atrophy, and seizures. PCH4 is characterized by hypertonia, joint contractures, olivopontocerebellar hypoplasia, and early death. Patients with PCH5 have cerebellar hypoplasia, which is apparent in the second trimester, and show seizures. PCH6 is associated with mitochondrial respiratory chain defects. All subtypes share common characteristics, including hypoplasia and atrophy of the cerebellum and pons, progressive microcephaly, and variable cerebral involvement. The brainstem pathology of PCH is mostly overshadowed by the pathology in the cerebellum, in which the neocerebellar hemispheres are severely atrophic with relative sparing of the flocculi and vermis and fragmentation of the cerebellar dentate nucleus. The basis pontis (the ventral or basilar part of the pons)

A distinctive form of pathology of the inferior olives occurs with transsynaptic degeneration when accessory and inferior olivary neurons lose synaptic input, such as from interruption of the transsynaptic degeneration of the inferior olivary nucleus after injury to the dentato-rubro-olivary pathway, as occurs in an infarct to the ipsilateral central tegmental tract, or surgical disruption in the removal of cerebellar tumors in childhood. Some patients develop palatal myoclonus. Histologically, unlike the usual atrophy and degeneration seen with other neurons of the CNS following deafferentation, the neurons of the inferior olives undergo hypertrophy with microscopic vacuolation, atypia, dispersal of Nissl substance, and even neurofibrillary tangle formation (Fig. 4.4).

Pyramidal Tract Anomalies Corticospinal tracts may display a variety of abnormalities, best visualized in the pyramids of the medulla. These include exaggerated fasciculation, in which the fascicles are divided into ovoid bundles separated by glial tissue.14 Aplasia of corticospinal tracts is a predictable feature of anencephaly, holoprosencephaly, or hydranencephaly; they also may be associated with X-linked congenital aqueductal stenosis.15 Corticospinal tracts may also show unilateral hypertrophy with associated asymmetric decussation, due to an actual increase in the number of fibers in the enlarged pyramid. This abnormality causes dorsal displacement of the ipsilateral inferior olive.

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Fig. 4.3  Inferior olivary abnormalities. (a) Normal inferior olives, including the dorsal accessory olivary nucleus (DAON), inferior olivary nucleus (ION), and the medial accessory olivary nucleus (MAON), which should not be confused with fragmentation of the ION in dysplastic conditions. (b) Olivary heterotopia. Case of Miller-Dieker syndrome. May be found along the migration route taken by their precursors from the rhombic lip to the ventral medulla. They may be single or multiple. Note the proximity of the largest heterotopia to the inferior cerebellar peduncle (ICP) while the ION is abnormally small

and dysplastic. c-f Olivary dysplasias. (c) Example of poorly convoluted and fragmented ION in Zellweger syndrome, with a dorsally thickened C-shape. A similar appearance may be seen in trisomy 13. (d) A coarse and thickened hook-shaped ION without undulations as seen in Joubert syndrome, with similar examples reported in dentato-olivary dysplasia with intractable seizure in infancy. (e) Case of Zellweger syndrome showing another example of a dorsally thickened C with fragmentation of the ION. (f) Excessive undulation of the ION as seen with pachygyria and thanatophoric dysplasia.

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Fig. 4.5 Axial section of brainstem and cerebellum showing significant brainstem displacement by an ependymoma from a child with “fatal gastroenteritis” due to intractable vomiting induced by brainstem compression. The vomiting was attributed to a gastrointestinal cause rather than unsuspected posterior fossa mass. Fig. 4.4  Inferior olivary hypertrophy. (a) Segment of right inferior olive is noticeably thickened (arrow) in comparison with ipsilateral and opposite normal convolutions  (Bielschowsky silver impregnation). (b) Abnormally enlarged, vacuolated, and dysplastic neurons within the hypertrophied segment  (hematoxylin and eosin). (c) Bielschowsky silver impregnation shows abnormal cytoskeletal changes in affected neurons.

■■ Tumors Tumors of the brainstem include many among the primary neuroepithelial tumors, including astrocytomas, glioneuronal tumors, and very rarely oligodendrogliomas. Given the predilection of childhood brain tumors to originate in the posterior fossa as a whole, it is important to make the distinction between tumors arising in the brainstem itself versus those originating in the cerebellum, such as medulloblastomas, cranial nerve tumors, and intraventricular tumors such as ependymomas, which may compress or encircle the brainstem secondarily (Fig. 4.5). This section will describe tumors that arise within or frequently involve the brainstem. Among these tumors, it is useful to subdivide those that typically arise in the midbrain, pons, or medulla.

Midbrain Tectal Glioma Clinical Features The tumor most associated with a primary location in the midbrain is also known as the tectal glioma. Its location is prone to cause aqueductal stenosis and obstructive hydrocephalus. Magnetic resonance imaging (MRI) examination typically reveals a dorsally exophytic mass extending from the quadrigeminal plate.16 Tectal gliomas tend to be indolent and rarely cause neurological impairment. Progression occurs in 15 to 25% of tumors.17 Management is usually directed toward relief of hydrocephalus by shunting or endoscopic third ventriculostomy followed by observation. Biopsy and adjuvant therapy are reserved for patients with radiographic and clinical progression.

Pathology Histological documentation, not to mention contemporary molecular profiling, is virtually nonexistent in published cases of tectal glioma. However, in keeping with their indolent clinical behavior,

the majority of these tumors that have been biopsied show lowgrade histology, diagnosed as World Health Organization (WHO) grade I or, more frequently, grade II astrocytomas, although other low-grade gliomas, including oligodendrogliomas and ependymomas, have been reported.18,​19

Pons Diffuse Intrinsic Pontine Glioma  Clinical Features A large series conducted by Schroeder et al found that 15% of malignant primary brain tumors in children under 20 years old arise in the brainstem, with the majority being the diffuse intrinsic pontine glioma  (DIPG) subtype.20 DIPG is a leading cause of brain tumor-related death in children, with a median survival of less than 1 year; more than 90% of children die within 2 years of diagnosis.21 The median age of diagnosis is 6–7 years, and patients typically present with brainstem dysfunction or CSF obstruction over a period of 1 to 2 months. Additional neurological signs include cranial neuropathies, long tract disturbances, and ataxia.22 DIPGs also account for 45 to 50% of brainstem gliomas in adults.23 The expansion of the pons with convex intrusion into the fourth ventricle is so characteristic of these lesions as a midsagittal radiographic finding that biopsy is usually considered unnecessary. No effective treatment has been found, despite the standard administration of radiation therapy and chemotherapy.24

Pathology The 2016 WHO classification of brain tumors includes the DIPG as a form of diffuse midline glioma that is H3K27-mutant and classified as WHO grade IV.21 The malignancy tends to produce distortion and enlargement of the pons by diffuse infiltration of the pontine parenchyma. Necrosis and hemorrhage may be seen. Microscopically, there is infiltrative growth into gray and white matter. The tumor cells vary from small and monotonous to large, pleomorphic forms (Fig. 4.6a, b). Nuclear morphology may be reminiscent of astrocytic differentiation, with hyperchromatic irregular shapes, or it can show oligodendroglial morphology. Ten percent lack mitotic figures, microvascular proliferation, and necrosis, and therefore qualify only by microscopic

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Fig. 4.6 H3K27-mutant, World Health Organization grade IV, diffuse intrinsic pontine glioma. (a) Features of a malignant glioma, including hypercellularity and pseudopallisading necrosis, with (b) infiltrative growth around neurons in pontine gray matter (hematoxylin and eosin). (c) H3K27M immunostain shows diffuse nuclear positivity in tumor cell, with (d) corresponding negativity for H3K27me3 in tumor cells and nuclear positivity in nonneoplastic endothelial and inflammatory cells.

criteria for WHO grade II status. The remainder show high-grade features with features of glioblastoma. Regardless, all forms are associated with the same dismal prognosis. The diagnosis of a H3K27M glioma can be reliably done by immunohistochemistry; however, diagnosis is aided by concurrent immunostaining for the H3K27me3  (trimethylated) protein, which is seen in H3K27 wild-type cells (Fig. 4.6c, d). Among pontine gliomas with the H3K27 mutation, a recent series shows that such tumors are highly represented within the pediatric patient population, with an average age at diagnosis of 7 years and only 1 adult among 18 patients with pontine gliomas that showed the H3K27 mutation. IDH1 mutations and H3K27 mutations are believed to be essentially mutually exclusive.25,​26 This report also underscores the particular association of H3K27 mutant gliomas with the pons; midbrain and medulla gliomas do not show the mutation. In adults, gliomas of higher grade may be seen that more closely correspond to the histology and molecular profile of supratentorial malignant gliomas.23,​27

Pilocytic Astrocytoma Clinical Features The pilocytic astrocytoma is a WHO grade I astrocytoma. It may occur in many locations within the CNS, especially the cerebellum and optic-hypothalamic regions. A minority arise in the brainstem, which is estimated to account for 9% of all pilocytic astrocytomas,28 or involve the brainstem by infiltrative growth from the cerebellum. In either circumstance, such tumors understandably carry a worse prognosis because of the difficulty in surgical options.29 Brainstem pilocytic astrocytomas present similarly to cerebellar examples, as circumscribed cystic or lobulated lesions with bright contrast enhancement, but solid types may arise as dorsally exophytic lesions of the brainstem, often from the pontomedullary region. Thus, radiographic localization and characterization are important in distinguishing

Fig. 4.7 Pilocytic astrocytoma, World Health Organization grade I. (a) Piloid cells arranged among microcytic mucinous spaces, creating a vaguely biphasic appearance. (b) Microvasculature may be prominent. Note the oligodendrocyte-like appearance of some intervening tumor cells. (c) Rosenthal fibers are most frequently encountered in the densely fibrillar regions of pilocytic astrocytomas.

brainstem pilocytic astrocytomas from diffuse astrocytomas. Brainstem pilocytic astrocytomas are particularly associated with NF1 as part of a spectrum of radiographically detected focal regions of brainstem enlargement, which can be seen with or without contrast enhancement. A series of 125 patients with NF1 and brainstem abnormalities included one biopsied patient with proven pilocytic astrocytoma. The other lesions were mostly indolent and many remained stable or even regressed.30

Pathology Pilocytic astrocytomas display a tan-pink color with a distinctly mucoid texture, often recognizable even in the smallest specimens. The most classic microscopic appearance of pilocytic astrocytomas is that of a microcystic tumor with a rich fibrillary background that shows a biphasic pattern, alternating between dense eosinophilic vasocentric regions and looser intervening areas  (Fig. 4.7a). Either of the two patterns may dominate the microscopic appearance of the specimen; therefore, the dense or compact differentiation when unaccompanied by looser areas is especially prone to misdiagnosis as a diffuse fibrillary

4   Pathology of the Brainstem astrocytoma. This may prove especially challenging with small brainstem biopsies. At the cytological level, astrocytes in these tumors have elongated profiles  (“piloid” or hair-like) with benign ovoid nuclei. Multinucleated cells may be prominent. Clear cell differentiation may be extensive, sometimes indistinguishable from that of oligodendrogliomas (Fig. 4.7b). Considering the distinct rarity of oligodendrogliomas in the brainstem, a clear cell glioma in the posterior fossa is in fact more likely to be a pilocytic astrocytoma. Vascular proliferation is characteristic and may be one of the most essential features, along with contrast enhancement, in distinguishing the pilocytic astrocytoma from a WHO grade II diffuse astrocytoma. Mitotic activity is very unusual, and when division figures are identified, they are often within vascular endothelial cells. Rosenthal fibers are eosinophilic elongate or beaded structures, usually within the compact perivascular compartments; these fibers are also quite useful in securing the diagnosis of pilocytic astrocytoma (Fig. 4.7c). Eosinophilic granular bodies (EGBs) are more frequent in loose regions, whereas Rosenthal fibers are found in denser, compact, typically perivascular areas. Both EGBs and Rosenthal fibers share immunoreactivity for glial fibrillary acidic protein (GFAP), ubiquitin, and αB crystallin,31 and EGBs may express α1-antichymotrypsin, α1-antitrypsin, and lysozyme.32 Pilocytic astrocytomas are quintessential WHO grade I gliomas. However, “malignant” forms exist, marked by numerous mitotic figures  (at least 4 mitoses/10 high-power fields at 400X), robust vascular proliferation, hypercellularity, and moderate-to-severe cytologic atypia, with or without necrosis, which may even be of the pseudopalisading type. A report of 34 cases did not appear to suggest that the brainstem is more vulnerable to this tumor type than it is to conventional pilocytic astrocytomas without anaplasia.33 The tumors may have had a WHO grade I pilocytic astrocytoma precursor, coexistent pilocytic astrocytoma, pilocytic astrocytoma documented by previous biopsy, or exhibited characteristic pilocytic features in an otherwise anaplastic astrocytoma. A clinical history of neurofibromatosis type I or radiation therapy may be present. P53 abnormalities may highlight the anaplastic portions of these tumors. High mitotic rates and necrosis appear to be the best predictors of a poor prognosis. Notwithstanding these disconcerting features, which might otherwise equate with a diagnosis of glioblastoma, such lesions should be designated “anaplastic” or WHO grade III.

Ganglioglioma, WHO grade I WHO grade I gangliogliomas consist of mixed glial and neuronal cell populations. The identification of gangliocytic dysplasia is of paramount importance, since other otherwise-pure astrocytomas may invade gray matter to the extent that the native preinvasion neuronal cytoarchitecture is not apparent. Binucleated forms and irregular cytoarchitectural orientations as defined by a haphazard array of cell processes are reliable findings (Fig. 4.8a). These structures may be accentuated by antineuronal antibody immunostaining, particularly for microtubule-associated protein 2 (MAP2), which helps reveal the haphazard and disorganized arrangement of neoplastic ganglion cells and multiple nuclei by their negative staining (Fig. 4.8b). The astrocytic portion of gangliogliomas, often highly reminiscent of pilocytic astrocytomas, is estimated to occur in approximately two-thirds of gangliogliomas. In lesions with strong contrast enhancement, prominent vasculature as is seen in pilocytic astrocytomas may also be found.

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Fig. 4.8 Ganglioglioma, World Health Organization grade I. (a) Loose arrangement of gangliocytic cells in a fibrillar background. Eosinophilic granular bodies (arrow) are usually found in the looser areas of gangliogliomas. (b) Microtubule-associated protein 2 (MAP2) immunohistochemistry highlights gangliocytic cells and multiple nuclei associated with dysplasia by their negative staining.

Subarachnoid spread is quite common in superficially located tumors, which does not necessarily portend a higher grade. Necrosis and mitotic activity are distinctly rare unless the astrocytic component warrants a worsening in grade, and according to current criteria, WHO grade II lesions are not formally recognized. Anaplastic examples warrant a WHO grade of III, which is determined by malignant changes in the glial component, such as increased cellularity, pleomorphism, and increased mitotic activity.34

BRAF Mutations in Gliomas Since the therapeutically targetable BRAF c.1799T>A  (p.V600E) (BRAFV600E) mutation is a key gene altered in most pediatric lowgrade gliomas, it is relevant to the pathology of brainstem gliomas. Brainstem pilocytic astrocytomas showed a rate of BRAFV600E mutation in 10% of tumors, compared with 33% of diencephalic examples.35 Another study showed that 1 of 8  (13%) brainstem pilocytic astrocytomas were BRAFV600E mutant.36 Gangliogliomas in all locations show a relatively high rate of BRAFV600E mutation compared with other gliomas, second only to pleomorphic xanthoastrocytomas and epithelioid glioblastomas. In the brainstem, pediatric gangliogliomas also show BRAFV600E mutation in 54% of patients (7 of 13), 2 of which had equivocal immunohistochemical results, but those results were confirmed by an RNA-sequencing approach.36

Rosette-Forming Glioneuronal Tumor Clinical Features Rosette-forming glioneuronal tumors typically show symptoms of obstructive hydrocephalus owing to the characteristic involvement of the midline location in the fourth ventricle and/or aqueduct, with possible cervical pain. They may extend into the adjacent brainstem, cerebellar vermis, pineal gland, or

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II  Anatomy, Development, and Pathology of the Brainstem, Thalamus, and Pineal Region Table 4.1  Rare intrinsic tumors of the brainstem

Tumor

Brainstem involvement

References

Hemangioblastoma, World Health Organization grade I

Medulla, sporadic

Neumann 1989112

Primitive neuroectodermal tumor (Central nervous system embryonal tumor)

Pons

Friedrich 201538

Metastatic

Most commonly from lung and breast primary tumors

Shuto 200339

Germ cell tumors, mostly germinomas

Diverse manifestations. Mostly favorable outcomes with chemotherapy and radiation therapy

Madden 200940

■ Infections Bacterial

Fig. 4.9  Rosette-forming glioneuronal tumor, World Health Organization grade I. (a) Bland small neurocytic cells forming rosettes with eosinophilic neuropil cores and perivascular pseudorosettes with cell processes radiating toward vessel walls. (b) Anti-synaptophysin antigen immunohistochemistry highlights the rosette cores. (c) Microtubule-associated protein 2 (MAP2) immunohistochemistry shows positivity in cell bodies and processes.

thalamus. Incidental findings on MRI occasionally are seen,37 Separate supratentorial locations have also been described, as well as dissemination throughout the ventricular system.37 Radiographically, they are usually relatively well-circumscribed with focal contrast enhancement.

Pathology Rosette-forming glioneuronal tumor is assigned a WHO grade of I. These tumors are composed of bland small neurocytic cells forming rosettes with eosinophilic neuropil cores and perivascular pseudorosettes with cell processes radiating toward vessel walls (Fig. 4.9a). There may be a microcystic mucinous matrix. An astrocytic component resembles pilocytic astrocytoma, including the presence of Rosenthal fibers and EGBs. Vessels are thin-walled, dilated, hyalinized, or thrombosed. Immunohistochemistry reveals strong synaptophysin positivity in the rosette cores  (Fig. 4.9b), possible neuN staining of neurocytic cells, and MAP2 positivity in cell bodies and processes  (Fig. 4.9c). Proliferative indices are low. Genetic markers include mutations in PIK3CA and FGFR1, but no BRAF abnormalities as seen in pilocytic astrocytomas and no IDH1/2 mutations or 1p19q codeletions (Table 4.1).

Listeria monocytogenes is a common cause of central nervous system infections, usually causing meningitis or meningoencephalitis, especially in immunosuppressed patients, infants, and elderly patients. Brainstem encephalitis  (“rhombencephalitis”) caused by L. monocytogenes is an uncommon form of central nervous system listeriosis; however, it is the most common presentation in immunocompetent individuals. Mortality rates are significant (51%), and the condition is fatal if not recognized and treated early.41 One fatal case disclosed necrotizing inflammation, with gram-positive bacilli in the brainstem and the cerebellum.42 Other bacterial causes of brainstem encephalitis43 include Mycoplasma pneumoniae44 and Borrelia burgdorferi. Causes of bacterial abscesses in the brainstem most commonly include streptococcus, staphylococcus, and Mycobacterium tuberculosis.43 Melioidosis in the form of brainstem microabscesses caused by Burkholderia pseudomallei has been reported in a 10-month-old girl.45 Interestingly, a predilection for brainstem infection may be attributable to retrograde transport along the trigeminal nerve from a nasopharyngeal infection. Also, B. pseudomallei may also deploy a Trojan horse strategy by which infected leukocytes infiltrate the central nervous system using L-selectin (CD62L)-mediated migration across the cerebral ­endothelium.46

Viral Poliomyelitis may involve the brainstem motor cranial nerve nuclei in the pons and medulla and reticular formation, in addition to other well-known regions of motor neuron involvement in the cortex, spinal cord, and cerebellum. Bulbar symptoms include cranial nerve palsies and cardiac arrhythmias and abnormal breathing patterns from reticular formation involvement. Pathological findings are the same as in all regions of involvement, with inflammation of leptomeninges and gray matter, neuronophagia, and microglial nodules.

4   Pathology of the Brainstem Another viral cause of predominantly brainstem infection is enterovirus 71, a cause of epidemic hand, foot, and mouth disease with peak incidence in the summer and fall. Young children are most commonly affected. In an outbreak that occurred in Taiwan, 41 cases of brainstem encephalitis were detected, substantiated by MRI examination in a subset in which the pontine tegmentum appeared to be where lesions were most common. Symptoms included myoclonic jerks and tremor, ataxia, cranial nerve involvement, and respiratory problems, with a significant incidence of residual neurological complications in survivors. The overall fatality rate was 14%.47 The other common cause of hand, foot, and mouth disease, coxsackievirus A16, has also been reported to cause brainstem encephalitis in a 23-month-old girl.48 Other viral causes of brainstem encephalitis include Herpes simplex,49 human herpesvirus-7,50 respiratory syncytial virus,51 West Nile virus, which is especially noteworthy for involvement of the substantia nigra and resulting Parkinsonism,52 tick-borne encephalitis virus,53 and Japanese encephalitis virus.54 Toxoplasmosis due to the protozoal agent Toxoplasma gondii of the brainstem has also been reported.55

■ Inflammatory Diseases Demyelinating Diseases Multiple Sclerosis  Clinical Features In multiple sclerosis (MS), signs and symptoms of brainstem deficits are recognizable presenting manifestations of demyelinating diseases of the brainstem. For example, diplopia, nystagmus, and internuclear ophthalmoplegia, sometimes with a conjugate horizontal gaze palsy in one direction (one-and-a-half syndrome), are attributable to lesions of the nerve nuclei of CNs III, IV, and VI and their outflow tracts, the medial longitudinal fasciculus and the paramedian pontine reticular formation. So-called pseudobulbar affect, which is characterized by laughing or crying uncontrollably without emotional congruence with the displayed affect, may be due to brainstem involvement, along with frontal and parietal subcortical white matter.56 The brainstem is sometimes involved in apparent isolation, producing ophthalmoplegia, which may occur as the first manifestation of clinically isolated demyelinating syndrome (CIS), which may be the precursor of true multifocal MS.57 Recognition of brainstem involvement by neuroimaging or other testing may identify asymptomatic lesions and caries prognostic importance, because there is a higher risk of progression with disability.58,​59

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cord that are involved in MS myelitis. Unilateral or bilateral optic neuritis is often severe with poor recovery. A third clinical hallmark is intractable nausea, vomiting, or hiccups. This is relevant to brainstem involvement in NMOSD, because of implication for involvement of regions of high AQP4 expression, such as the area postrema, causing nausea and vomiting, and other regions of the medulla involving bilateral nucleus tractus solitarius.60 Interestingly, a patient with newly diagnosed breast cancer and brainstem and limbic encephalitis with neuromyelitis opticaimmunoglobulin G in serum and CSF, which improved with cancer treatment, raises the possibility that the NMOSD may represent a paraneoplastic phenomenon in some cases, prompting the need to screen such patients for a tumor in certain instances of neuromyelitis optica.61

Pathology The microscopic pathology of demyelinating diseases in the brainstem is quite similar to that which occurs in other locations. The diagnosis of brainstem involvement by MS or NMOSD would rely mostly on clinical, radiological, and other testing rather than biopsy. Thus, the following description pertains to the pathological diagnosis of a demyelinating process in general. Microscopic features of active lesions show hypercellularity with a relatively dense perivascular and parenchymal infiltrate of macrophages and mostly perivascular lymphocytes. Scattered reactive astrocytes may be quite pleomorphic, multinucleated, or contain multiple irregular nuclear fragments along with glassy eosinophilic cytoplasm, known as a granular mitosis or Creutzfeldt astrocyte. The conventional histological method of demonstrating a demyelinating process is by performing a myelin stain, most commonly the Luxol fast blue  (LFB)-periodic acidSchiff  (PAS) stain, and an axonal stain such as by Bielschowsky silver impregnation. In a selective demyelinating process, there is loss of myelin with relative preservation of axons. The border of demyelination is often abrupt (Fig. 4.10), and the region of demyelination may contain macrophages and reactive astrocytes in abundance. Careful scrutiny of the axonal stain may reveal irregularities in axonal profiles with small varicosities or discontinuities;

Neuromyelitis Optica Spectrum Disorder  Neuromyelitis optica spectrum disorder (NMOSD) is a severe inflammatory demyelinating disease of the CNS that is distinct from MS. Originally described as a monophasic illness characterized by the co-occurrence of optic neuritis and transverse myelitis, it is now known that NMOSD patients typically have recurrent attacks, and the disease is not limited to the optic nerves and spinal cord. Although there is overlap with the presentation of MS, the disease has a distinct pathologic antibody, anti-aquaporin 4(AQP4)-IgG, which is both a sensitive and highly specific serum autoantibody present in 70% of NMOSD patients in serum or CSF. The most common clinical syndrome is longitudinally extensive transverse myelitis, as opposed to the short segments of spinal

Fig. 4.10  Multiple sclerosis plaques affecting the medulla. Note the sharply demarcated areas of myelin loss (arrowheads) (myelin basic protein immunohistochemistry). (Courtesy of Bette K. Kleinschmidt-DeMasters, MD)

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II  Anatomy, Development, and Pathology of the Brainstem, Thalamus, and Pineal Region

however, a hypoxic-ischemic lesion or a neoplasm or other destructive lesion will show axonal loss commensurate with demyelination. Immunohistochemistry is not usually necessary to strengthen the diagnosis. Macrophage markers such as CD68 or CD163 show abundant macrophages and GFAP identifies reactive astrocytes, with their characteristically slender and delicate processes. Leukocyte markers reveal a predominance of T lymphocytes in both the perivascular and interstitial infiltrates. In NMOSD, pathological studies of the area postrema in autopsied and confirmed cases showed tissue rarefaction, blood vessel thickening without obvious neuronal or axonal pathology, and preservation of myelin in the subependymal medullary tegmentum. AQP4 immunoreactivity was lost or markedly reduced in all cases, with microglial activation, moderate to marked perivascular and parenchymal lymphocytic inflammatory infiltrates, and eosinophils in half of the cases. Complement deposition in astrocytes, macrophages, or in a perivascular distribution, with an associated astrocytic reaction, were also present. Area postrema lesions were highly associated with clinically documented nausea and vomiting.

Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids  Clinical Features Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) was first described in 201062 as a distinct form of brainstem encephalitis centered on the pons, with a predominantly T cell infiltrate. It is responsive to immunosuppression with glucocorticosteroids; therefore, CLIPPERS symptoms reflect brainstem pathology. Since biopsies are scarce in this disorder, characteristic neuroimaging findings are of key importance in considering the diagnosis. MRI typically shows punctate and curvilinear gadolinium enhancement predominantly in the pons that is almost always symmetric, and also in the cerebellar peduncles, midbrain, and medulla. Involvement of the spinal cord, thalamus, basal ganglia, internal capsule, corpus callosum, and cerebral white matter has also been described. Exacerbation may occur with withdrawal of steroids; therefore, long-term immunosuppressive therapy may be required for durable improvement.63

Fig. 4.11 Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). (a) Perivascular and parenchymal lymphocytic infiltrates in the white matter (hematoxylin and eosin [H&E]). (b) The infiltrate is composed predominantly of CD4-positive T lymphocytes. (c) CD68-immunopositive perivascular macrophages and parenchymal microglial cells. (d) Chronic vascular injury with hyalinization and minimal inflammation, resulting in fibrosis, particularly of the adventitia (H&E). (Courtesy of Bette K. Kleinschmidt-DeMasters, MD)

clinical and radiological findings, biopsies or autopsy studies are exceedingly rare. One postmortem examination disclosed brainstem perivascular lymphocytic infiltrates, microglial nodules, and chromatolysis of the trigeminal motor nucleus, along with grumose degeneration in the cerebellar dentate nucleus.68

Paraneoplastic Brainstem Encephalitis Brainstem encephalitis as a paraneoplastic phenomenon is usually seen with cerebellar involvement and occasionally with limbic encephalitis and may be related to the presence of anti-Hu antibodies,69,​70 anti-Ma2 antibodies,71 anti-Ri antibodies,72 and others. Pathological studies are rare in this disorder. One report included two autopsied patients, one with anti-Hu antibodies and one with no autoantibody detected. There was extensive brainstem gliosis, perivascular inflammation, and cell loss in the pontine and midbrain tegmentum. This was believed to explain the ophthalmoparesis noted in the patients.73

Pathology The reported neuropathology of CLIPPERS is based mostly on single case reports as well as some case series.64 Most cases show perivascular and parenchymal lymphocytic infiltrates with associated macrophages, microglia, and occasional plasma cells and neutrophils; true granulomas and demyelination are not present  (Fig. 4.11). When lymphocytic subsets have been immunophenotyped, CD4-positive cells were more frequent than CD8-positive lymphocytes or CD20-positive B cells.

Bickerstaff's Brainstem Encephalitis Bickerstaff's brainstem encephalitis was first described in 1951 in three patients with drowsiness, ophthalmoplegia, and ataxia.65 The condition was later linked with anti-GQ1b IgG antibodies66 which have also been associated with the Fisher clinical triad of ophthalmoplegia, ataxia, and areflexia.67 Other reports have identified a subset of the disorder with Guillain-Barré syndrome.68 Since the overall prognosis is good and the diagnosis rests upon

■■ Metabolic and Toxic Injury Central Pontine Myelinolysis Clinical Features Central pontine myelinolysis (CPM) occurs most commonly with the rapid correction of electrolyte imbalances, especially chronic hyponatremia, but may also be seen with hypophosphatemia, giving rise to the alternative term osmotic demyelination syndrome. Affected patients may be nutritionally debilitated, may have severe liver disease, may have previously undergone liver transplantation, or have HIV/AIDS or severe burns.74 The condition was often associated with a fatal outcome until contemporary radiological studies allowed for the early diagnosis. Involvement of the basis pontis leads to quadriparesis, dysarthria, and dysphagia and oculomotor abnormalities if the tegmentum is involved.

4   Pathology of the Brainstem

Fig. 4.12  Central pontine myelinolysis. (a) Cross section of pons stained for myelin, showing central region of sharply circumscribed demyelination  (Luxol fast blue/periodic acid-Schiff stain). (b) High-power magnification showing the edge of the process, with numerous lipid-laden macrophages but no lymphocytes or other inflammatory cells.

Pathology CPM involves a demyelinating process in the form of a grossly recognizable central triangular or butterfly-shaped lesion of the basis pontis, with loss of myelin with myelin stains, and relative preservation of axons in early lesions, with a distinct absence of lymphocytic infiltration, a helpful distinguishing feature from other inflammatory demyelinating processes  (Fig. 4.12). Ultrastructurally, there is intracellular and intramyelinic edema along with subsequent vasogenic edema.75 Swelling of the myelin sheaths is followed by oligodendrocyte degeneration. Later forms show axonal degeneration and the accumulation of macrophages. Extrapontine lesions are well-recognized, in the form of involvement by the cerebellum, lateral geniculate body, external capsule, hippocampus, putamen, and cerebral cortex.76

Multifocal Pontine Leukoencephalopathy Disseminated necrotizing leukoencephalopathy was a term coined by Rubinstein for a severe and progressive disease originally described in children with acute lymphoblastic leukemia who received methotrexate and whole-brain irradiation.77 Pathological features included foci of coagulative necrosis with distinctive axonal varicosities. Interestingly, two of the five reported cases had prominent involvement of the pons. Subsequent reports confirmed cerebellar and brainstem involvement, and even note a predilection for pontine involvement in patients who were immunocompromised for various reasons.78,​79,​80 Pathologically, there is a broad spectrum of findings, ranging from axonal swellings seen with myelin pallor and oligodendrocyte loss in grossly normal tissue to more extensive and visibly necrotic lesions showing severe axonal swelling (Fig. 4.13), dystrophic calcification, and minimal inflammation.81

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Fig. 4.13  Multifocal pontine leukoencephalopathy. (a) Focal lesion showing prominent axonal swellings, recognizable in hematoxylin and eosinstained sections. (b) In a less severe focus, dystrophic neurites highlighted by Bielschowsky silver impregnation.

■■ Vascular Arteriovenous Malformations Clinical Features Arteriovenous malformations (AVMs) of the brainstem represent approximately 2 to 6% of all intracranial AVMs.82,​83,​84 The natural history of untreated brainstem AVMs suggests a higher risk of hemorrhage compared to those in other locations, and the deleterious effects on critical brainstem structures is associated with mortality rates approaching 33% in treated and 66% in untreated patients.85,​86,​87 Management issues have arisen over the increasing incidence of the radiographic diagnosis of unruptured AVMs88 especially with limited neurosurgical options in the brainstem, although brainstem AVMs may differ from those in other locations because initial presentation with hemorrhage has been reported in 76 to 100% of patients.83,​89 Dural arteriovenous fistulas in the brainstem region may also mimic brainstem gliomas because of the mass effect resulting from venous congestion and compounded by the effects of possible subarachnoid hemorrhage.90,​91

Pathology Low-power microscopy shows a tortuous and disorganized aggregate of vascular channels of varying diameter and wall thicknesses, some containing laminated thrombi  (Fig. 4.14a). “Cushions” formed through intimal hyperplasia associated with nonlaminar blood flow may be a valuable histologic finding in distinguishing the blood vessels of an AVM from a merely ectatic native blood vessel. Intervening brain tissue may show significant gliosis, macrophage accumulation, and evidence of recent and remote hemorrhage with hemosiderin deposition. Calcification

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II  Anatomy, Development, and Pathology of the Brainstem, Thalamus, and Pineal Region

Fig. 4.14  Arteriovenous malformation (AVM). (a) Thick-walled, abnormally large vessels of varying diameters (hematoxylin and eosin). (b) Endothelial cushion of proliferating intimal cells, with irregular dark-staining internal elastic lamina (arrow) showing duplication and absence, a key diagnostic component of the “arterialized vein” of an AVM (elastin van Gieson stain).

Fig. 4.15  Cavernous malformation (CM). (a) Tightly packed array of ectatic vessels with variable hyalinization of the walls, and perivascular hemosiderin attesting to prior hemorrhage (arrow). (b) The elastin van Gieson stain shows a complete absence of internal elastic lamina, distinguishing the CM from an arteriovenous malformation.

may be seen in both parenchymal and vascular components of an AVM. An important adjunct to the diagnosis is the elastin van Gieson stain which will highlight the internal elastic lamina of arterial blood vessels (Fig. 4.14b). AVMs characteristically show discontinuous, duplicated, or otherwise incomplete elastica in blood vessels that may be considered “arterialized” veins.

Capillary telangiectasias are incidental findings, often in the pons, that consist of thin-walled, small-caliber, vascular channels with no surrounding reactive change or evidence of prior hemorrhage.

Cavernous Malformation Clinical Features Cavernous malformations (CMs) are also known as cavernous hemangiomas or cavernomas. Brainstem CMs account for 9 to 35% of all CNS CMs.92 Most are sporadic but some occur as a familial disorder in which they may be multiple. A number of genetic loci have been linked with familial CMs,93 including linkage of a Mexican kindred to a locus at proximal 7q.94,​95 These lesions are less likely to be detected by angiography than AVMs and are traditionally revealed by characteristic appearance on computed tomography (CT) or MRI scans. Reports suggest that they have a higher rate of hemorrhage than superficial CMs, as well as high rates of repeat hemorrhage.

Pathology CMs are classically described as a tightly packed array of ectatic vessels with variable hyalinization of the walls (Fig. 4.15). They may often be surrounded by abundant old hemorrhage and reactive gliosis. The lack of intervening brain tissue between abnormal blood vessels has been considered a distinguishing feature from AVMs; however, exceptions exist.

Hypoxia-Ischemia The brainstem tegmentum represents a watershed or border zone of vascular perfusion. Consequently, clinical examples of severe hypotension may produce irreversible symmetrical necroses of many tegmental brainstem nuclei, including motor cranial nerve nuclei, superior and inferior colliculi, cuneate and gracilis nuclei, originally known as hypotensive brainstem necrosis.96 Later, the common occurrence of cardiac arrest in both pediatric and adult examples was emphasized.97 In the developing brain, it has been postulated that the same phenomenon may underlie brainstem dysfunction such as that producing central hypoventilation, dysphagia, Möbius syndrome, and micrognathia98 because of the same effects cited above, namely affecting the nuclei of CNs III–XII, the nucleus and tractus solitarius or central pneumotaxic center, and the nucleus ambiguus and other somatic motor nuclei that innervate muscles of swallowing, mastication, and tongue movement.

■■ Trauma Duret Hemorrhages Raised intracranial pressure of sufficient magnitude may cause downward axial or caudal displacement of therostral brainstem that results in secondary brainstem hemorrhages and infarction.

4   Pathology of the Brainstem

65

Lewy bodies, frontotemporal lobar degenerations, and motor neuron disease.

■■ Neurodegenerative Diseases

Fig. 4.16 Duret hemorrhage affecting the midbrain, with characteristic midline position causing local mass effect.

These hemorrhages are referred to as Duret hemorrhages. They are a common finding in fatal brain injuries,99 although they have been reported in patients with favorable outcomes, so should not be considered always fatal.100 They occur in the midline of the midbrain and pons, and rarely in the medulla, and are believed to result from vascular congestion and rupture of paramedian pontine branches of the basilar artery.101 The usual pathological appearance is of an extensive hemorrhagic lesion of the midbrain and pons roughly in the midline, sometimes producing mass effect from the hemorrhagic process  (Fig. 4.16).

Most neurodegenerative diseases exhibit selective vulnerability by their respective pathological processes in specific regions of the CNS, thus producing the characteristic clinical signs and gross and microscopic changes characteristic of the particular disorder. The brainstem is involved in many of the major forms of neurodegeneration (Fig. 4.17, Table 4.2), while some produce the dominant clinical manifestations. These include so-called brainstem forms of Lewy body disease, bulbar amyotrophic lateral sclerosis and other forms of motor neuron disease, and pontocerebellar degeneration. Even if the brainstem is not the region which is predominantly involved in the onset of the disease, the brainstem contains many different structures that are involved in functions ranging from controlling homeostasis to influencing the cognitive functions of the cerebral cortex, which may ultimately become involved with the disease. Recently, the intriguing observation was reported that in the most common dementing disease of the aged, sporadic Alzheimer disease, the earliest evidence of a tauopathy was found in the brainstems of early young adults, specifically in noradrenergic projection neurons of the locus ceruleus, long before the development of beta-amyloid pathology in the transentorhinal region.104

Traumatic Axonal Injury In traumatic brain injury from diverse causes, the brainstem is usually listed as a region of possible axonal injury, since the mechanical forces of acceleration and deceleration of the head frequently involve the brainstem. In the seminal descriptions of axonal injury in nonmissle head trauma, brainstem involvement carried pivotal importance in grading the injury: in grade 1, there is axonal injury in the white matter of the cerebral hemispheres, the corpus callosum, the brainstem, and possibly the cerebellum; in grade 2, there is a focal involvement of the corpus callosum; and in grade 3, there is in addition a focal lesion in the dorsolateral quadrant or quadrants of the rostral brainstem.102 The most characteristic locations of lesions in the brainstem associated with diffuse traumatic axonal injury are seen as clusters of petechial hemorrhages or foci of hemorrhagic softening in the dorsolateral parts of the midbrain and rostral pons. Subsequent descriptions in the context of chronic traumatic encephalopathy (CTE) of sport and military service103 also include the brainstem as an important component of the clinicopathological entity. Multifocal axonal injury was found in numerous locations, including the brainstem, in survivors who died within 6 months of sports-related concussions.103 Cases of stage II/IV CTE begin to demonstrate pallor of the locus ceruleus and substantia nigra as a correlate to parkinsonism, and TDP43-positive neuropil threads and inclusions in the brainstem and elsewhere. With the escalation of staging in CTE with brainstem involvement as a key indicator of the degree of injury, it is important to note that CTE is associated with the development of other neurodegenerative diseases, including Alzheimer disease, dementia with

Fig. 4.17  Distribution of neurofibrillary tangles (NFTs) (yellow) and senile plaques  (SPs)  (green) in a parasagittal section of the brainstem from a patient with Alzheimer disease, showing their location relative to the inferior colliculus (arrow) and inferior olive (arrowhead). There is a sharp increase in the total number of NFTs at the level of midpons and a large number of SPs at the level of midbrain, with an abrupt transition from the absence of NFTs or SPs in the caudal raphe nuclei to a severe pathological alteration of the rostral raphe nuclei.

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Table 4.2  Neurodegenerative conditions with significant brainstem involvement

Diseases

Brainstem involvement

References

Alzheimer disease (AD)

Phase 4 of 5 in β-amyloidosis. Aβ deposits occur in the following lower brainstem nuclei: substantia nigra (SN), red nucleus, central gray matter, superior and inferior colliculi, inferior olivary nucleus, and intermediate reticular zone; and, in phase 5 of 5 in the cerebellum and additional brainstem nuclei: pontine nuclei, locus ceruleus, parabrachial nuclei, reticulo-tegmental nucleus, dorsal tegmental nucleus, and oral and central raphe nuclei (Fig. 4.17) Tangles seen in the cholinergic pedunculopontine tegmental nucleus pars compacta (PPTgpc), parabrachial nucleus, rostral raphe complex, nucleus cuneiforme, and periaqueductal gray matter Pathological changes in brainstem nuclei important to autonomic functions may cause autonomic dysfunction in AD Affected brainstem nuclei are the main source of serotonergic, adrenergic, and cholinergic projections to thalamus, basal forebrain, and cerebral cortex and may contribute to behavioral, affective, and cognitive impairments in AD Extrapyramidal symptoms linked with loss of pigmented substantia nigra compacta (SNc) neurons and tau aggregates in both SNc and locus ceruleus (LC) TDP-43 deposition in SN, midbrain tectum, and inferior olive in later-stage AD

Thal 2002105 Parvizi 2001106 Attems 2007107 Josephs 2016108

SNc, especially ventrolateral tier, and LC neuronal loss with Lewy bodies, pale bodies, melanophages. Also: substantia innominata, dorsal motor nucleus of the vagus, serotinergic raphe nuclei, pedunculopontine nucleus, and Edinger-Westphal nucleus Same brainstem distribution as in PD Brainstem nuclei affected in virtually every case of DLB Severity of brainstem pathology highly variable Scoring system:

Ellison and Love 2013109

Synucleinopathies Parkinson disease (PD)

Dementia with Lewy bodies (DLB)

McKeith 2007110

• 0 = None • 1 = Mild (sparse LBs or Lewy neurites (LNs)) • 2 = Moderate (more than one LB in a low-power field and sparse LNs) • 3 = Severe (four or more LBs and scattered LNs in a low-power field) • 4 = Very severe (numerous LBs and numerous LNs)

Multiple system atrophy (MSA)

Progressive supranuclear palsy

Motor neuron diseases Amyotrophic lateral sclerosis X-linked bulbospinal neuropathy (spinobulbar muscular atrophy, Kennedy disease)

Spinal muscular atrophies Bulbar hereditary motor neuropathies (progressive bulbar palsy)

Brainstem predominantly involved in the cerebellar form (MSA-C) Gross: atrophy of pons, inferior olivary nuclei, pallor of SN and LC Microscopic: neuronal loss, α-synuclein positive glial (oligodendrocyte), and neuronal cytoplasmic and nuclear Gross: atrophy of midbrain and pontine tegmentum, pallor of SN > LC, dilatation of aqueduct and fourth ventricle Microscopic: hyperphosphorylated tau-positive globose neurofibrillary tangles in neurons and glia in the ventrolateral SN, LC, colliculi, midbrain and pontine tegmentum, periaqueductal gray matter, red nucleus, oculomotor complex, trochlear nucleus, basis pontis, and inferior olivary nucleus Bulbar type: progressive bulbar palsy Pontine and medulla motor neurons show changes identical to those of spinal anterior horn cell Inclusions are TDP-43, ubiquitin, p62 immunopositive Expansion of CAG repeat in the androgen receptor gene on the X chromosome Degeneration of facial nerve (CN VII), hypoglossal (CN XII) nuclei Cranial nerves III, IV, VI spared Neurogenic tongue atrophy Ubiquitin positive neuronal and nonneural tissue inclusions SMA1 (Werdnig-Hoffmann disease) Hypoglossal nerve (CN XII) and other pons and medulla motor neuron loss Type I (Brown-Vialetto-van Laere syndrome) Recessive Abrupt onset 1–30 years, bilateral deafness then lower cranial neuropathies Type II (Fazio-Londe disease). 3 subtypes: Dominant, onset 4–20 years, dysphagia/dysarthria, progressive and fatal Recessive, onset 5 years, dysphagia/dysarthria, facial weakness, longer survival Types I and II: degeneration of motor cranial nuclei

Ellison and Love 2013111 Ellison and Love 2013111

Ellison and Love 2013111 Ellison and Love 2013111

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Section III Examination, Imaging, and Monitoring for Brainstem Surgery

5 Imaging Anatomy and Pathology of the Brainstem, Thalamus, and Pineal Region

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5

Imaging Anatomy and Pathology of the Brainstem, Thalamus, and Pineal Region Jeremy N. Hughes and John P. Karis

Abstract

This chapter introduces the reader to the common imaging modalities used to investigate the brainstem, thalamus, and pineal region. It also presents an overview of the pertinent imaging anatomy of these regions. Here, we provide a framework for the unique imaging anatomy of these regions that will allow accurate interpretation of imaging studies in patients with brainstem pathology. This anatomy includes that which can be directly viewed using clinical magnetic resonance imaging (MRI) and that which can be inferred by reproducible anatomical landmarks. In addition, we describe the imaging features of the common pathology of the brainstem, thalamus, and pineal region. Keywords:  brainstem, brainstem pathology, computed tomography, imaging, magnetic resonance imaging, radiology

■■ Imaging Modalities Used to Investigate the Brainstem, Thalamus, and Pineal Region Magnetic Resonance Imaging Routine clinical magnetic resonance imaging (MRI) sequences used to evaluate the brainstem include T1-weighted (short TR, short TE), T2-weighted (long TR, long TE), fluid-attenuated inversion recovery (FLAIR), T2*-weighted (gradient-recalled echo [GRE]), and diffusion-weighted imaging. Three-dimensional (3D) T2-weighted turbo spin-echo (TSE) and steady-state free precession imaging are also commonly used in the assessment of the posterior fossa, including the brainstem. These techniques provide an excellent contrast of the cisternal segments of dark cranial nerves (CNs) as they course through bright cerebrospinal fluid  (CSF); however, they do not allow for the assessment of brainstem nuclei.1,​2 Steady-state free precession imaging is the preferred technique in patients without skull base region susceptibility-induced field distortions, and it is commonly referred to by trade names (i.e., CISS [constructive interference into steady state, Siemens] and FIESTA [fast imaging employing steady-state acquisition, General Electric]). Three-dimensional TSE imaging yields less sharply defined cisternal CNs, but it is less adversely affected by the susceptibility-induced field distortions of dental amalgam. Proton density sequences (long TR, short TE) have been shown to improve the visualization of some thalamic nuclei.3 Advanced MRI techniques include diffusion tensor imaging, associated 3D fiber tractography, and functional MRI. Diffusion tensor imaging provides the benefit of assessing ascending and descending projection fibers, as well as commissural and association fibers.4 In contrast, functional MRI is useful in localizing

nuclei of the brainstem on the basis of the performance of their respective tasks; however, in the brainstem, the technique is not routinely performed in clinical practice.5 Experimental high-fieldstrength (7T) imaging of magnetic susceptibility maps and quantitative maps of relaxation rates have shown improved visualization of brainstem nuclei.6

Computed Tomography Compared to MRI, computed tomography (CT) captures the exquisite anatomy of the brainstem, thalamus, and pineal region in broad strokes, given the relatively decreased contrast resolution of CT. In addition, CT assessment of the brainstem and posterior fossa is often made more difficult by beam-hardening artifact from the calvarium and osseous skull base. Nonetheless, CT remains the mainstay of first-line imaging in the emergency, inpatient, and outpatient settings. Despite these challenges, a great deal of information can be obtained by CT. The primary role of this modality in the clinical context of patients with brainstem lesion signs is the exclusion of hemorrhage, edema, mass lesion, and ischemia. CT cisternography may be used to assess the cisternal segments of CNs in patients who have a contraindication to MRI.

■■ Imaging Anatomy of the Brainstem, Thalamus, and Pineal Region The brainstem, thalamus, and pineal region can be embryologically subdivided into the myelencephalon, metencephalon, mesencephalon, and diencephalon.7 Nomenclature more practical to clinical imaging would be the anatomical divisions of the medulla, pons, midbrain, and separately, the thalamus and pineal regions. A detailed description of the anatomy of this region can be found in Chapter 2, Anatomy of the Brainstem, Thalamus, Pineal Region, and Cranial Nerves. Although MRI reveals this anatomy in exquisite detail, there are limitations to which structures can be discerned by imaging. In this chapter, the reader will be introduced to the imaging anatomy of these complex regions. Certainly, some anatomical structures can be visualized by routine clinical MRI sequences. For example, the red nucleus can be easily identified within the midbrain. In addition to the anatomy that can be directly visualized, there are reproducible anatomical landmarks which, when appropriately identified and understood, allow for an accurate estimation of the location of adjacent nuclei and white matter tracts. These landmarks are the external contours of the brainstem and the location of exiting CNs and their proximity and relationship to the anatomy that can be directly visualized by imaging. Knowledge of this anatomy is essential to interpreting images, to correctly localizing lesions, and to accounting for, or predicting, a patient’s clinical presentation.

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Key white matter tracts and the boundaries they demarcate provide a framework for the study of the imaging anatomy of the brainstem. The brainstem can be divided at all levels into anterior, middle, and posterior compartments. These compartments are the basis, the tegmentum, and the tectum, respectively. The basis largely consists of corticospinal and corticobulbar tracts. These tracts descend from the precentral gyrus, with corticobulbar fibers terminating at various levels throughout the brainstem. The corticospinal tracts continue to descend, and the majority of the fibers decussate at the level of the lower medulla within the pyramids. The middle compartment of the brainstem is referred to as the tegmentum, which contains white matter tracts and CN nuclei that will be detailed in this chapter. The posterior compartment of the brainstem is the tectum. At the level of the midbrain, the tectum comprises the superior and inferior colliculi. At the level of the pons, the tectum comprises the superior medullary velum, which forms the roof of the fourth ventricle, and the upper part of the inferior medullary velum. At the level of the medulla, the tectum consists of the inferior part of the inferior medullary velum. The tectum of the brainstem contains no ascending or descending tracts and no CN nuclei. The medial lemniscus is a white matter tract that can be viewed as an approximate boundary between the anterior compartment (the basis) and the middle compartment (the tegmentum) of the midbrain and pons. Importantly, the medial lemniscus is not observed in the same location at all levels of the brainstem. Rather, the course is oblique, as will be detailed. Functionally, the medial lemniscus is the second-order neuron system of the dorsal column pathway that transmits fibers from the nucleus gracilis and the nucleus cuneatus to the ventroposterolateral nucleus of the thalamus. These nuclei receive afferent fibers from the dorsal column system of the spinal cord, the fasciculus gracilis and the fasciculus cuneatus. This system relays information related to fine touch and proprioception from the upper and lower extremities, respectively. With this framework in mind, we will further explore the imaging anatomy of the brainstem from the top down, beginning with the midbrain.

Midbrain In the axial imaging plane, the midbrain is roughly heart-shaped. The CSF spaces that border the midbrain include the interpeduncular cistern anteriorly, the ambient cisterns anterolaterally, and the quadrigeminal plate cistern posteriorly (Fig. 5.1). These three cisterns can be collectively referred to as the perimesencephalic cisterns. The interpeduncular and ambient cisterns are subunits of the greater suprasellar cistern. An easily identifiable landmark within the midbrain is the cerebral aqueduct. The cerebral aqueduct courses through the midline posterior aspect of the midbrain and connects the third ventricle above and the fourth ventricle below. The cerebral aqueduct is surrounded by the periaqueductal gray matter, which can be seen on clinical MRI (Fig. 5.2). At the level of the midbrain, the medial lemniscus is situated approximately along the posterolateral margin of the substantia nigra. The anterior compartment of the brainstem contains the substantia nigra and the somatotopically organized corticospinal, corticobulbar, and corticocerebellar fibers.8 Immediately posterior lies the midbrain tegmentum, which extends to the cerebral aqueduct. Posterior to the cerebral aqueduct lies the tectal plate. The midbrain can be further

Fig. 5.1  Axial T2-weighted magnetic resonance image through the level of the suprasellar cistern demonstrates the perimesencephalic cisterns: the interpeduncular cistern, the ambient cisterns, and the quadrigeminal plate cistern.

divided into superior and inferior segments at the level of the superior and inferior colliculi, respectively.

Level of the Superior Colliculi Anteriorly and superiorly, the midbrain is contiguous with the cerebral peduncles. The red nuclei lie at the level of the superior colliculi and are clearly seen on clinical MRI (Fig. 5.2). The paired red nuclei are located anteriorly and near the midline within the tegmentum. The substantia nigra lies between the red nuclei and the cerebral peduncles and is divided into the pars reticulata and the pars compacta. These subcomponents can only be roughly delineated by clinical MRI. The ventral tegmental area is associated with the substantia nigra and is part of the dopaminergic system. The ventral tegmental area is bounded posteriorly by the red nucleus, anterolaterally by the substantia nigra, and anteromedially by the interpeduncular cistern. It extends approximately 4 mm laterally from the midline.9 High-field-strength  (7T) MRI can separately identify the pars compacta and the pars reticulata of the substantia nigra, as well as the ventral tegmental area and the vascularized and non-vascularized components of the red nucleus10; however, this level of detailed anatomy cannot be detected by current clinical magnets. The oculomotor nuclear complex (ONC) is composed of somatic and visceral nuclei. The somatic nuclei control several extraocular muscles: the superior, inferior, and medial recti; the inferior oblique muscles; and the levator palpebrae.8,​11 The Edinger-Westphal nucleus lies posteromedial. The EdingerWestphal nucleus provides parasympathetic preganglionic motor input to the ciliary ganglion to control pupillary constriction and accommodation. The ONC is situated between the periaqueductal gray matter and the red nuclei within the paramedian midbrain, at the level of the superior colliculi.8 The fasciculi of the oculomotor nerve (CN III) exit the ONC and course ventrally, traversing the medial aspect of the red nuclei to exit the brainstem at the level of the lateral wall of the interpeduncular fossa (Fig. 5.2). The ONC and the fasciculi of the oculomotor nerve cannot be directly visualized on clinical imaging; however, they can be inferred by the location of the

5  Imaging Anatomy and Pathology of the Brainstem, Thalamus, and Pineal Region

Fig. 5.2  Axial short tau inversion recovery magnetic resonance image of the midbrain at the level of the superior colliculus. The paired red nuclei are clearly visible as rounded foci of hypointense signal within the central midbrain tegmentum. The oculomotor nuclei lie at the midline between the periaqueductal gray (white arrow) and the red nuclei. The fasciculi of the oculomotor nerve (cranial nerve [CN] III) course anteriorly to exit the brainstem along the lateral walls of the interpeduncular cistern (curved dashed line).

periaqueductal gray matter, the red nuclei, and the cisternal course of the oculomotor nerve.

Level of the Inferior Colliculi At the level of the inferior colliculi, the decussation of the superior cerebellar peduncles occupies the central midbrain anterior to the periaqueductal gray matter4 (Fig. 5.3) directly inferior to the red nuclei. The trochlear nuclei are located near the midline, inferior to the level of the ONC. That is, they are located posterior to the decussation of the superior cerebellar peduncles and anterior to the cerebral aqueduct and the periaqueductal gray at the level of the inferior colliculi. From the trochlear nuclei, the trochlear nerve (CN IV) wraps around the periaqueductal gray matter to decussate within the superior medullary velum and exit the brainstem posteriorly (Fig. 5.3). The trochlear nerve is unique in that it exits the brainstem posteriorly. The trochlear nerve is also the CN with the longest cisternal course.

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Fig. 5.3  Axial short tau inversion recovery magnetic resonance image of the midbrain at the level of the inferior colliculus. The basis of the midbrain contains the corticospinal and corticobulbar fibers. The periaqueductal gray is evident as hyperintense signal surrounding the cerebral aqueduct. The trochlear nuclei lie just ventral to the periaqueductal gray at the midline. Just anterior to this lies the decussation of the superior cerebellar peduncles (curved hatch lines) The fasciculus (curved dashed line) of the trochlear nerve (cranial nerve [CN] IV) courses posteriorly and decussates within the superior medullary velum to exit the brainstem posteriorly.

Within the pons, the approximate location of the medial l­emniscus may be inferred as a region of subtle change in signal intensity on 3D TSE imaging (Fig. 5.4). The pontine tegmentum contains the nuclei of the trigeminal nerve, the abducens nerve (CN VI), the facial nerve (CN VII), and the vestibulocochlear nerve (CN VIII). These nuclei cannot be directly visualized by clinical imaging. The pontine tegmentum is much smaller than the pontine basis, and it is directly contiguous with the midbrain above and the medulla below. Posteriorly and superiorly within the pons, the cerebral aqueduct transitions into the fourth ventricle. The roof of the fourth ­ventricle consists of the superior medullary velum, a structure easily seen in the sagittal plane (Fig. 5.5). Anatomical landmarks within the pons, which can be identified on clinical MRI and therefore serve as useful sections for further study, include the root entry zone of the trigeminal nerves and the facial colliculus.

Pons

Level of the Root Entry Zone of the Trigeminal Nerve

The transition from the midbrain to the pons is demarcated by the pontomesencephalic sulcus. The bulbous basilar pons constitutes the majority of the pons and primarily houses corticospinal, corticobulbar, and corticopontine tracts; pontine nuclei; and transverse pontine fibers. The transverse pontine fibers can be divided into superficial and deep, as well as superior and inferior fibers. The superficial and deep transverse pontine fibers are demarcated by their position relative to the corticospinal tracts.12 The superior and inferior transverse pontine fibers are separated by their orientation relative to the root entry zone of the trigeminal nerve (CN V), a landmark easily identified on clinical MRI. These transverse pontine fibers course posteriorly and laterally to form the middle cerebellar peduncles.

The root entry zone of the trigeminal nerve is easily identified on MRI at the lateral margin of the pons, where the nerve courses anteriorly along the cisternal segment toward the gasserian ganglion within Meckel’s cave (Fig. 5.4). The trigeminal nerve has both motor and sensory components. The smaller motor fibers of the cisternal segment of the trigeminal nerve and the larger sensory fibers are not distinguishable by imaging. The four nuclei of the trigeminal nerve consist of a single motor nucleus, which is the main motor nucleus of the trigeminal nerve, and three sensory nuclei: the primary sensory nucleus, the mesencephalic nucleus, and the trigeminal spinal nucleus. These nuclei are not located at a single level within the brainstem but rather course variably in the craniocaudal direction. The sensory nuclei are roughly organized in a craniocaudal

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Fig. 5.4 Axial short tau inversion recovery magnetic resonance images of the pons (a) above, (b) at, and (c) below the level of the root entry zone of the trigeminal nerve (cranial nerve [CN] V). (a) The large basilar pons contains corticospinal and corticobulbar tracts and transverse pontine fibers. The approximate The transition from the basilar pons to the pontine tegmentum can be inferred by a subtle change in signal intensity (curved line). The superior cerebellar peduncles (white arrow). are visible posteriorly. (b) At the level of the root entry zone of CN V, the complex of the motor nucleus and the primary sensory nucleus of CN V (circle) lies within the lateral pontine tegmentum, which is just anterolateral to the superior cerebellar

peduncles (black arrow). (c) Below the level of the root entry zone, the facial colliculus (black arrow) can be appreciated as a contour along the posterior aspect of the tegmentum. Deep to the facial colliculus are the abducens nucleus and the fasciculus of the facial nerve (CN VII), which is referred to as the internal genu of CN VII (white dots). The shepherd's crook–shaped line is the path of the CN VII-VIII nerve fibers. The fasciculi of the abducens nerve arc anteriorly and laterally to exit the ventral pons. The medial fasciculus (dashed line) lies medial to the abducens nuclei. CN VII and the vestibulocochlear nerve (CN VIII) (white arrow) follow a cisternal course toward the internal auditory canal. Abbreviations: Sup. cerebellar ped., superior cerebellar peduncle.

The mesencephalic nucleus is located slightly posterior and medial to the complex of the main motor nucleus and the primary sensory nucleus of the trigeminal nerve at the level of the root entry zone (Fig. 5.4). The mesencephalic nucleus and tract extend superiorly to the midbrain. As the tract ascends, it assumes a position just along the lateral margin of the central aspect of the periaqueductal gray. The spinal trigeminal nucleus and tract originate just inferior to the complex of the main motor nucleus and the primary sensory nucleus, approximately at the level of an axial slice just inferior to the root entry zone (Fig. 5.4). As they descend, the spinal trigeminal nucleus and tract course lateral to the facial nerve. These fibers continue to the level of the upper cervical spine.

Level of the Facial Colliculus

Fig. 5.5 Sagittal T2-weighted magnetic resonance image through the brainstem. The tectum at the level of the midbrain is the tectal plate formed by the superior and inferior colliculi. The tectum at the level of the pons is the superior medullary velum and the superior aspect of the inferior medullary velum. The entire inferior medullary velum is not visible on this image.

fashion such that the main sensory nucleus is the most centrally located, with the mesencephalic nucleus above and the trigeminal spinal nucleus below. At approximately the level of the root entry zone, the complex of the main motor nucleus and the primary sensory nucleus of the trigeminal nerve is situated at the lateral aspect of the pontine tegmentum, just anterior to the superior cerebellar peduncle (Fig. 5.4). The motor nucleus is located medially and the sensory nucleus laterally. From this complex, the sensory and motor fibers of the trigeminal nerve course anterolaterally through the posterior aspect of the basilar pons to exit the brainstem at the root entry zone.

The facial colliculus appears as a bump along the floor of the fourth ventricle (Fig. 5.4). Deep to the facial colliculus lie the abducens nuclei and fibers of the facial nerve. These structures cannot be directly visualized by clinical MRI; however, direct visualization of the facial colliculus bump and an understanding of the course of the facial nerves allow for an accurate estimation of the location of the facial and abducens nuclei and their central fasciculi. As part of this discussion, it is important to introduce the medial longitudinal ­fasciculus (MLF) and its relationship to a ­ djacent anatomy. The MLF is a network of heavily myelinated fibers responsible for the coordination of horizontal eye movements connecting the nuclei of the oculomotor nerve, the trochlear nerve, the abducens nerve, and the vestibulocochlear nerve, among others.13,​14 The MLF consists of paramedian tegmental tracts that run from the midbrain inferiorly to the level of the upper cervical spine.14 A lesion of the MLF results in internuclear ophthalmoplegia, which clinically presents as impaired adduction of the ipsilateral eye and normal abduction of the contralateral eye with gaze away from the lesion. The MLF, which is approximately 1 mm wide, occupies the paramedian pontine tegmentum at the level of the facial colliculus (Fig. 5.4).12 Just lateral to the MLF, at the level of the facial ­colliculus, lie the abducens nuclei. The abducens fasciculi arise

5  Imaging Anatomy and Pathology of the Brainstem, Thalamus, and Pineal Region from the anterior margin of their corresponding nuclei and course anterolaterally to the corticospinal tracts within the basilar pons to exit the brainstem anteriorly. The facial nerve nuclei are situated anterior and lateral to the abducens nuclei, roughly bounded by the medial lemniscus anteriorly and the inferior cerebellar peduncle posterolaterally (Fig. 5.4). They are situated approximately 5.5 mm from the roof of the fourth ventricle in an anterolateral direction.12 The facial nerve fasciculi originate at the posterior aspect of their nuclei and course posteriorly and medially. The facial nerve courses between the abducens nuclei and the MLF to wrap around the abducens nuclei and then courses anterolaterally to exit the brainstem at the pontocerebellar junction. Both the vestibular and cochlear nerves have bipolar neurons. The fibers of the superior and inferior vestibular nerves converge near the level of the porus acusticus of the internal auditory canal to form the vestibular nerve. Just medial to this point, the vestibular nerve merges with fibers from the cochlear nerve. At this point, the nerve is referred to as the vestibulocochlear nerve, and from there it enters the brainstem at the lateral pontomedullary junction. This entrance into the brainstem can be seen on high-resolution MRI (Fig. 5.4). The cochlear nerve has two nuclei: the ventral and dorsal cochlear nuclei. These nuclei are situated laterally within the brainstem and extend in the craniocaudal direction through the medulla and lower pons. Within the medulla, these nuclei lie lateral to the restiform body, which is a component of the inferior cerebellar peduncle. The vestibular nerve has four nuclei: the superior, inferior, medial, and lateral nuclei. These nuclei form a complex that is located at the level of the lower aspect of the pons, roughly along the lateral aspect of the fourth ventricle.

Medulla The medulla is the inferior extent of the brainstem and is contiguous with the upper cervical spinal cord. The nuclei of the glossopharyngeal nerve (CN IX), vagus nerve (CN X), spinal accessory nerve (CN XI), and hypoglossal nerve (CN XII) are located within the medulla. As mentioned previously, the dorsal column tracts of the spinal cord extend superiorly to their corresponding nuclei gracilis and cuneatus at the level of the medulla. The nucleus gracilis and its associated tract are located at the paramedian posterior-most aspect of the lower medulla. The nucleus cuneatus and its associated tract are located just lateral to the nucleus gracilis. From these nuclei, fibers of the medial lemniscus first decussate at the mid-medulla and then ascend superiorly to the thalamus. The decussation of the corticospinal tracts also occurs at the level of the medulla within the pyramids, which are located anteriorly. The pyramids form characteristic contours of the anterior medulla, which can be identified by clinical imaging  (Fig. 5.6). The midline ventral sulcus of the medulla separates the pyramids. Lateral to the pyramids, an additional highly reproducible contour can be identified: the olives. Deep to the olives lie the inferior olivary nuclei. The preolivary sulcus lies between the pyramids and the olives, and the postolivary sulcus lies farther posterolateral to the olives (Fig. 5.6). The anterolateral system, including the spinothalamic tract, lies deep to the postolivary sulcus. The nucleus ambiguous is the shared nucleus of the bulbar motor nerve fibers of the glossopharyngeal nerve, the vagus

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Fig. 5.6  Axial short tau inversion recovery magnetic resonance image at the level of the medulla. The median sulcus of the medulla appears as a cleft along the midline anteriorly. Just lateral is the pyramid. Posterior and lateral to the pyramid is the olive. The preolivary sulcus lies between the pyramid and the olive, and the postolivary sulcus lies posterior to the olive. The hypoglossal nerve (cranial nerve [CN] XII) exits the brainstem at the preolivary sulcus (curved dashed line), and the glossopharyngeal nerve (CN IX), vagus nerve (CN X), and spinal accessory nerve (CN XI) exit at the postolivary sulcus. The hypoglossal eminence appears as a contour along the posterior aspect of the medullary tegmentum. The hypoglossal nucleus (asterisk) lies deep to this eminence.

nerve, and the spinal accessory nerve. This nucleus lies in the mid-medullary tegmentum, just medial to the descending spinal trigeminal nucleus and tract, and its location can only be roughly estimated with imaging. The glossopharyngeal nerve has additional sensory and parasympathetic fibers, which terminate in the solitary tract nucleus, the spinal trigeminal nucleus, and the inferior salivatory nucleus. In addition, the vagus nerve has sensory and parasympathetic fibers that project to the dorsal vagal nucleus and the solitary tract nucleus. The spinal accessory nerve has an additional nucleus located within the upper spinal cord, the spinal nucleus of the spinal accessory nerve. These nuclei cannot be seen on clinical MRI. The glossopharyngeal, vagus, and spinal accessory nerves collectively exit the brainstem at the postolivary sulcus. The hypoglossal nucleus sits at the paramedian posterior aspect of the medulla and forms a subtle contour into the floor of the fourth ventricle, the hypoglossal eminence (hypoglossal trigone) (Fig. 5.6). The hypoglossal eminence lies superior to the nucleus gracilis and its tract. The central course of the hypoglossal nerve arcs from its nucleus anterolateral to the root exit zone at the preolivary sulcus (Fig. 5.6). The hypoglossal nerve at this level consists of multiple nerve fibers that span approximately 12.5 mm in the craniocaudal direction.15 These nerve rootlets converge to form the cisternal segment of the hypoglossal nerve and eventually pierce the dura at the hypoglossal canal.

Thalamus The thalamus is the principal site for the relay of sensory input. The dorsal thalamus (commonly referred to as just the thalamus) is part of the diencephalon, along with the subthalamus, which includes the subthalamic nucleus; the epithalamus, which

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Fig. 5.7 Axial short tau inversion recovery magnetic resonance image through the thalamus. The thalamus is bounded anterolaterally by the posterior limb of the internal capsule and medially, continuing posteriorly, by the third and lateral ventricles. The thalamus has a homogeneous signal intensity that does not allow for the distinction of the many nuclei located therein.

includes the pineal gland and habenular nuclei; and the hypothalamus. Neuroanatomy atlases reveal a rich network of nuclei and tracts throughout the thalami that are not discernible by routine clinical imaging. However, experimental high-field-strength 7T imaging has been shown to be able to identify many subcomponents of the thalami.16 The thalamus is bound anterolaterally by the posterior limb of the internal capsule and medially, continuing posteromedially, by the third and lateral ventricles (Fig. 5.7). From a clinical imaging perspective, the thalamus is homogeneous in signal intensity, which does not allow for discrimination of specific thalamic nuclei. Pathology in the dorsomedial thalamus, the pulvinar, can be identified in various disease states and is a classic description of variant Creutzfeldt-Jakob disease. In the sagittal plane, the connection between the two thalami is referred to as the massa intermedia.

Pineal Region The pineal gland is responsible for the rhythmic nighttime production and secretion of melatonin and functions to regulate circadian rhythm and the sleep-wake cycle.17 The pineal gland is an ellipsoid pinecone-shaped structure, measuring approximately 79±30.2 mm3, that is located centrally deep within the brain.18 Complex pineal region anatomy can be imaged with routine clinical MRI. The sagittal plane offers the best appreciation of this anatomy. The imaging boundaries of the pineal region are as follows: superiorly—the splenium of the corpus callosum; inferiorly—the tectal plate of the midbrain; anteriorly—the third ventricle and its posterior recesses; posteriorly—the posterior aspect of the quadrigeminal plate cistern; and laterally—the pulvinar of the thalamus (Fig. 5.8). The pineal gland lies centrally within this region and is oriented with its base anterior and superior, and its apex posterior and inferior (Fig. 5.8). The pineal gland is suspended within the quadrigeminal plate cistern. The base of the pineal gland is

Fig. 5.8 Sagittal paramedian T2-weighted magnetic resonance image through the pineal gland. The superior border of the pineal region is the splenium of the corpus callosum. The fornices lie inferior to the corpus callosum. Below the fornices, the internal cerebral vein (v.) courses within the velum interpositum. The pineal gland lies inferior to the internal cerebral vein with its base oriented anterior and superior, and its apex oriented posterior and inferior. Superior and inferior lamina attach to the pineal gland at its base. The habenular commissure (black arrow) courses within the superior lamina, and the posterior commissure (white arrow) courses within the inferior lamina. The apex of the superior and inferior lamina forms the pineal recess of the third ventricle. The suprapineal recess of the third ventricle lies above the pineal recess. The pineal gland is suspended within the quadrigeminal plate cistern.

attached to superior and inferior laminae (Fig. 5.8). The fibers of the habenular commissure course within the superior aspect of the superior lamina and communicate laterally with the habenular nuclei. The fibers of the posterior commissure course within the inferior lamina and communicate laterally with the thalamus. The apex of the superior and inferior lamina, at the level of the base of the pineal gland, forms the pineal recess of the third ventricle (Fig. 5.8). The inferior lamina continues inferiorly to merge with the tectal plate. Superior to the habenular commissure is another posterior third ventricular recess, the suprapineal recess (Fig. 5.8). As noted previously, the splenium of the corpus callosum forms the superior border of the pineal region (Fig. 5.8). The fornices course along the inferior aspect of the corpus callosum. The velum interpositum is situated beneath the fornices, and the internal cerebral veins (ICVs) are enclosed within the velum interpositum. The velum interpositum and ICVs lie superior to the pineal gland as well as the third ventricle. This relationship provides a useful frame of reference to localize a mass within or outside the pineal gland. That is, in the presence of a large pineal region mass, if the ICVs are displaced superiorly, the mass may arise from the pineal gland or other cells of origin inferior to the ICVs. If the ICVs are displaced inferiorly, the mass is not pineal parenchymal in origin. Anterior to the pineal gland, the third ventricle lies inferior to the velum interpositum. The choroid plexus wraps along the roof of the third ventricle and forms an imaging demarcation between the third ventricle below and the velum interpositum above.

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Table 5.1  Lesions of the brainstem, thalamus, and pineal region

Lesion and location Type Neoplasm Brainstem

Diffuse infiltrative brainstem glioma Focal brainstem glioma Metastases Lymphoma

Thalamus

Glioma Lymphoma

Pineal region

Pineal parenchymal tumors Germ cell tumors Other

Infection

Abscess Encephalitis or rhombencephalitis

Fig. 5.9  Posterior circulation magnetic resonance angiography maximum intensity projection demonstrates the major branches of the vertebrobasilar system: vertebral artery (VA), basilar artery (BA), posterior inferior cerebellar artery (PICA), anterior inferior cerebellar artery (AICA), pontine perforators, superior cerebellar artery (SCA), and posterior cerebral artery (PCA).

Cryptococcus Inflammatory

Multiple sclerosis Acute disseminated encephalomyelitis Progressive multifocal leukoencephalopathy Hepatic encephalopathy

Vascular Anatomy Arterial supply to the brainstem, thalamus, and pineal gland is chiefly through the vertebrobasilar circulation. Large dominant branches of the vertebrobasilar system include the posterior inferior cerebellar arteries, the anterior inferior cerebellar arteries, the superior cerebellar arteries, and the posterior cerebral arteries. In addition to these large vessels, there are smaller perforating vessels of the vertebrobasilar circulation that supply the brainstem, thalamus, and pineal gland. As a general rule, more peripheral regions of the brainstem are supplied by the larger dominant branches, whereas paramedian regions are supplied by the smaller perforating branches. Magnetic resonance angiography (MRA) and CT angiography (CTA) are noninvasive imaging studies that allow for an excellent assessment of the large posterior circulation. The vertebrobasilar system and its dominant feeding vessels are well depicted by MRA (Fig. 5.9), although the smaller perforating vessels cannot be seen on imaging.

Vasculitis Vascular

Lesions of the brainstem, thalamus, and pineal region, like pathology elsewhere within the central nervous system, are of varied etiology. Table 5.1 is a non-exhaustive list of the more common lesions.

Tumors Brainstem Glioma The term brainstem glioma includes two groups of tumors with marked differences in terms of imaging appearance, prognosis, and clinical presentation. Brainstem gliomas are classified by the World Health Organization (WHO) as grades II–IV tumors. ­Diffuse infiltrative brainstem gliomas are the higher-grade variant. These

Arteriovenous malformation Cavernous malformation Capillary telangiectasia Developmental venous anomaly Ischemia Chronic microvascular ischemic disease

Neurodegenerative

Multisystem atrophy Pontocerebellar olivary degeneration Supranuclear palsy Amyotrophic lateral sclerosis

Congenital

Dermoid Epidermoid

Normal variant

Dilated perivascular spaces

Traumatic

Shear injury Parenchymal hemorrhage

Reactive

■■ Imaging Pathology of the Brainstem, Thalamus, and Pineal Region

Osmotic demyelination

Hypertrophic olivary degeneration Wallerian degeneration

­ ggressive tumors have an extremely poor prognosis and are coma monly centered within the pons. Focal brainstem gliomas are lower-grade tumors, typically of the pilocytic variety, that usually occur within the medulla and midbrain. Brainstem gliomas are tumors commonly found in the pediatric population and represent 10 to 20% of central nervous system (CNS) tumors in children. Unfortunately, 80% of brainstem gliomas are of the diffuse infiltrative variety, and the remainder are focal lower-grade gliomas.19 These two types of tumors share a variable hyperintense signal on T2-weighted imaging. As the names imply, the diffuse infiltrative tumors tend to demonstrate more ill-defined margins, whereas focal brainstem gliomas are more typically well demarcated. In contradistinction to many other CNS

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Fig. 5.10  Diffuse infiltrative brainstem glioma. (a) Axial fluid-attenuated inversion recovery magnetic resonance image (MRI), (b) T2-weighted MRI, and (c) contrast-enhanced T1-weighted MRI at the level of the pons demonstrate

an expansile non-enhancing mass. Note vascular encasement (b, arrow) and absence of enhancement in this high-grade tumor.

Fig. 5.11 Tectal plate glioma. (a) Axial fluid-attenuated inversion recovery magnetic resonance image (MRI), (b) sagittal T2-weighted MRI, and (c) sagittal contrast-enhanced T1-weighted MRI demonstrate

a well-circumscribed non-enhancing focal mass (a, arrow) of the tectal plate. Note the mass effect on the cerebral aqueduct and associated hydrocephalus.

­ eoplastic processes, the higher-grade infiltrative tumors tend n to demonstrate minimal to no enhancement on administration of gadolinium (Fig. 5.10). Focal gliomas demonstrate variable enhancement, and tumors of the pilocytic variety, although low grade, may show pronounced enhancement. The diffuse infiltrative tumors may demonstrate exophytic tumor growth into surrounding cisterns and encasement of adjacent vasculature. Tectal plate glioma is an anatomically specific focal brainstem glioma that occurs within the tectum of the midbrain (Fig. 5.11). The unique anatomy of this region, in close proximity to the cerebral aqueduct, often results in obstruction of the aqueduct with resultant third and lateral ventricular hydrocephalus.

features that aid in the diagnosis of tumors in this region include the sex and age of the patient and associated laboratory findings, including serum and CSF oncoproteins. Here, we describe the imaging appearance of the most frequently encountered pineal parenchymal tumors and GCTs. The “other” category includes lesions discussed elsewhere in this chapter (e.g., tectal plate gliomas, arteriovenous malformations [AVMs], and cavernous malformations [CMs]) and lesions beyond the scope of this chapter (e.g., meningiomas, dermoid cysts, and epidermoid tumors). Pineal region lesions, regardless of cell of origin, may have a similar clinical presentation. Given their proximity to the cerebral aqueduct, these lesions may result in an obstructive hydrocephalus of the third and lateral ventricles. Lesions in this region may present with Parinaud’s syndrome, with the patient having multiple deficits, including paralysis of upward gaze.

Pineal Region Tumors Tumors of the pineal region can be divided into three categories: tumors of pineal parenchymal origin, germ cell tumors (GCTs), and a broad grouping of “other” tumors and non-neoplastic lesions whose cell of origin is of adjacent extrapineal anatomy. The imaging appearance of pineal region tumors demonstrates tremendous overlap, and rarely can a specific ­diagnosis be confidently made with the use of imaging alone. Key clinical

Germ Cell Tumors GCTs can be divided into germinomatous (germinoma) and non-germinomatous GCTs (yolk-sac tumors, choriocarcinomas, teratomas, embryonal cell carcinomas, and mixed GCTs). ­Statistically, GCTs are the most common tumors of the pineal region, accounting for 35% of pineal region tumors.20

5  Imaging Anatomy and Pathology of the Brainstem, Thalamus, and Pineal Region Histologically, germinomas are highly cellular tumors with sheets of primitive germ cells intermixed on a background of lymphocytes. Pure germinomas are WHO grade II lesions. In total, 65% of germinomas occur in the pineal region, whereas 25 to 35% occur in the suprasellar region, and the remainder occur in the basal ganglia and thalami.21 GCTs in the pineal region have a strong male predilection with a 10:1 male-to-female ratio. This preponderance in males is in contrast to that for suprasellar GCTs, which have no sex predilection.21 Germinomas are primarily tumors of children and adolescents.22 The imaging appearance of germinomas is that of an enhancing hypointense-to-intermediate signal intensity mass on T1-weighted imaging with a variable degree of hyperintense signal on T2-weighted imaging. Because of their increased cellularity, germinomas may demonstrate increased attenuation on CT and restricted diffusion on MRI sequences  (Fig. 5.12). The degree of enhancement can be quite striking and homogeneous. Germinomas have the potential to seed the CSF; therefore, if a germinoma is included as a differential consideration, the entire neural axis should be imaged to assess for distant CSF dissemination of the tumor. Susceptibility on GRE (T2*) is not an uncommon finding, and it typically reflects calcification, as hemorrhage in germinomas is rare. Although a pattern of calcification is frequently described, it has not been found to be a reliable discriminating factor for distinguishing germinomas from other tumors. The classically described calcification pattern

Fig. 5.12 Germinoma. (a) Sagittal post-contrast T1-weighted magnetic resonance image (MRI), (b) axial diffusion-weighted image, and (c) axial apparent diffusion coefficient map demonstrate a heterogeneously enhancing pineal region mass (a, black arrow). Diffusion restriction reflects the increased cellularity of the mass. Note the suprasellar enhancing mass (a, white arrow) reflecting the associated suprasellar germinoma. In an adolescent male, the presence of suprasellar enhancement in the setting of a diffusion-restricting pineal region mass strongly suggests germinoma.

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is that of germinomas engulfing pineal calcium and pineoblastomas peripherally displacing calcium. Pineal region non-germinomatous GCTs include those GCTs observed elsewhere throughout the body (yolk sac tumors, embryonal cell carcinomas, teratomas, choriocarcinomas, and mixed GCTs). These tumors are hormonally active, and an analysis of serum and CSF for circulating oncoproteins, including alpha-fetoprotein, beta-hCG (human chorionic gonadotropin), and placental alkaline phosphatase, assists in preoperative assessment.21 As observed with other teratomas, pineal region teratomas demonstrate imaging features reflective of the three germ cell layers (mesoderm, endoderm, and ectoderm) of which they are composed, including soft tissue, fatty components, calcification, and teeth. The other non-germinomatous GCTs have no classic imaging features, and their diagnosis relies upon clinical features, laboratory analysis, and tissue sampling.

Pineal Parenchymal Tumors Pineal parenchymal tumors include pineocytoma (WHO grade I), pineal tumor of intermediate differentiation (WHO grade II or III), primary papillary tumor of the pineal gland (WHO grade II or III), and pineoblastoma (WHO grade IV).23 These tumors are intentionally grouped together in this text rather than being described separately, as there are no distinguishing imaging features among them (Fig. 5.13). However, there are some imaging findings that can be suggestive and may aid in diagnosis. In addition, specific clinical features are important to consider when evaluating pineal region tumors. Pineal parenchymal tumors are typically hypointense on T1-weighted imaging; however, they can be of variable signal intensity on T1-weighted imaging. Of note, intrinsic T1 shortening has been described as a feature of the primary papillary tumor of the pineal gland, although it is not specific (Fig. 5.14).24 Enhancement is variable, ranging from mild patchy enhancement to uniform avid enhancement. These tumors are typically hyperintense on T2-weighted imaging. Areas of internal cystic change may be seen within any of these tumors; however, it is important to note that such change may also be found in a normal pineal gland. An enhancement pattern can suggest a specific tumor, although it is not diagnostic. Pineocytomas may show smooth rim enhancement with an enhancing nodule, or they may be identified as an enhancing mass without direct extension into adjacent structures. The presence of slightly nodular or thickened rim enhancement surrounding a cystic region within the pineal gland helps to distinguish a subtle pineocytoma from the more common pineal cyst. Higher-grade pineal parenchymal tumors tend toward more aggressive behaviors and enhancement patterns, and they may demonstrate invasion of adjacent structures. Fig. 5.13  Pineal parenchymal tumors. (a–c) Sagittal post-contrast T1-weighted magnetic resonance images demonstrate the significant overlap of imaging features of the pineal parenchymal tumors. In all cases, there is a variable degree of enhancing tumor and cystic change. Imaging features alone do not allow for differentiation of these tumors. (a) Pineoblastoma, (b) pineocytoma, and (c) primary papillary tumor of the pineal gland.

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Fig. 5.14  Primary papillary tumor of the pineal gland (PPTP). (a) Sagittal pre-contrast T1-weighted magnetic resonance image (MRI) and (b) sagittal post-contrast T1-weighted MRI demonstrate an enhancing pineal region mass. Note the background of intrinsic hyperintense signal on T1-weighted imaging (a, arrow) within the mass on pre-contrast imaging. Although not specific, this hyperintensity has been described as a feature of PPTP.

In addition, within the setting of a pineal region tumor, the presence of CSF dissemination of the tumor suggests a highergrade lesion, such as a pineoblastoma.

Vascular Malformations Cavernous Malformation CMs, also referred to as venous angiomas, cavernomas, cavernous hemangiomas, and angiographically occult vascular malformations, are vascular lesions composed of sinusoids of abnormal blood vessels containing blood products of variable age without a background of normal brain parenchyma. CMs are the second most common CNS vascular abnormality and account for 10 to 15% of vascular lesions in the CNS.25 CMs may occur sporadically and are typically isolated in this clinical scenario.26 Multiple CMs may be found in two populations. The first is a hereditary occurrence in patients with cerebral CM 1, 2, or 3 (CCM1, CCM2, or CCM3) genetic mutations.26,​27 Alternatively, multiple CMs may be radiation induced.27 CMs range in size from tiny lesions, which are visible only on GRE (T2*) imaging, to giant lesions measuring more than 6 cm.28 In one series, the average size of a CM of the brainstem was 19 mm.29 The MRI appearance of these lesions varies on the basis of the age of internal blood products. Zabramski et al26 have classified CMs into types I to IV (Table 5.2).

Fig. 5.15  Cavernous malformation. Axial pre-contrast T1-weighted magnetic resonance image demonstrates a left posterior temporal intra-axial mass with central intrinsic T1 shortening and a hematocrit fluid level. Note perilesional hyperintense edema (arrow) on T1-weighted imaging, a feature that has been described in cavernous malformations and metastatic disease.

Non-hemorrhagic CMs are not associated with surrounding edema. Therefore, the presence of hyperintense edema surrounding a CM on T2-weighted and FLAIR sequences suggests a recent hemorrhage. Although not specific, perilesional T1-weighted hyperintense edema has been described as an imaging feature of CMs (Fig. 5.15).30 Classically, CMs do not demonstrate contrast enhancement, which highlights the genesis of the older terminology, angiographically occult vascular malformations. However, in clinical practice, it is not atypical to see a variable degree of enhancement associated with CMs. This may be a reactive enhancement from a prior hemorrhage or it may be secondary to an adjacent developmental venous anomaly (DVA), as there is a well-documented association of CMs with DVAs.31,​32,​33

Table 5.2  Zabramski classification of cavernous malformations*

Variable

Type I

Type II

Type III

Type IV

Age and type of blood products

Subacute (methemoglobin) Chronic (peripheral hemosiderin)

Mixed ages (intracellular or extracellular methemoglobin, intracellular deoxyhemoglobin, hemosiderin)

Predominantly chronic (hemosiderin)

Chronic (hemosiderin)

Imaging appearance

Hyperintense on T1 Variable signal on T2 Peripheral hypointense rim on T2

Mixed signal on T1 or Predominantly isointense T2, layering hematocrit to hypointense on T1 levels, peripheral and T2 hypointense rim on T2 Popcorn ball lesion

Abbreviations: GRE, gradient-recalled echo; T1, T1-weighted imaging; T2, T2-weighted imaging. *Reproduced with permission from Zabramski et al 1994.26

Microhemorrhages, only seen as punctate hypointense signal on GRE (T2*), black dots

5  Imaging Anatomy and Pathology of the Brainstem, Thalamus, and Pineal Region

Arteriovenous Malformation AVMs are vascular lesions characterized by an abnormal connection of an artery to a vein without an intervening ­capillary bed. The incidence of AVMs ranges from 1 to 1.3 per 100,000 per year, and the prevalence is estimated at 10 to 18 per 100,000 person-years.34,​35 The arteriovenous connection is a disorganized tangle of vessels forming a nidus. These lesions may be congenital or acquired. The majority of cerebral AVMs are of the subpial variety, whereas approximately 10 to 15% are dural AVMs found within the walls of dural venous sinuses.34 AVMs may be discovered on imaging as incidental non-hemorrhagic lesions, or they may be identified as the culprit lesion following presentation with hemorrhage. The most commonly used classification system for AVMs is the Spetzler-Martin grading system, which grades AVMs on a scale from I to V on the basis of size, venous drainage, and adjacency to eloquent brain (Table 5.3).36 In the symptomatic patient, initial evaluation with non-contrast head CT will often reveal nonspecific hemorrhage. This hemorrhage is most commonly intraparenchymal. Secondary intraventricular extension or a purely intraventricular hemorrhage may be encountered when lesions are located near the ependymal surface. Subarachnoid hemorrhage may be found, especially in the setting of a rupture of an associated intranidal aneurysm or a feeding pedicle artery aneurysm. The AVM nidus may or may not be seen on the non-contrast head CT. Even in quite large AVMs, these lesions can be occult on non-contrast imaging; however, they will become readily apparent on CTA (Fig. 5.16). Calcification may be observed within AVMs.

Table 5.3  Spetzler-Martin grading scale for AVMs*

Feature

Points assigned

Size 6 cm

3

Location Non-eloquent parenchyma

0

Eloquent parenchyma

1

Venous drainage Superficial only

0

Deep

1

*Reproduced with permission from Spetzler and Martin 1986.36

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Noninvasive angiographic imaging, including CTA or MRA, is indicated following the non-contrast head CT. These examinations allow for characterization of the feeding arterial system, characterization of the nidus, and classification of the venous drainage. AVM feeding arteries commonly emanate from the anterior or posterior intracranial arterial systems or from branches of the external carotid artery. Because of the high-flow state of these lesions, the feeding artery or arteries may be dilated compared to normal vessels. Aneurysms, including intranidal aneurysms and feeding pedicle artery aneurysms, can be found in association with AVMs. As size is a discriminating feature that influences treatment decisions, the nidus should be measured with care to exclude feeding arteries, draining veins, and adjacent recruited angiogenesis. These features often demonstrate enhancement that overlaps that of the true nidus. On routine MR evaluation of AVMs, lesions can be identified by heterogeneous signal intensity with multiple hypointense flow voids on T2-weighted imaging corresponding to enlarged feeding arteries, the nidus, and draining veins (Fig. 5.17). In recently hemorrhaged AVMs, surrounding hyperintense vasogenic edema on T2-weighted and FLAIR imaging with associated mass effect will be present. This hyperintensity with mass effect is distinct from hyperintense signal on T2-weighted and FLAIR imaging with associated volume loss or absence of mass effect, which suggests gliosis from a remote insult. Gliosis may relate to a prior hemorrhagic event or may indicate steal phenomenon, in which the high-flow state of these lesions “steals” blood supply from adjacent parenchyma, resulting in perilesional ischemia. Hypointense signal on GRE (T2*) sequences surrounding an AVM represents hemosiderin staining related to prior hemorrhage. This finding is important prognostic information confirming a prior hemorrhage, which increases the risk of future hemorrhage. Although enhanced and unenhanced CT and MR imaging are essential in the evaluation of AVMs, the diagnostic hallmark of these lesions is early venous drainage on catheter angiography (Fig. 5.18).

Capillary Telangiectasia Capillary telangiectasias are benign vascular lesions of the CNS that are composed of dilated capillaries superimposed on a background of normal brain parenchyma. Capillary telangiectasias can be observed anywhere in the brain, but they have a predilection for involvement of the brainstem, specifically the central pons. These lesions can range in size from very small to several centimeters. Imaging features of capillary telangiectasias include a paintbrush-like tuft of enhancement on postcontrast

Fig. 5.16 Arteriovenous malformation (AVM). (a) Axial non-contrast computed tomography (CT) and (b) CT angiography (CTA) images through the level of the middle cranial fossa. On pre-contrast imaging, only subtle heterogeneity of attenuation is visible within the right temporal lobe. On CTA examination, a large arteriovenous malformation becomes readily apparent. In the absence of hemorrhage or calcification, AVMs may be subtle on non-contrast CT images of the head.

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Fig. 5.18  Arteriovenous malformation. Lateral projection digital subtraction angiogram demonstrates a large early draining basal vein of Rosenthal (arrow). An early draining vein is the diagnostic hallmark of an arteriovenous malformation. Fig. 5.17 Arteriovenous malformation. Coronal T2-weighted magnetic resonance image demonstrates a large tangle of flow voids (white arrow), representing an arteriovenous malformation nidus in the upper midbrain with involvement of the bilateral thalami. Note the dominant left draining basal vein of Rosenthal (black arrow). The small amount of hyperintense signal on T2-weighted imaging surrounding the nidus represents perilesional edema or gliosis.

­imaging  (Fig. 5.19). There may or may not be an associated hyperintense signal on T2-weighted and FLAIR ­ imaging; h ­ owever, if there is a signal, it is not expansile or mass-like in quality. These lesions should be stable over time. Hypointense signal on GRE imaging is characteristic and represents increased local concentration of deoxyhemoglobin from stagnant venous flow within the venous side of the dilated capillaries. Occasionally, these lesions may present as incidentally identified enhancement with or without associated signal abnormality on T1-weighted and T2-weighted imaging and no corresponding hypointensity of GRE. The absence of suusceptibility on GRE can present a diagnostic dilemma, and these lesions may be confused for a process such as neoplasm or demyelination. Susceptibility-weighted imaging (SWI) improves sensitivity for detection of deoxyhemoglobin and has been shown to more consistently demonstrate hypointense signal in capillary telangiectasias than GRE (T2*). This information may be beneficial in limiting misdiagnosis.37

Developmental Venous Anomaly DVAs are structurally normal venous vessels with aberrant venous drainage. DVAs are common lesions with an incidence of 2.6% in large autopsy series.38 In normal venous drainage patterns, the inner one-half to one-third of the brain parenchyma drains to the deep cerebral venous system. The more peripheral brain parenchyma drains into the superficial venous system via cortical veins and then into the major dural venous sinuses. DVA venous drainage may cross these normal boundaries with drainage from deep parenchyma into the superficial venous system and vice versa. DVAs provide venous drainage for the local region in which they occur, and

Fig. 5.19  Capillary telangiectasia. (a) Axial pre-contrast T1-weighted magnetic resonance image (MRI), (b) axial post-contrast T1-weighted MRI, (c) axial T2-weighted MRI, and (d) coronal gradient-recalled echo (GRE) MRI demonstrate a paintbrush-like tuft of enhancement of the left anterior pons (b, white arrow). Note the absence of any mass effect. There is no associated signal abnormality on T2-weighted MRI, and there is focal rounded hypointense signal on GRE, representing an increased concentration of deoxyhemoglobin. Also note a partially imaged developmental venous anomaly (d, black arrow) within the left middle cerebellar peduncle.

their removal will result in ischemic injury. There is a welldocumented association of DVAs with CMs; however, DVAs also have been associated with other lesions and syndromes,

5  Imaging Anatomy and Pathology of the Brainstem, Thalamus, and Pineal Region

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including capillary telangiectasias, cortical dysplasias, and blue rubber bleb syndrome.39,​40,​41,​42 DVAs vary in size, ranging from so small that they are undetectable by routine clinical imaging to giant lesions. These lesions are described as umbrella-shaped or caput medusae. Multiple small feeding medullary veins typically converge onto a larger central collector vein (Fig. 5.20). These vessels show enhancement similar to that of a venous blood pool. Large lesions demonstrate MRI signal isointense to dural venous sinuses. As these vessels are not pathologic, most commonly, there is no associated parenchymal signal abnormality on FLAIR and T2-weighted imaging, although adjacent signal abnormality has been reported in up to 7.8% of DVAs not associated with CMs.43 In addition, hemorrhage of DVAs is a reported, albeit rare, occurrence.44

sequences (Fig. 5.21). On T1-weighted imaging, these lesions may be isointense or hypointense. There is debate as to whether MS plaques that are hypointense on T1-weighted imaging, also referred to as black holes, correlate more closely with a patient’s clinical status when compared to other imaging features.47,​48,​49 Enhancement suggests an acute demyelinating plaque, although enhancing lesions may be subclinical. Enhancement patterns vary and include patchy, ill-defined, ring or incomplete ring enhancement  (Fig. 5.22).50 The enhancing side of this incomplete ring corresponds to active demyelination, a feature common to other demyelinating diseases. Active demyelinating plaques may also demonstrate diffusion restriction.51 Importantly, patients with brainstem lesions suggestive of MS should be screened for characteristic lesions within the supratentorial compartment and within the cervical and thoracic spinal cord to increase diagnostic confidence.

Inflammatory

Acute Disseminated Encephalomyelitis

Demyelination

ADEM is a demyelinating process that is more commonly found in the pediatric population but may occur at any age. ADEM may occur spontaneously; however, it typically f­ ollows a viral illness or vaccination. Clinically, ADEM is most commonly a monophasic process in contradistinction to MS. ­Initial presentation is typically that of multifocal neurologic abnormalities.52 The imaging appearance of ADEM also differs from that of MS (Fig. 5.23). These demyelinating lesions tend to be much

Many demyelinating processes occur in the brainstem. The most common of these are multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), and osmotic demyelination syndrome (ODS). Although these entities share the pathologic process of demyelination, they have unique clinical and imaging features.

Multiple Sclerosis MS is a progressive autoimmune, inflammatory, demyelinating disease. Full understanding of the pathogenesis of MS remains incomplete. Clinically, patients may present with sensory and motor disturbances, optic neuritis, and brainstem signs such as internuclear ophthalmoplegia.45 The 2010 revised McDonald criteria require clinical or imaging evidence of dissemination in space and time to make the diagnosis of MS.46 In patients with a confirmed diagnosis of MS, demyelinating lesions within the brainstem are common. Lesions may occur in any part of the brainstem. Although a lesion within the middle cerebellar peduncle is not specific to MS, it should raise suspicion for MS because few other processes involve the middle c­ erebellar peduncles. The imaging appearance is that of oval or rounded foci of hyperintense signal abnormality on T2-weighted and FLAIR

Fig.  5.20  Developmental venous anomaly. Coronal post-contrast T1-weighted magnetic resonance image maximum intensity projection demonstrates the classic imaging features of a brainstem developmental venous anomaly (arrow). Multiple small medullary veins converge on a single collector vein.

Fig. 5.21  Multiple sclerosis. (a) Sagittal fluid-attenuated inversion recovery magnetic resonance image (MRI) and (b) axial T2-weighted MRI demonstrate multiple small rounded and oval foci of signal abnormality throughout the brainstem indicative of multiple sclerosis (MS). Note involvement of the middle cerebellar peduncles, a feature not diagnostic but suggestive of MS. Also note multiple lesions within the corpus callosum with involvement of the callososeptal interface (arrows in both a and b).

Fig. 5.22 Enhancing multiple sclerosis plaque. (a) Sagittal post-contrast T1-weighted magnetic resonance image (MRI) and (b) axial post-contrast T1-weighted MRI demonstrate a focus of enhancement corresponding to a lesion that is characteristically hyperintense on T2-weighted imaging (not shown) in the right dorsal medulla.

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III  Examination, Imaging, and Monitoring for Brainstem Surgery Fig. 5.23  Acute disseminated encephalomyelitis. (a) Axial fluid-attenuated inversion recovery magnetic resonance image (MRI), (b) pre-contrast T1-weighted MRI, and (c) postcontrast T1-weighted MRI demonstrate bilateral asymmetric signal abnormality involving the right temporal subcortical white matter with extension into the bilateral midbrain and cerebral peduncles. There is patchy enhancement on administration of gadolinium (arrow).

Fig. 5.24 Osmotic demyelination. (a) Axial fluid-attenuated inversion recovery (FLAIR) magnetic resonance image (MRI) and (b) diffusionweighted MRI demonstrate the classic imaging appearance of pontine osmotic demyelination with diffusion and FLAIR signal abnormality of the central pons, with characteristic sparing of the corticospinal tracts. Note sparing of the periphery.

larger than MS plaques, both in the brain and in the spinal cord. ADEM is commonly bilateral but asymmetric, in contrast to MS, which tends toward more symmetry. There is a propensity for involvement of supratentorial subcortical white matter and deep gray matter nuclei, including the thalamus. Brainstem involvement may also occur. These lesions are hyperintense on T2-weighted and FLAIR imaging. The enhancement pattern, similar to MS, is that of patchy, ring, or incomplete ring enhancement. Acute demyelinating lesions may demonstrate diffusion restriction, which is also similar to MS.

Osmotic Demyelination Syndrome ODS, a disorder secondary to cell injury from osmotic stress, encompasses the entities central pontine myelinolysis and extrapontine myelinolysis.53 ODS is most commonly attributed to rapid overcorrection of hyponatremia, and it is associated with disorders such as alcoholism, malnutrition, malignancy, and diabetes mellitus, as well as with hepatic and renal failure.53,​54 Clinical presentation ranges from confusion, dysphagia, and dysarthria to variable paresis, coma, locked-in syndrome, and death.55,​56 When there is involvement of the brainstem, the pons is almost exclusively involved. Imaging features include symmetric central pontine hyperintense signal on T2-weighted and FLAIR sequences without mass effect and with characteristic sparing of the periphery and the central corticospinal tracts (Fig. 5.24).53 Signal on T1-weighted imaging is variable. Acutely, diffusion restriction may be seen, and diffusion-weighted imaging is the most sensitive sequence early in the course of the disease.53 Although ODS is classically described as a non-enhancing process, a large series of cases showed that up to 21% demonstrate some degree of enhancement.56 Hemorrhage is uncommon. ODS may partially or completely resolve. It may also result in chronic coagulative necrosis and gliosis.

Ischemia Statistically common among other brainstem lesions, ischemia is an important consideration in the differential diagnosis of a brainstem abnormality. Risk factors for stroke include hypertension, hyperlipidemia, diabetes, smoking, obesity, heart disease, and oral contraceptives. In younger patients, dissection should be considered. Causes of dissection include trauma, fibromuscular dysplasia, and chiropractic manipulation.57 The imaging appearance of focal diffusion restriction in an arterial distribution with corresponding hyperintense signal on T2-weighted and FLAIR imaging rarely presents a diagnostic dilemma. However, there are several specific anatomical regions of involvement that have characteristic corresponding clinical presentations (Fig. 5.25, Table 5.4).57,​58,​59,​60,​61

Secondary Degeneration Wallerian Degeneration Wallerian degeneration (WD) refers to antegrade degeneration of axons and their myelin sheaths secondary to an insult involving either a neuronal cell body or its axon.62 The offending insult may be of variable etiology, although it is commonly ischemic.63 Specifically, WD is frequently observed along the corticospinal tracts secondary to a supratentorial cortical or subcortical perirolandic insult (Fig. 5.26). Four stages of WD and their associated imaging findings have been described (Table 5.5).64 Although acute imaging is typically normal, diffusion restriction of the involved tracts may be observed in patients with developing myelin.65 diffusion tensor imaging with measurement of fractional

5  Imaging Anatomy and Pathology of the Brainstem, Thalamus, and Pineal Region

Fig. 5.25  Wallenberg syndrome. Axial (a) fluid-attenuated inversion recovery magnetic resonance image (MRI), (b) diffusion-weighted MRI, and (c) T2-weighted MRI demonstrate an acute infarct involving the right dorsolateral medulla (b, arrow) secondary to right vertebral artery dis-

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section. Note absent right vertebral artery flow void on T2-weighted MRI (c, arrow). Additional areas of acute ischemia involving the right cerebellar hemisphere are also visible.

Table 5.4  Brainstem syndromes

Syndrome

Anatomical location

Vascular distribution

Major clinical findings

Wallenberg syndrome (lateral medullary syndrome)

Lateral medulla

Vertebral artery, posterior inferior cerebellar artery

• Crossed hemisensory disturbance оо Ipsilateral facial sensory disturbance оо Contralateral trunk or extremity sensory disturbance • Ipsilateral Horner syndrome • Ipsilateral vestibular dysfunction • Ipsilateral cerebellar signs • Ipsilateral bulbar motor dysfunction

Dejerine syndrome (medial medullary syndrome)

Medial medulla

Vertebral artery, anterior spinal artery

• Contralateral hemiparesis • Contralateral loss of fine touch and proprioception of the trunk or extremities • Ipsilateral hypoglossal palsy

Anteromedial pontine syndrome

Anteromedial pons

Basilar artery (perforators) • Ipsilateral internuclear ophthalmoplegia

Facial colliculus syndrome

Facial colliculus (dorsal paramedian pontine tegmentum)

Basilar artery (perforators) • Ipsilateral peripheral facial palsy

Claude syndrome

Ventral medial midbrain

Posterior cerebral artery (perforators)

• Ipsilateral oculomotor palsy • Contralateral ataxia

Weber syndrome

Ventral midbrain

Posterior cerebral artery (perforators)

• Ipsilateral oculomotor palsy • Contralateral hemiparesis

• Ipsilateral lateral rectus palsy • Ipsilateral horizontal gaze paresis • Contralateral facial palsy • Contralateral hemiparesis • Contralateral ataxia • Contralateral sensory disturbance (trunk, extremities) • Ipsilateral conjugate gaze palsy

­ nisotropy of d a ­ egenerated tracts has been shown to correlate well with clinical motor function scales.66

Hypertrophic Olivary Degeneration The dento-rubro-olivary pathway (Guillain-Mollaret triangle) is a transsynaptic circuit connecting the ipsilateral inferior olivary and red nuclei with the contralateral dentate nucleus (Fig. 5.27).67 A lesion along this pathway results in deafferentation of the corresponding inferior olivary nucleus and

hypertrophic olivary degeneration (HOD). Patients commonly present clinically with palatal myoclonus and ataxia, although HOD may be asymptomatic and incidentally discovered on imaging.68 HOD can be unilateral or bilateral. Imaging may reveal a lesion along the course of the dento-rubro-olivary pathway (Fig. 5.28), although idiopathic HOD has been reported in more than half of cases of bilateral HOD and in 13% of cases of unilateral HOD.68 On imaging, HOD manifests as hyperintense signal on T2-weighted imaging and hypertrophy involving the corresponding ipsilateral

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III  Examination, Imaging, and Monitoring for Brainstem Surgery

Fig. 5.26  Wallerian degeneration. Multiple axial fluid-attenuated inversion recovery magnetic resonance images at the level of (a) the perirolandic cortex, (b) the corona radiata white matter, (c) the posterior limb of the

internal capsule, and (d) the pons. Note the postoperative resection cavity in the left frontoparietal lobe with secondary Wallerian degeneration along the course of the corticospinal tract extending into the pons (a–d, arrows).

Table 5.5  Stages of Wallerian degeneration*

Variable

Stage 1

Stage 2

Stage 3

Stage 4

Time

0–4 weeks

4–14 weeks

>14 weeks

Years

Pathology

Axonal degeneration Myelin intact

Myelin protein breakdown Myelin lipid intact Decreased myelin protein: lipid

Myelin lipid breakdown Increased edema

Atrophy

T1 signal

No change

No change

Decreased

Decreased, atrophy

T2 signal

No change (in adults)

Decreased

Increased

Increased, atrophy

*Reproduced with permission from Kuhn et al 1989.

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Fig. 5.28  Hypertrophic olivary degeneration. Axial fluid-attenuated inversion recovery (FLAIR) magnetic resonance images at the level of (a) the pons and (b) the medulla demonstrate a focus of FLAIR hypointense signal indicating a cavernous malformation within the right dorsal pons along the course of the fibers of the dento-rubro-olivary pathway. The secondary swelling and increased signal in the ipsilateral inferior olivary nucleus (b, arrow) are compatible with hypertrophic olivary degeneration.

Fig. 5.27 Guillain-Mollaret triangle (dento-rubro-olivary pathway). The Guillain-Mollaret triangle is a transsynaptic pathway connecting the ipsilateral inferior olivary nucleus (blue dot) and the red nucleus (red dot) with the contralateral dentate nucleus (green dot).

5  Imaging Anatomy and Pathology of the Brainstem, Thalamus, and Pineal Region inferior olivary nucleus. The temporal course of the imaging features of HOD has been described.69,​70 In the acute phase, there are no changes on imaging. This phase corresponds roughly to the first month following an insult. Hyperintense signal on T2-weighted imaging is present at about one month. Hypertrophy of the inferior olivary nucleus may be observed as early as six months and can persist as long as four years following the insult. The resolution of mass effect is in contradistinction to the hyperintense signal on T2-weighted imaging, which persists for many years and may be permanent.

■■ Conclusion The brainstem, thalamus, and pineal region are host to a wide array of pathologies. Improved imaging protocols now allow for the distinction of many pathologic subtypes involving these regions. However, clinical correlation and biopsy remain cornerstones of diagnosis. Continued improvements in imaging modalities will result in further distinction of pathologic entities and will improve not only the diagnosis but also the tailored treatment of patients with disease in these eloquent regions. References 1. Sheth S, Branstetter BF, IV, Escott EJ. Appearance of normal cranial nerves on steady-state free precession MR images. Radiographics 2009; 29(4):1045–1055 2. Chavhan GB, Babyn PS, Jankharia BG, Cheng HL, Shroff MM. Steady-state MR imaging sequences: physics, classification, and clinical applications. Radiographics 2008;28(4):1147–1160 3. Kanowski M, Voges J, Tempelmann C. Delineation of the nucleus centre median by proton density weighted magnetic resonance imaging at 3 T. Neurosurgery 2010;66(3, Suppl Operative):E121–E123, discussion E123 4. Nagae-Poetscher LM, Jiang H, Wakana S, Golay X, van Zijl PC, Mori S. High-resolution diffusion tensor imaging of the brain stem at 3 T. AJNR Am J Neuroradiol 2004;25(8):1325–1330 5. K omisaruk BR, Mosier KM, Liu WC, et al. Functional localization of brainstem and cervical spinal cord nuclei in humans with fMRI. AJNR Am J Neuroradiol 2002;23(4):609–617 6. Deistung A, Schäfer A, Schweser F, et al. High-resolution MR imaging of the human brainstem in vivo at 7 tesla. Front Hum Neurosci 2013;7:710 7. Angeles Fernández-Gil M, Palacios-Bote R, Leo-Barahona M, Mora-Encinas JP. Anatomy of the brainstem: a gaze into the stem of life. Semin Ultrasound CT MR 2010;31(3):196–219 8. Ruchalski K, Hathout GM. A medley of midbrain maladies: a brief review of midbrain anatomy and syndromology for radiologists. Radiol Res Pract 2012;2012:258524 9. Alberico SL, Cassell MD, Narayanan NS. The vulnerable ventral tegmental area in parkinson’s disease. Basal Ganglia 2015;5(2–3):51–55 10. Eapen M, Zald DH, Gatenby JC, Ding Z, Gore JC. Using high-resolution MR imaging at 7T to evaluate the anatomy of the midbrain dopaminergic system. AJNR Am J Neuroradiol 2011;32(4):688–694 11. Yamaguchi K. Development of the human oculomotor nuclear complex: somatic nuclei. Ann Anat 2014;196(6):394–401 12. Yagmurlu K, Rhoton AL, Jr, Tanriover N, Bennett JA. Three-dimensional microsurgical anatomy and the safe entry zones of the brainstem. Neurosurgery 2014;10 Suppl 4:602–619, discussion 619–620 13. Wang C, Paling D, Chen L, et al. Axonal conduction in multiple sclerosis: a combined magnetic resonance imaging and electrophysiological study of the medial longitudinal fasciculus. Mult Scler 2015;21(7):905–915 14. McNulty JP, Lonergan R, Bannigan J, O’Laoide R, Rainford LA, Tubridy N. Visualisation of the medial longitudinal fasciculus using fibre tractogra-

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phy in multiple sclerosis patients with internuclear ophthalmoplegia. Ir J Med Sci 2016;185(2):393–402 15. Yousry I, Moriggl B, Schmid UD, et al. Detailed anatomy of the intracranial segment of the hypoglossal nerve: neurovascular relationships and landmarks on magnetic resonance imaging sequences. J Neurosurg 2002;96(6):1113–1122 16. Horn A, Kühn AA. Lead-DBS: a toolbox for deep brain stimulation electrode localizations and visualizations. Neuroimage 2015;107:127–135 17. Sapède D, Cau E. The pineal gland from development to function. Curr Top Dev Biol 2013;106:171–215 18. Bumb JM, Schilling C, Enning F, et al. Pineal gland volume in primary insomnia and healthy controls: a magnetic resonance imaging study. J Sleep Res 2014;23(3):274–280 19. Green AL, Kieran MW. Pediatric brainstem gliomas: new understanding leads to potential new treatments for two very different tumors. Curr Oncol Rep 2015;17(3):436 20. Dumrongpisutikul N, Intrapiromkul J, Yousem DM. Distinguishing between germinomas and pineal cell tumors on MR imaging. AJNR Am J Neuroradiol 2012;33(3):550–555 21. Smith AB, Rushing EJ, Smirniotopoulos JG. From the archives of the AFIP: lesions of the pineal region: radiologic-pathologic correlation. Radiographics 2010;30(7):2001–2020 22. Shankar S, Wu X, Kalra VB, Huttner AJ, Malhotra A. Ectopic intracranial germinoma. J Clin Neurosci 2016;31(Apr):192–195 23. Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007;114(2):97–109 24. Chang AH, Fuller GN, Debnam JM, et al. MR imaging of papillary tumor of the pineal region. AJNR Am J Neuroradiol 2008;29(1):187–189 25. Washington CW, McCoy KE, Zipfel GJ. Update on the natural history of cavernous malformations and factors predicting aggressive clinical presentation. Neurosurg Focus 2010;29(3):E7 26. Zabramski JM, Wascher TM, Spetzler RF, et al. The natural history of familial cavernous malformations: results of an ongoing study. J Neurosurg 1994;80(3):422–432 27. Cutsforth-Gregory JK, Lanzino G, Link MJ, Brown RD, Jr, Flemming KD. Characterization of radiation-induced cavernous malformations and comparison with a nonradiation cavernous malformation cohort. J Neurosurg 2015;122(5):1214–1222 28. Linsler S. Giant cavernous malformations. J Neurosci Rural Pract 2016;7(2):197–198 29. Garcia RM, Ivan ME, Lawton MT. Brainstem cavernous malformations: surgical results in 104 patients and a proposed grading system to predict neurological outcomes. Neurosurgery 2015;76(3):265–277, discussion 277–278 30. Yun TJ, Na DG, Kwon BJ, et al. A T1 hyperintense perilesional signal aids in the differentiation of a cavernous angioma from other hemorrhagic masses. AJNR Am J Neuroradiol 2008;29(3):494–500 31. Perrini P, Lanzino G. The association of venous developmental anomalies and cavernous malformations: pathophysiological, diagnostic, and surgical considerations. Neurosurg Focus 2006;21(1):e5 32. Frischer JM, Göd S, Gruber A, et al. Susceptibility-weighted imaging at 7 T: improved diagnosis of cerebral cavernous malformations and associated developmental venous anomalies. Neuroimage Clin 2012;1(1):116–120 33. Bertalanffy H, Benes L, Miyazawa T, Alberti O, Siegel AM, Sure U. Cerebral cavernomas in the adult. Review of the literature and analysis of 72 surgically treated patients. Neurosurg Rev 2002;25(1–2):1–53, ­discussion 54–55 34. Barreau X, Marnat G, Gariel F, Dousset V. Intracranial arteriovenous malformations. Diagn Interv Imaging 2014;95(12):1175–1186 35. Malhotra S, Kim T, Zager J, et al. Use of an oncolytic virus secreting GM-CSF as combined oncolytic and immunotherapy for treatment of colorectal and hepatic adenocarcinomas. Surgery 2007;141(4):520–529 36. Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg 1986;65(4):476–483

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37. Chaudhry US, De Bruin DE, Policeni BA. Susceptibility-weighted MR imaging: a better technique in the detection of capillary telangiectasia compared with T2* gradient-echo. AJNR Am J Neuroradiol 2014;35(12):2302–2305 38. Gökçe E, Acu B, Beyhan M, Celikyay F, Celikyay R. Magnetic resonance imaging findings of developmental venous anomalies. Clin Neuroradiol 2014;24(2):135–143 39. Chong W, Patel H, Holt M. Developmental venous anomalies (DVA): What are they really? Neuroradiol J 2011;24(1):59–70 40. Chung JI, Alvarez H, Lasjaunias P. Multifocal cerebral venous malformations and associated developmental venous anomalies in a case of blue rubber bleb nevus syndrome. Interv Neuroradiol 2003;9(2):169–176 41. Sarac H, Telarović S, Markeljević J, Perić B, Pavlisa G, Rados M. Symptomatic capillary telangiectasia of the pons and intracerebral developmental venous anomaly—a rare association. Coll Antropol 2011;35 Suppl 1: 333–338 42. Kalani MY, Zabramski JM, Martirosyan NL, Spetzler RF. Developmental venous anomaly, capillary telangiectasia, cavernous malformation, and arteriovenous malformation: spectrum of a common pathological entity? Acta Neurochir (Wien) 2016;158(3):547–550 43. Linscott LL, Leach JL, Zhang B, Jones BV. Brain parenchymal signal abnormalities associated with developmental venous anomalies in children and young adults. AJNR Am J Neuroradiol 2014;35(8):1600–1607 44. Li X, Wang Y, Chen W, et al. Intracerebral hemorrhage due to developmental venous anomalies. J Clin Neurosci 2016;26:95–100 45. Katz Sand I. Classification, diagnosis, and differential diagnosis of multiple sclerosis. Curr Opin Neurol 2015;28(3):193–205 46. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011;69(2):292–302 47. Thaler C, Faizy T, Sedlacik J, et al. T1- thresholds in black holes increase clinical-radiological correlation in multiple sclerosis patients. PLoS One 2015;10(12):e0144693 48. Radue EW, Sprenger T, Vollmer T, et al. Daclizumab high-yield process reduced the evolution of new gadolinium-enhancing lesions to T1 black holes in patients with relapsing-remitting multiple sclerosis. Eur J Neurol 2016;23(2):412–415 49. Tam RC, Traboulsee A, Riddehough A, Sheikhzadeh F, Li DK. The impact of intensity variations in T1-hypointense lesions on clinical correlations in multiple sclerosis. Mult Scler 2011;17(8):949–957 50. Smirniotopoulos JG, Murphy FM, Rushing EJ, Rees JH, Schroeder JW. ­ Patterns of contrast enhancement in the brain and meninges. Radiographics 2007;27(2):525–551 51. Hannoun S, Roch JA, Durand-Dubief F, et al. Weekly multimodal MRI follow-up of two multiple sclerosis active lesions presenting a transient decrease in ADC. Brain Behav 2015;5(2):e00307 52. Koelman DL, Mateen FJ. Acute disseminated encephalomyelitis: current controversies in diagnosis and outcome. J Neurol 2015;262(9):2013–2024

53. Alleman AM. Osmotic demyelination syndrome: central pontine myelinolysis and extrapontine myelinolysis. Semin Ultrasound CT MR 2014;35(2):153–159 54. King JD, Rosner MH. Osmotic demyelination syndrome. Am J Med Sci 2010;339(6):561–567 55. Tavare AN, Murray D. Images in clinical medicine: central pontine myelinolysis. N Engl J Med 2016;374(7):e8 56. Singh TD, Fugate JE, Rabinstein AA. Central pontine and extrapontine myelinolysis: a systematic review. Eur J Neurol 2014;21(12):1443–1450 57. Ortiz de Mendivil A, Alcalá-Galiano A, Ochoa M, Salvador E, Millán JM. Brainstem stroke: anatomy, clinical and radiological findings. Semin Ultrasound CT MR 2013;34(2):131–141 58. Fukuoka T, Takeda H, Dembo T, et al. Clinical review of 37 patients with medullary infarction. J Stroke Cerebrovasc Dis 2012;21(7):594–599 59. Kim JS. Pure lateral medullary infarction: clinical-radiological correlation of 130 acute, consecutive patients. Brain 2003;126 ­ (Pt 8):1864–1872 60. Bassetti C, Bogousslavsky J, Mattle H, Bernasconi A. Medial medullary stroke: report of seven patients and review of the literature. Neurology 1997;48(4):882–890 61. Jacobs DA, Galetta SL. Neuro-ophthalmology for neuroradiologists. AJNR Am J Neuroradiol 2007;28(1):3–8 62. Inoue Y, Matsumura Y, Fukuda T, et al. MR imaging of Wallerian degeneration in the brainstem: temporal relationships. AJNR Am J Neuroradiol 1990;11(5):897–902 63. Kuhn MJ, Johnson KA, Davis KR. Wallerian degeneration: evaluation with MR imaging. Radiology 1988;168(1):199–202 64. Kuhn MJ, Mikulis DJ, Ayoub DM, Kosofsky BE, Davis KR, Taveras JM. Wallerian degeneration after cerebral infarction: evaluation with sequential MR imaging. Radiology 1989;172(1):179–182 65. Mazumdar A, Mukherjee P, Miller JH, Malde H, McKinstry RC. Diffusionweighted imaging of acute corticospinal tract injury preceding Wallerian degeneration in the maturing human brain. AJNR Am J Neuroradiol 2003;24(6):1057–1066 66. Puig J, Pedraza S, Blasco G, et al. Wallerian degeneration in the corticospinal tract evaluated by diffusion tensor imaging correlates with motor deficit 30 days after middle cerebral artery ischemic stroke. AJNR Am J Neuroradiol 2010;31(7):1324–1330 67. Murdoch S, Shah P, Jampana R. The Guillain-Mollaret triangle in action. Pract Neurol 2016;16(3):243–246 68. Konno T, Broderick DF, Tacik P, Caviness JN, Wszolek ZK. Hypertrophic olivary degeneration: a clinico-radiologic study. Parkinsonism Relat Disord 2016;28:36–40 69. Goyal M, Versnick E, Tuite P, et al. Hypertrophic olivary degeneration: metaanalysis of the temporal evolution of MR findings. AJNR Am J Neuroradiol 2000;21(6):1073–1077 70. Birbamer G, Buchberger W, Felber S, Aichner F. MR appearance of hypertrophic olivary degeneration: temporal relationships. AJNR Am J Neuroradiol 1992;13(5):150:1–1503

6 

Neuromonitoring for Brainstem Surgery Christian Musahl and Nikolai J. Hopf

Abstract

Neuromonitoring during brainstem surgery is essential to ensure patient safety and good outcomes for patients who undergo these challenging procedures. Neuromonitoring can assist the surgeon in localizing important neural structures and can thereby provide a safe entry zone for an atraumatic approach to the lesion using mapping protocols. It also provides a continuous assessment of the functional integrity of neural pathways via the monitoring of important tracts and nuclei. Intraoperative neuromonitoring covers a large variety of methods that must be selected according to the pathology at hand. This chapter focuses on the most important and widely used monitoring techniques, such as somatosensory evoked potentials, motor evoked potentials, brainstem auditory evoked potentials, visual evoked potentials, and electromyography of cranial nerves, as well as the mapping of cranial nerve motor nuclei and their tracts. These techniques are explained and discussed with an emphasis on their limitations and relevance for specific pathologies. Keywords:  brainstem mapping, corticobulbar tract, corticospinal tract, cranial nerves, electromyography, evoked potentials, intraoperative neuromonitoring

■■ Introduction and Indications Surgery in and around the brainstem is extremely challenging because of the brainstem’s complex neuroanatomy and the high risk of injury to vital neurologic functions. Pathology in this area can further distort the anatomy, making it impossible to recognize typical anatomical landmarks. Even though neuroimaging has advanced tremendously, it is often not possible to predict the location of certain neural structures with regard to the pathology at hand. Advanced intraoperative neuromonitoring (IONM) can assist the surgeon in localizing important neural structures and can thereby provide a safe entry zone for an atraumatic approach to the lesion using mapping protocols. It also provides a continuous assessment of the functional integrity of neural pathways via the monitoring of tracts and nuclei. Cranial nerves (CNs) and their motor nuclei or fiber tracts can be located at their origin, at the floor of the fourth ventricle, or within the brainstem by direct stimulation. Continuous monitoring of sensory, motor, and auditory pathways can directly influence the operative strategy and can thereby prevent complications such as the impairment or loss of neural function. Neurologic deficits can be reduced, or even avoided, only if the evoked potentials mirror the current state of surgery (time equivalence), meaning that changes must correlate with surgical steps. The availability of new computer technology has made this technical accuracy possible. Specifically, the ability to average data and compare it

to a baseline study (evoked potentials) have made modern monitoring of complex neurosurgical procedures possible. In this way, IONM can provide critical, decision-guiding information as it is needed. IONM covers a large variety of different methods that must be selected according to the pathology at hand.1 In this chapter, we focus on the most important and widely used monitoring techniques, such as somatosensory evoked potentials (SSEPs), motor evoked potentials (MEPs), brainstem auditory evoked potentials (AEPs), visual evoked potentials (VEPs), and electromyography (EMG) of CNs, as well as the mapping of CN motor nuclei and their tracts.

■■ Methods Anesthetic Considerations An experienced neuroanesthesiologist is a mandatory member of the surgical team because IONM is highly dependent on anesthesia. Analgesic sedation must be sufficiently and precisely controlled with the aspiration of achieving a marginal but predictable effect on neuronal activity. If possible, the neuroanesthesiologist should create a stable anesthetic environment before the baseline signal is attained, and the technique should ideally not be varied during the procedure. Pharmacologic and physiologic factors can both affect SSEPs and MEPs. For example, evoked potential waveforms can be changed by a drug that alters axonal impulse conduction. However, all monitoring modalities are not equally sensitive to anesthetic technique. Sensitivity is enhanced in long pathways with more synapses. SSEPs are, in general, less sensitive to anesthetics than MEPs.2 Also, a signal from an upper extremity is easier to obtain than a signal from a lower extremity. Thus, lower-extremity MEPs are the most difficult signals to obtain. Controversy exists over which anesthetic regimen should be used during surgery with intraoperative monitoring. Inhalational anesthetics and, to a lesser extent, intravenous anesthetics both decrease waveform amplitude and increase latency. Both agents also depress signal obtainment. However, at equal minimum alveolar concentrations, inhalational anesthetics result in greater depression.3 In sensory evoked potential monitoring, the use of inhalational agents, compared with intravenous agents, results in a more severe reduction of amplitudes and delay of latency. Furthermore, at an inhalation concentration above 0.5 of minimum alveolar concentration, the motor threshold becomes significantly elevated. Thus, we recommend the use of total intravenous anesthesia using propofol in combination with an opioid. Bolus injections should be avoided completely, if possible, because these injections carry the risk of an acute loss of

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­ euromonitoring signals. Inhalational anesthetics can be used, n if necessary, but only with a minimum alveolar concentration below 0.5. Short-acting muscle relaxants, such as pancuronium, should be used during the opening and approach to the brainstem lesion. However, there should be no residual effect of the muscle relaxant at the start of brainstem mapping or monitoring, and muscle relaxants are prohibited from this point onward in the surgery. In any event, communication between the anesthesiologist and neurosurgeon regarding change in anesthetic technique or bolus administration is important for accurate interpretation of the signals obtained. Signal depression from an anesthetic agent would be global in nature, whereas true injury may be specific to the surgical area. Bispectral index monitoring can be used to measure the depth of anesthesia. This noninvasive continuous measurement is provided by a strip-like sensor that is positioned on the patient’s forehead. The range of measurement that is derived from electroencephalogram (EEG) data reaches from 0 (equivalent to EEG silence) to 100 (equivalent to fully awake) with a desired bispectral index value between 40 and 60 during neurosurgical procedures. A significant reduction in anesthesia awareness during surgery can be achieved by using bispectral index monitoring.4

Monitoring Evoked Potentials Evoked potentials are a specific response that follows an electrical stimulation of a certain part of the nervous system. In the case of brainstem monitoring, these evoked potentials are usually somatosensory, motor, or auditory. The latency and size of the amplitude of these potentials carry important information about the monitored system. Consequently, evoked potentials present a functional testing of the respective neuronal pathways and allow conclusions to be made about their integrity. A precise analysis of these specific responses has only been made possible through the introduction of monitoring computers that sum and average evoked potentials, eliminate additional “noise” from baseline EEG and muscles, and amplify the naturally low nerve potentials.

Somatosensory Evoked Potentials SSEPs enable the reliable monitoring and control of the somatosensory system. Depending on the location of the procedure, different peripheral nerves may be stimulated. Typical stimulation sites include the posterior tibial nerve at the middle ankle, the common perineal nerve behind the knee, the median and ulnar nerves at the wrist, and the ulnar nerve at the cubital tunnel at the elbow. Stimulation is performed using a bipolar probe, which is directly placed over the corresponding nerve. Detection of the action potential, spreading along the ascending fibers of the dorsal column into the primary sensory cortex, is performed using electrodes in the scalp over the contralateral postcentral gyrus (C3, C4 international 10–20 EEG system)5,6 (Fig. 6.1).7 Stable potentials with an adequate signal-to-noise ratio are expected by averaging 250 single potentials. The stimulation intensity can be as high as 50 mA. Prolongation of the single stimulus and reduction of the frequency of stimulation can be used to increase the quality of the evoked potentials, if desired. Depending on the location of surgery, additional recording e ­ lectrodes can be

Fig. 6.1 Intraoperative somatosensory evoked potential (SSEP) monitoring with baseline at the bottom. The highlighted section shows a decrease in SSEP amplitudes correlating with intraoperative temporary vessel occlusion. After reopening of the artery, SSEPs return to normal. (Reproduced with permission from Musahl, Weissbach, and Hopf 2015.7)

placed at peripheral locations (popliteal fossa and Erb’s point) and along the cervical spine (C2, C7). Factors that may influence changes in SSEPs independent of surgical manipulations are a decrease in body temperature or blood pressure, pneumocephalus, and changes in anesthesia.

Motor Evoked Potentials MEPs enable the reliable control of the motor system. Potentials are evoked by direct electrical or magnetic stimulation of the exposed motor cortex or by transcranial stimulation. Transcranial electrical stimulation with a train or multipulse stimulation technique has become the standard procedure for intraoperative

6  use. Stimulation is best performed using corkscrew electrodes over the precentral gyrus  (C3 and C4 international 10–20 EEG system). The detection of MEPs descending along the pyramidal and corticospinal tract is best performed using subdermal needle electrodes in the corresponding muscles on the side contralateral to the stimulation. Typical muscles for intraoperative use are the abductor pollicis brevis and flexor muscles of the forearm for the upper extremity, as well as the abductor hallucis brevis and anterior tibial muscle for the lower extremity. A stimulation intensity of 100 mA is generally adequate. The intensity can be as high as 200 mA but should not exceed this level to avoid adverse effects, such as burns and epileptic seizures. In the case of direct stimulation of exposed motor cortex, an intensity of only 10–20 mA is adequate. Changes in latency, amplitude, or motor threshold suggest structural damage of the motor system. Factors strongly influencing MEPs in a negative manner are halogenated anesthetics  (e.g., enflurane, desflurane, and isoflurane) and muscle relaxants. Other factors include blood pressure changes and compression of peripheral nerves in cases of poor patient positioning.

Corticobulbar Tract MEP Monitoring The exact anatomy of the corticobulbar tract (CBT) is not known. According to magnetic resonance imaging–based studies,8,​9 the CBT follows the corticospinal tract to the brainstem where multiple CBT branches connect with the cranial motor nuclei (CMN). In contrast to brainstem mapping, which maps the CMN and the peripheral CNs, CBT-MEP monitors the entire CN motor pathway from its origin at the cerebral cortex all the way to the targeted muscle. It is a modification from transcranial MEP monitoring of the corticospinal tract using the same method, electrodes, and stimulation sites, while the target muscles correspond to brainstem monitoring. The orbicularis oculi muscle, however, is not suitable for CBT-MEP because it is too closely situated to the stimulation site. The main methodologies for CBT-MEP monitoring and standard MEP monitoring do not differ. During brainstem resection, transcranial stimulation is performed every 1 to 2 minutes with a train of stimuli. Therefore, the required electrodes are placed at C3 and C4 (international 10–20 EEG system). The surgeon uses CBT-MEP to obtain online feedback about the preservation of the motor function of CMNs without the need to interrupt the surgical flow. However, limb muscle MEPs should be monitored in addition to CBT-MEPs, because CBT and the corticospinal tract can be damaged separately. It is possible that motor CNs are activated directly during CBTMEP monitoring if transcranial stimulation is performed with high-current intensities. This might lead to false-positive results and must be avoided. EMG responses following a train of stimuli combined with silence after a single stimulus is a strong indication that the EMG responses are conducted through the CBT.10

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6 ms and a very low amplitude of less than 1 mV. Therefore, amplification should be as high as possible. High-frequency stimulation allows for fast detection of relevant clinical changes and for single-impulse discrimination at the same time. The AEP signal is evoked in the cochlea and runs all the way to the primary auditory cortex, passing through the cochlear nerve and nucleus, the contralateral lateral lemniscus, the inferior colliculus, and the medial geniculate body along its way. Stimulation in the described technique will evoke approximately 20 distinct waves within 1 second. However, only waves I through V are of clinical relevance (Fig. 6.2).7 Each wave represents a distinct antomical landmark within the brainstem along the auditory pathway. Wave I originates in the distal cochlear nerve, wave II in the proximal cochlear nerve, wave III in the cochlear nucleus in the caudal part of the pons, wave IV in the lateral lemniscus, and wave V in the inferior colliculus. Changes in latency and amplitude are of clinical relevance; a decrease in amplitude of more than 50% is defined as significant for predicting a permanent clinical deficit.11 Interpeak latencies are a much more useful clinical marker than peak latencies. They are less susceptible to external influences than peak latencies and are therefore more reliable.12 The cutoff for a concerning change of latencies compared to baseline values of any wave is considered to be 1 ms. A decrease in hearing ability should be expected in these cases, whereas a complete loss of wave I usually results in complete hearing loss on the respective side. Limitations of brainstem AEPs include a substantial time delay of several minutes, which is caused by the averaging process needed to obtain waves of sufficient amplitude.13,​14 Furthermore, factors such as patient blood pressure and temperature, cold irrigation, loud noises (e.g., drilling), and cerebellar retractors can have a negative influence on the ability to obtain potentials without true damage to the nervous system.

Brainstem Auditory Evoked Potentials Brainstem AEPs allow intraoperative control of the auditory pathway. Stimulation is performed by repetitive “click” sounds of 95 dB volume at the corresponding ear and deafening of the contralateral ear with a continuous noise of 65 dB. Stimuli are administered by single-use earplugs. For reliable brainstem AEPs, up to 4,000 single potentials may have to be averaged. Detection is performed by an electrode placed directly anterior to the tragus. Brainstem AEPs have a short latency of less than

Fig. 6.2 Regular brainstem auditory evoked potentials recorded during a surgical procedure, with baseline measurement at the bottom and continuous intraoperative measurements on top. Waves I, III, and V are marked. (Reproduced with permission from Musahl, Weissbach, and Hopf 2015.7 )

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Visual Evoked Potentials

Electromyography of Cranial Nerves

VEPs allow control of the visual system during brainstem surgery. VEPs are obtained by placing the recording needle electrodes 4 cm above the external occipital protuberance (Oz; international 10–20 system) and 4 cm to each side  (O1 and O2, international 10–20 system). A reference electrode is placed on the forehead  (Fz; international 10–20 system). The recorded measurements have to be averaged because the potentials are very small. Indications for intraoperative use are aneurysms of the posterior circulation, pituitary adenomas, craniopharyngiomas, and other lesions in close relation to the optic radiation. Intraoperative monitoring of VEPs has long been debated in the medical literature.15,​16,​17 However, some promising studies have demonstrated the usefulness of intraoperative VEPs,15,​18 but correlation of intraoperative VEP changes and postoperative visual outcomes is still poor. Powerful light-emitting diodes enable at least a stable technical stimulation of the visual system.19 However, further studies on technical standards and clinical utility of intraoperative use are necessary. Thus, VEP monitoring is not yet considered a standard procedure during neurosurgical procedures in most institutions and therefore is not dealt with in detail here.

EMG of CNs has a long history and today is seen as an essential part of surgery around the brainstem. Preservation of nerve function during vestibular schwannoma surgery was first demonstrated by intracranial stimulation of the facial nerve and by deriving EMG potentials from facial muscles in 1979 by Delgado et al.20 The recording of potentials by intramuscular needle electrodes after monopolar or bipolar CN stimulation has become a standard procedure since Møller and Jannetta’s publication in 1985.21 With the introduction of multimodal intraoperative monitoring, this technique was extended to all motor CNs.22,​23 Two monitoring techniques must be differentiated. Monitoring of spontaneous CN activity is provided by free-run EMG, whereas identifying and monitoring nerve function are done by direct stimulation or triggered EMG. The recording of free-run EMG to monitor spontaneous CN activity is possible using paired needle electrodes, which are placed approximately 1 cm apart within the respective muscles24 as illustrated in Fig. 6.3.7 Before the start of surgery, the correct placement of the electrodes has to be confirmed, and baseline studies have to be performed. Irritation of the nerve through Fig. 6.3 Standard needle positioning for electromyography monitoring of cranial nerves. Note that the electrode for monitoring the vagus nerve (cranial nerve [CN] X) is located within the respiratory tube. Abbreviations: III, oculomotor nerve (CN III); IV, trochlear nerve (CN IV); V, trigeminal nerve (CN V); VI, abducens nerve (CN VI); VII, facial nerve (CN VII); VIII, vestibulocochlear nerve (CN VIII); IX, glossopharyngeal nerve (CN IX); XI, spinal accessory nerve (CN XI); XII, hypoglossal nerve (CN XII). (Reproduced with permission from Musahl, Weissbach, and Hopf 2015.7)

6  manipulation or injury can be made audible to the surgeon and is recognized immediately. The surgeon thereby is able to monitor nerve irritation of any kind while carrying on with the surgical procedure. The feedback that is provided occurs simultaneously with surgical action and thus supports the safety of the procedure. However, two kinds of EMG potentials must be differentiated. An electric activity that is observed parallel to surgical manipulation around a nerve and that stops directly after manipulation ends is called contact activity. A pathologic reaction, or pathologic spontaneous activity during surgical manipulation, is defined as contact activity and generally does not lead to postoperative deficits. In contrast, a pathologic reaction or pathologic spontaneous activity that exceeds surgical manipulations as well as long-lasting activities with high frequency and amplitude, so-called EMG A-trains indicating a loss of nerve fibers, reliably indicate clinically relevant structural damage of neural tissue. Short and uniform activity in multiple channels is generally caused by artifacts. Stimulation of CNs is performed using a monopolar or bipolar stimulation probe with an intensity of 0.05 to 2 mA. The signal is detected by the MEP needle electrode within the corresponding muscle (Fig. 6.3). Sequential stimulation of the respective CN in different locations (i.e., proximal and distal) enables distinct control of its function. For adequate interpretation, it is important to know that the latency of the potential is lower for proximal than for distal stimulation in an intact nerve. A positive reaction only for distal stimulation indicates proximal damage of the nerve and a postoperative deficit is accordingly expected. Fluids within the surgical field, such as irrigation or cerebrospinal fluid, can cause misleading measurements. Identical latencies after proximal and distal stimulation of a nerve might be caused by transmission through the fluid. When this occurs, the surgical field should be freed of fluids and the measurement should be repeated. The effect of anesthetic medication on EMG monitoring is minimal, with the exception of neuromuscular blocking agents.

Mapping Brainstem surgery requires an excellent understanding of the anatomy at hand. Knowledge of fiber tract pathways and the localization of CMN, as illustrated in Fig. 6.4 and Fig. 6.5, is essential. However, individual anatomical variations and displacement by pathologic lesions severely complicate the localization of CMN and safe entry zones. Brainstem mapping has been available in neurosurgery for a little more than two decades24,​25,​26 and presently is considered to be an indispensable tool for surgical procedures within the brainstem. The primary goal is localization of CMN on the surface of the brainstem to define the safest entry point into the brainstem.27 Generally, the “no incision before mapping” strategy has prevailed.22 Furthermore, mapping also is increasingly used along the resection cavity to control the extent of resection28 and thus it supports the surgeon when adjusting the operative strategy becomes necessary. Electrical stimulation of CMN is performed either with a handheld monopolar or with a bipolar probe.24 The respective surface of the brainstem is scanned with the probe in 1-mm

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intervals for not more than 5 seconds at each spot, starting with 2 mA. An intensity exceeding 2 mA or a stimulation time of more than 5 seconds has been reported to generate cardiovascular instability.29,​30 When a maximal muscle response is received, the current is then reduced in a stepwise fashion to obtain the individual threshold intensity, which is needed to more precisely localize the CMN. In most instances, the optimal stimulation frequency is between 2 and 4 Hz.31 Besides mapping the CMN, mapping the descending corticospinal tracts and CBT that pass through the brainstem is an option.10,​32 This is achieved by direct stimulation of the CBTs in the cerebral peduncle. Detection is achieved using the same muscle electrodes as used for transcranial stimulation. Alternatively, potentials may be recorded by epidural strip electrodes inserted at C1-C2 through a suboccipital craniotomy.33 This potential is called the D-wave, and it represents a relative parameter for the number of fast-conducting fibers in the corticospinal tracts. D-waves can even be detected in the presence of neuromuscular blockade. An intraoperative reduction of the D-wave amplitude usually happens gradually. In general, an irreversible injury correlates with an amplitude reduction of more than 50%. In combination with muscle MEPs, monitoring the D-wave amplitude allows a fairly precise prediction of the neurologic outcome. An intraoperative loss of muscle MEPs combined with a D-wave reduction of 50% or more is predictive of a long-lasting or even permanent motor deficit. In cases in which the D-wave potentials stay intact, the postoperative deficit is usually temporary.34 With regard to the triggered EMG potentials of the CMN, no clear cutoff measure will predict neurologic deficits. Postoperative deficits are highly unlikely if EMG responses do not decrease during surgery. An amplitude reduction of less than 50% is not considered to be critical, and postoperative deficits are usually transient. The complete loss of a compound muscle action potential will usually predict a permanent deficit.

