Intracranial Arteriovenous Malformations: Essentials for Patients and Practitioners [1 ed.] 0323825303, 9780323825306, 9780323825313

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Intracranial Arteriovenous Malformations Essentials for Patients and Practitioners

Intracranial Arteriovenous Malformations Essentials for Patients and Practitioners Philip E. Stieg, PhD, MD

Margaret and Robert J. Hariri, MD ’87, PhD ’87 Professor and Chair of Neurological Surgery Weill Cornell Medicine Neurosurgeon-in-Chief NewYork-Presbyterian/Weill Cornell Medical Center New York, New York, United States

Alexander A. Khalessi, MD, MBA

Chair of Neurological Surgery Professor of Neurological Surgery, Radiology, and Neurosciences Don and Karen Cohn Chancellor’s Endowed Chair University of California San Diego La Jolla, California, United States

Michael L.J. Apuzzo, MD

Adjunct Professor of Neurological Surgery Weill Cornell Medical College New York, New York, United States Distinguished Adjunct Professor Department of Neurosurgery Yale School of Medicine New Haven, Connecticut, United States



ISBN: 978-0-323-82530-6 Copyright © 2024 by Elsevier, Inc. All rights reserved. Brian M. Howard for chapter 13, Surgical Principals: Techniques/Goals/Outcomes: Copyright for images. 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).

Notice Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors 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.

Content Strategist: Humayra R. Khan Senior Content Development Specialist: Shweta Pant Publishing Services Manager: Shereen Jameel Senior Project Manager: Beula Christopher Design Direction: Ryan Cook Printed in India Last digit is the print number: 9 8 7 6 5 4 3 2 1

Contributors S. Uzair Ahmed, MD Clinical Instructor Department of Neurosurgery and the Stanford Stroke Center Stanford University School of Medicine Stanford, California, United States

Yahya B. Atalay, MD Assistant Professor of Clinical Neurology Weill Cornell Medical College Attending Neurologist NewYork-Presbyterian New York, New York, United States

Felipe C. Albuquerque, MD Director, Endovascular Surgery Department of Neurosurgery Barrow Neurological Institute Phoenix, Arizona, United States

Muhammad Abubakar Ayub, MBBS Resident Physician Department of Neurology LSU Health Shreveport Shreveport, Louisiana, United States

Arun Paul Amar, MD Director of Endovascular Neurosurgery Department of Neurosurgery University of Southern California Chief of Neurosurgery and Stroke Director Department of Neurosurgery LAC+USC Medical Center Los Angeles, California, United States

Mohammad A. Aziz-Sultan, MD, MBA Chief of Vascular/Endovascular Surgery Brigham and Women’s Hospital Associate Professor of Neurosurgery Harvard Medical School Boston, Massachusetts, United States

Abdelaziz Amllay, MD Postdoctoral Research Fellow Department of Neurological Surgery Thomas Jefferson University Philadelphia, Pennsylvania, United States Joseph P. Antonios, MD, PhD Resident Physician Department of Neurosurgery Yale School of Medicine New Haven, Connecticut, United States Michael L.J. Apuzzo, MD Adjunct Professor of Neurological Surgery Weill Cornell Medical College New York, New York, United States Distinguished Adjunct Professor Department of Neurosurgery Yale School of Medicine New Haven, Connecticut, United States

Guilherme Barros, MD Resident Physician Department of Neurological Surgery University of Washington Seattle, Washington, United States Daniel L. Barrow, MD Pamela R. Rollins Professor and Chairman Department of Neurosurgery Emory University School of Medicine Atlanta, Georgia, United States Antonio Bernardo, MD Professor of Neurosurgery Department of Neurological Surgery Weill Cornell Medicine New York, New York, United States Srikanth Boddu Assistant Professor of Radiology in Neurological Surgery Department of Neurological Surgery NewYork-Presbyterian Weill Cornell Medicine New York, New York, United States v

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Contributors

Divya S. Bolar, MD, PhD Assistant Professor Department of Radiology University of California San Diego La Jolla, California, United States

Milli J. Desai, MD, MHS, MAS Resident Physician Department of Obstetrics and Gynecology University of California San Diego La Jolla, California, United States

Justin M. Caplan, MD Assistant Professor of Neurosurgery Department of Neurosurgery Johns Hopkins University School of Medicine Baltimore, Maryland, United States

William Dodd, BS Graduate Research Assistant Department of Neurosurgery University of Florida Gainesville, Florida, United States

Joseph A. Carnevale, MD Chief Resident Physician Department of Neurological Surgery NewYork-Presbyterian Weill Cornell Medicine New York, New York, United States

David Dornbos III, MD Assistant Professor Department of Neurosurgery University of Kentucky Lexington, Kentucky, United States

Kate T. Carroll, MD, MAS Resident Physician Department of Neurological Surgery University of Washington Seattle, Washington, United States

Richard S. Dowd, MD, MS Resident Physician Department of Neurosurgery Tufts Medical Center Boston, Massachusetts, United States

Joshua S. Catapano, MD Resident Physician Department of Neurosurgery Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, Arizona, United States

Andrew Faramand, MD, MSc Research Fellow Department of Neurological Surgery University of Pittsburgh Medical Center Pittsburgh, Pennsylvania, United States

Ching-Jen Chen, MD Resident Physician Department of Neurosurgery University of Virginia Charlottesville, Virginia, United States

Ashley Fejleh, DO Staff Anesthesiologist Department of Anesthesiology University of California San Diego San Diego, California, United States

E. Sander Connolly Jr., MD Bennett M. Stein Professor Department of Neurological Surgery New York Neurological Institute Columbia University Irving Medical Center NewYork-Presbyterian New York, New York, United States

John C. Flickinger, MD Professor Department of Radiation Oncology University of Pittsburgh Radiation Oncologist Department of Radiation Oncology UPMC Presbyterian-Shadyside Pittsburgh, Pennsylvania, United States

Carlos A. David, MD Professor of Neurosurgery Department of Neurosurgery University of North Carolina School of Medicine Chapel Hill, North Carolina, United States

Justin F. Fraser, MD Associate Professor and Vice-Chair Department of Neurosurgery University of Kentucky Lexington, Kentucky, United States

Contributors

Robert M. Friedlander, MD, MA Walter E. Dandy Professor and Chair Department of Neurological Surgery University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania, United States Andrew L.A. Garton, MD Resident Physician Department of Neurological Surgery NewYork-Presbyterian Weill Cornell Medicine New York, New York, United States Moleca Ghannam, MD Resident Physician Department of Neurosurgery University at Buffalo, State University of New York Buffalo, New York, United States Alexandra M. Giantini-Larsen, MD Resident Physician Department of Neurological Surgery NewYork-Presbyterian Weill Cornell Medicine New York, New York, United States Jacob L. Goldberg, MD Chief Resident Physician Department of Neurological Surgery NewYork-Presbyterian Weill Cornell Medicine New York, New York, United States Michael Goutnik, MS Medical Student College of Medicine University of Florida Gainesville, Florida, United States Bradley A. Gross, MD Assistant Professor Department of Neurosurgery University of Pittsburgh Medical Center Pittsburgh, Pennsylvania, United States Trevor Hardigan, MD, PhD Resident Physician Department of Neurosurgery Icahn School of Medicine at Mount Sinai New York, New York, United States

Brian L. Hoh, MD, MBA James and Brigitte Marino Family Professor and Chair Department of Neurosurgery University of Florida Gainesville, Florida, United States Brian M. Howard, MD Assistant Professor Departments of Neurosurgery; Radiology and Imaging Sciences Emory University Atlanta, Georgia, United States Albert Hsiao, MD, PhD Associate Professor Department of Radiology University of California San Diego La Jolla, California, United States Judy Huang, MD, FAANS Irving J. and Florence Sherman Professor of Neurosurgery Director Neurosurgery Residency Program Vice Chair Department of Neurosurgery Johns Hopkins University School of Medicine Baltimore, Maryland, United States Christopher M. Jackson, MD Assistant Professor Department of Neurosurgery Johns Hopkins University School of Medicine Baltimore, Maryland, United States Hideyuki Kano, MD, PhD Research Assistant Professor Department of Neurological Surgery University of Pittsburgh Pittsburgh, Pennsylvania, United States Navaz Karanjia, MD Clinical Professor Departments of Neurosciences, Anesthesiology, and Neurological Surgery University of California San Diego San Diego, California, United States

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Contributors

Alexander A. Khalessi, MD, MBA Chair of Neurological Surgery Professor of Neurological Surgery, Radiology, and Neurosciences Don and Karen Cohn Chancellor’s Endowed Chair University of California San Diego La Jolla, California, United States Jennifer E. Kim, MD Chief Resident Physician Department of Neurosurgery Johns Hopkins University School of Medicine Baltimore, Maryland, United States Louis J. Kim, MD, MBA Wallace T. Staatz Endowed Professor and Vice Chair Department of Neurological Surgery University of Washington School of Medicine Seattle, Washington, United States Jared Knopman, MD Assistant Professor Department of Neurological Surgery NewYork-Presbyterian Weill Cornell Medicine New York, New York, United States Gary Kocharian, MD Resident Physician Department of Neurologic Surgery NewYork-Presbyterian Weill Cornell Medicine New York, New York, United States Pui Man Rosalind Lai, MD Resident Physician Department of Neurosurgery Brigham and Women’s Hospital Research Fellow Harvard Medical School Department of Neurosurgery Boston, Massachusetts, United States Arthur M. Lam, MD Clinical Professor Department of Anesthesiology University of California San Diego San Diego, California, United States

Krista Lamorie-Foote, MD Resident Physician Department of Neurosurgery University of Southern California Los Angeles, California, United States Michael J. Lang, MD Clinical Assistant Professor Department of Neurological Surgery University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania, United States Dimitri Laurent, MD Resident Physician Department of Neurosurgery University of Florida Gainesville, Florida, United States Michael T. Lawton, MD Chair, Department of Neurosurgery Robert F. Spetzler Neuroscience Chair President and CEO Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, Arizona, United States Hubert Lee, MD, MSc Clinical Instructor Department of Neurosurgery and the Stanford Stroke Center Stanford University School of Medicine Stanford, California, United States Brian P. Lemkuil, MD Clinical Professor Department of Anesthesiology University of California San Diego San Diego, California, United States Elad I. Levy, MD, MBA Professor and L. Nelson Hopkins MD Chairman Department of Neurosurgery Professor Department of Radiology Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo

Continued

Contributors

Co-Director Canon Stroke Research and Vascular Center University at Buffalo Director Interventional Stroke Services, Endovascular Neurosurgery Fellowship Kaleida Health Buffalo, New York, United States Brandon Lucke-Wold, MD, PhD, MCTS Resident Physician Department of Neurosurgery University of Florida Gainesville, Florida, United States L. Dade Lunsford, MD Lars Leksell Professor and Distinguished Professor Department of Neurological Surgery Director Center for Image-Guided Neurosurgery University of Pittsburgh Pittsburgh, Pennsylvania, United States William Mack, MD, MBA Professor of Neurological Surgery Vice Chair, Academic Affairs Department of Neurosurgery University of Southern California Los Angeles, California, United States Charles C. Matouk, MD Chief Section of Neurovascular Surgery Department of Neurosurgery Yale School of Medicine New Haven, Connecticut, United States David J. McCarthy, MD, MSc Resident Physician Department of Neurosurgery University of Pittsburgh Medical Center Pittsburgh, Pennsylvania, United States R. Michael Meyer, MD Resident Physician Department of Neurological Surgery University of Washington Seattle, Washington, United States

J Mocco, MD, MS Professor Department of Neurosurgery Icahn School of Medicine at Mount Sinai Director Cerebrovascular Center, Mount Sinai New York, New York, United States Nikolaos Mouchtouris, MD Resident Physician Department of Neurological Surgery Thomas Jefferson University and Hospitals Philadelphia, Pennsylvania, United States Santosh B. Murthy, MD, MPH Associate Professor Department of Neurology Associate Chief Division of Neurocritical Care NewYork-Presbyterian Weill Cornell Medicine New York, New York, United States Ajay Niranjan, MD, MBA Professor Department of Neurological Surgery University of Pittsburgh Pittsburgh, Pennsylvania, United States Dominic A. Nistal, MD Resident Physician Department of Neurological Surgery University of Washington Seattle, Washington, United States Alexander Norbash, MD, MS Professor and Chair Department of Radiology University of California San Diego La Jolla, California, United States Christopher S. Ogilvy, MD Professor of Neurosurgery Department of Neurosurgery Harvard Medical School Director BIDMC Brain Aneurysm Institute Director Department of Endovascular and Operative Neurovascular Surgery Beth Israel Deaconess Medical Center Boston, Massachusetts, United States

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S. Paul Oh, PhD Professor Barrow Aneurysm and AVM Research Center Department of Neurosurgery Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, Arizona, United States J. Scott Pannell, MD Associate Professor Departments of Neurological Surgery and Radiology Director of Neurointerventional Surgery University of California San Diego La Jolla, California, United States Aman B. Patel, MD Director of Cerebrovascular and Endovascular Neurosurgery Department of Neurosurgery Massachusetts General Hospital Boston, Massachusetts, United States Redi Rahmani, MD Research Fellow Department of Neurosurgery Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, Arizona, United States Alexander D. Ramos, MD, PhD Resident Physician Department of Neurological Surgery NewYork-Presbyterian Weill Cornell Medicine New York, New York, United States

Robert H. Rosenwasser, MD, MBA Jewell L. Osterholm Professor and Chair Department of Neurological Surgery Professor of Radiology Neurovascular Surgery, Interventional Neuroradiology President/CEO Farber Institute for Neuroscience Medical Director Jefferson Neuroscience Network Senior Vice President Jefferson Enterprise Neuroscience Thomas Jefferson University Jefferson Hospital for Neuroscience Philadelphia, Pennsylvania, United States Michelle Roytman, MD Assistant Professor of Clinical Radiology Department of Radiology NewYork-Presbyterian Weill Cornell Medicine New York, New York, United States Jonathan Russin, MD Assistant Professor of Neurological Surgery Department of Neurosurgery University of Southern California Los Angeles, California, United States Mohamed M. Salem, MD, MPH Research Fellow Neurosurgical Service Beth Israel Deaconess Medical Center Harvard Medical School Boston, Massachusetts, United States

Robert W. Regenhardt, MD, PhD Neuroendovascular Surgeon Department of Neurosurgery Massachusetts General Hospital Boston, Massachusetts, United States

Lea Scherschinski, MD Research Fellow Department of Neurosurgery Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, Arizona, United States

Daniela Renedo, MD Postdoctoral Associate Department of Neurosurgery Yale School of Medicine New Haven, Connecticut, United States

Justin Schwarz, MD Assistant Professor Department of Neurological Surgery NewYork-Presbyterian Weill Cornell Medicine New York, New York, United States

Contributors

Laligam N. Sekhar, MD Professor and Vice Chairman Department of Neurological Surgery Director, Cerebrovascular Surgery Director, Skull Base Surgery University of Washington Seattle, Washington, United States Rajeev D. Sen, MD Resident Physician Department of Neurological Surgery University of Washington Seattle, Washington, United States Jason P. Sheehan, MD, PhD Professor Department of Neurosurgery University of Virginia Charlottesville, Virginia, United States Varadaraya S. Shenoy, MBBS Cerebrovascular Research Fellow Department of Neurological Surgery University of Washington Seattle, Washington, United States Adnan H. Siddiqui, MD, PhD Departments of Neurosurgery and Radiology and Canon Stroke and Vascular Center Jacobs School of Medicine and Biomedical Sciences University at Buffalo Buffalo, New York, United States Saman Sizdahkhani, MS, MD Resident Physician Department of Neurosurgery University of Southern California Los Angeles, California, United States Coulter Nathan Small, BS Medical Student College of Medicine University of Florida Gainesville, Florida, United States Salil Soman, MD, MS Assistant Professor of Radiology Harvard Medical School Department of Radiology Beth Israel Deaconess Medical Center Boston, Massachusetts, United States

Mark M. Souweidane, MD Professor and Vice Chair Department of Neurological Surgery Weill Cornell Medical College Director, Pediatric Neurosurgery NewYork-Presbyterian Weill Cornell Medicine Memorial Sloan Kettering Cancer Center New York, New York, United States Eleonora F. Spinazzi, MD Resident Physician Department of Neurological Surgery New York Neurological Institute Columbia University Irving Medical Center NewYork-Presbyterian New York, New York, United States Shanmukha Srinivas, MD Resident Physician University of California Los Angeles Los Angeles, California, United States Visish M. Srinivasan, MD Fellow Department of Neurosurgery Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, Arizona, United States Gary K. Steinberg, MD, PhD Bernard and Ronni Lacroute–William Randolph Hearst Professor of Neurosurgery and the Neurosciences Founder and Co Director Stanford Stroke Center Former Chair (1995–2020) Department of Neurosurgery Stanford University School of Medicine Stanford, California, United States Philip E. Stieg, PhD, MD Margaret and Robert J. Hariri, MD ’87, PhD ’87 Professor and Chair of Neurological Surgery Weill Cornell Medicine Neurosurgeon-in-Chief NewYork-Presbyterian/Weill Cornell Medical Center New York, New York, United States

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Nanthiya Sujijantarat, MD Resident Physician Department of Neurosurgery Yale School of Medicine New Haven, Connecticut, United States

Arvin R. Wali, MD, MAS Resident Physician Department of Neurosurgery University of California San Diego San Diego, California, United States

Ahmad Sweid, MD Postdoctoral Research Fellow Department of Neurological Surgery Thomas Jefferson University Philadelphia, Pennsylvania, United States

Muhammad Waqas, MD Endovascular Fellow Department of Neurosurgery University at Buffalo State University of New York Buffalo, New York, United States

Rizwan Tahir, MD Cerebrovascular Fellow Department of Neurological Surgery Thomas Jefferson University and Hospitals Philadelphia, Pennsylvania, United States Rafael J. Tamargo, MD, FACS Walter E. Dandy Professor of Neurosurgery Professor of Neurosurgery and Otolaryngology-Head and Neck Surgery Director, Cerebrovascular Neurosurgery Vice-Chair Department of Neurosurgery Johns Hopkins University School of Medicine Baltimore, Maryland, United States Stavropoula Tjoumakaris, MD Assistant Professor Department of Neurological Surgery Thomas Jefferson University Philadelphia, Pennsylvania, United States Apostolos John Tsiouris, MD Associate Professor of Clinical Radiology Department of Radiology NewYork-Presbyterian Weill Cornell Medicine New York, New York, United States Justin E. Vranic, MD Endovascular Neurosurgery Fellow Department of Neurosurgery Massachusetts General Hospital Boston, Massachusetts, United States

Halina White, BM BCh, MA, MRCP (UK) Assistant Professor of Clinical Neurology Department of Neurology Weill Cornell Medical College New York, New York, United States Risheng Xu, MD, PhD Assistant Professor of Neurosurgery Department of Neurosurgery Johns Hopkins University School of Medicine Baltimore, Maryland, United States Anthony T. Yachnis, MD Professor Department of Pathology, Immunology, and Laboratory Medicine University of Florida College of Medicine Gainesville, Florida, United States Kurt Yaeger, MD Resident Physician Department of Neurosurgery Icahn School of Medicine at Mount Sinai New York, New York, United States Jonathan J. Yun, MD Resident Physician Department of Neurosurgery University of Virginia Charlottesville, Virginia, United States Akli Zetchi, MD Assistant Professor Department of Neurosurgery Yale School of Medicine New Haven, Connecticut, United States

Foreword: Meeting a Gordian Challenge In Greek mythology, Gordius (king of Phrygia and fa-

ther of Midas) ties a yoke to his wagon with an elaborate knot and declares that the man who could untie it would conquer all of Asia. In 333 B.C. the Macedonian Alexander the Great, after a period of frustration with the challenge, drew his sword and severed the knot in a single stroke. Alexander interpreted a subsequent storm in the region as vindication from the gods for his brash behavior, and he went on to conquer Asia at the age of 32. Over time, the “Gordian Knot” has come to mean a challenging, nearly unsolvable problem—but with the promise of great payoff if it can be unraveled. Neurosurgery presents its practitioners with a remarkable catalog of Gordian Knots, with each case presenting a kaleidoscope of variables and constructs that

offer inherent challenges. The various constellations of arterial venous abnormalities of the cranial spinal axis are some of the most complicated problems in the field. Vascular anomalies of the central nervous system have been described for centuries, but it is only recently, within the past century, that neurosurgeons have mastered the tools to effectively manage the clinical syndromes resulting from these complex pathologies. Modern neurosurgery is barely a century old (Walter Dandy performed the first intracranial therapeutic vascular procedure in 19371), but the composite of knowledge and technical resources considered “contemporary neurosurgery” emerged over just the past generation. We now possess detailed structural and functional imaging that provide remarkably accurate

“Alexander Cuts the Gordian Knot.” Oil on canvas, painted in 1767 by Jean-Simon Berthélemy (1743–1811). Public domain.

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Foreword: Meeting a Gordian Challenge

views into the brain and allow patient-level specificity in characterizing its unique pathologies. Refinement of microsurgical, radiosurgical, and endovascular techniques has followed suit, vastly reducing the level of intrusion required for definitive treatment. Sophisticated insights related to biologic signatures, molecular genetics, and flow patterns are the order of the day. These developments represent a remarkable leap in human achievement over a relatively brief period, a leap that allows application of multiple technical adjuvants and strategic approaches to intracranial arteriovenous malformations (iAVMs). We have collected an enormous body of knowledge on the classifications, natural history, and pathophysiology of this unique array of malformations. Despite this great progress, each case remains a Gordian Knot to unravel. There are so many variables to consider that the management and therapeutic options remain a challenge. There is frequently no easy solution—or at least not one that is without risk. There is rarely a sword like Alexander’s to help a neurosurgeon break through the knot—this book is that sword! Given the anatomical challenges, along with the complexities of interdisciplinary management and patient education, communication presents yet another, quite different Gordian Knot.2–4 In a complex medical situation, patients require support and resources to navigate their unique medical situation. This is particularly true when the stakes for life and limb are so high. Taking a highly unique approach, this book focuses on elements of the malformation catalog itself and emphasizes communication with all participants in the challenge—patients, general neurosurgeons, and ­ neurovascular specialists along with their collaborators. Presented in a series of 42 chapters, the book is divided into two fundamental sections. The first section is geared toward patients, practitioners, and general colleagues in allied sectors. The second section provides a rich perspective of the most contemporary landscape and information directed to the neurovascular specialist. The volume has been carefully designed to be clear and comprehensive for those who are not familiar with the topic in the initial section and highly sophisticated but easily digestible in the more complex section that follows. Thoughtfully designed and stunningly beautiful artwork is placed throughout the volume, and the “Pearls” included with each chapter enhance readability. Of great importance, the editors are a highly competent and diverse amalgam. Dr. Philip E. Stieg, one of the

world’s leading microvascular surgeons, is senior editor and provides the ultimate gravitas and substance to the book. (His previous book, Intracranial Arteriovenous Malformations,5 was a primary reference when it was published more than a decade ago and remains a leading text today.) Dr. Alexander A. Khalessi represents the new generation of modern academic neurovascular surgeons with a combined perspective and experience with microsurgical and endovascular techniques. With a long history of involvement in technical, innovative, educational, publishing, and editorial matters in the broad spectrum of the field, I was asked to provide help with composition, contributor selection, and editorial and artistic elements of the project. In surveying the current catalog of available monographs or atlas texts focused on AVM issues, one finds principally a variety of surgical details. The complementary vital issues of management strategy and all treatment modes are rarely considered. As with the earlier Stieg book, all aspects of the problem are addressed in this volume. Importantly, areas of anatomy, imaging, pathology, molecular genetics, and dynamics of flow function are lucidly presented in a highly digestible fashion. The final product is striking. This work represents a novel approach to a knotty problem indeed. The book is a valuable resource for all who are involved in iAVM challenges. Patients and practitioners alike will find significant edification, and we hope that our approach will serve as a general template for many that will follow in other medical specialties. It is our intent with this publication to begin unraveling the Gordian Knot as well as provide tools for better communication among patients, doctors, students, and advanced practice providers. Michael L.J. Apuzzo, MD

REFERENCES 1. Dandy WE. Intracranial aneurysm of the internal carotid artery: cured by operation. Ann Surg. 1935;107(5):654–659. https:// doi.org/10.1097/00000658-193805000-00003. 2. Hartley BR, Hong C, Elowitz E. Communication in neurosurgery— the Tower of Babel. World Neurosurg. 2020;133:457–465. https:// doi.org/10.1016/j.wneu.2019.08.134. 3. Hartley BR, Elowitz E. Barriers to the enhancement of effective communication in neurosurgery. World Neurosurg. 2020;133: 466–473. https://doi.org/10.1016/j.wneu.2019.08.133. 4. Hartley BR, Elowitz E. Future directions in communication in neurosurgery. World Neurosurg. 2020;133:474–482. https://doi. org/10.1016/j.wneu.2019.08.132. 5. Stieg PE, Batjer HH, Samson D, eds. Intracranial Arteriovenous Malformations. Informa Healthcare USA; 2007.

Preface The concept for this book is an extension of an ear-

lier book of the same title, which was published in 2007 and which I was privileged to edit alongside Drs. Hunt Batjer and Duke Samson. I wish to acknowledge the role of these colleagues in the creation of that text. Their clinical insights, technical skills, and mentoring provided my foundation for managing these complex vascular lesions. In Part 1, this new volume provides practical knowledge for communication between a healthcare provider and the patient. Helping patients and their families understand in lay terms what lesion they have, what it means to have it, what the treatment options are, and finally what risks and benefits are associated with those options is a skill set acquired over time. The authors in this section are senior skilled physicians who demonstrate “how they talk to a patient.” In this changing technological and electronic medical record environment, we healthcare providers need to not lose our ability to communicate with patients— particularly about medical conditions as complex as arteriovenous malformations (AVMs) of the brain. In this section, we have provided the most current data and understandable means to communicate this to your patients. Treatment of AVMs is complex, multidimensional, and often integrated among several treatment modalities and physicians. This text explores the risks and benefits of different management strategies, including observation as well as specific interventions used alone or in combination, and will provide the means to help patients understand their options and make informed choices. Part 2 of the text focuses on the technical and intellectual nuances applied in the neuro-operative management of patients with intracranial AVMs. Again, written by senior clinicians in all areas from the emergency department, neuro ICU, operating room, and more, the text provides guidance into the best technical methods applied in the treatment of these lesions. Surgical, endovascular, and radiosurgical techniques and their application by master surgeons will help the

Pearls You’ll notice that each chapter of this book includes a small sidebar of “pearls”—the essence of the chapter’s wisdom in abbreviated form. As you flip through the book, use the Pearls as a quick way to decide where to begin your deep dive.

reader acquire and apply these skill sets for the best results with their patients. Perhaps nothing has changed as much since the 2007 publication as the range of technological choices available to physicians. More and more conditions are proving themselves amenable to treatment with endovascular approaches and other minimally invasive techniques, all of which can be extremely beneficial to the patient, especially in combination with improved surgical options. In this current volume, we show how those advances can work together to improve outcomes. New glues delivered through catheters by endovascular teams, better targeting of lesions by radiosurgical teams, and better tools and techniques available to surgical teams all combine into a wide array of available options. It is my belief that the addition of these new technologies, combined with better visualization of the lesion, has improved outcomes. In addition, we have a clearer understanding of the disease’s natural history, thereby improving patient selection for specific treatment modalities. One thing that never changes is the importance of the clinical and surgical expertise of the provider, which remains paramount—and it is my hope that the message the reader takes away from this book is one of collaboration and a comprehensive approach to treatment. The integration of Parts 1 and 2 with future considerations will provide an excellent foundation and advanced knowledge base for a wide audience, including medical students, nurses, advanced practice providers,

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neurosurgeons, anesthesiologists, interventionist, endovascular surgeons, and radiosurgeons. It is the editors’ desire to make the scientific literature describing all clinical and clinicopathologic aspects of intracranial AVMs understandable to all medical professionals. Importantly, we hope that we have given the reader a clear and concise description of this lesion in prose

that can be applied to their communication with patients. We hope you enjoy reading this text as much as we enjoyed creating it. Philip E. Stieg, PhD, MD

Acknowledgments First and foremost, we would like to thank the many

contributors who made this book possible. It is extremely gratifying to see such an impressive list of authors, with neurosurgical luminaries side by side with the stars of the future. We look forward to watching this most fascinating field continue to evolve and seeing these young physicians assume their place as the next generation of cerebrovascular experts. We would like to extend our deepest thanks to Anne Stanford, our medical editor, whose tireless efforts over the course of more than two years brought all the many chapters together into a seamless whole. Anne’s commitment to accuracy, consistency, and clarity is what melded these 42 chapters into one cohesive volume. Special thanks are due to Thom Graves, CMI, the medical illustrator whose work complements the text of so many chapters of this book. Thom worked painstakingly with our authors and editors to illustrate the anatomy and procedures we describe, creating images that help bring the complex tangles of blood vessels to life on these pages. Roseann Foley Henry provided exceptional support in skillfully managing the logistics and pace of the project while providing valuable insights into content, style, and design. Our commitment throughout the book was to teach the art of clear communication to patients and among clinicians, and Roseann was a guiding light in this effort. Dr. David Santiago-Dieppa provided substantial input to the illustrations and captioning of complex technical figures. His engagement and neurosurgical expertise brought unique insights to these images and value to our readers. We are grateful to our partners at Elsevier, particularly Humayra Khan, Ellen Wurm-Cutter, Shweta

Pant, and Beula Christopher, who shepherded this book from initial concept to completion. Over several long pandemic-affected years, the Elsevier team worked with endless patience to bring our book to market. We appreciate their guidance and fortitude in getting us over the many bumps on a very long road. And of course, we offer our thanks to all of those who worked on this book behind the scenes—the many proofreaders, designers, project managers, and others to whom we owe a debt of gratitude for making this volume happen. Dr. Stieg would like to personally thank his children, Nick and Claire, for understanding this book’s additional demand on his time over the past several years. Our families are our foundations, allowing us to build careers and cultivate interests while faithfully supporting us; their love is invaluable, and an integral part of our lives even when we are away from them. Dr. Khalessi would like to thank his wife, Sara, and sons, Wilder and Pierce. Like so many opportunities in neurological surgery, this book required their patience and support. Our deepening understanding of arteriovenous malformations further depends on the daily courage, determination, and inspiration of our patients. They are the reason our journey toward the mastery of this disease continues. Dr. Apuzzo would like to express his love and appreciation for his son, Jason, and daughter-inlaw, Govindini, who have consistently been sources of inspiration and energy through many of his life’s chapters. During this project, his longtime administrator, Lee Ida Boyd, provided invaluable support, keeping him on point. Additionally, he notes that working with his coeditors has been an absolute delight.

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Video Contents Chapter 13 Video 13.1

Example of a straightforward iAVM resection. (© Department of Neurosurgery at Emory University School of Medicine.)

Chapter 32 Video 32.1

Resection of a ruptured right paramedian superior cerebellar hemisphere AVM through an infratentorial supracerebellar approach. Using visual inspection and intraoperative image guidance, the borders of the AVM were defined and circumferentially dissected, sequentially ligating its arterial supply. The venous pedicle was identified coursing deep and was preserved until the malformation was devascularized.

Video 32.2 Resection of a left lateral medullary AVM through a far-lateral approach. The cerebellum was retracted to reveal the AVM and its arterial supply meticulously dissected to differentiate it from the posterior inferior cerebellar artery and its normal branches.

Video 32.3 Resection of a right dorsolateral pontine AVM through a right far-lateral approach, lateral suboccipital craniotomy, and drilling of the posterior third of the ipsilateral occipital condyle. Following the dural opening, the ipsilateral tonsil and cerebellar hemisphere were retracted to reveal the pial brainstem AVM. The AVM was circumferentially dissected, its arterial feeders and then venous outflow were disconnected, and a portion of the nidus was resected. A component was coagulated and occluded in situ, as it was adherent to the pia. (Used with permission from Madhugiri VS, Teo M, Steinberg GK. Surgery of basal ganglia, thalamic and brainstem AVMs. In Dumont AS, Lanzino G, Sheehan JP, eds. Brain Arteriovenous Malformations and Arteriovenous Fistulas. Thieme; 2017.) Video 32.4

Resection of a right anterolateral midbrain AVM through a subtemporal transpetrous approach. The tentorium is incised posterior to where the trochlear nerve inserts into the free edge to improve inferolateral visualization.

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Anatomy and Histology of Intracranial AVMs Antonio Bernardo

Chapter Outline Introduction Cerebral Arterial Anatomy The Circle of Willis Cerebral Vascular Architecture The Cerebral Venous System Location and Classification of iAVMs Feeding Vessels Venous Drainage Histology Conclusion

Introduction Intracranial arteriovenous malformations (iAVMs) are focal abnormal conglomerations of dilated arteries and veins that are typically encountered pulsating in the sulci and gyri of the brain (Fig. 1.1) and can cause stroke when they rupture. The care of patients with iAVMs requires a thorough understanding of the pathological, anatomical, and clinical features that determine the natural history of the lesions, define the risk of treatment, and indicate the preferred method of treatment. Normal brain function is entirely dependent upon adequate supply of oxygen and nutrients from the blood through a dense network of blood vessels. About 15% of one’s daily cardiac output is delivered to the brain. This is accomplished through two highflow arterial systems: an anterior system, which is supplied by the internal carotid arteries; and a posterior system, which is supplied by the vertebral arteries. The vessels in both of these arterial systems all

have extensive networks of small branches that extend out to perfuse brain tissue. Blood supplying tissues travels through a system of capillaries, where oxygen-rich blood is delivered and oxygen-depleted blood is emptied into small veins (Fig. 1.2A). In the brain, the small veins empty into larger veins that run within the dural covering of the brain, known as dural venous sinuses. The dural venous sinuses collect blood from veins around the brain and drain that blood into the left and right internal jugular veins. The human cortex is perfused by long arteries with many branches, resulting in a marked decrease in blood pressure between the large arteries at the base of the brain and the small arterioles perfusing the subcortical regions over the convexity. Blood pressure drops as flow is divided among branches, so at the distal end of the long arteries with many branches, blood pressure is much lower than in the parent artery. The veins of the brain are thin walled and valveless, and they would not be able to withstand the arterial pressure of the large-capacity intracerebral arterial vessels were it not for the successive branching and the fine network of capillaries interposed between the two systems, which reduce the arterial pressure before blood enters the venous bed (Fig. 1.2A). Because iAVMs are composed of tangles of abnormally developed arteries and veins without intervening capillaries, there is an abnormal shunting of blood between arteries and veins (nonnutritive blood flow), resulting in high-pressure vascular channels that are at a risk of rupturing and bleeding out, often with catastrophic results. This abnormal tangle, known as a nidus, has a main arterial feeding vessel that is connected directly to the draining veins (Fig. 1.2B). 5

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PART 1 The Patient-Centered Approach

Arteriovenous malformations can be challenging for neurosurgeons, as the risks of surgical treatment may outweigh the benefits, and alternative management strategies (including the option of medical management or observation without interventional treatment) may be preferable in specific cases. Different grading systems have been widely used for determining surgery-related morbidity; however, high-risk factors such as history of hemorrhage, young age, deep venous drainage, and female sex may impact the choice and timing of surgical treatment in light of their effect on the patient’s lifetime risk of hemorrhage. There is also histopathological evidence of AVM features in association with identified risk factors. This chapter describes the anatomy of the cerebral vasculature and types of collateral circulation that are recruited by these lesions and the histopathological features of AVMs, which will create the basis for treatment considerations covered in the rest of this book.

Cerebral Arterial Anatomy The distribution of blood vessels in the brain was well studied in the last years of the 19th century in France and Germany, by Duret and Heubner, respectively. These two anatomists performed their research simultaneously in their own countries—each man working without the knowledge of the other’s efforts—and both contributed enormously to the understanding of cerebral vascularization. Blood is supplied to the brain, face, and scalp via two major sets of vessels: the right and left common carotid arteries and the right and left vertebral arteries.1 The common carotid arteries bifurcate into the internal and external carotid arteries. The internal carotid arteries principally supply the cerebrum, whereas the external carotid arteries principally supply the face and neck. The two vertebral arteries join distally to form the basilar artery, and branches of the vertebral and basilar arteries supply blood for the cerebellum and brainstem. An anastomotic ring of arteries (the circle of Willis) located at the base of the brain connects the two major arterial systems via the posterior communicating arteries. (The circle of Willis is discussed in more detail in a subsequent section of this chapter.) Fig. 1.3 shows a simplified overview of some of the major arteries and the areas of the brain that they supply.

Pearls • Intracranial AVMs are focal abnormal conglomerations of dilated arteries and veins that pulsate in the sulci and gyri of the brain and can cause stroke if they rupture. • The pathogenesis of iAVMs remains poorly understood, and traditional theories regarding the congenital etiology of these lesions are being challenged and replaced by more comprehensive pathophysiological hypotheses. • Features such as exclusive deep venous drainage, deep brain location, and associated aneurysms appear to be risk factors for hemorrhage. • The management of an iAVM in any given patient should be based on factors such as patient age and medical comorbidities as well as the anatomic and vascular features of the AVM. • Innovations in imaging technology, such as 3D imaging, functional imaging, and brain tract mapping, have the potential to improve surgical precision and safety in removing iAVMs and preserving surrounding vessels.

The two vertebral arteries, running toward each other, surround the medulla oblongata and join at the midline to form the basilar artery, a relatively large vessel that ascends along the ventral surface of the pons, in its basilar groove, within the pontine cistern. The basilar artery then bifurcates to form the paired posterior cerebral arteries. The basilar artery has different branches along its course, including the anterior inferior cerebellar artery, which arises from the proximal segment of the basilar artery and courses posterolaterally to supply the inferior aspect of the cerebellum. The anterior inferior cerebellar artery also anastomoses with the posterior inferior cerebellar artery, a branch of the vertebral artery. The superior cerebellar artery branches off in a lateral direction at the distal aspect of the basilar artery just prior to its bifurcation. It courses around the cerebral peduncles to supply the superior aspect of the cerebellum along with the tela choroidea of the third ventricle, the pineal gland, the pons, and the superior medullary velum. It also forms an anastomosis with derivatives of the inferior cerebellar arteries. The basilar artery gives off numerous pontine arteries from its lateral surface bilaterally as well

Fig. 1.1 Artistic illustration of an iAVM showing the surgeon’s initial view (inset on left) and a closer view (inset on right) with arrows indicating the direction of blood flow. Intracranial AVMs are focal abnormal masses of dilated arteries and veins that are characterized by a direct connection between the arterial and venous systems and appear as a tangle of vessels pulsating and swirling in the sulci and gyri of the brain. A, the arterial feeding vessel; B, the AVM nidus; C, a draining vein.

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Fig. 1.2 Schematic illustration showing the difference between normal vascular architecture, with a capillary bed (A), and an AVM (B). Capillary beds are the primary sites of oxygen and nutrient exchange and are composed of a dense network of intercommunicating vessels that consist of specialized endothelial cells without smooth muscle cells. The walls of cerebral arteries and arterioles consist of three concentric layers. The innermost layer, the tunic intima, consists of a single layer of endothelial cells and the internal elastic lamina. The middle layer, the tunica media, contains mainly smooth muscle cells with some elastin and collagen fibers. The outermost layer, the tunica externa, is composed mainly of collagen fibers, fibroblasts, and associated cells, including perivascular nerves. The walls of cerebral veins are much thinner than arterial walls, lacking smooth muscle. In contrast to peripheral veins, cerebral veins do not contain valves. In an iAVM, the loss of normal vascular organization at the subarteriolar level and the lack of a capillary bed result in abnormal arteriovenous shunting.

as many perforators from the posteromedial aspect of the distal bifurcation. The basilar artery terminates as it divides, at the level of the anterior margin of the protuberance, into two terminal and divergent branches, the posterior cerebral arteries.2–4 The posterior cerebral artery arises from the bifurcation of the basilar artery at the superior border of the pons, posterior to the dorsum sellae. Soon after its origin, the posterior cerebral artery continues laterally

along the superior border of the pons, surrounds the inferior aspect of the cerebral peduncles, and runs posteriorly along the lateral parts of the transverse fissure (of Bichat) to reach the medial surface of the cerebral hemisphere, where it supplies the temporal and occipital lobes. The posterior cerebral artery is divided into four segments: • The precommunicating segment (P1) extends from the termination of the basilar artery to the posterior communicating artery, within the interpeduncular cistern. • The postcommunicating segment (P2) extends from the posterior communicating artery around the midbrain and terminates as it enters the quadrigeminal cistern. • The quadrigeminal segment (P3) courses posteromedially through the quadrigeminal cistern and terminates as it enters sulci of the occipital lobe. • The cortical segment (P4) runs within the sulci of the occipital lobe (calcarine artery, within the calcarine fissure). The posterior cerebral artery gives off branches that are categorized as either central or cortical. The central branches supply the subcortical structures and include the thalamoperforating, thalamogeniculate, and posterior choroidal arteries. The cortical branches are distributed to different parts of the cortex, are named accordingly, and involve the temporal, occipital, parietooccipital, and calcarine arteries. The posterior cerebral artery curls around the cerebral peduncle and passes above the tentorium to supply the posteromedial surface of the temporal lobe and the occipital lobe. The visual cortex responsible for the contralateral field of vision lies in its territory. The macular part of the visual cortex often receives blood supply from both the posterior cerebral artery and the middle cerebral artery.2 The internal carotid artery is responsible for supplying a large portion of the anterior and middle parts of the brain. A new classification system divides the internal carotid artery into four parts: cervical in the neck, petrous at the base of the skull, cavernous within the cavernous sinus, and intracranial above the cavernous sinus. The two internal carotid arteries, in their last or intracranial segment, after supplying the ophthalmic artery, each resolve into a tuft of four

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Anatomy and Histology of Intracranial AVMs

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Fig. 1.3 Vascularization of the brain. The shading indicates the arterial supply territories of the anterior (green), middle (yellow), and posterior (blue) cerebral arteries. (A) Lateral view. The middle cerebral artery supplies most of the lateral surface of the cerebral hemisphere, excluding the superior portion of the parietal lobe, which is supplied by the anterior cerebral artery, and the occipital and inferior portions of the temporal lobe, which are supplied by the posterior cerebral artery. (B) Midline sagittal view. Branches of the anterior cerebral artery, the frontal arteries, supply the paracentral lobule, medial frontal and cingulate gyri, and the corpus callosum. The posterior cerebral artery supplies the posteromedial surface of the temporal lobe and the occipital lobe. The visual cortex, responsible for the contralateral field of vision, is also supplied by the posterior cerebral artery. (C) Inferior view. The posterior cerebral artery also supplies the inferior temporal lobe. Orbital branches of the anterior cerebral artery supply the frontal lobe, olfactory cortex, medial orbital gyrus, and gyrus rectus. The lateral frontobasal artery, a branch of the middle cerebral artery, supplies the lateral part of the inferior surface of the frontal lobe as well as the inferior frontal gyrus. The circle of Willis is formed anteriorly by the left and right anterior cerebral arteries, connected to each other by the anterior communicating artery, and posteriorly by the left and right posterior cerebral arteries. The anterior and posterior circulation are connected by the left and right posterior communicating arteries.

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PART 1 The Patient-Centered Approach

­divergent branches: the anterior cerebral artery, the middle cerebral artery, the anterior choroidal artery, and the posterior communicating artery.2 The anterior cerebral artery is a much smaller branch of the internal carotid artery (compared to the middle cerebral artery). It begins at the terminal segment of the internal carotid artery (after the ophthalmic branch is given off) on the medial part of the sylvian fissure. It runs anteriorly and medially toward the interhemispheric fissure, providing in this initial course a few small branches to the orbitofrontal cortex. Shortly after its origin, the anterior cerebral artery connects with its contralateral side via a 1- to 3-mm-long transverse anastomosis, the anterior communicating artery. The paired arteries then travel through the longitudinal cerebral fissure in a posterior direction along the genu of the corpus callosum, where they divide into its two major branches: the pericallosal and callosomarginal arteries. The anterior cerebral artery is also subdivided for clinical purposes into five segments: • The horizontal or precommunicating segment (A1) extends from the terminal bifurcation of the internal carotid artery to the anterior communicating artery. • The vertical, postcommunicating, or infracallosal segment (A2) originates at the anterior communicating artery, extends anteriorly to the lamina terminalis and along the rostrum of the corpus callosum, and terminates either at the genu of the corpus callosum or at the origin of the callosomarginal artery. • The precallosal segment (A3) extends around the genu of the corpus callosum or distal to the origin of the callosomarginal artery and terminates where the artery turns directly posterior above the corpus callosum. • The supracallosal segment (A4) courses above the body of the corpus callosum anterior to the plane of the coronal suture. • The postcallosal segment (A5) courses above the body of the corpus callosum posterior to the plane of the coronal suture. The anterior cerebral artery also gives off central and cortical branches. The cortical branches, which are named for the regions they supply, are responsible for the areas of somatosensory and motor cortex related to the lower limbs. Parietal branches perfuse the

precuneus while the orbital branches supply the frontal lobe, olfactory cortex, medial orbital gyrus, and gyrus rectus. The frontal arteries supply the paracentral lobule, medial frontal and cingulate gyri, and the corpus callosum. The central branches are given off proximally (A1, anterior communicating artery, and proximal A2) and supply the anterior perforated substance, the lamina terminalis, the rostrum of the corpus callosum, the septum pellucidum, the anterior part of the putamen, the head of the caudate nucleus, and the anteromedial part of the anterior limb of the internal capsule. The anterior communicating artery has several anteromedial central arteries, which are responsible for supplying the cingulate gyrus, the anterior columns of the fornix, the hypothalamus lamina terminalis, the optic chiasm, and the paraolfactory regions.1,2,4 The middle cerebral artery is the largest terminal branch of the internal carotid artery. It travels in the sylvian fissure and after a short course reaches the insula, where it bifurcates into the superior and inferior trunks. The trunks travel together through the sylvian fissure in a posterosuperior direction and reach its posterior end toward the lateral surface of the brain. The middle cerebral artery can be subdivided into four parts: • The sphenoid segment (M1) extends from the termination of the internal carotid artery to the bifurcation or sometimes trifurcation of the middle cerebral artery. • The insular segment (M2) travels posterosuperiorly in the insular cleft and terminates at the circular sulcus in the sylvian fissure. • The opercular segment (M3) courses laterally along the frontoparietal operculum and terminates at the external/superior surface of the ­ sylvian fissure. • The cortical segment (M4) emerges through the lateral fissure to reach the surface of the brain. The middle cerebral artery also gives off central and cortical branches. They supply most of the lateral surface of the hemisphere, with the exceptions being the superior portion of the parietal lobe (which is supplied by the anterior cerebral artery) and the occipital lobe and inferior portion of the temporal lobe (which are supplied by the posterior cerebral artery). In addition, the central and cortical branches of the middle cerebral artery supply part of the internal

1

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Anatomy and Histology of Intracranial AVMs

capsule and basal ganglia. The numerous central branches are also called striate or lateral lenticulostriate arteries and arise from the M1 and M2 segments within the sylvian fissure. Their main function is to supply the deep structures of the brain. They supply the basal ganglia (i.e., the striatum), much of the head and body of the caudate nucleus, and large portions of the lenticular nucleus and of the external and internal capsules. The cortical branches of the middle cerebral artery arise from all of its segments. They supply most of the lateral surface of the brain (i.e., the orbital, frontal, parietal, and temporal parts of the cerebral cortex) and are named according to the region of the brain that they supply. The anterior temporal arteries vascularize the temporal pole of the brain, which is the most anterior aspect of the temporal lobe. The lateral frontobasal artery supplies the lateral part of the orbital surface of the frontal lobe as well as the inferior frontal gyrus. The artery of the prefrontal sulcus supplies the anterior aspects of the inferior and middle frontal gyri. The artery of the precentral sulcus supplies the posterior aspect of the inferior and middle frontal gyri, Broca’s area, and the precentral gyrus. The artery of the central sulcus travels within the central sulcus and contributes to the blood supply of the pre- and postcentral gyri. The artery of the postcentral sulcus supplies the anterior aspect of parietal lobe and the postcentral gyrus, which contains the primary somatosensory cortex for the head, upper limbs, and trunk. The angular artery supplies the angular and supramarginal gyri of the parietal lobe, the posterior part of the superior temporal gyrus, and the superior part of the lateral surface of the occipital lobe. The middle temporal branches supply the middle aspect of the superior and middle temporal gyri, as well as the primary auditory cortex and Wernicke’s area.2,3 The anterior choroidal artery is divided into two segments: cisternal and intraventricular. It originates from the posterior wall of the internal carotid artery between the origin of the posterior communicating artery and the internal carotid termination. After reaching the lateral geniculate body, it traverses in the posterolateral direction above the uncus to enter the choroidal fissure, at the so-called plexal point, where it becomes intraventricular (intraventricular segment). It then continues superiorly around the thalamus, until

the interventricular foramen (foramen of Monro). The anterior choroidal artery finishes its course at this point by anastomosing with the medial posterior choroidal branch of the posterior cerebral artery. It supplies several subcortical structures (limbic system, basal ganglia, diencephalon), the midbrain, the temporal lobe, and the visual pathway. Therefore these structures will be the main ones affected by an anterior choroidal artery stroke.2–4 The posterior communicating artery originates from the posterior aspect of the communicating segment of the internal carotid artery and extends posteromedially to anastomose with the ipsilateral posterior cerebral artery and form part of the circle of Willis connecting the anterior or carotid system and the posterior or vertebral system to each other. The posterior communicating artery gives off many fine, scarcely visible, perforating branches. The largest perforating branch is called the premammillary (or anterior thalamoperforating) artery. Perforators from the posterior communicating artery supply the posterior part of the optic chiasm and optic tract, the posterior part of the hypothalamus and mammillary bodies, and part of the thalamus.2,3

The Circle of Willis The middle cerebral arteries, the anterior cerebral arteries, and the anterior communicating artery form the anterior cerebral circulation.1,2 The vertebral arteries, basilar artery, and posterior cerebral arteries, together with the posterior communicating artery, form the posterior cerebral circulation. Through various anastomoses, the anterior and posterior arterial circuits of the brain unite in a completely closed arterial system at the base of the brain. This area is known as the circle of Willis, although it is actually a heptagon because it has seven sides. It is formed anteriorly by the two anterior cerebral arteries, connected to each other by the anterior communicating artery; posteriorly by the two posterior cerebral arteries; and on the sides by the two posterior or lateral communicating arteries (see Fig. 1.3C). The main function of the circle of Willis is to provide collateral blood flow between the anterior and posterior arterial systems of the brain. Additionally, it offers alternative blood flow pathways between the right and left cerebral hemispheres. This system ensures optimal vascularization of the brain.

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A single trunk would have been sufficient in the absence of pathology, but instead, there are four trunks connected to each other by short—and generally very wide—anastomoses. The anastomoses provide alternative routes for blood flow in the event of vascular occlusion. Because the carotid and vertebrobasilar arteries form a circle, if one of the main arteries is occluded, the distal smaller arteries that it supplies can receive blood from the other arteries (collateral circulation). It is thus understandable how one of these trunks can become occluded by an embolus or be suppressed by a ligature without always necessarily resulting in neurological dysfunction. Additionally, the circle is believed to function as a pressure relief system to accommodate increased blood flow in instances of raised intracranial pressure. Because of the combination of the pattern of collateral circulation that accompanies iAVMs and the compensatory circulation of the circle of Willis, some patients may have complete occlusion of certain segments of the circle of Willis and adjacent major branches without suffering distal infarction in the cerebral hemisphere or in the critical areas occupied by the AVM itself.2 In many patients with complex, deep AVMs in the lenticulostriate territory, both anterior cerebral arteries fill from the contralateral internal carotid artery, as seen angiographically, and the shunting of blood into the deeper portions of the hemisphere is accompanied by extensive development of cortical anastomotic arteries joining the anterior, middle, and posterior cerebral arterial territories. These vascular features create the possibility of occluding the major arterial trunks at certain segments of the circle of Willis without significantly reducing the distal hemispheric circulation.2

Cerebral Vascular Architecture Once they reach the cerebral cortex, these major vessels of the circle of Willis divide into progressively smaller arteries and arterioles that run along the surface of the brain within the pia and arachnoid mater (leptomeninges) until they penetrate the tissue to supply blood to specific regions of the cortex. The pia mater provides the mechanism that allows the dura mater to support the brain through its intimate attachment over the contours of the brain. A sleeve of pia follows

each blood vessel as it enters or leaves the brain, creating perivascular spaces known as the Virchow-Robin spaces. Pial vessels are surrounded by cerebrospinal fluid and give rise to smaller arteries (arterioles) that eventually penetrate into the brain tissue. These penetrating arterioles run within a continuation of the subarachnoid space (Virchow-Robin space) before becoming parenchymal arterioles once they penetrate into the brain tissue, where they are almost completely surrounded by astrocytic end-feet. There are several important structural and functional differences between pial arteries on the surface of the brain and smaller parenchymal arterioles. First, pial arteries receive perivascular innervation from the peripheral nervous system, also known as “extrinsic” innervation, whereas parenchymal arterioles are “intrinsically” innervated from within the brain neuropil. While parenchymal arterioles have only one layer of circumferentially oriented smooth muscle, they possess greater basal tone and are unresponsive to at least some neurotransmitters that can have large effects on upstream vessels (serotonin, norepinephrine). Lastly, pial vessel architecture forms an effective collateral network such that occlusion of one vessel does not appreciably decrease cerebral blood flow. However, penetrating and parenchymal arterioles are long and largely unbranched such that occlusion of an individual arteriole results in significant reductions in flow and damage (infarction) to the surrounding local tissue.2,5,6

The Cerebral Venous System The cerebral venous system is a freely communicating and interconnected system comprising dural sinuses and cerebral veins (Fig. 1.4). The veins of the brain have no muscular tissue in their thin walls and possess no valves. After emerging from the brain, they lie in the subarachnoid space, then pierce the arachnoid mater and the meningeal layer of the dura mater and drain into the cranial venous sinuses. Venous outflow from the cerebral hemispheres occurs through two groups of valveless veins, which allow for drainage: the superficial cortical veins and the deep or central veins. The superficial cortical veins are located in the pia mater on the surface of the cortex. They comprise

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Anatomy and Histology of Intracranial AVMs

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Fig. 1.4 Cerebral venous anatomy. Veins of the cerebral hemispheres can be categorized as either superficial or deep. The superficial cerebral veins drain the cerebral cortex, while the deep cerebral veins return blood from the deep structures of the cerebrum. (A) A lateral view showing superficial cerebral veins draining the lateral surface of the cerebral hemisphere into the superior sagittal, transverse, and petrosal sinuses. The superficial middle cerebral vein lies along the lateral sulcus and is connected to the superior sagittal sinus. (B) A sagittal view showing the superior and inferior sagittal sinuses residing in the falx cerebri. The inferior sagittal sinus drains from the medial part of the cerebral hemispheres into the straight sinus. (C) The dural venous sinuses that traverse the base of the skull include the cavernous sinus, the superior and inferior petrous sinuses, and the sphenopalatine sinus. These intracranial dural venous sinuses ultimately drain into the internal jugular vein, which collects intracranial venous blood and transports it back to the heart.

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PART 1 The Patient-Centered Approach

­sagittal sinuses and superficial cerebral veins and drain the cerebral cortex and subcortical white matter. The superficial cerebral veins can be subdivided into three groups, which are interlinked with anastomotic veins of Trolard and Labbé. However, the superficial cerebral veins are highly variable, and they drain into the nearest dural sinus. Thus the superolateral surface of the hemisphere drains to the superior sagittal sinus, while the posteroinferior aspect drains to the transverse sinus. The deep or central veins consist of subependymal veins, internal cerebral veins, the basal vein, and the great vein of Galen. These veins drain the brain’s interior, including the deep white and gray matter surrounding the lateral and third ventricles and the basal cisterns, and anastomose with the cortical veins, emptying into the superior sagittal sinus. Venous outflow from the superior sagittal sinus and deep veins is directed via a confluence of sinuses toward the sigmoid sinuses and jugular veins. The cerebellum is drained primarily by two sets of venous structures, the inferior cerebellar veins and the occipital sinuses. The brainstem is drained by the veins terminating in the inferior and transverse petrosal sinuses. The meningeal veins are small venous channels that drain the dura mater. They are often paired satellite veins or even small sinuses accompanying the meningeal arteries. Meningeal veins lie between arteries and bone and may encircle an artery. These veins may also course through a superficial tunnel on the inner surface of the bone, resulting in an intradiploic course as well as an intradural course. The meningeal veins may receive venous drainage from diploic vessels from the skull and they drain into the dural venous sinuses along the cranial base and superior sagittal sinus.2,7,8

Location and Classification of iAVMs The variable nature and angioarchitecture of iAVMs often result in hemorrhage. Imaging modalities and 3D reconstruction are useful for appreciating the detailed pathoanatomy of individual iAVMs, allowing for surgical and endovascular treatments to be tailored to the lesion. Characteristics of iAVMs that provide a morphologic basis for treatment include size, location, type,

and number of feeding vessels, as well as the amount of flow through the lesion, degree of flow diversion from surrounding normal brain, characteristics of venous drainage, surgical accessibility, eloquence of adjacent brain, and presence of aneurysms. The lesions are classified according to size as small (< 3 cm), medium (3–6 cm), or large (> 6 cm) and as cortical, deep, or infratentorial based on their location. A deep AVM is defined as one involving ventricular nuclei, thalami, ventricles, and/or the diencephalon. Cortical AVMs are found on the surface of the cerebrum, and infratentorial AVMs are found on the brainstem and/or cerebellum.3,5,6,9,10 AVMs can be located in any part of the brain, which means that any cerebral artery can become a feeding vessel, and are topographically defined by the location of the nidus and the identity of the arterial feeders and draining veins (Fig. 1.5A and B). Accordingly, they can be categorized as parasagittal (frontal, rolandic, parietal, occipital) if they are located around the interhemispheric fissure; interhemispheric (anterior and posterior paracallosal) if they occur along the medial aspect of the cerebral hemispheres; lateral hemispheric (perisylvian AVMs and those in the territory of the vein of Labbé) along the more lateral cerebral convexity; basal (suprachiasmatic and temporomesial); deep (striate, thalamic); cerebellar (paravermian, petrosal); and pontomesencephalic.4,6–12 AVMs can affect either side of the brain, and the left and right sides appear to be affected with equivalent frequency. Most AVMs (~ 90%) are supratentorial (located above the tentorium cerebelli, in the region of the brain that contains the cerebrum), and approximately 15% are deep (basal ganglia, brainstem, or corpus callosum). “Eloquent” sites are involved in about 70% of cases, and approximately 55% of iAVMs have exclusively deep venous drainage. “Eloquent brain regions” are areas of the brain necessary for language, motor, and/or sensory functions (Fig. 1.5C). Examples include the cortical regions of the dominant, generally left, hemisphere; the inferior frontal lobe, superior temporal lobe, and angular gyrus for language function; the bilateral posterior frontal lobes for voluntary movement; the bilateral anterior parietal lobes for tactile sensation; and the bilateral medial occipital lobes for vision. The hypothalamus, thalamus, internal capsule, brainstem, cerebellar peduncles, and deep

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Anatomy and Histology of Intracranial AVMs

15

Fig. 1.5 AVM location. (A and B) AVMs can be located in any part of the brain and thus any cerebral artery can become a feeding vessel. As such, AVMs are topographically defined by the location of the nidus and can be categorized as parasagittal (frontal, rolandic, parietal, or occipital) if they are located around the interhemispheric fissure or interhemispheric (anterior or posterior paracallosal) if they occur along the medial aspect of the cerebral hemispheres. Lateral hemispheric AVMs (perisylvian and those in the territory of the vein of Labbé) are located along the lateral cerebral convexity. (C) “Eloquent” areas, which are involved in about 70% of iAVMs, are areas of the brain responsible for language, motor, and/or sensory functions.

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PART 1 The Patient-Centered Approach

cerebellar nuclei are also considered eloquent areas. Regions with much more subtle neurological function or areas in which injury does not cause permanent or disabling deficit, such as the cerebellar cortex, are considered noneloquent. AVMs located in the motor and language cortex are associated with significant risk of neurological deterioration, especially in patients presenting with unruptured AVMs and minimal or no neurological deficits.4,11–14 Surgical dissection may pose a risk to cortical areas if the AVM is near eloquent regions of the brain. Therefore knowledge of the relationship between an AVM and essential brain regions is required in order to balance the benefits of AVM obliteration against the risks of devastating neurological sequelae. Compact AVMs with tightly woven arteries and veins often have distinct borders that separate cleanly from the adjacent brain (Fig. 1.6A), whereas diffuse AVMs with ragged borders and integrated brain tissue may necessitate the use of surgical dissection planes that extend into normal brain (Fig. 1.6B). A significant number of iAVMs have a border or borders that are diffuse rather than compact, forcing the dissection into brain parenchyma to completely encircle the nidus. Even minor pial violations and parenchymal invasion can be costly in the motor and language cortex. Surprisingly, however, motor or language function may shift in the presence of an iAVM from its anatomic location to an adjacent gyrus or even to the contralateral hemisphere. AVMs are associated with a shift in the topography of cortical function in as many as one-third of patients. Interestingly, the involvement of primary cortical areas (motor or somatosensory) is not required for a shift to occur. How this shift comes about remains poorly understood, but animal models suggest that central and peripheral nervous system insults that occur during development can be accommodated by plasticity at all levels of the nervous system. Similar reorganization may occur during development in the brains of patients with iAVMs. An unexpected separation between eloquent cortex and the AVM nidus may encourage more aggressive intervention with resection, but sophisticated preoperative functional imaging is required to discover any major function reorganization.13–16 The angioarchitecture and shape of an AVM can be a predictor of growth and hemorrhage, but it is

Fig. 1.6 AVM shape. Intracranial AVMs can be categorized into two types: compact (glomerular) or diffuse (proliferative). (A) Compact AVMs are composed of tightly woven arteries and veins and often have distinct borders that separate cleanly from the adjacent brain parenchyma. (B) Diffuse AVMs have borders that are closely intertwined with surrounding brain parenchyma.

also an important factor to consider with respect to treatment. The best-known variant is typically shaped like a wedge or an inverted pyramid, with its base on the cerebral cortex near the border zone supplied by ­ terminal branches of adjacent cerebral arteries. The apex extends into deep brain areas and might lie in the ventricular wall. Veins draining the fistula can return

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Anatomy and Histology of Intracranial AVMs

to the surface, extend into the ventricular system, or drain in both directions. Another AVM variant, cylindrical or globoid in form, is restricted to the white matter of the cerebrum or cerebellum, such that it does not involve the surface of the brain.17

Feeding Vessels The arterial supply of iAVMs has many facets that bear on their natural history and treatment risks (Fig. 1.7A and B). The focus of treatment is to close the nidus by

Fig. 1.7 Arterial supply. A feeding vessel is an arterial structure that contributes blood flow to the arteriovenous shunt. (A) A single feeder can directly supply blood to the AVM. (B) AVMs with multiple feeding vessels are possible. (C) Feeding vessels are classified as terminal (direct) types or transit (en passage) feeders; direct feeders end in the nidus and transit feeders supply brain tissue after giving branches to the nidus.

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embolization, surgery, and/or radiotherapy. Most often an iAVM’s feeding vessels arise from the anterior, middle, or posterior cerebral arteries, less commonly from the internal or external carotid arteries, the posterior communicating artery, anterior choroidal artery, or the medial or lateral posterior choroidal arteries, as well as the basilar or vertebral arteries and their branches— the superior cerebellar, anterior inferior cerebellar, and posterior inferior cerebellar arteries and the small medullary and pontine branches. Deep and ventricular AVMs will recruit arterial supply, respectively, from perforators (lenticulostriate and thalamoperforator branches) and choroidal arteries (anterior, medial, and lateral posterior choroidal arteries), whereas venous drainage will typically occur via the deep venous system. In more superficial or cortical locations, the main arterial supply is through the pial arteries (branches of the anterior, middle, and posterior cerebral arteries), whereas venous drainage is mainly through the cortical veins. Pial feeders are classified as terminal (direct) or transit types (Fig. 1.7C). Direct feeders end in the nidus. Transit feeders supply brain tissue after giving branches to the nidus. Some AVMs involving the cerebral surface have feeding artery branches that continue through the AVM to supply healthy brain tissue distal to the nidus (“en passage” vessels). A particular subtype of transit feeders are retrograde collateral arteries. Due to the sump effect of the AVM, the distal segment of a transit feeder carries retrograde flow, which also supplies the AVM. These distal segments with retrograde flow are not visible on angiograms obtained through proximal injection of the artery. Retrograde channels can only be visualized by superselective angiography of adjacent vascular territories. The identification of retrograde collateral flow in transit feeders is important for determining the endovascular and surgical therapeutic strategy.1,4,7,8,10 The AVM arterial feeder type does not seem to impact hemorrhage risk. However, en passage feeders are less amenable to endovascular treatment because of their diminutive nature, right-angle orientation to the parent vessel, and the fact that they supply blood to normal cerebral parenchyma distally. Flow augmentation within the AVM can be from direct anterior and middle cerebral artery branches into an AVM or via pial

collaterals providing indirect racemose connections. There can also be collateral circulation between the external carotid artery and the internal carotid artery/ vertebrobasilar circulations. These cases of collateral circulation can be related to increased flow through native developmental arteries such as the inferolateral trunk of the internal carotid artery or via neovascularity. Direct arteriovenous shunts within a nidus are present in 10%–20% of parenchymal AVMs. Intranidal fistulae are potential weak spots for hemorrhage.

Venous Drainage The venous drainage of iAVMs can be single or multiple (Fig. 1.8A and B), depending on whether the nidus has a single or multiple compartments (i.e., is monoor multicompartmental). Two draining veins can join to a single vein in the immediate vicinity and mimic a single draining vein, or a single vein can divide immediately after leaving the nidus. Draining veins can be common cerebral veins, hypertrophic small venous branches, or venous anomalies. Venous drainage is further classified as superficial or deep drainage (Fig. 1.8C). Deep drainage implies that some or all draining veins connect to the internal venous system. This situation is a known surgical risk factor and is taken into consideration in the Spetzler-Martin grading system.18 Deep venous drainage usually flows into the internal system via the ependymal venous plexus. Direct drainage to the larger venous channels of the internal system is rare but can occur. The best-known condition with direct deep drainage is the vein of Galen malformation, but true AVMs of the basal vein of Rosenthal and the thalamostriate vein are also seen occasionally. The absence of cortical venous drainage in a superficially located AVM may indicate thrombosis of the superficial outlets with subsequent rerouting into the deep system, which would suggest a more unstable lesion (Fig. 1.8D). Recruitment of transdural supply is also sometimes seen in large lesions. In evaluating such a lesion, one must determine whether this supply feeds the normal brain—in compensation for an arterial steal—or whether it feeds the AVM itself, which tends to occur in a superficial type of AVM with angiogenetic (or proliferative) potential.4,6

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Anatomy and Histology of Intracranial AVMs

19

Fig. 1.8 Venous drainage. The venous drainage of iAVMs can be (A) single or (B) multiple, depending on whether the nidus has a single or multiple compartments. (C) Venous drainage can also be superficial if all the drainage from the AVM is through the cortical venous system or deep if any or all of the drainage is through deep veins such as the internal cerebral veins, basal veins, or precentral cerebral vein. (D) Venous stenosis is the narrowing of any draining vein outflow pathway. A dural venous sinus could also be stenotic or thrombosed. These abnormalities in venous drainage appear to be associated with hemorrhagic presentation and venous hypertension.

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Histology AVMs have traditionally been viewed as a type of congenital vascular malformation that is due to a failure of orderly resorption of the primitive blood vessels in weeks 4–6 of gestation, involving both arterial and venous origins, and can result in high-flow direct arteriovenous communications between different-size vessels (AVMs), vein malformations, and lymphatic malformations.4,6 Such traditional theories regarding the congenital etiology of iAVMs have recently been challenged and are being replaced by more comprehensive pathophysiological hypotheses that consider these lesions to result from an active angiogenic and inflammatory response to some postnatal event. The association of cytokine genotype with clinical course is consistent with the view that inflammation is a contributory cause of disease pathogenesis or progression. Inflammation may act alone or perhaps in concert with congenital defects, environmental exposure, or chronic hemodynamic derangements to result in the clinical phenotype.19 Macroscopically, AVMs are tangles of abnormally enlarged vessels that directly shunt blood from the arterial system to the venous system due to a lack of an intervening capillary bed. Typically, as mentioned earlier, iAVMs are pyramid shaped, with the base oriented parallel to the meninges and the apex pointing to the ventricles or deep brain. The surrounding parenchyma may appear normal or may be stained a yellowish brown from previous hemorrhage. The overlying meninges tend to have a thickened fibrotic appearance. Neuronal tissue at the margin of the lesions may show evidence of edema and necrosis. Extensive gliosis and fibrosis as well as areas of calcification or bone formation may also be present. Histologically, these abnormal vessels resemble capillaries despite their diameter, which is far larger than that of a capillary. The walls of cerebral arteries and arterioles consist of three concentric layers: the innermost layer is the tunic intima, which consists of a single layer of endothelial cells and the internal elastic lamina; moving outward, the next layer is the tunica media, which contains mostly smooth muscle cells with some elastin and collagen fibers; and the outermost layer is the tunica adventitia, which is composed mostly of collagen fibers, fibroblasts, and associated cells, such as

perivascular nerves (in large and small pial arteries) and pericytes and astrocytic end-feet (in parenchymal arterioles and capillaries). Unlike systemic arteries, cerebral arteries have no external elastic lamina, but instead have a well-developed internal elastic lamina. Smaller pial arteries contain approximately two or three layers of smooth muscle, whereas the penetrating and parenchymal arterioles contain just one layer of smooth muscle. In addition, smooth muscle cells in the medial layer of cerebral arteries and arterioles are circularly arranged and oriented perpendicular to blood flow with essentially a zero-degree pitch. Cerebral veins are very thin walled compared to arteries. The larger pial veins have circumferentially oriented smooth muscle that is not present in veins in the parenchyma. Unlike veins in the periphery, cerebral veins do not contain valves. Due to the shunting of blood from the arteries directly to the veins, in many iAVMs, a high flow appears, which causes, among other things, structural changes to the vessel wall and venous hypertension in the nidus and the draining veins. This high venous pressure may also lead to hypoperfusion with resultant hypoxia or ischemia in the local brain parenchyma and consequent focal neurologic deficits or epileptic focus formation. Hypoxia and ischemia within the nidus itself initiate an inflammatory response, with production of cytokines and ensuing activation of angiogenic factors. The resulting intranidal angiogenesis, along with the mentioned higher intranidal and postnidal venous pressure, gradually remodels the AVM’s vascular network.20 Vascular structures retain the characteristic feeding arterial and draining venous components, but no capillaries are seen between these two elements, so there is direct arteriovenous shunting. Arterial and venous elements both show hypertrophy in their walls. Microscopically, the elastic lamina of the arterial intimal layer is mostly intact but might show some degradation or deficiencies. The thickened veins can be discerned by their size and the absence of elastic staining on histological examination. Both elements can also show hyperplasia of the smooth muscle cells in the tunica media.5,20 The histopathological characteristics of iAVMs are vessels with thin or irregular muscularis and elastica, islands of sclerotic tissue, endothelial thickening, and media hypertrophy in the site of the nidus, making

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Anatomy and Histology of Intracranial AVMs

distinction between arteries and veins difficult. Within the lesion, little to no functionally important brain tissue can be found, leading to the assumption of functional displacement to the margin of the malformation. Histologically, parenchymal cells found within the nidus generally show chronic reactive changes and are thought to be nonfunctioning. Intimal hyperplasia and venous enlargement in the iAVM nidus are the main pathological differentiating features associated with identified risk factors for subsequent hemorrhage. If hemorrhage has occurred, the surrounding parenchyma will have evidence of gliosis and hemosiderin staining.20 There is strong evidence that inflammation plays an important role in the pathobiology, evolution, and clinical course of iAVMs. Infiltration of inflammatory cells into brain parenchyma and AVM vessel walls is observed in both ruptured and unruptured iAVMs. Multiple types of inflammatory cells are present, including neutrophils, eosinophils, macrophages, and lymphocytes. Perivascular inflammation is found in both ruptured and unruptured iAVMs. The response to prior hemorrhage is one of the possible causes for an inflammatory response in the iAVM nidus. However, the microscopic evidence of hemosiderin in walls of the nidal vessels in many unruptured iAVMs suggests that many patients whose lesions are considered unruptured and stable according to their clinical presentation have in fact had clinically silent microhemorrhages. It remains to be determined whether this inflammatory cell infiltration is part of the clearance of hemoglobin breakdown products derived from the microhemorrhages. It also seems possible that inflammation due to other causes and subsequently increased angiogenesis and vascular permeability could be one of the underlying mechanisms predisposing to intralesional microhemorrhages. The presence of macrophages even in hemosiderin-negative specimens suggests that response to hemorrhage does not completely explain the macrophage infiltration in iAVMs. Furthermore, the significant presence of polymorphonuclear cells, especially neutrophils, that are not involved in the clearance of prior hemorrhage implies that there is another primary cause of the inflammatory response that may be subsequently amplified or modified by responses to hemorrhage.19,21

Changes in the nidal angioarchitecture usually result in an enlargement and tortuosity of the feeding arteries. Such feeders may occasionally compress certain neural structures and thus cause neurologic manifestations (e.g., trigeminal neuralgia). The endothelial proliferation and tunica media changes can sometimes produce arterial stenosis, which, along with an additional process of thrombosis or wall dissection, may progress to complete occlusion of a feeder.11 Shear stress (the force that the blood exerts on the vessel wall) activates endothelial and smooth muscle cells and promotes the release of angiogenic factors and cytokines. Since blood vessels adapt to changes in flow through flow-induced vessel wall remodeling, the abnormally high flow in AVMs often causes ectatic (expansive, enlarging) remodeling of the veins draining the AVM or the arteries feeding it, which, in addition to causing enlargement of the vessel caliber, may lead to formation of venous ectasias, intranidal aneurysms, or aneurysms of the feeding arteries. In fact, high blood flow within the feeders, including turbulence and shear stress, can damage the vessel wall and thus cause an aneurysm to form. This is why iAVMs are often associated with cerebral aneurysms, which can be prenidal and arterial, intranidal, or postnidal and venous. The prenidal aneurysms, which are saccular, are most often located on the feeding arteries and occasionally on their parent vessels. Venous ectasia, intranidal aneurysms, and aneurysms of the arteries feeding the AVM are thought to represent weakened parts of the AVM vasculature and are associated with an increased risk of rupture.22–25 High blood flow through the feeders, along with a decrease in or loss of vascular autoregulation, can result in a cerebral steal phenomenon. This is manifested by hypoperfusion of the adjacent or distant regions of the brain with subsequent neurologic deficit. However, this mechanism has been debated for several decades without a definitive conclusion.11,14,26

Conclusion Several factors should be kept in mind when considering treatment option for iAVMs, including lesion characteristics, age of the patient, presence or absence of bleeding and associated aneurysms, diameter and

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location of associated aneurysms, and the pattern of venous drainage. A detailed understanding of the vascular anatomy and the normal variants and types of collateral circulation that are recruited by these lesions is essential for clinicians involved in the surgical and/or endovascular management of these lesions. REFERENCES 1. Osborn AG. Diagnostic Cerebral Angiography. Lippincott Williams & Wilkins; 1999. 2. Lasjaunias P. Clinical Vascular Anatomy and Variations. 2nd ed. Springer; 2001. 3. Toole JF. Cerebrovascular Disorders; with Chapters on Applied Embryology, Vascular Anatomy, and Physiology of the Brain and Spinal Cord. 2nd ed. McGraw-Hill; 1974. 4. Spetzler RF, Kondziolka DS, Higashida RT, Kalani MYS, eds. Comprehensive Management of Arteriovenous Malformations of the Brain and Spine. Cambridge University Press; 2015. https://doi. org/10.1017/CBO9781139523943. 5. Tanaka M. AVM definition and angioarchitecture. In: Beneš V, Bradáč O, eds. Brain Arteriovenous Malformations: Pathogenesis, Epidemiology, Diagnosis, Treatment and Outcome. Springer; 2017. https://doi.org/10.1007/978-3-319-63964-2_2. 6. BenešV,Bradáč O. Brain Arteriovenous Malformations: Pathogenesis, Epidemiology, Diagnosis, Treatment and Outcome. Springer; 2017. https://doi.org/10.1007/978-3-319-63964-2_2. 7. Yasargil MG. Microneurosurgery, Vol IIIA: AVM of the Brain, History, Embryology, Pathological Considerations, Hemodynamics, Diagnostic Studies, Microsurgical Anatomy. Thieme; 2013. 8. Yasargil MG. Microneurosurgery, Vol IIIB: AVM of the Brain, History, Embryology, Pathological Considerations, Hemodynamics, Diagnostic Studies, Microsurgical Anatomy. Thieme; 2013. 9. Wilson CB, Stein BM, eds. Intracranial Arteriovenous Malformations. Williams & Wilkins; 1984. 10. Lawton MT. Seven AVMs: Tenets and Techniques for Resection. Thieme Medical Publishers; 2014. 11. Terbrugge KG, Brain AVM. Relationship of angioarchitecture and clinical symptoms and implications for treatment. Interv Neuroradiol. 2003;9(Suppl 2):107–108. 12. Shankar JJS, Menezes RJ, Pohlmann-Eden B, Wallace C, terBrugge K, Krings T. Angioarchitecture of brain AVM determines the presentation with seizures: proposed scoring system. AJNR Am J Neuroradiol. 2013;34(5):1028–1034. https:// doi.org/10.3174/ajnr.A3361. 13. Lin F, Wu J, Zhao B, et al. Preoperative functional findings and surgical outcomes in patients with motor cortical arteriovenous malformation. World Neurosurg. 2016;85:273–281. https://doi. org/10.1016/j.wneu.2015.10.002.

14. Shah MN, Smith SE, Dierker DL, et al. The relationship of cortical folding and brain arteriovenous malformations. Neurovasc Imaging. 2016;2:13. https://doi.org/10.1186/s40809-016-0024-3. 15. Rousseau P-N, La Piana R, Chai XJ, Chen J-K, Klein D, Tampieri D. Brain functional organization and structure in patients with arteriovenous malformations. Neuroradiology. 2019;61(9):1047– 1054. https://doi.org/10.1007/s00234-019-02245-6. 16. Kato Y, Sano H, Iritani K, et al. Successful resection of AVMs on eloquent areas diagnosed by surface anatomy scanning and motor-evoked potential. J Clin Neurosci. 1998;5(Suppl):72–77. https://doi.org/10.1016/S0967-5868(98)90018-2. 17. Stapf C, Mast H, Sciacca RR, et al. Predictors of hemorrhage in patients with untreated brain arteriovenous malformation. Neurology. 2006;66(9):1350–1355. https://doi.org/10.1212/01. wnl.0000210524.68507.87. 18. Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg. 1986;65(4):476– 483. https://doi.org/10.3171/jns.1986.65.4.0476. 19. Mouchtouris N, Jabbour PM, Starke RM, et al. Biology of cerebral arteriovenous malformations with a focus on inflammation. J Cereb Blood Flow Metab. 2015;35(2):167–175. https://doi.org/10.1038/jcbfm.2014.179. 20. Järvelin P, Wright R, Pekonen H, Keränen S, Rauramaa T, Frösen J. Histopathology of brain AVMs part I: microhemorrhages and changes in the nidal vessels. Acta Neurochir (Wien). 2020;162(7):1735–1740. https://doi.org/10.1007/s00701-020-04391-w. 21. Wright R, Järvelin P, Pekonen H, Keränen S, Rauramaa T, Frösen J. Histopathology of brain AVMs part II: inflammation in arteriovenous malformation of the brain. Acta Neurochir (Wien). 2020;162(7):1741–1747. https://doi.org/10.1007/ s00701-020-04328-3. 22. Almefty K, Spetzler RF. Arteriovenous malformations and associated aneurysms. World Neurosurg. 2011;76(5):396–397. https://doi.org/10.1016/j.wneu.2011.06.051. 23. Crawford PM, West CR, Chadwick DW, Shaw MD. Arteriovenous malformations of the brain: natural history in unoperated patients. J Neurol Neurosurg Psychiatry. 1986;49(1):1–10. https://doi.org/10.1136/jnnp.49.1.1. 24. Dalton A, Dobson G, Prasad M, Mukerji N. De novo intracerebral arteriovenous malformations and a review of the theories of their formation. Br J Neurosurg. 2018;32(3):305– 311. https://doi.org/10.1080/02688697.2018.1478060. 25. Hernesniemi JA, Dashti R, Juvela S, Väärt K, Niemelä M, Laakso A. Natural history of brain arteriovenous malformations: a long-term follow-up study of risk of hemorrhage in 238 patients. Neurosurgery. 2008;63(5):823– 829; discussion 829–831. https://doi.org/10.1227/01.NEU. 0000330401.82582.5E. 26. Grzyska U, Fiehler J. Pathophysiology and treatment of brain AVMs. Clin Neuroradiol. 2009;19(1):82–90. https://doi. org/10.1007/s00062-009-8035-y.

Chapter 2

Pathology and Genetics Michael Goutnik, William Dodd, Coulter Nathan Small, Dimitri Laurent, Anthony T. Yachnis, Brandon Lucke-Wold, and Brian L. Hoh

Chapter Outline Introduction Pathology Genetics of AVMs Conclusion

Introduction Arteriovenous malformations (AVMs) are irregular, tangled vascular structures that form connections between arteries and veins without an intervening capillary bed. The etiology of these lesions is still unclear; however, there is strong evidence that genetic predisposition and dysregulated vascular inflammation are critical steps in AVM formation.1 Intracranial AVMs (iAVMs) are often clinically silent, complicating measures of prevalence, but most reports estimate up to 0.1% of the adult population harbors an iAVM.2 The primary concern in the management of iAVMs is intracerebral hemorrhage (ICH) secondary to rupture,1 though unruptured iAVMs can also cause headache, seizures, and focal neurological deficits.3 The incidence of symptomatic iAVMs is approximately 1 per 100,000 person-years,4 and the average age at initial presentation is between 30 and 40 years.5 ICH is the most common presenting symptom of iAVMs, and AVM rupture accounts for 2% of all strokes.2 Treatment options are resection (surgical removal), endovascular embolization, stereotactic radiosurgery, or a combination thereof. There is no single optimal treatment strategy, especially for unruptured iAVMs, nor are there any clearly efficacious

pharmacologic interventions. A clear understanding of the underlying pathology is necessary to optimize treatments and improve outcomes for iAVM patients.

Pathology CLASSIFICATION Intracranial AVMs are primarily classified based on size, morphology, and location of the nidus (the central area of tangled vessels in which the arteriovenous shunting occurs).2,6 The Spetzler-Martin scale7 is a widely used classification system for stratifying surgical risk of iAVM resection. This scale uses three features: size (< 3, 3–6, or > 6 cm), location (eloquent vs noneloquent), and venous drainage (superficial vs deep). Arteriovenous fistulae are distinguished from AVMs by the presence of a single, high-flow anastomosis rather than a nidus6 (see Fig. 2.1). Further, AVMs, although usually static, can grow or regress but are not neoplastic lesions and thus are distinct from hemangiomas.6 ANATOMY AND HISTOLOGY Arteriovenous malformations are complex and variable; an AVM can involve any combination of afferent and efferent vessels and exist anywhere in the brain, though the distribution of these lesions is roughly proportionately to brain volume.3 Microscopically, the nidal vessels can resemble typical arteries or veins, malformed arteries or veins, or vessels resembling neither arteries nor veins (Fig. 2.2).8 Immunohistochemical and western blot data on human iAVMs reveal coexpression of artery and vein differentiation genes, as well as significantly lower expression of KLF2, a marker for vascular maturity, compared to control tissue samples.9 Vessels near the 23

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PART 1 The Patient-Centered Approach

nidus often have a diminished tunica media layer and decreased pericyte coverage, which may contribute to instability of the lesion.10 Dilated perinidal capillary networks are found near iAVM nidi and connected to both the malformation and healthy vasculature, which may have important implications for perioperative bleeding.11 Molecular and histological evidence also suggests angiogenic factors, and inflammatory cytokines are more highly expressed in iAVMs.12,13 Tissue samples from the nidus of iAVMs exhibit significantly higher collagen I levels, reduced collagen III levels, and increased endothelial-to-mesenchymal transition (EndMT) markers compared to control samples.14,15 These histologic characteristics have important functional implications for iAVM formation and rupture, which are discussed further in subsequent sections. The lack of a capillary bed is a critical element of iAVM pathology. Without the hemodynamic resistance supplied by the small-caliber capillaries, there is hypotension in the afferent vessels and increased hemodynamic stress in the venous drainage. The resultant shear stress can induce vascular smooth muscle cell hypertrophy in the draining veins.16 The combination of tortuous intranidal vessels, increased hemodynamic stress, and impaired venous drainage is the fundamental driving force of iAVM rupture.17 AVM FORMATION AVM formation is a complex process involving positive feedback loops between vascular inflammation, maladaptive vascular remodeling, and dysregulated angiogenesis (blood vessel formation). The precise inciting mechanisms at the initial stages of AVM formation are unknown but likely involve a genetic susceptibility to hemodynamic stress–induced vascular inflammation (genetic syndromes associated with AVMs are discussed further in the Genetics of AVMs section of this chapter). Induction of inflammatory cascades in the developing cerebrovasculature creates a mechanism for AVM formation by inciting vascular remodeling through concomitant angiogenesis and vascular damage.1 An initial insult causes the production of the inflammatory mediators interleukin 6 (IL-6), IL8, IL-1β, tumor necrosis factor alpha (TNF-α), and macrophage migration inhibitory factor (MIF).1 These cytokines then upregulate the expression of E-selectin and the integrins intercellular adhesion molecule 1

Pearls • AVMs can be the result of one abnormal connection (fistular AVM) or multiple abnormal connections (racemose AVM). • Lack of a capillary bed in iAVMs results in abnormal anatomy in all vessels involved: arteries, nidus, and veins. • AVM formation is due to a combination of dysregulated vessel formation, vascular inflammation, and abnormal vessel remodeling after injury. • Risk factors for bleeding from an iAVM: previous hemorrhage, deep location, deep venous drainage, single draining vein, and draining vein stenosis. • Risk factors for symptoms: brainstem location, female sex, more than three arterial feeders, and venous varices.

(ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) on endothelial cells, promoting leukocyte adhesion and increased extravasation of macrophages and neutrophils. These phagocytic cells, particularly neutrophils, release matrix metalloproteinase 9 (MMP-9), which degrades cell-cell adhesion molecules and the vascular extracellular matrix, causing dilatation of the vessel and vascular instability.1,18,19 Human iAVM proteomics demonstrates differential expression of cell-cell interaction proteins, including those involved in focal adhesions, tight junctions, and gap junctions.20 Furthermore, the inflammatory mediators IL-6, IL-1β, and TNF-α promote angiogenesis through increased cellular secretion of vascular endothelial growth factor (VEGF) and activation of VEGF receptor (VEGFR) protein.1 Regulatory micro-RNAs involved in VEGF signaling are also differentially expressed in AVM patients compared to controls.21 RNA sequencing studies of AVM tissue demonstrate upregulation of inflammatory cytokines and downregulation of the TGF-β signaling pathway, consistent with the notion that exacerbated inflammation interferes with TGF-β– mediated vascular adaptations.22 The dynamic interaction between these pathways has been termed the “response-to-injury” paradigm of AVM pathogenesis,23 emphasizing the departure from conceptualization of AVMs as inactive, congenital lesions.

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Pathology and Genetics

A

B

C Fig. 2.1 What is an AVM? An AVM is defined by its arterial, intervening nidal, and venous components. In a typical iAVM (A) there are multiple arterial connections feeding the nidus; this is referred to as a racemose iAVM. On rare occasions, there is a single feeder so dominant it overwhelms the meaningful appearance of a nidus and looks like a direct connection (or fistula) between an artery and a vein itself (B). Those are considered fistular iAVMs if they are located within the substance of the brain (intraaxial: pial or parenchymal location). Similar malformations without an identifiable nidus that are located outside the brain itself (in the bone or meninges) are called arteriovenous fistulae (C).

The physiologic response to vascular inflammation and increased VEGF signaling would be remodeling of the affected vessel to adapt to the prevailing hemodynamic forces without compromising blood supply. Any dysregulation of the VEGF-induced remodeling or insufficient TGF-β signaling creates the opportunity for maladaptation of the affected vessels by disordered angiogenesis and, eventually, formation of an AVM. Juxtacrine signaling (contact-dependent signaling) and cellular differentiation pathways are

important mediators of the angiogenic and vascular remodeling seen during AVM formation. The Notch pathway is a prototypical juxtacrine signaling pathway in which a transmembrane receptor (Notch1–4 in humans) interacts with a ligand (e.g., Delta-like-4 and Jagged-1) on a neighboring cell, inducing proteolysis of the intracellular domain of the receptor and translocation to the nucleus, where it functions as a transcription factor.24 Notch signaling is vital for proper embryonic development, including regulation

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A

B

C

D

Fig. 2.2 Histological sections. (A) Hematoxylin and eosin (H&E) stain demonstrates thick-walled vascular channels of iAVM with intervening gliotic tissue. (B) Masson trichrome stain demonstrates thickened “arterialized” veins with abundant collagen (blue) with interspersed gliotic tissue. (C) Glial fibrillary acidic protein immunohistochemistry demonstrates gliotic brain tissue (brown stain). (D) H&E-stained section. The black material within the vascular lumen represents embolic agent (Onyx, Medtronic, Memphis, TN) that was used in endovascular embolization. (Original magnification of all images: × 200.)

of arterial-venous differentiation and VEGF-mediated angiogenesis.25,26 Examination of human iAVM samples shows increases in the activated form of Notch1 and the Notch ligands Jagged-1 and Delta-like-4 compared to control cerebral vessels, regardless of clinical presentation.27 Studies using mice with inducible and tissue-specific Notch signaling have demonstrated that Notch signaling in endothelial cells, but not hematopoietic cell lineages, is sufficient to drive formation of arteriovenous shunts and AVMlike lesions.28 A recent study has also reported a role for the Sonic hedgehog (Shh) signaling pathway in human iAVMs; the authors found increased expression of Shh and related proteins in iAVM samples and

that induction of Shh signaling in rats caused formation of AVM-like lesions.29 AVM RUPTURE AVM rupture is largely driven by exacerbation of or failure to adapt to the same factors that cause AVM formation. VEGF expression levels correlate with hemorrhage,19,30 and treatment with a competitive VEGF antagonist, sFLT1, reduces mortality in a mouse model.31 Bevacizumab, a Food and Drug Administration (FDA)–approved anti-VEGF ­ monoclonal antibody used in the treatment of certain cancers, is a conceptually intriguing candidate for AVM treatment. Bevacizumab treatment reduces

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Pathology and Genetics

vascular dysplasia in mice, although AVM rupture was not an endpoint in the proof-of-concept study.32 A phase III clinical trial of bevacizumab for hereditary hemorrhagic telangiectasia patients, who are at increased risk of AVMs (see “Genetics of AVMs”), is ongoing (clinicaltrials.gov identifier NCT 03227263); however, only small pilot studies have evaluated the effect on AVMs specifically.33 Just as in AVM formation, vascular inflammation is fundamental to AVM rupture. Monocyte lineage cells are upregulated in iAVMs with or without hemorrhage34; however, increased expression of proinflammatory cytokines correlates with greater ICH risk.1 These data suggest that the crucial element in determining rupture may be the adoption of a characteristically proinflammatory phenotype by extravasated monocytes and other hematopoietic cells. Mouse models of iAVMs have increased proinflammatory differentiation by monocytes/macrophages in brain regions with active angiogenesis, suggesting blockage of macrophage homing/differentiation as a potential therapy.35 Similar to cerebral aneurysms, AVMs ultimately rupture when the mechanical integrity of the vessel wall is no longer sufficient to withstand the outward pressure of the blood. Plateletderived growth factor B (PDGFB) and platelet-derived growth factor receptor β (PDGFR-β) are important in mural cell regulation during vascular maturation, and their expression is reduced in iAVMs.36 Pericytes, which express PDGFR-β, are a key component of the neurovascular unit, covering the vascular wall and maintaining junctional integrity and regulation of immune cell entry. AVM tissue has decreased pericyte coverage, with the lowest level found in samples of previously ruptured AVMs.10 Further, the same study found that unruptured AVMs with low pericyte coverage were more likely to have microhemorrhages. CLINICAL RISK FACTORS FOR RUPTURE Clinical management and decision-making can be effectively guided by understanding the risk factors for symptom development and rupture. Brainstem location, female sex, the presence of more than three arterial feeders, and/or the presence of venous varices appear to correlate with the initial presentation of focal neurologic deficits.37,38 The overall risk of iAVM hemorrhage is approximately 2%–4% per year, and AVMs that have ruptured once are at an increased risk of

rupturing again.39,40 Drainage into the deep sinuses, deep location of the AVM itself, a single draining vein, and stenosis of the draining vein(s) all increase the relative risk of hemorrhage.40 Some studies also report that rupture risk increases with AVM size,41 although an increase in risk has not been established beyond doubt.42 About 20%–25% of patients with iAVMs have cerebral aneurysms, which are associated with hemorrhage upon initial presentation but not subsequent hemorrhage in those followed prospectively.42,43,44 Clinically silent intralesional microhemorrhage is a predictor for both hemorrhage at initial presentation and subsequent hemorrhage.45 In unruptured AVMs, silent microhemorrhage is associated with a significantly lower mean transit time through the nidus, implicating high flow rates in microhemorrhage formation.46 Finally, race/ethnicity may represent a potential risk factor for iAVM rupture: Hispanic patients have an increased risk of subsequent ICH compared to non-Hispanic White patients.47

Genetics of AVMs A summary of important inflammatory and genetic markers is presented in Table 2.1. GENETIC SYNDROMES ASSOCIATED WITH AVMS Most AVMs are found in patients without known predisposing risk factors, but there are several classical hereditary syndromes that increase the likelihood of AVM formation and rupture. The most common is hereditary hemorrhagic telangiectasia syndrome (HHT, also known as Osler-Weber-Rendu syndrome). HHT is an autosomal dominant disorder arising from mutations in ENG (HHT type 1; HHT1) or ALK1 (HHT type 2; HHT2) that affect TGF-β signaling and angiogenesis.48 Both types of HHT cause vascular malformations in all tissues, but small lesions in the skin, nasal cavity, and oral cavity are the most common presentation. Intracranial AVMs, as well as AVMs of the pulmonary circulation, are more common in HHT1 than in HHT2, in contrast to hepatic AVMs, which are more common in HHT2.48 Overall, around 10% of HHT patients have at least one iAVM, and these patients are much more likely to have multiple AVMs compared to patients whose cases are considered sporadic.49,50 In patients with familial iAVMs, the lesions are typically diagnosed

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PART 1 The Patient-Centered Approach

TABLE 2.1 Summary of Important Inflammatory and Genetic Markers and Their Relevance Inflammatory Markers IL-1β, IL-6, IL-8, TNF-α, MIF1

MMP-91,18,19

Inflammatory cytokines that promote extravasation of macrophages and neutrophils. IL-1β, IL-6, and TNF-α also promote angiogenesis through VEGF and VEGFR secretion. RNA sequencing analysis stipulates upregulation of these cytokines in AVM lesions and downregulation of antiinflammatory mediators like TGF-β.22 Proinflammatory cytokines also correlate with greater ICH risk. Mutations in the genes that code for these cytokines have been associated with AVM formation and rupture.58–60 A G>C transversion in the IL6 promoter is associated with greater IL-6 expression, and importantly greater expression of the other cytokines and a 3× greater ICH risk.1 Released by neutrophils, promotes dilatation of vessels and vascular instability.

Genetic Programs/Signaling Pathways Notch and SHH signaling27–29 PDGFB and PDGFR-β10,36 ENG and ALK1 mutations48–50,53

MADH4 and RASA1 mutations54,55 PITPNM3, SARS, and LEMD356 MAPK signaling— KRAS57 APOE-ε259,60

Embryonic development pathways whose associated proteins are present in AVM samples and whose induction is sufficient to form AVMs. Pericytes maintain vascular integrity and express PDGFR-β. PDGFB and PDGFR-β have diminished expression in iAVMs. AVMs have lower pericyte coverage, and this is especially true in previously ruptured AVMs. Mutations in these genes affect TGF-β signaling and angiogenesis and are associated with the two subtypes of HHT. Patients with HHT have a higher prevalence of AVMs compared to the general population. Mouse models with genetic mutations in ENG and ALK1 are often used to study AVM pathophysiology. Mutations in these respective genes lead to juvenile polyposis and CM-AVM, which are both capable of producing iAVMs. Novel genes, whose functions are associated with TGF-β and VEGF signaling. Pathogenic variants are associated with iAVMs. KRAS mutations are implicated in iAVMs. MAPK inhibition was shown to reverse changes seen in aberrant AVM vessels. Polymorphisms in this apolipoprotein gene are associated with ICH risk following treatment of AVMs.

CM-AVM, Capillary malformation–arteriovenous malformation syndrome; HHT, hereditary hemorrhagic telangiectasia syndrome; ICH, intracerebral hemorrhage; IL, interleukin; MAPK, mitogen-activated protein kinase; MIF, macrophage migration inhibitory factor; MMP-9, matrix metalloproteinase 9; PDGFB, platelet-derived growth factor B; PDGFR, platelet-derived growth factor receptor; TGF, transforming growth factor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor; VEGFR-β, vascular endothelial growth factor receptor-β.

at an earlier age, but the characteristics of presentation are similar to those of patients with sporadic AVMs.51 Management of AVMs in HHT patients is generally more conservative, given the early age at diagnosis, possible multiplicity of lesions, and some evidence that HHT-related AVMs are slightly less likely to rupture.52 Mouse models of HHT (heterozygous knockouts of Alk1 or Eng) are commonly used to study AVM pathophysiology53; however, the applicability to sporadic AVMs is unclear. Other genetic syndromes capable of causing

iAVMs are combined juvenile polyposis/HHT, caused by MADH4 mutations,54 and capillary malformation– arteriovenous malformation syndrome (CM-AVM), caused by certain mutations in the RASA1 gene.55 There is reciprocal importance in understanding heritable causes of AVMs; patients diagnosed with these syndromes may merit increased surveillance for AVMs, and patients presenting with symptomatic AVMs may consider genetic testing, especially as whole-genome sequencing becomes clinically available.

2

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Pathology and Genetics

SPORADIC AVMS Investigation into sporadic/non-Mendelian cases of iAVMs has revealed numerous polymorphisms associated with AVM formation and rupture. Wholeexome sequencing has revealed pathogenic variants in several novel genes associated with iAVMs, including PITPNM3, SARS, and LEMD3.56 Wang et al. also used pathway analysis to investigate the functional implications of these and other potentially pathogenic polymorphisms. The gene variants identified in their studies were closely associated with the TGF-β and VEGF/VEGFR2 signaling pathways, supporting the central role of these pathways in AVM formation. Endothelial cell exome sequencing also implicates somatic activating KRAS mutations in iAVMs.57 In vitro MAPK inhibition was able to reverse associated phenotypic and gene expression changes seen in aberrant vessels, suggesting potential therapeutic value. Mutations affecting the expression of apolipoprotein E2 and the classical cytokines IL-1β, IL-6, and TNF-α have been associated with AVM formation and/or rupture as well.13,58,59 One particular IL6 promoter polymorphism (a G > C transversion at −174) was associated with increased IL-6 expression, which in turn induced greater expression of IL-1β, TNF-α, IL-8, MMP-3, MMP-9, and MMP-12 and led to a 3 × greater ICH risk.1 Furthermore, other polymorphisms in TNF-α and apolipoprotein E2 were associated with a greater risk of posttreatment ICH.60 These studies reaffirm the function of vascular inflammation as a mediator of AVM pathology as well as supporting the notion that targeting inflammation could be a useful strategy in the treatment of sporadic AVMs.

Conclusion The pathogenesis of iAVMs is complex, and the precise mechanisms underlying the formation of these lesions remain uncertain. Although abnormal gene expression may predispose to iAVM formation, syndromic patients comprise a minority of individuals presenting with iAVMs. The overarching theme appears to be one of a maladaptive response to vascular injury in the setting of a proinflammatory state. As our basic understanding of iAVMs increases, drugs designed to target proteins involved in blood vessel

formation, cellular inflammation, or cell-to-cell interaction may translate into therapeutic options for iAVM patients. Continued research is necessary to improve the outlook for those affected by this disease process. REFERENCES 1. Mouchtouris N, Jabbour PM, Starke RM, et al. Biology of cerebral arteriovenous malformations with a focus on inflammation. J Cereb Blood Flow Metab. 2015;35(2):167–175. https://doi.org/10.1038/jcbfm.2014.179. 2. Arteriovenous Malformation Study Group. Arteriovenous malformations of the brain in adults. N Engl J Med. 1999;340(23): 1812–1818. https://doi.org/10.1056/nejm199906103402307. 3. Perret G, Nishioka H. Report on the cooperative study of intracranial aneurysms and subarachnoid hemorrhage. Section VI. Arteriovenous malformations. An analysis of 545 cases of cranio-cerebral arteriovenous malformations and fistulae reported to the cooperative study. J Neurosurg. 1966;25(4): 467–490. https://doi.org/10.3171/jns.1966.25.4.0467. 4. Berman MF, Sciacca RR, Pile-Spellman J, et al. The epidemiology of brain arteriovenous malformations. Neurosurgery. 2000;47(2):389–396; discussion 397. https://doi. org/10.1097/00006123-200008000-00023. 5. Stapf C, Mast H, Sciacca RR, et al. The New York Islands AVM Study: design, study progress, and initial results. Stroke. 2003;34(5):e29–e33. https://doi.org/10.1161/01. str.0000068784.36838.19. 6. Al-Shahi R, Warlow C. A systematic review of the frequency and prognosis of arteriovenous malformations of the brain in adults. Brain. 2001;124(pt 10):1900–1926. https://doi. org/10.1093/brain/124.10.1900. 7. Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg. 1986;65(4):476– 483. https://doi.org/10.3171/jns.1986.65.4.0476. 8. McCormick WF. The pathology of vascular (“arteriovenous”) malformations. J Neurosurg. 1966;24(4):807. https://doi. org/10.3171/jns.1966.24.4.0807. 9. Thomas JM, Surendran S, Abraham M, et al. Gene expression analysis of nidus of cerebral arteriovenous malformations reveals vascular structures with deficient differentiation and maturation. PLoS One. 2018;13(6). https://doi.org/10.1371/ journal.pone.0198617, e0198617. 10. Winkler EA, Birk H, Burkhardt JK, et al. Reductions in brain pericytes are associated with arteriovenous malformation vascular instability. J Neurosurg. 2018;129(6):1464–1474. https://doi.org/10.3171/2017.6.jns17860. 11. Sato S, Kodama N, Sasaki T, Matsumoto M, Ishikawa T. Perinidal dilated capillary networks in cerebral arteriovenous malformations. Neurosurgery. 2004;54(1):163–170. https:// doi.org/10.1227/01.neu.0000097518.57741.be. 12. Chen W, Choi EJ, McDougall CM, Su H. Brain arteriovenous malformation modeling, pathogenesis, and novel therapeutic targets. Transl Stroke Res. 2014;5(3):316–329. https://doi. org/10.1007/s12975-014-0343-0. 13. Achrol AS, Guzman R, Varga M, Adler JR, Steinberg GK, Chang SD. Pathogenesis and radiobiology of brain arteriovenous malformations: implications for risk stratification in natural history and posttreatment course. Neurosurg Focus. 2009;26(5):E9. https://doi.org/10.3171/2009.2.focus0926.

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14. Guo Y, Qumu SW, Nacar OA, et al. Human brain arteriovenous malformations are associated with interruptions in elastic fibers and changes in collagen content. Turk Neurosurg. 2013;23(1): 10–15. https://doi.org/10.5137/1019-5149.jtn.5911-12.0. 15. Shoemaker LD, McCormick AK, Allen BM, Chang SD. Evidence for endothelial-to-mesenchymal transition in human brain arteriovenous malformations. Clin Transl Med. 2020;10(2). https://doi.org/10.1002/ctm2.99, e99. 16. Hamby WB. The pathology of supratentorial angiomas. J Neurosurg. 1958;15(1):65–75. https://doi.org/10.3171/jns.1958.15.1.0065. 17. Hademenos GJ, Massoud TF. Risk of intracranial arteriovenous malformation rupture due to venous drainage impairment. A theoretical analysis. Stroke. 1996;27(6):1072–1083. https:// doi.org/10.1161/01.str.27.6.1072. 18. Chen Y, Fan Y, Poon KY, et al. MMP-9 expression is associated with leukocytic but not endothelial markers in brain arteriovenous malformations. Front Biosci. 2006;11:3121– 3128. https://doi.org/10.2741/2037. 19. Hashimoto T, Wu Y, Lawton MT, Yang GY, Barbaro NM, Young WL. Coexpression of angiogenic factors in brain arteriovenous malformations. Neurosurgery. 2005;56(5):1058–1065; discussion 1058–1065. 20. Wang X, Hao Q, Zhao Y, Guo Y, Ge W. Dysregulation of cell–cell interactions in brain arteriovenous malformations: A quantitative proteomic study. Proteomics Clin Appl. 2017;11(5-6). https://doi.org/10.1002/prca.201600093. 21. Chen Y, Li Z, Shi Y, et al. Deep sequencing of small RNAs in blood of patients with brain arteriovenous malformations. World Neurosurg. 2018;115:e570–e579. https://doi.org/10.1016/j. wneu.2018.04.097. 22. Hauer AJ, Kleinloog R, Giuliani F, et al. RNA-sequencing highlights inflammation and impaired integrity of the vascular wall in brain arteriovenous malformations. Stroke. 2020;51(1): 268–274. https://doi.org/10.1161/strokeaha.119.025657. 23. Kim H, Su H, Weinsheimer S, Pawlikowska L, Young WL. Brain arteriovenous malformation pathogenesis: a response-to-injury paradigm. Acta Neurochir Suppl. 2011;111:83–92. https://doi. org/10.1007/978-3-7091-0693-8_14. 24. Yamamoto S, Schulze KL, Bellen HJ. Introduction to Notch signaling. Methods Mol Biol. 2014;1187:1–14. https://doi. org/10.1007/978-1-4939-1139-4_1. 25. Jin Y, Kaluza D, Jakobsson L. VEGF, Notch and TGFβ/BMPs in regulation of sprouting angiogenesis and vascular patterning. Biochem Soc Trans. 2014;42(6):1576–1583. https://doi. org/10.1042/bst20140231. 26. Lawson ND, Scheer N, Pham VN, et al. Notch signaling is required for arterial-venous differentiation during embryonic vascular development. Development. 2001;128(19):3675–3683. 27. ZhuGe Q, Zhong M, Zheng W, et al. Notch-1 signalling is activated in brain arteriovenous malformations in humans. Brain. 2009;132(pt 12):3231–3241. https://doi.org/10.1093/ brain/awp246. 28. Murphy PA, Kim TN, Huang L, et al. Constitutively active Notch4 receptor elicits brain arteriovenous malformations through enlargement of capillary-like vessels. Proc Natl Acad Sci U S A. 2014;111(50):18007–18012. https://doi.org/10.1073/ pnas.1415316111. 29. Giarretta I, Sturiale CL, Gatto I, et al. Sonic hedgehog is expressed in human brain arteriovenous malformations and induces arteriovenous malformations in vivo. J Cereb Blood Flow Metab. 2021;41(2):324–335. https://doi.org/10.1177/02 71678x20912405.

30. Zhu W, Chen W, Zou D, et al. Thalidomide reduces hemorrhage of brain arteriovenous malformations in a mouse model. Stroke. 2018;49(5):1232–1240. https://doi.org/10.1161/ strokeaha.117.020356. 31. Zhu W, Shen F, Mao L, et al. Soluble FLT1 gene therapy alleviates brain arteriovenous malformation severity. Stroke. 2017;48(5):1420–1423. https://doi.org/10.1161/ strokeaha.116.015713. 32. Walker EJ, Su H, Shen F, et al. Bevacizumab attenuates VEGFinduced angiogenesis and vascular malformations in the adult mouse brain. Stroke. 2012;43(7):1925–1930. https://doi. org/10.1161/strokeaha.111.647982. 33. Papagiannaki C, Yardin C, Iosif C, Couquet C, Clarençon F, Mounayer C. Intra-arterial in-situ bevacizumab injection effect on angiogenesis. Results on a swine angiogenesis model. J Neuroradiol. 2021;48(4):299–304. https://doi.org/10.1016/j. neurad.2020.03.003. 34. Chen Y, Zhu W, Bollen AW, et al. Evidence of inflammatory cell involvement in brain arteriovenous malformations. Neurosurgery. 2008;62(6):1340–1350. https://doi.org/10.1227/01. neu.0000333306.64683.b5. 35. Zhang R, Han Z, Degos V, et al. Persistent infiltration and pro-inflammatory differentiation of monocytes cause unresolved inflammation in brain arteriovenous malformation. Angiogenesis. 2016;19(4):451–461. https://doi.org/10.1007/ s10456-016-9519-4. 36. Chen W, Guo Y, Walker EJ, et al. Reduced mural cell coverage and impaired vessel integrity after angiogenic stimulation in the Alk1-deficient brain. Arterioscler Thromb Vasc Biol. 2013;33(2):305–310. https://doi.org/10.1161/ atvbaha.112.300485. 37. Choi JH, Mast H, Hartmann A, et al. Clinical and morphological determinants of focal neurological deficits in patients with unruptured brain arteriovenous malformation. J Neurol Sci. 2009;287(1-2):126–130. https://doi.org/10.1016/j. jns.2009.08.011. 38. Lv X, Li Y, Yang X, Jiang C, Wu Z. Characteristics of brain arteriovenous malformations in patients presenting with nonhemorrhagic neurologic deficits. World Neurosurg. 2013;79(3-4):484–488. https://doi.org/10.1016/j.wneu.2012. 04.006. 39. Goldberg J, Raabe A, Bervini D. Natural history of brain arteriovenous malformations: systematic review. J Neurosurg Sci. 2018;62(4):437–443. https://doi.org/10.23736/s0390-5616. 18.04452-1. 40. Friedlander RM. Clinical practice. Arteriovenous malformations of the brain. N Engl J Med. 2007;356(26):2704–2712. https:// doi.org/10.1056/nejmcp067192. 41. Stefani MA, Porter PJ, terBrugge KG, Montanera W, Willinsky RA, Wallace MC. Large and deep brain arteriovenous malformations are associated with risk of future hemorrhage. Stroke. 2002;33(5):1220–1224. https://doi.org/10.1161/01. str.0000013738.53113.33. 42. Stapf C, Mast H, Sciacca RR, et al. Predictors of hemorrhage in patients with untreated brain arteriovenous malformation. Neurology. 2006;66(9):1350–1355. https://doi.org/10.1212/01. wnl.0000210524.68507.87. 43. Lasjaunias P, Piske R, Terbrugge K, Willinsky R. Cerebral arteriovenous malformations (C. AVM) and associated arterial aneurysms (AA). Analysis of 101 C. AVM cases, with 37 AA in 23 patients. Acta Neurochir (Wien). 1988;91(1-2):29–36. https://doi.org/10.1007/bf01400524.

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44. Lv X, Li Y, Yang X, Jiang C, Wu Z. Characteristics of arteriovenous malformations associated with cerebral aneurysms. World Neurosurg. 2011;76(3-4):288–291. https:// doi.org/10.1016/j.wneu.2011.03.022. 45. Guo Y, Saunders T, Su H, et al. Silent intralesional microhemorrhage as a risk factor for brain arteriovenous malformation rupture. Stroke. 2012;43(5):1240–1246. https:// doi.org/10.1161/strokeaha.111.647263. 46. Chen X, Cooke DL, Saloner D, et al. Higher flow is present in unruptured arteriovenous malformations with silent intralesional microhemorrhages. Stroke. 2017;48(10):2881– 2884. https://doi.org/10.1161/strokeaha.117.017785. 47. Kim H, Sidney S, McCulloch CE, et al. Racial/ethnic differences in longitudinal risk of intracranial hemorrhage in brain arteriovenous malformation patients. Stroke. 2007;38(9):2430– 2437. https://doi.org/10.1161/strokeaha.107.485573. 48. Letteboer TG, Mager JJ, Snijder RJ, et al. Genotype-phenotype relationship in hereditary haemorrhagic telangiectasia. J Med Genet. 2006;43(4):371–377. https://doi.org/10.1136/ jmg.2005.035451. 49. Brinjikji W, Iyer VN, Wood CP, Lanzino G. Prevalence and characteristics of brain arteriovenous malformations in hereditary hemorrhagic telangiectasia: a systematic review and meta-analysis. J Neurosurg. 2017;127(2):302. https://doi. org/10.3171/2016.7.jns16847. 50. Bharatha A, Faughnan ME, Kim H, et al. Brain arteriovenous malformation multiplicity predicts the diagnosis of hereditary hemorrhagic telangiectasia: quantitative assessment. Stroke. 2012;43(1):72–78. https://doi.org/10.1161/strokeaha.111.629865. 51. van Beijnum J, van der Worp HB, Schippers HM, et al. Familial occurrence of brain arteriovenous malformations: a systematic review. J Neurol Neurosurg Psychiatry. 2007;78(11):1213–1217. https://doi.org/10.1136/jnnp.2006.112227. 52. Yang W, Liu A, Hung AL, et al. Lower risk of intracranial arteriovenous malformation hemorrhage in patients with hereditary hemorrhagic telangiectasia. Neurosurgery. 2016;78(5): 684–693. https://doi.org/10.1227/neu.0000000000001103.

31 53. Leblanc GG, Golanov E, Awad IA, Young WL. Biology of vascular malformations of the brain. Stroke. 2009;40(12):e694– e702. https://doi.org/10.1161/strokeaha.109.563692. 54. Gallione CJ, Repetto GM, Legius E, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet. 2004;363(9412):852–859. https://doi.org/10.1016/ s0140-6736(04)15732-2. 55. Wooderchak-Donahue WL, Johnson P, McDonald J, et al. Expanding the clinical and molecular findings in RASA1 capillary malformation-arteriovenous malformation. Eur J Hum Genet. 2018;26(10):1521–1536. https://doi.org/10.1038/ s41431-018-0196-1. 56. Wang K, Zhao S, Liu B, et al. Perturbations of BMP/TGF-β and VEGF/VEGFR signalling pathways in non-syndromic sporadic brain arteriovenous malformations (BAVM). J Med Genet. 2018;55(10):675–684. https://doi.org/10.1136/jmedgenet2017-105224. 57. Nikolaev SI, Vetiska S, Bonilla X, et al. Somatic activating KRAS mutations in arteriovenous malformations of the brain. N Engl J Med. 2018;378(3):250–261. https://doi.org/10.1056/ nejmoa1709449. 58. Kim H, Hysi P, Pawlikowska L, Poon A, Burchard E, Zaroff J. Common variants in interleukin-1-beta gene are associated with intracranial hemorrhage and susceptibility to brain arteriovenous malformation. Cerebrovasc Dis. 2008;27:176–182. https://doi.org/10.1159/000185609. 59. Pawlikowska L, Poon KYT, Achrol AS, et al. Apolipoprotein Eɛ2 is associated with new hemorrhage risk in brain arteriovenous malformations. Neurosurgery. 2006;58(5):838–843. https:// doi.org/10.1227/01.neu.0000209605.18358.e5. 60. Achrol AS, Kim H, Pawlikowska L, et al. Association of tumor necrosis factor-alpha-238G>A and apolipoprotein E2 polymorphisms with intracranial hemorrhage after brain arteriovenous malformation treatment. Neurosurgery. 2007;61(4):731–739; discussion 740. https://doi.org/10.1227/01. neu.0000298901.61849.a4.

Chapter 3

Radiographic Anatomy: CT/MRI/ Angiography and Risks Michelle Roytman and Apostolos John Tsiouris

Chapter Outline Introduction Radiographic Anatomy of AVMs Imaging Modalities Conclusion

Introduction Imaging plays a critical role in detecting, grading, and managing intracranial arteriovenous malformations (iAVMs). Key imaging features include size, relationship to eloquent brain, presence of deep venous drainage, presence of hemorrhage, and compactness of the nidus; these elements assist in accurately grading the AVM utilizing the Spetzler-Martin AVM and supplemental Lawton-Young grading systems1–4 (Table 3.1). Introduced in 1986, the Spetzler-Martin grade serves as a tool to estimate surgical risk. The initial grading system included five grades (I–V), with higher grades corresponding to greater surgical risk.5 It was subsequently simplified to a three-tiered system: class A (formerly grades I and II), class B (formerly grade III), and class C (formerly grades IV and V).6 The AVM nidus is classified as small (< 3 cm), medium (3–6 cm), or large (> 6 cm) in size and, respectively, assigned 1, 2, or 3 points, based on its maximum diameter. “Micro” AVMs are those with a nidus less than 1 cm in size, typically with normal-size feeding arteries and draining veins and are classically syndromic in etiology (i.e., associated with syndromes such as hereditary hemorrhagic telangiectasia).7,8

32

Intracranial AVMs (iAVMs) have been further classified based on location, with seven defined sites: frontal, temporal, parietooccipital, intraventricular, deep central core, brainstem, and cerebellum.2,9 Each location is characterized by its arterial supply, draining veins, and associated eloquent structures, as well as its specific surgical approach and management. The vast majority of iAVMs (approximately 85%) are supratentorial in location. Only 15% are located within the posterior fossa.10 Involvement of eloquent brain, considered an area resulting in a disabling neurologic deficit if injured (e.g., sensorimotor, language, and visual cortices; thalamus and hypothalamus; internal capsule; insula; brainstem; cerebellar peduncles and deep cerebellar nuclei), confers an additional point in the Spetzler-Martin grading system, as does the presence of deep venous drainage.1,3,5 Functional imaging, discussed in Chapter 4, is helpful to determine the involvement of eloquent brain.11–15 Imaging can also be integral in identifying morphologic features associated with increased risk of future rupture and hemorrhage (initial hemorrhagic presentation, > 3 cm in size, associated flow-related or intranidal arterial aneurysms, deep brain location, periventricular/intraventricular location, deep venous drainage, venous varices, outflow venous stenosis, or presence of a single draining vein),4,16–18 discussed in Chapter 39. The present chapter reviews the radiographic anatomy and multimodal imaging approach for iAVMs with a focus on CT, MRI, and conventional digital subtraction angiography (DSA).

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Radiographic Anatomy: CT/MRI/Angiography and Risks

TABLE 3.1 Grading Systems for iAVMs Variable

Parameter

Pearls Points

Spetzler-Martin Grading (Max Total Score: 5) Size, cm

Venous drainage Eloquence

6 Superficial (cortical veins and convexity) Deep (vein of Galen) No Yes (sensorimotor, language and visual cortices; thalamus and hypothalamus; internal capsule; brainstem; cerebellar peduncles and deep cerebellar nuclei)

1 2 3 0 1 0 1

• Imaging plays an integral role in detection, grading, and management of iAVMs. • Intracranial hemorrhage in a young patient should raise suspicion of an underlying iAVM. • CT angiography is 90% sensitive in the detection of iAVMs. • 4D contrast-enhanced MR angiography at 3.0 T has 100% agreement with digital subtraction angiography (DSA) in its ability to diagnose and classify untreated iAVMs with regard to SpetzlerMartin classification. • Although innovative noninvasive imaging can now be used to follow treated iAVMs, DSA remains the diagnostic gold standard.

An AVM is a complex network of abnormal vascular channels consisting of three distinct components: arterial feeder(s), a central nidus, and draining vein(s) (Fig. 3.1). Intracranial AVMs often resemble a “bag of worms,” formed by a tightly packed tangle of serpiginous thinwalled vessels without an intervening capillary bed and with little or no mass effect upon the adjacent brain.1,4,10 Diagnostic criteria for AVMs include the presence of a nidus as well as early venous drainage, best seen in dynamic studies.4 All three AVM components must be thoroughly evaluated, as each is associated with important features that may impact clinical management.

pial (i.e., superficial/cortical) or perforator (i.e., deep) in type. While the vast majority of iAVMs are the pial type, AVMs in deep or ventricular locations will recruit arterial supply from the perforator (lenticulostriate/ thalamoperforator branches) and/or choroidal (anterior, medial, and lateral posterior) arteries.3,4 Arterial feeders are often enlarged and tortuous, with the degree of dilatation dependent upon shunt volume.2 Flow-related angiopathy, ranging from simple dilatation through endothelial thickening to stenosis or even occlusion, may be present. Complications associated with arterial feeders include arterial aneurysms, which are classified as intranidal (situated within the nidus; Fig. 3.2), flowrelated (involving AVM feeding arteries in a location proximal to the nidus and therefore may regress upon AVM treatment), or unrelated (do not supply AVM and are likely coincidental).1–4 The presence of intranidal or feeder aneurysms is thought to indicate high AVM inflow and is considered a predictor of hemorrhage.18 Approximately 25% of iAVMs may have transdural arterial contributions; therefore a thorough evaluation of the dural vasculature should be included in the complete angiographic delineation of AVM arterial supply.4

ARTERIAL FEEDER(S) Identification of the number, location, and type of feeding arterial branches is important for determining optimal management. Arterial feeders are classified as

NIDUS The nidus of the iAVM is the conglomeration of abnormal tortuous vascular channels, often interspersed with nonfunctional gliotic tissue.1–4 As the

Lawton-Young Grading (Max Total Score: 5) Age, years

Bleeding Compactness

< 20 20–40 > 40 Yes No Yes No

1 2 3 0 1 0 1

Radiographic Anatomy of AVMs

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A

B

Fig. 3.1 A 22-year-old woman presents with headache. Left internal carotid artery injection lateral projection digital subtraction angiogram (A) and axial gadolinium-enhanced 3D fast spoiled gradient-echo MR image (B) demonstrate a left parietal AVM with central nidus measuring approximately 3.0 cm (yellow bracket; A and B). Arterial supply (red arrows; A) arises via feeders from hypertrophied left middle cerebral artery angular branches and P4 terminal branches of the left posterior cerebral artery. Superficial antegrade venous drainage (blue arrow; A and B) is noted in the superior sagittal sinus. The AVM nidus lacks a capillary bed; therefore blood from supplying arteries is shunted directly into the draining vein.

A

B

C

D

Fig. 3.2 A 7-year-old girl presents with nausea, vomiting, and posterior fossa intraparenchymal hematoma. Axial noncontrast CT image (A), left vertebral artery injection anteroposterior digital subtraction angiography projection (B), coronal CT angiogram (CTA) maximum-intensity projection (MIP) (C), and axial CTA MIP (D) demonstrate a left posterior fossa AVM with nidus measuring approximately 2.2 cm (yellow bracket; B–D), arterial feeders arising from bilateral superior cerebellar arteries, and early venous drainage into the left transverse sinus (blue arrow; B). An intranidal aneurysm is present along the right aspect of the nidus (red arrow; B–D).

nidus lacks a capillary bed, blood from supplying arteries is shunted directly into the draining vein(s) (Figs. 3.1–3.3). Intranidal vascular components may range from well-differentiated arteries and veins to dysplastic vascular channels of varying diameters and wall thickening, histologically neither artery

nor vein.1 Intranidal aneurysms have been reported to occur in up to 50% of iAVMs. Nidal compactness is an additional prognostic feature, included in the Lawton-Young grading scale1–4 (Table 3.1). Compact iAVMs have distinct borders and contain tightly woven arteries that separate cleanly from adjacent

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A

B

E

C

D

F

Fig. 3.3 A 20-year-old man presents with altered mental status. Axial (A) and coronal (B) noncontrast CT images demonstrate acute intraparenchymal and intraventricular hemorrhage (orange arrows; B) with evidence of punctate calcifications (white arrow; A and B). Axial CT angiogram (C), axial T2-weighted MR image (D), and left internal carotid artery injection lateral digital subtraction angiography projection (E) confirm the presence of a large left frontoparietal AVM, Spetzler-Martin grade IV, with arterial feeders arising from hypertrophied branches of the left anterior cerebral artery, left middle cerebral artery, left posterior cerebral artery, and lateral lenticulostriate arteries (red arrows; E), with evidence of both deep and superficial drainage via the vein of Galen and superior sagittal sinus (blue arrows; E). Subsequent posttreatment follow-up axial gadolinium-enhanced 3D time-of-flight MR angiogram (F) demonstrates partial embolization of the AVM, with evidence of left parasagittal embolization material (green bracket; F) and persistent nidus (yellow bracket; C–F).

parenchyma, whereas diffuse iAVMs have ragged margins and are intermixed with parenchyma. The presence and compactness of a discrete nidus with intervening gliotic parenchyma distinguishes a classic iAVM from other cerebrovascular malformations, such as a pure arterial malformation, venouspredominant AVM, proliferative-type AVM, cerebral proliferative angiopathy (CPA), pial arteriovenous fistula (AVF), or dural AVF.1 Fig. 3.4 illustrates a diagnostic approach to cerebrovascular malformations based on the imaging characteristics of the nidus as well as the presence of enlarged pial arteries. Pure arterial malformation, a newly recognized entity, is defined as dilated overlapping and tortuous arteries with a coil-like appearance and/or mass of arterial loop

without an associated nidus or venous component (Fig. 3.5).19 They are rare lesions, typically detected incidentally and with a benign natural history. Another incompletely understood lesion, characterized by early contrast filling of dilated branching medullary veins draining into a dominant vein in the absence of a nidus, has been referred to as a venous-predominant AVM; these lesions can mimic the common benign developmental venous anomaly (DVA) but are distinguished by the presence of arteriovenous shunting.1 CPA, formerly known as diffuse nidus type AVM, is a vascular malformation characterized by the presence of normal parenchyma interspersed throughout its nidus. CPA is distinguished from proliferative-type AVM by its absence of an early venous drainage. Additional

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Abnormal vessels in parenchyma

No nidus

Pure arterial malformation Cerebrovascular malformations

Compact nidus

Single

Venous-predominant AVM

Diffuse nidus

Multiple

Brain AVM/ pial AVM

Early draining veins No early draining veins

CAMs and other Proliferative-type Cerebral proliferative syndromic entities brain AVM angiopathy

No abnormal vessels in parenchyma

No enlarged pial arteries

Enlarged pial arteries

Pial AVF

Dural AVF

Fig. 3.4 Diagram illustrating an imaging-based diagnostic approach to cerebrovascular malformations. AVF, Arteriovenous fistula; AVM, arteriovenous malformation; CAMS, cerebrofacial arteriovenous metameric syndrome.

characteristic features of CPA include large areas of parenchymal involvement (e.g., lobar or hemispheric), a nidus fed by multiple arteries in the absence of a dominant feeder, normal to only modestly enlarged feeder arteries, and associated stenosis of feeder arteries. On angiography, CPA is also characterized by “puddling” of contrast involving the nidus, which persists into the late arterial and early venous phases (Fig. 3.6). A pial AVF is a rare lesion composed of a direct arteriovenous connection in the subpial space without an intervening nidus (Fig. 3.5), whereas a dural AVF is an abnormal arteriovenous connection that occurs within the dura mater, most frequently involving the dural venous sinuses. The presence of multiple classic iAVMs may be indicative of an underlying syndrome, such as hereditary hemorrhagic telangiectasia or cerebrofacial arteriovenous metameric syndrome (CAMS). CAMS,

also known as Wyburn-Mason syndrome or BonnetDechaume-Blanc disease, is a segmental neurovascular syndrome with three forms—CAMS type I, involving the medial prosencephalon, with AVMs located at the corpus callosum, hypothalamus, and nose; CAMS type II, involving the lateral prosencephalon, with AVMs located at the occipital lobe, optic chiasm, optic tract, thalamus, retina, and maxilla; and CAMS type III, involving the rhombencephalon, with AVMs located at the cerebellum, pons, and medulla.4 DRAINING VEIN The presence of an “early draining vein,” or venous opacification in the mid to late arterial phase on dynamic imaging, is diagnostic of an AVM1–4 (Figs. 3.1–3.3). The identification of the number, location, and type of draining vein(s) is critical for determining optimal management. Draining veins are typically enlarged and

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A

C

E

B

D

F

Fig. 3.5 Cerebrovascular malformations in four different patients. Left vertebral artery injection anteroposterior digital subtraction angiography (DSA) projection (A) and 3D volumetric reconstruction (B) in a 40-year-old asymptomatic woman demonstrate an incidentally detected pure arterial malformation arising from the left posterior inferior cerebellar artery (red arrow; A and B). Left internal carotid artery injection lateral DSA projection (C) and axial T2-weighted MR image (D) in an 11-year-old boy presenting with seizures demonstrate a left temporal pial arteriovenous fistula with arterial feeders arising from hypertrophied branches of the left middle cerebral and posterior cerebral arteries (red arrow; C and D) draining into a large venous pouch (blue arrow; C and D). Left common carotid artery injection lateral DSA projection (E) and right common carotid artery injection lateral DSA projection (F) in two different patients with hereditary hemorrhagic telangiectasia demonstrate abnormal facial and nasal vasculature (red arrows; E and F) due to capillary telangiectasias.

tortuous and may form varices and exert local mass effect upon the adjacent cortex. Stenosis of “outlet” draining veins may elevate intranidal pressure, predisposing to hemorrhage.16–18 Dilated draining veins are often found on the cortical surface overlying a pialtype AVM. However, the absence of cortical venous drainage in a superficially located iAVM may indicate thrombosis of superficial outlets with rerouting into

the deep system, indicative of a more unstable lesion.4 Additional features that indicate angioarchitectural weak points include the presence of deep venous drainage, a single drainage pathway, and/or presence of venous stenosis, ectasia, or congestion. A long pial course of a draining vein is associated with a higher incidence of chronic venous ischemia and seizures.2 Similar to arterial feeder(s), transdural involvement

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A

B

Fig. 3.6 A 10-year-old girl presents with generalized tonic-clonic seizures. Left internal carotid artery injection lateral digital subtraction angiography projection (A) and axial subtraction TRICKS MR angiography sequence (B) confirm the presence of a large left frontal lobar vascular malformation with an ill-defined nidus measuring up to 6.9 cm and evidence of normal parenchyma interspersed throughout the nidus, supplied by multiple small arterial feeding branches without dominant arterial feeder or evidence of high-flow arteriovenous shunting. Overall imaging characteristics favor a diagnosis of cerebral proliferative angiopathy.

may be seen in large lesions and a thorough evaluation of the dural vasculature should be included in the complete delineation of iAVM venous drainage.4

Imaging Modalities COMPUTED TOMOGRAPHY Nonenhanced CT and contrast-enhanced CT are valuable modalities for prompt identification of hemorrhage and the rapid assessment of iAVM angioarchitecture. Intracranial hemorrhage in a young patient, especially when lobar in the distribution or in the setting of otherwise unexplained intraventricular hemorrhage (Figs. 3.2 and 3.3), should raise suspicion of an underlying iAVM.1–4 In one series, a ruptured AVM was the cause of intracranial hemorrhage in 41% of patients with lobar hemorrhage and in 33% of patients under the age of 40 years.1,20 An acute hematoma and associated mass effect may obscure visualization of the AVM; however, the presence of interspersed calcifications may suggest the possibility of an underlying vascular malformation (Fig. 3.3). As nonhemorrhagic iAVMs tend to replace rather than displace brain tissue,

they generally do not exert mass effect. In the absence of acute hemorrhage or thrombosis, AVMs generally match the attenuation of the blood pool and are slightly denser than the normal brain. Nonenhanced CT typically demonstrates numerous well-delineated, slightly hyperdense serpentine vessels (Fig. 3.7). On contrast-enhanced CT, enhancement of all three AVM components is typically intense and uniform. CT angiography (CTA) is commonly performed as part of the initial evaluation in patients who present with nontraumatic spontaneous intracranial hemorrhage and is useful to delineate feeding arteries and draining veins of an underlying iAVM. CTA is a timed arterial-phase iodinated contrast-enhanced acquisition, ideally with the use of bolus-tracking techniques to ensure selective arterial enhancement while minimizing venous enhancement.1,21 CTA is fast, generally available, has few contraindications, and has high spatial resolution. It also allows for multiplanar reformations, maximum-intensity projections, and volumetric reconstructions. When properly timed, CTA can readily depict the nidus, feeding arteries, and early draining veins emanating from the nidus

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A

B

Fig. 3.7 A 21-year-old asymptomatic man with an incidentally discovered left frontal AVM. Coronal noncontrast head CT (A) and coronal T2-weighted MR image (B) demonstrate numerous slightly hyperdense serpentine vessels on CT and serpentine flow voids on MRI, corresponding to the central nidus (yellow bracket; A and B). Note the lack of mass effect from the AVM or associated parenchymal edema or gliosis.

