Intracranial Arteriovenous Malformations

Intracranial Arteriovenous Malformations Edited by

Philip E. Stieg

Weill Medical College of Cornell University New York, New York, U.S.A.

H. Hunt Batjer

Feinberg School of Medicine Northwestern University Chicago, Illinois, U.S.A.

Duke Samson

University of Texas Southwestern Medical Center Dallas, Texas, U.S.A.

New York London

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Informa Healthcare USA, Inc. 270 Madison Avenue New York, NY 10016 © 2007 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid‑free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number‑10: 0‑8247‑0993‑4 (Hardcover) International Standard Book Number‑13: 978‑0‑8247‑0993‑8 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any informa‑ tion storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http:// www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978‑750‑8400. CCC is a not‑for‑profit organization that provides licenses and registration for a variety of users. For orga‑ nizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com

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Preface

The important thing in science is not so much to obtain new facts as to discover new ways of thinking about them. —Sir William Bragg (1862–1942)

During the past twenty years, great strides have been made in the management of intracranial arteriovenous malformations. This success has resulted not so much from greater understanding of the pathophysiology or anatomy of the lesions as it has from new technologies applied in their management. The greatest advances have been multifactorial. Endovascular therapy, which improves our ability to resect complex lesions, is probably the most important cause for the reduction in the incidence of postoperative hemorrhage. Intraoperative angiography, which allows confirmation of complete resection, again reduces the incidence of postoperative hemorrhage. Improvements in surgical instrumentation, such as microscopes and the bipolar cautery, have made microsurgery more effective. Improved surgical approaches have allowed the successful resection of more complex lesions. Surgical planning has been facilitated by more sophisticated preoperative imaging, including angiography, magnetic resonance imaging, magnetic resonance angiography, computed tomography angiography, and functional magnetic resonance imaging. Stereotactic radiosurgery has provided an avenue for the treatment of deep, small arteriovenous malformations. The perioperative care of our patients has been enhanced with advances in anesthesia and the creation of neurointensive care units. Each of these parameters is thoroughly reviewed in this volume, and, more importantly, all are coordinated into a cohesive management scheme. In this text we seek to document current understanding of the management of intracranial arteriovenous malformations and to define advances in the field. We begin with a review of the anatomy, classification, and pathophysiology of arteriovenous malformations. We then progress to detailed discussion of diagnosis and management. Preoperative evaluation with diagnostic and functional imaging as well as surgical planning is reviewed in detail. We conclude with consideration of future directions for treatment. A review of these chapters will enable the reader to provide the patient with better preoperative risk analyses, a thorough review of the treatment options and their risks, and a general outline of a specific treatment regimen. Selecting patients for therapy or not, and then selecting the appropriate therapy are the greatest challenges presented to the treating physician. Once treatment is recommended, integration of the complex modalities is essential. The authors of these chapters provide the reader with such insight. Each arteriovenous malformation presents clinical challenges on the basis of its size and location. These issues, which play a large part in our success in treating these lesions, are dealt with in individual chapters. The authors thoroughly discuss the surgical nuances of arteriovenous malformations in specific locations. The application of endovascular therapy as curative or, more commonly, as an adjuvant therapy is reviewed. Current understanding of the limits and complications of stereotactic radiosurgery, as well as the promise of future applications, is presented. Risks and benefits for each form of therapy are fully detailed. Finally, the application of each treatment modality is integrated into treatment algorithms based on history, location, size, and risk benefit analysis. It is the intent of the editors and authors to provide the reader with a framework for understanding and treating these complex lesions. This volume is designed for all individuals involved in the management of intracranial arteriovenous malformations. It is the only text that comprehensively reviews the subject. The authors have provided an extensive and thorough discussion of the scientific data from the literature in a prose that is easily readable and understandable for clinical application. The reader is offered an integrated system, including medical management, anesthesia, radiation therapy, neuroradiology, endovascular therapy, and microsurgery, for the management of one

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of the most challenging lesions presented to physicians involved in the care of patients with neurologic disease. We are indebted to the members of our families for the time they gave up with us so that this volume could be created. We thank Mr. Robert Gallavan and Ms. Jessica Kazmier at our institutions for their dedicated assistance. We are grateful for the skillful editorial guidance of Ms. Arlene Stolper Simon, who spent countless hours editing chapters and working with the authors. Finally, we acknowledge the support and direction provided by our Informa Healthcare USA team, Ms. Vanessa Sanchez and Mr. Alan Kaplan. Philip E. Stieg H. Hunt Batjer Duke Samson

Contents

Preface . . . . iii Contributors . . . .

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SECTION I: ANATOMY AND PHYSIOLOGY 1. Surgical Anatomy 1 Helder Tedeschi, Evandro de Oliveira, Wen Hung Tzu, and Albert L. Rhoton, Jr. Introduction . . . . . . 1 Frontal Lobe AVMs . . . . . . 1 Parietal Lobe AVMs . . . . . . 2 Temporal Lobe AVMs . . . . . . 3 Occipital Lobe AVMs . . . . . . 5 Mediobasal Temporal Lobe AVMs . . . . . . 5 Interhemispheric Parafalcine and Callosal Region AVMs . . . . . . 9 Basal Ganglia Region AVMs . . . . . . 11 AVMs of the Posterior Fossa . . . . . . 18 References . . . . . . 19

2. Pathology and Genetic Factors 21 Ronald F. Moussa, John H. Wong, and Issam A. Awad Pathology . . . . . . 21 Genetic Factors . . . . . . 25 References . . . . . . 27

3. Hemodynamic Properties Michael Morgan

31

Introduction . . . . . . 31 Hemodynamic Effect within the Interstices of an AVM . . . . . . 32 Hemodynamic Effect on Cerebral Blood Vessels in the Presence of an AVM . . . . . . 33 Hemodynamic Effect on the Microcirculation of the Brain Associated with an AVM . . . . . . 37 Autoregulation and Reactivity to Changes in PaCO2 . . . . . . 38 Hemodynamic Effect on Cerebral Blood Vessels at the Time of AVM Ablation . . . . . . 40 Hemodynamic Effect on the Brain at the Time of AVM Ablation . . . . . . 40 Arterio-Capillary-Venous Hypertensive Syndromes . . . . . . 41 References . . . . . . 42

4. Use of Modeling for the Study of Cerebral Arteriovenous Malformations William L. Young, Erzhen Gao, George J. Hademenos, and Tarik F. Massoud Introduction . . . . . . 49 Importance of Modeling for AVMs . . . . . . 49 Specific Modeling Attempts–Model Construction . . . . . Model Applications . . . . . . 55 Long-Term Objectives of Computational Modeling . . . . Animal Modeling . . . . . . 59 Summary . . . . . . 61 Appendix 1. Description of a Computational AVM Model Appendix 2. Mathematical and Computational Approach Appendix 3. Vascular Stress . . . . . . 67 References . . . . . . 68

49

. 50 . . 58

. . . . . . 61 . . . . . . 63

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SECTION II: CLINICAL PRESENTATION AND DIAGNOSTIC EVALUATION 5. Natural History 73 Bernard R. Bendok, Christopher Eddleman, Joseph G. Adel, M. Jafer Ali, H. Hunt Batjer, and Stephen L. Ondra Introduction . . . . . . 73 Presenting Symptoms . . . . . . 73 Morbidity and Mortality Related to Hemorrhage . . . . . . 75 AVMs in the Gravid Woman . . . . . . 77 Anatomical Factors Influencing the Natural History of AVMs . . . . . . 77 Spontaneous Regression . . . . . . 78 References . . . . . . 79

6. Classification and Grading Systems 81 Kai U. Frerichs, Philip E. Stieg, and Robert M. Friedlander Introduction . . . . . . 81 Classification and Grading Parameters . . . . . . 81 Grading Scales . . . . . . 84 Discussion . . . . . . 91 References . . . . . . 92

7. Radiographic Diagnosis 95 R. Anthony Murray and Eric J. Russell Introduction . . . . . . 95 Epidemiology and Natural History . . . . . . 95 Therapeutic Options and Classification . . . . . . 96 Computed Tomography . . . . . . 97 Magnetic Resonance Imaging and Angiography . . . . . . 98 Conventional Angiography . . . . . . 105 Angiographically Occult AVMs . . . . . . 109 Conclusion . . . . . . 109 References . . . . . . 110

8. Functional Evaluation and Diagnosis 115 Shervin R. Dashti, Jeffrey L. Sunshine, Robert W. Tarr, and Warren R. Selman Introduction . . . . . . 115 Parenchymal Function . . . . . . 115 Relative Perfusion . . . . . . 118 Blood Pressure and Flow Analysis . . . . . . 119 Invasive Provocation . . . . . . 120 Conclusion . . . . . . 120 References . . . . . . 120

SECTION III: BASIC CONSIDERATIONS 9. Decision Analysis for Asymptomatic Lesions James McInerney and Robert E. Harbaugh

123

Introduction . . . . . . 123 Decision Analysis and Markov Modeling for the Treatment of Asymptomatic AVMs . . . . . . 124 Data Collection . . . . . . 127 Sensitivity Analysis . . . . . . 130 Conclusion . . . . . . 132 References . . . . . . 133

10. Multimodality Therapy: Treatment Algorithms 135 Philip E. Stieg, Vallabh Janardhan, and Howard A. Riina Introduction . . . . . . 135 Pathology of the AVM . . . . . . 135 Location of the AVM . . . . . . 136 Natural History . . . . . . 136

Contents

Patient Characteristics . . . . . . 137 Diagnostic Imaging . . . . . . 137 Management Options . . . . . . 138 Decision Analysis for the Management of Unruptured AVMs . . . . . . 140 Decision Analysis for the Management of Ruptured AVMs . . . . . . 140 Conclusions . . . . . . 141 References . . . . . . 141

11. Surgical Principles 145 Christopher C. Getch, Christopher Eddleman, Melanie K. Swope, and H. Hunt Batjer Introduction . . . . . . 145 Preoperative Imaging . . . . . . 145 Embolization . . . . . . 149 Anesthesia . . . . . . 149 Neurosurgical Emergency: Intracranial Hemorrhage Related to AVM Rupture . . . . . . 151 Surgical Resection . . . . . . 152 Conclusion . . . . . . 157 References . . . . . . 157

12. Endovascular Principles 159 Charles J. Prestigiacomo and John Pile-Spellman Introduction . . . . . . 159 Historical Perspective . . . . . . 159 Role of Endovascular Therapy . . . . . . 160 Hemodynamic Considerations and Staging of Embolization . . . . . . 165 Anesthetic Considerations and Monitoring . . . . . . 166 Functional Testing . . . . . . 167 Equipment . . . . . . 168 Strategy and Technique . . . . . . 171 Outcomes . . . . . . 172 Complications and Complication Avoidance . . . . . . 172 Future Directions . . . . . . 174 References . . . . . . 174

13. Radiosurgical Principles 177 Susan C. Pannullo, Jordan Abbott, and Robert Allbright Introduction . . . . . . 177 History of Radiosurgery for AVMs . . . . . . 177 Radiobiology of AVM Radiosurgery . . . . . . 177 Pathologic Changes of AVMs After Radiosurgery . . . . . . 178 Radiosurgery Platforms . . . . . . 178 Stereotactic Radiosurgery Technique . . . . . . 178 Evaluation of Treatment Response . . . . . . 182 Complications . . . . . . 183 Combined Modality Management of AVMs . . . . . . 183 Single Fraction Versus Fractionated Therapy . . . . . . 183 Future Directions for AVM Radiosurgery . . . . . . 184 References . . . . . . 184

14. Combined Therapy: The Team Approach 189 C. Michael Cawley, III, Harry J. Cloft, Nelson M. Oyesiku, and Daniel L. Barrow Introduction . . . . . . 189 Goals of Therapy . . . . . . 189 Therapeutic Strategies . . . . . . 190 Remedies for Palliation . . . . . . 196 Conclusion . . . . . . 198 References . . . . . . 198

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SECTION IV: THERAPEUTIC MANAGEMENT 15. Anesthetic Considerations 201 Tomoki Hashimoto and William L. Young General Considerations . . . . . . 201 Cerebral Circulatory Changes in Patients with AVMs . . . . . . 202 Anesthetic Management During Surgery . . . . . . 203 Anesthetic Management During Interventional Neuroradiologic Procedures . . . . . . 206 References . . . . . . 211

16. Supratentorial Lobar Arteriovenous Malformations 215 John E. Wanebo, Jeffrey G. Ojemann, and Ralph G. Dacey, Jr. Introduction . . . . . . 215 General Considerations . . . . . . 215 Frontal Lobe AVMs . . . . . . 228 Temporal Lobe AVMs . . . . . . 231 Parietal Lobe AVMs . . . . . . 233 Occipital Lobe AVMs . . . . . . 235 References . . . . . . 237

17. Perisylvian Arteriovenous Malformations Harold J. Pikus and Roberto C. Heros

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Introduction . . . . . . 243 Presentation . . . . . . 244 Diagnostic Studies . . . . . . 244 Management . . . . . . 246 Results . . . . . . 254 References . . . . . . 254

18. Supratentorial Periventricular Arteriovenous Malformations Charles J. Prestigiacomo and Robert A. Solomon

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Introduction . . . . . . 259 Epidemiology, Presentation, and Natural History . . . . . . 259 Anatomical Considerations . . . . . . 260 Evaluation of Patients with Periventricular AVMs . . . . . . 262 Therapeutic Options . . . . . . 263 Surgical Approaches . . . . . . 264 Conclusions . . . . . . 269 References . . . . . . 270

19. Corpus Callosum Arteriovenous Malformations 273 Vallabh Janardhan, Howard A. Riina, and Philip E. Stieg Introduction . . . . . . 273 Epidemiology . . . . . . 273 Anatomy of the Corpus Callosum . . . . . . 274 Functions of the Corpus Callosum and Callosal Syndromes . . . . . . 275 Clinical Presentation . . . . . . 275 Classification/Grading Systems for AVMs of the Corpus Callosum . . . . . . 277 Treatment . . . . . . 278 Summary . . . . . . 282 References . . . . . . 283

20. Arteriovenous Malformations of the Cerebellar Vermis and Hemispheres 285 Andrew D. Fine, Curtis L. Beauregard, and Arthur L. Day Introduction . . . . . . 285 Cerebellar Surface Anatomy and Vascular Supply . . . . . . 285 Cerebellar Functional Anatomy . . . . . . 288 Clinical Presentation . . . . . . 289 Classification and Risk Stratification . . . . . . 289

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Treatment . . . . . . 290 Summary . . . . . . 295 References . . . . . . 296

21. Infratentorial Cerebellopontine Angle Arteriovenous Malformations Giuseppe Lanzino and L. Nelson Hopkins

299

Introduction . . . . . . 299 Regional Anatomy . . . . . . 299 Clinical Presentation . . . . . . 302 Diagnosis . . . . . . 303 Therapy . . . . . . 304 Surgical Technique . . . . . . 305 Complications . . . . . . 310 Summary . . . . . . 311 References . . . . . . 312

22. Brainstem Arteriovenous Malformations Steven D. Chang and Gary K. Steinberg

315

Introduction . . . . . . 315 Natural History . . . . . . 315 Classification of Brainstem AVMs . . . . . . 315 Arterial Supply and Venous Drainage . . . . . . 316 Clinical Presentation . . . . . . 316 Indications and Contraindications for Surgery . . . . . . 316 Potential Risks . . . . . . 317 Preoperative Preparation . . . . . . 317 Anesthetic Technique . . . . . . 317 Surgical Approaches and Positioning . . . . . . 319 Closure Techniques and Postoperative Management . . . . . . 323 Special Perioperative Equipment/Techniques . . . . . . 323 Stereotactic Radiosurgery . . . . . . 324 Embolization . . . . . . 324 Clinical Outcome . . . . . . 326 Complications and Complication Avoidance . . . . . . 327 Summary . . . . . . 327 References . . . . . . 327

23. Intraoperative and Postoperative Angiography 329 Michael A. Lefkowitz, Fernando Vinuela, and Neil Martin Introduction . . . . . . 329 Intraoperative Angiography . . . . . . 329 Intraoperative Embolization . . . . . . 336 Postoperative Angiography . . . . . . 337 References . . . . . . 341

24. Associated Aneurysms 343 Bernard R. Bendok, Christopher C. Getch, and H. Hunt Batjer Introduction . . . . . . 343 Classification . . . . . . 343 Incidence . . . . . . 343 Pathophysiology . . . . . . 344 Natural History . . . . . . 344 Management . . . . . . 344 Conclusions . . . . . . 348 References . . . . . . 349

25. Arteriovenous Malformations in Pregnancy 351 Eli M. Baron, Sumon Bhattacharjee, Robert Wienecke, and Christopher M. Loftus Introduction . . . . . . 351 Epidemiology . . . . . . 351 Physiologic Changes Associated with Pregnancy . . . . . . 351 Radiologic Diagnosis of AVM in Pregnancy . . . . . . 352

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Medical Management . . . . . . 353 Surgical Management . . . . . . 354 Embolization and Radiosurgical Procedures . . . . . . 355 Ethical Considerations . . . . . . 355 Conclusions . . . . . . 355 References . . . . . . 356

26. Diagnosis and Management of Pediatric Arteriovenous Malformations Jeffrey P. Greenfield and Mark M. Souweidane Introduction . . . . . . 359 Epidemiology . . . . . . 359 Developmental Biology of AVMs in Children . . . . . . 359 Natural History . . . . . . 360 Presentation and Evaluation of AVMs in Children . . . . . . 361 Considerations for Intervention . . . . . . 363 Timing of Intervention . . . . . . 363 Preoperative Embolization . . . . . . 364 Stereotactic Radiosurgery . . . . . . 365 Surgical Technique . . . . . . 366 Complications Avoidance . . . . . . 366 Outcomes . . . . . . 367 References . . . . . . 368

27. Management of Residual Arteriovenous Malformations Daniel P. McCarthy, Stefan A. Mindea, Bernard R. Bendok, Christopher C. Getch, and H. Hunt Batjer

371

Introduction . . . . . . 371 Residual Malformations after Endovascular Embolization . . . . . . 372 Residual Malformations after Radiosurgery . . . . . . 375 Residual Malformations after Microsurgical Resection . . . . . . 378 Conclusion . . . . . . 380 References . . . . . . 380

SECTION V: SPECIAL PROBLEMS 28. Critical Care Management 383 Mark R. Harrigan and B. Gregory Thompson Introduction . . . . . . 383 Neurological Monitoring and Imaging . . . . . . 383 Perioperative Cerebral Edema . . . . . . 384 Cardiovascular Management . . . . . . 386 Pulmonary Management . . . . . . 387 Fluids and Electrolytes . . . . . . 387 Nutrition and Diabetic Management . . . . . . 388 Infectious Disease . . . . . . 389 Sedation and Analgesia . . . . . . 389 Glucocorticoids . . . . . . 390 Thrombotic Complications . . . . . . 390 Seizure Prophylaxis and Treatment . . . . . . 390 References . . . . . . 390

29. Surgical Complications 393 Sean D. Lavine and Steven L. Giannotta Introduction . . . . . . 393 Preoperative Considerations . . . . . . 393 Intraoperative Considerations . . . . . . 395 Postoperative Considerations . . . . . . 400 Summary . . . . . . 403 References . . . . . . 403

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30. Endovascular Therapy: Indications, Complications, and Outcome Adnan H. Siddiqui, P. Roc Chen, and Robert H. Rosenwasser

407

Introduction . . . . . . 407 Cerebrovascular Malformations . . . . . . 407 Natural History of AVMs . . . . . . 408 Indications for Treatment . . . . . . 408 Management Principles for Endovascular Treatment . . . . . . 417 Complications: Avoidance and Management . . . . . . 422 The Jefferson Hospital for Neuroscience Experience . . . . . . 424 Summary . . . . . . 424 References . . . . . . 424

31. Radiosurgical Complications 429 Alan C. Hartford, Paul Chapman, Philip E. Stieg, Christopher S. Ogilvy, and Jay S. Loeffler Historical Background . . . . . . 429 Risk of Hemorrhage . . . . . . 430 Transient Effects on Normal Brain Tissue . . . . . . 434 Radionecrosis and Other Long-Term Effects . . . . . . 440 Conclusions . . . . . . 446 References . . . . . . 447

SECTION VI: FUTURE CONSIDERATIONS 32. Endovascular Techniques 451 Harry J. Cloft and Jacques E. Dion Introduction . . . . . . 451 Microcatheters . . . . . . 452 Embolic Materials . . . . . . 452 Reduction of Complications . . . . . . 454 Conclusion . . . . . . 455 References . . . . . . 455

33. Radiosurgery 457 Douglas Kondziolka, L. Dade Lunsford, and John C. Flickinger Introduction . . . . . . 457 Radiobiology of Vascular Malformation Radiosurgery . . . . . . 457 Indications for AVM Radiosurgery . . . . . . 458 Clinical Experience . . . . . . 458 Stereotactic Radiosurgery Technique . . . . . . 458 AVM Obliteration . . . . . . 461 Postradiosurgery Effects . . . . . . 461 Repeat Radiosurgery . . . . . . 463 Staged Volume Radiosurgery . . . . . . 463 Future Roles for AVM Radiosurgery . . . . . . 463 Summary . . . . . . 465 References . . . . . . 465

34. Molecular Biology of Arteriovenous Malformations 469 Michael L. DiLuna, Turker Kilic, Issam A. Awad, and Murat Gunel Introduction . . . . . . 469 Angiogenesis and Vasculogenesis . . . . . . 469 Mendelian Forms of AVMs . . . . . . 471 Molecular Information on Sporadic AVMs . . . . . . 475 Future Research . . . . . . 479 References . . . . . . 479

35. Surgical Approaches 483 Daniel P. McCarthy, Bernard R. Bendok, Christopher C. Getch, and H. Hunt Batjer Introduction . . . . . . 483 Drug Delivery Systems . . . . . . 483

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Surgical Instrumentation . . . . . . 484 Anatomical, Physiological, and Operatively Integrated Imaging . . . . . . 486 Advanced Operating Suite . . . . . . 488 Conclusion . . . . . . 489 References . . . . . . 489

Index . . . .

491

Contributors

Jordan Abbott Department of Neurological Surgery, Weill Medical College of Cornell University, NewYork-Presbyterian Hospital, New York, New York, U.S.A. Joseph G. Adel Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, U.S.A. M. Jafer Ali Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, U.S.A. Robert Allbright Division of Radiation Oncology, Department of Radiology, Weill Medical College of Cornell University, NewYork-Presbyterian Hospital, New York, New York, U.S.A. Issam A. Awad Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, and Evanston Northwestern Healthcare, Evanston, Illinois, U.S.A. Eli M. Baron Department of Neurosurgery, Temple University School of Medicine, Philadelphia, Pennsylvania, U.S.A. Daniel L. Barrow Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia, U.S.A. H. Hunt Batjer Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, U.S.A. Curtis L. Beauregard Southeast Neuroscience Center, Houma, Louisiana, U.S.A. Bernard R. Bendok Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, U.S.A. Sumon Bhattacharjee

Neuroscience Group of Northeast Wisconsin, Neenha, Wisconsin, U.S.A.

C. Michael Cawley, III Departments of Neurosurgery and Neuroradiology, Emory University School of Medicine, Atlanta, Georgia, U.S.A. Steven D. Chang Department of Neurosurgery and the Stanford Stroke Center, Stanford University School of Medicine, Stanford, California, U.S.A. Paul Chapman Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A. P. Roc Chen Department of Neurosurgery, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, U.S.A. Harry J. Cloft Departments of Radiology and Neurosurgery, Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A. Ralph G. Dacey, Jr. Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri, U.S.A. Shervin R. Dashti Department of Neurosurgery, Case Western Reserve University School of Medicine, and University Hospitals of Cleveland, Cleveland, Ohio, U.S.A. Arthur L. Day Cerebrovascular Center, Department of Neurological Surgery, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts, U.S.A. Evandro de Oliveira Department of Neurosurgery, State University of Campinas - UNICAMP, Sa˜o Paulo, Brazil Michael L. DiLuna Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, U.S.A.

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Jacques E. Dion Departments of Radiology and Neurosurgery, Emory University Hospital, Atlanta, Georgia, U.S.A. Christopher Eddleman Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, U.S.A. Andrew D. Fine Neurosurgery and Spine Specialists, Sarasota, Florida, U.S.A. John C. Flickinger Departments of Neurological Surgery and Radiation Oncology, The Center for Image Guided Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, U.S.A. Kai U. Frerichs Cerebrovascular Center, Department of Neurosurgery, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts, U.S.A. Robert M. Friedlander Cerebrovascular Center, Department of Neurosurgery, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts, U.S.A. Erzhen Gao Supertron Technologies Inc., Newark, New Jersey, U.S.A. Christopher C. Getch Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, U.S.A. Steven L. Giannotta Department of Neurosurgery, University of Southern California, Los Angeles, California, U.S.A. Jeffrey P. Greenfield Department of Neurological Surgery, Weill Medical College of Cornell University, NewYork-Presbyterian Hospital, New York, New York, U.S.A. Murat Gunel Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, U.S.A. George J. Hademenos Science Department, Richardson High School, Richardson, Texas, U.S.A. Robert E. Harbaugh Department of Neurosurgery, The Pennsylvania State University, Hershey, Pennsylvania, U.S.A. Mark R. Harrigan Alabama, U.S.A.

Department of Neurosurgery, University of Alabama, Birmingham,

Alan C. Hartford Section of Radiation Oncology, Department of Medicine, Dartmouth-Hitchcock Medical Center, Dartmouth Medical School, Lebanon, New Hampshire, U.S.A. Tomoki Hashimoto Department of Anesthesia and Perioperative Care, UCSF Center for Cerebrovascular Research, University of California, San Francisco, California, U.S.A. Roberto C. Heros Florida, U.S.A.

Department of Neurological Surgery, University of Miami, Miami,

L. Nelson Hopkins Departments of Neurosurgery and Radiology, Toshiba Stroke Research Center, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York, U.S.A. Vallabh Janardhan Division of Interventional Neuroradiology, Department of Radiology, Weill Medical College of Cornell University, NewYork-Presbyterian Hospital, New York, New York, U.S.A. Turker Kilic Vascular and Oncological Neurosurgery, Gamma-Knife Radiosurgery, Marmara School of Medicine, Istanbul, Turkey Douglas Kondziolka Departments of Neurological Surgery and Radiation Oncology, The Center for Image Guided Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, U.S.A. Giuseppe Lanzino Departments of Neurosurgery and Radiology, Illinois Neurological Institute, University of Illinois College of Medicine at Peoria, Peoria, Illinois, U.S.A. Sean D. Lavine Departments of Neurological Surgery and Radiology, Columbia University, College of Physicians and Surgeons, New York Neurological Institute, New York, New York, U.S.A.