■■ Conclusion Just as preoperative images are of the utmost importance for understanding the anatomy and planning the surgical approach, neurophysiologic evaluation is critical during surgical procedures for identification and monitoring of relevant brainstem structures.33 Conventional evoked potential monitoring, consisting of SSEPs, MEPs, and brainstem AEPs, is the most commonly used combination of monitoring techniques for brainstem surgery because these methods are well established. The new standard for intraoperative neurophysiologic monitoring in current brainstem surgery has become a combination of brainstem mapping and CBT-MEP.10 This technique enables localization of vital structures such as motor CNs as well as the intramedullary part of CNs, CBTs, and corticospinal tracts. Thus, neurophysiologic evaluation is not only crucial for localizing the safest entry zone for approaching the lesion but also for safe surgical manipulations during resection of a lesion similar to white-matter stimulation during supratentorial surgery. Furthermore, the combination

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Fig. 6.4  Schematic representation of cranial nerve nuclei and their fiber tracts within the brainstem as seen from a posterior view. Motor cranial nerve nuclei are pictured on the right side, sensory cranial nerve nuclei on the left. Abbreviations: Ncl. n., nucleus of the nerve; III, oculomotor nerve (cranial nerve [CN] III); IV, trochlear nerve (CN IV); V, trigeminal nerve

(CN V); VI, abducens nerve (CN VI); VII, facial nerve (CN VII); VIII, vestibulocochlear nerve (CN VIII); IX, glossopharyngeal nerve (CN IX); X, vagus nerve (CN X); XI, spinal accessory nerve (CN XI); XII, hypoglossal nerve (CN XII). (Adapted from Putz R, Pabst R. Sobotta–Atlas der Anatomie. Urban & Schwarzenberg; 1993.)

of CBT-MEP and standard muscle MEP monitoring enables realtime feedback on the function of motor CNs and corticospinal tracts. However, interpretation of intraoperative changes and the correlation between changes in amplitude or threshold and

the clinical outcome, as well as technical requirements, have not yet been fully defined in CBT-MEP monitoring. Therefore, additional data and clinical experience are necessary to perfect the CBT-MEP technique.

6 

Fig. 6.5  Schematic representation of cranial nerve nuclei and their fiber tracts within the brainstem seen from a lateral view. Abbreviations: Ncl. n., nucleus of the nerve; III, oculomotor nerve (cranial nerve [CN] III); IV, trochlear nerve (CN IV); V, trigeminal nerve (CN V); VI, abducens nerve (CN VI);

References 1. Nuwer MR, Dawson EC. Intraoperative evoked potential monitoring of the spinal cord: a restricted filter, scalp method during Harrington instrumentation for scoliosis. Clin Orthop Relat Res 1984(183):42–50 2. Deletis V, Kiprovski K, Morota N. The influence of halothane, enflurane, and isoflurane on motor evoked potentials. Neurosurgery 1993;33(1):173–174 3. Sloan TB, Heyer EJ. Anesthesia for intraoperative neurophysiologic monitoring of the spinal cord. J Clin Neurophysiol 2002;19(5):430–443 4. Myles PS, Leslie K, McNeil J, Forbes A, Chan MT. Bispectral index monitoring to prevent awareness during anaesthesia: the B-Aware randomised controlled trial. Lancet 2004;363(9423):1757–1763 5. Grundy BL. Monitoring of sensory evoked potentials during neurosurgical operations: methods and applications. Neurosurgery 1982;11(4):556–575 6. Grundy BL, Nelson PB, Doyle E, Procopio PT. Intraoperative loss of somatosensory-evoked potentials predicts loss of spinal cord function. Anesthesiology 1982;57(4):321–322 7. Musahl C, Weissbach C, Kopf NJ. Neuormonitoring. In: Spetzler RF, Kalani MYS, Nakaji P, eds. Neurovascular Surgery. 2nd ed. New York: Thieme Medical Publishers; 2015:150–166. 8. Urban PP, Wicht S, Vucorevic G, et al. The course of corticofacial projections in the human brainstem. Brain 2001;124(Pt 9):1866–1876 9. Terao S, Miura N, Takeda A, Takahashi A, Mitsuma T, Sobue G. Course and distribution of facial corticobulbar tract fibres in the lower brain stem. J Neurol Neurosurg Psychiatry 2000;69(2):262–265

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VII, facial nerve (CN VII); VIII, vestibulocochlear nerve (CN VIII); IX, glossopharyngeal nerve (CN IX); X, vagus nerve (CN X); XI, spinal accessory nerve (CN XI); XII, hypoglossal nerve (CN XII). (Adapted from Putz R, Pabst R. Sobotta–Atlas der Anatomie. Urban & Schwarzenberg; 1993.) 10. Morota N, Ihara S, Deletis V. Intraoperative neurophysiology for surgery in and around the brainstem: role of brainstem mapping and corticobulbar tract motor-evoked potential monitoring. Childs Nerv Syst 2010;26(4):513–521 11. Francis L, Mohamed M, Patino M, McAuliffe J. Intraoperative neuromonitoring in pediatric surgery. Int Anesthesiol Clin 2012;50(4):130–143 12. Markand ON. Brainstem auditory evoked potentials. J Clin Neurophysiol 1994;11(3):319–342 13. Oh T, Nagasawa DT, Fong BM, et al. Intraoperative neuromonitoring techniques in the surgical management of acoustic neuromas. Neurosurg Focus 2012;33(3):E6 14. James ML, Husain AM. Brainstem auditory evoked potential monitoring: when is change in wave V significant? Neurology 2005;65(10):1551–1555 15. Luo Y, Regli L, Bozinov O, Sarnthein J. Clinical utility and limitations of intraoperative monitoring of visual evoked potentials [published correction appears in PLoS One 2015;10(7):e0133819. https://doi. org/10.1371/journal.pone.0133819]. PLoS One 2015;10(3):e0120525 16. Harding GF, Bland JD, Smith VH. Visual evoked potential monitoring of optic nerve function during surgery. J Neurol Neurosurg Psychiatry1990;53(10):890–895 17. Jones NS. Visual evoked potentials in endoscopic and anterior skull base surgery: a review. J Laryngol Otol 1997;111(6):513–516 18. Hayashi H, Kawaguchi M. Intraoperative monitoring of flash visual evoked potential under general anesthesia. Korean J Anesthesiol 2017;70(2):127–135

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19. Kodama K, Goto T, Sato A, Sakai K, Tanaka Y, Hongo K. Standard and limitation of intraoperative monitoring of the visual evoked potential. Acta Neurochir (Wien) 2010;152(4):643–648

27. Sala F, Krzan MJ, Deletis V. Intraoperative neurophysiological monitoring in pediatric neurosurgery: why, when, how? Childs Nerv Syst 2002;18(6–7):264–287

20. Delgado TE, Bucheit WA, Rosenholtz HR, Chrissian S. Intraoperative monitoring of facila muscle evoked responses obtained by intracranial stimulation of the facila nerve: a more accurate technique for facila nerve dissection. Neurosurgery 1979;4(5):418–421

28. Ishihara H, Bjeljac M, Straumann D, Kaku Y, Roth P, Yonekawa Y. The role of intraoperative monitoring of oculomotor and trochlear nuclei–safe entry zone to tegmental lesions. Minim Invasive Neurosurg 2006;49(3):168–172

21. Møller AR, Jannetta PJ. Monitoring of facial nerve function during removal of acoustic tumor. Am J Otol 1985; Suppl:27–29

29. Morota N, Deletis V. The importance of brainstem mapping in brainstem surgical anatomy before the fourth ventricle and implication for intraoperative neurophysiological mapping. Acta Neurochir (Wien) 2006;148(5):499–509, discussion 509

22. Eisner W, Schmid UD, Reulen HJ, et al. The mapping and continuous monitoring of the intrinsic motor nuclei during brain stem surgery. Neurosurgery 1995;37(2):255–265 23. Romstöck J, Strauss C, Fahlbusch R. Continuous electromyography monitoring of motor cranial nerves during cerebellopontine angle surgery. J Neurosurg 2000;93(4):586–593 24. Strauss C, Romstöck J, Nimsky C, Fahlbusch R. Intraoperative identification of motor areas of the rhomboid fossa using direct stimulation. J Neurosurg 1993;79(3):393–399 25. Katsuta T, Morioka T, Fujii K, Fukui M. Physiological localization of the facial colliculus during direct surgery on an intrinsic brain stem lesion. Neurosurgery 1993;32(5):861–863, comment 863 26. Morota N, Deletis V, Epstein FJ, et al. Brain stem mapping: neurophysiological localization of motor nuclei on the floor of the fourth ventricle. Neurosurgery 1995;37(5):922–929, discussion 929–930

30. Suzuki K, Matsumoto M, Ohta M, Sasaki T, Kodama N. Experimental study for identification of the facial colliculus using electromyography and antidromic evoked potentials. Neurosurgery 1997;41(5):1130– 1135, discussion 1135–1136 31. Karakis I. Brainstem mapping. J Clin Neurophysiol 2013;30(6):597–603 32. Neuloh G, Bogucki J, Schramm J. Intraoperative preservation of corticospinal function in the brainstem. J Neurol Neurosurg Psychiatry 2009;80(4):417–422 33. Sala F, Manganotti P, Tramontano V, Bricolo A, Gerosa M. Monitoring of motor pathways during brain stem surgery: what we have achieved and what we still miss? Neurophysiol Clin 2007;37(6):399–406 34. Deletis V, Sala F. Intraoperative neurophysiological monitoring of the spinal cord during spinal cord and spine surgery: a review focus on the corticospinal tracts. Clin Neurophysiol 2008;119(2):248–264

7

Neurologic Examination of the Brainstem and Thalamus Yazan J. Alderazi and Mohamed S. Teleb

Abstract

The neurologic examination of the brainstem and the thalamus is rapid, informative, inexpensive, and clinically useful. The examination is central to lesion localization, determining the extent of neurologic dysfunction, prognostication, monitoring of patients for potential deterioration, monitoring of patients’ recovery, and planning treatment and rehabilitation strategies. We explore the components of the neurologic examination as they apply to the brainstem and thalamus. A practical, clinically oriented approach to lesion localization is presented. We provide useful heuristics and mnemonics to aid rapid patient assessment. A summary of thalamic syndromes and typical vascular brainstem syndromes is presented. Keywords:  ataxia, brainstem disease, brainstem stroke, crossedsigns, localization, thalamic aphasia, thalamic lesion

■■ Introduction The examination of the brainstem and thalamus is necessary for lesion localization, determining the extent of neurologic dysfunction, prognostication, monitoring of patients for potential deterioration, monitoring of patients’ recovery, and planning treatment and rehabilitation strategies. Although improved access to neuroimaging has undoubtedly improved our diagnostic capabilities, the neurologic examination is necessary and more useful for most of these tasks. The examination of the brainstem and thalamus can be a difficult task  (see Table 7.1 and Table 7.2 for lists of common lesions afflicting the brainstem and thalamus). The presentation is not always classic and can be a combination of different syndromes, affecting multiple cranial nuclei and numerous tracts  (e.g., sensory, oculomotor, parasympathetic, and sympathetic). We review the basic examination steps, examine the most well-known stroke syndromes, and reveal multiple heuristics and shortcuts for localization. We emphasize anatomy and vascular supply, as appropriate. The brainstem is organized into three parts: the midbrain, pons, and medulla. In addition the thalamus, cerebellum, and spinal cord are adjacent structures in the central nervous system with tracts flowing in and out of the brainstem. The key to localization remains a good neurologic examination and understanding of functional neuroanatomy. Lesion localization requires all the aspects of a neurologic examination, including mental status, cranial nerve (CN) examination, motor examination, sensory examination, coordination assessment, and ataxia assessment. An efficient clinical assessment requires two steps:

lesion ­localization, followed by etiologic differential diagnosis. Lesion localization is the requisite first step, as this allows a differential diagnosis focused on the most likely pathologies in the affected area. For example, the list of conditions affecting the pons is different from the list of those affecting the thalamus.

■■ Examination Mental Status The mental status examination involves two parts: (1) assessment of the level of consciousness, and (2) assessment of the cognitive domains—language, memory, attention, and praxis—as well as testing for agnosia. The patient’s level of consciousness should be assessed using verbal, tactile, and painful stimuli, as necessary. The level of consciousness can be graded in unambiguous terms of decreasing consciousness: (1) awake and alert; (2) awake and lethargic; (3) stuporous or obtunded; and (4) comatose. Decreased level of consciousness indicates dysfunction of the reticular activating system, the thalamus, or the bilateral cerebral hemispheres. The so-called “structural causes” of coma—brainstem or thalamic infarction, and hemorrhages or mass lesion—are often responsible for this dysfunction. Structural causes must be distinguished from nonstructural causes of coma, which are essentially a severe manifestation of toxic-metabolic encephalopathy. Encephalopathy is a disorder of consciousness that is characterized by inattention, lethargy, or, in severe cases, stupor and coma. Encephalopathy is usually mediated by nonstructural causes, such as sodium imbalance, hypoglycemia, renal failure, liver failure, and hypercapnia, and it can lead to nonstructural coma in severe cases. The key distinction is that structural causes affecting the brainstem will also usually result in CN dysfunction, affecting ocular motility and pupil symmetry in particular. A screening assessment of higher cortical functions is necessary because aphasia, agnosia, neglect, inattention, visual disturbances, visual field defects, and memory impairment may all indicate thalamic injury. These symptoms are more commonly caused by lesions in the cortical structures, but they can be caused by thalamic lesions. The thalamus has reciprocal connections with the various structures within the frontal, parietal, temporal, and occipital lobes.1,​2 These connections include the primary and associative cortices. In addition, the thalamus has relays to the limbic system and the cerebellum. Through these connections, thalamic lesions may mimic cortical or cerebellar lesions and may also cause psychiatric manifestations such as mania, depression, and psychosis.3 Thalamic aphasia with left thalamus lesions, thalamic neglect with

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Table 7.1  Common brainstem syndromes

Classical name

Symptoms

Location or structures

Vascular supply

Dejerine syndrome (medial medullary syndrome)

Ipsilateral Hypoglossal nerve (CN XII) palsy Contralateral Hemiparesis; vibration and proprioception sensory loss; variable manifestations (e.g., isolated hemiparesis, tetraparesis, hemiparesis, ataxia, vertigo, nystagmus, dysphagia, facial palsy)

Hypoglossal nerve (CN XII) Corticospinal tract (in the pyramid); medial lemniscus

Vertebral artery: anteromedial artery Anterior spinal artery: anteromedial artery

Wallenberg syndrome (lateral medullary syndrome)

Ipsilateral Facial pain; facial sensory loss Ataxia (arm, leg, and gait at times) Nystagmus; nausea; vomiting; vertigo Hoarseness; dysphagia Horner syndrome Contralateral Hemisensory loss of pain and temperature sense Nonlateralized Hiccups

Trigeminal nerve (CN V) nucleus Restiform body; cerebellum Vestibular nucleus Nucleus ambiguous Descending sympathetic tracts Spinothalamic tract

Vertebral artery: distal branches Vertebral artery: superior lateral medullary artery Posterior inferior cerebellar artery: less common than vertebral artery

Foville syndrome (inferior medial pontine syndrome)

Ipsilateral Entire face weakness; lateral gaze palsy Contralateral Hemiparesis

Dorsal pontine tegmentum; caudal pons Facial nerve (CN VII) nucleus/ fascicle; PPRF or abducens nerve (CN VI) nucleus; corticospinal tract

Basilar artery: paramedian branches Basilar artery: short circumferential arteries

Marie-Foix syndrome (lateral pontine syndrome)

Ipsilateral Corticopontine cerebellar tracts Ataxia (arm and leg) Corticospinal tracts Contralateral Spinothalamic tract Hemiparesis; variable hemisensory loss of pain and temperature sense

Basilar artery: long circumferential branches Anterior inferior cerebellar artery

Raymond syndrome (ventral pontine syndrome; RaymondCestan-Chenais syndrome; alternating abducens hemiplegia)

Ipsilateral Lateral abduction (lateral rectus) palsy Contralateral Hemiparesis

Abducens nerve (CN VI) fascicle; pyramidal tract

Basilar artery: paramedian branches

Millard-Gubler syndrome (ventral pontine syndrome)

Ipsilateral Entire face weakness; lateral abduction (lateral rectus) palsy Contralateral Hemiparesis

Basis pontis (pyramidal tract); abducens nerve (CN VI) fascicle; facial nerve (CN VII) fascicle

Basilar artery: short circumferential branches Basilar artery: paramedian branches

Weber syndrome

Ipsilateral Lateral gaze weakness Contralateral Hemiparesis (upper and lower extremities)

Midbrain: base Oculomotor nerve (CN III) Corticospinal tract

Posterior cerebral artery: penetrating branches to midbrain

Benedikt syndrome

Ipsilateral Oculomotor nerve (CN III) palsy Contralateral Hemiparesis; involuntary movements (e.g., chorea, athetosis); tremor

Paramedian midbrain syndrome Oculomotor nerve (CN III) Cerebral peduncle; red nucleus; substantia nigra

Posterior cerebral artery: penetrating branches to midbrain

Claude syndrome

Ipsilateral Oculomotor nerve (CN III) palsy Contralateral Ataxia; cerebellar outflow tremor; hemiparesis (upper and lower extremities)

Midbrain Brachium conjunctivum, including dentato-rubro-thalamo-cortical tract Tegmentum Red nucleus Cerebral peduncle (corticospinal tract)

Posterior cerebral artery

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(Continued) Table 7.1  Common brainstem syndromes

Classical name

Symptoms

Location or structures

Vascular supply

Nothnagel syndrome (dorsal midbrain syndrome)

Ipsilateral Oculomotor nerve (CN III) palsy; ataxia; nystagmus Contralateral Oculomotor nerve (CN III) palsy (less severe); ataxia

Superior and inferior colliculi

Usually not vascular; neoplasms are common etiology

Anton syndrome

Cortical blindness; unawareness or denial of blindness

Cerebral hemisphere: bilateral occipital lobes

Posterior cerebral artery: bilateral Basilar artery: tip of basilar artery

Abbreviations: CN, cranial nerve; PPRF, paramedian pontine reticular formation.

right thalamus lesions, abulia due to anterior thalamic lesions, coma due to bilateral paramedian thalamic lesions, and contralateral ataxia due to ventral thalamic lesions are all examples of dysfunction of distant brain areas caused by failure of the functional network.4,​5,​6,​7 This dysfunction of distant areas is referred to as diaschisis and is typical of thalamic lesions. In addition, bilateral paramedian thalamic lesions can cause vertical gaze palsy.8

Cranial Nerves Examination of the CNs is necessary when evaluating oculomotor, sensory, and motor function. Specifically, CN dysfunction is an important clue to the presence of brainstem dysfunction. It is also the most reliable clinical method of determining the location of dysfunction within the brainstem: midbrain, pons, or medulla.9

CN I: Olfactory Nerve The olfactory nerve and sense of smell are rarely tested. However, test results can indicate a mass lesion in the anterior cranial fossa or some early neurodegenerative conditions such as Alzheimer

disease. Testing the olfactory nerve is of no localization value for lesions of the brainstem and thalamus.

CN II: Optic Nerve There are four components to the optic nerve examination: (1) visual acuity,  (2) visual fields,  (3) pupillary responses, and (4) funduscopy. Decreased visual acuity may localize to the optic nerve and the retina, or it may represent refractive error and thus not localize to the brainstem or thalamus. Thalamic lesions can cause visual field defects, namely, homonymous quadrant­anopia or macular-sparing homonymous hemianopia, with damage to the lateral geniculate body. Rarely, lateral genicular nucleus lesions can cause macular-involving homonymous hemianopia, if damage is complete. This can occur in an interruption of the dual supply to the macular connections in the lateral geniculate body. Anisocoria (i.e., unequal pupils) indicates impaired balance between parasympathetic and sympathetic input into the pupil. Dilation of the impaired pupil (i.e., mydriasis) represents loss of parasympathetic input. This occurs in dysfunction of the efferent limb of the pupillary response, namely, damage to the midbrain,

Table 7.2  Common Thalamic Syndromes Classical name

Symptoms

Location or structures

Vascular supply

Anterior thalamic syndrome

Decreased level of consciousness; impaired memory, impaired executive function, abulia; hemispatial neglect (right-sided lesions)

Anterior nucleus and ventral anterior nuclei of the thalamus; mammillothalamic tract; amygdalofugal pathway

Tuberothalamic artery (arises from middle third of posterior communicating artery)

Paramedian thalamic syndrome

Decreased level of consciousness; memory impairment, cognitive impairment, and disinhibition; thalamic aphasia (left)

Dorsomedial nucleus; centromedian nucleus

Paramedian arteries (arising from P1 segment) Artery of Percheron variant (a single artery supplying bilateral paramedian arteries)

Inferolateral thalamic syndrome

Contralateral Hemisensory loss; hemiataxia; hemiparesis; hemianopia (involving the macula); postlesional thalamic pain syndrome with hemibody pain

Ventral posterior nuclei (lateral VPL, medial VPM, and inferior VPI); ventrolateral nucleus; medial geniculate body

Inferolateral arteries (arises from P2 segment)

Posterior thalamic syndrome

Homonymous hemianopia; homonymous quadrantanopia; aphasia (left-sided lesions); variable dystonia or sensory loss

LGN; pulvinar; midbrain; subthalamic nucleus

Posterior choroidal arteries (arises from P2 segment); lateral and medial choroidal artery branches

Abbreviations: LGN, lateral geniculate nucleus; VPI, ventral posterior inferior; VPL, ventral posterolateral; VPM, ventral posteromedial.

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the oculomotor nerve (CN III) nucleus, the CN III within or external to the brainstem, or damage to the Edinger-Westphal nucleus within the midbrain. Alternatively, loss of pupillary sympathetic input causes constriction of the pupil (i.e., miosis). Miosis is part of Horner syndrome, which is also characterized by partial ptosis and anhidrosis. Pupillary constriction may indicate dysfunction of the sympathetic nervous system within the brainstem, and it may be particularly important for identifying lateral medullary lesions or damage to the sympathetic system outside the brainstem (e.g., within the hypothalamus, the spinal cord, or the sympathetic chain or along the carotid artery). Funduscopy is uncommonly abnormal for lesions of the brainstem or the thalamus; however, it may demonstrate papilledema in cases of concomitantly raised intracranial pressure, or it may demonstrate findings of underlying etiology in patients with hypertensive or diabetic retinopathy.

CN III: Oculomotor Nerve CN III function is examined during testing of ocular movements, first by asking the patient to visually follow an “H” pattern made by the examiner’s finger movements and then by examining the pupillary responses. The oculomotor nerve controls eye motion, and the parasympathetic portion of the nerve controls pupillary response. The nerve may be damaged within the brainstem or along its extra-axial course to the extraocular muscles. Third nerve palsy is usually classified as CN III palsy involving the pupil when the pupil is dilated and as pupil-sparing CN III palsy when there is normal pupil function. CN III palsy involving the pupil usually indicates compressive lesions such as aneurysms  (particularly those of the posterior communicating artery), tumors, or inflammatory mass lesions. Such is the case because compressive lesions interrupt both the oculomotor fibers supplying the extraocular muscles and the parasympathetic fibers supplying the pupil. Pupil-sparing CN III palsy occurs with noncompressive lesions, in particular with microvascular infarction of the nerve due to small vessel disease in patients with diabetes mellitus or hypertension. Infarction damages the inner nerve fibers supplying the extraocular muscles but spares the outer nerve fibers supplying parasympathetic control. In older terminology, impaired ocular motility is referred to as external ophthalmoplegia and pupillary dysfunction is referred to as internal ophthalmoplegia. In an examination of ocular motility, the eye demonstrates ptosis and disconjugate movement in the primary position. Ptosis may be complete or incomplete, depending on the severity of dysfunction. The same is true for impaired ocular motility. The affected eye is “down-and-out” (i.e., inferiorly and laterally deviated due to unopposed actions of superior oblique and lateral rectus muscles). Adduction and supraduction are weak. In an examination of a patient with anisocoria, it is important to determine whether the dysfunction is in the constricted pupil, indicating Horner syndrome, or in the dilated pupil, indicating CN III palsy or a midbrain lesion. Diplopia occurs with CN III palsy but not with isolated Horner syndrome. The oculomotor nerve may be damaged anywhere along its course from the midbrain to the subarachnoid space, the lateral wall of the cavernous sinus, the superior orbital fissure, or the extraocular muscles.

CN IV: Trochlear Nerve The trochlear nerve (CN IV) is examined during testing of ocular movements. The trochlear nerve causes the internal rotation

of the eye and partially depresses the eye via its activation of the superior oblique muscle. Trochlear nerve palsy results in diplopia. Often, the patient’s head is tilted to the contralateral side to compensate for lack of internal rotation of the eye. Trochlear nerve palsy is usually determined when one pupil is higher than the other. The higher pupil, the affected eye, is referred to as hypertropic. This difference may be subtle and may require the cover-uncover test to detect it. During this test, the patient fixates at a point  (e.g., the examiner’s nose). Then the eyes are covered and uncovered one at a time. The examiner notices the corrective movement of the eye after it is uncovered. Usually, both the affected eye and the unaffected eye demonstrate corrective movement. Trochlear nerve palsy and a weak inferior rectus muscle can be differentiated by performing the three-step Bielschowsky (or Parks-Bielschowsky) head tilt test: •• Step 1: Identify which eye is hypertropic in the primary position. •• Step 2: Assess whether the hypertropia increases in the right or left lateral gaze. The oblique muscles have the greatest vertical movement during adduction. •• Step 3: Determine whether the hypertropia increases on right or left head tilt. Recent studies have questioned the sensitivity of this test.10,​11 Midbrain lesions can cause hypertropia of one of the eyes. This ocular misalignment is referred to as skew deviation and can be detected with use of the cover-uncover test. The trochlear nerve may be damaged anywhere along its course from the midbrain to the subarachnoid space, the lateral wall of the cavernous sinus, the superior orbital fissure, and the superior oblique muscle.

CN V: Trigeminal Nerve The trigeminal nerve is tested with the corneal reflex and sensation over the three trigeminal areas over the face:  (1) the V1  (forehead area),  (2) the V2  (maxillary area), and  (3) the V3  (mandibular area at the chin). It is affected by brainstem lesions because of the location of its nuclei running from pons to medulla. Pathology in the Meckel cave (i.e., trigeminal cave) or inflammatory infectious pathology can affect it as well. The examination of the corneal reflex is essential in patients with suspected brainstem injury or suspected brain death. Although the trigeminal nerve has motor and parasympathetic function, these are not tested in routine clinical practice. The muscles of mastication supplied by the trigeminal nerve are strong and are only rarely impaired by severe denervation.

CN VI: Abducens Nerve The abducens nerve (CN VI) is examined by testing ocular movements. The abducens innervates the lateral rectus muscle, causing abduction of the eye. Minor palsies manifest with horizontal diplopia that worsens when looking at objects at a distance. The CN VI nucleus is in the pons, and the nerve has a long course. It is susceptible to dysfunction from many lesions, including shifts in the brain position due to increased intracranial pressure, hydrocephalus, or intracranial hypotension. Thus, CN VI palsy may be a false localizing sign. Within the pons, the CN VI nucleus is intimately related to the paramedian pontine reticular formation  (PPRF), which is the major brainstem center for lateral gaze control. Dysfunction of the CN VI nucleus or PPRF leads

7  Neurologic Examination of the Brainstem and Thalamus to gaze deviation away from the lesion. Lesions in this area are often accompanied by contralateral hemiparesis as the lesion also interrupts the descending corticospinal tract. It is important not to mistake this presentation for frontal lobe seizure, because it can also cause gaze deviation toward the side where the hemiparesis occurs. In addition the nerve can be damaged along its course through the subarachnoid space, the medial portion of the cavernous sinus, and the superior orbital fissure to the lateral rectus muscle.

CN VII: Facial Nerve The facial nerve  (CN VII) controls facial expression and taste on the anterior two-thirds of the tongue. Facial symmetry and movement are tested clinically. Movements of several muscles are tested: the frontalis, orbicularis oculi, buccinators, orbicularis oris, and platysma. Lower motor neuron facial nerve palsies manifest as dysfunction in all these muscles fairly equally. Unilateral upper motor neuron lesions of the corticobulbar tract to the facial nucleus allow sparing of the frontalis muscle and orbicularis oculi as they are innervated bilaterally. The facial nerve is located in the pons, and dysfunction is common in the adjacent CN VI nerve and the corticospinal tract. Lesions involving the facial nerve and the corticospinal tract lead to the classic cross-signs of unilateral lower motor neuron pattern facial palsy ipsilateral to the lesion with contralateral hemiparesis.

CN VIII: Vestibulocochlear Nerve The vestibulocochlear nerve  (CN VIII) is tested by examining hearing and by conducting the Rinne test and the Weber test. In comatose patients, oculocephalic and vestibulo-ocular reflexes are used for vestibular testing. There are two components to the nerve: cochlear and vestibular. Cochlear nerve dysfunction is detected on the basis of hearing loss, nonpulsatile tinnitus, the Rinne test (which is used to assess for conduction defects), and the Weber test (which helps lateralize the lesion). Due to organization of the auditory pathways, the system has bilateral connections immediately after entering the brainstem. Therefore, most hearing loss is peripheral in origin. The only causes of hearing loss in the central nervous system are lesions in the lateral pons. These lesions can occur after infarction of the anterior inferior cerebellar artery, which also supplies the labyrinthine artery.12 Dysfunction of the vestibular component leads to nystagmus and true vertigo. In clinical practice, subtle brainstem lesions that cause central vertigo are detected by the HINTS  (head impulse, nystagmus direction, test of skew) battery. A positive test result on this battery suggests the presence of the central cause of vertigo, mandating further or repeat imaging.13,​14 The latter of these two is tested for with use of the cover-uncover test as described above in the section on the trochlear nerve. The head impulse test relies on intact connections between the vestibular nuclei and the CNs of ocular motility: the oculomotor, trochlear, and abducens nerves (CN III, CN IV, and CN VI). In the test, the patient's head is passively rotated quickly to either side with eyes fixed, and the examiner observes eye movement. The normal response to the impulse test is that the eyes stay focused. In an abnormal test response, refixation saccade occurs, indicating a central vestibular disorder.15,​16,​17 A discussion of nystagmus is beyond the scope of this chapter. Suffice it to say that vertical nystagmus localizes to the­

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brainstem or has toxic causes (e.g., alcohol or phenytoin toxicity). Spontaneous horizontal nystagmus that is direction fixed occurs with vestibular neuritis, and rotatory horizontal nystagmus occurs with benign paroxysmal positional vertigo. Horizontal nystagmus that changes direction  (i.e., that is not direction fixed) indicates brainstem dysfunction.14,​18 Finally, testing in comatose patients examines the oculocephalic reflex and includes cold caloric testing of the vestibuloocular reflex. These tests are performed to assess brainstem integrity, along with other brainstem tests.19

CN IX-XI: Glossopharyngeal, Vagus, and Spinal Accessory Nerves The glossopharyngeal, vagus, and spinal accessory nerves (CN IX-XI) are clinically important but usually do not help localize acute brainstem or thalamic lesions. With lesions of the upper motor neuron, there is usually transient dysfunction of the glossopharyngeal and spinal accessory nerves. However, this dysfunction is usually transient because of the bilateral innervation of these structures. With skull-base syndromes, these nerves are essential to localization and prompt appropriate imaging and treatment planning for jugular foramen syndrome, retropharyngeal space syndrome, and intercondylar space syndrome.20

CN XII: Hypoglossal Nerve Dysfunction of the hypoglossal nerve (CN XII) usually manifests with ipsilateral tongue deviation, and it is typically involved in medial medullary syndrome because of medial medullary infarcts.21 Skull-base syndromes (e.g., the hypoglossal canal syndrome) are also in the differential diagnosis for patients with tongue deviation.

Motor Examination The motor examination of the limbs is part of the assessment of the brainstem and the thalamus. Tone and strength are assessed and graded in all limbs and in the face. In addition, observation for tremor or ataxia at rest and on action is part of this examination. The cardinal motor manifestations in the limbs of brainstem lesions are hemiparesis or quadriparesis with CN dysfunction. Common signs are classical crossed signs of facial palsy, contralateral to the side of weakness, and gaze deviation toward the side of hemiparesis. Quadriparesis with any CN dysfunction should point to lesions in the brainstem rather than the spinal cord. In addition, the anterior location of the corticospinal tracts within the brainstem allows localization to the anterior tegmentum when weakness is present. Also of note is that tonic posturing can occur with brainstem lesions. This sign is prominent with basilar artery thrombosis and, in some cases, with hydrocephalus. These movements can occur in sequence, mimicking seizures.22 As for motor dysfunction with thalamic lesions, contralateral hemiparesis is often noted. Usually, it relates to nearby dysfunction of the internal capsule. However, mild hemiparesis may occur due to ventrolateral nucleus dysfunction. Thalamic lesions also cause hemiataxia of the limbs due to interruption of the dentato-rubro-thalamo-cortical tract, the major outflow tract of the cerebellar hemispheres.

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Sensory Examination The sensory examination completes the usual thalamic and brainstem clinical tests. This examination includes all modalities (pain, temperature, light touch, and vibration) in all four extremities and the face. Most sensory tracts (spinothalamic and medial lemniscus) and sympathetic tracts are laterally located in the tegmentum. Dysfunction of these modalities can allow localization to the lateral brainstem. In multiple sclerosis and in lateral circumferential infarcts, these fibers are often affected. Thus, thoughtful historytaking and examination can lead to early detection and therapy.

■■ Gaze and Ocular Motility Internuclear Ophthalmoplegia, One-and-a-half Syndrome, and Wall-eyed Bilateral Internuclear Ophthalmoplegia Internuclear ophthalmoplegia (INO) occurs with damage to the medial longitudinal fasciculus  (MLF). The MLF connects the upper cervical spinal cord with the vestibular nuclei, the ipsilateral oculomotor nerve  (CN III), and the contralateral abducens nerve (CN VI). It is the rostral connection between the ipsilateral oculomotor nerve and the contralateral abducens nerve that is clinically relevant. It is necessary for conjugate lateral gaze. INO manifests as diplopia on lateral gaze. When the patient looks opposite to the affected MLF, the eye ipsilateral to the affected MLF fails to adduct, and the contralateral eye abducts laterally but demonstrates nystagmus. One-and-a-half syndrome is a term used to describe INO and horizontal gaze palsy due to MLF and ipsilateral PPRF damage. In this case, the ipsilateral eye fails to adduct and also cannot abduct. The contralateral eye can abduct laterally with nystagmus but is unable to adduct medially. INO and one-and-a-half syndrome localize to the pons. The typical differential diagnosis includes multiple sclerosis, pontine infarction, pontine hemorrhage, and Wernicke-Korsakoff syndrome. Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) refers to bilateral INO that occurs when the rostral-most portion of the MLF is damaged within the midbrain. The patient has bilateral exotropia (divergent gaze) in the primary position and is unable to adduct either eye. WEBINO may be accompanied by other midbrain findings.23

Horizontal Gaze Palsy The PPRF is the major brainstem center for lateral gaze control. It receives inputs from the frontal lobe eye fields for volitional gaze, reflex input, vestibular nuclei, and internuclear inputs. Damage to this structure leads to deviation of the gaze away from the lesion to the contralateral side. It is important to distinguish PPRF lesions clinically from frontal eye field seizures and contralateral frontal eye field stroke or dysfunction. Usually, doing so requires a high index of clinical suspicion and careful assessment of the rest of the neurologic examination for other brainstem or cortical signs.

Skew Deviation As described previously in the section on the trochlear nerve (CN IV), the cover-uncover test is used to disclose subtle vertical

ocular misalignment. Such misalignment can occur because of trochlear nerve or midbrain lesions.

Vertical Gaze Palsy Vertical gaze is controlled by a different system from the one that controls horizontal gaze. The system that controls vertical gaze is located primarily within the midbrain and has supranuclear inputs. Vertical gaze impairment is encountered in neurodegenerative conditions such as progressive supranuclear palsy. It is also encountered in Parinaud syndrome (dorsal midbrain syndrome) and in some cases of unilateral paramedian midbrain infarction.24 Parinaud syndrome occurs because of compression of the midbrain tectum such as that caused by pineal region tumors. The syndrome consists of upgaze palsy, pupillary light-near dissociation (pupils that constrict to accommodation but not to light), and conversionretraction nystagmus that occurs on attempted upgaze. The lesion localizes to the rostral interstitial nuclei (Cajal nuclei) of the medial longitudinal fasciculus.25

■■ Cerebellar Ataxia (CerebellarMidbrain-Thalamic Localization) Hemiataxia The cerebellar outflow tract, the dentato-rubro-thalamo-cortical tract, projects from the dentate nucleus of the cerebellum through the superior cerebellar peduncle to the contralateral thalamus and then to the cerebral cortex contralateral to the cerebellum. This tract is the major outflow from the cerebellar hemispheres. It may be interrupted at any point along its course, leading to hemiataxia. Thus, it is relevant to lesions of the midbrain and the ventrolateral nucleus of the thalamus.

Astasia-Abasia Thalamic lesions can cause a form of cerebellar ataxia called astasia-abasia. The patient is unable to stand or walk without assistance. Astasia-abasia localizes to the ventral group of thalamic nuclei. This syndrome may occur without any other signs. Unfortunately, in the neurosurgery literature, the term is also used to denote psychogenic ataxia.

Wernicke-Korsakoff Syndrome Wernicke-Korsakoff syndrome is a prototypical example of brainstem-thalamic dysfunction. Initially, the syndrome is characterized by certain conditions or disorders, each explained by a corresponding interruption: ataxia, in the cerebellar tracts; encephalopathy, in the reticular activating system; and ophthalmoplegia, in the internuclear connections. These structures exist near the periaqueductal gray matter of the midbrain, where the imaging and pathologic abnormalities exist. The later phase of the illness is characterized by severe, short-term memory loss and the inability to form new memories. This cognitive dysfunction is due to damage of the anterior nucleus of the thalamus and the mammillary bodies, leading to interruption of thalamic relays to the cortex and limbic system. The damaged areas correlate with imaging and pathologic findings.26

7  Neurologic Examination of the Brainstem and Thalamus

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■■ Compressive Syndromes and Herniation Brainstem compression can occur due to direct compression by posterior fossa lesions, or it may occur in Parinaud syndrome, as previously described in the section on vertical gaze palsy. It may also occur with two of the herniation syndromes: transtentorial herniation and tonsillar herniation.

Transtentorial Herniation The later phases of transtentorial herniation are characterized by dysfunction of the midbrain ipsilateral to the herniation. The mass effect from a supratentorial lesion leads to herniation of the temporal lobe uncus along the tentorium and compression of the midbrain. This compression leads to decreased consciousness, contralateral hemiparesis, and ipsilateral oculomotor nucleus palsy with ptosis and pupil dilatation. The syndrome worsens until the contralateral side and the pons are affected, which leads to bilateral pinpoint pupils and quadriplegia. The detection of the early phase of herniation is essential to avoid further damage to vital structures. In rare cases, the midbrain may be compressed along the contralateral tentorium, which leads to false localization with the findings on the opposite side.

Tonsillar Herniation Tonsillar herniation occurs because of posterior fossa lesions or as the result of transtentorial herniation. The key feature is that tonsillar herniation from posterior fossa lesions typically occurs without the typical sequence of transtentorial herniation. There is no predictable sequence. Features of CN dysfunction due to direct brainstem compression may exist before progression to coma. In other cases, progression may occur directly to a decreased level of consciousness preceding coma without clear CN dysfunction until the patient is comatose. This lack of a predictable sequence highlights the need for vigilance and consideration of early prophylactic interventions in this patient population.

Direct Brainstem Compression Posterior fossa lesions may cause direct compression of the brainstem. In this case, the features are those of the compressed level of the brainstem. The findings typically do not respect vascular territories. Midbrain compression may be characterized by skew deviation or anisocoria. Pontine compression often leads to horizontal gaze palsy. Hiccups and Horner syndrome are often clues to the presence of medulla compression. These findings may herald tonsillar herniation in patients with unstable lesions.

Fig. 7.1 Axial T2-weighted magnetic resonance imaging at 3 tesla shows midbrain lesions in idealized territories. Weber syndrome (yellow), Claude syndrome (red), Benedikt syndrome (green), and Nothnagel syndrome (blue). Clinical lesions may be smaller or larger, depending on etiology.

the large trunks causes infarctions in multiple small vessels and ischemia of distal territories, such as the thalamus and occipital lobe. With basilar artery thrombosis, bilateral lesions are typical. In small vessel disease, the infarction is usually unilateral because these vessels respect the midline. At each level of the brainstem (midbrain, pons, or medulla), there are paramedian and lateral circumferential stroke syndromes (Fig. 7.1, Fig. 7.2, Fig. 7.3, Fig. 7.4). Due to the more medial presence of the corticospinal tracts within the brainstem, paramedian vessel infarction usually causes weakness. In addition, the CN motor nuclei reside medially, as does the medial lemniscus, which supplies vibration and proprioception tracts. Interruption of motor CNs or vibration or proprioception tracts also localizes to a medial lesion. The lateral circumferential arteries often spare this medial area, and patients present with syndromes that do not have weakness of the limbs or CNs. Ischemic stroke is easily missed by the inattentive examiner who does not examine pain, temperature, and facial sensation or who does not assess for Horner syndrome or ataxia, as these modalities are supplied by the lateral structures. The lateral medullary syndrome is often an example of this clinical pitfall. The thalamus is supplied by four perforating arteries that arise from the P1 and P2 segments of the posterior cerebral artery. The anteriormost branch, the tuberothalamic artery, may arise as a branch of the posterior communicating artery. These vessels supply the anterior, medial, lateral, and posterior areas

■■ Vascular Lesions The cardinal feature of ischemic stroke is that it follows a vascular distribution. Therefore, the injured area crosses brainstem, thalamic, and cortical structures with a different syndrome from that of mass lesions that tend to be retained in a single region. The arterial blood supply of the brainstem is organized in large trunks represented by the vertebral artery, the basilar artery, and the posterior cerebral artery, and also by small perforating arteries: paramedian and lateral circumferential arteries. Damage to

Fig. 7.2 Axial T2-weighted magnetic resonance imaging at 3 tesla shows pontine lesions in idealized territories. Raymond-Cestan syndrome, also known as ventral pontine syndrome (yellow); MillardGubler syndrome, also known as ventral pontine syndrome (blue); and Marie-Foix syndrome, also known as lateral pontine syndrome or base of pons syndrome (red). Clinical lesions may be smaller or larger, depending on etiology.

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Fig. 7.3 Axial T2-weighted magnetic resonance imaging at 3 tesla shows caudal pontine lesion in idealized territory. Foville syndrome, also known as inferior medial pontine syndrome, in dorsal pons tegmentum (red). Clinical lesions may be smaller or larger, depending on etiology.

of the thalamus (Fig. 7.5). Each vessel has 2 to 4 synonyms. Each territory has a classic syndrome related to the underlying structures. In practice, these syndromes are often incomplete, and overlapping syndromes may also occur. Nonetheless, these syndromes remain clinically useful. The anterior thalamic syndrome occurs due to infarction of the tuberothalamic artery, which is also known as the polar artery of the thalamus. The syndrome manifests with impaired memory, impaired executive function, and a decreased level of consciousness. Hemispatial neglect may occur with right-sided anterior thalamic lesions. The medial thalamic syndrome occurs because of infarction of the paramedian artery (formerly known as the thalamoperforating pedicle) and manifests with memory impairment, cognitive impairment, and disinhibition. Thalamic aphasia in dominant-side lesions may also occur. Bilateral medial thalamic lesions can occur via the artery of Percheron variant, which is a single perforator group that supplies bilateral medial territories.27 Bilateral medial thalamic lesions manifest as decreased level of consciousness. The lateral thalamic syndrome occurs because of infarction of the inferolateral artery (formerly known as the thalamogeniculate pedicle) and manifests with contralateral hemiataxia, hemisensory loss, hemiparesis, and macula-involving homonymous hemianopia.28 Postlesional thalamic pain syndrome may occur after recovery. It manifests as hemibody pain contralateral to the lesion. The

Fig. 7.4  Axial T2-weighted magnetic resonance imaging at 3 tesla shows midbrain lesions in idealized territories. Dejerine syndrome, also known as medial medullary syndrome (yellow), and Wallenberg syndrome, also known as lateral medullary syndrome (blue). Clinical lesions may be smaller or larger, depending on etiology.

Fig. 7.5  Axial T2-weighted magnetic resonance imaging at 3 tesla shows thalamic lesions in idealized territories. Anterior tuberothalamic artery syndrome (yellow), medial paramedian artery syndrome (blue), lateral inferolateral artery syndrome (red), and posterior choroidal artery syndrome (green). Clinical lesions may be smaller or larger, depending on etiology.

posterior thalamic syndrome occurs because of infarction of the posterior choroidal artery, and it manifests with homonymous hemianopia, homonymous quadrantanopia with variable dystonia, or sensory loss, depending on the concomitant damage to the midbrain. Left-sided posterior thalamic lesions can also lead to thalamic aphasia.

■■ Brainstem and Thalamic Lesion Localization Brainstem and Thalamic Lesion Localization Overview As with other areas in the brain, the signs that are present are of more localizing value than the signs that are absent. For example, the presence of a sensory deficit points toward dysfunction of the sensory tract, whereas an intact sensory tract on examination does not exclude subclinical lesions of the tract. The quintessential feature of brainstem disease is the presence of CN dysfunction accompanied by dysfunction of the ascending or descending long tracts. For example, the presence of a CN III palsy and contralateral hemiparesis localizes to dysfunction of the medial midbrain. The level of dysfunction within the brainstem is usually determined by which CN is affected. CN III or CN IV dysfunction suggests midbrain lesions  (Fig. 7.1). CN V-VIII–dysfunction suggests pontine lesions (Fig. 7.2, Fig. 7.3), and CN IX-XII–dysfunction suggests medullary lesions (Fig. 7.4). The exception is that CN V may be dysfunctional with lesions outside the pons because the CN V nucleus is large and extends beyond the pons. The laterality of the lesion is usually determined by assessing the descending or ascending long tract and the laterality of the affected CNs.29 The lesion is usually ipsilateral to the affected CN. For example, a right-sided CN III nerve palsy with left-sided hemiparesis localizes toward the right midbrain, which is an example of crossed-signs typical of brainstem lesions. Furthermore, the long tracts that are involved will help determine whether the lesion is located medially or laterally within the brainstem. The motor tracts are located medially within the brainstem,

7  Neurologic Examination of the Brainstem and Thalamus whereas the sensory tracts, the sympathetic tracts, and the cerebellar tracts are located laterally. The motor nuclei of CN III, CN IV, CN VI, and CN XII are located medially, whereas the sensory nuclei of CN V are located laterally. The MLF is a connection between CN III and CN VI; therefore, it is also located medially. Thus, weakness (e.g., hemiparesis, CN palsy, or INO) occurs with medial lesions, whereas sensory dysfunction, ataxia, and Horner syndrome occur with lateral lesions. Also of note is that motor tracts are usually more anterior within the brainstem, and sensory tracts are usually more posterior.30,​31 Ataxia may be a mild or prominent component of brainstem dysfunction. Ataxia typically occurs with disruption of the cerebellar outflow tract and with midbrain lesions that cause hemiataxia. In addition, appendicular ataxia can occur with pontine lesions because of the interruption of the frontopontine cerebellar tracts, which represent the main input to the cerebellum. Lesions of the medulla can also cause cerebellar ataxia. When the input to the cerebellum from the inferior cerebellar peduncle is interrupted, vertigo or nystagmus often manifests. The diagnosis of thalamic lesions using neurologic examination results can be particularly challenging. The thalamus is in the center of the various cortical regions, the limbic system, the reticular activating system, the visual apparatus, the cerebellum, and the ascending and descending long tracts through the brainstem. The diagnosis is usually made by careful assessment of a group of signs. In addition, the position of the thalamus immediately superior to and adjacent to the midbrain is of localization value. For example, cognitive dysfunction with midbrain signs localizes to the thalamus rather than the cortex. Lesions of the thalamus may mimic lesions in other locations because of reciprocal connections or because the thalamus is located along the long tracts. Aphasia from dominant-sided thalamic lesions may mimic dominanthemisphere cortical lesions. Notably, repetition is intact in thalamic aphasias, whereas repetition is impaired in cortical aphasia. Ataxia from ventral posterolateral thalamic lesions mimics cerebellar hemisphere tract lesions and cerebellar outflow tract lesions. Bilateral medial thalamic lesions can cause decreased consciousness, mania, or psychosis that may mimic metabolic encephalopathy or psychiatric conditions. Lateral thalamic lesions may result in a hemisensory loss, hemiparesis, and, occasionally, hemiataxia. These findings may mimic the effects of lesions of the corona radiata, the internal capsule, or the cerebellar hemispheres. Finally, visual field defects occur with thalamic lesions that may mimic hemianopia that occurs with optic tract or visual cortex lesions. The unique finding in infarcts of the lateral geniculate nucleus of the thalamus is a macular-sparing homonymous hemianopia due to a dual supply of macular fibers. This visual defect localizes to the thalamus. However, hemianopia involving the macula can occur with other thalamic lesions. Although it is a drastic oversimplification of thalamic function, it is most useful from a clinical standpoint to know the classic four thalamic syndromes  (tuberothalamic artery syndrome anteriorly, paramedian artery syndrome medially, inferolateral artery syndrome laterally, and posterior choroidal artery syndrome posteriorly) and to recognize incomplete and overlapping syndromes (Fig. 7.5).1,​32

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Brainstem and Thalamic Lesion Localization Heuristics Multiple mnemonics and heuristics are available to use for quick lesion localization at the bedside. These include the Ds of posterior circulation strokes, the Rule of 4.

The Ds of Posterior Circulation Strokes There are multiple mnemonics with 4 Ds, 5 Ds, or 6 Ds. These include signs and symptoms that suggest brainstem involvement. The mnemonics are useful when attempting to obtain more history from the patient with suspected brainstem disease and when examining the patient for dysfunction. The Ds include diplopia, dysarthria, dysphagia, dizziness (vertigo), “dystaxia” (ataxia), and “drop attack” (syncope). It is important to note two inaccuracies with the mnemonic—that dizziness without vertigo has poor localization value and that the term drop attacks is primarily used in atonic attacks rather than with syncope.

The Rule of 4 for Localizing in the Brainstem The rule of 4 is a mnemonic likely first described by Peter Gates.30 It is used as a way to remember the basic principles of brainstem localization. There are four rules in the rule of 4:   1. The four medial structures begin with M: a) Motor pathway (corticospinal tract) b) Medial lemniscus (vibration and proprioception) c) MLF d) Motor nucleus and nerves (CN III, CN IV, CN VI, and CN XII)   2. The four lateral structures begin with S: a) Spinothalamic tract b) Spinocerebellar tract c) Sympathetic tract d) Sensory nucleus of CN V   3. There are four CNs in each of the following areas: the medulla, the pons, and superior to the pons. a) The four CNs in the medulla: CNs IX-XII b) The four CNs in the pons: CNs V-VIII c) The four CNs superior to the pons: CN I, CN II, CN III (midbrain), and CN IV (midbrain)   4. There are four motor CNs near the midline: CN III, CN IV, CN VI, and CN XII. All four CN numbers can be divided evenly into 12.

■■ Conclusion In this chapter, we outlined the methods of examining the brainstem and the thalamus, with an emphasis on clinically useful findings to aid localization. We also elaborated on the thought process involved in localization. Even in the era of neuroimaging, the examination is essential for diagnosis, monitoring of disease and therapy, prognostication, and planning of therapeutic and rehabilitation strategies. Careful yet rapid clinical bedside assessment is possible using simple rules that are grounded in functional neuroanatomy and observation of clinical pathology.

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References 1. Serra C, Ture U, Krayenbuhl N, Sengul G, Yaşargil DC, Yaşargil MG. Topographic classification of the thalamus surfaces related to microneurosurgery: a white matter fiber microdissection study. World Neurosurg 2016;97:438–452 2. Rangel-Castilla L, Spetzler RF. The 6 thalamic regions: surgical approaches to thalamic cavernous malformations, operative results, and clinical outcomes. J Neurosurg 2015;123(3):676–685 3. Carrera E, Bogousslavsky J. The thalamus and behavior: effects of anatomically distinct strokes. Neurology 2006;66(12):1817–1823 4. Ozeren A, Sarica Y, Efe R. Thalamic aphasia syndrome. Acta Neurol Belg 1994;94(3):205–208 5. Kuljic-Obradovic DC. Subcortical aphasia: three different language disorder syndromes? Eur J Neurol 2003;10(4):445–448 6. Afzal U, Farooq MU. Teaching neuroimages: thalamic aphasia syndrome. Neurology 2013;81(23):e177 7. Schmahmann JD. Vascular syndromes of the thalamus. Stroke 2003;34(9):2264–2278 8. Gooneratne IK, Caldera MC, Liyanage DS, Pathberiya L, Vithanage K, Gamage R. Pearls & Oy-sters: ocular motor abnormalities in bilateral paramedian thalamic stroke. Neurology 2015;84(20):e155–e158 9. Damodaran O, Rizk E, Rodriguez J, Lee G. Cranial nerve assessment: a concise guide to clinical examination. Clin Anat 2014;27(1):25–30

review of bedside diagnosis in acute vestibular syndrome. CMAJ 2011;183(9):E571–E592 18. Pavlin-Premrl D, Waterston J, McGuigan S, et al. Importance of spontaneous nystagmus detection in the differential diagnosis of acute vertigo. J Clin Neurosci 2015;22(3):504–507 19. Wijdicks EF, Varelas PN, Gronseth GS, Greer DM; American Academy of Neurology. Evidence-based guideline update: determining brain death in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2010;74(23):1911–1918 20. Bone I, Hadley DM. Syndromes of the orbital fissure, cavernous sinus, cerebello-pontine angle, and skull base. J Neurol Neurosurg Psychiatry 2005;76 Suppl 3:iii29–iii38 21. de Oliveira-Souza R. Damage to the pyramidal tracts is necessary and sufficient for the production of the pyramidal syndrome in man. Med Hypotheses 2015;85(1):99–110 22. Saposnik G, Caplan LR. Convulsive-like movements in brainstem stroke. Arch Neurol 2001;58(4):654–657 23. Kim JS, Jeong SH, Oh YM, Yang YS, Kim SY. Teaching NeuroImage: walleyed bilateral internuclear ophthalmoplegia  (WEBINO) from midbrain infarction. Neurology 2008;70(8):e35 24. Hommel M, Bogousslavsky J. The spectrum of vertical gaze palsy following unilateral brainstem stroke. Neurology 1991;41(8):1229–1234

10. Muthusamy B, Irsch K, Peggy Chang HY, Guyton DL. The sensitivity of the Bielschowsky head-tilt test in diagnosing acquired bilateral superior oblique paresis. Am J Ophthalmol 2014;157(4):901–907.e2

25. Pierrot-Deseilligny CH, Chain F, Gray F, Serdaru M, Escourolle R, Lhermitte F. Parinaud’s syndrome: electro-oculographic and anatomical analyses of six vascular cases with deductions about ­vertical gaze ­organization in the premotor structures. Brain 1982;105(Pt 4): 667–696

11. Manchandia AM, Demer JL. Sensitivity of the three-step test in diagnosis of superior oblique palsy. J AAPOS 2014;18(6):567–571

26. Sullivan EV, Pfefferbaum A. Neuroimaging of the Wernicke-Korsakoff syndrome. Alcohol Alcohol 2009;44(2):155–165

12. Chiang CI, Chou CH, Hsueh CJ, Cheng CA, Peng GS. Acute bilateral hearing loss as a “worsening sign” in a patient with critical basilar artery stenosis. J Clin Neurosci 2013;20(1):177–179

27. Perren F, Clarke S, Bogousslavsky J. The syndrome of combined polar and paramedian thalamic infarction. Arch Neurol 2005;62(8):1212–1216

13. Saber Tehrani AS, Kattah JC, Mantokoudis G, et al. Small strokes causing severe vertigo: frequency of false-negative MRIs and nonlacunar mechanisms. Neurology 2014;83(2):169–173 14. Kattah JC, Talkad AV, Wang DZ, Hsieh YH, Newman-Toker DE. HINTS to diagnose stroke in the acute vestibular syndrome: three-step bedside oculomotor examination more sensitive than early MRI diffusionweighted imaging. Stroke 2009;40(11):3504–3510 15. Colebatch JG, Halmagyi GM, Lorenzano S. Vestibular projections: beyond the reflex. Neurology 2016;86(2):112–113 16. Kerber KA, Meurer WJ, Brown DL, et al. Stroke risk stratification in acute dizziness presentations: a prospective imaging-based study. Neurology 2015;85(21):1869–1878 17. Tarnutzer AA, Berkowitz AL, Robinson KA, Hsieh YH, NewmanToker DE. Does my dizzy patient have a stroke? A systematic

28. Caplan LR, DeWitt LD, Pessin MS, Gorelick PB, Adelman LS. Lateral thalamic infarcts. Arch Neurol 1988;45(9):959–964 29. Silverman IE, Liu GT, Volpe NJ, Galetta SL. The crossed paralyses: the original brain-stem syndromes of Millard-Gubler, Foville, Weber, and Raymond-Cestan. Arch Neurol 1995;52(6):635–638 30. Liu GT, Crenner CW, Logigian EL, Charness ME, Samuels MA. Midbrain syndromes of Benedikt, Claude, and Nothnagel: setting the record straight. Neurology 1992;42(9):1820–1822 31. Searls DE, Pazdera L, Korbel E, Vysata O, Caplan LR. Symptoms and signs of posterior circulation ischemia in the New England Medical Center Posterior Circulation Registry. Arch Neurol 2012;69(3):346–351 32. Hale JR, Mayhew SD, Mullinger KJ, et al. Comparison of functional thalamic segmentation from seed-based analysis and ICA. Neuroimage 2015;114:448–465

Section IV Surgical Approaches to the Brainstem, Thalamus, and Pineal Region

  8 Surgical Approaches to the Ventral Brainstem and Thalamus

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  9 Approaches to the Dorsal Brainstem, Thalamus, and Pineal Region

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Surgical Approaches to the Ventral Brainstem and Thalamus Jayson Sack, Siviero Agazzi, and Harry R. van Loveren

Abstract

Surgical approaches to the ventral brainstem and thalamus have been designed on the basis of the risks and complexities of a region densely populated with nuclear tissue and fiber tracts that are unforgiving if transgressed. With so few cases available and with limited cumulative experience for any one surgeon, each case often requires surgical innovation in addition to extensive anatomical knowledge and personal confidence. Therefore, this chapter includes two principles that can be applied to guide the design of surgical approaches to lesions of the ventral brainstem and thalamus. The first principle is to “let the lesion do the talking” because the lesion will determine the timing and goals of surgery and will guide the operative approach. The second principle is to “build the approach from the inside out.” Using the second principle, one is to start with the target, proceed to the safe entry zone, continue the trajectory, and conclude with the craniotomy. Five basic cases are described in which these two principles were applied. Standard surgical approaches are described for these common scenarios to serve as guidance for early-career surgeons operating on the brainstem and thalamus. The chapter also includes an overview of the basic knowledge and skills required to enter the practice of brainstem and thalamus surgery (e.g., anatomy, skull base approaches, transfacial approaches, endoscopic skills). Keywords:  anatomy, brainstem, endoscopic skull base surgery, skull base approaches, thalamus, transfacial approaches

■■ Designing the Surgical Approach Only a small subset of neurosurgeons is willing to tackle the complexities and risks associated with surgery of the ventral brainstem and thalamus. With so few cases available and with limited cumulative experience for any one surgeon, one must often be innovative to meet the demands of each case, while also applying anatomical knowledge and drawing on personal confidence. Surgical approaches for the ventral brainstem and thalamus are considered complex and often require experience in skull base surgery. Additionally, the target “real estate” is densely populated with nuclear tissue and fiber tracts that are unforgiving if transgressed. To address these issues, this chapter emphasizes two principles in the design of surgical approaches to lesions of the ventral brainstem and thalamus. The first principle is to “let the lesion do the talking” because the lesion will determine the timing of surgery, the goals of surgery, and the operative approach. The second principle is to “build the approach from the inside out,” meaning that one should start with the target, proceed to the safe entry zone, continue to the trajectory, and conclude with the craniotomy.

Let the Lesion Do the Talking First and foremost, you must develop an understanding of what the lesion can tell you. Surgical planning begins by understanding the characteristics and allowances of the target lesion. For example, cavernous malformations reside in a hematoma cavity that, once entered, can be explored with little risk to surrounding tissues. Gliomas in the brainstem are diffusely infiltrative and thus allow only biopsy or resection of exophytic components. Arteriovenous malformations in the thalamus become operative when nonfatal hemorrhage creates a period of neurologic deficit, a hematoma cavity that helps to define the approach, and a compelling indication for intervention that makes surgery palatable both to the surgeon and to the patient. Once the lesion is understood and the goals of surgery (e.g., biopsy, partial resection, radical resection) are defined, the safe entry zone should be determined to minimize operative morbidity. These zones represent small areas that are devoid of critical fibers, nuclei, or perforating vessels. Anatomical assessments of the safe entry zones for the anterolateral brainstem have been reported.1,​2,​3 However, no true safe entry zones exist within the thalamus itself. Instead, for the thalamus, some semblance of a safe entry zone can be maintained by avoiding transgression of the basal ganglia as well as the genu and posterior limb of the internal capsule. For the ventral brainstem, the “no-go zone” means avoiding transgression of the nuclei and the pyramidal tracts. Once the safe entry zone is defined, a trajectory should be plotted to it that minimizes the amount of brain tissue traversed and maximizes the use of natural tissue planes for dissection (e.g., sulci, cisterns, ventricles). After the approach trajectory is defined, so is the entry point on the skull. Therefore, surgeons should be familiar with all variations of incisions and craniotomies, which include the orbitozygomatic osteotomies, endoscopic clivectomies, and anterior and posterior petrosectomies. Competency in these craniotomies and osteotomies often is best achieved with a multidisciplinary team rather than an individual.

Build the Approach from the Inside Out The second principle of designing surgical approaches to lesions of the ventral brainstem and thalamus—“build the approach from the inside out”—conveys the idea that surgical planning should start with the target lesion, plot a path outward to reach the skull, and conclude with a craniotomy that takes into consideration the cosmesis of the incision. Because of the high risk associated with resection of the target lesion, the indications for surgery must be rigidly defined. For lesions deep below the brainstem surface, aggressive interventions should be avoided, and other treatment modalities should be considered instead.

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Fig. 8.1 Pontine cavernous malformation. Axial T2-weighted magnetic resonance images (MRIs) demonstrated (a) a small pontine lesion consistent with a cavernous malformation during surveillance, (b) later additional hemorrhage on the immediate preoperative MRI, with expansion of the hematoma cavity to the anterolateral surface of the pons, and (c) complete resection of the lesion postoperatively. (d) Artist’s illustration depicts an “inside out approach” with the surgical trajectory via a temporal craniotomy (dashed outline) and an anterior petrosectomy. In this case, the lesion extends to the surface of the pons and creates a safe entry zone. Lesions that do not extend completely to the surface are often approached using the peritrigeminal safe entry zone. (e) Brainstem cross-section at the level of the root entry zone illustrates the peritrigeminal safe entry zone (green shading). Entrance is located in front of the trigeminal nerve (cranial nerve V) root safe entry zone, with a deeper trajectory between corticospinal tracts anteriorly and the motor and sensory nuclei of the trigeminal nerve posteriorly. The mean distance between the trigeminal nerve and the corticospinal tracts was estimated to be 4.64 mm (range 3.8–5.6 mm), whereas the mean depth of dissection to the trigeminal nuclei is 11.2 mm (range 9.5–13.1 mm). (Data from Recalde et al, 2008.1 Illustration © Glia Media. Reproduced with permission.)

The availability of advanced technology is critical. For example, certain cases are better suited to the use of stereotactic frameless guidance to locate the lesion, fiber tracking to avoid critical pathways, neurophysiologic monitoring to determine a safe entry zone, or intraoperative imaging  (e.g., intraoperative computed tomography, intraoperative magnetic resonance imaging, intraoperative angiography) to assess the progress or completion of surgery. The surgeon must maintain competency in a variety of approaches, techniques, and instruments, and must have the courage to innovate. In addition, a detailed understanding of the anatomy of the lesion, coupled with experience with neuromonitoring and image guidance, is paramount. Furthermore, knowledge of brainstem safe entry zones is critically important to minimize operative morbidity. Specifically, these zones represent small areas that are devoid of critical fibers, nuclei, or perforating vessels. Although there are no true safety zones within the thalamus itself, those for the anterolateral brainstem have recently been more intimately defined.1,​2,​3 For example, Rangel-Castilla and Spetzler4 reclassified the thalamus into six different anatomical regions on the basis of the optimal surgical approach. Nonetheless, surgical experience and knowledge of the optimal surgical approach to thalamic lesions remain limited.

■■ Surgery by Design: Five Easy Targets Unlike other areas of neurosurgery, brainstem and thalamus surgery does not follow a “cookie cutter” approach. In fact, a neurosurgeon must possess a diverse armamentarium and skill

set. This section includes five safe approaches to five easy target lesions in the ventral brainstem and thalamus. These cases are neither exotic nor unique but instead are typical of their type of lesion, and the surgical approaches to these lesions are neither complex nor innovative, making them suitable for early-career surgeons of the brainstem and thalamus. Each case demonstrates the basic knowledge and skills required to meet the goals of surgery (e.g., knowledge of the anatomy of the cranium and brain, skull base approaches, transfacial approaches, and endoscopic skills). With mastery of these basics, one can begin to innovate. Truly innovative approaches can be found in case reports and short case series in the peer-reviewed surgical literature, and they can be found in operating rooms around the world where master surgeons are at work.

Target 1: Pontine Cavernous Malformation Case 1 A 25-year-old woman with a pontine cavernous malformation was initially placed under observation after presenting with transient neurologic symptoms and deficits. Later, after further hemorrhage and when the hematoma cavity had reached the surface of the brainstem, surgery was performed (Fig. 8.1a-c).

Strategy Using the concept of “let the lesion do the talking” to define the timing, goals, and approach for this patient, we opted to delay surgery until the lesion demonstrated its own natural history of repetitive hemorrhagic episodes. With repeat hemorrhage, a lesion will expand to the surface of the pons, which will then determine its own safe entry zone. At this point, we then use the strategy to “build the approach from the inside out” by designing the trajectory directly from the safe entry zone outward to the cranium (i.e., the area where the hematoma cavity presents itself at the surface of the pons with the least overlying normal tissue). In this patient, that area was within the peritrigeminal zone, a well-known and well-defined safe entry zone to the pons. To reach that zone safely, we used a subtemporal approach, which was expanded caudally using an anterior petrosectomy (Kawase approach) that necessitated a temporal craniotomy (Fig. 8.1d, e).

Surgery Overview Before the patient is positioned, a lumbar drain is inserted and cerebrospinal fluid is drained to decrease retraction injury to the temporal lobe. The patient is placed supine with a wedge under the shoulder, and the patient’s head is rotated until the sagittal suture is parallel to the floor. The head is then tilted down about 15° so that the zygoma is the highest point in the surgical field. A straight vertical incision is begun in the preauricular crease at the level of the tragus and then is extended superiorly to the level of the superior temporal line. Underlying muscle and fascia are opened along the same line of incision. Two bur holes are placed (one over the root of the zygoma, one at the superior aspect of the exposure), and a 6 × 6-cm craniotomy is performed. Using rongeurs or a drill with a cutting bur, the surgeon extends the inferior edge of the craniotomy down to be flush with the floor of the middle cranial fossa. In the early years of performing this surgery, we would “down fracture” the zygomatic root and

8  mobilize the temporalis muscle to be below the base of the skull. We no longer do this when approaching lesions in this posterior middle fossa location. That is, we came to realize that the zygomatic root and middle fossa floor are at the same level, unlike the anterior middle fossa, where the floor is much lower and the zygomatic osteotomy still offers some benefit. Elevation of the temporal lobe dura mater in a posterior-toanterior direction along the anterior face of the petrous bone and middle fossa floor exposes the arcuate eminence, which is absent in some patients, and the greater superficial petrosal nerve (GSPN) as it exits the facial hiatus. The posterior-to-anterior direction of dissection avoids the possibility of a dissector getting under the GSPN and avulsing it and causing a stretch injury to the geniculate ganglion and facial nerve (cranial nerve [CN] VII). The GSPN can be confirmed by stimulation; it will cause retrograde firing of the facial nerve at sufficient amplitude. The middle meningeal artery is identified, coagulated, and divided at the foramen spinosum. Elevation of the temporal lobe dura along with the dural sleeve of the mandibular nerve (V3) exposes the trigeminal depression. Sharply incising the V3 dural sleeve horizontally will allow mobilization of the dura propria upward with exposure of the inferior inner dural sleeve, which covers the gasserian ganglion, and will further relax the dura in that area. The dura on the anterior face of the temporal bone is dissected medially until the false edge of the petrous ridge is identified. Next, the superior petrosal sinus is elevated to expose the true edge of the petrous bone where retractors can then be hooked to expose the entire meatal plane for drilling. The location of the internal auditory canal is approximated by a line that bisects the angle between the arcuate eminence and GSPN. Some patients do not have a visible arcuate eminence; in these patients, the internal auditory canal can be estimated by dropping an imaginary plumb line down the external auditory canal across the middle fossa floor. An anterior petrosectomy is then performed using specific anatomical structures as key landmarks for the extent of bony removal. A rhomboid-shaped volume of bone is formed by the petrous ridge medially, the GSPN laterally, the trigeminal nerve (CN V) anteriorly, and the arcuate eminence posteriorly.5 Additionally, care must be taken while removing bone anteromedial and inferior to the geniculate ganglion to avoid injury to the cochlea. The hard bone of the cochlea can be “blue lined” in this location by the neuro-otologist. A neurosurgeon performing this maneuver tends to be more conservative, leaving a bit more bone in the area to be safe. The dura is opened along the inferior temporal lobe and reflected inferiorly. The dural flap is then split in the midsection down to the superior petrosal sinus. After placement of vascular clips across the superior petrosal sinus, the sinus is sectioned and the adjacent tentorium is incised down to the insertion of the trochlear nerve (CN IV). With the opening of the arachnoid membrane of the basilar cisterns, additional cerebrospinal fluid egress occurs and the anterolateral pons can be well visualized. Alternatively, an intradural anterior transpetrosal approach may be used and tailored to the extent of bony resection required for optimal exposure.6 At this point, cavernous malformations that extend to the pial surface may be identified by the discoloration of tissue and can be approached directly. If such malformations are not well visualized or are below the pial surface, neuronavigation is used to assist in localization of the lesion and to plan a surgical corridor via the peritrigeminal or supratrigeminal zone, both of which are considered safe entry zones to the lateral pons.

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Once the hematoma cavity is entered, microdissection under microscopic magnification is used to determine the plane between the brainstem parenchyma and the outermost layer of the organized hematoma. Dissection in this plane, along with piecemeal removal of the hematoma, will reveal the actual cavernoma as a distinct mass of thin-walled channels. In this area, a minimal amount of bipolar coagulation may be necessary to completely remove the actual malformation. At the conclusion of our case, the dura would not allow a watertight closure, so small fat grafts were placed to obliterate dead space and avoid cerebrospinal fluid leakage. A temporary pseudomeningocele, although not uncommon, is usually self-limiting.

Target 2: Ventral Medullary Cavernous Malformation Case 2 A 27-year-old woman presented with symptoms of brainstem dysfunction  (e.g., right hemibody numbness, dizziness, headaches). A brainstem cavernoma of the medullary region was identified, but because of its small size, observation was recommended. Although evidence of hemorrhage was seen, the cavernoma appeared to be deeply buried in the medulla oblongata. Since it had not reached the surface of the medulla oblongata, any surgical approach increased the risk for additional neurologic deficits  (Fig. 8.2a). Given that the natural history of brainstem cavernomas can occasionally be benign, our strategy is to wait until at least the second clinical manifestation or ­radiographic

Fig. 8.2  Ventral medullary cavernous malformation. (a) Surveillance axial T2-weighted magnetic resonance image (MRI) demonstrated a small lesion within the depths of the medulla, consistent with a cavernous malformation. The patient subsequently had progressive hemorrhage accompanied by acute neurologic symptoms. Axial T2-weighted MRIs showed (b) immediate preoperative expansion of the left hemimedulla and extension of the hematoma cavity to the anterior surface of the medulla and (c) complete resection of the lesion postoperatively. (d) Artist’s illustration depicts the ventral endoscopic transclival approach, which was used to gain access to the ventral medulla for resection of the cavernous malformation. Lesions that do not extend completely to the surface are sometimes approached by the olivary safe entry zone. (d, inset) Preoperative diffusion tensor imaging–based fiber-tracking (tractography) demonstrated posterolateral displacement of the motor fibers. In this case, the lesion determined the safest entry zone to be an anterior approach. (e) A brainstem cross-section at the level of the olivary nucleus illustrates the olivary safe entry zone (green shading). Anatomically, the olive is limited anteriorly by the pyramids, medially by the hypoglossal nerve (cranial nerve XII) fibers and medial lemniscus, and posteriorly by the tectospinal and spinothalamic tracts. A safe depth (4.7–6.9 mm) and vertical length (13.5 mm) of dissection, whereby the olive is traversed, has been reported. (Data from Recalde et al 2008.1 Illustration © Glia Media. Reproduced with permission.)

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evidence of progression before recommending definitive surgical treatment. Our patient had recovered fully from the initial episode and had remained asymptomatic for 3 years when she arrived in our emergency department with acute onset of nausea, dizziness, imbalance, and swallowing difficulties. Imaging showed that the cavernoma had enlarged and was now reaching the surface and expanding the left hemimedulla (Fig. 8.2b). Motor examination showed the patient to be intact, so we assumed that the lesion had displaced but not destroyed the pyramidal tracts. Diffusion tensor imaging  (DTI)–based fiber tracking  (tractography) confirmed that the pyramidal tracts were displaced posteriorly and laterally. We were faced with deciding between two options: (1) to approach the lesion by the traditional safe entry zone into the medulla (far lateral approach and olivary sulcus) with the risk of retracting the pyramidal tracts, or (2) to approach the lesion by a straight anterior trajectory. Trusting that the fiber tracking correctly depicted the actual location of the pyramidal tracts in this patient, we were able to achieve complete resection (Fig. 8.2c) using an endoscopic transnasal transclival approach (Fig. 8.2d, e).

Strategy Lateral access into the brainstem is generally considered to be more forgiving than access via a direct ventral approach because of the ventral location of the corticospinal tracts and motor brainstem nuclei. These concerns are heightened in surgical approaches to the compact brainstem medulla. In general, intramedullary surgery is seldom pursued. When used, it is usually for biopsy or partial resection of the exophytic component of an intrinsic medullary tumor. The surgical approach is usually suboccipital or far lateral to the posterior or lateral medulla. However, whether any truly safe entry zone exists in the medulla is debatable. One potential safe entry zone is the olive, which is located anterolaterally and can be reached from a posterior approach.7 For lesions that are directly ventral, a transoral approach has been proposed.8 However, large transoral series have demonstrated significant morbidity associated with the approach, even for extra-axial lesions.9 Safe entry zones to the ventral medulla have been described. However, the medulla, more than any other structure in the brain, is unforgiving of even minor damage to fiber tracts and nuclei. Therefore, in this region of the brainstem more so than in any other, the surgeon must “let the lesion do the talking” such that it creates its own safe entry zone. Advances in neuroimaging (e.g., DTI tractography) have provided surgeons with additional information to aid operative decision-making. As a result, the best operative approach can be formulated by supplementing traditional imaging with technologies that provide advanced anatomical information about the direction of the fiber pathway displacement (Fig. 8.2). In this patient, the lesion defined the safe entry zone as the anterolateral sulcus and olivary zone. To reach that zone safely, we utilized an endoscopic transclival approach that necessitated a clivectomy.

Surgery Overview Case 2 illustrates quite well the concept of “let the lesion do the talking.” Because of our concern about the patient’s possible further deterioration in swallowing and our aim to achieve

an unobstructed surgical field, we first established a surgical tracheostomy for use during the procedure for mechanical ventilation. The patient is positioned supine with the head in neutral alignment. In a binostril approach, vascularized nasal septal flaps are elevated on both sides for final reconstruction of the lower clivus. A wide sphenoidotomy and posterior nasal septectomy are performed to facilitate bimanual surgery. The face of the sphenoid rostrum is then identified. The nasal septal flaps are stored in the sphenoid sinus. A small rim of the rostrum is preserved to keep the flaps out of the working area. Intraoperative neuronavigation facilitates identification of anatomical landmarks. The basopharyngeal fascial flap is raised by cutting the fascia from one eustachian tube to the other. The longus capitis and rectus capitis muscles are elevated with the fascial flap in an inverted U-shaped fashion. A diamond drill is used to remove bone from the lower clivus to the foramen magnum, and the underlying dura is exposed. The dura is opened in an inverted U-shaped fashion with the pedicle toward the arch of C1. Both vertebral arteries are identified. Cavernoma-related hemosiderin products can be visualized at the surface of the brainstem. Using small curets and an arachnoid knife, the surgeon resects the cavernoma piecemeal. In our patient, somatosensory evoked potentials and motor evoked potentials (MEPs) used during the entire procedure remained intact during the brainstem corticotomy and removal of the bulk of the cavernoma. Nevertheless, as we were curetting the posterior aspect of the residual cavity, a decrease was noted in MEPs. On awakening, the patient was right hemiplegic, which corroborated the decrease in MEPs in the latter part of the procedure. On postoperative day 5, she progressively began to recover strength, and 10 days later she was discharged to rehabilitation. Two months later, she had regained normal swallowing and full strength in her upper extremities, which included fine motor movements of the hand. Nonetheless, she had a slow gait and a minor limp of her right leg that persisted because of residual 4+/5 weakness of the right foot dorsiflexion. Given the location of the cavernoma, this clinical outcome can be considered satisfactory, but it also serves as a warning that surgery in the medulla oblongata seldom results in a neurologically intact postoperative patient.

Target 3: Exophytic Brainstem Glioma Case 3 A 33-year-old woman presented with an 8-week history of headache that resulted in a diagnosis of exophytic brainstem glioma. This case highlights how a target lesion self-determines the goals of surgery (Fig. 8.3a, b). No procedure for a maximally safe resection exists for the infiltrative component of a glioma that is intrinsic to the brainstem, its nuclei, and its tracts. Therefore, such a lesion allows only biopsy or partial resection of the exophytic component of tumor.

Strategy In alignment with the principle to “build the approach from the inside out,” the transsylvian approach offers the best approach to tumors in the upper pontine cistern that arise from or enter the ventral midbrain or pons (Fig. 8.3c). Because the intrinsic tumor

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Target 4: Thalamic Arteriovenous Malformation Case 4 A 7-year-old girl presented with headache and vomiting due to a spontaneous intraventricular hemorrhage that caused hydrocephalus. Subsequent imaging demonstrated a right thalamic arteriovenous malformation that extended superiorly and medially into the lateral and third ventricles (Fig. 8.4a, b).

Strategy

Fig. 8.3  Exophytic brainstem glioma. Preoperative (a) axial T2-weighted and (b) sagittal T1-weighted magnetic resonance images demonstrating a diffuse intrinsic midbrain and pontine mass. There was no maximally safe entry zone for resection of this tumor, so only a biopsy was performed. (c) Artist’s illustration depicts the transsylvian approach (arrow) via a pterional craniotomy (dashed outline). (Illustration © Glia Media. Reproduced with permission.)

that infiltrates the brainstem cannot be resected, the concept of a safe entry zone does not apply. Thus, attention is redirected to avoid vascular catastrophe caused by injuring the encased basilar artery and its perforators and to avoid entry into functioning brainstem territory through a loss of surgical orientation. Critical to this task are reliable stereotactic guidance technology and neurophysiologic monitoring of somatosensory evoked potentials, MEPs, and CN electromyography. The transsylvian approach will lead the neurosurgeon to use a pterional craniotomy or one of its variations. In this case, we chose a simple frontotemporal craniotomy. This craniotomy with the frontotemporal orbitozygomatic (FTOZ) osteotomy enhances exposure. Compared with a standard frontotemporal craniotomy, the orbital rim osteotomy has been shown to increase exposure of the posterior clinoid, the edge of the tentorium, and the basilar tip by 26 to 39%.10 The addition of a zygomatic osteotomy confers an additional 13 to 22% increase in exposure. However, an FTOZ also increases operative time and can increase approach-related morbidity. As with all skull base approaches, its use should be applied judiciously. In this case, the lesion renders the concept of a safe entry zone immaterial. It is best accessed via a transsylvian approach, prompting use of a pterional or an FTOZ craniotomy.

Given that the thalamus does not have safe entry zones, the locations of the lesion and the hematoma define the surgical approach. In this patient, the arteriovenous malformation and hematoma cavity were in direct communication with the ventricular system. Thus, the safe entry zone was medial to the internal capsule. We used an interhemispheric transcallosal transventricular approach (Fig. 8.4c) with a bilateral frontal parasagittal craniotomy.

Surgery Overview The patient is positioned supine with the thorax elevated 15° and the neck flexed. A U-shaped incision is made; its center is positioned anterior to the coronal suture (two-thirds anterior), crossing the midline, with the base positioned laterally (on the ipsilateral side of the lesion). Two sets of bur holes straddle the sinus (anterior and posterior), and another set of bur holes is placed laterally on the ipsilateral side. Next, the dura over the superior sagittal sinus is stripped away from the bone. A bone flap  (about 4 × 6 cm) positioned two-thirds anterior and onethird posterior to the coronal suture is created. Image navigation may be helpful in planning the craniotomy with the aim of limiting the inclusion of major draining veins.

Surgery Overview A standard frontotemporal craniotomy is performed, and the pterion is further reduced using a drill and rongeurs. The sylvian fissure is opened, and dissection progresses proximally along the M1 segment of the middle cerebral artery toward the supraclinoid internal carotid artery. Opening the opticocarotid cistern releases cerebrospinal fluid and provides additional brain relaxation. Next, the carotico-oculomotor triangle is identified and entered. The deeper membrane of Liliequist is opened sharply, and the interpeduncular and crural cisterns are identified. The oculomotor nerve (CN III) is followed back to its entry zone into the cerebral peduncle. The exophytic component of the lesion should be visible and biopsied or resected accordingly. Biopsy results showed oligoastrocytoma, grade II, with 1p but not 19q deletion. No neurologic deficit was incurred as a result of the biopsy, and the patient subsequently underwent adjuvant therapy.

Fig. 8.4  Thalamic arteriovenous malformation (AVM). Preoperative (a) axial T2-weighted magnetic resonance image (MRI) and (b) angiogram demonstrate an AVM of the right thalamus. Hemorrhage and nidus were largely confined to the medial thalamus. Arterial feeders included the anterior and posterior choroidal arteries and the posterior cerebral arteries. Deep venous drainage involved the internal cerebral vein and the vein of Galen. In this case, the lesion and associated hematoma cavity extended to the medial surface of the thalamus and, in essence, were in direct communication with the lateral and third ventricles. (c) Artist’s illustration depicts the interhemispheric transcallosal transventricular approach (arrow) and frontal parasagittal craniotomy (dashed outline) that were performed to access this lesion directly and to avoid transgression of normal cortex and injury to the internal capsule. Postoperative (d) axial T2-weighted MRI and (e) angiogram showed no evidence of residual nidus. (Illustration © Glia Media. Reproduced with permission.)

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The dural incision, which follows the margin of the craniotomy, is reflected medially toward the superior sagittal sinus. Self-retaining retractors are inserted. The frontal lobe is retracted laterally, whereas the sinus and falx cerebri are retracted medially. Dissection of adhesions is performed, and the retractors are repositioned more deeply to aid visualization of the callosomarginal and pericallosal arteries. Once the pericallosal arteries are dissected laterally, the body of the corpus callosum is visualized. A 3-cm callosotomy is performed using sharp dissection. With opening of the lateral ventricle, cerebrospinal fluid is aspirated and the ventricle is inspected. In this patient, the organized clot that was encountered was aspirated. The anterior and lateral margins of the malformation were then developed using a microsurgical technique. Next, a transchoroidal approach was performed to access the third ventricle and the medial aspect of the malformation. The choroidal fissure was identified and opened, with the approach proceeding posteriorly from the foramen of Monro along the taenia fornicis. Blunt opening of the superior membrane of the tela choroidea exposed the velum interpositum (containing the medial posterior choroidal branches and internal cerebral veins). As dissection continued along the medial side of the malformation, arterial feeding branches were identified and disconnected. Finally, the deep venous drainage was sectioned close to the malformation, and the malformation was removed. Postoperatively, the patient had no evidence of residual nidus on MRI or angiogram (Fig. 8.4d, e) but was densely hemiparetic on the left side. She gradually improved over several months with rehabilitation. At last follow-up (28 months), she continued to have mild left hemiparesis, with 4+/5 lower extremity strength and 3/5 hand strength.

Target 5: Thalamic Glioma Case 5 A 13-year-old boy presented with nausea, vomiting, headaches, and a syncopal episode. He had a slight left facial droop determined to be caused by a thalamic pilocytic astrocytoma (Fig. 8.5a, b).

Strategy Coronal magnetic resonance imaging showed that the tumor involved both the medial and lateral regions of the thalamus. With the expanded thalamus partially filling the third ventricle, one’s first inclination would be to use one of the well-described transventricular approaches (i.e., ipsilateral or contralateral, transcortical or transcallosal, or transchoroidal or transforaminal). Each variation provides subtle yet uniquely important differences in the main axis of the surgical trajectory. All have been successfully applied to the resection of more discrete thalamic lesions, such as cavernous malformations.4 Selection of the most appropriate surgical axis should not only allow the surgeon to reach the entire lesion but also prevent any retraction or mobilization of three critical paraventricular structures: (1) the genu of the internal capsule, located just lateral to the foramen of Monro; (2) the body of the fornices, located medial to each choroidal fissure; and (3) the columns of the fornices, located in the roof and anterior border of the foramen of Monro. Indeed, along with venous infarction from inadvertent sacrifice of the major ventricular veins, damage to the internal capsule or the fornices is among the most dreaded complications of any transventricular surgery.

Fig. 8.5  Thalamic pilocytic astrocytoma. Preoperative (a) axial T1-weighted magnetic resonance image (MRI) with contrast and (b) coronal MRI without contrast demonstrate a large, enhancing thalamic mass extending from the temporal horn laterally to the third ventricle medially. (c) Artist’s illustration depicts how the location and extent of the lesion made it well suited for a transtemporal transventricular approach (arrow) and a temporal craniotomy (dashed outline), which yielded the most direct route to the bulk of the tumor while avoiding injury to the internal capsule and fornices. Postoperative (d) axial and (e) coronal T1-weighted MRIs with contrast demonstrate removal of most of the tumor. (Illustration © Glia Media. Reproduced with permission.)

In this patient, a contralateral transchoroidal approach would have provided excellent exposure to the medial compartment. In contrast, none of the transventricular approaches would have allowed us to safely reach the lateral extent of the tumor without undue retraction on the internal capsule or compromise of the fornices. The lateral aspect of the tumor could be reached by either of two well-described routes: (1) the transsylvian transinsular approach, similar to the approach used for selective amygdalohippocampectomy,11 or (2) a transtemporal transventricular approach. Once again, the coronal magnetic resonance image showed the evident differences in the main surgical axis (Fig. 8.5b). Although the transsylvian approach would provide a more superior-to-inferior view, we considered that it would likely necessitate some retraction on the posterior limb of the internal capsule to expose the medial part of the tumor. Conversely, the transtemporal approach would provide a more inferior-to-superior view, for a trajectory more in line with the main axis of the tumor, from its lateral to its medial edge. In cases like this one, the safe entry zone really converts into a “no-go zone,” meaning that the posterior limb and genu of the internal capsule must be avoided. Applying our principles of “let the lesion do the talking” and “build the approach from the inside out,” we opted for a transtemporal transventricular approach via a temporal craniotomy to the thalamic tumor. Thus, we used the lateral part of the tumor for our entry point and the medial part of the tumor as the final target (Fig. 8.5c). The inferior fibers of the Meyer loop are relatively unavoidable, even with a low approach through the inferior temporal gyrus. We accepted a risk of injury to the ipsilateral optic tract in exchange for a greater margin of safety for the ipsilateral motor fibers and contralateral memory pathways.

Surgery Overview The patient is positioned supine with the head turned to the left. With use of stereotactic frameless guidance, a surgical trajectory is plotted directly into and through the temporal horn of the lateral

8  ventricle to the bulging, discolored tumor on the medial wall of the temporal lobe. During the temporal craniotomy, bony removal is brought flush to the floor of the middle fossa. Because the approach is across the posterior portion of the middle fossa, there is no advantage to a zygomatic osteotomy. The brain will relax as soon as the temporal horn of the lateral ventricle is entered; however, this relaxation also initiates the process of brain shift that, in turn, decreases the accuracy of the stereotactic guidance information. The surgeon will have to progressively depend on the tumor’s visual appearance and texture to distinguish it from normal brain tissue. After surgery, our patient had a permanent homonymous hemianopia, but no other negative effects were discernible; the residual tumor was controlled with radiation (Fig. 8.5d, e). This case best demonstrates how a thalamic tumor can dictate a specific  (and sometimes unique) surgical approach. Specifically, its extension in a certain direction forces the surgeon to follow. In doing so, the lesion defines and sometimes creates its own safe entry zone.

■■ Conclusions These five classic cases emphasize the two principles to follow in the design of surgical approaches to five basic target lesions of the ventral brainstem and thalamus. Our first principle of “let the lesion do the talking” determined the timing and goals of surgery and the operative approach. Our second principle of “build the approach from the inside out” suggested that the surgeon begin with the target itself, further define the safe entry zone, plan a trajectory, and conclude with a craniotomy. Although these basic cases offer ­beginner-level strategies for the maturing brainstem-thalamus surgeon, the two principles offer timeless perspectives and provide a foundation for a new generation of master surgeons who will contribute their own innovations to the treatment of patients with these complex ventral brainstem and thalamic lesions.

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References 1. Recalde RJ, Figueiredo EG, de Oliveira E. Microsurgical anatomy of the safe entry zones on the anterolateral brainstem related to surgical approaches to cavernous malformations. Neurosurgery 2008;62(3) Suppl 1:9–15, discussion 15–17 2. Cavalcanti DD, Preul MC, Kalani MY, Spetzler RF. Microsurgical anatomy of safe entry zones to the brainstem. J Neurosurg 2016;124(5):1359–1376 3. Yağmurlu K, Rhoton AL Jr, Tanriover N, Bennett JA. Three-dimensional microsurgical anatomy and the safe entry zones of the brainstem. Neurosurgery 2014;10 Suppl 4:602–619, discussion 619–620 4. Rangel-Castilla L, Spetzler RF. The 6 thalamic regions: surgical approaches to thalamic cavernous malformations, operative results, and clinical outcomes. J Neurosurg 2015;123(3):676–685 5. Day JD, Fukushima T, Giannotta SL. Microanatomical study of the extradural middle fossa approach to the petroclival and posterior cavernous sinus region: description of the rhomboid construct. Neurosurgery 1994;34(6):1009–1016, discussion 1016 6. Steiger HJ, Hänggi D, Stummer W, Winkler PA. Custom-tailored transdural anterior transpetrosal approach to ventral pons and retroclival regions. J Neurosurg 2006;104(1):38–46 7. Oshiro S, Yamamoto M, Fukushima T. Direct approach to the ventrolateral medulla for cavernous malformation—case report. Neurol Med Chir (Tokyo) 2002;42(10):431–434 8. Reisch R, Bettag M, Perneczky A. Transoral transclival removal of anteriorly placed cavernous malformations of the brainstem. Surg Neurol 2001;56(2):106–115, discussion 115–116 9. Steinberger J, Skovrlj B, Lee NJ, et al. Surgical morbidity and mortality associated with transoral approach to the cervical spine. Spine 2016;41(9):E535–E540 10. Schwartz MS, Anderson GJ, Horgan MA, Kellogg JX, McMenomey SO, Delashaw JB Jr. Quantification of increased exposure resulting from orbital rim and orbitozygomatic osteotomy via the frontotemporal transsylvian approach. J Neurosurg 1999;91(6):1020–1026 11. Kovanda TJ, Tubbs RS, Cohen-Gadol AA. Transsylvian selective amygdalohippocampectomy for treatment of medial temporal lobe epilepsy: surgical technique and operative nuances to avoid complications. Surg Neurol Int 2014;5:133

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Approaches to the Dorsal Brainstem, Thalamus, and Pineal Region M. Yashar S. Kalani, Nikolay L. Martirosyan, and Robert F. Spetzler

Abstract

Approaches to the dorsal brainstem, thalamus, and pineal region are essential for the surgical resection of lesions in the brainstem. Thus, facility and knowledge of skull base approaches and safe entry zones are requisite. For lesions located in the dorsal or dorsolateral brainstem, surgeons must traverse deep venous structures, cranial nerves, and critical arteries to safely remove lesions. This chapter is dedicated to approach selection and the nuances of approaching the dorsal brainstem for removal of intrinsic pathologies. The pertinent anatomy, surgical approach, and nuances of operative technique are presented. Keywords:  brainstem, dorsal, safe entry zone, surgical approach, thalamus

■■ Introduction The selection of an approach is one of the most critical parts of planning an operation for lesions in the brainstem or deep locations in the brain. The choice of approach is heavily influenced by surgeon experience and comfort with the approach. Therefore, for optimal results, surgeons should be familiar and comfortable with a variety of approaches. Key factors to consider for management of intrinsic lesions are the availability of a safe entry zone, the path of least morbidity, and the approach that allows the best exposure to the lesion yet minimizes the need to traverse the brainstem structures. A lesion can often be approached equally well from several different approaches. In these cases, a combination of the path of least morbidity, surgeon experience, and patient habitus dictates the choice of approach. In this chapter, we review the common approaches to the dorsal brainstem and thalamus and highlight the key steps of each approach. A discussion of approach selection that is based on safe entry zones is provided to guide surgeons in their management of intrinsic brainstem and deep-seated pathologies.

been described with several variations: midline, lateral, and extreme lateral approaches (Fig. 9.1). The midline SCIT approach provides a robust route to the pineal gland and pineal pathology. Lateral SCIT and extreme variants7 can be used to gain access to dorsal and dorsolateral mesencephalic and pontomesencephalic pathology and to posterior thalamic lesions, notably cavernous malformations (CMs).4,​8 The SCIT space has the potential to be readily developed after the disconnection of the arachnoid membrane and the sacrifice of small tentorial veins. This space provides a direct posterior approach to the pineal region and the posterior incisura. The pineal region can be exposed after traversing the arachnoid membrane covering the pineal region in a lateral to medial direction and ensuring preservation of the superior cerebellar vein, when possible. The view into the pineal region can be obstructed by the vein of Galen and the splenium of the corpus callosum, but these structures can be readily mobilized to approach pineal pathology and are at times mobilized by the pathology itself. Lateral variants of the SCIT displace the vein of Galen complex and provide a robust approach to intrinsic lesions. The anatomy of the pineal, thalamic, and mesencephalic regions is covered in Chapter 2 (“Anatomy of the Brainstem, Thalamus, Pineal Region, and Cranial Nerves”) and will not be further discussed here.

■■ Approaches Supracerebellar Infratentorial Approach The supracerebellar infratentorial (SCIT) approach is a workhorse for pathology in the pineal region,1,​2,​3 the dorsal thalamus, and the dorsal mesencephalon down to the pontomesencephalic junction.4 The SCIT approach was first utilized in 1911 by Oppenheim and Krause5 and subsequently popularized by Stein6 for lesions in the pineal region. The SCIT approach has

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Fig. 9.1  Illustration shows the trajectories of attack for midline (dark blue arrow), lateral (light blue arrow), and extreme lateral (green arrow) variants of the supracerebellar infratentorial approach. (Used with permission from ­Barrow Neurological Institute, Phoenix, Arizona.)

9  Approaches to the Dorsal Brainstem, Thalamus, and Pineal Region

Fig. 9.2 Midline variant of the supracerebellar infratentorial (SCIT) approach. (a) Drawing shows patient’s position and skin incision (dashed line). (b) Alternatively, the patient can be placed in a sitting position for this approach. (c) Drawing shows craniotomy and dural opening (dashed lines). (d) Exposing the sinus and placing tack-up sutures allows the sinus to be retracted to provide additional working room. (e) Drawing illustrates the area of exposure (shaded area).

■■ Midline Supracerebellar Infratentorial Approach The patient should be placed in the prone position with the head flexed  (Fig. 9.2a). Alternatively, the patient can be placed in the sitting position (Fig. 9.2b). The sitting position allows for gravity retraction of the cerebellum and drainage of blood from the surgical field, but it is less comfortable for the surgeon, and it has been associated with an increased potential for air embolism. The surgeon should perform a linear midline skin incision that extends from the occipital protuberance to the upper cervical spinous processes. The rostrocaudal length of the incision can be extended, depending on the habitus of the patient. The neuronavigation system should be used to identify the location of the transverse sinus and torcula. Although exposure of the transverse sinus is not necessary, it should be blue-lined so that it can be retracted with the tentorium. The dura mater is opened with one pedicle based on the transverse sinus and retracted to expose the cerebellum (Fig. 9.2c). The superior extent of the craniotomy dictates how low on the craniocaudal axis the surgeon can see. This view is maximized by using tack-up stitches to superiorly retract the transverse sinus and torcula (Fig. 9.2d). Next, depending on whether the procedure is performed

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(f) Anatomical dissection demonstrates microsurgical view of the anatomy in a cadaveric specimen from a midline SCIT. Abbreviations: IC, inferior colliculus; M.P.Ch.A., medial posterior choroidal artery; PCA, posterior cerebral artery; Pi, pineal; SC, superior colliculus; SCA, superior cerebellar artery; Tent., tentorium; 3rd Vent., third ventricle. (Used with permission from Barrow Neurological Institute, Phoenix, Arizona.)

microscopically or endoscopically, a piece of Telfa (Covidien) is placed on the cerebellum to protect it while the SCIT potential space is developed. To do so, the surgeon coagulates and cuts the small arachnoid bands and the occasional bridging vein between the superior surface of the cerebellum and the tentorium. Avulsion of these bridging veins can result in bleeding, which can be stopped by placing hemostatics, such as Surgicel Nu-Knit (Ethicon), over the bleeding site. The dissection proceeds to the quadrigeminal cistern, where the vein of Galen and the complex of veins draining into it must be identified and protected. The midline SCIT approach provides robust access to the superior colliculus. Opening the cerebellomesencephalic fissure allows visualization of the inferior colliculus down to the frenulum of the superior medullary velum and visualization of the safe entry zones associated with these structures (Fig. 9.2e).9 The posterior wall of the third ventricle is located anterior to the superior colliculi and the pineal gland (Fig. 9.2f). The pulvinar of the thalamus is lateral to these structures. For improved exposure of the pineal region, the veins of the cerebellomesencephalic fissure and the precerebellar vein can be coagulated and cut without risk of avulsion injury to the veins. Case 1 (Fig. 9.3) illustrates the use of the midline SCIT approach for a brainstem CM.

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Fig. 9.3  Case 1. A 69-year-old woman presented with ataxia and tremor. Preoperative (a) axial T2-weighted, (b) axial fluid-attenuated inversion recovery (FLAIR), and (c) sagittal T1-weighted magnetic resonance images (MRIs) demonstrate a cavernous malformation of the brainstem abutting the pos-

■■ Lateral Supracerebellar Infratentorial Approach For the lateral SCIT, the patient is placed in a position similar to that for the midline SCIT, but the head is rotated to the side ipsilateral to the craniotomy (Fig. 9.4a). Alternatively, the patient can be placed in the park bench position. The more lateral the position of the craniotomy, the more the slope of the tentorium can be used, and the less need there is for retraction on the cerebellum (Fig. 9.4b). A craniotomy is placed lateral from the midline. The size of the craniotomy should be tailored to the size and depth of the lesion. To enhance exposure, the surgeon opens the dura with a pedicle based on the transverse sinus to allow for retraction of the sinus and the tentorium (Fig. 9.4c). There is rarely any need for the placement of permanent retractors, and the cerebellum can often be retracted dynamically using gravity. The lateral SCIT approach provides enhanced exposure of the ipsilateral tectal plate and the superior cerebellar peduncle,

terior incisural space. The lesion was approached using a midline supracerebellar infratentorial approach. Postoperative (d) axial T2-weighted, (e) axial FLAIR, and (f) sagittal T1-weighted MRIs confirm gross total resection. (Used with permission from Barrow Neurological Institute, Phoenix, Arizona.)

and it uses the slope of the tentorium to minimize cerebellar retraction (Fig. 9.4d, e). Case 2 (Fig. 9.5) illustrates the use of the lateral SCIT approach for the resection of a brainstem CM.

■■ Extreme Lateral Supracerebellar Infratentorial Approach The extreme lateral SCIT approach is performed with the patient in the park bench position (Fig. 9.6a). Alternatively, this approach can be performed with the patient supine and the head maximally turned to the contralateral side. The key to the extreme lateral SCIT approach is to extend the head toward the floor to allow for the cerebellum to dynamically retract and to increase the surgeon’s ability to develop the SCIT space. This maneuver places the mastoid at the highest point of the field. A linear skin incision is placed over the transverse sinus at the level of the sigmoid sinus, down to the mastoid tip. A retrosigmoid craniotomy is performed, taking care to ensure that the edge of the transverse

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Fig. 9.4 Lateral supracerebellar infratentorial approach. Illustrations depict (a) patient's position and skin incision (dashed line) used for the approach, (b) the relative angle of the tentorium from midline to lateral, (c) the craniotomy and dural incision (dashed lines), and (d) the area of exposure (shaded area). (e) Anatomical dissection demonstrates

­ icrosurgical view of the anatomy in a cadaveric specimen. Abbreviam tions: IC, inferior colliculus; PCA, posterior cerebral artery; Pi, pineal; SC, superior colliculus; SCA, superior cerebellar artery; Tent., tentorium. (Used with permission from Barrow Neurological Institute, ­Phoenix, Arizona.)

sinus is exposed so that it can be retracted by the dura (Fig. 9.6b). The transverse-sigmoid junction is exposed to allow access to the cerebellopontine angle, as needed, for the release of cerebrospinal fluid  (CSF) for cerebellar relaxation. The dura should be opened with one pedicle at the transverse sinus and with another pedicle at the sigmoid sinus. Retraction of the tentorial surface allows for exposure of the ambient cistern. Care should be taken during this approach to preserve Dandy’s vein when entering the cerebellopontine angle to release CSF. Dissection of the superior cerebellar surface allows visualization of the lateral mesencephalon and identification of the trochlear nerve  (cranial nerve [CN] IV), branches of the superior cerebellar artery, the tectal plate, the superior cerebellar peduncle, and the lateral mesencephalic safe entry zone (Fig. 9.6c, d).9 Case 3 (Fig. 9.7) demonstrates the use of the extreme lateral SCIT approach for resection of a brainstem CM.

popularized by Yonekawa et al11 for resection of lesions in the posteromedial temporal lobe. Yonekawa and colleagues subsequently used this approach to resect a CM of the thalamus.12 Türe et al13 and de Oliveira et al4 described modifications of this approach that provided access to the entire mesial temporal structure. Endoscopic-assisted variants of this approach have been reported for the resection of posteromedial temporal lesions and thalamic lesions. The patient’s position for the SCTT approach is supine, with the head maximally turned to the contralateral side, the neck flexed toward the contralateral shoulder, and the head extended toward the floor (Fig. 9.8a). The ipsilateral shoulder should be elevated, especially for patients who do not have a supple neck. Alternatively, the SCTT approach can be performed with the patient in the sitting,11 park bench, or prone position.14 A linear skin incision is made so that the craniotomy allows for exposure of the transverse sinus in the upper one-fourth of the opening. The optimal placement of the craniotomy allows the surgeon to retract the transverse sinus dynamically to increase working space. Additional considerations r­ egarding the craniotomy

Supracerebellar Transtentorial Approach The supracerebellar transtentorial  (SCTT) approach was first reported in 1976 by Voigt and Yaşargil,10 and it was later

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IV  Surgical Approaches to the Brainstem, Thalamus, and Pineal Region Fig. 9.5  Case 2. A 41-year-old woman presented with diplopia. Preoperative (a) axial, (b) sagittal, and (c) coronal T1-weighted and (d) axial T2-weighted magnetic resonance images (MRIs) demonstrate a brainstem cavernous malforma­tion abutting the posterior incisural space. The lesion was approached using the lateral supracerebellar infra-tentorial approach. Postoperative (e) axial and (f) sagittal T1-weighted and (g) axial and (h) coronal T2-weighted MRIs confirm gross total resection.(Used with permission from Barrow Neurological Institute, Phoenix, Arizona.)

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Fig. 9.6 Extreme lateral variant of the supracerebellar infratentorial approach. Illustrations depict (a) patient’s position and skin incision (dashed line); (b) the craniotomy and dural incision (dashed lines); and (c) the area of exposure (shaded area). (d) Anatomical dissection demonstrates microsurgical view of the anatomy in a cadaveric specimen. 

Abbreviations: CN, cranial nerve; CN IV, trochlear nerve; CN V, trigeminal nerve; IC, inferior colliculus; PCA, posterior cerebral artery; Pet. V., petrosal vein; SC, superior colliculus; SCA, superior cerebellar artery; Tent., tentorium. (Used with permission from Barrow Neurological Institute, Phoenix, Arizona.)

location include optimal placement to make use of the angle of the tentorium to minimize cerebellar relaxation. In general, the more paramedian the craniotomy, the shallower the angle of the tentorium and the more working space the surgeon will have access to. The dural opening should be performed with a pedicle at the transverse sinus, and stitches should be used to assist with retraction and mobilization of the sinus (Fig. 9.8b). In cases where the craniotomy is placed at the junction between the transverse and sigmoid sinuses, CSF can be released from the cerebellopontine angle. Alternatively, the craniotomy can be extended so that CSF can be released from the foramen magnum cistern to achieve brain relaxation. Like the SCIT approach, the SCTT approach develops the potential space between the cerebellum and the tentorium until the surgeon arrives at the optimal point for resection of the lesion (Fig. 9.8c). The optimal point for tentorial disconnection can be identified using neuronavigation. In general, we do

not advocate opening the entire tentorium and instead place a small opening in the tentorium immediately adjacent to the lesion, making sure to prevent injury to CN IV. The tentorium is coagulated and incised using a No. 11 blade. Scissors are used to expand the opening, which is then retracted to improve visualization of the lesion. We do not repair the tentorial opening. The craniotomy is repaired in the usual fashion. Case 4 (Fig. 9.9) illustrates the use of the SCTT for resection of a thalamic or p ­ osterior temporal CM.

Occipital Transtentorial Approach The occipital transtentorial  (OTT) approach was first described by Poppen15 and modified by Jamieson16 to the form that is used today. The OTT approach is an alternative approach to the SCIT for pineal pathology17 and vein of Galen malformations.18,​19 The OTT is especially suitable for lesions in the posterior incisura

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Fig. 9.7  Case 3. A 63-year-old woman presented with left-sided numbness, double vision, dysphagia, gait ataxia, and dizziness. Preoperative (a) axial and (b) sagittal T1-weighted and (c) axial T2-weighted magnetic resonance images (MRIs) demonstrate a brainstem cavernous malformation abutting

the posterior incisural space. The lesion was approached using an extreme lateral variant of the supracerebellar infratentorial approach. Postoperative (d) axial and (e) sagittal T1-weighted MRIs confirm gross total resection. (Used with permission from Barrow Neurological Institute, Phoenix, Arizona.)

Fig. 9.8 Supracerebellar transtentorial approach. Illustrations depict (a) patient’s position and skin incision (dashed line); (b) the craniotomy and dural incision (dashed lines); and (c) the area of exposure (shaded

area). (Used with permission from Barrow Neurological Institute, Phoenix, Arizona.)

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Fig. 9.9 Case 4. A 10-year-old girl with a history of familial cavernous malformations presented with new-onset headache and diplopia. Preoperative (a) axial and (b) sagittal T1-weighted and (c) coronal g ­ radient echo magnetic resonance images (MRIs) demonstrate a lesion in the ­posterior

temporal lobe, abutting the thalamus. The lesion was approached using a supracerebellar transtentorial approach. ­Postoperative (d) axial and (e) coronal T1-weighted MRIs demonstrate complete removal of the lesion. (Used with permission from Barrow Neurological Institute, Phoenix, Arizona.)

and posterior fossa; dorsal brainstem lesions with supratentorial extension; and lesions in the posterior thalamus, the splenium of the corpus callosum, and the mesial temporal structures.20 There are two variations of this approach: the interhemispheric OTT approach and the lateral OTT approach.

of permanent retractors (Fig. 9.10a). A linear skin incision is placed just lateral to midline and crossing the transverse sinus. The craniotomy should cross both the superior sagittal sinus and the transverse sinus so that dural flaps can be based on these sinuses that can be retracted with stitches to increase working angles (Fig. 9.10b). Opening the dura allows the release of CSF from the interhemispheric fissure, and there is usually a vein-sparse region in the posterior third of the sinus that can be used to expose the interhemispheric fissure. When large veins are encountered, working corridors should be expanded around the veins. Venous sacrifice is never appropriate in this area. The release of CSF and the expansion of the posterior interhemispheric fissure allow the surgeon to arrive at the pineal region (Fig. 9.10c). The tentorium adjacent to the confluence of the deep venous system should be carefully opened, ensuring that injury to the vein of Galen is avoided (Fig. 9.10d). Arachnoid bands overlying the ambient cistern, the quadrigeminal cistern, and the precentral cerebellar fissure are cut sharply to visualize the vein of Galen complex (Fig. 9.10e). Appropriate patient positioning obviates the need for fixed retractors, thus reducing the risk of injury to the visual cortex. Closure is performed in the standard fashion.

■■ Interhemispheric Occipital Transtentorial Approach The interhemispheric OTT approach is best used for midline lesions in the posterior incisural space and for lesions extending into the third ventricle, the medial thalamus, and the velum interpositum. However, reports in the literature cite postoperative visual deficits in the range of 19 to 100%21,​22,​23,​24 associated with the use of this approach, which is why this approach is rarely used at our institution. The surgeon should take this factor into consideration when choosing an approach. The patient is positioned prone or in the park bench (left shoulder down) position, and the head is flexed and turned to allow for gravity retraction of the occipital lobe without the use

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Fig. 9.10  Interhemispheric occipital transtentorial approach. Illustrations depict (a) patient’s position and skin incision (dashed line), (b) the craniotomy and dural incision (dashed lines), (c) the area of exposure

■■ Lateral Occipital Transtentorial Approach Like the lateral SCIT approach, the lateral OTT approach makes use of the softer angle of the tentorium as one proceeds laterally from the midline. This approach can be used to resect lesions in the posterior thalamus, pineal region, and midbrain, while allowing the surgeon to look to the contralateral side. The patient is positioned in the park bench position (ipsilateral shoulder down), although this approach can also be performed with the patient in the prone position, in the supine position with the head maximally turned to the contralateral side and the chin tucked, or in the sitting position (Fig. 9.11a). A linear paramedian skin incision is placed so that it crosses the transverse sinus. This craniotomy should be performed so that the transverse sinus is in the lower third of the craniotomy. This allows the surgeon to use stitches to retract the sinus and tentorium inferiorly (Fig. 9.11b). This maneuver reduces the likelihood of injury to the visual cortex. Small tentorial draining veins may have to be sacrificed to develop the supratentorial potential space between the occipital lobe and the tentorium. The surgeon should avoid opening the tentorium in its entire length. Instead, neuronavigation

(shaded area), (d) the site of the tentorial incision (dashed line), and (e) the anatomy that is exposed after the tentorium is opened. (Used with permission from Barrow Neurological Institute, Phoenix, Arizona.)

should be used to arrive at the optimal site of the tentorial opening. The tentorium should be coagulated and cut sharply, taking care to ensure that the trochlear nerve is protected during this maneuver (Fig. 9.11c). Arachnoid bands overlying the ambient cistern, the quadrigeminal cistern, and the precentral cerebellar fissure are cut sharply to visualize the vein of Galen complex (Fig. 9.11d). Closing is performed in the standard fashion.

■■ Far Lateral and Extreme Far Lateral Approaches The far lateral approach was described by Heros25 and popularized by George et al,26 Sen and Sekhar,27 and Spetzler and Grahm28 for lesions at the foramen magnum and for intrinsic lesions at the pontomedullary junction, medulla, and cervicomedullary junction.29,​30,​31 The far lateral approach allows the surgeon a caudocranial view of the dorsal and dorsolateral brainstem. Further dissection and mobilization of the lower CNs and the vertebrobasilar junction can provide glimpses of the ventral brainstem to the level of the pons.

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Fig. 9.11 Lateral occipital transtentorial approach. Illustrations depict (a) patient position, skin incision (dashed line), and craniotomy; (b) the craniotomy and dural incision (dashed lines); (c) the site of the tentorial

­incision (dashed line); and (d) the anatomy that is exposed after the tentorium is opened. (Used with permission from Barrow Neurological Institute, Phoenix, Arizona.)

The patient is positioned in the park bench position with the contralateral shoulder dropped, the head turned contralateral to the side of approach and maximally flexed toward the chest, before being finally flexed laterally toward the contralateral shoulder (Fig. 9.12a, b). The head should be positioned so that the ipsilateral mastoid is the highest point in the surgical field. Caudal retraction of the ipsilateral shoulder increases the craniocervical angle and the surgeon’s working angles. Pressure points are padded, and the patient is secured to the bed so that the surgeon may rotate the bed, allowing for additional surgical working corridors. The skin incision used for the far lateral

craniotomy should be tailored to the pathology. Typically, we use a paramedian skin incision. Alternatively, the skin incision can be a hockey stick opening that starts at the ipsilateral mastoid above the superior nuchal line, curves to the midline, and extends to the upper cervical spine (Fig. 9.12c). The paramedian incision can increase the likelihood of vertebral injury, but this risk can be minimized by using neuronavigation and diligently performing the dissection in layers. Regardless of the type of skin incision used, a small muscular cuff should be maintained at the superior nuchal line to allow for reapproximation of the muscles of the neck. The muscles of the neck are retracted laterally and caudally

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Fig. 9.12  Far lateral approach. (a) Illustration depicts patient position and skin incision for the far lateral approach; a paramedian incision (solid line) or a hockey stick incision (dashed line) can be used. (b) Illustration demonstrates three key movements of the head to optimize positioning for the far lateral approach: (1) the head is flexed so that the chin is 1 cm from the sternum; (2) the head is then rotated contralaterally to the lesion, maximally increasing the angle between the atlas and the foramen magnum; and (3) the head is laterally flexed approximately 30° toward the ­contralateral

shoulder. The contralateral arm is dropped below the level of the body and padded. (c) Illustration depicts a paramedian skin incision (solid line). The hockey stick skin incision (dashed line) can also be used; this incision starts at the tip of the ipsilateral mastoid, continues above the superior nuchal line, and then curves to the midline and down to the upper cervical spine. (d) Drawing illustrates removal of the ipsilateral half of the posterior arch of C1. The horizontal portion of the vertebral artery is identified at the level of the sulcus arteriosus and is protected during the drilling.

to optimize the working space by flattening the surgeon’s view to the craniocervical junction. The far lateral craniotomy is performed as a lateral suboccipital craniotomy and a C1 laminectomy (Fig. 9.12d). We first expose the C1 posterior elements, following the arch laterally to the sulcus arteriosus, where the vertebral artery is identified and protected. The vertebral artery demarcates the lateral extent of the exposure. In rare cases when the

­ xtradural vertebral artery needs to be exposed for proximal e control or when a lesion mandates a more lateral view, which is generally for lesions in the ventral foramen magnum or for intrinsic lesions that are ventrally located, the vertebral artery can be skeletonized and mobilized from the sulcus arteriosus (Fig. 9.12e).32 The vertebral artery can be readily ­identified anatomically or by using neuronavigation. A rich venous plexus usually covers the vertebral artery at the craniovertebral

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Fig. 9.12 (continued)  (e) Illustration depicts the lateral suboccipital craniotomy (dashed line). In rare circumstances, the vertebral artery may need to be released from its bony coverings and mobilized (upper left) to obtain a more lateral view of the brainstem. (f) Drawing illustrates the drilling of the occipital condyle to obtain a flatter view of the ventrolateral brainstem. (g) The dura is opened in a curvilinear fashion. The dural flap is laterally hinged to maximize the lateral-to-medial exposure. (h) Drawing illustrates the view of the cervicomedullary junction obtained after a far lateral craniotomy is performed.

­ bbreviations: CN, cranial nerve; CN IX, glossopharyngeal nerve; CN X, vagus A nerve; CN XI, spinal accessory nerve; CN XII, hypoglossal nerve; C2, second cervical vertebra; PICA, posteroinferior cerebellar artery. (Figs. 9.12a-c,g are used with permission from Barrow Neurological Institute, Phoenix, Arizona. Figs. 9.12d-f, h are reproduced with permission from Baldwin HZ, Miller CG, van Loveren HR, et al. The far lateral/combined supra and infratentorial approach. A human cadaveric prosection model for routes of access to the petroclival region and ventral brain stem. J Neurosurg 1994;81:60–68.)

j­unction, and brisk bleeding may be encountered during dissection. The bleeding from the veins responds well to hemostatics and pressure. The vertebral artery should be identified and protected while performing the C1 laminectomy and the lateral suboccipital craniotomy and while drilling the occipital condyle (Fig. 9.12e, f). The arch of C1 can be removed using a drill or rongeurs. The foramen magnum lip is identified, and a footplate is used to perform the lateral suboccipital craniotomy. With the lateral suboccipital bone removed, the surgeon can visualize the occipital condyle and evaluate the degree of bony removal that is necessary. The degree of condyle removal is dictated by the pathology, but it should not exceed 50% of the condyle to avoid instability of the craniovertebral junction (Fig. 9.12f).33 Drilling the condyle flattens the view of the ventrolateral brainstem.

The dura is opened in a curvilinear fashion and retracted using sutures (Fig. 9.12g). Release of CSF from the foramen magnum cistern allows for brain relaxation and visualization of the cervicomedullary junction (Fig. 9.12h). At the completion of the procedure, the surgeon should obtain a watertight closure of the dura. Closure is performed in the standard fashion. When possible, the suboccipital bone and the posterior arch of C1 should be replaced with plates. Case 5 (Fig. 9.13) illustrates the use of the far lateral approach for resection of an intrinsic brainstem lesion.

■■ Suboccipital and Telovelar Approaches The suboccipital approach was first reported by Woolsey and popularized by Krause.34 The suboccipital approach is a

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Fig. 9.13  Case 5. A 26-year-old woman presents after multiple episodes of hemorrhage. Preoperative (a) sagittal T1-weighted, (b) coronal gradient echo, and (c) axial T2-weighted magnetic resonance imaging (MRI) demonstrates a lesion in the ventral cervicomedullary ­junction.

The lesion was approached and completely removed using a far ­lateral approach. (d) Postoperative axial T2-weighted MRI demonstrates complete removal of tumor.

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Fig. 9.14 Midline suboccipital approach. Illustrations depict (a) patient’s position and skin incision (dashed line); (b) the craniotomy and dural opening (dashed lines); and (c) the anatomy that is exposed after the middle suboccipital area is opened. (Used with permission from Barrow Neurological Institute, Phoenix, Arizona.)

workhorse approach for lesions in the posterior fossa. The midline approach can be used to address lesions in the cerebellum, the dorsal cervicomedullary junction, the medulla, and the pons. When the suboccipital approach is combined with the telovelar extension, and the clefts in the cerebellomedullary fissure are opened, the suboccipital approach can address lesions in the fourth ventricle that extend to the lateral recess.

■■ Suboccipital Approach The patient is positioned prone with the neck flexed toward the sternum (Fig. 9.14a). A linear midline skin incision is performed to expose the suboccipital and upper cervical spine (Fig. 9.14b). The extent of the skin incision is dictated in part by patient

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Fig. 9.15  Case 6. A 56-year-old man presented with sudden-onset facial weakness and diplopia. Preoperative (a) axial and (b) sagittal T1-weighted magnetic resonance imaging (MRI) demonstrates a pontine cavernous malformation that abuts the floor of the fourth ventricle. The lesion

was approached using a midline suboccipital approach. Postoperative (c) ­ sagittal T1-weighted and (d) axial T2-weighted MRI demonstrates ­complete removal of the lesion.

habitus and in part by how far rostrally the surgeon needs to visualize. For rostrally located lesions, more exposure of the cervical spine and more head flexion are required to gain the necessary working angles. The neck muscles are dissected and stripped to expose the occipital bone and the foramen magnum. Once the lip of the foramen magnum is identified, a footplate is used to perform a suboccipital craniotomy. The lateral extents of the craniotomy are dictated by the pathology and its location, but the opening rarely needs to have a diameter greater than 5 cm. The dura is opened in a Y fashion and tacked back. The release of CSF from the foramen magnum cis-

tern allows for brain relaxation. For lesions in the midline, the arachnoid bands connecting the cerebellar hemispheres are sharply dissected, with care taken to avoid injuring any loops of the posterior inferior cerebellar artery that may be attached to the undersurface of the cerebellar hemisphere (Fig. 9.14c). Closure is performed in the standard fashion, but care must be taken to obtain watertight closure of the dura of the posterior fossa and the fascia to prevent CSF leakage. Case 6 (Fig. 9.15) illustrates the use of the midline suboccipital craniotomy for resection of a CM in the posterior pons abutting the pia of the floor of the fourth ventricle.

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Fig. 9.16  Telovelar suboccipital approach. The patient is placed in the same position as for a suboccipital approach. Illustrations depict (a) the anatomy of the uvulotonsillar space; (b) the inferior medullary velum and tela choroidea; and (c) the opening of the inferior medullary velum to allow exposure and visualization of the contents of the foramen of Luschka. (Used with ­permission from Barrow Neurological Institute, Phoenix, Arizona.)

■■ Suboccipital Telovelar Approach Using a standard suboccipital approach, the surgeon exposes the cerebellomedullary fissure and the uvulotonsillar space  (Fig. 9.16a).35 Sharp dissection of the uvulotonsillar space releases the cerebellar tonsils from the uvula and the cervicomedullary junction. Lateral retraction of the cerebellar tonsils allows for exposure of the inferior medullary velum and the tela choroidea (Fig. 9.16b). The tela choroidea, which forms the caudal part of the roof of the fourth ventricle, is sharply incised from the foramen of Magendie and followed laterally to the foramen of Luschka. Next, the inferior medullary velum is opened to increase the working room (Fig. 9.16c). These maneuvers allow

the surgeon to retract the uvula and increase working corridors. Case 7 (Fig. 9.17) illustrates the use of the suboccipital telovelar approach for a laterally placed dorsal pontine CM.

■■ Approach Selection, Two-point Method, and Safe Entry Zones The selection of an approach for intrinsic brainstem pathology should take into consideration the risk of morbidity associated with the approach. Table 9.19 and Table 9.29 summarize the regions of the brainstem and the safe entry zones that are exposed with each approach.

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Fig. 9.17  Case 7. A 32-year-old woman with multiple episodes of hemorrhage and diplopia. Preoperative (a) axial, (b) sagittal, and (c) coronal T1-weighted magnetic resonance imaging (MRI) demonstrates a dorsal pontine cavernous malformation that is deep and eccentric to the left

side. The lesion was approached using a telovelar suboccipital approach. (d) Postoperative axial T1-weighted MRI demonstrates complete removal of the lesion.

In general, three considerations should be used to select an approach. First, the approach should minimize the traversal of critical neural pathways. For example, if a lesion is located in the mesencephalon and could be approached either through an orbitozygomatic craniotomy or through a retrosigmoid craniotomy, the surgeon should consider using the more lateral approach to minimize injury to the ventrally placed corticospinal tract (Fig. 9.18). Second, the surgeon should preferentially

approach an intrinsic lesion at the point where it comes closest to a pial surface, but not at the risk of traversing critical tracts. The best path is not always the shortest. This strategy has been called the two-point method,36 and it consists of drawing a line from a point at the center of the lesion to the point where the lesion most closely approaches a pial surface (Fig. 9.19). Third, safe entry zones9 should be used, when possible, to gain entry into the brainstem, especially for deep lesions.

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Table 9.1  Surgical approaches to the brainstem according to lesion location

Lesion location

Anterior

Lateral

Posterior

Midbrain

OZ, mini-OZ, PT

Anterolateral: OZ, mini-OZ, ST

Median SCIT

Posterolateral: Paramedian or extreme lateral SCIT Pons

ST ± TT ± AP, RL, RS

RS

SOTV ± C1 laminoplasty

Medulla

FL

Upper medulla: FL, RS

SOTV

Lower medulla: FL Abbreviations: AP, anterior petrosectomy; FL, far lateral; OZ, orbitozygomatic; PT, pterional; RL, retrolabyrinthine; RS, retrosigmoid; SCIT, supracerebellar infratentorial; SOTV, suboccipital telovelar; ST, subtemporal; TT, transtentorial. Adapted from from Calvacanti et al 2016.9

Table 9.2  Accessible safe entry zones by surgical approach

Approach

Safe entry zones

Orbitozygomatic

AMZ, IZ

Subtemporal

AMZ

Subtemporal transtentorial

AMZ, STZ

Anterior petrosectomy

AMZ, STZ, PTZ

Suboccipital telovelar

MS

Median SCIT

LMS, IC, LP, SC, IF

Extreme lateral SCIT

LMS, IC, LP, SC, IF

Retrosigmoid

LMS, STZ, PTZ, LPZ, AL, PM, LMZ

Far lateral

AL, PM, LMZ, olivary

Retrolabyrinthine

LMS, STZ, PTZ, LPZ, AL, PM, LMZ, olivary

Abbreviations: AL, anterolateral sulcus of medulla; AMZ, anterior mesencephalic zone; IC, intercollicular; IF, infracollicular; IZ, interpeduncular zone; LMS, lateral mesencephalic sulcus; LMZ, lateral medullary zone; LP, lateral pontine; LPZ, lateral pontine zone; MS, median sulcus of fourth ventricle; PM, posterior median sulcus of medulla; PTZ, peritrigeminal zone; SC, supracollicular; SCIT, supracerebellar infratentorial; STZ, supratrigeminal zone. Adapted from Cavalcanti et al 2016.9

Fig. 9.18 Illustration depicts the location of the corticospinal tract and its ventral displacement by a lesion in the mesencephalon. Although an orbitozygomatic approach (pink arrow) can be used, a lateral approach, such as the retrosigmoid (green arrow), minimizes morbidity to the ventrally located motor pathways. (Used with permission from Barrow Neurological Institute, Phoenix, Arizona.)

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Fig. 9.19 Examples of the two-point method using two different lesion locations near the corticospinal tract. (a,b) One point is placed in the center of the lesion (1), and another point is placed where the lesion most closely approaches the pial surface (2). (c) A line between the two points is extended to the surface of the skull to determine the craniotomy. In the examples shown here, one lesion (shown in a) is best approached through

■■ Conclusions The selection of approaches to deep-seated lesions and to lesions in the brainstem is an art form. Safe entry zones, paths of least morbidity to the lesion, surgeon experience with approaches, and patient habitus influence the choice of approach. There is often more than one approach to a lesion, and the surgeon must weigh the pros and cons of the possible approaches to select the approach that optimizes patient outcome. References 1. Kulwin C, Matsushima K, Malekpour M, Cohen-Gadol AA. Lateral supracerebellar infratentorial approach for microsurgical resection of large midline pineal region tumors: techniques to expand the operative corridor. J Neurosurg 2016;124(1):269–276 2. Uschold T, Abla AA, Fusco D, Bristol RE, Nakaji P. Supracerebellar infratentorial endoscopically controlled resection of pineal lesions: case series and operative technique. J Neurosurg Pediatr 2011;8(6):554–564 3. Zaidi HA, Elhadi AM, Lei T, Preul MC, Little AS, Nakaji P. Minimally invasive endoscopic supracerebellar-infratentorial surgery of the pineal region: anatomical comparison of four variant approaches. World Neurosurg 2015;84(2):257–266 4. de Oliveira JG, Lekovic GP, Safavi-Abbasi S, et al. Supracerebellar infratentorial approach to cavernous malformations of the brainstem: surgical variants and clinical experience with 45 patients. Neurosurgery 2010;66(2):389–399 5. Oppenheim H, Krause F. Operative Erfloge bei Geschwulsten der Sehh ugel-und Vierhugelgeggend. Berl Klin Wochenschr 1913;50:2316–2322 6. Stein BM. Supracerebellar-infratentorial approach to pineal tumors. Surg Neurol 1979;11(5):331–337 7. Vishteh AG, David CA, Marciano FF, Coscarella E, Spetzler RF. Extreme lateral supracerebellar infratentorial approach to the posterolateral mesencephalon: technique and clinical experience. Neurosurgery 2000;46(2):384–388, discussion 388–389

a subtemporal ­craniotomy (yellow arrow and shading) and the other (shown in b) is best approached through an orbitozygomatic craniotomy (red arrow and shading). This method allows the surgeon to select the path that traverses the least amount of sensitive tissue while approaching deep-seated lesions. (Used with permission from Barrow Neurological Institute, Phoenix, Arizona.)

8. Rangel-Castilla L, Spetzler RF. The 6 thalamic regions: surgical approaches to thalamic cavernous malformations, operative results, and clinical outcomes. J Neurosurg 2015;123(3):676–685 9. Cavalcanti DD, Preul MC, Kalani MY, Spetzler RF. Microsurgical anatomy of safe entry zones to the brainstem. J Neurosurg 2016;124(5):1359–1376 10. Voigt K, Yaşargil MG. Cerebral cavernous haemangiomas or cavernomas: incidence, pathology, localization, diagnosis, clinical features and treatment. Review of the literature and report of an unusual case. Neurochirurgia (Stuttg) 1976;19(2):59–68 11. Yonekawa Y, Imhof HG, Taub E, et al. Supracerebellar transtentorial approach to posterior temporomedial structures. J Neurosurg 2001;94(2):339–345 12. Otani N, Fujioka M, Oracioglu B, et al. Thalamic cavernous angioma: paraculminar supracerebellar infratentorial transtentorial approach for the safe and complete surgical removal. Acta Neurochir Suppl (Wien) 2008;103:29–36 13. Türe U, Harput MV, Kaya AH, et al. The paramedian supracerebellartranstentorial approach to the entire length of the mediobasal temporal region: an anatomical and clinical study. Laboratory investigation. J Neurosurg 2012;116(4):773–791 14. Kalani MY, Martirosyan NL, Nakaji P, Spetzler RF. The supracerebellar infratentorial approach to the dorsal midbrain. Neurosurg Focus 2016;40 Video(Suppl 1)–FocusVid 1, 15462 15. Poppen JL. The right occipital approach to a pinealoma. J Neurosurg 1966;25(6):706–710 16. Jamieson KG. Excision of pineal tumors. J Neurosurg 1971;35(5):550–553 17. Kalani MY, Wilson DA, Koechlin NO, et al. Pineal cyst resection in the absence of ventriculomegaly or Parinaud’s syndrome: clinical outcomes and implications for patient selection. J Neurosurg 2015;123(2):352–356 18. McLaughlin N, Martin NA. The occipital interhemispheric transtentorial approach for superior vermian, superomedian cerebellar, and tectal arteriovenous malformations: advantages, limitations, and alternatives. World Neurosurg 2014;82(3–4):409–416 19. Cavalcanti DD, Kalani MYS, Spetzler RF. Microsurgical treatment of vein of Galen malformations. In: Sptezler RF, Kalani MYS, Nakaji P, eds. Neurovascular Surgery. 2nd ed. New York: Thieme;2015:886–899

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20. Moshel YA, Parker EC, Kelly PJ. Occipital transtentorial approach to the precentral cerebellar fissure and posterior incisural space. Neurosurgery 2009;65(3):554–564, discussion 564

29. Deshmukh VR, Rangel-Castilla L, Spetzler RF. Lateral inferior cerebellar peduncle approach to dorsolateral medullary cavernous malformation. J Neurosurg 2014;121(3):723–729

21. Ausman JI, Malik GM, Dujovny M, Mann R. Three-quarter prone approach to the pineal-tentorial region. Surg Neurol 1988;29(4):298–306

30. Abla AA, Turner JD, Mitha AP, Lekovic G, Spetzler RF. Surgical approaches to brainstem cavernous malformations. Neurosurg Focus 2010;29(3):E8

22. Kurokawa Y, Uede T, Hashi K. Operative approach to mediosuperior cerebellar tumors: occipital interhemispheric transtentorial approach. Surg Neurol 1999;51(4):421–425 23. Nazzaro JM, Shults WT, Neuwelt EA. Neuro-ophthalmological function of patients with pineal region tumors approached transtentorially in the semisitting position. J Neurosurg 1992;76(5):746–751 24. Chi JH, Lawton MT. Posterior interhemispheric approach: surgical technique, application to vascular lesions, and benefits of gravity retraction. Neurosurgery 2006;59(1, Suppl 1):ONS41–ONS49, discussion ONS41–ONS49 25. Heros RC. Lateral suboccipital approach for vertebral and vertebrobasilar artery lesions. J Neurosurg 1986;64(4):559–562 26. George B, Dematons C, Cophignon J. Lateral approach to the anterior portion of the foramen magnum: application to surgical removal of 14 benign tumors. Technical note. Surg Neurol 1988;29(6):484–490 27. Sen CN, Sekhar LN. An extreme lateral approach to intradural lesions of the cervical spine and foramen magnum. Neurosurgery 1990;27(2):197–204 28. Spetzler RF, Grahm TW. The far lateral approach to the inferior clivus and the upper cervical region. Technical note. Barrow Neurological Institute Quarterly 1990;6:35–38

31. Lanzino G, Paolini S, Spetzler RF. Far lateral approach to the craniocervical junction. Neurosurgery 2005;57(4, Suppl):367–371, discussion 367–371 32. Kawashima M, Tanriover N, Rhoton AL Jr, Ulm AJ, Matsushima T. Comparison of the far lateral and extreme lateral variants of the atlanto-occipital transarticular approach to anterior extradural lesions of the craniovertebral junction. Neurosurgery 2003;53(3):662–674, discussion 674–675 33. Vishteh AG, Crawford NR, Melton MS, Spetzler RF, Sonntag VK, Dickman CA. Stability of the craniovertebral junction after unilateral occipital condyle resection: a biomechanical study. J Neurosurg 1999;90(1, Suppl):91–98 34. Dandy WE. Results of removal of acoustic tumors by the unilateral approach. Arch Surg 1941;42(6):1026–1033 35. Mussi AC, Rhoton AL Jr. Telovelar approach to the fourth ventricle: microsurgical anatomy. J Neurosurg 2000;92(5):812–823 36. Brown AP, Thompson BG, Spetzler RF. The two-point method: evaluating brain stem lesions. Barrow Neurological Institute Quarterly 1996;12:20–24

10

Skull Base Approaches to the Lateral Brainstem and Cranial Nerves Takanori Fukushima

Abstract

Various microsurgical approaches to the lateral brainstem are described, including their concepts, application, microanatomy, and surgical techniques. Beginning with the basic retrosigmoid approach, the “cerebellopontine angle rule of three” is defined to provide a better understanding of microvascular decompression surgeries. The technique of internal auditory canal unroofing is described for resection of intracanalicular tumors. The retrolabyrinthine transsigmoid approach and translabyrinthine approach, two variations of a mastoidectomy, are specified to show how to obtain an anterior corridor to the lateral brainstem. Two types of transcondylar approaches are defined that can be used with pathologies situated in the jugular foramen, with and without extension to the high cervical area. For lesions situated rostrally or with more extension into the supratentorial area, the middle fossa rhomboid anterior petrosectomy or combined petrosal approach can be applied. Finally, optimum approaches to brainstem cavernous malformations are described. Keywords:  brainstem cavernoma, cerebellopontine angle, combined petrosal, lateral brainstem, middle fossa, petrosectomy, retrosigmoid, transcondylar, vestibular schwannoma

■■ Introduction Surgery of parabrainstem lesions and cranial nerve (CN) disorders is one of the most exciting and challenging subjects for neurosurgeons, particularly for skull base specialists. The senior author (T.F.) of this chapter has experience with more than 10,000 cases of parabrainstem lesions (Table 10.1). In many of these cases, microvascular decompressions were performed through a retrosigmoid approach. However, for radical resection of parabrainstem tumors, 731 extended middle fossa approaches (including the anterior petrosectomy approach), 271 far lateral transcondylar approaches, and 254 combined petrosal approaches were used. Since 1980, revolutionary changes have been made in skull base surgery. From conventional intradural microsurgery to extradural microsurgery, skull base techniques and skull base approaches have become a definitive subspecialty in the neurosurgical field. The field has seen developments of many new skull base operative approaches, improved dissection techniques, and development of special skull base microsurgical instruments, as well as production of innovative equipment, such as electric power drills and ultrasonic aspirators. Innovative extradural skull base approaches have been established, such as the combined transpetrosal approach, middle fossa rhomboid anterior petrosectomy approach, and extreme lateral infrajugular transcondylar exposure (ELITE) approach (Fig. 10.1). These

approaches were mostly developed in the 1980s and include the revolutionary development of the extradural anteromedial transcavernous approach by Dolenc1 and also others by Japanese neurosurgeons such as Hakuba, Kawase,2 and Fukushima. After the development of such skull base approaches and extradural dissection techniques in the 1980s, a boom of skull base surgery occurred in the 1990s all around the world. Along with the expansion in the number and types of approaches, tremendous advances were made in neuroradiology imaging, monitoring, and neurosurgical instruments. Magnetic resonance imaging (MRI) technology was invented in 1982, and high-resolution 1.5- and 3-tesla MRI equipment was developed in the late 1990s and in 2000. Ultrasound technology has also significantly advanced with high-resolution intraoperative imaging. Nowadays, we have three-dimensional fused computed tomography and MRI images, with functional MRI as well as fiber tracking images of the brain and brainstem, which can be used intraoperatively. Development of highly accurate three-dimensional computerized volumetric navigational systems enabled us to precisely indicate the Table 10.1  Surgical experience with parabrainstem lesions (1980–2015)

Lesion type

No. of patients

Tumors

3,763

• Neurinomas (CN III–XII)

2,332

• Meningiomas

1,431

–– Petroclival

588

–– Foramen magnum and jugular foramen

130

–– Dorsal

77

–– Epidermoids and dermoids

361

–– Chordomas

131

–– Glomus tumors

56

–– Ependymomas

31

–– Exophytic gliomas

29

–– Hemangioblastomas

15

–– Choroid plexus papillomas

13

Cavernomas

108

• Intra-axial

102

• Extra-axial

6

Microvascular decompressions

6,560

• Hemifacial spasm

3,605

• Trigeminal neuralgia

2,867

• Glossopharyngeal neuralgia

88

Total

10,431

Abbreviation: CN, cranial nerve.

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Fig. 10.1 Schema of surgical approaches to reach lesions in the lateral brainstem (right side view). Abbreviations: app., approach; CPA,

cerebellopontine angle; ELITE, extreme lateral infrajugular transcondylar exposure.

important cranial base neurovascular structures, tumor size, and extensions preoperatively and intraoperatively. Extradural bone shaving, drilling, and removal facilitate closer and less invasive access to the lesion with minimum brain manipulation. What makes surgery to the lateral brainstem so difficult? Is it the temporal bone covering and protecting the brainstem with vital structures, such as the internal carotid artery (ICA), venous sinuses, vestibular and auditory system, or other CNs tunneling through the area? Is it the narrow corridor between the cerebellum and the medial wall of the petrosal bone? Or is it the CNs that arise from the brainstem and run through this narrow cistern? All of these are obstacles that surgeons encounter in reaching the lateral brainstem. That is why a neurosurgeon inevitably needs to understand the precise microanatomy, pathologic process, and surgical approach thoroughly before sufficiently and safely performing lateral brainstem surgery. In this chapter, approaches to the lateral brainstem are divided into posterior fossa intradural lateral approaches, combined suprainfratentorial approaches, and the combined petrosal approach and are discussed in detail, whereas approaches to cavernous malformations in the lateral brainstem are briefly described.

Retrosigmoid Approach (Transtemporal Retrolabyrinthine)

■■ Posterior Fossa Intradural Lateral Approaches Four types of intradural approaches through the posterior fossa that give access to the lateral portion of brainstem are discussed below: (1) retrosigmoid (transtemporal retrolabyrinthine), (2) retrolabyrinthine transsigmoid, (3) translabyrinthine, and (4) far lateral transcondylar exposure, or ELITE.