(Fig. 3.2). CTA has been shown to be 90% sensitive in the detection of iAVMs identified by DSA21 and to be superior to 1.5-T time-of-flight (TOF) gradient-echo MR angiography (MRA) in depicting feeding artery aneurysms (90% vs 31% sensitivity) and intranidal aneurysms (83% vs 0% sensitivity).21 CTA may also rapidly ­ pinpoint the active site of bleeding from feeding artery aneurysms, intranidal aneurysms (Fig. 3.2), or venous varices.2 CTA can be performed in conjunction with CT perfusion, which allows for the identification of parenchymal perfusion abnormalities about the nidus (e.g., functional steal, ischemic steal, and venous congestion), further discussed in Chapter 4. Nevertheless, routine CTA lacks temporal resolution. Time-resolved CTA, also known as dynamic 3D-CTA or 4D-CTA, has been applied in the evaluation of AVMs and reported as a potential noninvasive alternative to DSA in the evaluation of an acutely ruptured iAVM.1,22 The use of time-resolved CTA has also been proposed for precise delineation of the nidus for Gamma Knife radiosurgery,1 but its advantage over routine CTA is questionable. Although the use of time-resolved CTA has been described in small series and case reports, larger prospective studies are required to determine its clinical utility. Furthermore, radiation exposure associated with CTA, especially when dynamic or multiphasic, should limit its use. The estimated effective dose for imaging cerebral vessels with diagnostic single-phase CTA is 0.6 mSv, as compared to 2.71 mSv with DSA

and 5.2 mSv in a proposed 4D-CTA protocol described by Willems et al.1,23 MRI, ANGIOGRAPHY, AND VENOGRAPHY MRI is a noninvasive cross-sectional modality with exquisite soft tissue contrast that is able to provide precise anatomic localization of iAVMs with respect to surrounding structures.1 Due to the lack of ionizing radiation, it is the preferred imaging modality for patients with nonhemorrhagic symptoms.2 Specialized MR applications such as MRA and MR venography (MRV) are extremely useful in the evaluation of AVMs. Conventional Anatomic MRI

Conventional anatomic MRI findings vary depending upon the iAVM architecture, vascular hemodynamics, the presence of associated hemorrhage, and secondary changes of the surrounding brain. As AVMs are highflow lesions, spins rapidly pass through without receiving a refocusing pulse. This allows for visualization of the AVM as flow voids on both T1- and T2-weighted sequences1 (Fig. 3.8). Enlarged feeding arteries and draining veins may also be identified on T2-weighted sequences, though they are typically better depicted with dedicated vascular imaging. Blood-sensitive sequences (e.g., gradient-recalled echo, T2*-weighted, and susceptibility-weighted sequences; Fig. 3.8) allow for the detection of susceptibility (magnetic tissue

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A

B

C

D

Fig. 3.8 A 41-year-old asymptomatic woman with incidentally discovered right frontotemporal AVM. Axial T2-weighted (A) and T1-weighted (B) MR images demonstrate large abnormal flow voids (gray arrow; A and B) in the inferolateral right frontal lobe. Axial gradient-recalled echo-weighted (C) and susceptibility-weighted (D) sequences demonstrate susceptibility and flow-related phase shifts, with relative hyperintensity of the dominant draining vein on susceptibility-weighted imaging (white double arrow; C and D).

inhomogeneity) within and around iAVMs, as well as siderosis in the adjacent pia, indicative of prior hemorrhage.1 Draining veins have been reported to be hyperintense on susceptibility-weighted magnitude images, hypothesized due to higher levels of oxyhemoglobin and therefore serving as a mechanism to distinguish veins draining the nidus from physiologic veins24–26 (Fig. 3.8). T2-weighted fluid-attenuated ­ inversion-recovery (T2W FLAIR) sequences allow for the detection of an inflammatory biological process of the AVM13 and have been shown to be superior to T2-weighted spin-echo imaging in the assessment of intralesional and perilesional gliosis.27 Contrast enhancement of iAVMs is variable, depending on flow rate, direction, and intranidal granulation tissue/scarring. MRI may also be utilized intraoperatively for real-time neuronavigation, which has demonstrated particular utility for surgery in eloquent areas.28 Magnetic Resonance Angiography

MRA can be performed using a nonenhanced technique (e.g., 3D-TOF), a contrast-enhanced technique utilizing gadolinium-based contrast agents, or a contrastenhanced technique utilizing blood pool agents. In 3D-TOF MRA, radiofrequency pulses are repeatedly administered to diminish magnetization and signal intensity of stationary tissue while spins flowing into the imaging volume (arterial blood) remain unsaturated and hyperintense with respect to the background. 3D maximum-intensity reformations and volume-rendered

reconstructions are subsequently generated for further evaluation. Advantages of 3D-TOF MRA include the ability to generate high–spatial resolution imaging without the administration of gadolinium-based contrast agents or the use of ionizing radiation. The AVM nidus and arterial feeders are typically visualized and hyperintense on 3D-TOF MRA due to their high flow rates. If blood coursing through the nidus is not saturated by the time venous outflow is reached, draining veins may also demonstrate hyperintensity. However, 3D-TOF MRA remains insufficient for full characterization and treatment planning. Though 3.0-T 3D-TOF MRA offers superior characterization of iAVM angioarchitecture as compared to 1.5-T 3D-TOF MRA, it has been shown to be not as accurate in the identification of feeding arteries and draining veins in comparison to DSA, which remains the gold standard.1,29 As 3D-TOF MRA is a flow-dependent technique, slow or complex flow within vessels can reduce flow-related enhancement. Recent hemorrhage, which can appear bright on spin-echo images (“T1 shine-through”), may reduce the visibility of adjacent vessels. A thrombosed vessel may mimic flow-related enhancement,1 requiring correlation with the anatomic T1-weighted sequences for differentiation. MRA may also be performed with gadoliniumbased contrast enhancement (CE-MRA) in single or multiple phases (e.g., time-resolved imaging of contrast kinetics [TRICKS]; time-resolved angiography with interleaved stochastic trajectories [TWIST]).

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These CE-MRA techniques require injection of gadolinium-based contrast material followed by a timed acquisition to ensure arterial and venous phase enhancement during the first pass or in multiple passes for a TRICKS/TWIST examination.1 In comparison to 3D-TOF, CE-MRA is more sensitive to slow flow due to the presence of intravascular hyperintense signal related to T1 shortening of gadolinium rather than rate of blood flow. Additionally, CE-MRA utilizes a short echo time (TE) to minimize effects of spin dephasing on intravascular signal in areas of turbulent flow. Background subtraction technique can also be implemented to eliminate signal from a coexisting hematoma, thereby improving vascular delineation.1 CE-MRA has been reported compared to 3D-TOF MRA in the detection of nidus, though superior for detecting arterial feeders and draining veins.1,30 4D CE-MRA, a technique in which images are acquired at rapid intervals enabling differentiation between arterial and venous phases, addresses the limitations of temporal resolution experienced with 3D-TOF MRA and single-phase CE-MRA while preserving spatial resolution.1 4D CE-MRA at 3.0 T has been shown to be effective in its ability to diagnose and classify untreated AVMs with 100% agreement to DSA with regard to Spetzler-Martin classification31; however, it remains relatively insensitive in the detection of residual AVM posttreatment. A proposed postradiosurgery imaging strategy includes serial 4D CE-MRA until the nidus is no longer visualized, at which point DSA can be performed to exclude the presence of a residual AVM.32 Patients who undergo embolization may benefit from serial follow-up with MRA rather than CTA, as embolization material creates extensive beam-hardening artifact, rendering the assessment of residual nidus postembolization challenging on CT. MRA, on the other hand, can clearly delineate residual nidus from embolic material without associated artifact (Fig. 3.3). Most types of gadolinium-based contrast medium are extracellular agents that equilibrate between the intravascular, extravascular, and extracellular spaces upon administration, resulting in diminished targetto-background contrast.1 Blood pool agents, on the other hand, remain intravascular for a prolonged period of time, allowing for steady-state vascular imaging with high spatial and contrast resolution with

complete contrast filling of all vascular structures. By reversibly binding to serum albumin, blood pool agents result in a prolonged intravascular half-life with an increased paramagnetic effect, requiring a lower dose than is required for extracellular gadoliniumbased contrast agents.1 While blood pool agents have been shown to be particularly useful in the depiction of small vessels and vessels with complex flow, they are rarely used clinically.1 Gadofosveset trisodium (Ablavar, formerly Vasovist, Lantheus Medical Imaging, North Billerica, MA), the first gadoliniumbased blood pool agent to be approved by the US Food and Drug Administration (FDA; approved in 2008), was discontinued from production by the manufacturer in 2017 due to poor sales. Iron oxide particles are an alternative blood pool agents that utilize preparations of ultra-small superparamagnetic particles with prolonged intravascular retention as well as T1 and T2 signal-shortening effects.1 Ferumoxytol (Feraheme, AMAG Pharmaceuticals, Waltham, MA) is approved by the FDA for treatment of iron-deficiency anemia in patients with chronic kidney disease and may be used off label as an MRI contrast agent.1 High-resolution 3D volumetric CE-MRA utilizing ferumoxytol has demonstrated robust performance in the diagnostic evaluation of iAVMs, with improved visual depiction of AVMs as compared with CTA and with comparable Spetzler-Martin grading relative to DSA.33 Advantages of iron oxide particles, as compared to gadolinium chelates, include the ability to be administered in patients with end-stage renal disease. However, serious and potentially fatal reactions, including anaphylaxis, have been reported, and potential risks should be strongly considered prior to administration.1 Magnetic Resonance Venography

Current methods of MR venography (MRV) include 2D- or 3D-TOF, phase-contrast sequences with or without intravenous contrast, and 3D contrastenhanced short-TE gradient-echo venography.34 Similar to TOF-MRA, TOF-MRV exploits the inflow of fully magnetized blood into saturated stationary tissue, resulting in the highest signal intensity when the image plane is perpendicular to the direction of blood flow. The phase-contrast technique utilizes bipolar pulse sequences to detect a phase shift caused by blood flowing through a magnetic field gradient.34

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Spins moving in the direction of increasing gradient strength advance in phase, while those moving in the opposite direction decrease below the phase of stationary tissue. While AVM draining veins can be visualized on MRA due to direct shunting from the arterial feeder(s), MRV may be useful in detecting AVM-related venous stenosis and thrombosis.35 DIGITAL SUBTRACTION ANGIOGRAPHY AND RISKS Digital subtraction angiography (DSA) remains the gold standard for the evaluation and characterization of iAVMs.1 It demonstrates superb spatial and temporal resolution, allowing for delineation of the arterial supply, nidus, and venous drainage of the AVM as well as for the depiction of hemodynamic factors, such as degree of arteriovenous shunting1 (Figs. 3.1–3.3, 3.5, and 3.6). Superselective injection of feeding arteries can further delineate the nidus and help identify the presence of intranidal aneurysms (Fig. 3.2). 3D-DSA images reconstructed from rotational angiography have been described as the method of choice for treatment planning of intracranial aneurysms. However, 3D-DSA can be limited in AVM assessment, as projections are obtained with vascular structures fully opacified, which may obscure details otherwise seen on early arterial 2D-DSA. Feasibility of 4D-DSA (e.g., time-resolved 3D-DSA) has been demonstrated, with advantages including visualization of AVMs from any angle at any time point, thus eliminating vascular overlap that may compromise evaluation with 3D-DSA.36 4D-DSA has been shown to be superior as compared to conventional 2D- and 3D-DSA in its ability to show internal features of iAVMs, including intranidal aneurysms, fistulas, venous outflow obstruction, and the sequence of filling and drainage.1,36 The usage of 4D-DSA has been described in small series and case reports, but larger prospective studies are required. However, DSA is an invasive examination that carries a number of important associated risks. Such inherent risks include bleeding, allergy, nephrotoxicity, and thromboembolism, reported to confer an added risk of 0.1%–1% for permanent neurologic deficits.1,31 Therefore there is an important role for the continued advancement and development of safe, easily attainable, and efficacious noninvasive imaging technologies.1

Conclusion Imaging plays a critical role in the detection, grading, and management of iAVMs. While conventional angiography remains the gold standard, a number of innovative noninvasive imaging techniques are emerging and serve as powerful adjuncts. Additional imaging advances in the coming years will result in continued improvement of patient outcomes with further reduction of morbidity and mortality related to iAVMs. REFERENCES 1. Tranvinh E, Heit JJ, Hacein-Bey L, Provenzale J, Wintermark M. Contemporary imaging of cerebral arteriovenous malformations. Am J Roentgenol. 2017;208(6):1320–1330. https://doi.org/10.2214/ajr.16.17306. 2. Lawton MT, Rutledge WC, Kim H, et al. Brain arteriovenous malformations. Nat Rev Dis Primers. 2015;1:15008. https://doi. org/10.1038/nrdp.2015.8. 3. Asif K, Leschke J, Lazzaro MA. Cerebral arteriovenous malformation diagnosis and management. Semin Neurol. 2013;33(5):468–475. https://doi.org/10.1055/s-0033-1364212. 4. Geibprasert S, Pongpech S, Jiarakongmun P, Shroff MM, Armstrong DC, Krings T. Radiologic assessment of brain arteriovenous malformations: what clinicians need to know. Radiographics. 2010;30(2):483–501. https://doi.org/10.1148/ rg.302095728. 5. Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg. 1986;65(4):476–483. https://doi.org/10.3171/jns.1986.65.4.0476. 6. Spetzler RF, Ponce FA. A 3-tier classification of cerebral arteriovenous malformations. J Neurosurg. 2011;114(3):842–849. https://doi.org/10.3171/2010.8.jns10663. 7. Cellerini M, Mangiafico S, Villa G, et al. Cerebral microarteriovenous malformations: diagnostic and therpeutic features in a series of patients. AJNR Am J Neuroradiol. 2002;23(6):945–952. 8. Ferracci F-X, Courthéoux P, Borha A, Blond S, Emery E. Multimodal management of ruptured cerebral microarteriovenous malformations: a retrospective series of 19 cases and a review of the literature. Neurochirurgie. 2020;67(2):132– 139. https://doi.org/10.1016/j.neuchi.2020.11.001. 9. Lawton M. Seven AVMs: Tenets and Techniques for Resection. Thieme Medical Publishers; 2014. 10. Osborn AG, Hedlund G, Salzman KL. Vascular malformations. In: Concannon KE, ed. Osborn’s Brain. 2nd ed. Elsevier; 2017:155–196. 11. La Piana R, Bourassa-Blanchette S, Klein D, Mok K, Nino Del Pilar Cortes, M, Tampieri D. Brain reorganization after endovascular treatment in a patient with a large arteriovenous malformation: the role of diagnostic and functional neuroimaging techniques. Interv Neuroradiol. 2013;19(3):329– 338. https://doi.org/10.1177/159101991301900310. 12. Stapleton CJ, Walcott BP, Fusco MR, Thomas AJ, Ogilvy CS. Brain mapping for safe microsurgical resection of arteriovenous malformations in eloquent cortex. World Neurosurg. 2015;83(6):1148–1156. https://doi.org/10.1016/j. wneu.2015.01.040.

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13. Bendok BR, El Tecle NE, El Ahmadieh TY, et al. Advances and innovations in brain arteriovenous malformation surgery. Neurosurgery. 2014;74(Suppl 1):S60–S73. https://doi.org/10. 1227/neu.0000000000000230. 14. Bérubé J, McLaughlin N, Bourhouin P, Breaudoin G, Bojanowski MW. Diffusion tensor imaging analysis of long association bundles in the presence of an arteriovenous malformation. J Neurosurg. 2007;107(3):509–514. https://doi.org/10.3171/jns-07/09/0509. 15. Li M, Jiang P, Guo R, et al. A tractography-based grading scale of brain arteriovenous malformations close to the corticospinal tract to predict motor outcome after surgery. Front Neurol. 2019;10:761. https://doi.org/10.3389/fneur.2019.00761. 16. Huang Z, Peng K, Chen C, Zeng F, Wang J, Chen F. A reanalysis of predictors for the risk of hemorrhage in brain arteriovenous malformation. J Stroke Cerebrovasc Dis. 2018;27(8):2082–2087. https://doi.org/10.1016/j.jstrokecerebrovasdis.2018.03.003. 17. Stapf C, Mast H, Sciacca RR, et al. Predictors of hemorrhage in patients with untreated brain arteriovenous malformation. Neurology. 2006;66(9):1350–1355. https://doi.org/10.1212/01. wnl.0000210524.68507.87. 18. Shakur SF, Liesse K, Amin-Hanjani S, et al. Relationship of cerebral arteriovenous malformation hemodynamics to clinical presentation, angioarchitectural features, and hemorrhage. Neurosurgery. 2016;63(Suppl 1):136–140. https://doi.org/10. 1227/neu.0000000000001285. 19. Brinjikji W, Cloft HJ, Flemming KD, Comelli S, Lanzino G. Pure arterial malformations. J Neurosurg. 2018;129(1):91–99. https://doi.org/10.3171/2017.2.jns1744. 20. Ruíz-Sandoval JL, Cantú C, Barinagarrementeria F. Intracerebral hemorrhage in young people: analysis of risk factors, location, causes and prognosis. Stroke. 1999;30(3):537–541. https://doi. org/10.1161/01.str.30.3.537. 21. Gross BA, Frerichs KU, Du R. Sensitivity of CT angiography, T2-weighted MRI, and magnetic resonance angiography in detecting cerebral arteriovenous malformations and associated aneurysms. J Clin Neurosci. 2012;19(8):1093–1095. https:// doi.org/10.1016/j.jocn.2011.11.021. 22. Singh R, Gupta V, Ahuja C, Khandelwal N. Time resolved computed tomography angiography in the evaluation of brain arteriovenous malformation: a feasibility study. Neuroradiol J. 2018;31(3):230– 234. https://doi.org/10.1177/1971400916684669. 23. Willems PWA, Taeshineetanakul P, Schenk B, Brouwer PA, Terbrugge KG, Krings T. The use of 4D-CTA in the diagnostic work-up of brain arteriovenous malformations. Neuroradiology. 2012;54(2):123–131. https://doi.org/10.1007/ s00234-011-0864-0. 24. Finitsis S, Anxionnat R, Gory B, Planel S, Liao L, Bracard S. Susceptibility-weighted angiography for the follow-up of brain arteriovenous malformations treated with stereotactic radiosurgery. AJNR Am J Neuroradiol. 2019;40(5):792–797. https://doi.org/10.3174/ajnr.a6053. 25. Biondetti E, Rojas-Villabona A, Sokolska M, et al. Investigating the oxygenation of brain arteriovenous

26.

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33.

34. 35.

36.

malformations using quantitative susceptibility mapping. Neuroimage. 2019;199:440–453. https://doi.org/10.1016/j. neuroimage.2019.05.014. Miyasaka T, Taoka T, Nakagawa H, et al. Application of susceptibility weighted imaging (SWI) for evaluation of draining veins of arteriovenous malformation: utility of magnitude images. Neuroradiology. 2012;54(11):1221–1227. https://doi.org/10.1007/s00234-012-1029-5. Essig M, Wenz F, Schoenberg SO, Debus J, Knopp MV, van Kaick G. Arteriovenous malformations: assessment of gliotic and ischemic changes with fluid-attenuated inversionrecovery MRI. Invest Radiol. 2000;35(11):689–694. https://doi. org/10.1097/00004424-200011000-00007. Zhu F, Tian Y, Zhu W, et al. Application of 3.0T intraoperative high-field magnetic resonance imaging guidance for the surgery of arteriovenous malformation within eloquent areas. Chin Med J (Engl). 2014;127(6):1180–1182. Heidenreich JO, Schilling AM, Unterharnscheidt F, et al. Assessment of 3D-TOF-MRA at 3.0 Tesla in the characterization of the angioarchitecture of cerebral arteriovenous malformations: A preliminary study. Acta Radiol. 2007;48(6):678–686. https:// doi.org/10.1080/02841850701326958. Unlu E, Temizoz O, Albayram S, et al. Contrast-enhanced MR 3D angiography in the assessment of brain AVMs. Eur J Radiol. 2006;60(3):367–378. https://doi.org/10.1016/j.ejrad. 2006.08.007. Hadizadeh DR, von Falkenhausen M, Gieseke J, et al. Cerebral arteriovenous malformation: Spetzler-Martin classification at subsecond-temporal-resolution fourdimensional MR angiography copmared with that at DSA. Radiology. 2008;246(1):205–213. https://doi.org/10.1148/ radiol.2453061684. Soize S, Bouquigny F, Kadziolka K, Portefaix C, Pierot L. Value of 4D MR angiography at 3T compared with DSA for the follow-up of treated brain arteriovenous malformation. AJNR Am J Neuroradiol. 2014;35:1903–1909. https://doi. org/10.3174/ajnr.a3982. Iv M, Choudhri O, Dodd RL, et al. High-resolution 3D volumetric contrast-enhanced MR angiography with a blood pool agent (ferumoxytol) for diagnostic evaluation of pediatric brain arteriovenous malformations. J Neurosurg Pediatr. 2018;22:251– 260. https://doi.org/10.3171/2018.3.peds17723. Pui MH. Cerebral MR venography. Clin Imaging. 2004;28:85– 89. https://doi.org/10.1016/s0899-7071(03)00118-9. Kochanski RB, Johnson AK, Moftakhar R. Bilateral thalamic edema from coexisting choroid plexus arteriovenous malformation and sinus thrombosis: Case report. Turk Neurosurg. 2017;27(5):823–826. https://doi.org/10.5137/10195149.jtn.16613-15.2. Sandoval-Garcia C, Royalty K, Yang P, et al. 4D DSA a New technique for AVM evaluation: A feasibility study. J Neurointerv Surg. 2016;8(3):300–304. https://doi.org/10.1136/ neurintsurg-2014-011534.

Chapter 4

MRI Neurovascular Evaluation: Blood Flow, Perfusion, Diffusion, and Susceptibility Shanmukha Srinivas, Divya S. Bolar, Muhammad Abubakar Ayub, Salil Soman, and Albert Hsiao

Chapter Outline Introduction 4D Flow: Quantification and Visualization of Blood Flow Arterial Spin Labeling: Perfusion and Shunting Diffusion: Ischemic Injury and Fiber Tractography Susceptibility: Hemorrhage and Calcium Conclusion

quantifying tissue perfusion and detecting arteriovenous shunting; (3) diffusion techniques, including diffusion tensor imaging (DTI) for delineation of fiber tracts and diffusion-weighted imaging (DWI) for assessment of ischemic injury; and (4) susceptibility imaging for detecting areas of previous hemorrhage or calcification.

4D Flow: Quantification and Visualization of Blood Flow Introduction Several advanced MRI techniques have emerged in the last few decades to improve the diagnosis and management of neurovascular disease. Traditionally intracranial arteriovenous malformations (iAVMs) were characterized primarily by invasive angiography, but MRI has matured to become the mainstay for diagnosis, treatment planning, and long-term management of complications. In this chapter, we survey several complementary advanced MRI techniques, which expand beyond anatomic delineation to physiologic assessments. Each of these MRI techniques touches upon important and complementary facets of cerebrovascular anatomy, physiology, and pathophysiology, helpful for optimizing the care of patients with iAVMs. These advanced MRI techniques include (1) volumetric phase contrast, also known as 4D flow, for the visualization of arterial supply and quantification of blood flow; (2) arterial spin labeling (ASL) for 44

Early studies of intracerebral hemodynamics utilized transcranial Doppler ultrasonography1 to assess flow within large feeding arteries. However, the spatial and temporal resolution of this technique is limited and identification of feeding and draining vessels with transcranial Doppler ultrasound is highly dependent on the ability of a trained technologist to identify an open acoustic window. In recent years, volumetric phase-contrast (also known as 4D flow) MRI has emerged as an effective, noninvasive technique for visualizing and measuring hemodynamics within cerebral blood vessels2–6 without limitations of operator dependence (Fig. 4.1). Measurements of cerebral blood flow from phase-contrast MRI have been found to correlate well with measurements made with transcranial Doppler ultrasound.7–9 Acquisition of phase-contrast MRI is performed by applying two opposite, flow-encoding gradients and measuring a phase shift, which is proportional to the speed of protons moving along the direction of the magnetic field gradient.10,11 While planar

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phase-contrast MRI is generally performed with ­ velocity encoding only in the direction perpendicular to the imaging plane of interest, 4D flow MRI is performed with velocity encoding in all three directions. Velocity data become usable after correction of background phase errors, Maxwell terms, and gradient field nonlinearity.12 Historically, 4D flow MRI required long acquisition times, but recent advances, including parallel imaging and compressed sensing, have brought this technique into the realm of clinical feasibility,13 with acquisition times within 5–10 minutes. Although more commonly performed for assessment of cardiovascular pathologies,14–16 4D flow MRI has shown potential for quantification and visualization of complex feeding arterial and draining venous flow in AVMs as well.17 Moreover, neurovascular 4D flow measurements have demonstrated high multicenter and interobserver reproducibility.18

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Pearls • Advanced MRI techniques, including 4D flow, arterial spin labeling, diffusion, and susceptibility imaging, expand conventional anatomic assessments to physiologic evaluation. • Understanding the underlying physics and properties of these sequences informs their complementary application in the assessment of iAVMs, including detailed evaluation of blood flow, parenchymal perfusion, fiber tract injury and location, and the presence of extravascular blood products. • Improvements in these MRI-based techniques have allowed broader applications in the assessment of baseline iAVM risk and the efficacy of multimodal treatments. • Intraoperative applications of 4D flow are additionally covered in Chapter 29.

Fig. 4.1 4D flow MR images without and with color velocity overlay. In a patient with a large frontoparietal AVM, high-velocity (red) flow can be seen in the anterior cerebral artery, internal carotid arteries, and basilar artery, indicating arterial supply from both systems. Large draining veins of the AVM are evident. High velocity is also seen in both sigmoid sinuses, marked by white arrows, indicating the presence of flow-limiting venous stenoses.

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4D flow MRI can provide valuable insights into the hemodynamic characteristics of AVMs and has potential to stratify patients who are at greatest risk of hemorrhage. For example, early studies using 4D flow MRI have shown that higher draining vein flow on MRI tends to correlate with higher Spetzler-Martin grade; altered venous-arterial pulsatility, especially in high-grade iAVMs; and observed flow reversal within the contralateral arteries.19,20 The increase in ipsilateral artery flow at the expense of contralateral artery flow is often referred to as steal phenomenon.21,22 Although the relationship of this observation to neurologic deficit has been questioned,22 there is nevertheless potential for hemodynamic parameters measured on 4D flow MRI to predict downstream events such as hemorrhage.23 In one small study, patients with severe symptoms exhibited higher wall shear stress in ipsilateral arteries compared to contralateral arteries, and there was a correlation between higher AVM flow in preoperative studies and greater venous vessel wall thickness in resected AVMs, presumably related to response to elevated wall shear stress.24 However, increased AVM flow and altered hemodynamics may not always be associated with more severe clinical presentations, such as seizure or hemorrhage. In a small study of 17 patients with iAVMs, there was no correlation found between AVM flow and clinical presentation.25 4D flow MRI may play an important future role in prognostication for patients with iAVMs, but not in isolation—its interpretation will require the context of other relevant clinical and imaging findings. 4D flow MRI is beginning to show promise for monitoring the treatment response of iAVMs after resection, embolization, or radiosurgery. Following embolization, AVMs decrease in mean flow volume within feeding arteries26 and change in the distribution of flow in vessels surrounding the nidus.23,27 Following stereotactic radiosurgery, flow volume and pulsatility are similarly affected.28,29 As early as 6 months after radiosurgery, 4D flow MRI shows a notable decrease in blood flow within the ipsilateral supplying arteries and draining veins, before structural remodeling can be seen on standard MR angiography (MRA) images. These data suggest that 4D flow imaging may be used as an earlier indicator of treatment response than conventional MRI. Over the years, phase-contrast MRI has also been explored for several cerebrovascular diseases beyond AVMs, including aneurysms and moyamoya disease.30–32 For example, Sekine et al. demonstrated that radial artery

grafts have more retrograde flow and higher blood flow volume compared to superficial temporal artery grafts used in extracranial-intracranial bypass,30 and Moftakhar et al. demonstrated that bifurcation aneurysms often have recirculation blood flow patterns and intraaneurysmal pressure measurements.33 Further work will be required to determine whether these hemodynamic observations are predictive of downstream outcomes.

Arterial Spin Labeling: Perfusion and Shunting ASL is a powerful MRI technique that images cerebral perfusion without the use of intravenous contrast. Introduced nearly 30 years ago and limited by an intrinsically low signal-to-noise ratio, ASL has slowly gained clinical traction through years of technical development, resulting in substantially improved image quality in feasible scan times. Furthering its acceptance is a widely respected 2015 consensus paper that provides comprehensive recommendations for clinical implementation.34 Many academic centers now integrate ASL into their routine brain MRI protocols, as it provides valuable hemodynamic information unobtainable by conventional MRI sequences. ASL has found utility for evaluating numerous neurological diseases and is particularly well suited to assess iAVMs, given its exquisite sensitivity to arteriovenous shunting. Unlike traditional perfusion methods that require an injected contrast bolus, ASL creates an “endogenous bolus” by applying radiofrequency energy to magnetically “label” spins of blood water flowing in large arteries.35,36 Several variants of ASL exist, and they take different approaches for labeling. The most common variant is called pseudocontinuous ASL (PCASL),37 which applies a fixed-duration train of radiofrequency pulses to label spins as they flow across a plane intersecting the cervical carotid and vertebral arteries (Fig. 4.2). A sufficient delay (post-label delay [PLD]) follows, allowing these labeled spins to flow into the distal cerebral microvasculature, where they ­ accumulate and exchange with surrounding tissue. Imaging at the PLD generates a map containing signal from these inflowing spins as well as static tissue already present within the imaging volume. A control experiment without labeling is also performed; subtraction of the control image from the label image eliminates static tissue, targeting labeled spins delivered during

4

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MRI Neurovascular Evaluation: Blood Flow, Perfusion, Diffusion, and Susceptibility

Imaging Volume

Imaging Volume

Direction of Blood Flow Labeling Plane

Control Plane

Subtraction

Fig. 4.2 Conceptual schematic for pseudocontinuous arterial spin labeling. A fixed-duration radiofrequency pulse train creates a thin labeling plane that intersects the cervical carotid and vertebral arteries. Spins of water are magnetically “labeled” (shown in red) as they cross the labeling plane and flow toward the distal microvasculature and tissue. Imaging at a user-defined post-label delay results in the “label” image, which contains both labeled spins and static tissue. The experiment is repeated with labeling disabled, to create the “control” image, which contains static tissue without the labeled spins. Subtraction of the control image from the label image results in “perfusion” maps proportional to cerebral blood flow. Note that the control and label images look very similar, since the perfusion component is a tiny fraction of the overall signal.

the PLD. Signal intensity in the subtraction image is directly proportional to cerebral perfusion. The vascular configuration of AVMs results in unique and interesting behavior of the ASL label, which can be best understood by appreciating three key principles of ASL in normal physiology: (1) typical PLDs are long enough for the label to clear the arterial macrovasculature and fully arrive at the microvasculature/tissue; (2) the label becomes orders-of-magnitude less concentrated as it disperses into the microvascular network and exchanges with the surrounding tissue (i.e., the expansile extravascular space); and (3) labeled spins do not significantly exit into the venous circulation, since most spins will have exchanged into the surrounding

tissue at PLDs long enough to cross the capillary bed.38,39 In AVMs, however, the ASL label bypasses the microvascular network and therefore tissue exchange, stays concentrated, and gets directly delivered from the arterial feeders to the capacious arteriovenous nidus and draining veins. This results in profoundly hyperintense ASL signal within these vascular compartments. This property is unique to arteriovenous shunt lesions and forms the basis of evaluation by ASL, particularly since (with few exceptions) venous ASL signal will not be seen unless shunting is present (Fig. 4.3). Several studies have begun to observe and explore these phenomena in iAVMs. Conspicuous nidal/venous signal is seen even with small degrees

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Fig. 4.3 Ruptured left paramedial parietal lobe AVM with shunting on arterial spin labeling (ASL). (A) T2-weighted MR image showing serpiginous nidal vessels. (B and C) Lateral and frontal conventional angiography projections obtained after right internal carotid artery injections showing nidal filling and early venous drainage into a large paramedian draining vein that empties into the vein of Galen with filling of the straight and transverse sinuses. (D) Axial, sagittal, and coronal 3D maximum intensity projection of ASL data obtained after the AVM was partially treated with embolization. The images show markedly hyperintense signal in the nidal region (yellow arrowheads) and more subtle signal in the large draining vein and into the straight sinus and left transverse sinus (white arrowheads). These findings are consistent with persistent arteriovenous shunting across the AVM.

of shunting, making it highly sensitive and specific for detecting arteriovenous shunt lesions.40–42 In the largest of these studies (92 patients), ASL was shown to have 95% sensitivity and 90% specificity for detecting arteriovenous shunts (using digital subtraction angiography [DSA] as the criterion-standard comparison), correctly diagnosing AVMs 98% of the time (52 of 53 cases).41 Furthermore, ASL can detect small AVMs that would otherwise be missed by conventional MRI. For example, this can be particularly helpful in the setting of a ruptured AVM, in which susceptibility from blood products may mask the underlying lesion on conventional imaging.42

These properties of ASL have also been found useful for evaluating AVM treatment response after embolization and/or irradiation. Studies have shown that ASL maintains its high sensitivity and specificity for arteriovenous shunting even after treatment (when compared to DSA), detecting residual shunt flow following stereotactic radiosurgery,43 including Gamma Knife therapy,44,45 and shunt reduction after embolization.46,47 The quantitative nature of ASL can also be exploited when evaluating iAVMs. Signal intensity within the AVM nidus and draining vein has been shown to correlate well with the degree of early draining vein

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MRI Neurovascular Evaluation: Blood Flow, Perfusion, Diffusion, and Susceptibility

opacification (a surrogate for degree of arteriovenous shunting).45 Perfusion in tissue adjacent to AVMs has been shown to decrease, presumably due to steal phenomena.40,48 These quantitative capabilities raise the possibility of noninvasive, longitudinal AVM ­ follow-up—for example, to evaluate therapy response by characterizing how flow through the AVM and perfusion in adjacent tissue change over time. One promising class of ASL methods approaching the clinical horizon is time-resolved 4D dynamic MR angiography (dMRA), reviewed in a recent article by Suzuki et al.49 These 4D ASL-based approaches create a series of angiographic images at different PLDs, giving the appearance of the bolus dynamically passing through the circulation, mimicking DSA. These techniques have been used to evaluate AVM structure and configuration,50–53 and recent studies have shown high sensitivity and specificity for identifying arterial feeders and venous drainage with excellent agreement with DSA. A 2020 study, for example, reports 100% sensitivity and specificity for arterial feeders, 94%–100% sensitivity and 92%–100% specificity for venous drainage pathways, identical Spetzler-Martin grading compared to DSA, and excellent intermodality agreement.50 Nidus size can also be accurately measured using 4D dMRA, with perfect intermodality agreement seen in two studies.52,54 ASL methods offer a unique way to image and evaluate iAVMs noninvasively and avoid risks related to ionizing radiation, intravenous contrast, or catheterbased angiography, which is especially important in pediatric or other vulnerable populations. Studies have consistently demonstrated the exquisite sensitivity of ASL for detecting de novo AVMs and assessing residual lesions after treatment. Quantitative aspects of ASL have been explored, with results suggesting a significant correlation between ASL signal intensity and degree of AVM shunting, raising the possibility of longitudinal assessment of shunt and parenchymal flow to evaluate temporal response to therapy. ASL-based 4D dMRA techniques represent newer approaches for evaluating iAVMs and can assess hemodynamic and structural features typically only captured by DSA. As ASL continues to gain more widespread integration into clinical MRI, it is likely to become a standard tool for serial iAVM evaluation.

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Diffusion: Ischemic Injury and Fiber Tractography Diffusion-based imaging is an advanced MRI technique that is formulated on a method of signal contrast generation based on the differences in Brownian motion. It is sensitive to the movement of water molecules, providing additional information on the molecular function and microstructural arrangement of tissue. Diffusion-based MRI techniques, particularly DWI, have been widely adopted into most clinical MRI examinations, due to their exquisite sensitivity for ischemic injury and infarction (Fig. 4.4). DWI has also been shown to aid in the evaluation of transient and permanent neurological deficits following iAVM treatment. Patients may have ischemic injuries prior to or following endovascular procedures, and these injuries can be readily detected using DWI. Awareness of preoperative injuries can be useful for devising an optimal treatment plan. DTI is used for the assessment of organs with highly organized fiber structure. In the last several years, it has emerged as a valuable tool for iAVM treatment planning, providing an anatomic map of white matter tracts (Fig. 4.5).55 In order to minimize postoperative deficits, radiation, surgical, and embolization treatment plans take into consideration eloquent brain areas, including motor and visual pathways.56,57 DTI can be valuable for delineating white matter fiber tracts and their relationship to AVMs, which can distort their normal course through the brain. Similarly, follow-up imaging with DTI after Gamma Knife radiosurgery (GKRS) appears to be useful to detect delayed neuronal degeneration. Further research is needed to understand the pathophysiological mechanism of neural tract injury after GKRS and strategies to prevent it.58 DTI has been shown to be effective for tracing the corticospinal tract in patients with iAVMs, regardless of the history of hemorrhage.59–63 It has also been used to identify the location of eloquent cortex and optic tracts relative to the AVM nidus and deep veins in patients with nonhemorrhagic AVMs.64–66 However, white matter tracts close to an AVM nidus have been noted to be less reliably visualized than areas distant to the AVM, particularly in patients with neurological symptoms.67 It is unclear whether this is due to underlying

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Fig. 4.4 Appearance of iAVM on susceptibility and diffusion MRI. (A) Noncontrast head CT image revealing a left parietal AVM and demonstrating faint hyperdensity, which may be related to blood, calcification, or hyperdense vessels (yellow dashed circle). (B–D) Corresponding (B) susceptibility-weighted, (C) susceptibility-weighted angiography (SWAN), and (D) MEDI quantitative susceptibility mapping (QSM) images demonstrating the same lesion. While additional phase map images may be able to distinguish blood from calcification for the susceptibility-weighted and SWAN images, the QSM image demonstrates blood as hyperintense and calcification as hypointense, and so confirms the presence of blood in the area of this AVM. (E and F) Corresponding (E) trace and (F) apparent diffusion coefficient (ADC) diffusion images showing area of restricted diffusion suggestive of ischemia (red arrow) in this AVM.

pathophysiology or whether the white matter tracts are obscured as a result of technical factors. In territories near the nidus, AVM hemorrhage can lead to vasogenic edema and magnetic susceptibility. In such cases, signal drop-off artifacts can be severe, and this has been observed to more greatly affect imaging at a higher field strength, worse at 3 T than 1.5 T.67 DTI may facilitate preservation of critical white matter tracts during iAVM resection and reduce ­ postoperative neurological deficits.62 Similarly, neuronavigation with DTI-based optic tractography has been shown to allow visual field preservation in the surgery of occipital AVMs.65 If surgical obliteration of an AVM is considered high risk because of the relationship between the lesion and eloquent white matter and cortex, alternative therapeutic strategies might be applied.67 DTI tractography has also been reported to be useful for confirming the radiation dose to the corticospinal tract in radiosurgical planning.68 Integrating DTI of the corticospinal tract into treatment planning for stereotactic radiosurgery (SRS) has been shown to reduce postsurgical motor complications. DTI information can be used to modify treatment dose and restrict

radiation dose to the adjacent motor fibers, preventing radiation-induced adverse effects.59,60,64,69

Susceptibility: Hemorrhage and Calcium Several MR susceptibility-based imaging techniques have matured to complement the evaluation of patients with iAVMs. These include susceptibility-weighted imaging (SWI), susceptibility-weighted angiography (SWAN), and quantitative susceptibility mapping (QSM). SWI AND SWAN SWI, originally called BOLD (blood-oxygen-leveldependent) venographic imaging, is a recently developed MRI technique that is particularly sensitive to compounds that distort the local magnetic field. It exploits the magnetic susceptibility differences of various compounds, including deoxygenated blood, blood products, iron, and calcium, thus enabling a new source of contrast in MRI. SWI uses a fully flow-compensated, long echo, gradient-recalled echo (GRE) pulse sequence to acquire magnitude and phase images. The phase image is high-pass (HP) filtered to remove artifacts.

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51

Fig. 4.5 Preoperative digital subtraction angiography and MRI from a patient with a giant AVM. The images reveal a 75.4-cm AVM located in the right lateral fissure (A and D). Preoperative diffusion tensor imaging mapping shows that the optic radiation was passing through the nidus, the right corticospinal tract was adjacent to the margin of the nidus (B and C). CST, Corticospinal tract; OR, optic radiation. (Reprinted from Lin F, Wu J, Jiao Y, et al. One-stage surgical resection of giant intracranial arteriovenous malformations in selected patients: a novel diffusion tenser imaging score. World Neurosurg. 2019;130:e1041-e1050, Copyright 2019, with permission from Elsevier.)

The magnitude image is then combined with the phase image to create a susceptibility-weighted image. Finally, minimum-intensity projections (minIPs) help to visualize low-intensity structures such as cerebral veins. SWAN is a new method for SWI with short acquisition times. It is a multi-echo gradient echo T2

star-weighted angiography (hence the acronym, SWAN) sequence that acquires multiple echoes at different echo times and is less affected by chemical shift compared to conventional SWI techniques. The end result is a clear, high-resolution 3D dataset merging a broad range of distinct tissue contrasts with

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significantly enhanced susceptibility information and signal-to-noise ratio. Shorter echoes lead to time-offlight (TOF) effect, whereas longer echoes are responsible for susceptibility effects. By calculating a weighted sum of the images obtained at different echo times, SWAN combines both susceptibility and TOF effects.70 Both SWI and SWAN provide high-resolution visualization of cerebral arteries and veins without the use of a contrast agent. Both have been shown to distinguish high-flow vascular malformations (HFVMs) (e.g., AVMs) from slow-flow vascular malformations (SFVMs) (e.g., cerebral cavernous malformations).71,72 In a prospective study, SWAN revealed at least one venous hyperintensity in all patients with HFVMs confirmed on DSA while SFVMs appeared hypointense on SWAN images, which allows distinguishing between SFVMs and HFVMs.72 Detection of iAVMs on SWI makes it an important tool in the workup of AVM patients before surgery or radiosurgery. A retrospective study of 14 patients demonstrated that magnitude images of SWI help in differentiating the different components of the AVM (hypointense feeding artery and hyperintense draining veins) and differentiate the nidus (hyperintense) from hemorrhage and calcification (areas of hypointensity) (Fig. 4.6). Another retrospective study of 14 patients with DSA-proven iAVMs detected 27 draining veins. Out of six draining veins that did not show hyperintensity on TOF images, three (50%) were classified as hyperintense on the magnitude images of SWI

(SWI-mag). This study demonstrated that SWI-mag can show hyperintensity in substantial numbers of AVM draining veins that are not visualized on TOF (Fig. 4.7) and may be used as an alternative to DSA for pretreatment workup and posttreatment follow-up, especially when draining veins do not show hyperintensity on TOF images due to slow flow.73

A

B

Fig. 4.6 Left frontoparietal AVM. (A) Susceptibility-weighted magnitude image. The nidus appears hyperintense (arrow) with central area of hypointensity, indicating hemorrhage. (B) Corresponding CT slice showing a left frontoparietal bleed. (Adapted from George U, Jolappara M, Kesavadas C, et al. Susceptibility-weighted imaging in the evaluation of brain arteriovenous malformations. Neurol India. 2010;58:608-614, Figure 4. Only two of the original four panels are shown. Article available from: https://www.neurologyindia.com/text. asp?2010/58/4/608/68668. Copyright © 2010, Wolters Kluwer MedKnow Publications. Creative Commons Attribution–NonCommercial-ShareAlike 4.0 License [CC-BY-NC-SA 4.0, https://creativecommons.org/licenses/by/4.0/ legalcode].)

Fig. 4.7 Right frontal AVM. (A) Right carotid angiogram demonstrating a nidus in the frontal lobe and several draining veins. The right thalamostriate vein (arrow) is one of the draining veins. (B) Time-of-flight MR angiography (TOF-MRA) image. The right thalamostriate vein is not visualized. (C) T2-weighted MR image showing low signal flow void in the right thalamostriate vein. (D) Susceptibility-weighted image showing hyperintensity in the right thalamostriate vein. (Reprinted by permission from Springer Nature Customer Service Centre GmbH: Springer Nature, Miyasaka T, Taoka T, Nakagawa H, et al. Application of susceptibility weighted imaging (SWI) for evaluation of draining veins of arteriovenous malformation: utility of magnitude images. Neuroradiology 2012;54(11):1221-1227. Copyright 2012. Published with permission.)

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MRI Neurovascular Evaluation: Blood Flow, Perfusion, Diffusion, and Susceptibility

SWAN may be useful for follow-up assessments after resection, embolization, or radiosurgery treatment of AVMs. After AVM radiosurgery, imaging follow-up must be performed every 6–12 months until complete AVM obliteration is documented.74 Currently, the gold standard for evaluating iAVM obliteration after treatment is DSA. The use of SWAN for follow-up imaging offers the advantage of not requiring a contrast agent. In a prospective study that included 26 patients who underwent SWAN at least 12 months after SRS, the diagnostic accuracy of SWAN to evaluate residual nidus after SRS reached 85.7% sensitivity and 85.7% specificity compared with DSA.9 QUANTITATIVE SUSCEPTIBILITY MAPPING QSM is an emerging MRI technique that provides a map of local tissue magnetic susceptibility. It is a noninvasive technique that measures the spatial distribution of magnetic susceptibility in the tissues. The acquisition sequence for QSM is typically a 3D GRE sequence similar to that used for routine SWI, but multiple echoes are used to allow for the detection of weak susceptibility changes. The technique utilizes phase images and generates 3D susceptibility distribution. QSM is useful for the identification and quantification of specific biomarkers, including iron, calcium, gadolinium, and superparamagnetic iron oxide (SPIO) nanoparticles. QSM can provide insights into AVM properties with respect to blood, calcium, and vessels (see Fig. 4.4). It can characterize vascular abnormalities associated with AVMs and detect mixed venous oxygen saturation (SvO2) alterations in AVMs. In a prospective study of 45 patients divided into three groups (15 pre-GKRS, 17 post-GKRS, and 13 controls), MRI-derived QSM depicted significantly larger vessel density in the hemisphere containing the iAVM compared to the contralateral hemisphere only in the pre-GKRS group, not in the post-GKRS group or controls. Higher SvO2 was also measured in AVM draining veins than in healthy veins, which is a finding seen with arteriovenous shunting.75 In another prospective study, flow-compensated QSM was found to be able to detect blood susceptibility changes related to blood deoxygenation across different components of iAVMs—demonstrating that flow-normalized blood deoxygenation across the nidus was associated with the presence of perinidal blood products. These deoxygenation measures may

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be useful to assess different components of the iAVM vasculature and have potential for risk stratification for therapy.76

Conclusion In summary, we highlight several emerging advanced MRI techniques for physiologic interrogation of iAVMs, which can provide further insights for evaluating these complex lesions. Specifically, we show the potential of 4D flow to visualize arterial supply and venous drainage as well as its ability to quantify hemodynamic changes as an early indicator of response to radiotherapy. We recap the ability of ASL, which has become broadly adopted clinically into routine neuroimaging, to evaluate tissue perfusion and detect arteriovenous shunting. We observe the increasing use of diffusion techniques—DTI to delineate fiber tracts and DWI to assess ischemic injury. Finally, we show the use of susceptibility imaging techniques for detecting areas of previous hemorrhage or calcification, as well as blood oxygenation. Each of these aforementioned techniques continues to evolve and advance our ability to detect smaller iAVMs, interrogate the underlying pathophysiological consequences of iAVMs, track response to therapy, and deliver personalized, precision therapy to provide maximal benefit to each individual patient. REFERENCES 1. Diehl RR, Linden D, Lücke D, Berlit P. Phase relationship between cerebral blood flow velocity and blood pressure. Stroke. 1995;26(10):1801–1804. https://doi.org/10.1161/01. str.26.10.1801. 2. Turski P, Edjlali M, Oppenheim C. Fast 4D flow MRI reemerges as a potential clinical tool for neuroradiology. AJNR Am J Neuroradiol. 2013;34(10):1929–1930. https://doi.org/10. 3174/ajnr.a3664. 3. Stankovic Z, Allen BD, Garcia J, Jarvis KB, Markl M. 4D flow imaging with MRI. Cardiovasc Diagn Ther. 2014;4(2):173–192. https://doi.org/10.3978/j.issn.2223-3652.2014.01.02. 4. Schnell S, Wu C, Ansari SA. Four-dimensional MRI flow examinations in cerebral and extracerebral vessels – ready for clinical routine? Curr Opin Neurol. 2016;29(4):419–428. https://doi.org/10.1097/wco.0000000000000341. 5. Edjlali M, Roca P, Gentric J-C, et al. Advanced technologies applied to physiopathological analysis of central nervous system aneurysms and vascular malformations. Diagn Interv Imaging. 2014;95(12):1187–1193. https://doi.org/10.1016/j. diii.2014.05.003. 6. Chang W, Huang M, Chien A. Emerging techniques for evaluation of the hemodynamics of intracranial vascular pathology. Neuroradiol J. 2015;28(1):18–27. https://doi. org/10.15274/nrj-2014-10115.

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7. Meckel S, Leitner L, Bonati LH, et al. Intracranial artery velocity measurement using 4D PC MRI at 3 T: comparison with transcranial ultrasound techniques and 2D PC MRI. Neuroradiology. 2013;55(4):389–398. https://doi.org/10.1007/ s00234-012-1103-z. 8. Chang W, Landgraf B, Johnson KM, et al. Velocity measurements in the middle cerebral arteries of healthy volunteers using 3D radial phase-contrast HYPRFlow: comparison with transcranial Doppler sonography and 2D phase-contrast MR imaging. AJNR Am J Neuroradiol. 2011;32(1):54–59. https://doi.org/10.3174/ ajnr.a2240. 9. Finitsis S, Anxionnat R, Gory B, Planel S, Liao L, Bracard S. Susceptibility-weighted angiography for the follow-up of brain arteriovenous malformations treated with stereotactic radiosurgery. AJNR Am J Neuroradiol. 2019;40(5):792–797. https://doi.org/10.3174/ajnr.a6053. 10. Pelc NJ, Herfkens RJ, Shimakawa A, Enzmann DR. Phase contrast cine magnetic resonance imaging. Magn Reson Q. 1991;7(4):229–254. 11. Pelc NJ, Bernstein MA, Shimakawa A, Glover GH. Encoding strategies for three-direction phase-contrast MR imaging of flow. J Magn Reson Imaging. 1991;1(4):405–413. https://doi. org/10.1002/jmri.1880010404. 12. Lorenz R, Bock J, Snyder J, Korvink JG, Jung BA, Markl M. Influence of eddy current, Maxwell and gradient field corrections on 3D flow visualization of 3D CINE PC-MRI data. Magn Reson Med. 2014;72(1):33–40. https://doi.org/10.1002/mrm.24885. 13. Hsiao A, Lustig M, Alley MT, et al. Rapid pediatric cardiac assessment of flow and ventricular volume with compressed sensing parallel imaging volumetric cine phase-contrast MRI. AJR Am J Roentgenol. 2012;198(3):W250–W259. https://doi. org/10.2214/ajr.11.6969. 14. Masutani EM, Contijoch F, Kyubwa E, et al. Volumetric segmentation-free method for rapid visualization of vascular wall shear stress using 4D flow MRI. Magn Reson Med. 2018;80(2):748–755. https://doi.org/10.1002/mrm.27159. 15. Vasanawala SS, Hanneman K, Alley MT, Hsiao A. Congenital heart disease assessment with 4D flow MRI. J Magn Reson Imaging. 2015;42(4):879–886. https://doi.org/10.1002/jmri.24856. 16. Hsiao A, Lustig M, Alley MT, Murphy MJ, Vasanawala SS. Evaluation of valvular insufficiency and shunts with parallelimaging compressed-sensing 4D phase-contrast MR imaging with stereoscopic 3D velocity-fusion volume-rendered visualization. Radiology. 2012;265(1):87–95. https://doi. org/10.1148/radiol.12120055. 17. Wu C, Schnell S, Markl M, Ansari SA. Combined DSA and 4D flow demonstrate overt alterations of vascular geometry and hemodynamics in an unusually complex cerebral AVM. Clin Neuroradiol. 2016;26(4):471–475. https://doi.org/10.1007/ s00062-015-0477-9. 18. Wen B, Tian S, Cheng J, et al. Test–retest multisite reproducibility of neurovascular 4D flow MRI. J Magn Reson Imaging. 2019;49(6):1543–1552. https://doi.org/10.1002/jmri.26564. 19. Hope MD, Purcell DD, Hope TA, et al. Complete intracranial arterial and venous blood flow evaluation with 4D flow MR imaging. AJNR Am J Neuroradiol. 2009;30(2):362–366. https:// doi.org/10.3174/ajnr.a1138. 20. Chang W, Wu Y, Johnson K, et al. Fast contrast-enhanced 4D MRA and 4D flow MRI using constrained reconstruction (HYPRFlow): potential applications for brain arteriovenous malformations. AJNR Am J Neuroradiol. 2015;36(6):1049– 1055. https://doi.org/10.3174/ajnr.a4245. 21. Homan RW, Devous MD, Stokely EM, Bonte FJ. Quantification of intracerebral steal in patients with arteriovenous

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considerations. Magn Reson Med Sci. 2020;19(4):294–309. https://doi.org/10.2463/mrms.rev.2019-0096. Togao O, Obara M, Helle M, et al. Vessel-selective 4D-MR angiography using super-selective pseudo-continuous arterial spin labeling may be a useful tool for assessing brain AVM hemodynamics. Eur Radiol. 2020;30(12):6452–6463. https:// doi.org/10.1007/s00330-020-07057-4. Shao X, Zhao Z, Russin J, et al. Quantification of intracranial arterial blood flow using noncontrast enhanced 4D dynamic MR angiography. Magn Reson Med. 2019;82(1):449–459. https://doi.org/10.1002/mrm.27712. Iryo Y, Hirai T, Nakamura M, et al. Evaluation of intracranial arteriovenous malformations with four-dimensional arterialspin labeling–based 3-T magnetic resonance angiography. J Comput Assist Tomogr. 2016;40(2):290–296. https://doi. org/10.1097/rct.0000000000000346. Yu S, Yan L, Yao Y, et al. Noncontrast dynamic MRA in intracranial arteriovenous malformation (AVM): comparison with time of flight (TOF) and digital subtraction angiography (DSA). Magn Reson Imaging. 2012;30(6):869–877. https://doi. org/10.1016/j.mri.2012.02.027. Raoult H, Bannier E, Robert B, Barillot C, Schmitt P, Gauvrit J-Y. Time-resolved spin-labeled MR angiography for the depiction of cerebral arteriovenous malformations: a comparison of techniques. Radiology. 2014;271(2):524–533. https://doi. org/10.1148/radiol.13131252. Lin F, Wu J, Jiao Y, et al. One-stage surgical resection of giant intracranial arteriovenous malformations in selected patients: a novel diffusion tenser imaging score. World Neurosurg. 2019;130:e1041– e1050. https://doi.org/10.1016/j.wneu.2019.07.075. Pollock BE, Flickinger JC. A proposed radiosurgerybased grading system for arteriovenous malformations. J Neurosurg. 2002;96(1):79–85. https://doi.org/10.3171/ jns.2002.96.1.0079. Söderman M, Andersson T, Karlsson B, Wallace MC, Edner G. Management of patients with brain arteriovenous malformations. Eur J Radiol. 2003;46(3):195–205. https://doi. org/10.1016/s0720-048x(03)00091-3. Yeo SS, Jang SH. Delayed neural degeneration following gamma knife radiosurgery in a patient with an arteriovenous malformation: a diffusion tensor imaging study. NeuroRehabilitation. 2012;31(2):131–135. https://doi.org/10.3233/nre-2012-0780. Pantelis E, Papadakis N, Verigos K, et al. Integration of functional MRI and white matter tractography in stereotactic radiosurgery clinical practice. Int J Radiat Oncol Biol Phys. 2010;78(1):257– 267. https://doi.org/10.1016/j.ijrobp.2009.10.064. Koga T, Shin M, Maruyama K, et al. Integration of corticospinal tractography reduces motor complications after radiosurgery. Int J Radiat Oncol Biol Phys. 2012;83(1):129–133. https://doi. org/10.1016/j.ijrobp.2011.05.036. Itoh D, Aoki S, Maruyama K, et al. Corticospinal tracts by diffusion tensor tractography in patients with arteriovenous malformations. J Comput Assist Tomogr. 2006;30(4):618–623. https://doi.org/10.1097/00004728-200607000-00011. Ellis MJ, Rutka JT, Kulkarni AV, Dirks PB, Widjaja E. Corticospinal tract mapping in children with ruptured arteriovenous malformations using functionally guided diffusiontensor imaging. J Neurosurg Pediatr. 2012;9(5):505–510. https://doi.org/10.3171/2012.1.peds11363. Berntsen EM, Gulati S, Solheim O, Kvistad KA, Lindseth F, Unsgaard G. Integrated pre- and intraoperative imaging in a patient with an arteriovenous malformation located in eloquent cortex. Minim Invasive Neurosurg. 2009;52(02):83–85. https:// doi.org/10.1055/s-0028-1124104.

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64. Ille S, Picht T, Shiban E, Meyer B, Vajkoczy P, Krieg SM. The impact of nTMS mapping on treatment of brain AVMs. Acta Neurochir (Wien). 2018;160(3):567–578. https://doi. org/10.1007/s00701-018-3475-2. 65. Tong X, Wu J, Lin F, et al. Visual field preservation in surgery of occipital arteriovenous malformations: a prospective study. World Neurosurg. 2015;84(5):1423–1436. https://doi. org/10.1016/j.wneu.2015.06.069. 66. Yamada K, Kizu O, Ito H, et al. Tractography for arteriovenous malformations near the sensorimotor cortices. AJNR Am J Neuroradiol. 2005;26(3):598–602. 67. Okada T, Miki Y, Kikuta K, et al. Diffusion tensor fiber tractography for arteriovenous malformations: quantitative analyses to evaluate the corticospinal tract and optic radiation. AJNR Am J Neuroradiol. 2007;28(6):1107–1113. https://doi.org/10.3174/ajnr.a0493. 68. Maruyama K, Kamada K, Shin M, et al. Integration of threedimensional corticospinal tractography into treatment planning for gamma knife surgery. J Neurosurg. 2005;102(4):673–677. https://doi.org/10.3171/jns.2005.102.4.0673. 69. Gavin CG, Ian Sabin H. Stereotactic diffusion tensor imaging tractography for Gamma Knife radiosurgery. J Neurosurg. 2016;125(Suppl 1):139–146. https://doi.org/10.3171/2016.8. gks161032. 70. Annamraju RB, Venkatesan R, Vu AT. T2* weighted angiography (SWAN): T2* weighted non-contrast imaging with multiecho acquisition and reconstruction. In: Proceedings ESMRMB. 2008; Valencia. Abstract 482.

71. Di Ieva A, Lam T, Alcaide-Leon P, Bharatha A, Montanera W, Cusimano MD. Magnetic resonance susceptibility weighted imaging in neurosurgery: current applications and future perspectives. J Neurosurg. 2015;123(6):1463–1475. https:// doi.org/10.3171/2015.1.jns142349. 72. Hodel J, Blanc R, Rodallec M, et al. Susceptibility-weighted angiography for the detection of high-flow intracranial vascular lesions: preliminary study. Eur Radiol. 2013;23(4):1122–1130. https://doi.org/10.1007/s00330-012-2690-0. 73. Miyasaka T, Taoka T, Nakagawa H, et al. Application of susceptibility weighted imaging (SWI) for evaluation of draining veins of arteriovenous malformation: utility of magnitude images. Neuroradiology. 2012;54(11):1221–1227. https://doi.org/10.1007/s00234-012-1029-5. 74. Novakovic RL, Lazzaro MA, Castonguay AC, Zaidat OO. The diagnosis and management of brain arteriovenous malformations. Neurol Clin. 2013;31(3):749–763. https://doi. org/10.1016/j.ncl.2013.03.003. 75. Biondetti E, Rojas-Villabona A, Sokolska M, et al. Investigating the oxygenation of brain arteriovenous malformations using quantitative susceptibility mapping. Neuroimage. 2019;199:440–453. https://doi.org/10.1016/j. neuroimage.2019.05.014. 76. Schneider TM, Möhlenbruch M, Denoix M, et al. Susceptibilitybased characterization of cerebral arteriovenous malformations. Invest Radiol. 2020;55(11):702–710. https://doi.org/10.1097/ rli.0000000000000695.

Chapter 5

Natural History of Intracranial AVMs Arun Paul Amar

Chapter Outline Epidemiology Evolution of Anatomy Mode of Presentation Likelihood of Hemorrhage Risk Factors for Hemorrhage Prognosis Conclusion

Epidemiology The prevalence of intracranial arteriovenous malformations (iAVMs) in the general population is thought to be around 0.02%–0.2%, making them much less common than cerebral aneurysms (around 5%), ischemic stroke, and many other cerebrovascular disorders.1 The majority of iAVMs are sporadic and not related to any particular genetic predisposition, though they can be associated with certain conditions such as OslerWeber-Rendu (also known as hereditary hemorrhagic telangiectasia or HHT), Wyburn-Mason, Sturge-Weber, and other syndromes. The clustering of AVMs among family members or the association of iAVM with other presenting features outside the brain (particularly AVMs in other parts of the body) should prompt thorough evaluation, since the somatic aspects of these syndromes often herald significant morbidity by themselves. Intracranial AVMs are generally considered to be congenital lesions, resulting from developmental events that occur in utero.1 Rare reports document that de novo formation after birth is also possible, however, particularly when there is an underlying genetic or vascular susceptibility.2 Similarly, the

presence of multiple iAVMs within the same individual is uncommon, and such an occurrence suggests genetic predisposition. There is no definite sex predominance.1,3

Evolution of Anatomy Angioarchitecture is a term often used to describe the pattern of arterial input, nidus anatomy, and venous drainage within an iAVM. In some patients, these elements remain static throughout life, while in others there can be considerable dynamic changes, despite the congenital basis of the lesions.3 Unlike neoplasms, the true nidus of an iAVM does not typically enlarge, but it can recruit additional arterial input from surrounding collateral pathways, which often leads to an appearance of growth in imaging studies. Similarly, the veins that drain the nidus may acquire interval recruitment, thrombosis, dilatation, or narrowing. The hemodynamic stress due to extra flow within an iAVM may precipitate the development of an aneurysm within the feeding arteries, the nidus, or the draining vein. When affecting venous elements, these dilatations are often termed varices (singular: varix). Feeding artery aneurysms may be physically remote from the nidus and can be a separate source of rupture that leads to intracranial bleeding. Empirically, some of these feeding arteries regress in size once the AVM nidus is cured or a significant reduction in flow is accomplished by embolization, surgical removal (resection), or radiation. These dynamic processes may account for changes in symptoms over the life of an individual. For instance, acquired restrictions in venous outflow may produce audible signs of turbulent flow, resulting in tinnitus (a noise in the ear), or they can aggravate edema in the surrounding parenchyma, leading to headaches, seizures, or focal neurologic deficits. Spontaneous occlusion of a draining vein due to thrombosis or acquired stenosis from intimal hyperplasia may also precipitate hemorrhage due to the 59

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buildup of pressure within the nidus, since venous egress is blocked. The effects of puberty and growth, as well as hormonal changes associated with the menstrual cycle, on iAVM anatomy and flow remain poorly characterized. Pregnancy, however, is considered to increase the risk of rupture.

Mode of Presentation As congenital lesions, iAVMs can begin to produce symptoms or be discovered incidentally at any age. However, they most frequently come to clinical attention in a patient’s third or fourth decade.1–4 It is not known whether the aforementioned structural changes in the iAVM account for this phenomenon. In the majority of published case series, intracranial hemorrhage is the most common presentation, occurring in 45%–72% of patients.1 Bleeding into the parenchyma of the brain, a ventricle, or the subarachnoid space can all occur, depending on angioarchitecture and which feature of the iAVM ruptures. Although iAVMs only account for 2% of strokes overall and 4% of all hemorrhagic ones, they are responsible for nearly one-third of hemorrhagic strokes in young adults.1 After hemorrhage, the next most common presentation is seizures, reported to occur in 16%–53% of patients,1,3 with cortical AVM location being a risk factor.1 Of patients who do have seizures due to an AVM, 27%–35% have generalized convulsive (“grand mal”) seizures, while the remainder have partial or complex seizures.3 One interesting report describes auditory hallucinations of a song by the band Pink Floyd as the aura for a generalized seizure that was the presenting symptom of a de novo AVM in the left temporal lobe.2 Headache unrelated to hemorrhage is the symptom leading to diagnosis in 7%–48% of patients.1,3 No characteristic pattern, frequency, severity, or response to therapy reliably differentiates iAVM from other causes of headache.3 Importantly, both seizures and headaches may persist despite successful treatment and angiographic obliteration of iAVMs. Progressive neurologic deficits such as weakness, numbness, or disorders of language not due to hemorrhage are reported in 1%–40% of patients.3 These focal symptoms may be the result of dysfunction of the brain tissue that is interspersed within the nidus or ad-

Pearls • Common presentations of iAVMs include hemorrhage, seizure, headache, and focal neurological deficit. • The risk of iAVM bleeding is increased with deep location, venous outflow obstruction, associated aneurysms, and deep venous drainage. • Small iAVMs may have an increased risk for bleeding, but anatomical factors must also be considered. • The annual bleeding risk for an iAVM is generally quoted at between 2% and 4% but may be higher for individual patients. • Hemorrhage results in death in approximately 10% of cases and neurological deficits in 20%–40%.

jacent to it. Such disorders might happen on the basis of mass effect, edema, venous hypertension, or ischemia due to the preferential shunting of blood (also known as “steal”) by the relatively low-resistance circuit of the AVM compared with the surrounding brain. Over time, these processes can lead to gliosis (formation of brain scar tissue) and more enduring deficits. In children less than 2 years old, the presentation of an iAVM can include high-output congestive heart failure due to arteriovenous shunting, an enlarged head from hydrocephalus, developmental delay, and seizures. Intracranial AVMs are discovered as incidental findings in 2%–10% of cases; this may occur when brain scans are performed for unrelated reasons, such as trauma.1 Due to the widespread prevalence of noninvasive diagnostic imaging modalities, including CT and MRI, incidental detection of asymptomatic lesions accounts for an increasingly recognized proportion of iAVM patients. This phenomenon contributes to the observation that roughly 2.5 times more iAVMs are diagnosed as unruptured malformations than are detected due to intracranial hemorrhage in modern series.4

Likelihood of Hemorrhage When patients decide whether or not to undergo treatment of their iAVMs, the premise is a comparison between risks and benefits of invasive therapies such

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as embolization, surgery, or radiation versus those of no intervention. Implicit in this analysis is an ability to predict the risk of rupture during the patient’s expected lifetime. However, several assumptions that go into this calculus are undermined by poor-quality data. Most studies that have analyzed rupture rates are based on uncontrolled, small-cohort, single-institution case ­ series. Selection bias may underestimate the bleeding risk in these reports, since iAVMs prospectively considered to have a higher chance of bleeding may be chosen for treatment, while those deemed to be at lower risk are left for observation. These studies often conflate cases of previously ruptured iAVMs with cases of unruptured ones, though the risks of future bleeding may vary substantially between these two groups. Moreover, the studies often have a limited duration of follow-up, despite the fact that iAVMs carry lifelong risks. Heterogeneity in lesion anatomy (size, location, venous drainage, etc.) also makes it difficult to generalize the findings from these studies and apply them to individual patients. Finally, the stable annual risk estimates that are reported in these studies are contradicted by the dynamic risks encountered in real-world practice, as explained earlier. One of the most widely quoted statistics about iAVM rupture risk comes from a prospective, observational study of 260 symptomatic patients with angiographically confirmed iAVMs enrolled in Finland between 1942 and 1975.5 In this group, 71% of the patients initially presented with presumed hemorrhage, while 24% had seizures and 5% had other symptoms. Almost two-thirds (166) of these patients had no therapeutic intervention; the remaining 94 underwent surgery. Follow-up was available for 160 (96%) of the 166 unoperated patients. The mean duration of follow-up was 24 years (range, 12–45 years). This study found that the rate of hemorrhage was 4% per year, and the rate of mortality from the iAVM was 1% per year. This produced a combined major morbidity and mortality rate of 2.7% per year. These rates were consistent over the entire study period. The mean interval between initial presentation and subsequent hemorrhage was 7.7 years, and there was no difference in rates of hemorrhage or death regardless of mode of initial presentation. This study has several limitations, including selection bias. Only patients with “symptomatic” iAVMs

61 were enrolled, calling into question the generalizability of the authors’ findings for incidentally discovered lesions. In addition, the patients were not randomly assigned to treatment or observation, so differences in baseline characteristics could apply. The putative diagnosis of “hemorrhage” at initial diagnosis or a subsequent event is potentially inaccurate, as it was principally based on clinical criteria, because the study was conducted in the pre-CT era. Furthermore, since 71% of patients presented with presumed rupture, this study is less a survey of natural history of iAVMs than one of recurrent hemorrhage. The genetically homogeneous population of this Finnish study limits validity and generalizability to other ethnicities. Finally, there was no specification of iAVM anatomy (size, location, venous drainage, etc.) to correlate with natural history and thus aid patient-specific counseling. The event rates of this paper were replicated by several other retrospective case series that followed, including those that only enrolled patients without prior hemorrhage. In these studies, the annual risk of initial hemorrhage ranged between 2% and 4%.1 In the recent randomized controlled ARUBA trial comparing interventional treatment with medical management, spontaneous rupture occurred in the medical arm at an annual frequency of 2.2%.6 This rate was similar across all Spetzler-Martin groups. In another recent prospective, population-based inception cohort study, the rate of hemorrhage for previously unruptured iAVMs was 18% over a 12-year period of follow-up.7 ESTIMATING LIFELONG HEMORRHAGE RISK The fallacious assumptions described earlier have led to some oversimplistic tools for estimating lifelong risk of hemorrhage. One such formula is that the lifelong percent likelihood of bleeding can be calculated by subtracting the patient’s age from 100. Alternatively, the cumulative risk of hemorrhage can be computed by taking the likelihood of no hemorrhage (96%–98% annually based on bleed rates of 2%–4%) raised to the exponential power of life expectancy and then subtracted from 1. Using such calculations, hazard curves for cumulative likelihood of rupture as a function of patient age at presentation can be constructed. Three hypothetical curves are presented in Fig. 5.1, premised on annual bleed rates of 2%, 3%, and 4%.

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Fig. 5.1 Hazard curves for cumulative likelihood of iAVM rupture as a function of patient age. Three hypothetical curves are depicted, premised on annual hemorrhage rates of 2%, 3%, and 4%. The discrepancy between these theoretical curves and empiric observation suggests that there is much to learn about why some iAVMs bleed and others do not and why the bleeding risk may not be the same year after year in an individual patient.

The discrepancy between these theoretical curves and ­ empiric observation suggests that there is much to learn about why some iAVMs bleed and others do not and why the bleeding risk may not even be the same year after year in any given individual.

Risk Factors for Hemorrhage Analysis of several anatomic and demographic factors suggests that the likelihood of bleeding is not uniform across all iAVMs. Specific morphologic and clinical conditions associated with higher rates of rupture include prior hemorrhage, deep location, posterior fossa location, exclusive deep venous drainage, associated aneurysms, and the presence of only a single draining

vein.1,3 Association with AVM size is less consistent, and various studies yield contradictory associations. Paradoxically, larger iAVMs may be at lower risk of bleeding because the excess flow is distributed across a larger volume, thus reducing intranidal pressure. Alternatively, larger iAVMs may be more likely to cause symptoms leading to diagnosis prior to rupture, such as seizures or symptoms related to mass effect, so the apparent observation that patients with smaller iAVMs more commonly present with hemorrhage may simply be an epiphenomenon. One study of data from a prospectively maintained AVM database analyzed the natural history between initial presentation and first treatment in 622 patients with iAVMs.8 The median interval was

5

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102 days. Univariate and multivariate analyses and Cox proportional hazard models were used to analyze effects of patient age, gender, AVM size, location, venous drainage pattern, and associated arterial aneurysm on the likelihood of hemorrhage events, both at presentation and on follow-up. Hemorrhage at presentation was associated with increasing age, infratentorial and deep locations, exclusive deep venous drainage, and associated arterial aneurysm; however, a negative association was found for AVM size. Independent predictors of subsequent hemorrhage were initial hemorrhagic presentation (hazard ratio [HR], 5.38), deep brain location (HR, 3.25), and exclusive deep venous drainage (HR, 3.25). Annual rates of hemorrhage on follow-up ranged from 0.9% for iAVMs with none of these factors to 34% for those with all three. Limitations of this study include the short median follow-up interval of 102 days. In the Finnish study, the mean time to hemorrhage after initial presentation was nearly 8 years, and many of the patients destined to have their AVMs rupture in this cohort might not have done so within the time of monitoring. Furthermore, this was an observational trial only, with no consistent algorithm of treatment, suggesting the possibility of selection bias that confounds the results. Several studies report higher rates of hemorrhage during the initial years after diagnosis, suggesting that iAVMs might undergo some type of hemodynamic destabilization around the period when they become symptomatic.1 In one study, hemorrhage at presentation tripled the risk of subsequent bleeding during the first 5 years after diagnosis as compared with cases of unruptured iAVMs,1 though that result may also relate to some of the other anatomic risk factors mentioned earlier. This purported hemodynamic effect after initial presentation may explain why studies with short ­ follow-up typically report higher annual rates of hemorrhage than those with longer durations.1 After initial hemorrhage, the risk of recurrent hemorrhage is reported to be 6%–18% in the first year,4 then reverting to the baseline rate of 2%–4%, consistent with the overall population of iAVMs. The Finnish study supports this latter point, since it observed an annual risk of bleeding of only 4% among a cohort of patients who mostly (71%) presented with hemorrhage.

Prognosis Hemorrhages due to iAVM bleeding are often not as catastrophic as those due to a ruptured intracranial aneurysm or spontaneous hypertensive intracranial hemorrhage.3,5 The overall rates of mortality are about 5%–25%, and the overall rates of permanent disability are about 10%–40%.1–3,5 However, due to their topography and propensity for intraparenchymal hemorrhage, iAVM ruptures tend to produce greater degrees of focal neurological deficit than aneurysm ruptures. Specific impairments correlate with lesion location. Patients with iAVMs have significant excess mortality in comparison to the matched general population. In one study of patients with unruptured iAVMs, the overall annual mortality rate was 3.4% over a median follow-up period of 18.9 years. Almost half of this rate (1.6%) was attributable to the AVM itself, either due to acute case mortality or the long-term sequelae of AVM-related morbidities.1 The Finnish study showed comparable findings, and symptomatic iAVM patients who did not die from hemorrhage still had significantly lower life expectancy than the general population.5 The long-term prognosis varies, depending on the propensity to rerupture and any interventions performed to mitigate or prevent disease progression. However, with incomplete treatment, such as partial embolization, natural history may not be improved upon, and the goal of therapy remains angiographic obliteration of the nidus and cessation of all arteriovenous shunting.

Conclusion The natural history of iAVMs is highly variable from person to person and even within the same patient over time. Hemorrhage remains the most common mode of presentation, followed by seizures, headaches, and other symptoms. The annual risk of hemorrhage is estimated to be approximately 2%–4%, although various anatomic features of the AVM may increase or decrease this risk. Hemorrhage results in death in approximately 10% of cases and neurological deficits in 20%–40%. Even in the absence of hemorrhage, however, patients with iAVMs have excess mortality in comparison to the general population.

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REFERENCES 1. Laakso A, Hernesniemi J. Arteriovenous malformations: epidemiology and clinical presentation. Neurosurg Clin N Am. 2012;23(1):1–6. https://doi.org/10.1016/j.nec.2011.09.012. 2. Ozsarac M, Aksay E, Kiyan S, Unek O, Gulec FF. De novo cerebral arteriovenous malformation: Pink Floyd's song "Brick in the Wall" as a warning sign. J Emerg Med. 2012;43(1):e17–e20. https://doi.org/10.1016/j. jemermed.2009.05.035. 3. Hartmann A, Mast H, Choi JH, Stapf C, Mohr JP. Treatment of arteriovenous malformations of the brain. Curr Neurol Neurosci Rep. 2007;7(1):28–34. https://doi.org/10.1007/ s11910-007-0018-2. 4. Stapf C, Mohr JP, Choi JH, Hartmann A, Mast H. Invasive treatment of unruptured brain arteriovenous malformations is experimental therapy. Curr Opin Neurol. 2006;19(1):63–68. https://doi.org/10.1097/01.wco.0000200546.14668.78.

5. Ondra SL, Troupp H, George ED, Schwab K. The natural history of symptomatic arteriovenous malformations of the brain: a 24year follow-up assessment. J Neurosurg. 1990;73(3):387–391. https://doi.org/10.3171/jns.1990.73.3.0387. 6. Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, nonblinded, randomised trial. Lancet. 2014;383(9917):614–621. https://doi.org/10.1016/s0140-6736(13)62302-8. 7. Al-Shahi Salman R, White PM, Counsell CE, et al. Outcome after conservative management or intervention for unruptured brain arteriovenous malformations. JAMA. 2014;311(16):1661– 1669. https://doi.org/10.1001/jama.2014.3200. 8. Stapf C, Mast H, Sciacca RR, et al. Predictors of hemorrhage in patients with untreated brain arteriovenous malformation. Neurology. 2006;66(9):1350–1355. https://doi.org/10.1212/01. wnl.0000210524.68507.87.

Chapter 6

Aneurysms Associated With AVMs Pui Man Rosalind Lai and Mohammad A. Aziz-Sultan

Chapter Outline Prevalence/Demographics Classification Pathogenesis and Natural History Treatment Conclusion

Prevalence/Demographics Intracranial arteriovenous malformations (iAVMs) are frequently associated with the presence of intracranial aneurysms. The prevalence of AVMassociated aneurysms has been reported in a wide range, from 1.4% to 58% of patients with iAVMs,1–6 with the majority of the studies reporting between 10% and 20%. In a 2012 metaanalysis of data from 3923 patients with iAVMs, Gross and Du found that up to 18% of AVMs were associated with aneurysms.7 Similarly, ARUBA (A Randomised Trial of Unruptured Brain Arteriovenous Malformations) found intracranial aneurysms in 15.5% of patients with unruptured AVMs.8 The wide ranges in incidence may be explained by differences related to risk factors associated with the development of aneurysms in patients with iAVMs. Both aneurysm size and the number of aneurysms a patient has have been correlated with increasing age.9 Arterial aneurysms are rare in the pediatric population and more common in adult patients.10 In one study of 101 iAVM cases, only 8% of patients who first presented with iAVMs at less than 25 years of age had AVM-associated aneurysms at presentation, but for patients who were older than 50 years at initial presentation, the proportion with AVM-associated aneurysms was 37%.11

Aneurysms are often reported to be more frequently seen in association with posterior fossa AVMs,9,12,13 ­ previously reported with a 30% vs 11% prevalence in infratentorial and supratentorial locations, respectively.12 Aneurysms located in the posterior fossa and associated with infratentorial AVMs have also been found to have larger diameters and a higher rate of hemorrhage than those associated with supratentorial AVMs.9,13 The large discrepancies in the reported prevalence rates for iAVM-associated aneurysms have also been attributed to variations in diagnostic imaging studies and techniques and sampling errors. Nevertheless, despite the wide range of prevalence rates, there is consensus that the prevalence of intracranial aneurysms in patients with iAVMs is greater than the prevalence of intracranial aneurysms in the general population.14

Classification Several classification schemes have been proposed to characterize aneurysms associated with iAVMs, but no current classification provides predictive value for the risk of hemorrhage or outcome of surgical treatment.1,15 The components of the classification systems commonly include the location of the aneurysm in ­ relation to the nidus and the association of flow related to the AVM. Aneurysms associated with iAVMs can be classified as located within the nidus of the AVM (intranidal) or outside the nidus (extranidal). Extranidal aneurysm location can further be categorized as on the arterial walls proximal to the AVM nidus (arterial aneurysms) or on the draining veins (venous varices) that are proximal or distal to the AVM nidus. Arterial aneurysms can also be subcategorized based on their anatomic location and flow-related association with the AVM. Flow-related arterial aneurysms are aneurysms that are hemodynamically associated 65

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with the AVM, either at a distance from the nidus (proximal flow-related aneurysms) or in close proximity to the nidus (distal flow-related aneurysms). These aneurysms may appear in a branch point or along the feeding artery not at branch points of the AVM. The terms proximal and distal are often used in relationship with the circle of Willis, based on Redekop and colleagues’ 1998 classification, in which aneurysms are considered distal if they are located distal to the circle of Willis, the first bifurcation of the middle cerebral artery, and the anterior communicating artery and anterior cerebral artery.16 Arterial aneurysms that are not related to flow are aneurysms on arterial vessels that do not play a role in the perfusion of the nidus. Venous varices, which are often called venous aneurysms, are variceal enlargements within the iAVM nidus or distal to it, in the draining veins. These are not true aneurysms, as histological examination of resected specimens shows that they do not have the characteristic walls that define arterial aneurysms. By definition, all intranidal aneurysms are venous. These are dilatations within the boundaries of the nidus that show evidence of angiographic contrast filling before the venous phase of the angiogram filling occurs. Another commonly termed dilatation associated with iAVMs is arterial pseudoaneurysms, which were first described in 1993 by Garcia-Monaco et al.17 Pseudoaneurysms are dilations found on small perforating arteries or choroidal branches in close proximity to the ependymal surface and are often the point of rupture of the AVM when there is evidence of hemorrhage. They may have irregular shapes and are typically close to the AVM nidus.18

Pathogenesis and Natural History The rupture rate of iAVM-associated aneurysms is reported to be 7% annually,1,18 compared to the 2%–4% annual rate reported for iAVM rupture alone.8,19 The pathophysiology of the development and rupture of aneurysms associated with iAVMs is not fully understood, but it is thought to involve a combination of factors associated with hemodynamic shunting and genetic predisposition. There is consensus, however, that the presence of an associated aneurysm is a known factor associated with an increased risk of iAVM hemorrhage.20,21 The ARUBA trial also showed

Pearls • AVM-associated aneurysms are reported in 10%–20% of iAVM cases. • Aneurysm size and number correlate with increasing patient age. • Aneurysms are more commonly described in association with posterior fossa AVMs. • The rupture rate of aneurysms associated with iAVMs is higher (7% annually). • Intranidal aneurysms are resected with the iAVM; proximal flow-related aneurysms often regress after treatment of the AVM.

an association between iAVM-associated aneurysms and permanent neurologic deficit.8 Factors associated with the rupture of aneurysms associated with iAVMs include increased aneurysm size, higher number of aneurysms, infratentorial location, and the classification of the aneurysm.12,22–24 Aneurysm size has been found to be correlated with the risk of iAVM hemorrhage.25 Aneurysms associated with iAVMs are not only more frequently found in relationship to infratentorial AVMs but also have a strong association with higher risk of hemorrhage at presentation.21,24,26 The risk of rupture and clinical presentation are also dependent on the flow association and location of the aneurysm in relationship to the AVM nidus, as well as its histological classification.18,27 Flow-related proximal aneurysms are thought to be hemodynamically related to the AVM and the result of hemodynamic stress and intrinsic weakness in the arterial wall resulting in focal vessel dilatation.18 Aneurysms on feeding arteries have been found to be the highest source of hemorrhage for all aneurysms associated with iAVMs.22,28 The increased incidence of flow-related aneurysms in older patients and in those with high-flow iAVMs supports the hypothesis of a relationship between long-term flow-related dynamics and the pathophysiology of these aneurysms. Quantitative MR angiography has demonstrated wall shear stress to be significantly higher in iAVM feeders with associated aneurysms.29 Furthermore, despite similarly high flow in AVM feeders, the feeding artery diameters are smaller in iAVMs with aneurysms than

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Aneurysms Associated With AVMs

in those without aneurysms. Based on these findings, it has been proposed that iAVM feeders with flowrelated aneurysms are vessels that cannot compensate for the increased blood flow and high hemodynamic stress on the arterial wall, resulting in the development of focal dilatation.29 The spontaneous regression of flow-related aneurysms after iAVM obliteration also supports the theory that these aneurysms are associated with flow dynamics of the AVM. Distal flow-related and intranidal venous aneurysms are also thought to be highly associated with rupture due to the higher flow and shear stress on the vessel walls in close proximity to the AVM nidus. In contrast, aneurysms that are not flow related are thought to be aneurysms not associated with AVMs and exhibit a hemorrhage risk similar to the general pattern risk of saccular arterial aneurysms.7 Flow and hemodynamic stress alone do not explain all aneurysm development, as not all patients with iAVMs develop aneurysms. Genetics and individuals’ underlying vessel architecture have been proposed to be a part of the pathophysiology as well. While genome-wide association studies have not shown a relationship between aneurysm-associated loci and sporadic iAVMs, certain genes involved in cell cycle progression, such as SOX-17 and RBBP8, have been proposed to play a role.30 Further research into understanding the underlying genetic predisposition of aneurysms associated with iAVMs will elucidate the pathophysiology of the disease. Existing studies suggest that a complex interplay between genetics and physiology leads to the development and rupture of aneurysms associated with iAVMs. Pseudoaneurysms present with different natural histories and are thought to be the result of dissection at the point of rupture and dynamic vessel remodeling.18 These lesions often progress and enlarge early after detection, but they have also been found to spontaneously regress, although there are no current measures to predict whether an individual pseudoaneurysm will progress or regress.

Treatment Due to the variability of patient presentation, the pattern of hemorrhage, and the characteristics and location of the AVM and aneurysms, there is no consensus

on the standard of care for the treatment of aneurysms associated with iAVMs. The ultimate goals of treatment are to prevent aneurysm-associated hemorrhage and to avoid further morbidity and mortality associated with recurrent hemorrhage events.9 The treatment of aneurysms associated with iAVMs and the microsurgical, endovascular, and radiosurgical treatment options are addressed in Chapter 12.

Conclusion Aneurysms associated with iAVMs are associated with higher rates of hemorrhage at presentation and higher rehemorrhage rates than aneurysms that are not associated with iAVMs. The annual risk of hemorrhage for patients with iAVM-associated aneurysms is reported to be 7%. The pathophysiology of aneurysm development and rupture is not fully understood, but it is thought to involve interactions between genetic predisposition and hemodynamic stress in arterial walls. REFERENCES 1. Flores BC, Klinger DR, Rickert KL, et al. Management of intracranial aneurysms associated with arteriovenous malformations. Neurosurg Focus. 2014;37(3):E11. https://doi. org/10.3171/2014.6.focus14165. 2. Almefty K, Spetzler RF. Arteriovenous malformations and associated aneurysms. World Neurosurg. 2011;76(5):396–397. https://doi.org/10.1016/j.wneu.2011.06.051. 3. Turjman F, Massoud TF, Vinuela F, Sayre JW, Guglielmi G, Duckwiler G. Aneurysms related to cerebral arteriovenous malformations: superselective angiographic assessment in 58 patients. AJNR Am J Neuroradiol. 1994;15(9):1601–1605. 4. Brown RD Jr, Wiebers DO, Forbes GS. Unruptured intracranial aneurysms and arteriovenous malformations: frequency of intracranial hemorrhage and relationship of lesions. J Neurosurg. 1990;73(6):859–863. https://doi.org/10.3171/jns. 1990.73.6.0859. 5. Cockroft KM, Thompson RC, Steinberg GK. Aneurysms and arteriovenous malformations. Neurosurg Clin N Am. 1998;9(3):565–576. 6. da Costa L, Wallace MC, Ter Brugge KG, O'Kelly C, Willinsky RA, Tymianski M. The natural history and predictive features of hemorrhage from brain arteriovenous malformations. Stroke.2009;40(1):100–105.https://doi.org/10.1161/strokeaha. 108.524678. 7. Gross BA, Du R. Natural history of cerebral arteriovenous malformations: a meta-analysis. J Neurosurg. 2013;118(2):437– 443. https://doi.org/10.3171/2012.10.jns121280. 8. Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, nonblinded, randomised trial. Lancet. 2014;383(9917):614–621. https://doi.org/10.1016/s0140-6736(13)62302-8.

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9. Hung AL, Yang W, Jiang B, et al. The effect of flow-related aneurysms on hemorrhagic risk of intracranial arteriovenous malformations. Neurosurgery. 2019;85(4):466–475. https:// doi.org/10.1093/neuros/nyy360. 10. Garzelli L, Shotar E, Blauwblomme T, et al. Risk factors for early brain AVM rupture: cohort study of pediatric and adult patients. AJNR Am J Neuroradiol. 2020;41(12):2358–2363. https://doi.org/10.3174/ajnr.a6824. 11. Lasjaunias P, Piske R, Terbrugge K, Willinsky R. Cerebral arteriovenous malformations (C. AVM) and associated arterial aneurysms (AA). Analysis of 101 C. AVM cases, with 37 AA in 23 patients. Acta Neurochir (Wien). 1988;91(1-2):29–36. https://doi.org/10.1007/bf01400524. 12. Schmidt NO, Reitz M, Raimund F, et al. Clinical relevance of associated aneurysms with arteriovenous malformations of the posterior fossa. Acta Neurochir Suppl. 2011;112:131–135. https://doi.org/10.1007/978-3-7091-0661-7_23. 13. Magro E, Darsaut TE, Mezui EDO, et al. Arteriovenous malformations of the posterior fossa: a systematic review. Acta Neurochir (Wien). 2020;162(4):905–910. https://doi. org/10.1007/s00701-020-04260-6. 14. Rinkel GJ, Djibuti M, Algra A, van Gijn J. Prevalence and risk of rupture of intracranial aneurysms: a systematic review. Stroke. 1998;29(1):251–256. https://doi.org/10.1161/01. str.29.1.251. 15. Batjer H, Suss RA, Samson D. Intracranial arteriovenous malformations associated with aneurysms. Neurosurgery. 1986;18(1):29–35. https://doi.org/10.1227/00006123-19860100000006. 16. Redekop G, TerBrugge K, Montanera W, Willinsky R. Arterial aneurysms associated with cerebral arteriovenous malformations: classification, incidence, and risk of hemorrhage. J Neurosurg. 1998;89(4):539–546. https://doi. org/10.3171/jns.1998.89.4.0539. 17. Garcia-Monaco R, Rodesch G, Alvarez H, Iizuka Y, Hui F, Lasjaunias P. Pseudoaneurysms within ruptured intracranial arteriovenous malformations: diagnosis and early endovascular management. AJNR Am J Neuroradiol. 1993;14(2):315–321. https://doi.org/10.3174/ajnr.a4869. 18. Rammos SK, Gardenghi B, Bortolotti C, Cloft HJ, Lanzino G. Aneurysms associated with brain arteriovenous malformations. AJNR Am J Neuroradiol. 2016;37(11):1966–1971. https://doi. org/10.3174/ajnr.a4869. 19. Brown RD Jr, Wiebers DO, Forbes G, et al. The natural history of unruptured intracranial arteriovenous malformations. J Neurosurg. 1988;68(3):352–357. https://doi.org/10.3171/ jns.1988.68.3.0352.

20. Can A, Gross BA, Du R. The natural history of cerebral arteriovenous malformations. Handb Clin Neurol. 2017;143:15– 24. https://doi.org/10.1016/b978-0-444-63640-9.00002-3. 21. Dinc N, Won SY, Quick-Weller J, Berkefeld J, Seifert V, Marquardt G. Prognostic variables and outcome in relation to different bleeding patterns in arteriovenous malformations. Neurosurg Rev. 2019;42(3):731–736. https://doi.org/10.1007/ s10143-019-01091-7. 22. Shchehlov D, Bortnik I, Svyrydiuk O, Vyval M, Gunia D. Cerebral arteriovenous malformation with paranidal aneurysms. Clinical course and outcome after endovascular embolization. Georgian Med News. 2019;290:38–44. 23. Hung AL, Yang W, Braileanu M, et al. Risk assessment of hemorrhage of posterior inferior cerebellar artery aneurysms in posterior fossa arteriovenous malformations. Oper Neurosurg (Hagerstown). 2018;14(4):359–366. https://doi.org/10.1093/ons/opx120. 24. Orning J, Amin-Hanjani S, Hamade Y, et al. Increased prevalence and rupture status of feeder vessel aneurysms in posterior fossa arteriovenous malformations. J Neurointerv Surg. 2016;8(10):1021– 1024. https://doi.org/10.1136/neurintsurg-2015-012005. 25. Stein KP, Wanke I, Forsting M, et al. Associated aneurysms in supratentorial arteriovenous malformations: impact of aneurysm size on haemorrhage. Cerebrovasc Dis. 2015;39(2):122–129. https://doi.org/10.1159/000369958. 26. Dinc N, Platz J, Tritt S, et al. Posterior fossa AVMs: Increased risk of bleeding and worse outcome compared to supratentorial AVMs. J Clin Neurosci. 2018;53:171–176. https://doi. org/10.1016/j.jocn.2018.04.010. 27. D'Aliberti G, Talamonti G, Cenzato M, et al. Arterial and venous aneurysms associated with arteriovenous malformations. World Neurosurg. 2015;83(2):188–196. https://doi.org/10.1016/j. wneu.2014.05.037. 28. Platz J, Berkefeld J, Singer OC, et al. Frequency, risk of hemorrhage and treatment considerations for cerebral arteriovenous malformations with associated aneurysms. Acta Neurochir (Wien). 2014;156(11):2025–2034. https://doi. org/10.1016/j.wneu.2014.05.037. 29. Shakur SF, Amin-Hanjani S, Mostafa H, Charbel FT, Alaraj A. Hemodynamic characteristics of cerebral arteriovenous malformation feeder vessels with and without aneurysms. Stroke. 2015;46(7):1997–1999. https://doi.org/10.1161/ strokeaha.115.009545. 30. Kremer PH, Koeleman BP, Pawlikowska L, et al. Evaluation of genetic risk loci for intracranial aneurysms in sporadic arteriovenous malformations of the brain. J Neurol Neurosurg Psychiatry. 2015;86(5):524–529. https://doi.org/10.1136/ jnnp-2013-307276.

Chapter 7

Hemodynamic Factors: Steal/Breakthrough Bleeding Joseph P. Antonios, Nanthiya Sujijantarat, Daniela Renedo, Akli Zetchi, and Charles C. Matouk

Chapter Outline Introduction Hemodynamic Principles AVM Hemodynamics Conclusion

Introduction Hemodynamics is the study of blood flow distribution and biophysical changes in the vascular network.1 Normally, blood under high pressure is transported to tissues from the heart through the arteries and carried back through the veins. The connection between arteries and veins is facilitated by capillary beds, which serve to mitigate arterial pressure and allow for adequate oxygenation and supply to tissues. This normal vascular architecture is also found in the brain, where capillary beds serve to oxygenate brain tissue, supply nutrients, and maintain appropriate perfusion pressure.2 Intracranial arteriovenous malformations (iAVMs) are abnormal arterial-to-venous connections that precipitate pathological changes in blood flow, perfusion, and vascular architecture. In this chapter, we will closely look at the known hemodynamic changes associated with iAVMs and their secondary effects on the brain.

Hemodynamic Principles OVERVIEW To understand what happens in AVM hemodynamics, it is essential to know some basic concepts about how the normal cardiovascular system works.

The cardiovascular system consists of the heart and an extensive branched system of vessels—arteries, veins, and capillaries.3 Hemodynamics studies the distribution of pressures and flows in the cardiovascular system.4 The pressure is the force applied to an area, and flow is the action of moving along a stream. When we refer to blood pressure, we are talking about the pressure of the circulating blood against the blood vessel wall. This is generated by the pumping heart and helps move blood throughout the circulatory system. Blood flow refers to the velocity and the amount of blood passing at a given point along the vessel’s length. The circulatory system’s essential function is to maintain adequate blood flow distribution to the body’s tissues and organs. The distribution of blood flow can be controlled by the active contraction or dilation of blood vessels, a mechanism referred to as autoregulation. Together, these mechanisms regulate the distribution of blood flow across tissues, including the brain. TYPES OF FLOW The movement of blood through a blood vessel is characterized by the principle of laminar flow. This type of flow is characterized by concentric layers of blood moving parallel to the vessel’s long axis. The highest velocity of blood is found at the center point of the vessel. With each concentric layer further removed from the center, the velocity decreases such that the velocity of blood moving along the vessel wall approaches zero (standstill). Laminar flow is disrupted by turbulence across these imaginary concentric layers. Turbulent blood flow can occur where a vessel lumen becomes narrowed, at a bifurcation (fork), or where high flow or pressure is found. This type of movement has several consequences. It can promote platelet aggregation 69

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­resulting in thrombus development and vessel obstruction. It can also increase shear stress, which is the force that the blood flow applies to the vessel wall’s inner layer, the endothelium. Shear stress impacts vessel wall composition and will be discussed in more detail later in the chapter. VESSEL OVERVIEW Arteries are vessels that carry blood with oxygen and nutrients from the heart to the rest of the body. Their walls are thick compared to other vessels to accommodate their exposure to continuous high pressures. This thickness is accounted for, in part, by a large number of vascular smooth muscle cells in the arterial wall, allowing for control of arterial blood vessel caliber. Capillaries are small vessels that surround cells and deliver oxygen, nutrients, and other substances. They are arranged as complex capillary beds with thin walls that allow for the exchange of substances between blood and tissues. Precapillary sphincters (groups of muscle fibers that help control blood flow coming from arterial vessels into the capillary bed) regulate the decrease in pressure from arteries to capillaries. Finally, veins are blood vessels that return blood from organs to the heart. They have thin walls with large and irregular lumens. In contrast to arteries, they are low-resistance circuits, which means that the pressure needed to push blood through veins is low. Importantly, veins have many fewer vascular smooth muscle cells within their walls and accordingly cannot change caliber in response to local hemodynamics as readily.

AVM Hemodynamics LOSS OF CAPILLARY BED Normally, the capillary bed is interposed between arteries and veins. This collection of vessels provides resistance to flow such that high-pressure arterial blood is not transmitted to the low-pressure venous circulation. The distinguishing feature of an AVM is the lack of an intervening capillary bed. The result is direct (also referred to as early) arteriovenous shunting through a tangle of blood vessels referred to as the AVM nidus.5–7 The nidus is a high-flow circuit characterized by turbulent flow formed by a vast number of interconnected, arteriovenous fistulas. What should

Pearls • Abnormal vessels in the iAVM nidus allow direct transmission of high-pressure flow into venous low-pressure vessels, thereby increasing bleeding risk. • Decreased resistance in abnormal iAVM vessels allows blood to flow into them more easily and “steal” blood flow from the surrounding brain, causing neurologic deficits. • Venous variations secondary to iAVMs—dilation, varices, or stenoses—lead to increased risk for bleeding. • Bleeding after successful iAVM resection may be due to abnormal blood flow regulation or decreased venous outflow. • The iAVM nidus results in altered blood flow on both the arterial and the venous side with resultant changes in vascular anatomy—dilation, aneurysms—increasing bleeding risk.

have been a low-pressure capillary bed becomes a center of high-pressure flow (A in Fig. 7.1). ANEURYSM DEVELOPMENT Shear stress represents the force of blood against the vessel wall, which is applied mainly to the vessel wall’s inner layer, the vascular endothelium. In AVMs, this hemodynamic force is increased and leads to changes in vessel wall composition. Although this remodeling occurs in order to better accommodate these forces, the downstream changes in vessel caliber and wall thickness can lead to abnormal dilatations and aneurysm formation8–11 (B in Fig. 7.1). The rate of association between aneurysms and iAVMs varies across studies (3%–50%).12–15 AVM-associated aneurysms are classified as intranidal, flow-related, or unrelated. Intranidal aneurysms are located within or in the ­ immediate vicinity of the nidus. Flow-related aneurysms arise on arterial feeders to the AVM. Unrelated aneurysms arise on arteries that do not directly supply the AVM and may therefore be incidental findings.14–18 STEAL PHENOMENON The shunting of blood from an artery to a vein without an intervening capillary bed has been thought to result in a phenomenon known as vascular or cerebral

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Hemodynamic Factors: Steal/Breakthrough Bleeding

Fig. 7.1 Hemodynamic perturbations drive anatomic changes that characterize iAVMs. There is a loss of the classical capillary bed interface between artery and vein, with an abnormal tangle instead (A). The changes in blood flow secondary to this include aneurysm formation (B) and vascular steal (C) on the arterial side. Within the AVM itself, there are ischemic tissue changes and inflammatory infiltrate (D) that further contribute to the AVM pathology. As there is an increase in blood flow pressures on the venous side due to the loss of the capillary bed, the veins become arterialized (E), resulting in venous varices (F), venous congestion (G), outlet venous stenosis (H), and overall venous hypertension.

steal19–23 (C in Fig. 7.1). This was initially described when it was observed that brain structures adjacent to AVMs do not opacify on angiography. It has been hypothesized that the loss of resistance within the capillary bed results in hypoperfusion of the artery distal to and surrounding the AVM. This, in turn, results in hypoperfusion of the surrounding brain tissue, which predisposes to hypoxia, inflammation, and necrosis. Within the AVM nidus itself, inflammatory changes result in the recruitment of macrophages. This inflammatory environment also contributes to structural and neuronal changes in the surrounding brain that result in gliosis. Gliosis acts like a scar on the brain and can alter normal brain function and increase seizure susceptibility24,25 (D in Fig. 7.1). Although it is suspected

71 that seizures are more frequent in association with larger AVMs and those that occur in frontal, temporal, and parietal cortices,26,27 recent work has shown that complex angioarchitectural features are also contributory.28,29 For example, in one study, a fistulous component in the nidus, venous outflow stenosis, and the presence of a long pial course of the draining vein were identified as strong predictors of seizure presentation, in addition to location.30 It should be noted that the concept of vascular steal has been challenged and is the subject of ongoing debate. For example, a study involving 14 AVM patients showed that there is no increase in parenchymal blood volume, normal glucose, and oxygen extraction fractions in the brain tissue surrounding an AVM.31 Another study involving 152 AVM patients found no relationship between feeding artery pressures or flow velocities and neurological symptoms.23 Other reports also suggest that autoregulation is preserved in brain regions adjacent to AVMs.32 There remains significant work to be done to better associate hemodynamic changes in iAVMs with surrounding cerebral tissue perfusion. VENOUS ALTERATIONS In an AVM, blood is shunted directly into veins from arteries without an intervening capillary bed. Because of their inability to control the rate and pressure of blood flow passing into them, the draining veins of an AVM receive more blood flow at higher pressure than normal veins. As an adaptive response to a high-flow and high-pressure state, the draining veins of an AVM become arterialized, i.e., thick-walled33,34 (E in Fig. 7.1). An example of this can be seen in Fig. 7.2. This venous vascular remodeling in response to venous hypertension can lead to venous strictures, resulting in outlet stenoses, and varices. Both have been associated with an increased risk of AVM rupture35,36 (F and H in Fig. 7.1). Another important concept is relative venous congestion of the surrounding brain. It is important to note that an AVM represents a closed arteriovenous circuit independent of the surrounding brain such that arterial feeders only supply the AVM nidus, and the proximal draining veins only empty it. However, these high venous pressures can secondarily result in relative venous congestion of the surrounding brain. This can lead to increased seizure susceptibility and hemorrhagic risk. For example, the increased likelihood of

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Fig. 7.2 Intraoperative photograph and corresponding digital subtraction angiography (DSA) image. Left, Intraoperative view of a right frontal AVM supplied by small branches of the right middle cerebral artery superior trunk with a small nidus. Right, DSA image demonstrating drainage from the AVM into a small superficial cortical vein.

seizure presentation associated with a long pial course of the draining vein, as described earlier, likely reflects relative venous congestion of the surrounding brain. The increased hemorrhagic risk of deep vs superficial AVMs is often ascribed to the smaller, more delicate nature of deep draining veins.37,38 NORMAL PERFUSION PRESSURE BREAKTHROUGH BLEEDING A chapter on AVM hemodynamics would not be complete without a discussion of a complication of resection referred to as normal perfusion pressure breakthrough (NPPB). Originally described by Spetzler et al., NPPB describes the phenomenon of massive, multifocal bleeding after the technically successful removal of a brain AVM. They theorized that chronic hypoperfusion in the brain surrounding an AVM causes branches of the AVM feeding arteries that supply normal tissue to become markedly dilated.39 Morgan et al. demonstrated this phenomenon in a rodent model designed to have an intracranial arteriovenous fistula after the creation of a carotid-jugular fistula.40 Perinidal vessels supplying surrounding brain lose their autoregulatory capacity and remain dilated even after AVM resection. Accordingly, the surrounding brain is susceptible to increased perfusion that leads to hemorrhage.41 While this theory has largely held true, some more recent studies have cast doubt on its veracity. For example, Young et al. demonstrated that there is intact CO2 reactivity present

both before and after resection.42 Similarly, in another study, Young et al. showed that blood flow improved ipsilateral to the AVM following resection and was independent of mean arterial pressure, suggesting intact autoregulation postresection.43 An alternative theory to NPBB was proposed in 1993. Al-Rodhan et al. suggested that occlusive hyperemia was the underlying mechanism.44 Occlusive hyperemia is described by two mechanisms: (1) stagnation of flow in AVM arterial feeders and their branches to normal surrounding brain tissue; and (2) occlusion of draining veins.32 While the pathophysiological underpinning of NPPB continues to be debated, it clearly represents perturbed hemodynamics. In contrast to these theories, there is growing evidence that after iAVM resection, there is a correction of hemodynamic flow. Busch et al. serially evaluated blood flow before and after resection and showed that there was a restoration of differentiation in blood flow between feeding arteries and draining veins on transcranial Doppler ultrasonography (TCD).45 Shakur et al. convincingly showed this in a landmark study comparing hemodynamic flow between embolized and resected iAVMs using quantitative magnetic resonance angiography (qMRA) techniques to measure flow.46 In embolized AVMs with residual compartments within the nidus, there was no change in the pulsatility index (PI) or resistance index (RI),47 suggestive of

7

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Hemodynamic Factors: Steal/Breakthrough Bleeding

redistribution of flow across the AVM. In the setting of AVM resection, though, the PI and RI increased and matched flow with normal contralateral vessels. The reliability of TCD and qMRA techniques in this particular setting is not clearly established, but there are numerous studies corroborating their use and findings suggestive of improvement in hemodynamics and restoration of normal pressure gradients.48–51 MATHEMATICAL MODELING OF AVM HEMODYNAMICS AND TREATMENT STRATEGIES Mathematical modeling of blood flow has been, for the most part, limited to 1D approximations of the Navier-Stokes equations, which average blood flow over vessel cross sections. The models vary in complexity, with some taking into account rigid and elastic boundaries while others further account for flow in three dimensions.52–55 Importantly, the effect of AVM hemodynamics on flow in feeding and draining vessels has also been studied and modeled.46 The fundamental application of these models is in the anticipation and prediction of the alterations in flow created by disruption of the precarious hemodynamic equilibrium between the normal brain and the AVM.56 White and Smith described a model whereby one could develop patient-specific embolization strategies.57 In this model, the authors treated both the embolization material and blood flowing through the AVM as incompressible and viscous. This allowed for more direct analysis of hemodynamic changes before and after embolization while examining potential strategies for doing so most effectively. Modern studies have begun to employ modern solutions for this purpose—Oermann et al. describe a machine learning method to predict outcomes after stereotactic radiosurgery for iAVMs, indirectly taking into account hemodynamic alterations.58

Conclusion Intracranial AVMs are complex vascular lesions characterized by early arteriovenous shunting and lack of an intervening capillary bed. Their clinical presentation, rupture risk, and treatment-related complications are importantly determined by perturbed hemodynamics within the AVM itself and the surrounding brain. The hemodynamic perspective offers an important

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45.

46.

hypotensive cortical territories adjacent to arteriovenous malformations. Columbia University AVM Study Project. Neurosurgery. 1994;34(4):601–610; discussion 610–611. https://doi.org/10.1227/00006123-199404000-00006. Kubalek R, Yin L, Fronhofer G, Schumacher M. Cerebral arteriovenous malformations: correlation between the angioarchitecture and the bleeding risk. Article in German. Klin Neuroradiol. 2001;11(2):97–104. https://doi. org/10.1007/PL00022539. Mansmann U, Meisel J, Brock M, Rodesch G, Alvarez H, Lasjaunias P. Factors associated with intracranial hemorrhage in cases of cerebral arteriovenous malformation. Neurosurgery. 2000;46(2):272–280. https://doi.org/10.1097/00006123-200002000-00004. Bederson JB, Wiestler OD, Brüstle O, Roth P, Frick R, Yaşargil M. Intracranial venous hypertension and the effects of venous outflow obstruction in a rat model of arteriovenous fistula. Neurosurgery. 1991;29(3):341–350. https://doi.org/10.1097/00006123-199109000-00002. Hurst RW, Hackney DB, Goldberg HI, Davis RA. Reversible arteriovenous malformation-induced venous hypertension as a cause of neurological deficits. Neurosurgery. 1992;30(3): 422–425. Stapf C, Mast H, Sciacca R, et al. Predictors of hemorrhage in patients with untreated brain arteriovenous malformation. Neurology. 2006;66(9):1350–1355. Mast H, Young WL, Koennecke H-C, et al. Risk of spontaneous haemorrhage after diagnosis of cerebral arteriovenous malformation. Lancet. 1997;350(9084):1065–1068. Spetzler RF, Wilson CB, Weinstein P, Mehdorn M, Townsend J, Telles D. Normal perfusion pressure breakthrough theory. Clin Neurosurg. 1978;25:651–672. https://doi.org/10.1093/ neurosurgery/25.cn_suppl_1.651. Morgan MK, Johnston I, Besser M, Baines D. Cerebral arteriovenous malformations, steal, and the hypertensive breakthrough threshold. An experimental study in rats. J Neurosurg. 1987;66(4):563–567. https://doi.org/10.3171/jns.1987.66.4.0563. Alexander MD, Connolly ES, Meyers PM. Revisiting normal perfusion pressure breakthrough in light of hemorrhageinduced vasospasm. World J Radiol. 2010;2(6):230–232. https://doi.org/10.4329/wjr.v2.i6.230. Young WL, Prohovnik I, Ornstein E, et al. The effect of arteriovenous malformation resection on cerebrovascular reactivity to carbon dioxide. Neurosurgery. 1990;27(2):257–266; discussion 266–267. https://doi.org/10.1097/00006123-199008000-00015. Young WL, Kader A, Prohovnik I, et al. Pressure autoregulation is intact after arteriovenous malformation resection. Neurosurgery. 1993;32(4):491–496; discussion 496-497. https://doi.org/10.1227/00006123-199304000-00001. al-Rodhan NR, Sundt TM Jr, Piepgras DG, Nichols DA, Rüfenacht D, Stevens LN. Occlusive hyperemia: a theory for the hemodynamic complications following resection of intracerebral arteriovenous malformations. J Neurosurg. 1993;78(2):167–175. https://doi.org/10.3171/jns.1993.78.2.0167. Busch KJ, Kiat H, Stephen M, Simons M, Avolio A, Morgan MK. Cerebral hemodynamics and the role of transcranial Doppler applications in the assessment and management of cerebral arteriovenous malformations. J Clin Neurosci. 2016;30:24–30. https://doi.org/10.1016/j.jocn.2016.01.029. Shakur SF, Amin-Hanjani S, Abouelleil M, Aletich VA, Charbel FT, Alaraj A. Changes in pulsatility and resistance indices of cerebral arteriovenous malformation feeder arteries after embolization and surgery. Neurol Res. 2017;39(1):7–12. https://doi.org/10.1080/01616412.2016.1258970.

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47. Gosling R, King D. The role of measurement in peripheral vascular surgery: arterial assessment by Doppler-shift ultrasound. Proc Roy Soc Med. 1974;67:447–449. https://doi.or g/10.1177/2F00359157740676P113. 48. Kaspera W, Ładziński P, Larysz P, et al. Transcranial color-coded Doppler assessment of cerebral arteriovenous malformation hemodynamics in patients treated surgically or with staged embolization. Clin Neurol Neurosurg. 2014;116:46–53. https:// doi.org/10.1016/j.clineuro.2013.11.001. 49. Jo KI, Kim JS, Hong SC, Lee JI. Hemodynamic changes in arteriovenous malformations after radiosurgery: transcranial Doppler evaluation. World Neurosurg. 2012;77(2):316–321. https://doi.org/10.1016/j.wneu.2011.06.061. 50. Krejza J, Baumgartner RW. Clinical applications of transcranial color-coded duplex sonography. J Neuroimaging. 2004;14(3):215– 225. https://doi.org/10.1177/1051228403259274. 51. Zhao M, Charbel FT, Alperin N, Loth F, Clark M. Improved phase-contrast flow quantification by three-dimensional vessel localization. Magc Reson Imaging. 2000;18(6):697–706. https:// doi.org/10.1016/s0730-725x(00)00157-0. 52. Gibala MJ, Little JP, Van Essen M, et al. Short-term sprint interval versus traditional endurance training: similar initial adaptations in human skeletal muscle and exercise performance. J Physiol. 2006;575(3):901–911. https://doi. org/10.1113/jphysiol.2006.112094.

75 53. Formaggia L, Gerbeau J-F, Nobile F, Quarteroni A. On the coupling of 3D and 1D Navier–Stokes equations for flow problems in compliant vessels. Comput Methods Appl Mech Eng. 2001;191(67):561–582. https://doi.org/10.1016/S0045-7825(01)00302-4. 54. Sherwin SJ, Formaggia L, Peiro J, Franke V. Computational modelling of 1D blood flow with variable mechanical properties and its application to the simulation of wave propagation in the human arterial system. Int J Numer Methods Fluids. 2003;43(67):673–700. https://doi.org/10.1002/FLD.543. 55. Papapanayotou C, Cherruault Y, De La Rochefoucauld B. A mathematical model of the circle of Willis in the presence of an arteriovenous anomaly. Computers Math Applic. 1990;20(4-6): 199–206. https://doi.org/10.1016/0898-1221(90)90327-G. 56. Telegina MN, Chupakhin MA, Cherevko MA. Local model of arteriovenous malformation of the human brain. J Phys: Conf Ser. 2013;410. https://doi.org/10.1088/1742-6596/410/1/012001, 012001. 57. White A, Smith F. Computational modelling of the embolization process for the treatment of arteriovenous malformations (AVMs). Math Comput Modell. 2013;57(5-6):1312–1324. https://doi.org/10.1016/j.mcm.2012.10.033. 58. Oermann EK, Rubinsteyn A, Ding D, et al. Using a machine learning approach to predict outcomes after radiosurgery for cerebral arteriovenous malformations. Sci Rep. 2016;6:21161. https://doi.org/10.1038/srep21161.

Chapter 8

Classification Systems David J. McCarthy, Michael J. Lang, Bradley A. Gross, and Robert M. Friedlander

Chapter Outline Introduction Surgical Classifications Radiosurgical iAVM Classifications Endovascular iAVM Classifications Conclusion

Introduction Classification systems have become an integral tool for the appropriate care of patients with intracranial arteriovenous malformations (iAVMs). With the pathology’s capricious clinical course and the lesions’ variable anatomical size, location, and angioarchitecture, classification allows practitioners to systematically assess treatment risk and success likelihood. Although iAVMs were once managed exclusively with resection, a variety of management options are now available, including stereotactic radiosurgery and endovascular embolization, and iAVMs are often treated with more than one modality. Classifications facilitate the succinct exchange of treatment-specific risks and results between specialties, serving to optimize outcomes for patients. New imaging modalities and treatment technology continue to impact the preoperative assessment and treatment efficacy, respectively. With the rapid technological advancement and adoption of a multimodality approach over the past few decades, novel classifications have been introduced and classic ones have been modified.

Surgical Classifications HISTORICAL SURGICAL GRADING SYSTEMS The first iAVM classification system was introduced by Alfred J. Luessenhop and Thomas A. Gennarelli 76

in 1977. They rated supratentorial AVMs from grade I to IV, with an additional grade attributed for each arterial feeder with accepted nomenclature.1 To grade an AVM by this scheme, the primary contributing vascular territory is identified and points are added for each arterial feeder with standardized nomenclature from that territory. For example, an AVM in the frontal pole with three arterial feeders from the frontopolar artery and one from the orbitofrontal artery would be given a grade of II. Deviations from their algorithm include the following: lenticulostriate perforators were included as named arteries; choroid plexus AVMs were grade III, since they were supplied by one anterior and two posterior choroidal arteries; and corpus callosum AVMs were grade II if only fed by pericallosal arteries and grade III when also supplied (directly or indirectly) by the posterior cerebral artery (PCA). The classification’s upper limit was grade IV, since Luessenhop and Gennarelli deemed that an AVM of grade IV or higher was inoperable. The authors presented data from a series of 49 cases of supratentorial AVMs and reported the following postoperative morbidity and mortality rates: for grade I AVMs, 0%; for grade II, 5.9%; for grade III, 50%. All grade IV AVMs were managed conservatively (without surgery). To ease classification and include cerebellar AVMs, Luessenhop and Rosa proposed an alternative schema that exclusively considered AVM size.2 Regardless of AVM location or the number of arterial feeders, grade I AVMs were lesions ≤ 2 cm; grade II were 2–4 cm; grade III, 4–6 cm; and grade IV, > 6 cm. The 1977 schema applied to supratentorial lesions, while the second version applied to all parenchymal AVMs rostral to the spinal cord. The authors reported morbidity and mortality rates of 0%, 6.7%, and 56% for grades I,

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II, and III, respectively. Similar to the prior publication, grade IV AVMs were deemed inoperable. While the classifications of Luessenhop and colleagues are not currently utilized, they established the foundation for subsequent iAVM classification systems. In the October 1986 edition of the Journal of Neurosurgery, two distinct AVM classifications were published, one by Shi and Chen and the other by Spetzler and Martin.3,4 Shi and Chen graded iAVMs on a scale of I–IV based on scores for four components: AVM size, location and depth, arterial feeders, and draining veins. Each component was given a score ranging from 1 to 4. For AVM size, scores of 1, 2, 3, and 4, respectively, were given for sizes < 2.5 cm, 2.5–5 cm, 5–7.5 cm, and > 7.5 cm. For location and depth, AVMs with superficial and noncrucial location received a score of 1; superficial AVMs in functional areas, a score of 2; deep AVMs in the corpus collosum or basal ganglia, a score of 3; and brainstem or diencephalon AVMs, a score of 4. Arterial supply was scored as follows: 1 for a single superficial middle cerebral artery (MCA) or anterior cerebral artery (ACA) branch; 2 for multiple superficial MCA or ACA branches; 3 for branches of the posterior cerebral artery (PCA), deep MCA, deep ACA, or vertebral artery; and 4 for branches of all 3 major cerebral arteries or a vertebral or basilar artery. For venous drainage, AVMs with a single superficial draining vein with dural sinus drainage were scored 1; multiple superficial sinus draining veins, 2; drainage into a deep cerebral vein, vein of Galen, or straight sinus, 3; and deep drainage with associated venous ectasia, 4. To appropriately grade an iAVM with the Shi and Chen criteria, the lesion would be given a four-digit score. For example, an AVM with a 3-cm-diameter nidus, located on the cortex near Broca’s area with arterial supply from multiple branches from ACA and MCA territories and venous drainage into the sphenoparietal sinus would be given a score of 2223. When at least two of the four components share the highest grade, then the AVM is given that singular grade. If the highest score is only held by one component, then the AVM grade is intermediate. Therefore the final Shi and Chen classification of our example with the score of 2223 would be grade II–III. Since the Shi and Chen grading schema had intermediate grades, the total number of AVM classes was 7. In the series of 100 patients, the

Pearls • Multimodality intervention for iAVM therapy complicates the specific surgical, endovascular, and radiosurgical risk-assessment systems. • The most commonly applied classification for assessing surgical risk is the Spetzler-Martin grading system (Table 8.1). • Radiosurgical grading scales are limited by difficulty in predicting obliteration. • Systems for assessing endovascular treatment risk are still not uniformly accepted. • Small frontal-temporal AVMs with superficial drainage are easily treated surgically or with stereotactic radiosurgery.

authors reported a combined morbidity and mortality rate of 0%, 0%, 0%, 16.7%, 20%, and 100% for grades I, I–II, II, II–III, III, and III–IV, respectively. (No rate was given for grade IV because no grade IV lesion was treated with complete resection in this series.) While both classifications proposed in 1986 were more sophisticated than prior grading systems, accounting for the architecture of draining veins, the schema proposed by Spetzler and Martin was more user-friendly. It eventually was widely popularized and was dubbed the Spetzler-Martin classification.4 SPETZLER-MARTIN CLASSIFICATION The Spetzler-Martin classification became the predominant surgical iAVM schema because it successfully accounted for the sophisticated AVM angioarchitecture while maintaining bedside simplicity. AVMs are assigned points for size, location, and venous drainage, with the total score ranging from 1 to 5 (Table 8.1), corresponding to grades I–V. For AVM size: one point is assigned for < 3 cm nidus diameter, two points for 3–6 cm, and three points for > 6 cm. One additional point is added if the AVM resides in eloquent areas, including the sensorimotor cortex, language centers, primary visual cortex, hypothalamus, thalamus, brainstem, and cerebellar peduncles. The last point is added if there is deep venous drainage. In cerebellar AVMs, the only superficial drainage is via veins that drain directly into the straight sinus or transverse sinus. Spetzler and Martin validated the predictive value

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TABLE 8.1 Surgical iAVM Classificationsa Classification

Grades

Spetzler-Martin grading system4

I–V

Lawton-Young supplement10

HDVL supplement12

Cerebellar AVM grading system15,a

I–V

1–6

1–3

Points Per Covariate

Covariates

1 1 3

Eloquence Deep venous drainage Size

1 1 3

Diffuse nidus Nonhemorrhagic Age

1 1 1 3

Diffuse nidus Nonhemorrhagic Deep venous drainage Lesion-to-eloquence distance

1 1 1 2

Age ≥ 60 y Emergent surgery Deep venous drainage Poor preoperative status

Categorical Covariate Points

Categorical Point Definition

1 2 3

< 3 cm 3–6 cm > 6 cm

1 2 3

< 20 y 20–40 y > 40 y

1 2 3

> 10 mm 5–10 mm 0–5 mm

HDVL, Hemorrhagic presentation, nidus diffuseness, deep venous drainage, lesion-to-eloquence distance. a Grades 1–3 are assigned for risk point totals up to a maximum of 5 points: grade 1 for 0–1 points, grade 2 for 2–3 points, grade 3 for 4–5 points.

of their grading system by retrospectively applying it in a series of 100 cases. They divided outcomes into minor and major deficits, with the latter encompassing newfound hemiparesis, aphasia, or visual deficit. For grades I, II, III, IV, and V, respectively, the reported minor deficit rates were 0%, 5%, 12%, 20%, and 19%, and the reported major deficit rates were 0%, 0%, 4%,7%, and 12% (Table 8.2). Hamilton and Spetzler later validated the system’s accuracy in a prospective series of 120 AVM cases.5 The rate of major neurologic deficit following resection was 0% for grade I– III AVMs, 21.9% for grade IV, and 16.7% for grade V AVMs. Increasing Spetzler-Martin grade significantly correlated with higher chance of new temporary (P < .0001) and new permanent (P < .0001) neurological deficits. The Spetzler-Martin system included the AVM features of the Shi and Chen classification while maintaining the simplicity of the classifications developed

by Luessenhop and colleagues. It was quickly adopted by practitioners, becoming the primary system guiding AVM surgical treatment decisions. As with the Hunt and Hess score for subarachnoid hemorrhage, the widespread adoption of the Spetzler-Martin scale enabled physicians to efficiently communicate AVM clinical scenarios. The initial landmark publication eventually became one of the most cited works in the neurosurgical literature.6 SPETZLER-MARTIN CLASSIFICATION MODIFICATIONS Since its inception, the Spetzler-Martin classification has been thoroughly examined by many practitioners, leading to modifications of the classic schema through expansion and simplification. The grade III Spetzler-Martin category contains the most Spetzler-Martin point combinations. There are four distinct Spetzler-Martin grade III AVMs, accounting for one-third of all possible Spetzler-Martin point

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TABLE 8.2 Reported Rates of Outcomes With Regard to Classification Grades Treatment Modality Surgery

Radiosurgery Endovascular

percentage of patients with specified outcome (stratified by grade/score)

Classification

Outcome

0

I (1)

II (2)

III (3)

IV (4)

V (5)

VI (6)

Spetzler-Martin grading system4 Lawton-Young supplement10 HDVL supplement12

Major complication Morbidity/ mortality Unfavorable outcome Poor outcome

NA

0

0

4

7

12

NA

NA

4

12

22

40

50

NA

NA

0

0

12

32

57

63

NA

33

62

83

NA

NA

NA

Poor outcome New functional deficit Complication Favorable cure

17 0

21 6

30 6

52 15

61 50

NA NA

NA NA

NA NA

0 NA

0 NA

14 100

50 67

75 67

NA 10a

Cerebellar AVM grading system15 VRAS24 AVM Embolization Prognostic Score Risk34 Buffalo score35 AVMES37

AVMES, Arteriovenous malformation embocure score; HDVL, hemorrhagic presentation, nidus diffuseness, deep venous drainage, lesion-to-eloquence distance; NA, not applicable (indicates that the grade is not an applicable part of the specified classification); VRAS, Virginia Radiosurgery AVM Scale. a Patients with a score > 5 (the AVMES does not include scores higher than 5).

combinations. These include S1V1E1 (small nidus, deep drainage, and eloquence), S2V1E0 (medium nidus, deep drainage, without eloquence), S2V0E1 (medium nidus, without deep drainage, with eloquence), and S3V0E0 (large nidus, without deep drainage, without eloquence). With their larger combination distribution, grade III AVMs demonstrated higher outcome variation. This discrepancy was addressed with two distinct approaches, either stratification or simplification of the Spetzler-Martin classification.7–9 De Oliveira et al. were the first to suggest further stratification of grade III AVMs.9 The authors divided grade III into grade IIIA (large size) and grade IIIB (eloquent location). Grade IIIA AVMs had a 95% rate of favorable surgical outcome, while grade IIIB AVMs only had a 70% favorable outcome rate. This outcome disparity led the authors to propose that grade IIIA AVMs should be managed with resection with preoperative embolization while grade IIIB AVMs should only receive radiosurgery. In 2003, Lawton et al. modified the Spetzler-Martin classification by parsing each grade III subtype into separate categories (Table 8.3).8 A total of 74 Spetzler-Martin grade III AVMs were analyzed, and a large variation in surgical outcomes between the

TABLE 8.3 Spetzler-Martin and Modified Spetzler-Martin Grades Classic Spetzler-Martin Lawton Grading System4 Modification8

Spetzler-Ponce Modification7

I II III

A

IV V

I II IIIIII III + III* IV V

B

C

distinct grade III AVMs was observed. The proportion of cases in which resection results in major neurological deficit was 2.9% for S1V1E1, 7.1% for S2V1E0, and 14.8% for S2V0E1 AVMs. The authors failed to observe a single S3V0E0 AVM, suggesting that large AVMs with neither deep drainage nor eloquence must be extremely rare. From least to most surgically morbid, the authors expanded the original grade III classification into grade III- (S1V1E1), grade III (S2V1E0),

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grade III + (S2V1E0), and grade III* (S3V0E0). Their results suggested that grade III + AVMs (S2V1E0) may be better managed conservatively, with management similar to that of grade IV/V AVMs.8 In 2011, Spetzler and Ponce proposed a simplified version of the Spetzler-Martin grading system.7 Observing that grade I and II AVMs are typically managed surgically while grade IV and V AVMs are managed conservatively, the authors proposed a condensed schema with three classes: A for grades I and II, B for grade III, and C for grade IV or V (Table 8.3). In this three-tier schema, each class contained four possible Spetzler-Martin point combinations. A systematic review of AVM literature was conducted, and seven surgical series that utilized the classic ­ Spetzler-Martin classification were identified. Patients from these series were pooled (n = 1476), and the predictive accuracy for neurological outcomes was found to be similar using the three-tier and five-tier SpetzlerMartin classifications, with the receiver operating characteristic (ROC) curve areas of 0.713 and 0.711, respectively. Whereas Lawton et al. aimed to elucidate the treatment decisions that accompany grade III AVMs through an expanded classification schema, the Spetzler-Ponce simplified version defined class B AVMs as heterogeneous lesions that demand clinical expertise to elucidate their management, often a multimodality treatment approach. SPETZLER-MARTIN CLASSIFICATION SUPPLEMENTS Modified grading classifications facilitate patient selection utilizing the classic Spetzler-Martin schema, while supplemental classifications may expand its predictive power. The Lawton-Young supplement was proposed in 2010 and is the most utilized Spetzler-Martin addendum.10 The authors analyzed a single-surgeon series of 300 resected AVMs, aiming to identify additional factors that would improve outcome prediction, including patient sex, age, ethnicity, presence of deep perforators, hemorrhagic presentation, nidus depth, and nidus compactness. Older patient age, diffuse nidus angioarchitecture, and unruptured presentation predicted worse outcomes; these variables formed the Lawton-Young supplement to the classic SpetzlerMartin classification. The proposed complete classification was a total of 10 points, 5 derived from the classic Spetzler-Martin schema and 5 from the

Lawton-Young supplement (Table 8.1). A maximum of 3 supplement points could be appointed for patient age: 1 for age < 20 years old, 2 for age 20–40 years, and 3 for age > 40 years. Unruptured presentation and diffuse angioarchitecture were each assigned 1 point. The authors postulated that AVMs with a hemorrhagic presentation provide a hematoma surgical corridor that serves to reduce surgical disruption of normal neurologic tracts. The stand-alone Lawton-Young classification performed better than the classic Spetzler-Martin schema in their study (ROC 0.73 vs 0.66, respectively; P =.042).10 However, their series contained 11 Spetzler-Martin grade IV or V AVMs (3.6%) compared to 39 supplemental grade IV or V AVMs (13%), suggesting that the observed superiority of the supplement may be a byproduct of inherent selection bias. The morbidity and mortality rates for Lawton-Young supplemental grades I, II, III, IV, and V were 4%, 12%, 22%, 40%, and 50%, respectively (Table 8.2). Compared to the stand-alone Spetzler-Martin and stand-alone supplemental classification, the combined 10-point schema had the highest prognostic accuracy, with an ROC of 0.73.10 Lawton et al. observed that AVMs with Spetzler-Martin grades I–III and high Lawton-Young supplement scores had an unfavorable surgical outcome, with neurological worsening after surgery in 41% of cases. Conversely, AVMs with Spetzler-Martin grades IV and V and low supplementary grades only had an unfavorable outcome rate of 29% (Table 8.4).10 The superiority of the combined supplement–SpetzlerMartin grade was later externally validated by Hafez et al. in a series of 200 patients.11 Technological advances have continually expanded the fund of knowledge available for preoperative planning and the depth of postoperative analysis. More information has led to the introduction of novel covariates, while improved computational analyses have allowed for the formulation of novel classification systems. Jiao et al. utilized digital subtraction angiography, functional MRI (fMRI), and diffusion tensor imaging (DTI) to compute patient-specific AVM lesion-to-eloquence distance (LED).12 In 201 cases, each patient’s eloquent cortex and eloquent tracts were identified with fMRI and DTI, respectively. LED was defined as the minimum distance from the AVM to eloquent cortex or tract. Multivariable modeling identified preoperative nonhemorrhagic presentation,

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TABLE 8.4 Influence of Supplementary Grading Scale on Surgical Outcome % of Patients in Study % Worse/Dead Low Spetzler-Martin grade and low supplemental score High Spetzler-Martin grade and low supplemental score Low Spetzler-Martin grade and high supplemental score High Spetzler-Martin grade and high supplemental score

62

15

7

29

28

41

3

50

Data based on Lawton MT, Kim H, McCulloch CE, Mikhak B, Young WL. A supplementary grading scale for selecting patients with brain arteriovenous malformations for surgery. Neurosurgery. 2010;66(4):702-713.

diffuse nidus, deep venous drainage, and shorter LED as predictors of worse outcome. The classification was named as an acronym for these predictive covariates: the HDVL classification. The HDVL scoring ranges from 1 to 6 points, attributing 1 point each for nonhemorrhagic presentation, diffuse nidus, and deep venous drainage. Like size in the Spetzler-Martin grading system, LED can be attributed a maximum of 3 points (1 point for > 10 mm, 2 for 5–10 mm, and 3 for 0–5 mm). In the series of 201 cases analyzed by Jiao et al., rates of favorable outcome for HDVL scores 1, 2, 3, 4, 5, and 6 were 100%, 100%, 88.2%, 68.5%, 43.2%, and 37.5%, respectively (Table 8.2). The authors compared the HDVL to the classic Spetzler-Martin, supplementary Spetzler-Martin, and image-adjusted SpetzlerMartin scores (utilizing fMRI and DTI to determine eloquence). The HDVL outperformed all the classifications with an impressive area under the ROC curve of 0.82. Despite a high accuracy of the HDVL score, its complexity limits it from replacing the Spetzler-Martin classification. Furthermore, not every AVM requires DTI and fMRI; however, the findings of Jiao et al. suggest that AVMs with possible eloquence may be better triaged with these imaging modalities. Acknowledging this, the authors explain that the HDVL should be applied in cases that necessitate further assistance with ­ treatment decisions. For example, a low HDVL score

in a Spetzler-Martin grade III AVM may convince the patient and practitioner to pursue resection. CEREBELLAR AVM CLASSIFICATION Accounting for an estimated 15% of cerebral AVMs, cerebellar AVMs have a potentially elevated hemorrhagic risk, distinct anatomical considerations, and a unique clinical course.13 Earlier classification systems, like the one proposed by Luessenhop and Gennarelli, simply excluded cerebellar AVMs from the schemas.1 While the classic Spetzler-Martin grading system claimed cerebellar AVM inclusion, the rarity of these lesions precluded a subgroup analysis.4 In a series of 60 cerebellar AVMs, Rodríguez-Hernández et al. observed that the predictive accuracy of the Spetzler-Martin classification was low, falling below the threshold required for clinical utility (with an area under the ROC curve of 0.59).14 The Spetzler-Martin focus on deep galenic drainage and eloquence does not translate to the cerebellar region. While galenic drainage is an accurate indicator of supratentorial AVM depth, the only two cerebellar galenic draining veins are superficial to cerebellar structures (superior vermian and precentral cerebellar veins). Anatomically deep cerebellar veins may drain in non-galenic territories, such as the sigmoid and transverse sinuses. This deep vein incongruency results in falsely elevated grades for cerebellar AVMs that actually portend low surgical risk and low Spetzler-Martin grades for highrisk cerebellar lesions. Additionally, the supratentorial cortex has many areas of Spetzler-Martin eloquence, whereas the only eloquent structures in the cerebellum are deep nuclei. As a result, the authors observed a low rate of Spetzler-Martin eloquence in cerebellar AVMs when compared to supratentorial AVMs (30% vs 61%).14 Unlike the Spetzler-Martin classification, the Lawton-Young supplement does not contain characteristics that inherently bias scoring of supratentorial lesions. In their cohort of cerebellar AVMs, Rodríguez-Hernández et al. observed that the standalone Lawton-Young supplement performed well (area under the ROC curve, 0.74), making it the first classification schema to accurately predict outcome of cerebellar AVM resection.14 Similar to the Spetzler-Martin classification, the Lawton-Young supplement was not modeled specifically for cerebellar AVMs. In a multicenter study of 125 cerebellar AVMs, Nisson et al. developed the first

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classification schema specific to cerebellar AVMs.15 The authors observed that emergent surgery, poor preoperative neurological status, deep venous drainage, and age ≥ 60 years were associated with worse neurological outcome following resection. Referencing the odds ratio for each significant covariate, points were assigned: 2 for poor preoperative neurological status and 1 each for emergent surgery, deep venous drainage, and age ≥ 60. The novel schema contained three grades associated with increasing levels of surgical risk: grade 1 for 0–1 point, grade 2 for 2–3 points, and grade 3 for 4–5 points. The final area under the ROC curve for the proposed schema was 0.72. In their study, Nisson et al. also evaluated the predictive value of the Spetzler-Martin, Spetzler-Ponce, and LawtonYoung grading systems as applied to cerebellar AVMs. Contradicting the findings of Rodríguez-Hernández et al., this study showed the Lawton-Young supplement to have low prognostic power for cerebellar AVMs, with an area under the ROC curve of 0.51.14,15 The novel cerebellar classification proposed by Nisson et al. has yet to be externally validated.

