Schmidek and Sweet: Operative Neurosurgical Techniques 7th Edition (Volume 1) [Volume 1, 7 ed.] 0323414796, 9780323414791

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SCHMIDEK & SWEET

Operative Neurosurgical Techniques Seventh Edition

Indications, Methods, and Results ALFREDO QUIÑONES-­H INOJOSA, MD

WILLIAM J. AND CHARLES H. MAYO PROFESSOR CHAIR, NEUROLOGIC SURGERY DEPARTMENT OF NEUROSURGERY MAYO CLINIC JACKSONVILLE, FLORIDA

Elsevier 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-­2899

SCHMIDEK & SWEET OPERATIVE NEUROSURGICAL TECHNIQUES: ISBN: 978-­0-­323-­41479-­1 INDICATIONS, METHODS, AND RESULTS,  Volume 1: 978-0-323-84721-6 SEVENTH EDITION Volume 2: 978-0-323-84722-3 Copyright © 2022, 2012, 2006, 2000, 1995, 1988, 1982 by Saunders, an imprint of Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Control Number: 2021930850

Content Strategist: Belinda Kuhn Director, Content Development: Laurie K. Gower Senior Content Development Manager: Laura Schmidt Content Development Specialist: Denise Roslonski Publishing Services Manager: Julie Eddy Senior Project Manager: Cindy Thoms Book Designer: Brian Salisbury Printed in Canada Last digit is the print number:  9  8  7  6  5  4  3  2  1

DEDICATION

I dedicated the 6th edition (the first edition where I served as Chief Editor) to Dr. Henry Schmidek, who was undoubtedly an extraordinary and visionary man. Dr. Schmidek was intellectually gifted with a voracious curiosity and never-­ ending gusto for knowledge and life. His immense love of his family was apparent to everyone who had the pleasure of his company. Dr. Schmidek died in the fall of 2008, but his legacy has continued through the 6th and now the 7th editions of this book. This book continues to be the most universal text in neurosurgery. This new 7th edition of Schmidek & Sweet Operative Neurosurgical Techniques is part of a legacy of academic excellence. I tried to keep the same spirit that characterized the prior editions of this book and made it a favorite among students, residents, health care providers, and faculty alike since its first printing. As I edited this text with the help of a superb team of section editors and contributors in the middle of the most extraordinary life-­altering COVID-­19 pandemic, I reflected on the many lives we have lost in the world and came to realize that it is not about how long we live but the contributions we make to this world, the people we touch, and the legacy we leave behind. I would like to thank my wife, Anna, and our children, Gabriella, David, and Olivia, for their extraordinary patience, love, and dedication to my career and life and, ultimately, their commitment to our patients, who are also part of our family. Our children keep me young, grounded,

and humble by asking me questions to which I do not have answers. Thanks to all my mentors thorough the decades since I came to the United States and special gratitude to our extraordinary team of nurses, administrators, anesthesiologists, neurologists, neurosurgeons, otolaryngologists, radiologists, endocrinologists, residents, fellows, and medical students who have dedicated their lives to the pursuit of perfection and patient care and who are an integral part of these advances in surgery—they all have helped me become a better surgeon and a compassionate physician. I have been given guidance and light during moments when the room was dark and the visibility was dimmed by moments of doubt and fear. A million thanks to my amazing patients and their families—they are the true unsung heroes who day after day stay positive and filled with hope despite their health struggles and often put their lives in our hands, ask questions, and constantly push us to be better physicians, surgeons, and human beings. Much gratitude and thanks also to Elsevier, Karim ReFaey, Laurie Gower, Denise Roslonski, Laura Schmidt, Belinda Kuhn, Cindy Thoms, and the extraordinary team who made this book possible. It has taken many years of work, many years’ experience and knowledge to produce this book. It would not have been possible without all of you. Alfredo Quiñones-­Hinojosa

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SECTION EDITORS

Section One

Section Four

Alfredo Quiñones-­Hinojosa, MD William J. and Charles H. Mayo Professor Chair, Neurologic Surgery Department of Neurosurgery Mayo Clinic Jacksonville, Florida

Daniele Rigamonti, MD Professor, Neurosurgery Johns Hopkins School of Medicine Baltimore, Maryland CEO Johns Hopkins Aramco Healthcare Dhahran, Eastern Province, Saudi Arabia

Surgical Management of Brain and Skull Base Tumors

Maryam Rahman, MD, MS Assistant Professor Neurosurgery University of Florida Gainesville, Florida

Abnormalities of Cerebrospinal Fluid Dynamics

Section Five

Stereotactic Radiosurgery

Vascular Diseases

Cesare Giorgi, MD Consultant Neurosurgeon Gamma Knife Unit Fondazione Poliambulanza Brescis, Italy

Michael T. Lawton, MD Professor and Chair, Department of Neurosurgery Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, Arizona

Daniel M. Trifiletti, MD Associate Professor Radiation Oncology Mayo Clinic Jacksonville, Florida

Rabih G. Tawk, MD Associate Professor Department of Neurosurgery Mayo Clinic Jacksonville, Florida

Section Six

Section Two

Brian L. Hoh, MD James & Brigitte Marino Family Professor and Chair Neurosurgery University of Florida Gainesville, Florida

Section Three

Operative Techniques in Pediatric Neurosurgery George I. Jallo, MD Professor, Neurosurgery, Pediatrics, and Oncology Division of Pediatric Neurosurgery Director, Institute for Brain Protection Sciences Johns Hopkins All Children’s Hospital St Petersburg, Florida

Functional Neurosurgery Emad N. Eskandar, MD Associate Professor, Neurosurgery Massachusetts General Hospital and Harvard Medical School Director, Stereotactic and Functional Neurosurgery Director, Neurosurgery Residency Program Massachusetts General Hospital Boston, Massachusetts Edward F. Chang, MD Associate Professor, Neurological Surgery School of Medicine University of California San Francisco, California

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SECTION EDITORS

Section Seven

Section Nine

Trauma

Neurosurgical Management of Spinal Disorders

J. Marc Simard, MD, PhD Professor Neurosurgery, Pathology, and Physiology School of Medicine University of Maryland Baltimore, Maryland

Ziya L. Gokaslan, MD, FAANS, FACS Julius Stoll, MD Professor and Chair, Department of Neurosurgery The Warren Alpert Medical School of Brown University Neurosurgeon-­in-­Chief, Rhode Island Hospital and The Miriam Hospital Clinical Director, Norman Prince Neurosciences Institute President, Brown Neurosurgery Foundation Providence, Rhode Island

Section Eight

Surgical Management of Nervous System Infections Rodrigo Ramos-­Zuniga Sr., MD, PhD Professor of Neurosciences Institute of Translational Neurosciences. Department of Neurosciences University of Guadalajara Guadalajara, Jalisco, Mexico Mohamed E. El-­Fiki, MBBCh, MS, MD, DNCh Professor, Neurosurgery University of Alexandria Alexandria, Egypt

Mohamad Bydon, MD Associate Professor Department of Neurologic Surgery Mayo Clinic Rochester, Minnesota

Section Ten

Surgical Management of the Peripheral Nervous System Robert J. Spinner, MD Chair, Department of Neurologic Surgery Neurosurgery Professor Departments of Anatomy, Neurologic Surgery, and Orthopedic Surgery Mayo Clinic Rochester, Minnesota

IN MEMORIAM

Frank Lugo Acosta Jr., MD

Edward H. Oldfield, MD

1975-2020

1947-2017

Dr. Frank Lugo Acosta Jr., MD, age 45, passed away on November 21, 2020. Frank grew up in East Los Angeles/ Montebello. As a kid, Frank was smart, loved science, and enjoyed soccer. He went to Don Bosco Tech for high school and excelled in science, counting units, and chess. He got accepted to every Ivy League school in the country, choosing Harvard University to pursue his passion in chemistry, math, and physics. Frank matriculated at Harvard Medical School where he completed an HHMI Research fellowship. Frank went to the University of California at San Francisco for his neurosurgical training. Frank specialized in complex spine surgeries, and he was known around the world for his clinical and scientific contributions to deformity and complex spine neurosurgery. He was a top spine neurosurgeon in the county, an amazingly gifted, talented, and a very educated young man. Frank was a beloved son, brother, husband, father, colleague, and friend who loved to make others laugh. He will be deeply missed by his family, daughter, friends, colleagues, and all who knew him.

Edward H. Oldfield, MD, passed away on September 1, 2017. His death was a significant loss to everyone who knew him, including the over 100 trainees he mentored worldwide. While neurosurgery has lost a giant, Ed’s life left an indelible mark through scientific discovery and surgical innovation, as well as generations of trainees and colleagues. Ed was born in the small town of Mount Sterling, Kentucky, on November 22, 1947, to Ellis and Amanda (née Miller) Oldfield. He was the second of five children, with one older sister, two younger brothers, and one younger sister. Ed’s father was a decorated World War II veteran, having been awarded two Bronze Stars and a Purple Heart. Ed continued to study physics at the University of Kentucky, during which he met Susan, the love of his life and future wife. Upon completing three years of college, Ed joined the University of Kentucky College of Medicine. Afterward, he joined Vanderbilt University Medical Center for his neurosurgical training. Dr. Oldfield made significant clinical and scientific contributions to neurosurgery. He excelled in spinal vascular malformations, Chiari I malformation and syringomyelia, pituitary adenomas, drug delivery, nervous system neoplasia, gene therapy, and vasospasm, which led to over 500 peer-­reviewed publications, an H-­index over 100, and over 43,000 citations.

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IN MEMORIAM

Evandro de Oliveira, MD, PhD 1944-2021

Dr. Evandro De Oliveira passed away on February 11, 2021. Evandro was from Santa Catarina, Brazil, and completed medical school at the Federal University of Santa Catarina and then Neurosurgery Residency at the Universidad del Republica, in Montevideo, Uruguay. He spent time with Al

Rhoton, Jr. and M. Gazi Yasargil, which led to a lifelong friendship and collaborations. Evandro led a philosophy based on the mastery of anatomy and microneurosurgery, where the anatomy learned in the lab must be applied in the operative room, in a clean, beautiful, and effective manner. Evandro was a uniquely dedicated surgeon-­artist in chase of perfection. Nothing but the best was acceptable. He took Brazilian neurosurgery to the next level and inspired generations. Through his multiple positions, including Director of Institute of Neurological Sciences, Sao Paulo, he mentored 92 clinical fellows, over 600 visiting fellows, and additional 7000 surgeons, who attended one or more of the 350 courses held in his lab in Sao Paulo. Evandro was passionate about his family, his friends, and about neurosurgery. He always cared for his personal and “surgical” families, including during his battle against ALS. He remains alive through his wife, daughters, and granddaughter and through his disciples. Undoubtedly, Evandro was “The Unbelievable” surgeon, mentor, and master and will be forever missed.

ABOUT THE AUTHOR/EDITOR

Dr. Alfredo Quiñones-­Hinojosa, commonly known as Dr. Q, received his medical degree from Harvard University where he graduated cum laude. He completed his residency in neurosurgery at the University of California, San Francisco, where he also completed a postdoctoral fellowship in developmental and stem cell biology. His career began at the Johns Hopkins University School of Medicine, where he became Professor of Neurosurgery and Oncology, Neurology, and Cellular and Molecular Medicine and Director of the Brain Tumor Stem Cell Laboratory. Nowadays, he is the “William J. and Charles H. Mayo Professor” and Chair of Neurologic Surgery at the Mayo Clinic in Jacksonville, Florida.

Dr. Q is an internationally renowned neurosurgeon and neuroscientist who leads NIH-­ funded research to cure brain cancer. He is the principal investigator at the Brain Tumors Stem Cell Laboratory at the Mayo Clinic. He has published more than 450 peer-­reviewed papers and 100 book chapters, edited 14 high-­impact neurosurgical textbooks, and published his memoir, Becoming Dr. Q, in both English and Spanish. Dr. Q is the founder and president of the nonprofit organization Mission:BRAIN, providing patients in need access to advanced neurosurgical procedures around the world. For all his work, Dr. Q has also been recognized with several prestigious awards, including being named as one of the 100 most influential Hispanics in the U.S. by Hispanic Business Journal; as 2014 Neurosurgeon of the Year by Voices Against Brain Cancer, where he was also recognized with the Gary Lichtenstein Humanitarian Award; and by the 2015 Forbes magazine as one of Mexico’s most brilliant minds in the world; he was also selected by Popular Science magazine as one of their 6th Annual Brilliant Ten in their search for young genius influencing the course of science. He has received honorary degrees from Southern Vermont College, Lackawanna College, Dominican University, University of Notre Dame, Loyola University, and Universidad Anahuac Mexico. He was awarded the Cortes de Cadiz Prize in the category of surgery by the city council of Cadiz, Spain, and was also named by Forbes as one of the most creative Mexicans. Dr. Q’s story was featured on the BBC and Netflix show “The Surgeon’s Cut” in December 2020, and more recently Annapurna Pictures and Plan B Entertainment productions announced that his inspirational life story is going to be featured in a movie.

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VIDEO AND CONTENT ASSOCIATE EDITOR

Qatari Royal Family and most recently by grants from the National Institutes of Health. Dr. ReFaey’s research focuses on gliomas and awake brain mapping to preserve speech and motor functions and preserve the crucial areas of the brain. Dr. ReFaey has published in clinical and translational research, producing close to 40 peer-­reviewed publications and more than 30 book chapters. His work involving the design and utilization of high-­density electrocorticography (HD-ECoG) in intraoperative monitoring during awake craniotomies and its effect on the patient’s outcome led to national invited presentations, high-tier clinical publications, as well as five US patents complementing this technology (one issued, PCT/US2018/039956; two pending, # 2019-388; # 2017-113; and two in submission). He has been recognized by the American Epilepsy Society for the impact of his work and was awarded the Young Investigator Award of the Year in 2017. Dr. ReFaey is applying for neurosurgery residency to pursue his career as a neurosurgeon-­scientist.

Dr. Karim ReFaey earned his medical degree from Ain Shams University in Cairo, Egypt. He conducts cutting-­ edge research in neurosurgery, neuro-­oncology, and oncoepilepsy, sponsored originally by a generous grant from the

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CONTRIBUTORS

Marlien W. Aalbers, MD, PhD Department of Neurosurgery University of Groningen University Medical Center Groningen Groningen, the Netherlands Hadi Abou-­El-­Hassan, MD Research Fellow Department of Neurological Surgery Mayo Clinic Jacksonville, Florida Frank Acosta, MD Associate Professor of Neurological Surgery University of Southern California Los Angeles, California P. David Adelson, MD Director, Barrow Neurological Institute at Phoenix Children’s Hospital Diane and Bruce Halle Chair of Pediatric Neurosciences Chief, Pediatric Neurosurgery, Phoenix Children’s Hospital Professor, Department of Child Health University of Arizona College of Medicine Phoenix, Arizona, Professor, Neurosurgery Mayo Clinic Scottsdale, Arizona John R. Adler Jr., MD Professor, Department of Neurosurgery Stanford University Stanford, California Vijay Agarwal, MD Director, Skull Base Center Assistant Professor, Department of Neurosurgery Montefiore Medical Center University Hospital for the Albert Einstein College of Medicine New York, New York Manish K. Aghi, MD, PhD Professor in Neurological Surgery University of California, San Francisco San Francisco, California

Manmeet S. Ahluwalia, MD Brain Tumor and Neuro-­Oncology Center Neurological Institute Taussig Cancer Institute Cleveland Clinic Department of Medicine Cleveland Clinic Lerner College of Medicine Case Western University Cleveland, Ohio A. Karim Ahmed, BS MD Candidate, Neurosurgery Research Fellow Department of Neurosurgery Johns Hopkins School of Medicine Baltimore, Maryland Pablo Ajler, MD Neurosurgery Hospital Italiano Buenos Aires, Argentina Oluwaseun O. Akinduro, MD Resident Physician, Department of Neurological Surgery Mayo Clinic Jacksonville, Florida Felipe C. Albuquerque, MD Assistant Director, Endovascular Surgery Professor of Neurosurgery Department of Neurosurgery Barrow Neurological Institute Phoenix, Arizona Philipp R. Aldana, MD Professor, Neurosurgery and Pediatric Neurosurgery Division of Pediatric Neurosurgery University of Florida Health Jacksonville Jacksonville, Florida Ram K. Alluri, MD Orthopaedic Surgery Resident Keck School of Medicine University of Southern California Los Angeles, California

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CONTRIBUTORS

Mohammed Ali Alvi, MD Research Fellow, Department of Neurologic Surgery Mayo Clinic Neuro-­Informatics Laboratory Mayo Clinic Rochester, Minnesota Luca Amendola, MD Orthopaedic Surgery and Traumatology Unit Maggiore Hospital Regional Trauma Center Bologna Local Health District Bologna, Italy Sepideh Amin-­Hanjani, MD Professor and Program Director, Department of Neurosurgery Co-­Director, Neurovascular Surgery University of Illinois at Chicago Chicago, Illinois Joshua M. Ammerman, MD Chief, Section of Neurosurgery Chairman, Department of Surgery Sibley Memorial Hospital Assistant Clinical Professor of Neurosurgery George Washington University School of Medicine Washington, DC Adjunct Assistant Professor of Neurosurgery Johns Hopkins School of Medicine Baltimore, Maryland William Anderson, MD Associate Professor of Neurosurgery Associate Professor of Biomedical Engineering Department of Neurosurgery Johns Hopkins School of Medicine Baltimore, Maryland Hugo Andrade-­Barazarte, MD, PhD Consultant Neurosurgeon Department of Neurosurgery and Cerebrovascular Diseases Henan Provincial People’s Hospital Zhengzhou, PR China Geoff Appelboom, MD, PhD Department of Neurosurgery Stanford University School of Medicine Stanford, California Paul M. Arnold, MD, FACS Professor and Chairman, Department of Neurosurgery Carle Illinois College of Medicine Urbana, Illinois Ashok Asthagiri, MD Associate Professor, Department of Neurological Surgery University of Virginia Health System Charlottesville, Virginia

Sonikpreet Aulakh, MBBS, MD Assistant Professor, Medicine Division of Hematology-­Oncology Department of Internal Medicine Department of Neurosciences West Virginia University School of Medicine Morgantown, West Virginia Khaled M. Aziz, MD Assistant Professor of Neurosurgery Director, Division of Complex Intracranial Surgery Neurosurgery Allegheny General Hospital Pittsburgh, Pennsylvania Tipu Aziz, F.Med.Sci Professor of Neurosurgery Nuffield Department of Surgical Sciences University of Oxford Oxford, England United Kingdom Joshua Bakhsheshian, MD Department of Neurological Surgery Keck School of Medicine University of Southern California Los Angeles, California Perry A. Ball, MD Professor Departments of Surgery and Anesthesiology Geisel School of Medicine Dartmouth-­Hitchcock Medical Center Lebanon, New Hampshire Stefano Bandiera, MD Coordinator of Specialist Reference Centre Spine Surgery prevalently Oncologic and Degenerative Istituto Ortopedico Rizzoli Bologna, Italy Nicholas M. Barbaro, MD Neurosurgeon Mulva Clinic for the Neurosciences Professor of Neurosurgery Dell Medical School University of Texas at Austin Austin, Texas Zachary R. Barnard, MD, MS Resident, Neurosurgery Cedars-­Sinai Medical Center Los Angeles, California Daniel L. Barrow, MD Pamela R. Rollins Professor and Chairman Department of Neurosurgery Emory University School of Medicine Atlanta, Georgia

CONTRIBUTORS

Thomas L. Beaumont, MD, PhD Department of Neurosurgery The Ohio State University Wexner Medical Center Columbus, Ohio Joshua Bederson, MD Professor and System Chair of Neurosurgery Department of Neurosurgery Icahn School of Medicine at Mount Sinai New York, New York Alexandra D. Beier, DO Associate Professor, Neurosurgery and Pediatrics Division of Pediatric Neurosurgery University of Florida Health Jacksonville Jacksonville, Florida Carlo Bellabarba, MD Professor and Vice Chair Department of Orthopaedics and Sports Medicine Joint Professor Department of Neurological Surgery University of Washington School of Medicine Chief of Orthopaedics Harborview Medical Center Seattle, Washington Lorenzo Bello, MD Professor, Neurosurgery Oncology and Hemato-­Oncology Neuro-­Oncological Surgery Università degli Studi di Milano Milano, Italy Alan J. Belzberg, MD Professor Neurosurgery Johns Hopkins Hospital Baltimore, Maryland Sharona Ben-­Haim, MD Assistant Professor, Department of Neurosurgery University of California–San Diego San Diego, California Netanel Ben-­Shalom, MD Department of Neurosurgery Rabin Medical Center Beilinson Campus New York, New York Matthew T. Bender, MD Assistant Professor, Department of Neurosurgery and Neurology University of Rochester Rochester, New York Bernard R. Bendok, MD Chair, Neurological Surgery in Arizona William J. and Charles H. Mayo Professor Professor of Neurosurgery Department of Neurosurgery Mayo Clinic Phoenix, Arizona

Ludwig Benes, MD Head, Department of Neurosurgery Klinikum Arnsberg Arnsberg, Germany Edward C. Benzel, MD Emeritus Chairman and Professor Department of Neurosurgery Lerner College of Medicine Neurological Institute Cleveland Clinic Cleveland, Ohio Helmut Bertalanffy, MD, PhD Professor, Neurosurgery Director of Vascular Neurosurgery International Neuroscience Institute Hannover, Germany Chetan Bettegowda, MD, PhD Professor, Department of Neurosurgery Johns Hopkins School of Medicine Baltimore, Maryland Priyal Vinod Bhagat, DO Department of Orthopaedic Surgery New York University Medical Center New York, New York Wenya Linda Bi, MD, PhD Department of Neurosurgery Brigham and Women’s Hospital Boston, Massachusetts Harvard Medical School Cambridge, Massachusetts Kelly Bijanki, PhD Assistant Professor Department of Neurosurgery Baylor College of Medicine Houston, Texas Allen T. Bishop, MD Division of Hand Surgery Department of Orthopedics Professor, Orthopedics and Neurosurgery Mayo Clinic Rochester Minnesota Erica F. Bisson, MD, MPH Professor of Neurosurgery Department of Neurosurgery University of Utah Salt Lake City, Utah Keith L. Black, MD Chair and Professor Department of Neurosurgery Director Maxine Dunitz Neurosurgical Institute Cedars-­Sinai Medical Center Los Angeles, California

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CONTRIBUTORS

Benjamin Blondel, MD Aix Marseille University Timone Hospital Department of Paediatric Orthopaedics Marseille, France Kofi Boahene, MD Professor of Otolaryngology–Head and Neck Surgery Johns Hopkins Medicine Baltimore, Maryland Angela M. Bohnen, MD Neurosurgeon NeurosurgeryOne Denver, Colorado Robert J. Bollo, MD, MS Associate Professor University of Utah Salt Lake City, Utah Markus Bookland, MD Associate Director of Academic Affairs Department of Pediatric Neurosurgery Connecticut Children’s Medical Center Hartford, Connecticut Assistant Professor Department of Surgery University of Connecticut School of Medicine Farmington, Connecticut Alireza Borghei, MD Post-­Doctorate Fellow Department of Neurosurgery Rush University Chicago, Illinois Hamid Borghei-­Razavi, MD Assistant Professor, Neurological Surgery Department of Neurosurgery Pauline Braathen Neurological Center Cleveland Clinic Florida Weston, Florida Stefano Boriani, MD GSpine4 Spine Surgery Division IRCCS Istituto Ortopedico Galeazzi Milan, Italy Sachin A. Borkar, MBBS, MCh, DNB, MNAMS Consultant and Associate Professor, Neurosurgery All India Institute of Medical Sciences and Jai Prakash Narain Apex Trauma Center New Delhi, India Weston, Florida Frank J. Bova, PhD Professor Department of Neurological Surgery University of Florida Gainesville, Florida

Bledi C. Brahimaj, MD Resident, Department of Neurosurgery Rush University Medical Center Chicago, Illinois Ryan J. Brandt, MD Assistant Professor Department of Radiology Dartmouth-­Hitchcock Medical Center Lebanon, New Hampshire Richard J. Bransford, MD Professor and Director of Spine Fellowship Department of Orthopaedics and Sport Medicine Joint Professor Department of Neurological Surgery University of Washington School of Medicine Seattle, Washington Jacques Brotchi, MD, PhD Emeritus Professor Department of Neurosurgery Erasme Hospital Brussels, Belgium Benjamin L. Brown, MD Assistant Professor, Department of Neurosurgery Mayo Clinic Jacksonville, Florida Jeffrey N. Bruce, MD Edgar M. Housepian Professor of Neurological Surgery Vice Chairman of Academic Affairs Neurological Surgery New York-­Presbyterian Columbia University Medical Center New York, New York Michael Bruneau, MD, PhD Professor Department of Neurosurgery Erasme Hospital Brussels, Belgium Ian A. Buchanan, MD Department of Neurological Surgery Keck School of Medicine University of Southern California Los Angeles, California Kim J. Burchiel, MD, FACS John Raaf Professor Department of Neurological Surgery Oregon Health & Science University Portland, Oregon

CONTRIBUTORS

Timothy G. Burke, MD Chairman Department of Neurosurgery Anne Arundel Medical Center Annapolis, Maryland Associate Professor Department of Neurosurgery The George Washington University Washington, DC

Ricardo L. Carrau, MD Professor Departments of Otolaryngology Head and Neck Surgery and Neurosurgery The Ohio State University Wexner Medical Center Columbus, Ohio

Ali Bydon, MD Professor of Neurosurgery Department of Neurosurgery Johns Hopkins University School of Medicine Baltimore, Maryland

Bob S. Carter, MD, PhD Neurosurgeon Chair, Department of Neurosurgery William and Elizabeth Sweet Professor of Neurosurgery Harvard Medical School Massachusetts General Hospital Boston, Massachusetts

Mohamad Bydon, MD Associate Professor Department of Neurologic Surgery Mayo Clinic Rochester, Minnesota

Laura Castana, MD “Claudio Munari” Epilepsy Surgery Center Department of Neuroscience ASST Grande Ospedale Metropolitano Niguarda Milan, Italy

Richard W. Byrne, MD Professor and Chair Department of Neurosurgery Rush University Medical Center Chicago, Illinois

Gabriel Castillo-Velazquez, MD Neurosurgeon Puerta de Hierro Medical Center Guadalajara, Mexico

Gustavo Augusto Porto Sereno Cabral Assistant, Neurosurgery Department Gaelão Air Force Hospital Rio de Janeiro, Brazil

Kaisorn L. Chaichana, MD Professor, Department of Neurosurgery Mayo Clinic Jacksonville, Florida

Francesco Cacciola, MD Consultant Neurosurgeon Department of Neurosurgery University Hospital of Siena Siena, Italy

Asher Chanan-­Khan, MBBS, MD Professor, Medicine Division of Hematology-­Oncology Department of Medicine Mayo Clinic Jacksonville, Florida

Jessica K. Campos, MD Department of Neurosurgery University of California–Irvine Irvine, California

Edward F. Chang, MD Professor of Neurological Surgery University of California–San Francisco San Francisco, California

Justin M. Caplan, MD Department of Neurosurgery Johns Hopkins Hospital Baltimore, Maryland

Steven D. Chang, MD Robert C. and Jeannette Powell Professor in the Neurosciences Department of Neurosurgery Stanford School of Medicine Stanford, California

Anthony J. Caputy, MD Hugo V. Rizzoli Professor of Neurosurgery The George Washington University Washington, DC Francesco Cardinale, MD “Claudio Munari” Epilepsy Surgery Center Department of Neuroscience ASST Grande Ospedale Metropolitano Niguarda Milan, Italy Lucas P. Carlstrom, MD, PhD Department of Neurologic Surgery Mayo Clinic Rochester, Minnesota

Aswin Chari, MA, BMBCh, MRCS GOSH Charity Surgeon-­Scientist Fellow and Neurosurgical Registrar Department of Neurosurgery Great Ormond Street Hospital London, United Kingdom Ching-­Jen Chen, MD Resident Physician, Neurological Surgery University of Virginia Charlottesville, Virginia

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CONTRIBUTORS

Douglas Chen, MD Neurotology Specialist Allegheny General Hospital Pittsburgh, Pennsylvania

Ray M. Chu, MD Clinical Chief, Neurosurgery Cedars-­Sinai Medical Center Los Angeles, California

James Chen, MD Interventional Radiology Charlotte Radiology Charlotte, North Carolina

William Clifton, MD Resident Physician Department of Neurosurgery Mayo Clinic Jacksonville, Florida

Selby Chen, MD Department of Neurologic Surgery Mayo Clinic Jacksonville, Florida Joshua J. Chern, MD, PhD Section of Pediatric Neurosurgery Riley Hospital for Children Department of Neurosurgery Indiana University School of Medicine Goodman Campbell Brain and Spine Indianapolis, Indiana John H. Chi, MD, MPH Director, Neurosurgical Spinal Oncology Department of Neurosurgery Brigham and Women’s Hospital Associate Professor, Neurosurgery Harvard Medical School Boston, Massachusetts E. Antonio Chiocca, MD, PhD Harvey W. Cushing Professor of Neurosurgery Neurosurgeon-­in-­Chief and Chairman Department of Neurosurgery Brigham and Women’s Hospital Boston, Massachusetts Rohan Chitale, MD Assistant Professor, Department of Neurological Surgery Residency Associate Program Director Neurological Surgery Vanderbilt University Medical Center Nashville, Tennessee Bhupal Chitnavis, BSc(Hons), MBBS, FRCS(Eng), FRCS(SN) Consultant Neurosurgeon Department of Neurosurgery London Bridge Hospital London, United Kingdom Omar A. Choudhri, MD Assistant Professor, Neurosurgery and Radiology University of Pennsylvania Director, Penn Center for Cerebral Revascularization Co-­Director Cerebrovascular and Endovascular Neurosurgery Philadelphia, Pennsylvania

Alan R. Cohen, MD Professor, Neurosurgery, Oncology, and Pediatrics Chief of Pediatric Neurosurgery Johns Hopkins University School of Medicine Baltimore, Maryland Salomon Cohen, MD Department of Neurologic Surgery Mayo Clinic Rochester, Minnesota Geoffrey P. Colby, MD, PhD Associate Professor, Neurosurgery and Radiology Director of Cerebrovascular Neurosurgery University of California, Los Angeles Los Angeles, California Tyler S. Cole, MD Resident Physician Department of Neurosurgery Barrow Neurological Institute Phoenix, Arizona Alessandro Consales, MD Department of Pediatric Neurosurgery Istituto Giannina Gaslini Genoa, Italy Alexander L. Coon, MD Director, Endovascular and Cerebrovascular Neurosurgery Carondelet Neurological Institute Tucson, Arizona Jared B. Cooper, BA, MS, MD Resident, Neurosurgery Westchester Medical Center Valhalla, New York William R. Copeland, MD Department of Neurologic Surgery Tenwek Hospital Bomet, Kenya Domagoj Coric, MD Chief, Department of Neurosurgery Carolinas Medical Center Chief, Spine Division Atrium Healthcare Musculoskeletal Institute Carolina Neurosurgery and Spine Associates Charlotte, North Carolina

CONTRIBUTORS

Frank M. Corl, MD Assistant Professor Biomedical Communications Mayo Clinic Rochester, Minnesota Brian M. Corliss, MD Department of Neurological Surgery University of Florida Gainesville, Florida Marcelo Corti, MD Chairman Division of HIV AIDS Infection Diseases FJ Muñiz Hospital University of Buenos Aires Buenos Aires, Argentina Massimo Cossu, MD “C. Munari” Epilepsy Surgery Center Department of Neuroscience ASST Grande Ospedale Metropolitano Niguarda Milan, Italy Bradford L. Currier, MD Professor Department of Orthopedic Surgery Professor Department of Neurologic Surgery Mayo Clinic Rochester, Minnesota William T. Curry, MD Co-­Director, Mass General Neuroscience Director of Neurosurgical Oncology Massachusetts General Hospital Boston, Massachusetts Guilherme Dabus, MD, FAHA Director, Fellowship Department of Neurointerventional Surgery Miami Cardiac and Vascular Institute Baptist Neuroscience Center Miami, Florida

Ronan M. Dardis, MD Consultant Department of Neurosciences University Hospitals Coventry and Warwickshire NHS Trust Coventry, United Kingdom Sunit Das, MD Associate Professor Department of Surgery University of Toronto Toronto, Ontario, Canada Hormuzdiyar H. Dasenbrock, MD, MPH Department of Neurosurgery Boston University School of Medicine Boston, Massachusetts Arthur L. Day, MD Professor and Co-­Chairman Department of Neurosurgery University of Texas Houston Health Science Center Houston, Texas Gaetano De Biase, MD Department of Neurologic Surgery Mayo Clinic Jacksonville, Florida Rafael De la Garza Ramos, MD Neurological Surgery Resident Department of Neurosurgery Montefiore Medical Center New York, New York H. Gordon Deen, MD Department of Neurological Surgery Mayo Clinic Jacksonville, Florida Vedran Deletis, MD, PhD Department of Neurosurgery University Hospital Dubrava Zagreb, Croatia, Albert Einstein College of Medicine New York, New York

Nader S. Dahdaleh, MD Associate Professor, Department of Neurosurgery Northwestern University Feinberg School of Medicine Chicago, Illinois

Jay Detsky, MD Assistant Professor Odette Cancer Centre Sunnybrook Health Science Centre Toronto, Ontario, Canada

Andrew T. Dailey, MD Professor of Neurosurgery Department of Neurosurgery University of Utah School of Medicine Salt Lake City, Utah

Brian J. Dlouhy, MD Assistant Professor Department of Neurosurgery University of Iowa Hospitals and Clinics University of Iowa Stead Family Children’s Hospital Iowa City, Iowa

David J. Daniels, MD, PhD Associate Professor, Pediatric Neurosurgery Assistant Professor of Pharmacology Mayo Clinic Rochester, Minnesota

Ricardo A. Domingo, MD Postdoctoral Fellow Clinical Neurosurgery Team Mayo Clinic Jacksonville, Florida

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CONTRIBUTORS

Joseph Domino, MD, MPH Resident Physician Department of Neurosurgery University of Kansas Medical Center Kansas City, Kansas Angela M. Donaldson, MD Senior Associate Consultant Otorhinolaryngology Head and Neck Surgery Mayo Clinic Jacksonville, Florida David Dornbos, MD Open Vascular and Endovascular Fellow Department of Neurosurgery Semmes-­Murphey Clinic University of Tennessee Health Science Center Memphis, Tennessee Michael J. Dorsi, MD Assistant Professor of Neurosurgery Ronald Reagan UCLA Medical Center Los Angeles, California Cassius Vinicius Corrêa Dos Reis, MD, PhD Chairman, Neurosurgery Hospital das Clinicas Universidade Federal de Minas Gerais Belo Horizonte, Brazil Thomas B. Ducker, MD Founder (Retired) Maryland Brain and Spine; Partner Emeritus Annapolis, Maryland Hugues Duffau, MD, PhD Professor and Chairman Neurosurgery and INSERM 1191 Montpellier University Medical Center Montpellier, France Ian F. Dunn, MD Department of Neurosurgery University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma Randy S. D’Amico, MD Assistant Professor, Neurological Surgery Department of Neurosurgery Lenox Hill Hospital, Northwell Health Donald and Barbara Zucker School of Medicine at Hofstra/ Northwell New York, New York Eric R. Eggenberger, DO Professor, Neuro-­Ophthalmology Department of Neurology and Ophthalmology Mayo Clinic Jacksonville, Florida Jeff Ehresman, BS Department of Neurosurgery Johns Hopkins School of Medicine Baltimore, Maryland

Ashraf N. El Naga, MD Assistant Clinical Professor and Co-­Director of Spine Trauma Service Department of Orthopaedics University of California, San Francisco School of Medicine San Francisco, California Turki Elarjani, MD Pre-­residency Fellow Department of Neurosurgery University of Miami Miami, Florida Benjamin D. Elder, MD, PhD Associate Professor Neurosurgery, Orthopaedic Surgery, and Biomedical Engineering Mayo Clinic School of Medicine Rochester, Minnesota Ahmed Elsharkawy, MD, PhD Senior Consultant Neurosurgeon Department of Neurosurgery Tanta University Tanta, Egypt Nancy E. Epstein, MD Clinical Professor, Neurological Surgery School of Medicine State University of New York at Stony Brook Editor-­in-­Chief Surgical Neurology International Garden City, New York Kadir Erkmen, MD Professor and Vice Chairman, Neurosurgery Lewis Katz School of Medicine Philadelphia, Pennsylvania Thomas J. Errico, MD Chief of Spine Orthopaedics New York University New York, New York Clifford J. Eskey, MD, PhD Professor of Radiology and Surgery Department of Radiology Dartmouth-­Hitchcock Medical Center Lebanon, New Hampshire Linton Evans, MD Neurosurgical Oncology Fellow Department of Neurosurgery The University of Texas MD Anderson Cancer Center Houston, Texas Megan C. Everson, MD Resident Physician Department of Neurosurgery Mayo Clinic Rochester, Minnesota

CONTRIBUTORS

Naomi Fei, MD PGY6 Hematology-­Oncology Fellow Division of Hematology-­Oncology Department of Internal Medicine West Virginia University School of Medicine Morgantown, West Virginia Richard G. Fessler, MD Professor Department of Neurosurgery Rush Medical College Chicago, Illinois Aaron G. Filler, MD, PhD, JD, FRCS Attending Physician Department of Neurosurgery Cedars Sinai Medical Center Los Angeles, California Bruno C. Flores, MD Department of Neurosurgery Barrow Neurological Institute Phoenix, Arizona Kevin T. Foley, MD Professor Neurosurgery, Orthopedic Surgery, and Biomedical Engineering University of Tennessee Health Science Center Chairman Semmes-­Murphey Clinic Memphis, Tennessee Roberto I. Foroni, PhD Department of Medical Physics University Hospital Verona, Italy Antonio J. Forte, MD, PhD Associate Professor of Plastic Surgery Division of Plastic and Hand Surgery Mayo Clinic Jacksonville, Florida Kostas N. Fountas, MD, PhD Director and Chairman Department of Neurosurgery Faculty of Medicine University of Thessaly Larisa, Greece W. Christopher Fox, MD Associate Professor Department of Neurologic Surgery Mayo Clinic Jacksonville, Florida William David Freeman, MD Neurologic Surgery, Neurology, and Critical Care Mayo Clinic Jacksonville, Florida

William Alan Friedman, MD Professor and Chairman Department of Neurological Surgery University of Florida Gainesville, Florida David M. Frim, MD, PhD Professor, Department of Surgery Section of Neurosurgery The University of Chicago Chicago, Illinois Fabio Frisoli, MD Department of Neurological Surgery New York University School of Medicine New York, New York Miki Fujimura, MD Director Department of Neurosurgery Kohnan Hospital Sendai, Japan Sara Ganaha, MD Postdoctoral Fellow, Department of Neurosurgery Mayo Clinic Jacksonville, Florida Dheeraj Gandhi, MBBS, MD Professor, Director of Interventional Neuroradiology Radiology, Neurology, and Neurosurgery Clinical Director, Center of Metabolic Imaging and Therapeutics Radiology University of Maryland School of Medicine Baltimore, Maryland Sirin Gandhi, MD Clinical Research Fellow Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, Arizona Mark Garrett, MD Neurosurgeon Partner Barrow Brain and Spine Director of Neurotrauma Chandler Regional Medical Center Chandler, Arizona Tomas Garzon-­Muvdi, MD, MSc Assistant Professor, Neurosurgery University of Texas Southwestern Dallas, Texas Alessandro Gasbarrini, MD Medical Director with Organisational duties at the Vertebral Surgery Department Spine Surgery prevalently Oncologic and Degenerative Istituto Ortopedico Rizzoli Bologna, Italy

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Kelly Gassie, MD Neurosurgery Resident Department of Neurosurgery Mayo Clinic Jacksonville, Florida Fred H. Geisler, MD, PhD Adjunct Professor Department of Medical Imaging College of Medicine at the University of Saskatchewan Saskatoon, Saskatchewan, Canada President Copernicus Dynamics Group, L.P. Chicago, Illinois George Georgoulis, MD Neurosurgeon Neurosurgery General Hospital of Athens “G.Gennimatas” Athens, Greece Brian J. A. Gill, MD Department of Neurological Surgery Columbia University New York, New York Felix Goehre, MD, PhD Adjunct Professor of Neurosurgery Department of Neurosurgery BG Hospital Bergmannstrost Halle Halle, Germany Atul Goel, MCh (Neurosurgery) Professor and Head Department of Neurosurgery Seth G. S. Medical College and K.E.M Hospital Mumbai, India Gunjan Goel, MD Neurosurgeon Neurosurgical Medical Clinic San Diego, California Ziya L. Gokaslan, MD, FAANS, FACS Julius Stoll, MD Professor and Chair Department of Neurosurgery The Warren Alpert Medical School of Brown University Neurosurgeon-­in-­Chief Rhode Island Hospital and The Miriam Hospital Clinical Director Norman Prince Neurosciences Institute President Brown Neurosurgery Foundation Providence, Rhode Island Katherine G. Gold, MD Assistant Professor Department of Ophthalmology Mayo Clinic Jacksonville, Florida

Diego F. Gomez, MD Neurologic Surgery Hospital Universitario Fundación Santa Fe de Bogotá, Colombia L. Fernando Gonzalez, MD Associate Professor, Neurosurgery Duke University Durham, North Carolina C. Rory Goodwin, MD Neurosurgeon, Spine Surgeon Duke Cancer Center Durham, North Carolina Chad R. Gordon, DO, FACS Professor and Director, Neuroplastic and Reconstructive Surgery Department of Plastic and Reconstructive Surgery Fellowship Director, Neuroplastic and Reconstructive Surgery Departments of Plastic Surgery and Neurosurgery Johns Hopkins University School of Medicine Baltimore, Maryland Anshit Goyal, MBBS, MS Research Fellow Department of Neurosurgery Mayo Clinic Rochester, Minnesota C. S. Graffeo, MD Resident, Department of Neurosurgery Mayo Clinic Rochester, Minnesota Andrew W. Grande, MD Associate Professor and Co-Director Earl Grande, Vel, V. Richard Zerling Stroke, Stem Cell, and Neuroimaging Laboratory Department of Neurosurgery University of Minnesota Minneapolis, Minnesota Ramesh Grandhi, MD Assistant Professor Department of Neurosurgery Clinical Neurosciences Center University of Utah Salt Lake City, Utah Alexander L. Green, FRCS(SN), MB BS, BSc Oxford Functional Neurosurgery Nuffield Department of Surgery University of Oxford Department of Neurological Surgery The West Wing The John Radcliffe Hospital Oxford, England United Kingdom

CONTRIBUTORS

Jeffrey P. Greenfield, MD, PhD Vice Chairman for Academic Affairs Associate Professor, Neurological Surgery Associate Professor, Pediatric Neurosurgery Associate Residency Director Department of Neurosurgery New York Presbyterian Hospital New York, New York Sanjeet S. Grewal, MD Assistant Professor, Department of Neurosurgery Mayo Clinic Florida Jacksonville, Florida Mari L. Groves, MD Assistant Professor Department of Neurosurgery Johns Hopkins University School of Medicine Baltimore, Maryland Jian Guan, MD Pacific Neuroscience Institute Torrance, California Gerardo Guinto, MD Neurosurgeon Centro Neurologico ABC Mexico City, Mexico Richard Gullan, MD Consultant Neurosurgeon King’s College Hospital London, England, United Kingdom Gaurav Gupta, MD Associate Professor, Neurosurgery Director, Cerebrovascular and Endovascular Neurosurgery Rutgers Robert Wood Johnson Medical School New Brunswick, New Jersey Nalin Gupta, MD, PhD Professor, Neurological Surgery and Pediatrics University of California San Francisco Chief, Division of Pediatric Neurosurgery UCSF Benioff Children’s Hospital San Francisco, California Vivek Gupta, MD Associate Professor Department of Radiology Mayo Clinic Jacksonville, Florida Raymond J. Hah, MD Assistant Professor, Orthopaedic Surgery and Neurosurgery Keck School of Medicine University of Southern California Los Angeles, California

Fernando Hakim, MD Chair, Neurologic Surgery Hospital Universitario Fundación Santa Fe de Bogotá, Colombia, Associate Professor of Neurologic Surgery Universidad de Bosque Professor Universidad de los Andes Bogotá, Colombia Dia Radi Halalmeh, MD Research Fellow Michigan Head and Spine Institute Department of Neurosurgery Southfield, Michigan Clayton L. Haldeman, MD, MHS Resident Department of Neurosurgery University of Wisconsin Hospitals and Clinics Madison, Wisconsin Neil Haranhalli, MD Assistant Professor Departments of Neurosurgery and Radiology Montefiore Medical Center Albert Einstein College of Medicine New York, New York Douglas A. Hardesty, MD Department of Neurosurgery The Ohio State University Wexner Medical Center Columbus, Ohio Trevor Hardigan, MD, PhD Resident Physician Department of Neurosurgery Icahn School of Medicine at Mount Sinai Hospital New York, New York James S. Harrop, MD, MSHQS, FACS Professor of Neurological Surgery and Orthopedics Sidney Kimmel Medical College at Thomas Jefferson University Section Chief, Division of Spine and Peripheral Nerve Disorders Thomas Jefferson University Hospital Philadelphia, Pennsylvania Sara Hartnett, MD Resident Department of Neurosurgery and Brain Repair University of South Florida Morsani College of Medicine Tampa, Florida Stefan Heinze, MD Neurosurgeon Department of Neurosurgery Philips University Marburg Marburg, Germany

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CONTRIBUTORS

Juha Hernesniemi, MD, PhD Emeritus Professor, Department of Neurosurgery Helsinki University Hospital and University of Helsinki Helsinki, Finland, Professor and Chairman, Department of Neurosurgery Henan Provincial People’s Hospital Zhengzhou, PR China David S. Hersh, MD Assistant Professor Division of Pediatric Neurosurgery Connecticut Children’s Harford, Connecticut Joaquin Hidalgo, MD Fellow Division of Pediatric Neurosurgery Johns Hopkins University School of Medicine Baltimore, Maryland Travis Hill, MD, PhD Department of Neurological Surgery New York University School of Medicine New York, New York Kevork N. Hindoyan, MD Orthopedic Surgery Huntington Hospital Pasadena, California Olivia Ho, MD, MMSc, FRCSC Senior Associate Consultant Plastic and Reconstructive Surgery Mayo Clinic Jacksonville, Florida Brian L. Hoh, MD James & Brigitte Marino Family Professor and Chair Department of Neurosurgery University of Florida Gainesville, Florida L. Nelson Hopkins, MD Departments of Neurosurgery and Radiology Jacobs School of Medicine and Biomedical Sciences University at Buffalo Department of Neurosurgery Gates Vascular Institute at Kaleida Health Canon Stroke and Vascular Research Center University at Buffalo Buffalo, New York Wesley Hsu, MD, FAANS Associate Professor, Division of Neurosurgery Director of Spinal Oncology Wake Forest Baptist Medical Center Winston-­Salem, North Carolina

Judy Huang, MD Professor and Vice Chair, Neurosurgery Director, Neurosurgery Residency Program Fellowship Director, Cerebrovascular Neurosurgery Johns Hopkins University School of Medicine Baltimore, Maryland Michael Huang, MD Department of Neurological Surgery Brain and Spinal Injury Center University of California San Francisco San Francisco, California Wei X. Huff, MD, PhD Section of Pediatric Neurosurgery Riley Hospital for Children Department of Neurosurgery Indiana University School of Medicine Goodman Campbell Brain and Spine Indianapolis, Indiana Sakibul Huq, BS Department of Neurosurgery Johns Hopkins School of Medicine Baltimore, Maryland Zain Hussain, MD Dermatologist and Mohs Micrographic Surgeon New Jersey Dermatology and Aesthetics Center Marlboro, New Jersey Natasha Ironside, MBChB Research Fellow Department of Neurological Surgery Columbia University College of Physicians and Surgeons New York, New York Rajiv R. Iyer, MD Department of Orthopedic Surgery Columbia University Medical Center Morgan Stanley Children’s Hospital of New York-­ Presbyterian New York, New York Pascal M. Jabbour, MD Professor, Neurosurgery Director, Division of Neurovascular Surgery and Endovascular Neurosurgery Thomas Jefferson University Hospital Philadelphia, Pennsylvania Christina Jackson, MD Resident Department of Neurosurgery Johns Hopkins Hospital Baltimore, Maryland

CONTRIBUTORS

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Christopher M. Jackson, MD Department of Neurosurgery Johns Hopkins Hospital Baltimore, Maryland

Bowen Jiang, MD Department of Neurosurgery Johns Hopkins University Baltimore, Maryland

Behnam Rezai Jahromi, MD Department of Neurosurgery and Neurosurgery Research Group Helsinki University Hospital and University of Helsinki Helsinki, Finland

Evan Joyce, MD, MS Neurosurgical Resident, Department of Neurological Surgery University of Utah School of Medicine Salt Lake City, Utah

George I. Jallo, MD Professor of Neurosurgery, Pediatrics, and Oncology Division of Pediatric Neurosurgery Director, Institute for Brain Protection Sciences Johns Hopkins All Children’s Hospital St Petersburg, Florida Alejandra Jaume, MD Neurosurgeon Neurosurgery Department Hospital Maciel Montevideo, Uruguay Mohsen Javadpour, MD Consultant Neurosurgeon Clinical Director of the National Neurosurgical Centre Beaumont Hospital Dublin, Ireland Andrew Jea, MD Professor and Chief, Section of Pediatric Neurosurgery Riley Hospital for Children Department of Neurosurgery Indiana University School of Medicine Goodman Campbell Brain and Spine Indianapolis, Indiana Mark Jentoft, MD Assistant Professor, Laboratory Medicine and Pathology Department of Pathology Mayo Clinic Jacksonville, Florida David H. Jho, MD, PhD Assistant Professor, Neurosurgery Departments of Neuroendoscopy and Neurosurgery Allegheny General Hospital (Allegheny Health Network) Pittsburgh, Pennsylvania

M. Yashar S. Kalani, MD, PhD Vice Chair and Associate Professor, Neurological Surgery University of Virginia School of Medicine Charlottesville, Virginias Eftychia Z. Kapsalaki, MD, PhD Professor, Department of Diagnostic Radiology Faculty of Medicine University of Thessaly Larisa, Greece Michael G. Kaplitt, MD, PhD Professor, Neurological Surgery Vice Chairman for Research Director of Stereotactic and Functional Neurosurgery Weill Cornell Medical College New York, New York Patrick Karas, MD Resident Physician Department of Neurosurgery Baylor College of Medicine Houston, Texas Selmin Karatayli-­Ozgursoy, MD Research Fellow Otorhinolaryngology Mayo Clinic Florida Jacksonville, Florida Takeshi Kawase, MD, PhD Honorary Professor, Neurosurgery School of Medicine Keio University Tokyo, Japan Uwe Kehler, PhD Department of Neurosurgery Asklepios Klinik Altona Hamburg, Germany

Diana H. Jho, MD Assistant Professor, Neurosurgery Department of Neurosurgery Milton S. Hershey Medical Center (Penn State Health) Hershey, Pennsylvania

Panagiotis Kerezoudis, MD, MS Resident Department of Neurologic Surgery Mayo Clinic Rochester, Minnesota

Hae-­Dong Jho, MD, PhD Professor and Chairman, Neuroendoscopy Departments of Neuroendoscopy and Neurosurgery Allegheny General Hospital (Allegheny Health Network) Pittsburgh, Pennsylvania

Drew S. Kern, MD, MS, FAAN Assistant Professor Movement Disorders Center Departments of Neurology and Neurosurgery University of Colorado School of Medicine Aurora, Colorado

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CONTRIBUTORS

Farhan A. Khan, BS Department of Neurological Surgery Columbia University New York, New York Nickalus R. Khan, MD Department of Neurosurgery Semmes-­Murphey Clinic Memphis, Tennessee Kathleen Khu, MD Clinical Associate Professor Division of Neurosurgery Department of Neurosciences College of Medicine and Philippine General Hospital University of the Philippines Manila Ermita, Manila, Philippines Daniel H. Kim, MD, FAAN, FACS Professor Department of Neurosurgery UT Health Science Center Houston, Texas Matthias Kirsch, Prof, MD Klinik für Neurochirurgie Asklepios Schildautalkliniken Seesen Karl-­Herold-­Str. 1, 38723 Seesen, Germany Molecular Neuroimaging Laboratory Medizinische Fakultät, Technische Universität Dresden Fetscherstraße, Dresden, Germany Petra Klinge, MD, PhD Lifespan Physician Group Pediatric Neurosurgery Providence, Rhode Island Matthew J. Koch, MD Resident Department of Neurosurgery Massachusetts General Hospital Boston, Massachusetts Michael Kogan, MD, PhD Fellow Department of Neurosurgery Thomas Jefferson University Philadelphia, Pennsylvania John Paul G. Kolcun, MD Resident Department of Neurological Surgery Rush University Medical Center Chicago, Illinois Douglas Kondziolka, MD Professor, Department of Neurological Surgery New York University School of Medicine New York, New York

Marcus Christopher Korinth, MD, PhD Prof. Dr. Med Neurosurgery University Hospital Aachen, Germany Rupesh Kotecha, MD Radiation Oncologist Miami Cancer Institute Miami, Florida Dietmar Krex Prof, MD Klinik und Poliklinik für Neurochirurgie Universitätsklinikum Carl Gustav Carus Dresden an der Technischen Universität Dresden Fetscherstraße, Dresden, Germany Chandan Krishna, MD Department of Neurological Surgery Precision Neuro-Therapeutics Innovation Lab Neurosurgery Simulation and Innovation Lab Mayo Clinic Phoenix, Arizona Kartik G. Krishnan, MD, PhD Department of Neurosurgery Center for Clinical Neurosciences Johann Wolfgang Goethe University Frankfurt, Germany Ajit Krishnaney, MD Department of Neurosurgery Neurologic Institute Cleveland Clinic Cleveland, Ohio Varun R. Kshettry, MD Assistant Professor, Neurological Surgery Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Cleveland Director of Advanced Endoscopic and Microscopic Neurosurgery Laboratory Cleveland Clinic Cleveland, Ohio Maureen Lacy, PhD Professor Department of Psychiatry and Behavioral Neuroscience The University of Chicago Chicago, Illinois Travis R. Ladner, MD Resident Physician Department of Neurosurgery Icahn School of Medicine at Mount Sinai Hospital New York, New York Jose Alberto Landeiro, MD, PhD Chairman Neurosurgery Department Hospital Universitario Antonio Pedro Niteroi, Rio de Janeiro, Brazil

CONTRIBUTORS

Frederick F. Lang, MD Professor and Chair Department of Neurosurgery The University of Texas MD Anderson Cancer Center Houston, Texas Michael J. Lang, MD Assistant Professor Department of Neurosurgery University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania Alexandra Giantini Larsen, BA Department of Neurosurgery Brigham and Women’s Hospital Boston, Massachusetts, Harvard Medical School Cambridge, Massachusetts Dimitri Laurent, MD Resident Physician Lillian S. Wells Department of Neurosurgery University of Florida Gainesville, Florida Michael T. Lawton, MD Professor and Chair Department of Neurosurgery Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, Arizona Bryan S. Lee, MD Neurosurgeon Department of Neurosurgery Barrow Neurological Institute Barrow Brain and Spine Phoenix, Arizona Allan Levi, MD, PhD, FACS Chair, Department of Neurological Surgery Professor of Neurological Surgery, Orthopedics, and Rehabilitation Medicine University of Miami Miller School of Medicine Chief of Neurosurgery Jackson Memorial Hospital Miami, Florida Marc Levivier, MD, PhD, IFAANS Department of Clinical Neurosciences Neurosurgery Service and Gamma Knife Center Centre Hospitalier Universitaire Vaudois (CHUV) University of Lausanne Faculty of Biology and Medicine (FBM) Lausanne, Switzerland Elad I. Levy, MD, MBA Departments of Neurosurgery and Radiology Jacobs School of Medicine and Biomedical Sciences Department of Neurosurgery Gates Vascular Institute at Kaleida Health Canon Stroke and Vascular Research Center University at Buffalo Buffalo, New York

Michael Lim, MD Professor and Chair, Department of Neurosurgery Stanford University School of Medicine Stanford, California Li-­Mei Lin, MD Carondelet Neurological Institute Tucson, Arizona Michelle Lin, MD Department of Neurosurgery Mayo Clinic Jacksonville, Florida Göran Erland Lind, MD, PhD Senior Consultant Neurosurgeon Department of Neurosurgery Karolinska University Hospital Karolinska Institutet Stockholm, Sweden Bengt Linderoth, MD, PhD Professor Emeritus, Neurosurgery Karolinska Institutet Stockholm, Sweden Michael J. Link, MD Professor Department of Neurologic Surgery Mayo Clinic Rochester, Minnesota Giorgio Lo Russo, MD “Claudio Munari” Epilepsy Surgery Center Department of Neuroscience ASST Grande Ospedale Metropolitano Niguarda Milan, Italy Christopher M. Loftus, MD, DHC(Hon), FACS First Vice President - Immediate Past World Federation of Neurosurgical Societies Professor and Former Chairman Temple University Lewis Katz School of Medicine Philadelphia, Pennsylvania Michele Longhi, MD, PhD Radiosurgery and Stereotactic Neurosurgery Section Department of Neuroscience University Hospital Verona, Italy Russell R. Lonser, MD Professor and Chairman Department of Neurological Surgery The Ohio State University Wexner Medical Center Columbus, Ohio Christopher E. Louie, MB, MPH Resident, Department of Surgery University of California, San Diego San Diego, California

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CONTRIBUTORS

Daniel C. Lu, MD, PhD Professor and Vice Chair, Research Department of Neurosurgery University of California Los Angeles, California

Justin R. Mascitelli, MD Cerebrovascular Fellow Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, Arizona

Christopher Ludtka, BEng J. Crayton Pruitt Family Department of Biomedical Engineering University of Florida Gainesville, Florida

Marcus D. Mazur, MD Assistant Professor of Neurosurgery Department of Neurosurgery University of Utah School of Medicine Salt Lake City, Utah

Larry B. Lundy, MD Associate Professor Otolaryngology and Neurosurgery Otolaryngology–Head and Neck Surgery Mayo Clinic Jacksonville, Florida

Paul C. McCormick, Jr., MD Resident Physician, Psychiatry New York Presbyterian Weill Cornell Medical Center New York, New York

Subu N. Magge, MD Vice Chair Department of Neurosurgery Lahey Hospital and Medical Center Burlington, Massachusetts Assistant Professor, Neurosurgery Tufts University Boston, Massachusetts Martijn J. A. Malessy, MD, PhD Professor of Nerve Surgery Department of Neurosurgery Leiden University Medical Center Leiden, The Netherlands Allen H. Maniker, MD Chief Department of Neurosurgery Beth Israel Medical Center New York, New York Geoffrey T. Manley, MD, PhD Department of Neurological Surgery Brain and Spinal Injury Center University of California San Francisco San Francisco, California Peiman Maralani, MD Affiliate Scientist Sunnybrook Health Sciences Centre Toronto, Ontario, Canada Lina Marenco-­Hillembrand, MD Department of Neurosurgery Mayo Clinic Jacksonville, Florida Meleine Martinez-­Sosa, MD Fellow, Pediatric Neurosurgery Institute for Brain Protection Sciences Johns Hopkins All Children’s Hospital St. Petersburg, Florida

Paul C. McCormick, MD, MPH Herbert and Linda Gallen Professor of Neurological Surgery Department of Neurosurgery Columbia University College of Physicians and Surgeons New York, New York José Hinojosa Mena-Bernal, MD Chief, Department of Neurosurgery Hospital Sant Joan de Deu (Barcelona) Barcelona, Spain Arnold H. Menezes, MD Professor and Vice Chairman Department of Neurosurgery University of Iowa Hospitals and Clinics Iowa City, Iowa Fredric B. Meyer, MD Uihlein Professor and Enterprise Chair Dean of Education Department of Neurologic Surgery Mayo Clinic Rochester, Minnesota Erik H. Middlebrooks, MD Associate Professor, Neuroradiology Department of Radiology Mayo Clinic Jacksonville, Florida Rajiv Midha, MD, MSc, FRCSC Professor of Neurosurgery and Head Department of Clinical Neurosciences University of Calgary Calgary, Alberta, Canada Anthony Mikula, MD Resident, Department of Neurological Surgery Mayo Clinic Rochester, Minnesota

CONTRIBUTORS

David Miller, MD Departments of Neurosurgery and Radiology Mayo Clinic Jacksonville, Florida

Yagmur Muftuoglu, PhD Department of Neurosurgery Stanford University School of Medicine Stanford, California

Jonathan P. Miller, MD Professor, Neurosurgery Department of Neurosurgery Case Western Reserve University Cleveland, Ohio

Sten Myrehaug, MD Assistant Professor of Radiation Oncology Sunnybrook Health Sciences Centre Toronto, Ontario, Canada

Bilal Mirza, MD, PHD Department of Neurosurgery Royal Hallamshire Hospital Sheffield, United Kingdom Zaman Mirzadeh, MD, PhD Assistant Professor, Neurosurgery Barrow Neurological Institute Phoenix, Arizona J. Mocco, MD, MS Professor and System Vice Chair Department of Neurosurgery Icahn School of Medicine at Mount Sinai Hospital New York, New York Camilo A. Molina, MD Assistant Professor of Neurosurgery and Orthopedic Surgery Deputy Director of Spine Innovation Center for Innovation in Neuroscience and Technology Washington University School of Medicine St. Louis, Missouri Alaa S. Montaser, MD Department of Neurosurgery The Ohio State University Wexner Medical Center Columbus, Ohio Jacques J. Morcos, MD, FRCS(Eng), FRCS(Ed), FAANS Professor and Co-­Chairman Department of Neurological Surgery Professor of Clinical Neurosurgery and Otolaryngology Director, Cerebrovascular Surgery Director, Skull Base Surgery University of Miami Division Chief, Cranial Neurosurgery Jackson Memorial Hospital Miami, Florida Chad J. Morgan, MD Neurosurgeon Springfield Neurological and Spine Institute Springfield, Missouri Abteen Mostofi, MA, MB, BChir, PhD, MRCS Clinical Lecturer in Neurosurgery Atkinson Morley Neurosciences Unit St George’s, University of London London, England, United Kingdom

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Arya Nabavi, MD, PhD, MaHM, IFAANS Professor and Director, Neurosurgery KRH Hanover Nordstadt Hannover, Germany Michael J. Nanaszko, MD Neurosurgery Barrow Neurological Institute Phoenix, Arizona Pranav Nanda, MD, MPhil Resident Physician, Department of Neurosurgery Massachusetts General Hospital Boston, Massachusetts Varun Naragum, MD Assistant Professor of Radiology University of Massachusetts Medical School Worcester, Massachusetts Rani Nasser, MD Assistant Professor of Neurosurgery University of Cincinnati Medical Center Cincinnati, Ohio Edgar Nathal, MD, DMSc Head, Department of Neurosurgery National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez” Professor of Vascular Neurosurgery Universidad Nacional Autónoma de México Professor of Vascular Neurosurgery National Institute of Neurology and Neurosurgery Chief of Service, Neurosurgery National Institute of Medical and Nutricional Sciences “Salvador Subirán” Mexico City, Mexico Timothy K. Nguyen, MD Radiation Oncologist Department of Radiation Oncology London Health Sciences Centre London, Ontario, Canada Marco Conti Nibali, MD Oncology and Hemato-­Oncology Neuro-­Oncological Surgery Università degli Studi di Milano Milano, Italy

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CONTRIBUTORS

Antonio Nicolato, MD Radiosurgery and Stereotactic Neurosurgery Section Department of Neuroscience University Hospital Verona, Italy Anitha Nimmagadda, MD Division of Occupational and Environmental Medicine University of Chicago Chicago, Illinois Richard B. North, MD Professor (ret.) Departments of Neurosurgery, Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine President Neuromodulation Foundation, Inc. Baltimore, Maryland President Institute of Neuromodulation Chicago, Illinois Eric Nottmeier, MD Professor of Neurosurgery Department of Neurosurgery Mayo Clinic Jacksonville, Florida Mohammad Hassan A. Noureldine, MD, MSc Postdoctoral Research Fellow, Neurosurgery Johns Hopkins University School of Medicine Baltimore, Maryland Postdoctoral Research Fellow Institute for Brain Protection Sciences Johns Hopkins All Children’s Hospital St. Petersburg, Florida W. Jerry Oakes, MD Hendley Professor of Pediatric Neurosurgery University of Alabama Birmingham School of Medicine Children’s of Alabama Birmingham, Alabama Christopher S. Ogilvy, MD Professor of Neurosurgery Department of Neurosurgery Harvard Medical School Director, BIDMC Brain Aneurysm Institute Director, Endovascular and Operative Neurovascular Surgery Beth Israel Deaconess Medical Center Boston, Massachusetts Jeffrey G. Ojemann, MD Professor of Neurological Surgery University of Washington Seattle, Washington Steven Ojemann, MD Associate Professor Department of Neurosurgery University of Colorado School of Medicine Aurora, Colorado

David O. Okonkwo, MD, PhD Professor, Neurological Surgery University of Pittsburgh Pittsburgh, Pennsylvania Alessandro Olivi, MD Institute of Neurosurgery Fondazione Policlinico A. Gemelli IRCSS Catholic University of Rome Rome, Italy Osarenoma U. Olomu, BA, MD Assistant Professor Otolaryngology–Head and Neck Surgery Mayo Clinic Jacksonville, Florida Alon Orlev, MD Department of Neurosurgery Rabin Medical Center Israel Brooks Osburn, MD Resident, Department of Neurosurgery and Brain Repair University of South Florida Morsani College of Medicine Tampa, Florida Nakao Ota, MD, PhD Consultant Neurosurgeon Department of Neurosurgery Sapporo Teishinkai Hospital Sapporo, Japan Bradley A. Otto, MD Departments of Otolaryngology Head and Neck Surgery and Neurosurgery The Ohio State University Wexner Medical Center Columbus, Ohio Dachling Pang, MD Consultant Paediatric Neurosurgeon Great Ormond Street Hospital for Children NHS Trust London, United Kingdom Professor of Pediatric Neurosurgery University of California, Davis Sacramento, California Ian Parney, MD, PhD Professor and Vice-­Chair (Research), Neurological Surgery Mayo Clinic Rochester, Minnesota José María Pascual, MD, PhD Consultant Neurosurgeon Department of Neurosurgery La Princesa University Hospital Madrid, Spain

CONTRIBUTORS

Aman B. Patel, MD Director of Cerebrovascular and Endovascular Neurosurgery Co-Director of the Neuroendovascular Program Department of Neurosurgery Massachusetts General Hospital Boston, Massachusetts Anoop Patel, MD Assistant Professor, Neurosurgery University of Washington Seattle, Washington Smruti K. Patel, MD Resident Physician Department of Neurosurgery University of Cincinnati College of Medicine Cincinnati, Ohio Rana Patir, MBBS, MS, MCh Chairman and Head of Department Department of Neurosurgery Fortis Memorial Research Institute New Delhi, India Richard D. Penn, MD Adjunct Professor, Bioengineering University of Illinois–Chicago Chicago, Illinois Zachary Pennington, BS Medical Student Department of Neurosurgery Johns Hopkins Hospital Baltimore, Maryland Giuseppe Maria Della Pepa, MD Institute of Neurosurgery Fondazione Policlinico A. Gemelli IRCSS Catholic University of Rome Rome, Italy Alexander Perdomo-­Pantoja, MD Department of Neurosurgery The Johns Hopkins Hospital Baltimore, Maryland Erlick A. C. Pereira, MA, BMBCh, DM, FRCS(SN) Senior Lecturer and Honorary Consultant in Neurosurgeon Department of Neurosurgery St. George’s University Hospitals London, England, United Kingdom Mick J. Perez-­Cruet, MD, MS Vice Chairman and Professor Director Minimally Invasive and Spine Program Department of Neurosurgery Oakland University William Beaumont Medical School Royal Oak, Michigan, Michigan Head and Spine Institute Southfield, Michigan

Maria Peris-­Celda, MD, PhD Associate Professor Department of Neurosurgery Mayo Clinic Rochester, Minnesota A. Perry, MD Resident Department of Neurosurgery Mayo Clinic Rochester, Minnesota Avital Perry, MD Department of Neurosurgery Sheba Medical Center Tel-­Aviv University Ramat-­Gan, Israel Federico Pessina, MD Neurosurgery Unit Humanitas Research Hospital Rozzano, Italy Jennifer L. Peterson, MD Associate Professor Radiation Oncology Mayo Clinic Jacksonville, Florida Martin H. Pham, MD Department of Neurological Surgery University of Southern California San Diego School of Medicine San Diego, California Mark Pichelmann, MD Assistant Professor of Neurologic Surgery Spine and Neurosurgery Mayo Clinic Health System Eau Claire, Wisconsin Carlos D. Pinheiro-­Neto, MD, PhD Associate Professor Department of Otolaryngology Mayo Clinic Rochester, Minnesota Phillip Pirgousis, MD Associate Professor Otolaryngology – Head and Neck Surgery Reconstructive Surgery Neurological Surgery Mayo Clinic Jacksonville, Florida Lawrence H. Pitts, MD Department of Neurological Surgery Brain and Spinal Injury Center University of California San Francisco San Francisco, California

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CONTRIBUTORS

Rick J. Placide, MD Professor Department of Orthopaedic Surgery Medical College of Virginia Virginia Commonwealth University Richmond, Virginia

Pablo A. Quevedo-Valdes, MD, PhD Department of Neurosurgery Brigham and Women’s Hospital Boston, Massachusetts Harvard Medical School Cambridge, Massachusetts

Puneet Plaha, MBBS, PhD, FRCS(SN) Consultant Neurosurgeon Oxford University Hospitals Oxford, United Kingdom

Alfredo Quiñones-­Hinojosa, MD William J. and Charles H. Mayo Professor Chair, Neurologic Surgery Department of Neurosurgery Mayo Clinic Jacksonville, Florida

Adam J. Polifka, MD Assistant Professor Lillian S. Wells Department of Neurosurgery University of Florida Gainesville, Florida Willem Pondaag, MD, PhD Neurosurgeon Department of Neurosurgery Leiden University Medical Center Leiden, the Netherlands Kalmon D. Post, MD Professor of Neurosurgery Department of Neurosurgery Icahn School of Medicine at Mount Sinai New York, New York Matthew B. Potts, MD Department of Neurological Surgery Northwestern University Feinberg School of Medicine Chicago, Illinois Lars Poulsgaard, MD Neurosurgeon, Director of Skull Base Surgery Department of Neurosurgery Rigshospitalet, Copenhagen, Denmark Alessandro Prete, MD Clinical Research Fellow Institute of Metabolism and Systems Research University of Birmingham Birmingham, United Kingdom Daniel M. Prevedello, MD Professor Department of Neurosurgery The Ohio State University Wexner Medical Center Columbus, Ohio Ruth Prieto, MD, PhD Consultant Neurosurgeon Department of Neurosurgery Puerta de Hierro University Hospital Madrid, Spain Ross C. Puffer, MD Staff Neurosurgeon Walter Reed National Military Medical Center Bethesda, Maryland

Leonidas M. Quintana, Sr., Professor Department of Neurosurgery Faculty of Medicine Valparaíso University Valparaiso, Chile Gazanfar Rahmathulla, MBBS (MD), FACS, IFAANS, MBA Medical Director, Neurosurgery Trauma Department of Neurosurgery University of Florida College of Medicine Clinical Assistant Professor Department of Neurosurgery University of Florida Jacksonville, Florida Rudy J. Rahme, MD Resident Physician Department of Neurological Surgery Northwestern University Feinberg School of Medicine and McGaw Medical Center Chicago, Illinois Seba Ramhmdani, MD Department of Neurosurgery Johns Hopkins University School of Medicine Baltimore, Maryland Juan F. Ramon, MD, MS Neurologic Surgery Hospital Universitario Fundación Santa Fe de Bogotá, Colombia Andres Ramos-Fresnedo, MD Postdoctoral Fellow Department of Neurosurgery Mayo Clinic Jacksonville, Florida Rodrigo Ramos-­Zuniga Sr., MD, PhD Professor of Neurosciences Institute of Translational Neurosciences Department of Neurosciences University of Guadalajara Guadalajara, Jalisco, Mexico

CONTRIBUTORS

Nathan J. Ranalli, MD Assistant Professor Departments of Neurosurgery and Pediatrics University of Florida Health Science Center Jacksonville Jacksonville, Florida

Angela M. Richardson, MD, PhD Cerebrovascular and Skull Base Fellow Department of Neurosurgery University of Wisconsin–Madison Madison, Wisconsin

Manish Ranjan, MD Neurosurgery Fellow Rockefeller Neuroscience Institute West Virginia University Morgantown, West Virginia

Daniele Rigamonti, MD Professor, Neurosurgery Johns Hopkins School of Medicine Baltimore, Maryland CEO Johns Hopkins Aramco Healthcare Dhahran, Eastern Province Saudi Arabia

Aaron Rapp, MD Resident Department of Neurosurgery Oakland University William Beaumont School of Medicine Royal Oak, Michigan United States Vijay M. Ravindra, MD, MSPH Adult and Pediatric Neurosurgery Department of Neurosurgery Naval Medical Center San Diego San Diego, California Pablo F. Recinos, MD Associate Professor Department of Neurological Surgery Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Cleveland Section Head,­Skull Base Surgery Cleveland Clinic Cleveland, Ohio Karim ReFaey, MD Postdoctoral Fellow, Neurosurgery Mayo Clinic Hospital Jacksonville, Florida Jean Régis, MD Stereotactic and Functional Neurosurgery Service and Gamma Knife Unit CHU Timone Marseille, France Katherine Relyea, MS Section of Pediatric Neurosurgery Riley Hospital for Children Department of Neurosurgery Indiana University School of Medicine Goodman Campbell Brain and Spine Indianapolis, Indiana Daniel K. Resnick, MD, MS Professor and Vice Chairman Department of Neurosurgery University of Wisconsin School of Medicine and Public Health Madison, Wisconsin

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Marco Riva, MD Oncology and Hemato-­Oncology Neuro-­Oncological Surgery Università degli Studi di Milano Milano, Italy Matteo Riva, MD Specialist in Neurosurgery KU Leuven Cancer Institute Leuven, Belgium Michele Rizzi, MD “C. Munari” Epilepsy Surgery Center Department of Neuroscience ASST Grande Ospedale Metropolitano Niguarda Milan, Italy Shimon Rochkind, MD, PhD Director, Division of Peripheral Nerve Reconstruction Head, Translational Medicine and Clinical Research Center for Nerve Reconstruction Tel Aviv Sourasky Medical Center Tel Aviv, Israel John D. Rolston, MD, PhD Assistant Professor Department of Neurosurgery University of Utah Salt Lake City, Utah William S. Rosenberg, MD Director Center for the Relief of Pain Research Medical Center Kansas City, Missouri Robert H. Rosenwasser, MD Professor and Chair, Department of Neurological Surgery Thomas Jefferson University and Hospitals Philadelphia, Pennsylvania Florian Roser, MD Professor and Chairman Neurological Institute Cleveland Clinic Abu Dhabi, Abu Dhabi United Arab Emirates

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CONTRIBUTORS

Marco Rossi, MD Oncology and Hemato-­Oncology Neuro-­Oncological Surgery Università degli Studi di Milano Milano, Italy Nathan C. Rowland, MD, PhD Neurosurgeon Medical University of South Carolina Charleston, South Carolina James T. Rutka, MD, PhD Director of The Arthur and Sonia Labatt Brain Tumour Research Centre Division of Neurosurgery The Hospital for Sick Children RS McLaughlin Professor and Chair Department of Surgery University of Toronto Toronto, Ontario, Canada George N. Rymarczuk, MD Fellow Spinal Neurosurgery Thomas Jefferson University Philadelphia, Pennsylvania Arjun Sahgal, MD Professor of Radiation Oncology and Surgery Deputy Chief, Department of Radiation Oncology Sunnybrook Health Sciences Centre Toronto, Ontario, Canada Francesco Sala, MD Professor of Neurosurgery Neurosciences, Biomedicine, and Movement Sciences Neurosurgery Verona, Italy Federico Salle, MD, MSc Neurosurgeon, University of the Republic Neurosurgery Department Hospital Maciel President of the Uruguayan Society of Neurosurgery Montevideo, Uruguay Sepehr Sani, MD Associate Professor, Neurosurgery Rush University Medical Center Chicago, Illinois LCDR. Gabriel F. Santiago, MD, MC USN Division Chief, Neuroplastic and Reconstructive Surgery Department of Otolaryngology – Head and Neck Surgery Naval Medical Center Portsmouth Assistant Professor, Surgery F. Edward Herbert School of Medicine Uniformed Services University of Health Sciences Bethesda, Maryland

Roberto Salvatori, MD Professor, Medicine and Neurosurgery Medical Director Pituitary Center Johns Hopkins University Baltimore, Maryland Jaime L. Martinez Santos, MD Neurosurgery Resident Department of Neurosurgery Medical University of South Carolina Charleston, South Carolina Christina E. Sarris, MD Resident Physician, Neurosurgery Barrow Neurological Institute Phoenix, Arizona Luis E. Savastano, MD, PhD Resident Neurosurgeon, Neurosurgery University of Michigan Ann Arbor, Michigan Amar Saxena, MBBS, MS, MCh(Neurosurgery), FRCS(Eng), FRCS(Surg Neurol) Chairman Higher Surgical Committee in Neurosurgery for West Midlands University Hospitals Coventry and Warwickshire Coventry, United Kingdom Gabriele Schackert, Prof, MD Klinik und Poliklinik für Neurochirurgie Universitätsklinikum Carl Gustav Carus Dresden an der Technischen Universität Dresden Fetscherstraße, Dresden, Germany Meic H. Schmidt, MD, MBA Professor and Chair, Department of Neurosurgery University of New Mexico Albuquerque, New Mexico Henry W. S. Schroeder, Prof, MD Universitätsmedizin Greifswald Klinik für Neurochirurgie Greifswald, Germany Joseph Schwab, MD, MS Chief, Orthopaedic Spine Surgery Director, Spine Oncology Co-Director, Stephan L. Harris Chordoma Center Associate Professor of Orthopedic Surgery Harvard Medical School Massachusetts General Hospital Boston, Massachusetts

CONTRIBUTORS

Theodore H. Schwartz, MD David and Ursel Barnes Professor in Minimally Invasive Surgery Professor of Neurosurgery, Neurology, and Otolaryngology Director, Center for Epilepsy and Pituitary Surgery Co-­Director, Surgical Neuro-­oncology Department of Neurosurgery New York Presbyterian Hospital New York, New York Tommaso Sciortino, MD Oncology and Hemato-­Oncology Neuro-­Oncological Surgery Università degli Studi di Milano Milano, Italy Daniel M. Sciubba, MD Professor Departments of Neurosurgery, Oncology, Orthopaedic Surgery, and Radiation Oncology Director Spine Tumor and Spine Deformity Research Johns Hopkins University School of Medicine Baltimore, Maryland Kyle W. Scott, BS College of Medicine University of Florida Gainesville, Florida Jonathan P. Scoville, MD Resident Department of Neurosurgery University of Utah Salt Lake City, Utah Alfred P. See, MD Department of Neurosurgery Barrow Neurological Institute Phoenix, Arizona Raymond F. Sekula, Jr., MD Professor Director, Cranial Nerve Disorders Program Director, Residency Training Program Vice Chair, UPMC Central Pa University of Pittsburgh Pittsburgh, Pennsylvania Amjad Shad, MBBS, FRCS(Ed), FRCS(SN)MR Department of Neurosurgery Radcliffe Infirmary Oxford, United Kingdom Jugal Shah, MD Department of Neurological Surgery New York University School of Medicine New York, New York Ali Shaibani, MD Departments of Radiology and Neurosurgery Northwestern University Feinberg School of Medicine Department of Medical Imaging Children’s Memorial Hospital Chicago, Illinois

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Ammar Shaikhouni, MD, PhD Assistant Professor Department of Neurological Surgery The Ohio State University Wexner Medical Center Columbus, Ohio Manish S. Sharma, MBBS Chair Department of Neurosurgery Mankato Hospital Mankato, Minnesota Associate Professor Department of Neurologic Surgery Mayo Clinic Rochester, Minnesota Jason Sheehan, MD Professor, Neurosurgery University of Virginia Charlottesville, Virginia John Paul Sheehy, MD Assistant Professor Department of Neurosurgery University of Cincinnati Cincinnati, Ohio Sameer Sheth, MD, PhD Associate Professor Neurosurgery, Psychiatry and Behavioral Sciences, Neuroscience McNair Scholar Baylor College of Medicine Adjunct Associate Professor Department of Electrical and Computer Engineering Rice University Houston, Texas Changbin Shi, MD Department of Neurosurgery Harbin Medical University Harbin, China Nir Shimony, MD Geisinger Medical Center Neurosurgery Neuroscience Institute Danville, Pennsylvania, Geisinger Commonwealth School of Medicine Neurosurgery Geisinger Commonwealth School of Medicine Scranton, Pennsylvania, Johns Hopkins University School of Medicine Neurosurgery Institute for Brain Protection Sciences St. Petersburg, Florida Alexander Y. Shin, MD Division of Hand Surgery Department of Orthopedics Professor of Orthopedics and Neurosurgery Mayo Clinic Rochester, Minnesota

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CONTRIBUTORS

Adnan H. Siddiqui, MD, PhD Departments of Neurosurgery and Radiology Jacobs School of Medicine and Biomedical Science Department of Neurosurgery Gates Vascular Institute at Kaleida Health Canon Stroke and Vascular Research Center University at Buffalo Buffalo, New York Roberto Leal Silveira, MD, PhD Skull Base Neurosurgery and Neurooncology Madre Teresa Institue Belo Horizonte, Brazil Nathan Simmons, MD Section of Neurosurgery Dartmouth-­Hitchcock Medical Center Lebanon, New Hampshire Marc Sindou, MD, DSc Professor Emeritus of Neurosurgery Neurosurgery University of Lyon Lyon, France Marco Sinisi, MD Neurosurgery The Wellington Hospital St. Johns Wood, London United Kingdom Edward R. Smith, MD Department of Neurosurgery Boston Children’s Hospital Harvard Medical School Boston, Massachusetts Joseph R. Smith, MD† Professor Emeritus, Department of Neurosurgery Augusta University Augusta, Georgia Kyle A. Smith, MD Assistant Professor, Department of Neurosurgery Semmes-­Murphey Clinic University of Tennessee Health Sciences Center Memphis, Tennessee Matthew D. Smyth, MD, FACS, FAAP Appoline Blair Professor of Pediatric Neurosurgery Professor of Neurological Surgery and Pediatrics Co-­Director, Washington University Pediatric Epilepsy Center at St. Louis Children’s Hospital Director, St. Louis Children’s Hospital Pediatric Neurosurgery Fellowship St. Louis, Missouri Hany Soliman, MD Affiliate Scientist Sunnybrook Research Institute Toronto, Ontario, Canada † Deceased

Mark M. Souweidane, MD Vice Chairman, Neurological Surgery Director of Pediatric Neurological Surgery Department of Neurosurgery New York Presbyterian Hospital New York, New York Edgardo Spagnuolo, MD Assistant Professor, Chairman Neurosurgical Department Maciel Hospital Honorary President Latin American Federation of Neurosurgical Societies Member of the WANS World Academy of Neurosurgeons Ex-­Vice President WFNS Montevideo, Uruguay Robert F. Spetzler, MD Director and J.N. Harber Chair of Neurological Surgery Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, Arizona Professor of Neurosurgery Department of Surgery University of Arizona College of Medicine Tucson, Arizona Robert J. Spinner, MD Chair, Department of Neurologic Surgery Neurosurgery Professor Departments of Anatomy, Neurologic Surgery, and Orthopedic Surgery Mayo Clinic Rochester, Minnesota Christopher J. Stapleton, MD Neurosurgeon Cerebrovascular and Endovascular Neurosurgery Department of Neurosurgery Massachusetts General Hospital Boston, Massachusetts Rachel Stein, MD Neurosurgery Resident Mayo Clinic Jacksonville, Florida Michael P. Steinmetz, MD Professor and Chairman Department of Neurosurgery Cleveland Clinic Lerner College of Medicine Cleveland, Ohio Scellig Stone, MD, PhD Department of Neurosurgery Boston Children’s Hospital Harvard Medical School Boston, Massachusetts

CONTRIBUTORS

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Geoffrey P. Stricsek, MD Resident Physician Neurological Surgery Thomas Jefferson University Philadelphia, Pennsylvania

Rabih G. Tawk, MD Associate Professor Department of Neurosurgery Mayo Clinic Jacksonville, Florida

Paola Suarez-Meade, MD Post-Doctoral fellow Department of Neurosurgery Mayo Clinic Jacksonville, Florida

John M. Tew, Jr., MD Professor of Neurosurgery Executive Director, Community Affairs Vice President of Community Affairs University of Cincinnati Gardner Neuroscience Institute Cincinnati, Ohio

Michael E. Sughrue, MD Centre for Minimally Invasive Neurosurgery Prince of Wales Private Hospital Randwick, NSW, Australia Ian Suk, MD Department of Art as Applied to Medicine Department of Neurosurgery Johns Hopkins University School of Medicine Baltimore, Maryland

Nicholas Theodore, MD Professor of Neurosurgery, Orthopaedic Surgery, and Biomedical Engineering Neurosurgery Johns Hopkins University School of Medicine Director, Neurosurgical Spine Center Co-­Director, Carnegie Center for Surgical Innovation Johns Hopkins University Baltimore, Maryland

Daniel Q. Sun, MD Assistant Professor Department of Otolaryngology Johns Hopkins University School of Medicine Baltimore, Maryland

B. Gregory Thompson Jr., MD Professor and Program Director Department of Neurosurgery University of Michigan Ann Arbor, Michigan

Samir Sur, MD Department of Neurosurgery MedStar Washington Hospital Center Assistant Professor of Neurosurgery Georgetown University School of Medicine Washington, District of Columbia

John A. Thompson, PhD Departments of Neurosurgery and Neurology University of Colorado Anschutz Medical Campus Aurora, Colorado

Ulrich Sure, MD Neurosurgeon Department of Neurosurgery Philipps University Marburg, Germany Ahmad Sweid, MD Postdoctoral Research Fellow, Neurosurgery Thomas Jefferson University Philadelphia, Pennsylvania Ian Tafel, MD Neurosurgery Resident Department of Neurosurgery Brigham and Women’s and Boston Children’s Hospitals Harvard Medical School Boston, Massachusetts Rafael J. Tamargo, MD Department of Neurosurgery Johns Hopkins Hospital Baltimore, Maryland

Fucheng Tian, MD Precision Neuro-Therapeutics Innovation Lab Neurosurgery Simulation and Innovation Lab Mayo Clinic Phoenix, Arizona, Department of Neurosurgery Harbin Medical University Harbin, China Wuttipong Tirakotai, MD, MSc Doctor, Department of Neurosurgery Prasat Neurological Institute Bangkok, Thailand Stavropoula Tjoumakaris, MD Professor, Neurological Surgery Thomas Jefferson University Philadelphia, Pennsylvania Nathan Todnem, MD Department of Neurosurgery Montefiore Medical Center Albert Einstein College of Medicine New York, New York

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CONTRIBUTORS

Teiji Tominaga, MD Professor and Chairman Department of Neurosurgery Tohoku University Graduate School of Medicine Sendai, Japan

Jamie J. Van Gompel, MD Associate Professor Departments of Neurosurgery and Otolaryngology Mayo Clinic Rochester, Minnesota

Daniel M. Trifiletti, MD Associate Professor, Radiation Oncology Mayo Clinic Jacksonville, Florida

Viren S. Vasudeva, MD Staff Neurosurgeon Georgia Neurological Surgery and Comprehensive Spine Center St. Mary’s Medical Group Athens, Georgia

Shashwat Tripathi, BSA MD, PhD Candidate 2027’ Feinberg School of Medicine Northwestern University Chicago, Illinois Eric Tseng, MD Affiliate Scientist Assistant Professor, Radiation Oncology Sunnybrook Health Sciences Centre Toronto, Ontario, Canada R. Shane Tubbs, MS, PA-­C, PhD Professor Department of Neurosurgery Tulane University School of Medicine New Orleans, Louisiana Riikka Tulamo, MD, PhD Adjunct Professor, Consultant Vascular Surgeon Department of Vascular Surgery Neurosurgery Research Group University of Helsinki and Helsinki University Hospital Helsinki, Finland Constantin Tuleasca, MD-­PhD Department of Clinical Neurosciences, Neurosurgery Service, and Gamma Knife Center Centre Hospitalier Universitaire Vaudois (CHUV) University of Lausanne, Faculty of Biology and Medicine (FBM) Swiss Federal Institute of Technology (EPFL), LTS-­5 Lausanne, Switzerland Ali H. Turkmani, MD Department of Neurological Surgery Precision Neuro-Therapeutics Innovation Lab Neurosurgery Simulation and Innovation Lab Mayo Clinic Phoenix, Arizona Kunal Vakharia, MD Department of Neurosurgery Jacobs School of Medicine and Biomedical Sciences University at Buffalo Department of Neurosurgery Gates Vascular Institute at Kaleida Health Buffalo, New York

Ana Luisa Velasco, MD, PhD Head of Neurology Head of the Epilepsy Clinic General Hospital Mexico Eduardo Liceaga Mexico City, Mexico Francisco Velasco, MD Unite for Stereotactic and Functional Neurosurgery General Hospital of Mexico Mexico City, Mexico Gregory J. Velat, MD Clinician, Department of Neurological Surgery Florida Hospital Memorial Medical Center Daytona Beach, Florida Vyshak Alva Venur, MD Alvord Brain Tumor Center Seattle Cancer Care Alliance Assistant Professor Division of Medical Oncology University of Washington School of Medicine UW Medicine Assistant Member Clinical Research Division Fred Hutchinson Cancer Research Seattle, Washington Angela Verlicchi, MD Neurology Service Anemos Neuroscience Reggio Emilia, Italy Tito Vivas-­Buitrago, MD Post-­Doctoral Fellow Department of Neurosurgery Mayo Clinic Jacksonville, Florida Alexander L. Vlasak, MD Resident Physician Department of Neurosurgery Mayo Clinic Hospital Jacksonville, Florida

CONTRIBUTORS

Frank D. Vrionis, MD, MPH, PhD Senior Member and Director, Spinal and Skull Base Oncology H. Lee Moffitt Cancer Center Professor of Neurosurgery, Orthopedics, and Oncology Department of Neurosurgery University of South Florida Tampa, Florida John Varmaa Wainwright, MD, MS Neurological Surgery Chief Resident Neurosurgical Spine Surgery Westchester Medical Center New York Medical College Valhalla, New York M. Christopher Wallace, MD Professor of Surgery Chair and Section Chief, Division of Neurosurgery Queen’s University School of Medicine Kingston General Hospital Kingston, Ontario, Canada Muhammad Waqas, MBBS Department of Neurosurgery Jacobs School of Medicine and Biomedical Sciences University at Buffalo Department of Neurosurgery Gates Vascular Institute at Kaleida Health Buffalo, New York Clarence B. Watridge, MD Professor Emeritus Department of Neurosurgery Mayo Clinic Jacksonville, Florida

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David M. Wildrick, PhD Surgery Publications Program Manager Department of Neurosurgery The University of Texas MD Anderson Cancer Center Houston, Texas D. Andrew Wilkinson, MD, MS Resident Neurosurgeon Neurosurgery University of Michigan Ann Arbor, Michigan Christopher J. Winfree, MD, FAANS Assistant Professor Department of Neurological Surgery Columbia University College of Physicians & Surgeons New York, New York Timothy Witham, MD Professor of Neurological and Orthopedic Surgery Director, Johns Hopkins Neurosurgery Spinal Fusion Laboratory Director, Johns Hopkins Bayview Medical Center’s Spine Program Co-­Program Director, Johns Hopkins Neurosurgery Residency Program Department of Neurosurgery Johns Hopkins University Baltimore, Maryland Amir Wolff, DMD Department of Maxillofacial Surgery Rambam Health Care Center Haifa, Israel

Nirit Weiss, MD Assistant Professor of Neurosurgery Neurosurgery Icahn School of Medicine at Mount Sinai New York, New York

Jean-­Paul Wolinsky, MD Professor of Neurosurgery and Orthopedic Surgery Vice Chairman of Neurosurgery Director of Spinal Oncology Northwestern University Feinberg School of Medicine Chicago, Illinois

Matthew E. Welz, MD Department of Neurological Surgery Precision Neuro-Therapeutics Innovation Lab Neurosurgery Simulation and Innovation Lab Mayo Clinic Phoenix, Arizona

Kyle C. Wu, MD Neurosurgery Resident Department of Neurosurgery Brigham and Women’s and Boston Children’s Hospitals Harvard Medical School Boston, Massachusetts

Erick M. Westbroek, MD Senior Resident Department of Neurosurgery Johns Hopkins University Baltimore, Maryland

Shaun Xavier, MD Department of Orthopaedic Surgery New York University New York, New York

Robert E. Wharen, MD Professor Emeritus Department of Neurosurgery Mayo Clinic Jacksonville, Florida

Kurt Yaeger, BS, MD Resident Physician Department of Neurosurgery Icahn School of Medicine at Mount Sinai Hospital New York, New York

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CONTRIBUTORS

Claudio Yampolsky, MD Chairman Neurosurgery Hospital Italiano Buenos Aires, Argentina

Eric L. Zager, MD Professor, Neurosurgery Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania

Reza Yassari, MD MS Professor of Neurosurgery Division Chief, Neurosurgery Spine Program Leo Davidoff Department of Neurosurgery Montefiore Medical Center Albert Einstein College of Medicine Bronx, New York

Bruno Zanotti, MD Neurosurgery Unit Neuroscience Department Carlo Poma Hospital Mantova, Italy

Yagiz Ugur Yolcu, MD Department of Neurologic Surgery Mayo Clinic Rochester, Minnesota Alexander K. Yu, MD Neurological Surgery Allegheny General Hospital Pittsburgh, Pennsylvania

Mehmet Zileli, MD Professor Department of Neurosurgery Ege University Izmir, Turkey Emanuele Zivelonghi, PhD Department of Medical Physics University Hospital Verona, Italy

VIDEO CONTENTS

Chapter 7

Chapter 17

Video 1: Right-sided Awake Craniotomy With ECoG and Brain Mapping for Glioma Resection Courtesy of Karim ReFaey and Alfredo Quiñones-­Hinojosa

Video: Endoscopic Endonasal Resection of Recurrent Craniopharyngioma Courtesy of Thomas Beaumont, Kyle VanKoevering, Ricardo Carrau, and Daniel Prevedello

Current Surgical Management of High-­Grade Gliomas; New and Recurrent

Video 2: Right-sided Redo Awake Craniotomy With ECoG and Brain Mapping for Recurrent Glioma Resection Courtesy of Karim ReFaey and Alfredo Quiñones-­Hinojosa

Chapter 9

Management of Primary Central Nervous System Lymphomas Video: Right-sided Stereotactic Needle Biopsy for Primary-CNS Lymphoma Courtesy of Karim ReFaey, Mark Jentoft, Erik H. Middlebrooks, and Alfredo Quiñones-­Hinojosa

Chapter 12

Endoscopic Endonasal Approach to Sellar, Parasellar, and Suprasellar Surgery Video 1: Endoscopic Trans-­sphenoidal Approach, Sphenoidotomy, and Septectomy Courtesy of Angela M. Bohnen, Angela M. Donaldson, Osarenoma U. Olomu, and Alfredo Quiñones-­Hinojosa

The Endoscopic Endonasal Approach for Craniopharyngiomas

Chapter 18

Minimally Invasive Surgeries for Deep-­Seated Brain Lesions Video: Minimally Invasive Exoscope-Assisted Trans-­sulcal Approach Courtesy of Kaisorn L. Chaichana, Sanjeet Grewal, and Alfredo Quiñones-­Hinojosa

Chapter 19

Surgical Approaches to Lateral and Third Ventricular Tumors Video: Endoscopic Transforaminal-­Transchoroidal Approach Courtesy of Oluwaseun O. Akinduro, Kaisorn L. Chaichana, Rabih G. Tawk, and Ronald Reimer

Chapter 20

Transcallosal and Endoscopic Approach to Intraventricular Brain Tumors

Video 2: Nasoseptal Flap Courtesy of Angela M. Bohnen, Angela M. Donaldson, Osarenoma U. Olomu, and Alfredo Quiñones-­Hinojosa

Video: Intraventricular Neuroendoscopy Courtesy of Gunjan Goel, Jeffrey P. Greenfield, Mark M. Souweidane, and Theodore H. Schwartz

Chapter 13

Chapter 22

Endoscopic Endonasal Approach to Lateral Cavernous Sinus Video: Endoscopic Endonasal Approach for Left-­Sided Cavernous Sinus Tumor Courtesy of Douglas A. Hardesty, Alaa S. Montaser, Bradley A. Otto, Ricardo L. Carrau, and Daniel M. Prevedello

Chapter 16

Transcranial Surgery for Pituitary Macroadenomas Video: Intraoperative Left Middle Cerebral Artery Injury in Case 3 and the Proper Management Courtesy of Hamid Borghei-­Razavi, Varun R. Kshettry, Florian Roser, Alfredo Quiñones-­Hinojosa, and Pablo F. Recinos

Management of Tumors of the Fourth Ventricle Video: Exophytic Brainstem Fourth Ventricle Pilomyxoid Astrocytoma Courtesy of Rajiv R. Iyer and Alan R. Cohen

Chapter 24

Surgical Approach to Falcine Meningiomas Video: Left Supratentorial Craniotomy for Resection of Falcine Meningioma Courtesy of Paola Suarez-­Meade, Karim ReFaey, and Alfredo Quiñones-­Hinojosa

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VIDEO CONTENTS

Chapter 26

Chapter 45

Supraorbital Approach Variants for Intracranial Tumors

Surgical Treatment of Moyamoya Disease in Adults

Video: Right Supraorbital Craniotomy With Eyelid Approach Courtesy of Karim ReFaey, Kelly Gassie, Olivia A. Ho, Antonio Jorge Forte, and Alfredo Quiñones-­Hinojosa

Video 1: Left Direct Bypass for Adult Moyamoya Disease Courtesy of Leonidas Quintana, Miki Fujimura, and Teiji Tominaga

Chapter 27

Video 2: Left Wide Encephaloduroarteriosynangiosis (EDAS) for Adult Moyamoya Disease Courtesy of Leonidas Quintana, Miki Fujimura, and Teiji Tominaga

Surgical Management of Sphenoid Wing Meningiomas Video 1: Giant Sphenoid Wing Meningioma Courtesy of Gerardo Guinto Video 2: Small Sphenoid Wing Meningioma Courtesy of Gerardo Guinto

Chapter 34

The OZ Chapter: Original OZ, Modified for Parietal, Modified for Frontal Cosmetic Results of the OZ Video: Orbitozygomatic Approach for Tumor Resection Courtesy of Karim ReFaey, Shashwat Tripathi, Andres Ramos-Fresnedo, Jaime L. Martinez Santos, Paola Meade-Suarez and Alfredo Quiñones-­Hinojosa

Chapter 38

Bypass Techniques Video: Dual STA-­MCA Bypass Courtesy of Oluwaseun O. Akinduro, Neil Haranhalli, Ricardo A. Domingo, Hadi Abou-­El-­Hassan, and Rabih G. Tawk

Chapter 39

Previously Coiled Aneurysms Video: Endoscopic-Assisted Clipping of Previously Coiled Pcomm Aneurysm Courtesy of Lina Marenco-­Hillembrand, Nathan Todnem, Neil Haranhalli, David Miller, and Rabih G. Tawk

Chapter 42

Management of Unruptured Intracranial Aneurysms Video 1: Acomm Aneurysm Clipping Courtesy of Omar A. Choudhri Video 2: PICA Aneurysm Clipping Courtesy of Omar A. Choudhri

Chapter 46

Surgical Treatment of Paraclinoid Aneurysms Video: Mini-­Pterional Approach for Ruptured Dorsal Proximal (Ophthalmic) Aneurysm Courtesy of Edgar Nathal, Oluwaseun O. Akinduro, Gabriel Castillo, and Rabih G. Tawk

Chapter 50

Surgical Management of Terminal Basilar and Posterior Cerebral Artery Aneurysms Video 1: Microsurgical Clipping of MCA and Basilar Tip Aneurysms Courtesy of Vijay Agarwal and Daniel L. Barrow Video 2: Subtemporal Approach to Basilar Tip Aneurysm Courtesy of Vijay Agarwal and Daniel L. Barrow

Chapter 57

Surgical Management of Cerebral Arteriovenous Malformations Video 1: Surgical Resection of Left Frontal AVM Courtesy of Edgardo Spagnuolo, Alejandra Jaume, and Federico Salle Video 2: Surgical Resection of Left Fronto-­Parietal AVM Courtesy of Edgardo Spagnuolo, Alejandra Jaume, and Federico Salle Video 3: Surgical Resection of Left Temporal Lobe AVM Courtesy of Edgardo Spagnuolo, Alejandra Jaume, and Federico Salle

Chapter 58

Surgical Management of Cerebral Arteriovenous Malformations Video 1: Microcatheterization of Unruptured Pcomm Artery Aneurysm Courtesy of D. Andrew Wilkinson, Luis E. Savastano, and B. Gregory Thompson, Jr.

VIDEO CONTENTS

xlix

Video 2: Partial Coil Deployment Within the Aneurysm Courtesy of D. Andrew Wilkinson, Luis E. Savastano, and B. Gregory Thompson, Jr.

Chapter 81

Video 3: Stent Deployment Across Aneurysm Neck, Jailing the Coiling Microcatheter Courtesy of D. Andrew Wilkinson, Luis E. Savastano, and B. Gregory Thompson, Jr.

Video: Technical Nuances of Ventriculo-­atrial Shunt Placement Courtesy of Tito Vivas-­Buitrago and Daniele Rigamonti

Chapter 61

Endovascular Treatment of Intracranial Occlusive Disease Video 1: Deployment of Wingspan Stent System Across the MCA Courtesy of Kunal Vakharia, Muhammad Waqas, L. Nelson Hopkins, Adnan H. Siddiqui, and Elad I. Levy Video 2: Navigation of Wingspan Stent System Across the MCA Courtesy of Kunal Vakharia, Muhammad Waqas, L. Nelson Hopkins, Adnan H. Siddiqui, and Elad I. Levy

Chapter 62

Endovascular Treatment of Extracranial Occlusive Disease Video: Carotid Artery Stenting Courtesy of Matthew John Koch

Chapter 64

Endovascular Management of Dural Arteriovenous Fistulas Video: Carotid Artery Stenting Courtesy of Bowen Jiang, Matthew T. Bender, Erick M. Westbroek, Jessica K. Campos, Li-­Mei Lin, Alexander L. Coon, and Geoffrey P. Colby

Chapter 66

Principles for Surgical Management of Hydrocephalus in the Adult

Chapter 83

Endoscopic Treatment of Hyrdrocephalus: Third Ventriculostomy, Aquaductoplasty, Septostomy Video: Endoscopic Third Ventriculostomy Courtesy of Anthony L. Mikula, Benjamin D. Elder, Tito Vivas-­Buitrago, and Daniele Rigamonti

Chapter 84

Surgical Management of Cysts: Intraventricular Cysts, Intraventricular Septations, and Extraventricular Arachnoid Cysts Video: Endoscopic Colloid Cyst Resection, ETV, and Septum Pellucidotomy Courtesy of Kelly Gassie and Alfredo Quiñones-­Hinojosa

Chapter 85

Management of Shunt Complications Video: Surgical Management of Shunt Infections Courtesy of Claudio Yampolsky and P. Ajler

Chapter 86

Management of Cerebrospinal Fluid Leaks Video: Management of Cerebrospinal Fluid Leaks Courtesy of Angela Bohnen, Christopher Louie, Ricardo A. Domingo, Gaetano De Biase, Angela M. Donaldson, Osarenoma U. Olomu, and Alfredo Quiñones-­Hinojosa

Endovascular Treatment of Head and Neck Bleeding

Chapter 98

Video 1: Bilateral Sphenopalatine Artery Embolization for Intractable Epistaxis Courtesy of Dimitri Laurent, Adam J. Polifka, and W. Christopher Fox

Video: Laser-­Ablation Techniques Courtesy of Tito Vivas-­Buitrago, Sanjeet S. Grewal, and Robert E. Wharen, Jr.

Video 2: Posttraumatic Vertebral Artery Jugular Venous Fistula Courtesy of Dimitri Laurent, Adam J. Polifka, and W. Christopher Fox

Chapter 74

Surgical Management of Spinal Dysraphism Video: L1-­5 Laminoplasty for Resection of Lipoma and Detethering of Spinal Cord Courtesy of Oluwaseun O. Akinduro and Philipp R. Aldana

Laser-­Ablation Techniques

Chapter 105

Implantation of Deep Brain Stimulation Electrodes Under General Anesthesia for Parkinson’s Disease and Essential Tremor Video: DREZ (Dorsal Root Entry Zone) Lesions for Brachial Plexus Avulsion Pain Courtesy of Kim J. Burchiel

l

VIDEO CONTENTS

Chapter 109

Lesion Procedures for Psychiatric Disorders Video: Stereotactic Lesion Procedures Courtesy of Kelly Bijanki, Patrick Karas, and Sameer Sheth

Video 2: Midline Suboccipital Craniotomy for Fourth Ventricular Cysticercosis Courtesy of Rodrigo Ramos-­Zúñiga, Tomás Garzón-­Muvdi, and Kaisorn L. Chaichana

Chapter 148

Chapter 112

Thoracoscopic Sympathectomy for Hyperhidrosis

Lumbar Spinal Arthroplasty: Clinical Experiences of Motion Preservation

Video: Bilateral Thoracoscopic Sympathotomy at T2 Courtesy of Karim ReFaey, Sanjeet Grewal, Mathew Thomas, and Robert E. Wharen, Jr.

Video: Total Disc Replacement (TDR) at L5-­S1 with Activ-­l TDR, and 11 Degrees of Lordosis Courtesy of Fred H. Geisler and Domagoj Coric

Chapter 113

Surgery for Intractable Spasticity Video: Surgery for Intractable Spasticity Courtesy of Marc Sindou and George Georgoulis

Chapter 120

Surgery for Intractable Spasticity Spinal Cord Stimulation and Intraspinal Infusions for Pain Video: Surgical Placement of Spinal Cord Internal Pulse Generator for Intractable Pain Courtesy of Karim ReFaey, Alexander Vlasak, Andres Ramos-­Fresnedo, Perry A. Ball, Ronald Reimer, and Eric Nottmeier

Chapter 126

Principles of Neuroplastic Surgery: Management of Scalp Defects and Neurocranial Reconstruction Video: Principles of Neuroplastic Surgery and Surgical Aspects of Cranioplasty Reconstruction Courtesy of Netanel Ben-­Shalom and Chad R. Gordon

Chapter 131

Neurocysticercosis Video 1: Intraventricular Resection of Cysticercosis Courtesy of Rodrigo Ramos-­Zúñiga, Tomás Garzón-­Muvdi, and Kaisorn L. Chaichana

Chapter 167

Management of Chiari Malformations and Syringomyelia Video: C1 Laminectomy for Chiari Malformation Revision Courtesy of Karim ReFaey, William Clifton, and Alfredo Quiñones-­Hinojosa

Chapter 174

Intradural Extramedullary Tumors Video 1: Thoracic Laminectomy Courtesy of Oluwaseun O. Akinduro and H. Gordon Deen Video 2: Surgical Resection of Lumbar Intradural Extramedullary Schwannoma Courtesy of Mohamad Bydon, Megan C. Everson, Anshit Goyal

Chapter 194

Robotic Spine Surgery Video: Robotically Assisted MIS L4-­S1 TLIF Courtesy of Selby Chen   

PREFACE

What we write today becomes history tomorrow. Books that continue to be updated are a testament that the concept stands strong but the field has continued to move, and the need for contemporary knowledge and updates is crucial to keep the concept alive and thriving. Drs. Schmidek and Sweet co­edited the first single volume entitled Current Techniques in Operative Neurosurgery in 1977. At the time, that first edition reflected their own interests in contemporary neurosurgical procedures. So much has changed in the field and in the world since then, but what has not changed is the thirst for knowledge and the need to make patient surgical care better and more efficient. In this new edition, in the middle of an enormous and life-­changing COVID-­19 pandemic, this book has continued the same tradition: to provide the working neurosurgeon and health care provider with information that would be useful when carrying for a patient with a neurosurgical disorder and/or taking a patient to the operating room. The chapters provided an overview of the topic, a discussion of available options, and results. In many cases, alternative surgical and nonsurgical options were included for dealing with a particular clinical situation. The goal from the inception of this book has been to provide a single source that would allow a neurosurgeon to develop a surgical plan for the patient and at the same time understand the nuances, potential complications, and expectations of surgery so the care of the patient is improved. The chapter references would be up to date and allow further immersion in the topic as needed. The success of these volumes places Operative Neurosurgical Techniques: Indications, Methods, and Results among the most widely used neurosurgical texts worldwide with an extraordinary number of authors from all over the world. Now in its seventh edition, this title is dedicated to all those unsung heroes around the world that despite monumental challenges as surgery stopped in many corners of the world due to the pandemic, they continued to provide care for patients and continued to put down their ideas in this new edition. The field of neurological surgery has experienced a tremendous evolution since I did the 6th edition and it fills me with pride and pleasure to know that our field continues to be innovative, exhilarating, and courageous. In this 7th edition, I continued the tradition that was started in the last edition to add multiple section editors,

which has allowed us to keep the current edition as contemporary as possible. The 7th edition continues to reflect the same underlying vision for the book and attempts to keep up to date with the rapidly evolving changes in neurosurgery. This new and improved edition consists of 10 sections and 193 chapters authored by 445 contributors representing neurosurgical services from several different countries. It was the original intention of Dr. Schmidek in the first five editions to reflect the ongoing worldwide changes, to include contributions of internationally renowned doctors, and to perpetuate the idea of a worldwide text in neurosurgery and we have continued this tradition in the 6th and 7th editions. This 7th edition has lived up to that goal with a more modern utilization of video and new surgical techniques. In this edition a large percentage of the chapters deal with material not previously addressed, including topics of pediatric neurosurgery, endovascular surgery, robotic spine, innovation, skull base minimally invasive techniques, and the updates of peripheral nerve management and surgery. Where appropriate, chapters published in earlier editions have been extensively rewritten. All the chapters have been reviewed by myself and my coeditors to ensure that they reflect the current state of the art. This edition could not have been accomplished without the enthusiastic participation of the section editors and contributors who put in extraordinary efforts to complete their chapters on time. Every effort has been made to produce a product worthy of the contributions. This could only have been accomplished with the professionalism of Laurie Gower, Denise Roslonski, Laura Schmidt, Belinda Kuhn, and Cindy Thoms at Elsevier, and my Fellow, Dr. Karim ReFaey. I extend to all the section editors, contributors, and staff members from Elsevier and Mayo Clinic Florida my most sincere thanks for a tremendous job, which was incredibly well done. I also thank our families and loved ones who have made tremendous sacrifices, as many of us write and edit our chapters during mornings, nights, and weekends and often take time away from our families who are there supporting us and encouraging us continuously—a big thank you! Alfredo Quiñones-­Hinojosa, MD, FACS, FAANS

xxxix

CHAPTER 1

Ensuring Patient Safety in Surgery: First Do No Harm and Applying a Systems-­Engineering Approach KADIR ERKMEN  •  WILLIAM DAVID FREEMAN

Primum non nocere—first do no harm. The Hippocratic statement epitomizes the importance the medical community places on avoiding iatrogenic complications.1 In the process of providing care, patients, physicians, and the entire clinical team join to use all available medical options to combat disease to avert the natural history of pathologic processes. Iatrogenic injury or, simply, “treatment-­related harm” occurs due to various reasons and sometimes gets confused with trying to help the very patient who is deteriorating from their disease. In essence, giving a patient a medication or performing surgery to help the patient may be associated with short-­term or long-­term worsening (“risks” of treatment), which may or may not be due to the treatment itself, and may or may not ultimately help the patient’s prognosis (“benefit” within a “risk vs. benefit ratio”). Due to advancements in care and emphasis on improving safety over time, society and the medical community have become increasingly intolerant of medical and surgical outcomes, both good and bad. Negligence is a medico-legal term when a patient is harmed due to an act or omission that deviates from an accepted standard of care. This chapter will review the science of human error in medicine and surgery and in particular a re­design approach used in systems engineering.

The Nature of Safety in Medicine and Surgery The earliest practitioners of medicine recognized and described iatrogenic injury. Iatrogenic (Greek, iatros = doctor, genic = arising from or developing from) literally translates to “disease or illness caused by doctors.” Famous examples exist of likely iatrogenic deaths, such as that of George Washington, who died while being treated for pneumonia with bloodletting. The Royal Medical and Surgical Society, in 1864, documented 123 deaths that “could be positively assigned to the inhalation of chloroform.”2 Throughout history, physicians have reviewed unexpected outcomes related to the medical care they provided to learn and improve that care. The “father” of modern neurosurgery, Harvey Cushing, and his contemporary Sir William

Osler modeled the practice of learning from error by publishing their errors openly so as to warn others on how to avert future occurrences.3–5 However, the magnitude of iatrogenic morbidity and mortality was not quantified across the spectrum of health care until the Harvard Practice Study, published in 1991.6 This seminal study estimated that iatrogenic failures occur in approximately 4% of all hospitalizations and is the eighth leading cause of death in America—responsible for up to 100,000 deaths per year in the United States alone.7 A subsequent review of over 14,700 hospitalizations in Colorado and Utah identified 402 surgical adverse events, producing an annual incidence rate of 1.9%.8 The nature of surgical adverse events was categorized by type of injury and by preventability. These two studies were designed to characterize iatrogenic complications in health care. While not statistically powered to allow surgical subspecialty analysis, it is likely that the types of failures and subsequent injuries this study identified can be generalized to the neurosurgical patient population. More recent literature supports the findings of these landmark studies.9–11 Over time health care systems have become increasingly complex, with multiple moving parts, more and more team members, increased complexity of equipment in the operating room (OR), and complex patients. The Institute of Medicine used the Harvard Practice Study as the basis for its report, which endorsed the need to discuss and study errors openly with the goal of improving patient safety.7 The Institute of Medicine report on medical errors, “To Err Is Human: Building a Safer Health,” must be considered a landmark publication.12 It was published in 1999 and focused on medical errors and their prevention. This was followed by the development of other quality improvement initiatives such as the Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) Sentinel Events Program.12 One might argue that morbidity and mortality reviews already achieve this aim. The “M&M” conference has a long history of reviewing negative outcomes in medicine and surgery to ultimately improve the quality and safety and systems of care involved with patient care. The ultimate goal of this traditional conference is to learn how to prevent future

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1  •  Ensuring Patient Safety in Surgery: First Do No Harm and Applying a Systems-Engineering Approach

patients from suffering similar harm, and thus incrementally improve care. However, frank discussion of error is limited in M&M conferences. Also, the actual review practices fail to support deep learning regarding systemic vulnerabilities13; indeed, historical M&M conferences did not explicitly require a systems-­design approach to errors to be reviewed, until recently. One prospective investigation of four US academic hospitals found that a resident vigilantly attending weekly internal medicine M&M conferences for an entire year would discuss a systematic approach to errors only once. Surgical versions of the M&M conference were historically better with some surgical or technical error discussion. However, while surgeons discussed adverse events associated with error 77% of the time, individual provider error was the focus of the discussion and cited as causative of the negative outcome in 8 of 10 conference discussions.13 Surgical conference discussion rarely identified system defects such as resource constraints, team communication, or other systematic problems that affected individual cases. Further limiting its utility, the M&M conference is reactive by nature and highly subject to hindsight bias or blaming a single individual rather than a systematic high-­level re-­design approach. This is the basis for most clinical outcome reviews, focusing solely on medical providers and their decision making.14 In their report on “Nine Steps to Move Forward from Error” in medicine, human factors experts Cook and Woods challenged the medical community to resist the temptation to simplify the complexities practitioners face when reviewing accidents post hoc. Premature closure by blaming the closest clinician hides the deeper patterns and multiple contributors associated with failure and ultimately leads to naïve “solutions” that are weak or even counterproductive.15 The Institute of Medicine has also cautioned against blaming an individual and recommending training as the sole outcome of case review.7 While the culture within medicine is to learn from failure, the M&M conference does not typically achieve this aim. The so-­called “Swiss cheese” model is an apt analogy for most medical and surgical errors, since it requires a constellation of issues to line up like holes in Swiss cheese to fall through rather than a single hole alone. 

A Human Factors Approach to Improving Patient Safety Murphy’s Law applied to medicine and surgery implies that whatever can go wrong will go wrong. Murphy’s law, however, can be “reverse-­engineered” to the science of quality and safety. For example, anticipated defects in the Swiss cheese model (i.e., anticipating things that can go wrong in advance) should be articulated prior to giving a medication and/or preoperative planning. In the realm of medical errors, medication allergies are a common high-­volume issue. If a patient is exposed and becomes allergic (e.g., identification) to a medication, this allergy broad communication in the medical record is a common “hole” to fill in the Swiss cheese model and helps prevent recurrent medication adverse events. The field of human factors or systems engineering grew out of a focus on human interaction with physical devices, especially in military or industrial settings. This initial focus on how to improve human performance addressed the problem of workers that are at high risk for

injury while using a tool or machine in high-­hazard industries. In the past several decades, the scope of this science has broadened. Human factors engineering is now credited with advancing safety and reliability in aviation, nuclear power, and other high-­hazard work settings. Membership in the Human Factors and Ergonomics Society in North America alone has grown to over 15,000 members. Human factors engineering and related disciplines are deeply interested in modeling and understanding mechanisms of complex system failure. Furthermore, these applied sciences have developed strategies for designing error prevention and building error tolerance into systems to increase reliability and safety, and these strategies are now being applied to the health care industry.16–21 The specialty of anesthesiology has employed this science to reduce the anesthesia-­related mortality rate from approximately 1 in 10,000 in the 1970s to over 1 in 250,000 three decades later.22 Critical incident analysis was used by a bioengineer (Jeffrey Cooper, PhD) to identify preventable anesthesia mishaps in 1978.23 Dr. Cooper’s seminal work was supplemented by the “closed claim” liability studies, which delineated the most common and severe modes of failure and factors that contributed to those failures. The specialty of anesthesiology and its leaders endorsed the precepts that safety stems more from improved system design than from increasing vigilance of individual practitioners. As a direct result, anesthesiology was the first specialty to adopt minimal standards for care and monitoring, preanesthesia equipment “checklists” similar to those used in commercial aviation, standardized medication labels, interlocking hardware to prevent gas mix-­ups, international anesthesia machine standards, and the development of high-­ fidelity human simulation to support crisis team training in the management of rare events. Lucien Leape, MD, a former surgeon, one of the lead authors of the Harvard Practice Study, and a national advocate for patient safety, has stated, “Anesthesia is the only system in healthcare that begins to approach the vaunted ‘six sigma’ (a defect rate of 1 in a million) level of clinical safety perfection that other industries strive for. This outstanding achievement is attributable not to any single practice or development of new anesthetic agents or even any type of improvement (such as technological advances) but to application of a broad array of changes in process, equipment, organization, supervision, training, and teamwork. However, no single one of these changes has ever been proven to have a clear-­cut impact on mortality. Rather, anesthesia safety was achieved by applying a whole host of changes that made sense, were based on an understanding of human factors principles, and had been demonstrated to be effective in other settings.”24 The Anesthesia Patient Safety Foundation, which has become the clearinghouse for patient safety successes in anesthesiology, was used as a model by the American Medical Association to form the National Patient Safety Foundation in 1996.25 Over the subsequent decade, the science of safety has begun to permeate health care. The human factors psychologist James Reason, PhD, has characterized accidents as evolving over time and as virtually never being the consequence of a single cause.26,27 Rather, he describes accidents as the net result of local triggers that initiate and then propagate an incident through a hole in one

1  •  Ensuring Patient Safety in Surgery: First Do No Harm and Applying a Systems-Engineering Approach

layer of defense after another until irreversible injury occurs (Fig. 1.1). This model has been referred to as the “Swiss cheese” model of accident causation. Surgical care consists of thousands of tasks and subtasks. Errors in the execution of these tasks need to be prevented, detected, and managed, or tolerated. As described above, the layers of the Swiss cheese model represent the system of defenses against such error. Latent conditions is the term used to describe “accidents waiting to happen” that are the holes in each layer that will allow an error to propagate until it ultimately causes injury or death. The goal in human factors system engineering is to know all the layers of Swiss cheese and create the best defenses possible (i.e., make the holes as small as possible). This very approach has been the centerpiece of incremental improvements in anesthesia safety. One structured approach designed to identify all of the holes in the major layers of cheese in medical systems has been described by Vincent.28,29 He classifies the major

Swiss cheese safety model

Threats

Holes or gaps in systems defenses line up to allow patient safety risks or events and outcomes

Outcomes FIGURE 1.1  A “Swiss cheese” model of accident causation originally described by Ransom. Accidents (adverse outcomes) require a combination of defenses to line up in sequence for it to occur.

• Dynamic factors

Patient

Team -NASA TLX -Huddles

Surgeon

Task

-NASA TLX

-Strategy -Equipment -Skill

• Societal and political factors

A

categories of factors that contribute to error as follows (Fig. 1.2)28–30: 1.  Patient factors: condition, communication, availability and accuracy of test results, and other contextual factors that make a patient challenging 2. Task factors: using an organized approach in reliable task execution, availability and use of protocols, and other aspects of task performance 3. Practitioner factors: deficits and failures by any individual member of the care team that undermines management of the problem space in terms of knowledge, attention, strategy, motivation, physical or mental health, and other factors that undermine individual performance 4.  Team factors: verbal/written communication, supervision/seeking help, team structure and leadership, and other failures in communication and coordination among members of the care team such that management of the problem space is degraded 5. Working conditions: staffing levels, skills mix and workload, availability and maintenance of equipment, administrative and managerial support, and other aspects of the work domain that undermine individual or team performance 6. Organization and management factors: financial resources, goals, policy standards, safety culture and priorities, and other factors that constrain local microsystem performance 7. Societal and political factors: economic and regulatory issues, health policy and politics, and other societal factors that set thresholds for patient safety A variety of systems-­engineering models have been proposed as above to help mitigate patient errors. If this schema is used to structure a review of a morbidity or mortality, that review will be extended beyond myopic attention to the singular practitioner. Furthermore, the array of identified factors that undermine safety can then be countered

• Working conditions

-Emergent or elective

3

Process A Enhanced patient safety

Process B

Identification of care management problem/ threat Surveillance source, story

Broad dissemination of effective countermeasures

Active error management cycle

Countermeasure evaluation and validation

• Organizational and management factors

Identification of contributory factors

Prioritization

Countermeasure design and local implementation

B

FIGURE 1.2  A, multiple factors that lead to safety and errors in health care described by Vincent.28,29 NASA-­TLX (Task Load Index)30 models are reported to impact both surgeon and teams (e.g., heavier loads can lead to more errors). Bottom image, example of cyclical patient safety improvement Process A and how the identification and changes in the initial process and refinement leads to a new Process B. (B copyright Blike 2002.)

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1  •  Ensuring Patient Safety in Surgery: First Do No Harm and Applying a Systems-Engineering Approach

Investigation of all contributory factors and systems defects

FIGURE 1.3  Sequence of steps for identifying vulnerabilities and then implementing corrective measures. Holes A, B, C line up and hazards can penetrate all three layers. Countermeasure plugs (blue) can plug these holes but require vigilance and systems awareness of these defects and how they line up to provide broad implementation of countermeasures.

A

Broad implementation of vaildated countermeasures to threats (plug the holes in the system defects A & B)

B

Prioritization of failure modes FMEA- failure modes effects analysis

Surveillance to identify possible threats (these holes line up)

C Development of countermeasures to mitigate threats

A

B

systematically by tightening each layer of defense, one hole at a time. I have adapted active error management as described by Reason and others into a set of steps for making incremental systemic improvements to increase safety and reliability. In this adaptation, a cycle of active error management consists of (a) surveillance to identify potential threats; (b) investigation of all contributory factors; (c) prioritization of failure modes; (d) development of countermeasures to eliminate or mitigate individual threats; and (e) broad implementation of validated countermeasures (Fig. 1.3). The goal is to move from a reactive approach based on review of actual injuries toward a proactive approach that anticipates threats based on a deep understanding of human capabilities and system design that aids human performance rather than undermines it. A comprehensive review of the science of human factors and patient safety is beyond the scope of this chapter; neurosurgical patient safety has been reviewed, including ethical issues and the impact of legal liability.31 Safety in aviation and nuclear power has taken over four decades to achieve the cultural shift that supports a robust system of countermeasures and defenses against human error. However, it is practical to use an example to illustrate some of the human factors principles introduced. Consider this case example as a window into the future of managing the most common preventable adverse events associated with surgery. 