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The transtemporal retrolabyrinthine or retrosigmoid approach is one of the most commonly used skull base approaches to access the cerebellopontine angle (CPA) and the lateral brainstem, particularly for resection of vestibular schwannomas or meningiomas. This approach is essential for preserving the hearing of patients when treating smaller vestibular schwannomas. The advantages of the retrosigmoid approach are that (1) it is simple and familiar, (2) anatomical landmarks are easily identifiable, (3) a wide range of access is created to the lateral brainstem from the tentorial edge down to the foramen magnum, and (4) no temporal lobe retraction or manipulation is necessary. The disadvantages are that (1) occasionally swelling occurs because of cerebellar retraction and edema; (2) it is difficult to visualize the very lateral portion (2–3 mm) and fundus of the internal auditory canal (IAC), when necessary; and (3) access to the supratentorial extension is limited. The retraction of the cerebellum can be minimized with the use of lumbar drains and adequate bone removal. Both insufficient and excessive opening can cause unnecessary problems to the vital structures, such as postoperative swelling or contusion of the cerebellum and thrombosis within the sigmoid or transverse sinuses. We propose that the approaches to the CPA be divided into three types, depending on the location of the target anatomy. This “CPA rule of three” provides a better understanding of the CPA microanatomy and dissection as described below. Retrosigmoid approaches to the CPA should be divided into three types: upper, middle, and lower (Fig. 10.1). This concept helps surgeons to understand where the keyhole opening should be placed when

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planning to remove a CPA lesion. The upper CPA approach is used for lesions in the trigeminal area; the middle CPA approach is mostly for lesions at and near the internal acoustic meatus; and the lower CPA approach is for lesions around the jugular foramen, such as glossopharyngeal neuralgias, hemifacial spasms, and tumors. The size of the craniotomy should be customized according to the size and extent of the tumor, but the surgeon should always keep the minimally invasive concept in mind to avoid unnecessarily large openings.

Fukushima Lateral Position and Head Fixation For any surgery, positioning the patient properly and safely is the first step in a successful surgery. The Fukushima lateral position is used for the retrosigmoid approach, along with many other approaches dealing with the lateral skull base (Fig. 10.2). After general anesthesia, the patient is placed in the lateral position with the backboard elevated approximately 20°. After the patient is placed in the lateral position, the patient’s back is brought close to the edge of the table so that the surgeon does not have to extend his or her arms during surgery, which can cause fatigue. The patient’s shoulders are positioned at the cephalad end of the surgical table, with an axillary roll placed underneath the axilla to prevent any compression of the brach­ ial plexus. The patient’s feet are laid toward the other side so the body lies obliquely across the table. This allows the patient’s back to roll slightly posteriorly in order to expose the abdomen. The patient’s lower leg is flexed 90° at the knee, while the other leg is kept only slightly flexed. Gel pads are placed underneath the trochanter, and pillows are placed between the legs to prevent decubitus ulcers. Both arms are outstretched

Fig. 10.2 Fukushima lateral patient position used for the retrosigmoid approach. (a) Illustration (superior view) of patient positioning, with the right arm placed at a 45° angle and the upper shoulder three-fourths lateral prone (dashed line) and with the right leg in an oblique lying position (dashed line).

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on arm boards with care taken to pad the ulnar nerve at the medial epicondyle and the radial nerve at the radial groove of the humerus. The dependent arm is positioned 90° to the longitudinal axis of the body while the upper arm is positioned 45° to the body to ensure space is available if abdominal fat is needed. The shoulder of the patient’s nondependent arm must be rolled anteriorly and pulled gently in the caudal direction to create space for the surgeon to “look up” in a caudal to cranial direction if necessary. The patient’s head is then placed in three-point fixation. The ultimate purpose is simply to make the mastoid the highest point and the surface of the mastoid parallel to the floor. This is achieved by first lifting up the patient’s head to secure space between the shoulder and the neck of the lower side to avoid obstruction of the venous pathways. Then the patient’s cranial vertex should be tilted slightly down to make the nose parallel with the floor, because the backboard has been elevated (Fig. 10.2a-c). This head position will provide the surgeon with access to the middle fossa, the CPA, the mastoid process, the petrous bone, and the far lateral skull base extending down to the foramen magnum and upper cervical spine.

Skin Incision After minimal shaving of the retroauricular area hair, all monitoring electrodes are placed. The mastoid body and tip, the root of the zygoma, and the supramastoid crest should be identified before planning the skin incision  (Fig. 10.3). As Day et al3 demonstrated, the line connecting the root of the zygoma to the inion approximates the course of the transverse sinus. A C-shaped postauricular incision measuring 5 cm or a lazy-S

(b) Illustration of patient placement (axial view) with whole head elevated from the lower shoulder and the vertex in the down position. (c) Preoperative photograph of patient placement (posterior view) with torso (head of bed) elevated 15°–20°.

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Fig. 10.3  Various skin incisions used for approaches to the lateral brainstem. (a) Retrosigmoid approach, C-shaped incision (black line); retrosigmoid approach, lazy-S incision (orange line); transmastoid approach (pink line); extended middle fossa approach (green line); and standard middle fossa

approach (purple line). (b) Combined petrosal approach, chef's hat incision (blue line) or large C-shaped or L-shaped incision (white line); anterolateral extreme lateral infrajugular transcondylar exposure (ELITE) approach (yellow line); and dorsolateral ELITE approach (red line). Abbreviation: app, approach.

i­ncision is made to obtain adequate exposure of the mastoid bone and the suboccipital region. Both incisions start from just above the supramastoid crest, passing 2 cm posterior to the body of the mastoid, terminating at the level of the mastoid tip. The C-shaped incision gives more medial to lateral axis than the lazyS incision. The lazy-S incision is mainly used for microvascular transposition surgeries. The scalp is elevated with the galea aponeurotica above the fascia of the suboccipital muscles. A fascial graft is harvested for watertight closure at this point. Suboccipital muscle is dissected in the same fashion as the skin incision and reflected anteriorly. Before the craniotomy is performed, the bony landmarks of the suboccipital region are appreciated.

edge of the incised dura. These small but imperative techniques will make significant changes in the operative axis, reducing the overhang of the dura and resulting in less retraction of the cerebellum. Furthermore, the dura protects the brain better than any artificial material, so an unnecessarily wide opening of the dura should be avoided.

Cerebrospinal Fluid Aspiration

A bur hole is made with a 5-mm extra-coarse diamond drill at the inferior corner of the digastric groove. A longitudinal groove is made at the posterior border of the mastoid body, safely exposing the sigmoid sinus. The groove is continued to identify the transverse sigmoid sinus junction, then shifts posteriorly to identify the caudal edge of the transverse sinus. Inferiorly, a groove can be drilled downward along the inferior edge of the proposed bone flap; it can go all the way down to open the foramen magnum. A craniotome can be used safely for the ­inferior and medial portion of the bone flap.

After the dural incision is made and before the surgeon begins to attack the pathology, cerebrospinal fluid (CSF) should be aspirated to relax the cerebellum and create a corridor to the lateral brainstem, which avoids the need for extensive retraction of the cerebellum. The optimal location for this initial CSF aspiration is by the cerebellomedullary cistern, and it is achieved by incising the arachnoid membrane caudal to the glossopharyngeal and vagus nerve complex (CN IX and CN X) behind the branch of the spinal accessory nerve (CN XII). Combined with other techniques to relax the posterior fossa, such as the use of hypertonic solution, diuretics, and hyperventilation, the release of CSF should relax the cerebellum enough that a tapered 2-mm spatula at the tip of a tubular retractor system will gently “hold” it, providing a wide and safe working space.

Dural Incision

Variations of the Retrosigmoid Approach

The dura is cut using either a C-shaped incision or a T-shaped incision (Fig. 10.4), according to where the main focus of manipulation will be. Two key points when cutting and reflecting the dura are to make the incision as close to the sinus as possible and to put a tack-up or stay suture closer to the sinus, not at the

Fukushima’s CPA rule of three is implied in the transtemporal retrolabyrinthine retrosigmoid approach, depending on the pathology to be treated. Especially for microvascular transposition surgeries, for which a wide opening is not always necessary, a small keyhole craniotomy should be planned according to this rule of three.

Craniotomy

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IV  Surgical Approaches to the Brainstem, Thalamus, and Pineal Region Fig. 10.4 Dural incision for the retrosigmoid approach. Either a T-shaped skin incision (green dashed lines) or a C-shaped skin incision (red dashed line) can be used for this approach.

Approach to the Upper Cerebellopontine Angle: Trigeminal Area Approaching the area around the trigeminal nerve (CN V) requires an opening only in the upper corner of the CPA inferoposterior to the transverse sigmoid sinus junction. An approximately 5-cm linear curve or a lazy-S skin incision (Fig. 10.3a) is made, starting from the supramastoid crest passing 2 cm posterior to the body of mastoid (within the hairline) and ending at the level superior to the mastoid tip. A 2.5 × 2.5-cm craniotomy is made at the transverse sigmoid sinus junction using a 4- or 5-mm diamond bur. It is essential to drill at least half of the bone covering the sinuses. Removal of the inner plate is crucial to do this efficiently. After the dura is opened, the surgeon should be able to identify the dura covering the medial petrous bone and the tentorium. One must be aware and cautious about the bridging veins that may interfere with the targeted pathology. First, in 5 to 10% of cases, the dorsal cerebellar pacchionian venous plexus may be encountered. This venous plexus exists under the transverse sigmoid junction and complements the draining function with petrosal veins and other draining systems in the posterior fossa. Slightly medial to this venous plexus is a dorsal cerebellar tentorial bridging vein in about 30% of patients. When these veins are damaged by retracting the cerebellum carelessly, intensive venous bleeding follows. Hence, when these veins are identified, they should be physically reinforced with small pieces of fibrin glue–soaked Surgicel (Ethicon) or Gelfoam (Pfizer) to prevent damage before the cerebellum is manipulated. The petrosal vein, which is encountered adjacent to the trigeminal nerve root, often comprises one to three branches that drain into the superior petrosal sinus (SPS). At further depth, the paratrigeminal or infratrigeminal clival vein is found in approximately 5% of patients. In the senior author’s (T.F.) experience, these veins

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should be preserved and protected at all times. When the veins are sacrificed, significant swelling of the cerebellum, especially the superior portion, may occur postoperatively.

Horizontal Fissure Approach In contrast to the approach of the CPA, a stronger retraction of the cerebellum is required to reach and obtain direct visualization of the upper pons. Dissection of the horizontal fissure of the cerebellum between the superior semilunar lobule and flocculus reduces the need for this excessive cerebellar retraction. The horizontal fissure approach will expose the root entry zone of the trigeminal nerve and the middle cerebellar peduncle by holding back the superior semilunar lobule. The lateral surface of the pons is easily visualized around the root entry zone. This approach is very useful not only for vascular compression causing trigeminal neuralgia but also for treating brainstem cavernous malformations.4

Approach to the Middle Cerebellopontine Angle: Internal Auditory Canal The middle CPA is mainly used as an approach to the IAC, most often to treat small intracanalicular vestibular schwannomas. The craniotomy is made in the middle between the transverse sigmoid sinus junction to the inferior point of the sigmoid sinus. Anteriorly, the sigmoid sinus should be exposed to obtain a straight-down view to the IAC.

Unroofing the Internal Auditory Canal Tumors originating from, situated only within, or extending into the IAC are most commonly vestibular schwannomas. For these tumors, the IAC needs to be opened for safe and complete resection. The IAC can be drilled either intradurally or extradurally. Intradural IAC drilling is performed after a retrosigmoid

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10  Skull Base Approaches to the Lateral Brainstem and Cranial Nerves craniotomy, and extradural drilling is accomplished after using a translabyrinthine approach.

Intradural Shaving of the Internal Auditory Canal IAC drilling should be performed before the arachnoid is dissected to prevent the spread of bone dust around the brainstem. The dura is elevated over the inner wall of the IAC by making a U-shaped incision using a No. 11 or No. 15 blade scalpel. The incision should begin 2 to 3 mm on either side of the porus acusticus and should extend superolaterally for approximately 10 mm, avoiding the endolymphatic sac. The dural flap is elevated from the bone using a sharp dissector. In recent years, an ultrasonic bone aspirator  (SONOPET; Stryker), which provides extremely safe and effective IAC unroofing, is typically used (Fig. 10.5a). The ultrasonic aspirator is compatible with cottonoids and other materials in the surgical field. The tool will not snag cotton patties as a conventional highspeed drill will. If a high-speed drill is used, the cerebellum surface should be covered and protected with flattened bone wax instead of cottonoids. The position of the endolymphatic sac and vestibule are the lateral limits of the exposure (Fig. 10.5b). Keep in mind the

Fig. 10.5 Shaving the internal auditory canal (IAC) posterior wall. (a) Intraoperative photograph showing the IAC posterior wall being shaved with an ultrasonic aspirator. (b) Illustration demonstrating the lateral limits of posterior wall shaving to protect the vestibule and

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possibility of a high jugular bulb when drilling inferior to the IAC (Fig. 10.5c). During removal of the posterior wall of the IAC, a relatively uniform depth should be maintained throughout the exposure until the dura of the canal is exposed (Fig. 10.5d). Because of the angle of approach, the length of exposure of the IAC is less than the lateral extent of bone removed from the petrous bone surface. Exposing the fundus of the IAC would require blind drilling around the corner, likely resulting in violation of the labyrinth or the vestibule. Thus, the length of IAC drilling from the porus should be kept to a maximum of 7 mm. Keep in mind that the morphology of the temporal bone varies substantially among patients. After the IAC is sufficiently exposed, the dura over the tumor can be excised.

Approach to the Lower Cerebellopontine Angle: Hemifacial Spasms and Glossopharyngeal Neuralgias The approach to the lower CPA focuses on the part of the CPA leading to the lower cranial nerve complex area. The cranial opening is made from the midpoint of the sigmoid sinus to the inferior sigmoid point (Fig. 10.1). This opening includes removing the bone formulating the condylar fossa. Hemifacial spasms and glossopharyngeal neuralgias are best treated with

posterior semicircular canal. (c) Illustration showing the relationship between the IAC and the jugular bulb. (d) Intraoperative photograph showing the 270° exposure of the IAC dura.

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this approach. ­Hemifacial spasms are caused by compression of the root exit zone of the facial nerve (CN VII) and not by compression of the nerve fibers in the cistern. Therefore, there is no need to even see the facial and vestibulocochlear (CN VIII) nerve complex (CN VII-VIII) because the compression point is just medial to the lower CNs. Transposition of the compressing vessel should be done between the choroid plexus and rostral side of the glossopharyngeal nerve. Glossopharyngeal neuralgia is caused by direct compression of the nerve, which can also be treated through this approach.

can be performed to widen the working space further (i.e., the translabyrinthine approach).

Surface Anatomy, Mastoid Triangles, and Skin Incision

The retrolabyrinthine transsigmoid approach exposes the presigmoid posterior fossa dura around the sigmoid sinus, posterior semicircular canal, jugular bulb, and SPS. Advantages of this approach are that (1) it gives a slightly lateral (or anterior) approach to the brainstem compared to the retrosigmoid approach, thereby minimizing brain retraction, and (2) the presigmoid dura may be used to protect the brain. The retrolabyrinthine presigmoid space is fairly limited because of the surrounding vital structures. Therefore, this approach is often combined with additional craniotomies, such as a retrosigmoid craniotomy, and removal of the labyrinth to produce a wider working space. Furthermore, ligation and removal of the sigmoid sinus are feasible. When ipsilateral hearing preservation is not a consideration, removal of the vestibule labyrinth and skeletonization of the IAC

The patient is placed in lateral position with the head fixed as mentioned above. Alternatively, a supine position with a pillow underneath the shoulder of the operative side and head rotation to the contralateral side on a gel ring or horseshoe headrest can be used. The bony landmarks mentioned in the retrosigmoid approach are appreciated here. Three triangles are associated with the mastoid (Fig. 10.6). The outermost triangle is identified by the asterion, the posterior point of the root of the zygoma, and the mastoid tip. This outer triangle is where the cortical bone is drilled away. The inner triangle is outlined by the sinodural angle, the superior aspect of the posterior semicircular canal, and the jugular bulb (Trautmann triangle) or by the sinodural angle, aditus, and digastric ridge (Fukushima triangle). This inner triangle is where the mastoid air cells are shaved away, and eventually the jugular bulb and semicircular canals are found at depth. The innermost triangle is the Macewen triangle, which is a flat or depressive triangular area of the mastoid ­surface behind the external auditory canal where the semicircular canals are discovered. A postauricular C-shaped skin incision is made, similar to that used in the retrosigmoid approach; however, with this retrolabyrinthine transsigmoid approach, the incision is e ­ xtended anteriorly about 2 to 3 cm to expose

Fig. 10.6 Mastoid triangles. Schema demonstrating the three triangles of the mastoid: the outer triangle (blue), where the cortical bone is drilled away; the inner triangle (red), where the mastoid

air cells are shaved away; and the innermost triangle (green), known as the Macewen triangle, which is where the semicircular canals are located.

Retrolabyrinthine Transsigmoid Approach

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10  Skull Base Approaches to the Lateral Brainstem and Cranial Nerves the whole outer triangle that contains all the bone that needs to be removed (Fig. 10.3a).

Mastoidectomy and Retrolabyrinthine Exposure Drilling of the mastoid will start by removing the cortical bones within the Fukushima triangle. The surgeon uses a high-speed drill with a large cutting bur and continuous suction irrigation to remove the cortex over the mastoid bone (Fig. 10.7a). It is important to know that the junction of anterior border and superior margin generally mark the surface projection of the mastoid antrum and the lateral semicircular canal.

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expose the compact bone of the bony labyrinth or the “solid angle.” The key landmark in this area is the mastoid antrum (Fig. 10.7b). This open space defines the anterior limit of bony removal and allows the surgeon to locate the lateral semicircular canal.

Identification of the Digastric Ridge, Facial Nerve, and Jugular Bulb

Bone removal proceeds 1 cm behind the sigmoid, maintaining a uniform depth as the sigmoid is completely exposed. After the sigmoid has been skeletonized, the mastoid air cells are removed anteriorly and superiorly to expose the middle fossa dura (temporal tegmen). Moving anteriorly, the air cells are drilled away to

As air cells are removed from the mastoid tip, the digastric ridge is encountered (Fig. 10.7c). The digastric groove is an important landmark for defining the exit of CN VII from the fallopian canal through the stylomastoid foramen. The stylomastoid foramen lies just medial to the anterior limit of the digastric ridge. For the transsigmoid approach, the drill can be put away at this point. However, for maximal exposure in the retrolabyrinthine approach, the posterolateral portion of the bony labyrinth must be completely defined. Anteriorly, approximately 12 to 15 mm deep to the outer edge of the external auditory meatus, lies the fallopian canal. Another landmark is the lateral semicircular canal, which exists 1 to 2 mm

Fig. 10.7 Cadaveric dissection illustrates the four steps of a mastoidectomy. (a) Cortical bone is removed and mastoid air cells are exposed. (b) The mastoid antrum is opened and the incus bone is identified. Compact bone of the lateral semicircular canal is found at the same depth. The bone over the temporal tegmen and sigmoid

sinus is thinned to the thickness of an eggshell. (c) The presigmoid dura, digastric ridge, and compact bone of the posterior semicircular canal are exposed. (d) Maximum exposure of the presigmoid dura is obtained by minimizing the bony labyrinth. The facial nerve, chorda tympani, and jugular bulb are exposed.

Identification of the Sigmoid Sinus and Mastoid Antrum

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posterior and parallel to the facial nerve. The facial nerve can be skeletonized from the external genu, inferiorly to the stylomastoid foramen (Fig. 10.7d). Care must be taken to radically thin the bone over the inferior sigmoid sinus and the jugular bulb because dura constructing these structures may be very thin. For completion of the transsigmoid approach, a retrosigmoid craniotomy is added to expose all extradural portions of the sigmoid sinus from the transverse sigmoid sinus junction to the inferior point of the sigmoid sinus. The dura is opened to allow resection of the sigmoid sinus; double ligation at both the transverse sigmoid sinus junction and the jugular bulb using 3–0 nonabsorbable sutures is necessary to prevent venous bleeding.

Translabyrinthine Approach When hearing preservation is not a goal, further exposure can be obtained by removing the bony labyrinth. The lateral and posterior semicircular canals are first opened with the drill. The ampulla end of the lateral canal is carefully removed, with attention paid to the close relationship of the tympanic portion of the facial nerve. Preservation of the anterior wall of the lateral semicircular canal will protect the tympanic segment of the facial nerve. Removal of the superior segment of the posterior semicircular canal will expose the common crus, which is shared with the superior semicircular canal. The superior semicircular canal is then also opened. The inferior ampulla limb of the posterior semicircular canal is followed to the vestibule. Drilling in this area, lateral and inferior to the vestibule, will expose the vestibular aqueduct as it courses laterally toward the e ­ ndolymphatic

sac. The vestibule is now opened by continuing to remove bone by following the common crus. The wall of the vestibule separating itself from the IAC is only a thin shell of bone. The compact bone surrounding the IAC is then defined by removing bone superior and inferior to the canal (Fig. 10.8). It is important to remove bone around the IAC such that more than one-half the circumference of the canal is skeletonized, making the innermost extent of the canal accessible.

Far Lateral Transcondylar Approach Management of lesions situated at the dorsolateral or anterior aspect of the craniovertebral junction and the upper cervical areas is a challenging neurosurgical problem. Total resection of these lesions was not feasible in the past, and patients experienced high morbidity and mortality rates. Development of the ELITE approach by Fukushima and others has allowed many of these lesions to be treated accurately and safely. The standard ELITE approach is the dorsolateral inferior skull base procedure, with the basic concept of transcondylar access to the ventral medullary area, as first described by Seeger in 1978.5 Later, this concept was further elaborated by Bertalanffy and Seeger,6 and Sen and Sekhar7 then performed the procedure on patients. The ELITE technique is suitable for vertebral artery–posterior inferior cerebellar artery (PICA) and vertebrobasilar junction aneurysms, lower clival and ventral foramen magnum lesions, and jugular foramen tumors such as glomus jugulare. The ELITE approaches to the foramen magnum, ventral medulla, lower clivus, and jugular foramen regions are basically divided

Fig. 10.8  The dura of the internal auditory canal is exposed in a cadaveric specimen after removal of the labyrinth via a translabyrinthine approach.

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into two types, a standard dorsolateral approach and an extended anterolateral approach. Selection of the proper approach depends upon the location, size, and extent of the tumor (Fig. 10.9). For intradural tumors (type A) and dumbbell-shaped tumors (type B), the dorsolateral approach is indicated through a lazy-S incision with the patient in a lateral position (Fig. 10.3b). When the tumor extends from the intracranial level to the high cervical area (snowman-shaped, type C tumor), the anterolateral approach is selected through a postauricular question mark incision with the patient in a supine position and the head rotated laterally on an ear, nose, and throat pillow. For maximum flat access to the lower clivus, adequate removal of the jugular tubercle is crucial. Drilling of the jugular tubercle provides a substantial increase in the direct microscopic view toward the clivus, the anterior foramen magnum, the anterior medullary

area, and the vertebrobasilar artery (Fig. 10.10). Drilling of the jugular tubercle is technically demanding because of the deep and narrow working space. With smooth or coarse diamond burs  (2 or 3 mm), the surgeon drills away the triangular bone between the C1 dura, hypoglossal canal, and the infrajugular membrane, 20 mm deep toward the clival junction. Extreme care must be taken not to damage the infrajugular membrane and the lower CNs.

Fig. 10.9 Schema of classification, surgical concept, and indication for extreme lateral infrajugular transcondylar exposure approach used to reach type A intradural tumors, type B dumbbell-shaped tumors, and type

C snowman-shaped tumors with high cervical extension (a-c, yellow shading). (a) Type A tumor situated within the cranium. (b) Type B tumor extending into the jugular foramen. (c) Type C tumor extending into the high cervical area.

Dorsolateral ELITE Approach Position and Skin Incision The patient is placed in a Fukushima lateral position and the head is fixed in the same fashion as in the retrosigmoid approach. The skin incision is made in a lazy-S shape, starting 2 to 3 cm behind the posterior ridge of the body of mastoid and p ­ assing

Fig. 10.10 (a) Cadaveric dissections demonstrate change in visual axis obtained by removing the jugular tubercle (arrowheads) using the extreme lateral infrajugular transcondylar exposure approach. (b) Intradural image of jugular tubercle interfering with the view to the ventral portion. A better view of the ventral structures is obtained after the jugular tubercle is removed.

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just over the asterion at the level of the superior auricular point (Fig. 10.3b). After reflection of a galea cutaneous scalp flap, suboccipital muscles are dissected so that the sternocleidomastoid (SCM) muscle is reflected anteriorly. Second- and thirdlayer muscles are either split or detached from the mastoid and occipital bone and reflected posteriorly. The C1 lamina (and the C2 and C3 laminae, if necessary) should be exposed through subperiosteal dissection to complete the muscular dissection. The extracranial V3 vertebral artery should always be identified; it is located in the suboccipital muscular triangle along the C1 condyle J groove. Exposure will be improved by hemilaminectomy of C1 at this point.

laterally, which leads to the condylar fossa. The occipital condyle is the bone anterolateral to this fossa, demarcated posteriorly by a facet. We have developed three variations of ELITE approaches in terms of bone removal: limited, standard, and extensive.

Limited ELITE A limited ELITE approach involves opening the

A retrosigmoid partial mastoidectomy, followed by a small inferior suboccipital osteoplastic craniotomy, is performed to expose the entire posterior portion of the sigmoid sinus and posterior fossa dura. Drilling of the occipital condyle is the key element of this approach. After a lateral suboccipital craniotomy is performed, the foramen magnum is opened. The bone edge is then followed

foramen magnum and performing a partial condylectomy. This is used for hypoglossal schwannomas and glossopharyngeal schwannomas of the intracranial type, vertebral artery– PICA aneurysms, and small foramen magnum meningiomas. The condylar fossa and occipital condyle are drilled away contiguously, often encountering venous bleeding from the posterior condylar emissary vein. Bone removal is next directed superiorly toward the inferomedial aspect of the jugular bulb. In approximately 30% of cases, when the superomedial part of the occipital condyle is drilled away (to a depth of approximately 10 mm), the hypoglossal canal can be identified in front of the C1 dura, parallel to the condylar facet, in a slightly cephalad (60°) direction (Fig. 10.11). Aggressive removal of the occipital condyle may cause craniovertebral instability and necessitate placement of hardware for

Fig. 10.11 Occipital condyle drilling and exposure of the hypoglossal canal with a limited extreme lateral infrajugular transcondylar exposure approach. (a) Illustration showing the relationship between the condylar triangle (yellow), the tubercular triangle (green),

and the hypoglossal canal. (b) Cadaveric specimen after occipital condyle drilling and exposure of hypoglossal canal. (c) Inferior view of the skull showing the surgeon’s view (yellow arrow) and the hypoglossal canal.

Craniotomy and Transcondylar Drilling

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10  Skull Base Approaches to the Lateral Brainstem and Cranial Nerves stabilization; however, bone removal to the extent described for this approach does not usually require hardware. In cases of dumbbell-shaped tumors with enlargement of the hypoglossal canal, additional drilling around the canal may provide suitable exposure of the tumor for removal of the extracranial component and result in the full exposure of the posteroinferior portion of the jugular bulb and the medial portion of the internal jugular vein at the entrance of the jugular foramen.

Standard ELITE The standard ELITE approach is used for intradural

tumors with hypoglossal canal or jugular bulb extension, vertebrobasilar junction aneurysms, foramen magnum-clival meningiomas, jugular foramen tumors, and C1-2 meningiomas. In addition to the drilling for a limited ELITE approach, the jugular tubercle is drilled to obtain a flat view, through triangular bone superior to the hypoglossal canal. The jugular tubercle is a bony structure located at the junction of the clivus and condylar portion of the occipital bone, which hinders surgical exposure of lesions situated at the lower clivus and premedullary areas. Drilling of the jugular tubercle is crucial to obtain a flat view to maximize surgical exposure without excessive cerebellum retraction (Fig. 10.10). CN IX, CN X, and CN XI are located just over the jugular tubercle. Drilling of the jugular tubercle goes deep, about 2 cm toward the clival junction. The newly developed ultrasonic bone aspirator (described earlier) may reduce the risk of lower CN injury during the shaving procedure.

Extensive ELITE The extensive ELITE approach requires a subtotal

condylectomy, vertebral artery transposition, and partial clivectomy. This approach is suitable for resection of large hypoglossal or glossopharyngeal schwannomas with caudal and peripheral extension through the foramen magnum, large invasive chordomas, and extracranial V3-V4 lesions. If the lesion extends toward the median or even to the contralateral side within the clivus, extensive removal of the clival bone is indispensable beyond the jugular tubercle. Thus, a hemilaminectomy of C1 and C2, accompanied by transposition of the vertebral artery, is necessary. This will allow sufficient manipulation of surgical instruments and create the ability to obtain a visual axis under

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the microscope. The drilling is done both superior and inferior to the hypoglossal canal. With this extensive approach, the working axis will ultimately lead to C5, the ascending portion, and C6, the petrous portion of the contralateral ICA.

Dural Incision The dural incision is a curvilinear type beginning superiorly several millimeters posterior to the sigmoid sinus, continuing inferiorly, and passing just behind the vetebral artery entrance through the dura (vertebral fibrous ring), ending just above the C2 lamina (Fig. 10.12). With the removal of the lateral edge of the foramen magnum, the superomedial portion of the occipital condyle and the jugular tubercle, the inferior CPA, and the craniovertebral junction should be viewed in a straight, flat line (Fig. 10.10).

Anterolateral ELITE Approach The anterolateral ELITE approach is an extended transcondylar approach with the SCM retracted posteriorly for a more anterior infrajugular exposure. The extent of the infrajugular and high cervical exposure is tailored, depending on the size, invasiveness, and origin of the tumor.

Position and Skin Incision The patient is placed in the supine position with the head rotated laterally on an ear, nose, and throat pillow (Fig. 10.3b). A question mark skin incision begins 2 to 3 cm behind and at the level of the superior auricular point. Then the incision curves gently posteroinferiorly, passing just behind the asterion, and continues inferiorly passing the anterior margin of the SCM toward the submandibular angle. After skin reflection, the SCM and the greater auricular nerve crossing over the SCM, which is located in the subcutaneous tissue about 2 to 3 cm below the mastoid tip, are exposed and can be seen to course obliquely.

Lateral Neck Dissection After the SCM is detached from the mastoid body and has been reflected posteriorly, the digastric muscle is reflected anteriorly. This allows maximum exposure of the high cervical portion of

Fig. 10.12  Illustration demonstrating the dural incision for the extreme lateral infrajugular transcondylar exposure approach.

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the ICA, carotid bifurcation, internal jugular vein, and parapharyngeal portion of the lower CNs, if necessary. During mobilization of the digastric muscle, care must be taken to preserve the small facial nerve branch. Carefully incising and opening the carotid sheath allows visualization of these neurovascular structures. CN XI can be identified beneath the SCM, both visually and electrophysiologically. The nerve can course rostrally either over the internal jugular vein (in 80% of cases) or under it (in 20% of cases) at the level of the transverse process of C1. The peripheral portion of the hypoglossal nerve (CN XII) is easily identified below the digastric muscle, just under the facial vein at the submandibular angle. The nerve is located under the ICA in the carotid sheath. CN XII courses cephalad over the external carotid artery and the ICA and joins with CN X at the level of the C1 transverse process. CN IX crosses over the high cervical ICA portion intermingled with the deep cervical fascia and is fairly difficult to identify. Precise dissection of the peripheral CN IX is better performed in conjunction with the exposure of the CN IX canal and the pars nervosa of the jugular bulb.

Exposure of the Extracranial Vertebral Artery The V3 horizontal segment of the extracranial vertebral artery is identified at the C1 vertebral sulcus  (J groove). One or two small muscular branches of the vertebral artery at the V3 posterior genu can be coagulated and divided without consequence. The posterior meningeal artery may also be seen originating from the vertebral artery just before it pierces the dura. The atlanto-occipital fibrous membrane  (ligament) and veins are next removed sharply to expose the underlying dura. The entire extradural course of the vertebral artery from C2 to the occiput should now be well defined.

Fig. 10.13 Illustrations of the anatomical relationships before and after sinus removal during the anterolateral extreme lateral infrajugular transcondylar exposure approach. (a) After mastoidectomy, condyle

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Mastoidectomy and Lateral Suboccipital Craniotomy Lateral suboccipital craniotomy and retrolabyrinthine and infralabyrinthine drilling are performed. In most cases, the semicircular canals and the basal turn of the cochlea are preserved to maintain hearing function. The bone removal is advanced ­inferiorly to shave the digastric groove to expose the entire jugular bulb.

Transcondylar and Transtubercular Bone Removal The posterior and superomedial one-third of the condyle is drilled to identify the hypoglossal canal. Opening the entire hypoglossal canal is the key to total tumor removal as it provides good exposure of the intracranial and intracanalicular parts of the anatomical structures. Drilling of the jugular tubercle is crucial to obtain a flat view to the lower clivus, foramen magnum, and premedullary area. Removal of the jugular tubercle is the key to maximizing the intradural exposure through this approach.

Dural Incision After dural incision, as performed in the dorsolateral ELITE approach, the superomedial portion of the occipital condyle, the jugular tubercle, the inferior CPA, and the craniovertebral junction should be viewed in a straight flat line. Sharp arachnoid dissection will reveal the lateral brainstem and the vertebral artery. The surgeon should clearly identify the following structures: CN IV through XII, PICA, anterior inferior cerebellar artery, vertebrobasilar junction, ICA, external carotid artery, and internal jugular vein (Fig. 10.13).

removal, and high cervical exposure. (b) After ligation and resection of the sinus from the sigmoid sinus to the internal jugular vein, revealing the pars nervosa containing the lower cranial nerves.

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10  Skull Base Approaches to the Lateral Brainstem and Cranial Nerves

■■ Combined Suprainfratentorial Approaches Middle Fossa Rhomboid Anterior Petrosectomy The extradural subtemporal approach through the middle fossa has become one of the most frequently used operative procedures in contemporary skull base surgery. This approach can be used to expose the lateral wall of the cavernous sinus, to resect the anterior petrous bone to reach the lateral portion of the midbrain and pons, or to open the IAC. Middle fossa surgery is used to excise intracanalicular acoustic neuromas, petrous and infracavernous chordomas, trigeminal neuromas, small- to medium-sized petroclival meningiomas, and vascular lesions relating to the basilar artery, posterior cerebral artery, and superior cerebellar artery. A full understanding of the microanatomy of the cavernous sinus region, middle fossa, and rhomboid construct is essential for this approach.

Standard Middle Fossa Approach Position, Skin Incision, Craniotomy, and Dural Elevation The patient is placed in a Fukushima lateral position, with the head fixed as described for the retrosigmoid approach. The incision begins in the preauricular crease at the level of the root of the zygoma and continues in a curvilinear fashion past the level

Fig. 10.14 Middle fossa rhomboid approach. Illustrations showing (a) the anatomical relations within the middle fossa and the rhomboid area; (b) the middle fossa after the bone has been removed from the rhomboid area; and (c) the dural incision (dashed lines). (d) Cadaveric

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of the squamous suture (Fig. 10.3a). The temporal muscle is split and a 5 x 5-cm temporal craniotomy, centered over the zygomatic root, is performed. The inferior edge of the craniotomy, especially the inner plate of the temporal bone, is drilled away to make this opening even with the floor of the middle fossa. The temporal lobe dura is elevated along the floor in an anterior to posterior direction. This direction of elevation is important as 15% of the geniculate ganglion lies under a dehiscence in the floor of the middle fossa. The position of the geniculate ganglion should be confirmed by stimulation with the facial nerve stimulator. The petrous ridge is identified laterally and a rigid extradural retractor is positioned. The arcuate eminence overlying the superior semicircular canal is identified (Fig. 10.14a). However, the surgeon should be aware that this structure does not always precisely overlie the canal. The relationship between the arcuate eminence and the superior semicircular canal should be defined using preoperative thin-cut computed tomography.

Drilling of the Internal Auditory Canal The surgeon must be oriented to the approximate location of the IAC before drilling the petrous bone. The orientation of the IAC is a direct medial extension of the external auditory canal. Identification of the greater superficial petrosal nerve (GSPN) provides a guide to the location of the geniculate ganglion and arcuate eminence, which can be used to approximate the location of the IAC. House,8 Fisch,9 and Garcia-Ibanez and Garcia-Ibanez10 have

image after dural opening. Abbreviations: EAC, external auditory canal; GSPN, greater superficial petrosal nerve; IAC, internal auditory canal; IPS, inferior petrosal sinus; MMA, middle meningeal artery.

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all described techniques for identification of the IAC. The medial drilling technique popularized by Garcia-Ibanez and GarciaIbanez10 is the simplest and safest. Once the arcuate eminence and geniculate ganglion are identified, the surgeon begins drilling medially on a line bisecting the angle between the arcuate eminence and the GSPN. It is safest to find the IAC by drilling close to the petrous ridge. Near the porus, the surgeon can skeletonize the IAC dura 270°. As the drilling proceeds toward the fundus of the IAC, only the roof of the canal can be removed. Overly aggressive lateral drilling of the fundus of the IAC will disrupt the cochlea anteriorly or the superior semicircular canal posteriorly. The dura should not be opened until the IAC exposure is complete. Drilling after opening the IAC dura risks damage to the IAC contents. Specific attention is focused on the lateral IAC. The labyrinthine segment of the facial nerve is followed from the IAC fundus to the geniculate ganglion (Fig. 10.14b).

Dural Opening and Tumor Resection Once the IAC is fully exposed, the dura of the IAC is opened along its posterior edge because the facial nerve is in the anterior compartment (Fig. 10.14c). If there is significant posterior fossa extension of the tumor, the SPS can be divided for wider access to the CPA portion of the lesion. This portion of the lesion must be approached with care as access is limited to the posterior fossa in the event of hemorrhage. If such a crisis occurs, the best solution is a rapid labyrinthectomy with a large cutting bur through the floor of the middle fossa to provide adequate CPA access to control bleeding.

Extended Middle Fossa and Anterior Petrosectomy Approach In addition to the standard middle fossa approach described above, in the extended middle fossa approach, the petrous ridge is followed more anteriorly to expose the porous trigeminus. The dura propria is separated from the mandibular branch of the trigeminal nerve. The rhomboid area between the IAC and the ICA is drilled away, exposing the transverse portion of the ICA (C6 segment), the entire course of CN VI, and the Dorello canal. This approach is indicated for patients with functional hearing and medium-size tumors (< 2 cm) limited to the petrous apex and petroclival junction. This approach is used for tumors that are based superiorly and that may extend anteriorly toward the cavernous sinus. The approach enables the surgeon to obtain a complete resection of the lesion, which is particularly important in younger patients who may live long enough to experience the consequences of tumor regrowth.

Dural Elevation The dura is elevated as described for the standard middle fossa approach, from posterior to anterior. The middle meningeal artery is divided at its entrance into the cranial vault, then the mandibular division of the trigeminal nerve is exposed as it enters the foramen ovale. The dura is elevated in the posterior direction toward the petrous ridge to expose the bone between the arcuate eminence and the trigeminal impression. Two selfretaining tapered retractors are placed to hold the temporal dura away from the middle fossa floor. The dura is sharply freed from the lateral trigeminal complex by developing the plane between the temporal dura and the connective tissue sheath of the nerve. This maneuver increases the width of the extradural corridor through which the procedure is performed. The middle fossa landmarks defining the “rhomboid” complex are then identified (Fig. 10.14a). These landmarks are (1) the intersection of the GSPN with the trigeminal nerve, (2) the porus trigeminus, (3) the intersection of the arcuate eminence and the petrous ridge, and (4) the intersection of the lines projected along the axes of the GSPN and the arcuate eminence. This complex, projected obliquely toward the clivus through the petrous pyramid, delimits the volume of bone that will be removed.

Extradural Bone Removal The drilling of the rhomboid area begins by exposing the IAC as previously described. After the IAC dura is uncovered, the GSPN and geniculate ganglion are addressed. Underneath the GSPN will be the C6 petrous portion of the ICA, which sometimes is not covered by bone at all. At the angle of the geniculate ganglion and IAC resides the cochlea. The soft, porous bone between the IAC and the ICA is removed, avoiding the posterior lateral volume of bone housing the cochlea. The posterior fossa dura can be exposed between the posterior edge of the trigeminal V3 branch and the arcuate eminence.

Exposure of the Inferior Petrosal Sinus and Petrous Apex Removal The posterior fossa dura is exposed inferior to the IAC by removing the bone between the IAC and the intrapetrous carotid artery. Next, the dura is exposed, moving inferiorly to expose the inferior petrosal sinus (Fig. 10.14b). The bone across this sinus is removed until the cancellous bone of the clivus is reached. At the anterior end, the apical bone of the petrous apex next to the foramen lacerum can be removed; it is situated underneath the gasserian ganglion. When the apex has been removed, the foramen lacerum is opened posteriorly.

Position, Skin Incision, and Craniotomy

Dural Opening and Trigeminal Dural Ring

The patient’s body and head are positioned in the same fashion as in the standard middle fossa approach. The skin incision is made in the shape of a question mark, concave anteriorly, as illustrated (Fig. 10.3a). The temporal muscle is freed from the root of the zygomatic process to allow the muscle to be pulled forward. This maneuver helps to provide an unobstructed view across the middle fossa floor without needing to perform a zygomatic osteotomy. A 5 x 5-cm craniotomy is made one-third behind and two-thirds in front of the external auditory canal. Any bone along the inferior edge of the craniotomy is removed to ensure a view parallel to the floor of the middle fossa and to obtain an unobstructed flat view along the floor of the middle fossa.

Opening the dura must be preceded by interruption of the SPS at the porus trigeminus. The dura superior to the SPS is incised from the porus trigeminus to the arcuate eminence (Fig. 10.14c). A second incision is made parallel to the first, inferior to the SPS in the posterior fossa dura. The sinus is ligated anteriorly at the porus trigeminus. A sagittal incision is made in the medial tentorium, 8 to 10 mm in length. A stitch is placed in the lateral corner of the incised tentorium, and this is retracted superiorly. The dura surrounding the trigeminal root at the porus trigeminus is opened (trigeminal dural ring opening). Next, the posterior fossa dura is incised at the medial and lateral margins of the exposure, toward the inferior petrosal sinus. The dura is incised along the

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10  Skull Base Approaches to the Lateral Brainstem and Cranial Nerves margin of the inferior petrosal sinus to completely excise this section of the posterior fossa dura. Through this opening, the trochlear, trigeminal, abducens, facial, and vestibulocochlear nerves (CN IV-VIII) and the basilar artery, anterior inferior cerebellar artery, posterior cerebral artery, and superior cerebellar artery should be appreciated (Fig. 10.14d). The extended middle fossa approach provides surgical access for posterior fossa lesions that involve the CPA and extend anteriorly into the cavernous sinus and inferiorly along the prepontine region of the clivus. Simultaneous access is possible for transtentorial tumor extensions and hearing preservation. The major limitation of this technique is the amount of temporal lobe retraction necessary, which can be much more extensive than that required for a standard middle fossa approach.

Combined Petrosal Approach Tumors around the petroclival and posterior cavernous sinus regions are the most difficult to operate on in neuro­surgical practice. The deep location, complex anatomy, and the involvement of multiple CNs, vessels, and the brainstem present neurosurgeons with a real challenge to achieving radical resection with minimal morbidity. Petroclival lesions include meningiomas, neurinomas, chordomas, c­hondrosarcomas, epidermoids, cavernomas, arteriovenous malformations, and basilar trunk aneurysms. For exposure of these petroclival lesions, many skull base operative approaches can be used, including the frontotemporal transcavernous approach, middle fossa anterior petrosectomy, translabyrinthine or retrosigmoid posterior fossa approach, and combined transpetrosal approach. The selection of the proper operative approach depends upon tumor size, extension, vascularity, and adhesions and the patient’s presenting symptoms and age. The combined petrosal approach is indicated for the majority of large petroclival lesions with supratentorial and infratentorial extension in healthy patients. The anatomy and dissection techniques of the combined petrosal approach have been progressively expanded by Fukushima since 1982. For cases in which further anterior ­ exposure is necessary, the mastoid technique can be modified from retrolabyrinthine to translabyrinthine, transcochlear, or transotic approaches. The combined supra-infra-transpetrosal approach provides the best and the most extensive microsurgical exposure of the anterior clinoid process from the oculomotor area to the lower CNs and the entire brainstem. This approach is a combination of the extended middle fossa approach, transmastoid approach, and retrosigmoid approach. The key elements of safe and secure exposure are proper positioning, continuous lumbar spinal drainage, preservation of the vein of Labbé, minimum subtemporal retraction, and preservation of all neurovascular structures as well as the brainstem surface. Precise cosmetic restoration should include a watertight dural closure, abdominal fat grafting, vascularized fasciopericranial flap transfer, and microsurgical titanium cranioplasty; this restoration is an important element to prevent head deformity, CSF leak, and infection.

Position and Skin Incision The patient’s body and head are positioned in the same manner as in the retrosigmoid approach. The skin is incised in a large postauricular C-shaped incision from a frontal to a temporal direction (4–5 cm above the external auditory canal),

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and occipital and ­suboccipital (2 cm behind the body of the mastoid and 1 cm behind the asterion) to 1 cm below the mastoid tip level (Fig. 10.3b). A chef’s hat incision can also be used (Fig. 10.3b).

Three-layer Elevation For this approach, a flap is indispensable for watertight closure at the end of the procedure. This flap requires a three-layer elevation. Traditionally, a galeocutaneous flap, fasciopericranial flap, and muscular flap were those three layers, and the fasciopericranial flap was used for the reconstruction. However, we have encountered a few cases where the flap diminished after several weeks, causing CSF leakage or infection. This outcome can be prevented by supplementing the fasciopericranial flap with a galeal layer that includes the superficial temporal artery; this is called a superficial temporal artery– enhanced galeofascial pericranial flap  (Fig. 10.15). This flap offers more thickness and high vascularity, so it is unlikely to shrink and thus prevents CSF leaks and infections. The temporalis muscle is reflected anteriorly, and suboccipital muscles are elevated off the mastoid as one block and retracted posteriorly and inferiorly to expose the mastoid body and occipital bone.

Retrolabyrinthine Mastoid Drilling and L-shaped Craniotomy For the mastoidectomy, the bony labyrinth can either be left as is or drilled away, depending on the extent of the surgery. After the mastoidectomy, an L-shaped craniotomy is performed, which is a combination of a lateral suboccipital and temporo-occipital craniotomy (Fig. 10.16).

Middle Fossa Extra Dural Dissection and Rhomboid Drilling After the retrolabyrinthine mastoidectomy, a large L-shaped bone flap elevation and dural tack-up stitches are completed and the middle fossa rhomboid exposure is created. The operative field should look slightly different from that of the middle fossa approach described previously in the section on the middle fossa rhomboid anterior petrosectomy. The mastoidectomy has been completed at this point, so the posterior aspect of the superior semicircular canal, which consists of the arcuate eminence, should already be drilled out (Fig. 10.17).

Dural Opening There are two types of dural-tentorial incisions. The conventional L-shaped dural incision starts at the presigmoid dura close to the junction of the sigmoid sinus and the jugular bulb in an L-shaped style (Fig. 10.18a). This incision crosses over the SPS 5 mm away from the junction of the sigmoid sinus and the transverse sinus, then gently curves anteriorly on the subtemporal dura. When a tentorium resection is required to obtain a wider operative field or for large petroclival meningiomas with wide attachment to the petroclival dura or tentorium, an L-shaped incision with a parallel incision is preferable (Fig. 10.18a). While this parallel incision is being made, it is crucial not to incise the dura along the transverse sinus in order to preserve the vein of Labbé. This innovative L-shaped incision provides sufficient operative space

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Fig. 10.15  A superficial temporal artery–enhanced, galeofascial pericranial flap used in the combined petrosal approach. (a) Intraoperative photograph of a vascularized flap prepared for the combined petrosal

approach. (b) Cadaveric dissection demonstrating the feasibility of obtaining a wide posterior peduncle (dashed line).

Fig. 10.16 Illustration of a craniotomy for a combined petrosal approach.

to expose the prepontine cistern, CPA parabrainstem region, and subtemporal brain base. It is important to avoid temporal lobe contusion and postoperative temporal lobe swelling, which cause major postoperative complications. During this surgical approach, the temporal lobe is held by two brain spatulas for several hours. To avoid complications from temporal lobe contusions or swelling, one should make the subtemporal incision as low and as parallel to the SPS as possible so that the temporal lobe remains protected by the dura mater.

Tentorial Resection (Shark’s Fin Resection) In the case of a petroclival meningioma or tentorial meningioma, the tentorium is resected in a rhomboid shape (Fig. 10.18b). The posterior incision is extended down to the tentorial edge and

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CN IV is separated (Fig. 10.18c). Next, the tentorial edge is followed anteriorly to identify the CN IV entrance into the tentorium. The dural sleeve of CN IV is incised about 6 to 8 mm (without entering the posterior cavernous sinus). From this point, the anterior tentorial incision is directed vertically up toward the trigeminal fibrous ring (posterior transcavernous detachment) and the dorsal portion of the trigeminal fibrous ring is resected (Fig. 10.18d). Any bleeding from the anterior end of the SPS or the cavernous sinus is controlled by packing Surgicel pieces and using bipolar coagulation. The cisternal segment of the trochlear nerve and the superior cerebellar artery and the P2 segment of the posterior cerebral artery are identified and preserved. The parallel incision of the subtemporal base extended already toward the trigeminal fibrous ring is gently retracted to incise the anterior end of the SPS and to resect the dorsal half

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Fig. 10.17 Middle fossa rhomboid drilling after mastoidectomy (combined petrosal approach in a cadaveric specimen). (a) Before removal of the rhomboid. (b) Completion of the total petrosectomy shows that the inferior petrosal sinus and clivus are exposed, with anterior translocation

of the trigeminal nerve.  Abbreviations: GSPN, greater superficial petrosal nerve; IAC, internal auditory canal; IPS, inferior petrosal sinus; MMA, middle meningeal artery; SCC, superior semicircular canal.

Fig. 10.18 Dural opening and tentorium removal after total petrosectomy (combined petrosal approach). (a) Illustration of two ways to open the dura: conventional L-shaped dural incision (black dashed line) and L-shaped incision with parallel incision (red dashed line). (b) Drawing by

the senior author (T.F.) shows dural incision and tentorium resection (left side). Cadaveric dissections show (c) ligation of superior petrosal sinus (SPS) and medial incision of the tentorium and (d) opening of the dural ring around the trigeminal nerve to complete the tentorium resection.

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of the trigeminal fibrous ring. The upper half of the trigeminal fibrous ring is incised to open the porus trigeminus widely. Through this approach, inferiorly through the presigmoid exposure, the surgeon can visualize CN VII to CN XI, as well as the anterior inferior cerebellar artery and the PICA. The entire intradural and extradural course of both CN VII and CN VIII are appreciated. CN V is identified ventrally between CN VIII and CN V, deep in the CN VII-VIII complex as it courses superiorly into the Dorello foramen. The upper CPA dissection exposes CN IV as it courses along the ambient cistern between the posterior cerebral artery and superior cerebellar artery. Around the anterior subtemporal area and the petrotentorial junction, the oculomotor nerve (CN III), the distal CN IV, the CN V root, and the upper basilar arterial system can be observed (Fig. 10.19).

Reconstruction and Closure To prevent any postoperative CSF leak or infection, use a watertight dural closure with a fascial graft and reconstruction using a vascularized flap (Fig. 10.15) and abdominal fat. The pedicles of the flap can be tailored so that the flap can be placed in the desired position. A small longitudinal incision on the base of the temporal muscle can be made to pass the flap through to be placed on the posterior side. When there is no margin to stitch on the posterior fossa dura, place the pericranial flap closely, covering the anterior middle fossa to the posterior fossa over the jugular bulb. Then place some titanium microplates onto the pericranial flap to fix it to the remaining cranial base for a watertight closure. Abdominal fat grafts are cut into multiple narrow strips and placed in the extradural space to fill the gap and bone defects.

Fibrin glue is used to secure the fat grafts in place. The vascularized flap can then be sutured to the temporal and postsigmoid dura covering the fat grafts.

■■ Approaches to Cavernous Malformations in the Lateral Brainstem For patients who receive a diagnosis of cavernomas in the lateral brainstem, a surgical approach that adequately exposes the brainstem cavernoma is essential. In the authors’ experience of 100 cases of brainstem cavernomas, surgical approaches are selected with two considerations: minimization of damage to surrounding structures of the brainstem and facilitation of complete resection of the lesion. With these considerations in mind, we select approaches through the pial or ependymal surfaces of the brainstem proximal to the cavernoma with bleeding cavities. MRI is thus used to determine the exact location of cavernomas with bleeding cavities and the proximity of the lesion to the pial or ependymal surface of the brainstem in all patients when selecting the surgical approach. The retrosigmoid approach is used for lateral mesencephalic, pontine, and medullary cavernomas. The occipital transtentorial approach is selected for thalamomesencephalic and mesencephalic cavernomas, and the combined petrosal approach is chosen for pontine cavernomas. In addition to these approaches, the middle fossa rhomboid approach has been used for one pontine case, and an ELITE approach has been used for one patient with a medulla oblongata lesion.

Fig. 10.19  Illustration demonstrating the view obtained after dural opening and tentorial resection. Abbreviations: AICA, anterior inferior cerebellar artery; GSPN, greater superficial petrosal nerve; III, oculomotor nerve (cranial nerve [CN] III; IV, trochlear nerve (CN IV); IX, glossopharyngeal nerve (CN IX); MMA, middle meningeal artery; PCA, posterior cerebral artery; SCA, superior cerebellar artery; V, trigeminal nerve (CN V); VI, abducens nerve (CN VI); VII, facial nerve (CN VII); VIII, vestibulocochlear nerve (CN VIII); X, vagus nerve (CN X); XI, spinal accessory nerve (CN XI).

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■■ Conclusions Mastery of skull base approaches is mandatory for a safe approach to and resection of lesions within or surrounding the brainstem. Students of brainstem surgery should familiarize themselves with these approaches and their variations and should judiciously apply approaches to make operations safe and effective for their patients. References

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9. Fisch U. [Transtemporal extralabyrinthine surgery of the internal auditory canal] Arch Klin Exp Ohren Nasen Kehlkopfheilkd 1969; 194(2):232–243

3. Day JD, Kellogg JX, Tschabitscher M, Fukushima T. Surface and superficial surgical anatomy of the posterolateral cranial base: significance for surgical planning and approach. Neurosurgery 1996;38(6):1079–1083, discussion 1083–1084

10. Garcia-Ibanez E, Garcia-Ibanez JL. Middle fossa vestibular neurectomy: a report of 373 cases. Otolaryngol Head Neck Surg 1980;88(4):486–490

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11

Endoscopic Approaches to the Brainstem Alaa S. Montaser, André Beer-Furlan, Ricardo L. Carrau, Bradley A. Otto, and Daniel M. Prevedello

Abstract

The ventral midline region of the posterior cranial fossa, including the clivus and the ventral aspect of the brainstem, is one of the most challenging areas to access. Because most midline posterior skull base lesions displace the neurovascular structures dorsally, rostrally, and laterally, it is appealing to attack these lesions via an anterior surgical approach through the natural endonasal corridor. Understanding the anatomical relationships of this region is crucial for a successful endoscopic endonasal approach. This chapter describes in detail the endoscopic endonasal approach to the posterior cranial fossa and ventral brainstem, highlighting the main anatomical relationships, preoperative planning, and different ways to approach the mesencephalon, pons, and medulla. Potential problems of the approach and technical nuances learned through years of experience are also discussed. Keywords:  endonasal, endoscopic, interpeduncular, fossa, ­transclival approach, ventral brainstem

■■ Introduction The ventral midline region of the posterior cranial fossa, including the clivus and the ventral aspect of the brainstem, is one of the most challenging areas to access. Different microsurgical approaches, including the subfrontal transbasal, Kawase’s anterior petrosectomy, retrosigmoid, presigmoid, and far lateral approaches, provide a focused and sometimes limited access to a particular region at the ventral skull base alongside having other disadvantages. These drawbacks include the extensive resection of the lateral skull base structures, brain retraction needed to reach deeper targets, and the limited exposure of the midline structures.1 Approaching the posterior cranial fossa through endoscopic endonasal corridors overcomes some of these disadvantages as it provides direct access to the lesions with better magnification and a closer view while avoiding brain retraction and minimizing manipulation of neurovascular structures, thus decreasing morbidity.2 Because most of the midline posterior skull base lesions displace the neurovascular structures dorsally, rostrally and laterally, attacking these lesions via an anterior surgical approach through the natural endonasal corridor is appealing. The application of the endoscopic techniques not only provides a dynamic closeup view of such deep areas but also helps visualize the neurovascular structures bordering the surgical corridor, consequently providing more safety.3 This chapter describes in detail the endoscopic endonasal approach to the posterior cranial fossa and ventral brainstem, highlighting the main anatomical relationships. Potential

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problems of the approach and technical nuances learned with the years of experience are also discussed.

■■ Surgical Anatomy Sphenoid Sinus The sphenoid sinus is variable in shape and size and the cavities within it are almost never symmetrical and frequently are divided by small septa, which are seldom located at the midline. Even when a single major septum divides the sinus (48% of individuals), it is often off the midline. A septation inside the sphenoid sinus can lead to the carotid artery in 87% of individuals.3,​4 The sphenoid sinus is rectangular in the coronal plane, and is usually larger laterolaterally than craniocaudally. Based on the degree of pneumatization, three types of sinuses can be distinguished: conchal, sellar, and presellar.5 In the conchal type, the sphenoid sinus is a solid block of bone without an air cavity, or it does not extend beyond the sphenoid conchae. This type is most commonly encountered in children younger than 12 years old. The presellar type contains an air cavity that extends no further posteriorly than a plane perpendicular to the sellar wall. This type occurs in about 11 to 24% of individuals. In the sellar type, an air cavity is present which extends into the body of the sphenoid below the sella and goes all the way posteriorly to the clivus. This type of pneumatization is the most common, being seen in as many as 76 to 86% of cases.3 The sphenoid sinus has an anterior wall, a floor, two lateral walls, a roof, and a posterior wall. The anterior wall of the sphenoid sinus comprises the sphenoidal concha, ostium, and rostrum. The sphenoidal crest is located at the anterior wall and gives attachment to the bony part of the nasal septum, which is formed by the vomer and the perpendicular plate of the ethmoid.3 The sphenoid rostrum lies on the anteroinferior wall of the sphenoid sinus and represents the inferior border of the sphenoid sinus floor. Occasionally, the pneumatization of the sinus may extend anteriorly through the rostrum into the septum. As a rule, the more the rostral pneumatization is extended, the more lateral the natural ostium is located.5 The sphenoid sinus ostium is a round or elliptic aperture, through which the sphenoid sinus opens into the sphenoethmoidal recess behind the superior turbinate. This recess is present in only 48.3% of individuals.5 Various landmarks can be recognized on the lateral wall of the sphenoid sinus, especially in a well-pneumatized sinus. In a superior to inferior direction, three prominences are visible: the optic nerve (CN II) canal, internal carotid artery (ICA), and maxillary nerve (V2).5 The bony lateral sphenoid sinus wall over the ICA and CN II is usually very thin and may be dehiscent in some areas.3 Some recesses and grooves can be visualized between

11  Endoscopic Approaches to the Brainstem these bony prominences. The lateral opticocarotid recess is a shallow recess formed by CN II superiorly and the ICA inferiorly, and it is visualized better when the optic strut is pneumatized. The medial opticocarotid recess represents the lateral aspect of the tuberculum sellae, which is the area of contact between the point of origin of the optic canal medially and the posterior margin of the parasellar carotid artery. That is to say, the tuberculum sellae connects with the medial opticocarotid recess on both sides.5 The vidian nerve (the nerve of the pterygoid canal) runs in the lateral part of the inferior wall of the sphenoid sinus toward the pterygoid fossa. Whenever the sphenoid sinus is well pneumatized, the nerve can be in direct contact with the mucosal membrane of the sinus due to absorption of the superior osseous wall of the pterygoid canal. Moreover, the nerve can protrude into the sphenoid sinus and then run in an osseous ridge. On the posterior wall, the clival recess is seen below the pituitary prominence. The clival recess is a wide groove corresponding to the sphenoidal portion of the clivus. On the roof of the sphenoid sinus, the tuberculum sellae, the prechiasmatic sulcus, and the planum sphenoidale are visible from posterior to anterior. The dorsum sellae and posterior clinoids comprise the posterior borders of the sella turcica and the cavernous sinuses constitute the lateral borders.5

Clivus The clivus (Latin for “slope”) separates the posterior cranial fossa from the nasopharynx. It is formed of two parts: basisphenoid and the basiocciput. The former corresponds to the posterior portion of the sphenoid body and the latter corresponds to the basilar part of the occipital bone.6 The clivus lies posterior and extends inferior to the sphenoid sinus. This anatomical relationship with the sphenoid bone is unique, making it surgically accessible through transsphenoidal and nasopharyngeal corridors.7 On the basis of the extracranial landmarks exposed in the transnasal approach, the clivus is classified into upper, middle, and lower parts. This classification helps facilitate segmental transclival approaches according to the location of the lesion and the particular area of interest to be exposed. Therefore, a thorough understanding of the relationships between the extra- and intracranial structures is required for an accurate endoscopic endonasal approach to the intracranial structures.1 From an endoscopic endonasal perspective, the clivus can be divided into three parts from rostral to caudal: •• The upper third includes the dorsum sellae and posterior clinoid processes, and it extends down to the level of the sellar floor. •• The middle third extends from the lower extent of the sella down to the sphenoid floor (when well pneumatized at the level of the roof of the choana). •• The lower third extends from the sphenoid floor/roof of choana down to the foramen magnum.8 The posterior fossa is approached via a transsphenoidal corridor through the upper two thirds of the clivus. On the other hand, a nasopharyngeal corridor is used to access the posterior fossa through the lower clivus. In this case, drilling the bone below the sphenoid rostrum is usually adequate.2 The intracranial surface of the upper third of the clivus is related to the sella and posteriorly leads us to the mesencephalon. The middle third of the clivus faces the pons. The lower third lies in front of the medulla. The extracranial surface of the clivus gives rise to the

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pharyngeal tubercle at the junction of the middle and lower clivus.6 The petroclival fissure separates the upper and middle clivus from the petrous portion of the temporal bone bilaterally.2 The foramen lacerum and the paraclival portion of the cavernous ICA lie lateral to the middle third of the clivus, whereas inferiorly, the clivus is bordered laterally by the petrooccipital fissure, which is grooved by the inferior petrosal sinus. The ICAs are farther lateral at this level; thus, the occipital condyles and the hypoglossal canals represent the lateral limits of the dissection.5,​6 The abducens nerve (CN VI) runs superiorly and laterally just above the vertebrobasilar junction (VBJ) along the ventral aspect of the clivus before it enters Dorello’s canal and cavernous sinus, which makes it vulnerable to injury.5,​6 Each third of the clivus has a respective nasal, bony, dural, cisternal subarachnoid anatomy, as well as relevant arteries, nerves, and a portion of the brainstem that can be analyzed in three different modules.8

Upper Clivus The rostral extension of the superior third of the clivus is bordered by the dorsum sellae in the midline and the posterior clinoids in the paramedian region. This approach is designed to reach the interpeduncular fossa and the pituitary gland lies in front of it. There are surgical settings in which the pituitary gland may be sacrificed because of prior established panhypopituitarysm. However, when the pituitary gland function is normal, a pituitary transposition is performed. In this scenario, it is important to understand that two layers of dura cover the inner side of the sella: the periosteal and the meningeal layers. These layers are found only where there is bone; otherwise, only a single (meningeal) layer is found. Accordingly, the sella has two layers in the face, floor, and posterior wall, between which run the venous channels that communicate with both cavernous sinuses, such as the superior, inferior, and posterior intercavernous sinuses, respectively. On the lateral walls, however, the sella has only a single meningeal layer separating it from the medial wall of the cavernous sinus. This is a very important concept when pituitary transposition is performed, in which the capsule of the gland should not be violated and the pituitary ligaments should be detached carefully from the medial cavernous sinus wall. In this way, the pituitary gland can be transposed superiorly.8 The posterior intercavernous sinus is located posterior to the pituitary gland and is kept attached to the gland while it is elevated. The clival dura harboring the basilar venous plexus is posterior to the dorsum sellae, which lies posterior to the posterior intercavernous sinus.8 While performing the pituitary transposition, it is very important to understand the anatomy of the superior and inferior hypophyseal arteries and their relationships with other sellar structures. The inferior hypophyseal artery arises from the meningohypophyseal trunk at the cavernous segment of the ICA and courses medially toward the pituitary gland. It travels within the cavernous sinus and then penetrates the medial wall posteriorly to supply mainly the posterior pituitary gland. The superior hypophyseal artery emerges from the medial aspect of the paraclinoid segment of the ICA. It travels from the carotid cave into the subarachnoid space in the direction of the pituitary stalk and chiasm.9 The left and right ICAs are closest to each other just below the tuberculum sellae with an average distance of 13.9 mm (range, 10–17 mm).3 Once the dorsum sellae is removed, the dura with the basilar plexus is exposed. Once the dura is open, the interpeduncular

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IV  Surgical Approaches to the Brainstem, Thalamus, and Pineal Region

Fig. 11.1 Endoscopic endonasal exposure of the mesencephalon and the interpeduncular fossa in a cadaveric specimen. (a) Transclival approach through the upper third with pituitary transposition. The dura (black star) over the posterior pituitary gland (PG) is kept intact and rolled up with the gland to preserve its venous drainage. The dorsum sellae (DS) and the posterior clinoid processes (PCPs) are visualized after the pituitary gland is transposed. The optic nerves (CNs II) can be seen superiorly. (b) After drilling the dorsum sellae and the posterior clinoid processes, and opening the dura, the interpeduncular fossa is exposed, with the o ­ culomotor

nerves (CNs III) representing the lateral limits. Posteriorly, the mesencephalon, the basilar apex with its bifurcation, the posterior cerebral arteries (PCAs, P1 and P2 segments), the superior cerebellar arteries (SCAs), the posterior communicating arteries (PCoAs), and their respective perforating branches are visualized. Close-up views with (c) a 0° lens and (d) a 45° lens.Note the clearly visible floor of the third ventricle (3rd V), mammillary bodies (MBs), and pituitary infundibulum (PIs). White arrows indicate perforator branches of the PCA; white arrowheads indicate perforator branches of the PCoA. Abbreviations: BA, basilar artery; ICA, internal carotid artery.

fossa is exposed. The mesencephalon is exposed posteriorly and can be directly visualized once the Liliequist’s membrane is removed. The basilar apex with all branches is also visualized in front of the brainstem. The oculomotor nerves (CNs III) form the lateral limit of the approach as they run lateral to Liliequist’s membrane in the crural cistern (Fig. 11.1).

the mid-clivus laterally.8 The paraclival portion of the cavernous ICA are separated at this region by an average distance of 17 mm.3 After the bone of the middle clivus is drilled, the clival dura harboring the basilar venous plexus is exposed.8 The basilar plexus (also called clival plexus) is a large intercavernous venous connection located between the layers of dura posterior to the clivus that extends across the posterior aspect of the dorsum sellae. It communicates with the cavernous sinuses superiorly, the inferior petrosal sinuses laterally, and the marginal sinus and epidural venous plexus inferiorly, creating a large venous confluence along the cavernous sinus posterior wall. It is the largest communicating channel between the two c­ avernous sinuses. CN VI often runs through the basilar plexus at the level of the

Middle Clivus The middle segment of the clivus is limited by the sellar floor superiorly and by the sphenoid rostrum inferiorly, which is located at the level of the sphenoid floor in well-pneumatized sphenoid sinuses. The paraclival protuberances of the ICA limit

11  Endoscopic Approaches to the Brainstem confluence with the inferior petrosal sinus to enter the posterior part of the cavernous sinus. This anatomical relationship is of great importance and should be considered while performing a clivectomy, to avoid injury to CN VI.2,​5 Once the dura is open and the basilar plexus is controlled, the prepontine cistern is entered and the pons can be visualized posteriorly with the basilar artery in front of it. This approach is limited laterally by CNs VI (Fig. 11.2).

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Inferior Clivus The inferior third of the clivus borders the anterior aspect of the foramen magnum inferiorly. The superior border is located at the sphenoid rostrum junction at the level of the sphenoid sinus floor. In contrast to the middle third, the inferior third of the clivus is not limited directly by the ICA on both sides, therefore, further lateral dissection can be performed safely. The petroclival synchondrosis is found laterally and can be traced all the way to the jugular foramen. The occipital condyles are located in the anterior portion of the foramen magnum and are considered the lateral limits while drilling the inferior part of the clivus. When the lateral exposure needs to be augmented to include the subarachnoid origin of the vertebral artery, a medial condylectomy is performed. In this scenario, the hypoglossal nerve (CN XII) tracking inside the hypoglossal canal is considered the lateral limit. Once the dura is opened, the premedullary cistern is reached, with the medulla posteriorly and the vertebral arteries laterally. CN XII runs lateral to the vertebral arteries in the cistern and also represents the limit of this approach intracranially (Fig. 11.3).

■■ Preoperative Planning •• A detailed medical history is obtained from the patient and a complete neurologic examination is performed with special emphasis on cranial nerve, sensorimotor, and cerebellar functions.5 Fig. 11.2  Endoscopic endonasal exposure of the pons in a cadaveric specimen. The dura underlying the middle third of the clivus is opened in the midline, and the two dural leaflets are reflected in an “open book” fashion. The prepontine cistern is exposed with the bilateral abducens nerves (cranial nerves [CNs] VI) limiting the space laterally. The cisternal segment of CNs VI courses superolaterally until it pierces the dura of the clivus (Dorello’s point). Note that the origin of CN VI at the brainstem is above the vertebrobasilar junction (VBJ). The pons and the basilar artery (BA) in front of it are visualized. The basilar apex with its bifurcation, the perforator branches of the BA (white arrows), and the anterior inferior cerebellar arteries (AICAs) are also visualized. The intradural segments of the vertebral arteries (VAs) join bilaterally to form the BA. A transclival approach through the middle part of the clivus allows exposure from the pontomesencephalic junction (white dashed line) to the pontomedullary junction (yellow dashed line). White arrows indicate perforator branches of the basilar artery. Abbreviation: SCA, superior cerebellar artery.

•• The nasal cavity should be assessed endoscopically before surgery to document any particular findings, such as sinus infection, septal deviations, and any other anatomical abnormalities.5 •• As appropriate for each individual patient, pituitary function is evaluated and preoperative visual assessment tests are performed, including visual acuity, fundus examination, and baseline computerized visual field.5 •• Preoperative imaging studies: A thorough understanding of the anatomical relationships of a certain region is very critical when taking a decision whether a lesion can be adequately and safely reached and resected via an

Fig. 11.3  Endoscopic endonasal exposure of the medulla in a cadaveric specimen. (a) A transclival approach through the lower third of the clivus with a medial condylectomy is performed and the dura is opened. The ventral aspect of the medulla is completely visible. The vertebral arteries (VAs), the vertebrobasilar junction (VBJ), and the right posterior inferior cerebellar artery (PICA) are visualized. The glossopharyngeal, vagus, and hypoglossal nerves (cranial nerves [CNs] IX, X, and XII) are exposed. (b) A close-up view of the right side of the approach with better visualization of the lower CNs. Note that CN XII courses toward the hypoglossal canal, representing the lateral limit of the approach. Abbreviations: AICA, anterior inferior cerebellar artery; BA, basilar artery; CN VI, abducens nerve.

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IV  Surgical Approaches to the Brainstem, Thalamus, and Pineal Region

endoscopic endonasal approach. Furthermore, the relationship of neurovascular structures and whether the lesion violates the pial planes are of great importance for preoperative planning as well. All these factors have a significant implication on the feasibility of resection of the lesion and the risk of injury to the important neurovascular structures while performing an endoscopic endonasal approach. Thus, appropriate preoperative imaging studies should be performed and critically reviewed.3 These studies include:  1. High-resolution computed tomography of the paranasal sinuses and the skull base. The study must be conducted with coronal and sagittal reconstruction and both soft tissues and bone algorithms. The following points should be specifically evaluated to determine the feasibility of the approach: • Nasal septum • The paranasal sinuses (especially the sphenoid sinus) should be checked for the following: –– The degree of pneumatization. For instance, in the case of a conchal-type sphenoid sinus, the clival recess below the sella is not visible, and the sphenoidal and nasopharyngeal segments of the clivus cannot be clearly distinguished, which makes the approach more difficult. –– Presence and location of intrasinus septations –– Presence of an Onodi cell, an ethmoidal air cell that lies posterior to the sphenoid sinus –– Presence of any inflammatory process • The skull base bony structure should be carefully assessed with special consideration of the following: –– Presence and extent of bone dehiscence, erosions, or hyperostosis of the skull base (especially at the level of both parasellar and paraclival carotid prominences, cavernous sinuses, and optic canals) –– Thickness of the clivus and the degree of its inclination (i.e., basal angle). The basal angle is of great importance and must be appraised when planning the skull base reconstruction. As a rule, the more obtuse the angle is, the higher the possibility of the nasoseptal flap to be too short to cover the inferior part of the skull base defect. –– Anatomy of the anterior and posterior clinoid processes –– The configuration of the vidian canal on both axial and coronal planes and its relationship to the foramen lacerum • Anatomical course of the ICAs (especially the paraclival segment) • The configuration of the craniovertebral junction2,​3  2. Magnetic resonance imaging with and without intravenous gadolinium contrast, with 3-mm sections in the axial, coronal, and sagittal planes. Magnetic resonance imaging is the best imaging modality for soft tissue assessment, and it is complementary to computed tomography.3  3. Angiographic studies such as high-resolution computed tomography angiography, magnetic resonance angiography, or conventional angiography with digital subtraction are performed to delineate the course of the ICA and to outline the anatomy of other vascular structures.3

Patient Positioning Patients are positioned on the operating table in a supine position. The head is placed in a Mayfield head holder, adjusted in a neutral position and slightly tilted to the left with the face turned to the right by 15 to 20°. If necessary, the head can be slightly flexed at 15°.5,​10 Neurophysiologic monitoring is implemented, depending on the needs of each patient, that includes cortical function (­ somatosensory evoked potentials), brainstem function (brainstem evoked responses), cranial nerve ­ monitoring (electromyography), and motor evoked potentials.5 The application of micro-Doppler can be very helpful to identify the course of the ICA, the vertebrobasilar arterial system, and other vascular structures.6 In our operating suite, the surgical team is positioned to the right side of the patient and the anesthesia team toward the feet of the patient. The scrub nurse can be positioned on either side of the bed but preferably on the same side as the surgeon. However, other arrangements are possible, depending on the geometry and dimensions of the operating room, the surgeon's handedness or preference, and body habitus. The surgical navigation device is positioned at the head of the patient. The monitor is placed opposite the surgeon on the other side of the patient.5

Creating the Nasal Corridor After optimal positioning of the patient, the nose is prepared by placing pledgets soaked with 0.02% oxymetazoline into each nostril, followed by application of povidone iodine solution over the nose, upper lip, and into each nostril using a cotton tip applicator.10 The periumbilical area is prepared by applying povidone iodine solution (to be ready in case an autologous free fat graft is needed during the skull base reconstruction). The right thigh is also prepared in the event that a muscle graft is needed for a major vascular injury repair.11 Bimanual dissection constitutes the basis of microneurosurgery and is also essential for endoneurosurgery. The bimanual dissection is of great importance while managing significant bleeding, because it provides better visualization while controlling the hemorrhage, which helps to prevent injury to the adjacent vital structures. A binasal approach allows for this bimanual dissection and therefore is always considered as an absolute prerequisite for all extended endoscopic approaches. Removal of enough bone at the skull base is also essential for these approaches to create a surgical corridor that is wide enough to allow for exposure of the key anatomical landmarks. The advantage of this binasal access through a wide corridor is to prevent crisscrossing of instruments, allow dynamic movement of the endoscope while minimizing soiling of its lens, improve the maneuverability of the instruments, and help maintain a wide unobstructed view of the surgical field.5,​10 The procedure is commenced by creation of a bilateral nasal corridor. Posterior septectomy is the cornerstone of this binasal approach as it allows improved bimanual maneuverability of the instruments while avoiding soiling of the endoscope lens, thus, optimizing visualization. A zero-degree rod lens endoscope (Karl Storz) is used to start the procedure. The lens of the endoscope is continuously cleaned to maintain a clear visualization either by manual irrigation with a 60-mL syringe or through an endoscopic sheath.11

11  Endoscopic Approaches to the Brainstem First, the inferior turbinates are lateralized to allow more space for the insertion and manipulation of the instruments. Then a right middle turbinectomy is usually performed, followed by hemostasis with suction electrocautery of the posterior attachment, which contains a branch of the sphenopalatine artery. In general, the contralateral middle turbinate is preserved and outfractured to allow for a wider corridor.11 At this point, a vascularized nasoseptal flap is harvested, commonly on the right side. The flap is pedicled on the posterior septal branch of the sphenopalatine artery. This flap is used at the end of the procedure for reconstruction of the skull base defect, but elevation of the flap or at least its pedicle (the so-called rescue flap) must precede the posterior septectomy, as otherwise its blood supply would be destroyed during the septectomy.3,​11 The flap designation is made according to the size and shape of the anticipated defect; however, it must be of a larger size. While harvesting the flap, the incisions are made with a monopolar diathermy needle to decrease the amount of bleeding from the free edge of the flap and the remaining mucosa in situ.6 The flap is then positioned on the lateral wall of the nasal cavity with a stitch stretching it and keeping it away from the nasal corridor. The flap can also be positioned in the nasopharynx when approaching the superior aspect of the clivus. In the event of revision cases or presence of a preexisting septal defect, the flap can be harvested from the lateral wall and nasal floor.6 A posterior nasal septectomy, wide bilateral sphenoidotomies extending laterally up to the level of the medial pterygoid plates, and posterior ethmoidectomies are performed to complete the nasal corridor.10,​11 Intrasphenoidal septations are drilled down carefully, while respecting the relationship to the ICAs and optic nerve canals.5 After removal of the sphenoid mucosa, the posterior wall of the sphenoid sinus is completely exposed and the anatomical landmarks are identified, as pointed out in the Surgical Anatomy section.5 At this stage, two surgical corridors can be used; one above and the other below the floor of the sphenoid sinus. The superior corridor gives access to the sellar area and to the sphenoidal segment of the clivus (i.e., the upper and middle thirds of the clivus), whereas the inferior corridor gives access to the nasopharyngeal portion of the clivus and the foramen magnum (i.e., the lower third of the clivus).3 The foundation of this exposure is to create a large single rectangular cavity within the sphenoid sinus. This allows for the progressive advancement of the endoscope closer to the target, which is essential for better visualization and magnification of the target. In the event of bleeding, placing the endoscope closer is also crucial. However, if the surgeon is working through a tight corridor with limited maneuverability of the equipment, this will often lead to soiling of the endoscope lens, which can be a frustrating limitation. A wide corridor is therefore helpful to avoid this limitation.10 The arrangement of instruments at the nares while performing the procedure is very important. To optimize this relatively small space, the endoscope is placed at the 12-o’clock position, and the suction is introduced at the 6-o’clock position in the right naris. The left naris is used to introduce the dissecting instruments into the surgical field10 (Fig. 11.4). It is critical that the adequate bone drilling needed to create an optimum intradural exposure must be completely accomplished before opening the dura.2

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Fig. 11.4  Arrangement of the instruments at the nares during endoscopic endonasal approaches. In the right nostril, the endoscope is placed at the 12 o’clock position, and the suction is introduced at the 6 o’clock position. The dissecting instruments are introduced into the surgical field through the left nostril. This arrangement is important because it helps optimize the relatively small space.

Modules of Approaches to the Brainstem Exposure of the Mesencephalon and the Interpeduncular Fossa The interpeduncular cistern, including the retroinfundibular area, is one of the most difficult regions to access surgically. When approaching this region through an endonasal corridor, the pituitary gland and infundibulum represent obstacles because they guard the region anteriorly.9 Thus, this region is exposed via a transclival approach through the upper third of the clivus or a transdorsum sellae approach with pituitary transposition.

Surgical Approach After the aforementioned steps in the general exposure are performed, the procedure is performed as follows: after the sphenoidotomy is widened enough to include the lateral recess of the sphenoid extending lateral to the carotid canal, and before removal of the intrasphenoidal septations, the exposure is extended rostrally to expose the posterior cells of the ethmoid sinus to define the junction between the planum sphenoidale and the tuberculum sellae. It should be emphasized that the posterior ethmoidal arteries are the anterior limit of the exposure, otherwise, olfaction will be affected.9 Removal of the bone covering the sellar face is extended laterally to expose the medial portions of the cavernous sinus on both sides and rostrocaudally to expose the superior intercavernous sinus (SIS), inferior intercavernous sinus (IIS), and sella-clival junction.8,​9 Using a high speed drill, the tuberculum sellae is thinned until the underlying SIS is seen through the residual eggshellthin bone. Then the thinned tuberculum sella is removed to create space for the pituitary gland to be elevated from the sella.9 At this point, the exposure of the dura mater over the entire pituitary fossa, the tuberculum, and the SIS is accomplished, and the dura is ready to be opened.12 During the opening, the dura overlying the sella is opened along the midline, and care should be taken not to transgress the pituitary capsule. Once the plane between the dura and the pituitary capsule is established, it is followed superiorly underneath the SIS.9 The SIS is ligated, ideally by coagulation using a bipolar cautery; however, clipping is also possible. It is then transected to connect the dural openings above and below it.8,​9 The dural opening over the sella is then completely widened laterally and inferiorly in a cruciate manner, to allow full exposure of the entire anterior face of the gland. The caliber of the IIS is variable, being frequently very narrow along the midline. The IIS is occasionally absent; however, if present, it must be transected in the same fashion.9

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The so-called pituitary ligaments are numerous fibrous projections connecting the pituitary capsule to the lateral sellar dura or medial cavernous sinus wall. These ligaments are traced and cut along the lateral contour of the gland in a systematic fashion, using a sequence of both blunt and sharp dissection. One of the key elements during performing the transposition is to preserve the pituitary capsule to avoid gland damage and facilitate dissection.8,​9 More recently we have kept the posterior gland still attached to the dura of the posterior aspect of the sella. The dura is rolled up with the gland to preserve the gland’s venous drainage. The dural projection covering the sella anteriorly is densely attached to the superior aspect of the pituitary capsule; thus, it has to be carefully dissected and then incised at the midline. The incision is extended along the midline all the way to the central aperture of the diaphragma sellae to free the pituitary stalk.8,​9 At this point, the pituitary gland is safely mobilized superiorly without any resistance.9,​12 Once the pituitary gland is transposed with the dura, the dorsum sellae and posterior clinoids are then directly visualized.8,​9 The dorsum sellae and the posterior clinoids are drilled until they can be mobilized medially. The posterior clinoids are very densely attached laterally by means of the posterior petroclinoid ligaments and anteriorly by means of the interclinoid ligaments. Therefore, sharp dissection is often used to cut these ligaments to allow complete removal of the posterior clinoids.9 The dura behind the dorsum sellae is then opened. It is to be anticipated that intense venous bleeding, which can be life threatening, can be generated if the basilar plexus is trespassed. This intense bleeding occurs especially in the situation of performing the clivectomy in normal tissue that is not invaded by tumor.8 The bleeding from the basilar plexus is controlled by using bipolar devices with a flat surface  (Aquamantys; Medtronic) to coagulate the basilar plexus combined with filling the space between the dural layers with thrombotic substances such as microfibrillar collagen and absorbable gelatin powder with thrombin.5 When the dura is opened, the interpeduncular cistern is exposed, guarded laterally by Liliequist’s membrane. The posterior communicating arteries with their perforators, and CNs III, which represent the lateral limit of the approach, are also visualized. Posteriorly, the mesencephalon, the basilar apex with its bifurcation, the posterior cerebral arteries, and the superior cerebellar arteries are exposed. The inferior horizontal lamina of Liliequist’s membrane forms the inferior boundary.8 Superiorly, the floor of the third ventricle can be visualized.3 CN III emerges from the midbrain on the medial surface of the cerebral peduncle, and courses between the superior cerebellar artery and the posterior cerebral artery. Then it runs along the lateral aspect of the anterior incisural space, inferomedial to the uncus, toward the roof of the cavernous sinus.3 The posterior communicating artery runs in a posteromedial direction below the floor of the third ventricle. Along its course, several perforators emerge from its superior and lateral aspects and penetrate the floor of the third ventricle between the cerebral peduncle and the optic chiasm.3 This approach through the dorsum sellae provides a direct view of the mammillary bodies and the floor of the third ventricle. A ventral cavernous malformation on the mesencephalon could be approached ventrally as described. However, the basilar perforators and the ventral blood supply to the brainstem must be taken in consideration.

Exposure of the Pons The middle third of the clivus is usually approached directly. In case of a well-pneumatized sphenoid sinus, the middle third of the clivus is often a very thin bone that forms the deep aspect of the clival recess of the sphenoid sinus. Approaching the middle third of the clivus separately is rarely performed; however, it is usually combined with the approach for the inferior third of the clivus or with a panclivectomy.8

Surgical Approach Following the aforementioned steps in the general exposure, the clival bone is then drilled, and the dura and the basilar plexus are exposed.8 In patients with nonpneumatized sphenoid sinus or in recurrent cases, using a neuronavigation device is very beneficial in defining the limits of bone removal.2 The approach is limited laterally by the paraclival ICAs. Drilling the ICA canals to expose the periosteum optimizes the corridor and also allows ICA mobilization for better retrocarotid visualization and dissection and better exposure of the anterolateral posterior fossa compartment when necessary.8 The vidian nerve and the pharyngobasilar fascia are important landmarks for this approach. The vidian nerve travels inside the vidian canal toward the anterior genu of the ICA at the level of the foramen lacerum. The pharyngobasilar fascia attaches laterally to the inferior aspect of the lacerum foramen. Hence, the lacerum ICA, vidian nerve and pharyngobasilar fascia triangulate at the foramen lacerum. Thus, it helps identify the petrous ICA in patients in whom the sphenoid sinus pneumatization is not favorable or in patients whose anatomy is deformed by disease.13 The underlying dura is opened at the midline after meticulous coagulation. CN VI pierces the dura laterally, traveling superolaterally behind the petrous apex to then enter Dorello’s canal. It is in the interdural segment that CN VI is more vulnerable. Nerve stimulation and neurophysiology are essential to identify whether CN VI may have been displaced by the tumor. Before opening the dura, the VBJ should be precisely located by the use of image guidance under computed tomography angiography visualization. The dura is then opened below the VBJ to ensure that the origin of CN VI at the brainstem remains above.3,​8 The prepontine cistern is exposed with the bilateral CNs VI limiting the space laterally.8 The cisternal segment of CN VI ends as it pierces the dura mater of the clivus (Dorello’s point). By directing the endoscope upward, the entry zone of the trigeminal nerve (CN V) can be exposed above CN VI.3 Posteriorly, the entire ventral surface of the pons, the basilar artery, and the branches of the basilar artery, including the anterior inferior cerebellar artery, can be visualized.8 A cavernous malformation of the ventral pons can be accessed using this approach with special attention paid to the small basilar branches to the brainstem and with proper white matter studies (diffusion tensor imaging) in order to evaluate the best angle to enter the brainstem.

Exposure of the Medulla The medulla is exposed via a transclival approach through the lower third of the clivus. The inferior third of the clivus can be approached separately, or more commonly combined with a panclivectomy (Fig. 11.5).

11  Endoscopic Approaches to the Brainstem

Surgical Approach To perform the posterior nasal septectomy, the nasal septum is first detached from the anterior surface of the sphenoid bone. Extensive mucous removal is essential to adequately expose the bony landmarks. Subsequently, the basopharyngeal fascia is completely stripped off the floor of the sphenoid sinus and clival face, and the longus capitis and longus colli muscles are removed or rotated inferiorly with a flap, followed by complete drilling of the sphenoid sinus floor down to the clivus.3,​8,​12 At this stage, the surgical field extends rostrally to the sphenoid sinus, caudally to the soft palate, and laterally to the eustachian tubes. It is crucial to perform wide sphenoidotomies to allow for identification of the key anatomical landmarks rostrally (such as

Fig. 11.5  Endoscopic endonasal exposure of the brainstem through a panclivectomy with pituitary transposition in a cadaveric specimen. The dura is opened in the midline and the dural leaflets  (black stars) are reflected in an “open book” fashion. The whole ventral aspect of the brainstem is exposed. The mesencephalon and the interpeduncular fossa are exposed through the upper third of the clivus (above the white dashed line), the pons is exposed through the middle third of the clivus (between the dashed lines), and the medulla is exposed through the lower third of the clivus (below the yellow dashed line). The intradural segments of the vertebral artery (VA) join bilaterally to form the basilar artery (BA) at the vertebrobasilar junction (VBJ). The basilar apex with its bifurcation is visualized. The branches of the vertebrobasilar arterial system are exposed, including the posterior inferior cerebellar artery (PICA), anterior inferior cerebellar artery (AICA), superior cerebellar artery (SCA), posterior cerebral artery (PCA, both P1 and P2 segments), and posterior communicating artery (PCoA), and their corresponding perforator branches. The cranial nerves limiting the approach laterally are the oculomotor nerve (CN III) superiorly, the abducens nerve (CN VI) in the middle part, and the hypoglossal nerve (CN XII) inferiorly. Note that the internal carotid artery (ICA) borders the clivus laterally on both sides only at the upper and the middle thirds (the cavernous and the paraclival segments, respectively). White arrows indicate perforator branches of the BA. Abbreviations: 3rd V, third ventricle; CS, cavernous sinus; ICA-c, cavernous segment of ICA; ICA-pc, paraclival segment of ICA; PG, pituitary gland; PI, pituitary infundibulum.

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the carotid canals, medial pterygoid plates, pterygoid canal, and the vidian nerve).12 The procedure is carried on with drilling of the anterior surface of the clivus carefully, down to the foramen magnum. Bleeding from the cancellous bone can be controlled by applying bone wax. The inner cortex is drilled down till it becomes eggshell thin, and then the residual bone is removed using Kerrison rongeurs.8,​12 Removal of the bone located under the horizontal petrous segment of the ICA should be performed carefully. Again, the vidian nerve and artery represent very important landmarks as they travel inside the vidian canal toward the anterior genu of the ICA. Thus, when drilling the clival bone rostral to the level of the vidian canal, it is necessary to drill only in-between the ICA canals. When drilling the petrous bone inferior and lateral to the anterior genu of the ICA, it should be performed from a caudal to rostral direction, with the vidian canal representing the superior limit.12 The amount of dural exposure depends on the pathological nature of the lesion, therefore, each approach should be tailored as appropriate to each individual patient. After the dura is opened, the medulla is exposed posteriorly, and the vertebral arteries are identified.8 In some cases, further lateral dissection at the level of the lower third of the clivus is needed to expose the lateral extensions of the tumor. Theoretically, this lateral dissection can be divided into three parts from rostral to caudal below the level of the petrous ICA, with approaches tailored to each part: (1) the infrapetrous approach, (2) the supracondylar or transjugular tubercle approach, and (3) the transcondylar approach. In the infrapetrous approach lateral extension, the petrous bone below the ICA is removed. Initially, adequate exposure of the area of the foramen lacerum is achieved, and transection of the dense fibrous tissue connections with eustachian tube is performed. The bone under V3 and below the petrous ICA is then drilled.8 In the supracondylar or transjugular tubercle approach, the occipital bone is drilled above the occipital condyle and medial to the petroclival synchondrosis. As the dissection is achieved along the petroclival synchondrosis inferiorly, the lower cranial nerves (the glossopharyngeal nerve [CN IX], vagus nerve [CN X], and CN XII) should be under neurophysiology monitoring.8 In the transcondylar lateral extension, a medial condylectomy is performed to allow exposure of the proximal segment of the vertebral artery. CNs XII represent the lateral limit. Again, neurophysiology monitoring is essential when performing this approach.8 A medial condylectomy is achieved by drilling the anterior third of the occipital condyles till approaching the hypoglossal canal, which is indicated by a change from cancellous to cortical bone. Care must be taken not to enter the hypoglossal canal to avoid bleeding from the venous plexus surrounding the nerve. The hypoglossal canal is located superior to the junction of the anterior and middle third of the occipital condyle, approximately 15 mm away from the midline and 9 mm superior to the point of intradural entry of the vertebral artery.3 The transclival approach through the inferior third of the clivus gives access to the premedullary cistern. The anterior surface of the medulla is seen posteriorly. The superior limit of the exposure is at the pontomedullary junction, which basically

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corresponds to the VBJ; therefore, CN VI is not vulnerable at this level. Extending the surgical field laterally through a supracondylar (transjugular tubercle) approach allows direct exposure of CNs IX, X, and XI, guarding the premedullary cistern laterally. When the bone of the middle and lower thirds of the clivus is removed, and the dural opening is extended from the floor of the sella superiorly all the way down to the foramen magnum inferiorly and between both carotid arteries laterolaterally, exposure of the anterior surface of the pons and medulla, CNs VI and XII and the verebrobasilar arterial system is obtained.

■■ Reconstruction Finally, reconstruction of the skull base defect is a fundamental basis of the endoscopic endonasal approaches and is a key element in reducing the incidence of cerebrospinal fluid (CSF) leaks and infective complications such as meningitis. The repair of dural defects in the clival region is more challenging, owing to the fact that these defects are subjected to more pressure than those higher in the cranium.6 Reconstruction of the skull base defect is achieved using a multilayer technique. First, a subdural inlay graft is placed between the brain and the dura mater to reconstruct the arachnoid layer. We prefer to use collagen matrix (Duragen; Integra Life Sciences) because it has good tissue-handling properties. Subsequently, a vascularized nasoseptal flap pedicled on the posterior nasal septal artery is used as a second layer. Basically, the nasoseptal flap is the cornerstone of the skull base reconstruction, as it has a significant advantage in reducing the incidence of CSF leak.3,​6,​9 It is essential to ensure that the flap is in a direct and complete contact with the bony edges of the defect to encourage vascularization and to improve its sealing effects. Once again, the flap should be larger than the size of the defect as it contracts and shrinks over time.9 Occasionally, in the situation of a foramen magnum exposure, the available nasoseptal flap may not be adequate to completely cover the skull base defect. Thus, the reconstruction must be augmented with the use of fat graft.8 Following reconstruction of the skull base defect, it is then buttressed with a Foley balloon or preferably with Merocel nasal packing (Medtronic) to diminish the possibility of flap migration.8,​9 Silastic (Dow Corning) splints are applied against the denuded septum to promote re-epithelialization and to prevent synechiae.2,​8 In the postoperative period, antibiotics are prescribed until the nasal packing is removed. A lumbar drain is rarely placed; however, it is often used in certain situations such as cases with high-flow CSF leaks, hemorrhage into the subarachnoid space, or in obese patients.8

■■ Conclusions Endoscopic approaches provide a direct route, albeit through a fortress of bony protective structures, for resection of lesions in the brainstem. The use of these approaches requires mastery of anatomy that is seen infrequently by neurosurgeons, facility with endoscopic techniques, and often a team approach to leverage the expertise of otolaryngology colleagues in endoscopy. References 1. Funaki T, Matsushima T, Peris-Celda M, Valentine RJ, Joo W, Rhoton AL, Jr. Focal transnasal approach to the upper, middle, and lower clivus. Neurosurgery 2013;73(2, Suppl Operative):ons155–ons190, discussion ons190–ons191 2. Beer-Furlan A, Vellutini EA, Balsalobre L, Stamm AC. Endoscopic endonasal approach to ventral posterior fossa meningiomas: from case selection to surgical management. Neurosurg Clin N Am 2015; 26(3):413–426 3. Stamm AC. Transnasal Endoscopic Skull Base and Brain Surgery Tips and Pearls. New York: Thieme; 2011 4. Fernandez-Miranda JC, Prevedello DM, Madhok R, et al. Sphenoid septations and their relationship with internal carotid arteries: anatomical and radiological study. Laryngoscope 2009;119(10):1893–1896 5. Draf W, Carrau RL, Bockmühl U, et al. Endonasal Endoscopic Surgery of Skull Base Tumors: An Interdisciplinary Approach. Stuttgart; New York: Thieme; 2015 6. Stamm AC, Balsalobre L, Hermann D, et al. Endonasal endoscopic approach to clival and posterior fossa chordomas. Oper Tech Otolaryngol—Head Neck Surg 2011;22:274–280 7. Mohyeldin A, Prevedello DM, Jamshidi AO, Ditzel Filho LF, Carrau RL. Nuances in the treatment of malignant tumors of the clival and petroclival region. Int Arch Otorhinolaryngol 2014;18(Suppl 2):S157–S172 8. Prevedello DM, Ditzel Filho LF, Solari D, Carrau RL, Kassam AB. Expanded endonasal approaches to middle cranial fossa and posterior fossa tumors. Neurosurg Clin N Am 2010;21(4):621–635, vi 9. Kassam AB, Prevedello DM, Thomas A, et al. Endoscopic endonasal pituitary transposition for a transdorsum sellae approach to the interpeduncular cistern. Neurosurgery 2008;62(3, Suppl 1):57–72, discussion 72–74 10. Kassam A, Snyderman CH, Mintz A, Gardner P, Carrau RL. Expanded endonasal approach: the rostrocaudal axis. Part I. Crista galli to the sella turcica. Neurosurg Focus 2005;19(1):E3 11. Kassam AB, Prevedello DM, Carrau RL, et al. Endoscopic endonasal skull base surgery: analysis of complications in the authors’ initial 800 patients. J Neurosurg 2011;114(6):1544–1568 12. Kassam A, Snyderman CH, Mintz A, Gardner P, Carrau RL. Expanded endonasal approach: the rostrocaudal axis. Part II. Posterior clinoids to the foramen magnum. Neurosurg Focus 2005;19(1):E4 13. Servian DA, Beer-Furlan A, Lima LR, et al. Pharyngobasilar fascia, Cas a landmark in endoscopic skull base surgery: The triangulation technique. Laryngoscope 2018 Dec 25. doi: 10.1002/lary.27608. [Epub ahead of print]

12

Safe Entry Zones to the Brainstem Daniel D. Cavalcanti

Abstract

In this chapter on safe entry zones to the brainstem, readers will gain detailed knowledge of the main skull base exposures, enhanced with images from cadaveric dissections, which allow neurosurgeons to reach lesions in the brainstem. Despite its minimal volume, the brainstem contains a rich concentration of nuclei and fibers in a small sectional area, resulting in an increased likelihood of morbidity after manipulation. Thus, whenever lesions do not rise to the pial or ependymal surface of the brainstem, it is essential to have a fundamental understanding of the concept of safe entry zones. Such zones represent entry points and trajectories where eloquent structures and perforators are sparse. Moreover, when manipulation is performed by experienced neurosurgeons through these corridors, deficits are minimized. Using the right combination of surgical approach and safe entry zone is key to reducing morbidity for any lesion that does not emerge to the pial or ependymal surface. In this chapter, we detail seven safe entry zones that have been described to manage mesencephalic lesions, seven zones for management of pontine pathology, and six for operating on medullary lesions. Keywords:  brainstem, cavernous malformation, microsurgery, safe entry zones, surgical anatomy, surgical approaches

■■ Introduction Numerous approaches can lead the neurosurgeon to the different structures of the brainstem and various locations on

the brainstem. Notably, similar lesions may demand different approaches, depending on the long axis of the lesion and its proximity to the surface and surrounding at-risk structures.1,​2,​3 However, when lesions do not reach a pial or ependymal surface, known safe entry zones should be selected to avoid or reduce surgical morbidity. These zones, which have been described in surgical series, anatomical reports, and electrophysiological reports, consist of entry points or trajectories where arterial perforators, nuclei, and tracts are sparse.2,​4,​5,​6,​7,​8,​9,​10,​11,​12 Baghai et al10 were pioneers in elucidating safe entry zones. In 1982, they described a safe entry zone between the emergence of the trigeminal nerve (cranial nerve [CN] V) and the facial nerve (CN VII) via a retrosigmoid approach as a rational alternative to transgression of the fourth ventricular floor. Since then, other specialty centers introduced additional safe entry zones for managing brainstem tumors and vascular malformations.9,​13,​14,​15,​16 Comprehensive knowledge of different skull base exposures, gained through laboratory dissections and training, allows neurosurgeons to select the correct corridor during careful imaging analyses. Moreover, combining safe entry zones with the two-point method enhances approach selection.1,​17 Combining the right window with the optimal trajectory increases surgical freedom and odds of gross total resection while reducing undesired deficits. Image guidance and intraoperative monitoring are crucial adjuncts for optimizing safety during brainstem surgery. This chapter focuses on the safe entry zones commonly used for resection of brainstem pathologies (Fig. 12.1).

AMZ AMZ SCZ

STZ STZ

ICR

LMS

IBTZ ICZ

PSC

PTZ PTZ PT TZ

LPZ LPZ

SFT

MS

PIC

LMZ

OZ OZ PMS

©2

ALS ALS

7 01 w rro Ba

a

b

PIS PLS

Fig. 12.1 Main safe entry zones to the brainstem. The colored ovals and dashed lines represent points where small neurotomies are possible to avoid small perforators, main nerve tracts, and nuclei. (a) Anterolateral view of brainstem illustrating some anterior and anterolateral safe zones. (b) Posterior view of brainstem demonstrating the safe entry zones on the surface of the quadrigeminal plate (green dashed lines), floor of the fourth ventricle  (blue dashed lines and colored ovals), and lower medulla (red dashed lines). Abbreviations: ALS, anterolateral sulcus; AMZ, anterior mesencephalic zone; ant., anterior; CN, cranial nerve; IBTZ, inferior brachium triangular zone; ICZ, infracollicular zone; ICR, intercollicular region; LMS, lateral mesencephalic sulcus; LMZ, lateral medullary zone; LPZ, lateral pontine zone; med., median; MS, median sulcus of fourth ventricle; OZ, olivary zone; ped., peduncle; PIC, paramedian infracollicular; PIS, posterior intermediate sulcus; PLS, posterior lateral sulcus; PMS, posterior median sulcus; PSC, paramedian supracollicular; PTZ, peritrigeminal zone; SCZ, supracollicular zone; SFT, superior fovea triangle; STZ, supratrigeminal zone. Used with permission from Barrow Neurological Institute, Phoenix, Arizona.

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■■ Mesencephalic Safe Entry Zones The midbrain connects the diencephalon to the pons and consists of two main parts, the tectum and the cerebral peduncles. The cerebral peduncles are divided into the crus cerebri and the tegmentum. Lesions within the midbrain are approached using seven safe entry zones accessed via anterior, posterolateral, and posterior approaches (Table 12.1, Fig. 12.2).1,​2 Two safe entry zones are available for resection of ventral midbrain pathology: the anterior mesencephalic zone (or the perioculomotor safe entry zone) and the interpeduncular safe entry zone.18 Both of these safe entry zones may be approached using a modified orbitozygomatic approach or one of two minimally invasive approaches, the minisupraorbital or the transciliary supraorbital approach (Fig. 12.3).19,​20 With a larger craniocaudal extension of a deep lesion, a wider craniotomy is desirable, increasing the need to add an orbital osteotomy to

Table 12.1  Mesencephalic safe entry zones by approach

Approach

Safe entry zones

Orbitozygomatic, pterional, minisupraorbital, transciliary

Anterior mesencephalic, interpeduncular

Subtemporal

Anterior mesencephalic, lateral mesencephalic sulcus

Subtemporal transtentorial

Anterior mesencephalic, lateral mesencephalic sulcus

Median supracerebellar infratentorial

Lateral mesencephalic sulcus, inferior brachial triangular zone, intercollicular, supracollicular, infracollicular

Extreme lateral supracerebellar Lateral mesencephalic sulcus, infratentorial inferior brachial triangular zone, intercollicular, supracollicular, infracollicular

Fig. 12.2  Mesencephalic safe entry zones. (a) Cross section of the midbrain at the level of the cerebral peduncle, showing its main safe zones: the anterior mesencephalic zone (AMZ), the interpeduncular zone (IPZ), the lateral mesencephalic sulcus (LMS), and the intercollicular region (ICR). (b) Anterior view of a brainstem revealing the AMZ, where the neurotomy is performed between the oculomotor nerve (cranial nerve [CN] III) and the projection of the main fibers of the corticospinal tract on the intermediate three-fifths of the peduncle. (c) Posterolateral view depicting the

various safe zones on the quadrigeminal plate (supracollicular zone [SCZ], infracollicular zone [ICZ], and ICR), the lateral surface (inferior brachium triangular zone [IBTZ]), and the LMS. Abbreviations: cerebell., cerebellar; CST, corticospinal tract; ICR, intercollicular region; Inf., inferior; interped., interpeduncular; Mid., middle; ped., peduncle; Pit., pituitary; Post., posterior; Rhomb., rhomboid; Sup., superior. Reproduced with permission from Cavalcanti DD, Preul MC, Kalani MYS, Spetzler RF. Microsurgical anatomy of safe entry zones to the brainstem. J Neurosurg 2016;124:1359-1376.

Fig. 12.3 The anterior mesencephalic zone (dashed line). (a) Anterior view of a cadaveric specimen showing the main neurovascular structures bounding the anterior mesencephalic zone (AMZ), namely the posterior cerebral artery (PCA) superiorly, the superior cerebellar artery (SCA) inferiorly, the oculomotor nerve (cranial nerve [CN] III) medially, and the projection of the main fibers of the corticospinal tract on the intermediate three-fifths on the peduncle laterally. Alternatively, to remove centromedian lesions in the mesencephalon, a small neurotomy may be placed between the mammillary bodies and the basilar apex, between the basilar perforators (the interpeduncular zone [IPZ]). (b) Surgical view provided by a right modified orbitozygomatic approach. After opening

the sylvian fissure, the chiasmatic and carotid cisterns are opened wide; the dissection is taken laterally to the internal carotid artery. The oculomotor nerve is then followed through the interpeduncular cistern until it emerges at the brainstem surface. Abbreviations: A1, A1 segment of the anterior cerebral artery; AICA, anterior inferior cerebellar artery; BA, basilar artery; ICA, internal carotid artery; M1, M1 segment of the middle cerebral artery; P1, P1 segment of the PCA; P2A, anterior part of the P2 segment of the PCA; PCoA, posterior communicating artery. Reproduced with permission from Cavalcanti DD, Preul MC, Kalani MYS, Spetzler RF. Microsurgical anatomy of safe entry zones to the brainstem. J Neurosurg 2016;124:1359-1376.

12  Safe Entry Zones to the Brainstem

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Fig. 12.4  Surgical windows provided by the subtemporal approach to the brainstem. (a) Surgical demonstration of a left subtemporal craniotomy on a cadaver. A linear vertical incision is placed in front of the tragus. A bur hole is made just above the root of the zygomatic arch, and the craniotomy is tailored according to a preoperative plan targeting a lesion on the surface or one of two safe zones. Different angles of approach and areas of exposures are provided according to both the size and location of the craniotomy over the anteroposterior axis. The lower edge of the craniotomy should be flush with the middle fossa floor. (b) The dura is opened with its base positioned over the caudal edge of the craniotomy. (c) Microsurgical dissection is carried out between the temporal lobe and tentorium: below the temporal lobe and above the tentorium to the tentorial edge. Lumbar drainage of cerebrospinal fluid and extensive opening of the arachnoid membrane reduces the need for brain retraction. (d) The subtemporal approach provides a view of the anterior and the entire lateral incisural space, allowing inspection of the lateral midbrain. (e) This approach also provides a lateral view of the anterior mesencephalic zone (AMZ); orthogonal manipulation may cause injury to the tract of the oculomotor nerve (cranial nerve [CN] III). (f) Dividing the tentorium significantly enhances the exposure of the pontomesencephalic junction and the lateral upper pons. Tentorial division allows the surgeon to view the superior cerebellar artery (SCA) and the trochlear nerve (CN IV). (g) Progressive increases to a traditional subtemporal approach, in both area and length of exposure, after the addition of a transtentorial extension, and then after an anterior petrosectomy. Abbreviations: a., artery; ICA, internal carotid artery; LMS, lateral mesencephalic sulcus; P2A, anterior part of the P2 segment of the posterior cerebral artery; P2P, posterior part of the P2 segment of the posterior cerebral artery; PCoA, posterior communicating artery; PMJ, pontomesencephalic junction; post., posterior; quad., quadrangular; SCA, superior cerebellar artery; tent., tentorial. Reproduced with permission from Cavalcanti DD, Preul MC, Kalani MYS, Spetzler RF. Microsurgical anatomy of safe entry zones to the brainstem. J Neurosurg 2016;124:1359-1376.

the procedure. Alternatively, a third safe entry zone is available for lesions located laterally on the midbrain: the lateral route via the lateral mesencephalic sulcus provides access by either a subtemporal or an extreme lateral supracerebellar infratentorial  (SCIT) approach  (Fig. 12.4, Fig. 12.5).21 The routine use of subtemporal dissection has been avoided because this dissection necessitates temporal lobe retraction and risks injury to the vein of Labbé. The SCIT approach, using the lateral mesencephalic sulcus, is the preferred approach for managing lateral and dorsolateral midbrain pathologies with minimal risk to neurovascular structures, tracts, and nuclei. Finally, the last four mesencephalic safe zones are accessible via the median, paramedian, or lateral SCIT approach, with selection being dictated by the long axis of the lesion.22 The routine employment of the two-point method is strongly recommended to identify the optimal corridor to deep-seated lesions.17

Anterior Mesencephalic Zone Pathology involving the anterolateral midbrain can be accessed through an intricate area on the cerebral peduncle

bounded medially by the intramesencephalic segment of the oculomotor nerve (CN III) and laterally by the corticospinal tract (Fig. 12.3 , Fig. 12.4g).3 This narrow corridor, also known as the perioculomotor zone, has an advantageous distribution of corticospinal tract fibers, which are mainly in the intermediate three-fifths of the peduncle. An additional benefit is that the red nucleus and the nigrostriatal circuit are located in a deep medial area. Inside the interpeduncular cistern, the superior limit of the entry point is the posterior cerebral artery and the inferior limit is the main trunk of the superior cerebellar artery.

Interpeduncular Zone As an alternative to the anterior mesencephalic safe entry zone, the surgeon may make use of the sparse density of motor fibers in the middlemost one-fifth of the cerebral peduncle to enter the brainstem.1 In this approach, known as the interpeduncular zone, the oculomotor nerve (CN III) is again used to trace the path back to the brainstem, but instead of disconnecting

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Fig. 12.5 The extreme lateral supracerebellar infratentorial (ELSCIT) approach is the main route to the posterolateral mesencephalic surface and its safe zones. Two surgical positions used to perform an ELSCIT, the semi-sitting (a) and the lateral (b) positions. The retroauricular incision is extended slightly cranially, allowing exposure of the transverse sinus; with slight retraction, this incision thus increases exposure of the cerebellomesencephalic fissure. (c) The dissection is carried out along the tentorial surface of the cerebellum to the limits of the posterior incisural space. Small bridging veins can be coagulated and divided close to the cerebellar surface to avoid avulsion from the tentorium. (d) The ELSCIT offers an oblique view of the quadrigeminal plate. A neurotomy over the inferior brachium triangular zone (IBTZ, dashed line) is depicted in this dissection.

the lateral arachnoid adhesions to the temporal lobe and tentorium to mobilize the oculomotor nerve (CN III), the surgeon should dissect the medial arachnoid adhesions of the oculomotor nerve (CN III) to allow it to be attached laterally. The surgeon then develops the narrow corridor between the internal carotid artery and the optic nerve to arrive between the mammillary bodies and the perforators from the top of the basilar artery. The brainstem is incised in the interpeduncular safe entry zone for resection of centromedian lesions. The choice of the approach is dependent on the relationship of the brainstem to the clivus and posterior clinoid and on where the lesion is closest to the surface of the brainstem.

Lateral Mesencephalic Sulcus Beginning at the medial geniculate body, the lateral mesencephalic sulcus extends downward in a concave fashion to the pontomesencephalic sulcus, separating the peduncular and tegmental surfaces of the midbrain facing the middle incisural space (Fig. 12.4, Fig. 12.5).23 The lateral mesencephalic vein is a helpful landmark, usually running along the sulcus. One study by Recalde et al5 reported the mean total length of

the sulcus as 9.6 mm  (range 7.4–13.3 mm). Several arteries and nerves cross the sulcus: superiorly, surgeons encounter the posterior P2 segment (P2P); centrally, one encounters the medial posterior choroidal artery; and inferiorly, one encounters the cerebellomesencephalic segments of the superior cerebellar artery, trochlear nerve (CN IV), and tentorial edge. The entry zone is located between the substantia nigra anterolaterally and the medial lemniscus posteriorly. The mean working­-channel length at this point is 8.0 mm (range 4.9–11.7 mm). The fibers of the oculomotor nerve  (CN III) that cross from the red nucleus to the substantia nigra limit dissection anteromedially.

Intercollicular Region Bricolo and Turazzi first suggested the use of the intercollicular region for resection of dorsal midbrain pathology.3,​9 The quadrigeminal plate or tectum comprises two superior rounded eminences (superior colliculi) and two inferior rounded eminences (inferior colliculi); these eminences represent the dorsal surface of the midbrain (Fig. 12.1b). The most appropriate

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Fig 12.5 (continued)  (e) A straightforward corridor to the lateral mesencephalic sulcus (LMS, dashed line) is possible with such an approach, retracting the superior cerebellar artery (SCA) and the trochlear nerve (cranial nerve [CN] IV). (f) Area of exposure provided by the ELSCIT approach, providing a wide view of the posterolateral midbrain as well as the safe zones cited above (dashed line represents the LMS safe entry zone). (g-n) A 44-year-old woman presented with left hemiparesis and a contralateral oculomotor nerve  (CN III) deficit. Axial (g) and coronal (h) T2-weighted magnetic resonance images show a large right lateral mesencephalic cavernous malformation. (i) Screenshot of imageguidance demonstrates the corridor through the ELSCIT used for resection of this lesion. (j) Surgical view of the cerebellomesencephalic fissure, after the quadrigeminal and ambient cisterns were opened. (k) The SCA and the trochlear nerve (CN IV) are dissected free and kept away from the resection field. (l) Final view of the microsurgical site through the LMS, depicting complete resection of the lesion. (m) Axial and (n) coronal 3-month follow-up magnetic resonance images reveal complete resection. ­ Abbreviations: IC, inferior colliculus; SS, sigmoid sinus; TS, transverse sinus. Fig. 12.5f is reproduced with permission from Cavalcanti DD, Preul MC, Kalani MYS, Spetzler RF. Microsurgical anatomy of safe entry zones to the brainstem. J Neurosurg 2016;124:1359-1376.

area for a small neurotomy on the posterior surface of midbrain has been described as the intercollicular region, because of its sparseness of fibers (Fig. 12.2c, Fig. 12.6). The superior colliculi are part of a network of areas responsible for spatial attention. They play a major role in initiation and execution of saccadic eye movements and visual fixation.24,​ 25 A superior brachium connects them to each lateral geniculate body; retinotectal fibers run in this path.26 Spinotectal and corticotectal fibers lead to the superior colliculi, while tectospinal, tectothalamic, and tectocortical tracts leave these structures. The inferior colliculi are part of the auditory system. They receive fibers from the contralateral cochlear nucleus, dorsal and ventral nuclei of the lateral lemniscus, contralateral and ipsilateral superior olive, ipsilateral medial superior olive, and descending projections from sensory areas through the corticollicular neurons. The inferior colliculi are connected by commissural fibers; these colliculi extend laterally through the inferior brachium to the medial geniculate body of the thalamus, which projects to the primary auditory cortex.

Supracollicular and Infracollicular Zones In the supracollicular and infracollicular safe entry zone approaches (also referred to as the suprafacial collicular and infrafacial collicular approaches1), small transverse neurotomies can be tolerated either immediately above the superior colliculi in the midline or immediately below the inferior colliculi, above the emergence of the trochlear nerve (CN IV) (Fig. 12.2c, Fig. 12.6).9,​27 Both incisions should be limited by the cerebral aqueduct, because traversing the aqueduct may injure the nuclei of the oculomotor nerve (CN III) and the trochlear nerve (CN IV) and the medial longitudinal fascicle.

Inferior Brachial Triangular Zone Ishihara et al.11 reported a safe zone delineated using intraoperative electrophysiological data. Monitoring of both oculomotor and trochlear nerves is performed during surgical procedures by placing needle electrodes in the i­nferior

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Fig. 12.6  Median supracerebellar infratentorial approach for posterior mesencephalic pathology. (a) Using the prone position with the head flexed, a cadaveric dissection demonstrates the linear medial incision from just above the external occipital protuberance down to the spinous process of the axis. The craniotomy should carefully expose the torcula and both transverse sinuses, allowing a wide operative view between the cerebellum and tentorium. (b,c) The vein of Galen, internal cerebral veins, and basal veins of Rosenthal occupy most of the field between the tentorium and anterior vermis, making the safe dissection and caudal

exposure of the quadrigeminal plate challenging. (d) This microdissection reveals the safe entry zones on the tectum, namely the intercollicular region (ICR, dashed line), supracollicular zone (SCZ), infracollicular zone (ICZ), and the inferior brachium triangle zone (IBTZ). Abbreviations: IC, inferior colliculus; ICR, intercollicular region; mesenceph., mesencephalic; PCA, posterior cerebral artery; PG, pineal gland; SC, superior colliculus; v., vein. Reproduced with permission from Cavalcanti DD, Preul MC, Kalani MYS, Spetzler RF. Microsurgical anatomy of safe entry zones to the brainstem. J Neurosurg 2016;124:1359-1376.

recti and superior oblique muscles, respectively. The encountered safe zone is bordered superiorly by the inferior margin of the superior brachium, inferiorly by the intramesencephalic path of the trochlear nerve, and laterally by spinothalamic tract (Fig. 12.2c, Fig. 12.6). The only drawback to the use of this safe zone is the unilateral damage to ascending projections from the inferior colliculus.

pontine surface. Seven safe zones are available for resection of pontine pathology (Table 12.2, Fig. 12.7). Table 12.2  Pontine safe entry zones by approach

Approach

Safe entry zones

Subtemporal transtentorial

Supratrigeminal

Anterior petrosectomy

Supratrigeminal, peritrigeminal

Suboccipital telovelar

Median sulcus of fourth ventricle, paramedian infracollicular, paramedian supracollicular, superior fovea triangular

Retrosigmoid

Supratrigeminal, peritrigeminal, lateral pontine

Retrolabyrinthine

Supratrigeminal, peritrigeminal, lateral pontine

■■ Pontine Safe Entry Zones The pons is the most common site of pathology afflicting the brainstem.3,​13 The basal pons is populated by both corticospinal and corticobulbar tracts and has limited accessibility due to its protection by the clivus and petrous bones. The middle cerebellar peduncle increases distance from its core while the rhomboid fossa is a very eloquent region and less forgiving than the lateral

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Fig. 12.7  Pontine safe entry zones. (a) Cross section of the pons just above the level of the trigeminal nerve (cranial nerve [CN] V) root entry zone illustrating the peritrigeminal zone (PTZ). (b) Four entry zones are available for resecting dorsal pontine pathology not abutting the ependymal surface: the median sulcus (MS), the paramedian supracollicular (PSC) area, the paramedian infracollicular (PIC) area, and the superior fovea triangle (SFT). (c) The lateral surface of the pons tolerates neurotomies and tiny dissections on three specific points, namely the supratrigeminal zone (STZ), the peritrigeminal zone (PTZ), and the so-called lateral pontine zone (LPZ) through the middle cerebellar peduncle. Abbreviations: Ant. med. fissure, anterior median fissure; Cerebral ped., cerebral peduncle; CST, corticospinal tract; ICZ, infracollicular zone; Mid. cerebell. ped., middle cerebellar peduncle; Med. long. fascicle, medial longitudinal fascicle; SCZ, supracollicular zone; Sup. cerebell. ped., superior cerebellar peduncle. Reproduced with permission from Cavalcanti DD, Preul MC, Kalani MYS, Spetzler RF. Microsurgical anatomy of safe entry zones to the brainstem. J Neurosurg 2016;124:1359-1376.

+ The lateral surface of the pons has traditionally been considered a safe region for entering the brainstem.2,​3,​4,​5,​10 Three safe zones adjacent to the trigeminal nerve (CN V) have been described and can readily be approached using the retrosigmoid craniotomy. The dorsal surface of the pons provides four additional safe entry zones and can be readily approached using the standard suboccipital and the suboccipital telovelar approaches.

the area around the site of the neurotomy, and shortening the distance to field.28 Other authors have supported this technique, using the narrow corridor provided by a neurotomy in the lateral pontine zone, but vertical manipulation is certainly restricted.3

Lateral Pontine Zone “Middle Cerebellar Peduncle Approach”

Using the white fiber dissection technique, Recalde et al5 quantified a safe trajectory in front of the root entry zone of the trigeminal nerve (CN V), lateral to the pyramidal tract, and anterior to the motor and sensory trigeminal nuclei (Fig. 12.7, Fig. 12.8g). A mean distance of 4.64 mm  (range 3.8–5.6 mm) was reported on the axial plane, between the trigeminal nerve (CN V) and the pyramidal tract. The mean depth of dissection was reported as 11.2 mm (range 9.5–13.1 mm) to the trigeminal nuclei. The fibers of the abducens (CN VI), facial (CN VII), and vestibulocochlear (CN VIII) nerves run downward, posterior to the trigeminal nuclei. The r­ etrolabyrinthine approach provides a less obtuse angle of approach to all lateral pontine safe zones when compared to the retrosigmoid approach (Fig. 12.9).

The lateral pontine safe zone exposed through a retrosigmoid approach has been the workhorse corridor for managing pathology at the level of the trigeminal nerve4 (Fig. 12.8). In 1982, Baghai et al10 recommended this safe corridor at the junction between the middle cerebellar peduncle and the pons, between the root entry zones of the trigeminal nerve and facial nerve/vestibulocochlear nerve complex. The lateral pontine safe zone is better exposed by an elegant dissection of the petrosal fissure, which was inspired by the concept of opening the sylvian or the cerebellomedullary fissures, clearing

Peritrigeminal Zone

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Fig. 12.8 The retrosigmoid approach is the surgical workhorse for pontine pathology. (a) Cadaveric dissection depicting the lateral decubitus position, with the mastoid region at the top, and the retroauricular linear incision positioned two fingerbreadths behind the pinna. (b) The asterion is exposed at the union of the parietomastoid, occipitomastoid, and lambdoid sutures. The keyhole is made over the asterion, at the end of the parietomastoid suture or guided by neuronavigation. (c) A craniotomy is performed. (d) The mastoid is drilled to unveil the posterior edge of the sigmoid sinus. (e,f) After opening the arachnoid membrane, the cerebellopontine angle is exposed, showing cranial nerves (CNs) V through XI, the superior cerebellar artery, the anterior inferior cerebellar artery (AICA), and the posterior inferior cerebellar artery (PICA). Carefully dissecting the arachnoid around the superior petrosal vein and the petrosal fissure improves views to both the supratrigeminal zone (STZ) and lateral pontine zone (LPZ). The LPZ, situated between the emergence of the sensory root of the trigeminal nerve (CN V) and the facial vestibulocochlear nerve (CN VII-CN VIII) complex is one of the most frequently used entry zones. (g) The shaded area represents the total area of exposure provided by a large retrosigmoid approach, depending on the vertical length of the bone opening. The three arrows represent the safe zones on the lateral surface of the pons: the STZ, peritrigeminal zone (PTZ), and LPZ.

Supratrigeminal Zone A third entry point has been used to manage lateral pontine pathology and is located just above the root entry zone of the trigeminal nerve (CN V) (Fig. 12.8).1 For this particular safe zone, the Kawase approach provides the optimal straight trajectory (Fig. 12.9d).2

Paramedian Supracollicular and Infracollicular Zones The floor of the fourth ventricle conceals an array of structures whose manipulation may provoke new neurological deficits  (Fig. 12.7b). Surface landmarks guide neurosurgeons

in protecting crucial structures located at the depth of the rhomboid fossa. At the floor of the fourth ventricle, the facial nerve (CN VII) passes around the nucleus of the abducens nerve (CN VI); this mingled round structure corresponds to the facial colliculus. Parallel to the median sulcus is the medial longitudinal fascicle. Similarly, the nuclei of the vagus  (CN X) and hypoglossal  (CN XII) nerves are located just caudal to the striae medullaris. Kyoshima et al.8 examined the topographic anatomy of the facial colliculi. Potential signs of neurological deficit were noted after manipulating the rhomboid fossa. They then described two safe entry zones that minimally displace surrounding neural structures in this region (Fig. 12.7). One is the suprafacial triangle. This triangle is delineated caudally by the facial nerve, lat-

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Fig. 12.8 (continued)  A 44-year-old woman presented with headache, nausea, and left-sided facial numbness. (h) Preoperative axial T1-weighted magnetic resonance image demonstrates a cavernous malformation in the left middle cerebellar peduncle. (i) A small retrosigmoid craniotomy is tailored and the cerebellopontine angle is exposed through gentle intermittent retraction of the petrosal surface of the cerebellum, avoiding the use of brain spatulas. A large suprameatal tubercle hides the trajectory of the trigeminal nerve (CN V) to Meckel’s cave, but does not alter the view and ideal trajectory to the LPZ and the lesion using the two-point method. (j) Opening the petrosal fissure widely affords better visualization of the middle cerebellar peduncle and the entry point without the need for fixed

retractors. (k) Final view showing gross total resection of the lesion and the clean operative site on the middle cerebellar peduncle. (l) Postoperative T1-weighted MRI demonstrates complete removal of the lesion and preservation of the developmental venous anomaly (asterisk). Abbreviations: Cerebell., cerebellar; LMZ, lateral medullary zone; MCP, middle cerebellar peduncle; Mid. cerebell. ped., middle cerebellar peduncle; PICA, posterior inferior cerebellar artery; SCZ, supracollicular zone; Sup., superior; Transv. pontine v., transverse pontine vein; V. of mid. cerebell. ped., vein of the middle cerebellar peduncle; v., vein. Figs. 128a-g are reproduced with permission from Cavalcanti DD, Preul MC, Kalani MYS, Spetzler RF. Microsurgical anatomy of safe entry zones to the brainstem. J Neurosurg 2016;124:1359-1376.

erally by the cerebellar peduncles, and medially by the medial longitudinal fascicle. The edges of the infrafacial triangle comprise the second safe entry zone; these edges are the striae medullaris caudally, the facial nerve laterally, and the medial longitudinal fascicle medially. When observing the variability of the striae medullaris, Strauss et al29 examined the possible damage to the trigeminal motor nucleus when using the suprafacial triangle and possible damage to the nuclei of the lower cranial nerves when using the infrafacial triangle. These investigators measured the dimensions of the facial colliculus and its distance to the midline, decussation of the trochlear nerve (CN IV), and vagal and hypoglossal trigones in a morphometric study and subsequently redefined the two main safe entry zones on the rhomboid fossa (Fig. 12.7b, Fig. 12.10). First, a paramedian supracollicular area measuring 13.8 mm vertically was defined between the facial colliculus and the decussation of the trochlear nerve (CN IV), 0.6 mm from the midline. The motor nucleus of the trigeminal nerve (CN V) limits the approach laterally, being located 6.3 mm from the midline. Second, a paramedian infracollicular area can be tai-

lored between the projection of the facial nerve (CN VII) fibers on the facial colliculus and the superior limits of the nucleus of the hypoglossal nerve  (CN XII) and the dorsal nucleus of the vagus nerve (CN X), extending a mean distance of 9.2 mm vertically and approximately 0.3 mm from midline.

Median Sulcus of the Fourth Ventricle For this safe zone, the fourth ventricular floor is exposed through a telovelar approach via a midline suboccipital craniotomy (Fig. 12.10).2,​30 The median sulcus is split, between the projection of the abducens and oculomotor nuclei on the ependymal surface.3 This incision takes advantage of the sparseness of crossing fibers. Minimal retraction is advised because the slightest lateral retraction may incite extraocular motility deficits by damaging the medial longitudinal fasciculus.

Superior Fovea Triangular Zone The superior fovea is a dimple corresponding to depression along the sulcus limitans, lateral to the facial colliculus.

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Fig. 12.9 Both posterior and anterior petrosectomies provide a more lateral exposure of the supratrigeminal zone (STZ), peritrigeminal zone (PTZ), and lateral pontine zone (LPZ), with theoretically better angles of approach to lateral pontine pathology extending dorsally within the pons. (a) A presigmoid retrolabyrinthine approach exposing Trautmann’s triangle. (b) Opening the dura along the anterior edge of the sigmoid sinus and lower edge of the superior petrosal sinus exposes the cerebellopontine angle and the petrosal fissure. (c) The three safe entry zones—the STZ, PTZ, and LPZ—are exposed within a quite limited

area of exposure. (d) The Kawase approach is performed to provide a very anterolateral view of the trigeminal nerve (cranial nerve [CN] V) root entry zone and both the STZ and PTZ. Abbreviations: AICA, anterior inferior cerebellar artery; LSC, lateral semicircular canal; Mid., middle; Mid. cerebell. ped., middle cerebellar peduncle; PSC, posterior semicircular canal; SCA, superior cerebellar artery; SSC, superior semicircular canal. Figs 12.9a-c are reproduced with permission from Cavalcanti DD, Preul MC, Kalani MYS, Spetzler RF. Microsurgical anatomy of safe entry zones to the brainstem. J Neurosurg 2016;124:1359-1376.

It resembles a triangle and is based over the sulcus limitans, limited superolaterally by the superior cerebellar peduncle and inferolaterally by the vestibular area.1 The superior edge of the triangle corresponds to the projection of the trigeminal motor nerve and its main sensory nuclei. Its apex is located at the transverse level identical to the upper edge of the facial colliculus. A lateral trans-superior fovea neurotomy running from the level of the apex to the vestibular area has been described and has been unveiled in detail in anatomical dissections (Fig. 12.7, Fig. 12.10).12

when manipulating lesions close to the medullary respiratory and vasomotor centers as damage to these structures may result in significant deficits with respiration, swallowing, and other vital functions. Respiratory control is accomplished by two areas: (1) the ventral respiratory group, comprising the nucleus ambiguus, retroambiguus, and retrofacialis, and (2) the dorsal respiratory group within the solitary tract.31 The vasomotor center is held bilaterally in the reticular formation of medulla at the floor of the fourth ventricle. The area controlling swallowing can be divided in two: (1) the dorsal medullary region, within the solitary tract and in adjacent reticular formation, providing neurons that initiate swallowing, and (2) the ventral medullary region, including the area around the nucleus ambiguous. A few specific zones are involved in controlling vomiting, mainly the solitary nucleus of the vagus and the lateral portion of the reticular formation.32

■■ Medullary Safe Entry Zones The medulla lies between the pons and the spinal cord, measuring roughly 2.5 cm long. Caution must be exercised

12  Safe Entry Zones to the Brainstem

Fig. 12.10  The telovelar approach to the fourth ventricle. (a) A formalin-fixed cadaveric specimen is dissected to simulate a median suboccipital craniotomy with C1 posterior arch osteotomy. (b) The telovelar approach is initiated by slight lateral retraction of the cerebellar tonsils, exposing and dividing both the tela choroidea and the inferior medullary velum. (c) A wide view of the rhomboid fossa is provided without cutting the vermis, from the cerebral aqueduct to the obex. (d) Posterior view of the brainstem demonstrating the area of exposure provided by the telovelar dissection (shaded area) also comprising

Table 12.3  Medullary safe entry zones by approach

Approach

Safe entry zones

Median suboccipital/ suboccipital telovelar Retrosigmoid Far-lateral

Posterior median sulcus of the medulla

Retrolabyrinthine

Lateral medullary Anterolateral sulcus of the medulla, lateral medullary, olivary, posterior median sulcus of the medulla Anterolateral sulcus of the medulla, olivary

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the median sulcus of fourth ventricle (MS), paramedian supracollicular (PSC) area, paramedian infracollicular (PIC) area, and superior fovea triangle (SFT). (e-n) A 19-year-old man presented with sudden headache, vomiting, persistent facial and right arm numbness, and diplopia. After imaging work-up, a large dorsal pontine cavernous malformation was identified. (e) Preoperative MRI demonstrates a dorsal partial cavernous malformation. (f) The patient was placed in a left lateral decubitus position. (continued)

Six main safe zones can be employed for managing intrinsic medullary lesions (Table 12.3, Fig. 12.11). An anterolateral route, provided by a small far-lateral approach or a low retrosigmoid craniotomy, provides access to the anterolateral sulcus entry zone and the olivary zone.1 A retrosigmoid approach is adequate to expose the medulla posterolaterally and its lateral medullary zone. Finally, a median suboccipital approach suffices to reach the medulla posteriorly, using one of three safe zones corresponding to the three posterior medullary sulci.

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IV  Surgical Approaches to the Brainstem, Thalamus, and Pineal Region Fig. 12.10 (continued) (g,h) A median suboccipital craniotomy was performed. (i) The dura was opened in a Y-shaped fashion and retracted cranially, and the cisterna magna was opened. (j) Exposure of the rhomboid fossa after opening of the tela and inferior medullary vellum. (k) Exposure of part of the cavernous malformation on the floor of the fourth ventricle.

Anterolateral Sulcus The rootlets of the hypoglossal nerve leave the brainstem on the preolivary or anterolateral sulcus, between the pyramid and olive (Fig. 12.11, Fig. 12.12). The brief gap between these rootlets and those of the first spinal nerve coincides with the decussation of the pyramidal tract. A paramedian oblique dissection may avoid the corticospinal tract and address lesions of the anterior lower medullary region.3

Olivary Zone The olives, which are marked oval eminences, are located on the anterolateral surface of the medulla. Their medial limits are the anterolateral sulcus and the pyramids as well as hypoglos-

sal nerve fibers and the medial lemniscus. The posterior reach is limited by the posterolateral sulcus (Fig. 12.11, Fig. 12.12) and mainly the tectospinal and spinothalamic tracts. At the inferior olivary nucleus, a cross-section shows fibers of the hypoglossal nerve separating it from the corticospinal tract running within the pyramids. A safe depth of dissection via the olive was identified by Recalde et al5 as ranging from 4.7 to 6.9 mm, with a vertical length of 13.5 mm.

Lateral Medullary or Inferior Cerebellar Peduncle Safe Zone Analogous to the lateral surface of the pons, the lateral medulla has recently been demonstrated by Deshmukh et al33 to harbor a

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Fig. 12.10 (continued)  (l) Final view showing the resection cavity after removal of the lesion. (m) Postoperative magnetic resonance images showing the complete resection of the lesion. (n) Patient’s appearance shortly before being discharged. The postoperative period was uneventful, and the patient was discharged on the fourth postoperative day. Abbreviations: PICA, ­posterior inferior cerebellar artery; Sup., superior. Figs 12.10a-d are reproduced with permission from Cavalcanti DD, Preul MC, Kalani MYS, Spetzler RF. Microsurgical anatomy of safe entry zones to the brainstem. J Neurosurg 2016;124:1359-1376.

relatively safe zone for resecting dorsolateral medullary pathology. Using the far-lateral approach for a small series of patients with dorsolateral medullary cavernous malformations, all lesions were totally resected via the foramen of Luschka through a neurotomy over the inferior cerebellar peduncle with excellent outcomes (Fig. 12.11, Fig. 12.12). We now advocate a low retrosigmoid approach, followed by a careful opening of the foramen of Luschka, and dissection of the origins of both the glossopharyngeal (CN IX) and vagus  (CN X) nerves.2,​34 Next, a small vertical incision is made in the inferior cerebellar peduncle inferior to the cochlear nuclei and posterior to the entry zone of both nerves. Alternatively, Lawton et al.35 described a supratonsillar approach traversing the tonsillar-biventral fissure and displacing the tonsil inferomedially to reach the inferior

cerebellar peduncle. In this particular case, a median suboccipital craniotomy with an optional C1 laminectomy is carried out.

Posterior Median Sulcus Splitting the posterior median sulcus provides a corridor near the center of the medulla oblongata akin to opening the dorsal midline raphe in the spinal cord.3,​36 This zone is bound superiorly by the obex and laterally by the clava, which covers the gracile nucleus (Fig. 12.11). Moreover, the two other posterior sulci, named the posterior intermediate and the posterior lateral sulci, can also serve as safe entry zones to posteriorly placed pathology (Fig. 12.13). One should avoid dissection on the calamus scriptorius, an extremely eloquent topography, populated by the lower cranial nerve nuclei.

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Fig. 12.11  Medullary safe entry zones. (a) Cross section of a human medulla oblongata demonstrating three safe entry zones: the olivary zone (OZ; dashed line), the anterolateral sulcus (ALS; arrow) safe entry zone, and the lateral medullary zone (LMZ; dashed arrow). (b) Anterolateral view of a brainstem showing suggested neurotomies for entering the olive (dashed line) and on the ALS just below the root of the hypoglossal nerve (cranial nerve [CN] XII). (c) Posterior view of the brainstem demonstrates the

posterior median sulcus (PMS) and LMZ safe entry zones. Abbreviations: Ant. med. fissure, anterior median fissure; Inf. colliculus, inferior colliculus; Inf. olivary nucleus, inferior olivary nucleus; Mid. cerebell. ped., middle cerebellar peduncle; Rhomb. fossa, rhomboid fossa; Sup. cerebell. ped., superior cerebellar peduncle; Sup. colliculus, superior colliculus. Reproduced with permission from Cavalcanti DD, Preul MC, Kalani MYS, Spetzler RF. Microsurgical anatomy of safe entry zones to the brainstem. J Neurosurg 2016;124:1359-1376.

Fig. 12.12 The far-lateral approach to anterolateral medullary pathology. (a-c) Patient position and skin incisions for a far-lateral approach using the park-bench position. A straight incision (a) is now preferred over the hockey

stick incision (b,c). The straight incision reduces operative time, blood loss, and muscle atrophy; however, care must be exercised in the region of the suboccipital triangle to prevent injury to the vertebral artery (VA).

12  Safe Entry Zones to the Brainstem

Fig 12.12 (continued)  (d) A cadaveric simulation of the elegant muscle dissection of the far-lateral approach needed to expose the suboccipital triangle containing the VA and its venous plexus. The triangle is limited by the superior and inferior oblique muscles and the rectus capitis posterior major muscle. (e) The C1 posterior arch and lateral mass are exposed; the lateral mass houses the V2 and V3 segment of the VA. (f) The craniotomy and C1 osteotomy are performed. (g) The occipital condyle is partially drilled and the VA can be mobilized. Each pathology will demand a different tailoring of the far-lateral approach with regard to size of the lateral suboccipital craniotomy, C1 posterior arch and lateral mass osteotomy, and occipital condyle drilling. (h) Exposure of the cerebellomedullary fissure and its main neurovascular content. It is possible to see the anterolateral sulcus (ALS). (i) Anterolateral view of the brainstem stressing the theoretical area of exposure (shaded area)

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provided by the far-lateral approach. Optimal neurotomies for both the olivary zone (OZ) and the ALS safe entry zone can be seen. (j) Posterolateral view of brainstem also stressing the theoretical area of exposure provided by the approach (shaded area). The ideal incisions for the lateral medullary zone and the posterior intermediate sulcus are depicted here. Abbreviations: C2 spin. proc., spinous process of C2; CN, cranial nerve; Inf. oblique m., inferior oblique muscle; PICA, posterior inferior cerebellar artery; Post. arch of C1, posterior arch of C1; Rec./Rectus cap. post. major m., rectus capitis posterior major muscle; Sup. oblique m., superior oblique muscle; Transv. proc. of C1, transverse process of C1; TS/SS junction, transverse sinus/sigmoid sinus junction. Figs. 12.12d-j are reproduced with permission from Cavalcanti DD, Preul MC, Kalani MYS, Spetzler RF. Microsurgical anatomy of safe entry zones to the brainstem. J Neurosurg 2016;124:1359-1376.

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Fig. 12.13 Posterior lower medullary entry zones. (a) This illustration depicts a posterior view of the cervicomedullary junction with optimal incisions for approaching medullary lesions, taking advantage of the three sulci on the posterior lower medulla, namely the posterior median sulcus (PMS),

■■ Conclusion Once a no man’s land, the brainstem has been exhaustively studied in anatomical, surgical, radiological, and electrophysiological endeavors by pioneers who paved the way to the advanced status of current brainstem surgery. With neurosurgeons now using the lateral pontine zone or another of the almost 20 safe entry zones described, patients with cavernous malformations, focal gliomas, hemangioblastomas, and other rare lesions benefit from safer surgeries and better outcomes. Whenever pathology is not evident on the pial or ependymal surface, meticulous analysis of the intrinsic lesion in all magnetic resonance imaging planes with assistance of the two-point method should guide neurosurgeons to one of the aforementioned surgical corridors and safe entry zones. Awareness of the cited safe entry zones aids in the decision-making process. An extended resection of focal brainstem lesions with better outcomes may be reached, with these six goals: (1) perfect surgical position, (2) selection of the optimal craniotomy, (3) optimal safe entry zone selected by the two-point method, (4) accurate image guidance, (5) clear intraoperative monitoring, and (6) respect for surrounding neurovascular structures during surgical resection. References 1. Kalani MYS, Yagmurlu K, Martirosyan NL, Cavalcanti DD, Spetzler RF. Approach selection for intrinsic brainstem pathologies. J Neurosurg. 2016; 125(6):1596–1607 2. Cavalcanti DD, Preul MC, Kalani MY, Spetzler RF. Microsurgical anatomy of safe entry zones to the brainstem. J Neurosurg. 2016; 124(5):1359–1376 3. Bricolo A, Turazzi S. Surgery for gliomas and other mass lesions of the brainstem. Adv Tech Stand Neurosurg. 1995; 22:261–341

the posterior intermediate sulcus (PIS), and the posterior lateral sulcus (PLS). (b) Drawing of a cross-sectional view of the medulla depicting the three safe zones cited above. (Used with permission from Barrow Neurological Institute, Phoenix, Arizona.)