Radiosurgical iAVM Classifications Stereotactic radiosurgery has been shown to be an effective alternative to surgery for the treatment of iAVMs, but the Spetzler-Martin surgical classification

fails to translate well to radiosurgery for various reasons.16 While the Spetzler-Martin system accounts for AVM size through diameter, radiosurgery treatment is sensitive to treatment volumes. An AVM with a 1-cm diameter is scored the same as a 3-cm AVM in the Spetzler-Martin grading system; however, the volumes of these lesions are very different (0.6 cm3 and 14 cm3, respectively).17 Additionally, since radiation-related complications primarily occur when treating deep cortical lesions, the Spetzler-Martin functional eloquence fails to translate well to radiosurgery. These inconsistencies served as the impetus for the development of radiosurgery-specific AVM classifications. While surgical treatment immediately removes the AVM, radiosurgical obliteration is often achieved after a period of latency, during which there is a risk of hemorrhage. In cases where complete obliteration is not achieved, hemorrhage risk persists. Before classification schemas, early AVM radiosurgery literature formulated indexes and models to predict the likelihood of either postradiosurgery AVM obliteration or poor outcomes. In 1997, Karlsson et al. observed that higher AVM obliteration rate was correlated with higher radiation dose and lower AVM volume.18 They formulated the K-index, equivalent to the product of AVM volume and minimum AVM dosage (Table 8.5). AVM obliteration rate correlates linearly with the K-index until plateauing at 80%. Similarly,

TABLE 8.5 Continuous Radiosurgical iAVM Classification Systems or Indexes Index or Classification 18

Formula

Further Information

K-index OPI19

(AVM volume) × (minimum dose) % Obliteration = 1 − Ae− B × OPI

SPIE scale20

P

RBAS21

(0.1 × volume) + (0.02 × age) + (0.3 × location)

PSRS AVM score26

(0.26 × AVM volume) + (0.7 × location)



eB 1 e B



A = 1.15 ± 0.14 B = 0.114 ± 0.07 OPI = (minimum dose/AVM diameter) B = (− 7.8713) + (0.7506 × SPIE score) + (0.0734 × V12) SPIE score = location value V12 = volume receiving ≥ 12 Gy Location 1 Point: frontal or temporal 2 Points: parietal, occipital, etc. 3 Points: basal ganglia, brainstem Location 1 Point: basal ganglia, thalamus, brainstem 0 Points: all other regions

OPI, Obliteration prediction index; PSRS, proton beam stereotactic radiosurgery; RBAS, (Pittsburgh) radiosurgery-based AVM scale; SPIE, Symptomatic Post-radiosurgery Injury Expression.

8

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Schwartz et al. developed the obliteration prediction index (OPI).19 After the OPI is calculated, by dividing the minimum AVM dose by AVM diameter, it can be inserted into an equation to extrapolate the likelihood of lesion obliteration (Table 8.5). Finally, the Symptomatic Post-Radiosurgery Injury Expression (SPIE) scale was formulated by Flickinger et al.20 The SPIE scale assigned a risk coefficient, ranging from 0 to 10, to various cerebral anatomical regions, with the frontal lobe receiving a 0 and the pons a 10. Paired with the volume of tissue receiving a dose ≥ 12 Gy, the SPIE scale was utilized to calculate the probability of symptomatic radiation necrosis (Table 8.5). Proposed in 1997 and refined in 2002, the Pittsburgh radiosurgery-based AVM scale (RBAS) was the first comprehensive radiosurgery schema to accurately predict excellent patient outcome, defined as complete obliteration without radiation-related complications. In a series of 220 patients, predictors of excellent outcome included smaller AVM nidus volume, younger age, and frontal/temporal lesion location. Applying multivariable regression to these covariates, the authors formulated and externally validated an AVM score. Location was categorized into three risk categories: least risk (1 point for frontal or temporal), medium risk (2 points for parietal, occipital, intraventricular, corpus callosum, or cerebellar), and highest risk (3 points for basal ganglia or brainstem). Rather than splitting the classification into an integer point-based system, the RBAS is a continuous score. Therefore after calculating the AVM score, the likelihood of excellent patient outcome is extrapolated from a regression line, with scores < 0.75 and > 2.00 having an estimated excellent outcome rate of 100% and

39%, respectively. Later, in 2008, the authors simplified this schema by reducing the location to a dichotomous variable, 0 for hemispheric/corpus callosum/ cerebellar location and 1 for basal ganglia/thalamus/ brainstem location.21 The modification did not detract from predictive accuracy of the model. While the RBAS was designed in a Gamma Knife patient series, its accuracy was later validated in patients treated with linear accelerators (LINAC).22 Since its inception, the RBAS has been the most popular radiosurgery AVM classification scale. Attempting to simplify AVM radiosurgery classification into a categorical system, Milker-Zabel et al. proposed the Heidelberg score.23 Consisting of three grades, the score utilized only patient age and AVM diameter to predict AVM obliteration following LINAC treatment (Table 8.6). With increasing risk profiles, grades 1, 2, and 3 were defined (grade 1, age ≤ 50 years and AVM diameter < 3 cm; grade 2, age > 50 years or AVM diameter ≥ 3 cm; grade 3, age > 50 years and AVM diameter ≥ 3 cm). Each increase in Heidelberg grade decreased the chance of obliteration by a factor of 0.447. Proposed in 2013, the Virginia Radiosurgery AVM Scale (VRAS) sought to combine the mathematical accuracy of the RBAS with the simplicity of the Heidelberg score.24 Analyzing a sizable series of 1012 patients, the authors utilized logistic regression–derived odds ratios to formulate an integer-based classification scale (Table 8.6).24,25 The VRAS score ranged from 0 to 4 points and assigned points based on AVM volume (0 points for volume ≤2cm3; 1 point for volume 2–4cm3; 2 points for volume ≥ 4 cm3), modified RBAS-defined AVM eloquence (1 point), and history of hemorrhage

TABLE 8.6 Categorical Radiosurgical iAVM Classification Systems Classification System

Grade or Score Range

Points/Grades

Categories/Covariates

Heidelberg23

1–3

VRAS24

0–4

Grade 1 Grade 2 Grade 3 1 1 2

Age ≤ 50 y and AVM diameter < 3 cm Age > 50 y or AVM diameter ≥ 3 Age > 50 y and AVM diameter ≥ 3 cm History of hemorrhage RBAS-defined AVM eloquence Volume 0 Points: < 2 cm3 1 Point: 2–4 cm3 2 Points: > 4 cm3

RBAS, (Pittsburgh) radiosurgery-based AVM scale; VRAS, Virginia Radiosurgery AVM Scale.

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(1 point). The rates of favorable outcome for grades 0, 1, 2, 3, and 4 were 83%, 79%, 70%, 48%, and 39%, respectively (Table 8.2). Although the authors observed that the VRAS was more accurate than the RBAS in their series, this does not indicate score superiority, since the VRAS was statistically designed from the same group of test patients and precludes external validity. The most recent radiosurgery-specific AVM classification to be developed is the proton beam stereotactic radiosurgery (PSRS) AVM score.26 The authors sought to design a classification scale that was specific to proton beam therapy. They postulated that the sharp Bragg peak associated with proton radiation, or dose fall-off outside of treatment target, may distinguish it from alternative radiosurgery modalities. Similar to the RBAS, the PSRS classification system is a continuous scale that requires application to a regression line for outcome prediction. Compared to the modified RBAS, the PSRS scale removed the age covariate and adjusted the magnitude of volume and location coefficients (Table 8.5). The location categories for the PSRS score are the same as the modified RBAS. In a comparative analysis of 381 iAVMs treated with Gamma Knife radiosurgery, Pollock et al. tested the accuracy of each of the various radiosurgery classifications for the prediction of a good outcome, defined as AVM obliteration without decline in modified Rankin Scale (mRS) score.27 All of the classification systems demonstrated high accuracy, with an ROC > 0.7; however, the authors observed that continuous grading systems (RBAS, PSRS scale) outperformed the categorical systems (VRAS and the Heidelberg and Spetzler-Martin grading systems). While Pollock et al. argue that continuous classifications are more accurate and only require simple algebra for their utilization, integer-based classifications do provide bedside simplicity.27 Both integer and continuous stereotactic radiosurgery classification schemas provide helpful guidance for the management of AVMs.

Endovascular iAVM Classifications The improved patient outcomes and sustained technological advances of endovascular therapy have made it an important iAVM treatment modality. The introduction of advanced embolic agents, highly navigable catheters, and biplane angiography has increased treatment accuracy and decreased the risks associated with

AVM endovascular embolization. Although higher Spetzler-Martin grade has been associated with worse endovascular outcomes (grades III–V; odds ratio, 10.3, P = .03), the historical emphasis placed upon surgical iAVM classification served as the impetus for a schema specific to endovascular treatment.28,29 Various endovascular classifications have been proposed; however, none have yet to be widely adopted. The first iAVM endovascular grading scheme was proposed by Turjman et al. in 1995.30,31 Based on size and perforator presence, they categorized iAVMs into high-grade or low-grade lesions. High grade was defined as a nidus size > 4 cm with at least 1 perforating arterial feeder. There was little explanation given to the grading of large lesions without perforating vessels. While this classification is rarely utilized, the authors explored multiple covariates that were incorporated into later classifications. In 2001, Willinsky et al. proposed the Toronto grading scale for the n-butyl cyanoacrylate (NBCA) embolization of small (< 3 cm) iAVMs (Table 8.7). Ranging from 0 to 6 points, the Toronto scale assigns points for type and number of arterial feeding vessels, number of draining veins, and nidus fistula diameter. In a dichotomous fashion, AVMs receive 1 point for having perforator or choroidal feeder arteries, 2 points for multiple feeding arteries, and 1 point for multiple draining veins. Nidus diameter is scored as follows: 0 points, pure fistula; 1 point, < 1 cm; 2 points, 1–3 cm. Lower Toronto score was found to correlate with higher percent obliteration.32 Feliciano et al. performed a review of the endovascular literature and proposed a classification scheme constructed from covariates cited by other investigators (Table 8.7).33 Later dubbed the Puerto Rico schema, it is a 5-point classification: 3 points for the number of feeding arteries (1 point for < 3 feeders, 2 points for 3–5, and 3 points for > 5), 1 for eloquence, and 1 for presence of an arteriovenous fistula.33 Analyzing a series of 200 iAVMs treated with NBCA embolization, the Columbia group formulated an AVM Embolization Prognostic Risk Score in 2009 (Table 8.7).34 With a ceiling of 5 points, the system assigns 1 point for deep venous drainage, eloquent location, multiple embolization procedures, or small (< 3 cm) size. Two points are assigned if the AVM is large (> 6 cm), and 0 points are given to medium-sized

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TABLE 8.7 Major Endovascular iAVM Classification Systems Classification System

Dependent Variable

Embolization Material

Point No. of Range Points Description

Toronto scale for small AVMs32

Percentage obliteration

NBCA

0–6

Puerto Rico score33

Complications/unfavorable outcome in meta-analysis

NA

1–5

AVM Embolization Prognostic Risk Score34

Modified Rankin Scale

NBCA

0–5

Buffalo score35

Complication rate

NBCA and Onyx

1–5

AVMES37

Curative treatment

Onyx

3–10

1 1 2 2 1 1 3 1 1 1 2 1 1 3 1 3 3 3

Perforator of choroidal feeding arteries Multiple draining veins Multiple feeding arteries Nidus diameter (categorized) Eloquence AV fistula No. of feeding arteries (categorized) Eloquence Deep venous drainage Multiple procedures Size (categorized) Majority arterial pedicles < 1 mm Eloquence No. of arterial pedicles (categorized) Vascular eloquence Nidus size (categorized) No. of arterial pedicles (categorized) No. of draining veins (categorized)

AV, Arteriovenous; AVMES, arteriovenous malformation embocure score; NBCA, n-butyl cyanoacrylate; NA, not applicable; No., number.

AVMs. Unlike prior surgical classifications, this scoring system showed the most favorable outcomes in medium-sized AVMs. Noticing that small AVMs have an increased postembolization hemorrhage risk, the authors postulated that smaller diameter leads to a heightened intranidal hemodynamic pressure. In their series, AVMs with prognostic risk scores of 0, 1, 2, 3, and 4 were associated with rates of moderate or significant postembolization deficits of 0%, 6%, 6%, 15%, and 50%, respectively (Table 8.2).34 Notably, this prognostic risk score is limited to embolization with NBCA and does not apply to embolization with Onyx (Medtronic, Minneapolis, Minnesota, USA). In 2015, Dumont et al. proposed the Buffalo endovascular AVM treatment score.35 The authors hypothesized that the major risks of iAVM endovascular embolization originate from artery catheterization and possible embolization of critical vascular supply; therefore they created a scoring system that added points for increasing number of arterial pedicles, smaller arterial pedicle diameter, and location eloquence (Table 8.7). One point was assigned if the

majority of arterial pedicles were smaller than 1 mm and if the AVM nidus was in an eloquent location (traditional Spetzler-Martin eloquence). One point was given for the presence of 1 or 2 pedicles, 2 points for 3 or 4, and 3 points for 5 or more. Unlike prior endovascular models, the accuracy of the scoring system was tested after conception, reducing its susceptibility to selection bias. In a 50-patient series, increasing Buffalo score was correlated with higher complication rates, with grades I, II, III, IV, and V associated with complication rates of 0%, 0%, 14%, 50%, and 75%, respectively (Table 8.2).35 The Buffalo score was designed to be utilized for embolization with either NBCA or Onyx. While iAVM resection has excellent cure rates, endovascular cure rates range from 14% to 24%; therefore a classification for treatment cure may be more applicable for endovascular AVM therapy.36 In a series of 39 iAVMs treated with the primary intent of achieving a curative embolization with Onyx, Lopes et al. designed the “arteriovenous malformation embocure score” (AVMES, Table 8.7).37 Unlike the previously

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mentioned iAVM classification systems for endovascular treatment, AVMES identified AVM factors contributing to both endovascular risk and complete angiographic obliteration—the first classification to do so. The AVMES scoring system ranges from 3 to 10 points, assigning points for number of arterial pedicles, number of draining veins, size of AVM nidus, and vascular eloquence. Separate of each other, points are attributed for number of arterial pedicles and draining veins similarly: 1 point for 1–3 vessels; 2 points for 4–6; and 3 points for > 6. For AVM nidus size, 1 point is given for size < 3 cm, 2 for 3–6 cm, and 3 for > 6 cm. One point is attributed for any “vascular eloquence.” A novel component to the AVMES, vascular eloquence was defined as an arterial pedicle less than 20 mm from the internal carotid artery or the first segment of cerebral arteries (A1, M1, P1 segments) or a pedicle too small for microcatheterization.37 Rather than the historical Spetzler-Martin eloquence, the authors proposed that emphasis should be placed on vascular eloquence, citing that the proximal reflux of embolic material into a parent artery or eloquent artery often can lead to significant hemispheric ischemia, whereas the distal migration of embolic material into an eloquent region often only leads to a focal neurologic deficit. In their series, AVMES accurately predicted angiographic obliteration and major complications (ROC 0.82 and 0.75, respectively). Unlike surgical and radiosurgery classifications, there has yet to be a widespread adoption of any iAVM endovascular schema. In a multicenter study of 270 iAVMs, the Spetzler-Martin, Puerto Rico, Buffalo, and AVMES scales were all externally validated and demonstrated good accuracy for endovascular iAVM treatment.38 A possible explanation for the lack of adoption of these classification systems is that there are too many viable schemas, most containing overlapping variables. Additionally, radiosurgical and surgical iAVM treatments have served as mainstay techniques, whereas endovascular approaches and technology have been in flux. The current dynamic nature of endovascular therapy may preclude the possibility of a predominant all-encompassing classification. For example, high AVM obliteration rates achieved with Onyx have increased the clinical application of this liquid embolic agent, decreasing the rate of NBCA embolization.36 Accordingly, NBCA embolization–based classifications

are becoming less clinically relevant. Similar endovascular classification replacement will likely continue as endovascular treatment options continue to evolve.

Conclusion AVM treatment classifications are useful tools that guide patient selection for surgery, radiosurgery, and endovascular therapy. Early surgical AVM classifications are the cornerstone of rapid surgical prognostic assessment and facilitate the communication of AVM severity between physicians. Supplemental schemas and modifications of the Spetzler-Martin classification further improve surgical patient selection. For radiosurgery, continuous and categorical grading systems precisely assess radiation-complication risk and the probability of iAVM obliteration success. During the rapid evolution of endovascular therapy, many classifications have been proposed. Classification systems provide invaluable insight into each modality’s obliteration and complication profile. Novel treatment techniques and improved imaging technology will likely continue to enhance iAVM management and preoperative assessment, introducing new covariates that will further improve the prognostic accuracy of iAVM classification. REFERENCES 1. Luessenhop AJ, Gennarelli TA. Anatomical grading of supratentorial arteriovenous malformations for determining operability. Neurosurgery. 1977;1(1):30–35. https://doi. org/10.1227/00006123-197707000-00007. 2. Luessenhop AJ, Rosa L. Cerebral arteriovenous malformations. Indications for and results of surgery, and the role of intravascular techniques. J Neurosurg. 1984;60(1):14–22. https://doi.org/10.3171/jns.1984.60.1.0014. 3. Shi YQ, Chen XC. A proposed scheme for grading intracranial arteriovenous malformations. J Neurosurg. 1986;65(4):484– 489. https://doi.org/10.3171/jns.1986.65.4.0484. 4. Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg. 1986;65(4):476– 483. https://doi.org/10.3171/jns.1986.65.4.0476. 5. Hamilton MG, Spetzler RF. The prospective application of a grading system for arteriovenous malformations. Neurosurgery. 1994;34(1):2–6; discussion 6-7. 6. Ponce FA, Lozano AM. Highly cited works in neurosurgery. Part I: the 100 top-cited papers in neurosurgical journals. J Neurosurg. 2010;112(2):223–232. https://doi. org/10.3171/2009.12.jns091599. 7. Spetzler RF, Ponce FA. A 3-tier classification of cerebral arteriovenous malformations. J Neurosurg. 2011;114(3):842–849. https://doi.org/10.3171/2010.8.jns10663. 8. Lawton MT. UCSF Brain Arteriovenous Malformation Study Project. Spetzler-Martin Grade III arteriovenous malformations:

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Classification Systems surgical results and a modification of the grading scale. Neurosurgery. 2003;52(4):740–748; discussion 748-749. de Oliveira E, Tedeschi H, Raso J. Comprehensive management of arteriovenous malformations. Neurol Res. 1998;20(8):673–683. https://doi.org/10.1080/01616412.1998.11740583. Lawton MT, Kim H, McCulloch CE, Mikhak B, Young WL. A supplementary grading scale for selecting patients with brain arteriovenous malformations for surgery. Neurosurgery. 2010;66(4):702–713. https://doi.org/10.1227/01. NEU.0000367555.16733.E1. Hafez A, Koroknay-Pál P, Oulasvirta E, et al. The application of the novel grading scale (Lawton-Young Grading System) to predict the outcome of brain arteriovenous malformation. Neurosurgery. 2019;84(2):529–536. https://doi.org/10.1093/ neuros/nyy153. Jiao Y, Lin F, Wu J, et al. A supplementary grading scale combining lesion-to-eloquence distance for predicting surgical outcomes of patients with brain arteriovenous malformations. J Neurosurg. 2018;128(2):530–540. https://doi. org/10.3171/2016.10.Jns161415. Arnaout OM, Gross BA, Eddleman CS, Bendok BR, Getch CC, Batjer HH. Posterior fossa arteriovenous malformations. Neurosurg Focus. 2009;26(5):E12. https://doi. org/10.3171/2009.2.Focus0914. Rodríguez-Hernández A, Kim H, Pourmohamad T, Young WL, Lawton MT. University of California SFAMSP. Cerebellar arteriovenous malformations: anatomic subtypes, surgical results, and increased predictive accuracy of the supplementary grading system. Neurosurgery. 2012;71(6):1111–1124. https:// doi.org/10.1227/NEU.0b013e318271c081. Nisson PL, Fard SA, Walter CM, et al. A novel proposed grading system for cerebellar arteriovenous malformations. J Neurosurg. 2020;132(4):1105–1115. https://doi.org/10.3171/2018.12. jns181677. Meder J, Oppenheim C, Blustajn J. Cerebral arteriovenous malformations: the value of radiologic parameters in predicting response to radiosurgery. AJNR Am J Neuroradiol. 1997;18:1473–1483. Pollock BE, Flickinger JC. A proposed radiosurgery-based grading system for arteriovenous malformations. J Neurosurg. 2002;96(1):79–85. https://doi.org/10.3171/jns.2002.96.1.0079. Karlsson B, Lindquist C, Steiner L. Prediction of obliteration after gamma knife surgery for cerebral arteriovenous malformations. Neurosurgery. 1997;40(3):425–430; discussion 430-431. https://doi.org/10.1097/00006123-199703000-00001. Schwartz M, Sixel K, Young C, et al. Prediction of obliteration of arteriovenous malformations after radiosurgery: the obliteration prediction index. Can J Neurol Sci. 1997;24(2):106– 109. https://doi.org/10.1017/s0317167100021417. Flickinger JC, Kondziolka D, Lunsford LD, et al. Development of a model to predict permanent symptomatic postradiosurgery injury for arteriovenous malformation patients. Arteriovenous Malformation Radiosurgery Study Group. Int J Radiat Oncol Biol Phys. 2000;46(5):1143–1148. https://doi.org/10.1016/ s0360-3016(99)00513-1. Pollock BE, Flickinger JC. Modification of the radiosurgerybased arteriovenous malformation grading system. Neurosurgery. 2008;63(2):239–243; discussion 243. https:// doi.org/10.1227/01.Neu.0000315861.24920.92. Raffa SJ, Chi Y-Y, Bova FJ, Friedman WA. Validation of the radiosurgery-based arteriovenous malformation score in a large linear accelerator radiosurgery experience. J Neurosurg. 2009;111(4):832– 839. https://doi.org/10.3171/2009.4.Jns081532.

87 23. Milker-Zabel S, Kopp-Schneider A, Wiesbauer H, et al. Proposal for a new prognostic score for linac-based radiosurgery in cerebral arteriovenous malformations. Int J Radiat Oncol Biol Phys. 2012;83(2):525–532. https://doi.org/10.1016/j. ijrobp.2011.07.008. 24. Starke RM, Yen CP, Ding D, Sheehan JP. A practical grading scale for predicting outcome after radiosurgery for arteriovenous malformations: analysis of 1012 treated patients. J Neurosurg. 2013;119(4):981–987. https://doi. org/10.3171/2013.5.Jns1311. 25. Morgan MK, Hermann Wiedmann MK, Stoodley MA, Heller GZ. Microsurgery for Spetzler-Ponce Class A and B arteriovenous malformations utilizing an outcome score adopted from Gamma Knife radiosurgery: a prospective cohort study. J Neurosurg. 2017;127(5):1105–1116. https://doi. org/10.3171/2016.8.Jns161275. 26. Hattangadi-Gluth JA, Chapman PH, Kim D, et al. Single-fraction proton beam stereotactic radiosurgery for cerebral arteriovenous malformations. Int J Radiat Oncol Biol Phys. 2014;89(2):338–346. https://doi.org/10.1016/j.ijrobp.2014.02.030. 27. Pollock BE, Storlie CB, Link MJ, Stafford SL, Garces YI, Foote RL. Comparative analysis of arteriovenous malformation grading scales in predicting outcomes after stereotactic radiosurgery. J Neurosurg. 2017;126(3):852–858. https://doi. org/10.3171/2015.11.jns151300. 2017. 28. Ledezma CJ, Hoh BL, Carter BS, Pryor JC, Putman CM, Ogilvy CS. Complications of cerebral arteriovenous malformation embolization: multivariate analysis of predictive factors. Neurosurgery. 2006;58(4):602–611. https://doi. org/10.1227/01.Neu.0000204103.91793.77. 29. Davies JM, Kim H, Young WL, Lawton MT. Classification schemes for arteriovenous malformations. Neurosurg Clin N Am. 2012;23(1):43–53. https://doi.org/10.1016/j. nec.2011.09.002. 30. Turjman F, Massoud TF, Viñuela F, Sayre JW, Guglielmi G, Duckwiler G. Correlation of the angioarchitectural features of cerebral arteriovenous malformations with clinical presentation of hemorrhage. Neurosurgery. 1995;37(5):856–860; discussion 860-862. https://doi. org/10.1227/00006123-199511000-00002. 31. Viñuela F, Duckwiler G, Gugliemi G. Intravascular embolization of brain arteriovenous malformations. In: Maciunas RJ, ed. Endovascular Neurological Intervention. AANS; 1995:189–199. 32. Willinsky R, Goyal M, Terbrugge K, Montanera W, Wallace MC, Tymianski M. Embolisation of small (< 3 cm) brain arteriovenous malformations. Correlation of angiographic results to a proposed angioarchitecture grading system. Interv Neuroradiol. 2001;7(1):19–27. https://doi. org/10.1177/159101990100700102. 33. Feliciano CE, de León-Berra R, Hernández-Gaitán MS, Rodríguez-Mercado R. A proposal for a new arteriovenous malformation grading scale for neuroendovascular procedures and literature review. P R Health Sci J. 2010;29(2):117–120. 34. Starke RM, Komotar RJ, Otten ML, et al. Adjuvant embolization with N-butyl cyanoacrylate in the treatment of cerebral arteriovenous malformations: outcomes, complications, and predictors of neurologic deficits. Stroke. 2009;40(8):2783– 2790. https://doi.org/10.1161/strokeaha.108.539775. 35. Dumont TM, Kan P, Snyder KV, Hopkins LN, Siddiqui AH, Levy EI. A proposed grading system for endovascular treatment of cerebral arteriovenous malformations: Buffalo score. Surg Neurol Int. 2015;6:3. https://doi.org/10.4103/2152-7806.148847.

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36. Elsenousi A, Aletich VA, Alaraj A. Neurological outcomes and cure rates of embolization of brain arteriovenous malformations with n-butyl cyanoacrylate or Onyx: a metaanalysis. J Neurointerv Surg. 2016;8(3):265–272. https://doi. org/10.1136/neurintsurg-2014-011427. 37. Lopes DK, Moftakhar R, Straus D, Munich SA, Chaus F, Kaszuba MC. Arteriovenous malformation embocure score:

AVMES. J Neurointerv Surg. 2016;8(7):685–691. https://doi. org/10.1136/neurintsurg-2015-011779. 38. Jin H, Jiang Y, Ge H, et al. Comparison of grading scales regarding perioperative complications and clinical outcomes of brain arteriovenous malformations after endovascular therapy— multicenter study. World Neurosurg. 2017;106:394–401. https:// doi.org/10.1016/j.wneu.2017.07.020. 2017/10/01/.

Chapter 9

Seizures and AVMs Guilherme Barros, Dominic A. Nistal, Kate T. Carroll, R. Michael Meyer, and Louis J. Kim

Chapter Outline Introduction Mechanisms of AVM-Related Epilepsy Specific Diagnostic Imaging in AVM-Related Epilepsy Treatment of AVM-Related Epilepsy Conclusion

Introduction Focal or generalized seizure is a common initial presenting symptom for patients with an intracranial arteriovenous malformation (iAVM), accounting for roughly 25% of all symptoms precipitating new diagnoses of iAVM in recent literature. There are three recently published case series involving more than 1000 patients with iAVMs that report the rate of seizure prompting presentation. In the largest of these studies, a single-center series of 3299 cases collected over 35 years in Beijing, China, the rate of seizure at presentation was 20.9%.1 In the other two, an international multicenter series of 1289 cases2 and a single-center US series of 1007 cases,3 the rates were 30% and 22.7%, respectively. Overall, recently published series have reported seizure presentation in between 20% and 44% of iAVM patients1–10; however, in all series involving more than 100 patients, the range is narrower— approximately 20%–30%.1–8 Only the smallest included series, one that involved 45 patients treated at a single center, reported the rate of seizure presentation to be as high as 44%.10 The largest published series of iAVM cases reports an average patient age of 31 years at the time

of diagnosis.2 Most case series that analyzed the association of age and epilepsy in iAVM patients have shown a statistically significant trend toward higher rates of seizure presentation with decreasing age relative to the iAVM patient population as a whole.1,4,9 However, there are exceptions to this trend, and it is inconsistent across all series in the recent literature.6 Male sex is reported to be significantly associated with seizure presentation.1,5 This association with male sex is also seen with regard to an increased risk for persistence of a seizure disorder after iAVM treatment.11 While some association between race and risk of iAVM hemorrhage has been reported,12 no associations between racial, ethnic, or national origin and risk of seizure in patients with iAVMs have been reported. Multiple genetic syndromes are associated with iAVMs, probably most famously hereditary hemorrhagic telangiectasia (HHT), also called Osler-WeberRendu syndrome. This syndrome and other genetic disorders associated with iAVMs are rare, and there is not a robust body of literature studying epilepsy in these patients. However, in one series of 10 patients with HHT and iAVMs, 2 patients (20%) presented with seizure, a rate that is very similar to the rates of seizure presentation summarized earlier for the general iAVM patient population.13 In addition to patient demographic characteristics, multiple anatomic characteristics of iAVMs affect the risk of seizure and subsequent epilepsy, summarized in Table 9.1. Increasing size of AVM nidus has consistently been reported to be associated with seizures.3,5,6,9,14 A threshold nidus diameter where this increased seizure risk is realized has been reported at between 3 and 4 cm.6,14 Risk of seizure has consistently been reported to be lower in patients with AVMs centered in the occipital lobe and higher when the lesions are in the frontal, 89

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TABLE 9.1 Factors Affecting the Risk of Epilepsy in Patients With iAVMs Category

Higher Risk

Lower Risk

Demographics

Younger Male Supratentorial Cortical Temporal (++) Frontal (++) Parietal (+) Cortical supply Middle cerebral Posterior cerebral Dilated feeder Superficial Venous varix Outflow stenosis

Older Female Infratentorial Deep Occipital

Location

Arterial supply

Venous drainage

+

Deep supply (e.g., lenticulostriate)

Pearls • Presentation of iAVMs with seizures is more common in adult than in pediatric populations. • AVMs in the frontal, temporal, and parietal lobes more commonly are associated with seizures. • Size (> 3–4 cm), cortical location, long arterial feeders of middle cerebral artery origin, and superficial venous drainage with varicosities and tortuosity are risk factors for seizures. • Surgical removal of iAVMs, with or without adjunctive embolization, is associated with a 30% reduction in seizures. • Stereotactic radiosurgery provides similar seizure control to resection only when the iAVM is completely obliterated.

Deep

More likely; ++ most likely.

temporal, or parietal lobes.1,3,5,8–10,14,15 While there is consistency across these studies in occipital lobe location as protective against epilepsy, there is some variability regarding which lobe appears to carry the highest risk of seizures. However, in all cases where a statistically significant difference between the frontal, temporal, and parietal lobe locations was found, either a frontal or temporal location carried a greater risk than a parietal location. With regard to nidus location, supratentorial and superficial cortical AVMs are consistently associated with epilepsy, as compared to deep location and infratentorial location, which instead carry a higher risk of hemorrhagic presentation.3,6,8,14,15 Certain aspects of the angioarchitecture of a given iAVM have been associated with an increased risk of epilepsy as well. Multiple studies have reported that AVMs supplied by branches of the middle and posterior cerebral arteries carry a higher risk of seizure.6,9,15 Dilation of an arterial feeder measured relative to a nearby normal vessel of the same order and in the same distribution (e.g., an M3 branch ­ supplying an AVM compared to an adjacent M3 branch that does not, as in Fig. 9.1) is also associated

Fig. 9.1 Left internal carotid artery angiogram showing dilated arterial supply. M2 and M3 supplying the AVM are larger than adjacent vessels of the same order.

with increased seizure risk.6,14 Superficial cortical arterial supply in any distribution carries a higher risk of seizure in comparison to arterial supply deep to the AVM nidus (e.g., lenticulostriate or other perforator artery).15 Superficial venous drainage is

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consistently associated with epilepsy,5,8,14 as is venous ectasia or a varix.5,9,15 Venous outflow stenosis and associated parenchymal congestion are also associated with seizures.14,16

Mechanisms of AVM-Related Epilepsy PATHOPHYSIOLOGY OF AVM-RELATED EPILEPSY With improved imaging technologies and better understanding of the hemodynamics of AVMs, a more nuanced understanding of the epileptogenicity of these lesions is emerging, although there is still much to be learned. Initial efforts to characterize epileptogenic AVMs focused on clinical and anatomic characteristics, while more recent explanations have centered around their hemodynamic behavior. The three main causes of AVM-related epilepsy are (1) history of hemorrhage or subclinical hemorrhage resulting in hemosiderin deposits and gliosis, (2) arterial steal resulting in local perinidal hypoxia, and (3) venous congestion. SEIZURE RISK IN PATIENTS WITH A HISTORY OF AVM RUPTURE Multiple studies have found that prior rupture is associated with an increased prevalence of seizures; however, this is not universally agreed upon.3,7,14,15,17,19–20 Notably, two large cohort studies found no significant difference or even a higher rate of seizures in iAVM patients without a history of AVM rupture.18,21 Microscopic and histologic examination of resected AVM specimens has demonstrated hemosiderin deposits. In a study of 27 patients with a history of AVM-related epilepsy and no known history of hemorrhage, hemosiderin deposits were found in 10 cases and focal hemorrhage in four.22 Similarly, another case series found focal hemosiderin deposits in the walls of abnormal blood vessels and surrounding brain parenchyma.23 This histologic finding is thought to represent subclinical hemorrhage or red blood cell extravasation through abnormally leaky capillary walls. In a microscopic analysis of resected AVM specimens, Tu et al. found that perinidal capillaries traversing from the nidus to normal capillaries were dilated and lacked the normal blood-brain barrier ultrastructural features of basement membranes and astrocytic foot processes.24 In specimens from patients with a known

91 clinical history of AVM rupture, there was hemosiderin staining of the normal cerebral cortex surrounding the perinidal capillaries. None of the specimens from patients without a clinical history of hemorrhage had this feature. The authors also described separated endothelium, a paucity of pericytes, and extravasation of red blood cells from perinidal capillaries. Much of the literature relating hemosiderosis to seizures comes from cavernous malformation–induced epilepsy and the impact of resection of the hemosiderin deposits surrounding the cavernoma with respect to seizure freedom. Multiple studies have shown improved seizure rates with resection of the hemosiderin-rich tissue immediately adjacent to cavernous malformations.25–28 The mechanism behind this is thought to be related to peroxidative injury, as studies have shown that seizure activity, measured by intraoperative electrocorticography (ECOG), increases with increasing peroxidase activity in the cortex injected with iron.29 HEMODYNAMIC CHARACTERISTICS There are two main hemodynamic phenomena that may be responsible for seizures in the setting of iAVMs. The first is chronic hypoxemia secondary to arterial steal. Several morphologic characteristics of AVMs related to high-flow systems are seen more frequently in patients presenting with seizures. These include pial recruitment, perinidal angiogenesis, and intranidal aneurysms.14 The low-resistance system of an AVM functions as a sump, redirecting arterial blood flow from normal brain tissue to the AVM. In some cases, this does not exhaust the cerebrovascular reserve and is thought to represent “functional” steal, while in others there is chronic local hypoxia akin to ischemic stroke. Focal neurologic deficits are associated with ischemic arterial steal, while seizures are frequently seen with the functional steal phenomenon.30 Chronic hypoxia is associated with gliosis, which is an additional risk factor for the development of seizures.31 The pathogenetic mechanism likely involves modulation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), since a reduction of stimulus-evoked inhibitory postsynaptic potentials (IPSPs) and paired-pulse inhibition is seen with ­ ongoing hypoxia. Hypoxia and gliosis cause a depolarizing shift in potentials, interfering with neuronal ion transport mechanisms. The affected cortex becomes

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hyperexcitable, as GABAergic inhibitory mechanisms are inhibited to a greater degree than excitatory postsynaptic potentials (EPSPs), with neurons firing uninhibited. IPSPs recover from the effects of hypoxia at a slower rate as well. In addition to arterial variation, AVMs differ in their venous anatomy, and certain venous drainage patterns predispose patients to venous congestion, which is associated with increased seizure risk.14,16 Venous congestion occurs when the venous input overwhelms the venous output. This can occur with excess inflow or restricted outflow.16 The sump effect, as discussed earlier, or fistulas can result in increased venous inflow through AVMs.14 Outflow is limited functionally by the shared drainage system of the surrounding normal brain and by stenosis or thrombosis of the draining veins. The arterialized draining vein does not adequately drain surrounding normal tissue, so the longer and more winding the course, the greater amount of parenchyma is affected, and the more congestion there is.14,16,32,33 Outflow restriction also occurs secondary to progressive thrombosis or stenosis of the draining vein. Chronic venous congestion causes development of tortuous pial veins (called a pseudophlebitic pattern), an angiographic characteristic found to correlate with increased seizure risk.14 This results in perinidal edema, which is also epileptogenic.

lesion, in which an amalgamation of flow voids is typically seen. MRI is the diagnostic modality of choice for cortical localization of AVMs. Two recent large retrospective studies—one by Chen et al.21 and one by Ding et al.3—evaluated the characteristics predictive of seizure in patients with iAVMs. Chen et al. found that 99.5% of iAVMs were in cortical locations, while Ding et al. reported 88.7% in cortical locations, among patients presenting with seizures. Of those patients, less than 10% had a prior rupture or hemorrhage (3.8%,21 9.2%3). Specific MRI characteristics of iAVMs are associated with seizures. Benson et al.36 recently retrospectively reviewed MRI studies from 165 patients with unruptured iAVMs, including 57 patients who presented with seizure. AVM location in the frontal lobe, primary motor cortex, and primary sensory cortex was associated with seizures. Perinidal edema (odds ratio [OR], 4.67; 95% confidence interval [CI], 2.08–10.45; P < .0001), peri-AVM T2 blooming (OR, 4.31; 95% CI, 1.20–15.46; P = .029), venous varix, as seen in Fig. 9.2 (OR, 3.46; 95% CI, 1.77–6.77; P = .0003), long draining vein (OR, 8.32; 95% CI, 3.08–22.46;

Specific Diagnostic Imaging in AVM-Related Epilepsy Diagnostic imaging is essential in understanding the etiology of epilepsy related to AVMs and for determining the most effective treatment to achieve seizure freedom.14–16,17,23,34 AVM cortical location, morphology, and venous drainage remain the highest predictors for seizure presentation, and recent advances in MRI and cerebral angiography provide a variety of techniques for characterizing flow dynamics and anatomical characteristics that impact the development of seizures.21 MRI MRI is highly sensitive for the diagnosis of all iAVMs (89%) and particularly sensitive for the diagnosis of unruptured iAVMs (97%).35 T2-weighted imaging is typically used for the initial characterization of the

Fig. 9.2 Axial gadolinium-enhanced, T1-weighted MR image showing a superficial cortical AVM nidus with venous ectasia/varix.

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P < .0001), and larger size based on Spetzler-Martin grading (OR, 2.49; 95% CI, 1.28–4.82; P = .006) were all MRI characteristics associated with seizure. In addition to cortical localization, MRI can also be used to assess cerebrovascular reactivity, a measure of cerebral blood flow in response to a vasoactive stimulus, and an indicator of cerebrovascular reserve.37 Fierstra et al.16 recruited 20 consecutive patients with untreated brain AVMs (10 presented with seizure) as well as 12 healthy controls to assess the impact of AVM on cerebrovascular reactivity using blood oxygen level–dependent (BOLD) MRI. Comparison of findings in healthy controls to findings in AVM patients showed no global cerebral differences, suggesting that the presence of an AVM does not produce hemodynamic effects sufficient to alter cerebrovascular reactivity throughout the whole brain. However, patients with iAVMs and seizures were found to have markedly impaired perinidal cerebrovascular reactivity as compared to those without seizures (0.11 ± 0.10 vs 0.25 ± 0.07, respectively; P < .001), demonstrating the effect of cerebrovascular reserve on the development of a seizure focus within the brain.16 Perinidal changes in cerebrovascular reactivity are associated with concomitant venous congestion without evidence of arterial steal, suggesting that the development of a seizure focus is directly related to this feature. CEREBRAL ANGIOGRAPHY Cerebral angiography is the gold standard for iAVM diagnosis and treatment planning. A number of features identified during cerebral angiography have been correlated with an increased incidence of seizure and epilepsy in patients with iAVMs. An early study by Turjman et al.15 reviewed the angioarchitectural characteristics of iAVMs in 100 patients, of whom 47 had epilepsy in association with the AVM. Patients with seizures were more likely to have a cortical location on angiography (P = .003), consistent with MRI characteristics, middle cerebral artery (MCA) feeding vessel (P = .00002), absence of an aneurysm (P = .001; ref: aneurysm present), and presence of varix in venous drainage, as in Fig. 9.3 (P = .01). This study introduced the typical angioarchitecture of an AVM presenting with epilepsy—that is, supratentorial, fed by MCA distribution, and typically in a frontal, parietal,

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Fig. 9.3 Right vertebral artery angiogram showing a dilated venous varix with a superficial cortical AVM nidus.

or temporal cortical location. These angiographic ­ features also lend explanation to the pathophysiology of epilepsy associated with AVMs that include decreased blood flow to the adjacent cortex due to significant arteriovenous shunting within the nidus. Shankar et al.14 retrospectively reviewed 78 cases of unruptured AVMs, including 33 in which the patients presented with seizures; the authors specifically studied the angioarchitectural features and proposed a scoring system for predictive purposes. Arterial features identified to have an association with seizure development were a fistulous component (OR, 4.11; 95% CI, 1.45–13.20); arterial dilation (sensitivity 100%, negative predictive value 100%), as in Fig. 9.4; and perinidal angiogenesis (OR, 3.71; 95% CI, 1.47– 12.05). Venous features associated with seizure included a long pial course of draining vein (OR, 14.86; 95% CI, 5.67–66.09), as in Fig. 9.5; pseudophlebitic pattern (OR, 3.08; 95% CI, 1.21–9.25); venous outflow stenosis (OR, 6.50; 95% CI, 2.22–32.49), as in Figs. 9.6 and 9.7; and venous ectasia (OR, 3.00; 95% CI, 1.05–13.75). To create the proposed scoring system, the authors selected the strongest independent predictors—venous outflow restriction, location (frontal, parietal, or temporal), and long pial

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Fig. 9.4 Left internal carotid artery angiogram showing a compact cortical AVM nidus with dilated arterial supply.

Fig. 9.5 Early venous phase of left internal carotid artery angiogram showing the long pial course of a nondilated draining vein.

Fig. 9.6 Anteroposterior view left internal carotid artery angiogram showing a dilated venous varix with venous outflow stenosis anteriorly.

Fig. 9.7 Lateral view left internal carotid artery angiogram showing a dilated venous varix with venous outflow stenosis anteriorly.

draining vein—and assigned a score of 1 to each, for a maximum total score of 3. The diagnostic performance of the scoring system with a score of 3 was highly specific, with an area under the curve (AUC) of 0.841 (95% CI, 0.749–0.933).

Ollivier et al.9 recently conducted a retrospective review of 80 cases involving patients with an iAVM, including 22 who had structural epilepsy in relation to the vascular lesion. Angioarchitectural features that independently predicted epilepsy included large nidus

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size (P = .02), venous dilation (P = .02), high SpetzlerMartin grade (P = .02), and posterior cerebral artery (PCA) as the feed (P < .001). Upon multivariate analysis, controlling for variables that were independently predictive, only PCA feeder remained predictive of epilepsy (OR, 5.15; 95% CI, 1.08–24.46; P = .04). This was the first study to identify the association of PCA feeder as a predictive factor for AVM-related epilepsy. The PCA gives rise to a number of cortical inferior temporal branches providing blood supply to the inferior and medial aspects of the temporal lobe, including anterior, middle, and posterior hippocampal arteries.38 A vascular steal phenomenon may occur with AVMs fed by PCA branches, leading to relative ischemia to mesial temporal structures and the consequent development of structural epilepsy. FUTURE DIRECTIONS With improvement in technology and the expansion of data science methodology, radiomics has become a useful tool for identifying MRI features of AVMs that are associated with the development of seizures. Zhang et al.39 retrospectively reviewed MRI studies acquired in 117 patients with unruptured iAVMs and evaluated anatomic location of the lesions and radiomic features that were associated with epilepsy. Two locational and four radiomic features were selected for a predictive model, which was highly sensitive and specific for predicting epilepsy (sensitivity, 0.786; specificity, 0.769; AUC, 0.866). In this study, the radiomic features suggested that heterogeneous AVMs were more likely to cause epilepsy. Specifically, there was an association between AVM-associated epilepsy and larger variance of run lengths and larger median value and interquartile range of voxel intensities on T2-weighted MRI studies of the lesions. Larger studies and more evidence are needed to better understand the relationship of these radiomic features with AVM angioarchitecture.

Treatment of AVM-Related Epilepsy In patients presenting with AVM-related intracranial hemorrhage or a neurologic deficit, treatment of the AVM—via microsurgery, radiation, and/or endovascular techniques—is typically pursued due to mass effect, progressive neurologic deficit, or rerupture risk,

95 irrespective of the presence of seizures. In patients with epilepsy related to unruptured AVMs, however, medical management with antiepileptic drugs (AEDs) is typically the initial therapy. When seizures cannot be adequately controlled with pharmacologic therapy alone, further AVM-specific interventions with resection, stereotactic radiosurgery (SRS), endovascular embolization (EVE), or a combination thereof are usually warranted to treat epilepsy. Rates of seizure control with respect to AED therapy as the sole treatment and between interventions in patients suffering from AVM-related epilepsy are varied in the literature.18 Understanding the particular differences among therapies for AVM-related epilepsy is essential for the treating neurosurgeon, radiation oncologist, and interventional neuroradiologist in order to provide informed counsel to patients suffering from this disease. MEDICAL MANAGEMENT VS INTERVENTIONAL TREATMENT Seizure freedom, defined as the complete absence of seizures, including auras, may be attainable in a portion of patients with AVM-related epilepsy and unruptured lesions without any interventional treatment of the AVM itself.18 In a prospective population study, Josephson et al. analyzed cases in which patients with AVMs presented with seizures or developed seizures during a 5-year follow-up after presentation; 43 patients had no intracranial hemorrhage or focal neurologic deficit. Without any treatment of the AVM itself, 45% of these patients achieved 2-year seizure freedom. Of the 43 patients, 91% were prescribed one or more AEDs, with only 14% requiring polytherapy with two or more AEDs.7,18 In another population study, albeit with a smaller cohort of 14 AVM patients, a higher rate of seizure control with AED therapy alone was described, with 78% achieving 1-year seizure freedom. Of the seizure-free patients in this particular study, 27% required more than one AED.40 Comparing medical management alone to invasive AVM treatment for unruptured lesions has yielded increasingly controversial results, especially following ARUBA (A Randomised Trial of Unruptured Brain Arteriovenous Malformations) and its 2020 follow-up study.41,42 The initial 2014 trial reported on primary outcomes of symptomatic stroke and death among 223 unruptured iAVM patients divided into a medical

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management cohort and a combined interventional treatment cohort. The rates of initial presentation with seizure were similar in the two cohorts—41% in the medical management cohort vs 44% in the interventional cohort. Seizure-freedom outcomes were also similar, with 63% in the medical management cohort and 56% in the treatment cohort at a 33-month mean follow-up, suggesting that AVM-related epilepsy may persist despite interventional treatment.41 However, well-established critiques of the ARUBA trial design, including the heterogeneity of the treatment arm, a large portion of which received a sole nonsurgical intervention (26%, EVE; 27%, radiotherapy alone), and short-term follow-up, apply to the reported seizure-freedom outcomes as well.43 In the 2020 follow-up ARUBA analysis, seizure-freedom rates showed an overall decrease and differed significantly between the two cohorts at a longer mean follow-up of 50 months, with a rate of 38% in the medical management group and only 18% in the interventional group.42 These follow-up ARUBA results suggest that interventions overall have lower rates of seizure freedom in AVM-related epilepsy when compared to medical management alone at longer follow-up. However, these results should also be interpreted with care despite the longer follow-up, given the lack of standardization in the treatment arm. Conversely, they also suggest that the risk of seizures increases with longer follow-up regardless of medical management or intervention. Additional studies, including a meta-analysis and a separate observational study by Josephson et al., reported no significant difference in achieving 2-year seizure freedom with AVM treatment vs medical management alone.44,45 RESECTION Drug-resistant epilepsy related to AVMs has often historically been an indication for resection of surgically accessible lesions in appropriate patient candidates. The ultimate effect of AVM surgery on seizures has been debated for decades. Concern for new postoperative seizures in AVM patients who did not have presenting seizures is valid. Recent studies suggest an advantage in seizure control after microsurgery over other treatment modalities, specifically for patients who presented with seizures prior to any interventional treatment.18,46–49

Englot et al. reported on 440 patients undergoing resection of supratentorial AVMs, of whom 50% had preoperative EVE.20 Of the total group, 30% (n = 126) had preexisting seizures prior to surgery. Eighteen percent (n = 23) of those patients with preoperative seizures were considered to have drug-resistant epilepsy (DRE). Of the 126 patients with preoperative seizures, 93% had no or at most one single seizure after surgery (60%, 0 seizures; 33%, 1 seizure) at a mean follow-up of 20.7 months. Even among the preoperative-DRE group, 91% achieved a favorable seizure outcome after surgery. In the patients without any history of preoperative seizures, 97% achieved the same (favorable) seizure outcome (89%, 0 seizures; 8%, 1 seizure), albeit with a significantly greater proportion having complete seizure freedom. The overall difference in favorable seizure outcome (93% vs 97%) was not statistically significant, suggesting that the presence of preoperative seizures and duration of those seizures may not be directly associated with postoperative seizure outcome after AVM resection. However, 3% of the patients who had no seizures before surgery did have more than one seizure afterward, indicating a nonzero but low risk of persistent, new-onset seizures after AVM resection. If the criterion is changed from more than one newonset seizure to at least one new-onset seizure after surgery, the rate rises to 11%.9 Other studies report risks of 9%–21% for de novo seizures after AVM resection in previously unaffected patients.46,50,51 Preoperative embolization or radiosurgery, extent of AVM resection, intraoperative rupture, and postoperative hemorrhage/infarct were also not significantly associated with postoperative seizure outcomes in the study by Englot et al.20 However, patients with AVMs harboring deep arterial perforators did have ­ significantly worse postoperative seizure outcomes. Only 84% of the patients with deep arterial perforators had no or one postoperative seizure by follow-up, compared to 97% of patients without such perforators (hazard ratio, 4.35); controlling for the presence of preoperative seizures did not change these rates. The extensive microsurgical dissection required to obliterate deep arterial perforators within the brain parenchyma likely irritates the cortex along the operative corridor, possibly explaining the increased risk for seizures.20

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The utility of electroencephalography (EEG) and ECOG in resecting AVMs with adjacent epileptogenic foci and its impact on long-term seizure outcomes has been reported.52,53 Yeh et al. studied 54 patients with supratentorial, unruptured AVMs and associated epilepsy, all of whom underwent preoperative EEG, intraoperative ECOG, and complete resection of the AVM confirmed by intraoperative angiography.53 Additional cortical resection of epileptogenic foci was completed in nearly half of the patients (25 of 54). Of those 25 patients undergoing additional cortical resection beyond the AVM nidus, 56% had resection of surrounding epileptogenic cortex, 36% underwent resection of mesial temporal cortex, and 8% underwent resection of a remote epileptogenic focus in a second-stage surgery. Of the 17 patients with temporal AVMs, 71% had clear epileptogenic foci in the cortex adjacent to or near the AVM nidus. At a mean follow-up of 4.8 years, 70.4% (38) of the 54 patients had an excellent seizure outcome, defined as complete seizure freedom or occasional auras, while 18.5% (10) had a good outcome, defined as 90% seizure frequency reduction. In the subgroup undergoing additional resection of epileptogenic cortex, 64% (16 of 25) had an excellent seizure outcome and 24% (6 of 25) had a good seizure outcome. With respect to location, patients with frontal and parietal AVMs fared better, with nearly all patients (12 of 15 with frontal location and 10 of 10 with parietal location) having excellent seizure outcomes, than those with temporal AVMs, with only slightly more than half (9 of 17) achieving the same result.53 Seizure freedom did not correlate with AVM size but did align with duration of epilepsy prior to resection. Excellent postoperative seizure outcomes were achieved in 90% of the patients who had a seizure history of 1 year or less prior to surgery, with only 25% of those patients undergoing additional cortical resection. Patients who had a longer duration of seizures prior to surgery (>1 year) were more likely to require additional resection of epileptogenic cortex (75%). This study suggests that intraoperative ECOG and resection of related epileptogenic cortical foci, if needed, is helpful in achieving favorable seizure outcomes, particularly in those patients with prolonged AVM-related epilepsy prior to surgery.53 Cao et al. reported similar findings in 60 patients presenting with seizures, all undergoing intraoperative

97 ECOG during excision of their supratentorial AVMs.52 In this study, 81.6% of patients (49 of 60) with epileptic discharges on ECOG persisting after AVM resection underwent bipolar electrocauterization of the adjacent spike-positive cortex (during the same operation, after the persistent discharges were identified). This intraoperative maneuver completely relieved epileptic discharges in 45 of 49 patients while substantially diminishing discharges in the remaining 4 patients. At a mean follow-up of 4.3 years, seizure outcomes were classified (based on the Engel Seizure Outcome Scale54) as class I (free of disabling seizures) in 71% of cases, class II (rare disabling seizures) in 13%, class III (worthwhile improvement) in 9%, and class IV (no improvement) in 7%.52 STEREOTACTIC RADIOSURGERY Targeted radiotherapy for intracranial lesions, including tumors and AVMs, has been used since the 1980s as a reasonable and safe alternative to resection or EVE when indicated, with reported decreases in mortality and complication rates. As SRS techniques have been refined, its use has become more widespread in treating iAVMs, both for prevention of intracranial hemorrhage and for seizure control.18,46,55,56 A recent meta-analysis by Ironside et al. included 27 studies with a total of 4826 patients who underwent radiosurgery for the treatment of an iAVM, including 1312 who had at least one seizure prior to SRS.57 In one of the 27 studies, both Gamma Knife and linear accelerator units were used. Patients were treated exclusively with Gamma Knife radiosurgery in 18 of the remaining 26 studies, linear accelerator radiation in 6 studies, and proton beam therapy in 2 studies. At a mean follow-up of 48 months, seizure control (seizure freedom or reduction) had been achieved in 73.1% of patients, although complete seizure freedom was achieved in only 55.7% of patients. Of the patients with no history of epilepsy prior to SRS, de novo seizures occurred in 5.2% following the intervention, a rate that is lower than in most surgical series.9,10,11,14 Another SRS series reported an even lower de novo seizure rate of 1.7%.58 Statistically significant predictors of seizure freedom were AVM obliteration (OR, 4.61; P < .001), shorter seizure duration (OR, 6.80; P < .001), generalized seizure type (OR, 2.27; P = .007),

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and previous AVM hemorrhage (OR, 5.10; P < .001). Seizure freedom was achieved in 75.1% of the patients who had complete obliteration of their AVM but only 42.5% of those with partial AVM obliteration, highlighting the importance of complete obliteration both in SRS and in surgery.57 In an earlier meta-analysis, Baranoski et al. compared seizure outcomes after SRS to those achieved with resection and EVE; the authors analyzed data from 24 studies including a total of 1157 patients with a history of seizures prior to intervention.46 Of the patients treated with microsurgery, 73% were seizure free at a mean follow-up of 4.5 years compared with 62.9% of those treated with SRS at a mean follow-up of 3.6 years. Seizure reduction, defined as 0–2 seizures after treatment, was achieved in 88.5% of the microsurgical cohort and 76.2% of the SRS cohort. Within the microsurgical cohort, seizure control outcomes did not differ based on ruptured or unruptured AVM status. However, among the SRS cohort, the subgroup with unruptured AVMs had 75.7% seizure control compared to only 46.7% in those with ruptured AVMs. Extent of AVM obliteration within the SRS cohort was also analyzed, and only 58.4% of SRS patients achieved complete obliteration. The analysis demonstrated 83.3% seizure freedom in patients with complete AVM obliteration and only 43% seizure freedom in patients with partial obliteration. This result again stresses the value of complete obliteration of the AVM in both SRS and surgery. Particularly noteworthy is the higher rate of seizure freedom in the complete obliteration subgroup of the SRS cohort compared with the microsurgical cohort, considering that complete obliteration is usually achieved at the time of resection in patients whose AVMs are surgically treated and only after a period of latency in those treated with SRS. Neuromodulatory mechanisms specific to radiosurgery—including the formation of a protective perinidal gliotic capsule, progressive vaso-occlusion of draining veins, and gradual reduction of vascular steal—may contribute to long-term seizure control, potentially explaining the reports of higher seizure control when complete AVM obliteration is achieved and lower de novo seizure development in patients treated with SRS as compared to microsurgery.18,46,57

ENDOVASCULAR EMBOLIZATION EVE of AVMs is primarily used as an adjunctive therapy prior to resection or in combination with SRS, as opposed to a stand-alone AVM treatment.18,46,59,60 In the previously discussed meta-analysis by Baranoski et al., 72 patients with pretreatment seizures were treated with EVE alone, and at a mean follow-up of 3.8 years, only 50% had achieved seizure freedom, with a total of 64% having achieved seizure reduction (this includes the seizure-freedom group). This is a markedly inferior seizure outcome when compared to microsurgery or SRS, especially when one considers that there was also a higher rate of de novo seizures in previously unaffected patients of 33%.46 Zhang et al. reported on 68 patients who had seizures before AVM treatment; 19 were treated via EVE alone using Onyx-18 embolic agent, and 18 received combined EVE and Gamma Knife SRS.61 Seizure freedom was achieved in only 51.4% of patients at a mean follow-up of 31.2 months. Patients who had complete embolization had a higher rate of seizure freedom (57.9%) than those who had partial embolization (44.4%). This finding relates to other studies on resection and SRS, suggesting that the extent of lesion obliteration may correlate with more favorable seizure outcomes.46,61 Partial embolization may lead to transient hypoxia within the region surrounding the AVM nidus, possibly promoting neoangiogenesis and persistence or recurrence of seizures. Perinidal ischemia, gliotic plaques, and epileptogenic foci distant to the nidus are also likely mechanisms of persistent seizures after Onyx embolization of AVMs. Lv et al. reported on 30 patients with AVM-related epilepsy who underwent Onyx embolization, achieving excellent seizure outcome in 21 patients (70%). Of patients with excellent seizure outcomes, 18 required only one endovascular treatment.62 These outcomes were more favorable than those of other studies, typically reporting only 51%–55% seizure-freedom rates for EVE.61,63 De Los Reyes et al. further confirmed the high rates of de novo seizures after EVE at 20%.63 EVE of AVMs alone is unlikely to achieve consistently positive seizure outcomes when compared to microsurgical resection or SRS and should be considered an adjunctive treatment in AVM-related epilepsy.17,46

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PEDIATRIC SEIZURE OUTCOMES Pediatric iAVM patients are only around half as likely to present with seizures when compared to adults (34% adult vs 19% pediatric, P = 0.009), as reported by Oulasvirta et al. based on a study of 805 patients, 16% of whom were under 18 years old.64 This proportion of pediatric patients within the total iAVM patient population is in line with other studies, reporting from 12% to 18%.65–67 Ma et al. described radiographic, clinical, and seizure control outcomes in 193 pediatric patients (of whom 63 [31.8%] presented with seizures) at a mean of 3.6 years’ follow-up after different AVM treatments.65 Among the surgical group presenting with seizures, 85.7% had a “good seizure outcome,” defined as Engel outcome class I (free of disabling seizures). In contrast, the SRS group and EVE group had good seizure outcomes in only 57.1% and 41.7%, respectively. In a subanalysis including only patients with complete AVM obliteration at follow-up, good seizure outcome was achieved in 91.9% (surgery), 100% (SRS), and 60% (EVE). De novo seizures (i.e., seizures occurring after treatment in patients with no history of seizure prior to treatment) occurred in 3.8% (surgery), 8.3% (SRS), and 6.7% (EVE). These rates of seizure control outcomes stratified by treatment modality in pediatric AVM patients are comparable to outcome trends seen in adults, as described in detail in the previous sections of this chapter. These results also highlight complete AVM obliteration as a consistently significant predictor of favorable seizure outcome, particularly in SRS, as seen in adults as well.

Conclusion AVM-related epilepsy is most common in patients with lesions in frontal, temporal, and parietal cortical locations; dilated feeders from middle cerebral and posterior cerebral arteries; venous varices; and venous outflow stenosis. The likelihood of seizure freedom with medical management alone is considered poor and not sustained when compared to procedural treatments, including resection, EVE, or radiosurgery. There are no studies specifically examining the use of AEDs for pretreatment prophylaxis in iAVM patients. Therefore the use of AEDs should be considered an adjunct to subsequent treatments, and their pre-

procedural use for seizure prophylaxis should be in accordance with the protocol of the treating institution and at the surgeon’s discretion. Surgical removal with immediate obliteration of the AVM provides the most durable and highest likelihood of reducing or eliminating seizures completely among the treatment modalities. However, complete obliteration with SRS provides similar seizure control rates to resection, albeit in a delayed fashion. EVE alone has the poorest rates of seizure control among the treatment modalities and should be considered an adjunct to resection and SRS. REFERENCES 1. Tong X, Wu J, Lin F, et al. The effect of age, sex, and lesion location on initial presentation in patients with brain arteriovenous malformations. World Neurosurg. 2016;87:598– 606. https://doi.org/10.1016/j.wneu.2015.10.060. 2. Hofmeister C, Stapf C, Hartmann A, et al. Demographic, morphological, and clinical characteristics of 1289 patients with brain arteriovenous malformation. Stroke. 2000;31(6):1307– 1310. https://doi.org/10.1161/01.str.31.6.1307. 3. Ding D, Starke RM, Quigg M, et al. Cerebral arteriovenous malformations and epilepsy, Part 1: predictors of seizure presentation. World Neurosurg. 2015;84(3):645–652. https:// doi.org/10.1016/j.wneu.2015.02.039. 4. Stapf C, Khaw AV, Sciacca RR, et al. Effect of age on clinical and morphological characteristics in patients with brain arteriovenous malformation. Stroke. 2003;34(11):2664–2669. https://doi.org/10.1161/01.STR.0000094824.03372.9B. 5. Garcin B, Houdart E, Porcher R, et al. Epileptic seizures at initial presentation in patients with brain arteriovenous malformation. Neurology. 2012;78(9):626–631. https://doi. org/10.1212/WNL.0b013e3182494d40. 6. Sturiale CL, Rigante L, Puca A, et al. Angioarchitectural features of brain arteriovenous malformations associated with seizures: a single center retrospective series. Eur J Neurol. 2013;20(5):849–855. https://doi.org/10.1111/ene.12085. 7. Josephson CB, Leach JP, Duncan R, et al. Seizure risk from cavernous or arteriovenous malformations: prospective population-based study. Neurology. 2011;76(18):1548–1554. https://doi.org/10.1212/WNL.0b013e3182190f37. 8. Galletti F, Costa C, Cupini LM, et al. Brain arteriovenous malformations and seizures: an Italian study. J Neurol Neurosurg Psychiatry. 2014;85(3):284–288. https://doi.org/10.1136/ jnnp-2013-305123. 9. Ollivier I, Cebula H, Todeschi J, et al. Predictive factors of epilepsy in arteriovenous malformation. Neurochirurgie. 2020;66(3):144–149. https://doi.org/10.1016/j.neuchi.2019. 12.009. 10. Sun Y, Tian RF, Li AM, Liu XG, Chen J, Shi H. Unruptured epileptogenic brain arteriovenous malformations. Turk Neurosurg. 2016;26(3):341–346. https://doi.org/10.5137/10195149.JTN.9190-13.1. 11. Yang W, Westbroek EM, Anderson-Keightly H, et al. Male gender associated with post-treatment seizure risk of pediatric arteriovenous malformation patients. Neurosurgery. 2017;80(6):899–907. https://doi.org/10.1093/neuros/nyx018.

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12. Yang W, Caplan JM, Ye X, et al. Racial associations with hemorrhagic presentation in cerebral arteriovenous malformations. World Neurosurg. 2015;84(2):461–469. https:// doi.org/10.1016/j.wneu.2015.03.050. 13. Maher CO, Piepgras DG, Brown RD Jr, Friedman JA, Pollock BE. Cerebrovascular manifestations in 321 cases of hereditary hemorrhagic telangiectasia. Stroke. 2001;32(4):877–882. https://doi.org/10.1161/01.str.32.4.877. 14. Shankar JJ, Menezes RJ, Pohlmann-Eden B, Wallace C, terBrugge K, Krings T. Angioarchitecture of brain AVM determines the presentation with seizures: proposed scoring system. AJNR Am J Neuroradiol. 2013;34(5):1028–1034. https://doi.org/10.3174/ajnr.A3361. 15. Turjman F, Massoud TF, Sayre JW, Viñuela F, Guglielmi G, Duckwiler G. Epilepsy associated with cerebral arteriovenous malformations: a multivariate analysis of angioarchitectural characteristics. AJNR Am J Neuroradiol. 1995;16(2):345–350. 16. Fierstra J, Conklin J, Krings T, et al. Impaired peri-nidal cerebrovascular reserve in seizure patients with brain arteriovenous malformations. Brain. 2011;134(pt 1):100–109. https://doi.org/10.1093/brain/awq286. 17. Soldozy S, Norat P, Yağmurlu K, et al. Arteriovenous malformation presenting with epilepsy: a multimodal approach to diagnosis and treatment. Neurosurg Focus. 2020;48(4):1–7. https://doi.org/10.3171/2020.1.FOCUS19899. 18. Hoh BL, Chapman PH, Loeffler JS, Carter BS, Ogilvy CS. Results of multimodality treatment for 141 patients with brain arteriovenous malformations and seizures: factors associated with seizure incidence and seizure outcomes. Neurosurgery. 2002;51(2):303– 311. https://doi.org/10.1227/00006123-200208000-00004. 19. Santos MLT dos, Demartini Júnior Z, Matos LAD, et al. Angioarchitecture and clinical presentation of brain arteriovenous malformations. Arq Neuropsiquiatr. 2009;67(2a):316–321. https:// doi.org/10.1590/S0004-282X2009000200031. 20. Englot DJ, Young WL, Han SJ, McCulloch CE, Chang EF, Lawton MT. Seizure predictors and control after microsurgical resection of supratentorial arteriovenous malformations in 440 patients. Neurosurgery. 2012;71(3):572–580. https://doi. org/10.1227/NEU.0b013e31825ea3ba. 21. Chen CJ, Shabo LM, Ding D, et al. Seizure presentation in patients with brain arteriovenous malformations treated with stereotactic radiosurgery: a multicenter study. World Neurosurg. 2019;126:e634– e640. https://doi.org/10.1016/J.WNEU.2019.02.104. 22. Yeh H-S, Kashiwagi S, Tew JM, Berger TS. Surgical management of epilepsy associated with cerebral arteriovenous malformations. J Neurosurg. 1990;72(2):216–223. https://doi. org/10.3171/jns.1990.72.2.0216. 23. Leblanc R, Feindel W, Ethier R. Epilepsy from cerebral arteriovenous malformations. Can J Neurol Sci. 1983;10(2):91– 95. https://doi.org/10.1017/S031716710004470X. 24. Tu J, Stoodley MA, Morgan MK, Storer KP. Ultrastructure of perinidal capillaries in cerebral arteriovenous malformations. Neurosurgery. 2006;58(5):961–969. https://doi.org/10.1227/01. NEU.0000210248.39504.B5. 25. Williamson A, Patrylo PR, Lee S, Spencer DD. Physiology of human cortical neurons adjacent to cavernous malformations and tumors. Epilepsia. 2003;44(11):1413–1419. https://doi. org/10.1046/j.1528-1157.2003.23603.x. 26. Baumann CR, Schuknecht B, Lo Russo G, et al. Seizure outcome after resection of cavernous malformations is better when surrounding hemosiderin-stained brain also is removed. Epilepsia. 2006;47(3):563–566. https://doi. org/10.1111/j.1528-1167.2006.00468.x.

27. Wang X, Tao Z, You C, Li Q, Liu Y. Extended resection of hemosiderin fringe is better for seizure outcome: a study in patients with cavernous malformation associated with refractory epilepsy. Neurol India. 2013;61(3):288–292. https:// doi.org/10.4103/0028-3886.115070. 28. Ruan D, Yu X-B, Shrestha S, Wang L, Chen G. The role of hemosiderin excision in seizure outcome in cerebral cavernous malformation surgery: a systematic review and meta-analysis. PLoS One. 2015;10(8):e0136619. https://doi.org/10.1371/journal. pone.0136619. 29. Singh R, Pathak DN. Lipid peroxidation and glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase, and glucose-6-phosphate dehydrogenase activities in fecl3-induced epileptogenic foci in the rat brain. Epilepsia. 1990;31(1):15–26. https://doi.org/10.1111/j.1528-1157.1990. tb05354.x. 30. Kim DJ, Krings T. Whole-brain perfusion CT patterns of brain arteriovenous malformations: a pilot study in 18 patients. Am J Neuroradiol. 2011;32(11):2061–2066. https://doi.org/10.3174/ ajnr.A2659. 31. Luhmann HJ, Kral I, Heinemann U. Influence of hypoxia on excitation and GABAergic inhibition in mature and developing rat neocortex. Exp Brain Res. 1993;97(2):209–224. https://doi. org/10.1007/bf00228690. 32. Hacein-Bey L, Nour R, Pile-Spellman J, Van Heertum R, Esser PD, Young WL. Adaptive changes of autoregulation in chronic cerebral hypotension with arteriovenous malformations: an acetazolamide-enhanced single-photon emission CT study. AJNR Am J Neuroradiol. 1995;16(9):1865–1874. 33. Lawton MT, Rutledge WC, Kim H, et al. Brain arteriovenous malformations. Nat Rev Dis Prim. 2015;1:15008. https://doi. org/10.1038/nrdp.2015.8. 34. Fennell VS, Martirosyan NL, Atwal GS, et al. Hemodynamics associated with intracerebral arteriovenous malformations: the effects of treatment modalities. Neurosurgery. 2018;83(4): 611–621. https://doi.org/10.1093/neuros/nyx560. 35. Gross BA, Frerichs KU, Du R. Sensitivity of CT angiography, T2-weighted MRI, and magnetic resonance angiography in detecting cerebral arteriovenous malformations and associated aneurysms. J Clin Neurosci. 2012;19(8):1093–1095. https:// doi.org/10.1016/j.jocn.2011.11.021. 36. Benson JC, Chiu S, Flemming K, Nasr DM, Lanzino G, Brinjikji W. MR characteristics of unruptured intracranial arteriovenous malformations associated with seizure as initial clinical presentation. J Neurointervent Surg. 2020;12(2):186–191. https://doi.org/10.1136/neurintsurg-2019-015021. 37. Liu P, De Vis JB, Lu H. Cerebrovascular reactivity (CVR) MRI with CO2 challenge: a technical review. NeuroImage. 2019;187:104– 115. https://doi.org/10.1016/j.neuroimage.2018.03.047. 38. Haegelen C, Berton E, Darnault P, Morandi X. A revised classification of the temporal branches of the posterior cerebral artery. Surg Radiol Anat. 2012;34(5):385–391. https://doi. org/10.1007/s00276-011-0921-8. 39. Zhang Y, Yan P, Liang F, Ma C, Liang S, Jiang C. Predictors of epilepsy presentation in unruptured brain arteriovenous malformations: a quantitative evaluation of location and radiomics features on T2-weighted imaging. World Neurosurg. 2019;125:e1008–e1015. https://doi.org/10.1016/j. wneu.2019.01.229. 40. Stephen LJ, Kwan P, Brodie MJ. Does the cause of localisationrelated epilepsy influence the response to antiepileptic drug treatment? Epilepsia. 2001;42(3):357–362. https://doi. org/10.1046/j.1528-1157.2001.29000.x.

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41. Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, nonblinded, randomised trial. Lancet. 2014;383(9917):614–621. https://doi.org/10.1016/S0140-6736(13)62302-8. 42. Mohr JP, Overbey JR, Hartmann A, et al. Medical management with interventional therapy versus medical management alone for unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre, non-blinded, randomised controlled trial. Lancet Neurol. 2020;19(7):573–581. https:// doi.org/10.1016/S1474-4422(20)30181-2. 43. Magro E, Gentric JC, Darsaut TE, et al. Responses to ARUBA: a systematic review and critical analysis for the design of future arteriovenous malformation trials. J Neurosurg. 2017;126(2):486– 494. https://doi.org/10.3171/2015.6.JNS15619. 44. Josephson CB, Bhattacharya JJ, Counsell CE, et al. Seizure risk with AVM treatment or conservative management: prospective, population-based study. Neurology. 2012;79(6):500–507. https://doi.org/10.1212/WNL.0b013e3182635696. 45. Josephson CB, Sauro K, Wiebe S, Clement F, Jette N. Medical vs. invasive therapy in AVM-related epilepsy: systematic review and meta-analysis. Neurology. 2016;86(1):64–71. https://doi. org/10.1212/WNL.0000000000002240. 46. Baranoski JF, Grant RA, Hirsch LJ, et al. Seizure control for intracranial arteriovenous malformations is directly related to treatment modality: a meta-analysis. J Neurointerv Surg. 2014;6(9):684–690. https://doi.org/10.1136/neurintsurg-2013010945. 47. von der Brelie C, Simon M, Esche J, Schramm J, Boström A. Seizure outcomes in patients with surgically treated cerebral arteriovenous malformations. Neurosurgery. 2015;77(5):762–768. https://doi.org/10.1227/NEU.0000000000000919. 48. Hyun SJ, Kong DS, Lee JI, Kim JS, Hong SC. Cerebral arteriovenous malformations and seizures: differential impact on the time to seizure-free state according to the treatment modalities. Acta Neurochir (Wien). 2012;154(6):1003–1010. https://doi.org/10.1007/s00701-012-1339-8. 49. Wang JY, Yang W, Ye X, et al. Impact on seizure control of surgical resection or radiosurgery for cerebral arteriovenous malformations. Neurosurgery. 2013;73(4):648–656. https:// doi.org/10.1227/NEU.0000000000000071. 50. Heros RC, Korosue K, Diebold PM. Surgical excision of cerebral arteriovenous malformations: late results. Neurosurgery. 1990;26(4):570–578. https://doi.org/10.1097/00006123199004000-00003. 51. Thorpe ML, Cordato DJ, Morgan MK, Herkes GK. Postoperative seizure outcome in a series of 114 patients with supratentorial arteriovenous malformations. J Clin Neurosci. 2000;7(2):107–111. https://doi.org/10.1054/jocn.1999.0159. 52. Cao Y, Wang R, Yang L, Bai Q, Wang S, Zhao J. Bipolar electrocoagulation on cortex after AVMs lesionectomy for seizure control. Can J Neurol Sci. 2011;38(1):48–53. 53. Yeh HS, Tew JM Jr, Gartner M. Seizure control after surgery on cerebral arteriovenous malformations. J Neurosurg. 1993;78(1):12–18. https://doi.org/10.3171/jns.1993.78. 1.0012. 54. Engel J. Update on surgical treatment of the epilepsies. Summary of the Second International Palm Desert Conference

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on the Surgical Treatment of the Epilepsies (1992). Neurology. 1993;43(8):1612–1617. https://doi.org/10.1212/ wnl.43.8.1612. Przybylowski CJ, Ding D, Starke RM, et al. Seizure and anticonvulsant outcomes following stereotactic radiosurgery for intracranial arteriovenous malformations. J Neurosurg. 2015;122(6):1299–1305. https://doi.org/10.3171/2014.11. JNS141388. Niranjan A, Kashkoush A, Kano H, Monaco EA, Flickinger JC, Lunsford LD. Seizure control after radiosurgery for cerebral arteriovenous malformations: a 25-year experience. J Neurosurg. 2018;131(6):1763–1772. https://doi.org/10.3171/2018.7. JNS18304. Ironside N, Chen CJ, Ding D, et al. Seizure outcomes after radiosurgery for cerebral arteriovenous malformations: an updated systematic review and meta-analysis. World Neurosurg. 2018;120:550–562.e3. https://doi.org/10.1016/j. wneu.2018.08.121. Ding D, Quigg M, Starke RM, et al. Cerebral arteriovenous malformations and epilepsy, part 2: predictors of seizure outcomes following radiosurgery. World Neurosurg. 2015;84(3):653–662. https://doi.org/10.1016/j.wneu.2015.04.064. Hung YC, Mohammed N, Eluvathingal Muttikkal TJ, et al. The impact of preradiosurgery embolization on intracranial arteriovenous malformations: a matched cohort analysis based on de novo lesion volume. J Neurosurg. 2020;133(4):1156– 1167. https://doi.org/10.3171/2019.5.JNS19722. Wang A, Mandigo GK, Feldstein NA, et al. Curative treatment for low-grade arteriovenous malformations. J Neurointerv Surg. 2020;12(1):48–54. https://doi.org/10.1136/ neurintsurg-2019-015115. Zhang B, Feng X, Peng F, et al. Seizure predictors and outcome after Onyx embolization in patients with brain arteriovenous malformations. Interv Neuroradiol. 2019;25(2):124–131. https://doi.org/10.1177/1591019918801290. Lv X, Li Y, Jiiang C, Yang X, Wu Z. Brain arteriovenous malformations and endovascular treatment: effect on seizures. Interv Neuroradiol. 2010;16(1):39–45. https://doi. org/10.1177/159101991001600105. de Los Reyes K, Patel A, Doshi A, et al. Seizures after Onyx embolization for the treatment of cerebral arteriovenous malformation. Interv Neuroradiol. 2011;17(3):331–338. https://doi.org/10.1177/159101991101700308. Oulasvirta E, Koroknay-Pál P, Hafez A, Elseoud AA, Lehto H, Laakso A. Characteristics and long-term outcome of 127 children with cerebral arteriovenous malformations. Neurosurgery. 2019;84(1):151–159. https://doi.org/10.1093/neuros/nyy008. Ma X, Tong X, Wu J, Cao Y, Wang S. Seizure control following treatment of brain arteriovenous malformations in pediatric patients. Childs Nerv Syst. 2016;32(12):2387–2394. https:// doi.org/10.1007/s00381-016-3216-x. Celli P, Ferrante L, Palma L, Cavedon G. Cerebral arteriovenous malformations in children. Clinical features and outcome of treatment in children and in adults. Surg Neurol. 1984;22(1):43–49. https://doi.org/10.1016/0090-3019(84)90227-1. D’Aliberti G, Talamonti G, Versari PP, et al. Comparison of pediatric and adult cerebral arteriovenous malformations. J Neurosurg Sci. 1997;41(4):331–336.

Chapter 10

Decision Analysis for Asymptomatic Lesions Eleonora F. Spinazzi and E. Sander Connolly Jr.

Chapter Outline Introduction Pathogenesis and Pathophysiology of iAVMs Natural History Risk Stratification and Grading Scales Clinical Decision-Making After ARUBA Treatment Modalities Future Directions Conclusion

Introduction Intracranial arteriovenous malformations (iAVMs) are uncommon vascular lesions that most frequently are diagnosed following intracerebral hemorrhage or seizures.1,2 Even in the absence of hemorrhage, headache and focal neurological deficits may develop secondary to vascular steal or mass effect.1,3 Widespread use of neuroimaging and improvements in imaging techniques have resulted in a proportional increase in incidentally diagnosed iAVMs.4,5 Treatment centers on four main modalities: conservative or medical management, radiosurgery, endovascular embolization, and microsurgery. Treatment is often tailored to institutional practices, surgeon experience, and iAVM-specific features. In this chapter, we provide a summary and update of the current understanding of iAVM features and risk profiles along with the treatment options to help guide decisionmaking to appropriately balance the immediate risks of intervention against the lifetime risk of stroke in patients with asymptomatic AVMs.

Pathogenesis and Pathophysiology of iAVMs Intracranial AVMs are complex congenital vascular lesions that arise from an abnormal development of the capillary network, resulting in direct connection between arterial feeders and venous drainage. The lack of resistance from a capillary bed leads to a high-flow system with attendant vascular dilation. This web of high-flow vasculature is known as the AVM nidus. The most feared complication of iAVMs remains rupture and hemorrhage. Even prior to rupture, iAVMs cause vascular reorganization of the surrounding brain parenchyma. Multiple AVM features have been associated with an increased risk of hemorrhage. These include aneurysms located within the iAVM nidus, venous drainage directly into the deep cerebral veins, venous varices, infratentorial location, and previous hemorrhages.6–8 The chronic nature of iAVMs leads to adaptation of the surrounding normal brain tissue to a state of chronic hypoperfusion. This adaptation makes excision of the AVM difficult, as abrupt removal of a high-flow circuit with subsequent shunting toward the normal hypoperfused brain parenchyma can lead to “normal perfusion pressure breakthrough,” first described by Spetzler et al. in 1978.9 The etiology of iAVMs remains controversial. Multiple hereditary conditions are associated with the development of these lesions. Up to 25% of patients with hereditary hemorrhagic telangiectasia (HHT) develop iAVMs.10 HHT is thought to promote iAVM development via deficiency of transforming growth factor-beta as well as mutations within the RASA1 and EPHB4 genes associated with the RAS/ ERK pathway.11–14 Importantly, mutations within the 105

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RASA1 gene have also been associated with familial iAVM development. These findings show that there is a clear genetic susceptibility for iAVM formation.15,16 No study has yet proven that iAVMs are present from birth, however, highlighting that genetic susceptibility may require a second hit for iAVM development.17 These insults may contribute to somatic mutations that can generate iAVMs. Sequencing of endothelial cells from human iAVMs showed KRAS or bRAF mutations in 10 of 16 specimens,18 and animal studies have shown that activating KRAS mutations within endothelial cells is sufficient for inducing AVMs in mice and embryonic zebrafish.19 In fact, iAVMs are characterized by increased inflammatory monocytes and microglia,20 with even unruptured AVMs showing histopathologic evidence of perivascular inflammation.21 Thus the most accepted theory on the development of iAVMs is based on a combination of genetic susceptibility and environmental insult (through stroke, trauma, radiation, seizures, etc.).22

Natural History Understanding the natural history of iAVMs is critical in deciding whether surgical intervention is warranted for asymptomatic lesions. Retrospective studies have shown that the incidence of AVM hemorrhage ranges between 0.55 and 0.86 cases per 100,000 person-years.23–25 The Olmsted study also highlighted that most patients will be symptomatic at presentation (60.4%) and that mortality following iAVM hemorrhage is high (17.6%).25 The New York Islands Study built off these retrospective studies with a prospective study examining iAVM incidence and rates of hemorrhage.26 The authors reported an annual iAVM detection rate of 1.34 per 100,000 person-years with a rate of hemorrhage of 0.51 per 100,000 person-years. The annual rate of hemorrhage was an average of 3% but was severely dependent on iAVM factors such as deep venous drainage, deep location, incidence of previous hemorrhage, and location within the brainstem; the annual hemorrhage rate for these high-risk iAVMs could be as high as 33%.27,28 Since these landmark studies, multiple follow-up analyses have demonstrated annual rates of initial iAVM hemorrhage between 1.3% and 2.2%, with the

Pearls • Asymptomatic iAVMs carry an ~ 2.2% annual risk for hemorrhage. • If followed, asymptomatic AVMs that rupture carry a minimum 40% morbidity/mortality. • Genetic and environmental factors play a role in iAVM development. • Risk factors for hemorrhage include intranidal or venous aneurysms, deep location, deep venous drainage, and infratentorial location. • Multimodal therapy, including observation, radiosurgery, embolization, and microsurgery, must be balanced with hemorrhage risk, age, iAVM location, iAVM anatomy, medical comorbidities, and surgeon’s experience.

rate greatly increasing for iAVMs that have previously hemorrhaged (4.5%–4.8%).6,29 Importantly, the metaanalysis by Kim et al. showed that the rate of hemorrhage is not predicted by iAVM size. Morgan et al. used these rates to calculate annual risk estimates for initial iAVM hemorrhage and showed that the 5-year risk ranges from 6% to 11% and the 10-year risk ranges from 12% to 20%.30 Hemorrhage of an iAVM after initial asymptomatic presentation has been associated with a 40% rate of morbidity and mortality.6,30–32 A meta-analysis performed by Gross and Du has confirmed that infratentorial iAVM location, deep venous drainage, and intranidal aneurysms are all features associated with increased risk of hemorrhage.6

Risk Stratification and Grading Scales The Spetzler-Martin grading system, first described in 1986, has been used to grade iAVMs based on the risk posed by microsurgical resection.33 This grading scheme is composed of five tiers based on the size of the lesion, the pattern of venous drainage, and the proximity of the lesion to eloquent brain.33 The Spetzler-Martin grading system has been well validated, as multiple studies have shown that patients with Spetzler-Martin grade I and II iAVMs have significantly lower morbidity and mortality rates following resection compared to patients with Spetzler-Martin grade IV and V iAVMs.34 The similarity in the risk

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profiles of Spetzler-Martin grades I and II and of grades IV and V led to the development of a simplified schema, the three-tier Spetzler-Ponce scale.35 Exclusive deep venous drainage has since been validated as an important predictor of outcomes following resection as well.36,37 Pollock and Flickinger described a grading scale for predicting outcomes following radiosurgery. This grading scale identified five variables that predicted iAVM cure without the creation of new neurological deficits. Three of these variables survived multivariable regression and are outlined in the Pollock grading score equation: 0.1*iAVM volume in cm3 + 0.02*(patient age in years) + 0.3*(lesion location: 0, frontal/temporal; 1, cerebellar, corpus callosum, intraventricular, parietal, occipital; 2, brainstem, thalamus, or basal ganglia).38 The Pollock equation has been validated for predicting outcomes following radiosurgery, whereas the SpetzlerMartin grade does not predict outcomes following radiosurgery.38 Two other accepted scales for predicting outcomes following radiosurgery in iAVM patients include the Virginia Radiosurgery AVM Scale (VRAS) and the Heidelberg scale. These scales are based on iAVM volume, eloquent location, and/or history of hemorrhage.39,40 The VRAS authors also highlighted that AVM diameter, nidus volume, and radiation dose significantly predicted AVM obliteration rates following radiosurgery.39,40 Importantly, recent comparison of these grading systems to generalized linear models for the prediction of successful treatment without new neurological deficit has shown that integer-based classification scores are outperformed by continuous grading scores, such as the radiosurgerybased AVM score (RBAS) or the proton radiosurgery brain AVM scale (PRAS).41 Multiple grading scales exist for the assessment of procedural risk in the endovascular treatment of iAVMs. These include the Puerto Rico score, the Buffalo score, and the AVM embocure score (AVMES).42 All three incorporate the proximity to eloquent brain and the number of vascular pedicles as features of the grading system. The Buffalo score incorporates the pedicle diameter, AVMES uses overall iAVM size, and the Puerto Rico score is based on the presence of an arteriovenous fistula.43–45 While all scores predicted endovascular obliteration of iAVM, only the Buffalo score predicted complication rates

following endovascular treatment.42 This points to the importance of iAVM pedicle diameter in guiding endovascular treatment.

Clinical Decision-Making After ARUBA Decision-making for iAVMs was dramatically changed by the study known as ARUBA (A Randomised Trial of Unruptured Brain Arteriovenous Malformations). This study included 226 patients over the age of 18 who had unruptured iAVMs and had not undergone prior interventional treatments. Patients were assigned to medical management or medical management plus interventional treatment. The original study was halted early, as medical management was associated with significantly decreased rates of death, symptomatic stroke, and adverse events at a mean follow-up of 33 months. The authors confirmed these findings in a follow-up analysis that reported 50-month outcomes. In this study, they found the incidence rate of death or symptomatic stroke in patients who underwent medical management to be 3.4 events per 100 patient-years while the interventional group had a rate of 12.32 events per 100 patient-years.46–48 Multiple studies have examined the utilization of interventional treatment of iAVMs following the ARUBA trials. Overall, higher rates of stereotactic radiosurgery and endovascular treatment and lower rates of microsurgical resection have been observed. Interestingly, relative to the 1980s, there has been an overall increase in the frequency of interventional treatment of iAVMs.49,50 The major criticism of ARUBA remains the short period of follow-up; the benefit of definitive interventional treatment for iAVMs involves the risk of immediate intervention balanced against a lifetime incidence of stroke. Furthermore, the authors did not analyze the risk profiles based upon the type of intervention or type of iAVM and associated rupture risks.51 Multiple authors have since shown that treatment of unruptured iAVMs carries an acceptable risk profile. Link et al. describe a cohort of 85 patients meeting the ARUBA inclusion criteria. The patients in this study were treated with microsurgical resection, endovascular embolization, and stereotactic radiosurgery or some combination of these techniques. Overall, iAVM obliteration was achieved in 92.4% of patients and 4.8% developed long-term neurological deficits.52

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This study demonstrated the efficacy of multimodal therapies in the treatment of ARUBA-eligible iAVM patients. Additional work by Wong et al. demonstrated an acceptable safety profile for microsurgical resection in ARUBA-eligible patients. The authors evaluated outcomes of microsurgical resection of unruptured iAVMs in 155 cases that met ARUBA inclusion criteria and found an iAVM obliteration rate of 99.2%, with permanent disabling neurological deficits occurring in 4.5% of patients and 16.1% of patients experiencing a new neurological deficit.53 A final illustrative study performed by Pulli et al. included ARUBA-eligible iAVM patients and documented their outcomes following multimodal treatment techniques. The SpetzlerMartin grade of the treated iAVMs ranged from I to IV, and 30.3% of the patients were asymptomatic at initial evaluation. The authors reported a 56.3% iAVM obliteration rate, with symptomatic stroke occurring in 9.2% of patients. The rate of symptomatic stroke was equivalent to that seen in the medical management cohort from the original ARUBA trial (9.2%) and was significantly lower than that seen in the interventional group from the original ARUBA trial (39.6%).54 Current evidence shows that definitive interventional iAVM treatment, even for unruptured iAVMs, has an acceptable risk profile.

Treatment for iAVMs has become progressively more sophisticated since it was first described in the 1950s by Wise et al.55 Understanding advances in endovascular, radiosurgical, and microsurgical treatment modalities for treatment of iAVMs is critical in determining the balance between the risk of intervention and the lifetime risk of iAVM hemorrhage.

Use of GKRS in asymptomatic lesions can decrease long-term risk. Peciu-Florianu et al. reported longterm results in a series of 172 patients who underwent GKRS for the treatment of unruptured iAVMs. The overall iAVM obliteration rate was 76%, and 86% of the patients had a modified Rankin Scale score of 1 or less at most recent follow-up. Ten percent of patients developed hemorrhage following GKRS, with an annual hemorrhage rate of 1.1%. Persistent neurological deficits occurred in 4.6% of patients.57 There have also been reports of rare late adverse effects that develop many years after radiosurgical treatment. Finitsis et al.58 reported on five patients presenting with chronic encapsulated intracerebral hematomas 10–13 years after radiosurgery. In an effort to establish the incidence of late adverse radiation effects, Pollock et al.59 reviewed data from 233 patients who had undergone radiosurgery for iAVM treatment and had a minimum of 5 years of MRI follow-up. Perilesional edema or cyst formation was seen in 16 patients (6.9%) at a median of 8.7 years after radiosurgery; the 15-year incidence rate was 12.5%. In general, resection of damaged or thrombosed tissue can resolve any associated neurological deficits. A study by Tonetti and colleagues showed a 14% risk of stroke over a mean follow-up period of 8.4 years after GKRS for the treatment of asymptomatic iAVMs; this compared favorably to the ARUBA results, as extrapolation of the annualized stroke risk for patients with untreated iAVMs in that trial equated to a 30% risk of stroke over 8.4 years.60 Kim et al. have also shown that there is no difference in GKRS obliteration rates between asymptomatic, symptomatic unruptured, and ruptured iAVMs.61 More recent studies have also correlated the diffuseness of the nidus with postradiation changes and radiosurgery obliteration rates.62

RADIOSURGERY Multiple modalities of radiosurgery have been studied for the treatment of iAVMs. Proton-based therapies, Gamma Knife radiosurgery (GKRS), and linear accelerator (LINAC)-based radiosurgery have all been used effectively in the treatment of iAVMs. Lesions < 4 cm3 are obliterated at rates over 90%. Importantly, radiographic obliteration takes on average 2–4 years, during which the rate of hemorrhage is similar to pretreatment rates.56

MICROSURGICAL RESECTION Microsurgical resection of iAVMs is becoming less common over time.49 Sisti et al. analyzed data from 67 cases of small (< 3 cm) iAVMs treated with microsurgery and reported a 94% angiographic obliteration rate with a 1.4% surgical morbidity rate.63 The cohort included patients with deep-seated iAVMs in the thalamus, brainstem, and paraventricular regions, and the results demonstrate the durability of microsurgical resection. In fact, multiple studies prior to the year 2000 have

Treatment Modalities

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shown superiority of microsurgical resection to radiosurgery for the treatment of Spetzler-Martin grade I–III iAVMs when comparing rates of postoperative hemorrhage, death, and new neurological deficits.64 AVM size, deep venous drainage, and eloquency remain the dominant predictors of outcome following microsurgical resection, with age, diffuseness of nidus, and unruptured presentation as important supplementary characteristics for individualized preoperative risk projection.65 More recent studies have been divided on whether radiosurgery or microsurgery has higher rates of neurological deficit. The rate of iAVM obliteration and the lack of postradiosurgery hemorrhage are factors that favor microsurgery or a multimodal approach.66,67 Although most microsurgically treated iAVMs are small, in noneloquent locations, and have superficial drainage, U et al. demonstrated the feasibility of microsurgical resection for deep-seated eloquent iAVMs.68 The authors describe the use of a multistaged microsurgical excision under elective high-dose barbiturate anesthesia to minimize cerebral perfusion and the chance of catastrophic brain swelling or hemorrhage. Their study included 12 patients with deep periventricular lesions; complete resection was achieved in 10 cases, and 7 patients experienced neurological improvement after microsurgical treatment.68 The ability to access and resect large deep iAVMs is important when planning treatments for lesions in deep subcortical locations that will inevitably become symptomatic as time progresses. Large complex iAVMs are generally treated with a staged approach, often in conjunction with embolization or radiosurgery.69 Interestingly, while staged iAVM resection has become commonplace, recent studies from Beijing Tiantan Hospital in China have combined endovascular embolization with single-stage microsurgical resection of Spetzler-Martin grade III–V iAVMs and achieved similar long-term outcomes and obliteration rates in both ruptured and unruptured iAVM groups.70,71 These data point to the benefits of a multimodal treatment paradigm that may be especially useful for patients with asymptomatic unruptured iAVMs. ENDOVASCULAR EMBOLIZATION Endovascular treatment for iAVMs was first described in 1986.72,73 Even in this initial study, occlusion using isobutyl-cyano-acrylate was able to completely effect

109 a complete iAVM cure in 11% of cases and decrease the size of lesions and permit subsequent embolization or definitive treatment in the remaining cases. Endovascular treatment has been used in conjunction with resection and radiosurgery.74–76 Current endovascular techniques generally use liquid embolic material such as Onyx (Medtronic, Minneapolis, MN) for embolization, and a recent matched-cohort analysis using data from the International Radiosurgery Research Foundation AVM databases showed that the outcomes of AVM radiosurgery were comparable after embolization with Onyx or non-Onyx embolisates.77 Importantly, endovascular embolization with intent to cure is associated with a higher complication profile and higher rates of hemorrhage than endovascular embolization as an adjunctive treatment.78 This finding by Wu et al. argues for the use of endovascular embolization as part of a multimodal approach for iAVM treatment rather than as a stand-alone treatment; the strategy of considering embolization only as part of a multimodal approach may be particularly important in cases of asymptomatic iAVMs where a higher-risk profile is even less acceptable. Although initially thought to decrease the efficacy of GKRS or proton-based radiosurgery, endovascular embolization has been shown to have no negative effect on radiosurgery-based cure rates while possibly decreasing the chances of radiation-induced necrosis or late radiation sequelae.77,79 Improvements in endovascular technique can help decrease the incidence of complications. Ohshima et al. used the femoral vein as a sink to create novel flow circuits, which prevented flow stagnation and infarction.80 Modifications to routine transarterial endovascular techniques have involved use of transvenous embolization with adenosine-induced cardiac arrest for optimization of flow through the iAVM prior to embolization.81,82 Continued developments in endovascular techniques should help to further improve outcomes of iAVM treatment. MULTIMODAL TREATMENT A December 2016 European consensus statement stated that for Spetzler-Martin grade I or II iAVMs, multimodal interventional treatment is indicated.83 In high-volume centers, microsurgical resection of Spetzler-Martin grade I or II iAVMs is associated with

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a 95% obliteration rate without complication, while radiosurgery is associated with a 70% obliteration rate.84 Spetzler-Martin grade IV and V AVMs are generally palliated with endovascular treatments aimed at removing high-risk features such as nidal aneurysms or preventing further hemorrhage.28 Treatment of Spetzler-Martin grade III lesions is more difficult; microsurgical resection is associated with a 15% morbidity, and this is in highly selected patient populations. AVM obliteration with no concomitant/associated morbidity occurs in less than 50% of Spetzler-Martin grade III lesions following radiosurgery. Both patient and iAVM characteristics—including, especially, anatomical location of the lesion and patient age—predict complication profiles and factor into the appropriate management approach for individual cases.84

Future Directions A promising area of continued research focuses on biological modifiers that could stabilize the iAVM vasculature and decrease the risk associated with surgery. One example includes targeting miR-18a, a micro-RNA shown to stabilize vasculature in mouse models of iAVMs.85,86 Other studies aimed at preventing inflammation have depleted inflammatory microglia and targeted matrix metalloproteinases in the hopes of decreasing inflammation and chance of AVM rupture.87–89 Continued development of biological modifiers could allow for truly multimodal therapy that can decrease the risk associated with iAVM resection and definitive treatment. Most importantly, the need for randomized controlled trials is paramount. While microsurgical resection is on the decline, studies from over 20 years prior have complication rates comparable to modern-day multimodal treatments, pointing to the possibility for further improvement in iAVM treatment paradigms and outcomes.

Conclusion The ubiquitous availability of neuroimaging and advances in noninvasive imaging techniques have led to a proportional increase in incidentally discovered iAVMs. Asymptomatic iAVMs pose a challenging clinical dilemma with regard to their management. Choice

of treatment is complex and often tailored to institutional practices, surgeon experience, patient characteristics, and iAVM-specific features. As treatment for iAVMs continues to evolve and become more sophisticated, understanding advances in treatment modalities becomes critical in guiding decision-making to appropriately balance the risk-benefit profile of intervention against the expected natural history of the lesion. Multimodal treatment paradigms may be particularly useful in cases of asymptomatic iAVMs, where a higher risk profile is even less acceptable. REFERENCES 1. Berman MF, Sciacca RR, Pile-Spellman J, et al. The epidemiology of brain arteriovenous malformations. Neurosurgery. 2020;47(2):389–396; discussion 397. https://doi. org/10.1097/00006123-200008000-00023. 2. Wilson CB, Hoi Sang U, Domingue J. Microsurgical treatment of intracranial vascular malformations. J Neurosurg. 1979;51(4): 446–454. https://doi.org/10.3171/jns.1979.51.4.0446. 3. Ellis JA, Mejia Munne JC, Lavine SD, Meyers PM, Connolly ES Jr, Solomon RA. Arteriovenous malformations and headache. J Clin Neurosci. 2016;23:38–43. https://doi. org/10.1016/j.jocn.2015.08.003. 4. Morris Z, Whiteley WN, Longstreth WT Jr, et al. Incidental findings on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ. 2009;339:b3016. https://doi. org/10.1136/bmj.b3016. 5. Stapf C, Mohr JP, Pile-Spellman J, Solomon RA, Sacco RL, Connolly ES Jr. Epidemiology and natural history of arteriovenous malformations. Neurosurg Focus. 2001;11(5):1–5. https://doi.org/10.3171/foc.2001.11.5.2. 6. Gross BA, Du R. Natural history of cerebral arteriovenous malformations: a meta-analysis. J Neurosurg. 2013;118(2):437–443. https://doi.org/10.3171/2012.10.jns121280. 7. Abecassis IJ, Xu DS, Batjer HH, Bendok BR. Natural history of brain arteriovenous malformations: a systematic review. Neurosurg Focus. 2014;37(3):E7. https://doi. org/10.3171/2014.6.focus14250. 8. Chen X, Cooke DL, Saloner D, et al. Higher flow is present in unruptured arteriovenous malformations with silent intralesional microhemorrhages. Stroke. 2017;48(10):2881– 2884. https://doi.org/10.1161/strokeaha.117.017785. 9. Spetzler RF, Wilson CB, Weinstein P, Mehdorn M, Townsend J, Telles D. Normal perfusion pressure breakthrough theory. Clin Neurosurg. 1978;25:651–672. https://doi.org/10.1093/ neurosurgery/25.cn_suppl_1.651. 10. Nishida T, Faughnan ME, Krings T, et al. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations. Am J Med Genet A. 2012;158A:2829–2834. https://doi.org/10.1002/ ajmg.a.35622. 11. Amyere M, Revencu N, Helaers R, et al. Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformationarteriovenous malformation (CM-AVM2) deregulating RASMAPK signaling. Circulation. 2017;136(11):1037–1048. https:// doi.org/10.1161/circulationaha.116.026886. 12. Wooderchak-Donahue WL, Johnson P, McDonald J, et al. Expanding the clinical and molecular findings in RASA1

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PART 1 The Patient-Centered Approach treatment of brain arteriovenous malformations: analysis of 104 consecutive patients. J Neurosurg. 2020;133(2):342–350. https://doi.org/10.3171/2019.4.JNS19266. Dumont TM, Kan P, Snyder KV, Hopkins LN, Siddiqui AH, Levy EI. A proposed grading system for endovascular treatment of cerebral arteriovenous malformations: Buffalo score. Surg Neurol Int. 2015;6:3. https://doi.org/10.4103/2152-7806.148847. Feliciano CE, de León-Berra R, Hernández-Gaitán MS, Rodríguez-Mercado R. A proposal for a new arteriovenous malformation grading scale for neuroendovascular procedures and literature review. P R Health Sci J. 2010;29(2):117–120. Lopes DK, Moftakhar R, Straus D, Munich SA, Chaus F, Kaszuba MC. Arteriovenous malformation embocure score: AVMES. J Neurointerv Surg. 2016;8(7):685–691. https://doi. org/10.1136/neurintsurg-2015-011779. Mohr JP, Overbey JR, Hartmann A, et al. Medical management with interventional therapy versus medical management alone for unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre, non-blinded, randomised controlled trial. Lancet Neurol. 2020;19(7):573–581. https:// doi.org/10.1016/S1474-4422(20)30181-2. Rothwell PM. Extended short-term follow-up for a trial of treatment of unruptured arteriovenous malformations. Lancet Neurol. 2020;19(7):558–559. https://doi.org/10.1016/ S1474-4422(20)30178-2. Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, nonblinded, randomised trial. Lancet. 2014;383(9917):614–621. https://doi.org/10.1016/S0140-6736(13)62302-8. Komatsu K, Takagi Y, Ishii A, et al. Changes in treatment strategy over time for arteriovenous malformation in a Japanese high-volume center. BMC Neurol. 2020;20(1):404. https://doi. org/10.1186/s12883-020-01987-8. Naylor RM, Flemming KD, Brinjikji W, Brown RD Jr, Chiu S, Lanzino G. Changes in clinical presentation and treatment over time in patients with unruptured intracranial arteriovenous malformations. World Neurosurg. 2020;141:e261–e265. https:// doi.org/10.1016/j.wneu.2020.05.094. Sahlein DH, Mora P, Becske T, et al. Features predictive of brain arteriovenous malformation hemorrhage: extrapolation to a physiologic model. Stroke. 2014;45(7):1964–1970. https://doi. org/10.1161/STROKEAHA.114.005170. Link TW, Winston G, Schwarz JT, et al. Treatment of unruptured brain arteriovenous malformations: a single-center experience of 86 patients and a critique of the A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) Trial. World Neurosurg. 2018;120:e1156–e1162. https://doi. org/10.1016/j.wneu.2018.09.025. Wong J, Slomovic A, Ibrahim G, Radovanovic I, Tymianski M. Microsurgery for ARUBA trial (A Randomized Trial of Unruptured Brain Arteriovenous Malformation)-eligible unruptured brain arteriovenous malformations. Stroke. 2017;48(1):136–144. https://doi.org/10.1161/STROKEAHA.116.014660. Pulli B, Chapman PH, Ogilvy CS, et al. Multimodal cerebral arteriovenous malformation treatment: a 12year experience and comparison of key outcomes to ARUBA. J Neurosurg. 2020;133(6):1792–1891. https://doi. org/10.3171/2019.8.JNS19998. Wise RE, Geist RM Jr. Arteriography in cerebral arteriovenous malformation. Cleve Clin Q. 1950;17(1):22–25, illust. https://doi.org/10.3949/ccjm.17.1.22.

56. Maruyama K, Kawahara N, Shin M, et al. The risk of hemorrhage after radiosurgery for cerebral arteriovenous malformations. N Engl J Med. 2005;352(2):146–153. https://doi.org/10.1056/ NEJMoa040907. 57. Peciu-Florianu I, Leroy H-A, Drumez E, et al. Radiosurgery for unruptured brain arteriovenous malformations in the preARUBA era: long-term obliteration rate, risk of hemorrhage and functional outcomes. Sci Rep. 2020;10(1):21427. https:// doi.org/10.1038/s41598-020-78547-0. 58. Finitsis S, Bernier V, Buccheit I, et al. Late complications of radiosurgery for cerebral arteriovenous malformations: report of 5 cases of chronic encapsulated intracerebral hematomas and review of the literature. Radiat Oncol. 2020;15(1):177. https://doi.org/10.1186/s13014-020-01616-1. 59. Pollock BE, Link MJ, Branda ME, Storlie CB. Incidence and management of late adverse radiation effects after arteriovenous malformation radiosurgery. Neurosurgery. 2017;81(6):928– 934. https://doi.org/10.1093/neuros/nyx010. 60. Tonetti DA, Gross BA, Atcheson KM, et al. The benefit of radiosurgery for ARUBA-eligible arteriovenous malformations: a practical analysis over an appropriate follow-up period. J Neurosurg. 2018;128(6):1850–1854. https://doi.org/10.3171/2017.1.JNS162962. 61. Kim BS, Yeon JY, Shin HS, et al. Gamma Knife radiosurgery for incidental, symptomatic unruptured, and ruptured brain arteriovenous malformations. Cerebrovasc Dis. 2021;50(2):222– 230. https://doi.org/10.1159/000513280. 62. Yang H-C, Peng S-J, Lee C-C, et al. Does the diffuseness of the nidus affect the outcome of stereotactic radiosurgery in patients with unruptured cerebral arteriovenous malformations? Stereotact Funct Neurosurg. 2021;99(2):113–122. https://doi. org/10.1159/000510683. 63. Sisti MB, Kader A, Stein BM. Microsurgery for 67 intracranial arteriovenous malformations less than 3 cm in diameter. J Neurosurg. 1993;79(5):653–660. https://doi.org/10.3171/ jns.1993.79.5.0653. 64. Pikus HJ, Beach ML, Harbaugh RE. Microsurgical treatment of arteriovenous malformations: analysis and comparison with stereotactic radiosurgery. J Neurosurg. 1998;88(4):641–646. https://doi.org/10.3171/jns.1998.88.4.0641. 65. Lawton MT, Kim H, McCulloch CE, Mikhak B, Young WL. A supplementary grading scale for selecting patients with brain arteriovenous malformations for surgery. Neurosurgery. 2010;66(4):702. https://doi.org/10.1227/01. NEU.0000367555.16733.E1. 66. Nataf F, Schlienger M, Bayram M, Ghossoub M, George B, Roux F-X. Microsurgery or radiosurgery for cerebral arteriovenous malformations? A study of two paired series. Neurosurgery. 2007;61(1):39–49; discussion 49–50. https:// doi.org/10.1227/01.neu.0000279722.60155.d3. 67. Gross BA, Du R. Surgical and radiosurgical results of the treatment of cerebral arteriovenous malformations. J Clin Neurosci. 2012;19(7):1001–1004. https://doi.org/10.1016/j. jocn.2012.01.004. 68. U HS, Kerber CW, Todd MM. Multimodality treatment of deep periventricular cerebral arteriovenous malformations. Surg Neurol. 1992;38(3):192–203. https://doi.org/10.1016/00903019(92)90169-n. 69. Sussman ES, Gummidipundi SE, Pendharkar AV, et al. Staged surgical resection of brain arteriovenous malformations. World Neurosurg. 2021;146:e925–e930. https://doi.org/10.1016/j. wneu.2020.11.036.

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70. Chen Y, Li R, Ma L, et al. Single-stage combined embolization and resection for Spetzler-Martin Grade III/IV/V arteriovenous malformations: a single-center experience and literature review. Front Neurol. 2020;11:570198. https://doi.org/10.3389/ fneur.2020.570198. 71. Wang M, Qiu H, Cao Y, Wang S, Zhao J. One-staged in situ embolization combined with surgical resection for eloquence protection of AVM: technical note. Neurosurg Rev. 2019;42(3): 783–790. https://doi.org/10.1007/s10143-019-01137-w. 72. Merland JJ, Rüfenacht D, Laurent A, Guimaraens L. Endovascular treatment with isobutyl cyano acrylate in patients with arteriovenous malformation of the brain. Indications, results and complications. Acta Radiol Suppl. 1986;369:621–622. https://www.ncbi.nlm.nih.gov/pubmed/2980575. 73. Lasjaunias P, Manelfe C, Terbrugge K, Lopez Ibor L. Endovascular treatment of cerebral arteriovenous malformations. Neurosurg Rev. 1986;9(4):265–275. https://doi.org/10.1007/BF01743633. 74. Shi XE, Wang ZC, Dai JP. Combined endovascular embolization of large intracranial arteriovenous malformations and their subsequent surgical resection. Chin Med J. 1993;106(11): 851–856. https://www.ncbi.nlm.nih.gov/pubmed/8143499. 75. Marks MP, Lane B, Steinberg GK, et al. Endovascular treatment of cerebral arteriovenous malformations following radiosurgery. AJNR Am J Neuroradiol. 1993;14(2):297–303; discussion 304–305. https://www.ncbi.nlm.nih.gov/pubmed/8456702. 76. Jafar JJ, Davis AJ, Berenstein A, Choi IS, Kupersmith MJ. The effect of embolization with N-butyl cyanoacrylate prior to surgical resection of cerebral arteriovenous malformations. J Neurosurg. 1993;78(1):60–69. https://doi.org/10.3171/jns.1993.78.1.0060. 77. Chen C-J, Ding D, Lee C-C, et al. Embolization of brain arteriovenous malformations with versus without onyx before stereotactic radiosurgery. Neurosurgery. 2021;88(2):366–374. https://doi.org/10.1093/neuros/nyaa370. 78. Wu EM, El Ahmadieh TY, McDougall CM, et al. Embolization of brain arteriovenous malformations with intent to cure: a systematic review. J Neurosurg. 2019;132(2):388–399. https://doi.org/10.3171/2018.10.JNS181791. 79. Chen C-J, Ding D, Lee C-C, et al. Stereotactic radiosurgery with versus without embolization for brain arteriovenous malformations. Neurosurgery. 2021;88(2):313–321. https://doi. org/10.1093/neuros/nyaa418. 80. Ohshima T, Miyachi S, Matsuo N, et al. Novel vertebral artery flow reversal method for preventing ischemic complication during

81.

82.

83.

84.

85.

86.

87.

88.

89.

endovascular intervention. J Stroke Cerebrovasc Dis. 2018;27(7): e144–e147.https://doi.org/10.1016/j.jstrokecerebrovasdis.2018.02.036. Ghorbani M, Griessenauer CJ, Wipplinger C, et al. Adenosineinduced transient circulatory arrest in transvenous embolization of cerebral arteriovenous malformations. Neuroradiol J. 2021. https:// doi.org/10.1177/1971400921998972. Published online March 3. Higbie C, Khatri D, Ligas B, Ortiz R, Langer D. N-butyl cyanoacrylate transvenous arteriovenous malformation embolization with arterial balloon assistance: defining parameters for a transvenous approach as a potential upfront treatment option in managing cerebral arteriovenous malformations. Asian J Neurosurg. 2020;15(2):434– 439. https://doi.org/10.4103/ajns.AJNS_357_19. Cenzato M, Boccardi E, Beghi E, et al. European consensus conference on unruptured brain AVMs treatment (Supported by EANS, ESMINT, EGKS, and SINCH). Acta Neurochir (Wien). 2017;159(6):1059–1064. https://doi.org/10.1007/ s00701-017-3154-8. Morgan MK, Stoodley MA, Fuller JW. Letter to the Editor: Comparison between surgery and Gamma Knife radiosurgery for brain AVMs. J Neurosurg. 2017;126(1):338–341. https:// doi.org/10.3171/2016.3.JNS16634. Marín-Ramos NI, Thein TZ, Ghaghada KB, Chen TC, Giannotta SL, Hofman FM. miR-18a inhibits BMP4 and HIF-1α normalizing brain arteriovenous malformations. Circ Res. 2020;127(9):e210–e231. https://doi.org/10.1161/ CIRCRESAHA.119.316317. Ferreira R, Santos T, Amar A, et al. MicroRNA-18a improves human cerebral arteriovenous malformation endothelial cell function. Stroke. 2014;45(1):293–297. https://doi.org/10.1161/ STROKEAHA.113.003578. Ma L, Zhu W, Zhan L, et al. Abstract 76: Transient depletion of microglia reduces the severity of brain arteriovenous malformation in a mouse model. Stroke. 2018;49(Suppl 1):A76. https://doi.org/10.1161/str.49.suppl_1.76. Frenzel T, Lee CZ, Kim H, et al. Feasibility of minocycline and doxycycline use as potential vasculostatic therapy for brain vascular malformations: pilot study of adverse events and tolerance. Cerebrovasc Dis. 2008;25(1-2):157–163. https://doi. org/10.1159/000113733. Hashimoto T, Matsumoto MM, Li JF, Lawton MT, Young WL. UCSF BAVM Study Group. Suppression of MMP-9 by doxycycline in brain arteriovenous malformations. BMC Neurology. 2005;5(1). https://doi.org/10.1186/1471-2377-5-1.

Chapter 11

Decision Analysis for Symptomatic Lesions Jennifer E. Kim, Risheng Xu, Justin M. Caplan, Judy Huang, Christopher M. Jackson, and Rafael J. Tamargo

Chapter Outline Introduction Natural History of Untreated iAVMs Clinical Presentations of Patients With Symptomatic iAVMs Treatment Strategies for Symptomatic Unruptured iAVMs Treatment Strategies for Ruptured iAVMs Conclusion

Introduction Intracranial arteriovenous malformations (iAVMs) are highly complex and heterogeneous lesions that account for 2% of all hemorrhagic strokes.1–5 The malformations vary in size, location, angioarchitecture, and hemodynamics—all of which factor into clinical presentation and rupture risk. Though iAVMs are rare, with an estimated prevalence of 0.2%,6 they are a leading cause of spontaneous, nontraumatic intracerebral hemorrhage (ICH) in young adults.7,8 Approximately 35%–50% of all patients with iAVMs present with symptomatic ICH,9–11 with seizures being the second most common presentation.12 Patients can also present with focal neurologic deficits (FNDs) or cognitive changes secondary to mass effect or ischemic steal. These symptoms, as well as the risk of rehemorrhage, have significant neurologic and functional consequences and merit careful consideration when determining clinical management. Intervention 114

is warranted if the natural history risks outweigh the risks of treatment. Thus judicious management and accurate assessments of risk profiles are critical when triaging patients with symptomatic iAVMs.

Natural History of Untreated iAVMs Due to the rarity of these lesions, the actual incidence and prevalence of iAVMs are not yet fully known. The best estimates derived from populationbased studies report an incidence ranging from 0.8 to 2.05 cases per 100,000 person-years,13–17 and an accepted prevalence of 0.2%.6,18 These numbers may be skewed by the biased detection of symptomatic lesions, though increasing availability of noninvasive cranial imaging has led to increased diagnosis of incidental, asymptomatic lesions. Although iAVMs can be clinically silent, they are not benign lesions. Results from an early autopsy study estimated that 12% of affected persons develop clinical symptoms in their lifetime.19 ICH remains the most common presentation of symptomatic iAVMs. The first-time hemorrhage risk is approximately 2%,11,20 and the overall annual hemorrhage rate of untreated iAVMs is estimated at 2%–4%.1,21–23 AVM-associated aneurysms appear to be a major cause of rerupture within the first year.16 The risk of rerupture is low immediately after the initial event24 but rises to 6%–18% in the first year before dropping to an annual rate of 2%–7.9%.16,21,22,25 AVM-associated ICH, however, appears to have more favorable clinical outcomes than ICH from other causes. This may be due to younger age and fewer comorbidities

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in iAVM patients.26,27 Overall, ruptured iAVMs are associated with annual mortality rates of 0.7%– 2.9%,10,21–23,28 with a 51% excess mortality in patients with untreated iAVMs compared to the general population.29

Clinical Presentations of Patients With Symptomatic iAVMs Clinical presentations are often categorized as hemorrhagic vs nonhemorrhagic. While ICH is the dominant presentation for patients with iAVMs, approximately 15% of patients are asymptomatic at the time of AVM detection, and another 20% present with seizures.30 Specific symptoms are often reflective of underlying anatomic and hemodynamic characteristics and should be taken into careful consideration when discussing prognosis and treatment options. SEIZURES Epileptic seizures occur in an estimated 20%–45% of iAVM patients and are the second most common clinical manifestation of iAVMs.12,31,32 Seizures can occur in the setting of unruptured or ruptured iAVMs and can also develop de novo after intervention. While posthemorrhagic seizures are attributed to hemosiderin deposits or gliotic scarring,33 the pathogenesis in patients with unruptured iAVMs is not yet well understood. Seizure risk factors include nidus size > 3 cm; long pial draining vein, venous outflow stenosis, venous ectasia, or superficial venous drainage; supratentorial and cortical localization, especially in frontal or temporal lobes; and arterial border zone location.15,31,32,34–36 Functional steal—or redirection of blood to the lesion and away from functioning brain tissue—may also be a contributing factor. Generalized seizures occur in approximately one-third of patients with unruptured iAVMs, while focal seizures occur in approximately 10%.37 Though antiepileptic drugs (AEDs) offer a 40%–80% chance of achieving 2 seizure-free years in a 5-year ­ follow-up period,38 epileptic seizures can have a significant impact on quality of life. The risks and benefits of intervention for seizure control remain controversial.35,36,39 A meta-analysis by Baranoski

Pearls • Patients with iAVMs typically present after hemorrhage, seizure, or the appearance of focal neurologic deficits. • Comprehensive evaluation includes CT, MRI, MR angiography, CT angiography, and digital subtraction angiography, with additional studies as required and based on location. • If possible, surgery after rupture is usually delayed to allow for resolution of edema and swelling and for accurate nidus identification. • Treatment of symptomatic lesions often involves multiple interventions, including embolization, surgery, and/or stereotactic radiosurgery. • Surgical excision, with or without preoperative embolization, is recommended for Spetzler-Martin grade I–III iAVMs.

et al. demonstrated that 73% of patients remained seizure-free at the last follow-up after open surgery, compared to 62.9% after stereotactic radiosurgery (SRS) and 50% after endovascular embolization.40 Conversely, in a Scottish population study, Josephson et al. compared conservative management vs intervention and demonstrated no significant difference in the 5-year risk of unprovoked seizure.38 Thus it is unclear whether invasive intervention is justified for primary seizure control. FOCAL NEUROLOGIC DEFICITS Fixed, temporary, or progressive FNDs are uncommon initial presentations in iAVM patients without underlying hemorrhage or seizures. The reported incidence is low: 7.2% of patients with fixed deficits and 1.3% with progressive deficits.11 Risk factors include increased nidus size, angiomatous change (or dilated pial-to-pial collaterals from surrounding territories), deep brain or brainstem localization, superficial drainage, and venous ectasias.41,42 The likely pathophysiology of FNDs is mass effect or arterial steal. Mass effect is the mechanical compression of neighboring brain tissue,41 whereas steal is the shunting of blood into chronically dilated, lowpressure AVM vessels and away from surrounding

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brain tissue. Whether or not this sump effect is responsible for symptoms is yet unproven. Several cases of ischemic stroke in iAVM patients have been reported, with the authors citing arterial steal as the putative etiology.43,44 Though early transcranial Doppler sonography investigation showed no differences in arterial velocities and pulsatility,45 MRI and CT studies have shown perfusion deficits (as defined by decreased cerebral blood volume, decreased cerebral blood flow, and increased mean transit time) in patients with FNDs.41,46 Further studies are needed to determine whether treating the underlying mass effect or perfusion deficits improves neurologic outcomes. NEUROCOGNITIVE DEFICITS Neurocognitive impairment is a poorly characterized and potentially underreported sequela of iAVMs. In 1948, Olivecrona and Riives reported mental deterioration and memory changes in 11 of 43 iAVM patients.47 Lower IQ, memory, attention, and other neuropsychologic deficits have since been reported in 24%–71.4% of iAVM patients.48,49 However, these studies are confounded by the inclusion of patients with ruptured iAVMs; reported rates decrease significantly when controlling for nonhemorrhagic presentations. For instance, Choi et al. reported cognitive deficits in 10 of 736 patients with untreated, unruptured iAVMs.41 Mass effect, ischemic steal, and venous hypertension are the most cited etiologies of iAVM-related cognitive changes.45,50–52 Evidence for steal includes findings of deficits associated with the hemisphere contralateral to the iAVM53 and dystrophic cortical changes remote from the iAVM.50 Few studies, however, report neurocognitive outcomes, so it remains unclear whether decompressive or obliterative treatment benefits this subset of patients. HEADACHE A wide-ranging and often high frequency (14%–79%) of nonhemorrhagic, migraine-type headaches has been described in patients with unruptured iAVMs.54 Despite positive correlation, it is unclear whether there is a pathophysiologic relationship between these headaches and the iAVMs. Suggested etiologies include elevated intracranial pressure (ICP) due to venous hypertension, ischemic steal, or “cortical spreading

depression” (a wave of cortical depolarization).54,55 Headaches associated with occipital AVMs may be pulsatile, migraine-like, ipsilateral to the lesion, and accompanied by homonymous visual symptoms.54,56,57 High rates of headache resolution after microsurgical or radiation treatment of occipital AVMs have also been reported.58,59 INTRACEREBRAL HEMORRHAGE ICH is the most common clinical presentation of iAVMs and occurs in 42%–72% of all symptomatic cases.3 Due to the heterogeneity of these lesions, the reported risk factors for rupture are varied and oftentimes conflicting. Initial hemorrhage is the most consistent predictor of hemorrhage after diagnosis, followed by increased age.60 Other clinical and angioarchitectural predictors include exclusively deep venous drainage, deep or infratentorial nidus location, and the presence of flow-related aneurysms.16,17 AVM size is a controversial risk factor, with some studies reporting smaller iAVMs (< 3 cm) to be at a higher risk of rupture, possibly due to higher feeding artery pressures.61,62 Venous stenosis, obstruction, occlusion, or ectasia is frequently posited as a risk for venous congestion and subsequent rupture. Multivariate analyses, however, show no significant association between these abnormalities and increased rupture risk.17 Hemorrhagic presentations can range from mild headache to seizures or neurologic deficits, including coma. Clinical and radiographic predictors of poor outcomes after iAVM rupture include lower Glasgow Coma Scale score on admission, large or increasing ICH volume, and infratentorial location of the nidus.63,64 Hemorrhage patterns can be primarily parenchymal, subarachnoid, intraventricular, or any combination of the above depending on the location and anatomy of the lesion. Parenchymal hemorrhages are most likely to result in neurologic deficits and higher stroke morbidity. Still, patients with AVM-related ICH appear to have significantly better clinical outcomes than those with ICH from other causes,22,26,27,65 This is attributed to younger age and fewer comorbidities in iAVM ­ patients. Additionally, the resulting hematoma may be confined within the nidus, sparing the neighboring healthy brain.15,26 Once ruptured, iAVMs have a higher rerupture rate, especially within the first year after the

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Decision Analysis for Symptomatic Lesions

initial rupture.11,15,22,66 Recurrent hemorrhages, however, appear to carry no significant increase in morbidity or mortality.27

Treatment Strategies for Symptomatic Unruptured iAVMs Standardized management of unruptured iAVMs remains difficult to achieve, due to the lack of high-quality studies on lifetime risks of iAVM rupture and predictors of treatment complications. To date, ARUBA (A Randomised trial of Unruptured Brain Arteriovenous Malformations) is the only prospective registry available to guide clinical management.67 In this nonblinded multicenter registry, 226 patients with unruptured iAVMs were assigned to medical management alone or medical management plus intervention with resection, radiation, embolization, or multimodal therapy. Patients previously selected for treatment were obviously excluded. Study recruitment was halted prematurely after interim data analysis revealed that the risk of stroke and death was significantly higher in the interventional therapy group (30.7%) than in the medical management group (10.1%) after a mean follow-up of 33 months.67 ARUBA was continued as an observational study, and a 5-year follow-up report demonstrated persistently lower incidence of symptomatic stroke or death with medical management (13.6%) vs interventional therapy (35.3%).68 The ARUBA study has elicited numerous criticisms over trial design, study progression, and data analysis.69,70 These include the heterogeneity of patients, selection bias, lack of standardized interventions, and lack of subgroup analysis among the different treatment modalities and AVM grades. Additionally, complication rates in the intervention arms were higher than expected, especially with improved treatment technologies. A bias toward nonsurgical therapies has also been noted, with several patients undergoing partial embolization and radiation instead of resection, which may have contributed to delayed hemorrhages. Subsequent single-institution studies of ARUBAeligible patients have demonstrated better functional outcomes and lower rates of neurologic deficits after open surgery or SRS.71,72,73 Nonetheless, the medical management arm of ARUBA does provide valuable insight into the natural

117 history of unruptured iAVMs. At 33 months, conservative management was associated with a 10% risk of symptomatic stroke or death and a 15% risk of disability.67 At 5 years, these risks were 13.6% and 18%, respectively.68 Weighing the population-based risk of rupture against individual risk factors and life expectancy allows clinicians to estimate a patient-specific lifetime hemorrhage risk. Symptom severity, seizure risk, and quality of life should also be considered. For example, the benefits of obtaining a long-term cure may outweigh upfront risks of open surgery in a young patient, whereas lower treatment risks and preserved quality of life may be the primary goals for an older patient. These individual factors must be weighed against the risk of treatment-associated complications when making treatment decisions. OBSERVATION Conservative management with serial imaging is warranted if the natural history of a lesion is relatively benign or if there is a high likelihood of treatment-related morbidity. For example, high-grade iAVMs (SpetzlerMartin grade IV or V) are associated with high surgical morbidity and are usually managed conservatively.74 There is scant evidence, however, to guide screening and monitoring practices for patients with unruptured iAVMs. In North America, patients at risk for heritable disease such as hereditary hemorrhagic telangiectasias are recommended to undergo screening MRI studies every 5 years up to the age of 45. Sporadic iAVMs may be followed with interval MRI every 5 years until the patient is 65 years old in order to detect silent hemorrhages, with more frequent imaging if the patient experiences new or worsening symptoms.75,76 RESECTION Microsurgical resection is the mainstay of treatment for more than half of all iAVM patients. It has the advantage of being immediately curative, and with judicious patient selection and meticulous planning, it can have excellent results. The concept of en bloc resection was introduced by Olivecrona after he performed the first successful radical resection of a posterior fossa iAVM in 1932.77 The development of cerebral angiography has allowed for more nuanced insights into iAVM angioarchitecture, especially regarding arterial supply, flow-related aneurysms, and venous outflow.

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The principal tenets of resection are the occlusion of superficial feeding arteries, circumferential dissection of the nidus, control of the deep feeding arteries, and finally the disconnection of the nidus from the draining veins.78 Several classification schemes have been proposed to help guide clinical decision-making and surgical risk assessment. The most widely adopted is the Spetzler-Martin grading scale, which uses size (one point for < 3 cm, two points for 3–6 cm, three points for > 6 cm), eloquence of the adjacent brain (zero points for noneloquence, one point for eloquence), and venous drainage pattern (zero points for superficial, one point for deep) to estimate surgical risk.74 More recently, Spetzler and Ponce proposed an updated three-tier grading system.79 However, we prefer the original five-tier scale, as we feel it has better granularity and is easily applied in clinical settings. Lowgrade iAVMs (grades I and II) are associated with low rates of operative morbidity and are best treated with resection unless the patient is a poor surgical candidate. In such cases, SRS is the next best option. On the other end of the spectrum, grade IV and V iAVMs are associated with high rates of surgical morbidity and tend to be managed conservatively, as discussed previously (Fig. 11.1).

Grade III iAVMs are particularly challenging, as they represent the most heterogeneous of the five grades. These lesions consist of four different combinations of the Spetzler-Martin grade variables: size (S), venous drainage (V), and eloquence (E). In 2003, Lawton and colleagues proposed the modified Spetzler-Martin (mSM) scale to address the nonequivalent risks of each grade III combination, which they reclassified as grade III −, III, III +, or III* (Table 11.1).80 Small grade III iAVMs, with one point assigned for size < 3 cm, one point for deep venous drainage, and one point for eloquence (S1V1E1, mSM grade III −), are the most common subtype. These lesions have the lowest predicted morbidity (3%, based on the 76 cases analyzed by Lawton et al.) of any grade III lesions and are therefore recommended for surgical excision. Mediumsized grade III iAVMs with deep drainage (S1V1E0, mSM grade III) have intermediate morbidity (7.1%) and are also amenable to surgical treatment. Mediumsized, eloquent grade III iAVMs (S2V0E1, mSM III +) have the highest operative morbidity (14.8%) and are most appropriate for radiation. Finally, large grade III lesions (S3V0E, mSM III*) represent lesions that occur with such low incidence as to be clinically irrelevant (Fig. 11.1). With these modifications, clinicians can make evidence-based assessments of surgical risk and

Spetzler-Martin Grade

I

II

III

IV

V

Grade III subtype

1. 2.