Illustrating Systems Improvement Over Time: Wrong-­Sided Brain Surgery Wrong-­site surgery is an example of an adverse event that seems as though it should “never happen.” However, there are more than 40 million surgical procedures annually, making this a potential area for improvement and systems improvement. The news media has diligently reported wrong-­site surgical errors, especially when they involve neurosurgery. Headlines such as “Brain Surgery Was Done on the Wrong Side, Reports Say” (New York Daily News, 2001) and “Doctor Who Operated on the Wrong Side of Brain Under Scrutiny” (New York Times, 2000) are inevitable when wrong-­site brain surgery occurs.32–34 As predicted, these are not isolated stories. A recent report from the state of Minnesota found 13 instances of wrong-­site surgery in a single year during which time approximately 340,000 surgeries were performed.35 No hospital appeared to be immune to what appears on the surface to be such a blatant mistake. Despite

the debut of the Universal Protocol at all JAHCO certified hospitals since 2004, the issue of wrong-­site surgery remains. From JAHCO data from 2014 through 2017, a total of 407 events with wrong site, wrong patients, or wrong procedures were documented. In a 2007 national survey,36 the incidence of wrong-­sided surgery for cervical discectomies, craniotomies, and lumbar surgery was 6.8, 2.2, and 4.5 per 10,000 operations, respectively. The sensational “front page news” media fails to identify the deeper second story behind these failures and how to prevent future failures through creation of safer systems.37 In this example, we provide an analysis of contributory factors associated with wrong-­site surgery to reveal the myriad of holes in the defensive layers of “cheese.” These holes will need to be eliminated to truly impact the frequency of this already rare event and create more reliable care for our patients. 

Contributory Factor Analysis PATIENT FACTORS ASSOCIATED WITH WRONG-­SITE SURGERY Patient Condition (Medical Factors That If Not Known Increase the Risk for Complications) Neurosurgical patients are at higher risk for wrong patient surgery than average patients and their surgical conditions contribute to error. When patients are asked what surgery they are having done on the morning of surgery, only 70% can correctly state and point to the location of the planned surgical intervention.38 Patients are a further source of misinformation of surgical intent when the pathology and symptoms are contralateral to the site of surgery, a common condition in neurosurgical cases. Patients scheduled for brain surgery and carotid surgery often confuse the side of the surgery with the side of the symptoms. Patients with educational or language barriers or cognitive deficits are more vulnerable, since they are unable to accurately communicate their surgical condition or the planned surgery. Certain operations in the neurosurgical population pose higher risk for wrong-­site surgery. While left-­right symmetry and sidedness represents one high-­risk class of surgeries, spinal procedures in which there are multiple levels is another.39 Also full disclosure before surgery to the patient about the potential need to operate or shift to the other side or extend surgery should be discussed up front in the consent phase and documented before the patient is under anesthesia.

1  •  Ensuring Patient Safety in Surgery: First Do No Harm and Applying a Systems-Engineering Approach

Patients with anatomy and pathology that disorient the surgical team to side or level are especially at risk. Anterior cervical discectomies can be approached by surgeons from either side. This lack of a consistent cue for the rest of the surgical team as to the approach for the same surgery makes it unlikely anyone would trap an error in positioning or draping. It is known that patient position and opaque draping can remove external cues as to left and right orientation of the patient and thus predispose surgeons to wrong-­sided surgery. When a patient is lateral, fully draped, and the table rotated 180 degrees prior to the attending surgeon entering the operating theater, it is difficult to verify right from left. Furthermore, the language for positioning creates ambiguity, since the terminology of left lateral decubitus, right side up, and left side down are used interchangeably by the surgical team to specify the position. A patient with bilateral disease, predominant right-­sided symptoms, and left-­sided pathology having a left-­sided craniotomy in the right lateral decubitus position with the table turned 180 degrees and fully draped obviously creates more confusion than a gallbladder surgery in the supine position. 

Communication (Factors That Undermine the Patient’s Ability to Be a Source of Information Regarding Conditions That Increase the Risk for Complications and Need to Be Managed) Obviously, patients with language barriers or cognitive deficits represent a group that may be unable to communicate their understanding of the surgical plan. This can increase the chance of patient identification errors that lead to wrong-­site surgery. In a busy practice, patients requiring the same surgery might be scheduled in the same OR. It is not uncommon to perform five carotid endarterectomies in a single day.40 When one patient is delayed and the order switched to keep the OR moving, this vulnerability is expressed. Patients with common names are especially at risk. A 500-­bed hospital will have approximately 1,000,000 patients in the medical record system. About 10% of patients will have the same first and last names. Five percent will have a first, middle, and last name in common with one other individual. Only by cross-­checking the name with one other patient identifier (either birth date or a medical record number) can wrong patient errors be trapped.41 Another patient communication problem that increases risk for wrong-­ site surgery consists of patients marking themselves. Marking the skin on the side of the proposed surgery with a pen is now common practice by the surgical team and part of the Universal Protocol. However, some patients have placed an X on the site not to be operated on. The surgical team has then confused this patient mark with their own in which an X specifies the side to be operated on. Patients are often not given information of what to expect and will seek outside information. For example, a neurosurgeon on a popular daytime talk show discussing medical mistakes stated incorrectly that patients should mark themselves with an X on the side that should not be operated on.42 This error in information reached millions of viewers, and was in direct violation of recommendations for marking provided by the Joint Commission on Accreditation of Healthcare Organizations (and endorsed by the American College of Surgeons, American Society of Anesthesiology,

5

and Association of Operating Room Nurses). Patients who watched this show and took the advice of the physician are now at higher risk than average for a wrong-­sided surgical error. 

Availability and Accuracy of Test Results (Factors That Undermine Awareness of Conditions That Increase the Risk for Complications and Need to Be Managed) Radiologic imaging studies can be independent markers of surgical pathology and anatomy. However, films and/or reports are not always available. Films may be lost or misplaced. Also, they may be unavailable because they were performed at another facility. New digital technology has created electronic imaging systems that virtually eliminate lost studies. However, space constraints have led many hospitals to remove old view boxes to make room for digital radiologic monitors. While less of an issue due to widespread adoption of electronic viewing systems, for patients who bring films from an outside hospital, this decision to eliminate view boxes prevents effective use of the studies. Even when available and in digital form, x-­rays and diagnostic studies are not correctly labeled with 100% reliability. Imaging studies have been mislabeled and/or oriented backward, leading to wrong-­sided surgery.43 

TASK FACTORS ASSOCIATED WITH WRONG-­SITE SURGERY Tasks are the steps that need to be executed to accomplish a work goal. It is especially important to structure tasks and task execution procedures when work domains are complex, the task must be executed under time pressure, and the consequences of errors in task execution are severe. Typical tools for structuring task execution are protocols, checklists, and algorithms. A high workload and intensity (i.e., being “on-­call” with emergency cases can be distracting and trying to do elective high-­complexity cases) are also factors being looked at in systems engineering. Sleep deprivation also is another factor inherent to medicine, surgery, and even hospitalized patients themselves.

Task Design and Clarity of Structure (Consider This to Be an Issue When Work Is Being Performed in a Manner That Is Inefficient and Not Well Thought Out) In large hospitals, ORs do not execute a consistent set of checks and balances to verify that the right patient, the surgical intent, and critical equipment and implants are present. If surgical team members think that they can announce the patient name and procedure aloud and that this will reliably prevent wrong-­ site surgery, they are mistaken. Structuring tasks for reliability such that current failure rates will be moved from approximately 1 in 30,000 to 1 in 1 million will take the kind of task structure and consistency seen on the flight decks of commercial planes. For decades, pilots have used well-­organized preflight checklists to perform the tasks to start up an engine and verify that all mission-­critical equipment is present and functional. An example of a mature use of checklists exists in anesthesiology. An anesthesia machine (and other critical equipment) must be present and functional prior to the induction of anesthesia and initiation of paralysis so that a patient can have an airway as well as breathing and circulatory support

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1  •  Ensuring Patient Safety in Surgery: First Do No Harm and Applying a Systems-Engineering Approach

Vaporizers

Full

Vaporizer caps

Tight

Open vaporizer to be used

Open

Low pressure leak test

No leak × 10 secs

Common gas line

Connected

Vaporizers closed

Vaporizors off

Machine main switch

Main on

Flowmeter O2 ratio protection

Intact

Power up High pressure system Oxygen analyzer calibration Low pressure systems Breathing system Scavenger system Ventilator Standard monitors

Floats

Do not stick

Final set-up

Decrease flows

Minimum flow

Example of electronic preanesthesia checklist used to train anesthesia residents into this standard procedure. Challenge response format used with indexing to allow one to know where they are, what is done, and steps remaining. Video help demonstrates proper execution of the checks.

Task done

Video help

FIGURE 1.4  Example of computerized safety checklist implementation shown in randomized fashion to reduce errors.

provided within seconds to avoid hypoxia and subsequent cardiovascular complications. Until 1990, equipment failures were a significant problem leading to patient injury in anesthesia, even though anesthesia machines and equipment had been standardized and were being used on thousands of patients in a given facility.44 At this time, a preanesthesia checklist was established to structure the verification of mission-­critical components required to provide the anesthetic state and to verify that these components functioned nominally.45 This checklist includes over 40 items and has included redundancy for checking critical components. It has been introduced as a standard operating procedure for the discipline of anesthesia and is now mandated by the US Food and Drug Association (Fig. 1.4).46 

Availability and Use of Protocols: If Standard Protocols Exist, Are They Well Accepted and Are They Being Used Consistently? The first attempts to establish standardized protocols for patient safety began with JCAHO.47 The JCAHO “Sentinel Event” system began monitoring major quality issues in the late 1980s about the same time the original AAOS Sign Your Site program launched. A sentinel event was defined as “an unexpected occurrence involving death or serious physical or psychological injury, or the risk thereof.”47 In addition to the reporting aspect of the program, a quality review is triggered that requires a root cause analysis to try to determine factors contributing to the sentinel event. This has been successfully adapted and studied, and specifically evaluated with respect to neurosurgery, utilizing a voluntary, confidential database with a subsequent aviation-­ derived root cause

analysis in order to identify systemic factors and best practices to prevent future events.1 The Universal Protocol was a logical extension of the Sentinel Events quality improvement program. Wrong-­ site surgery is considered a sentinel event. Because of the mandatory reporting of Sentinel Events, some of the best data on the incidence and anatomic location of wrong-­site surgeries come from the JCAHO. Before implementation of the Universal Protocol, the JCAHO analyzed 278 reports of wrong-­site surgery in the Sentinel Events database up to 2003.48 This review showed that in 10% of the cases the wrong procedure had been performed, in 12% surgery had been performed on the wrong patient, and a further 19% of the reports characterized miscellaneous wrong. Thus it was felt that a protocol to address this issue must include provisions to avoid wrong patient, wrong procedure, as well as wrong-­site surgery. In May 2003, the JCAHO convened a “Wrong-­Site Surgery Summit” to look into possible quality initiatives (QI) in this area. The three most effective measures identified were patient identification, surgical site marking, and calling a “time out” before skin incision to verify factors such as the initial patient identification, patient allergies, completion of preoperative interventions such as intravenous antibiotics, the procedure to be performed, available medical records, imaging studies, equipment, etc. When correlated to Sentinel Event Data, it was found that only 12% of wrong-­ site surgeries occurred in institutions with 2 of 3 protocols applied.49 More importantly, no incidences of wrong-­sided surgery were detected in institutions with all three measures in place. Therefore these three key processes became the

1  •  Ensuring Patient Safety in Surgery: First Do No Harm and Applying a Systems-Engineering Approach

Core Elements of the Universal Protocol, which is a mandatory quality screen in all JCAHO certified hospitals since July 1, 2004.49 The universal protocol for preventing wrong patient, wrong-­site errors is based on checklist principles, but there is not yet a validated comprehensive checklist that will trap errors in the way aviation checklists do. This is largely due to the lack of consistent execution of the checklists in a challenge-­response format that is identical in procedure and practice throughout a single hospital’s ORs.50,51 This protocol is a first step, but the barriers to effective implementation are extensive at present and hinder improved safety.52,53 Compliance with standardized checklists is paramount to deriving the benefits that may be associated with utilizing the protocols. Another hazard is the lack of clarity for marking surgical sites. Marking the surgical site has been endorsed to improve safety and is a major component of the Universal Protocol. However, as described previously, the mark can be a source of error when placed inappropriately by the patient or any other member of the surgical team. Some specifics regarding the details of what, when, and how to mark are lacking. Do you mark the incision site or the target of the surgery? What constitutes a unique and definitive mark? What shape and color should be used? What type of pen should be used? Does the ink pose any risk for infection or is it washed off during the course of preparation? Who should place the mark? What are the procedures that get marked and which should not? Are there any patients for whom the mark is dangerous? How do you mark for a left liver lobe resection or other procedures like brain surgery in which there is a single organ but still sidedness that is critical? I worked with over 10 surgical specialties to develop specific answers to these questions. Multiple marks and pens were tested. Not all symbols and pens were equally effective. Many inks did not withstand preparation and remain visible in the operative field. We now use specific permanent pens (Carter fine and Sharpie very fine) and a green circle to mark only “sided” procedures. We specified that the target is marked rather than the incision, the mark must be done by the surgeon, and the mark must be placed in a manner in which it is visible during the pre-­incision check after the position, preparation, and drape have been completed. For example, a procedure requiring cystoscopy to inject the right ureteral orifice to treat reflux is now marked on the right thigh so that the green circle mark is a cue to all members of the surgical team and can be seen even when the patient is prepared and draped. Again, we used the mark to specify the target, not the incision or body entry point. In addition, we have had every procedure in our booking system labeled as “mark required” or “mark not required,” because this was not always clear. Even with this level of specificity, we have found marking to be erroneous and inconsistent during our initial implementation. Marking the skin for spine surgery to indicate the level may increase the risk of wrong-­site errors.54 A superior method for “marking” to verify the correct spinal level to be operated upon is to perform an intraoperative radiologic study with a radiopaque marker. We expect that many revisions to this type of safety checklist of measures will be needed before the marking procedure is robust and truly adds safety value. Cross-­checking procedures in aviation were developed and matured over decades to achieve the reliability and consistency now observed.55

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The first two quarter statistics after implementation of the Universal Protocol were encouraging.56 It appeared that reports of wrong-­site surgeries had declined below the rate of approximately 70 cases per year for the previous 2 years. However, after a full year’s statistics had been accumulated, it was found that the incidents of wrong-­site surgery had actually increased to about 88 for 2005.12 Overall, wrong-­ site surgery had climbed to the number 2 ranking in frequency of Sentinel Events. Whether these data represent a true increase in the frequency of wrong-­site surgery or are simply explained by better awareness and reporting is unclear at this time. Currently the direction in patient safety is more toward a holistic surgical checklist, including all aspects of a patient visit to the hospital and not only the limited time out before surgery.57 A number of studies have been conducted that evaluated the use of checklists in medicine and their effect in behavior modification.57 To that effect, the WHO surgical checklist was developed.58 The features of the Universal Protocol have been integrated in this checklist with the addition of pre­procedural and postprocedural check points. Results from the implementation of the WHO checklist are encouraging. These initial attempts have been extended to the development of checklists, like the SURPASS checklist,59 that cover the whole surgical pathway from admission to discharge. Implementation of the WHO safety checklist has led to improved communication between surgeons and anesthesiologists and improvements in length of stay, adverse events, and readmissions on neurosurgical services.60 Overall, although it has been shown that aviation-­based team training elicits initially sustainable responses, effects may take years to be part of the surgical culture.61 

PRACTITIONER (HUMAN) FACTORS ASSOCIATED WITH WRONG-­SITE SURGERY Knowledge, Skills, and Rules (Individual Deviation From Standard of Care Due to Lack of Knowledge, Poor Skills, or a Failure to Use Rules Associated With Best Practice) Knowledge deficits are often due to overreliance on memory for information used rarely. Measures that increase availability of referent knowledge when needed would be helpful. Unfortunately, references at the point of care on the day of surgery are not standard or reliable. Three descriptions of the surgery often exist. The operative consent lists the planned surgery in lay language patients should be able to understand. The surgical preoperative note may provide a technical description of the planned surgery but often is incomplete, failing to include such information as the specific reason for surgery, sidedness, target, approach, position, need for implants, and/or special equipment. The booking system will often use a third nomenclature to describe the planned surgery that is administrative and linked to billing codes. The use of three different references for the same surgical procedure creates ambiguity. A “right L3–L4 facetectomy in the prone position” may be listed on the consent form as a “right third lumbar vertebrae joint surgery” and a CPT code “LUMBAR FACETECTOMY 025-­36047.”62 Subtle knowledge deficits are more likely to reach a patient and cause harm when individuals are charged to do work that is at the limits of their competency. The culture

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1  •  Ensuring Patient Safety in Surgery: First Do No Harm and Applying a Systems-Engineering Approach

of medicine does not encourage knowledge calibration, the term used to describe how well individuals know what they know and know what they do not know.63 At our institution, when preoperative nurses were assigned the role of marking patients to identify sidedness, they routinely marked the wrong site or marked in a manner such that the mark was not visible after the position, prep, and drape. These nurses accepted this assigned role because our medical culture encourages guessing and assertiveness. On further review we have found that only the surgeon has knowledge required to specify the surgical plan in detail and to mark patients correctly. Other members of the surgical team often have subtle knowledge deficits regarding surgical anatomy, terminology, and technical requirements such that they are prone to err in marking or positioning patients. Similarly, nurses and anesthesiologists in the presurgical areas are not able to verify or reconcile multiple differing sources of information as to the surgical plan. Instead they often propagate errors and/or enter new misinformation into scheduling systems and patient records. 

ATTENTION AND FACTORS THAT UNDERMINE ATTENTION Task execution is degraded when attention is pulled away from the work being performed. Distraction and noise are significant problems in the operating theater that can dramatically affect performance and vigilance. Because the wall and floor surfaces are designed to be cleaned easily, noise levels in the OR are similar to those on a busy highway.64,65 The pre-­incision interval is a very active time, when the patient is being given anesthesia, being positioned, and being prepared. This may be further exacerbated during extenuating situations such as emergent procedures, which have been shown to decrease compliance with checklists and interestingly in one study, compliance decreased over the period of the study thought partially to be secondary to fatigue in performing repetitive checklists.66 These parallel activities represent competing priorities that conflict with a coordinated effort by the entire surgical team to verify surgical intent. Other distractions in human-­systems engineering are being recognized such as high workload as well as dynamic intensity and complexity that occurs with humans (e.g., being on call and being distracted with calls while simultaneously dealing with OR cases, or a previously stable patient rapidly deteriorates who had been stable in the workload) and sleep deprivation, among others. The analogy here that must be recognized in health care is very complex and dynamic. Physicians are similar to airline pilots, yet physicians don’t fly just “well airplanes” but are asked to fly the ones with major systems issues (e.g., single or bilateral engine failure in an emergency setting yet asked to land the plane safely routinely, which mathematically may be impossible). Thus the chance of success is not the same in well-­checked airplanes before they take off as those midflight with sudden, expected emergencies which are much more common in medicine and surgery. This fundamental issue is key, since outcomes in sick patients who are crashing and physicians are asked last minute to “save” are going to be different than elective “well” planned and nonemergent cases. The combination of managing “sick/crashing” patients with simultaneous well/ elective planned out surgeries or patients must be accounted for as well.

Strategy (Given Many Alternatives, Was the Strategy Optimized to Minimize Risks Through Preventive Measures and Through Recovery Measures That Use Contingency Planning and Anticipatory Behaviors?) Strategic planning is not a major contributory factor for wrong-­site surgery in most cases as described above. However, we have found that our initial attempts to use the exact same pre-­incision checklist for all types of surgical populations was a strategic error and overly simplistic. Given the diversity of neurosurgical cases, subspecialty-­specific checklists have been developed with a goal of decreasing procedural errors and diminishing complications. For example, deep brain stimulation procedures reliant on the coordination of multiple sequential steps have built-­in redundancies in order to achieve optimal therapeutic efficacy. Errors during the procedure may result in suboptimal targeting, consequently limiting therapeutic benefit, prolonging procedure times, and increasing cost. As a result, a DBS-­specific checklist was employed in order to decrease errors and improve DBS outcomes.67 Specific checklists for neurointerventional procedures have been developed as well, with data demonstrating improved communication and decreased adverse events after implementing a three-­part, 20-­item checklist specific for neurointerventional procedures.68 The utility of these checklists may be further extended to specific events such as open intraoperative aneurysmal ruptures or perforation during endovascular treatment, and basic neurosurgical procedures such as external ventricular drain placement in order to reduce complications such as infection rates. 

Motivation/Attitude (Motivational Failures and Poor Attitudes Can Undermine Individual Performance—the Psychology of Motivation Is Complex) Because wrong-­site surgery is a rare event, motivating the operative team to invest significant energy into preventive measures can be challenging. Even though the career risk for performing a wrong-­site surgery is significant, the rarity of this complication predisposes surgeons to deny this complication as a significant problem. Part of the problem is that surgeons do not have an adequate understanding of human vulnerabilities and the potential for error. Many surgeons see wrong-­site surgery as purely a failure in vigilance by an individual surgeon. The motivation to lead a team effort and accept cross-­checking is therefore low. Human error training in surgery is just now beginning to address the decreased performance associated with fatigue, personal stress, production pressure, and so forth. Motivational barriers are not limited to the surgeon. Many nurses and anesthesiologists see wrong-­site surgery as an isolated surgeon failure and believe they should have no responsibility for verifying patient and/ or procedure. Individual training about human error is needed across all members of the operative team to increase motivation to change behavior and use new methods (such as a team-­executed checklist) to prevent wrong-­site surgery. 

Physical/Mental Health (Provider Performance Deviations From Standard “Competencies” Can Be Due to Physical or Mental Illness) Industries that have come to accept the human component as having requirements for optimal man-­machine system performance have thus promoted regular “fit for duty”

1  •  Ensuring Patient Safety in Surgery: First Do No Harm and Applying a Systems-Engineering Approach

examinations.69 In the aviation industry, job screening includes a “color-­blindness” test for air traffic controllers since many of the monitors encode critical information in color.70 Some specific provider health conditions can predispose to wrong-­site surgery. Surgeons and other members of the perioperative team with dyslexia and related neuropsychiatric deficits have particular difficulty with sidedness and left-­right orientation. 

TEAM FACTORS ASSOCIATED WITH WRONG-­SITE SURGERY A complex work domain will overwhelm the cognitive abilities of any one individual and not permit expertise of the entire field of practice. A common strategy for managing the excess demands that complex systems (like that of human physiology and pathophysiology) place on any individual is to subspecialize. Breaking a big problem into smaller parts that are then more manageable by a group of individuals is rational. However, by “fixing” the problem of individual cognitive work overload, a new class of problems manifests—those due to team communication and coordination failure. Many human factors experts consider team failures to be the most common contributory factor associated with error in complex sociotechnical work systems.71 Crisis resource management training and team training in aviation is considered to have played a major role in improving aviation safety.72 These methods are just now being applied in medicine.73 Furthermore, compliance with any checklist or protocol requires that all members of the team participate in the manner needed in order to deploy the checklist successfully. One of the most significant barriers to implementation of a checklist was due to resistance or noncompliance from an individual member of the OR team, undermining not only the function of the checklist but also overall team performance and communication.74

Verbal/Written Communication (Any Communication Mode That When It Fails Leads to a Degradation in Team Performance) Verbal communications fail due to noise (just do not hear) or content comprehension (mismatch between what was intended and what was understood). Noise should be minimized to support verbal communication in the OR. Comprehension problems have many mechanisms. Human-­ to-­human communication requires “grounding,” which is the process whereby both parties frame the communication episode based on how the one conveying a message discovers the frame of reference of the one receiving the message. This activity represents a significant part of effective communication. Agreeing on a common language and structuring communication goes a long way toward increasing accuracy and speed of communication of mission-­critical information.17,18,75 While isolated examples of structured communication across members of the operative team exist, it is usually confined to individuals knowledgeable in safety science and the use of structured communication in the military and in aviation. Awareness of the level of communication between team members is also critical. A prospective study evaluating the changes in safety climate and teamwork in the implementation of a revised WHO checklist found profound disagreement in the effectiveness of communication, with doctors often rating their communication as

9

“good” when it was rated to the contrary by the nursing staff.76 

Supervision/Seeking Help (Any Member of the Team Who Fails to Mobilize Help When Getting Into a Work Overload Situation, or a Team Member in a Supervisory Role Failing to Provide Adequate Oversight, Especially in Settings in Which There Are Learners and/or Transient Rotating Team Members) True team performance is only realized when a group of individuals share a common goal, divide work tasks between individuals to create role delineation and role clarity within the team, and know each other’s roles well enough to provide cross-­checks of mission-­critical activities.77 On medical teams, data gathering and treatment implementation tend to be nursing roles, and diagnostic decision ­making and treatment selection tend to be physician roles.78 A myriad of supporting clinicians and nonclinicians are vital in medical teams. The nurse, nurse practitioner, medical student, physicians, and others must be able to detect problem states or deviations from the “expected course” and activate control measures. When a practitioner fails to work within his or her competencies or is on the learning curve for his or her role on the team, failure to get or provide supervision comes into play. For wrong-­site surgery errors, this issue manifests when one surgeon does the preoperative consultation and operative planning and the other starts the surgery with incomplete knowledge. For example, a resident or fellow may fail to call an attending physician to seek clarification of the operative plan. 

Team Structure and Leadership (Teams That Do Not Have Structure, Role Delineation, and Clarity, and Methods for Flattening Hierarchy While Resolving Conflict Will Have Suboptimal Team Performance) Teams will inevitably have to face ambiguous situations that need immediate action. Authority gradients prevent junior members of the team from questioning the decision making and action planning of the leader (a nurse might be hesitant to tell a senior surgeon that he or she is violating a safety procedure, and/or the surgeon might disregard the nurse).77 Methods for flattening hierarchy will lead to more robust team situational awareness and support cross-­ checking behavior. In contrast, it is essential to have efficient ways of resolving conflict, especially under emergency conditions. Some surgeons view the Universal Protocol as a ridiculous requirement forced upon them by regulatory bodies responding to liability pressure. This can create a void in leadership regarding team behaviors that would otherwise help to trap errors that predispose to wrong-­site surgery. 

WORKING CONDITIONS ASSOCIATED WITH WRONG-­SITE SURGERY Individuals and teams cannot perform optimally when they have inadequate resources to manage the work at hand. Typically, workers have little control over the conditions in which they are required to work. Managers make decisions that ultimately aid or constrain practitioners in terms of ratios of patients per provider, the physical space available, and the tools and/or technology available to front-­line

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1  •  Ensuring Patient Safety in Surgery: First Do No Harm and Applying a Systems-Engineering Approach

workers. However, if room design and other factors are identified, they can be redesigned to enhance patient-­system flow.79

Staffing Levels, Skills Mix, and Workload (Managers Facing Financial Pressures, a Nursing Shortage, and Increasing Patient Acuity Can Choose to Institute Hiring Freezes and Reduce Staffing Ratios to Decrease the Costs Associated With Care) While institutions and providers that have high surgical case volumes have been noted to have the best surgical outcomes, medical mishaps occur even in these institutions. Providing exceptional care to a few patients is easier than providing reliable care to everyone.80 Indeed, excessive production pressure and patient volumes are associated with safety violations due to cutting corners when productivity goals are unrealistic. Over two-thirds of wrong-­site surgeries occurred in ambulatory surgery settings in which patient acuity is the lowest but productivity pressures are high.81 Financial constraints have forced more ORs to be staffed by temporary traveling position nurses, have resulted in nursing orientations that have been reduced, and have increased production pressure on surgeons to increase their utilization of OR time. Unfortunately, such aggressive measures to utilize all the capacity of the OR resources conflicts with the need for some reserve capacity to manage the inherent uncertainty and variability associated with medical disease and surgical care. As a result, emergency situations can easily overwhelm care systems that lack reserve resources. Providers calling in sick during flu season and/or a flurry of surgical emergencies can create dangerous conditions for elective surgery due to the need to redirect those resources that might otherwise be available. 

Availability and Maintenance of Equipment (Technology and Tools Vary in Their Safety Features and Usability: Equipment Must Be Maintained or It Can Become a Liability) For preventing wrong-­site surgery, we have found that the specific marking pen we are utilizing needs to be stocked and available throughout the hospital to allow surgeons to perform the safety practice we have required. Surgeons unable to find a green marker will use alternative pens, resulting in a variation in practice that degrades the value of the safety measure. Other aspects of our wrong-­site surgery safeguards have proved difficult to maintain. A computerized scheduling system had triggers to cue the operative team as to the marking protocol and special equipment needs. When a new procedure was added to the scheduling system, the programmers overlooked the “needs to be marked” trigger, and for a period of time these patients were not marked. The operative team had been using technology designed to support their work, but that technology was not maintained. The best team of practitioners can perform even better when provided state-­of-­the-­art working conditions. For example, patient identification technology that utilizes bar coding and radiofrequency identification tags will virtually eliminate wrong-­patient errors.82 Although this technology is currently available, few organizations have been able to afford it. 

Administrative and Managerial Support (In Complex Work Settings, Domain Experts That Perform the Work Need to Be Supported by Personnel Who Are Charged With Managing Resources, Scheduling, Transcription, Billing, etc.) Clinical information systems (e.g., an OR scheduling system) are not reliable or robust at confirming operative intent early in the process or planning for surgery.52 Busy surgical clinics often do not have efficient and reliable mechanisms for providing a scheduling secretary with the information they need or for verifying that booking information is accurate. Secretaries may be using a form that is illegible or may simply be working from a verbal description of the planned surgery. Because these support personnel may not understand the terminology, errors are common. In addition, busy surgeons may forget that other information, such as the operative position required, the need for surgical implants, or the requirement for special equipment, is not obvious, and thus fail to be explicit. In addition, this work and the expertise required are often undervalued. The result can be to hire inexperienced secretaries and accept high support staff turnover. 

ORGANIZATIONAL FACTORS ASSOCIATED WITH WRONG-­SITE SURGERY Organizations must make safety a priority. If production pressure and economic goals are in conflict with safety, organizations must have structure and methods for ensuring safety as the priority.83 Independent offices of patient safety and patient safety officers with the authority to stop operations when necessary are examples of organizational structures designed to maintain safety in the face of economic pressure.

Financial Resources (Safety Is Not Free; the Costs Associated with Establishing Safe Practices and Acquiring Safety Technology May Be Prohibitive) Many organizations have implemented the Universal Protocol but have done so in an incomplete manner, doing the minimum to pass a regulatory review. Given the rarity of wrong-­ site surgery, the cost of preventing each instance would appear significant (although good safety habits or practice can or should be generalizable). The financial impact of correcting computer system flaws, improving secretarial support, and slowing down throughput to perform safety checks is unknown. Costs are a significant barrier to implementing safeguards robustly. Creativity, however, can be key to making lower-­cost systems that are safe. Checklists were designed to be one universally inexpensive way to improve safety and quality. 

Goals and Policy Standards (Practice of Front-­line Workers Is Shaped by Clear Goals and Consistent Policies That Are Clinically Relevant) Policies and procedures regarding prevention of wrong-­ site surgery are difficult to develop. Legal liability tends to constrain medical policy makers to be purposely vague. Explicit procedures that are standardized would be helpful. Unfortunately, newly developed procedures may be recommended as policy prior to proper testing and validation for

1  •  Ensuring Patient Safety in Surgery: First Do No Harm and Applying a Systems-Engineering Approach

Sided, multiples, internal, position, special equipment

Procedures NOT defined for Motivation verification, low, nurses marking, and final marking check

True team behaviors lacking

11

Safety Production programs weak pressure high

Wrong patient, procedure, or site 1 per 30,000 that will suffer event

Providers’ Team Working Org. priority Sociopolitical Patients with Patients and Structured procedures approach or knowledge, cross-checking conditions, of safety procedure process skills, multiple cues staffing, at risk done attention, workload motivation FIGURE 1.5  This graphic summarizes the major vulnerabilities identified as contributory toward wrong site surgical error.

effectiveness. For example, the Universal Protocol has not been fully validated and yet this protocol has been mandated. 

Safety Culture and Priorities (A Safety Culture of an Organization May Be Pathologic, Reactive, Proactive, or Generative) Most hospitals today are reactive in their culture of safety.27 The result is that those institutions that have had the most public wrong-­site surgeries have done the most to establish safety countermeasures to prevent future wrong-­site surgery. Proactive action to invest in creating safeguards is beyond the capability or commitment of most health care organizations in a continued challenging economic environment. 

SOCIOPOLITICAL FACTORS ASSOCIATED WITH WRONG-­ SITE SURGERY Economic, Regulatory Issues, Health Policy, and Politics We practice medicine within large national health care systems. Currently, third-­party payers wish for safety to be a priority. However, organizations that invest in safety technologies to avert error do not typically get a return on that investment. In fact, hospital investment to prevent iatrogenic injury directly benefits third-­party payers, not the hospital. Similarly, our legal system does not serve as a strong incentive for safety because jury verdicts do not accurately identify and punish negligent care. Rather, patients with negative outcomes that were not preventable still win jury verdicts, while patients that truly suffered a preventable adverse event commonly fail to seek legally allowed compensation.84 Systems-­based improvement or QI do remain exempt from legal discovery for medical/surgical teams to continuously improve process and one we believe should remain protected. 

Summary of Contributory Factor Analysis This example of wrong-­site surgery was used to illustrate the multiple contributory factors that allow error to propagate

and evolve into an injury causing accident. Even with an error as blatant as wrong-­brain surgery, one can identify multiple vulnerabilities in the multiple layers of our complex medical care systems (Fig. 1.5). While hindsite bias tempts one to blame the individuals involved as the sole causative factor, it is clear that the individuals are part of a complex system with multiple latent conditions (hazards and “accidents waiting to happen”). High-reliability organizations as outlined by Reason are notable for their dedication to systematically identify all hazards and then counter each one. These organizations understand that failure is multidimensional and so is maximizing safety. While the above outlines an approach to risk factor identification, there are quality and safety models used to mitigate or eliminate these risks. For example, failure mode effects analysis (FMEA) is one method the military has used that some medical centers use to mitigate systems-­ level issues by assigning the frequency of the procedure, the severity of injury and mitigation/defensibility to prioritize resources, as well as Design Measure Analyze Improve Control (DMAIC).85,86 FMEA is simple to use, assigning a risk priority number (RPN) to prioritize threat levels to assign resources to “defense.” RPN is a multiped score of three variables (S × O × D), where S = severity of the outcome (1 = none, 5 fatal), O = outcome likelihood, 1 = rare, 5 = common, and D = defensibility, 1 = easily detected/defensed, 5 = failure to defense). Ishikawa (“fishbone”) diagrams can be used to help identify the defects in the defenses that lead to a particular outcome similar to root cause analysis (Fig. 1.6). Finally, “DMAIC” is a common quality improvement method in Lean Six Sigma methodology used to reduce errors and improve efficiency and productivity (Fig. 1.7). 

Perspective The plethora of factors associated with breaches in patient safety underline the complexity of this phenomenon and the protean solutions required to address it. This need is now more imperative than ever, especially in the face of the adoption by the Centers for Medicare and Medicaid Services

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1  •  Ensuring Patient Safety in Surgery: First Do No Harm and Applying a Systems-Engineering Approach

Ishikawa diagram Initial event FIGURE 1.6  Ishikawa (Fishbone) diagram of factors that input into a final outcome. Each part of the fishbone is a relevant factor contributing or attempting to mitigate an eventual outcome. This type of diagram can be used at M&M/ quality initiative (QI) meetings to visualize a sequence of events and consider application of failure mode effects analysis/ risk priority number score allocation to build a systems design to increase health system defenses or improve quality for some outcomes similar to engineering flow models. OR, Operating room.

Dynamic factors

Other factor

Diagnostic test

Factor/timepoint #3 Systems factors 1st

attempt for surgical planning or visit

Define

Control

Medical therapy #1 stabilize Stabilization #2

Factor or timepoint #2

Measure

Outcome X

OR team activation Plan OR for OR checklists

Consent Decision making

did not previously exist. Thus, the goal is to trade in the old problems for new ones that are more bearable. The future is hopeful as new safety sciences support medicine’s quest to “first do no harm.” KEY REFERENCES

Intervene

Analyze

FIGURE 1.7  Design Measure Analyze Improve Control Six Sigma methodology. D = definition of the quality or safety problem to address, M = measurement of the problem, A = analysis of the model at baseline and cycles after attempts after improvement, I = intervention made in the model to reduce errors.

(CMS) of a non-­reimbursement policy for certain “never events.”87 This initiative has been powered by the trend to motivate hospitals to improve patient safety by implementing standardized protocols. These newly defined “never events” limit the ability of the hospitals to bill Medicare for adverse events and complications. The non-­reimbursable conditions apply only to those events deemed “reasonably preventable” through the use of evidence-­based guidelines. The need to address this problem effectively and to verify the solution through double-­blind placebo controlled randomized trials is therefore imperative. 

Summary Reducing iatrogenic injury has become a priority in health care. The scientific disciplines that have advanced safety in other high-­hazard industries such as aviation and nuclear power are just beginning to be used to help advance safety in health care. The causes of iatrogenic injury are complex, as are robust solutions. Success in other industries has been achieved through the use of a global strategy based on small incremental changes to identify threats and then systematically counter each one. Aviation started using this approach over 40 years ago. This strategy appears viable in health care but requires a long-­term commitment. In addition, the battle to improve reliability and safety will be ongoing. Eliminating one set of vulnerabilities always reveals new ones that

Intervening history, events, factors that lead to ultimate outcome “X”

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Leape LL, Rennan Ta, Laird N, et al. The nature of adverse events in hospitalized patients. Results of the Harvard Medical Practice Study II. N Engl J Med. 1991;324:377–384. Lembitz A, Clarke TJ. Clarifying “never events” and introducing ­“always events”. Patient Saf Surg. 2009;3(1):26. [Epub ahead of print]. Makary MA, Mukherjee A, Sexton JB, et al. Operating room briefings and wrong-­site surgery. J Am Coll Surg. 2007;204(2):236–243. National Patient Safety Foundation. The NPSF is an independent, nonprofit research and education organization. http://www.npsf .org/html/research/rfp.html. Sax HC, Browne P, Mayewski RJ, et al. Can aviation-­based team training elicit sustainable behavioral change? Arch Surg. 2009;144(12):­ 1133–1137.

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Smith CM. Origin and uses of primum non nocere—above all, do no harm!. J Clin Pharmacol. 2005;45:371–377. Vincent N, et al. Patient safety: understanding and responding to ­adverse events. N Engl J Med. 2003;348(11):1051–1056. Wong DA. The Universal Protocol: a one year update. AAOS Bulletin. Am Acad Orthoped Surg. 2005;53:20. Wong DA, Watters 3rd WC. To err is human: quality and safety issues in spine care. Spine (Phila Pa 1976). 2007;32(suppl 11):S2–8. Wilson I, Walker I. The WHO surgical safety checklist: the evidence. J Perioper Pract. 2009;19(10):362–364. Numbered references appear on Expert Consult.

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1. Smith CM. Origin and uses of primum non nocere—above all, do no harm!. J Clin Pharmacol. 2005;45:371–377. 2. Cushing H. The establishment of cerebral hernia as a decompressive measure for inaccessible brain tumors; with the description of intra-­muscular methods of making the bone defect in temporal and occipi-­tal regions. Surg Gynecol Obstet. 1905;1:297–314. 3. Pinkus RL. Mistakes as a social construct: an historical approach. Kennedy Inst Ethics J. 2001;11:117–133. 4. Bliss M, Osler W. A Life in Medicine. Toronto: University of Toronto Press; 1999. 5. Report of the Committee Appointed by the Royal Medical and Surgical Society to Inquire into the Uses and Physiological, Therapeutical and Toxical Effects of Chloroform. London: JR Adlarto; 1864. 6. Brennan TA, Leape LL, Laird NM, et al. Incidence of adverse events and negligence in hospitalized patients—results of the harvard medical practice study I. N Engl J Med. 1991;324(6):370–376. 7. Kohn LT, Corrigan JM, Donaldson MS, eds. To Err Is Human: Building a Safer Health System. Washington, DC: National Academy Press; 2000. 8. Gawande AA, Thomas EJ, Zinner MJ. The incidence and nature of surgical adverse events in Colorado and Utah in 1992. Surgery. 1999;126(1):66–75. 9. Leape LL, Rennan T, Laird N, et al. The nature of adverse events in hospitalized patients. Results of the Harvard Medical Practice Study II. N Engl J Med. 1991;324:377–384. 10. Vincent C, Neale G, Woloshynowych M. Adverse events in British hospitals: preliminary retrospective record review. BMJ. 2001;322:517–519. 11. Wilson RM, Harrison BT, Gibberd RW, Hamilton JD. An analysis of the causes of adverse events from the Quality of Australian Health Care Study. Med J Aust. 1999;170:411–415. 12. Wong DA, Watters 3rd WC. To err is human: quality and safety issues in spine care. Spine (Phila Pa 1976). 2007;32(suppl 11):S2–S8. 13. Pierluissi E, Fischer MA, Campbell AR, Landefeld CS. Discussion of medical errors in morbidity and mortality conferences. J Am Med Assoc. 2003;290(21):2838–2842. 14. Woods DD, Cook RI. Perspectives on human error: hindsight bias and local rationality. In: Durso FT, Nickerson RS, eds. Handbook of Applied Cognition. New York: John Wiley & Sons; 1999. 15. Woods DD, Cook RI. Nine steps to move forward from error. Cognition Technol Work. 2002;4:137–144. 16. Gawande A. Complications: A Surgeon’s Notes on an Imperfect Science. New York: Picador; 2002. 17. Wickens CD, Gordon SE, Liu Y. An Introduction to Human Factors Engineering. Reading, MA: Addison-­Wesley; 1998. 18. Sanders MS, McCormick EJ. Human Factors in Engineering and Design. 7th ed. New York: McGraw-­Hill; 1993. 19. Bogner MS. Human Error in Medicine. Mahwah, NJ: Lawrence Erlbaum; 1994. 20. deLeval MR, Carthey J, Wright DJ, et al. All United Kingdom Pediatric Cardiac Centers. Human factors, and cardiac surgery: a mul-­ticenter study. J Thorac Cardiovasc Surg. 119:661–672. 21. Douchin Y, Gopher D, Olin M, et al. A look into the nature and causes of human errors in the intensive care unit. Crit Care Med. 1995;23:298. 22. Keats AS. Anesthesia mortality in perspective. Anesth Analg. 1990;71:113–119. 23. Cooper JB, Newbower RS, Long CD, McPeek B. Preventable anes-­thetic mishaps: a study of human factors. Anesthesiology. 1978;49:399–406. 24. Leape L, Berwick DM, Bates DW. What practices will most improve safety? J Am Med Assoc. 2002;288:501–507. 25. National Patient Safety Foundation: The NPSF Is an Independent, Nonprofit Research and Education Organization. http://www.npsf .org/html/research/rfp.html. 26. Reason J. Human Error. New York: Cambridge University Press; 1990. 27. Reason J. Managing the Risks of Organizational Accidents. Ashgate; 1997. 28. Vincent C, Taylor-­Adams S, Chapman EJ, et al. How to investigate and analyze clinical incidents: clinical risk unit and association of litigation and risk management protocol. BMJ. 2000;320:777–781. 29. Vincent N, et al. Patient safety: understanding and responding to adverse events. N Engl J Med. 2003;348(11):1051–1056.

30. Law KE, Lowndes BR, Kelley SR, et al. NASA-­task load Index differentiates surgical approach: opportunities for improvement in colon and rectal surgery. Ann Surg. 2018. https://doi.org/10.1097/ SLA.0000000000003173. [Epub ahead of print]. 31. Bernstein M, Hebert PC, Etchells E. Patient safety in neurosurgery: detection of errors, prevention of errors, and disclosure of errors. Neurosurg Q. 2003;13(2):125–137. 32. Brain Surgery Was Done on the Wrong Side, Reports Say. New York Daily News; 2001. 33. Brain Surgeon Cited in Bungled ‘95 Case Faces a New Inquiry. New York Times; 2000. 34. Altman LK. State Issues Scathing Report on Error at Sloan-­Kettering. New York Times; 1995. 35. Report details Minnesota hospital errors. Wall Street J. 2005. 36. Jhawar BS, Mitsis D, Duggal N. Wrong-­sided and wrong-­level neurosurgery: a national survey. J Neurosurg Spine. 2007;7(5):467– 472. 37. Cook RI, Woods DD, Miller C. A Tale of Two Stories: Contrasting Views of Patient Safety. Chicago, IL: National Patient Safety Foundation; 1998. Available at http://www.npsf.org/exec/front.html. 38. Schlosser E. Dartmouth-­Hitchcock Medical Center Wrong Site Surgery Observational Study. Unpublished report; 2004. 39. Joint Commission of Accreditation of Healthcare Organizations. Lessons Learned: Wrong Site Surgery, Sentinel Event, No. 6; 2001. Available at http://www.jcaho.org/edu_ p ub/sealert/sea6.html. 40. Harbaugh R. Developing a neurosurgical carotid endarterectomy practice. Am Assoc Neurol Surg Bull. 1995;4(2). 41. Campion P. Dartmouth-­Hitchcock Medical Center Report on Patient Misidentification Risk. Unpublished report; 2004. 42. Gupta S. Patient Checklist. Outrageous Medical Mistakes—Oprah Winfrey Show; 2003. Available at http://www2.oprah. com/health/y ourbody/health_yourbody_ g upta.jhtml. 43. Warnke JP, Kose A, Schienwind F, Zierski J. Erroneous laterality mark-­ing in CT of head. A case report. Zentralbl Neurochir. 1989;50:190–192. 44. Cooper JB, Newbower RS, Kitz RJ. An analysis of major errors and equipment failures in anesthesia management: considerations for prevention and detection. Anesthesiology. 1984;60:34–42. 45. U.S. Food and Drug Administration. Anesthesia apparatus checkout recommendations. Federal Registry. 1994;59:35373–35374. 46. Blike G, Biddle C. Preanesthesia detection of equipment faults by anesthesia providers at an academic hospital: comparison of standard practice and a new electronic checklist. AANA J (Am Assoc Nurse Anesth). 2000;68:497–505. 47. Joint Commission of Accreditation of Healthcare Organizations. Sentinel Event Statistics; 2003. Available at http://www.jcaho.org/ ac credited+organizations/hospitals/sentinel+events/sentinel+events+ statistics.htm. 48. Joint Commission on the Accreditation of Healthcare Organizations. Sentinel Event Alert. Oakbrook, IL: Joint Commission on the Accreditation of Healthcare Organizations; 2003. 49. Joint Commission on the Accreditation of Healthcare Organizations. Universal Protocol Toolkit. Oakbrook, IL: Joint Commission on the Accreditation of Healthcare Organizations; 2004. 50. Johnston G, Ekert L, Pally E. Surgical site signing and “time out”: issues of compliance or complacence. J Bone Joint Surg Am. 2009;91(11):2577–2580. 51. Makary MA, Mukherjee A, Sexton JB, et al. Operating room briefings and wrong-­site surgery. J Am Coll Surg. 2007;204(2):236–243. 52. Rogers ML, Cook RI, Bower R, et al. Barriers to implementing wrong site surgery guidelines: a cognitive work analysis. IEEE Trans Systems Man Cybernetics. 2004;34(6):757–763. 53.  Agency for Healthcare Research and Quality. Prevention of misiden-­tifications: strategies to avoid wrong-­site surgery. Chapter 43.2, 2003. Available at http://www.ahrq.gov/clinic/ptsafety/chap4 3b.htm. 54. Adverse Health Events in Minnesota Hospitals: First Annual Public Report 2004. Includes Hospital Events Reported July 2003–October 2004. Available at http://www.health.state.mn.us/patientsafe ty/ aereport0105.pdf. 55. Degani A, Wiener EL. Cockpit checklists—concepts, design, and use. Hum Factors. 1993;35:345–359. 56. Wong DA. The Universal Protocol: a one year update. AAOS Bulletin. Am Acad Orthoped Surge. 2005;53:20.

13.e1

13.e2

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57. Nilsson L, Lindberget O, Gupta A, Vegfors M. Implementing a pre-­operative checklist to increase patient safety: a 1-­year follow-­ up of personnel attitudes. Acta Anaesthesiol Scand. 2009. [Epub ahead of print]. 58. Wilson I, Walker I. The WHO surgical safety checklist: the evidence. J Perioper Pract. 2009;19(10):362–364. 59. de Vries EN, Hollmann MW, Smorenburg SM, Gouma DJ, Boermeester MA. Development and validation of the SURgical PAtient safety system (SURPASS) checklist. Qual Saf Health Care. 2009;18(2):121–126. 60. Lepanluoma M, Rahi M, Takala R, Loyttyniemi E, Ikonen TS. Analysis of neurosurgical reoperations: use of a surgical checklist and reduction of infection-­related and preventable complication-­ related reoperations. J Neurosurg. 2015;123(1):145–152. https:// doi.org/10.3171/2014.12.JNS141077 [doi]. 61. Sax HC, Browne P, Mayewski RJ, et al. Can aviation-­ based team training elicit sustainable behavioral change? Arch Surg. 2009;144(12):1133–1137. 62. Current Procedural Terminology CPT ICD9-­CM. AMA Press; 2005. Available at https://catalog.ama-­assn.org/Catalog/cpt/cpt_home.jsp. 63. Cook R, Woods DD, Chapter X, Bogner MS. Human Error in Medicine. Mahwah, NJ: Lawrence Erlbaum; 1994. 64. Shapiro RA, Berland T. Noise in the operating room. N Engl J Med. 1972;287(24):1236–1238. 65. Firth-­Cozens J. Why communication fails in the operating room. Quality Safety Health Care. 2004;13:327. 66. Fargen KM, Velat GJ, Lawson MF, Firment CS, Mocco J, Hoh BL. Enhanced staff communication and reduced near-­ miss errors with a neurointerventional procedural checklist. J Neurointerv Surg. 2013;5(5):497–500. https://doi.org/10.1136/neurintsurg-­ 2012-­010430 [doi]. 67. Russ SJ, Sevdalis N, Moorthy K, et al. A qualitative evaluation of the barriers and facilitators toward implementation of the WHO surgical safety checklist across hospitals in england: lessons from the “surgical checklist implementation project”. Ann Surg. 2015;261(1):81– 91. https://doi.org/10.1097/SLA.0000000000000793 [doi]. 68. Erestam S, Haglind E, Bock D, Andersson AE, Angenete E. Changes in safety climate and teamwork in the operating room after implementation of a revised WHO checklist: a prospective interventional study. Patient Saf Surg. 2017;11:6. eCollection 2017. https://doi.org/10.1186/s13037-­017-­0120-­6 [doi]. 69.  Federal Aviation Administration, Aerospace Medical Certification Division: Pilot medical certification questions and answers, AAM-­ 300. Available at http://www.cami.jccbi.gov/AAM-­ 300/amcdfaq.html. 70. Can corrective lenses effectively improve a color vision deficiency when normal color vision is required? J Occup Environ Med. 1998;40(6):518–519. 71. Helmreich RL, Foushee HC. Why crew resource management? The history and status of human factors training programs in avia-

tion. In: Wiener E, Kanki HR, eds. Cockpit Resource Management. New York: Academic Press; 1993. 72. Helmreich RL, Wilhelm JA. Outcomes of crew resource management training. Int J Aviat Psychol. 1991;1:287–300. 73. Howard SK, Gaba DM, Fish KJ, et al. Anesthesia crisis resource management training: teaching anesthesiologists to handle critical incidents. Aviat Space Environ Med. 1992;63(9):763–770. 74. Russ SJ, Sevdalis N, Moorthy K, et al. A qualitative evaluation of the barriers and facilitators toward implementation of the WHO surgical safety checklist across hospitals in england: lessons from the “surgical checklist implementation project”. Ann Surg. 2015;261(1):81– 91. https://doi.org/10.1097/SLA.0000000000000793 [doi]. 75. Monan B. Readback hearback. Aviation Safety Reporting System Directline, No. 1, March 1991. Available at http://asrs.arc.nasa.gov/ directline_issues/dl1_read.htm. 76. Erestam S, Haglind E, Bock D, et al. Changes in safety climate and teamwork in the operating room after implementation of a revised WHO checklist: a prospective interventional study. Patient Saf Surg. 2017;11:6. eCollection 2017. https://doi.org/10.1186/ s13037-­017-­0120-­6 [doi]. 77. Salas E, Dickinson DL, Converse SA, et al. Toward an understanding of team performance and training. In: Swezey RW, Salas E, eds. Teams: Their Training and Performance. Norwood, NJ: Ablex; 1992. 78. Surgenor SD, Blike GT, Corwin HL. Teamwork and collaboration in critical care: lessons from the cockpit [Editorial]. Crit Care Med. 2003;31:992–993. 79. Freeman WD, Barett KM, Nordan L, et al. Lessons from mayo clinic’s redesign of stroke care. Harv Bus Rev. 2018. Available at https://hbr.org/2018/10/lessons-­from-­mayo-­clinics-­redesign-­of-­ stroke-­care. 80. Berwick DM. Errors today and errors tomorrow. N Engl J Med. 2003;348(25):2570–2572. 81. Joint Commission on Accreditation of Healthcare Organizations. Sentinel Event Alert: Follow-­Up Review of Wrong Site Surgery. No. 24; 2001. 82. VeriChip expands hospital infrastructure: hackensack University Medical Center becomes the second major medical center to adopt the VeriChip system. Delray Beach, FL. Business Wire, March 14, 2005. 83. Cook R, Rasmussen J. “Going solid”: a model of system dynamics and consequences for patient safety. Qual Safety Health Care. 2005 (in press). 84. Studdert DM, Mello MM, Brennan TA. Medical malpractice. N Engl J Med. 2004;350:283–292. 85.  Forrest G. Quick guide to failure mode and effects analysis. ISIXSIGMA. Available at https://www.isixsigma.com/tools-­ templates/fmea/fmea-­quick-­guide/. 86.  Terry K. What is DMAIC? ISIXSIGMA. Available at https://www.isixsigma.com/new-­to-­six-­sigma/dmaic/what-­dmaic/. 87. Lembitz A, Clarke TJ. Clarifying “never events” and introducing “always events”. Patient Saf Surg. 2009;3(1):26. [Epub ahead of print].

CHAPTER 2

Surgical Navigation With Intraoperative Imaging: Special Operating Room Concepts ARYA NABAVI  •  RON KIKINIS

Introduction One of the most challenging developments in neurosurgery encompasses the interdisciplinary effort to integrate microneurosurgery and technology, in particular imaging. Neurosurgical techniques have reached a high level of sophistication. Increasing understanding of neurophysiology as well as neuropathology, precise preoperative imaging, small tailored approaches, and specialized instruments, as well as detailed monitoring techniques have led to improved results, and generated higher standards and demands for safety and outcome. But there were no intraoperative means to confirm the surgeon’s impression, whether the surgical objective was achieved. Postoperative imaging for neurooncologic, neurovascular, and instrumented spine surgery demonstrated the need to obtain intraoperative quality assurance. For high-­grade gliomas, Albert et al. (1994)1 reported that postoperative imaging showed tumor remnants in 77% of patients who were presumed to have undergone gross total resection. In 2006 Stummer et al.2 published a multicenter randomized study, which showed residual tumor in 64% of the control group (patients undergoing standard conventional microsurgical tumor resection). Since the importance of the extent of resection for high-­3 as well as low-­grade gliomas4-­8 has been documented, these findings emphasize the need for objective intraoperative resection control. In neurovascular surgery the routine use of intraoperative angiography has been advocated to avoid undetected residual disease.9,10 In spinal surgery, even with modern navigation techniques in addition to conventional imaging, misplaced screws are found in approximately 5%.11 Thus various surgical groups proceeded to integrate imaging into their procedures. The earliest attempts to image intraoperatively beyond plain x-­ray were made with ultrasound (US) and computed tomography (CT). The immediate impact on surgical procedures was small. The resolution (US and CT) was limited and the integration into the operating room cumbersome (CT). Another avenue opened with the introduction of image-­ guided neuronavigation (IGN) systems.12,13 These systems allowed the transfer of increasingly refined presurgical image information into the operating theater to guide surgical procedures. However, intraoperative changes (“brain shift”) critically limited their application accuracy.14,15 To

14

overcome this limitation the concept of intraoperative imaging resurfaced. With magnetic resonance (MRI) becoming the method of choice for the imaging of the central nervous system, pioneering efforts introduced this modality into surgery.16-­18 These initial experiences with intraoperative MRI (iMRI)19-­21 ignited a rapidly evolving field with interesting diversification. The integration of surgery and imaging technology, especially MRI, demands consideration of safety, as well as procedural and architectural issues. In this chapter, we focus on those imaging technologies that have resulted in modified operating room (OR) designs and changes in the surgical workflow as well as the development it sparked. 

Computer-­Assisted Image-­Guided Neuronavigation The major link between imaging and integration of this information into surgery is provided by navigation systems. Diagnostic computer-­based image analysis and three-­ dimensional (3D) modeling facilitated the spatial definition of complex pathologic processes. The desire to use this information directly in the surgical field to facilitate surgical decision making led to the introduction of IGN systems in the mid-­1980s12,13 and their commercial availability in the early 1990s. These systems provided the surgeon with a tool that allowed the transfer of presurgical image information in an intuitive and interactive fashion into the surgical field. Meanwhile, the technology has proceeded from being a novelty to an established asset for neurosurgical procedures. Questions of application accuracy and integration of instruments were overcome. However, the major shortcoming was the dependence on preoperative image data. Since intraoperative changes (e.g., CSF drainage, tumor resection, sagging of the cortex, swelling of underlying tissue, summarized as “brain shift”) accumulate throughout surgery, preoperative information is progressively invalidated.14,15,22 This has particular impact on glioma surgery. While enabling precise approach, planning, and localization, resection control is generally beyond the capacity of these systems, since they cannot account for intraoperative changes and deformations. Intraoperative imaging resolved this issue directly as

2  •  Surgical Navigation With Intraoperative Imaging: Special Operating Room Concepts

it enabled continued use of these systems with the newly acquired accurate data. Mathematical models investigate a different avenue to compensate for various brain shift patterns. Various algorithms characterize and calculate deformation matrixes.14,15,23 Various “brain shift” patterns were identified. A multimodal approach uses intraoperative “sparse” US data24-­26 to calculate a deformation matrix, which is then used to elastically deform preoperative MRI images. 

Intraoperative Imaging We provide an overview and comprehensive organizational framework for imaging modalities that influence surgical workflow and OR-­suite design.

INTRAOPERATIVE FLUOROSCOPY Operating theaters for stereotactic neurosurgery had built­in biplane x-­ray to eliminate parallax artifacts in imaging of electrode placement. With the specialized scope these ORs remained rare and have largely been replaced by standard fluoroscopy, intraoperative MRI,27,28 and more recently by a fusion of presurgical MRI to intraoperative CT. In instrumented spinal surgery, fluoroscopy is used as an online imaging modality for planning and verifying screw positioning. Combinations with navigation systems have been propagated. Intraoperative angiography has been employed by major vascular centers for quality assurance in aneurysm and AVM surgery.9,10 For both angiography and spinal instrumentation, a major shortcoming was the planar imaging, providing indirect spatial information. While the integration of IGN added this dimension, reservations about accuracy led to reevaluation of CT for spinal instrumentation. The development of 3D rotation fluoroscopy already resulted in an easier way to obtain spatial information. Initial questions as to the spatial accuracy of these systems have been addressed in more contemporary generations. Recently hybrid angiography ORs combining neurointervention and neurosurgery for neurovascular cases have been introduced. 

15

Major indications are circumscribed lesions, such as metastasis, cavernomas, vascular pathologies, and for spinal intradural lesions. With its integration into conventional navigation systems and in combination with iMRI38 the unfamiliarity with this modality might potentially be overcome. Current research providing online 3D reconstruction and functional US in animal experiments holds promise for the evolution of this technology, which can readily be integrated into the surgical workflow. 

INTRAOPERATIVE COMPUTED TOMOGRAPHY Shalit et al. and Lundsford first reported the integration of a stationary CT into the operation room.39,40 The next generation of CTs was mobile, permitting shared application in the OR and ICU. However, image quality and radiation exposure limited the application and further implementation of this modality. Further advances in CT-­and OR-­table technology and integration with navigation systems have led to a reappraisal. Modern CT-­OR (Fig. 2.1) solutions use a rail system to move the CT between a parking position and the patient for scanning41 which provides full access to the patient. In spine surgery, intraoperatively acquired images can be used to update navigation systems and to guide and confirm correct positioning. For neurovascular surgery, intraoperative CT-­angiography has the potential to provide information on obtained occlusion of vascular pathologies, but also with perfusion CT on potential vascular compromise. For the definition of brain tumors—particularly low-­ grade lesions, but also high-­grade gliomas—the intraoperative imaging quality remains less informative. Gross total surgical resection may be documented, but the sensitivity to detect residual tumor, even with the present CT generation, remains inferior to MRI. Furthermore, cumulative radiation exposure limits the number of potential intraoperative scans. Despite these limitations, further developments have arisen such as having two surgical suits served by one CT mounted

INTRAOPERATIVE ULTRASOUND Intraoperative US (IoUS) was one of the first intraoperative imaging modalities in neurosurgery.29 During subsequent generations, image quality improved and miniaturization of the handpieces enhanced applicability. Advantages are the dynamic, surgeon-­driven, online character of the information.30 Particularly in vascular surgery, the flow-­related analysis of duplex sonography provides additional flexibility. Further major developments were the introduction of spatially accurate 3D ultrasound,31 of contrast agents,32 and the integration of US into navigation systems.30,33-­35 In particular the last aspect provided the means for easier interpretation of the images, which generally demands experience. For the last 20 years IoUS has been regarded as the most promising system for online information acquisition in neurosurgery. Still, these systems remain limited in their distribution. Potential reasons may be the unfamiliarity with the technique of ultrasound and its limitations in tissue differentiation,36 differing from the most widely distributed primary diagnostic modality of MRI.37

FIGURE 2.1  Overview of intraoperative computed tomography (iCT) unit. The computed tomography is moved along the patient axis on a rail system. Navigation system in the left corner of the image is mobile. (From Uhl E, Zausinger S, Morhard D, et al. Intraoperative computed tomography with integrated navigation system in a multidisciplinary operating suite. Neurosurgery. 2009;64:231–239, Fig. 1D.)

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2  •  Surgical Navigation With Intraoperative Imaging: Special Operating Room Concepts

on rails,42 equivalent to the “shared resources” design described for MRI below, and scanners with larger aperture. 

INTRAOPERATIVE MAGNETIC RESONANCE IMAGING MRI is the diagnostic method of choice for lesions of the central nervous system. Its imaging capability extends beyond pure anatomic resolution into function (fMRI) and connectivity (DTI), as well as pathophysiologic conditions (spectroscopy, perfusion). Postoperative MRI remains the gold standard for defining the extent of resection in neurooncology1,2 and pituitary lesions.43 The desire to employ MRI to monitor open neurosurgical procedures, as a means of quality assurance, resection control, and complication detection led to the combination of MRI and surgery.17 Presently intraoperative MRI is used primarily for gliomas and pituitary lesions,43-­45 but also for vascular46 and epilepsy surgery.47 In the mid-­ 1990s, two major approaches spearheaded the implementation of intraoperative MRI for neurosurgical procedures. The “twin operating theater”18,20 combined surgery and imaging (low-­field open 0.2 T MR system with a horizontal opening) by using two adjacent rooms. The patient was transferred between surgical and imaging site. Thus conventional operating room equipment can be used without MR safety or compatibility issues. To minimize the time for the transfer, this approach was modified by operating in the vicinity of the MRI, the “fringe-­field.”48,49 The open magnet design (“double doughnut”)16,17,21 aimed at a full integration of surgery and MRI. The vertical opening provided the surgeon with access to the patient. Surgical and imaging site were merged and transfer was unnecessary. For practical reasons, surgery was discontinued during scanning. However, this design held the potential to provide real-­time imaging, during biopsies or through “continuous imaging” protocols.50 Furthermore, a navigation system was an integral part of the MRI. The surgeon could also control the scanning plane of the MRI interactively.51,52 Specially developed software for intraoperative navigation extended the functionality.53,54 This solution is closest to the symbiosis of surgery and imaging. However due to constraints in regard to technical equipment, the 56-­cm gap for the surgeon, and the need for non-­ ferromagnetic instruments, microneurosurgical standards were challenged. Nevertheless, these pioneering clinical experiences proved that the vision55 to bring MRI into the surgical surrounding could be realized. It also became evident that the synthesis of open surgery and MRI into a comprehensive new method was too complex to remain practical on a general basis. While various systems of low-­and mid-­field range persist, the limitations of the prototypes, regarding field strength and thus image quality as well as patient access, led to combinations of surgery and imaging which were, while closely associated, spatially separated. Installations with various MR designs and a wide, increasing range of field strength (0.15 to 3.0 T) are currently in use. A minimized, compact open MRI which fits beneath the surgical table traded increased accessibility for field strength (0.12 T, 0.15 T).56,57

However, the main effort went into integrating higher field MRI (1.5 T and higher) into the surgical workflow. This can be achieved within an integrated OR-­MR design (“dedicated”)19,45,58 or by arranging MR and OR into separate adjacent modules/rooms46,59-­61 (“shared resources”) even serving multiple surgical theaters. Since the original concept was to merge surgery and imaging, it is reasonable to use workflow to distinguish among different installations. However, specific issues for the integration of MRI into the surgical surrounding such as MR safety and compatibility of equipment, field strength, shielding, MR design,52,62,63 and imaging characteristics have to be outlined before discussing various MR-­OR integrations. 

Magnetic Resonance Safety and Compatibility, Shielding The introduction of a magnet into a surgical surrounding raises safety issues pertaining to the interaction of the magnetic field and the OR equipment.52,64-­66,63 The magnet can exert a pull on ferromagnetic instruments. Generally, the strength of the pull is related to field strength (and MR shielding) and distance to the MRI. The so-­called 5-­gauss line demarcates the inner area, in which the pull increases and the outer zone, in which ferromagnetic instruments can be safely used without being drawn into the MRI. In most MR-­ORs, this demarcation is indicated visually. The immediate area around the 5-­gauss line, which is within the magnetic field but still has no significant pull, is called the “fringe” field. Nonferromagnetic instruments and equipment can be used in either area without being drawn into the MR. These are called MR-­safe. However, they may cause image artifacts when left in the imaging field during scanning or cause electrical interference with the imaging. Equipment that is neither magnetic nor interferes with the imaging is called MR-­compatible. Shielding is necessary to prevent the interaction of the magnet with radiofrequency (RF) technology. Normally the entire room is shielded to prevent the magnet’s influence on electrical devices and vice versa. All nonessential electrical equipment can be turned off during scanning, or primarily based outside the shielded room (e.g., the computer for image-­guided navigation). Special anesthesia equipment is used to prevent image artifacts from RF noise. 

Magnetic Resonance Design (“OpenBore” and “Closed-Bore” Systems) and Field Strength The magnetic field of the MRI is generated within its bore. In open-­ bore (i.e., open-­ magnet) systems, the magnet is divided into two poles. The gap, which allows access to the patient, can be oriented either horizontally or vertically (“double doughnut”).64 Diagnostic high-­field scanners have a closed bore/tunnel. With improved MR design, so-­called “short-­bore” systems became available, providing some access to the patient. Thus smaller operations like biopsies or deep brain stimulation

2  •  Surgical Navigation With Intraoperative Imaging: Special Operating Room Concepts

(DBS) electrode placement can be performed within the bore (“in-­bore” procedures). Generally the open-­ magnet design has lower field strength than the “short-­bore” closed systems and necessitates additional room shielding. Higher field strength generally promotes acquisition speed (temporal resolution) as well as quality of the subsequently acquired images (spatial resolution). A wider bandwidth of image sequences is available (e.g., spectroscopy, DTI, fMRI, dynamic scanning).19,67,68 Furthermore, the homogeneity of the magnetic field improves, reducing geometric distortions. Homogeneity becomes a challenge with low-­and mid-­field scanners. Phantom studies performed on the compact 0.12 T system provided acceptable application accuracy.57 However, studies in only slightly stronger magnetic fields (mid-­field 0.5 T, open MR system) proved that significant geometric distortions are present,69 which are machine-­and patient-­induced. These findings have to be considered when using non-­high field MR units (below 1 T) for resection control and updated neuronavigation. 

Imaging Selection Choice of imaging technique depends on the lesion’s imaging characteristics in diagnostic studies. Enhanced and nonenhanced T1WI, T2, and occasionally FLAIR answer most questions.44,45,58,59,67,70 For low-­grade lesions, T2 and FLAIR images are the most appropriate.45,58,59 For enhancing lesions, pre-­and post-­contrast T1 images are acquired. Further sequences may potentially yield additional information,58 such as location of functional centers or fiber tracts.71 The intraoperative MRI is essentially a surgical tool with imaging to support surgical decision making. Thus the surgeon has to define the surgical goal and limitations, that is, extent and limit of resection (complication avoidance). It is essential that the surgeon acquires a good working knowledge of MRI to compile the individual imaging protocol and analyze the images according to surgical objectives.45,46,58,67 Practical challenges in interpreting intraoperative images largely pertain to nonspecific contrast enhancement (“spread enhancement”) and signal changes at the resection border. Contrast enhancement in high-­ grade gliomas merely reflects the local breakdown of the blood-­ brain barrier. When imaging is repeated at given time intervals, subsequent contrast spread into surrounding regions is detectable. While almost inconsequential in diagnostic imaging, acknowledging this phenomenon is of major importance for iMRI, to avoid over-­resection (“following the contrast”). Thus scans for the initial neuronavigation-­assisted resection should be acquired the day before surgery. Occasional practice of contrast-­ enhanced MRI immediately before craniotomy can seriously impede image interpretation. Intraoperative imaging for resection control consists of pre-­ and post-­ contrast T1 images and subtraction to identify residual contrast enhancement. New sequences capturing the dynamic nature of neovascularized areas, in particular dynamic susceptibility contrast-­ weighted perfusion MRI, provide more accurate intraoperative information than conventional contrast-­enhanced T1WI.72 Future development of specific contrast media may lead to a resolution of this problem.73,74

17

T2 and FLAIR are susceptible to local edematous changes, blood adhesions, and oxygen saturation. Careful comparison is needed to detect these changes, which may also lead to erroneous readings. Potential remedy to the problems of “resection-­border” changes may be found in combination with optical imaging methods, discussed below. 

Integration of Intraoperative Navigation and Magnetic Resonance Imaging The shortcomings of image-­guided navigation in detecting intraoperative changes were a major motivation to implement intraoperative imaging. IGN provides the essential link between imaging and surgery.45,75,76 In most MRI installations, navigation systems are ceiling mounted. Initial navigation is performed with preoperative images until the surgeon deems an update necessary to regain accurate navigation. The intraoperative images are sent directly from the scanner console to the navigation system and fused (automated image fusion algorithm) to the already registered preoperative images (Fig. 2.2). With the DRF reattached in its original position, the images can be used for updated navigation without additional re-­referencing. Thus intraoperative updates for neuronavigation can be acquired at the surgeon’s discretion and used for updated navigation. 

Operating Room-­Magnetic Resonance integrations After the initial multitude of arrangements, two major designs persisted: the integration of MRI and surgery in one “dedicated MR-­OR” or the separation of MR and OR in adjacent rooms, as shared resources. 

Dedicated Operating Room-­Magnetic Resonance Environment Dedicated systems integrate MRI and surgery within one OR-­MR environment. 

Dedicated Low-­Field System The 0.15-­T MRI (previous generation 0.12 T) is an open-­ bore system with two poles.56,57,77 The MRI is positioned beneath the patient’s head (Fig. 2.3). On demand the magnet is raised to place the surgical field in the imager. Images are acquired and transmitted to the connected navigation unit for updated navigation. The OR has to be shielded to avoid RF interference, and all other nonessential equipment has to be turned off. Alternatively, the patient and the scanner can be shielded separately.78 The application can be integrated into a conventional OR, provided shielding is implemented and used on demand by raising the poles to imaging level. Despite the application comfort, the low field has limitations regarding homogeneity (spatial resolution and geometric distortions) and field of view (120 to 160 mm vs. 220 mm in high-­field systems). These systems are used for intraoperative imaging in glioma56,57 and pituitary surgery.79,80 

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2  •  Surgical Navigation With Intraoperative Imaging: Special Operating Room Concepts

IntraOp #2 MRI #1 Axial

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IntraOp #2 MRI #2 Axial

FIGURE 2.2  Updated navigation with intraoperative images (screen shot of navigation system display). Images were acquired after tumor (anaplastic astrocytoma) bulk resection for localization of residual tumor. T2 and T1WI intra-­and pre-­operative for comparison. (Intraoperative images taken in MR-OR set-up depicted in Figure 2.4.)

IntraOp #1 MRI #1 Axial

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FIGURE 2.3  Compact low-­field magnetic resonance imaging (0.12 to 15 T). Position before draping. Ceiling-­mounted navigation system. Special headrest with integrated coil and flexible coil positioned for pituitary surgery. (Courtesy of M. Hadani, Sheba Medical Center; Tel Hashomer, Israel.)

Dedicated High-­Field System These installations combine a fully equipped neurosurgical OR with a high-­field scanner, primarily 1.5-­T MR units, into a comprehensive unit.19,45,58 Two main setups provide this dedicated environment.19,45,58 The 5-­gauss border

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FIGURE 2.4  Fully integrated operating room–­magnetic resonance (OR-­MR) (1.5 T) environment at the authors’ institution. Patient is turned away from MR axis by 30 degrees to position the head into the primary surgical area outside the 5-­gauss line. Ceiling-­mounted navigation system. Open procedure for left frontal glioma. (OR-­MR setup in Kiel/Germany.)

represents a demarcation that permits the spatial division of the OR-­MR suite into surgical and imaging site.45,58,65 They are connected by a surgical table, which attaches directly to the scanner. The surgical area is reached by disconnecting the table and rotating it either by 30 degrees19,45 (Fig. 2.4) or

2  •  Surgical Navigation With Intraoperative Imaging: Special Operating Room Concepts

FIGURE 2.5  Depiction of the system with table turned away 160 degrees from magnetic resonance (MR) axis, to position head outside 5-­gauss line (1.5 T MR). Pituitary surgery. (Courtesy Prof. C. Nimsky, OR-­MR setup in Erlangen, Germany.)

160 degrees58 (Fig. 2.5) away from the MR axis, to place the operating field outside the 5-­gauss line. The primary surgical site, which is fully equipped for microneurosurgery, is outside the 5-­gauss line, where ferromagnetic tools and equipment (e.g., microscope, ultrasonic aspirator, bipolar coagulation) can be used unimpeded. For lesions in eloquent areas the authors’ group utilizes the technique of awake craniotomy with cortical stimulation.81 The rigid head fixation has to be fully MR compatible. The material of the pins has no influence on the overall imaging (local artifacts with metal pins). The head fixation can be integrated into the rigid RF coil with restricted degrees of freedom.58 More flexibility for positioning is achieved by a modified carbon-­ fiber, MR-­ compatible Mayfield clamp attached to the table top used with surface coils.45 Imaging can be initiated at every point the surgeon deems feasible. Ferromagnetic material is removed and the surgical field covered with additional sterile drapes. The table is returned into the MR axis, connected, and the patient transferred to the imaging site. In both arrangements,45,58 the interval from stopping the surgery to initial scanning commonly takes about 3 to 5 minutes. The surgeon determines the imaging protocols based on presurgical imaging characteristics. The images are transferred to the navigation system as soon as they are acquired for updated accurate navigation.45,76 The surgical field is redraped on top of the previous draping. If residual tumor is identified, updated neuronavigation allows the precise localization for resection. If no further resection is necessary or deemed feasible, surgery is concluded. Biopsies and burr-­hole procedures in a dedicated, high-­ field MRI can be performed in the primary surgical site outside the 5-­gauss line with standard equipment (conventional stereotactic frames; computer-­guided, navigated free-­hand biopsies; navigated endoscopy).45 However, more sophisticated in-­ bore procedures use the capacity of real-­ time

19

imaging. Burr-­hole and dural opening are performed outside the 5-­gauss line with standard equipment. After an MR-­ compatible burr hole mounted device is attached, the patient is transferred into the MR for scanning. The mounted guide is fixed to preserve the planed trajectory. During the probe’s advance, in-­plane imaging (1 to 3 images/s) provides real-­ time control and final image confirmation of the target point.82 With short-­bore MRs, the needle can be advanced by the surgeon reaching into the bore. However, remote control or robotic devices provide more comfortable reach and can be potentially employed within MRIs with less access.82,83 Current studies discuss in-­bore procedures for DBS28 and interstitial laser therapy. Within the integrated system originally described by Hall et al.19 a secondary surgical site can be used for specific tasks.45,70 When the MRI table is extended beyond the back of the MRI, the patient’s head can be accessed freely for surgery. This area is within the 5-­gauss line, thus necessitating the use of MR-­safe equipment. Ultrasonic aspirator and bipolar coagulation can be used in this site. The transfer to the MRI is much shorter and repeated imaging becomes easier. However, as long as microneurosurgical techniques are hampered, the utility of this area is limited to smaller interventions. Interestingly despite this restrain, the secondary surgical site allowed a major development: the inception of an integrated, dedicated 3-­T system within an operating theater.84,85 This setup is the only one to attempt the combination of intraoperative 3-­T system and surgery. While there are still significant drawbacks, this installation provides the proof of concept that dedicated OR-­MR rooms at and beyond 3t field strength can be realized.84-­86 

Shared Resources and Multimodal Imaging Operating Room Concepts Meanwhile the majority of MRI setups adheres to the “shared resources” design. The separated room concept for surgical and imaging sites was developed to allow the unimpeded usage of surgical tools as well as perfect imaging particularly with increasing field strengths. An additional economic aspect was that while surgery was progressing, the idle MRI could be used for routine imaging—hence, the notion of shared resources. However, this demands special arrangements for connecting surgical and imaging sites. Potentially, the patient can be brought to the MRI or the MRI to the patient. Mobile MRI (Fig. 2.6) was pioneered in Calgary.46 The 1.5-­T unit is mounted on a ceiling rail system, which permits transporting the MRI into the surgical area (overhead crane technology). The specially designed operating table is MR-­ compatible, as patient positioning can be adjusted hydraulically. Furthermore, the RF coils are integrated into the surgical table. The upper detachable portion can be repositioned for imaging. The MRI usually resides in a separate room. On its way in and during scanning, ferromagnetic instruments have to be removed from its path and beyond the 5-­gauss line. If not needed during the procedure, the magnet can be potentially used as a shared resource for conventional scanning or serve adjacent ORs connected by a common rail system.

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2  •  Surgical Navigation With Intraoperative Imaging: Special Operating Room Concepts

Stationary MRIs in separate rooms are presently 3-­T MRI units, where the higher field necessitates more elaborate shielding (Fig. 2.7). The 5-­gauss line extends farther away from the MRI, raising demands on MR-­ safe and compatible equipment and instruments.59,61 The surgical site is a conventional operating theater. The patient is positioned on a surgical OR table with a floating top, which can be docked to the MR system. Either a rail system61 or a wheeled transfer table59 is used. The head-­holder can be either separated from flexible surface coils61 or integrated into the rigid imaging coils.59 In the latter case, a removable sterile top portion is disconnected for surgery and replaced for scanning. The rooms have additional entrances to provide access to the MR while surgery progresses in the adjacent room. Thus during the surgical time, routine diagnostics can be performed. Costs and function can be shared between neurosurgery and radiology. While the economic aspect

is appealing, the concept of obtaining image information on demand for surgical decision making is impeded. If the MR is occupied, the surgical patient has to wait. Presently the transfer distance, as well as the preparations to provide safety, represents an additional delay.61 It becomes cumbersome and thus less likely that repeated intraoperative scans, which disrupt the surgical workflow, are obtained. The separation of imaging and surgery into adjacent rooms establishes the core of a modular design. Subsequently either multiple operating rooms can be arranged around a single imaging unit or multiple imaging modules around a single conventional operating theater. Examples for the latter are the MRXO which mostly addresses vascular and oncologic neurosurgery and the AMIGO which broadens the field to oncologic surgery and percutaneous intervention without specialty restrictions. In the MRXO60 concept (Fig. 2.8), the central OR-­ angiography room is connected to a 1.5-­T MRI and a CT suite. Both suites have separate entrances to admit patients from radiology (MRI) and the emergency room (CT), adherent to the shared-­resources concept. This setup is primarily designed for neurosurgical applications. In the AMIGO (advanced multimodality image guided operative)87 design, the fully equipped surgical room (fluoroscopy, US, navigation system) is flanked by a 3-­T MRI unit and a PET-­CT. With this design, the applicability of the suite is not only as a shared resource regarding simultaneous imaging of other patients during surgery, but also expandable to an interdisciplinary suite serving different specialties. The main objective is to cross-­validate different modalities as used in a wide array of surgical procedures and to determine which imaging modality would be the best for specific indications. Naturally, these multi­modal setups are limited to specialized centers.

INTRAOPERATIVE OPTICAL IMAGING FIGURE 2.6  Ceiling-­mounted, mobile magnetic resonance imaging (MRI) (1.5 T) in Calgary. Overhead crane technology permits the transfer of the MRI to the surgical site. (From Kaibara T, Saunders JK, Sutherland GR. Advances in mobile intraoperative magnetic resonance imaging. Neurosurgery. 2000;47:131–138, Fig. 4.)

Alternative methods for intraoperative information gathering had been investigated previously. However, the success of intraoperative MRI intensified the initiative to provide less elaborate, inexpensive, and intraoperative imaging methods, which are more closely integrated into the surgical

Control room

OR-hall

MRI waiting room 0.5G 1G ioMRI-OR FIGURE 2.7  Example of shared-­resources layout. MRI, Magnetic resonance imaging; OR, operating room. (From Pamir MN, Ozduman K, Dincer A, et al. First intraoperative, shared-­resource, ultrahigh-­field 3-­tesla magnetic resonance imaging system and its application in low-­grade glioma resection. J Neurosurg. 2010;112:57–69, Fig. 1.)

Gantry

2  •  Surgical Navigation With Intraoperative Imaging: Special Operating Room Concepts

Technical room

Storage

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Shaft

Operation light ER

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CT Angio OP

workflow. The most prominent and immediately intuitive method for neurosurgeons is the implementation of technology into the operating microscope. Optical imaging88 uses the multispectral properties of light to detect differences in tissue properties. Generally different wavelengths elicit effects, based on the absorption and reflection of energy. Different detectors or filters can be used to differentiate tissue regarding biological and structural characteristics. The most prominent and thoroughly studied modality is fluorescence-­guided surgery employing protoporphyrin IX, a metabolite of 5ALA. This method has been shown to facilitate more complete resection of primary glioblastomas2,89 and in a phase II study for recurrent lesions90 as well. However, the principle of adding fluorophores is applicable in a multitude of ways. Presently a major shortcoming is the more or less pronounced non-­selectivity, which can lead to different interpretations between fluorophores,91 but also for the same fluorophore over time (diffusion into surrounding). Optical coherence tomography,92 widely used in ophthalmic surgery, has a very high resolution up to a depth of about 10 to 15 mm. This permits the distinction of structural abnormalities, that is, infiltration zones. Technical advances have made this modality much faster, and potentially applicable in surgery. The present limitations of this plethora of methods is the need to adapt the microscope, the non-­specific nature of most labeling fluorophores, as well as the size of effectors/cameras and detectors. Developments will have to be directed toward digital microscopes that detect and record the entire spectral bandwidth, which then can be analyzed to display specific wavelength information at the discretion of the surgeon. Nanotechnology may yield composite fluorophores, which by their combination yield more detailed and specific information. Miniaturization of detectors and their robotic handling92 can overcome the time constraints presently encountered by systems for OCT and spectroscopy. Optical imaging93 has enormous potential. However, to employ the information correctly an in-­depth knowledge of the technology and the potential limitations is crucial. 

ROBOTS AND INTRAOPERATIVE IMAGING Medical robotics is a swiftly expanding field, which justifies a more extensive discussion. While a definition of “a robot”

FIGURE 2.8  Multimodality imaging operating room (OR) layout for the modular expansion of shared-­ resources twin-­OR. Due to the modular design, various modalities can be used. CT, Computed tomography; MRI, magnetic resonance imaging. (From Matsumae M, Koizumi J, Fukuyama H, et al. World’s first magnetic resonance imaging/x-­ray/ operating room suite: a significant milestone in the improvement of neurosurgical diagnosis and treatment. J Neurosurg. 2007;107:266–273, Fig. 1.)

is beyond this chapter, two aspects are addressed. The integration into the imaging surrounding and surgeon-­robot interaction. There are two major ways robots can be integrated with imaging and surgery in specialized OR settings: as support for the imaging or as adjunct to surgery. Modern imaging systems in vascular and spine surgery, using cone beam technology, are mounted on robotic arms,94 which provide higher flexibility while conserving accuracy. For surgical applications, the interaction of robot and surgeon are the distinguishing characteristic. The two ends of current applications are essentially systems, which are developments of stereotactic devices and those in which a surgeon interacts with mechatronic devices. The former basically uses a robotic arm to perform trajectory-­based procedures (biopsies, electrode implantation, spinal screw trajectory).95 Hallmark is the co-­registration of robot, navigation, and occasionally imaging device, to provide a workflow with minimal registration inaccuracies. Once the trajectory is confirmed by the surgeon, these systems perform the set task, that is, placement of a straight tool automatically. Instrument direction in open surgery is more flexible but also more complex. Robot and surgeon can share the same space (SCOT)96 or through a remote control in spatial separation (neuroarm).83 These systems are generally set up to be closely guided by the surgeon, rather in a cooperative fashion, with low autonomy of the robot. A major challenge of these cooperative robots, particularly when controlled remotely, encompasses the haptic feedback,97,98 which is so crucial in surgery. However, one of the major advantages is that the ergonomic remote manipulation of the instruments can be done within very confined space. Thus the notion of an MR-­compatible robotic system, with surgery taking place within the MRI.83 At present all systems demand a high level of surgeon control. Whether the autonomy of robotic systems can and should be increased largely depends on those systems’ capacity for closed-­loop feedback and the capacity to adjust to intraoperative changes. While we can provide intraoperative information to a high level of sophistication, further challenges remain to ensure safety.99 It remains the surgeon’s task to be actively involved in the development of these systems to ensure the transfer of knowledge necessary to develop “intelligent” systems capable of adaptive adjustments. 

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2  •  Surgical Navigation With Intraoperative Imaging: Special Operating Room Concepts

Summary Intraoperative imaging addresses the crucial need to support surgical decision making with online information to improve quality control and complication avoidance. The main modalities are US, fluoroscopy, CT, and MRI. Ultrasound can be easily integrated into the surgical workflow. Combination with navigation systems facilitates interpretation. The capacity to simultaneously capture flow and structure is particularly useful in vascular malformations. Contrast-­enhanced ultrasound is a major advancement, which may facilitate differentiation for glioma resection. Mobile fluoroscopy has been integrated into conventional ORs for spinal surgery and DBS. The biplane representation has been extended to a 3D perspective by rotating units. This enhances their potential application for vascular neurosurgery and spinal instrumentation, where 3D rotational fluoroscopy may become a competitor for intraoperative CT. The evolution of IoUS and fluoroscopy has facilitated integration into the surgical surrounding. Current-­generation equipment has been reduced in size, while significant improvements have been achieved in functionality. CT and MRI are less prone to undergo simultaneous miniaturization and refinement. These cut-­plane imaging modalities are primarily integrated through workflow and suite design. The latest intraoperative computed tomography (iCT) generation shows significant improvement in image quality and integration into the surgical workflow. Spinal instrumentation and vascular neurosurgery are the main indications. In brain tumor surgery, the use of iCT is less conclusive, though there have been significant improvements, in particular for low-­grade gliomas. In iMRI suites, intraoperative imaging has taken its most elaborate form. Despite its cost, special requests, and labor intensiveness, this field keeps expanding, due to the unparalleled imaging capabilities for the analysis of structural pathology as well as physiologic investigations of the central nervous system (e.g., neurooncology, epilepsy surgery). Various groups reported more complete resections for high-­grade gliomas and pituitary lesions employing intraoperative low-­57,100, mid-­101,102, and high-­field systems.44,103 Increased resection percentages were also shown for low-­ grade lesions.6,58 The attempt to decrease MRI size to facilitate integration resulted in a compact low-­field system, albeit with limited imaging potential.56 Higher-­ field MRIs providing diagnostic imaging capability are integrated primarily through their suite design, which separates surgical and imaging site within the same (dedicated systems) or adjacent rooms (twin operating theater, shared resource). In dedicated systems, the transfer between surgical and imaging site is faster than in the shared resources concept.45,58 Shared resources use a modular suite arrangement which can potentially be expanded by various imaging modalities (CT, PET-­CT, and high-­field MRI) adjacent to a hybrid neurointerventional-­ neurosurgical OR (angiography and US). Such installations represent a major research opportunity to evaluate the impact and value of different imaging modalities against each other. In these setups the

navigation system becomes pivotal with its capacity to register, display, and transfer pre-­and intra­operative multimodal image information in a comprehensive way for surgical guidance.76,104-­106 The advantage of unimpeded microsurgical techniques in modular setups is traded in by disrupted surgical workflow prolonged procedures. Thus intraoperative imaging represents a compromise balancing the additional value of the imaging information versus timely conclusion of the surgery. Especially for MRI, the overabundance of high-­quality image information becomes a challenge in its own right. Fiber tracking has been employed in sophisticated ways, delineating the major fiber connections.107,108 Spectroscopy has been used to guide stereotactic biopsies,109 and with further refinement may yield information on resection borders in open surgery.59 This developing intraoperative “information gap” can be potentially filled by alternative methods, such as optical imaging. Intraoperative information gathering has to be carefully balanced to minimize delay while obtaining the best information possible. Any device used for intraoperative imaging becomes a surgical tool and has to be employed with the same scrutiny and deliberation. It remains the surgeon’s obligation to decide, and to understand the potential and the limitations of imaging modalities to gather the information needed for surgical decision making. 

Conclusion Intraoperative imaging and navigation have developed from a vision55 to a neurosurgical reality. The development of various OR designs to accommodate intraoperative imaging and surgery has accelerated. Solutions apparently prohibitive in scope and cost 10 years ago have been implemented and surpassed. The higher the expectation of image information, the more complex the resulting design. Intraoperative MRI has been successfully combined with standard microneurosurgical and navigation techniques into comprehensive units for neurosurgical procedures.55,104 The multitude of designs, implementations, and field strengths make this a most multifaceted area of expertise. Incorporation of magnets with increasing field strengths and multimodal imaging concepts (MRXO) including metabolic information (AMIGO) represent the next challenges. Further refinements may lead back to the original concept of merging therapy and MRI, with robotic devices for surgery, focused US for noninvasive ablative procedures,104 or open high-­field magnet designs. However, technological advances appear to gain autonomous momentum. It is essential to ensure that surgical needs remain at the core of this multidisciplinary effort. At present, it is the surgeon’s obligation to resist the technological temptation and use the tools judiciously. At the same time curiosity beyond our field has driven the significant advances sketched in this chapter and will be imperative to advance.

Acknowledgments I thank all friends from Boston (The MRT crew and SPL) at Brigham and Women’s Hospital, Colleagues in Kiel from Anesthesiology, Tec and OR Team.

2  •  Surgical Navigation With Intraoperative Imaging: Special Operating Room Concepts

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Black PM, Moriarty T, Alexander 3rd E, et al. Development and implementation of intraoperative magnetic resonance imaging and its neurosurgical applications. Neurosurgery. 1997;41:831–842. Coburger J, Merkel A, Scherer M, et al. Low-­grade glioma surgery in intraoperative magnetic resonance imaging: results of a multicenter retrospective assessment of the german study group for intraoperative magnetic resonance imaging. Neurosurgery. 2016;78: 775–786. Hadani M, Spiegelman R, Feldman Z, et al. Novel, compact, intraoperative magnetic resonance imaging-­guided system for conventional neurosurgical operating rooms. Neurosurgery. 2001;48:799–807. Hall WA, Galicich W, Bergman T, Truwit CL. 3-­Tesla intraoperative MR imaging for neurosurgery. J Neurooncol. 2006;77:297–303. Jankovski A, Francotte F, Vaz G, et al. Intraoperative magnetic resonance imaging at 3-­T using a dual independent operating room-­ magnetic resonance imaging suite: development, feasibility, safety, and preliminary experience. Neurosurgery. 2008;63:412–424. Jolesz FA, Nabavi A, Kikinis R. Integration of interventional MRI with computer-­assisted surgery. J Magn Reson Imaging. 2001;13:69–77. Matsumae M, Koizumi J, Fukuyama H, et al. World’s first magnetic resonance imaging/x-­ray/operating room suite: a significant milestone in the improvement of neurosurgical diagnosis and treatment. J Neurosurg. 2007;107:266–273. Nabavi A, Black PM, Gering DT, et al. Serial intraoperative magnetic resonance imaging of brain shift. Neurosurgery. 2001;48:787–797. Nabavi A, Dorner L, Stark AM, Mehdorn HM. Intraoperative MRI with 1.5 Tesla in neurosurgery. Neurosurg Clin North Am. 2009;20:163–171. Nabavi A, Goebel S, Doerner L, et al. Awake craniotomy and intraoperative magnetic resonance imaging: patient selection, preparation, and technique. Top Magn Reson Imaging. 2009;19:191–196.

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Nimsky C, Ganslandt O, Cerny S, et al. Quantification of, visualization of, and compensation for brain shift using intraoperative magnetic resonance imaging. Neurosurgery. 2000;47:1070–1079. Nimsky C, Ganslandt O, Kober H, et al. Intraoperative magnetic resonance imaging combined with neuronavigation: a new concept. Neurosurgery. 2001;48:1082–1089. Nimsky C, Ganslandt O, Von Keller B, et al. Intraoperative high-­field-­ strength MR imaging: implementation and experience in 200 patients. Radiology. 2004;233:67–78. Pamir MN, Ozduman K, Dincer A, et al. First intraoperative, shared-­ resource, ultrahigh-­field 3-­Tesla magnetic resonance imaging system and its application in low-­grade glioma resection. J Neurosurg. 2010;112:47–69. Schichor C, Terpolilli N, Thorsteinsdottir J, Tonn JC. Intraoperative computed tomography in cranial neurosurgery. Neurosurg Clin N Am. 2017;28:595–602. Schulder M. Intracranial surgery with a compact, low-­field-­strength magnetic resonance imager. Top Magn Reson Imaging. 2009;19:179–189. Steinmeier R, Fahlbusch R, Ganslandt O, et al. Intraoperative magnetic resonance imaging with the magnetom open scanner: concepts, neurosurgical indications, and procedures: a preliminary report. Neurosurgery. 1998;43:739–747. Sutherland GR, Kaibara T, Louw D, et al. A mobile high-­field magnetic resonance system for neurosurgery. J Neurosurg. 1999;91:804–813. Sutherland GR, Latour I, Greer AD. Integrating an image-­guided robot with intraoperative MRI: a review of the design and construction of neuroarm. IEEE Eng Med Biol Mag. 2008;27:59–65. Tronnier VM, Wirtz CR, Knauth M, et al. Intraoperative diagnostic and interventional magnetic resonance imaging in neurosurgery. Neurosurgery. 1997;40:891–900. Numbered references appear on Expert Consult.

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70. Hall WA, Martin AJ, Liu H, Nussbaum ES, Maxwell RE, Truwit CL. Brain biopsy using high-­field strength interventional magnetic resonance imaging. Neurosurgery. 1999;44:807–813. 71. Nimsky C, Ganslandt O, Hastreiter P, et al. Preoperative and intraoperative diffusion tensor imaging-­based fiber tracking in glioma surgery. Neurosurgery. 2007;61:178–185. 72. Ulmer S, Hartwigsen G, Riedel C, Jansen O, Mehdorn HM, Nabavi A. Intraoperative dynamic susceptibility contrast MRI (iDSC-­MRI) is as reliable as preoperatively acquired perfusion mapping. Neuroimage. 2009. 73. Neuwelt EA, Varallyay CG, Manninger S, et al. The potential of ferumoxytol nanoparticle magnetic resonance imaging, perfusion, and angiography in central nervous system malignancy: a pilot study. Neurosurgery. 2007;60:601–611. 74. Knauth M, Egelhof T, Roth SU, Wirtz CR, Sartor K. Monocrystalline iron oxide nanoparticles: possible solution to the problem of surgically induced intracranial contrast enhancement in intraoperative MR imaging. AJNR Am J Neuroradiol. 2001;22:99–102. 75. Wirtz CR, Bonsanto MM, Knauth M, et al. Intraoperative magnetic resonance imaging to update interactive navigation in neurosurgery: method and preliminary experience. Comput Aided Surg. 1997;2:172–179. 76. Nimsky C, Ganslandt O, Kober H, Buchfelder M, Fahlbusch R. Intraoperative magnetic resonance imaging combined with neuronavigation: a new concept. Neurosurgery. 2001;48:1082–1089. 77. Schulder M, Azmi H, Biswal B. Functional magnetic resonance imaging in a low-­field intraoperative scanner. Stereotact Funct Neurosurg. 2003;80:125–131. 78. Levivier M, Wikler D, De Witte O, Van de Steene A, Baleriaux D, Brotchi J. PoleStar N-­10 low-­field compact intraoperative magnetic resonance imaging system with mobile radiofrequency shielding. Neurosurgery. 2003;53:1001–1006; discussion 7. 79. Baumann F, Schmid C, Bernays RL. Intraoperative magnetic resonance imaging-­guided transsphenoidal surgery for giant pituitary adenomas. Neurosurg Rev. 2009. 80. Gerlach R, du Mesnil de Rochemont R, Gasser T, et al. Feasibility of Polestar N20, an ultra-­low-­field intraoperative magnetic resonance imaging system in resection control of pituitary macroadenomas: lessons learned from the first 40 cases. Neurosurgery. 2008;63:272–284. 81. Nabavi A, Goebel S, Doerner L, Warneke N, Ulmer S, Mehdorn M. Awake craniotomy and intraoperative magnetic resonance imaging: patient selection, preparation, and technique. Top Magn Reson Imaging. 2009;19:191–196. 82. Hall WA, Liu H, Martin AJ, Maxwell RE, Truwit CL. Brain biopsy sampling by using prospective stereotaxis and a trajectory guide. J Neurosurg. 2001;94:67–71. 83. Sutherland GR, Latour I, Greer AD. Integrating an image-­guided robot with intraoperative MRI: a review of the design and construction of neuroArm. IEEE Eng Med Biol Mag. 2008;27:59–65. 84. Hall WA, Galicich W, Bergman T, Truwit CL. 3-­Tesla intraoperative MR imaging for neurosurgery. J Neuro Oncol. 2006;77:297–303. 85. Truwit CL, Hall WA. Intraoperative magnetic resonance imaging-­guided neurosurgery at 3-­T. Neurosurgery. 2006;58:338– 345. ONS. 86. Kim PD, Truwit CL, Hall WA. Three-­tesla high-­field applications. Neurosurg Clin N Am. 2009;20:173–178. 87.  Advanced Multimodality Image Guided Operating (AMIGO) Suite. http://wwwncigtorgt/pages/AMIGO 2008. 88. Morgenstern U, Sobottka SB, Meyer T, Kirsch M, Malberg H, Schackert G. Intraoperative optical imaging in neurosurgery. Biomed Tech. 2013;58:213–215. 89. Diez Valle R, Hadjipanayis CG, Stummer W. Established and emerging uses of 5-­ALA in the brain: an overview. J Neuro Oncol. 2019. 90. Nabavi A, Thurm H, Zountsas B, et al. Five-­aminolevulinic acid for fluorescence-­guided resection of recurrent malignant gliomas: a phase ii study. Neurosurgery. 2009;65:1070–1076; discussion 6-­7. 91. Schwake M, Stummer W, Suero Molina EJ, Wolfer J. Simultaneous fluorescein sodium and 5-­ALA in fluorescence-­guided glioma surgery. Acta Neurochir. 2015;157:877–879. 92. Finke M, Kantelhardt S, Schlaefer A, et al. Automatic scanning of large tissue areas in neurosurgery using optical coherence tomography. Int J Med Robot. 2012;8:327–336.

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Section One Surgical Management of Brain and Skull Base Tumors

     

INTRA-AXIAL TUMORS CHAPTER 3

Diffusion Tensor Imaging and Functional Tractography ASWIN CHARI  •  PUNEET PLAHA  •  ERLICK A.C. PEREIRA Diffusion tensor imaging (DTI) is a noninvasive technique that makes it possible to assess the integrity and location of subcortical white matter tracts in vivo. Its importance is underscored by the developing understanding that neurologic outcomes are more dependent on the integrity of the subcortical white matter tracts than specific cortical areas.1 Indications for the clinical use of DTI are rapidly broadening. Although it is still confined mainly to the field of surgical neuro-­oncology, it has also been found useful for planning treatment and predicting outcome in functional neurosurgery,2–4 stereotactic radiosurgery,5–8 epilepsy surgery,9–11 magnetic resonance–guided thermal ablative techniques,12 ischemic and hemorrhagic stroke,13–17 traumatic brain injury,18 neurodegenerative disorders,19 and spinal pathology.20 This chapter focuses on the science behind DTI, its practical considerations, and its application in the surgical management of intra-­axial brain tumors and the planning of deep brain stimulation (DBS).

The Science of Diffusion Tensor Imaging and Tractography The concepts of diffusion-­weighted imaging and DTI are based on measuring the random (Brownian) movement of water molecules. Water molecules in different environments (e.g., intracellular vs. extracellular water) have different diffusivities that may be influenced by structural barriers (e.g., cell membranes) and the molecular densities of tissue. To measure this diffusivity, magnetic resonance imaging (MRI) scanners exploit the loss of signal between two gradient pulses (usually 20 to 50 ms apart) as water moves; therefore areas with high diffusion have low signal and areas of restricted diffusion have higher signal.21 Diffusivity can be described as isotropic (Fig. 3.1A) or anisotropic (Fig. 3.1B). Isotropic diffusion is the same in all directions, as would be the case in areas of fluid without a microstructure, such as cerebrospinal fluid. On the other hand, tubular structures, such as neurons, have anisotropic diffusion, where water diffuses more freely along the axis of the neuron than in the other two perpendicular axes. DTI sequences are designed to measure the diffusivity of water molecules in each voxel in at least six different gradients (directions), which are amalgamated to build up a tensor

describing the magnitude of diffusivity, termed eigenvalues, in each of three orthogonal dimensions, termed eigenvectors. Using these three eigenvalues and eigenvectors, a number of descriptive properties of the tissue can be described including the fractional anisotropy (FA), axial diffusivity, radial diffusivity, and mean diffusivity (Fig. 3.1C), properties that may serve as useful markers of tissue characteristics such as fiber diameter, fiber density and myelination. Of these, FA is probably the widely used. FA ranges between 0 (isotropic diffusion) and 1 (anisotropic diffusion), with high FA values associated with white matter tracts. Mathematical algorithms can then be used to map these white matter tracts. These mathematical algorithms can be broadly split into two different techniques. The original methods (including FACT and TEND22,23) used deterministic modelling, which assigns each voxel with a directional orientation and uses the orientations of nearby voxels to map tracts. Newer probabilistic methods consider an orientation distribution function for each voxel, thereby generating a statistical likelihood map for the location of white matter tracts.1,24,25 Although the deterministic method is more commonly used by commercial software and intraoperative neuronavigation systems, it is susceptible to areas of low FA, as can be the case with peritumoral edema or areas where there are intersecting fiber tracts in multiple directions. Probabilistic mapping is limited by its computational intensity, often taking days on traditional machines; the advent of graphic processing units has allowed probabilistic tractography to be sped up.26 Both methods require cautious interpretation as they may be susceptible to producing false-­positive and false-­negative tracts and do not have the ability to assign directionality (afferent vs. efferent) to the tracts.27 Both types of mapping require a starting “seed” voxel that can either be performed by the user based upon anatomically preserved foci or be based on relevant areas of cortex identified through fMRI.28 For example, the corticospinal tract can be identified by selecting the cerebral peduncles as an anatomically preserved focus or by identifying areas of the primary motor cortex using an fMRI finger-­tapping task. The output of this processing, the estimation of the location of white matter tracts, can be presented via color-­coded maps on two-­dimensional slice MR projections or be integrated into three-­ dimensional reconstructions to portray fiber pathways (Fig. 3.2).29–33 

27

28

Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

Fractional anisotropy (FA) = λ1

(λ1 – λ2)2 + (λ2 – λ3)2 + (λ1 – λ3)2

λ1

λ2

λ2

2(λ12 + λ22 + λ32)

λ3

λ3

Axial diffusivity = λ2 Radial diffusivity = (λ1 + λ3)/2

A

Isotropic diffusion

B

Anisotropic diffusion

C

Mean diffusivity = (λ1 + λ2 + λ3)/3

FIGURE 3.1  Depiction of (A) isotropic and (B) anisotropic diffusion of water molecules. (C) In cases of anisotropic diffusion, key measures include fractional anisotropy (FA), axial diffusivity, radial diffusivity, and mean diffusivity.

A

B

FIGURE 3.2  Output of fiber-­tracking algorithms can be viewed on (A) two-­dimensional (2D) magnetic resonance imaging (MRI) slice projections or (B) as a three-­dimensional (3D) map, which can be integrated into intraoperative neuronavigation systems. In the 2D projection (A), there is a color convention whereby red represents fibers in the x-­axis (left-­right), green represents fibers in the y-­axis (anterior-­posterior) and blue represents fibers in the z-­axis (cranial-­caudal).

Rationale for Diffusion Tensor Imaging in Surgical Neuro-­oncology The field of surgical neuro-­oncology has placed significant focus on the so-­called oncofunctional balance with the aim of maximizing the extent of resection (EoR) of intra-­axial brain tumors while preserving neurologic function and quality of life.34 Although the importance of EoR has been established in numerous studies of high-­and low-­grade gliomas,35–40 it has also clearly been shown that causing a neurologic deficit affects outcome adversely.41 More recent developments have even advocated for supratotal resection of gliomas, switching from a paradigm of “image-­guided” resection to “functionally guided” resection.42–44 There are multiple techniques in a surgeon’s armamentarium that can be used in pursuit of this oncofunctional balance (Table 3.1), but novel MRI modalities have undoubtedly been central to progress. Modern intraoperative neuronavigation systems enable the coregistration of tractographic maps to traditional structural imaging sequences, thus facilitating pre-­and intraoperative visualization. A basic understanding of the location and function of main white matter tract systems is a prerequisite for the use of DTI in surgical neuro-­oncology (Table 3.2). 

Preoperative Use The most important and obvious preoperative application of tractographic imaging is for the localization of known white matter fiber tracts (see Table 3.2) in relation to brain tumors. DTI imaging allows for the assessment of white matter tract location and integrity. This can help the patient and clinician in terms of assessing the possibility of gross total resection and the risk of postoperative neurologic deficits. It also plays a crucial role in informing the surgeon about safe corridors of approach to the tumor, again reducing the risk of postoperative deficits (Fig. 3.3). This has been shown to be beneficial in intra-­axial brain tumors45 and even deep thalamic and brain-­stem cavernomas.46–48 In fact, the DTI evaluation of cavernomas has revealed that the hemosiderin rim is often intimately associated with viable white matter tracts.48 An evolving use of DTI is in differentiating peritumoral edema from invasion, which, along with the white matter tractographic data, can aid in the decision-making about the EoR for intrinsic tumors.49–51 It is thought that peritumoral edema, especially in high-­grade tumors, increases MD and decreases FA due to the destruction of the extracellular matrix structures by the malignant cells, but the FA is reduced even more when malignant cells infiltrate this

3  •  Diffusion Tensor Imaging and Functional Tractography

Table 3.1  Techniques Designed to Maximize the Extent of Resection While Preserving Neurologic Function and Quality of Life Adjuncts That Help to Increase Extent of Resection

Adjuncts That Help to Preserve Neurologic Function

Fluorsecence-­guided resection (5-­amino-­levulinic acid [5-­ALA]) Intraoperative MRI (iMRI)

Functional MRI (fMRI) Diffusion tensor imaging (DTI)

MRI, Magnetic resonance imaging.

29

tissue, which can appear normal on traditional T2-­weighted sequences. In fact, this disproportionate reduction in FA (compared with the increase in MD) has been shown to be predictive of tumor invasion and recurrence.50,52 Preoperative DTI can also be used as part of the repertoire of advanced MRI sequences that help to characterize tumor type.53–60 This may be helpful in aiding treatment planning, although definitive histology and molecular markers are likely to continue to play a central role to the tailored treatment of brain tumor patients.61 

Table 3.2  Important White Matter Tracts and Their Role in Surgical Neuro-­oncology Tract

Function

DTI Pointers

Corticospinal tract (CST)

Primary motor output. Damage results in paresis.

Arcuate fasciculus

Fibers connect the inferior frontal lobe (pars opercularis) to the superior temporal gyrus. The right arcuate fasciculus is involved in language (repetition, speech production), the left is involved in visuospatial processing and language (prosody). Damage results in phonemic paraphasias, repetitions, and nonfluent “expressive” aphasia. Can be split into SLF-­I, SLF-­II, SLF-­III and temporoparietal fibers (SLF-­tp); these generally connect frontal and parietal association areas with roles in language and attention. SLF-­III is best characterized, and damage causes dysarthrias. Connects the superior temporal pole to the inferior parietal lobe but its functions remain unclear. Temporo-­occipital association fibers, involved in visual perception (including facial recognition), reading. Damage results in visual agnosias, alexias, prosopagnosia. Connects the frontal operculum to a poorly defined region of occipital cortex that merges with the ILF in its course near the posterior temporal lobe. Damage causes visual semantic deficits. Connects primary motor cortex and pars opercularis to SMA. Damage results in SMA syndrome (hemiparesis, difficulty with speech initiation), which is typically transient. Ventral bundle connecting temporal pole to orbitofrontal cortex, involved in emotional processing. Fibers connecting optic tracts to primary visual cortex. Split into temporal (Meyer) and parietal divisions. Damage results in visual field defects including scotomas and quadrantanopias. Medial associative bundle within the cingulate gyrus, involved in attention, memory, and emotion.

Amenable to DES but useful to gain understanding of relation of the tumor to CST prior to intervention. May also help to decide whether DES is necessary intraoperatively. Consistent tracing for medial CST fibers but more variable in lateral CST, improved by probabilistic tractography. Pre-­and postoperative integrity has been shown to correlate well with lasting postoperative language deficits

Superior longitudinal fasciculus (SLF)

Middle longitudinal fasciculus (MdLF) Inferior longitudinal fasciculus (ILF)

Inferior fronto-­occipital fasciculus (IFOF)

Frontal aslant tract

Uncinate fasciculus Optic radiation

Cingulum

Pre-­and postoperative integrity has been shown to correlate well with lasting postoperative language deficits

High intersubject variability in cortical terminations. Commonly invaded by gliomas with good correlation between DTI tract reconstruction and intraoperative DES localization.

High-­fidelity DTI of tracts means that surgery can be carried out under GA with mapping of radiation to prevent visual field defects.

DES, Direct electrical stimulation; DTI, diffusion tensor imaging; GA, general anaesthesia; SMA, supplementary motor area. Adapted from Voets NL, Bartsch A, Plaha P. Brain white matter fibre tracts: a review of functional neuro-­oncological relevance. J Neurol Neurosurg Psychiatr. 2017;88(12):1017–1025. Catani M, Thiebaut de Schotten M. A diffusion tensor imaging tractography atlas for virtual in vivo dissections. Cortex. 2008;44(8): 1105–1132.

30

Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

Preop

L

L

Postop

A

B

Intraoperative Use The intraoperative use of white matter tractography has been facilitated by the ability of commercially available neuronavigation machines to integrate tractographic maps into the navigation systems (Fig. 3.4). These integrated navigation images may be used to plan the surgical access to the tumor (craniotomy and corcicotomy), be used judge the EoR in relation to the white matter tracts, or be used to guide other adjuncts such as direct electrical stimulation in awake patients.

FIGURE 3.3  Cases showing how diffusion tensor imaging (DTI) can be useful in resective tumor surgery. (A) Case of a 47-­year-­old, right-­handed male who presented with seizure. Magnetic resonance imaging (MRI) shows a left temporal low-­grade nonenhancing glioma. Preoperative MRI shows the tumor in relation to white fiber tracts (probabilistic method); corticospinal tract (blue), superior longitudinal and arcuate fasciculi (pink), inferior fronto-­occipital fasciculus (green), inferior longitudinal fasiculus (yellow), and optic radiation (cyan). He underwent awake surgery with subcortical fiber mapping. Postoperative MRI shows complete tumor resection with preservation of the tracts. DTI helped in planning the surgical approach and showing tract location during surgery. (B) MRI shows a medial right temporal high-­grade glioma. The scan was acquired using commercial software (deterministic method) for navigation in the operating theater. It shows the tumor’s close proximity to the corticospinal tract (blue).

The evidence of its efficacy comes from a randomized controlled trial of 238 brain tumor patients, comparing traditional neuronavigation to neuronavigation plus integrated corticospinal tractography.62 The tractography arm showed increased EoR (74.5% vs. 33.3% gross total resection for high-­grade tumors, P < .001), less incidence of motor deterioration (15.3% vs. 32.8%, P < .001), better functional outcomes (6-­ month Karnofsky performance status of 86 vs. 74, P < .001) and better survival (21.2 months vs. 14.0 months for high-­grade tumors, P = .048)

3  •  Diffusion Tensor Imaging and Functional Tractography

31

A

B FIGURE 3.4  Screenshots of tractographic maps and tumor delineation using the Brainlab navigation system workstation and Brainlab’s commercially available iPlan software. (A) Illustrates a whole brain tractographic map and a right parietal tumor (red); (B) illustrates the same tumor with isolation of the corticospinal tract, which is predominantly anterolateral to the tumor, thus aiding the planning of the surgical approach and indicating the limits of resection.

than the control arm. A Cochrane database systematic review could provide only a low-­grade recommendation for the use of neuronavigation with DTI due to potential biases in the trial.63 Despite the apparent benefits, there are some limitations that need to be taken into account. In addition to the methodologic

and computational limitations associated with the use of deterministic tractography in commercially available neurnavigation machines (see earlier), there is also loss of signal quality in areas of peritumoral edema and crossing fibers.64,65 Perhaps the biggest limiting factor of DTI, however, is that of shifting white matter tracts during the surgical

32

Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

procedure. This was evaluated as far back as 2005, illustrating that tracts can shift both inward and outward up to 15 mm.66,67 Integrating real-­time imaging by using iMRI to update the location of the white matter tracts can be time consuming and resource intensive but has been shown to accurately correlate with tract locations as determined by direct stimulation.68 Assessing the marginal utility of tractography on its own, therefore, is probably not appropriate, and the paradigms must shift to assessing the utility of multimodal strategies in improving patient outcomes (see Table 3.2). For example, DTI may be used to guide direct electrical stimulation in awake patients to preserve function while 5-­ALA is simultaneously used to identify tumor tissue. 

Postoperative Use DTI may also have an important role in postoperative therapy. Cognitive deficits have been shown to correlate with long-­term fiber tract integrity, which may be affected by radiotherapy. DTI may therefore be used to guide radiation therapy doses so as to minimize exposure to sensitive white matter tracts.69–71 It is possible that chemotherapy could also affect tract integrity, although this has so far been studied more extensively in cancers outside of the central nervous system.72–74 Diffusion MR parameters may also be useful in differentiating between tumor response, progression, and pseudoprogression,75,76 although it is likely that MR spectroscopy may have a more important role in this context. Outcome prediction, based on pre-­and postoperative DTI imaging, is a currently underexplored area that holds promise. DTI has been shown to be able to predict language recovery following the resection of gliomas77 and visual recovery following the resection of pituitary adenomas based on the postoperative change in FA of the optic chiasm.78,79 What is extremely interesting is the concept that functional connectivity is plastic and may change with time, enabling longitudinal monitoring of structural connections that may facilitate further resections of tumor tissue at later stages.80–82 It remains to be elucidated whether this is a practical and functionally superior approach to the management of low-­grade gliomas, and if so, what the optimal timing for follow-­up imaging and repeat resection would be. 

Diffusion Tensor Imaging in Other Contexts Developments in DTI and white matter tractography have been central to the concept of connectomic neurosurgery with the aim of preserving neurologic function through the study, appreciation, and preservation of subcortical white matter tracts. It therefore follows that developments in neuro-­oncology can and have been translated into other neurosurgical subspecialties. DTI has been used to define the functional limits of dominant temporal lobectomy9,10,83 and has been shown to have a role in predicting verbal fluency and cognitive outcomes following resection.84 From the perspective of functional preservation, neuro-­oncology and the neurosurgical management of epilepsy have a lot in common, and the future

lies in being able to reliably assess and predict outcomes of surgery in multiple areas including sensorimotor, visual, language, cognitive, and emotional domains. Where DTI and tractography may have a slightly different role is in the sphere of functional neurosurgery. As the gamut of indications for DBS increases, there is a growing role for the use of DTI and tractography in optimizing target locations and stimulation settings based on an analysis of white matter connectivity.33,85,86 For example, it has been shown that contacts with connections to specific cortical regions are associated with best response to tremor, bradykinesia, and rigidity in subthalamic nucleus stimulation for Parkinson disease, with the best overall response probably localized to the superior border of the nucleus.87–89 Tools, such as StimVision,90 have even been developed specifically for the intraoperative use of DTI in electrode targeting, and an ongoing randomized trial is comparing the efficacy of standard targeting to DTI-­based targeting for essential tremor.91 In the future, DTI may also be used to explore the connectivity associated with side effects,92 and preoperative DTI may play a crucial role in patient selection for DBS.33 

Limitations of Diffusion Tensor Imaging It is important to consider the limitations of DTI and tractography. First and foremost, it is imperative to remember that the technique provides only an estimation of fiber orientation based upon anisotropic water diffusion, and is by no means absolute.93,94 The resolution of a voxel is much bigger than individual fiber diameters, and therefore the spatial resolution is limited. DTI also provides structural but no functional information so needs to be complemented by other techniques such as fMRI, electroencephalography, and magnetoencephalography to provide functional information.93–95 From a technical perspective, there are also limitations. Most of the published studies applying tractography in neurosurgery employ deterministic algorithms, the limitations of which have been discussed. Probabilistic algorithms are perhaps more difficult to interpret in clinical neurosurgery, as they provide probabilities of white matter tract locations that require more complex and nuanced intraoperative interpretation. The processing is also limited by interrater variability due to the manual selection of seed regions96–98; when these seed regions are based on fMRI, especially in brain tumor patients with pre-existing neurologic deficits, the reliability of fMRI and the means to reliably identify these cortical seed regions remain to be established. 

Future Directions There is a bright and expanding future for DTI and tractography in neurosurgery. In this expanding field, the key to progress is being able to compare techniques and outcomes between studies. This can be achieved by standardizing acquisition and processing protocols for DTI images, such as advocating the routine use of probabilistic tractography and developing clear, uniform ways of defining seed voxels for specific tracts to reduce interuser variability.1 There also need to be more links to function for the various tracts. Studies that correlate DTI tracts to direct electrical stimulation68 are important to better understand the role

3  •  Diffusion Tensor Imaging and Functional Tractography

of some of the less well understood tracts (see Table 3.2). There is also a demand to systematically link DTI imaging to standardized batteries of cognitive tests, something that is being pushed by the European Low Grade Glioma Network.99 This collaboration will facilitate the amalgamation of large datasets to make correlations between tractographic changes and cognitive outcome changes preoperatively, postoperatively, and with longitudinal follow-­up. There are also advances in DTI techniques with impressive potential. High angular resolution diffusion imaging uses more diffusion directions than traditional DTI sequences, improving angular resolution,100,101 whereas diffusion spectrum imaging uses higher b-­values.102 Generalized Q-­sampling imaging and novel DTI processing

33

algorithms such as constrained spherical deconvolution allow for more than one fiber tract to be present in a single voxel, thus improving the resolution in areas of crossing fibers.64,103,104 The newest technique is termed high-­definition fiber tractography, which uses a combination of diffusion-­spectrum imaging and Q-­sampling techniques.65,105 These new techniques have better potential to elucidate tracts in perilesional edema and areas of crossing fibers, but the limitations—such as longer image acquisition time, processing time, and computational intensity—must be taken into consideration for streamlined clinical use. Numbered references appear on Expert Consult.

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84. Osipowicz K, Sperling MR, Sharan AD, Tracy JI. Functional MRI, resting state fMRI, and DTI for predicting verbal fluency outcome following resective surgery for temporal lobe epilepsy. J Neurosurg. 2016;124(4):929–937. 85. Torres CV, Manzanares R, Sola RG. Integrating diffusion tensor imaging-­based tractography into deep brain stimulation surgery: a review of the literature. Stereo Funct Neurosurg. 2014;92(5):282– 290. 86. Calabrese E. Diffusion tractography in deep brain stimulation surgery: a review. Front Neuroanat. 2016;10:45. 87. Vanegas-­Arroyave N, Lauro PM, Huang L, et al. Tractography patterns of subthalamic nucleus deep brain stimulation. Brain :J Neurol. 2016;139(Pt 4):1200–1210. 88. Akram H, Sotiropoulos SN, Jbabdi S, et al. Subthalamic deep brain stimulation sweet spots and hyperdirect cortical connectivity in Parkinson’s disease. Neuroimage. 2017;158:332–345. 89. Horn A, Reich M, Vorwerk J, et al. Connectivity predicts deep brain stimulation outcome in Parkinson disease. Ann Neurol. 2017;82(1):67–78. 90. Noecker AM, Choi KS, Riva-­Posse P, Gross RE, Mayberg HS, McIntyre CC. StimVision software: examples and applications in subcallosal cingulate deep brain stimulation for depression. Neuromodulation : J Int Neuro Society. 2017. 91. Sajonz BE, Amtage F, Reinacher PC, et al. Deep Brain Stimulation for Tremor Tractographic Versus Traditional (DISTINCT): study protocol of a randomized controlled feasibility trial. JMIR Research Protocols. 2016;5(4):e244. 92. Mahlknecht P, Akram H, Georgiev D, et al. Pyramidal tract activation due to subthalamic deep brain stimulation in Parkinson’s disease. Mov Disord : Official J Mov Dis Society. 2017;32(8):1174– 1182. 93. Jbabdi S, Johansen-­Berg H. Tractography: where do we go from here? Brain Connectivity. 2011;1(3):169–183. 94. Jones DK, Cercignani M. Twenty-­five pitfalls in the analysis of diffusion MRI data. NMR Biomed. 2010;23(7):803–820. 95. Jbabdi S, Behrens TE. Long-­range connectomics. Ann N Y Acad Sci. 2013;1305:83–93.

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96. Pujol S, Wells W, Pierpaoli C, et al. The DTI Challenge: toward standardized evaluation of diffusion tensor imaging tractography for neurosurgery. J Neuroimaging: Official J Am Society Neuro. 2015;25(6):875–882. 97. Jones DK, Knosche TR, Turner R. White matter integrity, fiber count, and other fallacies: the do’s and don’ts of diffusion MRI. Neuroimage. 2013;73:239–254. 98. Christidi F, Karavasilis E, Samiotis K, Bisdas S, Papanikolaou N. Fiber tracking: a qualitative and quantitative comparison between four different software tools on the reconstruction of major white matter tracts. Eur J Radiol Open. 2016;3:153–161. 99. Rofes A, Mandonnet E, Godden J, et al. Survey on current cognitive practices within the European Low-­Grade Glioma Network: towards a European assessment protocol. Acta Neurochirurgica. 2017;159(7):1167–1178. 100. Kuhnt D, Bauer MH, Egger J, et al. Fiber tractography based on diffusion tensor imaging compared with high-­angular-­resolution diffusion imaging with compressed sensing: initial experience. Neurosurgery. 2013;72(suppl 1):165–175. 101. Tuch DS, Reese TG, Wiegell MR, Makris N, Belliveau JW, Wedeen VJ. High angular resolution diffusion imaging reveals intravoxel white matter fiber heterogeneity. Magnetic Resonance Med. 2002;48(4):577–582. 102. Wedeen VJ, Hagmann P, Tseng WY, Reese TG, Weisskoff RM. Mapping complex tissue architecture with diffusion spectrum magnetic resonance imaging. Magnetic Resonance Med. 2005;54(6):1377–1386. 103. Yeh FC, Wedeen VJ, Tseng WY. Generalized q-­sampling imaging. IEEE Transactions on Medical Imaging. 2010;29(9):1626–1635. 104. Tournier et al. Robust determination of the fibre orientation distribution in diffusion MRI: Non-negativity constrained superresolved spherical deconvolution. NeuroImage. 2007;35:1459– 1472. 105. Fernandez-­Miranda JC, Pathak S, Engh J, et al. High-­definition fiber tractography of the human brain: neuroanatomical validation and neurosurgical applications. Neurosurgery. 2012;71(2):430– 453.