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Michael A. Lefkowitz New York, U.S.A.

Long Island Neurological Associates, New Hyde Park,

Jay S. Loeffler Department of Radiation Oncology, Northeast Proton Therapy Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A. Christopher M. Loftus Department of Neurosurgery, Temple University School of Medicine, Philadelphia, Pennsylvania, U.S.A. L. Dade Lunsford Departments of Neurological Surgery and Radiation Oncology, The Center for Image Guided Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, U.S.A. Neil Martin Division of Neurosurgery, UCLA School of Medicine, University of California–Los Angeles, Los Angeles, California, U.S.A. Tarik F. Massoud University Department of Radiology, University of Cambridge School of Clinical Medicine, Cambridge, U.K. Daniel P. McCarthy Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, U.S.A. James McInerney Department of Neurosurgery, The Pennsylvania State University, Hershey, Pennsylvania, U.S.A. Stefan A. Mindea Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, U.S.A. Michael Morgan Department of Neurosurgery, School of Advanced Medicine, Macquarie University, Sydney, Australia Ronald F. Moussa Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, U.S.A. R. Anthony Murray Illinois, U.S.A.

Department of Radiology, Northwestern Memorial Hospital, Chicago,

Christopher S. Ogilvy Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A. Jeffrey G. Ojemann Department of Neurosurgery, University of Washington/Children’s Hospital and Regional Medical Center, Seattle, Washington, U.S.A. Stephen L. Ondra Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, U.S.A. Nelson M. Oyesiku Georgia, U.S.A.

Department of Neurosurgery, Emory University School of Medicine, Atlanta,

Susan C. Pannullo Department of Neurological Surgery, Weill Medical College of Cornell University, NewYork-Presbyterian Hospital, New York, New York, U.S.A. Harold J. Pikus

Department of Neurological Surgery, University of Miami, Miami, Florida, U.S.A.

John Pile-Spellman Departments of Radiology, Neurosurgery, and Neurology, New York Neurological Institute, Columbia University Medical Center, NewYork-Presbyterian Hospital, New York, New York, U.S.A. Charles J. Prestigiacomo Departments of Neurological Surgery and Radiology, Neurological Institute of New Jersey, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, U.S.A. Albert L. Rhoton, Jr. Department of Neurological Surgery, University of Florida College of Medicine, Gainesville, Florida, U.S.A. Howard A. Riina Departments of Neurological Surgery, Neurology, and Radiology, Weill Medical College of Cornell University, NewYork-Presbyterian Hospital, New York, New York, U.S.A.

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Robert H. Rosenwasser Department of Neurosurgery, Division of Cerebrovascular Surgery and Interventional Neuroradiology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, U.S.A. Eric J. Russell Department of Radiology, Northwestern Memorial Hospital, and the Northwestern University Feinberg School of Medicine, Chicago, Illinois, U.S.A. Warren R. Selman Department of Neurosurgery, Case Western Reserve University School of Medicine, and Department of Neurological Surgery, University Hospitals of Cleveland, Cleveland, Ohio, U.S.A. Adnan H. Siddiqui Department of Neurosurgery, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, U.S.A. Robert A. Solomon Department of Neurological Surgery, New York Neurological Institute, Columbia University Medical Center, NewYork-Presbyterian Hospital, New York, New York, U.S.A. Mark M. Souweidane Department of Neurological Surgery, Weill Medical College of Cornell University, NewYork-Presbyterian Hospital, New York, New York, U.S.A. Gary K. Steinberg Department of Neurosurgery and the Stanford Stroke Center, Stanford University School of Medicine, Stanford, California, U.S.A. Philip E. Stieg Department of Neurological Surgery, Weill Medical College of Cornell University, NewYork-Presbyterian Hospital, New York, New York, U.S.A. Jeffrey L. Sunshine Department of Radiology, Case Western Reserve University School of Medicine, and Division of Magnetic Resonance Imaging, University Hospitals of Cleveland, Cleveland, Ohio, U.S.A. Melanie K. Swope Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, U.S.A. Robert W. Tarr Division of Neuroradiology, Department of Radiology, Case Western Reserve University School of Medicine, and University Hospitals of Cleveland, Cleveland, Ohio, U.S.A. Helder Tedeschi Department of Neurosurgery, State University of Campinas - UNICAMP, Sa˜o Paulo, Brazil, and University of Florida, Gainesville, Florida, U.S.A. B. Gregory Thompson Michigan, U.S.A.

Department of Neurosurgery, University of Michigan, Ann Arbor,

Wen Hung Tzu Department of Neurosurgery, University of Sa˜o Paulo School of Medicine, Sa˜o Paulo, Brazil, and University of Florida, Gainesville, Florida, U.S.A. Fernando Vinuela Department of Radiological Sciences, Endovascular Therapy Service, UCLA School of Medicine, University of California–Los Angeles, Los Angeles, California, U.S.A. John E. Wanebo Department of Neurosurgery, National Naval Medical Center, Bethesda, Maryland, U.S.A. Robert Wienecke

Neuroscience Specialists, Oklahoma City, Oklahoma, U.S.A.

John H. Wong Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, U.S.A. William L. Young Departments of Anesthesia and Perioperative Care, Neurological Surgery, and Neurology, UCSF Center for Cerebrovascular Research, University of California, San Francisco, California, U.S.A.

Section I

ANATOMY AND PHYSIOLOGY

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Surgical Anatomy Helder Tedeschi Department of Neurosurgery, State University of Campinas - UNICAMP, Sa˜o Paulo, Brazil, and University of Florida, Gainesville, Florida, U.S.A.

Evandro de Oliveira Department of Neurosurgery, State University of Campinas - UNICAMP, Sa˜o Paulo, Brazil

Wen Hung Tzu Department of Neurosurgery, University of Sa˜o Paulo School of Medicine, Sa˜o Paulo, Brazil, and University of Florida, Gainesville, Florida, U.S.A.

Albert L. Rhoton, Jr. Department of Neurological Surgery, University of Florida College of Medicine, Gainesville, Florida, U.S.A.

INTRODUCTION The advances in microneurosurgical equipment and techniques, combined with the evolution of endovascular and radiosurgical treatments, have greatly facilitated the management of arteriovenous malformations (AVMs) of the brain. The continuous development in the field of neuroimaging has contributed enormously to the understanding of the anatomical characteristics of AVMs. Nevertheless, the intricate anatomy related to AVMs still presents a problem to the average neurosurgeon (1). Although the vessels involved with the arterial supply and with the venous drainage of AVMs appear disorganized, they usually follow the same pattern of the normal vasculature. Detailed three-dimensional anatomical knowledge of the normal brain structures enables the surgeon to understand and access an AVM with less difficulty and to perform surgical resection in a rational way. In this chapter, we describe the basic anatomical features to be considered in planning surgical strategy for AVMs of different areas of the brain. These areas include the frontal, parietal, temporal, and occipital convexities, the mesial temporal region, the interhemispheric parafalcine region (includes the frontal, parietal, occipital, and callosal regions), the region of the basal ganglia (includes ventricular and insular AVMs), and the region of the posterior fossa (includes cerebellar and brain stem lesions). FRONTAL LOBE AVMs Neural Relationships The lateral surface of the frontal lobe is bounded posteriorly by the central sulcus, which separates the frontal from the parietal lobes, and above by the superior border of the hemisphere, which parallels the superior sagittal sinus. The lower border of the lateral surface has an anterior part, the superciliary border, which rests on the orbital roof, and a posterior part, the sylvian border, which faces the temporal lobe across the sylvian fissure. The lateral surface is traversed by three sulci that divide it into one vertical gyrus, which parallels the central sulcus, and three horizontal gyri, which are oriented in the same direction as the sylvian fissure. The precentral gyrus, which parallels the central sulcus, is bounded behind by the central sulcus and in front by the precentral sulcus. The surface in front of the precentral sulcus is divided by two sulci, the superior and inferior frontal sulci, into three roughly horizontal convolutions, the superior, middle, and inferior frontal gyri.

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The inferior frontal convolution, which is situated between the sylvian fissure and the inferior frontal gyrus, is divided from anterior to posterior into a pars orbitalis, a pars triangularis, and a pars opercularis by the anterior horizontal and anterior ascending rami of the sylvian fissure. The inferior surface of the frontal lobe is concave from side to side and rests on the cribriform plate, orbital roof, and the lesser wing of the sphenoid bone. The olfactory sulcus, which overlies the olfactory bulb and tract, divides the orbital surface into a medial strip of cortex, the gyrus rectus, and a larger lateral part, the orbital gyri. The lateral gyri are divided by the orbital sulci into the anterior, medial, posterior, and lateral orbital gyri. Arterial Relationships AVMs situated in the lateral and basal surfaces of the frontal lobe usually derive their arterial supply from the M1 and M2 branches of the middle cerebral artery. In larger lesions, or in those situated close to the margins of the hemispheres, the arterial supply may involve branches from segments of both the anterior and middle cerebral arteries. Venous Relationships The veins draining AVMs in the lateral surface of the frontal lobe are divided into an ascending group, which empties into the superior sagittal sinus, and a descending group, which courses toward the sylvian fissure to join the superficial sylvian veins. Basal surface frontal AVMs are drained through an anterior group of veins, which course toward the frontal pole and empty into the superior sagittal sinus, and a posterior group, which drain backward to join the veins at the medial part of the sylvian fissure, where they converge on the anterior perforated substance to form the basal vein (2,3). Most AVMs located in the lateral and basal surfaces of the frontal lobe can be managed through a fronto-temporo-sphenoidal craniotomy. Those AVMs that reach, or that are located in, the upper convexity require that the craniotomy be extended to the midline to secure the branches of the anterior cerebral artery during surgery (Fig. 1A, B, and C). PARIETAL LOBE AVMs Neural Relationships The lateral surface of the parietal lobe is demarcated anteriorly by the central sulcus, posteriorly by a line joining the preoccipital notch to the point where the parietooccipital sulcus reaches the superior edge of the hemisphere, and inferiorly by a line directed along the posterior ramus of the sylvian fissure. The lateral surface is subdivided into three areas by the postcentral and intraparietal sulci. The postcentral sulcus divides the parietal lobe into an anterior convolution, the postcentral gyrus, situated behind and parallel to the central sulcus, and a large posterior part, which is subdivided by the intraparietal sulcus, into the superior and inferior parietal lobules. The inferior parietal lobule is divided into an anterior part formed by the supramarginal gyrus, which arches over the upturned end of the posterior ramus of the sylvian fissure, and a middle part formed by the angular gyrus, which arches over the upturned end of the inferior temporal sulcus and extends onto the anterior part of the occipital lobe. The superior parietal lobule extends from the intraparietal sulcus to the superior margin of the hemisphere. Arterial Relationships AVMs located in the lateral surface of the parietal lobe usually derive their arterial supply from branches of the anterior and middle cerebral arteries. At times, these malformations may receive perforators from a ventricular branch of the posterior cerebral artery, the lateral posterior choroidal artery (Fig. 2A and B). Venous Relationships The veins that drain AVMs located in the lateral surface of the parietal lobe are divided into an ascending group, which empties into the superior sagittal sinus, and a descending group, which drains into the veins along the sylvian fissure.

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Figure 1 (A) Anatomical venous dissection of the right cerebral hemisphere: 1. Vein of Trolard; 2. superficial sylvian vein; 3. vein of Labbe´. (See color insert.) (B) Right digital carotid angiogram of a frontal opercular arteriovenous malformation (AVM) showing the usual venous drainage pattern of such lesions. (C) Intraoperative view of the same patient showing the enlarged superficial veins that drain the AVM. (See color insert.) (D) Right digital carotid angiogram of a sylvian AVM showing the usual venous drainage pattern of such lesions.

Large parietal lobe AVMs are usually associated with a high risk of surgical morbidity. The feeding vessels from the middle cerebral artery are usually pathologically tortuous and elongated with fragile walls that are at times extremely difficult to coagulate. TEMPORAL LOBE AVMs Neural Relationships The lateral surface of the temporal lobe is situated below the sylvian fissure and anterior to an imaginary line extending upward from the preoccipital notch to the parietooccipital sulcus. The lateral surface of the temporal lobe is divided by two sulci, the superior and inferior temporal sulci, into three gyri, the superior, middle, and inferior temporal gyri, which are oriented parallel to the sylvian fissure. The superior temporal gyrus lies between the sylvian fissure and the superior temporal sulcus. It is continuous around the lip of the fissure with the transverse temporal gyri, which extend obliquely forward and laterally from the border of the insula to form the lower wall of the deep portion of the sylvian fissure. The middle temporal gyrus lies between the superior and inferior temporal sulci. The inferior temporal gyrus lies below the inferior temporal sulcus and continues around the inferior border of the hemisphere to form the lateral part of the inferior surface of the lobe. The inferior surface of the temporal lobe is formed, from medial to lateral, by the parahippocampal and occipitotemporal gyri and by the lower surface of the inferior temporal gyrus. The parahippocampal gyrus forms the medial part of the inferior surface and is separated laterally from the occipitotemporal gyrus by the collateral and rhinal sulci. The parahippocampal gyrus extends backward from the temporal pole to the posterior margin of the corpus callosum, where it is continuous around the splenium with the cingulate gyrus. The anterior end of the parahippocampal gyrus projects medially to form a hook-like prominence called the uncus.

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Figure 2 (A) Anatomical dissection of the brain with the frontal lobes removed to the level of the anterior perforated substance to expose the anterior portion of the poligone of Willis: 1. Corpus callosum; 2. lateral ventricle; 3. basal ganglia; 4. M2 branches of the middle cerebral artery; 5. anterior communicating artery; 6. recurrent artery of Heubner; 7. lenticulostriate arteries; 8. M4 segment of the middle cerebral artery; 9. M1 segment of the middle cerebral artery; 10. A1 segment of the anterior cerebral artery; 11. internal carotid artery. (See color insert.) (B) Left digital carotid angiogram of an arteriovenous malformation (AVM) located in the convexity of the parietal lobe. (C) Right digital carotid angiogram of an AVM located in the uncus of the temporal lobe.

The occipitotemporal gyrus is separated laterally by the occipitotemporal sulcus from the lower surface of the inferior temporal gyrus. Arterial Relationships According to their location, AVMs arising at the lateral and basal surfaces of the temporal lobe may derive their arterial supply from branches of the internal carotid artery and from the middle and posterior cerebral arteries. AVMs located in the temporal pole are usually supplied by branches of the M1 segment of the middle cerebral artery and at times by branches of the anterior choroidal artery and of the P2 segment of the posterior cerebral artery (Fig. 2C). Those AVMs located in the superior temporal gyrus are usually supplied by branches of the middle cerebral artery, although they may also receive deep tributaries from intraventricular arteries. AVMs located in the middle and inferior temporal gyri are often supplied by both the middle and posterior cerebral artery territories. Inferior temporal surface AVMs are invariably supplied by branches of the posterior cerebral artery. Venous Relationships The veins that drain AVMs arising in the lateral surface of the temporal lobe are divided into an ascending group, the temporosylvian veins, which course toward the sylvian fissure, and a descending group, which empty into the venous sinuses below the temporal lobe. AVMs arising in the basal surface of the temporal lobe are drained by two groups of veins. The lateral group drains into the sinuses in the anterolateral part of the tentorium. The medial group, formed by the uncal, anterior hippocampal, and medial temporal veins, empties into the basal vein as it courses along the medial edge of the temporal lobe. The part of the basal surface circa the temporal pole is commonly drained by the temporosylvian veins.

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OCCIPITAL LOBE AVMs Neural Relationships The lateral surface of the occipital lobe is poorly delimited from the parietal lobe. It lies behind a line joining the preoccipital notch to the point where the parietooccipital sulcus, which is prominent on the medial surface of the hemisphere, intersects the superior margin of the hemisphere. The lateral surface is composed of a number of irregular convolutions that are divided by a short horizontal sulcus, the lateral occipital sulcus, into the superior and inferior occipital gyri. The inferior surface of the occipital lobe lies behind a line that extends laterally from the anterior end of the calcarine sulcus to the preoccipital notch. The inferior surface is formed by the lower part of the lingula and the posterior part of the occipitotemporal and inferior temporal gyri. Arterial Relationships AVMs located in the lateral and inferior surfaces of the occipital lobe are usually supplied by terminal branches of the middle and posterior cerebral arteries. Venous Relationships The lateral surface of the occipital lobe is drained by the occipital vein, which arises from tributaries that drain the lateral surface of the occipital pole. This vein usually empties into the lower margin of the superior sagittal sinus 4 to 5 cm from the torcular (2). The inferior surface of the occipital lobe is drained by the inferior occipital vein that empties into the lateral tentorial sinus. MEDIOBASAL TEMPORAL LOBE AVMs The mediobasal temporal region can be divided into three parts: anterior, middle, and posterior. The anterior part is limited posteriorly by a transverse line passing at the posterior end of the uncus, and the middle and posterior parts are separated by an extension of the anterior splenial line. Neural Relationships The anterior part has three surfaces: anterosuperior, inferior, and medial. The anterosuperior surface, consisting of the semilunar and ambient gyri, faces the medial end of the sylvian fissure and the carotid cistern. The inferior surface is the parahippocampal gyrus, which is separated anterolaterally from the occipitotemporal gyrus by the rhinal sulcus. This sulcus continues posteriorly as the collateral sulcus in the middle part of the mediobasal temporal region. More laterally over the inferior surface the occipitotemporal sulcus, another anteroposteriorly oriented sulcus, separates the occipitotemporal gyrus from the inferior temporal gyrus. The medial surface of the anterior part contains the anterior end of the parahippocampal gyrus and the uncus. These structures face the anterior two-thirds of the cerebral peduncle, with the crural cistern interposed between the peduncle and the uncus. The middle part of the mediobasal temporal region has two surfaces: inferior and medial. On the inferior surface the collateral sulcus separates the most medially situated parahippocampal gyrus from the occipitotemporal gyrus. Lateral to the occipitotemporal gyrus, and separated from it by the occipitotemporal sulcus, is the inferior temporal gyrus. The parahippocampal gyrus ends at the level of the anterior splenial line. From this point, the lingual gyrus continues posteriorly, and the isthmus of the cingulate gyrus continues posteriorly and superiorly. The occipitotemporal gyrus is a long gyrus extending from the anterior temporal base to the occipital pole. The collateral sulcus extends from the anterior to the posterior parts of the mediobasal temporal region. The occipitotemporal sulcus usually has its course close to the inferolateral margin of the temporal lobe, over the temporal base. From inferior to superior, the medial surface of the middle part consists of the subiculum of the parahippocampal gyrus, the dentate gyrus, and the fimbria of the fornix. It faces the posterior one-third of the cerebral peduncle and the tegmentum of the mesencephalon and is separated from them by the ambient cistern. The posterior part of the mediobasal temporal region includes part of the occipital and parasplenial area to which some AVMs may extend. This part has three surfaces: inferior,

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medial, and anterior. On the inferior surface, continuous with the posterior part of the parahippocampal gyrus, is the lingual gyrus, which is separated laterally from the occipitotemporal gyrus by the collateral sulcus. The parasplenial region forms the medial surface of the posterior part. It contains the isthmus of the cingulate gyrus anteriorly, surrounding the splenium of the corpus callosum, and the inferior extension of the precuneus, posterior to the isthmus from which it is separated by the subparietal sulcus. Inferolaterally to these two gyri is the lingual gyrus, separated from them by the anterior part of the calcarine sulcus. The anterior surface is composed of the anterior end of the isthmus of cingulate gyrus, the posterior end of the dentate gyrus and the fasciolar gyrus, which is continuous anteriorly with the dentate gyrus. This surface faces the tectum of the mesencephalon and the pulvinar of the thalamus, from which it is separated by the posterior end of the ambient cistern and by the quadrigeminal cistern. From a practical point of view, the posterior part of the mediobasal temporal region can be divided into a superior and inferior area, the former superoanterior to the anterior part of the calcarine sulcus and the latter inferoposterior to this sulcus. Arterial Relationships The arterial supply of the anterior surface of the anterior part comes mainly from the early branches of the M1 segment of the middle cerebral artery. The most medial area of this surface may receive a branch from the carotid artery and also receives a branch from the anterior choroidal artery, called the uncal artery. The inferior surface receives branches from the first cortical branch of the posterior cerebral artery, the hippocampal arteries (Fig. 3A). The medial surface is supplied by branches of the anterior choroidal artery and by the hippocampal artery. The inferior surface of the middle part of the mediobasal temporal region receives branches from the posterior cerebral artery: the anterior, middle, and posterior temporal arteries. These arteries originate from the lateral surface of the posterior cerebral artery, pass through the ambient cistern laterally, and cross the tentorial edge to reach the temporal base. Passing under the parahippocampal gyrus, they enter the collateral sulcus. After exiting this sulcus, these arteries run over the occipitotemporal gyrus and enter the occipitotemporal sulcus. They end finally over the surface of the inferior temporal gyrus. The medial surface of the middle part has the choroidal fissure at its highest point. The anterior choroidal artery enters through this fissure at its anteroinferior end, the inferior choroidal point. Several posterior choroidal arteries enter the choroidal fissure posteriorly to the anterior choroidal artery. In the posterior part of the mediobasal temporal region, the two major terminal branches of the posterior cerebral artery, the parietooccipital and calcarine arteries, cross posterolaterally over the anteroinferior end of the isthmus of the cingulate gyrus. The parietooccipital artery sends branches to the posterior half of the precuneus and also to the anterior half of the cuneus. The calcarine artery sends branches to the posterior half of the cuneus and to the lingual gyrus. Venous Relationships The venous system related to the mediobasal temporal region is mainly the basal vein system. The vein of Galen may receive veins that drain the temporooccipital junction area and the parasplenial area. The anterosuperior surface of the anterior part of the mediobasal temporal region is drained by the uncal vein. This vein drains into the deep middle cerebral vein or directly into the first segment of the basal vein of Rosenthal. The medial surface is also drained by the uncal vein and by the anterior hippocampal vein, which runs posteriorly and drains into the main trunk of the inferior ventricular vein or directly into the second segment of the basal vein. The inferior surface of the middle part of the mediobasal temporal region is drained by the medial temporal vein, which drains directly into the basal vein. The anterior longitudinal hippocampal vein runs over the medial surface of the middle part and drains into the inferior ventricular vein, the anterior hippocampal vein, or the basal vein at the inferior choroidal point. The inferior surface of the posterior part of the mediobasal temporal region is drained by the occipitotemporal vein, which drains into the third segment of the basal vein. The medial

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Figure 3 (A) Anatomical dissection of the posterior cerebral artery and its branches (viewed from the basal surface of the brain): 1. Internal carotid artery; 2. posterior communicating artery; 3. anterior choroidal artery; 4. posterior cerebral artery; 5. posterior thalamoperforating artery; 6. medial posterior choroidal artery; 7. anterior temporal artery; 8. medial temporal artery; 9. posterior temporal artery; 10. parietooccipital artery; 11. calcarine artery. (See color insert.) (B) Digital vertebral angiogram of a right-sided anterior mediobasal temporal lobe arteriovenous malformation (AVM). (C) Digital vertebral angiogram of a right-sided middle mediobasal temporal lobe AVM. (D) Digital vertebral angiogram of a right-sided posterior mediobasal temporal lobe AVM. (See color insert.)

surface of this posterior part is drained by the internal occipital vein, which frequently joins the posterior pericallosal vein near the splenium before terminating into the internal cerebral vein or into the vein of Galen. The anterior surface of this posterior part is drained by the posterior longitudinal hippocampal vein, which may drain into the third segment of the basal vein, the internal cerebral vein, the lateral atrial vein, or the medial atrial vein. Temporal Horn of the Lateral Ventricle In addition to the superficial anatomy, a thorough knowledge of the anatomy of the temporal horn of the lateral ventricle is of major importance in the surgical approach to vascular malformations of the mediobasal temporal region. The temporal horn extends forward from the atrium below the pulvinar into the medial part of the temporal lobe and ends blindly immediately behind the amygdaloid nucleus. The floor of the temporal horn is formed medially by the hippocampus and laterally by the collateral eminence. The roof is formed medially by the inferior surface of the thalamus and the tail of the caudate nucleus, which are separated by the striothalamic sulcus, and laterally by the tapetum of the corpus callosum, which sweeps inferiorly to form the lateral wall of the temporal horn. The medial wall is little more than a narrow cleft, the choroidal fissure, situated between the inferolateral part of the thalamus and the fimbria of the fornix.