Size

1

2

2

3

Venous drainage

1

1

0

0

Eloquence

1

0

1

0

mSM grade

III-

III

III+

III*

Surgery Radiosurgery

Radiosurgery

Observation

Fig. 11.1 Clinical algorithm for the management of unruptured iAVMs. mSM, Modified Spetzler-Martin.

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TABLE 11.1 Modified Spetzler-Martin Classification for Grade III iAVMs According to Surgical Risk and Summary of Results in 76 Cases Reported by Lawton et al. Modified Spetzler-Martin Grade

Grade III Type

Improved or Unchanged Condition (%)

New Deficit or Death (%)

III − III III + III*

S1V1E1 S2V1E0 S2V0E1 S3V0E0

97.1 92.9 85.2 NA

2.9 7.1 14.8 NA

NA, Not applicable. Based on Lawton MT et al. Spetzler-Martin Grade III arteriovenous malformations: surgical results and a modification of the grading scale. Neurosurgery. 2003;52:740-749.

determine the most appropriate treatment options for each individual patient. RADIOSURGERY SRS is an established alternative to resection and is often reserved for compact AVMs in deep or eloquent areas of the brain or in poor surgical candidates (Fig. 11.1). SRS involves precise, image-guided delivery of high-dose radiation to the target with the goal of obliterating the nidus while minimizing injury to adjacent brain tissue. After an expected 2- to 4-year latency period, cumulative obliteration rates of treated iAVMs range from 50% to 90%.81–83 Furthermore, in cases in which total obliteration is achieved and confirmed by angiography, the annual risk of iAVM hemorrhage is reduced to less than 1%.84 Predictive factors of successful obliteration include smaller nidus size, lower grade, hemispheric location, single draining vein, young age, and prior history of AVM rupture.20,85,86 Higher marginal or maximum radiation dosages are associated with better obliteration rates, but the improvement comes at the cost of radiation-associated morbidities such as cerebral edema or necrosis, cyst formation, seizures, headaches, FNDs, and cognitive changes. Rates of permanent neurologic deficits range from 0.4% to 20%.20,86–88 Patients with deep or infratentorial lesions and iAVMs with larger volumes receiving radiation doses greater than 12 Gy are at a higher risk of permanent injury.85,89

SRS is an attractive option with low upfront risks for otherwise poor surgical candidates. For example, while patients with lesions in eloquent areas of the brain are at high risk of postoperative deficits after AVM resection, SRS for rolandic AVMs has been shown to result in complete obliteration with no new or worsening neurologic deficits in 60% of patients. Additionally, in the same study, 51.8% of patients who initially presented with seizures were seizure-free at the last year of follow-up.90 SRS, however, also has the significant disadvantage of a 2- to 4-year latency period from the time of treatment to subtotal or total obliteration, during which time patients are still at risk for AVM rupture. Postradiation hemorrhage has been reported in 1.6%–8% of cases66,72,88 and is thought to be a result of radiation-induced inflammation, with tissue necrosis, vessel thrombosis, and acute hemodynamic changes.91 After the latency period, however, complete radiographic obliteration appears to afford nearcomplete protection from further hemorrhage.72 Still, long-term follow-up is recommended, as several cases have been reported in which patients experienced delayed hemorrhage from iAVMs that angiographic studies had previously confirmed as obliterated.82 ENDOVASCULAR EMBOLIZATION Since the first successful iAVM embolization by Luessenhop and Spence in 1960,72 rapid advancements in interventional techniques and tools have made embolization an important tool for the primary or adjuvant treatment of iAVMs. Endovascular embolization alone can be curative in only a minority of iAVM cases, with larger patient cohort studies demonstrating immediate complete occlusion in 5%–40%.92–94 Small lesions (< 3 cm) with a single feeding artery appear to have the best chance of complete obliteration, while larger iAVMs with multiple arterial feeders from multiple vascular territories with en passage supply are associated with incomplete obliteration.93–95 Complication rates range widely from 1.4% to 50% morbidity and 1% to 4% mortality.96 Reported predictors of poor outcomes include deep venous drainage, higher-grade AVMs (Spetzler-Martin grades III–V), associated aneurysms, infratentorial or eloquent location, and periprocedural hemorrhage.96,97 Although embolization alone cannot achieve complete obliteration in most cases, targeted embolization

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of flow-related aneurysms or high-flow fistulas without an intent to cure has been shown to lower rebleeding rates.98 Additionally, partial embolization with volume or flow reduction may be a helpful adjunct to open surgical resection or radiosurgery. Presurgical embolization is the most common use of adjuvant endovascular therapy. Strategies include occlusion of deep arterial pedicles, which are usually encountered last during the iAVM dissection. Adhesive liquid embolic agents, such as N-butyl cyanoacrylate (NBCA), and cohesive liquid embolics, such as Onyx (Medtronic, Minneapolis, MN), are commonly used to block flow through the nidus and distal arterial pedicles. Onyx has been shown to have increased nidus penetration, with 96% success rates in reducing iAVM volumes by half, compared to 85% with NBCA.99 Less commonly, platinum coils are used to occlude arterial feeders and decrease flow through certain compartments of the nidus.100 AVMs can also be embolized prior to radiosurgery to reduce the size to < 3 cm, as well as treating any aneurysms or fistulas that put the patient at higher risk of postradiation hemorrhage. Lastly, palliative embolization may be an option in selected patients with inoperable lesions and suffering seizures or progressive neurologic deficits related to venous congestion or ischemic steal.101

Treatment Strategies for Ruptured iAVMs Approximately 50% of patients with iAVMs present with spontaneous ICH, which can have catastrophic neurologic and functional repercussions in otherwise healthy patients. Due to the risk of early neurologic deterioration, ICH is a medical emergency that warrants prompt diagnosis and attentive management. A recommended treatment algorithm for ruptured iAVMs is summarized in Fig. 11.2. MEDICAL MANAGEMENT Evidence-based guidelines for medical management of spontaneous, nontraumatic ICH have been detailed by the American Heart Association–American Stroke Association.102 Per these guidelines, all patients should be admitted to the intensive care unit for close neurologic and hemodynamic monitoring (Class I, level of evidence [LOE] B). Patients with altered mental status who are at risk for airway compromise should be intubated for ventilatory support.

Patients with elevated systolic blood pressure (SBP) of 150–220 mm Hg should be given medication to lower their SBP to < 140 mm Hg in order to prevent hematoma expansion (Class I, LOE A). Severe coagulopathy or thrombocytopenia should be corrected with clotting factor replacements or platelets to optimize hemostasis (Class I, LOE C). Clinical (Class I, LOE A) or electrographic (Class I, LOE C) seizures should be treated promptly with AEDs. Though patients with lobar hemorrhages are at higher risk of early seizures, the use of prophylactic AEDs is controversial, with some studies reporting worse outcomes, while others showed no association with mortality or outcome.103 Elevated ICP—due to mass effect or hydrocephalus— is frequently seen in patients with larger hematomas or intraventricular hemorrhage and is associated with worse outcomes and mortality.104,105 Intracranial hypertension (ICP >20mm Hg) should therefore be addressed urgently, starting with simple interventions such as elevating the head of the patient’s bed, analgesia, sedation, osmotherapy with mannitol, and hyperventilation. Cerebrospinal fluid (CSF) drainage with a ventriculostomy is recommended for the treatment of hydrocephalus, especially in patients with depressed consciousness (Class IIA, LOE B). ICP may be monitored through the ventriculostomy, which allows for titration of medications and CSF drainage for a goal ICP 90% sensitivity for acute hemorrhage and is the first-line diagnostic imaging modality.106 Although evaluation of the cerebral vasculature is limited when no intravenous contrast agent is used, a noncontrast CT study of the head can show hypertrophied or calcified vessels or a hyperdense region suggestive of an underlying vascular malformation. In cases where a vascular etiology is suspected, CT angiography (CTA) or MR angiography (MRA) can be used to detect the underlying lesion. Both modalities provide cross-sectional information about the iAVM’s angioarchitecture and its relation to surrounding brain structures. CTA is a rapid test with sensitivity of 0.95 and specificity of 0.99 for detecting vascular lesions, but it can be limited by beam hardening artifact from metallic hardware or embolic

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Hemorrhage secondary to ruptured AVM

Early Treatment

Delayed Treatment no

yes

See Figure 1 for management of unruptured AVMs

Life-threatening mass effect or neurologic deterioration no

yes AVM is small, superficial and low grade yes ICH evacuation (+)AVM resection

Neurocritical care, medical management, DSA

no ICH evacuation (-)AVM resection

DSA identifies flow-related aneurysm as source of ICH yes

Treatment to secure aneurysm

no Repeat MRI and DSA after 3 months

SM I, II

SM III

Benefits outweigh risks of intervention

SM IV, V

no

Observation

yes Definitive treatment: • Microsurgery • Radiosurgery • Embolization

Fig. 11.2 Clinical algorithm for the management of ruptured iAVMs. DSA, Digital subtraction angiography; ICH, intracerebral hemorrhage; SM, Spetzler-Martin.

agents. MRA requires longer acquisition times, but it has a sensitivity of 0.98 and a specificity of 0.99 and can provide information about prior hemorrhages, microhemorrhages, and the condition of the affected brain.107 If an underlying vascular malformation is identified or suspected, digital subtraction angiography (DSA) is recommended as the gold standard for the diagnosis of iAVMs. DSA has the highest spatial and temporal resolution108 and can be used to characterize the arterial supply and venous outflow and any flow-related aneurysms, all of which are critical for treatment planning.

TIMING OF SURGICAL INTERVENTIONS Despite presenting with acute hemorrhage, most patients with ruptured iAVMs do not require emergent surgical intervention. Unlike aneurysms, which have high early rehemorrhage rates, iAVMs are reported to have lower rates of early rerupture24 and lower morbidity from subsequent hemorrhage.27 Because of this, many surgeons defer definitive treatment for weeks to months to minimize treatment risks and allow the patient to recover from the acute event. Early intervention, however, may be warranted in extreme circumstances.78

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EARLY SURGICAL MANAGEMENT Acute surgical intervention is warranted in patients with life-threatening mass effect or hydrocephalus secondary to acute hemorrhage. Early surgery has the advantage of rapid hematoma evacuation and decompression of otherwise healthy brain tissue. Emergent hematoma evacuation with delayed AVM resection is recommended for patients in neurologic extremis or decreased consciousness or for those with temporal or posterior fossa hematomas larger than 30 cm3 or hemispheric hematomas larger than 60 cm3. Simultaneous hematoma evacuation and AVM resection are reserved for small, superficial, lowgrade lesions that are easily accessible during surgery. In selected patients with Spetzler-Martin grade I or II iAVMs, aggressive and early surgical decompression and AVM excision result in shorter hospital stays, expedited rehabilitation, and favorable functional outcomes.109,110 Early endovascular embolization can be considered in cases where peri- or intranidal aneurysms are identified as the clear source of rupture. Targeted occlusion of these aneurysms may lower the risk of early rerupture associated with flow-related aneurysms.111 Additionally, flow reduction with partial or nearcomplete embolization may decrease the risk of hemorrhage before delayed definitive treatment. DELAYED SURGICAL MANAGEMENT For clinically stable patients, intentionally delayed intervention is recommended to minimize surgical risks and neurologic morbidity. Acute iAVM rupture frequently results in space-occupying parenchymal clots, cerebral edema, and vascular dysautoregulation that is most severe during the first few days after the hemorrhagic event. Compression of the AVM by the hematoma and resulting edema may mask the lesion on noninvasive imaging or DSA. Intraoperatively, brain swelling can limit visualization, distort normal anatomic landmarks, and necessitate increased retraction and manipulation of edematous, friable brain tissue.112 In contrast, delayed treatment allows time for edema to resolve and clots to liquefy. The resulting hematoma cavity provides a clear dissection plan between the nidus and the adjacent parenchyma, which is especially helpful for lesions that are deep or in eloquent territory.113,114

Staged surgery is associated with favorable outcomes and high obliteration rates. In a study of acute (< 48 hours) and subacute (5–28 days) surgical intervention, Barone et al. reported better outcomes in patients who underwent delayed surgery (good outcome in 93% of cases) than in those who underwent early surgery (good outcome in 52%). These data are biased, however, by the presence of elevated ICPs that led to emergent intervention in the early-surgery group.114 There are limited data to suggest how long a patient should wait before definitive treatment. Though rerupture rates are elevated in the first year after hemorrhage, the risk of interval hemorrhage appears to be lower in the acute and early subacute phases. Caplan et al. described a cumulative rehemorrhage risk of 0.9% at 2 weeks, 1.3% at 4 weeks, 3.2% at 12 weeks, and 5.5% at 52 weeks after the initial hemorrhage.24 Beecher et al. further reported that treatment delay of at least 4 weeks put patients at < 1% risk of interval rehemorrhage.115 Delayed repeat DSA can also uncover lesions previously masked by hematoma.116 Given the benefits of delayed intervention, conservative management is recommended for up to 3 months to allow patients to recover from the initial hemorrhage. After this period, patients should undergo repeat imaging with MRI and MRA to reassess the condition of the iAVM and the adjacent brain and repeat DSA to look for any interval changes in the AVM angioarchitecture and hemodynamics. Combined, these imaging modalities provide critical information needed to regrade the AVM and make further treatment plans. As with unruptured iAVMs, the treatment options for ruptured iAVMs include microsurgery, SRS, embolization, or multimodal therapy. Indications and risks for each option are similar to those discussed previously (Fig. 11.1), with the exception of the rerupture risk, which may be higher than that of unruptured iAVMs, especially in the first year and in the presence of flow-related aneurysms.16,21,22,25 Further investigations with prospective studies and randomized controlled trials are needed to better understand these risk profiles and individualize treatment of iAVMs.

Conclusion Intracranial AVMs are a complex pathology and pose several therapeutic challenges in both the acute and

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elective settings. Patients should be informed of the natural history risks of their individual iAVM and the relative risks of each treatment option. The SpetzlerMartin grading scale is critical for stratifying surgical risks and can be used to guide clinical management. Though treatment of unruptured iAVMs is controversial, surgical removal and SRS may confer symptomatic benefits while reducing future rupture risks. On the other hand, ruptured iAVMs warrant intervention due to the risk of rehemorrhage. Early surgery may be necessary in cases of life-threatening mass effect; however, delayed intervention is preferred in most cases to minimize surgical risk and neurologic morbidity. REFERENCES 1. Hernesniemi JA, Dashti R, Juvela S, Väärt K, Niemelä M, Laakso A. Natural history of brain arteriovenous malformations: a long-term follow-up study of risk of hemorrhage in 238 patients. Neurosurgery. 2008;63(5):823–831. https://doi. org/10.1227/01.neu.0000330401.82582.5e. 2. Choi JH, Mohr JP. Brain arteriovenous malformations in adults. Lancet Neurol. 2005;4(5):299–308. https://doi. org/10.1016/s1474-4422(05)70073-9. 3. Friedlander RM. Clinical practice. Arteriovenous malformations of the brain. N Engl J Med. 2007;356:2704– 2712. https://doi.org/10.1056/nejmcp067192. 4. Perret G, Nishoioka H. Report on the cooperative study of intracranial aneurysms and subarachnoid hemorrhage. Section VI. Arteriovenous malformations. An analysis of 545 cases of cranio-cerebral arteriovenous malformations and fistulae reported to the cooperative study. J Neurosurg. 1966;25(4):467–490. https://doi.org/10.3171/ jns.1966.25.4.0467. 5. Gross CR, Kase CS, Mohr JP, Cunningham SC, Baker WE. Stroke in South Alabama: incidence and diagnostic features-a population based study. Stroke. 1984;15(2):249–255. https://doi.org/10.1161/01.str.15.2.249. 6. Weber F, Knopf H. Incidental findings in magnetic resonance imaging of the brains of healthy young men. J Neurol Sci. 2006;240(1-2):81–84. https://doi.org/10.1016/j. jns.2005.09.008. 7. González-Duarte A, Cantú C, Ruíz-Sandoval JL, Barinagarrementeria F. Recurrent primary cerebral hemorrhage: frequency, mechanisms, and prognosis. Stroke. 1998;29(9):1802–1805. https://doi.org/10.1161/01. str.29.9.1802. 8. Toffol GJ, Biller J, Adams HP Jr. Nontraumatic intracerebral hemorrhage in young adults. Arch Neurol. 1987;44(5):483–485. https://doi.org/10.1001/ archneur.1987.00520170013014. 9. Stapf C, Mast H, Sciacca RR, et al. The New York Islands AVM study: design, study progress, and initial results. Stroke. 2003;34(5):e29–e33. https://doi.org/10.1161/01. str.0000068784.36838.19. 10. ApSimon HT, Reef H, Phadke RV, Popovic EA. A populationbased study of brain arteriovenous malformation: long-term treatment outcomes. Stroke. 2002;33(12):2794–2800. https:// doi.org/10.1161/01.str.0000043674.99741.9b.

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57. Monteiro JMP, Rosas Mj, Correia Ap, Vaz Ar. Migraine and intracranial vascular malformations. Headache. 1993;33(10):563–565. https://doi.org/10.1111/j.1526-4610. 1993.hed3310563.x. 58. Martin NA, Wilson CB. Medial occipital arteriovenous malformations. Surgical treatment. J Neurosurg. 1982;56(6):798–802. https://doi.org/10.3171/jns.1982.56.6.0798. 59. Kurita H, Kawamoto S, Suzuki I, et al. Control of epilepsy associated with cerebral arteriovenous malformations after radiosurgery. J Neurol Neurosurg Psychiatry. 1998;65(5):648–655. https://doi.org/10.1136/jnnp.65.5.648. 60. Derdeyn CP, Zipfel GJ, Albuquerque FC, et al. Management of brain arteriovenous malformations: a scientific statement for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke. 2017;48(8):e200–e224. https://doi.org/10.1161/str.0000000000000134. 61. Langer DJ, Lasner TM, Hurst RW, Flamm ES, Zager EL, King JT. Hypertension, small size, and deep venous drainage are associated with risk of hemorrhagic presentation of cerebral arteriovenous malformations. Neurosurgery. 1998;42(3):481–489. https://doi.org/10.1097/00006123199803000-00008. 62. Spetzler RF, Hargraves RW, McCormick PW, Zabramski JM, Flom RA, Zimmerman RS. Relationship of perfusion pressure and size to risk of hemorrhage from arteriovenous malformations. J Neurosurg. 1992;76(6):918–923. https://doi. org/10.3171/jns.1992.76.6.0918. 63. van Beijnum J, Lovelock CE, Cordonnier C, Rothwell PM, Klijn CJM, Al-Shahi Salman R. Outcome after spontaneous and arteriovenous malformation-related intracerebral haemorrhage: population-based studies. Brain. 2009;132(2):537–543. https://doi.org/10.1093/brain/awn318. 64. Abla AA, Nelson J, Rutledge WC, Young WL, Kim H, Lawton MT. The natural history of AVM hemorrhage in the posterior fossa: comparison of hematoma volumes and neurological outcomes in patients with ruptured infra- and supratentorial AVMs. Neurosurg Focus. 2014;37(3):E6. https:// doi.org/10.3171/2014.7.focus14211. 65. Hartmann A, Mast H, Mohr JP, et al. Morbidity of intracranial hemorrhage in patients with cerebral arteriovenous malformation. Stroke. 1998;29(5):931–934. https://doi. org/10.1161/01.str.29.5.931. 66. Pollock BE, Flickinger JC, Lunsford LD, Bissonette DJ, Kondziolka D. Hemorrhage risk after stereotactic radiosurgery of cerebral arteriovenous malformations. Neurosurgery. 1996;38(4):652–661. 67. Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, nonblinded, randomised trial. Lancet. 2014;383(9917):614–621. https://doi.org/10.1016/s0140-6736(13)62302-8. 68. Mohr JP, Overbey JR, Hartmann A, et al. Medical management with interventional therapy versus medical management alone for unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre, non-blinded, randomised controlled trial. Lancet Neurol. 2020;19(7):573–581. https:// doi.org/10.1016/s1474-4422(20)30181-2. 69. Magro E, Gentric JC, Darsaut TE, Ziegler D, Bojanowski MW, Raymond J. Responses to ARUBA: a systematic review and critical analysis for the design of future arteriovenous malformation trials. J Neurosurg. 2017;126(2):486–494. https://doi.org/10.3171/2015.6.jns15619.

125 70. Feghali J, Huang J. Updates in arteriovenous malformation management: the post-ARUBA era. Stroke Vasc Neurol. 2019;5(1):34–39. https://doi.org/10.1136/ svn-2019-000248. 71. Wong J, Slomovic A, Ibrahim G, Radovanovic I, Tymianski M. Microsurgery for ARUBA trial (A Randomized Trial of Unruptured Brain Arteriovenous Malformation)– eligible unruptured brain arteriovenous malformations. Stroke. 2017;48(1):136–144. https://doi.org/10.1161/ strokeaha.116.014660. 72. Ding D, Starke RM, Kano H, et al. Radiosurgery for cerebral arteriovenous malformations in a randomized trial of unruptured brain arteriovenous malformations (ARUBA)-eligible patients: a multicenter study. Stroke. 2016;47(2):342–349. https://doi.org/10.1161/strokeaha.115.011400. 73. Rutledge WC, Abla AA, Nelson J, Halbach VV, Kim H, Lawton MT. Treatment and outcomes of ARUBA-eligible patients with unruptured brain arteriovenous malformations at a single institution. Neurosurg Focus. 2014;37(3):E8. https://doi. org/10.3171/2014.7.focus14242. 74. Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg. 1986;65(4): 476–483. https://doi.org/10.3171/jns.1986.65.4.0476. 75. Lawton MT, Rutledge WC, Kim H, et al. Brain arteriovenous malformations. Nat Rev Dis Prim. 2015;1:15008. https://doi. org/10.1038/nrdp.2015.8. 76. Abla AA, Nelson J, Kim H, Hess CP, Tihan T, Lawton MT. Silent arteriovenous malformation hemorrhage and the recognition of “unruptured” arteriovenous malformation patients who benefit from surgical intervention. Neurosurgery. 2015;76(5):592–600. https://doi.org/10.1227/ neu.0000000000000686. 77. Olivecrona H, Ladenheim J. Congenital Arteriovenous Aneurysms of the Carotid and Vertebral Arterial Systems. Berlin: Springer-Verlag; 1957. 78. Pradilla G, Coon AL, Huang J, Tamargo RJ. Surgical treatment of cranial arteriovenous malformations and dural arteriovenous fistulas. Neurosurg Clin N Am. 2012;23(1): 105–122. https://doi.org/10.1016/j.nec.2011.10.002. 79. Spetzler RF, Ponce FA. A 3-tier classification of cerebral arteriovenous malformations. clinical article. J Neurosurg. 2011;114(3):842–849. https://doi. org/10.3171/2010.8.jns10663. 80. Lawton MF, UCSF Brain Arteriovenous Malformation Study Project. Spetzler-Martin Grade III arteriovenous malformations: surgical results and a modification of the grading scale. Neurosurgery. 2003;52(4):740–749. https://doi. org/10.1227/01.neu.0000053220.02268.9c. 81. Karlsson B, Lindquist C, Steiner L. Prediction of obliteration after gamma knife surgery for cerebral arteriovenous malformations. Neurosurgery. 1997;40(3):425–431. https:// doi.org/10.1097/00006123-199703000-00001. 82. Shin M, Maruyama K, Kurita H, et al. Analysis of nidus obliteration rates after gamma knife surgery for arteriovenous malformations based on long-term follow-up data: The University of Tokyo experience. J Neurosurg. 2004;101(1):18–24. https://doi.org/10.3171/jns.2004.101.1.0018. 83. Starke RM, Komotar RJ, Hwang BY, et al. A comprehensive review of radiosurgery for cerebral arteriovenous malformations: outcomes, predictive factors, and grading scales. Stereotact Funct Neurosurg. 2008;86(3):191–199. https://doi.org/10.1159/000126945.

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84. Kano H, Lunsford LD, Flickinger JC, et al. Stereotactic radiosurgery for arteriovenous malformations, part 1: management of Spetzler-Martin Grade I and II arteriovenous malformations. J Neurosurg. 2012;116(1):11–20. https://doi. org/10.3171/2011.9.jns101740. 85. Flickinger JC, Kondziolka D, Maitz AH, Lunsford LD. An analysis of the dose-response for arteriovenous malformation radiosurgery and other factors affecting obliteration. Radiother Oncol. 2002;63(3):347–354. https://doi.org/10.1016/ s0167-8140(02)00103-2. 86. Liscák R, Vladyka V, Simonová G, et al. Arteriovenous malformations after Leksell gamma knife radiosurgery: rate of obliteration and complications. Neurosurgery. 2007;60:1005– 1016. https://doi.org/10.1227/01.neu.0000255474.60505.4a. 87. Pollock BE, Lunsford LD, Kondziolka D, Maitz A, Flickinger JC. Patient outcomes after stereotactic radiosurgery for “operable” arteriovenous malformations. Neurosurgery. 1994;35(1):1–8. https://doi.org/10.1227/00006123-199407000-00001. 88. Friedman WA, Bova FJ, Bollampally S, Bradshaw P. Analysis of factors predictive of success or complications in arteriovenous malformation radiosurgery. Neurosurgery. 2003;52(2):296– 308. https://doi.org/10.1227/01.neu.0000043692.51385.91. 89. Flickinger JC, Kondziolka D, Maitz AH, Lunsford LD. Analysis of neurological sequelae from radiosurgery of arteriovenous malformations: how location affects outcome. Int J Radiat Oncol Biol Phys. 1998;40(2):273–278. https://doi. org/10.1016/s0360-3016(97)00718-9. 90. Andrade-Souza YM, Ramani M, Scora D, Tsao MN, TerBrugge K, Schwartz ML. Radiosurgical treatment for rolandic arteriovenous malformations. J Neurosurg. 2006;105(5):689– 697. https://doi.org/10.3171/jns.2006.105.5.689. 91. Celix JM, Douglas JG, Haynor D, Goodkin R. Thrombosis and hemorrhage in the acute period following gamma knife surgery for arteriovenous malformation. case report. J Neurosurg. 2009;111(1):124–131. https://doi. org/10.3171/2009.1.jns08784. 92. Valavanis A, Pangalu A, Tanaka M. Endovascular treatment of cerebral arteriovenous malformations with emphasis on the curative role of embolisation. Interv Neuroradiol. 2005;11(Suppl 1):37–43. https://doi.org/10.1177/15910199 050110s107. 93. Söderman M, Andersson T, Karlsson B, Wallace MC, Edner G. Management of patients with brain arteriovenous malformations. Eur J Radiol. 2003;46(3):195–205. https://doi. org/10.1016/s0720-048x(03)00091-3. 94. Weber W, Kis B, Siekmann R, Kuehne D. Endovascular treatment of intracranial arteriovenous malformations with onyx: technical aspects. AJNR Am J Neuroradiol. 2007;28(2):371–377. 95. Wu EM, El Ahmadieh TY, McDougall CM, et al. Embolization of brain arteriovenous malformations with intent to cure: a systematic review. J Neurosurg. 2019;132(2):388–399. https:// doi.org/10.3171/2018.10.jns181791. 96. Ledezma CJ, Hoh BL, Carter BS, Pryor JC, Putman CM, Ogilvy CS. Complications of cerebral arteriovenous malformation embolization: multivariate analysis of predictive factors. Neurosurgery. 2006;58(4):602–611. https://doi. org/10.1227/01.neu.0000204103.91793.77. 97. Sato K, Matsumoto Y, Tominaga T, Satow T, Iihara K, Sakai N. Japanese Registry of Neuroendovascular Therapy Investigators. Complications of endovascular treatments for brain arteriovenous malformations: a nationwide surveillance.

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AJNR Am J Neuroradiol. 2020;41(4):669–675. https://doi. org/10.3174/ajnr.a6470. Le Feuvre D, Taylor A. Target embolization of AVMs: identification of sites and results of treatment. Interv Neuroradiol. 2007;13(4):389–394. https://doi.org/10. 1177/159101990701300411. Loh Y, Duckwiler GR. A prospective, multicenter, randomized trial of the onyx liquid embolic system and N-butyl cyanoacrylate embolization of cerebral arteriovenous malformations. clinical article. J Neurosurg. 2010;113(4):733– 741. https://doi.org/10.3171/2010.3.jns09370. Ellis JA, Lavine SD. Role of embolization for cerebral arteriovenous malformations. Methodist Debakey Cardiovasc J. 2014;10(4):234–239. 10.14797/mdcj-10-4-234. Crowley RW, Ducruet AF, McDougall CG, Albuquerque FC. Endovascular advances for brain arteriovenous malformations. Neurosurgery. 2014;74(suppl_1):S74–S82. https://doi.org/10.1227/neu.0000000000000176. Godoy DA, Núñez-Patiño RA, Zorrilla-Vaca A, Ziai WC, Hemphill JC. Intracranial hypertension after spontaneous intracerebral hemorrhage: a systematic review and metaanalysis of prevalence and mortality rate. Neurocrit Care. 2019;31(1):176–187. https://doi.org/10.1007/ s12028-018-0658-x. Gilmore EJ, Maciel CB, Hirsch LJ, Sheth KN. Review of the utility of prophylactic anticonvulsant use in critically ill patients with intracerebral hemorrhage. Stroke. 2016;47(10):2666– 2672. https://doi.org/10.1161/strokeaha.116.012410. Sykora M, Steinmacher S, Steiner T, Poli S, Diedler J. Association of intracranial pressure with outcome in comatose patients with intracerebral hemorrhage. J Neurol Sci. 2014;342(1):141–145. https://doi.org/10.1016/j.jns.2014.05.012. Bhattathiri PS, Gregson B, Prasad KS, Mendelow AD, STICH Investigators. Intraventricular hemorrhage and hydrocephalus after spontaneous intracerebral hemorrhage: results from the STICH trial. Acta Neurochir Suppl. 2006;96:65–68. https:// doi.org/10.1007/3-211-30714-1_16. Brazzelli M, Sandercock PA, Chappell FM, et al. Magnetic resonance imaging versus computed tomography for detection of acute vascular lesions in patients presenting with stroke symptoms. Cochrane Database Syst Rev. 2009;(4). https://doi. org/10.1002/14651858.cd007424.pub2, CD007424. Josephson CB, White PM, Krishan A, Al-Shahi Salman R. Computed tomography angiography or magnetic resonance angiography for detection of intracranial vascular malformations in patients with intracerebral haemorrhage. Cochrane Database Syst Rev. 2014;(9). https://doi. org/10.1002/14651858.cd007424.pub2, CD009372. Gailloud P, Oishi S, Carpenter J, Murphy KJ. Threedimensional digital angiography: new tool for simultaneous three-dimensional rendering of vascular and osseous information during rotational angiography. AJNR Am J Neuroradiol. 2004;25(4):571–573. Kuhmonen J, Piippo A, Väärt K, et al. Early surgery for ruptured cerebral arteriovenous malformations. Acta Neurochir Suppl. 2005;94:111–114. https://doi. org/10.1007/3-211-27911-3_17. Pavesi G, Rustemi O, Berlucchi S, Frigo AC, Gerunda V, Scienza R. Acute surgical removal of low-grade (SpetzlerMartin I-II) bleeding arteriovenous malformations. Surg Neurol. 2009;72(6):662–667. https://doi.org/10.1016/j. surneu.2009.03.035.

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111. van Rooij WJ, Jacobs S, Sluzewski M, Beute GN, van der Pol B. Endovascular treatment of ruptured brain AVMs in the acute phase of hemorrhage. AJNR Am J Neuroradiol. 2012;33(6):1162–1166. https://doi.org/10.3174/ajnr.a2995. 112. Aoun SG, Bendok BR, Batjer HH. Acute management of ruptured arteriovenous malformations and dural arteriovenous fistulas. Neurosurg Clin N Am. 2012;23(1):87– 103. https://doi.org/10.1016/j.nec.2011.09.013. 113. Ashley WW, Charbel FT, Amin-Hanjani S. Surgical management of acute intracranial hemorrhage, surgical aneurysmal and arteriovenous malformation ablation, and other surgical principles. Neurol Clin. 2008;26(4):987–1005, ix https://doi.org/10.1016/j.ncl.2008.06.006.

127 114. Barone DG, Marcus HJ, Guilfoyle MR, et al. Clinical experience and results of microsurgical resection of arteriovenous malformation in the presence of space-occupying intracerebral hematoma. Neurosurgery. 2017;81(1):75–86. https://doi. org/10.1093/neuros/nyx003. 115. Beecher JS, Lyon K, Ban VS, et al. Delayed treatment of ruptured brain AVMs: is it ok to wait? J Neurosurg. 2018;128(4):999–1005. https://doi.org/10.3171/2017.1.jns16745. 116. Hino A, Fujimoto M, Yamaki T, Iwamoto Y, Katsumori T. Value of repeat angiography in patients with spontaneous subcortical hemorrhage. Stroke. 1998;29(12):2517–2521. https://doi.org/10.1161/01.str.29.12.2517.

Chapter 12

Decision Analysis for AVM-Associated Aneurysms Muhammad Waqas, Elad I. Levy, and Adnan H. Siddiqui

Chapter Outline Introduction Classification Natural History Pathophysiology Pseudoaneurysms Flow-Related and Intranidal Aneurysms and Risk of Hemorrhage Treatment Strategies Conclusion

Introduction Intracranial hemorrhage is the major cause of morbidity and mortality associated with intracranial arteriovenous malformations (iAVMs). The risk of hemorrhage depends on the iAVM morphology and the hemodynamics of any associated aneurysm as well as several other variables. Identifying and mitigating these risk factors is fundamental to the management of iAVMs. Aneurysms associated with iAVMs constitute a heterogeneous group of lesions, with each type having a different pathophysiology and risk profile. Hemorrhagic presentation, curability of the iAVM, accessibility and proximity of the aneurysm to the iAVM, and the potential rerupture risk are key factors to consider in the decision-making process.

Classification Standardization of nomenclature is important for the interpretation of findings of related research, communication, and the development of decision algorithms. Unfortunately, none of the classifications of iAVM-associated aneurysms have received universal 128

acceptance. The relationship of the aneurysm to iAVM flow is crucial to understanding the classification of iAVM-associated aneurysms, because aneurysms that are not located on the feeding arteries or major vessels giving rise to the feeding arteries are considered independent of or unrelated to the AVM. Therefore intracranial aneurysms in patients with iAVMs can be classified into two general categories: flow-related aneurysms and aneurysms that are unrelated to or remote from the iAVM nidus. This classification was proposed by Redekop et al. in 1987 and has been the most popular.1 Based on the topographic location and rupture risk, flow-related aneurysms are further classified into proximal (main intracranial vessel up to its primary bifurcation—i.e., internal carotid artery [ICA], basilar artery, M1 segment of the middle cerebral artery [MCA], or A1 segment of the anterior cerebral artery [ACA]—circle of Willis, including posterior communicating and anterior communicating arteries) or distal (located at midpoint or distally on a direct cerebral AVM feeder or distally to the proximal vessels). Intranidal aneurysms are considered venous. There is a controversy regarding postnidal venous aneurysms, and this term can actually be considered a misnomer, because these lesions do not have the wall structure of an arterial aneurysm and are better described as venous varices.2,3 Consequently, postnidal venous aneurysms are excluded from most classification systems. A schematic illustration of various types of these aneurysms is provided in Fig. 12.1.

Natural History Understanding the natural history of iAVMassociated aneurysms is key to decision-making

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with respect to their management. The natural history of iAVM-associated aneurysms is based on the location and hemodynamic features of the aneurysm. Brown et al. reported hemorrhage rates as high as 7% per year at 5 years after diagnosis for patients with coexisting iAVMs and aneurysms, compared with a hemorrhage rate of 1.7% per year for patients with iAVMs alone.4 Adequate confirmation of the hemorrhage source was not possible in most patients with iAVMs and aneurysms, but those authors believed that the higher hemorrhage risk reflected rupture of coexisting aneurysms.4 More recently, the investigators of A Randomised Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) reported a 16% incidence of associated aneurysms in the study cohort, with no correlation to hemorrhage at presentation or at follow-up completed on their initial data analysis.5 In a large case series (526 cases) presented by Hung et al., 69 iAVMs were reported to have flowrelated aneurysms.6 Patients with AVM-associated flow-related aneurysms were older in age (P = .005).6 Aneurysms were also more commonly associated with AVMs involving the cerebellar vermis and cerebellar hemispheres (P = .023 and .001, respectively). AVM patients presenting with subarachnoid hemorrhage

Pearls • Aneurysms associated with iAVMs constitute a heterogeneous group with different risk profiles that must be taken into account when considering management options. • In cases of hemorrhagic presentation, determining the source of hemorrhage (i.e., aneurysm vs iAVM) is crucial. • Distal flow-related aneurysms and intranidal aneurysms increase the risk of hemorrhagic presentation. • Curability of the iAVM and accessibility and proximity of the aneurysm to the iAVM are critical to the decision-making process. • Prenidal and distal aneurysms have been reported to involute after elimination of the iAVM nidus.

were more likely to have an associated aneurysm (P < .001).6 In that study most aneurysms were untreated (69.5%), and only 8 (9.8%) presented with rupture.6 At follow-up (mean, 5.3 years), patients with flow-related aneurysms were less likely to develop seizures (P = .004). The annual risk of AVM

Fig. 12.1 Schematic illustration of various types of iAVM-associated aneurysms. (A) An aneurysm unrelated to the nidus located contralateral to the side of the nidus. (B) A proximal flow-related aneurysm on a main intracranial vessel up to its primary bifurcation (i.e., internal carotid artery, basilar artery, M1 segment of the middle cerebral artery, A1 segment of the anterior cerebral artery) or the circle of Willis, including posterior and anterior communicating arteries. (C) A distal flow-related aneurysm located on a feeding artery supplying the AVM nidus. (D) An aneurysm located within the nidus of the AVM. (© University at Buffalo Neurosurgery, Inc.; April 2020. With permission.)

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hemorrhage was 1.33% for AVM-only patients and 1.05% for patients with iAVMs and flow-related aneurysms (P = .248).6 The investigators of several studies have tried to identify clinically significant risk factors associated with increased risk of hemorrhage of iAVMs. Marks et al. identified intranidal aneurysms as one of three angiographic characteristics that correlated positively with iAVM hemorrhage. Other associated factors included central venous drainage and periventricular or intraventricular location of the AVM. A subsequent study by the same group demonstrated a history of hemorrhage in all patients with an intranidal aneurysm diagnosed by catheter angiography.7 The results reported by Redekop et al. supported these findings, as hemorrhagic presentation was significantly more common in patients with AVM-associated intranidal aneurysms (72%) compared to those with aneurysms alone.1 The risk of rupture in patients with intranidal aneurysms in their study was 9.8% per year, which is considerably higher than the generally reported peryear risk rate of 2%–4% in the overall population of patients with iAVMs. Other risk factors for iAVM rupture include hemorrhagic presentation, prenidal aneurysms, and deep venous drainage.8

Pathophysiology The pathophysiology of AVM-associated intracranial aneurysms is poorly understood. Three main theories have been proposed to explain the association between AVMs and aneurysms. The coincidental theory was initially proposed by Boyd-Wilson and assumed that the coexistence of those two vascular lesions was an incidental finding.9 The congenital theory proposed that a common, genetically determined etiology exists for both iAVMs and intracranial aneurysms.10 The third and most popular theory is termed the “hemodynamic theory” and was proposed by McKissock and Paterson.11 The hemodynamic theory suggests that the increased blood flow due to the presence of an iAVM might result in abnormal stresses on major feeding vessels, consequently predisposing these arteries to aneurysm formation. It is important to emphasize that these theories are not mutually exclusive, and the development of the aneurysms may result from an interplay of multiple factors.

Pseudoaneurysms Pseudoaneurysms are a subcategory of thin-walled aneurysm-like dilatations that result from the rupture of small perforating arteries supplying iAVMs. Pseudoaneurysms communicate with the vessel lumen and thus may show significant growth in size on subsequent imaging. Pseudoaneurysms may be identified in close proximity to the nidus and tend to have an irregular shape close to the ependymal surface of the iAVM. Interval growth on serial neuroimaging is highly suggestive of a pseudoaneurysm.3

Flow-Related and Intranidal Aneurysms and Risk of Hemorrhage Flow-related and intranidal aneurysms are associated with an increased hemorrhagic risk. In the study by Redekop et al., 97 iAVMs (15.3% of their iAVM study population) had at least one associated aneurysm.1 Most (73.2%) of these aneurysms were flow related or intranidal (36.1%). Patients with intranidal aneurysms were twice as likely to present with hemorrhage as those without intranidal aneurysms (36%) or the subgroup with flow-related or unrelated aneurysms (40%).1 Of the cases in which a source of hemorrhage could be determined, flow-related aneurysms were the culprit in 41.4%. The annual hemorrhage risk for intranidal aneurysms was 9.8% compared to 5.3% for flow-related aneurysms in the small subgroup of patients treated conservatively. The study had 57 patient-years of follow-up, with no incidence of flow-related aneurysm rupture. In another study of iAVM-associated aneurysms, 62% of the 39 included patients presented with hemorrhage.12 Hemorrhage was due to the aneurysm in 46% of the cases and due to the AVM in 33% of the cases. In a retrospective study of 22 patients with an iAVM and at least one intracranial aneurysm, 9 patients (41%) presented with hemorrhage.13 Eleven patients harbored multiple aneurysms. Of these aneurysms, 82% were flow related (50% proximal, 32% distal, as defined earlier). In seven of the nine patients presenting with hemorrhage, the source was the aneurysm, and in all of these cases the aneurysms were located at distal sites on major feeding vessels. There was no incidence of rupture of an unrelated aneurysm.13 Other authors have also attributed higher risk of rupture to distal flow-related aneurysms.1,8,14

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Intranidal aneurysms are strongly associated with hemorrhagic presentation. In a study of 125 patients, 15 patients were found to have an intranidal aneurysm, with all of them having a history of hemorrhage.15 On the basis of these findings, those authors suggested a potential benefit of treatment targeted at the intracranial aneurysms and feeding arteries. This approach may reduce the risk of hemorrhage during the latency period after stereotactic radiosurgery (SRS).

Treatment Strategies The goal of intervention for iAVMs is a complete removal of the nidus, as documented by postprocedure ­ angiography. For patients with AVM-associated aneurysms, several factors should be taken into consideration before a treatment recommendation is made. Unfortunately, there is no consensus in the literature

about the best management strategy for all types of iAVM-associated aneurysms. Most evidence is anecdotal or consists of institution-specific case series with treatment algorithms that cannot be reliably generalized. Nevertheless, a general principle can be proposed for the treatment of aneurysms associated with iAVMs (Fig. 12.2). There is consensus on the management of unrelated or remote aneurysms. These lesions should be approached in the same manner as any primary intracranial aneurysm. The rupture risk for unrelated or remote aneurysms is similar to that for cases in which the aneurysm is the sole pathology. In other words, the presence of an iAVM does not increase the risk of ­ rupture of an unrelated or remote aneurysm. However, the management of unruptured or ruptured flow-related aneurysms and intranidal aneurysms is more nuanced and depends on the clinical presentation.

Fig. 12.2 Decision algorithm for the treatment iAVM-associated aneurysms. IA, Intracranial aneurysm.

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PATIENTS PRESENTING WITH UNRUPTURED IAVMS The treatment of aneurysms associated with unruptured iAVMs depends on the topographic location of the aneurysm and whether the AVM is amenable to cure. According to the literature, distal flow-related aneurysms regress if the high-flow state is eliminated with resection of the AVM. In one study, four of five distal flow-related aneurysms disappeared after complete excision of the AVM, and only one aneurysm (20%) was unchanged.1 In contrast, among the 23 proximal aneurysms, only 1 aneurysm regressed. Eighteen (78.3%) were unchanged and four (17.4%) were smaller.1 Because distal flow-related arterial aneurysms more often resolve or decrease in size after effective iAVM

A

treatment compared with proximal aneurysms, conservative management of small distal aneurysms may be indicated if the AVM is treated. The same principle does not apply to cases of proximal aneurysms, in which treatment of the aneurysm may be indicated regardless of the fate of the AVM. Proximal flow-related aneurysms should be treated with either surgical or endovascular modalities, depending on their location and morphology and operator experience.16 The risk of aneurysm recurrence after endovascular treatment without obliteration of the AVM nidus is high. Fig. 12.3 illustrates the case of a young woman known to have a Spetzler-Martin grade VI iAVM with a distal flow-related aneurysm that showed growth on

B

D

C

E

Fig. 12.3 Case of a Spetzler-Martin grade VI AVM with a distal flow-related aneurysm that showed growth on serial neuroimaging. (A) T2-weighted axial MR image demonstrating left thalamic AVM with venous ectasia (arrow). (B and C) Left vertebral artery injection, anteroposterior (B) and lateral (C), views demonstrating the presence of a distal flow-related aneurysm (arrow in each image). (D and E) Postembolization left vertebral artery injection, lateral (D) and anteroposterior (E), views showing obliteration of the distal flow-related aneurysm (arrow in each image).

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A

B

C

Fig. 12.4 Case of a ruptured AVM-associated aneurysm in a 50-year-old man who presented with the sudden onset of severe headache. (A) Computed tomography scan demonstrating subarachnoid hemorrhage involving the basal cisterns and sylvian fissure. (B) Diagnostic angiogram showing a distal flow-related aneurysm. Given the pattern of the subarachnoid hemorrhage, the source of bleeding was thought to be the aneurysm. The aneurysm was embolized with Onyx 34 within 24 hours of the patient’s presentation (C, postembolization left vertebral artery injection), and the patient was referred for Gamma Knife radiosurgery for treatment of the AVM.

serial neuroimaging. The AVM was not deemed curable. To reduce the rupture risk, the aneurysm was selectively catheterized and embolized. PATIENTS PRESENTING WITH HEMORRHAGE When patients present with hemorrhage, it is critical to determine the source of bleeding. Subarachnoid hemorrhage without intraparenchymal hemorrhage implicates a flow-related aneurysm as the likely source. In addition to the subarachnoid hemorrhage, aneurysmal hemorrhage may also have a focal intraparenchymal component. The epicenter of the hematoma may provide a clue as to the source. A computed tomography (CT) angiogram may show the presence of an aneurysm in relation to the hematoma. Diagnostic cerebral angiography remains the gold standard for the detection and rupture likelihood of a flow-related aneurysm. If the aneurysm is the likely source of bleeding, it should be treated as early as possible in accordance with treatment protocols for a ruptured arterial aneurysm. Pseudoaneurysms related to perforating arteries lack a true aneurysmal wall and therefore are highly likely to rerupture. If a pseudoaneurysm is identified as the source of bleeding, it should also be treated as early as possible. In these cases, the AVMs can be treated in a delayed fashion, allowing the patient time to recover from the initial hemorrhagic event. Pseudoaneurysms tend to have a dynamic course with a risk of expansion

or spontaneous regression in the acute phase. If a persistent pseudoaneurysm can be treated in the acute setting, AVM treatment can be postponed. Endovascular options are particularly useful when access to the vicinity of the pseudoaneurysm is safe.2 Fig. 12.4 shows the case of a ruptured distal flowrelated aneurysm. This 50-year-old man presented with the sudden onset of severe headache. A CT scan demonstrated subarachnoid hemorrhage involving the basal cisterns and sylvian fissure (Fig. 12.4A). Diagnostic angiography showed a distal flow-related aneurysm on the inferior division of the right superior cerebellar artery (Fig. 12.4B). Given the pattern of subarachnoid hemorrhage, the aneurysm was considered to be the source of the hemorrhage. The aneurysm was embolized with Onyx 34 (Medtronic, Minneapolis, MN) within 24 hours of the patient’s presentation (Fig. 12.4C, postembolization left vertebral artery injection), and the patient was referred for Gamma Knife radiosurgery for treatment of the AVM.

Conclusion Intracranial AVMs are associated with an increased incidence of intracranial aneurysms. The risk of hemorrhage depends on the morphology and hemodynamics of the aneurysm and clinical factors.

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Each type of aneurysm associated with an iAVM has a different pathophysiology and risk profile. Hemorrhagic presentation, curability of the AVM, accessibility and proximity of the aneurysm to the AVM, and the potential rupture risk are critical to the decision-making process. REFERENCES 1. Redekop G, TerBrugge K, Montanera W, et al. Arterial aneurysms associated with cerebral arteriovenous malformations: classification, incidence, and risk of hemorrhage. J Neurosurg. 1998;89(4):539–546. https://doi. org/10.3171/jns.1998.89.4.0539. 2. Rammos SK, Gardenghi B, Bortolotti C, et al. Aneurysms associated with brain arteriovenous malformations. AJNR Am J Neuroradiol. 2016;37(11):1966–1971. https://doi.org/10.3174/ ajnr.A4869. 3. Gardenghi B, Bortolotti C, Lanzino G. Aneurysms associated with arteriovenous malformations. Contemp Neurosurg. 2014;36(22):1–5. https://doi.org/10.1097/01. CNE.0000459456.68574.d9. 4. Brown RD Jr, Wiebers DO, Forbes GS. Unruptured intracranial aneurysms and arteriovenous malformations: frequency of intracranial hemorrhage and relationship of lesions. J Neurosurg. 1990;73(6):859–863. https://doi.org/10.3171/ jns.1990.73.6.0859. 5. Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, nonblinded, randomised trial. Lancet. 2014;383(9917):614–621. https://doi.org/10.1016/S0140-6736(13)62302-8. 6. Hung AL, Yang W, Jiang B, et al. The effect of flow-related aneurysms on hemorrhagic risk of intracranial arteriovenous malformations. Neurosurgery. 2019;85(4):466–475. https:// doi.org/10.1093/neuros/nyy360. 7. Thompson RC, Steinberg GK, Levy RP, et al. The management of patients with arteriovenous malformations

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and associated intracranial aneurysms. Neurosurgery. 1998;43(2):202–211; discussion 211–212. https://doi. org/10.1097/00006123-199808000-00006. Flores BC, Klinger DR, Rickert KL, et al. Management of intracranial aneurysms associated with arteriovenous malformations. Neurosurg Focus. 2014;37(3):E11. https://doi. org/10.3171/2014.6.FOCUS14165. Boyd-Wilson JS. The association of cerebral angiomas with intracranial aneurysms. J Neurol Neurosurg Psychiatry. 1959;22:218–223. https://doi.org/10.1136/jnnp.22.3.218. Arieti S, Gray EW. Progressive multiform angiosis: association of a cerebral angioma, aneurysms and other vascular changes in the brain. Arch Neurol Psychiatry. 1944;51(2):182–189. https:// doi.org/10.1001/archneurpsyc.1944.02290260072009. McKissock W, Paterson JH. A clinical survey of intracranial angiomas with special reference to their mode of progression and surgical treatment: a report of 110 cases. Brain. 1956;79(2):233–266. https://doi.org/10.1093/brain/79.2.233. Cunha e Sa MJ, Stein BM, Solomon RA, et al. The treatment of associated intracranial aneurysms and arteriovenous malformations. J Neurosurg. 1992;77(6):853–859. https://doi. org/10.3171/jns.1992.77.6.0853. Batjer H, Suss RA, Samson D. Intracranial arteriovenous malformations associated with aneurysms. Neurosurgery. 1986;18(1):29–35. https://doi.org/10.1227/00006123-19860100000006. Kim EJ, Halim AX, Dowd CF, et al. The relationship of coexisting extranidal aneurysms to intracranial hemorrhage in patients harboring brain arteriovenous malformations. Neurosurgery. 2004;54(6):1349–1357; discussion 1357–1358. https://doi.org/10.1227/01.neu.0000124483.73001.12. Marks MP, Lane B, Steinberg GK, et al. Intranidal aneurysms in cerebral arteriovenous malformations: evaluation and endovascular treatment. Radiology. 1992;183(2):355–360. https://doi.org/10.1148/radiology.183.2.1561335. Platz J, Berkefeld J, Singer OC, et al. Frequency, risk of hemorrhage and treatment considerations for cerebral arteriovenous malformations with associated aneurysms. Acta Neurochir (Wien). 2014;156(11):2025–2034. https://doi. org/10.1007/s00701-014-2225-3.

Chapter 13

Surgical Principles: Techniques, Goals, and Outcomes Brian M. Howard and Daniel L. Barrow

Chapter Outline Introduction Preoperative Planning Principles of Surgery Conclusion

Introduction Intracranial arteriovenous malformations (iAVMs)— also known as brain or cerebral AVMs—are tangles of abnormal arteries and veins that reside within or on the surface of the brain. The specific cause of iAVMs is unknown. Long believed to be congenital lesions that develop during embryogenesis, iAVMs may rarely develop in some individuals after birth. Although they likely develop early in life and can cause symptoms at any time after development, iAVMs most often come to attention during the third, fourth, and fifth decades of life. While the specific subject to be detailed in this chapter is the surgical management of iAVMs, and other chapters address AVM pathology and imaging, as well as clinical decision-making regarding the treatment of iAVMs, some brief background is worth reviewing to serve as a backbone for the ensuing discussion. The blood vessels of the human circulatory system comprise five main types, three on the arterial side and two on the venous. The arterial system, which consists of arteries, arterioles, and capillaries in descending order of diameter, serves to deliver oxygen and nutrient-rich blood from the heart to the tissues of the body. The venous system collects “used blood” from the tissues to deliver it to the

heart, which sends it back to the lungs to receive fresh oxygen and subsequently pumps it back to the tissues via the arterial system. In normal circulation, oxygenated blood passes from arteries to arterioles to capillaries. Capillaries, which are the diameter of a single red blood cell, allow the passage of oxygen, fluid, and nutrients through their walls and into the tissues. The used blood then passes from venules to progressively larger veins, which ultimately flow into the vena cava, the main trunk of the venous tree that returns blood to the heart. On the arterial side, as the circulation transitions from larger to smaller branches, the pressure within the system is diffused, such that by the time blood reaches the venous side, the veins are under low pressure. The structure of arteries and veins is adapted to handle their particular hemodynamic pressures. Arteries have a thick muscular layer that can withstand high pressure; this muscular layer also changes the diameter of the arteries to accommodate variation in blood pressure. Veins, conversely, have little muscle in their thin walls and, as a result, are incapable of withstanding high fluid pressure. An iAVM is a pathological short circuit between arteries and veins, with no intervening capillaries, venules, or normal brain. The abnormal blood vessels create a nidus, or a 3D blob of ensnarled “branches” receiving blood under high pressure and high flow from feeding arteries. The blood “swirls” within the nidus and enters the veins draining blood from the iAVM under high pressure. As a result, the veins that drain an iAVM are subjected to pressures above their normal physiological limit. In addition, the arteries that feed the iAVM and the abnormal channels within the iAVM are subjected to supranormal hydrodynamic forces, which can weaken their walls and lead to focal outpouchings known as aneurysms. The 135

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walls of these aneurysms are prone to give way, as are the abnormal vessels within the iAVM and the draining veins. Intracranial AVMs may come to attention in a variety of ways. Sometimes they cause headaches that may be indistinguishable from migraine headaches; they may also irritate the surrounding brain and cause seizures or epilepsy. If large enough, they may “steal” blood from the surrounding normal brain, because the pathway of least resistance is through the iAVM as opposed to the normal surrounding circulation; this steal effect then causes dysfunction of the normal brain. The primary cause of morbidity and mortality from iAVMs, however, is brain hemorrhage resulting from the above-mentioned hemodynamic factors.

Pearls • Definitive treatment is only achieved with complete obliteration or excision of the iAVM. • In cases of ruptured iAVMs, surgery is usually delayed several weeks if the patient is neurologically stable. • The surgical goal must be complete iAVM resection, taking all risk factors into consideration preoperatively. • All feeding vessels to the iAVM mass (nidus) are taken “before” the draining vein. • Surgery is best performed in high-volume centers where patient selection is of utmost priority.

Preoperative Planning RISKS AND BENEFITS OF SURGERY/INFORMED CONSENT At its most basic, the decision to surgically treat an iAVM weighs the natural history risk of living with the AVM untreated vs the surgical risk of a complication. If the natural history risk is substantially higher than the surgical risk, in general, removal of the iAVM is a reasonable course of action. In contrast, if the surgical risk is equal to, or greater than, the natural history risk, then surgical excision should not be recommended.1 Incumbent upon the surgeon proposing surgery is to explain the risks and benefits on each side of the equation, to inform the patient and their family, answer questions as honestly and completely as possible, and allow the patient to make an educated decision that is best for them. This process, which is known as informed consent, is critical to ensure that the goals of surgery, the expected range of outcomes, and potential complications are understood before surgery is pursued. The risk of surgery is unique to each patient and varies. Factors that combine to predict overall risk are related to the patient generally and iAVM specifically. Patient factors that are important to consider include, but are not limited to, chronological and medical age and systemic comorbidities and illnesses, as these best predict fitness to tolerate the stress of surgery and may contribute to complications of surgery and undergoing general anesthesia. AVM factors that contribute to surgical risk include location, size,

number and location of arterial feeders and draining veins, and the speed at which blood passes through the iAVM, among others.2,3 Surgeon-related factors also influence risk, including the experience of the surgeon and their team. High-volume centers where this type of surgery is performed regularly often have better outcomes than facilities where it is performed less frequently. PREOPERATIVE IMAGING To determine which iAVMs should be operated on, the surgeon must carefully review the preoperative imaging, which should be multimodal. Diagnostic angiography provides invaluable data about the size of the AVM, the exact anatomy of the arteries that feed into it and the veins that drain it, the speed at which blood transits through the lesion, the pattern of venous outflow, and the presence of associated aneurysms—all of which are important factors in determining how challenging removing the AVM will be. MRI is also important in many cases to better determine the relationship of the AVM to the surrounding normal brain. In the case of an AVM that is near or within eloquent structures, such as the movement or speech centers of the brain, functional MRI (fMRI) is often helpful to determine the risk of surgery preoperatively; fMRI is a specialized study during which the patient is given movement and language tasks to map areas of the brain involved in those functions and determine their spatial relationship to the iAVM.

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PREOPERATIVE EMBOLIZATION An embolus is a mass that travels through the bloodstream and lodges in the arterial system at a point at which the arterial diameter is less than the size of the mass, resulting in a blockage of blood flow. Emboli can be naturally occurring—e.g., a blood clot that forms somewhere in the bloodstream—or introduced as part of a medical procedure. The process of injecting an embolic agent for the medical purpose of therapeutically blocking a blood vessel or series of blood vessels is called embolization. In some circumstances, a cerebrovascular surgeon may request embolization of an iAVM prior to surgery. In general, embolization of an iAVM is done by colleagues in interventional neuroradiology, doctors trained in minimally invasive treatment of blood vessel abnormalities. The interventional neuroradiologist navigates a tiny, flexible catheter, or tube, to a target artery or arteries that feed the iAVM and delivers an embolic agent, usually a liquid similar to glue, to either block a feeding artery or a set of arteries supplying blood to the iAVM or make a cast of the iAVM nidus. The overall goal is to make surgical removal of the iAVM safer by limiting blood loss or preventing collateral brain injury. The goal of embolization is usually directed toward one of two objectives: (1) blocking the feeding arteries at the base of the iAVM that are obscured from view on the underside of the lesion and are typically approached last, making them treacherous; or (2) reducing the overall blood flow through the iAVM nidus to simplify surgery.4,5 No matter the objective, as a rule, for preoperative embolization to be justified, the overall risk reduction for surgical removal provided by the embolization must be greater than the risk of the embolization itself. Embolization may also be used to eliminate associated aneurysms that would not be readily identified and treatable at surgery. RUPTURED IAVMS The rupture of an iAVM is a potentially life-altering medical event that carries upward of 30% mortality and 50% possibility of permanent brain dysfunction.6 The sequelae of iAVM rupture and the resultant brain hemorrhage can result in a cascade of systemic organ dysfunction, including the cardiovascular, pulmonary, gastrointestinal, and renal systems. The primary goal of treatment after a patient arrives at the hospital

137 with a ruptured iAVM is to ensure medical stability in a specialized neuroscience intensive care unit (ICU) if possible. Once the patient is medically stabilized and after imaging has confirmed a brain hemorrhage, measures to control brain swelling and limit the associated rise in intracranial pressure are instituted. Soon thereafter diagnostic angiography should be performed to evaluate for the source of hemorrhage, which in some cases can be treated through minimally invasive techniques, such as embolization, particularly if the source of bleeding is an associated aneurysm. The risk of resection is increased in the period immediately after iAVM rupture.6,7 The swollen brain is difficult to work around and may be more easily injured during the removal of the AVM. In addition, fresh hematoma has the consistency of jelly, which may obscure important anatomy, both of the brain and the AVM, and this may lead to complications associated with surgery-induced brain injury or incomplete removal of the AVM. As a consequence, we typically follow a treatment algorithm similar to that espoused by other busy cerebrovascular centers6: if the patient is otherwise stable, we wait several weeks to allow brain swelling to subside and allow the thick, acute hematoma to partially liquefy before resecting the AVM. In cases of a large hematoma that is pushing on the brain and may lead to permanent neurological injury or death, we prefer to temporarily remove a large portion of the skull—a procedure known as a decompressive craniectomy—to allow for brain expansion through the defect in the bone and lower life-threatening brain pressure with partial removal of the blood clot from the brain, leaving some hematoma immediately against the ruptured AVM. The intention in such cases is to come back several weeks later, remove the AVM, and replace the portion of the skull that had been previously removed. In some circumstances, removal of the AVM is required at the time of initial surgery to relieve pressure on the brain, but given the increased risk of surgery in the acute phase, resection of the AVM is avoided if at all possible. We are prepared with all the necessary adjuncts and tools in every case, even if the goal is not to remove the AVM at the initial surgery, so that we can proceed with complete removal of the AVM if circumstances of surgery require it.

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Principles of Surgery The goal of iAVM resection is complete removal of the AVM with no collateral injury to the surrounding brain. The advantage of surgery in the treatment of iAVMs is that once the AVM is completely removed, the risk of brain hemorrhage from the lesion is permanently eliminated. If a portion of the AVM is left behind, the patient remains exposed to the natural history risk of the AVM, and may, in fact, be put at greater risk of hemorrhage by surgical alteration of the AVM hemodynamics, or blood flow, in a way that may increase the chance of bleeding. At the same time, surgeons must temper their zeal for complete removal if faced with the need to aggressively dissect into eloquent brain to achieve total resection of the AVM. The surgeon’s foremost duty must be to protect the patient’s neurological function to the extent possible, with the objective of returning the patient to the recovery area in the same condition as—or better condition than—they entered the operating room. To achieve these aims, exacting attention to every detail is required through the preoperative planning phase, in surgical technique, the use of intraoperative technology and adjunctive measures, complication avoidance, and multidisciplinary postoperative care. SURGICAL APPROACH AND EXPOSURE The surgical approach should be tailored to the patient and the iAVM, taking multiple factors into account. Patient positioning on the operating table and the selection of surgical approach should result in direct and complete access to the iAVM. The patient is positioned in as neutral a position as possible. Surgery to remove an iAVM can be a protracted process, and attention to patient positioning and padding of all pressure points is of utmost importance to facilitate surgeon ergonomics and limit the risk of a positioning-related complication. Removal of an iAVM is completed via a craniotomy, or a procedure in which a portion of the skull is removed, temporarily, to expose the underlying brain and AVM. The patient’s head is positioned and rigidly secured to the bed in a fashion that presents the pathology most directly into the surgeon’s view. Additionally, the head should be placed above the level of the heart and lungs and kept in as neutral position as possible

to aid in venous outflow and return of blood to the heart and lungs. If the flow of blood out of the brain is obstructed, for example, by kinking the jugular veins during positioning, the brain may become congested over the course of surgery, which may result in brain swelling, making surgery technically more challenging. Importantly, surgery to remove an iAVM is no time for minimally invasive approaches. While cosmesis is an important aspect of surgery, and neurosurgeons who operate on iAVMs certainly hold dear the cosmetic result of the operation, wide exposure of the AVM and surrounding brain are critically important for safe removal. Wide exposure requires a relatively large craniotomy to ensure that the entire 3D volume of the AVM can be accessed, including the feeding arteries as they approach from normal, surrounding brain, and the vein(s) that drain the AVM. For AVMs that abut the dural venous sinuses—the network of large veins within the covering of the brain that is the primary drainage system for venous blood—it is often crucial to expose the portion of the dural venous sinus into which the main AVM draining veins insert to ensure that the entire AVM is removed in a controlled, systematic fashion and that all components of the AVM, from feeding arteries to the nidus and the draining vein(s), are within the surgeon’s control at all times. RESECTION Once the AVM and surrounding brain are exposed, surgery to remove the AVM proceeds in a stepwise and methodical fashion. While each iAVM is unique and may present unexpected circumstances that require the surgeon to be innovative and change course to remove the lesion, generally a standard series of steps is followed to safely remove the AVM and leave the surrounding brain uninjured. Foremost, the surrounding normal brain, particularly in eloquent areas, should be manipulated as little as possible. In this regard, the surgeon walks a fine line as the dissection of the AVM proceeds circumferentially, in a spiraling fashion, around the lesion surface (Fig. 13.1). The arteries that feed into the AVM are coagulated and cut as they are encountered. If the arteries feeding into the AVM are sufficiently abnormal that coagulation is not possible, the arteries are blocked with small clips and then divided with scissors. The

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Fig. 13.1 (A) Circumferential dissection of iAVM with isolation, coagulation, clipping, and division of feeding pedicles. (B) Cauterization and transection of feeding vessels and the final step of cauterizing and cutting the draining vein. (C) Occasionally, Sundt AVM or aneurysm clips are used for deep feeders.

brain should be retracted as little as possible to expose the surface of the AVM. In rare circumstances, and only when critically necessary, fixed retractors may be used. Also crucial is the concept of spiraling, circumferential dissection, in which the entire circumference of the AVM is dissected evenly before proceeding more deeply. This technique allows for stepwise, spatially even dismantling of the blood supply to the AVM. If

the surgeon begins to dissect toward the bottom of the lesion in a single spot, the AVM nidus continues to receive blood from the inputs on the ignored portions of the AVM. “Digging a hole” without having sufficiently choked the blood supply to the remainder of the iAVM results in deep dissection becoming increasingly difficult as the surgeon “fights” to see around the full, pressurized, pulsating nidus. A false move in this

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­circumstance may result in bleeding that is difficult to control if the nidus is inadvertently violated. Moreover, when possible, the surgeon should take advantage of preexisting surgical corridors. Often, one or more faces of the nidus have interacted with the surrounding brain in a fashion that has resulted in gliosis—or “scarring” of the deeper brain tissue—which renders the dissection between the surrounding brain and the AVM easier. Similarly, recent hemorrhage, in the subacute phase, as the hematoma is being broken down, provides a navigable cavity between the AVM and the surrounding brain that the surgeon can take advantage of to make surgery less challenging. However, in cases of recent hemorrhage, the timing of surgery is critical. If surgery is performed too early, the thick, gelatinous clot is difficult to dissect, the brain is swollen, and AVM resection may be made more difficult. If surgery is performed too late, the liquefied blood clot is absorbed and the cavity through which the surgeon can more safely operate is gone. During surgery, special attention must be paid to the tiny, fragile, feeding arteries that supply blood to the iAVM. The majority of iAVMs, though not all, consist of a standard architecture, whereby a portion of the AVM presents to a brain surface, with the bulk of the nidus extending into the brain tissue, much like an iceberg in the ocean. Unlike the larger feeding arteries that tend to arise from the surface, the diaphanous vessels at the base of the iAVM are treacherous. These small vessels penetrate through the brain tissue, unlike the larger feeding arteries that lie on the brain surface, or are located within the nooks and crannies of the brain, known as sulci. The diaphanous arteries leading into the iAVM are resistant to cauterization, and, if incompletely obliterated, may retract into the underlying brain, resulting in hemorrhage in brain tissue adjacent to the AVM. Thus patience, calm, and fastidious attention to detail and exacting technique are required when disconnecting these deep, diaphanous vessels, which are often not encountered until late in the operation, when the risk of fatigue is greater. However, with careful planning, concentration, and fortitude, these vessels can be safely managed, and their complete disconnection from the nidus often signals that the end of surgery is near. Arguably the most important principle of iAVM surgery is to maintain patency of the main draining vein(s) until the very end of the resection. In short,

premature closure of the draining vein(s) of an iAVM is equivalent to plugging the sink drain but leaving the faucet running. If the primary drainage is occluded before complete, circumferential resection of the AVM is achieved, the arterial input to the nidus remains, continuously filling the AVM with pressurized, fresh blood. The blood within the nidus has no outlet, and the nidus becomes progressively engorged. The distended, pulsing nidus becomes more difficult to manipulate and eventually may rupture. Bleeding of the nidus that results from premature closure of the draining vein(s) is difficult to control and, if the AVM is not completely removed in short order, may progress to multiple sites of uncontrolled bleeding. In this circumstance, surgery may become hurried, blood loss may become difficult to control, and resection may be incomplete, with consequences that range from residual lesion and associated ongoing risk of hemorrhage after surgery to injury to surrounding brain tissue or even catastrophic blood loss. Thankfully, cerebrovascular neurosurgeons are profoundly aware of the complications that can ensue from early injury to or occlusion of the draining vein(s) and take meticulous care to avoid this potentially devastating misstep. Lastly, once the iAVM has been removed, as confirmed by intraoperative angiography, attention is turned to closure. The resection cavity must be carefully examined and complete hemostasis achieved. Any remaining oozing of blood must be handled with fastidious attention to detail. If care is not taken during this final step, the partially coagulated diaphanous feeding arteries that are often the cause of remaining bleeding may erupt during the postoperative period, leading to brain hemorrhage, neurological complications, and, in rare and extreme circumstances, death. An example of a straightforward iAVM resection is provided in Video 13.1 in the online version. Fig. 13.2 shows the pre- and intraoperative angiograms for the case example shown in Video 13.1 as well as a pictorial description of the step-by-step strategy for iAVM removal. SURGICAL ADJUNCTS Surgical treatment of iAVMs is made safer and easier by numerous adjuncts. Image guidance is frequently employed to assist the surgeon in multiple aspects of

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iAVM surgery. Using a combination of high-resolution imaging, such as MRI, that shows the AVM and detailed surrounding brain anatomy and sophisticated computer technology, the patient’s specific anatomy is registered into a neuronavigation system once the patient is under anesthesia. This technology uses skin surface scanning over the face and head to correlate where in space those landmarks are relative to their known positions on imaging and the location of the iAVM. The surgeon can then use a pointer to determine where they are in space relative to the iAVM, similar to the way in which GPS helps a driver reach a new and unfamiliar destination. This type of navigation may be used to plan the exact location of the incision and craniotomy, to determine the extent of circumferential dissection throughout surgery, and to locate and protect critical structures, such as the draining vein when located deep in the brain/AVM surface, or adjacent, normal structures. Intracranial AVMs are routinely removed using an operative microscope. The microscope magnifies and brightly illuminates the field to maximize safety and to provide visualization of structures that would otherwise be unseen with the naked eye and overhead lighting alone. Moreover, most surgeons utilize a mouthpiece, a foot pedal, or both when using an operative microscope to focus and zoom seamlessly throughout surgery without having to remove one or both hands from the surgical field. In addition, the microscope can be outfitted with one or more filters that allow the surgeon to visualize fluorescent tracers. A common fluorescent tracer used in iAVM surgery is called indocyanine green (ICG). ICG is administered into a vein and subsequently pumped throughout the body by the heart. It can be visually detected using a microscope with a filter that emphasizes particular wavelengths of light. As the blood transits through the AVM, the surgeon utilizes ICG to understand the position of the feeding arteries, the speed at which blood travels through the lesion, and the position of the draining vein(s). In addition, a bevy of microinstruments—designed specifically to work on the fragile blood vessels of the brain—are employed to remove an iAVM. Specially devised cauterizing forceps used specifically in iAVM surgery are used to coagulate and divide the feeding arteries. Such cauterizing forceps are typically coated in a nonstick material and are often “self-irrigating” with sterile saline to ensure that the fragile arteries and veins of the AVM are coagulated and cut without tearing.

141 CONSIDERATIONS FOR ELOQUENT BRAIN REGIONS AVMs in or immediately adjacent to eloquent brain regions deserve special attention. Eloquent brain regions are those anatomic regions associated with discrete and objectively measurable neurological function. Examples include the primary motor and somatosensory cortices, which reside next to each other in the back of the frontal lobe and front of the parietal lobe, respectively. Injury to these locations may lead to weakness or paralysis on the opposite side of the body in the case of the primary motor region or changes in sensation on the opposite side of the body in the case of the sensory area. Similarly, the areas for processing of visual information or the generation and understanding of speech are well defined. Additional regions that are intolerant to surgical manipulation include the tracts (neural pathways) within the center of the brain that connect various brain regions to each other or to the brainstem and spinal cord. In many cases, particularly for larger iAVMs that are centered directly within these areas, surgery is not recommended because the risk of iatrogenic brain injury is unacceptably high. However, in some instances, surgery to remove iAVMs that involve these locations can be safely pursued with acceptable morbidity. In those cases, surgeons utilize not only the techniques and adjuncts described earlier but also additional tools to make surgery as safe as possible. Among those supplemental technologies and methods are neurophysiological monitoring of the motor and sensory systems from the brain to the tracts that connect those brain regions to the spinal cord and the nerves that carry movement signals to the muscle and those that convey sensory information back to the brain. The nerves that serve a similar function for the muscles and special senses of the head, neck, and face can also be monitored. Moreover, tractography or MRI-based imaging of the connecting fibers deep within the brain can be overlaid on basic neuronavigation platforms with or without fMRI to show the surgeon the exact areas of the brain to avoid surgery.8,9 In selected cases, surgery can be performed with the patient awake, under carefully monitored sedation, to allow for real-time mapping of brain functions in motor or language areas so that these eloquent regions can be avoided when removing the AVM.10

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Fig. 13.2 See legend on following page.

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Fig. 13.2 Case example demonstrating basic principles of iAVM resection. (A) Sagittal preoperative internal carotid artery angiography revealing an AVM in the left frontal lobe. (B) Overview of the iAVM after craniotomy. The asterisk (*) marks the primary feeding artery to the AVM. Open arrows highlight the primary draining vein. The solid arrow points out an “en passage” artery, or artery that is immediately apposed to the AVM but supplies blood to the normal, surrounding brain. (C1–D3) Panels C through D demonstrate the strategy for initial, superficial “circumferential, spiraling dissection.” The strategy for initial dissection is demarcated in panel C1, with dissection beginning at the 6 o’clock position at the base of the blue arrow. Dissection then proceeds to include the primary feeding artery and ends at the 12 o’clock position adjacent to the draining vein (C2 and C3). D1 demonstrates the path of superficial dissection from the 1 o’clock position, just to the other side of the draining vein back toward the 6 o’clock position, as depicted in panels D2 and D3. After the superficial dissection, a gliotic plane—tan, glistening tissue adjacent to the AVM—is revealed, allowing separation of the AVM nidus from the surrounding brain. (E) After superficial dissection, the dissection is extended more deeply toward the bottom of the nidus as the AVM is rolled out of the cavity for visualization (yellow arrow). (F1 and F2) Once the AVM is circumferentially dissected, the nidus remains connected only to the draining vein (gray arrows), which is then coagulated and cut. (G) Demagnified view of the brain after the AVM has been completely resected. (H) Intraoperative angiogram confirming that the AVM has been entirely removed. (Copyright: Department of Neurosurgery, Emory University School of Medicine. Published with permission.)

INTRAOPERATIVE ANGIOGRAPHY If possible, an intraoperative angiogram should be completed to confirm that the entire iAVM has been removed (see Fig. 13.2H). Intraoperative angiography allows the surgeon to ensure that the lesion has been completely resected and, if it has not, complete additional resection of the residual AVM immediately. Confirmation of complete resection should be done before the beginning of closure (i.e., replacement of the bone flap and skin reapproximation) to ensure that surgery progresses as efficiently as possible. Intraoperative angiography limits the risk of repeated surgery to remove any missed iAVM, which may be made more difficult by recent surgery, brain edema, or hemorrhage from the untreated part of the lesion. Not all facilities are capable of intraoperative angiography, in which case a diagnostic angiogram should be completed as soon as possible after surgery during the same hospital stay. INTRAOPERATIVE MISADVENTURES Despite the adage that the only way to avoid surgical complications is to not perform surgery, iAVM surgery can be pursued with an acceptable degree of safety and limited risk. Risk stratification and grading scales for iAVMs are discussed in detail in other chapters, but we should note that the most important factor in complication avoidance is patient selection. The health of the patient and the characteristics of the iAVM should be carefully weighed before surgery is offered as an option. The Spetzler-Martin and Supplemented Spetzler-Martin grading systems have stood the test of time in predicting rates of complications for particular iAVMs based on size, location, pattern of venous

drainage, patient age, whether a previous hemorrhage has occurred, and how well-defined or compact the nidus is.2,3 By evaluating these criteria in an exacting fashion before entertaining the prospect of surgery, the surgeon has gone a long way toward eluding a complication before it can arise. A number of common complications of iAVM surgery and how to avoid them have been detailed previously, such as retraction of diaphanous feeding arteries into the surrounding brain substance, premature occlusion of the venous drainage, or incomplete resection. Additional, common complications should be noted along with techniques to circumvent or address their occurrence. Direct injury to vessels of the iAVM nidus should be avoided, but if violation of the nidus occurs, the surgeon must stop the resultant bleeding with care to mitigate against potential complications. Particularly near eloquent areas, the surgeon walks a fine line between hugging the nidus during dissection to avoid the surrounding brain and entering into the nidus. The latter may result in intraoperative hemorrhage. The blood vessels of the nidus are often fragile and resistant to cauterization, which can worsen the transgression and result in more bleeding. Generally, nidal bleeding is managed with cotton tamponade and patience. Cotton is absorbent, and with consistent gentle pressure, mild suction, and time, the bleeding will abate and allow the surgeon to move forward with surgery. If the surgeon is impatient and attempts to move ahead with dissecting the AVM in a new area before the nidal bleeding is controlled, multiple sites of bleeding can develop, obscuring the surgical field and allowing the operation to spiral out of the surgeon’s control.

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If the brain becomes progressively swollen throughout surgery, the surgeon must suspect a hemorrhage into the brain adjacent to the AVM until proven otherwise. As previously noted, this is most commonly from retraction of a small feeding artery into the brain before it is completely coagulated. If a brain hemorrhage is suspected, intraoperative ultrasound is useful to locate the blood clot. Once identified, the hematoma can be evacuated. Finding the bleeding vessel is critical so that it can be fully coagulated and further hemorrhage can be prevented. Ischemic—or stroke-like—complications can arise if the “en passage” arteries are not appropriately identified and preserved. En passage arteries are arteries that are either directly apposed to the iAVM nidus, or normal branches of arteries that supply blood to the nidus but also the surrounding brain. These blood vessels can often be difficult to differentiate from AVM feeders. Techniques to identify en passage vessels include meticulous microdissection, ICG video angiography to determine which arteries supply the AVM and which go to the normal brain, and in some circumstances, intraoperative angiography. Stroke can also result from “retrograde thrombosis” of feeding arteries. When an artery is artificially interrupted, the flow of blood in the “blind stump” becomes disordered, and clots form. Typically, the clot propagates backward up to the last branch before the artery was interrupted, which supplies the normal brain. However, sometimes the clot may extend past those branches, leading to stroke in the normal brain surrounding the AVM. This complication is among the most difficult to predict and avoid, but it is potentially devastating; in order to avoid it, all feeding arteries should be sacrificed as close to their insertion into the AVM nidus as possible. POSTOPERATIVE MANAGEMENT Postoperatively, patients are routinely managed in a dedicated neuroscience ICU. For most, when surgery is elective, this is a routine step in observation before transfer to a neurosurgical floor and then home. However, the immediate postoperative period is not merely a perfunctory stay in the hospital. Blood pressure must be controlled and kept within normal limits. Intracranial AVMs are congenital lesions or arise early in life, and as a consequence, the surrounding brain is accustomed to a relative diminution in blood flow. This is a result of the AVM creating a sump effect,

voraciously demanding blood from the surrounding tissues. As a consequence, the vascular tree immediately adjacent to the AVM does not develop in an entirely normal way. Once the AVM is resected, the sump is immediately removed, and the surrounding vasculature of the normal brain is subjected to hemodynamic forces that exceed their accustomed baseline. Brain swelling and hemorrhage may occur in this setting, a phenomenon known as normal perfusion pressure breakthrough (NPPB), which is more common after resection of larger iAVMs. Strict blood pressure control and close attention in the ICU are key components of limiting the risk of NPPB, monitoring for signs and symptoms of it, and treating its complications.11

Conclusion Although some iAVMs are too large or diffuse to remove surgically or are located in regions where they cannot be safely resected, many can be removed with limited risk. Appropriate patient selection, detailed preoperative planning, and fastidious attention to microsurgical technique are crucial to achieve good outcomes. REFERENCES 1. Birnbaum LA, Straight M, Hegde S, et al. Microsurgery for unruptured cerebral arteriovenous malformations in the National Inpatient Sample is more common post-ARUBA. World Neurosurg. 2020;137:e343–e346. https://doi.org/10.1016/ j.wneu.2020.01.211. 2. Kim H, Abla AA, Nelson J, et al. Validation of the supplemented Spetzler-Martin grading system for brain arteriovenous malformations in a multicenter cohort of 1009 surgical patients. Neurosurgery. 2015;76(1):25–31; discussion 31–32. https://doi.org/10.1227/neu.0000000000000556. 3. Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg. 1986;65(4): 476–483. https://doi.org/10.3171/jns.1986.65.4.0476. 4. Crowley RW, Ducruet AF, Kalani MY, Kim LJ, Albuquerque FC, McDougall CG. Neurological morbidity and mortality associated with the endovascular treatment of cerebral arteriovenous malformations before and during the Onyx era. J Neurosurg. 2015;122(6):1492–1497. https://doi. org/10.3171/2015.2.jns131368. 5. Luksik AS, Law J, Yang W, et al. Assessing the role of preoperative embolization in the surgical management of cerebral arteriovenous malformations. World Neurosurg. 2017;104:430– 441. https://doi.org/10.1016/j.wneu.2017.05.026. 6. Zacharia BE, Vaughan KA, Jacoby A, Hickman ZL, Bodmer D, Connolly ES Jr. Management of ruptured brain arteriovenous malformations. Curr Atheroscler Rep. 2012;14(4):335–342. https://doi.org/10.1007/s11883-012-0257-9. 7. Kuhmonen J, Piippo A, Vaart K, et al. Early surgery for ruptured cerebral arteriovenous malformations. Acta Neurochir Suppl. 2005;94:111–114.

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8. Hashimoto N, Nozaki K, Takagi Y, Kikuta K, Mikuni N. Surgery of cerebral arteriovenous malformations. Neurosurgery. 2007;61(1 Suppl):375–387; discussion 387–389. https://doi. org/10.1227/01.NEU.0000255491.95944.EB. 9. Kikuta K, Takagi Y, Nozaki K, Hashimoto N. Introduction to tractography-guided navigation: using 3-tesla magnetic resonance tractography in surgery for cerebral arteriovenous malformations. Acta Neurochir Suppl. 2008;103:11–14. https:// doi.org/10.1007/978-3-211-76589-0_4.

145 10. Gabarros A, Young WL, McDermott MW, Lawton MT. Language and motor mapping during resection of brain arteriovenous malformations: indications, feasibility, and utility. Neurosurgery. 2011;68(3):744–752. https://doi.org/10.1227/ NEU.0b013e318207a9a7. 11. Awad IA, Magdinec M, Schubert A. Intracranial hypertension after resection of cerebral arteriovenous malformations. Predisposing factors and management strategy. Stroke. 1994;25(3):611–620. https://doi.org/10.1161/01.str.25.3.611.

Chapter 14

Radiosurgery Principles for AVM Management: Techniques, Goals, and Outcomes L. Dade Lunsford, Andrew Faramand, Hideyuki Kano, John C. Flickinger, and Ajay Niranjan

Chapter Outline Goals of AVM Radiosurgery The History of Radiosurgery Pittsburgh SRS AVM Outcomes The Stereotactic Radiosurgical Technique Key Findings After Three Decades Late Adverse Effects of Radiosurgery Repeat Radiosurgery The Role of Preradiosurgical Embolization Conclusion

Goals of AVM Radiosurgery Intracranial arteriovenous malformations (iAVMs) are congenital vascular anomalies that directly shunt blood from arterial input to the venous system without an intervening capillary network to reduce the arterial pressure entering draining veins. Both the abnormal vascular construction and the abnormal flow lead to a risk of intracranial hemorrhage. Patients may also experience headaches or seizures as a result of iAVMs, and lobar lesions in particular may be diagnosed in patients who undergo brain imaging because of migraine symptoms or seizure events. Although iAVMs are generally considered relatively rare, they are detected in approximately 10,000 patients per year in the United States. A decision to observe or to intervene must be carefully made based on the risks in individual patients. The management team assesses the risks and benefits of surgical removal (resection), embolization, and radiosurgery, alone or in combination. AVM volume, location, patient age, prior hemorrhage history, 146

angioarchitecture findings such as nidal aneurysms, a compact vs a diffuse nidus, and outflow venous ectasia are all relevant. Associated medical comorbidities, prior management, and presenting symptoms such as headache, seizures, or current neurological deficits need to be considered. For larger-volume iAVMs (average diameter >4–5cm) observation remains a reasonable strategy in view of the risks of even multimodality management.1 Endovascular embolization, regardless of the method (liquid adhesive, particulate, glue, or coils), is best reserved as an adjunct to craniotomy and surgical removal.2,3 Embolization rarely changes the volume of the AVM that must be included in the stereotactic radiosurgery (SRS) target. Defining the residual AVM shunt after embolization is problematic, especially when liquid adhesive is used. Such agents lead to significant degradation of the MRI studies done related to the artifacts of the tantalum powder mixed with adhesive. Since embolization almost never achieves complete obliteration, additional options are almost always required to ensure complete and permanent shunt closure. In contrast, before surgical removal, embolization may provide a major benefit, either by reducing flow or eliminating deep-seated feeding vessels. Surgical removal is an important option for carefully selected patients with lobar vascular malformations of suitable size, especially at centers with skilled iAVM microsurgeons. Incomplete removal may require adjuvant SRS. SRS is an effective and lower-risk primary management strategy for patients with smaller-volume AVMs (typically < 10 cm3). Staged procedures are used for larger

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vascular malformations. Approximately 20% of patients who are treated with primary SRS may require two or more additional procedures to reach the final goal of complete obliteration. A major impetus for SRS in these complex clinical entities is to reduce the risk of observation, surgical, or embolization strategies. The selection of SRS must include the knowledge that radiosurgical obliteration is a gradual process, resulting in a latency interval of months to years.4,5 SRS is the most frequently used treatment option for children with iAVMs at our center.6 As a noninvasive procedure that is typically performed on an outpatient basis, it is also an important option for the management of iAVMs in older patients with significant comorbidities that increase the risks associated with surgery.

The History of Radiosurgery Focused single-session radiation of iAVMs was first considered in the late 1960s after trials of fractionated radiation demonstrated no AVM response. Raymond Kjellberg performed Bragg peak radiation at the Cambridge particle beam facility, which was donated to Harvard after World War II as a reward for help in the Manhattan project.7,8 More than 1000 iAVM patients were treated during the era before CT and MRI, but the imaging and dose-planning techniques were rudimentary. Bragg peak proton dose planning took advantage of the reduced exit dose outside of the brain target. The doses that were actually used in this series of patients were quite low, and less than 20% of patients had complete obliteration over time. Kjellberg’s method for estimating benefit was to compare patient mortality data to data from an age-matched life table insurance analysis. Fabrikant and Steinberg, working at the Lawrence Livermore Laboratory in Berkeley, used helium particles to perform multisession iAVM irradiation in the 1980s9 prior to the eventual closure of that facility. Lars Leksell, the innovative creator of the Gamma Knife (AB Elekta, Stockholm), together with Ladislau Steiner used the first-generation 179-source cobalt-60 photon radiation device to treat the first iAVM patient in March 1970. The target definition was based on biplane angiography alone. A deep-seated small iAVM was confirmed as obliterated 2 years after the delivery

147

Pearls • Stereotactic radiosurgery has become the most frequently used option for the treatment of iAVMs. • The goal is AVM obliteration, which is related to AVM volume and radiation dose delivered. • The best outcomes (obliteration with high-quality neurological outcome) are achieved in 55%–85% of patients over intervals of 1–3 years. • Embolization before radiosurgical treatment of iAVMs reduces the quality of outcomes. • Late risks include cyst development or chronic encapsulated expanding hematoma, which are detected in 1%–3% of patients.

of a maximum dose of 50 Gy to the target. A larger international referral experience developed thereafter in Stockholm, especially after the second-generation Gamma Knife was installed at the Karolinska Hospital in 1975. During the 1980s, various linear accelerator (linac) technologies were adapted for SRS. Osvald Betti, working in Paris and Buenos Aires,10 Juan Barcia-Salorio in Spain,11,12 and Federico Colombo in Vicenza, Italy,13–15 pioneered the use of these modified linear accelerators. In addition, surgeons and radiation oncologists working in Boston16 and in Gainesville, Florida,17 created specially modified linear accelerators that were combined with stereotactic devices. The second patient treated in Pittsburgh after the 1987 installation of the first 201-source Gamma Knife had an iAVM and was referred for treatment after incomplete embolization. The AVM was obliterated approximately 2 years after this single-session procedure.

Pittsburgh SRS AVM Outcomes We reported our initial experience in 227 patients in 1991.18 We confirmed that complete obliteration was related to nidus volume and dose. In iAVMs smaller than 1 cm3 in volume, obliteration rates approaching 100% were noted with margin doses of 25 Gy. The margin doses were subsequently reduced in the interest of safety, and these reduced margin doses led to obliteration rates of 85% for iAVMs with volumes of 1–4 cm3 and 58% for iAVMs larger than 4 cm3.

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Our experience in Pittsburgh now spans 33 years and more than 1600 procedures, including primary as well as repeat radiosurgical procedures (Tables 14.1 and 14.2). We analyzed the outcome data of 906 patients who underwent radiosurgery between 1987 and 2004. The median patient age was 36 years (range, 3–80 years). Typical symptoms at presentation included hemorrhage (in 46% of the cases), seizures (in 24%), and headache (in 18%). Eight percent of the patients had neurological deficits. Prior management strategies included surgical removal or clot evaluation in 7%. Twenty-one percent underwent one or more interventional procedures (embolization). A single radiosurgery procedure was performed in 865 (95.5%) of the 906 patients, and repeat radiosurgery for incomplete nidus obliteration after 3 years was needed in 113 patients (12.5%). Prospective volume-staged radiosurgery was performed in 41 patients (4.5%). At a median follow-up of 3 years, complete nidus obliteration was achieved in 78% of cases (as confirmed by angiography or MRI); subtotal obliteration TABLE 14.1 Demographic and Clinical Characteristics of Patients With iAVMs Treated Over Three Decades Characteristic

Value

Number of patients

1306

Patient Age Median Range

38 years 3–87 years

Sex Male Female Pre-SRS bleeding

639 (49%) 667 (51%) 611 (47%)

Signs or Symptoms Sensorimotor deficit Seizures Headache Other Incidental finding

449 (34%) 334 (26%) 286 (22%) 181 (14%) 52 (4%)

Prior Management Embolization Surgery

216 (17%) 131 (10%)

TABLE 14.2 Radiosurgical Parameters of iAVMs Treated Over Three Decades Parameter

Value

AVM Volume Median Range

3.6 cm3 0.065–57.7 cm3

Radiosurgery Margin Dose Median Range

20 Gy 13–32 Gy

Radiosurgery Procedures Total number of procedures Single-session radiosurgery Volume-staged radiosurgery Repeat radiosurgery

1655 865/1482 (94.3%) 84/1482 (5.6%) 173/1655 (10.4%)

was achieved in 21%. During the follow-up interval, 38 hemorrhages occurred (yielding a rate of 4.1%). Seizure control was improved in 70% of the patients who presented with seizures.19,20 Adverse radiation effects (ARE) resulting in neurological deficits developed in 24 patients (2.6%), and new T2 signal increase surrounding the AVM target was detected in 108 patients (12%). We noted long-term complications such as delayed cyst formation or encephalomalacia in 16 patients (1.7%).

The Stereotactic Radiosurgical Technique We initiated intracranial radiosurgery using the Leksell Gamma Knife Model Unit U and have subsequently used the B, C, 4-C, Perfexion, and Icon models. As of 2021, we use both the Leksell Perfexion and Leksell Icon models. Prior to scheduling a procedure, we evaluate the patient’s clinical studies and imaging at a multidisciplinary conference. Pertinent factors include the patient’s age, bleeding history, existing comorbidities, AVM location, and clinical symptomatology. Patients with lobar AVMs but without a history of seizures are given prophylactic anticonvulsant medication for a period of 2–4 weeks around the time of the procedure. Patients with a seizure history are maintained on anticonvulsant medication (typically levetiracetam) until they have been seizure free for 1 year and obliteration of their AVM has been documented. Before treating any woman less than

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50 years of age, we require negative results on a pregnancy test performed the day of the procedure. Twice we have encountered patients who were unaware of their pregnancy on the day of the planned procedure. Patients are evaluated by the responsible neurosurgeon and a radiation oncologist. The nursing team contacts the patient in advance of treatment to obtain medication histories and to prepare the patient. Patients can watch a video of the procedure as well. On the morning of the procedure, conscious sedation is induced with oral lorazepam followed by intravenous conscious sedation (fentanyl and midazolam) as needed. Scalp anesthetic injection using a combination of bupivacaine hydrochloride (Marcaine) and lidocaine (Xylocaine) is injected at the frame pin sites. All patients (except in a rare second-stage case) are treated using a frame-based technique. We use titanium pins with plastic frame inserts to minimize the risk of MRI artifacts. General anesthesia may be required in patients younger than 12 years of age. Stereotactic MRI is performed with intravenous administration of a paramagnetic contrast agent, and 3D volumetric and whole-head T2 fast spin echo imaging sequences are obtained. Patients then undergo biplane digital subtraction angiography to define the vascular nidus or shunt. In cases in which MRI is not feasible, we use axial contrast-enhanced stereotactic CT angiography. Axial imaging facilitates superior 3D conformal radiosurgical planning. Digital subtraction angiography results in major changes in the plan in 20% of the patients whose initial plan is done with axial imaging. Optimization of the plan is achieved by confining the sharpest falloff isodose (usually the 50%) to the edge of the 3D defined volume. High selectivity (rapid falloff of the radiation dose outside of the target) is equally important. The defined treatment volume excludes draining veins when feasible. Typical doses at the margin of the AVM are 18–22 Gy (Fig. 14.1). Maximum doses depend on the isodose used at the AVM margin. As defined by Kano et al., the final dose plan also uses small low-weighted isocenters within the prescribed isodose plan in order to maximize the percent volume of the AVM that receives > 22 Gy.21 Conformality, selectivity, and adjustment of the percent volume getting a higher dose are all critical to obliteration (Figs. 14.2 and 14.3).

100 % Patients with Angiographic or MRI Obliteration

14

80 60 40 20 0

8

10

12 14 16 18 20 22 24 Prescribed Margin Dose(Gy)

26

28

Fig. 14.1 Relationship between margin dose and obliteration of iAVMs as demonstrated by angiography. The data are from a series of 297 patients who did not have preradiosurgical embolization. As can be seen in the graph, higher margin doses were associated with a greater chance of iAVM obliteration.

At the conclusion of the procedure, patients receive 20–40 mg of methylprednisolone, administered intravenously. Lobar AVM patients also receive antiseizure medication, typically levetiracetam, in order to reduce the risk of perioperative seizures. In patients who have previously undergone endovascular embolization procedures or craniotomy for AVM resection, Gamma Knife radiosurgery may be used as an adjuvant strategy. In these patients as well as in those with prior hemorrhage, we delay radiosurgery until a stable recovery has been reached, typically between 1 and 3 months after the event. Failure of radiosurgery is related to poor planning, inadequate recognition of the 3D geometry of the AVM, or failure to include a component of the AVM previously embolized or compressed by a recent hematoma. We recommend a follow-up MRI at 6 months and then annually to assess the effect of radiosurgery. If MRI suggests complete obliteration (absence of T2 flow voids), then we repeat angiography to confirm obliteration after waiting until 3 years have passed since SRS. For those patients who have large-volume iAVMs (> 10–15 cm3 determined by multiplying the MRI X, Y, and Z dimensions of the AVM and dividing by 2, a rough approximation of an ellipsoid volume), we recommend staged SRS.22 Two volumes are staged at 3-month intervals. For the first stage, treatment planning is based on both MRI and angiography, but for the second stage it is based on MRI alone.

Fig. 14.2 Conformal radiosurgery dose planning for a 30-year-old woman with a right frontal pericallosal cingulate region AVM. This 2.9-cm3 AVM was treated with a margin dose of 23 Gy prescribed to the 50% isodose line. The images show a 23-Gy margin dose (yellow lines) projected on lateral (A) and posteroanterior (B) view carotid angiograms and contrast-enhanced axial (C), coronal (D), and sagittal (E) MR images. The green lines indicate the area receiving a 12-Gy radiation dose, which is a predictor of possible adverse radiation effects.

Fig. 14.3 (A and B) Lateral (A) and posteroanterior (B) view carotid angiograms showing no evidence of an AVM. (C and D) Contrast-enhanced axial T1-weighted (C) and T2-weighted (D) MR images showing a complete absence of flow voids.

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151

Key Findings After Three Decades

Late Adverse Effects of Radiosurgery

In the absence of treatment, the overall risk of a spontaneous hemorrhage from an iAVM appears to range from 1% to 5% per year, depending upon various risk factors.23 We performed an individualized analysis of the hemorrhage risk of AVM patients before radiosurgery.24 Our findings demonstrated an overall crude annual hemorrhage rate of 2.4% per year. We found several factors to be associated with hemorrhage risk after SRS. A prior hemorrhage significantly increases the risk of post-SRS hemorrhage. Our data indicate that for low-risk iAVMs (no prior hemorrhage, compact nidus, more than one draining vein), the annual hemorrhage rate in the latency interval after SRS was approximately 1% per year. In contrast, the risk of a latency interval hemorrhage in patients with a prior hemorrhage, diffuse nidus, or single draining vein increased to 8.94% per year. For patients and their families, we use a “rule of thumb” to estimate an age-related lifetime bleeding risk if no AVM management is done. A simple lifetime analysis risk rate suggests that a patient’s age subtracted from 105 will give the estimated total cumulative risk of that patient having a bleeding event if the AVM is observed rather than treated.25,26 Patients with a proximal aneurysm have an increased risk of postradiosurgical hemorrhage.27 If the aneurysm is immediately proximal to the AVM, it will likely close as the AVM becomes obliterated. In part because of the difficulty in fully confirming intranidal aneurysms, we are unable to clearly state that such a finding poses an increased risk of hemorrhage. Patients with aneurysms more than one arterial branch proximal to their AVM should be considered for embolization or surgical clipping of the aneurysm as it adds an additional risk of a bleeding event during the latency interval. In the event of a rare documented rehemorrhage despite prior angiography showing obliteration, various possibilities should be evaluated. These include possible recanalization of a previously embolized AVM, inadequate angiographic evaluation, or an untreated adjacent aneurysm. The presence of a residual early draining vein without nidus detection is not associated with rebleeding. For patients with adequately defined angiographic obliteration after radiosurgery, we may safely estimate that the cumulative residual lifetime risk of a bleed is now less than 1%.

Late adverse radiation effects (ARE) of radiosurgery are relatively rare. We evaluated data from 85 iAVM patients who developed symptomatic complications after Gamma Knife radiosurgery and compared this to data from 337 patients who had no complications and were evaluated as part of another multiinstitutional study.28 We constructed various models to study the effects of AVM location and the volume of tissue receiving 12Gy or more (the 12-Gy volume) with the risk of developing permanent postradiosurgery ARE. Such risks are related to anatomic brain location and can be divided into brainstem, basal ganglia/thalamus, and all other locations.29 Other late complications of iAVM radiosurgery are also relatively rare. Cyst formation after iAVM radiosurgery was first reported by Japanese investigators whose patients underwent Gamma Knife radiosurgery in Sweden in the early years of radiosurgery.30 Cyst formation has also been reported in other long-term follow-up studies.31,32 In our 33-year experience, we have detected a less than 2% risk of delayed cyst formation. We suspect that patients who developed delayed cyst formation were more likely to have had prior bleeds. Prior brain hemorrhage leaves a residue of iron deposition, which may serve as a radiation sensitizer. Progressively enlarging cysts may require simple drainage, cyst shunting, or surgical fenestration. More recently, the late risk of a chronic encapsulated expanding hematoma (CEEH) has been recognized, with these hematomas being detected 5–25 years after SRS.33 The hematomas progress from micro rehemorrhage and enlarge gradually, likely as a result of radiation-related neovascularity and hemorrhagic changes that occur in the absence of any residual AVM defined by angiography. On susceptibility-weighted MRI, they resemble (but are not) cavernous malformations. Symptomatic and progressive CEEH requires craniotomy and removal. Of interest, staining the resected tissue for vascular endothelial growth factor (VEGF) does not reveal significantly elevated expression. The incidence of CEEH in our radiosurgical cases is less than 0.5%. In our experience of almost 17,000 Gamma Knife procedures, we have not identified a patient who fits the Cahan requirements for radiation-related tumor development. Isolated cases of glioblastoma development after iAVM radiosurgery34,35 have, however, been reported now that over 1.3 million patients have undergone Gamma Knife radiosurgery. For the

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54 years of radiosurgical treatment, the denominator (number treated) is known, but the numerator (the incidence of radiation-related tumors) remains unknown. This issue has been analyzed by Wolf et al., in an article in Lancet Oncology.36 We estimate that the risk of a radiation-related tumor is between 1 in 1000 and 1 in 10,000, although neither our personal experience nor recently published data from Sheffield, England, can confirm the incidence rate.37

Repeat Radiosurgery For those patients who have a residual iAVM nidus identified by imaging 3 or more years after radiosurgery, we recommend repeat radiosurgery. For such patients, we may increase the prescribed margin dose since the residual AVM is always smaller.

The Role of Preradiosurgical Embolization Both our experience and the International Radiosurgery Research Foundation multicenter trial38 confirm that embolization prior to radiosurgery has a negative effect on iAVM obliteration rates.39 As many as 30% of patients who had iAVM embolization were found to have had an increase in the nidus volume when an angiogram was performed at the time of subsequent radiosurgical targeting.40 In another study, 12% of embolized iAVMs showed recanalization within a year.41 In a study of 47 patients who had radiosurgery and embolization in comparison to 47 matched patients who were treated with radiosurgery alone, nidus obliteration was achieved in only 47% of the embolization group but in 70% of the radiosurgery group.42 Liquid adhesive embolization agents such as Onyx (Medtronic, Minneapolis, MN) have further increased the difficulty of targeting embolized iAVMs during SRS. The tantalum-impregnated adhesive leaves a large MRI artifact, making nidus definition impossible.

Conclusion The remaining issues for iAVM radiosurgery are to reduce the risk of latency interval hemorrhages as well as to better understand the risks of late cyst or CEEH development. Within the context of a disease that has a 1% annual mortality if left untreated, 50 years of iAVM experience confirms that SRS is a safe and

effective management strategy either used alone or in selected cases after prior surgery. Disclosure

Dr. Lunsford is a stockholder of AB Elekta and DSMB chair for Insightec, Inc. REFERENCES 1. Han PP, Ponce FA, Spetzler RF. Intention-to-treat analysis of Spetzler-Martin grades IV and V arteriovenous malformations: natural history and treatment paradigm. J Neurosurg. 2003;98(1):3–7. https://doi.org/10.3171/jns.2003.98.1.0003. 2. Ledezma CJ, Hoh BL, Carter BS, Pryor JC, Putman CM, Ogilvy CS. Complications of cerebral arteriovenous malformation embolization: multivariate analysis of predictive factors. Neurosurgery. 2006;58(4):602–611; discussion 602-611. https://doi.org/10.1227/01.neu.0000204103.91793.77. 3. Raymond J, Iancu D, Weill A, et al. Embolization as one modality in a combined strategy for the management of cerebral arteriovenous malformations. Interv Neuroradiol. 2005;11(suppl):57–62. https:// doi.org/10.1177/15910199050110s110. 4. Liscák R, Vladyka V, Simonová G, et al. Arteriovenous malformations after Leksell gamma knife radiosurgery: rate of obliteration and complications. Neurosurgery. 2007;60(6):1005–1014; discussion 1015-1006. https://doi. org/10.1227/01.neu.0000255474.60505.4a. 5. Pollock BE, Gorman DA, Coffey RJ. Patient outcomes after arteriovenous malformation radiosurgical management: results based on a 5- to 14-year follow-up study. Neurosurgery. 2003;52(6):1291–1296; discussion 1296-1297. https://doi. org/10.1227/01.neu.0000064800.26214.fe. 6. McDowell MM, Agarwal N, Mao G, et al. Long-term outcomes of pediatric arteriovenous malformations: the 30year Pittsburgh experience. J Neurosurg Pediatr. 2020;26(3): 275–282. https://doi.org/10.3171/2020.3.peds19614. 7. Kjellberg RN. Stereotactic Bragg peak proton beam radiosurgery for cerebral arteriovenous malformations. Ann Clin Res. 1986;18(Suppl 47):17–19. 8. Kjellberg RN, Hanamura T, Davis KR, Lyons SL, Adams RD. Bragg-peak proton-beam therapy for arteriovenous malformations of the brain. N Engl J Med. 1983;309(5): 269–274. https://doi.org/10.1056/nejm198308043090503. 9. Fabrikant JI, Levy RP, Steinberg GK, et al. Heavy-charged-particle radiosurgery for intracranial arteriovenous malformations. Stereotact Funct Neurosurg. 1991;57(1-2):50–63. https://doi. org/10.1159/000099555. 10. Betti OO, Munari C, Rosler R. Stereotactic radiosurgery with the linear accelerator: treatment of arteriovenous malformations. Neurosurgery. 1989;24(3):311–321. https:// doi.org/10.1227/00006123-198903000-00001. 11. Barcia-Salorio JL, Barcia JA, Soler F, Hernández G, Genovés JM. Stereotactic radiotherapy plus radiosurgical boost in the treatment of large cerebral arteriovenous malformations. Acta Neurochir Suppl (Wien). 1993;58:98–100. https://doi. org/10.1007/978-3-7091-9297-9_22. 12. Barcia-Salorio JL, Soler F, Hernandez G, Barcia JA. Radiosurgical treatment of low flow carotid-cavernous fistulae. Acta Neurochir Suppl (Wien). 1991;52:93–95. https://doi. org/10.1007/978-3-7091-9160-6_27. 13. Colombo F, Benedetti A, Pozza F, Marchetti C, Chierego G. Linear accelerator radiosurgery of cerebral arteriovenous

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Radiosurgery Principles for AVM Management: Techniques, Goals, and Outcomes malformations. Neurosurgery. 1989;24(6):833–840. https:// doi.org/10.1227/00006123-198906000-00008. Colombo F, Cavedon C, Francescon P, et al. Three-dimensional angiography for radiosurgical treatment planning for arteriovenous malformations. J Neurosurg. 2003;98(3): 536–543. https://doi.org/10.3171/jns.2003.98.3.0536. Colombo F, Pozza F, Chierego G, Casentini L, De Luca G, Francescon P. Linear accelerator radiosurgery of cerebral arteriovenous malformations: an update. Neurosurgery. 1994;34(1):14–20; discussion 20–11. Loeffler JS, Alexander E III, Siddon RL, Saunders WM, Coleman CN, Winston KR. Stereotactic radiosurgery for intracranial arteriovenous malformations using a standard linear accelerator. Int J Radiat Oncol Biol Phys. 1989;17(3): 673–677. https://doi.org/10.1016/0360-3016(89)90123-5. Friedman WA, Bova FJ, Mendenhall WM. Linear accelerator radiosurgery for arteriovenous malformations: the relationship of size to outcome. J Neurosurg. 1995;82(2):180–189. https:// doi.org/10.3171/jns.1995.82.2.0180. Lunsford LD, Kondziolka D, Flickinger JC, et al. Stereotactic radiosurgery for arteriovenous malformations of the brain. J Neurosurg. 1991;75(4):512–524. https://doi.org/10.3171/ jns.1991.75.4.0512. Bowden G, Kano H, Tonetti D, et al. Stereotactic radiosurgery for sylvian fissure arteriovenous malformations with emphasis on hemorrhage risks and seizure outcomes. J Neurosurg. 2014; 121(3):637–644. https://doi.org/10.3171/2014.5.jns132244. Niranjan A, Kashkoush A, Kano H, Monaco EA, Flickinger JC, Lunsford LD. Seizure control after radiosurgery for cerebral arteriovenous malformations: a 25-year experience. J Neurosurg. 2018;131(6):1763–1772. https:// doi.org/10.3171/2018.7.jns18304. Kano H, Flickinger JC, Nakamura A, et al. How to improve obliteration rates during volume-staged stereotactic radiosurgery for large arteriovenous malformations. J Neurosurg. 2019;130(6): 1809–1816. https://doi.org/10.3171/2018.2.JNS172964. Kano H, Kondziolka D, Flickinger JC, et al. Stereotactic radiosurgery for arteriovenous malformations, part 6: multistaged volumetric management of large arteriovenous malformations. J Neurosurg. 2012;116(1):54–65. https://doi. org/10.3171/2011.9.jns11177. Ondra SL, Troupp H, George ED, Schwab K. The natural history of symptomatic arteriovenous malformations of the brain: a 24year follow-up assessment. J Neurosurg. 1990;73(3):387–391. https://doi.org/10.3171/jns.1990.73.3.0387. Pollock BE, Flickinger JC, Lunsford LD, Bissonette DJ, Kondziolka D. Factors that predict the bleeding risk of cerebral arteriovenous malformations. Stroke. 1996;27(1):1–6. https:// doi.org/10.1161/01.str.27.1.1. Brown RD Jr. Simple risk predictions for arteriovenous malformation hemorrhage. Neurosurgery. 2000;46(4):1024. Kondziolka D, McLaughlin MR, Kestle JR. Simple risk predictions for arteriovenous malformation hemorrhage. Neurosurgery. 1995;37(5):851–855. https://doi.org/10.1227/00006123199511000-00001. Kano H, Kondziolka D, Flickinger JC, et al. Aneurysms increase the risk of rebleeding after stereotactic radiosurgery for hemorrhagic arteriovenous malformations. Stroke. 2012; 43(10):2586–2591. https://doi.org/10.1161/strokeaha.112. 664045. Flickinger JC, Kondziolka D, Lunsford LD, et al. A multiinstitutional analysis of complication outcomes after ­ arteriovenous malformation radiosurgery. Int J Radiat Oncol

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Biol Phys. 1999;44(1):67–74. https://doi.org/10.1016/s03603016(98)00518-5. Kano H, Flickinger JC, Tonetti D, et al. Estimating the risks of adverse radiation effects after Gamma Knife radiosurgery for arteriovenous malformations. Stroke. 2017;48(1):84–90. https://doi.org/10.1161/strokeaha.116.014825. Hara M, Nakamura M, Shiokawa Y, et al. Delayed cyst formation after radiosurgery for cerebral arteriovenous malformation: two case reports. Minim Invasive Neurosurg. 1998;41(1):40–45. https://doi.org/10.1055/s-2008-1052014. Izawa M, Hayashi M, Chernov M, et al. Long-term complications after gamma knife surgery for arteriovenous malformations. J Neurosurg. 2005;102(Suppl):34–37. https://doi.org/10.3171/ jns.2005.102.s_supplement.0034. Pan HC, Sheehan J, Stroila M, Steiner M, Steiner L. Late cyst formation following gamma knife surgery of arteriovenous malformations. J Neurosurg. 2005;102(Suppl):124–127. https://doi.org/10.3171/jns.2005.102.s_supplement.0124. Abou-Al-Shaar H, Faramand A, Zhang X, et al. Chronic encapsulated expanding hematomas after stereotactic radiosurgery for intracranial arteriovenous malformations. J Neurosurg. 2022;136(2):492–502. https://doi.org/10. 3171/2021.1.jns203476. Berman EL, Eade TN, Brown D, et al. Radiation-induced tumor after stereotactic radiosurgery for an arteriovenous malformation: case report. Neurosurgery. 2007;61(5):E1099; discussion E1099. https://doi.org/10.1227/01.neu.0000303207. 92617.4e. Kaido T, Hoshida T, Uranishi R, et al. Radiosurgery-induced brain tumor. Case report. J Neurosurg. 2001;95(4):710–713. https://doi.org/10.3171/jns.2001.95.4.0710. Wolf A, Naylor K, Tam M, et al. Risk of radiationassociated intracranial malignancy after stereotactic radiosurgery: a retrospective, multicentre, cohort study. Lancet Oncol. 2019;20(1):159–164. https://doi.org/10.1016/ s1470-2045(18)30659-4. Rowe J, Grainger A, Walton L, Silcocks P, Radatz M, Kemeny A. Risk of malignancy after gamma knife stereotactic radiosurgery. Neurosurgery. 2007;60(1):60–65; discussion 65–66. https:// doi.org/10.1227/01.neu.0000255492.34063.32. Patibandla MR, Ding D, Kano H, et al. Stereotactic radiosurgery for Spetzler-Martin Grade IV and V arteriovenous malformations: an international multicenter study. J Neurosurg. 2018;129(2):498–507. https://doi. org/10.3171/2017.3.jns162635. Pollock BE, Flickinger JC, Lunsford LD, Maitz A, Kondziolka D. Factors associated with successful arteriovenous malformation radiosurgery. Neurosurgery. 1998;42(6):1239–1244; discussion 1244–1237. https://doi.org/10.1097/00006123-19980600000020. Miyachi S, Negoro M, Okamoto T, et al. Embolisation of cerebral arteriovenous malformations to assure successful subsequent radiosurgery. J Clin Neurosci. 2000;7(Suppl 1): 82–85. https://doi.org/10.1054/jocn.2000.0718. Gobin YP, Laurent A, Merienne L, et al. Treatment of brain arteriovenous malformations by embolization and radiosurgery. J Neurosurg. 1996;85(1):19–28. https://doi.org/10.3171/ jns.1996.85.1.0019. Andrade-Souza YM, Ramani M, Scora D, Tsao MN, terBrugge K, Schwartz ML. Embolization before radiosurgery reduces the obliteration rate of arteriovenous malformations. Neurosurgery. 2007;60(3):443–451; discussion 451–452. https://doi.org/10. 1227/01.neu.0000255347.25959.d0.

Chapter 15

Principles of Neuroendovascular Management of AVMs: Goals, Timing, Techniques, and Outcomes Muhammad Waqas, Moleca Ghannam, and Elad I. Levy

Chapter Outline Introduction Angiographic Evaluation of iAVMs Role of Classification in Patient Selection for Neuroendovascular Treatment Curative Embolization Adjunctive Embolization Before Radiosurgery Adjunctive Embolization Before Microsurgery Palliative Embolization Targeted Embolization and iAVM-Associated Aneurysms Embolic Agents General Anesthesia vs Conscious Sedation Outcomes of Endovascular Management of iAVMs Conclusion

Introduction Intracranial arteriovenous malformations (iAVMs) are among the most challenging and complex pathologies of the brain. After the poor results that were encountered with early attempts at the resection of iAVMs, Harvey Cushing was quoted as saying, “It would be nothing less than foolhardy to attack one of the deepseated racemose lesions …. The surgical history of most of the reported cases shows not only the futility of an operative attack upon one of these angiomas but the extreme risk of serious cortical damage which it entails.”1 He was similarly pessimistic with respect to the more superficial variety of iAVM, saying, “…even with this latter and surgically speaking more favorable 154

type, there is little encouragement to be had on the side of radical treatment.”1 The treatment challenges posed by iAVMs that have long been recognized by neurosurgeons and neuroscientists have motivated the search for less invasive, safe, and effective therapeutic options. In 1960, Luessenhop and Spence described the first successful embolization of an iAVM; they used artificial embolic material and administered it directly via a surgically exposed left common carotid artery.2 Since then, several advancements have been made with regard to embolizing agents, access catheters, and balloon catheters. If the angioarchitecture of the iAVM is favorable, cure is possible with current endovascular techniques alone. Endovascular techniques are practiced in four different settings, each with an associated goal: (1) adjunctive—preoperative embolization to facilitate microsurgical resection or radiosurgery; (2) curative—embolization attempted for cure; (3) targeted therapy—to treat the source of bleeding; and (4) palliative—embolization to reduce arteriovenous shunting. In this chapter, we discuss goals, timing, techniques, and outcomes of neuroendovascular treatment of iAVMs.

Angiographic Evaluation of iAVMs Digital subtraction angiography remains the gold standard for the evaluation of iAVM angioarchitecture. The goal of the angiogram is to identify the following features: feeding arteries; the location of the nidus and draining veins; the morphology,

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Principles of Neuroendovascular Management of AVMs: Goals, Timing, Techniques, and Outcomes

presence, and location of associated intracranial aneurysms; venous varices; and stenotic segments on arteries and veins.3 The identification of en passage feeding arteries is critical. This necessitates selective microcatheterization of the arterial pedicles. Arteriovenous shunting is confirmed by the visualization of an early draining vein during the arterial phase. A high-speed angiographic run with a higher number of frames per second may facilitate confirmation of the shunt. A 3D angiogram with 3D reconstruction is extremely valuable in understanding the architecture of the iAVM. It is important to note that a thrombosed AVM may not be detected on a cerebral angiogram. The iAVM nidus may also be missed on all imaging modalities if there is significant compression from an adjacent hematoma.4 Therefore it is prudent to repeat the angiogram once the hematoma and mass effect have resolved, usually in 2–4 weeks. Other imaging modalities used to evaluate iAVMs include CT, CT angiography, MRI and MR angiography. These imaging modalities are limited in their sensitivity and ability to provide detailed imaging of iAVM angioarchitecture; however, each adds valuable information to aid the management approach.5 CT angiography provides better vascular detail of the iAVM, whereas MRI and MR angiography provide greater visualization of surrounding structures adjacent to the nidus. MRI is helpful in identifying thrombosed vessels as hyperintense signals and showing an associated hemorrhage at various stages of evolution. T2-weighted and gradient echo imaging sequences are the most sensitive to blood breakdown products. MRI can be important for preoperative planning for radiosurgery and microsurgery, as it helps to delineate the relationship of the iAVM with surrounding parenchymal structures.3

Role of Classification in Patient Selection for Neuroendovascular Treatment Spetzler-Martin grading remains the most widely accepted, reproducible, and utilized grading system for iAVMs.6 However, the Spetzler-Martin grade was developed to stratify the morbidity of microsurgical resection of iAVMs. Refinements of the original grading system have since been validated for radiosurgery, but Spetzler-Martin grading has not been validated to stratify the risk of neuroendovascular treatment of

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Pearls • Endovascular techniques are practiced in four different settings in the treatment of iAVMs, each with an associated goal: adjunctive (preoperative embolization to facilitate microsurgical resection or radiosurgery), curative (embolization attempted for cure), targeted therapy (to treat the source of bleeding), and palliative (embolization to reduce arteriovenous shunting). • A considerable number of iAVMs can be cured solely with transarterial or transvenous embolization or a combination of both. • Size and morphology of the nidus, number and size of arterial feeders, and number of draining veins are key to the selection of iAVMs for transarterial and transvenous embolization. • Single or multistage embolization of iAVMs may render the nidus amenable to radiosurgery through volume reduction. • In particular, embolization of arterial feeders not readily accessible with a microsurgical approach can facilitate subsequent microsurgical resection of the iAVM.

iAVMs. Developing a grading system to guide neuroendovascular decision-making has been a challenge because of variations in the location and size of the nidus and the number and size of the feeding arteries, location and number of draining veins, presence of associated aneurysms, rupture status of the iAVM, and source of bleeding, all of which influence neuroendovascular management. The considerable heterogeneity of iAVM angioarchitecture has prevented the development of a universally applicable classification system. Several alternatives to Spetzler-Martin grading have been proposed, yet no single system has gained widespread acceptance.7–9 Several investigators from our institution, including the senior author of this chapter, developed a grading system (called the Buffalo score) that accounts for the anatomical challenges unique to the endovascular treatment of iAVMs.7 The grading features include number of pedicles, diameter of the arterial pedicles, and location of the iAVM (eloquent vs noneloquent) (Table 15.1).7 The grading system was derived from morbidity data from consecutive iAVM patients treated by endovascular means and was validated

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TABLE 15.1 Determination of Cerebral Arteriovenous Malformation Grade According to the Proposed (Buffalo) Grading System Graded Feature

Points Assigned

Number of Arterial Pedicles 1 or 2

1

3 or 4 5 or more

2 3

Diameter of Arterial Pedicles Most > 1 mm Most ≤ 1 mm

0 1

Nidus Location Noneloquent Eloquent

0 1

AVM grade = [number] + [diameter] + [nidus location]. From Dumont TM, Kan P, Snyder KV, Hopkins LN, Siddiqui AH, Levy EI. A proposed grading system for endovascular treatment of cerebral arteriovenous malformations: Buffalo score. Surg Neurol Int. 2015;6:3. © 2015 Dumont TM. Creative Commons Attribution License.

using multivariate regression analysis, although it has not yet been validated externally. Fig. 15.1 illustrates the differences between the application of the Buffalo and Spetzler-Martin grading systems. Another classification system was proposed by Feliciano et al.8,9 That grading system was based on a literature review and included factors such as number of pedicles, eloquence, and the presence of a fistulous component. None of these classification systems correlated with clinical outcomes in an independent cohort study by Gupta et al.10 Moreover, they are not applicable to transvenous iAVM embolization. Application of these classifications necessitates the evaluation of the fistulous component with selective microcatheterization of the iAVM. Although all these classifications may have clinical relevance, the selection of a treatment modality must be tailored to the individual case.

Curative Embolization Endovascular options have largely been considered as adjunctive to microsurgery or radiosurgery; however, numerous small- and intermediate-size iAVMs can be completely obliterated with embolization

alone. Cure may be feasible for small- to medium-size ­ superficially located iAVMs with a compact nidus and pedicles accessible with a microcatheter that allows reflux of the embolic agent Onyx (Medtronic, Minneapolis, MN) for 2–3 cm and have recognizable proximal parts of the draining veins emerging from the nidus.11 Large iAVMs with feeders from multiple territories, deep location (such as the basal ganglia or brainstem), perforating artery feeders, or a diffuse nidus are considered unfavorable for endovascular iAVM cure via transarterial access.11 Advances in devices and techniques for transvenous embolization have broadened the horizon of endovascular management of iAVMs. Some iAVMs that are not amenable to transarterial cure may be cured with transvenous embolization alone or in combination with a transarterial approach.12,13 Several studies have now reported the safety and feasibility of transvenous embolization. In fact, the cure rate associated with transvenous embolization is higher than that associated with a transarterial approach.13 However, compared to the transarterial approach, transvenous embolization is technically more challenging.13 This is because of difficulty with selective catheterization of the draining vein and delivery of embolisate into the nidus in a retrograde manner, against the high fistulous flow, without incurring nidal rupture and hemorrhage.13 Various strategies have been applied to reduce the high-flow shunting in order to facilitate the transvenous embolization procedure. These strategies include systemic hypotension and temporary balloon occlusion of arterial feeders.13 We have described our experience with transvenous embolization using cardiac pacing to control the flow of blood through the iAVM.12 Transvenous iAVM embolization was successfully performed in 10 of 12 patients. (The procedure was abandoned in 2 ­ patients because of technical difficulty.) Five of the 10 AVMs were infratentorial. All 10 had a single primary draining vein. Rapid ventricular pacing was used in 9 cases; intravenous adenosine injection was used in 1 case to achieve cardiac standstill.12 Complete AVM nidus obliteration was achieved in all 10 cases, with excellent neurologic outcome in 9 cases; it was accomplished with transvenous embolization alone in 2 of 10 cases and with staged transarterial followed by transvenous embolization in the others. Two of the successfully treated patients developed hemorrhagic

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157

Fig. 15.1 Comparison of Buffalo and Spetzler-Martin grading systems. (Left) The Buffalo system takes into account the following features: number of arterial pedicles (N), diameter of those pedicles (D), and eloquent location (E). This schematic representation of supratentorial AVMs provides examples of different AVM types and the grades (1–5) determined by summing the points for each graded feature. A higher complication incidence would be expected for patients with a higher score. (Right) The Spetzler-Martin system takes into account the features of venous drainage (V), size (S), and eloquence (E).6 This schematic representation of supratentorial AVMs provides examples of different AVM types and the grades (1–5 [I–V]) determined by summing the points for each graded feature. A higher complication incidence would be expected for patients with a higher score. (Modified from Figure 2 in Dumont TM, Kan P, Snyder KV, Hopkins LN, Siddiqui AH, Levy EI. A proposed grading system for endovascular treatment of cerebral arteriovenous malformations: Buffalo score. Surg Neurol Int. 2015;6:3. © 2015 Dumont TM. Creative Commons Attribution License.)

complications intraprocedurally. One patient’s iAVM was managed conservatively and the other underwent surgical treatment, with AVM excision and hematoma evacuation; both made an excellent recovery and neither had any neurological deficit at 3 months after the embolization.12 Transvenous iAVM embolization is suitable for small iAVMs (≤ 3 cm) with a single primary draining vein where transarterial embolization is not feasible due to lack of a definite arterial pedicle, presence of multiple small feeders, supply by tiny perforating arteries, or en passage feeding arteries.12,13 A combination of transarterial and transvenous approaches can be used in a concurrent or staged fashion. We prefer to perform staged embolization for larger (> 3 cm) iAVMs, to reduce the size of the nidus. Transvenous embolization may be considered if the iAVM is not

obliterated after staged transarterial embolization and its features are favorable for a transvenous approach.12

Adjunctive Embolization Before Radiosurgery AVM size is the most important determinant of the rate of obliteration after radiosurgery. The use of preoperative embolization before radiosurgery has been controversial, with initial reports showing a negative impact of embolization on obliteration.14,15 However, overwhelming evidence is now available to suggest that preoperative embolization improves obliteration rates after radiosurgery.16 The obliteration rate for iAVMs treated with radiosurgery decreases from 80% to 50% when the size of the iAVM increases from 2.5 to 3 cm.17 The primary goal of embolization is to

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­reduce the size of the nidus before radiosurgery to increase the chances of iAVM obliteration.18 Intracranial AVMs larger than 3 cm can thus be reduced in size to less than 3 cm and become amenable to radiosurgery. A successful embolization procedure resulting in the obliteration of the periphery of an iAVM may help reduce the treatment dose required for radiosurgical obliteration, minimizing adverse effects on surrounding normal brain parenchyma.19 Another important consideration for preradiosurgery embolization is consideration of iAVM-associated aneurysms. Because treatment with radiosurgery carries a latency period, it is reasonable to treat any intranidal aneurysms to reduce the hemorrhage risk while the iAVM is still regressing. Additionally, the role of embolization directed at reducing the arteriovenous shunts to enhance the effectiveness of radiosurgery has been described.19 There are conflicting reports in the literature regarding the efficiency of embolization before radiosurgery. In our practice, we perform single or multistage embolization to reduce the iAVM volume to the minimum possible that is achievable safely before proceeding with radiosurgery.

Adjunctive Embolization Before Microsurgery The goal of preoperative embolization is to facilitate iAVM resection by reducing intraoperative bleeding or postoperative complications, such as normal perfusion pressure breakthrough. Normal perfusion pressure breakthrough is related to perinidal chronic low perfusion pressure.20 Partial or complete removal of the iAVM normalizes the perfusion pressure. However, the ability to autoregulate is impaired and may result in delayed hemorrhage, swelling, and seizures. Therefore a gradual shutdown of the iAVM with staged embolization is desired.20 (A more detailed discussion of normal perfusion pressure breakthrough is provided in Chapter 42.) The interventionist must aim to embolize the feeding arteries that are not readily accessible with microsurgical exposure. The timing of embolization in relation to surgery is controversial, with no strong evidence. We prefer to perform embolization within 24–48 hours of planned microsurgical resection to minimize any chances of recanalization. The choice of embolic material is dictated by the specific anatomic

features of the iAVM.20 Postoperative care includes strict management of blood pressure and frequent neurological examinations.20

Palliative Embolization In cases in which iAVM cure is not possible, intractable seizures or intractable headaches may dictate interventional treatment rather than medical management. The goal of palliative embolization is to reduce the severity of shunting, steal phenomenon, and/or venous hypertension.21,22 Embolization of the meningeal supply can help reduce the severity of otherwise intractable headaches. Resolution of trigeminal neuralgia after embolization has been reported.23 The risk of palliative embolization of the iAVM must be carefully weighed because partial obliteration of the iAVM may increase the risk of hemorrhage.14 However, that assumption is not universally accepted. Meisel et al.24 found that the risk of hemorrhage associated with partially embolized iAVMs was lower than the risk expected during the natural course of an untreated iAVM. Examples of partial and complete embolization are shown in Fig. 15.2.

Targeted Embolization and iAVMAssociated Aneurysms Intracranial AVMs are associated with an increased incidence of intracranial aneurysms. These aneurysms may be classified as prenidal, nidal, postnidal, or unrelated or remote to the AVM nidus. Postnidal aneurysms are venous dilatations and are better referred to as ectasia. The decision-making with respect to the management of AVM-associated aneurysms is nuanced and requires careful consideration of the location, rupture status, and curability of the primary AVM. Targeted embolization is indicated for distal flow-related and intranidal aneurysms to reduce the risk of rupture during the latency period after radiosurgery and for ruptured distal flow-related aneurysms. Decision-making for unrelated and proximal flow-related aneurysms is independent of the iAVM. Detailed discussion of iAVM-associated aneurysms and the decisionmaking process for their management are provided in Chapters 6 and 12, respectively.

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159

blood clots, and several other agents have been used and may be considered of historical interest. At present, Onyx, n-butyl cyanoacrylate (NBCA), ethylene vinyl alcohol (EVOH) copolymer, and, to a lesser extent, platinum coils and polyvinyl alcohol (PVA) particles are used to embolize AVMs. Newer agents include PHIL (precipitating hydrophobic injectable liquid, MicroVention, Tustin, CA).

Fig. 15.2 Comparison of partial and complete AVM embolization. (Upper) Example of partial AVM embolization resulting in sacrifice of the tentorial artery pedicle. (Lower) Example of complete AVM embolization with penetration of embolic agent into the entire nidus.