CHAPTER 4

Intraoperative Neurophysiology: A Tool to Prevent and/or Document Intraoperative Injury to the Nervous System VEDRAN DELETIS  •  FRANCESCO SALA Over the past 25 years, intraoperative neurophysiology (ION) has established itself as a clinical discipline that uses neurophysiologic methods—especially developed or modified from existing methods of clinical neurophysiology—to detect and prevent intraoperatively induced neurologic injuries. Recent developments have solidified its role in neurosurgery and other surgical disciplines. Ideally, ION not only predicts but also serves to prevent intraoperatively induced injury to the nervous system. Furthermore, ION can be used to document the exact moment when the injury occurred. As a result, it can be used for both educational and medicolegal purposes. Generally, ION techniques can be divided in two groups: mapping and monitoring. Neurophysiologic mapping is a technique that, when applied intraoperatively, enables us to identify anatomically indistinct neural structures by their neurophysiologic function. This allows the surgeon to avoid lesioning critical structures in the course of the surgical procedure. In essence, the information gained from neurophysiologic mapping allows the surgeon to operate more safely. The following procedures use a neurophysiologic mapping technique: identification of the primary motor cortex with direct cortical stimulation, identification of the cranial nerve motor nuclei on the surgically exposed floor of the fourth ventricle, mapping of the corticospinal tract (CT) subcortically (i.e., at the level of the cerebral peduncle or at the spinal cord), mapping of the pudendal afferents in the sacral roots, before selective dorsal rhizotomy, and so on. Neurophysiologic monitoring is a technique that continuously evaluates the functional integrity of nervous tissue and gives feedback to the (neuro)surgeon. This feedback can be instantaneous, as in a recently developed technique of monitoring motor-­evoked potentials (MEPs) from the epidural space of the spinal cord or limb muscles. If the surgical procedure allows us to combine monitoring with mapping techniques, then optimal protection of nervous tissue can be achieved during neurosurgery. Furthermore, ION uses provocative tests to examine their influence on neurophysiologic signals before the surgical procedure. A temporary clamping of the carotid artery during endarterectomy with monitoring of somatosensory-­ evoked potentials (SEPs) or electroencephalography is a

34

typical example of a provocative test that measures the ability of the collateral cerebral circulation to supply a potentially ischemic hemisphere. Endovascular injection of a short-­ acting barbiturate or lidocaine into a vascular malformation of the spinal cord, before embolization, and observation of its influence on the neurophysiologic signals is another example of a provocative test.

Supratentorial Surgery Surgery for brain gliomas has become more and more aggressive. This is based on clinical data that support better patient survival and quality of life after gross total removal of both low-­and high-­grade lesions;1,2 however, the resection of tumors located in eloquent brain areas, such as the rolandic region and frontotemporal speech areas, requires the identification of functional cortical and subcortical areas that must be respected during surgery. Moreover, the dogmatic assumption that tumoral tissue could not retain function has been repeatedly questioned by neurophysiologic and functional magnetic resonance imaging studies.3–5 In response to the need for a safe surgery in eloquent brain areas, the past decade has seen the development of a number of techniques to map brain functions, including, but not limited to, functional magnetic resonance imaging, magnetoencephalography, and positron emission tomography.6–11 The neurophysiologic contribution to brain mapping has been evident since the late 19th century with the pioneering work of Fritsch and Hitzig12 and Bartholow.13 In the 20th century, Penfield and colleagues14,15 made invaluable contributions through intraoperative mapping of the sensorimotor cortex, whose findings have been substantiated by a number of recent studies.16–18

SOMATOSENSORY-­EVOKED POTENTIAL PHASE-­ REVERSAL TECHNIQUE To indirectly identify the central sulcus, SEPs can be recorded from the exposed cerebral cortex by using the phase-­reversal technique. SEPs are elicited by stimulation of the median nerve at the wrist and the posterior tibial nerve at the ankle (40 mA intensity, 0.2 ms duration, 4.3 Hz repetition rate). Recordings are performed from the scalp

4  •  Intraoperative Neurophysiology: A Tool to Prevent and/or Document Intraoperative Injury to the Nervous System

N20

35

Cz

P30 1

tral cen

2 3

1

5 6

Phase reversal

P20

N30

3

4

C4

T4 Inion

7 8

2

7

cus sul

4

6 5

8

– 40µV + 50 ms

FIGURE 4.1  Identification of the central sulcus by phase reversal of median nerve cortical somatosensory-­evoked potentials. To the right is a schematic drawing of the exposed brain surface with a grid electrode position orthogonally to the central sulcus. On the left are the recorded evoked potentials phase reversed between electrode 6 and 7, showing a mirror image of the evoked potential between the motor and sensory cortices, depicting the central sulcus lying between electrodes 6 and 7. (From Deletis V. Intraoperative neurophysiological monitoring. In: McLone D, ed. Pediatric Neurosurgery: Surgery of the Developing Nervous System. 4th ed. Philadelphia: WB Saunders; 1999:1204–1213.)

at CZ′-­FZ (for legs) and C3′/C4′-­CZ′ (for arms) according to the 10 to 20 International Electroencephalography System. After craniotomy, a strip electrode is placed across the exposed motor cortex and primary somatosensory cortex, transversing the central sulcus. This technique is based on the principle that an SEP, elicited by median nerve stimulation at the wrist, can be recorded from the primary sensory cortex.19 Its mirror-­image waveform can be identified if some of the contacts of the strip electrode are placed on the opposite side of the central sulcus, over the motor cortex (Fig. 4.1).20–22 For phase reversal, a strip electrode with four to eight stainless steel contacts with an intercontact distance of 1 cm is used. In the literature, the success rate of the phase reversal technique to indirectly localize the primary motor cortex ranges between 91%20,21 and 97%.18 Interestingly, identification of the central sulcus by magnetic resonance imaging provided contradictory results when compared with intraoperative phase reversal.20 Although it is expected that ongoing progress in the field of functional magnetic resonance imaging will eventually replace the need for neurophysiologic tests, ION still retains the highest reliability in mapping of the motor cortex and language areas when compared with functional neuroimaging.23–26 

DIRECT CORTICAL STIMULATION (60-­HZ PENFIELD TECHNIQUE) Once the motor strip has indirectly been identified by the phase reversal technique, direct cortical stimulation is required to confirm the localization of the motor cortex. Most current methods are based on the original Penfield technique. This calls for continuous direct cortical stimulation over a period of a few seconds with a frequency of stimulation of 50 to 60 Hz and observation of muscle movements.14,16,27 An initial current intensity of 4 mA is used

and, if no movements are elicited in contralateral muscles of the limbs and face, stimulation is increased in steps of 2 mA to the point at which movements are elicited.16 Muscle responses can either be observed visually or documented by multichannel electromyography, which appears to be more sensitive.28 If no response is elicited with an intensity as high as approximately 16 mA, that area of cortex is considered not functional and can therefore be removed.29 It should be emphasized that a negative mapping does not always ensure safety. To increase the chances of obtaining a positive mapping result, technical and anesthesiologic drawbacks have to be carefully ruled out and cortical exposure should be generous. More in general, a limitation to the reliability of cortical mapping is the large variability of threshold for a positive mapping response across and within individuals.30 A motor response from the same muscular group can be elicited from more than one cortical site, using different stimulation intensities. Therefore, function localization may vary in different studies as a result of stimulation parameters and mapping strategies. Mapping strategies appear as one of the main variables that may affect the results of stimulation. Two different theories underline the choice of one or the other strategy: 1. Some authors apply the concept that thresholds (the minimum stimulation current required to induce functional changes) vary across the exposed cortex depending on the task being assessed and the location being mapped. This is in keeping with the observation that even afterdischarge (AD) thresholds can vary significantly, not only across the population but also in the same subject at different cortical sites.30,31 Accordingly, they attempt to maximize stimulation currents at each cortical site to ensure the absence of eloquent function. Doing so, it is

36

Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

A - Tumor removed B - Hemostasis C - C2/17ST130MA D - PA 90/50 mmHg E - Papaverine PA 100/50 mmHg F - PA 120/65 mmHg

T

Papaverine 10' after papaverine

C

G - Closing

MCA L-APB

L-TA

FIGURE 4.2  Upper left: Preoperative axial contrast-­enhanced, magnetic-­resonance, T1-­weighted image of a right frontotemporoinsular anaplastic astrocytoma that was removed with the assistance of intraoperative neurophysiologic monitoring. Lower left: Intraoperative view at the end of tumor resection. The internal capsule (C) has been identified using mapping of the subcortical motor pathways with the short train of stimuli technique. The temporal lobe (T) and branches of the middle cerebral artery (MCA) are on view. Right: Motor-­evoked potentials (MEPs) recorded intraoperatively from the left abductor brevis pollicis (L-­APB) and tibialis anterior (L-­TA) muscles. MEP recordings at the end of tumor removal (A); MEP loss during hemostasis (B); transitory MEP reappearance by increasing stimulation to seven stimuli and 130 mA intensity (C); new disappearance of MEPs despite increased stimulation (D); progressive MEP reappearance after papaverine infusion and increased systemic blood pressure (E and F); MEPs at the end of the procedure (G). (Modified from Sala F, Lanteri P. Brain surgery in motor areas: The invaluable assistance of intraoperative neurophysiological monitoring. J Neurosurg Sci. 2003;47:79–88.)

more common to exceed AD thresholds in adjacent cortices, and there is a higher risk of distal activation owing to current spreading to adjacent sites. 2. Other authors29,32,33 keep stimulation intensity constant while mapping the entire cortex and set threshold just below the lowest current observed to induce AD. This strategy is aimed to minimize the risk of inducing ADs (which may invalidate the results) and clinical seizures but may miss the identification of eloquent cortical sites. Spreading of the current using the 60 Hz stimulation technique is limited to 2 to 3 mm as detected by optical imaging in monkeys.34 Accordingly, one can assume that using this technique is safe for removal of tumors very close to the motor and sensory pathways as long as stimulation is repeated whenever a 2 to 3 mm section of tumoral tissue is removed.29 Similarly, this technique allows us to map motor pathways subcortically while removing tumors that arise or extend to the insular, subinsular, or thalamic areas.27,35 At the subcortical level, the stimulation intensity required to elicit a motor response is usually lower than that required for cortical mapping. When performing subcortical mapping, however, we have to keep in mind that a distal muscle response after stimulation of subcortical motor pathways can be misleading. Although this stimulation activates axons distal to the stimulation point, the possibility of damage to the pathways proximal to that point cannot be ruled out. This is a concern,

especially when dealing with an insular tumor where there is a risk of cortical or subcortical ischemia induction secondary to manipulation of perforating vessels (Fig. 4.2). Despite its popularity in the past, this 60 Hz Penfield technique has some disadvantages. With the exception of speech mapping, it is our opinion that these disadvantages should prevent its use as a motor cortex/pathways mapping technique. First, this technique can induce seizures in as many as 20% of patients, despite therapeutic levels of anticonvulsants and regardless of whether there is a preoperative history of intractable epilepsy.36,37 Second, in children younger than 5 years old, direct stimulation of the motor cortex for mapping purposes may not yield localizing information because of the relative unexcitability of the motor cortex.19,38 Third, because this is a mapping and not a monitoring technique, no matter how often cortical or subcortical stimulation is repeated, the functional integrity of the motor pathways cannot be assessed continuously during surgery. 

DIRECT CORTICAL STIMULATION AND MOTOR-­EVOKED POTENTIAL MONITORING (SHORT TRAIN OF STIMULI TECHNIQUE) Recently, mapping techniques have integrated monitoring techniques to continuously assess the functional integrity of the motor pathways and therefore increase the safety of these procedures.20,39–41 The following is a description of

4  •  Intraoperative Neurophysiology: A Tool to Prevent and/or Document Intraoperative Injury to the Nervous System

the technique that we use at our institutions and have found suitable for both mapping and monitoring. Muscle MEPs are initially elicited by multipulse transcranial electrical stimulation (TES). Short trains of five to seven square-­wave stimuli of 500 μs duration with an interstimulus interval of 4 ms are applied at a repetition rate of as high as 2 Hz through electrodes placed at C1 and C2 scalp sites, according to the 10 to 20 International Electroencephalography System. The maximum stimulation intensity should be as high as 200 mA, which is strong enough for most cases. Muscle responses are recorded via needle electrodes inserted into the contralateral upper and lower extremity muscles. We usually monitored the abductor pollicis brevis and the extensor digitorum communis for the upper extremities and the tibialis anterior and the abductor hallucis for the lower extremities. For the face area, the orbicularis oculi and orbicularis oris muscles are typically used. After exposure of the cortex and once phase reversal has been performed, direct cortical stimulation of the motor cortex can be achieved by using a monopolar-­stimulating probe to identify the cortical representation of contralateral facial and limb muscles. The same parameters of stimulation used for TES, except for a much lower intensity (≤20 mA), can be used.39 Sometimes, the short train of stimuli technique requires slightly higher current intensities than those required by the Penfield technique; however, by using a very short train, the charge applied to the brain is significantly reduced42 and, consequently, the risk of inducing seizures. The number of pulses in the short-­train technique is five to seven pulses per second, whereas in the Penfield technique there are 60 pulses per second. The effect of stimulation on the cerebral cortex, from a neurophysiologic point of view, differs between the Penfield technique and the short train of stimuli technique. The Penfield technique delivers one stimulus every 15 to 20 ms continuously for a couple of seconds. The short train of stimuli technique delivers five to seven stimuli in a period of approximately 30 ms with a long pause between trains (470 to 970 ms, which depends on train repetition rate—1 or 2 Hz). Therefore, the Penfield technique is more prone to produce seizures, activating the cortical circuitry more easily than short-­train stimuli do. Furthermore, compared with the Penfield technique, the short-­ train technique does not induce strong muscle twitches that may interfere with the surgical procedure. Responses are usually recorded from needle electrodes used to record muscle MEPs elicited by TES; however, any combination of recording muscles can be used, according to the tumor location. The larger the number of monitored muscles, the lower the chance of a false-­negative mapping result. We suggest that stimulation of the tumoral area should always be performed to rule out the presence of some functional cortex. As already described, this is especially true in the case of low-­grade gliomas.3–5 In the illustrative case presented in Fig. 4.2,39 an impairment of muscle MEPs occurred at the end of tumor removal when opening and closing mapping procedures had already been done and confirmed the integrity of motor pathways distal to the stimulation point at the level of the internal capsule. However, ischemia of the pyramidal tracts secondary to severe vasospasm of the main perforating branches of the middle cerebral artery occurred during hemostasis and was detected by muscle MEP monitoring. If not detected

37

in time, this event would have likely resulted in an irreversible loss of muscle MEPs and, consequently, a permanent motor deficit. Mapping techniques are unlikely to detect these events because they do not allow a continuous “online” assessment of the functional integrity of neural pathways. In our experience with using the short-­train technique, a threshold lower than 5 mA for eliciting muscle MEPs usually indicated proximity to the motor cortex. When muscle responses are elicited through higher stimulation intensities, activation of the CT is of less localizing value because of the possibility of spreading of the current to adjacent areas.39 Once mapping of the cortex has clarified the relationship between eloquent motor areas and the lesion, continuous MEP monitoring of the contralateral muscles can be sustained throughout the procedure to assist during the surgical manipulation. To do so, one of the same contacts of the strip electrode can be used as an anode for stimulation while the cathode is at Fz. The stimulation point on the motor cortex with the lowest threshold used to elicit muscle MEPs from contralateral limbs or face usually corresponds with the contact from which the largest amplitude of the mirror-­ image SEPs was obtained. The same stimulation parameters as those used for the short-­train mapping technique can be used. When removing a tumor that extends subcortically, preservation of muscle MEPs during monitoring from the strip electrode will guarantee the functional integrity of motor pathways and avoid the need for periodic remapping of the cortex at known functional sites.39 For insular tumors where the motor cortex is not exposed by the craniotomy, a strip electrode can still be gently inserted into the subdural space to overlap the motor cortex. Phase reversal and/or direct cortical stimulation can be used to identify the electrode with the lowest threshold to elicit muscle MEPs. The use of MEPs during surgery for insular tumors has proved very useful to identify impending vascular derangements to subcortical motor pathways in time for corrective measures to be taken. In spite of the observation that intraoperative MEP changes occurred in nearly half of the procedures, these were reversible in two thirds of the cases.43 

WARNING CRITERIA AND CORRELATION WITH POSTOPERATIVE OUTCOME Still debated are the warning criteria for changes in muscle MEPs that are used to inform the surgeon about an impending injury to the motor system. It should be stressed that although for spinal cord surgery, a “presence/absence” of muscle MEPs criterion has proved to be reliable and strictly correlates with postoperative results,44,45 there are not definite MEP parameters indicative of significant impairment during supratentorial surgery.46 We believe that the predictive value of muscle MEPs is different for supratentorial and spinal cord surgeries. As such, different warning criteria must be employed. This judgment is based on the difference in types of CT fibers in supratentorial portion of the CT as compared with the spinal cord. Different groups with established experience in this field have proposed similar criteria,40,46 suggesting that a shift in latency between 10% and 15% and a decrease in amplitude of more than 50% to 80% correlate with some degree of postoperative motor deficit. However, a permanent new motor deficit has consistently

38

Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

correlated only with irreversible complete loss of muscle MEPs.46 A persistent increase in the threshold to elicit muscle MEPs or a persistent drop in muscle MEP amplitude, despite stable systemic blood pressure, anesthesia, and body temperature, represents a warning sign. However, it should be noted that muscle MEPs are easily affected by muscle relaxants, bolus of intravenous anesthetics and high concentrations of volatile (and other) anesthetics such that wide variation in muscle MEP amplitude and latency can be observed.47 Due to this variability, the multisynaptic nature of the pathways involved in the generation of muscle MEPs, and the nonlinear relationship between stimulus intensity and the amplitude of muscle MEPs, the correlation between intraoperative changes in muscle MEPs (amplitude and/or latency) and the motor outcome are not linear. Further clinical investigation is required to clarify sensitive and specific neurophysiologic warning criteria for brain surgery. 

Subcortical Stimulation Traditionally, in neurosurgery, most of the interest and research with regards to brain tumor surgery in so-­called eloquent areas was focused on cortical—rather than subcortical—­mapping. This was due to the classical concept of eloquent cortex, in which location of function was reputed to be mostly located in specific cortical regions. Yet the large inter-­individual variability of brain functional organization—for example in language47a—and the lack of consistency in the clinical presentation of damage to the same cortical region, challenged the concept of rigid cortical functional organization. Therefore, while cortical mapping has been, for many decades, the focus of ION during brain tumor surgery, subcortical mapping has emerged over the past decade as an invaluable technique to preserve white matter functional boundaries and, ultimately, to decide when to stop tumor resection. As the brain is composed of localized but connected specialized areas, an injury to white matter tracts may induce irreversible neurological deficits, since damage to these tracts may cause as much deficit as damage to cortical areas. Subcortical mapping, therefore, is essential because it enables investigation into the functional role of specific subcortical networks. The concept of brain connectome and hodotopy47b,47c and the advent of tractography47d have contributed further to the increasing popularity of subcortical mapping. Over the past decade, a few technical aspects related to subcortical mapping have been addressed and clarified, especially with regards to motor pathways. First, it is now well accepted that the CT can be localized at a subcortical level using the same techniques as for direct cortical stimulation, although cathodal rather than anodal stimulation should be used. A short train of stimuli delivered through a monopolar probe proved to be the most successful technique for subcortical mapping.47e Second, several studies attempted to understand the relationship between the threshold current necessary to elicit a subcortical motor response (subcortical threshold) and the distance between the stimulation site and the CT itself. With minor inconsistencies, current evidence

suggests that a subcortical threshold current of 1 mA roughly corresponds to a 1 mm distance between the stimulation site and the CT.47f,47g Yet, this correlation is based on the assumption that cathodal stimulation and a stimulus duration of 0.5 to 0.7 ms is used. If either anodal stimulation and/or shorter (0.3 ms) duration are used, then the correlation varies substantially.47h A third matter of discussion is what should be considered a safe subcortical threshold to avoid post-­operative motor deficits. Obviously, the lower the threshold capable of eliciting a response, the higher the risk of postoperative deficit because low threshold means proximity to the CT. A cut-­off value of 3 mA has been consistently reported in the literature suggesting that the risk increases when the CT is only 3 to 4 mm away from the dissection.47f,47i,47j Nowadays new tools such us suction devices47k or ultrasonic aspirators combined with a stimulating probe are available, and increase the temporo-­spatial resolution of subcortical mapping. Using these technical advances, subcortical threshold as low as 1 to 2 mA might be tolerated. However, this challenge should be based on very robust experience combining expertise in both ION and brain tumor surgery. In general, any subcortical thresholds below 5 mA should be considered at risk of some motor derangements and should prompt careful attention by the surgeon in order to not injure the CT. Overall, with regards to the preservation of the CT, the best neurophysiological approach should combine both continuous MEP monitoring and subcortical mapping. The first is aimed to monitor the functional integrity of motor pathways from the motor cortex to the muscles, and is the only technique that can detect, and possibly revert or minimize, an impending vascular injury to subcortical motor pathways. Subcortical mapping cannot detect vascular injuries but is essential to determine the distance from the CT and avoid a mechanical injury to this pathway. 

Brain Stem Surgery The human brain stem is a small and highly complex structure containing a variety of critical neural structures. These include sensory and motor pathways; sensory and motor cranial nerve nuclei; cardiovascular and respiratory centers; neural networks supporting swallowing, coughing, articulation, and oculomotor reflexes; and the reticular activating system. In such a complex neural structure, even small lesions can produce severe and life-­threatening neurologic deficits. The neurosurgeon faces two major problems when attempting to remove brain stem tumors. First, if the tumor is intrinsic and does not protrude on the brain stem surface, approaching the tumor implies a violation of the anatomic integrity of the brain stem. Knowledge of the location of critical neural pathways and nuclei is mandatory when considering a safe entry into the brain stem,48,49 but may not suffice when anatomy is distorted. Morota and colleagues50 reported that visual identification of the facial colliculus based on anatomic landmarks was possible in only three of seven medullary tumors and was not possible in five pontine tumors. The striae medullares were visible in four of five patients with pontine tumors and in five of nine patients with medullary tumors. Therefore, functional rather than anatomic localization of brain stem nuclei and pathways should be used to identify safe entry zones.

4  •  Intraoperative Neurophysiology: A Tool to Prevent and/or Document Intraoperative Injury to the Nervous System

MAPPING TECHNIQUES Neurophysiologic mapping techniques have been increasingly used to localize CT and cranial nerve motor nuclei on the lateral aspect of the midbrain and on the floor of the fourth ventricle.61-­65 

MAPPING OF THE CORTICOSPINAL TRACT AT THE LEVEL OF THE CEREBRAL PEDUNCLE This is a recently described technique used to map the CT tract within the brain stem at the level of the cerebral peduncle.65,66 To identify the CT, we use a hand-­held monopolar-­ stimulating probe (0.75 mm tip diameter) as a cathode, with a needle electrode inserted in a nearby muscle as an anode. If the response (D wave) is recorded from an epidural electrode, a single stimulus is used. Conversely, if the response is recorded as a compound muscle action potential from one or more muscles of contralateral limbs, a short train of stimuli should be used. We usually increase stimulation intensity to 2 mA. When a motor response is recorded, the probe is then moved in small increments of 1 mm to find the lowest threshold to elicit that response. This technique is particularly useful for midbrain tumors that have displaced the CT tract from its original position. Usually, the so-­called midbrain lateral vein described by Rhoton67 represents a useful anatomic landmark because it allows an indirect identification of the CT tract, located anterior to the vein. However, when an expansive lesion distorts anatomy, only neurophysiologic mapping allows the identification of the CT and, consequently, a safe entry zone to the lateral midbrain. In the case of a cystic midbrain lesion, sometimes mapping of the CT is negative at the beginning of the procedure, but a positive response can be recorded when mapping from within the cystic cavity toward the anterolateral cystic wall.68 

MAPPING OF MOTOR NUCLEI OF CRANIAL NERVES ON THE FLOOR OF THE FOURTH VENTRICLE This technique is based on intraoperative electrical stimulation of the motor nuclei of the cranial nerves on the floor of the fourth ventricle, using a hand-­held monopolar stimulating probe. Compound muscle action potentials are then elicited in the muscles innervated by the cranial motor nerves. A single stimulus of 0.2 ms duration is delivered at a repetitive rate of 2.0 Hz. Stimulation intensity starts at approximately 1 mA and is then reduced to determine the point with the lowest threshold that elicits muscle responses corresponding with the mapped nucleus (Fig. 4.3). No stimulation intensity higher than 2 mA should be used.61,62 To record the responses from cranial motor nerves VII, IX/X, and XII, wire electrodes are inserted into the orbicularis oculi and orbicularis oris muscles, the posterior wall of the pharynx, and the lateral aspect of the tongue muscles, respectively. Based on mapping studies, characteristic patterns of motor cranial nerve displacement, secondary to tumor growth, have been described (Fig. 4.4).69 The case described in Fig. 4.5 is consistent with this observation. A similar methodology can be applied to identify the motor nuclei of cranial nerves innervating ocular muscles (nerves III, IV, and VI) during a dorsal approach to midbrain lesions as well as quadrigeminal plate, tectal, and pineal region tumors.70,71

39

Despite the relative straightforwardness of the fourth ventricle mapping technique and its indisputable usefulness in planning the most appropriate surgical strategy to enter the brain stem, postoperative functional outcome is not always predicted by postresection responses.61 In the case of mapping of the motor nuclei of the seventh cranial nerve, brain stem mapping cannot detect injury to the supranuclear tracts originating in the motor cortex and ending on the cranial nerve motor nuclei. Consequently, a supranuclear paralysis would not be detected, although lower motoneuron integrity has been preserved. Similarly, the possibility of stimulating the intramedullary root more than the nuclei itself exists. This could result in a false-­negative peripheral response still being recorded despite an injury to the motor nuclei.61 Mapping of the glossopharyngeal nuclei is also of limited benefit. Recording activity from the muscles of the posterior pharyngeal wall after stimulation of the ninth cranial nerve motor nuclei on the floor of the fourth ventricle assesses the functional integrity of the efferent arc of the swallowing reflex. This technique, however, does not provide information on the integrity of afferent pathways and afferent/efferent connections within brain stem, which are indeed necessary to provide functions involving reflexive swallowing, coughing, and the complex act of articulation. Recently, however, Sakuma and colleagues72 succeeded in monitoring glossopharyngeal nerve compound action potentials after stimulation of the tongue in dogs, opening the possibility of a new field of investigation in humans. Functional magnetic resonance imaging of the brain stem has also provided a new, yet experimental, tool to localize cranial nerve nuclei in humans.73 An intrinsic limitation of all mapping techniques, however, is that these do not allow the continuous evaluation of the functional integrity of a neural pathway. The identification of the safe entry zone for approaching a pontine astrocytoma, as in Fig. 4.5, does not provide any information on the wellbeing of the adjacent corticospinal, corticobulbar, sensory, and auditory pathways during the surgical manipulation aimed to remove the tumor. Therefore, it is essential to combine mapping with monitoring techniques. 

MONITORING TECHNIQUES SEPs and brain stem auditory-­evoked potentials have been extensively used to assess the functional integrity of the brain stem, and we refer the reader to the related literature for a review of these classic techniques. Unfortunately, SEPs and brain stem auditory-­evoked potentials can evaluate only approximately 20% of brain stem pathways.74 As a result, their use is of limited value when the major concern is related to corticospinal and cranial nerve motor function. Still, brain stem auditory-­evoked potentials can provide useful information on the general wellbeing of the brain stem, especially during those procedures in which a significant surgical manipulation of the brain stem and/or of the cerebellum is expected. When interpreting brain stem auditory-­evoked potential recordings, a thoughtful analysis of the waveform and of their correlation with neural generators provides useful information about the localization of the changes. When an initial myelotomy is performed at the region of dorsal column nuclei of the medulla, further monitoring with SEPs is compromised due to limitations similar to those related to intramedullary spinal cord tumor surgery after myelotomy.65 For pontine and midbrain tumors, SEPs have

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Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

FIGURE 4.3  Mapping of the brain stem cranial nerve motor nuclei. Upper left: Drawing of the exposed floor of the fourth ventricle with the surgeon’s handheld stimulating probe in view. Upper middle: The sites of insertion of wire hook electrodes for recording the muscle responses are depicted. Far upper right: Compound muscle action potentials recorded from the orbicularis oculi and oris muscles after stimulation of the upper and lower facial nuclei (upper two traces) and from the pharyngeal wall and tongue muscles after stimulation of the motor nuclei of cranial nerves IX/X and XII (lower two traces). Lower left: Photograph obtained from the operating microscope shows the hand-­held stimulating probe placed on the floor of the fourth ventricle (F). A, Aqueduct. (Reproduced from Deletis V, Sala F, Morota N. Intraoperative neurophysiological monitoring and mapping during brain stem surgery: A modern approach. Oper Tech Neurosurg. 2000;3:109–113.)

lt. VII rt. VII Tumor

lt. VII rt. VII Tumor

rt. XII

rt. XII lt. XII

lt. XII Lower pontine tumor

Upper pontine tumor

lt. VII

lt. VII

rt. VII

rt. VII rt. XII

Tumor

Medullary tumor

rt. XII lt. XII

lt. XII Tumor Cervicomedullary junction spinal cord tumor

FIGURE 4.4  Typical patterns of cranial nerve motor nuclei displacement by brain stem tumors in different locations. Upper and lower pontine tumors: Pontine tumors typically grow to push the facial nuclei around the edge of the tumor, suggesting that precise localization of the facial nuclei before tumor resection is necessary to avoid their damage during surgery. Medullary tumors: Medullary tumors typically grow more exophytically and compress the lower cranial nerve motor nuclei ventrally; these nuclei may be located on the ventral edge of the tumor cavity. Because of the interposed tumor, in these cases mapping before tumor resection usually does not allow identification of cranial nerve IX/X and XII motor nuclei. Responses, however, could be obtained close to the end of the tumor resection when most of the tumoral tissue between the stimulating probe and the motor nuclei has been removed. At this point, repeat mapping is recommended because the risk of damaging motor nuclei is significantly higher than at the beginning of tumor debulking. Cervicomedullary junction spinal cord tumors: These tumors simply push the lower cranial nerve motor nuclei rostrally when extending into the fourth ventricle. (Reproduced from Morota N, Deletis V, Lee M, et al. Functional anatomic relationship between brain stem tumors and cranial motor nuclei. Neurosurgery. 1996;39:787–794.)

4  •  Intraoperative Neurophysiology: A Tool to Prevent and/or Document Intraoperative Injury to the Nervous System

41

Pre-op

Post-op

B

A 1.5 mA

0.5 mA

0.2 mA

0.2 mA

A

C

RU

RL

LU

LL

D

FIGURE 4.5  Upper panel: (Top): Preoperative contrast-­enhanced, T1-­weighted magnetic resonance imaging (MRI) of an upper left pontine low-­grade astrocytoma in a 16-­year-­old female. Bottom: Postoperative MRI study showing complete tumor removal. Surgery was performed under neurophysiologic guidance. Middle panel: Direct mapping of the facial nerve motor nuclei on the floor of the fourth ventricle. The tumor was approached through a median suboccipital craniectomy. When the floor of the fourth ventricle was exposed, the median sulcus appeared dislocated to the right and the left median eminence was expanded. Electromyographic wire electrodes were inserted bilaterally in the left (LU) and right (RU) orbicularis oculi and left (LL) and right (RL) orbicularis oris muscles for mapping and monitoring of the seventh nerve, and in the abductor pollicis brevis (LA and RA) for continuous monitoring of the corticospinal tract integrity. We initially stimulated on the left side, approximately 1.5 cm rostral to the striae medullares, where the motor nuclei were expected to be according to normal brain stem functional anatomy. A response was obtained from the left orbicularis oculi (LU) at a stimulation intensity of 1.5 mA (A). By moving the stimulating probe

little localizing value but can still be used to provide nonspecific information about the general functional integrity of the brain stem (because it is expected that a major impending brain stem failure will be detected by changes in SEP parameters). Similar to what has occurred for brain and spinal cord surgery, the major breakthrough in modern ION of the brain stem has been the advent of MEP-­related techniques. With regard to motor function within the brain stem, standard techniques for continuously assessing the functional integrity of motor cranial nerves relies on the recording of spontaneous electromyographic activity in the muscles innervated by motor cranial nerves.71,75,76 Several criteria have been proposed to identify electromyographic activity patterns that may anticipate transitory or permanent nerve injury, but these patterns are not always easily recognizable and criteria remain vague or at least subjective. Overall, convincing data

regarding a clinical correlation between electromyographic activity and clinical outcomes is still lacking.71,75, Seeking more reliable techniques in the neurophysiologic monitoring of motor cranial nerve integrity, the possibility of extending the principles of CT monitoring to the corticobulbar tracts (CBTs) is currently under investigation.68,77

Monitoring of Corticobulbar (Corticonuclear) Pathways For this purpose, TES with a train of four stimuli, with an interstimulus interval of 4 ms and a train-­stimulating rate of 1 to 2 Hz, intensity between 60 and 100 mA can be used. The stimulating electrode montage is usually C3/Cz for right-­ side muscles and C4/Cz for left-­ side muscles. For recording muscle MEPs, electromyographic wire electrodes are inserted in the orbicularis oris and orbicularis oculi muscles for nerve VII, in the posterior pharyngeal wall for the

42

Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

I A

B

C

D

B

2:LL+/LL–

4:LA+/LA–

FIGURE 4.5 CONT’D  caudally and to the right, a consistent response from the left orbicularis oris (LL) was recorded at a stimulation intensity of 0.5 mA (B). At this point, we moved the stimulation probe more laterally to the right side, approximately 1 cm above the striae medullares, and a clear response was recorded from the right orbicularis oris (RL) at the lowest threshold intensity of 0.2 mA (C). Finally, by moving the stimulating probe paramedially to the left side, a few millimeters above the striae medullares, a consistent response was recorded from both the left orbicularis oris (LL) and orbicularis oculi (LU), using the same low threshold (0.2 mA) (D). The conclusion was drawn that the tumor displaced caudally the facial nerve motor nuclei, especially on the left side. Based on mapping results, the surgeon decided to enter the brain stem on the left side in correspondence with the higher threshold stimulating point (A). Lower left: Schematic summary of mapping results. A and B represent the original position of the left and right facial colliculi, as expected according to brain stem anatomy. A, B, C, and D correspond to the stimulating point illustrated in the upper panel. C and D also correspond to the lower threshold to elicit a consistent response from, respectively, the right and left muscles innervated by the facial nerve. The conclusion was made that real location of facial nerve motor nuclei (C and D) was more caudal than expected, especially on the left side, due to the tumor mass effect. Accordingly, initial incision (I) was carried on transversely in correspondence with stimulating point A. Lower right: Continuous neurophysiologic monitoring of muscle motor-­evoked potentials during tumor removal. Electromyographic wire electrodes were inserted in the left orbicularis oris (LL) and abductor pollicis brevis (LA) muscles for continuous monitoring of, respectively, the corticobulbar and corticospinal tract integrity, after transcranial electrical stimulation (electrode montage C4/ Cz; short train of four stimuli; intensity 50 mA). (Modified from Sala F, Lanteri P, Bricolo A. Intraoperative neurophysiological monitoring of motor evoked potentials during brain stem and spinal cord surgery. Adv Tech Stand Neurosurg. 2004;29:133–169.)

cranial motor nerves IX and X, and in the tongue muscles for the hypoglossal nerve (i.e., in the same manner as described for mapping of motor nuclei of the cranial nerves). Reproducible muscle MEPs can be continuously recorded from the facial, pharyngeal, and tongue muscles while the brain stem is surgically manipulated (see Fig. 4.5). This technique allows one to monitor the entire pathway, from the motor cortex down to the neuromuscular junction, so that a supranuclear injury can be detected. However, the CBT monitoring technique is still far from becoming standardized due to some theoretical and practical drawbacks. First, from a neurophysiologic perspective, use of the lateral montage as an anodal stimulating electrode (C3 or C4) increases the risk that strong TES may not activate the corticobulbar pathways but the cranial nerve directly. Accordingly, an injury to the corticobulbar pathway rostral to the point of activation may be masked by a misleading preservation of the muscle MEP. To minimize this risk, stimulation intensity should be kept as low as possible. One of the ways to recognize the structure generating this response is as follows; 90 ms after delivering train of stimuli a single stimulus was delivered through the same stimulating montage. The rationale for this kind of stimulation is the fact that in most patients under general anesthesia, only a short train of stimuli can elicit “central” responses generated by the motor cortex or subcortical part of CBT. If a single stimulus elicits a response, this should be considered a “peripheral” response, which activates the cranial nerve directly by spreading current more distally.78

Furthermore, given the continuous fluctuations in the threshold required to elicit muscle MEPs intraoperatively (i.e., due to variability in room temperature, anesthesiologic regimen, and physiologic variability in muscle MEP threshold, and so on), the appropriate threshold for monitoring corticobulbar pathways should be rechecked throughout the surgical procedure. Another limitation of this technique is that spontaneous electromyographic activity can sometimes hinder the recording of reliable muscle MEPs from the same muscles. In our experience, this spontaneous activity appears to be more common in the pharyngeal muscles as compared with the facial and tongue muscles. Further experience with this technique will indicate the extent to which monitoring of the CBT predicts postoperative function and allows an impending injury to the motor cranial nerves to be recognized in time to be corrected (see Fig. 4.5). Due to the complexity of the brain stem’s functional anatomy, the more neurophysiologic techniques that can be rationally integrated, the better the chances for successful monitoring.79 The battery of techniques to be used should be tailored to each individual patient according to tumor location and clinical status. Keeping this in mind, SEPs and brain stem auditory-­evoked potentials should always be considered. However, unlike in the past decade when these classic monitoring methods allowed only a very limited assessment of the brain stem functional integrity, current techniques of MEP monitoring and motor nuclei mapping are receiving increasing credit in assisting the neurosurgeon during brain stem surgery. 

4  •  Intraoperative Neurophysiology: A Tool to Prevent and/or Document Intraoperative Injury to the Nervous System

Spinal and Spinal Cord Surgery These surgeries are potentially burdened with serious neurologic deficits such as para-­or quadri-­plegia (paresis). As a rule, the closer to the spinal cord that the neurosurgeon operates, the higher the risk of injury. Of course, there is always the possibility that surgeries on the bony structures of the spinal cord can result in paraplegia.80,81 Furthermore, long-­ lasting intraoperative hypotension can be disastrous for the spinal cord if neurophysiologic monitoring has not been used because no other routine methods are available to evaluate the functional integrity of the spinal cord during hypotension. It has been shown that the use of SEPs to monitor the functional integrity of the spinal cord is inadequate and can result in false-­negative results (i.e., no changes in SEP parameters intraoperatively, but the patient wakes up paraplegic after surgery).80,81 Therefore, it is mandatory that during spinal and spinal cord surgeries, monitoring of both sensory and motor modalities of evoked potentials is conducted. Each of these methods evaluates different long tracts; SEPs evaluate the dorsal columns, whereas MEPs evaluate CT. If a lesion to the spinal cord is diffuse in nature, affecting both long tracts, monitoring one of them may suffice. Unfortunately, this is not always the case. A typical example is anterior spinal cord artery syndrome with preservation of SEPs and disappearance of MEPs.81 Surgery for intramedullary spinal cord tumors requires a special approach concerning monitoring with MEPs. During this type of surgery, very precise surgical instruments are used, such as the Contact Laser System (SLT, Montgomeryville, PA),82 and a very selective lesion within the spinal cord can occur. Therefore, monitoring this type of surgery using only MEPs recorded from limb muscles can be insufficient. Monitoring the D wave (i.e., recording descending activity of the CT using catheter electrodes placed over the exposed spinal cord) should be combined with MEP recording from limb muscles. Combining both these techniques proved highly effective in preventing paraplegia/quadriplegia. This gives the neurosurgeon the opportunity to be more radical in tumor resection. This combined type of monitoring can precisely predict transient postoperative motor deficits45,83 and clearly distinguish them from permanent ones.

NEUROPHYSIOLOGIC MONITORING OF THE SPINAL CORD AND SPINAL SURGERIES WITH MOTOR-­EVOKED POTENTIALS A schematic drawing of techniques for eliciting MEPs by TES or direct electrical stimulation of the exposed motor cortex while recording them from the spinal cord (D wave) or limb muscles (muscle MEPs) is presented in Fig. 4.6. Table 4.1 summarizes the results from the combined use of D-­wave and muscle MEP recordings during surgery for intramedullary spinal cord tumors. The neurosurgeon can proceed with the surgery aggressively, without jeopardizing the patient’s motor status despite the complete disappearance of the muscle MEPs during surgery. This is only allowed when the D-­wave amplitude does not decrease more than 50% from the baseline amplitude. After disappearance of muscle MEPs, patients will have only transient postoperative motor deficits, with a full recovery of muscle strength later on. Therefore, to achieve a good postoperative motor outcome, it is imperative that the critical decrement in D-­wave amplitude not be permitted. The neurophysiologic explanation for transient paraplegia is that the D wave is generated exclusively by the descending activity of the

Transcranial C2

Cz

C4

A

43

Direct

C1

C3

B

6 cm

Grid electrode

Epidural recording D-wave

I-waves

20 µV 2 ms

C

S Muscle recording

D FIGURE 4.6  (A) Schematic illustration of electrode positions for transcranial electrical stimulation of the motor cortex according to the 10-­20 International Electroencephalography System. The site labeled 6 cm is 6 cm anterior to Cz. (B) Illustration of grid electrode overlying the motor and sensory cortexes. (C) Schematic diagram of the positions of the catheter electrodes (each with three recording cylinders) placed cranial to the tumor (control electrode) and caudal to the tumor to monitor the descending signal after passing through the site of surgery (left). In the middle are D and I waves recorded rostral and caudal to the tumor site. On the right is depicted the placement of an epidural electrode through a flavectomy/flavotomy when the spinal cord is not exposed. (D) Recording of muscle motor-­evoked potentials from the thenar and tibial anterior muscles after eliciting them with a short train of stimuli applied either transcranially or over the exposed motor cortex. (Modified from Deletis V, Rodi Z, Amassian VE. Neurophysiological mechanisms underlying motor evoked potentials in anesthetized humans. Part 2: Relationship between epidurally and muscle recorded MEPs in man. Clin Neurophysiol. 2001;112:445–452.)

transcranially activated fast neurons of the CT, whereas muscle MEPs are generated by the combined action of the fast neurons of the CT and propriospinal and other descending tracts within the spinal cord (of course, with consecutive activation of alpha motoneurons, peripheral nerves, and muscles). The selective lesion to the propriospinal and other descending tracts can occur with the use of precise neurosurgical instruments (e.g., contact laser with a tip of 200 μm, producing minimal collateral damage).82 Lesioning of the propriospinal system and other descending tracts can be functionally compensated postoperatively, whereas a lesion to the fast neurons of the CT cannot. Empirically, we have discovered that decrements in the amplitude of the D wave occur in a stepwise fashion (except in the case of anterior spinal artery lesion). Therefore, the neurosurgeon has enough

44

Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

Right anterior tibial

Table 4.1  Principles of Motor-­Evoked Potential Interpretation D Wave

Muscle MEPa

Motor Status

Unchanged or 30%–50% decrease Unchanged or 30%–50% decrease >50% decrease

Preserved

Unchanged

Lost uni-­or bilaterally

Transient motor deficit

Lost bilaterally

Long-­term motor deficit

aIn

the tibial anterior muscle(s). MEP, Motor-­evoked potential. From Deletis V. Intraoperative neurophysiological monitoring. In: McLone D, ed. Pediatric Neurosurgery: Surgery of the Developing Nervous System. 4th ed. Philadelphia: WB Saunders; 1999:1204–1213.

time to make a decision and can immediately stop the surgery when a critical decrement in D-­wave amplitude occurs. The previous statement has been tested in 100 surgeries for intramedullary spinal cord tumors performed by one neurosurgeon and using a combined monitoring method. This approach showed a sensitivity of 100% and a specificity of 91%.45 Based on these results, Table 4.1 was produced to explain the meaning and predictive features of combined monitoring of the spinal cord surgery using muscle MEPs and D wave. Combined monitoring of MEPs in one typical patient with an intramedullary spinal cord tumor showed a disappearance of muscle MEPs and a sustained D wave. This resulted in a transient postoperative paraplegia, with a complete recovery from paraplegia, as presented in Fig. 4.7. 

MAPPING OF THE CORTICOSPINAL TRACT WITHIN THE SURGICALLY EXPOSED SPINAL CORD Further improvement in the prevention of lesioning of the CT during spinal cord surgery has been achieved by introducing a neurophysiologic method of mapping the CT by using a D-­ wave collision technique. This technique has recently been developed by our group and has allowed us to precisely map the anatomic location of the CT when the anatomy of the spinal cord has been distorted.84,85 The anatomic position of the CT is difficult to determine by visual inspection alone. D-­wave collision is accomplished by simultaneously stimulating the exposed spinal cord (with a small handheld probe delivering a 2 mA intensity stimulus), with TES to elicit a D wave. Because the resulting signals are transmitted along the same axons, the descending D wave collides with the ascending signal carried antidromically along the CT (Fig. 4.8). This results in a decrease in the D-­wave amplitude recorded cranially to the collision site. This phenomenon indicates that the spinal cord-­ stimulating probe is in close proximity to the CT. This could potentially guide surgeons to stay away from the “hot spot.” Mapping of the CT is now in the process of a technical refinement. Its initial use indicates an impressive ability to selectively map the spinal cord for the CT’s anatomic location. Using this method, the CT can be localized within 1 mm. This is in concordance with the other CT mapping techniques used within the brain stem that show the same degree of selectivity.61 

MAPPING OF THE DORSAL COLUMNS OF THE SPINAL CORD To protect the dorsal columns from lesioning during myelotomy, a novel neurophysiologic technique has been developed.

Baseline

Left anterior tibial

Right anterior tibial Closing

Left anterior tibial

10 ms

10 µV D wave

Baseline

D wave Closing

2 ms

25 µV

FIGURE 4.7  A 9-­year-­old boy underwent gross total resection of a pilocytic astrocytoma of the thoracic spinal cord that spanned four spinal segments. Preoperatively, there were no motor deficits. During surgery, the muscle motor-­evoked potentials from the left and right tibial anterior muscles were lost (upper) and the D wave decreased, although not less than 50% of baseline value (lower). Postoperatively, the patient was paraplegic. Within 1 week, he regained antigravity force in both legs, and by 2 weeks he walked again. (Reproduced from Kothbauer K, Deletis V, Epstein FJ. Intraoperative spinal cord monitoring for intramedullary surgery: An essential adjunct. Pediatr Neurosurg. 1997;26:247–254.)

To approach an intramedullary tumor, accepted neurosurgical techniques require a midline dorsal myelotomy. Distorted anatomy, however, often does not allow a precise determination of the anatomic midline by visual inspection and anatomic landmarks. Therefore, to facilitate the precise determination of the medial border between the left and right dorsal columns of the spinal cord, a technique for dorsal column mapping has been developed.86 Dorsal column mapping is based on two basic principles. First, after stimulation of the peripheral nerves, evoked potentials traveling through the dorsal columns can be recorded. Second, the area over the dorsal columns of the spinal cord where the maximal amplitude of the SEPs is recorded represents the point on the recording electrode in closest proximity to the dorsal columns. For recording these traveling waves, a miniature multielectrode is placed over the surgically exposed dorsal columns of the spinal cord. This electrode consists of eight parallel wires, 76 μm in diameter and 2 mm in length, placed 1 mm apart and embedded in a 1 cm2 (approximately) silicone plate (Fig. 4.9). An extremely precise amplitude gradient of the SEPs is recorded as the conducted potentials pass beneath the electrodes after alternating stimulation of the tibial nerves.

45

4  •  Intraoperative Neurophysiology: A Tool to Prevent and/or Document Intraoperative Injury to the Nervous System

TES C2 C1 Collision site R

S2

S2 + S 1

S1 D1

S1

S2 + S1 D2

D1

D2

50 µV

mm

S1

50 µV

0

5

10

15

20

25

30

35

Negative mapping - no collision, D1 = D2

40 ms

0

5

10

15

20

25

30

35

40 ms

Positive mapping - collision occurs, D2 = 42% of D1

FIGURE 4.8  The neurophysiologic basis for intraoperative mapping of the corticospinal tract (CT). Mapping of the CT by the D-­wave collision technique (see text for details). S1, Transcranial electrical stimulation (TES); S2, spinal cord electrical stimulation; D1, control D wave (TES only); D2, D wave after combined stimulation of the brain and spinal cord; R, the cranial electrode for recording D wave in the spinal epidural space. Lower left: Negative mapping results (D1 = D2). Lower right: Positive mapping results (D2-­wave amplitude significantly diminished after collision). Inset: Handheld stimulating probe over the exposed spinal cord. (Modified from Deletis V, Camargo AB. Interventional neurophysiological mapping during spinal cord procedures. Stereotact Funct Neurosurg. 2001;77:25–28.)

R.P., 18 y.o. C2-7 syrinx

SSEP - LPTN

SSEP - RPTN

1

1

2

2

3

3

4

4

5

5

6

6

7

7

8

8 0

10

20

30

40

50 ms

10 µV 0

10

20

30

40

50 ms

FIGURE 4.9  Dorsal column mapping in an 18-­year-­old patient with a syringomyelic cyst between the C2 and C7 segments of the spinal cord. Upper right: Magnetic resonance imaging shows the syrinx. Lower middle: Placement of miniature electrode over surgically exposed dorsal column; vertical bars on the electrode represent the location of the underlying exposed electrode surfaces. Sensory-­evoked potentials after stimulation of the left and right tibial nerves showing maximal amplitude between electrodes 1 and 2 (lower left and right). These data strongly indicate that both dorsal columns from the left and right lower extremities have been pushed to the extreme right side of the spinal cord. Using these data as a guideline, the surgeon performed the myelotomy using a YAG laser through the left side of the spinal cord and inserted the shunt to drain the cyst (upper middle). The patient did not experience a postoperative sensory deficit. SSEP-LPTN, Somatosensory evoked potential from left posterior tibial nerve; SSEP-RPTN, somatosensory evoked potential from right posterior tibial nerve. (Reproduced from Krzan MJ. Intraoperative neurophysiological mapping of the spinal cord’s dorsal column. In: Deletis V, Shils JL, eds. Neurophysiology in Neurosurgery. A Modern Intraoperative Approach. San Diego: Academic Press; 2002:153–164.)

46

Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

The amplitude gradient of the conducted potentials indicates the precise location of the functional midline corresponding to the dorsal fissure of the spinal cord (i.e., the optimal site for myelotomy). These data can be used by the neurosurgeon to prevent injury to the dorsal columns that could occur through an imprecise midline myelotomy. This is especially useful during surgery for intramedullary spinal cord tumors or during the placement of a shunt to drain syringomyelic cysts (see Fig. 4.9).85 

NEUROPHYSIOLOGIC MONITORING DURING SPINAL ENDOVASCULAR PROCEDURES Endovascular procedures for the embolization of spinal and spinal cord vascular lesions carry the risk of spinal cord ischemia.87 Whenever these procedures are performed under general anesthesia, only neurophysiologic monitoring can provide an “online” assessment of the functional integrity of sensory and motor pathways. Monitoring of SEPs and muscle MEPs is performed in the same fashion as described for monitoring of intramedullary spinal cord tumor surgery.88,89 The D wave, in contrast, is usually not monitored during these procedures because these patients receive a considerable amount of heparin in the perioperative period and the percutaneous placement of the recording epidural electrode would expose the patient to the risk of an epidural bleed. Besides safety issues, there is also no evidence that monitoring the D wave is an essential adjunct to muscle MEPs during these endovascular procedures. Both peripheral and myogenic MEPs have, in fact, been proven to be more sensitive than the D wave in detecting spinal cord ischemia. Similar results have been consistently reported both in experimental and clinical studies, supporting the hypothesis that whenever the mechanism of spinal cord injury is purely ischemic, muscle MEPs may suffice.90-­93 Given the complexity of spinal cord hemodynamics, which is even more unpredictable in the presence of a spinal cord hypervascularized lesion, it is mandatory to perform both SEP and MEP monitoring to enhance the safety of these risky procedures.89 A critical step regarding neurophysiologic monitoring during these procedures consists of the provocative tests.89,94,95 These tests rely on the properties of two drugs, lidocaine and amobarbital, to selectively block axonal and neuronal conduction (respectively) when injected intra-­ arterially in the spinal cord.96 Provocative tests are usually performed once the endovascular catheter has reached the embolizing position, before any embolizing material is injected. If that specific vessel not only feeds the target of the embolization (e.g., spinal cord arteriovenous malformation, hemangioblastoma, arteriovenous fistula) but also perfuses normal spinal cord, it is expected that the provocative drug will block the white and/or gray matter conduction, and this will be reflected in neurophysiologic tests. Criteria for positive provocative tests are the disappearance of the MEPs and/or a 50% decrease in SEP amplitude. If the test is positive, embolization from that specific catheter position is not performed and embolization from a different feeder or from a more selectively advanced catheter position is attempted. Provocative tests mimic the effect of the embolization and select those patients amenable to a safe embolization. Although the specificity of provocative tests has not been tested (because the procedure is abandoned whenever provocative tests are consistently positive), their sensitivity

has proven to be very high, and no false-­negative results (i.e., new postoperative neurologic deficit despite embolization performed after a negative provocative test) have so far been reported.89 

Surgery of the Lumbosacral Nervous System Intraoperative monitoring during surgery of the lumbosacral nervous system is a very demanding task and is still not developed in comparison with monitoring of the surgeries for other parts of the central and peripheral nervous systems. The neurophysiologic techniques used to monitor the lumbosacral nervous system are dependent on the pathology and structures involved. Generally, monitoring of the lumbosacral system involves the epiconus, conus, and cauda equina. These structures are essential in both voluntary and reflexive control of micturition, defecation, and sexual function as well as somatosensory and motor innervation of the pelvis and lower extremities. So far, only methodologies for monitoring and mapping of the somatomotor and somatosensory components of the lumbosacral nervous system have been developed. Intraoperative monitoring of the vegetative component of the lumbosacral nervous system is still in the embryonic stage.97 One of the most widely used applications of intraoperative monitoring of the lumbosacral nervous system, at least in the pediatric population, is for patients undergoing surgery for a tethered spinal cord. During these procedures, the surgeon cuts the filum terminale or removes the tethering tissue that envelopes the conus and/or the cauda equina roots. In a large series of patients operated on for tethered spinal cords, permanent neurologic complications have been described in as many as 4.5%.98,99 The rate increased to 10.9% when transient complications were considered. Due to the tethering, the lumbosacral nerve roots leave the spinal cord in different directions than in a healthy spinal cord. Furthermore, the cord may be skewed and sometimes a nerve root may pass through a lipoma. Nerve roots may also be involved in the thickened filum terminale that is cut during untethering. Direct electric stimulation of these structures in the surgical field or direct recording from them after peripheral nerve stimulation has proven helpful. Using mapping techniques, functional neural structures of the lumbosacral region can be correctly identified and thus possibly preserved. In Fig. 4.10, schematic drawings of the most important neurophysiologic techniques for monitoring afferent and efferent events (i.e., recording and monitoring neurophysiologic signals from sensory or motor parts of the lumbosacral system) are presented. During intraoperative testing with these techniques, it has been found that some of them are more important than others, from a pragmatic point of view. Only these are described.

PUDENDAL DORSAL ROOT ACTION POTENTIALS In the treatment of spasticity (e.g., in cerebral palsy), sacral roots are increasingly being included during rhizotomy procedures.100 Children who underwent L2–S2 rhizotomies had an 81% greater reduction in plantar/flexor spasticity compared with children who underwent only L2–S1 rhizotomies. However, as more sacral dorsal roots have been

4  •  Intraoperative Neurophysiology: A Tool to Prevent and/or Document Intraoperative Injury to the Nervous System

Afferent events

47

Efferent events

Pudendal SEPs (Traveling waves) Stimulation

1. 1 µV

10 ms

Anal M-wave

4. Pudendal DRAP

2. 50 µV

100 µV 5 ms Anal MEP

4 ms Pudendal SEPs (Stationary wave)

50 µV

5. 20 ms

3. 10 µV

BCR

6. 10 ms

70 µV 50 ms

FIGURE 4.10  Neurophysiologic events used to intraoperatively monitor the sacral nervous system. Left: Afferent events after stimulation of the dorsal penile/clitoral nerves and recording over the spinal cord: 1, pudendal somatosensory-­evoked potentials (SEPs), traveling waves; 2, pudendal dorsal root action potential; and 3, pudendal SEPs, stationary waves recorded over the conus. Right: Efferent events: 4, anal M wave recorded from the anal sphincter after stimulation of the S1–S3 ventral roots; 5, anal motor-­evoked potentials recorded from the anal sphincter after transcranial electrical stimulation of the motor cortex; 6, bulbocavernosus reflex obtained from the anal sphincter muscle after electrical stimulation of the dorsal penile/ clitoral nerves. BCR, Bulbocavernosus reflex; DRAP, dorsal root action potentials; MEP, motor-­evoked potential. (From Deletis V. Intraoperative neurophysiological monitoring. In: McLone D, ed. Pediatric Neurosurgery: Surgery of the Developing Nervous System. 4th ed. Philadelphia: WB Saunders; 1999:1204–1213.)

included in rhizotomies, neurosurgeons have experienced an increased rate of postoperative complications, especially with regards to bowel and bladder functions. To spare sacral function, we have attempted to identify those sacral dorsal roots carrying afferents from pudendal nerves using recordings of dorsal root action potentials after stimulation of dorsal penile or clitoral nerves. Patients were anesthetized with isoflurane, nitrous oxide, fentanyl, and a short-­acting muscle relaxant introduced only at the time of intubation. The cauda equina was exposed through a T12– S2 laminotomy/laminectomy, and the sacral roots were identified using bony anatomy. The dorsal roots were separated from the ventral ones, and dorsal root action potentials were recorded by a hand-­held sterile bipolar hooked electrode (the root being lifted outside the spinal canal) (Fig. 4.11). The dorsal root action potentials were evoked by electrical stimulation of the penile or clitoral nerves. One hundred responses were averaged together and filtered between 1.5 and 2100 Hz. Each average response was repeated to assess its reliability. Afferent activity from the right and left dorsal roots of S1, S2, and S3 were always recorded, along

with occasional recordings from the S4–S5 dorsal roots. Of special relevance was the finding that in 7.6% of these children, all afferent activity was carried by only one S2 root (see Fig. 4.11C and F). These findings were confirmed by a later analysis of results of mapping in 114 children (72 male, 42 female; mean age, 3.8 years).101 Mapping was successful in 105 of 114 patients. S1 roots contributed 4%, S2 roots 60.5%, and S3 roots 35.5% of the overall pudendal afferent activity. The distribution of responses was asymmetrical in 56% of the patients (see Fig. 4.11B, C, and F). Pudendal afferent distribution was confined to a single level in 18% (see Fig. 4.11A) and even to a single root in 7.6% of patients (see Fig. 4.11C and F). Fifty-­six percent of the pathologically responding S2 roots during rhizotomy testing (using electrical stimulation of dorsal roots with spreading activity in adjacent myotomes) were preserved because of the significant afferent activity (as demonstrated during pudendal mapping). None of the 105 patients developed long-­term bowel or bladder complications. All our results in the early series of dorsal root mapping with 19 patients have been confirmed by analysis of the

48

Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

Patient: W. A., 4y Dg: Cerebral palsy RIGHT

Patient: L. M., 3y Dg: Cerebral palsy

LEFT

RIGHT S1

S2

S2

S3

S3 S

40 µV S 5 ms

A

RIGHT

S3 S

S

C Patient: R. S., 4y Dg: Cerebral palsy RIGHT

LEFT

LEFT

S2

S

Patient: L. M., 6y Dg: Cerebral palsy

LEFT

RIGHT

LEFT

S1

S1

S1

S2

S2

S2

S3

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S3 S

D

RIGHT S1

B Patient: Z. M., 4y Dg: Cerebral palsy

S

LEFT

S1

S

Patient: M. G., 4y Dg: Cerebral palsy

S

E

S

S

S

F

FIGURE 4.11  Six characteristic examples of dorsal root action potentials showing the entry of a variety of pudendal nerve fibers to the spinal cord via S1–S3 sacral roots. (A) Symmetrical distribution of dorsal root action potentials confined to one level (S2) or three levels (D). Asymmetrical distribution of dorsal root action potentials confined to the one side (B), only one root (C and F), or all roots except right S1 (E). Recordings were obtained after electrical stimulation of bilateral penile/clitoral nerves. (From Vodušek VB, Deletis V. Intraoperative neurophysiological monitoring of the sacral nervous system. In: Deletis V, Shils J, eds. Neurophysiology in Neurosurgery: A Modern Intraoperative Approach. San Diego: Academic Press; 2002:197–217.)

larger series of 105 patients.101 With this series, we showed that selective S2 rhizotomy can be performed safely without an associated increase in residual spasticity while preserving bowel and bladder function by performing pudendal afferent mapping.100 Therefore, we suggest that the mapping of pudendal afferents in the dorsal roots should be employed whenever these roots are considered for rhizotomy in children with cerebral palsy without urinary retention. In children with cerebral palsy with hyper-­reflexive detrusor dysfunction, in whom sacral rhizotomy may be considered to alleviate the problem, preoperative neurologic investigation of the child should help in making appropriate decisions. In any case, intraoperative mapping of sacral afferents should make selective surgical approaches possible and provide the maximal benefit for children with cerebral palsy. Mapping of pudendal afferents has been further expanded by introducing methodology that maps afferents from the anal mucosa by stimulating them using anal plug electrodes and recording them in the same way as penile/clitoral afferents.102 

MAPPING AND MONITORING OF MOTOR RESPONSES FROM THE ANAL SPHINCTER These responses can be elicited by direct stimulation of the S2 to S5 motor roots and recording from the anal sphincters, after surgical exposure of the cauda equina, or by TES of the motor cortex. The first method of cauda equina stimulation, using a small hand-­held monopolar probe, is easy to perform with recording of responses from each anal hemisphincter

with intramuscular wire electrodes identical to the ones used to record the bulbocavernosus reflex.103 This mapping method is very useful when it becomes necessary to identify roots within the cauda equina during tethered cord or tumor surgeries in which the normal anatomy is distorted. To perform mapping, the surgeon must stop surgery and map the roots with a monopolar probe. To continuously monitor the functional integrity of parapyramidal motor fibers (for volitional control of the anal sphincters) and the motor aspects of the pudendal nerves from the anterior horns to the anal sphincters, the method of TES and recording of anal responses was introduced. Because the response recorded from the anal sphincter after TES has to pass multiple synapses at the level of the spinal cord, this method is moderately sensitive to anesthetics and rather light anesthesia should be maintained. So far, no clinical correlation using this method has been published. 

MONITORING OF THE BULBOCAVERNOSUS REFLEX The bulbocavernosus reflex is an oligosynaptic reflex mediated through the S2–S4 spinal cord segments that is elicited by electrical stimulation of the dorsal penis/clitoris nerves with the reflex response recorded from any pelvic floor muscles. The afferent paths of the bulbocavernosus reflex are the sensory fibers of the pudendal nerves and the reflex center in the S2–S4 spinal segment. The efferent paths are the motor fibers of the pudendal nerves and anal sphincter muscles. In neurophysiologic laboratories, the bulbocavernosus reflex

4  •  Intraoperative Neurophysiology: A Tool to Prevent and/or Document Intraoperative Injury to the Nervous System

is usually recorded from the bulbocavernosus muscles, and this is where it gets its name. We have described an intraoperative method for recording the bulbocavernosus reflex from the anal sphincter muscle, with improvement in methodology reported by others.103-­105 The advantage of bulbocavernosus reflex monitoring is that it tests the functional integrity of the three different anatomic structures: the sensory and motor fibers of the pudendal nerves and the gray matter of the S2–S4 sacral segments (see Fig. 4.10). Because of a lack of published statistical data collected for large groups of patients, the reliability of monitoring for conus and cauda equina surgeries remains unclear.

Special Consideration for Intraoperative Neurophysiology in Children ION techniques are extensively used in adult neurosurgery and, in their principles, can be applied to the pediatric population. However, especially in younger children, the motor system is still under development, making both mapping and monitoring techniques more challenging. With regard to D-­ wave monitoring, Szelenyi et al. reviewed D-­wave data from 19 children aged 8 to 36 months operated on for intramedullary spinal cord tumors.106 The D wave was present in 50% of children aged 21 months or older but was never recorded in children younger than 21 months. Although the preoperative neurologic status of these children was not specified, a 50% D-­wave monitor ability rate compares unfavorably to the data reported in adults, where mean monitor ability rate is approximately 66% and reaches 80% in patients in McCormick grade I.45 This is likely caused by the immaturity of the CT in younger children where incompletely myelinated fibers have variable conduction velocities resulting in desynchronization.107 A few studies have recently looked at the feasibility of muscle MEP monitoring in children after TES, and consistently reported higher threshold in younger children.106,108,109 Our data are in agreement with those reported by Journee et al., who suggested preconditioning TES to overcome some of the limitations in eliciting MEPs in this subgroup of patients.107,110 According to Nezu, electrophysiologic maturation of the CT innervating hand muscles is complete by the age of 13 and the CT appears to be the only spinal cord pathway with incomplete myelination at birth.111,112 There is likely a discrepancy between the anatomic and neurophysiologic development of the CT. Cortico-­motoneuronal connections reach sacral levels between 18 and 28 weeks PCA, and are completed at birth.113 Myelination of the lumbar spinal cord occurs between 1 and 2 years of age, with a slower development for lower extremities than for upper extremities.114 However, the neurophysiologic maturation of the CT progresses throughout childhood and adolescence with myelogenesis and synaptogenesis that continues in to the second decade of life. Overall, a transition from development to motor control function exists for the CT.115 In conclusion, in pediatric neurosurgery, essentially the same techniques used in adults can be applied to map and monitor the motor system. Yet, younger children have less excitable motor cortex and pathways due to their neurophysiologic—rather than anatomic—immaturity. Different stimulating parameters may be required to overcome these limitations.

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47c. De Benedictis A, Duffau H. Brain hodotopy: From esoteric concept to practical surgical applications. Neurosurgery. 2011;68 (6):1709–1723. 47d. Voets NL, Bartsch A, Plaha P. Brain white matter fibre tracts: a review of functional neuro-oncological relevance. J Neurol Neurosurg Psychiatry. 2017 Dec;88(12):1017–1025. 47e. Szelényi A, Senft C, Jardan M, et al. Intra-operative subcortical electrical stimulation: A comparison of two methods. Clin Neurophysiol. 2011;122(7):1470–1475. 47f. Nossek E, Korn A, Shahar T, et al. Intraoperative mapping and monitoring of the corticospinal tracts with neurophysiological assessment and 3-dimensional ultrasonography-based navigation. J Neurosurg. 2011;114(3):738–746. 47g. Ohue S, Kohno S, Inoue A, et al. Accuracy of diffusion tensor magnetic resonance imaging-based tractography for surgery of gliomas near the pyramidal tract. Neurosurgery. 2012;70(2):283– 294. 47h. Shiban E, Krieg SM, Haller B, et al. Intraoperative subcortical motor evoked potential stimulation: how close is the corticospinal tract? J Neurosurg. 2015;123(3):711–720. 47i. Seidel K, Beck J, Stieglitz L, Schucht P, Raabe A. The warningsign hierarchy between quantitative subcortical motor mapping and continuous motor evoked potential monitoring during resection of supratentorial brain tumors. J Neurosurg. 2013;118(2):287– 296. 47j. Plans G, Fernández-Conejero I, Rifà-Ros X, Fernández-Coello A, Rosselló A, Gabarrós A. Evaluation of the High-Frequency Monopolar Stimulation Technique for Mapping and Monitoring the Corticospinal Tract in Patients With Supratentorial Gliomas. A Proposal for Intraoperative Management Based on Neurophysiological Data Analysis in a Series of 92 Patients. Neurosurgery. 2017 Oct 1;81(4):585–594. 47k.  Raabe A, Beck J, Schucht P, Seidel K. Continuous dynamic mapping of the corticospinal tract during surgery of motor eloquent brain tumors: evaluation of a new method. J Neurosurg. 2014;120(5):1015–1024. 48. Bricolo A, Turazzi S. Surgery for gliomas and other mass lesions of the brainstem. In: Symon L, ed. Advances and Technical Standards in Neurosurgery. Vol. 22. Vienna: Springer-­Verlag; 1995:261–341. 49. Kyoshima K, Kobayashi S, Gibo H, et al. A study of safe entry zones via the floor of the fourth ventricle for brain-­stem lesions. J Neurosurg. 1993;78:987–993. 50. 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;37:922–930. 51. Suzuki K, Matsumoto M, Ohta M, et al. Experimental study for identification of the facial colliculus using electromyography and antidromic evoked potentials. Neurosurgery. 1997;41:1130–1136. 52. Strauss C, Romstock J, Fahlbusch R. Intraoperative mapping of the floor of the fourth ventricle. In: Loftus CM, Traynelis VC, eds. Intraoperative Monitoring Techniques in Neurosurgery. New York: McGraw-­Hill; 1994:213–218. 53. Strauss C, Romstock J, Fahlbusch R. Pericollicular approaches to the rhomboid fossa. Part II: neurophysiological basis. J Neurosurg. 1999;91:768–775. 54. Deletis V, Sala F, Morota N. Intraoperative neurophysiological monitoring and mapping during brain stem surgery: a modern approach. Oper Tech Neurosurg. 2000;3:109–113. 55. Quiñones-­Hinojosa A, Russ L, Rose D, Lawton M. Intraoperative motor mapping of the cerebral peduncle during resection of a midbrain cavernous malformation: technical case report. J Neurosurg. 2005;56:E439. 56. Rhoton AL. The posterior fossa veins. Neurosurgery. 2000;47:S69– S92. 57. Sala F, Lanteri P, Bricolo A. Intraoperative neurophysiological monitoring of motor evoked potentials during brain stem and spinal cord surgery. Adv Tech Stand Neurosurg. 2004;29:133–169. 58. Morota N, Deletis V, Lee M, et al. Functional anatomic relationship between brain stem tumors and cranial motor nuclei. Neurosurgery. 1996;39:787–794. 59. Sekiya T, Hatayama T, Shimamura N, et al. Intraoperative electrophysiological monitoring of oculomotor nuclei and their intramedullary tracts during midbrain tumor surgery. Neurosurgery. 2000;47:1170–1177.

60. Schlake HP, Goldbrunner R, Siebert M, et al. Intra-­operative electromyographic monitoring of extra-­ocular motor nerves (Nn. III, VI) in skull base surgery. Acta Neurochir. 2001;143:251–261. 61. Sakuma J, Matsumoto M, Ohta M, et al. Glossopharyngeal nerve evoked potentials after stimulation of the posterior part of the tongue in dogs. Neurosurgery. 2002;51:1026–1033. 62. Komisaruk 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;23:609–617. 63. Fahlbusch R, Strauss C. The surgical significance of brain stem cavernous hemangiomas. Zentralbl Neurochir. 1991;52:25–32. 64. Grabb PA, Albright L, Sclabassi RJ, et al. Continuous intraoperative electromyographic monitoring of cranial nerves during resection of fourth ventricular tumors in children. J Neurosurg. 1997;86:1–4. 65. Romstock J, Strauss C, Fahlbusch R. Continuous electromyography monitoring of motor cranial nerves during cerebellopontine angle surgery. J Neurosurg. 2000;93:586–593. 66. Dong CC, Macdonald DB, Akagami R, et al. Intraoperative facial motor evoked potential monitoring with transcranial electrical stimulation during skull base surgery. Clin Neurophysiol. 2005;116(3):588–596. 67. Ulkatan S, Deletis V, Fernandez-­Conejero I. Central or peripheral activations of the facial nerve? J Neurosur. 2007;106(3):519–520. 68. Sala F, Krzan MJ, Deletis V. Intraoperative neurophysiological monitoring in pediatric neurosurgery: why, when, how? Childs Nerv Syst. 2002;18:264–287. 69. Jones SJ, Buonamassa S, Crockard HA. Two cases of quadriparesis following anterior cervical discectomy, with normal perioperative somatosensory evoked potentials. J Neurol Neurosurg Psychiatry. 2003;44:273–276. 70. Minahan RE, Sepkuty JP, Lesser RP, et al. Anterior spinal cord injury with preserved neurogenic “motor” evoked potentials. Clin Neurophysiol. 2001;112:1442–1450. 71. Jallo G, Kothbauer K, Epstein F. Contact laser microsurgery. Childs Nerv Syst. 2002;18:333–336. 72. Deletis V. Intraoperative neurophysiology and methodology used to monitor the functional integrity of the motor system. In: Deletis V, Shils JL, eds. Neurophysiology in Neurosurgery: A Modern Intraoperative Approach. San Diego: Academic Press; 2002:25–51. 73. Deletis V, Camargo AB. Interventional neurophysiological mapping during spinal cord procedures. Stereotact Funct Neurosurg. 2001;77:25–28. 74. Yanni DS, Ulkatan S, Deletis V, et al. Utility of neurophysiological monitoring using dorsal column mapping in intramedullary spinal cord surgery. J Neurosurg. 2010;12:623–628. 75. Krzan MJ. Neurophysiology in Neurosurgery: A Modern Intraoperative Approach. San Diego: Academic Press; 2002:153–164. 76. Berenstein A, Lasjaunias P. Spine and spinal cord vascular lesions. In: Berenstein A, Lasjaunias P, eds. Surgical Neuroangiography: Endovascular Treatment of Spine and Spinal Cord Lesions. Berlin, Heidelberg: Springer; 1992:1–109. 77. Berenstein A, Young W, Benjamin V, Merkin H. Somatosensory evoked potentials during spinal angiography and therapeutic transvascular embolization. J Neurosurg. 1984;60:777–785. 78. Sala F, Niimi Y. Neurophysiological monitoring during endovascular procedures on the spine and the spinal cord. In: Deletis V, Shils JL, eds. Neurophysiology in Neurosurgery: A Modern Intraoperative Approach. San Diego: Academic Press; 2002:119–151. 79. de Haan P, Kalkman CJ, de Mol BA. Efficacy of transcranial motorevoked myogenic potentials to detect spinal cord ischemia during operations for thoracoabdominal aneurysms. J Thorac Cardiovasc Surg. 1997;113:87–101. 80. de Haan P, Kalkman CJ, Jacobs MJ. Spinal cord monitoring with myogenic motor evoked potentials: early detection of spinal cord ischemia as an integral part of spinal cord protective strategies during thoracoabdominal aneurysm surgery. Semin Thorac Cardiovasc Surg. 1998;10:19–24. 81. Konrad PE, Tacker Jr WA, Levy WJ, et al. Motor evoked potentials in the dog: effects of global ischemia on spinal cord and peripheral nerve signals. Neurosurgery. 1987;20:117–124. 82. Kai Y, Owen JH, Allen BT, et al. Relationship between evoked potentials and clinical status in spinal cord ischemia. Spine. 1994;19:1162–1168.

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83. Sadato A, Taki W, Nakamura I, et al. Improved provocative tests for the embolization of arteriovenous malformations: technical note. Neurol Med -­Chir. 1994;34:187–190. 84. Touho H, Karasawa J, Ohnishi H, et al. Intravascular treatment of spinal arteriovenous malformations using a microcatheter: with special reference to serial Xylocaine tests and intravascular pressure monitoring. Surg Neurol. 1994;42:148–156. 85. Tanaka K, Yamasaki M. Blocking of cortical inhibitory synapses by intravenous lidocaine. Nature. 1966;209:207–208. 86. Vodušek DB, Deletis V. Sacral roots and nerves, and monitoring for neuro-­urologic procedure. In: Nuwer M, ed. Monitoring Neural Function during Surgery. New York: Elsevier; 2007:423–433. 87. Choux M, Lena G, Genitori L, et al. The surgery of occult spinal dysraphism. Adv Tech Stand Neurosurg. 1994;21:183–238. 88. Piere-­Kahn A, Zerah M, Renier D, et al. Congenital lumbosacral lipomas. Childs Nerv Syst. 1997;13:298–335. 89. Lang FF, Deletis V, Valasquez L, et al. Inclusion the S2 dorsal rootlets in functional posterior rhizotomy for spasticity in children with cerebral palsy. Neurosurgery. 1994;34:847–853. 90. Huang JC, Deletis V, Vodusek DB, et al. Preservation of pudendal afferents in sacral rhizotomies. Neurosurgery. 1997;41:411– 415. 91. Deletis V, Krzan MJ, Bueno de Camargo A, Abbott R. Functional anatomical asymmetry of pudendal nerve sensory fibers. In: Bruch HP, Kocherling F, Bouchard R, Schug-­Pass C, eds. New Aspects of High Technology in Medicine. Bologna, Italy: Monduzzi; 2001:153–158. 92. Deletis V, Vodusek DB. Intraoperative recording of the bulbocavernosus reflex. Neurosurgery. 1997;40:88–92. 93. Deletis V. Intraoperative neurophysiological monitoring. In: McLone D, ed. Pediatric Neurosurgery: Surgery of the Developing Nervous System. Philadelphia: WB Saunders; 1999:1204–1213.

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94. Rodi Z, Vodusek DB. Intraoperative monitoring of bulbocavernous reflex—the method and its problems. Clin Neurophysiol. 2001;112:879–883. 95. Szelenyi A, Bueno de Camargo A, Deletis V. Neurophysiological evaluation of the corticospinal tract by D-­wave recordings in young children. Childs Nerv Syst. 2003;19:30–34. 96. Sala F, Manganotti P, Grossauer S, et al. Intraoperative neurophysiology of the motor system in children: a tailored approach. Childs Nerv Syst. 2010;26:473–490. 97. Frei FJ, Ryhult SE, Duitmann E, et al. Intraoperative monitoring of motor-­evoked potentials in children undergoing spinal surgery. Spine. 2007;32:911–917. 98. Liebermann A, Jeremy Lyon R, Diab M, Gregory AG. The effect of age on motor evoked potentials in children under propofol/ isoflurane anesthesia. Anesth Analg. 2006;103:316–321. 99. Journee HL, Hoving E, Mooij J. Stimulation threshold-­age relationship and improvement of muscle potentials by preconditioning transcranial stimulation in young children. Clin Neurophysiol. 2006;117:115. 100. Nezu A, Kimura S, Uehara S, et al. Magnetic stimulation of motor cortex in children: maturity of corticospinal pathway and problem of clinical application. Brain Dev. 1997;19:176–180. 101. Kubis N, Catala M. [Development and maturation of the pyramidal tract]. Neurochirurgie. 2003;49:145–153. 102. Eyre JA. Development and plasticity of the corticospinal system in man. Neural Plast. 2003;10:93–106. 103. Brody BA, Kinney CH, Kloman AS, Gilles FH. Sequence of central nervous system myelination in human infancy. I. An autopsy study on myelination. J Neuropathol Exp Neurol. 1997;46:283–301. 104. Meng Z, Li Q, Martin JH. The transition from development to motor control function in the corticospinal system. J Neurosci. 2004;24:605–614.

CHAPTER 5

Cortical and Subcortical Brain Mapping HUGUES DUFFAU

Introduction The ultimate goal of brain surgery, especially in neuro-­ oncology, is to maximize the extent of resection (EoR) while preserving or even improving the patient’s quality of life (QoL)—that is, to optimize the oncofunctional balance.1,2 Indeed, maximal safe resection of gliomas, when feasible, is currently the first treatment both in low-­grade gliomas (LGGs)3 and high-­grade gliomas.4 All the recent surgical series that have objectively calculated the EoR on repeated postoperative magnetic resonance imaging (MRI) have supported EoR as a statistically significant predictor of overall survival (OS). In World Health Organization (WHO) grade II gliomas—when a simple biopsy is obtained at diagnosis eventually followed by chemotherapy and/or radiotherapy—the survival is around 6 to 7 years,5,6 whereas the OS is about 14 to 15 years with early surgical resection, in particular when there is no residue but also if the residual tumor volume is less than 10 to 15 mL.6–10 In the case of glioblastomas, it has also been found that complete removal of the enhanced part of the tumor (controlled on postsurgical MRI) significantly increased the median survival.4,11,12 Moreover, because the tumoral cells diffuse beyond the signal abnormalities on neuroimaging, the principle of removing a “security margin” around the lesion visible on FLAIR-­ weighted MRI has recently been suggested.13 In LGGs, this “supracomplete” resection prevented malignant transformation with a long-­term follow-­up of 11 years (range 8 to 16.5 years).14 In glioblastoma, the removal of more than 53.21% of the surrounding FLAIR abnormalities resulted in a significantly longer OS compared to the resection of only the contrast-­enhanced area.15 Therefore these improved oncologic results have challenged the dogma of a “watch and see” policy, especially in LGG, as well as the classical concept of achieving a simple tumorectomy in brain neoplasms: quite the opposite, they support the principle of an early and supramarginal surgical resection.3 However, such aggressive management can result in a higher rate of neurologic deterioration. Indeed, because supratentorial gliomas are often situated near or within the eloquent structures and because they have an infiltrative (poorly demarcated) nature, for a long time it was believed that the chances of achieving an extensive glioma excision were low while the risk of causing permanent postoperative deficits was high. Indeed, in the old literature, many surgical

50

series have reported a rate of persistent and severe neurologic impairment between 13% and 27.5% after the removal of intra-­axial tumors (for a review, see Ref. 16). This may be explained by the fact that although the removal of anatomic landmarks is crucial during brain surgery, that is not sufficient, since there is considerable interindividual variation in anatomic function. This is particularly true in cases of gliomas that can generate functional reorganization, explaining why many patients have no or only mild deficits before surgery, especially in the case of slow-­growing tumors such as LGGs.17 In this setting, to preserve neural function while achieving a more radical removal, an emerging philosophy suggests performing individual functional mapping-­guided resection18 as opposed to image-­assisted surgery as classically proposed. This optimization of the benefit-­to-­risk ratio of surgery, aiming at improving QoL as well as prolonging OS,2 can be implemented only by studying the distribution of the parallel, delocalized, large-­scale cortical-­subcortical neural circuits at the individual level by means of intraoperative electrical mapping and real-­time cognitive monitoring in awake patients.19 In this regard, surgical resection is pursued until eloquent structures have been reached—that is, up to functional boundaries—with no margin left around the networks critical for brain function.20 A perfect comprehension of the hodopical organization of the brain—namely the dynamics of the neural subcircuits mediating specific subfunctions, their interactions, as well as their potentials and limitations of functional compensation—is mandatory to optimize the oncofunctional balance of surgery.21 In this connectomal view of cerebral processing, breaking with the traditional localization model, mechanisms of neuroplasticity can be efficient only if subcortical connectivity is preserved in order to permit spatial communication and temporal synchronization within and between interconnected distributed subcircuits.22 In summary, it is crucial to investigate for each patient (1) the individual cortical functional organization, (2) the subcortical connectivity, and (3) the brain’s plastic potential, with the aim of tailoring the resection according not only to oncologic but also to cortical-­subcortical functional limits (i.e., to the functional connectome). The goal of this chapter is to review how the philosophy of cognitive monitoring during resection combined with intraoperative electrostimulation mapping (IESM), both at cortical and subcortical levels, can result in significantly

5  •  Cortical and Subcortical Brain Mapping

better results of glioma surgery. It can intervene in the natural history of the tumor by delaying its malignant transformation and thus increasing OS, and also by preserving QoL. The fundamental implications of IESM in cognitive neurosciences are also discussed. 

Preoperative Neurocognitive Assessment in Glioma Patients: A Necessary Baseline Diffuse gliomas, especially LGGs, are usually revealed by inaugural seizures in young adults who enjoy a normal life, with no or only slight neurologic impairments. As mentioned, this can be explained by mechanisms of brain reshaping allowing functional compensation in case of slow-­growing lesions due to the recruitment of perilesional or remote areas within the ipsilesional hemisphere and/or the recruitment of contrahemispheric homologous areas.23 However, recent series in which objective neuropsychologic examinations have been performed before treatment have revealed that most glioma patients had cognitive disturbances—especially concerning executive functions, speed and information processing, language, visual perception, working memory, attention, reasoning, learning or semantics as well as emotional and behavioral function—deficits that have long been underestimated.24,25 Even in incidentally discovered LGGs, only two-­thirds of patients reported not only subjective complaints at diagnosis (in particular, fatigue and attentional deficits) but also objective disorders of neurocognitive functions (in particular concerning executive functions, working memory, and attentional processes).26 This means that the standard neurologic examination is too crude to be capable of detecting subtle cognitive alterations. Furthermore, neuropsychologic evaluation is useful to tailor the appropriate individualized therapeutic sequence27— for example, to propose upfront chemotherapy rather than surgical resection in very diffuse “gliomatosis-­like” gliomas that have already generated severe neurocognitive deterioration28 or to adapt the surgical methodology on the basis of the presurgical neuropsychologic scores (especially to select the best intrasurgical tests for awake mapping, see later) as well as to elaborate specific programs of postoperative cognitive neurorehabilitation.3 Moreover, the existence of an abnormal baseline neurocognitive score is a strong predictor of shorter OS in glioma patients.29 Of note, these deficits are related to the migration of glioma cells along the white matter fibers. For example, a significant relationship between scores of semantic fluency and the infiltration of the subcortical tracts underlying the ventrolateral connectivity (i.e., the inferior fronto-­occipital fascicle [IFOF]) has been demonstrated.30 In the same spirit, deterioration in mentation (a key function in understanding and performing complex social interactions) was correlated to the degree of glioma invasion of the right frontoparietal connectivity.31 These findings show that the migration of glioma cells along the subcortical bundles can cause specific cognitive or mood disorders depending on the neural subcircuits invaded by the neoplasm. This is explained by the fact that the limitations of cerebral plastic potential are mainly represented by the axonal pathways, as revealed by a recent atlas of neuroplasticity32–34—conversely to the huge

51

potential of cortical neuroplasticity—making it possible to perform extensive resections in eloquent cortex without inducing permanent impairments.22 Of note, the recent integration of these concepts into therapeutic strategy has resulted in dramatic changes in the surgical management of glioma patients, with an increase of surgical indications within eloquent regions classically considered as “inoperable” on the condition that the white matter connectivity is not predominantly invaded (see later).35 In addition to objective neurocognitive scores, the individual patient’s QoL must be subjectively defined by the patient before surgery based on personal criteria such as job, hobbies, lifestyle, and projects. Therefore “mapping à la carte” must be elaborated in agreement with the needs of the patient, resulting in the selection of the best tasks to perform throughout surgery according to preoperative discussion with the patient and his or her relatives. For instance, mapping different languages and the capacity to voluntarily switch from one language to another will be performed in multilingual patients, particularly in translators; calculation will be tested intraoperatively in mathematicians or schoolteachers; spatial awareness will be mapped in dancers or athletes; working memory can be monitored in managers or businesspeople; bimanual coordination in surgeons or pianists; syntax in writers; cross-­modal judgment in lawyers; theory of mind in medical doctors, to preserve their empathy; visual field in taxi drivers; and so forth.36 In other words, intraoperative neurocognitive monitoring must be personalized according to the QoL of the patient and not according to the lobar location of the tumor.37,38 In summary, a systematic and standardized preoperative neuropsychologic assessment is now recommended39 (1) to search the possible cognitive and mood disorders not detected by a standard neurologic examination, (2) to plan the operative procedure accordingly (e.g., optimal selection of intraoperative tasks for the real-­time cognitive monitoring), (3) to benefit from a presurgical baseline allowing a comparison with the postsurgical evaluation, and (4) to plan a personalized functional rehabilitation. 

Limitations of Functional Neuroimaging for Individual Preoperative Mapping Details regarding the science and usefulness of diffusion tensor imaging (DTI) and functional imaging are discussed elsewhere in this book. Advances in functional neuroimaging techniques—namely, functional magnetic resonance imaging (fMRI) and tractography by DTI—enable noninvasive mapping of the entire brain. Yet fMRI is not reliable enough at the individual level to be used routinely in surgical practice as it does not directly reflect the reality of brain processing but gives only a very indirect approximation of cerebral functions based upon biomathematic reconstructions.40 Comparison between fMRI and intraoperative electrostimulation mapping (IESM) found only 71% of positive correlations for motor function.41 Poor correlations have also been found for language (about 33%), with a sensitivity around 66% (specificity from 0% to 97%).42 By comparing preoperative language fMRI and IESM, Kuchcinski et al.43 observed a sensitivity of fMRI at 37.1% and a specificity at 83.4%. In a review on fMRI and language, Giussani et al.

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Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

concluded that the contradictory results of these studies did not allow consideration of language fMRI as an alternative tool to direct cortical stimulation in tumors located in language areas.44 Moreover, fMRI cannot differentiate areas that are essential for brain function and that should be preserved during surgery from areas involved in but not critical to a given function—that is, areas that can be surgically removed because functional compensation will occur. In practice, due to the frequent false-positive results of fMRI, there is a risk of failing to select a tumor patient for surgery, resulting in a loss of opportunity from an oncologic perspective. This issue has been described for gliomas located within the so-­called Broca area and Wernicke area or the insula: these tumors have nonetheless been excised with a very good recovery, although these sites were wrongly thought to be critical according to the results of the preoperative fMRI. Additionally, because of frequent false-­negative fMRIs, the other risk is to remove a glioma involving a structure that ultimately proved to be critical for brain functions but was not identified by the preoperative fMRI, with a loss of opportunity from a functional point of view.18 Besides activation task-­based fMRI, a recent investigation comparing IESM mapping with preoperative resting-­state fMRI in 98 LGG patients revealed that 96% ± 11% of sensorimotor stimulation was located within 10 mm sensorimotor independent component analysis maps versus 92% ± 21% for language.45 Moreover, 3.1% and 15% of excised cortex overlapped sensorimotor and language circuits, respectively. Therefore, even if resting-­state fMRI succeeded to some extent in distinguishing eloquent versus resectable sensorimotor and language sites, these original findings revealed a high interindividual variability of mapping accuracy and a rate about 80% in the detection of functional cortical areas—making it clearly insufficient to use resting-­state fMRI on its own for presurgical mapping. Further validation studies are needed to increase the reliability of this technique for surgical planning, especially by using network automatic identification and/or subnetwork analysis.45 In conclusion, fMRI is not ready for prime time in guiding glioma resection.46 DTI is a useful adjunct, but when dealing with abnormal or distorted fiber tract anatomy induced by gliomas, the risk of erroneous DTI results is increased because diffusion properties can be affected by the neoplasm. These drawbacks explain why correlation studies between DTI and IESM have found concordance in only 82% of cases.47 Consequently, negative tractography does not mean that no critical tracts are present within the glioma. In other words, DTI is unable to provide any information about the functionality of a specific fiber: it can give only indirect data concerning its structure. DTI is not currently reliable for surgical indications or planning.40 Of note, there is no article in the literature demonstrating that the use of fMRI and/ or DTI for tumor surgery resulted both in an increase in EoR and a decrease in postoperative morbidity in the same patients—in contrast to IESM (see later). The danger for young neurosurgeons who use fMRI/DTI routinely in the operating room (incorporated into a neuronavigational system or acquired in real time with intraoperative MRI) is to become dependent on neuroimaging. They will not be able to operate on the brain without intrasurgical neuroimaging on the sole basis of their knowledge of the functional anatomy validated by online feedback provided by

cognitive monitoring and IESM in awake patients. In fact, functional neuroimaging must be seen as an educational and a research tool outside the operating room48—for example to explore the mechanisms of neuroplasticity in longitudinal fMRI studies49,50 but not as a clinical tool into the operating room. 

The Gold Standard: Intraoperative Cognitive Monitoring and Cortical-­ Subcortical Stimulation Mapping in Awake Patients Due to major anatomic-­functional variability across patients and possibly within the same patient over time because of cerebral reorganization (particularly in LGG), intraoperative functional mapping must be systematically achieved under local anesthesia in all glioma patients—at least those who do not have severe deficits before surgery.1 Indeed, even though motor mapping can be done under general anesthesia by means of intrasurgical electrophysiologic monitoring using motor evoked potentials,51 this technique is nonetheless unable to map motor cognition with the same accuracy as in awake patients, especially regarding complex movements or bimanual coordination (see later).52 IESM is currently the sole technique that enables the direct identification (and then the preservation) of cortical-­subcortical networks critical for neural functions.53 In practice, bipolar electrode tips spaced 5 mm apart and delivering a biphasic current (pulse frequency 60 Hz, single-­ pulse phase duration 1 ms) are applied to the brain. The current intensity adapted to each patient is determined by progressively increasing the amplitude in 1-­mA increments from a baseline of 1 mA until a functional response is elicited, with 5 mA as the upper limit under local anesthesia with the goal of avoiding seizures.54 The patient is never informed when the brain is stimulated. Each cortical site (size 5 by 5 mm, due to the spatial resolution of the probe) of the entire cortex exposed by the bone flap is tested three times to determine whether it is functionally crucial by generating disturbances during the three stimulations and with normalization of the function as soon as the stimulation is stopped. At least one picture presentation without stimulation must separate each stimulation, and no site is stimulated twice in succession so as to avoid seizures. However, in cases of stimulation-­induced seizures, irrigation with cold Ringer lactate is recommended to abrogate the seizure activity. In addition, it is crucial to benefit from positive cortical mapping before beginning to remove the tumor with the goal of tailoring the resection according to the distribution of the neural networks in the given patient at the given moment. In series supporting negative mapping, 1.6% to 9% of new permanent neurologic deteriorations have been observed.55–57 It is recommended to perform a wider bone flap with the goal of obtaining systematic functional responses prior to surgical excision by exposing at least the ventral premotor cortex (vPMC); this will generate articulatory disturbances in all cases during stimulation, whatever the hemisphere.58 Moreover, positive mapping might also enable optimization of the EoR, since the resection can be pursued until eloquent areas are encountered (i.e., with no margin around the

5  •  Cortical and Subcortical Brain Mapping

functional structures); this may increase the rate of supratotal resections. In a consecutive and homogeneous series of 115 LGGs in the left hemisphere, the rate of permanent deficits remained lower than 2% despite the absence of margin around the language sites.59 Of note, due to the use of low-­ intensity electrostimulation (mean of about 2.25 mA in the author’s personal experience), electrocorticography is not necessary to obtain positive mapping and to limit the risk of intraoperative epilepsy. This was obtained in about 3% in a recent prospective series with 374 supratentorial brain lesions without any aborted awake procedures.54 Therefore “minimal invasive neurosurgery” means “minimal morbidity” and not “minimal bone flap size.” To benefit from extensive and reliable neurocognitive assessment throughout the resection, it is crucial that a speech therapist/neuropsychologist/neurologist be present in the operating room in order to interpret the kinds of disturbances caused by IESM—for example, arrest of movement, involuntary limb/face movement or ocular saccades, speech arrest, anarthria, speech apraxia, phonologic disturbances, semantic paraphasia, anomia, syntactic errors, nonverbal semantic disorders, deficits in visual attention, perseveration, dyscalculia, mentalizing deficit, and so on. Thus IESM is able to identify in real-­time the cortical sites

essential for function before the beginning of the resection in order to select the best surgical approach and to define the cortical limits of lesion removal (Fig. 5.1). The other critical issue after identification of the eloquent cortical areas is the mapping of subcortical connectivity.53 Indeed, brain lesion studies have taught us that damage to the white matter pathways generates more severe deficits than cortical injury, with only a very low rate of recovery. Therefore the subcortical tracts subserving motor, somatosensory, visuospatial, auditory-­vestibular, language, executive, and emotional functions must be detected during lesion removal in order to preserve the anatomic-­functional connectivity while optimizing the EoR—namely, to stop the resection only when these deep eloquent pathways are encountered.60 Of note, since the patient can be tired after 1 to 2 hours of continuous tasks, glioma removal should be started directly into the contact of the functional structures detected using cortical and axonal IESM in order to avoid the waste of time. The aim is to disconnect the part of the brain invaded by the glioma and not to debulk the tumor from inside by coming closer to the critical regions only at the end of the resection, when the patient is less cooperative. Once the infiltrated brain is disconnected up to functional limits provided by individual mapping, it can be resected

B

A

C

53

D

FIGURE 5.1  (A) Preoperative language functional magnetic resonance imaging (fMRI) in a patient with no deficit, showing a low-­grade glioma involving the left inferior frontal gyrus (the so-­called Brocas area), with an activation immediately in front the tumor (within the anterior insula). Intraoperative views before (B) and after (C) glioma resection (the tumor was delineated by letter tags). Intraoperative electrostimulation mapping shows reshaping of the cortical map (cortical sites are marked by number tags), with recruitment of perilesional language sites located behind the glioma. There was no crucial site within the left inferior frontal gyrus. Thus an extensive resection of the Broca area was possible while preserving the subcortical connectivity in the depth of the cavity (50, corresponding to the anterior part of the arcuate fasciculus). Stimulation of the anterior insula and the fibers running in the temporal stem (inferior frontooccipital fasciculus) generated anomia.160 (D) Postoperative axial FLAIR-­and coronal T2-­weighted magnetic resonance imaging demonstrating a complete resection of the glioma in a patient with no deficit who resumed a normal life.

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Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

under general anesthesia, since real-­time feedback from the patient is no longer useful.58 IESM is highly sensitive for detecting the cortical and axonal eloquent structures; it also provides a unique opportunity to study brain connectivity, since each area responsive to stimulation is in fact an input gate into a large-­scale network and not an isolated discrete functional site.53 

Mapping the Connectome: What We Have Learned from Intraoperative Electrostimulation Mapping Recent advances in cognitive neuroscience resulted in a paradigmatic shift from a traditional rigid and localizationist view of brain organization (in which one given area corresponds to one specific function, with no recovery if this area is damaged) to a dynamic hodotopical model, in which the central nervous system is organized in parallel and interconnected large-­scale cortical-­subcortical circuits.22 In this networking account of brain processes, IESM plays a major role to map the connectome for each patient—that is, to identify the hubs and pathways subserving neural functions with the aim of optimizing the oncofunctional balance of surgery.60 Here, the goal is to detail the functional anatomy of these subnetworks as well as their interactions.

SENSORIMOTOR SUBNETWORK Recent IESM explorations have changed our view of the neural basis underlying movement away from a hierarchical organization and toward complex circuits. Indeed, voluntary movement engages a set of highly sophisticated neurocognitive processes called motor cognition—namely, intention to act, motor planning, motor initiation, action control, and so forth. A basic way to monitor all aspects of voluntary movement during surgery is to ask the patient to do a simple dual motor task involving the upper limb (i.e., to lower the arm and open the hand, then to raise the arm and close the hand (the lower limb may be also tested, or both upper and lower limbs at the same time). In addition to controlling the velocity and the accuracy of the movement throughout surgery, this task makes it possible to map critical structures for motor cognition using IESM.61 Typically, stimulation of the supplementary motor area (SMA) can lead to motor initiation disorders. Other motor tasks may also be performed to map more specific motor abilities (e.g., to ask the patients to perform coordinated movements with both hands, which is crucial for certain professions such as manual work or performance on a musical instrument).52 In the same vein, the patient can achieve more complex movements to assess fine-­grained motor abilities such as drumming or to perform reflexive praxis (e.g., imitation of meaningless movements) to evaluate movement planning. IESM has confirmed that the corticospinal tract originates from the primary motor cortex, runs with a somatotopical distribution within the corona radiata (with, from medial to lateral, the pyramidal tract of the lower limb, upper limb, and the face), and then within the posterior limb of the internal capsule (with, from anterior to posterior, the pyramidal tract of the face, upper limb, and lower limb) before reaching the brain stem and spinal cord.62 Moreover, the existence of an additional network involved in motor control has recently

been evidenced: IESM of this circuit evokes arrest or acceleration of movement in awake patients, with no loss of consciousness.61 The axonal stimulation sites are distributed in a veil-­like pattern, anterior to the primary motor fibers, supporting the existence of descending tracts originating from the SMA, premotor cortex, and anterior cingulate, known for negative motor response characteristics, and running to the striatum through the frontostriatal tract.63 Additionally, these white matter bundles mediating the control of movement are somatotopically organized. In fact, IESM of the fibers from lateral to mesial and from anterior to posterior causes arrest of movement of the face/speech (laterally and anteriorly), upper limbs, and lower limbs (mesially and posteriorly).64 Further stimulation areas in the anterior arm of the internal capsule have indicated a large-­scale motor control network.61 Bilateral negative motor responses can also be induced by unilateral axonal IESM. Such data support the existence of a bilateral cortical-­subcortical circuit connecting the premotor cortices, basal ganglia, and spinal cord involved in the control of bimanual coordination.52 Finally, an IESM study that investigated the neural underpinnings of eye movement (implicated in the control of the spatial orientation of attention), revealed that the oculomotor tract originating from the frontal eye field could be part of this motor control network.65 Posterior thalamocortical somatosensory pathways and their somatotopy have also been studied by IESM, which evokes dysesthesias or tingling in awake patients.62,66 It is worth noting that axonal stimulation of the white matter behind the central sulcus can also cause disorders in movement control, likely explained by a transient inhibition of U fibers within the central region.61,67 In addition, in patients who had interference with movement during subcortical IESM, pathways that elicited inhibition or acceleration were located immediately posterior to the thalamocortical somatosensory fibers. Thus, a thalamoparietal connection distinct from somatosensory pathways is probable.67 Based on these original IESM findings, the existence of a wide frontothalamoparietal sensorimotor subnetwork has been proposed.61 In other words, these stimulation-­based findings gave evidence that the circuit subserving motor control is not centered on the frontal lobe but extends to other regions because it includes frontal and parietal white matter pathways as well as projection fibers with inhibitory and excitatory features. 

SUBNETWORK MEDIATING VISUOSPATIAL ATTENTION The optic tract originates from the lateral geniculate body in three bundles. The anterior bundle, the so-­called Meyer loop, curves anterolaterally above and in front of the temporal horn and then loops backward along the inferolateral wall of the atrium. The middle bundle runs laterally around and turns posteriorly along the lateral wall of the atrium and the occipital horn. The posterior bundle runs directly backward, again along the lateral wall of the atrium and occipital horn.68 In patients with lateral homonymous hemianopia, driving is prohibited in many countries, and several activities such as reading become difficult. Therefore, visual pathways also have to be mapped in awake patients. A protocol was recently proposed in which, with the vision being fixed at the center of the screen, patients are asked to name successively two pictures disposed in the two opposite quadrants,

5  •  Cortical and Subcortical Brain Mapping

knowing that it is essential to preserve the inferior quadrant (the superior being compensable in daily life). Whereas IESM of visual pathways usually elicits a range of phenomena subjectively described by the patient (either “inhibitory phenomena,” such as blurred vision or impression of shadow, or “excitatory phenomena,” such as phosphenes of visual illusions), the described task makes it possible to benefit from a more objective confirmation of the transient visual disorders evoked by electrostimulation: in fact, the patient is not able to name the picture presented in the inferior quadrant contralateral to the tumor.69 The amplitude of visual saccades or the possible increase of naming response time in the visual field under scrutiny must also be taken into consideration. The extent of the visual field must regularly be checked manually. The inferolateral occipitotemporal cortex plays a major role in object recognition: injury of this system can result in visual agnosia (i.e., a disabling inability to recognize object with the visual modality). A simple way to map such high-­ order visual processes during awake surgery is to ask the patient to engage in a picture-­naming task. When IESM causes disorders of object recognition, the patient usually commits a non–semantically related “visual paraphasia.” Furthermore, axonal IESM of the inferior longitudinal fasciculus (ILF) may elicit contralateral visual hemiagnosia, supporting the existence of an occipitotemporal pathway connecting occipital visual input to higher-­level processing in temporal lobe structures, in particular the fusiform gyrus and the anterior temporal lobe.70 These stimulation findings support a crucial role for the ILF in visual recognition, with specialization of this bundle for visuospatial processing in the right hemisphere and language processing in the left hemisphere—inducing alexia71 or lexical retrieval difficulties72 when stimulated. It is worth noting that bilateral disconnection of ILF can provoke prosopagnosia.73 Unilateral spatial neglect is characterized by the failure to explore and allocate attention in the space contralateral to the injured hemisphere (especially the right) and has a major impact on QoL—for example, regarding the ability to drive. A classical test to evaluate spatial neglect during surgery is the bisection line task. In a touch-­screen environment, the patient is asked to show the true center of an 18-­cm line. If IESM elicits a significant rightward deviation (typically 7 mm or slightly more), the brain structure is considered as eloquent for visuospatial cognition.74 This task is helpful in mapping the posterior parietal cortex, including the inferior and superior parietal lobules and to a lesser extent the posterior temporal cortex.75,76 In addition, IESM of layer II of the superior longitudinal fasciculus (SLF), which connects the superior and inferior parietal lobules with the posterior middle frontal gyrus, also generates rightward deviation during a line-­bisection task.75 These data suggest that parietal-­ frontal communication, thought to maintain information exchange between the ventral and the dorsal attention systems, is necessary for symmetric processing of the visual scene. Thus spatial awareness depends not only on the cortical areas of the temporoparietal junction but also on a larger parietofrontal network communicating via the right SLF. In this regard, a recent IESM investigation evidenced that the right inferior frontooccipital fasciculus (IFOF)—a brain-­ wide white matter tract connecting the occipital, parietal, and temporal lobes and the prefrontal cortex77—also plays

55

a role in spatial cognition, since its stimulation may cause a transient hemineglect.78 In summary, the use of a simple line-­bisection task makes it possible to map and spare critical subnetworks for spatial attention. Indeed, the effectiveness of the IESM was demonstrated by a recent study reporting that, whereas about half of the patients with a glioma experienced a transient neglect in the immediate postoperative period, none presented a permanent spatial neglect.79 Finally, stimulation of another subcircuit in the right SLF can generate a central vestibular syndrome with vertigo due to a transitory disruption of the vestibular inputs assembled in the temporoparietal areas and the prefrontal cortex.80 This finding demonstrates the role of the SLF in the network coordinating body posture and spatial orientation. 

LANGUAGE SUBNETWORK To avoid aphasia, the naming task remains the gold standard during awake surgery because it is very sensitive to all levels of language processing. IESM may evoke different kinds of disturbances: speech arrest, dysarthria (disturbance of motor programming), anomia (disturbance of lexical retrieval), phonologic paraphasia (disturbance of phonologic encoding: production of a word with phonologic deviations such as phelephant for elephant), semantic paraphasia (disturbance of semantic processing, production of a word semantically related to the target word, such as cow for horse) or perseveration (disturbance of inhibitory control mechanisms, repetition of a prior word in front of a new picture).81,82 Beyond classic language-­related cortical areas, the naming task enables the surgeon to map the main associative connectivities—the arcuate fascicle (AF) for phonologic processes, the lateral SLF for articulatory processes, the IFOF for semantic control processes (see later), and the ILF for lexical retrieval—as well as certain intralobar tracts, such as the frontal aslant tract (involved in speech initiation and control).53,83 Based on IESM findings, a dual-­stream model for visual language processing has been proposed83 with a ventral route dedicated to mapping visual information to meaning (semantics) and a dorsal stream dedicated to mapping visual information to articulation through visuophonologic conversion. In comparison with other neurocognitive or computational models (e.g., by Hickock and Poeppel),84 this model has the great advantage of integrating anatomic constraints, especially the white matter connectivity information. The first step of this model is object recognition. As mentioned, IESM of the ILF, especially in the right hemisphere, typically elicits (hemi-­)visual paraphasia, showing that the patient is no longer able to correctly recognize the picture.85 These problems of visual cognition are usually caused by IESM of the posterior part of the ILF, which interconnects the primary visual cortex with the visual word form area (VWFA) located in the fusiform gyrus. Of note, stimulation (or surgical resection) of the same white matter fibers in the left hemisphere, especially those interconnecting the primary visual cortex and the VWFA, leads to pure alexia.71 Disruption of the VWFA per se generates different forms of alexia depending the site of stimulation (i.e., posterior, dorsal, or anterodorsal). The language network is mediated by two main pathways that work in parallel while interacting: the phonologic dorsal stream and the semantic ventral stream.86 A double

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Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

dissociation between phonemic and semantic errors has been found during axonal IESM, showing that the two processes are performed in a synergetic manner.83 The dorsal pathway is underpinned by the SLF and consists of two subparts.87 The deep part is the classic arcuate fascicle (AF) that connects the posterior temporal structures (mostly the middle and inferior gyri) to the inferior frontal gyrus (mainly the pars opercularis). IESM of this subpart elicits conduction aphasia, or a combination of phonemic paraphasia (supporting a role for this subpart in phonologic processing) and repetition disorders, but without semantic paraphasia.88 Interestingly, the posterior cortical origin of this tract corresponds to the VWFA,85 a functional hub involved both in phonologic processing dedicated to visual material and in semantics.89 The superficial portion of the dorsal route is underlain by the lateral part of the SLF (also called the SLF III), stimulation of which generates anarthria (articulatory disorders).90 This lateral operculo-­ opercular component of the SLF plays a pivotal role in articulation, by connecting the junction between the posterior part of the superior temporal gyrus (which receives feedback information from somatosensory and auditory areas) and the supramarginal gyrus, with the vPMC (which receives afferents bringing phonologic–phonetic information to be translated into articulatory motor programs).91 During word repetition, this loop also enables the conversion of auditory input, which is processed in the verbal working memory system, into phonologic and articulatory representations within the vPMC. This observation is in line with recent data obtained from cortical IESM (probabilistic atlas based on 771 stimulation sites), which demonstrated that the Broca area is not the speech output region,92 thereby challenging the classic theories on language. The ventral pathway is divided into a direct tract (the IFOF) and an indirect pathway formed by the anterior ILF and the uncinate fascicle (UF). These fascicles relay information to one another in the temporal pole.93 The IFOF connects the posterior occipital lobe and the fusiform gyrus to anterior corticofrontal areas, including the inferior frontal gyrus and dorsolateral prefrontal cortex.77,94 IESM of this white matter connectivity revealed a major role in verbal semantics because its stimulation reproducibly elicited semantic paraphasias.82 Nonetheless, recent studies have shown that this bundle is also implicated in nonverbal semantic cognition in the left95 as well as the right96 hemisphere, demonstrating that the nonverbal semantic system is distributed bilaterally. The indirect ventral semantic pathway has a relay at the level of the temporal pole, which represents a semantic “hub” that enables plurimodal integration of the multiple signals emanating from the unimodal systems.97 This indirect ventral stream includes the anterior part of the ILF, which connects the fusiform gyrus with the temporal pole, and information is then relayed by the UF, which links the temporal pole with the pars orbitalis of the inferior frontal gyrus. IESM of this indirect pathway does not cause semantic paraphasia98 but may nonetheless elicit nonverbal semantic disturbances.99 This ventral semantic pathway seems to contribute to the repetition of real words or pseudowords and may also participate in proper name retrieval.99 The difference between UF and IFOF stimulation during picture naming could reflect their distinct frontal terminations. Because picture naming requires minimal

levels of semantic control,100 this might explain the negligible effects of UF stimulation on this process. Naming at a more specific level (including naming of people) might be somewhat more executively demanding; thus UF stimulation does have an effect. Of note, the middle longitudinal fascicle, which connects the angular gyrus with the superior temporal gyrus up to the temporal pole, may also be part of the ventral semantic route.101 Yet subcortical IESM of this fascicle failed to generate any naming disturbances,102 so its exact functional role in the language network is still unclear. Beyond picture naming, IESM showed that syntactic processing was underpinned by delocalized cortical regions (left inferior frontal gyrus and posterior middle temporal gyrus) connected by a subpart of the left SLF. Axonal IESM of the SLF can induce specific problems involving grammatical gender, thus disrupting one subfunction without interfering with the others. Indeed, this subnetwork interacts with but is independent of the subnetwork involved in naming, as demonstrated by double dissociation between disruption of syntactic and naming processes during IESM. These findings support parallel rather than serial theory, calling into question the concept of the “lemma”—an abstract lexical representation of a word before its phonologic properties are assigned.103 

SUBNETWORK UNDERLYING EXECUTIVE FUNCTIONS IESM also showed the existence of an executive system— including prefrontal cortex, anterior cingulate, and caudate nucleus—that plays a major role in the cognitive control of more dedicated subcircuits, as for example the subnetwork involved in language switching, itself constituted by a large-­ scale corticosubcortical circuit comprising posterotemporal areas, supramarginal and angular gyri, inferior frontal gyrus, and a subportion of the SLF.104 Additionally, the frontal aslant tract, which connects the pre-­SMA and anterior cingulate with the inferior frontal gyrus, is also involved in language control, in particular in planning of speech articulation.63 Thus IESM of this tract may cause stuttering.105 In the same spirit, a cortical-­subcortical loop involving the deep gray nuclei, especially the caudate nucleus, also participates in the control of language (selection/inhibition), since IESM of the head of the left caudate nucleus regularly evokes perseveration.106 Anatomically, this corticostriatal loop seems to be mediated by the frontostriatal tract.63 IESM of the IFOF may also elicit nonverbal comprehension disturbances during a nonverbal semantic association test such as the Pyramid and Palm Trees Test. The patients were no longer able to make a semantic choice during stimulation, although some were still able to produce a short verbal description of their feelings, such as “what do I have to do?” “I don’t know at all,” “I don’t understand anything.”95 These difficulties were mainly induced by stimulating the deep layer of the IFOF and caused a double dissociation: semantic paraphasia with normal nonverbal semantic choice during IESM of the superficial layer of the IFOF and the opposite during IESM of the deep layer of the IFOF. Thus the existence of a superficial component involved in verbal semantics (see earlier) and a deep component involved in amodal semantic processing was proposed.95,96 Indeed, these findings are in line with the cortical terminations of the IFOF (prefrontal, temporal-­basal, and parietal areas), that correspond to the cortical subcircuit involved in semantic control.107 

5  •  Cortical and Subcortical Brain Mapping

SUBNETWORK SUBSERVING SOCIAL COGNITION Human beings are talented in understanding and predicting the behavior of others. This complex ability, commonly referred to as “mentalizing” or “theory of mind,” is one of the main foundations on which social cognition is built. Patients with mentalizing disorders have trouble understanding their social environment, resulting in abnormal behaviors and lack of social flexibility. To avoid long-­term postoperative impairments in social cognition, an adapted version of a well-­used mentalizing task (i.e., The Read the Mind in the Eyes task) can be used in awake patients. The task consists of the presentation of photographs depicting the eye region of human faces. For each of them, two affective states are suggested and participants are asked to select the one that best describes what the person in the photograph is currently feeling or thinking. Indeed, patients with resection of the pars opercularis of the right inferior frontal gyrus may not completely recover following glioma surgery,108,109 justifying clinically the use of this new intraoperative task. Crucial cortical epicenters have been detected by IESM—with, however, some degree of interindividual variability—in the right posterior inferior frontal gyrus, the dorsolateral prefrontal cortex, and the posterior superior temporal gyrus.109,110 Furthermore, critical sites have also been pinpointed along the inferior IFOF and within the white matter fibers supplying the dorsolateral prefrontal cortex (DLPFC),110 suggesting that the functional integrity of both the direct ventral connectivity and the dorsal connectivity via the SLF are required for accurately inferring complex mental states from human faces. These original findings have shown that mentalizing is made possible by parallel functioning of three neurocognitive subsystems. The first subcircuit, the mirror system, processes low-­level perceptual aspects of mentalizing and is subserved by the AF/SLF complex in the right hemisphere.31,109 The second subnetwork, the mentalizing system per se, is essential for high-­level, inference-­based mentalizing processing (i.e., the ability to overtly attribute mental states to others) and is supported by the cingulum, which interconnects two crucial cortical structures of the mentalizing network on the medial face of the brain (i.e., the medial prefrontal cortex and the precuneus). The third subcircuit is supported by the right IFOF and seems to be involved in face-­based mentalizing, such as facial emotion processing.110 Indeed, because the IFOF provides direct connections between cortical areas known to participate in emotion processes, especially the occipitotemporal visual association areas and prefrontal areas, its disconnection by IESM can generate transient disturbances of the processing involved in decoding facial emotional cues, which is necessary for an accurate affective mentalizing. 

SUBNETWORK MEDIATING CONSCIOUS INFORMATION PROCESSING Interestingly, IFOF may also play a pivotal role not only in verbal and nonverbal semantics (see earlier) but also in the awareness of amodal semantic knowledge, namely noetic consciousness. From a phylogenic perspective, because recent investigations in the primate failed to find this bundle, one could suggest that the IFOF is the proper human fascicle. This multifunction fascicle enables humans to produce and understand language, to manipulate concepts, to apprehend and understand the world (i.e., metalinguistics, conceptualization,

57

and awareness of knowledge); it contributes to making humans what they are, with their infinite wealth of mind.95 Indeed, in semantics, visual information is processed at the level of the occipital and temporobasal associative cortices, and auditory information is processed at the level of the temporal and parietal associative cortices. They are transmitted directly by the IFOF on an amodal shape to the prefrontal regions, which exert a top-­down control over this amodal information in order to achieve successful semantic processing in a given context. IESM of this pathway results in a disruption of these rapid direct connections. The transient semantic disorganization observed when the IFOF is stimulated would therefore be induced by a dissynchronization within this large-­scale circuit, interrupting simultaneously the bottom-­up transmission and the top-­down control mechanisms.95 In a step forward, IESM can be used to map structures involved in the maintenance of conscious information processing. In particular, IESM of the white matter originating from the dorsal posterior cingulate cortex may evoke a breakdown in conscious experience characterized by a transitory behavioral unresponsiveness with loss of external connectedness (retrospectively, a patient described himself as in a dream, outside of the operating room).111,112 These data suggest that functional integrity of the posterior cingulate connectivity is necessary to maintain consciousness of the environment. In other words, IESM can open the door to the investigation of the connectomal anatomy underlying distinct levels of awareness, including the pathways involved in monitoring of the human level of consciousness related to semantic memory (noetic consciousness), as well as the pathways that sustain consciousness of the external world. Cortical and axonal IESM can also be used to investigate the dynamic interactions between these subcircuits, and the functional regulation of their intrinsic activity by other subnetworks, such as the cingulothalamic system.111,112 In summary, these new insights gained from IESM strongly support the fact that brain functions are subserved by delocalized circuits comprising both the cortical epicenters and the white matter connections between these “hubs.”22 In this hodopical account—from cortical centers (“topology”), subcortical pathways (“hodology”), and interactive processing of both gray and white matters (“hodotopy”)21— challenging the traditional localizationist model, neurologic function comes from the synchronization between different epicenters, working in phase during a given task, knowing that the same hub may take part in several functions depending on the other cortical regions with which it is temporarily connected at any one time. Thus complex neural processes are made possible only because dynamic interactions exist between these parallel large-­ scale subnetworks, with different levels of subcircuits recruitment according to the task required. In other words, brain processing should not be conceived as the sum of several subfunctions but as the result from the integration and potentiation of parallel and interconnected subnetworks, in a connectomal account of brain functioning.53 In this context, the concept of brain connectome has recently emerged, with the goal of capturing the characteristics of spatially distributed dynamic neural processes at multiple spatial and temporal scales. This new science of brain connectomics, which aims to map the neural connections, contributes both to theoretical and computational models of the brain as a complex system.113

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Consequently it is crucial for neurosurgeons to improve their knowledge of such a dynamic anatomic-­ functional connectivity and then to integrate it more systematically the concept of IESM both at cortical and subcortical levels in their surgical strategy. Indeed, the gliomas involve both gray and white matter tracts; thus they alter the connectivity. On the other hand, if this connectivity is preserved intraoperatively, as in a connectomal organization of brain processes, it may explain why some epicenters considered as “eloquent” in a localizationist model, for instance the Broca area, can in certain conditions be involved by a tumor and even surgically removed with no permanent neurologic impairment due to a functional compensation within a large distributed network (i.e., so-­called neuroplasticity).114 

New Insights Into Neuroplasticity Gained from Intraoperative Electrostimulation Mapping and Surgical Applications POTENTIALS AND LIMITATIONS OF BRAIN PLASTICITY In the traditional theory of localizationism, the brain was supposed to be organized (1) in highly specialized functional areas, called “eloquent” regions (as the Rolandic, Broca, and Wernicke areas), whereby any injury gives rise to major permanent neurologic deficits, and (2) in “noneloquent” regions, with no functional consequences when damaged. However, due to regular reports of improvement of the functional status after lesions of cerebral structures considered as “eloquent,” this view of a fixed brain organization was called into question in the past decades. Indeed, faced with the damage of neural tissue, the brain can reallocate the remaining physiologic resources to maintain a satisfactory level of function in a cognitively and socially demanding environment. Therefore, many investigations have been performed, initially in vitro and in animals and then in humans, with the goal of exploring the mechanisms underpinning these compensatory phenomena. Thus the concept of neuroplasticity was born.23 Cerebral plasticity is a form continuous processing allowing short, middle, and long-­term remodeling of neural-­synaptic organization with the aim of optimizing the functioning of neural networks during phylogenesis, ontogeny, physiologic learning, and following lesions involving the peripheral as well as the central nervous system. Indeed, recent advances in functional mapping techniques have dramatically changed the classical rigid modular model for a new dynamic and distributed perspective of cerebral organization able to reorganize itself both in everyday life (learning) and after a pathologic event such as the development of a brain tumor.22 Interestingly, despite some literature reports on cases of functional recovery or adaptation in various neurologic contexts, the most persuasive body of evidence for the brain’s astonishing, lesion-­induced plasticity comes from the field of surgical neuro-­oncology.17,115 Indeed, probabilistic atlases of the brain’s plastic potential have recently been built on the basis of experience with glioma patients and residual tumor voluntarily left because of positive responses obtained during IESM.32–34 Anatomic-­functional correlations were achieved by computing for each brain voxel its probability to be surgically spared because of its functionality as demonstrated by

the postoperative MRI. These atlases demonstrate the crucial role of subcortical white matter fibers for postlesional redistribution. From an oncologic perspective, these atlases represent a tool for the prediction of tumor resectability116 because the ability to observe residual nonresectable neoplasms (i.e., noncompensable area) is known for each brain voxel. Remarkably, a low probability of residual tumor was observed on the cortex, while the vast majority of areas with a high probability of residual glioma were found in the axonal fibers. This means that the white matter tracts have a lower plastic potential than cortical regions, leading to the proposal of a “minimal common brain” necessary for basic cognitive functions.32–34 This knowledge is crucial in neuro-­ oncologic surgery, because gliomas migrate along the subcortical fibers117 that represent the deep limits of surgical resection. In other words, these tracts are the main obstacle to radical glioma removal. This supports early surgery rather than a wait-­and-­see attitude (especially in the case of LGGs) to prevent a too large glioma diffusion within the subcortical connectivity, especially when the neoplasm involves functional networks.118 

NEUROPLASTICITY AND INTRAOPERATIVE ELECTROSTIMULATION MAPPING: ITS IMPLICATIONS FOR GLIOMA SURGERY Recent surgical series have demonstrated that it is possible to undertake wide surgical resection of gliomas involving regions of the brain conventionally deemed to be inoperable due to the use of these mechanisms of neuroplasticity— but on the condition of preserving subcortical connectivity. Extensive glioma removals have therefore been carried out without generating irrevocable neurologic deficits in the following eloquent cerebral structures (Fig. 5.2):

Resection of Gliomas Involving the Broca Area Surgical resection of neoplasms within the pars opercularis and/or triangularis of the left inferior frontal gyrus can be achieved with no persistent deficits.119–122 Language compensation is mediated by the recruitment of adjacent regions, primarily the vPMC, the pars orbitalis, the dorsolateral prefrontal cortex and the insula (see Fig. 5.1).119 By contrast, the left vPMC (located behind the pars opercularis) cannot be completely excised because it is the final common pathway for speech—whereas the Broca area can be compensated after removal.90,123 Indeed, extensive neurocognitive examination after resection of the Broca area has confirmed complete functional recovery.120 A transopercular surgical approach through the Broca area, even if not invaded by the tumor, was even proposed in left insular LGGs in order not to split the sylvian fissure and then to reduce the risk of vascular injuries and spasms: no permanent language deficits arose.124,125 As mentioned, a recent probabilistic map for critical cortical epicenters of brain functions based on over 700 IESM readings obtained in 165 consecutive patients who underwent awake mapping for LGG resection challenged the traditional theories of neural organization by showing that the Broca area is not the speech output area.92 

Resection of Gliomas Involving the Wernicke Area Language compensation after the excision of gliomas within the posterior part of the left dominant superior temporal

5  •  Cortical and Subcortical Brain Mapping

59

A

B

C

D

E

F

G FIGURE 5.2  Examples of extensive glioma resection performed within eloquent areas using intraoperative electrostimulation mapping with preservation of the quality of life due to compensatory neuroplasticity. (A) Right and left supplementary motor areas; (B) entire left frontal lobe including the “Broca area”; (C) primary sensorimotor area of the face and primary motor area of the hand; (D) primary somatosensory area and parietal lobe; (E) right paralimbic system and left insula; (F) anterior/middle and posterior left dominant temporal lobe; (G) corpus callosum.