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The choroid plexus in the lateral ventricle has a C-shaped configuration that parallels the fornix. It is attached to the tela choroidea along the choroidal fissure, the narrow C-shaped cleft situated between the fornix and the thalamus in the medial part of the body, atrium, and temporal horn. The inferior termination of the choroidal fissure, called the inferior choroidal point, is located just behind the uncus and amygdaloid nucleus and just lateral to the lateral geniculate body (4,5). The choroid plexus of the lateral ventricles is supplied by the anterior and posterior choroidal arteries, each giving branches to the neural structures along their course. The choroid plexus of the temporal horn is supplied by the anterior choroidal artery and by the lateral posterior choroidal arteries. The roof and lateral wall of the temporal horn are drained predominantly by the inferior ventricular vein, and the floor is drained by the transverse hippocampal veins. The veins from the temporal horn join the basal vein or its tributaries. The posterior part of the roof and floor of the temporal horn may be drained by the veins coursing in the walls of the atrium, the medial and lateral atrial veins. According to their location, mediobasal temporal lobe AVMs are divided into three groups: anterior, middle, and posterior. The anterior mediobasal temporal lobe AVMs are located in the uncus, anterior area of the parahippocampal gyrus, and amygdala (Fig. 3B). They are supplied by the proximal branches of the M1 segment of the middle cerebral artery, by branches of the anterior choroidal artery, by perforating branches of the internal carotid artery, and by temporal branches of the posterior cerebral artery, especially the hippocampal artery. The venous drainage is in general by the basal vein of Rosenthal through numerous tributaries draining the cortex of the uncus and parahippocampal gyrus. When there is stenosis or absence of the basal vein of Rosenthal, the drainage occurs initially through the superficial sylvian vein, and then retrogradely to the sphenoparietal sinus, longitudinal sinus, or lateral sinus. Many surgeons approach anterior mediobasal temporal lobe AVMs by a transsylvian route through a fronto-temporo-sphenoidal (pterional) craniotomy (6–9). We use a combination of the pterional and subtemporal approaches, called a pretemporal approach with complete exposure of the temporal pole (10–12). Through a wide opening of the sylvian cistern we initially expose the afferent branches from the proximal portion of M1 segment of the middle cerebral artery, from the internal carotid artery, and from the anterior choroidal artery. By retracting the temporal pole posteriorly, we can expose and coagulate the afferent branches from the posterior cerebral artery and then start the last phase of the surgery, the resection of the vascular lesion. Whenever possible, we initiate the resection of the AVM only after the complete occlusion of the afferent vessels. Sometimes the AVM can be approached through the inferior sulcus of the insula at the level of the limen insula, as described by Yasargil et al. (13). The middle mediobasal temporal lobe AVMs involve the parahippocampal gyrus posterior to the uncus and are limited posteriorly by the anterior splenial line (Fig. 3C). Medially they are related to the cerebral peduncle and superomedially to the thalamus, optic pathways, and lateral geniculate body. Eventually these AVMs may extend laterally, compromising the fusiform gyrus, the hippocampus, and the choroid plexus of the temporal horn. These AVMs are mainly supplied by cortical temporal branches of the posterior cerebral artery. When the vascular lesion extends laterally, it can be supplied by branches of the intraventricular segment of the anterior choroidal artery. Venous drainage is usually from the posteromedial aspect of the malformation to the basal vein of Rosenthal. Rarely, these lesions drain superficially to the transverse sinus through cortical veins on the inferior surface of the temporal lobe. The middle mediobasal temporal lobe AVMs can be accessed by a subtemporal approach (7,14,15) through a cortical incision on the superior or middle temporal gyrus (16), through a cortical incision on the inferior temporal gyrus or on the fusiform gyrus (6,15), through a cortical incision on the parahippocampal gyrus (17), through the resection of a small portion of the inferior temporal gyrus (4,15), or through the collateral sulcus (8). We approach middle mediobasal temporal lobe AVMs through the occipitotemporal sulcus, crossing the temporal horn of the lateral ventricle and using the choroidal fissure to get to the ambient cistern. We rarely use the collateral sulcus because in addition to being too medial over the inferior surface of the temporal lobe, it has a medial to lateral orientation toward the ventricle that requires great cerebral retraction to adequately expose the lesion. When these middle AVMs are slightly more anterior, they can also be approached through the inferior

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sulcus of the insula. After the identification of the anterior choroidal artery inside the ventricle and of the posterior cerebral artery in the ambient cistern, these arteries are followed posteriorly up to the AVM, occluding the branches to the malformation, and preserving the medial branches to the brain stem and basal ganglia. The excision of the AVM localized in the parahippocampal gyrus follows an anterior to posterior direction, because its venous drainage is generally from the posteromedial aspect of the lesion to the basal vein of Rosenthal. The posterior mediobasal temporal lobe AVMs are localized in the posterior part of the parahippocampal gyrus, posteriorly to the anterior splenial line (Fig. 3D). They may extend also to the isthmus of the cingulate gyrus, the anterior area of the precuneus, and the lingual gyrus. These AVMs are related to the medial portion of the ventricular trigone, to the mesencephalic tegment, and to the pulvinar of the thalamus. Sometimes they extend inferiorly to involve the fusiform gyrus and/or superiorly to involve the cingulate gyrus around the splenium of the corpus callosum. Usually their posterior limit is the occipitoparietal sulcus. The arterial supply to these malformations comes from branches of the posterior cerebral artery, including the posterolateral choroidal branches. When the AVM extends superiorly, it can receive afferents from the distal segment of the pericallosal artery. The venous drainage is to the distal segment of the basal vein of Rosenthal, directly to the vein of Galen, or, rarely, to the straight sinus or to the transverse sinus through a dural sinus localized in the tentorium. The posterior mediobasal temporal lobe AVMs are also difficult to approach and excise. When the lesion extends to the posterior region of the ventricular trigone, it can be accessed through the choroidal fissure, using the occipitotemporal sulcus. The complexity of the group of veins that form the vein of Labbe´ is frequently a great obstacle for the utilization of this approach. The approach is complicated as well by the deep location of the AVM and by the curvature of the tentorium. When the lesion extends superiorly to the cingulate gyrus, we prefer an interhemispheric parafalcine posterior approach through the calcarine and occipitoparietal sulci with minimum retraction of the brain. The inconveniences of this approach are the great distance to the arterial afferents and the premature access to the venous drainage of the lesion. INTERHEMISPHERIC PARAFALCINE AND CALLOSAL REGION AVMs AVMs that arise along the interhemispheric fissure can compromise the medial cortical surface of the cerebral hemispheres, the corpus callosum, and the midline structures related to the walls of the cerebral ventricles. These AVMs can present different anatomical and surgical features according to their location along the interhemispheric fissure. AVMs that compromise the medial cortical surface of the cerebral hemispheres in the anterior third of the interhemispheric fissure are usually supplied by branches of the proximal A2 segment of the anterior cerebral artery and drain into the anterior third of the superior sagittal sinus (Fig. 4). Those interhemispheric malformations

Figure 4 (A) Anatomical dissection of the medial aspect of the left cerebral hemisphere. 1. Cingulate gyrus; 2. body of corpus callosum; 3. splenium of corpus callosum; 4. genu of corpus callosum; 5. rostrum of corpus callosum; 6. body of lateral ventricle; 7. fornix; 8. internal cerebral vein; 9. vein of Galen; 10. third ventricle; 11. anterior cerebral arteries. (See color insert.) (B) Left carotid digital subtraction arterial angiogram of an arteriovenous malformation located in the anterior part of the cingulate gyrus and body of the corpus callosum. Note the arterial supply through the anterior cerebral artery and the venous drainage through the septal vein into the internal cerebral vein.

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that are located in proximity to the gyrus rectus, i.e., to the basal surface of the frontal lobe, can also be supplied by branches of the A1 segment of the anterior cerebral artery. According to their size, these malformations can extend laterally and recruit vessels from branches of the middle cerebral artery. AVMs that involve the corpus callosum alone are not common (Fig. 5). These lesions usually involve portions of the cingulate gyrus, and sometimes may extend inferiorly to include the midline structures of the lateral and third ventricles. Those AVMs that involve the anterior third of the corpus callosum are supplied by branches of the anterior cerebral artery. They may have superficial drainage into the superior sagittal sinus or drain into the septal and thalamostriate veins in the ventricles. AVMs arising in the middle third of the interhemispheric fissure are usually very difficult to approach. The exposure is usually hampered by the veins that drain either the malformation or the normal brain, and by the proximity of the sensory-motor cortex that prohibits any excessive retraction. These malformations are usually supplied by branches of the pericallosal or callosomarginal arteries, and when the malformation extends to the ventricles, by branches of the posterior choroidal arteries. The venous drainage to the superficial system occurs through bridging veins to the superior or inferior sagittal sinuses, and at times, to the deep venous system through ependymal veins and the internal cerebral veins. AVMs that arise in the posterior third of the interhemispheric fissure comprise those located in the posterior parietal and mesial occipital regions, which are related to the posterior third of the falx cerebri.

Figure 5 (A) Anatomical dissection of the right cerebral hemisphere. 1. Cingulate gyrus; 2. body of corpus callosum; 3. genu of corpus callosum; 4. rostrum of corpus callosum; 5. fornix; 6. splenium of corpus callosum; 7. right anterior cerebral artery; 8. third ventricle; 9. internal cerebral vein; 10. vein of Galen; 11. straight sinus. (See color insert.) (B) Magnetic resonance image (sagittal view) of an arteriovenous malformation (AVM) located in the entire corpus callosum supplied by the anterior cerebral arteries and drained through the internal cerebral veins into the vein of Galen. (C) Anatomical dissection of the brain where both hemispheres were separated in the midline to show the interhemispheric course of the anterior cerebral arteries. The optic chiasm was displaced inferiorly to show the anterior communicatinganterior cerebral artery complex. 1. Orbital surface of the frontal lobe; 2. olfactory nerve; 3. gyrus rectus; 4. corpus callosum; 5. right anterior cerebral artery; 6. anterior communicating artery; 7. right middle cerebral artery; 8. internal carotid artery; 9. optic chiasm; 10. posterior cerebral artery. (See color insert.) (D) Right carotid digital subtraction arterial angiogram of the same case showing the interhemispheric AVM supplied by the anterior cerebral arteries.

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Figure 6 (A) Anatomical dissection of the neural and arterial structures of the interhemispheric aspect of the right cerebral hemisphere: 1. Superior frontal gyrus; 2. cingulate gyrus; 3. precuneus; 4. corpus callosum; 5. fornix; 6. splenium of the corpus callosum; 7. parietooccipital sulcus; 8. cuneus; 9. anterior cerebral artery; 10. lamina terminalis; 11. third ventricle; 12. posterior medial choroidal artery; 13. parietooccipital artery; 14. calcarine artery; 15. calcarine fissure; 16. optic chiasm; 17. cerebral peduncle; 18. internal carotid artery; 19. posterior cerebral artery. (See color insert.) (B) Left vertebral angiogram of an arteriovenous malformation located in the depths of the parietooccipital sulcus (anteroposterior view) supplied by branches of the posterior cerebral artery and drained along the basal surface of the temporal lobe to the vein of Labbe´. (C) Same in lateral view.

The medial surface of the occipital lobe is separated from the parietal lobe by the parietooccipital sulcus. The calcarine fissure, which extends forward from the occipital pole toward the splenium, divides this surface into an upper part, known as the cuneus, located between the parietooccipital and the calcarine sulci, and a lower part, the lingula. Posterior-third parafalcine AVMs can be located in the cuneus, in the cortex of the precuneus adjacent to the parietooccipital sulcus, and may involve the isthmus of the cingulate gyrus and the lingula. These AVMs are usually supplied by branches of the posterior cerebral artery, the parietooccipital and calcarine arteries, and occasionally by branches of the middle cerebral artery and posterior branches of the anterior cerebral artery. Depending on the extension of the AVM, these lesions can reach the ventricular trigone and be supplied by branches of the lateral posterior choroidal arteries (Fig. 6). The venous drainage is through cortical veins into the superior sagittal sinus or through the group of veins that drain into the vein of Galen. AVMs that involve the splenium of the corpus callosum are supplied by branches of the posterior pericallosal artery, lateral posterior and medial posterior choroidal arteries, and from the posterior cerebral artery. In cases in which the AVM extends to the ventricles, it may drain through subependymal veins into the basal vein of Rosenthal and then into the vein of Galen. The surgical approach to posterior-third parafalcine AVMs is somewhat difficult because, similar to those AVMs in the mesial temporal lobe, these lesions tend to be buried in the depths of the sulci. BASAL GANGLIA REGION AVMs The region of the basal ganglia has as its anterior limit an imaginary line that passes just anterior to, and between the frontal horn of the lateral ventricle and the anterior portion of the circular sulcus of the insula. It is limited anteroinferiorly by the anterior extent of the

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anterior perforated substance; laterally by the insular cortex; medially by the inferior portion of the lateral wall and floor of the lateral ventricle and by the wall of the third ventricle; and posteriorly where the lateral and medial limits meet at the level of the pulvinar of the thalamus. The superior and inferior limits are somewhat imprecise. The deep cerebral white matter located above the ventricles is the superior limit, and the inferior limit corresponds to the inferior aspect of the thalamus. Anteroinferior Limit The superior aspect of the anterior limit is related to the frontal horn of the lateral ventricle and to the anterior limit of the circular sulcus of the insula. The structures that form the anteroinferior aspect of the anterior limit are of extreme importance and are reviewed in detail. Neural Relationships The anterior perforated substance is limited anteriorly by the lateral and medial olfactory striae; posteriorly by the optic tract and uncus of the temporal lobe; laterally by the limen insulae; and medially it extends above the optic chiasm to the interhemispheric fissure. The deep cerebral structures located directly above the anterior perforated substance are the frontal horn of the lateral ventricle and the anterior part of the caudate nucleus, putamen, and internal capsule. Arterial Relationships The arteries passing below and sending branches to the anterior perforated substance are the internal carotid, the anterior choroidal, the middle and anterior cerebral, and the recurrent arteries. The anterior perforating arteries pass through the parts of the caudate nucleus, putamen, and internal capsule directly above the anterior perforating substance, and spread posteriorly to supply larger parts of these structures and the adjacent areas of the globus pallidus and thalamus. The internal carotid branches penetrating the anterior perforating substance irrigate the genu of the internal capsule, the adjacent part of the globus pallidus, the posterior limb of the internal capsule, and the thalamus. The anterior choroidal artery supplies the medial two segments of the globus pallidus, the inferior part of the posterior limb of the internal capsule, and the anterior and ventrolateral nuclei of the thalamus. The middle cerebral artery branches, the lenticulostriate arteries, supply the upper part of the internal capsule, the body and head of the caudate, and the lateral part of the globus pallidus. The A1 branches of the anterior cerebral artery supply the area around the optic chiasm, the anterior commissure, the anterior hypothalamus, the genu of the internal capsule, and the anterior part of the globus pallidus. The recurrent artery supplies the most anterior and inferior parts of the head of the caudate nucleus and putamen, and the adjacent part of the anterior limb of the internal capsule (18). Venous Relationships The area of the anterior perforated substance is drained by the anterior segment of the basal vein of Rosenthal. This segment begins below the anterior perforated substance, at the union of the deep middle cerebral and anterior cerebral veins. It receives tributaries from the deep middle cerebral, anterior cerebral, insular, frontoorbital, olfactory, uncal, peduncular, and inferior striate veins (11). Anteroinferior Type AVMs Basal ganglia region AVMs of the anteroinferior type are located in the region of the anterior perforated substance. They may be medial to the internal carotid bifurcation and receive arterial supply from perforating branches of the A1 (lenticulostriate arteries) and A2 segments of the anterior cerebral artery, recurrent artery of Heubner, and anterior communicating artery, or they may be lateral to the internal carotid bifurcation and receive arterial supply from the recurrent artery of Heubner and the lenticulostriate arteries of the M1 segment of the middle cerebral artery. Venous drainage occurs through the small veins to the basal vein of Rosenthal (Fig. 7A and B). These lesions are considered for surgical treatment only in very selected cases, such as in cases of repeated bleeding or in the presence of a hematoma. In those cases the approach is

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Figure 7 (A) Anatomical dissection of the brain where the right frontal lobe was removed at the level of the anterior perforated substance in order to expose the basal ganglia. In the left cerebral hemisphere the frontal and the parietal lobes have been removed, and the insula and basal ganglia were sectioned along the choroidal fissure to expose the course of the posterior cerebral artery and of the vein of Labbe´ in the ambient cistern: 1. Calcarine artery; 2. choroid plexus; 3. M2 branches of the middle cerebral artery; 4. fimbria of the fornix; 5. temporal horn; 6. posterior cerebral artery; 7. basal vein of Rosenthal; 8. middle cerebral artery; 9. internal carotid artery; 10. anterior cerebral artery; 11. lenticulostriate arteries; 12. lenticular nucleus; 13. internal capsule; 14. caudate nucleus; 15. vein of Galen. (See color insert.) (B) Anteroinferior basal ganglia arteriovenous malformation (AVM). Right side (anteroposterior) digital carotid angiogram showing a laterally located anteroinferior basal ganglia AVM. (C) Medial anterior basal ganglia AVM. Right side (anteroposterior) digital carotid angiogram showing a basal ganglia AVM located in the head of the right caudate nucleus. (See color insert.)

carried out through the transsylvian route. Depending on location, some of these AVMs can be approached through the superior portion of the circular sulcus of the insula. Lateral Limit The lateral limit of the region of the basal ganglia is related to the cortex of the insula and to the structures immediately adjacent to it. It is divided into anterior, middle, and posterior portions that are related to the insula and to the frontoparietal and temporal operculae. Neural Relationships The insula has a pyramidal shape and is situated deep to the frontoparietal and temporal operculae in the depths of the sylvian fissure. Its apex, or anterior pole, is directed inferomedially toward the limen insula, which delineates the insula from the anterior perforated substance. The central sulcus of the insula, which runs in a posterosuperior direction from the anterior pole and limen, divides the insula into two groups of short and long gyri. The outer periphery of the insula is surrounded incompletely by a sulcus, referred to as the circular sulcus. The circular sulcus forms a cleft between the insula and the opercula, termed the insular cleft

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(19). The anterior part of the lateral limit is located in the anterior-most portion of the sylvian cistern, lateral to the limen insulae and between the frontal and temporal operculae. The middle part of the lateral limit is located over the cortex of the insula, in the middle portion of the sylvian cistern. At the posterior-most extension of the sylvian cistern the surface of the insula lies very deep, as the insular cleft and the space between the temporal and parietal lobes are almost virtual. At this point the surface of the insula lies in close proximity to the lateral ventricle. The deep cerebral structures located directly adjacent to the insular cortex are the extreme capsule, the claustrum, the external capsule, and the putamen. Arterial Relationships The arterial supply to the lateral limit of the region of the basal ganglia is predominantly from branches of the middle cerebral artery. The M1 segment of the middle cerebral artery arises from the internal carotid artery at the medial end of the sylvian fissure and passes laterally below the anterior perforated substance to become the M2 segment at the level of the limen of the insula. The M2 segment courses over the insula, lateral to the body of the lateral ventricle. The middle cerebral artery sends a series of perforating branches, called lenticulostriate arteries, which supply structures in the area lateral to the frontal horn and body of the lateral ventricle. The anterior portion of the lateral limit receives mainly branches from the lateral group of lenticulostriate arteries and branches from the M2 segment of the middle cerebral artery. The middle and posterior portions of the lateral limit of the region of the basal ganglia are supplied mainly by branches of the M2 segment. Venous Relationships The veins of the cortex of the insula predominantly drain through connections between the deep sylvian vein and the superficial cortical veins bordering the sylvian fissure, i.e., sylvian vein, vein of Labbe´, and vein of Trolard. They may also drain into the basal vein of Rosenthal. Lateral Type AVMs Basal ganglia region AVMs of the lateral type are located on the insular cortex. They can be subdivided into anterior, middle, and posterior types. These AVMs are usually approached through the transsylvian route (Fig. 1D). Anterior lateral AVMs are located in the most anterior portion of the insula, between the frontal and temporal operculae, lateral to the limen insulae. They may project to the frontal or the temporal operculae or to the anterior perforated substance. They usually are supplied by perforating branches originating from the M1 or M2 segments of the middle cerebral artery and at times by perforating branches from the A1 segment of the anterior cerebral artery. Venous drainage is through the deep sylvian vein into the basal vein of Rosenthal or through a superficial sylvian vein into the sphenoparietal sinus (Fig. 1A). These AVMs are located in a usually wide cisternal space and can be surgically approached in cases were there is no extension into the anterior perforated substance. Middle lateral AVMs are located over the cortex of the insula, medial to the M2 branches of the middle cerebral artery and lateral to the internal capsule, in the middle portion of the sylvian cistern. They are supplied by branches of the M2 segment of the middle cerebral artery and, depending on their extension and size, can receive perforators from the M1 segment of the middle cerebral artery and at times also from the A1 segment of the anterior cerebral artery. The venous drainage is usually superficial through the superficial sylvian vein, the vein of Labbe´, or the vein of Trolard. Surgical indications for these malformations depend on the depth of the lesion, and surgery is always difficult because of the necessity to work between the branches of the middle cerebral artery. Posterior lateral AVMs are situated in the most posterior extension of the cortex of the insula. At this point the space between the temporal and parietal lobes is almost virtual, and the sylvian cistern is very deep and in close proximity to the lateral ventricle. The vascular supply to these AVMs is through the M2 and M3 branches of the middle cerebral artery and at times from ventricular branches of the lateral posterior choroidal artery. The venous drainage is through the superficial system. In larger cases, where branches of the lateral posterior choroidal artery contribute to the vascular supply, the venous drainage may be through the deep system. Due to their location and vascular supply, posterior lateral AVMs, especially those on the left side, are sometimes technically very difficult to approach.

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Medial Limit The medial limit of the region of the basal ganglia is closely related to the lateral wall and floor of the lateral ventricle and to the lateral wall of the third ventricle. It is divided into an anterior part, related to the head of the caudate nucleus; a middle part divided by the internal cerebral veins into a superior portion, related to the floor of the body of the lateral ventricle; and an inferior portion, related to the wall of the third ventricle; and a posterior part, related to the pulvinar of the thalamus. Neural Relationships The lateral wall of the frontal horn, the part of the lateral ventricle located anterior to the foramen of Monro, constitutes the anterior portion of the medial limit of the region of the basal ganglia. The frontal horn has a medial wall formed by the septum pellucidum, an anterior wall formed by the genu of the corpus callosum, a narrow floor formed by the rostrum of the corpus callosum, and a lateral wall formed by the head of the caudate nucleus. The columns of the fornix, as they pass anterior to the foramen of Monro, are in the posteroinferior part of the medial wall. The middle portion of the medial limit of the region of the basal ganglia is divided into a superior and an inferior part by the body of the fornix. The middle superior portion corresponds to the floor and lateral wall of the body of the lateral ventricle, and the middle inferior portion corresponds to the lateral wall of the third ventricle. The body of the lateral ventricle extends from the posterior edge of the foramen of Monro to the point where the septum pellucidum disappears and the corpus callosum and fornix meet. The roof is formed by the body of the corpus callosum, the medial wall by the septum pellucidum above and the body of the fornix below, the lateral wall by the body of the caudate, and the floor by the superomedial aspect of the thalamus (5). The caudate nucleus and the thalamus are separated by the striothalamic sulcus, the groove in which the stria terminalis and the thalamostriate vein course. The third ventricle is located between the cerebral hemispheres, the two halves of the thalamus, and the two halves of the hypothalamus. It communicates at its anterosuperior margin with each lateral ventricle through the foramen of Monro. The third ventricle has a roof formed by the body of the fornix, and by two thin membranous layers of tela choroidea that contain the internal cerebral veins and their tributaries, and the medial posterior choroidal arteries and their branches. Parallel strands of choroid plexus project downward on each side of the midline from the inferior layer of tela choroidea into the superior part of the third ventricle. The lateral margin of the roof is formed by the cleft between the lateral edge of the fornix and the superomedial surface of the thalamus known as the choroidal fissure. The lateral wall is formed by the thalamus superiorly and the hypothalamus inferiorly. The anterior half of the floor of the third ventricle is formed by diencephalic structures, and the posterior half is formed by mesencephalic structures. The anterior wall viewed from within the third ventricle is formed, from superior to inferior, by the columns of the fornix, foramen of Monro, anterior commissure, lamina terminalis, optic recess, and optic chiasm. The posterior wall viewed from within the third ventricle is formed, from superior to inferior, by the suprapineal recess, the habenular commissure, the pineal body and its recess, the posterior commissure, and the aqueduct of Sylvius (20). The posterior portion of the medial limit of the region of the basal ganglia is related to the pulvinar of the thalamus. The pulvinar constitutes the anterolateral wall of the atrium of the lateral ventricle. The roof of the atrium is formed by the body, splenium, and tapetum of the corpus callosum. The medial wall is formed by the bulbus of the corpus callosum, and by the calcar avis. The lateral wall has an anterior part, formed by the caudate nucleus as it wraps around the lateral margin of the pulvinar, and a posterior part formed by the fibers of the tapetum of the corpus callosum. The anterior wall has a medial part composed of the crus of the fornix as it wraps around the posterior part of the pulvinar, and a lateral part, formed by the pulvinar of the thalamus. Arterial Relationships The arterial supply to the anterior portion of the medial limit of the region of the basal ganglia is provided predominantly by the medial group of lenticulostriate arteries originating from the M1 segment of the middle cerebral artery but may also occur through perforating branches from the A1 segment of the anterior cerebral artery (Figs. 2A and 4A). The middle and posterior

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portions receive arterial supply from the internal carotid and from the anterior, middle, and posterior cerebral arteries. The branches from the posterior communicating artery penetrate the floor of the third ventricle and hypothalamus to reach the thalamus in the area below the body of the lateral ventricle. The choroidal segment of the internal carotid artery sends branches through the anterior perforated substance to supply structures in or near the walls of the lateral ventricles. The recurrent artery and the segment of the anterior cerebral artery proximal to the anterior communicating artery also send branches into the area of the lateral wall of the frontal horn and body. The intermediate and lateral groups of lenticulostriate arteries pass through the putamen and adjacent part of the globus pallidus and arch medially and posteriorly to supply the upper anteroposterior parts of the internal capsule and body and head of the caudate nucleus. The medial lenticulostriate arteries irrigate the lateral part of the globus pallidus, the superior part of the anterior limb of the internal capsule, and the anterior superior part of the head of the caudate nucleus. The anterior choroidal artery sends branches along its course that, among other structures, will supply the globus pallidus, genu and posterior limb of the internal capsule, tail of the caudate, and the thalamus. The lateral posterior choroidal artery arises from the posterior cerebral artery or its cortical branches and enters the ventricle, passing laterally around the pulvinar and through the choroidal fissure at the level of the fimbria or the crura of the fornix to reach the choroid plexus in the temporal horn, atrium, and body. Along its course it sends branches to the thalamus, geniculate bodies, cerebral peduncle, pineal body, posterior commissure, caudate nucleus, and splenium. The medial posterior choroidal artery arises from the proximal posterior cerebral artery and encircles the midbrain to enter the roof of the third ventricle at the sides of the pineal gland to course in the velum interpositum, between the thalami, adjacent to the internal cerebral vein. It supplies the choroid plexus in the roof of the third ventricle and may send branches to the cerebral peduncles, geniculate bodies, tegmentum, colliculi, pulvinar, pineal body, posterior commissure, habenula, stria medullaris thalami, occipital cortex, and thalamus. The anterior and posterior thalamoperforating arteries branch from the posterior communicating artery and the P1 segment of the posterior cerebral artery, respectively, and enter the brain through the posterior perforated substance to supply the anterior two-thirds of the thalamus in the area below the floor of the body of the lateral ventricle, the cerebral peduncles, hypothalamus, and internal capsule. The thalamogeniculate arteries enter the brain in the area of the geniculate bodies and send branches into the posterolateral part of the thalamus and the adjacent part of the internal capsule (5). Venous Relationships The lateral aspect of the frontal horn of the lateral ventricle is drained by the anterior caudate veins that course on the ventricular surface of the head of the caudate nucleus and terminate near the foramen of Monro in the thalamostriate vein or join the posterior caudate veins in the body of the lateral ventricle. In the middle part, the thalamostriate vein arises from tributaries that drain the lateral wall of the body and pass forward in the striothalamic sulcus, between the caudate nucleus and the thalamus, to penetrate the foramen of Monro and enter the velum interpositum to join the internal cerebral veins. The veins from the superior and medial portions of the thalamus empty into the internal cerebral or great vein or their tributaries, and those from the inferior and lateral portions of the thalamus drain into the basal vein or its tributaries. The lateral atrial veins course forward on the lateral wall of the atrium across the tail of the caudate nucleus where they turn medially on the posterior surface of the pulvinar and pass through the choroidal fissure to reach the quadrigeminal cistern and join the internal cerebral, basal, or great vein. The venous relationships in the quadrigeminal cistern medial to the atrium are extremely complex because the internal cerebral, basal, great vein and their tributaries converge to that area. The veins from the frontal horn, body, and part of the atrium drain into the internal cerebral veins that course through the velum interpositum and terminate in the great vein. The basal vein terminates within the quadrigeminal cistern by joining the internal cerebral or great vein. The great vein passes below the splenium to enter the straight sinus at the tentorial apex. Medial Type AVMs Basal ganglia region AVMs of the medial type are also subdivided into three types: anterior, middle, and posterior.