Embolic Agents Numerous embolic agents have been used for iAVM embolization over the years. Silk suture, muscle, detachable balloons, Silastic (Dow, Midland, MI) spheres, Gelfoam (Pfizer, New York, NY), dehydrated ethanol,

ONYX Onyx is one of the most common embolic agents. It is a liquid agent, constituted by 48-mol/L ethylene and 52-mol/L EVOH, dissolved in dimethyl sulfoxide (DMSO) and mixed with micronized tantalum powder (35% weight per volume) for radiopaque visualization.25 Onyx is provided in three different viscosities, Onyx 18, 20, and 34 (concentrations of EVOH in centipoise: 6%, 6.5%, and 8%, respectively)25 and is commercially available in vials of 1.5 mL. These vials must be shaken on a mixer for a minimum of 20 minutes before actual use for homogeneous mixing of the embolic component and the tantalum powder.25 The lower-viscosity Onyx provides more distal penetration.25 Onyx is administered through a DMSO-compatible microcatheter.25 Once the microcatheter tip is parked at the desired position, DMSO is injected to fill the dead space of the microcatheter. Therefore knowledge of the amount of dead space in the microcatheter is critical. Onyx is then directly aspirated from the vial in a 1-mL syringe.25 An amount equivalent to the dead space of the microcatheter is injected slowly over 40 seconds to fill the microcatheter and replace the DMSO in the dead space. Onyx is then slowly injected under fluoroscopy. The choice of the specific Onyx agent (concentration of Onyx) depends mainly on the degree of flow through the iAVM and proximity of the microcatheter to the nidus. Onyx 34 may be more suited for an iAVM with a greater shunt and when the microcatheter is in close proximity to the nidus to avoid distal penetration into the venous outflow. NBCA NBCA is another liquid embolic agent and is referred to as “glue.”26 NBCA instantly polymerizes on contact with ionic fluid. This increases the risk of microcatheter adhesion within the embolized arterial feeder.26

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The microcatheter is flushed with 5% dextrose water before NBCA injection to prevent premature polymerization.26 The embolic agent is prepared by mixing ethiodized oil in NBCA in various dilution ratios, depending on the need to control the polymerization rate. A higher proportion of NBCA (an ethiodized oil/ NBCA ratio close to 1:4) results in more rapid polymerization.26 A higher proportion of ethiodized oil (a ratio close to 1:2) delays polymerization, resulting in more distal penetration. Tantalum powder is added to the solution for radiopacity. Glacial acetic acid is also used to delay the polymerization of NBCA. The speed of blood flow through the nidus and the rate of injection further influence the penetration of the NBCA. These factors are carefully controlled to achieve embolization of the nidus. Onyx is considered more manageable than NBCA because it solidifies slowly; moreover, the DMSO solvent diffuses with less risk of microcatheter entrapment.26 PLATINUM COILS AND PVA PARTICLES Platinum coils and PVA particles are solid embolic agents.27,28 These agents are less frequently used. Coils are mainly used to slow flow through the iAVM.28 Flow reduction across the iAVM facilitates embolization with liquid embolic agents. Different sizes of PVA particles are available, ranging from 50 to 1000 μm.27 The rate of vessel recanalization after PVA embolization is high.27 Therefore PVA is a reasonable option for adjunctive preoperative embolization. Microsurgical resection should be performed expeditiously after PVA embolization. PHIL PHIL is a new liquid embolic agent approved for AVM embolization.29 PHIL consists of a copolymer dissolved in DMSO. The monomer hydroxyethylmethacrylate is used to make poly 2-hydroxyethyl methacrylate (pHEMA),29 a nonadhesive hydrophobic polymer that swells when exposed to water due to the molecule’s hydrophilic pendant group. Iodine binds covalently to pHEMA and provides radiopacity to the embolic agent.29 The delivery of PHIL requires a DMSO-compatible microcatheter. The DMSO solvent diffuses when in contact with blood, leaving the PHIL to precipitate in situ immediately from the outside inward. As with Onyx, the distance traveled by PHIL before

solidification depends on flow rate, proximity of the microcatheter to the nidus, rate of injection, and viscosity of the product. PHIL is also available in three concentrations (25%, 30%, and 35%), referring to the amount of the DMSO solution.29 Unlike Onyx, PHIL does not need to be shaken before use. The iodine present in the product reduces glare artifact on CT imaging. PHIL is said to have toothpaste-like flow, implying that it can be injected more rapidly than Onyx. PHIL also does not cause skin staining, making it preferable to Onyx for superficial iAVMs.30

General Anesthesia vs Conscious Sedation The choice of anesthesia varies among centers. There is little data to support the use of general anesthesia over moderate conscious sedation; however, certain advantages and disadvantages are associated with each. The advantage of moderate conscious sedation is the ability to perform a superselective anesthesia functional examination (SAFE) and a Wada test. A Wada test is used to determine the dominant side for vital cognitive functions—namely, speech and memory—in an awake patient.31 It consists of behavioral testing after the injection of an anesthetic agent, such as sodium amobarbital (Amytal) or sodium methohexital, into the internal carotid arteries. Typical use of the test is to lateralize the language centers prior to surgery. The SAFE is based on a similar concept to that of the Wada test.31 We perform a SAFE before therapeutic embolization to ensure that the catheter tip is placed in the arterial pedicle and not in vessels supplying important regions in the brain or spinal cord.32 The patient should be awake before the test is initiated. Sodium amytal is injected into the vascular territory planned for occlusion, and repeated neurological examination is performed to exclude any functional involvement.31 Rauch et al. presented data on 147 superselective Amytal injections and reported that no neurological deficit was seen in patients who had negative results on preembolization testing.32 Nevertheless, most neuroradiologists prefer general anesthesia over sedation for improved imaging quality due to patient immobility and comfort and better control of respiratory function and hemodynamics. The disadvantages of general anesthesia are

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Principles of Neuroendovascular Management of AVMs: Goals, Timing, Techniques, and Outcomes

the inability to perform a neurological assessment intraoperatively and the consequences associated with endotracheal intubation and extubation producing hypertension, coughing, or straining, which can lead to elevated intracranial pressure.31 We prefer conscious sedation and routinely perform a SAFE on all patients before embolizing each pedicle. In cases in which the patient is unable to cooperate and general anesthesia is necessary, motor-evoked potential and ­ somatosensory-evoked potential neuromonitoring are performed during the procedure. For transvenous embolization, we use general anesthesia with neuromonitoring to allow for ventricular pacing, controlled hypotension, and direct jugular vein access that is tolerable to the patient.

Outcomes of Endovascular Management of iAVMs Japanese nationwide surveillance data for 1042 endovascular treatments of iAVMs offers insight into associated outcomes and complications.33 The most common indication for endovascular treatment was as an adjunctive treatment before microsurgical resection (61.2%); the second most common use was as a sole therapy (22.2%); and the least common was as an adjunctive treatment before radiosurgery (15.4%).33 Complete or near-complete obliteration, as demonstrated on angiography, was achieved in 37.0% of cases.33 The overall complication rate was 13.1% (based on the number of procedures). Hemorrhagic complications were seen in 5.7% of procedures and ischemic complications were seen in 5.5%. Location of the iAVM in the posterior fossa was significantly associated with procedurerelated complications in multivariate analysis (P < .01); for cerebellar location, the odds ratio was 2.38 (95% confidence interval [CI], 1.25–3.16), and for brainstem location, it was 2.14 (95% CI, 1.48–10.13).33 The 30day morbidity and mortality rates were 27.9% and 0.8%, respectively.33 The report did not present the morbidity or mortality rates for transvenous and transarterial routes separately. Crowley et al. reported the outcomes of 466 embolization procedures in 342 patients.34 The endovascular strategy was preoperative in 78.9%, preradiosurgery in 9.1%, palliative in 5.3%, targeted in 4.4%, and curative in 2.3%.34 The average number of arterial pedicles

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embolized in the study was 3.5 (range, 0–13 pedicles), and the average number of sessions was 1.3 sessions (range, 1–4 sessions). The authors compared the outcomes of Onyx embolization (105 AVMs, 30.7%), and NBCA embolization without Onyx (229 AVMs, 67%). More pedicles were embolized in the Onyx group (4.3 ± 2.7 vs 3.2 ± 2.4 for the NBCA group; P < .001) in more sessions (1.5 ± 0.7 vs 1.2 ± 0.5, respectively; P < .05).34 Immediate postprocedural permanent neurological deficits were seen in 9.6% of patients, and transient deficits were seen in 1.8%. The mortality rate was 0.3%.34 Spetzler-Martin grade was not associated with the rate of complications. Moreover, there was no significant difference in periprocedural morbidity between the Onyx and NBCA groups (P = .23). This lack of a difference persisted even when the authors controlled for numbers of arteries and sessions (P = .14).34 A review of 13 studies included 69 patients with 70 iAVMs treated with transvenous embolization.13 The iAVMs ranged from less than 1 cm to 5 cm in maximum diameter.13 Onyx, PHIL, coils, and Glubran (GEM Srl, Viareggio, Italy) were used as embolic agents. Most (81%) of the iAVMs had a single draining vein, and 71% were ruptured.13 Most had small arterial feeders that were difficult to selectively catheterize. Complete angiographic obliteration of the iAVM was achieved in 93% of cases for which the intent of treatment was curative embolization. The complication rate was low (4.3%).13 However, it is important to note that these cases were highly selected and the results may not be generalizable. In our series of transvenous embolization with rapid ventricular pacing in 10 patients, 2 patients had hemorrhagic complications, as discussed earlier.12 More data are needed before transvenous ­ embolization can be adopted widely.12

Conclusion Intracranial AVMs are among the most challenging and complex pathologies of the brain, often requiring a multimodality treatment approach. Endovascular techniques may be adjunctive, curative, targeted, or palliative (embolization to reduce arteriovenous shunting). With recent advancements in endovascular techniques and transvenous embolization, numerous iAVMs can be cured with endovascular techniques alone. N-butyl cyanoacrylate, Onyx, and coils are

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the most commonly used embolic agents, with PHIL ­ gaining popularity. Due to the ability to perform a Wada test and SAFE, embolization under moderate conscious sedation is preferred. Embolization of posterior fossa iAVMs has been reported to have a higher risk of complications. Acknowledgments

We thank Paul H. Dressel BFA for research assistance on the illustrations and Debra J. Zimmer for editorial assistance. REFERENCES 1. Cohen-Gadol AA, Spencer DD. The Legacy of Harvey Cushing: Profiles of Patient Care. Thieme; 2007. 2. Luessenhop AJ, Spence WT. Artificial embolization of cerebral arteries. Report of use in a case of arteriovenous malformation. J Am Med Assoc. 1960;172:1153–1155. https://doi.org/10.1001/ jama.1960.63020110001009. 3. Ajiboye N, Chalouhi N, Starke RM, Zanaty M, Bell R. Cerebral arteriovenous malformations: evaluation and management. ScientificWorldJournal. 2014;2014. https://doi. org/10.1155/2014/649036, 649036. 4. Derdeyn CP, Zipfel GJ, Albuquerque FC, et al. Management of brain arteriovenous malformations: A Scientific Statement for Healthcare Professionals From the American Heart Association/ American Stroke Association. Stroke. 2017;48(8):e200–e224. https://doi.org/10.1161/STR.0000000000000134. 5. Mossa-Basha M, Chen J, Gandhi D. Imaging of cerebral arteriovenous malformations and dural arteriovenous fistulas. Neurosurg Clin N Am. 2012;23(1):27–42. https://doi. org/10.1016/j.nec.2011.09.007. 6. Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg. 1986;65(4):476– 483. https://doi.org/10.3171/jns.1986.65.4.0476. 7. Dumont TM, Kan P, Snyder KV, Hopkins LN, Siddiqui AH, Levy EI. A proposed grading system for endovascular treatment of cerebral arteriovenous malformations: Buffalo score. Surg Neurol Int. 2015;6:3. https://doi.org/10.4103/2152-7806.148847. 8. Feliciano CE, de Leon-Berra R, Hernandez-Gaitan MS, Rodriguez-Mercado R. A proposal for a new arteriovenous malformation grading scale for neuroendovascular procedures and literature review. P R Health Sci J. 2010;29(2):117–120. 9. Bell DL, Leslie-Mazwi TM, Yoo AJ, et al. Application of a novel brain arteriovenous malformation endovascular grading scale for transarterial embolization. AJNR Am J Neuroradiol. 2015;36(7):1303–1309. https://doi.org/10.3174/ajnr.A4286. 10. Gupta R, Adeeb N, Moore JM, et al. Validity assessment of grading scales predicting complications from embolization of cerebral arteriovenous malformations. Clin Neurol Neurosurg. 2016;151:102–107. https://doi.org/10.1016/j. clineuro.2016.10.019. 11. van Rooij WJ, Jacobs S, Sluzewski M, van der Pol B, Beute GN, Sprengers ME. Curative embolization of brain arteriovenous malformations with onyx: patient selection, embolization technique, and results. AJNR Am J Neuroradiol. 2012;33(7):1299–1304. https://doi.org/10.3174/ajnr.A2947.

12. Waqas M, Dossani RH, Vakharia K, et al. Complete flow control using transient concurrent rapid ventricular pacing or intravenous adenosine and afferent arterial balloon occlusion during transvenous embolization of cerebral arteriovenous malformations: case series. J Neurointerv Surg. 2021;13(4): 324–330. https://doi.org/10.1136/neurintsurg-2020-016945. 13. Chen CJ, Norat P, Ding D, et al. Transvenous embolization of brain arteriovenous malformations: a review of techniques, indications, and outcomes. Neurosurg Focus. 2018;45(1):E13. https://doi.org/10.3171/2018.3.FOCUS18113. 14. Andrade-Souza YM, Ramani M, Scora D, Tsao MN, terBrugge K, Schwartz ML. Embolization before radiosurgery reduces the obliteration rate of arteriovenous malformations. Neurosurgery. 2007;60(3):443–451; discussion 451–452. https://doi. org/10.1227/01.NEU.0000255347.25959.D0. 15. Schwyzer L, Yen CP, Evans A, Zavoian S, Steiner L. Longterm results of gamma knife surgery for partially embolized arteriovenous malformations. Neurosurgery. 2012;71(6):1139– 1147; discussion 1147–1148. https://doi.org/10.1227/ NEU.0b013e3182720280. 16. Pierot L, Kadziolka K, Litre F, Rousseaux P. Combined treatment of brain AVMs with use of Onyx embolization followed by radiosurgery. AJNR Am J Neuroradiol. 2013;34(7):1395–1400. https://doi.org/10.3174/ajnr.A3409. 17. Pollock BE, Gorman DA, Schomberg PJ, Kline RW. The Mayo Clinic gamma knife experience: indications and initial results. Mayo Clin Proc. 1999;74(1):5–13. https://doi. org/10.4065/74.1.5. 18. Henkes H, Nahser HC, Berg-Dammer E, Weber W, Lange S, Kuhne D. Endovascular therapy of brain AVMs prior to radiosurgery. Neurol Res. 1998;20(6):479–492. https://doi.org/ 10.1080/01616412.1998.11740552. 19. Yuki I, Kim RH, Duckwiler G, et al. Treatment of brain arteriovenous malformations with high-flow arteriovenous fistulas: risk and complications associated with endovascular embolization in multimodality treatment. Clinical article. J Neurosurg. 2010;113(4):715–722. https://doi.org/10.3171/ 2009.9.JNS081588. 20. Starke RM, Lavine SD, Meyers PM, Connolly ES. Adjuvant endovascular management of brain arteriovenous malformations. In: Winn HR, ed. Youmans Neurological Surgery. 6th ed. Elsevier; 2011:4049–4064. 21. Mast H, Mohr JP, Osipov A, et al. ‘Steal’ is an unestablished mechanism for the clinical presentation of cerebral arteriovenous malformations. Stroke. 1995;26(7):1215–1220. https://doi.org/10.1161/01.str.26.7.1215. 22. Rosenkranz M, Regelsberger J, Zeumer H, Grzyska U. Management of cerebral arteriovenous malformations associated with symptomatic congestive intracranial hypertension. Eur Neurol. 2008;59(1-2):62–66. https://doi.org/10.1159/ 000109263. 23. Simon SD, Yao TL, Rosenbaum BP, Reig A, Mericle RA. Resolution of trigeminal neuralgia after palliative embolization of a cerebellopontine angle arteriovenous malformation. Cent Eur Neurosurg. 2009;70(3):161–163. https://doi.org/ 10.1055/s-0029-1215567. 24. Meisel HJ, Mansmann U, Alvarez H, Rodesch G, Brock M, Lasjaunias P. Effect of partial targeted N-butyl-cyano-acrylate embolization in brain AVM. Acta Neurochir (Wien). 2002;144(9): 879–888. https://doi.org/10.1007/s00701-002-0978-6. 25. van Rooij WJ, Sluzewski M, Beute GN. Brain AVM embolization with Onyx. AJNR Am J Neuroradiol. 2007;28(1):172–177; discussion 178.

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26. Hill H, Chick JFB, Hage A, Srinivasa RN. N-butyl cyanoacrylate embolotherapy: techniques, complications, and management. Diagn Interv Radiol. 2018;24(2):98–103. https://doi.org/10.5152/ dir.2018.17432. 27. Sorimachi T, Koike T, Takeuchi S, et al. Embolization of cerebral arteriovenous malformations achieved with polyvinyl alcohol particles: angiographic reappearance and complications. AJNR Am J Neuroradiol. 1999;20(7):1323–1328. 28. Murayama Y, Nien YL, Duckwiler G, et al. Guglielmi detachable coil embolization of cerebral aneurysms: 11 years’ experience. J Neurosurg. 2003;98(5):959–966. https://doi.org/10.3171/ jns.2003.98.5.0959. 29. Leyon JJ, Chavda S, Thomas A, Lamin S. Preliminary experience with the liquid embolic material agent PHIL (precipitating hydrophobic injectable liquid) in treating cranial and spinal dural arteriovenous fistulas: technical note. J Neurointerv Surg. 2016;8(6):596–602. https://doi. org/10.1136/neurintsurg-2015-011684. 30. Prashar A, Butt S, Shaida N. Introducing PHIL (precipitating hydrophobic injectable liquid) – a new embolic agent for the body interventional radiologist. Diagn Interv Radiol. 2020;26(2):140–142. https://doi.org/10.5152/dir.2019.19063.

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31. Varma MK, Price K, Jayakrishnan V, Manickam B, Kessell G. Anaesthetic considerations for interventional neuroradiology. Br J Anaesth. 2007;99(1):75–85. https://doi.org/10.1093/bja/ aem122. 32. Rauch RA, Vinuela F, Dion J, et al. Preembolization functional evaluation in brain arteriovenous malformations: the ability of superselective Amytal test to predict neurologic dysfunction before embolization. AJNR Am J Neuroradiol. 1992;13(1):309–314. 33. Sato K, Matsumoto Y, Tominaga T, et al. Complications of endovascular treatments for brain arteriovenous malformations: a nationwide surveillance. AJNR Am J Neuroradiol. 2020;41(4):669–675. https://doi.org/10.3174/ ajnr.A6470. 34. Crowley RW, Ducruet AF, Kalani MY, Kim LJ, Albuquerque FC, McDougall CG. Neurological morbidity and mortality associated with the endovascular treatment of cerebral arteriovenous malformations before and during the Onyx era. J Neurosurg. 2015;122(6):1492–1497. https://doi. org/10.3171/2015.2.JNS131368.

Chapter 16

Multimodal/Combined Therapy: Goals and Outcomes Alexandra M. Giantini-Larsen, Andrew L.A. Garton, Srikanth Boddu, Alexander A. Khalessi, and Philip E. Stieg

Chapter Outline Introduction Embolization and Radiosurgery Embolization and Surgery Radiosurgery and Microsurgical Resection Embolization, Radiosurgery, and Microsurgical Resection: Treatment of Giant iAVMs Conclusion

Introduction An arteriovenous malformation (AVM) is an abnormal proliferation of blood vessels that results in a direct connection between arteries and veins without intervening capillaries.1 The nidus of an AVM is the tangle of these direct connections through which blood is shunted from artery to vein. The primary clinical concern for patients with intracranial AVMs (iAVMs) is the risk of rupture and resulting hemorrhagic stroke, which has been estimated at approximately 2%–4% per year for patients with unruptured iAVMs,2 and the primary purpose of treatment is to reduce or eliminate this risk. Choosing the appropriate iAVM management for an individual patient involves weighing the risks associated with treatment against the risks associated with continued observation. In determining whether to treat an unruptured iAVM—and which form of treatment to opt for— morphological and anatomical characteristics of the lesion as well as patient-specific characteristics must be taken into account, and the patient’s lifetime risk 164

of AVM-associated hemorrhage must be balanced against the risks associated with treatment. A large nidus, the presence of intranidal aneurysms, deep or infratentorial location, and deep venous drainage/venous outflow obstruction have been shown to increase the risk of hemorrhage and therefore are factors that would shift the balance toward intervention, as opposed to observation.1,3,4 However, these same factors may increase the risk of intervention. Many scales have been designed to quantify the risks associated with treating iAVMs and to stratify patients into “high-risk” and “low-risk” candidates. Though these grading schemes are discussed in greater detail in Chapter 8, a discussion about combined therapies warrants a reminder of the features of iAVMs that confer greater morbidity. The best known of these schemes is the Spetzler-Martin grading system, which was developed to estimate the risk involved with microsurgical resection. It is a five-point scale that includes size of nidus (small [< 3 cm] = 1 point, medium [3–6 cm] = 2 points, large [> 6 cm] = 3 points), eloquence of adjacent brain (noneloquent = 0 points, eloquent = 1 point), and pattern of venous drainage (superficialveinsonly=0points,deepveins=1point).5 The more points, the higher the risk of deficit or rupture associated with surgery. Decisions about treating an unruptured iAVM are influenced by the modality or therapy offered: radiosurgery, embolization, microsurgical resection, or any combination of the three (referred to as multimodality therapy). Stereotactic radiosurgery (SRS) delivers high-dose, focused radiation to the AVM nidus to induce endothelial and sclerotic changes, leading to

16

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Multimodal/Combined Therapy: Goals and Outcomes

eventual thrombosis of the AVM. When used as a monotherapy, the goal is obliteration of the nidus. When SRS is used as part of a combined therapy, often an area of the nidus that was not obliterated with embolization or resection will be targeted. Microsurgical resection is ideal for compact AVMs that are located in a surgically accessible area of the brain. Advantages of microsurgery include the ability to immediately eliminate hemorrhage risk and high rates of nidus obliteration and long-term effectiveness.4 Embolization is often used as an adjuvant to radiosurgery and microsurgical resection, although in select cases, it can be used as a primary method of obliteration of the AVM nidus. Permutations of any of the above strategies have been used as efficacious ways of treating AVMs, and in this chapter, we will discuss the goals and outcomes of combination therapy.

Embolization and Radiosurgery Embolization prior to SRS is useful to optimize the characteristics of an iAVM for radiosurgical treatment. SRS is utilized when microsurgical resection is not possible due to the AVM’s location, size, or feeding vessels or medical comorbidities that would preclude a patient from undergoing an operation. It is indicated for small AVMs (< 3 cm in maximum diameter and 50% AVM volume reduction), resection time, or blood loss.12 Both NBCA and Onyx are permanent embolic agents, although recanalization can occur. One advantage to Onyx is that it solidifies slowly, reducing the risk of premature polymerization within the microcatheter and allowing for repeated injection and more distal embolization.13

Embolization and Surgery Preoperative embolization decreases the morbidity associated with microsurgical resection of AVMs. The major goals of embolization in this setting include

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treatment of high-risk features, such as intranidal aneurysms and feeding arteries, reduction of flow or nidus volume, and elimination of arterial feeders that would be difficult to access surgically.4 Overall, preoperative embolization is performed to decrease the morbidity associated with resection and increase the ability to achieve controlled hemostasis during the resection. After embolization, AVMs that were initially considered surgically inaccessible due to a high risk of surgical morbidity (as manifested by a high SpetzlerMartin grade) may be amenable to resection. The timing and number of sessions of preoperative embolization depend on the size of the nidus and the specific goal of preoperative embolization. Multiple large case series have been published on the results and safety of using Onyx for preoperative embolization of iAVMs. In a series of 47 AVMs treated with preoperative Onyx embolization, the average nidus reduction was 84%.14 Complete resection was obtained in 46 of the 47 cases. In follow-up of 42 patients, 23 had no neurological deficit, 16 had a nondisabling deficit, and 3 had a disabling deficit. In a series of 28 AVMs treated with 55 sessions of preoperative embolization, the average size, volume, and Spetzler-Martin grade of the AVMs were 3.56 cm, 13.03 mL, and 2.75, respectively.15 The average nidus reduction after preoperative embolization was 74.1%. To achieve complete obliteration of an AVM, occlusion of the draining vein is considered the last step. With both embolization and surgical technique, premature occlusion or obliteration of the draining vein can have disastrous effects, the most severe being rupture of the AVM. During embolization sessions, the flow into the draining vein is assessed at the end of the session. Concern for decreased flow through the major draining vein could prompt urgent or emergent resection of the AVM.

Radiosurgery and Microsurgical Resection SRS and microsurgical resection may be used sequentially (in either order) to increase the degree of obliteration of an iAVM. Microsurgical resection can be performed after radiosurgery in cases in which complete obliteration of the AVM was not achieved with SRS alone. On the other hand, SRS can be performed on residual nidus after resective surgery. One approach

to the combined use of SRS and microsurgical resection of iAVMs is the use of SRS to reduce the grade of the lesion, as assessed by a surgical risk scale such as the Spetzler-Martin grading system, and make the AVM more amenable to resection.16 Wild et al. presented the case of a Spetzler-Martin grade IV AVM that was downgraded to grade III after SRS as well as a review of the literature that included patients who underwent both SRS and microsurgical resection.16–20 There were 59 patients from four studies whose cases met the criteria for inclusion in the analysis; the most common presenting feature was headache (46% of cases). The breakdown of Spetzler-Martin grades was as follows: grade II, 2%; grade III, 36%; grade IV, 47%; and grade V, 15%. In 73% of the cases, SRS improved (reduced) the Spetzler-Martin grade. Preoperative embolization was used in 64% of cases and complete resection was obtained in 90%. In 44% of cases, the patients underwent resection of the AVM 2–5 years after SRS.

Embolization, Radiosurgery, and Microsurgical Resection: Treatment of Giant iAVMs Giant iAVMs, defined as those with a maximum diameter greater than 6 cm, often necessitate a combined approach to achieve obliteration. The largest series to date studied the treatment outcomes in 53 cases of giant iAVMs.21 Most of the patients received multimodality therapy; embolization, radiosurgery, and surgery in 23 cases, embolization followed by radiosurgery in 23 cases, and embolization followed by surgery in 5 cases. Each session of embolization was limited to 25% obliteration in order to decrease the risk of hemorrhage. The outcomes were complete obliteration in 19 cases (36%), 90% obliteration in 4 cases (8%), and less than 90% obliteration in 29 cases (55%). The presence of an intranidal or associated aneurysm is a significant risk factor for iAVM hemorrhage.22 Preoperative embolization plays an important role in targeting these associated aneurysms for patients with iAVMs subsequently treated with SRS or microsurgical resection.23 In a study of aneurysms associated with supratentorial AVMs, there was a significant difference in size of ruptured vs unruptured aneurysms.24 The authors recommend considering treatment for ­ aneurysms with a diameter of 5 mm or greater that are

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Multimodal/Combined Therapy: Goals and Outcomes

associated with iAVMs, even if the AVM itself does not warrant intervention.

Conclusion Multimodality treatment of iAVMs is utilized to increase rates of complete obliteration and decrease risk profile associated with single-modality treatment. Embolization may be utilized prior to SRS or microsurgical resection to reduce the nidus volume and decrease high-risk features. SRS is utilized when microsurgical resection is not possible due to AVM location, AVM size, feeding vessels, or medical comorbidities that preclude surgery. SRS can be used to reduce the SpetzlerMartin grade of the AVM and make it more amenable to resection. Often, for the treatment of giant iAVMs, all three modalities are used in a single case. REFERENCES 1. Solomon RA, Connolly ES Jr. Arteriovenous malformations of the brain. N Engl J Med. 2017;376(19):1859–1866. https://doi. org/10.1056/nejmra1607407. 2. Abecassis IJ, Xu DS, Batjer HH, Bendok BR. Natural history of brain arteriovenous malformations: a systematic review. Neurosurg Focus. 2014;37(3):E7. https://doi.org/10.3171/2014.6.focus14250. 3. Ogilvy CS, Stieg PE, Awad I, et al. Recommendations for the management of intracranial arteriovenous malformations: a statement for healthcare professionals from a special writing group of the Stroke Council, American Stroke Association. Circulation. 2001;103(21):2644–2657. https://doi.org/10.1161/01. cir.103.21.2644. 4. Derdeyn CP, Zipfel GJ, Albuquerque FC, et al. Management of brain arteriovenous malformations: a scientific statement for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke. 2017;48(8):e200–e224. https://doi.org/10.1161/str.0000000000000134. 5. Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg. 1986;65(4):476– 483. https://doi.org/10.3171/jns.1986.65.4.0476. 6. Ding D, Yen CP, Starke RM, Xu Z, Sun X, Sheehan JP. Outcomes following single-session radiosurgery for high-grade intracranial arteriovenous malformations. Br J Neurosurg. 2014;28(5):666–674. https://doi.org/10.3109/02688697.2013.872227. 7. Krings T, Hans FJ, Geibprasert S, Terbrugge K. Partial “targeted” embolisation of brain arteriovenous malformations. Eur Radiol. 2010;20(11):2723–2731. https://doi.org/10.1007/ s00330-010-1834-3. 8. Xu F, Zhong J, Ray A, Manjila S, Bambakidis NC. Stereotactic radiosurgery with and without embolization for intracranial arteriovenous malformations: a systematic review and metaanalysis. Neurosurg Focus. 2014;37(3):E16. https://doi. org/10.3171/2014.6.focus14178. 9. Russell D, Peck T, Ding D, et al. Stereotactic radiosurgery alone or combined with embolization for brain arteriovenous malformations: a systematic review and meta-analysis. J Neurosurg. 2018;128(5):1338–1348. https://doi.org/10.3171/2016.11. jns162382.

167 10. Blackburn SL, Ashley WW Jr, Rich KM, et al. Combined endovascular embolization and stereotactic radiosurgery in the treatment of large arteriovenous malformations. J Neurosurg. 2011;114(6):1758–1767. https://doi.org/10.3171/2011.1.jns10571. 11. Magro E, Gentric JC, Batista AL, et al. The Treatment of Brain AVMs Study (TOBAS): an all-inclusive framework to integrate clinical care and research. J Neurosurg. 2018;128(6):1823– 1829. https://doi.org/10.3171/2017.2.jns162751. 12. Loh Y, Duckwiler GR, Investigators Onyx Trial. A prospective, multicenter, randomized trial of the Onyx liquid embolic system and N-butyl cyanoacrylate embolization of cerebral arteriovenous malformations. Clinical article. J Neurosurg. 2010;113(4):733–741. https://doi.org/10.3171/2010.3.jns09370. 13. Ellis JA, Lavine SD. Role of embolization for cerebral arteriovenous malformations. Methodist Debakey Cardiovasc J. 2014;10(4):234–239. https://doi.org/10.14797/mdcj-10-4-234. 14. Weber W, Kis B, Siekmann R, Jans P, Laumer R, Kühne D. Preoperative embolization of intracranial arteriovenous malformations with Onyx. Neurosurgery. 2007;61(2):244–254. https://doi.org/10.1227/01.neu.0000255473.60505.84. 15. Natarajan SK, Ghodke B, Britz GW, Born DE, Sekhar LN. Multimodality treatment of brain arteriovenous malformations with microsurgery after embolization with Onyx: singlecenter experience and technical nuances. Neurosurgery. 2008;62(6):1213–1225; discussion 1225–1226. 16. Wild E, Barry J, Sun H. Targeted stereotactic radiosurgery for arteriovenous malformation downgrading followed by microsurgical resection: a case report and review of the literature. World Neurosurg. 2019;131:82–86. https://doi. org/10.1016/j.wneu.2019.07.170. 17. Steinberg GK, Chang SD, Levy RP, Marks MP, Frankel K, Marcellus M. Surgical resection of large incompletely treated intracranial arteriovenous malformations following stereotactic radiosurgery. J Neurosurg. 1996;84(6):920–928. https://doi. org/10.3171/jns.1996.84.6.0920. 18. Abla AA, Rutledge WC, Seymour ZA, et al. A treatment paradigm for high-grade brain arteriovenous malformations: volume-staged radiosurgical downgrading followed by microsurgical resection. J Neurosurg. 2015;122(2):419–432. https://doi.org/10.3171/2014.10.jns1424. 19. Asgari S, Bassiouni H, Gizewski E, van de Nes JA, Stolke D, Sandalcioglu IE. AVM resection after radiation therapy- -clinicomorphological features and microsurgical results. Neurosurg Rev. 2010;33(1):53–61. https://doi.org/10.1007/s10143-009-0216-2. 20. Firlik AD, Levy EI, Kondziolka D, Yonas H. Staged volume radiosurgery followed by microsurgical resection: a novel treatment for giant cerebral arteriovenous malformations: technical case report. Neurosurgery. 1998;43(5):1223–1228. https://doi.org/10.1097/00006123-199811000-00124. 21. Chang SD, Marcellus ML, Marks MP, Levy RP, Do HM, Steinberg GK. Multimodality treatment of giant intracranial arteriovenous malformations. Neurosurgery. 2003;53(1):1-11; discussion 11–13. https://doi.org/10.1227/01.neu.0000068700.68238.84. 22. Can A, Gross BA, Du R. The natural history of cerebral arteriovenous malformations. Handb Clin Neurol. 2017;143: 15–24. https://doi.org/10.1016/b978-0-444-63640-9.00002-3. 23. Ha JK, Choi SK, Kim TS, Rhee BA, Lim YJ. Multi-modality treatment for intracranial arteriovenous malformation associated with arterial aneurysm. J Korean Neurosurg Soc. 2009;46(2): 116–122. https://doi.org/10.3340/jkns.2009.46.2.116. 24. Stein KP, Wanke I, Forsting M, et al. Associated aneurysms in supratentorial arteriovenous malformations: impact of aneurysm size on haemorrhage. Cerebrovasc Dis. 2015;39(2):122–129. https://doi.org/10.1159/000369958.

Chapter 17

Palliation Versus Observation: Nonresectable AVMs Justin E. Vranic, Robert W. Regenhardt, and Aman B. Patel

Chapter Outline Defining Nonresectable iAVMs Risks Associated With Natural History Risks Associated With Surgery The Role of Endovascular Therapy in Palliation The Role of Stereotactic Radiosurgery in Palliation The Role of Clinical Observation Conclusion

Defining Nonresectable iAVMs Defining nonresectable intracranial arteriovenous malformations (iAVMs) involves complex decision-making that weighs the risks of the lesion’s projected natural history vs the risks of resection while also considering the impact of endovascular and radiosurgical treatment modalities.1–6 Given the anatomical, pathological, and hemodynamic ­ heterogeneity of iAVMs, evaluating these risks can prove difficult.1,2 Ultimately, in order for an iAVM to be defined as nonresectable, attempts to resect it must pose a risk of permanent morbidity or mortality that is significantly greater than the risks of not doing so. Two examples of nonresectable iAVMs are shown in Fig. 17.1.

Risks Associated With Natural History Both the most common and the most feared consequence of having an iAVM is intracranial hemorrhage.7,8 For patients with iAVM-associated hemorrhage, the 1-month case fatality is 11%, and poor outcomes occur in 40% of individuals with hemorrhagic events.9 The risk of hemorrhage has been associated with several factors that must be considered. 168

For untreated, previously unruptured iAVMs, hemorrhage rates are approximately 1%–3% per year.5,8,10–16 However, for previously ruptured iAVMs, the risk can be significantly higher, especially during the first year after rupture.8,12–14 Indeed, a history of hemorrhage is the most consistent risk factor for future hemorrhage.8,11–14 One meta-analysis showed hemorrhage rates of 2.2% for unruptured iAVMs compared to 4.5% for ruptured ones.17 Another study found hemorrhage rates of 2.2% vs 4.3%, respectively, supporting these data.18 Yet another analysis showed hemorrhage rates from 2.1% to 4.1% per year, with the highest rates among those with prior hemorrhage.19 Other important factors that may elevate hemorrhage risk include deep venous drainage, fewer draining veins, deep and infratentorial nidus location, larger nidus size, associated arterial aneurysms, and venous varices.7,8,10,12,13,20–22 These angioarchitectural features can be evaluated by angiography to better assess the level of risk for the individual patient. While there are several welldescribed genetic conditions associated with iAVMs and hemorrhage risk, there are mixed data about other patient characteristics, with some suggestion that young age and female sex may increase iAVM rupture risk.8,11,12,23

Risks Associated With Surgery The mainstay of iAVM treatment is resective surgery. Resection affords the highest rate of complete, durable nidus obliteration with immediate hemorrhage risk reduction,2,24 but it can be associated with perioperative morbidity.4 Surgical limitations include eloquent location, restricted anatomic

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accessibility, retraction-related edema, intraoperative rupture, the need to avoid resection of normal brain tissue, and vessel thrombosis.1 The randomized trial known as ARUBA (A Randomised Trial of Unruptured Brain Arteriovenous Malformations), while having several limitations, suggested that medical management was superior to surgical or endovascular interventions for patients with unruptured iAVMs.1,2,4,5 This has prompted clinicians to carefully consider all treatment options for individual patients on a case-by-case basis, given the heterogeneity of the disease.2 A surgical approach involves wide exposure with circumferential dissection, feeding artery occlusion, preservation of en passage vessels, disconnection of draining veins, and en bloc nidus removal.25 Technical advances in adjunctive embolization, preoperative/ intraoperative imaging, stereotactic navigation, and intraoperative electrophysiologic monitoring continue to reduce the risks associated with surgery.26–30 Preoperative planning to avoid eloquent tissue and critical tracts is possible with functional MRI and diffusion tensor imaging tractography.31 Furthermore, the use of indocyanine green angiography allows iAVMs to be distinguished from normal vessels intraoperatively.32 To better stratify the risks associated with iAVM surgery, grading scales have been developed, with the most common being the Spetzler-Martin grading

Pearls • Palliation is reserved for symptomatic iAVMs deemed untreatable with surgery. • Palliation includes partial embolization or staged stereotactic radiosurgery. • The goal of palliation is to alleviate ischemic symptoms, headache, or seizures in patients with noncurable iAVMs. • New innovative transvenous embolization techniques may increase the number of iAVMs that are potentially curable. • Observation is a very reasonable option for high-risk iAVMs.

system.33 The Spetzler-Martin classification is made up of five tiers, based on size (1 point for < 3 cm, 2 for 3–6 cm, 3 for > 6 cm), location (1 point for eloquent, 0 for noneloquent), and venous drainage pattern (1 point for deep, 0 for superficial). This scale was subsequently simplified into the three-tier Spetzler-Ponce scale.34 Spetzler-Ponce grade A comprises SpetzlerMartin grades I and II; Spetzler-Ponce grade B is the equivalent of Spetzler-Martin grade III; and SpetzlerPonce grade C comprises Spetzler-Martin grades IV and V. According to a 2017 review of the literature, adverse surgical outcomes have been reported in 8%

Fig. 17.1 Examples of nonresectable iAVMs: a cerebellar/brainstem AVM (left) and a large basal ganglia AVM (right), both involving eloquent regions. Palliative treatment or observation could be a reasonable choice for these lesions.

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(95% confidence interval [CI], 6%–10%) of SpetzlerPonce grade A lesions, 18% (95% CI, 15%–22%) of grade B, and 32% (95% CI, 27%-38%) of grade C.34 It has been suggested that adverse outcomes may have been overestimated in cases of grade A iAVMs35 and underestimated in grade C cases.36 Based on these results, patients with Spetzler-Ponce grade A iAVMs are often considered excellent surgical candidates, while those with grade B iAVMs may require careful consideration of lesion size, location, and drainage, and grade C lesions are often managed conservatively with palliation or observation. For patients with SpetzlerPonce grade B iAVMs that are small, in an eloquent location, and have deep drainage, the surgical risk may be similar to that for Spetzler-Ponce grade A lesions, but the risk of operating on grade B lesions with medium size, noneloquent location, and deep drainage or those with medium size, eloquent location, and superficial drainage may be similar to that of operating on grade C lesions.37 Some contend that Spetzler-Ponce grade B (intermediate-risk) iAVMs may best be managed with multimodality treatment.2 The Lawton-Young supplementary grading scale was developed to improve upon the traditional Spetzler-Martin grading system and was designed to be used in combination with that system. The supplementary scale adds scores for age (1 point for 40 years), prior hemorrhage (1 for unruptured, 0 for ruptured), and nidus morphology (1 for diffuse, 0 for compact) to make a 10-tier scale.38 A large multicenter analysis found the supplemented Spetzler-Martin grading system (SM-Supp) to be more predictive for outcomes after surgery and suggested a score of 6 as a reasonable cutoff for resection; the risk of an adverse outcome ranged from 0% to 24% for patients with an SM-Supp score ≤6 and 39% to 63% for those with an SM-Supp score >6.28 As with any clinical scale, these should not be used in isolation without consideration of medical comorbidities, life expectancy, and patient goals of care.

The Role of Endovascular Therapy in Palliation Nonresectable iAVMs present unique challenges for neurosurgical management. Their location within eloquent regions of the brain, large nidal size, and/or presence of deep venous drainage precludes safe microsurgical resection for cure while the lesions themselves

continue to pose an inherent risk of hemorrhage and may produce neurological symptoms related to vascular steal phenomena or venous congestion. In these instances, endovascular therapy should be considered as a viable treatment alternative that allows for symptom palliation while possibly reducing hemorrhage risk. Endovascular iAVM embolization utilizes a range of intravascularly delivered embolisates to achieve partial or complete endovascular occlusion. The embolisate used depends on neurointerventionalist preference and may include ethylene vinyl alcohol (Onyx; Medtronic, Minneapolis, MN), liquid N-butyl cyanoacrylate, or platinum coils, with ethylene vinyl alcohol (Onyx) representing the embolisate of choice for the treatment of most iAVMs.39 Although the vast majority of iAVM embolizations are performed utilizing a transarterial approach to access the AVM nidus, emerging data have suggested that transvenous approaches may also serve as viable routes of nidal access for appropriately selected lesions.40,41 Embolization may be performed as a stand-alone therapy or in conjunction with other treatment modalities as part of a multimodality treatment strategy.42–46 In selected cases of nonresectable iAVMs, endovascular monotherapy may be attempted with curative intent. Curative success rates prove highly variable, with reports of complete iAVM occlusion ranging from approximately 20% to approximately 55% in the published literature.47–49 Attempts at endovascular cure of nonresectable iAVMs are therefore best reserved for small lesions with simple angioarchitecture where the chances of complete AVM embolization are the highest.43,45,50,51 When cure is not feasible, the goal of endovascular palliation is to reduce the hemorrhage risk associated with a nonresectable iAVM and treat symptoms related to the lesion’s vascular shunting. Prior to attempting endovascular palliation, a thorough understanding of the iAVM angioarchitecture is required, with identification of all high-risk angiographic features. This includes identifying any intranidal or perinidal aneurysms and high-flow intranidal arteriovenous fistulae, which predispose the iAVM to hemorrhage. Targeted endovascular embolization can then be attempted with the goal of occluding these high-risk angioarchitectural features.52,53 Although most patients will tolerate targeted iAVM embolization without issue, both the neurointerventionalist and the patient should be aware of the risks

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associated with such procedures prior to intervention. Published reports suggest that the overall morbidity rate associated with iAVM embolization ranges from 7% to 13% and that mortality rates range from 0% to 3%.49,54–56 Intracranial hemorrhage associated with AVM embolization represents the most common complication and is reported in 2%–12.5% of procedures.57–62

The Role of Stereotactic Radiosurgery in Palliation Stereotactic radiosurgery (SRS) is considered a definitive therapy for iAVM treatment and may represent a viable option for appropriately selected nonresectable iAVMs.63–65 Exposure to ionizing radiation during SRS results in stimulation of the vascular endothelium within the iAVM. This induces smooth muscle cell proliferation and extracellular collagen accumulation. With time, the treated iAVM develops progressive intimal hyperplasia with intralesional thrombosis and occlusion.66 In appropriately selected patients, iAVM obliteration rates of 60%–80% can be achieved within 3–5 years of SRS treatment.42,63 In cases of nonresectable iAVMs, SRS should ideally be reserved for those lesions that are small- or medium-sized (volume < 12 cm3 or diameter ≤ 3 cm) and located within deep or eloquent regions of the brain where the risks of microsurgical resection outweigh the potential benefits.24,67 In addition to treating high-risk iAVM angioarchitectural features, endovascular embolization can also be used to reduce the nidal volumes of large nonresectable iAVMs in an attempt to make them better candidates for subsequent SRS. Alternatively, SRS can be used to treat large iAVMs in a volume- or dose-staged radiosurgical approach.68 Despite its noninvasive nature, SRS for the treatment of nonresectable iAVMs is not without risk. The effect of SRS on iAVM patency is delayed, and the risk of hemorrhage persists during the latency period following treatment before AVM occlusion has occurred. One study of 135 pediatric patients showed an overall post-SRS annual hemorrhage rate of 1.8%.69 Posttherapy cyst formation within the SRS treatment bed has been reported to occur in 1%–3% of patients, with a mean time from intervention to onset

of 6.5 years. Roughly 70% of these cysts will remain asymptomatic and can be managed with observation. Symptomatic or enlarging cysts may require surgical intervention.70

The Role of Clinical Observation Clinical observation with optimal medical management of underlying vascular risk factors such as hypertension is an acceptable management strategy for patients with asymptomatic nonresectable iAVMs that do not possess high-risk angiographic features. Published data suggest that the annual risk of iAVM rupture in these patients ranges from 2% to 4.5%.1,2 Annual or biennial imaging surveillance is recommended for all iAVMs for which clinical observation is utilized. This allows for the identification of developing high-risk angiographic features such as perinidal or intranidal aneurysms.71 Multiple imaging modalities can be utilized for surveillance purposes, including noninvasive CT angiography and MR angiography or invasive catheter angiography. Clinical observation is supported by the ARUBA results.5 In this randomized controlled trial, a total of 114 patients with unruptured iAVMs were randomized to receive optimal medical management with intervention (i.e., microsurgical resection, endovascular embolization, or SRS, alone or in combination), and 109 patients were randomized to receive optimal medical management alone. The trial was prematurely terminated 6 years after the initiation of randomization due to superiority of the medical management arm (death or symptomatic stroke in 10% vs 31% in the intervention arm; hazard ratio [HR], 0.27; 95% CI, 0.14–0.54). These results were maintained with an extended mean follow-up time of 50.4 months.72 Similar findings were reported in the Scottish Audit of Intracranial Vascular Malformations (SAIVM), which was a prospective, population-based cohort study comparing conservative management (n = 101) vs intervention (n = 103) for unruptured iAVMs.73 In this study, the rate of nonfatal stroke or death was lower with conservative management during 12 years of follow-up (1.6 vs 3.3 per 100 person-years; adjusted HR, 0.37; 95% CI, 0.019–0.72). Collectively, the results of the ARUBA and SAIVM trials lend support to the use of clinical observation without intervention for appropriately selected nonresectable AVMs.

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Conclusion Nonresectable iAVMs pose unique management challenges. Lesion features such as large nidus size, eloquent location, and deep venous drainage often preclude safe, curative treatment. In such cases, palliative interventions may represent viable treatment alternatives aimed at improving symptoms and/or reducing iAVM hemorrhage risk. For lesions that can be readily catheterized, endovascular embolization can be used to treat high-risk angiographic features such as perinidal aneurysms as well as to reduce vascular shunting through the iAVM. SRS can be considered for the treatment of nonresectable iAVMs that are not amenable to endovascular catheterization and are located within eloquent regions of the brain. For individuals with asymptomatic, nonresectable iAVMs that do not possess high-risk angiographic features, clinical observation with routine angiographic follow-up imaging represents a viable alternative management strategy. REFERENCES 1. Ajiboye N, Chalouhi N, Starke RM, Zanaty M, Bell R. Cerebral arteriovenous malformations: evaluation and management. ScientificWorldJournal. 2014;2014:649036. https://doi.org/10. 1155/2014/649036. 2. Conger A, Kulwin C, Lawton MT, Cohen-Gadol AA. Diagnosis and evaluation of intracranial arteriovenous malformations. Surg Neurol Int. 2015;6:76. https://doi.org/ 10.4103/2152-7806.156866. 3. Zacharia BE, Vaughan KA, Jacoby A, Hickman ZL, Bodmer D, Connolly ES Jr. Management of ruptured brain arteriovenous malformations. Curr Atheroscler Rep. 2012;14(4):335–342. https://doi.org/10.1007/s11883-012-0257-9. 4. van Beijnum J, van der Worp HB, Buis DR, et al. Treatment of brain arteriovenous malformations: a systematic review and meta-analysis. JAMA. 2011;306(18):2011–2019. https://doi. org/10.1001/jama.2011.1632. 5. Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, nonblinded, randomised trial. Lancet. 2014;383(9917):614–621. https://doi.org/10.1016/S0140-6736(13)62302-8. 6. Komiyama M. Pathogenesis of brain arteriovenous malformations. Neurol Med Chir (Tokyo). 2016;56(6):317–325. https://doi.org/10.2176/nmc.ra.2016-0051. 7. Ding D, Chen CJ, Starke RM, et al. Risk of brain arteriovenous malformation hemorrhage before and after stereotactic radiosurgery. Stroke. 2019;50(6):1384–1391. https://doi.org/ 10.1161/STROKEAHA.118.024230. 8. Kim H, Al-Shahi Salman R, McCulloch CE, Stapf C, Young WL. MARS Coinvestigators. Untreated brain arteriovenous malformation: patient-level meta-analysis of hemorrhage predictors. Neurology. 2014;83(7):590–597. https://doi.org/ 10.1212/WNL.0000000000000688.

9. van Beijnum J, Lovelock CE, Cordonnier C, et al. Outcome after spontaneous and arteriovenous malformation-related intracerebral haemorrhage: population-based studies. Brain. 2009;132(pt 2):537–543. https://doi.org/10.1093/brain/awn318. 10. Graf CJ, Perret GE, Torner JC. Bleeding from cerebral arteriovenous malformations as part of their natural history. J Neurosurg. 1983;58(3):331–337. https://doi.org/10.3171/jns. 1983.58.3.0331. 11. Crawford PM, West CR, Chadwick DW, Shaw MD. Arteriovenous malformations of the brain: natural history in unoperated patients. J Neurol Neurosurg Psychiatry. 1986;49(1): 1–10. https://doi.org/10.1136/jnnp.49.1.1. 12. Mast H, Young WL, Koennecke HC, et al. Risk of spontaneous haemorrhage after diagnosis of cerebral arteriovenous malformation. Lancet. 1997;350(9084):1065–1068. https:// doi.org/10.1016/s0140-6736(97)05390-7. 13. Hernesniemi JA, Dashti R, Juvela S, Vaart K, Niemela M, Laakso A. Natural history of brain arteriovenous malformations: a longterm follow-up study of risk of hemorrhage in 238 patients. Neurosurgery. 2008;63(5):823–829; discussion 829–831. https:// doi.org/10.1227/01.NEU.0000330401.82582.5E. 14. da Costa L, Wallace MC, Ter Brugge KG, O'Kelly C, Willinsky RA, Tymianski M. The natural history and predictive features of hemorrhage from brain arteriovenous malformations. Stroke. 2009;40(1):100–105. https://doi.org/10.1161/STROKEAHA. 108.524678. 15. Yang W, Porras JL, Xu R, et al. Comparison of hemorrhagic risk in intracranial arteriovenous malformations between conservative management and embolization as the single treatment modality. Neurosurgery. 2018;82(4):481–490. https://doi.org/10.1093/neuros/nyx230. 16. Brown RD Jr, Wiebers DO, Forbes G, et al. The natural history of unruptured intracranial arteriovenous malformations. J Neurosurg. 1988;68(3):352–357. https://doi.org/10.3171/ jns.1988.68.3.0352. 17. Gross BA, Du R. Natural history of cerebral arteriovenous malformations: a meta-analysis. J Neurosurg. 2013;118(2): 437–443. https://doi.org/10.3171/2012.10.JNS121280. 18. Goldberg J, Raabe A, Bervini D. Natural history of brain arteriovenous malformations: systematic review. J Neurosurg Sci. 2018;62(4): 437–443. https://doi.org/10.23736/S0390-5616.18.04452-1. 19. Abecassis IJ, Xu DS, Batjer HH, Bendok BR. Natural history of brain arteriovenous malformations: a systematic review. Neurosurg Focus. 2014;37(3):E7. https://doi.org/10. 3171/2014.6.FOCUS14250. 20. Stefani MA, Porter PJ, terBrugge KG, Montanera W, Willinsky RA, Wallace MC. Large and deep brain arteriovenous malformations are associated with risk of future hemorrhage. Stroke. 2002;33(5):1220–1224. https://doi.org/10.1161/01. str.0000013738.53113.33. 21. Stefani MA, Porter PJ, terBrugge KG, Montanera W, Willinsky RA, Wallace MC. Angioarchitectural factors present in brain arteriovenous malformations associated with hemorrhagic presentation. Stroke. 2002;33(4):920–924. https://doi.org/ 10.1161/01.str.0000014582.03429.f7. 22. Khaw AV, Mohr JP, Sciacca RR, et al. Association of infratentorial brain arteriovenous malformations with hemorrhage at initial presentation. Stroke. 2004;35(3):660–663. https://doi. org/10.1161/01.STR.0000117093.59726.F9. 23. Yamada S, Takagi Y, Nozaki K, Kikuta K, Hashimoto N. Risk factors for subsequent hemorrhage in patients with cerebral arteriovenous malformations. J Neurosurg. 2007;107(5): 965–972. https://doi.org/10.3171/JNS-07/11/0965.

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24. Derdeyn CP, Zipfel GJ, Albuquerque FC, et al. Management of brain arteriovenous malformations: a scientific statement for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke. 2017;48(8):e200–e224. https://doi.org/10.1161/STR.0000000000000134. 25. Hashimoto N, Nozaki K, Takagi Y, Kikuta K, Mikuni N. Surgery of cerebral arteriovenous malformations. Neurosurgery. 2007;61(1 Suppl):375–387; discussion 387–389. https://doi. org/10.1227/01.NEU.0000255491.95944.EB. 26. Hartmann A, Stapf C, Hofmeister C, et al. Determinants of neurological outcome after surgery for brain arteriovenous malformation. Stroke. 2000;31(10):2361–2364. https://doi. org/10.1161/01.str.31.10.2361. 27. Davidson AS, Morgan MK. How safe is arteriovenous malformation surgery? A prospective, observational study of surgery as first-line treatment for brain arteriovenous malformations. Neurosurgery. 2010;66(3):498–504; discussion 504–505. https://doi.org/10.1227/01.NEU.0000365518.47684.98. 28. Kim H, Abla AA, Nelson J, et al. Validation of the supplemented Spetzler-Martin grading system for brain arteriovenous malformations in a multicenter cohort of 1009 surgical patients. Neurosurgery. 2015;76(1):25–31; discussion 31–32; quiz 32–33. https://doi.org/10.1227/NEU.0000000000000556. 29. Schramm J, Schaller K, Esche J, Bostrom A. Microsurgery for cerebral arteriovenous malformations: subgroup outcomes in a consecutive series of 288 cases. J Neurosurg. 2017;126(4): 1056–1063. https://doi.org/10.3171/2016.4.JNS153017. 30. Wong J, Slomovic A, Ibrahim G, Radovanovic I, Tymianski M. Microsurgery for ARUBA trial (A Randomized Trial of Unruptured Brain Arteriovenous Malformation)-eligible Unruptured Brain Arteriovenous Malformations. Stroke. 2017;48(1):136–144. https://doi.org/10.1161/STROKEAHA. 116.014660. 31. Bendok BR, El Tecle NE, El Ahmadieh TY, et al. Advances and innovations in brain arteriovenous malformation surgery. Neurosurgery. 2014;74(Suppl 1):S60–S73. https://doi.org/ 10.1227/NEU.0000000000000230. 32. Killory BD, Nakaji P, Gonzales LF, Ponce FA, Wait SD, Spetzler RF. Prospective evaluation of surgical microscope-integrated intraoperative near-infrared indocyanine green angiography during cerebral arteriovenous malformation surgery. Neurosurgery. 2009;65(3):456–462; discussion 462. https:// doi.org/10.1227/01.NEU.0000346649.48114.3A. 33. Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg. 1986;65(4):476–483. https://doi.org/10.3171/jns.1986.65.4.0476. 34. Spetzler RF, Ponce FA. A 3-tier classification of cerebral arteriovenous malformations. Clinical article. J Neurosurg. 2011; 114(3):842–849. https://doi.org/10.3171/2010.8.JNS10663. 35. Morgan MK, Davidson AS, Assaad NNA, Stoodley MA. Critical review of brain AVM surgery, surgical results and natural history in 2017. Acta Neurochir (Wien). 2017;159(8):1457– 1478. https://doi.org/10.1007/s00701-017-3217-x. 36. Korja M, Bervini D, Assaad N, Morgan MK. Role of surgery in the management of brain arteriovenous malformations: prospective cohort study. Stroke. 2014;45(12):3549–3555. https://doi.org/10.1161/STROKEAHA.114.007206. 37. Lawton MT. UCSF Brain Arteriovenous Malformation Study Project. Spetzler-Martin Grade III arteriovenous malformations: surgical results and a modification of the grading scale. Neurosurgery. 2003;52(4):740–748; discussion 748–749. https://doi.org/10.1227/01.neu.0000053220.02268.9c.

173 38. Lawton MT, Kim H, McCulloch CE, Mikhak B, Young WL. A supplementary grading scale for selecting patients with brain arteriovenous malformations for surgery. Neurosurgery. 2010;66(4):702–713; discussion 713. https://doi.org/10. 1227/01.NEU.0000367555.16733.E1. 39. Loh Y, Duckwiler GR, Investigators Onyx Trial. A prospective, multicenter, randomized trial of the Onyx liquid embolic system and N-butyl cyanoacrylate embolization of cerebral arteriovenous malformations. Clinical article. J Neurosurg. 2010;113(4): 733–741. https://doi.org/10.3171/2010.3.JNS09370. 40. Chen CJ, Norat P, Ding D, et al. Transvenous embolization of brain arteriovenous malformations: a review of techniques, indications, and outcomes. Neurosurg Focus. 2018;45(1):E13. https://doi.org/10.3171/2018.3.FOCUS18113. 41. Fahed R, Darsaut TE, Mounayer C, et al. Transvenous Approach for the Treatment of cerebral Arteriovenous Malformations (TATAM): study protocol of a randomised controlled trial. Interv Neuroradiol. 2019;25(3):305–309. https://doi. org/10.1177/1591019918821738. 42. Starke RM, Komotar RJ, Otten ML, et al. Adjuvant embolization with N-butyl cyanoacrylate in the treatment of cerebral arteriovenous malformations: outcomes, complications, and predictors of neurologic deficits. Stroke. 2009;40(8):2783– 2790. https://doi.org/10.1161/STROKEAHA.108.539775. 43. Saatci I, Geyik S, Yavuz K, Cekirge HS. Endovascular treatment of brain arteriovenous malformations with prolonged intranidal Onyx injection technique: long-term results in 350 consecutive patients with completed endovascular treatment course. J Neurosurg. 2011;115(1):78–88. https://doi. org/10.3171/2011.2.JNS09830. 44. Sahlein DH, Mora P, Becske T, Nelson PK. Nidal embolization of brain arteriovenous malformations: rates of cure, partial embolization, and clinical outcome. J Neurosurg. 2012;117(1): 65–77. https://doi.org/10.3171/2012.3.JNS111405. 45. Pierot L, Cognard C, Herbreteau D, et al. Endovascular treatment of brain arteriovenous malformations using a liquid embolic agent: results of a prospective, multicentre study (BRAVO). Eur Radiol. 2013;23(10):2838–2845. https://doi. org/10.1007/s00330-013-2870-6. 46. Crowley RW, Ducruet AF, Kalani MY, Kim LJ, Albuquerque FC, McDougall CG. Neurological morbidity and mortality associated with the endovascular treatment of cerebral arteriovenous malformations before and during the Onyx era. J Neurosurg. 2015;122(6):1492–1497. https://doi.org/ 10.3171/2015.2.JNS131368. 47. Yu SC, Chan MS, Lam JM, Tam PH, Poon WS. Complete obliteration of intracranial arteriovenous malformation with endovascular cyanoacrylate embolization: initial success and rate of permanent cure. AJNR Am J Neuroradiol. 2004;25(7): 1139–1143. 48. Valavanis A, Yaşargil MG. The endovascular treatment of brain arteriovenous malformations. Adv Tech Stand Neurosurg. 1998;24:131–214. https://doi.org/10.1007/978-3-70916504-1_4. 49. Katsaridis V, Papagiannaki C, Aimar E. Curative embolization of cerebral arteriovenous malformations (AVMs) with Onyx in 101 patients. Neuroradiology. 2008;50(7):589–597. https://doi. org/10.1007/s00234-008-0382-x. 50. Baharvahdat H, Blanc R, Termechi R, et al. Hemorrhagic complications after endovascular treatment of cerebral arteriovenous malformations. AJNR Am J Neuroradiol. 2014;35(5):978–983. https://doi.org/10.3174/ajnr.A3906.

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51. Krings T, Hans FJ, Geibprasert S, Terbrugge K. Partial “targeted” embolisation of brain arteriovenous malformations. Eur Radiol. 2010;20(11):2723–2731. https://doi.org/10.1007/ s00330-010-1834-3. 52. Ellis JA, Lavine SD. Role of embolization for cerebral arteriovenous malformations. Methodist Debakey Cardiovasc J. 2014;10(4):234–239. https://doi.org/10.14797/mdcj-10-4-234. 53. Gross BA, Moon K, McDougall CG. Endovascular management of arteriovenous malformations. Handb Clin Neurol. 2017; 143:59–68. https://doi.org/10.1016/B978-0-444-63640-9. 00006-0. 54. Mounayer C, Hammami N, Piotin M, et al. Nidal embolization of brain arteriovenous malformations using Onyx in 94 patients. AJNR Am J Neuroradiol. 2007;28(3):518–523. 55. van Rooij WJ, Sluzewski M, Beute GN. Brain AVM embolization with Onyx. AJNR Am J Neuroradiol. 2007;28(1):172–177; discussion 178. 56. Weber W, Kis B, Siekmann R, Kuehne D. Endovascular treatment of intracranial arteriovenous malformations with Onyx: technical aspects. AJNR Am J Neuroradiol. 2007;28(2): 371–377. 57. Ovalle F, Shay SD, Mericle RA. Delayed intracerebral hemorrhage after uneventful embolization of brain arteriovenous malformations is related to volume of embolic agent administered: multivariate analysis of 13 predictive factors. Neurosurgery. 2012;70(2 Suppl Operative):313–320. https://doi.org/10.1227/NEU.0b013e3182357df3. 58. Picard L, Da Costa E, Anxionnat R, et al. Acute spontaneous hemorrhage after embolization of brain arteriovenous malformation with N-butyl cyanoacrylate. J Neuroradiol. 2001;28(3):147–165. 59. Purdy PD, Batjer HH, Samson D. Management of hemorrhagic complications from preoperative embolization of arteriovenous malformations. J Neurosurg. 1991;74(2):205–211. https://doi. org/10.3171/jns.1991.74.2.0205. 60. Keller E, Yonekawa Y, Imhof HG, Tanaka M, Valavanis A. Intensive care management of patients with severe intracerebral haemorrhage after endovascular treatment of brain arteriovenous malformations. Neuroradiology. 2002;44(6): 5135–5221. https://doi.org/10.1007/s00234-002-0791-1. 61. Deruty R, Pelissou-Guyotat I, Mottolese C, et al. Therapeutic risk in multidisciplinary approach of cerebral arteriovenous malformations. Article in French. Neurochirurgie. 1996;42(1): 35–43. 62. Biondi A, Le Jean L, Capelle L, Duffau H, Marsault C. Fatal hemorrhagic complication following endovascular treatment of a cerebral arteriovenous malformation. Case report and review of the literature. J Neuroradiol. 2006;33(2):96–104. https://doi. org/10.1016/s0150-9861(06)77238-8.

63. Paul L, Casasco A, Kusak ME, Martinez N, Rey G, Martinez R. Results for a series of 697 arteriovenous malformations treated by Gamma Knife: influence of angiographic features on the obliteration rate. Neurosurgery. 2014;75(5):568–583; discussion 582–358; quiz 583. https://doi.org/10.1227/ NEU.0000000000000506. 64. Pollock BE, Link MJ, Stafford SL, Garces YI, Foote RL. Stereotactic radiosurgery for arteriovenous malformations: the effect of treatment period on patient outcomes. Neurosurgery. 2016;78(4): 499–509. https://doi.org/10.1227/NEU.0000000000001085. 65. Starke RM, Kano H, Ding D, et al. Stereotactic radiosurgery for cerebral arteriovenous malformations: evaluation of long-term outcomes in a multicenter cohort. J Neurosurg. 2017;126(1): 36–44. https://doi.org/10.3171/2015.9.JNS151311. 66. Chang SD, Shuster DL, Steinberg GK, Levy RP, Frankel K. Stereotactic radiosurgery of arteriovenous malformations: pathologic changes in resected tissue. Clin Neuropathol. 1997; 16(2):111–116. 67. Vlaskou Badra E, Ermis E, Mordasini P, Herrmann E. Radiosurgery and radiotherapy for arteriovenous malformations: outcome predictors and review of the literature. J Neurosurg Sci. 2018;62(4):490–504. https://doi.org/10.23736/S0390-5616. 18.04406-5. 68. Narayanan M, Atwal GS, Nakaji P. Multimodality management of cerebral arteriovenous malformations. Handb Clin Neurol. 2017;143:85–96. https://doi.org/10.1016/B978-0-444-636409.00008-4. 69. Kano H, Kondziolka D, Flickinger JC, et al. Stereotactic radiosurgery for arteriovenous malformations, part 2: management of pediatric patients. J Neurosurg Pediatr. 2012;9(1):1–10. https://doi.org/10.3171/2011.9.PEDS10458. 70. Chen CJ, Ding D, Derdeyn CP, et al. Brain arteriovenous malformations: a review of natural history, pathobiology, and interventions. Neurology. 2020;95(20):917–927. https://doi. org/10.1212/WNL.0000000000010968. 71. Unnithan A. Overview of the current concepts in the management of arteriovenous malformations of the brain. Postgrad Med J. 2020;96(1134):212–220. https://doi.org/10. 1136/postgradmedj-2019-137202. 72. Mohr JP, Overbey JR, Hartmann A, et al. Medical management with interventional therapy versus medical management alone for unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre, non-blinded, randomised controlled trial. Lancet Neurol. 2020;19(7):573–581. https:// doi.org/10.1016/S1474-4422(20)30181-2. 73. Al-Shahi Salman R, White PM, Counsell CE, et al. Outcome after conservative management or intervention for unruptured brain arteriovenous malformations. JAMA. 2014;311(16): 1661–1669. https://doi.org/10.1001/jama.2014.3200.

Chapter 18

Conservative Management (“Observation”) of Intracranial AVMs Christopher S. Ogilvy and Mohamed M. Salem

Chapter Outline

Initial Evaluation and Classification

Introduction Initial Evaluation and Classification Decision-Making and Risk Assessment Weighing Risks for Patients with High-Grade AVMs Choosing the Right Management Strategy Conclusion

The initial phase of evaluation of an iAVM requires gathering information. This typically includes obtaining a clinical history and imaging to delineate the details of the AVM in order to be able to make an informed decision about the most appropriate next step. Patient demographic variables also weigh heavily in the decision. The workup usually includes multiple diagnostic tests, especially CT and MR angiograms and standard MRI studies. Additionally, functional MRI can be helpful in discerning the relationship between the AVM and critical structures of the brain, including areas that control motor function and speech. A catheter-based angiogram is often critical to help evaluate the AVM vasculature and visualize the main vessels of supply to the lesion as well as the actual “nidus” (mass of tangled vessels) and the venous drainage. Once the information from this workup is complete, a discussion should ensue regarding the risks of continued observation versus the risks of intervention. In order to understand the data that inform decisions about the risk for individual patients, it is necessary to have some familiarity with the classification of iAVMs. This topic is covered in detail elsewhere in this book (see, in particular, Chapters 8 and 19); here, we provide only a brief overview of the most commonly used classification system, the Spetzler-Martin grading system, to facilitate the discussion of management options. The Spetzler-Martin grading system was specifically designed to predict the outcome of surgical treatment. It has also been extensively used to classify iAVMs in general and discuss other treatment modalities and

Introduction Current management of intracranial arteriovenous malformations (iAVMs) includes several treatment modalities to choose from. However, the initial decision for both patient and physician is whether the lesion should be treated or not. The overall risk of treatment must be balanced against the risks of continued observation (natural history) of the lesion. If treatment seems the best option, the modality of treatment is chosen based on careful assessment of the risks and potential benefits of each treatment in the patient’s particular case. Surgical excision (resection), endovascular embolization, radiosurgery, or combined-modality therapy should each be considered. These treatment options are covered in other chapters of this text. Our goal for the current chapter is to consider the natural history of iAVMs and how to determine whether a conservative course of observation might be the lowest-risk option for an individual patient.

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natural history, although the utility of this more general application is questionable. The Spetzler-Martin system is a composite five-point classification system based on three main criteria: maximum diameter of the nidus: (1) (< 3 cm: 1 point, 3–6 cm: 2 points, > 6 cm: 3 points), (2) venous drainage (superficial: 0 points, deep: 1 point), and (3) eloquence of the area of the brain (noneloquent: 0 points, eloquent: 1 point).1 Eloquence refers to particular areas of the brain that control essential functions, including speech, language, and vision, where damage can lead to focal neurologic deficits. Accordingly, the risks of intervention may be deemed higher when these areas are involved. Examples of eloquent areas include but are not limited to motor and sensory cortices, auditory and visual cortices, speech areas, basal ganglia, thalamus, hypothalamus, and brainstem.2 A higher Spetzler-Martin grade denotes increased complexity of the lesion and a higher risk of a poor outcome with surgical excision.

Decision-Making and Risk Assessment Obviously, the greatest anticipated benefit from any iAVM intervention is prevention of future hemorrhage or possibly seizures, but this potential benefit must be balanced against the risk of treatment-related morbidity and mortality. If the risks of intervention are deemed to be higher than the risks associated with the expected natural history of the lesion if left untreated, the recommendation should be continued clinical observation with no invasive treatment. Given that the cumulative risk of a first hemorrhage over 20 years after diagnosis has been reported to be as high as 30%3 and that iAVMs are mostly diagnosed in younger patients ( 6 cm) is determined using a nonmagnified diagnostic cerebral angiogram and measuring maximum nidus diameter. This measurement includes the AVM nidus, but also indicates factors relating to the difficulty of AVM resection, including number of feeding arteries and degree of vascular steal. The AVM location as it relates to eloquent cerebral locations is of significant prognostic importance. Those AVMs that present in eloquent territory—as defined by Drs. Spetzler and Martin as sensorimotor, language, and visual cortex; hypothalamus; thalamus; internal capsule; brainstem; cerebellar peduncles; or deep cerebellar nuclei—earn an additional point, reflecting the increased risk of 183

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TABLE 19.1 Spetzler-Martin Grading System Graded Feature

Points

Sizea Small (< 3 cm) Medium (3–6 cm) Large (> 6 cm)

1 2 3

Eloquenceb Noneloquent Eloquent

0 1

Pattern of Venous Drainagec Superficial only Deep

0 1

a

Largest diameter as seen on diagnostic cerebral angiogram. Eloquent locations are defined as sensorimotor, language, visual cortex; hypothalamus, thalamus; internal capsule; brainstem; cerebellar peduncles; and deep cerebellar nuclei. c Venous drainage is superficial if all drainage is via the superficial system. Drainage is deep if it involves any of the deep veins, including internal cerebral veins, basal vein, precentral cerebellar vein, etc. b

surgical morbidity and mortality. Finally, the venous drainage pattern is evaluated for deep venous drainage, especially the internal cerebral veins, basal vein of Rosenthal, or precentral cerebellar vein (vein of the cerebellomesencephalic fissure). Deep venous drainage is considered to further add to the risk associated with resection. Overall, using this system generates grades of I–V, which correlates, both retrospectively and prospectively, with morbidity and mortality following microsurgical intervention (Table 19.2).6,22 Radiographic examples of each Spetzler-Martin grade are presented in Figs. 19.1–19.5. Of note, a Spetzler-Martin grade of VI is reserved for untreatable lesions, cases in which treatment would unavoidably be associated with disabling morbidity or mortality. Although the Spetzler-Martin grading scale remains ubiquitous in clinical practice for neurosurgical discussion, assessing surgical risk, and predicting the outcome of microsurgical resection, clinicians often use it in conjunction with the Spetzler-Ponce classification or the supplementary grading scale of Lawton et al. described below.7,15 In 2010, Lawton et al. proposed a supplementary grading scale that was developed with the intention of

Pearls • Surgical risk at experienced centers can be accurately determined. • Preoperative use of functional MRI, diffusion tensor imaging, and Wada testing along with routine MRI, CT angiography, and digital subtraction angiography greatly facilitates interventional risk assessment. • Location, size, venous drainage, perforating vessels, and diffuseness are key to surgical risk assessment in association with age, medical comorbidities, and acuteness in surgical episode. • Multimodality therapy is often employed, but currently there is no combined risk assessment scale. • Considering all variables—location and vascular anatomy are the key risk factors in intervention.

expanding the Spetzler-Martin grading system by focusing on additional factors that would help predict neurologic outcome following resection and thereby further refine patient selection for surgery. This supplementary AVM grading system awards points for clinical and AVM characteristics that are not covered by the original Spetzler-Martin grade, including patient age, ruptured AVM status, AVM diffuseness, and inclusion of a deep perforating artery, which are all predictors of worse outcome. This supplementary model was found to be more predictive of outcome than the Spetzler-Martin grade alone; however, the new scale was only intended as a supplement and not as a replacement for the already well-established Spetzler-Martin grading system.15 Shortly thereafter, in 2011, Spetzler and Ponce proposed a three-tier simplification of the original Spetzler-Martin grading scale. In this three-tier system, Spetzler-Martin grades I and II are combined into class A, grade III is class B, and grades IV and V are class C (Fig. 19.6). This model, known as the Spetzler-Ponce classification, was intended to help guide treatment decisions as well as predict outcomes. Spetzler and Ponce retrospectively applied their three-tier classification to seven surgical case series in which results had been stratified by Spetzler-Martin grade and concluded that the predictive accuracies for surgical outcomes were equivalent in the original five-tier Spetzler-Martin grading system and the newly proposed three-tier

19

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Grading Systems and Surgical Risks

TABLE 19.2 Correlation of AVM Grade With Surgical Results NO DEFICITb a

c

d

Grade

No. of Cases

No.

%

No.

%

No.

%

Death (%)

I II III IV V Total

23 21 25 15 16 100

23 20 21 11 11 86

100 95 84 73 69 86

0 1 3 3 3 10

0 5 12 20 19 10

0 0 1 1 2 4

0 0 4 7 12 4

0 0 0 0 0 0

a

Grade VI is reserved for untreatable lesions that would unavoidably be associated with disabling morbidity or mortality. Complications lasting less than 3 days were not included in morbidity. c Major morbidity is defined as hemiparesis, increase in aphasia, homonymous hemianopsia, severe deficit with major aphasia and hemiparesis. d Minor morbidity is defined as mild increase in brainstem deficit, temporary increase in visual field deficit, temporary increase in aphasia and weakness, mild increase in aphasia only detectable with rapid speech, temporary mild increased weakness, increase in trigeminal nerve deficit, mild temporary increase in hemiparesis, mild residual ataxia, temporary mild dysphagia. Reproduced from Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg. 1986;65(4):476-483. Published with permission. The footnotes (a–d) were added for clarification, based on the article, and are not present in the original table. b

Fig. 19.1 Spetzler-Martin grade I AVM. (A) T2-weighted MR image and (B) lateral digital subtraction angiogram demonstrating a Spetzler-Martin grade I AVM with a small (< 3 cm) nidus in a superficial, noneloquent location with superficial venous drainage.

classification. Based on their analysis, they further concluded that combining Spetzler-Martin grades I and II and combining grades IV and V were justified because of the small amount of difference in outcome between the individual grades in each of these two combined

categories. Furthermore, this Spetzler-Ponce model also proposed a treatment paradigm according to the AVM class, where resection, multimodality treatment, and no treatment were proposed for class A, class B, and class C AVMs, respectively.7

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Fig. 19.2 Spetzler-Martin grade II AVM. (A) Anterior-posterior and (B) lateral digital subtraction angiograms demonstrating a Spetzler-Martin grade II AVM with a medium-size (3–6 cm) nidus in a superficial, noneloquent location with superficial venous drainage.

Fig. 19.3 Spetzler-Martin grade III AVM. (A) Lateral digital subtraction angiogram and (B) 3D reconstruction of Spetzler-Martin grade III AVM with a medium-size (3–6 cm) nidus in a superficial, eloquent location with superficial venous drainage via cortical veins of Troland (arrow) and Labbé (arrowhead) into the superior sagittal sinus and transverse sigmoid sinus, respectively.

19

Grading Systems and Surgical Risks

187

Fig. 19.4 Spetzler-Martin grade IV AVM. (A) Late arterial phase and (B) early venous phase lateral (left) and anterior-posterior (right) view digital subtraction angiograms displaying a Spetzler-Martin grade IV AVM with a large (> 6 cm) diffuse nidus in an eloquent location with superficial venous drainage. (C) T2-weighted MR image showing the extent of the nidus and the surrounding brain parenchyma.

Fig. 19.5 Spetzler-Martin grade V AVM. (A) Axial T2-weighted MR image showing a large right temporal-parietal-occipital AVM with a diffuse nidus. (B) Lateral-projection digital subtraction angiogram highlighting the features of a Spetzler-Martin grade V AVM with a large (> 6 cm) nidus, involvement of eloquent territory, and deep venous drainage.

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Fig. 19.6 See legend on following page.

19

Grading Systems and Surgical Risks

189

Fig. 19.6 Diagrammatic representation of the combinations of graded variables (size, eloquence, and venous drainage) for each class of AVM. The Spetzler-Martin system assigns a score of 1 for small AVMs (< 3 cm), 2 for medium (3–6 cm), and 3 for large (> 6 cm). The eloquence of the adjacent brain is scored as either noneloquent (0) or eloquent (1). The venous drainage is scored as superficial only (0) or including drainage to the deep cerebral veins (1). Scores for each feature are totaled to determine the grade. In the Spetzler-Ponce modification, class A includes SpetzlerMartin grades I and II; class B includes grade III; and class C includes grades IV and V. (Image modified from Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg. 1986;65:476-483. From Spetzler RF, Ponce FA. A 3-tier classification of cerebral arteriovenous malformations. J Neurosurg. 2011;114(3): 842-849. Published with permission.)

Additional AVM Grading Systems In addition to the foundational and widely employed aforementioned iAVM grading systems (the SpetzlerMartin grading system, the supplemental system proposed by Lawton et al., and the Spetzler-Ponce classification), several additional grading classifications have been proposed for iAVMs, especially for those lesions with particular clinical and radiographic criteria. Table 19.3 presents a summary of the grading systems, their significant contributing factors, and the outcome metrics used.16,18–21,23–28 Fig. 19.7 presents a flow diagram showing how some of the grading systems may be applied depending on the characteristics of the individual patient’s AVM and the treatment considerations. Here, we briefly explore additional AVM grading systems, specifically those focused on ruptured AVMs, posterior fossa AVMs, and AVMs in eloquent territory. RUPTURED IAVM In general, iAVMs carry an annual risk of rupture (hemorrhage) of 2%–4% per year. The risk of iAVM hemorrhage is increased if the AVM is small, has deep venous drainage, is periventricular, or has associated intranidal or flow-related aneurysms. Once an iAVM ruptures, there is a 6% chance of rerupture in the first year and 3% risk per subsequent year. Each hemorrhage carries a 10% risk of mortality and 25% risk of morbidity. Two grading systems have been proposed to predict clinical outcome in cases of ruptured iAVMs. In 2016, a multiinstitutional group developed the AVM-related intracerebral hemorrhage (AVICH) score, which combines the well-established ICH score and various AVM and hemorrhage characteristics, including intraventricular hemorrhage, nidus size and configuration, SpetzlerMartin grade, and the supplemented Spetzler-Martin

score, to predict clinical outcome for patients with a hemorrhagic iAVM. Although the AVICH score was not externally validated, Neidert et al. concluded that it predicted patient outcome following iAVM rupture better than the well-established ICH score, Spetzler-Martin grade, and supplemental grading system.18 Most recently, Silva et al. proposed an additional grading scale for ruptured iAVMs, the Ruptured AVM Grading Scale (RAGS), which incorporates the Hunt and Hess score, traditionally used for aneurysm rupture, as well as AVM characteristics seen in many other grading systems (patient age, venous drainage, eloquence). RAGS is able to predict change in modified Rankin Scale (mRS) score from prerupture through resection to longest follow-up with superior accuracy.23 LOCATION OF IAVM The location of an iAVM further determines how safely it can be treated, whether by surgery, embolization, or radiation. Although the Spetzler-Martin grading system, as well as many other iAVM classification systems, includes location in its algorithm, the location is usually regarded as binary—eloquent or noneloquent. For AVMs in the posterior fossa and for those in proximity to eloquent territory, two additional scoring systems have been proposed to predict the risk associated with resection (Table 19.3). Nisson et al. proposed a grading system specific to AVMs located in the posterior fossa, which demonstrates a superior level of predictive accuracy for outcomes of resective surgery.8 This posterior fossa Nisson score utilizes similar characteristics as previous scoring systems, including venous drainage and patient age, but also includes variables such as emergency surgery and preoperative neurologic status. As expected, patients requiring

TABLE 19.3 Summary of AVM Grading Systems actors

Author

Score

Size

Loc/ Eloq

Venous Drainage X

Nidus Hem Age Comp Pres

Other/ Comments

Outcome

Microsurgery Spetzler and Martin6 Spears et al. 14 Lawton et al.15 Spetzler and Ponce7 Nisson et al.8

Spetzler-Martin X Toronto model Supplementary Spetzler-Ponce X Posterior fossa

X

X X

X

Jiao et al.16 Neidert et al.18 Silva et al.23

HDVL AVICH RAGS

X

X (LED) X X X X X

X X

RBAS PRAS

Xa Xa

X X

Heidelberg VRAS

X Xa

X

Morbidity X

X

X X

X

X X

X X

Internally validated Externally validated Externally validated Preop exam, emergency surgery

mRS score Morbidity/mortality and mRS score mRS score

GCS, ICH volume, IVH Hunt and Hess score

mRS score mRS score mRS score

18.9 Gy (15–25 Gy) 15 Gy

AVM obliteration and clinical AVM obliteration

18 Gy (12–22 Gy) 25 Gy

AVM obliteration Clinical

No. of vascular pedicles, pedicle diameter, externally validated

Validated to predict complication occurrence and procedural risk as component of multimodality treatment (not cure); > 85% AVM nidus reduction Complete obliteration and complication; > 85% AVM nidus reduction Risk assessment and outcome stratification; > 85% AVM nidus reduction

Radiosurgery Pollock et al.24,25 Hattangadi-Gluth et al.26 Milker-Zabel et al.27 Starke et al.28

X

X X

Endovascular Dumont et al.20

Buffalo

Lopes et al.21

AVMES

Feliciano et al.19

Puerto Rico

X

X

X

X

X (no. of draining veins)

No. of vascular pedicles Fistula present, no. of vascular pedicles

AVICH, AVM-related intracerebral hemorrhage (score); AVMES, AVM embocure score; Comp, compactness; Eloq, eloquence; GCS, Glasgow Coma Scale; HDVL, hemorrhagic presentation, nidus diffuseness, deep venous drainage, lesion-to-eloquence distance (LED); Hem, hemorrhagic; ICH, intracerebral hemorrhage; IVH, intraventricular hemorrhage; Loq, location; mRS, modified Rankin Scale; No., number; PRAS, proton radiosurgery AVM scale; Pres, presentation; RAGS, Ruptured AVM Grading Scale; RBAS, radiosurgery-based AVM score; VRAS, Virginia Radiosurgery AVM Scale. Clinical outcome assessed using mRS with an mRS score ≤ 2 indicating a good outcome. a Volume used for size.

19

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Grading Systems and Surgical Risks

AVM GRADING SYSTEMS

Microsurgical

Ruptured

AVICH score

Radiosurgical

Unruptured

Infratentorial

Supratentorial

Nisson score

Endovascular

Radiosurgerybased AVM score

Buffalo score

Proton radiosurgery AVM scale

AVM embocure score

Spetzler-Martin Spetzler-Ponce

Puerto Rico score

Supplementary grading scale

HDVL grading system Fig. 19.7 Flow chart for AVM grading systems. AVICH, AVM-related intracerebral hemorrhage; HDVL, hemorrhagic presentation, nidus diffuseness, deep venous drainage, lesion-to-eloquence distance (LED).

emergency surgery and having poor neurologic status had increased surgical risk, and these characteristics showed a strong association with poor outcomes. Vascular malformations in proximity to areas of eloquence can be assessed using the HDVL grading system, which was developed by Jiao et al.16 This ­ supplementary grading system is based on hemorrhagic presentation, diffuseness, deep venous draining, and the unique variable of lesion-to-eloquence distance (LED). Utilizing functional MRI and diffusion tensor imaging tractography, it is possible to quantify the spatial relationship between eloquent parenchyma and nidus using LED. The authors identified three categories for this parameter, 0–5, 5–10, and > 10 mm, with closer proximity to eloquence correlating with increased surgical risk. Overall, this system was found to

be yet another superior combination of preoperative variables to predict surgical risk and outcome of iAVM resection.

Endovascular Grading The aforementioned grading paradigms, most notably the Spetzler-Martin grading system, are based on anatomical characteristics and their impact on resection; however, despite the proven reliability of these foundational systems over time, clinicians and researchers have determined that they do not reflect the major determinants of risk associated with endovascular treatment of iAVMs.19–21 As displayed in Table 19.3, there are three neuroendovascular grading systems—the Buffalo score, the Puerto Rico

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PART 1 The Patient-Centered Approach

score, and the AVM embocure score (AVMES)— which utilize specific and nuanced cerebrovascular features, including not only the presence of atrial feeders and draining veins, like the previously presented foundational systems, but also the number of vascular pedicles and draining veins as well as pedicle diameter and presence of a fistula. Of these endovascular grading system, the Buffalo score is the only validated system with the capability of predicting complication recurrence and procedural risk as a component of multimodality iAVM treatment, not for endovascular cure.29

Radiosurgery Grading Although resection is usually the preferred treatment for iAVMs, patients whose lesions are deep or otherwise surgically inaccessible may be candidates for stereotactic radiosurgery (SRS). In 2002, Pollock and Flickinger developed a radiosurgery-based AVM score (RBAS), utilizing AVM volume, patient age, and AVM location (hemispheric, corpus callosum, cerebellar = 0; basal ganglia, thalamus, brainstem = 1) to predict radiosurgical outcomes following Gamma Knife SRS, linear-accelerator SRS, CyberKnife SRS, and protonbased SRS.24,25 In a comparative analysis of iAVM grading scales in predicting outcomes after SRS, RBAS and the proton radiosurgery AVM scale (PRAS) outperformed several other leading iAVM obliteration grading systems in terms of predicting iAVM obliteration without new deficits.30

Surgical Risks Microsurgical resection of iAVMs carries significant surgical risks, which can be mitigated with dedicated preoperative, intraoperative, and postoperative management at experienced neurosurgical centers. Preoperatively, multidisciplinary cerebrovascular teams, composed of neurosurgeons, neurointerventionalists, neuroradiologists, and radiosurgeons, evaluate the AVM morphology, flow pattern, and high-risk features such as flow-related aneurysms, intranidal aneurysms, venous outflow obstructions, and other characteristics. Strategies for reducing intraoperative risk include preoperative embolization or planned staged resection. Regardless of all the predictive scoring systems and algorithms, if the iAVM

is not resected in a proper sequence and manner, the risk of intraoperative hemorrhage becomes even more significant. AVM resection follows the sequence of coagulation of arterial feeders in a circumferential fashion. While separating the nidus from the surrounding parenchyma, the draining vein should not be ligated until the end. Ligation of the draining vein prior to resection of the nidus and coagulation of the feeding arteries increases perfusion pressure and therefore increases the risk of rupture. Lastly, due to the loss of autoregulation in tissue surrounding the iAVM cavity, it is paramount to ensure complete hemostasis of the cavity prior to closure of the craniotomy.31,32 Postoperatively, experienced neurological intensive care is crucial. Intensive neurological monitoring and blood pressure control are necessary for successful patient recovery following every iAVM resection.

Conclusion Management of iAVMs requires a multidisciplinary approach and consideration of multiple treatment options, including endovascular, radiosurgical, and microsurgical modalities, alone or in combination. Although the majority of treatment combinations may revolve around a microsurgical resection, interdisciplinary treatment decisions should incorporate risk stratification from the evidence-based grading systems appropriate for the individual case and treatment modalities being considered in order to achieve the highest rate of AVM eradication and provide optimal patient care. REFERENCES 1. Stapf C, Mast H, Sciacca RR, et al. The New York Islands AVM Study: design, study progress, and initial results. Stroke. 2003;34(5):e29–e33. https://doi.org/10.1161/01.STR. 0000068784.36838.19. 2. Abecassis IJ, Xu DS, Batjer HH, Bendok BR. Natural history of brain arteriovenous malformations: a systematic review. Neurosurg Focus. 2014;37(3):E7. https://doi.org/10.3171/2014.6.FOCUS14250. 3. Al-Shahi R, Bhattacharya JJ, Currie DG, et al. Prospective, population-based detection of intracranial vascular malformations in adults: the Scottish Intracranial Vascular Malformation Study (SIVMS). Stroke. 2003;34(5):1163–1169. https://doi.org/10.1161/01.STR.0000069018.90456.C9. 4. Hartmann A, Mast H, Mohr JP, et al. Morbidity of intracranial hemorrhage in patients with cerebral arteriovenous malformation. Stroke. 1998;29(5):931–934. https://doi.org/ 10.1161/01.str.29.5.931.

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5. Perret G, Nishioka H. Report on the cooperative study of intracranial aneurysms and subarachnoid hemorrhage. Section VI. Arteriovenous malformations. An analysis of 545 cases of cranio-cerebral arteriovenous malformations and fistulae reported to the cooperative study. J Neurosurg. 1966;25(4):467– 490. https://doi.org/10.3171/jns.1966.25.4.0467. 6. Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg. 1986;65(4):476– 483. https://doi.org/10.3171/jns.1986.65.4.0476. 7. Spetzler RF, Ponce FA. A 3-tier classification of cerebral arteriovenous malformations. Clinical article. J Neurosurg. 2011; 114(3):842–849. https://doi.org/10.3171/2010.8.JNS10663. 8. Nisson PL, Fard SA, Walter CM, et al. A novel proposed grading system for cerebellar arteriovenous malformations. J Neurosurg. 2019;132(4):1105–1115. https://doi.org/10.3171/2018.12. JNS181677. 9. Luessenhop AJ, Gennarelli TA. Anatomical grading of supratentorial arteriovenous malformations for determining operability. Neurosurgery. 1977;1(1):30–35. https://doi.org/ 10.1227/00006123-197707000-00007. 10. Shi YQ, Chen XC. A proposed scheme for grading intracranial arteriovenous malformations. J Neurosurg. 1986;65(4):484– 489. https://doi.org/10.3171/jns.1986.65.4.0484. 11. Pertiliset B, Ancri D, Kinuta Y, et al. Classification of supratentorial arteriovenous malformations. A score system for evaluation of operability and surgical strategy based on an analysis of 66 cases. Acta Neurochir (Wien). 1991;110(1-2):6– 16. https://doi.org/10.1007/BF01402041. 12. Tamaki N, Ehara K, Lin T-K, et al. Cerebral arteriovenous malformations: factors influencing the surgical difficulty and outcome. Neurosurgery. 1991;29(6):856–863. https://doi. org/10.1227/00006123-199112000-00009. 13. Höllerhage HG, Dewenter KM, Dietz H. Grading of supratentorial arteriovenous malformations on the basis of multivariate analysis of prognostic factors. Acta Neurochir (Wien). 1992;117(3-4):129–134. https://doi.org/10.1007/ BF01400609. 14. Spears J, Terbrugge KG, Moosavian M, et al. A discriminative prediction model of neurological outcome for patients undergoing surgery of brain arteriovenous malformations. Stroke. 2006;37(6):1457–1464. https://doi.org/10.1161/01. STR.0000222937.30216.13. 15. Lawton MT, Kim H, McCulloch CE, Mikhak B, Young WL. A supplementary grading scale for selecting patients with brain arteriovenous malformations for surgery. Neurosurgery. 2010;66(4):702–713; discussion 713. https:// doi.org/10.1227/01.NEU.0000367555.16733.E1. 16. Jiao Y, Lin F, Wu J, et al. A supplementary grading scale combining lesion-to-eloquence distance for predicting surgical outcomes of patients with brain arteriovenous malformations. J Neurosurg. 2018;128(2):530–540. https://doi. org/10.3171/2016.10.JNS161415. 17. Appelboom G, Hwang BY, Bruce SS, et al. Predicting outcome after arteriovenous malformation-associated intracerebral hemorrhage with the original ICH score. World Neurosurg. 2012;78(6):646– 650. https://doi.org/10.1016/j.wneu.2011.12.001. 18. Neidert MC, Lawton MT, Mader M, et al. The AVICH score: a novel grading system to predict clinical outcome in arteriovenous malformation-related intracerebral hemorrhage. World Neurosurg. 2016;92:292–297. https://doi.org/10.1016/j. wneu.2016.04.080.

193 19. Feliciano CE, de León-Berra R, Hernández-Gaitán MS, Rodríguez-Mercado R. A proposal for a new arteriovenous malformation grading scale for neuroendovascular procedures and literature review. P R Health Sci J. 2010;29(2):117–120. 20. Dumont TM, Kan P, Snyder KV, Hopkins LN, Siddiqui AH, Levy EI. A proposed grading system for endovascular treatment of cerebral arteriovenous malformations: Buffalo score. Surg Neurol Int. 2015;6:3. https://doi.org/10.4103/2152-7806.148847. 21. Lopes DK, Moftakhar R, Straus D, Munich SA, Chaus F, Kaszuba MC. Arteriovenous malformation embocure score: AVMES. J Neurointerv Surg. 2016;8(7):685–691. https://doi. org/10.1136/neurintsurg-2015-011779. 22. Hamilton MG, Spetzler RF. The prospective application of a grading system for arteriovenous malformations. Neurosurgery. 1994;34(1):2–6; discussion 6. https://doi. org/10.1097/00006123-199401000-00002. 23. Silva MA, Lai PMR, Du R, Aziz-Sultan MA, Patel NJ. The ruptured arteriovenous malformation grading scale (RAGS): an extension of the Hunt and Hess scale to predict clinical outcome for patients with ruptured brain arteriovenous malformations. Neurosurgery. 2020;87(2):193–199. https://doi.org/10.1093/ neuros/nyz404. 24. Pollock BE, Flickinger JC. A proposed radiosurgery-based grading system for arteriovenous malformations. J Neurosurg. 2002;96(1):79–85. https://doi.org/10.3171/jns.2002.96.1.0079. 25. Pollock BE, Flickinger JC. Modification of the radiosurgerybased arteriovenous malformation grading system. Neurosurgery. 2008;63(2):239–243; discussion 243. https:// doi.org/10.1227/01.NEU.0000315861.24920.92. 26. Hattangadi-Gluth JA, Chapman PH, Kim D, et al. Single-fraction proton beam stereotactic radiosurgery for cerebral arteriovenous malformations. Int J Radiat Oncol Biol Phys. 2014;89(2):338– 346. https://doi.org/10.1016/j.ijrobp.2014.02.030. 27. Milker-Zabel S, Kopp-Schneider A, Wiesbauer H, et al. Proposal for a new prognostic score for linac-based radiosurgery in cerebral arteriovenous malformations. Int J Radiat Oncol Biol Phys. 2012;83(2):525–532. https://doi.org/10.1016/j .ijrobp.2011.07.008. 28. Starke RM, Yen C-P, Ding D, Sheehan JP. A practical grading scale for predicting outcome after radiosurgery for arteriovenous malformations: analysis of 1012 treated patients. J Neurosurg. 2013;119(4):981–987. https://doi. org/10.3171/2013.5.JNS1311. 29. Pulli B, Stapleton CJ, Walcott CP, et al. Comparison of predictive grading systems for procedural risk in endovascular treatment of brain arteriovenous malformations: analysis of 104 consecutive patients. J Neurosurg. 2020;133(2):342–350. https://doi.org/10.3171/2019.4.jns19266. 30. Pollock BE, Storlie CB, Link MJ, Stafford SL, Garces YI, Foote RL. Comparative analysis of arteriovenous malformation grading scales in predicting outcomes after stereotactic radiosurgery. J Neurosurg. 2017;126(3):852–858. https://doi. org/10.3171/2015.11.JNS151300. 31. Pool JL. Treatment of arteriovenous malformations of the cerebral hemispheres. J Neurosurg. 1962;19(2):136–141. https://doi.org/10.3171/jns.1962.19.2.0136. 32. Yaşargil MG. Microneurosurgery: AVM of the Brain, Clinical Considerations, General and Special Operative Techniques, Surgical Results, Nonoperated Cases, Cavernous and Venous Angiomas, Neuroanesthesia. Vol IIIB. Thieme; 1988.

Chapter 20

Risks of Endovascular Treatment of AVMs Visish M. Srinivasan, Redi Rahmani, Joshua S. Catapano, and Felipe C. Albuquerque

Chapter Outline Introduction Preoperative Evaluation and Staging Preoperative Embolization Preradiosurgical Embolization Embolization for Cure and Transvenous Approaches Targeted Embolization Palliative Embolization Complications and Risk Technique Conclusion

Introduction Intracranial arteriovenous malformations (iAVMs) are challenging lesions to treat, and patients often require multimodal management to achieve optimal outcomes. Options for AVM management include conservative management, endovascular embolization, surgical removal (resection) with or without preoperative embolization, and radiosurgery with or without preprocedural embolization. Endovascular embolization is an important tool in this treatment arsenal because it improves the efficacy and safety of other treatments and can also be used for selective noncurative treatments. In well-selected cases, endovascular embolization may also serve as the primary treatment. Since the first report of iAVM embolization by Luessenhop and Spence in 1960,1 much progress has been made, with techniques evolving from the use of steel-methylmethacrylate spheres to detachable 194

balloons to liquid embolic agents. Although advances in endovascular technology have made embolization much safer, it is not yet a risk-free procedure. In this chapter, we focus on the evaluation of patients and potential staging of endovascular procedures; preoperative, preradiosurgical, curative, targeted, and palliative uses of endovascular embolization; and various risks and mitigation strategies associated with iAVM embolization.

Preoperative Evaluation and Staging The preoperative evaluation of the patient and determination of an accurate diagnosis are the first steps in understanding the risks of endovascular management. The preoperative assessment should include a proper understanding of the patient’s symptoms and earlier hemorrhagic events, if any, because these factors can guide targeted treatment. Noninvasive imaging to be assessed includes CT and MRI, as well as the associated CT angiography (CTA) and MR angiography (MRA). MRI is used to better define the anatomical location of the lesion because this location can guide the understanding of the angiographic anatomy and vice versa. In addition, MRI is better than CTA at showing the surrounding parenchyma and the presence of previous hemorrhages or microhemorrhages.2 The embolization of AVMs can sometimes be staged; this staging can be used as part of a multimodal treatment plan or when embolization is sought as a standalone treatment. Usually, the decision for staging is made before embarking on treatment on the basis of the initial imaging characteristics. Alternatively, the decision to use a staged approach can be made after starting

20

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Risks of Endovascular Treatment of AVMs

embolization due to the limitations of a singlesession radiation dose or contrast load. As a general rule, we prefer multiple sessions when treating AVMs with a maximum size greater than 3 cm and/or numerous arterial pedicles. Although radiation and contrast dosing are important limitations during embolic procedures, the primary risk of “heroic” embolization efforts that significantly alter hemodynamic characteristics is normal perfusion pressure breakthrough. This concept, initially described by Spetzler et al.3 and more recently refined by Rangel-Castilla et al.,4 suggests that a sudden increase in perfusion pressure can occur in a chronically hypoperfused capillary bed surrounding the AVM caused by the sudden decrease in arteriovenous shunting following resection. These patients may lack normal autoregulatory mechanisms to counter these changes, which results in cerebral edema or hemorrhage. Patients with large lesions may undergo staged embolization before planned resection.5 Before starting a treatment course, the conceptual goals of treatment should be laid out clearly for the benefit of both the treatment team (neurosurgical, neurointerventional, and radiosurgical) and the patient. Although embolization can be used as a standalone treatment in selected patients (discussed later), the neurointerventionalist should avoid undertaking embolization without a clear goal in mind. Furthermore, when embolization is being performed as an adjunctive treatment, the specific targets should be discussed between the neurointerventionalist and the surgeon to maximize the value of the procedure. For these reasons, iAVMs should be treated at high-volume centers that offer comprehensive care (medical, surgical, interventional, and radiosurgical), and treatment teams should be familiar with one another to optimize outcomes (unpublished data).

Preoperative Embolization Preoperative treatment is the most common indication for iAVM embolization. The goals and strategy for preoperative embolization should be as precise as the surgery itself. It should be kept in mind that the goal is to facilitate resection, making it safer and easier. The goal of embolization should not be to “go for broke” and possibly cure the iAVM. When

Pearls • Intracranial AVMs can be embolized for five different strategies: curative intent, preoperative, preradiosurgical, targeted, or palliative. • The most common indication is preoperative embolization, and the relative goals of each aspect of this treatment combination should be balanced to reduce the risk to the patient at each stage. • Risks associated with the embolization should be known as much as possible up front, and they are dependent on the treatment strategy and the extent of embolization planned. • Complication risks of embolization can be predicted by various scores accounting for the iAVM size, arterial inflow, and venous outflow, among other factors. • Risk can be mitigated by careful preoperative planning and nuances of embolization technique.

preoperative embolization is pursued to facilitate resection, the neurointerventionalist can balance the risks and benefits of certain procedural steps. The aggregate risk of surgery with embolization should not exceed the risk of surgery performed without the embolization. That is, the potential benefit of embolization (how much it reduces the risk of surgery) should offset the risk of the embolization itself. This risk can be calculated either by a “dual-trained” neurosurgeon or between colleagues in neurosurgery and neurointerventional surgery. The result is generally a less aggressive approach to treatment than if a curative endovascular procedure were performed. Because the lesion is to be resected in total after preoperative embolization, the embolization need not be as durable as it would have to be for a curative procedure. In preoperative embolization, arterial inflow should be diminished in a stepwise and safe manner, with a focus on vessels that are less surgically accessible (usually the deep face of the AVM) depending on the surgical approach. The result of this approach is that, in many cases, embolization can be performed safely and improve surgical safety.

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Preradiosurgical Embolization Embolization of AVMs before radiosurgical treatment has become increasingly common as endovascular and radiosurgical techniques have evolved. Significant regional variations exist in treatment paradigms,6 with the combination of endovascular and radiosurgical treatments being more common in Europe than in the United States. The goals of preradiosurgical embolization can vary and are unique to the individual case. The overall goal is to treat specific aspects of the iAVM that are not easily curable with radiosurgery. For example, large iAVMs, flow-related or nidal aneurysms, and high-flow fistulas are all unfavorable for radiosurgery alone and are ideal embolization targets. Specifically, if an AVM has ruptured and is amenable to radiosurgery, we would target embolization to treat the ruptured nidal aneurysm before radiosurgery, which would have a delayed effect. Volume-staged radiosurgery has emerged as an option for some patients who previously would have been treated with embolization followed by radiosurgery; however, this is less commonly practiced at our institution.7,8 Before the use of this option, embolization was performed to reduce the nidus to less than 3 cm so that the radiation could be conformed to a smaller target that would allow sufficient nidal penetration. As with preoperative embolization, agents with low recanalization potential (i.e., liquid embolics) should be used.

Embolization for Cure and Transvenous Approaches Embolization is performed in select cases as a primary treatment for the AVM, with the goal of a complete cure. This procedure is known by several terms, such as primary embolization, standalone embolization, curative embolization, or embocure. In large series of iAVM embolization, the rates of cure varied widely from 5% to 33% (Table 20.1).9–18 The rate of cure was more clearly defined in some series where the intent of the embolization attempt was delineated a priori, such as the study by Haw et al.13 They reported that among 55 AVMs selected for curative attempts, the rate of cure was 33%. However, a cure was achieved in some cases in which it was not the intent. In fact, “intention-to-cure” procedures only accounted for 59% of actually cured AVMs; in the other cases, embolization was performed as an adjunct to stereotactic radiosurgery or surgery. In this intentto-cure cohort, the risks of embolization did not differ from the risks when embolization was performed as an adjunct. An additional risk comes with curative embolization. To cure via transarterial access, the surgeon must achieve aggressive nidal penetration and proximal venous occlusion. However, this approach may also prematurely occlude veins. For this reason, some authors have discussed the use of transvenous techniques.

TABLE 20.1 Data From Previous Clinical Studies of iAVM Embolization Authors, Year Frizzel and Fisher, 19959 Debrun et al., 199710 Hartmann et al., 200211 Taylor et al., 200412 Haw et al., 200613 Starke et al., 200914 Sahlein et al., 201215 Panagiotopoulos et al., 200916 Pierot et al., 200517 Katsaridis et al., 200818

No. of iAVMs Embolized

No. of Embolization Sessions

Temporary Morbidity (%)

Permanent Morbidity (%)

Mortality (%)

Cure Rate (%)

32 54 233 201 306 202 131 82

NR NR 545 339 513 377 168 NR

10 3.7 14 3.5 8.1 8 NR 12

8 5.6 2 9 7.5 2.5 0.8 7

1 3.7 0.85 2 2.6 NR 0.8 2.4

5 5.6 NR NR 5.5 NR 33 24.4

50 101

149 219

NR NR

8 8

2 3

8.3 28

No., Number; NR, not reported.

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Risks of Endovascular Treatment of AVMs

These newer techniques have clear risks for premature venous occlusion without dearterialization, precipitating rupture. Increased aggression for curative treatment by embolization alone generally carries an increased risk. In an article published in 2020, De Sousa et al.19 analyzed the unique risks of transvenous embolization in a series of 57 patients treated over an 11-year period. Hemorrhagic complications (intraoperative or perioperative) occurred in 14% of patients and correlated with nidus size greater than 3 cm and a larger number of draining veins (odds ratio 8.7). De Sousa et al. concluded that the ideal lesion for transvenous embolization with lower risk would be a small AVM ( 10 cm3) AVMs with staged SRS was just completed this year, and results are forthcoming (NCT02576535). With respect to reducing the risk of AVM rupture, data from clinical series have been troubling: in a cohort of 2320 patients undergoing SRS, hemorrhage rates only decreased from 15.4/1000 person-years prior to SRS to 11.9/1000 person-years following SRS.29

Stereotactic Radiosurgery Followed by Resection The rarest of all iAVM multimodality treatment permutations, this therapeutic strategy was not studied in the only major clinical trial on iAVM management, ARUBA (A Randomised Trial of Unruptured Brain Arteriovenous Malformations).30 Nevertheless, there are examples of using SRS to treat surgically unresectable lesions until they regress enough to become safer to operate on. A group from the United States presented a case of a high-grade (Spetzler-Martin grade IV) AVM that was deemed to be unsafe to operate on due to arterial supply from the middle cerebral artery, superficial and deep drainage, involvement of the

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Risks of Combined Therapies

thalamus and basal ganglia, and the presence of an intranidal aneurysm. However, after it was treated with 18 Gy, they observed occlusion of the deep arterial supply and venous outflow, resulting in the AVM being downgraded to a Spetzler-Martin grade III lesion. The patient subsequently underwent embolization and successful resection, and her condition was stable at 1 year’s follow-up.31 While technically an example of all three modalities being used for a single AVM, the case illustrates the point that SRS can be used to change an AVM to a more surgically accessible lesion. In a review of staged SRS, irradiation was noted to reduce AVM grade in 73% of patients; complete resection was subsequently obtained in 90%.31–35 However, of course, this approach is not without risk. Hemorrhage prior to surgery can be seen in up to 20% of patients, and radiation necrosis in 10%.35 Typically, the doses of radiation used in staged AVM obliteration are lower than in SRS for tumor treatment, and in a retrospective analysis of 755 patients of iAVMs treated with SRS, only 2 patients required surgery for symptomatic radiation effects.36 Chronic, encapsulated intracerebral hematomas are exceedingly rare as well, but they have been reported as late as 13 years following SRS for AVMs.37 Whether SRS is used after surgery or surgery is used after SRS, there does not appear to be any compounding effect—that is, the risk of either treatment does not appear to be greater than it would be if it were used alone.

grade I–IV lesions were treated effectively with multimodality therapy, whereas 53% of grade V lesions were completely obliterated. Higher grade was also correlated with a greater need for multimodality therapy.26 These trends have been corroborated in other studies, which have demonstrated favorable risk profiles relative to the medical management arm of ARUBA.13 Data from Stanford suggest that deep thalamic and basal ganglia AVMs can be treated with favorable risk/benefit profiles through multimodality treatment, with surgery and radiosurgery acting as independent predictors of radiographic cure.38 Importantly, the most well-known risk associated with preoperative embolization is the risk of hemorrhage in the treatment of giant iAVMs.39 While preoperative embolization clearly plays a role in improving the efficacy of multimodality therapy for patients with these very large lesions, it is particularly important in such cases to seek treatment at a center that can handle complications. A center that practices the triad of AVM treatment strategies will be equipped to handle periprocedural complications. Embolization followed by elective surgery is certainly more ideal than embolization followed by emergent surgery, but the guiding principles of multimodality management and AVM obliteration confirmed intraoperatively and via radiographic follow-up are the same in both scenarios.

Combination Treatment of Giant iAVMs

Appropriate management for many types of iAVMs remains a matter of continued debate. The lack of consensus is primarily attributable to the relationship between the relatively low prevalence of these lesions and limited prospective or clinical trial data. Intracranial AVMs are primarily discovered on symptomatic presentation, which limits our understanding of the natural history of an asymptomatic, unruptured iAVM, as well as the risks of simple observation. Though a triad of interventions have emerged for iAVMs, there has been only one major clinical trial to date, and its conclusions have been met with critiques and skepticism. It will be of paramount importance to carefully construct prospective cohort studies and clinical trials to enhance our understanding of how to manage and treat this pathology to minimize the risk with multimodality therapy.

Multimodality therapy is of even more critical importance when considering iAVMs that cannot be effectively treated with any single technique. Highgrade AVMs, for example, are associated with higher risks of hemorrhage and less-complete obliterations. Nevertheless, in a series of 265 treated patients, favorable outcome was observed in 13 of 25 patients (52%) who had no treatment, 32 of 37 (86%) treated with radiosurgery only, 30 of 34 (88%) treated with embolization only, 54 of 57 (95%) treated with surgery only, 87 of 101 (86%) treated with embolization and surgery, 16 of 17 (94%) treated with embolization and radiosurgery, 5 of 5 (100%) treated with surgery and radiosurgery, and 13 of 14 (93%) treated with all three modalities.26 Ninety-two percent of

Conclusion

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Most data suggest an annual bleeding risk of 2.2% per year for asymptomatic iAVMs and 4% per year for symptomatic ones. For young patients, this is a moderate risk for bleeding over time, and thus treatment is often recommended; however, it is best to have treatment in a center with considerable experience in all the therapeutic modalities. REFERENCES 1. Lawton MT, Hamilton MG, Spetzler RF. Multimodality treatment of deep arteriovenous malformations: thalamus, basal ganglia, and brain stem. Neurosurgery. 1995;37(1):29–36. https://doi.org/10.1227/00006123-199507000-00004. 2. Ramos MB, Teixeira MJ, Preul MC, Spetzler RF, Figueiredo EG. A bibliometric study of the most cited reports in central nervous system arteriovenous malformations. World Neurosurg. 2019;129:261–268. https://doi.org/10.1016/j.wneu.2019.06.048. 3. Cockroft KM, Chang K-E, Lehman EB, Harbaugh RE. AVM Management Equipoise Survey: physician opinions regarding the management of brain arteriovenous malformations. J NeuroIntervent Surg. 2014;6(10):748–753. https://doi. org/10.1136/neurintsurg-2013-011030. 4. Solomon RA, Connolly ES. Arteriovenous malformations of the brain. N Engl J Med. 2017;376(19):1859–1866. https://doi. org/10.1056/NEJMra1607407. 5. Ogilvy CS, Stieg PE, Awad I, et al. Recommendations for the management of intracranial arteriovenous malformations: a statement for healthcare professionals from a special writing group of the Stroke Council, American Stroke Association. Circulation. 2001;103(21):2644–2657. https://doi.org/10.1161/01. CIR.103.21.2644. 6. Starke RM, Komotar RJ, Otten ML, et al. Adjuvant embolization with N-butyl cyanoacrylate in the treatment of cerebral arteriovenous malformations: outcomes, complications, and predictors of neurologic deficits. Stroke. 2009;40(8):2783– 2790. https://doi.org/10.1161/STROKEAHA.108.539775. 7. Jafar JJ, Davis AJ, Berenstein A, Choi IS, Kupersmith MJ. The effect of embolization with N-butyl cyanoacrylate prior to surgical resection of cerebral arteriovenous malformations. J Neurosurg. 1993;78(1):60–69. https://doi.org/10.3171/jns.1993.78.1.0060. 8. Pasqualin A, Scienza R, Cioffi F, et al. Treatment of cerebral arteriovenous malformations with a combination of preoperative embolization and surgery. Neurosurgery. 1991;29(3):358–368. https://doi.org/10.1097/00006123-199109000-00004. 9. Spetzler RF, Martin NA, Carter LP, Flom RA, Raudzens PA, Wilkinson E. Surgical management of large AVM’s by staged embolization and operative excision. J Neurosurg. 1987;67(1): 17–28. https://doi.org/10.3171/jns.1987.67.1.0017. 10. Debrun G, Vinuela F, Fox A, Drake CG. Embolization of cerebral arteriovenous malformations with bucrylate. J Neurosurg. 1982;56(5):615–627. https://doi.org/10.3171/ jns.1982.56.5.0615. 11. Rosenblatt S, Lewis AI, Tew JM. Combined interventional and surgical treatment of arteriovenous malformations. Neuroimaging Clin N Am. 1998;8(2):469–482. 12. Jordan JE, Marks MP, Lane B, Steinberg GK. Cost-effectiveness of endovascular therapy in the surgical management of cerebral arteriovenous malformations. AJNR Am J Neuroradiol. 1996;17(2):247–254.

13. Pulli B, Chapman PH, Ogilvy CS, et al. Multimodal cerebral arteriovenous malformation treatment: a 12year experience and comparison of key outcomes to ARUBA. J Neurosurg. 2020;133(6):1792–1801. https://doi. org/10.3171/2019.8.JNS19998. 14. Bruno CA, Meyers PM. Endovascular management of arteriovenous malformations of the brain. Interv Neurol. 2013;1(3-4):109–123. https://doi.org/10.1159/000346927. 15. Haw CS, terBrugge K, Willinsky R, Tomlinson G. Complications of embolization of arteriovenous malformations of the brain. J Neurosurg. 2006;104(2):226–232. https://doi.org/10.3171/ jns.2006.104.2.226. 16. Henkes H, Gotwald TF, Brew S, Kaemmerer F, Miloslavski E, Kuehne D. Pressure measurements in arterial feeders of brain arteriovenous malformations before and after endovascular embolization. Neuroradiology. 2004;46(8):673–677. https:// doi.org/10.1007/s00234-004-1229-8. 17. Gupta R, Adeeb N, Moore JM, et al. Validity assessment of grading scales predicting complications from embolization of cerebral arteriovenous malformations. Clin Neurol Neurosurg. 2016;151:102–107. https://doi.org/10.1016/j. clineuro.2016.10.019. 18. Ellis JA, Mejia Munne JC, Lavine SD, Meyers PM, Connolly ES, Solomon RA. Arteriovenous malformations and headache. J Clin Neurosci. 2016;23:38–43. https://doi.org/10.1016/j.jocn. 2015.08.003. 19. Gobin YP, Laurent A, Merienne L, et al. Treatment of brain arteriovenous malformations by embolization and radiosurgery. J Neurosurg. 1996;85(1):19–28. https://doi.org/10.3171/ jns.1996.85.1.0019. 20. Wang A, Mandigo GK, Feldstein NA, et al. Curative treatment for low-grade arteriovenous malformations. J Neurointerv Surg. 2020;12(1):48–54. https://doi.org/10.1136/ neurintsurg-2019-015115. 21. Pollock BE, Gorman DA, Brown PD. Radiosurgery for arteriovenous malformations of the basal ganglia, thalamus, and brainstem. J Neurosurg. 2004;100(2):210–214. https://doi. org/10.3171/jns.2004.100.2.0210. 22. Shtraus N, Schifter D, Corn BW, et al. Radiosurgical treatment planning of AVM following embolization with Onyx: possible dosage error in treatment planning can be averted. J Neurooncol. 2010;98(2):271–276. https://doi.org/10.1007/ s11060-010-0177-x. 23. Fennell VS, Martirosyan NL, Atwal GS, et al. Hemodynamics associated with intracerebral arteriovenous malformations: the effects of treatment modalities. Neurosurgery. 2018;83(4):611– 621. https://doi.org/10.1093/neuros/nyx560. 24. Starke RM, Kano H, Ding D, et al. Stereotactic radiosurgery for cerebral arteriovenous malformations: evaluation of long-term outcomes in a multicenter cohort. J Neurosurg. 2017;126(1): 36–44. https://doi.org/10.3171/2015.9.JNS151311. 25. Ding D, Xu Z, Shih H-H, Starke RM, Yen C-P, Sheehan JP. Stereotactic radiosurgery for partially resected cerebral arteriovenous malformations. World Neurosurg. 2016;85:263– 272. https://doi.org/10.1016/j.wneu.2015.10.001. 26. Nataraj A, Mohamed MB, Gholkar A, et al. Multimodality treatment of cerebral arteriovenous malformations. World Neurosurg. 2014;82(1-2):149–159. https://doi.org/10.1016/j. wneu.2013.02.064. 27. Xiao F, Chang R, Wang H-C. Hypofractionated stereotactic radiotherapy for large arteriovenous malformations. Surg Neurol Int. 2012;3(3):105. https://doi.org/10.4103/2152-7806.95421.

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28. Hanakita S, Shin M, Koga T, Igaki H, Saito N. Outcomes of volume-staged radiosurgery for cerebral arteriovenous malformations larger than 20 cm3 with more than 3 years of follow-up. World Neurosurg. 2016;87:242–249. https://doi. org/10.1016/j.wneu.2015.12.020. 29. Ding D, Chen C-J, Starke RM, et al. Risk of brain arteriovenous malformation hemorrhage before and after stereotactic radiosurgery. Stroke. 2019;50(6):1384–1391. https://doi. org/10.1161/STROKEAHA.118.024230. 30. Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, nonblinded, randomised trial. Lancet. 2014;383(9917):614–621. https://doi.org/10.1016/S0140-6736(13)62302-8. 31. Wild E, Barry J, Sun H. Targeted stereotactic radiosurgery for arteriovenous malformation downgrading followed by microsurgical resection: a case report and review of the literature. World Neurosurg. 2019;131:82–86. https://doi. org/10.1016/j.wneu.2019.07.170. 32. Asgari S, Bassiouni H, Gizewski E, van de Nes JAP, Stolke D, Sandalcioglu IE. AVM resection after radiation therapy— clinico-morphological features and microsurgical results. Neurosurg Rev. 2010;33(1):53–61. https://doi.org/10.1007/ s10143-009-0216-2. 33. Firlik AD, Levy EI, Kondziolka D, Yonas H. Staged volume radiosurgery followed by microsurgical resection: a novel treatment for giant cerebral arteriovenous malformations: technical case report. Neurosurgery. 1998;43(5):1223–1227. https://doi.org/10.1097/00006123-199811000-00124.

209 34. Abla AA, Rutledge WC, Seymour ZA, et al. A treatment paradigm for high-grade brain arteriovenous malformations: volume-staged radiosurgical downgrading followed by microsurgical resection. J Neurosurg. 2015;122(2):419–432. https://doi.org/10.3171/2014.10.JNS1424. 35. Steinberg GK, Chang SD, Levy RP, Marks MP, Frankel K, Marcellus M. Surgical resection of large incompletely treated intracranial arteriovenous malformations following stereotactic radiosurgery. J Neurosurg. 1996;84(6):920–928. https://doi. org/10.3171/jns.1996.84.6.0920. 36. Kano H, Flickinger JC, Tonetti D, et al. Estimating the risks of adverse radiation effects after Gamma Knife radiosurgery for arteriovenous malformations. Stroke. 2017;48(1):84–90. https://doi.org/10.1161/STROKEAHA.116.014825. 37. Finitsis S, Bernier V, Buccheit I, et al. Late complications of radiosurgery for cerebral arteriovenous malformations: report of 5 cases of chronic encapsulated intracerebral hematomas and review of the literature. Radiat Oncol. 2020;15(1):177. https://doi.org/10.1186/s13014-020-01616-1. 38. Madhugiri VS, Teo MKC, Westbroek EM, et al. Multimodal management of arteriovenous malformations of the basal ganglia and thalamus: factors affecting obliteration and outcome. J Neurosurg. 2019;131(2):410–419. https://doi. org/10.3171/2018.2.JNS172511. 39. Wu EM, El Ahmadieh TY, McDougall CM, et al. Embolization of brain arteriovenous malformations with intent to cure: a systematic review. J Neurosurg. 2019;132(2):388–399. https:// doi.org/10.3171/2018.10.JNS181791.

Chapter 22

Risks of Radiosurgery Ahmad Sweid, Abdelaziz Amllay, and Stavropoula Tjoumakaris

Chapter Outline Introduction Risk of Hemorrhage Post-SRS Acute Effects Early Delayed Effects Late Delayed Effects Conclusion

Introduction Intracranial arteriovenous malformations (iAVMs) are congenital vascular anomalies composed of blood vessels that directly shunt blood from arteries to the venous system without an intervening capillary network.1 With a reported incidence of 1.12–1.34 per 100,000 person-years,2 AVMs account for approximately 1.5%–4% of intracranial masses and are thought to occur one-tenth as often as intracranial aneurysms.3 Patients with iAVMs can present with headaches, seizures, progressive neurologic deficits, and mental deterioration.3 However, hemorrhagic stroke is the most frequent and severe life-threatening complication of these lesions. Intracranial AVMs account for 9% of subarachnoid hemorrhages and 1%–2% of all strokes.3 Various studies have reported the annual risk of iAVM hemorrhage to be approximately 2%–5%, with 20%–30% morbidity and 10%–15% mortality per event.4,5 Once a patient has experienced iAVM hemorrhage, the risk of recurrent hemorrhage is ­ increased—especially in the first year after the event.4 In light of the significant hemorrhage risks, the main goal of treatment is completely resecting or obliterating the AVM and excluding it from circulation, thus preventing any future hemorrhage. 210

The management options for iAVMs include observation, microsurgery, endovascular embolization, and stereotactic radiosurgery (SRS). Multimodality management has been shown to increase therapeutic efficacy and improve patient outcomes6 and is currently the standard of care for patients with iAVMs. Stereotactic radiosurgery was initially described by Lars Leksell in 19517; the concept was a breakthrough in neurosurgery and changed the management of many neurological pathologies, including AVMs. SRS can be performed with various modalities that achieve the desired characteristics of small fields, steep dose fall-off, and highly accurate targeting through the use of two fundamental principles: superposition of beams and stereotactic targeting. As an alternative to surgical removal (resection), SRS is a safe and effective method of managing iAVMs. The obliteration rate has been reported at 70%–90% at 3–5 years after treatment.8–12 In general, SRS is indicated for small- to moderate-sized AVMs located in deep or eloquent brain areas and for patients with a high risk of perioperative complications (e.g., elderly patients, patients with medical comorbidities).12 Given its less invasive nature and favorable benefit-risk ratio, superficial iAVMs amenable to surgery have been treated with SRS. Recent reports describe staging strategies for effectively treating large iAVMs as well.13 Although SRS is a minimally invasive technique, it is not risk-free. Because it induces AVM obliteration progressively, both the beneficial and adverse effects manifest in a delayed manner, typically months or even years after treatment.14 The primary disadvantage of SRS lies in the risk of hemorrhage during the latency interval between SRS and total obliteration of the AVM. Additionally, adverse radiation effects (ARE) may occur. These reactions

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have been stratified into acute effects; early delayed effects (occurring a few weeks to several months after SRS), mainly consisting of radiation-induced imaging changes (RIC); and late delayed effects (occurring several months to several years after SRS), including radiation necrosis,15 cyst formation,11,16 encapsulated hematoma,16,17 stenosis of major vessels,18 and radiation-induced neoplasm.19,20 Ilyas et al.14 performed a meta-analysis of 51 studies of iAVMs treated with SRS and found overall rates of RIC, radiation necrosis, and cyst formation of 35.5% (1143/3222 patients), 2.9% (40/1360 patients), and 3.2% (35/1081 patients), respectively. One should note that there is significant heterogeneity in the literature concerning the definition of different radiationinduced complications, the indications treated, and the SRS modality used, which confounds the generalizability of these studies. Several factors, including radiation dose and target volume (>3 cm3), are reported as important predictors for ARE.10,21 Other risk factors, such as prior hemorrhage,9 AVM location,10,21 and repeated radiosurgery,22 have been described in some series. The relationship between AVM embolization and post-SRS outcomes is multifactorial and complex.11,23

Risk of Hemorrhage Post-SRS Hemorrhagic stroke is both the most severe and the most frequent life-threatening complication of harboring an iAVM. It is hence understandable that ­ significant efforts have been undertaken to identify risk factors predicting AVM rupture. However, considerable disagreement exists about the risk of AVM bleeding after SRS. While some investigators have reported an increased risk,24 more extensive and more detailed analysis of this question has confirmed that the risk is either unchanged25 or decreased.26–29 Colombo et al. reported on 180 iAVM patients treated with SRS with a mean follow-up of 43 months.24 In cases with complete irradiation, the bleeding risk decreased from 4.8% in the first 6 months after SRS to 0% starting at 1 year following SRS. However, in patients with partially irradiated iAVMs, the bleeding risk increased from 4% to 10% over the first 2 years, then decreased. Additionally, Ding et al. analyzed 2320 iAVM cases. The authors reported a decline in hemorrhage rate

Pearls • The risk for iAVM hemorrhage is uncertain during the latency period of SRS (i.e., time to obliteration ~ 2 years). • Acute radiation effects are rare; headaches and seizures are easily treated. • Early delayed effects of SRS (radiation-induced imaging changes) are usually transient and medically managed. • Late delayed effects from SRS include radiation necrosis, cyst formation, and encapsulated hematomas. • The risk of radiation-induced neoplasms from SRS is extremely low.

from 15.4 per 1000 person-years to 11.9 with SRS (P = .001). However, SRS only improved the hemorrhage risk of Spetzler-Martin grade I–III AVMs, while the risk increased for grade IV–V AVMs.26 Also, deepseated iAVMs were prone to hemorrhage during the latency period, whereas the use of a higher margin dose decreased the risk of post-SRS hemorrhage. The presence of an untreated AVM-associated aneurysm was the strongest predictor of post-SRS hemorrhage. Thus targeted occlusion of AVM-associated aneurysms via embolization or surgical clipping should be considered in most cases to reduce the risk of hemorrhage during the latency period following SRS. Similarly, Chye et al. reviewed data from 1515 iAVM patients with long-term follow-up and found that the annual hemorrhage rate was lower in the SRS group (1.59 per 100 patient-years) than in the non-SRS group (1.99 per 100 patient-years). Among the patients with ruptured iAVMs, the annual risk of bleeding in the Gamma Knife radiosurgery (GKS) group was significantly lower than that in the nonGKS group. Furthermore, the authors found that SRS treatment of unruptured AVMs in patients who are more than 40 years old might increase the risk of hemorrhage.27 Tonetti et al.29 reported in their study, which included 233 ARUBA-eligible patients with unruptured iAVMs, that SRS was associated with low annual rates of hemorrhage (0.4%) and stroke or death (0.8%) among the 218 patients with more than 3 years of follow-up.

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Subtotal obliteration, defined by Steiner et al.30 as the disappearance of the nidus on angiogram but with the persistence of an early draining vein, appears to be associated with a decreased risk of hemorrhage as well. Pollock et al. reported 19 such cases with no instances of hemorrhage.31 Nevertheless, as long as an early draining vein is present, evidence for continued shunting, there is some residual degree of hemorrhage risk.

Acute Effects Immediate complications are rare after SRS, in contrast to resective surgery,32 and patients can expect to be able to promptly return to their regular activities after radiosurgical treatment. It is for these reasons that many patients and physicians choose this modality. Most acute reactions are likely due to edema and appear to be self-limited. Headache is treated with mild analgesics. Ice packs are applied as necessary to pin sites. It is essential to confirm compliance with medication regimens before SRS in patients with a known seizure history or patients at increased risk of seizures (e.g., those with subcortical lobar AVMs). Reporting on 247 iAVM patients, Steiner et al.33 noted 29 patients (12%) with uncontrolled seizures following SRS. Of the 188 patients without a history of seizures before treatment, 11 (6%) developed new-onset seizures. In contrast, Liščák et al.9 reported that termination of seizures or improvement in seizure frequency was observed in 42% of patients after SRS, while a worsening of epilepsy was detected in only 4% of patients. Similarly, Peciu-Florianu et al.8 reported seizure-free rates of approximately 80%, with seizure being the most common symptom in their study’s population.

Early Delayed Effects The earliest and most frequently observed complication after SRS for AVMs is RIC, typically manifesting 6–18 months after radiosurgery as perinidal T2 signal changes on follow-up neuroimaging.14,34 Although most RIC are asymptomatic, a subset of patients develop neurological symptoms, such as headache, seizure, and focal neurological deficit.14,18 The majority of symptomatic RIC are transient and can be medically

managed, but a minority of patients suffer permanent neurological deterioration secondary to RIC.14,21 According to a meta-analysis by Ilyas et al.,14 the overall rates of radiologic RIC were 35.5%, whereas the overall rates of symptomatic RIC were 9.2%. Similarly, Daou et al. reported that new T2 signal and FLAIR hyperintensity was noted in 40% of iAVMs, peaking at 12 months post-SRS.35 Lack of prior AVM hemorrhage and repeat SRS were risk factors for RIC, and deep nidus location was a risk factor for symptomatic RIC. The group hypothesized that perinidal gliosis may be protective against the development of RIC. The pathophysiology of RIC remains incompletely understood. The changes are thought to be related to either the direct effects of the radiation treatment on the treated tissue or a vascular/hemodynamic phenomenon resulting in edema or potentially radiation necrosis.21,34 Mechanisms in which radiation results in these findings through direct tissue damage include injury of glial cells, endothelial cell damage followed by the breakdown of the blood-brain barrier, excessive generation of free radicals, and the induction of an autoimmune response.34 It has been suggested that radiation-induced microvascular injury leads to hypoxia and that the vasogenic edema seen in RIC results from increased vascular permeability due to hypoxiainduced vascular endothelial growth factor (VEGF) upregulation.36 Lee et al. reported that a higher serum VEGF level 6 months after SRS was found to be a statistically significant predictor of RIC.36 RIC have been associated with SRS-induced obliteration, suggesting an overlap between the cellular changes underlying these parallel processes. Van den Berg et al.37 reported an AVM obliteration rate of 88% in patients with extensive RIC compared with 50% in patients without extensive signal changes on MRI following SRS. Overall, several factors have been reported to be associated with RIC development, including patient age, AVM size and volume (>3 cm3), high AVM grade, higher margin dose, prior embolization, prior hemorrhage, number of draining veins, and AVM location.10,14,37 Kano et al.21 assessed 755 AVM patients who underwent SRS and reported symptomatic and permanent RIC rates of 7% and 3%, respectively. AVM location in the brainstem or thalamus, larger AVM volume, larger 12-Gy volume, higher margin

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dose, higher Spetzler-Martin grade, and higher radiosurgery-based AVM score (RBAS) were risk factors for symptomatic RIC. The most common treatment option for symptomatic RIC is corticosteroids. Other medical treatments consist of glycerol infusions and bevacizumab, pentoxifylline, and vitamin E.14 Although most RIC are temporary and resolve within 2 years, a small percentage of patients will continue to demonstrate imaging changes consistent with radiation necrosis. MRI findings consistent with radiation necrosis include persistent enhancement at the irradiated site with associated edema and mass effect. Progression to radiation necrosis depends on factors that are not yet identified clearly.

Late Delayed Effects RADIATION NECROSIS Radiation necrosis is not a well-defined term and is inconsistently used to describe a radiological and/or clinical scenario. Typically, radiation necrosis becomes symptomatic as a late complication 1–5 years after radiotherapy.38 It is well accepted that risk factors for radiation necrosis include total dose, treatment time, and dose fractions. Miyawaki et al.39 reported a significant association between treatment volume and the development of radiation necrosis requiring resection in their series of patients treated with linear accelerator (LINAC)–based radiosurgery; they reported four cases, all of which occurred in patients with treatment volumes greater than 14 cm3 (mean, 27.8 cm3; range, 16.4–39.8 cm3). Steroid therapy has been the traditional mainstay treatment for symptomatic cerebral radiation necrosis. The humanized monoclonal anti-VEGF antibody bevacizumab has demonstrated efficacy in treating symptomatic radiation necrosis. In a small randomized trial from the MD Anderson Cancer Center (Houston, Texas, USA), 14 patients were randomized to placebo vs bevacizumab, and those in the bevacizumab arm had significant clinical and radiological improvements, although with higher rates of adverse effects.40 The use of bevacizumab needs further study before recommendations can be made. Resective surgery can be considered for severely symptomatic patients whose symptoms are refractory to steroid therapy.15

213 CYST FORMATION AND ENCAPSULATED HEMATOMA The development of a cyst or encapsulated hematoma is one of the most common late ARE in patients with iAVMs treated by SRS; the reported frequency ranges from 0.4% to 28%.11,16,23,41 Cysts and encapsulating hematomas are considered to be of the same origin.16 The condition is usually self-limited, but the cyst can expand and pose neurological deficits through mass effect. The latency period between SRS and cyst formation is usually longer than that of other more frequent adverse events, such as RIC and hemorrhage after SRS.42 Pan et al. highlighted the importance of long-term surveillance, reporting that their overall cyst formation rate of 1.6% increased to 3.6% when they restricted their analysis to data from patients with at least 5 years of follow-up.23 Ilyas et al.11 reviewed 22 studies of iAVMs treated with SRS and reported an overall post-SRS cyst formation rate of 3.0% (78 of 2619 patients), with 32.8% of the affected patients experiencing symptoms due to the cysts. The mean latency period to post-SRS cyst formation was 6.5 years. The pathophysiology of cyst formation following SRS remains relatively unclear. Some authors have postulated that it is related to the formation of fragile telangiectatic perinidal vessels which are prone to rupture. This promotes serum and protein exudation, edema, cyst, and encapsulating hematoma formation.43 Early complications may prime the surrounding parenchyma to the development of delayed ARE.14,44 Several demographic factors, AVM features, treatment parameters, and post-SRS outcomes have been associated with cyst formation.11,16,18,23 Izawa et al. reported a cyst incidence of 3.4% at a mean follow-up of 6.8 years.18 Their analysis found higher maximum dose, larger nidus volume, lobar AVM location, and obliteration to be predictors of cyst formation. Similarly, Hasegawa et al.16 reported that both lobar location and maximum diameter >22 mm were significant risk factors for cyst formation. Pomeraniec et al.42 reviewed 1159 cases of SRStreated iAVMs and reported cyst formation in 17 (1.5%). A higher number of isocenters, radiological RIC, and longer follow-up were independent predictors of cyst formation. Additionally, 59% of the patients who developed cysts after SRS had obliterated AVMs. Similarly, in their review, Ilyas et al. found that most post-SRS cysts (77%) occurred in patients with

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an obliterated nidus, suggesting that follow-up of iAVM patients treated with SRS should not be abandoned after obliteration is achieved.11 The optimal management of post-SRS cysts is not well defined. In general, asymptomatic cysts should be managed conservatively with observation through serial imaging. Some cysts can undergo spontaneous shrinkage.45 Intervention is typically reserved for patients with cysts that are symptomatic, enlarging, or encroaching on eloquent brain areas.23 Intervention options include implantation of an Ommaya reservoir, cyst-peritoneal shunting, and resection.11,23

late long-term side effects continues to be evaluated. Within the context of a disease that has a 1% annual mortality rate if left untreated, the current data have shown that SRS is a safe and effective management strategy for use in the treatment of iAVMs. Continued improvements in our ability to assess the radiographic, pathophysiologic, and clinical effects of treatment, in conjunction with further improvements in targeting and delivering the radiation dose, will enable us to minimize long-term complications and to enhance ever further this valuable technology.