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gyrus (and its junction with the inferior parietal lobule) is made possible because this complex function is organized in multiple parallel subcircuits (see earlier). Therefore, in addition to the recruitment of regions immediately adjacent to the surgical cavity (such as the supramarginal gyrus), the long-­term reorganization may also be based on progressive recruitment of remote areas within the left dominant hemisphere (e.g., the pars triangularis of inferior frontal gyrus or other left frontolateral regions) as well as contralateral regions in the right hemisphere due to transcallosal disinhibition.126 Indeed, by using both fMRI and IESM, the existence of a wide bilateral cortical-­subcortical network capable of compensating for surgical resection of the left Wernicke area invaded by a LGG has been demonstrated.127 

Resection of Glioma Involving the Insular Lobe Despite a possible hemiparesis after right insular glioma excision, likely because this region is a nonprimary motor area, and despite possible transitory speech disorders following resection of a left dominant insular LGG, most patients in our experience recovered except in rare cases (2%) of deep stroke related to an injury of the lenticulostriate arteries.124,128–130 QoL was even improved in some one-­third of patients who had preoperative intractable epilepsy and in whom resection of the insular tissue (with, if necessary, additional excision of the temporomesial structures) led to complete relief of seizures.131 Moreover, resection of the claustrum did not generate any cognitive disorders (despite its role supposed in consciousness) in right non-­dominant frontotemporoinsular gliomas.132 The right striatum was also excised when invaded by LGG with no motor deterioration or movement disorders, even after a long-­term follow­up over 10 years: this compensation may be explained by a recruitment of parallel subcortical circuits such as pallidoluysopallidal, strionigrostriate, corticostrionigrothalamocortical, and corticoluysal networks.133 

Resection of Gliomas Involving the Primary Sensorimotor Area of the Face Despite a possible transitory cerebral facial paralysis, the bilateral hemispheric cortical representation of the sensorimotor area of the face explains why all patients recovered following its resection.134 Of note, if the insula is also invaded, a transient Foix-­Chavany-­Marie syndrome with a transient bilateral orofacial pharyngeal-­laryngeal paralysis can occur.135 

Resection of Gliomas Involving the Primary Motor Area of the Upper Limb The ‘‘fixed’’ somatotopical organization of the homunculus must be replaced by a more dynamic view of the functioning of sensorimotor cortex based on the existence of redundancies both within the primary motor cortex and between the pre - ­and retrocentral regions. IESM of the precentral gyrus regularly generates somatosensory responses, whereas IESM of the retrocentral gyrus can result in involuntary muscle contractions or in an arrest of movement, indicating the existence of a complex central network and not a succession of discrete independent sites (see earlier).61,67 Unmasking of the latent subnetworks can be observed in real time in the operating theater due to phenomena of acute neuroplasticity, enabling sensorimotor remapping within a few minutes

and leading to more complete resection with no permanent impairments.136,137 Additionally, long-­term reorganization effects (months or years after the first operation) can also arise, optimizing tumor excision during a reoperation compared with the initial surgery, including within the “knob of the hand” (see later).138,139 

Resection of Gliomas Involving the Primary Somatosensory Area Due to this dynamic organization of the central region, longitudinal pre-­and postoperative functional neuroimaging investigations have suggested the possible recruitment of “redundant” eloquent sites around the cavity within the postcentral gyrus after removal of a glioma within the primary somatosensory cortex. Similarly, IESM has revealed unmasking of redundant somatosensory sites during resection, likely due to a decrease in corticocortical inhibition. Recruitment of secondary somatosensory areas and/or posterior parietal cortex, primary motor area (due to strong anatomic-­ functional connections between the pre-­and retrocentral gyri), and contralateral primary somatosensory area can also contribute to functional compensation to various degrees.138,140 

Resection of Gliomas Involving the Supplementary Motor Area Resection of the SMA usually produces a typical syndrome with a transitory akinesia and possible mutism (particularly after surgery in the left hemisphere) that improves rapidly and then resolves after a few weeks following intensive rehabilitation.141,142 Pre-­and postoperative task-­based and resting-­state fMRI has evidenced a recruitment of the contralateral SMA and premotor cortex as well as a modulation of intra-­and inter-­hemispheric connectivity, contributing to recovery.49,143 Nonetheless, a more detailed cognitive assessment may reveal permanent subtle but objective long-­ term difficulties, particularly regarding complex movements and bimanual coordination.142 For this reason, the preservation of subnetworks mediating movement control can be proposed in selected patients according to their jobs, hobbies, and lifestyle (e.g., a pianist or surgeon).52,61,64 

Resection of Gliomas Involving a Subsection of White Matter Fascicles Although neuroplasticity is constrained by subcortical connectivity (see earlier), some parts of white matter tracts may nevertheless be excised with no severe persistent functional deterioration. Indeed, in a tract-­based cluster analyses reported in a recent probabilistic atlas of functional plasticity, most individual bundles were usually divided into a subsection with a low and a subsection with a higher functional compensation index—suggesting that groups of fibers within the same tract may differ in their neuroplastic potential. A typical example is the ILF, which connects the temporal pole to the occipital cortex and the occipitotemporal junction: while the posterior part of the ILF is always functional for a set of cognitive processes (including reading aloud85 and visual recognition71), its anterior part appears to abandon its functional role once invaded by a LGG. These gradients of plasticity in the basal inferotemporal system can be analyzed by taking into account the connectivity patterns in the occipitotemporal area. Indeed, in addition to projections

5  •  Cortical and Subcortical Brain Mapping

from the ILF, this area receives widespread neural connections from the posterior segment of the SLF, the IFOF, the AF, and even the vertical occipital fasciculus. Accordingly one might speculate that the information broadcast by the ILF toward the temporal pole under normal circumstances could be redistributed via other connectivities if functional compensation is prompted by the glioma growth.93,98 In the same vein, a part of the corpus callosum invaded by a glioma may also be removed with no morbidity.144 Nonetheless, as already mentioned, despite these rare exceptions, the axonal connectivity must be spared in the vast majority of cases to allow for the occurrence of neuroplasticity mechanisms within a wide bilateral cortical-­subcortical circuit also involving the deep gray nuclei and cerebellum, as recently evidenced by means of resting-­state fMRI before and after the resection of LGGs.50 

TOWARD A MULTISTAGE SURGICAL APPROACH AND THE ROLE OF SERIAL MAPPING When complete glioma resection is not possible due to neoplastic invasion of structures that are still eloquent, reoperation a few months or years later can be envisioned, particularly in LGGs, when neuroplasticity phenomena have provoked functional remapping. The second resection can be increased while preserving QoL.22,114 Indeed, several reports have evidenced that such a remapping was not a theoretical concept but a concrete reality in hum ans.17,138,145 Postoperative functional neuroimaging performed some months or years after LGG surgery in patients with a complete recovery revealed the recruitment of perilesional areas and/or remote regions within the ipsilesional hemisphere and/or of controlateral structures127,143,146 with changes in the intrinsic connectivity (see earlier).49,50 Based on these findings, a second surgery was proposed in patients with partial resection, who continued to enjoy a normal life before the onset of new symptoms (except possibly seizures) because the volume of the residual glioma increased.147 The second surgery was also conducted under the guidance of cortical and axonal IESM in order to validate the mechanisms of neural reorganization presumed but not proven by preoperative functional neuroimaging.140,145,146 The preliminary results have supported the efficacy and the safety of such a multistage surgical strategy for LGG not completely excised during a first surgery for functional reasons. Indeed, in a recent series, 74% of resections were complete or subtotal (less than 10 mL of residue) after the reoperation despite no additional serious neurologic deterioration—on the contrary, with functional improvement in 16% of cases. The seizures were reduced or disappeared in 82% of patients who experienced intractable epilepsy before the second surgery. The median time between the two operations was 4.1 years, and all patients were still alive with a median follow­up of 6.6 years despite an initial partial resection.147 These data showed that, due to neuroplastic potential, it is possible to reoperate on patients with LGG within eloquent areas with minimal morbidity and an increase of the EoR. Interestingly, these results have been recently been reproduced by the UCSF team.148 Therefore, it was suggested to “overindicate” an early reintervention with the goal OF anticipating the second surgery before malignant transformation.147 Such a multistage surgical approach was particularly useful for optimizing the EoR in traditional critical areas such as

61

the Broca, Wernicke, and Rolandic areas (see earlier) (Fig. 5.3). Moreover, one may currently consider performing functional neuroimaging also after postoperative rehabilitation, which is known to induce a significant improvement in patients with brain tumors,149 and after recovery following a second surgery in order to open the door to a possible third or even fourth resection several years after the previous operations. The aim is both to enable the patient to continue to enjoy a normal life as well as to increase the OS.3 Operations can also be integrated within a dynamic therapeutic strategy including chemotherapy and radiotherapy, especially when a radical removal is not possible for functional issues.150 To this end, neoadjuvant chemotherapy was recently proposed in LGG with the goal of inducing shrinkage of the neoplasm before an operation or a reoperation28 but also possibly to facilitate functional brain reshaping.150 

Outcome After Awake Craniotomy With Intraoperative Electrical Mapping Both functional and oncologic outcomes following glioma surgery have dramatically improved due to the use of cortical-­subcortical IESM. First, IESM in awake patients has resulted in a significant increase of the surgical indications for tumors involving the eloquent areas compared with classical series of glioma resection achieved under general anesthesia without intraoperative mapping.16 As mentioned, maximal surgical excision can be achieved for gliomas located in structures dogmatically considered as being unresectable with no or only minimal postoperative morbidity (see Fig. 5.1). A meta-­analysis reported over 8000 patients who underwent resection for a low-­ grade or high-­ grade glioma: it showed that the use of IESM permitted a significant reduction of the rate of postsurgical permanent deficits151 and that the rate of surgical selection for neoplasms situated within presumed essential structures had increased. Additionally, the EoR was increased.151 These findings are in line with previous series that have compared functional and oncologic outcomes in two consecutive series of LGGs removed without and then with IESM at the same institution.16 Again, IESM enabled a significant increase in the rate of surgical resections within areas conventionally deemed inoperable; simultaneously, the postoperative morbidity significantly decreased and the rate of total or subtotal resection significantly increased. In recent experiences based on IESM, the rate of permanent deterioration is less than 2%, including for tumors within language regions.54,56,59 In LGG patients who underwent two consecutive surgeries, with a first operation performed under general anesthesia without mapping and a reoperation achieved in awake patients using IESM, the EoR was improved in all cases after the second surgery, with no persistent impairments.152 In 281 patients bearing gliomas in presumed eloquent areas, Chang et al. reported that the use of IESM-­guided resection, which enabled a reliable identification of true functional and nonfunctional sites, permitted both a maximization of EOR and a significant improvement of long-­term OS.153 Awake surgery was also recently used for LGG located in noneloquent areas, with the goal of pursuing the resection beyond the visible part of the glioma on FLAIR-­weighted MRI: no malignant

62

Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

A

B

C

E

D

F

FIGURE 5.3  The multistage surgical approach. (A) Preoperative language functional magnetic resonance imaging (fMRI) in a patient without deficit shows a low-­grade glioma involving the left premotor area: language activation was very close to the posterior part of the tumor (arrow). (B) Intraoperative views before (left) and after (right) resection of the glioma, delineated by letter tags. Intraoperative electrostimulation mapping shows reshaping of the eloquent maps, including recruitment of perilesional language sites, enabling subtotal resection with, however, a posterior residue that was left due to invasion of crucial areas (number tags). (C) Immediate postoperative enhanced T1-­weighted magnetic resonance imaging (MRI) shows the residual tumor. (D) Postoperative language fMRI four years after the first fMRI shows recruitment of the contralateral hemisphere as well as posterior displacement of activation previously located at the posterior border of the tumor. (E) Intraoperative view during the second surgery, confirming the remapping and enabling more extensive tumor resection with no permanent deficit. (F) Postoperative axial FLAIR-­weighted MRI sh .

5  •  Cortical and Subcortical Brain Mapping

63

transformation arose with a mean follow-­up of 132 months (range 97 to 198 months) after such a supramarginal resection, supporting that the concept of functional mapping and resection may also be applied to noneloquent zones.13,14 Last but not least, it is worth noting that the EoR is significantly correlated with the control of seizures in LGG patients— thus also improving their QoL.9 In summary, more than 98% of patients will recover their presurgical functional status after glioma resection, even within critical neural networks, when guided by IESM.54,56,59 Patients with LGGs can also improve their cognitive status as demonstrated by postoperative neuropsychologic assessment compared with the presurgical examination,154,155 and 80% of patients with presurgical intractable epilepsy can benefit from the relief of their seizures.9 In other words, glioma surgery is currently capable not only of preserving brain functions but may also improve QoL, supporting the existence of additional neuroplastic mechanisms occurring after the operation, facilitated by a systematic and adapted rehabilitation.149 Therefore, to optimize the oncofunctional balance, all gliomas must be removed up to functional limits provided by IESM in awake patients, not only when performing surgery within presumed eloquent structures as language pathways but also when the tumor does not directly infiltrate critical structures (for example, in the so-­ called right nondominant hemisphere): indeed, the rate of supratotal resection is increased and the oncologic impact is greater. In other words, the surgical dogma supporting the role of awake surgery for left tumors while achieving resection under general anesthesia for right tumors must be discarded. 

interactions between these neural subnetworks and multimodal systems—such as working memory, attention, executive functions, and even consciousness—can be studied by IESM. In this networking model, brain functioning results from the integration and potentiation of parallel and interconnected subcircuits.156 Application of this original philosophy is essential to solve the traditional dilemma opposing the increase of EoR versus the preservation of QoL in patients with brain neoplasms. Based on this new concept of a “hodotopic and plastic brain,”21 the next surgical goal in gliomas is to move toward personalized serial therapeutic approaches.150 Thus, to optimize the oncofunctional balance at the individual level,2 the benefit-­risk ratio of different strategies of resection must be weighed according to the brain structures actually invaded and by their plastic potential. To select the best candidates for operation or reoperation, new biomathematical models could be helpful to examine the brain connectome with the aim of predicting before surgery the patterns of postsurgical remapping at the individual scale on the basis of the data provided by longitudinal functional neuroimaging.157 In other words, to increase both the quantity of life and the length of time with a normal QoL, therapeutic management should be adapted to each patient over time according to the strong interactions between the tumor course, brain reorganization, and multistage surgical approach. This opens the window to the principle of “functional surgical neuro-­ oncology.”158 Indeed, in the era of evidence-­based medicine, it is crucial not to forget “individually based medicine,” taking into account the huge interindividual anatomic and functional variability of the brain.159

Conclusions and Perspectives

KEY REFERENCES

Recent structural-­functional investigations using IESM have changed our view of brain processes from a hierarchical and rigid modular account toward a dynamic organization based on parallel and interconnected neural subnetworks. This reexamination of cognitive models in the era of connectomics has resulted in the redefinition of the surgical anatomy of the central nervous system and is particularly useful for glioma resection. In other words, cognitive neurosciences represent a valuable aid to neuro-oncology by opening new doors to elaborate original therapeutic strategies and ultimately to improve both QoL and OS. Resecting a part of the brain invaded by diffuse tumoral cells up to the individual functional limits—constituted by the “minimal common core,” mostly composed of axonal pathways as the main limitation of neuroplasticity—has permitted the evolution of the new concept of connectomal neurosurgery. Indeed, IESM of cortical hubs as well as white matter tracts has offered an unprecedented opportunity to explore the function of the connectomal anatomy in humans. This unique methodology, in which real-­time anatomic-­functional correlations are performed in awake patients, has provided new insights into the neural circuits underpinning the sensorimotor, visuospatial, language, cognitive, and mentalizing systems.53 Based on these original findings, the first functional atlas of human white matter has recently been developed.33 In addition,

Chang EF, Clark A, Smith JS, et al. Functional mapping-­guided resection of low-­grade gliomas in eloquent areas of the brain: improvement of long term survival. J Neurosurg. 2011;114:566–573. de Witt Hamer PC, Gil Robles S, Zwinderman A, et al. Impact of intraoperative stimulation brain mapping on glioma surgery outcome: a meta-­analysis. J Clin Oncol. 2012;30:2559–2565. Duffau H. Stimulation mapping of white matter tracts to study brain functional connectivity. Nat Rev Neurol. 2015;11:255–265. Duffau H. Long-­term outcomes after supratotal resection of diffuse low-­grade gliomas: a consecutive series with 11-­year follow-­up. Acta Neurochir (Wien). 2016;158:51–58. Duffau H. In: Duffau H, ed. Diffuse Low-­Grade Gliomas in Adults. 2nd ed. London: Springer; 2017. Herbet G, Maheu M, Costi E, et al. Mapping the neuroplastic potential in brain-­damaged patients. Brain. 2016;139:829–844. Jakola AS, Skjulsvik AJ, Myrmel KS, et al. Surgical resection versus watchful waiting in low-­grade gliomas. Ann Oncol. 2017;28:1942– 1948. Sanai N, Mirzadeh Z, Berger MS. Functional outcome after language mapping for glioma resection. N Engl J Med. 2008;358:18–27. Sarubbo S, de Benedictis A, Merler S, et al. Towards a functional atlas of human white matter. Hum Brain Mapp. 2015;36:3117–3136. Tate MC, Herbet G, Moritz-­Gasser S, et al. Probabilistic map of critical functional regions of the human cerebral cortex: Broca’s area revisited. Brain. 2014;137:2773–2782. Vilasboas T, Herbet G, Duffau H. Challenging the myth of right “non-­ dominant” hemisphere: Lessons from cortico-­subcortical stimulation mapping in awake surgery and surgical implications. World Neurosurg. 2017;103:449–456.

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68. Sarubbo S, De Benedictis A, Milani P, et al. The course and the anatomo-­functional relationships of the optic radiation: a combined study with ‘post mortem’ dissections and ‘in vivo’ direct electrical mapping. J Anat. 2015;226:47–59. 69. Gras-­Combes G, Moritz-­Gasser S, Herbet G, et al. Intraoperative subcortical electrical mapping of optic radiations in awake surgery for glioma involving visual pathways. J Neurosurg. 2012;117:466–473. 70. Fernández Coello A, Duvaux S, De Benedictis A, Matsuda R, Duffau H. Involvement of the right inferior longitudinal fascicle in visual hemiagnosia: a brain stimulation mapping study. J Neurosurg. 2013;118:202–205. 71. Zemmoura I, Herbet G, Moritz-­Gasser S, et al. New insights into the neural network mediating reading processes provided by cortico-­ subcortical electrical mapping. Hum Brain Mapp. 2015;36:2215–2230. 72.  Herbet G, Moritz-­ Gasser S, Boiseau M, et al. Converging evidence for a cortico-­ subcortical network mediating lexical retrieval. Brain [Epub ahead of print]. 73. Corrivetti F, Herbet G, Moritz-­Gasser S, et al. Prosopagnosia induced by a left anterior temporal lobectomy following a right temporo-­occipital resection in a multicentric diffuse low-­grade glioma. World Neurosurg. 2017;97:756.e1–756.e5. 74. Bartolomeo P, de Schotten MT, Duffau H. Mapping of visuospatial functions during brain surgery: a new tool to prevent unilateral spatial neglect. Neurosurgery. 2007;61:E1340. 75. Thiebaut de Schotten M, Urbanski M, Duffau H, et al. Direct evidence for a parietal-­frontal pathway subserving spatial awareness in humans. Science. 2005;309:2226–2228. 76. Roux FE, Dufor O, Lauwers-­Cances V, et al. Electrostimulation mapping of spatial neglect. Neurosurgery. 2011;69:1218–1231. 77. Sarubbo S, De Benedictis A, Maldonado IL, et al. Frontal terminations for the inferior fronto-­occipital fascicle: anatomical dissection, DTI study and functional considerations on a multi-­ component bundle. Brain Struct Funct. 2013;218:21–37. 78. Herbet G, Yordanova YN, Duffau H. Left spatial neglect evoked by electrostimulation of the right inferior fronto-­ occipital fasciculus. Brain Topogr. 2017. https://doi.org/10.1007/ s10548-­017-­0574-­y. [Epub ahead of print]. 79. Charras P, Herbet G, Deverdun J, et al. Functional reorganization of the attentional networks in low-­grade glioma patients: a longitudinal study. Cortex. 2015;63:27–41. 80. Spena G, Gatignol P, Capelle L, Duffau H. Superior longitudinal fasciculus subserves vestibular network in humans. Neuroreport. 2006;17:1403–1406. 81. Duffau H, Capelle L, Sichez N, et al. Intraoperative mapping of the subcortical language pathways using direct stimulations: an anatomo‐functional study. Brain. 2002;125:199–214. 82. Duffau H, Gatignol P, Mandonnet E, Peruzzi P, Tzourio-­ Mazoyer N, Capelle L. New insights into the anatomo-­functional connectivity of the semantic system: a study using cortico-­ subcortical stimulations. Brain. 2005;128:797–810. 83. Duffau H, Moritz-­Gasser S, Mandonnet E. A re-­examination of neural basis of language processing: proposal of a dynamic hodotopical model from data provided by brain stimulation mapping during picture naming. Brain Lang. 2014;131:1–10. 84. Hickok G, Poeppel D. The cortical organization of speech processing. Nat Rev Neurosci. 2007;8:393–402. 85. Mandonnet E, Gatignol P, Duffau H. Evidence for an occipito-­ temporal tract underlying visual recognition in picture naming. Clin Neurol Neurosurg. 2009;111:601–605. 86. Kümmerer D, Hartwigsen G, Kellmeyer P, et al. Damage to ventral and dorsal language pathways in acute aphasia. Brain. 2013;136:619–629. 87. Catani M, Jones DK, Ffytche DH. Perisylvian language networks of the human brain. Ann Neurol. 2005;57:8–16. 88. Maldonado IL, Moritz-­Gasser S, Duffau H. Does the left superior longitudinal fascicle subserve language semantics? A brain electrostimulation study. Brain Struct Funct. 2011;216:263–264. 89. Vigneau M, Beaucousin V, Herve PY, et al. Meta-­analyzing left hemisphere language areas: phonology, semantics, and sentence processing. Neuroimage. 2006;30:1414–1432.

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90. Van Geemen K, Herbet G, Moritz-­Gasser S, Duffau H. Limited plastic potential of the left ventral premotor cortex in speech articulation: evidence from intraoperative awake mapping in glioma patients. Hum Brain Mapp. 2014;35:1587–1596. 91. Duffau H, Gatignol P, Denvil D, Lopes M, Capelle L. The articulatory loop: study of the subcortical connectivity by electrostimulation. Neuroreport. 2003;14:2005–2008. 92. Tate MC, Herbet G, Moritz-­Gasser S, et al. Probabilistic map of critical functional regions of the human cerebral cortex: Broca’s area revisited. Brain. 2014;137:2773–2782. 93. Duffau H, Herbet G, Moritz-­ Gasser S. Toward a pluri-­ component, multimodal, and dynamic organization of the ventral semantic stream in humans: lessons from stimulation mapping in awake patients. Front Syst Neurosci. 2013;7:44. 94. Martino J, Vergani F, Robles SG, et al. New insights into the anatomic dissection of the temporal stem with special emphasis on the inferior fronto-­occipital fasciculus: implications in surgical approach to left mesiotemporal and temporoinsular structures. Neurosurgery. 2010;66:4–12. 95. Moritz-­Gasser S, Herbet G, Duffau H. Mapping the connectivity underlying multimodal (verbal and non-­verbal) semantic processing: a brain electrostimulation study. Neuropsychologia. 2013;51:1814–1822. 96. Herbet G, Moritz-­ Gasser S, Duffau H. Direct evidence for the contributive role of the right inferior fronto-­occipital fasciculus in non-­ verbal semantic cognition. Brain Struct Funct. 2017;222:1597–1610. 97. Lambon-­Ralph MA. Neurocognitive insights on conceptual knowledge and its breakdown. Philos Trans R Soc Lond B Biol Sci. 2013;369:20120392. 98. Mandonnet E, Nouet A, Gatignol P, Capelle L, Duffau H. Does the left inferior longitudinal fasciculus play a role in language? A brain stimulation study. Brain. 2007;130:623–629. 99. Papagno C, Miracapillo C, Casarotti A, et al. What is the role of the uncinate fasciculus? Surgical removal and proper name retrieval. Brain. 2010;134:405–414. 100. Jefferies E, Lambon Ralph MA. Semantic impairment in stroke aphasia versus semantic dementia: a case-­ series comparison. Brain. 2006;129:2132–2147. 101. Makris N, Preti MG, Wassermann D, et al. Human middle longitudinal fascicle: segregation and behavioral-­ clinical implications of two distinct fiber connections linking temporal pole and superior temporal gyrus with the angular gyrus or superior parietal lobule using multi-­tensor tractography. Brain Imaging Behav. 2013;7:335–352. 102. De Witt Hamer P, Moritz-­Gasser S, Gatignol P, Duffau H. Is the human left middle longitudinal fascicle essential for language? A brain electrostimulation study. Human Brain Mapp. 2011;32:962– 973. 103. Vidorreta JG, Garcia R, Moritz-­Gasser S, Duffau H. Double dissociation between syntactic gender and picture naming processing: a brain stimulation mapping study. Hum Brain Mapp. 2011;32:331–340. 104. Moritz-­Gasser S, Duffau H. Cognitive processes and neural basis of language switching: proposal of a new model. Neuroreport. 2009;20:1577–1580. 105. Kemerdere R, de Champfleur NM, Deverdun J, Cochereau J, Moritz-­Gasser S, Herbet G, et al. Role of the left frontal aslant tract in stuttering: a brain stimulation and tractographic study. J Neurol. 2016;263:157–167. 106. Gil Robles S, Gatignol P, Capelle L, Mitchell MC, Duffau H. The role of dominant striatum in language: a study using intraoperative electrical stimulations. J Neurol Neurosurg Psychiatry. 2005;76:940–946. 107. Binder J, Marshall R, Lazar R, et al. Distinct syndromes of hemineglect. Arch Neurol. 1992;49:1187–1194. 108. Herbet G, Lafargue G, Bonnetblanc F, et al. Is the right frontal cortex really crucial in the mentalizing network? A longitudinal study in patients with a slow-­ growing lesion. Cortex. 2013;49:2711–2727. 109. Herbet G, Lafargue G, Moritz-­Gasser S, et al. Interfering with the neural activity of mirror-­related frontal areas impairs mentalistic inferences. Brain Struct Funct. 2015;220:2159–2169.

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110. Yordanova YN, Duffau H, Herbet G. Neural pathways subserving face-­ based mentalizing. Brain Struct Funct. 2017. https://doi.org/10.1007/s00429-­017-­1388-­0. [Epub ahead of print]. 111. Herbet G, Lafargue G, De Champfleur NM, et al. Disrupting posterior cingulate connectivity disconnects consciousness from the external environment. Neuropsychologia. 2014;56:239–244. 112. Herbet G, Lafargue G, Duffau H. The dorsal cingulate cortex as a critical gateway in the network supporting conscious awareness. Brain. 2015;139.e23–e23. 113. Sporns O, Tononi G, Kötter R. The human connectome: a structural description of the human brain. PLoS Comput Biol. 2005;1:e42. 114. Desmurget M, Bonnetblanc F, Duffau H. Contrasting acute and slow growing lesions: a new door to brain plasticity. Brain. 2007;130:898–914. 115. Duffau H. Brain plasticity and tumors. Adv Tech Stand Neurosurg. 2008;3:3–33. 116. Mandonnet E, Jbabdi S, Taillandier L. Preoperative estimation of residual volume for WHO grade II glioma resected with intraoperative functional mapping. Neuro Oncol. 2007;9:63–69. 117. Mandonnet E, Capelle L, Duffau H. Extension of paralimbic low grade gliomas: toward an anatomical classification based on white matter invasion patterns. J Neurooncol. 2006;78:179–185. 118. Duffau H. Diffuse low-­grade gliomas and neuroplasticity. Diagn Interv Imaging. 2014;95:945–955. 119. Benzagmout M, Gatignol P, Duffau H. Resection of WHO Health Organization Grade II gliomas involving Broca’s area: methodological and functional considerations. Neurosurgery. 2007;61:741–752. 120. Plaza M, Gatignol P, Leroy M, et al. Speaking without Broca’s area after tumor resection. Neurocase. 2009;9:1–17. 121. Lubrano V, Draper L, Roux FE. What makes surgical tumor resection feasible in Broca’s area? Insights into intraoperative brain mapping. Neurosurgery. 2010;66:868–875. 122. Duffau H. The “frontal syndrome” revisited: lessons from electrostimulation mapping studies. Cortex. 2012;48:120–131. 123. Duffau H, Capelle L, Denvil D, et al. The role of dominant premotor cortex in language: a study using intraoperative functional mapping in awake patients. Neuroimage. 2003;20:1903–1914. 124. Michaud K, Duffau H. Surgery of insular and paralimbic diffuse low-­ grade gliomas: technical considerations. See comment in PubMed Commons below. J Neurooncol. 2016;130:289–298. 125. Duffau H, Moritz-­Gasser S, Gatignol P. Functional outcome after language mapping for insular World Health Organization Grade II gliomas in the dominant hemisphere: experience with 24 patients. Neurosurg Focus. 2009;27:E7. 126. Duffau H, Capelle L, Denvil D, et al. Functional recovery after surgical resection of low grade gliomas in eloquent brain: hypothesis of brain compensation. J Neurol Neurosurg Psychiatry. 2003;74:901–907. 127. Sarubbo S, Le Bars E, Moritz-­Gasser S, et al. Complete recovery after surgical resection of left Wernicke’s area in awake patient: a brain stimulation and functional MRI study. Neurosurg Rev. 2012;35:287–292. 128. Duffau H, Bauchet L, Lehéricy S, et al. Functional compensation of the left dominant insula for language. Neuroreport. 2001;12:2159–2163. 129. Duffau H, Taillandier L, Gatignol P, et al. The insular lobe and brain plasticity: lessons from tumor surgery. Clin Neurol Neurosurg. 2006;108:543–548. 130. Duffau H. A personal consecutive series of surgically treated 51 cases of insular WHO Grade II glioma: advances and limitations. J Neurosurg. 2009;110:696–708. 131. Ghareeb F, Duffau H. Intractable epilepsy in paralimbic Word Health Organization Grade II gliomas: should the hippocampus be resected when not invaded by the tumor? J Neurosurg. 2012;116:1226–1234. 132. Duffau H, Mandonnet E, Gatignol P, et al. Functional compensation of the claustrum: lessons from low-­grade glioma surgery. J Neurooncol. 2007;81:327–329. 133. Duffau H, Denvil D, Capelle L. Absence of movement disorders after surgical resection of glioma invading the right striatum. J Neurosurg. 2002;97:363–369.

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134. Schucht P, Ghareeb F, Duffau H. Surgery for low-­grade glioma infiltrating the central cerebral region: location as a predictive factor for neurological deficit, epileptological outcome, and quality of life. J Neurosurg. 2013;119:318–323. 135. Duffau H, Karachi C, Gatignol P, et al. Transient Foix-­Chavany-­ Marie syndrome after surgical resection of a right insulo-­ opercular low-­grade glioma. Neurosurgery. 2003;53:426–431. 136. Duffau H, Sichez JP, Lehéricy S. Intraoperative unmasking of brain redundant motor sites during resection of a precentral angioma. Evidence using direct cortical stimulations. Ann Neurol. 2000;47:132–135. 137. Duffau H. Acute functional reorganisation of the human motor cortex during resection of central lesions: a study using intraoperative brain mapping. J Neurol Neurosurg Psychiatry. 2001;70:506– 513. 138. Duffau H, Denvil D, Capelle L. Long term reshaping of language, sensory and motor maps following glioma resection: a new parameter to integrate in the surgical strategy. J Neurol Neurosurg Psychiatry. 2002;72:511–516. 139. Gayoso Garcia S, Herbet G, Duffau H. Vivid mental imagery of biomechanically impossible movements elicited by cortical electrostimulation of the central region in an awake patient. Stereotact Funct Neurosurg. 2015;93:250–254. 140. Duffau H, Capelle L. Functional recovery following lesions of the primary somatosensory fields. Study of the compensatory mechanisms. Neurochirurgie. 2001;47:557–563. 141. Krainik A, Lehéricy S, Duffau H, et al. Role of the supplementary motor area in motor deficit following medial frontal lobe surgery. Neurology. 2001;57:871–878. 142. Krainik A, Lehéricy S, Duffau H, et al. Postoperative speech disorder after medial frontal surgery: role of the supplementary motor area. Neurology. 2003;60:587–594. 143. Krainik A, Duffau H, Capelle L, et al. Role of the healthy hemisphere in recovery after resection of the supplementary motor area. Neurology. 2004;62:1323–1332. 144. Duffau H, Khalil I, Gatignol P, et al. Surgical removal of corpus callosum infiltrated by low-­grade glioma: functional outcome and oncological considerations. J Neurosurg. 2004;100:431–437. 145. Ghinda CD, Duffau H. Network plasticity and intraoperative mapping for personalized multimodal management of diffuse low-­grade gliomas. Front Surg. 2017;4:3. 146. Robles SG, Gatignol P, Lehéricy S, et al. Long-­term brain plasticity allowing a multistage surgical approach to World Health Organization Grade II gliomas in eloquent areas. J Neurosurg. 2008;109:615–624.

147. Martino J, Taillandier L, Moritz-­Gasser S, et al. Re-­operation is a safe and effective therapeutic strategy in recurrent WHO grade II gliomas within eloquent areas. Acta Neurochir (Wien). 2009;151:427–436. 148. Southwell DG, Hervey-­Jumper SL, Perry DW, et al. Intraoperative mapping during repeat awake craniotomy reveals the functional plasticity of adult cortex. J Neurosurg. 2016;124:1460– 1469. 149. Gehring K, Sitskoorn MM, Gundy CM, et al. Cognitive rehabilitation in patients with gliomas: a randomized, controlled trial. J Clin Oncol. 2009;27:3712–3722. 150. Duffau H, Taillandier L. New concepts in the management of diffuse low-­grade glioma: proposal of a multistage and individualized therapeutic approach. Neuro-­Oncology. 2015;17:332–342. 151. de Witt Hamer PC, Gil Robles S, Zwinderman A, et al. Impact of intraoperative stimulation brain mapping on glioma surgery outcome: a meta-­analysis. J Clin Oncol. 2012;30:2559–2565. 152. de Benedictis A, Moritz-­Gasser S, Duffau H. Awake mapping optimizes the extent of resection for low-­grade gliomas in eloquent areas. Neurosurgery. 2010;66:1074–1084. 153. Chang EF, Clark A, Smith JS, et al. Functional mapping-­guided resection of low-­ grade gliomas in eloquent areas of the brain: improvement of long term survival. J Neurosurg. 2011;114:566–573. 154. Satoer D, Visch-­Brink E, Smits M, et al. Long-­term evaluation of cognition after glioma surgery in eloquent areas. J Neurooncol. 2014;116:153–160. 155. Teixidor P, Gatignol P, Leroy M, et al. Assessment of verbal working memory before and after surgery for low-­grade glioma. J Neurooncol. 2007;81:305–313. 156. Duffau H. The error of Broca: From the traditional localizationist concept to a connectomal anatomy of human brain. J Chem Neuroanat. 2017. pii: S0891 -0618(16)30150-8. https://doi.org/ 10.1016/j.jchemneu.2017.04.003. [Epub ahead of print]. 157. Marrelec G, Bellec P, Krainik A, et al. Regions, systems and the brain: hierarchical measures of functional integration in fMRI. Med Image Anal. 2008;12:484–496. 158. Duffau H. Surgery of low-­grade gliomas: towards a “functional neurooncology.” Curr Opin Oncol. 2009;21:543–549. 159. Duffau H. A two-­ level model of interindividual anatomo-­ functional variability of the brain and its implications for neurosurgery. Cortex. 2017;86:303–313. 160. Pujol S, Wells W, Pierpaoli C, et al. The DTI Challenge: toward standardized evaluation of Diffusion Tensor Imaging tractography for neurosurgery. J Neuroimaging. 2015;25:875–882.

CHAPTER 6

Chemotherapy for Brain Tumors VYSHAK ALVA VENUR  •  MANMEET S. AHLUWALIA

Factors Influencing the Delivery of Chemotherapy to the Brain BLOOD-­BRAIN BARRIER Treatment of brain tumors with systemic chemotherapy poses unique challenges. Concentrations of chemotherapeutic agents within the central nervous system (CNS) depend on multiple factors, including ability of the agents to cross the blood-­brain barrier (BBB), the volume of distribution of the drug in the brain parenchyma, and the extent to which the drug is actively transported out of the brain.1 Therefore, many promising compounds fail in CNS drug development due to limited access to the target sites in the brain. Foremost is the BBB, which impedes delivery of adequate concentrations of most chemotherapeutic agents to the tumor; the others include brain-­tumor barrier (BTB), the blood–cerebrospinal fluid (CSF) barrier, and the brain-­CSF barrier.2 Paul Ehrlich first described BBB in 1985 when he noted that all body tissues except the brain were stained when certain vital dyes were injected intravenously into animals.3 The BBB critically controls the passage of drugs or other compounds from the blood to the CNS and protects the brain from the foreign and undesirable molecules. The major component of the BBB is a monolayer of brain capillary endothelial cells. The restriction of brain penetration arises from the presence of tight junctions between adjacent endothelial cells and interaction between astrocytes and endothelial cells.4 In contrast to other blood vessels in the body, the endothelial cells of brain capillaries lack intercellular fenestrations and have high electrical resistance and low ionic permeability, rendering them relatively impermeable to many water-­soluble compounds.2,4 The principal route to cross the BBB is by the process of lipid-­mediated transport of small nonpolar molecules, either by passive diffusion or less frequently by catalyzed transport.5 For a drug to successfully reach the brain parenchyma requires its uptake across the luminal (blood-­facing) membrane into the endothelial cells, its transport across their transcellular membrane, and finally efflux across the abluminal side (brain parenchyma–facing membrane into the interstitial fluid). The key to successful chemotherapy for brain tumors is adequate drug delivery to the tumor-­infiltrated brain and the individual tumor cells. To cross the BBB, chemotherapeutic drugs administered

64

systemically must be less than approximately 200 daltons in size, lipid soluble, not bound to plasma proteins, and minimally ionized.2,4 As a result, there is a positive correlation between lipophilicity of the drug and its ability to cross BBB. 

ROLE OF STEROIDS Steroids are important in the management of patients with brain tumors, particularly in patients with bulky disease and those who have hydrocephalus. Dexamethasone has the best CNS penetration of any of the steroids and is most commonly used in practice.6 Steroids decrease CSF production and cerebral blood flow and help to reduce vasogenic edema associated with tumor. However, the steroid can impair delivery of the chemotherapeutic agents to the tumor and blunt the effect of immunotherapy.7 The assessment of response to treatment can also be affected by steroid use. The steroids can potentially decrease the degree of gadolinium enhancement that is a surrogate for the leakiness of the blood vessels and decrease the measurable volume of the tumor.8 The guidelines for determining response criteria to chemotherapy currently require that the patient be on the same or a lower steroid dose as compared with baseline before determining an objective response.9,10 

Mechanisms of Drug Resistance and Strategies to Overcome Resistance EFFLUX TRANSPORTERS Extrusion by active efflux pumps along the BBB is another reason for lower than predicted uptake of drugs. Drug transporters belong to two major superfamilies: adenosine triphosphate–binding cassette (ABC) and solute carrier transporters.11,12 ABC transporters are integral membrane proteins, many of which are located in the plasma membrane and are primary active transporters; they couple ATP hydrolysis causing active efflux of their substrates against concentration gradients.13 The most extensively studied BBB transporter of the ABC family is P-­glycoprotein (P-­ gp), initially discovered in 197614; additionally members of the multidrug resistance-­associated protein (MRP)15 family and breast cancer resistance protein (BCRP)16 have also been identified in brain endothelial cells and choroid plexus epithelial cells. Anticancer agents were among the first drugs

6 •  Chemotherapy for Brain Tumors

that were identified to be substrates of BBB efflux transporters (i.e., of P-­gp as well as MRPs and BCRP). 

DNA REPAIR ENZYMES Methylguanine methyltransferase (MGMT) is an enzyme that removes chloroethylation or methylation damage from the O(6) position of guanine following alkylating chemotherapy and hence is involved in DNA repair.17 Clinical response to alkylating agents such as temozolomide (TMZ) in glioblastoma (GBM) patients has been correlated to the activity of the MGMT repair enzyme.18 Clinical attempts at targeting the MGMT gene have been unsuccessful; for example, O(6)-­benzylguanine an AGT substrate that inhibits AGT by suicide inactivation, caused systemic toxicity when combined with TMZ.19,20 Poly (ADP-­ribose) polymerase-­1 (PARP-­1) is an enzyme that catalyzes the transfer of β-­nicotinamide adenine dinucleotide to poly(ADP-­ribose).21 PARP-­1 enzyme catalyzes the synthesis of polymers for DNA repair after injury, and PARP-­ 1 influences both direct repair and base excision repair of DNA after injury from alkylating agents or ionizing radiation and is a key enzyme in the DNA repair pathways complementary to and downstream of MGMT.21 Hence the PARP-­1 enzyme inhibition is an attractive target for glioma therapy; PARP-­1 inhibitors have also been shown to overcome resistance to TMZ in both mismatch repair–proficient and mismatch repair–deficient gliomas cells in culture, and numerous PARP-­1 inhibitors are in clinical trials in patients with high-­grade gliomas.22,23 

Strategies to Improve Drug Delivery to Treat Brain Tumors Most cytotoxic agents do not cross the BBB, and conventional methods of drug delivery often results in low levels of drug to the brain; therefore, innovative treatments and alternative delivery techniques are needed. These have included intra-­arterial drug administration, high-­dose chemotherapy (HDCT), the use of drug embedded in a controlled-­release, biodegradable matrix delivery system, disruption of the BBB by hyperosmolar solutions or biomolecules, and convection-­ enhanced delivery (CED).

INTRA-­ARTERIAL CHEMOTHERAPY The goal of this approach is to deliver chemotherapy intra-­ arterially so that the tissue perfused by that artery is exposed to higher plasma concentrations of the drug during the first passage through the circulation. The principal advantage to this approach is to maximize the amount of drug crossing through the BBB and minimize systemic side effects. Theoretical modeling suggests that intra-­arterial infusion can produce a 10-­ fold increase in peak drug concentrations as compared with intravenous (IV) infusion.24 However, two phase III trials failed to show a survival benefit for IAC chemotherapy.25,26 A large trial of more than 300 patients with newly diagnosed malignant glioma conducted by Brain Tumor Study Group to assess the efficacy of IAC chemotherapy in which patients were randomly assigned to IAC or IV BCNU with or without IV 5-­fluorouracil and radiation therapy (RT). This study was closed early when an interim analysis showed shorter survival times in patients

65

receiving IAC.26 The side effects of the IAC in these two studies included catheter-­related complications such bleeding, infection, thrombosis, treatment-­ related neurotoxicity, leukoencephalopathy, cortical necrosis, and ipsilateral blindness.25,26 

INTRA-­CEREBROSPINAL FLUID CHEMOTHERAPY Intra-­CSF chemotherapy involves administration of drugs either into the lateral ventricle, usually through a surgically implanted subcutaneous device, such as an Ommaya reservoir,27 or instilling the drug into the lumbar subarachnoid space (i.e., intrathecal therapy). A benefit of this approach is that small doses of chemotherapeutic agents given intrathecally can produce high concentrations within the CSF with minimal systemic toxicity. However, abnormal CSF flow and obstruction either due to tumor or scarring from prior surgical interventions impair its utility in the treatment for primary brain tumors. Intrathecal administration of drug has limited penetration into the brain parenchyma and is generally used in treatment or prophylaxis of leptomeningeal disease.28 Side effects include increased risks of neurotoxicity (especially with radiation) and chemical meningitis. 

MANIPULATING THE PERMEABILITY OF THE BLOOD-­ BRAIN BARRIER OR METHODS TO CAUSE BLOOD-­BRAIN BARRIER DISRUPTION Various agents have been used to modify BBB and/or BTB in an attempt to increase the drug concentration in the tumor.29 Drug delivery to brain tumors can potentially be improved by increasing the permeability of the BBB with hyperosmolar solutions such as mannitol and vasoactive compounds such as bradykinin analogues that induce an osmotic opening of the BBB and BTB.29,30 Hyperosmolar solutions increase capillary permeability by temporarily opening the intercellular tight junctions of the brain endothelium that results in increased movement of water-­soluble substances. Complications with this approach include increased risk of stroke and seizures,31 and no clinical benefit has been demonstrated with this approach so far.32 High-dose chemotherapy (HDCT) is theoretically promising as it theoretically should increase the peak concentration of an unbound drug in the circulation and result in greater transfer of a drug across the BBB. The associated myelosuppression seen with this approach requires use of autologous hematopoietic cell rescue, and treatment-­related morbidity is substantial. The survival using this approach is similar to that achieved by conventional chemotherapy or targeted therapy, and its use has largely been abandoned.33,34 

WAFERS/IMPLANTABLE POLYMERS Surgical implantation of solid-­phase reagents permits constant drug delivery into the tumor without significant systemic or local side effects. The most commonly used “wafer” is a copolymer matrix with carmustine that is implanted directly into the tumor resection cavity at the time of surgical intervention. This therapy has been approved for patients with newly diagnosed and recurrent high-­grade gliomas.35,36 

CONVECTION-­ENHANCED DELIVERY CED involves direct intratumoral infusion with various chemotherapeutic drugs. It was designed to use pharmacologic agents that would not normally cross the BBB, and this

66

Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

approach is particularly useful for the delivery of large molecules.37 Drugs are delivered through one to several catheters placed stereotactically directly within the tumor mass or around the tumor or the resection cavity, and it allows distribution of substances throughout the interstitium via positive-­pressure infusion.38 Several classes of drugs are amenable to this technology, including chemotherapeutics, immunotherapies, or targeted drugs.39 Two multicenter randomized controlled trials in patients with recurrent GBM (PRECISE and TransMID) demonstrated that CED of agents was safe and well tolerated; however, there was no difference in efficacy compared with standard method of delivery.40 

Chemotherapy for Various Central Nervous System Tumors LOW-­GRADE GLIOMAS Low-­grade gliomas (LGGs) comprise approximately 20% CNS glial tumors, with approximately 1800 new cases of LGG diagnosed each year in the United States.41 With the 2016 edition of the World Health Organization (WHO) classification, the classification of glioma has changed to include not only the histopathologic appearance but molecular patterns.42 In fact, in certain cases the molecular and chromosomal patterns take higher precedence than histologic appearance. The codeletion of 1p and 19q chromosome is a defining feature of oligodendrogliomas, which represent 3.7% of all primary brain and CNS tumors.41 Oligodendrogliomas could be classified into either WHO grade II or grade III tumors based on the cellular atypia, presence of mitosis, vascular proliferation, and necrosis. Astrocytic tumors have intact 1p and 19q chromosomes, and they are divided by the presence or absence of IDH1/2 mutations. The patients with IDH wild-­type low-­grade astrocytoma have poor outcomes almost comparable to IDH wild-­type GBM.43 Patients with LGG typically present between the second and fourth decades of life. The optimal role of surgical resection in the long-­term outcome of patients with LGG remains controversial, and the debate about the effect on outcome of its timing and extent persists. Nevertheless, surgery continues to be indispensable to provide tissue for histopathologic diagnosis and importantly molecular characterization that is prognostic and helps to determine therapy approach. Retrospective studies have shown that more extensive resection rather than simple debulking is more beneficial and greater than 99% resection yields improved overall survival (OS) and progression-­free survival (PFS).44

Radiation Therapy The value of RT in the management of LGG is controversial. This is due to the prolonged natural history of LGG, and these patients are more likely to live long enough to suffer from the late effects of RT. In addition, the dose of RT to treat LGG is not clear. The most commonly used RT for the treatment of LGGs is 54 Gy, with a range of 45 to 60 Gy. This is based on the results of the European Organization for Research and Treatment of Cancer (EORTC) trial 2284445 and North Central Cancer Treatment Group/

Radiation Therapy Oncology Group (RTOG)/Eastern Cooperative Oncology Group study.46 In the EORTC trial 22844, there was no significant difference in OS and PFS in patients of LGG treated with 59.4 Gy in 33 treatments or 45 Gy in 25 treatments.45 In the multigroup trial there was no survival benefit of using 64.8 Gy compared with 50.4 Gy.46 A higher dose of RT (64.8 Gy) resulted in higher rates of radiation necrosis, and consequently doses greater than 60 Gy are avoided in this patient group.46 In summary, low-­dose RT (45 to 54 Gy) is recommended for patients with LGG; however, given the poor prognosis in those without IDH mutation, a higher RT dose of approximately 60 Gy could be considered given that these patients behave more like GBM. Moreover, the benefit of RT is limited to improvement in PFS without translating into any improvement in OS, as was demonstrated by a large meta-­analysis of data from three phase III trials (EORTC trial 22845 and 22844 and NCCTG 86-­72-­51).47,48 The EORTC 22845 clinical trial, as an example, evaluated the role of upfront RT versus observation in LGG; 311 patients were treated with immediate RT (54 Gy in 6 weeks) or no therapy until progression.47 Upfront RT significantly prolonged the median PFS (5.4 years vs. 3.7 years) but did not result in improvement in OS (7.4 years vs. 7.2 years).47 This suggests that radiation may have a comparable effect whether it is administered early or at subsequent tumor progression. 

Chemotherapy There is no level 1 evidence that postoperative chemotherapy significantly prolongs survival in patients with LGGs. The RTOG 98-­ 02 was a three-­ arm trial in which 111 patients with a favorable prognosis (age 70%) but can be the first manifestation of cancer approximately 5% of the patients.225

IMMUNOTHERAPY FOR BRAIN METASTASES Immunotherapy has revolutionized the management of several malignancies, including melanoma and NSCLC. Anti– CTLA-­4 antibodies and anti–PD-­1 antibodies have been evaluated in BMs. In a phase II clinical trial of an anti–CTLA-­4 antibody, ipilimumab, in melanoma, patients with BM showed a median survival of 7 months among those not on dexamethasone.219 The combination of ipilimumab and nivolumab (anti–PD-­1 antibody) in melanoma patients with BMs led to an impressive 6-­month OS of 76%.220,221 Ongoing phase II study of pembrolizumab has enrolled patients with BMs from melanoma and NSCLC; the preliminary report is encouraging, but final results are awaited.222 

Radiation Therapy External beam radiotherapy (RT) is often used in patients with LMD.226 RT is used in the LM for palliation of symptoms (cauda equina syndrome), for correction of CSF flow abnormalities, and if bulky disease is present when IFRT is the modality used. RT is used to treat bulky disease because intrathecal chemotherapy (IT) is limited by diffusion to 3 mm penetration into tumor nodules and is not effective in bulky disease.227 

Intrathecal Chemotherapy IT is the mainstay of treatment of LM. The most commonly used IT chemotherapeutic agents for LM MTX,228 cytarabine (Ara-­C),229 depocyt,230 and, less commonly, thiotepa.231 A usual schedule includes induction phase (4 to 6 weeks), followed by consolidation phase and maintenance phase. Complications of IT include those related to the ventricular reservoir and due to chemotherapy itself.227 Chemical aseptic meningitis is the most frequent complication seen, and leukoencephalopathy can occur especially when the combination of RT and IT is used.230 Numbered references appear on Expert Consult.

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is prophylactic treatment of high-­grade gliomas with levetiracetam and cessation of therapy by 4 weeks after surgery. It is also our first-­line therapy in patient with brain tumors who present with seizures. 

Radiological Imaging Studies PREOPERATIVE RADIOLOGICAL IMAGING STUDIES Preoperative imaging in patients with high-­grade gliomas is a must for establishing a proper differential diagnosis and surgical planning with the ultimate goal of safe surgical treatment. Since its introduction, MRI has been the main imaging tool for brain tumor evaluation. Consensus recommendations agree that a standard brain tumor MRI protocol include the following sequences on a 1.5 tesla imaging system: 3D T1 weighted precontrast, axial 2D fluid-­attenuated inversion recovery (FLAIR), axial 2D diffusion-­ weight imaging (DWI), axial 2D T2 weight noncontrast, and 3D T1 weighted postcontrast.24 Each imaging sequence has its own utility in making a differential diagnosis and in operative planning (Fig. 7.1). Normal and abnormal anatomical tissue architecture is best delineated by T1 weighted precontrast and postcontrast with gadolinium and T2 weighted imaging sequences. Gadolinium-enhancing tissue is indicative of breakdown in the normal blood-­brain barrier (BBB), which is seen in most high-­grade gliomas.25,26 T1 weighted postcontrast and T2 weighted images are very useful in operative decisionmaking, as extent of safe resection can be estimated, which has implications for morbidity and survival outcomes. T2 weighted FLAIR sequence is mostly important for evaluating peritumoral vasogenic or infiltrative edema.27 FLAIR sequences have gained significant attention recently as a surrogate for assessment of tumor infiltration, recurrence, and extent of resection. Diffusion weighted imaging identifies areas of random motion of water molecules, which is then quantified in the apparent diffusion coefficient map (ADC). Restricted diffusion, DWI hyperintensity and ADC hypointensity is most often used for identifying acute stroke but may also be used to identify tumors with high cellularity. Although not commonly used in the clinical realm, low ADC values have been shown to correlate with high-­grade tumors.28–30 Newer MRI techniques employed recently for aid in surgical planning include perfusion, diffusion tensor imaging (DTI), and functional MRI (fMRI). MR perfusion has multiple different techniques most commonly used is dynamic susceptibility contrast (DSC). Relative cerebral blood volume (rCBV) maps in perfusion imaging shows elevations in tumors related to angiogenesis distinguishing it from low rCBV in other pathologies.30 DTI is being heavily evaluated for its utility in determining important white matter tracts (tractography) for planning a surgical approach (see Fig. 7.1). It has been investigated as a tool to determine whether a tumor is invading important fiber tracts or displacing them, allowing for a safer gross total resection (GTR).31 There are limitations to DTI imaging which have prevented its widespread clinical application. Currently, it is only able to determine unidirectional fiber tracts within a single voxel. Since most fiber tracts are

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Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

DWI

T1-Pre-contrast

ADC

T1 post-contrast

T2

FLAIR

Perfusion-TTP

DTI-tractography

FIG. 7.1  Fifty-­one year-­old female with 1-­year history of left-­sided weakness and forgetfulness. Magnetic resonance imaging of the brain demonstrated a right frontal infiltrative ring enhancing mass with an area of central necrosis. Right frontal craniotomy and resection of the tumor revealed glioblastoma isocitrate dehydrogenase wild type. ADC, Apparent diffusion coefficient; DTI, diffusion tensor imaging; DWI, diffusion weight imaging; FLAIR, fluid-­attenuated inversion recovery.

multidirectional within a voxel, the accuracy of tractography is limited.29 Overall, DTI has two potentially very important implications for surgery of high-­grade gliomas. It allows for better delineation of tumor borders, leading to superior extent of resection, and illumination of important white matter tracts, possibly improving safety of surgical resections. fMRI has been used as an adjunct to preoperative planning for certain tumors including high-­grade gliomas in eloquent areas (Fig. 7.2). Task-­based fMRI is an indirect measure of cortical function by looking at changes in blood oxygen level dependent signal while performing certain motor and language tasks. Unfortunately, the correlation of task-­based fMRI has been variably correlated with the gold standard of intraoperative direct cortical stimulation (DCS). When using fMRI for motor cortex mapping there is better correlation with DCS than with its use for language mapping, likely due to the complexity of language-­ related tasks and variability in techniques.32,33 More recently, a technique called resting state fMRI (rs-­fMRI) has been developed that does not rely on a patient to perform tasks, can be done under sedation, and therefore can be used in pediatric patients as well as other patients that are unable to complete task-­based fMRI.33 Another advantage is that multiple functional networks can be assessed from the same MR acquisition, as opposed to the multiple acquisitions necessary for task-­based fMRI. fMRI has been used extensively, with most benefit likely in preoperative motor cortex localization. 

POSTOPERATIVE IMAGING AND ASSESSMENT OF TREATMENT EFFECT Postoperative serial MR imaging for patients undergoing resection of high-­grade gliomas is necessary for multiple reasons. It is important to understand the extent of resection, assess for postoperative ischemic strokes, postoperative hemorrhage, and have a baseline measurement to compare at serial time points in response to medical and radiation treatment effects. In this section we will focus on serial MRI imaging characteristics as they relate to tumor treatment effects and tumor progression. Assessing for tumor recurrence is the main objective of serial MR imaging in high-­grade gliomas. Classically, high-­ grade glioma response to treatment has been evaluated by the McDonald criteria.34 In order to address the issues of pseudoprogression and pseudoresponse, the Response Assessment in Neuro-­ oncology (RANO) working group developed new guidelines for determining tumor progression termed the “modified RANO criteria.”35 They included assessment of T2 FLAIR when determining tumor progression.36 Separate iRANO criteria were made for assessing pseudoprogression in the context of immunotherapy treatments and NANO criteria for assessing neurological function. These criteria have helped standardize treatment responses and enrollment in clinical trials, but they are not without limitations. Pseudoprogression—a temporary increase in gadolinium enhancement and edema after chemoradiation—has been

7  •  Current Surgical Management of High-Grade Gliomas: New and Recurrent

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FIG. 7.2  Functional MRI during a silent speech task in a patient with a glioblastoma of the left temporal lobe (left and right are reversed).

observed in 10% to 36% of patients.36,37 Interestingly, pseudoprogression has been observed in patients due to recently introduced immunotherapies.38 Pseudoresponse is a phenomenon that has come to light with development of angiogenesis augmenting therapies such as bevacizumab. Gadolinium enhancement of high-­ grade gliomas relies on increased vascular permeability in the tumor. Anti-­ angiogenic treatments can significantly reduce vascular permeability and MRI enhancement as soon as 1 to 2 days after initiation, leading to the false assumption of tumor regression.35 

Surgical Objectives The goals of surgical resection of high-­grade gliomas are symptom relief, tissue histopathological and genetic diagnosis, and maximally safe extent of resection. It is important to emphasize the safety of surgical resection, as causing postoperative deficits in patients may lead to worse survival.39 In this section we will focus on the extent of surgical resection (EOR) as it applies to patient outcomes and consideration of tumor location.

EXTENT OF TUMOR RESECTION Throughout the literature there is debate as to the extent of resection of high-­grade gliomas and their associated outcomes. Surgical options include biopsy, subtotal resection (STR), GTR or image complete resection, and the newly described supratotal resection (SuTR).40 These options are all related to the EOR on the T1 weighted contrast enhancing portion of the tumor, except for SuTR. When discussing SuTR, this describes complete resection of the contrast-enhancing portion of the tumor,

including as much of the T2 weight FLAIR hyperintensity that is surgically safe. Multiple prospective studies and even meta-­ analyses of these studies have been performed, and still there is no consensus on the EOR and their associated survival comparisons.41–45 One major reason is that studies do not have a consensus on the definition of STR. It may mean that 20% or 80% of the enhancing part of a tumor was resected. Lacroix and colleagues published a series of 416 patients with glioblastoma that determined that 98% tumor resection was necessary in order to confer a survival benefit of surgery.43 This effectively meant that only GTR was an acceptable outcome of surgical resection. Sanai and colleagues, published on 500 consecutive patients with newly diagnosed glioblastoma, showing graded survival benefit to STR as minimal as 78%. Median survival for EOR ≥ 78% was 12.5 months, EOR ≥ 80% was 12.8 months, EOR ≥ 90% was 13.8 months, and GTR was 16 months, whereas the overall median survival for the 500 patients, which included all STRs, was 12.2 months.42 A recent meta-­analysis comparing biopsy, STR, and GTR showed that patients undergoing GTR were 61% more likely to survive at 1 year, 19% more likely to survive at 2 years, and 51% more likely to be progression-­free at 12 months when compared to patients having STR. When analyzing the survival benefit of STR compared to biopsy there was a significant survival benefit at 1 year in the STR; however, this did not translate to 2-­year survival benefits.41 Recently a new philosophy of brain tumor resection has emerged, supratotal resection. This has mostly been assessed for low-­grade gliomas but has recently been looked at for a series of glioblastoma patients.46,47 In this study they looked retrospectively at the use of selective cortical mapping and

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subpial resection broader than the contrast enhancing regions in noneloquent regions. In the subpial technique they would continue resection in noneloquent areas until the pia was reached, instead of stopping at the edge of contrast enhancement and normal tissue. If the contrastenhancing portion was adjacent to eloquent cortex, then they would only remove visible tumor. This subpial technique resulted in GTR resections of greater than 95% in 29% of patients for an overall survival of 54 months. When the patients were divided by 100% EOR compared to 90% to 99% EOR, there was a statistically better overall survival in the patients experiencing 100% EOR.46 In another retrospective study of over 1200 glioblastomas, patients who had 100% resection of the enhancing portion of the tumor and had greater than 53% resection of T2 weighted FLAIR imaging demonstrated increased median survival of 23.2 months over those who had less than 53% FLAIR resection, who had a median survival of 18.7 months.48 Overall, the extent of tumor resection is very important when planning surgery. If the surgeon feels that they are able to resect 78% or more without causing harm, then surgery should be attempted. Ultimately the goal should be 100% resection of the enhancing portion of the tumor and possibly, in noneloquent areas, extending that to include areas of FLAIR hyperintensity using a subpial surgical technique. However, this must be balanced with causing neurological deficits, which has been demonstrated to lead to worse overall survival.39 

Surgical Considerations by Tumor Location FRONTAL LOBE High-­grade gliomas are most commonly found in the frontal lobe, as it occupies one-­third of the surface of the brain and is the largest lobe.49 The frontal lobe tolerates unilateral surgical resection well. This results in a greater ability for GTR. Unfortunately, for tumors with significant growth into the corpus callosum and across the midline, surgical resection is unlikely to provide a benefit to overall survival and therefore only a biopsy may be advocated. 

MOTOR CORTEX For lesions in the posterior frontal lobe, operative anatomy and imaging are not always sufficient to make adequate surgical plans. fMRI can reliably identify the motor strip, but even with modern neuronavigation systems, surgical resection is safer with some type of functional evaluation. Two current ways to identify motor cortex include intraoperative cortical stimulation mapping (discussed below) and placement of a subdural grid for mapping outside of the operating room. Proponents of subdural grid placement argue that electrocorticography out of the operating room and without sedation is superior because time is not limited and residual effects of anesthetics and narcotics can be minimized. Operating-­ room time at resection is minimized, but the patient requires two surgeries. The additional risks of the second surgery for grid removal and surgical resection are minimal. However, some surgeons prefer intraoperative testing to subdural grid placement. Intraoperative mapping

may gain an extra margin of safety from continuous testing during surgical resection. 

BROCA AREA Approximately 95% of right-­handed, 85% of ambidextrous, and 75% of left-­handed persons will have left-­sided cerebral dominance for language.50 Broca area encompasses the middle and posterior parts of the inferior frontal gyrus, that is, the pars opercularis and the pars triangularis. Protection of language area via awake craniotomy and intraoperative corticography or subdural electrode placement for cortical mapping is essential for tumors adjacent to Broca area. However, given the variability of language, there have been many reports of GTR of Broca-­area tumors with little or no postoperative neurological deficit.51 

PREMOTOR AREA Deficits from surgical resection in the premotor area can generally recover over a period of weeks to months through reorganization. 

SUPPLEMENTARY MOTOR AREA The supplementary motor area (SMA) occupies the posterior third of the superior frontal gyrus and is responsible for planning of complex movements of contralateral extremities and ipsilateral planning to a small extent. The full “SMA syndrome” involves speech arrest, contralateral weakness, and likely near-­total recovery in weeks to months. For tumors involving the SMA, fMRI shows ipsilateral decreased SMA activity compensated by increased contralateral activity.52 After resection in the SMA, the motor deficit is further compensated for by recruitment of activity in the contralateral SMA and premotor cortex.

TEMPORAL LOBE Anterior temporal lobe lesions are amenable to gross total surgical resection. Decompression of mass effect in this area is especially important due to proximity to the brain stem. Resection is generally safe back to 4 cm from the temporal tip on the dominant hemisphere and 6 cm back on the nondominant side. Removal of temporal lobe back to 6 cm is often associated with the possibility of a rim of visual defect in the contralateral superior quadrant. On the dominant side, resection at or behind 4 cm back from the tip of the middle cranial fossa requires either intraoperative electrocorticography or subdural grid placement for identification of Wernicke’s area. When a lesion involves the hippocampus, it is most likely that the contralateral hippocampus is compensating for function, but for the dominant hemisphere, this may be proven with a Wada test prior to surgery. 

PARIETAL LOBE Tumors of the dominant parietal lobe can be characterized by Gerstmann syndrome, which consists of left/right confusion, digit agnosia, acalculia, and agraphia.53 Lesions of the dominant superior parietal lobule alone rarely cause the full syndrome; the angular gyrus has to be involved.54 Surgery within the nondominant parietal lobe is generally tolerated well as long as there is not a large parietal stroke that can lead to significant neglect of the contralateral side. Motor strip mapping may add an extra layer of safety. 

7  •  Current Surgical Management of High-Grade Gliomas: New and Recurrent

OCCIPITAL LOBE Occipital lobe surgery almost invariably results in some form of visual field cut, although most high-­grade tumors that present in this location have already caused a visual defect. It is very difficult to improve visual symptoms with resection in this area. Some tumors that present more laterally may leave less visual field disturbance but may cause occipital association symptoms such as visual auras, color agnosia, or episodic blindness.

Surgical Adjuncts to for Maximizing Safe Surgical Resection NEURONAVIGATION The use of intraoperative frameless-­stereotactic neuronavigation based on MRI has allowed for planning of better tumor surgeries, minimizing surgical incisions and allowing for minimal damage to critical structures. This technique incorporates a preoperatively obtained MRI with or without fiducial markers. In the operating room, these markers or contours of the face can be registered in reference to a frame that is visualized by a computer. Although neuronavigation is a staple in brain tumor surgery, there is little literature to support its use in improving patient outcomes.55,56 The rationale for improving patient outcome is that it will inherently improve the EOR. One randomized controlled trial that showed a decreased mean amount of residual tumor tissue in brain tumors resected using neuronavigation to 13.8% from 28.9%. This did not translate into any survival benefit, and the trial only included 45 patients.56 A Cochrane Review looked at its efficacy in the published literature and there was little support found for neuronavigation.55 The downside to neuronavigation is its degree of accuracy. During surgery there may be a significant amount of brain shift, up to 2 cm, which can limit accuracy and give a false sense of comfort during resection.57 Despite little literature support, most tumor neurosurgeons today include it as a common practice to aid in reducing the size of craniotomy and corticotomy. 

INTRAOPERATIVE MAGNETIC RESONANCE IMAGING Another technology that has been gaining more widespread use is intraoperative MRI (iMRI) for improving extent of resection. Multiple studies have been done that focused on the use of iMRI, which used the endpoints of extent of additional tumor resection after initial resection and its impact on survival.58,59 Different types of iMRIs are available, with the main difference being the field strength of the magnets (low-­field ≤ 0.5 T, high-­field 1.5 to 3.0 T). Low-­field magnets are lower cost and require less special equipment but produce lower-quality imaging and fewer sequence capabilities.60,61 One retrospective study of low-­and high-­grade gliomas using a 0.5 T iMRI showed a significant increase in GTR and overall survival, with a similar rate of surgery-­ associated neurological deficits.59 These trends held true when subgroups of eloquent compared to noneloquent brain and low-­grade compared to high-­grade tumors were subdivided. Another study assessed high-­field 3.0 T iMRI in a prospective, randomized, triple-­blinded study in low-­and high-­grade gliomas with outcomes being measures of overall survival, progression-­free survival, and reduction in morbidity.58 In the iMRI resection group, prior to iMRI 48% of

81

patients had a GTR, which increased to 86% after iMRI and repeat resection. In the non-­iMRI group GTR was achieved in 54% of patients. When the high-­grade glioma subgroup analysis was performed, however, the significant difference in the number of patients with GTR did not hold true; it did, however, for low-­grade gliomas. Unfortunately, GTR and PFS did not reach significance in the high-­grade glioma subgroup, and overall survival was not analyzed.58 Intraoperative MRI may have the potential to influence the extent of resection on high-­grade gliomas, but more evidence is necessary prior to implementing this costly technique. 

INTRAOPERATIVE ULTRASOUND Although neuronavigation and iMRI have been shown to be useful for improving surgical resection, they have their faults. With large tumors, brain shift associated with neuronavigation is a significant concern, as it can create unreliability. ­Intraoperative MRI is more accurate but is time consuming and only shows one point in time. One tool that gives a continuous real-­time image and also does not require the time associated with iMRI is intraoperative ultrasound (IoUS). The downside associated with IoUS is that it is dependent upon the familiarity of the operator. Also its sensitivity for tumor detection decreases as the size of the residual decreases. Recently a meta-­analysis of its use in glioma resections showed a gross total rate of 77% in all gliomas. The concordance of IoUS with postoperative MRI was 82%, with both a false-­positive and false-­negative rate of 9%. Unfortunately, outcomes of most of these patients were not assessed.62 Ultimately, in conjunction with other intraoperative tools, IoUS provides a cost-­effective, rapid method for identifying residual tumor. 

MOTOR STRIP MAPPING Surgery in the parietal lobe or the posterior frontal lobe may require motor strip mapping. Short-­acting muscle relaxants are used during induction, and anesthetics are lightened for the mapping, but the patient does not need to emerge from anesthesia fully. Rather than identification of the motor cortex itself, this technique relies on identification of the sensory cortex by looking for somatosensory evoked potentials (SSEPs). A 1 × 8 subdural electrode is used (other sizes may also be used). By noting the electrodes with a positive (precentral) as opposed to a negative (postcentral) amplitude and noting the two electrodes between which there is phase reversal, the primary motor cortex can be identified and protected. This technique has good correlation to magnetoencephalography when integrated into the surgical navigation system.63

AWAKE CRANIOTOMY Awake craniotomy with cortical mapping affords the best protection for surgery in or near language areas. Multiple protocols have been established for the safety of the procedure.64–69 In one option, patients are never intubated—they are merely sedated with an agent like Propofol, which takes effect quickly and wears off quickly. Proponents of this pattern appreciate that patients’ airways are less irritated and that language testing is better quality. The other way to a­ccomplish the anesthesia is for patients to be nasotracheally intubated so that the endotracheal tube can later be withdrawn out of the vocal cords and language tasks can be performed. In addition to a local anesthetic at the incision site, a field block to the scalp in the area of the incision as well as the Mayfield pins

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is performed with a long-­acting anesthetic such as bupivacaine. Muscle relaxants may be used at induction, but they must be short-­acting. When draping, it is important that the patient has an unobstructed view so that visual naming and interaction with the neuropsychologist are possible. Once the craniotomy is created, anesthetics are lightened, the endotracheal tube is withdrawn from the vocal cords, and a handheld bipolar stimulator is used to stimulate areas likely to have language function or areas of planned resection to determine the effect. Continuous language testing can be performed during resection to reconfirm safety. Many case series have been done to describe the techniques and outcomes related to awake craniotomy and intraoperative monitoring. One meta-­analysis of these case series showed that in over 8000 patients who underwent resection with or without intraoperative mapping the rate of late severe neurological deficit was 3.4% versus 8.2%, respectively. When the extent of resection was compared, 75% had radiographic GTR with intraoperative mapping while only 58% had GTR without intraoperative mapping.64 Once resection is complete, the endotracheal tube is replaced and general anesthesia is reinstated for closure (Videos 7.1 and 7.2).67,68,70–73 

CASE ILLUSTRATION This is a case of 74-­year-­old man who presented to an outside hospital emergency room with altered mental status. The brain MRI showed a right parietal lobe lesion with significant vasogenic edema. The decision was to take the patient to the operating room for right-­sided awake craniotomy for resection of the tumor, as in our experience, patients who underwent awake craniotomies tend to have a higher extent of resection, better postoperative KPS (Karnofsky Performance Scale), lower exposure to anesthetic agents, and less postoperative hospital stay (see Video 7.1). The patient was taken to the operating room in a supine position; we proceeded with a curvilinear incision; afterward, we elevated the musculocutaneous flap. Burr holes were made and connected via footplate. After the elevation of the bone flap, we injected the dura with a local anesthetic. We opened the dura in cruciate fashion. After the opening of the dura, we brought the high-­density grid for recording the afterdischarges, followed by the novel circular grid (patent application no. PCT/US2018/039956),72,73 where we proceeded with brain mapping using the Ojemann stimulator. After we were satisfied with the tumor resection, we proceeded with hemostasis and closure in a water-­tight fashion. The patient tolerated the surgery well. The pathology was consistent with glioblastoma (WHO grade IV), IDH-­ wild-­ type. Postoperatively, he received concurrent temozolomide (TMZ) and radiation therapy. The patient was followed with series of MRIs, and on his 12-­month follow-­up, his surveillance MRI showed evidence of the growth of the residual tumor, in comparison to the previous MRI, with increases in the surrounding edema (see Video 7.2). He was taken back to the operating room for resection of the residual tumor. The patient tolerated the surgery well, and GTR was achieved. The pathology was consistent with recurrent glioblastoma (WHO grade IV), IDH-­wild-­type. 

FLUORESCENCE-GUIDED RESECTION Fluorescence-­guided resection of high-­grade gliomas has been a significant area of research and development over the past few years. The most extensively researched has been 5-­aminolevulinic acid (5-­ALA) and fluorescein sodium.74–81

5-­ALA is a precursor molecule in the protoporphyrin IX pathway that, when excited by violet-­blue light (370 to 440 nm), will fluoresce. It has been shown to be preferentially taken up by brain tumor cells and not by normal tissue.74 In a systematic review of 5-­ALA, sensitivity and specificity for WHO grade III gliomas was 83% and 100%, whereas in WHO grade IV gliomas it was 85% and 82%, respectively. Interestingly, in low-­grade gliomas the sensitivity was only 3%.74 Utility and outcomes associated the use of 5-­ALA have been assessed in a phase III multicenter randomized controlled study.78 A total of 322 patients were randomized to resection with 5-­ALA assistance or white light resection. In the 5-­ALA group 65% of the patients had a GTR compared to 36% in the white light group. Six-­month progression-­free survival in the 5-­ALA group was significantly different: 41% compared to 21% in the white light group. Unfortunately, this difference did not translate to a difference in overall survival.78 5-­ALA has been extensively used in Europe and has recently been approved by the United States Food and Drug Administration for use in patients with high-­grade gliomas. Fluorescein sodium salt has been used in the past for glioma surgery, and has gained a resurgence due to the incorporation of new filters into operating microscopes. One small study with matched controls showed a GTR rate of 83% with fluorescein compared to 52% without. Unfortunately there have been few comparison studies completed on fluorescein.81 Fluorescence remains a viable option for improving EOR, but requires more efficacy with respect to patient survival prior to its universal implementation. 

Surgery for Recurrent High-­Grade Gliomas The role of surgery for recurrent high-­grade gliomas must take into account many principles discussed within this chapter. Primarily, a decision must be made whether a tumor has recurred or radiological imaging findings are related to the phenomenon of pseudoprogression. Currently the modified RANO (Response Assessment in Neuro-­oncology Clinical Trials) criteria (Table 7.1) is used as a measure for assessing therapeutic efficacy and recurrence in patients with glioblastoma.82 Once tumor recurrence has been determined as probable, then the question remains: Which patients will benefit from surgical resection? This question has become more complicated recently with the reclassification of high-­grade gliomas including genetic markers. There is a possibility that certain genetic markers may be beneficial when determining if repeat surgical resection will impact patient survival. There have been multiple studies on the changes of the tumor microenvironment and genetic expressions at recurrence when compared with the genetics of primary tumors. Some studies suggest that local recurrent tumors have only 60% genetic similarity with the initial primary tumor while distant recurrences only have 30% similarities.83 This was demonstrated in multiple longitudinal genomic studies of patients who had extensive genetic studies on the primary tumor as well as their recurrence showing eradication of some tumor clones and proliferation of others.84–88 Interestingly, in one of the studies IDH mutant compared to IDH wild-­type genetic mutations were assessed between initial and recurrent tumors with response to TMZ treatment. It was shown that in the IDH mutant group, TMZ

7  •  Current Surgical Management of High-Grade Gliomas: New and Recurrent

83

Table 7.1  Response Assessment in Neurooncology Criteria for Assessing Tumor Recurrence in High-grade Gliomas Response Assessment in Neuro-Oncology Clinical Trials Criteria

Complete Response

Partial Response

Stable Disease

Progressive Disease

T1-postgadolinium + T2-FLAIR New lesion Corticosteroids Clinical status Requirement for response

None Stable or↓ None None Stable or↑ All

≥50%↓ Stable or↓ None Stable or↓ Stable or↓ All

< 50% ↓–< 25% Stable or↓ None Stable or↓ Stable or↑ All

≥25%↑ ↑ Present NA ↓ Any

FLAIR, Fluid-attenuated inversion recovery.

caused a number of new mutations in DNA mismatch repair genes while there were no TMZ-­associated mutations in the IDH wild-­type group.88 Given that there may be significant genetic alterations in recurrent high-­grade tumors, it may be reasonable to attempt biopsy or resection of the recurrent tumor not only for cytoreduction but also to drive future precision medical therapy. Repeat surgery for recurrent glioblastoma has been assessed regarding survival benefits. In the Director trial cohort 71 patients underwent repeat resection at first recurrence. In the patients for whom GTR of the enhancing portion of the tumor was achieved, post-­recurrence survival was 12.9 months, compared to 6.5 months in those with STR.89 Another retrospective analysis of surgery for recurrent glioblastoma showed an increase in both overall and progression-­free survival, when compared to patients who only had one surgical resection.90 These types of studies have bias associated with them, due to the fact that patients are chosen as to whether or not the neurosurgeon believes the tumor is resectable. Many recurrent tumors are considered nonresectable due to invasion of eloquent brain structures. Overall, repeat resection has the advantage of providing genetic characteristics of the recurrent tumor, which may be necessary for proceeding with medical treatment and possible improved survival. 

laser will determine how much heat is distributed into the tissues. Tissues with higher hemoglobin and water content and light wavelengths in the infrared range have higher penetration.91 Currently, there are two major systems used in neurosurgery, NeuroBlate System and Visualase thermal therapy system. The use of LITT in high-­grade gliomas has been mostly studied in the recurrent glioblastoma patient population.94,95 Recently a phase I clinical trial of 10 patients in recurrent glioblastoma using the NeuroBlate System was completed. It showed a median survival of 316 days with three patients neurologically improving, 6 neurologically stable, and one neurologically worsening.95 Another small study of 16 patients showed an increase in median survival in recurrent glioblastoma patients to 11.2 months after thermal ablation therapy.94 Although these studies are small, they have shown safety and promise for a new approach to treating high-­grade gliomas. The use of LITT for high-­grade gliomas has received significant interest, especially for patients where surgery may cause significant neurological deficit. Further randomized trials will be necessary prior to using LITT therapy as an adjuvant or even a replacement for surgical intervention in high-­grade gliomas.  

FUTURE DIRECTIONS

Summary

There have been a number of advances in the medical treatment of high-­ grade gliomas, including immunotherapy, anti-­ angiogenesis therapeutics, small molecule inhibitors, and more. Unfortunately, none have had a major impact on overall survival of patients. Surgical advancements for high-­grade gliomas have been even more elusive. Recently, a new method of surgical treatment, laser interstitial thermal therapy (LITT), has been developed and shows promise for the future.91 LITT was first introduced by S.G. Brown in 1983 for use in brain tumors. However, it was not until its incorporation with MRI in 1995 that the technology began to show promise.92,93 Currently the technique comprises a laser inserted into the tumor under stereotactic guidance and then thermal ablation undertaken under MRI guidance. The laser emits photons that are absorbed by adjacent tissue, causing release of thermal energy by way of conduction and convection. The properties of the tissue and the energy of the

Surgical treatment of high-­grade gliomas relies on a few principles with newly emerging assistive techniques. The major guiding principle is to safely maximize removal of the enhancing tumor. In the future this may extend to removal of as much FLAIR component as possible, as this may represent infiltrative tumor. Adjuncts for improving the safety of surgical procedures include better preoperative MRI technologies such as fMRI and DTI-­tractography, awake craniotomies, and intraoperative mapping. Assistive technologies to aide in maximal resection include neuronavigation, intraoperative MRI, and fluorescence-guided tumor removal. For assessing recurrent high-­grade gliomas for surgical resection, genetic markers will be essential for determining which patients will show benefit from surgery. Lastly, LITT has shown significant promise and could potentially cause a revolution in surgical treatment of high-­grade gliomas.

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Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

KEY REFERENCES

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51. Rolston JD, Englot DJ, Benet A, Li J, Cha S, Berger MS. Frontal operculum gliomas: language outcome following resection. J Neurosurg. 2015;122(4):725–734. https://doi.org/10.3171/2014.11.JNS132172. PubMed PMID: 25635477; PubMed Central PMCID: PMCPMC5241131. 52. Krainik A, Duffau H, Capelle L, et al. Role of the healthy hemisphere in recovery after resection of the supplementary motor area. Neurology. 2004;62(8):1323–1332. PubMed PMID: 15111669. 53. Gerstmann J. Syndrome of finger agnosia, disorientation for right and left, agraphia, and acalculia. Arch Neurol Psychiatry. 1940;(44):398–408. 54. Roux FE, Boetto S, Sacko O, Chollet F, Tremoulet M. Writing, calculating, and finger recognition in the region of the angular gyrus: a cortical stimulation study of Gerstmann syndrome. J Neurosurg. 2003;99(4):716–727. https://doi.org/10.3171/jns.2003.99.4.0716. PubMed PMID: 14567608. 55. Barone DG, Lawrie TA, Hart MG. Image guided surgery for the resection of brain tumours. Cochrane Database Syst Rev. 2014;(1):CD009685. https://doi.org/10.1002/14651858.CD009685.pub2. PubMed PMID: 24474579. 56. Willems PW, Taphoorn MJ, Burger H, Berkelbach van der Sprenkel JW, Tulleken CA. Effectiveness of neuronavigation in resecting solitary intracerebral contrast-enhancing tumors: a randomized controlled trial. J Neurosurg. 2006;104(3):360–368. ; discussion 77. doi: 10.1007/s00701-003-0204-1. PubMed PMID: 15057531. 57. Reinges MH, Nguyen HH, Krings T, Hutter BO, Rohde V, Gilsbach JM. Course of brain shift during microsurgical resection of supratentorial cerebral lesions: limits of conventional neuronavigation. Acta Neurochir. 2004;146(4):369–377; discussion 77. https:// doi: 10.1007/s00701-003-0204-1. PubMed PMID: 15057531. 58. Wu JS, Gong X, Song YY, et al. 3.0-T intraoperative magnetic resonance imaging-guided resection in cerebral glioma surgery: interim analysis of a prospective, randomized, triple-blind, parallel-controlled trial. Neurosurgery. 2014;61(suppl 1):145–154. https://doi.org/10.1227/NEU.0000000000000372. PubMed PMID: 25032543. 59. Olubiyi OI, Ozdemir A, Incekara F, et al. Intraoperative magnetic resonance imaging in intracranial glioma resection: a singlecenter, retrospective blinded Volumetric study. World Neurosurg. 2015;84(2):528–536. https://doi.org/10.1016/j.wneu.2015.04.044. PubMed PMID: 25937354; PubMed Central PMCID: PMCPMC4532608. 60. Steinmeier R, Fahlbusch R, Ganslandt O, et al. Intraoperative magnetic resonance imaging with the magnetom open scanner: concepts, neurosurgical indications, and procedures: a preliminary report. Neurosurgery. 1998;43(4):739–747; discussion 747-748. PubMed PMID: 9766299. 61. Tronnier VM, Wirtz CR, Knauth M, et al. Intraoperative diagnostic and interventional magnetic resonance imaging in neurosurgery. Neurosurgery. 1997;40(5):891–900; discussion -2. PubMed PMID: 9149246. 62. Mahboob S, McPhillips R, Qiu Z, et al. Intraoperative ultrasoundguided resection of gliomas: a meta-analysis and review of the literature. World Neurosurg. 2016;92:255–263. https://doi.org/10.1016/ j.wneu.2016.05.007. PubMed PMID: 27178235. 63. Romstock J, Fahlbusch R, Ganslandt O, Nimsky C, Strauss C. Localisation of the sensorimotor cortex during surgery for brain tumours: feasibility and waveform patterns of somatosensory evoked potentials. J Neurol Neurosurg Psychiatry. 2002;72(2):221–229. PubMed PMID: 11796773; PubMed Central PMCID: PMCPMC1737735. 64.  De Witt Hamer PC, Robles SG, Zwinderman AH, Duffau H, Berger MS. Impact of intraoperative stimulation brain mapping on glioma surgery outcome: a meta-analysis. J Clin Oncol. 2012;30(20):2559–2565. Epub 2012/04/25. https://doi:10.1200/ JCO.2011.38.4818. PubMed PMID: 22529254. 65. Hervey-Jumper SL, Li J, Lau D, et al. Awake craniotomy to maximize glioma resection: methods and technical nuances over a 27-year period. J Neurosurg. 2015;123(2):325–339. https://doi.org/10.3171/2014.10.JNS141520. PubMed PMID: 25909573. 66. Quiñones-Hinojosa A, Steven GO, Nader S, William PD, Mitchel SB. Preoperative correlation of intraoperative cortical mapping with magnetic resonance imaging landmarks to predict localization of the Broca area. J Neurosurg. 2003;99(2):311–318. https://doi.org/10.3171/jns.2003.99.2.0311.

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81. Catapano G, Sgulo FG, Seneca V, Lepore G, Columbano L, di Nuzzo G. Fluorescein-guided surgery for high-grade glioma resection: an intraoperative “Contrast-Enhancer.” World Neurosurg. 2017;104:239–247. https://doi.org/10.1016/j.wneu.2017.05.022. PubMed PMID: 28512039. 82. Ellingson BM, Wen PY, Cloughesy TF. Modified criteria for radiographic response assessment in glioblastoma clinical trials. Neurotherapeutics. 2017;14(2):307–320. https://doi.org/10.1007/s13311016-0507-6. PubMed PMID: 28108885; PubMed Central PMCID: PMCPMC5398984. 83. Campos B, Olsen LR, Urup T, Poulsen HS. A comprehensive profile of recurrent glioblastoma. Oncogene. 2016;35(45):5819–5825. https://doi.org/10.1038/onc.2016.85. PubMed PMID: 27041580. 84. Erson-Omay EZ, Henegariu O, Omay SB, et al. Longitudinal analysis of treatment-induced genomic alterations in gliomas. Genome Med. 2017;9(1):12. https://doi.org/10.1186/s13073-017-0401-9. PubMed PMID: 28153049; PubMed Central PMCID: PMCPMC5290635. 85. Kim H, Zheng S, Amini SS, et al. Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution. Genome Res. 2015;25(3):316– 327. https://doi.org/10.1101/gr.180612.114. PubMed PMID: 25650244; PubMed Central PMCID: PMCPMC4352879. 86. Johnson BE, Mazor T, Hong C, et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science. 2014;343(6167):189–193. https://doi.org/10.1126/science.1239947. PubMed PMID: 24336570; PubMed Central PMCID: PMCPMC3998672. 87. Wang J, Cazzato E, Ladewig E, et al. Clonal evolution of glioblastoma under therapy. Nat Genet. 2016;48(7):768–776. https://doi.org/10.1038/ng.3590. PubMed PMID: 27270107. 88. Kim J, Lee IH, Cho HJ, et al. Spatiotemporal evolution of the primary glioblastoma genome. Canc Cell. 2015;28(3):318–328. https://doi.org/10.1016/j.ccell.2015.07.013. PubMed PMID: 26373279. 89. Suchorska B, Weller M, Tabatabai G, et al. Complete resection of contrast-enhancing tumor volume is associated with improved survival in recurrent glioblastoma-results from the DIRECTOR trial. Neuro Oncol. 2016;18(4):549–556. https://doi.org/10.1093/neuonc/nov326. PubMed PMID: 26823503; PubMed Central PMCID: PMCPMC4799687. 90. Delgado-Fernandez J, Garcia-Pallero MA, Blasco G, et al. Usefulness of reintervention in recurrent glioblastoma: an indispensable weapon for increasing survival. World Neurosurg. 2017. https://doi.org/10.1016/j.wneu.2017.09.062. PubMed PMID: 28939537. 91. Silva D, Sharma M, Juthani R, Meola A, Barnett GH. Magnetic resonance thermometry and laser interstitial thermal therapy for brain tumors. Neurosurg Clin N Am. 2017;28(4):525–533. https://doi.org/10.1016/j.nec.2017.05.015. PubMed PMID: 28917281. 92. Bown SG. Phototherapy in tumors. World J Surg. 1983;7(6):700– 709. PubMed PMID: 6419477. 93. De Poorter J. Noninvasive MRI thermometry with the proton resonance frequency method: study of susceptibility effects. Magn Reson Med. 1995;34(3):359–367. PubMed PMID: 7500875. 94. Schwarzmaier HJ, Eickmeyer F, von Tempelhoff W, et al. MRguided laser-induced interstitial thermotherapy of recurrent glioblastoma multiforme: preliminary results in 16 patients. Eur J Radiol. 2006;59(2):208–215. https://doi.org/10.1016/j.ejrad.2006.05.010. PubMed PMID: 16854549. 95. Sloan AE, Ahluwalia MS, Valerio-Pascua J, et al. Results of the NeuroBlate system first-in-humans phase I clinical trial for recurrent glioblastoma: clinical article. J Neurosurg. 2013;118(6):1202– 1219. https://doi.org/10.3171/2013.1.JNS1291. PubMed PMID: 23560574.

CHAPTER 8

Low(er) Grade Gliomas: Surgical Treatment LORENZO BELLO  •  MARCO ROSSI  •  MARCO CONTI NIBALI  •  TOMMASO SCIORTINO  •  MARCO RIVA  •  FEDERICO PESSINA

Introduction Low-­grade gliomas are a group of intrinsic brain tumors, mainly occurring with seizures in young patients, appearing on conventional magnetic resonance imaging (MRI) as highly infiltrative nonenhancing masses, well visible in fluid-­attenuated inversion recovery (FLAIR) images, involving one to multiple lobes, occasionally presenting with small enhancing nodules inside the tumor mass. More than 90% of these tumors have IDH1 mutation and share a common biological behavior and a similar clinical prognosis, less influenced by the histologic grade.1,2 They are comprehensive of diffuse low-­grade (grade II) and intermediate-­grade gliomas (grade III), and have been recently defined as lower grade gliomas (LGGs), a term that has replaced “low-­grade” in the current clinical practice. Less than 10% of these infiltrative gliomas do not have an IDH1 mutation,3 but they share with the earlier similar clinical and radiologic presentation, and do not differ in the method of surgical treatment. Surgical treatment for LGGs is the topic of the present chapter. LGGs have become a major focus in neurooncology. (1) Their incidence in the global population is increasing due to improved diagnosis and higher exposure to several risk factors, arising as a side effect of socioeconomic and technological growth. (2) In contrast to glioblastomas, LGGs usually develop in the younger population and are typically associated with seizures; their occurrence predominantly in the more active portion of the population strongly impairs the patients’ ability to maintain a normal social and working life, and they have important economic and social impacts. (3) LGGs invariably progress toward a more malignant phenotype. (4) Their natural history is long and quite variable; some are almost indolent and progress very slowly; others quickly progress to glioblastomas despite a good molecular profile. (5) Many therapeutic advances have been achieved through the use of maximal surgical resection and upfront chemotherapy (CHT) eventually associated with radiotherapy, with the aim in low-­grade gliomas to postpone the onset of recurrence and malignant transformation (progression), and in intermediate-­grade gliomas to reach long-­term tumor control. Nevertheless, although these important advances have significantly affected the natural history of the disease, LGGs ultimately recur and progress.4,5

Little is currently known about the clinical and molecular factors influencing the tendency of LGGs to recur, progress, or respond to available therapies. Clinical determinants of LGG behavior are age at diagnosis, tumor volume and extension at diagnosis, speed of growth, histology, and residual tumor after surgery. The rate of recurrence is lower in the case of younger age, small initial tumor volume, and oligodendroglial—1p/19q codeletion features. The speed of growth has been recently identified as an independent prognostic factor.6 The extent of resection (EOR) recently has been suggested as an important factor, able to change the natural history of the tumor, and is the first significant step of treatment.5,7 Extensive resection (GTR, gross tumor resection) is usually associated with a better prognosis and a lower rate of malignant transformation in low grades.4,8 EOR (GTR) is used to stratify patients as at low risk (those who received a GTR) and at high risk (those in whom a GTR was not achieved). GTR is also associated with seizure control, another parameter included in the definition of low-­risk (seizure-­controlled) or high-­risk (seizure-­uncontrolled) tumors. Generally, low-­risk patients are submitted to clinical and radiologic follow-­up in case of grade II gliomas, or to adjuvant therapies in case of intermediate grade, whereas high-­risk patients are always treated (according to molecular profile), usually at least initially with chemotherapy, or when malignant transformation has occurred, with adjuvant concomitant radio-­and chemotherapy.5,8,9 Relatively little is known about the biological factors influencing the natural history of LGGs, their invasive patterns, or their tendency to recur or respond to therapy. Generally, histology seems to be predictive: tumors with astrocytic features recur earlier than those with oligodendroglial features. The main flaw of histologic classification is the consistent degree of intraobserver variability.1,2 In addition to histologic characteristics, several molecular markers for LGGs have been identified and recently introduced in clinical practice.10,11 The Cancer Genome Atlas Network has proposed a molecular classification of LGGs. They performed genome-­wide analyses of 293 LGGs from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes.11 The

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Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

integration of genome-­wide data from multiple platforms delineated three molecular classes of LGGs that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Grade II and III gliomas were subdivided in three prognostic categories according to the IDH1/2 and 1p19q status: 1p19q codeleted gliomas have the best outcome, the IDH1/2 mutated/non-­1p19q codeleted gliomas have an intermediate survival (most of them are mutated for p53), and the gliomas nonmutated for IDH1/2 (none of which are codeleted for 1p19q and very few are mutated for p53) have the worst survival and were molecularly and clinically similar to glioblastoma, with which they shared aggressive biological behavior. The importance of adding molecular data to histology to better stratify tumor patients has been also proposed by the WHO tumor classification assembly1,2; an integrated diagnosis has been recommended for routine pathologic practice, in which molecular data obtained from the most representative area of the tumor are associated to histologic appearance; this helps in the classification of the tumor.1,2 Accordingly, oligodendrogliomas are the tumors characterized by the presence of 1p19q codeletion. The presence of 1p19q codeletion is always associated with IDH1 mutation. Astrocytomas are characterized by the absence of 1p19q codeletion and presence of ATRX mutation. ATRX mutation, often associated with p53 mutation, is not exclusively associated with IDH1 mutation, and IDH1 wild-type tumors with the histologic grade of low-­grade gliomas may be present. Integrated diagnosis seems to better correlate with biological behavior, and helps also in the decision-­to-­treat process.1 The optimal treatment for low(er)-­ grade gliomas has yet to be determined. Watchful observation, needle biopsy, open biopsy, as well as surgical resection have all been advocated by different authors.5,9,12–19,20 No evidence concerning class I or II exists regarding the optimal management of these patients, even if the more modern tendency is to obtain at least some type of tissue diagnosis,8,21 advocating a maximal resection whenever possible.5,9 The rationale behind the observational or “wait and see” policy was the occasionally indolent or very slow progress of these tumors.17,20 On the other hand, following modern oncologic concepts, and the recent advances in molecular classification of these tumors, most authors recommended a biopsy, in order to have a histopathologic and molecular confirmation of the nature of the neoplasm.1,2,9 Surgical resection of low-­grade gliomas is still a matter of debate, although recent studies are increasingly supporting this choice.8,13,15,22–30 Surgery can in fact achieve multiple aims: it allows a more reliable histologic diagnosis and eventually yields the molecular profile (e.g., IDH1 mutation, 1p/19q codeletion, and O(6)-Methylguanine-DNA methyltransferase [MGMT] status); it relieves symptoms; when a GTR has been achieved, it has a beneficial effect on seizure control; in addition, GTR could decrease the rate of recurrence and of malignant transformation.8,15,24 In addition, surgery may change the natural history of the tumor, even when this is considered within the molecular stratification.25,26,30 Furthermore, the response to adjuvant treatment is influenced by the EOR, being generally higher in patients in whom a GTR has been reached.30 Nevertheless, surgery carries unavoidable risks, which can potentially and permanently affect the patient’s quality of life.

Given this general information on lower-­grade glioma behavior and the possibility of treatment, it is clear that a modern surgical approach to these tumors seeks to maximally resect the mass, minimizing postoperative morbidity to preserve a patient’s functional integrity.4,8,11,15,22,24,31 Since the natural history of the tumor can be relatively long (with or without surgery), the conservation of simple and complex neurologic functions of the patient is mandatory. To achieve the goal of a satisfactory tumor resection associated with the full preservation of the patient’s abilities, a series of neuropsychological, neurophysiologic, neuroradiologic, and intraoperative investigations have to be performed. In this chapter, we will describe the rationale, the indications, and the modality for performing a safe and rewarding surgical removal of low(er)-grade gliomas. 

Rationale of Surgical Treatment The major aims of surgical treatment are: (1) obtaining adequate specimens and representative tissue to reach a correct histologic and molecular diagnosis; (2) achieving a cytoreduction to decrease the rate of recurrence and malignant transformation, possibly prolonging survival; (3) improving the neurologic symptoms of the patients; (4) obtaining a better seizure control. 

The Concept of Functional Neuro-­ Oncology: Resection According to Functional Boundaries Surgery for LGGs aimed at maximal tumor resection, associated with full patient functional integrity.4,15,32 Various strategies have been developed to achieve this result. In the recent past, different intraoperative imaging techniques, including those (such as intraoperative MR) that have led to an increase in maximal resection, have been implemented, without contributing to a significant impact on the maintenance of patient functional integrity.33–36 The most relevant oncologic impact, both in terms of amount of tissue removal and preservation of function, has been produced by the introduction of brain-­mapping techniques.4,12,21,22,37–43 This term refers to a group of techniques, which allow safe and effective lesion removal from eloquent or functional areas, preserving the functional integrity of the patients. They allow the identification and preservation at time of surgery of cortical and subcortical sites involved in specific functions. The concept of detecting and preserving the essential functional cortical and subcortical sites has been recently defined as “surgery according to functional boundaries,” and it is summarized with the term “functional neuro-­oncologic approach.” The shift of the paradigm from image-­ based surgery to surgery based on functions finds its rationale in various considerations: most LGGs are located in areas of the brain traditionally defined as eloquent (language and motor areas);44 therefore, resection of tumors within these areas have to be necessarily associated with function preservation.4,11,22,41,42 LGGs are highly infiltrative tumors, in which cells could be found beyond the borders of the tumors as visualized in FLAIR images, which makes approaches based on pure images quite limited in terms of oncologic results45;

8  •  Low(er) Grade Gliomas: Surgical Treatment

From the tumor to the patient Pre-operative functional studies Clinical History

Epilepsy History

Psychological Evaluation

Imaging

Pre-operative functional reorganization

Feasibility of resection FIGURE 8.1  Scheme of the preoperative studies to be put in place to evaluate the chance of surgical treatment for a low(er)-­grade glioma patient. Clinical data, epilepsy history, neuropsychological and psycho-­oncologic findings, along with imaging data, are put together to evaluate the degree of functional reorganization reached by the individual patient brain. The overall judgment of these data is used to design the feasibility of resection.

LGGs are characterized by a slow rate of growth,6 which induces a progressive reorganization of surrounding brain areas, modifying and reshaping brain functional organization in a way that is patient-­specific and that cannot be fully depicted by functional imaging techniques (e.g., functional magnetic resonance imaging [fMRI]).4,15,46 The functional approach exploits the functional reorganization reached by the patient’s brain, allowing the surgeon to remove as much of the tumor as is feasible, possibly extending resection far beyond the tumor margins visible and detectable by conventional MR images, preserving functional integrity.4,32,47 The new paradigm (or philosophy) stands in looking for functional brain boundaries independently from where they are located in respect to tumor borders.

HOW TO MANAGE A PATIENT WITH A PRESUMPTIVE DIAGNOSIS OF A LOWER-GRADE GLIOMA Using a functional approach, the management of the patient entering the outpatient clinic with a diagnosis of a presumptive low(er)-­grade glioma must be aimed at defining the degree of functional reorganization achieved by the patient brain surrounding the tumor.4,32,48 This information defines the feasibility of resection and the possible degree of tumor removal that can be achieved in the individual patient. The management must therefore arrange a careful interview of the patient, associated with a detailed neuropsychological evaluation; data obtained from these analyses have to be integrated with those obtained from imaging, to design a comprehensive map of patient brain functional reorganization. This information is used for making the eventual decision to treat, and for planning the resection (Fig. 8.1).

Patient Interview This must take into account the symptoms and the duration of the clinical history. Most patients report a history of epileptic seizures. A careful anamnesis shows that seizures are often preceded by minor manifestations, generally abortive seizures. In addition, patients with a long history of seizures often describe a progressive increase in their frequency, and in those who are already taking antiepileptic drugs (AEDs),

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a progressive increase in dosage and number of drugs that are taken, with the development of drug-­ resistant epilepsy.24,49–51 The cases of patients with tumors affecting the insular region, or the region of the ventral premotor or of the supplementary motor area, are typical. The careful analysis of the semiology of the seizures provides information on the progression of the neoplasm and its temporal and current extension, as well as important information on the degree of functional reorganization achieved by the surrounding brain due to the presence, growth, and extension of the neoplasm itself. In case of dominant insular tumors, the onset of focal seizures with speech arrest indicates the activity of the ventral premotor and of the underlying connection bundles, indicative of a partial or not complete language reorganization; on the contrary, in the same tumors, the appearance of generalized seizures in the absence of focal symptoms or focal sensorimotor seizures indicates the reorganization of the language circuits; similarly, the onset of mesial temporal seizures suggests both the extension of the tumor to the temporal region and a high degree of reorganization of the circuits. In the first case a subtotal or partial removal may be expected; in the latter, a complete resection can be predicted. A careful interview must also be aimed at highlighting the appearance of signs and symptoms of involvement of deep associative circuits, such as the occurrence of mood changes in the case of frontal or limbic tumors.52–54 The presence of such disturbances highlight the need to extend the intra-­operative mapping with appropriate tests capable of identifying and sparing such networks.25,52,53,55–57 The patient’s interview is associated with the neurologic examination, which is often completely normal. The percentage of patients with motor and/or language deficits varies between 2% and 15% according to the various series.56,58 Other additional data to be evaluated are patient educational level, job and future career development, current hobbies, and future pregnancy in the case of female patients.59 These data (referred to as patient needs) have to be carefully discussed with the patient for the elaboration of a tailored surgical strategy, particularly in the context of the permanent effects that surgery may exert on the quality of life.4,47 

Neuropsychologic Evaluation and Psycho-­Oncological Interview Psychological evaluation consists of two components: neuropsychological and psycho-­oncologic evaluation. The neuropsychological evaluation evaluates the degree of functional reorganization achieved by the individual patient, and prepares the patient for intraoperative testing. Extensive testing is used and explores all functional domains.60,61 The types of tests vary according to language and population, taking also into account the age and level of education. In our institute we have developed, and have been using for many years, a battery that explores five main functional domains: memory, language, praxis, executive functions, and fluid intelligence (Table 8.1).19 The duration of the evaluation takes about 1 hour and 30 minutes, and it is generally well tolerated. During the preoperative evaluation, the battery, administered by a neuropsychologist, shows some degree of impairment in several functional domains in most patients , even when the complete neurologil examination is normal. Executive function is the domain most frequently affected.58,62,63 The neuropsychological evaluation

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Table 8.1  Neuropsychological Tests Included in the Milano-­Bicocca Battery Preoperative Neuropsychological Test Functional Domains

Test

Memory

Digit forward and backward, Corsi forward and backward, Rey auditory, verbal words learning test (RAVLT) immediate and delayed recall, Rey complex figure recall Token, pictures naming words and sentences comprehension, actions naming, semantic and phonemic fluencies, words and nonwords and sentences repetition Rey complex figure copy, ideomotor apraxia test, oral-­motor apraxia test Attentive matrices test, trail-making test, Stroop test

Language

Praxis Attentive and executive functions

The tests exploring the five large functional domains are reported.

allows staff to prepare and select, for the individual patient a series of tests to be carried out at the time of surgery, selecting among the available items those that the patient performs in a more constant and stable way.12,40,61,64–67 The reproducibility of the selected items must be repeated in a further evaluation carried out the day immediately before the procedure, to carefully calibrate them to the individual patient condition. The psycho-­ oncologic evaluation is a complementary investigation and assesses the patient’s needs, the presence of anxiety disorders, the understanding of the state of the disease and of the therapeutic process to which the patients will go through, along with the ability to perform part of the procedure in awake anesthesia if needed.28,32,47,68 The assessment consists of a psychological interview and the administration of welfare questionnaires. In our institute, a psychotherapist generally carries out the psychological interview and administers the well-­ being questionnaires (see EORTC questionnaire for brain tumors) or those for assessing anxiety and depression69 (see Hospital Anxiety and Depression Scale). Patients with normal or slightly impaired neuropsychological assessment scores often show important changes in the psycho-­oncologic assessment scales, which result in the development of discomfort in the conduct of normal daily activities, which could significantly affect quality of life. Data generated during patient interviews and neuropsychological and psycho-­ oncologic evaluations are then matched with those obtained by imaging. 

Imaging Work-­Up The imaging methods are divided into basic and advanced methods.

Basic Methods: Magnetic Resonance Standard Evaluation The volumetric investigations after contrast define tumor-­ vascular relationships, the involvement of deep (perforating) vessels and their origin with respect to the tumor mass, and detect any area of tumor transformation toward a more aggressive histology. The volumetric FLAIR sequences define the tumor volume, the extent and number of lobes involved, the involvement of deep brain structures and/or of the corpus callosum, the eventual tumor extension toward

the contralateral hemisphere, the presence of any other tumor distant localization, and the relationships of the tumor mass with sites or structures that can be defined anatomically as functional (Fig. 8.2). Tumor volume is calculated using semi-­automatic segmentation methods, and the same approach is used to measure, after surgery, the EOR.8,41,70,71 Further important information deducible from the evaluation of serial volumetric FLAIR images, usually carried out at a 3 to 6 month interval, concerns the calculation of the growth rate (rate of growth), an important parameter for assessing prognosis, for the decision to treat, and the time to treat.6,41 

Advanced Magnetic Resonance Evaluation The advanced image methods were generally used to obtain information on the degree of functional reorganization achieved by the tumor-­surrounding brain. At the cortical level, fMRI was generally used for visualizing motor or language functional sites. In the past, various studies have been performed to define the correlation between the data obtained with fMRI and intraoperative stimulation.12,37,72–80 In general, the presence of areas of activation in an fMRI map does not preclude the chance of performing a surgical treatment, and therefore should not be used for the treatment decision at the individual patient level. On the other hand, an area without bold effects on fMRI can be found to be eloquent during the intraoperative testing. In this case, the removal of a negative area in fMRI can result in a postoperative deficit. At the subcortical level, the visualization and reconstruction of the subcortical bundles or tracts was generally carried out by tractography based on diffusion i­mages.37,51,70,81–84 Various acquisition techniques and different algorithms of reconstruction were used in different studies, obtaining completely different tracts for reconstruction (in terms of path or size) in the same individual patient, making a general judgment at the individual level quite problematic.85,86 In general, the information obtained with the tractography can be quite useful for the reconstruction of the three-­ dimensional map of tracts representing the functional networks surrounding and involving the tumor, which the surgeon should reach and encounter during the resection. This may have an important impact on surgical planning, patient positioning, and flap design (Fig. 8.3).87 However, the finding of tract infiltration by a tumor, as detected by the preoperative tractography, does not necessarily imply that at in this point the tract is functional and resection should be stopped. It is a common experience that considerable large portions of tracts depicted as infiltrated or within the tumor area in the preoperative tractography maps are found to be not functional during the intraoperative mapping and can be safely removed. This again supports the concept that tractography, although useful for designing a general map of the networks surrounding a tumor, should not be used to predict the EOR at the individual patient level.85,87 On the contrary, diffusion imaging provides important data concerning tumor structural information, the so-­ called texture analysis.88–93 LGGs are highly heterogeneous tumors based on classical histopathologic criteria.94 Diffusion, either isotropic or anisotropic, has been used to delineate structural features of LGGs, and it has been also used to assess response to treatment, such as chemotherapy.88 More

8  •  Low(er) Grade Gliomas: Surgical Treatment

89

A

B

C

FIGURE 8.2  Example of low(er)-­ grade glioma imaging presentation. FLAIR (on the left of each panel) and postGd T1 weighted (at the right of each panel) images. A lower-­grade glioma may present as a small diffuse mass with ill-­ defined tumor borders and no sign of mass effect (A, nondominant frontal oligodendroglioma—IDH1 mutated, grade II), a medium-­ size mass with clear-­cut tumor borders and little signs of mass effect (B, dominant frontal ventral premotor astrocytoma—IDH1 mutated, grade II), or a giant fronto-­temporo-­insular mass, with mass effect, and ill-­defined tumor borders (C, dominant oligodendroglioma—IDH1 mutated, grade III). In the latter, the tumor is involving the corpus callosum and extending toward the contralateral hemisphere.

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A

B FIGURE 8.3  Integration of imaging modalities in lower-­grade gliomas. MR and Metionine-­PET imaging. (A) A case of nondominant frontal tumor involving the ventral-­premotor and dorsal-­premotor area appearing as a quite discrete mass in FLAIR (axial, left panel) and postGd T1 weighted (axial, middle panel) images, with two small contrast-­enhancing nodules in its context. MET-­PET imaging (axial, right panel) showed two hotspots corresponding to the two small nodules. Histologic and molecular analysis showed an astrocytoma (IDH1 mutated), grade III. (B) A case of dominant frontotemporoinsular lower-­grade glioma. The tumor has ill-­defined borders and extends over the corpus callosum to the contralateral hemisphere (axial FLAIR image, left panel); it shows no contrast enhancement (postGd T1 weighted axial image, middle panel); MET-­PET images shows an intense hot-­spot in an area of the tumor that does not show any enhancement in postG1 T1 MR images. FLAIR, Fluid-­attenuated inversion recovery; MR, magnetic resonance.

data are available on the use of metabolic imaging. Functional biomarkers such as radiolabeled amino acids (e.g., L-­[11C]methyl-­methionine) in FET PET have been used to visualize amino acid transport and protein synthesis95,96 and have also helped in glioma patient management.95,97,98 Hotspots visualized with metabolic imaging have been sampled separately, and have revealed anaplastic foci, or areas of increased cellular density (Fig. 8.4). 

Decision for Surgery The integration of clinical, neuropsychological, and imaging data allows the surgeon to evaluate the operability of the tumor and to estimate the chances of resection. In light of these data, a tumor can be judged as amenable to surgical resection, or as untreatable.

There are no specific guidelines for the operability of a tumor, and the decision is of course dependent on surgeon personal experience and expertise (volume load). However, these general recommendations can be made: • A presumptive LGGs is defined as a tumor that appears as a generally not enhancing mass lesion in FLAIR images, with eventually a few small enhancing nodule(s) in its context. • T umor size and extension, the number of lobe(s) involved, the involvement of the corpus callosum, or of anatomically defined eloquent structures (e.g., Broca area, motor pathways) do not represent a priori an exclusion or criteria limiting the chance to perform an extensive resection, if the clinical and neuropsychological data support a high level of brain reorganization.

8  •  Low(er) Grade Gliomas: Surgical Treatment

A

91

B

FIGURE 8.4  Subcortical time of resection: functional disconnection of the tumor. During the subcortical time of resection the mapping was started at the tumor margins, locating functional boundaries all around the tumor mass. At the end of the subcortical time, the tumor appeared in place but functionally and anatomically disconnected from the surrounding brain (A, intraoperative field image showing the tumor and the resection borders around it). An intraoperative snapshot (B, axial fluid-­attenuated inversion recovery image) was taken with the help of the neuronavigation system in a subcortical site where high-­frequency stimulation located a functional (motor) boundary at the posterior margin of the tumor (a green dot indicates the tip of the navigation probe).

• T  he level of brain reorganization is the limiting criterion for an extensive resection, irrespective of the size and extension of the tumor. • The surgical plan and the predicted extension of resection should be made at patient individual level; these are also influenced (and in occasional cases limited) by patient-­specific needs. Accordingly, when the decision to submit a patient with a presumptive lower grade to surgery is taken, the surgeon must then proceed toward the design of the detailed surgical procedure, which must be tailored to the individual case and needs. In all the other cases (diffuse lower grade involving multiple lobes or extending contralaterally) it may be useful to perform a (needle or open) biopsy, to ascertain the molecular histologic profile of the tumor, and to evaluate, in a multidisciplinary setting, the opportunity to start with an adjuvant treatment, aimed at controlling the growth of the disease.

INTRAOPERATIVE ANESTHESIA Various anesthetic strategies can be used, from completely awake to asleep-­ awake, or to asleep-­ awake-­ asleep procedures.47,99–106 In the first, defined as conscious sedation, the patient receives an important sedation in the opening and closing phases; in the asleep-­awake or asleep-­awake-­asleep setups, the patient is put under general anesthesia for the opening phase, is awakened in the central phase to perform the intraoperative mappings, and goes back to sleep in the final; no standard could be reported. In our institute we initially started with conscious sedation in late 1990, then moved toward an asleep-­awake set-­up in early 2000, and for 7 years we have been using an asleep-­awake-­asleep set-­up. This technique involves the use of laryngeal masks for the initial phase and again a mask or a tube for the final asleep phase. This technique reduces patient discomfort linked to

opening and closing phases, and facilitates hemostasis during the final phase, ensuring good arterial and venous blood pressure control.103,104 Various anesthesiologic regimens could be used. The most common is the combined use of propofol and remifentanyl in the asleep phase and a low dosage of remifentanyl in the awake phase. The suspension of propofol for the transition from the asleep to awake phase leads to the patient awakening in a time interval ranging from 15 minutes to more than 40 to 60 minutes, depending on the patient. A different regimen based on the use of dexmedetomidine (dex) is also adopted, allowing an important sedation in the initial phase, a quick awakening and collaboration of the patient in the central one, followed by new sedation or falling asleep (with or without mask positioning) in the final one.106 Drawbacks of the use of dex concern the interference that this drug produces (when used at high dosage) at the motor level, with cortical and subcortical high-­frequency stimulation both for motor evoked potential (MEP) monitoring and for motor mapping.55,107 

INTRAOPERATIVE NEUROPHYSIOLOGY SETTING Intraoperative neurophysiology techniques are divided into mapping techniques and monitoring techniques.

Mapping Techniques The mapping techniques consist of brain stimulation techniques using electricity to evoke responses during various intraoperative tests.28,42,108–110 The two applied stimulation techniques are those at low or high frequency (LF and HF). They can be administered with both monopolar or bipolar probes. In the HF technique, the stimulus has a monophasic form, a duration of 0.5 ms, is administered as a train of stimuli (generally five, train of five) separated by 4 ms (ISI, interstimulus interval), and delivered every 1 second (repetition rate 1 Hz) or every 2 seconds (repetition rate 0.5 Hz). The

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Frontal aslant tract SLF I SLF II

Anterior segment Posterior segment

Middle longitudinal fasciculus Uncinate

A

B

Inferior longitudinal fasciculus

C

FIGURE 8.5  Resection of a dominant parietal glioma, involving the supramarginalis gyrus and underlying white matter (A, axial fluid-­attenuated inversion recovery [FLAIR] image). B, The complex functional network architecture is highlighted by the diffusion tensor imaging (DTI) reconstruction of the tracts running around the tumor mass (3T MR, spherical deconvolution courtesy Etta Howells). During the subcortical time of resection these tracts were progressively identified and disconnected from the tumor mass, leading to a complete resection of the tumor (C, postoperative immediate axial FLAIR image). Histologic and molecular analysis showed an oligodendroglioma (IDH1 mutated), grade III.

HF is generally delivered with a monopolar probe, toward a reference electrode; less frequently it can be delivered by a bipolar probe, providing more focal stimulation. In the LF technique, the stimulus has a biphasic form, a duration of 0.5 ms, and each stimulus is interspersed by 20 ms. LF stimulation is continuous, lasting several seconds, and generally delivered via a bipolar probe. Usually, the HF technique is used for motor mapping, at cortical and subcortical levels, while the LF technique is generally applied in the awake setting for language and cognitive mapping. 

Monitoring Techniques Various monitoring techniques can be used. Electroencephalogram (EEG) and electrocorticography (ECoG) are used to evaluate status of patient’s anesthesia and appearance during the stimulation of abnormal electrical activity, such as electrical or focal seizures. Evaluating the MEPs allows one to continuously evaluate the state of functionality of the motor pathways; this is very sensitive to vascular damage.110 Often the use of MEP is associated with that of the somatosensitive evoked potentials (SSEPs), which provide additional information on the maintenance of good vascular supply.18,111,112 The use of monitoring techniques is debated, especially that of the ECOG and MEP; they are considered by some authors to be nonmandatory.113,114 Others, especially in the case of use of LF stimulation, consider the use of ECOG useful for detecting interferences not due to stimulation itself but due to the diffusion of the current, and to detect artifacts of false positive responses.110 ECOG is usually used during LF stimulation, as this technique is associated with the onset of stimulation-­induced seizures (ranging from 2% to 25%, according to series).115 

SURGICAL TIME In the classical scheme, the surgical time is subdivided into a cortical and a subcortical time. Cortical time. It is used to identify the functional relationships between the tumor edge and the surrounding areas. It includes the identification of functional landmarks, of working currents, of the entry points and design of the extent of corticectomy. The required time varies between 5 and 15 minutes. Subcortical time. It represents the most critical phase, since it is what affects the extent of the resection and the functional

result of surgery. In this phase, with the aid of subcortical mapping methods, the functional limits of the tumor are identified. Limits are sought at the periphery, starting from the cortical areas that were judged as nonfunctional during the cortical phase. The surgeon must have in his/her mind the architecture of the functional map of the networks surrounding the tumor, adopting and varying the tests to be performed during the intraoperative mapping, to identify and recognize each of them during the various stages of the procedure. In this way, a functional disconnection of the tumor is progressively obtained, and a resection precisely achieved according to functional limits (Figs. 8.4 and 8.5). In the classical organization of the procedure, the awake phase includes the cortical time and part of the subcortical resection during which the identification of the functional limits requires the active collaboration of the patient, while the disconnection on the purely motor boundaries and the removal of the already disconnected tumor is generally carried out during the asleep phase.41,110 During the subcortical time, resection must be associated with the mapping, either alternately or continuously; in this last case the stimulator is coupled to the ultrasonic suction or is positioned close to its tip by the assistant surgeon. During the resection phase careful respect must be given to the vascular architecture within and around the tumor mass. The surgeon must keep most of the vessels, from the smallest to those of greater size. From this point of view, the technique of subpial resection, with careful respect to the arachnoid and pial coat at each level, allows the surgeon to maintain and safeguard most of the vascularization. The coagulation must be minimal, and most of the resection is carried out without using bipolar coagulation, using aspiration or the ultrasonic suction at the lowest power. Abundant irrigation and the use of cottonoids help to obtain a good compression hemostasis. The use of monitoring with MEP or SSEP helps in detecting the occurrence of any vascular damage.41,110,112 At the end of the resection phase, the various vascular trees identified and saved are covered, along with the surgical cavity walls, with Surgicel and other hemostatic materials, inserting into the surgical cavity hemostatic cottonoids that, together with a prolonged irrigation, allow one to obtain a good and effective compression hemostasis (Fig. 8.6). Some highlights related to the techniques of motor, language, and cognitive mapping will be presented below. 

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A

93

B

FIGURE 8.6  End of the resection: intraoperative images of the surgical field at the last phase of the resection of a case of dominant frontal SMA tumor (A) or nondominant parietal tumor (B). The surgical cavity is covered by Surgicel. Cottonoids are also put in place to help hemostasis (A); vessels are covered with Surgicel as well (B).

MOTOR MAPPING Motor mapping is recommended for all the lesions that involve motor areas/pathways. These include of course the primary motor cortex and originating fibers, but also the nonprimary motor areas, such as ventral premotor and parietal areas, and supplementary motor areas.21,41,112,116 Motor mapping can be performed either with LF or HF stimulation techniques. Data from the literature indicate that LF can be used in about 30% of tumors affecting the motor pathways, when the primary motor cortex and its originating pathways are compressed and only partially infiltrated.41 Particular attention must be given to the simultaneous use of LF and ultrasonic aspirators, since the latter can cause false negatives.88 The use of LF in cases of tumors different from the previous ones (i.e., characterized by high infiltration or compression of the motor pathways) is more difficult and often associated with the appearance of epileptic seizures resulting from stimulation, or apparently negative responses. In this case, the occurrence of negative responses induced by stimulation generated the term “negative mapping.” However, this term must be understood clearly, since the failure to evoke a response during the stimulation (usually performed with LF) is not necessarily a sign of true negative/absent response; it can also be linked to the inability of the stimulation paradigm in use to evoke one (false negative).41 The response evoked with LF motor stimulation can be either directly highlighted as an overt movement, or with the use of electromyography (as a trace in the free-­running EMG) (Fig. 8.7). The use of HF (train of stimuli) is instead applicable to most tumors, even in the presence of high infiltration of the motor pathways, marked motor pathways compression, history of uncontrolled seizures, or previous treatments. Furthermore, such stimulation is not influenced by the simultaneous use of an ultrasonic aspirator. In the case of tumors in which the motor pathways are difficult to stimulate, it

is possible to change some of the parameters of stimulation (e.g., the number of stimuli, or amplitude of the single stimulus), which allows one to obtain a motor response in most cases, reducing the cases in which a mapping is not obtained (and avoiding the case of negative mapping).41,110 These data support the concept that HF stimulation is the most efficient way to investigate the motor system.41,109,110 However, the motor response evoked by HF stimulation (motor-­evoked potential) requires the use of electromyography to be recorded (see Fig. 8.5). A fundamental concept during stimulation is the identification at each site of the threshold of motor stimulation, that is, the identification of the lowest current intensity that evokes the smallest detectable motor response (at the point of stimulation) visible on the EMG.41 The stimulation threshold must be identified both at the cortical and the subcortical level (see Fig. 8.7): the cortical level threshold helps in evaluating the level of excitability of the primary motor cortex, which gives insight into the “well-­being” status of the motor system (for hand muscle responses: generally 3 to 7 mA in the awake patient; 9 to 12 mA in the asleep patient when the HF is used)41; at the subcortical level such a threshold allows one to evaluate the distance from the motor fibers; in the case of the use of HF there is a relationship between the amount of current delivered by the stimulator and the distance from the motor tract (1 mA of current used for stimulation and 1 mm of distance from the corticospinal tract; 1 mA-­1 mm rule).41,110 A subcortical stimulation threshold of 3 to 5 mA is the minimum recommended to achieve a safe resection and not endanger the motor tract.41,110 While stimulation of the primary motor cortex and of its originating fibers can be performed while the patient is in resting condition (either asleep or awake), the identification of motor responses originating from other motor areas and pathways (ventral premotor, or supplementary, parietal) requires the patient’s collaboration (awake setting).117,118 

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A First dorsal interosseous

Abductor pollicis brevis

10 mV 30 ms

B

Abductor digiti minimi

100 µV

2 mV 30 ms

30 ms

C

FIGURE 8.7  Motor mapping: example of motor responses obtained with low-­frequency (A) and high-­frequency (B) stimulation techniques applied over the primary motor cortex. (A) free-­running electromyography (EMG) during a low-­frequency stimulation of M1, hand region (the box shows the point of stimulation acquired intraoperatively by neuronavigation on a post-­GD T1 weighted MR; the M1 component of the reconstructed corticospinal tract [by DTI FT] superimposed to MR image is highlighted in white). Low-­frequency stimulation induced a motor response involving several hand and upper limb muscles, clearly visible as an increasing amplitude of the EMG traces. The stimulus artifact is highlighted in the blue box. Intensity of stimulation was 7 mA, bipolar probe. (B) High-­frequency stimulation induced motor-­voked potential motor responses in different hand muscles. High-­frequency stimulation was applied over different sites of the hand region of the primary motor cortex with a monopolar probe (4 mA). (C) Identification of cortical motor threshold with the monopolar high-­frequency stimulation. Decreasing the current intensity (from 6 mA, train of five) caused a reduction of amplitude of tibialis anterioris motor evoked potentials (MEPs) until the motor threshold was reached. Under this threshold (2 mA, train of five) no stable MEPs were evoked.