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Anterior medial AVMs are located in the region of the head of the caudate nucleus. They are supplied by perforators from the M1 segment of the middle cerebral artery and by perforators from the A1 segment of the anterior cerebral artery. The venous drainage is through caudate veins to the internal cerebral veins. We prefer to approach these lesions directly through a transsulcal route through the posterior portion of the superior frontal sulcus, as we find there is need for excessive brain retraction when the transcallosal route is used (Fig. 7A and C). The middle medial AVMs are located superiorly to the internal cerebral veins and thus are related to the floor and lateral wall of the lateral ventricle or are located inferior to the vein and related to the wall of the third ventricle. Those related to the floor of the lateral ventricle are usually in close relationship to the body of the caudate and to the superior aspect of the thalamus. They are supplied by branches of the lateral posterior choroidal artery and at times by posterior thalamoperforating arteries. Venous drainage occurs through the internal cerebral veins. We approach such lesions through a transcallosal transventricular route. Lesions located on the walls of the third ventricle are supplied by branches from the medial posterior choroidal artery and by anterior and posterior thalamoperforating arteries from the internal carotid artery and the P1 segment of the posterior cerebral artery, respectively. Venous drainage occurs through the internal cerebral veins. Surgery for these lesions is controversial. The risk of major neurological deficits is high because of the technical difficulties posed by their very deep location and by the difficulties encountered in controlling the arterial perforators (Fig. 8).

Figure 8 (A) Anatomical dissection showing the venous drainage pattern of the right cerebral hemisphere: 1. Body of corpus callosum; 2. body of lateral ventricle; 3. splenium of corpus callosum; 4. internal cerebral vein; 5. vein of Galen; 6. straight sinus; 7. basal vein of Rosenthal (cut); 8. third ventricle; 9. posterior cerebral artery. (See color insert.) (B) Right vertebral digital subtraction arterial angiogram of a similar arteriovenous malformation (AVM) located in the third ventricle in the anterior thalamus supplied by the posterior thalamoperforating arteries and drained into the internal cerebral vein. Note that the internal cerebral vein is a reliable landmark for the exact location of the AVM. (C) Right vertebral digital subtraction arterial angiogram of an AVM located in the third ventricle in the anterior thalamus and velum interpositum cistern supplied by the posterior thalamoperforating arteries and drained into the internal cerebral vein.

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Medial posterior AVMs are located in the posterior limit of the region of the basal ganglia in the medial portion of the pulvinar of the thalamus. These AVMs can be supplied by the medial and lateral posterior choroidal arteries and by the thalamogeniculate artery. They usually drain into the vein of Galen through the basal vein of Rosenthal or through the internal cerebral vein. These lesions are amenable to surgical treatment although it may be technically very difficult as the deep draining veins tend to be in the way of the approach to the malformation. We prefer an interhemispheric parietal approach where a small portion of the splenium of the corpus callosum has to be resected, or a interhemispheric occipital supratentorial approach, where the tentorium cerebelli is opened and the AVM is approached through the isthmus of the cingulate gyrus. These cases are sometimes referred for preoperative embolization. Superior Type AVMs Basal ganglia region AVMs of the superior type are related to the deep cerebral white matter that surrounds the ventricles. They are usually related to the ventricular walls and may invade the nuclei in the basal ganglia. The arterial supply is through branches of the M2 and M3 segments of the middle cerebral artery and the lenticulostriate arteries. Venous drainage usually is through the deep venous system. AVMs OF THE POSTERIOR FOSSA For surgical purposes, AVMs presenting in the posterior fossa can be classified into three major groups: those entirely located in the cerebellum (either in the hemispheres or in the vermis), those that exclusively involve the brain stem, and those that have mixed cerebellar and brain stem components. According to their location, these malformations then can be subdivided into superficial and deep lesions. Anatomically the superficial AVMs that involve the cerebellum are classified according to the cortical surface that they involve. Lesions that involve the tentorial surface of the cerebellum are supplied primarily by branches of the superior cerebellar artery. These lesions usually drain anteriorly into the vein of Galen and into the straight sinus through an anterior branch of the superior vermian vein, or they may drain directly into the torcular through a posterior branch of the superior vermian vein. AVMs located in the tentorial surface of the cerebellum are preferably approached through a supracerebellar infratentorial route. In cases where the AVM extends inferiorly, the craniotomy also should include exposure of the suboccipital surface of the cerebellum. Some AVMs that are located anteriorly in the cerebellar hemispheres, i.e., those in the quadrangular lobule of the cerebellum, can be approached through a pretemporal (10) exposure with section of the tentorium. Lesions that involve the petrosal surface of the cerebellum are supplied primarily by branches of the anterior inferior cerebellar artery (AICA) and drained through the superior petrosal vein—formed by the union of the transverse pontine vein, vein of the middle cerebellar peduncle, vein of the cerebellomedullary fissure, and the pontotrigeminal vein—into the superior petrosal sinus. AVMs located in the petrosal surface are best approached through a suboccipital retromastoid approach that reaches the level of the foramen magnum with exposure of the transverse and sigmoid sinuses. Those AVMs that are located in the suboccipital surface of the cerebellum are usually supplied by branches of the posterior inferior cerebellar artery (PICA) and drain through the inferior vermian vein and cortical hemispheric veins into the transverse sinus. These lesions are usually approached through a large midline suboccipital craniotomy or craniectomy that often includes the resection of the posterior arch of the atlas. Large lesions can receive blood supply from all three arterial systems in the posterior fossa and at times can recruit meningeal branches from the extracranial vertebral artery. Such lesions should be approached following the same principles of wide exposure of the cisterns, blood supply, and venous drainage involved with the lesion. Lesions that involve the cerebellar vermis are usually supplied by vermian branches of the superior cerebellar or posterior inferior cerebellar arteries. Vermian AVMs located in the tentorial surface are drained primarily through the superior vermian veins, which are divided

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into an anterior and a posterior group. Lesions in the anterior portion of the superior vermis are drained through the anterior vermian vein, whereas those in the posterior portion are drained through the posterior vermian vein. Vermian AVMs located in the suboccipital surface are usually drained through the inferior vermian vein. Deep cerebellar AVMs that involve the cerebellar peduncles can be surgically excised when the lesion does not involve the structures located in front of the level of the flocculus. Lesions extending beyond that point are intimately related to important structures of the brain stem. Lesions involving the brain stem are surgically approached only in cases where a pial surface can be identified. The arterial supply to such lesions usually comes from perforating branches from the superior cerebellar artery, AICA, and PICA. In our opinion lesions that are located deeply in the brain stem are beyond the scope of any of today’s available treatments. AVMs located in the dorsal aspect of the midbrain, i.e., posterior to the lateral mesencephalic sulcus, can be approached through the supracerebellar infratentorial route, whereas those located in the lateral aspect of the midbrain are best approached through a pretemporal transtentorial approach. Lesions located in the lateral surface of the pons or of the medulla are approached through the suboccipital retrosigmoid route. REFERENCES 1. de Oliveira E, Tedeschi H, Siqueira MG, Ono M, Rhoton AL Jr., Peace D. Anatomic principles of cerebrovascular surgery for arteriovenous malformations. Clin Neurosurg 1993; 41:364–380. 2. Ono M, Kubik S, Abernathey CD. Atlas of the Cerebral Sulci. Stuttgart: Georg Thieme Verlag, 1990: 35–135. 3. Ono M, Rhoton AL Jr., Peace D, et al. Microsurgical anatomy of the deep venous system of the brain. Neurosurgery 1984; 15:621–657. 4. Ono M, Ono M, Rhoton AL Jr., Barry M. Microsurgical anatomy of the region of the tentorial incisura. J Neurosurg 1984; 60:365–399. 5. Timurkaynak E, Rhoton AL Jr., Barry M. Microsurgical anatomy and operative approaches to the lateral ventricles. Neurosurgery 1986; 19:685–723. 6. Ojemann RG, Heros RC, Crowell RM. Surgical Management of Cerebrovascular Disease. 2d ed. Baltimore: Williams & Wilkins, 1988:347–413. 7. Stein BM. Arteriovenous malformations of the medial cerebral hemisphere and the limbic system. J Neurosurg 1984; 60:23–31. 8. Yasargil MG. Microneurosurgery. AVM of the Brain. Vol. IIIB. Stuttgart: Georg Thieme Verlag, 1988:204–367. 9. de Oliveira E, Siqueira MG, Tedeschi H, Peace DA. Technical aspects of the fronto-temporosphenoidal craniotomy. In: Surgical Anatomy for Microneurosurgery VI. Japan, 1994:3–8. 10. de Oliveira E, Tedeschi H, Siqueira MG, Peace D. The pretemporal approach to the interpeduncular and petroclival regions—technical note. Acta Neurochir 1995; 136(3–4):204–211. 11. Sano K. Temporo-polar approach to aneurysm of the basilar artery at and around the distal bifurcation: technical note. Neurol Res 1980; 2:361–367. 12. de Oliveira E, Tedeschi H, Siqueira M G, Peace D. Surgical approaches for aneurysms of the basilar artery bifurcation. In: Surgical Anatomy for Microneurosurgery VI. Japan, 1994:34–44. 13. Yasargil MG, Teddy PJ, Roth P. Selective amygdalo-hippocampectomy, operative anatomy and surgical technique. In: Symon L et al., eds. Advances and Technical Standards in Neurosurgery. Vol. 12. Wien: Springer-Verlag, 1985:93–119. 14. Drake CG. Cerebral arteriovenous malformations: considerations for and experience with surgical treatment in 166 cases. Clin Neurosurg 1979; 26:145–208. 15. Heros RC. Arteriovenous malformations of the medial temporal lobe. Surgical approach and neuroradiological characterization. J Neurosurg 1982; 56:44–52. 16. Wilson CB, Martin NA. Deep supratentorial arteriovenous malformations. In: Wilson CB, Stein BM, eds. Intracranial Arteriovenous Malformations. Baltimore: Williams & Wilkins, 1984:184–208. 17. Solomon RA, Stein BM. Surgical management of arteriovenous malformations that follow the tentorial ring. Neurosurgery 1986; 18:708–715. 18. Rosner SS, Rhoton AL Jr., Ono M, Barry M. Microsurgical anatomy of the anterior perforating arteries. J Neurosurg 1984; 61:468–485. 19. Gibo H, Carver CC, Rhoton AL Jr, Lenkey C, Mitchell RJ. Microsurgical anatomy of the middle cerebral artery. J Neurosurg 1981; 54:151–169. 20. Yamamoto I, Rhoton AL Jr., Peace DA. Microsurgery of the third ventricle: part 1. microsurgical anatomy. Neurosurgery 1981; 8:334–356.

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Pathology and Genetic Factors Ronald F. Moussa and John H. Wong Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, U.S.A.

Issam A. Awad Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, and Evanston Northwestern Healthcare, Evanston, Illinois, U.S.A.

PATHOLOGY In the middle of the 18th century, Hunter (1757) (1) and Petit (1774) (2) developed the first systematic description of human vascular anomalies. During the next century, the works of Hooper (1841) (3), Bell (1815) (4), and Virchow (1863) (5) led to further terminology to describe vascular lesions. A more rational analysis was later developed by Reinhoff (6) and Malan (7), who based developmental pathogenesis on errors in embryogenesis that occur at specific time points and their consequences on vasculogenesis. Their efforts led to a classification system of vascular anomalies with four categories on the basis of developmental considerations: capillary, venous, arteriovenous, and troncular arteriovenous anomalies. Most recently, the pathoanatomic works of McCormick et al. (8–12), and Russel and Rubinstein (13) led to the foundation for the current widely accepted classification system for cerebral vascular anomalies. This classification system consists of four categories: arteriovenous malformations (AVMs), cavernous malformations, venous malformations, and capillary telangiectasias. Several mixed lesion types have been described with transitional or mixed features in the same lesion (14,15). Location and Angioarchitecture Cerebral AVMs are encountered throughout the central nervous system. They seem to predominate in areas supplied by the middle cerebral artery (8). Ninety-three percent are located supratentorially in the frontotemporal lobes. Intracranial dura may be affected, leading to the formation of dural vascular malformations. Angiography remains the gold standard method for diagnosing and evaluating AVMs and provides invaluable information about their angioarchitecture. Analysis of vascular patterns is useful in understanding the pathology of this disease. Arterial Supply Cerebral AVMs typically receive their blood supply from intracranial branches of the internal carotid artery and vertebrobasilar systems. Arterial feeders are often multiple, but may sometimes be unique in arteriovenous fistulas. Valavanis in 1996 proposed a classification of arterial feeders based on embryological studies (16). The first type of arterial feeder is termed a terminal or dedicated type that ends in the nidus itself and corresponds to primitive penetrating vessels. The second type is the pseudoterminal ‘‘functional’’ type or vessels ‘‘de passage,’’ which supply the brain beyond the nidus. These vessels are hypothesized to have initiated growth at a later stage or have developed from an established arterial source. The last type is the indirect type and represents ‘‘satellite’’ branches from an artery in close proximity to the nidus. They correspond to vessel ingrowth after final structural development of the brain has been completed. Other sources of blood supply to AVMs may exist, such as those emerging from the choroid plexus (17) or meningeal branches of the external carotid artery. The frequency of meningeal arterial contribution is significantly higher in superficial AVMs, especially in the temporal, parietal, and occipital regions. Larger AVMs and lesions with higher degrees of angiographic arteriovenous shunting with steal phenomena are also factors that favor meningeal arterial development. Meningeal feeders were previously thought to be congenital, but recent evidence suggests that they may develop during growth of the AVM (18).

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Stenoses of the feeding arteries to cerebral AVMs have been reported in approximately 20% of cases. It is possible that if these stenoses progress, thrombosis of the AVM may occur (19). Nidus Architecture The nidus is best conceived as a functional unit rather than a pathoanatomic entity. Yasargil described two types of arteriovenous connections within the lesion nidus: a direct fistulous connection between arteries and veins, and a plexiform pattern with ramifications existing between afferent and efferent vessels (20). Houdart et al. (21) in 1993 proposed three types of niduses based upon hemodynamic and radiological features: the arteriovenous fistula, where direct communications exist between arteries and veins; the arteriolovenous fistula that exists between several arterial branches and a vein; and the arteriolovenulous fistula, which is the most classical type and is marked by ramifications between arteries and venules. Venous Drainage Venous blood from the AVM can drain through a single or multiple channels toward the superficial or deep venous systems. In high flow fistulas, an aneurysmal dilatation of the great vein of Galen can be observed (22). Multiplicity and Associated Lesions Multiple intracranial AVMs are exceptional (23,24). The occurrence of multiple AVMs in one patient should raise the diagnosis of hereditary hemorrhagic telangiectasia (HHT). The association of intracranial and intraspinal AVMs is also rare (25). Other unusual associations include AVM and multiple congenital cardiac defects or tumors (26). Oligodendrogliomas and metastases have been reported to occur in proximity to AVMs, raising the question of whether there is a pathophysiological relationship between the two entities (27,28). Associated aneurysms are reported to occur with AVMs in 3% to 28% of patients in most case series (29–31). Three types of aneurysms have been described in relation to the location of the nidus: those related to vessels feeding the AVM, those remote from the AVM, and those that are intranidal. Perata et al. classified aneurysms associated with AVMs into four categories (32). Type 1 aneurysms are dysplastic lesions located on the circle of Willis independent from the nidus. Type 2 aneurysms are located on the circle of Willis on the same artery supplying the AVM. Type 3 lesions are related to a vessel feeding the AVM. Type 4 aneurysms are intranidal. Gross Pathology Autopsy analysis provides valuable information about the macroscopic features of AVMs. The postmortem appearance of an AVM is often less impressive than its intraoperative appearance because of the collapse of previously distended vessels (13). The living appearance of an AVM can in some measure be restored by the postmortem intravascular injection of a suitable medium. The most typical gross appearance is that of a ‘‘bag of worms’’ (Fig. 1). The mass is often wedge shaped, extending from the leptomeningeal surface deep into the parenchyma,

Figure 1 Gross appearance of a cerebral arteriovenous malformation in the occipital lobe. Source: Courtesy of J.H. Kim. (See color insert.)

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Figure 2 Histologic appearance of cerebral arteriovenous malformation nidus. Hematoxylin and eosin stain, 40x. Thrombosed red blood cells (red); arterialized vessel walls (purple); gliotic brain (blue). Source: Courtesy of J.H. Kim. (See color insert.)

frequently reaching or entering the ventricular system. This configuration accounts for the occurrence of bleeding within the intracranial compartment with the potential of extension toward the ventricles or the subarachnoid space. The vessels vary in size and may exceed one centimeter in diameter. Conversely, very small AVMs can be totally missed on pathologic examination even with thin slices. These malformations are typically cryptic or angiographically occult (33). They may be responsible for intraparenchymal hemorrhage where no etiology is found on angiographic or even intraoperative examinations. The vessel walls are variably thickened, and atheroma or calcification may be encountered macroscopically (8). Associated aneurysms may be observed on feeding or intranidal vessels. The arachnoid covering is usually discolored and thickened, while adjacent convolutions show variable degrees of atrophy as a result of chronic ischemia (13). Pigmentation from previous hemorrhage may be present in the adjacent brain, with loss of normal distinction between gray and white matter. Histopathology The histologic appearance of AVMs may range from relatively well-differentiated arteries and veins to malformed, thickened, or thin-walled hyalinized vessels (Fig. 2) (8,34). Arteries and arterialized veins may be difficult to distinguish from one another. A normal capillary bed interposed between arteries and veins is lacking (22). Ultrastructural analysis reveals that the endothelium of these vessels is different from other cerebrovascular endothelium (20). Segmental dilatation of vessels is often present with deposition of amyloid-like material in the vessel wall. Ossification is rare (8). A close analysis of the arterial component of the AVM reveals that the usual lamination of elastic and muscle fibers in the vessel wall is altered in that the internal elastic lamina may be reduplicated or interrupted (Fig. 3). The muscular media varies in thickness even within the

Figure 3 Histologic demonstration of elastic fibers in the arterialized vessels of a cerebral arteriovenous malformation. Elastic von Gieson stain, 40x. Source: Courtesy of J.H. Kim. (See color insert.)

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same blood vessel. In areas of maximal thinning, aneurysms may develop, whereas thickened areas can evoke leiomyoma nodules (35). The use of monoclonal antibody against vascular musculature has permitted the identification of actin abnormalities of the muscular layer. Described abnormalities included partially developed media, two layers of the media separated by a well-formed internal elastic membrane, total or partial disarray of the muscle coat, and partial absence of the media. Vessels previously thought to be large capillaries have been determined to be postcapillary venules by virtue of the presence of a distinct muscular layer (34). Determining the presence of actin can be a useful adjunct to conventional histologic stains for the accurate and selective detection of smooth muscle cells (36). Atheroma, fibrosis, and patchy calcification can also be observed in the vessel wall. On the venous side, thickening of the vein due to collagenous tissue is usually noted. Thrombosis may be found. The brain parenchyma within the nidus is typically discolored and gliotic. The parenchyma around and within the malformation is consistently degenerated with multiple foci of lymphocytic infiltration (8). Neuronal loss in the brain secondary to a vascular steal phenomenon by the AVM (37) and increase in fibrillary glia are usually reported. Hemosiderin pigment is commonly found, especially within hemosiderin granules in macrophages (8,13). Immunohistochemistry Immunostaining studies can be used to analyze protein expression associated with AVMs (Fig. 4). Rothbart et al. demonstrated the expression of vascular endothelial growth factor (VEGF) in a study of surgically excised vascular malformations (38). VEGF expression was predominantly identified in the subendothelial layer and media of vessels of all sizes in AVMs. Basic fibroblast growth factor was faintly expressed around individual monocytes and fibrocytes. Structural and matrix proteins have also been examined with immunohistochemical and immunofluorescent techniques. The expression of laminin, factor VIII antigen, and fibronectin was variable. These proteins may play important roles in homeostasis of the vessel wall and in its permeability and response to injury. The vascular cellular adhesion molecule and intercellular adhesion molecule-1 were also expressed in some AVMs, consistent with developing vessels in early phases of embryogenesis. AVMs also expressed collagen type IV and alpha smooth muscle actin. The pattern of expression of these different factors suggests diffuse activation of angiogenesis without specific relation to individual vessel types or recent hemorrhage. Defining the role of angiogenesis in vascular malformations can provide insight into their pathogenesis and suggest novel strategies for modification of their behavior. Effect of Embolization and Radiation Therapy The increasing use of embolization and radiosurgery as surgical adjuncts for the treatment of AVMs has allowed study of their pathological responses to such interventions. Embolization induces a chain of events that results from interaction between the embolizing agent and the vessel wall (39) and depends on the type of embolizing agent used such as bucrylate

Figure 4 Immunohistochemical analysis of arteriovenous malformation (AVM) vessels. (A) Laminin (a component of the basement membrane that regulates vessel wall stability) immunoexpression in an AVM vessel, 20x. (B) VEGF immunoexpression in an arterialized draining vein of an AVM specimen, 40x. (C) Flk-1 (an endothelial-specific receptor tyrosine kinase) immunoexpression in the endothelium of an AVM vessel, 40x. (See color insert.)