4. Hebb MO, Spetzler RF. Lateral transpeduncular approach to intrinsic lesions of the rostral pons. Neurosurgery. 2010; 66(3) Suppl Operative:26–29, discussion 29 5. Recalde RJ, Figueiredo EG, de Oliveira E. Microsurgical anatomy of the safe entry zones on the anterolateral brainstem related to surgical approaches to cavernous malformations. Neurosurgery. 2008; 62(3, Suppl 1):9–15, discussion 15–17 6. Ferroli P, Sinisi M, Franzini A, Giombini S, Solero CL, Broggi G. Brainstem cavernomas: long-term results of microsurgical resection in 52 patients. Neurosurgery. 2005; 56(6):1203–1212, discussion 1212–1214 7. Cantore G, Missori P, Santoro A. Cavernous angiomas of the brain stem. Intra-axial anatomical pitfalls and surgical strategies. Surg Neurol. 1999; 52(1):84–93, discussion 93–94 8. Kyoshima K, Kobayashi S, Gibo H, Kuroyanagi T. A study of safe entry zones via the floor of the fourth ventricle for brain-stem lesions. Report of three cases. J Neurosurg. 1993; 78(6):987–993 9. Bricolo A, Turazzi S, Cristofori L, Talacchi A. Direct surgery for brainstem tumours. Acta Neurochir Suppl (Wien). 1991; 53(Suppl. 53):148–158 10. Baghai P, Vries JK, Bechtel PC. Retromastoid approach for biopsy of brain stem tumors. Neurosurgery. 1982; 10(5):574–579 11. Ishihara H, Bjeljac M, Straumann D, Kaku Y, Roth P, Yonekawa Y. The role of intraoperative monitoring of oculomotor and trochlear nuclei-safe entry zone to tegmental lesions. Minim Invasive Neurosurg. 2006; 49(3):168–172 12. Yagmurlu K, Kalani MYS, Preul MC, Spetzler RF. The superior fovea triangle approach: a novel safe entry zone to the brainstem. J Neurosurg. 2017; 127(5):1134–1138 13. Abla AA, Lekovic GP, Turner JD, de Oliveira JG, Porter R, Spetzler RF. Advances in the treatment and outcome of brainstem cavernous malformation surgery: a single-center case series of 300 surgically treated patients. Neurosurgery. 2011; 68(2):403–414, discussion 414–415 14. Konovalov AN, Spallone A, Makhmudov UB, Kukhlajeva JA, Ozerova VI. Surgical management of hematomas of the brain stem. J Neurosurg. 1990; 73(2):181–186 15. Teo C, Siu TL. Radical resection of focal brainstem gliomas: is it worth doing? Childs Nerv Syst. 2008; 24(11):1307–1314

12  Safe Entry Zones to the Brainstem 16. Zhou LF, Du G, Mao Y, Zhang R. Diagnosis and surgical treatment of brainstem hemangioblastomas. Surg Neurol. 2005; 63(4):307–315, discussion 315–316 17. Brown AP, Thompson BG, Spetzler RF. The two-point method: evaluating brain stem lesions. BNI Q. 1996; 12(1):20–24 18. Kalani MY, Yagmurlu K, Spetzler RF. The interpeduncular fossa approach for resection of ventromedial midbrain lesions. J Neurosurg. 2018; 128:834–839 19. Cavalcanti DD, García-González U, Agrawal A, et al. Quantitative anatomic study of the transciliary supraorbital approach: benefits of additional orbital osteotomy? Neurosurgery. 2010; 66(6) Suppl Operative:205–210 20. Figueiredo EG, Deshmukh V, Nakaji P, et al. An anatomical evaluation of the mini-supraorbital approach and comparison with standard craniotomies. Neurosurgery. 2006; 59(4) Suppl 2:ONS212–ONS220, discussion ONS220 21. Vishteh AG, David CA, Marciano FF, Coscarella E, Spetzler RF. Extreme lateral supracerebellar infratentorial approach to the posterolateral mesencephalon: technique and clinical experience. Neurosurgery. 2000; 46(2):384–388, discussion 388–389 22. de Oliveira JG, Lekovic GP, Safavi-Abbasi S, et al. Supracerebellar infratentorial approach to cavernous malformations of the brainstem: surgical variants and clinical experience with 45 patients. Neurosurgery. 2010; 66(2):389–399 23. Ono M, Ono M, Rhoton AL, Jr, Barry M. Microsurgical anatomy of the region of the tentorial incisura. J Neurosurg. 1984; 60(2):365–399 24. Fischer B, Weber H. Express saccades and visual attention. Behav Brain Sci. 1993; 16(3):553–567 25. Munoz DP, Wurtz RH. Fixation cells in monkey superior colliculus. I. Characteristics of cell discharge. J Neurophysiol. 1993; 70(2):559–575

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26. Hubel DH, LeVay S, Wiesel TN. Mode of termination of retinotectal fibers in macaque monkey: an autoradiographic study. Brain Res. 1975; 96(1):25–40 27. Bricolo A. Surgical management of intrinsic brain stem gliomas. Oper Tech Neurosurg. 2000; 3(2):137–154 28. Kalani MY, Yagmurlu K, Martirosyan NL, Spetzler RF. The retrosigmoid petrosal fissure transpeduncular approach to central pontine lesions. World Neurosurg. 2016; 87:235–241 29. Strauss C, Lütjen-Drecoll E, Fahlbusch R. Pericollicular surgical approaches to the rhomboid fossa. Part I. Anatomical basis. J Neurosurg. 1997; 87(6):893–899 30. Mussi AC, Rhoton AL, Jr. Telovelar approach to the fourth ventricle: microsurgical anatomy. J Neurosurg. 2000; 92(5):812–823 31. Miller AD, Bianchi AL, Bishop BP. Neural Control of the Respiratory Muscles. Taylor & Francis; 1997 32. Raimondi AJC. M.; Di Rocco, C. Posterior Fossa Tumors. Vol 1. New York: Springer-Verlag; 1993 33. Deshmukh VR, Rangel-Castilla L, Spetzler RF. Lateral inferior cerebellar peduncle approach to dorsolateral medullary cavernous malformation. J Neurosurg. 2014; 121(3):723–729 34. Safavi-Abbasi S, de Oliveira JG, Deshmukh P, et al. The craniocaudal extension of posterolateral approaches and their combination: a quantitative anatomic and clinical analysis. Neurosurgery. 2010; 66(3) Suppl Operative:54–64 35. Lawton MT, Quiñones-Hinojosa A, Jun P. The supratonsillar approach to the inferior cerebellar peduncle: anatomy, surgical technique, and clinical application to cavernous malformations. Neurosurgery. 2006; 59(4) Suppl 2:ONS244–ONS251, discussion ONS251–ONS252 36. Mitha AP, Turner JD, Spetzler RF. Surgical approaches to intramedullary cavernous malformations of the spinal cord. Neurosurgery. 2011; 68(2) Suppl Operative:317–324, discussion 324

Section V Comprehensive Management of Tumors of the Brainstem, Thalamus, and Pineal Region

13  Adult Brainstem Gliomas

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14  Pediatric Brainstem Tumors

210

15 Tumors of the Thalamus

219

16 Tumors of the Third Ventricle

226

17 Tumors of the Fourth Ventricle

255

18 Tumors of the Cerebellopontine Angle

276

19 Pineal Region Tumors

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20 Stereotactic Radiosurgery for Tumors of the Brainstem, Thalamus, and Pineal Region

298

21 Radiotherapy for Pineal, Thalamic, and Brainstem Tumors

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22 Neuro-oncologic Considerations for Pineal, Thalamic, and Brainstem Tumors

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V

13 

Adult Brainstem Gliomas

Helmut Bertalanffy, Yoshihito Tsuji, Rouzbeh Banan, and Souvik Kar

Abstract

An overview of brainstem gliomas in adult patients is provided in this chapter as well as results from a retrospective study of 73 consecutive adult patients harboring intrinsic brainstem gliomas who underwent surgical treatment between 1996 and 2017. At present, surgical treatment of brainstem gliomas is still not generally accepted, and many neurologists, neuro-oncologists, and even neurosurgeons consider these tumors to be inoperable. The most important aspects of these tumors to be considered when evaluating surgical options are the natural history of the disease, epidemiology, clinical and neuroradiologic features, tumor classification, and available treatment modalities. In the retrospective study, clinical parameters before and after surgery, neuropathologic features of various tumor entities, surgical aspects, and outcomes were analyzed. Using these data, we present a classification system that enables surgical candidates to be identified. However, no general rule is applicable to adult brainstem glioma patients, and patient selection must remain a highly individualized decision in each case. The choice of the surgical approach and the respective surgical window for brainstem exposure play key roles in the success of surgery. At least in patients with low-grade brainstem gliomas, radical tumor removal should be attempted whenever possible. Excellent long-term results can be achieved in these patients. Even in patients with high-grade tumors, surgery can offer much more than only good palliative care. Thus, the term inoperable should not be generally applied to brainstem gliomas. Keywords:  adults, brainstem glioma, classification, outcome, surgery, treatment

■■ Introduction Brainstem gliomas constitute a heterogeneous group of tumors with a common feature, namely their localization within the midbrain, pons, or medulla oblongata. The biology of brainstem gliomas is different for pediatric and adult patients. Brainstem gliomas account for 20% of all brain tumors in children, and their clinical course is generally unfavorably poor. In contrast, adult brainstem glioma is a rare disease accounting for only 1% to 2% of adult glial brain tumors, which form a heterogeneous group of lesions with a variable prognosis.1,​2,​3 Sometimes the term brainstem glioma is used synonymously with diffuse intrinsic pontine gliomas (DIPGs) because of the relative high frequency of the latter tumors within the grouping of brainstem gliomas. In actual fact, however, the term comprises all primary intrinsic glial tumors that arise from the brainstem. Brainstem gliomas in both children and adults were regarded as inoperable tumors

in the early history of neurosurgery. Even today, despite evidence of successful brainstem glioma surgery in certain patient groups, as described in the pertinent medical literature,4,​5,​6,​7,​8,​9 a similar concept persists among neurologists, oncologists, and even neurosurgeons, who still believe that with open surgery the final result is worse than outcomes with nonsurgical treatment. The purpose of this book chapter is to show that surgery for removal of focal brainstem gliomas is feasible in many instances and that excellent long-term results may be achieved in select cases.

■■ Overview of Adult Brainstem Gliomas Until 2001, when Guillamo et al10 first reported their series of 48 adult patients with brainstem gliomas, the majority of previous publications had dealt with pediatric patients alone, offering a good overview of the biology and treatment of this disease in children. Only few publications also included adult brainstem glioma cases in their analyses.2,​11,​12,​13 Accordingly, little information existed about the natural history and management of adult brainstem gliomas until that time. After the report of Guillamo et al,10 other authors reported their treatment experience exclusively in adult brainstem glioma patients,14,​15,​16,​17,​18,​19 and two recent review articles have dealt with this subject.1,​3

Natural History and Epidemiology Brainstem gliomas account for less than 2% of all gliomas in adults, whereas pediatric brainstem gliomas constitute 20% of pediatric brain tumors.3,​18 The median survival time of adult patients with brainstem gliomas is estimated to range between 30 and 40 months, which is apparently longer than the median survival of 10 months in pediatric brainstem glioma patients.20 Because adult brainstem gliomas comprise a heterogeneous group of various tumor entities, the prognosis of each individual adult patient harboring a brainstem glioma is difficult to predict. In the most recent literature, four types of brainstem gliomas with different epidemiology were distinguished.3,​21 (1) Diffuse intrinsic low-grade gliomas seen in young adults 20 to 50 years of age are the most common brainstem lesions  (45%–50%). (2) Enhancing malignant gliomas that occur in patients older than 40 years of age account for 30% of all adult brainstem tumors. (3) Focal tectal brainstem gliomas, which are well-circumscribed but rare tumors, constitute only 8% of brainstem gliomas in adults. (4) Exophytic brainstem gliomas are rare among adults, in contrast to their prevalence among children. Table 13.1 compares several characteristic features of brainstem gliomas in adult and pediatric patients.

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Table 13.1  Differences between brainstem gliomas in the adult and pediatric populations

Tumor features

Adults

Pediatric patients

Percentage of brain tumors

1–2%

20%

Median age at diagnosis

35 y

7y

Male : female ratio

60% : 40%

50% : 50%

Contrastenhancement on MRI

40%

Only rarely

Location within the brainstem

In all segments

Mostly in the pons

Gene mutations

IDH1 and TP53

ACVR1 in 20–30%, K27M-H3F3A in 70%, HIST1H3B in 78%

Tumor grade

Up to 80% low grade 50–60% high grade

2-year survival rate

> 50%

< 25% in diffuse intrinsic pontine gliomas, > 90% in others

Abbreviation: MRI, magnetic resonance imaging.

Clinical Presentation The most frequent symptoms encountered in patients with a brainstem tumor are headache, gait disturbance, and diplopia. Some authors divide the clinical presentations of patients into four categories: symptoms and signs of raised intracranial pressure, cranial nerve dysfunction, cerebellar dysfunction, and long tract signs. Mood and behavioral changes also occur frequently. Usually, symptoms of cranial nerve dysfunction correlate well with tumor location in the brainstem—eye movement disorders with lesions of the midbrain; sixth nerve palsy, facial weakness, and facial sensory deficits with pontine lesions; and dysphagia and dysarthria in medullary tumors. In patients with bulbar impairment, sometimes a tracheostomy and nasogastric tube feeding or percutaneous endoscopic gastrostomy may become necessary. Symptoms can fluctuate, and often patients may deteriorate clinically before radiologic changes are clearly visible because any space-occupying neoplasm within the brainstem can cause some dysfunction because of the high density of critical structures in a very limited space.1,​12

Diffuse and Focal Tumors The most common and typical diffuse brainstem tumor is the DIPG, which is encountered mostly in the pediatric population.7 These DIPGs have characteristic features on magnetic resonance imaging (MRI)—they are hypointense on T1-weighted and hyperintense on T2-weighted images, usually with little or no contrast enhancement. These tumors usually have no clearcut margin. Generally, the tumors involve the entire pons, which will show signs of swelling, sometimes with exophytic portions. In the 2016 World Health Organization (WHO) classification of brain tumors, DIPGs now constitute a separate entity.22 Only rarely are they encountered in adult patients. These tumors carry a poor prognosis, with patients having a survival time similar to the clinical course of patients with glioblastomas.

Focal gliomas are demarcated lesions. They can be solid or cystic, and in the vast majority of cases there is a clear-cut interface between the tumor and brainstem parenchyma. Most focal gliomas show contrast enhancement, and the majority correspond to lowgrade tumors. They tend to originate more frequently within the midbrain and medulla oblongata, and they represent only approximately 9% of tumors arising within the pons.23

Neuroradiologic Evaluation Computed tomography played a role in evaluating patients with brainstem tumors until the 1980s,13 when it was rapidly replaced by MRI, which became the main diagnostic tool. MRI gives a first and very clear impression about the site, extent, and direction of tumor growth, as well as other morphological features, such as whether the lesion is focal, diffuse, solid, or cystic. Thus, MRI allowed clinicians to establish a more precise characterization of brainstem gliomas and to identify tumor location and the biological behavior of brainstem tumors.2 Typically, diffuse low-grade gliomas appear on MRI as infiltrative and poorly demarcated tumors in the medulla (60%) and in the pons (30%). Images are isointense or hypointense on T1-weighted MRI and hyperintense on T2-weighted or fluidattenuated inversion recovery (FLAIR) images. They usually lack contrast enhancement. Sometimes infiltration along the middle cerebellar peduncle into the cerebellum or directly into the midbrain can be observed. Malignant brainstem gliomas in adults appear as contrast-enhancing tumors accompanied by perifocal edema. The ring-like enhancement on MRI suggests intralesional necrosis. Often differential diagnosis is necessary because other pathologic entities resemble this type of brainstem glioma with similar contrast enhancement (lymphoma, inflammatory disease, abscess, metastasis, demyelinating disease, ependymoma, hemangioblastoma, and infarction). Focal tectal brainstem gliomas are well-defined lesions in the tectal plate or in the periaqueductal region. These tumors appear as isointense or hypointense on T1-weighted images and as hyperintense on T2-weighted images. Contrast enhancement is usually not present. Typically, they remain morphologically stable for many years. An exophytic brainstem glioma often appears as a mass originating from the floor of the fourth ventricle. Such lesions can be misdiagnosed as ependymoma or choroid plexus papilloma in cases of contrast enhancement. Magnetic resonance spectroscopy can be useful for differential diagnosis, similar to its use in patients with supratentorial lesions. Salmaggi et al18​ first reported the elevation of the choline/N-acetyl-aspartate ratio in adult brainstem gliomas. However, the application of magnetic resonance spectroscopy in the brainstem is limited so far by the relatively small size of the brainstem and by the close vicinity of adjacent skull base structures, such as bone and fat tissue. Single-voxel magnetic resonance spectroscopy is currently used to evaluate pontine lesions with a diameter of more than 2 cm.3,​21 Fluorodeoxyglucose and fluoroethyl-L-tyrosine positron emission tomography (FDG-PET and FET-PET, respectively) can be effective in detecting the aggressive part of a brainstem glioma. It is known that neoplastic lesions show significantly higher 18 F-FET uptake than nonneoplastic lesions. In all gliomas, 18F-FET uptake is observed in about 80% of grade I gliomas, 92% of both grade II and grade III gliomas, and 100% of grade IV gliomas.21,​24

13   Adult Brainstem Gliomas Therefore, FET-PET can be used to distinguish a low-grade glioma from a high-grade brainstem lesion or to define the biopsy target and the extent of surgical resection.

Tumor Classification Since the 1980s, various brainstem tumor classifications based on tumor location, growth pattern, and histopathologic criteria have been introduced. Epstein and McCleary5 and Epstein and Wisoff   6,​7 were the first to classify brainstem tumors according to their appearance on computed tomography; other authors followed with slightly modified classifications. The authors’ main purpose was to identify those patients who might benefit from tumor resection surgery. In 1985, Epstein et al25 distinguished three tumor types according to their growth pattern: exophytic (subdivided into diffuse, focal, and cervicomedullary types), intrinsic  (subdivided into cerebellopontine angle, brachium pontis, and fourth ventricle types), and disseminated. In the 1990s, a new classification system based on MRI described the management of brainstem gliomas.2 This improved imaging technique enabled identification of tumor location and better understanding of their biological behavior.2 MRIdependent classification was also proposed for brainstem gliomas in adults, distinguishing diffuse intrinsic low-grade tumors, enhancing malignant gliomas, focal tectal gliomas, and exophytic gliomas.3,​21 Because biopsy or open surgery was often considered inappropriate in adult patients with diffusely infiltrating gliomas, this type of MRI-based classification remained important in the management of brainstem gliomas in adults.

The 2016 WHO Classification of Tumors of the Central Nervous System In previous editions of the WHO classification of tumors of the central nervous system  (CNS), tumors were always classified only on the basis of their morphological characteristics, relying on the histopathologic appearance of tumors using light microscopy and the immunohistochemical expression of certain proteins in tumor cells.22,​26 Significant improvements in the field of molecular pathology during the past two decades achieved by surrogate genotyping assays and high-throughput technologies, such as next-generation sequencing, allowed for many genetic alterations that underlie the genesis of CNS tumors to be identified and opened new horizons for a novel classification concept of these neoplasms.26,​27 The idea of using these newly identified molecular features in tumor classification was first applied in the 2016 version of the WHO classification of CNS tumors, where genetic parameters were combined with histologic characteristics to offer a combined phenotypic-genotypic diagnostic concept. As a result, dramatic modifications occurred in some tumor category classifications. Thus, a number of previously known tumor entities were eliminated and several new entities were defined on the basis of their similar genetic features. For example, the diffuse H3 K27M-mutant midline glioma is a new molecularly defined entity carrying mutations in the K27 position of the genes encoding histone proteins H3.3  (H3F3A), H3.1  (HIST1H3B), and H3.2  (HIST1H3C).27 These tumors with a predominantly astrocytic appearance, including those previously referred to as DIPGs, are more common in children and grow in all midline CNS structures, preferentially in the thalamus, brainstem, and spinal cord.22 They correspond to WHO

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grade IV even though their morphological appearance ranges from a diffuse low-grade to a highly malignant glioma. Oligodendrogliomas encountered a dramatic alteration in the 2016 WHO classification. These diffusely infiltrating gliomas are now genetically defined through evidence of mutation in the IDH gene together with co-deletion of chromosomal arms 1p/19q, regardless of presence or absence of a partial or dominant astrocytic differentiation in histology. With respect to this definition, the diagnosis of oligoastrocytoma (grade II or III) is now strongly discouraged. Except for rare “true” cases of oligoastrocytomas reported in the literature, only oligoastrocytoma NOS (not otherwise specified) is an offered diagnosis in case of testing failure or absence of appropriate diagnostic genetic assays.22,​26,​27 Anaplastic pleomorphic xanthoastrocytoma WHO grade III is another new entity that has replaced the previously known pleomorphic xanthoastrocytoma with anaplastic features.22 Among the mixed neuronal-glial tumors, diffuse leptomeningeal glioneuronal tumor is a newly defined entity; it was formerly also known as diffuse oligodendroglial leptomeningeal tumor because of its oligodendroglioma-like morphology. Meanwhile, the newly identified genetic alterations in these tumors, including BRAF-KIAA1549 duplications and deletions, are found in a similar fashion in pilocytic astrocytomas.22,​27

History of Management Since the early years of neurosurgery, a brainstem neoplasm was regarded as an inoperable tumor. Accordingly, even if neurosurgical interventions in brainstem tumors were considered, they were not primarily directed at tumor removal but occasionally were directed at reducing the increased intracranial pressure or at obtaining tumor tissue for histopathologic diagnosis and rarely were directed at tumor debulking to improve the clinical situation. Walker et al12 mentioned that surgery of brainstem tumors in children should not be termed “impossible” but rather “unhelpful.” Management of brainstem tumors mainly consisted of combined radiochemotherapy.1 Surgical treatment of adult brainstem gliomas has been mentioned in the literature only since 1968,28 but there is no consensus among specialists regarding the optimal treatment. According to Reyes-Botero et al,3 each type of adult glioma requires a different treatment principle. In adults with diffuse intrinsic low-grade gliomas, total resection is regarded as technically impossible. MRI-guided stereotactic biopsy is recommended to obtain a histologic diagnosis. Radiotherapy is the standard treatment for this subgroup of adult brainstem gliomas, similar to treatment applied for pediatric DIPGs. The conventional radiotherapy is performed with a median dose of 50 to 55 Gy. Chemotherapy has not proven to be effective for this type of adult glioma. The median survival of adults with diffuse intrinsic low-grade gliomas is 4.9 to 7.3 years.3 In enhancing malignant adult brainstem gliomas, only a limited biopsy or shunt replacement is considered. Radiotherapy does not have a significant effect on this subgroup. Chemotherapy combined with radiotherapy can be an option. Theeler et al19 demonstrated that the standard Stupp regimen for brainstem glioblastomas was effective in comparison with no treatment, but there is no prospective study that strongly supports the efficacy of chemotherapy in this subgroup of adult brainstem glioma. Focal tectal brainstem glioma forms a different

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group of brainstem tumors with good prognosis; median survival among patients who receive this diagnosis is more than 10 years. Usually, observation is deemed appropriate, sometimes with shunt placement. Exophytic brainstem glioma is regarded as an extremely rare subgroup in adults; in only a few cases have lesions been found to extend into the fourth ventricle, which then allowed the lesions to become amenable to surgical resection. These treatment recommendations are based only on radiologic images. Because of the small number of patients with adult brainstem gliomas reported in the literature and the lack of histologic verification, the value of such treatment strategies has yet to be elucidated.

Role of Open Surgery Until the 1980s, brainstem gliomas in children or adults were considered absolutely nonsurgically treated diseases. However, during the 1980s, several neurosurgeons began to operate on certain brainstem gliomas and subsequently reported their results.4,​5,​6,​7,​8,​9 These reports introduced the notion that open surgery is suitable in select patients with brainstem gliomas. In 1999, Walker et al12 mentioned the role of surgery in brainstem tumors. They considered tumor debulking for midbrain tectal gliomas, for other focal gliomas in the midbrain and pons, as well as for exophytic pontine gliomas. If stereotactic biopsy was not possible for a certain reason, open surgery was considered for histologic examination. Diffuse gliomas, however, were excluded from surgical consideration. In 2003, Jallo et al2 also noted that surgery for brainstem glioma could be achieved successfully when careful attention was paid to proper selection of the patients. Their indication criteria for surgery were focal, dorsally exophytic, and cervicomedullary lesions. Patients with diffuse infiltrating gliomas were not considered surgical candidates. In the 2010s, several reports focusing on adult brainstem glioma were published.14,​15,​17,​19 The percentage of surgical resection ranged from 9.7% to 33%. Zhang et al13 noted a consensus regarding the role of surgery for brainstem glioma. In their experience, patients with dorsally exophytic tumors could be treated well with surgery and often could be cured. Cervicomedullary gliomas are mostly low-grade tumors, and surgery seems effective in improving the patient’s prognosis. Focal midbrain and medulla oblongata gliomas are mostly low-grade tumors; surgery for these tumors is safe as well, but it does not significantly improve the prognosis. Focal pontine gliomas are mostly high-grade tumors; therefore, surgery is not considered feasible in this subgroup.13

Role of Stereotaxy Until the 1990s, stereotaxy was used as an invasive tool to obtain a precise histopathologic diagnosis,13,​29 but it was thereafter replaced by MRI. Stereotactic brainstem biopsy is regarded as a relatively safe procedure with a morbidity rate of 4% and rare mortality.30 Radiologic diagnosis in the brainstem region is sometimes inaccurate; for instance, 30% of low-grade brainstem gliomas diagnosed radiologically turned out to be another type of disease, such as different tumors, inflammation, or vascular diseases.31 Accordingly, stereotactic biopsy within the brainstem has been recommended in addition to radiologic examination by several authors.30,​31,​32 Although the tissue sample obtained by stereotactic biopsy is relatively small and may not represent the

entire lesion, its significance was reevaluated in the late 2000s13 and, in light of modern molecular neuropathology, has also been reevaluated more recently.19

Role of Steroid Medication Dexamethasone medication can improve life-threatening symptoms for a short period by reducing elevated intracranial pressure, but in the long term it is associated with significant adverse effects, such as progressive Cushing syndrome and mood problems.33,​34 Therefore, once dexamethasone has exerted its positive effect, it is better to reduce or completely discontinue the treatment.

Role of Radiotherapy Radiotherapy is the upfront standard treatment for adult brainstem glioma and for pediatric DIPG. Conventional radiotherapy is performed with a median dose of 54 to 60 Gy. However, the prognosis in pediatric patients is very poor with a median survival time of 12 to 18 months.21 In contrast to the dismal results in pediatric patients with DIPG, radiotherapy produces neurologic improvement and prolongs the survival time to between 6 and 7 years in adults with diffuse brainstem gliomas. Clinical improvement is seen in at least 60% of cases of adult diffuse brainstem glioma in contrast to only 3% in malignant brainstem glioma cases.21 Re-irradiation can be an option for recurrent brainstem glioma in adults.1

Role of Chemotherapy Since the 1980s, most trials of chemotherapy alone failed to show prolonged survival time in patients with brainstem glioma.12 The main agents used for treatment of this disease were carmustine, lomustine, procarbazine plus lomustine plus vincristine, vincristine, cisplatin, carboplatin, and temozolomide.17 For pediatric DIPG, chemotherapy failed to show any efficacy when used in addition to radiotherapy.35,​36 So far, no chemotherapy without radiation is considered sufficiently effective for adult or pediatric brainstem gliomas.17 Theeler et al19 reported that adult patients harboring tumors histologically diagnosed as brainstem glioblastoma and treated with a Stupp regimen had a longer survival time than those who did not receive this treatment (23.1 months vs 4.0 months, respectively). Despite the small number of patients (28 individuals), this study provides the best supporting data for chemotherapy combined with radiotherapy.1 In some instances, temozolomide medication is used in patients with adult brainstem glioma in combination with radiotherapy. Bevacizumab is effective in reducing the vasogenic edema around the lesion. Patients receiving dexamethasone for a long time can taper the dosage when bevacizumab is used at the same time.1 It is expected that histologic and molecular knowledge of this disease will continue developing in the future, with the perspective that new and more efficient chemotherapeutic agents will become available.

■■ Author’s Patient Series During the past two decades, in addition to treating brainstem gliomas, the senior author (H.B.) has also surgically treated around 250 patients who harbored intrinsic brainstem

13   Adult Brainstem Gliomas

191

cavernous malformations. This vast experience with exposing and removing such intrinsic vascular malformations37 proved to be most valuable for brainstem glioma surgery as well, both in adults and in children. In this chapter, the authors focus only on the adult patient population with brainstem gliomas. This population constitutes a personal series of 73 adults treated by the senior author, who performed all surgical procedures. Table 13.2 gives an overview of the distribution of various tumor types within the three portions of the brainstem, as seen in this patient series, with typical examples shown in Fig. 13.1. Table 13.3 summarizes the histo­ pathologic tumor entities encountered in this patient series. As additional information and for comparison, this table offers the number of brainstem tumors found in pediatric patients treated surgically during the same period (not further analyzed in this chapter).

Patient Selection

Histology

No. of adult patients

No. of pediatric patients

Table 13.2  Distribution of brainstem gliomas within the brainstem (senior author’s series)

Pilocytic astrocytoma

22

21

Anaplastic astrocytoma

21

6

Fibrillary astrocytoma

10

6

Glioblastoma

6

4

Rosette-forming glioneuronal 4 tumor

1

Diffuse astrocytoma

4

2

Anaplastic ganglioglioma

2

0

Ganglioglioma

1

7

Papillary glioneuronal tumor

1

0

Pleomorphic xanthoastrocytoma

1

1

Deciding whether surgery is indicated in a specific case is one of the most difficult aspects in brainstem glioma management. Because no widely accepted criteria are available, patient selection was highly individualized and based on the senior author’s experience and subjective estimation of each individual case. He took great care to identify those individuals for whom a real benefit from surgery could be expected and, conversely, to exclude from microsurgical management those for whom surgery was predicted to be unhelpful. Patients in this series were selected as surgical candidates in the majority of cases when the tumor appeared Table 13.3  Types of brainstem gliomas in adult and pediatric patients (senior author’s series)

Tumor location

Brainstem segment

N

Midbrain

Peduncle/tegmentum intrinsic

4

Peduncle/tegmentum with thalamic extension

3

Peduncle laterally exophytic

4

Tectal intrinsic

9

Tectal exophytic

18

Pons intrinsic

4

Pons with brachium pontis extension

12

Medulla intrinsic

8

Medulla dorsally exophytic

5

Anaplastic oligodendroglioma

1

1

Medulla laterally exophytic

6

Total no. of patients

73

49

Pons

Medulla oblongata

Fig. 13.1  Illustrative magnetic resonance images (MRIs) demonstrate typical brainstem glioma types and tumor distribution within the

brainstem. (a) Axial, (b) coronal, (c) axial, (d) axial, (e) sagittal, and (f-j) axial MRIs.

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as a focal lesion, when it was estimated that at least a significant amount of tumor mass could be removed without adding substantial morbidity by surgical manipulation within the brainstem, and when concomitant long-term survival or even cure was deemed possible. In very few cases was it considered favorable to undertake only an open tumor biopsy to clarify the histopathologic diagnosis (in recent years, based on molecular criteria), to perform an endoscopic third ventriculostomy in case of obstructive hydrocephalus, or to release local pressure by evacuating an associated compressive tumor cyst.

Goals of Surgery The main goal of surgery was to remove as much of the tumor mass as possible without additional damage to the brainstem parenchyma, with the hope of offering the patient much more than just good palliative care. In low-grade tumors, particularly pilocytic astrocytomas, rosette-forming glioneuronal tumors, and papillary glioneuronal tumors, even total tumor removal was possible in many patients, provided the tumor had not yet extensively invaded the brainstem. In the majority of such cases, we encountered a well-defined tumor-brainstem interface that enabled precise dissection. In other tumor types, for instance in diffuse or in high-grade gliomas, total tumor removal was not even attempted because of the lack of a clear-cut tumor border. In these latter cases, a significant tumor debulking was considered favorable for the patient in addition to obtaining a precise histopathologic diagnosis.

Timing of Surgery Once a brainstem glioma was diagnosed and the patient was determined to be a good surgical candidate, tumor resection was undertaken at the earliest convenience to avoid further tumor growth. In a few patients with concomitant occlusive hydrocephalus, however, it seemed useful to apply cerebrospinal fluid (CSF) diversion (endoscopic third ventriculostomy or placement of a ventriculoperitoneal shunt) before tumor resection to facilitate the main surgical procedure that followed 1 to 2 weeks later. A similar tactic has been employed by others.38

Preoperative Planning After careful assessment of the surgical resectability of a brainstem tumor, the entire surgical procedure was meticulously planned. High-quality neuroradiologic imaging provided the basic morphological features of the lesion to be treated. Once these details were available, it was important to plan the surgical intervention in the reverse order of how the procedure would later be performed; first, the optimal entry zone into the brainstem was assessed, particularly in patients with nonexophytic lesions that would not be readily visible on the surface of the brainstem. This was followed by the second step, namely choosing an adequate exposure of the brainstem via the most suitable surgical approach. In patients with exophytic lesions, the decision for the optimal surgical approach was easier, as the lesion and the direction of its expansion dictated the choice of the best access route. Once the decision for the surgical approach was taken, patient positioning and skin incision were easily planned in a third step. Care was taken to ensure that patients and families provided informed consent and fully understood the aim of surgery and the possibilities of tumor resection in each specific case, the amount of tumor that might safely be removed, and the risks of

the scheduled surgical intervention. Additionally, the expected immediate surgical outcome and the necessity of postoperative adjuvant therapies were explained in detail.

Anesthesia, Intraoperative Guidance, and Monitoring Details of the planned surgical procedure were always discussed with the anesthetist before surgery. It was important to avoid excessive venous congestion during the procedure by proper patient positioning, and adequate anesthesia facilitated achieving this goal. During surgical exposure and manipulation around the tentorium or within the brainstem, patients occasionally developed a vagal reaction with sudden bradycardia or a sudden rise in blood pressure. Therefore, the anesthetist was prepared for such events, and, if necessary, took appropriate action. Intraoperative guidance using a neuronavigation system was applied in some cases; however, its benefit was limited in brainstem gliomas, and the navigation system was not always sufficiently reliable. We considered it more advantageous to identify well-known anatomical landmarks during surgery. The topographic anatomy of the brainstem with the exit points of cranial nerve rootlets offered valuable information for precise intraoperative orientation. In contrast, electrophysiological monitoring during brainstem glioma surgery is a most powerful tool that we consider mandatory for such procedures. In all instances, we routinely monitored motor, somatosensory, and auditory evoked potentials throughout the entire surgical intervention.39 Depending on which region of the brainstem was exposed, mapping of the rhomboid fossa40 and cranial nerve electromyography were applied as well. In three patients, intraoperative MRI was used and found to be most helpful in identifying residual tumor portions that were not easily recognized during surgery.

Selection of Surgical Approaches and Patient Positioning The surgical approaches used in the present patient series are listed in Table 13.4. We selected the most suitable surgical approach in each individual case according to the following criteria: the approach should allow for an optimal viewing trajectory toward the brainstem tumor, in the same direction as the tumor's longitudinal axis, if applicable; venous congestion during surgery should be avoided; and the approach should allow for sufficient craniocaudal exposure without excessive compression or retracTable 13.4  Surgical approaches used to treat 73 adult patients with brainstem gliomas (senior author’s series)

Surgical approach

No. of patients

Supracerebellar infratentorial

23

Cerebellopontine angle

16

Dorsal midline

13

Subtemporal

8

Transcondylar

4

Telovelar

3

Transcallosal

2

Transcortical transventricular (endoscopy)

2

Frontal interhemispheric

1

Combined supracerebellar and telovelar

1

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tion of surrounding structures, such as the temporal lobe or cerebellum. The semisitting position has many advantages and is used by other authors as well.20 When performing surgery on younger patients, we preferred having the patient in the semisitting position whenever it was deemed useful; however, in patients older than 60 years, especially when the patient had associated hydrocephalus, the semisitting position could lead to excessive loss of CSF during surgery and was therefore used with great caution or, more often, the patient was placed in the prone position. Tumor exposure for tectal gliomas was undertaken mainly with patients in the semisitting position via the supracerebellar infratentorial route. Focal tectal gliomas were approached via a lateral suboccipital infratentorial trajectory. Tumors involving the midbrain tegmentum have been approached through a subtemporal route. A lateral suboccipital craniotomy with cerebellopontine angle (CPA) exposure was applied for most pontine gliomas. To access the fourth ventricle, we used the midline suboccipital craniotomy and the telovelar approach. For

cervicomedullary tumors without an exophytic part or pial presentation, a cervical laminotomy and midline myelotomy were undertaken.

Fig. 13.2  This 23-year-old man had progressive headache, diplopia, and slight memory deficit. Preoperative axial T2-weighted (a) and sagittal T1-weighted (b) magnetic resonance images (MRIs) demonstrate evidence of a large intrinsic midbrain tumor involving the peduncle and tegmentum bilaterally. These MRIs show slight contrast enhancement; the tumor caused occlusive hydrocephalus that was not treated before surgery. The patient underwent surgery in the supine position via a frontobasal median craniotomy (c). Tumor exposure was achieved by the frontal

interhemispheric approach (a, arrow), and the lesion, a pilocytic astrocytoma World Health Organization grade I, was completely removed as documented on postoperative axial (d) and sagittal (e) MRIs. The tumor was mainly accessed through the lamina terminalis, superior to the anterior communicating artery that was preserved, as seen in the intraoperative photograph (f). The patient had no perioperative complications and no additional neurologic or cognitive deficits; he was completely independent and had not experienced tumor recurrence at 5 years after surgery.

Surgical Approaches to the Midbrain Midbrain gliomas were exposed anteriorly, laterally, and posteriorly. An anterior lesion of the peduncle and tegmentum that extended into the anterior part of the thalamus and third ventricle was exposed via the anterior frontobasal interhemispheric approach (Fig. 13.2). We have also performed this procedure in treating other lesion types with or without dividing the anterior communicating artery.41 Intrinsic lesions of the peduncle or midbrain tegmentum were exposed either laterally via the subtemporal transtentorial approach or dorsolaterally via the lateral supracerebellar infratentorial or transtentorial route. Before subtemporal exposure of a midbrain tumor, we usually placed an external lumbar CSF drain that facilitated temporal lobe retrac-

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Fig. 13.3  A 30-year-old woman became symptomatic with double vision and a slight right-sided hemiparesis. Preoperative axial (a) and sagittal (b) magnetic resonance images (MRIs) demonstrated a partially solid, partially cystic contrast-enhancing intrinsic midbrain tumor mainly involving the tegmentum. The lower cystic portion extended into the upper pons. The patient was initially treated elsewhere with stereotactic cyst aspiration and interstitial radiotherapy, and the tumor was diagnosed as a pilocytic astrocytoma. Despite this therapy, the tumor grew. Under these circumstances, we offered the patient microsurgical tumor removal. (c) Surgery was undertaken with the patient in the supine position and the head turned to the right. Tumor exposure was achieved via the left-sided subtemporal route. A lumbar drain was placed beforehand, and cerebrospinal fluid was released during exposure to relax the brain and avoid temporal lobe

damage. (d) Great care was paid to the vein of Labbé, which was detached from the temporal lobe by incising its surrounding arachnoid layer. This allowed the temporal lobe to be elevated without traction on the vein, which was maintained intact until the end of the procedure. (e) The tumor was removed using a small Cavitron Ultrasonic Surgical Aspirator (CUSA; Integra LifesSiences Corp.) probe while preserving the adjacent trochlear nerve (arrows). There were no complications, wound healing was normal (f), and the patient had an excellent outcome without additional neurologic deficits. Histopathologic examination confirmed the diagnosis as pilocytic astrocytoma World Health Organization grade I. Complete tumor excision was achieved, as noted on postoperative axial (g) and sagittal (h) MRIs. Repeated follow-up MRIs documented the absence of tumor recurrence 9 years after the microsurgical intervention.

tion until the ambient cistern was opened. Also, we took great care to preserve bridging veins of the temporal lobe, such as the vein of Labbé and its tributaries (Fig. 13.3). Lesions of the midbrain tectum were approached via the supracerebellar paraculminal infratentorial exposure, similar to the exposure of pineal region pathology (Fig. 13.4). This surgical exposure required a number of precautions to avoid postoperative acute cerebellar swelling.42

quently, we applied the transcondylar approach to expose lesions

Surgical Approaches to the Pons The pons was exposed either laterally or from the dorsal midline via the floor of the fourth ventricle. To expose the pons laterally, we used three different approaches: the subtemporal transtentorial route to expose lesions of the upper pons, the CPA route via a retrosigmoid craniotomy to expose lesions of the middle pons (Fig. 13.5), and the inferolateral route via the transcondylar approach to expose lesions of the anterolateral lower pons or the pontomedullary area.43

Surgical Approaches to the Medulla Exposure of medullary lesions is straightforward and less demanding than procedures to access the midbrain or pons. Tumors located within the medulla oblongata were either totally intrinsic or dorsally or laterally exophytic (Fig. 13.1). In most instances, a dorsal midline exposure (median suboccipital craniotomy) with or without a C1 laminectomy was used (Fig. 13.6, Fig. 13.7). Less fre-

that extended anterolateral to the medulla.44

Selection of the Optimal Entry Zone to the Brainstem We have encountered two types of glioma with regard to their growth pattern within the brainstem. Some lesions had their origin within the brainstem but extended far beyond its boundaries in an exophytic fashion. In such cases, the tumor became directly visible at exposure without being covered by the ependymal or pial surface of the brainstem. Other lesions were confined to the brainstem and remained entirely intrinsic. In smaller lesions, the brainstem was either slightly distorted or not distorted at all, showing an apparently normal superficial aspect upon exposure. More voluminous intrinsic lesions distorted the brainstem, which caused it to bulge asymmetrically (Fig. 13.7). Selection of the optimal entry zone to the brainstem made sense only for the latter lesion type. Similar to the exposure used for intrinsic brainstem cavernous malformations, the brainstem could be opened and entered in several regions without creating significant morbidity. The most commonly used sites for entering the brainstem in our patients were the lateral center of the midbrain peduncle exposed via the subtemporal route (Fig. 13.3, Fig. 13.8), the dorsal midline between the left and right superior colliculus of

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Fig. 13.4  This 20-year-old woman had neurofibromatosis type I with several cutaneous manifestations. She became symptomatic with severe headache and diplopia due to aqueductal occlusion caused by a contrast-enhancing intrinsic tectal tumor, as seen on axial (a) and sagittal (b) magnetic resonance imaging (MRI). The symptoms rapidly disappeared after endoscopic ventriculocisternostomy. (c) She underwent surgery in the semisitting position, and the tumor was exposed via the left-sided lateral supracerebellar infratentorial route. At inspection the tectal plate was bulging posteriorly but was apparently intact. (d) The entire lateral tectal region was exposed, inferiorly up to the exit of the trochlear nerve (arrow). (e) The entry point into the brainstem was chosen lateral to the superior colliculus, and the

final tumor resection cavity was measured with a millimeter scale. Total tumor removal was achieved as documented on postoperative axial (f) and sagittal (g) MRIs. Histopathologically, a pilocytic astrocytoma World Health Organization grade I was found with a MIB-1 index of 3%. The patient had no complications and no additional neurologic deficits. The postoperative course was uneventful, and the patient remained tumor recurrence-free for 5 years, at which point follow-up MRIs revealed a new supratentorial lesion, distant and not connected to the previous one, which was rather suggestive of a high-grade glioma. Except for headache, the patient continued to remain free of symptoms. The new lesion was treated at another institution in her home country.

the tectal plate (Fig. 13.4), the lateral pons in the paratrigeminal area, the lateral part of the rhomboid fossa below the facial colliculus, and the dorsal midline or paramedian region of the lower medulla oblongata (Fig. 13.6, Fig. 13.7).

the tumor boundaries was performed cautiously, while great care was taken to avoid penetrating the surrounding edematous brainstem parenchyma. In diffusely infiltrating tumors, such as diffuse astrocytomas, tumor removal was more difficult because the tumor tissue was not sufficiently distinguishable from the normal brainstem parenchyma. In these cases, we only attempted a certain volume of reduction on the basis of preoperative measurements on MRI. We found it advantageous to use a small millimeter scale intraoperatively that helped determine the extent of resection. To obtain sufficient hemostasis within the resection cavity after tumor removal, we usually used bipolar coagulation with low-current intensity.

Microsurgical Dissection Technique The dissection technique varied according to lesion type. Wellcircumscribed focal low-grade gliomas were the best candidates for gross total tumor resection. Once the tumor tissue was identified by its different color, vascularization, and consistency, gradual debulking of the tumor mass was performed, preferably using a Cavitron Ultrasonic Surgical Aspirator (Integra LifeSciences Corp.). It was important to harvest sufficient tumor material for histopathologic investigations. In the final stage, we meticulously dissected the transition zone between tumor and brainstem parenchyma in a fashion similar to that used when removing a focal tumor of the spinal cord. Small surgical cottonoids were very helpful in separating tumor tissue from the brainstem and in maintaining a bloodless surgical field. We always mobilized the tumor tissue away from the brainstem, avoiding any compression or displacement of brainstem parenchyma. Also, we usually coagulated and sharply divided small feeding arteries or draining veins of the tumor. A similar technique was applied in high-grade gliomas; generally, however, there was no clear-cut tumor-parenchyma interface in these lesions. Hence, the dissection toward

■■ Tumor Entities The following is a brief description of low-grade and high-grade brainstem tumors encountered in this patient series. Only astrocytic, oligodendroglial, neuronal, and mixed neuronal-glial tumors found in adults were considered; ependymal or other tumor entities involving the brainstem that behave quite differently from these types of tumors were not included in this series.

Pilocytic Astrocytoma Pilocytic astrocytomas are well-circumscribed tumors  (WHO grade I) that are found most commonly in children

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Fig. 13.5  A 34-year-old man presented with a 6-month history of left-sided facial sensory loss, hearing deficit, slight facial palsy, and right-sided hemiparesis. Preoperative axial (a), coronal (b), and sagittal (c) magnetic resonance images (MRIs) demonstrate an extensive lesion involving the left side of the pons, the brachium pontis, and the cerebellum. (d) Preoperative diffusion tensor imaging with fiber tracking shows displacement of the corticospinal tract. As a low-grade glioma could not be ruled out and in light of the spaceoccupying effect of the tumor, surgery was offered to the patient with the aim of significant tumor debulking and histopathologic clarification. The tumor was exposed via the left cerebellopontine angle, and more than half of the tumor mass was successfully removed. The majority of the cranial nerve (CN) rootlets (CNs V-XI) were involved by the tumor. These nerve rootlets were left

intact as no attempt was made to completely free them from the tumor. There were no complications and, except for slight temporary gait ataxia, the patient did not experience new neurologic deficits. Histopathologic examination revealed a glioblastoma World Health Organization grade IV, IDH1-and BRAFnegative; the p53 protein was focally positive in up to 50%, and the O6-methylguanine-DNA methyltransferase (MGMT) promoter was hypermethylated. The patient underwent postoperative radiochemotherapy according to the Stupp protocol. Repeated postoperative MRI showed a gradual involution of the remaining tumor, and the patient continued doing well clinically. Four years after surgery he was totally independent, with no visible tumor remnant or recurrence on axial contrast-enhanced T1-weighted MRIs of the medulla (e) and pons (f).

and adolescents but can be encountered in adults as well. Generally, these tumors are solid or cystic lesions that have a slow rate of tumor growth and, accordingly, symptoms also develop slowly. These tumors can occur within the entire neuraxis, frequently within the cerebellum, but they tend to grow in midline structures, including the optic pathways, hypothalamus, thalamus, and brainstem.26,​45 In the brainstem, they are likely to occupy the dorsal areas and the pontomedullary junction, often with an exophytic growth into the fourth ventricle or CPA.26,​45,​46 In adults, they are more often supratentorial and show a preferential incidence in the temporal lobes.47 The NF1-associated type occurs in very rare cases in the brainstem, most commonly in the optic pathways. Pilocytic astrocytoma is the most common glioma in children and occurs with the highest frequency during the first two decades of life,26 whereas the incidence among patients with CNS tumors who are older than 18 years ranges from 20% to 25%.47 In the brainstem, pilocytic astrocytomas typically cause cranial nerve deficits as well as occlusive hydrocephalus and, less frequently, serious signs of brainstem dysfunction. MRI

reveals a well-defined lesion of a round-to-oval shape with cystic appearance in about 65% of cases, and a central or adjacent enhancing mural nodule with occasional calcifications. Histologically, these tumors show a biphasic architecture and a cystic pattern with bipolar elongated cells and usually abundant thickened Rosenthal fibers as well as eosinophilic granular bodies called protein droplets.26,​45 Over 90% of cerebellar cases and a smaller percentage of cases associated with other locations show a fusion of BRAF and KIAA1549 genes.26 According to the new WHO classification, the presence of this gene fusion in correlation with the histopathologic morphology is highly suggestive of a diagnosis of pilocytic astrocytoma. BRAF V600E mutation occurs in rare cases, and FGFR1 alterations are more frequently found in brainstem tumors.26 Prognosis is favorable, with an overall survival rate of 95% at 5 and 10 years after a pure surgical intervention.26 However, the extent of resection plays a key role in patient prognosis. In brainstem pilocytic astrocytomas, the progression rate could be higher, as total resection cannot be performed in all cases.

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Fig. 13.6  A 29-year-old man developed a left-sided hemisensory syndrome during a period of 5 months, when a right-sided intrinsic lesion of the medulla oblongata was diagnosed elsewhere. He underwent a first surgical intervention at another institution, where the tumor was diagnosed as a ganglioglioma grade I. Conservative management was recommended; however, repeated axial (a) and sagittal (b) magnetic resonance imaging (MRI) demonstrated tumor proliferation and a dorsal epidural cyst that remained from the first surgical intervention. Because of these circumstances, we proposed a second microsurgical intervention. (c) Exposure was obtained with the patient placed in the prone position via a dorsal midline exposure, including a C1 laminectomy. (d) At surgery, a highly vascular tumor was found within the lower medulla oblongata. (e) With meticulous microsurgical dissection, more than half of the tumor mass was resected,

leaving only a small anterior tumor portion behind as demonstrated on postoperative axial (f) and sagittal MRIs (g). There were no complications, and the patient was initially extubated. However, due to impaired deglutition, he underwent tracheostomy and percutaneous endoscopic gastrostomy, which he needed for only 3 months. Both tubes were then removed, and the patient became independent and was able to walk, eat, and drink without major restriction. Histopathologically, the tumor was diagnosed as a glioblastoma World Health Organization grade IV, of O6-methylguanine-DNA methyltransferase (MGMT) promoter nonmethylated type. The patient underwent combined radiochemotherapy according to the Stupp protocol and remained in clinically good condition for more than 1 year. He died 1.5 years after the microsurgical tumor removal because of local tumor recurrence.

Patients with pilocytic astrocytomas form the largest group in this patient series (22 patients), comprising 14 men and 8 women with a mean age of 32.4 years. However, four individuals (all males) were 55 years of age or older (55, 56, 61, and 67 years, respectively). The mean age among the remaining 18 patients was 27.4 years (range, 20–36 years), reflecting that pilocytic astrocytomas affect younger adults. Pilocytic astrocytomas were encountered in all portions of the brainstem with the following types: 1 peduncle intrinsic, 3 peduncle laterally exophytic, 3 tectal intrinsic, 7 tectal exophytic (Fig. 13.9, Fig. 13.10), 1 pons intrinsic and 1 with brachium pontis extension, 4 medulla intrinsic, and 2 medulla laterally exophytic. Patients underwent surgery in the following positions: 13 semisitting, 6 supine, and 3 prone. The supracerebellar infratentorial or transtentorial route was used in 8, the subtemporal in 5, the suboccipital dorsal midline approach in 4, the CPA in 3, and the frontal interhemispheric as well as the transcondylar exposure in 1 individual each. Gross total tumor removal was achieved in 13 patients, near-total resection in 3, and subtotal resection in 5; 1 individual underwent only tumor cyst fenestration (Table 13.5).

Although Two patient was lost to follow-up (Table 13.6), 16 of the remaining 21 patients showed no neurologic deficits or no additional neurologic deficits after the operation, 1 patient developed transient hemiparesis and recovered within 3 months (Fig. 13.8), 1 had vocal cord paresis, and 2 had transient gait ataxia. 2 patients with medullary tumors required postoperative temporary tracheostomies because of dysphagia. In 20 patients, there were no perioperative complications; 2 patients in whom the supracerebellar infratentorial route was used developed postoperative cerebellar hemorrhage and swelling that requiring surgical repair. Ultimately, both patients had an excellent outcome with total tumor removal confirmed on MRI. One patient, a 67-year-old man with a poorly circumscribed medullary tumor, died 7 months after surgery because of rapid tumor progression and complications related to dysphagia. It remained unclear whether the diagnosis of pilocytic astrocytoma was correct in this case because the clinical and radiologic courses were rather typical for a high-grade midline glioma. Tumor remnants that were present in seven patients subsequently developed a slight progression visible on MRI, but none required reoperation.

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Fig. 13.7  The main presenting symptoms in this 43-year-old man were dysphonia, dysphagia, and minimal left-sided motor weakness and sensory disturbance. Axial T2-weighted (a) and coronal (b) and sagittal (c) T1-weighted contrast-enhanced magnetic resonance images (MRIs) demonstrated a contrast-enhancing intrinsic medullary tumor. Surgery was offered to the patient to reduce the tumor volume as much as possible. (d) He underwent the microsurgical procedure in the prone position. The lower brainstem was exposed via a median suboccipital craniectomy. (e) At intradural inspection, the right side of the medulla was bulging because of the underlying tumor, but the ependyma of the lower rhomboid fossa and the pial surface of the medulla were intact. (f) After electrophysical mapping, a decision was made to enter the brainstem from the left posterolateral side of the medulla oblongata. Approximately 75 to 80% of the tumor volume was safely resected, while the responses of motor and somatosensory

evoked potentials remained intact. (g) Meticulous hemostasis was achieved with gentle bipolar coagulation. (h) There were no complications, and the patient did not experience additional neurologic deficits except for accentuated hemisensory syndrome. Postoperative axial (i) and sagittal (j) MRIs confirmed subtotal tumor resection. Histopathologically, a glioblastoma World Health Organization grade IV with hypermethylated O6-methylguanineDNA methyltransferase (MGMT) promoter was diagnosed, and the patient received postoperative radiochemotherapy according to the Stupp protocol. The patient's course was uneventful for 2 years, then he became symptomatic because of a local cyst dorsal to the medulla. Surgical cyst evacuation led to rapid improvement of symptoms and the patient remained independent and in very good condition throughout 4 years after the surgical intervention. Eventually, he died of local tumor recurrence that spread diffusely into the entire lower brainstem.

Five patients with residual tumor underwent postoperative radiotherapy, and three received additional chemotherapy. None of the 21 patients with known follow-up underwent a second surgical exploration for the initial brainstem tumor. A large tumor size and an apparently diffuse infiltration of the brainstem by pilocytic astrocytoma did not preclude safe total tumor removal with excellent long-term result (Figs. 13.9, Fig. 13.10).

Patients harboring an anaplastic astrocytoma of the brainstem form the second largest group of this series, accounting for 12 men and 9 women with a mean age of 36.5 years. The tumors had the following distribution within the brainstem: 1 peduncle intrinsic, 3 peduncle with thalamic extension, 4 tectal exophytic, 3 pons intrinsic, 3 pons with brachium pontis extension, 5 medulla dorsally exophytic, and 2 medulla laterally exophytic. Patients underwent surgery in the following positions: 15 semisitting, 3 lateral park bench, 2 supine, and 1 prone. The CPA approach was used in 8 patients, the dorsal midline in 6, the supracerebellar infratentorial route in 4, the transcallosal in 2, and the subtemporal exposure in 1. Gross total, near-total, and subtotal tumor removal was achieved in 5 patients for each category, and tumor debulking was performed in 6 individuals. There were no major perioperative complications. Eight individuals experienced neurological deterioration; 1 female patient developed severe disturbance of consciousness after the operation. In the remaining 12 patients, no additional neurologic deficits occurred after surgery. The following additional symptoms were found in 8 patients after the operation: transient dysphagia without need for tracheostomy in 3, dysphagia with subsequent tracheostomy in 2, facial palsy in 2, transient gait ataxia in 1, and cognitive deficits in 1. Three patients were lost to follow-up. Of the remaining 18 individuals, 9 survived in good clinical condition between 1 and 12 years after the operation (mean survival time, 6.2 years), and 2 of these patients required a second surgical

Anaplastic Astrocytoma Anaplastic astrocytomas are defined as diffusely infiltrating astrocytomas with a focal or dispersed anaplasia (WHO grade III). In the brainstem, this is a subgroup entity of adult diffuse intrinsic brainstem gliomas with the same distribution pattern as WHO grade II tumors (Fig. 13.11). Clinical symptoms vary according to tumor localization with a relatively short preoperative history.3 On neuroimaging, anaplastic astrocytomas present as poorly defined T1-hypointense lesions, usually with partial contrast enhancement. Perifocal edema may be present in more aggressive cases.26 Histologically, they show a diffusely infiltrating growth pattern with focal or diffuse hypercellularity, moderate to high polymorphism, and increased mitotic activity. Necrosis and vascular proliferation are absent. IDH mutations are rare in adult diffuse brainstem astrocytomas, mostly in non-R132H variants that are associated with a more aggressive clinical course compared with diffuse IDH-mutant astrocytomas.1 Studies of adult diffuse brainstem gliomas have shown that increasing tumor grade and contrast enhancement are associated with a significantly reduced survival rate.19,​48

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Fig. 13.8  The only preoperative symptoms of this 26-year-old woman consisted of left-sided facial paresthesia that developed during the previous 4 months. Axial (a), coronal (b), and sagittal (c) magnetic resonance images furnish evidence of a well-circumscribed tumor with inhomogeneous contrast enhancement within the right midbrain peduncle and tegmentum that compressed the thalamus superiorly and the upper pons inferiorly. As the images were suggestive of low-grade glioma, surgery was offered to the patient with the aid of intraoperative BrainSuite MRI software. The procedure was performed with the patient placed in the supine position on the special MRI-compatible operating table, and the head was turned to the left and fixed in the special head holder. A temporobasal craniotomy was undertaken to use the subtemporal access route, while draining cerebrospinal fluid from a lumbar drain that was placed preoperatively. The tentorium was incised posterior to the entry point of the trochlear nerve into the tentorial incisura. (d) When the ambient cistern was opened, the exposed midbrain peduncle showed a normal superficial aspect. (e) The peduncle was opened slightly anterior to the lateral mesencephalic sulcus and between the posterior cerebral artery and vein of Rosenthal. Several millimeters below the surface, a jelly-like tumor, macroscopically compatible with pilocytic astrocytoma, was found. Later, histopathologic

examination confirmed the diagnosis of pilocytic astrocytoma World Health Organization grade I; there were no IDH1, BRAF, or H3F3A mutations and no hyperexpression of p53 protein; Ki67 was focally positive up to 2%. The slightly vascularized tumor of soft consistency was clearly discernible from the surrounding brainstem parenchyma. After removal of apparently the entire tumor mass, intraoperative 1.5-T MRI was used to assess resection. Surprisingly, some residual tumor that was not readily recognized could be detected in the most superior part of the resection cavity. This area was difficult to expose because of the unfavorable viewing trajectory and the initial reluctance to further retract the temporal lobe. The operating table was then returned to the surgical position, and the remaining tumor portion was completely resected as as verified by direct inspection (f) and by a second intraoperative MRI. There were no perioperative complications. After the operation, grade 3 hemiparesis was present that improved during the following days. One year after surgery, the patient had no tumor recurrence as demonstrated on axial (g) or coronal (h) MRI. The patient was completely independent and could walk unaided, but a slight weakness of the left leg and reduced fine motor movement of the left hand were still present. According to our expectations, this mild residual motor deficit should further improve or even normalize as has been observed in other similar cases.

intervention. The other 9 patients died of their primary tumor between 6 months and 10 years after the initial surgical procedure (mean survival time, 25.1 months). Except for 1 individual, all patients underwent postoperative radiochemotherapy. Fig. 13.12 shows an exemplary case of a large intrinsic tumor in a critical area of the lower brainstem, the medulla oblongata, extending into the upper cervical cord.

of molecular criteria, these tumors most probably would be diagnosed differently today, with the majority being diagnosed as diffuse astrocytomas, some perhaps even as anaplastic astrocytomas. In the series of patients who received a diagnosis of fibrillary astrocytomas, 4 patients were men and 6 were women, with a mean age of 45.5 years. Four tumors were tectal exophytic, 2 were tectal intrinsic, 3 were located in the pons extending into the brachium pontis, and 1 was a medullary intrinsic tumor. The following surgical approaches were used: supracerebellar infratentorial in 4, telovelar with tumor biopsy in 2, endoscopic ventriculostomy with tumor biopsy in 2, CPA in 1, and dorsal midline in 1. Six patients were operated on in the sitting position, 2 in the prone position, and another 2 in the supine position for endoscopic procedures. The extent of tumor resection is summarized in Table 13.5. No patient had perioperative complications. After the operation, 1 patient had facial palsy and sensory deficits, and another patient had temporary Parinaud syndrome. The remaining patients did not experience postoperative deterioration. Five patients received postoperative radiotherapy, and 4 received additional chemotherapy. Only 1 patient harboring

Fibrillary Astrocytoma In the 2016 version of the WHO classification of CNS tumors, a fibrillary astrocytoma is no longer defined as a variant of diffuse astrocytomas WHO grade II.26 The fibrillary astrocytoma is now defined histologically as the most frequent morphology of diffuse astrocytomas with relatively well-differentiated neoplastic astrocytes in a dense fibrillary matrix  (see also diffuse astrocytoma). In 10 patients of the present series who underwent surgery in the period 1996–2006, the histopathologic diagnosis was fibrillary astrocytoma  (Fig. 13.13); however, as noted above, the use of the term fibrillary astrocytoma is no longer recommended in the 2016 WHO classification. On the basis

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Fig. 13.9  This 28-year-old woman had progressive gait ataxia and slight diplopia. A midbrain tectal tumor was diagnosed in her home country 4 years before her presentation to our clinic. The patient underwent 2 surgical explorations in other hospitals, and each time no more than a tumor biopsy was undertaken. Histopathologically, a pilocytic astrocytoma was diagnosed. As the tumor continued proliferating, the patient was advised elsewhere to undergo radiotherapy and thereafter chemotherapy with temozolomide for a period of 12 months. When the patient presented to our institute for the first time, the tumor had reached a very large size, extending from the midbrain into the thalamus, pons, and cerebellum

bilaterally as shown on preoperative axial (a,b) and sagittal (c) magnetic resonance images (MRIs). As none of the previous therapies achieved efficient tumor control, we offered the patient extensive tumor resection. (d) She agreed and underwent the procedure in the semisitting position. Complete removal of this exophytic pilocytic astrocytoma World Health Organization grade I tumor was successful as documented on postoperative axial (e,f) and sagittal (g) T1-weighted contrast-enhanced MRIs. The patient experienced no additional neurologic deficits, and her subsequent course was uneventful. (h) At 10-year follow-up after radical tumor removal, the patient continued to do well and remained recurrence-free.

a focal tectal tumor underwent a second and later a third microsurgical procedure due to malignant tumor transformation. The patient survived 6 years. Seven patients could be followed up and were alive and independent at least 5 years after surgery.

sis, these tumors have a variable histology. The majority of these glioblastomas show an astrocytic differentiation, but they can also show an oligodendroglial-like morphology. Moreover, they mimic a WHO grade II glioma in 10% of cases, while presenting high-grade characteristics in other cases containing mitoses with or without foci of necrosis and microvascular proliferation. The brainstem glioblastomas lacking K27M mutations are most commonly found in adult patients older than 40 years. Histologically, they appear as pleomorphic, highly cellular astrocytomas with multiple mitotic figures as well as microvascular proliferations or necrosis. Prognosis is poor, with most patients dying within 15 to 18 months after diagnosis. The 5-year survival rate is less than 5%. Younger age (< 40 years), complete macroscopic tumor resection, and, on a molecular level, presence of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation are associated with a better prognosis. Six patients in this series underwent surgery for removal of a brainstem glioblastoma, 5 men and 1 woman, with a mean age of 37.7 years. One tumor was located in the midbrain tegmentum (Fig. 13.1c), two were found in the pons with brachium pontis extension (Fig. 13.5), and three were medullary intrinsic (Fig.13.1h, Fig. 13.6, Fig. 13.7). Debulking and resection of a significant amount of tumor mass was possible in all cases. Except for one individual (the 29-year-old man shown

Glioblastoma Glioblastomas are less common in the brainstem than in supratentorial regions of the brain. These tumors preferentially affect children and young adults and are found most frequently in the pons, where they correspond to the previously termed malignant brainstem gliomas and diffuse intrinsic pontine gliomas. It is now well-known that these tumors carry mutations at codon 27 of the genes coding histone proteins H3.3  (H3F3A), H3.1 (HIST1H3B), and H3.2 (HIST1H3C), resulting in alterations of histone protein H3, which are associated with an aggressive clinical course and poor prognosis. These newly described molecular features, which were later found in other midline structures of the CNS, set the basis to define a new tumor entity, diffuse midline gliomas H3-K27M mutant WHO grade IV, in the 2016 edition of the WHO classification of tumors of the CNS. Despite their common malignant clinical implications and poor progno-

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Fig. 13.10  This 20-year-old woman had extreme headache due to obstructive hydrocephalus caused by a large dorsally exophytic midbrain tumor. At first glance, preoperative axial (a,b) and sagittal (c) contrastenhanced magnetic resonance imaging (MRI) was suggestive of a highgrade tumor involving the midbrain and upper pons. However, as the patient had no neurologic deficits, tumor malignancy seemed rather unlikely, and the possibility of low-grade glioma was discussed with the patient and her family. We offered her direct surgery without initially treating the occlusive hydrocephalus. (d,e) The patient agreed and underwent the surgical intervention in the semisitting position; transesophageal echocardiography was continuously monitored throughout the procedure for early detection of possible air embolism. A large median suboccipital craniotomy was performed, and the tumor was accessed via the telovelar approach through the fourth ventricle. According to the intraoperative mapping of the rhomboid fossa, the tumor was located

superior to the left facial colliculus. As the tumor was well distinguishable from the surrounding brainstem parenchyma, gross total tumor resection was achieved and confirmed on postoperative MRI. While the patient’s motor function was fully intact after surgery, she complained only of slight hemisensory disturbance and minimal diplopia caused by mild sixth nerve palsy. Histopathologic examination revealed a pilocytic astrocytoma World Health Organization grade I. The patient received no postoperative adjuvant therapy, and her symptoms gradually resolved. Her further clinical course was uneventful. Repeated postoperative MRIs documented the absence of local tumor recurrence or other intracranial abnormality. (f) Eleven years after surgery, the patient was in excellent clinical condition and had normal eye movement and only minimal, nondisturbing sensory deficits in the fingers of her right hand. Axial (g) and sagittal (h) MRIs at 11-year follow-up show that the patient remains free of tumor remnants or recurrence.

in Fig. 13.6) who required a postoperative tracheostomy for 3 months, patients did not experience postoperative neurologic deterioration. All received postoperative adjuvant therapy, in recent years according to the Stupp protocol, but only one patient remained alive at the time of this writing (the 34-year-old man shown in Fig. 13.5). The other 5 patients died between 6 months and 3 years after the operation (mean survival time, 20.8 months).

focal contrast enhancement. These tumors are composed of a dominant pilocytic-like glial component and a neuronal differentiated component forming neurocytic rosettes and perivascular pseudorosettes. Despite the histologic similarity between RGNTs and pilocytic astrocytomas, KIAA1549-BRAF fusions and BRAF V600E mutations have not been described in RGNTs; also these tumors have no evidence of IDH1/2 mutations or 1p/19q co-deletions. Patients with RGNTs have a favorable prognosis.26 Four patients harboring RGNTs were encountered in the present series (2 men and 2 women ages 24, 35, 35, and 45 years at diagnosis, respectively). Three had focal midbrain tectum tumors, all with a similar appearance on MRIs to that of the illustrative case shown in Fig. 13.14, while one tumor was located in the pons and extended into the brachium pontis (Fig. 13.1g). The latter tumor was exposed via the CPA; the other tumors were reached via the supracerebellar infratentorial exposure (two patients in semisitting and one in prone position). Gross total tumor removal was achieved in three individuals, while in one patient only about 40% of tumor volume could be resected. There were no additional

Rosette-forming Glioneuronal Tumor Rosette-forming glioneuronal tumors (RGNTs) are slow growing  (WHO grade I) tumors that have a higher incidence rate among young adults than among the remaining population, arise mainly in midline structures, occur preferentially in or around the fourth ventricle, and tend to extend into adjacent regions such as the brainstem and cerebellum. Headache caused by hydrocephalus and occasional cervical pain are common clinical symptoms. MRI reveals a relatively well-defined T1-hypointense, T2-hyperintense lesion with focal or multi-

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Table 13.5  Extent of tumor resection among adult brainstem glioma patients (senior author’s series)

Type of lesion

N

Gross total resection (99–100%)

Near-total resection (90–98%)

Subtotal resection (50–89%)

Pilocytic astrocytoma

22

13

3

5

Anaplastic astrocytoma

21

5

5

5

6

Fibrillary astrocytoma

10

3

2

2

1

Glioblastoma

6

1

2

3

Rosette-forming glioneuronal tumor

4

3

Diffuse astrocytoma

4

Anaplastic ganglioglioma

2

Ganglioglioma

1

Papillary glioneuronal tumor

1

Pleomorphic xanthoastrocytoma

1

Anaplastic oligodendroglioma

1

1

Total

73

29

11

14

16

2

1

40%

15%

19%

22%

3%

1%

Percentage*

Biopsy or debulking (< 50%)

ETV and tumor biopsy

Cyst fenestration and biopsy 1

2

1 1

3

2 1 1 1

Abbreviation: ETV, endoscopic third ventriculostomy. *Percentages total >100% due to rounding. Table 13.6  Postoperative characteristics of 73 adult brainstem glioma patients (senior author’s series)

Outcome

Pilocytic astrocytoma

Anaplastic astrocytoma

Fibrillary astrocytoma

Glioblastoma

RGNT and diffuse astrocytoma

Anaplastic ganglioglioma, gangliglioma, PGNT, PXA, and anaplastic oligodendroglioma

Lost to follow-up

1

3

3

0

0

1

No new neurologic deficits

16

12

8

5

6

5

Additional postoperative morbidity

6

9

2

1

2

1

Surgical complications

2

0

0

0

0

1

Tumor progression or recurrence

7

10

5

5

2

3

Repeat tumor surgery

0

2

1

0

0

0

Disease-related death

1

9

1

5

0

2

Abbreviations: PGNT, papillary glioneuronal tumor; PXA, pleomorphic xanthoastrocytoma; RGNT, rosette-forming glioneuronal tumor.

neurologic deficits. Patients did not receive adjuvant therapy after surgery; they were monitored with repeated MRIs. All patients remained in excellent condition at follow-up of 4 to 7 years after the surgical intervention.

Diffuse Astrocytoma Diffuse astrocytomas are slow-growing diffusely infiltrating lowgrade gliomas (WHO grade II) that may be located in any part of CNS, including the spinal cord, but they grow preferentially in the brain. In the brainstem, they are the most common type of diffuse intrinsic brainstem gliomas with the highest incidence rate among younger adults 20 to 50 years old (median age, 34 years at diag-

nosis).3 They grow most frequently within the pons and rarely in the medulla and midbrain.48 Clinical symptoms vary, depending on tumor localization, from visual disturbances, muscle weakness of extremities, and gait disorder in most cases to cranial nerve deficits, long tract signs, hydrocephalus, and rarely signs of brainstem dysfunction in other cases.3 On MRI, diffuse astrocytomas present as poorly defined nonenhancing lesions with hypointensity on T1-weighted images and with higher signal intensity on T2-weighted or FLAIR images, usually with brainstem enlargement.45 Histologically, they have a moderate cell density and are composed of well-differentiated astrocytes in a loose fibrillary matrix, diffusely infiltrating the surrounding brain tissue. In contrast to supratentorial lesions, brainstem diffuse astrocytomas of adults (grades II and III) only in rare cases show IDH mutation variants (with a higher

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Fig. 13.11  Illustrative axial (a,b) and sagittal (c-j) magnetic resonance images (MRIs) of 10 patients in this series who harbored typical anaplastic

astrocytomas of the brainstem. All of the patients in the MRIs shown here were 21 to 39 years old.

Fig. 13.12  This 36-year-old man presented with a 4-month history of sensory disturbance involving the entire left side of his body and a slight hemiparesis. Preoperative axial (a), coronal (b), and sagittal (c) T1-weighted magnetic resonance images (MRIs) show an almost nonenhancing, homogeneous, space-occupying tumor (a, arrow) in the lower medulla extending into the cervical cord. The patient agreed to undergo surgery with the aim of debulking as much tumor as possible and obtaining a precise histopathologic diagnosis. (d) Surgery was performed with the patient placed in the semisitting position. The tumor was exposed via a median suboccipital craniectomy and C1 laminectomy. At least 50% of the tumor mass was

removed, as can be seen on postoperative sagittal T2-weighted MRI (e) and on sagittal T1-weighted, contrast-enhanced MRIs (f,g). (h) Fortunately, he had no additional neurologic deficits after surgery. Histopathologic examination furnished evidence of an anaplastic astrocytoma World Health Organization grade III, without H3F3A or IDH1 mutation; he had no combined 1p/19q deletion, no hyperexpression of p53 protein and no O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. After the operation, the patient underwent local radiotherapy combined with temozolomide therapy. No further tumor progress was observed 1 year after surgery, and the patient remained independent.

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Fig. 13.13  Illustrative sagittal magnetic resonance images (MRIs) show typical fibrillary astrocytomas involving the brainstem. These

MRIs demonstrate tumors in seven patients (a-g) in the present surgical series who were 19 to 70 years old.

non-R132H/R132H ratio), which predicts a more aggressive clinical course in adults.1,​26 Four patients of the present series had diffuse astrocytoma of the brainstem, three women (ages 37, 38, and 41 years at diagnosis) and 1 man (age 25 years). One tumor was located in the midbrain (laterally exophytic), One in the pons with extension into the brachium pontis, and two other very large tumors extended inferiorly into the pons as well as superiorly into the thalamus. Two neoplasms were WHO grade II, and two were WHO grade III. Near-total resection was achieved in the laterally exophytic midbrain tumor. In the remaining three patients, only partial tumor removal (debulking) was possible. No patient experienced perioperative complications, and no significant morbidity was added to the preoperative symptoms. All four patients underwent postoperative conventional radiotherapy and were alive at 6 years, 5 years, 2 years, and 1 year after the surgical intervention, respectively.

one study in three of six cases.49 Five-year overall survival and progression-free intervals were shown in two studies to be unfavorable in anaplastic gangliogliomas, while another study did not confirm a significant correlation between prognosis and tumor grade.26 Two patients in this series harbored an anaplastic ganglioglioma. In one woman (age 19 years), the tumor was located in the medulla oblongata; in one man (age 30 years), the tumor was within the posterior pons and left brachium pontis. In both cases, we achieved gross total tumor resection without adding new neurologic deficits. Regrettably, after an initially uneventful postoperative course, the young woman experienced aggressive local tumor recurrence after 1 year despite postoperative radiotherapy. Repeat surgery was offered, but the patient and her family refused any further intervention, and shortly thereafter she died. The man underwent conventional radiotherapy and remained symptom-free more than 1 year after surgery. To date, he has had no tumor recurrence on MRI.

Anaplastic Ganglioglioma This rare malignant type of ganglioglioma  (WHO grade III) does not have a preferential temporal lobe location and shows a more even distribution in the entire CNS.45 Microscopically, the tumor shows a dense pleomorphic cellular appearance with high mitotic activity. Necrosis and vascular proliferation are usually present. BRAF V600E mutation could be detected in

Ganglioglioma Gangliogliomas (WHO grade I) are slow growing and the most frequent mixed neuronal-glial tumors45 with the highest incidence rate among children and young adults. They grow in the temporal lobe in 70% of cases but can also be located in the brainstem, cerebellum, and spinal cord.26,​45 Focal seizures

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Fig. 13.14  A 35-year-old woman became symptomatic with headache only; she had no neurologic deficits. Axial T1-weighted (a) and T2-weighted (b) and sagittal T2-weighted (c) magnetic resonance images (MRIs) show a typical intrinsic tectal tumor (a, arrow) that does not reach the surface of the brainstem. (d) The patient underwent surgery in the semisitting position via the supracerebellar paraculminal infratentorial approach. Histopathologically, a rosette-forming glioneuronal tumor was found with an MIB1 index of 1%. Postoperative axial (e) and sagittal

(f) MRIs documented total tumor removal. The patient had no perioperative complications, and no additional postoperative neurologic deficits except for an upward gaze palsy (Parinaud’s syndrome) (g), which resolved within 8 weeks after surgery. However, minimal diplopia persisted that was treated ophthalmologically with a squint operation 2 years after tumor surgery. Thereafter, her eye movement normalized. At her 5-year postoperative follow-up, she remained tumor recurrence-free and in excellent clinical condition.

in cases of supratentorial location are the most common clinical features of gangliogliomas, reflecting the tendency for the tumor to grow in the temporal lobe. For this reason, gangliogliomas are most frequently associated with chronic temporal lobe epilepsy. On MRI, they usually present as a well-circumscribed cortical lesion composed of a cystic (or multicystic) component and a nodular, frequently enhancing solid mass. Calcification is found in 30% of cases.26 Histologically, they typically show a well-differentiated phenotype composed of dysplastic ganglion cells and a neoplastic glial component that can mimic the morphology of a fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma.26,​45 BRAF V600E mutation is the most frequent genetic alteration in gangliogliomas, and it is found in up to 60% of cases (most commonly in younger patients), while IDH mutation is absent. Prognosis is favorable, and 97% of patients have a recurrence-free interval of 7.5 years.26 However, a study in a series of pediatric patients, mainly with extratemporal gangliogliomas, showed an association of BRAF V600E mutation with a shorter recurrence-free survival.26 In this series, we encountered only one patient (female, 53 years old) harboring a huge ganglioglioma WHO grade I in the lower brainstem. The tumor originated from the medulla oblongata and infiltrated the lower brainstem, including the lower portion of the pons and the brachium pontis. The patient became symptomatic with headache, gait imbalance, and progressive dysphagia. Tumor debulking was performed

to protract the evolution of neurologic deficits. As no clear tumorbrainstem interface was found at surgery, a significant amount, but less than 50%, of the tumor mass was removed. The patient had no perioperative complications other than a urinary tract infection (successfully treated) and no additional neurologic deficits.

Papillary Glioneuronal Tumor A papillary glioneuronal tumor  (PGNT) is a rare WHO grade I tumor with astrocytic and neuronal differentiation, showing a pseudopapillary architecture.26 This tumor occurs preferentially in young adults in the supratentorial area, often in proximity to the ventricles. Its MRI appearance is that of a focal cystic or solid mass with contrast enhancement. The genetic profile is characterized by a SLC44A1-PRKCA fusion oncogene present in a high proportion of cases. With gross total resection, the prognosis is good. The only patient in the present series who harbored a PGNT originating from the midbrain tectum and extending inferiorly into the fourth ventricle confirms the favorable long-term result in such tumors. The patient (a 36-year-old woman; Fig. 13.15) underwent complete tumor resection. She had no additional postoperative deficits and remained free of tumor recurrence as documented on repeated MRIs with the last follow-up 11 years after the surgical intervention.

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Fig. 13.15  A 36-year-old woman had severe headache and gait ataxia due to occlusive hydrocephalus, which was caused by an exophytic tectal tumor. The symptoms disappeared after placement of a ventriculoperitoneal shunt in another hospital. Axial (a), coronal (b), and sagittal (c) T1-weighted contrast-enhanced magnetic resonance images (MRIs) demonstrate the exact tumor location and its caudal extension into the fourth ventricle (c, arrows). (d) The patient underwent surgery in the semisitting position. The superior

tumor portion was resected via the supracerebellar infratentorial route, and the remaining inferior part via the telovelar exposure through the fourth ventricle in the same surgical procedure. Histopathologically, a papillary glioneuronal tumor was diagnosed. Postoperative axial (e), coronal (f), and sagittal (g) MRIs documented total tumor removal. The last MRI was performed 11 years after the surgical procedure. (h) The patient remained symptomfree and was leading an independent life.

Pleomorphic Xanthoastrocytoma

Anaplastic Oligodendroglioma

Pleomorphic xanthoastrocytoma is a very rare astrocytic neoplasm (less than 1% of all astrocytic tumors) mainly affecting children and young adults. This tumor grows superficially and involves the subarachnoid space.45 In about 98% of cases, the tumor is located supratentorially, most frequently in the temporal lobe. Cerebellar and spinal localizations have also been reported.26 Patients experience long-term epilepsy due to the superficial cerebral location. MRI reveals a superficial well-defined lesion composed of a cystic portion and a strongly enhancing mural solid mass with occasional leptomeningeal contrast enhancement. The tumor has a typical histologic diversity composed of pleomorphic multinucleated cells with an occasional lipidized giant cell component. Moreover, numerous eosinophilic granular bodies and a dense reticulum-positive matrix are found in this lesion. BRAF point mutations, particularly of the V600E, occur in 50 to 78% of cases; in contrast, no IDH mutations have been detected yet.26,​45 Patients have a relatively favorable prognosis. One study showed a 5-year overall survival of 75% and an overall survival rate of 67% after 10 years.50 The extent of resection seems to be the major predictive factor of recurrence.26 The only patient of this series with pleomorphic xanthoastrocytoma (male, 51 years old) harbored a mesencephalic tumor. Because of a lack of clear tumor-parenchyma interface, less than 50% of the tumor mass was removed. He had no perioperative complications and no additional neurologic deficits except for slight hemisensory syndrome. Unfortunately, the patient was lost to long-term follow-up.

Anaplastic oligodendrogliomas are malignant gliomas accounting for approximately one-third of all oligodendroglial tumors. They most commonly occur among adults, with the highest rate among patients age 45 to 50 years.45 They are frequently found in the frontal lobe, followed by the temporal lobe, but they also originate in other sites of the CNS in rare cases.26 Anaplastic oligodendrogliomas develop either primarily (de novo) with a short preoperative clinical history or secondarily as transformed low-grade oligodendrogliomas.45 They commonly generate focal neurologic or cognitive deficits as well as epilepsy. The variable evidence of necrosis, cystic degeneration, intratumoral hemorrhage, and calcification confers these tumors with a heterogeneous appearance on MRI. Homogeneous or patchy contrast enhancement is usually present.26,​45 The histologic appearance of tumor cells is that of oligodendrocytes with a clear cell differentiation (perinuclear haloes). They have high mitotic activity and a diffuse infiltrating growth pattern. Like low-grade oligodendrogliomas, they are now genetically defined through IDH mutation and codeletion of the chromosomes 1p and 19q. Also, TERT promoter mutation occurs in the vast majority of these tumors. Evidence was found that patients with anaplastic oligodendrogliomas have a much better prognosis than those with IDH-mutant but 1p/19q-intact or IDH-wildtype anaplastic astrocytic gliomas. Younger age at diagnosis, higher Karnofsky Performance Scale score, and greater extent of resection constitute the main predictive factors of patients’ survival rate.26

13   Adult Brainstem Gliomas In this series, we encountered only one patient (male, 50 years old) harboring an isolated anaplastic oligodendroglioma of the midbrain tectum. Two years before the brainstem intervention, the patient underwent surgery for removal of an anaplastic oligodendroglioma with similar neuropathologic features in the left frontal region. The frontal tumor was completely excised at that time, and the patient received postoperative radiochemotherapy. His brainstem tumor, not present at the time when the frontal tumor was detected, was completely resected as well; there were no perioperative complications, and the patient underwent additional combined radiochemotherapy. Although the brainstem remained free of tumor, the patient died 3 years later due to recurrence and aggressive proliferation of the supratentorial tumor.

■■ Results The value of neurosurgical management can be better understood by clearly distinguishing outcomes among patient groups according to the underlying tumor entity. As could be expected and already described above, clinical results were generally better in patients with low-grade compared with high-grade tumors. Nevertheless, satisfactory results can also be achieved in patients with malignant brainstem gliomas. Here we have summarized several pertinent aspects related to treatment results in all 73 individuals to offer an overview of our entire series of adult patients with brainstem gliomas.

Extent of Tumor Resection As mentioned previously in the section on the goals of surgery, we attempted to remove as much of the brainstem tumor mass as possible, while paying great attention not to affect the normal parenchyma by surgical manipulation. Our attention during surgery also focused on preserving brainstem-supplying vessels to avoid ischemic parenchymal alterations. As expected, removing a greater amount of tumor was easier in focal low-grade tumors but was far more difficult in high-grade and diffuse lesions. Table 13.5 gives an overview of the amount of tumor that was removed in each separate tumor entity subgroup. As for the entire series of 73 patients, gross total tumor removal was achieved in 40% (n = 29), near-total resection in 15% (n = 11), subtotal resection in 19% (n = 14), biopsy or debulking in 22% (n = 16), ventriculostomy and tumor biopsy in 3% (n = 2), and cyst fenestration and biopsy in 1% (n = 1). Considering that gross total and near-total tumor removal (resection of at least 90% of tumor volume) are quite satisfactory results, this high rate of resection was achieved in 73% of pilocytic astrocytomas, in 48% of anaplastic astrocytomas, in 50% of fibrillary astrocytomas, and in 55% of the entire patient series.

Clinical Outcome, Morbidity, and Mortality Two aspects are most important in the context of surgical outcome: the early postoperative results and the long-term result in terms of overall survival with sufficiently high quality of life. Surgery on the brainstem is one of the most challenging neurosurgical procedures. Thus, zero morbidity after an extensive brainstem surgery cannot be taken for granted, although we have observed quite a number of patients with exactly this kind of excellent postoperative result, as we have illustrated in this

207

chapter and as shown in Table 13.6. At least 30 individuals of this highly select series of 73 patients (41%) experienced an excellent long-term outcome, namely no or absolutely minor neurologic deficits and no tumor progression or recurrence at least 5 years after the initial surgical intervention. Some of them, such as the patients shown in Fig. 13.10 and Fig. 13.15, remained recurrence-free for more than 10 years. When operating on a brainstem tumor, however, one should expect minor and transient morbidity in any case. Accordingly, postoperative morbidity was present in many instances (Table 13.6). Patients in this series and their families were prepared for such postoperative events. In our entire patient population, no one experienced direct surgical mortality. All patients who did not ultimately survive died because of the underlying brainstem glioma and not as a consequence of surgery. Only one female patient harboring a large pontine anaplastic astrocytoma experienced significant postoperative deterioration of consciousness and remained thereafter in poor clinical condition. She died 6 months later because of tumor progression. However, according to the preoperative evolution of her symptoms and the morphological aspect of her tumor, a similar course with rapid clinical deterioration would have occurred without surgical intervention. Fortunately, this was the only patient in the series with a very unsatisfactory outcome. Surgical complications were observed in three patients; one was minor (urinary infection) and two were severe (cerebellar hemorrhagic swelling after surgery via the infratentorial, supracerebellar approach), the latter requiring surgical repair. As shown in Table 13.6, in the majority of patients (52/73, 71%), the surgical intervention did not cause additional morbidity. As for the long-term outcome, not all patients could be followed up, and some were lost to follow-up. Nevertheless, in many instances clinical information was available between 6 months and more than 10 years after the initial surgery. Patients with highgrade tumors usually underwent combined radiochemotherapy after surgery according to well-established protocols. Tumor progression or recurrence was observed in 32 of 65 individuals (49% of the population). For various individual reasons, repeat surgery to remove tumor recurrence was undertaken in only three patients.

■■ Lessons Learned •• For the surgical treatment of adult patients with brainstem gliomas, patient selection is crucial, and with good-quality imaging, surgical candidates such as those as presented in this series can be identified. •• MRI may not always be reliable in predicting the type of the underlying tumor and its microsurgical resectability; lesions that apparently have no clear tumor-brainstem interface on MRI can still be well circumscribed at surgery. •• Retrospectively, our decision-making for surgical intervention in brainstem glioma may be slightly different today than it was 15 or 20 years ago; in many cases, for instance with tectal gliomas, we can achieve more than just tumor biopsy and CSF diversion. •• In light of modern molecular neuropathology, surgical intervention in brainstem gliomas gains new significance. •• The choice of the optimal surgical approach and the amount of tumor mass that is removed are most important factors that determine the success of surgery.

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V  Comprehensive Management of Tumors of the Brainstem, Thalamus, and Pineal Region

•• Continuous intraoperative electrophysiological monitoring guides the surgeon and should always be applied in brainstem surgery.

■■ Conclusions Brainstem gliomas are all primary glial tumors that arise from the brainstem. Hence, they comprise a great variety of pathologic entities with different histopathology, molecular features, growth patterns, aggressiveness, clinical implications, and tendencies for proliferation and recurrence. The term “inoperable” should not be generally applied to brainstem gliomas. Microsurgical tumor removal is feasible in many cases, but patients must be selected well. We have shown a different classification system that enables identifying the surgical candidates; however, there is no general rule, and patient selection must remain a highly individualized decision in each case. The choice of the surgical approach and the respective surgical window for brainstem exposure play key roles in the success of surgery. At least in patients with low-grade brainstem gliomas, radical tumor removal should be attempted whenever possible. The rate of tumor resection may influence the long-term outcome. Excellent long-term results can be achieved, at least in patients harboring a low-grade glioma. Even in patients with high-grade tumors, surgery can offer much more than only good palliative care. During the surgical procedure, close collaboration with the anesthetist and continuous electrophysiological monitoring add to the success of surgery. References 1. Hu J, Western S, Kesari S. Brainstem glioma in adults. Front Oncol 2016; 6:180 2. Jallo GIFD, Roonprapunt C, Epstein F. Current management of brainstem gliomas. Ann Neurosurg 2003; 3(1):1–17 3. Reyes-Botero G, Mokhtari K, Martin-Duverneuil N, Delattre JY, LaigleDonadey F. Adult brainstem gliomas. Oncologist 2012;17(3):388–397 4. Alvisi C, Cerisoli M, Maccheroni ME. Long-term results of surgically treated brainstem gliomas. Acta Neurochir (Wien) 1985;76(1–2):12–17 5. Epstein F, McCleary EL. Intrinsic brain-stem tumors of childhood: surgical indications. J Neuro Oncol 1986;64(1):11–15 6. Epstein F, Wisoff J. Intra-axial tumors of the cervicomedullary junction. J Neurosurg 1987;67(4):483–487 7. Epstein F, Wisoff JH. Intrinsic brainstem tumors in childhood: surgical indications. J Neuro Oncol 1988;6(4):309–317 8. Hoffman HJ. Brainstem gliomas. Clin Neurosurg 1997;44:549–558 9. Stroink AR, Hoffman HJ, Hendrick EB, Humphreys RP. Diagnosis and management of pediatric brain-stem gliomas. J Neurosurg 1986; 65(6):745–750 10. Guillamo JS, Monjour A, Taillandier L, et al; Association des NeuroOncologues d’Expression Française  (ANOCEF). Brainstem gliomas in adults: prognostic factors and classification. Brain 2001;124 (Pt 12):2528–2539 11. Grimm SA, Chamberlain MC. Brainstem glioma: a review. Curr Neurol Neurosci Rep 2013;13(5):346 12. Walker DA, Punt JA, Sokal M. Clinical management of brain stem glioma. Arch Dis Child 1999;80(6):558–564 13. Zhang L, Pan C-c, Li D. The historical change of brainstem glioma diagnosis and treatment: from imaging to molecular pathology and then molecular imaging. Chinese Neurosurgical Journal 2015;1(1):4 14. Babu R, Kranz PG, Agarwal V, et al. Malignant brainstem gliomas in adults: clinicopathological characteristics and prognostic factors. J Neuro Oncol 2014;119(1):177–185

15. Hundsberger T, Tonder M, Hottinger A, et al. Clinical management and outcome of histologically verified adult brainstem gliomas in Switzerland: a retrospective analysis of 21 patients. J Neuro Oncol 2014; 118(2):321–328 16. Kesari S, Kim RS, Markos V, Drappatz J, Wen PY, Pruitt AA. Prognostic factors in adult brainstem gliomas: a multicenter, retrospective analysis of 101 cases. J Neuro Oncol 2008;88(2):175–183 17. Reithmeier T, Kuzeawu A, Hentschel B, Loeffler M, Trippel M, Nikkhah G. Retrospective analysis of 104 histologically proven adult brainstem gliomas: clinical symptoms, therapeutic approaches and prognostic factors. BMC Cancer 2014;14:115 18. Salmaggi A, Fariselli L, Milanesi I, et al; Associazione Italiana di Neurooncologia. Natural history and management of brainstem gliomas in adults: a retrospective Italian study. J Neurol 2008;255(2):171–177 19. Theeler BJ, Ellezam B, Melguizo-Gavilanes I, et al. Adult brainstem gliomas: correlation of clinical and molecular features. J Neurol Sci 2015; 353(1–2):92–97 20. Bricolo A. Surgical management of intrinsic brain stem gliomas. Operative Techniques in Neurosurgery 2000;3(2):137–154 21. Purohit B, Kamli AA, Kollias SS. Imaging of adult brainstem gliomas. Eur J Radiol 2015;84(4):709–720 22. Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 2016;131(6):803–820 23. Fischbein NJ, Prados MD, Wara W, Russo C, Edwards MS, Barkovich AJ. Radiologic classification of brain stem tumors: correlation of magnetic resonance imaging appearance with clinical outcome. Pediatr Neurosurg 1996;24(1):9–23 24. Tscherpel C, Dunkl V, Ceccon G, et al. The use of O-(2–18F-fluoroethyl)L-tyrosine PET in the diagnosis of gliomas located in the brainstem and spinal cord. Neuro Oncol 2017;19(5):710–718 25. Epstein F. A staging system for brain stem gliomas. Cancer 1985; 56(7, Suppl):1804–1806 26. Louis D, Ohgaki H, Wiestler O, et al; International Agency for Research on Cancer. WHO Classification of Tumours of the Central Nervous System, Revised. 4th ed. Lyon, France: IARC Press; 2016 27. Banan R, Hartmann C. The new WHO 2016 classification of brain tumors—what neurosurgeons need to know. Acta Neurochir (Wien). 2017; 159(3):403–418 28. Pool JL. Gliomas in the region of the brain stem. J Neurosurg 1968; 29(2):164–167 29. Cartmill M, Punt J. Brain stem gliomas, the role of biopsy. Br J Neurosurg 1997;11:177 30. Samadani U, Stein S, Moonis G, Sonnad SS, Bonura P, Judy KD. Stereotactic biopsy of brain stem masses: decision analysis and literature review. Surg Neurol 2006;66(5):484–490, discussion 491 31. Rachinger W, Grau S, Holtmannspötter M, Herms J, Tonn JC, Kreth FW. Serial stereotactic biopsy of brainstem lesions in adults improves diagnostic accuracy compared with MRI only. J Neurol Neurosurg Psychiatry 2009;80(10):1134–1139 32. Kickingereder P, Willeit P, Simon T, Ruge MI. Diagnostic value and safety of stereotactic biopsy for brainstem tumors: a systematic review and meta-analysis of 1480 cases. Neurosurgery 2013;72(6):873–881, discussion 882, quiz 882 33. Teo C, Siu TL. Radical resection of focal brainstem gliomas: is it worth doing? Childs Nerv Syst 2008;24(11):1307–1314 34. Glaser AW, Buxton N, Walker D. Corticosteroids in the management of central nervous system tumours. Kids Neuro-Oncology Workshop (KNOWS). Arch Dis Child 1997;76(1):76–78 35. Jones C, Karajannis MA, Jones DT, et al. Pediatric high-grade glioma: biologically and clinically in need of new thinking. Neuro Oncol 2017; 19(2):153–161 36. Vanan MI, Eisenstat DD. DIPG in children—what can we learn from the past? Front Oncol 2015;5:237 37. Bertalanffy H, Burkhardt J-K, Kockro RA, Sarnthein J, Bozinov O. Resection of cavernous malformations of the brainstem. In: Rigamonti D, ed.

13   Adult Brainstem Gliomas Cavernous Malformations of the Nervous System. Cambridge, England, UK: Cambridge University Press; 2011:143-160 38. Jallo GI, Biser-Rohrbaugh A, Freed D. Brainstem gliomas. Childs Nerv Syst 2004;20(3):143–153 39. Sarnthein J, Bozinov O, Melone AG, Bertalanffy H. Motor-evoked potentials (MEP) during brainstem surgery to preserve corticospinal function. Acta Neurochir (Wien) 2011;153(9):1753–1759 40. Bertalanffy H, Tissira N, Krayenbühl N, Bozinov O, Sarnthein J. Inter- and intrapatient variability of facial nerve response areas in the floor of the fourth ventricle. Neurosurgery 2011;68(1, Suppl Operative):23–31, wdiscussion 31 41. Teramoto S, Bertalanffy H. Predicting the necessity of anterior communicating artery division in the bifrontal basal interhemispheric approach. Acta Neurochir (Wien) 2016;158(9):1701–1708 42. Bertalanffy H. Avoidance of postoperative acute cerebellar swelling after pineal tumor surgery. Acta Neurochir 2016;158(1):59-62 43. Bertalanffy H, Bozinov O, Sürücü O, et al. Dorsolateral approach to the craniocervical junction. In: Cappabianca P, Iaconetta G, Califano L, eds. Cranial, Craniofacial and Skull Base Surgery. Milan, Italy: Springer-Verlag Italia; 2010:175–196

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44. Bertalanffy H, Bozinov O, Sürücü O, Benes L, Sure U, Kappus C. Intraaxial lesions of the foramen magnum. In: George B, Bruneau M, Spetzler RF, eds. Pathology and surgery around the vertebral artery. Paris, France: Springer-Verlag France; 2011:457–471 45. Love S, Louis DN, Ellison DW, eds. Greenfield's Neuropathology. 8th ed. Boca Raton, FL: CRC Press; 2008 46. Ellison D, Love S, Chimelli L, et al. Neuropathology: A Reference Text of CNS Pathology. 3rd ed. New York, NY: Elsevier Mosby; 2012 47. Norden AD, Reardon DA, Wen PYC, eds. Primary Central Nervous System Tumors: Pathogenesis and Therapy. New York, NY: Humana Press; 2010 48. Reyes-Botero G, Giry M, Mokhtari K, et al. Molecular analysis of diffuse intrinsic brainstem gliomas in adults. J Neuro Oncol 2014;116(2):405–411 49. Schindler G, Capper D, Meyer J, et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 2011;121(3):397–405 50. Perkins SM, Mitra N, Fei W, Shinohara ET. Patterns of care and outcomes of patients with pleomorphic xanthoastrocytoma: a SEER analysis. J Neuro Oncol 2012;110(1):99–104

14

Pediatric Brainstem Tumors Roberta Rehder and Alan R. Cohen

Abstract

Pediatric brainstem tumors include lesions of the midbrain, pons, and medulla. These neoplasms constitute a heterogeneous group with regard to clinical presentation, tumor localization, histopathology, management, and prognosis. The most common and ominous subgroup of pediatric brainstem neoplasms comprises the diffuse intrinsic pontine gliomas, which account for 80% of cases. Less common subgroups affecting the brainstem include focal intrinsic lesions of the midbrain and the cervicomedullary junction and dorsally exophytic neoplasms arising from the floor of the fourth ventricle. Advances in imaging technology have enabled clinicians and surgeons to develop treatment plans, implement image-guided therapies, and determine tumor response to treatment. Comprehensive understanding of these lesions will provide a means to develop new strategies for effective treatment, reduce morbidity, and, most importantly, improve the overall survival and quality of life of affected children. Keywords:  adjuvant therapy, brainstem tumors, cervicomedullary, diffuse intrinsic pontine gliomas, midbrain, tectum

■■ Introduction

children in the United States and Canada.1,​8,​9 Brainstem tumors constitute approximately 11% of all primary brain tumors in persons younger than 19 years of age, with peak incidence occurring between the ages of 5 and 8 years.10,​11 Although these lesions affect both boys and girls, boys have a slightly better 5-year survival rate.10 Primary brain and CNS neoplasms are the most common type of cancer in persons between the ages of 15 and 19 years, and brainstem neoplasms account for approximately 12% of cases.12,​13 The most common and aggressive pediatric brainstem tumors are the DIPGs, which represent approximately 80% of neoplasms. These lesions are nonpilocytic astrocytomas, World Health Organization (WHO) grade II or higher. Pediatric low-grade gliomas constitute the remaining 20% of brainstem tumors and follow a more indolent course.5,​14,​15,​16

Etiology Established risk factors for pediatric brain tumors include certain cancer syndromes and ionizing radiation. Familial syndromes associated with increased brain tumor susceptibility are neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), tuberous sclerosis (TSC1 and TSC2), Li-Fraumeni (TP53 and CHEK2), nevoid basal cell carcinoma (PTCH), Turcot (APC), Cowden (PTEN), hereditary

Pediatric brain neoplasms are the second leading cause of malignancy in children.1,​2,​3 Brainstem tumors, defined as lesions located between the diencephalon and the cervicomedullary junction, account for 15 to 20% of primary brain neoplasms in children.4 These lesions arise in the midbrain, pons, and medulla, and they include tectal tumors, diffuse intrinsic pontine gliomas (DIPGs), and cervicomedullary lesions (Fig. 14.1).5,​6,​7 Advances in imaging technology, histopathologic analysis, and clinical trials have provided clinicians and surgeons with a new understanding of childhood brainstem neoplasms. These tumors comprise a heterogeneous group of lesions, for which the clinical presentation, prognosis, and treatment are dictated by tumor location, configuration, and biological behavior. In this chapter, the authors review the different pediatric brainstem neoplasms and propose strategies for clinical and surgical management.

■■ Epidemiology, Etiology, and Natural History of Disease Epidemiology Brain neoplasms and central nervous system (CNS) malignancies are the second most common cause of cancer-related death in

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Fig. 14.1  Illustration showing different locations of brainstem tumors. Midbrain lesions often occur in the tegmentum and tectal plate. The most common pontine lesions are diffuse intrinsic pontine gliomas. Exophytic components may arise from the pontine tumors and protrude into the fourth ventricle. Cervicomedullary gliomas are often low-grade tumors, affecting the medulla and the upper cervical spine.

14  Pediatric Brainstem Tumors retinoblastoma (RB1), and Rubinstein-Taybi (CREBBP).1,​17,​18,​19,​20 Head and neck radiation is another established risk factor for the development of brain neoplasms. Other potential risk factors associated with brain tumor predisposition include advanced parental age, birth defects, computed tomography (CT) imaging, maternal diets containing nitrosamine compounds, and pesticide exposure.21,​22,​23 Several studies indicate that children with congenital anomalies have more than a twofold risk of developing CNS lesions.1,​24 Contrarily, allergies may protect against childhood brain tumor development. An inverse association has been found between the development of brain neoplasms and allergic conditions, such as allergies, asthma, and elevated levels of serum immunoglobulin E.1,​25,​26

Natural History of Disease Prognostic factors for children with brainstem tumors include age at presentation, duration of symptoms, pathology, location, surgical resection, and associated adjuvant therapy.2 Predictors of favorable outcome are long-term duration of symptoms, focal and exophytic neoplasms, and lesions in the dorsal midbrain or medulla oblongata. Tumors affecting the midbrain and medulla are low-grade gliomas in 98% of cases, and pontine lesions are low-grade neoplasms in only 25% of patients.16 Brain tumors and CNS neoplasms are less responsive to adjuvant therapy than any other type of solid tumor. Several factors contribute to this lack of responsiveness, including the presence of the blood-brain barrier, which restricts drug penetration into the CNS; multiple signaling pathways in high-grade neoplasms; and the development of primary or acquired drug resistance.27,​28 Thus, effective approaches to treat brainstem lesions often require combined targeted regimens.

■■ Clinical Presentation Clinical presentation depends on the affected region of the brainstem.11,​29 The most common signs and symptoms include coordination and gait abnormalities (78%), cranial nerve (CN) palsies (52%), pyramidal signs (33%), and headache (23%).11,​30 Other clinical manifestations are ophthalmoplegia (19%), focal motor weakness (19%), facial palsy (15%), papilledema (13%), unspecified symptoms of increased intracranial pressure  (ICP)  (10%), and abnormal eye movements (6%). Signs and symptoms can be nonspecific, and manifestations of behavioral changes or academic difficulties are common.29

■■ Perioperative Evaluation Advances in neuroimaging techniques have provided significant information on tumor status at diagnosis and follow-up.31 Magnetic resonance imaging (MRI) is the most useful study to define infiltration and to assess response to treatment.32,​33 Correlation between the MRI findings and brain tumor histology has the potential to predict brain tumor behavior. Craniospinal MRI investigation is essential to assess the neuraxis and to check for tumor spread and drop metastasis at diagnosis.33 Different studies have described the significant role of diffusion MRI as a prognostic indicator and a potential biomarker of tumor response to treatment. Diffusion-weighted imaging,

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a technique based on the rate of water mobility in tissue, is described by a variable called the apparent diffusion constant (ADC). Diffusion-weighted imaging has proven sensitivity to cellular status, density, and tissue organization, distinguishing between cytotoxic and vasogenic edema. Increased water tissue in edema will increase the values of ADC, and high cell density zones in tumors will decrease the ADC.34,​35 Diffusion tensor imaging (DTI), a technique that detects anisotropic diffusion, provides information on the delineation of the major fiber tracts in the brainstem.35 Clinical application focuses on using DTI maps and tractography to localize white matter fiber tracts that are crucial for language, motion, and vision.35,​36 This imaging modality characterizes tumors and assesses perilesional involvement of white matter tracts using ADC and fractional anisotropy to evaluate treatment response and subsequent disease progression.35 Reports have described the application of DTI for early detection of DIPG.37,​38 Techniques such as DTI facilitate early detection of the tumor extension before it becomes apparent on conventional MRI. Susceptibility-weighted imaging is the modality of choice to identify tumor bleeding or calcification.33 Other imagining modalities include perfusion MRI, magnetic resonance spectroscopy (MRS), and positron emission tomography (PET). MRS improves the diagnostic capability of routine MRI studies, providing a means to differentiate between neoplastic and nonneoplastic lesions.39 Proton MRS provides important information on tumor activity and tissue characteristics.40 This imaging modality has been used as a reliable indicator of response to treatment and as a predictor of survival.

■■ Differential Diagnosis Nonneoplastic lesions affecting the brainstem include vascular malformations, hemangioblastomas, epidermoid cysts, granulomas, histiocytic lesions, demyelinating diseases, infectious etiologies, and multiple sclerosis.39 The differential diagnosis of posterior fossa tumors affecting the brainstem includes embryonal lesions, ependymomas, atypical teratoid-rhabdoid tumors, radiation-induced neoplasms, and gangliogliomas (Fig. 14.2).

Role of Biopsy The role of biopsy in the diagnosis of brainstem tumors is controversial. A complete patient investigation that includes clinical history, laboratory tests, and MRI studies can provide useful information about brainstem lesions. However, these neoplasms often have various histopathologic entities with heterogeneous clinical, biological, and radiologic features. The sensitivity and specificity of MRI for diagnosing low-grade gliomas have been reported to be as low as 63% and 47%, respectively, whereas for high-grade lesions, sensitivity and specificity have been 58% and 62%, respectively.41 Stereotactic biopsy provides diagnostic success in approximately 96% of cases.42 The technique is considered a reliable tool in tumor diagnosis, as it provides a means to perform further molecular and genetic analyses. However, the procedure is not risk-free, as it is associated with overall morbidity and mortality of approximately 7.8% and 0.9%, respectively. There is also a risk of sampling error in brainstem stereotactic biopsy.42

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V  Comprehensive Management of Tumors of the Brainstem, Thalamus, and Pineal Region Fig. 14.2  A 6-year-old girl presented with progressive gait ataxia due to a posterior fossa ganglioglioma. (a) Axial T1-weighted magnetic resonance image  (MRI) with contrast showing isointense non-enhancing left periventricular lesion compressing the fourth ventricle. (b) Axial T2-weighted MRI showing a cerebellar isointense lesion with perilesional edema. (c) Midsagittal T1-weighted MRI showing an isointense cerebellar lesion.

■■ Classification and Management Midbrain Tumors Tumors affecting the midbrain usually arise from the tectum, tegmentum, and periaqueductal regions, and they are rarely located in the ventral region of the midbrain. Midbrain neoplasms are often hamartomas of the tectal plate or focal indolent tumors. Regardless of their histologic features, these lesions are usually accompanied by late-onset aqueductal stenosis and symptoms of increased ICP.43,​44 Historically, early deaths were commonly related to uncontrolled hydrocephalus and surgical complications rather than tumor progression. Advances in imaging technology have provided information that enables physicians to diagnose midbrain lesions and manage them promptly. Tectal plate gliomas are rare dorsal midbrain lesions, accounting for 5% of brainstem tumors and 20% of midbrain neoplasms.45 These lesions are often accompanied by noncommunicating hydrocephalus secondary to enlargement of the tectal plate and obstruction of the aqueduct of Sylvius (Fig. 14.3).

Clinical Presentation Approximately 50 to 70% of children with tectal lesions typically present with symptoms of increased ICP, often without associated brainstem signs. The median age of clinical onset ranges from 9 to 10 years.43,​46 Common symptoms include headache, nausea, vomiting, and visual impairment. Bilateral papilledema is present in 25 to 34% of patients.47,​48 Some infants may present with macrocephaly as a result of hydrocephalus. Other associated symptoms include pyramidal symptoms, gait ataxia, nystagmus, Parinaud syndrome, abducens nerve  (CN VI) palsy, and diplopia. Cognitive symptoms associated with tectal gliomas include memory deficits, decline in academic performance, personality change, and developmental delay. Hydrocephalus can precipitate precocious puberty and slow growth.45 A clinical history of NF1 has been reported in association with tectal lesions.48 Tumors in the tegmentum account for 33 to 57% of midbrain neoplasms.11,​30 Patients usually present with brainstem symptoms caused by the compression of long fiber tracts or CN nuclei. Such symptoms include hemiparesis, hemihypesthesia, headache, ataxia, and multiple cranial palsies. Signs and symptoms of increased ICP can be present; however, they do not occur as frequently as in tectal tumors. Periaqueductal lesions, also known as pencil gliomas, constitute 13 to 23% of midbrain neoplasms.45 Children affected by periaqueductal lesions usually present with symptoms of increased ICP caused by aqueductal obstruction. Other associated clinical presentations include gait ataxia, nystagmus, hemiparesis, and tremors.

Fig. 14.3  A 4-year-old child presented with noncommunicating hydrocephalus secondary to a tectal glioma obstructing the aqueduct of Sylvius (arrow). Midsagittal T1-weighted magnetic resonance image with contrast showing an isointense, nonenhanced tectal lesion and a posterior fossa arachnoid cyst.

Histology Tectal brainstem tumors are generally low-grade astrocytomas, with fibrillary and pilocytic astrocytomas accounting for 21% and 36% of cases, respectively.43 Other benign lesions include hamartomas, gangliogliomas, and oligoastrocytomas. Highgrade tumors in the tectal plate are rare, but lesions with anaplastic features and poor outcomes can occur. Tegmental tumors can be low-grade or high-grade gliomas.4,​30 Low-grade neoplasms are often nonpilocytic lesions. Neoplasms of the tegmentum are usually more malignant than neoplasms in other regions of the midbrain. High-grade astrocytomas account for 75% of cases. Histologically, fibrillary astrocytomas, which are usually low-grade lesions, are the most commonly reported periaqueductal neoplasm. Other periaqueductal tumors include ependymomas, subependymomas, and oligodendrogliomas.

Imaging Focal tectal tumors are often well-defined ellipsoid neoplasms without perilesional edema. On CTs, these neoplasms are isodense and calcifications may be observed over time. Tectal gliomas are usually hypointense or isointense on T1-weighted MRI and hyperintense on proton density–weighted and T2-weighted MRI, with little or no contrast enhancement.45,​49 Tectal gliomas with atypical behavior or progression often present as large contrast-enhanced lesions with cystic degeneration greater than 10 cm3 in volume. Tegmental lesions show low signal intensity on T1-weighted MRI, high signal intensity on T2-weighted MRI, and a

14  Pediatric Brainstem Tumors heterogeneous pattern of contrast enhancement on MRI.50 These lesions can extend upward to the thalamus and downward to the pons, displacing the adjacent structures rather than infiltrating them. Cystic components are often observed in tegmental lesions.4 Periaqueductal tumors are usually not identified on CT and are typically isointense on both T1-weighted and T2-weighted MRI.50 These lesions show homogeneous contrast enhancement of a cord-like structure located in the aqueduct. Therefore, patients presenting with hydrocephalus with aqueduct obstruction should undergo contrast MRI.

Treatment In most cases, the management of midbrain lesions is conservative and the only required treatment is cerebrospinal fluid diversion by endoscopic third ventriculostomy or ventriculoperitoneal shunt. Several authors recommend endoscopic third ventriculostomy over ventriculoperitoneal shunt for the management of associated hydrocephalus, both initially and at recurrence.11,​44 Tumor biopsy is reserved for atypical cases at presentation and for patients with progressive or recurrent disease. Aggressive treatment, such as surgical resection and adjuvant therapy, is reserved for patients presenting with tumor progression or recurrence. However, neurologic deficits are not always reversed by aggressive treatment.44

Prognosis and Follow-up Overall, tectal gliomas have a relatively benign and indolent course, and patients have a good long-term prognosis. These lesions often remain stable in size for several years. However, tumor progression has been reported in approximately 25% of cases.45 Poor prognostic factors include contrast-enhanced lesions, tumor extension to the surrounding structures, and neurologic deficits at presentation. Correlation between size and outcome has been reported for tectal lesions, which can be classified as follows44:  1. Small lesions (2–4 cm3): this group comprises more than 50% of patients, and tumors likely represent hamartomas. Patients should remain under surveillance for a mean period of 3.5 years.  2. Medium-sized lesions (4–10 cm3): this group constitutes approximately 27% of cases, and patients should remain under surveillance for approximately 7 years.  3. Large lesions (>10 cm3): tumors larger than 10 cm3 represent 20% of cases, High-grade astrocytomas are usually diagnosed in this population, and aggressive treatment is often required.

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Pons DIPGs are the most common and aggressive subtype of brainstem tumors, accounting for 10 to 15% of pediatric CNS lesions.51,​52 These neoplasms are highly infiltrative astrocytic lesions, representing 85% of all brainstem gliomas. DIPGs affect 200 to 300 children between the ages of 5 and 10 years annually in the United States.33,​53 The median overall survival is approximately 1 year, despite the use of adjuvant therapy.53,​54,​55 DIPGs are biologically heterogeneous lesions. Although these are high-grade tumors, they are distinct from adult high-grade gliomas and pediatric nonbrainstem gliomas. Recent genomic studies in pediatric DIPGs identified new oncogenic mutations that connect tumorigenesis and chromatin regulators, differentiating them from other high-grade lesions. For example, none of the DIPGs show amplification of EGFR (epidermal growth factor receptor), which is one of the most frequently amplified genes in adult high-grade gliomas.2 Several investigators postulate that DIPGs result from disruptions of postnatal neurodevelopmental processes, because these neoplasms that are located in the ventral pons mainly affect children.56,​57,​58

Clinical Presentation The most typical clinical presentation is in a previously healthy child with a short history of progressive neurologic symptoms, such as diplopia, asymmetric smile, loss of balance, decreased strength, and difficulty walking. Clinical findings include CN impairment, ataxia, and long tract signs, such as clonus and hyperreflexia. Pontine expansion may cause signs or symptoms of increased ICP in patients with DIPGs.53,​59 Clinical diagnostic criteria for DIPGs are neurologic symptoms that are less than 6 months in duration, at least two or three signs of brainstem dysfunction, and diffuse enlargement of the pons greater than 50%.51

Differential Diagnosis Although the diagnosis of DIPGs can be made on the basis of clinical and imaging findings, it may be difficult to distinguish them from other pontine gliomas, such as embryonal tumors (previously known as primitive neuroectodermal tumors).60,​61 Embryonal neoplasms are often located in the cerebellar vermis; however, pontine lesions have been reported, particularly in children younger than 3 years.62 Nonneoplastic tumors in the pons include demyelinating and vascular malformations.51,​63

Histology DIPGs range from WHO grade II to IV; however, tumor grade does not affect prognosis in patients with these lesions (Fig. 14.4).64,​65,​66

Fig. 14.4  An 8-year-old boy with glioblastoma multiforme  (World Health Organization grade IV) of the pons with exophytic component presented with a 2-week history of gait ataxia, nausea, and vomiting. (a) Axial T2-weighted magnetic resonance image (MRI) demonstrating heterogeneous lesion within the pons compressing the fourth ventricle. (b) Midsagittal T1-weighted MRI with contrast demonstrating pontine lesion with exophytic component protruding into the fourth ventricle. (c) Intraoperative view of the fourth ventricle showing exophytic component of the pontine high-grade lesion.

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V  Comprehensive Management of Tumors of the Brainstem, Thalamus, and Pineal Region

Neoplastic cells are predominantly fibrillary. Overall, DIPGs are infiltrative tumors with parenchymal distortion and expansion.53 Leptomeningeal dissemination at presentation confers shorter overall survival and has been observed in 20% of patients.67

Molecular Pathways Biopsy and autopsy specimens have provided a means to understand the biology of DIPGs and to acknowledge them as a separate entity from both adult and pediatric supratentorial high-grade tumors. The revised 2016 WHO classification of CNS neoplasms introduced molecular markers as new tools in the armamentarium of tumor diagnosis.68,​69 According to the revised classification, most DIPGs are “diffuse midline glioma, H3 K27M–mutant,” which is a new definition for midline tumors in the brainstem, thalamus, and spinal cord.69 DIPGs can be classified into three groups: MYCN, silent, and H3 K27M subtypes.70  This classification system characterizes DIPGs with respect to differential profile expression, methylation, copy number alteration, and mutations.70 Tumors in the MYCN group lack recurrent mutations characterized by hypermethylation and high-grade histology. Therapies targeting histone modifications would not be effective in this particular group.70  The silent group includes low-grade DIPGs. Children in this group are usually younger than those in the other two groups, and overexpression of WNT pathway genes is often observed. DIPGs within the MYCN group or the silent group do not show amplification of the receptor tyrosine kinase gene; therefore, inhibitors targeting tyrosine kinases may be less effective in patients in these groups.70 Tumors in the H3 K27M group have highly mutated profiles in either histone H3.3 or histone H3.1 and also have unstable genomes.56,​68,​69,​71,​72,​73,​74 Characteristically, most H3 K27M–mutant neoplasms are high-grade gliomas, such as anaplastic astrocytoma or glioblastoma, which confers a poor prognosis. According to several investigators, histone H3 K27M mutations arise first, followed by specific alterations in TP53 cell-cycle (TP53/PPM1D) or growth factor pathways (ACVR1/PIK3R1).70 Mutations in the TP53 gene account for 68% of patients. Given the heterogeneity of genetic alterations found in the H3 K27M group, multimodality therapy may be required to target mutations in histones or histone modifiers.70 The most recurrently mutated gene in DIPG after H3F3A and TP53 is ACVR1. DIPGs harboring ACVR1 mutations affect younger children, predominantly girls, and pediatric patients with these tumors have a longer overall survival rate than patients with wild-type tumors. The ACVR1 mutation, observed in 20 to 30% of DIPG samples, is strongly associated with H3.1

K27M.68,​70,​74 Somatic mutations in DIPGs are similar to those in patients with fibrodysplasia ossificans progressive, an autosomal dominant disorder of skeletal malformation caused by sporadic mutations in ACVR1.75 Although all mutation sites recently described in DIPGs are seen in fibrodysplasia ossificans progressiva, the genetic syndrome is not associated with cancer predisposition. Some investigators suggest that DIPGs originate from the disruption of neurodevelopmental processes, including neural embryogenesis and oligodendrogenesis.56,​76 This hypothesis is supported by the overexpression of specific factors, including Pair Box 3 (PAX3), SOX2, Nestin, and OLIG2. PAX3 is observed in 40% of brainstem gliomas and is exclusive of H3.1 K27M and ACVR1 mutations.76 Some investigators have correlated the high expression of SOX2 and Nestin with a poor prognosis.76,​77 Other mutations observed in DIPGs include the amplification of platelet-derived growth factor receptor in 36% of patients.78 The tyrosine kinase receptor EGFR, frequently overexpressed in malignant gliomas, has been reported in approximately 66% of patients with DIPGs.76 Mutations in the alpha-thalassemia/mental retardation syndrome X-linked gene (ATRX) are frequently found in older children with DIPG.56

Imaging DIPGs are often hypodense or isodense on CT.50 These lesions are infiltrative and expansive on MRI, often involving more than 50% of the axial diameter of the pons.53 They are hypointense or isointense on T1-weighted MRI and hyperintense on T2-weighted fluid-attenuated inversion recovery MRI, and they show minimal to no contrast enhancement (Fig. 14.5).32,​48,​59 Engulfment or displacement of the basilar artery by the engorged pons is a common finding. Tumor infiltration into the midbrain and middle cerebellar peduncles is often observed. Some investigators consider a clear pontomedullary demarcation on sagittal imaging as a classical finding of DIPGs.51 Calcification and hemorrhage are rare findings.50 Areas of necrosis with ring-enhancement and exophytic components can be observed in some cases. Although leptomeningeal dissemination may occur, it is uncommon at presentation. Diffusion imaging techniques provide significant information on tissue characterization, tumor cellularity, grading, and response to treatment. The baseline ADC values are increased and fractional anisotropy is reduced in DIPGs.18,​32 PET using 18 F-labeled fludeoxyglucose  (18F-FDG) fused with MRI can be helpful in demonstrating hypermetabolic activity of brainstem lesions. In these cases, high FDG uptake correlates with tumor malignancy and shorter overall survival.31,​32,​46,​50,​79,​80,​81 Fig. 14.5  A 7-year-old boy with a 3-week history of diplopia and loss of balance. (a) Axial T1-weighted magnetic resonance image  (MRI) with contrast demonstrating diffuse enlargement of the pons and isointense nonenhanced lesion suggestive of diffuse intrinsic pontine glioma. (b) Axial T2-weighted MRI demonstrating an isointense lesion with compression of the fourth ventricle. (c) Midsagittal T1-weighted MRI demonstrating an isointense lesion with more than 50% diffuse enlargement of the pons.

14  Pediatric Brainstem Tumors Advanced imaging techniques using MRS, including single and multivoxel spectroscopy, are promising tools to assess therapy management response and potentially predict survival.82 Some investigators emphasize the benefits of using DTI and white matter fiber tracking to differentiate DIPGs from demyelinating lesions.63 White matter fibers are often distorted and pushed laterally by the tumor.63 Although pyramidal fibers can be truncated, the white matter fibers remain in their anatomical position in demyelinating diseases.63

Tumor Biopsy The Consensus Conference on Pediatric Neurosurgery held in Paris, France, in 2011  (CPN2011) provided recommendations for optimal management of pediatric DIPGs.14 According to the CPN2011’s consensus statements, biopsy of DIPGs should be considered as follows: •• Typical DIPG on MRI investigation: the procedure is justified if the patient is enrolled in an ethically approved clinical study and tissue sample will be used to investigate the role of tumor markers after treatment selection or molecular tumor grading. •• Atypical DIPG on MRI investigation: (a) the biopsy is indicated to confirm the diagnosis and guide therapy; (b) an atypical pontine region tumor would be considered separately from classic DIPG for treatment or research purposes.

Treatment Given the anatomical location of DIPGs, surgical resection is not possible. Radiotherapy is considered the standard palliative treatment, with a total dose of 54 to 60 Gy for 6 weeks.51,​56 Although radiation therapy provides transient improvement of neurologic function and may delay time to progression, the overall survival of patients with DIPGs is less than 10 months.28,​56,​83 Hyperfractionated radiotherapy has not produced better results than conventional radiation. In addition, higher radiation dose has not improved survival. Several prospective clinical trials investigating the benefits of chemotherapy or biological therapy have failed to improve the outcome associated with DIPGs  (ClinicalTrials.gov NCT00418327, NCT00001502, NCT00275002). Alkylating agents (e.g., carboplatin, cisplatin, and temozolomide), either alone or in combination with radiotherapy, have not been shown to increase the survival rate of patients. Immunotherapy is a promising tool for targeting

Fig. 14.6  A 10-year-old boy with a progressive history of hemiparesis and ataxia. (a) Midsagittal fat-saturated T1-weighted magnetic resonance image (MRI) with contrast demonstrating a well-defined contrast-enhanced lesion in the cervicomedullary junction. (b) Coronal T1-weighted MRI

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glioma-associated antigen epitopes highly expressed in pediatric gliomas, including those of interleukin-13 receptor subunit, alpha 2 (IL13RA2), EPHA2, and survivin.51,​84 In particular, IL13RA2 is being developed as a potential drug target for DIPG, and reliable detection of the protein will be crucial for the success of future clinical trials.84 Resistance to therapy is another challenge in the treatment of DIPGs. For years, pediatric tumors have been treated with chemotherapeutic agents that target genetic alterations of adult lesions. Molecular profiling analysis indicates that pediatric neoplasms are biologically distinct from adult lesions. Obtaining a better understanding of tumor biology will ultimately provide a means to effectively treat these lesions using individualized therapy.

Prognosis and Follow-up Younger children seem to have a better survival rate than older children.55,​66 Children usually respond positively to initial radiation.85 However, disease progression may occur as early as 5 months after radiotherapy. In the event of recurrence, radiation is recommended. DIPG metastases, including isolated parenchymal disease, leptomeningeal, and subependymal dissemination, have been reported in 17% of patients with DIPGs.67,​86,​87 After recurrence, the average life span is approximately 3 months. Treatment monitoring has led to an increased awareness of the effects of radiotherapy on the brain parenchyma. Therapyinduced necrosis and related clinical symptoms can resemble tumor recurrence; thus, distinguishing between the two conditions is crucial.88 Pseudoprogression, defined as any early transient radiologic changes occurring after treatment, can simulate tumor progression. Pseudoprogression is a local inflammatory reaction that occurs in response to radiation, which might be enhanced by temozolomide.89 The patient may or may not have symptoms that worsen. Carceller et al90 reported pseudoprogression in 6 of 44 patients with DIPG, for a rate of only 13.6%. Histologic study of biopsy samples obtained at recurrence is the gold standard method to differentiate tumor recurrence from radiation necrosis. However, reoperation is uncommon for this lesion. Functional imaging techniques, such as diffusion-weighted MRI, perfusion MRI, MRS, and PET CT, are the most promising tools to distinguish between recurrence and pseudoprogression.

Medulla Oblongata Tumors in the medulla oblongata include pontomedullary, medullary, and cervicomedullary lesions. Cervicomedullary gliomas are rare heterogeneous lesions, affecting the medulla and the upper cervical spine  (Fig. 14.6).6,​91 These tumors have been

with contrast demonstrating a midline cervicomedullary lesion. (c) Intraoperative view showing bulging of the cervicomedullary junction due to tumor mass effect. (d) Intraoperative postresection view of the low-grade cervicomedullary glioma.

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reported as intramedullary neoplasms in the cervical region with upper extension into the caudal medulla.92 Cervicomedullary lesions are often low-grade noninfiltrative gliomas, affecting children between the ages of 6 and 8 years.

recurrence and can be associated with a poor outcome.91,​93 The risk factors for sagittal deformity, a potential complication after surgery, include young age at surgery, the presence of a syrinx, multilevel surgery, and preoperative deformity.91

Clinical Presentation

■■ Conclusions

Clinical presentation is usually associated with lower brainstem impairment and myelopathy. Children with lower brainstem dysfunction will present with nausea and vomiting, dysphonia, dysarthria, or dysphagia. Failure to thrive is a common manifestation. Other related symptoms include sleep apnea, medullary syndrome, and head tilt. Children with myelopathy may also present with lower CN dysfunction and pyramidal tract signs, including hemiparesis (52%), ataxia (48%), and neuropathies (45%).91

Histology Low-grade gliomas, including astrocytomas, gangliogliomas, and oligoastrocytomas, account for approximately 84% of cases.91,​93 Although high-grade lesions are less frequent, anaplastic ependymoma and glioblastoma have been reported in 16% of patients.

Imaging Cervicomedullary lesions are hypointense or isointense on T1-weighted MRI and hyperintense on T2-weighted MRI, and they show contrast enhancement on MRI.11,​50 Solid or cystic nodules are common findings. Postoperative deficits have been observed more commonly in patients whose tumor–white matter interface was undefined on preoperative MRI. DTI for fiber tractography may help to differentiate lesions from edema and normal brainstem, and therefore provide information for surgical planning.

Despite remarkable genomic discoveries, therapeutic progress for some brainstem lesions has lagged behind treatments for lesions in other sites. Potential mechanisms of therapy failure include drug delivery, target selection, target-drug pairing, and secondary resistance. For years, drug selection to target pediatric brainstem tumors has been based on studies conducted in adults with highgrade gliomas. Pediatric DIPGs exhibit a pattern of secreted proteins detectable in cerebrospinal fluid that is distinct from those of supratentorial gliomas, thus suggesting a unique pathway of pediatric gliomagenesis. A novel approach to improve drug penetration is the direct convection-enhanced delivery of antineoplastic agents to the tumor. Targeted immunotherapies have the potential to improve the outcome of patients with DIPG, thus minimizing treatment-related complications and expediting patient survival. Current large-scale genomic profiling is providing the basis for new insights in understanding and classifying pediatric brain tumors. High-resolution genome sequencing will continue to generate invaluable genetic and epigenetic data to classify lesions by subtype, to improve risk stratification, and to identify specific targets. Such a strategy will provide a means for the development of individualized therapies. Further studies on genetic and molecular analyses of brainstem neoplasms will elucidate the behavior of these lesions with respect to malignancy, recurrence, and resistance to therapy. Consequently, new therapeutic strategies will be developed to effectively target tumor receptors, thus optimizing overall survival and quality of life. References

Treatment The treatment of cervicomedullary tumors is often multimodal, including surgery and adjuvant therapy.91 Surgical resection provides a means to make the diagnosis, to decompress adjacent structures, and to treat associated obstructive hydrocephalus or syrinx. Intraoperative MRI, ultrasound, and neurophysiologic monitoring are important considerations in surgical planning to achieve maximal safe resection.94 A clear tumor–white matter interface is usually seen in lowgrade lesions during surgery, thus facilitating surgical resection with a low risk of neurologic injury. In high-grade gliomas, such an interface is not well defined, which precludes aggressive operative resection. If the preoperative MRI shows tumor infiltration or unclear borders, open biopsy is recommended, followed by adjuvant therapy. Chemotherapy should be considered in conjunction with surgery or as a salvage treatment for recurrent or progressive disease, especially in younger children for whom radiotherapy is not an option.91

Clinical Outcome The overall survival of patients with cervicomedullary lesions ranges from 88 to 100%.91,​93 Tumor progression is observed in 45% of patients, for whom further treatment is required.91 High-grade lesions have been considered the sole predictor of

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82. Steffen-Smith EA, Venzon DJ, Bent RS, Hipp SJ, Warren KE. Single- and multivoxel proton spectroscopy in pediatric patients with diffuse intrinsic pontine glioma. Int J Radiat Oncol Biol Phys 2012;84(3):774–779 83. Jansen MH, van Vuurden DG, Vandertop WP, Kaspers GJ. Diffuse intrinsic pontine gliomas: a systematic update on clinical trials and biology. Cancer Treat Rev 2012;38(1):27–35 84. Joshi BH, Puri RA, Leland P, et al; US Pediatric Brain Tumor Consortium. Identification of interleukin-13 receptor alpha2 chain overexpression in situ in high-grade diffusely infiltrative pediatric brainstem glioma. Neuro Oncol 2008;10(3):265–274 85. Fontanilla HP, Pinnix CC, Ketonen LM, et al. Palliative reirradiation for progressive diffuse intrinsic pontine glioma. Am J Clin Oncol 2012;35(1):51–57 86. Gururangan S, McLaughlin CA, Brashears J, et al. Incidence and patterns of neuraxis metastases in children with diffuse pontine glioma. J Neurooncol 2006;77(2):207–212 87. Donahue B, Allen J, Siffert J, Rosovsky M, Pinto R. Patterns of recurrence in brain stem gliomas: evidence for craniospinal dissemination. Int J Radiat Oncol Biol Phys 1998;40(3):677–680 88. Verma N, Cowperthwaite MC, Burnett MG, Markey MK. Differentiating tumor recurrence from treatment necrosis: a review of neuro-oncologic imaging strategies. Neuro Oncol 2013;15(5):515–534 89. Brandsma D, Stalpers L, Taal W, Sminia P, van den Bent MJ. Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol 2008;9(5):453–461 90. Carceller F, Fowkes LA, Khabra K, et al. Pseudoprogression in children, adolescents and young adults with non-brainstem high grade glioma and diffuse intrinsic pontine glioma. J Neurooncol 2016;129(1):109–121 91. McAbee JH, Modica J, Thompson CJ, et al. Cervicomedullary tumors in children. J Neurosurg Pediatr 2015;16(4):357–366 92. Di Maio S, Gul SM, Cochrane DD, Hendson G, Sargent MA, Steinbok P. Clinical, radiologic and pathologic features and outcome following surgery for cervicomedullary gliomas in children. Childs Nerv Syst 2009;25(11):1401–1410 93. Robertson PL, Allen JC, Abbott IR, Miller DC, Fidel J, Epstein FJ. Cervicomedullary tumors in children: a distinct subset of brainstem gliomas. Neurology 1994;44(10):1798–1803 94. Cheng JS, Ivan ME, Stapleton CJ, Quiñones-Hinojosa A, Gupta N, Auguste KI. Intraoperative changes in transcranial motor evoked potentials and somatosensory evoked potentials predicting outcome in children with intramedullary spinal cord tumors. J Neurosurg Pediatr 2014;13(6):591–599

15

Tumors of the Thalamus

Ziev B. Moses, Gabriel N. Friedman, Muhammad M. Abd-El-Barr, and E. Antonio Chiocca

Abstract

Tumors of the thalamus represent a rare yet heterogeneous group of neoplasms usually found in the pediatric population. Although outcomes are generally positive in the pediatric population because most tumors are low grade, outcomes in adults mirror the often high-grade equivalents in the lobar region. Most thalamic tumors are of glial origin, but there are a variety of other primary thalamic entities. In light of the central location of the thalamus, patients with neoplasms in this region often present with signs and symptoms such as elevated intracranial pressure, ocular disturbances, and hemiparesis. Patients being treated for thalamic tumors warrant a thorough perioperative evaluation, including imaging and assessment for hydrocephalus. The deep location of the thalamus and its interface with critical neurovascular structures have traditionally made surgery in this region prohibitively challenging. However, various surgical approaches currently exist for accessing thalamic tumors, and with modern technical advancements, surgery has become the mainstay of treatment for most thalamic tumors. Surgical adjuncts, including intraoperative navigation, ultrasound, and neurophysiologic monitoring, have all contributed to acceptable safety levels. The pathobiology of thalamic tumors often mirrors that of their counterparts in the lobar region; thus, chemoradiotherapy schedules are often adopted, as appropriate. Surgical innovations, combined with adjuvant measures when necessary, are associated with increased survival rates. Keywords:  glioma, pediatric tumors, surgical approaches, thalamic tumors

■■ Pathophysiology, Incidence, Epidemiology, and Natural History of Thalamic Tumors The vast majority of primary thalamic tumors are glial in origin.1 In adults, high-grade astrocytic tumors represent nearly onehalf of thalamic gliomas, with a large case series demonstrating roughly similar proportions of anaplastic astrocytoma and glioblastoma.2 It was previously believed that high-grade tumors were much less common among children (comprising only 10% of all pediatric tumors); reexamination has suggested that highgrade tumors may be just as prevalent in the pediatric population.3 Thalamic tumors in children have been categorized into three growth patterns: unilateral tumors, which have their epicenter within the thalamus; thalamopeduncular tumors, which originate from the interface between the thalamus and cerebral peduncle; and bilateral tumors, which are distinct from infiltrative unilateral tumors and are associated with a poor prognosis.4,​5 Of tumors with these three growth patterns, unilateral tumors

are the most common and have been reported to comprise approximately 80% of all thalamic tumors.4,​6 In terms of molecular pathology, immunohistochemistry procedures performed on thalamic gliomas have been demonstrated to be positive for the presence of the following proteins: p53, O-6-methylguanine-DNA methyltransferase (MGMT), phosphatase and tensin homolog (PTEN), epidermal growth factor receptor (EGFR), and oligodendrocyte lineage transcription factor 2 (Oligo2).7 Indeed, changes have been made in the classification of central nervous system tumors with the 2016 publication of the World Health Organization update on central nervous system tumors.8 This release marks a shift toward incorporating insights gained in molecular biology into the classification of central nervous system tumors. One particular change in diagnosis pertinent to thalamic gliomas is the use of the histone H3 lysine 27-to-methionine (K27M) mutation, which characterizes a new entity known as diffuse midline glioma, an H3 K27M-mutant.8 This mutation has been associated with midline tumors, including both thalamic and brainstem gliomas, and it has not been associated with a worse prognosis for patients with tumors of the thalamus than for patients with tumors in the brainstem.9 Less than 20% of primary thalamic tumors are germinomas, gangliogliomas, oligodendrogliomas, dysembryoplastic neuroepithelial tumors, and neurocytomas.10 Thalamic tumors are a relatively rare subset of central nervous system tumors more commonly found in the pediatric population. They comprise approximately 4% of the central nervous system tumors found in children and approximately 1% of those found in adults.1,​6,​11,​12 Epidemiologic data are scarce, given the rarity of these tumors and their tendency to be categorized along with other “central” tumors, such as those in the brainstem, hypothalamus, and corpus callosum. Patients with untreated thalamic tumors generally die as a result of tumor progression or complications from obstructive hydrocephalus, whereas patients with thalamic tumors who undergo ventriculoperitoneal cerebrospinal fluid diversion procedures have been shown to have longer survival.7 Patients with tumor progression can have local extension into the brainstem, basal ganglia, internal capsule, or contralateral thalamus, in addition to distant progression elsewhere.7 Factors associated with a poorer prognosis include short symptom duration, highgrade histologic features, tumor volume greater than 30 mL, and limited extent of resection.4

■■ Clinical Presentation The mean age of adult patients who presented with thalamic tumors in one series was 30 to 33 years, whereas in an exclusively pediatric series, the mean age at presentation was 8 to 10 years.2,​10,​13

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Patients with thalamic tumors can present with symptoms of short duration and a wide variety of manifestations, given the diverse functions of the thalamus and its close proximity to nearby structures in the diencephalon.14 In one series of 57 patients who received a diagnosis of infiltrative thalamic astrocytoma, 34 (60%) presented with headache, 30 (53%) with hemiparesis or hemiplegia, 22 (39%) with papilledema, and 17 (30%) each with mental status changes and abnormal reflexes.15 The most common clinical features of thalamic tumors include symptoms related to increased intracranial pressure (ICP)  (e.g., frontal headache, lethargy, and vomiting) and signs of papilledema on fundoscopic examination; in infants, bulging fontanelles and split sutures are common. Elevated ICP can be caused by the presence of a space-occupying lesion or by obstructive hydrocephalus from intraventricular tumor extension. A tumor of the dorsomedial thalamus often results in noncommunicating hydrocephalus because of its proximity to the ventricles. In contrast, tumors of the ventrolateral thalamus, which includes afferent sensory tracts, can lead to contralateral sensory deficits and to hemiparesis when nearby capsular fibers of the corticospinal tract are affected.3 Similarly, inferior compression of the pyramidal tracts of the midbrain can also produce motor deficits.10 Several other less common signs have also been associated with the onset of thalamic tumors. Ocular manifestations can include visual loss, palsies of the oculomotor nerve  (cranial nerve [CN] III) and the trochlear nerve (CN IV), mydriasis, convergence impairment, and hemianopia due to optic tract compression.3,​11 In light of the role of the thalamus in motor control, movement disorders such as dystonia and spasticity are surprisingly rare.1 Seizures can occur with wide variability, affecting 7 to 35% of patients who have thalamic tumors.7,​10 Thalamic tumors that extend into the hypothalamus can lead to menstrual irregularities in addition to other endocrinopathies.3 The classic thalamic pain syndrome (Dejerine–Roussy syndrome), which includes contralateral motor and sensory losses, ataxia, and pain, is quite rare as a presenting set of symptoms for patients with these tumors. However, when the symptoms do occur, they are believed to be caused by involvement of thalamocortical fibers within the lateral nuclei.10,​13

■■ Perioperative Evaluation As stated previously, the most common presentations for patients with thalamic tumors are symptoms of increased ICP and motor and sensory deficits.7 Thus, it is imperative to obtain a comprehensive history from patients who may have a thalamic tumor and to conduct a comprehensive physical examination. Pertinent medical history includes any history of headaches, nausea, or vomiting. It is also important to ask for any family history of brain tumors, as patients with familial diseases, such as neurofibromatosis 1, have been shown to have a predilection for midline tumors involving the basal ganglia and thalamus.16,​17 The physical examination should include a careful examination of the CNs, noting any false localizing signs such as dysfunction of the abducens nerve (CN VI), which is a well-known sign of increased ICP. Ophthalmologic evaluation is also crucial for patients who are thought to have increased ICP. Patients with evidence of increased ICP and ventriculomegaly require cerebrospinal fluid shunting. For most unilateral thalamic tumors, shunt placement should be done on the contralateral side of the

tumor to avoid hemorrhages.7 The endoscopic biopsy of lesions, combined with endoscopic third ventriculostomy, may be a good method to temporize while obtaining tissue specimens in cases in which the diagnosis is not clear.18,​19 Also, one must take note of any motor or sensory dysfunction, as either can be an indication of the proximity of the tumor to the corticospinal pathway or an indication of the infiltrative nature of the tumor. Detailed intracranial imaging is required in the work-up of patients who may have thalamic tumors. Because many of these patients present with symptoms of increased ICP, imaging of the ventricular system can be just as important as imaging of the tumor to assess for hydrocephalus. Magnetic resonance imaging (MRI) is the modality of choice for imaging thalamic tumors. The use of contrast is necessary, as enhancement can indicate the type of pathology and, for glial tumors, can provide a possible initial indication of the histopathologic grade.20,​21 In their series of 33 adult patients with unilateral thalamic gliomas, Zhang et al7 found that more than 90% of tumors had enhancement with contrast. For those tumors that do not enhance with contrast, evidence exists that fluid-attenuated inversion recovery (FLAIR) MRI may be useful in determining the extent of a tumor.22 Kurian et al23 report that neuroradiologic imaging may result in an underestimation of the grade found on histopathologic assessment of thalamic gliomas. Furthermore, interest in using diffusion tensor imaging has increased for the purpose of understanding the relationship between the corticospinal pathway and thalamic tumors, especially those tumors of the thalamopeduncular type.24,​25 In addition to focusing on ventricular anatomy and tumor margins, one should assess the vascular anatomy when possible. For interhemispheric approaches, one must be cognizant of the bilateral anterior cerebral arteries. The thalamus receives most of its vascular supply from the posterior cerebral arteries.26 This blood supply requires the thalamus to be approached from above to limit having to deal with en passage vessels. The venous drainage is also important. During interhemispheric approaches, one must take note of superficial veins that drain into the superior sagittal sinus. Taking note of the deep drainage is particularly important in posterior approaches. Most of this information can be gleaned from the T2-weighted MRI. It has not been our practice to acquire specific vascular imaging, such as computed tomography angiograms of thalamic tumors, unless imaging shows the presence of multiple large vessels in the tumors, which is indicative of arterial or venous structures feeding the tumors or passing through them. Finally, it is important to consider the patient’s appropriateness for surgery. This process includes understanding coexisting comorbidities and other medical or surgical issues that may affect the outcomes of surgery. Our group has published quality measures on platelets, body mass index, and anticoagulation that are appropriate for surgery and how these may generally affect outcomes in patients with brain tumors.27,​28,​29

■■ Surgical and Chemoradiotherapy Approaches Controversy exists regarding the optimal treatment approaches for thalamic tumors. Past reports have advocated a conservative approach, usually involving biopsy or partial resection followed by chemoradiotherapy, because of the challenging anatomy and the morbidity and mortality associated with more invasive

15  Tumors of the Thalamus

Fig. 15.1  Axial T2-weighted fluid-attenuated inversion recovery magnetic resonance imaging [MRI]) demonstrating a pilocytic astrocytoma. A 17-year-old girl presented with a 2-year history of progressive right wrist weakness followed by right shoulder weakness.  (a) MRI demonstrated a complex cystic mass in the left thalamus with extension into the brainstem. The patient underwent microsurgical resection via an anterior interhemispheric transcallosal approach.  (b) Postoperative MRI demonstrated no residual tumor. The patient did not receive adjuvant therapy, and repeat imaging at 1-year follow-up (not shown) indicated no evidence of recurrence.

techniques.30 However, improvements in surgical technique, coupled with advances in multimodal treatment options, have led to lower rates of morbidity and mortality and to a more aggressive surgical stance toward these tumors. Patients with circumscribed tumors without tumor infiltration, as seen on radiographic imaging, are the best candidates for total resection. Patients with these low-grade lesions are often among the youngest patients to receive a thalamic tumor diagnosis, and their neurologic deficits result from mass effect. The thalamus can be thought of as a tetrahedron with three free surfaces in contact with the ventricular system and a fourth inferior surface interfacing with critical neurovascular structures. In addition to stereotactic and endoscopic approaches, numerous surgical approaches have been described, including an anterior interhemispheric transcallosal approach, a transcortical transventricular approach, a contralateral infratentorial supracerebellar approach, a posterior interhemispheric parasplenial approach, and a transsylvian transinsular approach.2,​31,​32,​33 Choosing the proper approach depends on the origin and growth pattern of the tumor in relation to normal structures. Importantly, the surgeon’s level of comfort and experience with the chosen approach is a driving factor, because the location of a thalamic tumor will often allow the use of any one of several approaches. Other considerations include the presence of hydrocephalus, the proximity of the tumor to critical neurovascular structures, and the location of important white matter structures (e.g., the corticospinal tracts) identified on diffusion tensor imaging.24 Regardless of the approach, the surgeon should have a thorough understanding of the surgical anatomy that will be encountered and should pay particular attention to the vascular structures encountered in each approach. The anterior interhemispheric transcallosal approach is the most appropriate for resecting thalamic tumors with most of their mass protruding into the lateral ventricle34 or for resecting large tumors in the dominant hemisphere where speech is lateralized.35 The medial approach avoids the need for a cortical incision and reduces the potential for neurologic deficit caused by damage to eloquent cortex  (e.g., visual field cut or speech deficit). However, as with any interhemispheric approach, care is required in planning the craniotomy because draining veins to

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the superior sagittal sinus can be troublesome. During surgery, image guidance can be of particular help in planning a trajectory that avoids a difficult configuration. After lateral mobilization of the pericallosal arteries, a small callosal incision can be used to gain access to the lateral ventricle. However, special care must be taken not to overstretch the pericallosal arteries, which would limit a lateral exposure. In addition, care should be taken in manipulating the fornices, as patients can experience transient memory deficits after this approach. The transcortical transventricular approaches provide straightforward access to thalamic tumors. Various approaches through frontal, parieto-occipital, and temporal trajectories have been described, including a middle frontal gyrus approach for thalamic tumors that displace the posterior limb of the internal capsule in an anterolateral direction.32 Compared with interhemispheric approaches, all these approaches involve cortical incisions and carry an increased risk of postoperative seizure. In addition, in patients without hydrocephalus, the amount of cortex and the amount of white matter that must be traversed are increased, as are potential difficulties with retraction. However, compared with interhemispheric approaches, these approaches minimize the possibility of injuring a draining vein to the sagittal sinus. Like

Fig. 15.2  An 18-year-old man presented with a 2-week history of headaches.  (a) Axial T2-weighted fluid-attenuated inversion recovery  (FLAIR) magnetic resonance image (MRI) and (b) fast-spin echo MRI demonstrated a left thalamic tumor compressing and displacing the third ventricle. Note the dilated foramen of Monro and evidence of hydrocephalus. The patient underwent biopsy and minimal resection via a left parieto-occipital craniotomy. Pathologic diagnosis was grade II diffuse astrocytoma. The patient was treated with one cycle of carmustine followed by one cycle of carmustine, and radiotherapy. The patient’s postoperative course was complicated by recurrent hydrocephalus, requiring a right frontal bur hole and ventriculoperitoneal shunt placement.  Postoperative axial (c) T2-weighted FLAIR MRI and (d) T2-weighted fast spin echo MRI were obtained 10 months postoperatively. The patient died from tumor progression after 12 months.