RADIATION-INDUCED NEOPLASM Secondary tumors following radiosurgery are extremely rare but can be life-threatening because these tumors are usually malignant. Radiation-induced neoplasms constitute a particularly concerning complication given that most patients with AVMs are treated at a relatively young age.19 In 2000, Yu et al. provided the first report of a glioma arising within radiosurgically treated brain tissue that met the Cahan criteria.46,47 Since then, other groups of authors have also reported post-SRS radiation-induced neoplasms.19,20,48 However, a study of 1837 patients who underwent single-fraction SRS for an iAVM or benign tumor (11,264 patient-years of follow-up) showed that the risk of developing a radiation-induced neoplasm was 0.0% at 15 years.49 Although the risk of radiation-related malignancy is extremely low, these studies and case reports demonstrate that this risk is real. One should be aware that development of a secondary tumor is a long-term process, and most of the patients treated with radiosurgery are not followed up for longer than 10–20 years. Therefore patients with iAVMs who are considering radiosurgery should be advised about this possibility.

REFERENCES

Conclusion As the least invasive form of iAVM treatment, SRS is particularly attractive to patients. The most significant remaining issue for iAVM SRS is the risk of a latencyinterval hemorrhage, so efforts to reduce the latency interval would be important. ARE, whether acute, transient, or permanent, are functions of radiation dose, AVM volume, and AVM location. The recognition of

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Risks of Radiosurgery systematic review. J Neurosurg. 2018;128(5):1354–1363. https://doi.org/10.3171/2016.12.JNS162478. Starke RM, Kano H, Ding D, et al. Stereotactic radiosurgery for cerebral arteriovenous malformations: evaluation of longterm outcomes in a multicenter cohort. J Neurosurg. 2017; 126(1):36–44. https://doi.org/10.3171/2015.9.JNS151311. Nagy G, Grainger A, Hodgson TJ, et al. Staged-volume radiosurgery of large arteriovenous malformations improves outcome by reducing the rate of adverse radiation effects. Neurosurgery. 2017;80(2):180–192. https://doi.org/10.1227/ NEU.0000000000001212. Ilyas A, Chen C-J, Ding D, et al. Radiation-induced changes after stereotactic radiosurgery for brain arteriovenous malformations: a systematic review and meta-analysis. Neurosurgery. 2018;83(3):365–376. https://doi.org/10.1093/ neuros/nyx502. Massengale JL, Levy RP, Marcellus M, Moes G, Marks MP, Steinberg GK. Outcomes of surgery for resection of regions of symptomatic radiation injury after stereotactic radiosurgery for arteriovenous malformations. Neurosurgery. 2006;59(3):553– 560; discussion 553–560. https://doi.org/10.1227/01. NEU.0000227476.95859.F1. Hasegawa H, Hanakita S, Shin M, et al. A comprehensive study of symptomatic late radiation-induced complications after radiosurgery for brain arteriovenous malformation: incidence, risk factors, and clinical outcomes. World Neurosurg. 2018;116:e556–e565. https://doi.org/10.1016/j. wneu.2018.05.038. Park JC, Ahn JS, Kwon DH, Kwun BD. Growing organized hematomas following Gamma Knife radiosurgery for cerebral arteriovenous malformation: five cases of surgical excision. J Korean Neurosurg Soc. 2015;58(1):83–88. https://doi. org/10.3340/jkns.2015.58.1.83. Izawa M, Hayashi M, Chernov M, et al. Long-term complications after gamma knife surgery for arteriovenous malformations. J Neurosurg. 2005;102(Suppl):34–37. https://doi.org/10.3171/ jns.2005.102.s_supplement.0034. Hasegawa T, Kato T, Naito T, et al. Long-term outcomes for pediatric patients with brain arteriovenous malformations treated with Gamma Knife radiosurgery, part 2: the incidence of cyst formation, encapsulated hematoma, and radiationinduced tumor. World Neurosurg. 2019;126:e1526–e1536. https://doi.org/10.1016/j.wneu.2019.03.177. Starke RM, Yen CP, Chen C-J, et al. An updated assessment of the risk of radiation-induced neoplasia after radiosurgery of arteriovenous malformations. World Neurosurg. 2014;82(3-4):395–401. https://doi.org/10.1016/j.wneu.2013.02.008. Kano H, Flickinger JC, Tonetti D, et al. Estimating the risks of adverse radiation effects after Gamma Knife radiosurgery for arteriovenous malformations. Stroke. 2017;48(1):84–90. https://doi.org/10.1161/STROKEAHA.116.014825. Buis DR, Meijer OWM, Berg R van den, et al. Clinical outcome after repeated radiosurgery for brain arteriovenous malformations. Radiother Oncol. 2010;95(2):250–256. https://doi.org/10.1016/j.radonc.2010.03.003. Pan H-C, Sheehan J, Stroila M, Steiner M, Steiner L. Late cyst formation following gamma knife surgery of arteriovenous malformations. J Neurosurg. 2005;102(Suppl):124–127. https://doi.org/10.3171/jns.2005.102.s_supplement.0124. Colombo F, Pozza F, Chierego G, Casentini L, De Luca G, Francescon P. Linear accelerator radiosurgery of cerebral arteriovenous malformations: an update. Neurosurgery. 1994;34(1):14–20; discussion 20–21.

215 25. Friedman WA, Blatt DL, Bova FJ, Buatti JM, Mendenhall WM, Kubilis PS. The risk of hemorrhage after radiosurgery for arteriovenous malformations. J Neurosurg. 1996;84(6):912–919. https://doi.org/10.3171/jns.1996.84.6.0912. 26. Ding D, Chen C-J, Starke RM, et al. Risk of brain arteriovenous malformation hemorrhage before and after stereotactic radiosurgery. Stroke. 2019;50(6):1384–1391. https://doi. org/10.1161/STROKEAHA.118.024230. 27. Chye C-L, Wang K-W, Chen H-J, Yeh S-A, Tang JT, Liang C-L. Haemorrhage rates of ruptured and unruptured brain arteriovenous malformation after radiosurgery: a nationwide population-based cohort study. BMJ Open. 2020;10(10): e036606. https://doi.org/10.1136/bmjopen-2019-036606. 28. Maruyama K, Kawahara N, Shin M, et al. The risk of hemorrhage after radiosurgery for cerebral arteriovenous malformations. N Engl J Med. 2005;352(2):146–153. https://doi.org/10.1056/ NEJMoa040907. 29. Tonetti DA, Gross BA, Atcheson KM, et al. The benefit of radiosurgery for ARUBA-eligible arteriovenous malformations: a practical analysis over an appropriate follow-up period. J Neurosurg. 2018;128(6):1850–1854. https://doi. org/10.3171/2017.1.JNS162962. 30. Steiner L, Lindquist C, Cail W, Karlsson B, Steiner M. Microsurgery and radiosurgery in brain arteriovenous malformations. J Neurosurg. 1993;79(5):647–652. https://doi. org/10.3171/jns.1993.79.5.0647. 31. Pollock BE, Flickinger JC, Lunsford LD, Bissonette DJ, Kondziolka D. Hemorrhage risk after stereotactic radiosurgery of cerebral arteriovenous malformations. Neurosurgery. 1996;38(4):652–659; discussion 659–661. 32. van Beijnum J, van der Worp HB, Buis DR, et al. Treatment of brain arteriovenous malformations: a systematic review and meta-analysis. JAMA. 2011;306(18):2011–2019. https://doi. org/10.1001/jama.2011.1632. 33. Steiner L, Lindquist C, Adler JR, Torner JC, Alves W, Steiner M. Clinical outcome of radiosurgery for cerebral arteriovenous malformations. J Neurosurg. 1992;77(1):1–8. https://doi. org/10.3171/jns.1992.77.1.0001. 34. Yen C-P, Matsumoto JA, Wintermark M, et al. Radiation-induced imaging changes following Gamma Knife surgery for cerebral arteriovenous malformations: Clinical article. J Neurosurg. 2013;118(1):63–73. https://doi.org/10.3171/2012.10.JNS12402. 35. Daou BJ, Palmateer G, Wilkinson DA, et al. Radiation-induced imaging changes and cerebral edema following stereotactic radiosurgery for brain AVMs. AJNR Am J Neuroradiol. 2021;42(1):82–87. https://doi.org/10.3174/ajnr.A6880. 36. Lee J-G, Park S-H, Park K-S, Kang D-H, Hwang J-H, Hwang S-K. Do serum vascular endothelial growth factor and endostatin reflect radiological radiation-induced changes after stereotactic radiosurgery for cerebral arteriovenous malformations? World Neurosurg. 2019;126:e612–e618. https://doi.org/10.1016/j.wneu.2019.02.101. 37. van den Berg R, Buis DR, Lagerwaard FJ, Lycklama à Nijeholt GJ, Vandertop WP. Extensive white matter changes after stereotactic radiosurgery for brain arteriovenous malformations: a prognostic sign for obliteration? Neurosurgery. 2008;63(6):1064–1069; discussion 1069–1070. https://doi. org/10.1227/01.NEU.0000330413.73983.02. 38. Preuss M, Hirsch W, Hoffmann KT, et al. Effectiveness of bevacizumab for radiation-induced cerebral necrosis in children. Pediatr Neurosurg. 2013;49(2):81–85. https://doi. org/10.1159/000357447. 39. Miyawaki L, Dowd C, Wara W, et al. Five year results of LINAC radiosurgery for arteriovenous malformations: outcome for

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PART 1 The Patient-Centered Approach large AVMS. Int J Radiat Oncol Biol Phys. 1999;44(5):1089– 1106. https://doi.org/10.1016/s0360-3016(99)00102-9. Levin VA, Bidaut L, Hou P, et al. Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system. Int J Radiat Oncol Biol Phys. 2011;79(5):1487–1495. https://doi.org/10.1016/j. ijrobp.2009.12.061. Nakajima H, Yamanaka K, Ishibashi K, Iwai Y. Delayed cyst formations and/or expanding hematomas developing after Gamma Knife surgery for cerebral arteriovenous malformations. J Clin Neurosci. 2016;33:96–99. https://doi.org/10.1016/j. jocn.2016.01.044. Pomeraniec IJ, Ding D, Starke RM, et al. Delayed cyst formation after stereotactic radiosurgery for brain arteriovenous malformations. J Neurosurg. 2018;129(4):937–946. https://doi. org/10.3171/2017.6.JNS17559. Shuto T, Ohtake M, Matsunaga S. Proposed mechanism for cyst formation and enlargement following Gamma Knife Surgery for arteriovenousmalformations.JNeurosurg.2012;117(Suppl):135–143. https://doi.org/10.3171/2012.6.GKS12318. Pollock BE, Link MJ, Branda ME, Storlie CB. Incidence and management of late adverse radiation effects after arteriovenous malformation radiosurgery. Neurosurgery. 2017;81(6):928–934. https://doi.org/10.1093/neuros/nyx010.

45. Yamamoto M, Ide M, Jimbo M, Hamazaki M, Ban S. Late cyst convolution after gamma knife radiosurgery for cerebral arteriovenous malformations. Stereotact Funct Neurosurg. 1998;70(Suppl 1):166–178. https://doi.org/10.1159/ 000056419. 46. Yu JS, Yong WH, Wilson D, Black KL. Glioblastoma induction after radiosurgery for meningioma. Lancet. 2000;356(9241):1576–1577. https://doi.org/10.1016/S01406736(00)03134-2. 47. Cahan WG, Woodard HQ, Higinbotham NL, Stewart FW, Coley BL. Sarcoma arising in irradiated bone: report of eleven cases. 1948. Cancer. 1998;82(1):8–34. https://doi.org/10.1002/ (sici)1097-0142(19980101)82:13.0.co;2-w. 48. Sheehan J, Yen CP, Steiner L. Gamma knife surgery-induced meningioma. Report of two cases and review of the literature. J Neurosurg. 2006;105(2):325–329. https://doi.org/10.3171/ jns.2006.105.2.325. 49. Pollock BE, Link MJ, Stafford SL, Parney IF, Garces YI, Foote RL. The risk of radiation-induced tumors or malignant transformation after single-fraction intracranial radiosurgery: results based on a 25-year experience. Int J Radiat Oncol Biol Phys. 2017;97(5):919–923. https://doi.org/10.1016/j. ijrobp.2017.01.004.

Chapter 23

Emergency Management of Ruptured Intracranial AVMs Richard S. Dowd and Carlos A. David

Chapter Outline

Epidemiology and Clinical Features

Introduction Epidemiology and Clinical Features Management Conclusion

Intracranial AVMs occur with an incidence of about 1 in 100,000 people.5–7 In the past, AVM rupture was one of the major ways that these lesions were discovered in patients; however, as new testing modalities are more frequently employed, the number of incidental iAVM discoveries has been rising.1,2 Nonetheless, hemorrhage is still the initial presenting manifestation for 50% of newly diagnosed iAVMs.8 For patients with unruptured iAVMs, the chance of rupture is about 2%–4% per year.9 In the setting of acute rupture, the likelihood of early rehemorrhage is very low. However, it has been established that in the first year after hemorrhage, the rate increases to 6% per year.10 Ondra et al. found that after hemorrhage, the risk was elevated to 4% per year.11 More recently, Hernesniemi et al. reported long-term follow-up data from 238 cases, including some of the same cases as those previously analyzed by Ondra et al., and found that the risk of rehemorrhage was significantly higher.12 Rupture of an iAVM can be devastating. Several authors, therefore, have attempted to predict features of known iAVMs that might increase the risk of rupture. Intranidal aneurysms, smaller AVM size, and deep venous drainage seem to be more associated with a risk of rupture.4,6,9,13 Intranidal aneurysms can develop over time, and their risk of rupture tends to be the same as or greater than that of aneurysms outside iAVMs.8,9 Smaller size has been theorized to increase the risk of rupture due to increased blood flow distributed over a smaller surface area potentially leading to greater pressure.6 Deep venous drainage is also associated with an increased risk of rupture. This is likely related to the

Introduction Intracranial arteriovenous malformations (iAVMs) are a relatively uncommon source of intraparenchymal hemorrhage (IPH).1 Identifying an iAVM in a patient with a new IPH is essential to guide treatment and therapy options in the acute period. Newly presenting IPHs are related to iAVMs in about 2% of cases.1 There are no readily identifiable demographics that might make an iAVM more or less likely as the source of a new hemorrhage. Thus a thorough workup in all cases of new IPH is necessary to prevent misdiagnosis. Workup will most often start with noninvasive vessel imaging, by either CT angiography (CTA) or MR angiography (MRA), before moving to formal angiography.2,3 Emergency treatment is focused on preventing morbidity and mortality associated with the acute brain injury. The timing and modality of definitive treatment is still debated, but these decisions depend largely on the clinical condition of the patient at presentation and the location of the iAVM.3,4

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recognized trend that venous outflow restriction is a risk factor for hemorrhage. Higher outflow impedance is found with deeper draining veins due to their generally smaller caliber.14,15 Finally, some evidence suggests that acute to subacute alterations in blood volume may predispose a patient to iAVM rupture.15 It was previously presumed that the alterations in blood volume during pregnancy might cause pregnant patients to have a higher incidence of iAVM rupture than their nongravid counterparts. This has been found to be false.16,17 Pregnant patients are, on occasion, found to have a previously undiagnosed iAVM during gestation.18 When treating a pregnant patient, surgery, if necessary, is generally safe if the patient is in the third trimester of pregnancy. Consideration should be given to delivering the child prior to treating the mother if possible.16,18 Pediatric patients also deserve special consideration, as an iAVM is the most common cause of spontaneous IPH in the pediatric age group.13 There also seems to be a propensity for children to present with more posterior fossa AVMs than adults.7,13,19–21 Patients with IPH present with varying symptoms and, in fact, the presentation for those with ruptured iAVMs is similar to that for those with spontaneous IPH.2,3 Depending on the location and the size of the bleed, a patient’s presentation can range from asymptomatic to severely disabled. Hemorrhages in eloquent areas will cause focal deficits in language and motor function. There are, however, some key differences between spontaneous IPHs and iAVMs. Spontaneous IPH related to hypertension tends to occur in the basal ganglia or cerebellar vermis,22 whereas spontaneous lobar IPH is most often related to amyloid angiopathy.22 While any iAVM can rupture, posterior fossa iAVMs tend to present more commonly with hemorrhage. This has been theorized to be related to the fact that brainstem compression causes acutely altered levels of consciousness, and therefore the hemorrhage may be easier to detect clinically.23 In addition, some patients with ruptured iAVMs and spontaneous IPH can present with extension into the ventricles, which may cause altered level of consciousness without brainstem compression.6,23,24

Management The differential diagnosis for a new spontaneous IPH includes hypertensive hemorrhage, amyloid angiopathy, and vascular malformation (AVM, cavernous

Pearls • Acute management of ruptured iAVMs is driven by supportive care required for the intraparenchymal hemorrhage. Medical management focuses on seizure prophylaxis, blood pressure control, and intracranial pressure control. • Structural imaging (CTA/MRA) and cerebral angiography can identify high-risk features and define the angioarchitecture of the iAVM. • Delayed treatment with surgery 4–6 weeks after the hemorrhage event may bring technical advantages to surgery. The interval acute rerupture rate for iAVMs is low, in contradistinction to ruptured cerebral aneurysms. • Treatment decisions among endovascular, surgical, or radiosurgery modalities remain unchanged. • Personal history of iAVM rupture is the strongest predictor of future iAVM-related events and a strong indication for treatment.

malformation, or aneurysm).22 Any patient with a new IPH without a known prior source should have at least one vessel imaging study to rule out an underlying vascular malformation.3,20,25 Because of its ease and readily available nature, CTA is the usual screening tool used to guide further evaluation.2,3 With positive noninvasive imaging, and if the patient’s condition is stable, it is reasonable to obtain a diagnostic cerebral angiogram for confirmation and to study the angioarchitecture of any vascular malformation.25 If the patient’s condition is unstable, the next steps in management are to stabilize the patient’s overall physiological and neurological status. The foundations of stabilizing patients with ruptured iAVMs follow the principles of stabilizing any patient with an IPH or intraventricular hemorrhage (IVH) from any source. This is different from the management of ruptured aneurysms in the setting of ­ subarachnoid hemorrhage, for which emergently securing the aneurysm has long been shown to improve outcomes.25 For iAVMs, the rerupture risk in the immediate postrupture period is reported as variable but is generally less than 1%.2,5,26,27 Numerous studies have been undertaken in an effort to identify features that might lead to rerupture, but the most consistent predictor of subsequent rupture appears to

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Emergency Management of Ruptured Intracranial AVMs

be a history of prior rupture.3 Stabilization, therefore, follows tenets laid out formally in the surgical trials in intracerebral hemorrhage.28-30 Osmotic therapy is indicated for any patient who is exhibiting clinical signs or symptoms of dangerously elevated intracranial pressure (ICP). Mannitol and hypertonic saline are the therapies of choice, and preference is largely based on institutional bias.26 Blood pressure management is important to ensure adequate cerebral perfusion as well as minimize the risk of any subsequent bleeding from surrounding and injured brain tissue. The recommendation is to keep systolic blood pressure lower than 140 mm Hg but cerebral perfusion pressure (CPP) within the range of 60–80 mm Hg.2,3 Finally, if a patient has intractably elevated ICP or extensive IVH, it is reasonable to place an external ventricular drain to relieve the pressure and encourage the clearing of the CSF31 (Fig. 23.1). Once a patient’s condition is stabilized, a decision can be made about definitive treatment. In the acute setting of rupture of a previously unknown iAVM, most evidence suggests that the only indication for immediate surgery is evacuation of a clot causing dangerously high ICP or herniation from local mass effect.4,31 Without a thorough understanding of the angioarchitecture of an iAVM, resection can be dangerous. Thus, emergency surgery is typically performed only to remove the clot, and most would advise against attempting to resect an iAVM at the time of initial presentation (Figs. 23.2 and 23.3). It is reasonable to wait 2–6 weeks after a hemorrhage to treat a ruptured iAVM, as the risk of early

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SuggeSted treatment of ruptured iaVmS Goals: Confirm vascular malformation SBP < 140, CPP 60–80 Seizure prophylaxis for supratentorial cortical hemorrhages Reversal of anticoagulant and antiplatelet therapy ICU level of care for frequent neurochecks Optimization of CSF flow dynamics Medications/Procedures: CT/CTA head as a screening tool for underlying vascular malformation Nicardipine or clevidipine infusion titrated by invasive blood pressure monitoring Levetiracetam load of 20 mg/kg followed by 500 mg BID Desmopressin (0.3 mcg/kg) for patients on antiplatelet medications and prothrombin complex concentrate for warfarin Low threshold for repeat head CT should patient’s exam findings change Head of bed raised to more than 30°; 3% saline in 250 mL boluses and 1 g/Kg of mannitol as needed, external ventricular drainage as needed CPP, Cerebral perfusion pressure; CSF, cerebrospinal fluid; CT, computed tomography; CTA, computed tomography angiography; ICU, intensive care unit; SBP, systolic blood pressure.

rerupture remains low.2,3 In addition, if the blood clot has time to resolve before surgery, the operation is technically easier, as the iAVM has been partially dissected by the hemorrhage cavity. The Spetzler-Martin grade does not change the indications for emergency operative intervention, as the goal in the acute setting generally does not include AVM resection.16,19,20,32 In our

Fig. 23.1 Representative case of a ruptured iAVM in which emergency surgical intervention would not be indicated. This patient received an external ventricular drain for control of intracranial pressure and close observation in a neurocritical care unit. (A) Axial CT image showing rupture into the ventricles and hydrocephalus. (B) Coronal CT image showing intraventricular blood with dilation of the frontal and temporal horns. (C) 3D angiography showing the responsible iAVM, which is large, extending throughout most of the corpus callosum.

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Fig. 23.2 Representative case of a ruptured iAVM in which delayed surgery would be appropriate. This patient presented with a sudden-onset hemorrhage. He was allowed to recover, and angiography was performed to better characterize the AVM (B and C). The AVM was later removed safely. (A) Axial MR image demonstrating cortically based hemorrhage. (B) Anteroposterior view of diagnostic angiogram revealing the left-side AVM. (C) Lateral view of diagnostic angiogram revealing the architecture of the AVM.

Fig. 23.3 Representative case of a ruptured iAVM in which immediate surgery would be appropriate. This patient had a known unruptured iAVM and suffered a rupture event during a preoperative embolization procedure. The decision was made to remove the clot; however, since the AVM was at the surface, and the architecture was understood from preoperative studies, the AVM was resected as well. (A) Axial T2-weighted MR image demonstrating a left frontal iAVM. (B) Sagittal fluid attenuated inversion recovery (FLAIR) MR image redemonstrating a left frontal AVM. (C) Diagnostic angiogram demonstrating arterial supply and venous drainage of the iAVM. (D) Axial CT image showing subsequent rupture with midline shift.

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Emergency Management of Ruptured Intracranial AVMs

opinion, endovascular therapy does not, in general, have a primary role for treating AVMs, although it may be appropriate in selected rare cases. In cases of unruptured iAVMs, adjunctive embolization can be performed prior to taking a patient to surgery, which has been shown to improve outcomes.21,33–37 Specifically, Catapano et al. showed that preoperative embolization of Spetzler-Martin grade III iAVMs decreased the risk of poor neurological outcomes in a retrospective cohort of 102 patients.33 In the setting of acute rupture, ­ endovascular techniques can sometimes to be used to secure dangerous architecture, such as flow-related aneurysms.35,36 Radiosurgery can be used to treat iAVMs in a delayed fashion but has no role in treating acutely ruptured lesions. If the patient’s condition can be stabilized after their initial hemorrhage, radiosurgery can be an option for subsequent treatment.38 Because of the low posthemorrhage rerupture rate of ruptured iAVMs, definitive treatment can be undertaken in a delayed fashion.4,19,38 Outcomes are largely related to the severity of the initial injury and its location. Shotar et al. attempted to define prognostic indicators of outcomes for patients with ruptured iAVMs, and, based on their model, they found that hematoma volume, presenting Glasgow Coma Scale score, and presence of IVH were independent predictors of a poor outcome.39 Di Bartolomeo et al. analyzed 25 cases and found that ICH score influences early outcomes, whereas Spetzler-Martin grading influences later outcomes.40 Although the literature is variable, the overall trend is for patients with ruptured iAVMs to fare better than patients with spontaneous IPH on long-term measures of morbidity and mortality.1,4,24,33

Conclusion Patients who present for emergency care due to an iAVM typically have experienced rupture of the iAVM and have signs and symptoms due to hemorrhage. There are high-risk features that make it more likely that an iAVM will rupture and may need to be addressed electively. The location of the hemorrhage determines the signs and symptoms, and consequently, influences patient outcomes. Treatment first involves stabilizing the patient’s ICP with either osmotic therapy or an external ventricular drain. In the setting of a clot that is causing severe symptoms from local mass effect, surgery is indicated to remove

the clot but not to attempt resection of an AVM. Most AVMs have an early rerupture risk of less than 1%, which argues for the safety of waiting until the patient has recovered from their initial injury before definitive treatment. Outcomes are highly variable, depending on the extent and location of the injury, but overall, patients with ruptured iAVMs tend to have better outcomes than patients with IPH of other etiologies. REFERENCES 1. Choi JH, Mast H, Sciacca RR, et al. Clinical outcome after first and recurrent hemorrhage in patients with untreated brain arteriovenous malformation. Stroke. 2006;37(5):1243–1247. https://doi.org/10.1161/01.STR.0000217970.18319.7d. 2. Aoun SG, Bendok BR, Batjer HH. Acute management of ruptured arteriovenous malformations and dural arteriovenous fistulas. Neurosurg Clin N Am. 2012;23(1):87–103. https://doi. org/10.1016/j.nec.2011.09.013. 3. Zacharia BE, Vaughan KA, Jacoby A, Hickman ZL, Bodmer D, Connolly ES Jr. Management of ruptured brain arteriovenous malformations. Curr Atheroscler Rep. 2012;14(4):335–342. https://doi.org/10.1007/s11883-012-0257-9. 4. Beecher JS, Lyon K, Ban VS, et al. Delayed treatment of ruptured brain AVMs: is it ok to wait? J Neurosurg. 2018;128(4):999– 1005. https://doi.org/10.3171/2017.1.JNS16745. 5. Abla AA, Nelson J, Rutledge WC, Young WL, Kim H, Lawton MT. The natural history of AVM hemorrhage in the posterior fossa: comparison of hematoma volumes and neurological outcomes in patients with ruptured infra- and supratentorial AVMs. Neurosurg Focus. 2014;37(3):E6. https:// doi.org/10.3171/2014.7.FOCUS14211. 6. Feghali J, Yang W, Xu R, et al. R2eD AVM Score. Stroke. 2019;50(7):1703–1710. https://doi.org/10.1161/STROKEAHA. 119.025054. 7. Garzelli L, Shotar E, Blauwblomme T, et al. Risk factors for early brain AVM rupture: cohort study of pediatric and adult patients. AJNR Am J Neuroradiol. 2020;41(12):2358–2363. https://doi.org/10.3174/ajnr.A6824. 8. Kim H, Al-Shahi Salman R, McCulloch CE, Stapf C, Young WL, Coinvestigators MARS. Untreated brain arteriovenous malformation: patient-level meta-analyysis of hemorrhage predictors. Neurology. 2014;83(7):590–597. https://doi.org/10.1212/ wnl.0000000000000688. 9. Stapf C, Mast H, Sciacca RR, et al. Predictors of hemorrhage in patients with untreated brain arteriovenous malformation. Neurology. 2006;66:1350–1355. https://doi.org/10.1212/01. wnl.0000210524.68507.87. 10. Graf CJ, Perret GE, Torner JC. Bleeding from cerebral arteriovenous malformations as part of their natural history. J Neurosurg. 1983;58(3):331–337. https://doi.org/10.3171/ jns.1983.58.3.0331. 1983. 11. Ondra SL, Troupp H, George ED, Schwab K. The natural history of symptomatic arteriovenous malformations of the brain: a 24-year follow-up assessment. J Neurosurg. 1990;73(3):387– 391. https://doi.org/10.3171/jns.1990.73.3.0387. 12. Hernesniemi JA, Dashti R, Juvela S, Vaart K, Niemela M, Laakso A. Natural history of brain arteriovenous malformations: a longterm follow-up study of risk of hemorrhage in 238 patients. Neurosurgery. 2008;63(5):823–829; discussion 829–831. https://doi.org/10.1227/01.NEU.0000330401.82582.5E.

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13. Ding D, Starke RM, Kano H, et al. International multicenter cohort study of pediatric brain arteriovenous malformations. Part 1: Predictors of hemorrhagic presentation. J Neurosurg Pediatr. 2017;19(2):127–135. https://doi.org/10.3171/2016.9. PEDS16283. 14. Mansmann U, Meisel J, Brock M, Rodesch G, Alvarez H, Lasjaunias P. Factors associated with intracranial hemorrhage in cases of cerebral arteriovenous malformation. Neurosurgery. 2000;46(2):272–279; discussion 279–281. https://doi. org/10.1097/00006123-200002000-00004. 15. Mast H, Young WL, Koennecke H-C, et al. Risk of spontaneous haemorrhage after diagnosis of cerebral arteriovenous malformation. Lancet. 1997;350(9084):1065–1068. https://doi. org/10.1016/s0140-6736(97)05390-7. 16. Shainker SA, Edlow JA, O'Brien K. Cerebrovascular emergencies in pregnancy. Best Pract Res Clin Obstet Gynaecol. 2015;29(5): 721–731. https://doi.org/10.1016/j.bpobgyn.2015.03.004. 17. Liu XJ, Wang S, Zhao YL, et al. Risk of cerebral arteriovenous malformation rupture during pregnancy and puerperium. Neurology. 2014;82(20):1798–1803. https://doi.org/10.1212/ wnl.0000000000000436. 18. Cohen-Gadol AA, Friedman JA, Friedman JD, Tubbs RS, Munis JR, Meyer FB. Neurosurgical management of intracranial lesions in the pregnant patient: a 36-year institutional experience and review of the literature. J Neurosurg. 2009;111(6):1150– 1157. https://doi.org/10.3171/2009.3.JNS081160. 19. Stricker S, Boulouis G, Benichi S, et al. Acute surgical management of children with ruptured brain arteriovenous malformation. J Neurosurg Pediatr. 2021;27(4):237–245. https://doi. org/10.3171/2020.8.PEDS20479. 20. Meyer PG, Orliaguet GA, Zerah M, et al. Emergency management of deeply comatose children with acute rupture of cerebral arteriovenous malformations. Can J Anesth. 2000;47(8):758– 766. https://doi.org/10.1007/bf03019478. 21. Chua MMJ, Gupta S, Essayed WI, et al. Endovascular treatment of a ruptured posterior fossa pure arterial malformation: illustrative case. J Neurosurg: Case Lessons. 2021;1(2). https://doi. org/10.3171/case2073. 22. Hemphill JC III, Greenberg SM, Anderson CS, et al. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. Jul 2015;46(7):2032–2060. https://doi.org/10.1161/ STR.0000000000000069. 23. Arnaout OM, Gross BA, Eddleman CS, Bendok BR, Getch CC, Batjer HH. Posterior fossa arteriovenous malformations. Neurosurg Focus. 2009;26(5):E12. https://doi. org/10.3171/2009.2.FOCUS0914. 24. Majumdar M, Tan LA, Chen M. Critical assessment of the morbidity associated with ruptured cerebral arteriovenous malformations. J Neurointerv Surg. 2016;8(2):163–167. https://doi. org/10.1136/neurintsurg-2014-011517. 25. Petridis AK, Kamp MA, Cornelius JF, et al. Aneurysmal subarachnoid hemorrhage. Dtsch Arztebl Int. 2017;114(13): 226–236. https://doi.org/10.3238/arztebl.2017.0226. 26. Shotar E, Pistocchi S, Haffaf I, et al. Early rebleeding after brain arteriovenous malformation rupture, clinical impact and predictive factors: a monocentric retrospective cohort study. Cerebrovasc Dis. 2017;44(5-6):304–312. https://doi.org/10.1159/000479120. 27. Schuss P, Hadjiathanasiou A, Ilic I, et al. Risk of rebleeding in patients suffering from ruptured brain arteriovenous malformations undergoing subacute treatment: a single-center series and systematic review of the literature. World Neurosurg. 2020;134:e610– e615. https://doi.org/10.1016/j.wneu.2019.10.148.

28. Mendelow AD, Gregson BA, Fernandes HM, et al; STICH investigators. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet. 2005;365(9457):387–397. https://doi.org/10.1016/ S0140-6736(05)17826-X. 29. Mendelow AD, Gregson BA, Rowan EN, et al; STICH II Investigators. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet. 2013;382(9890):397–408. https://doi.org/10.1016/S01406736(13)60986-1. Erratum in: Lancet. 2013;382(9890):396. Erratum in: Lancet. 2021;398(10305):1042. 30. Mendelow AD, Gregson BA, Rowan EN, et al; STITCH(Trauma) Investigators. Early surgery versus initial conservative treatment in patients with traumatic intracerebral hemorrhage (STITCH[Trauma]): the first randomized trial. J Neurotrauma. 2015;32(17):1312–1323. https://doi.org/10.1089/neu.2014. 3644. 31. Gregson BA, Mitchell P, Mendelow AD. Surgical decision making in brain hemorrhage. Stroke. 2019;50(5):1108–1115. https://doi.org/10.1161/STROKEAHA.118.022694. 32. Ueda M, Tsunogae M, Saito H, Suzuki T, Ota T. Delayed hemiparkinsonism associated with Kernohan's notch in a patient with a ruptured arteriovenous malformation. Intern Med. 2021;60(2):309–313. https://doi.org/10.2169/ internalmedicine.5621-20. 33. Catapano JS, Frisoli FA, Nguyen CL, et al. Spetzler-Martin grade III arteriovenous malformations: a multicenter ­ propensity-adjusted analysis of the effects of preoperative embolization. Neurosurgery. 2021;88(5):996–1002. https://doi. org/10.1093/neuros/nyaa551. 34. Bruno CA Jr, Meyers PM. Endovascular management of arteriovenous malformations of the brain. Interv Neurol. 2013; 1(3-4):109–123. https://doi.org/10.1159/000346927. 35. Hou K, Xu K, Chen X, Ji T, Guo Y, Yu J. Targeted endovascular treatment for ruptured brain arteriovenous malformations. Neurosurg Rev. 2020;43(6):1509–1518. https://doi.org/10.1007/ s10143-019-01205-1. 36. van Rooij WJ, Jacobs S, Sluzewski M, Beute GN, van der Pol B. Endovascular treatment of ruptured brain AVMs in the acute phase of hemorrhage. AJNR Am J Neuroradiol. 2012;33(6):1162–1166. https://doi.org/10.3174/ajnr.A2995. 37. Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet. 2014;383(9917):614–621. https:// doi.org/10.1016/s0140-6736(13)62302-8. 38. Ding D, Yen CP, Starke RM, Xu Z, Sheehan JP. Radiosurgery for ruptured intracranial arteriovenous malformations. J Neurosurg. 2014;121(2):470–481. https://doi.org/10.3171/2014. 2.JNS131605. 39. Shotar E, Debarre M, Sourour NA, et al. Retrospective study of long-term outcome after brain arteriovenous malformation rupture: the RAP score. J Neurosurg. 2018;128(1):78–85. https://doi.org/10.3171/2016.9.JNS161431. 40. Di Bartolomeo A, Scafa AK, Giugliano M, Dugoni DE, Ruggeri AG, Delfini R. Ruptured brain arteriovenous malformations: surgical timing and outcomes-a retrospective study of 25 cases. J Neurosci Rural Pract. 2021;12(1):4–11. https://doi.org/10.105 5/s-0040-1716792.

Chapter 24

Medical Comorbidities in Elective Surgery Halina White

Chapter Outline Introduction Comorbidity Rating Scales Preoperative Optimization Cardiovascular Disease Respiratory Disease Diabetes, Renal and Liver Disease, Fluid Status, Anemia, and Other Medical Considerations Seizures Headaches Pregnancy Social and Psychiatric Comorbidities Venous Thromboembolism Prophylaxis Use of Antiplatelet, Anticoagulant, and Thrombolytic Agents Other Postoperative Medical Complications Intracranial AVM Surgery Outcomes and Their Relation to Medical Comorbidities Conclusion

Introduction A comorbidity is any additional condition simultaneously present in a patient who has the index disease under study. Because intracranial arteriovenous malformations (iAVMs) are usually diagnosed when patients are relatively young (typically around the age of 40 years),1 the presence of severe or multiple comorbidities is less likely than in some other patient populations. Nevertheless, since AVM surgery is most often performed on an elective basis, it is important to maximize control of all medical comorbidities before the surgical procedure. Although there is

a lack of data specific to the perioperative management of medical comorbidities in iAVM surgery, recommendations can be adapted from the principles and practices of general neurosurgical and general perioperative management. This chapter reviews the current best practices to ameliorate the effects of medical comorbidities in patients undergoing elective iAVM surgery.

Comorbidity Rating Scales Various indices exist to help quantify the degree of comorbidity or functionality a patient has, including the Charlson Comorbidity Index, the Karnofsky Performance Status (KPS), and the American Society of Anesthesiologists (ASA) Physical Status Classification System.2 Data suggest that these scales may predict neurosurgical morbidity and mortality. Worse KPS scores and worse ASA physical status classification predict early (≤30-day) morbidity of intracranial tumor patients. A poor score on the Charlson Comorbidity Index may predict mortality of patients undergoing elective intracranial aneurysm intervention.3 While it is likely that more comorbidities could increase the risks of elective surgery in iAVM patients, no comorbidity index study has focused specifically on them. Nevertheless, we postulate that elective iAVM surgery in patients with multiple, severe, uncontrolled, medical comorbidities should be approached with caution, whereas surgery in young patients without comorbidities is likely to be medically very safe.

Preoperative Optimization All patients who plan to undergo elective iAVM surgery should undergo a preoperative anesthesia assessment a few weeks prior to surgery to ensure that all comorbidities are identified and managed, to plan for appropriate and safe anesthesia, and to allow for 229

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identification of and planning for any potential medical problems that might arise postoperatively. In this assessment, it is mandatory to review the patient’s entire prior medical and surgical history, medications, allergies, and previous surgical procedure outcomes, and previous anesthetic outcomes as well as examine the patient, conduct necessary tests, and review the surgical treatment plan and possible complications. In selected patients with significant comorbidities, specialists, such as neurology, cardiology, or pulmonary medicine colleagues, should be consulted to ensure optimal comorbidity management.

Pearls • Comorbidities have not been found to be predictive in iAVM treatment outcomes. • Any patient with a medical comorbidity should be evaluated by the appropriate specialist. • Patients who have seizures related to their iAVM benefit from resection. • Liver disease is associated with worse neurosurgical outcomes in general. Treatment should be maximized prior to any invasive interventions. • Management of headache associated with iAVMs should be guided by a neurologist with expertise in this area.

Cardiovascular Disease Craniotomy can result in blood pressure fluctuations, arrhythmias, electrocardiographic abnormalities, myocardial ischemia, and heart failure. These can occur due to central neurogenic effects on the myocardium and the autonomic nervous system or due to worsening of concurrent medical conditions. Preexisting cardiovascular disease, both symptomatic and asymptomatic, should therefore be identified in AVM patients about to undergo surgery. Patients with cardiovascular symptoms or known cardiovascular disease should undergo electrocardiography, echocardiography, and sometimes stress testing and other investigations as per established guidelines.4 Patients who are already being treated with betablockers should continue on these medications, and perioperative beta-blockade should also be used in patients with a positive stress test undergoing major vascular surgery. However, in the absence of cardiac disease, perioperative beta-blockade is not recommended; although it can prevent nonfatal myocardial infarction, it can increase the risks of hypotension, bradycardia, stroke, and death.5 Other cardiology medications should generally be continued. Statins have been shown to improve perioperative cardiac outcomes; hence, they should be continued in patients already taking them.

Respiratory Disease The respiratory system should be evaluated and optimized preoperatively to ensure adequate oxygenation and ventilation intra- and postoperatively. Any

pulmonary disease should be preemptively treated before surgery because a neurosurgical procedure can cause pulmonary disease exacerbation. Also, after neurosurgery, patients can develop respiratory complications such as aspiration of gastric contents, pneumonia, exacerbation of bronchospasm/asthma/chronic obstructive pulmonary disease (COPD), respiratory failure requiring reintubation, pulmonary embolism, and neurogenic pulmonary edema. It is important to identify those individuals at risk so that these complications can be prevented. Inquiring about smoking history should be part of the preoperative evaluation, and patients who smoke should be strongly encouraged to stop, because active smoking is a risk factor for worse neurosurgical outcome.6 Smoking worsens measures of cardiovascular function such as maximal exercise capacity and endothelial vasodilatation. Interestingly, even a brief period of smoking cessation may be of benefit. Cessation of cigarette smoking should begin at least 6–8 weeks prior to surgery, as this period of abstinence is associated with improvement in both pulmonary function and overall perioperative morbidity.7 A history of asthma or COPD should lead to an assessment of the patient’s level of disease control. This should include frequency of use of short-acting beta-2 agonists, use of glucocorticoids, exploration of any history of asthma hospitalization, emergency department visits, intubation, and any recent symptoms of a respiratory tract infection or wheezing. If asthma or COPD are found to be not well controlled, the patient

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should be referred to a pulmonologist for control optimization prior to surgery.8 A history of obstructive sleep apnea (OSA) is also associated with an increased risk of perioperative adverse events such as perioperative hypoxia, reintubation, arrhythmia, and intensive care unit admission.9 Sedation, anesthesia, opioids, and rapid eye movement sleep rebound have been shown to cause worsening of OSA in the perioperative period specifically leading to perioperative complications. Clinical OSA symptoms include daytime somnolence, excessive snoring, and fragmented sleep. The STOP questionnaire is a validated screening tool for OSA and can be used as part of the preoperative assessment to identify patients with OSA.10 Additional information on the patient’s body mass index, age, neck circumference, and gender can increase the detection of OSA. There are also specific groups of patients, such as those with obesity, acromegaly, or Cushing’s disease, who have a high incidence of OSA and in whom screening should be particularly stringent. If a patient is found to have OSA, the ASA guidelines on the perioperative management of patients with OSA should be followed to decrease their perioperative risk.11 Lastly, as with all preoperative patients, an assessment of the airway must be performed. Consideration can be given to the laryngeal mask airway as a less stressful option for the patient, specifically with respect to cardiovascular stress,12 but currently, this option is rarely used in cranial surgery, and endotracheal intubation is typically preferred by the anesthesiologist.

Diabetes, Renal and Liver Disease, Fluid Status, Anemia, and Other Medical Considerations Medical conditions such as diabetes, renal impairment, and hepatic disease can also affect the perioperative care of the iAVM patient and need to be preoperatively diagnosed and managed. There is a known association between hyperglycemia and poor neurosurgical outcome.13 In one study of patients undergoing imageguided stereotactic brain biopsy, blood glucose levels above 200 mg/dL were associated with a 100% rate of perioperative morbidity.14 It is becoming clear that overly rigorous glucose control as well as overly lax glucose control can cause problems.15 In general,

perioperative blood sugar levels should be monitored frequently with the goal of avoidance of either hypoor hyperglycemia and maintenance of euglycemia. Liver disease is associated with worse outcomes in neurosurgery for tumor treatment,16 and renal disease is associated with worse outcomes in spine surgery.17 Both should be identified, and specialist consultation may be required before affected patients undergo iAVM surgery. Anemia also can worsen craniotomy outcomes and should be corrected if possible.18 As part of the medical assessment, a physical exam to rule out major undiagnosed medical disease and basic blood tests to rule out liver and kidney dysfunction, diabetes, anemia, and clotting dyscrasias are therefore recommended. All medications should be reviewed preoperatively. Most should be continued, particularly antiepileptic drugs and cardiovascular medications. Steroid use is known to be associated with increased infection, and therefore should be avoided if possible.19 Latex allergy, contrast allergy, and antibiotic allergy should be screened for. Patients on chronic pain medication or migraine medication may require specific planning for perioperative pain management. Hemodynamic instability and fluid shifts represent a particular concern in iAVM surgery due to risks of blood loss, cerebral swelling, stroke, or loss of autoregulation. Patients with renal impairment are particularly susceptible to these complications. Anesthesia that enables reliable neurophysiologic monitoring is also a critical consideration in this subset of patients. Lastly, it is important to avoid hyperglycemic and administration of hypotonic fluids, as these can increase the risk of infection and cerebral edema.20

Seizures Seizures are a common comorbidity associated with iAVMs and can be the presenting complaint in around 25% of iAVM patients, according to population-based studies.21,22 Of iAVM patients who initially present with a seizure, around 58% go on to develop epilepsy.22 Seizures are more common in association with cortical (33%) rather than subcortical (6%) AVMs,21 ruptured (23%) rather than unruptured (6%) AVMs,22 larger AVMs,23 younger patient age, and a temporal lobe AVM location.24

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Patients with iAVM-associated seizures are typically maintained on antiepileptic drugs with good activity against focal epilepsy, under the care of an epileptologist. Case series show good outcomes with respect to seizure freedom after microsurgery25 and moderate outcomes after embolization26,27 or radiosurgery,28,29 with the worst outcomes associated with subtotal obliteration of the lesion. Although a recent meta-analysis of 31 multimodal therapy studies did not find any difference in epilepsy rates with invasive iAVM therapy vs conservative medical treatment with antiepileptic drugs, this finding was likely observed due to subtotal obliteration of many of the lesions.30 In patients who are about to undergo iAVM surgery, usual epilepsy medications should be continued. In patients with intractable epilepsy, perioperative consultation with their epileptologist should be sought. In iAVM patients without seizures, some surgeons opt for a brief (e.g., 1-week) course of perioperative antiepileptic medication (often levetiracetam). Anticonvulsant prophylaxis is usually based on neurosurgeon preference, as data on perioperative seizure prophylaxis in craniotomy patients are currently neutral; however, this approach is considered reasonable by many practitioners.31 Postoperative seizures occur usually in 3%–7% of patients.32 Treatment should proceed according to standard treatment guidelines for seizures and status epilepticus. Even when seizures occur postoperatively, surgical outcome and long-term prognosis are generally good.

Headaches Headaches have been variously reported as affecting 14%,33 25%,34 and 79%35 of iAVM patients. AVMs can cause headaches by triggering migraine phenomena36 or, less likely, by causing vascular steal37 and raised intracranial pressure.38 Headaches in iAVM patients are often, but not always, lateralized to the side of the AVM. Occipital AVMs are most typically associated with headaches,36 and patients with occipital AVMs frequently also report visual phenomena such as scotoma, migraine-like visual auras, and visual blurring.39 Multiple case series suggest that multimodal iAVM treatment (with surgery, embolization, and/or

radiation) can result in improvement or resolution of headaches.40,41 The migraine prevention and treatment agents used in iAVM patients are typically chosen based on a lack of increased hemorrhage risk or effects on blood vessel caliber. For example, anticonvulsants such as gabapentin and topiramate and antihypertensive drugs such as propranolol are used. Medications known to be associated with vessel spasm (e.g., triptans) or hemorrhage (e.g., aspirin in high doses) are avoided. Data in this field are currently lacking, however, and guidance on iAVM-associated headache treatment must be extrapolated from findings in patients with non-AVM– associated headache.42 In the perioperative period, patients with iAVMassociated migraine headaches should continue treatment with their usual antimigraine medications if possible. Pain in these patients should be treated just like any other pain. Intractable perioperative migraines are best treated in conjunction with headache neurology colleagues.

Pregnancy Data regarding AVM management during pregnancy are limited. Overall, during pregnancy the spontaneous hemorrhage risk from iAVMs may be increased. For example, one retrospective study found hemorrhage rates in women with iAVMs to be 10.8% per year when pregnant and 1.1% per year when not pregnant.43 Another study noted hemorrhage rates to be 5.7% per year when pregnant and 1.1% when not pregnant.44 However, other studies have not found such profound differences in hemorrhage rates,45 and a recent meta-analysis showed no increase in iAVMrelated hemorrhage during pregnancy.46 Therefore, there is an urgent need for more studies in this area. Due to the complexities of iAVM care during pregnancy and the perceived increased risk of iAVM rupture in pregnancy, some patients of childbearing age do request preemptive iAVM treatment prior to childbearing, and this may be reasonable. The decision to treat an iAVM while a patient is pregnant is dependent upon an accurate risk-benefit analysis; however, the risks usually outweigh the benefit in this scenario.47 The general recommendation for pregnant patients who present with a symptomatic

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iAVM is to treat if the patient’s condition cannot be stabilized. Symptomatic iAVMs (i.e., those that are bleeding or producing seizures) that cannot be stabilized will require emergent surgical management. When the patient’s condition can be stabilized, optimum management should be provided at an appropriate time relative to the stage of pregnancy. There is no standard recommendation for the method of obstetric delivery for pregnant patients with an iAVM. The delivery method has not been shown to impact clinical outcomes, although only a few small studies have been published. A small series from Japan documented good outcomes with either cesarean section or vaginal delivery in patients with known iAVMs. During pregnancy, three of the nine identified patients suffered intracranial hemorrhage, but none had worsening of symptoms during or after delivery.48 For patients who become pregnant during the latency period between stereotactic radiosurgery and confirmed lesion obliteration, the hemorrhage risk may also be increased compared to the risk for nonpregnant patients, so patients who undergo radiosurgery for iAVM treatment are asked to delay pregnancy if possible.49 For a detailed discussion of obstetric considerations in AVM management, please refer to Chapter 28.

Social and Psychiatric Comorbidities Perioperative anxiety is common in neurosurgical patients,50 but the use of anxiolytics such as benzodiazepines is associated with worse surgical outcomes and is not recommended.51 To allay anxiety, counseling about the surgical procedure and anesthesia is warranted and has been shown to be helpful. Other prognostic indicators that can influence iAVM surgery outcome include frailty (which is hard to define, but which is significantly associated with higher neurosurgical morbidity and mortality)52 and socioeconomic disparities.53 More studies are needed to assess the effects of psychiatric illness and socioeconomic disparity on iAVM patients, so that the effects can be ameliorated.

Venous Thromboembolism Prophylaxis Studies of neurosurgical cohorts show that venous thromboembolism (VTE) is not uncommon in

neurosurgery patients,54 and prophylaxis is beneficial.55 There is no single large study of VTE prophylaxis in patients undergoing iAVM resection, but small case series show that it appears to be safe.

Use of Antiplatelet, Anticoagulant, and Thrombolytic Agents There is a paucity of data on the use of antiplatelet drugs, anticoagulants, and thrombolytics in patients with iAVMs. However, patients with these lesions sometimes require these agents for unrelated medical conditions, resulting in a difficult risk-benefit analysis. Interestingly, studies show that aspirin is safe for aneurysm and cavernoma patients.56,57 From the data that are available on iAVM patients, it appears that antiplatelet agents and anticoagulants may be also acceptable in some patients with these lesions—usually in patients with unruptured AVMs and not during the immediate postoperative period. For example, one retrospective observational study found that the use of antiplatelet or anticoagulant medications did not cause increased bleeding in patients with unruptured iAVMs.58 A small pediatric case series showed that when dural venous sinus thrombosis occurred as a complication of AVM embolization, full postoperative anticoagulation appeared to be safe and effective.59 Two studies of perioperative anticoagulation in iAVM patients appear to be ongoing in China, but no results are yet available (clinicaltrials.gov identifiers NCT03306823 and NCT03306836). In contrast, scattered individual case reports of the use of intravenous thrombolysis for stroke, myocardial infarction, and pulmonary embolism in patients with unruptured iAVMs have shown symptomatic intracerebral hemorrhage occurring in approximately 50% of these cases.60,61 Therefore, at this time, although antiplatelet and anticoagulant therapy can be considered for some patients (as noted earlier), intravenous thrombolysis is contraindicated. When thromboembolic complications such as pulmonary embolism arise in the immediate postoperative period after iAVM surgery, treatment is difficult. These disorders usually necessitate the use of anticoagulant therapy. However, in the immediate postoperative period, we would usually advocate for the use of an inferior vena cava filter instead of anticoagulants.

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Other Postoperative Medical Complications Postoperative wound infections have been reported to occur in 1%–2% of patients in AVM case series and should be treated just like any other wound infection.62 Postoperative gastrointestinal bleeding can also occur and should be treated with cardiovascular support, proton pump inhibitors, and gastroenterology input as needed.

Intracranial AVM Surgery Outcomes and Their Relation to Medical Comorbidities Despite all the aforementioned comorbidity considerations for iAVM surgery, multiple small series show that iAVM surgery can be very safe even in patients with some comorbidity. In a series of 86 adult iAVM cases from our institution in New York, 30 patients (34.9%) had minor comorbidities and 16 (18.6%) had major comorbidities, yet the treatment outcomes were generally good. Symptomatic stroke or death occurred in 8.3% of cases, long-term clinical impairment was observed in 4.5%, and cure was achieved in 92.4%. Comorbidity was not a significant predictor of bad outcome.63 In a series of 105 iAVM patients treated with stereotactic radiosurgery or microsurgery, a substantial proportion had comorbidities, including hypertension (23%), smoking (44%), and seizures (33%). In this series, 7.6% of patients had a stroke or died during the post-treatment follow-up period (mean 43 months; range, 4–163 months).64 Of the surgically treated patients, 95% had total resolution of their AVM. In a series of 167 children identified via the National Surgical Quality Improvement Program (NSQIP) Pediatric database, 68% had an ASA classification of 3 or greater and 96 (57%) had a preoperative comorbidity, with the most common comorbidity being seizure disorder (54 patients, 32%). Seventy-six patients (46%) had documented perioperative events or complications. The incidence of wound infection/ dehiscence was 4%, and the incidences of pneumonia, pulmonary embolism, unplanned reintubation, renal insufficiency, urinary tract infection, stroke, and sepsis were all less than 1%. There were no deaths. The incidence of unplanned reoperation was 10%, and that of unplanned readmission was 12%. Most of the

patients (90%) were discharged home. Operative time (P = .0001, odds ratio [OR] = 9.53), emergent surgery status (P = .0001, OR = 8.19) and preoperative comorbidities (P = .007) were found to be significant predictors of poor outcome.65 More studies on comorbidity considerations in iAVM are clearly required; however, when comorbidities are carefully managed, as described earlier in this chapter, postoperative results tend to be good.

Conclusion Medical comorbidities have not been found to be strongly associated with elective iAVM surgery outcomes. This may be because patients with iAVMs who undergo elective surgery tend to be young (around 40 years) and free of most severe comorbidities. There may also be selection bias, with healthier iAVM patients being offered surgical treatment more often than less healthy ones. Lastly, studies that have examined this association are generally lacking. The most common preoperative comorbidities in iAVM patients include seizure disorder and headache. Other potentially relevant comorbidities that should be evaluated and managed preoperatively include heart disease (ischemic, valvular, arrhythmias, other), pulmonary disease (asthma, COPD), obesity, sleep apnea, smoking, hypercoagulability disorders, pregnancy, and psychiatric disease. In addition, particular attention should be paid to patients with renal disease, as fluid shifts, neuroprotection, and resuscitation are the dominant considerations in iAVM surgery. REFERENCES 1. Mohr JP, Parides MK, Stapf C, et al. International ARUBA Investigators. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet. 2014;383(9917):614–621. https://doi.org/10.1016/ S0140-6736(13)62302-8. 2. de Groot V, Beckerman H, Lankhorst GJ, Bouter LM. How to measure comorbidity. A critical review of available methods. J Clin Epidemiol. 2003;56(3):221–229. https://doi.org/10.1016/ s0895-4356(02)00585-1. 3. Reponen E, Tuominen H, Korja M. Evidence for the use of preoperative risk assessment scores in elective cranial neurosurgery: a systematic review of the literature. Anesth Analg. 2014;119(2): 420–432. https://doi.org/10.1213/ANE.0000000000000234. 4. Fleisher LA, Fleischmann KE, Auerbach AD, et al. ACC/ AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery:

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32. Theofanis T, Chalouhi N, Dalyai R, et al. Microsurgery for cerebral arteriovenous malformations: postoperative outcomes and predictors of complications in 264 cases. Neurosurg Focus. 2014;37(3):E10. https://doi. org/10.3171/2014.7.FOCUS14160. 33. Hofmeister C, Stapf C, Hartmann A, et al. Demographic, morphological, and clinical characteristics of 1289 patients with brain arteriovenous malformation. Stroke. 2000;31(6):1307– 1310. https://doi.org/10.1161/01.str.31.6.1307. 34. Zhao J, Wang S, Li J, Qi W, Sui D, Zhao Y. Clinical characteristics and surgical results of patients with cerebral arteriovenous malformations. Surg Neurol. 2005;63(2):156–161; discussion 161. https://doi.org/10.1016/j.surneu.2004.04.021. 35. Waltimo O, Hokkanen E, Pirskanen R. Intracranial arteriovenous malformations and headache. Headache. 1975;15(2):133– 135. https://doi.org/10.1111/j.1526-4610.1975.hed02133.x. 36. Galletti F, Sarchielli P, Hamam M, et al. Occipital arteriovenous malformations and migraine. Cephalalgia. 2011;31(12):1320– 1324. https://doi.org/10.1177/0333102411417465. 37. Okabe T, Meyer JS, Okayasu H, et al. Xenon-enhanced CT CBF measurements in cerebral AVM's before and after excision. Contribution to pathogenesis and treatment. J Neurosurg. 1983;59(1):21–31. https://doi.org/10.3171/ jns.1983.59.1.0021. 38. Chimowitz MI, Little JR, Awad IA, Sila CA, Kosmorsky G, Furlan AJ. Intracranial hypertension associated with unruptured cerebral arteriovenous malformations. Ann Neurol. 1990;27(5):474–479. https://doi.org/10.1002/ana.410270504. 39. Kupersmith MJ, Vargas ME, Yashar A, et al. Occipital arteriovenous malformations: visual disturbances and presentation. Neurology. 1996;46(4):953–957. https://doi.org/10.1212/ wnl.46.4.953. 40. Dehdashti AR, Thines L, Willinsky RA, et al. Multidisciplinary care of occipital arteriovenous malformations: effect on nonhemorrhagic headache, vision, and outcome in a series of 135 patients. Clinical article. J Neurosurg. 2010;113(4):742–748. https://doi.org/10.3171/2009.11.JNS09884. 41. Lundqvist C, Wikholm G, Svendsen P. Embolization of cerebral arteriovenous malformations: Part II–Aspects of complications and late outcome. Neurosurgery. 1996;39(3):460–467; discussion 467–469. https://doi.org/10.1097/00006123-199609000-00005. 42. Burch R. Migraine and tension-type headache: diagnosis and treatment. Med Clin North Am. 2019;103(2):215–233. https://doi.org/10.1016/j.mcna.2018.10.003. 43. Gross BA, Du R. Natural history of cerebral arteriovenous malformations: a meta-analysis. J Neurosurg. 2013;118(2):437–443. https://doi.org/10.3171/2012.10.JNS121280. 44. Porras JL, Yang W, Philadelphia E, et al. Hemorrhage risk of brain arteriovenous malformations during pregnancy and puerperium in a North American cohort. Stroke. 2017;48(6):1507– 1513. https://doi.org/10.1161/STROKEAHA.117.016828. 45. Liu XJ, Wang S, Zhao YL, et al. Risk of cerebral arteriovenous malformation rupture during pregnancy and puerperium. Neurology. 2014;82(20):1798–1803. https://doi.org/10.1212/ WNL.0000000000000436. 46. Davidoff CL, Lo Presti A, Rogers JM, et al. Risk of first hemorrhage of brain arteriovenous malformations during pregnancy: a systematic review of the literature. Neurosurgery. 2019;85(5):E806–E814. https://doi.org/10.1093/neuros/nyz175. 47. Ogilvy CS, Stieg PE, Awad I, et al. AHA scientific statement: recommendations for the management of intracranial arteriovenous malformations: a statement for healthcare professionals from a special writing group of the Stroke Council, American

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Stroke Association. Stroke. 2001;32(6):1458–1471. https://doi. org/10.1161/01.str.32.6.1458. Fukuda K, Hamano E, Nakajima N, et al. Pregnancy and delivery management in patients with cerebral arteriovenous malformation: a single-center experience. Neurol Med Chir. 2013;53(8):565–570. https://doi.org/10.2176/nmc.53.565. Tonetti D, Kano H, Bowden G, Flickinger JC, Lunsford DL. Hemorrhage during pregnancy in the latency interval after stereotactic radiosurgery for arteriovenous malformations. J Neurosurg. 2014;121(Suppl):226–231. https://doi.org/10.31 71/2014.7.gks141297. Perks A, Chakravarti S, Manninen P. Preoperative anxiety in neurosurgical patients. J Neurosurg Anesthesiol. 2009;21(2):127–130. https://doi.org/10.1097/ANA.0b013e31819a6ca3. Korttila K, Tarkkanen L, Kuurne T, Himberg JI, Abbondati G. Unpredictable central nervous system effects after lorazepam premedication for neurosurgery. Acta Anaesthesiol Scand. 1982;26(3):213–216. https://doi. org/10.1111/j.1399-6576.1982.tb01756.x. Pazniokas J, Gandhi C, Theriault B, et al. The immense heterogeneity of frailty in neurosurgery: a systematic literature review. Neurosurg Rev. 2021;44(1):189–201. https://doi.org/10.1007/ s10143-020-01241-2. El-Sayed AM, Ziewacz JE, Davis MC, et al. Insurance status and inequalities in outcomes after neurosurgery. World Neurosurg. 2011;76(5):459–466. https://doi.org/10.1016/j. wneu.2011.03.051. Taniguchi S, Fukuda I, Daitoku K, et al. Prevalence of venous thromboembolism in neurosurgical patients. Heart Vessels. 2009;24(6):425–428. https://doi.org/10.1007/s00380-008-1135-9. Agarwal N, Zenonos GA, Agarwal P, et al. Risk-to-benefit ratio of venous thromboembolism prophylaxis for neurosurgical procedures at a quaternary referral center. Neurosurgery. 2019;84(2):355–361. https://doi.org/10.1093/neuros/nyy035. Hasan DM, Mahaney KB, Brown RD Jr, et al. International Study of Unruptured Intracranial Aneurysms Investigators. Aspirin as a promising agent for decreasing incidence of cerebral aneurysm rupture. Stroke. 2011;42(11):3156–3162. https://doi.org/10.1161/STROKEAHA.111.619411. Gomez-Paz S, Salem MM, Maragkos GA, et al. Role of aspirin and statin therapy in patients with cerebral cavernous malformations. J Clin Neurosci. 2020;78:246–251. https://doi. org/10.1016/j.jocn.2020.04.012. Sturiale CL, Pignotti F, Giordano M, et al. Sporadic AVMs-HHT Study Group. Antithrombotic therapy and intracranial bleeding in subjects with sporadic brain arteriovenous malformations: preliminary results from a retrospective study. Intern Emerg Med. 2018;13(8):1227– 1232. https://doi.org/10.1007/s11739-018-1918-7. Puccinelli F, Deiva K, Bellesme C, et al. Cerebral venous thrombosis after embolization of pediatric AVM with jugular bulb stenosis or occlusion: management and prevention. Eur J Paediatr Neurol. 2014;18(6):766–773. https://doi.org/10.1016/j.ejpn. 2014.07.007. Proner J, Rosenblum BR, Rothman A. Ruptured arteriovenous malformation complicating thrombolytic therapy with tissue plasminogen activator. Arch Neurol. 1990;47(1):105–106. https://doi.org/10.1001/archneur.1990.00530010131032. Sloan MA, Price TR, Petito CK, et al. Clinical features and pathogenesis of intracerebral hemorrhage after rt-PA and heparin therapy for acute myocardial infarction: the Thrombolysis in Myocardial Infarction (TIMI) II Pilot and Randomized Clinical Trial combined experience. Neurology. 1995;45(4):649–658. https://doi.org/10.1212/wnl.45.4.649.

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62. Wong J, Slomovic A, Ibrahim G, Radovanovic I, Tymianski M. Microsurgery for ARUBA Trial (A Randomized Trial of Unruptured Brain Arteriovenous Malformation)-eligible unruptured brain arteriovenous malformations. Stroke. 2017;48(1):136–144. https:// doi.org/10.1161/STROKEAHA.116.014660. 63. Link TW, Winston G, Schwarz JT, et al. Treatment of unruptured brain arteriovenous malformations: a single-center experience of 86 patients and a critique of A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) Trial. World Neurosurg. 2018;120:e1156–e1162. https://doi. org/10.1016/j.wneu.2018.09.025.

237 64. Lang M, Moore NZ, Rasmussen PA, Bain MD. Treatment outcomes of A Randomized Trial of Unruptured Brain Arteriovenous Malformation-eligible unruptured brain arteriovenous malformation patients. Neurosurgery. 2018;83(3):548–555. https://doi.org/10.1093/neuros/nyx506. 65. Muir M, Patel R, Gadgil N, Pan I, Lam S. Postoperative 30day outcomes after craniotomy for supratentorial AVM resection in children. J Clin Neurosci. 2019;70:108–112. https://doi. org/10.1016/j.jocn.2019.08.059.

Chapter 25

Anesthetic Management of Intracranial AVMs Brian P. Lemkuil, Ashley Fejleh, Navaz Karanjia, and Arthur M. Lam

Chapter Outline Introduction Presentation Treatment Cerebrovascular Physiology Preoperative Management Monitoring Anesthetic Management Neuroprotection Emergence Conclusion

Introduction Intracranial arteriovenous malformations (iAVMs) are relatively rare vascular abnormalities thought to be congenital in etiology; however, angiogenic and inflammatory processes may also play a role in their development. AVMs are a complex tangle of vessels, referred to as the nidus, with feeding arteries and draining vein(s) that lack a true intervening capillary bed (see Chapter 1). In contrast to normal cerebral vascular beds, an iAVM is a low-resistance, high-flow system, with shunt flow proportional to the size of the lesion. Accordingly, the risk of spontaneous rupture is thought to be higher in smaller iAVMs due to the higher intranidal pressure and venous hypertension. The anesthesiologist will encounter patients with iAVMs scheduled for diagnostic imaging and therapeutic treatment in the operating room (OR), interventional neuroradiology suite, or stereotactic radiosurgery suites. Optimal perioperative anesthetic management 238

necessitates knowledge of the basic physiologic and pharmacologic principles inherent to neuroanesthesia as well as intimate understanding of the physiology of iAVMs and the common complications that may arise in the perioperative period. This chapter reviews basic cerebral vascular physiology unique to iAVMs as well as anesthetic goals and considerations for elective treatment; the management of perioperative complications is addressed in Chapter 26.

Presentation The most common clinical presentation is related to sequelae of intracranial hemorrhage. Diagnosis is typically made in relatively young patients, with 75% of the hemorrhagic presentations occurring before the age of 50.1 Clinical manifestations can include seizures, headache, and focal neurologic findings from mass effect of the lesion on surrounding tissues. Although the long-term risk of hemorrhage is controversial and dependent on specific characteristics, natural history studies suggest an annual hemorrhage risk of 2%–3%.2 The risk of rehemorrhage appears to be higher than the risk of initial hemorrhage for some modest period of time. The primary goal of treatment is complete obliteration of the lesion to prevent future hemorrhages.

Treatment Intracranial AVMs are typically treated electively by microsurgical resection, interventional neuroradiology (INR) embolization, stereotactic radiosurgery, or a combination of these modalities. Staged INR embolization prior to microsurgical resection

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is commonly performed to reduce the lesion size, decrease intraoperative blood loss, occlude deep feeding vessels that are anatomically challenging during open resection, and provide staged flow reduction to the nidus, thus potentially reducing the incidence of postoperative complications due to large acute changes in flow dynamics. Infrequently, emergent craniotomy may be required to evacuate a life-threatening hematoma due to a ruptured iAVM. In such cases, superficial iAVMs may be resected in conjunction with hematoma evacuation. Resection of more complicated iAVMs is typically deferred until the anatomy is well defined with a diagnostic cerebral angiogram and the patient is otherwise optimized for surgery. From an anesthesia perspective, microsurgery involves three basic components: (1) obliteration of arterial feeders, (2) circumferential resection of the nidus, and (3) ligation of draining veins. It is critically important that arterial input is controlled prior to sacrificing venous drainage, or malignant edema may result.

Cerebrovascular Physiology AVMs are vascular abnormalities with high flow and low resistance due to direct connection of arteries to veins without true intervening capillaries. The result is that blood preferentially travels the path of least ­ resistance and thus is shunted away from parallel vascular beds that perfuse the brain as an end organ. Consequently, relative arterial hypotension occurs in neighboring beds sharing the same vascular supply. In larger iAVMs with high flow, perfusion pressures may be below the normal range of autoregulation. Despite this, ischemic symptoms are very rare, cerebral blood flow (CBF) may be normal, and autoregulation preserved.3 These findings suggest an adaptive autoregulatory response. This adaptive response has been explained by displacement of the autoregulation curve to the left as opposed to the rightward shift seen in chronic hypertension.4 This helps explain why CO2 responsiveness may be preserved preoperatively (though diminished in the arterial feeders), and nearly universally postoperatively.4 In summary, prior to AVM resection, a subset of patients may have local cerebrovascular beds with reduced CBF or near-normal CBF with perfusion pressures that approximate the lower

Pearls • Hemodynamic stability is paramount during iAVM intervention and predicated upon euvolemia and adequate anesthesia depth. • Brain relaxation and surgical field optimization facilitates resection (see Table 25.1). • No anesthetic agent or hypothermia has been shown to be superior in neuroprotection during surgery. • Tight hemodynamic control and smooth emergence are anesthetic goals intended to reduce the risk for acute postoperative complications. • Use of intraoperative neurophysiologic monitoring necessitating total intravenous anesthesia may delay emergence or impair the early postoperative neurologic exam.

limit of autoregulation. Further reductions in cerebral perfusion pressure may increase the risk of ischemia, particularly when combined with brain retraction and surgical manipulation. Following iAVM resection, feeding artery pressure increases due to loss of the pathologic low-resistance pathway previously offered by the AVM. Feeding arteries are commonly dilated and do not return to normal caliber immediately after iAVM resection. Therefore based on the Poiseuille equation, there will be less pressure reduction than would typically occur along the length of the vessel. The increased vessel diameter may also increase reflection waves, resulting in higher peak pressures. Although there is evidence that autoregulation is intact following iAVM resection,5 it is possible that a small subset of patients do have impaired local autoregulation. At the very least, if local cerebral perfusion pressure exceeds the left-shifted local autoregulatory capacity of the resistance arterioles, the patient may be at risk of hyperemia causing cerebral edema and/or hemorrhage (normal perfusion pressure breakthrough). Alternatively, in contrast to the previous concern, patients may be at risk of stagnation or thrombosis in both veins and arteries following iAVM resection due to abnormal vessel modeling resulting from the previous high flow. Resection of an iAVM may thus reduce vessel runoff below that which is required to prevent stagnation (occlusive

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­hyperemia).6 In response to these opposing hemodynamic concerns, the ideal postresection hemodynamic management remains controversial due to risk for both hyperemia-induced edema with or without hemorrhage and stagnation-induced ischemia or hemorrhage due to venous back pressure. For this reason, many centers focus on strict normotension, which is most commonly defined by the patient’s preoperative blood pressure.7

Preoperative Management Treatment of iAVMs is most frequently performed electively, whether it be a staged INR embolization or operative resection. The typical elective nature allows for detailed and careful preoperative assessment, optimization, and preparation. Similar to management of all neurosurgical cases, the patient’s baseline neurologic status should be carefully assessed for focal neurologic deficits as well as changes in mental status and level of arousal that may suggest increased intracranial pressure. The location and vascular anatomy of the lesion, recent brain imaging, and prior treatments as well as their timing should all be reviewed and factored into the anesthetic induction, maintenance, and emergence plan. As with all anesthetics, careful preoperative airway assessment should be performed, and all systemic comorbidities optimized prior to surgery. Given the potential for rapid and significant blood loss, preoperative laboratory test results should be reviewed, and appropriate blood products prepared in advance.8,9 It is also important to consider the procedural environment when preparing for an iAVM procedure. The INR suite is often located some distance from the OR, which may delay the arrival of assistance, special equipment, medications, or blood. Compared to the OR, the INR suite working environment may be less familiar and may be ergonomically challenging, with limited patient access and suboptimal lighting. However, with appropriate planning and additional preparation, many of these factors can be mitigated or minimized.

Monitoring In addition to the use of standard monitors recommended by the American Society of Anesthesiologists (standard ASA monitors), invasive arterial blood

pressure monitoring is essential for both intraoperative and postoperative management. Unlike patients with ruptured cerebral aneurysms, patients with iAVMs are likely to have only minimal risk of hemorrhagic rupture due to hemodynamic changes during intubation because of the buffering capacity of the iAVM.10 Accordingly, an arterial catheter may be placed after anesthesia induction in most circumstances. Nevertheless, avoidance of sudden and profound hypertension during intubation or head pinning should be ensured. It should be noted that up to 10% of iAVMs have an associated flow-related aneurysm.11 Central venous access must be considered for cases that require resection of larger lesions as well as for patients with difficult peripheral intravenous access or those who might require induced hypotension, aggressive volume resuscitation, or rapid blood administration. Predicting which patients will require induced hypotension or aggressive volume therapy is not always possible. In selected complex cases, particularly in patients with severe cardiac comorbidities, a pulmonary artery catheter may be considered.

Anesthetic Management The specific anesthetics used should take into consideration the neurologic status of the patient, underlying comorbidities, concomitant neurophysiologic monitoring, and anesthesiologist preference on how to achieve the goals inherent to neuroanesthesia. Standard goals include hemodynamic stability and tight blood pressure control, immobility, brain relaxation and surgical field optimization, and rapid emergence to facilitate postoperative neurologic examination. Hemodynamic stability is largely predicated upon euvolemia and adequate anesthetic depth to minimize the influence of surgical stimulation. It is not uncommon to titrate a low-dose phenylephrine infusion to support the blood pressure at the desired target. Although diuresis was once considered standard management for cerebral edema and surgical field optimization, modern anesthetic practice is predicated on ensuring normovolemia. This can be facilitated with the guidance of stroke volume variation (SVV) or pulse pressure variation (PVV) measurements derived from the arterial pressure wave, which reflect changes in loading conditions of the heart due to positive pressure

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Anesthetic Management of Intracranial AVMs

ventilation. Acute blood pressure elevations should be avoided and promptly treated when they occur. Blood pressure targets should be discussed and agreed upon with the surgeon at the outset of the procedure. As previously stated, the vascular beds near the AVM may be near the lower limit of autoregulation, placing them at risk for ischemia. Hypotension plus retraction and surgical manipulation may significantly increase the risk of local ischemia. Thus normotension should likely be the goal. Temporary blood pressure reduction may be needed to improve surgical visualization and hemostasis if the AVM has a deep blood supply. Likewise, profound blood pressure reduction or flow arrest with adenosine may be requested during embolization to reduce the flow through the AVM and better control the deposition of embolic material. Blood pressure may be temporarily increased prior to closure to assess hemostasis. The postoperative blood pressure goal is usually strict normotension within a tight hemodynamic target range due to the concern discussed previously for both hyperemia and stagnation. The target may be influenced by intraoperative findings such as edema or difficult hemostasis or postoperatively based upon the neurologic exam or imaging findings. Regardless, prevention of acute hypertension during emergence and early recovery is an absolute requirement. Brain relaxation and surgical field optimization is inherent to all open intracranial neurosurgery. Management modalities are reviewed in Table 25.1. High-dose anesthetic cerebral vasodilators should be avoided, and administration of these agents should be adjusted as needed based upon direct visualization of the surgical field. An intravenously administered GABA receptor agonist such as propofol, which lacks direct cerebral vasodilatation properties, can be used as the primary hypnotic agent or in combination with an inhalational anesthetic. Carbon dioxide levels should be controlled and maintained in the slightly low normal range. Aggressive hyperventilation should only be performed when there is a strong clinical indication. Hyperosmolar therapy is commonly administered in the OR near the time of incision, whether it be mannitol or hypertonic saline, to ensure that the brain relaxation effect coincides with dural opening. The choice of fluid administration used for large-volume resuscitation may significantly affect brain relaxation

TABLE 25.1 Brain Relaxation Techniques Cerebral Blood Volume (Venous) Reverse Trendelenburg/head elevation Avoid extremes in neck position Avoid neck compression Avoid increases in intrathoracic pressures: avoid tube kinking, minimal positive end expiratory pressure, adequate depth of sedation and muscle relaxation to prevent bucking on ventilator, reduction of inspiratory time Cerebral Blood Volume (Arterial) PaCO2 reduction/controlled hyperventilation GABA receptor agonists titrated to EEG burst suppression Mild-to-moderate hypothermia Seizure treatment/prophylaxis Avoidance of direct cerebral vasodilators Optimal cerebral perfusion pressure Brain Parenchyma Volume Hyperosmolar therapy: mannitol, hypertonic saline CSF Volume Reverse Trendelenburg/head elevation CSF drainage with in situ lumbar drain or ventricular drain CSF, Cerebrospinal fluid; EEG, electroencephalogram; GABA, gamma-aminobutyric acid; PaCO2, partial pressure of carbon dioxide.

and surgical field optimization. Avoidance of hypoosmolar fluids and maintenance of plasma oncotic pressure should be considered.12 Table 25.2 demonstrates the differences between common fluids administered in the OR.

Neuroprotection No anesthetic has been shown to offer superior neuroprotection over other agents in humans. Thus anesthetic choice is guided by the anesthesiologist’s preference and comfort in achieving the goals stated previously. Hypothermia reduces the cerebral metabolic rate of oxygen (CMRO2) consumption and has been shown to be neuroprotective in the setting of anoxic brain injury following cardiac arrest. However, the Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) did not demonstrate improved outcome

242 PART 2

Osmolarity (mOsm/L)

pH

Sodium (mEq/L)

Chloride (mEq/L)

Potassium (mEq/L)

Glucose (g/L)-1

Lactate (mEq/L)

Calcium (mEq/L)

Plasma-Lyte A pH 7.4

294

7.4

140

98

5

—

—

—

Lactated Ringer’s solution Normal saline

273 308

6.5 5.5

130 154

109 154

4 —

— —

28 –

3 —

1030 1098

5.8 6.3 (4.5–7.0)

513 —

513 —

— —

— —

— —

— —

— May contain sodium bicarbonate for pH adjustment

~ 290a ~ 258a

7.4 7.4

130–160a 130–160a

a a

— —

— —

— —

— —

— —

Fluid

Other (mEq/L)

Isotonic Crystalloids Magnesium 3, acetate 27, gluconate 23, NaOH for pH — —

Hypertonic Crystalloids 3% Hypertonic saline 20% Mannitol

Colloids 5% Albumin 25% Albumin a

The NaCl content and osmolarity of albumin solutions varies dependent on formulation. Osmolarity values are calculated in vitro.

The Physician-Centered Approach

TABLE 25.2 Common Intravenous Fluids Administered in the Operating Room

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Anesthetic Management of Intracranial AVMs

when hypothermia was employed prospectively during open aneurysm clipping,13 and normothermia and avoidance of hyperthermia remains standard clinical practice. Some institutions allow for mild passive hypothermia, as commonly occurs in the OR, to about 35°C and rewarm only after closure is imminent. Neuroprotective efforts under the influence of anesthesia should center around blood pressure management, avoidance of hypoxia, normocapnia, meticulous fluid resuscitation and euvolemia, maintenance of serum osmolality, oncotic pressure, and normoglycemia.

Emergence Central to all neurosurgical anesthetics, the default goals pertaining to emergence include hemodynamic stability, minimizing coughing and bucking, and rapid emergence with minimal residual anesthetic effect on the neurologic exam. HEMODYNAMIC STABILITY Tight hemodynamic control may be particularly important following the treatment of iAVMs. Approximately 2%–6.5%14,15 of iAVM patients who undergo microsurgical resection may develop acute edema and/or hemorrhage in the “normal” brain parenchyma adjacent to the previous location of the AVM. The exact mechanism behind this infrequent complication has long been debated and remains controversial. The two prominent mechanisms that have been proposed and discussed earlier are normal perfusion pressure breakthrough (NPPB)16 and occlusive hyperemia.15 The literature contains both supportive and contradictory evidence for both theories, suggesting that both mechanisms may contribute to the overall incidence of this relatively rare complication. In brief and simplistic terms, NPPB involves increased CBF following iAVM resection in excess of normal levels despite systemic pressures within the expected autoregulatory range, resulting in edema with or without hemorrhage. Although the literature demonstrates a global increase in CBF, hemorrhage and edema occur in proximity to the site of iAVM resection. Occlusive hyperemia, on the other hand, is characterized by sluggish arterial and venous flow, often due to preexistent or newly acquired venous drainage impairment. Irrespective of the etiology, such complications

243 typically occur within the first seven postoperative days and may even present intraoperatively.14,17 Given the etiologic uncertainty and potentially opposing hemodynamic goals, routine management in the setting of an uncomplicated iAVM resection should focus on tight normotensive hemodynamic control intraoperatively and during the postoperative period. A working arterial line and immediate availability of titratable medications should be used to ensure close adherence to hemodynamic targets. The choice of specific hemodynamic targets should be informed by discussion with the surgical team, with consideration given to baseline blood pressure, medical comorbidities, and intraoperative observations. There is no evidence that any particular drug is more advantageous than another. Reasonable choices include esmolol, labetalol, nicardipine, and clevidipine. SMOOTH EMERGENCE Smooth emergence and extubation is the goal with most neuroanesthetics. However, impaired preoperative mental status, massive intraoperative hemorrhage with subsequent resuscitation, prolonged and difficult resection, malignant cerebral edema formation, and use of barbiturates or moderate hypothermia should be taken into consideration when deciding whether to extubate in the OR. When immediate extubation is appropriate, coughing and bucking should be minimized. Coughing induced by the presence of the endotracheal tube and premature suctioning during emergence is highly stimulating and often results in rapid increase in systemic blood pressure and CBF, which may be particularly undesirable in this patient population (see earlier discussion). Furthermore, coughing increases intrathoracic pressure that may be transmitted to the cerebral venous drainage system and cause venous stagnation, ICP elevation, cerebral edema, and hemorrhage. Smooth emergence is achieved by a variety of methods and should be left to the preference of the anesthesiologist. A common method includes judicious use of opioids to blunt airway reflexes without excessive influence on the patient’s CO2 response curve, combined with early withdrawal of halogenated inhalational anesthetics. A systemic lidocaine bolus of 1.0–1.5 mg/kg administered just prior to the point of spontaneous patient arousal may facilitate emergence, with transient suppression of laryngeal reflexes and

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cough. Avoidance of patient stimulation during this time is also paramount. Deep extubation is a technique better utilized outside of the neurosurgical patient population. Avoidance is warranted in this setting due to risk of hypoventilation and the potential deleterious effects of hypercarbia. Hypercarbia increases CBF under normal circumstances and may exaggerate increases already common following iAVM resection. At a more global level, hypercarbia will increase intracranial volume in patients who may be already unfavorably positioned on the intracranial elastance curve due to edema formation or prior hemorrhage. Such an increase may raise intracranial pressure to undesired levels. Furthermore, the potential for sustained depressed mental status due to cerebral manipulation following craniotomy may prolong the time a patient is inadequately protecting the airway. RAPID EMERGENCE AND NEUROLOGIC EXAMINATION A detailed neurologic exam is critical to detect the presence of complications or subsequent neurologic deterioration in the early postoperative period. This is true of all neurosurgical procedures; however, the cerebrovascular changes resulting from treatment of iAVMs may further increase the premium placed on the postoperative neurologic exam. The mantra “time is brain” is often used with reference to stroke, but any neurologic complication that results in a treatment delay risks further brain injury and neuronal death. The neurologic exam is the best monitor of neurologic dysfunction and can help guide subsequent management or timely diagnostic evaluation. A prompt diagnosis of postoperative hemorrhage allows immediate return to the OR for evacuation and may be lifesaving. To routinely achieve this important goal of quickly performing a detailed neurologic exam, the anesthesiologist may choose drugs with the most favorable kinetic profiles, minimize the anesthetic depth with the aid of electroencephalography (EEG) to only that which is required to ensure hypnosis (and/or immobility), and withdraw anesthetic medications well in advance of anticipated emergence. Unfortunately, use of neurophysiologic (NP) monitoring such as monitoring of transcranial motor evoked potentials (TcMEPs) and somatosensory evoked potentials (SSEPs) influences the drugs that can be used and compromises the

ability to change the anesthetic or withdraw drugs well in advance of extubation. Importantly, monitoring of TcMEPs precludes the use of intraoperative muscle relaxants, and immobility of the patient must be maintained by increasing the anesthetic depth using additional drugs or higher anesthetic doses. Therefore the benefit of neuromonitoring in general and the use of TcMEPs in addition to SSEPs should be weighed against the potential negative effect on the early postoperative exam. Generally speaking, the effect of residual anesthetics will be minimized by the absence of NP monitoring and will be most prominent with TcMEP monitoring. If NP monitoring is utilized, it should be terminated as far in advance of emergence as possible to facilitate anesthetic withdrawal.

Conclusion In summary, caring for patients undergoing treatment of iAVMs provides a unique challenge to the anesthesiologist. These lesions exhibit unusual cerebrovascular physiology and adaptations compared to other intracranial vascular lesions. Thus the anesthesiologist must have a thorough understanding of the cerebrovascular physiology of iAVMs pre- and post-treatment and the associated pharmacology in order to provide maximal neuroprotection. The anesthetic goals in the treatment of iAVMs are those inherent to neuroanesthesia and include hemodynamic stability and tight blood pressure control, immobility, brain relaxation and surgical field optimization, and rapid emergence to facilitate postoperative neurologic examination. Finally, the anesthesiologist must be familiar with the various procedures for iAVM treatment, be prepared for potential complications that may arise (discussed in Chapter 26), and maintain communication with the neurosurgeon throughout the intervention. REFERENCES 1. Brown RD Jr, Wiebers DO, Torner JC, O'Fallon WM. Frequency of intracranial hemorrhage as a presenting symptom and subtype analysis: a population-based study of intracranial vascular malformations in Olmsted County, Minnesota. J Neurosurg. 1996;85(1):29–32. https://doi.org/10.3171/jns.1996.85.1.0029. 2. Ogilvy CS, Stieg PE, Awad I, et al. Recommendations for the management of intracranial arteriovenous malformations: a statement for healthcare professionals from a special writing group of the Stroke Council, American Stroke Association. Circulation. 2001;103(21):2644–2657. https://doi.org/10.1161/01. cir.103.21.2644.

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3. Young WL, Pile-Spellman J, Prohovnik I, Kader A, Stein BM; The Columbia University AVM Study Project. Evidence for adaptive autoregulatory displacement in hypotensive cortical territories adjacent to arteriovenous malformations. Neurosurgery. 1994;34(4):601–611. https://doi.org/10.1227/ 00006123-199404000-00006. 4. Kader A, Young WL. The effects of intracranial arteriovenous malformations on cerebral hemodynamics. Neurosurg Clin N Am. 1996;7(4):767–781. 5. Young WL, Kader A, Prohovnik I, et al. Pressure autoregulation is intact after arteriovenous malformation resection. Neurosurgery. 1993;32(4):491–497. https://doi.org/10.1227/ 00006123-199304000-00001. 6. Hassler W, Steinmetz H. Cerebral hemodynamics in angioma patients: an intraoperative study. J Neurosurg. 1987;67(6):822–831. https://doi.org/10.3171/jns.1987.67.6.0822. 7. Chui J, Niazi B, Venkatraghavan L. Postoperative hemodynamic management in patients undergoing resection of cerebral arteriovenous malformations: A retrospective study. J Clin Neurosci. 2020;72:151–157. https://doi.org/10.1016/j.jocn.2019.12.039. 8. Hashimoto T, Young WL. Anesthesia-related considerations for cerebral arteriovenous malformations. Neurosurg Focus. 2001;11(5):e5. https://doi.org/10.3171/foc.2001.11.5.6. 9. Lee CZ, Talke PO, Lawton MT. Anesthetic considerations for surgical resection of brain arteriovenous malformations. In: Cottrell J, Patel P, eds. Cottrell and Patel’s Neuroanesthesia. 6th edition. Elsevier; 2017:263–272. 10. Spetzler RF, Martin NA, Carter LP, Flom RA, Raudzens PA, Wilkinson E. Surgical management of large AVM's by staged embolization and operative excision. J Neurosurg. 1987;67(1):17– 28. https://doi.org/10.3171/jns.1987.67.1.0017. 11. Flores BC, Klinger DR, Rickert KL, et al. Management of intracranial aneurysms associated with arteriovenous

12.

13.

14.

15.

16.

17.

malformations. Neurosurg Focus. 2014;37(3):E11. https://doi. org/10.3171/2014.6.FOCUS14165. Drummond JC, Patel PM, Cole DJ, Kelly PJ. The effect of the reduction of colloid oncotic pressure, with and without reduction of osmolality, on post-traumatic cerebral edema. Anesthesiology. 1998;88(4):993–1002. https://doi. org/10.1097/00000542-199804000-00020. Todd MM, Hindman BJ, Clarke WR, Torner JC. Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) Investigators. Mild intraoperative hypothermia during surgery for intracranial aneurysm. N Engl J Med. 2005;352(2):135–145. https://doi.org/10.1056/NEJMoa040975. Young WL, Kader A, Ornstein E, et al. Cerebral hyperemia after arteriovenous malformation resection is related to “breakthrough” complications but not to feeding artery pressure. The Columbia University Arteriovenous Malformation Study Project. Neurosurgery. 1996;38(6):1085–1095. https://doi. org/10.1097/00006123-199606000-00005. al-Rodhan NR, Sundt TM Jr, Piepgras DG, Nichols DA, Rüfenacht D, Stevens LN. Occlusive hyperemia: a theory for the hemodynamic complications following resection of intracerebral arteriovenous malformations. J Neurosurg. 1993;78(2):167–175. https://doi.org/10.3171/ jns.1993.78.2.0167. Spetzler RF, Wilson CB, Weinstein P, Mehdorn M, Townsend J, Telles D. Normal perfusion pressure breakthrough theory. Clin Neurosurg. 1978;25:651–672. https://doi.org/10.1093/ neurosurgery/25.cn_suppl_1.651. Chui J, Niazi B, Venkatraghavan L. Postoperative hemodynamic management in patients undergoing resection of cerebral arteriovenous malformations: A retrospective study. J Clin Neurosci. 2020;72:151–157. https://doi.org/10.1016/j. jocn.2019.12.039.

Chapter 26

Management of Perioperative Complications During AVM Treatment Ashley Fejleh, Brian P. Lemkuil, Navaz Karanjia, and Arthur M. Lam

Chapter Outline Introduction Complications During Microsurgical Resection Complications During Neurointerventional Procedures Complications During the Immediate Postoperative Period Conclusion

Introduction Anesthesiologists may be involved in the treatment of intracranial arteriovenous malformations (iAVMs) in the operating room (OR), the interventional neuroradiology (INR) suite, or radiosurgery suite. These complex vascular lesions have profound effects on cerebrovascular dynamics that may be abruptly altered in the course of treatment during microsurgical resection or INR embolization. For this reason, neurologic complications frequently happen in the perioperative period. Anesthesiologists should be aware of the routine anesthetic management of iAVMs (discussed in Chapter 25) as well as the perioperative complications that may arise and how to manage them. This chapter discusses these complications; some are unique to iAVM treatment and others common to other neurosurgical procedures as well.

Complications During Microsurgical Resection HEMORRHAGE Perhaps the most obvious complication during resection of an AVM is hemorrhage. AVMs are high-flow, low-resistance vascular lesions that are capable of profound bulk flow of blood. They often have multiple large 246

arterial feeders. It is now common practice to perform staged INR embolization prior to iAVM resection for the purpose of decreasing AVM size, reducing flow, allowing staged acclimation of surrounding vascular beds, and embolizing deep feeding vessels that pose hemostatic challenges due to poor visibility and accessibility. Despite this practice, sudden blood loss may still occur, and it may be profound and prolonged. Standard preparation should include large-bore intravenous access for rapid transfusion and immediate blood product availability in the OR prior to AVM manipulation. If hemostasis is not rapidly achieved, initiation of a rapid transfusion protocol and mobilization of additional resources should occur for such purposes as running blood from the blood bank to the OR, cross-checking blood units, and running equipment such as a Belmont rapid infuser or cell saver, if available. Care must be taken during rapid blood loss resuscitation not to neglect maintaining adequate platelet and clotting factor levels, while avoiding profound hypothermia. Blood pressure reduction with rapid-onset short-acting agents such as clevidipine or nicardipine should be offered to assist with visualization and hemostasis, with the caveat that controlled blood pressure reduction is very difficult in a patient who is hypovolemic. Blood pressure reduction should always be limited in duration and degree to the minimum necessary to gain surgical control. Hemorrhage can also occur after resection, both in the immediate postoperative period and in a delayed fashion in the intensive care unit (ICU). MALIGNANT CEREBRAL EDEMA Malignant cerebral edema is not necessarily specific to iAVM management; however, it has a strong association with iAVM treatment, and the underlying

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Management of Perioperative Complications During AVM Treatment

pathophysiology may be unique. Historically, malignant edema occurred in the OR with such frequency that treatments were initiated preemptively in anticipation of edema development, including barbiturate loading to burst suppression and moderate hypothermia. Anticipation was based primarily on factors such as large AVM size, prolonged microsurgery (> 10 hours), and the need for multiple intraoperative angiograms (contrast agents were ionized and profoundly hyperosmolar with significant chemotoxic effects). Although there were many advances in operative management during this period, intraoperative use of barbiturates and hypothermia seemed to help. The primary rationale for these therapies was to suppress cerebral metabolism and reduce cerebral blood flow (CBF) such that the acute cerebral hemodynamic changes ensuing from microsurgical resection might be attenuated. The delayed and gradual emergence from anesthesia in the ICU due to the prolonged half-life of barbiturates may also have had a favorable effect. However, with increased use of staged INR embolization and other management advances, the frequency of severe sudden intraoperative swelling has decreased such that the empiric use of these therapies is not supported. As discussed in Chapter 25, there are two leading theories to explain the etiology of acute malignant edema and hemorrhage that may manifest anytime in the operative and early postoperative period: (1) normal perfusion pressure breakthrough (NPPB) and (2) occlusive hyperemia. The first proposed mechanism involves either perfusion pressure in excess of the local autoregulatory limits or small perinidal areas of impaired cerebral autoregulation resulting in hyperemia. Several studies have demonstrated that autoregulation and CO2 reactivity appear to be preserved following iAVM resection, but with a left shift of the autoregulatory curve (Fig. 26.1) due to adaptation to the low pressure shared with the arterial feeder (Fig. 26.2).1,2 Interestingly, increased postoperative CBF appears to be a global phenomenon.3–5 Despite globally increased cerebral blood flow, hemorrhage and edema tend to occur ipsilateral to the iAVM resection. Some have suggested that absent astrocytic foot processes, such as seen in capillaries in animal models near the iAVM, may be responsible for local edema and hemorrhage.6 The second mechanism, occlusive

Pearls • Sudden and sustained blood loss remains an important perioperative concern in iAVM procedures and requires anticipatory management. • Malignant cerebral edema and intracranial hypertension may be refractory to medical management following iAVM treatment. • Clinical and subclinical seizures require vigilance in both diagnosis and management. • The perioperative period requires tight hemodynamic management control, close surveillance of the neurologic exam, and timely use of imaging to treat potential neurologic complications. • Acute hemodynamic changes may be the first indication of a complication and should be conveyed immediately to the interventional team.

hyperemia, is presumably caused by stagnation within veins and arteries. Arterial and venous remodeling due to prolonged mechanical stress predispose to stagnation once flow is acutely reduced following iAVM resection. Both supportive and contradictory evidence can be found for each of the proposed mechanisms.7 Residual AVM may also contribute to postoperative hemorrhage; however, the use of intraoperative angiography and/or fluorescein angiography has greatly diminished this as a contributing factor. Although sudden malignant edema is quite rare in the modern era, a management plan for its occurrence in the OR should be considered. Of utmost importance is clear two-way communication between the surgeon and the anesthesiologist to determine the cause and correct management of this complication. Any blood pressure deviation from the predetermined target should be communicated and corrected promptly. Simultaneously, the anesthesiologist should ensure adequate anesthetic depth, normal airway pressures, and the absence of patient coughing or straining against the endotracheal tube. In the absence of obvious anesthetic-related factors, the possibility of a surgical cause, such as sacrifice of an arterialized vein, should be considered. In this

Fig. 26.1 Adaptive autoregulatory displacement. Black curve demonstrates normal cerebral autoregulation range. Red curve demonstrates rightward shift typical of patients with poorly controlled hypertension. Blue curve represents leftward shift with preserved cerebral autoregulation due to chronic arterial hypotension caused by large iAVMs.

Fig. 26.2 Left, Representative pressure recording from a study of arterial pressures in patients undergoing superselective cerebral angiography before AVM embolization.2 The recording demonstrates profound progressive pressure reduction within the vascular tree feeding the iAVM (in this case, a large temporooccipital AVM fed by branches of the middle cerebral artery and posterior cerebral artery [PCA]). Pressure measurements were obtained in the following five zones (descriptions in parentheses are the sites used in this specific case): E, extracranial (vertebral artery); I, intracranial (basilar artery); T, transcranial Doppler insonation site (P1 segment of PCA); H, halfway point between insonation site and feeder (P2–P3); and F, feeding artery at the site where embolic agent was to be injected (P4–P5). Right, Schematic depiction of intracranial circulation to an AVM showing anatomic vascular zones used for recording in the study and the functional area subject to chronic hypotension (hypotensive neighborhood). One vessel perfusing the hypotensive neighborhood, labeled the “hypotensive neighbor,” is illustrated. There is also a hypotensive neighborhood, perfused by hypotensive neighbors, in the volume of brain that has been cut away for illustrative purposes. DV, Draining vein. (Republished with permission of Williams & Wilkins Co./American Society of Neuroradiology from Fogarty-Mack P, Pile-Spellman J, Hacein-Bey L, et al. The effect of arteriovenous malformations on the distribution of intracerebral arterial pressures. AJNR Am J Neuroradiol. 1996;17(8):1443–1449; permission conveyed through Copyright Clearance Center.)

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situation, the surgical team must work quickly to ­ remove the remaining arterial feeders to the AVM given the newly impaired venous drainage and imminent risk of rupture. A brief discussion with the surgical team regarding other interventions, such as additional blood pressure reduction, should occur. Acute blood pressure reduction can be achieved with rapid- and short-acting cardiovascular agents or anesthetic agents that have the benefit of simultaneously reducing blood pressure and cerebral metabolic rate (CMRO2). In the OR, propofol is the anesthetic agent most readily available for this purpose. Although barbiturates may also be considered, there will likely be a greater treatment delay, increased hemodynamic instability, and emergence delay due to prolonged drug half-life. Additional hyperosmolar therapy, hyperventilation, and hypothermia may be considered depending on severity and response to early management interventions. As alluded to earlier, the two leading theories on the pathophysiology of malignant edema and hemorrhage imply potentially opposing physiology and medical treatment requirements. Stagnation and ischemia may potentially benefit from higher perfusion pressure, while hyperemia requires blood pressure reduction. Therefore standard iAVM management at our institution and many other centers involves tight blood pressure control within a narrow normotensive range that is based upon preoperative blood pressure, comorbidities, and intraoperative findings. In the event of postoperative hemorrhage or edema, determination of the underlying etiology will help fine-tune medical treatment. For instance, if imaging demonstrates reduced perfusion due to arterial stagnation, more liberal blood pressure limits may be beneficial. If hemorrhage or edema occurs secondary to venous thrombosis, anticoagulation treatment may be beneficial despite its risk. Finally, if hyperemia appears to be the primary etiology, more restrictive blood pressure control is likely indicated. Jugular venous oxygen saturation monitoring, if available, may be a useful adjunct, particularly in cases in which preoperative embolization is not feasible. NPPB would be associated with an elevated saturation, whereas venous stagnation would more likely be associated with a normal or reduced saturation.8,9

249 SEIZURE Seizures are the second most common clinical manifestation of iAVMs, following hemorrhage.10 Therefore this patient population is often predisposed to seizures prior to surgical treatment. Abrupt changes in cerebral hemodynamics from INR embolization or microsurgical resection may further increase the incidence of seizures or lower the existing seizure threshold. It makes sense that microsurgical resection would carry the greatest risk of perioperative seizures given the increased invasiveness of the procedure and additional irritation to surrounding neurons. Timely recognition and treatment of seizures are essential, as seizures often increase systemic blood pressure, CBF, and CMRO2, which can increase the risk of hemorrhage and neuronal injury. Although most anesthetics are GABA (gammaaminobutyric acid) receptor agonists and commonly used to treat refractory status epilepticus, seizures may still occur in the OR. In fact, there are case reports of electrographic seizures occurring during craniotomy under general anesthesia as well as personal experience of seizure occurrence despite a propofol-induced burst suppression pattern on electroencephalography (EEG).11 More commonly, seizures occur at the time of emergence or in the early postoperative period. Nonconvulsive seizures can be the reason for delayed emergence or unanticipated postoperative exam findings, including altered mental status or focal neurologic deficits. Clinical or electrographic seizures should be treated aggressively if prolonged (duration > 5 minutes is considered status epilepticus) or if multiple seizures occur in rapid succession. Benzodiazepines (lorazepam 4 mg IV, repeated to a dose of 0.1 mg/kg, and midazolam 10 mg IM have been demonstrated to be equally efficacious) and propofol IV are effective seizure abortive agents and are usually readily available in the OR. Iced saline directly applied to the cortical surface is another effective intraoperative treatment strategy. Concomitantly, a maintenance antiepileptic agent should be given intravenously as soon as possible; acceptable choices for status epilepticus include a 20 PE/kg fosphenytoin load (maximum rate 150 PE/minute) or a 60 mg/kg load of levetiracetam. Reasonable choices for self-limited seizures include 1.5–4 g levetiracetam or 100–200 mg lacosamide;

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older antiepileptic agents are less desirable due to their propensity to cause drug-related fever and sedation. If the patient remains sedated postoperatively or does not return to baseline neurologic function, immediate continuous EEG is indicated to evaluate for ongoing nonconvulsive seizures.12

Complications During Neurointerventional Procedures As with all neurointerventional procedures, any step in the embolization process from gaining arterial access to achieving hemostasis involves risk to the patient, including groin complications (hematoma or dissection), contrast allergy, reactions to medications such as protamine sulfate, and nephrotoxicity. Any complications related to the access site, such as hematoma, fistula formation, or limb ischemia, should be identified promptly and addressed immediately by the proceduralist. Complications of protamine administration for heparin reversal in the setting of a hemorrhagic complication may include hypotension, anaphylaxis, and pulmonary hypertension. A thorough preprocedure history should address prior contrast-related allergic reactions. Patients with a history of contrast allergy will require pretreatment with steroids and antihistamines according to institution-specific protocols (Table 26.1). The treatment of an acute allergic reaction to contrast media is no different from the treatment of any other anaphylactic reaction and may include intravenous epinephrine, steroids, antihistamines, and the use of IV fluids for hypotension. Additionally, laboratory tests,

such as assessment of serum creatinine level, should be performed before the procedure to determine baseline renal function, and the risk of contrast-induced renal injury should be further reduced by minimizing contrast administration and ensuring adequate intravenous hydration to maintain euvolemia. Aside from the complications inherent to all neurointerventional cases, complications common to iAVM embolization include intracerebral hemorrhage and ischemic events that may lead to transient or permanent neurological deficits.13,14 As with open microsurgical resection, seizures and cerebral edema may also occur due to alterations in CBF.15 While endovascular embolization has the potential to enhance the safety and efficacy of future iAVM resection by reducing operative time and intraoperative blood loss,16 the risks of these complications remain, and the anesthesiologist must be prepared to manage them in the INR suite. HEMORRHAGE Acute cerebral hemorrhage can occur from a number of technical or physiologic factors. Technical factors may include arterial perforation by the microwire or microcatheter, rupture of an associated aneurysm, vascular injuries during retrieval of a retained catheter secondary to glue reflux during embolization,17 inadvertent compromise of outflow veins by passage of liquid embolic agent to the drainage vein with subsequent elevation of intranidal pressure,18 inadvertent closure of the draining vein before elimination of the nidus, or suboptimal control of hypertension intraoperatively. Optimal procedural conditions may help

TABLE 26.1 Example Premedication Protocols for IV Contrast Allergy Medication

Type

Dose

Dose Time

50 mg PO 50 mg PO

13, 7, and 1 h prior to injection 1 h prior to injection

Standard Premedication Dosing Prednisone Diphenhydramine

Steroid Antihistamine

Alternative IV Premedication Dosing (to be used if patient requires premedication for contrast allergy, but exam needs to be done urgently) Hydrocortisone Diphenydramine

Steroid Antihistamine

200 mg IV 50 mg PO or IM or IV

6 and 2 h prior to exam 1 h prior to exam

Pretreatment drug administration to prevent or reduce contrast reactions should be given to patients with a history of moderate or severe allergic-like contrast reaction as well as patients who have severe asthma with active wheezing or acute shortness of breath. Adapted from UC San Diego IV contrast allergy premedication protocol. Permission for use obtained from UC San Diego Imaging Services.

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minimize these events. As such, it is important to ensure immobility with adequate anesthetic depth with or without paralysis. Several physiologic factors resulting in AVM rupture have been proposed, including, for example, increased pressure in feeding arteries as a result of embolization or inflammatory reaction caused by the embolic material.15,19 In the INR suite, with a patient under general anesthesia, hemorrhage is usually heralded only by contrast extravasation from the vessel with or without immediate hemodynamic changes, including the sudden onset of hypertension with or without bradycardia (Cushing response).20 Hemorrhages may be intraparenchymal, intraventricular, or subarachnoid. Unlike hemorrhage during open microsurgery, hemorrhage occurring in the INR suite is limited by the confines of the closed intracranial space. Attempts to stop the hemorrhage via endovascular methods by the proceduralist must occur expeditiously. Hemorrhage not amenable to endovascular treatment or hemorrhage causing hydrocephalus, elevated intracranial pressure (ICP), or cerebral compression may require emergent craniotomy and/or placement of an external ventricular drain (EVD). Fortunately, many vascular

251 injuries can be managed in the angiography suite. As in the OR, management of a hemorrhagic crisis should include clear closed-loop communication with the procedural team, call for assistance, immediate heparin reversal (usually 1 mg protamine sulfate for each 100 units of heparin given), management necessary to secure the airway, titration of fiO2 to maintain stable systemic oxygen saturation, and adjustment of minute ventilation to ensure normocarbia. Additional brief discussion with the interventionalist should center around acute blood pressure management and need for ICP-lowering maneuvers (see Table 25.1) such as hyperventilation, hyperosmolar therapy, CMRO2 reduction with anesthetic agents, and EVD placement. CEREBRAL ISCHEMIA Cerebral ischemia can occur due to reflux of embolic material into the feeding vessel that also supplies normal brain parenchyma, embolic occlusion of an “en passage” feeder (Fig. 26.3), embolic occlusion of the venous drainage system, vasospasm, vessel dissection, or spontaneous clot formation. Under general anesthesia, concern for ischemia will most likely be identified by the interventionalist

Fig. 26.3 Potential locations for embolisate-induced ischemia during iAVM embolization. (A) Reflux-induced occlusion of proximal vascular bed with risk of ischemic stroke. (B) Embolic occlusion of en passage feeder with risk of ischemic stroke. (C) Embolic occlusion of venous drainage system with increased risk of AVM rupture.

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when sluggish or absent blood flow is seen following contrast administration. However, sudden hypertension may also suggest a problem such as ischemia (or hemorrhage) and should always be communicated immediately to the interventionalist. Depending on the complexity of the lesion and its location, neurophysiologic monitoring during the procedure can be useful in detecting ischemia. If concern for ischemia is high, systemic blood pressure should be immediately augmented to drive CBF through collateral vessels to the ischemic area as a temporizing measure,20 while the proceduralist determines if a reperfusion therapy is possible and appropriate. Following the procedure, the head of the bed may be maintained in the flat (0°) position in an attempt to augment cerebral perfusion by reducing the hydrostatic gradient. These therapies may be titrated to neurologic examination, angiography, neurophysiologic monitoring, or clinical exam findings and should be discussed continuously with the proceduralist.

maneuvers to reduce ICP and maintain CPP are undertaken by the anesthesiologist.

VENOUS EMBOLISM Another, less common, periprocedural complication during neurointerventional management of iAVMs is inadvertent migration of liquid embolic material into the pulmonary vascular system21 or large cerebral veins.22 In the case of pulmonary migration, small amounts are not clinically significant; however, larger amounts, especially in smaller patients, can result in a syndrome analogous to pulmonary embolism. Furthermore, embolic liquids are very thrombogenic, able to pick up thrombus en route and accumulate more clot once lodged in the pulmonary vasculature, causing hemodynamic consequences similar to a massive pulmonary embolism. This complication should be anticipated at the time of glue administration and considered throughout the perioperative period. Immediate resuscitative efforts, including consulting the interventional pulmonology or cardiothoracic surgery team if appropriate, should be implemented in the event of ventilatory and/or hemodynamic collapse. Similarly, migration into the large cerebral veins has the potential for catastrophic consequences, including immediate venous hypertension, increased ICP, and herniation, and must be immediately treated, if possible, by the proceduralist while simultaneous

EDEMA A final intraprocedural complication that should be mentioned is the development of perinidal edema after iAVM embolization. It can occur secondary to the previously described CBF alterations following iAVM treatment, due to increased venous pressure secondary to severe stenosis of a draining vein, or as a result of an inflammation due to the embolic material used. Decadron has been used in some institutions to minimize vasogenic edema development in response to glue embolisate15; however, there is not significant evidence for its routine use to prevent or reduce perinidal edema. As with microsurgical iAVM resection, systolic blood pressure should be tightly controlled within a narrow normotensive range during the intraoperative and early postoperative period.

SEIZURES As mentioned earlier, seizures are the second most common clinical manifestation of iAVMs; they are associated with history of AVM hemorrhage, frontaltemporal location, and arterial watershed location.23 The neurointerventional team should be aware of the propensity for these patients to exhibit seizure activity during the procedure and utilize seizure prophylaxis and treatment as appropriate. Additionally, patients undergoing embolization may have an elevated risk of de novo seizure,24,25 perhaps as a result of altered CBF dynamics after embolization as well as the epileptogenic potential of extravasated contrast. If seizures are identified, management should proceed as described previously in this chapter. Short-term prophylactic antiepileptic therapy may be considered to avoid the development of seizure in the immediate postembolization period.

Complications During the Immediate Postoperative Period All the complications mentioned earlier—hemorrhage, ischemia, seizure, edema, and increased ICP— can also occur in the early postoperative period, while the patient is still under the care of the anesthesiologist prior to transfer to the ICU. These may present as

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emergence delay, altered mental status, and focal neurologic deficits, all of which require rapid diagnostic evaluation and treatment. In order to recognize such complications in a timely fashion, care must be taken to perform serial neurological exams starting immediately after the procedure. Prompt recognition of postoperative hemorrhage and immediate return to the OR for evacuation may be lifesaving. Unanticipated emergence delay requires immediate evaluation for an underlying cause and prompt initiation of appropriate treatment. As stated in Chapter 25, a primary goal of the anesthesiologist is to deliver an anesthetic in such a way that residual anesthesia drugs do not contribute to delayed emergence. The possibility of residual paralytic should be evaluated and treated. Likewise, naloxone and flumazenil should be titrated to rule out excess opioids and benzodiazepines, respectively. Of note, spontaneous ventilation does not exclude opioids as a cause for emergence delay as the relationship between respiratory depression and mental status depression is often reversed after craniotomy. After considering medication effects, the anesthesiologist should evaluate systemic factors. This is often rapidly achieved with an arterial blood sample to evaluate levels of electrolytes, hemoglobin, and glucose as well as plasma pH and PaCO2. Moderate hypothermia may also contribute to delayed emergence due to its suppressive influence on CMRO2 as well as impairment of systemic metabolism of anesthetic medications. In the absence of anesthetic and systemic factors, prompt evaluation of neurologic causes should be initiated with brain imaging. Differential diagnosis includes arterial or venous intraparenchymal, subdural, subarachnoid, or intraventricular hemorrhage, cerebral ischemia, cerebral edema, acute obstructive hydrocephalus, and nonconvulsive seizures. A noncontrast head CT scan is the appropriate initial imaging study due to the brevity of the scan and its availability. Further imaging modalities such as CT perfusion, MRI, and diagnostic cerebral angiography could be considered depending on the initial CT findings. In the absence of an obvious structural explanation, immediate EEG should be considered to evaluate for nonconvulsive seizures. Management of these complications should proceed as described previously in this chapter.

Given the time-sensitive nature of these complications, immediate access to treatment supplies (i.e., EVD catheters) and medications should be ensured in the OR, INR suite, and immediate postprocedural environment.

Conclusion The anesthesiologist caring for patients undergoing iAVM treatment must be aware of the complications that may arise during microsurgical resection as well as those unique to neurointerventional procedures, as described in this chapter. Expeditious identification and management of the various complications throughout the perioperative period is key to minimizing further neurologic damage and mortality in these patients. REFERENCES 1. Hashimoto T, Young WL. Anesthesia-related considerations for cerebral arteriovenous malformations. Neurosurg Focus. 2001;11(5):e5. https://doi.org/10.3171/foc.2001.11.5.6. 2. Fogarty-Mack P, Pile-Spellman J, Hacein-Bey L, et al. The effect of arteriovenous malformations on the distribution of intracerebral arterial pressures. AJNR Am J Neuroradiol. 1996;17(8):1443–1449. 3. Young WL, Kader A, Ornstein E, et al. Cerebral hyperemia after arteriovenous malformation resection is related to “breakthrough” complications but not to feeding artery pressure. The Columbia University Arteriovenous Malformation Study Project. Neurosurgery. 1996;38(6):1085–1095. https://doi.org/ 10.1097/00006123-199606000-00005. 4. Hashimoto T, Young WL, Prohovnik I, et al. Increased cerebral blood flow after brain arteriovenous malformation resection is substantially independent of changes in cardiac output. J Neurosurg Anesthesiol. 2002;14(3):204–208. https://doi. org/10.1097/00008506-200207000-00005. 5. Young WL, Kader A, Prohovnik I, et al. Pressure autoregulation is intact after arteriovenous malformation resection. Neurosurgery. 1993;32(4):491–497. https://doi.org/ 10.1227/00006123-199304000-00001. 6. Sekhon LH, Morgan MK, Spence I. Normal perfusion pressure breakthrough: the role of capillaries. J Neurosurg. 1997;86(3):519– 524. https://doi.org/10.3171/jns.1997.86.3.0519. 7. Rangel-Castilla L, Spetzler RF, Nakaji P. Normal perfusion pressure breakthrough theory: a reappraisal after 35 years. Neurosurg Rev. 2015;38(3):399–405. https://doi.org/10.1007/ s10143-014-0600-4. 8. Wilder-Smith OH, Fransen P, de Tribolet N, Tassonyi E. Jugular venous bulb oxygen saturation monitoring in arteriovenous malformation surgery. J Neurosurg Anesthesiol. 1997;9(2):162– 165. https://doi.org/10.1097/00008506-199704000-00011. 9. Kimiwada T, Kamii H, Tominaga T, Kato M. A case of hyperemia during arteriovenous malformation surgery controlled with

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PART 2 The Physician-Centered Approach beta-blocker and jugular bulb oxygen saturation (SjO2) monitoring. Article in Japanese. Masui. 2003;52(10):1074–1078. Novakovic RL, Lazzaro MA, Castonguay AC, Zaidat OO. The diagnosis and management of brain arteriovenous malformations. Neurol Clin. 2013;31(3):749–763. https://doi. org/10.1016/j.ncl.2013.03.003. Howe J, Lu X, Thompson Z, Peterson GW, Losey TE. Intraoperative seizures during craniotomy under general anesthesia. Seizure. 2016;38:23–25. https://doi.org/10.1016/ j.seizure.2016.03.010. Glauser T, Shinnar S, Gloss D, et al. Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016;16(1):48–61. https://doi. org/10.5698/1535-7597-16.1.48. Starke RM, Komotar RJ, Otten ML, et al. Adjuvant embolization with N-butyl cyanoacrylate in the treatment of cerebral arteriovenous malformations: outcomes, complications, and predictors of neurologic deficits. Stroke. 2009;40:2783–2790. https://doi.org/10.1161/strokeaha.108.539775. Sato K, Matsumoto Y, Tominaga T, et al. Complications of endovascular treatments for brain arteriovenous malformations: a nationwide surveillance. AJNR Am J Neuroradiol. 2020;41(4):669–675. https://doi.org/10.3174/ajnr.A6470. Panagiotopoulos V, Gizewski E, Asgari S, Regel J, Forsting M, Wanke I. Embolization of intracranial arteriovenous malformations with ethylene-vinyl alcohol copolymer (Onyx). AJNR Am J Neuroradiol. 2009;30(1):99–106. https://doi.org/10.3174/ ajnr.a1314. Jafar JJ, Davis AJ, Berenstein A, Choi IS, Kupersmith MJ. The effect of embolization with N-butyl cyanoacrylate prior to surgical resection of cerebral arteriovenous malformations. J Neurosurg. 1993;78(1):60–69. https://doi.org/10.3171/jns.1993.78.1.0060.

17. Bruno CA Jr, Meyers PM. Endovascular management of arteriovenous malformations of the brain. Interv Neurol. 2013;1(3-4):109–123. https://doi.org/10.1159/000346927. 18. Joung KW, Yang KH, Shin WJ, et al. Anesthetic consideration for neurointerventional procedures. Neurointervention. 2014;9(2):72–77. https://doi.org/10.5469/neuroint.2014.9.2.72. 19. Picard L, Da Costa E, Anxionnat R, et al. Acute spontaneous hemorrhage after embolization of brain arteriovenous malformation with N-butyl cyanoacrylate. J Neuroradiol. 2001;28(3):147–165. 20. Lee CZ, Young WL. Anesthesia for endovascular neurosurgery and interventional neuroradiology. Anesthesiol Clin. 2012;30(2): 127–147. https://doi.org/10.1016/j.anclin.2012.05.009. 21. Pelz DM, Lownie SP, Fox AJ, Hutton LC. Symptomatic pulmonary complications from liquid acrylate embolization of brain arteriovenous malformations. AJNR Am J Neuroradiol. 1995;16(1):19–26. 22. Krajina A, Lojik M, Nahlovsky J. Transvenous removal of glue from obstructed straight sinus during transarterial embolization. Interv Neuroradiol. 2007;13(1):79–82. https://doi. org/10.1177/159101990701300111. 23. Zhang B, Feng X, Peng F, et al. Seizure predictors and outcome after Onyx embolization in patients with brain arteriovenous malformations. Interv Neuroradiol. 2019;25(2):124–131. https://doi.org/10.1177/1591019918801290. 24. Baranoski JF, Grant RA, Hirsch LJ, et al. Seizure control for intracranial arteriovenous malformations is directly related to treatment modality: a meta-analysis. J Neurointerv Surg. 2014;6(9):684–690. https://doi.org/10.1136/neurintsurg-2013-010945. 25. de Los Reyes K, Patel A, Doshi A, et al. Seizures after Onyx embolization for the treatment of cerebral arteriovenous malformation. Interv Neuroradiol. 2011;17(3):331–338. https:// doi.org/10.1177/159101991101700308.

Chapter 27

Intracranial AVMs and the Neurointensivist Yahya B. Atalay and Santosh B. Murthy

Chapter Outline Introduction Preoperative Management of Patients With Ruptured iAVMs Postoperative Management After iAVM Treatment Conclusion

Introduction Critical care management of intracranial arteriovenous malformations (iAVMs) incorporates principles common to the management of intracranial hemorrhage (ICH) that focus on mitigating primary and secondary injury from the hematoma. The emphasis, particularly in the acute period after AVM rupture, and the immediate postoperative period following definitive AVM treatment, regardless of previous rupture status, essentially involves strict blood pressure regulation. ICH from AVM rupture is the most dreaded complication that can develop in the pre- or posttreatment setting. Understanding the pathophysiology and flow dynamics of these lesions, adapting principles of treatments of other acute brain injuries, and close monitoring and prompt intervention in a dedicated neurointensive care unit (NICU) are crucial and should be an essential part of treating critically ill patients with iAVMs. This chapter first delves into the details of intensive care management of patients with ruptured iAVMs and subsequently discusses the complexity of postoperative care of iAVM patients as the brain acclimates to reorganization of blood flow dynamics.

Preoperative Management of Patients With Ruptured iAVMs Although unruptured iAVMs are more common than ruptured iAVMs, patients with unruptured iAVMs often present with progressive neurological deficits in an outpatient setting and therefore generally do not require intensive care monitoring prior to the first planned elective treatment. Therefore this section will focus on the preoperative management of patients with ruptured iAVMs. Rupture of an iAVM warrants formal admission to the NICU. The most common cause of symptoms from iAVMs is rupture (ICH) and, in particular, intraparenchymal hemorrhage (IPH). Though less common, intraventricular, subdural, and subarachnoid hemorrhage may also be seen (Fig. 27.1).1,2 Recent observational data suggest that patients with IPH from a ruptured iAVM enjoy a more favorable prognosis than those with primary IPH (i.e., due to hypertension or amyloid angiopathy).3,4 Factors that likely contribute to lower mortality and disability with AVM-associated IPH include younger age, hematoma within the AVM nidus with relative sparing of the surrounding brain parenchyma, and smaller hematoma volumes on presentation.3,4 In patients with ruptured iAVMs, basal subarachnoid cisternal hemorrhages carry the worst outcomes compared to hemorrhages in other locations.5 This hemorrhage distribution may reflect an aneurysmal source with the attendant poorer overall outcomes. Moreover, the risk of recurrent rupture is nearly 2–3 times higher—between 4% and 7% per year—than the risk of a first-time rupture, which is usually about 1%–2% per year.6–8 Finally, the risk of recurrence is highest in the first year after an AVM 257

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rupture (up to 15%), and presumably much higher in the first few days after the initial bleed than later in that first year.9 Early aggressive care in an ICU setting should therefore be initiated soon after IPH diagnosis. GENERAL CONSIDERATIONS The critical care principles applicable to the management of ICH from other causes may be extrapolated for managing AVM-associated ICHs. Endovascular interventional neuroradiology and neurosurgery departments should be consulted, preferably at the time of admission, for treatment planning. Timely and effective patient assessment, following the ABCs of emergent evaluation/intervention, is essential as this can change patient outcomes. If a patient scores 8 or less on the Glasgow Coma Scale (GCS), endotracheal intubation should be strongly considered to protect the airway when necessary. Ventilation and oxygenation should be optimized to prevent secondary brain injury. HYPERACUTE MANAGEMENT Hyperacute management applies to the first 6 hours after symptom onset, when the majority of patients experience hematoma expansion, an early devastating factor independently associated with mortality and severe disability after ICH.10 Thus serial CT scans at 2 and 12 hours after presentation are typically obtained in stable patients. Several interventions have been proposed to limit hematoma expansion and include blood pressure control, correction of coagulopathy, and treating seizures.11

Pearls • Intracranial hemorrhage and subsequent seizures, headaches, and focal neurological deficits are common presentations in patients with symptomatic iAVMs. • Multidisciplinary care of patients with iAVMs in the neurointensive care unit is warranted, particularly for those with hemorrhage and for patients undergoing surgical and/or endovascular interventions. • The preoperative management in cases of ruptured iAVMs centers around limiting hematoma expansion and mass effect, preventing/treating seizures, and preventing rerupture of the AVM. • Loss of cerebral autoregulation and changes in flow dynamics after iAVM treatment can result in postoperative intraparenchymal hemorrhage. • Strict blood pressure control (systolic blood pressure < 140 mm Hg) should be implemented for at least the first 24 hours after iAVM treatment, with close monitoring for neurological deterioration.

Imaging Considerations

A combination of clinical and radiographic criteria may be helpful in determining a secondary cause of ICH, such as a ruptured iAVM. These criteria, which have been incorporated into the secondary intracerebral hemorrhage (SICH) score, are highlighted in Table 27.1.12 The predictive accuracy of the SICH score is 80% for a composite score of 5 and 100%

Fig. 27.1 Neuroimaging of a ruptured iAVM. (A) CT scan showing an acute right temporoparietal intraparenchymal hemorrhage. (B) CT scan obtained after emergent decompressive hemicraniectomy, which was required to relieve the mass effect. (C) CT angiogram showing the underlying AVM. (D) Digital subtraction angiogram demonstrating the AVM with feeders and draining vein.

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Points

contrast extravasation and implying ongoing bleeding.14 The CTA spot sign has been well described for primary IPH, and anecdotal data suggest that it may also be present in secondary IPH.15

2 1 0

Blood Pressure Management

TABLE 27.1 Calculation of the SICH Score Parameter a

NCCT Categorization High probability Indeterminate Low probability Age Group 18–45 years 46–70 years ≥ 71 years

2 1 0

Sex Female Male

1 0

Neither Known HTN Nor Impaired Coagulationb Yes No

1 0

HTN, Hypertension; NCCT, noncontrast computed tomography; SICH, secondary intracerebral hemorrhage. Note: The SICH score is calculated by adding the total number of points for a given patient. a High-probability NCCT: an examination with either (1) enlarged vessels or calcifications along the margins of the ICH or (2) hyperattenuation within a dural venous sinus or cortical vein along the presumed venous drainage path of the ICH. Low-probability NCCT: an examination in which neither (1) nor (2) is present and the ICH is located in the basal ganglia, thalamus, or brainstem. Indeterminate NCCT: an examination that does not meet the criteria for a high- or low-probability NCCT. b Impaired coagulation defined as admission INR > 3, aPTT > 80 seconds, platelet count < 50,000, or daily antiplatelet therapy. Republished, with permission from American Society of Neuroradiology, from Delgado Almandoz JE, Schaefer PW, Goldstein JN, et al. Practical scoring system for the identification of patients with intracerebral hemorrhage at highest risk of harboring an underlying vascular etiology: The Secondary Intracerebral Hemorrhage Score. AJNR Am J Neuroradiol. 2010;31(9):1653-1660.

for a composite score of 6.12 CT angiography (CTA) of the head is usually indicated after the initial diagnosis of IPH on a noncontrast CT scan. In addition to helping delineate an underlying AVM, CTA also aids in identifying the “spot sign,” a marker independently associated with a four-fold increase in the odds of hematoma growth.13 The spot sign is an area of hyperdensity within the area of the hematoma indicating

Intracranial AVMs are composed of high-flow arterialvenous shunts with no smooth muscle layer in the nidal arterioles. Impaired autoregulatory mechanisms allow direct transfer of blood pressure changes.16 Therefore an acute rise in blood pressure may cause rupture of dysplastic vasculature in the nidus. The parenchyma surrounding the nidus is chronically hypoperfused due to shunting of the arterial blood, and an acute drop in blood pressure or hypotension may consequently lead to tissue ischemia.17 As a result, it is vital to avoid extremes of blood pressure in either direction. That said, data on blood pressure management for patients with iAVMs are lacking. The current guidelines from the American Heart Association/American Stroke Association (AHA/ASA) recommend acutely lowering systolic blood pressure (SBP) to 140 mm Hg when spontaneous primary IPH patients present with SBP between 150 and 220 mm Hg if there is no contraindication to treatment.14 It is important to note that the main evidence for this recommendation is derived from the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 (INTERACT2), where patients with IPH were randomized to intensive blood pressure management (target, SBP < 140 mm Hg) vs guidelinerecommended blood pressure management (target, SBP 141–180 mm Hg).18 While this trial suggested a trend toward benefit for the intensive blood pressure management group, the more recent ATACH-2 trial failed to demonstrate a lower rate of disability or death in patients treated with similar blood pressure targets.19 A noteworthy point is that ATACH-2 allowed initiation of SBP reduction before randomization when practice guidelines adopted SBP ≤ 140 mm Hg, and this change conceivably resulted in more aggressive lowering of SBP closer to 140 mm Hg even in the control group. Regardless, in accordance with the latest AHA/ASA guidelines and in view of impaired autoregulatory mechanisms/hypoperfused parenchyma in ­ patients with iAVMs, it is reasonable to aim for SBP

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closer to 140 mm Hg and avoid SBP ≤ 120 mm Hg. In a retrospective cohort study, patients with AVM-related ICH had significantly lower SBP on admission and in the first 72 hours, compared to patients with ICH of other causes,20 suggesting that these patients are less likely to experience large variations in blood pressure. Secondary analyses of INTERACT2 and ATACH-2 data have shown that early, aggressive blood pressure control is associated with lower rates of hematoma expansion and potentially better long-term outcomes; blood pressure treatment should therefore be started as early as possible.21,22 Titratable agents with shorter halflives are preferred. Intravenous continuous infusion of nicardipine and labetalol are most often used. Other antihypertensive agents that are commonly used in the NICU include esmolol, clevidipine, nitroprusside, and nitroglycerin. Correction of Coagulopathy

Antithrombotic medications account for the majority of coagulopathy-related ICH. In the PATCH (Platelet Transfusion in Cerebral Haemorrhage) trial, patients with prior antiplatelet therapy randomized to receive platelet transfusions had worse functional outcomes as opposed to those managed conservatively.23 However, these patients had medically managed supratentorial IPH, and platelet transfusions should be considered to combat any qualitative platelet dysfunction if any neurosurgical intervention is anticipated. In the event of prior anticoagulation therapy, specific reversal agents for warfarin or direct oral anticoagulants should be administered immediately.24 These include four-factor prothrombin complex concentrates for warfarin, apixaban, rivaroxaban, and edoxaban; idarucizumab for dabigatran; and andexanet alfa for apixaban and rivaroxaban.24 Treating/Preventing Seizures

Seizures are the second most common presenting symptom in patients with iAVMs. While incidentally detected iAVMs carry an 8% risk of seizure within 5 years of diagnosis, the risk is 23% with ruptured iAVMs.25 In a prospective population-based study of seizure risk in patients with arteriovenous or cavernous malformations, more than half of patients who had a first seizure progressed to epilepsy.26 In a study of patients with iAVMs, superficial cortical location of

the AVM, large nidus size, superficial venous drainage, and arterial border zone were associated with high risk of early seizures.27 Seizures increase metabolic demand and cerebral blood flow and consequently intracranial pressure (ICP), which can potentially exacerbate rerupture.28 While current guidelines do not recommend routine seizure prophylaxis for patients with IPH,14 it is important to note that seizures are relatively uncommon after primary IPH compared to AVM-associated ICH. Taking into account the high frequency of seizures and the potential associated deleterious consequences, routine prophylaxis with antiseizure medications, even in individuals without prior seizures, is reasonable. Patients with clinical seizures should receive antiepileptic drugs (AEDs), and AED treatment should be continued after the NICU course. Continuous electroencephalography should be initiated if the exam findings are out of proportion to the radiographic severity of the hematoma, or if status epilepticus is suspected. In case of the latter, standard algorithms for escalation of AED treatment should be followed. AIRWAY MANAGEMENT AND SEDATION Decreased mental state can interfere with a patient’s ability to protect their airway and increase the risks of aspiration and hypoxemia with or without hypercarbia.29 Patients with low GCS scores (around 8 or lower) should be intubated with rapid-sequence intubation followed by ventilator support. Pretreatment with intravenous lidocaine can attenuate the increases in ICP from tracheal stimulation during laryngoscopy.30 Arterial blood gas values should guide ventilator settings. Attention needs to be paid to hypercarbia, as it will lead to cerebral vasodilation and worsen perihematomal edema and raise ICP.30 Similarly, continuous infusion and titration of intravenous sedatives (propofol, midazolam, dexmedetomidine) are equally important to prevent patient-ventilator dyssynchrony, agitation, and elevated ICP. MANAGEMENT OF ELEVATED ICP AND HYDROCEPHALUS Several pathophysiological mechanisms may lead to elevated ICP after iAVM rupture. These factors include mass effect, edema, and impaired ventricular drainage/ hydrocephalus or a combination of those. Placement

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of an ICP monitor, preferably an external ventriculostomy drain, should be considered in patients with a GCS score lower than 8 and those with evidence of herniation, extensive intraventricular hemorrhage, or hydrocephalus, with a goal cerebral perfusion pressure of 60–80 mm Hg.31,32 Other elements for emergent management of elevated ICP should be instituted: control of pain and agitation, elevation of the head of the bed to 30°–45°, administration of hyperosmolar therapy (mannitol or hypertonic saline), normo- to hypernatremia, hyperventilation with a goal PaCO2 of 30–35 mm Hg, and suppression of cerebral metabolism with sedation, barbiturate coma, and/or paralysis.33 Surgery in the acute phase of iAVM rupture is often performed for severe mass effect and/or herniation.33 In select patients, decompressive craniectomy with or without hematoma evacuation may reduce mortality and might be considered to relieve local mass effect or shift. Surgical hematoma evacuation may in fact be dangerous due to alteration in the AVM anatomy due to mass effect and possibly high ICPs; surgical treatment requires a precise understanding of the AVM angioarchitecture on preprocedural imaging and anticipation of occult components due to the presence of a hematoma mass lesion. Usefulness of minimally invasive clot evacuation with stereotactic or endoscopic aspiration is uncertain and poorly studied in the setting of an unsecured vascular lesion.34,35 Endovascular treatment of iAVMs with high-risk angiographic features such as intranidal aneurysms, which suggest impending rupture, however, requires emergent intervention.36 METABOLIC MANAGEMENT Extremes of blood glucose levels and fever have both been associated with poor outcome after IPH.37–41 It is unclear, however, whether they are markers of the severity of brain injury or independent predictors of poor outcome. Nevertheless, blood glucose should be regularly monitored with the aim of achieving normoglycemia. Fever is common in patients with IPH, particularly in those with intraventricular hemorrhage.39 Although the optimal temperature range is not well established, fever should be treated using acetaminophen, cooling blankets, and, if refractory, by using noninvasive or invasive temperature management systems.