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(isobutyl-2-cyanoacrylate), silk, or polyvinyl alcohol. Histologic reactions vary from patchy mural angionecrosis, thinning of the vessel wall with rupture, mononuclear infiltration, necrotizing vasculitis, and an intense granulomatous response (39,40). Radiosurgery can induce pathologic changes in and around the AVM. Nataf et al. proposed a classification scheme of postradiosurgical effects identified on magnetic resonance imaging, ranging from no parenchymal change (grade 1) to contrast enhancement with central and peripheral hypointensity suggesting necrosis (grade 4) (41). The latter finding was significantly related to clinical deterioration. Postradiation changes have also been studied in surgical and autopsy AVM specimens. Schneider et al. used routine histopathological stains and immunohistochemical techniques to detect smooth-muscle actin, factor VIII, and type IV collagen in nine AVM specimens obtained 10 months to more than 5 years after gamma knife radiosurgery (42). Blood vessels in the AVMs showed progressive changes leading to narrowing or obliteration of the lumen. The earliest change was damage to endothelial cells. The next change was progressive thickening of the intimal layer caused by proliferation of smooth muscle cells that elaborate an extracellular matrix, which includes type IV collagen. Finally, cellular degeneration and hyaline transformation were noted. The degree of histopathological change and the relative number of vessels showing such changes were significantly correlated with time after radiosurgery and with reduction in AVM size demonstrated on follow-up imaging. The authors concluded that radiosurgery of AVMs causes endothelial damage, which induces the proliferation of smooth muscle cells and the elaboration of extracellular collagen by these cells, leading to progressive stenosis and obliteration of the AVM nidus. Normal surrounding blood vessels may also be affected by high-dose, single-fraction irradiation, although the abnormal AVM vessels have been reported to be more susceptible (43). However, segmental hyalinization of AVM vessels with a patent nidus has been reported and may explain the occurrence of hemorrhage after radiosurgery (44). Recurrence and Spontaneous Obliteration Sonstein et al. described several children who developed recurrent AVMs despite normal postoperative angiography after surgical resection (45). On the basis of the increased levels of VEGF found on immunocytochemistry staining, they hypothesized that VEGF produced by perilesional astrocytes may lead to the formation or recurrence of cerebral AVMs, especially in children, due to an immature cerebral vasculature or dysregulation of blood vessel formation during early development. This study suggests that ongoing angiogenesis plays a role in the growth or recurrence of AVMs. The recurrence of AVMs after partial embolization and recruitment of feeding vessels from distant vascular beds also suggest that angiogenic paracrine signaling pathways participate in the development of AVMs. AVMs of the cerebral circulation rarely regress spontaneously. Abdulrauf et al. identified a total of 30 cases of AVMs, including those in the medical literature, that obliterated spontaneously without definitive treatment (46). The majority of such lesions presented with hemorrhage, had a small vascular nidus, and had a single draining vein possibly predisposing to lesion thrombosis. Using immunohistochemical studies, the authors also found that AVM nidal vessels demonstrated possible ongoing angiogenesis after documented angiographic obliteration. GENETIC FACTORS Careful assessment of the genetic background of patients harboring AVMs is important not only during clinical assessment and screening, but also in understanding potential underlying hereditary disease and molecular factors. AVMs may be related to possible genetic mechanisms in several ways. A genetic basis underlying an AVM may be clearly identified such as in patients suffering from HHT. However, cases of familial AVMs have been described where several relatives harbor cerebrovascular pathology without clear demonstration of any known genetic defect (47). AVMs may also be present in association with neurocutaneous disorders that arise from embryonic maldevelopment such as Sturge–Weber disease and Wyburn–Mason syndrome. In 1928, Pfeifer hypothesized that AVMs arise from the persistence of one of multiple arteriovenous fistulas that normally form and disappear during development. This theory was rejected by Campbell (48), Scharrer (49), and Vidyasagar (50), all of whom favored the

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hypothesis that AVMs develop from a fistula created by fetal transverse veins crossing at right angles to developing longitudinal arteries before the fetus reaches 80 mm in length. This hypothesis was supported by the observation that adult AVMs frequently demonstrate evidence of an early failure in venous maturation. Deshpande et al. (51) identified arterialized venous channels in AVMs that microscopically resembled persistent embryonic veins. These authors proposed that the intimal lining of the persistent embryonic veins reflects the approximate fetal age during which the arteriovenous fistula is likely to have occurred. Mullan et al. suggested that a combination of congenital predisposition and extrinsic factors might result in the AVM development (47), thus offering an explanation for why these presumably congenital lesions become symptomatic in later life. The report of growth of an AVM in a newborn confirms the evolution of these lesions (52). The role of abnormal gene regulation in the pathogenesis of cerebral AVMs has also been investigated. Repression of the preproendothelin-1 gene in intracranial AVMs has been studied by Rhoten et al. (53). They demonstrated the absence of endothelin-1 peptide and preproendothelin-1 messenger ribonucleic acid in the intranidal AVM vasculature, whereas these factors were predominantly expressed in control subjects with normal cerebral vasculature. This study provides supplementary evidence for the role of genetic defects in the genesis and development of AVMs. Hereditary Conditions Hereditary Hemorrhagic Telangiectasia Known as Osler-Weber-Rendu disease, HHT belongs to a group of familial inherited disorders with transmission of an autosomal dominant trait and high penetrance (54,55). HHT typically involves multiple dermal, mucosal, and visceral telangiectasias and AVMs, leading to recurrent bleeding episodes. The prevalence of neurological symptoms ranges from 8% to 27% (56), including headache, seizures, brain abscess, hepatic encephalopathy, infarct, and intracerebral and subarachnoid hemorrhage (57). Structural cerebral lesions are characterized by vascular malformations that represent abnormal arteriovenous connections that fail to differentiate into arteriolar, capillary, and venular channels (58). Neurologic complications such as cerebral ischemic events can occur secondary to pulmonary AVMs. In a recent study, Fulbright et al. showed that the prevalence of cerebral vascular malformations on magnetic resonance imaging was 23% in a series of patients afflicted with HHT (56). Among these lesions, most (76%) were indeterminate lesions with variable signal intensity, 8% were venous malformations, and 16% were AVMs. Other lesions encountered include pial arteriovenous fistulas, telangiectasias, and aneurysms (57). Multiple AVMs in the same patient were present in one-third of all HHT patients with cerebral AVMs. This entity has never been reported sporadically in a single patient (59,60). Genetic studies have shown that HHT disease expression is linked to chromosome 9q33-q34 in certain families and to chromosome 12q in others (55,61). On chromosome 9, the defect has been localized to a gene (ENG) that codes for endoglin, a protein abundant in endothelial cells. This protein normally binds to the transforming growth factor-b and initiates responses to growth factors (54). The locus on chromosome 12q, named ORW2, has been identified as active in receptor-like kinase gene (ACVRLK1) expression (62). Other Genetic Syndromes Associated with Cerebral AVMs Bannayan syndrome is an inherited autosomal dominant disease involving hamartomas (usually hemangiomas and lipomas) and macrocephaly with other inconstant features. Complex intracranial AVMs occurring in one family have been reported (63). Autosomal dominant polycystic kidney disease, a relatively common genetic disorder, has been associated with intracranial AVMs as well as with intracranial aneurysms (64). Sporadic Conditions Sturge–Weber Syndrome Sturge–Weber disease is a neurocutaneous syndrome characterized by facial ‘‘port wine’’ nevi in the cutaneous region served by the ophthalmic division of the trigeminal nerve, angiomatous lesions of the leptomeninges, retinal angiomas, hemiatrophy, and cortical calcifications. Also known as encephalotrigeminal angiomatosis (65), the neurological picture is characterized by seizures along with moderate to severe mental retardation.

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Radiological studies demonstrate the characteristic ‘‘tram track’’ type of calcification seen on plain film radiography and extensive cortical enhancement on computed tomographic and magnetic resonance imaging (66). The use of technetium-99m-hexamethylpropyleneamine oxime brain single-photon emission computed tomography to detect regions of hypoperfusion not otherwise evident on imaging has been advocated (67). Pathological examination typically reveals a plexus of telangiectatic capillaries or venules lying between the pia and arachnoid with adjacent cerebral cortical atrophy (68). The genetic cause of this disease is unknown. A number of families with lesions affecting several members in successive generations due to incomplete manifestation of a familial form of this disease have been reported (69). Wyburn–Mason Syndrome Also known in the literature as the ‘‘bonnet-blanc-dechaume’’ syndrome or mesencephalooculo-facial angiomatosis, Wyburn–Mason syndrome is a developmental nonhereditary condition characterized by a unilateral retinocephalic vascular malformation. Bilateral intracranial vascular anomalies and large deeply located AVMs have been reported (70). Other Syndromes Associated with Cerebral AVMs The association of cerebral and cutaneous vascular hamartomas distinct from the Sturge– Weber syndrome has been reported and constitutes a distinct, hereditary entity with autosomal dominant inheritance and variable penetrance. The clinical manifestations of this syndrome are visible, painful vascular nevi, epilepsy, cerebral hemorrhage, and focal neurological deficits. The preponderance of male patients with the full expression of this ill-defined syndrome suggests a possible hormonal influence on disease expression (71). Whether this entity is a separate genetic disorder or an incomplete form of Sturge–Weber disease has yet to be established. Familial Cases of AVMs Familial AVMs have been reported to occur in several members of a family unrelated to any known genetic disorders such as HHT (72). A possible autosomal dominant inheritance pattern has been reported in a family where AVMs were present in three successive generations (73). In cases of suspected familial AVM, screening and treatment of asymptomatic persons with a family history of cerebral vascular malformation is an important consideration (74–79). REFERENCES 1. Hunter W. The history of an aneurysm of the aorta with some remarks on aneurysms in general. Med Observ Inquir 1757; 1:323. 2. Petit JL. Traie des maladies chirurgicales et operation. Paris: Didot, 1774. 3. Hooper R. Lexicon Medicum. New York: Harper and Brothers, 1841. 4. Bell J. The Principles of Surgery. London: Longman, Hurst, Ree, 1815:456–489. 5. Virchow R. Angiome. Die Krankhaften Geschwulste. Berlin: August Hirschwald, 1863:306–425. 6. Reinhoff WF. Congenital arteriovenous fistula, an embryological study, with report of a case. Bull Johns Hopkins Hosp 1924; 35:271. 7. Malan E. Vascular malformations (angiodysplasias). Milan: Carlo Erba Foundation, 1974:15–26. 8. McCormick WF. The pathology of vascular (‘‘arteriovenous’’) malformations. J Neurosurg 1966; 24:807–816. 9. McCormick WF, Nofzinger JD. Cryptic vascular malformations of the central nervous system. J Neurosurg 1966; 24:865–875. 10. McCormick WF, Hardman JM, Boulter TR. Vascular malformations (angiomas) of the brain, with special reference to those occurring in the posterior fossa. J Neurosurg 1968; 28:241–251. 11. McCormick WF. Pathology of vascular malformations of the brain. In: Wilson CB, Stein BM, eds. Intracranial Arteriovenous Malformations. Baltimore: Williams & Wilkins, 1984:44–63. 12. McCormick WF. The pathology of angiomas. In: Fein J, Flamm ES, eds. Cerebrovascular Surgery. New York: Springer-Verlag, 1985:1073–1095. 13. Russel DS, Rubinstein LJ. Pathology of Tumors of the Nervous System. Vol. 3rd. Baltimore: William & Wilkins, 1971:93–102. 14. Houkin K, Sato M, Echizenya K, Nakagawa T. Mixed pial–dural arteriovenous malformation. Case report. No Shinkei Geka 1984; 12:347–352.

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15. Awad IA, Robinson JR Jr., Mohanty S, Estes ML. Mixed vascular malformations of the brain: clinical and pathogenetic considerations. Neurosurgery 1993; 33:179–188. 16. Valavanis A. The role of angiography in the evaluation of cerebral vascular malformations. Neuroimaging Clin N Am 1996; 6:679–704. 17. Miyasaka Y, Yada K, Ohwada T, et al. Choroid plexus arteriovenous malformations. Neurol Med Chir (Tokyo) 1992; 32:201–206. 18. Miyachi S, Negoro M, Handa T, Sugita K. Contribution of meningeal arteries to cerebral arteriovenous malformations. Neuroradiology 1993; 35:205–209. 19. Omojola MF, Fox AJ, Vinuela F, Debrun G. Stenosis of afferent vessels of intracranial arteriovenous malformations. Am J Neuroradiol 1985; 6:791–793. 20. Yasargil MG. Microneurosurgery. Vol. 3A. New York: Thieme Medical Publishers, 1987. 21. Houdart E, Gobin YP, Casasco A, Aymard A, Herbreteau D, Merland JJ. A proposed angiographic classification of intracranial arteriovenous fistulae and malformations. Neuroradiology 1993; 35: 381–385. 22. Okazaki H. Cerebrovascular disease. In: Fundamentals of Neuropathology: Morphologic Basis of Neurologic Disorders. New York: Igaku–Shoin, 1989:27–94. 23. Willinsky RA, Lasjaunias P, TerBrugge K, Burrows P. Multiple cerebral arteriovenous malformations (AVMs). Review of our experience from 203 patients with cerebral vascular lesions. Neuroradiology 1990; 32:207–210. 24. Stone JL, Crowell RM, Lisner BM, Naseem M, Oldershaw JB. Bilateral parietal arteriovenous malformations: report of a case. Neurosurgery 1983; 13:587–592. 25. Wilkins RH. Natural history of intracranial vascular malformations: a review. Neurosurgery 1985; 16:421–430. 26. Hirano A, Salomon S. Arteriovenous aneurysms of the vein of Galen. Arch Neurol 1960; 3:589–593. 27. Scardigli K, Biller J, Ghobrial M, Ross E, Badrinath K. Brain stem vascular malformation simulating a hemorrhagic metastasis: report of a case with pathologic correlation. Eur Neurol 1984; 23: 240–246. 28. Nazek M, Mandybur TI, Kashiwagi S. Oligodendroglial proliferative abnormality associated with arteriovenous malformation: report of three cases with review of the literature. Neurosurgery 1988; 23:781–785. 29. Berenstein A, Lasjaunias P. Classification of brain arteriovenous malformations. In: Surgical Neuroangiography. New York: Springer-Verlag, 1991:1–88. 30. Brown RDJ, Wiebers DO, Forbes GS. Unruptured intracranial aneurysms and arteriovenous malformations: frequency of intracranial hemorrhage and relationship of lesions. J Neurosurg 1990; 73: 859–863. 31. Marks MP, Lane B, Steinberg GK, Snipes GJ. Intranidal aneurysms in cerebral arteriovenous malformations: evaluation and endovascular treatment. Radiology 1992; 183:355–360. 32. Perata HJ, Tomsick TA, Tew JMJ. Feeding artery pedicle aneurysms: association with parenchymal hemorrhage and arteriovenous malformation in the brain. J Neurosurg 1994; 80:631–634. 33. Daumas-Duport C, Mann M, Munari C, et al. Cryptic vascular malformations diagnosed by stereotactic biopsies—a preliminary study. Appl Neurophysiol 1985; 48:440–443. 34. Isoda K, Fukuda H, Takamura N, Hamamoto Y. Arteriovenous malformation of the brain—histological study and micrometric measurement of abnormal vessels. Acta Pathol Jpn 1981; 31:883–893. 35. Takashima S, Becker LE. Neuropathology of cerebral arteriovenous malformations in children. J Neurol Neurosurg Psychiatry 1980; 43:380–385. 36. Mandybur TI, Nazek M. Cerebral arteriovenous malformations. A detailed morphological and immunohistochemical study using actin. Arch Pathol Lab Med 1990; 114:970–973. 37. Costantino A, Vinters HV. A pathologic correlate of the ’steal’ phenomenon in a patient with cerebral arteriovenous malformation. Stroke 1986; 17:103–106. 38. Rothbart D, Awad IA, Lee J, Kim J, Harbaugh R, Criscuolo GR. Expression of angiogenic factors and structural proteins in central nervous system vascular malformations. Neurosurgery 1996; 38:915–924. 39. Germano IM, Davis RL, Wilson CB, Hieshima GB. Histopathological follow-up study of 66 cerebral arteriovenous malformations after therapeutic embolization with polyvinyl alcohol. J Neurosurg 1992; 76:607–614. 40. Schmutz F, McAuliffe W, Anderson DM, Elliott JP, Eskridge JM, Winn HR. Embolization of cerebral arteriovenous malformations with silk: histopathologic changes and hemorrhagic complications. Am J Neuroradiol 1997; 18:1233–1237. 41. Nataf F, Ghossoub M, Missir O, et al. Parenchymal changes after radiosurgery of cerebral arteriovenous malformations. Preliminary report of a proposed classification. Stereotact Funct Neurosurg 1997; 69:143–146. 42. Schneider BF, Eberhard DA, Steiner LE. Histopathology of arteriovenous malformations after gamma knife radiosurgery. J Neurosurg 1997; 87:352–357. 43. Yamamoto M, Jimbo M, Ide M, et al. Gamma knife radiosurgery for cerebral arteriovenous malformations: an autopsy report focusing on irradiation-induced changes observed in nidus-unrelated arteries. Surg Neurol 1995; 44:421–427.

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44. Elisevich K, Redekop G, Munoz D, Fisher B, Wiese K, Drake C. Neuropathology of intracranial arteriovenous malformations following conventional radiation therapy. Stereotact Funct Neurosurg 1994; 63:250–254. 45. Sonstein WJ, Kader A, Michelsen WJ, Llena JF, Hirano A, Casper D. Expression of vascular endothelial growth factor in pediatric and adult cerebral arteriovenous malformations: an immunocytochemical study. J Neurosurg 1996; 85:838–845. 46. Abdulrauf SI, Malik GM, Awad IA. Spontaneous angiographic obliteration of cerebral arteriovenous malformations. Neurosurgery 1999; 44:280–287. 47. Mullan S, Mojtahedi S, Johnson DL, Macdonald RL. Embryological basis of some aspects of cerebral vascular fistulas and malformations. J Neurosurg 1996; 85:1–8. 48. Campbell ACP. The vascular architecture of the cat’s brain: a study by vital injection. Res Nerv Ment Dis 1938; 18:69–93. 49. Scharrer E. Arteries and veins in the mammalian brain. Anat Rec 1940; 78:173–196. 50. Vidyasagar C. Persistent embryonic veins in arteriovenous malformations of the brain. Acta Neurochir (Wien) 1978; 40:103–116. 51. Deshpande DH, Vidyasagar C. Histology of the persistent embryonic veins in arteriovenous malformations of brain. Acta Neurochir (Wien) 1980; 53:227–236. 52. Haase J, Hobolth N, Ringsted J. Growing intracranial arteriovenous malformation in a newborn. Childs Nerv Syst 1986; 2:270–272. 53. Rhoten RL, Comair YG, Shedid D, Chyatte D, Simonson MS. Specific repression of the preproendothelin-1 gene in intracranial arteriovenous malformations. J Neurosurg 1997; 86:101–108. 54. McAllister KA, Grogg KM, Johnson DW, et al. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 1994; 8:345–351. 55. Shovlin CL, Hughes JM, Tuddenham EG, et al. A gene for hereditary haemorrhagic telangiectasia maps to chromosome 9q3. Nat Genet 1994; 6:205–209. 56. Fulbright RK, Chaloupka JC, Putman CM, et al. MR of hereditary hemorrhagic telangiectasia: prevalence and spectrum of cerebrovascular malformations. Am J Neuroradiol 1998; 19:477–484. 57. Roma´n G, Fisher M, Perl DP, Poser CM. Neurological manifestations of hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease): report of 2 cases and review of the literature. Ann Neurol 1978; 4:130–144. 58. Bird RM, Jacques WE. Vascular lesions of hereditary hemorrhagic telangiectasia. N Engl J Med 1959; 260:597–599. 59. Putman CM, Chaloupka JC, Fulbright RK, Awad IA, White RIJ, Fayad PB. Exceptional multiplicity of cerebral arteriovenous malformations associated with hereditary hemorrhagic telangiectasia (OslerWeber-Rendu syndrome). Am J Neuroradiol 1996; 17:1733–1742. 60. King CR, Lovrien EW, Reiss J. Central nervous system arteriovenous malformations in multiple generations of a family with hereditary hemorrhagic telangiectasia. Clin Genet 1977; 12:372–381. 61. Vincent P, Plauchu H, Hazan J, Faure´ S, Weissenbach J, Godet J. A third locus for hereditary haemorrhagic telangiectasia maps to chromosome 12q [published erratum appears in Hum Mol Genet 1995; 4(7):1243]. Hum Mol Genet 1995; 4:945–949. 62. Johnson DW, Berg JN, Baldwin MA, et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 1996; 13:189–195. 63. Palencia R, Ardura J. Bannayan syndrome with intracranial arteriovenous malformations. Anales Espanoles de Pediatria 1986; 25:462–466. 64. Proesmans W, Van Damme B, Casaer P, Marchal G. Autosomal dominant polycystic kidney disease in the neonatal period: association with a cerebral arteriovenous malformation. Pediatrics 1982; 70: 971–975. 65. Smirniotopoulos JG, Murphy FM. The phakomatoses. Am J Neuroradiol 1992; 13:725–746. 66. Osborn AG. Disorders of histogenesis. Neurocutaneous syndromes. In: Diagnostic Neuroradiology. St. Louis Mosby-Year Book, 1994:72–113. 67. Bar-Sever Z, Connolly LP, Barnes PD, Treves ST. Technetium-99m-HMPAO SPECT in Sturge-Weber syndrome. J Nucl Med 1996; 37:81–83. 68. Barkovich AJ. The phacomatoses. In: Pediatric Neuroimaging. New York: Raven Press, 1995:277–319. 69. Louis-Bar D. Sur l’heredite de la maladie de Sturge-Weber-Krabbe. Confina Neurologica 1947; 7: 238–244. 70. Patel U, Gupta SC. Wyburn-Mason syndrome. A case report and review of the literature. Neuroradiology 1990; 31:544–546. 71. Leblanc R, Melanson D, Wilkinson RD. Hereditary neurocutaneous angiomatosis. Report of four cases. J Neurosurg 1996; 85:1135–1142. 72. Boyd MC, Steinbok P, Paty DW. Familial arteriovenous malformations. Report of four cases in one family. J Neurosurg 1985; 62:597–599. 73. Larsen PD, Hellbusch LC, Lefkowitz DM, Schaefer GB. Cerebral arteriovenous malformation in three successive generations. Pediatr Neurol 1997; 17:74–76. 74. Aberfeld DC, Rao KR. Familial arteriovenous malformation of the brain. Neurology 1981; 31:184–186. 75. Roussey M, Le Marec B, Le Francois C, Senecal J. Familial occurrence of arteriovenous malformation of the brain. J Neurosurg 1991; 74:585–589.

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76. Yokoyama K, Asano Y, Murakawa T, et al. Familial occurrence of arteriovenous malformation of the brain. J Neurosurg 1991; 74:585–589. 77. Zellem RT, Buchheit WA. Multiple intracranial arteriovenous malformations: case report. Neurosurgery 1985; 17:88–93. 78. Allard JC, Hochberg FH, Franklin PD, Carter AP. Magnetic resonance imaging in a family with hereditary cerebral arteriovenous malformations. Arch Neurol 1989; 46:184–187. 79. Barre RG, Suter CG, Rosenblum WI. Familial vascular malformation or chance occurrence? Case report of two affected family members. Neurology 1978; 28:98–100.

3

Hemodynamic Properties Michael Morgan Department of Neurosurgery, School of Advanced Medicine, Macquarie University, Sydney, Australia

INTRODUCTION The hemodynamic properties of arteriovenous malformations (AVMs) have been the subject of observation and speculation for many years. The first hemodynamic observations about arteriovenous fistuale were made by William Hunter, who reported in 1764 on a ‘‘particular species of aneurysm... where there is an anastomosis... between the artery and vein... so that blood passes immediately from the trunk of the artery into the trunk of the vein’’ arising as a complication of phlebotomy at the elbow (1). He observed ‘‘the artery... will become larger in the arm, and smaller at the wrist, than it was in the natural state’’ and the vein ‘‘will be dilated or become varicose.’’ He defined the anatomical changes as due to hemodynamic factors, as he explained ‘‘the stream from the (proximal) artery (becomes) larger.’’ This observation clearly demonstrates many of the key features present in AVMs of the brain. The progress in understanding the hemodynamics of AVMs of the brain expanded after the advent of angiography. However, the initial emphasis was on the hemodynamic effects on the brain rather than on the hemodynamics of the lesion itself. Elvidge reported the poor angiographic visualization of arteries in the immediate vicinity of AVMs in 1938 (2). Olivecrona and Riives in 1948 reported the first large series of patients with cerebral AVMs that had been studied angiographically and proposed that progressive deficits, cognitive dysfunction, and cerebral atrophy were due to ‘‘anoxemia of the brain due to shunting of the blood’’ (3). Shortly thereafter, Norlen reported improvement in angiographic visualization of vessels surrounding the AVM upon its resection (4). This preferential diversion of blood from brain to shunt became known by the emotive term ‘‘steal’’ (5). Despite the increasing evidence for circulatory perturbations arising as a consequence of arteriovenous shunting in the brain, the lack of quantification of this disturbance has created significant controversy. As late as 1987 Yasargil published that ‘‘the controversy regarding cerebrovascular steal has not been so much a question as to whether it occurs . . . but whether it is of clinical significance’’ (6). Indeed, as recently as 1982 Malis argued that steal should only occur if there is a restriction of collateral flow to the AVM because of a compensatory increase in carotid flow (7). This argument is based on an understanding of the cerebral circulation that dates back more than 300 years. Willis suggested that carotid flow could increase markedly to supply ‘‘changing needs’’: ‘‘in an humane head, where the generous affections, and the great forces and ardours of the souls are stirred up, the approach of the blood to the confines of the brain, ought to be free and expeditious; and it is behoveful for its river not to run narrow and manifoldly divided rivulets, which would scarce drive a mill, but always with a broad and open channel, such as might bear a ship under sail’’(8). This comment provides some insight into Willis himself, who originally commenced training as a minister of religion, and early speculation into the ability of the flow within the carotids to increase in velocity. A second controversy of AVM hemodynamics is the consequence of their removal. A year before the first successful removal of a cerebral AVM in 1889 by Pean [cited by Yasargil (6)], Gowers described a condition called ‘‘congestive apoplexy’’ as the most severe complication of cerebral congestion (9). He defined ‘‘partial active congestion’’ as that occurring ‘‘when an artery is obstructed, and the adjacent branches of the main vessel receive too much blood.’’ This hyperemia appears to be the central argument today applied to the controversy of hemorrhage and edema complicating surgery for large AVMs. The underlying pathophysiological disturbance has been attributed to loss of autoregulation and has been termed the ‘‘normal perfusion pressure breakthrough’’ theory (10). Challenges to this theory and alternate pathophysiological mechanisms are exemplified by ‘‘occlusive hyperemia’’(11).