8  •  Low(er) Grade Gliomas: Surgical Treatment

Table 8.2  Neuropsychological Tests Performed During Cognitive Mapping in Different Brain Regions Intraoperative Cognitive Mapping Frontal lobe • Counting • Object naming • Action naming (writing, reading) • Motor cognition • Cognition Temporal lobe • Counting • Object naming • Action naming • Semantic association task • Cognition • Visual test

Parietal lobe • Counting • Object naming • Action naming • Numbers recognition • Semantic association task • Motor cognition • Visual test Insula • Counting • Object naming • Action naming • Numbers recognition • Motor cognition • Semantic association task • Cognition

No significant differences according to brain regions are present.

LANGUAGE AND COGNITIVE MAPPING This is generally used by most authors in case of tumors affecting language areas and/or pathways, generally in the dominant hemisphere.22,37,38,40,60,61,65,67,119 The current trend, however, is to extend cognitive mapping also in the traditionally termed nondominant hemisphere, to assure the identification and maintenance of higher cognitive functions.53,54,58,120,121 In all cases, this type of mapping requires the patient’s collaboration, for which therefore the patients must be awakened during at least a phase of the procedure. During this type of mapping, the current is applied over a site while the patient executes a specific task; if the stimulated site is relevant for the function the task is investigating, the current produces a characteristic interference, indicating that the stimulated area, at the level of the cortex or subcortical white matter, belongs to a language or cognitive network. The stimulation most widely used for this purpose is the LF. The first step in stimulation is the identification of the working current, i.e., the current (generally the lowest current) that produces an interference at the level of the terminal effector of the language network, represented by the ventral premotor area. In this case the patient performs a counting or naming task, and the current is delivered over the area starting from the lowest level (usually 2 mA), and progressively increasing in intensity, looking for interferences in the task, choosing as the working one the lowest possible current intensity that produces a stable disruption (anarthya).22,37,38,40,60,61,65,67,119 The same current is then used to stimulate the remaining network, both cortical and subcortical. The language network is well known and its organization can be found in various reference works.122 The surgeon must have a clear idea of the organization of this network and of the relationship that it may have with the tumor, carrying out various tests depending on the area in which he/she is resecting. In general, naming is the most common task used; others, such as the semantic association test, are required for the exploration of the circuits at the anterior and posterior temporal level.122 Given the complexity of the circuit, there are no specific tests for individual areas, and the surgeon requires a neuropsychologist to perform a varied and complex test battery, varying according to the site and the functional relationships identified (Table 8.2). Generally a site is defined as functional if it

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evokes an interference at least three times in separate stimulations.21,37,38,40,60,61,65,71,119 In addition, each site identified at the subcortical level is not usually specific for an individual function; it carries multiple functions, depending on the type of test that is administered. For example, the third branch of the superior longitudinal fasciculus is involved both in visuospatial, motor cognition, and decision-­making activities.53,54,120 More complex, and still at an initial stage, is the mapping of higher cognitive functions such as emotions, executive functions, mentalization, or memory.53,54,58,120,121 This complex mapping is generally performed during the resection of tumors located in the traditionally defined nondominant hemisphere; resection in this area is frequently associated with executive function deficits. While LF stimulation is the most used for performing cognitive mapping, in the case of patients with a long history of epileptic seizures, uncontrolled seizures, or previous treatments, in which the LF may not evoke responses or may induce epileptic seizures, the HF delivered. The monopolar probe can be used, varying the repetition rate from 1 Hz to 3 Hz.123 

HOW TO MANAGE INTRAOPERATIVE COMPLICATIONS Given that the surgical procedure largely requires the patient to be awake, the most frequent complications relate to the loss of cooperation by the patient or the inability to make an appropriate mapping. The loss of cooperation has been described by various authors as a percentage varying from 2% to 15%, and as mainly dependent on the duration of the collaboration phase.121,124 The use of the asleep-­awake-­asleep technique has significantly reduced the percentage of noncollaboration. Furthermore, the strategy of immediately locating functional margins from the early stages of subcortical resection reduces the time of awakening and collaboration, increasing the proportion of patients in whom a collaboration is obtainable.4,47,104 A further complication of the technique is linked to the deterioration of the patient’s neurologic condition and the reduction or disappearance of the evoked motor responses. The intraoperative deterioration of the patient’s responses can occur when the procedures involve particular areas such as the supplementary motor (by progressive appearance of the syndrome during the procedure, as a result of the disconnection of the supplementary motor area (SMA) from the motor system) or in the dominant parietal area as a result of transient impairment of language tracts. Rapid subcortical mapping and the adoption of asleep strategies using intraoperative neurophysiology reduce the patient’s intraoperative discomfort. Preoperative patient preparation by the neuropsychologist and his/her assuring of the patient during the procedure are equally important to reduce the impact on the patient.110,112,121 Regarding the deterioration or disappearance of MEPs, it is often related to the occurrence of imminent suffering or damage to the vascular component. In these cases, the surgeon interrupts the resection in the affected area, covers the perimeter of the surgical cavity with Surgicel and other hemostatic materials, applies abundant irrigation, asks the anesthetist to increase the arterial pressure. In most cases, thanks to these maneuvers, it is possible to recover the evoked motor response, which allows for reduction in the percentage of permanent motor deficits.110,121 

FUNCTIONAL RESULTS OF SURGERY When brain-­mapping techniques are applied to lower-­grade glioma surgery, functional results can be evaluated at early (within 1 week) to late (from 1 month to 3 months) periods

96

Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

after surgery. Evaluation is generally performed with neurologic examination, along with neuropsychological and psycho-­oncologic evaluation.47,60,61,63 The purpose of brain-­ mapping techniques is to identify and preserve cortical and subcortical essential sites at the time of surgery. Resection is in fact stopped when language and/or motor, or visuospatial, or cognitive cortical or subcortical areas are encountered. In most cases, functional disturbances are evoked inside the tumor mass as well as at tumor margins, or even outside them, depending on the location of the functional boundaries in respect to the tumor, as visible in the conventional MR. The preservation of functional boundaries is therefore critical for patient integrity.12,41,64,65,101,108 Evaluation of motor or language deficits during postoperative course and at follow­up showed that the chance of developing a new deficit or to worsen a preexisting one in the immediate postoperative period was 72.8% and 65.4%, when language-­or motor-­related areas were identified subcortically during resection.20,39 The chance was also higher in patients with a pre-­existing motor or language deficit, which correlates with the higher percentage of subcortical tracts identified in the same patients, or with a higher involvement (and sufferance) of such critical structures induced by the tumor.65 This is not surprising when it is taken into account that when surgery is tailored to reach functional boundaries whenever they are located, the chance of inducing permanent deficits is significantly high, because the surgeon reaches them in all the cases.41 Most of the immediate deficits were transient and disappeared within 1 month from surgery. The likelihood of developing a permanent deficit varied between 0.5% and 3.8%, independently from histology and location, and reached 7% in patients with pre-­existing motor or language deficits.41,65,101,125 These percentages further reinforce the concept that when a subcortical site is found, the surgeon is very close to the subcortical pathway.41,64,101 If no subcortical structures are found, the resection can be continued, because the chance of damaging essential structures is low, and the resection should progress until boundaries are eventually found. The fact that most of the deficits were transient suggests that in these cases resection was conducted close to the tracts, and the development of the postoperative disturbances may be due to edema or transient retraction injury, without permanent damage. The postoperative deficits in patients in which no subcortical tracts were identified are usually due to vascular damage and at the sites of ischemic areas. MEP monitoring can help in preventing the appearance of motor deficits due to vascular injury.18,110 When subcortical stimulation was systematically applied during resection of LGGs located within language areas or pathways, only 1.3% showed a long-­term impairment. Similar or even lower figures were observed for resection of gliomas close to motor areas or pathways (0.5% of deficits). These functional results were totally different from those obtained when subcortical stimulation was not applied.43,64,101 These data support the relevance of subcortical stimulation as a useful surgical adjunct during removal of lesions involving motor or speech areas, as further demonstrated by the high percentage of patients (95.8%) who returned to work at 3 months after surgery.47,64 

The effect of surgery on the incidence of seizures has been recently documented by several authors.49,47,51,126 Seizures play an important role in the clinical presentation and postoperative quality of life of patients who undergo surgical resection of LGGs.32,49,51,126 Cortical location and oligodendroglioma and oligoastrocytoma subtypes are significantly more likely to be associated with seizures, compared with deeper midline locations and astrocytoma. 49% of patients have pharmacoresistant seizures before surgery. A particular case is that of insular or paralimbic tumors. In these cases, intractable epilepsy is observed in 30% to 58% of cases and patients may experience up to 10 partial seizures per day despite more than 2 AEDs. Seizure control is more likely to be achieved after GTR than after subtotal resection/biopsy alone.127 In fact, when total or subtotal resection is achieved, in more than 80% of cases a positive impact on seizures is documented, with reduction in the number of AEDs administered.51,126 In addition, suppression of AEDs is possible in 30% of cases.51,126 Also, in more than 80% of cases of insular LGGs with intractable epilepsy, a positive impact on seizures can be again documented. It is relevant to remember than in the LGG patient in which seizure control has been reached after initial surgery, seizure recurrence is associated with tumor progression.51 When a functional neuro-­oncologic approach is used, resection is performed according to functional boundaries. At surgery, boundaries can be found either within the tumor mass, at the tumor border, or definitely outside the tumor border visible in volumetric FLAIR images. In the first case, a partial or subtotal removal is obtained. In the latter, a total or supratotal resection is achieved.128 The ability to reach a consistent resection is critical for the further management of the patient; in fact, when a GTR resection is reached (95% of previous mass), patients are classified as belonging to the low-­risk class, and in the case of grade II tumors a watchful attitude is generally recommended; when this is not feasible, patients are categorized in the high-­risk class, and independently from the tumor grade, a further adjuvant treatment is always recommended. A large amount of class III and II evidence suggests that more extensive resection at the time of initial diagnosis may be a favorable prognostic factor for this type of tumor13,15,22,25–27,101,108,129 and may significantly change the natural history of the tumor in comparison to a wait-­and-­see attitude or simple biopsy and imaging follow-­up only.25,26 The evaluation of EOR is usually performed on postoperative FLAIR volumetric images, by the aid of semi-­automatic segmentation software.27,71,129 EOR could be categorized as percentage of resection in comparison to the preoperative volume; alternatively, EOR could be categorized as the amount of residual tumor volume.28,71 In the latter case, a complete resection is defined when no abnormalities are seen on postoperative FLAIR images, and a subtotal resection when a postoperative volume on volumetric postoperative FLAIR images is less than 10 mL.70 The ability to achieve a complete or subtotal resection is influenced by both the preoperative tumor volume and by tumor involvement of eloquent tissue, particularly at the subcortical level.8 This stresses the point that the smaller the tumor, the better the patient outcome. 

ONCOLOGIC RESULTS OF SURGERY

STRATEGY FOR LARGE, DIFFUSE OR RECURRENT TUMORS; THE CONCEPT OF BRAIN PLASTICITY

The ability of surgery to impact the natural history of the tumor is now less a matter of debate.23,25,26,65 Simple biopsy without resection to direct patients toward adjuvant treatment is not theoretically any more acceptable, unless a resection is not feasible.

LGGs may present as a variable type of tumors ranging from discrete and apparently well-­defined lesions to diffuse and less-­ discrete lesions. The therapeutic strategy for the majority of tumors are those we previously described. Large diffuse tumors,

8  •  Low(er) Grade Gliomas: Surgical Treatment

involving multiple lobes and/or extending to both hemispheres, still represent a challenge. The majority of these tumors contain functional subcortical tracts, and a total or subtotal resection as initial strategy is quite difficult to achieve. Although partial removal may still be beneficial,8,23,51 the majority of these patients underwent stereotactic biopsy only, followed by adjuvant treatments. A strategy to increase the rate of resection in these tumors, as well as in those tumors in which a contralateral invasion of tumor cells is present, is represented by the use of upfront preoperative chemotherapy.88,130,131 Alternatively, chemotherapy may be used as adjuvant treatment, after partial removal.25,43 Recent data, however, stressed the point that a temozolomide (TMZ)-­ based CHT regimen could produce TMZ-­induced mutations, and further tumor transformation.94,125 In the case of large tumors, a two-­time surgical strategy may be chosen, particularly for large tumors involving language areas or pathways. In our institution we adopted the policy of waiting up to 4 to 6 months before submitting the patient to a second surgery. This is done to enable patient recovery from the initial surgery, and also to let the phenomenon of brain plasticity take place.4,15,46,132,133 Despite aggressive and early treatment, LGGs tend to recur. The rate of recurrence is influenced by the preoperative tumor volume and to a lesser extent by the extent of surgical remo val.8,13,29,134 A tumor recurrence may still retain the morphologic features of LGGs, or may show signs of tumor progression, such as contrast enhancement. Generally, when a total or subtotal removal was achieved at the time of initial surgery, the recurrent tumors have a higher chance to recur, still as low grade. When a tumor recurs, various therapeutic options are available: surgery, chemotherapy, radiotherapy.9 Surgery usually is intermingled with the other therapeutic modalities, and is the treatment of choice when a subtotal or even a total removal can be predicted, such as in discrete lesions. When this is feasible, the prognosis of the patient is still favorable. Brain-­mapping techniques can be still applicable in case of recurrent tumors, even after radiotherapy. Alternatively, surgery may be used to decrease the tumor volume, in order to enhance the effect of chemo-­or radiotherapy. Generally, a patient with LGGs may undergo several surgeries during the entire course of the disease, and surgery is used for different purposes, and strictly associated with the other therapeutic modalities.128 Up to 30% of patients in our series underwent four surgeries, and 12% submitted to five operations. An important observation that helps in planning surgeries is the occurrence of the phenomenon of brain plasticity.4,15,46,132,133,135 Plasticity may occur at a cortical level or, less frequently, at a subcortical level, where it can be explained by the recruitment or unmasking of parallel and redundant subcortical circuits.46,54 The occurrence of such phenomena of compensation is of particular relevance because it allows the extension of surgical indications. After an initial surgery, a functional reshaping phenomenon can be observed for a period of up to 6 months, allowing one to perform a more radical second surgery with an increase in the oncologic benefit for the patient. The neurosurgeon should gain a better knowledge of these plasticity phenomena, and their variability among patients, in order to integrate this potential into the surgical indications and in dynamic surgical planning.4,15,46,132,133 

Conclusions LGGs are slow-­growing intrinsic lesions that induce a progressive functional reshaping of the brain. Surgical removal

97

of these lesions requires the combined efforts of a multidisciplinary team of neurosurgeons, neuroradiologists, neuropsychologists, neurophysiologists, and neuro-­oncologists that together contribute to the definition of the location, extension, and extent of functional involvement that a specific lesion has induced in an individual patient. It is important to keep in mind that each tumor has induced particular and specific changes to the functional network, which varies among patients. This requires that each treatment plan be tailored to the tumor and to the patient. When the treatment plan is established, surgery should be accomplished according to functional and anatomic boundaries, and aims to maximally resect the mass and to maximally preserve patient functional integrity. This can be reached at the time of the initial surgery, depending on the functional organization of the brain, or may require additional surgeries, eventually intermingled with adjuvant treatments. The use of so-­called brain-­mapping techniques extends surgical indications, and improves EOR with greater oncologic impact, minimization of morbidity, and increase in quality of life. Data available at this time indicate that LGGs at the time of radiographic diagnosis benefit from surgery because aggressive early surgery influences the incidence of recurrence, time to tumor progression, time to malignant transformation, and provides seizure control. If the tumor at the time of initial diagnosis is smaller, the possibility of reaching a complete surgical resection is higher, the prognosis in terms of recurrence is better, and the tendency to malignant transformation is lower. These points stress the need to treat smaller lesions and to reduce the time spent on observation. KEY REFERENCES

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132. Duffau H, Capelle L, Denvil D, et al. Functional recovery after surgical resection of low grade gliomas in eloquent brain: hypothesis of brain compensation. J Neurol Neurosurg Psychiatry. 2003;74:901–907. Available: http://www.ncbi.nlm.nih.gov/pub med/12810776, Accessed 9 April 2018. 133. Duffau H, Khalil I, Gatignol P, Denvil D, Capelle L. Surgical removal of corpus callosum infiltrated by low-­grade glioma: functional outcome and oncological considerations. J Neurosurg. 2004;100:431–437. Available: http://thejns.org/doi/10.3171/ jns.2004.100.3.0431, Accessed 9 April 2018.

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134. Chaichana KL, McGirt MJ, Laterra J, Olivi A, Quiñones-­ Hinojosa A. Recurrence and malignant degeneration after resection of adult hemispheric low-­grade gliomas. J Neurosurg. 2010;112:10–17. Available: http://www.ncbi.nlm.nih.gov/pub med/19361270, Accessed 9 April 2018. 135. Krainik A, Duffau H, Capelle L, et al. Role of the healthy hemisphere in recovery after resection of the supplementary motor area. Neurology. 2004;62:1323–1332. Available: http://www.ncbi .nlm.nih.gov/pubmed/15111669, Accessed 9 April 2018.

CHAPTER 9

Management of Primary Central Nervous System Lymphoma SONIKPREET AULAKH  •  NAOMI FEI  •  MARK JENTOFT  •  ERIK H. MIDDLEBROOKS  •  KARIM REFAEY  •  ALFREDO QUINONES-­HINOJOSA  •  ASHER CHANAN-­KHAN

Management of Primary Central Nervous System Lymphoma in Immunocompetent Patients PRESENTATION Primary central nervous system lymphoma (PCNSL) is a category of extranodal lymphoma restricted to the nervous system accounting for approximately 3% of all brain tumors. Histologically, the majority of these tumors are identified as large B-­cell lymphomas; however, T-­cell lymphoma cases have also been reported (Fig. 9.1). PCNSL most commonly presents as a single intracranial mass; however, in 20% to 40% of immunocompetent patients, multiple masses may be observed (Fig. 9.2).1 Classically, periventricular white matter involvement is seen, though any craniospinal structure can be involved. Uncommonly, these lymphomas can arise in the spinal cord, meninges, and eyes. These brain lesions are frequently accompanied by leptomeningeal and ocular dissemination. PCNSLs are histologically hypercellular with minimal vascularization, resulting in several characteristic imaging findings. On computed tomography (CT) imaging with contrast, these highly cellular lesions appear as high density.2,3 On magnetic resonance imaging (MRI), PCNSLs have intense and homogenous nodular enhancement with a well-­defined margin in immunocompetent patients (see Fig. 9.2A). Perilesional vasogenic edema is often observed (see Fig. 9.2B). Similar to other intracranial tumors, PCNSLs appear hypointense to gray matter on T1 weighted imaging. They may be differentiated on T2 weighted imaging, as their hypercellularity implies short T2 relaxation times, resulting in an isointense to hypointense appearance.1 In the setting of high cellularity, restricted diffusion of water is noted on diffusion-­weight imaging. This results in hyperintensity on DWI trace images and hypointensity on apparent diffusion coefficient maps (Fig. 9.3).4 

DIAGNOSIS AND PROGNOSIS If central nervous system (CNS) lymphoma is suspected based on imaging findings, assessment for extracranial

98

disease should be performed to differentiate primary from secondary CNS lymphoma. Evaluation should include routine physical exam, blood studies, contrast-­enhanced total-­ body CT scan or positron emission tomography (PET)/CT with contrast, and testicular ultrasound. In up to 8% of cases thought to be PCNSL, systemic disease has been found.5 PCNSL, in contrast to secondary CNS lymphoma involvement, is overwhelmingly parenchymal in location. Rarely, PCNSL may present as primary dural lymphoma mimicking meningioma or as primary leptomeningeal lymphoma mimicking other causes of leptomeningitis. In immunocompetent patients, PCNSL is more commonly a solitary and homogenously enhancing mass but may be multifocal in up to 40% of cases and show ringlike enhancement in ∼10%. Edema is frequently present but often disproportionately low compared to other aggressive neoplasms, such as solid organ metastases and high-­grade glioma. Likewise, there is also often disproportionately less mass effect than would be expected for the size. Features such as hemorrhage and calcification are rare in untreated, immunocompetent patients. Although classically described as having an affinity for the basal ganglia, only ∼⅓ are present in the basal ganglia. More commonly, the supratentorial white matter is involved, with frequent extension to the ependymal and/ or meningeal surface. The frontal lobe white matter and corpus callosum are affected more often. Typical imaging features reflect the high cellularity and the increased nuclear-­cytoplasmic ratio, including hyperdensity on noncontrast CT, iso-­to hypointense on T2-­weighted imaging, features that are less commonly seen in metastatic disease and gliomas. Additionally, the low interstitial water content and high nuclear-­cytoplasmic ratio results in restricted water movement on diffusion-­weighted imaging. Perfusion imaging shows a relatively mild increase in cerebral blood volume (CBV) compared to most metastatic lesions and high-­grade gliomas. In the immunocompromised patient, atypical features are more common, including higher incidence of multifocality, frequent necrosis and heterogenous enhancement, and occasional hemorrhage (particularly in AIDS-­related cases, compared to other causes of immune suppression).

9  •  Management of Primary Central Nervous System Lymphoma

99

HISTOGENESIS OF PCNSL

Germinal center

Early

Postgerminal center

Late

Early

Late

CD10 BCL-6 MUM1

A

D

B

E

C

F

CD138

PCNSL Systemic diffuse large B cell lymphoma FIGURE 9.1  A model for the histogenesis of primary central nervous system lymphoma (PCNSL) based on the developmental stage of B-­cell arrest as indicated by antigen expression. (Adapted from Camilleri-­Broet S, Criniere E, Broet P, et al. A uniform activated B-­cell-­ like immunophenotype might explain the poor prognosis of primary central nervous system lymphomas: analysis of 83 cases. Blood. 2006;107:190–196. Copyright © 2006 American Society of Hematology. Published by Elsevier Inc. All rights reserved.)

A

B

FIGURE 9.2  T1-­enhanced (A) and FLAIR (B) MRI showing the infiltrative character of primary central nervous system lymphoma (PCNSL). Arrow shows small satellite area of enhancement that on the FLAIR seems to be connected to the larger lesion.

FIGURE 9.3  T1-­enhanced (A), FLAIR (B), and DWI (C) magnetic resonance imaging of patient with primary central nervous system lymphoma at the time of diagnosis (A, B, and C) and after five cycles of chemotherapy (D, E, and F).

Stereotactic biopsy is indicated for pathologic confirmation of PCNSL (Video 9.1). Of note, B-­cell lymphomas are steroid sensitive; thus previous exposure to steroids may result in loss of diagnostic histologic findings. If PCNSL is suspected, steroids should be avoided when possible with expedient biopsy pursued. Upon diagnosis of PCNSL, baseline staging evaluation includes cerebrospinal fluid (CSF) sampling, ophthalmologic evaluation, and bone marrow biopsy.6 Additional pretreatment evaluation should include hepatic, renal, and cardiac functionality tests, HIV status, and hepatitis B and C panel. PCNSL, when left untreated in immunocompetent patients, results in median overall survival (OS) of less than 4 to 5 months. However, the median OS after the introduction of combination modality high-­dose (HD) methotrexate (MTX)–based regimens shows survival of 2 to 5 years. Prognosis can be determined through various clinical models. The International Extranodal Lymphoma Study Group (IELSG) scoring model includes age greater than 60

years, elevated serum LDH, Eastern Cooperative Oncology Group score (ECOG) greater than 2, involvement of deep brain structures, and raised CSF protein levels. Two-­year OS was 80%, 48%, 15% for patients with scores of 0 to 1, 2 to 3, and 4 to 5, respectively.7 Memorial Sloan-­Kettering Cancer Center proposed a simplified score model including only age greater than 50 years and Karnofsky Performance Score (KPS) greater than 70. Patients less than 50 years old had a median survival of 8.5 years (95% CI, 4.7 to 16.8). Patients older than 50 with KPS greater than 70 had a median survival of 3.2 years (95% CI, 2.6 to 4.3). Patients older than 50 with KPS less than 70 had a median survival of only 1.1 years (95% CI, 1.4 to 4.3).8 

INDUCTION THERAPY Unlike most intracranial malignancies, primary surgical resection is not indicated for PCNSL. This is largely due to the diffuse, infiltrative nature of the tumor, with histopathology demonstrating an angiocentric growth pattern

Video 9.1

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A

B

C

D

FIGURE 9.4  (A) H&E showing an area of involvement in the brain by lymphoma. Note high cell density and high nuclear-­to-­cytoplasmic ratio of the cells, (B) CD20 confirms that the cells are predominantly B cells and morphologically large, (C) CD3 highlights only occasional T-­cells that are morphologically small, and (D), Ki67, demonstrates a high level of proliferative activity within the neoplastic cell population.

(Fig. 9.4). While lesions may appear well­defined, microscopic disease often extends beyond the visualized border.9 Additionally, the steroid sensitivity of PCNSL obviates the need for debulking surgery. Indeed, upfront surgery has been proven to be associated with worse outcomes. In a retrospective study of 248 immunocompetent patients with PCNSL, 132/248 underwent stereotactic biopsy for diagnosis of PCNSL, resulting in a procedure-­related morbidity of 3.7% and no mortality. The remaining 116/248 underwent surgical resection with a mortality rate as high as 3.4%. Multivariate analysis revealed that surgical resection was an unfavorable prognostic factor10 and may increase functional deficits.11 Instead, PCNSL utilizes induction chemotherapy for 6 to 8 cycles to achieve complete radiographic response (CR) before proceeding to consolidation therapy. MTX is the backbone of PCNSL induction regimens, proving more effective than radiation alone or regimens without MTX.12 While MTX crosses the blood-­brain barrier, CSF levels are only 3% to 10% of plasma concentrations; thus HD MTX is necessary. While the optimal dose has not been determined, expert consensus recommends MTX ≥ 3 g/m2 by a 3-­hour infusion.13 MTX is an antifolate metabolite that irreversibly inhibits dihydrofolate reductase and interferes with

deoxyribonucleic acid (DNA) synthesis, repair, and cellular proliferation. Initial administration of HD MTX inhibits proliferation of rapidly dividing malignant cells. Leucovorin is administered for 2 to 3 days afterwards in order to “rescue” benign cells from the potentially lethal dose of MTX. MTX may precipitate in the renal tubules, leading to renal insufficiency and impaired drug elimination. Concurrent administration of high-­volume hydration with urine alkalinization of pH greater than 7 is indicated to ensure appropriate renal clearance. In NABTT 96-­07, use of HD single-­agent MTX 8 mg/ m2 revealed median progression-­free survival (PFS) of 12.8 months and median OS of 22.8 months.14 NOA-­03 trial used single-­agent HD MTX and reported median OS benefit of 25 months.15 In a retrospective single-institution study, HD MTX without whole-­brain radiation therapy (WBRT) provided PFS benefit of greater than 3 years and OS of greater than 7 years.16 MTX-­ based combination regimens demonstrate improved outcomes, as detailed below. There is a paucity of data directly comparing various combination regimens; therefore decisions based on the patient’s comorbidities and performance status are considered when choosing a regimen (Table 9.1).

9  •  Management of Primary Central Nervous System Lymphoma

101

Table 9.1  Methotrexate-Based Induction Regimens for Primary Central Nervous System Lymphoma Author

Year et al.14

Batchelor Herrlinger et al.15 Zhu et al.38

2003 2005 2009

Holdhoff et al.17

2014

Glass J et al.18

2016

Rubenstein et al.19

2013

Morris et al.39

2013

Shah et al.40

2007

Abrey et al.41

2000

Ferreri et al.20 Ferreri et al.21

2009 2016

Regimen mg/m2

HD-­MTX 8 every 2 weeks HD-­MTX 8 mg/m2 every 2 weeks × 6 cycles HD-­MTX 3.5–8 g/m2 every 2 weeks, median 8 cycles HD-­MTX 8 mg/m2 + Rituximab 375 mg/m2 every 2 weeks for 24 cycles Induction: MTX 3.5 mg/m2, Rituximab 375 mg/m2, TMZ 100 mg/m2 Consolidation: Hyperfractionated WBRT and TMZ 100 mg/m2 Induction: MTX 8 mg/m2, Rituximab 375 mg/m2, TMZ 150 mg/m2 Consolidation: Etoposide 40 mg/kg, Cytarabine 2g/ m2/day Induction: MTX 3.5 mg/m2, Rituximab 500 mg/m2, Vincristine 1.4 mg/m2, Procarbazine 100 mg/m2 Consolidation: reduced-dose WBRT and cytarabine 3 g/m2/day Induction: MTX 3.5 gm/m2, Rituximab 500 mg/m2, Vincristine 1.4 mg/m2, Procarbazine 100 mg/m2 Consolidation: dose-­reduced WBRT vs. WBRT Induction: MTX 3.5 g/m2, Procarbazine 100 mg/ m2/day, Vincristine 1.4 mg/m2 Consolidation: WBRT with Cytarabine MTX 3.5 g/m2, Cytarabine 2 g/m2 MTX 3.5 g/m2, Cytarabine 2 g/m2, Thiotepa 30 mg/ m2, Rituximab 375 mg/m2

PFS

OS

CR (%)

12.8 m 10 m 7.1 m

NR at 22.8 m 25 m 37 m

52 30 60

26.7 m

NR

73

63.6% at 2 years

80.8% at 2 years

85.7

2.4 years

NR

66

7.7 years

NR

47

57% at 2 years

67% at 2 years

78

n/a

60 m

90

38% at 3 years 61% at 2 years

46% at 3 years 69% at 2 years

46 49

CR, Complete response; MTX, methotrexate; OS, overall survival; NR, not reached; PFS, Progression-­free survival; TMZ, temozolomide; WBRT, Whole-­brain radiotherapy.

Rituximab, a monoclonal antibody against the CD-­ 20 antigen, enables complement-­ mediated destruction of mature B-­lymphocytes. The addition of rituximab to HD-­ MTX compared to HD-­MTX alone is well tolerated. Compared to HD-­MTX alone, addition of rituximab resulted in improved CR rate (36% to 73%), median PFS (4.5 to 26.7 months), and OS (16.4 months to not yet reached).17 Rituximab should be used cautiously in patients with active infections, and anti-­viral prophylaxis is indicated for patients with chronic hepatitis B infection to prevent reactivation. Temozolomide (TMZ), an alkylating agent, has been added to HD-­MTX and rituximab for induction (MTR). As an oral agent that is well tolerated, TMZ is an attractive therapeutic option. In a phase II multicenter trial of 53 patients, MTR with consolidation regimen of hyperfractionated WBRT and TMZ resulted in objective response rate of 85.7% with 2-­year OS and PFS of 80.8% and 63.6%, respectively.18 The CALGB 50202 trial examined MTR with consolidation of cytarabine (DNA polymerase inhibitor) and etoposide (topoisomerase II inhibitor). With this regimen, PFS rates were 64%, 57%, 47% at 1, 2, 4 years, and OS rates were 75%, 70%, 65% at 1, 2, 4 years.18,19 The addition of cytarabine to HD-­MTX alone has also resulted in improved response rates.20 As a pyrimidine analog, cytarabine is incorporated into DNA and inhibits DNA polymerase to decrease DNA synthesis. In a randomized phase 2 trial, HD-­MTX with cytarabine compared to HD-­MTX alone achieved CR of 46% (31 to 61) and 18% (95% CI 6 to 30), respectively. It should be noted, hematologic toxicity was more commonly noted in the HD-­MTX

plus cytarabine group; therefore careful administration is required. Yet another induction regimen includes HD-­MTX, procarbazine (a DNA alkylator with inhibition of tRNA synthesis), and vincristine (a microtubule inhibitor). This regimen (MPV) has been studied followed by consolidation with reduced-dose WBRT and cytarabine, resulting in median PFS of 3.3 years and median OS of 6.6 years. More recently, MTX, cytarabine, thiotepa (alkylating agent) and rituximab (MATRix) has been studied for induction. The MATRix regimen was compared to HD-­ MTX plus cytarabine and HD-­ MTX, cytarabine, and rituximab in a randomized trial by IELSG. The MATRix regimen resulted in a superior CR rate of 49% (95% CI 38 to 60), compared with 23% (14 to 31) of those receiving methotrexate-­cytarabine alone and 30% (21 to 42) of those receiving methotrexate-­cytarabine plus rituximab.21 Interestingly, while grade 4 hematologic toxicity was more common in the MATRix regimen compared to the other groups, similar rates of infectious complications were reported among all three groups. 

INDUCTION IN ELDERLY PATIENTS In patients older than 60 years, HD-­MTX may result in greater toxicity. In a phase II study of patients older than 60, 7% to 10% treated with MTX less than 3.5 g/m2 discontinued treatment due to toxicity, and 26% to 44% had renal dysfunction requiring dose reduction.22 Additional chemotherapies to HD-­MTX must be carefully considered in the elderly population. A meta-­analysis of immunocompetent

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Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

Table 9.2  Response Criteria for Primary Central Nervous System Lymphoma Response

Brain Imaging

Eye Examination

CSF Cytology

Corticosteroid Dose

CR Cru

No contrast enhancement No contrast enhancement Minimal abnormality

Negative Negative Negative

None Any Any

PR

50% decrease in enhancing tumor

Normal Normal Minor retinal pigment epithelium abnormality Minor retinal pigment epithelium abnormality Decrease in vitreous cells or retinal infiltrate Recurrent or new ocular disease

Negative

Irrelevant

Persistent or suspicious

Irrelevant

Recurrent or positive

Irrelevant

No contrast enhancement PD

25% increase in lesion Any new site of disease: CNS or systemic.

CNS, Central nervous system; CSF, cerebrospinal fluid; CR, complete response; Cru, unconfirmed complete response; PR, partial response; PD, progressive disease. Adapted from Abrey LE, Batchelor TT, Ferreri AJM, et al. Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol. 2005;23(22):5034–5043.

patients more than 60 years old receiving induction therapy found no difference between HD-­MTX plus oral chemotherapy and more aggressive HD-­MTX based therapies.23 The PRIMAIN trial examined the addition of rituximab to HD-­MTX and oral alkylators followed by weekly procarbazine maintenance courses.24 CRR was 36% with 2-­year PFS 37%. Thus, HD-­MTX, rituximab, and an alkylating agent is a reasonable induction regimen for patients older than 65 years.25 

RESPONSE ASSESSMENT During active therapy, response should be measured by gadolinium-­ enhanced MRI scans approximately every 2 months, or at change of therapy. After completion of planned induction therapy, gadolinium-­enhanced MRI scan should be obtained within 2 months. If initial ophthalmologic examination of lumbar puncture cytology was abnormal, these studies should be repeated for response evaluation. Response criteria are based on radiologic, anatomic, and laboratory studies (Table 9.2).6 Complete response (CR) requires complete disappearance of all enhancing abnormalities on gadolinium-­enhanced MRI, no evidence of active ocular lymphoma on ophthalmic exam, and negative CSF cytology. Steroids must have been discontinued for at least 2 weeks at time of CR determination. 

CONSOLIDATION TREATMENT In patients who achieve appropriate response, consolidation therapy with either chemotherapy and autologous stem cell transplantation (ASCT) or WBRT is indicated to prevent relapse. The PRECIS trial compared these two consolidation regimens after HD-­MTX containing induction.26 Two-­year PFS was 63% (95% CI, 49% to 81%) and 87% (95% CI, 77% to 98%) in the WBRT and ASCT arms, respectively. In patients receiving WBRT, cognitive impairment was observed, while in patients with ASCT, cognitive functions were preserved or improved. Given the significant neurotoxicity implied in WBRT consolidation, chemotherapy with ASCT is favored in younger patients.27 ASCT requires leukapheresis for peripheral-­blood stem-­cell harvesting prior to administration of HD chemotherapy. These stem cells are then reinfused after chemotherapy to rescue bone marrow function. Chemotherapy regimens including CNS penetrating agents

such as carmustine, thiotepa, and busulfan are favored. A phase-­2 single-­arm trial using HD-­MTX–based induction therapy followed by carmustine and thiotepa consolidation with ASCT noted CRR of 77% and 3-­year PFS and OS of 67% and 81%, respectively. Unexpected toxicity was not reported at median follow-­up of 57 months.28 In elderly or frail patients unable to tolerate HD chemotherapy with ASCT, WBRT may be considered. The neurotoxicity implied in WBRT is dose dependent and progressive over time. Using 36 Gy of consolidative WBRT, the IELSG32 trial reported immediate improvement in cognitive functions after treatment; however, at 2-­year follow-­up, patients treated with WBRT showed significant impairment in attention and executive functions.29 WBRT patients with dose reduction to 23 Gy reported stable cognitive functions for up to 2 years.30 Therefore, the baseline functionality, life expectancy, and dose of radiation to be given must be considered in consolidative WBRT. In patients unsuitable for either of the above consolidation strategies, maintenance therapy with oral alkylating agents may be considered. TMZ maintenance at 150 mg/ m2 daily, days 1 to 5 of a 28-­day cycle after MTX-­cytarabine induction, resulted in a 2-­year OS of 60% in patients older than 65.31 Procarbazine maintenance after rituximab-­ procarbaxine-­MTX induction resulted in a 2-­year OS of 47% in patients older than 65.24 While these findings are limited by lack of placebo comparison, they are nonetheless options to discuss with patients unable to undergo ASCT or receive WBRT. 

RELAPSED/REFRACTORY PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA After completion of consolidation therapy, surveillance should include MRI of the brain every 3 months for 2 years, every 6 months until 5 years, then annually indefinitely. In patients with initial spinal or ocular involvement, CSF sampling and ophthalmologic follow-­up should be performed as clinically indicated. In patients with relapsed disease, second-­line treatments are guided by initial therapies received. In patients who did not receive radiation therapy, WBRT or involved-­field RT in the second-­line setting may be pursued. Patients initially treated with HD-­MTX who achieved response greater than 1 year are candidates for retreatment with HD-­MTX–based

9  •  Management of Primary Central Nervous System Lymphoma

chemotherapies. In comparison, if duration of response was less than 1 year after HD-­MTX treatment, other systemic therapies or clinical trials should be considered. Available chemotherapies result in variable response rates. HD cytarabine achieved CR 40% to 70%. HD cytarabine plus etoposide resulted in approximately 47% response rates.32 Combination of TMZ and rituximab resulted in objective RR of 53% with median OS of 14 months and median PFS of 7.7 months.33,34 In a small study, use of pemetrexed resulted in reasonable response rates.35 Use of lenalidomide as maintenance is currently being investigated in a clinical trial (NCT01956695). Ibrutinib, a Bruton tyrosine kinase inhibitor, which crosses the blood-­brain barrier when used as a single agent, albeit in a small number of patients, resulted in partial and CRs.36 Currently, ibrutinib is being investigated in prospective studies. Auto-­HCT has limited data in determining the efficacy in relapsed/refractory PCNSL.37 KEY REFERENCES

Abrey LE, et al. Primary central nervous system lymphoma: the Memorial Sloan-­Kettering Cancer Center prognostic model. J Clin Oncol. 2006;24(36):5711–5715. Abrey LE, et al. Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol. 2005;23(22):5034–5043. Bataille B, et al. Primary intracerebral malignant lymphoma: report of 248 cases. J Neurosurg. 2000;92(2):261–266. Batchelor T, et al. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-­07. J Clin Oncol. 2003;21(6):1044–1049. Cobert J, et al. Monotherapy with methotrexate for primary central nervous lymphoma has single agent activity in the absence of radiotherapy: a single institution cohort. J Neurooncol. 2010;98(3):385–393. Ferreri AJ, et al. High-­dose cytarabine plus high-­dose methotrexate versus high-­dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet. 2009;374(9700):1512– 1520. Ferreri AJ, et al. Prognostic scoring system for primary CNS lymphomas: the International Extranodal Lymphoma Study Group experience. J Clin Oncol. 2003;21(2):266–272.

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Ferreri AJ, Reni M, Villa E. Therapeutic management of primary central nervous system lymphoma: lessons from prospective trials. Ann Oncol. 2000;11(8):927–937. Glass J, et al. Phase I and II study of induction chemotherapy with methotrexate, rituximab, and temozolomide, followed by whole-­ brain radiotherapy and postirradiation temozolomide for primary CNS Lymphoma: NRG oncology RTOG 0227. J Clin Oncol. 2016;34(14):1620–1625. Haldorsen IS, et al. CT and MR imaging features of primary central nervous system lymphoma in Norway, 1989–­ 2003. AJNR Am J ­Neuroradiol. 2009;30(4):744–751. Haldorsen IS, Espeland A, Larsson EM. Central nervous system lymphoma: characteristic findings on traditional and advanced imaging. AJNR Am J Neuroradiol. 2011;32(6):984–992. Herrlinger U, et al. NOA-­03 trial of high-­dose methotrexate in primary central nervous system lymphoma: final report. Ann Neurol. 2005;57(6):843–847. Herrlinger U, et al. Primary central nervous system lymphoma: from clinical presentation to diagnosis. J Neurooncol. 1999;43(3):219–226. Holdhoff M, et al. High-­dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma. Neurology. 2014;83(3):235–239. Koeller KK, Smirniotopoulos JG, Jones RV. Primary central nervous system lymphoma: radiologic-­pathologic correlation. Radiographics. 1997;17(6):1497–1526. Nabavizadeh SA, et al. Neuroimaging in central nervous system lymphoma. Hematol Oncol Clin North Am. 2016;30(4):799–821. O’Neill BP, et al. Occult systemic non-­Hodgkin’s lymphoma (NHL) in patients initially diagnosed as primary central nervous system lymphoma (PCNSL): how much staging is enough? J Neurooncol. 1995;25(1):67–71. Reni M, et al. Clinical relevance of consolidation radiotherapy and other main therapeutic issues in primary central nervous system lymphomas treated with upfront high-­dose methotrexate. Int J Radiat Oncol Biol Phys. 2001;51(2):419–425. Rubenstein JL, et al. Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol. 2013;31(25): 3061–3068. Yun J, Iwamoto FM, Sonabend AM. Primary central nervous system lymphoma: a critical review of the role of surgery for resection. Arch Cancer Res. 2016;4(2). Numbered references appear on Expert Consult.

REFERENCES

1. Haldorsen IS, et al. CT and MR imaging features of primary central nervous system lymphoma in Norway, 1989-­2003. AJNR Am J Neuroradiol. 2009;30(4):744–751. 2. Nabavizadeh SA, et al. Neuroimaging in central nervous system lymphoma. Hematol Oncol Clin North Am. 2016;30(4):799–821. 3. Koeller KK, Smirniotopoulos JG, Jones RV. Primary central nervous system lymphoma: radiologic-­pathologic correlation. Radiographics. 1997;17(6):1497–1526. 4. Haldorsen IS, Espeland A, Larsson EM. Central nervous system lymphoma: characteristic findings on traditional and advanced imaging. AJNR Am J Neuroradiol. 2011;32(6):984–992. 5. O’Neill BP, et al. Occult systemic non-­ Hodgkin’s lymphoma (NHL) in patients initially diagnosed as primary central nervous system lymphoma (PCNSL): how much staging is enough? J Neurooncol. 1995;25(1):67–71. 6. Abrey LE, et al. Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol. 2005;23(22):5034–5043. 7. Ferreri AJ, et al. Prognostic scoring system for primary CNS lymphomas: the International Extranodal Lymphoma Study Group experience. J Clin Oncol. 2003;21(2):266–272. 8. Abrey LE, et al. Primary central nervous system lymphoma: the Memorial Sloan-­Kettering Cancer Center prognostic model. J Clin Oncol. 2006;24(36):5711–5715. 9. Yun J, Iwamoto FM, Sonabend AM. Primary central nervous system lymphoma: a critical review of the role of surgery for resection. Arch Cancer Res. 2016;4(2). 10. Bataille B, et al. Primary intracerebral malignant lymphoma: report of 248 cases. J Neurosurg. 2000;92(2):261–266. 11. Herrlinger U, et al. Primary central nervous system lymphoma: from clinical presentation to diagnosis. J Neurooncol. 1999;43(3):219–226. 12. Ferreri AJ, Reni M, Villa E. Therapeutic management of primary central nervous system lymphoma: lessons from prospective trials. Ann Oncol. 2000;11(8):927–937. 13. Reni M, et al. Clinical relevance of consolidation radiotherapy and other main therapeutic issues in primary central nervous system lymphomas treated with upfront high-­dose methotrexate. Int J Radiat Oncol Biol Phys. 2001;51(2):419–425. 14. Batchelor T, et al. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-­ 07. J Clin Oncol. 2003;21(6):1044–1049. 15. Herrlinger U, et al. NOA-­03 trial of high-­dose methotrexate in primary central nervous system lymphoma: final report. Ann Neurol. 2005;57(6):843–847. 16. Cobert J, et al. Monotherapy with methotrexate for primary central nervous lymphoma has single agent activity in the absence of radiotherapy: a single institution cohort. J Neurooncol. 2010;98(3):385– 393. 17. Holdhoff M, et al. High-­dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma. Neurology. 2014;83(3):235–239. 18. Glass J, et al. Phase I and II study of induction chemotherapy with methotrexate, rituximab, and temozolomide, followed by whole-­ brain radiotherapy and postirradiation temozolomide for primary CNS lymphoma: NRG oncology RTOG 0227. J Clin Oncol. 2016;34(14):1620–1625. 19. Rubenstein JL, et al. Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol. 2013;31(25):3061–3068. 20. Ferreri AJ, et al. High-­ dose cytarabine plus high-­ dose methotrexate versus high-­ dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet. 2009;374(9700):1512–1520. 21. Ferreri AJ, et al. Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-­32 (IELSG32) phase 2 trial. Lancet Haematol. 2016;3(5):e217–e227.

22. Hoang-­Xuan K, et al. Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years: a multicenter phase II study (26952) of the European Organization for Research and treatment of cancer brain tumor group. J Clin Oncol. 2003;21(14):2726–2731. 23. Kasenda B, et al. First-­line treatment and outcome of elderly patients with primary central nervous system lymphoma (PCNSL)—­a systematic review and individual patient data meta-­analysis. Ann Oncol. 2015;26(7):1305–1313. 24. Fritsch K, et al. High-­ dose methotrexate-­ based immuno-­ chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study). Leukemia. 2017;31(4):846–852. 25. Citterio G, et al. Primary central nervous system lymphoma. Crit Rev Oncol Hematol. 2017;113:97–110. 26. Houillier C, et al. Radiotherapy or autologous stem-­cell transplantation for primary CNS lymphoma in patients 60 years of age and younger: results of the intergroup ANOCEF-­GOELAMS randomized phase II PRECIS study. J Clin Oncol. 2019;37(10):823–833. 27. Kasenda B, et al. Prognosis after high-­dose chemotherapy followed by autologous stem-­cell transplantation as first-­line treatment in primary CNS lymphoma—­a long-­term follow-­up study. Ann Oncol. 2012;23(10):2670–2675. 28. Illerhaus G, et al. High-­dose chemotherapy with autologous haemopoietic stem cell transplantation for newly diagnosed primary CNS lymphoma: a prospective, single-­arm, phase 2 trial. Lancet Haematol. 2016;3(8):e388–e397. 29. Ferreri AJM, et al. Whole-­brain radiotherapy or autologous stem-­ cell transplantation as consolidation strategies after high-­ dose methotrexate-­ based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-­32 phase 2 trial. Lancet Haematol. 2017;4(11):e510–e523. 30. Herrlinger U, et al. Early whole brain radiotherapy in primary CNS lymphoma: negative impact on quality of life in the randomized G-­PCNSL-­SG1 trial. J Cancer Res Clin Oncol. 2017. 31. Pulczynski EJ, et al. Successful change of treatment strategy in elderly patients with primary central nervous system lymphoma by de-­escalating induction and introducing temozolomide maintenance: results from a phase II study by the Nordic Lymphoma Group. Haematologica. 2015;100(4):534–540. 32.  del Rio MS, et al. Platine and cytarabine-­ based salvage treatment for primary central nervous system lymphoma. J Neurooncol. 2011;105(2):409–414. 33. Enting RH, et al. Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide. Neurology. 2004;63(5):901–903. 34. Wong ET. Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide. Neurology. 2005;64(5):934; author reply 934. 35. Raizer JJ, et al. Pemetrexed in the treatment of relapsed/refractory primary central nervous system lymphoma. Cancer. 2012;118(15):3743–3748. 36. Lionakis MS, et al. Inhibition of B cell receptor signaling by Ibrutinib in primary CNS lymphoma. Cancer Cell. 2017;31(6):833–843. e5. 37. Soussain C, et al. Intensive chemotherapy followed by hematopoietic stem-­cell rescue for refractory and recurrent primary CNS and intraocular lymphoma: Societe Francaise De Greffe De Moelle Osseuse-­Therapie Cellulaire. J Clin Oncol. 2008;26(15):2512–2518. 38. Zhu JJ, et al. High-­dose methotrexate for elderly patients with primary CNS lymphoma. Neuro Oncol. 2009;11(2):211–215. 39. Morris PG, et al. Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced-­ dose whole-­ brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: final results and long-­ term outcome. J Clin Oncol. 2013;31(31):3971–3979. 40. Shah GD, et al. Combined immunochemotherapy with reduced whole-­brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol. 2007;25(30):4730–4735. 41. Abrey LE, Yahalom J, DeAngelis LM. Treatment for primary CNS lymphoma: the next step. J Clin Oncol. 2000;18(17):3144–3150.

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CHAPTER 10

Cerebellar Tumors in Adults WENYA LINDA BI  •  PABLO QUEVEDO-­VALDES  •  ALEXANDRA GIANTINI LARSEN  •  E. ANTONIO CHIOCCA

The cerebellum serves as the principal site of disease in 2.6% of all primary central nervous system tumors, with a much higher prevalence in children than in adults.1 The clinical impact of a mass in the cerebellum belies its relatively low incidence, and involvement of contiguous brainstem structures significantly increases the morbidity and mortality of these tumors. A wide spectrum of pathologies is observed among cerebellar tumors. This chapter will focus on intrinsic cerebellar tumors in adults, with considerations for commonly observed extrinsic tumors, such as meningiomas or schwannomas, to be discussed elsewhere.

Clinical Presentation Cerebellar tumors commonly present as one of several distinct scenarios. Headache, nausea, imbalance, and gait dysfunction are the most frequent complaints, attributable to mass effect and/or hydrocephalus. Involvement of the adjacent brainstem, tectum, and cranial nerves are less common presenting findings. The cerebellum demonstrates functional localization; cerebellar signs often correlate with the location of the cerebellar lesion.2 Lesions involving the cerebellar hemispheres are more likely to show limb ataxias and associated dysmetria. Midline lesions, affecting the cerebellar vermis and midline cerebellar nuclei, are more likely to demonstrate truncal instability. The midline fastigial nuclei play a role in postural ataxia, whereas globus, embolliform, and dentate nuclei are important for limb ataxia. Injury to the dentate nuclei can lead to dysarthria and mutism in some patients. Examination should look for presence of dysmetria in finger-­to-­nose or heel-­to-­shin testing, and dysdiadochokinesis on testing of rapid alternating movements. Gait and postural stability are important elements of the physical exam for patients with a cerebellar tumor. Hydrocephalus and increased intracranial pressure are some of the most feared presentations and complications of cerebellar tumors, given the potential for rapid evolution of symptoms. This may result from compression and primary obstruction of the aqueduct or fourth ventricular outflow by a mass. It may also result from chemical irritation and nonobstructive hydrocephalus such as by leptomeningeal disease

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in the posterior fossa. Headache and nausea are early harbingers of elevated intracranial pressure, which may be compartmentalized to the posterior fossa. Emesis and lethargy should trigger urgent intervention, either through resection of the offending mass or temporization with an external ventricular drain. 

Imaging Upon presentation with symptoms and signs suggestive of a cerebellar mass, a computed tomography (CT) and/or magnetic resonance imaging (MRI) is typically obtained next. CT scans have the advantage that they can be done rapidly and thus help to determine immediate treatment upon initial presentation of the patient. MRI offers more definitive visualization of the mass in determining differential diagnosis and surgical strategy. Cerebellar tumors can be solid or cystic. Solid masses are frequently isointense to gray matter on T1-­and T2-­weighted images; however, tumors such as pilocytic astrocytomas can appear isointense to cerebrospinal fluid (CSF) on T2.3,4 Highly cellular tumors, such as medulloblastoma, frequently demonstrate restricted diffusion with high signal on diffusion-­weighted imaging and low apparent diffusion coefficient signal.4 Tumors that have abnormal vessels, such as in Lhermitte-­Duclos, or those with evidence of prior hemorrhage, will benefit from susceptibility-­ weighted imaging sequences, which are sensitive to blood.5 Cystic tumors are generally hypointense on T1 and hyperintense on T2 due to the liquid component; fluid-­ attenuation inversion recovery sequences can be helpful in tumors such as hemangioblastomas where the cystic component is different from CSF.4 Tumors with a large percentage of fat-­containing substance, such as in cerebellar liponeurocytomas, can be identified by hyperintense streaks on T1, and fat suppression sequences can aid in their diagnosis.6 The pattern of contrast enhancement after the administration of gadolinium is also useful in narrowing the differential diagnosis. Systemic imaging should be considered for adults with an enhancing cerebellar mass, when clinically appropriate, to evaluate for a primary cancer that metastasized to the cerebellum or drop metastases from the cerebellum to the rest of the neuraxis. 

10 •  Cerebellar Tumors in Adults

Tumor Subtypes HEMANGIOBLASTOMAS Clinical Features Hemangioblastomas are the most common primary tumors of the cerebellum in adults (76%), accounting for 1.5% to 2.5% of intracranial tumors and 7% to 8% of posterior fossa tumors in adults. They can be divided into sporadic tumors, which accounts for approximately 75% of hemangioblastomas, or those associated with von Hippel-­Lindau (VHL) disease (10% to 40%).2 Hemangioblastomas have a slight male predominance in sporadic patients, and female predominance in VHL patients. In sporadic cases, they are more common in the fifth and sixth decades of life, whereas in VHL, patients are usually diagnosed in the second and third decade of life. The most common locations include cerebellum (>70%), brainstem (>20%), fourth ventricle (2%), cerebellopontine angle (2%), and craniocervical junction (2%). Furthermore, 5% of all spinal cord primary neoplasms are hemangioblastomas.2–9 Hemangioblastomas are benign, well-­circumscribed, and highly vascular lesions. MRI features of an enhancing nodule associated with a peritumoral cyst in the cerebellum, with low T1-­ weighted signal and high-­ contrast enhancement, with flow voids on T2-­weighted imaging, raise suspicion for the diagnosis. Morphologically, tumors can be divided into solid (48%), cystic (26%), cystic with mural nodule (21%), and both solid and cystic (5%), with the solid type dominating across both sporadic and VHL subtypes. Multiple lesions are almost exclusively associated with VHL.2–12 

Biology Histologic examination of hemangioblastomas shows an extensive vascular network with neoplastic stromal cells with abundant cytoplasm and lipid vacuoles with a typical clear cell morphology. Markers for vimentin (100%), vascular endothelial growth factor (VEGF; 100%), CD34 (82%), neuron-­specific enolase (93%), S-­100 (81%), and glial fibrillary acidic protein (50%) are frequently immunopositive.7 VHL disease is transmitted in an autosomal dominant manner with an incidence of 1/36,000. It is caused by a mutation in the VHL gene on chromosome 3p25-­26, resulting in loss of function for the VHL tumor suppressor, which serves as a negative regulator of VEGF. Criteria for diagnosis of VHL include positive germline mutation on peripheral blood, family history of VHL disease and VHL-­associated tumor, negative family history with two or more central nervous system (CNS) hemangioblastomas, or one hemangioblastoma and a VHL-­associated tumor. Additional tumors observed in VHL include retinal angiomas, renal cell carcinomas pheochromocytomas, pancreatic tumors, renal and epididymis cysts, and endolymphatic sac tumors. Neurosurgeons should be aware of these associations to ensure adequate multidisciplinary treatment. The current recommendations for patients with newly suspected hemangioblastomas are to perform imaging of the full neuroaxis, ophthalmoscopy, abdominal ultrasound, testing for metanephrines, vanillylmandelic acid (VMA), and auditory screening.2,6–10,12,13 Retinal angiomas are found in 60% of VHL patients and can lead to vision loss if untreated. As such, patients should undergo systematic screening and treatment with effective

105

results in 70% of cases. Renal disease occurs in greater than 60% of patients, with a mean onset of 44 years of age, requiring systematic screening and intervention based on the encountered pathology (e.g., surveillance in renal cysts to partial nephrectomy in renal cell carcinoma). Patients with pheochromocytomas can present with a classic pattern of paroxysmal hypertension, headache, sweating, and tachycardia and are found in up to 10% of VHL patients. These patients require adequate preoperative work-­up to minimize perioperative mortality.2,6–10,12,13 

Treatment Surgical resection is the mainstay of treatment for hemangioblastoma, providing potential cure in sporadic cases.2 Patients have a favorable outcome in more than three-­ quarters of cases, with no significant differences between VHL and sporadic cases. Nevertheless, VHL patients have significant morbidity due to their systemic disease and disease recurrence with growth of additional hemangioblastomas.5 Thus the clinical decision-­making and timing for intervention for VHL patients should take into account the higher likelihood that lesions will become symptomatic with close observation. Tumor/cyst size greater than 69 mm3 or growth greater than 112 mm3 per month are strong predictors of symptomatic progression.14 Radiation therapy may play a role in select cases. Studies suggest improved progression-­free survivals in smaller, solid tumors and with margin doses of greater than 15 Gy.15,16 Follow-­up recommendations for sporadic cases are less well developed but include MRI of the neuroaxis at 6 and 12 months postoperatively. Patients with VHL disease are recommended to undergo annual MRI of the neuroaxis with additional examinations including ophthalmoscopy, abdominal ultrasound, audiometry, and studies for pheochromocytoma. 

Case Report: Hemangioblastoma A 25-­year-­old female presented with positional headaches, associated with nausea, vomiting, and dizziness. Exam revealed dysmetria on finger-­ to-­ nose testing. Imaging revealed an enhancing mural nodule near the torcula (Fig. 10.1A, arrow) within a large cystic lesion (see Fig. 10.1B). Imaging of the neuraxis did not reveal any additional lesions. However, chest, abdomen, and pelvis CT scans revealed multiple pancreatic cysts and kidney lesions, suspicious for VHL. The patient was brought to the operating room for a suboccipital craniotomy. She was positioned prone with the back elevated. A large cystic lesion was encountered and decompressed first to allow for cerebellar relaxation prior to gross total resection of the mural nodule and lesion (see Fig. 10.1C and D). The pathology was consistent with hemangioblastoma. The patient had resolution of her symptoms following surgery and was referred to genetics for evaluation of VHL. 

PILOCYTIC ASTROCYTOMA Clinical Features Pilocytic astrocytoma is a benign astrocytic tumor of the central nervous system classified as World Health Organization

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Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

A

B

C

D

FIGURE 10.1  Hemangioblastoma. (A) T1 magnetic resonance imaging (MRI) with gadolinium shows a hypointense cerebellar lesion with a small enhancing mural nodule (arrow). (B) The lesion is primarily cystic, with minimal fourth ventricular effacement. (C and D) Postoperative T1-­weighted gadolinium-­enhanced MRI demonstrates gross total resection, including resection of the mural nodule.

Treatment

(WHO) grade I.17 The majority of pilocytic astrocytomas appear as a cystic mass with an enhancing mural nodule.18 However, they can also present as solid tumors or a heterogenous admixture of cystic and solid components. More than a third of pilocytic astrocytomas are found in the cerebellum.19 Although the tumor is most common in children aged 0 to 4 and 15 to 19 years old, it can occur in the adult population.20 A population-­based study of 865 patients aged 20 and older who were diagnosed with pilocytic astrocytoma reported that survival rates in the population decreased with increasing age. Symptoms at presentation commonly include headache, nausea, vomiting, nystagmus, vertigo, and cerebellar signs.21 Cerebellar pilocytic astrocytomas have been noted on T2-­weighted MRI images to be isointense to CSF.22 

Surgery with curative intent by gross total resection is the treatment of choice for pilocytic astroctyomas.25 Even though pilocytic astrocytomas are classified as WHO grade I, they can exhibit an aggressive nature in adults. Survival rates for pilocytic astrocytoma are correlated with age, with a 96.5% 60-­month survival in patients aged 5 to 19 years and a 52.9% survival in patients aged 60 and older.20 In a study of 44 adult patients with pilocytic astrocytomas, which included all brain locations, disease progression or tumor recurrence was noted in 30% of patients, with mortality in 18% of patients associated with the disease.21 

Biology

MALIGNANT GLIOMAS Clinical Features

On histology, pilocytic astrocytomas have alternating regions of microcystic, loosely organized cells and compact bipolar cells with eosinophilic Rosenthal fibers.18 Eosinophilic granular bodies are dispersed through both areas. Recent genetic studies have sought to classify the molecular characteristics that distinguish the different grades of astrocytomas. Pilocytic astrocytomas have a duplication at chromosome band 7q34 with a BRAF-­KIAA1549 gene fusion in 70% of cases and lack the IDH1/2 mutation.23,24 

Primary cerebellar glioblastoma represents 1% of all cases of glioblastoma multiforme (GBM).26 In a review of 78 cases of malignant (WHO grade III to IV) cerebellar gliomas, the tumors were slightly more common in the cerebellar hemispheres (59%) compared with the midline vermis (41%).27 Compared with supratentorial glioblastomas, cerebellar glioblastomas are more likely to be associated with neurofibromatosis type I.28 

10 •  Cerebellar Tumors in Adults

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Biology

Biology

Given the relatively rare nature of cerebellar glioblastomas, studies of their molecular properties are largely composed of small case series. Cerebellar gliomas are believed to be largely IDH1 wild type and p53 positive.28–30 The histone H3K27M mutation is observed in approximately 20% of cerebellar high-­grade gliomas, with higher predisposition in the midline tumors.31 

Medulloblastomas have undergone a transformation in classification, amalgamating molecular taxonomy with histologically defined variants, as reflected by the updated 2016 WHO classification of tumors (Table 10.1).13,39 Medulloblastoma is a WHO grade IV tumor with classic, desmoplastic/nodular, large cell/anaplastic, and extensive nodularity histologic classes; most medulloblastomas have a classic histopathology.39 Four molecular subgroups of medulloblastoma also exist and include wingless (WNT)-­activated (10%), sonic hedgehog (SHH)-­ activated (30%), group 3 (25%), and group 4 (35%), with stratification in prognosis and response to therapies across these groups. Epidemiologically, WNT tumors are typically seen in both children and adults, SHH and group 4 tumors have a bimodal distribution of younger than 4 and older than 16 years of age, and group 3 tumors are observed in infants and children.38,43,44 The 2016 WHO classification of tumors has further stratified medulloblastomas into five clinically relevant integrated subgroups: WNT, SHH-­TP53 wild type, SHH-­TP53 mutant, non-­WNT/non-­SHH (groups 3 and 4), and medulloblastoma-­not otherwise specified (see Table 10.1).13,37–40,44–46 The WNT subgroup has activation of the WNT pathway in up to 20% of cases with common mutations in exon 3 of β-­catenin (CTNNB1) (85% to 90%) and chromosome 6 monosomy (70% to 80%). Diagnosis is usually established with somatic mutations in exon 3 of CTNNB1, DNA methylation or gene expression profiling, immunohistochemistry, FISH, or DNA copy number array profiling of monosomy 6. This subgroup frequently invades the lateral recess of the brainstem.3 Patients younger than 16 years of age have excellent prognosis (5-­year overall survival >95%), whereas adult WNT patients are at higher risk. TP53 mutations in WNT tumors is not prognostic unlike in SHH tumors, where it confers a worse prognosis.44,47 The SHH subgroup predominates in children less than 3 years old and in adults and are mostly located in the

Treatment

Surgery and radiation are associated with a longer survival for cerebellar glioblastoma, as is the case for this pathologic entity elsewhere in the brain.32–34 In a study of prognostic factors in adults with cerebellar glioblastoma, cerebellar location was independently associated with poor survival.34 Conflicting results regarding extent of resection for cerebellar tumors in the literature may be attributed to the small cohort size and variations between patient condition at the time of surgery.32 

MEDULLOBLASTOMAS Clinical Features Medulloblastomas account for 1.5% of primary CNS tumors1 but represent up to 20% to 30% of pediatric intracranial tumors. The mean age at presentation is 9 years, with 70% occurring in male children younger than the age of 16 (2:1 male to female ratio).35–40 In adults, medulloblastomas have an incidence of approximately 0.5 per million35,36 and are rarely seen beyond the fifth decade of life, with 80% occurring in patients 21 to 40 years of age. In children, these tumors usually arise from the floor of the fourth ventricle; are well defined, homogeneous, and solid in appearance; and demonstrate marked contrast enhancement on T1-­weighted magnetic resonance (MR) images, without necrosis. In adults, they are frequently less defined, heterogeneous, and cystic in appearance, with variable contrast enhancement, and presence of necrosis.41,42 

Table 10.1  Classification of Medulloblastomas Subgroup

Age

Gender (M:F)

Histology

Molecular Features

WNT

Least common; children, adults Infants, children, adults

1:01

Classic, rarely LCA

WNT pathway activation

1:01

D/N, classic, LCA

SHH pathway activation

Group 3

Infants, children

2:01

Classic, LCA

Group 4

Children > adults > infants

2:01

Vlassic, LCA

Elevated MCY and GABRA5-­ overexpression Lmx1 A expression

SHH

LCA, Large cell anaplastic; SHH, sonic hedgehog; WNT, wingless.

Genetic Alterations

Metastases

Recurrence

CTNNB1 (50%), monosomy 6 (85%), DDX3X (50%), TERT (31%), SMARCA4 (25%), TP53 (12%) Copy number aberrations 9q (35%)/10q (22%)/17q (18%), PTCH1 (25%), TERT (20%, adults), SMO (15%, adults), TP53 (15%, children), SUFU (10%), MYCN (8%), GLI2 (5%) I17q (40%), GFM/lb activation (25%), MYC (15%), S MARC A4 (10%), OTX2 (7%) H7q (70%), 11 p loss (28%), amplifications of CDK6 and MYCN (5%–10%), and SNCAIP duplication (10%), KDM6A (10%)

1 cm in maximal diameter

KPS, Karnofsky performance scale.

who identified three prognostic groups of patients with brain metastases based on a recursive partitioning analysis (RPA) of 1200 patients enrolled in three consecutive Radiation Therapy Oncology Group (RTOG) trials conducted between 1979 and 1993 that were originally designed to evaluate radiation fractionation paradigms and radiation sensitizers.45 The analysis identified three prognostic categories: class I included patients with a KPS score greater than 70, age younger than 65 years, controlled primary cancer, and no extracranial metastases; class III was defined by patients with a KPS score less than 70; and class II included all other patients. These RPA groups correlated with outcome as the median survival times of class I, II, and III patients were 7.1, 4.2, and 2.3 months, respectively. Tendulkar et al. validated the RPA classification in a retrospective study of 271 patients undergoing surgical resection of a single metastasis. The median survival correlated with RPA classification; it was approximately 21 and 9 months for class I and class III participants, respectively.46 Based on this analysis, it has been suggested that class I patients are appropriate candidates for aggressive treatment including surgical resection, whereas class III patients are not. Stratification of individuals by RPA classification has not been adopted in routine clinical use. Regardless, it is frequently used in clinical investigations to design, stratify, and assess treatment results of a clinical trial. An understanding of this classification is important in critically evaluating the current neuro-­oncology literature. Another frequently used prognostic index is the Graded Prognostic Assessment (GPA) score.47 The GPA score was developed from analysis of nearly 2000 patients with cerebral metastases enrolled across four RTOG protocols and is a composite score determined by age, KPS score, number of intracranial lesions, and systemic disease status. 

HISTOLOGIC ASSESSMENT The type of malignancy and its relative sensitivity to radiation are essential considerations in selecting the most appropriate treatment (Table 11.3). In this context, treatment with WBRT or SRS is strongly preferred for individuals with highly radiosensitive tumors, such as lymphoma, multiple myeloma, germ cell tumors, and small cell lung cancer. The most frequently occurring brain metastases, breast and non–small cell lung cancer, exhibit intermediate sensitivity to conventional fractionated radiotherapy, whereas melanoma, renal cell carcinoma, and sarcoma are resistant. For these malignancies, surgical resection or SRS have a central role in management. Although this categorization is useful for conventional fractionated radiotherapy, the same

Data from JG Cairncross, JH Kim, JB Posner. Radiation therapy for brain metastases. Ann Neurol. 1980;7:529–541; and FF Lang, R Sawaya. Surgical management of cerebral metastases. Neurosurg Clin North Am. 1996;7(3):459–484.

does not necessarily hold true for SRS. Radioresistant histologies frequently respond well to radiosurgery. The reason behind this difference in response to WBRT and SRS is not completely understood. Relative to conventional radiation therapy, radiosurgery has been proposed to have enhanced tumoricidal effect through increased DNA damage and injury to the tumor microvasculature and endothelium, as well as enhancing the antitumor immune response.48,49 

Surgical Technique Successful extirpation of cerebral metastases is based on proper neurosurgical techniques in conjunction with technologies assisting with tumor localization and functional brain mapping. A clear understanding of the surgical anatomy of these lesions results in safe and effective tumor removal.

SURGICAL ANATOMY Cerebral metastases consist of solid tumor without intervening brain tissue. Although there may be infiltration of tumor cells into the surrounding brain, this is usually less than 1 to 3 mm.9 Typically, the mass of tumor cells is surrounded by a gliotic capsule separating the tumor from the surrounding edematous parenchyma. Recent surgical and autopsy series have demonstrated that different malignancies exhibit variable tendencies and patterns of infiltration.50,51 In melanoma, malignant cells were frequently seen extending into the surrounding brain through vascular co-­option, whereas renal cell metastases exhibited a dense desmoplastic capsule without infiltration.52 Regardless of histology, lesions typically appear at the gray-­white matter junction, where a reduction in blood vessel caliber in addition to the branching of capillaries causes embolic tumor cells to become trapped.53 Within the cerebral hemispheres, metastases can be classified by their relationship to surrounding sulci and gyri.53,54 Metastases may reside under the cortex and fill a gyrus (subcortical), deep within a gyrus adjacent to a sulcus (subgyral), below a sulcus (subsulcal), deep within the hemispheric white matter (lobar), or within the ventricle (intraventricular).55 In the posterior fossa, cerebellar metastases can be categorized as occurring in either deep or hemispheric locations; hemispheric lesions can be considered as lateral or medial. A subset arises directly within the vermis. Understanding the relationship between the tumor and adjacent sulcus is particularly important because it may determine the appropriate surgical path to the tumor (see the following). Another important aspect of the surgical anatomy is the location of blood vessels. Arterialized veins draining the mass are frequently evident on the cortical surface, and surgeons

11  •  Surgical Management of Cerebral Metastases

must carefully consider the venous drainage when resecting the lesion. More importantly, the arterial supply to most metastases arises from vessels parasitized from branches of larger vessels that arise within the sulci. 

RESECTION METHODS Careful planning and meticulous attention to detail are necessary to minimize surgical complications. The surgeon must devote appropriate attention to each stage of the operative procedure, including positioning, opening, tumor resection, and closure. The technique must result in complete removal of the lesion, with preservation of neurologic function and minimal disruption of the surrounding brain. 

POSITIONING After review of the preoperative imaging and correlation with known anatomic landmarks, it should be possible to identify the approximate location of the tumor as it projects onto the scalp and to tentatively define the incision prior to immobilization of the head and final positioning of the patient. This is a useful exercise not only as confirmation of the image-­guidance system (see the following) and to minimize absolute reliance on such devices but also to aid in proper placement of the head immobilizer and to determine the most appropriate position for the patient. Typically, patients are positioned with the guiding principle that the lesion should be at the top of the operative field. After selection of the most appropriate position for the patient, the head is rigidly fixed in a neurosurgical head-­holder (e.g., the Mayfield 3-­pin clamp) and then secured to the operating table. The tumor location can then be marked out on the scalp using the neuronavigation system, if available. After the location of the tumor has been determined, a final appropriate skin incision is planned. The authors generally prefer linear skin incisions, where possible, because the risk of compromising the vascular supply to the scalp is decreased relative to the use of flaps. To enhance wound healing, the craniotomy should be planned to avoid placement of cranial fixation plates directly beneath the incision at the conclusion of surgery. In addition, preservation of the pericranium should be considered. It is useful in closing dura or repairing defects, cranialization of the frontal sinus, or serving as an additional tissue layer over the cranial fixation system. This patient population is at increased risk of wound complications due to prolonged steroid use, cranial irradiation, and potential reoperation for tumor recurrence. Thus meticulous attention to planning the incision is imperative. 

EXPOSURE AND OPERATIVE APPROACH Standard neurosurgical principles of blood vessel preservation, avoidance of excessive retraction, and minimizing injury to surrounding tissues guide the operation. Frameless stereotaxy is not mandatory but allows for smaller surgical exposures, decreasing the amount of exposed brain, and assists in determining an optimal trajectory or surgical corridor to the tumor. In addition, data from diffusion-tensor imaging (DTI) or functional fMRI (fMRI) is routinely incorporated into the intraoperative neuronavigation, offering an understanding of the relationship between the tumor and vital neurologic structures. A limitation of current image-­guidance systems is the inaccuracy imposed as a consequence of brain shift as cerebrospinal fluid is lost and the

119

surgical resection proceeds. In centers with intraoperative CT or MRI, the imaging and navigation are updated during the procedure as needed. The surgical approach to a metastasis is based on its anatomic location.53 Supratentorial subcortical lesions are best resected by an incision in the apex of the gyrus and circumferential dissection of the tumor (transcortical approach). Removal of a cortical plug above the lesion improves exposure; this may be problematic when the lesion arises within eloquent cortex. In such a situation, a longitudinal incision dictated by local functional mapping performed with direct brain stimulation (see the following) may minimize injury to the surrounding brain. Lesions in subgyral or subsulcal locations are best approached by splitting the sulcus leading to the lesion. Subgyral tumors are removed by making an incision in the side of the split sulcus, whereas subsulcal lesions are entered at the sulcal base (transsulcal approach). Metastases located deep within the white matter, independent of a single sulcus or gyrus (lobar), may be accessed either transcortically or transsulcally. Tumors in the subinsular cortex may be approached by splitting the sylvian fissure. An interhemispheric corridor provides access to midline metastases with additional exposure laterally obtained by splitting or entering a deep gyrus. Resection of intraventricular tumors is achieved effectively through transcortical or transsulcal routes (Fig. 11.1). Cerebellar tumors are approached along the shortest transparenchymal route to the lesion. Superior hemispheric lesions are accessed through the supracerebellar cistern followed by a cerebellar corticotomy at the closest point to the tumor. This requires a high suboccipital craniotomy with exposure of the transverse sinus. Lateral hemispheric lesions are approached directly from a posterior trajectory. Inferior cerebellar tumors require opening of the foramen magnum whereas midline tumors can be resected after splitting the vermis. 

LESION EXTIRPATION Once the lesion is encountered, resection typically proceeds in a circumferential, en bloc manner by dissection along the gliotic pseudocapsule surrounding the lesion. Circumferential dissection is carried out in this gliotic plane without violating the wall of the mass. This technique ensures gross-­ total resection (because tumor cells rarely infiltrate beyond the gliotic plane) and also reduces spillage of cells and seeding of the surrounding tissue. For lesions located directly in eloquent locations (e.g., motor strip or speech centers), a longitudinal incision parallel to the orientation of the gyrus can be made and the tumor debulked in a piecemeal resection, rather than en bloc. Piecemeal removal may also be preferred for large lesions in difficult areas (e.g., within the ventricle). In a retrospective study of 1033 individuals with CNS metastases, Patel et al. analyzed whether surgical complication rates and functional outcomes were associated with surgical methodology.56 Approximately two-­thirds of the tumors were removed in an en bloc resection, with the remaining lesions removed in a piecemeal manner. There was a significantly (P = .007) lower complication rate with en bloc resection (13%) compared with piecemeal (19%). However, when considering tumors in eloquent locations, there was not a significant association between resection

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method and complication rates. The rates of major and minor complications were 13% and 24% for en bloc and piecemeal resections, respectively. The baseline characteristics of the two cohorts were not identical. Tumors that were not resected en bloc were more often symptomatic, larger, and located in eloquent regions. The results were similar even when tumor volume and eloquence were controlled in subset analysis. The authors concluded that an en bloc resection was not associated with an increase in morbidity or mortality relative to internal debulking and should be performed whenever feasible.56 The importance of performing an en bloc resection has been demonstrated in a retrospective study conducted by Suki et al., in which 260 patients with one to two posterior fossa metastases were analyzed based on the type of resection for the development of leptomeningeal disease (LMD; i.e., carcinomatous meningitis).57 Only 6% of 123 patients who underwent en bloc resection developed LMD, whereas 14% of 137 patients who had a piecemeal resection developed LMD. In a related study of 542 patients with supratentorial metastases from the same investigators, similar results were noted.58 Specifically, of 191 patients who underwent piecemeal resection, 9% developed LMD, whereas LMD developed in only 3% of 351 patients who had en bloc resections. These results remain significant even after controlling for other covariates including tumor volume, tumor type, extent of resection, and patient characteristics such as age,

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KPS score, and extracranial disease burden. In both studies, the rates of LMD were comparable between SRS and en bloc resection. Through a separate retrospective analysis of 570 subjects, local recurrence was found to be influenced by tumor volume and an en bloc resection.59 Tumor control was superior with a tumor volume of 9.7 cc or less and when an en bloc resection was completed. Although these findings have yet to be confirmed in a prospective manner, they support efforts to perform an en bloc resection and avoid violation of the tumor capsule. During resection of cerebral metastases, particularly en bloc resections, care must be taken to preserve the main arteries that lie within sulci. Most metastases receive their blood supply from several small branches arising from the main vessel. It is critical to identify these branches and to individually coagulate and cut them. This step reduces bleeding during resection and ensures that the main artery is not damaged. Likewise, particular care should be taken to preserve all surface veins so that the drainage of the normal brain is not disrupted. 

TECHNICAL ISSUES IN RESECTING MULTIPLE METASTASES When resecting multiple brain metastases, special attention must be given to planning the operation. Resection of multiple metastases can be performed via one craniotomy that encompasses all the lesions or via multiple, separate

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FIGURE 11.1  Intraventricular metastatic renal cell carcinoma. Preoperative axial (A) and sagittal contrast-­enhanced (B) magnetic resonance images showing a metastasis in the atrium of the left lateral ventricle. The lesion was completely resected using a transcortical approach through the superior parietal lobule (C and D). (From Vecil GG, Lang FF. Surgical resection of metastatic intraventricular tumors. Neurosurg Clin North Am. 2003;14(4):593–606.)

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11  •  Surgical Management of Cerebral Metastases

FIGURE 11.2  Occipital lobe metastasis. The contrast-­enhanced magnetic resonance image (A) and the intraoperative ultrasound image (B) are shown. The central hypodensity on the ultrasound image represents necrosis within the tumor.

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craniotomies. The decision to perform multiple craniotomies is determined by the proximity of the lesions to each other: lesions that are some distance apart generally require separate craniotomies. When multiple craniotomies are required, it is usually possible to perform all the craniotomies simultaneously without having to re-­drape the patient. The patient may be placed in a neutral position and turned from side to side on the operating table so that the lesion that is being operated on is positioned at the top of the operative field. Linear skin incisions are particularly effective when performing multiple craniotomies, and they also reduce the risk of compromising the vascular supply to the scalp. To maximize efficiency, each step of the operation (i.e., skin incision, bone flap elevation, dural opening, tumor removal, hemostasis, and closure) is performed at each location before the next step is performed. This approach is preferred over removing one lesion at one site and closing that wound and then removing one lesion at another site, not only because it is more efficient but also because it minimizes the time between hemostasis and patient awakening. Thus any untoward events (e.g., hematoma formation) do not go undetected while the patient is under anesthesia. 

therefore changes in the tumor, as well as brain shift, are readily identifiable as the resection proceeds. Ultrasound also allows for visualization of the adjacent sulci and other intracranial landmarks (e.g., the ventricle), thus assisting in selection of a corridor to approach the tumor. Ultrasound can aid in the determination of the extent of tumor resection because gross-­ total resection corresponds to complete removal of the echogenic mass. However, in cases of recurrent tumors after radiotherapy, radiation necrosis may obscure the boundaries of the lesion, making determination of the extent of resection more difficult.66 

STEREOTAXIS Advances in localization technology have allowed for the evolution of rigid frame-­based stereotaxy into frameless systems. These image-­guidance systems allow neurosurgeons to navigate the brain based on the preoperative images. These systems are particularly useful for planning the skin incision and craniotomy and the initial trajectory to the lesion. However, they suffer from the inability to compensate for intraoperative changes such as brain shift unless they can be updated with intraoperative imaging (usually MR images or even ultrasonography).67 Thus, the authors generally rely on ultrasound as the resection proceeds. 

SURGICAL ADJUNCTS The safe and effective resection of cerebral metastases requires accurate identification of the location of each lesion and the surgical corridor through which it can be resected. The ability to identify the lesion is enhanced by the use of computer-­ assisted image-­ guided stereotaxis, intraoperative ultrasonography, tumor fluorescence,60–65 and intraoperative MRI. Other useful adjuncts include somatosensory evoked potentials (SSEPs) and intraoperative direct brain stimulation, both of which allow for identification of functional (eloquent) brain regions. 

INTRAOPERATIVE MAGNETIC RESONANCE IMAGING The inability of neuronavigation systems to track intraoperative changes in real time has led to the development of intraoperative MRI. Surgery may be performed within the bore of the MRI unit itself or outside of it, necessitating that the patient be moved into the unit or that the unit be transported to the patient. The main functions of these systems are to update the image-­guidance system during the operation, to confirm the extent of tumor resection, and to rule out intracranial complications prior to exiting the operating room. The cost of current systems and needed infrastructure has precluded widespread application of intraoperative MRI, particularly for well-­demarcated lesions such as brain metastases. 

ULTRASOUND Intraoperative ultrasound is a valuable adjunct available to the surgeon, which provides a relatively low-­cost method for visualizing tumors below the surface of the brain. Most brain metastases appear homogeneously hyperechogenic, although those with necrotic centers or cysts may be hypoechoic centrally (Fig. 11.2). Compared with other methods of localization, ultrasound has the advantage of real-­time imaging;

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FUNCTIONAL MAPPING For resection of metastases within or near eloquent structures, functional mapping is vital to safe tumor resection. Preoperative identification of sensory, motor, and language

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cortices is assisted by fMRI, navigated transcranial magnetic stimulation, or magnetoencephalography;68,69 and DTI allows for identification of white matter tracts (e.g., corticospinal).70 However, these preoperative studies are only a general guide, and precise localization of function usually requires verification during the surgical resection. Consequently, functional mapping methods have been used to precisely define eloquent brain regions intraoperatively. Neurophysiologic techniques, such as SSEP, can be used to identify the reversal of phase that occurs between the motor and sensory cortices. A strip electrode is placed on the cortical surface, and stimulation of median, ulnar, or posterior tibial nerves results in cortical potentials that are detected by the electrodes. A reversal of phase is seen when the electrode covers both the motor and the sensory cortex, because the motor potentials are typically positive and sensory potentials negative. This permits indirect identification of motor and sensory cortices intraoperatively. The technique has also been used to continuously monitor the potentials throughout the operative procedure guiding resections adjacent to the primary somatosensory cortex.71 Direct cortical electrical stimulation can be used to identify eloquent cortex and is particularly useful in the localization of language areas. The technique involves stimulation of the cerebral cortex at a frequency of 60 Hz for 1 ms with biphasic square wave pulses and a current of 1 to 15 mA

FIGURE 11.3 Intraoperative photographs depicting removal of a metastasis from the motor area of the brain. (A) The brain prior to resection demonstrating slightly clouded leptomeninges along with an enlarged gyrus. (B) A bipolar cortical stimulator was used to electrically stimulate the cerebral cortex, and a motor response was elicited. (C) The cortical stimulation resulted in hand movement in the area marked by the white label (Hst). The white arrowhead marks a sulcus overlying the tumor. (D) The tumor has been completely resected and all vascular structures preserved using a transsulcal approach through the sulcus identified in C. The patient experienced no permanent alteration of neurologic function.

(Fig. 11.3).72–74 Stimulation of the motor cortex elicits a motor response in the patient, thus resulting in an objective response, which is an advantage over the SSEP technique. Stimulation of subcortical motor pathways can also be performed in a similar manner; however, the results are somewhat less reliable than with cortical stimulation.75 Although motor mapping can be performed with patients under general anesthesia, language mapping requires an awake patient. The authors’ current method of awake craniotomy uses intubation with a laryngeal mask and brief duration of anesthetics, along with a local anesthetic supraselective scalp block prior to placement of the three-­point head fixator.76 The muscle (if exposed) and dura are infiltrated with local anesthetic. Once the craniotomy is completed, the patient is awakened, and the laryngeal mask is removed. Cortical stimulation with mapping of speech may then commence. Speech areas are usually defined as sites where electrical stimulation elicits speech arrest. In addition, patients can continue to converse during the resection of the tumor, to avoid loss of function as the resection proceeds. Once the resection is completed, the laryngeal mask may be replaced and the patient anesthetized, if required; or a short-­ acting sedative, along with a narcotic, may be given during the closure. This awake method allows for the safe removal of the tumor from eloquent brain and provides the patient with maximal comfort. 

11  •  Surgical Management of Cerebral Metastases

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Table 11.4  Results of Surgical Resection of Single Brain Metastases, Including Mortality and Morbidity SURVIVAL Study

No.

Histology

WBRT

Mortality

Ferrara et al. Patchell et al. (1990)14 Bindal et al. (1993)30 Vecht et al. (1993)22

100 25 26 32

Mixed Mixed Mixed Mixed

71% 100% 54% 100%

6% 4% 0% 9%

Wronski et al. (1995)143 Bindal et al. (1996)81 Pieper et al. (1997)144 Muacevic et al. (1999)100 Wronski et al. (1999)145 Schoggl et al. (2000)146 O’Neill et al. (2003)102

231 62 63 52 73 66 74

Lung Mixed Breast Mixed Colon Mixed Mixed

84% 66% 86% 100% 43.8% 100% 82%

3% 0% 5% 1.6% 4% 0% N/A

Paek et al. (2005)32

132

Mixed

19%

N/A

Overall

936

71%

3%

(1990)83

Morbidity N/A 8% 8% (0% neuro) 41% total 13% (major) 17% (neuro) 5% N/A 7.7% N/A 4.5% 13.5% (neuro) 9.5% (systemic) 5.3% (neuro) 9.1% (non-­neuro) 15%

Median (Months)

1 Year

13 10 14 10

N/A 45% 50% 41%

11 16.4 16 17 8.3 9 N/A

46% 58% 62% 53% 31.5% 83% 62%

8

N/A

11.5

53%

WBRT, Whole-­brain radiation therapy.

Outcomes After Surgical Resection SURGICAL MORTALITY Mortality is typically defined as death occurring within 30 days of surgery, although some surgeons have used shorter intervals.77–79 Other series include deaths after 30 days if the patient was not discharged from the hospital.42,80 Surgical mortality has decreased dramatically since the first reports. For example, Cushing found that the mortality after resection of brain metastases was quite high (38%).76 In contrast, modern series report surgical mortalities of 3% or less (Table 11.4). In fact, some of the more recent series report no mortality after surgery for brain metastases.41,66,81,82 In the randomized trial of Patchell and colleagues,14 the 30-­day operative mortality and the 30-­day postradiotherapy mortality were both 4%. In a comprehensive analysis of 400 craniotomies for all types of brain tumors, the overall 30-­day mortality for patients with cerebral metastases was 2% (4/194), with the cause of death being sepsis in two individuals and progressive leptomeningeal carcinomatosis in two others.33 A more recent surgical series including 1033 patients with cerebral metastases reported a 3% 30-­day mortality rate.56 

SURGICAL MORBIDITY Postoperative morbidity following resection of cerebral metastases includes neurologic and nonneurologic events (e.g., postoperative hematoma, wound infection, deep venous thrombosis, pneumonia, and pulmonary embolism). Some studies separate these two aspects of morbidity,30,32,41,43,56 others consider them together,14,22,28 a few report only neurologic morbidity,44,77,83–85 and many do not report morbidity at all (see Table 11.4).29,42,78,79,86,87 One of the most comprehensive analyses of postoperative complications for brain metastases was conducted by Sawaya and colleagues.33 This series from a large tertiary cancer center reviewed the complications that occurred after 194 craniotomies for brain metastases performed using all the modern technologies described previously.

Importantly, complications were categorized as either neurologic (directly producing neurologic compromise), regional (at the surgical site), or systemic (more generalized medical problems). Complications were considered to be minor (not life threatening and not prolonging the length of the hospital stay) when they resolved within 30 days without surgical intervention. They were considered to be major when they persisted for more than 30 days (reducing the quality of life) or required aggressive treatment because of their life-­threatening nature. The rates of major neurologic, regional, and systemic complications were 6%, 3%, and 6%, respectively. In a critical analysis of factors contributing to complications, the authors reported that the most important variable affecting the frequency of neurologic complications was the relationship of the tumor to functional (eloquent) brain. Specifically, tumors located within or near eloquent brain had more neurologic complications than did those in noneloquent areas. Nevertheless, the risk of major neurologic complications, even when the lesion was within eloquent areas, was low (13%). Based on their extensive data, the authors used a statistical model to predict the risk of major complications from any source. They found that patients who were relatively young (age 40 years), with a KPS score of 100 and a metastasis in noneloquent brain, had a 5% risk of a major complication, whereas, at the opposite extreme, for a relatively old patient (age 65 years) with a low KPS score (of 50) and a tumor in eloquent brain, this risk rose to 23%. As discussed, en bloc resections of metastases in eloquent and noneloquent locations were not associated with increased operative morbidity or mortality.56 

RECURRENCE Tumor recurrence is usually notable following resection because surgery typically removes the entire gadolinium contrast-­enhancing tumor mass (as visualized by MRI) and causes regression of the secondary brain edema.

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Table 11.5  Local and Distant Recurrence Following Resection of Single Brain Metastasis Study

No. (1990)14

Local Recurrence

Distant Recurrence

Both

Latency (Median) 15 months (l) 25% at 6 months N/A N/A 15 months N/A 3.6 months 3.9 months (l) 3.7 months (d) N/A 11.1 months (l) 8.7 months (d) 9.7 months

Patchell et al. Bindal et al. (1993)30 Wronski et al. (1995)143 Bindal et al. (1996)81 Pieper et al. (1997)144 Muacevic et al. (1999)100 Wronski et al. (1999)145 Schoggl et al. (2000)90

25 26 231 62 63 52 73 66

20% 16% 23.8% 13% 17% 25% at 1 year 49.3% 16.7%

20% 27% 36.6% 26% 16% 10% at 1 year Overall 15.2%

12% 8% 3% 5% N/A N/A

O’Neill et al. (2003)102 McPherson et al. (2010)119

74 358

18% 19%

18% 44%

5.4% N/A

1030

22%

26%

5%

Overall

N/A

d, Distant; l, local; N/A, not applicable.

Thus reappearance of a contrast-­ enhancing mass and edema on an MRI scan is usually striking and represents recurrent tumor, although minimal postoperative contrast enhancement may be present for up to 3 months after surgery. In addition, one must distinguish between recurrence at the surgical site (i.e., local recurrence), treatment effect such as radiation necrosis, and the development of new lesions in the brain at sites outside the initial resection site (i.e., distant recurrence). These events represent distinct biologic processes. Local recurrence represents regrowth of microscopic residual disease after surgery, whereas distant recurrence is believed to arise from hematogenous dissemination of tumor cells to the brain from the primary site. When evaluating rates of local and distant tumor recurrence, it is important to know whether the patient received adjuvant radiation therapy. In the study by Patchell and colleagues of patients with single brain metastases who were then randomized either to receive or not to receive WBRT after surgery,88 the local recurrence rate after surgery alone was 46% (21 of 46 patients), whereas the distant recurrence rate was 37% (17 of 46 patients). Other studies have reported rates of local recurrence as low as 10% to 15%59,89 and up to 60% at 2 years.90,91 Table 11.5 lists the local and distant recurrence rates in noteworthy surgical series of brain metastases. 

SURVIVAL Most series from the modern neurosurgical era that include metastases of differing histology indicate a median patient survival time of 11 months and a 1-­year survival rate of 53% (see Table 11.4). Kelly and colleagues53 reported a 1-­year survival rate of 63% using computer-­assisted stereotactic craniotomy. Studies from a large tertiary cancer center reported a median survival time of 14 months, with a 1-­year survival rate of 50% for patients with single brain metastases.30,41 Similar median (14 months) and 1-­ year (55%) survival values were observed in patients with multiple metastases in whom all the lesions were removed. 30 In most studies, variables associated with poor survival are the presence of multiple metastases, extensive and progressive systemic cancer, and a poor KPS score. 

Stereotactic Radiosurgery SRS delivers large and highly conformal doses of radiation to a precise target from a Cobalt-­60 source (Gamma Knife) or linear accelerator (LINAC). Typically, the radiation is imparted as a single fraction, or less commonly in several fractions as hypofractionated SRS. Regardless, larger doses of radiation are administered per fraction, and in far fewer sessions, than conventional WBRT. There is a rapid fall-­off of radiation into the surrounding tissues allowing for focused destruction of a lesion localized stereotactically. A significant advantage of radiosurgery over surgical resection is that inaccessible or eloquent tumors may be treated with minimal morbidity. Previously, tumors considered unresectable would have been treated by WBRT. Radiosurgery is now an option to treat such lesions, avoiding the neurocognitive sequelae of WBRT and offering increased efficacy over conventional radiation for radioresistant histologies such as melanoma, renal cell carcinoma, or sarcoma. Additional benefits of SRS compared with surgery include lower cost, being noninvasive, shorter hospital stays, and being offered to individuals unable to tolerate surgery. Most systems require rigid fixation of a stereotactic frame; however, some institutions are able to offer frameless SRS. Based on retrospective reports, SRS is effective in treating cerebral metastases, with local control rates ranging from 80% to 95% and median survival times of 7 to 13 months.92–103 These results compare favorably with local recurrence rates as low as 10% to 25% reported after surgical resection.59,86,87,89 Nevertheless, radiosurgery has several important limitations compared with surgery. First, due to dose limitations, treatment is restricted to small lesions, usually not exceeding 3 cm in maximum diameter (volume 2 mg weekly). Quinagolide is a non-­ ergot dopamine agonist and is not associated with an increased risk of cardiac valve abnormalities.

Therapeutic Efficacy Bromocriptine is 75% to 80% effective at normalizing PRL levels and shrinking tumor mass for microprolactinomas, whereas the success rate is around 70% for macroprolactinomas.2,11,12 The improvement in headaches and visual field defects (mass effect of the pituitary tumor) is rapid and dramatic in most patients, occurring within a few days after the first dose. These changes often precede radiographic evidence of tumor shrinkage. Likewise, gonadal and sexual function may improve even before complete normalization of serum PRL levels, although sometimes normalization of testosterone may require several months of normal PRL levels.2 The degree of tumor shrinkage seen with bromocriptine does not necessarily correlate with the nadir PRL level or the extent of decline in PRL levels.2 Although most prolactinomas remain responsive to bromocriptine over time, the drug is generally not curative, as hyperprolactinemia and tumor growth will often recur after withdrawal of therapy. Prolonged use of bromocriptine has been associated with perivascular fibrosis and increased tumor consistency in prolactinomas that ultimately are surgically removed; the extent of fibrosis seems to correlate with the duration of presurgical treatment with bromocriptine and may affect the technical ease of surgical resection.13,14 Early studies found cabergoline to be 80% to 95% effective at normalizing PRL levels, with varying degrees of tumor reduction seen in 70% to 90% of patients.15,16 Although there is considerable variability among studies with respect to tumor shrinkage, a large study showed a significant (>50%) tumor shrinkage in 80% of patients, and complete disappearance of the tumor mass in 57% of patients.17 Cabergoline is able to induce tumor shrinkage

more effectively in DA naïve patients compared with those who have received prior DA treatment. Furthermore, cabergoline offers the potential for cure after several years of treatment, allowing for withdrawal of therapy.18,19 The beneficial effects of cabergoline on gonadal function are well documented in both sexes. Compared with bromocriptine, cabergoline is more effective at normalizing PRL levels and restoring ovulation and is associated with fewer, milder, and shorter-­lived side effects.11 Serum testosterone levels have been shown to normalize in the majority of male patients, with concurrent improvement in sperm count and parameters.20 Quinagolide normalized PRL levels in 70% to 100% of patients with microadenomas and 65% to 88% of patients with macroadenomas.10,21 Significant tumor reduction was seen in 22% to 55% of patients with microadenomas and 25% to 75% of patients with macroadenomas.10,21 

Tolerability and Side Effects The most common side effects of DA include gastrointestinal, cardiovascular, and neurologic symptoms (see Table 14.1). In general, if a patient cannot tolerate the first DA administered, a trial of a second drug should be given. Among the DA, bromocriptine is the least well-­tolerated, with up to 12% of patients being unable to tolerate therapeutic doses.2 Up to one-third of patients will experience nausea and vomiting, an effect that can be minimized by initiating a low dose and uptitrating very slowly.2 Taking the medication with a small snack may also reduce these symptoms.2 A gradual dose titration and taking the medication at bedtime may also help reduce postural hypotension and dizziness experienced by as many as 25% of patients.2

14  •  Medical Management of Hormone-Secreting Pituitary Tumors

Syncope is rare but has been reported even with small initial doses.22 Tolerance to postural hypotension usually develops rapidly.22 Drowsiness, headache, and nasal congestion are common complaints as well. The safety of bromocriptine in psychiatric patients has not yet been established; there are case reports of onset or exacerbation of preexisting psychosis. Other psychiatric symptoms associated with high doses of bromocriptine include anxiety, depression, insomnia, paranoia, and hyperactivity.22 At higher doses used in the treatment of Parkinson disease, reversible pleuro-­pulmonary changes and retroperitoneal fibrosis have been reported, but these changes are unlikely to occur at the doses used to treat prolactinomas.2 While cabergoline and bromocriptine have similar side effect profiles, cabergoline has been shown to be better tolerated in several large comparative studies.17,23 Compared with bromocriptine, the side effects of cabergoline are generally less frequent, milder, and of shorter duration.2 Nausea and vomiting are most commonly observed, followed by headache and dizziness.2 In a multicenter randomized trial of hyperprolactinemic women, 3% could not tolerate cabergoline compared with 12% who had to stop taking bromocriptine.11 It has been proposed that fluctuations in concentrations of DA are the main cause of side effects; cabergoline would be better tolerated due to its long half-­life and relatively steady plasma concentration.22 Quinagolide has also shown better tolerability compared with bromocriptine. In a double-­blind comparative study of 47 hyperprolactinemic patients, quinagolide was tolerated by 90% of patients versus 75% of patients treated with bromocriptine.24 As with the other DA, the most frequent side effects include nausea, vomiting, headache, and dizziness. These effects are transient and occur within the first few days of starting therapy or during dose adjustments.22 

Dopamine Agonists and Valvular Heart Disease The safety of DA has been brought into question after two large population-­based studies showed an increased risk of cardiac valvular disease in Parkinson disease patients being treated with high doses of these drugs, and particularly cabergoline and pergolide.25,26 It is now recognized that one of the off-­target effects of ergot-­derived DA is activation of the serotonin (5-­HT) receptor, of which there are seven distinct subtypes.27 High concentrations of the subtype 5-­HT2B receptor are found on cardiac valves and the pulmonary arteries.27 Both pergolide and cabergoline have been implicated in the development of cardiac valvular fibrosis because of their agonist effects at the 5-­ HT2B receptor.27 Bromocriptine, which is only a partial agonist at the 5-­HT2B receptor, had not been thought to pose an increased risk of cardiac valvular disease.27 However, some authors have questioned this and suggested that bromocriptine may, in fact, be equally associated with the development of cardiac valvulopathy at high cumulative doses.28,29 Several studies have examined the effect of cabergoline on cardiac valvular disease in patients with prolactinomas.30 These patients typically receive much lower doses (10 to 20 times less) than in Parkinson disease. One study reported an increased risk of moderate tricuspid regurgitation in patients who had received cumulative cabergoline doses greater than 280 mg.31 However, in another study, patients receiving cabergoline (0.25 to 4 mg/week) for 3 to 4 years (mean

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cumulative dose of 311 mg) had no increased prevalence of clinically significant valvular heart disease.32 Even in patients treated with cabergoline for 8 years who received cumulative doses as high as 1728 mg, there was no increased risk of clinically relevant heart disease.33 Other reports suggest that treatment with cabergoline in prolactinomas may correlate with the development of subclinical cardiac valvular disease,34 although a recent meta-­analysis on the use of DA in patients with hormone-­ secreting pituitary tumors (prolactinomas, acromegaly, and CD) did not confirm this association.35 In conclusion, conventional doses of cabergoline and bromocriptine used in prolactinomas may be associated to a slightly increased prevalence of clinically insignificant cardiac valve fibrosis and insufficiency.34,36-­38 However, it may be prudent to monitor patients requiring higher doses of ergot-­derived dopamine agonists with serial echocardiograms (e.g., cabergoline > 2 to 3 mg/week, or bromocriptine > 10 mg/daily).31 If valvulopathy develops, it may be reasonable to switch to quinagolide, which is non-­ergot derived and has low affinity for the 5-­HT2BR. If quinagolide is not available, a reasonable option would be to switch from cabergoline to bromocriptine, which has a lower affinity for the 5-­HT2B receptor. Alternatively, surgical resection may be appropriate. This issue underscores the importance of using the smallest effective dose and attempting withdrawal from cabergoline treatment in patients who achieve normalization of PRL levels and significant tumor shrinkage to minimize their cumulative lifetime exposure to the drug.30 

Dopamine Agonist Resistance A subset of patients with PRL-­secreting pituitary tumors demonstrate “biochemical” resistance (failure to normalize PRL levels) or “mass” resistance (absence of tumor shrinkage) to DA.2 Resistance to DA occurs in both micro-­and macroadenomas and is believed to be mediated by the down-­ regulation of pituitary D2 receptors.39 Biochemical resistance has been estimated to occur in approximately 10% to 20% of patients on DA. Mass resistance has been estimated to occur in approximately 30% to 40% and 15% of patients taking bromocriptine and cabergoline, respectively.2,39 The prevalence of resistance to quinagolide is unclear given the lack of data regarding its use in DA-­naïve patients.7 Most tumors resistant to bromocriptine will respond to cabergoline. When switched to cabergoline, 85% of patients resistant to bromocriptine and quinagolide achieved normal PRL levels, and 70% had some change in tumor size.40 A large study showed that cabergoline normalized PRL levels in 61% and 50% of bromocriptine-­resistant microprolactinomas and macroprolactinomas, respectively.17 Therapeutic options in the management of DA-­resistant prolactinomas include (1) increasing the dose of the DA, (2) switching to an alternative DA, (3) trans-­ sphenoidal surgery, and (4) radiation therapy (RT). In most cases, the resistance to DA is partial, and a response can be achieved by progressively increasing the dose of the medication. A study showed that in more than 95% of patients resistant to bromocriptine PRL normalized with individualized high-­ dose cabergoline treatment (mean dose 5.2 mg/week).9 Bromocriptine-­ resistant patients generally require higher doses of cabergoline and have less tumor shrinkage compared to treatment-­naïve patients.41 In general, switching from cabergoline to bromocriptine is unlikely to be effective.

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While trans-­sphenoidal surgery is almost never a first-­line treatment for macroprolactinomas (see below), it remains an important option for patients who cannot tolerate DA or when medical therapy is ineffective at controlling symptoms or restoring reproductive function. There is little long-­term outcome data regarding patients with macroprolactinomas treated with DA who subsequently proceed to surgery. In a study of 72 patients, 35% of subjects required trans-­ sphenoidal surgery due to resistance and/or intolerance to DA.42 This study, which is an outlier given the disproportionately high number of DA-­resistant patients, showed that additional tumor shrinkage was achieved in 57% of operated patients, while only 22% were able to attain normoprolactinemia without DA following surgery. Surgery was associated with a high incidence of hypopituitarism regardless of whether patients received subsequent RT.42 The remission rate for surgery when used as second-­ line treatment for macroprolactinomas is quite low (around 20%). Surgery often plays only a “debulking” role, and therefore should be reserved for patients who, despite maximal medical therapy, have progressive tumor enlargement and are at risk of visual compromise or neurological deficits. Conventional fractionated RT should be considered a last-­line option in the management of DA-­resistant prolactinomas given the delayed treatment effects and the high rate of hypopituitarism. 

Dopamine Agonist Withdrawal The optimal duration of therapy for patients with prolactinomas is uncertain. Until recently, DA treatment had been considered a “lifelong” requirement. However, after a landmark study by Colao et al. demonstrated disease remission in a considerable proportion of patients following withdrawal from cabergoline, attention shifted toward defining selection criteria for withdrawal and identifying predictors of long-­term remission.18,43 Defining the optimal timing and appropriate candidates for withdrawal is difficult because of the heterogeneity of studies that have examined this issue, which differ with respect to the causes of hyperprolactinemia (idiopathic vs. micro/macroprolactinoma), the type and duration of DA treatment, and the treatment prior to the start of DA therapy.44 Despite the inherent difficulty in extrapolating from these disparate studies, criteria for withdrawal include (1) normoprolactinemia and (2) tumor absence or markedly reduced tumor volume after a minimum of 2 years of DA treatment.16 A study tested the applicability of these criteria and found a recurrence rate of 54% after withdrawal of long-­term cabergoline treatment.19 In this study, most patients had recurrence of disease within 1 year of discontinuation, and a similar recurrence rate (52% vs. 55%) was seen in patients with microprolactinomas and macroprolactinomas. The size of the tumor remnant prior to withdrawal appears to be predictive of recurrence risk.19 A meta-­analysis showed that long-­term remission occurs in only 21% of patients following DA withdrawal.44 A retrospective analysis of 213 patients with prolactinomas evaluated which factors predict a satisfactory response to DA treatment and the recurrence rate after discontinuing DA using the above criteria.44a Thirty-seven percent of patients were able to discontinue DA treatment; those with smaller tumor diameter, no extrasellar extension, and rapid reduction of PRL levels after initiating DAs were more

likely to achieve withdrawal. However, hyperprolactinemia recurred in 75% of cases, with most cases recurring within 5 years. Patients who did not have cavernous sinus invasion at presentation and those with more pronounced PRL reduction immediately after starting DA were more likely to maintain long-term remission.44a These results emphasize that recurrence of hyperprolactinemia is common after discontinuing DA and patients with prolactinomas require long-term follow-up. Moreover, patients who are likely to need life-long DA treatment could be identified soon after diagnosis. This could allow for tailored management, e.g. considering surgery early in the management of patients with DA-related cardiac abnormalities, psychiatric symptoms, and behavioral changes.  The best chance for a long-­term remission is seen in patients treated with cabergoline for more than 2 years, whereas remission is seen in only 20% of patients withdrawn from bromocriptine.44 Considering the financial burden, occasional problems with tolerability, and potential risk of valvulopathy with long-­term DA treatment, it is reasonable to attempt withdrawal in patients who have been on a DA (particularly if cabergoline) for 2 years or more. Kwancharoen et al.45 tried to stop cabergoline a second time in a patient who previously failed withdrawal. In those who received an additional 2-­year course of low-­dose cabergoline (≤1 mg/week), persistent normoprolactinemia was observed in 35% of patients after withholding the medication.45 

Surgery as a First-­Line Option in Microprolactinomas Medical treatment with DA is the mainstay in the primary management of macroprolactinomas and symptomatic microprolactinomas. However, surgery may be considered as a first-­line treatment in selected patients, including: 1. Patients taking antipsychotic medications: DA can cause exacerbation of the preexisting psychosis, and if the medical treatment is started the patient has to be followed up closely by the psychiatry service as well; 2. Women with large macroprolactinomas wishing to become pregnant. In fact, these patients (even if they are likely to respond to DA) would have to withhold medical treatment after conception and the adenoma may increase in size during pregnancy; 3. Patients with symptomatic hyperprolactinemia not willing to receive long-­term medical treatment. The latter scenario is gaining increasing attention in recent years, especially in terms of surgical approach to symptomatic microprolactinomas in patients with a long life expectancy. In fact, while macroprolactinomas are rarely surgically curable, trans-­sphenoidal surgery can provide a safe, effective, and definitive cure in patients with microprolactinomas. On balance, successful surgery can avoid long-­term medical treatment with DA, which are potentially associated with adverse events, albeit very rare. Trans-­sphenoidal surgery for microprolactinomas leads to normal PRL in 71% to 100% of patients, with low rates of postoperative hypogonadism and permanent diabetes insipidus (0% to 6%) and minor neurosurgical complications (0% to 2%).46 The long-­term recurrence of hyperprolactinemia in patients with normal postoperative PRL is around 10%.47 A recent cost analysis suggested that surgery may be a more cost-­effective treatment for prolactinomas than medical management, although the cost difference was not impressive.48

14  •  Medical Management of Hormone-Secreting Pituitary Tumors

In conclusion, initial surgery can be an option in selected patients. The risks and benefits of surgery should be discussed extensively with the patient, provided that an experienced neurosurgeon is available.46,47 

TEMOZOLOMIDE Temozolomide is an alkylating agent used for several high-­ grade brain tumors. It has been proven to be effective in improving residual disease control in patients with locally aggressive or malignant prolactinomas and other aggressive pituitary tumors.49-­52 This drug should be administered with the supervision of an expert neuro-­oncologist. 

MANAGEMENT OF PROLACTINOMAS DURING PREGNANCY Two principal considerations arise in the management of women with prolactinomas who either desire fertility or become pregnant: (1) the risk of tumor growth due to physiologic stimulation of tumoral lactotrophs induced by pregnancy, and (2) the effects of DA on fetal development. These two considerations should be weighed against each other on an individualized basis, taking into account the initial size of the pituitary tumor, response to DA treatment, and the patient’s ability to tolerate side effects of treatment. It has been estimated that the risk for significant tumor enlargement during pregnancy is 1.6% to 5.5% in microprolactinomas and 10% to 36% in macroprolactinomas.7,22,52a Due to the low risk of tumor growth (especially in patients with microprolactinomas), discontinuation of dopaminergic therapy is generally recommended at the time of diagnosis of pregnancy. PRL does not need to be measured during pregnancy, as it is expected to rise physiologically. Similarly, routine MRI during pregnancy is not recommended.16 On the other hand, close clinical follow up should be arranged during pregnancy (every 3 months, or even earlier for larger macroadenomas). Clinicians should assess signs and symptoms consistent with pituitary tumor enlargement (visual disturbances, unremittent headache) and instruct the patient to report if any symptoms arise in between the visits. Visual fields should be arranged at baseline and every 3 months for large adenomas abutting the optic chiasm or in those patients complaining of visual disturbances. If the patient develops abnormal visual fields and/or severe headache, a pituitary MRI should be arranged. DA should be resumed and titrated up rapidly if there is MRI evidence of significant tumor growth. If DA treatment is necessary, we advise restarting the same medication that was prescribed prior to conception. For patients with macroadenomas, especially those in close proximity to the optic chiasm or cavernous sinuses, contraception should be encouraged while attempting to reduce the size of the tumor prior to pregnancy. If a patient with a macroprolactinoma becomes pregnant, there are several different therapeutic approaches that can be offered: (1) DA may be stopped after conception with neuro-­ ophthalmological exams performed throughout pregnancy, (2) DA may be continued throughout pregnancy, (3) trans-­ sphenoidal surgery may be performed in later stages of pregnancy if the enlarged tumor does not respond to resumption of DA, or (4) delivery if tumor growth cannot be controlled and the pregnancy is advanced enough.2 Bromocriptine has conventionally been the drug of choice in women with prolactinomas who desire fertility

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or who become pregnant. There is substantial evidence showing that exposure to bromocriptine at the time of conception does not cause birth defects or increase the risk of spontaneous abortions, ectopic pregnancies, trophoblastic disease, or multiple pregnancies.53 However, evidence is also accumulating to show that cabergoline may have an equally good safety record in terms of pregnancy outcomes. A 12-­year prospective study of cabergoline use in 329 pregnancies showed no increased risk of miscarriage or fetal malformation.54 Breastfeeding does not seem to increase the risk of growth of prolactinomas.55 Therefore, if the tumor size remained stable during pregnancy and the patient did not experience visual disturbances, women can breastfeed, and DA can be withheld up to the end of breastfeeding. Finally, it is interesting to note that many women have spontaneous remission of hyperprolactinemia after delivery.56,57 Therefore, PRL levels should be re-­checked 2 to 3 months after delivery or cessation of lactation before restarting DA. 

Growth Hormone-­Secreting Pituitary Tumors (Acromegaly) GENERAL CONSIDERATIONS The treatment algorithm for acromegaly due to a GH-­ secreting pituitary tumor is reported in Fig. 14.2. The overall aim of the management of acromegaly is to (1) achieve control of GH hypersecretion and normalization of serum insulin-­ like growth factor 1 (IGF-­ 1), (2) prevent the detrimental effects on target organs and reduce mortality, (3) remove the pituitary tumor, to avoid or correct the mass effect on the brain and the optic chiasm, and (4) preserve the pituitary function. Trans-­sphenoidal surgery is the first-­line treatment approach in acromegaly, with cure rates of microadenomas as high as 80% in the hands of an experienced neurosurgeon.58 Surgery is also indicated for decompressive purposes in the cases of large tumors that cause optic chiasm compression and extend laterally into the cavernous sinus prohibiting complete resection for cure. Since the biochemical cure rate of macroadenomas following surgery is less than 50% (particularly if extrasellar extension of the tumor is present), many patients will require some form of adjuvant treatment following surgical resection.58-­60 In addition, medical therapy should be considered as primary approach for patients without vision compromise who either have higher than normal surgical risk or whose tumor is deemed not to be surgically curable.61 There are three classes of medications used in the treatment of acromegaly, each with different receptor target actions (Fig. 14.3): 1. Somatostatin analogs (SSAs: octreotide, lanreotide, and pasireotide) inhibit somatotroph cell proliferation and GH secretion by binding to the somatostatin receptors on tumoral cells. SSAs are often considered first-­ line treatment for persistent acromegaly after surgery (chiefly long-­acting preparations of octreotide and lanreotide). 2. DA bind to dopamine D2 receptors expressed on both somatotroph and mammotroph cells, exerting negative control. DA therapy may be associated to SSAs in patients with either a mixed GH/PRL-­secreting adenoma or in partially SSA-­resistant acromegalics.

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Diagnosis of acromegaly (GH-secreting pituitary tumor)

Is the patient eligible for surgery?

Medical treatment prior to surgery (not routinely) 1

No

Yes

PITUITARY SURGERY 2

Consider repeated surgery 4

Persistence or recurrence of GH excess

FOLLOW UP 3

MEDICAL THERAPY First-line treatment: first-generation SSA alone or DA alone 5

Good biochemical response to treatment:

Partial biochemical response: Several options are available: • Increase the dose of SSA or DA and/or reduce the interval between doses; • If DA alone is used, switch to SSA; • Give SSA + other therapies (DA or pegvisomant); • Give DA in combination with pegvisomant; • Switch to pasireotide LAR.

Continue SSA or DA, aiming to the lowest dose and/or the largest interval between doses.

No biochemical response: Consider switching to pegvisomant.

RADIOTHERAPHY 6 Can be considered at any stage after surgery if: • A tumor residue is clearly visible; • Medical therapies are not available, unsuccessful or not tolerated. 1

Consider medical treatment prior to surgery (3–6 months of treatment):

• In patients with increased surgical and anesthesiological risk because of the GH excess (severe pharyngeal thickening, severe OSAS, heart failure); • In patients unlikely to be cured with surgery alone because of tumor extension. However, if the tumor causes chiasmal compressoin or visual impairment, surgery should not be delayed. 2

Proceed to surgery even if the pre-surgery probability of cure is unlikely because of the tumor extension. Debulking surgery might improve the responsiveness to adjuvant therapies.

3

Biochemical follow up should include random GH and IGF-1:

• IGF-1 should fall within the age-adjusted reference range; • Random GH should be 20%) shrinkage and similar biochemical response.75 Although this study was not powered to show superiority of medical vs. surgical treatment, it suggests that medical therapy may be used safely in patients who are not surgical candidates. Another argument for primary SSA treatment is the potential beneficial effect of presurgical treatment on surgical cure. Carlsen et al.76 conducted the first prospective, randomized trial comparing the outcome of a short course

(6 months) of octreotide LAR pretreatment with that of surgery alone. The authors showed that in macroadenomas postsurgical normalization of IGF-­1 was achieved in 45% of pretreated patients, compared with 23% of patients who underwent direct surgery.76 Another prospective, randomized study also suggested that preoperative treatment with SSA may improve the chance of surgical cure in patients with GH-­secreting macroadenomas.77 Conversely, it has been shown that the success of medical therapy by SSAs may be enhanced by debulking surgery.78 Finally, the potential for reduced perioperative cardiovascular complications due to GH excess may be

14  •  Medical Management of Hormone-Secreting Pituitary Tumors

another reason to consider preoperative SSA treatment.79 In conclusion, SSA may be used as a first-­line treatment (1) in patients refusing pituitary surgery, (2) in poor surgical candidates, or (3) in those patients with pituitary tumors that are unlikely to be cured with surgery alone.80,81 However, surgery should not be delayed if there is evidence of chiasmal compression and vision impairment. 

Tolerability and Side Effects SSAs are generally well tolerated. The most common side effects are gastrointestinal symptoms, such as abdominal cramps, flatulence, diarrhea or constipation, and nausea (see Table 14.2). Biliary tract abnormalities, such as gallstones, sediment and sludge, and dilatation, are fairly common, occurring in as many as 50% of patients during the first 2 years of treatment, although they tend not to progress thereafter.58 Local skin irritation and pain at the injection site is mild and usually dose-­dependent. Rarely, patients may develop subcutaneous nodules in the gluteal area, believed to be a granulomatous reaction to the drug.82 Sinus bradycardia and conduction abnormalities have been described in 10% to 25% of patients, and medications that prolong the QT interval should not be used with SSAs.58 Impairment of pancreatic insulin secretion by first-­generation SSAs may result in mild hyperglycemia, particularly in patients who have preexisting glucose intolerance, although a clear diabetogenic effect of these medications has not been found.83 Pasireotide LAR had a similar safety profile as that of octreotide LAR, except for a significantly higher frequency and degree of hyperglycemia (see Table 14.2). 

DOPAMINE AGONISTS As monotherapy, DA have a limited role in acromegaly given their inferior efficacy compared with SSA. Bromocriptine is only 15% effective at normalizing GH levels when used in high doses in acromegalic patients.58 Initial studies with cabergoline as primary treatment in acromegaly showed biochemical efficacy of 27% to 39% and suggested a higher likelihood of success in pituitary tumors that co-­secrete GH and PRL.84,85 Interestingly, however, studies show that neither basal PRL concentrations nor co-­immunostaining of GH and PRL predicts a more favorable response.86,87 Instead, prior RT appears to be associated with an enhanced efficacy of GH response to DA compared with SSAs.86 In general, DA are reserved as adjuvant treatment to optimize medical therapy in partially SSA-­resistant acromegalic patients; in these patients, if IGF-­1 is less than two times the upper limit of the normal range, the addition of cabergoline to an SSA normalized IGF-­1 levels in 42% of cases.87 

PEGVISOMANT Pharmacological Aspects Pegvisomant, a genetically engineered GH analogue, is a competitive inhibitor acting at the receptor level that prevents that action of endogenous GH. The drug is administered as a subcutaneous injection, with an initial loading dose of 40 to 80 mg, followed by an initial dose of 10 mg daily (see Table 14.2). Since pegvisomant typically causes elevations in serum GH levels, only serum IGF-­1 levels can be used as

157

markers of effective dose response. Doses are adjusted by 5 to 10 mg increments at 4-­to 6-­week intervals according to IGF-­1 levels. 

Therapeutic Efficacy Pegvisomant was found in initial trials to be highly effective at normalizing IGF-­ 1 levels (90% to 97% patients) and controlling acromegalic symptoms. However, a post-­ marketing analysis shows that pegvisomant results in IGF-­1 normalization in 63% of acromegalics after 5 years of treatment (patients receiving either pegvisomant alone or pegvisomant+SSA).88 Use of submaximal doses may explain this discrepancy. 

Tolerability and Side Effects Pegvisomant is usually well tolerated, with the most common side effects listed in Table 14.2. The main concern is the risk of liver damage, with up to 9% of patients reported to have elevated transaminases, sometimes as high as 8 to 10 times the upper limit of normal.58 Liver function tests should be assessed before treatment and monthly for the first 6 months of treatment, quarterly for the next 6 months, and biannually the following year. Because of its mechanism of action at the peripheral level, pegvisomant does not reduce tumor size or GH levels.89 Conversely, the potential risk of tumor growth via blockade of negative feedback by IGF-­1 on the pituitary gland has been investigated. A 5-­year observational study found a risk of tumor growth in 5% of patients treated with pegvisomant, which is higher than the expected 2.2% risk of continuous tumor progression during SSA treatment.90 Another 5-­year observational study found a 2.8% incidence of increased tumor growth, which appears reassuring; however, this study had a lower biochemical normalization rate raising the possibility that the lower rate of tumor growth may be influenced by failure to titrate to therapeutic dose ranges.91 Given the uncertainty about tumor growth related to pegvisomant, it is recommended that patients on this drug be followed with serial MRI studies at least every 12 months.58,92 In acromegalic patients who are partially resistant to treatment with SSA alone, the addition of once weekly subcutaneous pegvisomant injections normalized IGF-­ 1 concentrations in 90% to 95% of cases.93 This reduced frequency dosing offers a financial advantage in patients who might otherwise require high-­dose pegvisomant monotherapy. Combination therapy with pegvisomant is currently reserved for those patients who achieve insufficient control after SSA therapy and surgical treatment. Of note, giving SSA+pegvisomant appears to be associated with a high risk of liver enzyme elevation (up to 38%).93 

FACTORS AFFECTING THE RESPONSE TO TREATMENT Acromegaly is a complex and multifaceted disease, and the response to treatment can vary substantially from patient to patient.94,95 Negative clinical and biochemical prognostic values for surgical and medical treatment are younger age, larger tumor volume (>20 mm), cavernous sinus and suprasellar invasion, and GH levels greater than 50 μg/L.96-­98 Moreover, GH-­secreting tumors due to genetic mutations (e.g., AIP-­ related pituitary adenomas, McCune-­ Albright

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syndrome, X-­ linked acrogigantism) respond poorly to treatment.99-­102 Recent evidence is shedding some light on which additional factors can influence the response to SSAs. Two main histological subtypes of GH-­ secreting tumors have been described, based on keratin patterns—the densely granulated and the sparsely granulated adenomas.103 Histology corresponds to different tumor behavior, and can have a prognostic significance. In fact, densely granulated GH-­ secreting adenomas are more likely to be smaller, to occur in older patients, to express higher levels of somatostatin receptor subtype 2, and to respond better to surgery and SSA treatment, in comparison to the sparsely granulated subtype.96,104,105 Furthermore, densely granulated adenomas are usually associated to higher levels of GH and IGF-­1 at baseline, which most likely cause an early, full-­blown acromegaly that allows an early diagnosis and treatment. Finally, an intermediate histological subtype has been described as well, and it seems to behave clinically more like the densely granulated adenomas.103 In terms of responsiveness to pasireotide, Iacovazzo et al.106 reported that sparsely granulated adenomas respond better to pasireotide compared to densely granulated ones, and also tumors expressing higher levels of somatostatin receptor type 5 benefit more from this treatment. Interestingly, these histology characteristics are likely reflected in different MRI appearance. Potorac et al.107 reported that hypointense pituitary tumors at T2-­weighted MRI correlate positively with GH and IGF-­ 1 reduction and tumor shrinkage after SSA initiation in treatment-­naïve patients. 

MANAGEMENT OF ACROMEGALY DURING PREGNANCY Pregnancy in acromegalic women should be postponed, if possible, until biochemical and radiological control is achieved. In case of persistent disease following surgery, medical treatment before pregnancy should aim at an optimal biochemical control, in order to lower the risk of gestational diabetes and systemic hypertension. Once pregnancy is confirmed, medical treatment is often stopped. The monitoring of GH and IGF-­1 during pregnancy is not recommended, as GH and IGF-­1 are expected to rise physiologically. Similarly, routine MRI during pregnancy is not needed, as most tumors do not increase in size.53,59 On the other hand, close clinical follow up should be arranged during pregnancy. Clinicians should assess signs and symptoms consistent with pituitary tumor enlargement (visual disturbances, unremittent headache), and serial visual fields (e.g., every 3 months) should be arranged in patients with macroadenomas or in those patients complaining of visual disturbances. If the patient develops abnormal visual fields and/or severe headache, a pituitary MRI should be arranged. Medical treatment should be resumed if there is MRI evidence of significant tumor growth. Data on the safety of first-­ generation SSAs during pregnancy are scarce, but there are case reports of octreotide LAR use in pregnant acromegalic women resulting in uneventful pregnancies and healthy babies.108 Although very limited, available evidence for the use of pegvisomant during pregnancy suggests that this medication does not significantly impact pregnancy outcomes.109 Data regarding the use of pasireotide LAR during pregnancy are not available, and its use is currently not recommended. 