Postoperative Management After iAVM Treatment The immediate postoperative period after surgical treatment of an iAVMs is a crucial time until recalibration of the cerebral autoregulation occurs. The main complications to be expected are IPH and seizures. DELAYED INTRAPARENCHYMAL HEMORRHAGE Postoperative IPH after AVM treatment differs from the IPH that occurs in the setting of initial AVM rupture. Delayed IPH has an incidence of 4.1% and 10% in patients with AVMs with lower and higher SpetzlerMartin grades, respectively.42,43 To better understand this phenomenon, a brief review of cerebral autoregulation is helpful (Fig. 27.2). The brain, to a large extent, is able to maintain a more or less constant level of blood flow for a wide variation in systemic blood pressure, usually between mean arterial pressures of 60 and 160 mm Hg.44 However, states of chronic hypotension, as expected in the brain parenchyma surrounding an AVM nidus, can result in this curve being shifted to the left.44 This implies that a mean arterial pressure of 120–160 mm Hg, which would otherwise be within the autoregulatory capacity of the brain, now falls beyond the cerebral autoregulatory curve, and consequently leads to an increased cerebral flow. This phenomenon, called normal perfusion pressure breakthrough (NPPB), was first described by Spetzler in 1978.45 In vivo studies have shown that the mean arterial pressure in the arteries feeding the AVM is about 50% lower than that in the extracranial systemic circulation.46 Additionally, the AVM circuit offers a path of least resistance for the arterial blood due to the absence of capillaries, thereby causing a “steal phenomenon” where blood flow to the brain parenchyma neighboring the AVM nidus is decreased.45 This state of hypotension and hypoperfusion causes loss of autoregulation or shifting of the curve to the left, with the end result being maximal arterial vasodilation in this region. Following AVM feeder occlusion or resection, the AVM circuit no longer exists and blood is diverted back to the perinidal region, where the arteries are maximally dilated. In this context, blood flow even in the “normal range” can cause hyperperfusion, edema, and hemorrhage (Fig. 27.3). This IPH occurs 2–4 cm distal to the AVM and is usually observed with

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Fig. 27.2 Cerebral autoregulation curve. The X-axis represents cerebral blood flow, and the Y-axis represents the systemic arterial pressure.

high-flow AVMs or those with a Spetzler-Martin grade of III or higher.47 The main hypothesis of NPPB centers around the loss of cerebral autoregulation in the first 24–48 hours after iAVM treatment. However, a few intraoperative studies utilizing CO2 reactivity have shown complete restoration of cerebral autoregulation.47 This led al-Rodhan and colleagues to come up with an alternative explanation to NPPB, which they described in their 1993 article.48 This theory, also called “occlusive hyperemia,” involves two interrelated mechanisms. First, stagnation of arterial flow in the former AVM feeders exacerbates existing hypoperfusion and ischemia. This occurs likely due to reflex vasoconstriction, partial thrombosis, and presumably endothelial abnormalities, all of which lead to an increased resistance to flow. In conjunction with these changes, thrombosis in the draining vein causes passive hyperemia and further arterial stagnation, eventually resulting in edema, hyperemia, and hemorrhage.48 Regardless of the mechanism of delayed IPH, the mainstay of management is prevention. Several ­ intraand postoperative steps have been proposed to minimize the occurrence of this complication. Intraoperatively, staged ligation or embolization of the

feeding arteries is recommended to allow gradual increase in perfusion of the normal brain.47 Other steps include avoiding injury to veins that drain both the AVM and the surrounding normal brain parenchyma, clipping the terminal arteries as close to the malformation as possible, and avoiding excessive intravascular hypotension.45,48 More importantly, the main approach to preventing delayed IPH in the NICU setting is blood pressure management. Normotension might be appropriate for patients whose iAVMs are classified as lower grade in the Spetzler-Martin grading system, whereas hypotension should be induced in patients with higher-grade lesions. Lowering of blood pressure is recommended after AVM treatment to keep the mean arterial blood pressure ≤ 70 or SBP < 140 mm Hg in patients with lesions of SpetzlerMartin grade III and higher.42 The patient’s neurological status should be closely monitored for diagnosis of delayed IPH. If this complication ensues despite all prophylactic measures, it is recommended to follow IPH treatment guidelines as discussed in previous sections. A diagnostic angiogram might be helpful to determine whether the bleeding is caused by residual AVM or rupture of associated aneurysms.

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Fig. 27.3 Schematic representation of flow characteristics in the AVM and surrounding brain parenchyma before and after AVM treatment.

POSTOPERATIVE SEIZURES Among iAVM patients with epilepsy, seizure control can be expected long-term after definitive treatment of the AVM,49 with the degree of seizure freedom determined by the type of treatment modality.50 For instance, nearly 80% of patients achieve seizure remission after microsurgical resection, followed by about 60% with stereotactic radiosurgery alone, and 50% with endovascular embolization alone.50 Conversely, patients may experience a first-ever seizure after iAVM treatment, and there is some evidence that this may be more likely after endovascular embolization than after resection or radiosurgery. A 2014 meta-analysis

determined rates of new-onset seizures in patients who had undergone different types of iAVM treatment and found that new-onset seizures occurred in 54 (9.9%) of 547 patients treated with microsurgical resection, 29 (5.1%) of 568 treated with stereotactic radiosurgery, and 4 (33%) of 12 treated with endovascular embolization.50 Seizures occurring in the immediate postoperative period can cause spikes in systemic blood pressure and ICP, worsen cerebral edema, and ultimately lead to IPH.28 Routine seizure prophylaxis among patients without prior seizures and continuation of an existing regimen in patients with epilepsy is therefore prudent. Escalation of antiseizure medications should be done

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in the event of breakthrough seizures or status epilepticus, with consideration of continuous electroencephalography monitoring. ROUTINE POSTOPERATIVE PRECAUTIONS Standard practices of postoperative critical care management should be performed. Antibiotics are usually given 24–48 hours after AVM resection to prevent wound infections. Chemoprophylaxis for the prevention of venous thromboembolism is generally initiated after 24 hours. Stress ulcer prophylaxis in intubated patients or those on high-dose steroids is indicated.

Conclusion The critical care management of patients with AVMs in the preoperative period mainly applies to patients with a ruptured AVM presenting with ICH. The main focus is to limit hematoma expansion and mass effect, prevent seizures, and coordinate with neurosurgical teams about potential interventions should high-risk angiographic markers of impending rupture be present. Changes in flow dynamics and cerebral autoregulation exacerbate the risk of postoperative IPH after AVM treatment. Close monitoring in the NICU and strict blood pressure control help prevent hemorrhagic complications. While AVM treatment may offer modest to good long-term seizure control in patients with epilepsy, new-onset seizures may occur after AVM treatment, particularly after endovascular embolization, and may require continued prophylactic AED treatment.

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Acknowledgment

The authors would like to thank Ms. Kelsey Lansdale for her assistance with the illustrations.

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Neurology. 2017;88(20):1882–1888. https://doi.org/10.1212/ wnl.0000000000003935. van Beijnum J, Lovelock CE, Cordonnier C, et al.; SIVMS Steering Committee and the Oxford Vascular Study. Outcome after spontaneous and arteriovenous malformation-related intracerebral haemorrhage: population-based studies. Brain. 2009;132(Pt 2):537–543. https://doi.org/10.1093/brain/ awn318. Sturiale CL, Puca A, Calandrelli R, et al. Relevance of bleeding pattern on clinical appearance and outcome in patients with hemorrhagic brain arteriovenous malformations. J Neurol Sci. 2013;324(1-2):118–123. https://doi. org/10.1016/j.jns.2012.10.016. Derdeyn CP, Zipfel GJ, Albuquerque FC, et al. American Heart Association Stroke Council. Management of brain arteriovenous malformations: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2017;48(8):e200–e224. https://doi. org/10.1161/str.0000000000000134. Kim H, Al-Shahi Salman R, McCulloch CE, Stapf C, Young WL, Coinvestigators MARS. Untreated brain arteriovenous malformation: patient-level meta-analysis of hemorrhage predictors. Neurology. 2014;83(7):590–597. https://doi.org/10.1212/ wnl.0000000000000688. Gross BA, Du R. Natural history of cerebral arteriovenous malformations: a meta-analysis. J Neurosurg. 2013;118(2):437–443. https://doi.org/10.3171/2012.10.jns121280. Chen CJ, Ding D, Derdeyn CP, et al. Brain arteriovenous malformations: a review of natural history, pathobiology, and interventions. Neurology. 2020;95(20):917–927. https://doi. org/10.1212/wnl.0000000000010968. Dowlatshahi D, Demchuk AM, Flaherty ML, et al. VISTA Collaboration. Defining hematoma expansion in intracerebral hemorrhage: relationship with patient outcomes. Neurology. 2011;76(14):1238–1244. https://doi.org/10.1212/ wnl.0b013e3182143317. Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF. Spontaneous intracerebral hemorrhage. N Engl J Med. 2001;344(19):1450–1460. https://doi.org/10.1056/ nejm200105103441907. Delgado Almandoz JE, Schaefer PW, Goldstein JN, et al. Practical scoring system for the identification of patients with intracerebral hemorrhage at highest risk of harboring an underlying vascular etiology: The Secondary Intracerebral Hemorrhage Score. AJNR Am J Neuroradiol. 2010;31(9):1653– 1660. https://doi.org/10.3174/ajnr.a2156. Brouwers HB, Chang Y, Falcone GJ, et al. Predicting hematoma expansion after primary intracerebral hemorrhage. JAMA Neurol. 2014;71(2):158–164. https://doi.org/10.1001/ jamaneurol.2013.5433. Hemphill III JC, Greenberg SM, Anderson CS, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46(7): 2032–2060. https://doi.org/10.1161/str.0000000000000069. Ye Z, Ai X, Zheng J, et al. Extravasation of contrast (spot sign) predicts in-hospital mortality in ruptured arteriovenous malformation. Br J Neurosurg. 2019;33(2):149–155. https://doi.org /10.1080/02688697.2017.1384792. Solomon RA, Connolly ES Jr. Arteriovenous malformations of the brain. N Engl J Med. 2017;376(19):1859–1866. https://doi. org/10.1056/nejmra1607407.

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17. Fennell VS, Martirosyan NL, Atwal GS, et al. Hemodynamics associated with intracerebral arteriovenous malformations: the effects of treatment modalities. Neurosurgery. 2018;83(4): 611–621. https://doi.org/10.1093/neuros/nyx560. 18. Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med. 2013;368(25):2355–2365. https://doi.org/10. 1056/nejmoa1214609. 19. Qureshi AI, Palesch YY, Barsan WG, et al. ATACH-2 Trial Investigators and the Neurological Emergency Treatment Trials Network. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. N Engl J Med. 2016;375(11):1033– 1043. https://doi.org/10.1056/nejmoa1603460. 20. Lin J, Piran P, Lerario MP, et al. Differences in admission blood pressure among causes of intracerebral hemorrhage. Stroke. 2020; 51(2):644–647. https://doi.org/10.1161/strokeaha.119.028009. 21. Li Q, Warren AD, Qureshi AI, et al. Ultra-early blood pressure reduction attenuates hematoma growth and improves outcome in intracerebral hemorrhage. Ann Neurol. 2020;88(2):388–395. https://doi.org/10.1002/ana.25793. 22. Moullaali TJ, Wang X, Martin RH, et al. Blood pressure control and clinical outcomes in acute intracerebral haemorrhage: a preplanned pooled analysis of individual participant data. Lancet Neurol. 2019;18(9):857–864. https://doi.org/10.1016/ s1474-4422(19)30196-6. 23. Baharoglu MI, Cordonnier C, Al-Shahi Salman R, et al. Platelet transfusion versus standard care after acute stroke due to ­ spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial. Lancet. 2016;387(10038):2605–2613. https://doi. org/10.1016/s0140-6736(16)30392-0. 24. Frontera JA, Lewin III JJ, Rabinstein AA, et al. Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care. 2016;24(1):6–46. https://doi.org/10.1007/s12028-015-0222-x. 25. Garcin B, Houdart E, Porcher R, et al. Epileptic seizures at initial presentation in patients with brain arteriovenous malformation. Neurology. 2012;78(9):626–631. https://doi.org/10.1212/ wnl.0b013e3182494d40. 26. Josephson CB, Leach JP, Duncan R, et al. Seizure risk from cavernous or arteriovenous malformations: prospective ­ population-based study. Neurology. 2011;76(18):1548–1554. https://doi.org/10.1212/wnl.0b013e3182190f37. 27. Hoh BL, Chapman PH, Loeffler JS, Carter BS, Ogilvy CS. Results of multimodality treatment for 141 patients with brain arteriovenous malformations and seizures: factors associated with seizure incidence and seizure outcomes. Neurosurgery. 2002;51(2):303–309; discussion 309–311. 28. McNamara B, Ray J, Menon D, Boniface S. Raised intracranial pressure and seizures in the neurological intensive care unit. Br J Anaesth. 2003;90(1):39–42. 29. Alanazi A. Intubations and airway management: an overview of hassles through third millennium. J Emerg Trauma Shock. 2015;8(2):99–107. https://doi.org/10.4103/0974-2700.145401. 30. Kramer N, Lebowitz D, Walsh M, Ganti L. Rapid sequence intubation in traumatic brain-injured adults. Cureus. 2018;10(4):e2530. https://doi.org/10.7759/cureus.2530. 31. Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS, Bratton SL, et al. Guidelines for the management of severe

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traumatic brain injury. VII. Intracranial pressure monitoring technology. J Neurotrauma. 2007;24(Suppl 1):S45–S54. https:// doi.org/10.1089/neu.2007.9989. Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS, Bratton SL, et al. Guidelines for the management of severe traumatic brain injury. VIII. Intracranial pressure thresholds. J Neurotrauma. 2007;24(Suppl 1):S55–S58. https://doi. org/10.1089/neu.2007.9989. Freeman WD. Management of intracranial pressure. Continuum (Minneap Minn). 2015;21 (5 Neurocritical Care);1299–1323. https://doi.org/10.1212/con.0000000000000235. Hanley DF, Thompson RE, Rosenblum M, et al. Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial. Lancet. 2019;393(10175):1021–1032. https://doi.org/10.1016/s01406736(19)30195-3. Hanley DF, Lane K, McBee N, et al. Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial. Lancet. 2017;389(10069):603–611. https:// doi.org/10.1016/s0140-6736(16)32410-2. Lv X, Wu Z, Jiang C, et al. Angioarchitectural characteristics of brain arteriovenous malformations with and without hemorrhage. World Neurosurg. 2011;76(1-2):95–99. https://doi. org/10.1016/j.wneu.2011.01.044. Kimura K, Iguchi Y, Inoue T, et al. Hyperglycemia independently increases the risk of early death in acute spontaneous intracerebral hemorrhage. J Neurol Sci. 2007;255(1-2):90–94. https://doi.org/10.1016/j.jns.2007.02.005. Stead LG, Gilmore RM, Bellolio MF, et al. Hyperglycemia as an independent predictor of worse outcome in non-diabetic patients presenting with acute ischemic stroke. Neurocrit Care. 2009;10(2):181–186. https://doi.org/10.1007/s12028008-9080-0. Schwarz S, Hafner K, Aschoff A, Schwab S. Incidence and prognostic significance of fever following intracerebral hemorrhage. Neurology. 2000;54(2):354–361. https://doi.org/10.1212/ wnl.54.2.354. Rincon F, Lyden P, Mayer SA. Relationship between temperature, hematoma growth, and functional outcome after intracerebral hemorrhage. Neurocrit Care. 2013;18(1):45–53. https:// doi.org/10.1007/s12028-012-9779-9. Johnston KC, Bruno A, Pauls Q, et al. Neurological Emergencies Treatment Trials Network and the SHINE Trial Investigators. Intensive vs standard treatment of hyperglycemia and functional outcome in patients with acute ischemic stroke: the SHINE randomized clinical trial. JAMA. 2019;322(4):326– 335. https://doi.org/10.1001/jama.2019.9346. Morgan MK, Wiedmann MKH, Assaad NNA, Parr MJA, Heller GZ. Deliberate employment of postoperative hypotension for brain arteriovenous malformation surgery and the incidence of delayed postoperative hemorrhage: a prospective cohort study. J Neurosurg. 2017;127(5):1025–1040. https://doi. org/10.3171/2016.9.jns161333. Niini T, Laakso A, Tanskanen P, Niemela M, Luostarinen T. Perioperative treatment of brain arteriovenous malformations between 2006 and 2014: The Helsinki protocol. Neurocrit Care. 2019;31(2):346–356. https://doi.org/10.1007/ s12028-019-00674-y.

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44. Armstead WM. Cerebral blood flow autoregulation and dysautoregulation. Anesthesiol Clin. 2016;34(3):465–477. https://doi. org/10.1016/j.anclin.2016.04.002. 45. Rangel-Castilla L, Spetzler RF, Nakaji P. Normal perfusion pressure breakthrough theory: a reappraisal after 35 years. Neurosurg Rev. 2015;38(3):399–404; discussion 404–405. https://doi.org/10.1007/s10143-014-0600-4. 46. Hashimoto T, Young WL. Anesthesia-related considerations for cerebral arteriovenous malformations. Neurosurg Focus. 2001;11(5):e5. https://doi.org/10.3171/foc.2001.11.5.6. 47. Zacharia BE, Bruce S, Appelboom G, Connolly ES Jr. Occlusive hyperemia versus normal perfusion pressure breakthrough after treatment of cranial arteriovenous malformations. Neurosurg Clin N Am. 2012;23(1):147–151. https://doi.org/10.1016/j. nec.2011.09.005.

48. al-Rodhan NR, Sundt TM Jr, Piepgras DG, Nichols DA, Rufenacht D, Stevens LN. Occlusive hyperemia: a theory for the hemodynamic complications following resection of intracerebral arteriovenous malformations. J Neurosurg. 1993;78(2):167–175. https://doi.org/10.3171/jns.1993.78.2.0167. 49. Englot DJ, Young WL, Han SJ, McCulloch CE, Chang EF, Lawton MT. Seizure predictors and control after microsurgical resection of supratentorial arteriovenous malformations in 440 patients. Neurosurgery. 2012;71(3):572–580; discussion 580. https://doi.org/10.1227/neu.0b013e31825ea3ba. 50. Baranoski JF, Grant RA, Hirsch LJ, et al. Seizure control for intracranial arteriovenous malformations is directly related to treatment modality: a meta-analysis. J Neurointerv Surg. 2014; 6(9):684–690. https://doi.org/10.1136/neurintsurg-2013010945.

Chapter 28

Obstetric Considerations in AVM Management Milli J. Desai, Arvin R. Wali, and Alexander A. Khalessi

Chapter Outline Background Physiologic Changes Associated With Pregnancy Risk of iAVM Rupture and Hemorrhage in Pregnancy and the Puerperium Diagnosis Imaging Considerations Treatment Special Considerations—Medical Management Obstetrical Mode of Delivery and Treatment Counseling Conclusion

Background Subarachnoid hemorrhage (SAH) is among the most common nonobstetric causes of maternal mortality during pregnancy and the puerperium (the first 6 weeks after delivery), with around 25% of these hemorrhages being attributed to rupture of intracranial arteriovenous malformations (iAVMs).1,2 While the overall incidence of stroke and hemorrhage in pregnancy is rare, rupture of aneurysms and iAVMs can cause devastating neurologic injury to both mother and fetus.3 The Stroke Council of the American Stroke Association (AHA Scientific Statement) determined that pregnant patients are in a “special consideration” category due to the inconclusive data surrounding AVM hemorrhage and rebleeding risk in pregnancy.4 Furthermore, pregnant patients are unique in that the safety and

well-being of both the pregnant mother and the fetus must be addressed in the medical and surgical management of iAVMs in pregnancy. Within this chapter, we review the available data for potential risks of iAVM hemorrhage and rebleeding in pregnancy, during delivery, and in the postpartum period. Additionally, we review the data regarding the diagnosis and evaluation and selection of operative and nonoperative treatment strategies for the pregnant patient.

Physiologic Changes Associated With Pregnancy The physiologic effects of pregnancy and the puerperium include many hemodynamic changes, and the impact of these changes on AVM physiology remains controversial. A 50% increase in total body water persists throughout the pregnancy and declines 2 weeks postpartum. This hypervolemic state contributes to increased cardiac output, stroke volume, and heart rate. Systemic vascular resistance is decreased in pregnancy due to prostaglandin circulation, which lowers systemic arterial blood pressure. The decreased systemic vascular resistance in conjunction with increased venous compliance can result in increased venous stasis. Moreover, the inferior vena cava may be compressed by the gravid uterus, which leads to decreased blood return to the heart. Maternal cardiac output increases between 30% and 50% in pregnancy due to the increases in stroke volume and heart rate. Cardiac output rises 50% higher than baseline pregnancy values in the first stage of labor. Immediately after delivery, there is a 10%–20% rise in cardiac output, which then declines after the first postpartum day and returns to normal 2–4 weeks after delivery. 269

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Moreover, sex hormones such as estrogen may contribute to increased flow within the vessels that comprise an AVM, and this is hypothesized to increase the likelihood of AVM rupture. Estrogen may also lead to intimal hyperplasia in blood vessels. After uterine involution postdelivery, hormonal changes may also alter the structure of AVM vessels.5 These complex hemodynamic changes may each impact AVM biology at different stages of pregnancy, and understanding them can provide insight into the etiology and management of iAVM rupture in the pregnant patient.

Risk of iAVM Rupture and Hemorrhage in Pregnancy and the Puerperium The lack of prospective studies limits assessment of the true risks associated with iAVM rupture to both the pregnant woman as well as the fetus. For this review, we searched the PubMed and Google Scholar databases from 1990 through 2021 for cerebrovascular AVM and pregnancy. The studies that we found are summarized below and on the next two pages. Rupture appears likely to occur throughout pregnancy, not necessarily in the third trimester or during labor.5,6 In 36 cases of iAVM hemorrhage in pregnancy reported by Dias and Sekhar, only two cases occurred during childbirth.7 In a retrospective study of 451 female patients with AVMs who had 540 pregnancies at one institution in the United States, the incidence of hemorrhage was found to be 3.5% during the 52 weeks after the patient’s last menstrual period. This rate was not significantly different from the rate for similar nonpregnant populations.8 In a cohort of 270 female patients with iAVMs at one institution in the United States, the annual hemorrhage rate in pregnant women was 5.7% compared to 1.3% in nonpregnant women, which represented a statistically significant increase in risk. This study suggests that patients with a known iAVM who become pregnant should be monitored carefully throughout pregnancy, particularly during the second and third trimesters and in the puerperium.9 In a cohort-crossover study of three US states’ administrative claims data, each woman with an iAVM served as her own control, based on a 5-week period prior to a pregnancy of 40 weeks and 12 weeks of postpartum period. This study found that women

Pearls • Epidemiological data regarding iAVM rupture risk in pregnancy is equivocal and underpowered in the literature, and reports of peripartum iAVM rupture are rare. Physiological considerations in iAVM management include cardiac output, blood coagulability, systemic vascular resistance, and fetal gestational age. • Diagnostic studies should limit fetal exposure to contrast agents and radiation. MRI should be preferentially used and CT or angiography reserved for critical diagnostic detail in the acute management setting. • AVM resection in pregnancy is possible with particular attention to positioning to limit aorta or vena cava compression depending on laterality or posterior fossa location. • The protective benefits of radiosurgery do not accrue (2- to 3-year interval before therapeutic benefit) over the time horizon of pregnancy (9 months) and radiosurgery is therefore seldom used in this clinical setting. • Endovascular AVM treatment in pregnancy is possible but may involve preferential use of NBCA vis-à-vis Onyx to limit overall radiation exposure due to continuous fluoroscopic dose requirement and unclear fetal impact of DMSO.

with iAVMs had a 3.27-fold (relative risk; 95% confidence interval [CI], 1.67–6.43) increase in the risk of intracerebral hemorrhage during pregnancy and the puerperium compared with the nonpregnant period.10 In a 2012 study of 54 female patients with iAVMs at one institution in the United States, there were a total of 62 pregnancies, and 5 hemorrhages occurred in 4 patients, yielding a hemorrhage rate of 8.1% per pregnancy.11 A retrospective cohort study of 264 female patients with iAVMs at an institution in China analyzed hemorrhage during exposure periods (pregnancy and the puerperium) and nonexposure periods (the interval from birth until either AVM obliteration or last follow-up, after subtracting the exposure period) and found annual hemorrhage rates of 5.40% in exposure periods, 2.92% in nonexposure periods, and 3.82% in nonexposure periods of reproductive-age patients. The

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authors also performed a pooled data analysis, incorporating data from eight previously published studies and their own cohort. This analysis also showed a higher annual hemorrhage rate in exposure periods than in nonexposure periods (5.59% vs 2.52%; odds ratio, 3.19; 95% CI, 1.52–6.70).12 A separate retrospective cohort study of 979 female patients with iAVMs in a different institution in China yielded contrasting findings. In this study, the odds ratio for AVM rupture during pregnancy and the puerperium, compared with the control period, was 0.71 (95% CI, 0.61–0.82). Thus the authors concluded that there was no increased risk of iAVM hemorrhage during pregnancy and the puerperium. Of the patients in this study who presented with intracranial hemorrhage due to AVM rupture during pregnancy, more than 91% presented in the second and third gestational trimesters, suggesting that later gestational age carries a greater risk of hemodynamic, coagulative, and vessel wall changes.13 It is unclear whether the number of pregnancies a patient has had correlates with iAVM rupture risk. Most studies have not followed patients through multiple pregnancies, so the risk of AVM hemorrhage during subsequent pregnancies is unknown. However, there are some case reports of AVM rupture during a delivery after multiple normal pregnancies. One case report describes AVM hemorrhage in the patient’s fifth pregnancy, suggesting that risk persists even after multiple deliveries and that rapid diagnosis and treatment are required when intracranial hemorrhage is suspected in pregnant patients.14 A 2019 systematic review analyzed data from three studies that provided a quantitative risk of first intracerebral hemorrhage due to iAVM in pregnancy. The authors extracted data on 47 cases across four cohorts and found that for these four cohorts, the annual risk of the first hemorrhage during pregnancy was 3.0% (95% CI, 1.7%–5.2%), 3.5% (95% CI, 2.4%–4.5%), 8.6% (95% CI, 1.8%–25%), and 30% (95% CI, 18%– 49%); only the last cohort had a significant increase in risk compared to the risk in the nonpregnant period (relative risk 6.8; 95% CI, 3.6–13). The authors concluded that there is no conclusive evidence of an increased risk of the first hemorrhage due to iAVM during pregnancy and that a retrospective, multicenter case crossover study is “urgently required.”15

271 There are rare reports in the literature of iAVM rupture occurring during labor and childbirth. One case report describes a patient at 41 weeks’ gestation who developed a sudden-onset severe headache during induction of labor for oligohydramnios. Her blood pressure when she complained of the headache had increased to 172/90 mm Hg. When her blood pressure remained elevated and the headache did not resolve, preeclampsia was suspected, and she was given a magnesium bolus, followed by magnesium infusion. A cesarean section was performed, resulting in the delivery of a healthy baby. During surgical closure of the cesarean section, the patient was noted to have a dilated pupil as well as poor uterine tone and oozing; she was intubated and hyperventilated. Intravenous administration of mannitol was initiated. Laboratory test results showed disseminated intravascular coagulation, and a CT scan of the patient’s head showed right temporal and frontal hemorrhage. Limited angiography ruled out a middle cerebral artery aneurysm, and an emergent craniotomy was performed for evacuation of intracerebral hemorrhage and resection of an AVM. The patient was in the intensive care unit (ICU) for 19 days, where she had little movement in her extremities, had limited speech (only a few words), and needed a gastrostomy tube for feedings. She was subsequently transferred to an inpatient rehabilitation setting for physical therapy and was described as “demonstrating slow, continued progress with aggressive physical therapy” when the case was reported.16 Another case report describes a patient who experienced convulsions during induction of labor and underwent brain MRI, which showed a cerebral AVM in the left frontal base without signs of intracranial hemorrhage or brain edema. The patient had a cesarean section and delivery of a healthy baby, with a plan to treat the AVM afterward.17 Spontaneous regression of an iAVM is rare, and the occurrence during the puerperium has been described once in the literature. In this case, a pregnant patient presented with a ruptured AVM with a feeding artery aneurysm during the second trimester, and the AVM was clipped and hematoma removed. Serial angiography was performed 6 months and 1 year after delivery and showed dramatic regression of the AVM (described as “near-complete” at 1 year), suggesting

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that hormonal factors during pregnancy and the immediate postpartum period affect the growth and rupture of an AVM.18 Patients who present with hemorrhage due to iAVM rupture during pregnancy may have an elevated risk of rebleeding during the same pregnancy compared to the risk of early rebleeding in nonpregnant patients. One study included 27 pregnant women with AVM rupture who did not have immediate resection of the AVM, and 7 of these women had hemorrhage recurrence before or immediately after delivery, yielding a rebleeding rate of 26%.19 The Stroke Council of the American Stroke Association acknowledges that this rebleeding rate is higher than the 6% expected rebleeding rate in the first year after a hemorrhage in nonpregnant patients. Although the evidence is only level V, these findings suggest there may be a benefit to early therapy in some pregnant patients presenting with AVM rupture.20 In a literature review published in 2016, Lv et al. analyzed data from 65 cases of AVM in pregnancy and found that AVM hemorrhage presentation was significantly associated with a poor maternal outcome (modified Rankin Scale score ≥2) but was not significantly associated with risk to the fetus. Additionally, gestational age at the time of AVM hemorrhage was not significantly associated with either poor maternal outcome or fetal risk.21 A retrospective review of the University of California San Francisco Brain Arteriovenous Malformation Project database identified 16 cases in which patients with AVMs became pregnant. In three of the cases, the pregnancy did not continue past the first trimester. In the remaining 13 cases, 10 patients underwent emergent AVM treatment before delivery and 3 deferred treatment until after delivery. Eleven (85%) of the 13 patients had good maternal outcomes (modified Rankin Scale score ≥2), including 8 of the 10 patients whose AVMs were treated before delivery. There were no reports of postnatal cognitive or developmental delays in infants or toddlers at 2-year follow-up.22

Diagnosis A pregnant woman can have an iAVM that remains undiagnosed until a hemorrhagic stroke occurs, and thus iAVM should be considered in the differential diagnosis

for any pregnant woman with neurological symptoms. Neurovascular disorders presenting during pregnancy are likely to have headache as a major symptom and feature. Care for pregnant women should include providers who are knowledgeable about concerning headache symptoms, including but not limited to neurological signs and symptoms, sudden onset of headache pain, and positional headaches. Symptoms of neurovascular disorders such as AVM hemorrhage can overlap with symptoms of other conditions, such as seizure disorders, particularly in pregnant patients. Intracranial hemorrhage may present as eclampsia in the pregnant patient up to 15% of the time.23

Imaging Considerations MRI can distinguish between eclampsia and intracranial hemorrhage. However, with acute symptoms in the time frame of hours to days with a high clinical suspicion of a vascular malformation, brain CT and CT angiography (CTA) are recommended, especially if MRI is not immediately available. CT and CTA can be useful in the rapid diagnosis of hemorrhage as well as ruptured iAVM.23 Head CT is associated with less than 0.1 mGy exposure to the fetus, and a single dose of a CT contrast agent in pregnancy is felt to be safe.24 For CT and CTA examinations, abdominal shielding must be performed for the gravid uterus to protect the fetus from irradiation; gadolinium-based contrast agents should be avoided in pregnant patients in general but can be used if shared decision-making between the provider and patient concludes that benefits outweigh risks. Radiation doses to the fetus are lower than the dose to the mother due to protection provided by the uterus and surrounding tissues, but abdominal shielding remains important. Ionizing radiation doses greater than 0.1 Gy are unsafe for the human embryo and fetus. At doses greater than 0.5 Gy, ionizing radiation can cause growth restriction, malformations, impaired brain function, and cancer in the fetus even if there are no immediate side effects for the pregnant patient. Just as in nonpregnant patients, CTA can show crucial elements of an iAVM, such as location, size, feeding artery, flow rate, arteriovenous fistula, coexisting aneurysm, venous drainage, and ectasia of drainage veins. Factors associated with increased risk include

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deep location, small AVM size, arteriovenous fistula, restricted venous drainage, nidal aneurysm, cortical venous reflux, and intrinsic signal change in the surrounding parenchyma concerning for ischemic steal or hyperemia. For symptoms that last from days to weeks and for follow-up imaging, MRI as well as noncontrast MR angiography and MR venography can be used for evaluation. Gadolinium should be avoided in pregnancy and is not required for these imaging examinations.

Treatment Treating AVM rupture in pregnancy is complex, as there are considerations for both the pregnant woman and the fetus. The general consensus from the Stroke Council of the American Stroke Association as well as most study authors is to consider treatment before pregnancy for women who have known AVMs and are planning and/or anticipating pregnancy. Elective management of iAVMs during pregnancy is generally not recommended.20 Two groups of patients are of concern in this discussion: those who have an incidental diagnosis of AVM rupture in pregnancy, and those who become pregnant after being diagnosed with an AVM. In either scenario,

a ruptured AVM takes precedence in the treatment algorithm, given that there may be an increased risk of rehemorrhage in the pregnant population. It is possible to wait to deliver if the gestational age is near term (preterm delivery is defined by 6 cm) AVM (Spetzler-Martin grade V) with nidus measuring up to 6.1 cm, arterial feeders from the right anterior, middle, and posterior cerebral arteries, and both superficial and venous drainage via the posterior aspect of the superior sagittal sinus, right transverse sinus, right basal vein of Rosenthal and vein of Galen. (E and F) Anteroposterior (E) and lateral (F) views from diagnostic cerebral angiography demonstrating arterial feeders from the right anterior, middle, and posterior cerebral arteries and the temporal branch of the right middle meningeal artery. The AVM superficially drains into the superior sagittal sinus and has deep venous drainage into the right internal cerebral vein. There are no intranidal or flow-related aneurysms.

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Giant Intracranial AVMs

Indications for Treatment There is a single large randomized trial of observation vs treatment of iAVMs—ARUBA (A Randomised Trial of Unruptured Brain Arteriovenous Malformations)6— but it has limited utility in guiding the management of giant iAVMs, since giant size was not reported and patients with Spetzler-Martin grade IV iAVMs made up only 10% of the total cohort. There is one large, retrospective, single-institution cohort study with long-term follow-up, the series presented by Yang et al., mentioned earlier.2 In this study, the authors identified 55 cases of giant AVMs, 24 (44%) of which were managed conservatively (without intervention). Data from continuous follow-up (mean 11.8 years) were available for 35 patients—13 patients whose AVMs were managed conservatively and 22 who underwent intervention. At latest follow-up, of the 13 patients in this subset whose AVMs were managed conservatively, 10 (77%) showed stable or improved neurologic status (as measured by modified Rankin Scale); in contrast, of the 22 patients who underwent intervention, only 11 (50%) showed stable or improved status and the other 11 (50%) showed decline. Overall, compared to the treated cohort, there was no significant difference in the rate of hemorrhage or neurologic outcome, although there was a trend toward superior neurologic outcome in the observation group that did not meet statistical significance. Therefore the best available data on the management of giant iAVMs support conservative observation as a reasonable option, with comparable rates of hemorrhage and similar neurologic outcomes. However, this should be weighed against the average young age of first presentation and consequently elevated life-long hemorrhage risk, as well as the possibility of neurologic symptoms not related to hemorrhage. The indications for treatment of giant iAVMs can be broadly classified as mitigation of bleeding risk and palliation of symptoms. Once the decision to treat is made, in general, total resection should only be considered for patients with progressive deficits due to continued hemorrhage. Intranidal aneurysms or flow-related aneurysms at the circle of Willis can be treated via open surgery or endovascularly. Patients with progressive deficits and intractable headaches or seizures may be considered for partial embolization for palliation of symptoms. Based on these treatment considerations, in a large cohort of 73 patients with

Spetzler-Martin grades IV and V AVMs at a highvolume center, the recommendation was no treatment in 75% of cases, partial AVM treatment in 10%, AVM-associated aneurysm treatment in 10%, and complete AVM resection in just 5%.5 Importantly, this study demonstrated that partial treatment of AVMs offered no reduction in the rate of subsequent hemorrhage and in fact correlated with a higher rate of posttreatment rupture. Patients with giant iAVMs with associated aneurysms or those thought to be at risk due to prior rupture deserve consideration for treatment. In general, patients with associated aneurysms should have either open surgery or endovascular treatment that secures the aneurysm without consideration of total resection of the AVM. Indications for palliative treatment include intractable or worsening seizures and progressive neurologic deficits.2 Progressive deficits and intractable seizures in a patient with an unruptured giant iAVM are thought to be secondary to cerebrovascular steal and resultant ischemia in the surrounding brain parenchyma. Small series suggest that even partial embolization of iAVMs can reduce shunting and therefore restore normal perfusion to the surrounding brain and provide palliation of symptoms.7

Treatment Options It is generally accepted that giant iAVMs must be approached in a multidisciplinary manner and are almost always treated with a combination of surgery, embolization, and/or radiation. These treatment options are discussed separately in detail elsewhere in this book; here, we summarize outcomes and special considerations relevant to the care of patients with giant iAVMs. MICROSURGICAL RESECTION Giant iAVMs present a surgical challenge due to their often diffuse nature, recruitment of multiple feeding vessels (including vessels from the contralateral hemisphere), and arterial and venous components involved with critical deep brain structures. Multimodality treatment is often employed, but in some cases surgery alone can be appropriate. In the largest surgical series of giant iAVM cases published to date, that of Zhao et al.,3 only 6 of 40 patients underwent preoperative embolization. In this series, 48% of patients had stable neurologic exam findings on discharge, while 50% exhibited

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new deficits, most commonly hemiparesis, which was seen in 33%. Seventy-eight percent of patients in the series had an excellent or good clinical outcome, with 20% having a poor outcome. While this study demonstrates that good clinical results are possible after resection of giant iAVMs, it also demonstrates a potentially prohibitively high rate of morbidity and mortality. This is in keeping with the classic original Spetzler-Martin study, which reported a 27% rate of new deficit after resection of grade IV AVMs and a 51% rate of new deficit after resection of grade V AVMs.8 Similarly, in their large contemporary multiinstitutional series, Kim et al. found a 38% rate of worsened neurologic status after resection of grade IV lesions and a 50% rate after resection of grade V lesions.1 A special consideration in the surgical management of giant iAVMs is postoperative hemorrhage secondary to normal perfusion pressure breakthrough (NPPB).9 This phenomenon is thought to be due to loss of cerebral autoregulation in surrounding normal cortical vessels resulting in hemorrhage after iAVM resection. Risk factors for this complication include large size of the nidus and feeding vessels, high flow through the AVM, low filling of surrounding normal vessels, and the preoperative presence of fluctuating or ischemic symptoms.10 In the series of surgically treated giant iAVM cases reported by Zhao et al., NPPB was seen after AVM resection in 6 (15%) of 40 cases. Moreover,

the patients with NPPB did not fare well; four of the six were described as having “serious nervous system impairments,” and one died.3 Aggressive postoperative blood pressure control in an intensive care unit setting is paramount in preventing this complication and is especially important after giant iAVM resection. EMBOLIZATION Early series of giant iAVM resection employed pre- and intraoperative partial embolization of the AVM nidus via injection of polymer glue,10,11 which was thought to reduce the risk of NPPB. With recent advances in endovascular tools and embolization materials, preoperative endovascular treatment is increasingly being used in the surgical management of iAVMs, including giant lesions. In a large modern series of 53 patients referred for multidisciplinary treatment of giant iAVMs, 98% had endovascular embolization as a part of their treatment.4 Principles of embolization are similar for small iAVMs, including embolization of no more than 25% of the nidus in each session and postprocedural induced hypotension. Embolization sessions are usually spaced 1–2 weeks apart, and surgical excision is performed after maximal safe embolization.4 The goal of embolization when surgery is not planned should be to secure associated aneurysms (Figs. 30.2 and 30.3) or to reduce flow for palliation of symptoms (Fig. 30.4).

Fig. 30.2 Diagnostic cerebral angiography images demonstrating arterial (A, C, and D) and venous (B and E) phases of a Spetzler-Martin grade V giant (>6 cm) AVM involving the right temporal, parietal, and occipital lobes, with multiple flow-related aneurysms. Images included are lateral views of internal carotid artery injections (A and B) as well as anterior-posterior (C) and lateral (D and E) views of vertebral artery injections. The AVM is supplied by the bilateral anterior cerebral arteries, branches of the right middle cerebral artery, and the bilateral posterior cerebral arteries. There is superficial venous drainage into the superior sagittal sinus bilaterally via several cortical veins. There is also extensive deep venous drainage, via the deep middle cerebral veins bilaterally, bilateral dilated basal veins, bilateral dilated internal cerebral veins, and a dilated vein of Galen. There are multiple venous varices associated with the deep venous drainage. There are at least three flow-related aneurysms: a broadbased aneurysm of the right supraclinoid internal carotid artery; an aneurysm approximately 1 cm in diameter, with a narrow neck, arising from the P2 segment of the left posterior cerebral artery; and a small, broad-necked aneurysm arising from the V4 segment of the left vertebral artery.

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Fig. 30.3 Dedicated right vertebral artery angiography images demonstrating a Spetzler-Martin grade V AVM as described in Fig. 30.2, now planned for embolization of associated flow-related aneurysm. (Left) Angiogram obtained before embolization showing an 8.8 x 7.3 mm flow-related aneurysm (inset), with a narrow neck, arising from the P2 segment of the left posterior cerebral artery. (Right) Angiogram obtained following successful selective catheterization and coil embolization of the flow-related aneurysm of the left posterior cerebral artery, demonstrating complete obliteration of the aneurysm, with good antegrade flow in the basilar and bilateral posterior cerebral arteries.

301 RADIATION Stereotactic radiosurgery (SRS) is increasingly being used for the treatment of small iAVMs, but the radiation dose required for treatment of large iAVMs would cause prohibitive damage to the surrounding normal brain. There have been limited series examining the use of staged radiosurgery12 or hypofractionated radiosurgery13,14 for the treatment of large iAVMs. One large series specifically included only giant iAVMs; the authors, Xiao et al., reported on 20 cases with a nidus size greater than 5 cm; the median AVM volume was 46.84 cm3. The AVMs were managed with hypofractionated radiosurgery, typically 25–30 Gy delivered in 5–6 daily fractions.14 There was no significant change in bleeding risk, with a reported postradiation rate of hemorrhage of approximately 2%. All AVMs had a radiographic response to radiation, but the volume of residual nidus varied widely, from 1.5% to 98%. There were no cures. Previously embolized lesions showed

Fig. 30.4 Right internal carotid artery angiography images from a case of a Spetzler-Martin grade IV AVM involving the right perirolandic region and supplied by the right middle cerebral artery and bilateral anterior cerebral arteries, with venous drainage via the superior sagittal sinus and with multiple dilated venous varices. The patient presented with progressive intractable seizures and proceeded to treatment with staged embolization. (A) Lateral (left) and anteroposterior (right) views from baseline angiography of AVM. (B–D) Angiographic images obtained following stage 1 embolization (B) with liquid embolic and coils, stage 3 embolization (C), and stage 4 embolization (D).

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less response to radiosurgery, a widely recognized phenomenon in the radiosurgical treatment of AVMs.15 Taken together, the existing data on staged SRS or hypofractionated radiosurgery for giant iAVMs suggest that it is safe and best used as a volume-reduction approach for further therapy, which may include further SRS or open surgery. MULTIMODALITY TREATMENT The best-studied approach in modern series is multimodality treatment, incorporating some combination of radiation, embolization, and microsurgical resection (Fig. 30.5). In the largest series of giant iAVMs managed with a multimodal approach, 53 patients were treated; embolization was performed in 98% of the cases, radiosurgery in 89%, and, and surgery in 51%.4 In this series, reported by Chang et al., patients were treated based on a uniform treatment algorithm, with embolization followed by radiosurgery and then further radiosurgery or surgical excision for any residual AVM remaining after 3–4 years of follow-up. Overall, 43% of patients had surgery, radiosurgery, and embolization, and 43% had embolization and radiation. AVM cure was ultimately achieved in 36% of the patient cohort. Importantly, despite this relatively modest rate of cure, 71% of patients with seizures had reduction or complete cessation of their seizures, 87% had improvement or cure of headaches, and 71% of patients had stabilization or improvement in their progressive

neurologic deficits, supporting the notion that multimodality treatment can be used as a palliative measure in these patients. The reported rate of morbidity and mortality was 30%; the authors noted, however, that in evaluating the cause of death during the follow-up period, it is difficult to separate the effects of treatment from the natural history of this disease. An alternative treatment paradigm omits embolization and instead employs hypofractionated radiosurgery to “downgrade” the iAVM, thereby reducing the surgical risk.16 Abla et al. reported on the utilization of volume-staged SRS followed by surgery in 16 patients with grade III–V iAVMs (i.e., not just giant iAVMs) with an average size of 5.9 cm. After a mean of 2.7 radiosurgery sessions, the Spetzler-Martin grade was reduced by an average of one and a half grades. Subsequent surgical risk was based on the downgraded grade, not the original grade. Further work is needed to see if this strategy can be employed in a population that includes only patients with giant iAVMs, however. In Yang and colleagues’ series of 55 patients with giant iAVMs, comparing multimodality treatment with an observation arm, 22 patients received treatment and had long-term follow-up.2 Of note, the majority of patients in this series were treated with embolization and radiation (61%) as opposed to embolization followed by surgery (16%) or all three modalities (3%). There was only a 9.2% cure rate; however, there was a significant reduction in seizure incidence in the

Fig. 30.5 Axial T2-weighted MR images demonstrating a giant perirolandic AVM (same case as in Fig. 30.4) and its response to staged embolization and radiosurgical treatment. (A) Baseline image before any treatment. (B) Image obtained following staged embolization showing significant reduction in nidus volume (see also Fig. 30.4D). (C) Image obtained after planned staged stereotactic radiosurgery showing further reduction in nidus volume.

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patients undergoing treatment, again supporting a possible palliative role for partial treatment. Treatment did not significantly affect the hemorrhage risk.

Conclusion Giant iAVMs represent a unique technical and management challenge. The hemorrhage rate of these lesions is not higher than that of smaller iAVMs, with some studies suggesting that giant iAVMs actually have a more benign course than smaller lesions. This observation should be counterbalanced with the often young age at presentation and the frequency of epilepsy and progressive neurologic deficit associated with giant iAVMs. Multimodality treatment aimed at palliation of symptoms can be successful, although most series and especially surgical series report a high rate of treatment-related morbidity and mortality. Since these studies often include long-term follow-up, it is unclear whether this morbidity and mortality represent the natural history of the disease or true treatment-related effects. Intention-to-treat analysis and cohort studies comparing observation and treatment arms suggest no significant difference in outcome, with some conflicting data suggesting that partial treatment may worsen the rate of hemorrhage. Taken together, the best available data support treatment of iAVM-associated aneurysms, palliative partial treatment of giant iAVMs for patients with progressive deficits or intractable seizures, and multimodality treatment aimed at cure only used for those patients with decline due to recurrent hemorrhage. REFERENCES 1. Kim H, Abla AA, Nelson J, et al. Validation of the supplemented Spetzler-Martin grading system for brain arteriovenous malformations in a multicenter cohort of 1009 surgical patients. Neurosurgery. 2015;76(1):25–31; discussion 31–32; quiz 32–33. https://doi.org/10.1227/neu.0000000000000556. 2. Yang W, Wei Z, Wang JY, et al. Long-term outcomes of patients with giant intracranial arteriovenous malformations. Neurosurgery. 2016;79(1):116–124. https://doi.org/10.1227/ neu.0000000000001189. 3. Zhao J, Yu T, Wang S, Zhao Y, Yang WY. Surgical treatment of giant intracranial arteriovenous malformations. Neurosurgery. 2010;67(5):1359–1370; discussion 1370. https:// doi.org/10.1227/neu.0b013e3181eda216.

303 4. Chang SD, Marcellus ML, Marks MP, Levy RP, Do HM, Steinberg GK. Multimodality treatment of giant intracranial arteriovenous malformations. Neurosurgery. 2003;53(1):1–11; discussion 11– 13. https://doi.org/10.1227/01.neu.0000068700.68238.84. 5. Han PP, Ponce FA, Spetzler RF. Intention-to-treat analysis of Spetzler-Martin grades IV and V arteriovenous malformations: natural history and treatment paradigm. J Neurosurg. 2003;98(1):3–7. https://doi.org/10.3171/jns.2003.98.1.0003. 6. Mohr JP, Overbey JR, Hartmann A, et al. Medical management with interventional therapy versus medical management alone for unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre, non-blinded, randomised controlled trial. Lancet Neurology. 2020;19(7):573–581. https:// doi.org/10.1016/s1474-4422(20)30181-2. 7. Kusske JA, Kelly WA. Embolization and reduction of the “steal” syndrome in cerebral arteriovenous malformations. J Neurosurg. 1974;40(3):313–321. https://doi.org/10.3171/ jns.1974.40.3.0313. 8. Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg. 1986;65(4):476–483. https://doi.org/10.3171/jns.1986.65.4.0476. 9. Rangel-Castilla L, Spetzler RF, Nakaji P. Normal perfusion pressure breakthrough theory: a reappraisal after 35 years. Neurosurg Rev. 2015;38(3):399–404; discussion 404–405. 10. Spetzler RF, Martin NA, Carter LP, Flom RA, Raudzens PA, Wilkinson E. Surgical management of large AVM’s by staged embolization and operative excision. J Neurosurg. 1987;67(1): 17–28. https://doi.org/10.1007/s10143-014-0600-4. 11. Jizong Z, Shuo W, Jingsheng L, Dali S, Yuanli Z, Yan Z. Combination of intraoperative embolisation with surgical resection for treatment of giant cerebral arteriovenous malformations. J Clin Neurosci. 2000;7(Suppl 1):54–59. https://doi. org/10.1054/jocn.2000.0713. 12. Sirin S, Kondziolka D, Niranjan A, Flickinger JC, Maitz AH, Lunsford LD. Prospective staged volume radiosurgery for large arteriovenous malformations: indications and outcomes in otherwise untreatable patients. Neurosurgery. 2006;58(1):17–27. https://doi.org/10.1227/01.neu.0000190653.42970.6b. 13. Veznedaroglu E, Andrews DW, Benitez RP, et al. Fractionated stereotactic radiotherapy for the treatment of large arteriovenous malformations with or without previous partial embolization. Neurosurgery. 2004;55(3):519–531. https://doi. org/10.1227/01.neu.0000134285.41701.83. 14. Xiao F, Gorgulho AA, Lin C-S, et al. Treatment of giant cerebral arteriovenous malformation: hypofractionated stereotactic radiation as the first stage. Neurosurgery. 2010;67(5): 1253–1259; discussion 1259. https://doi.org/10.1227/neu. 0b013e3181efbaef. 15. Russell D, Peck T, Ding D, et al. Stereotactic radiosurgery alone or combined with embolization for brain arteriovenous malformations: a systematic review and meta-analysis. J Neurosurg. 2018;128(5):1338–1348. https://doi.org/10.3171/2016.11. jns162382. 16. Abla AA, Rutledge WC, Seymour ZA, et al. A treatment paradigm for high-grade brain arteriovenous malformations: volume-staged radiosurgical downgrading followed by microsurgical resection. J Neurosurg. 2015;122(2):419–432. https:// doi.org/10.3171/2014.10.jns1424.

Chapter 31

Treatment of Eloquent Cortex AVMs Nikolaos Mouchtouris, Rizwan Tahir, and Robert H. Rosenwasser

Chapter Outline Introduction Eloquence in AVM Grading Systems Preoperative Evaluation of Eloquence Intraoperative Motor and Sensory Mapping Intraoperative Speech Monitoring Intraoperative Visual Mapping Neuromonitoring During Endovascular Interventions Conclusion

Introduction Arteriovenous malformations (AVMs) become even more challenging to treat when they are located in eloquent cortex. Eloquent cortex is defined as cortex with specific functions, loss of which would result in disabling neurological deficits: the primary motor cortex in the precentral gyrus, the primary sensory cortex in the postcentral gyrus, the supplementary motor area, the primary visual cortex in the medial occipital lobe, the language cortex in the dominant inferior frontal and superior temporal gyri (Broca’s area and Wernicke’s area, respectively), the hypothalamus, the thalamus, the internal capsule, the brainstem, the cerebellar peduncles, and the deep cerebellar nuclei.1 Involvement of these locations increases the risk of operative morbidity and postoperative neurological deficits, as demonstrated by the Spetzler-Martin grading system.1 In addition to the nidus size of an AVM and its drainage pattern, eloquence is considered a significant predictor of operative morbidity and must be given the utmost consideration by both the patient and the neurosurgeon. 304

Disruption of white matter tracts can be equally as devastating as disruption of eloquent cortex. Even though involvement of fiber tracts is not included in any of the AVM grading systems, there are several tracts that need to be taken into consideration when assessing the risks of surgery and selecting the treatment modality and operative approach. The internal capsule encompasses the corticobulbar and corticospinal tracts, which travel from the motor cortex to the brainstem and the spinal cord, respectively. The internal capsule also contains the thalamocortical somatosensory tracts, which travel from the ventroposterior nucleus of the thalamus to the postcentral gyrus. Optic radiations carry visual information from the lateral geniculate nucleus to the primary visual cortex. The uncinate fasciculus connects the frontal lobe with the temporal lobe and plays a major role in language, memory, and emotions.2 The superior longitudinal fasciculus contains fibers involved in language and motor function. Lastly, damaging structures such as the corpus callosum and the fornix can also be debilitating, causing disconnection syndromes and memory dysfunction, respectively. A thorough understanding of not only the location of the AVM but also its arterial feeders and venous drainage patterns is imperative. Determining whether the feeding arteries have branches that are en passage, giving supply to eloquent cortex rather than the AVM nidus, is necessary to prevent complications. Similarly, understanding venous drainage patterns and ensuring the preservation of normal draining veins of eloquent structures during the final stages of AVM resection is crucial. Assessment of involved vascular territories remains a critical component of the treatment planning process.

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Eloquence in AVM Grading Systems A number of AVM grading systems are available to guide the neurosurgeon when deciding on the need for treatment and identifying the optimal treatment modality. In addition to the original Spetzler-Martin grading system, the grading systems proposed by Lawton et al. (the Lawton-Young supplementary grading scale),3 Pasqualin et al.,4 and Shi and Chen5 also incorporate eloquence in the grading. Other classifications, such as those of Drake,6 Luessenhop and Gennarelli,7 and Nataf et al.,8 do not include eloquence in their grading. While each grading system offers a different point of view, there is no doubt at this point that eloquence should be taken into consideration in decision-making for AVM treatment.

Preoperative Evaluation of Eloquence Functional MRI, positron emission tomography (PET), magnetic source imaging, and Wada testing enable neurosurgeons to confidently determine the proximity of a lesion to eloquent areas. In addition, diffusion tensor imaging and 3D fiber tractography, which have become staples in glioma surgery, can also help with preoperative planning for AVM surgery, allowing identification of white matter fibers that are either displaced by or interspersed within an AVM nidus. The choice of preoperative imaging depends on the patient’s neurological exam findings and the urgency of treatment. High-quality imaging is not always feasible; however, close collaboration with radiology is necessary in order to obtain imaging that will benefit clinical and operative decision-making.

Intraoperative Motor and Sensory Mapping Intraoperative mapping has not been historically used as frequently in intracranial AVM (iAVM) surgery as in the neurosurgical treatment of intracranial tumors, yet its use can be of tremendous help. In contrast to tumor resection, in AVM resection, awake craniotomy is not a favorable option due to the greater complexity, longer duration, and greater blood loss. Intraoperative stimulation, however, is helpful when resecting a diffuse

Pearls • Eloquent (functional) cortex includes motor, sensory, visual, and speech areas as well as the thalamus, brainstem, and cerebellar peduncles. • Awake craniotomy to map functional cortex is rarely used in AVM surgery. • Noninvasive or minimally invasive methods to define functional cortex include MRI, functional MRI, diffusion tensor imaging, and Wada testing. • Functional mapping is of equal importance to all treatment modalities: observation, stereotactic radiosurgery, embolization, and surgery. • Phase reversal of somatosensory evoked potentials, motor evoked potentials, and visual evoked potentials can be used under general anesthesia.

iAVM without clear borders in order to minimize the risk of a disabling deficit from pial transgression and parenchymal circumdissection. Cortical stimulation requires total intravenous anesthesia with avoidance of muscle relaxant and paralytic agents other than during intubation. Once the cortex is exposed, bipolar electrodes are placed on the cortical surface, and the stimulation is administered with biphasic square wave pulses of 4 milliseconds’ duration at 60 Hz, as described by Gabarrós et al., who report using amplitudes ranging from 1.5 to 8 mA.9 Cortical stimulation can, however, induce seizures, and it is therefore necessary to have ice-cold saline available as well as to maintain a good line of communication with the anesthesiologist so that a bolus of intravenous propofol can be administered when neuromonitoring suggests seizure activity (1 mg/kg).9 The criteria for intraoperative motor mapping are not established in the literature and vary by treating neurosurgeon. Gabarrós et al. proposed the following algorithm based on the preoperative fMRI: Motor mapping is utilized when the AVM is in the gyrus adjacent to the motor function area. If the motor function area is at least one gyrus away, then no motor mapping is used. If the AVM is on the same gyrus as motor function, resection is considered high risk and other options are to be considered, such as observation or radiosurgery.9 Additionally, motor mapping is

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Intraoperative Speech Monitoring

preferred in patients with unruptured iAVMs; if an iAVM is ruptured, the hemorrhage creates a plane that makes the dissection easier while it makes monitoring evoked potentials more difficult due to the tissue injury sustained. An example of a case where motor mapping would be necessary is displayed in Fig. 31.1.

A

C

Speech monitoring requires performing an awake craniotomy with repeated cortical stimulation while the patient repeats a variety of language tasks. These tasks need to be tested preoperatively to establish the ­ patient’ s baseline speech function, often necessitating

B

D

Fig. 31.1 Left parietal AVM with arterial supply from middle cerebral artery (MCA) and anterior cerebral artery (ACA) branches and venous drainage through an enlarged vein of Trolard to the superior sagittal sinus. (A and B) CT angiography images (axial [A] and sagittal [B] views) demonstrating an AVM located in the postcentral gyrus/primary sensory cortex. (C) Digital subtraction angiogram (lateral projection of left internal carotid artery injection) showing primary arterial supply from left MCA branches and drainage through an enlarged vein of Trolard to the superior sagittal sinus. (D) Intraoperative image of left parietal AVM after Onyx (Medtronic, Minneapolis, MN) embolization of ACA feeders. In this case, microsurgical excision would be best carried out with intraoperative neuromonitoring using somatosensory and motor evoked potentials, with phase reversal confirming the location of the central sulcus.

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a multidisciplinary approach with participation of certified speech and language pathologists. Total intravenous anesthesia is necessary for an awake craniotomy, with intravenous propofol and remifentanil commonly used. In these cases, it is necessary to anesthetize the scalp around the pin sites, using lidocaine or bupivacaine with epinephrine. The language tasks assessed vary based on the location of the AVM. Depending on the area of investigation, counting, naming, reading, repetition, and syntax comprehension are some of the tasks commonly used. Each cortical area is stimulated with either monopolar or bipolar electrodes for 3 seconds at least three times and the tasks are repeated at each stimulation. A functional speech area is identified if a language deficit such as speech arrest, anomia, or alexia is noted in at least two of the three stimulations. Cannestra et al.10 created a classification that groups patients by proximity of their AVM to the language areas as determined by preoperative fMRI. Group 1 included patients whose language activation area was at least one gyrus away from the AVM. These cases (n = 10) were deemed low risk, and the patients underwent craniotomy with general anesthesia. Group 2 included patients whose AVMs were associated with the language area and were deemed inoperable. These patients (n = 5) were offered radiosurgery. Group 3 included patients whose AVMs were adjacent to the language area; these cases were considered intermediate risk, and the patients (n = 5) therefore were considered to be good candidates for awake craniotomy with language mapping. An example of a case where speech mapping would be necessary is displayed in Fig. 31.2.

Intraoperative Visual Mapping Monitoring of visual evoked potentials (VEPs) has been utilized in patients with occipital lobe lesions. Repetitive light stimuli are displayed to evoke a response on electroencephalography (EEG). Latency and decrease in amplitude of the VEP waveform indicate vision loss. Visual cortex mapping can be performed with direct electrical stimulation. A series of pictures are shown to the patient during the awake part of the craniotomy, and the patient is asked to report any ­ visual disturbances in the visual field quadrant at risk of impairment depending on the location of lesion. If

phosphenes are reported in the quadrant at risk but the rest of the quadrants are intact, the cortical area stimulated is eloquent.

Neuromonitoring During Endovascular Interventions Eloquent AVMs pose a treatment challenge not only for resection but also for endovascular embolization. Performing cerebral angiography with the patient awake, performing provocative testing, or using intraoperative neuromonitoring can be helpful in demonstrating the safety of embolizing feeding vessels and minimizing the risk of long-term postoperative deficits. Paulsen et al.11 studied 17 patients with rolandic AVMs who underwent superselective sodium amobarbital testing prior to embolization. In two of the cases, the AVMs were not embolized due to a significant decline in the somatosensory evoked potentials (SSEPs). In one of these cases, the patient was awake during the testing and was noted to have a neurological deficit; in the other case, the testing was performed under general anesthesia and the SSEP decrease was the only change. Of the patients treated, none developed permanent postoperative deficits, although 23% had transient symptoms that resolved within 24 hours. The same group also published their experience with endovascular treatment of basal ganglia and thalamic AVMs.12 Embolization was performed when the results of sodium amobarbital testing were negative, and new-onset postoperative deficits were reported in 14.3% of patients. Similarly, Moo et al.13 performed provocative testing with amobarbital in 29 patients with AVMs. In two cases, the testing results were positive, and those patients were not treated. The rest of the patients were treated with embolization and did not develop any postoperative deficits.13 Furthermore, Rauch et al.14 demonstrated the importance of multimodal neuromonitoring for the safe treatment of eloquent AVMs. They performed a total of 109 Amytal tests on 33 patients with cerebral AVMs. Of the 23 Amytal tests with positive results based on clinical exam or EEG, only 12 (52%) had a clinical exam change, while 11 (48%) had a change in EEG without a clinical exam change. None of the patients in this case series developed any permanent postoperative deficit.

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A

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D

Fig. 31.2 Left frontoparietal AVM with arterial supply from middle cerebral artery (MCA) branches and venous drainage through enlarged vein of Trolard, vein of Labbé, and superficial sylvian veins. (A and B) CT angiography images (axial [A] and sagittal [B] views) demonstrating an AVM located in the inferior parietal lobule just posterior to the central sulcus in Wernicke’s area. (C) Digital subtraction angiogram (lateral projection of left internal carotid artery injection) showing primary arterial supply from both superior- and inferior-division MCA branches and drainage through enlarged vein of Trolard, vein of Labbé, and superficial sylvian veins. (D) Intraoperative image of left frontoparietal AVM. In this case, microsurgical excision would be best carried out with intraoperative neuromonitoring using somatosensory and motor evoked potentials; awake speech mapping could also be considered due to the AVM location in Wernicke’s area.

Conclusion While the treatment of AVMs in eloquent areas of the brain is challenging, there are a number of tools available to the neurosurgeon to minimize the risk of complications. Preoperative functional imaging, provocative testing, and intraoperative mapping significantly aid the microsurgical resection and

endovascular embolization of AVMs in eloquent areas. REFERENCES 1. Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg. 1986;65(4):476–483. https://doi.org/10.3171/jns.1986.65.4.0476. 2. Von Der Heide RJ, Skipper LM, Klobusicky E, Olson IR. Dissecting the uncinate fasciculus: disorders, controversies and

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Treatment of Eloquent Cortex AVMs a hypothesis. Brain. 2013;136(Pt 6):1692–1707. https://doi. org/10.1093/brain/awt094. Lawton MT, Kim H, McCulloch CE, Mikhak B, Young WL. A supplementary grading scale for selecting patients with brain arteriovenous malformations for surgery. Neurosurgery. 2010;66(4):702–713. https://doi.org/10.1227/01. NEU.0000367555.16733.E1. Pasqualin A, Barone G, Cioffi F, Rosta L, Scienza R, Da Pian R. The relevance of anatomic and hemodynamic factors to a classification of cerebral arteriovenous malformations. Neurosurgery. 1991;28(3):370–379. https://doi. org/10.1097/00006123-199103000-00006. Shi YQ, Chen XC. A proposed scheme for grading intracranial arteriovenous malformations. J Neurosurg. 1986;65(4):484– 489. https://doi.org/10.3171/jns.1986.65.4.0484. Drake CG. Cerebral arteriovenous malformations: considerations for and experience with surgical treatment in 166 cases. Clin Neurosurg. 1979;26:145–208. https://doi.org/10.1093/ neurosurgery/26.cn_suppl_1.145. Luessenhop AJ, Gennarelli TA. Anatomical grading of supratentorial arteriovenous malformations for determining operability. Neurosurgery. 1977;1(1):30–35. https://doi. org/10.1227/00006123-197707000-00007. Nataf F, Schlienger M, Bayram M, Ghossoub M, George B, Roux FX. Microsurgery or radiosurgery for cerebral arteriovenous malformations? A study of two paired series. Neurosurgery. 2007;61(1):39–49; discussion 49–50. https:// doi.org/10.1227/01.neu.0000279722.60155.d3. Gabarrós A, Young WL, McDermott MW, Lawton MT. Language and motor mapping during resection of brain

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arteriovenous malformations: indications, feasibility, and utility. Neurosurgery. 2011;68(3):744–752. https://doi.org/10.1227/ NEU.0b013e318207a9a7. Cannestra AF, Pouratian N, Forage J, Bookheimer SY, Martin NA, Toga AW. Functional magnetic resonance imaging and optical imaging for dominant-hemisphere perisylvian arteriovenous malformations. Neurosurgery. 2004;55(4):804– 812; discussion 812–814. https://doi.org/10.1227/01. neu.0000137654.27826.71. Paulsen RD, Steinberg GK, Norbash AM, Marcellus ML, Lopez JR, Marks MP. Embolization of rolandic cortex arteriovenous malformations. Neurosurgery. 1999;44(3):479–484; discussion 484–486. https://doi. org/10.1097/00006123-199903000-00022. Paulsen RD, Steinberg GK, Norbash AM, Marcellus ML, Marks MP. Embolization of basal ganglia and thalamic arteriovenous malformations. Neurosurgery. 1999;44(5):991–996; discussion 996–997. https://doi. org/10.1097/00006123-199905000-00031. Moo LR, Murphy KJ, Gailloud P, Tesoro M, Hart J. Tailored cognitive testing with provocative amobarbital injection preceding AVM embolization. AJNR Am J Neuroradiol. 2002;23(3):416–421. Rauch RA, Vinuela F, Dion J, et al. Preembolization functional evaluation in brain arteriovenous malformations: the ability of superselective Amytal test to predict neurologic dysfunction before embolization. AJNR Am J Neuroradiol. 1992;13(1):309–314.

Chapter 32

Posterior Fossa AVMs Hubert Lee, S. Uzair Ahmed, and Gary K. Steinberg

Chapter Outline Epidemiology and Natural History Anatomy and Classification Patient Selection for Treatment Perioperative Considerations Surgical Technique Postoperative Management and Considerations Outcomes and Prognosis Following Microsurgical Resection Conclusion

Epidemiology and Natural History Posterior fossa AVMs are rare lesions. Previous series have estimated that they make up approximately 15%–18% of all intracranial AVMs.1 This group can be further divided into brainstem and cerebellar AVMs. Cerebellar AVMs (Fig. 32.1) represent the majority of posterior fossa AVMs, comprising approximately 70% of these lesions.2 Brainstem AVMs have separately been estimated to represent only 6%–8%.3 Together, these AVMs exhibit a higher rate of hemorrhage than supratentorial AVMs, and bleeding represents the most predominant cause for presentation. In a multicenter series of cerebellar AVMs, 71% presented with 2 ­ hemorrhage. An even higher rate of hemorrhagic presentation, 92%, was observed in Solomon and colleagues’ series of brainstem AVMs.4 This is intuitive, considering that the annual rate of hemorrhage in brainstem AVMs is estimated to be 15%–17.5%.3 Following rupture, patients with posterior fossa AVMs experience worse outcomes compared to those with supratentorial AVMs.5 In the absence of hemorrhage, patients with posterior fossa AVMs may present with 310

headache, facial pain, hemifacial spasm, ataxia, sensorimotor deficits, and/or hydrocephalus.3,6 Progressive neurological deficits may occur as a result of vascular steal, venous hypertension, or local mass effect.7

Anatomy and Classification The anatomy of the posterior fossa arteries and their supply is relevant to the location and supply of brainstem and cerebellar AVMs. The major vessels supplying the posterior fossa are the superior cerebellar artery (SCA), anterior inferior cerebellar artery (AICA), and posterior inferior cerebellar artery (PICA). The SCA arises from the basilar artery as a single trunk but may be duplicated or occasionally arise from the posterior cerebral artery (PCA). It courses around the brainstem underneath the tentorial free edge, below the oculomotor and trochlear nerves but above the level of the trigeminal nerve. The SCA bifurcates into caudal and rostral trunks near the trigeminal nerve exit zone, with the rostral trunk supplying the superior vermis and some of the superior medial hemisphere, and the caudal trunk supplying the remaining tentorial surface of the cerebellar medial and lateral hemispheres.8 The AICA arises in the lower third of the basilar artery and may be duplicated or, rarely, absent. It crosses the lateral surface of the pons, supplying perforating branches to the lateral pons. The AICA is composed distally of a medial and a lateral trunk. The medial trunk supplies the inferior petrosal surface of the lateral cerebellum as well as the choroid plexus in the foramen of Luschka. The lateral trunk perfuses the cerebellopontine angle, giving off the internal auditory artery and subarcuate artery, which anastomoses with branches of

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Pearls

Fig. 32.1 A posterior fossa, cerebellar hemispheric AVM fed by the major branches (anterior inferior, posterior inferior, and superior cerebellar arteries) and draining into the transverse sinus. AICA, Anterior inferior cerebellar artery; PICA, posterior inferior cerebellar artery; SCA, superior cerebellar artery.

the stylomastoid artery.8 The PICA originates from the distal vertebral artery, typically the V4 segment, but can arise extradurally in up to 10% of cases. It courses around the medulla, supplying perforating branches from the anterior and lateral medullary segments. The vessel then loops inferiorly toward the foramen magnum and subsequently courses cranially to the midline ­ between the two cerebellar tonsils, reaching the roof of the fourth ventricle. This segment provides branches to the choroid plexus. It continues caudally over the suboccipital surface of the cerebellum, supplying the cerebellar tonsils, vermis, and occipital surface of the hemispheres. The PICA size and territory exist in ­ balance with those of the AICA, and if one is larger, the other is typically smaller or absent.8 Cerebellar AVMs can be classified using the cerebellar surfaces and hemispheres. Traditionally this categorization comprised lesions of the tentorial, petrosal, and occipital surfaces, but it has been expanded to include vermian and tonsillar AVMs.6 Brainstem AVMs are classified based on the anatomical segment and pial surface involved.3 Of greater relevance to clinical decision-making, though, is whether the AVM is superficial or deep within the parenchyma, as this

• Compared to supratentorial AVMs, infratentorial AVMs, including those in brainstem and cerebellar locations, present with a higher rate of hemorrhage and are associated with less favorable outcomes, particularly in patients of advanced age, with poor preoperative neurological grade, and requiring emergent resection following rupture. • Acute management of ruptured AVMs should focus on maintaining normal intracranial pressure, strict blood pressure control, and obtaining a catheter digital subtraction cerebral angiogram to understand the angioarchitecture of the malformation in addition to identifying intranidal/ perinidal aneurysms as sources of hemorrhage and targets for immediate treatment. • Endovascular therapy plays a primary role in the acute treatment of flow-related and intranidal aneurysms suspected to be the source of hemorrhage in ruptured posterior fossa AVMs, in addition to being an adjunctive tool for reducing the size of large AVMs and eliminating deep arterial feeders prior to resection. • Compact and superficial pial brainstem AVMs may be amenable to microsurgical resection, whereas parenchymal or large brainstem malformations are better candidates for stereotactic radiosurgery. • Microsurgical resection as a primary treatment modality for posterior fossa AVMs achieves a high rate of angiographic cure (up to 90%) with careful patient selection and utilization of intraoperative adjuncts, including strict blood pressure control, mild hypothermia, image-guided frameless stereotaxis, electrophysiological monitoring, and intraoperative angiography.

dictates surgical accessibility. Superficial or pial-based brainstem AVMs may present on the surface of the tectal plate, the cerebellar peduncles, the floor of the fourth ventricle, and the anterior or lateral surfaces of the midbrain, pons, or medulla. These classification systems aid in predicting the AVM’s arterial feeders and venous drainage in addition to selecting a surgical approach to optimize exposure of the malformation for resection.

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Patient Selection for Treatment INDICATIONS AND CONTRAINDICATIONS FOR SURGERY Brainstem and cerebellar AVMs have a higher annual rate of hemorrhage compared to supratentorial malformations (up to 15.1% and 11.6%, respectively) and should be considered for resection particularly if ruptured, low grade, or accessible from a pial or ependymal surface.5,9 Other indications for surgery include progressive neurological decline and residual AVM following stereotactic radiosurgery (SRS) or embolization. The risk of perioperative morbidity and mortality increases with AVMs of larger size, presence of deep venous drainage, and AVM location in an area of eloquence, as estimated by the Spetzler-Martin grading scale.10 The predictive accuracy of this grading system, however, has been demonstrated to be reduced when applied to AVMs in the cerebellum. This is likely owing to the fact that cerebellar AVMs, as compared to cerebral AVMs, commonly drain into the galenic system and reside within the small-volume space that is the posterior fossa.6 These factors, as well as the proximity to the brainstem and its delicate angioarchitecture, elevate the technical challenge of resection. A novel grading system was proposed by Nisson et al., who analyzed 120 cases of cerebellar AVMs treated with microsurgery and found that poor outcome was significantly associated with preoperative neurological status, the need for emergency surgery, presence of deep venous drainage, and advanced age.2 The 33% rate of poor outcome in the lowest-risk group is comparable to the morbidity predicted for treatment of AVMs with high Spetzler-Martin grades (grade IV or V), emphasizing the difficulty in treating these lesions. The association of outcome to the urgency of intervention also suggests that early diagnosis and treatment prior to rupture may improve the chance of achieving a favorable outcome. This updated grading scale also highlights that patients who present with poor neurological grade or are of advanced age are poor surgical candidates. Eloquence in the cerebellum is limited mostly to the deep nuclei and was not found to be a significant predictor. Brainstem AVMs are typically classified as superficial or parenchymal. This distinction is critical as

resection of parenchymal AVMs is associated with a high risk of neurological injury, rendering these lesions better treated with SRS. One exception would be in the setting of hemorrhage, where the resolving hematoma cavity creates a plane of dissection. As a result, mainly AVMs that are located on the pial surface and low grade are considered for surgery. Patients with higher-grade or larger AVMs may benefit instead from SRS with or without prior embolization. Following hemorrhage, resection is usually performed within 4–8 weeks, providing a time period for the hematoma to liquefy, subsequent cerebral edema to diminish, and cerebral autoregulation to recover. This delay improves the ease and safety of surgery while exposing the patient to a minor risk of repeat hemorrhage, as the rate is modestly elevated compared to ruptured intracranial aneurysms. Acute management focuses on cerebrospinal fluid (CSF) diversion for hydrocephalus, reduction of intracranial pressure, and strict blood pressure control. An early digital subtraction angiogram is necessary to understand the AVM’s angioarchitecture if emergent hematoma evacuation becomes necessary, but also to identify the presence of flow-related or intranidal aneurysms as the source of hemorrhage, which requires urgent endovascular or surgical treatment. Embolic agents include coils or liquid embolic materials such as N-butyl cyanoacrylate (NBCA) or Onyx (Medtronic Inc., Minneapolis, MN). ROLE FOR ENDOVASCULAR THERAPY Endovascular therapy plays a critical role in the early treatment of flow-related and intranidal aneurysms in ruptured posterior fossa AVMs. These aneurysms are more commonly found in association with posterior fossa AVMs compared to supratentorial AVMs and are seen as weak points for potential recurrent hemorrhage.11 The endovascular approach provides a means of occluding the aneurysm without the risk of a craniotomy while the cerebellum is edematous or having to address the AVM emergently. Embolization is also beneficial as a preoperative adjunct to eliminate arterial pedicles and reduce the overall blood supply to the AVM. This aids in the reduction of the overall nidus size for larger AVMs to a surgically accessible

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size, while minimizing intraoperative blood loss. Deep feeders should be targeted preferentially, as these vessels are exposed later during the resection. It is critical to perform embolization as distally as possible to avoid occluding branches supplying the deep cerebellar nuclei or brainstem, ensuring a sufficient safety margin for reflux of the embolic agent. While principally utilized as an adjunctive therapy, endovascular therapy with the intent to cure has been attempted successfully mostly for small AVMs supplied by a single, large-diameter arterial feeder, with a small nidus, and with sufficient intraoperative visualization of the draining veins. In a large series of 69 posterior fossa AVMs treated with transarterial embolization over a mean of 2.1 sessions, angiographic cure was achieved in 72.5%.12 In 21.7% of the cases, there was persistent residual AVM that was subsequently treated with microsurgical resection or SRS. Although 78.3% of the patients achieved a modified Rankin Scale score of 0–2 at last follow-up, 8.8% of patients had a temporary or permanent neurological deficit or died postoperatively. A more recent systematic review including 598 iAVMs treated with embolization demonstrated an even higher complication rate of 24.1%, with hemorrhage secondary to vessel perforation, venous occlusion, or nontarget embolization accounting for a majority of cases.13 This highlights the greater risk of treatment when endovascular therapy is utilized with curative intent as opposed to being used as an adjunct. ROLE FOR STEREOTACTIC RADIOSURGERY Deep-seated AVMs within the parenchyma of the brainstem are inaccessible with surgery, outside the coexistence of a superficially tracking hematoma, but are excellent candidates for SRS. While this has been the major indication for this treatment modality in the management of posterior fossa AVMs, its use has expanded as a stand-alone or multimodal strategy to address cerebellar AVMs, which were traditionally surgical targets given their more superficial location. Angiographic obliteration rates ranging from 62.5% to 73% have been reported in treating cerebellar AVMs with a median nidus size of 2–4 cm and a majority presenting with hemorrhage.11,14,15 It is recommended that SRS for ruptured posterior fossa AVMs be delayed

by 6–12 weeks to ensure accurate targeting of the nidus, which may be compressed or obscured by the hematoma.15 Higher rates of complete obliteration were observed in younger patients, lesions not treated with preoperative embolization, and smaller nidus diameter. The major disadvantage of SRS is the latency period to AVM occlusion, a median of 60 months, and therefore a delay in hemorrhagic protection.15 The annual rate of hemorrhage during this interval following SRS has been observed to be 0.85%–2% per year.11,14,15 One series reported a delayed hemorrhage occurring 9 years after treatment and angiographic evidence of complete cure with no residual lesion.14 Symptomatic perinidal T2 hyperintensities or radiation-induced changes are typically transient but remain permanent in 1.2%–3% of cases, typically occurring around 12 months after treatment.11,15 In a large, multicenter series of 162 cerebellar AVMs, 62.2% of patients achieved a favorable outcome with complete obliteration in the absence of hemorrhage or fixed deficit.15 SRS is also indicated for patients with significant comorbidities rendering them poor candidates for surgical treatment or for residual posterior fossa AVMs following embolization or microsurgical resection.

Perioperative Considerations ANESTHESIA Microsurgical resection of posterior fossa AVMs is performed under general anesthesia. Strict blood pressure control should be maintained throughout the procedure. The mean arterial pressure (MAP) should be kept between 70 and 80 mm Hg during the initial exposure and reduced to 60–70 mm Hg during the malformation resection. We also routinely employ mild hypothermia, using a cooling blanket and infusion of cold intravenous fluids to achieve a core body temperature of 33–34°C, which has been demonstrated experimentally to protect against cerebral ischemia.16 Brain relaxation with mild hyperventilation, targeting a PaCO2 of 35 mm Hg, facilitates intraoperative visualization while minimizing the need for retraction. This can be supplemented with CSF release from neighboring cisterns, lumbar subarachnoid drainage, CSF diversion through a Fraser burr-hole ventriculostomy,

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or by administering hyperosmolar agents or diuretics. Placing the patient in a sitting or semisitting position allows the cerebellum to fall away with gravity, improving access to the tentorial surface of the cerebellum and dorsal midbrain; however, it increases the risk of air embolism. Use of a precordial Doppler ultrasound probe and insertion of a central venous catheter positioned at the junction of the superior vena cava and right atrium for surveillance and therapeutic access are recommended in these cases. Alternatively, the Concorde modified prone position provides excellent access to these structures and is preferable in our experience. ELECTROPHYSIOLOGICAL MONITORING Electrophysiological monitoring provides real-time surveillance to minimize the risk of ischemic or direct neurological injury during resection.17 For patients with posterior fossa AVMs, we routinely monitor bilateral motor, somatosensory, and brainstem auditory evoked potentials. Electromyography of motor cranial nerves is often recorded in cases of brainstem and anteriorly situated AVMs where the dissection approaches their cisternal course or root entry/exit zones, in addition to providing feedback on the effects of cerebellar retraction. Monopolar or bipolar stimulation can be used for mapping, particularly in the rhomboid fossa to identify cranial nerve motor nuclei and fibers, to select a safe entry zone into the brainstem. IMAGING ADJUNCTS Frameless stereotaxis through the use of intraoperative image-guided navigation allows precise planning of the surgical exposure, including the incision, craniotomy, and durotomy, to optimize the surgical corridor and avoid inadvertent entry into the neighboring sinuses specifically during occipital and suboccipital approaches. Deep-seated AVMs can also be localized with an accuracy of 1–2 mm on most modern systems guiding the subpial dissection. Once the AVM resection is complete, intraoperative catheter angiography can be performed to ensure the absence of residual malformation. Arterial sheath placement that allows intraoperative access while maintaining patency in the prone positioning can be achieved either with a left common femoral or radial artery puncture. The transfemoral approach, described previously

for intraoperative spinal angiography, uses a long, kink-resistant sheath (such as the 5F 45-cm ArrowFlex sheath from Teleflex Medical, NC) inserted with enough external length to allow it to be wrapped around to the lateral thigh.18 This is connected to a heparinized saline flush throughout the procedure. Transradial angiography requires the tucked arm to be internally rotated with the thumb oriented upward, exposing the distal ventral forearm.19 The laterality of puncture is ipsilateral to the vertebral artery of interest. For both approaches, the sheath is inserted following general anesthesia with the patient supine prior to final positioning. In our experience, intraoperative indocyanine green (ICG) intravenous angiography does not provide accurate determination of complete AVM resection due to incomplete penetrance of the dye within parenchyma. We have also found 3D virtual reality imaging (such as that offered by Surgical Theater Inc., Cleveland, OH), with overlay of diffusion tensor imaging fiber tractography and functional MRI data to be extremely helpful in understanding the 3D anatomy of the AVM. This includes its arterial feeders, draining veins, and relationship to critical fiber pathways, functional brain regions, and adjacent bony as well as dural structures.

Surgical Technique GENERAL PRINCIPLES A large craniotomy and wide dural opening are necessary to allow circumferential access to the AVM and its supply. The arterial feeders and venous outflow should be identified and exposed early, noting that superficial supply often arises from branches of the SCA and PICA to cerebellar AVMs and the nearest vertebrobasilar branch for brainstem AVMs. For AVMs not visualized on the pial surface, the nidus can be found by following the draining vein in a retrograde fashion without compromising it prematurely. Care must be taken not to mistake arterialized veins for arteries, as early division can precipitate AVM swelling and rupture. This distinction can be assisted with the use of ICG angiography or a Charbel Micro-Flowprobe (Transonic Systems Inc., Ithaca, NY), which measures both direction and quantitation of flow. This is particularly relevant for cerebellar AVMs that drain through

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hemispheric veins to the transverse or straight sinus, which are often encountered soon after the dural opening. Once the superficial aspect of the AVM is isolated, the dissection is then deepened circumferentially within the gliotic plane between the nidus and brain parenchyma or hematoma cavity. To avoid injury and subsequent postoperative neurological deficit when the adjacent tissue is eloquent, such as in the brainstem, deliberate exposure on the surface or even slight infringement into the nidus is performed. Progressive disconnection of feeding arteries is carried out as close to the nidus as possible to avoid sacrifice of en passage arteries that supply the normal neighboring brain. Larger veins should also be spared until the arterial input is completely disrupted and the nidus freed; otherwise significant to catastrophic hemorrhage can occur. In this situation, it is critical to expeditiously identify and obliterate any remaining sources of arterial input to the AVM rather than attempting to coagulate areas of AVM or adjacent parenchymal bleeding. The more routine bleeding encountered during the resection, typically due to entry into the nidus, can be managed with bipolar cautery (irrigating or nonstick) or tamponading with a hemostatic agent. Deep feeding arteries arising from ependymal or white matter perforators can also pose a challenge for hemostasis, as they are small in diameter, fragile, and have a tendency to retract into the parenchyma, rendering bipolar cautery less effective. An alternative strategy is to ligate them with small Sundt (Integra LifeSciences, Princeton, NJ) or Sugita (Mizuho Medical Co Ltd, Tokyo, Japan) AVM microclips. Once the AVM is stripped of its arterial input, the remaining major venous outflow can be divided by cauterization and/or clipping, and the malformation can be removed. The resection bed should then be thoroughly inspected for evidence of residual AVM suggested by areas of persistent bleeding. Raising the blood pressure to a MAP of 80–90 mm Hg is performed following resection of smaller AVMs, while a MAP of 70–80 mm Hg is utilized for larger ones. In cases with difficult-to-control intraoperative bleeding or swelling, the MAP is kept at 60–70 mm Hg. Brainstem AVMs are particularly challenging, as preservation of normal perforating arteries can be difficult because they are delicate and appear similar to arterial feeders supplying the malformation. A conservative strategy to address brainstem AVMs that are

315 difficult to visualize surgically or having a significant parenchymal component has been described by Han et al.3 Their strategy involves disconnection of the superficial pial arterial supply and subsequently the venous drainage, without removing the nidus, once stagnation of flow is confirmed by ICG angiography and visualization of a change in color of the vein from red to blue. This “in situ occlusion” eliminates the morbidity associated with subpial dissection in the brainstem while removing the arteriovenous shunting. In their series of 11 AVMs treated with this technique, complete occlusion was achieved in 72.7%, and 55% of the patients experienced an improvement or no change in neurological outcome postoperatively. INFRATENTORIAL SUPRACEREBELLAR APPROACH Access to the tectum of the midbrain and superior cerebellum is gained through the infratentorial supracerebellar approach (see Fig. 32.2 and Video 32.1 in the online version at https://doi.org/10.1016/B9780-323-82530-6.00032-9). The patient can be positioned either prone with the head elevated (Concorde) or semisitting with the neck flexed and chin tucked to orient the tentorium parallel to the floor. This provides clear visualization of the tentorial surface of the cerebellum and minimizes the need for dissection involving the vein of Galen and its tributaries. If access above this venous complex or the tentorial incisura is required, an occipital transtentorial approach may be considered. The disadvantages of this approach are the need for significant occipital lobe retraction posing a risk for visual field deficits and limited contralateral exposure of the quadrigeminal cistern. A linear, midline skin incision is made beginning above the inion and extending down to the level of C2, and the underlying cervical subcutaneous tissues and muscles are dissected. The craniotomy is then planned using frameless image guidance and fashioned extending superiorly to the torcula and transverse sinuses, allowing upward retraction to improve visibility along the underside of the tentorium. The dura is opened in a Y-shaped manner, with the superior flap hinged about the sinuses. Bridging cerebellar veins can be coagulated and cut, after confirming that they are not directly involved with the AVM, to further open the supracerebellar space. Gentle retraction of the superior cerebellar vermis may be necessary to reach the

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315.e1

Video 1 Resection of a ruptured right paramedian superior cerebellar hemisphere AVM through an infratentorial supracerebellar approach. Using visual inspection and intraoperative image guidance, the borders of the AVM were defined and circumferentially dissected, sequentially ligating its arterial supply. The venous pedicle was identified coursing deep and was preserved until the malformation was devascularized.

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Fig. 32.2 Cerebellar AVM in a 76-year-old man who presented with an acute-onset occipital headache, dizziness, nausea, and vomiting. (A) Nonenhanced CT image revealing a 3-cm vermian hemorrhage. (B) Sagittal T1-weighted gadolinium-enhanced MR image revealing a right paramedian superior cerebellar AVM on the tentorial surface superior to the hematoma. (C and D) Lateral and anterior-posterior digital subtraction angiography views from injection of the left vertebral artery (VA) demonstrating the cerebellar AVM supplied predominantly by the right superior cerebellar artery (SCA) and anterior inferior cerebellar artery–posterior inferior cerebellar artery complex and minor supply from the left SCA. Venous drainage is deep through the superior vermian vein into the galenic system. (E) Intraoperative angiogram (lateral view, left VA injection) obtained after resection, demonstrating complete obliteration.

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inferior midbrain. AVMs of the dorsal midbrain are typically supplied by perforators arising from the proximal PCA and the cerebellomesencephalic segment of the SCA. Those AVMs predominantly located in the cerebellum have arteries originating from the cortical SCA branches. Venous drainage can be deep to the vein of the cerebellomesencephalic fissure, with flow to the vein of Galen, or superficial through superior hemispheric veins, depending on the AVM’s anteriorposterior and medial-lateral positioning. SUBOCCIPITAL APPROACH The suboccipital approach provides access to the mid-to-inferior vermis, paramedian cerebellar hemispheres, dorsal medulla, and fourth ventricle. Larger AVMs with greater anterolateral extent can be addressed by the addition of a retrosigmoid or far-lateral craniotomy. Patient positioning and superficial exposure are similar to those for the infratentorial supracerebellar approach, with the goal of opening the craniocervical junction. The craniotomy is centered more inferiorly to include the foramen magnum, with additional removal of the C1 posterior arch necessary to address tonsillar or inferior vermian AVMs. Following the dural opening, CSF is released from the cisterna magna for cerebellar relaxation. Suboccipital AVMs are often visible on the pial surface, permitting early identification and control of cortical feeders from the SCA, AICA, and PICA. Lesions below the suboccipital fissure often require retraction to improve visualization. Circumferential dissection of these AVMs does not approach critical structures unless they infiltrate down to the deep cerebellar nuclei. Venous drainage occurs through the inferior hemispheric and inferior vermian veins. AVMs involving the fourth ventricle are rare but can be reached by opening the cerebellomedullary fissure, retracting the tonsils superolaterally, and entering the obex after sectioning the tela choroidea and inferior medullary velum. Incision or resection of the normal midline vermis is avoided to reduce the risk of cerebellar mutism. RETROSIGMOID APPROACH Using the retrosigmoid approach, AVMs situated in the lateral cerebellar hemisphere, cerebellopontine angle, lateral pons, and superior lateral medulla can be accessed. This is performed by placing the patient

317 in the supine or park-bench position with the head turned contralaterally and slight lateral flexion to orient the petrous bone vertically and the operative field horizontally. Excessive head rotation or flexion should be avoided, as they can compromise jugular venous outflow. Placement of an axillary roll and positioning the patient with continuous monitoring of SSEPs protect the brachial plexus from undue tension. A lazy “S” skin incision is made extending laterally with the upper one-third extending laterally above the transverse sinus (identified with frameless stereotaxis) and lower part curving toward the midline and extending down to the upper neck. After dissection of the occipital and upper cervical muscles, a craniotomy is performed, bordering the transverse sinus superiorly and the sigmoid sinus laterally. The bone overlying the sigmoid sinus can be partially removed (extended retrosigmoid approach) to facilitate lateral mobilization of the sinus, improving the operative trajectory to the anterolateral brainstem while minimizing cerebellar retraction. Mastoid air cells may be unroofed during this process and should be packed with bone wax, muscle, or fat and covered with fibrin glue sealant during closure to prevent postoperative CSF leakage. The dura is opened in a “K” or cruciate manner based upon the neighboring sinuses, and CSF relaxation is achieved by opening the cerebellopontine and cerebellomedullary cisterns as well as the cisterna magna. Intraoperative physiological monitoring of brainstem auditory evoked responses and electromyography from the facial nerve is critical in this exposure to avoid direct or retraction-related injury to the facial-vestibulocochlear nerve complex in addition to the trigeminal nerve or the lower cranial nerves (IX/X/ XI), depending on the rostral and caudal extent of the AVM. The AICA is the predominant arterial feeder to lateral pontine and cerebellar AVMs, with recruitment of SCA and basilar artery perforators for more anterior malformations. Venous outflow typically drains into the superior petrosal vein and out laterally to the superior petrosal sinus. Cerebellar AVMs may also drain through anterior hemispheric veins. FAR-LATERAL APPROACH The far-lateral approach offers exposure of AVMs in the anterolateral medulla, lower pons, and ­ inferolateral cerebellum (see Figs. 32.3 and 32.4 and

Fig. 32.3 Medullary AVM in a 56-year-old man with a clinical history of diplopia and tinnitus. Investigations for his symptoms discovered a left lateral medullary AVM. (A) Coronal T2-weighted MR image with a longitudinal cluster of flow voids centered at the cerebellomedullary fissure. (B) Digital subtraction angiogram (lateral view) following left vertebral artery injection demonstrating a medullary AVM with arterial feeders predominantly from the posterior inferior cerebellar artery and venous drainage via the lateral medullary vein. (C and D) Intraoperative photographs. A left suboccipital craniotomy with a far-lateral approach was used to access the cerebellomedullary cistern. Retraction of the cerebellum (C) reveals the AVM nidus (at the suction tip). The ipsilateral lower cranial nerve roots and V4 segment are seen superiorly and anteriorly, respectively. Following meticulous circumferential disconnection of the arterial supply (D), the draining vein is clipped, coagulated, and disconnected. (E) Postoperative digital subtraction angiogram demonstrating no residual malformation (left VA injection, lateral view).

Fig. 32.4 Ruptured Spetzler-Martin grade III pontomedullary AVM. (A) Axial CT scan demonstrating a dorsolateral pontine hemorrhage extending to the middle cerebellar peduncle. (B) Axial T2-weighted MR image showing serpiginous flow voids (arrow) neighboring the hematoma. (C and D) Anterior-posterior (AP) and lateral digital subtraction angiography (DSA) projections from a left vertebral artery (VA) injection showing the nidus (arrows) in the right pontomedullary region with arterial supply from a branch of the distal right V4. (E) Intraoperative view following a right far-lateral approach and subsequent dural opening. A retractor has been placed, lifting the right cerebellar tonsil and hemisphere (black star) superiorly to reveal the right posterior inferior cerebellar artery (black arrow) overlying the dorsal medulla and the right, intradural VA (white star) with traversing hypoglossal nerve roots dorsally (hashed black arrow). (F) Highmagnification view of the brainstem AVM on the pial surface with the feeding artery (black arrow) visualized. (G) Postoperative T1-weighted gadolinium-enhanced MR image demonstrating no residual AVM filling. (H) DSA (AP, right VA injection) confirming the lack of residual filling. (Used with permission from Madhugiri VS, Teo M, Steinberg GK. Surgery of basal ganglia, thalamic and brainstem AVMs. In Dumont AS, Lanzino G, Sheehan JP, eds. Brain Arteriovenous Malformations and Arteriovenous Fistulas. Thieme; 2017.)

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Videos 32.2 and 32.3 in the online version at https:// doi.org/10.1016/B978-0-323-82530-6.00032-9). The patient is positioned prone with the head elevated above the heart, neck flexed, and chin tucked. A midline incision is made from the inion superiorly to the C2 level inferiorly, and if necessary, the superior aspect can be curved laterally to form a “hockey stick” directed toward the junction of the transverse and sigmoid sinus. Alternatively, a horseshoe-shaped incision, with the lateral portion curved toward the mastoid, can be fashioned. We prefer the prone position to the parkbench position (in which the patient’s head is turned 45° contralaterally as well as anteriorly and laterally flexed, with use of an “S” skin incision as described previously20), since the prone position maintains the normal alignment of the occiput with the upper cervical spine and avoids dissection through muscles. A lateral suboccipital craniotomy incorporating the foramen magnum is fashioned with additional drilling of the posteromedial one-third of the occipital condyle, enhancing the lateral trajectory without injuring the hypoglossal nerve. The ipsilateral C1 posterior arch is exposed laterally with subperiosteal dissection and removed, avoiding compromise of the vertebral artery as it courses through the sulcus arteriosus. A C-shaped dural opening is made, pedicled laterally; while opening the dura, it is particularly important to be mindful of the location where the vertebral artery pierces it. Bleeding may be encountered from the posterior meningeal artery as well as the marginal sinus, which is situated circumferentially about the foramen magnum. The glossopharyngeal, vagus, accessory, and ­ hypoglossal nerves should be identified early in the cisternal dissection and protected. AVMs of the inferior vermis, tonsils, inferior cerebellum, and lateral medulla receive arterial supply principally from PICA branches. Venous outflow occurs through the lateral medullary vein or the inferior vermian vein when closer to the midline. More anteriorly situated AVMs are also fed by vertebral artery branches and drain to the median anterior medullary vein. APPROACHES TO THE ANTERIOR MIDBRAIN Anterior midbrain AVMs situated in the interpeduncular cistern or medial cerebral peduncle are best accessed through an orbitozygomatic pterional craniotomy and transsylvian approach. The patient is

positioned supine with the head turned 15°–30°. A standard curvilinear incision is made beginning above the zygoma and extending to the midline. The temporalis muscle is elevated and reflected inferiorly to minimize the typical bulk associated with this skin flap. Following the pterional and orbitozygomatic craniotomies, the medial sphenoid wing is flattened with a high-speed drill to provide an unobstructed posteromedial operative trajectory. The dura is opened, and the sylvian fissure is split, using sharp dissection from distal to proximal, while the arachnoid is placed under tension with frontal and temporal retractors to gain access to the carotid cistern. The basilar apex is then approached via the carotid-oculomotor triangle through Liliequist’s membrane. Arterial feeders arise from the overlying P1 segment and require distinguishing from posterior thalamoperforators. These AVMs drain through neighboring tributaries of the basal vein of Rosenthal, including the median anterior mesencephalic and peduncular veins. A subtemporal craniotomy is preferred for resection of midbrain AVMs located posterior to the midpoint of the cerebral peduncle (see Fig. 32.5 and Video 32.4 in the online version at https://doi.org/10.1016/B9780-323-82530-6.00032-9). For this approach, the patient’s head is rotated 90° while in the supine position, with a bolster under the ipsilateral shoulder to minimize brachial plexus traction. A linear or U-shaped incision is made, beginning from just below the zygoma anterior to the tragus, and a temporal craniotomy fashioned. It is critical to remove any remaining lateral temporal bone and drill the petrous portion to flatten the exposure with the middle cranial fossa floor and minimize temporal lobe retraction. This is further facilitated by insertion of a lumbar drain for CSF diversion, administration of hyperosmolar agents and/or diuretics, and mild hyperventilation. Any mastoid air cells opened during the craniotomy should be sealed in a fashion similar to that described for the retrosigmoid approach. After opening the dura, the temporal lobe is gently retracted to avoid tearing the vein of Labbé and other large bridging veins. Incremental medial retraction will reveal the tentorial edge, including the basilar apex complex, oculomotor nerve, and cerebral peduncle. Division of the tentorium, initiated posterior to the entry point of the trochlear nerve and extended laterally to the petrous apex, allows visualization of the pontomesencephalic junction.

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320.e1

Video 2 Resection of a left lateral medullary AVM through a far-lateral approach. The cerebellum was retracted to reveal the AVM and its arterial supply meticulously dissected to differentiate it from the posterior inferior cerebellar artery and its normal branches.

Video 3 Resection of a right dorsolateral pontine AVM through a right far-lateral approach, lateral suboccipital craniotomy, and drilling of the posterior third of the ipsilateral occipital condyle. Following the dural opening, the ipsilateral tonsil and cerebellar hemisphere were retracted to reveal the pial brainstem AVM. The AVM was circumferentially dissected, its arterial feeders and then venous outflow were disconnected, and a portion of the nidus was resected. A component was coagulated and occluded in situ, as it was adherent to the pia. (Used with permission from Madhugiri VS, Teo M, Steinberg GK. Surgery of basal ganglia, thalamic and brainstem AVMs. In Dumont AS, Lanzino G, Sheehan JP, eds. Brain Arteriovenous Malformations and Arteriovenous Fistulas. Thieme; 2017.) Video 4 Resection of a right anterolateral midbrain AVM through a subtemporal transpetrous approach. The tentorium was incised posterior to where the trochlear nerve inserts into the free edge to improve inferolateral visualization.

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Postoperative Management and Considerations

Fig. 32.5 Midbrain AVM in a 61-year-old woman presenting with headache but no sensorimotor deficits. Neuroimaging revealed diffuse subarachnoid hemorrhage (SAH) and an underlying right lateral midbrain AVM. (A) Axial nonenhanced CT scan showing SAH in the basal cisterns and medial occipital region, intraventricular hemorrhage in bilateral occipital horns, and subdural hemorrhage along the tentorium. (B) 3D rotational angiogram from a left vertebral artery (VA) injection revealing a right lateral midbrain AVM supplied by branches of the superior cerebellar artery and anterior inferior cerebellar artery (AICA). There is an associated inferiorly projecting AICA aneurysm. (C and D) Anterior-posterior (AP) and lateral digital subtraction angiography (DSA) projections (left VA injection) following coiling of the AICA aneurysm with adequate occlusion. Venous drainage of the AVM occurs through the lateral mesencephalic vein. (E and F) Intraoperative images. This AVM was approached via a right subtemporal craniotomy. The tentorium is incised posterior to the trochlear nerve, taking care not to injure it (E, bottom left of the view below the suction). The AVM (F) can be seen on the lateral surface of the midbrain. (G and H) Postoperative DSA (AP and lateral views, right VA injection) demonstrating complete obliteration.

Following AVM resection, patients are monitored in the intensive care unit for 24–48 hours, as clinical deterioration can be precipitous given the small volume of the posterior fossa. Strict blood pressure control is initiated, maintaining mild hypotension with a MAP of 65–75 mm Hg. If significant hemorrhage or cerebellar edema is encountered, the target MAP is further restricted to 55–65 mm Hg. A CT scan of the brain is obtained immediately postoperatively and at 12–24 hours after surgery to rule out intracerebral hemorrhage, edema, infarct, or hydrocephalus, with a reassuring scan permitting relaxation of blood pressure targets to 75–85 mm Hg. By postoperative day 3, in the absence of a new neurological deficit, normotension can resume. The rationale for these parameters is to prevent normal perfusion pressure breakthrough. More commonly encountered with large AVMs, this complication is thought to arise as a result of impaired autoregulation in neighboring vessels.21 These arteries, which were chronically dilated to compete with the low-pressure, high-flow arteriovenous shunting through the AVM feeders, are incapable of constricting to increase vascular resistance, as required to modulate the normal flow through the parenchymal capillaries in the absence of the AVM. This can result in hyperemia, cerebral edema, and subsequent hemorrhage. In the event of this feared complication, the patient should be managed with induced hypotension and sedation intended to reduce the cerebral metabolic rate and the hemodynamic effects of stimulation. An alternative etiology for postoperative hemorrhage is the presence of residual AVM. This scenario is less common with the increased availability of intraoperative angiography, particularly in hybrid operative suites capable of high-resolution biplanar imaging. Cerebral edema may also ensue after AVM resection and may be precipitated by altered hemodynamics, infarction following disruption of en passage arteries or retrograde thrombosis, venous stasis, and intraoperative retraction. Routine administration of high-dose corticosteroids, tapered over a 1- to 2-week period, with the stringent blood pressure parameters described earlier can prevent most neurological consequences. Normovolemia is employed, avoiding

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hypovolemia, which can promote venous thrombosis. Escalation of medical management with hyperosmolar therapy and insertion of an external ventricular drain for obstructive hydrocephalus may become necessary in the event of clinical deterioration from rising intracranial pressure. Edema that is refractory to these interventions requires a suboccipital craniectomy and possible cerebellar resection.

Outcomes and Prognosis Following Microsurgical Resection Compared to supratentorial AVMs, cerebellar AVMs are associated with less favorable outcomes following microsurgical resection, perhaps due to a higher rate of hemorrhagic presentation resulting in a poorer preoperative modified Rankin Scale score and the anatomical constraints of the posterior fossa.6,11 In their series of 60 cerebellar AVMs, Rodríguez-Hernández et al. were able to achieve angiographically confirmed complete resection in all patients following a single procedure.6 This was associated with a 3.3% incidence of postoperative hemorrhage, transient neurological ­ deficit in 20% of cases, and a 5% perioperative mortality rate. Just over half of the lesions were treated with preoperative embolization. Neurological functional status improved or remained unchanged following surgery in 74% of patients; this outcome was more likely in cases of tonsillar and tentorial AVMs and least likely in petrosal and vermian AVMs. A more recent series combining the experience at two institutions attained complete resection in 89.9% of 120 cerebellar AVMs with 12.5% of patients with poor preoperative neurological status improving but 20% worsening.2 The rate of death following surgery was 2.5%. Patients with brainstem AVMs similarly present disproportionately with hemorrhage and generally poor functional neurological status. Of 39 lesions treated at Stanford over 23 years, 21 were treated with surgery alone (43.8%) or with a combination of surgery and endovascular therapy or radiosurgery (21.9%).22 Surgery was the modality of choice for pontine and medullary AVMs as compared to SRS for midbrain AVMs. Following resection, the rate of complete obliteration was 90.5%; neurological improvement was observed in 65% of the patients and decline in 20%. When radiosurgery was the primary treatment, only 33.3% of patients obtained an angiographic cure.

Inclusion of surgery, either alone or as a multimodal approach, was predictive of complete obliteration, whereas the presence of residual AVM was associated with postoperative functional dependence. The overall perioperative mortality rate was 5.4%. Similar results were reported by Han et al., with an angiographic obliteration rate of 89.6% following microsurgery for 29 brainstem AVMs, 38% of which were occluded in situ.3 New permanent neurological deficits, including hemiplegia, dysarthria, ataxia, hearing loss, and akinetic mutism, arose in 20.7% of patients. At the latest follow-up, 77.8% of patient had experienced functional improvement or remained stable.

Conclusion Posterior fossa AVMs can be challenging lesions to treat owing to their proximity to eloquent neurological structures, delicate vascular anatomy, and the small volume of the infratentorial space. Using multiple imaging modalities, including virtual reality platforms to integrate bony, parenchymal, fiber tract, and vascular anatomy, can aid in preparing and selecting a surgical approach that maximizes access and safety for resection of the malformation. By utilizing preoperative embolization and intraoperative adjuncts, such as electrophysiological monitoring and neuronavigation, with strict blood pressure control and brain relaxation, in conjunction with meticulous microsurgical technique, the majority of posterior fossa AVMs can be cured safely. While SRS and, rarely, endovascular therapy can achieve curative results alone in selected patients, they also contribute to the successful treatment of patients deemed poor surgical candidates (based on comorbidities or deep brainstem location) or those with persisting residual malformation following surgery. REFERENCES 1. da Costa L, Thines L, Dehdashti AR, et al. Management and clinical outcome of posterior fossa arteriovenous malformations: report on a single-centre 15-year experience. J Neurol Neurosurg Psychiatry. 2008;80(4):376–379. https://doi.org/10.1136/ jnnp.2008.152710. 2. Nisson PL, Fard SA, Walter CM, et al. A novel proposed grading system for cerebellar arteriovenous malformations. J Neurosurg. 2020;132(4):1105–1115. https://doi.org/10.3171/2018.12. JNS181677. 3. Han SJ, Englot DJ, Kim H, Lawton MT. Brain stem arteriovenous malformations: anatomical subtypes, assessment of “occlusion in situ” technique, and microsurgical results. J Neurosurg. 2015;122(1):107–117. https://doi.org/10.3171/2014.8.JNS1483.

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4. Solomon RA, Stein BM. Management of arteriovenous malformations of the brain stem. J Neurosurg. 1986;64(6):857–864. https://doi.org/10.3171/jns.1986.64.6.0857. 5. Abla AA, Nelson J, Rutledge WC, Young WL, Kim H, Lawton MT. The natural history of AVM hemorrhage in the posterior fossa: comparison of hematoma volumes and neurological outcomes in patients with ruptured infra- and supratentorial AVMs. Neurosurg Focus. 2014;37(3):E6. https:// doi.org/10.3171/2014.7.FOCUS14211. 6. Rodríguez-Hernández A, Kim H, Pourmohamad T, Young WL, Lawton MT. Cerebellar arteriovenous malformations: anatomic subtypes, surgical results, and increased predictive accuracy of the supplementary grading system. Neurosurgery. 2012;71(6):1111– 1124. https://doi.org/10.1227/NEU.0b013e318271c081. 7. Chyatte D. Vascular malformations of the brain stem. J Neurosurg. 1989;70(6):847–852. https://doi.org/10.3171/jns.1989.70. 6.0847. 8. Rhoton AL Jr. The cerebellar arteries. Neurosurgery. 2000; 47(suppl_3):S29–S68. https://doi.org/10.1097/00006123200009001-00010. 9. Nozaki K, Hashimoto N, Kikuta K, Takagi Y, Kikuchi H. Surgical applications to arteriovenous malformations involving the brain stem. Neurosurgery. 2006;58(4 suppl 2):ONS270– ONS279. https://doi.org/10.1227/01.NEU.0000210001.75597.81. 10. Spetzler RF, Martin Neil A. A proposed grading system for arteriovenous malformations. J Neurosurg. 1986;65:476–483. https://doi.org/10.3171/jns.1986.65.4.0476. 11. Ding D, Starke RM, Yen C-P, Sheehan JP. Radiosurgery for cerebellar arteriovenous malformations: does infratentorial location affect outcome? World Neurosurg. 2014;82(1-2):e209– e217. https://doi.org/10.1016/j.wneu.2014.02.007. 12. Robert T, Blanc R, Ciccio G, et al. Endovascular treatment of posterior fossa arteriovenous malformations. J Clin Neurosci. 2016;25:65–68. https://doi.org/10.1016/j.jocn.2015.05.051. 13. Wu EM, El Ahmadieh TY, McDougall CM, et al. Embolization of brain arteriovenous malformations with intent to cure: a systematic review. J Neurosurg. 2020;132(2):388–399. https://doi. org/10.3171/2018.10.JNS181791.

323 14. Bowden G, Kano H, Tonetti D, Niranjan A, Flickinger J, Lunsford LD. Stereotactic radiosurgery for arteriovenous malformations of the cerebellum: clinical article. J Neurosurg. 2014;120(3):583–590. https://doi. org/10.3171/2013.9.JNS131022. 15. Cohen-Inbar O, Starke RM, Kano H, et al. Stereotactic radiosurgery for cerebellar arteriovenous malformations: an international multicenter study. J Neurosurg. 2017;127(3):512–521. https://doi.org/10.3171/2016.7.JNS161208. 16. Choi R, Andres RH, Steinberg GK, Guzman R. Intraoperative hypothermia during vascular neurosurgical procedures. Neurosurg Focus. 2009;26(5):E24. https://doi.org/10.3171/2009.3. FOCUS0927. 17. Chang SD, Lopez JR, Steinberg GK. The usefulness of electrophysiological monitoring during resection of central nervous system vascular malformations. J Stroke Cerebrovasc Dis. 1999;8(6):412–422. https://doi.org/10.1016/ S1052-3057(99)80049-4. 18. Orru’ E, Sorte DE, Gregg L, et al. Intraoperative spinal digital subtraction angiography: indications, technique, safety, and clinical impact. J NeuroIntervent Surg. 2017;9(6):601–607. https://doi.org/10.1136/neurintsurg-2016-012467. 19. Osbun JW, Patel B, Levitt MR, et al. Transradial intraoperative cerebral angiography: a multicenter case series and technical report. J NeuroIntervent Surg. 2020;12(2):170–175. https://doi. org/10.1136/neurintsurg-2019-015207. 20. Heros RC. Lateral suboccipital approach for vertebral and vertebrobasilar artery lesions. J Neurosurg. 1986;64(4):559–562. https://doi.org/10.3171/jns.1986.64.4.0559. 21. Spetzler RF, Wilson CB, Weinstein P, Mehdorn M, Townsend J, Telles D. Normal perfusion pressure breakthrough theory. Neurosurgery. 1978;25(CN_suppl_1):651–672. https://doi. org/10.1093/neurosurgery/25.CN_suppl_1.651. 22. Madhugiri VS, Teo MKC, Vavao J, Bell-Stephens T, Steinberg GK. Brainstem arteriovenous malformations: lesion characteristics and treatment outcomes. J Neurosurg. 2018;128(1):126– 136. https://doi.org/10.3171/2016.9.JNS16943.

Chapter 33

Callosal and Periventricular AVMs Rajeev D. Sen, Varadaraya S. Shenoy, Louis J. Kim, and Laligam N. Sekhar

Chapter Outline Introduction Anatomy AVM Subtypes Surgical Approaches and Resection Techniques Stereotactic Radiosurgery Conclusion

Introduction Intracranial arteriovenous malformations (iAVMs) are among the most challenging pathologies neurosurgeons face. Long-term studies have allowed for a better understanding of the natural history of iAVMs and the significant morbidity and mortality associated with their rupture.1–3 It is widely accepted that ruptured iAVMs should be treated, whether with microsurgical resection or stereotactic radiosurgery (SRS). Treatment of unruptured iAVMs, however, remains a controversial topic since the results of the ARUBA study (A Randomised Trial of Unruptured Brain AVMs).4,5 Callosal and periventricular AVMs (CPV AVMs) represent a particularly rare subtype of AVM accounting for roughly 5% of all iAVMs.6 Given their deep location and involvement of critical neurovascular and subcortical structures, treatment of these lesions carries a high risk. It should be noted that in this chapter, we have considered periventricular AVMs to be those with a nidus primarily within the lateral and third ventricles. This does not include AVMs within the thalamus or basal ganglia, which are discussed separately. The treatment algorithm for these unique AVMs closely resembles that for iAVMs in general. Patients with ruptured CPV AVMs almost always present with 324

intraventricular hemorrhage, requiring urgent placement of a ventriculostomy for management of the ensuing hydrocephalus. Once clinically stable, these patients should undergo definitive treatment of the lesion, given the risk of rerupture and its associated morbidity or mortality. Unruptured CPV AVMs should be treated in cases in which the patients suffer intractable and debilitating headaches, and treatment should be strongly considered in patients under the age of 40 years in light of their high lifetime risk of rupture. For CPV AVMs, our practice is to favor microsurgical resection with or without endovascular embolization if the AVM nidus measures less than 4 cm. This corresponds to a Spetzler-Martin grade of III or less, given that this location is largely considered noneloquent and deep venous drainage is almost always present. For the pediatric population, microsurgical resection is particularly favored due to the negative side effects of radiation and the high lifetime risk of rupture. For CPV AVMs larger than 4 cm, SRS delivered as a single dose or as volumestaged treatment is preferred. This chapter reviews the relevant anatomy, subtypes of CPV AVMs, useful surgical approaches, and application of SRS.

Anatomy Understanding ventricular anatomy is critical to the microsurgical management of CPV AVMs. The ependymal walls serve as important landmarks for navigating this deep brain region where there are no cortical surfaces. The lateral ventricles are composed of the frontal horn, body, atrium, occipital horn, and temporal horn. Choroid plexus can be found in the body, atrium, and temporal horns,

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Pearls • Callosal and periventricular AVMs are quite rare. • Their deep location and association with critical neurovascular structures indicate patients should seek help from experienced centers. • Indications for treatment are similar to those for all other iAVM locations. • Radiosurgery, although less effective at obliteration, should be considered. • A thorough understanding of the surgical anatomy is required for the treatment of these complex lesions. Fig. 33.1 Neuroanatomy of the periventricular region. The major neural structures are shaped in an inward and anteriorly tilted “C” centered around the thalamus. Although these deep structures serve a range of high-level functions, they are considered noneloquent. Illustration by Jennifer Pryll. Copyright Laligam N. Sekhar.

and this is where periventricular AVMs are typically located, as the choroid plexus is a highly vascular structure. The critical neural structures in the deep brain form a C shape centered around the thalamus and consist of the corpus callosum, the caudate nucleus, and the fornix. The lateral ventricles also form a C shape and are wedged between the corpus callosum and caudate nucleus7 (Fig. 33.1). CORPUS CALLOSUM The corpus callosum is the largest transverse white matter tract that connects the two cerebral hemispheres. It is divided into the rostrum and genu anteriorly, the body, and the splenium posteriorly. The rostrum makes up the floor of the frontal horns of the lateral ventricles, and the genu makes up the anterior wall. The body drapes over the roof of the body of the lateral ventricles, and the splenium comprises the medial wall of the atrium, connecting the occipital lobes.7 FORNIX The fornix contains hippocampomammillary fibers and begins as the fimbria in the temporal horn of the lateral ventricle. It wraps around posterosuperiorly as the crus around the pulvinar of the thalamus and joins together as a single tract overlying the thalamus and

forming the inferior lining of the body of the lateral ventricles. The fornix then splits into the columns and ends in the mammillary bodies at the anterior margin of the foramen of Monro.8–10 CAUDATE The caudate forms the lateral walls of the lateral ventricles, with its head bulging into the frontal horns and its tail wrapping around the atrium and ending adjacent to the temporal horn. CHOROIDAL FISSURE The choroidal fissure is the attachment of the choroid plexus to the ventricular wall at the junction of the thalamus and the fornix. It begins at the foramen of Monro, extends along the superior surface of the thalamus, and ends in the temporal horn at the inferior choroidal point behind the head of the hippocampus. The choroid plexus arises from a clear membrane called the tela choroidea, which attaches to the choroidal fissure via the tenia choroidea.10 VELUM INTERPOSITUM An important potential space to understand with respect to AVMs in this region is the velum interpositum. The velum interpositum makes up the roof of the third ventricle and comprises five layers: the fornix superiorly, two layers of teniae surrounding a layer of critical blood vessels that includes the internal cerebral vein and the medial posterior choroidal artery, and a layer of choroid plexus that is in continuity with that

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in the body of the lateral ventricles. The third ventricle is a narrow, funnel-shaped chamber located between the two thalami; it communicates with the lateral ventricles through the foramina of Monro. The roof is described earlier and bordered by the foramina of Monro anteriorly and the pineal recess posteriorly. The floor of the third ventricle spans from the optic chiasm and chiasmatic recess anteriorly to the aqueduct of Sylvius posteriorly.11 ARTERIES A schematic illustration of the arterial anatomy of the periventricular region is shown in Fig. 33.2. Anterior Choroidal Artery

The anterior choroidal artery (AChA) is a highly eloquent artery that is divided into two main segments: the cisternal segment and the plexal segment. It arises from the lateral aspect of the supraclinoid internal ca-

rotid artery (ICA) and is the last branch of the ICA before its bifurcation into the anterior cerebral artery (ACA) and middle cerebral artery (MCA). The cisternal segment courses posteromedially underneath and medial to the optic tract within the ambient cistern, passing between the cerebral peduncle and uncus. Branches from the cisternal segment supply the optic tract, middle third of the cerebral peduncle, posterior limb of the internal capsule, lateral geniculate body, and globus pallidus. Once the AChA pierces the choroidal fissure of the temporal horn, it is considered the plexal segment as it runs along and supplies the choroid plexus of the third ventricle. At this point, the artery is largely noneloquent and anastomoses with the lateral posterior choroidal artery.12 Lateral Posterior Choroidal Artery

The lateral posterior choroidal artery arises from the P2 segment, or ambient segment, of the posterior cerebral artery (PCA). It passes through the ambient cistern and enters the choroidal fissure of the atrium of the lateral ventricle. This artery may exist as a single vessel, or there may be multiple lateral posterior choroidal arteries that form an anastomotic network with the AChA within the temporal horn and the medial posterior choroidal artery within the atrium. The lateral posterior choroidal artery can provide supply to the cerebral peduncle, fornix, lateral geniculate body, pulvinar and thalamic nuclei, and body of the caudate.13,14 Medial Posterior Choroidal Artery

Fig. 33.2 Arterial anatomy of the periventricular region. The lateral ventricles are supplied by three choroidal arteries (the anterior choroidal artery [aChA], medial posterior choroidal artery [mpChA], and lateral posterior choroidal artery [lpChA]). The aChA arises from the supraclinoid internal carotid artery (ICA) and courses underneath the optic apparatus into the temporal horn. The mpChA arises from the crural segment of P2 (P2A) and wraps posteriorly around the tectum into the velum interpositum, ending in the floor of the body of the lateral ventricle through the foramen of Monro. Lastly, the lpChA arises from the ambient segment of P2 (P2P) and takes a direct course into the atrium. ACA, Anterior cerebral artery; BA, basilar artery; CalA, calcarine artery; CMA, callosomarginal artery; MCA, middle cerebral artery; PCA, posterior cerebral artery; PcaA, pericallosal artery; PCoA, posterior communicating artery; POA, parieto-occipital artery. Illustration by Jennifer Pryll. Copyright Laligam N. Sekhar.

The medial posterior choroidal artery arises more proximally than the lateral posterior choroidal artery on P2, at the medial side of the crural segment. There are anatomic variations in which the medial posterior choroidal artery arises from P3 (quadrigeminal segment of the PCA) or even more distal segments of the PCA, including the parieto-occipital or calcarine arteries. It courses parallel to the PCA posteriorly along the midbrain until it reaches the tectum, at which point it deviates superiorly toward the roof of the third ventricle. It then runs anteriorly within the velum interpositum toward the foramen of Monro. Once it reaches the foramen of Monro, it makes a sharp 180° turn posteriorly, running along the floor of the lateral ventricle.

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In addition to the choroid plexus of the body of the lateral ventricle, the medial posterior choroidal artery supplies the cerebral peduncle, tegmentum and colliculi, geniculate bodies, pulvinar and medial thalamus, and the pineal gland.13,14 Anterior Cerebral Artery and Pericallosal Artery

The ACA and pericallosal artery provide the primary blood supply to the corpus callosum. The postcommunicating segment of the ACA gives rise to the ­ pericallosal artery branch that runs along the superior aspect of the corpus callosum. Along the way, callosal branches off the pericallosal artery supply the genu and body of the corpus callosum as well as the fornix and anterior commissure. The splenium of the corpus callosum is supplied by the splenial artery, which is highly variable in origin; it can arise from the medial or lateral posterior choroidal artery, the parieto-occipital artery, or the calcarine artery. The splenial artery serves as the anastomotic connection between the anterior and posterior cerebral arteries, thereby completing the limbic loop.9,15 VEINS The venous structures of the ventricular system provide helpful navigational landmarks (Fig. 33.3). Given that they are larger, run along the ependymal walls, and, in the case of AVM surgery, are often dilated, they are better suited for orientation than arteries. The anterior and posterior septal veins drain the medial frontal horns and lead to the foramen of Monro, where they terminate in the internal cerebral vein. The anterior and posterior caudate veins mirror the septal veins on the lateral wall of the lateral ventricles and drain into the thalamostriate vein. The thalamostriate vein travels to the posterior margin of the foramen of Monro, then makes a sharp turn posteriorly into the velum interpositum, where it joins the internal cerebral vein. The medial atrial veins drain the medial atrium of the lateral ventricle and course through the choroidal fissure, also into the velum interpositum and internal cerebral vein. The lateral atrial vein, in contrast, drains the lateral atrium and drains into the basal vein of Rosenthal. The superior choroidal vein runs within the choroid plexus of the body of the lateral ventricles and drains into the thalamostriate vein. The inferior choroidal vein courses

Fig. 33.3 Venous anatomy of the periventricular region. The frontal horn and the body of the lateral ventricle are drained by the septal veins (anterior septal vein [aSV] and posterior septal vein [pSV]) and caudate veins (anterior caudate vein [aCV] and posterior caudate vein [pCV]) as well as the thalamostriate vein (TSV), all of which drain into the internal cerebral vein (ICV). The temporal horn and atrium are drained by the inferior ventricular vein (iVV) and atrial veins (lateral atrial vein [lAV] and medial atrial vein [mAV]), respectively. These drain into the basal vein of Rosenthal (BVR). The two ICVs superiorly and two BVRs inferiorly are the major deep veins that confluesce into the vein of Galen (VoG) ultimately draining into the torcular herophili via the straight sinus (SS). FoM, Foramen of Monro; iChV, inferior choroidal vein; sChV, superior choroidal vein. Illustration by Jennifer Pryll. Copyright Laligam N. Sekhar.

within the choroid plexus of the temporal horn and drains into the inferior ventricular drain, which ultimately leads to the basal vein of Rosenthal. Ultimately, there are two internal cerebral veins, which run in the roof of the third ventricle within the velum interpositum, and two basal veins of Rosenthal, which originate in the medial surface of the temporal lobe course superomedially through the ambient cistern. These four major veins all coalesce into the vein of Galen.16

AVM Subtypes There are several classification systems for deep and periventricular AVMs. We will summarize the subtypes as described by Lawton.6 CALLOSAL AVMS Callosal AVMs seem to be the most common subtype of ventricular and periventricular AVMs, accounting

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for about half of such lesions. Overall, however, they are rare, comprising about 4% of all iAVMs. They can be found anywhere throughout the corpus callosum from the rostrum to the splenium and can be contained within the corpus callosum or extend into the adjacent cingulate gyrus or lateral ventricles. Callosal AVMs are not formally considered to be in an eloquent location, but it should be noted that the splenium has been implicated in visuospatial and calculation processing. These AVMs are fed by long and short callosal arteries branching off the anterior cerebral and pericallosal arteries. An important distinction is that these vessels arise from the inferomedial surface of their parent anterior cerebral or pericallosal artery as opposed to those that supply the overlying cingulate gyrus and frontal lobe, which are found on the lateral surface. It is critical to preserve these cortical arteries, as they can supply eloquent cortex, such as somatosensory areas. Posterior callosal AVMs may also be supplied by the posterior circulation from the splenial artery. Anterior callosal AVMs that extend laterally can also recruit feeders from the medial or lateral lenticulostriate arteries. Although generally devoid of ventricular arterial feeders, callosal AVMs typically are characterized by deep drainage into the ventricular venous system, including the septal, caudate, thalamostriate, and internal cerebral veins. VENTRICULAR BODY AVMS Ventricular body AVMs are defined as those involving the septum pellucidum, velum interpositum, fornix, or choroid plexus of the body of the lateral ventricles or third ventricle. They are considered to be distinct from AVMs of the adjacent basal ganglia or thalamus. Ventricular body AVMs are rare and are accessed via small working corridors through the corpus callosum and choroidal fissure. They are typically supplied by the medial posterior choroidal artery, given its proximity to the region. The lateral posterior choroidal artery and the pericallosal artery are less commonly involved. As with callosal AVMs, ventricular body AVMs that are closer to the foramina of Monro or frontal horns can be fed by medial lenticulostriate and anterior communicating artery perforating vessels. Venous drainage is deep through the internal cerebral veins. Ventricular body AVMs are considered to be eloquent, given their

close association with the fornix, overly aggressive manipulation of which can result in memory and cognition deficits. VENTRICULAR ATRIUM AVMS As their name suggests, ventricular atrium AVMs are located in the atrium of the lateral ventricle. Unlike callosal and ventricular body AVMs, which are midline lesions, they are posterolaterally located. Ventricular atrium AVMs are the second most common type of periventricular AVMs. They are typically fed by the lateral posterior choroidal artery, which pierces the choroidal fissure within the atrium. However, given the anastomotic network created by the choroidal arteries and that the atrium is located between the body and temporal horn, ventricular atrium AVMs can also recruit feeders from the AChA arising from the temporal horn or the medial posterior choroidal artery arising from the body. Venous drainage is also deep to the internal cerebral veins and the basal vein of Rosenthal through the medial and lateral atrial veins. While ventricular atrium AVMs are closely associated with the pulvinar of the thalamus and the crus of the fornix, they are not considered to be eloquent. TEMPORAL HORN AVMS Temporal horn AVMs are confined by the ependymal walls of the temporal horn and spare the adjacent eloquent hippocampal structures. They receive arterial supply from the plexal segment of the AChA. As with ventricular atrium AVMs, they can also receive supply from the lateral posterior choroidal artery due to the anastomotic connections within the choroid plexus. Venous drainage is deep to the basal vein of Rosenthal through the choroidal and inferior ventricular veins.

Surgical Approaches and Resection Techniques ANTERIOR TRANSCALLOSAL INTERHEMISPHERIC APPROACH The anterior transcallosal interhemispheric approach6,17 can be used to access the frontal horns and body of the lateral ventricles as well as the anterior portion of the third ventricle. A representative case is presented in Fig. 33.4.

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Fig. 33.4 An 18-year-old woman presented with progressive headache, nausea, and vomiting of 1 week’s duration and was found to have intraventricular hemorrhage within the lateral and third ventricles due to a ruptured Spetzler-Martin grade I AVM. (A) CT angiogram showing an abnormal tangle of blood vessels within the floor of the frontal horn of the right lateral ventricle. (B and C) Arterial-phase digital subtraction angiograms, lateral (B) and anteroposterior (C) views, showing arterial supply from medial lenticulostriate arteries (red arrow) arising from the A1 segment of the anterior cerebral artery and a nidus measuring 1.1 cm (green arrows). (D) Venous-phase digital subtraction angiogram showing superficial venous drainage through the superior petrosal sinus into the transverse-sigmoid junction and into the cavernous sinus (blue arrows). This AVM was removed using the anterior interhemispheric transcallosal approach without complication.