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Our understanding of the hemodynamic properties of AVMs is far from complete. Nonetheless it is timely to bring the current clinical controversies into focus against what is known about the hemodynamics that underscore the clinical scenarios thought to be due to perturbations of this physiology. HEMODYNAMIC EFFECT WITHIN THE INTERSTICES OF AN AVM The hemodynamic consequences of AVMs depend in large part on the cross-sectional area of the narrowest point in the communication between the arterial-type vessel and the venoustype vessel. The smallest communications identified in shunting have been suggested to range from less than 0.05 mm (12) to greater than 3.0 mm (as evident by reports of spheres not arrested during embolization procedures) (13–16). That a significant proportion of AVMs have as their narrowest points cross-sectional diameters of greater than 100 mm and at least occasionally greater than 300 mm (12–17) is of significance because in the normal circulation the greatest part of the pressure reduction (therefore, the site of maximal resistance) occurs in vessels of diameter less than 300 mm (18) with the maximum resistance occurring in vessels less than 100 mm (19). Thus, the hemodynamic response results from the low resistance to flow. The consequence of this low resistance has a huge impact on the cerebral circulation, including its effect within the AVM interstices itself. One clinical manifestation of this effect is the development of a bruit. The audible bruit known to be characteristic of AVMs well before the introduction of angiography (20,21) arises as a consequence of vessel wall vibration (22). This vibration occurs as a consequence of the random fluctuation of velocity and pressure within the vessel, i.e., turbulence (23). Turbulence has a significant impact on both the vessel wall within the AVM and the blood itself. The site of turbulent flow within the nidus is influenced by the velocity of flow, diameter of the vessels, change in vessel diameter, and branch morphology. The velocity of flow and the vessel diameter are related in the Reynolds number (Re ¼ qVD/m, where q ¼ density of the fluid (gm/mL), V ¼ velocity (cm/s), D ¼ diameter of the tube, and m ¼ fluid viscosity (poise)). The Re for steady flow through straight tubes predicts the transition from laminar to turbulent flow; the higher the Re, the more likely the flow will be turbulent. Although blood flow in the AVM nidus is not in straight tubes, the general relationship is likely to be applicable. The superimposition of focal stenosis and dilatations present in AVMs lowers the threshold for turbulent flow predicted by the Re. A further potential site for the generation of turbulence is at branch points. If the branch-to-trunk area ratio is one or greater, turbulence is likely to ensue (24). Turbulence has a significant effect on the vessel wall. Three main physiological events account for this effect (25). These are conversion of kinetic energy of blood moving with high velocity into potential energy with consequent lateral pressure; random fluctuation of pressure creating impact shocks leading to distension; and high frequency pressure fluctuation causing structural fatigue. These factors lead to focal dilatations characteristic of the venous varix found in proximity to the AVM nidus. Downstream from the venous varix (in a region of laminar flow), the higher than normal measured velocity and the high measured venous pressure (as high as 21 to 23 mmHg) (26,27) must result in a high shear stress. Inasmuch as the propensity for structural fatigue is less marked with the transition of flow from turbulent to laminar, it can be surmised that shear stress and wall structural fatigue are even greater in the region of turbulence (i.e., the variceal segments). These forces leading to dilatation are also those predisposing to the site of rupture within the nidus of an AVM. Thus, one site of likely rupture is where turbulence occurs on the venous side of the nidus. Turbulent flow may incite more than a mechanical response leading to fatigue in the vessel wall. An increase in endothelial DNA synthesis is reported to occur (28), and endothelial turnover may well be influenced by these shear stresses. A modulation of endothelial transport, an increase in endothelial microfilament bundles, and ultrastructural changes in the subendothelial layer all have been reported to result from high shear stress (29–31). Therefore, the observed pathological changes in normal vessel wall histology may well be, at least in part, an acquired response to the hemodynamic perturbations rather than related to genetically determined structural abnormalities. The high-frequency fluctuations of velocity and pressure associated with turbulence-producing high shear stresses can be detrimental to blood elements. Although no major study of the direct measurements of the Reynolds shear stress in the region of the venous varix has been

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published, evidence that such shear stresses may be of significance is suggested in the experimental arteriovenous fistula, where the introduction of turbulence produced platelet aggregation (32). High shear stress can lead to platelet activation, platelet aggregation, and hemolysis of red cells. HEMODYNAMIC EFFECT ON CEREBRAL BLOOD VESSELS IN THE PRESENCE OF AN AVM Arteries Modeling the pressure flow relationship in the vessels of the brain has often involved invoking the equation of Poiseuille published in 1846 (33). This equation is a special solution of the Navier-Stokes equations of the motion of viscous liquids and was considered as such by Hagenbach (34), who solved the constant in Poiseuille’s equation by producing the equation presented in the familiar form in Table 1. Despite considerable deviation from the ideal, Green and Rapela demonstrated that Poiseuille’s equation can be reasonably applied to vessels of diameter above 100 mm (35), i.e., the size of vessels involved in AVMs. Thus, it is applicable to the arteries that feed AVMs. The lower than normal resistance arising as a consequence of the absence of the smallest arteries and arterioles results in an increase in volume flow per unit time. This circumstance produces a dilatation of the feeding arterial and draining venous systems in response to the high shear stress on the wall and the low transmural pressure. That vessels enlarge with time in response to arteriovenous shunting (the hemodynamic forces) was first described by Hunter in 1764 and conceptively applied to AVMs of the brain in 1958 by Hook and Johanson (36). Physiological parameters measured in AVMs of the brain include blood flow, which has been known for more than 50 years to be as high as three times that of the normal cerebral circulation (37). More invasive measures include the pressure of the dilated feeding vessels, first measured by Nornes and Grip to be between 40 and 70 mmHg with vessel flow velocities as high as 550 cc min
1 (at a systemic arterial pressure of between 95 and 105 mmHg at the time of the study) (26). Hassler and Steinmetz (38) found this measurement at the time of craniotomy to range from 45% to 62% of that of the radial artery. These pressures were considered to be significantly below that expected of arteries at this site not supplying AVMs (Fig. 1). Independent investigators have confirmed these observations with pressures calculated in the intact skull with angiographic microcatheters. Although this catheter technique suffers from comparing the cerebral catheter in a downstream direction (thus being lower than the true lateral pressure by the kinetic energy of flow in that vessel) with a catheter directed upstream (thus being higher than the true lateral pressure by the kinetic energy of flow in that vessel), similar results are obtained, with the average feeding artery being 67% to 71% that of the pressure in the femoral catheter (39,40). In comparison, the distal cortical arterial pressure (pial arteries) in individuals without AVMs has been measured at 90% of systemic arterial pressure (41–43). One study of pial artery pressures found that on the side of the AVM they were 6l% of the peripheral systemic pressure and were significantly less than 78% on the matched contralateral side (44) (Table 1). Again, the difference in kinetic energy of flow between the two sides needs to be considered and may reduce this difference. The point of measurement of pressure is crucial as the pressure will be influenced by the distance along the arterial feeder system (Fig. 1). Fogarty-Mack et al. showed this to be the case for a group of AVMs predominantly 2.5–4 cm in diameter. For these cases the pressure in the artery proximal to the AVM when compared with peripheral systemic Table 1 Poiseuille Equation Q ¼ pR4(P1
P2)/8mL Q ¼ volume flow per unit time; R ¼ internal radius; P1
P2 ¼ pressure drop along L; L ¼ the length of the tube; m ¼ viscosity. The conditions under which Poiseuille’s equation apply include the following:  The fluid is homogeneous, and its viscosity is the same at all rates of shear.  The liquid does not slip at the wall.  The flow is laminar (i.e., the liquid at all points is moving parallel to the walls of the tube).  The rate of flow is steady.  The tube is long.  The tube is rigid.

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Figure 1 Profile of the pressure along the length of the vascular pathway in the brain. The maximal deviation from the normal is where resistance in the AVM is no greater than that of the arterial system (straight fistula). The vasculature within the sphere of influence of the AVM will deviate from normal and toward this curve. On occlusion of the fistula, the curve will move towards the maximal response anticipated, which will be above the normal curve, because the arteries have a larger diameter than is normal (see text). In addition, the pulsatility will increase above normal because of the increased reflectance. Abbreviations: AVM, arteriovenous malformation; lCA, intemal carotid artery; A1, M1, P1, pressure in these arteries; AVM or capillary, pressure at the level of the AVM or capillary. (See color insert.)

arterial pressure was 97% in the supraclinoid internal carotid artery (ICA) (or basilar artery); 75% in the A1, M1, or P1; 61% in the artery halfway from the above to the nidus; and 50% in the terminal feeder immediately prior to the nidus (44) (Table 1). These differences were significant. In a study of larger AVMs, the range of feeding artery pressures varied considerably, and half the cases had pressures less than 50% of the femoral pressure (45). There was a tendency for the larger AVM and the terminal feeder to have the lowest pressures (39,40). Studies of the responsiveness of the feeding artery to various stimuli show a response ranging from normal to reduced. In those where there is a reduced response to CO2 inhalation or hyperventilation in vivo (46,47) or where in vitro testing demonstrated no spontaneous activity and a reduced response to vasoactive substances (such as serotonin) (48), there is an increased likelihood of hemodynamic perturbations both before and after resection. The responsiveness detected is likely a result of the degree of arteriovenous shunting rather than an intrinsically distinct population of feeding arteries. The response of the feeding arteries of the AVM to systemic elevations or falls in blood pressure would be predicted to be dampened given the paucity of small resistance arteries and arterioles. Without the intrinsic control of autoregulation in the feeding arterial system (indeed, there is no microcirculation to protect within the arteriovenous interstices), elevations in proximal blood pressure would be expected to lead to a lesser increase in feeder pressure (Fig. 1). This blunted response has been demonstrated to occur by using microcatheters and systemic blood pressure elevation with phenylephrine (49). Aneurysm Formation The development of aneurysms is likely to be related to sites of maximal shear stress [shear stress being the product of m ¼ fluid viscosity and the shear rate (du/dx) (u ¼ axial stream velocity, x ¼ distance from wall)] and the consequent structural fatigue. Shear stress is further compounded by the repetitive cyclic change of stress seen with pulsatile flow (50), and is maximal at the distal carina of branch points or changes in direction.

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Hemodynamic stress induced by arteriovenous shunting as a cause of aneurysm formation was first reported more than 40 years ago (51). In more than 600 cases of AVMs, aneurysms have been reported to be present on arteries that feed the AVM in 11.2% of cases, but are present on arteries not feeding the AVM in only 0.8% of cases (52). This relatively high prevalence of aneurysms on feeding vessels has been reported in other large series (7–10%) of more than 400 cases (6,53–55). These findings compare with a prevalence of 1% in a similarly aged population undergoing angiography for reasons other than cerebrovascular disease (56). The high incidence of aneurysms on the feeding artery of AVMs is almost certainly related to the hemodynamic stress, given that angiographically and historically these aneurysms are identical to other saccular aneurysms (the etiology of which is thought to be on the basis of hemodynamic stress) (57–63) and that removal of the stress can lead to spontaneous disappearance of the aneurysm (52,54,55). That the aneurysm is within the hemodynamic sphere of influence of the fistula is underscored by the cases of aneurysmal rupture on shunt ablation—an event that must be associated with elevated pressure in the feeding artery (55,64). Further evidence in support of the hemodynamic etiology of aneurysm formation in AVMs is the tendency for aneurysms to be located more proximally in the arterial feeding network of large AVMs and closer to the nidus with smaller lesions (59). This observation is in keeping with the lower transmural pressures anticipated in the distal feeding artery of larger shunting AVMs. Associated aneurysms are a predictor of hemorrhage in patients with AVMs (59,65). The risk of hemorrhage in patients with an unruptured AVM with an associated arterial aneurysm is 7% per year compared with 1.7% if no aneurysm is present (59). The annual risk of hemorrhage has been estimated to be 5.3% for those aneurysms on the proximal arteries feeding an AVM and 9.8% when the aneurysm is within the AVM nidus (52). The increased risk of hemorrhage in patients with both aneurysm and AVM can only be partially explained by the sum of the individual risks of rupture from AVM and aneurysm, because in patients presenting with hemorrhage with both aneurysm and AVM, at least 50% of the time the origin of hemorrhage is the AVM (52). Therefore, the dramatically increased risk of hemorrhage from 1.7% to 7% with the presence of a feeding artery aneurysm would not be seen if the risks of the two lesions were merely additive. The presence of aneurysms should more correctly be considered a marker of advanced wear and tear on the integrity of the vasculature. Relationship of Feeding Artery Pressure and Prediction of Hemorrhage Hemorrhage from a blood vessel can be expected at some point with elevation in transmural blood pressure. In the case of AVMs, feeding artery blood pressure and wall fragility must interplay to predict the likelihood of hemorrhage. Indeed, a positive correlation between feeding artery pressure and the likelihood of AVM presentation with hemorrhage has been clinically verified (66–68). However, a distinction needs to be made between presentation of hemorrhage and risk of hemorrhage because of the increased likelihood that large AVMs with their lower feeding artery pressures will herald their presence by other means (e.g., seizure). The two explanations for high feeding artery pressure are first, that the fistula shunting is so minimal that the physiological perturbations are minimal, and second, that there has been high shear stress damage to the vasculature in the past but feeding artery pressure has recently risen (e.g., a recently acquired venous outflow obstruction). In the former case, one would expect that the shear stress would be approaching that of the normal circulation and thus would not be a significant risk for hemorrhage. In the second case, a rise in feeding artery pressure may precipitate hemorrhage where the damage from high shear stress is more recently accompanied by venous occlusive disease. Veins Predicted by the lack of intervening resistance vessels between feeding arteries and draining veins is an elevation in draining vein pressure that drops on AVM resection (Fig. 1). This prediction has been confirmed to be the case for human AVMs (49). The draining vein pressure correlates with the feeding artery pressure with the difference between the two inversely proportional to the AVM nidus size. The nature of flow within the draining vein of the AVM has been found to be pulsatile with high velocity (in contradistinction to the normal venous circulation) (69). Coupling the higher than normal pressure, pulsatility with high peak pressures, and higher than normal velocity of flow results in a higher than normal shear stress on the vein wall.

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Nornes and Grip demonstrated that the venous flow close to the AVM nidus was turbulent and became non-turbulent at a distance from the AVM (26). As with the discussion above on the consequences of high shear stress within the AVM nidus, endothelial turnover may well be altered and ultrastructural changes in the subendothelial layer may occur (29–31). These

Figure 2 (Caption on facing page)

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possibilities may explain the development of variceal dilatation and the acquisition of venous webs in the venous outflow of AVMs. Yasargil reported that 30% of all AVMs have associated venous abnormalities and that the incidence of venous abnormalities was positively correlated with AVM size (6). These observations have been confirmed by others (70). An increase in venous resistance, as caused by venous drainage occlusion, can lead to an increase in the risk of hemorrhage (70–73). If the venous occlusive or stenotic lesion is acquired in response to the AVM shunt flow (and this is likely to be the case), then the pressure in the AVM nidus and feeding artery will increase with time. This increase is likely to be the predominant hemodynamic factor in AVM hemorrhage associated with venous abnormalities (see above). HEMODYNAMIC EFFECT ON THE MICROCIRCULATION OF THE BRAIN ASSOCIATED WITH AN AVM Critical to the function of brain is the transmural pressure at the beginning and end of the capillary. Either a reduction in arterial pressure or an elevation of venous pressure can threaten brain function. Both events occur in brain surrounding an AVM to a varying extent (Fig. 2). Three questions are raised by this phenomenon: Is the arterial hypotension and/or venous hypertension sufficient to compromise cerebral blood flow (CBF)? If there is a reduction in CBF, is it sufficient to become clinically manifest? If there is a reduction in CBF, how does the microcirculation respond to further alterations in cerebrovascular physiology? Effect of Brain AVMs on Cerebral Blood Flow A baseline reduction in CBF may occur in the presence of an AVM. Direct measurements of CBF by intraoperative cortical CBF techniques (using intravenous 133xenon clearance, laser doppler blood flow, and thermal diffusion probes), single photon emission tomography (SPECT), and positron emission tomography (PET) have demonstrated that some patients have regional reductions in CBF adjacent to the AVM nidus (12,27,74–84). However, not all studies have confirmed evidence for reduced CBF in association with AVMs. Of note is the largest published study of a group of patients undergoing intraoperative CBF measurements (85). However, very few of the patients in that study had measurements of CBF adjacent to the AVM; most had local measurements of CBF more than 4 cm from the AVM margin, a distance beyond that expected to have the maximal impact on CBF (27). It is reasonable to conclude from the clinical evidence that in some patients the reduction in feeding artery pressure and the elevation in venous draining pressure are sufficient to compromise CBF in the resting state adjacent to the AVM. However, CBF is rarely, if ever, reduced at a distance from the AVM. The effects on CBF caused by the arteriovenous shunt flow in the absence of the physical nidus (eliminating the error inherent in having the AVM nidus in close proximity to the CBF region of interest) has been investigated in a rat model of AVM, and the findings confirmed the reduction in flow suggested by many human studies (86–89). Thus, the reduction in CBF in humans adjacent to the AVM is likely to be a response due to the arteriovenous shunting. As the magnitude of the shunting is variable, so too will be the magnitude of CBF response.

Figure 2 (Facing page) Model of possible arterio-capillary-venous units coming under the influence of an AVM. (A)The pressure within the artery and vein of the AVM drop over a short distance at the point of turbulence within the AVM and at the point of venous stenosis (if this exists). (B) The quantification of this pressure drop is variable. As shown in (A) parenchymal arteries and veins can arise at a distance (1 ¼ artery branch; 4 ¼ venous tributary) or in close proximity (2 ¼ artery branch; 3 ¼ venous tributary) to the fistula, producing the four classes of arterio-capillary-venous units: A, B, C and D. Pressure profiles will be determined by the specific parenchymal vascular pathway, and many such profiles will be present around an AVM. Examples of such profiles are illustrated by the pressure profiles between points 1 and 3, points 1 and 4, points 2 and 3, and points 2 and 4, representing the various arterio-capillary-venous units, shown in (B). With occlusion of the fistula the pressure profile within the arteriocapillary-venous units will rise towards the line indicating ‘‘profile from maximal effect from fistula ablation,’’ which is higher on the arterial side and lower on the proximal venous side than normal because of the dilatation of the vasculature (see text). Thus, at any one point in the arterio-capillary-venous unit, the pressure after ligation can be traced with a vertical line from the arterio-capillary-venous unit to the post-ligation pressure. It should also be remembered that these lines represent mean pressures and peak pressures, and the increase in pulsatility will be even greater. Abbreviations: AVM, arteriovenous malformation; ICA, internal carotid artery; A1, proximal anterior cerebral artery; M1, proximal middle cerebral artery; P1, proximal posterior cerebral artery. (See color insert.)

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Clinical Response to Blood Flow Disturbance ‘‘Steal’’ is the term for the preferential diversion of blood from functional brain to fistula flow (5). It has been considered the basis for neurologic deficits and seizures for more than five decades (3,4,14,64,90–96). However, Drake has raised the possibility that occult hemorrhage may be responsible for symptoms ascribed to steal (64). Moreover, seizure foci can be associated with hemosiderin (arising as a consequence of hemorrhage), and this too may be responsible for deficits thought to be ‘‘steal’’ (97,98). A second explanation for symptoms ascribed to ‘‘steal’’ is pulsatile compression by the AVM mass. In support of this explanation is the bone erosion that can arise in response to the AVM (64,99) and the vascular compressive syndromes that lead to neuronal dysfunction in other states (100–102). A third explanation for ‘‘steal’’ symptomatology is venous hypertension (in the absence of concurrent arterial hypotension). Both generalized venous hypertension leading to a malabsorption of cerebrospinal fluid (CSF) and localized venous hypertension arising from parenchymal drainage have been posed as explanations for the clinical presentation of ‘‘steal’’ (27,95,103–108). In support of this possibility is the role of venous hypertension in the clinical presentation of spinal dural AVMs (109–113). ‘‘Steal’’ has been considered by some to be a term applied to clinical disorders confined to reduced feeding artery pressure as opposed to reduced perfusion pressure. In this narrow definition confined to arterial hypotension, physiological evidence in support of ‘‘steal’’ is contradictory (114). Indirect evidence in support of ‘‘steal’’ comes from the knowledge that non-hemorrhagic presentations (due either to serendipity or to a circulatory disorder) have as a group a lower feeding artery pressure compared with those presenting with hemorrhage (66,68). However, the feeding artery pressure is only part of the equation determining microvascular flow and ‘‘steal.’’ There is a correlation between feeding artery pressure and draining vein pressure (49). Thus, an assessment of the difference in these two pressures may be a more accurate measure of the validity of the concept of clinical ‘‘steal,’’ as a low feeding artery pressure was generally matched with a low draining vein pressure. Cerebral blood flow evidence that ‘‘steal’’ may be clinically relevant comes from studies showing hypoperfusion correlating with sites of epileptic focus and cognitive impairment (76). The concept that the presence of an arteriovenous fistula resulting in non-infarctional cerebral hypoperfusion may lead to altered brain function is supported by neurophysiological evidence of impaired neuronal function and behavior in rats (115–117). These studies confirm a clinical response to altered neuronal function secondary to chronic non-infarctional ischemia induced by an arteriovenous fistula. As the fistula is remote from the brain, there can be no hemorrhage, compression, infarction, or other mechanisms to explain the results. In summary, the hypoperfusion resulting from the variable combinations of reduced arterial pressure and increased venous pressure is likely to be clinically manifest in some patients with AVMs. However, the emotive term ‘‘steal’’ should be replaced with terminology that more appropriately reflects the physiological perturbations such as arterial hypotension and venous hypertension.

AUTOREGULATION AND REACTIVITY TO CHANGES IN PaCO2 Autoregulation Some evidence suggests that autoregulation is preserved in the brain surrounding AVMs even when the microcirculation of this brain is compromised because of low perfusion pressure (39). Such evidence stems from the measurement of regional CBF while measuring feeding artery pressure during an acute rise in systemic arterial pressure. However, because autoregulation of CBF can be defined both in terms of CBF constancy over a wide range of perfusion pressures (118) and an inverse relationship between arterial radius change and perfusion pressure change (119), a change in feeding artery pressure may not reflect the magnitude of change in perfusion pressure. Therefore, a true assessment of autoregulation also requires an understanding of the venous pressure. Under normal circumstances the venous side of this equation contributes minimally to perfusion pressure, but not in the case of AVMs. In the presence of an AVM a rise in arterial pressure is accompanied by a rise in draining venous pressure (49). The rise in venous draining pressure will, in part, be experienced by the perinidal brain tissue.

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This event has a negative impact on the potential for any planned perfusion pressure change arising as a consequence of systemic arterial pressure change during autoregulation challenge. Therefore, caution needs to be exercised in interpreting studies of altered systemic arterial pressure in terms of whether or not autoregulation is intact. In the experimental model of AVMs where baseline CBF is reduced by 25% to 50% (but insufficient to cause infarction) (86), attempts at assessing autoregulation by systemic blood pressure changes yield results that are analogous to that found in humans, i.e., blood flow is lower than normal but unaltered with elevations or reductions in blood pressure (88,120). However, when perfusion pressure is reduced by elevations in intracranial pressure with continuous ventricular infusion of artificial CSF, CBF is reduced in fistula animals at a lower intracranial pressure than it is in control animals (121). This finding is consistent with either no autoregulation or being below the lower limit of autoregulation. Thus, a ‘‘pseudo-autoregulation’’ may be seen when autoregulation is tested by measuring changes in systemic arterial pressures rather than the true perfusion pressure at the level of the microcirculation of interest. In summary, the constancy of blood flow in the face of alterations in systemic blood pressure in the brain surrounding the AVM may reflect true autoregulation where the impact on the microcirculation is insufficient to affect CBF, or it may reflect ‘‘pseudo-autoregulation’’ if the impact on the microcirculation in the resting state is significant. ‘‘Pseudo-autoregulation’’ is the preferred term because no arterial radius change is responsible for maintaining this constant but low CBF. Whether or not the arterioles can constrict (and at what pressure) with restoration of normal perfusion pressure cannot be determined by the usual methods of studying autoregulation. Reactivity to Changes in PaCO2 The effect of AVMs on cerebrovascular reactivity to carbon dioxide is of great interest. Although some patients with reduced CBF exhibit a predicted increase in the volume of ischemic tissue with acetazolamide challenge (78), other patients with low CBF experience a paradoxical increase in CBF in response to acetazolamide (78,80,84). The paradox is that if these regions are capable of increasing their blood flow, why do they remain ischemic at rest? The answer must in part be explained by the mechanism of blood flow increase. In normal brain, this increase must reflect the response of the arteries, all of which (except for choroidal vessels) are supplying similarly functioning microcirculations. However, for the brain adjacent to an AVM nidus, the influence of the arteriovenous fistula must be taken into consideration. In a passive microcirculation, both in parallel with an arteriovenous fistula and in parallel with a microcirculation capable of normal physiological responses, it can be anticipated that with a generalized stimulus for arterial dilatation (e.g., in response to an increase in PaCO2 or acetazolamide) the branch arteries from the feeding artery to the AVM will have a drop in their pressure due to the generalized reduction in total cerebrovascular resistance. This will lead to a reduction in arteriolar pressure and a reduction in microcirculation flow in a system that is unable to further vasodilate. As a result, some patients with reduced CBF exhibit an increase in the volume of ischemic tissue with acetazolamide challenge. However, in addition to this response, the fistula flow itself will be reduced with the reduction in the feeding artery pressure, and this will result in a reduction in the draining vein pressure. Microcirculations feeding into this system will then experience a fall in their resistance and a tendency to increase their blood flow even without a capacity to further vasodilate. Hence, some patients with low CBF may experience a paradoxical increase in blood flow in response to acetazolamide. The balance between the reduction in arterial pressure into a microcirculation and the reduction in venous pressure will determine the overall effect. When this balance favors a paradoxical increase in blood flow with acetazolamide, the risk for the development of edema and hemorrhage with AVM excision is likely to increase (84). Reactivity to changes of PaCO2 occurs in animal models of arteriovenous fistula despite hypoperfusion (87). It has not been determined whether this is due to a disconnection between the autoregulation response and CO2 reactivity, which can occur (87), or to a disproportionately greater effect of a reduction in venous pressure over a reduction in arterial pressure with the reduced fistula flow. Retention of CO2 reactivity may be possible despite being on the pressure-cerebral blood flow curve below the lower limit of autoregulation in the chronic hypoperfusion state.