Adrenocorticotropic Hormone-­Secreting Pituitary Tumors (Cushing Disease) GENERAL CONSIDERATIONS The treatment algorithm for CD is reported in Fig. 14.4. Trans-­sphenoidal surgery is the definitive treatment in CD; in the hands of an experienced neurosurgeon, the cure rate of ACTH-­ secreting pituitary microadenomas is high.110 However, approximately 10% to 30% of patients will not be cured or will recur and will require some form of adjuvant treatment, including conventional RT, stereotactic radiosurgery, medical therapy, or bilateral adrenalectomy.111,112 This subset of patients with refractory or residual CD poses a significant management challenge, as each of these secondary therapeutic options carries adverse risks.113 These patients are best managed in a multidisciplinary setting, such as in dedicated pituitary centers, where there is close collaboration between experienced neurosurgeons, endocrinologists, and radiation therapists. 

MANAGEMENT OF PERSISTENT AND RECURRENT CUSHING DISEASE Once the diagnosis of persistent or recurrent CD is confirmed, treatment options should be considered in the context of the individual patient.114 Repeating trans-­sphenoidal surgery should be considered in most patients, especially those with accessible tumor visible on MRI. Cure rates for repeated surgery range from approximately 40% to 70%.111 The main risk associated with repeated surgery is the development of hypopituitarism. Conventional RT may not be effective until months to years following treatment, which is often not acceptable in a patient with persistent, severe hypercortisolemia. Single-­ treatment stereotactic radiosurgery offers the advantage of minimized radiation to normal pituitary or adjacent structures, and has been reported to have a remission rate of about 40% to 80%.113,115 A study using stereotactic radiosurgery as either primary or adjuvant therapy in the treatment of secretory pituitary adenomas (acromegaly, CD, prolactinomas) found a 23% incidence of hypopituitarism at 4-­to 8-­year follow-­up.115 Medical therapy is generally a temporary measure in patients with residual CD. The goal of medical therapy is to attain control of hypercortisolemia and thereby minimize the associated negative health consequences (hypertension, hyperglycemia, gastrointestinal ulcerations, infection, osteoporosis, etc.) of patients awaiting the therapeutic effects of radiation treatment or planning to undergo repeat surgery. Medications used to treat hypercortisolemia (alone or in combination) include pituitary-­directed medications, adrenal steroidogenesis inhibitors, and a glucocorticoid receptor antagonist (Fig. 14.5 and Table 14.3). 

PITUITARY-­DIRECTED MEDICATIONS Pasireotide The somatostatin receptor type 5 is the predominant receptor type expressed by ACTH-­secreting adenomas (in comparison to type 2, which is highly expressed in GH-­ secreting pituitary tumors). Compared with first-­generation SSA, pasireotide displays a 40-­fold higher binding affinity for somatostatin receptor type 5, and this makes it an ideal

14  •  Medical Management of Hormone-Secreting Pituitary Tumors

159

Diagnosis of CD (ACTH-secreting pituitary tumor)

Is the patient eligible for surgery?

No

Yes Consider medical treatment 1 PITUITARY SURGERY

Initial remission

Persistent remission 2

Recurrent CD 3

Yes

Persistent CD 4

Is repeated surgery feasible and expected to be successful?

No

PITUITARY SURGERY 5 Recurrent or Persistent CD

PITUITARY RADIOTHERAPY 6

MEDICAL THERAPY 7

BILATERAL ADRENALECTOMY 8

1 Transsphenoidal surgery is the first-line treatment for CD. However, patients may have severe cortisol-related comorbidities that increase significantly their surgical risk. In selected patients a temporary treatment with cortisol-lowering medications can be used to reduce the surgical risk and improve patient outcomes. 2 ‘Cured’ CD: the complete resection of the pituitary adenoma causes a drop in the ACTH levels. This leads to a temporary adrenal insufficiency (usually lasting months to years), until the HPAA recovers. Initial remission occurs in 79%–90% of patients undergoing pituitary surgery for CD. Persistent remission is observed in 60%–70% of adults and 45%–50% of pediatric patients. 3 ‘Recurrent’ CD: surgery is able to remove the pituitary tumor almost completely. After initial fall of the ACTH (and subsequent temporary adrenal insufficiency), autonomous ACTH production from the residue leads to recurrence of the hypercortisolism. 4

‘Persistent’ CD: autonomous ACTH production persists immediately after surgery because of a partial resection of the pituitary tumor. The patient remains hypercortisolemic.

5

A major indication for repeat surgery is the postoperative evidence on MRI of a clear, resectable, and noninvasive tumor, particularly if the initial surgery was not performed by an experienced pituitary surgeon. Selective adenomectomy, partial hypophysectomy, and total hypophysectomy can be considered - the decision on the best approach should be made on a single-case basis, possibly after multidisciplinary discussion. The success rate of surgical reintervention is lower than that for primary pituitary surgery, and repeat neurosurgery is associated with a higher risk of complications and hypopituitarism. 6 Stereotactic techniques or radiosurgery should be favoured over conventional radiotherapy. Consider the latter option if the residue is very large or too close to the optic chiasm. Radiotherapy takes months to years to control ACTH production; therefore, a temporary "bridging" medical therapy is usually needed. 7 Available medications are cabergoline, pasireotide. ketoconazole, metyrapone, osilodrostat, mifepristone and etomidate (to be used in inpatient settings only). The efficacy of medications in the control of hypercortisolism and its metabolic effects is undisputed, but positive clinical and biochemical responses during medical therapy cannot be considered "curative," as drug discontinuation results in the recurrence of symptoms. 8 Bilateral adrenalectomy can be associated or not with pituitary radiotherapy. The major advantage of adrenal surgery is that it provides an immediate and definitive resolution of hypercortisolism, with rapid improvement of the clinical picture, despite a lifelong need of glucocorticoid and mineralocorticoid replacement and risk of developing Nelson’s syndrome (corticotroph tumor progression). Prophylactic pituitary radiotherapy before or immediately after adrenal surgery may reduce the risk of developing Nelson's syndrome or delaying its onset.

FIGURE 14.4  Management of Cushing disease. ACTH, Adrenocorticotropic hormone; CD, Cushing disease; HPAA, hypothalamic-­pituitary-­adrenal axis; MRI, magnetic resonance imaging.

candidate for patients with CD. Pasireotide is currently approved as twice a day subcutaneous injection for patients with CD after surgery has failed or is not an option. This medication has proven to be effective in achieving good clinical and biochemical responses as well as in reducing tumor volume in approximately 25% of patients.116 A recent report describes similar results (urinary free cortisol normalization in 40% of patients) with monthly LAR injections (10 or 30 mg).117 In both studies, a normal urinary free cortisol level was achieved more frequently in patients with baseline levels not exceeding five times the upper limit of the normal range than in patients with higher baseline levels. However, a major concern is the risk of developing hyperglycemia, which is as

high as 78%.116 If persistent hyperglycemia develops and a decision is made to continue pasireotide, an adequate medical treatment should be started (metformin, followed by the addition of a dipeptidyl pepidase-­4 inhibitor or a glucagon-­ like peptide-­1 agonist if needed).118 

Cabergoline The dopamine receptors, D2 and D4, are expressed in about 75% of ACTH-­pituitary adenomas, making DA a potential treatment option. A study has shown that 75% and 40% of patients treated with large doses of cabergoline (1-7 mg/ week). Achieve significant reduction of 24-hour urinary free cortisol and improvement of several clinical parameters at 0.3 and 2 years, respectively.119 Another work showed a

160

Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

Adrenal gland

Posterior pituitary

Cortisol Glucocorticoid target cell Cytoplasm

Anterior pituitary

GR

Nucleus

ACTH-secreting adenoma

Kidney

ACTH Pituitary-directed medications Pasireotide Cabergoline

Adrenal steroidogenesis inhibitors Ketoconazole Metyrapone Osilodrostat Mitotane Etomidate

GR antagonist Mifepristone

Site of action of adrenal steroidogenesis inhibitors Ketoconazole etomidate Cholesterol

Ketoconazole Mitotane Etomidate

CYP11A1

Mitotane

3 -HSD2 HSD3B2

StAR

Ketoconazole

17 -hydroxylase CYP17A1 17 -hydroxylase

17,20-lyase

Pregnenolone

17OH-pregnenolone

Dehydroepiandrosterone

Progesterone

17OH-progesterone

Androstenedione

11-deoxycorticosterone

11-deoxycortisol

Testosterone

21-hydroxylase CYP21A2

11 -hydroxylase CYP11B1

Mitotane Metyrapone Osilodrostat

Aldosterone synthase CYP11B2

Corticosterone Ketoconazole Metyrapone Osilodrostat Mitotane Etomidate

18OH-corticosterone

Aldosterone

Cortisol

FIGURE 14.5  Mechanism of action of medications used to treat hypercortisolemia. ACTH, Adrenocorticotropic hormone; CYP, cytochrome P450; GR, glucocorticoid receptor.

good biochemical response to high doses of cabergoline (significant reduction of urinary free cortisol in 30% of patients after 3 years of treatment),120 although a recent trial did not confirm these observations.121 Due to frequent escape, cabergoline is not seen as a viable long-­term treatment for CD. 

ADRENAL STEROIDOGENESIS INHIBITORS Ketoconazole Ketoconazole is often used to lower cortisol levels in CD patients. This oral antifungal agent, at higher doses, blocks cortisol production by inhibiting several adrenal steroidogenic enzymes (see Fig. 14.5).89 Ketoconazole is

approved in Europe for patients over the age of 12 years with CD. The use is off-­label in the United States. Invisible pituitary tumors can appear during ketoconazole treatment, and patients can therefore be sent to surgery. This approach could be considered in patients with “mild” CD. Typical starting doses are 200 mg twice daily, titrated up to a maximal dose of 400 mg three times daily based on serum cortisol levels and 24-­hour urine free cortisol levels. In order to be absorbed, ketoconazole requires low gastric pH. Absorption is therefore reduced in patients with achlorhydria or on proton pump inhibitors or H2 blockers. The

14  •  Medical Management of Hormone-Secreting Pituitary Tumors

161

TABLE 14.3  Medications Used for the Management of Endogenous Hypercortisolemia Pituitary-­ directed medications

Adrenal steroidogenesis inhibitors

Glucocorticoid receptor antagonist

Medication

Brand name

Dosage Form

Typical Starting Dose Maximum Dosage

Side Effects

Pasireotide

Signifor

0.6–0.9 mg twice daily

1200 mcg 2 times daily

Hyperglycemia, nausea, vomiting, diarrhea, biliary sludge/gallstones, liver enzyme elevations, QTc prolongation.

Cabergoline (off-­label use)

Dostinex

SubQ inj: 0.3 mg/mL SubQ inj: 0.6 mg/mL SubQ inj: 0.9 mg/mL Tablet: 0.5 mg

0.5 mg 1–2 times weekly

7 mg weekly

Ketoconazole

Nizoral

Tablet: 200 mg

400–600 mg daily in 2 or 3 divided doses

1200 mg daily in 2 or 3 divided doses

Metyrapone

Metopirone

Capsule: 250 mg

250 mg 4 times daily

1500 mg 4 times daily

Osilodrostat

Isturisa

Tablet: 1 mg Tablet: 5 mg Tablet: 10 mg

2 mg twice daily (1 mg twice daily in patients of Asian ancestry)

30 mg twice daily

Mitotane (off label use)

Lysodren

Tablet: 500 mg

250–500 mg 3 times daily

9000 mg in three divided doses, with the largest dose given in the evening to minimize discomfort

Etomidate (off label use)

Amidate

Injection 2 mg/mL

Bolus of 0.03 mg/ kg IV, followed by infusion 0.1 mg/ kg/h

Infusion of 0.3 mg/ kg/h

Mifepristone

Korlym

Tablet: 300 mg

300 mg daily

20 mg/kg/day (maximum dose 1200 mg, to be reduced to 600 mg if a concomitant therapy with a strong CYP3A inhibitor is given)

Nausea, vomiting, postural hypotension, dizziness, syncope (rare), headache, drowsiness, exacerbation of preexisting psychosis (rare), dyskinesias (high-­dose treatment), cardiac valve abnormalities (high-­dose treatment). Pruritis, nausea, vomiting, abdominal pain, diarrhea, fever, headache, gynecomastia, hemolytic anemia, hepatotoxicity, hypogonadism/ impotence, leukopenia, thrombocytopenia, somnolence, testosterone deficiency, vitamin D deficiency. Serious hepatotoxicity, including cases with a fatal outcome or requiring liver transplantation has occurred with the use of oral ketoconazole. Patients should be closely monitored when started on oral ketoconazole. Headache, dizziness, sedation, allergic rash, nausea, vomiting, abdominal discomfort/pain, bone marrow suppression (rare), adrenal insufficiency, systemic hypertension, hypokalemia, hirsutism, acne. Adrenal insufficiency, hypokalemia, hypotension, anorexia, dizziness, headache, syncope, tachycardia, skin rash, hirsutism, acne, QTc prolongation, abnormal liver function tests, corticotroph tumor growth CNS depression, lethargy/ somnolence, dizziness/vertigo, skin rash, anorexia, nausea, vomiting, diarrhea, weakness, headache, confusion, muscle tremor, adrenal insufficiency, dysarthria, ataxia, paresthesias. Nausea, vomiting, pain at injection site, myoclonus, hiccups, coughing, apnea, arrhythmia, bradycardia/ tachycardia, systemic hypertension, hyper/ hypoventilation, laryngospasm, adrenal insufficiency, nephrotoxicity, sedation, anaphylaxis, myoclonus. Adrenal insufficiency, hypokalemia, endometrial thickening/vaginal bleeding, ACTH elevation (possible tumor growth)

162

Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

use of acidic drinks such as Coca-­Cola improves absorption of the drug.122 Although control rates of cortisol excess on ketoconazole have been reported in 25% to 76% of patients, the medication is generally poorly tolerated, and carries a high risk of hepatitis at the chronically high doses often required to treat hypercortisolemia.89 Hepatitis occurs in as many as 12% of patients and therefore close monitoring of liver function tests is required when this medication is started or the dose is increased. Moreover, adrenal insufficiency has been described in 5% of patients treated with ketoconazole, and patients should be monitored for clinical signs of this severe adverse event. Ketoconazole is a potent inhibitor of the 17,20-­ lyase activity of the cytochrome P450 17A1. This is an important step of androgen biosynthesis, and its inhibition can cause hypotestosteronemia.123 The increased risk of hypogonadism in men may be a reason to consider metyrapone as an alternative in this patient population. The 2S,4R enantiomer of ketoconazole (levoketoconazole) may have favorable efficacy, safety, and tolerability compared with ketoconazole. Twice-daily oral levoketoconazole was found to significantly reduce 24-hour urinary free cortisol in patients with endogenous hypercortisolism.123a 

to target proteins within adrenal cells resulting in oxidative damage and adrenal cortical atrophy.125 Typical therapeutic doses range from 2 to 4 g, with the maximum daily dose of 9 g.127 The main drawbacks to this medication are its slow onset of action (weeks) and poor tolerability due to gastrointestinal and central nervous system side effects. Careful monitoring of mitotane blood levels is required.127 Cortisol blood levels cannot be used to monitor treatment efficacy, as mitotane causes the cortisol-­binding globulin to rise, leading to falsely elevated cortisol values. 

Metyrapone

GLUCOCORTICOID RECEPTOR ANTAGONIST (MIFEPRISTONE)

Metyrapone is approved for patients with Cushing syndrome, although its availability is limited in the United States. This medication works by blocking the final step in cortisol synthesis and is 80% effective at controlling hypercortisolemia.124 Cortisol suppression can be maintained chronically with doses of 500 to 2000 mg/day.125 Nausea, vomiting, and dizziness may occur with metyrapone, possibly due to sudden cortisol withdrawal and relative adrenal insufficiency.125 Another adverse side effect is acne and hirsutism (in women), which results from shunting of steroidogenic precursors toward the androgen pathway. This side effect may be a reason to favor ketoconazole in female patients. Cortisol blood levels measured through immunoassays should be interpreted cautiously in patients using metyrapone. In fact, this medication causes a sharp rise of 11-­ deoxycortisol levels, which can cross-­ react with cortisol, leading to falsely high values. If available, liquid chromatography-­mass spectrometry should be favored to check serum cortisol in these patients.126 

Osilodrostat Osilodrostat (LCI699) is a novel adrenal steroidogenesis inhibitor that has recently approved for the treatment of endogenous hypercortisolism in adults. Osilodrostat is an inhibitor of 11-beta hydroxylase, the enzyme that catalyzes the final step of cortisol biosynthesis, and has been proven to effectively reduce 24-hour urinary free cortisol and improve the signs and symptoms of Cushing syndrome.126a 

Mitotane Mitotane, a cytotoxic drug primarily used in the treatment of patients with adrenocortical carcinoma, can be used at lower doses to control hypercortisolemia. The mechanism of the adrenolytic effect is postulated to involve covalent binding

Etomidate Etomidate is an imidazole-­containing anesthetic agent used for the induction of general anesthesia. It is a potent steroidogenesis inhibitor that can be used to treat severe hypercortisolemia (intravenous infusion). Etomidate therapy is reserved for situations where rapid control of cortisol levels is required and there are barriers to oral therapy (e.g., sepsis, respiratory failure, psychosis).127 Short-­term continuous infusions of etomidate reduce serum cortisol in 11 to 24 hours, which must be monitored closely.125 Treatment with intravenous hydrocortisone is often necessary to prevent adrenal insufficiency. 

Mifepristone is a progesterone and glucocorticoid receptor antagonist. It is approved to treat hyperglycemia in patients with Cushing syndrome and type 2 diabetes/glucose intolerance after unsuccessful surgery, or if surgery is not an option.128 This medication is very effective in improving the metabolic consequences of hypercortisolemia. However, it is associated to potentially severe adverse events including adrenal insufficiency (due to excessive receptor blockade), profound hypokalemia (caused by ACTH rise and overstimulation of aldosterone production), and persistent vaginal bleeding (due to the anti-­progestin activity). Serum cortisol is expected to rise during treatment with mifepristone and must not be used to diagnose adrenal insufficiency. Given that the glucocorticoid receptors are blocked, very high doses of glucocorticoids are needed to overcome this blockade and treat adrenal insufficiency—2 to 8 mg of dexamethasone are the preferred option. 

MANAGEMENT OF CUSHING SYNDROME DURING PREGNANCY Pregnancy is rare in patients with hypercortisolism, since it usually leads to hypogonadism and reduced fertility. When a diagnosis of CD is made, control of hypercortisolemia should be pursued in order to reduce maternal and fetal complications.129 The first-­line treatment remains pituitary surgery, to be performed (when possible) between the end of the first trimester and the early second trimester. If medical treatment is necessary, metyrapone has been used with no adverse fetal outcomes. Cabergoline is also considered to be safe during pregnancy. Bilateral adrenalectomy might be a viable option in patients with uncontrolled CD. The use of mitotane and ketoconazole is discouraged because of their potential teratogenic effects. 

14  •  Medical Management of Hormone-Secreting Pituitary Tumors

163

Diagnosis of TSH-oma (TSH-secreting pituitary tumor)

PITUITARY SURGERY 1 (patients should have a normal thyroid function prior to surgery)

Consider medical treatment prior to surgery 2: • Somatostatin analogs (first choice, if tolerated) • Dopamine agonists • Thionamides • Beta-blockers

Persistence or recurrence

MEDICAL TREATMENT 2

RADIOTHERAPY 3

1

Surgery is considered the treatment of choice for TSH-omas, unless contraindicated. However, it can have a low success rate (50%–60% or lower, especially in macroadenomas), making adjuvant therapy often necessary. In fact, TSH-producing tumors tend to be large, to invade the surrounding structures and to be very hard (fibrosis), making surgical resection difficult.

2

Medical treatment can be used: • Prior to surgery, to control the hyperthyroidism and reduce the risks of anesthesia. Somatostatin analogs can frequently reduce the tumor volume - whether this improves the surgical outcomes in unclear; • As adjuvant therapy, after failure of pituitary surgery. Medications can be given alone or in combination. The following medications are available: • Somatostatin analogs (first-line treatment): they are very effective in reducing the volume of the pituitary tumor and in restoring normal thyroid function (blockade of autonomous TSH secretion); • Dopamine agonists: they can be useful in control tumor growth and hormonal secretion, especially in mixed TSH/PRL-adenomas. The response rate to dopamine agonists reported in the literature is rather mixed; • Thionamides and beta-blockers: they can be used to restore a normal thyroid function and control the signs and symptoms of hyperthyroidism. Thionamides may increase TSH secretion and stimulate tumor growth - they should be used only if other treatments (somatostatin analogs, dopamine agonists) are non effective or not tolerated.

3

Stereotactic techniques or radiosurgery should be favoured over conventional radiotherapy. Medical treatment is usually necessary to control hyperthyroidism until the effects of radiotherapy become evident.

FIGURE 14.6  Management TSH-­secreting tumors. PRL, Prolactin; TSH, thyroid-­stimulating hormone.

Thyroid-­Stimulating Hormone-­Secreting Pituitary Tumors The treatment algorithm for TSH-­secreting pituitary tumors is reported in Fig. 14.6. These adenomas are an exceedingly rare cause of thyrotoxicosis (secondary hyperthyroidism). The goals of therapy include tumor removal and restoration of a normal thyroid function. While trans-­sphenoidal surgery is the first approach, because most patients are diagnosed when adenomas are macros, the reported cure rate is only around 38%.130 For those patients who do not achieve surgical remission, adjuvant medical therapy offers promising results. Medical treatment relies mainly on the use of SSA, which inhibit thyrotroph cell growth by binding to the somatostatin receptor found on both normal pituitary and tumoral cells. Octreotide is 90% effective at normalizing thyroid hormone levels and 50% effective at reducing tumor size.15 As with growth-­hormone secreting tumors, there is evidence that presurgical treatment with SSAs may impact the ease of surgical removal.131 Typically, the doses of SSAs required to normalize TSH levels are lower than the doses used in the treatment of GH-­secreting tumors: octreotide SC (300 mg/day), lanreotide SR (30 mg every 14 days), and octreotide LAR (10 mg/day).15 However, due to the rarity of this disease, it is difficult to make generalizations about dose requirements, so each patient’s response and tolerance to SSA therapy should be considered individually.

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46. Tampourlou M, Trifanescu R, Paluzzi A, Ahmed SK, Karavitaki N. Therapy OF ENDOCRINE disease: surgery in microprolactinomas: effectiveness and risks based on contemporary literature. Eur J Endocrinol. 2016;175(3):R89–R96. 47. Salvatori R. Surgical treatment of microprolactinomas: pros. Endocrine. 2014;47(3):725–729. 48. Zygourakis CC, Imber BS, Chen R, et al. Cost-­ effectiveness analysis of surgical versus medical treatment of prolactinomas. J Neurol Surg B Skull Base. 2017;78(2):125–131. 49. Strowd RE, Salvatori R, Laterra JJ. Temozolomide retreatment in a recurrent prolactin-­secreting pituitary adenoma: hormonal and radiographic response. J Oncol Pharm Pract. 2016;22(3):517–522. 50. Lim S, Shahinian H, Maya MM, Yong W, Heaney AP. Temozolomide: a novel treatment for pituitary carcinoma. Lancet Oncol. 2006;7(6):518–520. 51. McCormack AI, McDonald KL, Gill AJ, et al. Low O6-­ methylguanine-­ DNA methyltransferase (MGMT) expression and response to temozolomide in aggressive pituitary tumours. Clin Endocrinol. 2009;71(2):226–233. 52. Whitelaw BC, Dworakowska D, Thomas NW, et al. Temozolomide in the management of dopamine agonist-­resistant prolactinomas. Clin Endocrinol. 2012;76(6):877–886. 52a. Barraud S, Guédra L, Delemer B, et al. Evolution of macroprolactinomas during pregnancy: a cohort study of 85 pregnancies. Clin Endocrinol (Oxf). 2020;92(5):421–427. https://doi.org/ 10.1111/cen.14162. PubMed PMID: 31957911. Epub 2020 Feb 4 . 53. Molitch ME. Pituitary disorders during pregnancy. Endocrinol Metab Clin North Am. 2006;35(1):99–116, vi. 54. Colao A, Abs R, Barcena DG, Chanson P, Paulus W, Kleinberg DL. Pregnancy outcomes following cabergoline treatment: extended results from a 12-­year observational study. Clin Endocrinol. 2008;68(1):66–71. 55. Holmgren U, Bergstrand G, Hagenfeldt K, Werner S. Women with prolactinoma-­-­effect of pregnancy and lactation on serum prolactin and on tumour growth. Acta Endocrinol. 1986;111(4):452–459. 56. Auriemma RS, Perone Y, Di Sarno A, et al. Results of a single-­ center observational 10-­ year survey study on recurrence of hyperprolactinemia after pregnancy and lactation. J Clin Endocrinol Metab. 2013;98(1):372–379. 57. Domingue ME, Devuyst F, Alexopoulou O, Corvilain B, Maiter D. Outcome of prolactinoma after pregnancy and lactation: a study on 73 patients. Clin Endocrinol. 2014;80(5):642–648. 58. Ben-­Shlomo A, Melmed S. Acromegaly. Endocrinol Metab Clin North Am. 2008;37(1):101–122, viii. 59. Katznelson L, Laws Jr ER, Melmed S, et al. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(11):3933–3951. 60. Mathioudakis N, Salvatori R. Management options for persistent postoperative acromegaly. Neurosurg Clin N Am. 2012;23(4):621–638. 61. Bush ZM, Vance ML. Management of acromegaly: is there a role for primary medical therapy? Rev Endocr Metab Disord. 2008;9(1):83–94. 62. Melmed S, Popovic V, Bidlingmaier M, et al. Safety and efficacy of oral octreotide in acromegaly: results of a multicenter phase III trial. J Clin Endocrinol Metab. 2015;100(4):1699–1708. 62a. Samson SL, Nachtigall LB, Fleseriu M, et al. Maintenance of acromegaly control in patients switching from injectable somatostatin receptor ligands to oral octreotide. J Clin Endocrinol Metab. 2020;10(105):e3785–e3797. 63. Salvatori R, Gordon MB, Woodmansee WW, et al. A multicenter, observational study of lanreotide depot/autogel (LAN) in patients with acromegaly in the United States: 2-­year experience from the SODA registry. Pituitary. 2017. 64. Salvatori R, Nachtigall LB, Cook DM, et al. Effectiveness of self-­ or partner-­ administration of an extended-­ release aqueous-­ gel formulation of lanreotide in lanreotide-­naive patients with acromegaly. Pituitary. 2010;13(2):115–122. 65. Colao A, Auriemma RS, Pivonello R, Kasuki L, Gadelha MR. Interpreting biochemical control response rates with first-­ generation somatostatin analogues in acromegaly. Pituitary. 2016;19(3):235–247. 66. Salvatori R, Woodmansee WW, Molitch M, Gordon MB, Lomax KG. Lanreotide extended-­ release aqueous-­ gel formulation, injected by patient, partner or healthcare provider in patients with acromegaly in the United States: 1-­year data from the SODA registry. Pituitary. 2014;17(1):13–21.

67. Colao A, Bronstein MD, Freda P, et al. Pasireotide versus octreotide in acromegaly: a head-­to-­head superiority study. J Clin Endocrinol Metab. 2014;99(3):791–799. 68. Gadelha MR, Bronstein MD, Brue T, et al. Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2014;2(11):875–884. 69. Melmed S, Sternberg R, Cook D, et al. A critical analysis of pituitary tumor shrinkage during primary medical therapy in acromegaly. J Clin Endocrinol Metab. 2005;90(7):4405–4410. 70. Mazziotti G, Giustina A. Effects of lanreotide SR and Autogel on tumor mass in patients with acromegaly: a systematic review. Pituitary. 2010;13(1):60–67. 71. Maiza JC, Vezzosi D, Matta M, et al. Long-­term (up to 18 years) effects on GH/IGF-­1 hypersecretion and tumour size of primary somatostatin analogue (SSTa) therapy in patients with GH-­ secreting pituitary adenoma responsive to SSTa. Clin Endocrinol. 2007;67(2):282–289. 72. Mercado M, Borges F, Bouterfa H, et al. A prospective, multicentre study to investigate the efficacy, safety and tolerability of octreotide LAR (long-­ acting repeatable octreotide) in the primary therapy of patients with acromegaly. Clin Endocrinol. 2007;66(6):859–868. 73. Colao A, Pivonello R, Auriemma RS, et al. Predictors of tumor shrinkage after primary therapy with somatostatin analogs in acromegaly: a prospective study in 99 patients. J Clin Endocrinol Metab. 2006;91(6):2112–2118. 74. Colao A, Auriemma RS, Pivonello R. The effects of somatostatin analogue therapy on pituitary tumor volume in patients with acromegaly. Pituitary. 2016;19(2):210–221. 75. Colao A, Cappabianca P, Caron P, et al. Octreotide LAR vs. surgery in newly diagnosed patients with acromegaly: a randomi­ zed, open-­ label, multicentre study. Clin Endocrinol. 2009;70(5): 757–768. 76. Carlsen SM, Lund-­Johansen M, Schreiner T, et al. Preoperative octreotide treatment in newly diagnosed acromegalic patients with macroadenomas increases cure short-­ term postoperative rates: a prospective, randomized trial. J Clin Endocrinol Metab. 2008;93(8):2984–2990. 77. Mao ZG, Zhu YH, Tang HL, et al. Preoperative lanreotide treatment in acromegalic patients with macroadenomas increases short-­term postoperative cure rates: a prospective, randomised trial. Eur J Endocrinol. 2010;162(4):661–666. 78. Colao A, Attanasio R, Pivonello R, et al. Partial surgical removal of growth hormone-­ secreting pituitary tumors enhances the response to somatostatin analogs in acromegaly. J Clin Endocrinol Metab. 2006;91(1):85–92. 79. Nemergut EC, Dumont AS, Barry UT, Laws ER. Perioperative management of patients undergoing transsphenoidal pituitary surgery. Anesth Analg. 2005;101(4):1170–1181. 80. Jacob JJ, Bevan JS. Should all patients with acromegaly receive somatostatin analogue therapy before surgery and, if so, for how long? Clin Endocrinol. 2014;81(6):812–817. 81. Grasso LF, Pivonello R, Colao A. Somatostatin analogs as a first-­ line treatment in acromegaly: when is it appropriate? Curr Opin Endocrinol Diabetes Obes. 2012;19(4): 288–284. 82. Debono M, Hon LQ, Bax N, Blakeborough A, Newell-­Price J. Gluteal nodules in patients with metastatic midgut carcinoid disease treated with depot somatostatin analogs. J Clin Endocrinol Metab. 2008;93(5):1860–1864. 83. Colao A, Auriemma RS, Savastano S, et al. Glucose tolerance and somatostatin analog treatment in acromegaly: a 12-­month study. J Clin Endocrinol Metab. 2009;94(8):2907–2914. 84. Abs R, Verhelst J, Maiter D, et al. Cabergoline in the treatment of acromegaly: a study in 64 patients. J Clin Endocrinol Metab. 1998;83(2):374–378. 85. Cozzi R, Attanasio R, Barausse M, et al. Cabergoline in acromegaly: a renewed role for dopamine agonist treatment? Eur J Endocrinol. 1998;139(5):516–521. 86. Sherlock M, Fernandez-­Rodriguez E, Alonso AA, et al. Medical therapy in patients with acromegaly: predictors of response and comparison of efficacy of dopamine agonists and somatostatin analogues. J Clin Endocrinol Metab. 2009;94(4):1255–1263. 87. Cozzi R, Attanasio R, Lodrini S, Lasio G. Cabergoline addition to depot somatostatin analogues in resistant acromegalic patients: efficacy and lack of predictive value of prolactin status. Clin Endocrinol. 2004;61(2):209–215.

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88. van der Lely AJ, Biller BM, Brue T, et al. Long-­term safety of pegvisomant in patients with acromegaly: comprehensive review of 1288 subjects in ACROSTUDY. J Clin Endocrinol Metab. 2012;97(5):1589–1597. 89. Patil CG, Hayden M, Katznelson L, Chang SD. Non-­surgical management of hormone-­secreting pituitary tumors. J Clin Neurosci. 2009;16(8):985–993. 90. Brue T. ACROSTUDY: status update on 469 patients. Horm Res. 2009;71(suppl 1):34–38. 91. Trainer PJ. ACROSTUDY: the first 5 years. Eur J Endocrinol. 2009;161(suppl 1):S19–S24. 92. Buhk JH, Jung S, Psychogios MN, et al. Tumor volume of growth hormone-­secreting pituitary adenomas during treatment with pegvisomant: a prospective multicenter study. J Clin Endocrinol Metab. 2010;95(2):552–558. 93. Feenstra J, de Herder WW, ten Have SM, et al. Combined therapy with somatostatin analogues and weekly pegvisomant in active acromegaly. Lancet. 2005;365(9471):1644–1646. 94. Asa SL, Kucharczyk W, Ezzat S. Pituitary acromegaly: not one disease. Endocr Relat Cancer. 2017;24(3):C1–C4. 95. Paragliola RM, Corsello SM, Salvatori R. Somatostatin receptor ligands in acromegaly: clinical response and factors predicting resistance. Pituitary. 2017;20(1):109–115. 96. Bhayana S, Booth GL, Asa SL, Kovacs K, Ezzat S. The implication of somatotroph adenoma phenotype to somatostatin analog responsiveness in acromegaly. J Clin Endocrinol Metab. 2005;90(11):6290–6295. 97. Nomikos P, Buchfelder M, Fahlbusch R. The outcome of surgery in 668 patients with acromegaly using current criteria of biochemical ‘cure’. Eur J Endocrinol. 2005;152(3):379–387. 98. Trepp R, Stettler C, Zwahlen M, Seiler R, Diem P, Christ ER. Treatment outcomes and mortality of 94 patients with acromegaly. Acta Neurochir. 2005;147(3):243–251; discussion 50–51. 99. Gadelha MR, Kasuki L, Korbonits M. The genetic background of acromegaly. Pituitary. 2017;20(1):10–21. 100. Salenave S, Boyce AM, Collins MT, Chanson P. Acromegaly and McCune-­ Albright syndrome. J Clin Endocrinol Metab. 2014;99(6):1955–1969. 101. Iacovazzo D, Korbonits M. Gigantism: X-­linked acrogigantism and GPR101 mutations. Growth Horm IGF Res. 2016;30–31:64–69. 102. Beckers A, Lodish MB, Trivellin G, et al. X-­linked acrogigantism syndrome: clinical profile and therapeutic responses. Endocr Relat Cancer. 2015;22(3):353–367. 103. Fougner SL, Casar-­Borota O, Heck A, Berg JP, Bollerslev J. Adenoma granulation pattern correlates with clinical variables and effect of somatostatin analogue treatment in a large series of patients with acromegaly. Clin Endocrinol. 2012;76(1):96–102. 104. Kiseljak-­Vassiliades K, Carlson NE, Borges MT, et al. Growth hormone tumor histological subtypes predict response to surgical and medical therapy. Endocrine. 2015;49(1):231–241. 105. Brzana J, Yedinak CG, Gultekin SH, Delashaw JB, Fleseriu M. Growth hormone granulation pattern and somatostatin receptor subtype 2A correlate with postoperative somatostatin receptor ligand response in acromegaly: a large single center experience. Pituitary. 2013;16(4):490–498. 106. Iacovazzo D, Carlsen E, Lugli F, et al. Factors predicting pasireotide responsiveness in somatotroph pituitary adenomas resistant to first-­ generation somatostatin analogues: an immunohistochemical study. Eur J Endocrinol. 2016;174(2):241–250. 107. Potorac I, Petrossians P, Daly AF, et al. T2-­weighted MRI signal predicts hormone and tumor responses to somatostatin analogs in acromegaly. Endocr Relat Cancer. 2016;23(11):871–881. 108. Maffei P, Tamagno G, Nardelli GB, et al. Effects of octreotide exposure during pregnancy in acromegaly. Clin Endocrinol. 2010;72(5):668–677. 109. van der Lely AJ, Gomez R, Heissler JF, et al. Pregnancy in acromegaly patients treated with pegvisomant. Endocrine. 2015;49(3):769–773. 110. Porterfield JR, Thompson GB, Young Jr WF, et al. Surgery for Cushing’s syndrome: an historical review and recent ten-­year experience. World J Surg. 2008;32(5):659–677. 111. Blevins Jr LS, Sanai N, Kunwar S, Devin JK. An approach to the management of patients with residual Cushing’s disease. J Neuro Oncol. 2009;94(3):313–319.

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112. Nieman LK, Biller BM, Findling JW, et al. Treatment of Cushing’s Syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(8):2807–2831. 113. Pivonello R, De Leo M, Cozzolino A, Colao A. The treatment of Cushing’s disease. Endocr Rev. 2015;36(4):385–486. 114. Prete A, Corsello SM, Salvatori R. Current best practice in the management of patients after pituitary surgery. Ther Adv Endocrinol Metab. 2017;8(3):33–48. 115. Castinetti F, Nagai M, Morange I, et al. Long-­term results of stereotactic radiosurgery in secretory pituitary adenomas. J Clin Endocrinol Metab. 2009;94(9):3400–3407. 116. Colao A, Petersenn S, Newell-­Price J, et al. A 12-­month phase 3 study of pasireotide in Cushing’s disease. N Engl J Med. 2012;366(10):914–924. 117. Lacroix A, Gu F, Gallardo W, et al. On behalf of the Pasireotide G2304 Study Group. Efficacy and safety of once-­monthly pasireotide in patients with Cushing’s disease: results from a 12-­month clinical trial. Lancet Diabetes Endocrinol. 2017 [in press]. 118. Colao A, De Block C, Gaztambide MS, Kumar S, Seufert J, Casanueva FF. Managing hyperglycemia in patients with Cushing’s disease treated with pasireotide: medical expert recommendations. Pituitary. 2014;17(2):180–186. 119. Pivonello R, De Martino MC, Cappabianca P, et al. The medical treatment of Cushing’s disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J Clin Endocrinol Metab. 2009;94(1):223–230. 120. Godbout A, Manavela M, Danilowicz K, Beauregard H, Bruno OD, Lacroix A. Cabergoline monotherapy in the long-­term treatment of Cushing’s disease. Eur J Endocrinol. 2010;163(5):709–716. 121. Burman P, Eden-­Engstrom B, Ekman B, Karlsson FA, Schwarcz E, Wahlberg J. Limited value of cabergoline in Cushing’s disease: a prospective study of a 6-­week treatment in 20 patients. Eur J Endocrinol. 2016;174(1):17–24. 122. Chin TW, Loeb M, Fong IW. Effects of an acidic beverage (Coca-­Cola) on absorption of ketoconazole. Antimicrob Agents Chemother. 1995;39(8):1671–1675. 123. Pont A, Williams PL, Azhar S, et al. Ketoconazole blocks testosterone synthesis. Arch Intern Med. 1982;142(12):2137–2140. 123a. Fleseriu M, Pivonello R, Elenkova A, et al. Efficacy and safety of levoketoconazole in the treatment of endogenous Cushing’s syndrome (SONICS): a phase 3, multicentre, open-label, single-arm trial. Lancet Diabetes Endocrinol. 2019;7(11):855–865. https://doi.org/10.1016/S2213-8587(19)30313-4. Epub 2019 Sep 18. Erratum in: Lancet Diabetes Endocrinol. 2019 Nov;7(11):e22. PMID: 31542384. 124. Shalet S, Mukherjee A. Pharmacological treatment of hypercortisolism. Curr Opin Endocrinol Diabetes Obes. 2008;15(3):234–238. 125. Schteingart DE. Drugs in the medical treatment of Cushing’s syndrome-­ -­ an update on mifepristone and pasireotide. Expert Opin Emerg Drugs. 2012;17(3):279–283. 126. Monaghan PJ, Owen LJ, Trainer PJ, Brabant G, Keevil BG, Darby D. Comparison of serum cortisol measurement by immunoassay and liquid chromatography-­tandem mass spectrometry in patients receiving the 11beta-­hydroxylase inhibitor metyrapone. Ann Clin Biochem. 2011;48(Pt 5):441–446. 126a. Pivonello R, et al. Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol. 2020;8(9):748–761. 127. Biller BM, Grossman AB, Stewart PM, et al. Treatment of adrenocorticotropin-­dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab. 2008;93(7):2454–2462. 128. Fleseriu M, Biller BM, Findling JW, et al. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. J Clin Endocrinol Metab. 2012;97(6):2039–2049. 129. Bronstein MD, Machado MC, Fragoso MC. Management OF ENDOCRINE disease: management of pregnant patients with Cushing’s syndrome. Eur J Endocrinol. 2015;173(2):R85–R91. 130. Beck-­Peccoz P, Persani L. Thyrotropinomas. Endocrinol Metab Clin North Am. 2008;37(1):123–134, viii-ix. 131. Beck-­Peccoz P, Brucker-­ Davis F, Persani L, Smallridge RC, Weintraub BD. Thyrotropin-­secreting pituitary tumors. Endocr Rev. 1996;17(6):610–638.

CHAPTER 15

Endoscopic Endonasal Pituitary and Skull Base Surgery DAVID H. JHO  •  DIANA H. JHO  •  HAE-­DONG JHO The use of the endonasal pathway for skull base surgery was initially reported in 1909 by Hirsch, who performed his first pituitary surgery in Vienna by approaching the sella through an endonasal route using multiple-­staged operations with unenhanced visualization. Despite his first endonasal transsphenoidal surgery having reported success, Hirsch subsequently converted to a transseptal submucosal approach. The first reported use of the endoscope for transsphenoidal surgery was reported by Guiot in 1963 via a sublabial approach.1 The sublabial and transfixional transseptal approaches became initially favored by neurosurgeons during the expansion of transsphenoidal surgery in the 1970s and 1980s, in conjunction with the operating microscope. Griffith and Veerapen revisited the endonasal pathway with the operating microscope in 1987, using a transsphenoidal retractor.2 Cooke and Jones reported that use of the endonasal route for microscopic pituitary surgery did not result in any increased sinonasal or dental complications.3 However, favoring of the direct endonasal route for pituitary surgery was facilitated by the neuroendoscope, with the initial use of sinonasal endoscopy in Europe during the 1970s. In the field of otolaryngology, the introduction of endoscopic sinus surgery kindled an evolution in surgical techniques with advancements in understanding of sinonasal pathophysiology. Successful advances in sinonasal endoscopy then enhanced interest in the use of endoscopy for transsphenoidal surgery. Endoscopic endonasal transsphenoidal surgery (EE-­ TS) started with endoscope use during biopsy of a sellar lesion, followed by endoscope use for visualization during insertion of transsphenoidal retractors and as supplement to microscopic removal of pituitary adenomas, and eventually the development of the pure form of EE-­TS.4–12 This chapter describes EE-­TS along with related endoscopic endonasal approaches to the midline skull base such as the anterior cranial fossa (EE-­ACF), optic nerve and/ or cavernous sinus (EE-­ CS), pterygoid fossa or petrous apex (EE-­Pterygoid or EE-­Petrous), clivus and posterior fossa (EE-­ PFossa), and craniocervical junction (EE-­ CC junction) (Table 15.1). EE-­TS is specifically an operation done completely with endoscopic visualization without any transsphenoidal retractor or nasal speculum. The physical nature of an endoscope with its optics at the tip and slender shaft allows simple access to the sella through the natural nasal air pathway via a nostril. The wide-­angled panoramic view, angled-­lens views, and a close-­up zoom view provide

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enhanced visualization at the surgical target site. Applying extension of principles from EE-­TS also allowed the surgical treatment of midline skull base pathologies (from the EE-­ACF to the clivus and EE-­PFossa along with the EE-­ CC) and paramedian skull base pathologies (from the optic nerve and cavernous sinus regions to the pterygoid fossa and petrous tip). Endoscopic endonasal techniques can potentially be applied to nearly any lesion within approximately 2-­cm width at the midline skull base from the crista galli at the anterior-­superior skull base to the foramen magnum and atlantoaxial region at the posterior-­inferior skull base.13–23

Preoperative Management and Surgical Indications All patients with pituitary adenomas undergo formal endocrine evaluations preoperatively and postoperatively. Hypopituitarism is among the important endocrine conditions requiring treatment starting preoperatively, particularly for hypocortisolism and hypothyroidism. In addition, it is important to distinguish prolactinomas, which might potentially be medically treated. For patients with preoperative visual symptoms or tumors impinging on the optic apparatus on magnetic resonance imaging (MRI), formal neuro-­ophthalmologic evaluation is obtained preoperatively with follow-­up visual examinations postoperatively. MRI of the brain with and without contrast enhancement (ideally with a pituitary-focused protocol and optionally with dynamic contrast imaging) is the diagnostic imaging modality of choice with best resolution for most pituitary adenomas. Patients who are unable to undergo MRI for various reasons can undergo the lesser alternative of computed tomography (CT) of the brain with pituitary focus and dynamic contrast protocol. Usually, the basic anatomy of the paranasal sinuses and any variations of an individual can be appreciated sufficiently on MRI for the purposes of transsphenoidal surgery. However, bone-­window CT scans with fine-­cut axial and coronal views can disclose the bony anatomy of the paranasal sinuses in detail and may be obtained as supplemental imaging depending on surgeon’s preference, or for patients who have had previous paranasal sinus or complex bony anatomy for transsphenoidal surgery. If intraoperative image-­guided system imaging is desired by the surgeon for EE-­TS, imaging protocol compatible with frameless stereotaxy may also be used.

15  •  Endoscopic Endonasal Pituitary and Skull Base Surgery

Table 15.1  Types of Techniques for Maximizing Resection Approach

Pros

Cons

EE-­TS (Transsphenoidal)

Most common and versatile

EE-­ACF (Anterior Cranial Fossa) EE-­CS (Cavernous Sinus)

Physical presence of an endoscope at the surgical corridor Challenges in skull base repair with potential CSF leak Limited to easily removable tumors

Direct anterior access to pathology without brain retraction Direct access to pathology medial to cranial nerves Direct route posterior-­ Access is medial lateral access petrous region and bony thickness can be limited Direct route P-­fossa Clival repair may have ventral access complexities

EE-­Petrous (Apex/Pterygoid Fossa) EE-­PFossa (Posterior Fossa/ Clivus) EE-­CC (Craniocervical Junction)

Alternative to transoral

Instrument maneuverability can be limited

Surgical indications can include goals of reducing anatomic mass effect and/or endocrine hormone abnormalities. Patients with hormonally active or functional pituitary adenomas causing acromegaly, Cushing disease, or secondary hyperthyroidism undergo transsphenoidal surgery as the primary mode of treatment. Patients with prolactinomas are operated upon only when they fail to respond appropriately to dopaminergic medications, develop intolerable side effects to the medications, or choose against the use of dopaminergic medications. Patients with hormonally inactive or nonfunctional pituitary adenomas may be operated upon when the tumors cause symptomatic compression of the optic apparatus, pituitary apoplexy, progressive hypopituitarism, or severe intractable frontotemporal headaches. Other symptomatic mass lesions or tumors at the pituitary fossa generally undergo surgery for anatomic mass effect or for histopathologic diagnosis. In contrast to conventional microscopic surgery, a large pituitary tumor with suprasellar extension can be directly visualized in EE-­TS, and bony exposure can be extended rostrally if further exploration at the planum sphenoidale is required. EE-­TS can thus enhance the chance for total pituitary tumor resection and potentially reduce the need for a supplemental transcranial approach. Following hundreds of EE-­TS cases, with the youngest patient being a teenager, we have yet to encounter a patient whose nasal passage was too small to undergo standard EE-­ TS. Notably, patients with acromegaly usually have hypertrophic turbinates and mucosal soft tissues such that the endonasal space can be disproportionately small. In addition, patients with Cushing disease often have narrow nasal airways due to swollen hypertrophic mucosa, which also tends to bleed easily. Among our patients who have undergone EE-­TS, two patients with Cushing disease required a two-­nostril technique with an endoscope inserted through one nostril and the surgical instruments inserted through the other. Reoperation by EE-­TS for patients who have undergone previous conventional transsphenoidal surgery is not difficult if an appropriate anterior sphenoidotomy was previously performed, although reoperation can be challenging if

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bony sellar structures were excessively eliminated, complications were encountered during previous surgery, or distorting extensive reconstruction was performed. 

Pertinent Sinonasal Anatomy To perform endoscopic pituitary surgery, the functional physiology and anatomy of the sinonasal cavity should be understood. In the paranasal sinuses (that include the sphenoid, ethmoid, maxillary, and frontal sinuses), mucociliary movement is orchestrated by the delivery of mucus flow to the sinus ostia then toward the nasopharynx. When the path of physiologic mucus flow is interrupted mechanically or functionally, the paranasal sinuses can retain stagnant mucus, which can subsequently become infected and result in sinusitis. The confluence of the draining mucus from the frontal sinus, anterior ethmoidal sinus, and maxillary sinus is located at the middle meatus. Mucosal drainage of the posterior ethmoidal sinus occurs at the superior meatus, and drainage of the sphenoid sinus is at the sphenoethmoidal recess, which is located between the posterolateral aspect of the middle turbinate, superior turbinate, and the rostrum of the sphenoid sinus. The nasal cavity itself is bordered medially by the nasal septum (composed of the septal cartilage, the perpendicular plate of the ethmoid bone, and the vomer); superiorly by the cribriform plate of the ethmoid bone and bridge of the nose (consisting of the nasal portion of the frontal bone, nasal bone, and frontal process of the maxilla); inferiorly by the floor of the nasal cavity (involving the palatine process of the maxilla and the horizontal plate of the palatine bone); and conchae or turbinates laterally (inferior, middle, superior, and sometimes supreme turbinates). The superior and middle conchae (along with the occasional supreme concha) are components of the ethmoid bone, whereas the inferior concha is a separate bone. The EE-­TS procedure traverses the region medial to the middle turbinate, between the middle turbinate and the nasal septum, on the way to the sphenoid sinus then the pituitary fossa at the sella turcica. Nasal septal deviation is not rare, such that sometimes the larger nasal cavity is selected as the route for EE-­TS based on preoperative imaging and intraoperative visualization. The lateral wall of the endonasal route (with numerous projections of the ethmoid bone and individual anatomic variability) has more complex anatomy than the medial wall, which consists of the nasal septum. From a surgical and anatomic embryology standpoint, the ethmoid at the lateral wall of the nasal cavity has been divided into five sequential lamella from anterior to posterior consisting of the uncinate process, ethmoid bulla, basal lamella of the middle turbinate, basal lamella of the superior turbinate, and occasionally the basal lamella of the supreme turbinate (if present). The basal lamella of the middle turbinate divides the ethmoid sinuses into anterior and posterior air cells, and the middle turbinate attachments lie in three different planes with the anterior segment oriented along a sagittal plane (attached to the lateral portion of the cribriform plate superiorly), middle segment oriented along a coronal plane (attached to the lamina papyracea), and the posterior segment oriented nearly along an axial plane (attached to the medial wall of the maxillary sinus and perpendicular plate of the palatine bone). The normal sinonasal anatomy located laterally to the middle

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Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

turbinate is referred to as the osteomeatal complex (OMC) and comprises a key set of structures for sinonasal function. The OMC consists of the middle turbinate, uncinate process, hiatus semilunaris, ethmoid infundibulum, and ethmoid bulla. Anterolateral to the middle turbinate is the uncinate process of the ethmoid bone, behind which lies a cleft between the uncinate and ethmoid bulla called the hiatus semilunaris, which is contiguous with the ethmoid infundibulum. The hiatus semilunaris is essentially a two-­dimensional (2D) crescent-­shaped opening leading from the middle meatus into the three-­dimensional (3D) funnel-­shaped ethmoid infundibulum to which the frontal sinus, anterior ethmoid sinus, and maxillary sinus usually drain. The frontal sinus drains anteriorly at the ethmoid infundibulum (via the hourglass-­shaped frontonasal recess), anterior ethmoid sinus drains into the midportion, and the maxillary sinus drains through its ostium posteriorly at the maxillary infundibulum. Along the posterior-­ superior bank of the hiatus semilunaris is the ethmoid bulla, which is considered one of the most constant and largest of the anterior ethmoid air cells. The ethmoid bulla is bordered medially by the lamina papyracea of the medial orbit and projects medially in the middle meatus, and the posterior-­superior portion of the hiatus semilunaris connects the middle meatus with the suprabullar and retrobullar recesses (collectively called the sinus lateralis), which are defined in relation to the ethmoid bulla. There are variations and debated nuances in the anatomic terminology of paranasal sinus anatomy, including debating of the precise borders of the ethmoid infundibulum in relation to the hiatus semilunaris. Regardless, the more important point is that there are individual structural variations, which can affect paranasal sinus physiology and surgical anatomy. For instance, there are three major variations to the superior attachment of the crescent-­shaped uncinate process, with the most common type attaching laterally to the lamina papyracea (∼70% in cadaveric studies) resulting in frontal sinus outflow medial to the uncinate process at the middle meatus. The two other major patterns of uncinate superior insertions include medial attachment to the base of the middle turbinate at the cribriform plate (20%) transsphenoidally may increase the risk of apoplexy. When apoplexy occurs in this setting, it can be associated with a high level of morbidity and mortality.38 It has already been reported that pituitary tumors are less vascular than the normal pituitary gland, and as the tumor grows it derives its blood supply from the inferior hypophyseal arteries and direct branches of the internal carotid arteries.38,39 When the tumor is removed via the transsphenoidal route, the arterial supply may be more likely to be compromised, and the residual tumor superiorly can undergo infarction leading to swelling. This can compromise the venous drainage and lead to hemorrhagic infarction of the tumor, compressing the vital structures and hypothalamus in the vicinity, leading to a fulminant course. However, when the tumor is removed via the transcranial route, this blood supply origin to the tumor may be preserved, and as such apoplexy might be less common even after subtotal resection; however, sufficient scientific evidence to support this is lacking (Fig. 16.7, Case 3). Some would argue for attempting the transsphenoidal approach first, since some suprasellar giant adenomas are soft and can be easily delivered to the sella for which a transsphenoidal approach is very effective and makes the second stage (transcranial) easier and safer. In addition, morbidity of apoplexy in the setting of a subtotal resection via a transsphenoidal route may be minimized by not entering the cisternal spaces, thus preserving a barrier separating the

PL

STL SON FIGURE 16.6  Supra-­orbital (keyhole) approach. (A) Mild extension and contralateral rotation of the head along with the early CSF drainage from the optico-­carotid cistern could be very useful to reach the tumor without using retractor. Using anatomical landmarks such as supraorbital notch (SON), Pitanguy line (PL), and superior temporal line (STL) will help to prevent temporary supraorbital hypoesthesia and temporary palsy of the frontal branch of the facial nerve. (B) Postoperative picture of the patient 3 weeks after surgery. (C) Preoperative sagittal T1-­MRI of a pituitary tumor with minimal suprasellar extension. (D) Postoperative MRI demonstrating tumor removal via a supra-­orbital approach. CSF, Cerebrospinal fluid; MRI, magnetic resonance imaging.

A

C

191

B

D

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A

FIGURE 16.7  (Case 3) An 18-­year-­ old female with acromegaly features and bilateral vision loss (R>L) for the last 2 years. The initial brain MRI showed a large sellar/ suprasellar mass with bilateral cavernous sinuses invasion and the complete encasement of the ICA. Two stages of the operation were planned for resection of the tumor: the first stage for endoscopic transsphenoidal, and the second stage for transcranial surgery 2 months later for further tumor debulking. The surgery was complicated by an intraoperative injury of the left middle cerebral artery requiring anastomosis, but there was no significant neurological deficit postoperatively (see Video 16.1). (A) Preoperative T1 coronal MRI with contrast. (B) Postoperative T1 coronal with contrast after transsphenoidal surgery. (C) Postoperative T1 coronal MRI with contrast after transcranial tumor debulking. (D) DWI MRI does not show any restriction diffusion postoperatively. DWI, Diffusion-­weighted imaging; ICA, internal carotid artery; MRI, magnetic resonance imaging.

B

A

C

D

intracranial space from the sellar space. Thus, even in cases of apoplexy, the blood is unable to enter the intracranial space to cause the associated morbidity. Some studies recommend a simultaneous “above-­and-­ below” technique. The rationale of this approach is that the degree of resection is increased and postoperative bleeding of the residual tumor is minimized; however, this increases surgical operative time and it is unclear whether craniotomy postsurgical infection may be increased.40,41 In sum, a combined approach is an excellent option for giant macroadenomas involving multiple midline and lateral intracranial compartments, but how they are implemented remains controversial. 

especially, by minimal brain retraction. A pattie or cotton strip should always be placed between the brain and the retractor. The retractor should be moved often, and should be removed when it is not needed. Splitting the sylvian fissure to separate the frontal and temporal lobes also minimizes the amount of retraction. If there is evidence of an area of soft, blue brain at the end of the operation, the surgeon should beware: this area may represent hemorrhagic infarction, which often causes postoperative bleeding and deterioration. Such areas should be removed surgically before closing the dura. There is an increasing trend toward retractorless skull base surgery, which minimizes brain manipulation during surgery and may minimize the associated complications of using retractors.17 

Complications

VASCULAR INJURY

FRONTAL LOBE DAMAGE Frontal lobe damage is perhaps the most common complication, although it is often unappreciated because its manifestations may be subtle. Frontal lobe damage is particularly likely to occur in the elderly and is caused by excessive frontal lobe retraction. The elderly take longer to recover from this surgery than from transsphenoidal surgery. There may be subtle changes of memory, judgment (on a social or professional level), concentration, and personality. These changes can be minimized by gentle surgical technique and,

The potential for harm to vascular structures, especially in giant macroadenomas necessitates accurate preoperative evaluation of the vessels using CT angiogram or angiography. The surgeon always has to be prepared to manage vascular injury during removal of these tumors especially when the preoperative study shows vascular encasement (see Fig. 16.7, Case 3; Video 16.1). Traumatic intracranial pseudoaneurysms can be caused by iatrogenic arterial injury during surgical procedures. Advances in endovascular techniques allow safer approaches to iatrogenic vascular lesions.42 

16  •  Transcranial Surgery for Pituitary Macroadenomas

ANOSMIA Unilateral or bilateral anosmia often reflects the vigor of frontal lobe retraction. If there is a significant subfrontal extension of the pituitary tumor, anosmia is inevitable. 

PERIOPERATIVE OPTIC NERVE DAMAGE If an eye is blind preoperatively, it will rarely recover postoperatively. If there are signs of optic atrophy/pallor or retinal nerve fiber layer loss on optical coherence tomography, it is also less likely to recover. If an already damaged optic nerve is manipulated at all, vision is likely to be lost altogether postoperatively. Thus the patient should be warned. The most vulnerable nerve is the ipsilateral optic nerve, which ideally should not be manipulated. Early optic decompression and opening the falciform ligament are necessary initial steps. Before teasing the tumor away, it should be debulked as much as possible; only at the last stage, when space has been created, should the remaining tumor be rolled away from the optic nerve. Meningiomas creep into the optic canal; however, pituitary tumors do not typically behave in that fashion. The blood supply of the optic nerve, nerves, and chiasm varies. The chiasm is supplied by small vessels from the anterior communicating artery, and these must be preserved. Any vessel running to the chiasm or optic nerves should be preserved. The superior hypophyseal artery (SHA) almost always supplies the infundibulum, optic chiasm, and proximal optic nerve. Compromising this artery can cause a visual deficit. Unilateral injury to the SHA is less likely to cause an endocrine deficit given the artery’s abundant anastomoses. A detailed understanding of the surgical anatomy of the SHA and its many variations may help surgeons when approaching challenging lesions in the suprasellar region.43 

HYPOPITUITARISM, INCLUDING DIABETES INSIPIDUS The most common pituitary aberration in the immediate postoperative period is DI. Patients should be allowed to drink ad libitum (at pleasure) during the initial postoperative period. Significant postoperative diuresis can be normal, especially in patients with completely resected growth-­ hormone-­secreting tumors.44 If the urinary output is greater than 250 mL/hour for 2 hours, plasma sodium and urinary-­ specific gravity are measured. If the former is greater than 145 and the latter is less than 1.006, this is consistent with DI. In such a case, vasopressin or longer acting desmopressin can be considered. 

SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION Hyponatremia from syndrome of inappropriate antidiuretic hormone (SIADH) secretion is a known post-­operative complication after pituitary surgery. Hyponatremia resulting from isolated SIADH, is the most common cause of 30-­day rehospitalization after pituitary surgery. It occurs in upwards of 25% of endoscopic transsphenoidal surgeries, with severe, symptomatic hyponatremia (i.e., Na 1 cm diameter). Offering surgery to avoid the possibility of rapid deterioration must be balanced by a true estimation of operative risk to the patient, bearing in mind that many of the patients will have normal-­ sized ventricles. 

SURGICAL TECHNIQUE It is strongly advised that familiarity and experience be obtained with intraventricular endoscopic surgery prior to treating colloid cysts or other intraventricular tumors. Preoperative intravenous corticosteroids are administered to reduce the potential risk of chemical ventriculitis and subsequent hydrocephalus that may occur as a result of intraventricular spillage of colloid material. It is not necessary to prepare the surgical site in anticipation of a craniotomy, except when the cyst is large (>2 cm in diameter). Because of the variability in each patient’s anatomy, surgical planning is critical in optimizing the surgical goal and reducing potential morbidity. Integrated stereotactic navigation is always used for surgical planning and optimizing ventricular cannulation (Fig. 20.7A–C). Laterality should be determined based on a preoperative MRI, with emphasis on the relative size of the frontal horns of the lateral ventricles and the dimensions of the foramen of Monro. Because the intent is to work below the ipsilateral column of the fornix, an entry site is used that is far forward of the coronal suture. In a sagittal dimension, the ideal trajectory passes just above the floor of the anterior horn, through the foramen of Monro, and below the roof of the third ventricle. In an axial and coronal plane, a trajectory is selected that passes between the head of the caudate and the column of the fornix into the foramen of Monro. Regardless of the entry site, a curvilinear incision is planned on the hairline with a variable length, depending upon the anterior location of the planned burr hole. Once the frontal horn of the lateral ventricle is entered, the anatomical landmarks of the frontal horn are identified. Using a 30-­degree angled lens, the endoscope is then rotated to offer a superiorly directed view toward the roof of the third ventricle, which is the site of attachment of the colloid cyst. The endoscope is then navigated toward the foramen of Monro, where typically the wall of the colloid

cyst is in clear sight obstructing the foramen of Monro (Fig. 20.8A and B). Generous bipolar coagulation of the choroid plexus is used to gain better visualization of the lateral cyst surface. Perforation of the cyst wall by either sharp dissection or electrocautery is utilized and followed by aspiration of the cyst contents. A graduated 6-­French endotracheal suction catheter that has had the distal fenestrations removed is preferred. With partial evacuation, the cyst can commonly be drawn into the foramen with grasping forceps. The superior aspect of the cyst can be dissected away from the roof of the third ventricle by using a rotary motion with grasping forceps, in effect pulling the cyst in an inferior direction toward the floor of the ventricle. When visualized, adherent portions of choroid plexus should be coagulated and sharply divided. The cyst may freely separate from the confines of the third ventricular roof. If this situation occurs, then the cyst should be removed by extracting the entire endoscope (Fig. 20.9). Because of the difference in size between the cyst and the working portal (1 to 2 mm), any attempt to extract the cyst through the sheath runs the risk of dislodging the cyst into the ventricular compartment. Alternatively, the cyst may be entirely evacuated of contents, leaving only adherent membrane. That membrane is then generously coagulated followed by sharp dissection. Some portions of the cyst wall may not be amenable to further removal due to adherence of venous structures. Any membrane remnants should be generously coagulated. Once the removal is complete, inspection of the third ventricle for a residual clot is performed. The placement of an externalized ventricular drain is advocated on an individual basis, depending upon the degree of intraventricular hemorrhage. Most drains are discontinued the day after surgery based on intracranial pressures within a normal range and postoperative imaging failing to indicate any appreciable hematoma within the third ventricle. 

Comparison Between Open Craniotomy and Neuroendoscopic Approaches Traditional transcallosal approaches for the lateral ventricles and the third ventricle are still valuable for tumor resection, especially for tumors larger than 2 cm. A recent meta-­analysis

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A

B

SP F

SV

TSV

CP

C

FIGURE 20.9  En bloc resection of a colloid cyst is often possible with bimanual endoscopic manipulation, but it requires removal of the entire endoscopic sheath with the cyst still adhered to the grasping forceps.

evaluating the difference between endoscopic versus microsurgical techniques for the resection of colloid cysts demonstrated a significantly higher gross total resection rate and a lower recurrence rate and decreased reoperation rate.29 Although there was no difference in the mortality rate, the overall morbidity rate was much lower in the endoscopic group. The overall morbidity was also lower in the patients

FIGURE 20.8  Anatomic familiarity with a normal foramen of Monro (A) helps orient surgical resection once the ventricle is cannulated when the anatomy is distorted by the pathology (B). The endoscope is then navigated toward the foramen of Monro, where the wall of the colloid cyst is typically in clear sight (C) obstructing the foramen of Monro. CP, Choroid plexus; F, fornix; SP, septum pellucidum; SV, septal vein; TSV, thalamostriate vein.

undergoing the transcallosal approach as opposed to the transcortical group. Shapiro et al. described an interhemispheric, transcallosal, subchoroidal approach sparing the ipsilateral fornix for approaching colloid cysts. In their study, gross-­total resection was achieved in all patients, with no deaths, infection, hemiparesis, seizures, or disconnection syndrome.30 In the presence of a cavum septum pellucidum and cavum vergae, endoscopic navigation into the third ventricle can be problematic via a transforaminal approach. Alternatively, a transcavum interforniceal route for endoscopic surgery in the third ventricle is suggested, with the rostral lamina and the anterior commissure as important anatomical landmarks. In such an approach, an interforniceal fenestration immediately behind the anterior commissure is used to enter into the third ventricle.13 ETV and endoscopic colloid cyst resection performed via a transcavum interforniceal route in patients with a coexistent septal cavum is a feasible and safe option. In Table 20.1, we outline and summarize some of the pros and cons of open surgery compared with intraventricular surgery.

POSTOPERATIVE MANAGEMENT Ventricular drainage for monitoring intracranial pressure is used on an individual basis, depending on the degree of intraventricular hemorrhage and preoperative symptoms. If, at the time of surgery, moderate intraventricular hemorrhage is experienced, then an external drain is typically

20  •  Transcallosal and Endoscopic Approach to Intraventricular Brain Tumors

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TABLE 20.1  Comparison of Intraventricular Endoscopy and Open Craniotomy for Brain Tumor Removal INTRAVENTRICULAR ENDOSCOPY

OPEN TRANSFRONTAL OR TRANSCALLOSAL

Pros

Cons

Pros

Cons

Minimize brain trauma Less memory impairment Faster recovery

Difficult to achieve hemostasis Poor bimanual surgery Difficult to remove larger tumors

Greater extent of resection Bimanual surgery Easier to achieve hemostasis

Shorter hospital stay

Incision may be visible in front of hairline Equipment costs and learning costs of new technique

Easier to remove larger tumors

More brain trauma Increased risk of memory loss Open track from ventricles to subdural space Longer recovery

Narrow track from ventricles to subdural space

used for postoperative CSF egress until the CSF clears and the patient tolerates clamping of the drain during pressure monitoring. External drainage is also used in situations where the patient had significant preoperative symptoms of raised intracranial pressure. Preoperative obtundation, a decreasing level of consciousness, or lethargy are all indicators that postoperative pressure monitoring is required, even when complete removal of the obstructing mass has been accomplished. The individual scenario gauges the duration of drainage or monitoring. If an externalized drain is to be used, consideration regarding the ultimate placement of a shunt should influence the site of externalization. A postoperative MRI or CT is routinely used during the early postoperative time period for assessment of the extent of resection, evidence of intraventricular hemorrhage, or degree of hydrocephalus. 

Summary Endoscopic surgical management for intraventricular brain tumors has burgeoned over the past decade to a field with clearly defined surgical indications, dedicated instrumentation, and general acceptance by the neurosurgical community. Patient selection requires a thorough understanding of neuro-­oncologic principles and the limitations of neuroendoscopic methods. The appeal of endoscopic management is enhanced with the ability to simplify CSF diversion through ETV or septal fenestration. Endoscopic tumor biopsy and colloid cyst resection have been shown to be highly successful, affording significant advantages over conventional neurosurgical techniques. Endoscopic excision of solid intraventricular tumors, although feasible, remains challenging due to technical limitations. Intraoperative stereotactic guidance contributes greatly toward a safer and more efficacious procedure and should be considered as an integral adjunct in patients undergoing endoscopic neurosurgery for third ventricular brain tumors or in patients without hydrocephalus. The potential of endoscopic

More comfortable for most surgeons Longer hospital stay not trained in neuroendoscopy

surgery for intraventricular brain tumors is expected to expand with technological advancements in compatible instrumentation. KEY REFERENCES

Cappabianca P, Cinalli G, Gangemi M, et al. Application of neuroendoscopy to intraventricular lesions. Neurosurgery. 2008;62(suppl 2):575–597; discussion 597–598. Delitala A, Brunori A, Chiappetta F. Purely neuroendoscopic transventricular management of cystic craniopharyngiomas. Childs Nerv Syst. 2004;20:858–862. Depreitere B, Dasi N, Rutka J, et al. Endoscopic biopsy for intraventricular tumors in children. J Neurosurg. 2007;106:340–346. Ellenbogen RG, Moores LE. Endoscopic management of a pineal and suprasellar germinoma with associated hydrocephalus: technical case report. Minim Invasive Neurosurg. 1997;40:13–15; discussion 16. Luther N, Cohen A, Souweidane MM. Hemorrhagic sequelae from intracranial neuroendoscopic procedures for intraventricular tumors. Neurosurg Focus. 2005;19:E9. Luther N, Edgar MA, Dunkel IJ, Souweidane MM. Correlation of endoscopic biopsy with tumor marker status in primary intracranial germ cell tumors. J Neuro-­Oncol. 2006;79:45–50. Pople IK, Athanasiou TC, Sandeman DR, Coakham HB. The role of endoscopic biopsy and third ventriculostomy in the management of pineal region tumours. Br J Neurosurg. 2001;15:305–311. Schwartz TH, Ho B, Prestagiacomo CJ, et al. Ventricular volume following third ventriculostomy. J Neurosurg. 1999;91:20–25. Shono T, Natori Y, Morioka T, et al. Results of a long-­term follow-­up after neuroendoscopic biopsy procedure and third ventriculostomy in patients with intracranial germinomas. J Neurosurg. 2007;107:193–198. Souweidane MM. Endoscopic management of pediatric brain tumors. Neurosurg Focus. 2005;18:E1. Souweidane MM. Endoscopic surgery for intraventricular brain tumors in patients without hydrocephalus. Neurosurgery. 2005;57:312–318; discussion 312–318. Souweidane MM, Luther N. Endoscopic resection of solid intraventricular brain tumors. J Neurosurg. 2006;105:271–278. Souweidane MM, Sandberg DI, Bilsky MH, Gutin PH. Endoscopic biopsy for tumors of the third ventricle. Pediatr Neurosurg. 2000;33:132–137. Souweidane MM, Hoffman CE, Schwartz TH. Transcavum interforniceal endoscopic surgery of the third ventricle. J Neurosurg Pediatr. 2008;2(4):231–236; PubMed PMID: 18831654.

Numbered references appear on Expert Consult.

REFERENCES

1. Cappabianca P, et al. Application of neuroendoscopy to intraventricular lesions. Neurosurgery. 2008;62(suppl 2):575–597; discussion 597–8. 2. Naftel RP, et al. Small-­ ventricle neuroendoscopy for pediatric brain tumor management. J Neurosurg Pediatr. 2011;7(1):104–110. 3. Souweidane MM. Endoscopic surgery for intraventricular brain tumors in patients without hydrocephalus. Neurosurgery. 2005;57(suppl 4):312–318; discussion 312–318. 4. Souweidane MM. Endoscopic surgery for intraventricular brain tumors in patients without hydrocephalus. Neurosurgery. 2008;62(6 suppl 3):1042–1048. 5. Ogiwara H, Morota N. Flexible endoscopy for management of intraventricular brain tumors in patients with small ventricles. J Neurosurg Pediatr. 2014;14(5):490–494. 6. Lee MH, et al. Neuroendoscopic biopsy of pediatric brain tumors with small ventricle. Childs Nerv Syst. 2014;30(6):1055–1060. 7. Belykh E, et al. Laser application in neurosurgery. Surg Neurol Int. 2017;8:274. 8. Karsy M, Patel DM, Bollo RJ. Trapped ventricle after laser ablation of a subependymal giant cell astrocytoma complicated by intraventricular gadolinium extravasation: case report. J Neurosurg Pediatr. 2018:1–5. 9. Catapano G, et al. Multimodal use of indocyanine green endoscopy in neurosurgery: a single-­center experience and review of the literature. Neurosurg Rev. 2017. 10. Sasagawa Y, et al. Narrow band imaging-­guided endoscopic biopsy for intraventricular and paraventricular brain tumors: clinical experience with 14 cases. Acta Neurochir (Wien). 2014;156(4):681–687. 11. Finger T, et al. Augmented reality in intraventricular neuroendoscopy. Acta Neurochir (Wien). 2017;159(6):1033–1041. 12. Delitala A, Brunori A, Chiappetta F. Purely neuroendoscopic transventricular management of cystic craniopharyngiomas. Childs Nerv Syst. 2004;20(11-­12):858–862. 13. Souweidane MM, Hoffman CE, Schwartz TH. Transcavum interforniceal endoscopic surgery of the third ventricle. J Neurosurg Pediatr. 2008;2(4):231–236. 14. Oppido PA. Endoscopic reconstruction of CSF pathways in ventricular tumors. Acta Neurochir Suppl. 2017;124:89–92. 15. Depreitere B, et al. Endoscopic biopsy for intraventricular tumors in children. J Neurosurg. 2007;106(suppl 5):340–346. 16. Souweidane MM. Endoscopic management of pediatric brain tumors. Neurosurg Focus. 2005;18(6A):E1.

17. Souweidane MM, et al. Endoscopic biopsy for tumors of the third ventricle. Pediatr Neurosurg. 2000;33(3):132–137. 18. Matsutani M, et al. Primary intracranial germ cell tumors: a clinical analysis of 153 histologically verified cases. J Neurosurg. 1997;86(3):446–455. 19. Huang X, et al. Recent advances in molecular biology and treatment strategies for intracranial germ cell tumors. World J Pediatr. 2016;12(3):275–282. 20. Luther N, Cohen A, Souweidane MM. Hemorrhagic sequelae from intracranial neuroendoscopic procedures for intraventricular tumors. Neurosurg Focus. 2005;19(1):E9. 21. Chrastina J, et al. Diagnostic value of brain tumor neuroendoscopic biopsy and correlation with open tumor resection. J Neurol Surg A Cent Eur Neurosurg. 2014;75(2):110–115. 22. Ellenbogen RG, Moores LE. Endoscopic management of a pineal and suprasellar germinoma with associated hydrocephalus: technical case report. Minim Invasive Neurosurg. 1997;40(1):13–15; discussion 16. 23. Luther N, et al. Correlation of endoscopic biopsy with tumor marker status in primary intracranial germ cell tumors. J Neurooncol. 2006;79(1):45–50. 24. Pople IK, et al. The role of endoscopic biopsy and third ventriculostomy in the management of pineal region tumours. Br J Neurosurg. 2001;15(4):305–311. 25. Shono T, et al. Results of a long-­term follow-­up after neuroendoscopic biopsy procedure and third ventriculostomy in patients with intracranial germinomas. J Neurosurg. 2007;107(suppl 3):193–198. 26. Qiao L, Souweidane MM. Purely endoscopic removal of intraventricular brain tumors: a consensus opinion and update. Minim Invasive Neurosurg. 2011;54(4):149–154. 27. Souweidane MM, Luther N. Endoscopic resection of solid intraventricular brain tumors. J Neurosurg. 2006;105(2):271–278. 28. Hidalgo ET, et al. Resection of intraventricular tumors in children by purely endoscopic means. World Neurosurg. 2016;87:372–380. 29. Sheikh AB, Mendelson ZS, Liu JK. Endoscopic versus microsurgical resection of colloid cysts: a systematic review and meta-­analysis of 1,278 patients. World Neurosurg. 2014;82(6):1187–1197. 30. Shapiro S, et al. Interhemispheric transcallosal subchoroidal fornix-­ sparing craniotomy for total resection of colloid cysts of the third ventricle. J Neurosurg. 2009;110(1):112–115.

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CHAPTER 21

Management of Pineal Region Tumors RANDY S. D’AMICO  •  JEFFREY N. BRUCE

History Pineal region tumors encompass a diverse group of tumors that can arise from pineal parenchymal cells, supporting cells of the pineal gland, or glial cells from the midbrain and medial walls of the thalamus. These tumors occupy a central position that is equidistant from various cranial points traditionally used as routes of exposure. The surgical management of these lesions remains complex and intimidating despite many advances in microsurgical techniques and associated outcomes. The deep central location places these tumors in intimate contact with important components of the deep venous system that lie dorsally, including the vein of Galen, the precentral cerebellar vein, and the internal cerebral veins.1 Although pineal region tumors affect a relatively small number of patients, their variable histology—carrying individual therapeutic and prognostic implications—in combination with the development of a variety of demanding yet adaptable surgical approaches has generated a comparatively large volume of literature. Importantly, neurosurgical intervention has remained vital to the diagnosis and management of pineal region lesions and ranges from biopsy to complete resection with variable benefit.2–5 Over the years, various supratentorial and infratentorial approaches have been developed by several prominent neurosurgeons including Dandy’s interhemispheric approach, Van Wagenen’s transventricular approach, and Poppen’s occipital transtentorial (OTT) approach.6 The supracerebellar infratentorial (SCIT) approach was first described in 1926, when Krause reported three cases of pineal region tumors which he approached through the posterior fossa, over the cerebellar hemispheres, and under the tentorium.7 In the 1970s, the increasing use of the operating microscope rekindled interest in direct surgical approaches to the pineal region.7–9 This led to considerable debate over the best surgical route to the pineal region and further stimulated interest in operating on these tumors to identify their nature and remove them whenever possible.10,11 A more aggressive approach to pineal region tumors resulted in a greater awareness of the histologic diversity of these tumors which generally exist along a spectrum from benign to highly malignant. Importantly, despite significant advances in radiographic imaging and increased experience with tumor markers, preoperative diagnostic tests have remained

226

insufficient, and accurate determination of histologic typing still requires operative intervention. With experience however, the mortality and morbidity rates from the various surgical approaches have dropped steadily and led to the current management philosophy for pineal tumors, which relies on an aggressive surgical approach for the removal of benign tumors and decompression and accurate histologic diagnosis of malignant tumors.2 This philosophy based on aggressive resection has yielded excellent long-­term outcomes for patients with benign disease and improved outcomes in patients with malignant lesions. 

Clinical Features PATHOLOGY Pineal parenchyma is comprised of lobules of pinealocytes surrounded by astrocytes with ependymal cells of the third ventricle lining the anterior border of the gland. The various cell types that comprise the mature pineal gland and surrounding region account for the diversity of histologic tumor subtypes that can occur in the pineal region. The term pinealoma was originally used by Krabbe to describe tumors arising within the pineal region and is a misnomer because it originally pertained to germ cell tumors.12 Eventually, the term was applied more generically to refer to any tumors of the pineal region. However, ultimately, the term became obsolete in favor of pineal region tumors for a general reference, or in favor of the individual tumor’s histology when specificity is preferred (e.g., astrocytoma of the pineal region). As such, pineal tumors are currently grouped into four main categories: germ cell tumors, pineal cell tumors, glial cell tumors, and miscellaneous tumors (covering a wide range of histology). Each category contains tumors existing along a continuum from benign to malignant and can include mixed tumors of more than one cell type.13 

PRESENTATION Regardless of their histology, tumors in the pineal region generally become symptomatic by three mechanisms:13 1. Increased intracranial pressure from hydrocephalus 2. Direct cerebellar or brain stem compression 3. Endocrine dysfunction Headache, the most common presenting symptom, occurs after obstruction of the third ventricle outflow at the

21  •  Management of Pineal Region Tumors

227

sylvian aqueduct. More advanced hydrocephalus can result in nausea, vomiting, papilledema, obtundation, and other cognitive deficits. Direct brain stem compression may lead to disturbances of extraocular movements, classically known as Parinaud syndrome. Involvement of the superior cerebellar peduncles can lead to ataxia and dysmetria. Hearing disturbances can occasionally occur, probably from compression of the inferior colliculi.14 Endocrine dysfunction is rare and may be caused by direct tumor involvement in the hypothalamus or from secondary effects of hydrocephalus.15 Diabetes insipidus and other neuroendocrine disturbances are often indicative of hypothalamic infiltration by tumor, even when not radiographically visualized. 

LABORATORY DIAGNOSIS α-­Fetoprotein (AFP) and β-­human chorionic gonadotropin (β-­hCG) are markers of germ cell malignancy and should be measured in serum and cerebrospinal fluid (CSF) if possible, as part of the preoperative workup in all pineal region tumor patients.2,16,17 Elevation of germ cell markers is pathognomonic for the presence of malignant germ cell elements and may preclude surgical intervention for tumors with sensitivities to chemotherapy and radiation, saving resection for residual or recurrent tumors only.18 In patients with marker-­ positive germ cell tumors, measurement of marker levels can also be useful to monitor therapeutic response and as a sensitive early sign of tumor recurrence.2,19 The absence of germ cell markers should be interpreted cautiously because malignant germ cell tumors such as germinomas and embryonal cell carcinomas cannot be ruled out. Specifically, AFP is associated with fetal yolk sac elements and is markedly elevated with endodermal sinus tumors, whereas smaller elevations occur with embryonal-­cell carcinomas and immature teratomas. Notably, elevations in AFP in the presence of a germinoma suggest a mixed tumor with embryonal-­cell or endodermal sinus tumor components. β-­ hCG is normally secreted by placental trophoblastic tissue and indicates the presence of choriocarcinoma, with smaller elevations associated with embryonal cell carcinomas and those occasional germinomas containing syncytiotrophoblastic giant cells.20 Importantly, most germinomas are nonsecretory and carry a better prognosis than β-­hCG positive germinomas.21 

FIG. 21.1  Sagittal magnetic resonance imaging with contrast shows a large pineal region tumor. The anatomic relationships of the tumor are well identified, including the third ventricle, aqueduct, and quadrigeminal plate.

IMAGING The standard diagnostic workup includes magnetic resonance imaging (MRI), with and without contrast. MRI provides information on type, size, and extent of the tumor, anatomic features such as degree of invasion, vascularity, and the anatomic relationships of the tumor with its surroundings, as well as permits the evaluation of associated hydrocephalus (Fig. 21.1). Some tumors can be suspected from the appearance of the scans, particularly teratomas, which contain multiple germ layers (Fig. 21.2). Angiography is only performed if the MRI suggests a vascular lesion such as a vein of Galen aneurysm or arteriovenous malformation. Despite this broad diagnostic armamentarium, the exact histologic nature of the tumor cannot be reliably determined without surgery.13 The increasing use of MRI has revealed a large number of patients with lesions of the pineal gland that are mostly

FIG. 21.2  Magnetic resonance imaging with contrast (axial view) demonstrates the typical variegated pattern of a mixed germ cell tumor of the pineal region. The heterogeneity of lesions such as this in the pineal region can lead to misdiagnosis from sampling error.

cystic but contain a small amount of solid tissue (Fig. 21.3).22,23 Initially, these lesions were considered to be low-­ grade cystic astrocytomas. However, after surgical removal, most were found to be composed of normal astrocytes and normal pineal cells. Histologically, pineal cysts are now considered normal anatomic variations of the pineal gland, and as experience with pineal cysts has increased, it has become clear that they should be managed conservatively with serial

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astrocytoma within the pineal region or be otherwise infiltrated by more malignant, diffusely infiltrative tumors of the pineal region, ultimately encompassing the aqueduct in the course of tumor growth. The most important aspects of the anatomy, which can be gleaned by radiographic imaging, are the relationship of the tumor to the third ventricle and quadrigeminal cistern, and the lateral and superior extent of the tumor. These features determine the route of the operation and the degree of difficulty likely to be encountered during surgery.1 

HYDROCEPHALUS

FIG. 21.3  Sagittal magnetic resonance imaging with contrast shows an incidental pineal cyst discovered during the workup for unrelated headaches. The aqueduct is not compromised, and there is no hydrocephalus. Pineal cysts are anatomic variants and do not require treatment except in rare instances when they become symptomatic.

MRI scans and without surgery. In most cases of pineal cysts, the aqueduct is not compromised and patients are otherwise asymptomatic. As a result, surgery is reserved for lesions that are symptomatic, progressing in size, or causing hydrocephalus. Dedicated spinal column imaging is critical as many malignant pineal region tumors may seed the spinal canal. Preoperative imaging avoids the difficulties of interpretation of postintervention imaging studies. 

Preoperative Considerations SURGICAL ANATOMY Most pineal region tumors arise from or develop attachments to the undersurface of the velum interpositum and tela choroidea with rare superior extension. As a result, these lesions involve the choroid plexus, deep venous system, and posterior choroidal arteries, and these structures may be tightly adjacent to the tumor or intimately involved, depending on the degree of tumor invasion. Tumor blood supply frequently comes from within the velum interpositum, mainly through small-­caliber posterior medial and lateral choroidal arteries with anastomoses to the pericallosal arteries and quadrigeminal arteries.1,24 These vessels generally do not supply any clinically significant areas of the brain. While some tumors extend ventrally to the foramen of Monro, most are centered at the pineal gland, extending to the midportion of the third ventricle and posteriorly to compress the anterior portion of the cerebellum. In rare instances, the internal cerebral veins are ventral to the tumor. More typically, however, the vein of Galen, internal cerebral veins, basal veins of Rosenthal, and precentral cerebellar vein surround or cap the periphery of these tumors. The quadrigeminal plate may give rise to an exophytic

Tumor-­associated compression of the cerebral aqueduct or the posterior third ventricle results in obstructive hydrocephalus in most patients and may be managed in several ways.2 Preoperative CSF diversion treats symptomatic hydrocephalus and offers an opportunity to identify the presence of tumor markers. If urgent, bedside placement of an external ventricular drain (EVD) can be performed. This strategy may also be utilized when a complete tumor removal is anticipated and a permanent ventriculoperitoneal shunt may not be necessary. Ventricular drains can be removed or converted to a permanent shunt on postoperative day 2 or 3, conditional with patient dependence on permanent CSF diversion. Occasionally, in mildly symptomatic patients, no preoperative or permanent CSF diversion is necessary, and the hydrocephalus resolves after complete tumor removal as there is a reduction of mass effect on the cerebral aqueduct and communication of the third ventricle with the quadrigeminal cistern through the operative corridor. Patients with more advanced symptomatology should be managed with an image-­guided stereotactic endoscopic third ventriculostomy (ETV) to allow a gradual reduction in intracranial pressure and resolution of symptoms.25 This method is preferable to ventriculoperitoneal shunting as it eliminates potential complications such as infection, over­ shunting, subdural hematoma, and peritoneal seeding of malignant cells classically associated with ventriculoperitoneal shunt insertion.26 Contraindications to ETV include the presence of tumor occupying the floor of the third ventricle or an unfavorable relationship between the floor of the third ventricle and the basilar artery. ETV also permits endoscopically assisted biopsy of pineal region tumors through the posterior ventricle during the same procedure in some situations. 

BIOPSY VERSUS RESECTION Tumor histology is critical for making decisions concerning adjuvant therapy, metastatic workup, prognosis, and long-­ term follow-­up for pineal region lesions. The wide diversity of pathology that can occur makes histologic diagnosis a necessity to optimize patient management decisions.2 This diversity remains problematic for even experienced neuropathologists, who can best resolve the subtleties of histologic diagnosis when free from the constraints of limited tissue sampling.27–29 As a result, the most reliable strategy to ensure accurate diagnosis is to ensure adequate tissue sampling. Strategies for tissue sampling include stereotactic and endoscopic biopsies or open surgical procedures. Passionate advocates for either approach can be found. However, it is important to recognize the relative advantages and disadvantages of each and use them in a complementary fashion

21  •  Management of Pineal Region Tumors

for appropriate patients rather than having an inflexible dedication to one. Ultimately, the radiographic and clinical features of the tumor and the surgeon’s experience will influence procedural decisions. Experienced neurosurgeons using current microsurgical techniques can expect favorable results with open surgery.2 Open procedures have the advantage of providing more extensive tissue sampling. This is particularly important for pineal region tumors where heterogeneity and mixed cell populations are common. Additionally, open procedures provide a clinical advantage by facilitating tumor removal.2,30,31 This is particularly important for the one third of patients with benign pineal tumors, in whom resection is usually complete but can also be useful for patients with malignant tumors in whom debulking may provide a more favorable response to adjuvant therapy and a better long-­ term prognosis. Additional advantages of aggressive tumor debulking include the ability to reduce mass effect on critical neural structures, the potential to relieve hydrocephalus without additional procedures, and the ability to control the risks of postoperative hemorrhage into an incompletely resected tumor bed.30 A disadvantage of open procedures is the relatively higher surgical morbidity compared with that of stereotactic biopsy, at least in the short term. This short-­ term disadvantage, however, may be a reasonable concession for the long-­term advantage of better tumor control. Any discussion about the relative risks and benefits of open procedures must recognize that the highly favorable outcome for patients with pineal tumors assumes an advanced level of experience, judgment, and expertise. Stereotactic procedures, in contrast, can be appealing because of their ease of performance. Biopsy may be preferred in patients with known primary systemic tumors, multiple lesions, or other comorbidities that may increase surgical risk. Biopsy may also be preferable for tumors that are clearly invading the brain stem. However, the degree of invasion is not always easily discernible, and tumors may have a surgically dissectible capsule that is not predicted on preoperative imaging studies. It is critical to understand that the pineal region is among the most hazardous areas in the brain to safely biopsy, and careful forethought must be given to planning the target and trajectory to minimize hemorrhagic risks.32 The potential for hemorrhage is increased because of several mechanisms including: bleeding from any of several pial surfaces that must be traversed, bleeding from highly vascular tumors, damage to the deep venous system, and bleeding into the ventricle, where the tissue turgor is insufficient to tamponade minor bleeding.33,34 Both techniques have been associated with risks of postoperative hemorrhage and obstructive hydrocephalus.35–38 Furthermore, tissue sampling is limited with either stereotactic or endoscopic biopsy and may result in inaccurate diagnosis due to sampling error. Despite these risks, several series have validated the effectiveness of stereotactic biopsy for these tumors.32,39 The exception to mandatory histologic diagnosis occurs in patients with elevated germ cell markers who can be treated with chemotherapy and radiation without a biopsy.19,20 A minority of these patients who undergo treatment for germ cell tumors based on presumptive CSF markers will ultimately require a delayed surgical resection to remove residual radiographic abnormalities that may represent residual tumor or recurrence.40 In all other situations, CSF cytology

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and radiographic examination are considered insufficiently consistent to supplant the need for a tissue diagnosis. 

STEREOTACTIC BIOPSY Advances in radiographic imaging and software planning provide several alternatives for safely planning biopsy trajectories. Stereotactically guided procedures are acceptable because of their high degree of accuracy and common availability. Although nearly any stereotactic frame system is sufficient, target-­centered stereotactic frame systems such as the Cosman-­Roberts-­Wells (CRW) have the versatility to facilitate even complex biopsies. Recent advances in frameless stereotactic guidance systems also provide a variety of accurate methodologies for accurate and safe stereotactic biopsy. Local anesthesia with mild sedation is safe and usually sufficient to perform biopsies. The most common surgical trajectory to the pineal region is via an anterolaterosuperior approach anterior to the coronal suture and lateral to the midpupillary line. This trajectory passes through the frontal lobe and the internal capsule. The ependyma of the lateral ventricle and the internal cerebral veins should be avoided. An alternative approach is a posterolaterosuperior approach through the parieto-­occipital junction, which is best suited for large tumors that have a lateral extension. Whenever possible, multiple serial biopsy specimens should be obtained. Obviously, the risks of bleeding for each additional specimen must be considered, taking into account the size of the mass. A frozen section intraoperatively may be useful in verifying pathologic tissue. However, the high diversity of tissue types reduces the accuracy of a frozen tissue diagnosis. 

ENDOSCOPY Advances in endoscopic technique have led to investigations of biopsies via this method.41–44 Endoscopy is sometimes performed in conjunction with ETV to relieve hydrocephalus. Performing a ventriculostomy and biopsy simultaneously requires the use of a flexible endoscope because of the limited trajectory to the tumor through the foramen of Monro. A rigid endoscope can be used but would necessitate a second burr hole and trajectory with a more inferior entry point on the forehead. The risks of an endoscopic biopsy are considerable due to the limited tissue sampling and difficulty achieving hemostasis within the ventricle. Even minor bleeding can obscure the operative field, making it difficult to identify the target. In general, given these limitations, a stereotactic biopsy is preferable to endoscopic biopsy in situations in which diagnostic tissue is desired. 

Surgical Approaches PREOPERATIVE CONSIDERATIONS Common approaches to the pineal region are broadly categorized as supratentorial or infratentorial and include the SCIT, OTT, and interhemispheric transcallosal (IHTC) (Fig. 21.4).13 The best approach relies on careful anatomic evaluation as well as the degree of familiarity and confidence that the surgeon has with a given approach (Fig. 21.5). In general, the SCIT approach is preferred for several reasons:

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Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

Interhemispheric transcallosal

Occipital transtentorial Straight sinus

Supracerebellar infratentorial

FIG. 21.4  Surgical approaches to the pineal region.

A

B

C

FIG. 21.5  Midsagittal gadolinium enhanced magnetic resonance images illustrate the preferred surgical approaches. (A) Meningioma of the velum interpositum with dorsal displacement of internal cerebral veins is best approached via the infratentorial supracerebellar corridor. (B) Pilocytic astrocytoma arising from the corpus callosum with ventral displacement of the internal cerebral veins is best approached via the posterior-­ interhemispheric corridor. (C) Tectal glioma is best approached via the occipital transtentorial corridor to facilitate access to the inferior portion of the tumor.

1. The approach is to the center of the tumor, which begins at the midline and grows eccentrically. 2. The approach is inferior to the velum interpositum and the deep venous system to which the tumor is often adherent. This minimizes the risk of damage to the vascular drainage of this critical region. 3. The exposure in the sitting position is comparable with that of other routes. 4. No normal tissue is violated along the operative corridor. Either the OTT or the IHTC approaches are used under the following circumstances: 1. Tumors that extend superiorly, involving or destroying the posterior aspect of the corpus callosum and deflecting the deep venous system in a dorsolateral direction 2. Tumors that extend laterally to the region of the trigone 3. Tumors that extend inferiorly into the quadrigeminal plate

4. In rare cases in which the tumor displaces the deep venous system in a ventral direction (often seen with meningiomas) In general, supratentorial approaches provide greater exposure than infratentorial approaches with the caveat that the surgeon must work carefully around the convergence of the deep cerebral veins. The IHTC approach can provide extensive exposure, although the subtentorial portion of the tumor on the contralateral side of the approach is not easily visualized. This approach requires retraction of the parietal lobe and the disruption of bridging veins between parietal lobe and the sagittal sinus, creating the potential for venous infarct and retraction injury. Like the transcallosal approach, the OTT approach has the disadvantage of encountering the deep venous system overlying the tumor. Once the tentorium is divided, however, this approach permits a wide view of the pineal region with particularly good visualization of

21  •  Management of Pineal Region Tumors

A

231

B

FIG. 21.6  (A) Seated position and (B) diagram of the patient position and operative setup for the supracerebellar approach.

the quadrigeminal plate. A major drawback is the high frequency of visual field deficits associated with this approach.45 

PATIENT POSITION Patient positioning is critical to successful surgery within the pineal region. There are three basic positions with variations and nuances of each that can be used somewhat interchangeably based on individual tumors and surgeon preferences with advantage^s and disadvantages to each. The three basic positions include: sitting position, lateral position, and prone. The sitting position is used most often for the SCIT approach. This position enables gravity to work in the surgeon’s favor by helping tumor dissection from the roof of the third ventricle and minimizing blood pooling in the operative field. It does carry the risk of air embolus or ventricular and cortical collapse with subsequent subdural hematoma or air. However, with proper precautions, these complications are infrequent. The OTT approach often uses the three-­quarter prone and lateral decubitus position, which, although avoiding many of the complications of the sitting position, does not allow gravity to work in the surgeon’s favor. The Concorde position was developed to combine aspects of both the prone and semisitting positions but still has the disadvantage of blood pooling in the operative field.46

Sitting Position The sitting position is preferred for the SCIT approach (Fig. 21.6). The sitting position is accomplished by raising the back of the table to its maximal position. The patient’s head, neck, and shoulders are brought forward by a pin vice head fixation device. The head must be strongly flexed so that optimal exposure of the tentorial notch can be achieved with the greatest comfort to the surgeon while care is taken to avoid kinking of the endotracheal tube, obstruction of venous outflow, and cervical spine injury. Ideally, the patient is positioned such that the tentorium is as parallel to the floor of the operating room as possible. The patient is tilted somewhat forward after being positioned on the operating table so that the surgeon actually works over the back of the patient’s shoulders to the posterior fossa. The legs should be

elevated and slightly flexed to facilitate venous return and minimize sciatic stretch injury. Risks of air embolism, pneumocephalus, and subdural hematoma should be anticipated and proper precautions taken. A Doppler probe, end tidal pCO2 evaluation, and modest positive pressure ventilation are used to recognize and avoid air embolism, which can occur during the bone opening or when large venous sinuses are exposed. Rarely, a central venous line may be placed in accordance with surgeon preference to remove entrapped air. A self-­retaining retractor such as Greenberg’s universal retractor is fixed via a bar to the operating table on the left side. The bars are then arranged in a rectangular configuration framing the operative field, facilitating placement of a retractor in the anterior position to depress the cerebellum. A cottonoid tray is fixed to the self-­retaining retractor system and held by one of the retractor’s arms. Gravity works to reduce pooling blood and CSF in the operative field and to allow the cerebellum to naturally retract with minimal fixed retractors. This also facilitates dissection off the deep venous system typically displaced dorsal to the tumor. 

Lateral and Three-­Quarter Prone Position The lateral position and its variant, the three-­quarter prone position, are generally preferred for the OTT approach. The lateral decubitus position is preferred with the dependent nondominant right hemisphere down. For the transcallosal approach, the head is raised approximately 30 degrees above the horizontal in the midsagittal plane, while with the OTT approach, the patient’s nose is rotated 30 degrees toward the floor. The three-­quarter prone position is a useful variant of this approach. It is an extension of the lateral position with the head at an oblique 45-­degree angle with the nondominant hemisphere in the dependent position. Again, gravity is exploited to facilitate natural retraction of the dependent hemisphere. Compared to the sitting position, the surgeon’s hands are on a horizontal plane and less prone to fatigue. This position can be cumbersome to set up, and it is important to avoid unnecessary pressure on the dependent axilla by placing in an axillary roll and supporting the right arm

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in a sling-­like fashion. A supporting roll is placed under the left thorax, and the head pin holder is used to support the head slightly extended and rotated to the left at a 45-­degree oblique angle. The patient must be securely strapped at the table, which will facilitate rotation of the table as needed. 

Prone Position The prone position can be useful in pineal region surgery and allows two surgeons to work together through the operative microscope. It is particularly useful for the supratentorial approaches, particularly the transcallosal, but can be cumbersome in infratentorial approaches where the benefits of gravity are lost. Without specialized operative tables, the head position can be considerably raised, making it difficult for the surgeon to be seated during the surgery. A variant of the prone position known as the Concorde position has been advocated for infratentorial approaches, particularly in the pediatric population. In the Concorde position, the position of the head is rotated 15 degrees away from the craniotomy side. 

OPERATIVE APPROACHES Supracerebellar Infratentorial The SCIT approach follows a relaxed, natural midline corridor to the pineal region and is best suited for tumors arising below the deep cerebral veins, without extensive lateral or caudal extension.2,5 Preoperative evaluation for a steep tentorial angle or a low-­lying torcula is critical and occasionally may suggest an alternate approach. Once the patient is optimally placed in the sitting position, a self-­retaining retractor, such as Greenberg’s Universal Retractor, is fixed via a bar to the operating table on the left side (see Fig. 21.6). The bars are then arranged in a rectangular configuration framing the operative field, facilitating placement of a retractor in the inferior position to depress the cerebellum. A cottonoid tray is fixed to the self-­retaining retractor system and held by one of the retractor’s arms. A long midline incision is made from just above the torcula to approximately the C4 spinous process so that the pericranium and muscle attachments can be elevated on each side without disrupting their continuity. Freeing up the muscle layer facilitates closure later. A wide craniotomy is performed to include the sagittal sinus above the torcula, the transverse sinuses bilaterally, and torcula but without extending to the foramen magnum. Generally, using a high-­ speed air drill to perform a suboccipital craniotomy centered just below the torcula is preferred so that the bone flap may be replaced at the end of the procedure, which reduces the incidence of postoperative aseptic meningitis, fluid collections, and discomfort. A craniotome is used to turn the flap after first exposing each of the dural sinuses to avoid tears. Bone edges are waxed and all venous bleeding controlled to mitigate air emboli. A wide craniotomy is preferred to provide room for instruments and adequate light from the microscope. Brain relaxation and cerebellar retraction can be facilitated by mannitol, ventricular drainage, or removal of cerebrospinal fluid from the cisterna magna. The dura is opened in a curvilinear fashion, reflected superiorly, and anchored with slight tension to maximize dural retraction while avoiding sinus occlusion. The dural opening should

FIG. 21.7  Dural opening prior to sacrifice of bridging veins.

extend bilaterally up to the inferior edge of the transverse sinus (Fig. 21.7). Once the dura is opened, the operating microscope should be brought to the operating table. A microscope capable of varying the objective length from 275 to 400 mm is desirable because the operating distance for the surgeon changes throughout the operation, going from the dorsal surface of the cerebellum to the center of the third ventricle. The use of a freestanding armrest is also helpful in minimizing fatigue. At this point, only bridging veins over the dorsal surface of the cerebellum interfering with the approach or sufficient retraction, including those over the hemispheres and vermis, can be sacrificed to free the cerebellum from the tentorium. Great effort is made to minimize disruption of the extensive collateral circulation by sparing thick bridging veins and lateral hemispheric bridging veins. Veins should be cauterized and divided midway to minimize sinus bleeding. The weight of cottonoids and a retractor, along with gravitational forces that are exerted in the sitting position, allow sufficient depression of the cerebellum to establish an unobstructed corridor to the pineal region under the tentorium. The dissection is continued ventrally until the arachnoid of the quadrigeminal region is encountered. The arachnoid in the quadrigeminal region and around the incisura is usually thickened and opaque in the presence of tumors and must be opened by microdissection techniques to expose the surface of the tumor. The precentral cerebellar vein, which can be seen extending from the edge of the vermis to vein of Galen, should be cauterized and divided as far as possible from the confluence of the basal veins of Rosenthal to avoid progression of thrombus and potential venous infarct (Fig. 21.8). The vein of Galen and the internal cerebral veins are usually well above the tumor and are not encountered in these initial maneuvers. Sacrifice of veins of the deep venous system is not advisable. Laterally, the medial aspect of the temporal lobe and Rosenthal’s veins can be seen as they course upward toward the confluence of veins. In general terms, the trajectory of the operation is toward the velum interpositum. This must be considered when attempting to remove segments of the tumor in the inferior portion of the third ventricle or directly

21  •  Management of Pineal Region Tumors

A

233

B

FIG. 21.8  Operative view shows exposure of the posterior surface of a tumor in the pineal region (A) before and (B) after sacrificing the precentral cerebellar vein.

over the quadrigeminal plate in relation to the anterior lobe of the cerebellum. At this point, the microscope and retractor (if still necessary after CSF removal) are adjusted to visualize the inferior portion of the tumor. The thickened arachnoid covering the pineal gland should be opened widely to appreciate the underlying anatomy. Using sharp dissection, the arachnoid opening must be kept close to the anterior surface of the vermis and cerebellar hemisphere to avoid injuring the deep venous system, keeping in mind that the initial trajectory is toward the vein of Galen. The anterior portion of the cerebellum is retracted by the inferior self-­retaining retractor to expose the posterior surface of the tumor. The central portion of the tumor is subsequently cauterized and opened and specimen taken and sent for frozen intraoperative pathological consultation. The tumor is debulked. Because many of these tumors extend well into the third ventricle, even to the region of the foramen of Monro, long instruments are required to reach the anterior margins of the tumor. With tumors of firm consistency, an ultrasonic aspirator with a long, curved tip can be helpful for debulking. A long focal length is desirable to accommodate the large instrument and maneuver into the operative field. The most difficult dissection involves the inferior portion of the tumor, where it is adherent to the collicular region of the dorsal midbrain. Small dental mirrors and angled instruments may be required to remove this portion of the tumor. Similarly, these techniques may be helpful for supratentorial tumor extensions. Further exposure can be gained by incising the tentorium if necessary. With sufficient internal decompression, separation of the tumor from the surrounding thalamus and midbrain becomes possible. Posterior choroidal arterial vessels along the lateral wall of the tumor need not be preserved. The tumor is finally lifted superiorly and removed from the junction of the brainstem with blunt and sharp dissection as necessary. Tumors that are benign or encapsulated can usually be removed completely (Fig. 21.9). With tumors that are incompletely resected, particularly vascular ones such as pineal cell tumors, meticulous hemostasis is crucial. Surgicel is the preferred hemostatic agent, and it should be placed

carefully so that it does not float and obstruct the aqueduct when the third ventricle fills with CSF. At the conclusion of the operation, after decompression of the tumor and the ventricular system, the dura can be closed to support the cerebellum. When a craniotomy has been performed, the bone flap is secured back in place. A greater degree of dural and bony closure seems to lower the incidence of postoperative aseptic meningitis. Risks associated with the SCIT approach reflect the sitting position and include air embolism, pneumocephalus, and subdural hematomas. 

Lateral Supracerebellar Infratentorial The lateral SCIT approach uses a paramedian corridor to the pineal region with a slightly longer trajectory over the quadrangular lobule that provides a less steep, more direct angle to the pineal region (Fig. 21.10). Use of the lateral SCIT avoids the apex of the culmen and the numerous bridging veins of the median supracerebellar region.47,48 Similar to the traditional SCIT, the lateral approach is performed in the sitting or lateral decubitus position. The head is rigidly immobilized, turned slightly, and flexed to ensure optimal utilization of the surgical corridor (see Fig. 21.10A). A spinal drain or occipital EVD is placed to assist with brain relaxation if CSF diversion has not already been employed. A 7-­to 8-­cm linear incision is made halfway between the inion and the transverse-­ sigmoid junction extending above and below the transverse sinus (see Fig. 21.10B). The suboccipital musculature is separated and retracted, permitting a small, paramedian craniotomy, which exposes the transverse sinus while leaving the torcula protected (see Fig. 21.10C). A single curved dural flap is opened and retracted toward the sinus, where tentorial retraction sutures are used to elevate the transverse sinus and expand the operative corridor (see Fig. 21.10D). CSF release through lumbar drainage facilitates retraction of the cerebellar hemisphere caudally. The surgical corridor is developed above the cerebellum and beneath the tentorium. Great effort is made to leave large median and lateral bridging veins intact if possible. Arachnoid dissection and tumor resection is carried out as with a standard SCIT with care to

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Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

A

B

FIG. 21.9  (A) preoperative post-­contrast magnetic resonance imaging of the brain demonstrating large pineal parenchymal tumor of intermediate differentiation extending ventrally into the third ventricle with minimal inferior extension. (B) Tumors that are benign or well encapsulated can be removed completely using the supracerebellar infratentorial approach.

A

D

B

E

C

F

FIG. 21.10  Lateral supracerebellar infratentorial approach. (A) The patient is placed in the sitting position with the head turned and flexed slightly in rigid fixation to optimize the operative corridor. (B) Incision is marked halfway between the inion and the transverse-­sigmoid junction, extending above and below the transverse sinus. (C) The suboccipital musculature is separated and retracted laterally, and a small paramedian craniotomy exposes the transverse sinus (blue line) while leaving the torcula protected. (D) The dura is opened as a single curved flap and retracted toward the sinus, exposing the operative corridor. (E) The operative corridor is developed with great effort to avoid sacrificing large median veins as well as lateral bridging veins, and the arachnoid covering the pineal gland is sharply opened, demonstrating the posterior surface of the tumor. (F) The tumor is internally debulked initially, and subsequently separated from the surrounding brain.

preserve the arachnoid membranes of lateral structures such as the SCA or the trochlear nerve (see Fig. 21.10E and F). 

Occipital Transtentorial The OTT approach is the most commonly used supratentorial approach. Performed via an occipital craniotomy, the

OTT approach provides a wide operative field with an unobscured view of the tentorial notch (Fig. 21.11).49 With division of the tentorium, the OTT provides excellent exposure and an ideal angle to approach tumors of the quadrigeminal plate and those that have an inferior extension from above (Fig. 21.12).31 A lateral or three-­quarter prone position can

21  •  Management of Pineal Region Tumors

A

Inferior sagittal sinus

235

B Corpus callosum

Vein of Galen

Tumor

Straight sinus

Tentorium

FIG. 21.11  (A) Diagram and (B) intraoperative photo of occipital transtentorial approach. A lateral, three-­quarter prone position is preferred for the occipital transtentorial approach. A paramedian linear incision and generous craniotomy extending to the opposite of midline results in a natural corridor between the falx medially, the tentorium inferiorly, and the medial occipital lobe laterally. The dura is opened and reflected toward the sinus. Microscopy and Doppler ultrasound are used to map the location and course of the straight sinus, and the tentorium is divided just lateral to the sinus. Splitting the tentorium offers panoramic supra-­and infratentorial views of the tumor, the surrounding venous structures, and the collicular plate. The arachnoid overlying the tumor and quadrigeminal cisterns are opened, and tumor removal proceeds with great care to avoid injury to the deep venous system. (A, From Bruce JN. Tumors of the pineal region. In: Batjer HH, Loftus CM, editors. Textbook of Neurological Surgery. Vol. 2. Philadelphia: Lippincott Williams and Wilkins; 2003:1365–1373.)

A

B

FIG. 21.12  (A) Preoperative post-­contrast magnetic resonance imaging of the brain demonstrating large pineal parenchymal tumor of intermediate differentiation extending posteriorly and inferiorly in a patient with a steeped tentorium. (B) Tumors that are benign or well encapsulated can be removed completely using the occipital transtentorial approach when applicable.

be utilized as it allows gentle, gravity-­assisted retraction of the dependent occipital lobe. A spinal drain may be useful if the patient has not required a preoperative third ventriculostomy or shunt. The OTT approach brings the surgeon at a slightly oblique angle, which can be disorienting for a

surgeon not familiar with the surgical anatomy, since most tumors are midline. A U-­shaped right occipital scalp flap or a linear incision centered in the midline can be used. The craniotomy should extend across the sagittal sinus to the contralateral occipital

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lobe and should begin just above the torcula. Although some surgeons tried to avoid crossing the sagittal sinus, the bony overhang can limit the operative view. A burr hole is placed and slotted over the sagittal sinus just above the torcula and then a second burr hole slotted over the sagittal sinus 6 to 10 cm above this. The craniotomy is extended 1 to 2 cm ipsilateral to the midline, providing an adequate exposure of the right occipital lobe. If the patient is positioned correctly, the occipital lobe will retract easily with gravity and brain relaxation. There are rarely any bridging veins near the occipital pole, and minimal retraction is desirable to avoid hemianopsia. If the brain is tight, mannitol and ventricular drainage can be useful adjuncts. The dura is opened in a U-­shaped fashion and reflected toward the sagittal sinus. The interhemispheric fissure is accessed, and the occipital lobe is gently retracted. Microscopy, navigation, or Doppler ultrasound are used to map the location and course of the straight sinus within the tentorium, which is divided adjacent and parallel to the straight sinus. The tentorium is often highly vascular, and monopolar cautery can facilitate the tentorial opening, being careful to avoid damage to the underlying cerebellum and brain stem. If necessary, the falx can be retracted or even divided although this is rarely necessary. Once the tentorium is divided, the arachnoid overlying the tumor and the quadrigeminal cisterns can be seen and widely opened. Similar to what is described earlier in the supracerebellar approach, the tumor is entered dorsally, internally debulked, then gradually peeled away from the surrounding brain stem, deep venous system, and thalamus. As many pineal lesions arise inferior to the deep cerebral veins, the OTT approach requires that surgeons work past the deep venous structures, whose injury while manipulating a number of instruments between them during tumor resection may prove neurologically devastating. Furthermore, while division of the tentorium provides excellent exposure of the quadrigeminal plate, the OTT offers a limited view of the contralateral quadrigeminal cistern. The OTT approach may result in transient postoperative hemianopsia due to excessive retraction on the occipital lobe, which becomes permanent in a small percentage of patients. Permanent morbidity is reduced by avoiding rigid retractors if possible. 

generally be controlled with routine hemostatic agents. In the sitting position, this bleeding is often less than another position. The dura is opened in a U-­shaped fashion and reflected toward the sagittal sinus. Sacrifice of bridging veins should be minimized to one if necessary. The operative angles mean that even a small opening at the superficial interhemispheric fissure can provide a wide angle of deep exposure. The hemisphere should be carefully protected and then gently retracted. If necessary, additional retraction can be placed on the falx, which may be divided inferiorly if further retraction is necessary. The interhemispheric fissure is otherwise a nonvascular corridor with few adhesions between the falx and the cingulate gyrus, and it should open easily without sacrificing any vessels. At the depth of the interhemispheric dissection, the corpus callosum is easily identified by its white appearance. The operating microscope is useful at this point to identify the pericallosal arteries as a paired structure running over the corpus callosum. Stereotactic guidance can be useful, particularly for those uncomfortable with the surgical anatomy. The corpus callosum is opened over the maximal geometric center of the tumor with gentle suction and cautery. A 2-­cm opening is usually sufficient for most tumors and should not result in any disconnection syndromes or cognitive impairment. The deep venous system will be found in the midline just deep to the corpus callosum and therefore, this should be looked for early on in the dissection to avoid damage to it. It is not safe to sacrifice the deep venous system. If necessary, even more posterior openings in the splenium can be safely performed. The tumors can often extend far laterally, and it is important to avoid damage to pericallosal arteries as the lateral aspects of the tumor are dissected. Once through the corpus callosum, the deep venous system is identified and the tumor is internally debulked. As with the other approaches, once the tumor is internally debulked, it is helpful to work along the tumor capsule to avoid damage to the surrounding structures. There is considerable debate whether or not one internal cerebral vein can be safely dissected. Although there may be times when it is possible to get away with this, it is not desirable and should be avoided at all costs. 

Interhemispheric Transcallosal

Transcortical Transventricular

The IHTC approach provides wide exposure between the falx and brain along the parietal occipital junction. One of the major drawbacks to this approach is the presence of bridging veins, which can cause serious venous infarct if damaged or divided. Normally, one vein can be sacrificed if necessary. A generous craniotomy is desirable to provide some flexibility in the trajectory to the tumor if bridging veins are in the way. Although the sitting approach is often used for this approach, the lateral and prone positions can also be used. Mannitol and spinal drainage may be used for additional brain relaxation if needed. Depending on where the tumor is located, the craniotomy is centered somewhere along the parietal lobe. Approximately 8 cm in length will provide the flexibility needed should bridging veins be in the way. It is desirable to extend the craniotomy across to the contralateral side, as this will allow the placement of retractors in the interhemispheric fissure and along the falx. Bleeding from the sagittal sinus can

This approach is rarely used given its limited exposure and the need for cortical incision. A standard craniotomy is planned over the desired approach to the lesion using navigation. A cortical entry point through non-­eloquent cortex is chosen. Stereotactic guidance is particularly useful in the setting of a tumor that extends into the lateral ventricle. 

COMPLICATIONS OF SURGERY Outcomes following microsurgical resection of pineal region tumors have improved as a result of advances in microsurgical technique, neuroanesthesia, and improved postoperative care. Modern series evaluating surgical outcomes since the 1990s report mortality rates between 0% and 2% and permanent minor morbidity in 3% to 20% of patients (Table 21.1).31,50,51 Serious complications of pineal tumor surgery, regardless of the route used, are related to the nature of the tumor and its potential for intra-­or postoperative hemorrhage.13

21  •  Management of Pineal Region Tumors

237

Table 21.1  Outcomes of Modern Surgical Series for Pineal Region Lesions Study

Year

No. Cases

Approach

GTR (%)

Mortality (%)

Major Morbidity (%)

Permanent Morbidity (%)

Bruce and Stein30

1995

160

45

4

3

19

Konovalov and Pitskhelauri31

2003

255

58

7.8a

15

15

Hernesniemi et al.50

2008

119

88

0

Cor-4

D

E

FIGURE 24.4  FForty-two-year-old female patient presented with neck pain and occipital headaches and found on workup to have a left-sided mass. A to C, T1-weighted images show a 2.9 × 2.2 × 2.2 cm left parasagittal extra-axial contrast enhancing mass demonstrating invasion into the posterior superior sagittal sinus (SSS). Associated mild mass effect upon the left parietal lobe with suggestion of pial invasion. D and E, Moderate to severe focal stenosis of the posterior third of the SSS (arrows) secondary to the invading mass. The remainder of the dural venous sinuses are patent. Histopathology revealed an atypical WHO grade II meningioma with increased mitotic activity.

tools to provide surgeons with intraoperative guidance. MR imaging can also be used as a tool for disease prognosis.7 Peritumoral edema, presence of heterogeneity, tumor necrosis, and tumors located in the falx or convexity have been demonstrated to correlate with high-­grade meningioma features that can be observed preoperatively on imaging.7 Cerebral angiography can provide essential information delineating the tumor’s arterial feeding pattern. Additionally, the arterial phase of the angiography can provide crucial information on the course, displacement, and possibly the encasement of the anterior cerebral arteries (ACAs), pericallosal arteries, and callosomarginal arteries. The venous phase of the angiogram is also vital toward determining the patency of the SSS, understanding the anatomy of the draining cortical veins in relation to the tumor, and the degree of collateral circulation.20–22 If the sinus is occluded, the anatomy of the draining collateral vessels needs to be clearly identified during preoperative planning and meticulously preserved during surgery.23 Inadvertent occlusion of collateral vessels may result in severe postoperative complications such as venous infarct and cerebral edema (Fig. 24.4). Digital subtraction angiography (DSA) provides a dynamic view of both the arterial and venous phases, better resolution of small vessel feeders, better accuracy in identifying sinus obstruction, and areas with reversal of normal venous flow. However, DSA is invasive and associated with

a small, but not insignificant, risk for strokes, vessel injury, post-­diagnostic hematoma, and possible renal injury from contrast use. Noninvasive means to evaluate the cerebral vasculature include MR angiography and CT angiography. MR angiography/venography capitalizes on its intrinsic sensitivity to flow to detect the patency of vessels. Vessels with high flow give rise to high signal intensity while the absence of flow is characterized by reduced signal intensity.24,25 The technical limitations to MR angiography include its susceptibility to flow-­related artifacts: for example, patent but obstructed regions of the sinus may appear completely occluded due to decrease in flow; intracellular deoxyhemoglobin/methemoglobin found in clot can create false signals to suggest a patent vessel. Other practical limitations include longer image acquisition times and sensitivity to patient movement. CT angiography/venography (CTA/CTV) is acquired using thin 0.625-­mm slices on a helical 64-­channel multidetector scanner during the peak arterial and venous enhancements. The acquired images can be viewed using maximum intensity projection (MIP) images, multiplanar reconstruction (MPR) images, and Vitrea 3D reconstruction images (Vital Images, Minnetonka, MN) to provide the surgeon a better sense of the tumor and its relationship to the vasculature (see Fig. 24.2F–J). The faster image acquisition times as well as the ability to maintain high spatial resolution has made CTA/ CTV one of the preferred methods for preoperative vessel

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Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

assessment. CTA/CTV has better small-­ vessel and sinus resolution and fewer motion and flow artifacts than MR venography.26,27 In a study by Wetzel and colleagues, CTV was compared to digital subtraction angiography. CTV was found to have an overall sensitivity of 95% and 91% specificity, while DSA had 90% sensitivity and 100% specificity.28 Additionally, the shorter image acquisition times allow for fewer motion artifacts, and thus makes CTA/CTV better suited for uncooperative or sick patients. 

Operative Technique The operative technique is highly influenced by tumor location, vasculature, relationship with adjacent structures, possible surgical corridor—and of course patient characteristics, symptoms, and comorbidities. After diagnosis, meningioma growth can be evaluated over time and treated conservatively. Surgical treatment is usually indicated for patients with neurologic symptoms, associated brain edema, increased intracranial pressure, and large tumor volumes. The goal of surgery should always be to achieve a maximum safe resection of the tumor, while minimizing complications by performing a careful identification and manipulation of blood vessels, protection of adjacent eloquent structures— such as the paracentral lobule in the case of middle falcine meningiomas—and avoiding excessive brain retraction. Postoperative extent of resection in meningioma surgery is determined by the Simpson Scale. Simpson Grade 1 to III are considered to be gross total resections, while Grade IV and V fall into the subtotal resection groups (Video 24.1).29

ANESTHESIA AND PREPARATIONS The patient is brought to the operating room and general anesthesia is administered via endotracheal intubation. A combination of intravenous furosemide, mannitol, and slight hyperventilation is used to reduce intracranial pressure. Preoperative antibiotics, stress dose steroids, and antiseizure prophylaxis (such as fosphenytoin) are also given prior to skin incision. If the preoperative plan involves resection or manipulation of the sagittal sinus, air emboli precautions are implemented. A precordial Doppler is securely placed over the right atrium to monitor for air emboli and an intra-­ atrial venous catheter is placed for aspirating the air bubbles if necessary. Intraoperative monitoring with somatosensory evoked potentials or direct cortical stimulation is often used when tumors are located adjacent to the motor or sensory areas, and attaching leads should be completed prior to incision. 

POSITIONING Patient positioning depends on the preoperative evaluation and classification of the tumor.10 For tumors located in the anterior third of the sagittal sinus, the patient is placed in a supine position with the head slightly elevated. Tumors around the middle third of the sagittal sinus can be approached with the patient supine with the head elevated and flexed, or, alternatively, a semiprone or lateral approach can be used, especially if the tumor is located more posteriorly. A semilateral, semisitting position with the head well elevated so that the scalp over the area of the tumor is at the highest point can also be considered for tumors in this area. For tumors involving the posterior third, the patient

is placed in the lateral position and the head is elevated and turned to the opposite side so that the center of the tumor is uppermost.30,31 The head is secured with the Mayfield 3-­point fixation head rest and the patient’s body is secured to the operative table with tape. Foam padding and gel rolls are used to pad all pressure points. 

NEURONAVIGATION SYSTEMS Advances in neuroimaging and development of frameless neuronavigational tools have been instrumental in improving surgical outcomes. After the patient’s head and body are securely positioned, neuronavigational tools are used to coregister the patient’s head with a high-­resolution MRI. Neuronavigation can be helpful in planning out the skin incision and the borders of the craniotomy; it also helps in localizing the neoplastic tissue. Increased surgical security, decreased tumor recurrence rates, less blood loss, and an overall better postoperative status have been associated with the use of neuronavigation technology for meningioma surgery.32 The accuracy of the neuronavigation needs to be considered after opening of the dura, as the degree of tumor resection and drainage of CSF can cause shifts in the anatomy. 

SKIN INCISION A bicoronal incision is used to approach tumors along the anterior third of the sagittal sinus. Tumors at the level of the coronal suture and the middle third of the sagittal sinus are approached via a horseshoe/U-­shaped incision that has its base laterally. For posterior-­third tumors, a horseshoe/­Ushaped incision that has its base toward the occiput provides the most flexibility and exposure. Care has to be taken to ensure that the base of all U-­shaped incisions is broader than the length of the flap. The skin incision will extend across the midline for cases when the tumor involves both sides of the falx. For these cases, the skin incision is based off the side with the largest tumor burden. It is important to have in mind that if the tumor presents with SSS invasion, is large in size, or is located more superficially, the need for a larger bone flap for greater tumor exposure will also increase incision size. 

CRANIOTOMY The craniotomy should encompass the borders of the entire tumor by an addition of a 1-­to 2-­cm margin. The craniotomy for tumors that extend across the midline may be turned as a single piece or in two sections. Several burr holes are placed laterally along the SSS and the sinus is carefully stripped away from the bone before the bone is cut with the craniotome. If the sinus cannot be separated from the cranium easily, the ipsilateral bone flap may be turned first. Then, under direct tangential vision, the sinus can be stripped from the cranium before turning the second contralateral section of the bone flap. For tumors that extend to the surface, the bone flap may be adherent to the underlying tumor and care should be taken when dissecting the bone flap off over this region to avoid injury to underlying cortex and veins. Bone that has been invaded by tumor may be very thick and it may be necessary to drill the bone away in a piecemeal fashion to avoid injury and tearing underlying cortex. Once the bone flap is off, bleeding points along the sagittal sinus are controlled with a combination of bipolar

24  •  Surgical Approach to Falcine Meningiomas

cautery and use of Surgicel (oxidized cellulose), thrombin-­ soaked Gelfoam, and cottonoid pads. Tears to the sinus need to be repaired using 5-­0 or 6-­0 Prolene sutures. Bone bleeding can be controlled with bone wax, and before closing, circumferential tenting sutures are used along the periphery to avoid further epidural bleeding. 