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Fig. 15.3  A 39-year-old man presented with a 1-week history of headaches, confusion, and somnolence.  (a)  Coronal T1-weighted spoiled gradient magnetic resonance imaging (MRI) and (b) axial T2-weighted contrast-enhanced MRI demonstrated a 4-cm enhancing mass with its epicenter in the left posterior thalamus, producing mass effect on the left occipital horn, and a smaller left parietal lobe mass. The patient underwent a left parietal craniotomy for biopsy and microsurgical resection of the parietal mass. Pathologic diagnosis was glioblastoma multiforme. He was treated with adjuvant temozolomide and radiotherapy but ultimately had new left frontal and insular lesions and died 15 months after initial diagnosis.

image guidance, B-mode ultrasound can be a useful intraoperative aid to help locate the tumor and plan a corticectomy with the shortest route to the tumor. It also allows dynamic assessment of the extent of resection, whereas most image-guided approaches do not show real-time brain shift during tumor removal. Several approaches have been described for posterior thalamic tumors situated in the pulvinar region, including the posterior interhemispheric parasplenial approach described by Yaşargil,36 the occipital and parieto-occipital transventricular approaches, and an infratentorial supracerebellar approach. While the interhemispheric parasplenial approach allows wider access to the parapineal region and pulvinar thalami, the infratentorial supracerebellar approach allows the possibility of remaining extra-axial and thus incurring a smaller risk of damage to the optic radiation. However, this approach has a limited window between the veins of Rosenthal, and tumors situated more than 1 cm lateral from midline are harder to excise. For ventral posterior thalamic tumors, including those in close proximity to the insula, Yaşargil36 described a pterional transsylvian transinsular approach. This approach involves a full sylvian fissure opening and a small incision in the postcentral sulcus of the insular cortex. Thalamic tumors in this region often displace the internal capsule and basal ganglia anteriorly, thereby minimizing any damage to these delicate structures. Two other options for reaching these tumors are the transcortical transtemporal approach described by Villarejo et al37 and the inferior temporo-occipital junction approach advocated by Kelly.38 However, these latter approaches necessitate a larger cortical incision. Thus, for tumors situated near the insula, Ozek et al31 have advocated for the transinsular approach, which they believe is less invasive. When a total resection is not feasible or is ill advised, such as in a patient with bilateral thalamic gliomas, stereotactic biopsy or endoscopic approaches for cerebrospinal fluid diversion may be preferable. Even for unilateral thalamic tumors, the initial use of stereotactic biopsy for tumor diagnosis can help surgeons to counsel their patients on whether total resection is warranted. With the incorporation of new technologies such as robot-assisted stereotactic biopsy, patients can undergo

precisely targeted brain biopsy through a minimal incision.39 Another novel technique involves the use of microelectrode recordings to augment stereotactic biopsy.40 Preliminary work by Ohye et al41 showed an absence of electrical activity when the microelectrode penetrated the tumor, in contrast to the presence of electrical activity outside the tumor. In a series of 12 patients who underwent deep-seated biopsy  (including 7 with thalamic lesions), 100% of the patients received a diagnosis after the use of microelectrode recordings as an adjunct to image guidance.40 Another alternative approach is endoscopic biopsy, which can often be helpful for patients who also require treatment for hydrocephalus.42 For patients with posterior thalamic tumors causing compression of the posterior third ventricle or aqueduct that results in obstructive hydrocephalus, an endoscopic third ventriculostomy combined with endoscopic biopsy is a viable option if resection is not undertaken first. When thalamic tumors distort the normal ventricular anatomy, resulting in obstructive hydrocephalus, another option might be an endoscopic septum pellucidotomy. If these endoscopic mechanisms fail to divert cerebrospinal fluid, or if anatomical distortion is too great, surgeons can resort to traditional shunting. The need for adjuvant chemoradiotherapy is dictated by histologic analysis of the tumor tissue. Surgery remains the mainstay of treatment for low-grade tumors, and surveillance imaging can often be used to monitor residual tumors in many cases of focal masses with near-complete resection. In addition, surgery for select tumors such as pilocytic astrocytoma often results in long-term control or cure (Fig. 15.1). Indications for adjuvant chemoradiotherapy often parallel those for lobar astrocytomas, and additional treatment is reserved for recurrent or progressive inoperable disease. Chemotherapy is often used before conventional radiotherapy, particularly among children, for low-grade gliomas because of the unique location of thalamic tumors and their close association with vascular structures, the optic apparatus, and the hypothalamus (Fig. 15.2). When total resection is not possible for a pilocytic astrocytoma, stereotactic radiotherapy or stereotactic radiosurgery can be administered if progression occurs. In their series of 12 patients with progressive pilocytic astrocytomas, Lizarraga et al43 noted that 2 patients with thalamic tumors had no further progression after treatment at 36 months of follow-up. High-grade gliomas are treated with surgery followed by radiotherapy (Fig. 15.3). The typical regimen for adults with high-grade gliomas is fractionated focal therapy up to 60 Gy and concomitant temozolomide.44 For children older than 3 years, surgery followed by focal irradiation of the tumor bed (54–60 Gy delivered in daily fractions of 1.8–2.0 Gy) is also standard practice for supratentorial high-grade gliomas.45 Although chemotherapy is often used as an adjuvant treatment in pediatric patients, no consensus exists on a standard regimen. However, most patients are enrolled in a clinical trial, and new drug targets are being identified as a result of advances in molecular biology.

■■ Patient Outcomes Outcomes for patients with thalamic tumors depend on several factors, including age, histologic grade, and extent of resection (Table 15.1).2,4,6,11,14,38,46 Children with low-grade gliomas generally have the most favorable clinical outcomes, with a 5-year overall survival rate as high as 80%, compared with

15  Tumors of the Thalamus

223

Table 15.1  Outcomes and characteristics of patients with thalamic tumors*

Series

Pediatric patients

Adult patients

Cao et al, 20152

0

Cuccia & Monges, 199711

WHO grade High-grade tumors

Low-grade tumors

111

50

61

26

0

17

Puget et al, 20074

54

0

Steiger et al, 200046

5

Perioperative mortality (%)

Median survival rate (mo) High-grade tumors

Low-grade tumors

4.5

12

40

9

8

12

34

22

32

4

21

> 60

9

10

4

0

15

21

Baroncini et al, 16 200714

0

9

7

0

11

37

Kelly, 198938

15

57

40

32

6.9

5

41

Bilginer et al, 20146

45

0

14

31

NR

15

85

Abbreviations: NR, not reported; WHO, World Health Organization. *Adapted from Cao et al 2015.2

Fig. 15.4  A 72-year-old woman presented with a 2-week history of left face, arm, and leg weakness.  (a)  Axial T1-weighted contrast-enhanced magnetic resonance imaging  (MRI) and  (b)  axial T2-weighted MRI demonstrated a 5-cm partially enhancing mass centered in the right thalamus

with extension into the surrounding basal ganglia and right midbrain. (c,d) The patient underwent robotic-assisted stereotactic biopsy, and (e) a postoperative computed tomogram indicated successful biopsy of the lesion. She was treated with radiotherapy and died 8 months after biopsy.

10% to 48% for those with high-grade tumors.4,​47 In a study of 37 children with unilateral thalamic tumors who were stratified, those who were 11 to 19 years old had increased survival, regardless of histologic grade, compared with those 3 to 10 years

old.6 Additionally, patients who undergo total or subtotal resection have significantly longer survival than those who undergo only partial resection or biopsy (Fig. 15.4).4 Although previous case series have shown extremely poor long-term survival for

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children with bilateral thalamic tumors, including low-grade subtypes,48,​49 a 2007 investigation found that most patients were still alive at a mean follow-up of 4.5 years.4 Unlike pediatric patients, adult patients with thalamic tumors typically have shortened survival. Overall survival rates among adults with unilateral thalamic gliomas are 68.1% at 1 year and 25.9% at 2 years.7 In a large cohort of patients with infiltrative thalamic astrocytomas, age older than 18 years was a statistically significant prognostic variable for decreased survival.15 In accordance with findings in the pediatric population, adults who undergo total or subtotal resection have increased survival compared with those who undergo partial resection or biopsy. With advances in microsurgical techniques, the rates of morbidity and mortality associated with resection of thalamic tumors have decreased. In 2004, pooled data from 5 surgical series comprising 65 patients demonstrated a morbidity rate of 12.5% and a mortality rate of 3%.50 This compares favorably with an older series of patients in which the mortality rate for patients who underwent resection was 42%.13 Reported postoperative complications include uncontrolled cerebral edema, visual field defects, hemiparesis, ataxia, dystonia, and infection.2,​14,​35 In a large 2015 study of 111 adult patients with unilateral thalamic tumors, 34.1%  (15 of 44) of those with preoperative motor deficits had postoperative improvement, whereas 21.7% (23 of 106) of patients had postoperative deterioration of motor function.2

■■ Best Evidence Practice At present, no accepted standard guidelines exist that are specific to the treatment of tumors in the thalamic region. Rather, most practitioners adopt treatment guidelines that parallel histologic equivalents in the lobar region, which often involve maximal resection, if possible, and chemoradiotherapy, as described previously in this chapter. Unlike tumors in the lobar region, tumors in the thalamus present a more challenging surgical target, and several approaches can be utilized to provide a safe and short surgical corridor for maximal tumor resection. Although authors may advocate particular approaches, no single approach has been shown—in a controlled environment—to be more effective. In a large 2016 multisite pediatric series of 72 Canadian patients, several approaches were used for the 39 patients who underwent surgical resection: transcortical frontal  (28%, n = 11), transcallosal frontal interhemispheric (26%, n = 10), transcortical temporal  (18%, n = 7), transcortical parieto-occipital  (13%, n = 5), suboccipital transtentorial  (8%, n = 3), and others (8%, n = 3).5 These findings differ from the results of a large 2015 Chinese series of 111 adults: transcortical parieto-occipital (48%, n = 53), frontal transcallosal interhemispheric  (27%, n = 30), transcortical temporal (8%, n = 9), transcortical frontal  (6%, n = 7), subtemporal (5%, n = 6), and biopsy alone (5%, n = 6).2 Some authors have also advocated staging surgery for large thalamic tumors abutting eloquent or ill-defined regions,4 but most patients in large series undergo a single initial procedure for tumor removal.2,​5,​6,​32

■■ Conclusions Before the advent of modern surgical approaches to the thalamic region, operative mortality rates for thalamic tumors reached 40%,51 leading some authors to advocate for early radiographic diagnosis and radiotherapy as a first-line treatment.30 Today, with a plethora of approaches at the surgeon’s disposal and with substantially decreased mortality rates, surgery is the mainstay of treatment. All patients undergoing thalamic surgery should be evaluated presurgically with high-resolution MRI, if feasible, to help determine whether the tumor is focal or diffuse and whether the tumor has imaging characteristics that suggest low- or high-grade status. In patients with asymptomatic hydrocephalus, cytoreduction will often alleviate the obstruction and reduce hydrocephalus. If a patient is not appropriate for cytoreductive surgery, as is the case for those with bilateral thalamic gliomas, treatment for hydrocephalus should be undertaken in conjunction with a biopsy for diagnosis, if possible. Postoperative management should incorporate the standard protocol after craniotomy, with special emphasis on any injury to structures involved in the surgical approach, such as venous infarct (particularly after interhemispheric approaches) and on visual field deficits (after posterior transcortical approaches), or with emphasis on any evidence of thalamic dysfunction  (e.g., sensorimotor deficits, memory disorders, and behavioral problems). Outcomes after surgery have been reported in several series, and in studies published since the 1980s, mortality has ranged from zero to 8% (Table 15.1). Future advances in surgical technology, such as robotic-assisted surgery and better understanding of the biology of thalamic tumors, will enable safer surgery and facilitate prolonged survival. References 1. Beks JW, Bouma GJ, Journée HL. Tumours of the thalamic region. A retrospective study of 27 cases. Acta Neurochir (Wien) 1987;85(3–4):125–127 2. Cao L, Li C, Zhang Y, Gui S. Surgical resection of unilateral thalamic tumors in adults: approaches and outcomes. BMC Neurol 2015; 15:229 3. Souweidane MM, Hoffman HJ. Current treatment of thalamic gliomas in children. J Neurooncol 1996;28(2–3):157–166 4. Puget S, Crimmins DW, Garnett MR, et al. Thalamic tumors in children: a reappraisal. J Neurosurg 2007;106(5)(Suppl):354–362 5. Steinbok P, Gopalakrishnan CV, Hengel AR, et al. Pediatric thalamic tumors in the MRI era: a Canadian perspective. Childs Nerv Syst 2016;32(2):269–280 6. Bilginer B, Narin F, Işıkay I, Oguz KK, Söylemezoglu F, Akalan N. Thalamic tumors in children. Childs Nerv Syst 2014;30(9):1493–1498 7. Zhang P, Wang X, Ji N, et al. Clinical, radiological, and pathological features of 33 adult unilateral thalamic gliomas. World J Surg Oncol 2016;14:78 8. Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 2016;131(6):803–820

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9. Feng J, Hao S, Pan C, et al. The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults. Hum Pathol 2015;46(11):1626–1632

30. Cheek WR, Taveras JM. Thalamic tumors. J Neurosurg 1966;24(2):505–513

10. Martínez-Lage JF, Pérez-Espejo MA, Esteban JA, Poza M. Thalamic tumors: clinical presentation. Childs Nerv Syst 2002;18(8):405–411

32. Sai Kiran NA, Thakar S, Dadlani R, et al. Surgical management of thalamic gliomas: case selection, technical considerations, and review of literature. Neurosurg Rev 2013;36(3):383–393

11. Cuccia V, Monges J. Thalamic tumors in children. Childs Nerv Syst 1997;13(10):514–520, discussion 521 12. Hou Y, Chen X, Xu B. Prediction of the location of the pyramidal tract in patients with thalamic or basal ganglia tumors. PLoS One 2012;7(11):e48585 13. Tovi D, Schisano G, Liljeqvist B. Primary tumors of the region of the thalamus. J Neurosurg 1961;18:730–740 14. Baroncini M, Vinchon M, Minéo J-F, Pichon F, Francke JP, Dhellemmes P. Surgical resection of thalamic tumors in children: approaches and clinical results. Childs Nerv Syst 2007;23(7):753–760 15. Krouwer HG, Prados MD. Infiltrative astrocytomas of the thalamus. J Neurosurg 1995;82(4):548–557 16. Epstein NE, Rosenthal AD, Selman J, Osipoff M, Hyman RA. Moderate grade astrocytoma presenting in a 4-month-old child with a family history of von Recklinghausen’s neurofibromatosis spanning four generations: a case report. Neurosurgery 1983;13(6):692–695 17. Wong TT, Ho DM, Chang TK, Yang DD, Lee LS. Familial neurofibromatosis 1 with germinoma involving the basal ganglion and thalamus. Childs Nerv Syst 1995;11(8):456–458 18. Roth J, Constantini S. Combined rigid and flexible endoscopy for tumors in the posterior third ventricle. J Neurosurg 2015;122(6):1341–1346 19. O’Brien DF, Hayhurst C, Pizer B, Mallucci CL. Outcomes in patients undergoing single-trajectory endoscopic third ventriculostomy and endoscopic biopsy for midline tumors presenting with obstructive hydrocephalus. J Neurosurg 2006;105(Suppl 3):219–226 20. Wang YY, Wang K, Li SW, et al. Patterns of tumor contrast enhancement predict the prognosis of anaplastic gliomas with IDH1 mutation. AJNR Am J Neuroradiol 2015;36(11):2023–2029 21. Narang AK, Chaichana KL, Weingart JD, et al. Progressive low-grade glioma: assessment of prognostic importance of histologic reassessment and MRI findings. World Neurosurg 2017;99:751–757 22. Bette S, Kaesmacher J, Huber T, et al. Value of early postoperative FLAIR volume dynamic in glioma with no or minimal enhancement. World Neurosurg 2016;91:548–559.e1 23. Kurian KM, Zhang Y, Haynes HR, Macaskill NA, Bradley M. Diagnostic challenges of primary thalamic gliomas-identification of a minimally enhancing neuroradiological subtype with aggressive neuropathology and poor clinical outcome. Clin Neuroradiol 2014;24(3):231–238 24. Broadway SJ, Ogg RJ, Scoggins MA, Sanford R, Patay Z, Boop FA. Surgical management of tumors producing the thalamopeduncular syndrome of childhood. J Neurosurg Pediatr 2011;7(6):589–595 25. Kis D, Máté A, Kincses ZT, Vörös E, Barzó P. The role of probabilistic tractography in the surgical treatment of thalamic gliomas. Neurosurgery 2014;10(Suppl 2):262–272, discussion 272 26. Schmahmann JD. Vascular syndromes of the thalamus. Stroke 2003;34(9):2264–2278 27. Dasenbrock HH, Devine CA, Liu KX, et al. Thrombocytopenia and craniotomy for tumor: a National Surgical Quality Improvement Program analysis. Cancer 2016;122(11):1708–1717 28. Dasenbrock HH, Liu KX, Chavakula V, et al. Body habitus, serum albumin, and the outcomes after craniotomy for tumor: a National Surgical Quality Improvement Program analysis. J Neurosurg 2017;126(3):677–689 29. Dasenbrock HH, Liu KX, Devine CA, et al. Length of hospital stay after craniotomy for tumor: a National Surgical Quality Improvement Program analysis. Neurosurg Focus 2015;39(6):E12

31. Özek MM, Türe U. Surgical approach to thalamic tumors. Childs Nerv Syst 2002;18(8):450–456

33. Jeelani NO, Dirks P. Thalamic tumors. In: Youmans Neurological Surgery. 6th ed. Philadelphia, PA: Saunders/Elsevier;2011 34. Bernstein M, Hoffman HJ, Halliday WC, Hendrick EB, Humphreys RP. Thalamic tumors in children: long-term follow-up and treatment guidelines. J Neurosurg 1984;61(4):649–656 35. Prakash B. Surgical approach to large thalamic gliomas. Acta Neurochir (Wien) 1985;74(3–4):100–104 36. Yaşargil MG. Microneurosurgery: IV A. CNS Tumors. New York, NY: Thieme Medical Publishers;1994 37. Villarejo F, Amaya C, Pérez Díaz C, Pascual A, Alvarez Sastre C, Goyenechea F. Radical surgery of thalamic tumors in children. Childs Nerv Syst 1994;10(2):111–114 38. Kelly PJ. Stereotactic biopsy and resection of thalamic astrocytomas. Neurosurgery 1989;25(2):185–194, discussion 194–195 39. Lefranc M, Capel C, Pruvot-Occean AS, et al. Frameless robotic stereotactic biopsies: a consecutive series of 100 cases. J Neurosurg 2015;122(2):342–352 40. Iijima K, Hirato M, Miyagishima T, et al. Microrecording and imageguided stereotactic biopsy of deep-seated brain tumors. J Neurosurg 2015;123(4):978–988 41. Ohye C, Shibazaki T, Hirai T, Matsumura M, Kawashima Y, Hirato M. Microrecording for the study of thalamic organization, for tumor biopsy and removal. Stereotact Funct Neurosurg 1989;52(2–4):136–144 42. Roth J, Ram Z, Constantini S. Endoscopic considerations treating hydrocephalus caused by basal ganglia and large thalamic tumors. Surg Neurol Int 2015;6:56 43. Lizarraga KJ, Gorgulho A, Lee SP, Rauscher G, Selch MT, DeSalles AA. Stereotactic radiation therapy for progressive residual pilocytic astrocytomas. J Neurooncol 2012;109(1):129–135 44. Stupp R, Tonn JC, Brada M, Pentheroudakis G; ESMO Guidelines Working Group. High-grade malignant glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;21(Suppl 5):v190–v193 45. Cage TA, Mueller S, Haas-Kogan D, Gupta N. High-grade gliomas in children. Neurosurg Clin N Am 2012;23(3):515–523 46. Steiger HJ, Götz C, Schmid-Elsaesser R, Stummer W. Thalamic astrocytomas: surgical anatomy and results of a pilot series using maximum microsurgical removal. Acta Neurochir  (Wien) 2000;142(12): 1327–1336, discussion 1336–1337 47. Kramm CM, Butenhoff S, Rausche U, et al. Thalamic high-grade gliomas in children: a distinct clinical subset? Neuro Oncol 2011;13(6):680–689 48. Reardon DA, Gajjar A, Sanford RA, et al. Bithalamic involvement predicts poor outcome among children with thalamic glial tumors. Pediatr Neurosurg 1998;29(1):29–35 49. Di Rocco C, Iannelli A. Bilateral thalamic tumors in children. Childs Nerv Syst 2002;18(8):440–444 50. Albright AL. Feasibility and advisability of resections of thalamic tumors in pediatric patients. J Neurosurg 2004;100(5)(Suppl Pediatrics):468–472 51. Arseni C. Tumors of the basal ganglia: their surgical treatment. AMA Arch Neurol Psychiatry 1958;80(1):18–24

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Tumors of the Third Ventricle

Srikant S. Chakravarthi, Melanie B. Fukui, Alejandro Monroy-Sosa, Juanita M. Celix, Jonathan Jennings, George Bobustuc, Ken Bastin, Richard Rovin, and Amin B. Kassam

Abstract

The third ventricle and its surrounding structures represent one of the most complex and intricate areas in the human brain. The area is the vital center of the human cerebrum, responsible for housing our critical neurocognitive functions. In addition, many of the tumors affecting this region are unique to this area. Thus, surgical management of the third ventricular region requires an organized and thorough understanding of the intricate underlying anatomy and a constructive understanding in accessing pathology. The pioneering work of Walter Dandy, Gazi Yaşargil, Michael Apuzzo, and Albert Rhoton Jr. paved the way for a better anatomical understanding of the third ventricle and how to access pathologies affecting this region both safely and effectively. Detailed knowledge of the intrinsic anatomy and its regional constraints is of vital importance in understanding surgical management of the third ventricle. In this review, in an effort to better conceptualize this region, we have organized the third ventricle and built a radial architecture system (outer radial corridor and inner radial corridor) based on the relative position of critical vascular, neural, and cisternal (cerebrospinal fluid–containing) structures. Next, on the basis of this architectural schema, we have highlighted the common pathologic entities affecting this region and integrated our newly structured anatomical concept to discuss perioperative and surgical management, with a focus on choosing the most appropriate surgical corridor using a decision-making algorithm needed to access this region. We hope that this chapter will provide the operator with a more organized and applicable framework in determining which surgical corridor to use in accessing this intimate space. Keywords:  cisterns, corridor, inner radial corridor, neural, outer radial corridor, port, third ventricle, transsulcal parafascicular, vascular

■■ Introduction The third ventricle should not be considered as an inert cerebrospinal fluid (CSF)–filled cavity but rather as a part of the central core of the human cerebrum that harbors critical structures responsible not only for our survival but also for our awareness. It is located at the very epicenter of the brain with an intricate geometry, housing a treasure trove of both limbic and neocortical pathways, imperative for survival functions. At the same time, the third ventricle is truly making us individuals by subserving memory, emotion, and even the seat of consciousness. The third ventricle is unique in that its constituents can generate and harbor a range of pathologies beyond those seen in most other regions of the brain, including inflammatory, neoplastic, vascular, and congenital pathologies. These pathologies

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can represent conditions varying from sarcoidosis to teratomas. Fortunately, many require only tissue diagnosis, which will guide a variety of precision-based medical and radiotherapies. Surgery for lesions within the third ventricle is inherently challenging because of the depth of the ventricle and the regional neuroanatomy, including the shielding limbic and neocortical white matter tracts. By maximizing the available technology at the time, pioneering neurosurgeons like Walter Dandy, Gazi Yaşargil, Michael Apuzzo, and Albert Rhoton Jr. devised ingenious approaches to the third ventricle. Recently, technological innovations in imaging, optics, white matter tractography, planning software, and robotics have been harmoniously integrated. As a result, these innovations have further enhanced corridor-based surgical approaches. Coupled with rapid advancements in molecular and genetic analysis, the indications for and goals of surgery for third ventricular pathology are being redefined. However, a sound anatomical understanding remains a foundation of treating these conditions irrespective of the modality. In this chapter, we review these concepts beginning with an understanding of the complex three-dimensional (3D) architectural framework of the region. We devote the initial portion of the chapter to contructing this architecture by building the neural, vascular, and CSF framework, beginning centrally and then spanning out radially. This architecture is important in understanding the variety of pathologies, differential diagnoses based on regional considerations, corridors for access, and absolute limitations imposed by the anatomy.

■■ Anatomical Considerations The third ventricular region is guarded by a complex glandular or regulatory, neural, vascular, and cisternal architectural framework that must be understood both to appreciate the various pathologic conditions that can cause malfunction and to design safe corridors for access. At the outset, it is important to emphasize that, because of the protected location of the third ventricle, surgical intervention for third ventricular lesions often represents only one aspect of multimodality treatment in their overall management. We find it useful to geographically divide the third ventricle into three anatomically distinct segments. This categorization forms the basis for a decision algorithm for corridor-based access. The surgical target within the appropriate third ventricle segment becomes the core from which a concentric or radial architecture is built (Fig. 16.1, Fig. 16.2, Fig. 16.3). The next layer is the apertures (membranes and foramina) through which the third ventricle can be accessed. This is followed by an inner radial corridor (IRC) consisting of CSF spaces immediately surrounding the third ventricular segment (ventricles/ cisterns) and vasculature. Finally, the outer radial corridor

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Fig. 16.1  Strategy for approaching the third ventricle. A decision algorithm has been created to organize and divide the anatomical frameworks into three segments: anterior, middle, and posterior. This categorization offers a structured approach to accessing the various pathologic conditions in or around the third ventricle. Algorithm demonstrates (a) access, beginning from the surface, either by way of endoscopic or transcranial approaches, to the lateral ventricle; and (b) the possible approaches from the lateral ventricle to the third ventricle, based on the anatomical framework constructed. EEA, expanded endonasal approach; MI, massa intermedia.

(ORC) consists of the neural structures (cortex, subcortical white matter tracts, and cranial nerves [CNs]) and outer CSF spaces (interhemispheric fissure and sulci). 

■■ Somatotopic Organization: Building a Radial Architecture Third Ventricle Segments The third ventricle is a narrow, cylindrically shaped, midline cavity located in the subcallosal central core of the cerebrum, which is encased by a series of variably sized CSF cavities (i.e., basal cisterns or lateral ventricles [IRCs]). In the following section, we will start with the central core that forms the third ventricle itself (Fig. 16.2) and then work radially to construct a 3D structural and functional architectural model of the region. At its core, the third ventricle represents a dynamic, fluid-filled region that provides a critical pathway for pulsatile flow. Along its

anterosuperior margin, it articulates superiorly with the lateral ventricles via the respective bilateral foramina of Monro, while the posteriorly located cerebral aqueduct of Sylvius provides singular outflow to the inferiorly located fourth ventricle. As previously discussed, based on its subcallosal location, at the anterior and posterior sagittal boundaries, the cylinder becomes C-shaped, carefully guarded by the umbrella of the overlying genu/rostrum of the corpus callosum anteriorly and the splenium of the corpus callosum posteriorly. Next, within each of the anterior, middle, and posterior segments of the third ventricle, it is helpful to consider the boundaries of the cylinder as a floor, a roof, and two lateral walls extending between the two C-shaped borders of the cylinder (i.e., anteriorly being the optic recess and posteriorly being the pineal recess). The third ventricle itself can be divided into three segments in the sagittal plane (Fig. 16.2). If we draw a line along the anterior commissure and venous angle, which represents the confluence of the caudate, septal, and thalamostriate veins as they join to form the origin of the internal cerebral veins (ICV), we

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Fig. 16.2  Separating the third ventricle into three segments. The third ventricle is divided into three distinct segments along the sagittal plane. A line is drawn along the anterior commissure (AC) and the venous angle, approximating the foramen of Monro (FM); all structures anterior to this line are considered to be the anterior segment. The middle segment is the

region from the AC to the posterior border of the massa intermedia (MI). The posterior segment consists of the region posterior to the MI, which includes the pineal gland. The coronal T1-weighted magnetic resonance images (left) correspond to these three divisions.

can consider all structures anterior to this as the anterior segment of the third ventricle. This region is well approximated by the foramen of Monro, and the anterior commissure is located directly anterior and slightly inferior to the foramen of Monro, which marks the venous angle. Continuing posteriorly along the sagittal plane, the lateral wall of the third ventricle takes on the shape of the thalamus as it creates bilateral large almond-shaped impressions along the ependyma, with the massa intermedia or interthalamic adhesion extending across the ventricle. We define the middle segment of the third ventricle as the region between the anterior commissure (the foramen of Monro as a surrogate landmark) anteriorly and the massa intermedia posteriorly. Therefore, the posterior segment now consists of the region posterior to the massa intermedia, incorporating the pineal gland, including the suprapineal and pineal recesses posteriorly (Fig. 16.2).

regulatory mechanisms of the hypothalamic core consisting of the tuber cinereum and a infundibulum. The mammillary bodies are also located in this segment. The remainder of the neural architecture consists of the roof of the anterior portion of the third ventricle, which is guarded sequentially in a radial fashion by the interhemispheric fissure, the base of the caudate, and the genus of the corpus callosum. The vascular framework consists superiorly of the venous angle marking the posterior boundary and transition between the anterior and middle third of the third ventricle, anteriorly by the anterior communicating artery complex and the hypothalamic perforators, and inferiorly by the basilar apex and the respective posterior cerebral artery (PCA) perforators (see section on cerebrovasculature).

Anterior Segment Within the anterior segment of the third ventricle, the critical neural framework moving radially outward along the lateral walls consists of the anterior portion of the hypothalamus, and the floor of the third ventricle is bordered rostrally by the optic chiasm and ventrally by the infundibular recess. These rostral and ventral borders are bounded by specific apertures that communicate with the anterior segment, namely, the lamina terminalis and infundibular recess (Fig. 16.1, Fig. 16.2, Fig. 16.3). In addition, the anterior segment harbors critical communication pathways and glandular/

Middle Segment There is a compact transitional zone between each of the segments that harbors critical structures. This is especially true for the zone between the anterior and middle segments. In keeping with the geometric theme of the corpus callosum, the fornix also bends along its anterior and posterior margins. The anterior arch consists of the fornicial bundles along the perimeter of the foramen of Monro in the transitional zone between the anterior and middle segments of the third ventricle. The remainder of the middle segment posterior to this transitional zone forms the body of the third ventricle. In this segment, the roof of the third ventricle is bordered bilaterally by the bodies and the crura of the fornices. Traversing posteriorly

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Fig. 16.3  Corridor-based approach to the third ventricle. (a-c) Access to the segments of the third ventricle can be organized by an outside-in approach based on anatomical corridors: (1) an outer radial corridor (ORC; yellow circle), (2) an inner radial corridor (light blue circle), and (3) a correlative aperture corridor (red circle). These corridors allow the use of a systematic decision algorithm when accessing any particular segment of the third ventricle (dark blue area). (d) This step-by-step process leads to the complete radial strategy for accessing the third ventricle. (e) The approach to the third ven-

tricle is strategically planned using the three radial corridors as frameworks: (1) the ORC (consisting of the transsulcal parafascicular [TSP] route, sylvian fissure, and interhemispheric fissure [IHF]); (2) the inner radial cisterm (consisting of the prechiasmatic cistern [PCC], interpeduncular [IPC] cistern, quadrigeminal cistern [QC], and lateral ventricle [LV]); and (3) the correlative aperture corridor as a natural opening (foramen of Monro [FM]) and as membranes (infundibular recess [IR], lamina terminalis [LT], velum interpositum [VI], and pineal stalk [PiS]).

along the roof of the third ventricle, the two fornices diverge laterally, and the ensuing gap is spanned by the hippocampal commissure. Beneath it lie the two layers of the tela choroidea and the intervening space, the velum interpositum, which contains the ICV. As they course through the velum interpositum, the ICV receive tributaries from the thalamus, the fornix, and the walls of the third ventricle.1 They will then exit the velum interpositum above the pineal body to enter the quadrigeminal cistern and join the great vein of Galen (see section on cerebrovasculature) (Fig. 16.4). Along the anterior transitional zone, the lateral walls of the third ventricle are intimately bordered on each side by the hypothalamus, which transitions into the anterior thalamus as one travels posteriorly along the body of the middle segment of the third ventricle. Of note, the internal capsule and genu of the corpus callosum are intimately located along the superolateral border. The massa intermedia, or interthalamic adhesion, travels

across the third ventricle connecting the respective thalami, and marks the posterior boundary of the middle segment. The floor of the middle segment is made up of the mammillary bodies and the diencephalon, as well as the critical anterior and posterior circulation perforators supplying this vital portion of the brain stem (see section on cerebrovasculature).

Posterior Segment There is an analogous posterior transition from the middle to the posterior segment that is most prominently formed by the posterior portion of the thalamus, located behind the massa intermedia. The roof of the posterior segment itself is formed by the relationship of the tela choroidea, velum interpositum, and ICV and their confluence with the great vein of Galen. The posterior segment harbors the habenula and body of the fornix, which is located just inferolaterally to the posterior margin of the thalamus.

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Fig. 16.3 (continued)  (f) Final decision-making algorithm of the corridor-based approach with the final entry point being the three respective segments of the third ventricle. (g) Magnified sagittal magnetic resonance image (MRI) of third ventricle showing the dorsal (D), rostral (R), and ventral (V) anterior corridors along their respective apertures (arrows). (h) Sagittal MRI sequence highlighted to demonstrate the same segmental or corridor-based principle. Abbreviations: A, anterior segment of third ventricle; AC, anterior commissure; EEA, expanded endoscopic endonasal

approach; ITSC, infratentorial supracerebellar; M, middle segment of third ventricle; MI, massa intermedia; OCC, opticocarotid cistern; OR, optic recess; P, posterior segment of third ventricle; PG, pituitary gland; PiG, pineal gland; POS, parieto-occipital sulcus; PS, pituitary stalk; PSF, proximal sylvian fissure; SSC, suprasellar cistern; STSO, supratentorial suboccipital; TC, transcortical; TG, transgyral; TSP, transsulcul parafascicular; VA, venous angle.

The posterior segment has two key CSF spaces, the cerebral aqueduct inferiorly and the suprapineal recess superiorly. The habenular commissure, pineal recess and pineal gland, and posterior commissure are all located within this space.

The posterior boundary of the cylinder, as previously noted, is C-shaped and located under the umbrella of the splenium of the corpus callosum. The pineal body projects from this posterior wall of the third ventricle into the quadrigeminal cistern, where

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 c) Inferior access, via an expanded endonasal approach (EEA) and pituitary transposition, allows access to the interpeduncular cistern and then, through a membrane, to the infundibular recess.  2. Middle segment: The middle segment can be reached anteriorly and superiorly.  a) Anterior access from the lateral ventricle is through a foramen, the foramen of Monro. Access is limited based on the dilation of the foramen of Monro.  b) Superior access from the lateral ventricle is through a membrane, the tela choroidea and velum interpositum.  3. Posterior segment: The posterior segment can be reached but surgical options are limited.  a) Superior access from the lateral ventricle is through a membrane, the tela choroidea and velum interpositum; however, the confluence of the ICV and massa intermedia preclude surgical application as the corridor becomes limited and constraining for bimanual dissection. Fig. 16.4  The venous system of the third ventricle. Understanding the venous system surrounding the third ventricle is crucial, especially when accessing the anterior and middle segments of the third ventricle, most commonly by way of the foramen of Monro. The deep venous system is intimately related to the third ventricle, with the internal cerebral vein (ICV) along the roof and the basal vein of Rosenthal  (BVR) along the floor. The thalamostriate vein (TSV) joins the anterior septal veins to form the ICV. The point of union of the thalamostriate and septal veins is referred to the venous angle. The great cerebral vein of Galen passes posterosuperiorly behind the splenium of the corpus callosum in the quadrigeminal cistern. (Arrowheads indicate bridging veins.)

it lies beneath the splenium of the corpus callosum and above the cerebellar vermis. Different from the anterior C-shaped boundary of the third ventricle, the lamina terminalis, the posterior C-shaped boundary is formed by a thin pineal stalk that extends from the thalamus to the overlying pineal gland. This is carefully guarded by vital structures that preclude it from being a meaningful aperture into the third ventricle. Knowledge of this difference is critical for understanding surgical corridors and their limitations.

Inner Radial Corridor: Cerebrospinal Fluid Spaces The third ventricle is unique in that it represents a CSF space that is radially surrounded by other CSF spaces and cavities, which are then separated from the third ventricle by membranes (lamina terminalis, infundibular recess, and tela choroidea/ velum interpositum) or foramina (foramen of Monro) and by the cerebral aqueduct of Sylvius (Fig. 16.1, Fig. 16.2, Fig. 16.3). In constructing 3D architecture that extends radially and, in particular, in understanding access corridors, knowledge of this anatomy becomes imperative. Explicitly, the third ventricle cannot be accessed directly without going through a CSF cistern and its bounding membrane or a CSF cavity through its foramen (Fig. 16.2):  1. Anterior segment: The anterior segment can be reached superiorly, anteriorly, and inferiorly.  a) Superior access from the lateral ventricle is through a foramen, the foramen of Monro.  b) Anterior access from the suprachiasmatic cistern is through a membrane, the lamina terminalis.

 b) Posterior access from the quadrigeminal cistern, unless following an extrinsic lesion, is impractical because there is no meaningful access membrane or foramen. From a rostrocaudal direction, the great vein of Galen, the pineal gland, and the tectal plate of the midbrain create a formidable barrier to entry from the quadrigeminal cistern.  c) Inferior access from the fourth ventricle through a foramen, the cerebral aqueduct of Sylvius, is also surgically impractical.

Inner Radial Corridor: Regional Cerebrovasculature While we have alluded to some key arterial and venous relationships in this region, it is imperative to understand them in detail in order to truly understand the 3D architectural framework that guards the third ventricle (Fig. 16.4). The anterior cerebral arteries and the anterior communicating artery lie immediately anterior to the anterior boundary (optic recess) of the anterior segment of the third ventricle, marked by the lamina terminalis. The perforators from the anterior communicating artery and the distal A1 segments supply the anterior wall. Similarly, the posterior wall (pineal recess) is situated next to the posterior cerebral, posterior choroidal, pericallosal, and superior cerebellar arteries. The floor of the third ventricle provides a perforated and fissured corridor for critical vessels, including the posterior communicating arteries and the apex of the basilar artery. Both the anterior and posterior cerebral arteries supply the roof of the third ventricle. Finally, it is important to note that all major intracranial vessels, such as the anterior and posterior cerebral arteries, internal carotid, anterior choroidal, and anterior and posterior communicating arteries, provide perforators that feed into the walls of the third ventricle.1 In effect, there is a rich radial plexus that supplies and irrigates this vital compact area. With respect to the venous plexus, the anterior and posterior transitional segments represent key confluences, specifically, the venous angle anteriorly with the ICV running along the body of the third ventricle, within the velum interpositum and toward its posterior confluence, the great vein of Galen, in the region of

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the suprapineal recess. The choroid plexus essentially runs along this venous framework and is intimately tied to it, particularly along the tela choroidea (Fig. 16.4).

Outer Radial Corridor: Neural Structures The ORC consists of a neural structure primarily composed of cortical structures, subcortical parenchyma, and CNs. The cortical structures are composed of the respective gyri, while the subcortical region consists of the underlying white matter fascicles. The largest white matter fascicle is represented by the corpus callosum, which represents the midline commissural fiber connecting the hemispheres. Again, consistent with the architectural theme of the midline structures, the corpus callosum is also divided into thirds (anterior, middle, and posterior). In addition to the corpus callosum, it must be noted that there is increasing evidence of the presence of eloquent and vital white matter fascicles, such as key association fibers (the superior longitudinal fasciculus and cingulum) and projection fibers (anterior limb of the internal capsule). These fibers are vital to neurocognitive, behavioral, and motor initiation pathways. Finally, the key CNs that form the ORC are represented by the optic apparatus, optic nerve, chiasm, and tract.

Outer Radial Corridor: Cerebrospinal Fluid Spaces The CSF pathways in this ORC consist of key sulci, the most prominent of which is the interhemispheric fissure separating the two hemispheres. Analogously, there are many such smaller intervening CSF spaces between the gyri (i.e., the sulci). These sulci can provide similar access to the IRCs, which is analogous to the interhemispheric fissure providing access to the lateral ventricle.

■■ Differential Diagnosis, Pathophysiology, and Natural History A variety of congenital and acquired lesions can affect the third ventricle. Furthermore, these may be intrinsic, intrinsic and exophytic, extrinsic, or extrinsic and endophytic. There are also age and segmental predilections. The most common representative pathologies are summarized in Table 16.1.

Congenital Pathology The transitional zone between the anterior and middle segment is most commonly affected by congenital lesions, of which colloid cysts are the most prevalent. Colloid cysts are round, welldefined, fluid-filled cysts that can range in size from several millimeters to 3 cm. The behavior of these cysts varies, as 90% are reported to be asymptomatic and stable, and 10% tend to enlarge and cause obstructive hydrocephalus.2 In fact, de novo cysts in adults are rare, and they are often dormant congenital remnants that eventually grow. However, the trigger for their sudden growth in adulthood remains unknown.3,​4,​5 We have classified colloid cysts into two types based on their primary site of attachment. Colloid cysts are commonly attached to the lateral ventricle, then grow inferiorly through the foramen of Monro and into the transitional zone entering the third ventricle. We refer to these cysts as type I colloid cysts. However, less commonly they can be attached along the roof of the third ventricle in the transitional zone between the anterior and middle segments. This location is just posterior to the venous angle, where they then can grow superiorly from this pedicled attachment along the roof of the middle segment toward the foramen

Table 16.1  The most common pathologies affecting the third ventricular region

Pathology

Congenital or acquired Intrinsic or extrinsic

Pediatric, adult, or both Segment of third ventricle

Craniopharyngioma

Congenital

Extrinsic

Both

Anterior

Colloid cyst

Congenital

Intrinsic

Both

Anterior, middle

Pituitary adenoma

Acquired

Extrinsic

Adult

Anterior

Meningiomas

Acquired

Extrinsic and intrinsic

Adult

Anterior, middle

Pineal region cysts

Congenital

Extrinsic

Both

Posterior to middle

Pineal region tumors

Congenital

Extrinsic

Both

Posterior to middle

Lymphoma

Acquired

Intrinsic

Both

Anterior

Hypothalamic/optic

Acquired

Extrinsic

Pediatric

Anterior

Aqueductal stenosis

Acquired

Extrinsic

Both

Anterior

Choroid plexus papilloma

Congenital

Intrinsic

Adults

Middle

Ependymal cysts

Congenital

Intrinsic

Both

Transitional

Langerhans cell histiocytosis Acquired

Intrinsic

Pediatric

Middle

Germinomas

Congenital

Intrinsic

Pediatric

Anterior

Neurocystercercosis

Acquired

Extrinsic and intrinsic

Both

Anterior

Dermoid and epidermoid

Congenital

Extrinsic

Both

Middle

Basilar artery aneurysms

Acquired

Extrinsic

Both

Middle

Subependymal giant cell tumor

Congenital

Extrinsic

Pediatric

Transitional

Hamartomas

Congenital

Extrinsic

Pediatric

Any

16  Tumors of the Third Ventricle of Monro, causing intermittent obstruction. We refer to these as type II colloid cysts. Type II colloid cysts create intermittent compression by swinging forward from their pedicle and obstructing the CSF flow until the intraventricular pressure within the lateral ventricle creates enough pressure to dislodge them from the foramen of Monro, which forces them to swing back into their original position. In essence, this represents a “ball-valve phenomenon." The clinical and surgical implications of type I and type II colloid cysts will be discussed subsequently. Other congenital intraventricular cysts are rare but may also represent important causes of hydrocephalus, especially in the pediatric population. Their origin can be arachnoidal, endodermal, or neuroepithelial, and they can occur in any segment of the third ventricle, resulting in obstruction at the level of the acqueduct of Sylvius or the foramen of Monro. Ependymal cysts are often small, benign, and asymptomatic and can also be found in the lateral ventricles extending into the third ventricle.2,​6

Acquired Pathology We have found that the segmentation scheme discussed above has also proven to be valuable because of the geographically dependent nature of acquired pathologies of or around the third ventricle. The differential diagnosis of extrinsic masses in the respective segment of the third ventricle should be considered on the basis of two factors: the age of the patient and the regional anatomy primarily affected.

Anterior Segment Extrinsic The age of the patient significantly impacts the likelihood of pathology, which dramatically differs between the pediatric and adult populations. Tumors in the anterior third ventricle can be divided into those arising from structures along the floor (sellarsuprasellar) and those arising from the lateral and anterior wall (hypothalamic-chiasmatic). Tumors originating in the sellarsuprasellar space that then extend upward toward the anterior recess and cause extrinsic compression most commonly include pituitary macroadenomas, craniopharyngiomas, and meningiomas. In contrast, the hypothalamic and optic gliomas represent more common extrinsic lesions of the lateral wall and the anterior terminus of the region, respectively. The age distribution is particularly important in considering these lesions. In the pediatric population, the most common extrinsic anterior mass among patients younger than 2 years is Langerhans cell histiocytosis. Hypothalamic-chiasmatic pilocytic astrocytomas and craniopharyngiomas tend to occur between the ages of 5 and 15 years. Craniopharyngiomas, in particular, tend to be heterogeneous in appearance, especially with the presence of calcifications. Independent of the nature of the specific lesion, they most often manifest physiologically with secondary impairment of the glandular and regulatory functions of the anterior third ventricle, such as diabetes insipidus and hypopituitarism, or secondary to mass effect on local structures, in particular the optic apparatus.

Intrinsic Intrinsic lesions of the anterior third ventricle are much rarer. Germinomas and lymphomas are the most common intrinsic lesions to occupy the anterior segment of the third ventricle. The incidence of germinoma peaks at approximately 10 to 12 years of age while lymphomas more commonly arise in

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the third or fourth decades of life. Other lesions in the adult population that should be considered as originating primarily intrinsic to the anterior third ventricle segment are papillary craniopharyngiomas. We have previously described these as type IV craniopharyngiomas, and their surgical implications will be discussed subsequently.7 While the site of origin may provide a clue in the case of extrinsic lesions, it can still be difficult to determine their nature; this is even more difficult in cases of intrinsic lesions. With respect to anterior masses affecting the third ventricle in the adult population, it can often be difficult to differentiate among the various potential pathologies to reach a final diagnosis. Mangetic resonance imaging (MRI) with gadolinium-enhanced sequences and, more recently, with cellular diffusion-weighted imaging may be of value. However, direct biopsy and CSF sampling are usually required to confirm clinical suspicion. Of the list of possible pathologies, pituitary macroadenomas and meningomas are the most common. Since these are slow-growing tumors, displacement, rather than invasion of the third ventricle, is the usual consequence. Craniopharyngiomas represent a unique entity. We have previously classified them into four categories. 1.  Type I: Suprasellar preinfundibular 2.  Type II: Suprasellar transinfundibular 3.  Type III: Interpeduncular retroinfundibular 4.  Type IV: Anterior recess intrinsic third ventricular While it can be difficult to determine the specifics on radiologic diagnosis, for the purposes of this chapter, the only relevant issue is whether the stalk and infundibular recess are normal. If so, the lesion is more likely to be type IV and intrinsic to the third ventricle, unlike other tumors that will impact the infundibulum, resulting in posterior displacement (type I), dilatation (type II), or anterior displacement of the stalk (type III). The surgical relevance will be discussed later but, in essence, if the stalk is normal (type IV), a ventral anterior endonasal route is not preferred and a transventricular route (dorsal anterior) is selected instead. Other pathologic processes, such as lymphomas, metastases, and granulomatous diseases, may have a similar appearance on computed tomography or MRI. Occasionally, parasellar and tuberculum meningiomas can extend far superiorly and thereby deform the anterior recess of the third ventricle.8,​9,​10 In addition, the anterior portion of the third ventricle and the hypothalamus are occasionally involved with other intrinsic tumors, such as ependymoma, glioblastoma multiforme, and ganglioglioma. Metastatic tumors rarely occur intrinsically in the anterior segment of the third ventricle without involving the choroid plexus directly.6,​11,​12,​13

Transitional Zone (Anterior/Middle Segment) Masses of the foramen of Monro frequently manifest with obstruction of the lateral ventricles. The most common pediatric lesion affecting the foramen of Monro is the subependymal giant cell tumor associated with tuberous sclerosis. Approximately 20% of patients with tuberous sclerosis have subependymal giant cell tumors, which typically occur in patients younger than 20 years of age. Subependymal nodules and hamartomas, which are key intracranial features of tuberous sclerosis, can occur anywhere along the ventricular walls. Subependymomas  (World Health Organization [WHO] grade I),

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which are closely related to SGCTs, more often occur in the fourth ventricle in middle-aged to elderly patients. However, supratentorially, this lesion can occur in the foramen of Monro as a small, lobulated, well-defined lesion that can invade both the lateral and third ventricles.14,​15,​16

Middle Segment Extrinsic Masses arising from the floor of the third ventricle are uncommon. Hypothalamic hamartomas are nonneoplastic processes that typically manifest in childhood and can upwardly distort the floor of the third ventricle. Dermoid, epidermoid, or arachnoid cysts that arise from the prepontine cistern can also cause compression of the floor. In addition, basilar artery aneurysms and basilar artery ectasias can project directly to the prepontine cistern, causing third ventricular compression and often even mimicking colloid cysts.17,​18,​19,​20

Intrinsic Intrinsically derived intraventricular lesions of the middle segment of the third ventricle are rare. Most of these lesions involve the choroid plexus.21 They include primary choroid plexus papilloma, choroid plexus carcinoma, metastatic processes, vascular malformation, and infectious processes (e.g., neurocysticercosis) infiltrating the plexus. Choroid plexus cysts are neuroepithelial in origin and are often associated with chromosomal abnormalities. In addition, seeding of both primary and secondary lymphomas may occur within the choroid plexus. These lesions, however, very rarely occur within the third ventricular space and instead are more common in the lateral and fourth ventricles. Choroid plexus papillomas, which more commonly occur in the fourth ventricle in adults, can grow in the third ventricle in 5% of the population. These lesions are derived from choroid plexus epithelium and often are associated with nonobstructive hydrocephalus due to CSF overproduction or impaired resorption. Chordoid glioma is also another rare, slow-growing, benign neoplasm that is derived from both chordoid and glial cellular progenitors. Of note, these can also involve the anterior segment.6,​11,​12,​13,​22,​23,​24

Posterior Segment Extrinsic While there is some controversy about whether lesions of the pineal regions should be considered intrinsic or extrinsic, we prefer to consider them extrinsic because of the location of the pineal gland within the quadrigeminal cistern. Most tumors of the posterior segment of the third ventricle that originate in the pineal gland are extrinsic to the ventricle but then grow toward and distort the suprapineal and pineal recesses along the posterior C-shaped terminus of the ventricle. These pathologic conditions represent the most relevant considerations with respect to lesions of the posterior third ventricle. A wide range of pathologic processes can occur—from asymptomatic cysts to pineocytomas, pineoblastomas, other germ cell tumors, and teratomas.25,​26 Tumors in this area in the adult population rarely cause obstruction and hydrocephalus. Pediatric tumors in the posterior pineal region tend to cause hydrocephalus even with small-sized lesions. Other tumors mentioned previously,

such as pineocytomas or pineoblastomas  (WHO grade IV), more often occur in teenagers and young adults and tend to be more aggressive. These tumors are considered to be neuroectodermal in origin, and they closely resemble medulloblastomas, ependymomas, retinoblastomas, and supratentorial primitive neuroectodermal tumors on imaging and histologically.

Intrinsic In the adult population, the most common intrinsic tumors in this region are germinomas and lymphomas.27

■■ Clinical Presentation The clinical manifestations of third ventricular lesions can be categorized by those that result in CSF obstruction and hydrocephalus and those that impact the function of the respective segments of the third ventricle via intrinsic invasion or extrinsic compression.

Cerebrospinal Fluid Pathways Most lesions within or surrounding the third ventricle result in hydrocephalus, which is caused by obstruction of either the foramen of Monro superiorly or the cerebral aqueduct inferiorly. Disruption of the contour, either by intrinsically or, more commonly, by extrinsically applied forces can result in dilation of the third ventricle. Symptoms related to increased intracranial pressure, including headache, nausea, vomiting, papilledema, and cognitive impairment, can occur in such patients.

Regional Effects Endocrinologic deficits and visual disturbances usually manifest from extrinsic tumors that compress the third ventricle, especially along its anterior wall or floor. This can be the case especially with tumors originating from the sellar-suprasellar-chiasmatic axis. Involvement of, or mass effect from, the hypothalamus on the third ventricle can cause diencephalic syndrome, which can result in alterations in satiety (emaciation or obesity) or alertness (somnolence and hyperalertness) in children. Lesions affecting the middle segment and transitional zone will often result in forniceal and limbic system impairment, with consequent memory and processing dysfunction. Lesions located along the posterior wall of the third ventricle can create mass effect on the pretectal region. Parinaud’s syndrome  (upward gaze palsy) can result, especially in infants, because this region is much more sensitive to compression at a young age.28,​29,​30

■■ Perioperative Evaluation and Surgical Management As hydrocephalus is a common presentation, the first course of action is often to reduce the intracranial pressure. This can be accomplished either by CSF flow diversion (i.e., ventriculoperitoneal shunt) or by opening internal membranes to allow diversion into the basal cisterns (e.g., endoscopic third ventriculostomy, septum pellucidotomy). Cytoreduction or obtaining diagnostic tissue, as well as restoration of CSF flow, are the typical surgical goals. Adjuvant chemotherapy or radiotherapy can be an effective addition to surgical treatment and will be discussed later in this chapter.

16  Tumors of the Third Ventricle

Chemotherapeutic Considerations The treatment of patients with high-grade and lower-grade gliomas affecting the third ventricle follows established treatment protocols. This section will focus on medical therapies for nonglioma lesions and rare third ventricle–specific glial or mixed neoplasms.

Pituitary Macroadenomas For residual or recurrent hormonally active adenomas or multiple recurrent nonsecreting tumors not amenable to surgical intervention, radiotherapy and chemotherapy can be options. For refractory or aggressive corticotrophin pituitary tumors with rapid growth, local invasion, evolving cranial neuropathies, and the potential for CSF dissemination, CAPTEM, a chemotherapeutic regimen combining capecitabine and temozolomide has been reported, in a small cohort, to lead to radiographically confirmed high control rates (in all four patients treated) associated with dramatic improvements in both neurologic deficits and symptoms of Cushing's disease.31 As expected, the dramatic treatment response (complete radiographic regression) to temozolomide correlated with low MGMT  (O6-methylguanine-DNA methyltransferase [a DNA damage repair gene]) expression levels and with an intact mismatch repair system (adequate expresion levels of MLH1, MSH2, MSH6, and PMS2).31 Temozolomide is emerging as a viable treatment option for pituitary adenoma. A correlative study on 136 consecutive prolactinoma specimens showed low MGMT expression  (< 25% immunopositivity) in more than 75% of the tumor specimens, correlating with a high rate of MGMT promoter methylation—a trend that was even more frequent in atypical prolactinomas.32 Furthermore, disulfiram,  an acetaldehyde inhibitor used in the treatment of alcoholism, has been reported to both directly inhibit MGMT expression in a variety of tumors33 and decrease MGMT levels by enhancing MGMT protein proteasomal degradation in an in vitro pituitary adenoma model,34 making DSF an attractive add-on to a temozolomide-containing regimen for treatment of refractory prolactinomas, particularly when MGMT is highly expressed.

Craniopharyngiomas Residual or recurrent craniopharyngioma not amenable to further surgical intervention should be considered for fractionated radiotherapy. Additional medical therapies are also being developed. Genomic profiling suggests that the treatment landscape of recurrent craniopharyngiomas will move rapidly beyond the accepted but infrequently used techniques of intracavitary treatment with radioactive phosphorus, bleomycin, or interferon-α, all technically and logistically cumbersome and all associated with unacceptable toxicities. Given some of the anatomical limitations and the risk of radiation toxicity, including the overall increased lifetime risk for radiation-induced gliomas, it is likely that genomic profiling will completely shift the focus away from initial aggressive surgery and radiation in the treatment of craniopharyngiomas. Papillary craniopharyngiomas, which occur almost exclusively in adults, show a high rate (90%) of BRAF V600E mutation35 constitutively activating the MAPK pathway, making BRAF and MEK inhibitor combinations potentially effective treatment alternatives.36 It is unclear whether BRAF and MEK inhibitor combinations will lead to durable radiologic results,

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and the most reasonable way toward a cure will likely require— after size reduction with combination therapy—radical resection of residual craniopharyngioma followed by radiotherapy.36 In a case report where there was significant reduction in size of a large craniopharyngioma with single-agent vemurafenib (a BRAF inhibitor), there was rapid regrowth within 6 weeks after discontinuation of therapy.37 Adamantinomatous craniopharyngiomas occur in both children and adults. They have been reported to exhibit a high β-catenin  (CTNNB1 [catenin β 1]) mutation rate  (over 90%). β-catenin is an integral part of the canonical WNT signaling pathway that upregulates MGMT,38 which suggests that an MGMT-targeted strategy may be a feasible treatment alternative in the treatment of adamantinomatous craniopharyngiomas.

Meningiomas Meningiomas can involve any part of the third ventricle. They are more frequently extrinsic lesions of the anterior segment, less frequently involving the posterior segment, and they are rarely found to be entirely intrinsic lesions. The upfront standard treatment of meningiomas, following surgery with the intent of maximal safe resection, is based on their proliferation index, type, and grade, with radiotherapy frequently being used to prevent regrowth. Some current guidelines recommend only three drugs as systemic therapy for refractory and high-grade meningioma— interferon α2b, hydroxyurea, and octreotide. However, none of these options is commonly used in daily clinical practice because of their modest clinical activity.39 Therapies initially explored in the early 1990s that combined interferon α2b and hydroxyurea have proven to have limited activity in recurrent high-grade meningiomas.40 They are also associated with moderate adverse effects and are not frequently used in the treatment of recurrent meningiomas in clinical practice. Various single-agent targeted therapies have been studied in clinical trials. These include somatostatin, temozolomide, irinotecan, interferon-α, mifepristone, megestrol acetate, PDGFR inhibition (imatinib), EGFR inhibition (erlotinib), and VEGFR inhibition (sunitinib and vatalanib), with modest results and often associated with significant toxicity.41,​42,​43 Bevacizumab remains the only single-agent therapy reported in case reports and limited trials (phase 2) to potentially lead to a more durable clinical control at times associated with radiologic response in the treatment of recurrent meningioma.44,​45,​46 However, some have questioned the radiologic response, suggesting that it may be due to effective treatment of the underlying radionecrosis,47 which could be easily determined, given the sophisticated MRI techniques uniformly available in clinical practice today. Bevacizumab dose and treatment density remain significant contentious issues across the cancer literature and reflect the current clinical trial design conceived to evaluate cytotoxic drugs, not allowing for the important distinction between maximum tolerated dose and optimal biologic dose.48,​49 There are interesting results reported with bevacizumab-based combinations using add-on drugs such as everolimus50 and paclitaxel.51 There is a rapidly growing body of literature involving genomics and pathologic correlative studies describing a relatively small number of oncogenic driver mutations, which turn out to be type-, grade-, and intracranial location–specific.52,​53 The NF2 gene is altered across all meningiomas, while AKT1, SMO, TRAF7, and KLF4 are altered in WHO grade I meningiomas; CDKN2A/C, SMARCE1, and TERT are altered in WHO grade II meningiomas; and CDKN2A/C

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and TERT are altered in WHO grade III meningiomas,52 with TERT promoter mutations predicting a shorter time to progression.54,​55

concomitant use of targeted therapies, given reports of a rate of V600E mutation in the BRAF oncogene as high as 60%, regardless of stage or organ involvement.59

Pilocytic Astrocytomas Pilocytic astrocytomas, including the pilomyxoid astrocytoma variant, are most often diagnosed in children. Those originating from the chiasmatic or hypothalamic region could expand into the anterior segment of the third ventricle. Pilocytic and pilomyxoid astrocytomas share many histopathologic features, with a few notable differences in both histology and behavior. Pilomyxoid astrocytomas commonly arise from the hypothalamic chiasmatic area and are significantly more aggressive. Patients have substantially shorter progression-free survival and a higher rate of recurrence and leptomeningeal spread. Gross total resection when safe is usually curative. Up to 20% of patients with pilocytic astrocytomas experience a very poor outcome. Most inoperable pilocytic astrocytomas are slow-growing tumors that can usually be monitored with formal visual fields and MRI, and they are best managed at time of growth with carboplatin-based combination chemotherapy. Radiotherapy should be avoided because it might trigger malignant transformation to a higher grade and lead to significant neurocognitive deficit in this location, and overall it has been associated with worse outcomes when used for upfront treatment. For the treatment of postsurgical residual pilomyxoid astrocytomas, some have advocated for upfront radiotherapy because of the more aggressive behavior of such tumors. At the time of rapid leptomeningeal spread, radiotherapy could stabilize the disease and limit neurologic functional loss. Genomic profiling in the near future will likely help redefine the role and timing of chemotherapy and radiotherapy. The most frequent genetic alteration identified in pediatric pilocytic astrocytomas is the KIAA1549-BRAF fusion, which typically results from a 2.0 Mb tandem duplication in chromosome band 7q34 with other less frequent abnormalities, including BRAF, FGFR, KRAS, and NF1 point mutations and whole chromosome gains.56 Whole chromosome 7 gain accompanies the KIAA1549-BRAF fusion, with the fusion likely arising first. Whole chromosome 7 gain is associated with a 5-fold increase in the risk of tumor recurrence, whereas the KIAA1549-BRAF fusion alone or a BRAF mutation alone is not associated with an increased risk of recurrence.56 Some reports suggest similar genomic abnormalities (KIAA1549-BRAF fusion, although it was unclear in this study whether the presence of the fusion was associated with whole chromosome 7 gain) as predictors of recurrent disease in the adult pilocytic astrocytomas, while the KIAA1549-BRAF fusion appears to be a marker of supratentorial pilocytic astrocytomas.57

Langerhans Cell Histiocytosis Langerhans cell histiocytosis, which is usually seen in children and young adults, could expand into the anterior segment of the third ventricle when it involves the pituitary hypothalamic area. Patients can present with a wide variety of manifestations. Classic imaging findings include vertebra plana, skull lesions with a beveled edge, the “floating tooth” sign, bizarre lung cysts, and an absent posterior pituitary bright spot with infundibular thickening.58 Systemic staging should be completed upfront to assess disease burden and help establish a baseline before treatment because imaging remains paramount to assessing treatment response. Primary treatment remains chemotherapy with genomic profiling, which suggests that upfront chemotherapy may be soon replaced or enhanced by

Germ Cell Tumors Germ cell tumors (GCTs) are classified as extragonadal if there is no evidence of a primary tumor in either the testes or the ovaries. The central nervous system is one of the most common sites of extragonadal involvement. More than 80% of GCTs arise in structures around the third ventricle. Most GCTs occur in the pineal gland and usually expand into the posterior segment of the third ventricle. Another frequent site of involvement for GCTs is the suprasellar/posterior pituitary compartment, with expansion into the anterior third ventricle. Histologic subtype is the single most important predictor of response to treatment and outcome. Whole neuraxis MR imaging, CSF cytology, and tumor biomarker  (α– fetoprotein and β-HCG) levels in CSF and serum are routine in the presurgical treatment assessment of GCTs. Pure germinomas are the most common GCTs and are generally associated with absent α-fetoprotein and β-HCG  (some may show a low β-HCG when they contain synctiotrophoblast that can secrete β-HCG). Nongerminomatous germ cell tumors include embryonal carcinomas, yolk sac tumors, choriocarcinomas, and teratomas, with a benign subtype that could be mature or immature and a more aggressive subtype with malignant transformation. Pure germinomas are exquisitely sensitive to radiation and chemotherapy, and subtotal or gross total resection does not offer any added benefit beyond biopsy. A radiation test dose could be used when biopsy is not safely possible. Nongerminomatous germ cell tumors  are often resistant to radiotherapy and chemotherapy, making a second operation (i.e., salvage surgery) the mainstay of treatment.60,61 For localized germinomas, whole ventricular field irradiation is usually preferred, with a boost to the area of enhancing disease except in cases of rare basal ganglia germinomas that require whole brain radiotherapy.62,63 Disseminated germinomas require craniospinal irradiation. A total radiation dose of less than 40 Gy is associated with a high risk of recurrence, as is treatment with chemotherapy alone. Almost all effective chemotherapy regimens include a platinum compound (cisplatin or carboplatin), etoposide, and a short list of other agents (ifosfamide, cyclophosphamide). Combining neoadjuvant chemotherapy with radiotherapy significantly improves outcomes. Patients with recurrence should be considered for salvage surgery, chemotherapy with local or whole neuraxis irradiation, or myeloablative chemotherapy with autologous blood stem cell rescue.

Lymphomas: Primary Central Nervous System Lymphomas Approximately 95% of primary central nervous system lymphomas (PCNSLs) are composed of a distinct subtype of a large B cell lymphoma arising from the brain, eyes, meninges, or spinal cord in the absence of significant lymphoma burden outside the central nervous system. These lesions are usually successfully treated with an upfront immunochemotherapy combination that includes high-dose methotrexate (3–4 g/m2 to ensure reaching the cytotoxic dose, ideally 8 g/m2), rituximab, and temozolomide followed by dose-intense consolidation therapy with infusional etoposide and high-dose cytarabine, with radiation delayed and used only as salvage therapy. Peak incidence in immunocompetent patients is in the sixth and seventh decades of life. Younger patients are usually immunocompromised. Among patients with

16  Tumors of the Third Ventricle HIV/AIDS, peak incidence is in the forties; among transplant recipients, it is in the mid-thirties; and among patients with inherited immunodeficiency, it is in the early teens. Patients with autoimmune disorders, such as rheumatoid arthritis and Sjögren's syndrome, run a high risk of development of PCNSL. The Epstein-Barr virus plays a major role in the oncogenesis of PCNSL in immunocompromised patients. The Epstein-Barr virus genome is present in tumor cells in more than 95% of immunocompromised patients, but in only up to 20% of immunocompetent patients.64 PCNSLs that arise from structures around the third ventricle, where the risk of a biopsy may not be justified, are frequently associated with obstructive hydrocephalus. Hydrocephalus can best be managed with an extraventricular drain, and when a diagnosis can be made by CSF sampling, by immediate initiation of immunochemotherapy. High-dose methotrexate and rituximab can lead to a rapid reduction in tumor size, resolution of obstructive hydrocephalus, and normalization of intracranial pressure, allowing a conversion from the extraventricular drain to an Ommaya reservoir and obviating the need for a shunt. PCNSL is recognized as a distinct subtype because of its distinct transcriptional features as well as the fact that it requires treatment regimens that are different from those for its systemic counterpart.64 In patients with PCNSL, BCL6 expression is high (50–90%), as is BCL2 expression (56–93%). Together with other significant markers of disease activity, such as high MYC expression and MYC translocation, high BCL6 and BCL2 expression predicts a poor response to therapy, and patients usually require rapid treatment escalation to autologous stem cell transplantation.64

Ependymomas Ependymomas are rare primary tumors of the central nervous system affecting both children and adults. Genetically distinct subgroups have been described with a phenotype more specific to the location or site of origin than age at time of diagnosis. The following distinct subgroups have been described: supratentorial ependymomas with C11orf95-RELA fusion or YAP1 fusion, infratentorial ependymomas with or without a hypermethylated phenotype, and spinal cord ependymomas.65 Surgery with the intent of gross total resection is the mainstay of therapy. Radiation is used for residual or recurrent disease in the classic WHO grades II and III ependymomas. To date, no potential oncogenic drivers as actionable biomolecular targets have been reported. Chemotherapy is reserved for large residual higher-grade ependymomas or for salvage therapy, with most studies focusing on combinations including platinum compounds (cisplatin or carboplatin) and etoposide.

Gangliogliomas Gangliogliomas are slow-growing tumors of mixed neural and glial origin for which radical surgery leading to gross total resection is frequently curative. Progression-free survival is determined by the extent of initial resection.66,​67 Some gangliogliomas have a propensity to transform into glioblastoma multiforme,68 a process that may be accelerated by radiotherapy.69,​70 Thus, defining the role of radiotherapy in the case of a very infrequent tumor like ganglioglioma has been somewhat difficult, but the growing evidence is overwhelmingly in favor of radiotherapy. Several institutional retrospective reviews suggest that adjuvant radiation may increase progression-free survival in patients with subtotal resections

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while salvage radiotherapy is significantly less effective in achieving long-term control.66,​67,​71,​72 For deep-seated periventricular (with or without intraventricular extension) tumors that are usually not amenable to radical resection but have imaging features suggestive of low-grade ganglioglioma, a period of observation is reasonable because radiotherapy in this location may lead to significant neurocognitive compromise. A diagnostic biopsy should be pursued in these cases, usually when growth is seen or there is a threat of anatomical compromise. When disease progression occurs, it is unclear whether radiotherapy alone improves overall survival, and thus we advocate a (temozolomide-based) chemoradiation approach that may be more effective. One could infer from the low-grade glioma literature that radiotherapy at the time of disease progression will only increase progression-free survival and will not impact overall survival. For patients wth anaplastic ganglioglioma, maximal surgical resection followed by temozolomide-based chemoradiation and adjuvant temozolomide may lead to better outcomes. Dysregulated genes reported in gangliogliomas have been related to the aberrant development of neuronal precursors. These genes are grouped into five categories: (1) chromatin state regulation and transcription factors (CDY1 and BCL11A downregulation); (2) intracellular signal transduction (HSJ2, ARF3, ST6GALNAC4, and PRKCB1 downregulation); (3) extracellular signal transduction and cell adhesion (NELL2 downregulation, MMP2 and PLAT upregulation); (4) cell cycle and proliferation control (TP53 and TRIB1 upregulation); and (5) development and differentiation  (NGFR, P75, and BDNF upregulation, and LMO4 and LDB2 downregulation).73 A BRAF (V600E) mutation has been found in 30 to 40% of patients with gangliogliomas, making for a high-risk group with significantly decreased postsurgical progression-free survival74. Inhibition of BRAF expression has been reported to lead to significant treatment-dependent control rates, with tumor regrowth within 8 to 12 weeks after discontinuation of BRAF inhibition.75 There are no reports at this time regarding synthetic BRAF-MAPK inhibition that combines BRAF inhibitors with MAPK (ERK/MEK) inhibitors, but given the experience with other tumors, such as melanoma, this may be a more clinically sustainable model, especially when used in a continuous intermittent manner.

Primitive Neuroectodermal Tumors Primitive neuroectodermal tumors  (PNETs), which are more frequent in children, are embryonal tumors composed of undifferentiated or poorly differentiated neuroepithelial cells that can differentiate along neuronal, astrocytic, ependymal, melanocytic, and muscular lines (cerebral neuroblastoma with distinct neuronal differentiation, glanglioneuroblastoma showing ganglionic cells, pineoblastoma originating in the pineal region, medulloepithelioma featuring neural tube formations, and ependymoblastoma showing ependymoblastic rosettes). PNETs have been grouped on the basis of their LIN28 and OLIG2 cell lineage marker expression levels, with increased LIN28 and decreased OLIG2 expression in group 1, increased OLIG2 and decreased LIN28 expression in group 2, and decreased expression of both LIN28 and OLIG2 in group 3.76 These groups have specific correlative characteristics in terms of sex, age of onset, propensity to develop metastases, median survival, and genetic characteristics, underlying signaling pathway. Group 1 tumors do not metastasize and show increased WNT and SHH signaling; group 2 tumors do not metastasize and show decreased WNT and SHH signaling; and group 3 tumors, usually metastatic, show increased TGF-β, PTEN, and semaphorin

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signaling.75 Gross total resection does not increase overall survival. There is no standard chemotherapy regimen. In children, vincristine chemoradiation is followed by an adjuvant combination of cisplatin, lomustine, and vincristine. In adults, cisplatin in combination with cyclophosphamide and vincristine is one of the more frequently used protocols.

Pineal Parenchymal Tumors Pineal parenchymal tumors include pineocytomas, pineal parenchymal tumors with intermediate differentiation, and pineoblastomas. Pineocytoma is a very rare low-grade tumor for which gross total resection is the best predictor of survival. The addition of radiotherapy in patients who incurred subtotal resections has not led to increased survival. The impact of adjuvant chemotherapy has not been prospectively studied.77 Pineal parenchymal tumors with intermediate differentiation and pineoblastomas benefit from maximal safe resection, radiotherapy, and chemotherapy (procarbazine, lomustine, and vincristine or platinumbased combinations such as carboplatin, cyclophosphamide, and etoposide or ifosfamide, carboplatin, and etoposide).

Abnormal mTOR signaling is a hallmark of a continuum of brain disorders termed TORopathies (e.g., subependymal giant cell astrocytoma or tuberous sclerosis complex, focal cortical dysplasia, hemimegalencephaly, dysembryoplastic neuroepthelial tumors, and gangliomas). They are all associated with intractable seizures and altered cortical architecture, likely due to migration abnormalities.84 Thus, the question has been raised of a possible developmental migration defect playing a role in the oncogenesis of chordoid gliomas. In a small multicentric series of 17 cases of chordoid gliomas, thyroid transcription factor 1 was constantly expressed, but there was no evidence of an IDH1/2 or BRAF mutation.83 Treatment remains largely surgical, with gross total resection as the primary goal leading to durable high rates of control. The role of adjuvant radiotherapy has yet to be determined because it does not seem to improve outcome. However, some authors advocate for the use of (focal) radiotherapy for postsurgical residual disease and as a way to obtain a better benefit-risk ratio with limited-scope resection surgeries that otherwise may be associated with unacceptable morbidity.86 Delaying surgery may be associated with a high risk of leptomeningeal intraventricular spread.87

Papillary Tumors of the Pineal Region Papillary tumors of the pineal region do not arise from the pineal gland itself but from the specialized cytokeratin- and nestin-positive ependymal cells deriving from the subcommissural organ. These tumors share various morphologic features with a number of other papillary-like tumors occurring in the pineal region: pineal parenchymal neoplasms, choroid plexus papillomas, papillary ependymomas, metastatic papillary carcinomas, papillary meningiomas, and GCTs. Tissue diagnosis is of paramount importance as gross total resection is usually associated with longer overall survival. Data are limited regarding treatment consolidation, but given high recurrence rates of up to 68% and a 5-year overall survival of 73%, one could strongly argue for postresection radiotherapy and chemotherapy.78

Subependymal Giant Cell Astrocytoma Subependymal giant cell astrocytomas, which are associated with tuberous sclerosis complex, are known to reach high partial response or control rates with treatment with everolimus (an mTOR inhibitor).79 Use of everolimus has also significantly improved control of otherwise pharmacoresistant seizures.80

Chordoid Gliomas The term chordoid glioma of the third ventricle may be a misnomer for a tumor of disputed origin reported to express both glial and ependymal markers81,​82 that are typically located in the anterior segment of the third ventricle. They are part of a spectrum of lineage-related neoplasms of the basal forebrain that share thyroid transcription factor 1 expression with organum vasculosum of the lamina terminalis and with pituicytic tumors (pituicytoma and spindle cell oncocytoma).83,​84 Chordoid gliomas of the third ventricle and pituicytic tumors also share mTOR pathway activation because phosphorylated ribosomal protein S6 has been found in both groups,85 suggesting that mTOR inhibition with everolimus may play a role in their treatment.

Radiosurgical Considerations The experienced radiation oncologist frequently encounters the need to irradiate the third ventricle and surrounding tissues. For both malignant and benign lesions, the surrounding radiation-sensitive structures dictate dose limitations both for conventionally dosed radiation (image-guided intensity-modulated radiotherapy) and for stereotactic radiosurgery (1–5 fractions). Radiobiologic modeling and clinical outcomes have generated generally accepted guidelines for radiation tolerance based on dose/volume determination.88,​89,​90,​91 Table 16.2 summarizes the relevant dose tolerances that are used, which are subject to revisions and updates. Hippocampal dose constraints are a subject of ongoing clinical investigations, with the underlying rationale to limit dose to the neural stem cells of the subgranular zone of the dentate gyrus and thus reduce cognitive decline.92 Hippocampal avoidance in whole-brain treatment, as reported in the study RTOG 0933,92 suggests potential benefit, and the current study NRG-CC001 is accruing. However, no guidelines are currently accepted for partial volume hippocampal radiation. The use of radiation therapy in or near the third ventricle is additionally based on histology and tumor volume. The choice of partial fractionated radiation instead of radiosurgery is based on the constraints discussed above, as well as on the ease of target definition and overall radiation volume required.

Surgical Considerations Over the years, multiple transcranial approaches have been described to access the region of the third ventricle, generating a confusing laundry list of approaches. These include the transcortical/transgyral, interhemispheric transcallosal, interforniceal, transforaminal, orbitozygomatic subfrontal, and supracerebellar infratentorial approaches. Alternatively, we favor an approach dictated by the anatomy within the radial architectural framework and by the goals of surgery.

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Table 16.2  Summary of relevant dose tolerances based on anatomic location

Risk organ

Radiation volume

Dose constraints

Toxicity

Reference

Chiasm/optic nerves

Entire structure

55 Gy at 1.8–2 Gy/fxn

Optic neuropathy

Marks et al 201090

Entire structure

20 Gy in 5 fxn

Optic neuropathy

Grimm et al 201189

0.2 mL

15 Gy in 3 fxn

Optic neuropathy

Timmerman 200891

0.2 mL

8 Gy in 1 fxn

Optic neuropathy

Timmerman 200891

Max point

19.5 Gy in 3 fxn

Optic neuropathy

Timmerman 200891

Max point

12 Gy in 1 fxn

Optic neuropathy < 7%

Grimm et al 201189

Partial brain

72 Gy at 1.8–2 Gy/fxn

Radionecrosis

Marks et al 2010 90

5–10 mL

12 Gy in 1 fxn

Radionecrosis risk < 20%

Emami et al 199188

Entire structure

54 Gy

Craniopathy

Entire structure

20 Gy in 5 fxn

Limited < 10 mL

59 Gy

1 mL

18 Gy in 3 fxn

Timmerman 200891

1 mL

10 Gy in 1 fxn

Grimm et al 201189

Max point

23 Gy in 3 fxn

Timmerman 200891

Max point

15 Gy in 1 fxn

Grimm et al 201189

Entire structure

45 Gy

Brain tissue Brainstem

Pituitary gland

Grimm et al 201189 Craniopathy

Panhypopituitarism

Emami et al 199188

Abbreviations: fxn, fraction; Gy, Gray; max, maximum.

Surgical Access Corridors As mentioned earlier, in designing an anatomically driven algorithmic approach, the first consideration is to define the specific segment of the third ventricle to be targeted. Hence, this creates an inside-out algorithm: third ventricle (target) ← aperture ← inner radial corridor (IRC) ← outer radial corridor (ORC) (Fig. 16.1, Fig. 16.2, Fig. 16.3).

Target Localization Anterior Segment of Third Ventricle The C-shaped nature of the anterior segment of the third ventricle precludes linear access to the entire segment via one corridor. This segment is complex and can be further divided into three subsegments (Fig. 16.3):  1. Dorsal: Immediately below the foramen of Monro and anterior commissure  2. Anterior: Optic recess  3. Ventral: Infundibular recess Each of these three subsegments has a CSF space along its immediate perimeter and a correlative aperture that provides an immediate access point into the underlying respective segment of the anterior third ventricle (Fig. 16.2, Fig. 16.3):  1. Dorsal: Lateral ventricle through the foramen of Monro  2. Anterior: Prechiasmatic cistern through the lamina terminalis  3. Ventral: Interpeduncular cistern through the membrane of the infundibular recess Similarly, there is an outer neural and CSF space that provides access to each of these inner CSF spaces located along the immediate perimeter of the respective segment of the third ventricle (Fig. 16.2, Fig. 16.3):

 1. Lateral ventricle: Various routes to the lateral ventricles have been described:  a) Transgyral via frontal gyrus  b) Transcallosal via the interhemispheric fissure  c) Transsulcal parafascicular via a series of individualized routes using sulci along parafascicular white matter corridors between the superior longitudinal fasiculus and the cingulum and along the long axis of the anterior limb of the internal capsule, which preserves the integrity of these large white matter tracts  2. Prechiasmatic cistern: Accessed through the proximal sylvian fissure and the opticocarotid cistern  3. Interpedencular cistern: Accessed ventrally via the EEA or, alternatively, accessed laterally via the orbitozygomatic and transslyvian approaches between the posterior communicating artery and the oculomotor nerve

Transitional Zone and Middle Segment The transitional zone and the middle segment of the third ventricle are best considered as a single target because the considerations are similar. Designing an access corridor through the outer parenchymal perimeter (ORC) can be restrictive because the transgyral options become more hazardous as one travels posteriorly in the frontal lobe toward the central sulcus; risks of supplementary motor deficits increase the more posterior the approach (Fig. 16.3). Similarly, transcallosal corridors may require middle third callosotomies, which have an increased risk of neurocognitive morbidity, especially if subcortical and limbic pathways are already affected by the pathology. Therefore, we prefer transsulcal parafascicular corridors into the lateral ventricle to access this segment (see discussion below) (Fig. 16.1, Fig. 16.2, Fig. 16.3). Once in the lateral ventricle, access to the transitional zone just posterior to the foramen of Monro or the middle segment can

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theoretically be achieved via the interforniceal route (Fig. 16.1, Fig. 16.2). However, in practice we do not find this route useful. The space between the fornices at the level of the foramen of Monro is limited; thus, creating a window between them without causing forniceal injury is highly unlikely. Therefore, when access to the transitional zone or middle segment of the third ventricle is needed, we prefer the tela choroidea approach through the velum interpositum (Fig. 16.2, Fig. 16.3). It should be noted that the tela choroidea approach is limited in its posterior extension to the massa intermedia. This interthalamic adhesion creates a relative boundary that makes accessing the posterior segment of the third ventricle via the lateral ventricle problematic.

Posterior Segment of the Third Ventricle Access to the posterior segment of the third ventricle can be divided into a series of radial corridors, with these posterior trajectories subdivided into dorsal and ventral orientations (Fig. 16.2, Fig. 16.3). It is useful to consider the radial corridors as being based on each of the three components—the ORC, the IRC, and the specific aperture that provides access to the posterior segment of the third ventricle. In so doing, it becomes apparent that in the case of the posterior third ventricle, the respective apertures represent the key limitations.

Dorsal Radial Corridors to the Posterior Segment of the Third Ventricle Irrespective of which ORC is used to access the posterior portion of the lateral ventricle, the IRC limits access to the posterior segment of the third ventricle because the intervening aperture is very limited. Explicitly stated, dorsally accessing the posterior segment of the third ventricle through the floor of the lateral ventricle is not only limited by the massa intermedia but also proves to be quite hazardous as one proceeds through the velum interpositum because the intervening space between the ICV narrows where they meet at the great vein of Galen (see section on surgical nuances below). Therefore, for practical purposes, this dorsal route is not helpful as there is no meaningful aperture between the target and the selected IRC (Fig. 16.3).

Posterior Radial Corridors to the Posterior Segment of the Third Ventricle Posterior ventral trajectories rely on the quadrigeminal cistern as the immediate perimeter CSF space to access the posterior segment of the third ventricle. The quadrigeminal cistern itself can be reached from a dorsal or ventral trajectory, depending on the ORC selected.

Dorsal Posterior Trajectory to the Quadrigeminal Cistern Dorsal posterior transparenchymal trajectories require access via an outer corridor that would entail creating windows through the posterior one-third of the corpus callosum and splenium (Fig. 16.2, Fig. 16.3). These approaches have not been generally pursued because of the risk of profound associated morbidity. Alternatively, we have used sulcal corridors to avoid injury to the parenchyma. Specifically, we have used the parietoccipital sulcus. We have primarily restricted the use of this corridor to large exophytic or extrinsic tumors when the lesion creates an acceptable window. Our experience has primarily

been in confluence meningiomas with anterior extension into the posterior segment of the third ventricle and in pineal region tumors warranting surgery.

Ventral Posterior Trajectory to the Quadrigeminal Cistern Going through the parenchyma can be avoided by using one of the more ventrally oriented ORC trajectories developed to provide direct access to the quadrigeminal cistern. In general, these can be achieved via a supratentorial (suboccipital) or infratentorial (supracerebellar) corridor (Fig. 16.2, Fig. 16.3). Surgeon experience and anatomical considerations, such as the angle of the tentorium and deep venous drainage (Dandy's vein), can have an impact on which trajectory is selected. However, regardless of the specific ORC trajectory that is selected, accessing the posterior segment of the third ventricle after reaching the quadrigeminal cistern can be exceptionally hazardous because there is no aperture into the third ventricle. The pineal stalk and membrane are guarded by an array of anatomically vital structures. In summary, there are very few radial corridors that allow safe access to the posterior segment of the third ventricle because of the limited apertures between the CSF spaces along its IRC. There are no foramina, and membrane access is limited by rich and crowded anatomy between the floor of the posterior portion of the lateral ventricle or the quadrigeminal cistern and the posterior segment of the third ventricle. Therefore, meaningful access to the posterior segment of the third ventricle is restricted to apertures of the anterior segments  (foramen of Monro) and the middle segments (tela choroidea and velum interpositum) anterior to the massa intermedia. Flexible endoscopes with working channels have been developed to overcome this limitation. With a through-channel endoscope (e.g., the Oi or the Little LOTTA [Karl Storz]), the posterior third ventricle now becomes accessible using a frontal engagement point, traversing the lateral ventricle and foramen of Monro.94 The technical differences in operating with a throughchannel endoscope and the port-based system have been summarized elsewhere.95 With the use of a port, a surgeon can operate with both hands, hemostasis is enhanced because of the air medium, and visualization is maintained even when there is bleeding. Therefore, the goals of surgery for lesions in the posterior segment of the third ventricle using the through-channel endoscope must be tempered. Lesions that are dense, fibrous, or vascular must be approached with caution and often are restricted for biopsy purposes. Cystic lesions, especially along the cyst wall, that are not especially thick or vascular can be fenestrated and drained. The Myriad (NICO) endoscopic handpiece is a useful tool for cyst wall penetration and aspiration of cyst contents. We restrict the use of the through-channel endoscope primarily to internal CSF diversion (anterior third ventriculostomies) and to lesions of the posterior segment of the third ventricle requiring biopsy or resection (if less than 3 cm, not vascular, and not fibrous). The nuances of through-channel endoscopy are beyond the scope of this chapter, but discussion of their indications is relevant. While the indications above are by no means absolute, we believe them to be good general guidelines. For lesions affecting the anterior or middle segment of the third ventricle, we prefer the use of a port via a transsulcal parafascicular approach over a through-channel endoscope because there is a viable aperture

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into these segments through the IRC of the lateral ventricle. The port facilitates bimanual dissection and microsurgical technique, and it provides an air medium that offers the advantages of hemostasis and visualization.

Surgical Nuances

General Surgical Considerations

Outer Radial Corridors

In our operating room, we prefer to plan our surgical cases using integration and coregistration of preoperative imaging (MRI/CT/DTI) and to construct a trajectory and corridor for the surgeon to use intraoperatively. The patient is also coregistered with the imaging sequences to offer a real-time, intraoperative, spatial map. This quality-control process aids the surgeon in trajectory planning, in avoiding key neurovascular structures, and in determining the extent of resection needed, while ensuring the preservation of critical neural pathways. One of the primary considerations in accessing the third ventricle is to be cognizant of the impact of the pathology on the neurocognitive pathways and to mitigate it by limiting approach-related injuries that can cause further impairment. We refer to this as zero-footprint surgery. It involves reviewing and visualizing the key elements of the neocortical, subcortical, and limbic systems that are well known to subserve these functions. Although there is still much ambiguity about the constituents of these systems, in our experience, the following considerations have proven useful:

The ORCs are divided into dorsal corridors to the lateral ventricle, rostral corridors to the prechiasmatic cistern, and ventral corridors to the interpeduncular cisterns (Fig. 16.2, Fig. 16.3). The rostral and ventral corridors provide access through cisterns analogous to the manner in which the dorsal corridors utilize the interhemispheric fissure. The respective cisternal corridors are the proximal sylvian fissure, the opticocarotid cistern rostrally, and the interpeduncular cisterns ventrally, the latter of which is accessed through the EEA. The rostral and ventral access corridors are reviewed in the following section on accessing the IRC cisterns. The ensuing section will focus exclusively on the dorsal ORCs to access the lateral ventricle.

Neurocognitive Systems  1. Neocortical governing system constituents  a) Dorsal forebrain: Superior and middle frontal gyri  b) Medial forebrain: Cingulate gyrus, gyrus rectus  2. Key subcortical white matter pathways  a) Superior longitudinal fasciculus

A detailed description of each of the variations of the radial corridor is beyond the scope of this chapter. However, in the ensuing section, we will consider specific key surgical nuances of the most relevant components of the radial corridors.

Transgyral Historically, a variety of transgyral corridors have been used that are primarily restricted to the frontal region, which was thought to be noneloquent cortex. Increasing awareness of the neurocognitive eloquence of the frontal region, particularly in the setting of pathology that can affect deeper critical neurocognitive pathways, has led to increasing caution in selecting transgyral approaches (see previous section on neurocognitive systems). In addition to issues of parenchymal injury, edema, and hemorrhage, concerns about seizures have also been raised. Finally, the use of transgyral corridors is restricted to the cortex anterior to the coronal suture, which is a key limitation.

 b) Cingulum

Interhemispheric fissure

 c) Anterior projection fibers

The ORCs have been migrated to the interhemispheric fissure in an effort to preserve the cortical mantle and provide progressively more posterior access beyond the coronal suture. The bone flap is generally made to straddle the midline with one-third to the left and two-thirds to the right. The approach usually proceeds with the sagittal sinus to the left and deepens along the right mesial frontal lobe. Some surgeons have advocated positioning the patient with the dependent side down and the falx superior to mitigate the effects of retraction. However, this position can be disorienting, especially once the lateral ventricle is reached. Thus, we prefer the neutral position. It is imperative to undertake a detailed assessment of the venous structures, in particular the bridging veins. Therefore, we prefer to use a CT venogram or a magnetic resonance venogram (Fig. 16.4). This approach can become quite limited in its anteroposterior direction by the relative position of the bridging veins. Although veins can be sacrificed, this must be done with care because it can lead to venous strangulation of the frontal lobe, with consequent edema and venous infarction. It is especially important to ensure that the cingulate gyrus, which runs just above the corpus callosum, is well protected from retraction and has preserved venous outflow because the corpus callosum and fornix will have to be manipulated (see previous section on neurocognitive pathways). The next stage in the approach requires mobilizing the overlying

 d) Inferior frontal occipital fasciculus  e) Corpus callosum  3. Limbic system  a) Fornix (all elements)  b) Mammilothalamic tracts  c) Limbic commissural fibers  i) Anterior commissure  ii) Massa intermedia  iii) Posterior commissure  4. Limbic regulators  1) Mammillary bodies  2) Habenula  3) Pineal gland Each of these segments is carefully visualized using appropriate preoperative imaging (i.e., MRI DTI). Corridors are designed to avoid injury as much as possible. In addition, in these particular cases, we prefer to have the patient awake during surgery in an effort to monitor the patient’s neurologic status. This is especially valuable for lesions around the fornix, such as colloid cysts, where memory functions can be closely monitored.

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distal segments of the anterior cerebral arteries  (A2), specifically the pericallosal and callosal marginal segments. It can be difficult to determine which side the respective A2 belongs to; thus, intraoperative computed tomography angiography with navigation can be helpful. Next, a limited callosotomy in the anterior or middle third ventricle is created. The exact location of the callosotomy takes into consideration the ideal angle into the respective aperture (i.e., the foramen of Monro or the middle third of the tela choroidea/ velum interpositum) (Fig. 16.3). Ideally, a relatively vertical direction with the specific aperture located just anterior to a direct perpendicular line is favored. This avoids toggling, thereby minimizing torque on the corpus callosum. It also allows the surgeon to be comfortable with residual CSF and any bleeding that drains posteriorly into the occipital horn. Most importantly, it minimizes disorientation by keeping the relevant anatomy in front of the surgeon. The preferred location of the callosotomy is posterior to the genu in a direction along the long axis of the fibers. The general belief has been that the more posterior the callosotomy, the greater the morbidity to the posterior third ventricle; thus, the opening into the posterior third ventricle and splenium are strongly discouraged.

geometric fit (Fig. 16.5, Fig. 16.6, Fig. 16.7). We have migrated to an integrated platform  (BrightMatter; Synaptive Medical), which allows for user-friendly rendering in 15 minutes with reliable 3D manipulation to plan individualized patient-specific corridors. Critical nuances in developing transsulcal parafascicular corridors to the third ventricle take into consideration the primary fibers that may be involved in neurocognitive pathways along each of the concentric radial corridors:  1. Outer radial corridor  a) Dorsal frontal cortex and supplementary motor regions  b) Cingulate gyrus  c) Corpus callosum  d) Cingulum  2. Inner radial corridor  a) Columns of the fornix  b) Body of the fornix  3. Third ventricle  a) Mammilothalamic tracts  b) Fimbriae of the fornix  c) Body of the fornix

Transsulcal parafascicular corridor Over three generations, significant evolution has occurred since the original pioneering work of Yaşargil, Patrick Kelly, and, more recently, Robert Spetzler in the field of microsurgery, specifically using transsulcal corridors. In an effort to add to this body of work, we have focused on two aspects of transsulcal surgery: the form of the corridor that is created and the trajectory that is selected. Although detailed discussion of transsulcal parafascicular surgery is beyond the scope of this chapter, we will review general principles that are relevant to accessing the third ventricle. Two primary forces, strain (force per unit area applied to adjacent structures) and shear (the angle at which force is applied), represent the most relevant considerations. Strain forces are secondary to the form of the corridor created, which includes the manner in which the corridor is maintained and sustained. In 2015, we published our experience with the use of a specific radial corridor that enters the sulci and dilates it from 2 mm to 13.5 mm using a specific atraumatic port (BrainPath; NICO).96 The primary concern in inserting a port through a sulcus has been the possibility of injury to the cerebrovasculature. However, we have not encountered this adverse event in our experience with 100 consecutive cases. The radial corridor allows dissipation of strain forces along the diameter of the port, which we have found leads to preservation of the underlying white matter tracts. Shear forces represent the likelihood of shearing the white matter tracts and are a function of not only the magnitude of the force but also the angle at which it is applied. Therefore, the second consideration in transsulcal trajectory-centric corridors is to design a specific trajectory that represents a line between the selected entry point and the specific target. In general, we have found that we can minimize shear forces by selecting corridors along the long axis of critical white matter tracts that are to be preserved, rather than at acute angles to them. We select angles that are within 30° of the long axis of the fiber in question. This necessitates being able not only to see the tracts but also to accurately render them in 3D space with reliable

 d) Crura of the fornix Pathology affecting the third ventricle will obviously significantly impact these neurocognitive pathways within the third ventricle; therefore, iatrogenic injury to critical structures along the ORC and IRC during access must be minimized. It is worth reemphasizing that transsulcal parafascicular corridors require the generation of an individualized trajectory for each patient that is created based on detailed MRI DTI tract rendering and coregistration. The ability to travel parafascicular along sulci, thereby preserving underlying subcortical white matter tracts, allows for more posteriorly centered ORC access corridors without the limitations of transgyral corridors. Our adoption of this approach has completely obviated the need for gyrectomies and callostomies.

Inner Radial Corridor and Apertures The surgical nuances of the IRCs and their respective apertures that lead to the segments of the third ventricle will be discussed together (Fig. 16.2, Fig. 16.3). At the outset, it should be noted that there is a key difference between intrinsic and extrinsic tumors when considering this element of the radial corridor. Endophytic extrinsic tumors can grow into the third ventricle, and exophytic intrinsic tumors can grow out of the third ventricle, in the process widening the respective apertures and creating a substantial window between the third ventricular segments and their respective IRCs. The ability to capitalize on these lesion-generated windows into the third ventricle makes otherwise inaccessible segments accessible. This can mitigate many of the limitations associated with purely intrinsic tumors without exophytic components. A prime example of this phenomenon is the craniopharyngioma. Type IV craniopharyngiomas represent lesions intrinsic to the third ventricle, with no distortion of the aperture (i.e., infundibular recess) precluding ventral access. These tumors are located within the walls of the anterior third ventricle, without growing into and through the infundibular recess. They are bounded along their floor by a normal tuber cinereum and a

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Fig. 16.5  Case 1: Dorsal anterior segment approach. Type II colloid cyst resection with the use of a port (BrainPath; NICO) and a robotically guided optical telescopic platform (ROVOT-m; Synaptive Medical) and intraoperative navigation. The tumor was located in the anterior segment of the third ventricle and was approached via a transsulcal parafascicular, lateral ventricle, foramen of Monro approach. (a) Axial (top row, left to right) computed tomogram (CT), T2-weighted fluid-attenuated inversion recovery (FLAIR) magnetic resonance image (MRI), and T1-weighted contrast-enhanced MRI. Axial (bottom left) T1-weighted MRI and sagittal (bottom right) T2-weighted FLAIR MRI demonstrating heterogeneous, rounded third ventricular mass consistent with a colloid cyst. The cyst is isodense on CT, and primarily hyperintense on T1- and T2-weighted images. It appeared to cause obstruction of the lateral ventricles, resulting in transependymal flow of cerebrospinal fluid (CSF). (b) Axial (left) and coronal (right) MRI diffusion-tensor imaging (DTI) tractography showing outward displacement of corticospinal tracts as a result of obstructive hydrocephalus of the lateral ventricle. (continued)

pituitary stalk, neither of which allows for safe ventral access. As a result, these tumors are generally accessed via dorsal routes, with the most common being via a port to provide the following route: transsulcal parafascicular (ORC) → lateral ventricle (IRC) → tela choroidea/velum interpositum (aperture) → infundibular recess (third ventricular target). In contrast, type II craniopharyngiomas dilate the pituitary stalk, creating a window between the tuber cinereum and the infundibular recess. This window provides excellent ventral access via the following route: EEA  (ORC)→ infundibular transposition  (ORC) → interpeduncular cistern  (IRC) → infundibular membrane, between the tuber cinereum (aperture) → infundibular recess (third ventricular target ). The IRCs and correlative apertures can generally be divided into dorsal, rostral, and ventral. The ventral corridor is limited by the diencephalon (Fig. 16.2, Fig. 16.3).

Dorsal Inner Radial Corridors and Correlative Apertures: Lateral Ventricle The lateral ventricle represents the IRC overlying all segments of the third ventricle. Independent of the ORC route into

the lateral ventricle, there are several key surgical nuances that are critical to discuss. As previously noted, it is important to place the ORC trajectory so that the apertures will be anterior to the surgeon, if possible. The first anatomical landmark is the choroid plexus that runs in the tela choroidea (Fig. 16.5). Upon entering the ventricle, one should place cottonoids laterally to protect the caudate and posteriorly to catch blood running dependently. The choroid plexus is followed forward until it disappears into the foramen of Monro. The thalamostriate vein, which usually runs along the choroid plexus of the left ventricle, must be carefully protected. It is followed forward until the septal vein is located medially and the caudate vein is located laterally. The foramen of Monro is marked by the confluence of all three veins and the disappearance of the choroid plexus. A critical first step is to perform a septostomy, particularly in the presence of hydrocephalus. We follow the column of the fornix proximally from its C-shaped location at the foramen of Monro. We then locate the septal vein and gently coagulate the thin and often translucent septum between the two structures. The septal vein, unlike the thalamostriate vein and caudate vein,

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Fig. 16.5 (continued)  Intraoperative views showing (c) intraoperative trajectory-centric coregistration, with the port in view showing intersecting tract fibers; (d) septal veins running across the septum to the venous angle; (e) septum pellucidotomy to allow for CSF flow to the opposite lateral ventricle; and (f) view of thalamostriate vein (TSV) and venous angle (VA) underneath

the blood with the fornix (F) and foramen of Monro (FM) located anteriorly. Comparison of preoperative (g) and postoperative (h) MRI-DTI tractography, with postoperative image showing preservation of the inferior fronto-occipital fasciculus (IFOF) and the posterior limb of the internal capsule (PLIC). C, cingulum; CST, corticospinal tract.

can be sacrificed. However, care must be taken to protect the caudate, which is located laterally, and even the internal capsule along its inferoposterior boundary. Once the septostomy is completed, the foramen of Monro is carefully examined to determine its suitability as an aperture into the third ventricle. If the lesion is exophytic or dilates the foramen of Monro, as in the case of a type I colloid cyst or subependymoma, then it can be used (Fig. 16.5). The choroid plexus should be cautiously coagulated at its entrance, being mindful of the venous angle immediately below it. The choroid plexus in

this region often harbors small arterial pedicles that supply the tumor, which should be kept in mind, especially in the case of colloid cysts. Significant arterial bleeding can occur if these pedicles are not identified and managed preventively. Lesions in this region can also be adherent to the constituents of the venous angle; however, sharp dissection can avoid traction and avulsion of these vital veins, which can then retract into the third ventricle (Fig. 16.5). If the foramen of Monro is not an adequate aperture into the third ventricle or a more posterior window into the middle

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Fig. 16.6  Case 2: Dorsal middle segment approach for a recurrent type I colloid cyst initially operated on at an outside institution. Sagittal (a) T1-weighted magnetic resonance image (MRI) (left) and T1-weighted contrast-enhanced MRI (right) demonstrate significant destruction of the middle third of the corpus callosum secondary to access in original surgery. Subsequent resection involved the use of a port system via a transsulcal parafascicular, lateral ventricle, foramen of Monro approach

Fig.16.6 (continued)  (b) Intraoperative photograph showing presurgical planning and trajectory using the port, which is coregistered with computed tomography (CT), magnetic resonance imaging (MRI), and diffusion tensor imaging (DTI). (c,d) Intraoperative imaging showing both contralateral (cF) and ipsilateral (iF) fornices (c) in close contact with cyst at right and (d) with contralateral fornix to left of cyst. (e) MRI DTIs (clockwise

from bottom left) in axial, coronal, sagittal, and orthogonal planes, with the fornix in view. The sequence is coregistered with the port to provide a real-time intraoperative view of tractography within the surgical corridor. (f) Final view of the ipsilateral fornix preserved after resection. (g) Comparison of the preoperative (left) and postoperative (right) sagittal MRIs demonstrates complete resection of the cyst.

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Fig. 16.7  Case 3: Dorsal middle segment approach. (a) Preoperative axial (top row and bottom left) and coronal (bottom right 1) magnetic resonance images (MRIs) showing a large, lobulated, heterogeneous, enhancing midline mass involving the lateral and third ventricles and causing hydrocephalus. The columns, body, and crus of the fornix, the body of the corpus callosum, and the internal cerebral veins are also involved. The

fornix has been completely effaced by the mass. (b) Preoperative planning utilized a coregistered port and MRI diffusion tensor imaging (DTI) tractography to visualize tracts along the entryway of the surgical corridor. (c) Postoperative sagittal (left) and axial (right) MRI DTI images demonstrate near total resection, with minimal residual tumor left along the fornices to preserve function.

segment is needed, we favor the tela choroidea approach over the interforniceal approach (Fig. 16.3). The intervening space between the columns of the fornix is limited, which precludes meaningful access because of the possibility of forniceal injury. This limited window is best demonstrated when looked at from below (Fig. 16.5). This is commonly the situation in a type II colloid cyst that is pedicled more posteriorly in the transitional zone along the roof of the middle segment, which may not have a dilated foramen of Monro associated with it. The tela choroidea approach is initiated by carefully lifting the choroid plexus proximal to the foramen of Monro and distal to the body of the thalamus upward, then insulating the thalamostriate vein before coagulating the choroid plexus. Care must also be taken to avoid manipulating the thalamostriate vein because it has multiple tributaries. The thalamostriate vein is usually located just along the border of the paramedian fissure created by the tela choroidea (Fig. 16.5). We prefer to open the velum interpositum in an anterior to posterior direction (i.e., from the foramen of Monro

toward the massa intermedia). We do not transect the massa intermedia, because doing so can lead to significant morbidity as it represents a key limbic commissural fiber. After the velum interpositum is opened, the ICV are identified along the lateral boundary. Any manipulation of the ICV must be avoided because they are tethered at their respective anterior and posterior confluences. Anterior inner radial corridor cisterns and correlative apertures The IRC cisterns in this location can be subdivided based on their relationship to the optic apparatus. Thus, they are either dorsal (prechiasmatic cistern/lamina terminalis) or ventral (interpedencular cistern/infundibular recess and membrane). Rostral anterior IRCs and correlative apertures: prechiasmatic cistern and lamina terminalis The proximal sylvian fissure and the opticocarotid cistern are key ORC cisterns that provide access to the inner prechiasmatic

16  Tumors of the Third Ventricle cistern that provides access to the inner prechiasmatic cistern (Fig. 16.2, Fig. 16.3). Key surgical nuances in accessing this IRC begin with creating a wide-enough split in the proximal sylvian fissure to allow unencumbered mobilization of the frontal lobe. A conventional pterional craniotomy may require considerable frontal lobe retraction to provide adequate visualization and allow bimanual dissection because of the angulation of the prechiasmatic cistern and lamina terminalis relative to the optic recess of the third ventricle. To mitigate this, we routinely perform a supralateral orbitotomy as a part of our ORC, which allows for an optimal working angle that minimizes frontal lobe retraction (Fig. 16.3). Care must be taken to protect the key perforators along the dorsal side of the anterior communicating artery that supply the anterior portion of the hypothalamus. The recurrent artery of Huebner represents an additional key perforator that should be preserved. Occasionally, the other outer radial cistern leading to the region (i.e., the interhemispheric fissure) may have to be opened to allow further mobilization of the frontal lobe. We prefer doing this rather than resecting the gyrus rectus (see previous section on neurocognitive systems) to access the lamina terminalis. If the anterior communicating artery itself must be mobilized to expose the lamina terminalis, we use small Teflon pledgets to hold the position. The lamina terminalis can be identified by following the respective optic nerves proximally, and it is usually marked by a relatively avascular zone that is translucent. We prefer to open it sharply and focally, then dilate it obliquely along the long access of the respective optic nerve using small forceps. After the CSF is released, the ventricle is entered. In the absence of an exophytic tumor that widens the corridor, this aperture is limited not only in diameter but also in angulation, which can be encumbering even when augmented with an orbitotomy. Torque should be prevented on the proximal window, which is represented by the chiasm as one travels distally into the ventricle. The chiasm essentially handcuffs the surgeon, preventing angulation into the ventricle. Therefore, we have found this window to be limited for exophytic or intrinsic tumors that widen the aperture but are generally limited to the optic recess of the anterior segment of the third ventricle (Fig. 16.3). However, we find it to be an excellent means of creating CSF diversion via an anterior third ventriculostomy. Ventral anterior IRCs and related apertures: Interpeduncular cistern and infundibular recess To access the infundibular recess, we must create a ventral ORC that consists of the EEA and pituitary transposition. As previously stated, we will discuss nuances of this ORC and the IRC together to provide a more cogent algorithm.

Outer Radial Corridor Expanded endonasal approach and pituitary transposition We have previously described the EEA and the pituitary transposition as an effective ORC to access the retrodorsal and retroinfundibular region. The most common lesions for which we have used this approach are pituitary macroadenomas, craniopharyngiomas, and chordomas, which usually extend directly into the anterior segment of the third ventricle (endophytic). Therefore, when access is needed, the IRC windows and aperture are

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widened in many cases to create viable corridors that can be followed into the infundibular recess (Fig. 16.8). As previously discussed, the notable exception is a type III craniopharyngioma that has a normal pituitary stalk associated with it. In these cases, mobilization of the pituitary gland and stalk is needed. There are four key elements to pituitary mobilization (Fig. 16.8c).  1. Identification of the two dural layers of the sella (meningeal and periosteal)  2. Sectioning of the pituitary ligaments along the lateral border between the two layers  3. Opening the pituitary aperture as it travels through the diaphragm to release it and allow anterior transposition  4. Preservation of the superior hypophyseal arteries along the perimeter because they represent a vital supply to the optic chiasm Patients will generally require pituitary replacement for the first month, but long-term gland preservation rates are excellent and exceed 87%.97 Independent of whether the pituitary gland is mobilized or whether there is a direct tumor corridor within the interpeduncular cistern, resection of the dorsum sella and posterior clinoids is still needed. The initial critical step requires drilling and removing the dorsum sella via shoulder osteotomies before mobilizing the respective posterior clinoids. Failure to do so will injure the paraclinoidal ICAs.98 IRC and correlative aperture Once the dorsum has been resected, an unprecedented view is provided of the interpeduncular fossa, with the following boundaries (Fig. 16.8):  1. Posterior: Mammillary body and basilar artery with respective branches  2. Laterally: Oculomotor nerves  3. Superiorly: Infundibular recess This superior boundary can now be exploited if the tumor is exophytic or extrinsic by widening the membrane of the infundibular recess. In type II and III craniopharyngiomas, the membrane is attenuated and the tumor usually dilates the limited space along the tuber cinerum and mammillary bodies, which provides excellent access. In type IV craniopharyngiomas, which are isolated and intrinsic to the anterior third ventricle, this is not the case. In these situations, there is a minimal safe corridor within the infundibular recess, so we prefer to approach through a dorsalcorridor. If the anterior third ventricle is accessible via this ventral corridor, several key surgical nuances must be considered. First, preservation of the superior hypophyseal artery and, in particular, the descending hypophyseal branch must be paramount to avoid pituitary dysfunction. Lateral extension into the hypothalamus is not uncommon for lesions in this region, and the wall of the hypothalamus must be protected even at the expense of leaving residual tumor. To achieve this, we use sharp dissection and nonablative resection tools that do not generate heat. The posterior extension of this approach is generally restricted to the massa intermedia. Occasionally, one can proceed more posteriorly if there is dorsal displacement of the thalami by the tumor, the posterior tumor that allows the posterior segment to

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V  Comprehensive Management of Tumors of the Brainstem, Thalamus, and Pineal Region Fig. 16.8  Case 4: Ventral anterior segment approach. Preoperative (a) axial (left) and sagittal (middle) T1-weighted contrast-enhanced magnetic resonance imaging (MRI) and axial (right) gradient recalled echo (GRE) MRI demonstrate a large, multiloculated, calcified (on GRE) intrasellar and suprasellar, primarily cystic lesion causing effacement of the anterior segment of the third ventricle, with imaging features of craniopharyngioma. The mass extends dorsally within the infundibulum, well above the hypothalamus and the level of the anterior commissure (AC) to the level of the foramen of Monro (FM). (b) Preoperative axial diffusion tensor imaging with structural T1-weighted MRIs shows the oculomotor nerve (cranial nerve [CN] III) immediately adjacent to the mass, in addition to the lateral position of the optic nerve (ON) and the inferior longitudinal fasciculus (ILF), which also constrained the medial corridor. (c) The selected surgical approach was a ventral expanded endonasal approach through the interpeduncular cistern and into the infundibular recess (IR) to access the anterior segment of the third ventricle. A pituitary transposition was needed to access the cisternal corridor.

be reached (Fig. 16.8d). Most of this work within the IRC and the anterior third ventricle is done with a 45° scope and a 70° scope with reverse posts. A step for the ventral EEA is to perform reconstruction using a vascularized pedicle flap (Fig. 16.8d). We have extensively reported our reconstruction technique but feel compelled to emphasize the need for vascularized reconstruction.97 Even in the setting of these large skull base defects, CSF leaks occur in approximately 5% of patients. We routinely use a lumbar drain and nasal packing for all of these approaches. We do not use bone or titanium buttresses or "gasket seals"; we believe that, if the approach is adequately performed, there is no safe area to wedge in these materials. Adequately vascularized reconstruction also obviates the need for such measures. Ventral posterior IRCs and correlative apertures: Quadrigeminal cistern and pineal stalk These corridors are only viable in the presence of exophytic or extrinsic tumors that provide widened corridors into the posterior segment of the third ventricle.

■■ Clinical Case Examples To demonstrate the practical applications of the radial architecture in designing individual patient-specific corridors, we present a series of clinical cases (Fig. 16.5, Fig. 16.6, Fig. 16.7, (Fig. 16.8, Fig. 16.9) that demonstrate the surgical approaches to the corridors. Each case illustrates the specific nuances and considerations focused on neurocognitive pathways to create zero-footprint precision corridors. Of note, both patients with colloid cysts were operated on under awake conditions to optimize neurocognitive outcomes. In addition, all the transcranial approaches were performed using a transsulcal parafascicular approach without the need for gyrectomy or callosotomies. Access was provided via the BrainPath system (Nico Corporation). This system is coregistered and calibarated for preoperative and intraoperative 3D rendering and patient-specific intraoperative navigation using BrightMatter. In 2016, we described this technology and its application in intraventricular and periventricular tumor surgery.94 Visualization and navigation are provided using a unique fully-integrated optical and guidance system: the Robotically

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Fig. 16.8 (continued)  (d) Final endoscopic view after resection demonstrates (i) anterior communicating artery (ACoA) and infundibular recess (IR), with pituitary stalk (PS) on right; and (ii) cerebrospinal fluid (star) in the posterior third ventricle draining toward the cerebral aqueduct, with the massa intermedia (MI) beneath the blood and the thalamus (T) at right. The choroid plexus (CP) is visible in the distance below the membrane of the IR (mIR). (iii) As the endoscope is advanced, the FM, the contralateral fornix (cF), and the venous angle (VA) running below the cF and the CP are encountered. (iv) Postre-

section endoscopic view of the basilar artery (BA) shows the posterior cerebral artery (PCA) and the superior cerebellar artery (SCA) in the foreground. (v) Full view of MI connecting the two thalami and bilateral FM separated by cF columns. (vi) View of nasoseptal flap placed over the defect (with image rotated 30° clockwise because the endoscopic camera was rotated). (e) A comparison of the preoperative (left) and postoperative (right) coronal (top) and axial (bottom) T1-weighted MRIs with contrast demonstrates decompression of the hypothalamus, cF, and optic chiasm (OC).

Operated Video Optical Telescopic-microscopy (ROVOT-m) system  (Synaptive Medical). The ROVOT-m represents an optical chain consisting of five components: (1) optical payload, (2) light source, (3) camera, (4) holder, and (5) display. The port is tracked dynamically in real time and rendered in 3D within a multimodality imaging volume demonstrating actual movements relative to the lesion and normal structures (ORC, IRC, and ventricular segment). In particular, critical white matter and limbic neurocognitive structures and white matter tracts are displayed in a geometrically accurate rendering. The ROVOT-m tracks the port in a hands-free manner and in real time, ensuring optimized coaxial light delivery at the epicenter of the access corridor. Unlike a conventional stereoscopic microscope, this

integrated system provides the operator with a larger field of view and increased depth of field (leading to an increased surgical volume of view) that is in focus and that provides resolvable and usable images.

Case 1. Target: Anterior Segment Case 1 (Fig. 16.5) was a patient with a type I colloid cyst of the third ventricle involving and dilating the foramen of Monro, therefore making the anterior segment of the third ventricle the surgical target. The selected corridor was as follows:  1. ORC: Anteromedial entry point for a transsulcul parafascicular corridor along the long axis of the superior

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Fig. 16.9  Case 5: Dorsal posterior segment approach. (a) Axial T2-weighted fluid-attenuated inversion recovery magnetic resonance image (MRI) and (b) sagittal and (c) coronal T1-weighted contrastenhanced MRIs demonstrate an enlarging, complex pineal region cysticappearing lesion with severe mass effect upon the tectum, especially the superior colliculi and the posterior segment of the third ventricle, causing

hydrocephalus as a result of compression of the aqueduct. The surgical approach that was used was a dorsal anterior segment approach via a transsulcal parafascicular, lateral ventricle, foramen of Monro corridor by through-channel endoscopy to reach the posterior segment of the third ventricle. Abbreviations: AC, anterior commissure; BVR, basal vein of Rosenthal; ICV, internal cerebral vein, SV, septal vein.

longitudinal fasciculus and cingulum, paralleling the anterior limb of the internal capsule. This entry point is significantly anterior and medial to the conventional entry point for accessing the lateral ventricle using Kocher’s point (Fig. 16.5c). The patient-specific MRI DTI directed this entry point and trajectory to optimize shear and strain forces.

s­ ubcortical neurocognitive system of the outer radial corridor. This included a defect in the middle third of the cingulum and the corpus callosum that was used for access. For this type II colloid cyst, the target was the middle segment of the third ventricle. Despite the large ORC that they created, the previous surgeons apparently were unable to access the middle segment using the foramen of Monro and therefore left significant residual cyst, which led to recurrence.  1. ORC: Similar to case 1, far anterior and medial tractpreserving transsulcal parafascicular approach. The destruction of the middle third of the corpus callosum led us to pay particular attention to preserving the frontal gyri, the anterior corpus callosum, and the residual cingulum.

 2. IRC: Lateral ventricle for entering the ependyma just medial to the caudate, lateral to the septum, and just behind the foramen of Monro. Immediately upon entering the ventricle, we performed a septostomy  (Fig. 16.5j).  3. Aperture: Foramen of Monro was dilated and could be effectively used to resect the cyst (Fig. 16.5)  4. Target: Anterior segment of the third ventricle and resection was at the base of the cyst, which was attached to region of the venous angle Therefore, our algorithm for this case was as follows: anterior segment of the third ventricle  (target) ← foramen of Monro  (aperture) ← lat­eral ventricle  (IRC) ← anteriorly based transsulcal parafascicular (ORC) approach. Postoperative imaging revealed a minimal surgical footprint and key tract preservation, as well as complete resection of the colloid cyst. Of anatomical importance, the internal cerebral, anterior septal, and thalamostriate veins and the venous angle were visualized. As a corollary, it is especially useful to course the venous structures as a road map to access the third ventricle.

Case 2. Target: Middle Third and Transitional Segment Case 2 (Fig. 16.6) was a patient who was operated on at an outside institution using a traditional middle third callosotomy to access a type II colloid cyst. The cyst recurred and the patient presented with progressive neurocognitive deficits. The MRI obtained at the time of recurrence demonstrated the footprint of the previous surgery, with substantial destruction of the

 2. IRC: Similar to case 1  3. Aperture: The foramen of Monro was completely obliterated and not visible because the colloid cyst had elevated the tela choroidea/velum interpositum and compressed the foramen of Monro, thinning the fornix substantially (Fig. 16.6b, c). Given the compromise of so many elements of the neurocognitive system, we decided that protection of the fornix was paramount. Therefore, we selected a tela choroidea/ tela choroidea/velum interpositum approach rather than an interforniceal approach. MRI DTI neuronavigation was used to provide real-time visualization of the fornix overlying the cysts (Fig. 16.6c).  4. Middle segment and transitional zone: After resection of the colloid cyst, the fornix was preserved, as was the thin residual velum interpositum (Fig. 16.6f) Our algorithm for this case was as follows: middle segment of the third ventricle  (target) ← tela choroidea/velum interpositum (aperture) ← lateral ventricle (IRC) ← anteriorly based transsulcal parafascicular (ORC) approach(Fig. 16.7). Postoperative MRI shows complete removal of the entire colloid cyst, including the portion that was in the middle segment of the third ventricle. No new tissue compromise was found, and the anterior portion of the corpus callosum was preserved.

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Case 3. Target: Dorsal Middle Segment Case 3 (Fig. 16.7) was a 50-year-old woman who presented with cognitive impairment. Preoperative MRIs demonstrated a heterogeneously enhancing multilobulated mass that distended both lateral ventricles and extended into the transitional zone (anterior/middle segment) of the third ventricle and the body of the left caudate nucleus. The lesion also extended through the transitional zone into the posterior segment. The lesion caused significant destruction of her neurocognitive systems from mass effect: (1) ORC: disruption of the middle third of the cingulum and corpus callosum; (2) IRC: columns of the fornix; and (3) third ventricle: body of the fornix. This provided useful information for planning the corridor to the middle and posterior segments, as follows:  1. ORC: Anterior transulcal parafascicular approach with the port to avoid further iatrogenic injury to the anterior cingulum or corpus callosum because of the impact of the tumor on middle third of the corpus callosum.  2. IRC: Anterior to posterior trajectory was taken to protect the fornix.  3. Aperture/third ventricular segment:  a) Both tumors within the lateral ventricle were accessed with a single port based on the trajectory.  b) The tumor in the roof of the third ventricle was removed, as was the component entering the anterior segment, using the tela choroideal/velum interpositum approach.  c) The tumor in the posterior transitional zone and posterior segment was left because of its benign nature and involvement with the ICV, thalamus, and hypothalamus. Therefore, our algorithm for this case was as follows: middle segment of the third ventricle (target) ← tela choroidea/velum interpositum (aperture) ← lateral ventricle (IRC) ← anteriorly based transsulcal parafascicular (ORC) approach. The lesion proved to be a chordoid meningoma and despite the large size, a port was used for the surgery and parafascicular approach. The postoperative MRI DTI showed a significant recovery of the neurocognitive governor systems.

Case 4. Target: Ventral Anterior Segment Case 4 (Fig. 16.8) was a 59-year-old woman who presented to the neurosurgery clinic with episodes of dizziness, headaches, and progressive vision loss in the right eye. Preoperative MRIs revealed a large, multilobulated, cystic-appearing mass involving the sella and extending into the suprasellar and retrochiasmatic cisterns. There was extension into the medial cavernous sinus, with suprasellar extension, as well as elevation of A1 segments and the anterior communicating artery. In addition, the lesion extended superiorly into the anterior segment of the third ventricle and elevated the venous angle, foramen of Monro, and anterior commissure. MRI DTI demonstrated superior displacement of the fornix, anterior displacement of the anterior commissure, and anterolateral displacement of the prechiasmatic cistern. Our algorithm for this case was as follows: anterior segment of third ventricle ← infundibular recess  (aperture)

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← interpedencu­lar cistern (IRC) ← EEA with pituitary transposition (ORC) approach. A decision was made to use an EEA, which we consider to be the ventral approach to the anterior segment of the third ventricle. A pituitary transposition was required to visualize the interpeduncular cistern en route to the infundibular recess, which functioned as an intervening aperture. A significant cystic component above the sella was observed. The superior hypophyseal arteries, optic chiasm, and anterior recess of the third ventricle, and finally the hypothalamus, were all visualized, and solid components were removed from these segments. In situations where lesions affecting the third ventricle are directly posterior to the pituitary gland and the pituitary stalk, optic chiasm, and vertebrobasilar artery complex, it is often difficult to access the entire lesion, especially in the EEA approach.

Case 5. Target: Posterior Segment Through-channel Case 5 (Fig. 16.9) was a 56-year-old woman who presented to the clinic with blurry vision that had been progressively worsening over several months. She also had been experiencing chronic episodes of depression and anxiety. Imaging revealed a rapidly enlarging, complex pineal region cystic-appearing lesion with severe mass effect on the tectum, superior colliculi, posterior segment of the third ventricle, and compression of the aqueduct, resulting in hydrocephalus. A decision was made to undergo fenestration of the cyst for the purposes of decompression. Our algorithm for this case was as follows: posterior segment of the third ventricle (target) ← foramen of Monro (aperture) ← lateral ventricle ← anteriorly based transsulcal parafascicular approach using through-channel endoscopy.

■■ Conclusion Tumors and malformations of the third ventricle are some of the most difficult lesions to access. The third ventricle, being in the center of the brain, is intimately surrounded by and connected to key anatomical structures. Thus, detailed knowledge of the arterial, venous, and cortical radial framework is imperative in approaching the third ventricle. The pioneering work of Walter Dandy and Albert Rhoton Jr. has laid the foundation for treatment and approaches to third ventricular tumors. In this chapter, we have presented a corridor-based algorithm for access to the third ventricle. We hope that it will provide the user with a more organized framework in deciding which surgical corridor to use in accessing this intimate space. In addition, in a further effort to stand on the shoulders of these giants, we have introduced the implementation of the port system in accessing and resecting lesions of the third ventricle—namely, the transsulcal parafascicular route. This may offer a safer, less invasive method in the effort to reduce cortical damage. Independent of the treatment paradigm, be it surgery, radiotherapy, or chemotherapy, the decision algorithm is driven exclusively by the anatomy. Today, this anatomy is at the level of macro- and microneuroanatomical structures, and it will progressively become molecular- anatomically driven.

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17

Tumors of the Fourth Ventricle Semra Isik, Saira Alli, and James T. Rutka

Abstract

Tumors of the fourth ventricle share common presenting features secondary to the obstruction of cerebrospinal fluid pathways and resultant hydrocephalus that tumors cause. However, these tumors are a histologically diverse group with differing molecular causation and prognoses. An understanding of the neuroimaging findings specific to each type of tumor can assist in operative planning and determining the best surgical strategy. The midline suboccipital telovelar approach is used most commonly for tumor resection and, in combination with surgical adjuncts (neuronavigation, neurophysiologic monitoring, and intraoperative magnetic resonance imaging), can reduce the likelihood of morbidity. Preservation of the floor of the fourth ventricle is essential yet challenging in patients with no clear boundary between tumor tissue and the brain. In recent decades, our understanding of the underlying genetic mutations and molecular pathways affected in these tumors has advanced significantly. We now know that these mutated pathways are of clinical significance, influencing patient presentation and prognosis. As a result, aspects of molecular subgrouping have been incorporated into the most recent 2016 World Health Organization classification of central nervous system tumors. The future of brain tumor treatment is therefore likely to be influenced by molecularly targeted therapies. In this chapter, we summarize the key tumor pathologies involving the fourth ventricle, their ­epidemiology, molecular biology, treatment, and prognoses. Keywords:  astrocytoma, atypical teratoid/rhabdoid tumor (AT/RT), choroid plexus papilloma/choroid plexus carcinoma (CPP/CPC), ependymoma, hemangioblastoma, hydrocephalus, ­medulloblastoma, pilocytic dermoid, suboccipital approach

■■ Clinical Presentation Tumors of the fourth ventricle produce symptoms and signs of raised intracranial pressure (ICP) due to obstructive hydrocephalus.1 Symptoms of neuronal dysfunction referable to brainstem or cerebellar involvement occur in later disease stages. Intermittent frontal or occipital headache is the most common presenting symptom, followed by nausea, vomiting, diplopia, and mental change, which worsen with increasing severity of hydrocephalus. Neurologic examination findings, such as papilledema, are related to increased ICP, abducens nerve  (cranial nerve [CN] VI) palsy, upgaze restriction, and hypoactive lower-limb deep-tendon reflexes. Hyperreflexia, pathologic reflexes, and spasticity indicate brainstem compression by the tumor.2

■■ Perioperative Evaluation Patients suspected of having a posterior fossa mass are often evaluated initially by computed tomography (CT), which can be obtained easily and rapidly. Contrast-enhanced magnetic resonance imaging (MRI) of the brain and spinal cord is the gold standard for evaluation, and it provides the correct diagnosis in more than 80% of cases. However, MRI may be insufficient to allow determination of a differential diagnosis, and further studies, including diffusion-weighted imaging (DWI) and magnetic resonance spectroscopy, are useful for improving predictive ­values (Table 17.1).3,4

■■ Management Surgical Approach Tumors of the fourth ventricle are best approached with a midline suboccipital craniotomy for an exposure from the superior aspect of the cerebellum down to the foramen magnum in the vertical plane. The options for patient positioning are sitting, semisitting, lateral oblique, and prone. The sitting position is used less frequently because of the high risk of complications, such as cardiovascular instability, air embolism, and subdural hematoma. Prone positioning is most commonly used with pin fixation or a headrest, along with a moderate degree of flexion of the upper cervical spine. A slight reverse Trendelenburg position eases venous return. The midline skin incision starts from the inion and moves toward the cervical region. Dissection is through the midline raphe of the occipital muscles to limit bleeding from muscle dissection. The periosteum is then dissected laterally. Bleeding from emissary veins can be controlled with bone wax. The craniotomy extends from just inferior to the transverse sinus down to the foramen magnum. The dura is opened in a Y-shaped fashion, being mindful of a prominent occipital sinus that may require ligation prior to incision, especially in young children. In the transvermian approach, the inferior vermis is split carefully such that the superior limit does not extend beyond the superior medullary velum and entry into the fourth ventricle is between the laterally retracted cerebellar lobes. The aim of splitting just the inferior vermis is to preserve the decussating fibers of the superior cerebellar peduncle that lie deep to it.5 However, splitting the vermis and retracting the dentate nuclei laterally within the cerebellar lobes, with bilateral disruption of the dentato-thalamo-cortical pathway, may lead to cerebellar mutism and equilibratory disturbance. Therefore, a modification of the midline approach has emerged that is known as the telovelar approach.6 This approach is directed through the

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Table 17.1  Imaging characteristics of tumors arising in the fourth ventricle

Tumor

Computed tomography

Magnetic resonance imaging

Magnetic resonance spectroscopy

Medulloblastoma

• Well-demarcated • Hyperdense • Homogeneous enhancement • Cyst formation or necrosis (40–50%) • Cerebellar hemisphere location in adults

• Arising from cerebellar vermis (75%) • T1: hypointense to gray matter • T2/FLAIR: hyperintense to gray matter • Homogeneous enhancement • Edema • DWI: restricted diffusion, low ADC

↓ NAA ↑↑ Choline ↑↑ Lipid ↑ Taurine

Ependymoma

• Calcification • Heterogeneous enhancement • Isodense or hypodense • Cystic • Hemorrhage

• Arising from floor of fourth ventricle • Extension through foramina of Luschka and Magendie • T1: isointense or hypointense to white matter • T2: hyperintense to white matter • Heterogeneous enhancement • SWI: confirms hemorrhage (or calcification) • DWI: difficult to interpret if calcification or hemorrhage is present

↑↑ Myo-inositol ↑↑ Lipid ↑ Choline ↑ Choline-creatine ratio ↓ NAA

Pilocytic astrocytoma

• Well-demarcated • Hypodense • Large cyst or multiple small cysts • Enhancing mural nodule • Variable cyst wall enhancement • Calcification (in 20%)

• T1: isointense or hypointense solid component ↓ Myo-inositol • T2 or FLAIR: hyperintense solid component ↓↓ Creatine • Mural nodule enhancement ↓ Total choline • DWI: unrestricted diffusion (high ADC)

Atypical teratoid/ rhabdoid tumor

• Isodense or hyperdense • Heterogeneous enhancement • Hemorrhage • Necrosis • Calcification

• T1: isointense or slightly hyperintense to gray matter • T2: hyperintense • Surrounding edema • Heterogeneous enhancement • DWI: variable diffusion restriction

↑ Lipid peak ↑ Choline ↓ NAA

Choroid plexus papilloma

• Lobulated • Isodense or hyperdense • Fine calcification (25%) • Homogeneous enhancement; irregular, frond-like

• Lobulated • T1: isointense or hypointense • T2: isointense or hyperintense • Homogeneous enhancement

↑↑ M  yo-inositol (compared to CPC) ↑ Creatine ↓ NAA ↑ Choline

Choroid plexus carcinoma

• Lobulated • Isodense or hyperdense • Fine calcification (25%) • Heterogeneous enhancement; hydrocephalus

• Lobulated • T1: isointense or hypointense • T2: isointense or hyperintense • Heterogeneous enhancement, parenchymal invasion • Magnetic resonance perfusion: ↑ rCBV ratio

↑↑ Choline (compared to CPP) ↑ Myo-inositol ↓ Creatine

Hemangio– blastoma

• Isodense mural nodule that enhances intensely • Nonenhancing cyst wall

• T1: isointense or hypointense • Enhancing mural nodule • T2: hyperintense mural nodule • Flow voids at cyst periphery (indicate dilated feeding or draining vessels) • Cyst fluid similar to CSF • Magnetic resonance perfusion: ↑ rCBV ratio

↑ Choline ↑ Creatine ↑ Lipid peak ↓ NAA (or absent NAA)

Dermoid cysts

• Low attenuation (due to fat content) • Midline location • May be hyperdense in posterior fossa • Rarely enhances

• T1: hyperintense (cholesterol) • Hyperintensities in subarachnoid space indicate rupture; pia may also enhance with contrast • T2: hypointense or hyperintense • FLAIR: hyperintense to CSF (unlike arachnoid cyst) • No surrounding edema • DWI: increased signal, variable restriction

Abbreviations: ↓, decreased; ↑, increased; ADC, apparent diffusion coefficient; CPC, choroid plexus carcinoma; CPP, choroid plexus papilloma; CSF, cerebrospinal fluid; DWI, diffusion-weighted imaging; FLAIR, fluid-attenuated inversion recovery; NAA, N-acetylaspartate; rCBV, relative cerebral blood volume; SWI, susceptibility-weighted imaging. Data from Ellenbogen et al 2018.4

cerebellomedullary fissure to the tela choroidea. Retracting the uvula superiorly and the tonsils laterally achieves exposure of the tela choroidea and inferior medullary velum. The fourth ventricle is entered with a view extending from the aqueduct to the

obex. For visualization of the foramen of Luschka, however, further opening of the tela laterally may be required.7 Care should be taken to preserve the rhomboid fossa, dentate nuclei (rostral to the tonsils), cerebellar peduncles, and posterior inferior

17  Tumors of the Fourth Ventricle c­ erebellar artery. The posterior arch of C1 is often removed to achieve decompression of the brainstem and the upper cervical cord as well as to improve access to the foramen of Luschka. This is likely required in patients with tonsillar herniation and large lesions.8

Complications A significant concern after posterior fossa surgery is the occurrence of cerebellar mutism—the sudden loss of speech in a patient who was verbalizing well in the immediate postoperative period. It usually occurs in the first few days after surgery and lasts, on average, for 7 to 8 weeks.9 The incidence of this complication is as high as 29% in some series, with affected children often experiencing long-term difficulties with speech and language.9,​10 Hypotonia, ataxia, and emotional lability may also occur. Higher cognitive functions are impaired in patients with a variation of the syndrome known as cerebellar cognitive affective syndrome (CCAS).11 These patients may demonstrate a change in personality or difficulty with executive functioning, language, and spatial cognition.12 CCAS is believed to be a consequence of injury to the cerebellar posterior lobe, whereas cerebellar mutism is attributed to bilateral damage to the dentato-thalamocortical pathway.13,​14 Damage to the floor of the fourth ventricle and the underlying CN nuclei (abducens, facial, vagus, and hypoglossal nerves [CNs VI, VII, X, and XII]) can result in ophthalmoparesis, facial weakness, dysphagia, dysphonia, and loss of the cough reflex. Attempts to prevent such morbidity may limit the surgeon from achieving gross total resection (GTR).