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HEMODYNAMIC EFFECT ON CEREBRAL BLOOD VESSELS AT THE TIME OF AVM ABLATION The ablation of an arteriovenous fistula removes from the brain the low resistance circulation that was in parallel with the normal circulation. The feeding artery pressure increases towards the systemic arterial pressure, and the pulsatility also increases (27,40) (Figs. 1 and 2). Because the radii of arteries feeding the AVM do not immediately return to normal after AVM ablation, the resistance to flow within these arteries will be lower than normal (as predicted by the Poiseuille equation, Table 1). The arterial pressure drop-off normally seen along the vessels before the arteriolar level will be reduced, and thus the pressure that occurs in these arteries after ablation of the fistula will be higher. This pressure can be expected to be greater than normal and may nearly approximate that of the extracranial carotid artery (Fig. 1). The Poiseuille equation predicts that if the radius is increased, as it is in the feeding artery, the pressure gradient must be reduced in order to supply the brain with the same blood flow as before AVM ablation (Fig. 1). In addition, the larger than normal diameter redundant feeding artery system, with its normal downstream microcirculation, will generate a larger reflected wave than a normal diameter vessel, resulting in a greater than normal pulsatility and hence even higher peak pressures within the cardiac cycle (122). This increase in pressure and pulsatility (above normal for the equivalent vessel in this location in a normal brain) may challenge the integrity of the arterial wall, particularly at sites of aneurysmal weakness, or of distal branches of the feeding artery that may have been extremely thin walled due to the chronic local hypotension. These vessels are modeled to the previous requirement for high flow to and from the AVM and, depending on the radius and the relevant requirement for run off, will have the propensity to develop stagnation and thrombosis (38). Thrombosis may develop either in arteries or in veins prone to stagnation, and veins in particular may be prone to delayed propagated thrombosis with their high incidence of stenotic lesions (see above). Propagated venous thrombosis of the major draining system is responsible for clinical deterioration in 1% to 3% of operated cases (11,123). After resection of an AVM, there is a high incidence of vasospasm despite a low volume of subarachnoid hemorrhage associated with those AVMs requiring extensive basal dissection (123,124). This occurrence suggests an increase in the vasoreactivity of these vessels. The mechanism may be that the increase in the pressure within the arteries (from low to normal) leads to an increase in contractile tone which, coupled with the normal predisposing factors of subarachnoid hemorrhage, produces an increased likelihood for the development of vasospasm. HEMODYNAMIC EFFECT ON THE BRAIN AT THE TIME OF AVM ABLATION Few topics in neurosurgery are as controversial as the hemodynamic consequences of AVM ablation. The three major questions are: Does the microcirculation of brain surrounding the AVM react to the restoration of normal arterial and venous pressures similarly to that of remote brain? If there are major physiological abnormalities, are they sufficient to produce a clinical problem? Are there additional pathophysiological insults to the microcirculation? After AVM resection, CBF may increase in the brain adjacent to the AVM (27,74,77,85, 120,125,126). Significant error may be present in the numerical value for the post-surgical increase in CBF depending on the methodology used (e.g., stagnant arteries and veins may allow diffusion of isotope into these ‘‘reservoirs’’ without this being correlated with blood flow). Thus, caution must be exercised in considering post-resection blood flow that may be returning from ischemic values as representing hyperemia. However, evidence in support of the likelihood of hyperemia in some cases arises from other clinical states of reversal of cerebral ischemia that produce hyperemia, such as after carotid endarterectomy (127–129) and large caliber vein bypass grafting (130). The common underlying mechanism is the sudden reversal of non-infarctional cerebral hypoperfusion. This mechanism is supported experimentally in cerebral hyperperfusion caused by arteriovenous fistula ablation where CBF was reduced by 25% to 50% of normal prior to ligation of the fistula (86,87,89). The mechanism for hyperemia after AVM resection has been ascribed to a loss of autoregulation (10), a resetting of the upper limit of autoregulation downward (131), and a neuropeptide-mediated disturbance (132). The resetting of the upper limit of autoregulation

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to a lower blood pressure is an attractive hypothesis as there is a precedent for this possibility in other physiological states with chronic alteration in cerebral perfusion pressure (133–135). It is argued that in these states, vasodilation of the larger caliber cerebral resistance vessels will induce a shift to the left of the upper and lower limits of autoregulation (136). Such chronic dilatation is certainly a feature of AVM feeding vessels. To assess pressure autoregulation after AVM resection, Young et al. performed intraoperative studies. They found that blood flow was the same after elevation of blood pressure to 20 mmHg (137). However, regional CBF was measured more than 5 cm from the nidus, and the PaCO2 was at 24 mmHg. The presence of hypocapnia confounds the effect of blood pressure on autoregulation (138). The fact that autoregulation is intact and shifted to the left is supported in animal models of arteriovenous fistula (89,120). Hyperemia alone may be insufficient to account for hemorrhage or edema. Many patients having an AVM excision with CBF monitoring have hyperemia without development of hemorrhage and edema (27,125,126). Furthermore, much higher CBF levels and more dramatic changes in CBF occur during seizures, a condition not characterized by brain swelling and hemorrhage (139–141). In summary, the evidence suggests that at least some cases of AVM excision are associated with hyperemia. This hyperemia is due to a restoration of normal pressure (in fact, this pressure may be greater than normal and may approach the more proximal systemic arterial pressure) within the feeding arterial system now perfusing brain where the autoregulation curve has been shifted to the left and its upper limit has been exceeded. However, hyperemia alone cannot account for the pathological processes variously termed ‘‘normal perfusion pressure breakthrough’’(10), ‘‘congestive apoplexy’’(9), ‘‘overload’’(64), or ‘‘vasogenic turgescence of the brain’’(142). Hyperemia may be an epiphenomenon of the malignant vascular process rather than the basis for the observed complications. ARTERIO-CAPILLARY-VENOUS HYPERTENSIVE SYNDROMES Many reported cases of postoperative hemorrhage or edema are thought to represent examples of ‘‘normal perfusion pressure breakthrough’’ (NPPB) (10,26,64,77,84,85,95,105,123,124,142–154). A similar phenomenon has been reported to complicate a sudden restoration of perfusion pressure to the brain after treatment of carotid and vertebral fistulae (155), carotid endarterectomy for high grade stenosis (127), and revascularization of the brain with large caliber bypass (130). The underlying mechanism remains in question. Spetzler et al. described three patients who developed brain swelling (two cases) or hemiplegia (one case) after surgery (one surgery being feeder ligation) as well as an experimental study of five cats with a carotid jugular fistula that developed a loss of both autoregulation and PaCO2 response after fistula ligation (10). The authors concluded that ‘‘the autoregulatory control, wherever it is located, possibly at the arteriolar level, having been chronically dilated, cannot sufficiently increase the resistance to the new perfusion pressure to protect the capillary, which leads to breakthrough with resultant edema or hemorrhage’’ (10). Central to this ‘‘NPPB’’ hypothesis is the loss of autoregulation and vascular damage at the level of the capillary. With evidence that autoregulation may be intact (although with curve shift to the left) (see above) and the concern that the hyperemia may be an epiphenomenon rather than a central process in the vascular destruction, some have questioned the existence of this syndrome as it stands (11,77,84,85). Indeed, several neurosurgeons with large operative series have argued strongly against the existence of NPPB (7,156,157). In addition, ‘‘normal’’ pressure is a misnomer, as both the mean pressure and the pulse pressure are greater than what they would have been had the AVM never existed (see above), even while the feeding system remains abnormally dilated. Alternate explanations that may appear to be clinically similar to those cases ascribed to have NPPB include proximal feeder vessel rupture and propagated venous occlusive syndromes. Both have as their underlying common pathophysiological perturbation a local intravascular pressure rise (Fig. 2) (11,123). This is the same underlying process that is alleged to occur in NPPB (i.e., intravascular—in this case capillary–hypertension), and a unifying pathophysiological label for each of these processes is ‘‘arterio-capillary-venous hypertensive syndrome’’ (123). The central role of hypertension in one region or another of the vasculature is the critical determinant for the genesis of these complications of AVM resection. Furthermore,

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the original site leading to intravascular hypertension can often be difficult to distinguish and may in fact be multifactorial. An example of arterio-capillary-hypertensive syndrome is when edema complicates resection of an AVM with large variceal draining veins. It is expected that a varix may thrombose after surgery, but in the presence of edema it is tempting to attribute the edema to the thrombosis rather than to it being a coincidental association. However, there can be no debate on the presence of intravascular hypertension, or on whether or not the venous thrombosis caused the edema. In addition to the intravascular hypertension contributing to a failure of the integrity of vascular wall and capillary function, a lowering of the threshold for such injury may not only be present in the thin-walled precapillary vessels but also in the capillary wall itself. In experimental models of arteriovenous fistula where chronic non-infarctional ischemia is produced, many capillaries can be identified to have no astrocytic foot processes (158). If this is the case in humans with AVM, it may suggest that either the blood-brain-barrier function or the wall integrity may be more easily breached than is the case in normal brain. The time course for resolution of the propensity to develop the ‘‘arterio-capillary-venous hypertensive syndrome’’ must depend on the time course in the normalization of vessel caliber and integrity. Therefore, AVM size, shunt flow, the degree of feeder and venous dilatation, and local intravascular pressure contribute to the time course. In a series of delayed deficits, no patient developed complications related to ‘‘arterio-capillary-venous hypertensive syndrome’’ more than eight days after surgery (123). It is likely that resolution of the risk for this complication has occurred in the majority of AVM patients during the first week to ten days after surgery.

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The association of arteriovenous angioma and saccular aneurysm of the arteries of the brain. J Pathol Bacteriol 1959; 77:101–110. 58. Batjer H, Suss RA, Samson D. Intracranial arteriovenous malformations associated with aneurysms. Neurosurgery 1986; 18:29–35. 59. Brown RD Jr., Wiebers DO, Forbes SG. Unruptured intracranial aneurysms and arteriovenous malformations: frequency of intracranial hemorrhage and relationship of lesions. J Neurosurg 1990; 73:859–863. 60. Okamoto S, Handa H, Hashimoto N. Location of intracranial aneurysms associated with cerebral AVM: statistical analysis. Surg Neurol 1984; 22:335–340. 61. Ferguson GG. Physical factors in the initiation, growth and rupture of human intracranial saccular aneurysms. J Neurosurg 1972; 37:666–677. 62. Ferguson GG. Turbulence in human intracranial saccular aneurysms. J Neurosurg 1970; 33:435–497. 63. Stehbens WE. Etiology of intracranial berry aneurysms. J Neurosurg 1981; 70:823–831. 64. Drake CG. Considerations for and experience with surgical treatment in 166 cases. Clin Neurosurg 1979; 26:145–206. 65. Turjman F, Massoud TF, Vinuela F, Sayre JW, Guglielmi G, Duckwiler G. Correlation of the angioarchitectural features of cerebral arteriovenous malformations with clinical presentation of hemorrhage. Neurosurgery 1995; 37:856–862. 66. 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; 76:918–923. 67. Kader A, Young WL, Pile-Spellman J, et al. The influence of hemodynamic and anatomic factors on hemorrhage from cerebral arteriovenous malformations. Neurosurgery 1994; 34:801–808. 68. Duong DH, Young WL, Vang MC, et al. Feeding artery pressure and venous drainage pattern are primary determinants of hemorrhage from cerebral arteriovenous malformations. Stroke 1998; 29: 1167–1176. 69. Murayama Y, Usami S, Hata Y, et al. Transvenous hemodynamic assessment of arteriovenous malformations and fistulas. Preliminary clinical experience in Doppler guidewire monitoring embolotherapy. Stroke 1996; 27:1358–1364. 70. Vinuela F, Nombela L, Roach MR, Fox AJ. Pelz DM: Stenotic and occlusive disease of the venous drainage system of deep brain AVMs. J Neurosurg 1985; 63:180–184. 71. Dobbelaere P, Jomin M, Clarrisse J, Laine E. Interet pronostique de letude du drainage verneux de aneurysms arterio-veneux cerebraux. Neurochirugie 1979; 25:178–184. 72. Marks MP, Lane B, Steinberg GK, et al. Hemorrhage in intracerebral arteriovenous malformations: angiographic determinants. Radiology 1990; 176:807–813. 73. Miyasaka Y, Yada K, Ohwada T, Kitahara T, Kurata A, Irikura K. An analysis of the venous drainage system as a factor in hemorrhage from arteriovenous malformations. J Neurosurg 1992; 76:239–243. 74. Okabe T, Meyer JS, Okayasu H, et al. Xenon-enhanced CT CBF measurement in cerebral AVMs before and after excision. J Neurosurg 1983; 59:21–31. 75. Tyler JL, Leblanc R, Meyer E, et al. Hemodynamic and metabolic effects of cerebral arteriovenous malformations studied by positron emission tomography. Stroke 1989; 20:890–898. 76. Homan RW, Devous MD Sr, Stokely EM, Bonte FJ. Quantification of intracerebral steal in patients with arteriovenous malformation. Arch Neurol 1986; 43:779–785. 77. Batjer HH, Devous MD Sr, Meyer, YJ, Purdy PD, Samson DS. Cerebrovascular hemodynamics in arteriovenous malformation complicated by normal perfusion pressure breakthrough. Neurosurgery 1988; 22:503–509. 78. 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 acetazolamideenhanced single-photon emission CT study. AJNR 1995; 16:1865–1874. 79. Spetzler RF, Martin NA, Carter LP, Flom RA, Raudzens PA, Wilkinson E. Surgical management of large AVMs by staged embolization and operative excision. 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81. Marks MP, O’Donahue J, Fabricant JI, et al. Cerebral blood flow evaluation of arteriovenous malformations with stable xenon CT. AJNR 1988; 9:1169–1175. 82. Jinkins JR. Encephalopathic cerebrovascular steal: dynamic CT of arteriovenous malformations. Neuroradiology 1988; 30:201–210. 83. Takeuchi S, Kikuchi H, Karasawa J, et al. Cerebral hemodynamics in arteriovenous malformations: evaluation by single-photon emission CT. AJNR 1987; 8:193–197. 84. Batjer HH, Devous MD. The use of acetazolamide-enhanced regional blood flow measurement to predict risk to arteriovenous malformation patients. Neurosurgery 1992; 31:213–217. 85. 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. Neurosurgery 1996; 38:1085–1095. 86. Morgan MK, Anderson RB, Sundt TM Jr. A model of the pathophysiology of cerebral arteriovenous malformations by a carotid-jugular fistula in the rat. Brain Research 1989; 496:241–250. 87. Morgan MK, Anderson RE, Sundt TM Jr. The effects of hyperventilation on cerebral blood flow in the rat with an open and closed carotid-jugular fistula. Neurosurgery 1989; 25:606–612. 88. Morgan MK, Sundt TM Jr., Anderson RE, Weber N. The hemodynamic consequences of a carotidjugular fistula in the rat during hypocapnia. J Clin Neurosci 1994; 1:193–196. 89. Irikura K, Morii S, Miyasaka Y, Yamada M, Tokiwa K, Yada K. Impaired autoregulation in an experimental model of chronic cerebral hypoperfusion in rats. Stroke 1996; 27:1399–1404. 90. Kusske JA, Kelly WA. Embolization and reduction of the ‘‘steal’’ syndrome in cerebral arteriovenous malformations. J Neurosurg 1974; 40:313–321. 91. Albert P. Personal experience in the treatment of 178 cases of arteriovenous malformations of the brain. Acta Neurochirurgia 1982; 61:207–226. 92. Girvin JP, Fox AJ, Vinuela F, Drake CG. Intraoperative embolization of cerebral arteriovenous malformations in the awake patient. Clin Neurosurg 1984; 31:188–247. 93. Davis CH, Symon L. The management of cerebral arteriovenous malformations. Acta Neurochirurgia 1985; 74:4–11. 94. Fox AJ, Girvin JP, Vinueia F, Drake CG. Rolandic arteriovenous malformations: Improvement in limb function by IBC embolization. AJNR 1985; 6:572–582. 95. Morgan MK, Johnston I. Intracranial arteriovenous malformations: an 11 year experience. Med J Aust 1988; 148:65–68. 96. Batjer HH, Devous MD Sr., Seibert GB, et al. Intracranial arteriovenous malformation: relationships between clinical and radiographic factors and ipsilateral steal severity. Neurosurgery 1988; 23: 322–328. 97. Hughes JT, Oppenheimer DR. Superficial siderosis of the central nervous system. A report on nine cases with autopsy. Acta Neuropath (Berlin) 1969; 13:56–74. 98. Leblanc R, Feindel W, Ethier R. Epilepsy from cerebral arteriovenous malformations. Can J Neurol Sci 1983; 10:91–95. 99. Azar-Kia, Palacios E, Danley R. Bone erosion associated with intracranial arteriovenous malformations. Illinois Med J 1977; 152:116–119. 100. Dandy WE. Concerning the cause of trigeminal neuralgia. Am J Surg 1934; 24:447–455. 101. Gardner WJ. The mechanism of tic doleureux. Trans Am Neurol Assoc 1953; 78:168–173. 102. Jannetta PJ. Observation on the etiology of trigeminal neuralgia. Definitive microsurgical treatment and results in 117 patients. Neurochir 1977; 20:145–154. 103. Weisberg LA, Pierce JF, Jabbari B. Intracranial hypertension resulting from cerebrovascular malformation. South Med J 1977; 70:624–626. 104. Vassilouthis J. Cerebral arteriovenous malformation with intracranial hypertension. Surg Neurol 1979; 11:402–404. 105. Barrow DL. Unruptured cerebral arteriovenous malformations presenting with intracranial hypertension. Neurosurgery 1980; 23:484–490. 106. Obrader S, Sato M, Silvela J. Clinical syndromes of arteriovenous malformations of the transversesigmoid sinus. J Neurol Neurosurg Psychiatry 1975; 38:436–451. 107. Houser OW, Campbell JK, Campbell RJ, Sundt TM Jr. Arteriovenous malformation affecting the transverse venous sinus—an acquired lesion. Mayo Clin Proc 1979; 54:651–661. 108. Lasjaunias P, Chiu M, TerBrugge K, Tolia A, Hurth M, Bernstein M. Neurologic manifestations of intracranial dural arteriovenous malformations. J Neurosurg 1986; 64:724–730. 109. Aminoff MJ, Barnard RO, Logue V. The pathophysiology of spinal vascular malformations. J Neurol Sci 1974; 23:255–263. 110. Logue V. Angiomas of the spinal cord: review of the pathogenesis, clinical features, and results of surgery. J Neurol Neurosurg Psychiat 1974; 42:1–11. 111. Symon L, Kuyama H, Kendall B. Dural arteriovenous malformation of the spine. J Neurosurg 1984; 60:238–247. 112. Yasargil MG, Syrnon L, Teddy PJ. Arteriovenous malformation of the spinal cord. In: Symon L, ed. Advances and Technical Standards in Neurosurgery (Wien). Vol II. Springer, 1984:61–198. 113. Oldfield EH, Di Chiro G, Quidlen EA, et al. Successful treatment of a group of spinal cord arteriovenous malformations by interruption of dural fistula. J Neurosurg 1983; 59:1019–1030.

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Bethesda, Maryland: American Physiological Society, 1983:137–182. 120. Rosen DM. Cerebral arteriovenous malformations: Cerebrovascular hemodynamics, collateral circulation, nitric oxide and hyperperfusion syndrome. Thesis submitted for PhD, The University of Sydney, 1997. 121. Jacobson E. Mechanics of CSF circulation. Thesis submitted for PhD, The University of Sydney, 1998. 122. Nichols WW, O’Rourke MF. McDonald’s Blood Flow in Arteries. Theoretic, Experimental and Clinical Principles, 3rd ed, London, Edward Arnold, 1990:254. 123. Morgan MK, Sekhon LHS, Finfer S, Grinnell V. Delayed neurological deterioration following resection of arteriovenous malformations of the brain. J Neurosurg 1999; 90:695–701. 124. Morgan MK, Day MJ, Little N, Grinnell V, Sorby W: The use of intra-arterial papaverine in the management of vasospasm complicating the resection of arteriovenous malformations of the brain: a report of two cases. J Neurosurg 1995; 82:296–299. 125. Young WL, Prohovnik I, Omstein E, et al. Monitoring of intraoperative cerebral hemodynamics before and after arteriovenous malformation resection. Anesth Analg 1988; 67:1011–1014. 126. Rosenblum BR, Bonner RF, Oldfield EH. Intraoperative measurement of cortical blood flow adjacent to cerebral AVM using laser Doppler velocimetry. J Neurosurg 1987; 66:396–399. 127. Piepgras DG, Morgan MK, Sundt TM Jr., Yanagihara T, Mussman LM. Intracerebral hemorrhage after carotid endarterectomy. J Neurosurg 1988; 68:532–536. 128. Schroeder T, Sillesen H, Sorensen O, Engell HC. Cerebral hyperperfusion following carotid endarterectomy. J Neurosurg 1987; 66:824–829. 129. Powers AD, Smith RR. Hyperperfusion syndrome after carotid endarterectomy: A transcranial Doppler evaluation. Neurosurgery 1990; 26:56–60. 130. Sundt TM Jr., Piepgras DG, Marsh WR, Fode NC. Bypass vein grafts for giant aneurysms and severe intracranial occlusive disease in the anterior and posterior circulation. In: Sundt TM Jr, ed. Occlusive Cerebrovascular Disease. Diagnosis and Surgical Management. Philadelphia: WB Saunders, 1987: 439–464. 131. Spetzler RF, Hamilton MG. Pressure autoregulation is intact after arteriovenous malformation resection. Neurosurgery 1993; 33:772–773. 132. Macfarlane R, Moskowitz MA, Sakas DE, Tasdemiroglu E, Wei EP, Kontos HA. The role of neuroeffector mechanisms in cerebral hyperperfusion syndromes. J Neurosurg 1991; 75:845–855. 133. Folkow B, Halba¨ck M, Lundgren Y, Silverston Y, Weiss L. Importance of adaptive changes in vascular design for establishment of primary hypertension, studied in man and in spontaneously hypertensive rats. Circ Res 1973; 32/33(suppl 11):l12–116. 134. Bill A, Linder J. Sympathetic control of cerebral blood flow in acute arterial hypertension. Acta Physiol Scan 1976; 96:114–121. 135. Barry Dl, Jarden JO, Paulson OB, Gaharn DL, Strandgaard S. Cerebrovascular effects of converting enzyme inhibition. Effects of intravenous captopril in spontaneously hypertensive and normotensive rats. J Hypertension 1984; 2:589–597. 136. Postiglione A, Bobkiewicz T, Vinholdt-Pedersen E, Lassen NA, Paulson OB, Barry DL. Cerebrovascular effects of angiotensin converting enzyme inhibition involving large artery dilatation in rats. Stroke 1991; 22:1363–1368. 137. Young WL, Kader, A, Prohovnik I, et al. Pressure autoregulation is intact after arteriovenous malformation resection. Neurosurgery 1993; 32:491–497. 138. Paulson OB, Strandgaard S, Edvinsson L. Cerebral autoregulation. Cerebrovasc Brain Metab Rev 1990; 2:167–192. 139. Nilsson B, Rehncrona S, Siesjo¨ BK. Coupling of cerebral metabolism and blood flow in epileptic seizures, hypoxia and hypoglycaemia. Ciba Found Symp 1978; 56:199–218. 140. Tenny RT, Sharbrough FW, Anderson RE, Sundt TM Jr. Correlation of intracellular redox states and pH. Ann Neurol 1980; 8:564–573. 141. Nitsch C, Suzuki R, Fujiwara K, Klatzo I. Incongruence of regional cerebral blood flow increase and blood-brain barrier opening in rabbits at the onset of seizures induced by bicuculline, methoxypyridoxine, and kainic acid. J Neurol Sci 1985; 67:67–79. 142. Pertuiset B, Sichez JP, Philippon J, Fohanno D, Horn YE. Mortality and morbidity following the surgical excision of 162 intracraniai arteriovenous malformations (1958–1978). Rev Neurol 1979; 35:319–327.

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143. Mullan S, Brown FD, Patronas MJ. Hyperemic and ischemic problems of surgical treatment of arteriovenous maiformations. J Neurosurg 1979; 51:757–764. 144. Day AL, Friedman WA, Sypert GW, Mickle P. Successful treatment of the normal perfusion pressure breakthrough syndrome. Neurosurgery 1982; 11:625–630. 145. Luessenhop AJ, Ferraz FM, Rosa L. Estimate of the incidence and importance of circulatory breakthrough in the surgery of cerebral arteriovenous malformations. Neural Res 1982; 4:177–190. 146. Solomon RA, Michelsen WJ. Defective cerebrovascular autoregulation in regions proximal to arteriovenous malformation of the brain. A case report and topic review. Neurosurgery 1984; 14:78–82. 147. Bonnal J, Born JD, Hans P. One-stage excision of high-flow arteriovenous malformations. J Neurosurg 1985; 62:128–131. 148. Aoki N, Mizutani H. Arteriovenous malformation in the territory of the occluded middle cerebral artery with massive intraoperative brain swelling. Case report. Neurosurgery 1985; 16:660–662. 149. Yamada K, Hayakawa T, Yashimine T, Nakao K, Ushio Y, Mogami H. Surgery of high-flow arteriovenous malformation with special reference to normal perfusion pressure breakthrough phenomenon. No Shinkei Geka 1986; 14:741–748. 150. U HS. Microsurgical excision of paraventricular arteriovenous malformations. Neurosurgery 1985; 16:293–303. 151. Morgan MK, Johnston IH, Sundt TM Jr. Normal perfusion pressure breakthrough complicating surgery for the vein of Galen malformation. Report of three cases. Neurosurgery 1989; 24:406–410. 152. Morgan MK, Sundt TM Jr., Houser OW. Arterio-inferior sagittal sinus fistula. Case report. Neurosurgery 1989; 25:971–975. 153. Morgan MK, Sundt TM Jr. The case against staged operative resection of cerebral arteriovenous malformations. Neurosurgery 1989; 25:429–432. 154. Morgan MK, Johnston IH, Hallinan JM, Weber N. Complications of surgery for arteriovenous malformations of the brain. J Neurosurg 1993; 78:176–182. 155. Halbach VV, Higashida RT, Hieshima GB, Norman D. Normal perfusion pressure breakthrough occurring during treatment of carotid and vertebral fistulas. AJNR 1987; 8:751–756. 156. Parkinson D. Staged treatment of arteriovenous malformations. J Neurosurg 1988; 68:658–659. 157. Yasargil MG, Curcic M, Kis M, Teddy PJ, Valavanis A. Microneurosurgery. Volume III B. New York, Thieme Medical Publishers, 1988. 158. Sekhon LHS, Morgan MK, Spence I, Weber NC. Normal perfusion pressure breakthrough: The role of capillaries. J Neurosurgery 1997; 86:519–524.

4

Use of Modeling for the Study of Cerebral Arteriovenous Malformations William L. Young Departments of Anesthesia and Perioperative Care, Neurological Surgery, and Neurology, UCSF Center for Cerebrovascular Research, University of California, San Francisco, California, U.S.A.

Erzhen Gao Supertron Technologies Inc., Newark, New Jersey, U.S.A.

George J. Hademenos Science Department, Richardson High School, Richardson, Texas, U.S.A.

Tarik F. Massoud University Department of Radiology, University of Cambridge School of Clinical Medicine, Cambridge, U.K.