DURAL OPENING A U-­ shaped dura incision is made starting laterally with the hinge parallel to the falx. Care needs to be taken when elevating the dural flap medially to avoid tearing potentially important bridging veins. Adhesions and bridging veins need to be dissected and freed. If a large cortical vein enters a dural sinus prior to emptying into the SSS, the cortical vein and the dural sinus need to be incised from the dural flap, and preserved as attachments to the midline sinus. Early devascularization of the tumor is a crucial step to minimize blood loss. For bilateral tumors, the dura on the contralateral side is also incised and the free ends of the dura can be sutured together to help with retraction out of the surgical field. 

TUMOR RESECTION Once the midline cortex is exposed and the falx and SSS are visualized, steps are taken in preparation to retract the hemisphere out laterally. Again, before getting to the tumor, attention must be paid to the anatomy of the cortical veins emptying into the SSS and the falx itself. While veins along the anterior third of the sinus can usually be ligated without neurologic consequences, the general principle is to preserve cortical veins since they may either directly drain eloquent areas or provide essential collateral drainage. If segments of the SSS are completely or partially occluded, preserving collateral drainage is vital to preventing venous infarcts and cerebral edema. Cortical veins traversing through the tumor, which are shown to be occluded by DSA imaging, can be resected or ligated. However, we re-­emphasize that interruption of all other large draining cortical veins that drain toward the midline, particularly at the level of the middle and posterior thirds of the SSS, is fraught with risk. Veins that are encased by tumor need to be dissected free to the greatest extent possible and preserved. For falcine meningiomas that are concealed beneath cortex, it is important to first establish the anterior and posterior limits of the tumor. From these limits, a corridor can be created by gently retracting the medial surface of the hemisphere. The cortex should not be retracted more than 2 cm away from the falx and the sinus, and excessive retraction should be avoided at all times. Overlying bridging veins that are within this corridor, again, need to be preserved and can be made slack by being dissected away from the SSS. If necessary, the bridging veins can also be freed from the cortex for a few millimeters to allow for the required retraction of the hemisphere without sacrificing the vessel. In rare cases where the tumor is exceedingly large or where the corridor is compromised by unyielding veins, the surgeon can create additional exposure by resecting some noneloquent cortex and white matter that is well anterior to the primary and supplementary motor areas. Resection of noneloquent cortex is preferable to taking cortical veins. The standard interhemispheric approach has been an effective method for resection over time and is often the preferred method

283

for the resection of these tumors. However, several techniques—the ipsilateral paramedian approach, the contralateral interhemispheric and transfalcine approaches—have also been reported.10,33–36 Contralateral approaches provide better access to blood vessels with better devascularization angles, and avoid ipsilateral cortical and edematous tissue manipulation.33,34 For giant bifalcine meningiomas, a unilateral approach was described by Karthgeyan and colleagues, using an oblique trajectory starting from the noneloquent hemisphere and moving to the contralateral hemisphere through the falx; in this way a safe tumor resection can be obtained with good vessel control, minimizing the risk of both venous and cortical lesions.35 Once the corridor has been established, the blood supply to the tumor from the falcine arteries is sectioned by cauterizing and sectioning the falx in the inferior-­to-­superior direction approximately 1 cm anterior and 1 cm posterior to the margins of the tumor. The exposed tumor capsule is then entered using bipolar cautery. Intracapsular enucleation is used to debulk the tumor. This can be accomplished using a combination of bipolar cautery, aspiration, and/or sonic aspiration (e.g., CUSA). Once the tumor is sufficiently debulked, the rest of the tumor can be delivered by invaginating the capsule into the hollowed tumor cavity. The capsule is carefully peeled away from the cortex using gentle retraction and bipolar cautery. Only small vessels parasitized from the pia and arachnoid that are entering the tumor from the brain can be divided. In areas where the capsule has been dissected from the cortex, the brain can be protected with either Gelfoam or Cottonoid pads. It should be noted that a cleavable pial–tumor plane is not always present. Sindou and Alaywan evaluated 150 patients with preoperative angiography.37 Only 34.8% of meningiomas with evidence of pial parasitization on angiogram were found to have a cleavable pial–tumor interface at surgery.37 Conversely, in meningiomas with primarily a dural supply, 83.6% had a cleavable plane. In addition, in cases where there is pial invasion in areas involving eloquent brain, total resection may result in significant and unacceptable postoperative deficits. In these conditions, it is advisable to attain maximal safe resection and leave a thin rim of tumor attached to the cortex rather than risk debilitating neurologic compromise.38 As the tumor is resected, the surgeon should be mindful of the branches of the ACA, including the pericallosal and callosomarginal arteries. These relationships should be identified preoperatively. Smaller arteries directly feeding the tumor can be coagulated and divided; however, traversing branches that are adherent or encased by tumor should be dissected and freed. Once the tumor capsule has been separated from the cortex, the tumor attachment to the falx and SSS is excised and coagulated. Tumors that extend bilaterally will also require complete resection of the involved falx. 

MANAGEMENT OF SINUS INVASION Falcine meningiomas can grow and extend to involve the SSS. Careful preoperative evaluation of SSS involvement and its relationship with the tumor determine the operative strategy, as it allows for preparation for sinus reconstruction. Although occurring less frequently than with parasagittal meningiomas, the surgical considerations for managing tumor infiltration into the sinus are essentially the same. Manipulation and opening of venous sinus to resect invading

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Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

tumors is associated with greater surgery-­related complications. When tumor extends into the sagittal sinus, surgeons are faced with the dilemma of leaving a fragment of invasive tumor and facing a higher rate of recurrence versus attempting to achieve a Simpson I resection but putting the venous circulation at greater risk. As is the case for all meningiomas, the likelihood of recurrence for falcine lesions depends on the Simpson grade at the time of initial resection.4 Most pertinently, the falx and the encroached-­upon SSS are the dural attachments associated with these tumors. In a recent case review of 68 falcine meningiomas, Chung and colleagues found that those with Simpson grade I or II resections had a recurrence rate of 3.6% (2 cases out of 56) while those with a grade III or greater had a rate of 44% (4 cases out of 9).4 The imperative for aggressive surgery needs to be tempered by the risks of unexpected and sudden occlusion of the middle or posterior thirds of the sagittal sinus. Such venous injury can lead to significant neurologic morbidity and mortality. Decisions regarding sinus management, therefore, should be tailored to individual patients based on their age, symptoms, tumor location, degree of sinus involvement, the robustness of the cortical veins, and presence of venous collaterals surrounding the falx. Three main surgical strategies can be employed in the management of sinus invasion. The first involves simple resection of the outer dural layer with the tumor and coagulation of the inner layer at the sites of tumor attachment. Simpson’s series from 1957 demonstrated that complete tumor resection and coagulation of attached dura had a recurrence rate of 16%, as compared to a 29% recurrence rate when gross total resection was performed without dural coagulation.29 Complete tumor resection with excision of attached dural attachments had the lowest rate of recurrence at 6%. The second technique for disease involving the SSS involves resecting the invaded sinus wall(s) and repairing the sinus by one of three techniques: (1) resection of the intraluminal tumor and suturing of the sinus edges primarily; (2) resection of the infiltrated wall(s) and repair with an autologous patch (e.g., venous or fascia temporalis); or (3) resection of the occluded portion with interposition of a bypass graft composed of either autologous vein (e.g., external jugular, internal saphenous vein) or a synthetic tube (e.g., Gore-­Tex). The third option for management would be simple coagulation of residual tumor or resection of the involved sinus without venous reconstruction.39 Sindou and Alvernia propose a six-­ stage classification scheme for progressive tumor invasion into the sinuses (Table 24.1).40 Type I lesions involve just the outer surface of the sinus wall. Type II lesions have the tumor extending into the lateral recess of the SSS. Type III tumors infiltrate into the lateral sinus wall; when tumor has invaded the roof of the sinus, it is characterized as a type IV lesion. Types V and VI tumors completely occlude the sinus, with and without wall invasion, respectively. For type I lesions, the tumor can be peeled off the wall of the sinus using bipolar cautery. Care is then taken to coagulate the areas of tumor attachment to prevent recurrence. Type II tumors that involve the lateral recess can be managed with opening the sinus edge, removing the residual plaque of tumor, and then progressively closing the edge of the sinus wall primarily with a continuous 5-­0 or 6-­0 Prolene suture. Types III and IV tumors involve the sinus walls to a greater extent and

TABLE 24.1  Progressive Meningioma Invasion Into the Sinuses40 Type I Type II Type III Type IV Type V Type VI

Involves only the outer surface of the sinus wall. Tumor extends into the lateral recess of the SSS Tumor infiltrates into the lateral sinus wall Tumor infiltrates into the lateral sinus wall and the roof of the sinus Tumor completely occludes the sinus without lateral sinus wall invasion Tumor completely occludes the sinus with lateral sinus wall invasion

SSS, Superior sagittal sinus.

require more extensive sinus reconstruction. Details for this reconstruction are detailed elsewhere.39–43 Type V and VI tumors can be approached on the basis of the location of sinus involvement: anterior, middle, and posterior. A partially or completely occluded SSS in the anterior third can usually be resected without risk of severe neurologic consequences. Traditionally, middle and posterior segments of the sinus that are found to be occluded on digital subtraction angiography can be resected without the need for venous reconstruction or bypass. Some authors advocate testing with temporary occlusion prior to excision.38 Sekhar temporarily occludes the sinus and measures proximal venous pressure for over 10 minutes.38 If there is no change in sinus pressure and if there is evidence of brain swelling, the sinus can be resected. However, some authors warn that cerebral edema, venous infarction, and subcutaneous cerebrospinal fluid collection can still occur and suggest the need for a venous reconstruction or sinus bypass. The 1955 study by Hoessly and Olivecrona evaluated 196 parasagittal meningiomas treated without venous reconstruction and reported perioperative morbidity of 12.3%, of which more than half was associated with venous drainage.44 Another examination study of 108 cases of falcine or parasagittal meningiomas invading the SSS described 9 cases of severe cerebral edema, of which 3 involved en bloc resection without venous reconstruction.45 A more recent study evaluating 84 patients with meningiomas involving major sinuses demonstrate that the use of adjuvant Gamma Knife radiosurgery is helpful in the case of residual or recurrent tumors invading the sinuses.46 However, despite these risks, surgeons are still advised to consider each case individually and weigh the options, which include adjuvant radiosurgery and radiotherapy for residual tumor. 

CLOSURE The dura can be closed primarily, or if necessary, a duraplasty can be performed using a pericranial graft harvested from the undersurface of the skin flap or with allograft. The dura and/or graft are sewn in a watertight fashion. The bone flap is re-­evaluated for possible tumor invasion. If the bone flap has been invaded with tumor, the patient will require a bone reconstruction using titanium mesh, acrylic cranioplasty, or customized synthetic cranioplasty flap. The reconstruction can be done at the time of the original surgery, or can be done in a delayed fashion, especially if the brain appears swollen at the time of closure. Bone flaps that are free of tumor can be secured to the cranium with titanium

24  •  Surgical Approach to Falcine Meningiomas

miniplates and screws. The galea is closed with interrupted, inverted absorbable sutures and the skin is typically closed using a running nylon stitch. 

Postoperative Care The patient emerges from general anesthesia and is transported to the intensive care unit (ICU) for standard postoperative care. Postoperatively, the patient should be kept well hydrated to prevent the propensity for delayed venous thrombosis. Steroids that were started preoperatively are continued for a short course that typically lasts through the first 72 hours and then is tapered rapidly. Antiepileptics should be continued for an additional 3 months in patients with no prior seizure history. Patients who present with seizure may require a longer course of antiepileptics, but may be weaned off therapy if a sleep-­deprived electroencephalogram shows no signs of further seizure activity. Postoperative imaging with noncontrast CT or MRI may be indicated if the patient has persistent or progressive lethargy or obtundation, or progressive focal neurologic deficits. CT or MR angiography/venography can be used to diagnose or follow evolving venous thrombosis. Evaluation of the extent of resection and residual tumor is preferably carried out within the first 24 to 72 hours after surgery with contrast-­enhanced MRI.15,47 Patients who have undergone a venous graft need to be started on anticoagulation. For the first 24 to 48 hours these patients should be placed on titratable heparin drip. The goal PTT should be in the therapeutic range of 60 to 80, but each case should be evaluated to avoid postoperative hematomas. Once the patient has been stabilized, the patient can be transitioned to weight-­based therapeutic doses of low-­molecular-­weight heparin and Coumadin. The low-­molecular-­weight heparin can be discontinued when the patient’s INR is between 2.0 and 3.0. Coumadin is then continued for at least 3 months postoperatively. 

Summary The surgical approach to falcine meningiomas is dictated by the tumor’s location relative to the SSS. Preoperative and intraoperative high-­ resolution gadolinium-­ enhanced MR images can aid in understanding tumor size and location and can be helpful in planning patient positioning, skin incision, and the size of the bone flap craniotomy. Standard digital subtraction and noninvasive CT and MR cerebral angiography can provide critical insight on osseous involvement and the course of the arterial feeders. Additionally, for cases where tumor infiltrates the SSS, cerebral angiography can reveal the degree of sinus occlusion and the anatomy of the collateral draining veins.23 Intraoperatively, the surgeon needs be judicious in the degree of cortex retraction and be meticulous in preserving surrounding cortical veins in order to avoid potentially devastating neurologic injuries. Occasionally falcine meningiomas can secondarily invade the SSS; in such cases, the surgeon needs to consider the patient’s age, symptoms, degree of tumor infiltration, and the role of adjuvant radiosurgery and radiotherapy. The options for sinus repair and/or venous bypass should be discussed at length before pursuing tumor within the sinus.

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Intraoperative verification of completely occluded sinuses using manometry and temporary clipping is recommended prior to sinus resection. Finally, the surgeon needs to be aware of the risks for delayed sinus thrombosis and to keep patients well hydrated postoperatively. KEY REFERENCES

Al-­Mefty O, Origitano TC, Harkey HL, eds. Controversies in Neurosurgery. New York: Thieme; 1996. Barajas Jr RF, Sughrue ME, McDermott MW. Large falcine meningioma fed by callosomarginal branch successfully removed following contralateral interhemispheric approach. J Neurooncol. 2009;97: 127–131. Casey SO, Alberico RA, Patel M, et al. Cerebral CT venography. Radiology. 1996;198:163–170. Chung SB, Kim CY, Park CK, et al. Falx meningiomas: surgical results and lessons learned from 68 cases. J Korean Neurosurg Soc. 2007;42:276–280. Dass KK, Gosal JS, Sharma P, et al. Falcine meningiomas: analysis of the impact of radiological tumor extensions and proposal of a modified preoperative radiological classification scheme. World Neurosurg. 2017;104:248–258. Demir MK, Iplikcioglu AC, Dincer A, et al. Single voxel proton MR spectroscopy findings of typical and atypical intracranial meningiomas. Eur J Radiol. 2006;60(1):48–55. DiMeco F, Li KW, Casali C, et al. Meningiomas invading the superior sagittal sinus: surgical experience of 108 cases. Neurosurgery. 2004;55:1263–1274. Hoessly GF, Olivecrona H. Report on 280 cases of verified parasagittal meningioma. J Neurosurg. 1955;12:614–626. Huang RY, Bi WL, Griffith B, et al. Imaging and diagnostic advances for intracranial meningiomas. Neuro-­Oncol. 2019;21(S1):44–61. Kim CY, Jung HW. Falcine meningiomas. In: Lee JH, ed. Meningiomas: Diagnosis, Treatment, and Outcome. London: Springer-­Verlag; 2008. Lawton MT, Golfinos JG, Spetzler RF. The contralateral transcallosal approach: experience with 32 patients. Neurosurgery. 1996;39(4):729– 735. Liauw L, van Buchem MA, Split A, et al. MR angiography of the intracranial venous system. Radiology. 2000;214:678–682. Longstreth WT, Dennis LK, McGuire VM. Epidemology of intracranial meningiomas. Cancer. 1993;72:639–648. Maiuri F, Iaconetta G, de Divitiis O, et al. Intracranial meningiomas: correlations between MR imaging and histology. Eur J Radiol. 1999;31(1):69–75. Ojemann RG. Management of cranial and spinal meningiomas. In: Selman W, ed. Clinical Neurosurgery. Baltimore: Williams and Wilkins; 1992. Ojemann RG, Ogilvy CS. Convexity, parasagittal and parafalcine meningiomas. In: Apuzzo MLJ, ed. Brain Surgery: Complication Avoidance and Managment. New York: Churchill Livingstone; 1993. Ozsvath RR, Casey SO, Lustrin ES, et al. Cerebral venography: comparison of CT and MR projection venography. AJR Am J Roentgenol. 1997;169:1699–1707. Sekhar LN, de Oliveira E, Riedel CJ. Parasagittal, falx meningiomas. Cranial Microsurgery: Approaches and Techniques. New York: Thieme; 1997. Simpson D. The recurrence of intracranial meningiomas after surgical treatment. J Neurol Neurosurg Psychiatry. 1957;20:22–39. Sindou M. Meningiomas invading the sagittal or transverse sinuses, resection with venous reconstruction. J Clin Neurosci. 2001;8(suppl 1):8–11. Sindou M, Alaywan M. Most intracranial meningiomas are not cleavable tumors: anatomic-­surgical evidence and angiographic predictability. Neurosurgery. 1998;42:476–480. Sindou M, Auque J. The intracranial venous system as a neurosurgeon’s perspective. Adv Tech Stan Neurosurg. 2000;26:131–216. Sindou M, Hallacq P. Venous reconstruction in surgery of meningiomas invading the sagittal and transverse sinuses. Skull Base Surg. 1998;8:57–64. Sindou MP, Alvernia JE. Results of attempted radical tumor removal and venous repair in 100 consecutive meningiomas involving the ­major dural sinuses. J Neurosurg. 2006;105:514–525.

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Sindou MP, Bokor J, Brunon J. Bilaeral thrombosis of the transverse sinuses: microsurgical revascularization with venous bypass. Surg Neurol. 1980;13:215–220. Tamiya T, Ono Y, Matsumoto K, Ohmoto T. Peritumoral brain edema in intracranial meningiomas: effects of radiological and histological factors. Neurosurgery. 2001;49(5):1046–1051. Vob KM, Spille DC, Sauerland C. The Simpson grading in meningioma surgery: does the tumor location influence the prognostic value? J Neurooncol. 2017;133(3):641–651.

Wetzel SG, Kirsh E, Stock KW, et al. Cerebral veins: comparative study of CT venography with intraarterial digital subtraction angiography. Am J Neuroradiol. 1999;20:249–255. Zhuo FX, Wan JH, Li XJ, et al. A proposed scheme for the classification and surgical planning of falcine meningioma treatment. J Clin Neurosci. 2012;19:1679–1683. Numbered references appear on Expert Consult.

REFERENCES

1. Ostrom QT, Cioffi G, Gittleman H, et al. CBTRUS statistical report: primary brain and other central nervous sy. stem tumors diagnosed in the United States in 2012–2016. Neuro Oncol. 2019;21(S5):1–100. 2. Lawton MT, Golfinos JG, Spetzler RF. The contralateral transcallosal approach: experience with 32 patients. Neurosurgery. 1996;39(4):729–735. 3. Longstreth WT, Dennis LK, McGuire VM. Epidemology of intracranial meningiomas. Cancer. 1993;72:639–648. 4. Chung SB, Kim CY, Park CK. Falx meningiomas: surgical results and lessons learned from 68 cases. J Korean Neurosurg Soc. 2007;42:276–280. 5. Kim CY, Jung HW. Falcine meningiomas. In: Lee JH, ed. Meningiomas: Diagnosis, Treatment, and Outcome. London: Springer-­ Verlag; 2008. 6. Cushing H, Eisenhardt L. Meningiomas: Their Classification, Regional Behavior, Life History, and Surgical End Results. Springfield, IL: Charles C. Thomas; 1938. 7. Hale AT, Wang L, Stroher MK, et al. Differentiating meningioma grade by imaging features on magnetic resonance imaging. J Clin Neurosci. 2018;48:71–75. 8. Yasargil MG. Microneurosurgery. Vol IVB. Stuttgart, New York: Georg Thieme Verlag; 1996. 9. Al-­Mefty O. Operative Atlas of Meningiomas. Philadelphia, New York: Lippincott-­Raven Publishers; 1998. 10. Zhuo FX, Wan JH, Li XJ, et al. A proposed scheme for the classification and surgical planning of falcine meningioma treatment. J Clin Neurosci. 2012;19:1679–1683. 11. Das KK, Gosal JS, Sharma P, et al. Falcine Meningiomas: analysis of the impact of radiological tumor extensions and proposal of a modified preoperative radiological classification scheme. World Neurosurg. 2017;104:248–258. 12. Lund M. Epilepsy in association with intracranial tumours. Acta Pscyhiatr Scand. 1952;81(suppl). 13. Eichberg D, Casabella S, Menaker AM, et al. Parasagittal and parafalcine meningiomas: integral strategy for optimizing safety and retrospective review of a single surgeon series. British J Neurosurg. 2019:1–6. 14. Heros RC. Meningiomas involving the sinus. J Neurosurg. 2006;105:511–513. 15. Huang RY, Bi WL, Griffith B, et al. Imaging and diagnostic advances for intracranial meningiomas. Neuro Oncol. 2019;21(S1):44– 61. 16. Maiuri F, Iaconetta G, de Divitiis O. Intracranial meningiomas: correlations between MR imaging and histology. Eur J Radiol. 1999;31(1):69–75. 17. Tamiya T, Ono Y, Matsumoto K, Ohmoto T. Peritumoral brain edema in intracranial meningiomas: effects of radiological and histological factors. Neurosurgery. 2001;49(5):1046–1051. 18. Nakano T, Asano K, Miura H. Meningiomas with brain edema: radiological characteristics on MRI and review of the literature. Clin Imaging. 2002;26(4):243–249. 19. Demir MK, Iplikcioglu AC, Dincer A. Single voxel proton MR spectroscopy findings of typical and atypical intracranial meningiomas. Eur J Radiol. 2006;60(1):48–55. 20. Al-­Mefty O, Origitano TC, Harkey HL, eds. Controversies in Neurosurgery. New York: Thieme; 1996. 21. Rossitti S. Preoperative embolization of lower-­falx meingiomas with ethylene vinyl alcohol copolymer: technical and anatomical aspects. Acta Radiol. 2007;48(3):321–326. 22. Wang X, Mang MY, Qian K, et al. Classification and protection of peritumoral draining veins of parasagittal and falcine meningiomas. World Neurosurg. 2018;117:362–370. 23. Yin T, Zhang H, Wang W, et al. Falcine sinus and prafalcine collateral veins in meningiomas invading the superior sagittal sinus. World Neurosurgery; 2019:E1–E9. 24. Khandelwal N, Agarwal A, Kochhar R, et al. Comparison of CT venography with MR venography in cerebral sinovenous thrombosis. AJR Am J Roentgenol. 2006;187:1637–1643.

25. Liauw L, van Buchem MA, Split A, et al. MR angiography of the intracranial venous system. Radiology. 2000;214:678–682. 26. Casey SO, Alberico RA, Patel M, et al. Cerebral CT venography. Radiology. 1996;198:163–170. 27. Ozsvath RR, Casey SO, Lustrin ES. Cerebral venography: comparison of CT and MR projection venography. AJR Am J Roentgenol. 1997;169:1699–1707. 28. Wetzel SG, Kirsh E, Stock KW. Cerebral veins; comparative study of CT venography with intraarterial digital subtraction angiography. Am J Neuroradiol. 1999;20:249–255. 29. Simpson D. The recurrence of intracranial meningiomas after surgical treatment. J Neurol Neurosurg Psychiatry. 1957;20:22–39. 30. Ojemann RG, Ogilvy CS. Convexity, parasagittal and parafalcine meningiomas. In: Apuzzo MLJ, ed. Brain Surgery: Complication Avoidance and Managment. New York: Churchill Livingstone; 1993:187–202. 31. Ojemann RG. Management of cranial and spinal meningiomas. In: Selman W, ed. Clinical Neurosurgery. Vol. 40. Baltimore: Williams and Wilkins; 1991:321–383. 32. Bir SC, Konar SK, Maiti TK, et al. Utility of neuronavigation in intracranial meningioma resection: a single center retrospective study. World Neurosurgery. 2016;90:546–555. 33. Barajas Jr RF, Sughrue ME, McDermott MW. Large falcine meningioma fed by callosomarginal branch successfully removed following contralateral interhemispheric approach. J Neuro Oncol. 2009;97:127–131. 34. Roser F, Rigante L. The endoscope-­assisted contralateral paramedian approach to large falcine meningiomas. Acta Neurochir. 2018;160(1):79–82. 35. Karthigeyan M, Rajasekhar R, Salunke P, et al. Modified unilateral approach for mid-­third giant bifalcine meningiomas: resection using an oblique surgical trajectory and falx window. Acta Neurochir. 2019;161(2):327–332. 36. Yu G, Wang X, Zhang X, et al. Gravity-­assisted ipsilateral paramedian approach for parafalcine meningioma resection: technical note. World Neurosurg. 2020;135:234–240. 37. Sindou M, Alaywan M. Most intracranial meningiomas are not cleavable tumors: anatomic-­ surgical evidence and angiographic predictability. Neurosurgery. 1998;42:476–480. 38. Sekhar LN, de Oliveira E, Riedel CJ. Parasagittal, falx meningiomas. Cranial Microsurgery: Approaches and Techniques. New York: Thieme; 1997. 39. Sindou M, Auque J. The intracranial venous system as a neurosurgeon’s perspective. Adv Tech Stan Neurosurg. 2000;26:131– 216. 40. Sindou MP, Alvernia JE. Results of attempted radical tumor removal and venous repair in 100 consecutive meningiomas involving the major dural sinuses. J Neurosurg. 2006;105:514–525. 41. Sindou M. Meningiomas invading the sagittal or transverse sinuses, resection with venous reconstruction. J Clin Neurosci. 2001;8(suppl 1):8–11. 42. Sindou M, Hallacq P. Venous reconstruction in surgery of meningiomas invading the sagittal and transverse sinuses. Skull Base Surg. 1998;8:57–64. 43. Sindou M, Mercier P, Bokor J, Brunon J. Bilateral thrombosis of the transverse sinuses: microsurgical revascularization with venous bypass. Surg Neurol. 1980;13:215–220. 44. Hoessly GF, Olivecrona H. Report on 280 cases of verified parasagittal meningioma. J Neurosurg. 1955;12:614–626. 45. DiMeco F, Li KW, Casali C, et al. Meningiomas invading the superior sagittal sinus: surgical experience of 108 cases. Neurosurgery. 2004;55:1263–1274. 46. Mohammed N, Narayan V, Patra D, et al. Management of meningiomas involving the major venous sinuses: a single-­institution experience. World Neurosurg. 2019;127:179–185. 47. Lescher S, Schniewindt S, Jourcoane A, et al. Time window for postoperative reactive enhancement after resection of brain tumors: less than 72 hours. Neurosurg Focus. 2014;37(6):1–6.

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CHAPTER 25

Surgical Management of Midline Anterior Skull Base Meningiomas MATTHIAS KIRSCH  •  HENRY W.S. SCHROEDER  •  DIETMAR KREX  •  GABRIELE SCHACKERT

Surgical Anatomy

Clinical Presentation

Meningiomas arising in the midline of the anterior fossa are generally separated into the more rostral olfactory groove meningiomas and the more dorsal planum sphenoidale and tuberculum sellae meningiomas (TSM). Planum sphenoidale/TSM occur at similar rates as olfactory groove meningiomas in our series of meningiomas, with both locations presenting less than 6% of all intracranial meningiomas but 21% of the anterior skull base meningiomas. Olfactory groove meningiomas arise over the cribriform plate of the ethmoid bone and the area of the fronto-­sphenoid suture. These tumors may grow symmetrically around the crista galli or extend predominantly to one side and may involve any part of the planum of the sphenoid bone. Planum sphenoidale/TSM arise from the roof of the sphenoid sinus and the tuberculum sellae, which is an area between the optic nerves and anterior clinoid processes. Posteriorly and medially to the optic foramen, the anterior clinoid process attaches to the tentorium cerebelli, which are frequently overgrown by the tumors, as are the posteriorly located dural folds of the sella turcica and the lateral adjacent cavernous sinus (Fig. 25.1). Whereas planum sphenoidale meningiomas usually push the optic nerves dorsally and caudally, tuberculum sellae meningiomas lead to an upward bulging of these structures. Both entities might grow between, around, and beyond the optic nerves. Branches of the ethmoidal, meningeal, and ophthalmic arteries enter through the midline of the base of the skull and constitute the primary blood supply of those tumors. In smaller tumors, the A2 segments of the anterior cerebral arteries are usually not involved in the tumor capsule, but are separated from the tumor by a rim of cerebral tissue and arachnoid. However, in large tumors, these and additional segments like the frontopolar or other small branches originating from the anterior cerebral arteries may be adherent to the posterior and superior tumor capsule. The olfactory nerves are either displaced laterally on the lower surface of the tumor or adherent, compressed, or even not visible while diffusely spread around the tumor capsule. Once the olfactory nerves are compressed by large tumors or even tightly adherent to the tumor capsule, it is difficult to preserve them, and it becomes almost impossible when the tumor has a broad attachment to the dura and infiltrates adjacent, often hypertrophic bone. 

Olfactory groove meningiomas have a gradual and slow onset of symptoms and are difficult to localize neurotopically. Personality changes, such as apathy and akinesia, occurred in our series in up to 13% of patients. Other common symptoms include headache and inferior visual deficits. The Foster-­Kennedy syndrome of unilateral optic atrophy and contralateral papilledema, although originally described in olfactory groove meningiomas, occurred in only a small number of patients. In our own series, smelling disorders up to anosmia were apparent in 64.5%, but they were only diagnosed during the routine preoperative workup. Only 7.1% were completely anosmic preoperatively. In Cushing’s series, the sense of smell was the primary symptom in only three of the 29 patients.1,2 Planum sphenoidale and TSM presented more frequently with visual pathway symptoms than olfactory groove meningiomas, such as acute vision loss or bitemporal hemianopia. 

Evaluation of Radiologic Studies in Planning the Operation MRI represents the standard diagnostic means for evaluation of such lesions because it can delineate the mass effect and the relationship to other important structures, such as the optic nerves, the anterior cerebral arteries, and the frontal lobes. However, cranial computer-­tomography (CT) and angiography are important adjuncts if the destruction of the anterior skull base, infiltration of the ethmoid bone, the relationship of the major vessels, and the vascular supply are of interest. Hyperostosis of the adjacent skull base is a common feature. Rarely, the tumor appears calcified. On T1-­weighted MR images, the tumor is of equivalent signal intensity compared to the surrounding brain, and T2-­weighted MR imaging reveals that the tumor signal is slightly increased compared with normal brain tissue, but less than that of cerebrospinal fluid. Fluid-­attenuated inversion recovery and T2-­ weighted MR imaging highlights surrounding edema. With administration of gadolinium contrast medium, MR imaging demonstrates homogeneous tumor enhancement. It is crucial to analyze the relationship of the optic nerves and anterior cerebral arteries to the

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Median bony ridge and origin of falx cerebri Yellow: olfactory groove and christa galli Blue: planum sphenoidale Red: tuberculum sellae

FIGURE 25.1  Anatomical skull base overview with the midline anterior skull base colored regarding to the most common origins of tumors: yellow describes the cribriform plate, olfactory grove, cribriform plate and christa galli, blue the planum sphenoidale, and red the tuberculum sellae area which reaches bilateral to the optic nerve canal (Adapted from Drake RL. Gray’s Atlas of Anatomy. International Edition, Churchill Livingstone, Philadelphia: Elsevier Publ., 2008.)

imaging reduces unnecessary exposition of the brain. With the advent of modern optics, endoscopy-­assisted approaches and purely endoscopic procedures have improved the surgical armamentarium and replaced more conventional craniotomies. However, even the most extensive approaches should remain in our armamentarium. 

Bifrontal Approach GENERAL CONSIDERATIONS The bifrontal approach was first described by Horsley2 and Cushing and was later also proposed by Tönnis,7 who preserved the frontal brain tissue via a subfrontal approach.8 Many others have used the bifrontal approach for large tumors of the frontal base (Al-­Mefty, Ransohoff and Nockels, Nakamura et al.9–11). A bifrontal craniotomy might be considered for patients with large tumors since this approach gives direct access to all sides of the tumor. Due to the wide exposure, retraction on the frontal lobes is minimal and allows the simultaneous interruption of the blood supply while preparing the frontobasal matrix of the tumor and concomitant decompression. There is usually no problem from the ligation of the anterior sagittal sinus. However, venous drainage should be evaluated by preoperative imaging. A navigation system might be used to avoid opening of the frontal sinus; however, if the frontal sinus is entered, meticulous closure of the defect should prevent any complications. 

OPERATIVE TECHNIQUE

The patient is placed in the supine position with the knees slightly flexed, and the head is slightly elevated and extended. A three-­point skeletal-­fixation headrest system is used. A tumor capsule. Modern imaging tools easily facilitate the coronal incision through the skin is prepared while preservcoregistration of many imaging modalities to visualize the ing the pericranial tissue, which might be used later on to tumor from any angle and to virtually plan the operation. cover the floor of the anterior fossa and to patch the convex In recent years, angiography is not generally indicated dura as needed. The skin flap and underlying tissue, includunless embolization is planned. However, one should be ing the pericranial tissue, are then pulled rostrally. The craaware of a considerable rate of hemorrhagic and ischemic niotomy is fashioned to the size and extension of the tumor complications when using small particles for embolization.3–6  (Figs. 25.2 and 25.3). After blunt dissection of the dura from the tabula interna of the skull bone, particularly in the midline area, the bone flap is usually cut in one piece (in rare cases protection of the sagittal sinus requires two-­sided bone flaps). The bone As the majority of meningiomas are benign well-­ is cut just above the supraorbital ridge from each side as far medially as possible. circumscribed extra-­axial tumors, complete surgical removal, The frontal sinuses are entered frequently. It remains including resection of infiltrated dura or removal of infilcontroversial as to whether the mucosa needs to be comtrated bone, should be the primary goal in most instances. pletely removed. A multilayered closure of the frontal sinus However, when tumors are firmly attached to the anterior is prepared. First, a layer of bone wax is used to close the vessels or the optic chiasm, a complete removal might consinus during the intracerebral part of the operation. For final stitute a high risk for damage to those structures. In these closure, a pericranial flap is formed (see Fig. 25.3) that can cases, a small piece of adherent capsule might remain and be inserted once the tumor is removed. The pericranial flap should be controlled by periodic MRI scans. Upon recurshould be sutured to the frontal edge of the dura and intrarence, reoperation and adjuvant radiation therapy may be durally as far posterior as possible to cover any defects (Fig. considered. 25.4). Use of Tachosil or a similar material is encouraged to SURGICAL APPROACHES add an additional layer. In addition, frontobasal dura gaps that occurred during tumor and dural matrix removal can be Surgical approaches have become more focused and smaller covered. In case of an opened ethmoid sinus, the pericranial over the last decades. Larger craniotomies do not necessartissue should cover this too. Sutures are placed along the ily provide better anatomical perception of the surgical field. edge of the craniotomy to control epidural bleeding. More importantly, the extensive analysis of preoperative

General Aspects of Surgical Management

25  •  Surgical Management of Midline Anterior Skull Base Meningiomas

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A slightly curved dural incision is performed over each medial inferior frontal lobe adjacent to the edge of the craniotomy opening but leaving a sufficient rim for safe and convenient closure of the dura. This incision can be tailored to the specific line of approach to the meningioma. Bridging veins from the anterior frontal lobe to the midline area might be coagulated and cut if necessary. To obtain a better exposure of the sagittal sinus, the frontal lobes might be carefully retracted. Then the sagittal sinus is divided between two silk sutures, and the falx is cut (see Fig. 25.3). The frontal lobes are gently retracted slightly laterally and posteriorly to open the view to the anterior and superior surface of the tumor, lying in the midline with attachments to the falx and crista galli.

FIGURE 25.2  Skin incision (red dashed line), craniotomy (grey dotted line), frontal sinus (grey filled) and the burr holes (green) are depicted in (A) for a bifrontal, in (B) for an extended bifrontal transbasal approach, in (C) for a limited right pterional/ subfrontal, and in (D) for an extended subfrontal approach that is sometimes used with an orbitozygomatic approach.

Generally, two alternative procedures are suggested. Particularly in large meningiomas, we prefer devascularization of the tumor as early as possible to prevent blood loss and allow convenient angles for dissection of the tumor capsule from the surrounding brain parenchyma. The dissection along the base is alternated with internal decompression of the tumor to gradually remove the bulk of the tumor. This brings down the rim of the tumor and the brain tissue toward the skull base. As an alternative procedure, debulking the core of the tumor can be done first. This will lead to higher blood loss and poorer control of the blood supply during debulking. However, preparation of the skull base after debulking of the tumor is easier compared to the initial devascularization procedure.

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A

B

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D

E

F

* H

G

J

K

I

L

FIGURE 25.3  Craniotomy and dural opening for a typical large olfactory groove meningioma that is suited for a bifrontal approach. (A–C) The fronto-­polar artery branches and the A2 segments are engulfed in the tumor and the capsule, the anterior skull base midline structures are involved, and hyperostosis and concurrent growth into the ethmoid sinus are seen (C). A bicoronal incision is made 2 to 3 cm behind the hairline (D, dotted line). A vascularized galeal—periosteal flap is prepared. (E–G) A bone flap is generated that can extend from the keyholes bilaterally on both sides to the frontal sinus (H, I; the opened frontal sinus is indicated by an asterisk) or that might be limited to 3 cm bilateral of the midline. Then, a slightly curved dural opening is made over both hemispheres, the anterior sagittal sinus is ligated (J–L), and the tumor is visualized growing around the falcine origin along the crista galli (L). (J, © 1993 Edith Tagrin.)

25  •  Surgical Management of Midline Anterior Skull Base Meningiomas

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pl.sph

L

gl

A

B

R opt

Flap

Frontal dura

C

D

E FIGURE 25.4  Closure of bifrontal approach. The infiltrated part of the dura and osseous skull base is removed (A) until the dural fold before the tuberculum sellae (B). After opening the frontal sinus during craniotomy, a temporary closure with Gelfoam and bone wax was used during tumor removal. Now, the definite 2-­layered covering is performed using Tachosil or similar and the vascularized periostal flap (C) with a running suture along the frontal dural margin (C, D). The flap is inserted and it is necessary to fix the flap posteriorly (E) and laterally with sutures to the remaining basal dura, otherwise the flap will retract over the next few days. Additionally, fibrin glue is used to reinforce closure of any remaining holes. gl, Protective piece of glove above the optic nerves; pl.sph., planum sphenoidale; opt, optic nerves and chiasm.

The preparation of the posterior tumor capsule is the most challenging step as branches of the anterior artery complex might be adjacent to or even involved in the tumor capsule. In most cases, at least the larger vessels can be separated by a small rim of cerebral cortex and arachnoid between the adventitia and the outer tumor capsule. However, when those vessels are firmly embedded within the tumor capsule, a tumor remnant might be left in place.12 The optic nerves and the anterior clinoid process can be visualized by preparing further back to the sphenoid wing and then medially. After identification of the involved adjacent neurological structures and removal of the bulk of the tumor, the area of dural attachment should be meticulously coagulated or

preferentially excised. Infiltrated hyperostotic bone should be removed by a high-­speed diamond drill. Hyperostosis may contain remaining tumor cells, and the osseus and tumorous vascular supply usually originates from this area. Similarly, any tumor entering the ethmoid sinus should be resected. The region of the excised dura should be covered with a sheet of Tachosil™, or a similar option; optimal closure includes a vascularized galea-­periost patch or fascia lata over the defect, which is sutured to the remaining dura margin and sealed at the border with fibrin glue (see Fig. 25.4). Another layer of gelatin sponge is placed over the fascia. The layers might be augmented with fibrin glue. The convexity dura is closed with an additional graft of pericranial tissue, and the bone flap is fixed by nonresorbable sutures or mini-­plates. The burr holes

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A

B

FIGURE 25.5  Schematic (A) and MR (B) presentation for olfactory groove tumors eligible for one-­sided removal, in this case a right-sided approach. The olfactory nerve and groove should be visible, the A2 segments should be approachable from this side.

are filled with bone dust or cranioplasty material. A subcutaneous wound-­drain should be left in place before wound closure. 

Unilateral Subfrontal Approach GENERAL CONSIDERATIONS The unilateral approach is preferred for posterior midline frontobasal tumors if the tumor grows prominently on one side and does not have an extensive basal dural attachment onto the contralateral side and the contralateral olfactory nerve is expected to have a clear plane of dissection (schematic view in Fig. 25.5). 

OPERATIVE TECHNIQUE The patient’s position depends on the involvement of the midline structures, displacement, and orientation of the A2 segments and the optic nerve structures. In general, the head is slightly extended posteriorly to allow the frontal lobes to follow gravity. A regular frontal skin incision behind the hairline is used, which may be extended over the midline if anterior and medial visualization is considered. A pericranial flap is always prepared to cover potential dural tears or removed tumor matrix in the case of anterior middle fossa involvement (Fig. 25.6). The craniotomy should aim to visualize the Sylvian fissure; if posterior retraction along the sphenoid wing is required, remain very low above the plane of the frontal skull base, and extend close to the midline as far as necessary. For isolated tuberculum sellae tumors, a regular pterional craniotomy suffices, whereas for very large tuberculum sellae tumors extending to the frontal base, a modified frontal approach might be necessary. 

DURAL OPENING The dural opening is preceded by many sutures along the craniotomy edges. Depending on the bony removal, the dural opening can be curved basally or upward. If the frontal sinus is opened, a multilayered closure should be accomplished, including a pericranial flap that is sutured as far basally as possible. Dural closure is usually not difficult since the dura is lifted from the frontal skull base. However, the dura is lifted in a tent-­like fashion that can lead to an epidural collection. If such an enlarged epidural space is created, the sinus covering should be double checked prior to closure. If necessary, additional sutures secure the graft’s attachment to the skull base. 

TUMOR REMOVAL As discussed, two principal approaches are feasible to begin tumor removal: first, detach the tumor from its vascularization and dural matrix by dissecting the dural plane, and then debulk the tumor safely; this is preferred by the authors because the tumor can be rendered bloodless. A narrow window is formed along the dural plane, which devascularizes the tumor and makes it moveable to a certain degree. Then, the interface of the tumor within the brain can be seen by gentle pulling off the tumor and continuous stepwise resection. The alternative technique to initial devascularization is debulking, which was introduced as early as 1938 in the classical monograph by Cushing and Eisenhardt.2 However, even central decompression rarely leads to shrinking of the tumor because these tumors are usually rather stiff and attached to the surrounding brain. Before approaching the dural matrix of the tumor, the olfactory nerve should be freed of the surrounding arachnoid scarring, which is easier from a lateral approach. Piecemeal preparation might be necessary to maintain olfactory nerve integrity because this nerve is particularly vulnerable to bipolar cauterization and inadvertent suctioning. The authors prefer to protect

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the nerve with a nonadherent covering, such as a Bicol™ collagen sponge, rather than potentially adherent cottonoids. If the optic nerves are reached by the tumor, dissection should proceed in an arachnoid plane, which can be of varying thickness and clarity. If a thin layer of tumor is approaching the optic nerves careful endoscopic inspection of this side should facilitate the visualization of all tumor compartments and allow its removal using curettes and coagulation of the remaining matrix with an angled bipolar cautery. Arteries are frequently embedded within thickened arachnoid layers of the tumor capsule. When the surgeon is in doubt, every single vessel is prepared with its arachnoid covering. TSM that push the optic structures upward and do not extend anteriorly can be approached from a pterional craniotomy. TSM extending anteriorly and pushing the optic nerves laterally should be considered for a modified frontal approach (Fig. 25.7). If the carotid artery is engulfed and the medial sphenoid wing or the cavernous sinus is involved, any combined approach, including a pterional opening, is recommended.

PCG

FIGURE 25.6  Left-­sided unilateral approach for an anterior olfactory groove meningioma. A, MRI of meningioma for typical onesided approach. B, Left-sided skin incision and subgaleal exposition of pericranial graft. C, The temporal muscle (T) and the pericranial graft (PCG) are scraped of the bone and are displayed (D) with vascular supply intact. The PCG is kept in a moistened pad. The temporal muscle is scraped off superiorly to expose the pterion where the first burr hole is made. A second burr-­hole is made over the superior sagittal sinus (E, in light blue).

Olfactory groove meningiomas most frequently required a radical removal (Simpson grade 1 and 2 in >94%), which is reflected in only two recurrences (3%) compared to 14% recurrences/residual tumors for all intracranial meningiomas in our series (Table 25.1). 

SURGICAL MORBIDITY Postoperative complications were significantly associated with tumor volume. The sense of smell improved in 10.3% of patients, 25% worsened upon initial follow-­up although the olfactory nerves were only rarely severed macroscopically. The symptoms that were most likely to improve were associated with massive space-­occupying lesions or massive surrounding edema. Neuropsychological symptoms and severe psychiatric symptoms improved for most patients. Also, edema-related symptomatic hemiparesis and motor dysphasia frequently improved. The most frequent postoperative non-­neurologic morbidity was symptomatic deep venous leg thrombosis in 6% of patients, in part associated with pulmonary embolism despite routine postoperative antithrombotic treatment. 

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A

B

C

FIGURE 25.7  Tuberculum sellae meningioma: (A) sagittal T2-­weighted MRI depicting the location and involvement of surrounding structures. (B) A fronto-­lateral right-­sided craniotomy was performed and a paramedian approach was chosen. After removal of the anterior skull base portion of the tumor, the reminder is gently pulled downward anteriorly. This is possible, since there are only limited attachments to the medial and vascular structures. In (C) the tumor is removed and the dura is coagulated and partially removed. The view from anterior and from lateral to the optic nerve including the use of micromirrors demonstrates complete macroscopic removal.

SURGICAL OUTCOME AND CONCLUSION Meningiomas of the anterior midline skull base have an excellent outcome compared to all other skull base meningiomas. They rarely recur, and the patients benefit from the removal of the space-­occupying lesion. Small tumors may be observed, whereas tumors with significant peritumoral edema or of large size should be removed. Rostral tumors should be exposed with an adequately sized craniotomy, whereas more dorsally situated tumors can easily be operated using a unilateral approach.

Recurring meningiomas are amendable to repeated surgical intervention. Stereotactic radiation represents an alternative to small residues or recurrences. 

Supraorbital Approach GENERAL CONSIDERATIONS The supraorbital approach is simply a smaller version of the frontolateral approach. Axel Perneczky advocated the

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Table 25.1  Results of Surgical Resection in Recent Series of Olfactory Groove Meningiomas

Authors, Year   Mayfrank and Gilsbach, 199631 Paterniti et al., 199932 Tsikoudas and Martin-­ Hirsch, 199933 Turazzi et al., 199934 Zevgaridis et al., 200135 Hentschel and DeMonte, 200336 Nakamura et al., 200710 Romani et al., 200937 Present series, 2011

An-­/ Dysosmia Pre -­> Post-­op

Mental Status Pre -­> Post-­op

Vision/Visual Field Deficits/ Double Vision Pre -­> Post-­op

Recurrence

Follow-­Up Median (Range)

Approach

Cases

Mean Size

Complete Resection

Interhemispheric

18

(cm) 1.5–7.0

(%) 100

(%) NA

(%) NA

(%) NA

(years) NA

Pterional

20

NA

100

NA

NA

0

1–21 years

Bifrontal

13

8>6

NA

NA

NA

4

NA

Pterional

37

23 > 6

100

100

100

0

4 years (1–8)

Frontal

5

5 (100)

NA

80

NA

5 years (2–8)

Bifrontal, Biorbital

13

6.7 (range 5.5–8) 5.6 (range 3.5–8)

85

85

83

0

2 years (0–5)

5

63 months

6

45 months (2–128) 7 years (1–16)

82 Lateral supraorbital Bifrontal, subfrontal one-­ sided

66 64

91 3.9

94%

64%/ 45%

13% pre-­op/6% post-­op

35%/13%

3%

Updated from Hentschel SJ, DeMonte F. Olfactory groove meningiomas. Neurosurg Focus. 2003;14:e4.

The supraorbital approach enables a very good overview of the entire frontal skull base. One limitation is the visualization of the olfactory groove, especially when it is very steep due to the low height of the craniotomy (2 cm). Another blind corner is the space underneath the ipsilateral optic nerve. Therefore, angled endoscopes (30-­or 40-­ degree endoscopes) are mandatory to inspect the groove.17,18 

OPERATIVE TECHNIQUE

FIGURE 25.8  Eyebrow three months after surgery with excellent cosmetic result.

eyebrow approach intensively and recommended it for various lesions of the frontal skull base.13–16 Usually, the supraorbital approach is performed via an eyebrow incision, but it can also be done via a skin incision behind the hairline according to the patient’s preference (Fig. 25.8).

Positioning of the patient is crucial to avoid unnecessary brain retraction. The patient is placed supine with the back elevated 15 degrees to reduce the venous pressure. The head is fixed in a Mayfield clamp in an extended position rotated to the contralateral side (30 degrees for tuberculum sellae and 45 degrees for olfactory groove meningiomas). The zygoma should be the highest point, allowing the frontal lobe to fall back by gravity (Fig. 25.9). The side of the approach depends on the tumor anatomy and location. If the tumor is mainly located on one side of the skull base, this determines the surgical approach (Fig. 25.10). If the smell is still intact on one side in olfactory groove meningiomas, the contralateral side is chosen for the surgical approach. If in TSM, there is tumor extension only into one optic canal, again the surgical approach is from the contralateral side because it allows a straight view to the medial optic canal without optic nerve manipulation. Ergonomic working is important, which includes a holding arm when bimanual dissection for tumor resection is required (Fig. 25.11). The incision begins laterally from the supraorbital notch to avoid injury to the supraorbital nerve (Fig. 25.12A). It is approximately 4 cm long, exactly within the eyebrow, and

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A

B

FIGURE 25.9  Positioning of the patient for an eyebrow approach: (A) Supine position with the body elevated 15 degrees. (B) Sharp head fixation with rotation to the contralateral side and hyperextension of the neck (zygoma highest point).

A

B

C

D

E

F

FIGURE 25.10  Endoscope-­assisted microsurgical resection of an olfactory groove meningioma via a left supraorbital approach. The 79-­year-­old female presented with headache and loss of smell. MR imaging revealed an olfactory groove meningioma with perifocal edema. (A–C) T1-­ weighted contrast-­enhanced axial (A) and coronal (C) and T2-­weighted sagittal (B) MR images showing an olfactory groove meningioma causing perifocal edema. (D–F) T1-­weighted contrast-­enhanced axial (D), sagittal (E), and coronal (F) MR images obtained 3 years after surgery revealed gross total tumor resection without recurrence. The edema resolved. (Created by H.W. Schroeder © Henry Schroeder 2017.)

ends usually at the lateral margin of the eyebrow. Then, the orbicularis muscle and fat tissue are incised. The skin and muscle are retracted upward with fish hooks. A periosteal flap attached to the skull base is cut and elevated (Fig. 25.12B). Thereafter, the temporal fascia and temporalis muscle is detached from the superior temporal line and retracted laterally (Fig. 25.12C). A small burr hole is made behind the superior temporal line (Fig. 25.12D) exactly over

the skull base. Then, a craniotomy of roughly 2.5 × 2 cm is flattened to the skull base (Fig. 25.12E, F). Whenever possible, the frontal sinus should not be entered to reduce the risk of a CSF leak. After dural detachment from the skull base (Fig. 25.12G), the inner margin of the craniotomy and any bony protuberances on the orbital roof are drilled with a diamond drill bit (Fig. 25.12H). Finally, a dural incision is made into the skull base (Fig. 25.12I).

25  •  Surgical Management of Midline Anterior Skull Base Meningiomas

A

FIGURE 25.11  In (A) operating room set-­up for endoscope-­assisted microsurgery. (B) Bimanual endoscopic dissection using the endoscope fixed in a mechanical holding arm and Gilsbach frame as hand rest.

B

Thereafter, the operating microscope is brought into the field, and microsurgical dissection gets started. The frontal lobe is protected with cottonoids and carefully retracted. Depending on tumor location and size, the Sylvian fissure or the chiasmatic cistern is opened for abundant release of CSF. The use of static retractors is minimized. Excessive retraction must be avoided because it can avulse the ipsilateral olfactory fibers at the cribriform plate. Then the tumor resection is performed according to the techniques described above and to Schroeder et al. 2016.19. Endoscopes are used whenever needed to look into the olfactory groove or under the ipsilateral optic nerve (Fig. 25.12J). After the tumor resection has been accomplished, the dura is closed in a watertight fashion using running sutures and TachoSil (Nycomed Austria GmbH, Linz, Austria). When the frontal sinus has been opened, it is closed with two additional layers of TachoSil. A watertight dural closure is crucial to avoid a CSF leak. Gelfoam is placed in the craniotomy, and the bone flap is fixed with mini-­plates close to the upper margin of the craniotomy (Fig. 25.12K). For cosmetic purposes, the craniotomy-­related bony defects should be filled with bone cement to avoid indentations of the forehead after scar formation. The wound is closed in a layered fashion (Fig. 25.12L). 

Endonasal Approach GENERAL CONSIDERATIONS The endonasal approach has recently become more and more popular in the treatment of anterior skull base meningiomas.20–24 Advantages compared with transcranial approaches are fewer manipulations of neurovascular structures, avoidance of brain retraction, and early devascularization of the tumor.25 In TSM, a better visual outcome has been reported.26 However, endonasal approaches have severe limitations as well. Only the midline skull base can be visualized. Since skull base meningiomas frequently have an en-­plaque growth along the skull base that is not seen on preoperative MR images, the risk of incomplete resections is higher. Furthermore, the surgery usually takes longer than a transcranial approach. For olfactory groove meningiomas, surgical times of 9 hours and staged surgeries have been reported.27 The rate of gross total resections is clearly lower, and the risk of CSF leakage is still higher.28 If the tumor is encasing

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important neurovascular structure, the microsurgical dissection is much easier and safer via a craniotomy. A favorable visual outcome in tuberculum sellae meningioma resections can be achieved with transcranial approaches as well.18 Therefore, our indications for endonasal approaches in anterior skull base meningiomas are very limited. We use the endonasal approach for selected small TSM (< 2 cm), especially when a very steep tuberculum sellae is present or the intrasellar space is involved or when the patient requests that approach. Further indications are olfactory groove meningiomas with loss of olfaction and significant growth into the nasal cavity. These lesions are usually recurrent tumors after trans­ cranial resection of large tumors. Rare meningiomas arising from the dorsum sellae are also better approached via the endonasal route because of their location under the chiasm. 

OPERATIVE TECHNIQUE The patient is in supine position (Fig. 25.13A), and the head is fixed with a Mayfield clamp and turned to the surgeon’s side (Fig. 25.13B). Three monitors are set up: one for the surgeon, one for the assistant holding the endoscope, and one displaying MR, CT, or navigation images (Fig. 25.13C). The left-­sided assistant holding the endoscope free-­handedly enables a dynamic visualization that provides a pseudo 3D impression (Figs. 25.13C and D). For extended endonasal approaches, the binostril 4-­hand technique should always be used (Figs. 25.13D and E). After disinfection, patties soaked with epinephrine 1:1000 are placed in both nasal cavities to decongest the mucosa. After draping, both nasal cavities are inspected with a 4-mm 0-­degree rigid rod lens endoscope attached to a HD camera (Karl Storz GmbH & Co. KG, Tuttlingen, Germany). The lower and middle turbinates are identified and displaced laterally. Then, the superior turbinates are mobilized laterally as well. The ostia of the sphenoid sinus can usually be seen in the sphenoethmoidal recess. They are located approximately 1.5 cm above the choana. In extended approaches that require an opening of the dura, a pedicled nasoseptal flap is raised, usually on the right side.29 On the contralateral side, a reverse flap is created and flipped over to cover the denuded septum where the flap was taken from.30 This accelerates the reepithelization dramatically and reduces the postoperative discomfort of crusting and nasal discharge. Then, the sphenoid sinus is opened wide. In a well-­pneumatized sinus, the anatomical landmarks,

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A

B

C

D

E

F

G

H

I

J

K

L

FIGURE 25.12  Left supraorbital approach (Created by H.W. Schroeder © Henry Schroeder 2017): (A) Marking of the skin incision. (B) Elevation of the periosteal flap. (C) Exposed cranium after detaching temporal muscle and fascia from the temporal line and adjacent bone. (D) Burr hole behind the temporal line. (E) Craniotomy with the craniotome. (F) Completed craniotomy. (G) Detaching of the dura from the orbital roof. (H) Drilling of the inner edge of the craniotomy. (I) Dura flap based to the skull base. (J) Coagulation of the tumor base in the olfactory groove under view of a 30-degree endoscope. (K) Fixation of the bone flap with titanium mini plates. (L) Computed tomography CT scan obtained 1 day after surgery showing the craniotomy flap.

25  •  Surgical Management of Midline Anterior Skull Base Meningiomas

A

C

299

B

D

E

FIGURE 25.13  Endonasal approach: (A) Positioning of the patient for an endonasal approach: Supine position with the body elevated 30 degrees. (B) Sharp head fixation with rotation to the ipsilateral side and tilting to the contralateral side. (C) Operating room set-­up for endoscopic endonasal surgery. (D) Positioning of the surgical team in endonasal surgeries. (E) Binostril approach using the 4-­hand technique.

such as carotid protuberances, optic nerves, and medial and lateral optic recesses, are easily identified. For TSM (Fig. 25.14A and B), the tuberculum sellae, sellar floor, and adjacent planum are drilled with a diamond bit and the basal dura is exposed (Fig. 25.14C), and the carotid arteries are verified using the micro Doppler (Fig. 25.14D). The superior intercavernous sinus is coagulated (Fig. 25.14E) and cut (Fig. 25.14F). After the dura has been opened in a V-­shaped fashion, the tumor is exposed (Fig. 25.14G) (in larger tumors at first debulked) and finally circumferentially dissected in the arachnoid plane (Fig. 25.14H). The infiltrated dura is excised while preserving the branches of the superior hypophyseal arteries (Fig. 25.14I). After meticulous hemostasis is confirmed, the skull base defect is reconstructed with fat (Fig. 25.14J) and the nasoseptal flap fixated with fibrin glue. It is necessary to drill the sphenoid septi flat and remove all mucosa from the area where the flap is to be placed to provide a good bed for the flap, which is a prerequisite for good healing and avoidance of a CSF leak. Finally, tamponades are placed bilaterally to secure the flap position.

In TSM, a lumbar drain is usually not required. MR imaging is performed on the next day to confirm the correct position of the nasoseptal flap. After extended endonasal approaches, a prolonged phase of nasal care with cleaning of the nasal cavity and irrigation with saline is required to achieve a good long-­ term nasal quality of life. 

Disclosure Henry W. S. Schroeder is consultant to Karl Storz GmbH & Co. KG (Tuttlingen, Germany).

Acknowledgment We are very grateful to Marc Matthes, M.Sc., for helping with the creation of Figs. 25.8–25.14. Numbered references appear on Expert Consult.

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D

SE

B

A

C

C C

C

C

E

D

F

T T CH

G

H

I

K

L

S

F

J

FIGURE 25.14  Endoscopic endonasal resection of a tuberculum sellae meningioma via a transtuberculum-­planunm approach. The 39-­year-­old male presented with headache. Visual field and visual acuity were normal. Although an incidental finding, the patient insisted on tumor removal via the endonasal route. MRI findings of T1-­weighted contrast-­enhanced sagittal (A) and axial (B) MR images reveal a small tuberculum sellae meningioma reaching the optic chiasm. (C) Exposed sella (SE) and basal dural (D) after drilling of the tuberculum and planum. (D) Identification of both internal carotid arteries (C) using the micro Doppler. (E) Coagulation of the superior intercavernous sinus between the carotid arteries (C). (F) Cutting of the superior intercavernous sinus. (G) Exposing the tumor (T) after opening of the dura. (H) Mobilization of the tumor (T) after bimanual dissection within the arachnoid plane. I: Inspection with a 30 degree endoscope after tumor removal showing the chiasm (CH), pituitary stalk (S), and branches of the superior hypophyseal artery (arrow). (J) Reconstruction of the skull base with fat (F). MRI findings of T1-­weighted contrast-­enhanced sagittal (K) and axial (L) MR images obtained 2 days after surgery showing total tumor removal. (Created by H.W. Schroeder © Henry Schroeder 2017.)

REFERENCES

1. Cushing H. The meningiomas arising from the olfactory groove and their removal by the aid of electrosurgery. Lancet. 1927;1:1329– 1339. 2. Cushing H, Eisenhardt L. Meningiomas: Their Classification Regional Behavior Life History and Surgical End Results. Springfield: Charles C. Illinois:Thomas; 2010. 3. Bendszus M, Monoranu CM, Schutz A, Nolte I, Vince GH, Solymosi L. Neurologic complications after particle embolization of intracranial meningiomas. AJNR Am J Neuroradiol. 2005;26:1413– 1419. 4. Carli DF, Sluzewski M, Beute GN, van Rooij WJ. Complications of particle embolization of meningiomas: frequency, risk factors, and outcome. AJNR Am J Neuroradiol. 2010;31:152–154. 5. Kallmes DF, Evans AJ, Kaptain GJ, et al. Hemorrhagic complications in embolization of a meningioma: case report and review of the literature. Neuroradiology. 1997;39:877–880. 6. Wakhloo AK, Juengling FD, Van VV, Schumacher M, Hennig J, Schwechheimer K. Extended preoperative polyvinyl alcohol microembolization of intracranial meningiomas: assessment of two embolization techniques. AJNR Am J Neuroradiol. 1993;14:571–582. 7. Tönnies W. Zur Operation der Meningeome der Siebbeinplatte. Zentralblatt Fur Neurochir.1938;1:1–7. 8. Hassler W, Zentner J. Pterional approach for surgical treatment of olfactory groove meningiomas. Neurosurgery. 1989;25:942–945. 9. Al-­Mefty O. Surgical technique for the juxtasellar area. In: Al-­ Mefty O, ed. Surgery of the Cranial Base (Foundations of Neurological Surgery). 2nd ed. Boston: Kluwer Academic Publishers; 2010:73– 89. 10. Nakamura M, Struck M, Roser F, Vorkapic P, Samii M. Olfactory groove meningiomas: clinical outcome and recurrence rates after tumor removal through the frontolateral and bifrontal approach. Neurosurgery. 2007;60:844–852. 11.  Ojemann Ransohoff J, Nockels RP. Olfactory groove and planum meningiomas. In: Apuzzo MLJ, ed. Brain Surgery Complication Avoidance and Management. New York: Churchill Livingstone; 1993:203–219. 12. Ojemann RG, Martuza RL. Surgical Management of olfactory groove meningiomas. In: Schmidek HH, Roberts DW, eds. Operative Neurosurgical Techniques: Indications Methods and Results. Philadelphia: W.B.Saunders Company; 2006:207. 13. Fries G, Perneczky A. Endoscope-­assisted brain surgery: part 2 -­ analysis of 380 procedures. Neurosurgery. 1998;42:226–232. 14. Perneczky A, Fries G. Endoscope-­assisted brain surgery: part 1 -­evolution, basic concept, and current technique. Neurosurgery. 1998;42:219–225. 15. Reisch R, Perneczky A. Ten-­year experience with the supraorbital subfrontal approach through an eyebrow skin incision. Neurosurgery. 2005;57:242–255. 16. Van Lindert E, Perneczky A, Fries G, Pierangeli E. The supraorbital keyhole approach to supratentorial aneurysma: concept and technique. Surg Neurol. 1998;49:481–490. 17. Schroeder HW, Hickmann AK, Baldauf J. Endoscope-­assisted microsurgical resection of skull base meningiomas. Neurosurg Rev. 2011;34:441–455. https://doi.org/10.1007/s10143-­011-­0322-­9. 18. Marx S, Clemens S, Schroeder HW. The value of endoscope assistance during transcranial surgery for tuberculum sellae meningiomas. J Neurosurg. 2017:1–8. https://doi.org/10.3171/2016.11.JNS16713. 19. Schroeder HW. Supraorbital approach. In: Cappabianca P, L.M C, Divitiis Od, Esposit F, eds. Midline Skull Base Surgery. Heidelberg: Springer; 2016:253–268.

20. de Divitiis E, Cavallo LM, Cappabianca P, Esposito F. Extended endoscopic endonasal transsphenoidal approach for the removal of suprasellar tumors: Part 2. Neurosurgery. 2007;60:46–58. 21. Fatemi N, Dusick JR, de Paiva Neto MA, Malkasian D, Kelly DF. Endonasal versus supraorbital keyhole removal of craniopharyngiomas and tuberculum sellae meningiomas. Neurosurgery. 2009;64:269– 284. https://doi.org/10.1227/01.NEU.0000327857.22221.53. 22. Fernandez-­Miranda JC, Gardner PA, Prevedello DM, Kassam AB. Expanded endonasal approach for olfactory groove meningioma. Acta Neurochir Wien. 2009;151:287–288. 23. Gardner PA, Kassam AB, Thomas A, et al. Endoscopic endonasal resection of anterior cranial base meningiomas. Neurosurgery. 2008;63:36–52. 24. Greenfield JP, Anand VK, Kacker A, et al. Endoscopic endonasal transethmoidal transcribriform transfovea ethmoidalis approach to the anterior cranial fossa and skull base. Neurosurgery. 2010;66:883– 892. 25.  de Divitiis E, Esposito F, Cappabianca P, Cavallo LM, de DO, Esposito I. Endoscopic transnasal resection of anterior cranial fossa meningiomas. Neurosurg Focus. 2008b;25:E8. https://doi.org/10.3171/FOC.2008.25.12.E8. 26. de Divitiis E, Esposito F, Cappabianca P, Cavallo LM, de DO. Tuberculum sellae meningiomas: high route or low route? A series of 51 consecutive cases. Neurosurgery. 2008a;62:556–563. https://doi.org/10.1227/01.neu.0000317303.93460.24. 27. Koutourousiou M, Fernandez-­Miranda JC, Wang EW, Snyderman CH, Gardner PA. Endoscopic endonasal surgery for olfactory groove meningiomas: outcomes and limitations in 50 patients. Neurosurg Focus. 2014;37:E8. 28. Komotar RJ, Starke RM, Raper DM, Anand VK, Schwartz TH. Endoscopic endonasal versus open transcranial resection of anterior midline skull base meningiomas. World Neurosurg. 2012;77:713– 724. https://doi.org/10.1016/j.wneu.2011.08.025. 29. Kassam AB, Thomas A, Carrau RL, et al. Endoscopic reconstruction of the cranial base using a pedicled nasoseptal flap. Neurosurgery. 2008;63:ONS44–ONS52. https://doi.org/10.1227/01.neu.0000335010.53122.75. 30. Caicedo-­Granados E, Carrau R, Snyderman CH, et al. Reverse rotation flap for reconstruction of donor site after vascular pedicled nasoseptal flap in skull base surgery. Laryngoscope. 2010;120:1550– 1552. https://doi.org/10.1002/lary.20975. 31. Mayfrank L, Gilsbach JM. Interhemispheric approach for microsurgical removal of olfactory groove meningiomas. Br J Neurosurg. 1996;10:541–545. 32. Paterniti S, Fiore P, Levita A, La CA, Cambria S. Basal meningiomas. A retrospective study of 139 surgical cases. J Neurosurg Sci. 1999;43:107–113. 33. Tsikoudas A, Martin-­Hirsch DP. Olfactory groove meningiomas. Clin Otolaryngol Allied Sci. 1999;24:507–509. 34. Turazzi S, Cristofori L, Gambin R, Bricolo A. The pterional approach for the microsurgical removal of olfactory groove meningiomas. Neurosurgery. 1999;45:821–825. 35. Zevgaridis D, Medele RJ, Muller A, Hischa AC, Steiger HJ. Meningiomas of the sellar region presenting with visual impairment: impact of various prognostic factors on surgical outcome in 62 patients. Acta Neurochir Wien. 2001;143:471–476. 36. Hentschel SJ, DeMonte F. Olfactory groove meningiomas. Neurosurg Focus. 2003;14:e4. 37. Romani R, Lehecka M, Gaal E, et al. Lateral supraorbital approach applied to olfactory groove meningiomas: experience with 66 consecutive patients. Neurosurgery. 2009;65:39–52.

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CHAPTER 26

Supraorbital Approach Variants for Intracranial Tumors KARIM REFAEY  •  RACHEL STEIN  •  KELLY GASSIE  •  OLIVIA A. HO   •  ANTONIO JORGE FORTE  •  ALFREDO QUIÑONES-­HINOJOSA The fundamental basis of “keyhole” neurosurgery lies in the fact that, if designed and tailored to the lesions, deep lesions can be approached via smaller incisions and craniotomies providing essentially the same anatomic visualization as the larger, more traditional cranial base approaches. The supraorbital craniotomy is the prime example of this trend in neurosurgery; with increased emphasis on maximizing cosmetic outcomes, minimizing tissue morbidity, and reducing hospitalization stays, there is now increased importance in understanding minimally invasive approaches (i.e., supraorbital craniotomy, keyhole craniotomies in general, and endoscopic endonasal approaches). Paramount to the success of these approaches is a thorough understanding of the anatomy, because they can be difficult for novice surgeons who do not have a solid grasp of microsurgical corridors and cranial base anatomy/ compartments. Anatomically relevant is the orbital bone because it forms the roof of the orbital cavity and a strategic part of the anterior floor of the skull base. The orbital ridge intersects with the zygomatic bone laterally and the ethmoid medially; the orbit is further contiguous with the anterior fossa and sphenoid bone. Consequently, it is an anatomic structure that is intimately associated with the orbital cavity and its structures, as well as with the intracranial region.1–5 The supraorbital craniotomy and its variants essentially provide a combined subfrontal-­anterolateral microsurgical approach. Anatomic structures such as the anterior clinoid, sphenoidal plane, and sellar region are keys to this corridor extending toward the region of the sylvian fissure. Therefore these anatomic structures are critical in planning any microsurgical trajectory to the anterior fossa floor, the middle fossa, the smaller wing of the sphenoid, and the sellar/parasellar region.1,6–17 In following this outlined corridor, the supraorbital approach can give the surgeon access to ipsilateral anterior cranial fossa, basal frontal lobe and frontal pole, medial temporal lobe, lateral wall of cavernous sinus, ipsilateral proximal Sylvian fissure, opticocarotid cistern, suprasellar region, superior sella, lamina terminalis, perimesencephalic/interpeduncular cistern, and medial/ superior aspect of contralateral optic nerve, chiasm, and carotid artery. In addition, adjunct use of an endoscope may help particularly with ensuring total tumor removal,

reaching deep aneurysms and accessing surgical regions such as the anterior olfactory groove, supra and intrasellar space, inferior space directly under ipsilateral optic nerve, interpeduncular/perimesencephalic cistern, ipsilateral medial middle fossa, medial temporal lobe, and the anterior third ventricle.8,10,11,15,18–22 Previous anatomic studies have critically evaluated anatomic corridors in this region and their utility in treating a variety of neurologic lesions; these studies have subsequently resulted in potential surgical alternatives. Such historical and fundamental contributions have been made by Durante, Krause, Frazier, Cushing, Heuer, Dandy, Yasargil, Brock and Dietz, Al-­Mefty, Zabramski, and Perneczky. Although the supraorbital approach is not a new strategy (initially described by Frazier with his epidural approach described in 1913),23 technological innovations have enhanced its applicability. This technique has continued to be refined over the past 20 years and routinely demonstrates comparable safety and efficacy to standard approaches. The introduction of new tools (e.g., endoscopy) and new approaches (i.e., orbital ridge osteotomy) has improved access to and visualization of cranial base lesions and, while the operative corridor is smaller in keyhole craniotomies, they still produce adequate deep exposure and maneuverability. Ultimately, neurosurgical and technological innovations have aimed to reduce morbidity under the concept of minimally invasive neurosurgery.9,12,15,20,24–27

Orbital Anatomy It is important to consider the orbital region as an anatomic compartment bound superiorly by the frontal bone, medially forming a close angle with the ethmoid bone, lacrimal bone, and lacrimal fossa. In addition, there are connections to the nasal region.28–31 In the inferior medial region, we find the adjacent palatine bone and in the lower border the maxillary bone, where the infraorbital foramen is located. Going toward the midlateral inferior region, we find the area of the zygomatic bone which in turn extends through the zygomatic arch toward the posterolateral aspect and going in an anterolateral location we find the facial zygomatic foramina. In the internal

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SF SOF

OC

Ethm FIGURE 26.1  (A and B) Overview of orbital anatomy. Ethm, Ethmoidal bone; FB, frontal bone; IOF, inferior orbital fissure; LWS, lesser wing of sphenoid; OC, optic canal; OS, optic strut; SF, supraorbital foramen; SOF, superior orbital fissure.

LWS

OS

FB

SOF Z

Z IOF

A

cavity of the orbital region the origin of the great wing of the sphenoid in its posterolateral portion is found—giving way to a virtual space between the small wing and the great wing of the sphenoid, known as the superior orbital fissure. Adjacent to the posterior medial portion are the optic canal located inferiorly and the inferior orbital fissure.2,32 The ethmoid bone represents a complicated component of the craniofacial skeleton with several critical components. Medially, the ethmoid presents a lamina to the nasal cavity while superiorly it presents the cribriform plate. In addition, the ethmoid bone articulates with the sphenoid bone and sphenoid sinus along several surfaces posteriorly and inferiorly. Furthermore, a majority of the volume of the ethmoid bone consists of trabeculated air spaces creating the ethmoid air cells. The posterosuperior orbital cone is made of the superior margin of the orbital fissure and the extension of the small wing of the sphenoid. The intracavitary foramina are the lacrimal foramen, the optic canal, the superior orbital fissure, the inferior orbital fissure, and in the extracavitary portion we find the notch or foramen for the infraorbital nerve and the orbital zygomatic foramen (Fig. 26.1).29 The optic canal and the anterior clinoid process are closely located and associated with the origin of the small wing of the sphenoid bone; the superior orbital fissure is divided by a bone strut (optic strut) supporting the anterior clinoid process. The most important structures involved in this region looking above (from the intracranial frontal floor perspective) are the anterolateral floor or the platform and the orbital arch. Toward the anterior medial portion, the crista galli and the cribriform plate of the ethmoid bone are found. The sphenoid plane and the wing of the sphenoid that meets the optic foramen are located in the deep plane (Fig. 26.2).33,34 The anatomic intraorbital structures are basically represented by the extraocular muscles, predominantly the rectal and medial and lateralis muscles, such as the levator muscle for eye movement. We also find the periorbital fat or periorbit and the globe itself, the optic nerve, and other nerve structures from the ophthalmic branch of the trigeminal nerve, such as the frontal, nasociliary, and lacrimal nerves. The rest of the ocular motor nerves—III, IV, and VI—converge in a particular anatomic site after passing through the cavernous sinus (Fig 26.3).33 The most important arterial structures are the ophthalmic artery, its variants in the lacrimal artery and its connections to the ciliary artery, and the central retinal artery, whose

B

Ethm

Sph. sinus

Fb

Acp

LWS

FIGURE 26.2  Sagittal cut of skull and right-­side view. Acp, Anterior clinoid process; Ethm, ethmoidal bone; Fb, frontal bone; LWS, lesser wing of sphenoid; Sph sinus, sphenoidal sinus.

venous return flows through the ophthalmic vein. The anterior ethmoidal artery is a significant vessel in the anteromedial region. It is closely related with the nasolacrimal region and the irrigation of the nasal mucosa, frequently managed in surgical procedures to control nose bleeds.28,31,35–39 This specific anatomy gives way to the possibility of removing the orbital roof to have wide access to all the orbital area and ocular contents, nerve structures, muscles and vessels, and additionally have an intracranial access. An important anatomic structure from the surgical perspective is the lacrimal gland, located in the superior external area of the orbit. This is a region that can be compromised when using a surgical approach where the orbital roof is removed.29 From the surgical perspective as well, it is important to emphasize the orbital surgical triangle, represented by

26  •  Supraorbital Approach Variants for Intracranial Tumors

303

E F A

FIGURE 26.4  Operative corridor to deeper lesions via supraorbital approach. (Victor © 2009.) C B D

FIGURE 26.3  Overview of intraorbital anatomy. (A) Superior oblique muscle. (B) Optic nerve. (C) Trochlear nerve. (D) Oculomotor nerve. (E) Supraorbital nerve. (F) Ophthalmic artery.(Victor © 2009.)

a geometric figure that, from its lateral projection, the base is the anterior part of the frontal bone and the orbital arch, the upper part is outlined by the base of the frontal lobe, and the inferior part is outlined by the periorbit.30 This triangle, with an anterior base and a posterior vertex, may offer several options for deep resection (also representing the angle of bone removal described in the transsupraorbital approach; Fig. 26.4).5,40 

Experimental Analysis of the Supraorbital Approach in Cadavers A series of cadaver specimens were studied to assess the variations described for the supraorbital craniotomy to evaluate the extent of surgical access in identifying different anatomic landmarks.11,15,27,41–45 The conventional supraorbital keyhole approach was used to examine the optic nerve, ipsilateral anterior clinoid, sphenoidal plane, and the dorsum sellae. This approach, compared with the transsupraorbital approach, showed some benefit with regard to accessibility and visualization.2–7,23–25,28–40,46 Subsequently, possible variants of this approach were analyzed in another experimental cadaveric study. In a series of 15 adult skulls, the differences between anatomic targets and the space around the sellar region were evaluated for these variants. Access to the following regions was assessed: the anterior clinoid process (ipsilateral), the chiasmatic sulcus, the optic canal, the center point of the sella turcica, and

the dorsum sellae. Table 26.1 presents measurements for the classical supraorbital approach versus the supraorbital craniotomy combined with removal of the orbital arch. Recognizing that the approach can be tailored, the craniotomy can be extended in different anatomic directions specific to the target pathology/region. For example, the supraorbital nerve can be mobilized in order to create a craniotomy more toward the midline. This modified approach facilitates a more comfortable and direct route to the prechiasmatic region, as well as other structures such as the crista galli, ethmoid lamina, olfactory bulb, sphenoidal plane, and anterior clinoid.25,47–52 On the other hand, lateral extension, as with the supraorbital-­pterional approach, permits greater pterional access. This modification permits greater access to the lateral targets in the frontotemporal neurosurgical corridor and their neurovascular structures.14,25,42,47,52–55 Finally, if the principles of minimally invasive surgery and skull base surgery are combined, using the supraciliary incision, it is possible to remove the orbital arch in a block in the medial and lateral portion, which provides an average of 1.5 cm more space to work in the craniotomy site, according to the anatomic studies of the transsupraorbital approach.39,56–58 All of these variations of the supraorbital approach provide greater versatility and several possible adaptations to meet the surgical goal under the concept of supraselective craniotomy, which is the fundamental basis of the “keyhole” craniotomy. There are six basic variants of the supraorbital approach (Fig. 26.5): 1. Supraorbital medial 2. Supraorbital anterolateral (classical) 3. Supraorbital pterional 4. Transsupraorbital 5. Eyelid (transpalpebral) supraorbital 6. Eyebrow supraorbital 

Intracranial Surgical Access and Its Variants The development of finer, more accurate, and angled instruments has been critical for success of the supraorbital

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Table 26.1  Volumetric Comparison of Exposure of Critical Structures (Mean ± Standard Deviation) Technique Classical supraorbital approach Supraorbital craniotomy with orbital ridge osteotomy

Anterior Clinoid Process Ipsilateral

Chiasmatic Sulcus

Optic Canal

Pituitary Fossa

Dorsum Sellae

5.57 ± 0.06 4.5 ± 0.09

5.5 ± 0.09 4.5 ± 0.09

5 ± 0.09 4 ± 0.12

6.5 ± 0.09 5.4 ± 0.09

6.97 ± 0.08 6 ± 0.12

Another advantage of this approach is preservation of the temporalis muscle in comparison to other anterolateral-­ based approaches (i.e., pterional). Even with lateral extension of this approach, the soft tissue dissection involves only minimal mobilization of the superior and anterior most aspect of the temporalis—in this process the deep neurovascular supply is preserved.8,12,16,19,42,53,66,73 To truly benefit from minimally invasive strategies, cases must be carefully selected upon consideration of the surgical objective, the patient’s individual anatomic variations, and the experience and comfort level of the surgical team. This strategy allows proper evaluation and ultimately helps the surgeon to identify the most adequate and beneficial approach for the patient.

PATIENT POSITIONING

FIGURE 26.5  Supraorbital approach and its variants. White, supraorbital (laterobasal) (classic). Blue, supraorbital pterional. Light blue, supraorbital medial. Green, transsupraorbital. (Victor © 2009.)

approach and its variants. Likewise, a major breakthrough was the use of the surgical microscope complemented with endoscopy-­assisted microneurosurgery. The concept of keyhole microsurgery set forth by Perneczky was based on this new technology that contributed to providing several new options. Although seemingly contradictory, keyhole cranial base surgery advocates maximal resection through the use of current surgical technology and methodology taking into consideration the patient’s condition and pathology. Thus variations in the orbital approach itself have led to improved extension and use in various surgical spaces granting access to the most important accessible structures.8,11,47,52–65 Synonymous with the development of keyhole surgery has been the increasing acceptance of using smaller incisions, such as the eyebrow incision. The use of smaller incisions can have cosmetic, functional, and even psychological benefits for the patient. However, this fact should not limit the final surgical plan in view of the surgical goal. For example, a displaced frontal scalp flap/craniotomy can also be chosen to apply the principle of selective craniotomy. In other words, minimally invasive surgery does not simply mean a minimal incision or minicraniotomy; instead, the goal is to spare craniofacial and neurovascular structures using a tailored approach as broad as necessary and as selective as experience allows, with every possible manipulation of a conventional procedure.8,61,65–74 For example, disadvantages of the brow approach can include potential posterior alopecia of the eyebrow or frontalis weakness that occurs as a result of damage to the frontal branch of the facial; however, this may be ameliorated with preoperative mapping using a nerve conduction study.75

One of the most significant factors in supraselective approaches is patient positioning as part of the operative plan. It is crucial to consider not only the surgical plan, but also the general and neurovascular anatomy of the patient. The effect of gravity and potential brain shift as a result of positioning may provide patient benefits by creating comfortable and wide access.28,71 Consequently, it is important to consider not only elevating the head above the chest in every case to facilitate the venous return but also retroflexing and rotating the head according to the surgical plan.72,76 In general, the operating table is in mild reverse Trendelenburg, the head placed in 20 degrees of extension and rotated to the contralateral side: 15 degrees for ipsilateral sylvian fissure, 20 degrees for lateral suprasellar, 30 degrees for anterior suprasellar, and 60 degrees for olfactory groove/cribriform plate regions. This will allow for gravity to naturally pull the frontal lobe away from the anterior fossa floor, therefore reducing the amount of frontal lobe retraction necessary.8,10,20,57,65,77 One of the goals is to have a three-­dimensional view that gives full access to the surgical target with the least possible retraction, considering the conventional anatomic spaces promoted by cisternal drainage and subarachnoid dissection—fundamental microsurgical principles.16,46,65 

SUPRAORBITAL VARIANTS Basic Access Through the Eyebrow Meticulous planning places the incision lateral to the supraorbital foramen extending to the area of the frontozygomatic suture. The skin flaps are retracted with elastic holding sutures. After exposing the muscles of the area, the frontalis muscle is sectioned sharply parallel to the orbital rim after which dissection of the orbicularis and the frontotemporal insertion of the temporalis muscle are also completed. Subsequently, the burr hole is made with a high-­speed drill, inferiorly to the temporal line, and use any of the variants described in the following.61,67,78

26  •  Supraorbital Approach Variants for Intracranial Tumors

305

When creating the craniotomy, caution should be taken with the proximity of the frontal sinus to prevent infection and cerebrospinal fluid (CSF) fistula. The frontal sinus can extend as lateral as 1.5 cm to the supraorbital notch and is larger in males.79,80 Although few patients may develop clinical signs of a frontal sinus breach, it has been reported that 25% of cases show a frontal sinus breach radiographically.81 Of note, using calcium phosphate cement in closing the craniotomy defect may decrease the incidence of CSF leak.82 

Medial Supraorbital Approach In selected cases, this approach basically provides access to the subfrontal region, the medial gyrus rectus, the anterior interhemispheric portion, and medial bone annexa such as the cribriform region, olfactory sulcus, and nasolacrimal region.28,32,38,46 This corridor gives access to several tumors in this area, including the basal interhemispheric region, the genu and rostrum of the corpus callosum, and the proximal pericallosal space. Direct access to the cribriform basal region and the olfactory nerves is provided (crista galli, olfactory groove, planum sphenoidale, tuberculum sellae, lamina terminalis, anterior third ventricle, pituitary stalk, anterior communicating artery, and dorsum sellae).11,23,33,38,48,70,72,76,78,83–86 An inconvenience of this approach is the decision to plan entry into the frontal sinus (unless the frontal sinus is reduced in size) and the potential external mobilization of the supraorbital nerve to obtain a totally medial access. Keep in mind that the supraorbital notch is approximately 32 mm from the superior temporal line in women and 34 mm in men. Infection and fistula from the frontal sinus access should be seriously considered as risk factors for this procedure, and it may be considered to routinely cranialize the frontal sinus with this approach.11,87 Nevertheless, when closure of the dura is meticulous and careful, the frontal sinus is cleaned thoroughly, and specific antibiotics are used, the procedure can be done without any problem (Fig. 26.6).31,46,71,85 

FIGURE 26.6  Relationship of frontal sinus to craniotomy. (Victor © 2009.)

Classic Supraorbital Approach (Laterobasal) The classic supraorbital approach—also called the frontolateral-­ basal approach—is the classic technique described by Perneczky. From this supraorbitolateral corner, access is obtained to the frontobasal region, sylvian fissure, and mesial temporal lobe. This approach provides such anatomic access due to the fundamental microsurgical principle of CSF drainage via opening cisterns.25,60 This approach provides access to the orbital roof, anterior clinoid process, posterior clinoid process, the roof and lateral wall of the cavernous sinus, translamina terminalis to the third ventricle, the basal portion of the frontal lobe, gyrus rectus, sylvian fissure, temporal lobe, uncus, hippocampus, and cranial nerves (CNs) of all this neurovascular corridor, including CN1, CNII, CNIII, and CNIV; and extensions of the internal carotid artery, middle cerebral artery, and posterior cerebral artery in their proximal segments (ICA, Opht A, PCoA, AChA; perforators A1, A2, M1, M2, P1, P2, SCA; and temporal vein) (Fig. 26.7).11,25,29,38,83–85,88,89 

Supraorbitopterional Approach This keyhole approach was created to achieve the angle of vision and advantages of the classic pterional approach but

FIGURE 26.7  Right supraorbital approach surgical view after excision of pituitary adenoma in prechiasmatic region and optic-­carotid cistern. (Victor © 2009.)

with less temporalis disruption, shorter hospital stays, and better cosmetic and masticatory results.42,90 This surgical approach is based on the anatomic location of the sphenoid ridge and its relationship with the sylvian fissure and basal cisterns. The initial incision is made over the hairline behind the external border of the eye on the selected side because

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the cosmetic outcome is better compared with an eyebrow incision. A skin and muscular flap is reflected anteriorly, and a small 3 × 3–cm craniotomy is completed around the external landmarks of the sphenoid ridge. Further extradural drilling of the greater or lesser sphenoid wings to increase the operative area of exposure is completed down to the anterior clinoid process. The dura is opened in a semilunar manner, and the sylvian fissure is opened completely to reach the sylvian and basal cisterns. Of course, if we consider that the actual microsurgical space is 20 mm (average surgical exposure volume of 23.6 mL versus 32.9 mL for pterional approach), this approach gives the same benefits as the conventional pterional approach and the benefits of the access through the transsylvian corridor, for a well-­outlined craniotomy at the usual extension of the dural opening (Fig. 26.8).14,42,45,54,55,58,65,91 A modified lateral supraorbital approach may also be applied for a more subfrontal and anterior trajectory than the pterional or supraorbital-­ pterional approaches. This method uses a wider incision behind the hairline starting from the zygomatic arch to 1 to 2 cm past midline. A MacCarty burr hole is used, and a 3 to 4 cm × 3 to 4 cm frontal craniotomy is performed. This method offers less violation of the temporalis muscle and does not involve extending the craniotomy into the sphenoid or temporal bones nor drilling down of the sphenoid wing. The MLSA is recommended for gaining early proximal control in an MCA aneurysm; however, it should not be used in PCoM aneurysms when the anterior clinoid needs to be excised. The MLSA is less invasive and has been shown to decrease operating times and achieve better cosmetic results.53,92 

Transsupraorbital Approach With the conventional technique, a 3-­cm incision is made through the eyebrow between the median line of the pupil and the external rim of the zygomatic-­orbital joint.93,94 In selected cases, the approach can be made through a frontotemporal skin incision close to the hairline, to prevent scarring in the eyebrow or a cosmetic compromise from weakness in the frontal branch of the facial nerve. After incision, the orbicularis muscle is dissected. Once the tissues are mobilized with elastic retraction, an en bloc craniotomy is performed with the following borders: median line–supraorbital foramen; external line–the zygomatic-­orbital joint; and in the lower border, the orbital arch and 1-­cm extension into the depth of the orbital roof until the intracranial portion is found. An en bloc resection is made at the superior margin of the frontal 1.5-­cm craniotomy, after removing the periosteum and protecting the orbital fat. The orbital bone is drilled with different boundaries and choices according to the surgical target. This procedure is a feasible alternative to large frontal craniotomies because it allows us to work in the intraorbital space, the intracranial-­extradural space, and the intracranial-­subarachnoid space.93–97 The removal of the orbital rim provides greater upward movement of instruments and better visualization.11,57–58 Once the drilling of the inner edges of the craniotomy is completed, the dura mater is opened under the microscope and the appropriate microsurgical corridor is dissected. The transsupraorbital approach provides access to the entire sellar region and its neurovascular structures, providing enough space for surgical manipulation in cases of

FIGURE 26.8  Supraorbital pterional approach. (Victor © 2009.)

pituitary tumors with extrasellar extension to the optic chiasm. In selected cases, endoscopy has been used11,64,66–74,76 (Aesculap, Ventriculoscope, Tuttlingen, Germany, 0 and 30 degrees) to confirm patency of neighboring arteries, explore the intrasellar space and cavernous extension of the tumor, and finally, evaluate the pituitary stalk and sellar diaphragm (Fig. 26.9).3,4,19,20,56,64,93,94,98,99 

Eyelid and Eyebrow Approach More recent supraorbital variants such as the eyelid and eyebrow approaches have been implemented to obtain better cosmetic results and minimal brain retraction while still maintaining the same operative corridor.16,19,20,100 Through providing better access through the subfrontal approach, the eyelid and eyebrow supraorbital variants allow access to extra-­axial and intra-­axial lesions located in the anterior and middle cranial fossa, mesial temporal lobe, sellar and parasellar regions, anterior circulation, and cranio-­orbital regions.8,10,11,12,19,20,87,95,96,101–103 These approaches only use minimal frontal lobe retraction, and once CSF cisterns are opened and adequate brain relaxation is achieved, the rest of the operation can be performed without the use of any brain retraction at all. An endoscope may also be implemented in conjunction with the eyelid and eyebrow approaches, especially when resecting deep lesions, which allows for a better light source, because the light from the microscope may be limited. Although these approaches afford a smaller craniotomy to access many superficial and deep regions in the anterior and middle fossa, one must exercise caution when deciding to use these approaches with vascular lesions, because it may be more difficult to obtain vascular control given the small operating window (1.5 to 2 cm).21,41,103,104

26  •  Supraorbital Approach Variants for Intracranial Tumors

307

Just like the other supraorbital variants, the eyelid and eyebrow supraorbital variants may cause injury to the supraorbital and frontalis nerves. as well as the frontal sinus. If orbital rim osteotomy is performed, postoperative periorbital edema and transient ophthalmoparesis may occur.9,100,111 

Benefits and Limitations

FIGURE 26.9  Transsupraorbital approach. (Victor © 2009.)

Regarding sellar and parasellar lesions, the question arises whether they should be approached from above via the supraorbital approach or below via the endoscopic endonasal approach. Both approaches have comparable outcomes and complication rates, so the decision largely is decided based on how large the lesions are. For lesions that extend more laterally toward the cavernous sinus and patients with a normal functioning pituitary gland, it may be recommended to adopt a supraorbital eyebrow approach versus an endoscopic endonasal approach, especially if the lesion is wider than 2 cm in the lateral extension. One may consider performing a combined supraorbital and endoscopic endonasal approach for large lesions to adequately access both the medial and lateral margins.18,41,43,105–108 The eyelid approach uses an incision in one of the folds of the eyebrow, starting several millimeters from the medial canthus and extending up to 2.5 cm past the lateral canthus. This incision allows for less contact with branches of the supraorbital and frontalis nerves. Intraorbital dissection releasing the periorbita from the orbital roof is necessary before the craniotomy is performed. It is important to monitor the blood pressure during intraorbital manipulation because the patient may become hypotensive according to the trigeminocardiac reflex.109 The craniotomy starts with the MacCarty burr hole (approximately 7 mm superior and 5 mm posterior to the frontozygomatic suture) and extends just lateral to the supraorbital notch including the anterior two-­thirds of the roof of the orbit and 2.5 cm of the frontal bone.45,103,110 The eyebrow approach involves an incision either just above or within the contour of the eyebrow. A burr hole is placed as laterally as possible into the frontal bone, extends medially to the supraorbital notch, and extends superiorly to remove a portion of the frontal bone. There is greater exposure of the frontal bone through the eyebrow versus the eyelid incision. The eyelid approach always involves an orbital rim osteotomy, whereas the eyebrow approach may or may not require orbital rim removal depending on the desired areas of approach. It is recommended to include an orbital ridge osteotomy when lesions are located posteriorly at the midline.

One of the main advantages of the minimally invasive concept used in neurosurgery is that it involves a strategy that preserves the anatomic integrity of all structures, insofar as is possible, using a supraselective tailored approach while still maintaining a wide area of exposure, proper angulation and maneuverability, and access to the ipsilateral and contralateral skull base.15,17,27,44,112 The latter should correlate specifically with the surgical target.3,4,8,47,48,56,65,78,93,94 Therefore the approach does not entail a reductionist or minimalist vision but rather one based on experience to find the proper balance in the design and size of the craniotomy aimed at achieving the surgical goal without subjecting the patient to unnecessary risk from tissue manipulation. A practical example is shown by the historical progression from initially using large craniotomies to clip elective aneurysms to current use of tailored approaches. This progression is based on two basic principles. First, considering that microsurgery involves a 20-­mm work space, it was concluded that resorting to greater exposure with the craniotomy was not strictly necessary (the evolution of a wide frontotemporal craniotomy to the pterional craniotomy). Second is inclusion anatomic integrity in the surgical plan, not only of cerebral structures with less retraction and manipulation, but also to preserve the craniofacial structures as well (avoiding atrophy of the temporal muscle, temporomandibular dysfunction, bone defects, fistula, flap necrosis, etc.).5,25,61,73,74,100,113 Aside from better cosmetic results, the supraorbital approach also drastically lowers the rate of postoperative CSF leaks, requires minimal brain retraction, and gives direct visualization to anterior fossa, suprasellar region, and more midline structures without needing to incise the sylvian fissure. In addition, because this minimally invasive approach has been demonstrated to reduce morbidity and shorten hospital stays compared with larger craniotomies an additional benefit is cost efficiency and minimization.10,16,19,20,23,77,99,114,115 Thus minimally invasive neurosurgery is not a discipline but a neurosurgical concept that may result in less morbidity due to the rational use and support of technology as part of the armamentarium and current multidisciplinary options used for the patient’s benefit.63 That is the reason why serious complications can result with a limited understanding of the principles of minimally invasive approaches and an overuse of technological support. Critical analysis of surgical experience accumulated thus far has demonstrated that major complications with minimally invasive approaches can occur if microsurgical principles are not properly followed. The key is to maintain a proper balance between overexposure and limited/reduced exposure. A crucial principle to obtain optimal outcome is that the selected approach must always allow performance of possible and necessary procedures, with conventional technology as support to facilitate the desired surgical goal with comfort and safety. Therefore it is about correct planning—taking into account the patient’s specific anatomy and disease as well as variables

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related to the availability and pertinent use of certain technologies, and finally the skills and ability of the neurosurgical team. 

Acknowledgment In memory of Axel Perneczky. The authors and the editors thank Dr. Shaan Raza and Dr. Rodrigo Ramos-­Zuniga for their contribution in the previous edition. KEY REFERENCES

Brock M, Dietz H. The small frontolateral approach for the microsurgical treatment of intracranial aneurysms. Neurochirurgia (Stuttg). 1978;21:185–191. Cohen AR, Perneczky A, Rodziewicz GS, Gingold SI. Endoscope-­ assisted craniotomy: approach to the rostral brain stem. Neurosurgery. 1995;36:1128–1129: discussion 1129–1130. Davies HT, Neil-­Dwyer G, Evans BT, Lees PD. The zygomatico-­ temporal approach to the skull base: a critical review of 11 patients. Br J Neurosurg. 1992;6:305–312. Delashaw Jr JB, Tedeschi H, Rhoton AL. Modified supraorbital craniotomy: technical note. Neurosurgery. 1992;30:954–956. Delfini R, Raco A, Artico M, et al. A two-­step supraorbital approach to lesions of the orbital apex. Technical note. J Neurosurg. 1992;77:959–961.

Jane JA, Park TS, Pobereskin LH, et al. The supraorbital approach: technical note. Neurosurgery. 1982;11:537–542. Jho HD. Orbital roof craniotomy via an eyebrow incision: a simplified anterior skull base approach. Minim Invasive Neurosurg. 1997;40:91–97. Noguchi A, Balasingam V, McMenomey SO, Delashaw Jr JB. Supraorbital craniotomy for parasellar lesions. Technical note. J Neurosurg. 2005;102:951–955. Ramos-­Zuniga R. The trans-­ supraorbital approach. Minim Invasive Neurosurg. 1999;42:133–136. Ramos-­Zuniga R, Velazquez H, Barajas MA, et al. Trans-­supraorbital approach to supratentorial aneurysms. Neurosurgery. 2002;51:125– 130: discussion 130–131. Raza SM, Boahene KD, Quinones-­Hinojosa A. The transpalpebral incision: its use in keyhole approaches to cranial base brain tumors. Expert Rev Neurother. 2010;10:1629–1632. Raza SM, Garzon-­Muvdi T, Boaehene K, et al. The supraorbital craniotomy for access to the skull base and intraaxial lesions: a technique in evolution. Minim Invasive Neurosurg. 2010;53:1–8. Reisch R, Perneczky A. Ten-­year experience with the supraorbital subfrontal approach through an eyebrow skin incision. Neurosurgery. 2005;57:242–255: discussion 242–255. Numbered references appear on expertconsult.com.

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73. Paladino J, Pirker N, Stimac D, Stern-­Padovan R. Eyebrow keyhole approach in vascular neurosurgery. Minim Invasive Neurosurg. 1998;41:200–203. 74. Papay FA, Stein JM, Dietz JR, et al. Endoscopic approach for benign tumor ablation of the forehead and brow. J Craniofac Surg. 1997;8:176–180. 75. Park J, Jung T, Kang D-­H, Lee S-­H. Preoperative percutaneous mapping of the frontal branch of the facial nerve to assess the risk of frontalis muscle palsy after a supraorbital keyhole approach. J Neurosurg. 2013;118(5):1114–1119. 76. Kaplan MJ, Jane JA, Park TS, Cantrell RW. Supraorbital rim approach to the anterior skull base. Laryngoscope. 1984;94:1137– 1139. 77. Lucas JW, Zada G. Endoscopic endonasal and keyhole surgery for the management of skull base meningiomas. Neurosurg Clin N Am. 2016;27(2):207–214. 78. Wiedemayer H, Sandalcioglu IE, Stolke D. The supraorbital keyhole approach via an eyebrow incision for resection of tumors around the sella and the anterior skull base. Minim Invasive Neurosurg. 2004;47:221–225. 79. Flanigan P, Kshettry VR, Mullin JP, Jahangiri A, Recinos PF. Frontal sinus Morphometry in relation to surgically relevant landmarks in the United States Population. World Neurosurg. 2016;91:12–15. 80. Lee MK, Sakai O, Spiegel JH. CT measurement of the frontal sinus -­Gender differences and implications for frontal cranioplasty. J Cranio-­Maxillofacial Surg. 2010;38(7):494–500. 81. Thaher F, Hopf N, Hickmann AK, et al. Supraorbital keyhole approach to the skull base: evaluation of complications related to CSF fistulas and opened frontal sinus. J Neurol Surgery, Part A Cent Eur Neurosurg. 2015;76(6):433–437. 82. Feroze RA, Agarwal N, Sekula RF. Utility of calcium phosphate cement cranioplasty following supraorbital approach for tumor resection. Int J Neurosci. 2018;128(12):1199–1203. 83. Chandler JP, Pelzer HJ, Bendok BB, et al. Advances in surgical management of malignancies of the cranial base: the extended transbasal approach. J Neuro Oncol. 2005;73:145–152. 84. Chandler JP, Silva FE. Extended transbasal approach to skull base tumors. Technical nuances and review of the literature. Oncology (Williston Park). 2005;19:913–919: discussion 920, 923–925, 929. 85. Delfini R, Raco A, Artico M, et al. A two-­ step supraorbital approach to lesions of the orbital apex. Technical note. J Neurosurg. 1992;77:959–961. 86. Feiz-­Erfan I, Han PP, Spetzler RF, et al. The radical transbasal approach for resection of anterior and midline skull base lesions. J Neurosurg. 2005;103:485–490. 87. Spiessberger A, Baumann F, Nevzati E, Kothbauer KF, Fandino J, Muroi C. Minimally invasive medial supraorbital, combined subfrontal-­ interhemispheric approach to the anterior communicating artery complex—a cadaveric study. Acta Neurochir. 2017;159(6):1079–1085. 88. Reisch R, Perneczky A. Ten-­year experience with the supraorbital subfrontal approach through an eyebrow skin incision. Neurosurgery. 2005;57:242–255: discussion 242–255. 89. Krishna V, Blaker B, Kosnik L, Patel S, Vandergrift W. Trans-­ lamina terminalis approach to third ventricle using supraorbital craniotomy: technique description and literature review for outcome comparison with anterior, lateral and trans-­sphenoidal corridors. Minim Invasive Neurosurg. 2011;54(5–6):236–242. 90. La Rocca G, Della Pepa GM, Sturiale CL, et al. Lateral supraorbital versus pterional approach: analysis of surgical, functional, and patient-­ Oriented outcomes. World Neurosurg. 2018;119:e192–e199. 91. Fujitsu K, Kuwabara T. Zygomatic approach for lesions in the interpeduncular cistern. J Neurosurg. 1985;62:340–343. 92. Hage ZA, Charbel FT. Clipping of bilateral MCA aneurysms and a coiled ACOM aneurysm through a modified lateral supraorbital craniotomy. Neurosurg Focus. 2015;38(videosuppl 1):Video19. 93. Ramos-­Zuniga R. The trans-­supraorbital approach. Minim Invasive Neurosurg. 1999;42:133–136. 94. Ramos-­Zuniga R, Velazquez H, Barajas MA, et al. Trans-­ supraorbital approach to supratentorial aneurysms. Neurosurgery. 2002;51:125–130: discussion 130–131.

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CHAPTER 27

Surgical Management of Sphenoid Wing Meningiomas GERARDO GUINTO Sphenoid wing meningiomas (SWMs) constitute about 14% to 20% of intracranial meningiomas.1 Although they originate from arachnoid cells, they are usually attached to dural thickening or folding, from which they receive their blood supply. Infiltration of the adjacent bone is not unusual; neither is growth around or inside the cranial base foramina.2 Most SWMs are relatively easy to remove; however, they are sometimes challenging, especially when they invade the cavernous sinus, internal carotid artery (ICA), and visual pathway. In these cases, total excision is extremely difficult, resulting in high morbidity and a high rate of regrowth or recurrence.3

Anatomic Observations The designation SWM refers to tumors that originate in any part of the bony crest formed by wings (lesser and greater) of the sphenoid bone, which represents the boundary between the anterior and the middle cranial floor.4 This anatomic portion is also known as the sphenoid ridge, where the lesser wing constitutes its internal two-­thirds and the greater wing its external third. The lesser wing is the most complex area because of its relationship with the orbit, ICA, cavernous sinus, optic foramen, superior orbital fissure, sylvian fissure, middle cerebral artery (MCA), tip of the temporal lobe, and basal surface of the frontal lobe. In contrast, the greater wing is located in the external portion and is in relation to the frontal and temporal lobes (predominantly with their opercular areas) in its intracranial surface and with the orbit and zygomatic fossa in its extracranial surface, where it serves as insertion to the temporal muscle. It also forms the pterion when it articulates with the frontal squama, temporal, and parietal bones.4 

Classification In 1938, Cushing and Eisenhardt classified SWMs into two main varieties: en plaque and globoid (Fig. 27.1).

EN-­PLAQUE MENINGIOMAS Also known as spheno-­orbital meningiomas or hyperostotic meningiomas of the sphenoid wing, en-­plaque meningiomas refer to tumors with a carpet-­like dural growth, which are associated with a reactive hyperostosis that, in most cases, is marked and principally responsible for clinical

manifestations (see Fig. 27.1A).5,6 Sphenoid wing hyperostosis has been reported in as many as 42% of all meningiomas in this area.7,8 Due to its extensive bone involvement, differential diagnosis should include fibrous dysplasia, osteoma, osteoblastic metastasis, Paget’s disease, hyperostosis frontalis interna, erythroid hyperplasia, and sarcoidosis.6,9,10 It frequently extends posteriorly toward the cavernous sinus and anteriorly toward the orbital apex, where it causes proptosis and oculomotor deficits, the primary clinical manifestations of these lesions.5 Hyperostosis in meningiomas was initially described by Brissaud and Lereboullet in 1903.11 Theories regarding the cause of hyperostosis include vascular disturbances, irritation of bone without actual invasion, previous trauma, bone production by tumor cells, or osteoblastic stimulation of normal bone. Currently, the most widely accepted theory is that this bone growth is actually bone invasion by tumor cells.3,11,12 

GLOBOID MENINGIOMAS Globoid meningiomas have traditionally been classified into three groups: (1) deep, inner, or clinoidal; (2) middle or alar; and (3) lateral, outer, or pterional (see Fig. 27.1B). Middle or alar meningiomas have radiologic characteristics similar to lateral or pterional meningiomas. Surgical resection and clinical results of both types are almost identical. For this reason, some authors suggest that globoid meningiomas of the sphenoid wing can be classified into only two groups: deep, inner, or clinoidal and lateral, outer, or pterional, discharging the middle or alar variety.13 Deep, inner, or clinoidal meningiomas represent the most complex variety of these tumors, whose resection, in most cases, implies increased morbidity and a high rate of recurrence.14–17 In this region, the cavernous sinus is the most critical area; therefore, clinoidal meningiomas are subclassified into two groups: tumors without extradural growth and tumors with extradural growth into the cavernous sinus.13,18 There is a third and debatable variety of SWMs. These are tumors that grow within the diploë without an epidural, subdural, or subcutaneous component and are referred to as intraosseous or intradiploic meningiomas.3,6 The origin of these tumors in the skull base is controversial. Arachnoid cells have been described, following the vessels and nerves in bone foramina or trapped within the sutures. However, some authors19 doubt the existence of these tumors, proposing that they are really a variety of en-­plaque meningiomas

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Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

b

c

a

FIGURE 27.1  Classification. (A) En plaque. Hyperostosis is the main finding, which is especially located on the sphenoid ridge and the orbital roof. (B) Globoid. This variety has been subclassified into three types: (a) deep, inner, or clinoidal; (b) middle or alar; and (c) lateral, outer, or pterional.

A

B

Diagnosis in which the dural component of the tumor is not well identified on preoperative imaging studies, mostly considering that many of these tumors were described before the era of magnetic resonance imaging (MRI). 

Clinical Course The most common clinical sign of en-­plaque meningiomas is proptosis, which usually is slowly evolving, unilateral, nonpulsatile, and irreducible.11 Possible causes of this sign are hyperostosis of the orbital walls, periorbital tumor invasion, intraorbital tumor, and venous stasis caused by compression of the ophthalmic veins. Related symptoms include headache, orbital pain, visual deficit, ptosis, diplopia, ectropion, conjunctivitis, corneal ulceration, and scleral hemorrhages. Unilateral loss of vision is rare and is caused by a narrowing of the optic foramen. In regard to clinoidal meningiomas, clinical manifestations are dominated by visual field problems presenting in virtually any pattern. On the other hand, visual acuity deficits are only somewhat variable and are reported in between 39% and 92% of patients.1,7 When these tumors invade the cavernous sinus, the most common symptoms are oculomotor deficit (especially on cranial nerve VI) and facial hypoesthesia. Middle or alar meningiomas usually produce late symptoms and, when detected, generally have reached larger dimensions than inner-­third meningiomas. Clinically, these are characterized by headache and signs or symptoms suggesting increased intracranial pressure, such as nausea, vomiting, and papilledema. Due to frontotemporal compression, it is not uncommon for patients to begin with memory impairment, olfactory hallucinations, personality changes, seizures, and hemiparesis. Finally, pterional meningiomas frequently cause a silent hyperostosis and also may be associated with seizures, headache, intracranial hypertension, hemiparesis, and speech alterations, mostly when located on the dominant side. 

Although clinical manifestations may be strongly suggestive of the diagnosis, especially in spheno-­orbital meningiomas, imaging studies are indispensable to establish the diagnosis and to propose the best therapeutic option (Fig. 27.2).

COMPUTED TOMOGRAPHY Computed tomography (CT) is predominantly useful in en-­ plaque meningiomas because it provides more precise information regarding the extent of bone invasion, also allowing correct planning for reconstruction (see Fig. 27.2A). The dural component of these tumors is typically found as an isodense image with contrast enhancement, being contiguous with the surrounding dura mater.11 However, it is not always possible to observe this, due to its carpet-­like appearance. Also, it may be occulted by the high hyperdensity of the contiguous bone growth. There is no correlation between size of the hyperostosis and size of the meningeal tumor. In fact, small dural components are frequently found associated with large bone masses. A bone window algorithm is mandatory in terms of obtaining better definition of bone thickening. Performing axial and coronal projections, as well as three-­dimensional (3D) reconstruction, also facilitates both complete resection and reconstruction. The most common locations of hyperostosis of en-­plaque meningiomas are, in order of frequency, the lesser wing of the sphenoid bone, the greater wing of the sphenoid, the roof of the orbit, the inferior orbital fissure, the infratemporal fossa, and the orbital rim. Globoid tumors appear on CT as well-­defined isodense lesions that present an intense and homogeneous contrast enhancement. Even though they are usually slow-­growing masses, it is not uncommon to find perilesional edema invading the temporal lobe and centrum semiovale, which is attributed to compression or occlusion in the superficial middle cerebral vein or sphenoparietal sinus; there is no direct relationship between the grade of edema and the size of the tumor. Clinoidal meningiomas usually show hyperostosis of the anterior clinoid process (ACP), causing narrowing of the

27  •  Surgical Management of Sphenoid Wing Meningiomas

A

C

311

B

FIGURE 27.2  Radiologic findings. (A) Contrast-­enhanced computed tomography axial view of a right en-­plaque meningioma. Observe the hyperostosis on the entire sphenoid ridge, associated with a small dural component. The figure also shows a contrast-­ enhanced, T1-­weighted axial magnetic resonance imaging view of three left globoid sphenoid wing meningiomas: clinoidal (B), alar (C), and pterional (D).

D

optic canal and the superior orbital fissure.1 CT has some limitations when these tumors infiltrate the cavernous sinus; however, CT angiography may help by providing more precise information about blood supply and vascular relations of the tumor. 

MAGNETIC RESONANCE IMAGING MRI is more useful in globoid meningiomas (see Fig. 27.2B to D) and for the correct evaluation of the dural component of en-­plaque meningiomas; however, this study’s principal limitation is the osseous tissue. Globoid meningiomas show different appearances on MRI. When their vascularity is not so marked, they usually present as a homogeneous isointense lesion in both T1-­and T2-­weighted images20; on the other hand, when they are highly vascularized (angioblastic meningiomas), multiple hypointense images (“empty signals”) can be seen in the interior of the tumor. Gadolinium enhancement is usually intense and uniform, and a T2-­weighted image is particularly useful in demonstrating perilesional edema. MRI is the ideal study for showing cavernous sinus invasion. MRI spectroscopy helps establish the differential diagnosis with other lesions; tractography, as well as functional MRI, shows critical cerebral pathways and eloquent areas of

the brain, but taking into account that these are extra-­axial lesions, spectroscopy, tractography, and functional MRI are not part of the routine workup of meningiomas. Finally, magnetic resonance angiography (MRA) demonstrates the pattern of displacement and permeability of the related neighboring vessels. 

ANGIOGRAPHY Considering the clear image of the vascular anatomy obtained with CT angiography and MRA, particularly with 3D reconstructions, angiography is indicated only in special SWM cases. Selective catheterization provides specific information about the blood supply of the tumor1 and allows the possibility of preoperative embolization. Another indication for angiography is for performing carotid occlusion tests, especially in tumors invading the cavernous sinus and when arterial bypass is planned. However, this procedure is only indicated in a very few selected cases. 

Treatment Surgical management is, without doubt, the best therapeutic option for SWMs. This treatment is indicated considering the following factors: size of the lesion, presence of signs or

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symptoms, patient’s condition, changes in the adjacent cerebral tissue (edema) on imaging studies, and surgeon’s experience. In general, surgery is indicated in all patients who are in good health and have a tumor size greater than 2.5 cm. For tumors smaller than this size that are not too close to the visual system, stereotactic radiosurgery might be considered. The goal of surgery in all cases should be radical excision of the tumor, which means resection of the lesion, along with the dural implant (1-­cm margin) and all hyperostotic bone. This objective is accomplished in the large majority of SWMs except in some spheno-­orbital and clinoidal meningiomas, particularly when they present invasion to the cavernous sinus. For these cases, most authors recommend excising the tumor, dura mater, and infiltrated bone on extracavernous areas but leaving the intracavernous portion for another adjuvant treatment, such as radiosurgery, because even in experienced hands, oculomotor morbidity is extremely high after a direct approach to this region.1,2,4,18,21

PREPARATION Patients are operated under intravenous general anesthesia. Antiepileptic drugs, broad-­spectrum antibiotics, and glucocorticoids are administered when beginning the anesthesia. Neurophysiologic monitoring, especially electromyography of the extraocular muscles, is indicated only when the orbit contents, the cavernous sinus, or both will be manipulated. 

POSITIONING The patient is placed in the supine decubitus position with the head fixed in a three-­pin headholder with slight extension and rotated toward the contralateral side of the tumor (Fig. 27.3). There are certain variations in this head rotation, depending on the exact location of the meningioma: for clinoidal tumors a lesser rotation (between 30 and 40 degrees) is preferred, whereas for alar and pterional lesions a major rotation (between 40 and 50 degrees) is indicated (see Fig. 27.3A and B).2 

A

B

SKIN INCISION Most SWMs can be operated on through a frontotemporal (pterional) curvilinear skin incision starting at the root of the zygomatic arch, just 5 mm in front of the tragus, which runs vertically upward. Once it passes the ear, it is curved rostrally and superiorly toward the ipsilateral frontal region until it reaches the midline or beyond, always keeping behind the hairline (see Fig. 27.3C). The midportion of the incision can be extended backward, especially in cases of pterional meningiomas with large infiltration of the pterion. If an orbitozygomatic (OZ) approach is required, it is necessary to extend the incision vertically down to the level of the earlobe. 

DISSECTION OF EPICRANIAL PLANES Beginning this dissection in the preauricular area of the incision is recommended for facilitating early identification of the superficial temporal artery, which must be preserved to maintain vascularity of the myocutaneous flap.11 In this region, this vessel usually has a posterior branch that has to be coagulated and cut to allow anterior displacement of the main trunk, along with the skin flap. Dissection continues until the temporal fascia is identified in the entire area of the skin incision. It is important not to perform a wide separation between the temporal fascia and the skin flap because if this is done injury to the frontotemporal branch of the facial nerve is unavoidable. There are two types of incision that can preserve this branch of the facial nerve. The first consists of making the cut in a single plane from skin to bone, including the cut in the skin, temporal fascia, and muscle fibers. In this way, a single fasciomyocutaneous flap is created, which is detached from the bone and displaced forward. This is a simple and safe form to preserve facial function; however, it presents some problems. First, the fasciomyocutaneous flap created in this way is bulky and sometimes interferes with the surgeon’s deep vision, especially when dealing with clinoidal tumors. Second, particularly in pterional meningiomas, there are some cases that present tumor infiltration to the temporal muscle that is not seen (and therefore not

C

FIGURE 27.3  Positioning and skin incision. The patient is placed in a supine position with the head slightly extended and rotated toward the contralateral side of the tumor. (A) For clinoidal meningiomas, a 30-­to 40-­degree rotation is preferred. (B) For pterional meningiomas, the rotation recommended is 40 to 50 degrees. (C) Skin incision.

27  •  Surgical Management of Sphenoid Wing Meningiomas

removed) because the muscle remains attached to the galea. For these reasons, there is another way to accomplish preservation of the facial branch, which consists of sectioning of the two layers (superficial and deep) of the temporal fascia in the same direction as the skin incision. In this way, the skin flap and the two layers of the temporal fascia (with the fat pad and the branch of the facial nerve lying between them) are separated from the temporal muscle fibers and reflected anteriorly.11 Once this is completed, detachment and separation of the temporalis muscle is done. It is recommended to perform this dissection in a retrograde direction (from downward to upward) to preserve the epicranial surface of the temporal muscle and reduce its atrophy.22 In this way, two epicranial planes are created: one composed by the skin and temporal fascia (fasciocutaneous flap) and the other formed by the temporal muscle alone (muscle flap). In this manner, the two flaps can be displaced in slightly different directions: the fasciocutaneous flap forward and the muscle flap downward, which facilitates exposure.11 

313

during craniotomy. Under this condition, a craniectomy is then preferred, removing the bony tumor from the onset by using a high-­speed drill until exposing the dural implant. 

ALAR

The shape and size of the craniotomy and tumor resection technique specifically depend on the anatomic variety of the meningioma. 

In alar tumors, osseous infiltration is usually not seen from the beginning; therefore, a frontotemporal craniotomy is performed with standard dimensions of a 6-­to 8-­cm diameter centered on the pterion. Craniotomy is followed by extradural resection of the lesser wing of the sphenoid bone. This step is sometimes troublesome because of bleeding, which may be profuse, generated when performing dural detachment.14,15 Bone removal is continued until complete exposure of the superior orbital fissure and base of the ACP. The dura mater is then opened following a curvilinear frontotemporal incision, reflecting the dural flap forward. Next, splitting of the sylvian fissure is done to gently separate the frontal and temporal lobes to expose the tumor. If the position is correct and cerebrospinal fluid (CSF) evacuation is adequate, it is usually not necessary to place automatic retractors. In these cases, en bloc resection is only possible in small tumors; therefore, initial debulking is preferred in the majority of these cases, leaving deeper portions and dural implant for the end of the procedure. 

PTERIONAL

CLINOIDAL

In pterional tumors, hyperostosis is usually seen immediately in the pterion once the temporal muscle is detached. Craniotomy is then planned around the bone infiltration, forming a bone flap of about 5 cm around it; if the hyperostosis is not seen, a standard pterional craniotomy is performed (Fig. 27.4A). To raise and remove the bone flap, it is often necessary to section the tumor, leaving in situ the dural infiltration (see Fig. 27.4B). This step must be done carefully because of risk of profuse bleeding that may be seen in some cases. Resection of the hyperostosis is done in the bone flap, being certain to remove at least a 1-­cm free margin. The meningeal portion of the tumor is then removed, also being certain to include at least a 1-­cm free margin of healthy dura mater (see Fig. 27.4C).2 However, in some cases of predominantly osseous tumors, its division is not possible

In clinoidal tumors, a frontotemporal or standard pterional craniotomy is performed, as previously mentioned. Bone management is begun extradurally with resection of the sphenoid ridge from the pterion to the base of the ACP. The superior orbital fissure is also completely opened14; if there is an orbital component of the tumor, the posterolateral wall of the orbit is also removed.14,16 In almost all clinoidal tumors, it is also necessary to perform an anterior clinoidectomy using a high-­speed drill, being careful to irrigate profusely to avoid damage to the optic nerve due to heat generated by the drilling. This anterior clinoidectomy can also be performed by holding the ACP with a rongeur and applying a gentle “wiggle and jiggle” movement of the surgeon’s wrist.23 This maneuver may be difficult in cases with marked hyperostosis. Drilling is continued until the optic

CRANIOTOMY AND TUMOR RESECTION

A

B

C

FIGURE 27.4  Craniotomy and tumor resection in pterional meningiomas. (A) Standard pterional craniotomy planning. (B) Cutting the tumor is usually necessary to elevate the bone flap. (C) Tumor resection with a 1-­cm free margin in the bone and the dura.

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FIGURE 27.5  Surgical exposure and resection of clinoidal meningiomas. (A) Exposing the tumor after a wide opening on the sylvian fissure. (B) Surgical bed after resection. The anterior clinoid process has to be drilled and removed, along with the dural implant.

FIGURE 27.6  Craniotomy and orbitozygomatic (OZ) osteotomy for en-­plaque meningiomas. (A) Craniotomy and osteotomy planning. (B) With a pterional OZ approach, the entire tumor is exposed.

A

A

canal is completely unroofed, being careful not to open the sphenoid or ethmoid sinus when working in the superomedial portion of this channel. The curvilinear dural incision is the same as described earlier, and if the tumor is invading the optic nerve, it is recommended to make another incision following bisection of the dural flap toward the optic sheath and extending across the falciform ligament to the annulus of Zinn. This allows initial identification and free mobilization of the optic nerve before tumor removal.15,16 Dural opening is followed by a wide splitting of the arachnoid membrane on the sylvian fissure and the free drainage of CSF (Fig. 27.5). Retractors are placed on the frontal and temporal lobes, more to protect their cortical surfaces than to actively retract them, and the lateral portion of the tumor is then identified (see Fig. 27.5A). Initially, the dural implants in the frontal and temporal regions are coagulated, which reduces vascular supply of the tumor and facilitates its resection. The distal branches of the MCA and, if possible, the main trunk of this artery are then identified, focusing special attention on early identification and preservation of lenticulostriate branches. Dissection is followed in a distal to proximal direction, which in a large tumor necessarily

B

B

implies an initial debulking. Arterial dissection is continued proximally to identify the carotid bifurcation and anterior cerebral, posterior communicating, and anterior choroidal arteries, reaching the ICA. The optic nerve is next referred intradurally and released from the tumor. Once macroscopic resection of the tumor is completed, extirpation of the dural implant is done, including margins as previously described (see Fig. 27.5B). However, this is extremely difficult to achieve in the vicinity of the ACP. Resection of intracavernous meningiomas deserves a special description. Due to its complexity, it is discussed in detail elsewhere in this book. This involves manipulation of the ICA and oculomotor nerves, as well as the first and second branches of the trigeminal nerve.21 In these tumors, it is mandatory to have initial proximal control of the ICA, preferably in its petrous portion, which also serves as anatomic orientation. To do this, it is necessary to combine pterional craniotomy with an OZ approach. It is recommended to begin tumor resection extradurally by finely peeling the lateral wall of the cavernous sinus. If necessary, it can be continued intradurally, entering through the different anatomic triangles. However, as has been previously mentioned, gross

27  •  Surgical Management of Sphenoid Wing Meningiomas

A

B

total resection is almost impossible when the tumor invades this region. 