Treatment of Hydrocephalus Most patients with tumors of the fourth ventricle will have either clinical symptoms or radiologic evidence of hydrocephalus at presentation. Between 10% and 40% of these patients will have persistent hydrocephalus after surgical resection of the tumor.3 Management of hydrocephalus can be conducted either early (before tumor resection) or late (after tumor resection), and it may be temporary (external ventricular drain) or permanent (endoscopic third ventriculostomy or ventriculoperitoneal shunt), with each permutation having its merits and pitfalls. In pediatric patients, Riva-Cambrin et al15 have validated a preoperative grading system known as the Canadian Preoperative Prediction Rule for Hydrocephalus. Patients are subsequently scored on factors of age (< 2 years), the presence of papilledema or metastases, the degree of hydrocephalus, and the likely tumor diagnosis. A score from 0 to 10 is formulated, which in turn corresponds to a probability of persistent hydrocephalus. Stratification into low-risk and high-risk groups can then be conducted, with low-risk patients managed expectantly after tumor resection and high-risk patients considered for permanent cerebrospinal fluid (CSF) diversion before resection.3

■■ Patient Outcomes Outcomes of patients treated for fourth ventricular tumors vary significantly by tumor type (Table 17.2).4 Patients with pilocytic astrocytomas have a significantly better prognosis than those with a choroid plexus carcinoma or an atypical teratoid/rhabdoid

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Table 17.2  Overall survival rates for patients with tumors of the fourth ventricle

Tumor

Overall survival rate

Pilocytic astrocytoma

85–95% at 10 years

Medulloblastoma

High-risk: 16 years)

Infants and children

Peak age: 10 years 50% of MBs in children 25% of MBs in adults

Sex ratio

M:F = 1:1

M:F = 1:1

M:F = 2:1

M:F = 3:1

Location

Midline or fourth ventricle, may infiltrate dorsal brainstem

Pediatric: midline or vermis Adults: cerebellar hemispheres

Midline or fourth ventricle

Midline or fourth ventricle

Histology

Classic Large-cell or anaplastic (rare)

Classic Large-cell or anaplastic Desmoplastic or nodular (rare in TP53 mutant) Extensive nodularity (only in TP53 WT)

Classic Large-cell or anaplastic

Classic Large-cell or anaplastic (rare)

Metastasis

5–10%

15–20%

40–50%

30–40%

Recurrence

Rare

Local

Leptomeningeal

Leptomeningeal

Prognosis

Classic histology: low risk Large-cell or anaplastic: uncertain significance

TP53 mutant: high risk TP53 WT: standard or low risk

Classic histology: standard risk Large-cell or anaplastic: high risk

Classic histology: standard risk Large-cell or anaplastic: uncertain significance

5-year survival

> 90%

75%

45–55%

75%

* Molecular subgroups of medulloblastoma have been shown to correspond to different patient demographics and clinical features. Histology and molecular genetics in combination are now used to inform prognosis. Abbreviations: F, female; M, male; MB, medulloblastoma; SHH, sonic hedgehog; TP53, tumor protein 53; WNT, wingless activated; WT, wild type. Data from Louis et al 201626 and Colucccia et al 2016.30

in adult patients with recurrent medulloblastoma.36 However, the effect was transient, which suggests the need for multiple agents acting on different elements of the tumor pathway. The emerging emphasis for future clinical trials in medulloblastoma is to be target directed rather than disease specific.37 There also is an emphasis on individualized therapy aimed at treating the unique molecular profile of the individual patient’s tumor.

Patient Outcomes The main determinants of overall survival in patients with medulloblastoma are patient age, molecular subgroup, metastatic status, craniospinal irradiation, and tumor location.35 Five-year survival rates for children with average-risk disease are 70 to 80%, whereas those for children with high-risk disease are 60 to 65%.38 For infants with localized disease, 5-year survival rates are 30 to 50%. Although survival rates in average-risk patients have improved, the burden of treatment is considerable, with patients experiencing endocrine dysfunction, hearing loss, premature aging, and poor neurocognitive function. These patients also have an increased risk of stroke and secondary malignancy.39

Ependymoma Epidemiology Ependymoma is the third most common brain tumor in children, representing 8 to 12% of tumors of the CNS. It is comparatively

rare in adults, accounting for only 2 to 6% of intracranial neoplasms. In children, the median age at presentation is 4 to 6 years, and boys are slightly more affected than girls. In the adult population, these tumors are observed in the third to fifth decades, with men and women affected equally.40,​41 Ten percent of ependymomas arise in the spine and are more commonly seen in adults. Of tumors arising intracranially, two-thirds occur in the posterior fossa. These tumors generally occur sporadically, but association with neurofibromatosis 2 may be seen.42

Pathophysiology The cells of origin of ependymomas are believed to be radial glial stem cells rather than the ependymal lining of the CSF compartments.43 The tumors are classified primarily into three histologic grades. Grade I includes myxopapillary and subependymoma, which are both regarded as benign tumors. Myxopapillary tumors arise predominantly in the lower spine at the level of the conus medullaris and below. In contrast, subependymomas are found most commonly in the fourth or lateral ventricles. Grade II is classic ependymoma, subdivided into papillary, clear-cell, and tanycytic, and grade III is anaplastic ependymoma. This histologic classification is thought to be of limited clinical use as tumor genetics better inform prognosis.44 The latest WHO classification of tumors has included a further molecular category of RELA fusion-positive ependymoma, which is responsible for 70% of supratentorial ependymomas in children and confers a poor prognosis.26,​45

17  Tumors of the Fourth Ventricle Key histologic features in ependymoma are perivascular pseudorosettes, which are ependymal cell cytoplasmic processes radially converging onto blood vessels, and ependymal rosettes, which are tumor cells arranged as single layers to form a lumen. Pseudopalisading necrosis and microvascular proliferation are common features in anaplastic ependymoma. Ependymomas are characteristically well circumscribed, with no infiltration of surrounding brain tissue.

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frequently extend into the cerebellomedullary or cerebellopontine cisterns and involve the inferior cerebellar peduncle, lower CNs, and posterior inferior cerebellar artery. Leptomeningeal dissemination occurs most commonly in the lumbosacral region in 8 to 12% of patients.54 These lesions typically appear as nodular or diffuse enhancement along the surfaces.

Management Molecular Biology Recent studies suggest nine different molecular subgroups of ependymoma within the CNS and two distinct subgroups arising in the posterior fossa based on genome-wide DNA methylation patterns.46,​47 The posterior fossa tumors have been designated group A and group B.46 Group A tumors have an increased occurrence of chromosome 1q gain and group B tumors largely show chromosomal aberrations. Clinically, group A tumors are found in infants and young children. They are more commonly laterally placed, exhibit an infiltrative phenotype, have higher rates of recurrence, and confer poorer survival (overall survival 69%). Group B tumors mostly occur in adolescents and young adults and have a midline location.46 The overall survival of patients with group B tumors is 95%. Other molecular changes in ependymoma that confer a poor outcome include PI3K/Akt and epidermal growth factor receptor  (EGFR) pathway activation and overexpression of hTERT and tenascin-C.48,​49,​50,​51 The occurrence of RELA fusion in supratentorial ependymoma refers to chromothripsis, causing fusion of the gene C11orf95 to RELA, which consequently activates the NF-κB transcription pathway.45

Clinical Presentation Presenting features of patients with ependymomas depend on the size, anatomical location, and tumor grade. Posterior fossa tumors classically cause symptoms and signs of raised ICP secondary to obstructive hydrocephalus. Cerebellar and brainstem features may arise in patients with large or invasive tumors. Patients with tumors within the cervical spine present with myelopathic features, whereas those with tumors in the lower spine more commonly present with back pain.42

Perioperative Evaluation Ependymomas are generally well-circumscribed lesions with cystic and calcified areas. MRI is the diagnostic modality of choice, and ependymomas are categorized into three variants based on MRI findings: mid-floor, lateral, and roof types. In the mid-floor type, the tumor develops from the obex, localizes only to the floor of the fourth ventricle, and is strictly exophytic. In the lateral type, the tumor develops from a lateral recess, extends into the cerebellopontine angle cistern, and involves the brainstem and CNs. In the roof type, the tumor develops from the inferior medullary velum and localizes to the roof of the fourth ventricle.52 The lateral type is distinguished radiologically by the lateral displacement of the brainstem and an absence of tumor infiltrating the obex, whereas the mid-floor type displaces the brainstem anteriorly and involves the obex53 (Fig. 17.326,30). Lateral tumors have been shown to confer poorer survival because of the difficulty in achieving GTR.52 These tumors

The management of ependymoma involves maximal safe surgical resection, treatment of persistent postoperative hydrocephalus, and focal radiotherapy. The extent of surgical resection is the most influential factor on tumor recurrence, overall survival, and progression-free survival.54,​55 However, GTR can be difficult to achieve in some infratentorial ependymomas because of tumor adherence to the floor of the fourth ventricle and involvement of eloquent structures, such as the brainstem, CN nuclei, and vasculature. The surgical adjuncts of neuronavigation, ultrasound, and neurophysiologic monitoring (sensory evoked potentials, motor evoked potentials, brainstem auditory evoked potentials, and electromyography) may assist in achieving GTR with reduced morbidity and mortality.40 The intraoperative finding of sustained CN activity on neuromonitoring or bradycardia resulting in hemodynamic instability indicates the need to limit further resection.56 Tumor recurrence in ependymoma patients is most commonly at the site of the primary tumor and a subsequent resection is advocated. Rates of metastatic spread have been noted to be higher on second recurrence.57 Radiotherapy is often delivered after a second surgery, as it has been shown to significantly increase progression-free survival.58 Postoperative adjuvant focal radiotherapy has been shown to improve progression-free survival in patients with ependymomas, particularly in cases of residual tumor or grade III histology.44 The benefit to patients with grade II histology in whom GTR is achieved is less clear. Recent evidence also suggests that the radiation effect on progression-free survival may be limited to tumors arising in the posterior fossa rather than in the supratentorial and spinal regions.59 Furthermore, patients with type B posterior fossa ependymomas have been shown to have a lower risk of relapse; it has therefore been suggested that a study be conducted to compare postoperative observation with irradiation in this cohort.60 Whole-brain or craniospinal irradiation is reserved for patients with disseminated disease, whereas conformal radiation is preferred for those with localized disease. The use of conformal radiation has helped reduce the radiation exposure to normal brain tissue, with corresponding improved neurocognitive outcomes.61 In addition, proton-beam therapy has shown promising results in a retrospective study demonstrating comparable survival with reduced morbidity.62 However, access to proton-beam therapy is limited internationally. Postoperative combination chemotherapy is an effective ­treatment in up to 40% of patients with ependymomas.63,​ 64 However, the superiority of radiotherapy has resulted in ­ ­chemotherapy being used primarily in children younger than age 3 years for whom radiation is ideally delayed. Limited efficacy has been demonstrated in treating recurrent ependymomas with targeted therapies, including EGFR inhibitors, farnesyltransferase inhibitors, integrin antagonists, and mechanistic target of rapamycin (mTOR) inhibitors.50 Decitabine,

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V  Comprehensive Management of Tumors of the Brainstem, Thalamus, and Pineal Region

Fig. 17.3  Ependymoma. (a) Axial and (b) sagittal T1-weighted, contrastenhanced magnetic resonance images (MRIs) of a right-sided lateral-type ependymoma extending into the cerebellopontine angle and involving

the brainstem. Postoperative (c) axial and (d) sagittal MRIs demonstrate ­residual tumor and highlight the difficulty in achieving gross total resection in lateral-type tumors.

a DNA-demethylating agent that affects tumor epigenetics, has shown promise in a preclinical study of patients with ­group A posterior fossa ependymomas.65

all ­pediatric CNS tumors, and 25 to 35% of tumors developing within the posterior fossa. Incidence is highest between the ages of 4 to 10 years (median age, 6 years) with no sex predilection. These tumors are believed to be found mostly in the cerebellar hemispheres; however, a large percentage of cerebellar astrocytomas also arise in the vermis, extending into the fourth ventricle. There is an association with the autosomal dominant genetic disorder neurofibromatosis 1, but the tumor in these cases typically arises in the optic nerves and chiasm.

Patient Outcomes A multivariate analysis of data on posterior fossa ependymoma patients demonstrated that tumor location and grade, patient age, and initial treatment contribute to progression-free survival.44 After surgical resection and radiotherapy, 5-year eventfree survival and overall survival are 23 to 57% and 50 to 71%, respectively.40 In one-third of patients, the median time to recurrence is within 2 years of primary diagnosis.54

Astrocytoma Epidemiology Cerebellar astrocytomas are the most common brain tumors in children, representing 5 to 6% of all gliomas, 12 to 17% of

Pathophysiology Cerebellar astrocytomas comprise histologically diverse tumor types; however, most are WHO grade I pilocytic astrocytomas.66 Their macroscopic appearance is that of a well-circumscribed, pink-gray, solid component, which is referred to as the mural nodule, with an accompanying cystic component within the tumor wall. The contents of the cyst are xanthochromic and may contain calcium and hemosiderin deposits. The wall of the cyst

17  Tumors of the Fourth Ventricle may consist of tumor tissue or nonneoplastic gliotic tissue.67,​68 Microscopically, pilocytic astrocytomas have biphasic architecture with areas of compact piloid tissue and loose glial tissue, with tumors demonstrating a predominance of one tissue type or the other.69 Regions of piloid tissue are characterized by bipolar cells (whose hair-like processes give rise to the term pilocytic) and Rosenthal fibers. Protoplasmic astrocytes, microcysts, vacuoles, and eosinophilic granular bodies are the components of loose glial tissue.67 Infiltration of adjacent brain tissue is seen in pilocytic astrocytomas, and those arising in the cerebellum often involve the overlying leptomeninges.2,​70

Molecular Biology The RAS–mitogen-activated protein kinase (MAPK) pathway is a key cellular pathway involved in cell differentiation, proliferation, and survival.71 Mutations resulting in altered activation of this pathway are known to cause several human cancers. BRAF is a member of the RAF serine-threonine kinase family, and it has a key role in the regulation of MAPK. The most common genetic alteration found in patients with pilocytic astrocytomas is segmental duplication at chromosome band 7q34, which results in fusion of BRAF with that of KIAA1549.72,​73 In addition, the most common point mutation in BRAF is referred to as BRAFV600E, which results in replacement of valine with glutamic acid at codon 600.74

Clinical Presentation Children with cerebellar astrocytomas typically show symptoms due to increased ICP from hydrocephalus, which is seen in more than 90% of patients.75 Symptoms are often present for several months and are either attributed to hydrocephalus (headache, lethargy, nausea, and vomiting) or involvement of the cerebellum (ataxia, nystagmus, and dysmetria). In undiagnosed cases, patients with untreated hydrocephalus may present with a reduced level of consciousness.

Perioperative Evaluation Fourth ventricular pilocytic astrocytomas are commonly solid tumors with irregular enhancement and the absence of a cystic component. However, pilocytic astrocytomas are known to have variable appearances, particularly in other brain regions, where they commonly consist of an avidly enhancing mural nodule and a cyst wall that may or may not enhance with contrast (Fig. 17.4). They can also appear as a large solid and cystic mass with a region of central necrosis.76 The presence of necrosis is not indicative of malignancy.77 It is perhaps surprising that pilocytic astrocytomas enhance with contrast, given their low histologic grade. This is because they are highly vascular tumors with the fluid contents of the cyst believed to enhance vascular proliferation.70 Solid components of the tumor appear hyperintense on T2-weighted imaging and hypointense or isointense on T1-weighted imaging.

Management Complete surgical excision of pilocytic astrocytomas is usually curative, with surgery targeted at resection of the mural nodule

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rather than the cyst wall. Extirpation of the cyst wall has not been shown to influence outcome, irrespective of whether it enhances on imaging.78 However, operative findings often influence surgical excision, with most surgeons opting to pursue cyst wall excision only if tumor tissue is visible within it.2 Postoperative MRI is performed within 48 to 72 hours and, when GTR is confirmed, the overall survival rate is as high as 90% at 10 years.79 GTR is achieved in 50 to 89% of patients.80 In patients in whom residual tumor is identified, reoperation is advisable if surgically amenable. Others advocate for surveillance, as disease progression is uncertain and cases of spontaneous tumor regression have been described.81 In most cases, resection of the tumor results in resolution of hydrocephalus. However, 15% of patients will develop persistent hydrocephalus requiring CSF diversion surgery.82 In patients in whom GTR is achieved, postoperative surveillance imaging is recommended at 3 to 6 months and at 1, 2, 3.5, and 5 years.83 Pilocytic astrocytomas usually recur within 5 years of primary surgery, thus more frequent imaging is not required because of the slow growth of these tumors. Surgery is also the main treatment option for recurrent or progressive tumors. When the tumor is unresectable (i.e., because of cerebellar peduncle or brainstem involvement), chemotherapy is preferable. The combination regimen of carboplatin and vincristine is often used as a first-line agent, although hypersensitivity develops in a substantial proportion of patients.84,​85 However, Shah et al86 have shown that a carboplatin rechallenge with either prolonged infusion and premedication or a desensitization protocol can resolve the problem of hypersensitivity. Radiotherapy appears to have no clear role in treating patients with pilocytic astrocytomas. There are conflicting reports on its effects on progression-free survival, but no benefit on overall survival has been shown.1,​87,​88 More recently, radiotherapy in patients following subtotal resection has been shown to reduce long-term overall survival in pediatric patients with low-grade gliomas, as well as causing a three-fold increase in the risk of all deaths.89 Molecularly targeted therapies (e.g., rapamycin) have shown some promise in the treatment of patients with pilocytic astrocytomas. Targets have primarily been the mTOR and BRAF pathways in recurrent tumors. Everolimus, an mTOR inhibitor, has shown partial efficacy in patients with recurrent low-grade glioma. The BRAF inhibitor dabrafenib produced a promising response in a phase 1 study of patients with low-grade glioma and the BRAFV600E mutation.90 Rather unfortunately, sorafenib, an alternative BRAF inhibitor, caused accelerated tumor growth in patients with BRAF fusion.91 Immunotherapy in the form of vaccines used to initiate an immune response to cancer-specific antigens is promising in the context of the intact immunity of childhood. A phase 2 study is currently recruiting pediatric patients with recurrent, unresectable low-grade glioma.

Patient Outcomes Rates of GTR for pediatric cerebellar astrocytomas have been as high as 90% in some series, although the corresponding permanent neurologic deficit was 18%.80 Thus, some authors advocate for a more conservative approach, accepting subtotal resection and monitoring residual tumor with interval MRIs.80 This approach is based in part on the fact that residual tumor has been shown to

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V  Comprehensive Management of Tumors of the Brainstem, Thalamus, and Pineal Region

Fig. 17.4  Pilocytic astrocytoma. T1-weighted, postcontrast-enhanced (a) axial, (b) sagittal, and (c) coronal magnetic resonance images (MRIs) of a pilocytic astrocytoma. An avidly enhancing mural nodule can be seen

with some enhancement of the cyst wall. (d) Coronal fluid-attenuated inversion recovery MRI demonstrates the large mass obstructing the fourth ventricle and causing hydrocephalus with transependymal edema.

stabilize or regress spontaneously in 30 to 60% of patients.79,​81,​92,​ 93 GTR is regarded as the single most important factor influencing progression-free survival.94 In incompletely resected tumors, the presence of BRAF fusion has been shown in a multivariate analysis to most significantly influence progression-free survival.95 Fusion-positive patients were found to have a 5-year progressionfree survival of 61% compared to 18% in fusion-negative patients. Complete surgical resection has been shown to correspond to a 10-year overall survival rate greater than 90%.79

onset is approximately 18 months, with a slight male predominance ranging from 1.3:1 to 1.5:1.97 AT/RTs in children can arise in the cerebellar hemispheres or fourth ventricle (50%), in the cerebral hemispheres and basal ganglia (34%), in the mesencephalic and pineal region (4%), and in the spine (1.7%).97 Although AT/RTs are considered pediatric tumors, 55 adult cases have been documented in the medical literature thus far.98 In adults, these tumors arise more commonly in the supratentorial compartment. Rhabdoid tumors have the potential to occur synchronously in two or more locations in the body, with one location, in most cases, being the CNS. This is usually due to the presence of a specific germline mutation.99 Metastatic spread through CSF is present in 22 to 30% of patients at diagnosis.97

Atypical Teratoid/Rhabdoid Tumor Epidemiology AT/RTs are highly aggressive, rare malignancies of the CNS.96 They account for 1 to 2% of pediatric brain tumors and 40 to 50% of all embryonal CNS tumors of infants. More than 90% of these tumors occur in children younger than 3 years of age. The median age of

Pathophysiology Histologically, AT/RTs appear to possess rhabdoid cells (arranged in sheets or nests), regions indistinguishable from primitive

17  Tumors of the Fourth Ventricle neuroectodermal tumors (PNETs), malignant mesenchymal elements, and epithelial differentiation.100 Rhabdoid cells have a distinct appearance of large, eccentric vesicular nuclei with prominent nucleoli and densely eosinophilic cytoplasmic inclusions (Fig. 17.5).101 Mitotic figures, necrotic foci, hemorrhage, and indistinct margins from adjacent brain tissue or dura mater are common findings.

265

The SWI/SNF complex is a multiprotein chromatin remodeler that mediates changes in chromatin  (DNA wrapped around

histone octamers), with the latter playing a role in gene regulation. The SWI/SNF complex consists of key proteins, SMARCC1, SMARCC2, and SMARCB1 with an ATPase (adenosinetriphosphatase) (either SMARCA4 or SMARCA2) and additional accessory subunits. Mutations in the SMARCB1 gene located on chromosome band 22q11.2 are the driver mutations in rhabdoid tumors.102 Biallelic loss of the gene leads to an absence of protein expression in the nucleus, which is detectable by immunohistochemistry. This is used to aid histologic diagnosis.103 Very few other gene mutations have been identified in AT/ RT. Instead, these tumors have been characterized into three

Fig. 17.5  Atypical teratoid/rhabdoid tumor. (a) Axial contrastenhanced computed tomogram showing a large, predominantly nonenhancing, isodense lesion slightly off the midline. Marked hydrocephalus can be seen that is caused by the dilated temporal horns Sagittal. (b) precontrast-enhanced and (c) postcontrast-enhanced T1-weighted magnetic resonance images show partial enhancement of the tumor,

along with anterior displacement of the brainstem and herniation of the cerebellar tonsils inferiorly. (d) Hematoxylin and eosin stain of an atypical teratoid/rhabdoid tumor demonstrating the distinct appearance of rhabdoid cells with large nuclei, prominent nucleoli, and eosinophilic cytoplasmic ­inclusions. Numerous mitotic figures can also be seen.

Molecular Biology

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V  Comprehensive Management of Tumors of the Brainstem, Thalamus, and Pineal Region

different epigenetic subgroups: AT/RT-TYR, AT/RT-SHH, and AT/RT-MYC.104 AT/RT-TYR tumors are predominantly found infratentorially and are characterized by overexpression of the enzyme tyrosine kinase  (TYR) and genes involved in ciliogenesis (DNAH11 and SPEF1). AT/RT-SHH tumors demonstrate SHH signaling and active NOTCH signaling. They can be found both supratentorially and infratentorially. The AT/RTMYC subgroup is marked by overexpression of the MYC oncogene and HOX cluster genes. These tumors are predominantly supratentorial in location. In addition, potential drug targets are overexpressed across AT/RT subgroups, including AURKA and HDAC1/2.

Clinical Presentation Patients with AT/RTs of the fourth ventricle usually present with symptoms secondary to raised ICP, such as macrocephaly, vomiting, abnormal eye movements, and posturing.105 Behavioral changes of irritability and delayed milestones may also occur. In addition, focal signs of CN VI and CN VII palsies have been noted, as has hearing loss.

Perioperative Evaluation The neuroimaging features of AT/RT are similar to those of PNETs and medulloblastomas. The degree of contrast enhancement is variable, and these tumors show restricted diffusion on DWI. They are generally large tumors at presentation (Fig. 17.5). Some radiologic features have been described that would make the diagnosis of AT/RT rather than PNET or medulloblastoma more likely. These features include an occurrence off midline, the presence of intratumoral hemorrhage, and peripheral cysts along with a more inhomogeneous hyperintensity on DWI.106 However, these findings were from a small cohort of patients and have not been validated in a larger series. Histologic analysis remains the mainstay of diagnosis of these tumors.

Management The optimal therapeutic approach to AT/RTs has yet to be determined. Factors influencing treatment include tumor location, initial staging, and patient age. At present, a multimodal approach is taken that combines surgical resection, craniospinal irradiation, and intensive chemotherapy. From a surgical perspective, GTR has been shown to confer a greater overall survival at 2 years than partial resection (60% vs. 21.7%, respectively).107 Because the peak incidence of AT/RTs is in children younger than 3 years of age, the risk of radiation necrosis and leukoencephalopathy from radiotherapy has led to a preference for chemotherapy as an adjuvant treatment. In general, multidrug regimens are used that consist of anthracyclines and alkylating agents.97 The benefits of high-dose chemotherapeutic regimes are unclear, but a phase 3 study by the Children’s Oncology Group is combining high-dose chemotherapy, radiotherapy, and autologous stem-cell transplant (ClinicalTrials.gov Identifier: NCT00653068). Radiotherapy has been shown to improve survival, with its effect being more pronounced in the immediate ­postoperative period and in children younger than 3 years of age.108,​109 Proton-beam therapy offers a means of more focal radiation

delivery and therefore fewer long-term sequelae. However, concerns regarding radiation necrosis, particularly in the brainstem, remain.110,​111 Numerous molecular therapies are currently in phase 1 or 2 trials for patients with AT/RTs. These trials are aimed at targeting aberrant signaling pathways and include inhibitors of cyclin D1/CDK4 and 6, aurora kinase A, and histone deacetylase.97

Patient Outcomes Survival rates of AT/RT patients have generally been poor, with median survival in the range of 6 to 11 months.112 Because treatment plans for patients with AT/RT vary widely, survival statistics are difficult to interpret. Published results from a single clinical trial specific to AT/RT in which patients received multiple phases of irradiation and chemotherapy after surgical resection demonstrated mean (standard deviation) 2-year progression-free survival and overall survival rates of 53% (13%) and 70% (10%), respectively.113

Choroid Plexus Papilloma and Choroid Plexus Carcinoma Epidemiology Tumors of the choroid plexus are rare, with an annual incidence of 0.3 cases per 1 million.114 They account for 0.4 to 0.8% of all primary intracranial neoplasms, occurring more frequently in the pediatric population, where they constitute 2 to 4% of all brain tumors.115 They range from the benign choroid plexus papilloma (CPP) (WHO grade I) to the malignant choroid plexus carcinoma (CPC) (WHO grade III), with papillomas being five times more common than carcinomas.115 CPPs can transform to give rise to CPC, but in most cases CPCs arise de novo. Choroid plexus tumors occur predominantly within the ventricular system, most commonly in the lateral ventricles (50–70%) and the fourth ventricle (20–40%). In adults, they have been known to arise in the cerebellopontine angle.116 Although generally sporadic in occurrence, choroid plexus tumors can arise in patients with the cancer predisposition syndrome Li-Fraumeni.117

Pathophysiology Macroscopically, choroid plexus tumors have a purple “cauliflower-like” appearance with an irregular but well-demarcated surface and variable calcification and vascularity.118 They are microscopically classified by the WHO into three tumor types: (1) CPP (grade I), (2) atypical CPP (ACPP) (grade II), and (3) CPC (grade III) (Table 17.4119,120). CPP resembles normal choroid plexus tissue and consists of a fibrovascular stalk surrounded by cuboidal epithelium arranged in a papillary configuration.119 Mitotic activity in these tumors is low. ACPP is characterized by increased mitotic activity compared to that in CPP; it shares features such as increased cellularity, nuclear pleomorphism, and necrosis with CPC. ACPP was acknowledged as a distinct entity only in 2007, in part because of its significantly higher risk of recurrence than CPP in patients older than 3 years of age.121 CPCs display classical features of malignant histology, including increased cellularity, high mitotic activity, nuclear pleomorphism, necrosis, and brain invasion.119

17  Tumors of the Fourth Ventricle

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Table 17.4  Summary of choroid plexus tumor characteristics

Features

Choroid plexus papilloma

Atypical choroid plexus papilloma

Choroid plexus carcinoma

WHO Grade

I

II

III

Histology

Fibrovascular stalk surrounding papillary configuration of cuboidal epithelium

Intermediate

Four of five features: increased cellularity, high mitotic activity, nuclear polymorphism, necrosis, and altered papillary architecture

Mitotic activity (per 10 HPFs)

2

>5

Radiology

Intraventricular, lobulated mass; well-demarcated; frond-like enhancement; noninvasive

CPP, but with some highgrade features (e.g., invasion, surrounding edema)

Large invasive mass with surrounding edema; heterogeneous enhancement; calcifications, necrosis, hemorrhage and metastatic spread are more likely

Probable 5-year survival

100%

89%

36%

Abbreviations: CPP, choroid plexus papilloma; HPF, high-power field; WHO, World Health Organization. Data from Safaee et al 2013119 and Wrede et al 2009.120

Molecular Biology

Perioperative Evaluation

In 2015, Merino et al used copy number, DNA methylation, and gene expression signatures to distinguish the three histologic types of choroid plexus tumors. They were able to show that CPP and ACPP are a single tumor entity with molecular homogeneity. This composition is in contrast to that of CPC, which show marked molecular heterogeneity. More recently, methylation profiles have been used to categorize choroid plexus tumors into three subgroups.123 Methylation cluster 1 consists of pediatric patients with CPP and ACPP tumors at low risk of progression. Methylation cluster 2 consists of adult patients, again with tumors at low risk of progression. Methylation cluster 3 consists of all three tumor types, but predominantly CPCs with a higher risk of tumor progression. This molecular classification is of particular clinical significance, as it can help identify the patients likely to progress and hence can help determine appropriate surveillance and lead to the implementation of potentially more aggressive treatment. This is ­particularly important for ACPPs, which may cluster in the lowrisk methylation clusters 1 and 2 or the high-risk methylation cluster 3. A subgroup of patients with CPC has been identified as having a poorer prognosis. These patients have mutations in the tumor suppressor gene TP53.122 Furthermore, patients with two copies of mutant TP53 have a worse overall survival at 10-year followup than patients with only one mutant copy of the gene (14.3% vs. 66.7%, respectively). 122

Clinical Presentation Patients may remain asymptomatic because of the intraventricular location of choroid plexus tumors until a significantly large mass has developed. Patients with tumors in the fourth ventricle present most commonly with symptoms of hydrocephalus, although cerebellar or brainstem symptoms may also occur. The mechanism of hydrocephalus is not solely obstructive, as these tumors may overproduce CSF, may hemorrhage, or may demonstrate metastatic spread. As a result, rates of persistent hydrocephalus after GTR are as high as 30%.124,​125

The modern diagnostic evaluation of choroid plexus tumors includes contrast-enhanced CT or MRI of the brain and spinal axis with concurrent magnetic resonance angiography (Fig. 17.6). The latter may be followed by a catheter cerebral angiogram to identify the location of the vascular supply to the tumor. In the posterior fossa, these are the choroidal branches of the posterior inferior cerebellar artery or the superior cerebellar arteries. In the context of a tumor, these arteries may appear enlarged and tortuous.

Management The primary management of patients with choroid plexus tumors is surgery aiming to achieve GTR. This can, however, be difficult because of the highly vascular nature of these tumors. Early coagulation of the vascular pedicle and quick bulk removal of the tumor can help reduce bleeding.125 Some centers advocate for preoperative embolization of the vascular supply to the tumor or for neoadjuvant chemotherapy.126,​127 In the pediatric population, it is essential to provide prompt volume replacement and adequate suction to maintain a clear operative field. GTR alone for CPPs results in excellent outcomes.128 Residual tumor is ­usually monitored, with either secondary resection or radiotherapy advised for recurrent or progressive disease. Achieving GTR in patients with CPC may be insufficient to achieve a cure. A second surgery has been shown to improve survival over that of patients who underwent only one surgery. However, it is unclear whether a second surgery should be done immediately after a primary surgery when residual tumor is noted or at the time of tumor progression.115 Radiotherapy has been shown to improve survival in patients with subtotally resected tumors and also in older patients in whom GTR has been achieved.115 However, due to the neuropsychologic sequelae of radiation in children younger than 3 years of age, it is generally avoided in infants. Chemotherapy has been shown to improve survival in patients with CPC. Wrede et al129 demonstrated the positive effect of chemotherapy in patients with subtotally resected tumors and in those in whom GTR was achieved but radiotherapy was not delivered. In their meta-analysis of cases of subtotally resected tumors, overall 2-year survival was highest

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Fig. 17.6  Choroid plexus papilloma. (a) Axial and (b) sagittal T1-weighted postcontrast magnetic resonance images (MRIs) of a choroid plexus papilloma arising in the obex of the fourth ventricle. The well-circumscribed

tumor enhances homogeneously and shows no radiologic evidence of brain invasion. Postoperative (c) axial and (d) sagittal MRIs demonstrate complete tumor resection.

when patients were treated with chemotherapy and radiotherapy (63%) rather than chemotherapy (44.5%) or radiotherapy (31.8%) alone.

therapy. ­Achieving GTR results in a 5-year overall survival rate of 58.1% compared to 20.9% for subtotal resection.129 When residual tumor is apparent, treatment with chemotherapy and irradiation achieves 2-year overall survival rates of 63%.129 The CPTSIOP-2000 study treated patients with choroid plexus tumors with maximal safe surgical resection. Patients older than 3 years of age, those with ACPP histology, and those with residual tumor, CPC histology, or evidence of metastatic disease were then treated with adjuvant chemotherapy and irradiation. The 5-year

Patient Outcomes Patients with CPPs have been shown to have 10-year survival rates as high as 77% with GTR alone.114 In CPCs, prognosis is influenced by the extent of resection and by the use of adjuvant

17  Tumors of the Fourth Ventricle overall survival probabilities were 100% for 39 patients with CPP tumors, 89% for 24 patients with ACPP tumors, and 36% for 29 patients with CPC tumors.120

Hemangioblastoma Epidemiology Hemangioblastomas are benign vascular lesions that can arise sporadically in the CNS (60–75%) or in association with the autosomal dominant von Hippel-Lindau (VHL) syndrome (25–40%).130 Hemangioblastomas account for 2% of all primary CNS tumors and are most frequently found in the cerebellum, followed by the brainstem, cerebellopontine angle, and supratentorial locations.131 In patients with VHL, the clinical spectrum includes retinal angiomas, renal cell carcinoma, pheochromocytoma, and cysts arising within the abdominal viscera. Hemangioblastomas more commonly affect adults, with peak incidence in the third and fifth decades of life.132 Men are more commonly affected than women, at a ratio of 1.3:1 to 2:1.133 Between 5 and 20% of hemangioblastomas arise in the brainstem, and these tumors often involve the fourth ventricle.134 They are categorized according to their location: type A hemangioblastomas are attached to the floor of the fourth ventricle, type E are partially embedded in the floor of the fourth ventricle, and type I are intramedullary within the medulla oblongata. Hemangioblastomas of the fourth ventricle arise from a vascular mesenchymal plate in the posterior medullary velum, which develops in the third month of fetal life.135

Pathophysiology Hemangioblastomas are macroscopically well circumscribed and usually consist of a solid, vascular, mural nodule with a surrounding cyst.136 The fluid content of the cyst is believed to be serum formed from vascular leakage from the mural nodule.137 The cyst wall is not a true epithelial-lined wall but rather the result of gliotic change in the surrounding parenchyma in reaction to the cyst fluid.132 Microscopically, hemangioblastomas consist of four cellular types: endothelial cells lining capillary spaces, pericytes with surrounding basement membrane, stromal cells, and mast cells.132 Of these cell types, only stromal cells are neoplastic in nature, but their embryonic origin is not known.

Molecular Biology Inactivation of the VHL gene (chromosome 3p25–26) is believed to be the central event causing hemangioblastoma formation in both sporadic and familial cases.138,​139 The VHL protein (VHLp) has a tumor-suppressor function and more specifically regulates the transcription factor, hypoxia-inducible factor (HIF). VHLp essentially preserves HIF in conditions of hypoxia, resulting in downstream effects of angiogenesis and proliferation, but it degrades HIF in normoxic conditions. However, inactivated VHLp cannot degrade HIF and thus the pathway remains constitutively active, resulting in tumor formation. Furthermore, stromal cells are believed to be distinct in cases of VHL inactivation, capable of paracrine signaling to surrounding endothelial cells, which results in the unique architecture of hemangioblastomas. Patients with VHL disease possess a germline mutation in a single copy of the gene but a further mutation in the wild type allele, within a susceptible organ, is required for hemangioblastoma formation.140

269

Clinical Presentation Patients with brainstem hemangioblastomas can present with symptoms and signs secondary to hydrocephalus as well as CN deficits (bulbar dysfunction) or long-tract signs. Tumors involving the obex can affect the underlying vagal nucleus and result in symptoms of food aversion, weight loss, and stomachache.141 Because these tumors are slow growing, symptoms are usually slowly progressive, although the acute onset of neurologic deficit may suggest hemorrhage. A unique clinical feature of hemangioblastomas is the presence of polycythemia in 40% of cases, which arises because of the secretion of erythropoietin by stromal cells.142

Perioperative Evaluation CT and MRI demonstrate an enhancing mural nodule with a typically nonenhancing cystic component. Brainstem heman­ gioblastomas have been noted to be predominantly solid with a much smaller cystic component (Fig. 17.7). Preoperative angiography can help ­delineate the vascular supply and drainage of these tumors, and some centers advocate for preoperative endovascular embolization.143

Management Microsurgery with considered postoperative care is the primary management of patients with brainstem hemangioblastomas.134,​135,​141 For symptomatic patients, the indications for surgery are clear. For asymptomatic patients, there is less clarity regarding the timing of intervention. It has, however, been shown that large brainstem hemangioblastomas (> 245 mm3) or those with a growth rate greater than 14 mm3 per month have a high probability of becoming symptomatic.144 Because hemangioblastomas have high rates of recurrence and their growth pattern is intermittent, the use of threshold criteria can prevent the number of surgical interventions that would otherwise be performed if radiologic growth alone was used as a surgical indication. With regard to surgery, a clear margin can be delineated between the tumor and the brainstem in most cases, thus facilitating resection. Hemorrhage can be controlled by circumferentially dissecting the tumor to gradually reduce its vascular supply.134 Preservation of the draining veins until the arterial supply has been controlled is important to preventing intraoperative swelling.134 Intraoperative monitoring can assist in safe surgical resection. Hemodynamic instability and bradycardia, in particular, can occur during surgery and may require pharmacologic management.141 Postoperatively, monitoring for evidence of bulbar or respiratory dysfunction is important to help avoid aspiration pneumonia.141 Although stereotactic radiosurgery has been used for hemangioblastomas in other regions of the brain, the limited experience of its use in brainstem hemangioblastomas, as well as the functional eloquence of the region, have resulted in a lack of guidelines for use of radiosurgery in this context.141,​145

Patient Outcomes Operative outcomes for brainstem hemangioblastomas have improved considerably with advances in microsurgical techniques.

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Fig. 17.7  Hemangioblastoma. (a) Axial and (b) sagittal T1-weighted contrast-enhanced magnetic resonance images (MRIs) of a predominantly solid, avidly enhancing hemangioblastoma of the fourth

ventricle. Flow voids at the superior aspect of the tumor can be seen on (b) the sagittal MRI. These voids represent the dilated feeding and draining vessels.

Recently published series report postoperative K ­ arnofsky Performance Status scores greater than 80 in more than 80% of patients and mortality rates ranging from 1.6 to 7.8%.146,​147,​148 However, morbidity rates can be as high as 25%.146 Large tumors are associated with a poorer postoperative outcome as they pose a greater operative challenge.147,​148

near the glabella or posteriorly near the inion) and with KlippelFeil syndrome.151,​154,​155,​156 Before the development of symptoms of mass effect and hydrocephalus, patients may present with infection or discharge from a dermal sinus tract.153 Aseptic meningitis is also a common cause of presentation that occurs because of rupture of the capsule and leakage of cyst fluid into the subarachnoid space.149 The latter may also cause hydrocephalus.

Dermoid and Epidermoid Tumors Epidemiology

Management and Patient Outcomes

Dermoid and epidermoid tumors are benign congenital lesions that constitute 1% of brain tumors. Dermoid tumors consist of both dermal and epidermal tissues, whereas epidermoid tumors do not contain dermal elements. These two types of tumors occur due to totipotent ectodermal cells remaining within the neural tube during embryonic development.149 Dermoid tumors are characterized by a midline location along the neuraxis. Although found predominantly in the supratentorial compartment, dermoid tumors can arise infratentorially, including within the fourth ventricle and brainstem.150,​151 Epidermoid tumors, however, are most commonly found in the cerebellopontine angle and fourth ventricle. Epidermoid tumors have a waxy white appearance caused by desquamation of their superficial layer of keratinized stratified squamous epithelium. Internally, they consist of cystic fluid containing debris, keratin, water, and cholesterol.152 Epidermoid tumors commonly grow along CSF pathways, progressively encasing nearby n ­ eurovascular structures.

Total surgical resection is curative; however, this approach may not be possible because of significant adhesions between the tumor capsule and surrounding neural tissue. In these circumstances, conservative resection is recommended.150

Clinical Presentation Clinical presentation usually occurs in the third to fourth decades of life because of the slow-growing nature of these lesions, but anatomical location may influence their development.153 The tumors are often associated with a dermal sinus tract (anteriorly

Other Tumors Dorsally exophytic tumors arising from the brainstem project posteriorly to fill the fourth ventricle (Fig. 17.8). These tumors usually have a low-grade histology, being pilocytic astrocytomas or gangliogliomas that arise from subependymal glial tissue.157 The challenge in surgical resection of these tumors is the lack of demarcation from the floor of the fourth ventricle. As a result, GTR is seldom achieved. Nonetheless, the combination of subtotal resection and CSF diversion has achieved long-term survival rates of more than 90%.158,​159 Tumor regrowth is managed with repeat resection or focal radiotherapy. It is important to distinguish other rare tumors of the fourth ventricle, such as meningiomas and subependymomas. Meningiomas in the ventricles are exceptional, accounting for 0.5 to 3% of intraventricular tumors. Of these, only 6% occur in the fourth ventricle.160 Meningiomas of the fourth ventricle arise mostly from the choroid plexus or inferior tela choroidea; however, they can extend into the posterior fossa. Surgical resection can be achieved with relatively low risk.161

17  Tumors of the Fourth Ventricle

271

Fig. 17.8  Dorsally exophytic brainstem tumor. (a) Axial and (b) sagittal T1-weighted, contrast-enhanced magnetic resonance images demonstrating an enhancing tumor extending posteriorly into the fourth ventricle, obstructing cerebrospinal fluid flow into the central canal, and causing

hydrocephalus. The ventral border of these tumors is often not clearly demarcated from the floor of the fourth ventricle, which limits the extent of surgical resection.

Subependymomas of the fourth ventricle account for less than 1% of all tumors in adults. They are mostly found in adults between the ages of 40 and 60 years, with men affected more than women. These tumors can arise in the caudal floor and in the roof and lateral recess of the fourth ventricle.162 Surgical resection, particularly when tumors are small, can achieve longterm tumor control.163,​164

   2. Bonfield CM, Steinbok P. Pediatric cerebellar astrocytoma: a review. Childs Nerv Syst 2015;31(10):1677–1685

■■ Conclusions

   6. Mussi AC, Rhoton AL Jr. Telovelar approach to the fourth ventricle: microsurgical anatomy. J Neurosurg 2000;92(5):812–823

Tumors of the fourth ventricle are a fascinating group of neoplasms that span the gamut of malignancy, from exceedingly benign to highly malignant lesions with metastatic potential. Significant clues to their diagnosis are provided preoperatively on the basis of clinical signs, symptoms, and neuroimaging studies. Surgery is a mainstay of treatment for most patients with these tumors. The neurosurgical adjuncts mentioned here— neuronavigation, intraoperative neuromonitoring, and microneurosurgical techniques—have made resection of these lesions possible with expected good neurologic outcomes. Molecular diagnostics are rapidly advancing for many of these tumors, providing hope for the future for more highly targeted chemotherapy. Although radiotherapy provides important curative treatment for many patients with malignant tumors of the fourth ventricle, its impact on the developing CNS gives pause for the use of this therapy unless it is absolutely required. Future advances in the diagnosis and management of these tumors may further improve patient outcomes.

   7. Mussi AC, Matushita H, Andrade FG, Rhoton AL. Surgical approaches to IV ventricle—anatomical study. Childs Nerv Syst 2015;31(10):1807–1814

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102. Jackson EM, Sievert AJ, Gai X, et al. Genomic analysis using high-density single nucleotide polymorphism-based oligonucleotide arrays and multiplex ligation-dependent probe amplification provides a comprehensive analysis of INI1/SMARCB1 in malignant rhabdoid tumors. Clin Cancer Res 2009;15(6):1923–1930

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104. Johann PD, Erkek S, Zapatka M, et al. Atypical teratoid/rhabdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes. Cancer Cell 2016;29(3):379–393 105. DiPatri AJ Jr, Sredni ST, Grahovac G, Tomita T. Atypical teratoid rhabdoid tumors of the posterior fossa in children. Childs Nerv Syst 2015;31(10):1717–1728 106. Jin B, Feng XY. MRI features of atypical teratoid/rhabdoid tumors in children. Pediatr Radiol 2013;43(8):1001–1008 107. Lafay-Cousin L, Hawkins C, Carret AS, et al. Central nervous system atypical teratoid rhabdoid tumours: the Canadian Paediatric Brain Tumour Consortium experience. Eur J Cancer 2012;48(3): 353–359 108. Buscariollo DL, Park HS, Roberts KB, Yu JB. Survival outcomes in atypical teratoid rhabdoid tumor for patients undergoing radiotherapy in a Surveillance, Epidemiology, and End Results analysis. Cancer 2012;118(17):4212–4219 109. Pai Panandiker AS, Merchant TE, Beltran C, et al. Sequencing of local therapy affects the pattern of treatment failure and survival in children with atypical teratoid rhabdoid tumors of the central nervous system. Int J Radiat Oncol Biol Phys 2012;82(5):1756–1763 110. Kralik SF, Ho CY, Finke W, Buchsbaum JC, Haskins CP, Shih CS. Radiation necrosis in pediatric patients with brain tumors treated with proton radiotherapy. AJNR Am J Neuroradiol 2015;36(8):1572–1578 111. McGovern SL, Okcu MF, Munsell MF, et al. Outcomes and acute toxicities of proton therapy for pediatric atypical teratoid/rhabdoid tumor of the central nervous system. Int J Radiat Oncol Biol Phys 2014;90(5):1143–1152 112. Packer RJ, Biegel JA, Blaney S, et al. Atypical teratoid/rhabdoid tumor of the central nervous system: report on workshop. J Pediatr Hematol Oncol 2002;24(5):337–342 113. Chi SN, Zimmerman MA, Yao X, et al. Intensive multimodality treatment for children with newly diagnosed CNS atypical teratoid rhabdoid ­tumor. J Clin Oncol 2009;27(3):385–389 114. Wolff JE, Sajedi M, Brant R, Coppes MJ, Egeler RM. Choroid plexus tumours. Br J Cancer 2002;87(10):1086–1091 115. Sun MZ, Oh MC, Ivan ME, et al. Current management of choroid plexus carcinomas. Neurosurg Rev 2014;37(2):179–192, discussion 192 116. Shi YZ, Wang ZQ, Xu YM, Lin YF. MR findings of primary choroid plexus papilloma of the cerebellopontine angle: report of three cases and literature reviews. Clin Neuroradiol 2014;24(3):263–267 117. Gozali AE, Britt B, Shane L, et al. Choroid plexus tumors; management, outcome, and association with the Li-Fraumeni syndrome: the Children’s Hospital Los Angeles  (CHLA) experience, 1991–2010. Pediatr Blood Cancer 2012;58(6):905–909 118. Gaudio RM, Tacconi L, Rossi ML. Pathology of choroid plexus papillomas: a review. Clin Neurol Neurosurg 1998;100(3):165–186 119. Safaee M, Oh MC, Bloch O, et al. Choroid plexus papillomas: advances in molecular biology and understanding of tumorigenesis. Neuro Oncol 2013;15(3):255–267 120. Wrede B, Hasselblatt M, Peters O, et al. Atypical choroid plexus papilloma: clinical experience in the CPT-SIOP-2000 study. J Neurooncol 2009;95(3):383–392

124. Ogiwara H, Dipatri AJ Jr, Alden TD, Bowman RM, Tomita T. Choroid plexus tumors in pediatric patients. Br J Neurosurg 2012;26(1):32–37

126. Haliasos N, Brew S, Robertson F, Hayward R, Thompson D, Chakraborty A. Pre-operative embolisation of choroid plexus tumours in children. Part II. Observations on the effects on CSF production. Childs Nerv Syst 2013;29(1):71–76 127. Schneider C, Kamaly-Asl I, Ramaswamy V, et al. Neoadjuvant chemotherapy reduces blood loss during the resection of pediatric choroid plexus carcinomas. J Neurosurg Pediatr 2015;16(2):126–133 128. Bettegowda C, Adogwa O, Mehta V, et al. Treatment of choroid plexus tumors: a 20-year single institutional experience. J Neurosurg Pediatr 2012;10(5):398–405 129. Wrede B, Liu P, Wolff JE. Chemotherapy improves the survival of patients with choroid plexus carcinoma: a meta-analysis of individual cases with choroid plexus tumors. J Neurooncol 2007;85(3):345–351 130. Patiroglu T, Sarici D, Unal E, et al. Cerebellar hemangioblastoma associated with diffuse neonatal hemangiomatosis in an infant. Childs Nerv Syst 2012;28(10):1801–1805 131. Le Reste PJ, Henaux PL, Morandi X, Carsin-Nicol B, Brassier G, Riffaud L. Sporadic intracranial haemangioblastomas: surgical outcome in a single institution series. Acta Neurochir (Wien) 2013;155(6):1003–1009, ­discussion 1009 132. Hussein MR. Central nervous system capillary haemangioblastoma: the pathologist’s viewpoint. Int J Exp Pathol 2007;88(5):311–324 133. Vates GE, Auguste KI, Berger MS. Hemangioblastomas. In: Berger MS, Prados MD, eds. Textbook of Neuro-Oncology. Philadelphia, PA: Elsevier; 2005:294–300 134. Agrawal A, Kakani A, Vagh SJ, Hiwale KM, Kolte G. Cystic hemangioblastoma of the brainstem. J Neurosci Rural Pract 2010;1(1):20–22 135. Fukushima T, Sakamoto S, Iwaasa M, et al. Intramedullary hemangioblastoma of the medulla oblongata—two case reports and review of the literature. Neurol Med Chir (Tokyo) 1998;38(8):489–498 136. Conway JE, Chou D, Clatterbuck RE, Brem H, Long DM, Rigamonti D. Hemangioblastomas of the central nervous system in von Hippel-Lindau syndrome and sporadic disease. Neurosurgery 2001;48(1):55–62, discussion 62–63 137. Gläsker S, Vortmeyer AO, Lonser RR, et al. Proteomic analysis of hemangioblastoma cyst fluid. Cancer Biol Ther 2006;5(5):549–553 138. Shankar GM, Taylor-Weiner A, Lelic N, et al. Sporadic hemangioblastomas are characterized by cryptic VHL inactivation. Acta Neuropathol Commun 2014;2:167 139. Dwyer DC, Tu RK. Genetics of von Hippel-Lindau disease. AJNR Am J Neuroradiol2017;38(3):469–470 140. Shanbhogue KP, Hoch M, Fatterpaker G, Chandarana H. Von HippelLindau disease: review of genetics and imaging. Radiol Clin North Am 2016;54(3):409–422 141. Pavesi G, Berlucchi S, Munari M, Manara R, Scienza R, Opocher G. Clinical and surgical features of lower brain stem hemangioblastomas in von Hippel-Lindau disease. Acta Neurochir (Wien) 2010;152(2):287–292 142. So CC, Ho LC. Polycythemia secondary to cerebellar hemangioblastoma. Am J Hematol 2002;71(4):346–347 143. Wu P, Liang C, Wang Y, et al. Microneurosurgery in combination with endovascular embolisation in the treatment of solid haemangioblastoma in the dorsal medulla oblongata. Clin Neurol Neurosurg 2013;115(6):651–657

17  Tumors of the Fourth Ventricle 144. Ammerman JM, Lonser RR, Dambrosia J, Butman JA, Oldfield EH. Long-term natural history of hemangioblastomas in patients with von Hippel-Lindau disease: implications for treatment. J Neurosurg 2006;105(2):248–255 145. Asthagiri AR, Mehta GU, Zach L, et al. Prospective evaluation of radiosurgery for hemangioblastomas in von Hippel-Lindau disease. Neuro Oncol 2010;12(1):80–86 146. Liu X, Zhang Y, Hui X, et al. Surgical management of medulla oblongata hemangioblastomas in one institution: an analysis of 62 cases. Int J Clin Exp Med 2015;8(4):5576–5590 147. Zhou LF, Du G, Mao Y, Zhang R. Diagnosis and surgical treatment of brainstem hemangioblastomas. Surg Neurol 2005;63(4):307–315, ­discussion 315–316 148. Ma D, Wang Y, Du G, Zhou L. Neurosurgical management of brainstem hemangioblastomas: a single-institution experience with 116 patients. World Neurosurg 2015;84(4):1030–1038 149. Orakcioglu B, Halatsch ME, Fortunati M, Unterberg A, Yonekawa Y. Intracranial dermoid cysts: variations of radiological and clinical features. Acta Neurochir (Wien) 2008;150(12):1227–1234, discussion 1234 150. Caldarelli M, Colosimo C, Di Rocco C. Intra-axial dermoid/epidermoid tumors of the brainstem in children. Surg Neurol 2001;56(2):97–105 151. Higashi S, Takinami K, Yamashita J. Occipital dermal sinus associated with dermoid cyst in the fourth ventricle. AJNR Am J Neuroradiol 1995;16(4, Suppl):945–948 152. Forghani R, Farb RI, Kiehl TR, Bernstein M. Fourth ventricle epidermoid tumor: radiologic, intraoperative, and pathologic findings. Radiographics 2007;27(5):1489–1494 153. Caldarelli M, Massimi L, Kondageski C, Di Rocco C. Intracranial midline dermoid and epidermoid cysts in children. J Neurosurg 2004;100(5) Suppl Pediatrics:473–480

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18

Tumors of the Cerebellopontine Angle Omar Arnaout and Ossama Al-Mefty

Abstract

This chapter summarizes the most common neoplastic lesions located in the region of the cerebellopontine angle, as well as the key facets of the pathophysiology, epidemiology, and clinical presentation of these lesions. Key aspects of perioperative evaluation and treatment options are also covered. We conclude by reviewing patient outcomes and provide highlights of the best evidence-based recommendations. Keywords:  cerebellopontine angle, epidermoid, meningioma, vestibular schwannoma

■■ Introduction

thought to arise at or near the Obersteiner-Redlich zone,8 which is the transition point between glial and Schwann myelination areas, although this hypothesis has been widely disputed.9 In more than 90% of VSs, the lesion arises from the inferior division of the vestibular nerve.10 A characteristic quality of schwannomas is the splaying and displacement of adjacent nerve fibers, in contrast to nerve fascicle involvement seen with neurofibromas, which are nonencapsulated spindle-cell tumors with proliferation of all elements of peripheral nerves. In Denmark, every patient with VS has been enrolled in a national database since the 1970s, and these data have contributed significantly to our understanding of the ­epidemiology and natural history of this disease.11 In Denmark, the annual incidence of VS is 2.3 per 100,000 population, while epidemiological

Sir Charles Ballance is often credited with the first report of surgical resection of a cerebellopontine (CP) angle tumor,1 which was suspected to be a meningioma given the patient’s lack of hearing loss and Ballance’s description of the wide dural attachment of the lesion.2 The surgical approach at the time focused on speed, using a blunt finger dissection method because, as Harvey Cushing phrased it, “the cerebellopontine angle, like the fence corner of the Gettysburg battlefield, might well be called the ‘bloody angle’.”2 Over the past century, surgery of the posterior fossa has advanced considerably, with surgical mortality dropping from the historical 70 to 80% range3 to 1%.4 Surgical intervention in this location continues to fascinate and challenge neurosurgeons. Modern surgery in the CP angle is safe and major morbidity is rare as the focus has shifted from preserving life to improving and preserving function, particularly with regard to the vestibulocochlear apparatus and the facial nerve. Although the most common mass lesion in the CP angle is vestibular schwannoma (VS), a variety of neoplastic and other mass lesions may occur in this location.5 Careful study of the clinical presentation and neuroimaging features often leads to the correct diagnosis and can help in designing a treatment strategy.

■■ Vestibular Schwannomas Vestibular schwannomas, also referred to as acoustic neuromas or acoustic neurinomas, account for 80% of all tumors occurring in the CP angle, making it the most common lesion in that location.5 Overall, VSs also account for 6 to 8% of all brain tumors (Fig. 18.1, Fig. 18.2).6

Pathophysiology, Incidence, Epidemiology, and Natural History Vestibular schwannomas are considered grade I tumors by the World Health Organization (WHO) classification.7 The lesions are

276

Fig. 18.1  A large vestibular schwannoma occupying the right cerebellopontine angle with mass effect on the brainstem and cerebellum shown in axial magnetic resonance imaging scans. The tumor also extends into the internal auditory canal and reaches the level of the fundus. (a) T1-weighted image without contrast reveals a lesion that is slightly hypointense to the adjacent brain parenchyma. (b) T1-weighted postcontrast image shows vivid contrast enhancement with mild heterogeneity. (c) Fluid-attenuated inversion recovery image shows a hyperintense lesion relative to adjacent brain parenchyma. (d) T2-weighted image reveals a heterogeneously hyperintense lesion.

18  Tumors of the Cerebellopontine Angle

277

Table 18.1  Most common clinical symptoms in 46 patients with vestibular schwannomas

Symptom

Number of patients

Percentage

Hearing loss

33

71.7%

Headache

4

8.7%

Altered balance

3

6.5%

Gait ataxia

3

6.5%

Facial pain

1

2.2%

Tinnitus

1

2.2%

Facial weakness

1

Data from Ojemann et al 1972.

2.2% 84

Table 18.2  Most common clinical signs in 46 patients with vestibular schwannomas

Fig. 18.2  A small vestibular schwannoma located in the left cerebellopontine (CP) angle shown in axial magnetic resonance images. The tumor has both a cisternal and canalicular component, with the canalicular component extending to near the mid-portion of the internal auditory canal (IAC). (a) T1-weighted noncontrast image reveals a small isointense lesion in the left CP angle. (b) T1-weighted postcontrast image reveals enhancement of the lesion and a well-demarcated portion in the cistern as well as in the IAC. There is no mass effect on the brainstem or cerebellum. (c) Fluid-attenuated inversion recovery image shows an isointense lesion relative to adjacent brain parenchyma. (d) T2-weighted image reveals a slightly hyperintense tumor with evidence of cerebrospinal fluid near the fundus.

Sign

Number of patients

Percentage

Auditory/vestibular

45

98%

Facial weakness

26

57%

Trigeminal sensory

26

57%

Altered taste

26

57%

Gait ataxia

19

41%

Limb ataxia

9

Data from Ojemann et al 1972.

20% 84

speech discrimination at presentation maintained good hearing at follow-up.19 Interestingly, hearing was lost during observation in cases of both tumor growth and stagnation15; this may be related to the known secretion of ototoxic molecules (including tumor necrosis factor alpha) by VSs.20

Clinical Presentation studies in the United States reveal a similar annual rate of 1.6 per 100,000 persons.12 Mean patient age at diagnosis is 58 years, and both sexes are affected equally. Histopathological studies of temporal bones demonstrate a significantly higher incidence of 0.57 to 2.5%, suggesting that the true incidence is higher, but the majority of these tumors never reach a symptomatic threshold.13 The natural history of tumor growth is variable; some lesions demonstrate continued growth while others will stagnate.11 The mean size at presentation is 11 mm and the mean annual growth rate is 3±1 mm.14 In a population study, 17% of intrameatal tumors grew into the cisternal space, and 30% of extrameatal tumors continued to grow while being observed.11 Among conservatively managed VSs, 1 to 8% demonstrate shrinkage at follow-up.15 Interestingly, there is a suggestion that tumors that did not show growth in the first 5 years of observation were unlikely to grow beyond that period,16 while the presence of tinnitus at presentation increased the odds of tumor growth three-fold.17 With regard to hearing preservation, 50% of conservatively managed patients lost functional hearing over a 5-year followup period.18 The presence of even small discrimination loss at presentation may predict an increased risk of hearing loss over time, with 38% of patients maintaining good hearing after 4.7 years of follow-up. However, 59% of patients who had 100%

The presentation of VS can be related to the tumor growth pattern. Initially, mass effect on the vestibular and cochlear divisions results in subjective hearing loss, with or without tinnitus, as well as dizziness. Although VS causes a similar mass effect on the facial nerve, it is exceedingly uncommon for patients to present with facial weakness; in fact, an alternative diagnosis should be pursued for patients with suspected VS who present with facial weakness. As the tumor grows, mass effect on the trigeminal nerve develops, which can lead to facial numbness, loss of the corneal reflex, and occasionally facial pain. As tumors grow larger, impingement on the lower cranial nerves is possible, leading to lower cranial neuropathies, including hoarseness and dysphagia. Further growth results in brainstem compression, which often manifests with gait difficulty, and later obstruction of the fourth ventricle, which leads to symptoms of hydrocephalus. Interestingly, communicating hydrocephalus is also seen in patients with VS and has been reported in the preoperative, as well as in the short-term and long-term postoperative periods; it is suspected to be due to secreted tumor factors resulting in elevated cerebrospinal fluid protein.21 The most common signs and symptoms of VS are summarized in Table 18.1 and 18.2.84

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A variant of VS, which is referred to as a “medial acoustic” tumor, does not extend into the internal auditory canal (IAC) and has a tendency to grow to a large size before manifesting clinically. These lesions tend to be hypervascular and may be associated with a higher rate of patient presentation with hydrocephalus. The origin and pattern of growth leads to arachnoidal rearrangement and resultant adherence to the brainstem interface at the time of surgery.22

Perioperative Evaluation All patients harboring suspected VS should undergo a complete radiographic assessment. At our institution, this typically includes an IAC-protocol magnetic resonance imaging (MRI) with thin cuts through the posterior fossa on T1-weighted sequences both before and after administration of intravenous contrast, as well as a thin-cut heavy T2-weighted sequence such as FIESTA (fast imaging employing steady-state acquisition) or CISS (constructive interference in steady-state). The MRI is complemented by a “dynamic” computed tomography (CT) angiogram, which is well-suited for the study of the three-dimensional bony anatomy, as well as the relationship of the tumor to arterial and venous structures in the region.23 This information is helpful when designing a surgical approach and for complication avoidance. Particular attention should be paid to anatomical variations, such as the dominance of transverse and sigmoid sinuses as well as the location and shape of the jugular bulb. The recognition of a high-riding jugular bulb is important, especially if the patient is placed in the sitting position. Some radiographic signs may be relevant to the prognosis of a patient with VS. Primarily cystic lesions may have the potential for sudden and dramatic growth24,​25 and may be more adherent to the nerves; treatment for these lesions may result in worse facial18,​26,​27 and hearing28 outcomes. Medial VSs are associated with marked tumor adherence to the brainstem and are frequently hypervascular.22 In addition to radiographic evaluation, all patients should undergo a formal audiogram to assess the quality and severity of hearing loss and to serve as a baseline for reference with postoperative results. For patients in whom involvement of the lower cranial nerves is suspected, formal swallow evaluation may also be considered.

Surgical and Nonsurgical Approaches The options available to patients with VSs consist of watchful observation, microsurgical resection, radiosurgery/radiotherapy, or a multimodal approach. A survey of the current practice pattern in the United States spanning a 10-year period suggests that microsurgery remains the most common treatment, having been performed on 53.4% of tumors. Radiosurgery/radiotherapy and watchful waiting have gained popularity, however, and are being applied to 24.2% and 22.4% of cases, respectively.29 The same pattern can be seen in Europe, where the enthusiasm for radiotherapy/radiosurgery is even greater.30 The Congress of Neurological Surgeons recently published a consensus statement for the treatment of patients with VS.85 The treatment plan must be tailored to each particular patient; general concepts are reviewed in this section. Patients who present with large tumors with resultant brainstem compression, hydrocephalus, or neurologic deficits require microsurgical resection. Additionally, documented enlargement

of a tumor occupying the CP angle is also an indication for treatment. The goal in both circumstances is the treatment of the neoplasm that induced, or would induce, neurologic deficit. In intracanalicular tumors, however, the only issue at patient presentation is hearing loss; watchful observation has thus become prevalent in the past few years. Observation is based on the rationale that 70% of the lesions remained unchanged.16 The management, therefore, is more complex if hearing preservation is the goal. Radiotherapy, and in particular stereotactic radiosurgery, is an increasingly popular treatment option for appropriately sized VSs and is applied in about 24% of cases in the United States. These cases are typically treated with a mean dose of 13 Gy,31 which is typically administered as a single fraction in an outpatient setting. The rate of control is 97% at 10 years,31 although the concept of “control” is elusive given the natural history of VSs, in which growth arrest may occur spontaneously.32 Furthermore, the CP angle houses several radiosensitive structures, including the brainstem and the auditory apparatus; the risk of delayed complications after radiosurgery should be carefully considered, especially when treating younger patients.33 In an attempt to reduce the risk of neurologic deficit while maximizing the rate of control, some centers have been administering stereotactic radiation over multiple sessions (often referred to as hyperfractionation), although the long-term results are yet to be elucidated.34 Microsurgical resection of VSs can be accomplished via a variety of approaches.35 Hearing-sparing approaches include the retrosigmoid and transmastoid approaches,36 or the middle cranial fossa approach. The translabyrinthine approach involves sacrifice of hearing and should primarily be considered for patients with large tumors who have already lost hearing. The choice of hearing-sparing approach depends, in part, on the surgeon’s experience and comfort level, as excellent outcomes have been well described with both approaches.4

Patient Outcomes Facial Function Preservation of facial nerve function is of cardinal importance in the treatment of VS; facial nerve injury is associated with facial deformity and attendant social implications, as well as functional deficits related to the ability to articulate speech, chewing, and swallowing. In an effort to preserve facial nerve function, Cushing advocated subtotal tumor resection for VSs.2 The introduction of the operative microscope to VS surgery by William House and the subsequent pioneering work establishing the translabyrinthine and middle fossa corridors were both aimed at maintaining facial nerve integrity while allowing more radical tumor resection.37,38 Contemporary surgical VS series estimate the likelihood of anatomical facial nerve preservation in the 93% range39 with a correlation between tumor size and risk of injury to the nerve.40 The routine use of intraoperative facial nerve monitoring allows for early detection of iatrogenic injury to the nerve, and affords the opportunity for its prevention.41 Contemporary radiosurgical series also report high rates of facial nerve function preservation, in the 99% range,31 suggesting the relative radioresistance of the facial nerve compared to surrounding structures.

18  Tumors of the Cerebellopontine Angle

279

Hearing Preservation Postoperative quality-of-life surveys of patients with VSs reveal that the primary patient-reported disability is hearing loss.42 Unlike facial nerve outcomes, the cochlear nerve results are less favorable in the literature. Distortion of cranial nerves from the presence of a mass lesion renders them more vulnerable to surgical manipulation, which is especially true for the cochlear nerve. The rate of hearing preservation in surgical series ranges from 47 to 92% and is optimized in male patients with small- to medium-sized tumors and good baseline hearing.43,​44 While any change in the hearing status can be ascertained relatively soon after surgical resection, an understanding of the hearing preservation results related to radiosurgical series requires long-term follow-up as radiation effects will present in a delayed fashion. Recent hearing-sparing microsurgical series report permanent hearing preservation in as many as 80% of patients, while 25 to 30% of patients will lose hearing during observation despite the fact that some tumors will not grow during the follow-up period.15 Radiosurgery/radiotherapy results in a high rate of hearing preservation initially, but in patients with useful hearing before radiosurgery, hearing is preserved in only 37% of patients at 10-year follow-up.45 Similar results are reported in other series with long-term follow-up.46,​47 Furthermore, even if surgery fails to preserve functional hearing, the call made nowadays for anatomical preservation of the cochlear nerve carries the hope for hearing restoration with cochlear implants in these patients.48

Best Evidence-Based Recommendations The optimal treatment of VS has yet to be clearly elucidated. Although several groups have proposed treatment algorithms, it is clear that there is no one-size-fits-all approach. It becomes ever more important, therefore, to discuss in detail with the individual patient the risks and benefits of all the available options. Patient age, preference, hearing status, tumor size, brainstem compression, and presence of hydrocephalus are just some of the factors to consider. In large compressive tumors, surgery is the obvious option. Surgery should still be considered the first-line treatment of small tumors in patients who can tolerate surgery and value preservation of hearing as it affords the best chance for a good outcome when considering a composite outcome of facial nerve and long-term hearing preservation. Perhaps the ideal patients for watchful observation are those harboring small tumors and complete hearing loss, the elderly who are unable to tolerate anesthesia, and those with small canalicular tumors and intact speech discrimination.44

■■ Meningiomas The second most common neoplastic lesions in the CP angle are meningiomas, which represent approximately 13% of all tumors in that location.49 The term posterior fossa meningiomas encompasses several lesions, including those arising near the foramen magnum, the jugular tubercle, and the dura overlying the clivus as well as the petroclival fissure. As it relates more specifically to the CP angle, Cushing and Eisenhardt50 reported on a series of

Fig. 18.3  A large cerebellopontine angle calcified meningioma arising from the posterior petrosal surface shown in axial magnetic resonance images. (a) T1-weighted non-contrast image shows a heterogeneous hypointense large lesion with mass effect on the adjacent cerebellum. (b) T1-weighted postcontrast image shows a heterogeneously enhancing tumor with an area of hypointensity reflecting intratumoral calcifications. Also present is a dural tail. (c) Fluid-attenuated inversion recovery image reveals a largely hypointense tumor with a hyperintense rim at the interface with the cerebellum. (d) T2-weighted image reveals a large hypointense tumor with areas of hyperintensity and a cerebrospinal fluid cleft at the interface with the cerebellum.

seven cases of meningiomas simulating acoustic neuromas. In the literature, the term CP angle meningioma is used in reference to tumors with diverse origins, including the tentorium, the petrosal sinus, the petrous ridge, the IAC, and the jugular foramen.51,​52 These tumors share the fact that they ultimately occupy, in part, the CP angle space; however, it is challenging to study these tumors as they constitute a heterogeneous set. The natural history of a petroclival meningioma is sufficiently different from those arising from the posterior face of the petrous bone that it warrants individual study. To avoid confusion, in this chapter, we use the term CP angle meningiomas to refer to tumors arising from the posterior face of the petrous bone (lateral to the trigeminal nerve), as they arise in the region of the CP angle and ultimately grow to occupy it (Fig. 18.3).53 We further confirm the importance of subdivision by Castellano and Ruggiero54 into tumors arising medial or lateral to the porus acusticus, which has implications for the anatomical distortion caused by the tumor as well as on the choice of surgical approach.

Pathophysiology, Incidence, Epidemiology, and Natural History Like meningiomas elsewhere in the central nervous system, CP angle meningiomas arise from progenitor cells that give rise to the arachnoid cap cells.54 Meningiomas account for 35.8% of all primary tumors of the central nervous system.55 Approximately

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9% of all intracranial meningiomas are located in the posterior fossa,56 the majority of which (42%) are tumors arising from the posterior face of the petrous bone.54 No reports suggest that the natural history of these lesions is different from the generally accepted natural history of intracranial meningiomas, the majority of which grow with an annual growth rate of less than 1 cm3.57 It is also plausible that these lesions, in addition to being rarer, are also less likely to be managed conservatively given their close proximity to the brainstem and cranial nerves, and thus a full understanding of their natural history has not yet been achieved. The location relative to the IAC is important, both in terms of understanding the presentation and treatment outcomes for patients with these tumors. While some authors classify these lesions as either anterior or posterior to the IAC,49 others further divide them into suprameatal and inframeatal.58

Clinical Presentation Otologic symptoms are the chief presenting complaint of most patients with CP angle meningiomas, followed by trigeminal symptoms. Observations from modern surgical series are summarized in Table 18.3.60,61 It has been observed that some patients present with clinical manifestation of vestibulocochlear dysfunction without radiographic evidence of tumor abutment or displacement of the vestibulocochlear nerve complex. Some postulate that in those patients compression of the endolymphatic sac mimics endolymphatic hydrops.59 Patients with meningiomas arising anterior to the IAC tend to present earlier than those with retromeatal tumors.49 Furthermore, patients with premeatal tumors are more likely to present with trigeminal neuropathy while those with retromeatal tumors are more likely to have cerebellar dysfunction.49 Table 18.3  Clinical presentation of patients with cerebellopontine angle meningiomas

Symptoms

Bassiouni et al 200460 (N = 50) No. (%)

Voss et al 200061 (N = 40)

Hearing loss

27 (54%)

28 (73%)

Dizziness

25 (50%)

4 (10%)

Tinnitus

14 (28%)

17 (43%)

Trigeminal neuropathy

9 (18%)

8 (20%)

Facial nerve dysfunction

3 (6%)

3 (7.5%)

Cerebellar signs

16 (32%)

20 (50%)

Perioperative Evaluation It is at times difficult to clearly distinguish between CP angle meningiomas and schwannomas solely on the basis of the patients’ presenting signs and symptoms. While certain features, including trigeminal neuropathy or hemifacial spasm,62 are more commonly reported in patients with meningiomas, these features are not diagnostic. Ultimately, radiographic evaluation, including MRI and CT, is necessary. The presence of a dural tail on postcontrast T1-weighted MRI sequence is suggestive of meningioma. While VSs tend to erode and expand the porus, this is not observed with meningiomas, which instead can be associated with hyperostosis that is best seen on CT. Intratumoral calcifications are relatively common in meningiomas but rare in schwannomas. On a T2-weighted MRI sequence, VSs tend to appear hyperintense relative to brain parenchyma, while meningiomas are usually isointense.63 The signs are summarized in Table 18.4. Differentiating between VSs and CP angle meningiomas preoperatively, as well as determining the site of origin of meningiomas, is important in ­trying to predict the direction of displacement of cranial nerves during surgical planning.64 Just as in treating patients with VSs, a complete audiologic assessment should be completed both preoperatively and post operatively in patients with suspected CP angle meningiomas.61 They also should undergo imaging of the venous and arterial trees, which can be accomplished with a dynamic CT study.23

Surgical and Medical Approaches The senior author has described a modification of the retrosigmoid approach, referred to as the transmastoid approach, whereby a partial mastoidectomy is performed in addition to the lateral suboccipital craniotomy, which allows for lateral displacement of the sigmoid sinus and reduced need for cerebellar retraction.36 Alternatively, for lesions that extend medial to the IAC or for those that extend above the tentorium, a petrosal approach is preferred.64 The petrosal approach affords an excellent exposure while preserving hearing and minimizing retraction of neurovascular structures. Although the approach can be used to achieve excellent outcomes in posterior fossa tumors such as petroclival meningiomas, it is seldom necessary for posterior petrosal meningiomas that are contained below the tentorium. As in all surgeries to remove meningiomas, resection of CP angle meningiomas is considered complete only if the underlying dura and the affected bone are removed to achieve a Simpson Grade I resection.65 In cases where the lesion extends into the internal auditory meatus, drilling of the posterior meatal wall is necessary for complete tumor removal.66

Table 18.4  Radiographic signs of cerebellopontine angle tumors

Lesion

CT

T1 MRI

T2 MRI

T1+ MRI

Special

Vestibular schwannoma

Isodense

Hypointense

Hyperintense

Enhancement

Widening of the porus

Meningioma

Hyperdense, may contain calcifications

Isointense

Variable

Homogeneous enhancement

Dural tail, hyperostosis

Epidermoid

Hypodense

Hypointense

Hyperintense

No enhancement

Diffusion restriction

Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; T1, T1-weighted; T1+, T1-weighted with contrast; T2, T2-weighted

18  Tumors of the Cerebellopontine Angle Currently, no medical options are available to treat meningiomas, although this remains an area of active interest and research.67 The role of radiation for WHO grade I CP angle meningiomas is limited because of the benign biology of the tumors and their proximity to radiosensitive structures.33

Patient Outcomes Patient outcomes after surgery for CP angle meningiomas depend upon the size, location relative to the porus acusticus, vascularity, and consistency of the tumor, as well as the degree of tumor adherence to surrounding structures, including the cranial nerves and brainstem. The likelihood of preservation of facial and hearing function is relatively diminished with tumors that arise medial to the porus compared to those arising lateral to it,58 although good facial nerve function is preserved in 89% of cases and the reported rate of hearing preservation is 91%.68,​69

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intermediate- or high-grade pathology on imaging, and considerable mass effect on neural elements at the time of diagnosis. An important note should be made about the use of hearingsacrificing approaches in patients with hearing loss and a posterior fossa meningioma. In contrast to results after treatment for VS, return of hearing function has been documented in the setting of meningiomas.70 Thus, every effort is made to preserve the hearing apparatus, even in patients with documented nonserviceable hearing on preoperative testing.

■■ Epidermoids Epidermoid cysts are lesions of congenital origin that are thought to arise from aberrant neural tube closure.71 Epidermoids are the most common embryonal tumors to occupy the intracranial space, and they are often located in the CP angle (Fig. 18.4).72

Best Evidence-based Recommendations

Pathophysiology, Incidence, Epidemiology, and Natural History

The indications for surgical intervention for meningiomas, including those in the CP angle, include the presence or development of neurologic symptoms, radiographic progression, suggestion of

Epidermoids are the third most common lesion in the CP angle location, accounting for 4 to 7% of the total.72,​73 The capsule of an epidermoid cyst is made up of stratified squamous epithelium

Fig. 18.4  A left cerebellopontine angle epidermoid cyst that extends along the incisura into the supratentorial compartment shown in axial magnetic resonance images. (a) T1-weighted noncontrast image reveals a hypointense lesion relative to adjacent brain with mass effect on the brainstem, middle cerebellar peduncle, and cerebellum with signal intensity similar to cerebrospinal fluid. (b) T1-weighted postcontrast image

reveals no enhancement. (c) Fluid-attenuated inversion recovery image reveals a mildly heterogeneous lesion that otherwise has intensity similar to that of cerebrospinal fluid. (d) T2-weighted image reveals a mildly heterogeneous lesion that otherwise has intensity similar to that of cerebrospinal fluid. (e) Diffusion-weighted image reveals significant diffusion restriction throughout the lesion, confirming the diagnosis of epidermoid.

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while the contents are made up of keratin, which gives rise to the “pearly white” appearance that is so characteristic of these lesions. Progressive desquamation of the stratified epithelium results in expansion of the cysts and growth pattern along the paths of least resistance within the cisterns of the posterior fossa.72 Because of their growth pattern, epidermoids tend to encapsulate neurovascular structures. This is in contrast to other space-occupying lesions of the posterior fossa that tend to displace cranial nerves and vessels. As time progresses, dense adhesions to neurovascular structures and the brainstem may develop, which has implications for complete surgical resectability.74

Clinical Presentation Patients with epidermoids tend to present in the third to fifth decades in life with long-standing hearing loss and tinnitus.75 Cyst rupture, while a rarely reported event, can be associated with episodes of aseptic meningitis and increased risk of ­hydrocephalus. The most common presenting signs and symptoms are summarized in Table 18.5.76

Perioperative Evaluation As for other posterior fossa lesions, comprehensive neuroimaging must be undertaken to understand the disease process and relevant anatomy. The main entity to consider in the differential diagnosis of epidermoids is arachnoid cysts. On CT imaging, both epidermoids and arachnoid cysts have similar imaging characteristics, although arachnoid cysts tend to have less mass effect on the cerebellum and brainstem and can be associated with bone remodeling, which is not seen with epidermoids. In patients with epidermoid cysts, both T1-weighted and T2-weighted MRI sequences reveal a lesion that is isointense to cerebrospinal fluid. In contrast to arachnoid cysts, however, epidermoids typically show heterogeneous intensity on T2-weighted and fluid-attenuated inversion recovery sequences. The hallmark of epidermoids, and the main radiographic criteria to differentiate them from arachnoid cysts, is the presence of restricted diffusion.77 Furthermore, while arachnoid cysts often have a smooth surface, the surface of an epidermoid is often irregular. It is noteworthy that epidermoids do not demonstrate contrast enhancement. In the setting of a known epidermoid that develops a contrast-enhancing portion, malignant transformation should be considered.78 Table 18.5  Clinical presentation of 40 patients with cerebellopontine angle epidermoids

In addition to neuroimaging, an audiogram should be performed for patients harboring epidermoids. In patients who present with vision complaints, or when the lesion extends past the incisura toward the ambient and interpeduncular cisterns, a complete neuro-ophthalmologic evaluation, including visual field examination and study of extraocular movements, should be undertaken. For lesions that involve the lower cranial nerves, especially when patients report difficulty swallowing, a formal swallow evaluation should be undertaken.

Surgical and Medical Approaches The treatment of choice for epidermoids is microsurgical resection; there are currently no alternative medical or radiation treatments. The most common approach reported in the literature for surgical resection of these lesions is the retrosigmoid approach,71,​79 although the advantages of the transmastoid approach are equally applicable to these lesions as to the others previously discussed.36 Unlike other lesions in the CP angle, epidermoids typically do not displace, but rather engulf the cranial nerves and vascular structures. This quality is particularly conducive to the combined microscopic and endoscopic approach.80 The goal of surgical resection is complete tumor removal to reduce the risk of postoperative recurrence.71 The capsule should be pursued after the contents have been extensively debulked; although challenging, the complete removal of the capsule is associated with improved function, low morbidity, and decreased chance of recurrence in de novo tumors.74 In areas where significant adhesions have formed, a small remnant of the capsule may be left behind if its removal would jeopardize neurologic function. In cases where the epidermoid has significant extension through the incisura and thus a significant presence in the middle cranial fossa, a petrosal approach64 should be considered. Regardless of the approach used, it is important to be vigilant during resection to avoid spillage of the tumor contents into the cerebrospinal fluid space. The contents are known to be a neural and meningeal irritant and are associated with the development of postoperative aseptic meningitis81 and, in a delayed fashion, hydrocephalus.82

Patient Outcomes Reported rates of radical removal of CP angle epidermoids range from 38 to 75%.72,​74,​79 The main surgical morbidity is related to cranial neuropathy, as well as to the development of aseptic meningitis, which may be ameliorated by a slow postoperative taper of steroids. Recurrence is a well-documented phenomenon related to epidermoids that are subtotally resected, with the possibility of delayed recurrences developing as late as three decades after removal.83

Signs & symptoms

% Presenting

Hearing loss

55%

Dizziness

40%

Gait disturbance

18%

Trigeminal neuralgia

13%

Tinnitus

11%

Best Evidence-based Recommendations

Diplopia

10%

Visual impairment

5%

Seizures

3%

Transient ischemic attack

3%

Surgical resection of symptomatic, large, or growing epidermoid cysts remains the mainstay of treatment. It is possible to achieve total resection with good neurologic outcome in the majority of cases. In patients with adherent disease, a residual can be left and observed for future growth.

Data from Samii et al 1996.76

18  Tumors of the Cerebellopontine Angle

■■ Conclusions Tumors of the CP angle are a heterogeneous group that often share a common clinical presentation but are typically distinguishable by virtue of radiographic characteristics. This chapter reviews various key aspects of the three most common mass lesions occurring in the CP angle. Altogether, they account for approximately 98% of extra-axial lesions in this location. Other less common extra-axial lesions are known to occur in the CP angle, including nonvestibular schwannomas such as those arising from the facial or trigeminal nerves, arachnoid cysts, endolymphatic sac tumors, choroid plexus tumors, and neurenteric cysts. References 1. B allance SCA. Some Points in the Surgery of the Brain and its Membranes. London: Macmillan; 1907 2. Cushing H. Tumours of the Nervus Acusticus and the Syndrome of the Cerebellopontile Angle. Philadelphia: W. B. Saunders Co.; 1917 3. Ramsden RT. The bloody angle: 100 years of acoustic neuroma surgery. J R Soc Med 1995;88(8):464P–468P 4. Samii M, Matthies C. Management of 1000 vestibular schwannomas (acoustic neuromas): surgical management and results with an emphasis on complications and how to avoid them. Neurosurgery 1997; 40(1):11–21, discussion 21–23

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6. Lanser MJ, Sussman SA, Frazer K. Epidemiology, pathogenesis, and genetics of acoustic tumors. Otolaryngol Clin North Am 1992;25(3):499–520

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10. Meyer S, Post K. Acoustic Neuroma. In Youmans Neurological Surgery. Vol 2. 6th ed. Philadelphia Saunders; 2011 11. Stangerup SE, Caye-Thomasen P. Epidemiology and natural history of vestibular schwannomas. Otolaryngol Clin North Am 2012;45(2):257–268, vii 12. Ostrom QT, Gittleman H, Liao P, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007–2011. Neuro-oncol 2014;16(Suppl 4):iv1–iv63 13. Yoshimoto Y. Systematic review of the natural history of vestibular schwannoma. J Neurosurg 2005;103(1):59–63 14. Sughrue ME, Yang I, Aranda D, et al. The natural history of untreated sporadic vestibular schwannomas: a comprehensive review of hearing outcomes. J Neurosurg 2010;112(1):163–167 15. Pennings RJ, Morris DP, Clarke L, Allen S, Walling S, Bance ML. Natural history of hearing deterioration in intracanalicular vestibular schwannoma. Neurosurgery 2011;68(1):68–77 16. Stangerup SE, Caye-Thomasen P, Tos M, Thomsen J. The natural history of vestibular schwannoma. Otol Neurotol 2006;27(4):547–552 17. Agrawal Y, Clark JH, Limb CJ, Niparko JK, Francis HW. Predictors of vestibular schwannoma growth and clinical implications. Otol Neurotol 2010; 31(5):807–812 18. Hoa M, Drazin D, Hanna G, Schwartz MS, Lekovic GP. The approach to the patient with incidentally diagnosed vestibular schwannoma. Neurosurg Focus 2012;33(3):E2 19. Stangerup SE, Thomsen J, Tos M, Cayé-Thomasen P. Long-term hearing preservation in vestibular schwannoma. Otol Neurotol 2010; 31(2):271–275

34. Hansasuta A, Choi CY, Gibbs IC, et al. Multisession stereotactic radiosurgery for vestibular schwannomas: single-institution experience with 383 cases. Neurosurgery 2011;69(6):1200–1209 35. Chamoun R, MacDonald J, Shelton C, Couldwell WT. Surgical approaches for resection of vestibular schwannomas: translabyrinthine, retrosigmoid, and middle fossa approaches. Neurosurg Focus 2012; 33(3):E9 36. Abolfotoh M, Dunn IF, Al-Mefty O. Transmastoid retrosigmoid approach to the cerebellopontine angle: surgical technique. Neurosurgery 2013; 73(1, Suppl Operative):ons16–ons23, discussion ons23 37. Camins MB, Oppenheim JS. Anatomy and surgical techniques in the suboccipital transmeatal approach to acoustic neuromas. Clin Neurosurg 1992;38:567–588 38. House WF. Surgical exposure of the internal auditory canal and its contents through the middle, cranial fossa. Laryngoscope 1961; 71:1363–1385 39. Samii M, Matthies C. Management of 1000 vestibular schwannomas (acoustic neuromas): the facial nerve--preservation and restitution of function. Neurosurgery 1997;40(4):684–694, discussion 694–695 40. Bloch O, Sughrue ME, Kaur R, et al. Factors associated with preservation of facial nerve function after surgical resection of vestibular schwannoma. J Neurooncol 2011;102(2):281–286 41. Arriaga MA, Luxford WM, Atkins JS, Jr, Kwartler JA. Predicting long-term facial nerve outcome after acoustic neuroma surgery. Otolaryngol Head Neck Surg 1993;108(3):220–224

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42. Rigby PL, Shah SB, Jackler RK, Chung JH, Cooke DD. Acoustic neuroma surgery: outcome analysis of patient-perceived disability. Am J Otol 1997;18(4):427–435 43. Samii M, Matthies C. Management of 1000 vestibular schwannomas (acoustic neuromas): hearing function in 1000 tumor resections. Neurosurgery 1997;40(2):248–260, discussion 260–262 44. Yamakami I, Ito S, Higuchi Y. Retrosigmoid removal of small acoustic neuroma: curative tumor removal with preservation of function. J Neurosurg 2014;121(3):554–563 45. Hasegawa T, Kida Y, Kobayashi T, Yoshimoto M, Mori Y, Yoshida J. Long-term outcomes in patients with vestibular schwannomas treated ­using gamma knife surgery: 10-year follow up. J Neurosurg 2005;102 (1):10–16 46. Carlson ML, Jacob JT, Pollock BE, et al. Long-term hearing outcomes following stereotactic radiosurgery for vestibular schwannoma: patterns of hearing loss and variables influencing audiometric decline. J Neurosurg 2013;118(3):579–587 47. Roos DE, Potter AE, Brophy BP. Stereotactic radiosurgery for acoustic neuromas: what happens long term? Int J Radiat Oncol Biol Phys 2012; 82(4):1352–1355 48. Upadhyay U, Almefty RO, Dunn IF, Al-Mefty O. Letter to the Editor: Save the nerve. J Neurosurg 2015;123(3):821–822 49. Schaller B, Merlo A, Gratzl O, Probst R. Premeatal and retromeatal cerebellopontine angle meningioma. Two distinct clinical entities. Acta Neurochir (Wien) 1999;141(5):465–471 50. Cushing H, Eisenhardt L. Meningiomas: Their Classification, Regional Behaviour, Life History, and Surgical End Results. In Classics of Neurology & Neurosurgery Library. Birmingham, Ala: The Classics of Neurology & Neurosurgery Library; 1988 51. Yaşargil MG, Mortara RW, Curcic M. Meningiomas of basal posterior cranial fossa. In: Krayenbühl H, et al. eds. Advances and Technical Standards in Neurosur­gery. Vol 7. Vienna: Springer; 1980: 3-115 52. Sekhar LN, Jannetta PJ. Cerebellopontine angle meningiomas. Microsurgical excision and follow-up results. J Neurosurg 1984;60 (3):500–505 53. Al-Mefty O. Meningiomas. New York: Raven Press; 1991 54. Castellano F, Ruggiero G. Meningiomas of the posterior fossa. Acta Radiol Suppl 1953;104:1–177 55. Ostrom QT, Gittleman H, Fulop J, et al. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008–2012. Neuro-oncol 2015;17(Suppl 4):iv1–iv62 56. Quest DO. Meningiomas: an update. Neurosurgery 1978;3(2):219–225 57. Nakamura M, Roser F, Michel J, Jacobs C, Samii M. The natural history of incidental meningiomas. Neurosurgery 2003;53(1):62–70, discussion 70–71 58. Samii M, Gerganov V. Surgery of Cerebellopontine Lesions. New York: Springer; 2013 59. Friedman RA, Nelson RA, Harris JP. Posterior fossa meningiomas ­intimately involved with the endolymphatic sac. Am J Otol 1996;17(4):612–616 60. Bassiouni H, Hunold A, Asgari S, Stolke D. Meningiomas of the posterior petrous bone: functional outcome after microsurgery. J Neurosurg 2004; 100(6):1014–1024 61. Voss NF, Vrionis FD, Heilman CB, Robertson JH. Meningiomas of the cerebellopontine angle. Surg Neurol 2000;53(5):439–446, discussion 446–447 62. Ogasawara H, Oki S, Kohno H, Hibino S, Ito Y. Tentorial meningioma and painful tic convulsif. Case report. J Neurosurg 1995;82(5):895–897 63. Mulkens TH, Parizel PM, Martin JJ, et al. Acoustic schwannoma: MR findings in 84 tumors. AJR Am J Roentgenol 1993;160(2):395–398 64. Al-Mefty O, Ayoubi S, Smith RR. The petrosal approach: indications, technique, and results. In: Koos W, Richling B, eds. Processes of the Cranial Midline. Vol 53. Vienna: Springer; 1991 65. Simpson D. The recurrence of intracranial meningiomas after surgical treatment. J Neurol Neurosurg Psychiatry 1957;20(1):22–39

66. Al-Mefty O. Operative Atlas of Meningiomas. New York: LippincottRaven; 1998 67. Chamberlain MC. The role of chemotherapy and targeted therapy in the treatment of intracranial meningioma. Curr Opin Oncol 2012; 24(6):666–671 68. Nassif PS, Shelton C, Arriaga M. Hearing preservation following surgical removal of meningiomas affecting the temporal bone. Laryngoscope 1992;102(12 Pt 1):1357–1362 69. Nakamura M. Facial and cochlear nerve function after surgery of cerebellopontine angle meningiomas. In: Ramina R, Pires de Aguiar PH, Tatagiba M, eds. Samii's Essentials in Neurosurgery. 2nd ed. Berlin: Springer; 2014, 251–264 70. Goebel JA, Vollmer DG. Hearing improvement after conservative approach for large posterior fossa meningioma. Otolaryngol Head Neck Surg 1993;109(6):1025–1029 71. Yaşargil MG, Abernathey CD, Sarioglu AC. Microneurosurgical treatment of intracranial dermoid and epidermoid tumors. Neurosurgery 1989; 24(4):561–567 72. deSouza CE, deSouza R, da Costa S, et al. Cerebellopontine angle epidermoid cysts: a report on 30 cases. J Neurol Neurosurg Psychiatry 1989; 52(8):986–990 73. Altschuler EM, Jungreis CA, Sekhar LN, Jannetta PJ, Sheptak PE. Operative treatment of intracranial epidermoid cysts and cholesterol granulomas: report of 21 cases. Neurosurgery 1990;26(4):606–613, discussion 614 74. Aboud E, Abolfotoh M, Pravdenkova S, Gokoglu A, Gokden M, Al-Mefty O. Giant intracranial epidermoids: is total removal feasible? J Neurosurg 2015;122(4):743–756 75. Mallucci CL, Ward V, Carney AS, O’Donoghue GM, Robertson I. Clinical features and outcomes in patients with non-acoustic cerebellopontine angle tumours. J Neurol Neurosurg Psychiatry 1999;66(6):768–771 76. Samii M, Tatagiba M, Piquer J, Carvalho GA. Surgical treatment of epidermoid cysts of the cerebellopontine angle. J Neurosurg 1996;84(1):14–19 77. Tsuruda JS, Chew WM, Moseley ME, Norman D. Diffusion-weighted MR imaging of the brain: value of differentiating between extraaxial cysts and epidermoid tumors. AJR Am J Roentgenol 1990;155(5):1059–1065, discussion 1066–1068 78. Mohanty A, Kolluri VR, Santosh V. Squamous cell carcinomatous change in a posterior fossa epidermoid: case report with a review of the literature. Br J Neurosurg 1996;10(5):493–495 79. Mohanty A, Venkatrama SK, Rao BR, Chandramouli BA, Jayakumar PN, Das BS. Experience with cerebellopontine angle epidermoids. Neurosurgery 1997;40(1):24–29, discussion 29–30 80. Abolfotoh M, Bi WL, Hong CK, et al. The combined microscopic-endoscopic technique for radical resection of cerebellopontine angle tumors. J Neurosurg 2015;123(5):1301–1311 81. Abramson RC, Morawetz RB, Schlitt M. Multiple complications from an intracranial epidermoid cyst: case report and literature review. Neurosurgery 1989;24(4):574–578 82. Ahmed I, Auguste KI, Vachhrajani S, Dirks PB, Drake JM, Rutka JT. Neurosurgical management of intracranial epidermoid tumors in children. Clinical article. J Neurosurg Pediatr 2009;4(2):91–96 83. Tancredi A, Fiume D, Gazzeri G. Epidermoid cysts of the fourth ventricle: very long follow up in 9 cases and review of the literature. Acta Neurochir (Wien) 2003;145(10):905–910, discussion 910–911 84. Ojemann RG, Montgomery WW, Weiss AD. Evaluationand surgical treatment of acoustic neuroma. N Engl J Med 1972 Nov 2;287(18):895–9. DOI: 10.1056/NEJM197211022871802 PMID:5075549 85. Olson JJ, Kalkanis SN, Ryken Timothy C. Congress of N ­ eurological Surgeons systematic review and evidence-based guidelines on the treatment of adults with vestibular schwannomas: executive ­summary. Neurosurgery 2018;82(2):129–134. DOI: 10.1093/neuros/ nyx586. PMID: 29309649.

19

Pineal Region Tumors

Stephen G. Bowden, Adam M. Sonabend, and Jeffrey N. Bruce

Abstract

Pineal region tumors have remarkable biological and histologic diversity that dictates nearly every step of their management. Tumor markers are required preoperatively to identify germ cell tumors, which are susceptible to chemotherapy, and to forgo surgical resection. If tumor markers are absent, a tissue diagnosis becomes imperative. The choice of biopsy versus surgical resection is multifactorial but must be made to maximize the likelihood of obtaining an accurate diagnosis. Diagnosis, in turn, guides subsequent management with regard to adjuvant therapy, patient prognosis, and clinical follow-up. Continued advancement of microsurgical techniques has kept aggressive surgical resection a mainstay of management. Nearly all patients with benign lesions have excellent long-term prognoses, while good outcomes are also achieved in a large percentage of patients with malignant tumors. Outcomes among this heterogeneous population will continue to improve with more clearly defined and more effective approaches to adjuvant therapy. Keywords:  germ cell tumor, microsurgery, occipital transtentorial approach, pineal cell tumor, pineal region, pineal region tumor, sitting position, supracerebellar infratentorial approach, teratoma

■■ Pathophysiology Pineal region tumors arise from a remarkable number of different cell types, rendering it one of the most pathologically diverse, and therefore complex, areas of the brain. Germ cell, pineal parenchymal cell, and glial cell tumors are the three most common tumor types found in the pineal region; in addition, a variety of miscellaneous tumors may occur, including meningiomas, melanomas, metastases, lymphomas, and cysts.1,​2 Mixed tumors that contain more than one cell type can also occur. Tumors within each of these groups range from benign to malignant.3 Vascular pathologies, such as cavernous malformations, arteriovenous malformations, and vein of Galen malformations, may also occur in this region.4 Germ cell tumors are pluripotent tumors of germ cell origin that span a wide range of histologic and malignant characteristics. Teratomas, dermoid tumors, and epidermoid tumors are benign, whereas endodermal sinus tumors, embryonal cell tumors, and choriocarcinomas are malignant. Germinomas and immature teratomas fall somewhere between these two extremes. Pineal cell tumors, also referred to as pineal parenchymal tumors, originate from pineal parenchymal cells within the pineal gland. They can be subdivided into pineocytomas, pineoblastomas, and mixed forms known as pineal parenchymal tumors of intermediate differentiation.

■■ Incidence and Prevalence Pineal region tumors are rare, accounting for only 1.2% of all central nervous system tumors according to the 2012 report from CBTRUS (Central Brain Tumor Registry of the United States).5 Historically, reported incidence has been approximately 1.0%, with the exception of several series reporting rates of up to 6.2% in Japanese populations.6 These reports have given rise to the traditional teaching that pineal region tumors are more common in Japan, but some authors suggest that these findings may be due to selection bias. Prospective studies of population-based incidence have failed to demonstrate any marked increase in Japan over other countries.7,​8,​9,​10 However, it is of particular importance to consider the incidence of different tumor subtypes, given the histologic diversity of this region of the brain. Germ cell tumors, cysts, and heterotopias account for 0.5% of all intracranial neoplasms seen in the United States according to the CBTRUS report, with an incidence of 0.10 per 100,000 person-years among the U.S. population.5 Germinomas comprise the majority of germ cell tumors, with teratomas, endodermal sinus tumors, embryonal cell tumors, and choriocarcinomas correspondingly less frequent.11 Moreover, large series have shown that mixed germ cell tumors account for 25% of germ cell tumors.12,​13,​14 Pineal cell tumors are less common, accounting for only 0.2% of all central nervous system tumors, with an incidence estimated at 0.01 per 100,000 persons per year in the United States.5,​15 The distribution of subtypes within this classification is mixed among prior reports, but aggregating cases from U.S. institutional reports yields 42% pineocytomas, 32% pineoblastomas, and 26% mixed-cell types.14,​15,​16 Notably, pineal cell tumors are less common in Japan, making up only 11% of tumors in the pineal region, compared with 30% of tumors in the pineal region in the United States. However, given Japan’s overall higher incidence of tumors in this region, the incidence of pineal cell tumors is about the same in both countries.6

■■ Epidemiology Age Distribution Pineal region tumors most commonly affect younger patients, with children particularly affected by some histologic subtypes. Nearly all intracranial germ cell tumors occur in the first three decades of life. Germinomas are relatively evenly distributed through this age range, but nongerminomatous germ cell tumors (NGGCTs) and choriocarcinomas occur more frequently in patients younger than 9 years. Teratomas are also common in the very young, but have an additional incidence peak between 16 and

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18 years of age. In contrast, endodermal sinus and embryonal cell tumors are common in middle and late adolescence, respectively. Pineal cell tumors occur more commonly in adult patients than germ cell tumors. Most patients present at 20 to 40 years of age, but patient ages range from infancy to old age.12,​15,​17 Patients with pineocytomas have an average age of presentation of 40 years, with these tumors generally occurring in young adults.12 The more malignant pineoblastoma occurs in a slightly younger population; in Schild et al's15 series, the average age at onset was 18 years.

Sex Distribution Germ cell tumors are more than twice as common among the male population as they are among the female population. Pure germinomas exhibit a slightly lower ratio of 1.88:1, whereas NGGCTs are much more likely to affect males than females, at a rate of 3.25:1. No sex preference is clearly apparent in large series of pineal cell tumors, but a slight male predominance has been suggested in the Japanese literature (7:5 male to female).6

Family History and Genetic Links Pineal region tumors, compared with other types of intracranial tumors, are less likely to be associated with familial links. Only isolated reports of germ cell or pineal parenchymal cells within families exist. However, one striking familial association is seen in the childhood syndrome trilateral retinoblastoma, which consists of pineoblastoma with bilateral retinoblastoma. Overlap between these two types of tumor may be attributed to the similar embryonic origins of the vestigial photoreceptors in the pineal gland and the retinal photoreceptors.18 Even without trilateral retinoblastoma, pediatric patients with pineoblastoma who have a familial mutation of the RB1 gene appear to have a worse prognosis than a similar population without mutated RB1.19

■■ Clinical Presentation Patients with pineal region tumors present most commonly with symptoms of obstructive hydrocephalus, brainstem or ­cerebellar compression, or endocrine dysfunction. Tumor-induced obstruction of the aqueduct of Sylvius often leads to the gradual onset of increased intracranial pressure (Fig. 19.1). Brainstem or

Fig. 19.1  Magnetic resonance imaging (MRI) of a 56-year-old man with a pineal parenchymal tumor. (a) Sagittal T1-weighted postcontrast MRI demonstrates mass effect anteriorly and compression of the aqueduct of Sylvius. (b) Axial T1-weighted MRI at the yellow cutline in the sagittal image (a) demonstrates resultant hydrocephalus with expansion of the lateral ventricles.

cerebellar compression is usually a direct, local effect of tumor growth and often leads to visual disturbances given the proximity of the tumor to the superior colliculus. Endocrine dysfunction is rare by comparison, but it can arise secondary to obstructive hydrocephalus or direct tumor infiltration of the hypothalamus. Headache is the most common initial complaint suggestive of hydrocephalus. The patient's history often indicates a subacute course. Without treatment, aqueductal obstructions can progress, causing nausea, vomiting, ataxia, papilledema, and cognitive impairment. Patients can also present acutely with symptoms in the setting of pineal apoplexy.20 Pineal cell tumors and, less commonly, choriocarcinomas have a greater predisposition to hemorrhage due to their increased vascularity (Fig. 19.2). Extraocular movement disorders are a frequent sign of midbrain compression. Parinaud syndrome, consisting of upgaze paralysis, convergence or retraction nystagmus, and light-near pupillary dissociation, is caused by compression at the level of the superior colliculus and is particularly common. Sylvian aqueduct syndrome, which includes paralysis of downgaze or horizontal gaze, can occur in conjunction with Parinaud syndrome when additional midbrain compression is present. Other signs of dorsal midbrain compression include lid retraction (Collier sign) or ptosis. Less commonly, fourth nerve palsies may give rise to diplopia, and head tilt may occur. Of note, both hydrocephalus and direct brain compression can prompt these visual disturbances. Symptomatic relief after cerebrospinal fluid (CSF) diversion is confirmatory for hydrocephalus as the inciting cause. Brainstem or cerebellar involvement can manifest in other ways, including ataxia and dysmetria from disturbance of the superior cerebellar peduncles or, rarely, hearing dysfunction or tinnitus, presumably due to interference with structures associated with the inferior colliculi.21 Germinomas that spread along the floor of the third ventricle can induce diabetes insipidus early in their course, even when radiographically occult. Pineal region lesions have also been linked to precocious puberty in the past, although there are few actual documented cases.22 This syndrome is more accurately described as precocious pseudopuberty, given the immaturity of the hypothalamic-gonadal axis. This syndrome is specific to male patients with choriocarcinoma or germinoma whose syncytiotrophoblastic cells ectopically produce β-human chorionic gonadotropin (β-hCG). In turn, β-hCG stimulates the Leydig cells of the testes to secrete androgens and cause premature sexual maturation characteristics.11,​22

Fig. 19.2  Magnetic resonance imaging (MRI) of a 24-year-old man who presented with headache and transient left-sided facial numbness. (a) Sagittal T1-weighted precontrast MRI demonstrates pineal region mass. (b) Axial fluid-attenuated inversion recovery MRI demonstrates fluid level consistent with pineal apoplexy.

19  Pineal Region Tumors

■■ Preoperative Evaluation The preoperative evaluation for patients with pineal region tumors consists of imaging, neurologic examination, and laboratory tests for tumor markers. Gadolinium-enhanced magnetic resonance imaging (MRI) is necessary to determine the relationship of the tumor to relevant neighboring structures, such as the third ventricle, quadrigeminal plate, deep cerebral veins, and tentorium. The degree of local tumor invasion is of particular importance, although it is often exaggerated by MRI. Attention should be paid to the potential presence of separate lesions of the suprasellar region, pituitary stalk, and third ventricle, as these can be seen with germ cell tumors. Spinal MRI is useful in identifying disseminated leptomeningeal disease or drop metastases (Fig. 19.3), which would confer a poor prognosis and warrant a more conservative, nonsurgical treatment. The measurement of α-fetoprotein (AFP) and β-hCG is required prior to any surgical intervention, as positivity for either is pathognomonic for malignant germ cell elements (Table 19.123).,​24,​26 Serum levels are less sensitive than CSF levels, but measurement of both is recommended.24,​25 Elevated AFP levels are diagnostic of fetal yolk sac elements, with higher levels associated with endodermal sinus tumors and lower levels indicating embryonal cell carcinoma or immature teratoma.11,​ 24,​25,​26 Similarly, elevated β-hCG levels indicate the presence of trophoblastic elements. Substantial elevations in β-hCG

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levels can be associated with choriocarcinoma, whereas lower levels are more suggestive of embryonal cell carcinoma and germinoma.11,​24,​25,​26 Although the presence of germ cell markers is specific for a malignant germ cell tumor, the absence of such markers should be interpreted cautiously. A germinoma or embryonal cell carcinoma may still be present even if both germ cell markers are absent.2 However, the specificity of these markers allows patients with positive assay results to forgo tissue diagnosis and instead be managed adequately with radiotherapy and chemotherapy. The presence or absence of obstructive hydrocephalus dictates the CSF sampling strategy  (Fig. 19.42). Intracranial pressure can be reduced gradually to resolve symptoms before a craniotomy using stereotactic-guided endoscopic third ventriculostomy to manage symptomatic patients. This method is preferable to ventriculoperitoneal shunting because it minimizes infection risk and negates the risk of shunt failure, overshunting, or peritoneal seeding. Placement of a ventricular drain at the time of surgery is a reasonable alternative for mildly symptomatic patients.27 Advantages of a ventricular drain are its ease of removal or conversion to a shunt as postoperative circumstances dictate. Mild or asymptomatic hydrocephalus often resolves after resection of the mass and does not require preoperative treatment.

■■ Surgical Considerations: Biopsy versus Resection Either biopsy or open resection can provide a tissue diagnosis, which is fundamental in guiding treatment decisions of patients with pineal region tumors and negative germ cell marker assays. The histologic subtype strongly influences postoperative management (i.e., determining the utility of a metastatic evaluation, estimating prognosis, and developing a long-term follow-up plan). Although MRI findings and CSF studies may, in combination, suggest a particular subtype, they are not an adequate alternative to tissue diagnosis.28 Strict dedication to either biopsy or resection is not appropriate, although some scenarios strongly favor one over the other. Stereotactic biopsy is appropriate for patients who have known primary systemic tumors, multiple lesions, or medical contraindications to safe open resection.24,27 Biopsy would seemingly be Table 19.1  Biological markers in germ cell tumors

Fig. 19.3  Sagittal T2-weighted magnetic resonance image of the cervical and thoracic spine demonstrating drop metastases.

Tumor

β-Human chorionic gonadotropin

α-Fetoprotein

Benign germ cell

–

–

Immature teratoma

?

+/–

Germinoma

–

–

Germinoma with syncytiotrophoblastic cells

+

–

Embryonal cell carcinoma

+/–

+/–

Choriocarcinoma

++

–

Endodermal sinus tumor

–

++

Modified with permission from Sonabend and Bruce 2017.23

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V  Comprehensive Management of Tumors of the Brainstem, Thalamus, and Pineal Region Fig. 19.4  Treatment algorithm for patients with pineal region lesions. Abbreviations: CSF, cerebrospinal fluid; GTR, gross total resection; MRI, magnetic resonance imaging; STR, subtotal resection; XRT/chemo, external radiotherapy and chemotherapy. (Modified with permission from Sonabend et al 2016.2)

Table 19.2  Extent of resection for 181 consecutive pineal region surgeries at the New York Neurological Institute (1990–2014)

Tumor type

Biopsy

Subtotal resection

Radical subtotal resection or gross total resection

Benign

2

5

70

Malignant

12

29

63

Total

14 (8%)

34 (19%)

133 (73%)

Note: Radical subtotal resection = no visible tumor at surgery or on postoperative magnetic resonance imaging, but tumor was not well encapsulated. Modified with permission from Sonabend and Bruce 2017.23

favored when there is evidence of brainstem invasion on MRI, but such evidence often does not correspond to intraoperative findings. Generally, open resection is favored over biopsy because of its provision of larger amounts of tissue for diagnostic evaluation, clinical advantage from tumor debulking, and probable cure in the case of benign lesions (Table 19.223).13,​16 Because of the histologic diversity and frequency of mixed-cell populations in these tumors, the histologic features of small specimens cannot readily be extrapolated to the entirety of the tumor.27,​29 In contrast, stereotactic biopsy offers relative ease of performance, often requiring only local anesthesia and resulting in reduced complications.30 Even so, some associated risks remain. The most concerning among these is the risk of hemorrhage. During biopsy, bleeding may occur when the tumors are highly vascular or when there is deep venous system damage. A particular concern is bleeding into the ventricle, as tissue turgor is insufficient to tamponade the bleeding.27,​29,​31 One isolated report of a patient with a pineoblastoma has described metastatic seeding along the biopsy tract.32 Endoscopic biopsy has become increasingly popular in recent years. Its principal

advantage stems from the use of flexible endoscopes, which allows a single bur hole to be used simultaneously for third ventriculostomy and biopsy. Notably, the risks and limitations of this approach are similar to those of stereotactic biopsy, including risks such as bleeding and limitations such as sampling bias.

■■ Biopsy Stereotactic Biopsy Stereotactic biopsy of pineal region lesions should be approached cautiously in spite of the relative technical ease of stereotactic biopsy procedures in most other regions. In particular, a thorough anatomical understanding of the planned trajectory to the biopsy site is critical. Most of the target-centered stereotactic frame systems that are available can be used, and both computed tomography and MRI are sufficiently accurate for targeting and tracking trajectories. A precoronal entry point, which provides an

19  Pineal Region Tumors anterolateral superior approach to the tumor, avoids the lateral ventricle and internal cerebral veins (Fig. 19.533).24,​30 A posterolateral superior approach near the parieto-occipital junction is used less commonly; however, this approach can be useful for tumors extending laterally or superiorly.33 Serial biopsies should be taken when possible because of the aforementioned issues with tissue sampling error, but the often small size of these lesions frequently limits serial sampling. During this procedure, a side-cutting cannula biopsy needle is preferable to a cup forceps, which has a higher risk of tearing a blood vessel. In the event of bleeding, irrigation with continuous suction may become necessary. When intraventricular bleeding is suspected, imaging should be obtained immediately and the degree of bleeding and hydrocephalus should be used to determine whether a ventricular drain is required.

Endoscopic Biopsy Biopsy can also be performed endoscopically through the ventricles. A major disadvantage of this alternative technique is the risk of bleeding that occurs with sampling along the ventricular surface of the tumor. This risk is not trivial, because bleeding in the CSF space is difficult to manage; the difficulty of controlling bleeding in this region is further compounded by the highly vascular properties of many pineal region tumors. A potential advantage of the endoscopic technique is the possibility of combining it with a ventriculostomy. Unfortunately, this advantage is limited by the different trajectories required for each procedure, rendering this combination challenging even with the use of a flexible endoscope.

Fig. 19.5  A stereotactic trajectory plan for the anterolateral or low anterior trajectory developed using iPlan stereotaxy software (Brainlab). Images (counterclockwise from upper left) are a three-dimensional reconstruction, an in-line view, a probe's eye view, and an alternative in-line view. (Modified with permission from Zacharia and Bruce 2011.33)

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■■ Surgical Resection Patient Positioning The pineal region can be approached through several different patient positions. These positions include the sitting, lateral, three-quarter prone, and prone positions. The sitting position (Fig. 19.6) is preferable for the supracerebellar infratentorial approach.27 This position utilizes gravity to reduce blood pooling in the operative field and to facilitate tumor dissection off deep venous structures. There are several risks specific to the sitting position, including air embolism, pneumocephalus, or subdural hematoma associated with cortical collapse.27,​34 However, these risks can be managed with proper precautions, such as end tidal pCO2 and Doppler monitoring to detect air emboli. Furthermore, if necessary, the presence of a central venous catheter may aid in removing entrapped air during the procedure. To set up the sitting position safely, the patient’s head should be flexed such that the tentorium is roughly parallel to the floor. Care must be taken to ensure greater than two fingerbreadths of space remain between his or her chin and sternum. The patient’s legs are then elevated to aid venous

Fig. 19.6  Preoperative photograph demonstrates lateral view of the final setup of the patient in the sitting position, which is commonly used in the supracerebellar infratentorial approach. Of note, the patient’s head is placed in flexion, such that the tentorium is parallel to the floor, while maintaining at least two fingerbreadths of space between the chin and sternum.

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return. A Greenberg self-retaining retractor or similar system framing the operative field can be useful in providing cerebellar retraction and holding Cottonoids. The lateral decubitus position is used more frequently for the occipital transtentorial approach. The patient’s head is fixed with the dependent, nondominant right hemisphere down at approximately 30° above the horizontal in the midsagittal plane; this placement is especially necessary when the transcallosal approach is used. When the occipital transtentorial approach is used, the patient’s head is positioned so that the nose is rotated approximately 30° toward the floor. The three-quarter prone position is a more desirable variation of the lateral position. The patient should be strapped, with legs flexed, to the operative table so that it can be freely rotated during the operation. The primary difference between the three-quarter prone position and the lateral position is that an oblique 45° angle is used for head fixation, which suits more posterior approaches, such as the occipital transtentorial. The nondominant hemisphere, aided by gravity and CSF drainage, requires minimal retraction. This position can be cumbersome, however, as it requires multiple additional supports. The patient’s right axilla is supported with an axillary roll, and the right arm is supported in a sling. A supporting roll is also placed under the left thorax, and a pillow should be placed between the legs of the patient to relieve pressure points. The prone position can sometimes be a simple and safe option for supratentorial approaches,27 but it is generally impractical for infratentorial approaches because of the tentorium’s steep angle. Although largely comfortable for the surgeon, the raised operative field makes it difficult to operate while seated. Two surgeons may work together if the operative microscope is equipped with a bridge. This position may be useful for pediatric patients and can be further facilitated with the patient’s head rotated 15° away from the side of the craniotomy; this variation is known as the Concorde position.35

Overview of Approaches Surgical approaches to tumors in the pineal region are generally categorized as either supratentorial or infratentorial. The occipital transtentorial and transcallosal interhemispheric approaches are two commonly used supratentorial approaches to this region. The only commonly used infratentorial approach is the supracerebellar infratentorial. Choosing between these approaches is a multifactorial decision, dependent on surgeon experience, comfort, and the anatomical properties of the tumor. Although the approaches are often interchangeable, some tumor features lend themselves to particular approaches. For example, a supratentorial approach is generally best for larger tumors with components extending supratentorially or laterally to the trigone of the lateral ventricle.27 Although such approaches commonly afford greater exposure, working around the convergence of the internal cerebral veins and the vein of Galen often interferes with tumor removal. The supracerebellar infratentorial approach has several advantages in approaching the infratentorial midline location of the majority of tumors in the pineal region.27 The natural corridor between the cerebellum and tentorium is augmented by gravity in the sitting position, causing the tumor to drop downward and facilitating its dissection off the velum interpositum and deep venous system. Furthermore, this approach largely avoids the deep venous system, which lies superior to the mass. Extra-long instruments allow for removal of tumors that extend anteriorly into the

third ventricle, although this approach becomes less favorable for tumors with concomitant supratentorial or lateral extension.

Supracerebellar Infratentorial Approach The supracerebellar infratentorial corridor is arguably the most routinely used approach to tumors in the pineal region. It is usually performed with the patient in the sitting position (Fig. 19.6).13,​27 If indicated, a ventricular drain can be placed in the trigone of the lateral ventricle using a bur hole in the midpupillary line at the lambdoid suture. A linear midline incision extends from just above the torcula and external occipital protuberance to the C4 spinous process. The bone is exposed with muscle and fascial retraction using a single low-profile self-retaining retractor. The craniotomy is centered just inferior to the torcula, creating a sufficiently large opening to provide adequate access for instruments and light from the operating microscope. A craniotomy is preferable to a craniectomy because the former minimizes the likelihood of postoperative aseptic meningitis, fluid collection, and discomfort. The craniotomy is begun by drilling four slots (i.e., over the superior sagittal sinus, just above the torcula, and over both lateral sinuses) (Fig. 19.7a). An inferior slot is also drilled approximately 1 or 2 cm above the foramen magnum in the midline. Removing sufficient bone above the transverse sinus is essential to ensure that the view along the tentorium is not obscured. There is added importance for waxing of bone edges and control of venous bleeding because of the risk of air emboli with the sitting position. The dural opening extends from the lateral aspects of the exposure in a gentle semilunar curve. Tenting sutures and rubber bands are used to retract the dural flap superiorly. Care should be taken to avoid excess tension, which can cause sinus obstruction (Fig. 19.7b). The inferior dura creates a sling that supports the cerebellar hemispheres. A ventricular drain or opening the cisterna magna can remove CSF if the posterior fossa appears tight. The arachnoidal adhesions and midline bridging veins are cauterized and divided between the dorsal surface of the cerebellum and the tentorium to open the corridor. It is prudent to preserve veins when possible, especially lateral veins, but extensive collateral circulation reduces risk from venous sacrifice.36 After the infratentorial corridor is opened, the cerebellum drops away from the tentorium. A synthetic hybrid neurosurgical patty (e.g., Telfa; Covidien) can be used to protect the dorsal surface of the cerebellum. If necessary, additional cerebellar retraction posteriorly and inferiorly can be achieved by using a small brain

Fig. 19.7  Intraoperative photographs of (a) the craniotomy and (b) the opening used in the supracerebellar infratentorial approach. Note craniotomy slots (a, black arrows) over the superior sagittal and lateral sinuses. Tenting sutures and rubber bands (b) are used to reflect the dural flaps superiorly without excess tension.

19  Pineal Region Tumors retractor. This retractor is generally removed as the surgery progresses and CSF removal has adequately decompressed the posterior fossa. Additional adhesions and bridging veins that become visible near the anterior vermis as the cerebellum is retracted can be divided. The opalescent arachnoid, which covers the pineal region, can be seen with retraction. At this stage, the operating microscope is brought in. The arachnoid membrane that overlies the quadrigeminal plate is opened sharply. Minimal cautery is required in this generally avascular plane. The precentral cerebellar vein is encountered and should be carefully dissected, cauterized, and divided (Fig. 19.8). There is generally little consequence to taking this vein; however, sacrifice of additional veins in the deep venous system should be avoided. Retraction on the cerebellum is then adjusted to expose the inferior aspect of the tumor. The microscope trajectory is similarly adjusted downward along the central axis of the tumor to avoid direct encounter with the vein of Galen. The posterior surface of the tumor can now be visualized (Fig. 19.9). The posterior surface of the tumor is cauterized and sharply opened in the usual fashion. Specimens taken from within the capsule can be sent for frozen diagnosis. The accuracy of frozen tis-

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sue diagnosis is variable, given the heterogeneity of these tumors. Such variability should be taken into consideration if frozen diagnosis is to guide operative decision-making. Internal debulking is continued and can usually be accomplished with a large-bore Japanese-style suction device, given the often soft nature of these tumors. The capsule is separated from the surrounding thalamus as the tumor is progressively decompressed. Preservation of the choroidal vessels along the capsule wall is not necessary. After visualization of the third ventricle, the tumor can be dissected inferiorly off the brainstem. This step is generally the most challenging aspect of the tumor dissection. Retracting the tumor superiorly and using blunt dissection under direct vision to establish a plane between the tumor and brainstem can aid the surgeon. Following this step, careful dissection from the velum interpositum and deep venous system allows for removal of the tumor’s superior aspect. The extent of resection that is pursued should be dictated by the degree of tumor invasion. More radical tumor resection is thought to improve response to adjuvant therapy and reduce the risk of postoperative hemorrhage. However, the benefits of aggressive resection must be weighed against the risks, particularly in the instance of brainstem invasion. Thus, Fig. 19.8  Intraoperative photograph demonstrates visualization of the precentral cerebellar vein through the operating microscope.

Fig. 19.9  (a) Illustration of the relevant anatomy visible with exposure of the posterior surface of a pineal region tumor using the supracerebellar infratentorial approach. (b) Corresponding intraoperative photograph

demonstrates the view of the tumor through the operating microscope. (Fig. 19.9a illustration is modified with permission from Eliza Bruce.)

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V  Comprehensive Management of Tumors of the Brainstem, Thalamus, and Pineal Region Fig. 19.10  An intraoperative photograph demonstrating the view into the third ventricle after tumor removal.

the degree of resection remains a key judgment in the safe resection of these tumors. After the tumor is removed, the surgeon will have a clear view into the third ventricle (Fig. 19.10). Flexible mirrors are used to examine the inferior tumor bed, to verify the extent of resection, and to remove any residual blood clots. Extensive use of hemostatic agents is avoided, as communications with the ventricular system can cause obstructions. If necessary, cellulose hemostatic dressing (e.g., Surgicel; Ethicon) can be draped over the surface of the cerebellum and on the tumor bed with a low risk of migration. A watertight dural closure is essential to preventing pseudomeningocele. The patient should be extubated with some head elevation to avoid shifting the decompressed brain.

Transcallosal Interhemispheric Approach The transcallosal interhemispheric approach uses a corridor along the parieto-occipital junction. The prone or sitting position is generally preferable for this approach. However, any of the previously described patient positions can be used. Planning for the craniotomy depends on where within the third ventricle the tumor is centered.12,​37 A U-shaped scalp flap that extends across the midline is made. A wide craniotomy approximately 8 cm long allows flexibility in choosing an entry corridor that avoids most bridging veins. A craniotomy over the vertex is used to minimize manipulation of the occipital lobe. We prefer anterior and posterior bur holes directly over the sagittal sinus. A craniotome is then used to turn a generous craniotomy 1 to 2 cm past the sagittal sinus to the contralateral side. A U-shaped dural opening is reflected medially toward the sagittal sinus. The bridging veins are inspected carefully, because minimizing their sacrifice dictates the optimum corridor in this approach. Sacrifice of one bridging vein is likely necessary to achieve adequate exposure, although further sacrifice should be avoided, if possible. A small opening provides a wide angle of exposure to deeply seated tumors. This opening is framed by covering the exposed hemisphere with a collagen sponge or a natural or synthetic hybrid neurosurgical patty and a retractor system. Two retractors can be used to gently draw back the parietal lobe, with an additional retractor along the falx. The falx can also be divided inferiorly to facilitate further exposure, if necessary.

The striking white appearance of the corpus callosum is easily identifiable with the operating microscope. The pericallosal arteries can be identified as a paired vascular structure overlying the corpus callosum. These can be gently retracted to one side or, using two retractors, to either side of the corpus callosum. A 2-cm opening into the corpus callosum should be centered over the maximal bulge of the tumor. Although splenium incisions are routinely performed without consequence, we favor a more anterior approach to minimize the risk of disconnection syndrome.2 Gentle suction and cautery are used to create this opening into the soft corpus callosum. The lateral extent of the opening is guided by tumor exposure while avoiding injury to the pericallosal arteries. If required, additional exposure can be provided by dividing the tentorium and falx. The dorsal surface of the tumor should now be visible. It is critical to identify veins of the deep venous system early to ensure that they remain undamaged. The importance of the deep venous system and the degree of venous collaterals are still not entirely known. Intuitively, any venous sacrifice is undesirable. Even so, it appears possible to sacrifice a single vein safely. However, the interruption of two veins would likely have a devastating result.2 After exposure of the tumor, removal is performed as previously described.

Occipital Transtentorial Approach The occipital transtentorial approach is an alternative supratentorial approach (Fig. 19.11).38 The patient is best positioned in the three-quarter prone position. The oblique trajectory used in this approach may initially be disorienting if the surgeon is not familiar with it. Dividing the tentorium, however, can achieve excellent exposure of the quadrigeminal plate and makes this technique particularly useful for inferiorly extending tumors. A U-shaped right occipital scalp flap is reflected inferiorly, with the medial aspect ending just left of midline, approximately at the level of the torcula.38,​39 One bur hole is made over the sagittal sinus just superior to the torcula, and a second one is made about 6 to 10 cm above it. Alternatively, the bur holes can be drilled adjacent to the sagittal sinus, avoiding any crossing of the midline or sinus. However, in this case, the bur holes should be placed as close as possible to the sagittal sinus to maximize the operative view.

19  Pineal Region Tumors

293

Fig. 19.11  (a) Illustration representing the relevant anatomy visible on exposure of the tentorium using the occipital transtentorial approach, with incision site demarcated (dashed line). (b) Corresponding intraoperative photograph

demonstrating the exposure of the tentorium visible through the operating microscope. (Fig. 19.11a illustration is modified with permission from Eliza Bruce.)

Fig. 19.12  (a) Illustration of the relevant anatomy seen with exposure of a pineal region tumor using the occipital transtentorial approach. (b) Corresponding intraoperative photograph demonstrating the view of the

tumor seen through the operating microscope. (Fig. 19.12a illustration is modified with permission from Eliza Bruce.)

Brain retraction and relaxation can be accomplished in several ways. As with the sitting position, the three-quarter prone position uses gravity to promote natural relaxation of the nondominant occipital lobe. Further retraction can be safely provided here because of the lack of bridging veins near the occipital pole. CSF drainage and mannitol are commonly used to further relax the brain and minimize manipulation of the occipital lobe. In the absence of obstructive hydrocephalus, a spinal drain provides good CSF drainage for brain relaxation, obviating the need for a ventricular drain. The tentorium is divided adjacent to the straight sinus under the operating microscope (Fig. 19.11). Exposure can be increased with a retractor on the falx, if necessary. Additional retraction can be gained through division of the inferior sagittal sinus and falx. The arachnoid mater overlying the mass and quadrigeminal cistern should now be visible. Tumor is removed as before, with care taken to avoid injuring the deep venous system  (Fig. 19.12, Fig. 19.13).

■■ Postoperative Care Patients require close attention and care in the postoperative period immediately after surgery for tumors in the pineal region. High–dose corticosteroids are administered in the early postoperative period, with a tapering dose as the patient’s condition improves.34,​39 Prophylactic antiepileptic drugs are also recommended during this early period after supratentorial approaches. Neurologic status may be difficult to evaluate in the immediate postoperative period, as lethargy and mild cognitive impairment are common. This is especially true in patients who have been in the sitting position, in which air accumulates in the subdural space. Regardless, any changes in neurologic status should be investigated with radiographic imaging, with particular attention paid to the presence of hydrocephalus, hemorrhage, or residual air. Our experience has shown that outcomes are improved with early mobilization and ambulation, with assistance from physical therapy

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V  Comprehensive Management of Tumors of the Brainstem, Thalamus, and Pineal Region prevent obstructive hydrocephalus. Venous infarct is also possible, and extension into the midbrain can be life-threatening. Unfortunately, this complication is unpredictable. A small unidentifiable subset of patients seems unable to tolerate the sacrifice of bridging veins and may experience this devastating complication. Air, blood, and operative debris frequently cause shunt malfunction in the immediate postoperative period. This is a particularly serious complication in shunt-dependent patients, as malfunction can cause rapid deterioration. Complications related to the sitting position are generally self-limited. Ventricular collapse, hygroma, and subdural hematoma often resolve with watchful waiting.13,​16,​34 Complications specific to supratentorial approaches also commonly resolve without intervention. These include hemiparesis from irritation or edema due to brain retraction or bridging vein sacrifice.34,​37 Parietal lobe retraction can cause sensory or stereognostic deficits on the opposite side.39 During the transtentorial approach, occipital lobe retraction can cause visual field defects.37,​38,​39 Disconnection syndrome is a commonly cited complication of incisions into the corpus callosum. Our experience has shown that this complication is rare, even with division of the splenium.12,​39 Generally speaking, complications are more common among patients who have undergone previous irradiation, patients who have invasive tumors, and patients who were symptomatic preoperatively.34 Patients with tumors in the pineal region are often young and have few medical comorbidities, so the incidence of medical complications is low.

Long-term Outcomes Fig. 19.13  Intraoperative photograph demonstrating the resection cavity after tumor removal using the occipital transtentorial approach.

and rehabilitation. Finally, a gadolinium-enhanced MRI should be performed 24 to 48 hours postoperatively to assess the extent of resection as well as to guide any adjuvant therapies following hospitalization.

■■ Patient Outcomes Complications Impairment in extraocular movement is the most common deficit after surgery in the pineal region, given its proximity to the brainstem. Limited upgaze and convergence are likely, but pupillary impairment and difficulty focusing may also occur.16,​34 These deficits usually resolve in the first several days postoperatively, although they may, in some instances, resolve over several months. Permanent major impairment is rare. Mild limitation of upgaze can occur but has little clinical significance. Similarly, ataxia is common, but usually resolves within days. Although mild transient complications can be expected, severe morbidity can also occur as a result of overzealous brainstem manipulation. Such manipulation can result in cognitive impairment or its extreme form, akinetic mutism. Hemorrhage into an incompletely resected tumor bed is a potentially devastating complication. Choriocarcinoma and malignant pineal parenchymal cell tumors, which tend to be highly vascular and invasive, confer the greatest risk.30,​34 Small hemorrhages can often be safely managed conservatively. Large hemorrhages, however, often require immediate evacuation to

Surgical resection of pineal region tumors remains an arduous challenge, but patient outcomes continue to improve with new techniques and greater surgeon expertise. Over the past several decades, operative mortality has been up to 4% and permanent morbidity up to 5.6% in large case series (Table 19.323).3,​16,​40,​41,​42,​43,​44 Long-term outcomes remain contingent on the tumor’s histologic features and susceptibility to adjuvant therapy. Benign tumors, such as well-differentiated ependymomas, meningiomas, teratomas, pineocytomas, and rarely seen pilocytic astrocytomas, demonstrate good outcomes. There is an unfortunately limited analysis of outcomes within each subtype because of the overall rarity of these tumors. Malignant tumors have more variable outcomes and are equally dependent on the tumor’s underlying histology and the efficacy of adjuvant radiotherapy or chemotherapy.13,​24,​27 Germinomas respond well to cytoreduction and adjuvant radiotherapy with good long-term control; 10-year survival has been reported to be 69%, but treatment failure can occur with the presence of syncytiotrophoblastic cells.45 NGGCTs respond remarkably well to radiotherapy or chemotherapy. Five-year survival rates have improved to more than 90% since the introduction of this approach.46 Outcomes of patients with glial tumors in the pineal region are particularly varied. Pineal astrocytomas and pineal region ependymomas with low-grade histologic features are relatively straightforward to resect and connote a good prognosis. In contrast, brainstem astrocytomas can be invasive despite being low grade, and resection is frequently associated with auditory deficits.13 Outcomes are poorer for younger patients with pineoblastoma and for patients with the presence of any metastatic dissemination. As a general rule, patients with benign tumors should undergo surgical resection, as gross total resection leads to

19  Pineal Region Tumors

295

Table 19.3  Summary of microsurgical series for pineal region tumors

Author, year

N

Approach

Age group

Pathology

GTR (%) Mortality (%)

Major morbidity (%)

Permanent minor morbidity (%)

Bruce and Stein 199516

160

SCIT TCIH OTT

A and P

All

45

4

3

19

Chandy and Damaraju 199840

48

SCIT OTT

A and P

“Benign lesions”

55

0

NA

NA

Kang et al 199841

16

OTT SCIT TCIH

A and P

All

37.5

0

0

19

Shin et al 199842

21

OTT

A and P

All

54.5

0

0

5

Konovalov and Pitskhelauri 20033

201

OTT SCIT

A and P

All

58

10

NA

>20

Hernesniemi et al 200843

119

SCIT OTT

A and P

All

88

0

1

4.9

Qi et al 201444

143

OTT

A and P

All

91.6

0.7

3.5

5.6

Bruce (unpublished data) 2014

181

SCIT TCIH OTT

A and P

All

73

2

2

NA

Abbreviations: A, adult; GTR, gross total resection; NA, not available; OTT, occipital transtentorial; P, pediatric; SCIT, supracerebellar infratentorial; TCIH, transcallosal interhemispheric. Modified with permission from Sonabend and Bruce 2017.23

excellent long-term prognoses in nearly all histologic subtypes. Treatment approaches and outcomes among malignant tumors are more varied, but surgery is beneficial except for tumor marker–secreting NGGCTs.

■■ Adjuvant Therapy Microsurgical resection remains the gold standard treatment approach to the majority of tumors in the pineal region, as outlined above. However, adjuvant therapies, including radiotherapy, chemotherapy, and stereotactic radiosurgery, have a growing role, particularly for patients with malignant subtypes. Few definitive treatment algorithms have been established to date, but these modalities are being actively researched to elucidate better adjuvant therapy for this difficult-to-treat and heterogeneous patient population.

Radiotherapy Malignant germ cell and pineal cell tumors should be treated with adjuvant fractionated radiotherapy. The recommended dose is distributed between the ventricular system and tumor bed, although some authors suggest that it may be sufficient to irradiate a more limited field, thereby reducing the adverse effects of ventricular exposure.24,​27 In contrast, histologically benign pineocytomas and ependymomas that have been completely resected do not warrant radiation treatment.13,​16,​27 Complete resection alone often yields excellent long-term control of these tumors. Even so, patients should undergo careful follow-up so that radiotherapy can be considered promptly upon evidence of tumor recurrence. Germinomas are the most radiosensitive malignant tumors in the central nervous system, with up to a 90% long-term control rate after fractionated radiation.15,​47 A dose of 50 Gy has achieved 5-year and 10-year survival rates greater than 75% and 69%, respectively, in reported series with long-term follow-up.45

The incidence of local failure can be expected to be higher at lower radiation doses.28,​45 The many long-term adverse effects of cranial radiation include cognitive deficits, hypothalamic and endocrine dysfunction, necrosis, and de novo tumor formation. These adverse effects have prompted investigations into methods of dose reduction, such as treatment strategies that combine radiotherapy with chemotherapy. Prophylactic spinal irradiation for pineal region tumors is controversial. In the past, craniospinal irradiation was recommended for all patients with malignant pineal tumors. The trend now is to pursue spinal irradiation only when spinal seeding is evident. The incidence of spinal seeding is generally low. It remains unknown whether prophylactic irradiation prevents spinal metastasis when there is no evidence of disease on postoperative staging. Even so, 35 Gy is the recommended dose for spinal lesions identified on either preoperative or postoperative spinal imaging.

Chemotherapy Chemotherapy is most effective for NGGCTs, as long-term outcomes have significantly improved with current protocols. Unfortunately, germinomas containing syncytiotrophoblastic giant cells connote a less favorable prognosis, and patients with these tumors thus may benefit from more aggressive chemotherapies.13,​23,​27 Most chemotherapy regimens have been extrapolated from the treatment of extracranial germ cell tumors, where success has been remarkable, but outcomes for intracranial germ cell tumors have not been so striking. Chemotherapy is frequently used for recurrent or disseminated pineal cell tumors.15 Combinations involving a variety of agents have been used with limited success. Thus, no clear-cut recommendations have been outlined. The combined role of radiotherapy and chemotherapy in these tumors is also unclear. It is uncertain whether radiotherapy improves survival over chemotherapy alone, but some approaches include both as

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adjuncts to surgical resection in an aggressive, three-pronged treatment approach. Delayed surgery after radiotherapy and chemotherapy is an established approach for residual tumor in patients whose germ cell markers have normalized, as this residual tumor is likely to be composed of radiation-resistant benign germ cell elements.48 In contrast, pure germinomas are exquisitely radiosensitive, making chemotherapy less compelling in these patients. Although this combination is a sound philosophy for reducing radiation dosages, the long-term results have not elicited remarkably better results than radiotherapy alone.

Radiosurgery Radiosurgery can be useful in the treatment of pineal region tumors. Although radiosurgery appears to be relatively safe, long-term follow-up results are not yet available. It is generally successful at treating the targeted mass, but size limitations and tumor recurrence outside the treatment volume remain problematic. The distinct radiobiological differences between radiosurgery and conventional fractionated radiotherapy must be taken into consideration when selecting a treatment strategy. Patients with germinomas have excellent responses to fractionated radiation, so radiosurgery is unlikely to further improve their outcomes. Additionally, the targeted nature of radiosurgery precludes coverage of the ventricular system and thus would not be beneficial in pineal cell and germ cell tumors, which are notably prone to ventricular recurrence. Radiosurgery may instead provide greater benefit in providing local adjuvant treatment to the tumor bed, which reduces exposure of the ventricles and surrounding brain to radiation.49 It remains plausible that radiosurgery could also be useful in cases of local recurrence. Most radiosurgical case series to date comprise small numbers for a given pathologic entity. Given the favorable natural history of benign tumors, good outcomes are expected after radiosurgery, whereas poor outcomes are common for patients with malignant lesions. Generally, radiosurgical treatment of pineocytomas has shown some success, but reports of radiosurgery-treated pineoblastomas indicate poorer outcomes.50 The role of stereotactic radiosurgery is even less established for NGGCTs. Overall, general consensus exists for the use of radiosurgery as an alternative treatment for pineal region tumors in patients with other medical contraindications to open surgical resection, in patients with disseminated or metastatic disease, and in postoperative patients requiring adjunct treatment for a small unresectable residual tumor that has demonstrated growth.