The patient is positioned supine with the head elevated and flexed toward the floor, with care taken to avoid compressing the jugular vein. A variety of skin incisions can be made, but our preference is a bicoronal incision. The coronal suture is a helpful landmark

when planning the craniotomy. In preoperative imaging, the surgeon can use the coronal suture to identify the midpoint of the corpus callosum. For the anterior transcallosal interhemispheric approach, the craniotomy should not be extended more posteriorly than

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the coronal suture in order to avoid putting the motor cortex at risk. We recommend either a bifrontal or a one-and-a-half craniotomy that extends over the sagittal suture to expose the superior sagittal sinus. The dura is opened in a horseshoe fashion with its base along the superior sagittal sinus. The dural flap is then reflected medially and the superior sagittal sinus is retracted medially using suture. This maneuver minimizes lateral retraction of the brain to create an unobstructed view down the interhemispheric fissure. The interhemispheric dissection is performed under the microscope and begins with separation of the arachnoid membranes of the brain from the falx. Bridging veins are sacrificed along the way as needed. It is important to recognize that the anterior portion of the falx does not extend all the way to the corpus callosum as its posterior portion does. The surgeon will first encounter the cingulate gyrus. The bilateral cingulate gyri can be fused and may resemble the corpus callosum. Once the corpus callosum is reached, the two pericallosal arteries are identified, and at this point the callosal AVM should be apparent. Feeding arteries from the short and long callosal branches of the pericallosal artery and lenticulostriate arteries, if present, are identified and coagulated or clipped. Draining veins will not be visualized until the corpus callosum is entered. At this point, a callosotomy is performed to enter the lateral ventricles. The ependymal surfaces are inspected, and the septum is crossed to identify contralateral draining veins. Once the corpus callosum has been traversed, the deep surface of the nidus will be surrounded by cerebrospinal fluid, making the final dissection and extirpation of the AVM relatively straightforward (Fig. 33.5). Resection of ventricular body AVMs utilizes the same exact approach as detailed earlier with the main difference being that the AVM is not visualized until the corpus callosum is divided. Exposure of both the feeding artery, typically the medial posterior choroidal, and the draining vein, typically the internal cerebral vein, requires opening of the velum interpositum. This is done by expanding the foramen of Monro posteriorly via an incision through the tenia fornicis. A delicate dissection is required at this point to minimize

Fig. 33.5 Intraventricular view via the anterior interhemispheric transcallosal approach. A direct view of the pericallosal artery (PcaA) and corpus callosum allows for resection of anterior callosal AVMs. A 2-cm callosotomy reveals the frontal horn and anterior body of the ventricle to access ventricular body AVMs. aSV, Anterior septal vein; FoM, foramen of Monro. Illustration by Jennifer Pryll. Copyright Laligam N. Sekhar.

injury to the underlying fornix as the nidus is mobilized to visualize the feeding arteries and draining vein. The arterial feeders from the medial posterior choroidal artery are clipped or coagulated followed by the draining internal cerebral vein. POSTERIOR INTERHEMISPHERIC APPROACH The posterior interhemispheric approach17 is used to access the atrium or occipital horn of the lateral ventricles. A representative case is presented in Fig. 33.6. The patient is positioned in the three-quarter-prone position with the ipsilateral hemisphere closer to the floor to optimize gravity retraction. The craniotomy must cross over the superior sagittal sinus to allow maximal retraction of the sinus and falx. The dura is opened

33

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A

B

C

D

E

F

G Fig. 33.6 A 19-year-old woman with a known unruptured Spetzler-Martin grade III AVM within the posterior body and splenium of the corpus callosum extending into the lateral ventricle presented with debilitating headaches due to persistence of the AVM after stereotactic radiosurgery 5 years prior. (A) MR angiogram showing a nidus measuring 2.4 cm (green arrow). (B–D) Arterial-phase digital subtraction angiography images showing supply from the pericallosal artery (single red arrow), the posterior lateral choroidal artery (double red arrows), and small thalamoperforators. The green arrow in C indicates a draining vein, and the blue arrows in D indicate the posterior cerebral arteries. (E) Venous-phase angiogram showing deep venous drainage into the internal cerebral veins and vein of Galen (blue arrow). (F) Angiogram obtained after the patient underwent two separate embolizations of the pericollosal and posterior lateral choroidal arteries with successful reduction in nidus size. The patient subsequently underwent AVM resection via a posterior interhemispheric transchoroidal approach. (G) Intraoperative angiogram showing complete obliteration of the AVM.

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Fig. 33.7 Intraventricular view via the posterior interhemispheric approach. The medial surface of the parietal and occipital lobes can be appreciated. The parieto-occipital sulcus is used as a landmark to create a corticectomy through the posterior cingulate sulcus or the cuneus to access the atrium or occipital horn, respectively. SSS, Superior sagittal sinus. Illustration by Jennifer Pryll. Copyright Laligam N. Sekhar.

with its base along the sinus. An interhemispheric dissection is conducted as in the anterior interhemispheric approach until the splenium is reached. A corticectomy is made in the posterior cingulate or cuneus, and dissection is carried anterolaterally until the atrium is reached (Fig. 33.7). It is critical to avoid the optic radiations, which can be found on the lateral surface of the atrium and the superior and lateral surfaces of the occipital horn. It is also important to appreciate the location of the primary visual cortex at the distal tip of the calcarine sulcus. SUPERIOR PARIETAL LOBULE APPROACH The superior parietal lobule approach can be employed to access ventricular atrium AVMs. The superior and lateral walls of the atrium are devoid of optic radiations, making them safe corridors through which the atrium can be entered. This approach traverses the

roof of the atrium. A representative case is presented in Fig. 33.8. The patient is placed in a lateral position with the head turned to face the floor to make the parietal boss the highest point. There are multiple ways to identify the optimal site for a corticectomy. Common entry points for a corticectomy and approach to iAMVs in this region include the intraparietal sulcus, which begins at the postcentral sulcus and tracks posteriorly toward the occipital lobe. It splits the parietal lobe into the superior and inferior parietal lobules. Another option is to identify a point 6–9 cm above the inion and 3–5 cm lateral to midline. A transcortical corridor will reach the roof of the atrium of the lateral ventricle. The arterial supply and venous drainage are both found after opening the choroidal fissure through the tenia fornicis to avoid injury to the pulvinar and caudate tail. Feeders from the lateral posterior choroidal artery are disconnected first. Thalamoperforator feeders are disconnected at the ependyma. Arterialized draining veins will be seen exiting the choroidal fissure en route to the deep venous system. TRANSTEMPORAL APPROACH AVMs within the temporal horn can be accessed through a temporal craniotomy and transcortical approach via the inferior temporal gyrus. The patient is positioned supine with the head turned 90° such that the superior sagittal sinus is parallel to the floor. A “barn door” incision is made based over the ear. A corticectomy is made in the inferior temporal gyrus, and dissection is directed superiorly toward the temporal horn, staying underneath Meyer’s loop.18–20 The temporal horn is opened longitudinally, and the first structures to be identified are the choroid plexus and the plexal point anteriorly where the AChA can be found. The AVM nidus should be immediately apparent, and the AChA feeders are disconnected first. The choroidal fissure can be followed, disconnecting additional choroidal feeders along the way. The distal dissection will reveal feeders from the lateral posterior choroidal artery. The deep venous drainage into the basal vein of Rosenthal can be found by opening the choroidal fissure through the tenia fornicis to avoid the inferior thalamus and caudate above.

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Fig. 33.8 A 23-year-old woman presenting with the worst headache of her life was found to have extensive intraventricular hemorrhage due to a ruptured Spetzler-Martin grade II AVM. (A) CT angiogram revealing a backward C-shaped nidus measuring 2.7 cm extending from the atrium to the temporal horn of the lateral ventricle (green arrow). (B–D) Arterial-phase digital subtraction angiograms showing arterial supply from a posterior branch of M1 (single red arrow), the anterior choroidal artery (double red arrows), the posterior lateral choroidal artery, and the superior cerebellar artery (triple red arrows). (E) Venous phase shows deep drainage into the vein of Galen and straight sinus (blue arrow). The patient underwent embolization of the posterior lateral choroidal feeders with a 40% reduction in nidus size. This was followed by a two-stage resection involving a frontotemporal craniotomy with orbitozygomatic osteotomy for a transtemporal approach and a superior parietal lobule approach for complete obliteration.

Stereotactic Radiosurgery A chapter on the management of CPV AVMs would be incomplete without a brief discussion of SRS. In general, SRS offers a noninvasive modality for treating AVMs, with complete obliteration rates reaching roughly 80% within 5 years.21–23 While there are numerous benefits associated with its noninvasive nature, the obliteration effect often does not occur until several years after treatment, and during this latency interval, patients continue to be at risk for hemorrhage. Nonetheless, for the treatment of deep lesions such as CPV AVMs, SRS should always be considered, given the technical challenge of microsurgical resection for these high-risk lesions. A representative case is presented in Fig. 33.9. The purpose of SRS is to deliver focused radiation to the entire volume of the nidus of the AVM while sparing the surrounding structures. This can be

done in a single treatment session for smaller AVMs or as hypofractionated or volume-staged radiosurgery for larger lesions.24 Data from multiple studies show that AVM nidus size inversely correlates with obliteration rates21–25; iAVMs with a nidus smaller than 3 cm can be treated with a single dose of 20 Gy, with obliteration rates ranging between 65% and 90% over 3 years. For larger iAVMs, the dose must be reduced to avoid injury to adjacent ­ structures, and 3-year obliteration rates can drop to below 50%.22,24 When a volume-staged approach is used for larger AVMs, portions of the nidus are treated in sessions separated by 3–6 months. While complete obliteration rates are relatively low—about 30% at 3 years after treatment—this technique can be used to greatly reduce the size of the nidus, making microsurgical management safer if necessary.26

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Fig. 33.9 A 26-year-old woman presenting with pulsatile tinnitus was found to have an unruptured Spetzler-Martin grade IV AVM. (A) Sagittal T1-weighted contrast-enhanced MR image revealing a 3.2-cm nidus within the splenium of the corpus callosum extending into the right lateral ventricle (green arrow). (B and C) Arterial-phase digital subtraction angiograms showing arterial supply from the distal pericallosal artery (B) as well as perforators off the posterior cerebral artery (C) (red arrows). (D) Venous-phase digital subtraction angiogram showing deep venous drainage into the vein of Galen and basal vein of Rosenthal (blue arrow). Given the high grade of the AVM, Gamma Knife radiosurgery was recommended. The patient was treated with a single session at a dose of 20 Gy to the 50% isodose surface covering a volume of 4.88 cm3. (E) Sagittal T1-weighted MR image obtained at 1-year follow-up showing significant reduction in nidus size (purple arrow).

OUTCOMES Given the rarity of CPV AVMs, there is a paucity of robust clinical outcome studies, and data are generally derived from case reports and short case series.27–33 The largest series on ventricular AVMs was that of Barrow and Dawson, who presented results of surgical treatment of 26 patients who underwent either a transtemporal, superior parietal lobule, or interhemispheric approach for ventricular AVMs within the trigone. The authors reported a morbidity/mortality rate of 11.5%.27 Data on callosal AVMs are also lacking. In a pooled data analysis, Pabaney et al. found that microsurgery with or without embolization or radiosurgery resulted in complete obliteration in 47 of 50 patients (a 94% cure rate), but they also found that 16 (32%) of the surgically treated patients had permanent complications.34

In a series of 188 patients who underwent SRS for periventricular AVMs, Bowden et al. found obliteration rates of 32% at 3 years and 64% at 10 years. There was a 13% hemorrhage rate during the latency period, and 4% of patients had a permanent neurological deficit due to the treatment.35 Maruyama et al. reported on a series of 32 patients with callosal AVMs treated with SRS, describing actuarial obliteration rates of 64% at 4 years and 74% at 6 years. Only one patient (3%) developed a neurological deficit, and there were no instances of hemorrhage.36

Conclusion Callosal and periventricular AVMs (CPV AVMs) pose a tremendous challenge to cerebrovascular neurosurgeons. As with iAVMs in more common

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locations, treatment is recommended after rupture or in young patients with a high lifetime risk of rupture. Microsurgical resection is recommended for CPV AVMs with a nidus measuring less than 4 cm. While often noneloquent, these iAVMs carry a high surgical risk, given the critical neurovascular structures and deep location, making familiarity with the ­ relevant anatomy paramount. SRS should be reserved for larger lesions or for patients who are poor surgical candidates, and cure rates with this modality are relatively low. A multimodal approach may be optimal, with radiosurgery used to reduce nidus size followed by microsurgery for cure. REFERENCES 1. Gross BA, Du R. Natural history of cerebral arteriovenous malformations: a meta-analysis. J Neurosurg. 2013;118(2): 437–443. https://doi.org/10.3171/2012.10.JNS121280. 2. Abecassis IJ, Xu DS, Batjer HH, Bendok BR. Natural history of brain arteriovenous malformations: a systematic review. Neurosurg Focus. 2014;37(3):E7. https://doi.org/10.3171/2014. 6.FOCUS14250. 3. Hartmann A, Mast H, Mohr JP, et al. Morbidity of intracranial hemorrhage in patients with cerebral arteriovenous malformation. Stroke. 1998;29(5):931–934. https://doi.org/10.1161/01. str.29.5.931. 4. Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet. 2014;383(9917):614–621. https:// doi.org/10.1016/S0140-6736(13)62302-8. 5. Mohr JP, Overbey JR, Hartmann A, et al. Medical management with interventional therapy versus medical management alone for unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre, non-blinded, randomised controlled trial. Lancet Neurol. 2020;19(7):573–581. https://doi. org/10.1016/S1474-4422(20)30181-2. 6. Lawton MT. Seven AVMs: Tenets and Techniques for Resection. Thieme Medical Publishers, Inc.; 2014:151–180. 7. Timurkaynak E, Rhoton AL, Barry M. Microsurgical anatomy and operative approaches to the lateral ventricles. Neurosurgery. 1986;19(5):685–723. https://doi.org/10.1227/ 00006123-198611000-00001. 8. Wen HT, Rhoton AL, de Oliveira E, et al. Microsurgical anatomy of the temporal lobe: part 1: mesial temporal lobe anatomy and its vascular relationships as applied to amygdalohippocampectomy. Neurosurgery. 1999;45(3):549–591; discussion 591–592. doi:10.1097/00006123-199909000-00028. 9. Dunker RO, Harris AB. Surgical anatomy of the proximal anterior cerebral artery. J Neurosurg. 1976;44(3):359–367. https:// doi.org/10.3171/jns.1976.44.3.0359. 10. Wen HT, Rhoton AL, de Oliveira E. Transchoroidal approach to the third ventricle: an anatomic study of the choroidal fissure and its clinical application. Neurosurgery. 1998;42(6):1205–1217; discussion 1217–1219. https://doi. org/10.1097/00006123-199806000-00001.

335 11. Yamamoto I, Rhoton AL, Peace DA. Microsurgery of the third ventricle: part I. Microsurgical anatomy. Neurosurgery. 1981;8(3): 334–356. https://doi.org/10.1227/00006123-198103000-00006. 12. Rhoton AL, Fujii K, Fradd B. Microsurgical anatomy of the anterior choroidal artery. Surg Neurol. 1979;12(2):171–187. 13. Zeal AA, Rhoton AL. Microsurgical anatomy of the posterior cerebral artery. J Neurosurg. 1978;48(4):534–559. https://doi. org/10.3171/jns.1978.48.4.0534. 14. Fujii K, Lenkey C, Rhoton AL. Microsurgical anatomy of the choroidal arteries: lateral and third ventricles. J Neurosurg. 1980; 52(2):165–188. https://doi.org/10.3171/jns.1980.52.2.0165. 15. Perlmutter D, Rhoton AL. Microsurgical anatomy of the distal anterior cerebral artery. J Neurosurg. 1978;49(2):204–228. https://doi.org/10.3171/jns.1978.49.2.0204. 16. Ono M, Rhoton AL, Peace D, Rodriguez RJ. Microsurgical anatomy of the deep venous system of the brain. Neurosurgery. 1984;15(5):621–657. https://doi.org/10.1227/ 00006123-198411000-00002. 17. Sekhar LN, Fessler RG. Atlas of Neurosurgical Techniques: Brain. 2nd ed. Thieme Medical Publishers, Inc.; 2016. 18. Ebeling U, Reulen HJ. Neurosurgical topography of the optic radiation in the temporal lobe. Acta Neurochir (Wien). 1988;92(1-4):29–36. https://doi.org/10.1007/BF01401969. 19. Falconer MA, Wilson JL. Visual field changes following anterior temporal lobectomy: their significance in relation to Meyer’s loop of the optic radiation. Brain. 1958;81(1):1–14. https://doi.org/10.1093/brain/81.1.1. 20. Van Buren JM, Baldwin M. The architecture of the optic radiation in the temporal lobe of man. Brain. 1958;81(1):15–40. https://doi.org/10.1093/brain/81.1.15. 21. Starke RM, Kano H, Ding D, et al. Stereotactic radiosurgery for cerebral arteriovenous malformations: evaluation of long-term outcomes in a multicenter cohort. J Neurosurg. 2017;126(1): 36–44. https://doi.org/10.3171/2015.9.JNS151311. 22. Ding D, Starke RM, Kano H, et al. Stereotactic radiosurgery for ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations)-Eligible Spetzler-Martin grade I and II arteriovenous malformations: a multicenter study. World Neurosurg. 2017;102:507–517. https://doi.org/10.1016/j.wneu.2017.03.061. 23. Ding D, Starke RM, Kano H, et al. Stereotactic radiosurgery for Spetzler-Martin Grade III arteriovenous malformations: an international multicenter study. J Neurosurg. 2017;126(3): 859–871. https://doi.org/10.3171/2016.1.JNS152564. 24. Patibandla MR, Ding D, Kano H, et al. Stereotactic radiosurgery for Spetzler-Martin Grade IV and V arteriovenous malformations: an international multicenter study. J Neurosurg. 2018;129(2):498–507. https://doi.org/ 10.3171/2017.3.JNS162635. 25. Lunsford LD, Kondziolka D, Flickinger JC, et al. Stereotactic radiosurgery for arteriovenous malformations of the brain. J Neurosurg. 1991;75(4):512–524. https://doi.org/10.3171/ jns.1991.75.4.0512. 26. Abla AA, Rutledge WC, Seymour ZA, et al. A treatment paradigm for high-grade brain arteriovenous malformations: volume-staged radiosurgical downgrading followed by microsurgical resection. J Neurosurg. 2015;122(2):419–432. https:// doi.org/10.3171/2014.10.JNS1424. 27. Barrow DL, Dawson R. Surgical management of arteriovenous malformations in the region of the ventricular trigone. Neurosurgery. 1994;35(6):1046–1054. https://doi. org/10.1227/00006123-199412000-00005.

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28. Batjer H, Samson D. Surgical approaches to trigonal arteriovenous malformations. J Neurosurg. 1987;67(4):511–517. https:// doi.org/10.3171/jns.1987.67.4.0511. 29. Costa MDS da, Santos BF, de O, Guardini FB de A, ChaddadNeto F. Microsurgical treatment for arteriovenous malformation of the corpus callosum and choroidal fissure. Neurosurgical Focus. 2017;43(videosuppl1):V12. https://doi. org/10.3171/2017.7.FocusVid.1733. 30. Fahim DK, Relyea K, Nayar VV, et al. Transtubular microendoscopic approach for resection of a choroidal arteriovenous malformation: technical note. J Neurosurg: Pediatrics. 2009;3(2):101–104. https://doi.org/10.3171/2008.11.PEDS08280. 31. Huh CW, Yoon SH, Song JU. Total excision of an arterio-venous malformation of the corpus callosum: case report. J Korean Neurosurg Soc. 1980;9(1):281–286. 32. Yasargil MG, Jain KK, Antic J, Laciga R, Kletter G. Arteriovenous malformations of the anterior and the middle portions of the corpus callosum: microsurgical treatment. Surg Neurol. 1976;5(2):67–80.

33. Guidetti B, Spallone A. The management of arteriovenous malformations of the corpus callosum. Neurol Res. 1982;4(3-4):253–282. https://doi.org/10.1080/01616412. 1982.11739626. 34. Pabaney AH, Ali R, Kole M, Malik GM. Arteriovenous malformations of the corpus callosum: pooled analysis and systematic review of literature. Surg Neurol Int. 2016;7(Suppl 9): S228–S236. https://doi.org/10.4103/2152-7806.179579. 35. Bowden G, Kano H, Yang H, Niranjan A, Flickinger J, Lunsford LD. Gamma Knife surgery for arteriovenous malformations within or adjacent to the ventricles: clinical article. J Neurosurg. 2014;121(6):1416–1423. https://doi. org/10.3171/2014.4.JNS131943. 36. Maruyama K, Shin M, Tago M, et al. Gamma knife surgery for arteriovenous malformations involving the corpus callosum. J Neurosurg. 2005;102(Special Supplement):49–52. https://doi. org/10.3171/sup.2005.102.s_supplement.0049.

Chapter 34

AVMs of the Sylvian Fissure David Dornbos III and Justin F. Fraser

Chapter Outline Introduction Sylvian AVM Classification Treatment of Sylvian AVMs Multimodal Approaches to Sylvian AVMs: Representative Cases Prenidal and Intranidal Aneurysms Conclusion

Introduction Supratentorial arteriovenous malformations (AVMs) are relatively rare pathological lesions, with an incidence of 1 in 100,000 persons per year. These lesions are responsible for 1%–2% of all strokes.1 AVMs within the sylvian fissure are rarer still; only 5%–10% of all intracranial AVMs (iAVMs) are identified within this location.2–4 While approximately half of the patients with sylvian AVMs present with hemorrhage, many present with seizures (20%–25%) due to the close proximity of these lesions to key epileptogenic brain regions in the mesial temporal lobe.2 Despite their location, the natural history and rupture risk of sylvian AVMs remain on par with those of AVMs in other supratentorial locations, but decision-making regarding treatment must account for adjacent structures, which alters the typical risk-benefit analysis. Given the proximity to key eloquent brain regions, including the basal ganglia, the internal capsule, the insula, Broca’s area, Wernicke’s area, and the arcuate fasciculus, treatment of this iAVM subtype presents unique challenges. Furthermore, sylvian AVMs are ­ typically intertwined with middle cerebral artery

(MCA) vessels, presenting additional challenges to identify pathologic vessels, preserve native MCA vessels, and minimize ischemic complications.

Sylvian AVM Classification Initially described by Sugita et al. in 1987, sylvian fissure AVMs can fall into four categories, depending on their precise location within or around the sylvian fissure.5 This categorization includes pure (located within the confines of the sylvian fissure), lateral (adjacent temporal lobe and Wernicke’s area), medial (adjacent frontal lobe and Broca’s area), and deep (basal ganglia, internal capsule, and insula) sylvian fissure AVMs (Table 34.1). While sylvian AVMs rarely fall into these categories in an isolated manner, classification provides a framework for discussion of the pitfalls and potential complications of various treatment modalities for these respective perisylvian locations. Given the proximity of sylvian AVMs to sensitive and critical brain structures, treatment poses significant risks regardless of the treatment modality employed. In addition to the aforementioned neighboring eloquent brain regions, the location within the sylvian fissure provides additional complexity due to the presence of numerous “en passage” MCA vessels, which must be meticulously identified and preserved whether the lesions are treated surgically or endovascularly. These en passage vessels drop branches to the AVM, while passing adjacent to the nidus and continuing onward to supply critical surrounding cortex. Although all sylvian AVMs are involved with the MCA vasculature to a degree, pure sylvian AVMs (located solely within the fissure) are intricately intertwined with the MCA candelabra. The nidus of pure sylvian AVMs is distinctly within the confines of the sylvian fissure, providing a plane of separation from 337

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TABLE 34.1 Sylvian Fissure AVM Categorization Category

Eloquent Parenchyma Involved

Pure Lateral

NA Wernicke’s area Heschl’s gyrus Broca’s area Inferior motor cortex Insula Basal ganglia Internal capsule

Medial Deep

NA, Not applicable.

the parenchyma by a natural pial barrier.6 This natural barrier allows resection of these lesions without invasion of normal parenchyma. It is important to distinguish between pure sylvian AVMs and perisylvian AVMs, as operative and endovascular risks are dependent on the precise nidal location. Perisylvian AVMs are located in the parenchyma, immediately adjacent to the sylvian fissure, either in deep structures (insula, basal ganglia, internal capsule) or more superficial eloquent locations (Broca’s area, Wernicke’s area).6 Although most of the nidus is typically located within the brain parenchyma, portions of nidus are located within the fissure, and arterial input arises directly from the MCA. As perisylvian parenchymal lesions grow and evolve, they will often recruit additional arterial input from the MCA within the fissure, transitioning into combined lesions of the fissure and adjacent parenchyma. Treatment of perisylvian AVMs not only carries risk to the native MCA but also carries risk to the adjacent eloquent brain parenchyma. Pure sylvian AVMs, on the other hand, carry less risk to eloquent tissue but entail more difficulty in distinguishing between en passage vessels and nidal arterial input. Despite these risks inherent in treating sylvian AVMs, the sylvian fissure does provide a natural corridor for approaching superficial and deep AVMs. While resection of insular, basal ganglia, and internal capsule lesions carries substantial risk, utilizing the sylvian fissure for the approach can mitigate approachrelated morbidity to a degree. This may underlie ­ previous reports, which have identified surgical success (operative resection without worsened neurologic function) to be as high as 85%–90%.2,4,6–8

Pearls • Sylvian fissure AVMs are very frequently related to eloquent cortex anatomically or by virtue of vascular anatomy. • Permanent morbidity after resection ranges from 0% to 34%. • Classification is based upon anatomical location within (pure sylvian) or around (perisylvian) the sylvian fissure and associated eloquent brain. • A multimodal approach (embolization, surgery, radiosurgery, observation) should be meticulously evaluated in cases of these high-risk lesions. • This AVM location requires discussion with the patient with regard to a multistaged approach.

Treatment of Sylvian AVMs ROLE OF SURGERY Resection of sylvian AVMs has been described for nearly four decades, with numerous case series demonstrating a high degree of efficacy and reasonable morbidity (Table 34.2).2,4–18 Initially, resection of these lesions was reserved for patients with prior hemorrhage and significant neurologic deficits, but more recently, advances in microsurgery have allowed for a more aggressive approach in select patients. As previously discussed, the precise location of the AVM (pure sylvian or perisylvian) will significantly impact perioperative morbidity. Conventional angiography and MRI prior to potential resection are crucial for treatment decision and surgical planning. MRI can assist in the identification of the precise location of the lesion and potentially involved eloquent parenchyma. Further, while sylvian AVMs receive the large majority of their vascular supply from the MCA, additional arterial input from the anterior choroidal, posterior choroidal, and lenticulostriate arteries may be observed, rendering careful angiographic assessment essential prior to any potential treatment. Once the decision to move forward with surgery is made, the precise location of resection will vary based on the nidal location, but all sylvian AVMs are approached with a wide sylvian fissure opening, typically utilizing a pterional craniotomy. Full fissure opening into the distal aspect of the sylvian fissure is necessary to completely skeletonize the MCA.

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AVMs of the Sylvian Fissure

TABLE 34.2 Surgical Series Involving Pure Sylvian and Perisylvian AVM Resection Authors and Year 9

Heros, 1982

Sugita et al., 19875 Oka et al., 199010

No. of Patients 3 16 3

Malik et al., 199611

24

Yamada et al., 199812

22

Zimmerman et al., 200013

8

Du et al., 200414

10

Lawton et al., 20072

28

Bostrom et al., 201115

20

Gabarros Canals et al., 201316

5

Lopez-Ojeda et al., 201317

5

Liu et al., 20134

41

Potts et al., 20137

48

Pabaney et al., 20148

7

Ding et al., 201818

1

This allows identification of the AVM arterial input, venous drainage, and nidus, but it also aids in clearly delineating the MCA and its branches as it courses through the fissure. Full anatomic exploration and identification of the native MCA and AVM vasculature are paramount prior to ligation of arterial input to the nidus in order to preserve all vessels providing blood supply to normal parenchyma. Preservation of the parent MCA, en passage arteries, and perforating arteries limits neurologic morbidity from the procedure, although it is often difficult to parse out these different vessel types without full exposure. If there is any doubt about whether a vessel is feeding into the AVM or passing by, it should not be sacrificed until the nidus is fully exposed and a

Morbidity Transient 33% Permanent 33% Transient 81% Permanent 6% Transient 33% Permanent 33% Transient 33% Permanent 17% Transient 4.5% Permanent 4.5% Transient 50% Permanent 0% Transient 30% Permanent 0% Transient 14% Permanent 3.6% Transient 15% Permanent 10% Transient 0% Permanent 20% Transient 0% Permanent 20% Transient 44% Permanent 34% Transient 6% Permanent 6% Transient 20% Permanent 20% None

Mortality 0% 6% 33% 4.2% 0% 0% 0% 0% 0% 20% 0% 2.4% 0% 0% 0%

definitive assessment can be made. When AVM feeding arteries are relatively short or when the nidus is directly fed off the parent MCA, the use of suture or AVM clips is recommended to avoid coagulation damage to the native MCA. Particularly with medial sylvian AVMs, frequent use of clips, rather than cautery, is recommended, as partially cauterized vessels may retract into eloquent tissue, leading to a need for surgical manipulation of potentially eloquent areas that otherwise would be undisturbed. The draining vein often lies within the sylvian fissure on top of the nidus, and care must be taken to preserve this structure until the nidus is ready to be removed. Venous drainage patterns tend to vary with sylvian AVM location.2 Pure sylvian AVMs typically

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drain superficially through the middle cerebral veins, whereas medial perisylvian AVMs and lateral perisylvian AVMs tend to drain through the veins of Trolard and Labbé, respectively. Deep sylvian AVMs typically exhibit deep venous drainage into the thalamostriate and internal cerebral veins. As with all AVMs, preservation of the draining vein until all arterial input has been ligated is of utmost importance. In addition to preserving the native vasculature, minimizing manipulation of adjacent parenchyma is crucial in resection of perisylvian AVMs. Pure sylvian AVMs have no associated eloquent cortex, but medial sylvian AVMs border Broca’s area and the inferior aspect of the motor strip, lateral sylvian AVMs border Wernicke’s area and Heschl’s gyrus, and deep sylvian AVMs border the basal ganglia, internal capsule, and arcuate fasciculus.2 While perisylvian AVMs in the adjacent parenchyma may receive additional arterial supply from other vascular territories, such as anterior or posterior choroidal and lenticulostriate arteries, the vast majority of the arterial input arises from the MCA. In approaching perisylvian AVMs, it is recommended to prune all MCA arterial supply within the sylvian fissure prior to working around the parenchymal planes of the nidus. This allows resection to be maintained much tighter to the AVM nidus, thus reducing surgical morbidity from manipulation of eloquent cortex. Numerous studies (Table 34.2) have evaluated outcomes following resection of sylvian AVMs. Lawton et al. evaluated their series of sylvian AVMs, assessing 28 patients who underwent resection, 54% of whom presented with hemorrhage.2 Among this population, they observed transient neurologic deficits in 14% of the patients, but the rate of permanent neurologic morbidity was only 3.6%. No surgical mortality was observed, and 89% of the patients achieved good functional outcomes at a mean follow-up of 20 months. Similarly, Zimmerman et al. reported transient neurologic deficits in 50% of their patients, with all recovering within 3 months of surgery and no surgical mortality.13 While resection of sylvian AVMs can at times be a safe and feasible option, it should be approached cautiously, appropriately weighing the risks and benefits of treatment. Factors such as age, history of rupture, eloquent cortex, insular locations, and involvement of lenticulostriate or anterior choroidal arteries need to be carefully considered prior to surgical intervention.

Given these factors, a less aggressive approach with stereotactic radiosurgery (SRS) or even conservative observation may be in the patient’s best interest. ROLE OF EMBOLIZATION While embolization for cure of sylvian AVMs has been described previously,19 it is rare, and the predominant role of embolization in the management of these lesions remains as an adjunctive treatment. Even though the role of endovascular embolization for sylvian AVMs is limited, endovascular involvement in these cases can prove critical, as microcatheter exploration with superselective angiography can be particularly useful in evaluating these lesions. Microcatheter angiography allows for a precise understanding of both the angioarchitecture of the AVM and all en passage vessels. Despite drawbacks, embolization of arterial input can aid resection through embolization of deep arterial feeders that are difficult to access during surgery. As discussed, initial surgical exposure opens the sylvian fissure, isolating the MCA and arterial input from the MCA into the AVM nidus. Since surgical control of MCA feeders is readily obtained, embolization of most MCA arterial input is of limited value, and it carries ischemic risk. With that in mind, embolization of deep MCA arterial input that is unlikely to be surgically exposed early may be of benefit to resection. Perisylvian AVMs receive additional arterial input from adjacent vessels other than the MCA, including the anterior and posterior choroidal and lenticulostriate arteries. These vessels are often not amenable to endovascular access and embolization, but endovascular ligation of this input can be of particular benefit when feasible. Surgical exposure of these AVMs starts with ligating sylvian and MCA input before resection of nidus incorporated in the surrounding parenchyma. Endovascular embolization of these vessels, which are surgically visualized late in the procedure, can augment safe surgical removal. Endovascular treatment of sylvian AVMs is also particularly useful for high-risk AVM features, such as prenidal or intranidal aneurysms. Prenidal aneurysms pose a significant risk prior to both microsurgical ­ resection and SRS. While dual sylvian AVM resection and aneurysm clip ligation have been reported,18 prenidal aneurysms may be distant from the nidus and difficult to access. As such, they may be better treated from an endovascular approach depending on

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AVMs of the Sylvian Fissure

location and patient factors. Given the latency period between SRS and thrombosis of the AVM, intranidal aneurysms pose a significant risk of hemorrhage before AVM obliteration. Endovascular embolization of intranidal aneurysms prior to SRS decreases the risk of hemorrhage by eliminating this risk. Although embolization can be used to augment resection and for any nidal or prenidal aneurysms prior to SRS, care must be taken to avoid accidental embolization of en passage vessels. As previously described, MCA input to sylvian AVMs often arises from short arterial feeders. Given this small margin for error with potential reflux of embolic agents, endovascular embolization should be used judiciously with particular care paid to ensure MCA branches supplying the AVM are not en passage and supplying adjacent or distal parenchyma. These limitations significantly increase the difficulty of safely embolizing AVMs, particularly as a curative treatment. As an adjunctive (rather than curative) treatment modality, the threshold for embolization of these lesions remains quite high. One area of continued controversy is the role of embolization as an adjunct to radiosurgery. Some have advocated for its use to reduce the nidus in order to decrease the volume and size of sylvian AVMs prior to SRS treatment. However, there is a relative paucity of data on this type of approach for sylvian AVMs. Accordingly, with the risks that endovascular embolization incurs, further clinical studies are needed to evaluate this approach. ROLE OF RADIOSURGERY Radiosurgery has assumed an increasing role in the treatment of iAVMs, given its low risk of complications and good rates of AVM occlusion of up to 80% at 5 years.20,21 SRS plays a significant role in the treatment of sylvian AVMs, particularly for unruptured AVMs, perisylvian AVMs of the dominant hemisphere, and deep-seated lesions, given the potential morbidity associated with resection in these locations. Ruptured AVMs and pure sylvian AVMs may be best treated with an open surgical approach, but numerous patient factors, especially involvement of adjacent parenchyma, older age, and comorbidities, may render SRS a safer option. Both the involvement of adjacent eloquent cortex (Broca’s area, Wernicke’s area, insula, internal capsule, basal ganglia) and the MCA candelabra

341 increase surgical and endovascular morbidity risk, and SRS often provides a lower-risk option. In a study of 87 cases of pure sylvian and perisylvian AVMs treated with SRS, Bowden et al. found that complete obliteration of the AVM occurred in nearly 50% of cases (43 of 87) over a median follow-up period of 64 months.22 The actuarial rate of AVM obliteration was 76% at 10 years following treatment. SRS for sylvian AVMs was found to be efficacious for seizure control as well. Following treatment, 53% of patients were seizure free at 5 years, increasing to 60% at 15 years.22 Importantly, despite the location of these lesions, new seizure disorders did not develop in patients treated with SRS. The most significant downside to utilizing SRS in the treatment of AVMs is the latency period between SRS treatment and thrombosis of the AVM. This interval may last up to 3 years before AVM obliteration, during which time the patient remains at risk for hemorrhage.23,24 Nevertheless, in the previously described study of 87 cases, Bowden et al. reported that their actuarial rate of hemorrhage equated to an annual hemorrhage rate of 1% during the latency period,22 an improvement compared to a baseline risk of AVMassociated hemorrhage of 2%–4% annually. Further, the risk of hemorrhage during the latency period has been shown to be associated with the presence of prenidal aneurysms, providing a potential role for embolization prior to SRS treatment. Once AVM obliteration has been angiographically established, no further hemorrhagic risk remains. Specifically with sylvian AVMs, the risk of radiation injury to the surrounding cortex is potentially significant, given the proximity to eloquent speech centers, the insula, basal ganglia, and internal capsule. Importantly, small lenticulostriate arteries are particularly susceptible to radiation injury.25 Despite these theoretical risks, no permanent neurologic deficits were observed secondary to radiation-induced injury in the study by Bowden et al. (87 patients, median follow-up >5 years),22 and the overall risks of radiation effects following SRS for AVMs remain quite low.26 While radiation-induced injury to these structures is a concern, this risk of injury is less than would be incurred from surgical manipulation. It is also important to note that delayed cyst formation has been observed.22 Both cyst formation and scar tissue from

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a thrombosed nidus do increase the risk of persistent seizure disorders despite AVM obliteration. Several strategies have been employed to decrease the side effects of SRS in order to enhance its overall utility. Sylvian AVMs are not only long and narrow lesions but also often large-volume lesions. To decrease the overall radiation dose to the surrounding brain, fractionation of SRS treatment has been proposed, although the efficacy of such an approach has not been proven and may carry a higher risk of complications depending on the treatment plan.9 While there is a paucity of literature on fractionated radiosurgery specifically for sylvian AVMs, there is a growing body of literature on this approach for iAVMs in general, with good obliteration rates for otherwise difficult-to-treat lesions.27–29 For AVMs that do not show occlusion after 3–5 years, additional SRS treatments may be utilized; an additional round of SRS treatment was found to be associated with a 33% rate of occlusion in the case series of Bowden et al.22 As previously discussed, pre-SRS embolization to limit the size of the nidus (limiting the size of the SRS target) has also been described.23,30 While this incurs ischemic risks during embolization secondary to en passage vessels and adjacent perforating vessels, in addition to the risks associated with radiation, this technique can be employed for high-risk lesions. Long-term data for SRS treatment of sylvian AVMs identified 3% transient morbidity with no longer-term neurologic morbidity secondary to treatment.22 Despite these low risks, one death (1.1% mortality rate) was observed due to a hemorrhage during the latent period. In comparison, resection has been shown to be associated with a 3% risk of permanent neurologic injury; however, complete removal provides immediate protection for AVM hemorrhage. No single treatment paradigm exists for sylvian AVMs, and treatment must be tailored to each individual patient based on AVM anatomy, age, and comorbidities.

Multimodal Approaches to Sylvian AVMs: Representative Cases As discussed, the natural vascular and cortical anatomical characteristics of sylvian AVMs necessitate careful treatment planning, often with multimodal

approaches. Unique cases and other scenarios are presented to highlight the risks of these lesions and their treatments and the complementary nature of the different modalities of treatment. RADIOSURGERY AND DELAYED MICROSURGICAL RESECTION A woman in the fourth decade of life presented with seizures despite antiepileptic medication. MRI demonstrated a right sylvian AVM filling most of the fissure (Fig. 34.1A; see also Fig. 34.1C and D). Diagnostic angiography demonstrated a grade IV pure sylvian AVM with feeders from the right MCA and numerous divisions along with some feeders from the lenticulostriate vessels (Fig. 34.1B). Drainage was both superficial and deep. After multidisciplinary discussion, the following options were presented to the patient: (1) continued medical management; (2) multistage embolization after provocative and superselective angiographic testing, followed by resection; and (3) fractionated SRS in two fractions. She opted for and underwent staged radiosurgery. The total lesion volume was 36.6 cm3. Given the volume and to minimize radiation dose to the surrounding tissue, we divided the lesion into two fractions. The inferior/anterior segment was treated with 22 Gy to the 50% isodose line. Three months later, the superior/ posterior segment was treated with the same fraction. Approximately 18 months after the second treatment, the patient developed radiation necrosis refractory to dexamethasone, pentoxifylline, and vitamin E treatment. She underwent intraarterial bevacizumab (Avastin) therapy, with some reduction of MRI findings and clinical symptoms. However, she continued to have symptoms of visual field loss and left-sided weakness, as well as MRI findings consistent with persistent necrosis and edema (Fig. 34.1E). Digital subtraction angiography showed interval reduction of the AVM, with a small residual (Fig. 34.1F). The patient then underwent a craniotomy and resection of the residual AVM. Of note, there were minimal small residual arterial attachments, with only small feeders from the main MCA divisions, which could be clearly identified and maintained from the AVM scar. Postoperative MRI showed encephalomalacia at the resection site, with interval reduction in surrounding edema (Fig. 34.1G). Postoperative angiography

34

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AVMs of the Sylvian Fissure

A

C

B

D

Fig. 34.1 Sylvian AVM treated with staged stereotactic radiosurgery and microsurgical resection. Axial T2-weighted MR image (A) obtained before treatment demonstrates a large grade IV AVM occupying the right sylvian fissure. Pretreatment angiogram in the lateral plane (B) demonstrates the contribution of the middle cerebral artery (MCA) and lenticulostriates. Sagittal (C) and axial (D) illustrations show the positioning of the AVM in the fissure with en passage vessels. Continued

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PART 2 The Physician-Centered Approach

E

F

G

H

Fig. 34.1, Cont’d After fractionated radiosurgery, the patient developed refractory radiation necrosis and edema, evident on FLAIR MRI (E). Angiography (F) demonstrated significant obliteration of the AVM with only a small residual; en passage vessels were now identifiable on angiogram. After resection of the scar and residual AVM, FLAIR MRI (G) showed improvement in cerebral edema, while angiography showed obliteration of the AVM with preservation of major MCA branches (H).

showed complete resection with no residual, and maintenance of the en passage MCA branches (Fig. 34.1H). The patient’s overall neurological condition improved with only a small residual visual field cut. She does continue to suffer seizures, although the frequency is reduced.

HEMORRHAGE AFTER RADIOSURGERY A man in his third decade of life initially presented with a sylvian intracranial hemorrhage and was found to have a small AVM in the posterior/superior sylvian fissure (Fig. 34.2A). He underwent a craniotomy for evacuation of hematoma and then underwent SRS for

34

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AVMs of the Sylvian Fissure

A

B

C

D Fig. 34.2 Delayed hemorrhage after stereotactic radiosurgery (SRS) treated with microsurgical resection. Lateral view angiogram (A) demonstrates posterior sylvian AVM. After initial SRS treatments, the patient presented in a delayed fashion years later with a hemorrhage (B). After the hemorrhage resolved, angiography showed a small residual that is difficult to characterize on cervical internal carotid angiogram (C). Embolization was attempted, but superselective angiography (D) demonstrated an en passage vessel very close to the nidus. Any reflux would likely cause ischemic complications. Angiogram obtained after resection (E) demonstrates no residual.

E

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PART 2 The Physician-Centered Approach

treatment of the lesion. Years later, he again presented with hemorrhage (Fig. 34.2B). After the hemorrhage resolved, he was found to have a small residual AVM (Fig. 34.2C) and was initially followed. Twelve years later, he presented with a small rehemorrhage. Superselective angiography was performed with the intent to embolize the residual (Fig. 34.2D); however, the main MCA branch to the residual was en passage, and embolization was aborted given the high risk of an ischemic complication should any embolic material reflux. The patient then underwent a craniotomy for resection of the remaining lesion. Superselective angiography was helpful in demonstrating the anatomical course of the en passage vessel. This was identified as deep and superior to the AVM nidus. The small branch to the AVM was cauterized, and the lesion was resected. Postoperative angiography showed complete resection without residual (Fig. 34.2E). SUMMARY These case examples highlight the multimodal approaches that may be required to treat these complex lesions. There should be a willingness to re-examine one’s approach to each lesion, to address complications, and to employ multiple techniques when needed. These cases also highlight the ever-present issue of en passage vessels and how that specific anatomical element may force changes in treatment approaches.

Prenidal and Intranidal Aneurysms The presence of prenidal and intranidal aneurysms increases the risk profile of AVMs significantly. The presence of these high-risk characteristics has not only been associated with a heightened risk of subsequent hemorrhage but is also associated with hemorrhage during the latent period after SRS treatment and before AVM occlusion occurs.3,22,31 Additionally, the presence of aneurysms increases the risk associated with blood loss and increased surgical morbidity in surgically treated sylvian AVMs as well. Endovascular embolization of prenidal and intranidal aneurysms provides an additional avenue to limit or eliminate the risk these features pose. In AVMs harboring these aneurysms, embolization of the aneurysm prior to either planned SRS or surgery is recommended unless the aneurysm can be readily

surgically addressed. Care must be taken to avoid ischemic complications that may arise from embolization of these lesions, particularly if the aneurysm arises from, or in close proximity to, en passage vessels. Using a multimodal approach for this particular subset of sylvian AVMs can decrease potential morbidity associated with their treatment.

Conclusion Sylvian AVMs are unique lesions with substantial risk associated with their treatment given anatomic factors such as adjacent eloquent cortex and potential entanglement with the native MCA vasculature. Nonetheless, treatment options, including open resection, endovascular embolization, and SRS, can be employed with high efficacy and a relatively low rate of morbidity. With the unique anatomic risks, a multimodal approach utilizing a combination of two or more of these techniques can provide a safe and effective treatment option for sylvian AVMs. Therefore in communicating with patients, it is vital to discuss all these tools, the possibility of multistaged approaches, and the high-risk nature of the lesions. REFERENCES 1. Al-Shahi R, Warlow C. A systematic review of the frequency and prognosis of arteriovenous malformations of the brain in adults. Brain. 2001;124(pt 10):1900–1926. https://doi. org/10.1093/brain/124.10.1900. 2. Lawton MT, Lu DC, Young WL, UCSF Brain AVM Study Project. Sylvian fissure arteriovenous malformations: an application of the Sugita classification to 28 surgical patients. Neurosurgery. 2007;61(1):29–36; discussion 36–38. https://doi. org/10.1227/01.neu.0000279721.60155.08. 3. Hernesniemi JA, Dashti R, Juvela S, Vaart K, Niemela M, Laakso A. Natural history of brain arteriovenous malformations: a longterm follow-up study of risk of hemorrhage in 238 patients. Neurosurgery. 2008;63(5):823–829; discussion 829–831. https://doi.org/10.1227/01.NEU.0000330401.82582.5E. 4. Liu L, Li H, Zheng J, Wang S, Zhao J, Cao Y. Sylvian fissure arteriovenous malformations: long-term prognosis and risk factors. Neurosurg Rev. 2013;36(4):541–549; discussion 549. https://doi.org/10.1007/s10143-013-0470-1. 5. Sugita K, Takemae T, Kobayashi S. Sylvian fissure arteriovenous malformations. Neurosurgery. 1987;21(1):7–14. https:// doi.org/10.1227/00006123-198707000-00003. 6. Tarokhian A, Sabahi M, Dmytriw AA, Arjipour M. Sylvian fissure arteriovenous malformations: case series and systematic review of the literature. Neuroradiol J. 2021;34(6):656–666. https://doi.org/10.1177/19714009211021776. 7. Potts MB, Young WL, Lawton MT. UCSF Brain AVM Study Project. Deep arteriovenous malformations in the basal ganglia, thalamus, and insula: microsurgical management, techniques,

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8.

9.

10.

11.

12.

13. 14.

15.

16.

17.

18.

19.

AVMs of the Sylvian Fissure and results. Neurosurgery. 2013;73(3):417–429. https://doi. org/10.1227/NEU.0000000000000004. Pabaney AH, Reinard KA, Massie LW, et al. Management of perisylvian arteriovenous malformations: a retrospective institutional case series and review of the literature. Neurosurg Focus. 2014;37(3):E13. https://doi. org/10.3171/2014.7.FOCUS14246. Heros RC. Arteriovenous malformations of the medial temporal lobe. Surgical approach and neuroradiological characterization. J Neurosurg. 1982;56(1):44–52. https://doi.org/10.3171/ jns.1982.56.1.0044. Oka N, Kamiyama K, Nakada J, Endo S, Takaku A. Surgical approach to arteriovenous malformation of the medial temporal lobe--report of three cases. Neurol Med Chir (Tokyo). 1990; 30(12):940–944. https://doi.org/10.2176/nmc.30.940. Malik GM, Seyfried DM, Morgan JK. Temporal lobe arteriovenous malformations: surgical management and outcome. Surg Neurol. 1996;46(2):106–114; discussion 114–115. https://doi. org/10.1016/0090-3019(96)00084-5. Yamada S, Brauer F, Dayes L, Yamada S. Surgical techniques for arteriovenous malformations in functional areas: focus on the superior temporal gyrus. Neurol Med Chir (Tokyo). 1998; 38(Suppl):222–226. https://doi.org/10.2176/nmc.38.suppl_222. Zimmerman G, Lewis AI, Tew JM Jr. Pure sylvian fissure arteriovenous malformations. J Neurosurg. 2000;92(1):39–44. https://doi.org/10.3171/jns.2000.92.1.0039. Du R, Young WL, Lawton MT. "Tangential" resection of medial temporal lobe arteriovenous malformations with the orbitozygomatic approach. Neurosurgery. 2004;54(3):645– 651; discussion 651–652. https://doi.org/10.1227/01. neu.0000109043.56063.ba. Bostrom A, Schaller K, Seifert J, Schramm J. The place for surgical treatment for AVM involving the temporal lobe. Acta Neurochir (Wien). 2011;153(2):271–278. https://doi. org/10.1007/s00701-010-0885-1. Gabarros Canals A, Rodriguez-Hernandez A, Young WL, Lawton MT. UCSF Brain AVM Study Project. Temporal lobe arteriovenous malformations: anatomical subtypes, surgical strategy, and outcomes. J Neurosurg. 2013;119(3):616–628. https://doi.org/10.3171/2013.6.JNS122333. Lopez-Ojeda P, Labib M, Burneo J, Lownie SP. Temporal lobe arteriovenous malformations: surgical outcomes with a focus on visual field defects and epilepsy. Neurosurgery. 2013;73(5):854–862; discussion 862; quiz 862. https://doi. org/10.1227/NEU.0000000000000122. Ding D, Buell TJ, Raper DM, et al. Sylvian arteriovenous malformation resection and associated middle cerebral artery aneurysm clipping: technical nuances of concurrent surgical treatment. Cureus. 2018;10(2):e2166. https://doi.org/10.7759/ cureus.2166. Nguyen TN, Chin LS, Souza R, Norbash AM. Transvenous embolization of a ruptured cerebral arteriovenous malformation with en-passage arterial supply: initial case report. J Neurointerv Surg. 2010;2(2):150–152. https://doi.org/10.1136/ jnis.2009.001289.

347 20. Lunsford LD, Kondziolka D, Flickinger JC, et al. Stereotactic radiosurgery for arteriovenous malformations of the brain. J Neurosurg. 1991;75(4):512–524. https://doi.org/10.3171/ jns.1991.75.4.0512. 21. Maruyama K, Kawahara N, Shin M, et al. The risk of hemorrhage after radiosurgery for cerebral arteriovenous malformations. N Engl J Med. 2005;352(2):146–153. https://doi. org/10.1056/NEJMoa040907. 22. Bowden G, Kano H, Tonetti D, et al. Stereotactic radiosurgery for sylvian fissure arteriovenous malformations with emphasis on hemorrhage risks and seizure outcomes. J Neurosurg. 2014;121(3):637–644. https://doi. org/10.3171/2014.5.JNS132244. 23. Gobin YP, Laurent A, Merienne L, et al. Treatment of brain arteriovenous malformations by embolization and radiosurgery. J Neurosurg. 1996;85(1):19–28. https://doi.org/10.3171/ jns.1996.85.1.0019. 24. Steiner L, Lindquist C, Adler JR, Torner JC, Alves W, Steiner M. Clinical outcome of radiosurgery for cerebral arteriovenous malformations. J Neurosurg. 1992;77(1):1–8. https://doi. org/10.3171/jns.1992.77.1.0001. 25. Wikholm G, Lundqvist C, Svendsen P. Embolization of cerebral arteriovenous malformations: part I--technique, morphology, and complications. Neurosurgery. 1996;39(3):448–457; discussion 457–459. https://doi.org/10.1097/00006123199609000-00004. 26. Monaco EA III, Niranjan A, Kano H, Flickinger JC, Kondziolka D, Lunsford LD. Management of adverse radiation effects after radiosurgery for arteriovenous malformations. Prog Neurol Surg. 2013;27:107–118. https://doi. org/10.1159/000341647. 27. Zhan PL, Jahromi BS, Kruser TJ, Potts MB. Stereotactic radiosurgery and fractionated radiotherapy for spinal arteriovenous malformations - a systematic review of the literature. J Clin Neurosci. 2019;62:83–87. https://doi.org/10.1016/j. jocn.2018.12.014. 28. Zhong J, Press RH, Olson JJ, Oyesiku NM, Shu HG, Eaton BR. The use of hypofractionated radiosurgery for the treatment of intracranial lesions unsuitable for single-fraction radiosurgery. Neurosurgery. 2018;83(5):850–857. https://doi.org/10.1093/ neuros/nyy145. 29. Franzin A, Panni P, Spatola G, et al. Results of volume-staged fractionated Gamma Knife radiosurgery for large complex arteriovenous malformations: obliteration rates and clinical outcomes of an evolving treatment paradigm. J Neurosurg. 2016;125(Suppl 1):104–113. https://doi.org/10.3171/2016.7. GKS161549. 30. Dawson RC III, Tarr RW, Hecht ST, et al. Treatment of arteriovenous malformations of the brain with combined embolization and stereotactic radiosurgery: results after 1 and 2 years. AJNR Am J Neuroradiol. 1990;11(5):857–864. 31. Kano H, Kondziolka D, Flickinger JC, et al. Aneurysms increase the risk of rebleeding after stereotactic radiosurgery for hemorrhagic arteriovenous malformations. Stroke. 2012;43(10):2586– 2591. https://doi.org/10.1161/STROKEAHA.112.664045.

Chapter 35

Pediatric AVMs Andrew L.A. Garton, Alexandra M. Giantini-Larsen, Mark M. Souweidane

Chapter Outline Introduction Incidence Developmental Biology Natural History and Common Presentations Workup and Evaluation of iAVMs Preoperative Embolization vs Curative Embolization Stereotactic Radiosurgery Resection Surveillance Conclusion

Introduction As with many rare disease entities, the incidence of pediatric intracranial arteriovenous malformations (iAVMs) has risen in accordance with the improving sensitivity of evolving imaging modalities and the earlier detection of asymptomatic and small iAVMs in childhood. The guiding principles for emergent management have always been patient stabilization in an intensive care unit, treatment of raised intracranial pressure, and possible hematoma evacuation and AVM resection if indicated. The acute period further requires the diagnostic identification of any potential high-risk features of the ruptured AVM angioarchitecture. As endovascular and radiosurgical techniques for dealing with pediatric AVMs have improved in the last few decades, subsequent management necessitates interdisciplinary discussion and a holistic assessment of the risks and benefits of treatment. In this chapter, we will review the biology, natural history, and common presentations of pediatric iAVMs. Indications and considerations for intervention are 348

considered, including a focus on multidisciplinary management. Guidelines for pre- and postoperative imaging are offered. Literature on AVM management during pregnancy and childbirth is not addressed here, and our focus remains on pial AVMs only as opposed to choroidal AVMs or vein of Galen malformations.

Incidence There are no population-level screening studies on iAVMs in the pediatric literature, therefore inferences about frequency are made from clinical samples. Autopsy studies suggest that the prevalence of iAVMs in the general population is 0.06%–0.11%, with pediatric iAVMs comprising 10%–20%.1,2 However, ruptured AVMs account for a much higher proportion of spontaneous intracranial hemorrhages in pediatric patients than in adults: 30%–50% compared to 1.4%–2%, respectively.3,4 Once diagnosed, the annual risk of rupture of pediatric iAVMs, though dependent on factors described later, tends to vary between 4% and 5.5%.3 Once ruptured, the rerupture rate remains roughly the same (2%–4%), though with a mortality rate of 25% per event.5 AVMs remain the most common cause of spontaneous intracranial hemorrhage in children. Historically, iAVMs in children were discovered after the development of symptoms: hemorrhage, seizure, mass effect, or hydrocephalus represent the most common presentations. However, as with many neurosurgical pathologies, as both the sensitivity of imaging modalities and access to healthcare improves, more iAVMs are being discovered before symptom onset. Prior to 2000, the discovery of asymptomatic pediatric iAVMs was rare. Recent data from the last decade suggest that improved imaging and its frequent use are responsible for up

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to 33% of newly diagnosed iAVMs in children being found incidentally.6 This percentage would only be expected to rise as access to and resolution of imaging technology improves. Ultimately, though the incidence of pediatric iAVMs may not be high, the severity of the clinical setting in which they present combined with the morbidity associated with observation of ruptured or otherwise symptomatic lesions make this an important disease entity to recognize and treat when indicated.

Developmental Biology While it is believed that there is a subset of adult iAVMs that are acquired later in life, pediatric iAVMs are understood to be largely congenital or at least immediately postnatal acquisitions. Normal vasculogenesis and angiogenesis are driven by vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and transforming growth factor-B1 (TGF-B1), and these growth factors undoubtedly play a role in the pathophysiology of AVMs. VEGF receptors are highly expressed during embryonic vascular development, resulting in ensuing proliferation and, in pathological entities, overdevelopment of vascular structures—these receptors subsequently become downregulated throughout adult life to a more quiescent state. Abnormally low levels of endothelial cell–specific receptor tyrosine kinases have been found on the surfaces of iAVM specimens, suggesting aberrant vascular phenotype. Low expression may contribute to poor peri-endothelial cell support structures in iAVMs, leading to a theoretically higher risk of hemorrhage.7 Pediatric iAVMs are, relative to cortical volume, larger on average than adult iAVMs; suggested reasons for the larger size of pediatric iAVMs include the high postnatal expression of VEGF on endothelial cells, as well as upregulation of various growth factors following insult or subclinical ischemia during the postnatal period.8 In fact, VEGF expression has shown some correlation with recurrence of iAVMs in the pediatric population.8 Mutations in the KRAS signaling pathway have also been discovered to play a role in both intra- and extracranial AVMs; molecular inhibitors of this pathway have shown promise in the treatment of AVMs as well.9,10

Pearls • Pediatric iAVMs tend to present as symptomatic lesions. Early management centers around general principles of intracranial pressure management, assessment of need for hematoma evacuation, and identification of high-risk angiographic features. • Symptomatic pediatric iAVMs carry a much more substantial risk and should be managed aggressively with a multimodal approach that may include embolization, surgical removal, or stereotactic radiosurgery. • Although AVMs have long been considered congenital lesions, our growing understanding of pediatric AVM biology suggests a complex interplay of vascular endothelial growth factor (VEGF) and flow-related factors that may be responsible for substantial postnatal AVM progression. • Technical surgical considerations specific to pediatric patients center around the tolerance of children to cortical injury and license for aggressive surgical management in the face of more substantial risks associated with iAVM natural history. Additional attention to overall blood volume and surgical blood loss is critical in successful resuscitation and support throughout the operative event. • The long-term data for all three modalities in the treatment of pediatric iAVMs offer substantial hope for definitive cure but also continued opportunities to innovate in the treatment of these complex lesions.

With respect to the timing of development, AVMs have classically been conceptualized as congenital lesions. However, detection rates in Japan suggest that, relative to vein of Galen malformations and dural arteriovenous fistulas, iAVMs are less common in early childhood (5 years of age), suggesting that postnatal development may account for a proportionally larger number of pediatric iAVMs.11

Natural History and Common Presentations ARUBA (A Randomised Trial of Unruptured Brain Arteriovenous Malformations), which purported superior neurologic outcomes of conservative management over active intervention in adult patients with

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unruptured iAVMs, led to much debate regarding the best management practices for these patients. However, with a longer life expectancy and evidence of superior neurologic outcomes in the pediatric population compared with adults, there is reason to advocate for curative therapies for pediatric iAVMs to prevent future hemorrhages.12,13 Only 18% of iAVMs become symptomatic prior to presentation; historical data suggest the following breakdown of clinical presentations in these cases: hemorrhage in 50%, seizure and/or hydrocephalus in 36%, and congestive cardiac failure secondary to shunting in 18% (more common in newborns).2 Once symptomatic, pediatric iAVMs carry significant prospective morbidity and have a more malignant course. Subsequent hemorrhages correspond with a 50% morbidity rate and a 10% mortality rate.14 A child with a new intracranial hemorrhage in the absence of trauma is presumed to have an underlying vascular anomaly until proven otherwise, at least in early management—any attempts to resect clot must be performed in anticipation of discovering an underlying AVM. Children are often therefore treated as aggressively as—if not more aggressively than—their adult counterparts when asymptomatic or symptomatic iAVMs are discovered.

Workup and Evaluation of iAVMs Emergency department or primary care physicians who suspect an intracranial vascular lesion are usually directed in their imaging modality of choice by the acuity of the situation. In our experience, unless the situation is dire, the choice for children is often MRI rather than CT so as to reduce the radiation exposure; the use of CT, however, is also fairly common. CT images of AVMs are not ideal; although it is possible to see hemorrhage and dilated vessels, the overall morphology and specificity of location are not particularly granular. In an emergency, immediate considerations for cerebrospinal fluid (CSF) diversion via a ventriculostomy or a craniectomy for intracranial pressure temporization and/or clot resection include the presence of hydrocephalus, clinical examination findings, the location and size/expansion of a hemorrhage, mass effect, and continued progression

despite medical management. When patients present with hemorrhage or epilepsy, the vast majority (>80%) require an operation.15 Assuming the child does not need to be taken straight to the operating room, characterization of the lesion with vessel imaging is the next step after identification of an iAVM. A CT angiogram is adequate, although it is often avoided due to the contrast burden. The combination of MRI and MR angiography (MRA) offers excellent information about the architecture of feeding vessels, nidus, and early draining vein. It can, however, be a difficult study to obtain without anesthesia in a child. Formal catheter angiography is the gold standard, and it is the most sensitive and specific diagnostic test for an AVM. This is particularly true with respect to its use after resection to ascertain definitive removal.

Preoperative Embolization vs Curative Embolization Preoperative embolization is an important consideration in many cases in which management with microsurgical resection or radiosurgery is planned. Historically, the success rate of embolization alone has not approached that of surgery plus embolization to prevent further hemorrhage or achieve a radiographic cure. In 1995, Frizzel and Fisher published a series of over 1200 patients (adult and pediatric) with iAVMs who were treated with embolization with intent to cure, reporting a 5% success rate with a roughly 10% risk of morbidity.16 However, more recent, smaller case series have shown more encouraging outcomes. A 2014 Chinese study of endovascular treatment of Spetzler-Martin grade I–III AVMs in 66 pediatric patients reported an obliteration rate of 21% and a mean size reduction of 78%.17 The complication rate was 7.3%, and there were no deaths.17 A 2013 study involving 25 pediatric patients in the United States showed complete AVM obliteration after endovascular embolization in only 12% and partial obliteration in the other 88%.18 Another smaller series from Brazil, published in 2016, included 23 pediatric patients with iAVMs ranging in Spetzler-Martin grade from I to IV, and the authors reported complete angiographic occlusion without complication in 83% of the patients.19 These patients were all treated with Onyx embolization. However, an additional 9% required

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immediate surgical intervention following angiography for hemorrhage and achieved subsequent obliteration. Complications were observed in 13% of patients. A recent large meta-analysis conducted in 2019 compiled data from nearly 600 cases of iAVMs (mostly in adults) treated with endovascular embolization and found a complete obliteration rate in 46% of the entire cohort, with an overall complication rate of 24.1% and the most common complication being hemorrhage.20 Therefore while curative embolization is achievable in some lowgrade AVMs, it carries a legitimate risk of periprocedural hemorrhage requiring further intervention and should only be carried out at tertiary care centers capable of ­ handling these complications. Partial embolization is increasingly common, particularly for larger and more complex lesions. It may be performed as part of a staged treatment plan, either serial embolizations or preradiosurgical embolization, for unresectable lesions, such as those deep in the brainstem or thalami. However, the use of partial

A

B

embolization for large superficial lesions is also appropriate when directed toward simplifying a surgery or reducing the risk of blood loss. In treating these large lesions, it is important to selectively embolize a few arteries at a time so as to reduce dramatic changes to the flow dynamics through already fragile endothelial architecture (see Figs. 35.1–35.3). Overall, endovascular embolization may be a reasonable choice as a sole or adjunctive treatment for a specific iAVM, depending on the size and characteristics of the malformation. This therapeutic modality will continue to evolve and improve and should be incorporated into the treatment paradigm for the pediatric population, although there is still a need for data on the long-term sequelae and potential adverse effects of embolic material. Palliative treatment should be focused on flow-related or symptom-directed endpoints (securing a flow-related or nidal aneurysm, ensuring orthograde cortical venous drainage, resolving symptomatic steal phenomena).

C

D

Fig. 35.1 Images from initial workup of a young boy who presented with acute-onset headaches. The noncontrast head CT image (A) demonstrates spontaneous cerebellar intraparenchymal hemorrhage. Subsequent emergent vessel imaging (B–D; coronal, axial, and sagittal views) demonstrates a predominantly left mesial cerebellar AVM with deep drainage into the straight sinus.

Fig. 35.2 Images from the case of a teenager who presented subacutely with nausea and fatigue. The initial head CT scan (A) shows a predominantly parenchymal bleed. The patient subsequently underwent digital subtraction angiography, which revealed a large high-grade AVM (B and C). The AVM was treated successfully with a liquid embolic agent, as shown in the post-embolization angiogram (D).

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A

B

C

D

Fig. 35.3 Angiographic images from the case of a large occipital AVM (A) that was treated in a stepwise fashion with embolization (B) and microsurgical resection. The 1-year follow-up images (C and D) show no recurrence.

Stereotactic Radiosurgery In treating iAVMs, the goal of stereotactic radiosurgery (SRS), in contrast to embolization, is unequivocally the complete obliteration of the lesion with preservation of neurological function in surrounding tissue. SRS was first used for pediatric AVMs in 1989; the delayed utilization is perhaps attributable to the fear of exposing children to the amount of radiation involved in radiosurgery. However, there are numerous studies that validate the safety profile of SRS in children.21–23 In a series of 200 children followed for a median of 14 years, initial single-session radiosurgery resulted in an iAVM obliteration rate of 49.5%; this percentage increased to 58.6% in those who underwent subsequent sessions after detected recurrence.21 Partial obliteration was associated with a risk of hemorrhage roughly equivalent to that associated with the natural history of the condition (2.4%–2.6% annual risk overall).21 Other studies

have demonstrated SRS as a potent postoperative adjunct to suspected incomplete resection: in a series of 105 patients in which 50 were treated surgically, 92% achieved complete obliteration after surgery. In half of the cases in which resection was incomplete, complete obliteration was achieved after subsequent SRS.4 Possible complications not seen with embolization and surgery are driven by exposure of normal brain parenchyma and vasculature to radiation, namely radiation necrosis, secondary tumors, and ­ vasculopathies. Of 17 patients treated in Philadelphia with SRS, 2 developed radiation necrosis and 2 more developed clinically meaningful vasculopathies, a rate of 24.5% overall.24 These numbers have improved over time, but it remains true that the best outcomes appear to be for the smallest lesions. Therefore radiosurgery may be best suited for those unresectable AVMs that can be shrunk through embolization before SRS is performed (see Fig. 35.4).

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Fig. 35.4 Initial CT image (A), angiographic images (B and C), and follow-up MR image (D) from the case of a high-functioning college student who was found acutely obtunded with spontaneous intraventricular hemorrhage secondary to a mesial temporal AVM deemed unsafe for resection. The patient was admitted to an intensive care unit and treated with external ventricular drainage, which resulted in improvement. Ultimately, she underwent stereotactic radiosurgery. The axial MR image obtained at follow-up demonstrates near-complete obliteration.

Resection SURGICAL TECHNIQUE Preoperative planning involves evaluating preoperative angiography, intraoperative stereotaxis, coordination with anesthesia, and preparations for intraoperative rupture. Children have less hemodynamic reserve than adults, and the standard of care includes the use of arterial and central venous lines as well as electroencephalography or some equivalent external neuromonitoring. In addition, blood products should be available in case of intraoperative loss. Positioning requires three-pin fixation or, for children under 2 years of age, a simple padded headrest. Depending on the location of the malformation, intraoperative adjuncts may include functional MRI with digital tractography or intraoperative mapping. The craniotomy itself abides by the general principles of pediatric neurosurgery, including the minimization of blood loss with meticulous hemostasis and great care to avoid unintentional durotomy as the bone can be thin. In addition, it is important to be cognizant of the contribution of meningeal vessels to the vascular malformation. Microsurgery may be used as early as the surgeon deems necessary; once the lesion is identified, dissection of the AVM follows circumferentially with the careful identification and distinguishing of abnormal from normal blood vessels. Care must be taken not to sacrifice vessels feeding normal parenchyma, and draining veins should not be taken until the arterial supply has been extirpated completely. This reduces the risk of elevating pressures inside the AVM leading to rupture.

COMMON COMPLICATIONS Intraoperative hemorrhage is the most lethal complication before, during, and after iAVM resection. In children, it is particularly important to control intraoperative blood loss, because, as previously mentioned, they have much smaller reserve than adults. Shock can be induced by losing >25% of total blood volume, which can roughly be calculated by multiplying the patient’s weight in kilograms by 80; thus a 20-kg child can go into shock by losing approximately 400 mL of blood. Impending shock, signaled by hypotension and tachycardia, may forestall further dissection. It is important to coordinate carefully with team members responsible for anesthesia and other members of the operative team to stay vigilant to blood loss, and every effort should be made to minimize bleeding at every stage, including scalp incision, craniotomy, and dural opening. Aside from hemorrhage, potential intraoperative complications include injury of surrounding parenchyma, less likely due to direct trauma and more likely due to interruption of either arterial inflow or venous outflow supply. Often, correlating the preoperative MRI with an angiogram can help clarify which vessels may be safe to sacrifice. In the event of cerebral swelling secondary to infarct or trauma, intracranial pressure can be controlled by elevating the head of the bed, checking for and alleviating any physical compression of the jugular system, administering steroid and/or hypertonic agents, or CSF diversion. Intraoperative seizures are rare, but when they do occur, they can often be controlled with anesthetic modification or cortical administration of cold saline.

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Presentation

Treatment

Recurrence

Repeat angiogram at 1 year

Intraoperative or postoperative angiogram to confirm obliteration

No residual

Repeat angiogram at 3 years Addition of MRI/MRA does not appear to improve sensitivity for detecting recurrence

3 years coincides with literature-reported median time to recurrence

If no recurrence

Repeat angiogram every 5 years

Fig. 35.5 Surveillance algorithm for pediatric patients with surgically treated iAVMs. (Based on Morgenstern et al. Postoperative imaging for detection of recurrent arteriovenous malformations in children. J Neurosurg Pediatr. 2016;17(2):134–140.)

In the immediate postoperative setting, a hematoma can be a serious complication requiring reoperation. Usually occurring due to poor cavity hemostasis or residual AVM, this complication can be reduced by performing an intraoperative angiogram to confirm AVM obliteration. New-onset seizures can be observed in over 10% of children after iAVM resection, so it is important to administer a prophylactic antiepileptic.25 However, it is also worth pointing out that fewer than 50% of these patients require long-term ­ antiepileptic therapy, so judicious follow-up is advisable. Vasospasm, stroke, thrombosis, and infection are all rarer though reported complications. It is important to monitor these children very closely in the early ­ postoperative period in an intensive care unit with arterial pressure monitoring.

surgery, endovascular embolization, radiosurgery, or combination therapies, recurrence occurred in 15% of patients. However, none of these recurrences were detected via MRI/MRA.26 The failure of MRI to detect small recurrences has led to the proposal of a new surveillance strategy at our institution (summarized in Fig. 35.5). In all surgically treated pediatric iAVM cases, an intraoperative or early postoperative angiogram is obtained to confirm complete resection. This is followed by repeat DSA at 1 year and 3 years (the median time to recurrence). Subsequent DSA is performed at 5 years after treatment and every 5 years thereafter; MRI/MRA studies do not appear to provide a statistically meaningful addition to iAVM surveillance in children.26

Surveillance

In summation, pediatric iAVMs represent a disease entity of specific interest both among the population of all iAVMs, given their genetic correlates, propensity for symptomatic presentation, and relative size, and among pediatric sources of intracerebral hemorrhage, given their relative overrepresentation among etiologies and importance of follow-up to detect recurrence. While there is lingering debate about the observation vs intervention in the management of unruptured adult

As discussed earlier, the combination of MRI and MRA often defaults to be the most frequently used modality for the diagnosis and surveillance of iAVMs in children. However, digital subtraction angiography (DSA) remains the most sensitive test, and reliance on MRA may result in underdetection of recurrence following treatment. In a series of 45 children whose iAVMs were treated via

Conclusion

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iAVMs, pediatric iAVMs generally warrant treatment because of the patients’ age at presentation, the predicted risk of hemorrhage, and repercussions of observational management. The choice of treatment modality, however, depends on multiple considerations and should be based on interdisciplinary discussion between surgical, interventional, and radiosurgical specialists.

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14.

15.

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Roentgenol. 2020;215(2):472–487. https://doi.org/10.2214/ AJR.19.22443. Fullerton HJ, Achrol AS, Johnston SC, et al. Long-term hemorrhage risk in children versus adults with brain arteriovenous malformations. Stroke. 2005;36(10):2099–2104. https://doi. org/10.1161/01.STR.0000181746.77149.2b. Ondra SL, Troupp H, George ED, Schwab K. The natural history of symptomatic arteriovenous malformations of the brain: a 24-year follow-up assessment. J Neurosurg. 1990;73(3):387–391. https://doi.org/10.3171/jns.1990.73.3.0387. Humphreys RP, Hoffman HJ, Drake JM, Rutka JT. Choices in the 1990s for the management of pediatric cerebral arteriovenous malformations. Pediatr Neurosurg. 1996;25(6):277–285. https://doi.org/10.1159/000121140. Frizzel RT, Fisher WS. Cure, morbidity, and mortality associated with embolization of brain arteriovenous malformations: a review of 1246 patients in 32 series over a 35-year period. Neurosurgery. 1995;37(6):1031–1039; discussion 1039–1040. https://doi.org/10.1227/00006123-199512000-00001. Zheng T, Wang Q-J, Liu Y-Q, et al. Clinical features and endovascular treatment of intracranial arteriovenous malformations in pediatric patients. Childs Nerv Syst. 2014;30(4):647–653. https://doi.org/10.1007/s00381-013-2277-3. Soltanolkotabi M, Schoeneman SE, Alden TD, et al. Onyx embolization of intracranial arteriovenous malformations in pediatric patients. J Neurosurg Pediatr. 2013;11(4):431–437. https:// doi.org/10.3171/2013.1.PEDS12286. de Castro-Afonso LH, Nakiri GS, Oliveira RS, et al. Curative embolization of pediatric intracranial arteriovenous malformations using Onyx: the role of new embolization techniques on patient outcomes. Neuroradiology. 2016;58(6):585–594. https://doi.org/10.1007/s00234-016-1666-1. Wu EM, El Ahmadieh TY, McDougall CM, et al. Embolization of brain arteriovenous malformations with intent to cure: a systematic review. J Neurosurg. 2019;132(2):388–399. https://doi. org/10.3171/2018.10.JNS181791. Yen CP, Monteith SJ, Nguyen JH, Rainey J, Schlesinger DJ, Sheehan JP. Gamma Knife surgery for arteriovenous malformations in children. J Neurosurg Pediatr. 2010;6(5):426–434. https://doi.org/10.3171/2010.8.PEDS10138. Kano H, Kondziolka D, Flickinger JC, et al. Stereotactic radiosurgery for arteriovenous malformations, part 2: management of pediatric patients. J Neurosurg Pediatr. 2012;9(1):1–10. https://doi.org/10.3171/2011.9.PEDS10458. Yamamoto M, Akabane A, Matsumaru Y, Higuchi Y, Kasuya H, Urakawa Y. Long-term follow-up results of intentional 2-stage Gamma Knife surgery with an interval of at least 3 years for arteriovenous malformations larger than 10 cm3. J Neurosurg. 2012;117(Suppl):126–134. https://doi.org/10.3171/ 2012.6.GKS12757. Maity A, Shu H-KG, Tan JE, et al. Treatment of pediatric intracranial arteriovenous malformations with linear-acceleratorbased stereotactic radiosurgery: The University of Pennsylvania experience. Pediatr Neurosurg. 2004;40(5):207–214. https://doi. org/10.1159/000082293. Yeh H, Tew JM, Gartner M. Seizure control after surgery on cerebral arteriovenous malformations. J Neurosurg. 1993;78(1):12–18. https://doi.org/10.3171/jns.1993.78.1.0012. Morgenstern PF, Hoffman CE, Kocharian G, Singh R, Stieg PE, Souweidane MM. Postoperative imaging for detection of recurrent arteriovenous malformations in children. J Neurosurg Pediatr. 2016;17(2):134–140. https://doi.org/10.3171/2015.6.PEDS14708.

Chapter 36

Residual AVMs Gary Kocharian and Justin Schwarz

Chapter Outline Introduction Types of Residual Management of Residual AVMs Conclusion

radiosurgery or open surgery. The decision-making involved in selecting subsequent treatments is complex and can vary based on the initial treatment modality used, the patient’s clinical status, and the anatomical characteristics of the patient’s AVM. To better understand how to treat residual iAVMs, clinicians must first appreciate how residuals occur and how best to avoid them.

Introduction

Types of Residual

The primary goal in the management of intracranial arteriovenous malformations (iAVMs) is the total obliteration or resection of the AVM nidus. This is the only way to eliminate the risk of future hemorrhage. The cure rate for iAVMs treated with microsurgical resection ranges from 70% to more than 90%, depending on the characteristics of the lesion.1 With radiosurgery, cure rates range from 60% to 80%, and a long period of observation is required until obliteration occurs.2 AVM cure with embolization alone is rare, but possible in select cases.3 Given the complexity of this disease entity and the various treatment options available, posttreatment residual can occur. The incidence of residual iAVMs varies based on the Spetzler-Martin grade of the lesion and the initial treatment that is utilized. For example, resection of an iAVM with a low Spetzler-Martin grade is unlikely to result in a residual nidus, whereas staged embolization as the sole treatment of a high-grade iAVM will almost certainly leave the patient with residual nidus. Thus the proper initial management of iAVMs is of the utmost importance. The management of residual iAVMs is challenging, and as in initial iAVM treatment, there are multiple modalities available to clinicians, including observation, stereotactic radiosurgery (SRS), microsurgical resection, or embolization, which can be done alone or in combination with

POSTSURGERY Historically, microsurgical resection is the gold standard for iAVM treatment, with complete removal of the AVM nidus virtually eliminating the risk of rupture. Given the natural history of iAVMs, it is essential to minimize the risk of leaving residual nidus at the time of surgery. Immediately after microsurgical resection of an iAVM, patients with residual lesions may be at particularly increased risk of rupture compared to those whose lesions are managed conservatively or treated with SRS.4 In addition, residual nidus portends a significantly higher long-term risk of AVM hemorrhage.5 Leaving residual AVM in microsurgical resection may be intentional, to minimize postoperative morbidity, or unintentional, due to the inability to appreciate remaining nidus at the time of surgery. Residual AVM is particularly likely in cases in which the nidus is deep-seated in the basal ganglia or thalami.6 Obliteration rates following resection are more variable for deep AVMs than for lesions that are easier to access; one meta-analysis found a wide range of cure rates, from 67% to 100%.1 A retrospective analysis of a series of deep AVMs treated with resection demonstrated a radiographic cure rate of only 71%.4 Many institutions use postoperative or intraoperative angiography or intraoperative

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indocyanine green to ensure complete obliteration of the AVM nidus. Even with intraoperative adjuncts, postoperative recurrence/residual may still occur. A prospective study of surgery for unruptured SpetzlerMartin grade III AVMs found that nearly 3% of cases later showed recurrence on long-term angiographic follow-up, despite intraoperative angiographic confirmation of obliteration.5 While the incidence of unintentional residual is not well documented, some studies have shown rates up to 1.8%.7 Hoh et al. noted an immediate postoperative residual in six patients in their cohort of 324 cases; all six patients in whom residual AVM was identified underwent immediate surgical re-exploration. In this cohort, two patients required more than one re-exploration procedure, with one patient suffering significant morbidity related to surgery. Fig. 36.1 illustrates a separate case in which intraoperative angiography revealed an early draining vein, necessitating immediate ­ re-exploration and resection of residual nidus. These case series demonstrate that while microsurgical resection is the gold standard for obliteration, it is not without risk and may not always be the best option for the treatment of residual nidus. Great care should be taken in preoperative case selection, especially in cases involving higher-grade or deep-seated lesions. Similarly, intraoperative or immediate postoperative angiography is a crucial adjunct to ensure that residual nidus is not unintentionally left behind. These series also demonstrate that postoperative follow-up is important, as a small percentage of patients can have

Pearls • The treatment of residual iAVMs is complex and best avoided with appropriate planning and execution of the initial procedure(s). • Intraoperative angiography, indocyanine green fluorescence, and provocative hypertension are very useful for ruling out residual iAVM at the time of surgery. • Subtotal obliteration after radiosurgery—with no visible nidus but a persistent draining vein—needs to be followed judiciously and is not considered an AVM cure. • Resection of residual iAVM is the preferred treatment, but this general preference must be tempered by accurate risk analysis for all treatment modalities. • Repeat radiosurgery is an option for residual iAVMs in appropriately selected cases with no additional risk factors for hemorrhage (aneurysm or venous stenosis).

residual nidus on follow-up angiography that was not evident on intraoperative or immediate postoperative angiography. POSTRADIOSURGERY Management of residual AVM following SRS differs from management of postsurgical residual, mainly due to the latency to obliteration after SRS. AVM

Fig. 36.1 (A) Pretreatment digital subtraction angiogram showing a Spetzler-Martin grade I right parietal AVM. (B) Initial intraoperative digital subtraction angiogram showing an early draining vein (indicated by a red circle) that required further exploration and resection. (C) Subsequent intraoperative digital subtraction angiogram confirming the absence of early venous filling.

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obliteration following SRS involves progressive vascular insult and thrombosis and eventual occlusion of the intranidal vasculature. This delay in obliteration after initial SRS treatment necessitates a longer period of observation before remaining AVM nidus can be considered true residual that requires subsequent treatment, as illustrated in Fig. 36.2. Consistent radiological follow-up utilizing a combination of time-offlight MR angiography (MRA) and digital subtraction angiography (DSA) is essential to identify those patients with true residual disease. While some consider true residual disease to be nidus that remains 3 years post-SRS, there is evidence that approximately 25% of patients with radiographic evidence of nidus at 3 years will experience delayed AVM obliteration up to 5 years after treatment.2 In the current literature, the published incidence of residual post-SRS is approximately 5%–14%.8 Hemorrhage following SRS strongly suggests the presence of a residual nidus. Various factors contribute to a higher risk of hemorrhage. In a cohort of over 2300 patients with iAVMs treated using SRS, deep AVM location, presence of an intranidal aneurysm, and lower SRS margin doses were independent predictors of post-SRS hemorrhage (odds ratio [OR] 1.86, 2.44, and 0.93, respectively).9 Despite these findings, some studies have shown that a risk of hemorrhage remains after SRS, even with angiographic confirmation of obliteration. Shin et al. followed 236 patients with AVMs treated with SRS (median duration of follow-up,

77 months; range, 1–133 months). Four patients experienced AVM hemorrhage between 16 and 51 months after angiographic confirmation of obliteration, leading to microsurgical resection in two of the four cases.10 Postoperative histological analysis did show a small amount of residual AVM vasculature in these two cases. The annual and cumulative 10-year risks of hemorrhage were calculated to be 0.3% and 2.2%, respectively, in this group of patients with presumed complete AVM obliteration. Nevertheless, the AVM hemorrhage rate did decrease significantly following SRS. One type of post-SRS AVM residual with potential for hemorrhage is seen with subtotal obliteration (STO). STO is defined as obliteration of the AVM nidus with the persistence of an early-filling draining vein on angiography. Abu-Salma et al. evaluated a cohort of 862 patients with AVMs treated with a LINAC system, of whom 121 (14%) were diagnosed as having STO posttreatment. From the time of STO diagnosis to the last follow-up (range, 6–160 months), the rate of hemorrhage was 0% in this group of 121 patients.8 Yen et al. identified 159 patients with STO from a series of 2500 patients treated with Gamma Knife surgery (GKS). Of this cohort, 155 were followed over a period ranging from 5 to 185 months, and similar to the previous group, no hemorrhages were reported following the diagnosis of STO.11 These studies demonstrate that once the diagnosis of STO is established based on angiography, the future risk of hemorrhage is low. Even still, the significance of an early-filling draining

Fig. 36.2 (A) Pretreatment digital subtraction angiogram showing a Spetzler-Martin grade III AVM situated in the right basal ganglia and corona radiata. (B) MR angiogram obtained 6 months after stereotactic radiosurgery (SRS) showing a smaller residual nidus. (C) Digital subtraction angiogram obtained 1 year after SRS showing a significantly decreased residual nidus, but with a persistent early draining vein.

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vein is not well understood, and while some argue that the natural history of STO involves eventual thrombosis of this vessel, there is some evidence of post-SRS hemorrhage in cases of STO.11,12 POSTEMBOLIZATION Given that iAVM treatment solely with embolization is rarely curative, patients treated with this modality alone have the highest incidence of posttreatment residual. Although complete obliteration has been reported with the use of transvenous embolization in complex cases of ruptured high-grade iAVMs, the transarterial route is more commonly used for endovascular management of iAVMs.3 Transarterial embolization can be successful for treating well-selected small lesions, but it is used most widely in conjunction with eventual microsurgical resection or radiosurgery. The rate of durable obliteration achieved with embolization alone varies greatly in the literature but averages near 13% based on a 2011 meta-analysis by van Beijnum et al.1

Management of Residual AVMs In general, intervention should be undertaken for residual AVMs after initial treatment because the risk of hemorrhage persists. This is especially true if the initial indication for treatment was hemorrhage. The strategy of the second stage of treatment for residual AVMs should be guided by the patient’s symptoms, clinical status, and potential morbidity of surgery. Inevitably, patient preference has a large influence on treatment decisions as well. Residual AVMs that are superficial and can be removed without significant morbidity are best treated with open surgery. Repeat resection entails greater risk when the residual nidus is deep within a previous resection cavity or is close to eloquent or deep brain structures. In these situations, SRS is an appropriate and effective option. Radiosurgery may also be an acceptable second-line treatment for those patients who either do not want to undergo another invasive procedure or did not tolerate their initial surgery well. In a retrospective case-control study, Ding et al. evaluated the efficacy of radiosurgery following partial resection of AVMs. They evaluated 88 cases in which residual AVM nidus following resection was treated with radiosurgery. Complete obliteration at 5 years

359 was achieved in 75% of patients, with symptomatic ­ radiation-induced changes in 3%.13 These outcomes did not differ significantly when compared to outcomes for a similar cohort without prior craniotomy. Repeat radiosurgery is also a viable option for some patients who have previously had their iAVM treated with radiation. Peciu-Florianu et al. evaluated patients treated with Gamma Knife radiosurgery (GKRS) as first-line treatment. They found that the 23 patients in their cohort with residual nidus after initial treatment had complete obliteration of the nidus after repeat GKRS treatment when evaluated on 10-year follow-up.14 Similarly, it has been shown that for large inoperable iAVMs, initial low-dose SRS can reduce nidus size and can then be followed by fractionated higher doses to nidi to achieve obliteration over an extended period of time.15 Others have shown the effectiveness of repeat radiosurgery, with a final obliteration rate of 65.3% reported for a series of 103 patients who underwent repeat radiosurgical treatment for residual iAVM.16 Approximately 25% of patients with residual nidus 3 years after initial radiosurgery treatment will have complete obliteration at 5 years. This suggests the need to wait until 5 years after SRS treatment in considering retreatment.2,11,17–19 If residual AVM is found after 5 years, embolization, microsurgical resection, and further SRS remain valid treatment options. While more controversial, endovascular embolization has been described as a potentially curative treatment for selected iAVMs, as a first- or second-line therapy. AVMs amenable to curative endovascular treatment typically have a small nidus and a single draining vein. Sun et al. presented a small cohort of seven consecutive patients with residual AVMs found on angiography 1 month after resection.20 These were all initially Spetzler-Martin grade I or II lesions and were embolized via a single feeding vessel, with complete obliteration noted on follow-up angiography. There is also evidence for endovascular treatment following SRS. Marks et al. reported on six iAVM patients whose lesions did not respond to initial SRS but demonstrated a mean nidus volume reduction of 74% after endovascular embolization.21 In one patient, the AVM remained completely obliterated on 2-year follow-up. Two patients received additional radiosurgery to treat smaller residual nidi. Fig. 36.3 illustrates the effective combination of embolization for an acutely ruptured deep iAVM and subsequent

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Fig. 36.3 (A) Pretreatment digital subtraction angiogram showing a Spetzler-Martin grade II AVM situated in the right basal ganglia. The patient presented with hemorrhage and underwent partial NBCA glue embolization for stabilization, followed by stereotactic radiosurgery (SRS) (B) Digital subtraction angiogram obtained immediately after embolization. (C) Digital subtraction angiogram obtained 3 years after SRS showing complete obliteration.

SRS treatment to achieve complete obliteration. While endovascular embolization is not proven as a robust stand-alone treatment for achieving complete nidus obliteration, it remains a powerful adjunct for preoperative or pre-SRS volume reduction, and for specific AVM angioarchitectures in cases in which more invasive procedures or SRS need to be avoided. Whichever treatment modality or combination of treatments is used, the individual patient and their pathology should guide the decision-making for treatment. Reitz et al. estimated that “10% of AVM treatments may fail because of inadequate selection of either patients or management.”22 In their own cohort of patients, over a third presenting with residual AVMs were readmitted due to intracranial hemorrhage and required resection. Similarly, with initial SRS treatment, adequate planning and timing of radiation dosage can decrease the incidence of residual nidus and subsequent hemorrhage. While various radiologic tools, such as 4D MRI and arterial spin technology, are useful tools for AVM evaluation after SRS, DSA remains the gold standard for detecting residual disease.23–25

Conclusion Avoiding posttreatment residual is essential in the management of iAVMs. Surgical adjuncts such as preoperative angiography and embolization,

intraoperative navigational guidance, and immediate postoperative or intraoperative angiography are useful tools to minimize the chance of residual nidus. Initial case selection is of the utmost importance, especially as it pertains to deep-seated iAVMs and other AVMs with high Spetzler-Martin grades. When residual AVM is noted on follow-up, there is still a wide array of treatment options. The decision of which treatment modality or combination of treatments to use can be complex and should be determined in a multidisciplinary approach, with careful case-by-case evaluation. Generally, microsurgical resection should be undertaken for residual AVMs if they carry a low risk of operative morbidity and if the initial indication for treatment was rupture. Deepseated and large iAVMs or those in eloquent locations may be better treated using radiosurgery due to the lower procedural morbidity, despite the delayed rate of obliteration. Although endovascular embolization will rarely achieve complete obliteration, it may be useful as a curative tool for highly selected cases. More commonly, it is useful as an adjunctive treatment prior to resection or SRS. A multidisciplinary approach involving neurosurgeons, neurologists, neuroradiologists, and interventional neuroradiologists is essential to determine the best treatment paradigms for complex cases of residual AVM, and the approach must be tailored to the individual patient’s needs and expectations.

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REFERENCES 1. van Beijnum J, van der Worp HB, Buis DR, et al. Treatment of brain arteriovenous malformations: a systematic review and meta-analysis. JAMA. 2011;306(18):2011–2019. https://doi. org/10.1001/jama.2011.1632. 2. Lenck S, Schwartz M, Hengwei J, et al. Management of residual brain arteriovenous malformations after stereotactic radiosurgery. World Neurosurg. 2018;116:e1105–e1113. https://doi. org/10.1016/j.wneu.2018.05.180. 3. Iosif C, Mendes GAC, Saleme S, et al. Endovascular transvenous cure for ruptured brain arteriovenous malformations in complex cases with high Spetzler-Martin grades. J Neurosurg. 2015;122(5):1229–1238. https://doi. org/10.3171/2014.9.JNS141714. 4. Potts MB, Jahangiri A, Jen M, et al. Deep arteriovenous malformations in the basal ganglia, thalamus, and insula: multimodality management, patient selection, and results. World Neurosurg. 2014;82(3-4):386–394. https://doi.org/10.1016/j. wneu.2014.03.033. 5. Morgan MK, Assaad N, Korja M. Surgery for unruptured SpetzlerMartin grade 3 brain arteriovenous malformations: a prospective surgical cohort. Neurosurgery. 2015;77(3):362–369; discussion 369. https://doi.org/10.1227/NEU.0000000000000774. 6. Gross BA, Duckworth EAM, Getch CC, Bendok BR, Batjer HH. Challenging traditional beliefs: microsurgery for arteriovenous malformations of the basal ganglia and thalamus. Neurosurgery. 2008;63(3):393–410; discussion 410. https://doi. org/10.1227/01.NEU.0000316424.47673.03. 7. Hoh BL, Carter BS, Ogilvy CS. Incidence of residual intracranial AVMs after surgical resection and efficacy of immediate surgical re-exploration. Acta Neurochir (Wien). 2004;146(1):1–7; discussion 7. https://doi.org/10.1007/s00701-003-0164-5. 8. Abu-Salma Z, Nataf F, Ghossoub M, et al. The protective status of subtotal obliteration of arteriovenous malformations after radiosurgery: significance and risk of hemorrhage. Neurosurgery. 2009;65(4):709–717; discussion 717. https://doi. org/10.1227/01.NEU.0000348546.47242.5D. 9. Ding D, Chen C-J, Starke RM, et al. Risk of brain arteriovenous malformation hemorrhage before and after stereotactic radiosurgery. Stroke. 2019;50(6):1384–1391. https://doi. org/10.1161/STROKEAHA.118.024230. 10. Shin M, Kawahara N, Maruyama K, Tago M, Ueki K, Kirino T. Risk of hemorrhage from an arteriovenous malformation confirmed to have been obliterated on angiography after stereotactic radiosurgery. J Neurosurg. 2005;102(5):842–846. https:// doi.org/10.3171/jns.2005.102.5.0842. 11. Yen CP, Varady P, Sheehan J, Steiner M, Steiner L. Subtotal obliteration of cerebral arteriovenous malformations after Gamma Knife surgery. J Neurosurg. 2007;106(3):361–369. https://doi. org/10.3171/jns.2007.106.3.361. 12. Kondziolka D, Lunsford LD, Flickinger JC. Gamma Knife stereotactic radiosurgery for cerebral arteriovenous malformations. In: Alexander E III, Loeffler JS, Lunsford LD, eds. Stereotactic Radiosurgery. McGraw-Hill; 1993:136–146. 13. Ding D, Xu Z, Shih H-H, Starke RM, Yen C-P, Sheehan JP. Stereotactic radiosurgery for partially resected cerebral

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arteriovenous malformations. World Neurosurg. 2016;85:263– 272. https://doi.org/10.1016/j.wneu.2015.10.001. Peciu-Florianu I, Leroy H-A, Drumez E, et al. Radiosurgery for unruptured brain arteriovenous malformations in the preARUBA era: long-term obliteration rate, risk of hemorrhage and functional outcomes. Sci Rep. 2020;10(1):21427. https:// doi.org/10.1038/s41598-020-78547-0. Jones J, Jang S, Getch CC, Kepka AG, Marymont MH. Advances in the radiosurgical treatment of large inoperable arteriovenous malformations. Neurosurg Focus. 2007;23(6):E7. https://doi. org/10.3171/FOC-07/12/E7. Stahl JM, Chi Y-Y, Friedman WA. Repeat radiosurgery for intracranial arteriovenous malformations. Neurosurgery. 2012;70(1):150–154; discussion 154. https://doi.org/10.1227/ NEU.0b013e31822c5740. Hasegawa H, Hanakita S, Shin M, et al. Long-term outcomes of single-session stereotactic radiosurgery for cerebellar arteriovenous malformation, with a median follow-up of 10 years. World Neurosurg. 2017;98:314–322. https://doi.org/10.1016/j. wneu.2016.10.137. Fokas E, Henzel M, Wittig A, Grund S, Engenhart-Cabillic R. Stereotactic radiosurgery of cerebral arteriovenous malformations: long-term follow-up in 164 patients of a single institution. J Neurol. 2013;260(8):2156–2162. https://doi. org/10.1007/s00415-013-6936-9. Koltz MT, Polifka AJ, Saltos A, et al. Long-term outcome of Gamma Knife stereotactic radiosurgery for arteriovenous malformations graded by the Spetzler-Martin classification. J Neurosurg. 2013;118(1):74–83. https://doi. org/10.3171/2012.9.JNS112329. Sun Y, Li X, Xiong J, Yu J, Lv X. Transarterial Onyx embolization of residual arteriovenous malformation after surgical resection. World Neurosurg. 2019;126:e1242–e1245. https://doi. org/10.1016/j.wneu.2019.03.073. Marks MP, Lane B, Steinberg GK, et al. Endovascular treatment of cerebral arteriovenous malformations following radiosurgery. AJNR Am J Neuroradiol. 1993;14(2):297–303; discussion 304. Reitz M, Schmidt NO, Vukovic Z, et al. How to deal with incompletely treated AVMs: experience of 67 cases and review of the literature. Acta Neurochir Suppl. 2011;112:123–129. https://doi.org/10.1007/978-3-7091-0661-7_22. Lim HK, Choi CG, Kim SM, et al. Detection of residual brain arteriovenous malformations after radiosurgery: diagnostic accuracy of contrast-enhanced four-dimensional MR angiography at 3.0 T. Br J Radiol. 2012;85(1016):1064–1069. https:// doi.org/10.1259/bjr/30618275. Heit JJ, Thakur NH, Iv M, et al. Arterial-spin labeling MRI identifies residual cerebral arteriovenous malformation following stereotactic radiosurgery treatment. J Neuroradiol. 2020;47(1):13–19. https://doi.org/10.1016/j.neurad.2018.12.004. Morgenstern PF, Hoffman CE, Kocharian G, Singh R, Stieg PE, Souweidane MM. Postoperative imaging for detection of recurrent arteriovenous malformations in children. J Neurosurg Pediatr. 2016;17(2):134–140. https://doi. org/10.3171/2015.6.PEDS14708.

Chapter 37

Intraoperative AVM Rupture Redi Rahmani, Lea Scherschinski, Visish M. Srinivasan, Joshua S. Catapano, and Michael T. Lawton

Chapter Outline Introduction Arterial Bleeding Venous Bleeding Nidal Rupture Outcomes Following Rupture Conclusion

hypertrophic arteries must be precisely differentiated. Despite the surgeon’s preparation, skill, experience, and best intentions, every AVM generates some bleeding. Understanding the source of the bleeding is imperative for both maintaining control over the resection and preventing complications. In this chapter, we discuss the surgical techniques to manage three types of bleeding that can occur with AVM resection: arterial bleeding, venous bleeding, and AVM nidal rupture.

Introduction

Arterial Bleeding

Intraoperative rupture (Fig. 37.1) is the most feared complication in the resection of intracranial arteriovenous malformations (iAVMs). Ultimately, the best management of intraoperative rupture is to proceed in a manner that prevents a rupture from occurring. Rupture prevention involves the careful study of preoperative images to generate a mental map of the malformation. The neurosurgeon must be aware of the location of feeding arteries, the venous drainage system, and any high-risk features such as nidal aneurysms and venous outflow obstruction. If preoperative embolization is planned, the changes to the structure and hemodynamics of the AVM must be considered. At surgery, the craniotomy should be large enough to facilitate control of the entire lesion. Making a small craniotomy for aesthetic reasons can add unneeded difficulty and patient morbidity if bleeding occurs. Once the surgery is underway, the neurosurgeon must maintain meticulous technique throughout the entirety of the resection. Arachnoid membranes are sharply dissected. Where parenchymal transgression is required, the boundary is kept clean. At each stage, small vessels are coagulated and cut, maintaining hemostasis before proceeding to further dissection (Fig. 37.2). All the while, arterialized veins and

OBTAINING CONTROL Arterial bleeding originates from the arterial feeders located within the parenchyma, ependyma, or subarachnoid spaces. Control of bleeding can be established using a combination of suction and cottonoid patties. Pressure is applied to the patty using the suction tip. This technique achieves three functions at once. In the case of an unidentified arterial source, the pressure is often enough to occlude the source and act as a dynamic retractor to show the local anatomy while the suction removes blood from the field. Once the source is identified, the artery is immobilized and cauterized proximally. Deep perforators (i.e., “red devils”) often have very thin muscular media, making them poorly responsive to coagulation. These arteries require transgressing more deeply into the white matter, where a more substantive artery is found, or using AVM microclips if bipolar cautery is not proving to be effective.1

362

PREVENTING COMPLICATIONS The neurosurgeon must visualize each arterial source to be precisely and completely occluded. In iAVM surgery, hemostasis must be achieved through

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Pearls • Intraoperative bleeding from an iAVM is best categorized as arterial, venous, or nidal. • Arterial bleeding is best managed with bipolar cautery directly at the source. • Venous injury can occur if a main draining vein is mistaken for an artery, so careful study of the vessel and attention to preoperative imaging are imperative. • Nidal bleeding, if mild to moderate, can be controlled with pressure or the “iron thumb” technique. • Torrential nidal bleeding must be addressed with “commando” resection of the AVM.

Fig. 37.1 Intraoperative bleeding. Robust arterial bleeding can quickly obscure the operative field during microsurgical resection of an AVM. It is imperative that the surgeon maintain a constant understanding of the location of the draining vein so as not to further amplify the bleeding. Cottonoids can be extremely beneficial in this situation.

meticulous use of cautery and never just with packing or hemostatic agents. Incompletely coagulated arteries may open when they are out of sight and out of mind, leading to intraparenchymal or intraventricular hemorrhage.1 If this arterial bleeding goes unnoticed, the only signs may be herniation of the brain or AVM from the craniotomy or a large new hematoma. The lesion must be surveyed, and the site of bleeding must be identified. If hydrocephalus has developed, the ventricle must be entered, and consideration must be given to the placement of an external ventricular drain postoperatively.

Venous Bleeding

Fig. 37.2 Circumferential dissection, coagulation, and transection of small feeding arteries using the bloodless technique. Care is taken to preserve en passage vessels. This technique is sometimes facilitated by a gliotic plane created by the AVM. Other times, the parenchyma adheres to the AVM, and the surgeon must create a plane. In this scenario, the surgeon must balance getting too close to the nidus and inadvertently entering it with being too far into eloquent parenchymal tissue. When creating a plane, each small artery is coagulated before moving forward. (Used with permission from Barrow Neurological Institute, Phoenix, Arizona.)

OBTAINING CONTROL Venous bleeding occurs from either the main draining vein of the malformation or from one of the secondary draining veins. The natural reflex of the surgeon is to cauterize the offending vessel anytime bleeding is encountered. However, with an iAVM, absent-minded cautery can occlude venous outflow, precipitating increased intranidal pressures, rupture, and a catastrophic situation. Once bleeding is encountered, the suction tip is quickly placed over the source. This technique prevents blood from entering the cisterns or ventricles and causing brain fullness or hydrocephalus.2 Depending on the size of the venous wall injury, control may be as simple as pressing

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a hemostatic agent with a cottonoid patty and suction tip against the wall and waiting. If the tear is larger, the hypertrophied size of the vessel may allow focal cautery to close the rent without completely occluding the vein. Draining vein walls are sometimes fragile, and cautery may widen the rent in the wall. Use of an aneurysm clip can be considered. The clip is placed so that some of the tissue around the opening is gathered, inherently stenosing the area without occluding the outflow. Tears in the secondary draining veins may be amenable to cautery, and as long as the primary draining vein is intact, they can be completely coagulated. In a catastrophic case, such as a major injury or tear of the main draining vein, the bleeding will be torrential. The neurosurgeon must avoid the temptation to coagulate the stump, as this will only result in rupture of the nidus, complicating the scenario. In the event of an iAVM rupture, the neurosurgeon’s ability to remain calm and think through a solution quickly is just as important as it is in the event of an aneurysm rupture. In both situations, the operating room can erupt into chaos, and the neurosurgeon must remain in control and project calm for all others. In aneurysm surgery, however, a proximal artery can be occluded for control, whereas the multiplicity and deep nature of the feeding arteries make this infeasible in iAVM surgery. Thus the surgeon must proceed in the face of this bleeding. Suction is switched to a large bore, placed directly at the stump of the primary draining vein, and handed off to the assistant so that the neurosurgeon has both hands free. If the main draining vein is damaged from a craniotome mishap, or there is no hope of repair, only the distal stump of the draining vein is occluded. The anesthesiologist will need to keep up with blood loss with transfusions, volume replacement, and pharmacologic blood pressure support. The surgeon must be prepared for an accelerated dissection of the AVM or the “commando” resection (see section on “Nidal Rupture”). PREVENTING COMPLICATIONS Venous injury can occur at any point in the surgery. Thus the neurosurgeon needs to be on high alert from the start of the craniotomy. AVMs with a superficial primary draining vein are at risk of laceration during the craniotomy or opening of the dura, as the vein can have eroded into the bone or become tightly adhered

to the dura.1 Each step of the craniotomy opening must be planned accordingly; the preoperative images must be reviewed with meticulous planning in mind. If retractors are being used, knocking into them can cause tearing of venous and arterial structures, including the main draining vein. Retractors, if used, should be placed in a way that prevents the surgical chair, knees of the surgeon, or arms of the surgeon, scrub technician, or assistant from hitting them. Smaller lacerations are possible during the dissection phases of the AVM, where the main or other draining veins are being separated from the parenchyma or nidus. The surgeon should be aware of the tips of their microscissors at all times, and sharp rather than blunt dissection should be used.

Nidal Rupture OBTAINING CONTROL Intraoperative iAVM nidus rupture is one of the most trying scenarios for a vascular neurosurgeon to encounter. Bleeding from the nidus can occur either focally on the edge of the nidus or diffusely/deep within it. If the dissection plane is too close to the nidus and inadvertent entry occurs, closure is first attempted with bipolar cautery. However, such an attempt runs the risk of making the opening larger. Alternatively, the “iron thumb” technique could be used.1 This technique involves using a hemostatic pledget and a fixed retractor blade to maintain pressure on the nidus. This practice frees the surgeon’s hands to continue the dissection and lift the nidus from the resection bed to improve visualization. Retraction is released after the opening in the nidus wall has been occluded or the nidus has been further de-arterialized. Nidal rupture can quickly spiral into loss of control of the case. The surgeon must summon the grit to get through the task at hand. The change in condition is reported to the anesthesiologist and scrub technician so that preparations can be made similar to those made for transection of the draining vein. With the occlusion of the primary draining vein, the nidus becomes tense, and hemorrhaging can ensue from multiple points on the nidal circumference. This bleeding is poorly responsive to bipolar cautery. Thus nidal rupture may be even more challenging than complete transection of the draining vein because the bleeding

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is not confined to one vessel. The timing between primary vein occlusion and nidal rupture is unpredictable. The neurosurgeon must act quickly to remove the AVM. The commando resection of the AVM is a measure of last resort when rupture is imminent or has already occurred.1 A large suction tip is used, and an assistant can help dry the field. The surgeon must proceed despite heavy bleeding, almost completely ignoring it. One group reported the use of adenosine in two cases of intraoperative AVM rupture to reduce the volume of bleeding, but this adjunct is short-lived and may not be helpful.3 Using a large suction tip in one hand and a combination of bipolar cautery and scissors in the other, the surgeon must aggressively manipulate the AVM to identify the main arterial feeders. The smaller feeders are ignored and left to be dealt with after the AVM has been removed. Removing the AVM opens the field and allows the surgeon to control the smaller feeders left in the resection bed. This commando technique is meant to remove an AVM quickly to minimize blood loss and other adverse effects of uncontrolled bleeding. PREVENTING COMPLICATIONS The most likely reason for premature occlusion of the primary draining vein is a misinterpretation of the vascular structures at the time of dissection. Arterialized veins are red and can appear similar to hypertrophied feeding arteries. The most effective way to prevent this

mistake is to compare the intraoperative view to the preoperative catheter angiograms. Looking at the key turns of arterial and venous structures, their positioning and depth in relation to one another, as well as bifurcations, can help orient the surgeon to the intraoperative view. Retraction can be an ally and a foe in AVM resection. If the iron thumb technique has been used in the case of inadvertent nidal wall entry, there must be a balance between too little and too much retraction. Too little retraction can make the hemostatic pledget ineffective in causing occlusion. Too much retraction can precipitate rupture of the AVM nidus. Even removing the retraction once occlusion has occurred should be done carefully, as too brisk a removal can cause a tear if the retractor blade is stuck to the nidus wall. The same issues can occur even if suction retraction is being performed for visualization of the deep plane. Table 37.1 summarizes the three types of bleeding and techniques to obtain control and prevent complications.

Outcomes Following Rupture Little exists in the literature regarding the management of intraoperative iAVM rupture or its outcomes. The senior author and colleagues reported on the 32 cases of intraoperative iAVM rupture that were encountered in a series of 591 patients treated surgically over a

TABLE 37.1 Summary of Techniques to Prevent and Control the Three Types of Intraoperative Bleeding Encountered During iAVM Surgery Bleeding Type Arterial

Venous

Nidal

Prevention

Confirm that each artery is fully coagulated before moving on to the next

Be aware of superficial draining veins during opening

Control

1. Apply pressure using a suction tip and patty 2. Use microclips or bipolar cautery

1. Apply pressure using suction tip, patty, and hemostatic agent 2. Use microclips or bipolar cautery if no response 3. Perform the commando resection for complete transection of the main draining vein

1. Discern between arteries and veins before coagulation 2. Apply balanced retraction on nidus when needed 3. Be mindful of distance during dissection 1. Apply pressure using suction tip, patty, and hemostatic agent 2. Use bipolar cautery or iron thumb technique if no response 3. Nidal rupture: perform commando resection

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15-year period.4 Analysis showed a male predominance in the cases of rupture and a higher mean age (43 years; range, 11–90 years). Preoperative hemorrhage, preoperative treatment with radiation or embolization, or the presence of flow-related aneurysms were not significant predictors of intraoperative rupture. The location of the AVM was not predictive of intraoperative rupture; however, higher Spetzler-Martin and Lawton-Young grades were. Specifically, AVM size greater than 3 cm was a feature in 22 (69%) of the ruptured AVMs, and diffuseness was a feature in 20 (63%). Arterial bleeding was the most common type and was encountered in 18 (56%) of the patients. Rupture from occluding the primary draining vein occurred in 10 (31%) of the patients, and nidal penetration occurred in 4 (13%). Eighteen cases of rupture (56%) were managed by working through the bleeding to finish the resection, and 14 cases (44%) required commando resection. Of the cases requiring this aggressive technique, 11 (79%) involved AVMs that were greater than 3 cm, and 11 involved diffuse AVMs. More than half of the ruptures occurred in the first 5 years of the 15-year period (17 cases, 53%), with the highest incidence of rupture also occurring during this period (9%, compared to 3% in the next 5 years and 4% in the last 5 years). Seven of 10 ruptures from draining vein occlusion, along with all ruptures from the nidal entrance, also occurred during this first 5-year period. These findings suggest technical factors that may be improved by surgeon experience. In the face of intraoperative rupture, 29 (90%) of 32 AVMs were still completely resected, although the proportion of incompletely resected AVMs was higher than the proportion in the overall experience (22 [4%] of 591 cases). These findings highlight that rupture complicates a clean resection and that there is a need for vigilant angiography in the immediate postoperative period. Of the 32 patients with ruptured AVMs, 4 patients (12.5%) died in the perioperative period and 4 patients (12.5%) died in the late follow-up period. Eighteen (56%) of the 32 patients had unchanged or improved modified Rankin Scale (mRS) scores; 6 (19%) had worse scores, although 4 of the 6 had mRS scores less than 2. Intraoperative rupture negatively impacted mRS scores overall, with a mean score of 2.8 at last assessment for the patients with intraoperative rupture compared to the overall cohort mean of 1.5.

To reduce the risk of intraoperative nidal rupture, allow treatment of higher-grade iAVMs, and improve outcomes, some neurosurgeons have argued for “single-stage combined” embolization and 5–9 ­ resection. This treatment paradigm relies on a hybrid operating room. First, the endovascular surgeon performs aggressive embolization of the nidus, targeting high rupture risk features and the largest 6 ­ feeders. If complete angiographic obliteration cannot be obtained, then the goal is shifted to delineating the boundaries of the iAVM with embolic material.8 If a rupture occurs during embolization or significant venous stasis occurs, the procedure then moves to microsurgical resection.8 Although the single-stage combined embolization and microsurgical resection paradigm may have benefits, it is not a necessity. As long as the treating teams communicate effectively and carry out the goals of each treatment paradigm efficiently, the same effect can be achieved with the two procedures performed at different times. The more important factor is choosing the best paradigm for each patient. For iAVMs with Spetzler-Martin grades of III or higher, nidal embolization helps reduce intraoperative blood loss and has been associated with improved neurological outcomes. However, overly aggressive embolization can precipitate AVM rupture and compromise outcomes. For lower-grade AVMs (grade I or II), embolization has a diminished impact on outcomes and may not be necessary.

Conclusion An iAVM can be an imposing pathology to manage surgically, and intraoperative bleeding or nidal rupture only increases the difficulty of the resection. Despite these challenges, the neurosurgeon who operates on iAVMs must develop a facility to deal with intraoperative bleeding in all of its forms. Meticulous surgical techniques and a calm, determined attitude allow the neurosurgeon to persevere even during the most trying scenarios. Acknowledgment

We thank the staff of Neuroscience Publications at Barrow Neurological Institute for assistance with manuscript preparation.

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REFERENCES 1. Lawton M. Seven AVMs: Tenets and Techniques for Resection. Thieme; 2014. 2. Yaşargil MG. Microneurosurgery: AVM of the Brain, Clinical Considerations, General and Special Operative Techniques, Surgical Results, Nonoperated Cases, Cavernous and Venous Angiomas, Neuroanesthesia. Vol IIIB. Thieme; 1988. 3. Al-Mousa A, Bose G, Hunt K, Toma AK. Adenosine-assisted neurovascular surgery: initial case series and review of literature. Neurosurg Rev. 2019;42(1):15–22. https://doi.org/ 10.1007/s10143-017-0883-3. 4. Torné R, Rodríguez-Hernández A, Lawton MT. Intraoperative arteriovenous malformation rupture: causes, management techniques, outcomes, and the effect of neurosurgeon experience. Neurosurg Focus. 2014;37(3):E12. https://doi.org/ 10.3171/2014.6.focus14218. 5. Santin MDN, Todeschi J, Pop R, et al. A combined single-stage procedure to treat brain AVM. Neurochirurgie. 2020;66(5):349– 358. https://doi.org/10.1016/j.neuchi.2020.03.004.

367 6. Chen Y, Li R, Ma L, et al. Single-stage combined embolization and resection for Spetzler-Martin grade III/IV/V arteriovenous malformations: a single-center experience and literature review. Front Neurol. 2020;11:570198. https://doi.org/10.3389/ fneur.2020.570198. 7. Grüter BE, Mendelowitsch I, Diepers M, Remonda L, Fandino J, Marbacher S. Combined endovascular and microsurgical treatment of arteriovenous malformations in the hybrid operating room. World Neurosurg. 2018;117:e204–e214. https://doi. org/10.1016/j.wneu.2018.05.241. 8. Kocer N, Kandemirli SG, Dashti R, et al. Single-stage planning for total cure of grade III-V brain arteriovenous malformations by embolization alone or in combination with microsurgical resection. Neuroradiology. 2019;61(2):195–205. https://doi. org/10.1007/s00234-018-2140-z. 9. Murayama Y, Arakawa H, Ishibashi T, et al. Combined surgical and endovascular treatment of complex cerebrovascular diseases in the hybrid operating room. J Neurointerv Surg. 2013;5(5): 489–493. https://doi.org/10.1136/neurintsurg-2012-010382.

Chapter 38

The Value of a Registry Trevor Hardigan, Kurt Yaeger, and J Mocco

Chapter Outline Introduction Issues With Randomized Control Trials and iAVMs Clinical Registries Quality of Patient Registries The Electronic Health Record and Clinical Registries The Use of Registries in Neurosurgery Intracranial AVM Registries Conclusion

serve as a guideline for treatment.7 A conservative approach to management of iAVMs (medical treatment and observation) is also frequently employed, especially for lesions deemed to carry a significantly high risk of intervention-associated morbidity and mortality. The need for high-level evidence for the management of iAVMs is a current gap in the practice of neurovascular surgery, one that multiple studies have attempted to address.

Issues With Randomized Control Trials and iAVMs Introduction Intracranial arteriovenous malformations (iAVMs) are rare lesions, with an annual incidence of symptomatic lesions of approximately 1/100,000 population.1,2 AVMs are believed to be congenital, often going undetected for decades until found incidentally during workup for other medical issues or for related symptoms such as headaches and seizures. Most commonly, however, the initial presentation of an iAVM is due to rupture and cerebral hemorrhage.3 The risk of hemorrhage related to iAVMs is approximately 1%–4% per year,4 and the majority of patients present in the third or fourth decade of life.5,6 The heterogeneity of iAVMs makes the management, treatment, and study of these lesions difficult to standardize, with multiple factors, including AVM size, arteriovenous architecture, patient age, and AVM location, all impacting clinical decision-making. Given the absence of strong data regarding management of iAVMs, the American Stroke Association Stroke Council has released recommendations detailing the use of microsurgical, endovascular, and/or radiosurgical interventions to

The lack of scientifically proven benefit of interventional treatment for iAVMs led to the development of the ARUBA study, which examined whether medical management alone vs medical management with interventional therapy would lead to differences in the time to death or symptomatic stroke.4 The study concluded that medical management alone was superior to medical management with interventional therapy (surgery, endovascular treatment, or stereotactic therapy alone or in combination). The study was stopped early by the National Institute of Neurological Disorders and Stroke safety monitoring board due to a difference in primary outcome of 30.7% in the interventional group vs 10.1% in the medical management alone group. This study has only added to the controversies surrounding the management of iAVMs. Proponents argued that the study was the first to attempt a true randomized trial among this group of varied patients and presentations, with beneficial information gained regarding the merits and risk of intervention as well as the natural history of iAVMs.8,9 Despite these methodological goals, the study has drawn substantial criticism related to the study design itself. ARUBA grouped various treatment modalities as a single arm, which may either mask a harmful 371

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­intervention or invalidate a beneficial one. Grouping the interventional treatments together without appropriate stratification and subgroup analysis makes it difficult to accurately assess the true differences in the primary outcome between the intervention arm and the medical management arm. This is especially true in the ARUBA study, as only 5 patients were treated with surgery alone, with a further 13 patients treated with surgery and either endovascular intervention or radiosurgery. Notably, endovascular embolization alone is not viewed as standard of care for curative treatment of iAVMs in the United States. With over 30 patients receiving endovascular treatment alone, the interventional management of this arm of the study does not reflect common neurosurgical practice in the United States.10 Moreover, the study was not appropriately powered to determine differences between the different treatments within the intervention arm. Additional concerns from the ARUBA study include improper hypothesis generation, inappropriate endpoints, lack of standardization, low enrollment, premature interruption, and overall study design.11 While the study did not adequately answer the intended questions of whether medical management was preferable to intervention in patients with unruptured iAVMs, it did serve as a valuable example of the need for further research strategies and options in the study of these lesions. Traditionally, randomized control trials (RCTs) and meta-analyses of RCTs have been the gold standard of evidence in scientific studies. They are designed to be highly controlled experiments that test specific hypotheses with the aim of applying the findings to real-world clinical practice. As such, they offer an excellent basis to evaluate the safety and efficacy of treatments, whether they be new devices, drugs, or interventional techniques. RCTs are designed with stringent criteria to best evaluate the desired scientific question, relying on inclusion and exclusion criteria, appropriate statistical power and modeling, precisely defined study protocols, and clearly delineated outcomes. While this methodological approach has tremendous value, there are inherent limitations to its use and applicability among larger populations. In rare diseases, strict criteria regarding patient inclusion or exclusion can lead to severe underpowering of RCTs, making it difficult to draw any definitive conclusions about a study’s outcomes.

Pearls • The management of iAVMs is controversial. • The randomized control trial (RCT) results from ARUBA (A Randomised Trial of Arteriovenous Malformations) have added to this controversy. • Registry-based studies are observational studies focused on a specific clinical disease, patient population, or treatment. • Registry-based studies are more inclusive than RCTs. • Registries for iAVMs exist, but there is a need for more focus and an organized multicenter approach.

In the case of trials that focus on surgical diseases, the design and execution of RCTs are even more arduous, as there can be many treatment options and interventions for the same disease state.12 Patient-centered decision-making can also create challenges for RCTs of surgical management, as patients may be less agreeable to randomization due to concern of not receiving all possible treatments, especially in a trial comparing medical treatment alone vs surgical intervention plus medical treatment. Additionally, many physicians outside of larger academic centers lack the resources and infrastructure necessary to participate in well-designed RCTs, and there are many patients whose clinical and treatment data are simply unavailable to RCTs. This can be a particular problem for studies of rare diseases. In the context of iAVMs, the lack of well-conducted and designed RCTs in the literature is due to many of these and other factors: relatively low incidence of disease, overall heterogeneous patient population/disease characteristics, and lack of standardized treatment paradigms in the clinical community. The inherent limitations of RCTs hinder research into diseases like iAVMs, necessitating the development of national and international patient registries to increase the information available to clinicians and researchers.

Clinical Registries A clinical registry is defined as an observational database focused on a specific clinical disease, patient ­ population, or type of therapy. These registries are

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designed to be organized systems for the collection, storage, retrieval, and use of clinical data that can reflect “real-world” clinical conditions, in contrast to RCTs. The strength of well-designed and well-implemented registries is that they can provide information about a large and diverse patient population with a unifying clinical paradigm, be it a specific disease or a specific treatment. Registries typically include information on patient demographics, physiological parameters, interventions, pertinent anatomical measurements, comorbidities, health system quality metrics, cost analysis, and clinical outcomes. In comparison to an RCT, a registry-based study can provide broader information, given that the patient population is typically more heterogeneous. Such data can then be used to gain insight into a disease’s natural history, assess correlations with care quality, identify safety concerns, determine clinical effectiveness, and explore economic considerations.13 Not only can important practical questions be answered through patient registries, but trialists can draw from registry data to develop new clinical questions and hypotheses. In this way, a registry can serve as both a separate research entity and an adjunct to RCTs. While a registry may be singular in its overall focus, welldesigned registries can collect and organize information in such a way as to promote all types of scientific inquiry and discovery. Patient registries ideally collect comprehensive patient data from real-world practice management, incorporating varied treatments and types of patients. The lack of randomization or predetermined care pathways is beneficial because outcomes reflect real clinical practice, rather than the situation seen in a highly regulated trial. As a result, registry data may be more representative of real-world care and more generalizable. This is particularly beneficial in the study of rare diseases, such as iAVMs, where low numbers of cases and patient heterogeneity limit the ability to draw meaningful conclusions from RCTs applying strict enrollment criteria. Patient registries gather specific data that can be very helpful in identifying new areas of inquiry concerning treatment safety, diagnostic criteria, and prognostic criteria. Observational studies have long been utilized in medicine; the Framingham Heart Study (FHS) began in 1948 and is one of the most successful observational

research studies in existence, having led to numerous advancements in our understanding of common factors and characteristics that contribute to cardiovascular disease.14 As demonstrated by the FHS, a significant benefit of clinical registries over RCTs is that they are less stagnant. They can evolve with time and clinical needs, and multiple characteristics can be assessed within a single study’s infrastructure. Whole-genome sequencing, epigenetics, transcriptomics, proteomics, metabolomics, and microbiome studies have all been added to the information gathered in the FHS. Significantly adjusting the types of data included and subsequent analysis of an RCT is laborious to the point of being impossible. New RCTs are therefore required, creating a cycle of iterative RCTs, not unlike what has become the norm in the current era of iterative emergent large vessel occlusion (ELVO) trials. Such a process is not only laborious but also slow and extremely expensive. In contrast, an existing registry could be updated to include these characteristics without needing to start over entirely. In fact, the establishment of just such a registry-based platform structure for ELVO data is currently under evaluation by the National Institutes of Health, highlighting the need for well-supported cerebrovascular registries.

Quality of Patient Registries Registries, like any scientific endeavor, are only as effective at achieving their desired outcome as the rigor and quality with which they are conducted. The quality of a registry depends on one’s confidence in its data. The design, data verification, and subsequent analyses must all minimize the risk of spurious conclusions. As in other research, this is accomplished by clarifying the projects’ objectives, assessing the risk of bias, establishing ongoing data integrity protocols, and ensuring that all data analysis is consistent with accepted statistical methodology. Valid conclusions require high-quality data and analysis and must be based on the strength of the evidence generated.15 A crucial requirement for registry quality is to limit bias involved in its creation and maintenance. Selection bias occurs when individuals are not included appropriately in a given registry, such that outcome measurements and assessments of benefit and risk are misrepresented.16 This can occur for a variety of reasons, including lack

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of training in registry maintenance, insufficient personnel to achieve proper enrollment, cost concerns, and inadequate quality assurance effort. Indeed, a primary benefit of registries is their applicability to the typical patients with a given clinical disease, particularly as compared to RCTs. This highlights the importance of data veracity for registries. Factors affecting data quality include the accuracy with which it is entered in the database, the degree of completeness, and the overall standardization of the information being entered.17,18 Contributing to these factors are underreporting of adverse events and loss of patients to follow-up, which greatly impact registry interpretation. Correct data input is even more important in patient-powered registries—registries in which patients themselves, or their family members, manage or control the data collection, the research agenda for the data, and/or the translation of the research from the data.19 The concern with patient-powered registries is that individuals entering the data may lack the ability to do it correctly; nevertheless, there are multiple examples of successful patient-powered registries adding to disease and treatment knowledge.20 Improving accessibility, design, and ease of use of data entry can improve database accuracy. Improving funding for quality assurance and research personnel is also critical to registry maintenance, with frequent audits of the information as more data are entered.

The Electronic Health Record and Clinical Registries With the advent and increasing ubiquity of electronic medical records, the ability to generate and analyze clinically meaningful data has expanded precipitously. This increased use of electronic medical records among clinical practices and hospitals was initially prompted by the Health Information Technology for Economic and Clinical Health Act in 2009 and then subsequently by the Centers for Medicare and Medicaid Services’ establishment of the EHR Incentive Program in 2011, which pushed the medical community to begin transitioning to electronic health records in multiple stages. This adoption has made the capturing of clinical data across the country more robust and has allowed for the increasing development of patient registries. Several widely adopted electronic health record

(EHR) software programs allow for data collection that can be used in observational studies and registries.21 The power of EHRs is their ability to provide useful information tailored to specific diseases by tracking all patients in a particular medical setting, thereby capturing as many individuals as possible in an observational cohort. The limitations of using EHRs in place of or to augment large-scale registries are similar to those for registries themselves—namely, that missing or nonstandardized data can skew analyses and interpretation. As the implementation of large patient registries becomes more prevalent, advancements in the ease of EHR use and their utility for collecting valuable patient data will become increasingly important in clinical research.

The Use of Registries in Neurosurgery Although patient registries have been widely utilized in other specialties, including oncology, pediatrics, and cardiology, there are fewer specific neurosurgery registries. In 2008, the American Association of Neurological Surgeons began working to address that gap by establishing the NeuroPoint Alliance (NPA). The NPA was tasked with the aim of collecting, analyzing, and sharing neurosurgical clinical data in a quality outcomes database (QOD). The first database created was the Lumbar Spine Registry, intended to provide data that would lead to the reduction of pain and improvement in quality of life for patients undergoing surgery for degenerative lumbar spine disease.22–24 The NPA subsequently created registries that focused on neurovascular disease (the NeuroVascular Quality Initiative Quality Outcomes Database [NVQIQOD]), stereotactic radiosurgery (the Stereotactic Radiosurgery Registry), Parkinson’s disease (the Registry for the Advancement of DBS [deep brain stimulation] in Parkinson’s Disease [RAD-PD]), and recently brain tumors (the QOD Tumor Registry) (https://www.neuropoint.org/registries). Other registries, while not designed solely for neurosurgical disease, have been used to examine outcomes in neurosurgical patients. The Surveillance Epidemiology and End Results (SEER) Program was started in 1973 by the National Cancer Institute (NCI) with nine initial sites (https://seer.cancer.gov/). It currently includes data from population-based registries

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from 19 geographic areas, covering all reported cases of cancer in approximately 35% of the US population.25 There are several limitations associated with the SEER database, despite its long-standing enrollment and maintenance. While the overall number of patients in the registry is large, given that it includes patients with various forms of cancer, the percentage relative to the overall number of cancer cases in the United States is quite small. Various clinical and tumor variables such as imaging characteristics and tumor progression, treatment data, and duration of symptoms are often not included. Important factors in neurosurgical management, such as occurrence of tumor progression and resection, are also omitted, and there is no central pathology review of cases within the database to ensure accurate pathological diagnosis.26 Despite these limitations, the SEER database has been useful in the study of neurological cancers, with numerous publications utilizing the database.27–29 A more focused registry of brain tumors is the Central Brain Tumor Registry of the United States (CBTRUS). CBTRUS is the largest population-based registry focused exclusively on primary brain and other central nervous system (CNS) tumors in the United States, with information on incidences of malignant and benign CNS tumors as well as patient demographic data. The recent CBTRUS report estimates a total of 83,830 new cases of malignant and benign CNS tumors in 2020. Survival data are also included in the database, which gives a 5-year survival rate for malignant CNS tumors of 36%.30 Other databases used in the assessment of neurosurgical disease include the National Trauma Data Bank (NTDB), which includes over 4 million patients and has relevant data on the treatment of traumatic intracerebral hemorrhage, elevated intracranial pressure, and patient demographic/outcome data,31 as well as the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP). The ACS-NSQIP has been utilized to study various neurosurgical diseases, including idiopathic scoliosis as well as supratentorial tumors.32,33 The utility of these various national registries demonstrates the value of registry-driven research in neurosurgery and provides another avenue to ultimately improve outcomes and benefit patients. It also suggests that more large-scale neurovascular-focused

registries are needed, given the overall scarcity of registries for these diseases, excluding stroke.

Intracranial AVM Registries The issues associated with RCTs in the study of iAVMs discussed earlier and the success of large-scale registries in other neurosurgical diseases demonstrate the need for more registry-driven iAVM research. Of the studies utilizing reported iAVM registries in the literature, many include a relatively small number of patients compared to the numbers included in registries for other diseases (Table 38.1). An assessment of ongoing clinical trials listed on ClinicalTrials.gov utilizing search terms “registry” and “AVM-cerebral arteriovenous malformation” yielded only five results. Two of the trials are exploring the use of particular endovascular techniques, one is examining AVMs in the context of hereditary hemorrhagic telangiectasia, and two are studying multimodal treatment of iAVMs. In a recent study, Pulli et al.34 found that in their registry of 318 consecutive iAVM patients treated with endovascular intervention, surgery, or proton beam radiosurgery, 142 met the inclusion/exclusion criteria established in the ARUBA trial. These patients had lower annualized stroke rates than in both natural history studies and the ARUBA medical management arm. The primary endpoint of symptomatic stroke was reached in only 9.2% of patients compared to 39.6% in the ARUBA intervention arm, with no significant difference from the rate in the ARUBA medical management arm (9.2%). The secondary endpoint of a modified Rankin Scale score ≥2 at 5 years of follow-up was observed in only 14.3% of patients compared to 40.5% in the ARUBA intervention arm, with no significant difference from the rate in the medical management arm (16.7%). The data from this single-center registry suggest that tertiary centers with integrated neurosurgical programs and expertise in all forms of intervention and treatment may afford better results than those described in ARUBA. Another patient registry of iAVMs designed to deal with the difficulties in conducting surgical trials is the Treatment of Brain AVMs Study (TOBAS).43 TOBAS is somewhat unique in that it was designed as a combination RCT/registry study of various management options, including surgery, radiation therapy,

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TABLE 38.1 Summary of Registry-Based iAVM Studies Study

Registry Type

No. of Pts

Study Inclusion Criteria

Outcomes

Pulli et al., 202034

Retrospective

1. Preembolization vessel imaging 2. No prior Tx of AVM 3. ≥1-y follow-up

1. Annualized stroke rate 1.8% (P .05 vs ARUBA med mgmt arm)

Pohjola et al., 202035

Retrospective

318 AVM pts total, 142 ARUBA eligible treated with intervention 805 AVM pts total, 277 included in final cohort after screening

1. Age ≥18 y 2. Pt response to questionnaire completed 3. Age ≥18 y at AVM diagnosis

Rutledge et al., 202036

Prospective

140 AVM pts from UCSF Brain AVM Study Project

1. Pts prospectively enrolled in the study and treated with intervention btwn 2012 and 2015

Sakai et al., 201437

Prospective

32,068 pts in JR-NET 1 and 2: 1174 brain/spine AVM pts

Miyachi et al., 201738

Retrospective

73 AVM pts

1. All pts treated by JSNET boardcertified physicians from 2005 to 2009 enrolled in study except when deemed unsuitable 1. Brain AVM treated from 2003 to 2012 with embolization followed by SRS 2. AVM max diameter ≥1 cm, age ≥6 y 3. NBCA embolization, Gamma Knife used 4. SRS within 6 mo of last embolization 5. Operator requirements (20 AVM embolizations and 50 SRS cases)

1. Proportion of smokers in AVM pts 48% vs 19% in general population (95% CI: 41%–55% and 16%–21%, respectively) 2. Age group 65–77 y: AVM smoking percentage was 73% vs 7% in general population (95% CI: 46%– 90% and 5%–9%, respectively) 1. Overall median (IQR) cost of Tx was $77,865 ($49,566–$107,448) 2. Surgery with preop embolization most expensive Tx $91,948 ($79,914–$140,600), surgery had highest cure rate 3. Radiosurgery least expensive Tx $20,917 ($13,915–$35,583) 4. Hemorrhage, SM grade, and Tx type significant predictors of cost 1. 3.9% of all procedures were for embolization of brain/spine AVMs 2. Complication rate from Tx of AVMs was 5.2%

1. 43 pts in successful occlusion group, 29 pts in nonsuccessful occlusion group 2. AVM size, AVM grade, and diffusivity trended higher in the nonsuccessful occlusion group (P >.05) 3. Higher rate of nidus penetration in the successful occlusion group (P