EN PLAQUE In en-­plaque tumors, it is easier to expose the entire hyperostosis if pterional craniotomy is combined with an OZ osteotomy, particularly when the lesion extends into the inferior orbital fissure, infratemporal fossa, or orbit (Fig. 27.6). This osteotomy is performed with a reciprocating saw, beginning the cut in the orbital rim at the level of the supraorbital notch or slightly medial to this. The cut is directed backward over the orbital roof to a distance of about 1.5 to 2 cm, at which point the direction is changed and continues laterally to reach the inferior orbital fissure. The bone cut is then continued on the orbital surface from the inferior orbital fissure toward the malar bone. The cut on this bone is completed on its extracranial surface, making an inverted V shape to facilitate relocation. Finally, a diagonal cut is made at the root of the zygomatic arch (see Fig. 27.6A). Once the OZ bar is extracted, it is easy to observe the totality of the hyperostosis from a lateral perspective and the drilling begins (see Fig. 27.6B). Drilling should be systematic and must include all bony structures of the region invaded by hyperostosis. Occasionally, due to extensive bone invasion, opening the ethmoid and sphenoid sinuses is unavoidable; in such cases, these sinuses should be occluded with fat and fibrin adhesive. Once excision of the osseous component of the tumor is finalized, the intradural portion and, finally, all infiltrated dura are resected, attempting to extend this resection beyond the area of dural enhancement seen on imaging studies. This step is facilitated with the use of neuronavigation systems. 

RECONSTRUCTION AND CLOSURE Considering that in all SWMs it is necessary to resect a free dural margin, closure of the dura mater necessarily implies application of a graft. For this purpose, local tissue can be used, such as aponeurotic galea, pericranium, or temporal fascia. Distant tissues such as fascia lata or abdominal fascia can also be used, as can synthetic and biologic materials, but with a slightly higher risk of infection. Watertight closure is mandatory and can be reinforced with the use

315

FIGURE 27.7  Contrast-­enhanced computed tomography axial view showing a radical removal of an en-­plaque right sphenoid wing meningioma. (A) Preoperative. (B) Postoperative.

of fibrin sealants. There is an ample variety of options for reconstruction of the pterional defect. Autologous materials such as split calvarial bone graft or ribs can be used, as well as synthetic materials such as methylmethacrylate and titanium, which have the advantage of offering a better cosmetic result. Reconstruction of the orbital walls is controversial. The only incontrovertible point regarding this issue is when the floor, the orbital rim, or both are removed; in these cases, all authors agree that reconstruction is required due to the high risk of orbital ptosis, postoperative diplopia, or cosmetic defect. The controversy focuses mainly on reconstruction of the superior and lateral walls of the orbit. Some authors mention that reconstruction is unnecessary when the roof is removed, as well as the greater and lesser wings of the sphenoid bone6; however, other authors have reported an increased risk of pulsatile enophthalmos or cosmetic deficit if this reconstruction is not performed.5,11,24 

Complications and Results Although surgery for an SWM has a high margin of safety, because in the majority of cases it is possible to get excellent surgical results (Figs. 27.7–27.9), there are some complications reported that must be considered. There is a risk of postoperative hematoma, especially epidural, due to the wide dural detachment done in some cases and the spaces created by resection of large bone formations. CSF leakage is another risk, which is secondary to wide resection of the dural implant. Possibility of seizures should also be considered because SWMs sometimes grow near potentially epileptogenic cortical areas. Finally, cosmetic results may be a problem after inadequate reconstruction. More serious complications are indeed rare. They are primarily associated with a lesion on functional areas of the brain, especially when they occur on the dominant side and are related to excessive manipulation of brain parenchyma, poor use of retractors, or vascular lesion in the MCA or its branches. Risk of infection is also present, especially when prosthetic materials are used for reconstruction or when frontal, ethmoid, or sphenoid sinuses are inadvertently opened. Finally, mortality after surgery for an SWM is very rare and, when this happens, is usually secondary to a concomitant preexisting problem or

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FIGURE 27.8  Contrast-­enhanced, T1-­weighted coronal magnetic resonance imaging view showing a complete resection of a large left alar sphenoid wing meningioma. (A) Preoperative. (B) Postoperative.

FIGURE 27.9  Contrast-­enhanced, T1-­weighted axial magnetic resonance imaging view showing a total removal of a large right clinoidal meningioma. (A) Preoperative. (B) Postoperative.

A

B

A

B

due to vascular damage, particularly in large clinoid tumors that surround ICA or its branches. For this reason, in some cases, it is better to leave a small piece of tumor close to these vessels in order to avoid this complication (Fig. 27.10).16 In general, the short-­and midterm follow-­up results after SWM resection are excellent. In the majority of cases, gross total resection is accomplished with minimal morbidity. However, the critical point is in long-­term follow-­up because of the high risk of recurrence, which is inversely proportional to the degree of tumor resection.11,18,19,25 Factors most commonly

reported to be associated with incomplete resection of these tumors are extent of bone invasion, undervaluation of the dural component, and invasion of adjacent neurovascular structures. In addition, biologic behavior of the tumor must be considered because if anaplasia is demonstrated or if there is a high proliferative index or complex karyotype, recurrence risk significantly increases. In general, 10-­year recurrence has been estimated to be between 9% and 15%, which increases to 19% in a 20-­year follow-­up. However, a 35% to 50% index of recurrence has been reported when associated with orbital extension.6

27  •  Surgical Management of Sphenoid Wing Meningiomas

A KEY REFERENCES

B

Bassiouni H, Asgari S, Sandalcioglu E, et al. Anterior clinoidal meningiomas: functional outcome after microsurgical resection in a consecutive series of 106 patients. J Neurosurg. 2009;111:1078–1090. Basso A, Carrizo AG, Duma C. Sphenoid ridge meningiomas. In: Schmidek HH, ed. Operative Neurosurgical Techniques, Indications, Methods and Results. Philadelphia: WB Saunders; 2000:316–324. Bikmaz K, Mrak R, Al-­Mefty O. Management of bone-­invasive, hyperostotic sphenoid wing meningiomas. J Neurosurg. 2007;107:905–912. Brotchi J, Pirotte B. Sphenoid wing meningiomas. In: Sekhar LN, Fessler RG, eds. Atlas of Neurosurgical Techniques. Brain. New York: Thieme; 2006:623–632. Carvi Y, Nievas MN. Volume assessment of intracranial large meningiomas and considerations about their microsurgical and clinical management. Neurol Res. 2007;29:787–797. Chang DJ. The “no-­drill” technique of anterior clinoidectomy: a cranial base approach to the paraclinoid and parasellar region. Neurosurgery. 2009;64(suppl 3):ONS96–ONS106. Cunha e Sa M, Quest DQ. Sphenoid wing meningiomas. In: Apuzzo MLJ, ed. Brain Surgery. Complication Avoidance and Management. New York: Churchill Livingstone; 1993:248–268. Goel A, Gupta S, Desai K. New grading system to predict resectability of anterior clinoid meningiomas. Neurol Med Chir (Tokyo). 2000;40:610–617. Guinto G, Abello J, Félix I, et al. Lesions confined to the sphenoid ridge. Differential diagnosis and surgical treatment. Skull Base Surg. 1997;7:115–121. Honeybul S, Neil-­Dwyer G, Lang DA, et al. Sphenoid wing meningiomas en plaque: a clinical review. Acta Neurochir (Wien). 2001;143:749–758. Kim KS, Rogers LF, Goldblatt D. CT features of hyperostosing meningiomas en plaque. AJR Am J Roentgenol. 1987;149:1017–1023. Leake D, Gunnlaugsson C, Urban J, et al. Reconstruction after resection of sphenoid wing meningiomas. Arch Facial Plast Surg. 2005;7:99–103. McCracken DJ, Higginbotham RA, Boulter JH, et al. Degree of vascular encasement in sphenoid wing meningiomas predicts postoperative ischemic complications. Neurosurgery. 2017;80:957–966. Nakamura M, Roser F, Vorkapic P, et al. Medial sphenoid wing

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FIGURE 27.10  Contrast-­enhanced, T1-­weighted axial magnetic resonance imaging view showing a big clinoid meningioma that surrounds internal carotid artery and invades inter-­peduncular fossa (A). A small piece of tumor was intentionally left behind during surgery, to avoid damaging the artery and the third cranial nerve (B). meningiomas: clinical outcome and recurrent rate. Neurosurgery. 2006;58:626–639. Oikawa S, Mizuno M, Muraoka S, et al. Retrograde dissection of the temporalis muscle preventing muscle atrophy for pterional craniotomy. J Neurosurg. 1996;84:297–299. Ouyang T, Zhang N, Wang L, Li Z, Chen. Sphenoid wing meningiomas: surgical strategies and evaluation of prognostic factors incluencing influencing clinical outcomes. Clin Neurol Neurosurg. 2015;134:85–90. Pamir MN, Belirgen M, Özduman K, et al. Anterior clinoidal meningiomas: analysis of 43 consecutive surgically treated cases. Acta Neurochir (Wien). 2008;150:625–636. Pieper DR, Al-­Mefty O, Hanada Y, et al. Hyperostosis associated with meningiomas of the cranial base: secondary changes or tumor invasion. Neurosurgery. 1999;44:742–747. Ringel F, Cedzich C, Schramm J. Microsurgical technique and results of a series of 63 spheno-­orbital meningiomas. Neurosurgery. 2007;60(4 suppl 2):ONS214–ONS222. Russell SM, Benjamin V. Medial sphenoid ridge meningiomas: classification, microsurgical anatomy, operative nuances, and long-­term surgical outcome in 35 consecutive patients. Neurosurgery. 2008;62(3 suppl 1):38–50. Simas NM, Farias JP. Sphenoid wing en plaque meningiomas: surgical results and recurrence rates. Surg Neurol Int. 2013;4:86. Sughrue ME, Rutkowski MJ, Chen CJ, et al. Modern surgical outcomes following surgery for sphenoid wing meningiomas. J Neurosurg. 2013;119:86–93. Verma SK, Sinha S, Sawarkar DP, et al. Medial sphenoid wing meningiomas: experience with microsurgical resection over 5 years and review of literature. Neurol India. 2016;64:465–475. Yang J, Ma SC, Liu YH, et al. Large and giant medial sphenoid wing meningiomas involving vascular structures: clinical features and management experience in 53 cases. Clin Med J (Engl). 2013;126:4470– 4476. Zhang J, Shrestha R, Cai BW, Zhou PZ, Li YP, Jiang S. Management of large medial sphenoid wing meningiomas: a series of 178 cases. Turk Neurosurg. 2014;24:664–671. Numbered references appear on Expert Consult.

REFERENCES

1. Basso A, Carrizo AG, Duma C. Sphenoid ridge meningiomas. In: Schmidek HH, ed. Operative Neurosurgical Techniques Indications Methods and Results. Philadelphia: WB Saunders; 2000:316–324. 2. Cunha e Sa M, Quest DQ. Sphenoid wing meningiomas. In: Apuzzo MLJ, ed. Brain Surgery Complication Avoidance and Management. New York: Churchill Livingstone; 1993:248–268. 3. Guinto G, Abello J, Félix I, et al. Lesions confined to the sphenoid ridge. Differential diagnosis and surgical treatment. Skull Base Surg. 1997;7:115–121. 4. Brotchi J, Pirotte B. Sphenoid wing meningiomas. In: Sekhar LN, Fessler RG, eds. Atlas of Neurosurgical Techniques. Brain. New York: Thieme; 2006:623–632. 5. Ouyang T, Zhang N, Wang L, Li Z, Chen. Sphenoid wing meningiomas: surgical strategies and evaluation of prognostic factors incluencing influencing clinical outcomes. Clin Neurol Neurosurg. 2015;134:85–90. 6. Simas NM, Farias JP. Sphenoid wing en plaque meningiomas: surgical results and recurrence rates. Surg Neurol Int. 2013;4:86. 7. Bassiouni H, Asgari S, Sandalcioglu E, et al. Anterior clinoidal meningiomas: functional outcome after microsurgical resection in a consecutive series of 106 patients. J Neurosurg. 2009;111:1078– 1090. 8. Goel A, Gupta S, Desai K. New grading system to predict resectability of anterior clinoid meningiomas. Neurol Med Chir (Tokyo). 2000;40:610–617. 9. Honeybul S, Neil-­ Dwyer G, Lang DA, et al. Sphenoid wing meningiomas en plaque: a clinical review. Acta Neurochir (Wien). 2001;143:749–758. 10. Kim KS, Rogers LF, Goldblatt D. CT features of hyperostosing meningiomas en plaque. AJR Am J Roentgenol. 1987;149:1017– 1023. 11. Bikmaz K, Mrak R, Al-­ Mefty O. Management of bone-­ invasive, hyperostotic sphenoid wing meningiomas. J Neurosurg. 2007;107:905–912. 12. Pieper DR, Al-­Mefty O, Hanada Y, et al. Hyperostosis associated with meningiomas of the cranial base: secondary changes or tumor invasion. Neurosurgery. 1999;44:742–747. 13. Russell SM, Benjamin V. Medial sphenoid ridge meningiomas: classification, microsurgical anatomy, operative nuances, and long-­

term surgical outcome in 35 consecutive patients. Neurosurgery. 2008;62(3 suppl 1):38–50. 14. Verma SK, Sinha S, Sawarkar DP, et al. Medial sphenoid wing meningiomas: experience with microsurgical resection over 5 years and review of literature. Neurol India. 2016;64:465–475. 15. Zhang J, Shrestha R, Cai BW, Zhou PZ, Li YP, Jiang S. Management of large medial sphenoid wing meningiomas: a series of 178 cases. Turk Neurosurg. 2014;24:664–671. 16. McCracken DJ, Higginbotham RA, Boulter JH, et al. Degree of vascular encasement in sphenoid wing meningiomas predicts postoperative ischemic complications. Neurosurgery. 2017;80:957–966. 17. Pamir MN, Belirgen M, Özduman K, et al. Anterior clinoidal meningiomas: analysis of 43 consecutive surgically treated cases. Acta Neurochir (Wien). 2008;150:625–636. 18. Nakamura M, Roser F, Vorkapic P, et al. Medial sphenoid wing meningiomas: clinical outcome and recurrent rate. Neurosurgery. 2006;58:626–639. 19. Ringel F, Cedzich C, Schramm J. Microsurgical technique and results of a series of 63 spheno-­orbital meningiomas. Neurosurgery. 2007;60(4 suppl 2):ONS214–ONS222. 20. Carvi y, Nievas MN. Volume assessment of intracranial large meningiomas and considerations about their microsurgical and clinical management. Neurol Res. 2007;29:787–797. 21. Yang J, Ma SC, Liu YH, et al. Large and giant medial sphenoid wing meningiomas involving vascular structures: clinical features and management experience in 53 cases. Clin Med J (Engl). 2013;126:4470–4476. 22. Oikawa S, Mizuno M, Muraoka S, et al. Retrograde dissection of the temporalis muscle preventing muscle atrophy for pterional craniotomy. J Neurosurg. 1996;84:297–299. 23. Chang DJ. The “no-­drill” technique of anterior clinoidectomy: a cranial base approach to the paraclinoid and parasellar region. Neurosurgery. 2009;64(suppl 3):ONS96–ONS106. 24. Leake D, Gunnlaugsson C, Urban J, et al. Reconstruction after resection of sphenoid wing meningiomas. Arch Facial Plast Surg. 2005;7:99–103. 25. Sughrue ME, Rutkowski MJ, Chen CJ, et al. Modern surgical outcomes following surgery for sphenoid wing meningiomas. J Neurosurg. 2103; 119:86–93.

317.e1

CHAPTER 28

Surgical Management of Cavernous Lesions TAKESHI KAWASE

Surgical Methods and the History Surgery of the cavernous sinus was first developed by pioneers Parkinson and Dolenc in the 1960–80s, mainly for cavernous sinus aneurysms.1,2 It was gradually applied to cavernous sinus tumors, by parallel development of bypass of the carotid artery.3 In the 1990s cavernous sinus surgery was the hottest surgical subject in neurosurgery, with parallel development of microsurgical anatomy.4,5 However the number of direct surgeries for primary cavernous sinus meningiomas gradually decreased after the millennium according to development of Gamma Knife radiosurgery, for ophthalmic complications could not be ignored for the patients. After the late 1990s, it has gradually been accepted that parasellar meningiomas are better treated in combination with surgical removal of the subdural part of the tumors and radiosurgery for the intra-­cavernous part. Epidural surgery for trigeminal schwannomas has an advantage to preserve ophthalmic functions. Endoscopic transsphenoidal surgery is developing recently for pituitary adenomas and chordomas invading into the cavernous sinus.

FRONT-­TEMPORAL EPI-­AND SUBDURAL APPROACH (DOLENC) This approach was originally indicated for C3 aneurysms.2 Today the indication is extended for clinoid meningiomas invading the apex of the cavernous sinus.2,6 The optional technique is the orbito-­zygomatic approach6 to access the tumors with orbital or infra-­temporal fossa extension. Bypass of the carotid artery has been added optionally in case of tumor invasion to the artery.7 

FRONTO-­TEMPORAL EPIDURAL (INTERDURAL) APPROACH This approach has been developed for trigeminal neurinomas extending in the middle fossa with or without orbital extension,8 and cavernous sinus hemangiomas. The basic method is constituted with anterior clinoidectomy, separation of periosteal membrane lateral to the superior orbital fissure, foramen rotundum, and ovale. Meningeal dura can be tacked to expose the tumor, and the temporal lobe is not necessary to expose. 

318

SUBTEMPORAL EPIDURAL (INTERDURAL) APPROACH This approach is indicated for middle fossa trigeminal neurinomas with or without invasion into infratemporal fossa and parasellar chordomas.9,10 A benefit of the approach is that opening superior orbital fissure is not necessary. For neurinomas, periosteal dura is cut to enter the interdural tumor space, without exposure of the temporal lobe. Zygomatic osteotomy is optionally added for large tumors or tumors invading infratemporal fossa to reduce retraction damage to the temporal lobe. 

SUBTEMPORAL ANTERIOR PETROSAL APPROACH (KAWASE) This approach was originally indicated for lower basilar trunk aneurysms11 and the indication has been extended to petroclival meningiomas invading the parasellar area.12 Accessibility both to middle and posterior fossae is a merit of this approach, and it has been indicated for dumbbell trigeminal neurimas9 and parasellar chordomas invading posterior fossa.13 Epidural resection of petrous apex, tentorial incision, and Meckel cave exposure with or without opening the posterior cavernous sinus are the fundamental surgical processes.14 Tumors extending into infratemporal fossa can be accessed by combination of zygomatic approach (zygomatic petrosal approach).9 

Meningeal Anatomy and Location of Lesions Parasellar structures are located in the interdural space between meningeal and periosteal layers of dura mater.15 Cranial nerves are located lateral to the cavernous sinus wrapped by the inner (deep) layer of the cavernous sinus, except for the abducens nerve. Parasellar lesions look similar, but they are situated in different anatomic locations, in consideration of the meningeal structures of the parasellar compartment: subdural tumor (meningiomas), interdural tumor lateral to the cavernous sinus (neurinomas), tumors in the cavernous sinus (hemangiomas and meningiomas), and epidural tumors (chordomas) (Fig. 28.1). Therefore an important surgical strategy of the parasellar tumors is how to preserve those meningeal structures to spare injury to the cranial nerves, carotid artery, and the temporal lobe.15,16 

28  •  Surgical Management of Cavernous Lesions

T

Neurinoma

319

T

Chordoma

T

T

Hemangioma

T

Meningioma

FIG. 28.1  Difference of tumor (T) location related to meningeal layers. Break line; meningeal dura, broad line; periosteal dura, dotted; inner layer. Trigeminal neurinomas locate in interdural space lateral to the cavernous sinus, wrapped with inner layer. Hemangiomas locate in the cavernous sinus, pushing internal carotid artery and abducens nerve medially. Parasellar chordomas locate epidurally invading skull base, pushing the cavernous sinus upward. Meningiomas of the sinus origin encase neurovascular structures with adhesive nature, extending into subdural space.

Parasellar Tumors and Surgical Approaches TRIGEMINAL NEURINOMAS Most of the parasellar neurinomas are originated from nerve V. In our series,17 71.9% of the trigeminal schwannomas had middle fossa compartment, and 57.9% showed dumbbell shaped tumors extending into other fossae: into posterior fossa (MP type, 38.6%) and into extracranial space such as orbit or infratemporal fossa (ME type, 12.3%). Pure middle fossa type tumors were 14%, and pure posterior fossa type tumors were 21.1%. The middle fossa part is located in interdural space lateral to the cavernous sinus, wrapped with inner layer, which separates cavernous sinus from the tumor. Therefore the middle fossa part can be removed without exposure of the temporal lobe, by the frontotemporal epidural approach or subtemporal epidural approach (Fig. 28.2).17 The dumbbell MP type can be removed by the anterior petrosal approach (Fig. 28.3), and dumbbell ME type can be removed by the zygomatic or orbito-­ zygomatic epidural (interdural) approach.9,18 Most of the tumor could be resected completely without surgical complication, except for mild facial hypesthesia which did not handicap their daily life. In contrast, in tumor regrowth after Gamma Knife, it was very difficult to remove the tumor surgically because of severe adhesiveness to the brain and cranial nerves.19 Therefore, radiosurgery should not be the first choice of the treatment.

TL 3

T

6

IC

Middle Fossa Tumors

FIG. 28.2  A schema of subtemporal epidural (interdural) approach (arrow) for trigeminal neurinoma (T). Break line; meningeal dura, broad line; periosteal dura, dotted; inner layer. By cutting periosteal dura lateral to the foramen ovale and rotundum, the tumor can be accessed without exposing the temporal lobe (TL). Preservation of thickened inner layer, which separates the cavernous sinus from the tumor, is important to protect internal carotid artery and other cranial nerves during tumor removal.

The subtemporal epidural (interdural) approach is indicated for parasellar (M) type tumors with or without minimal extension to the posterior fossa. Zygomatic osteotomy is optionally added for larger tumors or younger patients to reduce retraction damage to the temporal lobe.

Case 1: Forty-­year-­old male. This patient was incidentally found to have a right parasellar tumor by asymptomatic MRI examination (Fig. 28.4A and B). By supine-­lateral position, temporal craniotomy was made and the dura was

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Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

EAM ZA MMA FO PN

EA IAM

TI GG ICA

PA

A

TU SPS

b a

TL TE

B

IV

elevated from the temporal base. The middle meningeal artery was coagulated and detached at foramen spinosum. Foramen rotundum and ovale was confirmed and the periosteal dura was incised lateral to the foramen. Meningeal dura was tacked superiorly and the tumor was exposed (see Fig. 28.4C). The tumor was removed cutting the inner, preserving trigeminal nerve fibers (see Fig. 28.4D). A small tumor extending into the posterior fossa was drawn out through the widened orifice of Meckel cave, and brain stem was seen after removal (see Fig. 28.4E). The patient had mild facial hypesthesia after surgery. MRI showed complete disappearance of the tumor (see Fig. 28.4F). 

Dumbbell Tumors The anterior petrosal approach is indicated for dumbbell-­ shaped tumors extending into the posterior fossa. Resection of petrous apex and detachment of the tentorium are added to the epidural subtemporal approach. Case 2: Twenty-­five-­year-­old unmarried female complained of right facial hypesthesia. MRI showed a dumbbell-­ shaped tumor extending into three fossae: middle fossa, infratemporal fossa, and the posterior fossa (Fig. 28.5A and B). Zygomatic osteotomy was combined with the anterior petrosal approach. The petrous apex was slightly eroded by the tumor. Greater superficial petrosal nerve was preserved at the time the petrous apex was resected. Middle

FIG. 28.3  (A) A drawing of right anterior petrosal approach. A break line is area of maximal resection of pyramidal apex (PA) for preservation of hearing. EA; Arcuate eminence; EAM; external auditory meatus; FO; foramen ovale; GG; Gasserian ganglion; ICA; internal carotid artery; MMA; middle meningeal artery; PN; petrosal nerve; TI; trigeminal impression; ZA; zygomatic arch. (B) Method of dural opening. Middle fossa dura is opened in T-­shape along the superior petrosal sinus (SPS). Ligation of SPS is followed by cutting the tentorium (TE, break line a), after opening the posterior fossa dura (break line b). TL, Temporal lobe; TU; tumor. (Modified from Kawase T. In: Torrens M., et al., eds. Operative Skull Base Surgery. Churchill Livingstone 1997:268–269, by author’s permission)

and infra-­temporal fossa tumor was exposed by resection of the temporal base between foramen rotundum and ovale, where tumor penetrated, and removed by the same technique of epidural subtemporal approach. For the posterior fossa part, the tentorium was detached after double ligation of the superior petrosal sinus. The technique of exposure and petrosectomy was described elsewhere.14 The tentorium was detached after double ligation of the superior petrosal sinus. The tumor was located medial to the trunk of trigeminal nerve (see Fig. 28.5C), and nerve fibers were mobilized and preserved except for nerves of the tumor origin. Thickened inner layer that separated the cavernous sinus was preserved. She had no surgical complication, and the tumor completely disappeared after surgery (see Fig. 28.5D). 

Parasellar Tumors Extending to Orbit and the Infratemporal Fossa The orbito-­zygomatic approach20 is indicated for the tumor extending from middle fossa to the orbit or infratemporal fossa. Case 3: 58-­year-­old female complained of left facial pain, mastication weakness, and hemifacial hypesthesia. She had a history of surgery by the subtemporal route 13 years before. The tumor regrowth was found on MRI, extending from middle fossa to infratemporal fossa (Fig. 28.6A). The middle skull base was eroded by the tumor. Orbitozygomatic osteotomy

28  •  Surgical Management of Cavernous Lesions

321

V neurinoma

R

A

C

B

D

E

FIG. 28.4  Case 1. Right parasellar type trigeminal neurinoma. (Upper left, middle, A): Preoperative Gd-­MRIs demonstrate parasellar tumor with minimal extension into the posterior fossa. (Upper right, B): Surgical view of the tumor by the subtemporal epidural approach. The tumor was covered with inner layer. (Lower left, C): After cutting the inner layer, the trigeminal nerve can be separated from the tumor. (Lower middle, D): Brain stem can be seen through widened Meckel cave after tumor removal. (Lower right, E): A contrast MRI after surgery demonstrates disappearance of the tumor, without injury to the temporal lobe.

was made to expose the tumor, and the tumor was exposed by the fronto-­temporal epidural approach. The medial part of the tumor invaded into the posterior cavernous sinus, and the cavernous sinus was opened, preserving the III, IV, and VI cranial nerves (see Fig. 28.6B). The trigeminal nerve adherent to the tumor was sacrificed. The patient had no oculomotor disturbance after surgery. She was relieved from facial pain. Postoperative MRI demonstrated total tumor removal. 

PARASELLAR MENINGIOMAS Surgical indication of parasellar meningiomas depends on degree of invasion to the cavernous sinus, for a particular character of cavernous sinus meningioma is its adherent tendency to neurovascular structures. If the tumor does not invade the lateral wall of the cavernous sinus, it may not be difficult to remove by the conventional pterional approach. However, in a case of the tumor invading into the cavernous sinus completely showing encasement of the carotid artery, it is very difficult to remove it completely without injury to the neurovascular structures. It is recent consensus that the subdural part of the tumor can be removed by surgery, and the cavernous sinus part is better treated by radiosurgery. In a case where the tumor invades the cavernous sinus partially, it is possible to remove it completely. They are demonstrated in the following cases.

Clinoid Meningioma Invaded the Cavernous Sinus Dolenc’s fronto-­temporal epi-­and subdural approach is indicated for patients with clinoid or parasellar meningiomas showing tumor invasion to the cavernous apex.

Case 4: A right clinoid meningioma invaded cavernous apex of a 65-­year-­old female complaining of visual disturbance. By pterional craniotomy with anterior clinoidectomy, the optic canal was opened and internal carotid artery (ICA) (C3) was confirmed behind the optic nerve. This exposure is important to imagine location and depth of ICA encased in the tumor, as well as to control tumor feeders epidurally (Fig. 28.7A). After removal of the subdural part of the tumor, the lateral wall of the cavernous sinus invaded by the tumor was separated from cranial nerves III and V-­1, preserving the inner layer. The tumor was removed with attached lateral wall (see Fig. 28.7B). 

Spheno-­Petroclival (Tentorial) Meningiomas The petrosal approach was extended to the parasellar area for spheno-­petroclival or tentorial meningiomas invading posterior cavernous sinus. Case 5: A large tentorial meningioma invading posterior cavernous sinus was found in a 26-­year-­old female complaining of double vision (IV nerve palsy) and left facial hypesthesia. Preoperative MRI showed a left meningioma extending from posterior pyramid to posterior cavernous sinus along the tentorium (Fig. 28.8A). After temporal craniotomy and petrosectomy with opening the internal auditory meatus, posterior fossa tumor was removed with tentorial attachment. Meckel cave and posterior cavernous sinus were opened, and the parasellar part of the tumor was removed with the tentorial attachment (see Fig. 28.8B). The trochlear nerve was sacrificed. Tumor in the internal auditory

322

Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

A

B Pterygoid process

F. ovale

MMA

Pterygoid v. plexus

GPN

Eminentia arcuata SPS

Zygomatic arch F. rotundum V

Tumor in Meckel cave

Tent

Tumor cyst in posterior fossa

C

III

PCP

IV

D FIG. 28.5  Case 2: Trigeminal neurinoma extending into three fossae. (A and B) Axial and sagittal Gd-­MRIs demonstrate a tumor extending from the middle fossa to posterior and infratemporal fossa, engulfing petrous apex. (C) A drawing of the tumor by the zygomatic petrosal approach,9 anterior petrosal approach plus zygomatic osteotomy. Three fossae overview was obtainable by zygomatic osteotomy and resection of the petrous apex with cutting the tentorium. GPN; Greater petrosal nerve; MMA; middle meningeal artery; PCP; posterior clinoid process; SPS; superior petrosal sinus. (D) A Gd-­MRI after surgery shows complete tumor removal without injury to the temporal lobe and brain stem. The cavernous sinus and auditory structures are intact. She had no neurologic deficit except for facial hypesthesia.

28  •  Surgical Management of Cavernous Lesions

323

Infratemporal fossa

Mandibular joint

Pterygoid process Fossa pterygopalatina

Ear

Inferior orbital fissure Orbit

C6 Petrous apex

Outer layer of cavernous sinus

Pons V

Dolenc’s triangle

Posterior clinoid

A

II Cavernous sinus

B

III

ICA

FIG. 28.6  Case 3: Recurrent trigeminal neurinoma. (A) A preoperative coronal section of Gd-­MRI shows a huge left parasellar tumor invading into the cavernous sinus and infratemporal fossa. (B) A surgical drawing after removal of the tumor, by left orbito-­zygomatic infratemporal approach. Lateral wall of the cavernous sinus was already lost by former surgery, and the cavernous sinus was opened. Cranial nerves IV and V were sacrificed. ICA; Internal carotid artery.

Dural ring C3 Lateral wall of cavernous sinus

I II

II III

Tumor

I

V•1

MCA

A

B

FIG. 28.7  Case 4: Right clinoid meningioma invading the lateral wall of the cavernous sinus. (A) A surgical drawing of the fronto-­temporal epi-­ and subdural approach (Dolenc’s approach). The tumor was devascularized and isolated by removal of the anterior clinoid process and opening the optic canal. Location of the internal carotid artery was imagined from the proximal carotid (C3) and the middle cerebral artery (MCA). (B) Lateral wall of the cavernous sinus was removed with the tumor attached. Cranial nerves III, IV, and V-­1 were preserved with inner layer that separated the cavernous sinus.

meatus was partially removed, for its adhesive nature to the facial nerve. Postoperatively, left hearing loss and mild facial hypesthesia were her permanent deficits. Most of the tumor disappeared on MRI except for a small residue around nerve VI and fundus of internal auditory meatus, and they were treated with Gamma Knife (see Fig. 28.8C). 

CAVERNOUS SINUS HEMANGIOMAS Hemangiomas originated from the cavernous sinus seldom result in local neurologic symptoms except for a huge one. For surgical removal, it is not necessary to open dura mater, and fronto-­temporal epidural approach with zygomatic osteotomy is the best surgical approach to confirm cranial nerves and to protect the temporal lobe. However, the amount of bleeding during surgery should not be optimized. Surgeons

are requested to have a high level of surgical skills to control hemorrhage both from the tumor and the opened cavernous sinus. There are two types of hemangioma: interstitial type, showing inhomogeneous content and cavernous type, showing homogenous content on Gd-­ MRI. Piecemeal tumor removal is possible for the former, but it is not possible for the latter because of severe hemorrhage. Preservation of abducens nerve may not be easy, for it is commonly located deeply in the tumor. Therefore the surgical removal can be indicated only for symptomatic tumors, such as visual disturbance or temporal lobe symptoms. Case 6: A right giant cavernous sinus hemangioma is found in a 59-­year-­old female who complained of memory disturbance. Content of the tumor was inhomogeneous on MRI-­Gd enhancement, which suggested interstitial type

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Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

(Fig. 28.9A). The carotid artery deviated medial to the tumor, and the tumor involved intercavernous sinus. The fronto-­temporal epidural approach plus zygomatic osteotomy was performed and the tumor was removed between the trigeminal nerves through antero-­lateral and lateral triangles (see Fig. 28.9B). Venous hemorrhage from re-­opened cavernous sinus had to be controlled constantly using Surgicel during tumor removal. Hemorrhage from the tumor could be controlled by tumor compression. Postoperative MRI showed subtotal removal without damage to the temporal lobe (see Fig. 28.9C). Her memory disturbance gradually improved after surgery, however, her abducens palsy was persistent. 

PARASELLAR CHORDOMAS Chordomas have their origin in epidural space, but sometimes invade subdural space or cavernous sinus, breaching dura mater. Therefore it must be cleared whether the tumor is located in epidural space, subdural space, or in

the cavernous sinus. The ideal approach to parasellar chordomas is subtemporal epidural approach, but recently it can be removed by a combination of endoscopic transsphenoidal or middle fossa approach,21 for it is commonly located in inferior cavernous sinus, showing upper deviation of the carotid artery. However, treatment of chordomas might not depend on surgery only, but recent radiosurgery (proton or carbon ion) has to be added to prevent tumor regrowth. Case 8: A parasellar chordoma invading posterior fossa is found in a 52-­year-­old female complaining of multiple right cranial nerve5–11 paresis and ataxia (Fig. 28.10A). The middle fossa petrosal approach (anterior plus posterior petrosal approach) was made and epidural tumor invading petrous apex was removed (see Fig. 28.10B). The subdural part in the posterior fossa was removed by cutting the tentorium (see Fig. 28.10C). Her ataxic gait improved after surgery. Numbered references appear on Expert Consult.

Middle ear

EM VI

IPS

Antrum

MMA

SS

3

SPS GG

Cerebellum

2 1

Cavernous sinus ICA III PCP

A

B

VII, VIII

AICA

SCA

V

C FIG. 28.8  Case 5: Left broad-­based spheno-­petroclival (tentorial) meningioma. (A) Preoperative Gd-­MRIs. The tumor has broad attachment along the tentorium, invading into the posterior cavernous sinus (left) and into the internal auditory canal (right). (B) A surgical drawing of left middle fossa petrosal approach after removal of the tumor. Total surface of the pyramid was resected, for the tumor extended posterior to the internal auditory meatus. The posterior cavernous sinus, invaded by the tumor, was opened after mobilizing the trigeminal nerve (V) inferiorly. The tentorium was removed with the tumor. AICA, Anterior inferior cerebellar artery; EM, external auditory meatus; GG, Gasserian ganglion; ICA, internal carotid artery; IPS, inferior petrosal sinus; MMA, middle meningeal artery; PCP, posterior clinoid process; SCA, superior cerebellar artery; SPS, superior petrosal sinus; SS, sigmoid sinus. (C) Postoperative Gd-­MRI shows nearly total removal, with small tumor residues around nerve VI and fundus of the internal auditory meatus.

28  •  Surgical Management of Cavernous Lesions

325

B

A

C FIG. 28.9  Case 6: Right huge cavernous sinus hemangioma of the interstitial type. (A) Note irregular enhancement of the tumor on Gd-­MRI. The tumor extended into the inter-­cavernous sinus. (B) Exposure of the tumor in the cavernous sinus by the fronto-­temporal epidural approach. Anterior clinoid was removed and periosteal dura was cut to expose the trigeminal nerve epidurally. The main surgical corridors removing the tumor were antero-­lateral (V1-­2) and lateral (V2-­3) triangles. (C) CT and Gd-­MRI images after surgery. The tumor is subtotally removed. Note no injury to the temporal lobe. The patient had abducens palsy after surgery.

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Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

Cavum tympani

EAM

MPN

Mastoid

MMA

Tumor in jugular F.

V-3 Parasellar tumor

Sigmoid S.

IAM Temporal lobe

B

A MPN MMA C6 Cavernous sinus

Tentorium (cut) Posterior fossa tumor VII, VIII

C FIG. 28.10  Case 7: Right parasellar chordoma invading the posterior fossa. (A) An axial Gd-­MRI image shows a huge tumor invading parasellar to cerebello-­pontine angle, destroying the petrous apex. (B) A surgical drawing of the tumor by the right middle fossa petrosal approach (anterior plus posterior petrosal approach). (C) Parasellar part of the tumor located in epidural space, and the cavernous sinus was not opened, preserving periost during tumor resection. EAM; External auditory meatus; IAM; internal auditory meatus; MMA; middle meningeal artery; MPN; major petrosal nerve. (C) Tumor in the posterior fossa was exposed by posterior petrous resection and cutting the tentorium. The posterior fossa tumor extended subdurally over the facial nerve. The tumor was totally removed.

REFERENCES

1. Parkinson D. Surgical approach to the cavernous portion of the carotid artery. J Neurosurg. 1965;23:474–483. 2. Dolenc VV. A combined epi-­and subdural direct approach carotidopthalmic artery aneurysms. J Neurosurg. 1985;62:667–672. 3. Sekhar LN, Moller AR. Operative management of tumors involving the cavernous sinus. J Neurosurg. 1986;64:879–889. 4. Rhoton Jr AL, Hardy DG, Chambers SM. Microsurgical anatomy and dissection of the sphenoid bone, cavernous sinus and sellar lesion. Surg Neurol. 1979;12:63–104. 5. Dolenc VV. Anatomy and Surgery of the Cavernous Sinus. New York: Springer Verlag; 1989. 6. Al-­Mefty O, Smith RR. Surgery of tumors invading the cavernous sinus. Surg Neurol. 1988;30:370–381. 7. Sekhar LN, Sen CN, Jho HD, Janecka IP. Surgical treatment of intracavernous neoplasms: a four-­ year experience. Neurosurgery. 1989;24:18–30. 8. Dolenc VV. Frontotemporal epidural approach to trigeminal neurinomas. Acta Neurochir. 1994;130:55–65. 9. Yoshida K, Kawase T. Trigeminal neurinomas extending into multiple fossae: surgical methods and review of the literature. J Neurosurg. 1999;91:202–211. 10. Goel A, Nadkarni T. Basal lateral subtemporal approach for trigeminal neurinomas. Report of an experience with 18 cases. Acta Neurochir. 1999;141:711–719. 11. Kawase T, Toya S, Shiobara R, Mine S. Transpetrosal approach for aneurysms of the lower basilar artery. J Neurosurg. 1985;63:857–861. 12. Kawase T, Shiobara R, Toya S. Anterior transpetrosal-­transtentorial approach for spheno-­ petroclival meningiomas: surgical method and results in 10 patients. Neurosurgery. 1991;28:869–876.

13. Kawase T. Epidural middle fossa approaches. In: Pamir NM, ­Al-­ Mefty O, Borba LAB, eds. Chordomas Technologies Technique and Treatment Strategies. New York, Stuttgart, Delhi, Rio de Janeiro: Thieme Publ; 2017:131–136. 14. Kawase T. Technique of anterior transpetrosal approach. Tech Neurosurg. 1999;2:10–17. 15. Kawase T, van Loveren H, Keller JT, Tew JM. Meningeal architecture of the cavernous sinus: clinical and surgical implications. Neurosurgery. 1996;39:527–536. 16. Kawase T. Meningeal structure of the cavernous sinus and surgical methods. Neurosurgeons. 1997;16:199–203, (Japanese, with Engl abstract and figures). 17. Fukaya R, Yoshida K, Ohira T, Kawase T. Trigeminal schwannomas: experience with 57 cases and review of the literature. Neurosurg Rev. 2011;34:159–171. 18. Youssef S, Kim EY, Aziz KM, Hemida S, Keller JT, van Loveren HR. The subtemporal interdural approach to dumbbell-­shaped trigeminal schwannomas: cadaveric prosection. Neurosurgery. 2006;59:270–278. 19. Kawase T. Management of trigeminal schwannoma: ­microsurgical removal vs. radiosurgery. In: Al-­ Mefty O, ed. Controversies in ­Neurosurgery II. New York, Stuttgart: Thieme Publ; 2014:92–94. 20. Al-­Mefty O, Ayoubi S, Gaber E. Trigeminal schwannomas: removal of dumbbell-­shaped tumors through the expanded Meckel cave and outcomes of cranial nerve function. J Neurosurg. 2002;96:453–463. 21. Rehder R, Cohen AR. Endoscope assisted microsurgical subtemporal keyhole approach to the posterolateral suprasellar region and basal cisterns. World Neurosurg. 2017;103:114–121.

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CHAPTER 29

Surgical Management of Lesions of the Clivus MARIA PERIS-CELDA  •  CARLOS D. PINHEIRO-NETO  •  JAMIE J. VAN GOMPEL

Anatomy of the Clivus The clivus a midline osseous anatomic structure in the skull base formed by the body of the sphenoid bone and the clival part of the occipital bone. Both bones join in a flat surface, the spheno-­occipital synchondrosis. The upper part of the clivus is formed by the sphenoid bone, whereas the middle and inferior part of the clivus are mainly formed by the occipital bone (Fig. 29.1). The sphenoid bone consists of a body, lesser and greater wings, and pterygoid processes. The clivus forms part of the body of the sphenoid, which also contains the sphenoid sinus. The sphenoid bone forms the upper part of the clivus, formed by the dorsum sellae and the posterior clinoids. The occipital bone has three parts: clival, squamous, and condylar. The clival part of the occipital bone is the osseous portion in midline from the spheno-­occipital synchondrosis to the foramen magnum, and forms the anterior part of the foramen magnum. The clival part forms the lower two-­thirds of the clivus. The paired condylar parts are situated along the anterolateral margin of the foramen magnum and connect the clival and squamous parts of the occipital bone. The squamous part of the occipital bone is lateral and posterior to the clival part and forms the remaining two-­thirds of the foramen magnum. The petrous part of the temporal bone has a triangular shape seen from above. It articulates with the sphenoid bone anteriorly and with the occipital bone posteriorly. The vertex of the triangle, the petrous apex, is located at the junction of the sphenoid bone, occipital bone, and petrous part of the temporal bone. The petroclival junction forms the posterior side of this triangle and is the articulation between the occipital portion of the clivus and the petrous part of the temporal bone. The petrous ridge, in the middle of the triangle, serves as attachment of the tentorium, which separates the supra and infratentorial compartments. The tentorial hiatus is formed by the two edges of the tentorium posteriorly and laterally and the clival dura mater anteriorly. The tentorial hiatus surrounds the midbrain, and leaves between the midbrain and the tentorial edge a space called the tentorial incisura. The clivus is mostly an infratentorial structure. When the dura mater of the tentorium joins the clival dura mater, it forms a dural fold called the posterior petroclinoidal fold. This fold, sometimes with a true ligament beneath it, is the continuation of the dura mater covering the petrous apex, which joins the posterior clinoid process.

It is of paramount importance to know the neurovascular relationships of the clivus. The brainstem (midbrain, pons, and medulla) in its anterior part is facing the clivus. Regarding cranial nerves (CNs), the nerve most closely related to the clivus is CN VI. CN VI exits the brainstem in the pontomedullary junction and pierces the inner layer of the dura mater of the clivus to be interdural in the Dorello canal until it passes medial to the petrous apex under the petrosphenoidal ligament (Gruber ligament) and enters the cavernous sinus (CS). The porus of the VI CN is 12 mm lateral to midline. The V1 division of the V CN is immediately lateral to CN VI in the CS. CN III and IV are in close relationship with the lateral aspect of the dorsum sellae superior to CN VI. A small bony groove for the CN III can be seen often in the lateral aspect of the dorsum sella just inferior to the posterior clinoids. The vascular relationships of the clivus can be divided in intradural and interdural/extradural. The carotid arteries are related to the clivus extradurally or interdurally (in the CS), whereas the vertebral arteries, basilar artery (BA), and their branches are intradural. The petrous segment of the internal carotid artery (ICA) in its medial or anterior genu is related to the petrous apex and thus to the spheno-­occipital synchondrosis and medial petroclival region. The cavernous segment of the ICA has a posterior bend and an anterior bend, which are closely related to the body of the sphenoid bone. The posterior bend is lateral to the upper clivus, whereas the anterior bend (parasellar carotid) is lateral to the anterior aspect of the sella turcica. The vertebral arteries and BA are closely related to the clivus as they travel anterior to the brainstem (see Fig. 29.1E). The clivus can be divided in three parts per two surgical classifications. The first one is the classical surgical classification based on the open approaches to the clivus; the second is a newer classification that has emerged after the endoscopic endonasal approaches based on the endonasal anatomy. Both are based on key anatomic landmarks of each approach. The classical surgical classification considers: upper clivus from the upper part of dorsum and posterior clinoids to the dural porus of the CN VI; middle clivus from the porus of the CN VI to the glossopharyngeal meatus; and lower clivus from there to the foramen magnum. The porus of the CN VI cannot be estimated in preoperative studies, but it is on average 3.4 mm inferior to the petrous apex. The glossopharyngeal meatus is located at the upper part of the

327

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Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

Sphenoid bone Ant. clin.

Temporal bone

Clivus

Post. clin.

Petrous apex

Dorsum

Sph.-occ. sync. and petro-clival fiss.*

For. magnum

Upper clivus

Middle clivus

Jug. For.

Lower clivus

Occipital bone

A

B

Sphenoid bone

Post . clin. Clivus Jug. For. Occipital bone

C FIG. 29.1  Surgical anatomy of the clivus. (A) Superior view of the occipital, sphenoid, and right temporal bones. The clivus is a midline structure formed by the sphenoid bone and the occipital bone. Note the relationship of the clivus with the petrous apex and petroclival junction. (B) Posterosuperior view of the clivus. The clivus can be divided by the upper clivus above the dural porus of CN VI (not seen in a dry skull, a few millimeters inferior to the petrous apex), the middle clivus between this and the upper aspect of the jugular foramina, and the lower clivus between the jugular foramina and the foramen magnum. (C) Right oblique view of the sphenoid and the occipital bones forming the clivus.

29  •  Surgical Management of Lesions of the Clivus

ICA

329

Optic N.

Post. Clin.

CN III

Clivus

CN VI

Midbrain

CN V

Pons

CN VII-VIII Temporal bone

CN IX, X, XI Medulla D

M1 ICA

A1 P1 CN III

Basilar A.

CN V

Clivus

CN VII-VII

CN VI CN IX, X, XI

Sig. sinus

Vert. A.

C1 E FIG. 29.1, cont’d  (D) Posterior view of the brainstem in the posterior fossa. (E) Posterior view of the clivus and related neurovascular structures.

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Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

A1 ICA

Midbrain

Optic N.

P1

ICA

P.com.

CN III CN IV CN VI CN V

Basilar A.

CN VI Clivus

CN VII-VIII

CN IX CN X

F

CN XI

Optic N. ICA A2

Post. Clin. A1

GG

P. Com.

P1

G

CN III

CN IV

CN V

CN VI

FIG. 29.1, cont’d  (F) Upper and middle clivus, posterior view. The right cavernous sinus has been opened and the nerves exposed. (G) Posterosuperior view of the upper clivus. The anterior clinoid process has been removed on the right side. The cavernous sinus has been dissected bilaterally.

29  •  Surgical Management of Lesions of the Clivus

331

Optic canal

Upper clivus

Lower clivus Nasopharynx

H

Paraclival ICA prominence

Clival recess

Middle clivus

Clivus

Parasellar ICA prominence

Sella

ET

ET

I

Midbrain

Orbit

PG

Pons

ICA

Clivus

J

V2

Maxillary sinus

C2

FIG. 29.1, cont’d  (H) Illustration of the endoscopic endonasal approach to the clivus in a skull. The transnasal route is a direct access to the clivus. (I) Endoscopic endonasal view of the clivus after opening the sphenoid sinus. The parasellar ICA defines the upper clivus, the paraclival ICA, the middle clivus, and the lower clivus is located between foramen lacerum and the foramen magnum, mostly below the floor of the sphenoid sinus. (J) Sagittal dissection of the skull base showing the clivus and the cavernous sinus on the left side. A, Artery; CN, cranial nerve; ET, Eustachian tube; Fiss., fissure; For., foramen; GG, gasserian ganglion; ICA, internal carotid artery; Jug., jugular; N., nerve; PG, pituitary gland; P. Com., posterior communicating artery; Post., posterior; Sig., sigmoid; Sph.-­occ, spheno-­occipital; Sync. synchondrosis; Vert., vertebral.

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Section One  •  SURGICAL MANAGEMENT OF BRAIN AND SKULL BASE TUMORS

jugular foramen and can be easily distinguished in preoperative studies.1 Regarding the endoscopic endonasal approaches, the classification is based on the endonasal view and localization of the different segments of the ICA. Three segments can be distinguished: upper clivus, defined by the parasellar portion of the carotid artery (anterior bend of the cavernous carotid), middle clivus defined by the paraclival carotid or vertical segment of the cavernous carotid up to foramen lacerum inferiorly (basically corresponds to the clival recess when it is present), and lower clivus from the inferior aspect of foramen lacerum to the foramen magnum. 

Philosophy of the Approaches Approaches to the clival area can be distinguished in those directed to the pathologies arising from the clivus as an osseous structure, and intradural pathologies that affect the interpeduncular, prepontine, and premedullary cisterns with possible lateral extensions. In general, when considering approach, we like to stay extradural for extradural lesions; it rarely makes sense to do an intradural approach for an extradural lesion in the clivus unless the approach offers less morbidity to the nerves of vessels. The most direct route to the clivus is the endoscopic endonasal route because it does not require any brain retraction or crossing neurovascular structures to access the bone. The equivalent in transcranial approaches is the transbasal approach, which requires a bifrontal craniotomy, sacrifice of olfaction, and frontal lobe retraction as part of the approach. For intradural pathologies in midline, the endoscopic endonasal approach does not require crossing nerves to reach the pathology. Lateral transcranial approaches require working in between the nerves to reach pathologies in midline. They are required for pathologies with lateral extension and, in some occasions, superior extension. Both approaches are complementary and are essential in the surgical armamentarium of the cranial base surgeon. The other essential aspect to consider for planning is the objective of the approach, complete resection versus biopsy if diagnosis is uncertain. Depending on the pathology, and given the potential morbidity of complete resection and sometimes irresectability of the pathologies, a multidisciplinary team approach is essential for management of these patients (Fig. 29.2). 

Pathologies of the Clivus DERIVED FROM THE NOTOCHORD REMNANTS Chordoma Chordoma is a malignant tumor arising from the remnants of the notochord. Approximately 32% of all the chordomas are localized in the clivus, 32.8% in the mobile spine, and 29.2% in the sacrum. These lesions are typically osteolytic and invasive and have hypointense in T1 and hyperintense in T2 with variable contrast enhancement (Fig. 29.3). These tumors are usually extradural, can have an intradural component, and are rarely primarily intradural. There are three histologic types of chordomas: classical, chondroid with a partially chondroid matrix, and dedifferentiated (or sarcomatous). The dedifferenciated type has a worse prognosis.

FIG. 29.2 Coronal (left) and superior view of a three-­dimensional (3D) model of a skull base tumor (blue) used for operative planning. We find 3D modeling extraordinarily important to planning for very complicated cases.

Chordomas are mainly confused with chondrosarcomas on radiologic diagnosis; however, chondrosarcomas typically have more true calcifications, whereas chordomas can have calcifications within them often representing eroded bone. Inmunohistologically these two lesions are clearly distinct entities separated by histologic sensitive markers cytokeratins and brachyury. Brachyury is a protein found in any tissue derived from the notochord. Chordomas tend to recur locally. Surgery is the most efficient treatment, and gross total resection is the most important prognostic factor. Endoscopic endonasal approaches are gaining acceptance for chordomas due to their location and direct access to this mostly extradural lesion. Considering their midline location, the endonasal approach avoids crossing CNs, and in some cases, intradural access can be avoided. Often chordomas require complementary transcranial approaches for resection of the involved bone, especially if the tumor has a lateral extension. In a recent meta-­analysis, endoscopic approaches showed less incidence of CN deficits and infections but higher rates of a postoperative cerebrospinal fluid (CSF) leak.2 Although en bloc resection may be curative in the spine, rarely in the skull base can such a strategy be used. However, an aggressive margin-­negative resection if able, or alternatively a radiographically negative postoperative image, is the preferred upfront treatment. Proton beam is gaining popularity as the most common adjuvant radiation; however, some centers use IMRT and stereotactic radiosurgery postoperatively. Proton beam therapy after surgery improved survival in some series, and it is proposed after surgical resection. Theoretically proton beam provides the highest treatment dose in close proximity to the brainstem. The average length of survival is 6.3 years, and overall survival is 67.6% at 5 years, 39.9% at 10 years, and 13.1% at 20 years, being better in children older than 5 years and worse in younger children. Metastases may occur but do not affect length of survival.2,3 

Ecchordosis Physaliphora Ecchordosis physaliphora is a benign, congenital lesion representing a notochordal remnant, which occurs particularly at the level of the clivus and sacrum. The magnetic resonance

29  •  Surgical Management of Lesions of the Clivus

A

B

C

FIG. 29.3  Lower clival chordoma: preoperative (A) sagittal T1 magnetic resonance imaging (MRI) with gadolinium demonstrating a contrast enhancing mass infiltrating the lower clivus and upper odontoid. (B) Axial T2 demonstrating the classic T2 hyperintensity of this extensive chordoma. Postoperative (C) Sagittal T1 MRI with gadolinium demonstrating removal of the lesion with preservation of the C1/2 joint with likely microscopic disease. (D) Axial T1 MRI with gadolinium demonstrating the resection and reconstruction.

D

*

A

333

B


110 mm Hg) Known intracranial vascular lesion or neoplasm Active internal bleeding Endocarditis Bleeding diathesis: [1] Platelets 1.7), [4] Direct thrombin or Xa inhibitor use Blood glucose MS at all time points

GKS > MS at all time points

MS 100% GKS 98%

MS 0% GKS 68%

MS 54% GKS 98%

MS 37.5% GKS 70%

MS 37% GKS 100%

MS 43% GKS 86%

MS 89% GKS 100%

MS 98% GKS 98%

90% at 10 years by most reports73 with few outliers.74 Extent of resection is the strongest predictor of tumor progression74,75 and subtotal resection is associated with 3x greater risk of recurrence.76 Intraoperative factors may limit the extent of resection including adhesion to the facial nerve, adhesion to the brainstem for very large tumors, and attempts to preserve hearing with tumors located in the fundus. All of these factors influence microsurgical tumor control rates to the extent that they limit the surgeon’s ability to achieve gross total resection. In most contemporary studies, tumor control rates obtained with radiosurgery and microsurgery are statistically indistinguishable. 

HEARING PRESERVATION For patients with functional hearing at the time of treatment, preservation of hearing is often a goal of treatment. Hearing loss after radiosurgery is a time-­dependent process that may relate to cochlear dose and patient age. Older treatment paradigms offered relatively poor hearing preservation and it wasn’t until the last decade when dose plans began to limit cochlear dose that hearing preservation rates improved. Contemporary dose plans that limit tumor marginal doses to less than 13 Gy and cochlear dose less than 4 Gy offer hearing preservation rates on the order of 50% to 70% at 5 years.14,39,77,78 However, based on current evidence, long-­ term hearing preservation rates are lower.79 Of note, one recent study reported superior hearing outcomes in younger patients and those with better hearing preoperatively.80 Of particular interest, these outcomes were assessed nearly 10 years after treatment. Unlike the time-­ dependent hearing loss associated with radiosurgery, hearing preservation after resection is normally durable but certainly can deteriorate over time. Most risk to hearing is assumed at the time of surgery.81,82 Between 20% and 70% of patients with serviceable hearing

preoperatively will have serviceable hearing after surgery, but this is dependent on tumor size, surgical experience and technique.66,81–83 Tumor size and location, extent of resection, approach, baseline neurophysiologic characteristics, and goals of surgery all influence postoperative hearing preservation rates.84–87 Overall, hearing preservation rates after microsurgical resection vary widely and correlate with many factors.79 

FACIAL NERVE PRESERVATION Facial nerve function is often intact when patients with vestibular schwannoma pursue treatment, yet it lies in close proximity to the 8th nerve and the vestibular schwannoma placing it at risk of iatrogenic injury. As a result, facial nerve preservation after stereotactic radiosurgery approaches 100% when using contemporary dose plans.13,66,88–92 A large meta-­ analysis by Yang and colleagues93 incorporating data from 23 studies involving 2204 patients across multiple treatment centers identified several factors that correlated with facial nerve preservation. They noted patients with tumor volumes less than 1.5 cc had significantly better facial nerve outcomes than those with larger tumors. Similarly, treatment plans with a margin dose greater than 13 Gy were associated with higher risk of facial nerve dysfunction than plans with lower margin doses. Finally, they reported that patients younger than 60 years of age were more likely to have good facial nerve preservation after treatment. Overall, stereotactic radiosurgery provides excellent preservation of facial nerve function, with 96% of patients maintaining their preoperative facial nerve function. Facial nerve preservation rates after microsurgical resection are not as good as those after radiosurgery, though specific centers and surgeons may report comparable preservation rates. Following resection, facial nerve function is preserved in 70% to 90% of patients.66,83,94 Early facial

94  •  Vestibular Schwannomas: The Role of Stereotactic Radiosurgery

weakness can improve in the first year as inflammation and nerve irritation resolve.84 Multiple factors have been correlated with facial nerve outcome including tumor size, neuromonitoring characteristics, and extent of resection and surgical approach.96–99 Bloch and colleagues100 performed a large single-­center study on prospectively collected data for 624 patients over 25 years and found that large tumors were associated with worse postoperative facial nerve function than smaller tumors. For tumors with an extra-­ canalicular diameter less than or equal to 1 cm, facial nerve palsies were reported in 24% of patients compared with facial nerve dysfunction in 56% of patients with tumors greater than 3 cm. When facial nerve preservation is the sole consideration, the current data unequivocally favors radiosurgery. 

1099

QUALITY OF LIFE There are two commonly used instruments for reporting quality of life for patients with vestibular schwannoma: the Short Form Health Survey (SF-­ 36) and the VS-­ specific Penn Acoustic Neuroma Quality of Life survey. Vestibular dysfunction and HA are the strongest predictors of long-­term quality of life in patients with sporadic vestibular schwannoma.101 However, when present, facial nerve dysfunction is consistently reported to have a large negative impact on quality of life.102,103 Most groups report that quality of life is comparable between patients treated with radiosurgery or resection.104–105 Radiosurgery offers superior quality of life in the short term, likely reflecting lower perioperative risk.104 An algorithm for management is shown in Fig. 94.6.

Tumor size, brainstem compression

Intracanalicular tumor

Tumor diamater 3 cm, symptomatic brainstem compression

Age, health

Review of treatments, goals, patients’ choice

Microsurgery

>75 yr.

50% of the TV) clear-­cell or chordoid morphology. WHO grade III MNs are defined as meningiomas with either 20 or more

1101

mitoses per 10 hpf, or predominant rhabdoid or papillary morphology.46–48 Interestingly, the 2016 classification introduced brain invasion as a criterion for the diagnosis of atypical MN (WHO grade II). While it has long been recognized that the presence of brain invasion in a grade I MN is associated with recurrence and mortality rates similar to those of a grade II MN in general, prior WHO classifications had considered invasion a staging feature rather than a grading feature and opted to discuss brain invasion under a separate heading. In the 2016 classification, brain invasion joins a mitotic count of 4 or more as a histological criterion that can suffice alone for an atypical MN diagnosis, WHO grade II.47,48 According to these new definition parameters and criteria, the incidence of grade II tumors, which recur earlier and in a more diffuse manner than benign MNs, has dramatically increased its frequency and now accounts for 20% to 35% of newly diagnosed MNs,49–51 instead of the 3% to 4% which it represented before the introduction of these new parameters. Furthermore, the discovery and definition of new biological markers and their correlation with prognosis, further helps in defining the nature and behavior of such tumors. Molecular alterations associated with less favorable clinical courses are expected to be valuable adjuncts to tumor grading when identifying patients at high risk for MN recurrence or progression. Compared with grade I MNs, the most prominent alteration in grade II and III MNs is a significant increase in chromosomal gains and losses, or copy number alterations, which may have behavioral implications. Monosomy of chromosome 2252,53 mutations of the NF2 gene on 22q12 in neurofibromatosis type 2 (NF2)—associated MNs,3,52 as well as amplification on 17q and loss on 9p (CDKN2 gene)2,54–56 and their correlation with WHO grading (more aggressive behavior) of MNs was already known. NF2-­positive WHO grade I and II MNs are at higher risk of recurrence and patients should be subjected to postsurgical imaging more frequently. Monosomy of chromosome 7 is frequently reported in radiation-­induced meningiomas (RIM).57 More recently, new biological markers’ expression of mutated genes has been described and correlated with MN outcome. First of all, protein telomerase reverse transcriptase (TERT) promoter mutations, irrespective of WHO grade, are an indicator for more aggressive growth in MN.58–59 Furthermore, the so-­called non-­NF2 mutations, which are frequently identified in WHO grade I MNs but the presence of a few non-­NF2 mutation variants may increase the risk of recurrence. In particular, tumor necrosis factor receptor-­associated factor 7 (TRAF7), phosphatidylinositol-­ 4,5-­ bisphosphate 3-­kinase catalytic subunit α (PIK3CA), oncogene homolog 1 (AKT1), Kruppel-­like factor 4 (KLF4), smoothened, frizzled class receptor (SMO), and RNA polymerase II subunit A (POLR2A) mutations are always associated to a benign behavior (WHO GI MNs), while the detection of v-­Akt murine thymoma viral oncogene homolog 1 (AKT1) mutations are usually expression of an intermediate MN aggressiveness.60–61 The promoter region of the TERT gene that encodes for TERT is mutated in several cancers. TERT mutations are present in approximately 6% of MN. MNs harboring TERT promoter mutations have variable location and are present in both skull base and cerebral convexities. TERT promoter mutations are more frequently observed in progressive and high-­grade MNs. When present in WHO grade I tumors,

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Section Five  •  STEREOTACTIC RADIOSURGERY

TERT C228T and C250T mutations are linked to high rates of recurrence and transformation to a higher grade. MNs with TERT promoter mutations should be recognized as aggressive and should undergo frequent imaging. Indeed, progression-­free survival is reduced from 179 to just 10 months in patients with TERT promoter mutations compared with patients with TERT wild types. TERT promoter mutations have been correlated with radiotherapy resistance in glioma and it will be important to determine if this is also the case for MN.60 Mutations in TRAF7 are the most frequently observed gene aberrations in non-­NF2 tumors, and they are present in approximately 25% of all MNs. TRAF7 mutations are most common in grade I tumors but are also observed in grade II and III. TRAF7 tumors are typically associated with meningothelial subtypes of the anterior cranial base but location and prognosis are influenced by whether AKT1, KLF4, or PIK3CA mutations are also present. PIK3CA mutations are present in approximately 7% of non-­NF2 tumors, with approximately 60% of this group also having a TRAF7 mutation. PIK3CA mutations are generally found in meningothelial and transitional grade I tumors of the skull base. Mutations in KLF4 almost always co-­occur with TRAF7 mutations. KLF4 mutations occur in about 12% of WHO grade I MN. Virtually all secretory MNs harbor KLF4 and TRAF7 co-­mutations. By contrast, SMO mutations, found in about 5.5% of WHO grade I MN, are mutually exclusive of TRAF7. MNs with an SMO mutation are mostly localized near the midline and at the medial anterior skull base. Mutations in POLR2A are found in 6% of MNs. POLR2A-­positive tumors are WHO grade I and have low risk of recurrence. AKT1 is mutated in 7% to 12% of WHO grade I tumors, is rare in WHO grade II, and mostly absent in WHO grade III MNs. Approximately 60% of AKT1 tumors also carry a mutation in TRAF7. AKT1 MNs are frequently located in the anterior cranial base. MN of the skull base may have a reduced time to recurrence if carrying an AKT1 mutation.60,61 In light of these recent data, we recommend that, in case of neuroradiological patterns suggesting an aggressive MN, when possible and safe, a more aggressive approach be taken to reach a clear and definitive biological and histopathological definition. From the radiosurgical point of view, in cases of “primary” treatment for MN with tumor location not amenable to surgery and in cases with very high surgical risk MN with imaging characteristics similar to an aggressive lesion, higher prescription doses than those used for WHO grade I MNs (range 10 to 16 Gy) should be delivered. In such cases, several authors suggest to administer prescription doses ranging between 15 Gy and 20 Gy, if allowed by anatomical conditions and radiobiological parameters.50,62–69 Furthermore, we suggest that patients affected with MN expressing biological markers for mutated genes that are correlated with a more aggressive biological behavior should receive more frequent postsurgical clinical and imaging follow-­ups. 

Guidelines and Evidence-­Based Recommendations The levels of evidence for the diagnosis and treatment recommendations for patients with MNs are low, allowing only

recommendations of level B, C, and good practice points, despite the high frequency of such tumors. Nevertheless, the different studies published over the last 6 years show interesting suggestions that deserve to be mentioned. Indeed, since 2012, several guidelines and reviews with level of evidence and grade of recommendations regarding the management of intracranial MNs have been published. In June 2012, the Alberta Health Services published the Clinical Practice Guideline CNS-­005 version 2 on intracranial MNs.70 Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial CNS Tumour Team and a Knowledge Management Specialist from the Guideline Utilization Resource Unit. For WHO grade I MN, the Alberta Provincial CNS Tumor Team recommends that small, asymptomatic, benign-­ appearing MNs that are found during a radiographic evaluation are followed without therapy, using CT and/or MRI imaging at regular intervals. Indeed, though most asymptomatic or incidentally detected MNs can be managed by observation with serial surveillance neuroimaging, there is no class I or II evidence to support this approach.60 The Alberta Provincial CNS Tumour Team recommends that microsurgery be the primary treatment for patients who are not candidates for management by a watch-­and-­wait approach (recommendation #1). Surgical intervention is recommended when the tumor begins to cause symptoms, or when it displays significant growth on consecutive CT or MRI images. Gross tumor removal (GTR) should always be the goal of surgery and offers the best possibility of a cure for low-­grade MNs. However, some meningeal tumors, particularly those involving the cavernous sinus, petroclival region, posterior aspect of the superior sagittal sinus, or optic nerve sheath (ONS), cannot be completely removed due to their relationship to vital neural or vascular structures. For incompletely resected or recurrent symptomatic grade I MNs, the Alberta Provincial CNS Tumour Team recommends the use of radiation therapy (RT) (recommendation #2). Thus, radiation treatments should be considered in cases in which tumor location precludes surgery, where the tumor is unresectable (as primary treatment), in symptomatic residual disease (as an adjuvant treatment), or where there is tumor recurrence (as a salvage treatment). Radiological diagnosis may be sufficient in these cases. Regarding the WHO grades II and III MNs, because of their high rates of postsurgical recurrence, the authors recommend that the standard treatment for such patients is microsurgery followed by postoperative RT (recommendation #3). Patients with selected tumors may be eligible for SRS (recommendation #4). This technique is most often used for patients who have small-­to medium-­sized MNs, have tumors that are surgically inaccessible, are not candidates for surgery, or have residual or recurrent tumors following surgery with a recommended marginal tumor dose ranging between 9 Gy and 20 Gy (median, 15 Gy).71–72 In cases where the tumor is unresectable or all other therapies have failed to prevent a recurrence, the Alberta Provincial CNS Tumour Team suggests that systemic treatment may be considered on a clinical trial basis (recommendation #5) although there are only limited data available on the use of systemic agents in the treatment of MNs. The National Health System (NHS) in England published in September 2013 the Clinical Commissioning Policy referring to SRS/Stereotactic Radiotherapy (SRT) for MN

95  •  Stereotactic Radiosurgery Meningiomas

(NHS England D05/P/e), prepared by the NHS England Clinical Reference Group for SRS.73 They also stated that the three management options for patients with MN are: (1) surgical removal; (2) RT: SRS (single fraction), SRT (2 to 5 fractions), multi-­fraction treatment (>5 fractions) with or without stereotactic localization techniques; and (3) no intervention/radiological surveillance. All treatment options must be considered by a multidisciplinary team (MDT) for all patients with intracranial MNs. These must be discussed with the patient, as patient choice is considered of fundamental importance. Microsurgery is the preferred treatment option in the management of patients with MNs where the operative risks are low or minimal. This enables histological diagnosis to be confirmed, provides an opportunity for complete excision, and permits cytoreduction, even if the tumor origin is not amenable to resection. However, evidence has grown over the past 20 years supporting the use of SRS as a primary treatment for MNs that are in anatomically unfavorable locations where microsurgery is deemed to have an unacceptably high risk of neurological deficit. These locations include, but are not confined to, the skull base, the posterior fossa, parasagittal, parafalcine, and intraventricular sites. They recommend that it is appropriate for clinicians to consider SRS for a small subset of patients with MN that are in a difficult and unacceptable high anatomical risk situation, where there is evidence of effectiveness for SRS, and where conventional surgery is contraindicated or the risk of functional disability would be increased with surgery. This recommendation is supported by the fact that evidence from large numbers of patients indicates that long-­ term tumor control is achieved in a high proportion of cases treated with SRS. Furthermore, when compared to microsurgery, SRS provides shorter hospitalization and a less detrimental impact on quality of life. Procedural mortality is avoided and there is a lower incidence of treatment-­related complications. Finally, there is evidence from a comparative study between microsurgical costs and SRS costs that the overall costs for microsurgery were more than double the costs of SRS. For patients undergoing SRS rather than microsurgery, the cost savings to the NHS can be substantial. SRS is usually delivered as a day-­case treatment under local anesthetic. Microsurgical resection is performed under general anesthetic. Operative times usually extend from 2 to 10 hours or more, depending on complexity. Microsurgery patients are managed for 12 to 24 hours minimum in an intensive care/high-­dependency care environment. Hospital stay is usually in the range of 4 to 10 days but may extend to several months if postoperative deficits and complications (such as cerebrospinal fluid leak) occur. This can put significant strain on neurological-­rehabilitation resources. In addition, SRS limits disease progression in most patients with low retreatment rates. Regarding the evaluation of response to SRS, post-­treatment volumetric assessment of the tumor has been suggested at 6 months, annually for 5 years, then every 2 years. From a costing perspective, postoperative patients also undergo regular surveillance scans at similar timepoints. The NHS England Clinical Reference Group for SRS focused their attention on the management of asymptomatic or incidentally detected MN as well. The absence of symptoms, a heavily calcified tumor, or a very small tumor may appropriately lead to conservative management with a radiological surveillance program. This is

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particularly appropriate in patients with more advanced age in whom symptomatic tumor progression is unlikely to occur. However, in many locations, further growth of the tumor after initial diagnostic imaging will make treatment of the tumor more difficult, leading to universal agreement that intervention should be considered appropriate. Furthermore, studies on the growth rates of MNs are characterized by an inability to reliably predict which tumors will grow and how quickly. Hence, since in many locations (e.g. skull base, parasagittal) any degree of tumor enlargement can lead to compression of adjacent neurological structures with associated permanent neurological deficits, there is universal agreement that intervention is appropriate for many patients with critically placed MNs. In these cases, the NHS England Clinical Reference Group for SRS recommended that a MDT of experienced SRS neurosurgeons, neuro-­oncologists, and neuro-­radiologists must be involved in determining the operative risks and the likelihood of involvement of adjacent structures for appropriate case selection, treatment planning, and delivery. Accordingly, the NHS England Clinical Reference Group for SRS concluded that because blinded trials cannot be conducted comparing the treatment of MNs with SRS and/or microsurgery and/or a conservative approach and given the fact that many MNs occur in critical areas of the brain, outcomes of treatment are potentially compromised by adopting a watch, wait, and re-­scan policy. At the end of their clinical commissioning policy study, the authors stated that indications for SRS/ SRT include newly diagnosed MNs (primary SRS/SRT), residual MN after microsurgical resection (adjuvant SRS/ SRT), and recurrent MNs (salvage SRS/SRT). In 2015, Sun et al.74 reported a comprehensive review of the literature on management of grade II and III MNs based on WHO 2000/2007 criteria and attempted to define optimal treatment strategies for these tumors given the most current evidence. For WHO grade II MNs, recent retrospective studies corroborate the importance of GTR (Simpson grade I–III) resection because maximal extent of resection has been associated with improved long-­term outcomes. GTR shows a significant benefit over STR (Simpson grade IV) for grade II MNs (EBM level 3, grade 1C recommendation). However, “maximal safe resection” may be a more appropriate strategy than GTR, given the surgical morbidity associated with resection in certain locations. Hence, while GTR is the goal, STR may be considered in selected patients through traditional open surgery or minimally invasive techniques. Regarding adjuvant RT after GTR, the authors reported that the current literature overall does not favor the addition of adjuvant RT for grade II MNs after GTR. Furthermore, complications of adjuvant RT should also be considered in clinical decision making. Radiation necrosis may occur in 4.2% to 10.2% of patients. Without definitive evidence that RT reduces the risk of tumor recurrence and subsequent retreatment for all 2000/2007 WHO grade II MNs after GTR, the risk of toxicity related to upfront RT needs to be carefully considered. Results from studies relying solely on 2000/2007 WHO guidelines support active surveillance after GTR of grade II MNs (EBM level 3, grade 1C recommendation). MDT management is recommended for those grade II MNs with particularly aggressive histological features. In contrast to gross totally resected WHO grade II MNs, it has been demonstrated that adjuvant RT

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after STR is associated with improved PFS. Overall, adjuvant RT is reasonable after STR (EBM level 3, grade 1C recommendation), but the results of STR and RT remain suboptimal, with a 5-­year PFS of 43% to 91%. Therefore, dose escalation of RT or novel approaches using radiosensitization should be investigated, especially for grade II MNs with necrosis. The authors reported that a review of modern literature on SRS suggests that this modality can be effective for biopsy-­proven WHO grade II MNs. In particular, adjuvant SRS following STR resulted in equivalent rates of long-­term LTC as adjuvant RT (EBM level 3, grade 2C recommendation), although SRS tended to be used for smaller residual tumors in a smaller resection bed. SRS is also used as a salvage measure for grade II MNs for which surgery and RT have failed. In summary, the authors concluded that RT and SRS are complementary strategies for management of WHO grade II MNs after STR or recurrence, with the volume of the residual or recurrent disease representing the discriminating factor: SRS for smaller residual tumors and RT for larger ones. For recurrent WHO grade II MNs, no studies of WHO 2000/2007 grade II MNs compare outcomes of salvage resection against salvage RT or SRS; for these tumors, the authors recommend tailoring treatment to the specific clinical scenario: salvage resection should be considered if the recurrent grade II MN is accessible, salvage SRS if the recurrent grade II MN is relatively small and localized, and salvage RT if the recurrent grade II MN is radiation-­naïve and of a relatively larger volume such that SRS is not feasible. In WHO grade III MNs, maximal but cautious resection strategy and consideration of repeat surgery for recurrence is recommended (EBM level 3, grade 1C recommendation). Authors stated that RT was associated with increased PFS and overall survival in grade III MNs and they conclude that evidence supports the use of RT for such tumors (EBM level 3, grade 1C recommendation). The role of SRS in WHO grade III MNs is limited to recurrent relatively small and localized tumors, nonsurgically accessible, with microsurgery and RT failure. Finally, the role of chemotherapy in WHO grade II and III MNs is still debated. The separate evaluation of the chemotherapy effect in grade II and III MNs is not available because most studies pooled both tumors together. Anyhow, chemotherapy for WHO grade II and III MNs has had limited success. Select trials have suggested that angiogenesis inhibitors (agents against VEGFR and VEGF, including RTK inhibitors and bevacizumab) may play a role in salvage therapy for recurrent or refractory grade II and III MNs (EBM level 2, grade 2B recommendation). At the end of their study, the authors suggested the following EBM classified recommendations for WHO grade II and III MNs: (A) EBM level 3, grade 1C recommendations: (1) maximal safe resection of grade II and III MNs; (2) active surveillance after GTR of grade II MNs; (3) adjuvant RT after subtotal resection of grade II MNs; (4) adjuvant RT after resection of grade III MNs. (B) EBM level 3, grade 2C recommendations: (1) selective RT for grade II MNs based on the absence of histopathological necrosis; (2) adjuvant SRS for small residual grade II MNs after STR. The MN task force of the European Association of Neuro-­Oncology (EANO) assessed the scientific literature and composed a framework of the best possible evidence-­ based recommendations for health professionals.58 The EANO recommendations are very similar to those of other

recent reported studies. Asymptomatic patients, especially if elderly, can be managed by observation. No class I or II evidence exists to support guidelines for observational management of MNs, but many retrospective series and several reviews validate this approach (evidence level III, recommendation level C). The suggestion to treat with surgery or SRS rather than to manage by observation alone should be made on the basis of a strong indication. If treatment is indicated in MN of any WHO grade, surgery is the first option and complete removal (Simpson grade I) is the primary goal of surgery: evidence level II, recommendation level B for WHO grade I MNs; evidence level III, recommendation level B for WHO grade II MNs; evidence level III, recommendation level C for WHO grade III MNs. Assessment of the extent of resection should be confirmed by MRI performed within 48 hours after surgery, or after 3 months, to avoid artifacts. SRS might be the first option in small WHO grade I MNs in specific locations. Patients with WHO grade I MN who cannot undergo surgery can be treated by fractionated RT or SRS: evidence level III, recommendation level B. Combining subtotal resection and SRS or fractionated RT should be considered to allow comprehensive tumor treatment while reducing the risk of adverse effects from treatment in WHO grade I MNs (evidence level IV, recommendation level C). Patients with incompletely resected WHO grade II MNs should receive fractionated RT or SRS if the tumors are small or if they are tumor remnants (evidence level III, recommendation level C). Pharmacotherapy is experimental in any grade of MN and should only be considered if no further surgical or RT options exist. Regarding the period of observation, the following recommendations are based more on expert consensus opinion than on evidence (recommendation level: good practice point). Follow-­up of WHO grade I MNs should be done annually, then every 2 years after 5 years; follow-­up of WHO grade II MNs should be done every 6 months, then annually after 5 years; follow-­up of WHO grade III MNs should be done every 3 to 6 months indefinitely. In summary, the authors recommend what follows. In WHO grade I MNs with GTR, there is no need for further irradiation, either SRS or fractionated RT. After STR, for elderly patients (older than 65 years), or for tumors not safely accessible by surgery, SRS can be offered for small tumors or fractionated, RT if the TV cannot be treated by a single fraction. In WHO grade II MNs with GTR, active surveillance is recommended without any routine adjuvant RT. For WHO grade II MNs with STR, progression or recurrence lesions, adjuvant/salvage RT or SRS for small tumors or tumor remnants should be considered. In WHO grade III MNs, surgical resection should be as radical as possible and always needs to be followed by fractionated RT. More recently, the Princess Margaret Cancer Centre has published its Clinical Practice Guidelines.57 The MDT put forth the following recommendations for each WHO grade MN. In WHO grade I MNs, complete surgical resection is the treatment of choice for most non–skull base tumors. Vertex parasagittal tumor locations present difficulty to achieve a Simpson’s grade I resection due to attachment of the tumor to the superior sagittal sinus. For newly diagnosed symptomatic MN for which surgery is not done (i.e., cavernous sinus, optic nerve, other skull base locations), upfront RT is usually recommended. For MNs where a partial resection has been done with residual disease, upfront RT or delayed RT

95  •  Stereotactic Radiosurgery Meningiomas

are possible options. For recurrent MNs, upfront RT is usually recommended. In WHO grade II MNs, GTR is recommended wherever possible; where a GTR has been done, then observation and RT for recurrence is (usually) recommended, as the 10-­year relapse rate is approximately 50%. For STR or recurrent tumor, RT is (usually) recommended. In WHO grade III: GTR wherever possible; postoperative RT is recommended in all cases regardless of degree of resection. With reference to SRS, the authors recommended the following indications: maximal tumor diameter should not exceed 3 cm; skull base MNs at initial presentation; residual/recurrent grade I MNs; recurrent grade II/III MNs after prior fractionated RT. The SRS-­advised doses range between 12 and 14 Gy, based on location and aggressiveness of tumor. In summary, evidence-­based and guideline studies published in recent years with reference to SRS for the treatment of intracranial MNs are in agreement on several points. First of all, there is an overall agreement about the effectiveness and safety of SRS in selected cases. Indeed, SRS is a shared recommendation as a primary or adjuvant/salvage treatment for WHO grade I MNs, particularly for those in anatomically unfavorable locations where microsurgery is deemed to have an unacceptably high risk of neurological deficit or when MNs cannot be completely removed due to their relationship to vital neural or vascular structures. These locations include, but are not limited to, the skull base and the posterior fossa (particularly, cavernous sinus and petroclival locations), the posterior aspect of the superior sagittal sinus, parasagittal, parafalcine, intraventricular, and ONS sites. Furthermore, SRS provides, when compared to microsurgery: shorter hospitalization; a less detrimental impact on quality of life; avoidance of procedural mortality and lower incidence of treatment-­related complications; much lower overall costs. Briefly, for elderly patients (older than 65 years), or for tumors not safely accessible by surgery, or after incomplete surgical resection, SRS can be carried out for small tumors. In WHO grade II MNs, SRS is most often used for patients who have small-­to medium-­sized MNs, have tumors that are surgically inaccessible and are not candidates for surgery (primary treatment), or have residual or recurrent tumors following surgery (adjuvant/salvage treatment). Results of SRS are similar to those of fractionated RT for small tumors or tumor remnants. Finally, SRS is deemed to be indicated in recurrent WHO grade III MNs that have undergone prior fractionated RT. 

Targeting Update The development of SRS has closely followed the impressive evolution of neuroradiologic techniques. The best example is perhaps the exponential increase of radiosurgical indications after the introduction of computerized imaging, particularly magnetic resonance imaging (MRI). Indeed, for routine SRS procedures, stereo-­MRI remains a mainstay in target localization. Coregistered multimodality acquisitions (MRI, computed tomography [CT], angiography, positron emission tomography-­magnetic resonance imaging [PET-­MRI] [Fig. 95.1], PET-­CT PET scan) have led on one side to the development of fusion algorithms based on contour definition, signal intensity, and voxel matching that allow detailed, interpolated 3D and 4D pictures, speeding up all the preoperative

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FIGURE 95.1  Biograph mMR—Simultaneous MR-­positron emission tomography scanner—Siemens.

procedures. On the other, advances in computerized integration of stereotactic and nonstereotactic imaging, including functional MRI and diffusion tensor imaging (DTI), are opening unexpected frontiers to SRS treatments.75 Improving safety and efficacy of radiosurgical planning is now possible via fusing the conventional sequences of a stereotactic MRI with the three Tesla pictures of corticospinal, visual, or arcuate DTI, with the aim of preserving the specific tract from undue damage (Fig. 95.2)76 CT and MRI scans sometimes may not adequately identify the regions of functional interest surrounding the planned target. Co-­registration of functional MRI becomes mandatory, albeit sometimes still inadequate. Molecular imaging may be the appropriate integration. Using stereo-­PET PET-­CT or PET-­MRI scan metabolic mapping, with FDG or a spectrum of amino acids radiotracer, particularly fluorodopa and 11C-­methionine, (68) Ga-­ DOTATOC77,78 scan be merged with conventional picture, thereby helping to identify the borders of the lesion as well as the metabolically active sites of the tumor or necrotic/radionecrotic foci on the basis of the differential uptake.79,80 Moreover, PET techniques allow us to differentiate the usually octreotide-­rich surfaces of MNs from other skull base tumors that generally lack these receptors.81,82 

Irradiation Techniques and Modalities Radiosurgery, in the absolute majority of cases, differs from conventional ab externo radiotherapy in various well-­known aspects: • A single fractionated high dose is used, with very few exceptions, as opposed to multiple small daily fractions. • The use of stereotactic technology entails considerable accuracy of the treatment (with a standard mechanical error of 0.3 mm). • The dose gradient is extremely steep; thus the resulting lesions are very sharply circumscribed. As a consequence, exposure outside of the target volume is minimized. • Radiotherapy relies on the difference in susceptibility between tumor tissue and normal brain tissue, whereas radiosurgery delivers an ablative dose to the target margin with a higher dose delivered centrally.

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Section Five  •  STEREOTACTIC RADIOSURGERY

A

B FIGURE 95.2  Cortico-­spinal tract reconstruction with diffuse tensor image algorithm and its registration on gamma plan: axial (A) and coronal (B) views.

Currently SRS techniques may utilize different types of penetrating energy, including particles such as protons or heavy-­charged particles, and photon devices such as linear accelerators (LINACs) or the GK. The details and functioning modalities referring to these devices when applied to SRS have been extensively presented and discussed in the

6th Edition chapter. The recent innovations introduced in the last 6 years can be summarized as follows (Fig. 95.3).

HADRON THERAPY Hadron therapy is a form of external beam radiotherapy using beams of energetic protons, neutrons, or positive

95  •  Stereotactic Radiosurgery Meningiomas

1107

ions.2,7 The tissue depth at which the Bragg ionization peak is maximal can be adjusted by cross-­firing systems according to the target position. The most common type of particle therapy as of 2012 is proton therapy. The drawbacks of this technique include the great expense of building and the use of these charged particles has developed rapidly in recent decades. 

resulting in good target coverage with high-­dose homogeneity and respecting organs-­at-­risk constraints.89 In addition, this technique allows treatment of larger brain lesions than GKS. Once again, the most important difference seems to be that the latter still maintains a better conformity index, and non-­negligible advantages in terms of the integral dose to the brain. 

LINEAR ACCELERATOR

GAMMA KNIFE

Linear accelerator-­ based radiosurgery uses x-­ ray beams. Multiple non-­coplanar arcs converge at a single isocenter, where a nearly sphere-­shaped dose distribution is created. This technique has proved to be an effective, alternative radiosurgical option, particularly in cases of larger target volumes, or whenever fractionated radiosurgical procedures are required.2,7,38 Comparative analyses of the literature concerning LINAC versus GK results in MNs, however, still show similar tumor control indexes on one side, and much higher complication rates with LINAC on the other, with comparable or shorter follow-­up periods.34,83–87 With the increasing use of SRS, the growing interest for highly sophisticated, photon linear accelerators has led to micro-­ multileaf (MML) technology and a flattening filter-­ free (FFF) linear accelerator, potentially more competitive with GK and proton beam devices, and characterized by an easy patient setup and greater possibilities of reaching any irradiation position. Basic parameters that allow complex field shaping with the LINAC include the volumetric modulated arc therapy (VMAT), patient couch angle, isocenter position, and collimator size. The Magnetic Resonance Linear Accelerator (MR-­LINAC) is a technology that enables simultaneous radiation delivery and fast acquisition of high-­ quality MR images. MRI yields superb soft-­tissue visualization (see Fig. 95.3A and B). 

The GK (Elekta, Sweden) contains an array of 192 (model Perfexion and Icon) (see Fig. 95.3E) individual60 Co sources aligned with a collimation system that directs each of the radiation beams to a very precise focal point. The Icon model integrated stereotactic Cone Beam CT for frameless treatment and gives clinicians the option to perform single or fractionated frame-­based or frameless treatments, allowing for more individualized delivery, without sacrificing precision and accuracy. GK treatments are therefore quite heterogeneous in terms of dose distribution inside and outside of the target; tumor control and tissue sparing is achieved via the steep dose gradient at the periphery rather than exploiting the radiobiological differential between normal and pathologic tissue as in fractionated radiotherapy. With the multiple isocenters routinely used, GK plans tend to be more conformal but less homogeneous than LINAC-­based plans. Due to the typically steep dose gradients of radiosurgery, an accurate alignment of the plan’s isocenter with the physical isocenter of the machine is a challenging issue.7 Moreover, the surgeon can modify the shooting collimator size using the sector drive motors that move the sources along their bushing to the correct position; the localization of each sector is monitored by linear and rotational encoders characterized by a positioning repeatability of less than 0.01 mm.90,91 

CYBERKNIFE

DOSE PLANNING

The CyberKnife (Accuray, Sunnyvale, CA) has clearly shown basic pros and cons of the technique.29–32,38,88 Regarding the latter, the absence of a stereotactic frame, as well as the mobility of the radiation source, should somehow entail a slightly superior error margin if compared to the GK. The CyberKnife (see Fig. 95.3C) combines a lightweight 6-­MeV LINAC designed for radiosurgery and mounted onto a highly maneuverable robotic arm that can position and point the LINAC. Internally controlled real-­time image guidance eliminates the need of skeletal fixation for either positioning or rigid immobilization of the target. Complex radiosurgical treatments may be performed, in which beams originate at arbitrary points in the workspace to target arbitrary points within the lesion. Even nonisocentric beams can be focused anywhere within a volume around the center. 

The goal of dose planning is to create an extremely conformal and selective isodose configuration, with complete covering of the tumor, and minimal exposure of the surrounding tissues. Using a combination of multiple isocenters of different sizes, differential weighting of the crucial shots, selective blocking of the collimated beams, and typical of the GK using hybrid shots,90 it is possible to produce dose plans that closely conform not only to the main shape of the MN but also to all the MRI-­documented dural attachments, while sparing the neighboring neural structures.91–93 These newer approaches in treatment planning have consistently improved Paddick’s conformity index,94 while reducing treatment times for GKR90,95,96 and for MML LINAC.95,97 To date, the recommended surface (SD), edge (ED), or peripheral (PD) doses for MNs range from 12 to 15 Gy at the 50% isodose; the higher levels are currently reserved for more aggressive histotypes.2,3 T1 contrast-­enhancing image plus a supposedly infiltrated margin of a few millimeters,3,98–102 to the controversial inclusion of the “dural tail” that—according to studies with extremely refined doses—should be essentially composed of hypervascular dura with none of the expected tumor colonies.3,103–105 Another deceptive variable in the definition of the target volume is represented by hyperostosis,3,106,107 particularly after the studies of Pieper et al.107 showing that (in a series of 26 consecutively operated patients)

TOMOTHERAPY Helical tomotherapy unit is a new modality for radiation treatments, the first dedicated to intensity-­modulated irradiation using a fully integrated image-­guided radiotherapy machine with on-­board megavoltage CT capability. The tomotherapy system (see Fig. 95.3D) uses a 6-­megavoltage accelerator and a binary. Radiation is delivered in a helical way, obtained by concurrent gantry rotation and couch/ patient movements. Tomotherapy has been used for the treatment of benign brain tumors (MNs and neurinomas),

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Section Five  •  STEREOTACTIC RADIOSURGERY

A

B

C

D

E FIGURE 95.3  Current stereotactic radiosurgery options: Edge Radiosurgery System Varian Medical Systems (A); Elekta Unity with Philips MR technology (B); CyberKnife System from Accuray (C); Tomotherapy from Accuray (D); Leksell Gamma Knife Icon-­Elekta (E). (Images courtesy of Elekta.)

hyperostotic bone was almost always present (25/26 cases), even where there was no evidence from imaging. In these cases, ablative radiosurgery on the hyperostotic bone might have the same meaning as Simpson’s grade 1 in surgical approaches. As mentioned previously, the novel and impressive advances in radiosurgical treatment strategies, particularly coregistration and fusion algorithms dose-­ planning software, and automatic positioning systems are helping to overcome some of the major constraints of SRS, and specifically GKR. We can reasonably target unusually larger volumes, even in crucial sites, by using lower dosages or by performing “staged” SRS procedures, via means of dose and/or volume fractionation.108,109

Published results are interesting, and there is no evidence of increased adverse radiation effects (AREs).26,108,109 In fact, the well-­known relationship between the dose-­volume integral and the risk of AREs does not seem to apply at lower-­ dose regimens.26,36,110,111 Nonetheless, in MN treatment, relevant limits, pitfalls, and risks remain to be tackled. An instructive example is represented by dosimetry planning for cavernous sinus MNs. The dose heterogeneity of these treatments usually requires an extremely careful evaluation of dose-­distribution algorithms,112–114 because of the occasional reported cases of radio-­induced vascular injury to the carotid arteries,112–114 and because of the morbidity that is still observed with this technique on sensory nerves,25 and

95  •  Stereotactic Radiosurgery Meningiomas

also because of the sometimes disappointing results in atypical and anaplastic lesions.2,25 Finally, a controversial issue in treatment planning is the so-­called “radiation-­induced meningiomas.”68,115–116 These tumors usually appear at variable intervals from radiation exposure, depending on the dose and timing. They are often deep seated, multifocal in 4.6% to 18.7% of the cases.115–116 Surgical resection is considered to be the best therapeutic option. However, when dealing with frail patients or with particularly crucial locations, radical surgery may be too risky, opening the question on the SRS alternative. The published literature is rather scanty.68,116 Eligibility criteria (limited volume, well-­defined imaging, etc.) adopted in these cases do not differ from standard protocols. Clinical-­radiologic results—particularly the LTC (75% to 78%) and the 5-­year PFS (similar)—are satisfactory, and only slightly inferior to the published data regarding regular MNs. Morbidity remains low (5%) with no reported cases of newcarcinogenesis.68,115–116 

Radiobiology Radiosurgery, like most radiation treatments, results in the formation of free radicals as electrons are freed from their atoms. Their main biological effect occurs at the DNA level: The transfer of energy results in breaks in the DNA strands (direct effect). Additional radiation damage to the DNA is mediated through reactive species of water (indirect effect). Whenever single-­strand breaks occur, the aberrations are of little eventual consequence, because the breaks are easily repaired. To the contrary, double-­strand breaks or chromosome breaks with the “sticky ends” rearranging and rejoining in grossly distorted, nonviable formations can lead to lethal aberrations (mutagenesis) and/or cell death. The number of lethal aberrations and subsequent killed cells is closely related to several conditioning factors: the specific oncotype and a complex series of cellular parameters (“alpha-­beta ratio,” superoxide-­ enzyme characterization, etc.) defining the specific radiosensitivity, the radiation dose, the TV, and the microscopic model of energy deposition. On the basis of these features, MNs mostly belong to relatively radiosensitive, late-­responding tissues. Effective dosages are in the lower range, not far from normal-­cell thresholds, while the time interval for the effect is close to the maximum in vivo doubling time.117–121 Moreover, all kinds of ionizing radiations are currently identified, not only according to dose level but also to characteristic pattern of energy transfer and consequent relative biological effectiveness (RBE).122 Linear energy transfer (LET) is defined as the average energy that is locally delivered by a particle in an absorbing medium divided by unit length of the crossed distance. Larger particles are correlated with higher LET values, with increasing ionization density and greater RBE. Some of the main reactive molecules produced by radiation beams (i.e., ion pairs and free radicals) are superoxide compounds with unpaired valence electrons, which break DNA-­protein chemical bonds. Therefore, in most cases the permanent effect of this free radical-­mediated injury is dependent on the presence of oxygen. When tumor cells rapidly divide, they outgrow their vascular supply and become chronically hypoxic. With increased LET beams, this close dependence on oxygenation for biological effect decreases. By contrast, low-­LET

1109

sources such as x-­rays and gamma-­rays rely significantly on local oxygen levels for their biological effect. Hence, the importance sometimes associated with the radiosurgically typical dose inhomogeneity that may compensate for this disadvantage is the hot spot in the “core” of a tumor, which may be desirable for several reasons. First, it offsets the relative protection offered by the poor oxygenation of the tumor core; second, it may increase the cell kill around the hot spot due to the “penumbra effect.” Fractionated radiation results in the distribution of lethal and sublethal effects within a wider targeted field. By contrast, the typically small targeted size and sharp dose fall-­off of radiosurgery allows the delivery of high radiation levels to a limited area. In SRS, the use of a single dose results in a higher incidence of lethal damage to cells, enhancing the biological efficacy of the beam. Additional factors may explain the spectrum of responses: (1) rate of cell proliferation, resulting in increased sensitivity of endothelial, glial, and subependymal plate cells; (2) vascular obliteration also seems to play a role in the death of tumor cells; and (3) due to the steep dose gradient at the margin of the target volume, normal tissue is exposed to lower levels than the target periphery, and this explains why SLD is of little concern. 

Radiosurgery Treatment Outcomes LONG-­TERM RESULTS Microsurgery is still the gold standard in the treatment of MNs. However, the actuarial 10-­and 15-­year local PFS rates for WHO grade I MNs after complete microsurgical resection (GTR) (Simpson grade I/III) have been reported to be 61% to 80% and 40% to 76%, respectively, and after STR (Simpson grade IV/V) 0% to 48% and 9% to 32%, respectively. After 20 years, the overall PFS dropped down to 43% after GTR and 32% after STR.123–125 Furthermore, if critical locations such as SBMs are considered, despite tremendous advances in neurosurgical technique and equipment, the incidence of postoperative permanent cranial nerve deficits has been reported to be as high as 56% and mortality rates as high as 9% (median, 3.6%) have been reported.126 During the last two decades, SRS has become an attractive alternative to microsurgery in selected cases. However, the length of follow-­up is an important criticism to the results achieved with SRS on MNs, particularly in cavernous sinus and other skull base MNs. In the 6th Edition chapter on SRS MNs, we reported the results of short to intermediate follow-­up interval studies—usually within 7 years mean observation period—because there were very few scientific articles reporting clinical and radiological outcome with longer observation periods. Actually, many studies described excellent short to intermediate period results with actuarial 5-­and 10-­year LTC rates ranging from 86% to 100% and from 69% to 97%, respectively,26,27,33,34,113,127–137 associated with very low rates of permanent symptomatic AREs/neurological toxicity (usually no severe complications) (6.0% to 17.9%),126 and no mortality. Since 2012, several studies dealing with outcomes of SRS over a 10-­year interval have reported long-­term results. Therefore, it is now possible to evaluate on large series of patients treated for benign (WHO grade I) intracranial MNs whether these favorable results in terms of LTC and neurological performance are maintained

1110

Author

Type of Study

# Pts.

Location

Mn/Md FU (Mos.)

Mn/Md TTV (mL)

Mn/Md PD (Gy)

Park K-­J, 2018, GK140

Retrospective analysis

200

GI CSMNs

101.0 Md

7.5 Md

13.0 Md

McClelland III S, 2018143

Systematic review

1.431

—

≥6 years

10 mL • A./S. SRS • Prior RT • GII/III • TTV >10 mL • A./S. SRS — • P  ./A. SRS • GII

A., Adjuvant SRS; CNs, cranial nerves; CSMNs, cavernous sinus meningiomas; FNO, favorable neurological outcome; FPPRT, fractionated proton photon radiation therapy; FU, follow-­up; Im.O., imaging outcome; Impr., improved; LTC, local tumor control; Md, median; Mn, mean; MNs, meningiomas; Mos., months; MS, microsurgery; MT, malignant transformation; Ne.O., neurological outcome; Ov., overall; P., primary SRS; PD, prescription dose; Perm. Symp. ARE, permanent symptomatic adverse radiation effect; Pts., patients; RT, radiation therapy; S., salvage SRS; SBMNs, skull base meningiomas; single-­Fx, single fraction; TTV, target treated volume.

Section Five  •  STEREOTACTIC RADIOSURGERY

TABLE 95.1  Stereotactic Radiosurgery Long-­Term Results for Intracranial Meningiomas: Summary of Literature

95  •  Stereotactic Radiosurgery Meningiomas

beyond 10 years after SRS and prove durable, with the aim of further consolidating the effectiveness and safety of this treatment for intracranial MNs (Table 95.1). Kondziolka et al.138 published a retrospective study on 290 consecutive patients treated with GK SRS for a MN (70% of them skull base located and 97% WHO grade I or with typical imaging features of a benign MN) between 1987 and 1997. The median tumor margin dose was 15 Gy and the median TV was 5.5 mL. Follow-­up imaging was available in 287 patients. The overall LTC rate was 91%. The 10-­and 20-­year actuarial rates of freedom from tumor progression of the targeted tumor after SRS was 85.3% ± 2.9% at both timepoints. They found no difference in long-­term LTC rates between patients who had undergone craniotomy before SRS (89%) and patients who underwent primary SRS (93.1%). The authors found that factors associated with a worse progression-­free survival included prior RT (P < .0001) and higher-­grade MN (P < .0001). Neurological outcomes were assessed in 268 patients. Of 234 patients who had symptoms before SRS, 26% improved and 54% had no change in symptoms. In their experience, the actuarial rate of freedom from symptom worsening was 73.3% ± 3.8% at both 15 and 20 years after SRS. No malignant transformation (MT) was identified in the six patients who underwent surgical resection following imaging-­ defined tumor progression after SRS. The authors concluded that SRS provides durable tumor control with low morbidity in MN patients. Furthermore, they wrote that their data suggested that tumor growth or symptom deterioration will present early in follow-­up and that long-­term outcomes after SRS for MNs are stable and favorable. Correa et al.139 carried out a retrospective cohort case study to evaluate the long-­term symptomatology, the image findings, and the toxicity on 32 patients with WHO grade I CSMs treated with SRS and compared them with 57 cases affected with larger than 3-cm-diameter benign MNs, with a volume greater than 14 mL, or very close to the visual pathways, treated with stereotactic RT using a 6 MV linear accelerator. The median single dose of SRS was 14 Gy and the median TV 6 mL. This study showed that the 15 years corresponding disease-­free survival rates was 90.3% both for the group treated by SRS and for the stereotactic RT group. During the long-­term period of observation, no severe complications were seen in the whole studied population (7% of the patients presented transient optic neuropathy, two patients had trigeminal neuropathy and improved rapidly, and one patient presented total occlusion of the internal carotid artery without neurological deficit: always grade 2 according to the Common Toxicity Criteria). Following the SRS/stereotactic RT treatments, no radiation-­ induced malignancies were noted during the 15-­year follow-­up. Similar results were obtained in the 57 patients treated with stereotactic RT. The authors concluded that as a result of their long-­term retrospective study, SRS and fractionated stereotactic RT were equally safe and effective in the management of symptomatic CSMs. In a retrospective single-­ center study,123 the Cologne team reported 148 patients with 168 typical intracranial MNs who underwent LINAC-­SRS and with an overall mean radiological follow-­up of 12.6 years. SBMs were 66% of the whole series. The median tumor surface dose was 12 Gy and the median target volume was 4.7 mL. The authors reported an overall LTC rate of 95.2% for all treated MNs with an estimated actuarial LTC rate after

1111

15 years of 93.6 %. The actuarial 15-­year PFS for nonoperated patients was significantly better than for MNs that were irradiated adjuvantly or as salvage treatment (92% vs. 86%). Target treated volume and choice of treatment time revealed to be prognostic factors for tumor progression: small TV (12 Gy ≤12 Gy

0.0% 0.0% 0.0% 1.1% Incr. Risk Incr. Risk 0.0%

AVP, Anterior visual pathway; RION, radiation-­induced optic neuropathy.

and more sophisticated treatment planning systems has allowed the increase of the tolerated dose exposure level to AOPs after SRS to ≤12 Gy. In fact, on the basis of recent studies, the risk of causing a radiologically induced optic neuropathy becomes significant with exposures of the optic nerve beyond 10 to 12 Gy (Table 95.2),192–197 a limit that is difficult to respect, especially in Schick stage 1a and 1b ONSMs. This is the reason why “multisession” SRS treatment, which integrates the advantages of fractionated radiotherapy (greater therapeutic index due to the different responses to fractionated radiation on the part of normal versus tumor tissue) with those of single-­session SRS (excellent precision, very high levels of conformation, and steep dose falloff) has been administered particularly to these patients during the last decade.40 In sum, several different alternatives have been recommended and used with rather successful results, including fractionated GKR95 or CyberK nife7,29,31,38 procedures, fractionated STR, proton-­photon therapy, and Perfexion-­guided hybrid shots.174 These treatments allow high radiation doses to be delivered during each session while keeping the risk of radiation toxicity to healthy surrounding tissues low.198 The ultimate goal of this innovative approach is to bring up the biologically effective radiation dose delivered to the tumor while keeping radiation reaching surrounding critical structures as low as possible.199 It is common for “multisession” radiosurgical treatments to be planned as 2 to 5 sessions, one every 12 or 24 hours, reaching a surrounding average cumulative median dose of around 20 Gy, according to the various published studies. Because the management of these patients is delicate and complex, the optimal treatment for para-­and perioptic MNs is still under discussion. In cases of incidental and asymptomatic ONSMs, various authors recommend conservative treatment.182,183,185 However, this approach is criticized by others because the slow but progressive evolution of these tumors relentlessly leads to visual deterioration and blindness.184 Andrews et al.188 compared visual function in a group of 20 patients with ONSMs subjected to fractionated radiotherapy (1,8 Gy/fraction X 28 fractions = 50 Gy cumulative dose) and a group of 18 patients who had preserved visual function at the time of evaluation and had conservative treatment. The study showed a significantly greater loss of vision in the group under observation compared to the group that received radiotherapy. (P = .0086). The goal of treatment of ONSMs should be control of tumor growth while preserving visual function.39,184 With this in mind, surgery would seem particularly problematic, given that the

risk of visual impairment and/or other permanent side effects is greater than 20%.183,184 In a series of 50 patients operated for ONSM, Margalit et al. reported at 6-­month follow-­up a worsening of visual acuity loss in 20% of cases, a worsening of visual field impairment in 18% of cases, permanent impairments of other cranial nerves in 6% to 8% of cases, and other permanent complications in 16% of cases.200 Furthermore, recurrence following surgical treatment alone is reported to take place in 25% of cases of ONSMs subjected to surgery.183,184 As a consequence, surgery is only considered an option in cases in which vision is already seriously compromised, in cases with large tumors, severe exophthalmos, or intracranial extension of the ONSM with diffusion into the contralateral optic nerve.39,182,184,188 Following the positive results obtained with intracranial MNs, fractionated radiotherapy started to be applied to ONSMs at the beginning of the 1990s,201 associated with surgery (adjuvant treatment) or as an alternative to surgery (primary treatment). This approach was shown to be effective in terms of LTC and in terms of visual acuity, which was either kept stable or was improved, but less so in terms of other neuro-­ ophthalmologic impairments (visual field deficits, diplopia, exophthalmos).182,184,185,188 However, the positive results did not persist in the long term and the occurrence of side effects such as radio-­induced optic neuropathy and retinopathy, or radionecrosis, have led to RT being replaced by novel radiation techniques which are highly conformational, like RT stereotactic fractionation, intensity-­ modulated radiotherapy (IMRT), etc. Thus, following this trend and considering the significant advantages that had already been described, SRS came into wide use for this kind of tumor. The literature reports more than 200 cases of ONSM treated with SRS, of which 2/3 received treatment as a single session and the rest as “multisession” treatment. LTC is high in all clinical series (75% to 100%). In GK series, LTC is 85.5% to 100%, without any significant difference between single session and “multisession” treatment regimens (Table 95.3). From the clinical perspective, however, the best ophthalmological results were found in patients treated with the “multisession” approach, with a stabilization or an improvement of visual acuity in 100% of cases in two GK series.39,40 Marchetti et al.41 reported 21 patients with ONSMs treated using frameless CyberKnife system multisession radiosurgery, with 5 fractions of 5 Gy each to a total dose of 25 Gy prescribed to the 75% to 85% isodose line. The median pretreatment TV was 2.8 mL and the mean follow-­up was 30 months. At the end of the study, no patients showed ONSM

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Section Five  •  STEREOTACTIC RADIOSURGERY

TABLE 95.3  Stereotactic Radiosurgery and Hypofractionated Stereotactic Radiosurgery for Peri-­and Paraoptic Meningiomas: Summary of Literature

Author Jin J,

2018202

Device IMRT (10 Pts) GK (3 Pts)

Mn/Md FU (Months)

# Pts

Mn/Md TTV (mL)

50.0 Md

13

2.1 Mn

Nicolato A, 201737

GK: 3 Ses (5–7 Gy/Ses)

37.5 Mn

180

6.29 Mn

Marchetti M, 201642

CK: 3–5 Ses

44.0 Mn

143

8.0 Md

Jo K-­I, 2012

GK: 4 Ses

38.0 Md

9

2.8 Md

Marchetti M, 201141

30.0 Mn

21

2.8 Md

34.5 Md 56.0 Md

84 30

5.1 Mn 3.6 Me

Kim J-­W 200840

CK: 5 Ses (5 Gy/Ses) GK: 1 Ses GK: 21p, 1 Ses 9p, 2 Ses GK: 3–4 Ses

29.0 Mn

13

4.7 Mn

Pham CJ, 2004199

CK: 2–5 Ses

26.0 Md

20

6.2 Md

Xu D, 2010290 Liu D, 2010183

Neurol. Impr./ Stab. (%)

Treat. Rel. Perm. Morb. (%)

Mn/Md PD (Gy)

Ov LTC (%)

IMRT: • 50 Gy/25 Fx GK:

100.0

75.0 (Impr. 33.3)

30.0 (3/10) (all IMRT)

95.5

95.5 (Remained w/o deficit or Impr. 86.0) 92.5 (Impr. 36.0) 100.0

4.5

100.0 (Impr. 57.0) Most Pts. 80.0 (Impr. 37.0) 100.0

0.0

90.0 (Impr. 25.0)

0.0

• 5  Gy 50%/3 Ses. • 6.5 Gy 50%/3 Ses. • 12 Gy 50%/1 Ses. MnCPD 19.5 (50%) MdCPD 25 (80%) MdCPD 20 (50%) MdCPD 25 (80%) 13.0 Md 13.3 Mn

95.0

MdCPD 20 (50%) MnCPD 18 (80%)

100.0

100.0 100.0 95.0 93.0

90.0

5.1 0.0

? 20.0 0.0

CK, Cyberknife; FU, follow-­up; Md, median; MdCPD, median cumulative prescription dose; Mn, mean; MN, meningiomas; Neurol. Impr./Stab., neurological improvement/stabilization; Ov. LTC, overall local tumor control; PD, prescription dose; Pts, patients; Ses, session; SRS, stereotactic radiosurgery; Treat. Rel. Perm. Morb., treatment related permanent morbidity; TTV, target treated volume.

progression and no patients had worsening of visual function or other toxicity-­ related impairments. A few years later, however, in a further study of the same group in a larger series of cases (143 patients) with MNs involving the AOPs and treated similarly, with longer follow-­up periods (mean, 44 months) and larger pretreatment TV (median, 8 mL), the PFS decreased (93% and 90% at 5 and 8 years, respectively) and visual function worsened in 5.1% of cases.42 Our team participated in the multicenter study of the Italian Gamma Knife Study Group for the treatment of MN close to anterior optic pathways or involving the ONS.37 Indications for stereotactic hypofractionation approach were as follows: histopathology or clinical and neuroimaging features consistent with MNs close to the AOP or with direct optic sheath invasion or anterior SBMNs exceeding 15 to 20 mL. From February 2006 to December 2014, in 5 GK Italian centers, 180 patients underwent stereotactic hypofractionation treatment following a protocol including 3 GK SRS daily hypofractionating treatments (1 session/24 hours; 5 to 7 Gy/session) and they were followed up for at least 2 years (mean follow­up, 37.5 months). Mean gross target volume (GTV) was 6.29 mL and mean cumulative prescription dose was 19.49 Gy according to GTV and AOP involvement. The overall LTC was 95.5% and in 4.5% of patients new visual deficits appeared or previous complaints worsened. The authors concluded that GK SRS hypofractionation approach seems to be a safe and effective therapeutic option in selected patients with AOP close-­fitting lesions and with ONS MNs

as well as in cases with MNs larger than 15 to 20 mL. Finally, Jin J. et al.202 followed for a median time of 50 months 13 patients with ONSM. Ten patients were treated by IMRT (50 Gy in 25 fractions) while three patients underwent GK SRS (5 Gy in 3 fractions at the 50% isodose line in one patients, 6.5 Gy in 3 fractions at the 50% isodose line in another patient, and single-­fractionation dose of 12 Gy at the 50% isodose line in the last one). The overall reported LTC was 100%, but visual acuity deteriorated in 25% of cases, all of them treated with IMRT. At the end, the authors concluded that IMRT and GK SRS could maintain visual acuity and stabilize TV in ONSM patients, suggesting that IMRT and GKS may be effective therapies for ONSM. To conclude, SRS has been shown to be an effective and safe therapeutic option for selected cases of para-­ and perioptic MNs, as an alternative to or combined with surgery. The introduction of the “multisession” modality has permitted a further reduction of the risk of complications while maintaining a high efficacy on LTC especially for lesions, like ONSMs which develop an intimate anatomical relationship with the AOPs. 

COMBINED MS–STEREOTACTIC RADIOSURGERY APPROACH FOR MENINGIOMAS A “combined microsurgical-­SRS approach in MNs” consists of a deliberate incomplete surgical resection, leaving a remnant near critical structures, followed by SRS. This can reduce the morbidity of treatment without affecting tumor

95  •  Stereotactic Radiosurgery Meningiomas

control.203 MNs are often histologically benign tumors,204 but their complete resection may be difficult because of their location. A partial resection increases the risk of tumor recurrence.205 The residual tumor must therefore be controlled by other therapeutic options. In cases of atypical of anaplastic MNs, adjuvant radiotherapy must be considered as a treatment option in oncological multidisciplinary discussion, regardless of the extent of resection.206,207 Concerning grade 1 MNs, because of their slow growth, only radiological monitoring is often performed after incomplete resection. Complete resection can be achieved in many cases, for MNs of the convexity, but rarely in cases of parasagittal MNs or skull base MNs208 as seen before. Cavernous sinus, Meckel cave involvement for skull base, or superior sagittal sinus invasion for parasagittal MNs does not allow a complete surgical resection, or makes it very dangerous.209 Current strategies include performing a large resection of the tumor and then performing SRS on the residual tumor located in the critical area. This surgical procedure is precisely defined by the neurosurgeon and by the patient to reduce morbidity. As seen in this chapter, GKR is a reliable technique, which has already demonstrated its effectiveness regarding tumor control of intracranial MNs (both grade I and grade II), with a low rate of side effects. Many authors recommend to perform an early postoperative GKR for patients with grade 1 MN when surgical resection is incomplete.26,34,127–134,138 Patients with high-­grade MN should be treated with early postoperative radiotherapy. The combination of surgery with radiosurgery is nowadays used by many neurosurgical teams for the treatment of intracranial MNs located on the skull base,146,210,211 and in some centers this strategy is decided with the patients before surgery.211 Several studies have shown tumor progression of untreated MNs and remnants of MNs for which monitoring was decided, even after Simpson 1 resection.128 Early SRS after surgical resection seems to prevent tumor progression in grade 1–grade 2 MNs, while in high-­grade MNs conventional radiotherapy must be considered.212 

INCIDENTAL MENINGIOMAS Incidental MNs are increasingly being diagnosed due to extensive use of brain imaging. Treatment options include surveillance, surgery, and SRS, but the natural history of these tumors is not fully understood.213 The reported incidence of tumor growth in the literature ranges from 0% to 37%. Concerning tumor growth speed, some studies found a tumor growth rate of 2.4 mm per year, others a mean growth rate of 0.796 cm3 per year (range 0.03 to 2.62 cm3/year), resulting in a 14.6% increase in volume per year and a mean tumor-­doubling time of 21.6 years.117,214 Others described a growth rate of 1.9 mm/year, calculated using the maximum tumor diameter.215 Factors reportedly related to the growth of asymptomatic MNs include: advanced patient age, a hyperintense lesion on T2-­weighted MR images (calcifications), and/or calcification.216 Considering surgery, there is no attitude in early intervention of such patients, because of morbidity (even if it is considered low −6.6%). Studies reported in the literature recommend close follow-­up by using neuroimaging and clinical monitoring, in particular for tumors that present as hyperintense regions on T2-­weighted MR images, and for tumors located

1119

near important anatomical structures in younger patients. An MRI scan at 3-­month intervals to check if the lesion is malignant and again at 6-­month intervals to detect tumor growth is recommended.215 With the use of SRS spreading extensively, treatment must be decided on the basis of the tumor’s natural history and location. Skull base tumors (in particular posterior fossa and cavernous sinus) must first be considered for early radiosurgery, and the same applies to convexity MNs with a maximal diameter inferior to 2 mm.217,218 

INTRAVENTRICULAR MENINGIOMAS MNs growing within the ventricular system are rare, and probably originate from arachnoidal “buds” partially embedded in the choroid plexus.219,220 Incidence has been reported as the 0.5% to 3.7% of all intracranial locations.219–221 The rationale for primary SRS, as in several other instances, is closely related to the limitations and morbidity that frequently characterize radical removal of these lesions. However, as recently reported,222 with the combined use of the most sophisticated operative techniques (advanced neuronavigation, third-­ generation ultrasonic aspirator, and molecular coagulation), total excision of these deep-­seated and usually highly vascularized tumors may be safely accomplished. It should be emphasized that when planning primary SRS and dealing with “imaging-­defined” lesions, it is extremely important to have a reliable diagnosis. Current strategies include a clearly defined picture via MRI—typical site and morphology, homogeneous contrast enhancement, and hyperintense signal on T2-­ weighted images219—and a spectrum MRI analysis. However, SRS has been used in adjuvant protocols on surgical residual or—as an alternative to surgery—in recurrences. Considering the very peculiar localization of the target—surrounded by variably thick, CSF films—higher than usual prescription doses (>20 Gy) had been used before 1995.223 The most recent literature has shown that reduced dosages (12 to 15 Gy) can obtain the same satisfactory results, while decreasing undue neurologic risks.24,29 

NEUROFIBROMATOSIS-­2–ASSOCIATED MENINGIOMAS NF2 is an autosomal dominant condition typically characterized by the development of bilateral vestibular schwannomas (VSs), ependymomas, and MNs. Regarding radiosurgery, two-­thirds of NF-­2 patients will develop multiple MNs.224 The treatment of enlarging or symptomatic NF2-­associated MNs is not well-­defined. In cases of small asymptomatic MNs, observation could be an option. As patients with multiple MNs will require some kind of intervention over many years of disease, a nonsurgical approach is preferred in order to avoid too many invasive procedures. The use of radiation for patients with NF2-­associated tumors is still under discussion. Some authors report that GKRS may not be as effective in halting the growth of NF2-­associated VS compared to sporadic VS.225 Others found a lower rate of tumor control in NF-­2 associated MNs compared to sporadic ones.134 There is also a suggestion that NF-­2 mutations could lead to a higher risk of MT.226 Even if MNs represent over half of the tumors seen in NF-­2 patients and MNs are the most commonly treated benign intracranial tumors, there are very few reports that specifically address the radiation treatment of these tumors in this population.227 LTC after

1120

Section Five  •  STEREOTACTIC RADIOSURGERY

SRS is reported to be between 92% and 96%. Side effects are manageable even with multiple treatments. For NF2 patients who developed distant progression and required repeat treatments elsewhere intracranially, secondary GKRS appeared safe as a retreatment option for de novo enlarging MNs.134,225–228 

STEREOTACTIC RADIOSURGERY RETREATMENT In some cases radiosurgery fails and further treatment is essential for tumor control. In these GKRS failure cases, re-­radiosurgery can be an option. However, the choice for the best treatment plan is still debated including observation, repeated surgery, or re-­radiosurgery. The role of re-­ radiosurgery is still controversial. The rate of irradiation is approximately 3% to 5% in the literature.229 Obviously WHO grade II/III MNs have worse PFS than grade 1 after irradiation. Wojcieszynski et al. reported on 19 reirradiated MNs with a median PFS of 57 months for grade 1 versus 8 months for grade 2/3. Other groups reported on 33 recurrent MNs reirradiated using SRS with a median PFS of 60 months for grade 1 versus 12 months for grade 2/3.230,231 Literature results encourage reirradiation as a salvage option for relapsed grade 1 MN after prior RT. For grade 2/3 MNs a simple dose escalation does not seem adequate to overcome the radiation-­resistant nature of recurrent grade 2/3 MNs after prior RT, and novel approaches need to be considered such as strategies combining reirradiation with immunotherapy.229 In WHO grade 1 MNs, second irradiation had an 8% response rate, which is certainly lower than the 40% to 60% response rate in most series on the first course of RT for grade 1 MNs.124 Some groups reported in the literature that grade 2/3 MNs were more likely to have radiologic responses than grade 1 MNs during the first course of RT.232 SRS is the best choice for reirradiation, particularly for smaller tumors. The particular features of SRS, such as the sharp dose falloff of SRS in a previously irradiated brain—while enabling delivery of high-­dose RT to the tumor—are preferred in many institutions.233 Although physicians may not recommend reirradiation because of delayed toxicity, a second treatment of selected recurrent MNs should be feasible with acceptable rates of symptomatic RN. Overall, grade 2 or higher RN incidences between 15% and 21% have been reported across multiple studies.230,231,234–235 A meta-­analysis on reirradiation of the brain suggests that the RN risk is low if the cumulative EQD2 is less than 100 to 120 Gy.236 In conclusion, re-­radiosurgery might be recommended for patients with unknown or benign MNs if their first SRS result is unsatisfactory. However, re-­radiosurgery should be considered with caution for recurrent high-­grade tumors.

Adverse Radiation Effect The variable (2.6% to 9.6%)84,237 occurrence of these AREs is essentially a function of the dose–volume integral, only marginally modulated by individual radiosensitivity thresholds.108,126,238 As a consequence, in most treatment protocols, large tumors have been receiving lower doses than the smaller ones.239–242 According to a broadly accepted notion, targets exceeding 3 to 3.5 cm in diameter and 14 to 22.5 cm3 in volume should never be treated by SRS. Violations of these principles might in time trigger the multistep

process of AREs, starting with the formation or the worsening of perifocal edema, followed by the focal vasculopathy and by other, more severe sequelae. 

Peritumoral Imaging Changes “Satellite” edema, particularly common in the parasagittal or in the convexity region, is the dominant feature—together with minor vascular sequelae—in the early stages of the peritumoral imaging changes. There have been reports showing the influence of the dose–volume factor in determining the severity and the timing of these processes, at least in standard dosimetry protocols.243–246 However, recent reports show that it is possible to maintain an adequate LTC without increasing side effects239,247,248 by treating larger MNs with reduced doses. According to Ganz et al.,113,249,250 at least in WHO grade 1 MNs, the straightforward relation between the dose–volume integral and the incidence of AREs may be too simplistic for lower-­dose protocols.108,109 Furthermore, the predominance of PRICs and AREs following SRS in non–skull base MNs compared with basal tumors observed in patients treated with GKS,84 MML-­LINAC,97 and CyberKnife,30 might be strictly dependent on the prescription dose adopted, becoming irrelevant at reduced dose regimens.108,109 

Vasculopathy–Radiation Necrosis These neuropathologic entities represent the next steps of the worsening AREs sequence, occurring in 1.5% to 4.6% of cases during mid-­to long-­term follow-­up.251 The typical process is comparable to the parenchymal multistep damage described in irradiated arteriovenous malformation (AVM) by Nataf et al.,251 including the specific radiation-­tolerance limits of neural tissue.252 The final pathophysiology of the radionecrotic stage is still poorly known. In a minority of cases, an obvious, solid fibromatous nodule further increases the edema—presumably related to vascular permeability factors. Surgical removal of the nodule is usually the most appropriate solution.253 

Cranial Neuropathy The various cranial nerves are characterized by a wide spectrum of radiosensitivity. As a rule, special sensory nerves— and especially their primary receptor fibers—such as those belonging to the cochlear (radiation threshold on 10 to 15 mm3 in single fraction, 5 to 6 Gy)254 and to the optic nerve (same landmark, 8 to 9 Gy)38,192,195 can easily be damaged. Somatic motor nerves like the oculomotor usually tolerate dose exposures superior to 20 Gy.25,192,255 

Other Effects Rare to extremely rare putative radiosurgical sequelae include persisting headache (2.5%),84 seizures (7%),84 and normal pressure256 or hypertensive84 hydrocephalus (1%). In the few reported cases of ventricular dilatation, the trigger mechanism is reminiscent of VS–related hydrocephalus, with an increased albumin concentration in the CSF.84,256 

PROGNOSTIC FACTORS Dose and Volume As extensively described in this chapter, SRS can be used both primary or adjunct to surgical resection of MNs of all grades, providing PFS rates compared to Simpson grade I

95  •  Stereotactic Radiosurgery Meningiomas

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TABLE 95.4  Summary of Prognostic Factors in the More Recent Literature Studies on Neurosurgical Resection and Stereotactic Radiosurgery for Intracranial Meningiomas Literature Group

Prognostic Factors

Significance (P)–Multiv.

Mansouri et al., 2015 (ARE)259

Prescription dose (Gy) CI RTOG Tumor volume ratio Conformity index Age Sex (male vs. female) Tumor vol (>10 vs. ≤10 cm3) Tumor location (parasagittal vs. falx) Prior resection (yes vs. no) Venous sinus invasion (no vs. yes) Brain edema prior to SRS (no vs. yes) Margin dose Maximum dose Age Gender Tumor volume Pre-­treatment edema Prescription dose Prescription isodose line Maximum dose Tumor coverage Homogeneity Conformity index Gradient index Grade (more than1 ) Larger target volume, Lower KPS, Recurrence after RT