■■ Conclusion Extensive histologic diversity is the hallmark of tumors in the pineal region, and histology guides nearly every step of their management. Measurement of tumor markers is required preoperatively in an effort to identify germ cell tumors that do not require surgery. The choice of biopsy versus surgical resection must be made to maximize the likelihood of obtaining an accurate tissue diagnosis. Furthermore, management decisions about adjuvant therapy, patient prognosis, and follow-up protocols also depend on the histologic diagnosis. Continued advances in microsurgical techniques have made aggressive surgical resection a mainstay of management, with excellent prognoses for nearly all patients with benign tumors and a

substantial percentage of patients with malignant tumors. Outcomes for this heterogeneous population will continue to improve with the development of more clearly defined and more effective approaches to adjuvant therapy, as well as with the stratification of outcomes by histologic subtypes. References 1. Bruce JN. Management of pineal region tumors. Neurosurg Q 1993; 3(2):103–119 2. Sonabend AM, Bowden S, Bruce JN. Microsurgical resection of pineal region tumors. J Neurooncol 2016;130(2):351–366 3. Konovalov AN, Pitskhelauri DI. Principles of treatment of the pineal region tumors. Surg Neurol 2003;59(4):250–268 4. Ventureyra EC. Pineal region: surgical management of tumours and vascular malformations. Surg Neurol 1981;16(1):77–84 5. Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro Oncol 2012;14(Suppl 5):v1–v49 6. Koide O, Watanabe Y, Sato K. Pathological survey of intracranial germinoma and pinealoma in Japan. Cancer 1980;45(8):2119–2130 7. Ojeda VJ, Ohama E, English DR. Pineal neoplasms and third-ventricular teratomas in Niigata (Japan) and Western Australia. A comparative study of their incidence and clinicopathological features. Med J Aust 1987; 146(7):357–359 8. Araki C, Matsumoto S. Statistical reevaluation of pinealoma and related tumors in Japan. J Neurosurg 1969;30(2):146–149 9. Schoenberg BS, Christine BW, Whisnant JP. The descriptive epidemiology of primary intracranial neoplasms: the Connecticut experience. Am J Epidemiol 1976;104(5):499–510 10. Barker DJ, Weller RO, Garfield JS. Epidemiology of primary tumours of the brain and spinal cord: a regional survey in southern England. J Neurol Neurosurg Psychiatry 1976;39(3):290–296 11. Jennings MT, Gelman R, Hochberg F. Intracranial germ-cell tumors: natural history and pathogenesis. J Neurosurg 1985;63(2):155–167 12. Bruce JN. Posterior third ventricle tumors. In: Kaye AH, Black PM, eds. Operative Neurosurgery. Vol 1. London , UK: Churchill Livingstone; 2000: 769 –775 13. Stein BM, Bruce JN. Surgical management of pineal region tumors (honored guest lecture). Clin Neurosurg 1992;39:509–532 14. Russell DS, Rubinstein LJ. Tumors of central neuroepithelial origin. In: Russell DS, Rubinstein LJ. Pathology of Tumours of the Nervous System. 5th ed. Baltimore , MD: Williams and Wilkins; 1989 15. Schild SE, Scheithauer BW, Schomberg PJ, et al. Pineal parenchymal tumors: clinical, pathologic, and therapeutic aspects. Cancer 1993; 72(3):870–880 16. Bruce JN, Stein BM. Surgical management of pineal region tumors. Acta Neurochir (Wien) 1995;134(3–4):130–135 17. Surawicz TS, McCarthy BJ, Kupelian V, Jukich PJ, Bruner JM, Davis FG. Descriptive epidemiology of primary brain and CNS tumors: results from the Central Brain Tumor Registry of the United States, 1990–1994. Neuro Oncol 1999;1(1):14–25 18. Bader JL, Meadows AT, Zimmerman LE, et al. Bilateral retinoblastoma with ectopic intracranial retinoblastoma: trilateral retinoblastoma. Cancer Genet Cytogenet 1982;5(3):203–213 19. Plowman PN, Pizer B, Kingston JE. Pineal parenchymal tumours: II. On the aggressive behaviour of pineoblastoma in patients with an inherited mutation of the RB1 gene. Clin Oncol (R Coll Radiol) 2004;16(4):244–247 20. Higashi K, Katayama S, Orita T. Pineal apoplexy. J Neurol Neurosurg Psychiatry 1979;42(11):1050–1053 21. Missori P, Delfini R, Cantore G. Tinnitus and hearing loss in pineal region tumours. Acta Neurochir (Wien) 1995;135(3–4):154–158 22. Fetell MR, Stein B. Neuroendocrine aspects of pineal tumors. In: Zimmerman EA, Abrams GM, eds. Neuroendocrinology and Brain Peptides. Vol 4. Philadelphia, PA: W. B. Saunders;1986

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38. Lapras C, Patet JD, Mottolese C, Lapras C, Jr. Direct surgery for pineal tumors: occipital-transtentorial approach. Prog Exp Tumor Res 1987;30:268–280

25. Allen JC, Nisselbaum J, Epstein F, Rosen G, Schwartz MK. Alphafetoprotein and human chorionic gonadotropin determination in cerebrospinal fluid: an aid to the diagnosis and management of intracranial germ-cell tumors. J Neurosurg 1979;51(3):368–374 26. Arita N, Ushio Y, Hayakawa T, et al. Serum levels of alpha-fetoprotein, human chorionic gonadotropin and carcinoembryonic antigen in patients with primary intracranial germ cell tumors. Oncodev Biol Med 1980; 1(4–5):235–240 27. Bruce JN, Ogden AT. Surgical strategies for treating patients with pineal region tumors. J Neurooncol 2004;69(1–3):221–236 28. Kersh CR, Constable WC, Eisert DR, et al. Primary central nervous system germ cell tumors. Effect of histologic confirmation on radiotherapy. Cancer 1988;61(11):2148–2152 29. Chandrasoma PT, Smith MM, Apuzzo ML. Stereotactic biopsy in the diagnosis of brain masses: comparison of results of biopsy and resected surgical specimen. Neurosurgery 1989;24(2):160–165 30. Dempsey PK, Kondziolka D, Lunsford LD. Stereotactic diagnosis and treatment of pineal region tumours and vascular malformations. Acta Neurochir (Wien) 1992;116(1):14–22 31. Regis J, Bouillot P, Rouby-Volot F, Figarella-Branger D, Dufour H, Peragut JC. Pineal region tumors and the role of stereotactic biopsy: review of the mortality, morbidity, and diagnostic rates in 370 cases. Neurosurgery 1996;39(5):907–912, discussion 912–914 32. Rosenfeld JV, Murphy MA, Chow CW. Implantation metastasis of pineoblastoma after stereotactic biopsy. Case report. J Neurosurg 1990; 73(2):287–290

39. Apuzzo M, Tung H. Supratentorial approaches to the pineal region. In: Apuzzo M, ed. Brain Surgery: Complication Avoidance and Management. New York , NY: Churchill Livingstone;1993:486–511 40. Chandy MJ, Damaraju SC. Benign tumours of the pineal region: a prospective study from 1983 to 1997. Br J Neurosurg 1998;12(3):228–233 41. Kang JK, Jeun SS, Hong YK, et al. Experience with pineal region tumors. Childs Nerv Syst 1998;14(1–2):63–68 42. Shin HJ, Cho BK, Jung HW, Wang KC. Pediatric pineal tumors: need for a direct surgical approach and complications of the occipital transtentorial approach. Childs Nerv Syst 1998;14(4–5):174–178 43. Hernesniemi J, Romani R, Albayrak BS, et al. Microsurgical management of pineal region lesions: personal experience with 119 patients. Surg Neurol 2008;70(6):576–583 44. Qi S, Fan J, Zhang XA, Zhang H, Qiu B, Fang L. Radical resection of nongerminomatous pineal region tumors via the occipital transtentorial approach based on arachnoidal consideration: experience on a series of 143 patients. Acta Neurochir (Wien) 2014;156(12): 2253–2262 45. Sung DI, Harisiadis L, Chang CH. Midline pineal tumors and suprasellar germinomas: highly curable by irradiation. Radiology 1978; 128(3):745–751 46. Balmaceda C, Heller G, Rosenblum M, et al. Chemotherapy without irradiation—a novel approach for newly diagnosed CNS germ cell tumors: results of an international cooperative trial. The First International Central Nervous System Germ Cell Tumor Study. J Clin Oncol 1996; 14(11):2908–2915

33. Zacharia BE, Bruce JN. Stereotactic biopsy considerations for pineal tumors. Neurosurg Clin N Am 2011;22(3):359–366, viii

47. Villano JL, Propp JM, Porter KR, et al. Malignant pineal germ-cell tumors: an analysis of cases from three tumor registries. Neuro Oncol 2008; 10(2):121–130

34. Bruce JN, Stein BM. Complications of surgery for pineal region tumors. In: Post KD, Friedman ED, McCormick PC, eds. Postoperative Complications in Intracranial Neurosurgery. New York , NY: Thieme; 1993:74–86

48. Friedman JA, Lynch JJ, Buckner JC, Scheithauer BW, Raffel C. Management of malignant pineal germ cell tumors with residual mature teratoma. Neurosurgery 2001;48(3):518–522, discussion 522–523

35. Kobayashi S, Sugita K, Tanaka Y, Kyoshima K. Infratentorial approach to the pineal region in the prone position: Concorde position. Technical note. J Neurosurg 1983;58(1):141–143

49. Casentini L, Colombo F, Pozza F, Benedetti A. Combined radiosurgery and external radiotherapy of intracranial germinomas. Surg Neurol 1990; 34(2):79–86

36. Ueyama T, Al-Mefty O, Tamaki N. Bridging veins on the tentorial surface of the cerebellum: a microsurgical anatomic study and operative considerations. Neurosurgery 1998;43(5):1137–1145

50. Mori Y, Kobayashi T, Hasegawa T, Yoshida K, Kida Y. Stereotactic radiosurgery for pineal and related tumors. Prog Neurol Surg 2009; 23: 106–118

20

Stereotactic Radiosurgery for Tumors of the Brainstem, Thalamus, and Pineal Region Amparo Wolf and Douglas Kondziolka

Abstract

Stereotactic radiosurgery (SRS) for tumors of the brainstem, thalamus, and pineal region allows patients to receive focused, conformal, and ionizing radiation to a target that is delineated by high-resolution imaging. This chapter reviews the basic technique of Gamma Knife radiosurgery and the evidence of its effectiveness in the most commonly treated benign and malignant tumors of the brainstem, thalamus, and pineal region, encompassing both intrinsic and extrinsic tumors. Because SRS is highly selective and delivers radiation to narrowly targeted areas, nearby tissue toxicity is reduced, thereby increasing the safety of SRS. This precision is particularly vital when treating tumors located within critical functional tissue. The role of SRS in focal brainstem gliomas, thalamic gliomas, and pineal region tumors is still evolving; SRS may be used as the primary modality treatment or as adjuvant treatment to surgical resection. Most clinicians advocate histological diagnosis of tumors when feasible. However, when a tissue diagnosis is not possible and when growth of a focal tumor within the brainstem, thalamus, or pineal region is documented, SRS may be an appropriate management strategy to maximize tumor control while maintaining neurological function and quality of life. Keywords:  brainstem, metastasis, pineal region, stereotactic radiosurgery, thalamus, vestibular schwannoma

■■ Introduction Since the advent of stereotactic radiosurgery (SRS) more than 30 years ago, the management of benign and malignant tumors of the brainstem, thalamus, and pineal region has evolved. SRS delivers focused, conformal, and ionizing radiation to a target that is delineated by high-resolution imaging. SRS is highly selective due to the steep falloff of radiation into the brain structures surrounding the target. This selectivity results in reduced tissue toxicity, thereby increasing the safety of SRS. This precision of SRS is particularly vital for tumors located within critical functional tissue. The biologic effects of radiosurgery are time and dose dependent and include inhibition of tumor cell division, thrombosis of neoplastic blood vessels, induction of apoptosis or necrosis, and alterations of the regional brain blood flow.1,​2,​3 Both intrinsic and extrinsic tumors of the brainstem can be managed with radiosurgery. This chapter reviews the basic technique of Gamma Knife radiosurgery and the evidence of its effectiveness in the most commonly treated tumors of the brainstem, thalamus, and pineal region. Several other less prevalent tumor types of the brainstem and posterior fossa that may be treated effectively with SRS but are not discussed in this chapter include

298

other schwannomas, glomus tumors, chordomas, hemangioblastomas, hemangiopericytomas, and other tumors.

■■ Gamma Knife Radiosurgery Procedural Basics Prior to undergoing radiosurgery, patients meet with their clinicians to discuss management options, goals, and potential risks of SRS. On the day of radiosurgery, patients are given a light sedative. The Leksell frame is placed with the patient under local anesthesia. High-resolution magnetic resonance imaging (MRI) or computed tomography (CT) images, including contrastenhanced images, are acquired with the frame in place. Target volumes are delineated on high-resolution images using software. Radiosurgical dose planning is performed by the neurosurgeon in collaboration with the radiation oncologist and medical physicist. For tumors of irregular shape, multiple isocenters of different sizes (4 mm, 8 mm, or 16 mm) and weighting may be used to conform the target volume to the selected treatment isodose. The margin dose is chosen on the basis of a balance of achieving high local control rates while minimizing risks related to tumor volume and location. Radiation is then delivered. At the end of the procedure, the stereotactic head frame is removed and a local dressing is applied. Most patients are discharged home the same day. Patients with malignant disease commonly have follow-up high-resolution imaging every 2 to 3 months, and those with benign conditions are followed-up every 6 to 12 months during the first few years after radiosurgery. Subsequent follow-up imaging is conducted at less frequent intervals. With the introduction of the Gamma Knife Icon (Elekta, Stockholm, Sweden) in 2015, it became possible to perform SRS using mask fixation. The unit integrates a cone beam CT, and CT images are coregistered with the preprocedural MRI. The unit has the capacity to detect and measure patient position changes, allowing adaptation in dose planning when necessary. The Icon increases treatment flexibility by allowing the physician to choose either single-session or fractionated delivery.

■■ Stereotactic Radiosurgery for Tumors of the Brainstem Brainstem Metastases Brainstem metastases account for 3 to 5% of intracranial metastases.4 The prognosis for patients with brainstem metastases remains poor, with a median overall survival of 4 to 6 months.5 Patients with tumors within the brainstem can present with progressive weakness, diplopia, unsteady gait, dysphagia,

20  Stereotactic Radiosurgery for Tumors of the Brainstem, Thalamus, and Pineal Region dysarthria, and headache, among other symptoms. Local progression of disease within the brainstem may result in an acute neurologic decline. Brainstem metastases are rarely accessible by open surgery. The response of brain metastases to systemic chemotherapies is unclear and unreliable. Compared with SRS, conventional whole-brain radiation therapy may result in lower rates of tumor control and increased global neurocognitive decline.6,​7,​8,​9 Several retrospective studies have evaluated the role of SRS in brainstem metastases and demonstrated its effectiveness. The UCSF group studied 42 patients with 44 tumors  (7 midbrain, 31 pons, 6 medulla) and reported local control rates of 90% at 6 months and 77% at 1 year.10 Four patients (9.5%) had brainstem adverse radiation effects  (AREs). Poor outcomes for patients with brainstem SRS were associated with melanoma histology, renal cell carcinoma histology, and volumes greater than 1 cm3. Another retrospective study looked at 53 patients  (8 midbrain, 42 pons, 3 medulla) with 37 patients having followup imaging.11 Thirty-two of the 37 tumors remained stable or showed partial response, with local progression in 5 tumors at a mean follow up of 9.8 months. The median overall survival was 11 months. The authors concluded that SRS prolongs survival compared with observation alone. Several other retrospective studies have been performed (Table 20.1).​10,​11,​12,​13,​14,​15,​16,​17,​18,​19,​20,​21 The International Gamma Knife Research Foundation recently published the largest series of patients with brainstem metastases, including 547 patients with 596 tumors.21 Actuarial local control at 1 year after SRS was approximately 82%. Higher local control rates were seen with increasing margin dose and maximum dose. Overall survival at 1 year was 33% and depended on age, sex, the number of metastases, tumor histology, and

299

performance score. Severe toxicity  (grade ≥ 3 based on the Common Terminology Criteria for Adverse Events) occurred in 7.4% of patients. Predictors of severe toxicity included larger tumor-volume margin dose and a history of whole-brain irradiation. Margin doses of 20 Gy and higher were associated with improved local control but higher toxicity.21 Fig. 20.1 depicts a patient with a large brainstem metastasis who underwent SRS at a margin dose of 14 Gy (maximum dose of 28 Gy) with significant regression on MRI 2 months after SRS. The conclusion from most of these retrospective studies is that SRS provides excellent local control of brainstem metastases with low morbidity. The severity of systemic disease remains the predominant factor determining the prognosis of patients with tumor metastases to the brainstem. As systemic therapies improve, including targeted therapies and immunotherapies, their combination with SRS may result in longer overall survival.

Vestibular Schwannomas The paradigm for the management of vestibular schwannomas (VS) has shifted over the last 20 years. Radiosurgery is an effective alternative to surgical removal and, at certain institutions, the favored approach for small-sized to moderate-sized VS. Patients often prefer radiosurgery, particularly when they are minimally symptomatic, to avoid the risks associated with microsurgery, which include higher rates of facial weakness, hearing loss, wound infection, cerebrospinal fluid leak, meningitis, and hemorrhage. The goals of radiosurgery are to prevent further tumor growth while preserving facial nerve (cranial nerve [CN] VII)

Table 20.1  Summary of key studies of stereotactic radiosurgery in patients with brainstem metastases

Study

N patients (N tumors)

Median dose (Gy), 50% isodose

Median tumor volume (cm3)

Local control

Symptomatic AREs

Huang et al 199912

26 (27)

16

1.1

95%, median F/U of 9.5 mo

None

Fuentes et al 200613

28 (28)

19.6

2.1

92%, median F/U of 11 mo

12.5% transient worsening 3 d after Gamma Knife

Yen et al 200611

53 (53)

17.6

2.8

86%, mean F/U of 9.5 mo

None

Kased et al 200810

42 (44)

16

0.26

77% at 1 y

9.5%

Koyfman et al 201014

43 (43)

15

0.37

85% at 1 y

9% (grade 1 and 2); no grade 3 or 4

Hatiboglu et al 201115

60

15 (LINAC)

1.0

35% at 1 y

20% early and delayed (hemiparesis, cranial nerve deficit, hemorrhage, nausea/ vomiting, headache)

Kawabe et al 201216

200 (222)

18

0.2

81.8% at 2 y

0.5%

Sengoz et al 2013

17

44 (46)

16

0.6

96%

None

Kilburn et al 201419

44 (52)

18

0.13

74% at 1 y

9.1%

91%

2.4%

a

Peterson et al 201418

41

17 

0.66 

Voong et al 201520

74 (77)

16

0.13

94% at median F/U of 5.5 mo

8%

Trifiletti et al 201621

547 (596)

16

0.8

81.8% at 1 y

7.4% (grade ≥ 3)

a

Abbreviations: ARE, adverse radiation effect; F/U, follow-up; LINAC, linear accelerator. a Mean value.

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Fig. 20.1  An 88-year-old man with gastrointestinal carcinoma metastases to the pons. (a) Axial, (b) sagittal, and (c) coronal T1-weighted gadolinium-enhanced magnetic resonance images (MRIs) with stereotactic radiosurgery (SRS) plan. The marginal dose was 14 Gy at 50% isodose, and

the target volume was 2.08 cm3. The 12 Gy isodose volume is delineated in green. Axial (d) T1-weighted MRI with gadolinium and (e) fluid-attenuated inversion recovery MRI obtained 2 months after SRS show significant regression of the tumor.

and trigeminal nerve (CN V) function. For patients with serviceable hearing, attempts are made to maintain hearing as long as possible. Multiple matched cohort studies in VS have shown comparable tumor control rates between microsurgery and radiosurgery of 95 to 98% over 10 years.22,​23,​24 SRS has the benefit of resulting in facial weakness in less than 1% of cases.24,​25 Trigeminal dysfunction occurs in 1 to 3% of patients.26 Symptoms of tinnitus and imbalance are similar between SRS and microsurgery. With the evolution of high-resolution imaging, patients with VS are now presenting earlier, with tumors that are smaller in size and with hearing that is still preserved. Patients with useful hearing before radiosurgery continue to report an approximate 60 to 85% overall rate for maintenance of serviceable hearing in the first years after the procedure.27 For patients with intracanalicular tumors, the rate of hearing preservation is greater than 80% and may be superior to rates of hearing preservation when patients are managed conservatively.28,​29 Predictors of hearing preservation after SRS include age, pre-SRS hearing status, and the mean dose to the cochlea.25 Maintaining a mean dose to the cochlea of less than 4 Gy appears to result in higher rates of useful hearing preservation.25 More recent retrospective studies have shown that SRS performed within 2 years of VS diagnosis in normal hearing patients, and prior to subjective hearing loss, results in greater retention of hearing compared with delayed SRS.30,​31 The average dose prescribed to the tumor margin is 12.5 Gy (12–13 Gy) at the 50% isodose line. Lower or higher doses can be used depending on hearing status, tumor volume, and clinical history. SRS has been shown to be effective in properly selected larger-sized VS measuring 3 to 4 cm, with few patients requiring a subsequent procedure.32,​33,​34 Although a limited number of reports have suggested that SRS is less effective in cystic VS,35

this may not be the case, and evidence is lacking (Fig. 20.2). In the early follow-up period after SRS, the VS will commonly show reduced central contrast uptake, and the patient may have transient expansion of the tumor capsule.35 Overall, radiosurgery has been established as a minimally invasive alternative to microsurgery for VS, with studies showing the long-term efficacy, safety, and cost-effectiveness of SRS.

Meningiomas Meningiomas commonly occur at the skull base, including at the foramen magnum, clivus, and petrous bone. Tumors within these locations can compress the brainstem. The evolution of SRS has impacted the management algorithm of cranial base tumors including meningiomas. In addition to offering surgical resection, observation, or fractionated radiation therapy, the multidisciplinary team can offer radiosurgery as a primary or adjuvant treatment. Meningiomas are excellent candidates for radiosurgery because their borders are clearly demarcated and they rarely invade the brain. The overall tumor control rate of SRS after prior resection of WHO grade I meningiomas is 93%.36 Similarly, tumor control is above 90% for meningiomas without a history of prior resection.36 Furthermore, rather than observing a patient after subtotal resection, such as residual tumor within the cavernous sinus or superior sagittal sinus, we advocate postoperative SRS to reduce the risk of complications from delayed progression.37 Because multiple studies have shown that untreated meningiomas grow over time, observation no longer seems to be the best choice, particularly for symptomatic meningiomas compressing the brainstem. Higher WHO grade, larger target volume, SRS after failed surgery, and convexity

20  Stereotactic Radiosurgery for Tumors of the Brainstem, Thalamus, and Pineal Region

301

Fig. 20.2  An 87-year-old man with reduced hearing in the left ear over several years and new onset of left facial numbness due to a large left cystic vestibular schwannoma. (a) Axial, (b) sagittal, and (c) coronal T1-weighted gadolinium-enhanced magnetic resonance images (MRIs) with stereotactic radiosurgery (SRS) plan to treat the cystic vestibular

schwannoma. The marginal dose was 11.5 Gy at 50% isodose, and the target volume was 6.16 cm3. Axial (d) T1-weighted gadolinium-enhanced MRI and (e) T2-weighted constructive interference steady-state MRI at 6 months and then again (f,g) at 14 months after SRS show collapse of the cyst and partial regression of the tumor.

tumors are predictors of lower tumor control.38 Control rates for WHO grade II and III tumors have been reported as 50% and 17%, respectively.36 Better control rates are obtained with tumor margin doses above 15 Gy,39 compared with margin doses of 12 to 14 Gy commonly used for WHO grade I tumors. Overall morbidity rates for all intracranial meningiomas have been reported at approximately 7%.40 In a study of 246 patients with benign skull base tumors causing brainstem compression, including 44 meningiomas, the control rate after SRS was 100% in meningiomas  (52.3% regressed, 47.7% stable).32 Brainstem compression improved in 50% of meningioma patients and was associated with symptom improvement in 43.2% of patients. Only one meningioma patient (2.3%) experienced an ARE of persistent facial weakness.32

Overall, radiosurgery is a minimally invasive option for patients with benign skull base tumors that compress or distort the brainstem (Fig. 20.3). SRS results in high rates of tumor control and preservation of neurological function, while avoiding the risks associated with open surgery of skull base lesions.

Brainstem Gliomas Brainstem gliomas constitute 1 to 2% of all intracranial tumors in adults and 10 to 20% of intracranial tumors in children.41,​42 Common presenting signs and symptoms are obstructive hydrocephalus, double vision, focal weakness, unsteady gait, dysphagia, and dysarthria. Clinical findings on examination may include a triad of CN deficits, long-tract signs, and ataxia.

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V  Comprehensive Management of Tumors of the Brainstem, Thalamus and Pineal Region

Fig. 20.3  A 60-year-old woman with recurrence of a previously resected WHO grade I right tentorial meningioma. (a) Axial, (b) sagittal, and (c) coronal T1-weighted gadolinium-enhanced magnetic resonance images (MRIs) with stereotactic radiosurgery (SRS) plan for recurrent tentorial

meningioma. The marginal dose was 12.5 Gy at 50% isodose and the target volume was 1.74 cm3. (d) Axial and (e) sagittal T1-weighted gadoliniumenhanced MRIs and (f) axial fluid-attenuated inversion recovery MRI show regression of meningiomas at 2 years after SRS.

The treatment of brainstem gliomas depends on the age of the patient, the exact location within the brainstem, tumor grade, and the presence of exophytic or cystic components. Management strategies include shunting followed by observation, tumor resection, fractionated external beam radiation or brachytherapy, and, more recently, SRS. The role of SRS in brainstem gliomas is still evolving, but it has emerged as an alternative management strategy for the treatment of focal brainstem gliomas. Small-sample, single-institution studies have been performed in patients with brainstem gliomas, including tectal gliomas with histologies of pilocytic astrocytomas and grade II astrocytomas (Table 20.2).43,​44,​45,​46,​47,​48,​49 In some of these studies, SRS was performed without an established tissue diagnosis; instead, treatment was based on imaging features consistent with a brainstem glioma. Because of the critical location and often indolent clinical course of tectal gliomas, their management is a subject of considerable debate. Management in the past has included shunting in the setting of obstructive hydrocephalus followed by serial imaging. However, SRS offers an alternative strategy providing good local control rates with low morbidity. Local control rates reported for lowgrade gliomas (pilocytic, grade II glioma), many of which were located in the brainstem, vary from 70 to 100% at 3-year to 5-year follow-up (Fig. 20.4).43,​44,​45,​46,​47,​48,​49 The incidence of AREs fluctuated across studies, ranging anywhere from 0 to 45%, likely due to the heterogeneity in reporting AREs (asymptomatic, imagingbased AREs vs symptomatic AREs). Some patients will develop peritumoral edema after radiosurgery with minimal clinical consequences. Dose reduction to minimize AREs is recommended in patients who have undergone fractionated cranial radiotherapy before radiosurgery. Overall, the studies in Table 20.2

support that SRS is an effective primary treatment or adjunct to open surgery for focal brainstem gliomas with an acceptable safety profile. However, these studies have few patients and are retrospective in nature, warranting prospective studies to assess the long-term efficacy and safety of SRS in low-grade brainstem gliomas. The role of SRS in malignant brainstem gliomas is less clearly defined. SRS may have a role as salvage therapy in anaplastic ependymomas, although further prospective studies are warranted.50,​51

■■ SRS for Tumors of the Thalamus With the exception of metastases, tumors of the thalamus are most commonly gliomas. Yet thalamic gliomas remain rare, constituting 1 to 5% of pediatric intracranial tumors.52 The natural history of thalamic gliomas is unpredictable, and the optimal management of these tumors remains uncertain. Thalamic tumors are classically considered inoperable due to their proximity to critical structures and the risk of major morbidity. Deep-seated tumors that are deemed inoperable, including thalamic gliomas, may benefit from SRS. Several retrospective and prospective studies have shown the benefit of SRS in the treatment of newly diagnosed and recurrent high-grade gliomas (for review, see Redmond and Mehta53). Patients with limited residual disease after surgery, younger age, and high-performance status may benefit the most from SRS with concurrent temozolomide in newly diagnosed glioblastoma (GBM).53 However, one randomized trial  (RTOG 93–05) has been performed, which failed to demonstrate survival benefit of SRS added to postoperative adjuvant radiotherapy and chemotherapy for newly diagnosed

20  Stereotactic Radiosurgery for Tumors of the Brainstem, Thalamus, and Pineal Region

303

Table 20.2  Summary of select recent studies of stereotactic radiosurgery in patients with low-grade brainstem gliomas

Study

N patients (location)

Histology

Median Median dose (Gy), volume 50% isodose (cm3)

Local control

Overall survival

AREs

Hadjipanayis et al 200343

49 (22 brainstem)

37 pilocytic, 12 grade II

15

3.3

67% at median F/U of 32 mo

91.8% at median F/U of 32 mo

4% symptomatic AREs

Wang et al 200644

21 (25 tumors, 5 brainstem)

8 pilocytic, 13 grade II

18

2.4

65% at 10 y

65% at 10 yr

40% peritumoral edema with no symptoms or mild symptoms

Yen et al 200745

20 (all brainstem)

5 pilocytic, 5 nonpilocytic, 10 unknown

13.5

2.5a

84% at 5 y

90% at mean F/U of 78 mo

5%

Kano et al 200946

14 adult (6 brainstem)

pilocytic

13.3

4.7

83.9% at 1 y 31.5% at 5 y

88.9% at 5 yr

None

Kano et al 200947

50 pediatric (13 brainstem)

pilocytic

14.5

2.1

91.7% at 1 y 70.8% at 5 y

98% at median F/U of 55 mo

10% peritumoral edema; 4% symptomatic

Weintraub et al 201248

24 (15 brainstem)

15 pilocytic, 4 grade II, 1 grade III, 4 unknown

15

2.4

83% at median F/U of 74 mo

96% at median F/U of 144 mo

12.5% peritumoral edema

El-Shehaby et al 201549

11 (all tectal)

5 pilocytic, 6 nonpilocytic

12

4.5

100% at median F/U of 40 mo

100% at median F/U of 40 mo

45% transient neurological symptoms, 36% cyst formation

Abbreviations: ARE, adverse radiation effect; F/U, follow-up. a Mean value.

Fig. 20.4  A 46-year-old woman with a recurrent right dorsolateral brainstem pilocytic astrocytoma that had undergone partial resection. (a) Axial, (b) sagittal, and (c) coronal T1-weighted gadolinium-enhanced magnetic resonance images (MRIs) with stereotactic radiosurgery (SRS) plan for the

brainstem pilocytic astrocytoma. The marginal dose was 13 Gy at 50% isodose and the target volume was 1.91 cm3 (d) Axial and (e) sagittal T1-weighted gadolinium-enhanced MRIs and (f) axial fluid-attenuated inversion recovery MRI demonstrate interval shrinkage of the tumor at 24-month follow-up.

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V  Comprehensive Management of Tumors of the Brainstem, Thalamus and Pineal Region

GBM.54 This trial did not encompass current standard-of-care management, including concurrent and adjuvant temozolomide. Additionally, SRS was delivered before radiotherapy in this trial. With the lack of studies providing higher levels of evidence, results to date do not support SRS alone or as a boost to external beam therapy in patients with newly diagnosed GBM. With respect to recurrent GBM, a published review of studies performing salvage SRS in patients with recurrent GBMs from 2005 to 2015 has reported median overall survival varying between 9 and 18 months from SRS, and median progression-free survival ranging from 4.6 to 15 months.55 Patients receiving multimodal therapy, including SRS and bevacizumab, may have the greatest survival advantage. To mitigate the effects of selection bias, a randomized controlled trial of SRS in recurrent GBM is needed. SRS is traditionally given to a previously irradiated brain, and thus radiation injury is concerning as a late complication. Mehta and colleagues56 reported 4 of 29 cases (14%) with clinically significant, biopsy-proven radiation necrosis in a series of newly diagnosed GBM patients. A prospective study of 114 patients reported AREs in 24% of patients who underwent SRS as a salvage treatment for recurrent malignant gliomas.57 Several prospective and retrospective studies have evaluated the addition of bevacizumab, a monoclonal antibody against vascular endothelial growth factor, to SRS in patients with recurrent GBM. Results to date have been favorable with overall survival rates ranging from 12 to 15 months, 1-year survival rates as high as 50%, and ARE rates of up to 10%.58,​59 Also, ongoing clinical trials are currently looking at the safety and efficacy of the combination of PD-1 inhibitors and SRS in patients with recurrent malignant gliomas. In pediatric patients, tumors of the thalamus are generally astrocytic, and more than half are benign.52 The Pittsburgh

group (Kano et al47) reported the largest retrospective study of 50 pediatric low-grade gliomas, including 6 thalamic gliomas (Table 20.2). They reported actuarial tumor control rates of 91.7%, 82.8%, and 70.8% at 1, 3, and 5 years, respectively, from SRS. In their adult series46 of 14 patients with low-grade gliomas, tumor control rates were 83.9%, 31.5%, and 31.5% at 1, 3, and 5 years, respectively. A report from Mayo Clinic on recurrent and unresectable pilocytic astrocytoma demonstrated similar tumor control rates of 65%, 41%, and 15% at 1, 5, and 10 years after SRS.60 Delayed cyst progression seemed to hinder long-term tumor control in these studies, particularly in adult patients.

■■ SRS for Tumors of the Pineal Region Tumors of the pineal region are heterogeneous in nature and comprise both benign and malignant tumors, including pineal parenchymal tumors (PPTs), germ cell tumors (GCTs), papillary tumors of the pineal region (PTPRs), glial tumors, primitive neuroectodermal tumors, and meningiomas. Because pineal region tumors are relatively uncommon, conducting comparative clinical trials to determine the optimal treatment strategy has not been feasible. Management of these tumors may include any combination of biopsy, microsurgical resection, radiotherapy, chemotherapy, and SRS. The role of radiosurgery in the management of pineal region tumors is expanding, both as a primary treatment modality and as an adjunct to surgery. A few studies have looked at the effectiveness of SRS in pineal region tumors (Table 20.3).61,​62,​63,​64,​65,​66,​67,​68 These single-institution series report local control rates of 67 to 100% at 2 to 5 years after SRS, including predominantly PPTs or mixed

Table 20.3  Summary of recent studies of patients with pineal tumors treated with stereotactic radiosurgerya

Study

No. of Median tumors (type) dose (Gy), 50% isodose

Median tumor Local control volume (cm3)

Overall survival

AREs

Kobayashi et al 200161

30 (mixed)

13.5–16.8

NA

73% at mean F/U of 23 mo

76.7% at mean F/U of 23 mo

NA

Hasegawa et al 200262

16 (PPT)

15b

5.0b

100% at mean F/U of 52 mo

75% at 2 y 67% at 5 y

12.5%

Amendola et al 200563

20 (mixed)

11

3.1

90%

85% at 2 y

None

Reyns et al 200664

13 (PPT)

15b

NA

91.7% (100% for pineocytoma)

83% at mean F/U of 34 mo

3.8%

Lekovic et al 200765

17 (mixed)

14

7.42

100% at mean F/U of 31 mo

82.3% at mean F/U of 31 mo

None

Kano et al 200966 20 (PPT)

15

4.4

89% at 5 y

95% at 1 y 69% at 5 y

NA

Mori et al 200967

49 (mixed)

9.9–25.7c

3.3b

Germinoma: 82% at 5 y Malignant GCT: 62% at 5 y Pineocytoma: 85% at 5 y Mixed/pineoblastoma: 30% at 2 y

68% at 5 y for GCT 100% at 5 y for PPT

NA

Yianni et al 201268

44 (mixed)

18

3.7b

93% at 1 y 77% at 5 y

95% at 1 y 83% at 5 y

None

Abbreviations: ARE, adverse radiation effect; F/U, follow-up; GCT, germ cell tumor; NA, not available; PPT, pineal parenchymal tumor a These studies are composed entirely of PPTs or a mixed series of PPTs and GCTs. Patients were treated with surgical resection followed by radiosurgery or with radiosurgery as the primary treatment. b Mean value c Range

20  Stereotactic Radiosurgery for Tumors of the Brainstem, Thalamus, and Pineal Region

305

series of PPTs and GCTs. The heterogeneity in tissue diagnoses and grade of tumors prevents a comparison of outcomes across studies. Because of the low prevalence of pineal region tumors, it has not been possible to study outcomes of SRS by histological subtype in large numbers. The initial tumor grade and a history of previous radiotherapy have been associated with worse outcomes after SRS.68 Patients with germinomas and pineocytomas have higher long-term control rates after SRS, whereas those with pineoblastomas and malignant GCTs have a higher chance of relapse.67 Improvements in diplopia and hydrocephalus have been reported in some patients after SRS.68 Pineocytomas are generally slow-growing tumors with a favorable prognosis. They tend to be resistant to conventional fractionated radiotherapy, and gross total resection is generally curative. However, in some cases, the tumor can recur or disseminate after surgical resection. High local control rates above 90% can be achieved with SRS for locally progressive pineocytomas.65,​69 Fig. 20.5 depicts a case of disseminated pineocytoma

treated with salvage SRS, showing good radiological response at 2-year follow-up. Only two case reports have looked at SRS in PTPR. These tumors are believed to arise from the specialized ependyma of the subcommissural organ.70 Their biological behavior resembles that of WHO grade II–III tumors. As this is a relatively new entity classified by WHO in 2007, it is possible that PTPR may have been misclassified in the past. These tumors frequently recur locally after surgical resection. Evidence conflicts regarding the role of conventional radiotherapy after surgery.71,​72 The two cases reported in the literature showed long-term local control of PTPR more than 5 years after SRS.73,​74 Because of the histological heterogeneity of pineal region tumors and the inability to achieve 100% diagnostic accuracy with MRI, biopsy is generally recommended to obtain tissue diagnosis before definitive treatment. However, risks are incurred when biopsying within the pineal region. A recent study from China, where the incidence of pineal region tumors is

Fig. 20.5  A 39-year-old man with a history of subtotal resection of a pineocytoma who developed multiple subarachnoid pineocytomas. Axial T1-weighted gadolinium-enhanced magnetic resonance images (MRIs) with stereotactic radiosurgery (SRS) plan for (a) a middle cranial fossa pineocytoma and (b) a left tentorial pineocytoma. The marginal dose was 16 Gy at 50% isodose. Target

volumes were 0.63 cm3 to the right middle cranial fossa and 0.439 cm3 to the left tentorial. The right optic nerve is delineated in blue. Axial T1-weighted gadolinium-enhanced MRIs (c) 2 years after SRS to the middle cranial fossa pineocytoma and (d) 1 year after SRS to the left tentorial pineocytoma demonstrate significant regression of the tumors.

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relatively higher at 2% of intracranial tumors, looked at outcomes after SRS in 147 patients with pineal region tumors that had not undergone histological confirmation and were treated primarily with SRS.75 Survival rates were 72% at 3 years and 66% at 5 years for all patients. For patients with radiographically and clinically defined GCTs, overall survival was 62% at 3 years and 55% at 5 years. Local control was 94% at 3 years and 91% at 5 years for all patients compared with 88% at 3 years and 77% at 5 years for GCTs. The authors concluded that Gamma Knife SRS is an effective, low-risk treatment option that can be widely used for pineal region tumors without requiring a histological diagnosis.75 This recommendation remains a topic of debate. Although clear management guidelines have yet to be established for certain pineal region tumors, results from these studies support radiosurgery as an alternative to surgical resection or as adjuvant therapy when gross total resection is not feasible. Prospective cohort studies with larger samples that compare SRS and other established therapies are needed.

■■ Conclusions SRS has resulted in a paradigm shift in the management of several neurosurgical diseases involving the brainstem, including benign tumors (VSs, meningiomas) and brainstem metastases. The role of SRS in focal brainstem gliomas, thalamic gliomas, and pineal region tumors is still evolving and may comprise SRS as the primary modality treatment or as adjuvant treatment to surgical resection. Most surgeons and oncologists currently advocate histological diagnosis when feasible. However, when a tissue diagnosis cannot be obtained, and when the growth of a focal tumor within the brainstem, thalamus, or pineal region is documented, SRS may be an appropriate management strategy to maximize tumor control while maintaining neurological function and quality of life. References 1. Kondziolka D, Lunsford LD, Claassen D, Maitz AH, Flickinger JC. Radiobiology of radiosurgery: Part I. The normal rat brain model. Neurosurgery 1992;31(2):271–279 2. Witham TF, Okada H, Fellows W, et al. The characterization of tumor apoptosis after experimental radiosurgery. Stereotact Funct Neurosurg 2005;83(1):17–24 3. Kamiryo T, Kassell NF, Thai QA, Lopes MB, Lee KS, Steiner L. Histological changes in the normal rat brain after gamma irradiation. Acta Neurochir (Wien) 1996;138(4):451–459 4. Delattre JY, Krol G, Thaler HT, Posner JB. Distribution of brain metastases. Arch Neurol 1988; 45(7):741–744 5. Trifiletti DM, Lee CC, Shah N, Patel NV, Chen SC, Sheehan JP. How does brainstem involvement affect prognosis in patients with limited brain metastases? results of a matched-cohort analysis. World Neurosurg 2016;88:563–568 6. Andrews DW, Suarez O, Goldman HW, et al. Stereotactic radiosurgery and fractionated stereotactic radiotherapy for the treatment of acoustic schwannomas: comparative observations of 125 patients treated at one institution. Int J Radiat Oncol Biol Phys 2001; 50(5):1265–1278 7. Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 2009;10(11):1037–1044 8. Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952–26001 study. J Clin Oncol 2011;29(2):134–141

9. Brown P, Asher A, Ballman K, et al. NCCTG N0574 (Alliance): a phase III randomized trial of whole brain radiation therapy (WBRT) in addition to radiosurgery (SRS) in patients with 1 to 3 brain metastases. Neuro Oncol 2015;17(5,Suppl):v45–v46 10. Kased N, Huang K, Nakamura JL, et al. Gamma Knife radiosurgery for brainstem metastases: the UCSF experience. J Neurooncol 2008;86(2):195–205 11. Yen CP, Sheehan J, Patterson G, Steiner L. Gamma Knife surgery for metastatic brainstem tumors. J Neurosurg 2006;105(2):213–219 12. Huang CF, Kondziolka D, Flickinger JC, Lunsford LD. Stereotactic radiosurgery for brainstem metastases. J Neurosurg 1999;91(4):563–568 13. Fuentes S, Delsanti C, Metellus P, Peragut JC, Grisoli F, Regis J. Brainstem metastases: management using Gamma Knife radiosurgery. Neurosurgery 2006;58(1):37–42, discussion 37–42 14. Koyfman SA, Tendulkar RD, Chao ST, et al. Stereotactic radiosurgery for single brainstem metastases: the Cleveland Clinic experience. Int J Radiat Oncol Biol Phys 2010;78(2):409–414 15. Hatiboglu MA, Chang EL, Suki D, Sawaya R, Wildrick DM, Weinberg JS. Outcomes and prognostic factors for patients with brainstem metastases undergoing stereotactic radiosurgery. Neurosurgery 2011;69(4): 796–806, discussion 806 16. Kawabe T, Yamamoto M, Sato Y, et al. Gamma Knife surgery for patients with brainstem metastases. J Neurosurg 2012;117(Suppl):23–30 17. Sengöz M, Kabalay IA, Tezcanlı E, Peker S, Pamir N. Treatment of brainstem metastases with Gamma-Knife radiosurgery. J Neurooncol 2013; 113(1):33–38 18. Peterson HE, Larson EW, Fairbanks RK, et al. Gamma Knife treatment of brainstem metastases. Int J Mol Sci 2014;15(6):9748–9761 19. Kilburn JM, Ellis TL, Lovato JF, et al. Local control and toxicity outcomes in brainstem metastases treated with single fraction radiosurgery: Is there a volume threshold for toxicity? J Neurooncol 2014;117(1):167–174 20. Voong KR, Farnia B, Wang Q, et al. Gamma Knife stereotactic radiosurgery in the treatment of brainstem metastases: The MD Anderson experience. Neurooncol Pract 2015;2(1):40–47 21. Trifiletti DM, Lee CC, Kano H, et al. Stereotactic radiosurgery for brain­ stem metastases: an international cooperative study to define response and toxicity. Int J Radiat Oncol Biol Phys 2016;96(2):280–288 22. Régis J, Pellet W, Delsanti C, et al. Functional outcome after Gamma Knife surgery or microsurgery for vestibular schwannomas. J Neurosurg 2013; 119(Suppl):1091–1100 23. Myrseth E, Møller P, Pedersen PH, Vassbotn FS, Wentzel-Larsen T, LundJohansen M. Vestibular schwannomas: clinical results and quality of life after microsurgery or Gamma Knife radiosurgery. Neurosurgery 2005; 56(5):927–935, discussion 927–935 24. Pollock BE, Driscoll CL, Foote RL, et al. Patient outcomes after vestibular schwannoma management: a prospective comparison of microsurgical resection and stereotactic radiosurgery. Neurosurgery 2006;59(1): 77–85, discussion 77–85 25. Kano H, Kondziolka D, Khan A, Flickinger JC, Lunsford LD. Predictors of hearing preservation after stereotactic radiosurgery for acoustic neuroma. J Neurosurg 2009;111(4):863–873 26. Flickinger JC, Kondziolka D, Niranjan A, Maitz A, Voynov G, Lunsford LD. Acoustic neuroma radiosurgery with marginal tumor doses of 12 to 13 Gy. Int J Radiat Oncol Biol Phys 2004;60(1):225–230 27. Lunsford LD, Niranjan A, Flickinger JC, Maitz A, Kondziolka D. Radiosurgery of vestibular schwannomas: summary of experience in 829 cases. J Neurosurg 2005;102(Suppl):195–199 28. Régis J, Carron R, Park MC, et al. Wait-and-see strategy compared with proactive Gamma Knife surgery in patients with intracanalicular vestibular schwannomas. J Neurosurg 2010;113(Suppl):105–111 29. Niranjan A, Mathieu D, Flickinger JC, Kondziolka D, Lunsford LD. Hearing preservation after intracanalicular vestibular schwannoma radiosurgery. Neurosurgery 2008;63(6):1054–1062, discussion 1062–1063 30. Akpinar B, Mousavi SH, McDowell MM, et al. Early radiosurgery improves hearing preservation in vestibular schwannoma patients with normal hearing at the time of diagnosis. Int J Radiat Oncol Biol Phys 2016;95(2):729–734

20  Stereotactic Radiosurgery for Tumors of the Brainstem, Thalamus, and Pineal Region 31. Mousavi SH, Niranjan A, Akpinar B, et al. Hearing subclassification may predict long-term auditory outcomes after radiosurgery for vestibular schwannoma patients with good hearing. J Neurosurg 2016; 125(4):845–852 32. Nakaya K, Niranjan A, Kondziolka D, et al. Gamma Knife radiosurgery for benign tumors with symptoms from brainstem compression. Int J Radiat Oncol Biol Phys 2010;77(4):988–995 33. Yang HC, Kano H, Awan NR, et al. Gamma Knife radiosurgery for larger-volume vestibular schwannomas: clinical article. J Neurosurg 2013; 119(Suppl):801–807 34. Williams BJ, Xu Z, Salvetti DJ, McNeill IT, Larner J, Sheehan JP. Gamma Knife surgery for large vestibular schwannomas: a single-center retrospective case-matched comparison assessing the effect of lesion size. J Neurosurg 2013;119(2):463–471 35. Hasegawa T, Kida Y, Yoshimoto M, Koike J, Goto K. Evaluation of tumor expansion after stereotactic radiosurgery in patients harboring vestibular schwannomas. Neurosurgery 2006;58(6):1119–1128, discussion 1119–1128 36. Kondziolka D, Mathieu D, Lunsford LD, et al. Radiosurgery as definitive management of intracranial meningiomas. Neurosurgery 2008; 62(1):53–58, discussion 58–60 37. Lee JY, Niranjan A, McInerney J, Kondziolka D, Flickinger JC, Lunsford LD. Stereotactic radiosurgery providing long-term tumor control of cavernous sinus meningiomas. J Neurosurg 2002;97(1):65–72 38. Kaprealian T, Raleigh DR, Sneed PK, Nabavizadeh N, Nakamura JL, McDermott MW. Parameters influencing local control of meningiomas treated with radiosurgery. J Neurooncol 2016;128(2):357–364 39. Sethi RA, Rush SC, Liu S, et al. Dose-response relationships for meningioma radiosurgery. Am J Clin Oncol 2015;38(6):600–604 40. Santacroce A, Walier M, Régis J, et al. Long-term tumor control of benign intracranial meningiomas after radiosurgery in a series of 4565 patients. Neurosurgery 2012;70(1):32–39, discussion 39 41. Albright AL, Price RA, Guthkelch AN. Brain stem gliomas of children: a clinicopathological study. Cancer 1983;52(12):2313–2319 42. Packer RJ, Nicholson HS, Vezina LG, Johnson DL. Brainstem gliomas. Neurosurg Clin N Am 1992;3(4):863–879 43. Hadjipanayis CG, Kondziolka D, Flickinger JC, Lunsford LD. The role of stereotactic radiosurgery for low-grade astrocytomas. Neurosurg Focus 2003;14(5):e15 44. Wang LW, Shiau CY, Chung WY, et al. Gamma Knife surgery for lowgrade astrocytomas: evaluation of long-term outcome based on a 10-year experience. J Neurosurg 2006;105(Suppl):127–132 45. Yen CP, Sheehan J, Steiner M, Patterson G, Steiner L. Gamma Knife surgery for focal brainstem gliomas. J Neurosurg 2007;106(1):8–17 46. Kano H, Kondziolka D, Niranjan A, Flickinger JC, Lunsford LD. Stereotactic radiosurgery for pilocytic astrocytomas part 1: outcomes in adult patients. J Neurooncol 2009;95(2):211–218 47. Kano H, Niranjan A, Kondziolka D, et al. Stereotactic radiosurgery for pilocytic astrocytomas part 2: outcomes in pediatric patients. J Neurooncol 2009;95(2):219–229 48. Weintraub D, Yen CP, Xu Z, Savage J, Williams B, Sheehan J. Gamma Knife surgery of pediatric gliomas. J Neurosurg Pediatr 2012;10(6):471–477 49. El-Shehaby AM, Reda WA, Abdel Karim KM, Emad Eldin RM, Esene IN. Gamma Knife radiosurgery for low-grade tectal gliomas. Acta Neurochir (Wien) 2015;157(2):247–256 50. Kano H, Niranjan A, Kondziolka D, Flickinger JC, Lunsford LD. Outcome predictors for intracranial ependymoma radiosurgery. Neurosurgery 2009; 64(2):279–287, discussion 287–288 51. Murphy ES, Chao ST, Angelov L, et al. Radiosurgery for pediatric brain tumors. Pediatr Blood Cancer 2016;63(3):398–405 52. Puget S, Crimmins DW, Garnett MR, et al. Thalamic tumors in children: a reappraisal. J Neurosurg 2007;106(5, Suppl):354–362 53. Redmond KJ, Mehta M. Stereotactic radiosurgery for glioblastoma. Cureus 2015;7(12):e413 54. Souhami L, Seiferheld W, Brachman D, et al. Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy

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with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93–05 protocol. Int J Radiat Oncol Biol Phys 2004; 60(3):853–860 55. Larson EW, Peterson HE, Lamoreaux WT, et al. Clinical outcomes following salvage Gamma Knife radiosurgery for recurrent glioblastoma. World J Clin Oncol 2014;5(2):142–148 56. Mehta MP, Masciopinto J, Rozental J, et al. Stereotactic radiosurgery for glioblastoma multiforme: report of a prospective study evaluating prognostic factors and analyzing long-term survival advantage. Int J Radiat Oncol Biol Phys 1994;30(3):541–549 57. Kong DS, Lee JI, Park K, Kim JH, Lim DH, Nam DH. Efficacy of stereotactic radiosurgery as a salvage treatment for recurrent malignant gliomas. Cancer 2008;112(9):2046–2051 58. Cuneo KC, Vredenburgh JJ, Sampson JH, et al. Safety and efficacy of stereotactic radiosurgery and adjuvant bevacizumab in patients with recurrent malignant gliomas. Int J Radiat Oncol Biol Phys 2012; 82(5):2018–2024 59. Park KJ, Kano H, Iyer A, et al. Salvage Gamma Knife stereotactic radiosurgery followed by bevacizumab for recurrent glioblastoma multiforme: a case-control study. J Neurooncol 2012;107(2):323–333 60. Hallemeier CL, Pollock BE, Schomberg PJ, Link MJ, Brown PD, Stafford SL. Stereotactic radiosurgery for recurrent or unresectable pilocytic astrocytoma. Int J Radiat Oncol Biol Phys 2012;83(1):107–112 61. Kobayashi T, Kida Y, Mori Y. Stereotactic gamma radiosurgery for pineal and related tumors. J Neurooncol 2001;54(3):301–309 62. Hasegawa T, Kondziolka D, Hadjipanayis CG, Flickinger JC, Lunsford LD. The role of radiosurgery for the treatment of pineal parenchymal tumors. Neurosurgery 2002;51(4):880–889 63. Amendola BE, Wolf A, Coy SR, Amendola MA, Eber D. Pineal tumors: analysis of treatment results in 20 patients. J Neurosurg 2005; 102(Suppl):175–179 64. Reyns N, Hayashi M, Chinot O, et al. The role of Gamma Knife radiosurgery in the treatment of pineal parenchymal tumours. Acta Neurochir (Wien) 2006;148(1):5–11, discussion 11 65. Lekovic GP, Gonzalez LF, Shetter AG, et al. Role of Gamma Knife surgery in the management of pineal region tumors. Neurosurg Focus 2007; 23(6):E12 66. Kano H, Niranjan A, Kondziolka D, Flickinger JC, Lunsford D. Role of stereotactic radiosurgery in the management of pineal parenchymal tumors. Prog Neurol Surg 2009;23:44–58 67. Mori Y, Kobayashi T, Hasegawa T, Yoshida K, Kida Y. Stereotactic radiosurgery for pineal and related tumors. Prog Neurol Surg 2009;23:106–118 68. Yianni J, Rowe J, Khandanpour N, et al. Stereotactic radiosurgery for pineal tumours. Br J Neurosurg 2012;26(3):361–366 69. Wilson DA, Awad AW, Brachman D, et al. Long-term radiosurgical control of subtotally resected adult pineocytomas. J Neurosurg 2012; 117(2):212–217 70. Fèvre-Montange M, Hasselblatt M, Figarella-Branger D, et al. Prognosis and histopathologic features in papillary tumors of the pineal region: a retrospective multicenter study of 31 cases. J Neuropathol Exp Neurol 2006;65(10):1004–1011 71. Fauchon F, Hasselblatt M, Jouvet A, et al. Role of surgery, radiotherapy and chemotherapy in papillary tumors of the pineal region: a multicenter study. J Neurooncol 2013;112(2):223–231 72. Edson MA, Fuller GN, Allen PK, et al. Outcomes after surgery and radiotherapy for papillary tumor of the pineal region. World Neurosurg 2015;84(1):76–81 73. Cardenas R, Javalkar V, Haydel J, et al. Papillary tumor of pineal region: prolonged control rate after Gamma Knife radiosurgery—a case report and review of literature. Neurol India 2010;58(3):471–476 74. Riis P, van Eck AT, Dunker H, Bergmann M, Börm W. Stereotactic radiosurgery of a papillary tumor of the pineal region: case report and review of the literature. Stereotact Funct Neurosurg 2013;91(3):186–189 75. Li W, Zhang B, Kang W, et al. Gamma Knife radiosurgery  (GKRS) for pineal region tumors: a study of 147 cases. World J Surg Oncol 2015;13:304

21

Radiotherapy for Pineal, Thalamic, and Brainstem Tumors Susan G. R. McDuff, Shannon M. MacDonald, and Kevin S. Oh

Abstract

Radiobiology

Keywords:  brainstem tumors, pineal tumors, radiation side effects, radiotherapy, radiotherapy treatment planning, thalamic tumors

The cytotoxic effects of radiation result primarily from damage to DNA.3 Radiation can either directly damage DNA  (direct action) or interact with other molecules in the cell, especially water, to produce free radicals that subsequently damage DNA  (indirect action) (Fig. 21.11). Approximately two-thirds of the damage caused by X-rays is via indirect action, and this damage has the potential to be mitigated with the use of free-radical scavengers. For heavy particles such as protons, a higher proportion of DNA damage occurs via direct action. Radiation is thought to damage DNA via multiple mechanisms and, in particular, radiation has been shown to induce single- or double-strand DNA breaks, induce base damage, induce abnormal crosslinks between DNA strands or between proteins and DNA, and induce chromosome aberrations.2,​3

The literature supporting the use of radiotherapy in the treatment of pineal, thalamic, and brainstem tumors is discussed in this chapter. An overview of the modalities of radiation delivery is provided, including external-beam radiotherapy, intensity-modulated radiotherapy, and proton beam radiotherapy. The special technical considerations of radiation delivery to pineal, thalamic, and brainstem tumors are reviewed, including organs at risk and dose constraints. Finally, the management of acute and long-term toxicities is addressed.

■■ Biology of Radiotherapy Introduction to Medical Radiation Radiation has been used for more than 100 years to treat cancer, since shortly after the X-ray was discovered by Röntgen in 1895.1 Many types of radiation are used in medical practice, including manufactured radiation and radiation from natural isotopes  (e.g., iridium, iodine, and cesium).2 The vast majority of radiation given for central nervous system  (CNS) malignancies is delivered via manufactured X-rays. X-rays are produced in a machine  (most commonly a linear accelerator [linac]). that accelerates electrons to a high energy and stops them in a target of tungsten or gold, thus producing highenergy X-rays.1 X-rays can be thought of as “packets” of energy comprising photons; the shorter the wavelength of the X-ray, the higher the energy.1 Linacs have the ability to deliver high doses of radiation to precise locations in the body, thus minimizing damage to normal tissues—this is termed external beam radiotherapy (EBRT).2 For linac-based radiotherapy to the CNS, the beam energy is typically 6 to 10 MV. Conversely, radiation emitted from natural isotopes is predominantly used for brachytherapy, with a radioactive source placed directly into the body  (e.g., into the resection cavity during intraoperative radiotherapy). Although the majority of medical radiation involves the use of electromagnetic radiation (e.g., X-rays), it is important to note the emerging use of particulate radiation in the treatment of CNS malignancies. In particular, protons are positively charged particles with a mass nearly 2,000 times greater than that of electrons.1 Given the size of protons, they require a cyclotron to be accelerated for therapeutic purposes and are favored for many CNS malignancies because of their favorable dose distribution.

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Fig. 21.1  Direct and indirect actions of radiation. (Reproduced with permission from Hall and Giaccia 2006.1)

21  Radiotherapy for Pineal, Thalamic, and Brainstem Tumors Radiosensitivity describes the effects of radiation on cells and is influenced by the degree of regression of tumor cells, how quickly they regress, and the duration of response.2 After exposure to radiation, cells might die during the next mitosis  (mitotic death) or via programmed cell death  (apoptosis).4 A cell’s DNA repair mechanisms influence its radiosensitivity: unlike normal cells, malignant cells are thought to be preferentially destroyed by low-dose radiation because of differences in DNA repair capabilities. After receiving a low dose of radiation (e.g., 1–2 Gy), tumor cells and normal cells sustain sublethal damage to their DNA. Normal cells can repair this sublethal damage relatively quickly compared to tumor cells. Thus, radiation is typically administered in a fractionated schedule  (low doses every day) because this schedule gives normal cells a chance to repair themselves while malignant cells accrue lethal damage.

■■ Overview of Radiation Delivery The majority of radiation for CNS malignancies is delivered via EBRT whereby radiation from an outside source is aimed at the body and delivered to the target. As radiation traverses the body, a dose is deposited in all tissues (malignant and nonmalignant) along the path. This section describes how radiation is delivered to maximize dose to the target and minimize the unavoidable normal-tissue toxicity.

Treatment Planning Treatment planning for radiotherapy consists of developing a plan for radiation delivery. The first step in treatment planning consists of patients undergoing a “simulation” or “mapping” scan that is typically a computed tomogram taken with consideration for the patient’s unique treatment position. The radiation target is defined by first outlining gross tumor volume, which should include all visible disease. The clinical target volume is then outlined such that the target is expanded to include areas of presumed microscopic disease spread. The clinical tumor volume depends on the known natural history of the tumor being treated as well as anatomical boundaries. Finally, the target is expanded uniformly into a planning target volume, which accounts for daily setup uncertainty. For brain tumors, a magnetic resonance image (MRI) is often fused to the computed tomogram to facilitate target delineation. For patients undergoing postoperative radiotherapy, the operative report is carefully reviewed with the surgeon to fully delineate areas at risk for microscopic disease. After the targets are defined, dosimetry consists of determining the number of radiation beams to use, the angle of beam entry, and the shape and size of treatment blocks in three dimensions with the goal of conforming dose around the target and minimizing normal-tissue toxicity. Dosimetry is an iterative process whereby the delivery of radiation dose is optimized such that the target is covered generally with 95 to 100% of the prescribed dose, and critical nearby structures do not receive what is considered to be an unacceptable toxic dose. All treatment plans are unique and depend on the size and shape of the target in the context of an individual’s unique anatomy. To maximize dose to the target and minimize dose to uninvolved brain parenchyma, radiation oncologists employ three-dimensional (3D) conformal radiotherapy (3D-CRT) in which multiple beams deliver radiation converging on the target. For targets with unfavorable geometry

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or proximity to critical structures, intensity-modulated radiotherapy (IMRT) is a sophisticated form of 3D-CRT in which optimization software creates fluence patterns of virtual beamlets to achieve greater conformity for irregular shapes.

Fractionation Schedules Radiation is typically given in a “fractionated” fashion, with low doses administered every day. The number of fractions corresponds to the number of radiation treatments delivered for a given treatment course. The ability of radiation to control or eradicate a tumor depends on the total dose delivered as well as the dose delivered per fraction. A higher dose per fraction results in more cell kill for both normal and malignant cells. Lower doses of radiation delivered over time allow for repair of normal tissues and have the potential to decrease late radiation effects on normal tissue. However, lower doses may allow for malignant cell regeneration between treatments, and therefore the cumulative treatment dose must be higher. The total therapeutic dose is calculated by multiplying the dose per fraction by the number of fractions.

Standard Fractionated External Beam Radiotherapy The traditional fractionated dose of EBRT is 1.8 to 2 Gy per fraction. As described in this chapter, the total doses typically used for the treatment of pineal, thalamic, and brainstem gliomas are in the range of 45 to 66 Gy. When SRS is delivered in 1.8 to 2 Gy per fraction, a total of 25 to 33 treatments is required to deliver the total therapeutic dose. Radiation is typically delivered Monday through Friday with weekend treatment breaks incorporated to minimize toxicity.

Stereotactic Radiosurgery Stereotactic radiosurgery  (SRS) involves the delivery of a high dose per fraction in one to five fractions with rigid immobilization and precise image guidance to achieve submillimeter precision. The term SRS specifically refers to treatment delivered in a single fraction. Doses for intracranial SRS range from 12 to 35 Gy in a single fraction, depending on the histology, size of target, proximity to critical structures, and goals of care. SRS is the primary focus of Chapter 20 (“Stereotactic Radiosurgery for Tumors of the Brainstem, Thalamus, and Pineal Region”). Several commercially available specialized radiation delivery systems have been developed to deliver SRS, including the Gamma Knife (Elekta) and the CyberKnife (Accuray). The Gamma Knife uses a hemispheric distribution of cobalt-60 sources that are precisely coordinated to converge at the target. Patients wear a metal collimator helmet when receiving treatment with the Gamma Knife. The CyberKnife uses radiation generated from a small linac with a robotic arm that allows the radiation to be delivered to the target from any direction. Patients wear a mask for head immobilization, but the CyberKnife also incorporates skull-base tracking methods to account for any movement of the target during treatment.

Indications for Standard Fractionated EBRT versus SRS The choice of standard fractionated EBRT versus SRS depends on a balance between safety and convenience. Fractionating the

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total dose into multiple low doses per fraction treatment affords greater safety and a wider therapeutic window with which to deliver a sufficient dose to the tumor while sparing nearby critical organs. SRS can be much more convenient than EBRT, but its use is limited by tumor target size and proximity to critical structures, which mandate careful patient selection. In general, standard fractioned EBRT is necessary for larger targets (>3 cm) and for targets that are near critical structures such as the brainstem, optic chiasm, and optic nerves. SRS can be used for smaller targets that are, in general, more than 5 to 10 mm away from critical structures.

Proton Beam Radiotherapy Given the importance of minimizing normal-tissue toxicity associated with radiation for CNS malignancies, there has been substantial interest in the last 50 years in developing proton beam radiotherapy. Protons are positively charged heavy particles that have an advantage over photon therapy because protons can deliver an equivalent dose to the target with a minimal exit dose  (i.e., the dose delivered to normal tissues beyond the target). Traditional photon beams or electron beams deposit most of their energy near the surface with a smaller dose in deeper tissues. Conversely, protons deposit a lower dose near the surface and leave most of their energy in the final millimeters of their trajectory. Tissues beyond the targeted tumor receive very little dose with proton beam therapy. The sharp localized dose is known as the Bragg peak. Compiling beams of successively lower energies and intensities creates a “spread-out Bragg peak” that is able to deliver the intended dose to a 3D target.5 Where it is available, proton therapy is a popular choice for the treatment of CNS malignancies, especially in pediatric populations (Fig. 21.26). Proton therapy has the dosimetric advantage of minimizing normal-tissue toxicity and the theoretical clinical advantages of minimizing risk of late neurocognitive and neuroendocrine deficits and second malignancies.7

emission computed tomography can be used to differentiate hypometabolic radionecrosis from hypermetabolic tumor progression.13 The risk of radionecrosis is less than 3% at a maximum dose of less than 60 Gy to the brain, but it increases to 5% with a maximum dose of 72 Gy and to 10% or greater with a maximum dose of 90 Gy.14 Particular attention is given to minimizing the risk of brainstem injury. The maximum dose to the brainstem should be kept at less than 54 to 64 Gy to keep the risk of brainstem neuropathy or necrosis at less than 5%.10,​14 If the volume of brainstem receiving 59 Gy or less is kept between 1 and 10 cm3, then the risk of neuropathy or necrosis is believed to be less than 5%.14 The risk of radiation-associated spinal cord myelopathy is estimated at 0.2% for a maximum dose of 50 Gy, 6% for a maximum dose of 60 Gy, and 50% for a maximum dose of 69 Gy.12,​14 Thus, 45 Gy is considered a conservative maximum dose of radiation for the spinal cord. Radiation-induced optic neuropathy is estimated to occur with maximum doses of less than 55 Gy at a rate of less than 3%.11,​14 The risk of optic neuropathy increases to 3 to 7% with maximum doses of 55 to 60 Gy, and is estimated to be 7 to 20% at maximum doses of greater than 60 Gy. Hearing loss is estimated to occur with a frequency of less than 30% at a maximum dose of 45 Gy to the cochlea.9,​14 Given these toxicities, careful treatment planning is necessary to ensure safe radiation delivery. Finally, it is important to note that frequently radiation is given concurrently with radiosensitizing chemotherapy. Since chemotherapy increases the expected toxicity of radiation, safe dose limits are likely lower than when radiation is delivered without chemotherapy.

Dose Limitations: Organs at Risk The location of pineal, thalamic, and brainstem tumors implies that in nearly all cases critical normal tissues will receive considerable radiation dose. The complications associated with radiation treatment arise as a function of the toxicity induced by radiation to nearby structures. The Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) guidelines8 serve as an important benchmark for normaltissue toxicity by establishing important dose limits for the brain, optic nerves and optic chiasm, brainstem, spinal cord, and cochlea.9,​10,​11,​12 This chapter focuses on normal-tissue toxicity in the setting of standard fractionated EBRT because it is important to understand that a different set of dose constraints applies to SRS, and these constraints are discussed in Chapter 20. A feared complication of CNS radiation is radionecrosis. The risk for radionecrosis is highest in the first 2 years after standard fractionated radiation.13 Symptomatic patients may exhibit nonspecific symptoms such as seizures, intracranial hypertension, and focal neurologic deficit. Unfortunately, radionecrosis is difficult to distinguish from tumor progression on MRI, but some data show that positron emission tomography or single-photon

Fig. 21.2  Comparison of proton and photon dosimetry. (a) Sagittal and (b) axial images of proton radiation (top) and photon radiation (bottom) in a pediatric patient receiving craniospinal irradiation. Radiation doses in cGy are displayed to the left of each panel. Proton radiation provides coverage equal to that of photon radiation, while limiting the dose distal to the target. (Reproduced with permission from Cotter et al 2012.6)

21  Radiotherapy for Pineal, Thalamic, and Brainstem Tumors

■■ Pineal Tumors Overview The pineal gland is located on the posterior wall of the third ventricle in the quadrigeminal cistern, surrounded by the splenium of the corpus callosum superiorly, the thalamus anteriorly, and the quadrigeminal plate and vermis inferiorly.15 The parenchyma comprises pinealocytes and supportive astrocytes.16 Although Descartes viewed the pineal gland as the seat of the soul, we now know that pinealocytes secrete melatonin, which is a hormone involved in the circadian rhythm.17 Pineal tumors are rare and comprise 1% of primary CNS tumors.15 Patients with pineal tumors can present clinically with signs of increased intracranial pressure  (e.g., nausea, vomiting, and headache) secondary to hydrocephalus because pineal tumors can obstruct the sylvian aqueduct, preventing cerebrospinal  (CSF) flow from the third to the fourth ventricle. Parinaud syndrome  (i.e., inability to gaze upward, convergence-retraction nystagmus, and impaired pupillary reaction to light and accommodation) is a classic presentation of patients with pineal tumors compressing the superior 16 colliculus. Compression of the periaqueductal gray matter can lead to mydriasis, convergence spasm, and pupillary inequality. Endocrine abnormalities, particularly precocious puberty and diabetes insipidus, can develop in patients with pineal tumors.16,​17 Pineal tumors exhibit a wide histopathologic heterogeneity due to the variety of structures that become neoplastic in the pineal region.15,​16 Embryonal remnants give rise to germ cell tumors, the ependymal layer gives rise to ependymomas, and the choroid plexus gives rise to choroid plexus papillomas.15 Furthermore, the subcommissural organ of the third ventricle can give rise to papillary tumors of the pineal region  (PTPR), the velum interpositum can transform into a meningioma, and the deep venous system can produce vascular malformations. Germ cell tumors are the most common tumor involving the pineal gland  (35%), followed by glial tumors  (including ependymomas and PTPR, 32%), and tumors of pineal parenchymal cells (28%).15,​18

Germ Cell Tumors Germ cell tumors typically affect adolescents and account for 3 to 5% of childhood brain tumors.19 These tumors typically occur in the pineal gland or suprasellar region. There is a male predilection for pineal gland tumors (5:1), whereas suprasellar tumors occur at equal frequency in males and females. Among germ cell tumors, 10% are bifocal. Germ cell tumors are divided into two prognostic histologic groups: germinomas, which have the most favorable prognosis, and nongerminomatous germ cell tumors  (NGGCTs), which have a less favorable prognosis.19 It is important to differentiate between pure germinomas and NGGCTs because this distinction has a profound impact on prognosis and treatment recommendations. Patients with a new diagnosis of a germ cell tumor should receive complete staging with contrast-enhanced MRI of the brain and spine, serum and CSF beta-human chorionic gonadotropin and alpha-fetoprotein tests, and CSF cytology. CSF should be obtained by lumbar puncture if this can be safely performed.

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Germinomas Radiotherapy is a standard component of care for patients with pure germinomas.16,​20 Historically, germinomas were treated with craniospinal irradiation  (CSI) alone.19 CSI involves treating the entire brain and spinal column to 18 to 36 Gy, which is then followed by a boost to the primary tumor to 50 to 54 Gy (Fig. 21.3). Durable control can be achieved with CSI (> 90%)21; however, CSI is associated with significant long-term neurocognitive and neuroendocrine adverse effects.19 MAKEI 83/86/89 was a prospective, nonrandomized study undertaken to investigate dose reduction in 60 patients with germinomas.22 In this study, CSI to 30 Gy with a 15-Gy boost was compared with CSI to 36 Gy with a 14-Gy boost. Complete remission (CR) was achieved in all patients, and the 5-year relapse-free survival was 91% at a mean follow-up of 59 months. For most patients with localized germinomas, wholeventricular system radiotherapy (WVRT) has replaced the use of CSI (Fig. 21.4). Rogers et al23 pooled outcomes from a large series of 788 germinoma patients compiled from 20 studies and found that relapse rates increased with smaller radiation volumes: 4% after CSI, 8% after whole-brain radiotherapy (WBRT) or WVRT, and 23% after focal treatment alone. Isolated spinal relapse was not different between CSI and WBRT/WVRT groups (1.2% vs 2.9%) but was significantly higher in the limited field/focal radiation group at 11%. Therefore, delivery of radiation to the whole ventricular system followed by a boost to the tumor bed has replaced CSI for localized germinomas.19 In the SFOP (Société Française d'Oncologie Pédiatrique) analysis of pattern of failure and outcome of 60 patients with nonmetastatic germinomas treated with chemotherapy and limited-field radiation, 16% of the cohort developed intraventricular relapse, illustrating the importance of utilizing WVRT in the initial treatment of localized germinoma.24 WVRT is necessary given the propensity of germinomas to spread along the ventricles. Proton therapy can be used in WVRT to reduce radiation of healthy tissues without compromising dose to the target compared with photon radiation given via 3D-CRT or IMRT modalities.19 To reduce the late adverse effects of radiotherapy for localized germinomas, pediatric oncologists favor the use of chemotherapy (most commonly carboplatin-etoposide for two to four cycles) followed by reduced dose/volume radiation.25 The most standard regimen for localized germinomas is chemotherapy followed by 21 Gy to the whole ventricles, followed by a boost to the tumor to a total dose of at least 30 Gy in 1.5-Gy fractions. The ongoing Children’s Oncology Group (COG) trial (ACNS1123) is investigating the safety of reducing the total radiation dose to 18 Gy to the whole ventricles, with a 12-Gy boost to the tumor in 123 patients with localized germinomas who exhibit a complete or partial response to four cycles of induction chemotherapy with carboplatin and etoposide. CSI is given only to patients with CSF-positive disease or metastatic disease. It is important to note that bifocal disease is considered to be localized disease.

Nongerminomatous Germ Cell Tumors NGGCTs are less common than germinomas and the prognosis is worse. The current favored treatment for NGGCTs includes platinum-based chemotherapy, CSI, and surgery if necessary.

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Fig. 21.4  (a) Axial and (b) sagittal computed tomograms showing a whole-ventricular system proton treatment plan for a patient with a suprasellar germ cell tumor. She received whole-ventricular system irradiation to 21 Gy with a boost of 15 Gy. The isodose lines (from outermost to innermost) that are shown are 10 GyE (orange), 15 GyE (blue), and 20 GyE (yellow). The pink line indicates the planning target volume, and the green line indicates the clinical target volume.

Fig. 21.3  Sagittal computed tomogram showing a proton treatment plan for a patient with a pineal nongerminomatous germ cell tumor who received craniospinal irradiation and a boost to the pineal and suprasellar regions. Treatment fields are shown with isodose lines (from outermost to innermost) of 10 GyE (orange), 15 GyE (blue), 26 GyE (red), 45 GyE (pink), 54 GyE (yellow), and 55.8 GyE (maroon).

In the United States and Europe, diagnosis is often made without biopsy based on elevated serum and CSF markers. It is rare to perform surgery upfront, but surgery is advised for patients

who do not have a complete response to induction chemotherapy. Series describing outcomes associated with radiation alone  (CSI plus a boost) report unsatisfactory rates of overall survival for NGGCT patients.26 The COG ACNS0122 trial was a phase II trial designed to assess the response rates and survival after neoadjuvant chemotherapy  (six cycles of carboplatin-etoposide alternating with ifos­famideetoposide) with or without second-look surgery before CSI in children with NGGCTs.27 The outcome data of 102 patients enrolled in ACNS0122 are very promising for patients who, after induction chemotherapy, achieved CR, which was defined as complete radiographic and tumor marker response, or partial remission  (PR), which was defined as more than a 65% reduction in measurable disease radiographically and normalization of tumor markers. Overall, induction chemotherapy produced an objective response rate of 69% (CR or PR) in the evaluable patients. Of the 15 patients who underwent second-look surgery after induction therapy, only 2 (13%) had residual NGGCTs. Nine patients had teratomas, six of which were mature and three of which were malignant. Patients proceeded to 36 Gy CSI followed by a tumor bed boost for a total dose of 54 Gy. The median follow-up time for the patients without an event was 5.1 years; 5-year event-free survival and overall survival were 84% and 93%, respectively. Patients who did not achieve CR or PR were recommended to undergo consolidation chemotherapy with thiotepa and etoposide followed by peripheral blood stem cell rescue and then CSI with tumor bed boost. The encouraging results of this study and efficacy of this chemotherapy regimen led to the use of the same chemotherapeutic regimen in the ongoing COG ACNS1123 (NCT01602666), in an attempt to maintain a relevant comparison group. As noted above, this trial is a phase II trial of response-based radiotherapy for patients with localized tumors. Patients need to achieve a CR either by chemotherapy alone or by chemotherapy and second-look surgery confirming mature teratoma, scarring, or fibrosis to receive radiation to the whole ventricle plus a tumor boost instead of CSI. The dose for NGGCT patients is 30.6 Gy to the whole ventricle followed by an involved field boost of 23.4 Gy for a total dose of 54 Gy. Results from this trial may influence practice patterns in the United States for children with localized NGGCTs who have an excellent response to chemotherapy.

21  Radiotherapy for Pineal, Thalamic, and Brainstem Tumors Thus, currently the preferred approach for NGGCTs is six cycles of chemotherapy  (carboplatin-etoposide alternating with ifosfamide-etoposide), followed by CSI to a dose of 36 Gy, followed by a boost to the primary tumor bed plus a margin  (involved field) to 54 Gy. Results from the ongoing COG trial  (ACNS1123) investigating the safety of delivering WVRT rather than CSI in 125 patients with NGGCTs who exhibit a good response to induction chemotherapy may allow a shift away from CSI in this patient population.

Pineal Parenchymal Tumors Pineal parenchymal tumors are a group of related tumors arising as primary neoplasms of the pineal gland. They are classified as pineocytomas  (World Health Organization [WHO] grade II), pineal parenchymal tumors of intermediate differentiation (WHO grade II or III), and pineoblastomas (WHO grade IV).

Pineocytomas Pineocytomas are well-differentiated low-grade tumors (WHO grade II) that have a lobular structure resembling the normal pineal gland and that display characteristic rosettes.18 Given the rarity of pineocytomas, the available data are limited to retrospective series.28,​29 Pineocytomas have the most favorable prognosis of all pineal tumors; the 5-year survival rate among patients with pineocytomas was 86% in one series that included nine patients with pineocytomas.29 The management strategy for a pineocytoma is generally extrapolated from those for WHO grade II gliomas. Occasionally, patients with indolent-appearing pineal tumors are followed up radiographically without therapy depending on their age, comorbidities, and goals of care. When therapy is required, the backbone is maximal safe resection. Postoperative radiotherapy is reserved for those with gross residual disease or those deemed to be at high risk for local failure.28 Radiation can be given as the definitive therapy for patients with asymptomatic and surgically inaccessible tumors. Patients undergoing adjuvant radiotherapy for pineocytomas should receive doses of 45 to 54 Gy in 1.8- to 2-Gy fractions.29 The radiation target consists of gross residual disease  (gross tumor volume), surfaces originally contacted by the preoperative tumor (clinical tumor volume), and a small margin of 1 to 5 mm for setup uncertainty (planning target volume). Minimal target expansion is required into surrounding parenchyma, as these tumors tend to be well circumscribed and displace rather than infiltrate surrounding tissue.

Pineal Parenchymal Tumors of Intermediate Differentiation Pineal parenchymal tumors of intermediate differentiation  (PPTIDs) were recognized in 2007 by the WHO as a new pineal parenchymal tumor of indeterminate malignancy (WHO grade II or III) between pineocytoma  (grade I) and pineoblastoma  (grade IV).30 PPTIDs are estimated to account for at least 20% of all pineal parenchymal tumors; PPTIDs can occur in patients of all ages  (peak incidence is in early adulthood) and occur slightly more often in women than men. A series of 30 patients with pineal parenchymal tumors included four patients with PPTIDs and described an overall improved local control with delivery of more than 50 Gy to the primary tumor.31 An improvement in tumor control was seen following administra-

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tion of CSI in tumors with seeding potential  (pineoblastomas, mixed tumors, and PPTIDs); however, this series was small. There are no well-established guidelines for the treatment of PPTIDs, and therefore their management extrapolates from guidelines for the management of both pineocytomas and pineoblastomas. Histologically favorable PPTIDs can be treated with involved-field radiotherapy to a total dose of 54 Gy in fractions of 1.8 to 2 Gy. Patients with histologically unfavorable disease and with evidence of dissemination along the craniospinal axis are often offered CSI to a dose of 23.4 to 36 Gy with concurrent chemotherapy, followed by an involved-field boost to a total dose of 54 to 55.8 Gy.

Pineoblastomas Pineoblastomas are high-grade (WHO grade IV) rapidly growing tumors that occur primarily in children and young adults. Microscopically, pineoblastomas are composed of dense sheets of blue cells and resemble medulloblastomas.18 Pineoblastomas have a strong tendency to invade into nearby structures and have high mitotic activity and necrosis. Generally speaking, patients with pineoblastomas should receive maximal safe resection, followed by adjuvant chemotherapy and CSI because of the tendency of the tumor to disseminate along the craniospinal axis. Trials attempting to eliminate or delay radiation in younger children have resulted in poorer outcomes.32,​33,​34 In the German experience of 11 children with pineoblastomas  (HIT-SKK87, HIT-SKK92, and HIT91), 5 of 6 children older than 3 years of age received immediate postoperative chemotherapy and CSI to 35.2 Gy with a 20-Gy local tumor boost.32 Five children younger than 3 years of age received postoperative chemotherapy until they were eligible for radiation (> 3 years of age or tumor progression). Five of the six older children experienced continuous CR with median overall survival of 7.9 years; all older children had M0 disease. In contrast, all five younger children died of progressive disease after a median survival of 0.9 years; the older children either had M1 disease or postoperative residual tumor. The authors concluded that postoperative chemoradiation is feasible and effective for patients older than 3 years and that more intensified regimens are necessary for children younger than 3 years. The Children’s Cancer Group 921 trial included 25 children with pineoblastomas.33 Eight infants younger than 18 months of age received chemotherapy  (8-in-1) without radiation. The remaining 17 patients older than 18 months were treated with CSI and randomized to receive vincristine/lomustine/prednisone or the 8-in-1 chemotherapy. All infants developed progressive disease and had a median progression-free survival of 4 months. Older children had a 3-year progression-free survival of 61%. The progression-free survival of the older pineoblastoma cohort was longer than that among children with other supratentorial primitive neuroectodermal tumors. Therefore, chemotherapy alone (8-in-1) seems ineffective for infants, and CSI plus chemotherapy is promising for older children. The Pediatric Oncology Group 1 was a prospective trial of 198 children with malignant brain tumors, which included a subset of 11 infants younger than 3 years old (8 of whom were younger than 1 year) with pineoblastomas.34 These infants underwent partial surgical resection and chemotherapy. Despite chemotherapy, none of the 11 patients experienced improvement, and survival ranged between 4 and 13 months. Thus, efforts to eliminate the use of radiation in treating young children with pineoblastomas have unacceptable outcomes.

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Pineoblastomas are rare in adults. The largest series of patients, from the Brain Tumor Registry of Japan, comprises 34 patients.35 In this series, which included 22 men, the median age was 35 years. Five patients underwent gross total resection, and 29 patients received CSI with a median dose of 50 Gy. The median overall survival was 2.2 years. CSI greater than 40 Gy and gross total resection were associated with improved survival.35 In a retrospective series of 11 adult patients with pineoblastoma from the University of California, San Francisco, the median age was 36 years.36 One patient underwent gross total resection, 10 of 11 received CSI of 24 to 45 Gy with a tumor boost to 54 to 59.4 Gy, and 7 received chemotherapy. For five patients with M+ disease, median progression-free survival was 10 months, and overall survival was 2.5 years. All five patients with M0 disease were alive at 2.2 years of follow-up. Thus, M0 patients can do well after surgery with adjuvant CSI. The current standard of care for both children and adults is surgery, followed by chemotherapy and CSI.

Papillary Tumors of the Pineal Region PTPRs are rare and were first classified as distinct entities by the 2007 WHO Classification of Brain Tumors.37 The mean age at presentation is 31 years, and there is a slight female predominance. PTPRs are usually well-circumscribed, contrast-enhancing, T2-hyperintense masses on MRI. A prominent histologic feature is papillary architecture. PTPRs exhibit frequent local recurrence but only occasional spinal dissemination.37 Patients with PTPRs have favorable survival rates, but the risk is high for local recurrence after surgical resection. Given the tendency for PTPRs to recur locally, many institutions recommend adjuvant radiotherapy after surgical resection, but there is no consensus regarding the dose or treatment volume because of the rarity of this disease.38,​39 In a large retrospective case series of 44 patients with histopathologically confirmed PTPRs from multiple centers across Europe and Japan, 64% received radiation and 18% received chemotherapy after surgery.38 At a median follow-up of 63 months, 73% were alive, and neither chemotherapy nor radiation influenced overall survival or disease-free survival, but the number of patients treated was low. In another case series of eight patients treated at MD Anderson Cancer Center, five underwent adjuvant radiotherapy.39 At 5-year follow-up, progression-free survival among patients receiving adjuvant radiotherapy was 64%.

■■ Brainstem and Thalamic Tumors The thalamus is a midline structure that serves the critical function of relaying sensory and motor information from the body to the cerebral cortex. The medial surfaces of the two halves of the thalamus comprise the upper lateral wall of the third ventricle, ,and the two halves are connected via the interthalamic adhesion. Axons carrying sensory and motor information synapse on neurons in thalamic nuclei, which then project via thalamocortical radiations to the cerebral cortex. The only sensory system that does not project to the thalamus is the olfactory bulb. Brainstem and thalamic tumors consist primarily of high- and low-grade gliomas and account for approximately 1 to 1.5% of all brain tumors.40,​41 Management of these gliomas is similar to management of gliomas elsewhere in the brain and depends upon the WHO grade. Patients with tumors of the thalamus may present with subtle contralateral hemisensory or motor impairment and cognitive or

gait disturbance.41 Tumors of the hypothalamus may be associated with appetite or emotional disturbance or visual field deficits because of the proximity to the optic tract and chiasm. Patients with thalamic tumors may present with increased intracranial pressure and hydrocephalus. Patients with brainstem tumors typically present with posterior fossa dysfunction (ataxia, cranial neuropathies, diplopia, nausea, and vertigo).42 Compression of the fourth ventricle may also lead to hydrocephalus.

Brainstem Gliomas In children, brainstem gliomas comprise approximately 10% of brain tumors and are classified into three separate categories: diffuse intrinsic pontine gliomas  (DIPGs), low-grade gliomas with a posterior contrast-enhancing exophytic component, and focal tectal gliomas.43 In adults, brainstem gliomas account for less than 2% of gliomas, and survival has been observed to be favorable compared with that of children with pediatric brainstem gliomas.

Diffuse Intrinsic Pontine Gliomas and Histone H3 Tumors Patients with DIPGs have the worst prognosis among all patients with any type of brain tumor, with a median survival of less than 1 year.43 A DIPG exhibits a diffuse enlargement of the brainstem on MRI. Histone H3 is frequently mutated in pediatric patients with high-grade gliomas, and up to 78% of patients with DIPGs and 36% of those with nonbrainstem gliomas carry a mutation in the H3 gene.44,​45 Patients who harbor the K27M-H3.3 mutation have worse overall survival than patients with wild-type DIPGs.46 In one series that investigated 42 patients with DIPGs, the group with the H3.3 mutation contained patients who, at autopsy, had tumors that would be classified as WHO grade II on the basis of histologic findings, but they had a short survival, as expected with classic DIPG.46 Thus, mutational status of H3.3 is likely to be more clinically useful than histology and grade alone in predicting outcomes for these patients.44,​45,​46 Treatment for diffuse brainstem glioma consists of combination chemotherapy and radiation, as for a high-grade astrocytoma. It is common for patients with DIPGs to experience a clinical and radiographic response shortly after completing radiotherapy. However, within a period of 6 to 9 months, the patients inevitably experience tumor recurrence that is difficult to salvage and ultimately leads to an extremely poor prognosis. Several attempts have been made to intensify treatment with the hopes of improving outcomes. The Pediatric Oncology Group 9239 was a phase III study that randomized 132 children with DIPG to receive radiation with concurrent cisplatin as either hyperfractionated radiation (117 cGy twice daily to a total dose of 70.2 Gy) or standard radiation (180 cGy daily to a total dose of 54 Gy).47 The median time to disease progression and overall survival were not improved with the hyperfractionated regimen and outcomes were poor in both arms, with a 2-year overall survival rate of 7%. Therefore, the current standard of care consists of radiotherapy to a total dose of 54 Gy in 1.8-Gy fractions.

Dorsally Exophytic Gliomas The slow-growing brainstem gliomas typically arise at the cervicomedullary junction or from the floor of the fourth ventricle.43 These low-grade gliomas commonly have a posterior

21  Radiotherapy for Pineal, Thalamic, and Brainstem Tumors contrast-enhancing exophytic component and are amenable to surgical resection. The median survival is greater than 5 years. Management of dorsally exophytic gliomas with radiotherapy is extrapolated from that for comparable gliomas located supratentorially. Radiotherapy to 50.4 to 54 Gy in 1.8-Gy fractions can be offered to patients with gross, residual, or symptomatic tumors or to patients with tumors with an expected aggressive behavior. Some patients are candidates for surveillance depending on the aggressiveness of disease balanced with the patient’s competing risks.

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The course for focal tectal gliomas is indolent, and median survival is more than 10 years, with many patients experiencing decades of disease-free survival. Tectal gliomas are often initially managed with CSF diversion and subsequent observation or radiotherapy. Patients with tegmental gliomas and dorsal exophytic focal brainstem gliomas may undergo surgical resection with or without postoperative therapy. Medullary focal brainstem gliomas are often treated with radiation to a dose of 45 to 54 Gy in 1.8-Gy daily fractions. Children with low-grade gliomas experience excellent longterm progression-free survival, with rates of 80 to 90% at 10 years.48 In a single-institution retrospective series of 181 children with low-grade gliomas, gross total resection was associated with an improved freedom from progression and better overall survival.48 Adjuvant radiotherapy improved freedom from progression but not overall survival. Location of the tumor in the optic pathway and hypothalamus was associated with decreased freedom from progression but not with worse overall survival because of the success of salvage therapy. Nearly 20% of the cohort had neurofibromatosis type 1. Thus, immediate adjuvant radiotherapy may be avoided in favor of early salvage radiation in this population.48

a prospective, multinational trial that enrolled 19 children with ependymomas  (median age 20 months) to receive multiagent chemotherapy (five induction cycles followed by one consolidation cycle of myeloablative chemotherapy and autologous hematopoietic cell rescue) after surgery with the goal of reducing or eliminating the use of radiation postsurgery.52 All three patients with supratentorial ependymoma and residual disease after surgery exhibited a complete response to chemotherapy, but only one of six patients with infratentorial disease achieved CR, and the disease of three infratentorial patients progressed during chemotherapy. In the current COG protocol (ACNS0831), patients with ependymomas are undergoing maximal safe surgical resection; adjuvant therapy depends on the extent of resection, supratentorial versus infratentorial location, and histology (classic vs anaplastic). Patients are undergoing observation only if they have a classichistology supratentorial tumor after a microscopic gross total resection. Patients with anaplastic histology, an infratentorial tumor location, or near-total resection are randomized to receive either radiotherapy alone or radiotherapy followed by four cycles of chemotherapy. Patients who received a subtotal resection then receive induction chemotherapy and further treatment based on their response to induction chemotherapy. For the radiation technique, a dose of 54 to 59.4 Gy is given in 1.8-Gy daily fractions. Because ependymomas can intercalate along ependymal surfaces  (e.g., foramen magnum, foramen of Luschka, foramen of Magendie), a 1-cm margin is given along these surfaces. Ependymomas have a low propensity to invade brain parenchyma and therefore require a minimal target expansion in these directions. CSI is not recommended for localized ependymoma. CSI may be considered in patients with disseminated disease along the neuraxis  (approximately 10% of cases). However, even in these cases, CSI may be omitted because the maximal safe radiation dose to the entire spinal cord  (approximately 36 Gy) is thought to be insufficient for sterilization of cells of glial origin (i.e., unlike medulloblastomas).

■■ Ependymomas

■■ Cerebral Metastasis

Ependymomas are the third most common brain tumor in children and comprise 10% of brain tumors in children under the age of 14 years.49 The median age at diagnosis is 3 to 5 years, although these tumors can also arise in infants. Ependymomas originate from ependymal cells and can arise in any part of the ventricular system or spinal canal. The majority  (90%) arise in the brain  (one-third are supratentorial and two-thirds are infratentorial),49 and 10% are in the spine. Survival after treatment remains moderate, with an overall 5-year survival rate of approximately 45%49; most of these patients then live on as longterm survivors. The mainstay of treatment for ependymomas is maximal safe resection followed by adjuvant postoperative radiotherapy.49 The extent of surgical resection is one of the most important predictors of outcome. In a series of 80 children with ependymomas, survival at 5 years was significantly improved for patients who underwent complete surgical resection (75% vs 41%, p = 0.001).50 Postoperative radiation significantly improves 10-year local control following gross total resection of posterior fossa ependymomas (100% vs 50%, p = 0.018).51 The role for chemotherapy in the management of ependymoma is limited. Head Start III was

Brain metastases are the most common intracranial tumor. Approximately 10 to 20% of adult patients with cancer will develop brain metastases during the course of their illness.53,​54 Patients with brain metastases present with headache, cognitive dysfunction, focal neurologic deficits, and seizure. The most common primary cancers that give rise to brain metastases are lung cancer, breast cancer, and melanoma. Most cerebral metastases develop in the gray-white junction of the cerebral hemispheres (80%) or in the cerebellum (15%), but a subset can occur in the brainstem (5%). The incidence of brain metastases is increasing, likely as a result of improved systemic therapies with associated survival gains and increased use of MRI for screening in this population. Treatment options for patients with cerebral metastases include supportive care, surgery, WBRT, SRS, systemic therapies with CNS penetration, or a combination of these treatments. Corticosteroids provide symptomatic relief by reducing inflammation. Surgical resection is indicated for immediate symptomatic relief and pathologic confirmation, and it is indicated in patients with a single brain metastasis on the basis of randomized data.55 WBRT was historically used for patients

Tectal, Hypothalamus, and Pediatric Focal Brainstem Gliomas

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with multiple brain metastases, although in the modern era it is used much less frequently on the basis of the results of multiple randomized trials. WBRT decreases intracranial failure (new or recurring intracranial tumors) but is not associated with a survival benefit in patients treated with surgery for a single metastasis56 or in patients with one to four metastases treated with SRS.57,​58,​59 More recently, SRS has had an increasing role in treating brain metastases because of its favorable toxicity profile in select patients. When treating a metastasis in the brainstem with radiation, it is especially important to respect dose constraints for the brainstem and optic chiasm. Patients with metastases in midline structures may not be ideal candidates for SRS. Often, hypofractionated radiation is necessary for treating metastases in the brainstem. For single-fraction SRS treatments, the risk of toxicity to the brainstem and optic chiasm increases for doses greater than 12 Gy.10,​11,​14 However, experience is accumulating on single-fraction or hypofractionated radiotherapy to the brainstem for metastatic disease.60

arise within a part of the body that was previously irradiated within an expected time frame. Generally speaking, a secondary malignancy requires 10 to 20 years to develop after radiation. Young children are more sensitive to the effects of radiation than are middle-aged adults. The volume of tissue irradiated appears to be a more significant predictor of effects than the total dose of radiation, and patients can have genetic risk factors that increase their risk of experiencing adverse radiation effects.61 The Childhood Cancer Survivor Study retrospectively analyzed 14,000 survivors of childhood cancer diagnosed between 1970 and 1986 and identified 76 malignant neoplasms arising in 1,877 (4.1%) pediatric survivors of CNS malignancies at a median age of 16 years.62 Patients who receive radiation are monitored over time and treated for secondary malignancies, depending on the type, as they arise.

■■ Management of Acute and Late Radiation Effects

Radiotherapy is an important component in the management of tumors of the pineal gland, thalamus, and brainstem. Given the diversity of tumor histologies in these locations, the outcomes of radiotherapy as a component of multidisciplinary treatment are variable. The technical aspects for treating the pineal gland, thalamus, and brainstem share many commonalities with respect to immobilization, image guidance, and treatment planning. Moreover, they share a common set of guidelines for dose limits on organs at risk to minimize toxicity to critical nearby structures  (e.g., optic nerves, optic chiasm, brainstem, spinal cord). The therapeutic window between maximizing clinical outcome and minimizing toxicity can be improved by recent improvements in treatment planning, particle therapy, stereotactic immobilization, image guidance, and other advanced techniques.

Radiation is associated with both short-term (weeks to months) and long-term  (months to years) adverse effects. The composition of such adverse effects is related to the normal structures nearby that receive a clinically significant dose of radiation. With respect to pineal, thalamic, and brainstem tumors, the organs at risk include the brainstem, brain parenchyma, optic nerves, and pituitary gland. By using technological advances in radiation planning and delivery, clinicians can minimize the dose to surrounding normal structures to decrease short- and long-term toxicity. This section focuses on adverse radiation effects after standard fractionated  (1.8–2 Gy/fraction) EBRT; the adverse effects commonly seen with SRS radiation are discussed in Chapter 20.

Headache Patients who present with malignant brain lesions often experience headache as a consequence of the disease process. Radiation may cause or exacerbate a headache by inducing transient inflammation or swelling. However, a short course of corticosteroids can be effective in decreasing swelling and improving headache for the duration of this early response.

Visual Disturbance Please see the preceding section on dose limitations for details on visual disturbance. The possibility of this adverse effect mandates careful treatment planning.

Radionecrosis When standard fractionation is used, radionecrosis involving brain parenchyma is relatively rare  ( 60% of patients with pineal GCTs have a 90% 10-year survival with treatment

Embryonal carcinoma

Poor prognosis

hCG + AFP

Chemotherapy ± resection of residual tumor, then radiation

Yolk sac tumor

Poor prognosis

AFP

Chemotherapy ± resection of residual tumor, then radiation

Choriocarcinoma

Poor prognosis

hCG

Chemotherapy ± resection of residual tumor, then radiation

Craniospinal irradiation + radiation boost to tumor bed or cranial radiation + systemic chemotherapy

Teratoma Mature

Excellent prognosis

Immature

Good prognosis

hCG

Surgical resection ± chemoradiation

Malignant

Poor prognosis

AFP, CEA

Surgical resection ± chemoradiation

Variable prognosis (depends on mixed components)

Variable

Chemotherapy ± resection of residual tumor, then radiation

Mixed GCT

Surgical resection

Abbreviations: AFP, alpha-fetoprotein; CEA, carcinoembryonic antigen; GCT, germ cell tumor; hCG, human chorionic gonadotropin; PLAP, placental alkaline phosphatase.

Germinomas are radiosensitive, with long-term control rates approaching 90%.57 The current standard of care is craniospinal irradiation with an additional boost to the tumor.57,​58 More recently, neoadjuvant chemotherapy has been used as a radiation-sparing strategy.58 Although complete tumor remission and long-term survival have been observed with chemotherapy alone, the relatively high rate of recurrence makes the use of such an approach questionable outside of clinical trials.55,​59 Nongerminomatous tumors (i.e., embryonal carcinomas, choriocarcinomas, and yolk sac tumors) are much less sensitive to radiation and carry a much less favorable prognosis.60 Upfront surgical resection has not proved to be of value other than to confirm a histologic diagnosis. Chemotherapy alone is effective in less than one-third of patients.61 Thus, an acceptable practice for these tumors is to start with upfront chemotherapy, followed by radiation or surgery. Platinum-based regimens are most commonly used to treat treat these tumors. After completion of chemotherapy, patients should be radiologically evaluated. If no response or a partial response to chemotherapy is obtained, then surgery should be considered before starting radiation. Second-look surgeries can also be used to remove nonresponsive components of mixed tumors and, in the case of growing teratoma syndrome, to remove a tumor that is growing despite initial response and normalization of tumor markers.62,​63 If a complete response has been attained, then radiation can be administered, with the dose and extent of radiation dependent on the initial evaluation of tumor spread. Mature teratomas can be radiologically identified and are usually not associated with elevated serum or CSF tumor markers. Characteristic findings on magnetic resonance imaging include multiloculated lesions with mixed signal intensity and areas of high signal intensity on T1-weighted images because of the lipid component. Calcification can also be seen as areas of low signal intensity on T1-weighted and T2-weighted images, although computed tomography is more useful in demonstrating calcium. Mature teratomas are benign tumors; the 10-year progression-free survival approaches 100% after complete resection.60 The results with immature teratomas are not as good,

although they still compare favorably with those of other GCTs. Malignant teratomas are more homogeneous, with less of a cystic component.3 They are aggressive, with a 50% 3-year survival rate, and thus should be treated aggressively with radiation and chemotherapy.60

■■ Brainstem Gliomas Despite their low-grade histologic appearance, brainstem gliomas involving the pons behave aggressively and are associated with a poor prognosis (with the exception of tectal gliomas). They are common in children and young adults, and a better prognosis is reported when they are diagnosed in patients at more advanced ages.64,​65 Commonly used classifications are based on anatomical location and the presence of exophytic growth. Grading is not typically used in this condition.10,​66 In general, radiotherapy is the main treatment for brainstem gliomas; surgery is reserved for limited indications because of its high risk, and chemotherapy is given only as a second-line treatment. Tectal gliomas represent 5% of all brainstem gliomas.17 In contrast to other brainstem gliomas, they demonstrate a more benign course.66 The most common presentation of patients with tectal gliomas is increased intracranial pressure caused by obstructive hydrocephalus. However, these tumors are most frequently detected serendipitously. Progression is observed in less than onethird of cases. Biopsy is usually not needed, and tumors are followed by serial imaging. In cases of tumor progression, surgical resection can be performed to remove either the exophytic components or the suspected pilocytic astrocytomas when there is a clear surgical plane.67,​68 Radiotherapy is the most frequently used adjuvant treatment in cases of progression, with 25% of cases sustaining tumor-free progression at 4-year follow-up.69 Diffuse intrinsic pontine glioma  (DIPG) is the most common brainstem glioma. It often occurs in young children and is associated with a poor prognosis. The standard current treatment

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V  Comprehensive Management of Tumors of the Brainstem, Thalamus, and Pineal Region

is conventional radiotherapy, which is only transiently helpful.70 Chemotherapy is at best marginally effective, and its use should be carefully considered in light of its potential toxicity.70,​71 The 2016 WHO CNS classification added a new entity of Diffuse midline glioma, H3 K27M–mutant (WHO grade IV).37 The high grade was assigned because of the malignant behavior observed in this specific group, regardless of the histologic features. This molecular diagnosis, made on the basis of K27M mutations in the histone

H3 gene H3F3A, has been advocated to replace DIPG. However, it has been suggested that DIPG in adults is a different pathologic entity that lacks the K27M mutation.64,​65,​72,​73 In addition to the use of radiation, the antiangiogenic agent bevacizumab can be used to produce effective palliation. We have used this agent in treating 11 patients with brainstem gliomas and used it as part of the initial treatment in two patients because of symptomatic mass effect  (Fig. 22.3). On the first follow-up, four Fig. 22.3  Illustrative case. A 28-year-old man presented with facial twitching and blurry vision. (a) Preoperative axial T1-weighted (left), T1-weighted with contrast (middle), and T2-weighted (right) magnetic resonance imaging (MRI) demonstrated a nonenhancing diffuse pontine lesion. A stereotactic biopsy was consistent with a low-grade diffuse astrocytoma, World Health Organization grade II. The patient received focal conformal radiation to the brainstem lesion  (54 Gy over 30 days). (b) At 9-month follow-up after radiation treatment, MRI showed partial response. The patient was clinically stable, and a decision was made to continue observation. (c) At 40-month followup after radiation, MRIs showed progressive disease; temozolomide was started and produced a partial response  (not shown). The patient completed 12 cycles of monthly temozolomide. At 60-month follow-up after radiation, MRI showed progressive disease (not shown). The patient was symptomatic, and he was started on lomustine and bevacizumab  (7.5 mg/kg every 2 weeks). (d) MRI obtained at 3 months after initiation of lomustine and bevacizumab (BEV) showed a partial response. The patient received four cycles of lomustine and bevacizumab, and then was treated with bevacizumab alone. After 10 months of single-agent treatment with bevacizumab, the bevacizumab was stopped because of stable clinical and radiologic disease. (e) MRI obtained at 4 months after bevacizumab was halted demonstrated progressive disease; bevacizumab alone was restarted with no significant clinical or radiologic response. (Case presented in oral presentation: “Bevacizumab Utility in Adult Diffuse, Brainstem Gliomas.” SANS 11th Annual Meeting, Riyadh, Kingdom of Saudi Arabia, 2017.)

22  Neuro-oncologic Considerations for Pineal, Thalamic, and Brainstem Tumors patients had a partial response, four had stable disease, and three had progressive disease. The overall survival after initiation of bevacizumab was 8 months, indicating a potential benefit for this agent. Dorsally exophytic gliomas that involve the medulla, including WHO grade I and grade II astrocytomas and subependymomas, are less common than DIPGs and are associated with a better prognosis.74,​75 Surgical resection is recommended because total resection, if feasible, can be curative. Even in cases with incomplete resection, we recommend observation until progressive disease is noted, at which time reoperation or irradiation can be considered.76 The location of many of these tumors within difficult-toaccess areas often raises the question of whether to obtain tissue confirmation. Until recently, avoiding surgical biopsy was advocated in the presence of clear radiologic diagnosis, as in the case of pontine gliomas,77,​78 on the basis of a reported surgical morbidity of more than 10% and a reported mortality of 0.9%.6,​79,​80 However, this approach should be reevaluated, as some reports suggest a substantial discrepancy between radiologic and histologic diagnosis, which can be as great as 39% among cases of brainstem lesions.6,​81,​82 In our practice, we encourage tissue sampling in addition to obtaining a histologic diagnosis because molecular marker analysis can guide treatment.

■■ Conclusions Tumors involving the thalamus, pineal gland, and brainstem represent a major challenge to the patient and the treatment team. The difficulties start when the patient presents for relief of symptoms and to obtain a diagnosis. In many scenarios, treatment will be determined on the basis of clinical, radiologic, or biological markers with no histopathologic diagnosis. The wide variety of tumors encountered in these locations and the broad spectrum of treatment strategies can be problematic. These patients should therefore be treated with a multidisciplinary approach to establish treatment protocols and improve the overall outcome.83

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53. Motiei-Langroudi R, Sadeghian H, Soleimani MM, Seddighi AS, Shahzadi S. Treatment results for pineal region tumors: role of stereotactic biopsy plus adjuvant therapy vs. open resection. Turk Neurosurg 2016;26(3):336–340 54. Al-Hussaini M, Sultan I, Abuirmileh N, Jaradat I, Qaddoumi I. Pineal gland tumors: experience from the SEER database. J Neurooncol 2009;94(3):351–358 55. Chen YW, Huang PI, Ho DM, et al. Change in treatment strategy for intracranial germinoma: long-term follow-up experience at a single institute. Cancer 2012;118(10):2752–2762 56. Mufti ST, Jamal A. Primary intracranial germ cell tumors. Asian J Neurosurg 2012;7(4):197–202 57. Reddy MP, Saad AF, Doughty KE, et al. Intracranial germinoma. Proc (Bayl Univ Med Cent) 2015;28(1):43–45 58. Kenjo M, Yamasaki F, Takayasu T, et al. Results of sequential chemoradiotherapy for intracranial germinoma. Jpn J Radiol 2015;33(6):336–343 59. Farng KT, Chang KP, Wong TT, Guo WY, Ho DM, Hu WL. Pediatric intracranial germinoma treated with chemotherapy alone. Zhonghua Yi Xue Za Zhi (Taipei) 1999;62(12):859–866 60. Kyritsis AP. Management of primary intracranial germ cell tumors. J Neurooncol 2010;96(2):143–149 61. Kellie SJ, Boyce H, Dunkel IJ, et al. Primary chemotherapy for intracranial nongerminomatous germ cell tumors: results of the second international CNS germ cell study group protocol. J Clin Oncol 2004;22(5):846–853 62. Bromberg JE, Baumert BG, de Vos F, et al. Primary intracranial germ-cell tumors in adults: a practical review. J Neurooncol 2013;113(2):175–183 63. Ogiwara H, Kiyotani C, Terashima K, Morota N. Second-look surgery for intracranial germ cell tumors. Neurosurgery 2015;76(6):658–661, discussion 661–662

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66. Grimm SA, Chamberlain MC. Brainstem glioma: a review. Curr Neurol Neurosci Rep 2013;13(5):346

68. Bayoumi Y, Sabbagh AJ, Mohamed R, et al. Clinicopathological features and treatment outcomes of brain stem gliomas in Saudi population. World J Clin Oncol 2014;5(5):1060–1067 69. Pollack IF, Pang D, Albright AL. The long-term outcome in children with late-onset aqueductal stenosis resulting from benign intrinsic tectal tumors. J Neurosurg 1994;80(4):681–688 70. Hargrave D, Bartels U, Bouffet E. Diffuse brainstem glioma in children: critical review of clinical trials. Lancet Oncol 2006;7(3):241–248

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50. Watanabe T, Mizowaki T, Arakawa Y, et al. Pineal parenchymal tumor of intermediate differentiation: treatment outcomes of five cases. Mol Clin Oncol 2014;2(2):197–202 51. Gener MA, Conger AR, Van Gompel J, et al. Clinical, pathological, and surgical outcomes for adult pineoblastomas. World Neurosurg 2015;84(6):1816–1824 52. Raghuram CP, Moreno L, Zacharoulis S. Is there a role for high dose chemotherapy with hematopoietic stem cell rescue in patients with relapsed supratentorial PNET? J Neurooncol 2012;106(3):441–447

73. Kesari S, Kim RS, Markos V, Drappatz J, Wen PY, Pruitt AA. Prognostic factors in adult brainstem gliomas: a multicenter, retrospective analysis of 101 cases. J Neurooncol 2008;88(2):175–183 74. Pollack IF, Hoffman HJ, Humphreys RP, Becker L. The long-term outcome after surgical treatment of dorsally exophytic brain-stem gliomas. J Neurosurg 1993;78(6):859–863 75. Ghodsi M, Mortazavi A, Shahjouei S, et al. Exophytic glioma of the medulla: presentation, management and outcome. Pediatr Neurosurg 2013;49(4):195–201 76. Stroink AR, Hoffman HJ, Hendrick EB, Humphreys RP, Davidson G. Transependymal benign dorsally exophytic brain stem gliomas in

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81. Massager N, David P, Goldman S, et al. Combined magnetic resonance imaging- and positron emission tomography-guided stereotactic biopsy in brainstem mass lesions: diagnostic yield in a series of 30 patients. J Neurosurg 2000;93(6):951–957 82. Manoj N, Arivazhagan A, Bhat DI, et al. Stereotactic biopsy of brainstem lesions: Techniques, efficacy, safety, and disease variation between adults and children: a single institutional series and review. J Neurosci Rural Pract 2014;5(1):32–39 83. El Saghir NS, Keating NL, Carlson RW, Khoury KE, Fallowfield L. Tumor boards: optimizing the structure and improving efficiency of multidisciplinary management of patients with cancer worldwide. Am Soc Clin Oncol Educ Book 2014:e461–e466

Section VI Comprehensive Management of Vascular Pathology of the Brainstem and Thalamus

23 Brainstem Ischemia, Stroke, and Endovascular Revascularization of the Posterior Circulation

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24 Microsurgical Embolectomy for Emergency Revascularization of the Brainstem

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VI 25 Brainstem and Thalamic Intraparenchymal Hemorrhage

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26 Surgical Management of Posterior Circulation Aneurysms

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27 Endovascular Management of Aneurysms of the Posterior Circulation  383 28 Surgical Management of Thalamic and Brainstem Arteriovenous Malformations

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29 Endovascular Management of Brainstem and Thalamic Arteriovenous Malformations

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30  S  urgery for Thalamic and Brainstem Cavernous Malformations

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31 Revascularization of the Brainstem

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32 Stereotactic Radiosurgery for Arteriovenous Malformations of the Basal Ganglia, Thalamus, and Brainstem

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23

Brainstem Ischemia, Stroke, and Endovascular Revascularization of the Posterior Circulation Stephan A. Munich, Jason Davies, Hussain Shallwani, and Elad I. Levy

Abstract

Symptoms of brainstem ischemia and stroke range from vague complaints of dizziness to devastating locked-in syndrome and death. Endovascular revascularization strategies are proving to be safe and effective treatments for patients with these symptoms. Endovascular strategies can be applied in young and old patients, extra- and intracranially, and in chronic and acute settings. Given the difficult microsurgical access to the brainstem and posterior circulation, endovascular treatments are rapidly becoming the first-line treatment for patients with these pathologies. In this chapter, we review the symptoms, diagnostic work-up, and endovascular treatments of posterior circulation ischemia and stroke. We review the results of these treatments as well as the technical nuances of various techniques. This chapter provides a comprehensive review of brainstem ischemia, stroke, and endovascular revascularization of the posterior circulation. Keywords:  angioplasty, basilar artery, cerebral ischemia, endovascular, posterior circulation, stenosis, stent, stroke, vertebral artery, vertebrobasilar insufficiency

■■ Incidence, Epidemiology, and Natural History Ischemia of the posterior (vertebrobasilar [VB]) circulation may manifest as a wide range of clinical entities, from the subtle and vague symptoms of VB insufficiency to the devastating lockedin syndrome. The most common causes of posterior circulation ischemia are cardioembolism, large-vessel (i.e., vertebral and basilar arteries) atherosclerosis, and small-vessel (i.e., brainstem perforating arteries) disease.1 Strokes of the posterior circulation account for approximately 20% of all ischemic strokes and may be caused by atherosclerosis (of both large and small vessels), cardioembolism, subclavian steal, arterial dissection, VB dolichoectasia (VBD), or hemodynamic compromise. An understanding of the anatomy of the posterior circulation is critical to endovascular intervention for ischemic pathology. The normal diameter of the vertebral artery (VA) is 3 to 5 mm,2 whereas the mean diameter of the basilar artery (BA) is 3 mm at the level of the pons. Anatomical variations of the posterior circulation are not uncommon, but the affected patients often do not have symptoms attributable to these variations. Asymmetric VAs may occur in up to two-thirds of the population with true unilateral hypoplasia identified in up to 12% of the population.3 Although persistent carotid–VB anastomoses may predispose to posterior circulation aneurysm formation, they are infrequently associated with ischemia. A fetal posterior cerebral artery (PCA) is a common anatomical variant that occurs in up to 30% of the general population. Recognition of

this variant is critical to the appropriate work-up of posterior circulation territory strokes occurring in these cases. Evaluation of the anterior circulation is essential, because the PCA territory is supplied by the carotid artery rather than the BA. When a fetal PCA is present, even carotid stenosis may lead to an occipital stroke. Another anatomical variant of clinical significance to posterior fossa ischemia is the artery of Percheron. This single thalamic perforating artery arises from the proximal P1 PCA segment and supplies the rostral mesencephalon and paramedian bilateral thalami. Though bilateral thalamic infarcts may also be caused by venous thrombosis and basilar apex occlusion, there should be high suspicion for embolism to this vessel when bilateral thalamic infarcts are present. Atherosclerosis most commonly affects the VA at its origin or in its distal segments. Intracranial atherosclerosis of the vertebral or basilar arteries is most frequently seen in African, African-American, and East Asian populations, whereas extracranial VB atherosclerotic disease is more common in whites and is associated with peripheral vascular disease.4 Atherosclerotic disease may result in thromboembolism to the downstream vessels or hemodynamic compromise. Large-vessel atherosclerosis has been associated with 35% of posterior circulation strokes, whereas small-vessel disease has been associated with 13%.5 Posterior circulation lacunar infarcts result from diseases of the small penetrating arteries of the intracranial VAs, BAs, and PCAs. Lipohyalinosis of these small vessels can result in lacunar infarction, which is most common among individuals with chronic hypertension. In the New England Medical Center Posterior Circulation Registry, which included 407 consecutive patients with posterior circulation stroke, arterial embolism was determined to be the most common etiology, accounting for 40% of strokes.6 Cardiac origin was the likely source in 24% of these cases and resulted in primarily infarcts in distal territory (i.e., rostral to the superior cerebellar artery); patients with PCA, superior cerebellar artery, or basilar apex infarcts had a high likelihood of having a cardiac source. VBD is an uncommon but ominous cause of both hemorrhagic and ischemic posterior circulation strokes. Although VBD is often diagnosed incidentally, patients may present with signs or symptoms of posterior circulation ischemia. The natural history of VBD includes a 10.1% risk of posterior circulation transient ischemic attacks (TIAs).3 The etiology of ischemia in VBD may be multifactorial, including distal emboli, hemodynamic compromise, and occlusion of small vessels due to progressive anatomical derangement. Although the aforementioned most common causes of VB ischemia are associated with chronic diseases and therefore most often manifest in older adults, VA dissection is an important cause of posterior circulation stroke in young adults. Dissections of the VA most commonly occur in the V2 or V3 segments of that artery,7 extending intracranially in 10% of cases.8 The

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VI  Comprehensive Management of Vascular Pathology of the Brainstem and Thalamus

posterior inferior cerebellar artery territory is the most common site of ischemia associated with VA dissection.3 However, isolated neck pain without ischemic symptoms has been observed in up to 12% of patients. Given their location within the foramen transversarium, the VAs are particularly vulnerable to neck manipulation and trauma in which the head violently moves. Therefore, the presence of stroke associated with a history of trauma or neck manipulation should raise clinical suspicion for VA dissection. Compared with patients with anterior circulation dissections, those with VA dissections tend to be younger and more commonly have neck pain and associated subarachnoid hem­orrhage; making the diagnosis tended to take longer, likely because the symptoms are often not well recognized.9 Rarely, spontaneous dissections can occur, particularly in patients with underlying connective tissue disorders (such as Marfan syndrome).

■■ Clinical Presentation As with any vascular disorder, the symptoms of VB ischemia are attributable to dysfunction of the regions supplied by these arteries—the brainstem, cerebellum, inferior temporal lobe, occipital lobe, and thalamus. As is typical of anterior circulation stroke, the symptoms of posterior circulation stroke are maximal at onset. Symptoms of posterior circulation ischemia range from relatively benign, transient symptoms of dizziness to devastating, widespread paresis (locked-in syndrome). In the New England Medical Center Posterior Circulation Registry, the most frequent symptoms were dizziness (47%), unilateral limb weakness (41%), dysarthria (31%), headache (28%), and nausea or vomiting (27%).10 The signs of posterior circulation ischemia were found to be similarly vague and included gait ataxia (31%), limb ataxia (30%), dysarthria (28%), and nystagmus (24%). Logistic regression analysis revealed some correlation between clinical symptoms and infarct location (Table 23.110). The presence of any of these symptoms in

Table 23.1  Correlation of clinical symptoms and affected vascular territory according to logistic regression analysis in the New England Medical Center Posterior Circulation Registry*

Vascular territory

Symptom(s)

P value

Proximal (vertebral artery)

Dysphagia

0.004

Nausea or vomiting

0.002

Dizziness

0.047

Horner's syndrome

0.001

Unilateral limb weakness

0.001

Facial nerve (CN VII) deficit

0.02

Limb sensory deficit

0.001

Lethargy

0.001

Visual field loss

0.001

Middle (basilar artery trunk)

Distal (rostral to the superior cerebellar artery origin)

Abbreviation: CN, cranial nerve. *Modified from Searls et al 2012.10

combination with neck pain (especially in young patients) should prompt suspicion for VA dissection.11,​12 A VB TIA may precede a posterior circulation stroke in up to 25% of cases.3 This fact, combined with the frequency of many symptoms of posterior circulation ischemia (e.g., dizziness, headache, nausea), emphasizes the need to achieve an accurate diagnosis and initiate appropriate treatment. Some clinicians consider the presence of diplopia, vertically oriented binocular visual field loss, vertigo, ataxia, impaired sensorium, or crossedfindings  (ipsilateral cranial nerve deficit with contralateral long-tract signs) to be localizing signs requiring prompt evaluation of posterior circulation patency.3 However, clinical evaluation alone is insufficient. Flossmann et al13 evaluated the reliability of clinical diagnosis of patients with symptoms of VB TIA or minor stroke by having three independent clinicians, blinded to brain imaging, predict the most likely affected vascular territory. The sensitivity of correct identification of VB territory involvement ranged from 54.2% to 70.8%, whereas the specificity ranged from 84.4% to 91.7%. Those authors found only the presence of visual symptoms to improve the accuracy of diagnosis.

■■ Periprocedural Evaluation Maintenance of a high level of suspicion for posterior circulation ischemia is critical to the proper evaluation of these patients. Contrast-enhanced magnetic resonance imaging (MRI) remains the most sensitive imaging modality for the detection of acute ischemia. This holds particularly true for ischemia of the posterior circulation, where the skull base creates artifact that may obscure subtle early ischemic changes on computed tomography (CT).14 Given the vague localizing signs and symptoms of posterior fossa ischemic disease, it is essential to image the entire posterior circulation, from the aortic arch and VA origin through the intracranial circulation. Duplex ultrasound imaging has been a mainstay of evaluation and monitoring of the extracranial carotid arteries. It is utilized much less commonly for evaluation of the posterior circulation. However, recent studies have demonstrated its utility.15,​16 Doppler studies are noninvasive, inexpensive, and easily obtained. They can be used to identify reversed flow, which is characteristic of subclavian steal syndrome, as well as turbulence and waveform dampening, as seen in stenosis (Fig. 23.1).17 Peak systolic velocity has been shown to be a reliable indicator of stenosis, with a range of velocities of >108 to 140 cm/s indicative of > 50% stenosis.15 The sensitivity and specificity of Doppler studies for the detection of 50 to 99% VA stenosis are 70.2% and 93.4%, respectively.18 For the detection of complete VA occlusion, the sensitivity is 98.8% and the specificity is 90.8%. Limitations of ultrasound examination of the VAs include the inability to visualize the entire artery and in fact that it is highly operator dependent. The features of more sophisticated machines, including the addition of color imaging, have improved the identification of VA dissections. Although these dissections sometimes can be visualized, the VA ostia may be difficult to directly examine with ultrasound, and surrogates (e.g., damped distal waveforms) may be necessary to identify disease at this location. Disease of the intracranial VAs is also not visualized with ultrasound. Despite these limitations, Doppler examination of the VAs

23  Brainstem Ischemia, Stroke, and Endovascular Revascularization of the Posterior Circulation

Fig. 23.1  (a) Doppler waveform of vertebral artery  (VA) stenosis demonstrating increased peak systolic velocity at the site of the stenosis.

can be used as a screening tool and as a means to routinely monitor patients with VA stenosis, both before and after treatment. Both CT angiography (CTA) and magnetic resonance angiography (MRA) are used to examine the entire VB system, including the VA ostia and intracranial vasculature. CTA requires the injection of iodinated contrast material and may be prohibited in patients with contrast allergies or renal insufficiency. In one study, CTA was found to have a sensitivity of 100% and a specificity of 95.2% for detection of 50 to 99% stenosis of the VA origin.19 However, a more recent comparison of ultrasound, CTA, and MRA for the diagnosis of VA stenosis found the sensitivity and specificity of CTA for the diagnosis of > 50% stenosis to be 68% and 92%, respectively.18 These rates improved to 80% and 99%, respectively, for the diagnosis of higher-grade stenosis (e.g., > 70%). MRA can be performed with or without contrast enhancement (e.g., time-of-flight technique). The sensitivity and specificity of time-of-flight MRA for the diagnosis of 50 to 99% stenosis are reported to be 71.4% and 95.1%, respectively.18,​20,​21 The addition of contrast material improves these rates to 93.9% and 94.8%, respectively.18,​22,​23,​24 In a blinded evaluation by three radiologists comparing ultrasound, CTA, and MRA, MRA was found to have the highest sensitivity and specificity for the detection of 50 to 99% VA stenosis.25 However, CTA and MRA were found to be equivalent for the diagnosis of VA origin stenosis. Although noninvasive imaging techniques (e.g., ultrasound, CT/CTA, and MR/MRA) continue to improve, cerebral digital subtraction angiography (i.e., catheter-based angiography) remains the gold standard for imaging disease of the VB system. Imaging of the entire VB circulation with this modality allows various pathologic conditions responsible for posterior circulation ischemia (including atherosclerosis and dissection) to easily be distinguished. In addition, dynamic imaging can be obtained easily. This technique is particularly valuable for the evaluation of patients noting symptoms associated with specific positions (e.g., bow hunter’s syndrome, which is a rotational

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(b) Dampening of the Doppler waveform can be seen immediately distal to the site of the VA stenosis.

occlusion of the VA). However, given the invasive nature of digital subtraction angiography, the risk of iatrogenic stroke or vessel injury is higher than that of noninvasive methods. The symptoms of posterior circulation ischemia may be vague and nonlocalizing. Therefore, it may be difficult to determine whether a patient is truly symptomatic from VB stenosis. Radiographic evaluation for ischemia may aid in the decision-making and treatment algorithms. Demonstration of high-grade stenosis, particularly with identification of associated restricted diffusion (e.g., evidence of acute stroke) or signs of previous infarct, suggests that the patient is symptomatic and therefore requires treatment.

■■ Treatment Options Endovascular options are available for most causes of posterior circulation ischemia. Indications and endovascular options for treatment are presented according to the most common sites of disease.

Subclavian Artery Steal or Stenosis Subclavian steal results in retrograde blood flow down the ipsilateral VA due to proximal subclavian artery stenosis (Fig. 23.2). Few patients with subclavian steal are symptomatic and require treatment. In their series, Labropoulos et al26 reported that only 1.4% of 7,881 patients required treatment and that an elevated arm pressure differential (> 40 mm Hg) was more commonly associated with symptoms and the need for intervention. Open surgical techniques for subclavian steal syndrome include carotid-subclavian bypass. This technique has been demonstrated to be safe and effective, with patency rates of 95% at 10 years and very low rates of surgical

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Fig. 23.2  (a) Anteroposterior  (AP) digital subtraction angiogram  (DSA) showing 88.57% stenosis of the right side of the proximal subclavian artery with steal. (b) Poststenting AP DSA showing resolution of stenotic lesion and good flow through the subclavian artery.

morbidity.27 The development of endovascular techniques has changed the management of this disease, maintaining similar technical and clinical results with minimal risk and without the need for general anesthesia. Endovascular treatment for subclavian artery stenosis includes angioplasty with or without stenting. In 2005, de Vries et al28 reported their 10-year experience comprising 110 patients treated with angioplasty alone. They noted technical success in 93%, with permanent morbidity in 1%. Patency at 5 years was observed in 89% of patients, and recurrent stenosis was successfully treated with repeat angioplasty in 7% of patients. More recently, Wang et al29 reported their experience with stenting of proximal subclavian artery obstructions in 61 patients. Technical success was achieved in 95%, with 6.5% procedure-related morbidity. Stent patency was found to be 98% at 1 year, 93% at 2 years, and 82% at 5 years. Data surrounding angioplasty alone versus angioplasty with stenting for subclavian artery stenosis are limited to retrospective reviews and observational studies. A recent systematic review found stenting to be superior to angioplasty alone with higher patency at 1 year.30 However, because of the lack of randomized control trials, both a 2011 Cochrane review and its 2014 update found insufficient evidence to favor one treatment over another.31,​32

Vertebral Artery Origin Stenosis VA origin stenosis (or VA ostial stenosis) of at least 50% in severity is found in approximately 20% of patients presenting with symptoms of VB ischemia.6,​33,​34 Treatment of these lesions can include medical, open surgical, or endovascular techniques. Open surgical procedures include endarterectomy, bypass, and transposition. Given the relative difficulty of surgical access, open treatment for VA origin stenosis has been associated with a high rate of complications, including Horner’s syndrome, lymphatic injury, and laryngeal nerve injury.35,​36,​37 With the development of endovascular techniques, preferred treatment has shifted to a minimally invasive, endovascular approach. Endovascular techniques include angioplasty, stenting, or concomitant use of both strategies. The preferred endovascular treatment for vertebral ostial stenosis has been stenting (with or without angioplasty). Initial experiences often utilized coronary balloons and stents.38,​39,​40,​41 Although the authors of these reports noted a high rate of technical success and often good clinical outcomes, the radiographic results were mixed. An early report

of six patients from Fessler et al40 demonstrated adverse neurologic sequelae and stent patency in all cases at a mean follow-up of 8.4 months. Conversely, Albuquerque et al42 noted moderate to severe restenosis in 43% at a mean follow-up of 16.2 months. In 2011, Stayman et al43 performed a systematic review of stenting and angioplasty for symptomatic VA stenosis. Echoing early reports, their review of 980 patients demonstrated a technical success rate of 99.3%. The periprocedural stroke rate (i.e., stroke occurring within 30 days of the procedure) was 1.2% and additional VB TIAs occurred in 0.9%. Mean follow-up was 21 months, during which 1.3% of patients experienced a VB territory infarct and 6.5% developed recurrent posterior circulation TIAs. The rates of restenosis were noted to be 11.2% when drug-eluting stents were used and 30% when bare-metal stents were used. Favorable clinical outcomes and low rates of procedurerelated morbidity have jettisoned endovascular angioplasty and stenting to the forefront of treatment for VA ostial stenosis. The clinical significance of restenosis is not clear. In part, this may be due to the generally vague, nonfocal symptomatology of posterior circulation ischemia making attribution of these symptoms difficult. However, the relatively high rate of restenosis should not be overlooked. The coronary literature has noted particularly high rates of in-stent restenosis at the ostia of branch vessels,44 an anatomical arrangement shared by VA ostial stenosis. Additionally, Lin et al41 demonstrated a correlation of lesion length with rates of in-stent restenosis of 21% in lesions < 5 mm long and 50% in lesions > 10 mm long. Given the difference in restenosis rates for drug-eluting stents compared with those for bare-metal stents, intimal hyperplasia is certain to contribute to in-stent restenosis at the VA origin. Stenting technique is also particularly important at the VA origin. As with stenosis in other locations, proper sizing (both in length and diameter) of the stent is essential. The plaque burden of these lesions is typically high because they often also involve the wall of the subclavian artery. Consequently, the ideal stent for treating such lesions would have high outward radial force.38 Balloon-mounted stents have been favored by some groups for this reason.38 Additionally, proper position may be of utmost importance at the VA ostium. By definition, an ostial lesion occurs at the very beginning of the VA and should be thought of as also including the wall of the subclavian artery. Therefore, extending the stent into the subclavian artery is critical. Failure to do this may result in incomplete lesion coverage and restenosis. The recent development of the Flash Ostial System  (Ostial Corp.) has aided in addressing this concern. This system consists of a dual balloon catheter (one traditional, noncompliant balloon and one ostial, compliant balloon). A stent is deployed using standard techniques with approximately 5 mm of the proximal stent within the subclavian artery. The Flash Ostial balloon is advanced with the distal noncompliant balloon within the stent, and the proximal noncompliant balloon is expanded (Fig. 23.345). This results in flaring of the proximal edges of the stent with apposition to the walls of the subclavian artery. A detailed technical description of this system has been reported by Dumont et al.45 Early experience with this technique has yielded good results according to Rangel-Castilla et al.33 Technical success was achieved in all patients; and although one groin complication occurred, there were no periprocedural complications attributed to the stent or the Flash Ostial system. In contrast to previous VA ostial

23  Brainstem Ischemia, Stroke, and Endovascular Revascularization of the Posterior Circulation

Fig. 23.3  (a) Schematic view demonstrating the vascular anatomy after stenting of a lesion originating in the vertebral artery (VA). The proximal opening of the stent is within the lumen of the subclavian artery, making endovascular catheterization difficult. (b,c) Anteroposterior (AP) angiograms of a right subclavian injection demonstrating the Flash Ostial System (Ostial Corp.) balloon catheter positioned with the ostium balloon

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centered at the origin of the VA; with the nonexpanded balloon (b); and with the expanded balloon (c). (d) AP angiogram of a right VA injection displaying opacification of the VA origin stent after angioplasty with the ostium balloon. The proximal end of the stent conforms to the VA origin anatomy, allowing simplified vascular access. (Reproduced with permission from Dumont et al 2013.45)

stenting series, there was no evidence of in-stent restenosis at a mean follow-up of 10.8 months. Although additional experience and follow-up are needed, the early success of this system may highlight the importance of coverage and apposition of proximal VA origin lesions.

Bow Hunter’s Syndrome Rotational VB insufficiency  (i.e., bow hunter's syndrome) refers to dynamic and reversible occlusion of the VA resulting in ischemia of downstream territories due to lack of collateral circulation. Patients often describe symptoms upon rotation or extension of the neck. Therefore, with such a history, it is critical to perform dynamic diagnostic angiography in a neutral position as well as in a symptomatic position (Fig. 23.446). The mainstay of treatment has been surgical, involving decompression with or without fusion. Although sparse, reports of endovascular therapies have been published, as described below. Endovascular stenting for treatment of bow hunter’s syndrome was first reported in 2009 by Sugiu et al.47 Darkhabani et al48 also reported their experience with the stenting of four patients with bow hunter’s syndrome. An Xpert stent (Abbott) was used in three patients and a Wallstent (Boston Scientific) was used in one patient. Technical success was achieved in all patients, with no procedure-related complications and resolution of all symptoms. Although the mainstay of treatment for bow hunter’s syndrome remains surgical decompression, endovascular stenting may emerge as a less invasive alternative. However, dynamic diagnostic angiography is critical to the identification of rotational VB insufficiency.

Vertebral Artery Dissection Dissection of the VA is one of the most common causes of stroke in patients younger than 45 years, occurring in 1 per 100,000 patients per year.11,​12 Although open surgical options exist, such as bypass, ligation, and interposition grafts, the associated high morbidity has limited their use. Therefore, treatment options for VA dissections include medical therapy (e.g., antiplatelet and anticoagulation treatment) and endovascular therapy. Traditionally, anticoagulation has been the preferred medical treatment,

Fig. 23.4  Illustrations demonstrating rotational vertebral artery (VA) occlusion. (a) Rotational VA occlusion showing stenosis or an anomaly of the VA on the left side, and (b) compression of the dominant VA at the C1–2 level (arrow) during contraversive head rotation. (Reproduced with permission from Choi et al 2013.46)

particularly in the presence of severe stenosis, occlusion, or pseudoaneurysm.49 However, the most recent American College of Cardiology Foundation/American Heart Association guidelines recommend the use of either an anticoagulant or antiplatelet agent for at least 3 to 6 months in patients with VA dissection associated with a TIA (class IIa evidence).50 Medical therapy is typically considered as the first-line therapy. However, failure of medical therapy or the need for immediate revascularization  (i.e., severe flow limitation) may warrant endovascular intervention. Although there are a variety of endovascular strategies (e.g., vessel sacrifice, balloon occlusion), stenting with or without angioplasty is the preferred endovascular treatment method. Technically, the stenting procedure for a VA dissection is similar to stenting for dissections at other locations. Although few in number, reports of stenting for VA dissections have yielded favorable results.49,​51 Rates of technical success exceed 90%. Angiographic follow-up has demonstrated durable patency in more than 85% of patients. Often, even in patients with restenosis or stent occlusion, no clinical sequelae are observed. The gradual stenosis of the stent may allow the development of ample collateral flow, which is in comparison to the acute stenosis experienced at the time of dissection. Adding to these endovascular stenting strategies, Cohen et al52 have described their experience using the Pipeline embolization device (Medtronic) in this setting. They hypothesize that the increased metal surface area of this flow-diversion stent serves as a more effective barrier against embolization.

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Intracranial Vertebrobasilar Stenosis Intracranial VA and BA stenosis comprised the most frequent locations of disease in the New England Medical Center Posterior Circulation Registry.6 However, optimal therapeutic strategy for patients with intracranial VB stenosis is ill defined. Medical therapy, specifically aspirin versus warfarin, was studied in the Warfarin-Aspirin Symptomatic Intracranial Disease  (WASID) trial, which included 107 patients with angiographically confirmed intracranial BV stenosis of 50 to 99%.53,54 The primary endpoint (stroke, hemorrhage, or death) occurred in 15% of patients receiving aspirin and in 28% of those receiving warfarin. Given the difficulty associated with microsurgical access of the intracranial vasculature, open surgical strategies are not typically considered for these patients. Although only 16% of the patients included in the Stenting vs. Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) trial had VB stenosis,55 the negative results of this study have generated much apprehension surrounding angioplasty and stenting of intracranial stenosis, including that of the VB circulation. Additional studies have echoed the results of the SAMMPRIS trial, finding high rates of periprocedural complications and successful secondary stroke prevention in many medically treated patients.56,​57,​58 The outcomes of these randomized controlled studies comparing endovascular therapy to medical therapy have resulted in the use of antiplatelet therapy as the first-line therapy for intracranial VB stenosis. However, because the risk of stroke has been reported to be 33% within 90 days after a TIA59 in patients with intracranial VB stenosis, one should not interpret these studies as a call to abandon endovascular strategies. In 2016, a systematic review and meta-analysis was conducted to evaluate the stroke recurrence rate among patients with symptomatic intracranial VB stenosis.60 A total of 592 patients received medical treatment, while 480 received endovascular therapy. The stroke recurrence rate was 9.6 per 100 person-years (95% CI 5.1–14.1) in the medical group and 7.2 per 100 person-years (95% CI 5.5–9) in the endovascular group. In both cohorts, the rate of stroke recurrence was found to be higher in patients with BA stenosis than those with VA stenosis. Although medical therapy may be the first-line therapy for secondary stroke prevention in patients with intracranial VB stenosis, there remains a portion of patients whose symptoms are refractory to this therapy. Indeed, the risk of stroke in patients with VB stenosis has been shown to be independent of other cardiovascular risk factors, suggesting the need for treatment of the stenosis rather than simply risk factor modification.59 In these patients, endovascular techniques must be considered as essential salvage strategies. The utility of endovascular techniques in this patient population is highlighted in a series of 97 patients with symptomatic intracranial VB stenosis of 70 to 99% despite medical treatment.61 Stenting was performed using either the Wingspan (Stryker Neurovascular) or Apollo (MicroPort Scientific) stent at the discretion of the treating physician, depending on factors such as lesion and access morphologies. Procedural success occurred in all patients. The mean preoperative stenosis was 83.7% and the mean residual stenosis was 10.2%. The primary outcome of any stroke, TIA, or death within 30 days occurred in 7.2% of patients. The recent application of coronary drug-eluting stents for intracranial arterial stenosis may also have a positive impact on endovascular outcomes. In their series, Liu et al61 noted technical

success in all 36 cases with no periprocedural complications or stroke within 30 days. Although additional studies with more long-term follow-up are needed, drug-eluting stents are certainly a valid addition to the endovascular armamentarium for the treatment of intracranial VB stenosis. The high rate of periprocedural complications has been cited as a primary reason to avoid endovascular revascularization of the intracranial vertebral and basilar arteries.62,​63 The primary source of symptomatic periprocedural morbidity occurs from perforating artery strokes. Perforating artery stroke can occur for several reasons, such as prolonged or repeated balloon inflation time, “snow plowing” of friable plaque with balloon inflation or stent deployment, and distortion of the VB vascular tree.63 Attention to the reduction of periprocedural morbidity will alter the risk-benefit profile and may result in the consideration of endovascular strategies as a first-line therapy. A recent report from Dumont et al64 evaluated the concept of submaximal angioplasty for symptomatic intracranial stenosis. Using Poiseuille’s law, submaximal angioplasty intends to restore flow via small changes in vessel diameter rather than radiographic restoration of anatomically normal vessel diameter (Fig. 23.5). In their report, Dumont et al64 described 24 patients  (including 4 patients with BA stenosis and 2 with VA stenosis) undergoing submaximal angioplasty. In the patients with stenosis of the posterior circulation, the periprocedural complication rate was 0% and the modified Rankin scale score was 0 in 5 patients and 1 in 1 patient. Validation of this technique in large prospective studies is required. However, this pre-

Fig. 23.5  (a) A three-dimensional reconstruction from the computed tomography angiogram demonstrating intracranial atherosclerotic disease of the basilar artery trunk. (b) Anteroposterior (AP) digital subtraction angiogram showing 80% stenosis. (c) A Gateway (Stryker Neurovascular) 1.5 × 15-mm balloon catheter (deinflated) was positioned at the level of the stenosis (arrow) and inflated submaximally  (inflation not shown). The balloon was intentionally undersized to achieve submaximal vessel dilation. (d) Control AP projection showing improvement in the stenosis, which measured 52.0% after the angioplasty. Applying the pre- and postangioplasty stenotic vessel diameter to Poiseulle’s law reveals that this modest increase in vessel diameter results in a 33-fold improvement in blood flow.

23  Brainstem Ischemia, Stroke, and Endovascular Revascularization of the Posterior Circulation liminary experience suggests that it may be a safe and effective technique for intracranial VB stenosis.

Acute Vertebrobasilar Occlusion Acute VB occlusion is an infrequent cause of stroke but is associated with the most devastating outcomes, characterized by locked-in syndrome, extensive cranial nerve dysfunction, and disruption of vasomotor and respiratory centers. Without treatment, mortality has been observed in 90% of patients. However, even with intravenous thrombolysis, the rate of death or dependency has been reported to be 78%.65 A systematic review comparing intra-arterial and intravenous thrombolysis for acute BA occlusion found that recanalization was achieved more frequently with intra-arterial thrombolysis (65% vs. 53%, p = 0.05).65 However, mortality and rates of death or dependency were equal. Barlinn et al66 reported that the combination of intravenous abciximab and intra-arterial thrombolysis with tissue plasminogen activator resulted in partial or complete recanalization in 85%, yet favorable function outcome was achieved in only 15%. Given these modest results, intra-arterial thrombolysis for VB occlusion remains an adjunctive therapy and is not approved by the U.S. Food and Drug Administration. The breakthrough in endovascular treatment of acute posterior circulation large-vessel occlusion occurred with the development of mechanical thrombectomy techniques. A recent systematic review of a decade of literature found that, although patients receiving mechanical thrombectomy were older, presented with more severe strokes, and were more likely to have received treatment more than 12 hours after symptom onset, the rates of survival and good clinical outcome at 3 months were higher than those in patients receiving intra-arterial throm-bolysis.67 Aspiration systems (Penumbra System; Penumbra) and stent retrievers (Solitaire; Medtronic; and Trevo; Stryker Neurovascular) have improved recanalization and clinical outcomes in these patients (Fig. 23.6).

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Early experience with the Penumbra aspiration system demonstrated patency in 75% of patients with a median improvement of 9 points on the National Institutes of Health Stroke Scale (NIHSS).68 Similar results have been replicated subsequently, with good clinical outcomes at 3 months in 44.4% and a mean modified Rankin scale score of 3.3 at 3 months.69 The use of stent retrievers has also yielded favorable radiographic and clinical results in patients with acute posterior circulation largevessel occlusion. Early in the adoption of this technique, successful recanalization (thrombolysis in cerebral infarction score 2b or 3) was found to be 75%, resulting in improvement of more than 10 points in NIHSS scores in 54% of patients at 3 months.70 A systematic review including 312 patients has confirmed these results.71 In that review, successful recanalization was achieved in 81%. Symptomatic intracerebral hemorrhage occurred in 4%. Good clinical outcome  (modified Rankin scale score ≤ 2) was achieved in 42% at 3 months, and mortality was 30%. A comparison of the Penumbra aspiration system and Solitaire retrievable stent has yielded similar results between the two techniques. Son et al69 found no statistically significant difference in successful recanalization (84.6% in the Solitaire group vs. 100% in the Penumbra group, P = 0.17), NIHSS score at discharge (17.6% vs. 16.4%, respectively, P = 0.83), or good outcome at 3 months (53.8% vs. 44.4%, respectively, P = 0.72). However, the procedural time was noted to be significantly faster in patients treated with the Penumbra system (62.3 minutes vs. 101.9 minutes in the Solitaire group, P = 0.02). The results of endovascular therapy for acute posterior circulation large-vessel occlusion must be compared with the natural history and pharmacologic therapy for the disease and not the results of endovascular therapy for anterior circulation large-vessel occlusion. Similar to the experience in the anterior circulation, although recanalization favorably affects clinical outcome, its presence does not guarantee a favorable clinical outcome. In addition, presenting clinical severity, high diffusion-weighted imaging posterior circulation Alberta Stroke Program Early CT Score (ASPECTS), and shorter thrombus length have also been found to be predictors of good outcome.72,​73

■■ Conclusion

Fig. 23.6  (a) Anteroposterior (AP) and (b) lateral digital subtraction angiograms (DSAs) showing mid-basilar thrombus (arrow) with no flow beyond the site of occlusion. (c) AP and (d) lateral DSAs after stent retriever thrombectomy showing complete revascularization and restoration of flow into distal vessels.

Identification of posterior circulation ischemia is critical. Given its often vague symptoms, a high level of clinical suspicion and a keen diagnostic eye are essential to its diagnosis. Failure to recognize early symptoms may result in devastating consequences, such as locked-in syndrome. The etiology of posterior circulation ischemia is variable, ranging from largevessel occlusion to small perforating vessel disease. The location of the offending lesion is similarly variable, ranging from subclavian artery stenosis to basilar apex occlusion. Diagnostic angiography is also critical to the accurate diagnosis and appreciation of posterior circulation ischemia. Collateral circulation may be robust, consisting of co-dominant VAs, hearty muscular collaterals, and posterior communicating arteries. On the contrary, a given territory may be isolated because of a severely hypoplastic VA and absent posterior communicating arteries.

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VI  Comprehensive Management of Vascular Pathology of the Brainstem and Thalamus

Difficult surgical access makes endovascular techniques appealing options for treatment of posterior circulation ischemia and stroke. In this chapter, we have outlined the low morbidity of such procedures. With additional development of endovascular techniques and technologies, outcomes can be expected to continue to improve.

References

22. Yang CW, Carr JC, Futterer SF, et al. Contrast-enhanced MR angiography of the carotid and vertebrobasilar circulations. AJNR Am J Neuroradiol 2005;26(8):2095–2101 23. Leclerc X, Martinat P, Godefroy O, et al. Contrast-enhanced three-dimensional fast imaging with steady-state precession (FISP) MR angiography of supraaortic vessels: preliminary results. AJNR Am J Neuroradiol 1998; 19(8):1405–1413 24. Kim SH, Lee JS, Kwon OK, Han MK, Kim JH. Prevalence study of proximal vertebral artery stenosis using high-resolution contrast-enhanced magnetic resonance angiography. Acta Radiol 2005;46(3):314–321

1. Markus HS, van der Worp HB, Rothwell PM. Posterior circulation ischaemic stroke and transient ischaemic attack: diagnosis, investigation, and secondary prevention. Lancet Neurol 2013;12(10):989–998

25. Khan S, Rich P, Clifton A, Markus HS. Noninvasive detection of vertebral artery stenosis: a comparison of contrast-enhanced MR angiography, CT angiography, and ultrasound. Stroke 2009;40(11):3499–3503

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6. Caplan LR, Wityk RJ, Glass TA, et al. New England Medical Center Posterior Circulation Registry. Ann Neurol 2004;56(3):389–398 7. Fusco MR, Harrigan MR. Cerebrovascular dissections—a review part I: Spontaneous dissections. Neurosurgery 2011;68(1):242–257, discussion 257 8. Debette S, Leys D. Cervical-artery dissections: predisposing factors, diagnosis, and outcome. Lancet Neurol 2009;8(7):668–678 9. von Babo M, De Marchis GM, Sarikaya H, et al. Differences and similarities between spontaneous dissections of the internal carotid artery and the vertebral artery. Stroke 2013;44(6):1537–1542 10. Searls DE, Pazdera L, Korbel E, Vysata O, Caplan LR. Symptoms and signs of posterior circulation ischemia in the New England Medical Center Posterior Circulation Registry. Arch Neurol 2012;69(3):346–351 11. Kristensen B, Malm J, Carlberg B, et al. Epidemiology and etiology of ischemic stroke in young adults aged 18 to 44 years in northern Sweden. Stroke 1997;28(9):1702–1709 12. Schievink WI. Spontaneous dissection of the carotid and vertebral arteries. N Engl J Med 2001;344(12):898–906 13. Flossmann E, Redgrave JN, Briley D, Rothwell PM. Reliability of clinical diagnosis of the symptomatic vascular territory in patients with recent transient ischemic attack or minor stroke. Stroke 2008;39(9):2457–2460 14. Chalela JA, Kidwell CS, Nentwich LM, et al. Magnetic resonance imaging and computed tomography in emergency assessment of patients with suspected acute stroke: a prospective comparison. Lancet 2007;369(9558):293–298 15. Hua Y, Meng XF, Jia LY, et al. Color Doppler imaging evaluation of proximal vertebral artery stenosis. AJR Am J Roentgenol 2009;193(5):1434–1438 16. Yurdakul M, Tola M. Doppler criteria for identifying proximal vertebral artery stenosis of 50% or more. J Ultrasound Med 2011;30(2):163–168 17. Sidhu PS. Ultrasound of the carotid and vertebral arteries. Br Med Bull 2000;56(2):346–366 18. Khan S, Cloud GC, Kerry S, Markus HS. Imaging of vertebral artery stenosis: a systematic review. J Neurol Neurosurg Psychiatry 2007;78(11):1218–1225 19. Farrés MT, Grabenwöger F, Magometschnig H, Trattnig S, Heimberger K, Lammer J. Spiral CT angiography: study of stenoses and calcification at the origin of the vertebral artery. Neuroradiology 1996;38(8):738–743 20. Strotzer M, Fellner C, Fraunhofer S, et al. Dedicated head-neck coil in MR angiography of the supra-aortic arteries from the aortic arch to the circle of Willis. Acta Radiol 1998;39(3):249–256 21. Wentz KU, Röther J, Schwartz A, Mattle HP, Suchalla R, Edelman RR. Intracranial vertebrobasilar system: MR angiography. Radiology 1994; 190(1):105–110

30. Chatterjee S, Nerella N, Chakravarty S, Shani J. Angioplasty alone versus angioplasty and stenting for subclavian artery stenosis—a systematic review and meta-analysis. Am J Ther 2013;20(5):520–523 31. Burihan E, Soma F, Iared W. Angioplasty versus stenting for subclavian artery stenosis. Cochrane Database Syst Rev. 2011(10):CD008461 32. Iared W, Mourão JE, Puchnick A, Soma F, Shigueoka DC. Angioplasty versus stenting for subclavian artery stenosis. Cochrane Database Syst Rev 2014(5):CD008461 33. Rangel-Castilla L, Gandhi S, Munich SA, et al. Experience with vertebral artery origin stenting and ostium dilatation: results of treatment and clinical outcomes. J Neurointerv Surg 2016;8(5):476–480 34. Wityk RJ, Chang HM, Rosengart A, et al. Proximal extracranial vertebral artery disease in the New England Medical Center Posterior Circulation Registry. Arch Neurol 1998;55(4):470–478 35. Imparato AM. Vertebral arterial reconstruction: a nineteen-year experience. J Vasc Surg 1985;2(4):626–634 36. Spetzler RF, Hadley MN, Martin NA, Hopkins LN, Carter LP, Budny J. Vertebrobasilar insufficiency. Part 1: Microsurgical treatment of extracranial vertebrobasilar disease. J Neurosurg 1987;66(5):648–661 37. Thevenet A, Ruotolo C. Surgical repair of vertebral artery stenoses. J Cardiovasc Surg (Torino) 1984;25(2):101–110 38. Wehman JC, Hanel RA, Guidot CA, Guterman LR, Hopkins LN. Atherosclerotic occlusive extracranial vertebral artery disease: indications for intervention, endovascular techniques, short-term and long-term results. J Interv Cardiol 2004;17(4):219–232 39. Chastain HD II, Campbell MS, Iyer S, et al. Extracranial vertebral artery stent placement: in-hospital and follow-up results. J Neurosurg 1999; 91(4):547–552 40. Fessler RD, Wakhloo AK, Lanzino G, Qureshi AI, Guterman LR, Hopkins LN. Stent placement for vertebral artery occlusive disease: preliminary clinical experience. Neurosurg Focus 1998;5(4):e15 41. Lin YH, Juang JM, Jeng JS, Yip PK, Kao HL. Symptomatic ostial vertebral artery stenosis treated with tubular coronary stents: clinical results and restenosis analysis. J Endovasc Ther 2004;11(6):719–726 42. Albuquerque FC, Fiorella D, Han P, Spetzler RF, McDougall CG. A reappraisal of angioplasty and stenting for the treatment of vertebral origin stenosis. Neurosurgery 2003;53(3):607–614, discussion 614–616 43. Stayman AN, Nogueira RG, Gupta R. A systematic review of stenting and angioplasty of symptomatic extracranial vertebral artery stenosis. Stroke 2011;42(8):2212–2216

23  Brainstem Ischemia, Stroke, and Endovascular Revascularization of the Posterior Circulation 44. Mathias DW, Mooney JF, Lange HW, Goldenberg IF, Gobel FL, Mooney MR. Frequency of success and complications of coronary angioplasty of a stenosis at the ostium of a branch vessel. Am J Cardiol 1991;67(6):491–495 45. Dumont TM, Kan P, Snyder KV, Hopkins LN, Levy EI, Siddiqui AH. Stenting of the vertebral artery origin with ostium dilation: technical note. J Neurointerv Surg 2013;5(5):e36 46. Choi  KD, Choi  JH, Kim  JS, et al. Rotational vertebral artery occlusion: mechanisms and long-term outcome. Stroke 2013;44(7):1817–1824 47. Sugiu K, Agari T, Tokunaga K, Nishida A, Date I. Endovascular treatment for bow hunter’s syndrome: case report. Minim Invasive Neurosurg 2009;52(4):193–195 48. Darkhabani MZ, Thompson MC, Lazzaro MA, Taqi MA, Zaidat OO. Vertebral artery stenting for the treatment of bow hunter’s syndrome: report of 4 cases. J Stroke Cerebrovasc Dis 2012;21(8):908.e1–908.e5 49. Mohan IV. Current optimal assessment and management of carotid and vertebral spontaneous and traumatic dissection. Angiology 2014; 65(4):274–283 50. Kernan WN, Ovbiagele B, Black HR, et al; American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014; 45(7):2160–2236 51. Pham MH, Rahme RJ, Arnaout O, et al. Endovascular stenting of extracranial carotid and vertebral artery dissections: a systematic review of the literature. Neurosurgery 2011;68(4):856–866, discussion 866 52. Cohen JE, Gomori JM, Moscovici S, Bala M, Itshayek E. The use of flow diverter stents in the management of traumatic vertebral artery dissections.J Clin Neurosci 2013;20:731–734 53. Kasner SE, Lynn MJ, Chimowitz MI, et al; Warfarin Aspirin Symptomatic Intracranial Disease (WASID) Trial Investigators. Warfarin vs aspirin for symptomatic intracranial stenosis: subgroup analyses from WASID. Neurology 2006;67(7):1275–1278 54. Caplan LR. The intracranial vertebral artery: a neglected species. The Johann Jacob Wepfer Award 2012. Cerebrovasc Dis 2012;34(1):20–30 55. Derdeyn CP, Chimowitz MI, Lynn MJ, et al; Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis Trial Investigators. Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): the final results of a randomised trial. Lancet 2014;383(9914):333–341 56. Compter A, van der Worp HB, Schonewille WJ, et al; VAST investigators. Stenting versus medical treatment in patients with symptomatic vertebral artery stenosis: a randomised open-label phase 2 trial. Lancet Neurol 2015;14(6):606–614 57. Coward LJ, McCabe DJ, Ederle J, Featherstone RL, Clifton A, Brown MM; CAVATAS Investigators. Long-term outcome after angioplasty and stenting for symptomatic vertebral artery stenosis compared with medical treatment in the Carotid And Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomized trial. Stroke 2007;38(5):1526–1530 58. Coward LJ, Featherstone RL, Brown MM. Percutaneous transluminal angioplasty and stenting for vertebral artery stenosis. Cochrane Database Syst Rev 2005(2):CD000516

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59. Gulli G, Marquardt L, Rothwell PM, Markus HS. Stroke risk after posterior circulation stroke/transient ischemic attack and its relationship to site of vertebrobasilar stenosis: pooled data analysis from prospective studies. Stroke 2013;44(3):598–604 60. Abuzinadah AR, Alanazy MH, Almekhlafi MA, et al. Stroke recurrence rates among patients with symptomatic intracranial vertebrobasilar stenoses: systematic review and meta-analysis. J Neurointerv Surg 2016; 8(2):112–116 61. Liu L, Zhao X, Mo D, Ma N, Gao F, Miao Z. Stenting for symptomatic intracranial vertebrobasilar artery stenosis: 30-day results in a high-volume stroke center. Clin Neurol Neurosurg 2016;143:132–138 62. Fiorella D, Chow MM, Anderson M, Woo H, Rasmussen PA, Masaryk TJ. A 7-year experience with balloon-mounted coronary stents for the treatment of symptomatic vertebrobasilar intracranial atheromatous disease. Neurosurgery 2007;61(2):236–242, discussion 242–243 63. Jiang WJ, Yu W, Du B, Wong EH, Gao F. Wingspan experience at Beijing Tiantan Hospital: new insights into the mechanisms of procedural complication from viewing intraoperative transient ischemic attacks during awake stenting for vertebrobasilar stenosis. J Neurointerv Surg 2010; 2(2):99–103 64. Dumont TM, Sonig A, Mokin M, et al. Submaximal angioplasty for symptomatic intracranial atherosclerosis: a prospective Phase I study. J Neurosurg 2016;125(4):964–971 65. Lindsberg PJ, Mattle HP. Therapy of basilar artery occlusion: a systematic analysis comparing intra-arterial and intravenous thrombolysis. Stroke 2006;37(3):922–928 66. Barlinn K, Becker U, Puetz V, et al. Combined treatment with intravenous abciximab and intraarterial tPA yields high recanalization rate in patients with acute basilar artery occlusion. J Neuroimaging 2012; 22(2):167–171 67. Mak CH, Ho JW, Chan KY, Poon WS, Wong GK. Intra-arterial revascularization therapy for basilar artery occlusion—a systematic review and analysis. Neurosurg Rev 2016;39(4):575–580 68. Roth C, Mielke A, Siekmann R, Ferbert A. First experiences with a new device for mechanical thrombectomy in acute basilar artery occlusion. Cerebrovasc Dis 2011;32(1):28–34 69. Son S, Choi DS, Oh MK, et al. Comparison of Solitaire thrombectomy and Penumbra suction thrombectomy in patients with acute ischemic stroke caused by basilar artery occlusion. J Neurointerv Surg 2016;8(1):13–18 70. Möhlenbruch M, Stampfl S, Behrens L, et al. Mechanical thrombectomy with stent retrievers in acute basilar artery occlusion. AJNR Am J Neuroradiol 2014;35(5):959–964 71. Gory B, Eldesouky I, Sivan-Hoffmann R, et al. Outcomes of stent retriever thrombectomy in basilar artery occlusion: an observational study and systematic review. J Neurol Neurosurg Psychiatry 2016;87(5):520–525 72. Yoon W, Kim SK, Heo TW, Baek BH, Lee YY, Kang HK. Predictors of good outcome after stent-retriever thrombectomy in acute basilar artery occlusion. Stroke 2015;46(10):2972–2975 73. Gilberti N, Gamba M, Premi E, et al. Endovascular mechanical thrombectomy in basilar artery occlusion: variables affecting recanalization and outcome. J Neurol 2016;263(4):707–713

24

Microsurgical Embolectomy for Emergency Revascularization of the Brainstem Felix Goehre and Rokuya Tanikawa

Abstract

Microsurgical embolectomy for emergency revascularization of the brainstem is necessary when embolic occlusion of a major intracranial vessel occurs, because embolic occlusion is a lifethreatening event. In particular, embolic occlusion of the basilar artery bifurcation can lead to brainstem ischemia and is thus associated with high mortality rates of up to 85% when left untreated. Active treatment within a narrow time window is therefore necessary for favorable outcomes. To date, intravenous or intra-arterial thrombolysis and endovascular mechanical embolectomy have been considered the best treatment options. Nevertheless, when performed by an experienced surgeon, microsurgical embolectomy represents a safe treatment, with high revascularization rates for select patients not amenable to endovascular or medical therapies. In this chapter, we describe the technique of microsurgical thromboembolectomy for emergency revascularization of the distal basilar artery and the proximal posterior cerebral artery, and we summarize general aspects of intracranial microsurgical embolectomies. Keywords:  basilar artery, embolism, internal carotid artery, intracranial vessel occlusion, microsurgical embolectomy, middle cerebral artery stroke, thromboembolectomy, thrombolysis in cerebral infarction

■■ Pathophysiology, Incidence, Epidemiology, and Natural History of Disease Ischemic stroke is one of the most common causes of death worldwide and one of the main reasons for physical and mental disability.1 Approximately 85% of all strokes are due to ischemia.2 Stroke prevention and modern stroke treatment have decreased the incidence of and mortality associated with cerebral ischemia in Western countries during recent decades.3 However, the expected demographic shift as the population ages will only heighten the importance of ischemic stroke management in the coming years. In general, ischemic strokes are caused by embolism, hemodynamic impairment, local vasculopathy, atheromatosis, and thrombosis. Other causes include internal carotid artery (ICA) and vertebral artery dissection, vasospasm, and iatrogenic injury. In this chapter, we will specifically address embolic causes of ischemic stroke affecting the brainstem blood supply.

Posterior Circulation Stroke Approximately 15 to 20% of ischemic strokes affect the posterior circulation. Acute basilar artery (BA) occlusion, either by arterial embolism or local atherosclerotic occlusion, accounts for less

340

than 1% of ischemic strokes and is associated with a high mortality rate.4,​5 Distal BA occlusion is typically caused by thromboembolism, because vascular segments with a clinically significant reduction in vessel diameter are predilection sites for embolic occlusions.6 Occlusion of the distal BA leads to ischemia of the thalami, midbrain, inferior temporal lobes, and occipital lobes.

Embolic Stroke Artery-to-artery and cardiac embolisms are the two most common causes of embolic stroke.2 Embolism occurs most commonly via cardiac sources and from atherosclerotic wall degeneration of the aortic arch,7 the common carotid artery, and the ICA.8,​9 Cardioembolism is responsible for 15 to 30% of nonhemorrhagic strokes.10,​11 The three primary mechanisms of cardioembolism are blood stasis and thrombus formation in the left cardiac chamber (due to atrial fibrillation, myocardial infarction, or heart failure); thrombus formation on a valvular surface (due more rarely to endocarditis, rheumatic mitral valve disease, mitral valve prolapse, mitral annulus calcification, or aortic valve disease); and paradoxical embolism (caused by residual patent foramen ovale). Carotid artery atherosclerosis causes approximately 20% of ischemic strokes in the anterior circulation.8,​9 Important mechanisms in this scenario are luminal thrombus formation after plaque surface rupture and the downstream flow of thrombus material in the bloodstream to distal vascular territories.

■■ Clinical Presentation The acute onset of symptoms in a previously asymptomatic patient suggests an embolic source for the stroke. However, symptoms can be varied and may differ considerably on the basis of the vascular territories that are affected. Clinical diagnosis can be further aggravated by a variety of symptoms, especially in patients with posterior circulation strokes.

Anterior Circulation The embolic occlusion of the ICA, the anterior cerebral artery, or the middle cerebral artery (MCA) is associated with contralateral paralysis, aphasia (left hemisphere), and contralateral central facial nerve (cranial nerve [CN] VII) paralysis. Malignant brain infarction with consecutive transtentorial herniation is life threatening.

Posterior Circulation Acute occlusion of the BA affects the function of the inferior temporal and occipital lobes, the midbrain, and the bilateral thalami. Conscious patients may experience the following symptoms: vertical gaze disturbance, convergence disorders, slowed pursuit

24  Microsurgical Embolectomy for Emergency Revascularization of the Brainstem movements, skew deviation, slowed or incomplete light reaction, dizziness, vomiting, dysarthria, dysmetria, and gait ataxia.5,​12,​13 Ipsilateral posterior cerebral artery (PCA) occlusion can lead to contralateral loss of vision, whereas bilateral PCA occlusion can result in cortical blindness. Midbrain infarction can result in oculomotor nerve (CN III) palsy, crossed hemiplegia, and hemiataxia; lower midbrain infarction can result in internuclear ophthalmoplegia and trochlear nerve (CN IV) palsy.5,​12,​13

■■ Time Management and Perioperative Evaluations Time Management Time management before and during hospitalization is the most critical modifiable factor affecting patient outcome. In particular, immediate transfer of the patient to a stroke center with facilities for interventional and surgical stroke management is of great importance, as hemorrhagic stroke cannot currently be fully excluded during the prehospitalization phase.14 Even in modern countries with a well-organized emergency system, only 10 to 20% of stroke patients arrive at a stroke center quickly enough to undergo stroke revascularization therapy.

Imaging Vascular imaging with computed tomography (CT) and magnetic resonance imaging (MRI) is time-consuming but invaluable in the decision-making process for revascularization.15,​16,​17,​18,​19 The infarct core and the salvageable tissue at risk must be carefully estimated. Furthermore, care must be taken to distinguish an embolic occlusion from a local atherosclerotic occlusion (Fig. 24.1). For example, only up to 35% of basilar occlusions are caused by cardiac or artery-to-artery embolization.10,​11

Fig. 24.1  Preoperative computed tomography angiography (CTA) reconstructions show typical embolic occlusions (arrows) of (a) the distal basilar artery and (b) the left proximal posterior cerebral artery. (c) An atherosclerotic

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Computed Tomography Plain CTs allow for the quick exclusion of hemorrhagic or tumor lesions. Intracranial CT angiography (CTA), with intravenous injection of a contrast agent during the arterial circulation phase, generates highly accurate angiograms in less than 5 seconds of scanning time. The speed of CT imaging is advantageous over that of other imaging modalities, especially for patients who are not cooperative. CTA also has high efficacy for evaluating large areas of stenosis and occlusions in intracranial vessels. However, CTA provides only a static image of angioarchitecture and is therefore inferior to digital subtraction angiography for evaluating flow rates and directions. CT perfusion imaging provides additional information about cerebral hemodynamics.15,​17

Magnetic Resonance Imaging Early MRI using diffusion-weighted imaging  (DWI) with apparent diffusion coefficient mapping provides high sensitivity for detecting ischemic strokes in the anterior and posterior circulation.16 This method can therefore provide early verification of a cerebral ischemic lesion. MRI DWI can visualize regions where the extracellular matrix with high water content is affected and displaced from ischemic cells by expansion from cytotoxic edema. Perfusion MRI also allows determination of the following parameters for each territory: time to peak, mean transit time, cerebral blood flow, and cerebral blood volume. The evaluation of these variables allows for the following conclusions: •• Perfusion and diffusion disorder (irreversible ischemia) •• Decreased perfusion and normal diffusion  (reversible ischemia) •• Perfusion disorder without diffusion disorder (penumbra)

occlusion (arrows) of the mid-basilar artery is depicted in digital subtraction angiography with internal carotid artery contrast agent injection and retrograde filling of the upper posterior circulation and midbasilar occlusion.

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VI  Comprehensive Management of Vascular Pathology of the Brainstem and Thalamus

■■ Nonsurgical Treatment Medical Treatment For the treatment of acute ischemic stroke in patients presenting within a 4.5-hour time window, intravenous application of recombinant tissue plasminogen activator (rTPA) is a level IA recommendation included in the treatment guidelines of several countries.20,​21,​22,​23 Contraindications to rTPA are summarized in Table 24.1. When an indication is present, 0.9 mg/kg rTPA is administered intravenously, to a maximum dose of 90 mg. The dose is divided as follows: 10% injected as a bolus and 90% administered continuously via a syringe pump over the course of the next hour. However, intravenous thrombolysis with rTPA has a limited effect on main branch occlusions  (ICA, proximal MCA, and BA).24,​25,​26

Endovascular Treatment During the last decade, endovascular treatment of major intracranial vessel occlusion has gained increasing importance. At first, intra-arterial lysis with rTPA or urokinase were treatment options, with some studies showing a beneficial effect regarding recanalization and improved outcomes.27,​28 During the last few years, rapid development of mechanical embolectomy devices has led to greater application of these techniques.11,​29,​30 Table 24.1  Contraindications to receiving rTPA

Variable

Value

Time window

> 4.5 hours

Oral anticoagulants or INR

> 1.7

Subarachnoid hemorrhage

Any history

Intracerebral hemorrhage

Yes

Cranial or spinal cord surgery

> 3 months

Intracranial aneurysm

Yes

Intracranial arteriovenous malformation or fistula

Yes

Endocarditis or pericarditis

Yes

Seizures at stroke onset

Yes

Meningitis

Yes

Delivery/childbirth

< 10 days

Gastrointestinal ulceration or bleeding

< 21 days

Esophagus varices

Yes

Acute pancreatitis

Yes

Thrombocytopenia

Stent retriever technology, in particular, has led to significant improvement in recanalization rates and outcomes.31,​32,​33,​34,​ 35 The application criteria for endovascular mechanical revascularization (based on the AHA/ASA [American Heart Association/American Stroke Association] guideline) are listed in Table 24.2.36,​37

■■ Microsurgical Treatment Welch38 reported the first surgical embolectomy of an intracranial vessel in 1956. Since then, there have been several promising reports of successful microsurgical embolectomies with high recanalization rates (Table 24.3).39,​40,​41,​42 The following section presents a common technical description of intracranial embolectomies, which can be applied to the ICA, MCA, distal BA, and proximal PCA. The microsurgical corridor to reach the BA is much deeper and narrower than the corridor needed to reach the MCA bifurcation (Fig. 24.2). The focused microsurgical dissection the lateral sulcus (i.e., sylvian fissure) is considered a standard neurosurgical procedure.43 The transsylvian medial anterior temporal approach for microsurgical dissection toward the upper posterior circulation is presented in Fig. 24.3.44,​45 A technical description of vessel management is provided in Fig. 24.4, which illustrates a complete BA embolectomy procedure. This technique can be applied to other intracranial ICA and MCA bifurcations, which have a predilection for embolic occlusions.

Craniotomy The patient is placed in supine position, with the head rotated in the direction opposite the affected side and slightly elevated above heart level to increase venous outflow. The head is fixed in a three-point head holder. A single-layer myocutaneous flap can be dissected quickly after making a curved frontotemporal skin incision. A frontotemporal craniotomy focused on the target vessel segment can typically be executed within 10 minutes after skin incision.

Table 24.2  Indications for endovascular mechanical revascularization for large vessel occlusion

Indication

Value

Prestroke mRS score

0–1

Intravenous rTPA within 4.5 hours of acute ischemic stroke onset per AHA/ASA guidelines

Yes

> 100 × 109/L

Causative occlusion of ICA or proximal MCA

Yes

Hypertension

> 185/110 mm Hg

Age

≥ 18 years

Hypoglycemia

< 50 mg/dL

NIHSS score

>5

Hyperglycemia

> 400 mg/dL

ASPECTS score

>5

NIHSS score (low)

25

Major surgery or trauma

< 2 weeks

Abbreviations: AHA/ASA, American Heart Association/American Stoke Association; ASPECTS, Alberta Stroke Program Early CT Score; ICA, internal carotid artery; MCA, middle cerebral artery; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; rTPA, recombinant tissue plasminogen activator.

Abbreviations: NIHSS, National Institutes of Health Stroke Scale; rTPA, recombinant tissue plasminogen activator.

24  Microsurgical Embolectomy for Emergency Revascularization of the Brainstem

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Table 24.3  Recanalization rates following microsurgical embolectomies

Author, year Horiuchi et al 2009

Cases, No.

Vessel

Recanalization, %

Favorable outcome, No./Total (%)

30

MCA

100

16/30 (53)

Inoue et al 201339

23

ICA, MCA

91

5/23 (22)

Meyer et al 1985

20

MCA

80

7/20 (35)

14

ICA, proximal MCA

100

4/14 (29)

Hino et al 2016

41

42

40

Abbreviations: ICA, internal carotid artery; MCA, middle cerebral artery. Fig. 24.2  The working space and distances in the surgical corridor differ significantly for (a) a basilar artery (BA) bifurcation embolectomy and (b) a middle cerebral artery bifurcation (MCAbif) embolectomy.

Focused Transsylvian Dissection to MCA Occlusions Careful preoperative planning allows for the focused opening of the sylvian fissure to expose the occluded MCA segment. In all cases, the exposure must provide the surgeon with the adequate working space necessary to perform the procedure.

Transsylvian Anterior Temporal Approach to Occlusions of the ICA, Proximal PCA, and Distal BA

impairment of the oculomotor nuclei and fascicle is possible. Despite the use of an anterior temporal approach, the surgical corridor is deep (7–8 cm) and narrow. If the oculomotor nerve and the trochlear nerve are not under direct visual control, intraoperative monitoring of the nerves can provide an additional tool for preventing permanent damage.

Vessel Management and Embolectomy

Meticulous extended dissection and mobilization of the superficial sylvian veins are crucial to optimally mobilize the anterior temporal lobe, to expose the carotid oculomotor triangle, and to microsurgically manage embolic occlusions of the ICA, proximal PCA, and distal BA. It is thereby possible to obtain sufficient working space for microsurgical maneuvers, as well as proximal and distal control of the affected vessel, in the deep surgical corridor. Major draining veins should be preserved, although mobilization of the draining veins at the temporal pole can be difficult.

The dissection should be wide enough for placement of temporary clips proximal and distal to the occluded segment. The distal clips are placed before performing the arteriotomy to prevent the formation of a secondary embolism. Usually a transverse arteriotomy of approximately two-thirds of the superficial vessel surface provides sufficient space to extract the embolus. The arteriotomy is placed on the border zone at the distal circumference of the embolus. The embolus can be mobilized and removed with bayonet plateau tip microsurgical forceps. After the evacuation procedure, temporary miniclips are placed proximal and distal to the arteriotomy. Next, the arteriotomy is repaired with 3 or 4 stitches using a 10–0 microthread suture.

Oculomotor Nerve

Intraoperative Evaluation

Working between the carotid artery and the oculomotor nerve, such as for the dissection necessary for the microsurgical transsylvian treatment of basilar apex aneurysms, can result in oculomotor nerve palsy.46 Direct mechanical irritation or vascular

After the procedure, the blood flow in the revascularized distal vessel segment should be confirmed. Doppler ultrasound and indocyanine green videoangiography are used to examine the extent of revascularization.47

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VI  Comprehensive Management of Vascular Pathology of the Brainstem and Thalamus Fig. 24.3  (a) A standard pterional craniotomy allows the exposure of the lateral sphenoid wing and the superficial sylvian fissure. (b) Lateral mobilization of the temporal pole requires dissection of the sylvian and temporal veins. (c) Opening of the arachnoid membranes medial (Liliequist's membrane) and lateral to the oculomotor nerve (cranial nerve [CN] III) allows visualization of the upper basilar artery (BA) and ipsilateral proximal posterior cerebral artery. (d) The dark blue embolus is visible through the arterial wall. Abbreviations: ATA, anterior temporal artery; FL, frontal lobe; ICA, internal carotid artery; PCoA, posterior communicating artery; SV, sylvian veins; TL, temporal lobe.

■■ Patient Outcomes We analyzed 30 patients who received a diagnosis of major intracranial vessel (ICA, MCA, BA, and PCA) occlusion and who were treated with microsurgical embolectomy between April 2012 and February 2016. Of the 30 patients, 14 were women and 16 were men. The median patient age was 72 years (range, 52–89 years). The median NIHSS (National Institutes of Health Stroke Scale) score at arrival was 14 (range, 6–40). All 30 patients had an apoplectic onset of symptoms, and embolic vessel occlusion was therefore suspected. The occlusions affected the ICA (n = 5), the MCA (n = 21), the BA (n = 3), and the PCA–P1 segment (n = 1). In all cases, the decision for micro-

surgical revascularization was based on a perfusion–diffusion mismatch (CTA and MRI). Our management times were as follows: the time between the onset of symptoms and emergency department arrival was a median of 58 minutes (range, 30–660 minutes); the time required for stabilization, evaluation, and imaging was a median of 67 minutes (range, 41–240 minutes); and the time between the decision for intervention and revascularization was a median of 36 minutes (range, 22–100 minutes). The efficacy of embolectomy was assessed using the Thrombolysis in Cerebral Infarction (TICI) (Table 24.4) grading system.48 In all 30 cases, complete recanalization (TICI 3) was achieved as confirmed by postoperative CTA imaging.

24  Microsurgical Embolectomy for Emergency Revascularization of the Brainstem

345

Fig. 24.4  The first priority in an embolectomy is to control all originating branch vessels with temporary clips (TCs). (a) For basilar artery (BA) embolectomy, both the superior cerebellar artery (SCA) and the posterior cerebral artery (PCA) are controlled. (b) A transverse arteriotomy over the distal embolus (E) allows for (c) the antegrade extraction of the embolic mate-

rial (arrows) with fine microsurgical forceps. (d) After thrombus extraction, the antegrade bleeding from the afferent vessel can be controlled by (e) fast application of TCs. (f) Finally, interrupted sutures (arrows) are used to close the arteriotomy. Abbreviations: BATC, basilar artery temporary clip; CA, clip applier; III, oculomotor nerve (cranial nerve III).

Preinterventional and postinterventional NIHSS assessment demonstrated improvement in all patients (median, 14 [range, 5–40] vs. 4 [range, 0–31]), with a difference greater than 10 in 12 patients. At 3-month follow-up, the following treatment results were achieved for occlusion: ICA (n = 5), 2 good and 3 moderate; MCA (n = 21), 8 good and 13 moderate; and BA or PCA (n = 4), 3 moderate and 1 poor. At 12-month follow-up, the modified Rankin Scale (mRS) (Table 24.5) was used to measure outcomes.49,​50 For further analysis, outcomes were categorized into three groups: good (mRS 0–1), moderate (mRS 2–4), and

poor (mRS 5–6). The best evidence practice recommendations are summarized in Table 24.6.

■■ Discussion The occlusion of major intracranial vessels, particularly acute occlusion of the BA, is associated with high mortality rates of 30 to 40%.4,​5 Modern stroke management with early revascularization strategies has improved outcomes. Modern standard therapies are intrave-

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Table 24.4  Thrombolysis in Cerebral Infarction (TICI) grading systema

Table 24.5  Modified Rankin Scalea

Grade

Description

Grade Description

0

No perfusion; no antegrade flow beyond the point of occlusion

0

No symptoms at all

1

No significant disability despite symptoms: able to carry out all usual duties and activities

2

Slight disability: unable to carry out all previous activities but able to look after own affairs without assistance

3

Moderate disability: requiring some help but able to walk without assistance

4

Moderately severe disability: unable to walk without assistance and unable to attend to own bodily needs without assistance

5

Severe disability: bedridden, incontinent, and requiring constant nursing care and attention

6b

Dead

1

Penetration with minimal perfusion; the contrast material passes beyond the area of obstruction but fails to opacify the entire cerebral bed distal to the obstruction for the duration of the angiographic run

2

Partial perfusion

2a

Only partial filling (less than two-thirds) of the entire vascular territory is visualized

2b

Complete filling of all the expected vascular territory is visualized but filling is slower than normal

3

Full perfusion with filling of all distal branches

a

Modified from Higashida et al 2003.4848

a

Modified from Van Swieten et al 1988.50 The original modifed Rankin Scale did not include grade 6 (dead).

b

Table 24.6  Best evidence practice guidelines for stroke management

Guideline • Early clinical diagnosis and patient stabilization • Fast transfer to stroke center with endovascular and surgical treatment options • Advanced critical care management • Advanced vascular imaging (CT, CTA, CT perfusion, MRI perfusion– diffusion) • Intravenous thrombolysis (with consideration of contraindications and time window): 0.9 mg/kg rTPA(10% as initial bolus and 90% continuously over 1 hour) • Interventional mechanical revascularization (image-based) • Microsurgical revascularization (individual treatment approach) • Critical care stroke management and prevention of stroke complications Abbreviations: CT, computed tomography; CTA, computed tomography angiography; MRI, magnetic resonance imaging; rTPA, recombinant tissue plasminogen activator.

nous thrombolysis with rTPA and interventional treatment with stent retrievers.36,​37 Microsurgical embolectomy is an additional treatment method39,​40,​41,​42 that should be made available for select cases in high-performance stroke centers. Such cases include the treatment of embolic occlusions that affect the distal BA and the proximal PCA, causing upper posterior circulation strokes.44,​45 However, time is the most important predictive factor for good patient outcome in stroke management. Rapid stroke management before and during hospitalization is essential for preserving neurologic function and life.14 After early prehospitalization stroke diagnosis, the patient should be transferred quickly to an experienced stroke center.36,​37 Transfer, primary stabilization, imaging, decision-making, and preparation for interventional treatment are all performed under time pressure. Neurovascular imaging is invaluable in the decision-making process. In general, small lesions observed on MRI DWI in patients with major vessel occlusion are considered treatable.36,​37 Furthermore, it is important to distinguish an embolic occlusion from a local atherosclerotic occlusion by examining the configuration of the occlusion border zone (Fig. 24.1). Atherosclerotic

occlusions commonly present with a spindle-shaped termination of contrast agent. Although there are strict contraindications to the use of thrombolysis by intravenous application of rTPA, its use within a 4.5-hour window is a level IA recommendation for the treatment of acute strokes in several countries.36,​37 Proximal intracranial vessel occlusions do not commonly respond well to systemic intravenous thrombolysis. Therefore, endovascular revascularization using intra-arterial pharmacologic thrombolysis and mechanical thromboembolectomy (using stent retrievers or other means) should be considered.31,​32,​33,​34,​35,​51,​52 High recanalization rates (72–88%) can be achieved with these techniques.31,​32,​33,​34,​35 In addition, several reports of successful microsurgical embolectomies with high recanalization rates (80–100%) in the anterior cerebral circulation have been published.39,​40,​41,​42 Outcomes are not only related to recanalization but also are greatly affected by other factors such as timing of surgery, localization of the vessel occlusion, and collateral flow. However, these direct microsurgical embolectomies are effective revascularization procedures. The rapid execution of the cranial and intracranial approach is indispensable. A standard frontotemporal approach allows fast access to the ipsilateral circle of Willis and the MCA. With mobilization of the anterior temporal lobe, the upper posterior circulation (BA, PCA, and superior cerebellar artery) can be approached.44,​45 Indocyanine green videoangiography and Doppler ultrasound allow for immediate evaluation of recanalization.47 An open surgical procedure after unsuccessful thrombolysis is possible; therefore, the risk is only minimally increased by the half-life of rTPA. The microsurgical intracranial dissection is performed through the subarachnoid space, with minimal effects on the neural tissue.

■■ Conclusion In experienced hands, open microsurgical thromboembolectomy of major intracranial vessels is a demanding, yet relatively safe, procedure when based on modern microsurgical techniques. Complete recanalization of large vascular segments, particularly

24  Microsurgical Embolectomy for Emergency Revascularization of the Brainstem

347

those with high clot burdens or those recalcitrant to medical and interventional techniques, may be better achieved by performing a microsurgical embolectomy than by using an endovascular embolectomy device.

20. Adams HP, Jr, Brott TG, Furlan AJ, et al. Guidelines for thrombolytic therapy for acute stroke: a supplement to the guidelines for the management of patients with acute ischemic stroke. A statement for healthcare professionals from a Special Writing Group of the Stroke Council, American Heart Association. Circulation 1996; 94(5):1167–1174

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1. Howard G, Howard VJ. Stroke disparities. In: Grotta JC, Albers GW, Broderick JP, et al, eds. Stroke: Pathophysiology, Diagnosis, and Management. New York, NY: 2016:204–216 2. Sacco RL, Ellenberg JH, Mohr JP, et al. Infarcts of undetermined cause: the NINCDS Stroke Data Bank. Ann Neurol 1989; 25(4):382–390 3. Towfighi A, Saver JL. Stroke declines from third to fourth leading cause of death in the United States: historical perspective and challenges ahead. Stroke 2011; 42(8):2351–2355 4. Israeli-korn SD, Schwammenthal Y, Yonash-Kimchi T, et al. Ischemic stroke due to acute basilar artery occlusion: proportion and outcomes. Isr Med Assoc J 2010; 12(11):671–675 5. Voetsch B, DeWitt LD, Pessin MS, Caplan LR. Basilar artery occlusive disease in the New England Medical Center Posterior Circulation Registry. Arch Neurol 2004; 61(4):496–504 6. Caplan LR. “Top of the basilar” syndrome. Neurology 1980; 30(1):72–79 7. Gore I, Collins DP. Spontaneous atheromatous embolization: review of the literature and a report of 16 additional cases. Am J Clin Pathol 1960; 33:416–426 8. Barnett HJ, Peerless SJ, Kaufmann JC. “Stump” on internal carotid artery—a source for further cerebral embolic ischemia. Stroke 1978; 9(5):448–456 9. Imparato AM, Riles TS, Gorstein F. The carotid bifurcation plaque: pathologic findings associated with cerebral ischemia. Stroke 1979; 10(3):238–245 10. Jung S, Mono ML, Fischer U, et al. Three-month and long-term outcomes and their predictors in acute basilar artery occlusion treated with intraarterial thrombolysis. Stroke 2011; 42(7):1946–1951 11. Schonewille WJ, Wijman CA, Michel P, et al; BASICS study group. Treatment and outcomes of acute basilar artery occlusion in the Basilar Artery International Cooperation Study (BASICS): a prospective registry study. Lancet Neurol 2009; 8(8):724–730 12. Mehler MF. The rostral basilar artery syndrome: diagnosis, etiology, prognosis. Neurology 1989; 39(1):9–16 13. Segarra JM. Cerebral vascular disease and behavior. I. The syndrome of the mesencephalic artery (basilar artery bifurcation). Arch Neurol 1970; 22(5):408–418 14. Prabhakaran S, Ward E, John S, et al. Transfer delay is a major factor limiting the use of intra-arterial treatment in acute ischemic stroke. Stroke 2011; 42(6):1626–1630 15. European Stroke Organisation (ESO) Executive Committee; ESO Writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008; 25(5):457–507 16. Förster A, Griebe M, Gass A, Hennerici MG, Szabo K. Recent advances in magnetic resonance imaging in posterior circulation stroke: implications for diagnosis and prognosis. Curr Treat Options Cardiovasc Med 2011; 13(3):268–277 17. Kan P, Snyder KV, Binning MJ, Siddiqui AH, Hopkins LN, Levy EI. Computed tomography (CT) perfusion in the treatment of acute stroke. World Neurosurg 2010; 74(6):550–551 18. Ostrem JL, Saver JL, Alger JR, et al. Acute basilar artery occlusion: diffusion-perfusion MRI characterization of tissue salvage in patients receiving intra-arterial stroke therapies. Stroke 2004; 35(2):e30–e34 19. Simonsen CZ, Madsen MH, Schmitz ML, Mikkelsen IK, Fisher M, Andersen G. Sensitivity of diffusion- and perfusion-weighted imaging for diagnosing acute ischemic stroke is 97.5%. Stroke 2015; 46(1):98–101

22. Hacke W, Donnan G, Fieschi C, et al; ATLANTIS Trials Investigators; ECASS Trials Investigators; NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004; 363(9411):768–774 23. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333(24):1581–1587 24. Hacke W, Kaste M, Bluhmki E, et al; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359(13):1317–1329 25. Lees KR, Bluhmki E, von Kummer R, et al; ECASS, ATLANTIS, NINDS, and EPITHET rt-PA Study Group. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010; 375(9727):1695–1703 26. Tomsick T, Brott T, Barsan W, et al. Prognostic value of the hyperdense middle cerebral artery sign and stroke scale score before ultraearly thrombolytic therapy. AJNR Am J Neuroradiol 1996; 17(1):79–85 27. Lindsberg PJ, Soinne L, Tatlisumak T, et al. Long-term outcome after intravenous thrombolysis of basilar artery occlusion. JAMA 2004; 292(15):1862–1866 28. Lindsberg PJ, Mattle HP. Therapy of basilar artery occlusion: a systematic analysis comparing intra-arterial and intravenous thrombolysis. Stroke 2006; 37(3):922–928 29. Lutsep HL, Rymer MM, Nesbit GM. Vertebrobasilar revascularization rates and outcomes in the MERCI and multi-MERCI trials. J Stroke Cerebrovasc Dis 2008; 17(2):55–57 30. Pfefferkorn T, Holtmannspötter M, Schmidt C, et al. Drip, ship, and retrieve: cooperative recanalization therapy in acute basilar artery occlusion. Stroke 2010; 41(4):722–726 31. Campbell BC, Mitchell PJ, Kleinig TJ, et al; EXTEND-IA Investigators. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 2015; 372(11):1009–1018 32. Costalat V, Machi P, Lobotesis K, et al. Rescue, combined, and stand-alone thrombectomy in the management of large vessel occlusion stroke using the solitaire device: a prospective 50-patient single-center study: timing, safety, and efficacy. Stroke 2011; 42(7):1929–1935 33. Goyal M, Demchuk AM, Menon BK, et al; ESCAPE Trial Investigators. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 2015; 372(11):1019–1030 34. Jovin TG, Chamorro A, Cobo E, et al; REVASCAT Trial Investigators. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med 2015; 372(24):2296–2306 35. Saver JL, Goyal M, Bonafe A, et al; SWIFT PRIME Investigators. Stentretriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med 2015; 372(24):2285–2295 36. Jauch EC, Saver JL, Adams HP, Jr, et al; American Heart ­ Association Stroke Council; Council on Cardiovascular Nursing;Council on Peripheral Vascular Disease;Council on Clinical Cardiology. ­Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013; 44(3):870–947 37. Powers WJ, Derdeyn CP, Biller J, et al; American Heart Association Stroke Council. 2015 American Heart Association/American Stroke Association focused update of the 2013 guidelines for the early management of patients with acute ischemic stroke regarding endovas-

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cular treatment: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2015; 46(10):3020–3035

46. Horikoshi T, Nukui H, Yagishita T, Nishigaya K, Fukasawa I, Sasaki H. Oculomotor nerve palsy after surgery for upper basilar artery aneurysms. Neurosurgery 1999; 44(4):705–710, discussion 710–711

38. Welch K. Excision of occlusive lesions of the middle cerebral artery. J Neurosurg 1956; 13(1):73–80

47. Raabe A, Beck J, Gerlach R, Zimmermann M, Seifert V. Near-infrared indocyanine green video angiography: a new method for intraoperative assessment of vascular flow. Neurosurgery 2003; 52(1):132–139, discussion 139

39. Inoue T, Tamura A, Tsutsumi K, Saito I, Saito N. Surgical embolectomy for large vessel occlusion of anterior circulation. Br J Neurosurg 2013; 27(6):783–790 40. Hino A, Oka H, Hashimoto Y, et al. Direct microsurgical embolectomy for acute occlusion of the internal carotid artery and middle cerebral artery. World Neurosurg 2016; 88:243–251 41. Horiuchi T, Nitta J, Ogiwara T, Sakai K, Hongo K. Outcome predictors of open embolectomy in middle cerebral artery occlusion. Neurol Res 2009; 31(9):892–894 42. Meyer FB, Piepgras DG, Sundt TM, Jr, Yanagihara T. Emergency embolectomy for acute occlusion of the middle cerebral artery. J Neurosurg 1985; 62(5):639–647 43. Elsharkawy A, Niemelä M, Lehečka M, et al. Focused opening of the sylvian fissure for microsurgical management of MCA aneurysms. Acta Neurochir (Wien) 2014; 156(1):17–25 44. Goehre F, Kamiyama H, Kosaka A, et al. The anterior temporal approach for microsurgical thromboembolectomy of an acute proximal posterior cerebral artery occlusion. Neurosurgery 2014; 10 Suppl 2:174–178, discussion 178 45. Goehre F, Yanagisawa T, Kamiyama H, et al. Direct microsurgical embolectomy for an acute distal basilar artery occlusion. World Neurosurg 2016; 86:497–502

48. Higashida RT, Furlan AJ, Roberts H, et al; Technology Assessment Committee of the American Society of Interventional and Therapeutic Neuroradiology; Technology Assessment Committee of the Society of Interventional Radiology. Trial design and reporting standards for intraarterial cerebral thrombolysis for acute ischemic stroke. Stroke 2003; 34(8):e109–e137 49. Rankin J. Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J 1957; 2(5):200–215 50. van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19(5):604–607 51. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA 1999; 282(21):2003–2011 52. Hill MD, Rowley HA, Adler F, et al; PROACT-II Investigators. Selection of acute ischemic stroke patients for intra-arterial thrombolysis with prourokinase by using ASPECTS. Stroke 2003; 34(8):1925–1931

25

Brainstem and Thalamic Intraparenchymal Hemorrhage Lynn B. McGrath and Michael R. Levitt

Abstract

Brainstem and thalamic intraparenchymal hemorrhage (IPH) are relatively rare conditions associated with high mortality and morbidity, traditionally treated by medical management, although the recent use of stereotactic aspiration has proven promising. Cases of brainstem IPH occur at a rate of about 10 to 20 cases per 100,000 persons worldwide. Patients with chronic hypertension have a fourfold risk of a brainstem IPH, and the rates of IPH are much higher in at-risk groups such as men, persons older than 55 years, and certain ethnic groups. The reported mortality rate ranges from 30 to 90%, and those who survive an IPH often experience the worst functional outcomes of patients with any type of stroke. Patients with brainstem IPH usually present with severe hypertension, followed by a rapid decline in mental status, pupillary abnormalities, respiratory derangements, and motor deficits. Medical management is the preferred method of treatment. However, minimally invasive procedures such as stereotactic aspiration are expanding the neurosurgical treatment options for this challenging disease. Keywords:  brainstem, intracerebral hemorrhage, intraparenchymal hemorrhage, pons, thalamus

■■ Pathophysiology Three types of brainstem hemorrhage are typically recognized: (1) nontraumatic spontaneous hemorrhages confined within the brainstem parenchyma, (2) spontaneous hemorrhages that spread superiorly into the midbrain or thalamus or that rupture into the ventricular system, and (3) petechial brainstem hemorrhages that arise from trauma due to supratentorial mass effect and subsequent transtentorial cerebral herniation. The pons is by far the most common location within the brainstem to be affected by intraparenchymal hemorrhage  (IPH), regardless of where the hemorrhage originates.1 Brainstem hemorrhage is a relatively rare condition characterized nearly exclusively by primary pontine hemorrhage (PPH) and thalamic hemorrhage (TH). Clinicopathologic investigations of cases of spontaneous IPH have largely focused on the much more common supratentorial forms of the disease. Although much of the accepted understanding of the mechanisms leading to supratentorial IPH can reasonably be applied to PPH and TH, each type of hemorrhage has a distinct system of blood supply with different cell populations that may react differently to IPH. It is therefore essential to continue efforts to develop specific animal models of PPH and TH.2,​3,​4 Long-term hypertension results in pathologic change within the arterial walls of vulnerable cerebral vasculature and is thus a major risk factor for IPH. This general relationship has been

posited for more than a century, but the exact mechanism by which rupture occurs remains a point of contention. In 1868, Charcot and Bouchard related IPH to the rupture of small pseudoaneurysms that form preferentially within the walls of the small arteries most often implicated in large spontaneous intracranial hemorrhages.2 Recent ultrastructural investigation has demonstrated that Charcot-Bouchard’s proposed mechanism is responsible for only a few IPH cases. Instead, most IPHs arise from arterial bifurcation points weakened by arteriosclerosis.5 Takebayashi and Kaneko5 were the first to report on an examination of these rupture points with electron microscopy. Lenticulostriate arteries were removed from patients who underwent surgery within 4 hours of an IPH, and for comparison, bilateral lenticulostriates and middle meningeal arteries were removed at autopsy from patients who had died. The small temporal cortical branches assessed as controls had normal smooth muscle cells within the media. However, the middle and distal portions of involved lenticulostriate arteries were severely atrophied or had complete obliteration of medial smooth muscle cells at rupture points, which occurred at or near vessel bifurcations. All the rupture sites demonstrated luminal dilatation, intimal thickening, and atrophied medial smooth muscle cells with a moth-eaten appearance due to increased amounts of cellular debris within the intercellular matrix. These small intracerebral vessels undergo degenerative changes largely due to chronic hypertension, which accelerates lipid infiltration, and the processes that reduce compliance in the vessel wall, such as arteriosclerosis with lipohyalinosis and fibrinoid necrosis. These degenerative changes leave vessels vulnerable to rupture from spontaneous fluctuations in blood pressure and seem to most severely affect the lenticulostriate arteries of the middle and anterior cerebral arteries. However, the Takebayashi and Kaneko5 study did demonstrate similar findings in four cases of PPH and TH. Takebayashi and Kaneko5 concluded that degeneration of medial smooth muscle cells at the branch points of small penetrating arteries is the primary mechanism resulting in IPH. Of the 61 cases examined, 2 cases involved ruptures of small segmental dilatations consistent with Charcot-Bouchard aneurysms. However, it was ultimately concluded that, although these aneurysms are a real phenomenon, they do not represent the main mechanism driving arterial rupture in patients with IPH. The Takebayahsi and Kaneko5 study focused mainly on ruptured lenticulostriate arteries causing supratentorial IPH treated by surgical decompression and resection. Although some of the mechanisms underpinning this phenomenon might be expected to also apply to PPH and TH, it would be inappropriate to assume that these pathways are identical. The development of a brainstem hemorrhage model with which to study the same processes in these distinct anatomical locations has proven challenging.4,​5

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One autopsy study of 18 patients with brainstem hemorrhage created a classification based on anatomical location (Fig. 25.16). Most PPH cases  (15 of 18) were found to originate in the region of the medial border between the basilar and tegmental parts of the middle level of the pons. This bleeding pattern was termed tegmentobasilar, as evident on magnetic resonance imaging (Fig. 25.2), and it was further subdivided into “upper tegmentobasilar” and “lower tegmentobasilar,” with nearly equal incidence. Few patients (3 of 18) demonstrated a bleeding origin in the tegmentum at the middle level of the pons, termed tegmental (Fig. 25.3). Tegmentobasilar pontine hemorrhages were found to spread in predictable patterns, namely via contralateral extension, ventrodorsal extension, and upward extension.6 In 15 of 18 patients, the bleeding extended contralaterally to form a PPH with bilateral involvement. Ventrodorsal extension also occurred in 15 patients, and 12 of these hemorrhages broke into the fourth ventricle. In 13 patients, upward extension was noted, with 11 of these hemorrhages penetrating into the midbrain and 2 reaching as far

as the thalamus. Among all 18 patients, 5 had hemorrhages that were confined to the pons. Direct extension into the medulla was not noted in any bleeding pattern. The cases of tegmentobasilar PPH were concluded to be arterial in nature because of the characteristic rapid onset and large volume (< 40 mL) of hemorrhage. The tegmental cases were believed to represent capillary or venous bleeding because of the small volume of hemorrhage (< 10 mL) and their typical unilateral confinement within the pons. Regardless of subtype, the hemorrhage initially forms when a single vessel ruptures, subsequently increasing tension and inducing rupture in adjacent arteries, rapidly giving rise to a larger hemorrhage involving multiple rupture points in an “avalanche” fashion.5 Histologic sections of brain affected by IPH are characterized by the presence of edema, neuronal damage, macrophages, and neutrophil infiltration of surrounding tissue.2 Hemorrhage is found to spread between planes of intact white matter embedded in the hematoma. The disruption of the blood-brain barrier and the process of neuronal death result in vasogenic and cytotoxic edema that usuFig. 25.1  (a,b) Illustrations show origins of pontine intraparenchymal hemorrhage. Numbers indicate how many of the 18 patients had hemorrhages in those areas. Abbreviations: IPL, intrapontine localization; MD, midbrain development; R4V, rupture into fourth ventricle; TBD, tegmentobasilar development; TD, thalamic development; TL, tegmental localization. (Reproduced with ermission from Goto et al 1980.6)

Fig. 25.2  (a) Axial and (b) sagittal magnetic resonance imaging gradient echo sequences of a patient with the tegmentobasilar subtype of pontine intraparenchymal hemorrhage.

25  Brainstem and Thalamic Intraparenchymal Hemorrhage

351

Fig. 25.3  (a) Axial and (b) coronal unenhanced computed tomograms of a patient affected unilaterally by the tegmental subtype of pontine intraparenchymal hemorrhage.

ally persists for 5 to 14 days.7 Although mechanical compression of surrounding tissue secondary to hematoma was once widely thought to be the primary factor in both initial and secondary ischemic injuries after IPH, blood and plasma by-products of neuronal death are now believed to drive secondary injury to neural tissue.2

■■ Incidence and Epidemiology Spontaneous cases of IPH occur at a rate of about 10 to 20 cases per 100,000 persons worldwide.2 This rate represents spontaneous bleeding in all sites throughout the brain. A 30-year review of all IPH-related hospital admissions in the United States identified 1,545,000 cases of IPH, representing 0.15% of all hospitalizations.8 A sharp increase in IPH-related admissions between 1979 and 1988 was attributed to the advent of computed tomography for neurologic emergencies and the 1979 introduction of the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Since this initial increase, the rate of admission for IPH has essentially remained stable as of 2008, the last year included in the study. Within this larger group, PPH is a relative rarity, representing a yearly incidence of 1 case per 50,000 people, accounting for nearly 140,000 cases per year worldwide. Although PPH accounts for only about 7 to 10% of the 2 million annual cases of IPH worldwide, it is characterized by the highest rates of mortality and morbidity of any stroke subtype.2,​3,​4,​9,​10,​11,​12,​13,​14 TH is a more common phenomenon, accounting for up to 30% of all cases of IPH, and it is also characterized by high morbidity and ­mortality.15,​16,​17 Patients with chronic hypertension have a fourfold risk of IPH.18 As might be expected, in light of the association of IPH with chronic hypertension, its incidence also increases as access to regular medical care decreases, and it is thus more common throughout impoverished and poorly educated populations.2 However, the rate of IPH is probably much higher in at-risk groups such as men, persons older than 55 years, and certain ethnic groups.2,​3,​4,​9,​10,​11 Several groups, such as Japanese and African American populations, have a disproportionately higher rate of PPH and TH. A study on the incidence of intracranial hemorrhage by anatomical location in a midwestern American population of African Americans and American whites found that African Americans had higher rates of IPH (risk ratio = 1.9).19

Despite this difference, the rate of lobar IPH was only nominally increased in African Americans (risk ratio = 1.4). The most important contributor to increased risk in the African American population arose from the increase in PPH and TH (risk ratio = 3.3). Furthermore, when the rate among younger African Americans (aged 35–54 years) was examined, the relative risk was substantially higher (risk ratio = 9.8).

■■ Natural History of Disease The prognosis after PPH and TH is generally poor. Certain clinical and radiographic features at presentation (initial Glasgow Coma Scale [GCS] score < 8, presence of hydrocephalus, male sex, large hemorrhage volume, and pupillary dysfunction) may portend a more dismal prognosis.9,​10,​12,​13,​14,​16,​20,​21 The reported mortality rate for PPH and TH ranges from 30 to 90%. Up to 62% of patients die within the first year, and 74% die within the first 3 years; most of those who do survive are severely disabled.4,​22 Death from systemic complications such as pneumonia is common and correlates highly with advanced age. As might be expected in light of the morbidity and mortality associated with the acute phase of the disease process, those patients who survive PPH and TH experience the worst functional outcomes of patients with any type of stroke.2,​3,​9,​10,​12,​13,​14,​16,​17,​20,​21

■■ Clinical Presentation Patients with PPH and TH often present with severe hypertension followed by a rapid decline in mental status, pupillary abnormalities, respiratory derangements, and motor deficits.6,​12,​21 These symptoms will differ by the type of pontine hemorrhage, and although rapid mental status decline can make examination difficult, findings can occasionally help pinpoint the hemorrhage location. For example, patients with either ophthalmoplegia or involuntary vertical eye movements may have lesions in the middle level of the ipsilateral or bilateral pontine tegmentum, and patients with respiratory disturbances may have involvement of the tegmentobasilar structures.6 In a profile of patients with TH, motor findings were common, with hemiparesis in 85%  (88 of 104) of patients and abnormal plantar reflex (Babinski sign) in 55% (57 of 104) of patients.17 Oculomotor dysfunction and pupillary abnormalities, including miosis, were observed in about one-third of the patients.

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■■ Perioperative Evaluation With such a morbid disease process, many patients with PPH and TH are either unstable for intervention or unsuitable for surgical treatment, which often has a grave prognosis. Frank discussion with family members and consideration of the patient’s wishes are paramount. Although few hemorrhage patterns in the brainstem or thalamus are appropriate for surgical intervention, basic criteria can be used in selecting surgical candidates. Some authors have advocated the location and volume of hemorrhage as viable guidelines in deciding whether to offer a minimally invasive procedure such as stereotactic aspiration. For example, Hara et al23 reported encouraging outcomes with the use of stereotactic aspiration in PPH of the bilateral tegmental and basal tegmental subtypes. For patients with TH, conservative therapies are generally applied in cases of small hemorrhage volumes (< 10 mL), as these patients will often have a favorable outcome that makes the morbidity of surgery prohibitive. Chen et al15 noted that, in most cases, large hemorrhage volume (> 30 mL) will lead to poor outcomes and high mortality regardless of treatment. Their 2012 study of stereotactic aspiration suggests that this treatment may be beneficial in patients with moderate hemorrhage volumes (10–30 mL). However, these selection criteria are controversial and have not been prospectively validated.

■■ Treatment Options In general, patients with PPH or TH present with a decreased level of consciousness and often require intubation for airway and secondary injury protection.24 Early decisions must be made regarding hyperventilation, use of osmotic therapy, and intraventricular catheterization for intracranial pressure monitoring and control. Guidelines on the initial treatment of intracranial pressure are the subject of considerable controversy,2,​25 although the 2015 American Heart Association guidelines suggest that ventricular drainage and maintenance of cerebral perfusion pressure between 50 and 70 mm Hg can be considered for patients with hydrocephalus and a GCS score ≤ 8.26 Although several authors have attempted to evaluate the use of aggressive invasive procedures in the treatment of PPH and TH, these methods remain a chronically understudied phenomenon. By 1996, there were more than 315 randomized clinical therapeutic trials for acute ischemic stroke and more than 75 trials for subarachnoid hemorrhage (SAH). During the same period, only four randomized surgical trials on IPH had been conducted, despite the fact that IPH is more than twice as common as SAH and more likely to lead to morbidity and death than either acute ischemic stroke or SAH.27 Unfortunately, the most important randomized trial of surgical treatment for IPH in the past decade (Surgical Treatment for Ischemic Heart Failure [STICH]) was performed to evaluate the treatment of supratentorial IPH exclusively, and it therefore shed no light on the treatment of pontine or thalamic hemorrhages.​28 Open craniotomy to evacuate PPH and TH results in almost universally poor outcomes, and the practice has fallen out of favor.29 Medical management remains the preferred method of

treatment for PPH and TH, despite efforts since 1978 to reduce TH volume using minimally invasive techniques.15 Computed tomography–guided and ultrasound-guided aspiration may remove an average of 71% and 81% of hematoma, respectively, with a rate of rebleeding approaching 5%, which is not significantly different from that for aspiration combined with the simultaneous administration of thrombolytics.27 Aspiration of supratentorial IPH is currently the subject of considerable research; however, most studies of such treatment frequently exclude patients with PPH and less frequently exclude patients with TH. There are some accounts of surgically treated patients with positive outcomes,6,​20,​29 the most significant of which demonstrated better functional outcomes and improved levels of consciousness in patients treated with stereotactic aspiration for bilateral and basal tegmental types of PPH.11,​22 In Chen et al’s15 2012 study of stereotactic aspiration in patients with moderate TH, an absolute reduction in hematoma volume of 12 mL was achieved in 3 days and an absolute reduction of 18 mL was achieved in 7 days. The authors approached the hemorrhage directly through the internal capsule, because this brain tissue is most commonly destroyed in the initial hemorrhage. The rate of rebleeding within 30 days was 9% for the aspiration group, which was not significantly different than the rate of 5% for the conservative treatment group. Most importantly, the authors found that patients treated with aspiration experienced favorable outcomes (GCS score > 3) at a rate of 51%, compared with 30% for those in the conservative treatment group. Likewise, patients undergoing aspiration had a 90-day cumulative mortality rate of 15% compared with 33% in the conservative treatment group.

■■ Patient Outcomes PPH and TH are highly lethal pathologies, resulting in mortality rates quoted variously throughout the medical literature as ranging from 30 to 90%, but most commonly considered to be in excess of 65% within the first year.2,​3,​4,​9,​10,​12,​13,​14,​16,​20,​21 Up to 74% of patients recovering from PPH will die within 3 years of ictus, and those who do survive are often severely disabled. Six months after IPH, up to 80% of rehabilitating patients will not have recovered to the point of independent living, and patients with PPH are so devastated that they are often unable to participate meaningfully in rehabilitation programs.​30,​31 Lekic et al3 postulate that this extraordinarily high mortality rate is due to the excess of ascending and descending thalamic and brainstem projections essential to maintaining normal reticular, respiratory, and cardiovascular functions. Qureshi et al2 and Broderick et al29,​32 found that patients with a GCS score < 9 and a large hemorrhage volume (< 60 mL) had a 90% mortality rate after 1 month, whereas patients with a GCS score > 9 and moderate hemorrhage volume (< 30 mL) had a mortality rate of 17% after 1 month. Balci et al12 found an overall mortality rate of 56% for patients with PPH. Patients had a significantly higher risk of death if they had an admission GCS score < 10; if they had ventrally located, bilateral, or massive tegmental hematomas; or if they had hydrocephalus. Furthermore, Balci et al12 also found significant associations among admission mental status, hematoma location, and presence of hydrocephalus.

25  Brainstem and Thalamic Intraparenchymal Hemorrhage In general, patients with large hemorrhage volume or hemorrhages originating in the bilateral tegmentum do worse, likely because of the proximity to cranial nerve nuclei, the reticular activating system, and the fourth ventricle. In contrast, Murata et al21 found that, in patients who experience a small hematoma  (≤ 20-mm transaxial size), pupillary abnormalities and the onset of hydrocephalus were related to worse outcomes after PPH.

■■ Conclusion PPH and TH are highly morbid disease processes that historically have proven refractory to neurosurgical intervention. Although these entities represent a small fraction of the total number of stroke cases, they are associated with the highest morbidity and mortality of any stroke subtype. Chronic hypertension is a major driver of changes in the cerebral vasculature that subsequently lead to hemorrhage. Although prevention through blood pressure regulation remains the mainstay of management, recent studies have demonstrated favorable results with the use of stereotactic aspiration of hemorrhage in select patients. Although surgery in these patients is far from the standard of care, continued innovation in the application of stereotactic techniques may expand the neurosurgical armamentarium for treating this challenging disease process in select patients. References 1. Scarabino T, Salvolini U, Jinkins JR, eds. Emergency Neuroradiology. New York, NY: Springer; 2006 2. Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF. Spontaneous intracerebral hemorrhage. N Engl J Med 2001; 344(19):1450–1460 3. Lekic T, Rolland W, Manaenko A, et al. Evaluation of the hematoma consequences, neurobehavioral profiles, and histopathology in a rat model of pontine hemorrhage. J Neurosurg 2013;118(2):465–477 4. Tao C, Zhang R, Hu X, et al. A novel brainstem hemorrhage model by autologous blood infusion in rat: white matter injury, magnetic resonance imaging, and neurobehavioral features. J Stroke Cerebrovasc Dis 2016;25(5):1102–1109 5. Takebayashi S, Kaneko M. Electron microscopic studies of ruptured arteries in hypertensive intracerebral hemorrhage. Stroke 1983;14(1):28–36 6. Goto N, Kaneko M, Hosaka Y, Koga H. Primary pontine hemorrhage: clinicopathological correlations. Stroke 1980;11(1):84–90 7. Zazulia AR, Diringer MN, Derdeyn CP, Powers WJ. Progression of mass effect after intracerebral hemorrhage. Stroke 1999;30(6):1167–1173 8. Rincon F, Mayer SA. The epidemiology of intracerebral hemorrhage in the United States from 1979 to 2008. Neurocrit Care 2013;19(1):95–102 9. Matsukawa H, Shinoda M, Fujii M, Takahashi O, Murakata A. Risk factors for mortality in patients with non-traumatic pontine hemorrhage. Acta Neurol Scand 2015;131(4):240–245 10. Seong JW, Kim MH, Shin HK, Lee HD, Park JB, Yang DS. Usefulness of the combined motor evoked and somatosensory evoked potentials for the predictive index of functional recovery after primary pontine hemorrhage. Ann Rehabil Med 2014;38(1):13–18 11. Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet 2009;373(9675):1632–1644 12. Balci K, Asil T, Kerimoglu M, Celik Y, Utku U. Clinical and neuroradiological predictors of mortality in patients with primary pontine hemorrhage. Clin Neurol Neurosurg 2005;108(1):36–39

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13. Takeuchi S, Suzuki G, Takasato Y, et al. Prognostic factors in patients with primary brainstem hemorrhage. Clin Neurol Neurosurg 2013; 115(6):732–735 14. Wessels T, Möller-Hartmann W, Noth J, Klötzsch C. CT findings and clinical features as markers for patient outcome in primary pontine hemorrhage. AJNR Am J Neuroradiol 2004;25(2):257–260 15. Chen M, Wang Q, Zhu W, et al. Stereotactic aspiration plus subsequent thrombolysis for moderate thalamic hemorrhage. World Neurosurg 2012;77(1):122–129 16. Osawa A, Maeshima S. Aphasia and unilateral spatial neglect due to acute thalamic hemorrhage: clinical correlations and outcomes. Neurol Sci 2016;37(4):565–572 17. Mori S, Sadoshima S, Ibayashi S, Fujishima M, Iino K. Impact of thalamic hematoma on six-month mortality and motor and cognitive functional outcome. Stroke 1995;26(4):620–626 18. Osborn AG. Osborn’s Brain: Imaging, Pathology, and Anatomy. Philadelphia, PA: Lippincott Williams & Wilkins; 2012 19. Flaherty ML, Woo D, Haverbusch M, et al. Racial variations in location and risk of intracerebral hemorrhage. Stroke 2005;36(5):934–937 20. Miyai I, Suzuki T, Kang J, Volpe BT. Improved functional outcome in patients with hemorrhagic stroke in putamen and thalamus compared with those with stroke restricted to the putamen or thalamus. Stroke 2000;31(6):1365–1369 21. Murata Y, Yamaguchi S, Kajikawa H, Yamamura K, Sumioka S, Nakamura S. Relationship between the clinical manifestations, computed tomographic findings and the outcome in 80 patients with primary pontine hemorrhage. J Neurol Sci 1999;167(2):107–111 22. Ye Z, Huang X, Han Z, et al. Three-year prognosis of first-ever primary pontine hemorrhage in a hospital-based registry. J Clin Neurosci 2015; 22(7):1133–1138 23. Hara T, Nagata K, Kawamoto S, et al. [Functional outcome of primary pontine hemorrhage: conservative treatment or stereotaxic surgery]. No Shinkei Geka 2001;29(9):823–829 24. Gujjar AR, Deibert E, Manno EM, Duff S, Diringer MN. Mechanical ventilation for ischemic stroke and intracerebral hemorrhage: indications, timing, and outcome. Neurology 1998;51(2):447–451 25. Toyoda K, Steiner T, Epple C, et al. Comparison of the European and Japanese guidelines for the acute management of intracerebral hemorrhage. Cerebrovasc Dis 2013;35(5):419–429 26. Hemphill JC III, Greenberg SM, Anderson CS, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2015;46(7):2032–2060 27. Broderick JP, Adams HP Jr, Barsan W, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 1999;30(4):905–915 28. Mendelow AD, Gregson BA, Rowan EN, Murray GD, Gholkar A, Mitchell PM; STICH II Investigators. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas  (STICH II): a randomised trial. Lancet 2013; 382(9890):397–408 29. Broderick JP, Brott T, Zuccarello M. Management of intracerebral hemorrhage. In: Batjer HH, ed. Cerebrovascular Disease. Philadelphia, PA: Lippincott-Raven; 1997;611–627 30. Ruhland JL, van Kan PL. Medial pontine hemorrhagic stroke. Phys Ther 2003;83(6):552–566 31. Gebel JM, Broderick JP. Intracerebral hemorrhage. Neurol Clin 2000; 18(2):419–438 32. Broderick JP, Brott TG, Duldner JE, Tomsick T, Huster G. Volume of intracerebral hemorrhage: a powerful and easy-to-use predictor of 30-day mortality. Stroke 1993;24(7):987–993

26

Surgical Management of Posterior Circulation Aneurysms

Behnam Rezai Jahromi, Tarik F. Ibrahim, Ferzat Hijazy, Danil A. Kozyrev, Felix Goehre, Hugo Andrade-Barazante, Hanna Lehto, and Juha Hernesniemi

Abstract

Posterior circulation aneurysms account for less than 10 to 16% of all intracranial aneurysms. Open microneurosurgical treatment of these lesions has always been challenging because of their close relationship to sensitive neuroanatomical structures. In this chapter, we review microsurgical approaches and techniques for complex aneurysms in the posterior circulation according to their location in the vertebrobasilar arterial system. Although individual surgical experience with posterior circulation aneurysms is declining as a result of improvements in endovascular techniques, the senior author (J.H.) of this chapter has treated more than 1,650 posterior circulation aneurysms, and the contents of this chapter are based on his personal experience. Keywords:  aneurysm, anterior inferior cerebellar artery, approaches, basilar, posterior cerebral artery, posterior inferior cerebellar artery, posterior circulation, superior cerebellar artery, vertebral artery

■■ Surgical Management of Posterior Circulation Aneurysms Posterior circulation aneurysms account for 10 to 16% of all intracranial aneurysms. Open microsurgical treatment of these lesions has always been challenging because of their close relationship to sensitive neuroanatomical structures.1,​2,​3,​4 During the last two decades, microsurgical treatment of these lesions has shifted mostly to endovascular strategies because of improvements in modern endovascular techniques. This shift has led to a decline in the surgical treatment of posterior circulation aneurysms. Despite endovascular advances, select complex lesions continue to require microsurgical treatment. Additionally, in the developing world, the prohibitive cost of endovascular technologies has resulted in the continued need for microsurgical expertise. Posterior circulation aneurysms often require complex skull base approaches because of the shape of the cranium, the narrowed basal cisterns, the proximity to cranial nerves (CNs), and the often tortuous course of the parent vessel. In general, these operations are performed in deep and narrow surgical corridors. Therefore, the microsurgical treatment of posterior circulation aneurysms cannot be uniformly described. In this chapter, we will present special anatomical features of aneurysms and structural anatomical relationships in the subsections on each aneurysm position. We will also present classical microsurgical approaches and procedures as well as treatment strategies for complex aneurysms according to their location in the vertebrobasilar arterial system (Fig. 26.1).

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■■ Surgical Approaches to Posterior Circulation Aneurysms Upper Basilar Segment Aneurysms Aneurysms of the upper basilar artery consist of aneurysms arising from the basilar bifurcation, posterior cerebral artery (PCA), superior cerebellar artery (SCA) junction, and proximal P1 segment of the PCA.5 Some of the major surgical routes to treat these aneurysms include the subtemporal approach; the pterional transsylvian approach, with all its surgical variations; and the temporopolar or “half-and-half” approach.6,​7,​8 An important landmark when choosing a surgical approach for upper basilar artery aneurysms is the relationship between the aneurysm neck and the posterior clinoid process. Aneurysms located 5 to 6 mm above the posterior clinoid process can be treated through a pterional transsylvian approach. However, when the aneurysm neck is not higher than 6 mm and not lower than 8 mm from the posterior clinoid process, a subtemporal approach is an appropriate surgical option. In the following sections, we will describe these surgical approaches and their modifications for upper basilar artery aneurysms.9,​10

Subtemporal Approach In 1954 and 1959, respectively, Olivecrona and Drake described the subtemporal approach to access basilar artery aneuryms.9,​11 Subsequently, this approach was also adopted for PCA aneurysms. Since the first description of the subtemporal craniotomy, this approach has undergone several modifications.12,​13 The subtemporal approach offers a good exposure and visualization of the middle fossa floor and the interpeduncular space. Mainly used for the treatment of upper basilar artery aneurysms, this approach allows additional exposure of the proximal P2 segment.7,​14

Positioning The patient is placed in the lateral park bench position, with the head fixed to the Sugita or Mayfield frame in a neutral position. The head is slightly elevated above the cardiac level, and the upper shoulder is retracted backward and caudally. During the subtemporal approach, cerebrospinal fluid  (CSF) should be released via a lumbar drain, which is placed after positioning, with approximately 50 to 100 mL of CSF drained before the dura is opened. This maneuver allows for the brain relaxation that is necessary to avoid excessive retraction of the temporal lobe.

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Fig. 26.1  Approach selection for the posterior circulation based on an angiogram in anteroposterior view.

Skin incision A horseshoe-shaped skin incision is made, starting 1 cm in front of the tragus, just above the zygomatic arch (Fig. 26.2a). The skin incision runs cranially, approximately 6 to 8 cm, and then curves posteriorly around the earlobe, reaching a line between the porion and the asterion. The skin is opened in a myocutaneous fashion and retracted caudally, using the Sugita frame spring hooks, which provide a strong retraction force. The monopolar cautery is used to detach the temporalis muscle, exposing the zygomatic arch and the suprameatal spine. During dissection, it is important to preserve and leave the external auditory canal intact because the skin around this area is very thin (Fig. 26.2b).

Craniotomy A single bur hole is performed at the most cranial and superior end of the skin flap; an additional and optional bur hole can be placed just above the zygoma (Fig. 26.2c). This particular bur hole is used to detach the dura mater and place a bypass when necessary. Once the dura is detached from the bone, a craniotomy of approximately 4 to 5 cm in diameter is obtained. The first cut with the craniotome starts from the first bur hole and is directed anteriorly and caudally to the base of the middle fossa. The second cut is made posteriorly toward the floor of the middle fossa. Finally, the bone is thinned down with the craniotome along the end of the previous two cuts, and then the bone flap is lifted and cracked (Fig. 26.2d). Multiple tack-up holes are drilled around the craniotomy to suspend the dura and prevent the formation of epidural hematoma.15 The craniotomy can be

widened using a diamond drill in the temporobasal direction, exposing the middle fossa floor.7,​13

Intracranial dissection The dura is opened in a curvilinear manner, with the base directed caudally, and the dura edges are elevated over the craniotomy with multiple tack-up sutures. The main goal of the subtemporal approach is to reach the tentorial edge quickly, without causing damage or excessive compression to the temporal lobe. The mobilization of the temporal lobe starts anteriorly on the temporal pole and proceeds posteriorly and across the caudal surface, avoiding abrupt retraction of the middle portion of the temporal lobe because of the risk of tearing the vein of Labbé, which can lead to temporal lobe swelling and venous infarction. The spinal drain can be closed at this time. Once the temporal lobe is mobilized and the tentorial edge is visible, a wide retractor is placed to elevate the uncus, exposing the interpeduncular cistern and the oculomotor nerve (CN III). CN III can be mobilized by cutting the surrounding arachnoid membrane adhesions, although a higher risk of CN III palsy exists with even minimal manipulation of the nerve. In some circumstances, even with the retraction of the uncus and mobilization of CN III, the interpeduncular cistern space remains narrow. This problem can be resolved by placing a small, straight miniclip on the tentorial edge, just at the insertion and intradural course of the trochlear nerve (CN IV), allowing upward retraction of the tentorial edge (Fig. 26.3).13 If a wider exposure is required, the tentorium can be divided by performing a perpendicular cut posterior to the insertion of CN IV; this cut should not be more

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than 10 mm long. The tentorial flap is then fixed with straight aneurysm clips, increasing the surgical exposure of the upper basilar artery.1 Venous bleeding from the tentorial cut can be stopped by injecting fibrin glue into this small opening. The dis-

section then continues, depending on the vascular segment to be treated. For low-lying basilar artery aneurysms, it is mandatory to split the tentorium. Careful preoperative planning is the key when deciding whether to split the tentorium to increase the surgical exposure (Fig. 26.4).

Frontotemporal Approach

Fig. 26.2  The left subtemporal approach. (a) This approach uses a horseshoe-shaped skin incision, starting 1 cm in front of the tragus, just above the zygomatic arch, then running cranially approximately 6 to 8 cm, and curving posteriorly around the earlobe, reaching a line between the porion and the asterion. (b) Monopolar cautery is used to detach the temporalis muscle, exposing the zygomatic arch and the suprameatal spine. Attention should be paid to preserve and leave intact the external auditory canal. A single bur hole is made at the most cranial and superior end of the skin flap. (c) Two cuts are made to complete the craniotomy. One cut starts from the bur hole, directing anteriorly and caudally to the base of the middle fossa; the second cut is made posteriorly toward the floor of the middle fossa. Finally, the bone is thinned down with the craniotome along the end of the previous two cuts. (d) The bone flap is lifted and cracked. The craniotomy can be widened using a diamond drill in the temporobasal direction to completely expose the middle fossa floor.

The approaches to the upper basilar artery have been grouped together to include the subtemporal approach, the pterional transsylvian approach, and the temporopolar or half-and-half approach. We have combined the pterional transsylvian and temporopolar approaches into the frontolateral or frontotemporal approaches, since both approaches follow a similar surgical route. However, slight intradural differences in these surgical approaches will be explained in more detail in the following sections. The frontolateral or frontotemporal approaches include the pterional, the lateral supraorbital, the extended lateral supraorbital, the anterior temporal, the temporopolar, and the orbitozygomatic approaches.6,​10,​16,​17,​18,​19 These approaches have been widely used to access aneurysms of the basilar bifurcation, proximal P1 segment, and SCA. The main objectives of the frontolateral approaches are to reduce retraction of the temporal lobe, to reduce damage to CN III and CN IV, to provide better exposure of the interpeduncular cistern anatomy, and to provide exposure necessary to treat other concomitant anterior circulation aneurysms.

Positioning, skin incision, and craniotomy For the frontolateral approaches, the patient is placed in the supine position with the head rotated 15° to 30° toward the contralateral side, with the degree of positioning different for each approach (Fig. 26.5). Frontolateral approaches are performed using a curvilinear frontotemporal skin incision. The

Fig. 26.3  Left subtemporal approach, tentorial opening. (a) Through a subtemporal exposure, the free edge of the tentorium (white arrow) is visualized. The trochlear nerve (CN IV) (black arrow) runs underneath the free edge of the tentorium before it enters the tentorium. (b) For a wider exposure, the tentorium can be divided. This is performed by coagulating a 10-mm-long segment of the tentorium posterior to the insertion of CN IV. (c) The tentorium is incised and coagulated carefully. Fibrin glue can be used to obtain hemostasis of venous bleeding. (d) A small Cottonoid (Johnson & Johnson) is inserted to protect the superior cerebellar artery in its course over the surface of the cerebellum. (e) The cut is continued medially through the coagulated tentorial layers toward the free edge, and the Cottonoid is pushed medially, step-bystep. (f) After the cut is completed, the tentorial flap is fixed with straight microclips, which provide wide exposure to the surgical field of the upper basilar artery.

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Fig. 26.4  Intracranial portion of the left subtemporal approach. (a) Through a subtemporal approach, the free edge of the tentorium and the interpeduncular cistern are visualized (white arrow). (b) More space is obtained to visualize the basilar trunk and superior cerebellar artery (SCA) (black arrow) by opening the interpeduncular cistern and releasing additional cerebrospinal fluid. (c) A wide retractor blade is placed to maintain the space that has been gained and to elevate the uncus. The oculomotor nerve (CN III) (black arrow) can be mobilized by cutting the surrounding arachnoid adhesions. A basilar artery–SCA aneurysm, with partially sclerotic sac, is visible. (d) CN III is mobilized to expose the neck of the aneurysm and to prepare it for clipping. (e) A curved clip is used to secure the aneurysm. Indocyanine green angiography can be used to confirm the occlusion of the aneurysm and the preservation of inflow and outflow vessels. (f) Intraoperative photograph demonstrates the depth of the surgical corridor necessary to traverse to treat aneurysms using the subtemporal approach.

length and extension of the skin incision vary, depending on the amount of exposure required. Table 26.1 summarizes the positioning, skin incision, and further craniotomy details of these approaches.

Intracranial Dissection (Pterional Transsylvian) The dura is opened in a semicircular fashion, and multiple tack-up sutures are placed from the dura toward the craniotomy edges to prevent further epidural bleeding. The sylvian fissure is opened by sharp dissection, starting at the level of the pars opercularis of the frontal gyrus and following the middle cerebral artery (MCA), until complete exposure of the internal carotid artery (ICA) bifurcation is obtained. The superficial sylvian veins should be carefully detached from the frontal region toward the temporal cortex to increase surgical exposure. The arachnoid adhesions covering the opticocarotid (chiasmatic) cistern, carotid cistern, and Liliequist's membrane are cut to obtain a wide exposure and to identify the posterior communicating artery (PCoA). The PCoA is followed posteriorly toward its junction with the ipsilateral PCA (P1–P2 segment). The basilar artery and its bifurcation are approached from an anterolateral direction between the ICA and the MCA. The dissection may continue laterally to the PCoA or medially to its perforators. Additionally, an alternative route, medially through the ipsilateral opticocarotid triangle, can be used as originally described by Yaşargil et al.20 However, this route is not frequently required. In special circumstances, such as in the case of a low-lying basilar artery aneurysm, a wider exposure can be obtained through a pterional transcavernous route or through a pretemporal transcavernous transzygomatic route.18,​19 The transcavernous approach, originally described by Dolenc et al,21 represents an expansion of the pterional approach. After a pterional approach is performed, the sphenoid wing is drilled off, from lateral to medial, until reaching the anterior clinoid process. Next, the superior orbital fissure is unroofed, exposing the meningo-orbital fold and the meningo-orbital artery. The meningo-orbital artery is subsequently coagulated

and cut, allowing stripping of the temporal dura propria from the lateral wall of the cavernous sinus. Additionally, the superior and lateral walls of the orbit are drilled off to increase surgical exposure, while preserving the periorbita. An extradural anterior clinoidectomy is then performed, and the dura is opened in a T-shaped fashion, with the vertical arm of the T following the sylvian fissure and the indentation of the sphenoid wing.6,​7,​10,​14 The dural cut extends all the way down to the entrance of CN III and into the oculomotor triangle. This maneuver helps to further mobilize CN III and exposes the interpeduncular fossa and the posterior clinoid process. Then, if drilling of the posterior clinoid process is necessary, it can be performed. For high-lying upper basilar artery aneurysms, an orbitozygomatic or an anterior temporal approach with zygomatic arch translocation enhances the subtemporal exposure of the middle fossa, providing a shallower depth of field to the temporal region and the upward trajectory for aneurysm exposure and dissection.

Intracranial Dissection (Anterior Temporal Approach) Similar to the pterional transsylvian approach, the anterior temporal approach requires, in its initial stages, a wide sylvian fissure dissection, allowing complete exposure of the M2 segments of the MCA and the supraclinoid portion of the ICA. As previously mentioned, the superficial sylvian veins should be detached and mobilized from the frontal cortex toward the temporal cortex, following the dissection until the entrance of the veins into the sphenoparietal sinus. The mobilization of the superficial sylvian veins represents the key point of the anterior temporal approach, allowing safe posterior and medial retraction of the temporal pole. Posterior retraction of the anterior temporal pole allows for visualization of the PCoA, anterior choroidal artery, and PCA (P1) (Fig. 26.6). Additionally, a lateral surgical trajectory can be obtained through the anterior temporal approach by retracting medially and elevating the anterior temporal pole from the middle fossa. This step requires the opening and sharp dissection of the arachnoid

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VI  Comprehensive Management of Vascular Pathology of the Brainstem and Thalamus Fig. 26.5  Left pterional approach to the top of the basilar artery. (a) The patient is placed in the supine position, and the head is rotated 15° to 30° toward the contralateral side and extended 20°. The skin incision is located behind the hairline and starts at the root of the zygoma, passing toward the midline. (b) A myocutaneous flap is performed and retracted frontally by spring hooks. The temporalis muscle is completely dissected. (c) A single bur hole is placed just under the temporal line, and the dura is detached from the bone with a curved dissector. (d) Two cuts are made from the bur hole: the first toward the region of the zygomatic process of the frontal bone and the second toward the temporal bone. (e) The two cuts are joined by thinning the bone between their ends, and the bone flap is cracked and lifted. The lateral sphenoid ridge is then drilled off to the superior orbital fissure. (f) Wide exposure is obtained of the frontal lobe (star), the temporal lobe (filled circle), and the sylvian fissure (arrow).

Table 26.1  P  ositioning, skin incision, and further craniotomy details of common approaches for posterior circulation aneurysms at or about the level of the basilar apex

Approach

Pterional

Lateral supraorbital

Orbitozygomatic

Anterior temporal or temporopolar

Position

Supine, head rotated 15–20° toward the contralateral side, head extended 20°

Supine, head rotated 15–30° toward the contralateral side, head flexed or extended according to the lesion

Supine, head rotated 30–90° toward the contralateral side, neck extended (highest point at ipsilateral malar eminence)

Supine, head rotated 30° to the contralateral side and slightly elevated above the cardiac level

Skin incision

Behind the hairline, starting at the root of the zygoma and passing the midline

Behind the hairline, beginning 3 cm above the zygoma to the ipsilateral midpupillary line

Behind the hairline, starting at the root of the zygoma and passing the midline toward the contralateral midpupillary line

Behind the hairline, starting at the root of the zygoma, extending posteriorly toward the retro-ocular area and passing the midline

Temporalis muscle dissection

Interfascial dissection, temporalis muscle completely dissected

Myocutaneous flap (only the superior and anterior aspect of temporalis muscle dissected)

Interfascial or subfascial dissection, temporalis muscle completely dissected

Interfascial or subfascial dissection, temporalis muscle completely dissected and retracted caudally

Location of craniotomy

Frontal, pterion, squamous temporal bone

Frontal, between zygomatic process of the frontal bone, greater sphenoid wing, and superior temporal line

Frontal, pterion, squamous temporal bone and orbitozygomatic osteotomy (orbital rim, orbital roof, lateral orbital wall, and zygomatic arch)

Frontal, pterion, squamous temporal bone; additionally, an orbitozygomatic osteotomy can be performed

Size of craniotomy

6 × 6 cm

4 × 4 cm

Approximately 8 × 8 cm (varies, depending on necessary frontal or temporal exposure)

Approximately 6–8 cm in diameter

Sphenoid drilling

To superior orbital fissure

Not required

To superior orbital fissure

To superior orbital fissure

26  Surgical Management of Posterior Circulation Aneurysms

359

Fig. 26.6  Intracranial dissection in the left pterional approach. All the procedures are performed under the operating microscope. (a) The dissection is started along the frontobasal surface of the frontal lobe, slightly medially from the proximal sylvian fissure, aiming to reach the right optic nerve (black arrow) and open the chiasmatic and carotid cisterns (white arrowhead) to release cerebrospinal fluid. (b) In this case, the optic-carotid triangle (dashed outline) is used to go more deeply (red arrow) toward the upper part of the basilar artery. (c) The sylvian fissure is opened proximally by sharp dissection to completely expose the internal carotid artery bifurcation. (d) The Liliequist membrane (arrow) is exposed and opened. (e) The top of the basilar artery is exposed to visualize the basilar tip aneurysm (arrow), which is dissected free for optimal clipping. (f) The aneurysm is clipped with a small curved clip. There is no temporary clipping in this patient, but in such cases we usually induce transient cardiac arrest by administering intravenous adenosine.

bands surrounding CN III and the ambient cistern until the PCA is visible.

Vertebrobasilar Aneurysms Presigmoid Approach (Posterior Petrosal Approach or Combined Supratentorial Infratentorial Approach) This approach is considered one of the most difficult approaches in neurosurgery. It was originally described for ventral brainstem lesions and clival tumors, but its indications expanded to vascular lesions inaccessible through the traditional subtemporal, pterional, or retrosigmoid routes. The presigmoid approach offers a combined exposure of the middle and posterior fossa, as well as good visualization of the midbasilar segment. In our practice, this approach has been used to gain access to low-lying basilar tip aneurysms and basilar trunk (BT) aneurysms.10,​14 As described and refined by Hakuba et al22 and Al-Mefty et al,23 the modified presigmoid approach requires a partial labyrinthectomy to reduce hearing loss, and it requires complete mobilization and skeletonization of the sigmoid sinus after division of the tentorium and superior petrosal sinus.10,​14

Positioning The patient is placed in the lateral park bench position, similar to the position for the subtemporal approach. As previously mentioned for the subtemporal approach, lumbar drainage or a ventriculostomy is necessary to obtain proper relaxation of the brain before proceeding with the approach (Fig. 26.7).

Skin incision A horseshoe-shaped skin incision, similar to the incision used in the subtemporal approach, is marked down, starting 1 cm anterior and superior to the root of the zygoma, directed upward

and curving posteriorly 2 to 3 cm over the ear, before stopping 2 cm behind the mastoid line. A myocutaneous one-layer flap is performed and retracted caudally, using multiple spring hooks. The temporal and occipital muscles are detached caudally, completely exposing the temporal bone, the zygomatic arch, and the mastoid process.

Craniotomy The craniotomy is made using three or four bur holes. The first one is at the most cranial part of the planned skin incision, the second one is just above the zygomatic arch, and the third one is at the posterior border of the skin incision, inferior to the transverse sinus projection. The fourth and optional bur hole is placed just superior to the expected course of the trans-verse sinus. This bur hole is helpful to detach the dura from the inner table and to reduce the risk of injury to the venous sinuses. A first cut is performed with a craniotome, starting at the most cranial bur hole and directed toward the zygomatic bur hole. The second cut begins at the posterior fossa bur hole and is directed anteriorly and superiorly toward the first bur hole (Fig. 26.7). The third cut starts at the zygomatic bur hole and is directed posteriorly toward the anterior aspect of the petrous bone. The remaining bone ridge is drilled off using a diamond drill, and the bone flap is cracked and lifted around this drilling line. Once the craniotomy is performed, an adequate exposure will demonstrate the transverse sinus, the dura of the posterior and middle fossa, and the sigmoid sinus.

Temporal bone drilling Under the operating microscope, the squamous temporal bone is drilled off with a diamond drill to obtain an adequate supratentorial surgical corridor with minimal retraction of the temporal lobe. The drilling continues to the superior and posterior segment of the

360

VI  Comprehensive Management of Vascular Pathology of the Brainstem and Thalamus Fig. 26.7  Right presigmoid approach. (a) A horseshoe-shaped skin incision is marked, starting 1 cm anterior and superior to the root of the zygoma, directing upward and curving posteriorly 2 to 3 cm over the ear, and stopping 2 cm behind the mastoid line. (b) The patient is placed in the lateral park bench position; a lumbar drain is placed or a ventriculostomy is performed to obtain proper brain relaxation before proceeding with the approach. (c) The myocutaneous flap is opened as a one-layer flap and retracted caudally, using multiple spring hooks. The temporal and occipital muscles are detached caudally, completely exposing the temporal bone, the zygomatic arch, and the mastoid process. (d) The craniotomy is made using three bur holes (white dashed circle): one at the most cranial part of the planned skin incision, one just above the zygomatic arch, and the last one at the posterior border of the skin incision, inferior to the transverse sinus projection. (e) After the bone is cut, the bone flap is cracked and lifted. Then under the operating microscope, the squamous temporal bone is drilled off using a diamond drill to obtain an adequate supratentorial surgical corridor with minimal retraction of the temporal lobe. The drilling continues to the superior and posterior segment of the mastoid region of the temporal bone. The dura anterior to the sigmoid sinus (SS) (white dashed line) is exposed, as necessary, and the drilling stops at the level of the antrum, without compromising the elements of the inner or middle ear. SPS, superior petrosal sinus (white dashed line); TS, transverse sinus (white dashed line). (f) The cuts made in the dura (black dashed lines) start at the posterior fossa dura, just a few millimeters anterior to the sigmoid sinus, and are directed toward the superior petrosal sinus, which is left intact. The middle fossa dura is cut in a curvilinear fashion and is also directed toward the superior petrosal sinus. The superior petrosal sinus is then ligated and cut.

mastoid region of the temporal bone, increasing the sinodural angle exposure. The dura anterior to the sigmoid sinus is exposed, as necessary, and the drilling stops at the level of the antrum, without compromising the elements of the inner or middle ear. A posterior petrosectomy, including skeletonization of the semicircular canals, can be performed to reduce the risk of hearing loss. If a semicircular canal is inadvertently opened, it must be sealed off with bone wax, fibrin glue, fat, or muscle graft.

a stepwise manner, starting with a small lateral cut on the tentorium and followed by bipolar coagulation to reduce the risk of bleeding. These two steps are repeated constantly, verifying supratentorially and infratentorially the course of CN IV, until the tentorium is completely split. The free flaps of the tentorium can be fixed to the dura of the temporal fossa using small aneurysm clips.13

Dural opening

Vertebral Artery and Posterior Inferior Cerebellar Artery Aneurysms

After the partial posterior petrosectomy is completed, the sigmoid sinus, the superior petrosal sinus, the presigmoid dura, and the temporal dura should be visible. The posterior fossa dura is opened under the microscope, just a few millimeters anterior to the sigmoid sinus. The opening is directed toward the superior petrosal sinus, which at the initial phase is left intact. The middle fossa dura is cut in a curvilinear fashion and directed toward the superior petrosal sinus. The superior petrosal sinus is then ligated using two sutures, and both previous cuts are connected, dividing the sinus and allowing for lifting of the dura by traction of the sutures.

Cutting the tentorium The tentorium is cut from lateral to medial, anterior to the vein of Labbé and posterior to the tentorial insertion of CN IV (Fig. 26.8). The retraction of the tentorium is performed subfrontally, and the splitting of the tentorium is conducted in

The most frequent approaches to access vertebral artery (VA) or VA and posterior inferior cerebellar artery (VA-PICA) aneurysms are the far lateral and the lateral suboccipital or retrosigmoid approaches.11,​24,​25,​26 There are two main parameters to consider when selecting an approach to aneurysms in these segments. The first is the relationship of the aneurysm with the foramen magnum; those at least 10 mm above the foramen magnum can be approached through a retrosigmoid craniotomy. The second is the size and projection of the aneurysm.24,​25,​26 Aneurysms located on the cortical PICA branches close to the midline require a median or paramedian suboccipital approach.

Far Lateral Approach Most surgeons have favored and widely used the far lateral approach for VA-PICA aneurysms. Originally described by Heros,27

26  Surgical Management of Posterior Circulation Aneurysms

361

Fig. 26.8  Cutting the tentorium from the right presigmoid approach. (a) After the dura of the posterior fossa and the middle fossa is opened, as shown in Fig. 26.7, then the superior petrosal sinus (arrow) is coagulated using bipolar forceps. (b) The superior petrosal sinus is ligated using two sutures, and both previous cuts are connected, dividing the sinus and allowing the lifting of the dura by traction of the sutures. (c) The tentorium is cut from lateral to medial, anterior to the vein of Labbé, and posterior to the tentorial insertion of the trochlear nerve (CN IV). (d) The splitting of the tentorium is conducted with a small lateral cut on the tentorium, followed by bipolar coagulation. These two steps are repeated constantly, verifying the course of CN IV until the tentorium is completely split. The free flaps of the tentorium can be fixed to the dura of the temporal fossa using small aneurysms clips.

this approach has undergone different modifications, including supracondylar, transcondylar, or paracondylar variants. Compared with the classic far lateral approach that requires removal of the posterior arch of C1 and almost complete drilling of the occipital condyle, this “enough lateral approach” is a fast and simpler modification, where the amount of condyle drilling is minimal and a hemilaminectomy of C1 is performed only when necessary.24,​25,​26,​28

Positioning The patient is placed in the lateral park bench position with the head elevated approximately 20 cm above the cardiac level. The head is fixed to the frame, slightly flexed forward and laterally tilted toward the floor. This positioning increases the viewing angle toward the foramen magnum in a caudal trajectory (Fig. 26.9).

Skin incision A linear skin incision is marked 2 cm behind the mastoid process, starting just below the zygomatic line and extending 4 to 5 cm caudally to the mastoid tip. The subcutaneous fat and muscles are divided in a linear fashion using monopolar cautery. A self-retaining retractor is placed cranially, and then a second one is placed caudally. The muscle dissection continues until complete exposure of the occipital bone is obtained. The posterior arch of C1 and the foramen magnum are identified by finger palpation. At this point, the approach is performed under the operating microscope. The main objective is to identify the extradural course of the VA close to the transverse process of C1. This can be done using a microDoppler ultrasound to localize the artery. The idea is to expose the extradural segment of the VA above the posterior arch of C1 and its intradural entrance at the foramen magnum. Once the VA and C1 are completely identified, the occipital bone can be safely cleaned from attached muscles, all the way down to the foramen magnum.

Craniotomy One bur hole is placed at the superior and posterior aspect of the exposed bone. Then a first cut with the craniotome is performed, directing slightly superior from the bur hole toward the mastoid as far as possible. A second cut directs slightly posterior and caudally toward the foramen magnum and as posterior as to where the VA

makes its intradural entrance. Then, without footplate protection or a diamond drill, the craniotome is used to thin down, lift, crack, and remove the bony ridge at the anterior and lateral aspect of the planned craniotomy. Venous bleeding from the paravertebral venous plexus can follow elevation of the bone flap. Elevating the head and packing with hemostatic agents and fibrin glue will readily control the bleeding. After the craniotomy is performed, the operating table is elevated to increase the surgical view toward the condyle. The bony window is then extended in an anterior direction with a diamond drill. Removal of the occipital condyle and skeletonization of the sigmoid sinus are rarely necessary. The drilling of the condyle is kept as minimal as possible, and the hypoglossal canal is left intact. When a more inferior exposure is needed, a C1 hemilaminectomy can be added to the approach. This can be done using a diamond drill or a rongeur, starting medially and then proceeding toward the transverse foramen.28

Intradural dissection The dura is opened in a linear fashion, starting posterior to the intradural origin of the VA and curving anterolaterally toward the most superior segment of the craniotomy. Multiple tack-up dural stitches are placed over the craniotomy edges. The lateral flap of the dura is tensed tightly to the muscles to increase the lateral angle of exposure. After the dura is opened, the arachnoid adhesions are cut sharply. Additional CSF can be drained from the cisterna magna medially to increase cerebellar relaxation. In cases of proximal VAPICA aneurysms, the VA is followed for a short distance toward the PICA, and the aneurysm can easily be seen at its origin. Larger aneurysms, or those located more distally along the PICA, require an approach between the lower CNs. Vertebrobasilar junction aneurysms are approached from a more inferolateral direction. The surgical corridor to these aneurysms still proceeds through the complex of lower CNs.24,​25,​26

Retrosigmoid Approach (Lateral Suboccipital Approach) For the treatment of VA-PICA aneurysms, Drake et al11 favored the retrosigmoid approach, which requires a simple and smaller crani-

362

VI  Comprehensive Management of Vascular Pathology of the Brainstem and Thalamus

Fig. 26.9  Left far lateral approach. (a) The patient is placed in the lateral park bench position. A linear skin incision is marked 2 cm behind the mastoid process, starting just below the zygomatic line and extending 4 to 5 cm caudally to the mastoid tip (filled black circle). (b) One bur hole is placed at the superior and posterior aspect of the exposed bone. Two cuts with the craniotome are then performed, directing slightly superior from the bur hole toward the mastoid, and posterior and caudal toward the foramen magnum. (c) When a more inferior exposure is needed, the C1 lamina (star) is exposed and a hemilaminectomy is performed. (d) The occipital condyle is not completely removed, and the sigmoid sinus (arrow) is seldom skeletonized using this approach. The drilling of the condyle is kept as minimal as possible. (e) After the dura is opened, the arach-

noid adhesions are cut sharply. The spinal accessory cranial nerve (CN XI) (arrow) is identified through its cranial course to the jugular foramen. (f,g) The jugular foramen, the glossopharyngeal nerve (CN IX), the vagus nerve (CN X), and CN XI (arrow) are visualized. (h) After the arachnoid bands surrounding the lower cranial nerves are dissected, the upper part of the surgical field is exposed to allow visualization of the facial nerve (CN VII)–vestibulocochlear nerve (CN VIII) complex (star). (i) In patients with a proximal vertebral artery (VA)–posterior inferior cerebellar artery (PICA) aneurysm (white star), the VA (black star) is followed for a short distance toward the PICA (filled black circle), and the aneurysm is readily identified at its origin. The neck of the aneurysm in this patient is covered by the fibers of the hypoglossal nerve (CN XII) (black arrow).

otomy than that for the far lateral approach. However, this smaller craniotomy requires a meticulous opening, the placement of a spinal drain to obtain maximal brain relaxation, and wide arachnoid dissection to provide the space necessary for aneurysm dissection.28

along the linear skin incision. The muscles are detached until the digastric groove is identified. The foramen magnum is identified by palpation. For the retrosigmoid approach, further dissection and exposure of the foramen magnum are not required.

Positioning and Skin Incision

Craniotomy

The patient is placed in the lateral park bench position; the head is fixed to the Sugita or Mayfield frame and flexed slightly and tilted laterally (Fig. 26.10). After the patient is positioned, a spinal drain is placed to obtain approximately 50 to 100 mL of CSF before the dura is opened. A linear skin incision is marked 2 cm posterior to the mastoid process, 2 to 3 cm above the zygomatic line, and 4 to 6 cm caudal to this line. The skin incision has to extend several centimeters below the planned craniotomy to improve the passage of the craniotome during the craniotomy. The subcutaneous fat and muscles are split

One bur hole is placed at the most superior and posterior aspect of the planned skin incision. The dura is detached from the inner table with a curved dissector without damaging the sigmoid or transverse sinus. Two cuts are then performed with the craniotome. The first one is made caudally toward the mastoid, and the second one is made superiorly and anteriorly toward the mastoid process. The bone ridge between these previous cuts is thinned down using the craniotome, without footplate protection or a diamond drill. The bone flap is then lifted and removed. A diamond drill is used to extend the craniotomy lat-

26  Surgical Management of Posterior Circulation Aneurysms

363

Fig. 26.10  Right retrosigmoid exposure for the clipping of an unruptured right posterior inferior cerebellar artery aneurysm. (a) A linear incision is used to expose the lateral suboccipital area and the tip of the mastoid process (star). (b) After mobilization of the muscle, the suboccipital bone is exposed down to the mastoid tip (arrow indicates mastoid emissary vein). (c) A single bur hole is used to expose the posterior fossa dura in preparation for turning the craniotomy (dashed semicircle). (d) The petrosal bone is drilled to optimize the exposure of the cerebellopontine angle. (e) The posterior inferior cerebellar artery aneurysm is visualized, and a temporary clip is placed on the vertebral artery to obtain proximal control. (f) A final straight clip is used to occlude the aneurysm, while preserving the flow in the inflow and outflow vessels.

erally until the sigmoid sinus is exposed. If the mastoid air cells are opened during the approach, they must be packed with fat, muscle, or fibrin glue to prevent a postoperative CSF leak.

Intradural Dissection The dura is opened in a curvilinear fashion, with the base directed toward the mastoid. Multiple tack-up sutures are then placed over the craniotomy edges. Alternatively, a three-leaf or Y-shaped dural opening can be performed for cases requiring exposure of the transverse and sigmoid sinuses. If the brain remains tight even after spinal drain placement, more CSF can be drained from the cisterna magna and the cerebellopontine cistern. After CSF is released and proper brain relaxation is achieved, the cerebellar hemisphere is gradually retracted and compressed. Arachnoid adhesions are sharply cut to enter the cerebellopontine cistern. Next, the lower CNs are identified. Special attention should be taken to preserve bridging veins, including the petrosal vein complex. Since the retrosigmoid approach is a tailored craniotomy, its optimal location and extension depend on the aneurysm relationship with the foramen magnum.

■■ Posterior Cerebral Artery Aneurysms Table 26.211,​14,​15,​19,​24,​26,​29,​30,​31,​32,​33,​34,​35,​36,​37,​38,​39,​40,​41,​42,​43,​44,​45,​46,​47,​48,​49,​50,​ 51,​52,​53,​54,​55,​56,​57,​58,​59,​60,​61,​62,​63,​64,​65,​66,​67,​68,​69,​70,​71,​72,73,74,75,76 summarizes the outcomes of the microsurgical treatment of posterior circulation aneurysms from some of the largest series in the surgical literature.

Epidemiology and Characteristics Aneurysms of the PCA are rare, with an overall incidence of less than 1%, representing roughly 5 to 7% of all the aneurysms of the posterior circulation. The most frequently used classification is that of Zeal and Rhoton,77 who divided the

artery into four main segments: P1, between the basilar artery bifurcation and the PCoA; P2, between the PCoA and the posterior edge of the lateral surface of the midbrain; P3, between the posterior edge of the lateral midbrain and the origins of the parieto-occipital and calcarine arteries; and P4, terminal branches. We consider aneurysms of the P1 segment and the P1–P2 junction as proximal PCA aneurysms belonging to the circle of Willis and aneurysms of the P2, P3, and P4 segments as distal PCA aneurysms. Most PCA aneurysms are smaller than 10 mm, even when ruptured. Distal PCA aneurysms are ruptured more often than proximal PCA aneurysms. The incidence of fusiform PCA aneurysms is about 25%, and the P2 segment is the segment most often affected by fusiform PCA aneurysms (Fig. 26.11). Saccular PCA aneurysms typically have a dome orientation in relation to the originating PCA segment: P1 segment, upward; P1–P2 junction, anterior or upward; P2 segment, lateral; and P3 segment, posterior.6,​7,​11,​12,​78

Clinical Presentation Subarachnoid hemorrhage (SAH) from aneurysm rupture is the most common presenting symptom of patients with PCA aneurysms. Additional intraventricular hemorrhage or intracerebral hemorrhage can be present, with different distribution patterns for proximal and distal PCA aneurysms. CN III palsy can be a presenting symptom in some patients. Patients with large and giant aneurysms often present with symptoms of ischemia, following embolism or local mass effect. Some patients are identified incidentally during work-up for other symptoms.

Microsurgical Treatment Options When selecting the microsurgical approach for intracranial aneurysm surgery, one must consider important factors such as the aneurysm configuration, the parent vessel course, and the exact location of the aneurysm in relation to the skull base and basal cisterns. Frontotemporal and subtemporal routes are the most com-

Patients

1

26

1

14

22

2

14

3

Sagoh et al 199730

Ogilvy et al 200231

Zhang et al 200332

Iizuka et al 200833

Sanai et al 200834

RodríguezHernández et al 201335

Nair et al 201515

Patra et al 201636

3

14

2

23

14

1

26

1

6

3

NA

NA

6

8

Samson et al 197837

Peerless et al 199438

Drake et al 199611

Sagoh et al 199730

Tanaka et al 200039

Microsurgical clipping

8

6

266

29

3

NA (NA)

4/6 (67)

NA (NA)

25/29 (86)

NA (NA)

2/3 (67)

14/14 (100)

NA (NA)

23/23 (100)

9/14 (64)

NA (NA)

20/26 (77)

NA (NA)

NA (NA)

Aneurysms Complete occlusion, no. (%)

Basilar artery–superior cerebellar artery

6

Gács et al 198329

Microsurgical clipping

Superior cerebellar artery

Author, year

0/9

0/6

NA

NA

NA

0/3

0/14

0/2

1/23

0/14

0/1

0/26

0/1

NA

Bypass

100

67

85

79

NA

33.3

64

100

68.1

70

0

73

100

67

Excellent/ good outcome, %

0

33

9

21

NA

33.3

21

0

31.9

30

0

21.7

0

33

Fair/poor outcome, %

11

17

6

10.3

NA

33.3

14.3

0

9.1

0

100

8.7

0

0

Mortality, %

NA

17

NA

NA

NA

NA

38.0

NA

4.5

4.3

0

NA

0

NA

Morbidity, %

Table 26.2  Results of microsurgical treatment of aneurysms of the posterior circulation from the largest series in the medical literature

5.1

NA

NA

NA

NA

2.4

2.8

0.7

13.6

NA

0

1

NA

NA

Follow-up, y

0

NA

NA

NA

NA

0

0

NA

0

NA

0

NA

NA

NA

Retreatment, no. (%)

0

NA

NA

3

NA

0

0

NA

0

0

0

NA

NA

NA

(Continued)

Rehemorrhage, no. (%)

364 VI  Comprehensive Management of Vascular Pathology of the Brainstem and Thalamus

37

1

12

9

Yasui et al 200340

Zhang et al 200332

Jin et al 201241

Patra et al 201636

9

12

1

37

113

NA

NA

8

Peerless et al 199438

Drake et al 199611

Samson et al 199943

Tanaka et al 200039

Basilar bifurcation Microsurgical clipping

7

RodríguezHernández et al 201335

8

303

895

NA

7

8

8

2

Sanai et al 200834

2

Ogilvy et al 200231

41

34

57

Drake et al 199611

2

Gonzalez et al 32 200442

2

Gács et al 198329

NA (NA)

231/246 (94)

NA (NA)

106/113 (94)

NA (NA)

8/8 (100)

31/34 (91)

1/2 (50)

34/41 (83)

NA (NA)

6/9 (67)

9/12 (75)

NA (NA)

NA (NA)

Aneurysms Complete occlusion, no. (%)

Anterior inferior cerebellar artery Microsurgical clipping

Patients

Author, year

0/9

NA

NA

NA

0/7

0/8

1/34

0/2

NA

NA

0/9

NA

0/1

NA

Bypass

100

81

84

82

89

75

44.1

50

88

50

77.8

66.7

100

68

Excellent/ good outcome, %

0

10

11

10

11

25

8.8

0

7

50

11.1

33.3

0

32

Fair/poor outcome, %

11

9

5

8

0

0

5.9

50

5

0

11.1

0

0

NA

Mortality, %

NA

14

NA

NA

NA

0

56

NA

NA

NA

NA

58.3

0

33

Morbidity, %

5.1

0.5

NA

NA

0.7

13.6

3.5

1

NA

NA

2.4

2.7

6

3

Follow-up, y

Table 26.2 (Continued)  Results of microsurgical treatment of aneurysms of the posterior circulation from the largest series in the medical literature

0

NA

NA

NA

NA

0

NA

NA

NA

NA

0

0

0

NA

Retreatment, no. (%)

0

NA

NA

36

NA

0

NA

NA

NA

NA

0

0

0

6

(Continued)

Rehemorrhage, no. (%)

26  Surgical Management of Posterior Circulation Aneurysms

365

72

111

4

98

50

105

28

37

96

Ogilvy et al 200231

Yasui et al 200340

Zhang et al 200332

Lozier et al 200444

Krisht et al 20071​9

Sanai et al 200834

Jin et al 200945

Sekhar et al 201346

Tjahjadi et al 201614

9

44

NA

16

3

5

16

Peerless et al 199438

Drake et al 199611

Peerless et al 199647

Seifert et al 200148

Ogilvy et al 200231

Sanai et al 200834

Lawton et al 201649

Basilar trunk Microsurgical clipping

Patients

Author, year

16

5

3

16

58

44

9

96

NA

NA

106

50

98

4

111

NA

NA (NA)

5/5 (100)

3/3 (100)

NA (NA)

NA (NA)

31/44 (70)

NA (NA)

62/96 (65)

34/37 (92)

19/26 (73)

103/106 (97)

49/50 (98)

36/84 (43)

NA (NA)

NA (NA)

60/72 (83)

Aneurysms Complete occlusion, no. (%)

16/16

0/5

0/3

NA

NA

NA

NA

NA

4/37

NA

1/106

0/50

1/84

0/4

NA

0/72

Bypass

6

100

67

69

81

79

66

78

39

71

57.1

92

67

100

74

83.3

Excellent/ good outcome, %

19

0

33

19

9

7

0

10

76

25

32.4

4

10.8

0

26

12.5

Fair/Poor outcome, %

75

0

0

12

10

14

44

12

19

4

10.5

4

22.3

0

NA

4.2

Mortality, %

NA

0

NA

NA

NA

NA

NA

NA

5

36

10.5

14

80

25

23

NA

Morbidity, %

2.8

13.6

1

NA

NA

NA

NA

0.3

3.5

2.4

13.6

2.7

7.3

6

3

1

Follow-up, y

Table 26.2 (Continued)  Results of microsurgical treatment of aneurysms of the posterior circulation from the largest series in the medical literature

NA

0

NA

NA

NA

NA

NA

NA

2.7

NA

0

0

NA

0

NA

NA

Retreatment, no. (%)

NA

0

NA

NA

NA

NA

NA

NA

0

NA

0

0

1

0

1

NA

(Continued)

Rehemorrhage, no. (%)

366 VI  Comprehensive Management of Vascular Pathology of the Brainstem and Thalamus

Patients

77

NA

8

2

1

7

Drake et al 199611

Peerless et al 199647

Seifert et al 200148

Ogilvy et al 200231

Zhang et al 200332

Kalani et al 201350

7

1

2

8

61

77

14

125

30

20

30

58

Drake et al 199611

Taylor et al 200352

Yonekawa et al, 201153

Wang et al 201554

Goehre et al 201655

Posterior cerebral artery Microsurgical clipping

Hacein-Bey et 1 al 199851

NA

NA

NA

NA

NA

1

52/58 (90)

29/30 (97)

20/20 (100)

28/28 (100)

123/125 (98)

1/1 (100)

NA (NA)

1/1 (100)

2/2 (100)

NA (NA)

NA (NA)

57/77 (74)

10/14 (71)

Aneurysms Complete occlusion, no. (%)

Combined endovascular–surgical treatment

14

Peerless et al 199438

Vertebrobasilar junction Microsurgical clipping

Author, year

4/58

5/30

3/20

0/28

0/125

0/1

7/7

0/1

0/2

NA

NA

NA

NA

Bypass

47

87

50

47

78

100

14

100

100

87.5

90

84

86

Excellent/ good outcome, %

NA

3

30

11

7

0

14

0

0

12.5

3

9

7

Fair/poor outcome, %

NA

1

20

4

6

0

43

0

0

0

7

7

7

Mortality, %

29

27

NA

NA

10

0

46

0

NA

NA

NA

NA

NA

Morbidity, %

1

0.08–6.5

1–15

1

1–35

2.8

6

6

1

NA

NA

NA

NA

Follow-up, y

Table 26.2 (Continued)  Results of microsurgical treatment of aneurysms of the posterior circulation from the largest series in the medical literature

2

NA

0

0

NA

0

14

0

NA

NA

NA

NA

NA

Retreatment, no. (%)

0

NA

0

0

2

0

NA

0

NA

NA

NA

NA

NA

(Continued)

Rehemorrhage, no. (%)

26  Surgical Management of Posterior Circulation Aneurysms

367

Patients

38

NA

16

6

27

NA

5

Andoh et al 199257

Drake et al 199611

Sano et al 199758

Bertalanffy et al 199859

Bohnstedt et al 201560

Lehto et al 201526

Saito et al 201661

8

NA

15

38

8

20

23

Gács et al 198329

Yamaura et al 198862

Bertalanffy et al 199859

Horowitz et al 199863

Matsushima et al 200164

Lewis et al 200265

Horiuchi et al 200366

VA-PICA and PICA Microsurgical clipping

19

Yamaura et al 199056

Vertebral artery Microsurgical clipping

Author, year

27

22

8

38

NA

68

8

5

125

NA

6

16

221

38

NA

NA (NA)

NA (NA)

NA (NA)

NA (NA)

NA (NA)

NA (NA)

NA (NA)

NA (NA)

NA (NA)

NA (NA)

NA (NA)

NA (NA)

191/221 (86)

NA (NA)

NA (NA)

Aneurysms Complete occlusion, no. (%)

1/23

2/20

0/8

NA

0/15

NA

NA

5/5

3/125

NA

0/6

NA

NA

NA

NA

Bypass

83

85

87

89

80

78

87

100

NA

NA

83

56

89.6

68

79

Excellent/ good outcome, %

17

10

0

4

13

22

0

0

NA

NA

0

19

5.9

5

21

Fair/Poor outcome, %

0

5

13

7

7

0

13

0

NA

NA

17

19

4.5

27

0

Mortality, %

NA

60

37

66

33

16

NA

60

50

NA

0

NA

NA

NA

26

Morbidity, %

NA

0.3

2.8

1

4.3

3.7

NA

3.3

6.8

1

5

3.7

NA

NA

5.5

Follow-up, y

Table 26.2 (Continued)  Results of microsurgical treatment of aneurysms of the posterior circulation from the largest series in the medical literature

NA

NA

0

NA

0

0

NA

NA

1

NA

0

NA

NA

NA

0

Retreatment, no. (%)

NA

NA

0

NA

0

0

NA

NA

3.2

NA

0

12

NA

NA

0

(Continued)

Rehemorrhage, no. (%)

368 VI  Comprehensive Management of Vascular Pathology of the Brainstem and Thalamus

7

20

13

52

3

20

80

27

38

22

35

9

Nussbaum et al 200367

D’Ambrosio et al 200468

Liew et al 200469

Al-khayat et al 200570

Lin et al 201271

Singh et al 201272

Lehto et al 201424

Viswanathan et al 201473

Bohnstedt et al 201560

Williamson et al 201574

Abla et al 201675

Sejkorová et al 201676

9

NA

22

NA

27

91

20

3

52

NA

20

7

7/7 (100)

31/35 (89)

NA (NA)

NA (NA)

27/27 (100)

NA (NA)

NA (NA)

NA (NA)

NA (NA)

NA (NA)

18/20 (90)

NA (NA)

Aneurysms Complete occlusion, no. (%)

Abbreviation: NA, not available.

Patients

Author, year

0/9

35

1/18

NA

0/27

3/91

0/20

NA

0/52

NA

0/20

6/7

Bypass

67

64

32

78

89

69

75

100

90

77

67

86

Excellent/ good outcome, %

11

6

63

NA

7

11

10

0

8

23

33

14

Fair/poor outcome, %

22

6

5

NA

4

20

15

0

2

0

0

0

Mortality, %

33

17

NA

NA

NA

16

NA

NA

48

NA

NA

NA

Morbidity, %

NA

1–17

3

1

0.5

8.8

0.5–2.5

NA

0.8

NA

1

1.5

Follow-up, y

Table 26.2 (Continued)  Results of microsurgical treatment of aneurysms of the posterior circulation from the largest series in the medical literature

NA

NA

NA

NA

0

2

0

NA

NA

0

10

0

Retreatment, no. (%)

0

3

NA

0

0

NA

0

NA

NA

0

5

0

Rehemorrhage, no. (%)

26  Surgical Management of Posterior Circulation Aneurysms

369

370

VI  Comprehensive Management of Vascular Pathology of the Brainstem and Thalamus

Fig. 26.11  Unruptured left posterior cerebral artery (PCA) aneurysm. Preoperative   (a) lateral and (b,c) anteroposterior digital subtraction angiograms and (d) axial, (e) sagittal, and (f) coronal computed tomography

angiograms clearly demonstrate a left fusiform P1–P2 segment PCA aneurysm. This aneurysm was clipped via a left subtemporal approach, with the patient in the park bench position.

mon approaches for PCA aneurysms. Regardless of the selected approach, the main challenges are avoidance of brain tissue injury from retraction; prevention of injury to the venous system (e.g., sylvian veins and the vein of Labbé); prevention of brainstem perforator injury; and prevention of PCA infarction to secure sufficient perfusion of the PCA territory.6,​7,​8,​12,​16,​77,​78,​79,​80,​81

transsylvian route is the preferred approach to high-riding P1 segment aneurysms.80

Frontolateral Approach Microsurgical access to proximal PCA aneurysms (P1 and P2) is often obtained using a frontolateral approach.8,​12,​80,​81 Frontolateral approaches provide additional access to the intracranial ICA, the proximal anterior cerebral artery (A1 segment), the anterior communicating artery complex, the anterior cerebral artery (A2 segment), and the MCA (M1 and M2 segments, and bifurcation), which allows the surgeon to address other aneurysms of the circle of Willis. These approaches require that the proximal sylvian fissure be opened to obtain enough space for the aneurysm dissection. However, the surgical corridor is deep and narrow, and it is in close proximity to very sensitive neurovascular structures. Sometimes a selective amygdalohippocampectomy is necessary to obtain enough working space to expose complex aneurysms. The removal of anterior or posterior clinoid processes may be required to improve visualization. The

Subtemporal Approach The subtemporal approach is an effective route to proximal PCA aneurysms that reside adjacent to the tentorial edge. This approach offers good visualization of the interpeduncular and ambient cisterns. With the subtemporal approach, the course of the P2 segment, which is parallel to the tentorium, allows for early proximal and distal vessel control. However, the subtemporal approach is not ideal for very distal PCA aneurysms and aneurysms that are more than 3 mm above the posterior clinoid process.6,​7,​11 The main drawbacks of the subtemporal approach are the required elevation of the temporal lobe and the potential problems associated with injury to the temporal lobe or vein of Labbé. Temporal lobe retraction can be minimized by the general release of CSF. CSF egress provides sufficient space for safely reaching the tentorial edge and the interpeduncular cistern, where additional CSF can be released. Severe brain edema or intracerebral hematoma can make the application of the subtemporal approach quite challenging; in our experience, this approach is not suitable for ruptured aneurysms.6,​7,​12,​78,​80

26  Surgical Management of Posterior Circulation Aneurysms

Posterior Interhemispheric Approach It is usually not possible to approach very distal PCA aneurysms (P3 and P4) directly through the frontolateral and subtemporal approaches. The direct treatment of P3 and P4 aneurysms requires different approaches. Yonekawa et al80 report that, for P3 segment aneurysms, the supracerebellar transtentorial approach conducted with the patient in the sitting position can be used to reach deeper locations around the posterior surface of the midbrain. The posterior interhemispheric approach is suitable to reach the terminal PCA (for treatment of P4-segment aneurysms).

Need for Revascularization The proximal occlusion of the PCA is often associated with consecutive ischemic infarction and blindness. In cases requiring sacrifice of the parent PCA, the surgeon should consider revascularization procedures to prevent cerebral infarctions of the PCA territory. Multiple bypass procedures with the PCA as the recipient vessel have been described, such as the occipital artery–PCA, the superficial temporal artery–PCA, the middle meningeal artery–PCA, and the extracranial carotid artery–radial artery–PCA, or the extracranial carotid artery–VA–PCA bypass as a high-flow bypass procedure.82

Patient Outcomes and Best Evidence Practice Because of the low incidence of PCA aneurysms, most series are small, with fewer than 25 cases analyzed using different evaluation standards. The following is a summary of the treatment results of the five most rigorous reports on PCA aneurysms, each with more than 30 patients, reported between 1996 and 2015. In 1996, Drake et al11 reported roughly 78% good or excellent results for 125 patients, with 75 patients having had an SAH. In 2003, Taylor et al52 analyzed 30 patients and reported that 8 (44%) of 18 patients with unruptured PCA aneurysms and 6 (50%) of 12 patients with ruptured PCA aneurysms achieved a good outcome at 1-year followup; however, 1 patient died during treatment. In 2010, Chang et al82 at Barrow Neurological Institute reported good or excellent results in 29 (87%) of 33 patients; however, 3 patients (9%) died, and 9 patients (27%) had an SAH initially. In the 2015 Helsinki and Kuopio series of 121 patients from Finland, treatment outcomes depended on location and admission status of the patients.6,​7,​12 Finally, in 2015, Wang et al54 reported that 26 (87%) of 30 patients had a good result, although there was 1 death. Eighteen (60%) of the patients had an initial aneurysm rupture, and 18 of the aneurysms were large or giant. Both endovascular and microsurgical treatments are suitable options for the occlusion of saccular nongiant PCA aneurysms. However, since parent artery occlusion is often associated with cerebral infarction, the treatment of complex and fusiform PCA aneurysms usually requires microsurgical treatment strategies with revascularization procedures.

371

■■ Superior Cerebellar Artery Aneurysms Epidemiology and Characteristics SCA aneurysms are rare lesions accounting for less than 1.2% of all intracranial aneurysms and for 15% of posterior circulation aneurysms according to the Helsinki Aneurysm Database. Previous studies have reported these aneurysms most commonly to be small, saccular, and laterally projecting (Fig. 26.12). They typically occur on the anterior pontomesencephalic or S1 segment  (classification by Rodríguez-Hernández et al35,​84,​), particularly at the basilar artery–SCA junction. In a series of patients with treated distal cerebellar aneurysms, only 4.4% of SCA aneurysms were found to be distal to the S1 segment. Drake et al11 noted that the origin of the SCA is commonly from the aneurysm instead of the basilar artery. An association with multiple intracranial aneurysms has been found in about 40% of patients with SCA aneurysms.

Clinical Presentation Most patients with SCA aneurysms present with SAH, and many of those who do are in poor clinical condition with high Hunt and Hess grades. Unruptured SCA aneurysms have been diagnosed during work-ups for diplopia because of aneurysm mass effect on the oculomotor or trochlear nerves, as well as incidentally on imaging obtained for headaches, vertigo, and other symptoms. CN IV palsy is less common than CN III palsy, because CN IV courses superior to the SCA in the lateral pontomesencephalic segment, and SCA aneurysms here are extremely rare.3,​4,​85,​86

Microsurgical Treatment Options The optimal surgical plan provides the shortest, most direct approach, with the least amount of risk to other vital neurovascular structures.15,​41,​87,​88,​89

Frontotemporal Approaches Most SCA aneurysms are proximally located at the anterior pontomesencephalic segment of the basilar artery and can therefore be approached with frontolateral craniotomies. Similar to patients with PCA aneurysms, patients with SCA aneurysms may harbor other aneurysms. Frontotemporal approaches allow access to many of these sites and to proximally located SCA aneurysms. Pterional, orbitozygomatic, and lateral supraorbital craniotomies have been used to approach these lesions. Visualization is the key, and the removal of the anterior or posterior clinoid process may very well be necessary for safe access. These approaches can also be used to access aneurysms located in the lateral pontomesencephalic segment of the SCA.35,​84

Subtemporal Transtentorial Approach The subtemporal transtentorial approach is used for SCA aneurysms, but it can also be used for PCA and basilar apex aneurysms. This approach is essential to the surgeon’s armamentarium

372

VI  Comprehensive Management of Vascular Pathology of the Brainstem and Thalamus

Fig. 26.12  Unruptured right superior cerebellar artery (SCA) aneurysm. Preoperative (a) coronal and (b) sagittal computed tomography angiograms (CTAs) demonstrate a right SCA aneurysm with superolateral projection. (c) Preoperative coronal three-dimensional reconstruction CTA (posterior to anterior view). The aneurysm was clipped with one curved clip

via a right subtemporal approach, with the patient in the park bench position. Postoperative (d) axial, (e) sagittal, and (f) coronal CTAs demonstrate complete occlusion of the aneurysm with preservation of flow through the right posterior cerebral artery and SCA.

for treating SCA aneurysms, because anterior and lateral pontomesencephalic segment aneurysms may reside caudal to the posterior clinoid, to the extent that even bone removal will not provide a safe surgical corridor. In these instances, the subtemporal approach using a horseshoe-shaped skin incision provides good lateral exposure of SCA aneurysms and allows for visualization of basilar perforators that may be obscured via a frontotemporal approach. The curved incision allows the craniotomy to be extended more posteriorly, with wider tentorial and CN IV exposure, which makes lifting and splitting the tentorium easier. The posterior trajectory also allows for less temporal lobe elevation, as the middle cranial fossa floor is less steep here.

The paramedian incision and unilateral suboccipital craniotomy protect the torcula and contralateral transverse sinus. There are fewer bridging veins in the route over the lateral cerebellum than in the median version, and the trajectory is more direct toward SCA aneurysms. Because of the angle of the tentorium, the lateral SCIT provides a less steep angle than the median version when the arachnoid membrane is dissected and the cerebellum falls away. However, the limitations of the SCIT approach still include a long operative corridor often associated with a steep angle.

Lateral Supracerebellar Infratentorial Approach The lateral supracerebellar infratentorial approach (SCIT) is a modification of the classic midline approach, and it can be used to access cerebellomesencephalic and cortical segment SCA aneurysms that are too distal to safely approach via the subtemporal route.

Other Approaches and Considerations The occipital transtentorial approach has also been used to reach SCA aneurysms of the first two segments, although we do not favor this technique. SCA aneurysms that are complex or fusiform may require trapping, and they may also require revascularization with similar techniques used for PCA aneurysm trapping. Superficial temporal artery–S1  (pretemporal) and superficial temporal artery–S2 (subtemporal) bypasses can be performed, if

26  Surgical Management of Posterior Circulation Aneurysms needed. Distal SCA aneurysms can be trapped without the need for revascularization because of a low likelihood of infarction.35,​84

373

structures determine the surgical approach for basilar bifurcation aneurysms, as described by Tjahjadi et al10,​14 and others.​18,​19

Patient Outcomes and Best Evidence Practice Among posterior circulation aneurysms, SCA aneurysms are thought to have a better surgical outcome than those at the basilar apex because of the lack of immediate perforators and because of better surgical access to the aneurysms. However, many SCA aneurysms are, in fact, basilar artery–SCA aneurysms, and the outcomes of these aneurysms are similar to those of aneurysms at the basilar apex. As of this writing, reports of cohorts with long-term follow-up on SCA aneurysms have not been published. We strongly believe that during long-term follow-up, clip ligation gives a better outcome than endovascular coiling, especially in patients with long life expectancy. However, we should not forget that most patients are elderly, present with SAH, and often have multiple aneurysms and other cardiovascular risk factors. These factors must be taken into account when selecting the optimal treatment regimen for patients.1,​2,​3,​17,​41,​87 Complex SCA aneurysms may require revascularization for the best outcome (see section on PCA aneurysms).

■■ Basilar Artery Aneurysms Epidemiology and Characteristics Aneurysms of the basilar artery are found in every section of the artery: the vertebrobasilar junction, basilar trunk, basilar bifurcation, and basilar artery–SCA (described elsewhere in this chapter), but basilar artery perforator aneurysms are rarely observed (Fig. 26.13, Fig. 26.14, Fig. 26.15, Fig. 26.16). Saccular aneurysms are mostly found in basilar bifurcation and basilar artery–SCA segments.1,​2,​3,​4,​83 Fusiform aneurysms are predominantly on the basilar trunk and the vertebrobasilar junction. Fusiform change or dolichoectasia of the entire vertebrobasilar circulation is possible (Fig. 26.16).5,​49,​90 Patients with dissection of the vertebrobasilar artery may present with ischemic symptoms and are often treated using endovascular techniques. Basilar artery perforator aneurysms are extremely rare, as are mycotic basilar artery aneurysms. The natural history of basilar artery aneurysms varies, depending on which segment of the artery is involved, and it is universally poorer than counterparts in the anterior circulation.

Basilar Bifurcation Aneurysms (Basilar Tip or Basilar Apex Aneurysms) Aneurysms at the basilar bifurcation (Fig. 26.13, Fig. 26.14) constitute 4% of all intracranial aneurysms. This number can be higher, as demonstrated by the Helsinki experience. Analyzing the Helsinki database reveals that 8% of the aneurysms were located at the posterior circulation. Basilar bifurcation aneurysms constitute 3% of all intracranial aneurysms and 37% of posterior circulation aneurysms. VA aneurysms constitute one-third of all vertebrobasilar circulation aneurysms, and the remaining aneurysms are located on the basilar trunk. Morphology, projection, and anatomical relation to n ­ eurovascular

Basilar Trunk Aneurysms Aneurysms of the basilar trunk are often fusiform, but saccular aneurysms do exist and may rupture, even at a small size (Fig. 26.15). Fusiform aneurysms constitute 1 to 2% of all intracranial aneurysms and are mostly observed in the posterior circulation; therefore, a significant number of these lesions are observed on the basilar trunk. Surgical treatment for fusiform and dolichoectatic aneurysms is often limited to proximal occlusion and trapping, with or without revascularization (Fig. 26.16).10,​14,​49,​91,​92,​93,​94

Vertebrobasilar Junction Aneurysms Aneurysms of the vertebrobasilar junction are rare lesions. They are often associated with fenestrations in the basilar artery.50

Clinical Presentation As described earlier, basilar artery aneurysms harbor a graver natural history than aneurysms in other locations, especially when patients present with them ruptured. Basilar artery aneurysms are rarely diagnosed secondary to mass effect and ischemia. Mass effect presents as local pressure on the brainstem and CNs, and symptoms are accordingly related to the location of the mass. Giant, fusiform, and dolichoectatic basilar artery aneurysms may be identified after a transient ischemic attack. Aneurysms may otherwise be identified during work-up for vertigo, visual disturbance, and other less specific symptoms.1,​5,​9,​11,​49,​95

Perioperative Evaluation The timing of intervention depends on the patient’s admission status, including the extent of SAH, Hunt and Hess grade, physical examination, and presence of hydrocephalus.92,​94,​95 Noninvasive imaging using computed tomography angiography is often the primary modality for visualizing the aneurysm in relation to bony structures that may hinder approach. In complex cases, especially when an aneurysm may be thrombosed or calcified, digital subtraction angiography should be performed to better delineate aneurysm anatomy. Angiography also allows the surgeon to evaluate collateral circulation, in anticipation of possible vessel sacrifice as a treatment modality. Patients with ruptured basilar artery aneurysms should be treated hyperacutely because the risk of rerupture and associated morbidity and mortality is greater than for other aneurysms. Intrinsic and extrinsic factors often determine the approach to these aneurysms.8,​10,​14,​79 Factors that should be considered when selecting approaches for basilar artery aneurysms include the location of the aneurysm in relation to the posterior clinoid process, the projection of the aneurysm, the fetal or variant nature of the PCoA–PCA, the size of the PCoA, and the potential need for revascularization.

374

VI  Comprehensive Management of Vascular Pathology of the Brainstem and Thalamus

Fig. 26.13  Ruptured basilar tip aneurysm. Preoperative (a) axial computed tomogram reveals diffuse subarachnoid hemorrhage, accompanied by hydrocephalus; (b) sagittal and (c) coronal computed tomography angiograms (CTAs) demonstrate a basilar tip aneurysm at the level of the

posterior clinoid process. This aneurysm was clipped via a right subtemporal approach, with the patient in the park bench position. Postoperative (d) axial, (e) sagittal, and (f) coronal CTAs demonstrate complete obliteration of the aneurysm sac and intact flow in posterior cerebral arteries.

Microsurgical Treatment Options

Subtemporal Approach

Many aneurysms arising from the basilar tip can be approached by most of the described approaches. The surgeon’s preference or experience determines the safest approach, guided by patientspecific anatomical factors.

Basilar artery aneurysms are often approached from the right side to avoid retraction injury to the dominant temporal lobe. For righthanded surgeons, operating from the right side is easier and more familiar. The greater the height above the dorsum sellae, the greater the degree of retraction required to obtain the necessary exposure to perform the operation. If the neck of the sac of the aneurysm reaches the apex of the interpeduncular space, both the neck of the aneurysm and the perforators can be hidden by the mammillary bodies in front and by the peduncle laterally and behind. These rare cases (