INTRODUCTION A model may be defined as a computational or physical construct that has some functional equivalence to a real system. Hypothetical essential properties of the real original system are represented, while the potentially confounding irrelevancies are ignored (1). Models may be useful in the understanding of relationships between cause and effect in a complex physiological or pathological process. Their great strength is a flexibility that is not possible with an intact system. Their great weakness is that they are critically dependent on the assumptions made in their construction. The critical importance of these two considerations must always be kept in clear perspective when attempting to construct a model of a biologic process (2). The general principles and philosophical premises of modeling in biomedical research have been reviewed in detail (2). Models can generally be used as a framework within which clinical phenomena may be better understood (2,3). Modeling results are generally not intended to be extrapolated immediately to single-patient management. Rather, they are to be used to better define issues and frame hypotheses for further experimental work. Models can narrow the field between a large number of potential avenues for designing experimental investigations, but successful modeling requires critical evaluation of results by comparison with experimental data (4). For the circulatory system, computational models might be termed an instrumentalist approach to describing vascular and circulatory behavior. Such an instrumental approach can be viewed merely as a mathematical tool for deducing one set of variables from another (5). Pioneered by physiologists such as Guyton (6), modeling has been used as a research technique at all levels of the cardiovascular system, from total system to capillary dynamics (7–17). In the neurosciences, efforts have been aimed at the level of neural systems (1) and in the study of the cerebrovasculature. For example, control mechanisms of cerebral blood flow (18–22) and the mechanical properties of cerebral aneurysms (23–26) have been studied. The primary focus of this chapter is computational models. However, mechanical and animal models have been described in the study of arteriovenous malformations (AVMs), and brief discussions or appropriate references are included. IMPORTANCE OF MODELING FOR AVMs Cerebral AVMs have long been regarded as a demanding clinical and experimental challenge. They are considered to be complex entities due to their anatomical and morphological heterogeneity, their hemodynamic and pathophysiological effects, and their unpredictable clinical

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natural history. This complexity is further compounded by their unknown etiology and pathogenesis. Of the three main compartments of an AVM (feeders, nidus, draining veins), the central core or nidus is the least accessible to study because at present (a) it is usually impossible to catheterize its plexiform microvessels (to gain intranidal hemodynamic information) due to their small size (average 250 mm) (27) and fragile nature, and (b) their small caliber precludes adequate spatial resolution (for intranidal morphological characterization) using current tomographic imaging modalities (magnetic resonance imaging, MRI). Therefore, the nidus of an AVM represents both an inaccessible ‘‘black box’’ and a system of considerable complexity with respect to its morphology and hemodynamics. The interaction of intranidal and surrounding extranidal environment yields a vascular bed that is highly susceptible to spontaneous rupture and hemorrhage. Under these circumstances, experimental model construction of cerebral AVMs provides a useful set of analytical tools for indirect investigatation (28) and can increase knowledge of vascular pathology that is otherwise not amenable to study by direct means (29–35). SPECIFIC MODELING ATTEMPTS–MODEL CONSTRUCTION Initial attempts at biomathematical models have simulated hemodynamics in AVMs using elementary feeding and draining pedicle anatomy and a nidus composed typically of a single or multiple array of parallel, compartmentalized vessels. A general review of published AVM models is shown in Table 1 (28–37). For example, the AVM model introduced by Lo et al. consisted of three linked compartments representing arterial feeders, shunting arterioles, and the core vessels of the AVM with flow draining into the central venous drainage (34,35,38). These investigators simulated hemodynamics within small and large AVMs and obtained results comparable to those clinically observed, but they neglected the appearance of draining veins. Hecht et al. expanded upon this concept with simulations in an AVM nidus composed of 1,000 nidus vessel compartments (37). Ornstein et al. introduced a more complex AVM model by considering the influence of inductance, conductance, and autoregulation (29). Extranidal Model As described in detail in the following sections, our group has expanded on these initial models (Fig. 1). To simulate the arteriolar resistance beds and brain tissue, Gao et al. (31) introduced ‘‘microvessel groups’’ (MVGs) as special compartments. The model contains 20 MVGs, each of them consisting of 5,000 parallel small vessels 0.1 mm in diameter. As shown in Figure 1, six of the 20 MVGs are perfused by the anterior cerebral artery (ACA), ten are perfused by the middle cerebral artery (MCA), and four are perfused by the posterior cerebral artery (PCA). They are symmetrically distributed in left and right hemispheres. Assuming a brain weight of 1500 g, each MVG represents a brain tissue weight of 75 g. The MVG also incorporates autoregulatory function into the normal (non-AVM) vasculature. Our model improves on all previous models in the following respects. In previous models, the AVMs were fed by a single arterial feeder with either a single or no draining vein. Our model consists of the major conductance arteries supplying the intracranial circulation, most major intracranial arteries and veins, and their major branches. This model is much more useful to simulate clinical observation and treatment of an AVM. For example, with our model, the effects of changing extranidal circulation (systemic hypertension or hypotension, or occlusion of normal vessels) on the AVM, the complex feeder and drainage configuration, and the effects of the AVM on different parts of the cerebral circulation can be simulated. Furthermore, the model uses an AVM with an intranidal structure, including plexiform and fistulous vessels, to study the effects of changing extranidal circulation patterns on different parts or compartments of an AVM. Results can be compared to previously reported experimental observations for normal circulatory parameters as well as pressure changes induced by high flow through an AVM shunt (39) (Fig. 2). There was good agreement between experimental observations (40) and modeled predictions. UCLA Intranidal Model A detailed analysis of intranidal hemodynamics has been offered by Hademenos, Massoud and colleagues to model the risk of AVM rupture (30,41,42).

No No

No No Yes No No No No No No

Elastic modulus

Pulsatile flow

Autoregulation

Pressure distribution

Velocity distribution

Shear stress

Vessel dilation

Consideration of vessel branching exponents Cerebral blood volume No

No

No

Yes

No

No

No

No

Yes

16 for normal structure

44

30

34,35 150 (105)

36

Yes Yes

No

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

ACA þ MCA þ PCA þ circle Same as left þ of Willis þ microvessels AVM nidus þ veins (bilateral) Yes Yes

No

No

No

No

No

No

No

No

Simple

121 (105)

31

Reference Numbers of Study

3 (62)

Abbreviations: ACA, anterior cerebral artery; MCA, middle cerebral artery; PCA, posterior cerebral artery.

No

No

No

No

Yes

Yes

Yes

Simple

Simple

Model structure

4

4

29

Number of compartments (vessels)

32,33

Table 1 Comparison of Published Models of Cerebral Arteriovenous Malformations

No

No

No

No

No

No

No

No

Intracranial þ extracranial þ AVM nidus No

139

28

No

No

No

No

No

No

No

No

No

Simple

3 (1002)

37

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Figure 1 Schematic diagram of the model of intracranial blood vessel network. A thick line represents a compartment that contains a number of identical vessels in parallel with each other. The numbers indicate the nodes. Between the arteries and the veins are 20 microvessel groups (MVGs), each of which consists of 5,000 microvessels. A thin line between an MVG and a vein does not represent a compartment but indicates a connection between these two compartments. A middle cerebral artery (MCA) arteriovenous malformation (AVM) used in several of the simulations is also shown. It connects nodes 90 and 91. Source: From Ref. 31.

By using electrical analogies, the circulatory network can be represented by an electrical circuit of connected wires with variable resistance through which current or flow, powered by an electrical voltage source or pressure gradient, traverses. The equivalent relationship between the parameters of electrical circuit and the hemodynamics are (a) current vs. flow and (b) voltage vs. pressure. Each wire or vessel represents a connection between nodes or location where flow converges or diverges. With respect to intranidal modeling of a cerebral AVM and its surrounding circulation, a node resembles the start or end of a vascular branch, e.g., a bifurcation or trifurcation.

Figure 2 Pressure ratios in zones E, I, T, H, F, and Hc compared with clinical observations. The predicted values of our model for the medium AVM are close to the mean values of the experimental observations of Fogarty-Mack et al. (78). E ¼ Extracranial: systemic pressure at level of coaxial catheter in extracranial vertebral artery or internal carotid artery; in this model, node 7. I ¼ Intracranial: supraclinoid internal carotid artery or basilar artery; in this model, node 11. T ¼ Transcranial Doppler insonation site: Al, Ml, or PI; in this model, node 23. H ¼ Halfway: arbitrarily ‘‘halfway’’ between T and the feeding artery; in this model, node 25. F ¼ Feeder; in this model, node 90. Hc ¼ Contralateral distal arterial pressure; in this model, node 26. The node numbers are as used in Fig. 1. E, I, T, H, F and Hc vascular zones taken from Fogarty-Mack et al. (40). Source: From Refs. 31, 40, 78.

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Figure 3 Schematic diagram of the electrical network describing the biomathematical AVM hemodynamic model. Source: From Ref. 42.

Electrical network analysis was used to construct a theoretical AVM intranidal model aimed at providing an accurate rendering of transnidal/intranidal hemodynamics (30). The AVM model was developed with four arterial feeders (AFs), two draining veins (DVs), and a nidus consisting of 28 interconnected plexiform and fistulous vessels, as shown in Figure 3. Parameters for construction of this intranidal model were derived from anatomic and physiological data obtained from published clinical, histopathological, and angiographic observations. There were two kinds of intranidal vessels: plexiform and fistulous. In this intranidal model, the vessel radius of plexiform was half of that of fistulous. The flow through the AVM nidus proceeds from the AF side to the DV side of the intranidal model and was calculated in accordance with two rules: (a) the algebraic sum of the currents at any node must be zero, i.e., flow into a node is equal to flow out of the node, and (b) the algebraic sum of the changes in potential (pressure gradient) encountered in a complete traversal of the circuit (loop) must be zero (30). These rules result in the derivation of nodal and loop equations for the circuit comprising the AVM intranidal model and yield a system of linear equations that can be solved with elementary matrix analysis. The solution yields the flow rate for each vessel in the vascular network. From the flow rate, other hemodynamic parameters, including the flow velocity and intravascular pressure gradient, were calculated. To determine the appropriateness of the hemodynamic and biophysical parameters used in the AVM intranidal model, a separate parameter sensitivity analysis and a qualitative validation study were performed with combinations and permutations of values for parameters used to construct the intranidal model (41). These parameters included systemic mean arterial pressure (SMAP), feeding mean arterial pressure (FMAP), draining vein pressure (DVP), cerebral venous pressure (CVP), and radii and length of plexiform and fistulous vessels. The risk of AVM rapture was based on the functional distribution of the critical radius of a cylindrical nidus vessel normalized to a possible range of clinically observed pressure gradients across the nidus. By using only the minimum and maximum values of each parameter to construct the model, it was found that there were approximately 200 combinations of values that could be used with this AVM intranidal model, each set of parameters providing a realistic representation of a different cerebral AVM. By inputting any set of parameter values from within the minimum to maximum range, it is theoretically possible to construct an infinite variety of AVM intranidal models. The corollary is that it is possible to fit the hemodynamic and structural characteristics of this AVM intranidal model to reflect/replicate those measured from cerebral AVMs in individual patients. For example, volumetric blood flow through one typical

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AVM intranidal model was 814 mL/min. Hemodynamic analysis of this AVM showed the flow rate to vary from 5.5 to 57.0 mL/min through the plexiform vessels and from 595.1 to 640.1 mL/min through the fistulous vessels. The risk of rupture for individual nidus vessels for this particular intranidal model ranged from 4.4% to 91.2%. Combined Intranidal and Extranidal Model The use of both an intranidal and an extranidal/whole brain approach may permit the formation of a more integrative view of AVM hemodynamics. Gao et al. explored the feasibility of using a computational model to simulate the risk of spontaneous AVM hemorrhage (64) combining aspects from previously published work on intranidal and extranidal components (36). Data from 12 patients were collected from a prospective databank that documented the angioarchitecture and morphologic characteristics of the AVM and the FMAP measured during initial superselective angiography before any treatment. By using previously developed intranidal and extranidal models, a new hybrid model was constructed to maximize the advantages of both models. The hybrid model with an AVM is shown in Figure 4A. The intranidal structure is detailed in Figure 4B.

Figure 4 Schematic diagram of the model combining the blood vessel network and the intranidal model. (A) A thick line represents a compartment that contains a number of identical vessels in parallel with each other. The numbers indicate the nodes. Between the arteries and the veins are 20 microvessel groups (MVGs), each of which consists of 5,000 microvessels. A thin line between an MVG and a vein does not represent a compartment but indicates a connection between these two compartments. Source: From Ref. 36. (B) The cerebral arteriovenous malformation intranidal network used in this model.

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Table 2 Geometric and Structural Parameters of the Vessels in Representative Model Compartments Compartment Number [N1 ! N2]

Diameter (mm)

Length (mm)

20 3.5 0.8 2.1 2.9 2.1 4 3.5 20 0.2 0.1

40 100 5 40 40 40 40 60 50 5 5

0 [1 ! 2] 7 [7 ! 9] 13 [13 ! 14] 23 [13 ! 21] 25 [11 ! 23] 31 [19 ! 86] 55 [49 ! 50] 60 [55 ! 49] 112 [0 ! 1] 141 [105 ! 108] 142 [106 ! 108]

Name Aortic arch Internal carotid artery (ICA) Anterior communicating artery (ACoA) Anterior cerebral artery (ACA) Middle cerebral artery (MCA) Posterior cerebral artery (PCA) Superior sagittal sinus Frontal ascending vein Heart Fistulous intranidal vessel Plexiforrn intranidal vessel

Abbreviations: N1, N2, Nodes representing the two ends of the compartment; Name, name of the vessel (or symbol used). Source: From Ref. 36.

The element used to construct the model was a compartment. The geometric parameters of the vessel (or compartment) network of this model, the position of its two ends within the model, are demonstrated by representative compartments in Table 2. The model construction is given in detail in Appendix 1. Intranidal structures were either (a) pure plexiform, (b) mixed plexiform and fistulous, or (c) pure fistulous. MODEL APPLICATIONS Cerebral Hyperemia Gao et al. evaluated the effects of step-wise shunt occlusion at normal cortical sites both near to and distant from the nidus (39). Cerebral blood flow (CBF) values were calculated for normal brain regions after AVM shunt flow obliteration in the absence of autoregulation, which is analogous to ‘‘vasomotor paralysis’’ of the arteriolar bed. There were two main findings. First, there was a very limited regional increase in CBF that was restricted to hypotensive circulatory beds adjacent to the AVM nidus (Fig. 5). Second, the degree of CBF increase was comparable to the hyperemia that is encountered clinically during, for example, CO2 inhalation (Fig. 6) (43). What remains to be explored further is the influence of shifts in the lower and upper limits of autoregulation in the presence of an AVM, thereby extending experimental observations (44,45) and a previously reported simulation (32,33). Increases in Feeding Artery Pressure with Embolization Therapy (Extranidal) Gao et al. used their model to study the magnitude of expected pressure changes along the vascular tree with shunt ablation to assess the hemodynamic risk of AVM treatment (39). They estimated the changes in intravascular pressure, velocity, biomechanical stress, and shear stress that might be expected from either endovascular or surgical ablation of an AVM. Two AVM sizes and two feeding artery constellations were simulated. The effect of different shunt flows on vascular pressure was modeled, and AVMs were occluded in a stepwise fashion. The effects of systemic hypertension and hypotension in the various vascular zones also were simulated. Because of the non-linearity of the arterial pressure increase that occurs with gradual occlusion of the shunt at the feeding artery level, the authors introduced the concept of ‘‘%occlusion at half-maximal pressure.’’ This corresponds to the percent of the AVM flow that must be cut off to increase feeding artery pressure from its baseline pretreatment level to a level midway to the final vascular pressure expected with complete occlusion of shunt flow (Fig. 7) (39). In the Gao et al. simulations, a large (1,000 mL/min) AVM was occluded, and feeding arterial pressure increased from 18 mmHg to 68 mmHg; the %-occlusion at half-maximal pressure increase was 92%. For a medium (500 mL/min) AVM, feeding arterial pressure increased from 37 mmHg to 66 mmHg; the %-occlusion at half-maximal pressure increase was 71%. Shunt obliteration increased pressure in the nidus and feeding arteries, but there was little effect on proximal vascular structures nearer the circle of Willis. During manipulation of the

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Figure 5 Regional cerebral blood flow (CBF) in the presence of a large middle cerebral artery (MCA) arteriovenous malformation (AVM) (located at the right hemisphere) compared with that after complete occlusion of the AVM. In the presence of the AVM, the CBF of ipsilateral fields MCA1, MCA2, and MCA3 decreased from normal values of 50 mL/ 100 g/min to 32, 21, and 26 mL/100 g/min, respectively. In other ipsilateral regions and the contralateral hemisphere, the CBF values were normal. After occlusion, the CBF of ipsilateral MCA1, MCA2, and MCA3 increased to approximately 70 mL/100 g/min due to the absence of autoregulation in these three regions, suggesting a limited potential for severe increases in CBF after shunt occlusion purely on a hemodynamic basis. Source: From Ref. 31.

systemic pressure, there was a "buffering" effect of the AVM fistula such that higher flow fistulas were exposed to smaller variations in intravascular pressure in feeding artery and nidal pressures during manipulation of systemic arterial pressure. Although the model was extensively compared to previously reported experimental observations (31), the paper addressing pressure changes and aneurysms (39) contained only a single case report as a means of verifying the predictions of the model simulations. However, the primary importance of the Gao et al. study was to generate a framework for interpretation

Figure 6 Illustration of the mean increase in cerebral blood flow after arteriovenous malformation obliteration in the various simulations of near-field regions with and without autoregulation. Source: From Ref. 31.

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Figure 7 Mean arterial feeding pressure (PF) changes during occlusion of two arteriovenous malformations (AVMs) fed by the anterior cerebral artery (ACA) and middle cerebral artery (MCA). (A) Mean systemic pressure was 80 mmHg. The simulations were carried out by a stepwise occlusion of the AVM from the initial blood flows of 1000 mL/min and 500 mL/min, respectively. The concept of ‘‘%-occlusion at half-maximal pressure increase’’ is also illustrated. As the 1000 mL/min AVM was occluded, PF increased from 18 mmHg to 68 mmHg, and increased by half of the maximal pressure increase at 92% occlusion (indicated by dashed lines). As the 500 mL/min AVM was occluded, PF increased from 37 mmHg to 66 mmHg, and increased by half of the maximal pressure increase at 71% occlusion (indicated by dotted lines). The observed changes in feeding artery pressure in the case report were similar to those that would be predicted for a shunt flow midway between the medium and large AVM model and are indicated in (A). (B) The two predicted curves are also shown for the arterial zone T (PT); there were no data from the case report available for this level of the circulation. Source: From Ref. 39.

of clinical phenomena and to generate further hypotheses. A model is most useful when it can predict values that are either difficult or impossible to measure clinically. Estimation of Hemorrhagic Risk (Intranidal) Intranidal modeling is somewhat hampered by the lack of precise details of intranidal threedimensional architecture. There have been two approaches, which are discussed below. Hademenos and Massoud investigated the theoretical hemodynamic consequences of venous drainage impairment on the risk of AVM rupture (42). Progressively greater stages of obstruction were simulated in the DVs. It was found that the risk reached 100% (i.e., rupture occurred) with a > 86% obstruction of DV1 (i.e., the DV fed by the intranidal fistula) and a patent DV2. Rupture was primarily due to the dramatic shift in the hemodynamic burden from the fistulous nidus vessels toward the weaker plexiform vessels. It was concluded that, on theoretical grounds, venous drainage impairment was predictive of AVM nidus rupture and was strongly dependent on AVM morphology (presence of intranidal fistulae and their spatial relationship to DVs) and transnidal hemodynamics. Estimation of AVM Rupture Risk (Combined) Two model risk (Riskmodel) calculations (hemodynamic- and structural-weighted estimates) were performed by using the patient-specific models (36). By using the University of California Los Angeles (UCLA) approach, a variable called Riskmodel was calculated with the simulated intranidal pressures related to its maximal and minimal values. Another variable, termed a structural-weighted estimate, was developed and described. This parameter included the vessel mechanical properties and probability calculation, which were considered in more detail than in the hemodynamic-weighted estimate. Riskmodel was then compared to

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experimentally determined risk, termed Riskexp, which was calculated with a statistical method for determining the relative risk of having initially presented with AVM hemorrhage (46). The Riskmodel calculated by both hemodynamic- and structural-weighted estimates correlated with experimental risks with v2 ¼ 6.0 and 0.64, respectively. The risks of the structural-weighted estimate were more highly correlated with experimental risks. Using two different approaches to the calculation of AVM hemorrhage risk, we found a general agreement with independent statistical estimates of hemorrhagic risk based on patient data. Computational approaches are feasible; future work can focus on specific pathomechanistic questions. Detailed patient-specific computational models can also be developed as an adjunct to individual patient risk-assessment for risk-stratification purposes (see below). A description of the mathematical treatment of the problem is presented in Appendix 2. LONG-TERM OBJECTIVES OF COMPUTATIONAL MODELING Patient-Specific Physiological Simulator A long-term goal is to be able to compile a real-time physiologic bedside model of an individual patient’s hemodynamic properties, analogous to current anatomic computer modeling, to aid in treatment planning. This compilation could be aided by adding detailed 3-D reconstructions of individual patient MR angiography data into the computational model. For example, all imaging and physiologic data could be loaded into a computational model for a given patient, and various manipulations could then be assessed for their hemodynamic consequences, such as vessel occlusion or degree of nidus obliteration. Technology Development It may be possible to use computational models to aid in the development of novel materials for endovascular therapy of cerebrovascular disease, e.g., new embolic materials and glues, or their delivery (47). Theoretical properties of known agents can be tested for optimal design of safety and efficacy studies. Likewise, the development of novel agents or techniques could be facilitated by having functional computational models to identify desired physical or physiological attributes. This applies to both agents and techniques, such as induced hypotension, or their delivery. Parameter Sensitivity Analysis Parameter sensitivity analysis is the investigation of the influence of external variables on the output of a closed system. Given a closed system (the AVM model with parameters that are fixed but can vary), we are interested in using the system to obtain a result (output). In this case, the output is hemodynamic data (flow/pressure), which depend on the fixed parameters of the AVM model. We have proceeded as well to the next step of relating the hemodynamic data to the probability of AVM rupture. Therefore, changing the fixed parameters of the AVM model influences the output or hemodynamic data, which in turn dictates the probability of AVM rupture. Parameter sensitivity analysis looks at all possible variations of parameters of the AVM model to ensure that the output is insensitive to the fixed parameters and hence rupture probability can be more accurately assessed. Real-time Physiologic Response and Mechanisms of CBF Regulation To achieve the long-term objective of compiling a real-time physiologic bedside model, the realtime physiologic response should be included in the model. The real-time responses are usually described by feedback loops that respond to changes in the circulation and influence the continued activity of the system. In our AVM model, three loops are involved for determining the blood flow in a vessel: (a) hemodynamic, (b) arterial pressure CBF autoregulation, and (c) shear stress-induced vasodilation, as shown in the light boxes in Figure 8. The hemodynamic feedback loop, described by physics and hemodynamics laws such as Poiseuille’s formula, is used for all vessels. The arterial pressure CBF autoregulation feedback loop is a descriptive response that determines the CBF in MVGs as a function of the arterial pressure in terms of the observed autoregulation curve or the observed response of cerebral arteries and arterioles to acute hypotension and hypertension. This loop is used for arteries and arterioles (MVG) only.

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Figure 8 Feedback loops (light boxes) in the Gao et al. arteriovenous malformation model. Source: From Ref. 31.

The shear stress-induced vasodilation feedback loop is used to calculate the radius change of normal large vessels due to the additional blood flow to the AVM. This loop is a relatively long-term feedback compared with a real-time physiologic response (31,36). The physiologic responses of the cerebral circulation system describe the mechanisms of CBF regulation. A representative investigation of CBF regulation has been demonstrated by Ursino (48). Unlike our cerebral blood circulation model for AVM study, which has large coverage of cerebral arterial and venous vessels, Ursino’s mathematical model is focused on the mechanisms of CBF regulation, in which the arterial tree is treated as a circulatory system with one blood flow loop. In Ursino’s model, the functional structure of the cerebrovascular bed has been analyzed in detail and the major feedback regulatory mechanisms, which are now assumed to work on the cerebral circulation have been separately examined, as shown in Figure 9. The introduction of the physiologic regulatory mechanisms described in Ursino’s model into our model will enable our model to predict the response of a patient’s cerebral blood circulatory system to designed treatments. Applications of AVM Models to Design of Clinical Trials Risk stratification is a necessary part of the design of clinical trials. Computational modeling can aid in the assessment of risk factors used to stratify treatment or interventional trials. It may be better able to predict which factors are more likely to be associated with an increased risk of hemorrhage, either in the natural course or perhaps even in the course of treatment. It is possible that high-risk patients could be better identified to evaluate treatment options. ANIMAL MODELING For many years, experimental research on cerebral AVMs was hampered by the lack of a suitable laboratory animal model possessing biological behavior and offering ‘‘biovariability’’ traits that are unavailable in mathematical or plastic models. The unavailability of an adequate in vivo AVM model has stemmed partly from the extreme rarity of naturally occurring animal AVMs. To construct an AVM model experimentally, two fundamental AVM characteristics

Figure 9 Block diagram describing the main subsystems involved in cerebral blood flow regulation and their mutual relationships in Ursino’s model. Source: From Ref. 48.

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Table 3 Characteristics of University of California Los Angeles Swine Rete AVM Model Advantages Model is simple to create. Surgery can be mastered relatively quickly. Large neck vessels can be surgically manipulated with ease during formation of a carotid-jugular fistula. Blood coagulation system of swine is similar to that of the human, a significant feature when attempting to model human vascular pathology. Use of swine is appropriate from an economical and ethical point of view. Nidus is composed of a plexus of microarteries of similar caliber to human AVM nidus vessels. Overall size is similar to small human AVMs. Nidus is easily accessible with angiographic catheters via the main arterial feeder and the main draining vein. All components of the AVM (feeders, nidus, drainers) are clearly demonstrable at angiography. Hemodynamic features are similar to simple human AVMs. The degree of blood shunting across the nidus is variable, thus simulating a spectrum of lower-flow and higher-flow AVMs. Model can be maintained chronically (for many months) for temporal hemodynamic, angiographic, and histologic studies, and for following up the effects of experimental treatment. All components of the model are easily accessible and removable en bloc at animal autopsy for gross examination and histological studies. Chronic histological features in the nidus vessels are those of a high-flow angiopathy; many changes are similar to those encountered in human AVMs. Model can be used as a laboratory simulator of simple human AVMs for the purpose of developing cognitive and technical skills in endovascular embolotherapy and for testing new embolization strategies and embolic materials and histopathological verification following embolotherapy. Disadvantages Model is a simplistic representation of most AVMs encountered in clinical practice. AVM is not surrounded by brain. It is situated at the skull base. Bilateral internal carotid arteries exit the nidus to supply the circle of Willis and the brain, whereas only veins drain human AVMs. Nidus vessels are composed of thick microarteries that do not rupture. Also, the draining vein is histologically an artery that carries retrograde flow and therefore drains (hemodynarnically speaking) the nidus. Abbreviation: AVM, arteriovenous malformation.

have to be replicated adequately: (a) a morphological component (a nidus composed of microvessels), and (b) a hemodynamic component (rapid blood shunting through the nidus). Previously reported so-called ‘‘AVM’’ models in rats (49,50), cats (51), and monkeys (52) were created mainly to investigate pathophysiological derangements accompanying AVMs, such as ‘‘cerebral steal’’ and ‘‘perfusion pressure breakthrough.’’ These models created carotid-jugular fistulae to mimic the high flow in conductance vessels that occurs with an AVM, but they do not possess an AVM nidus. Table 4 Comparison of Human, Animal, and Computational Models Purpose (Ref.) Simulator for training in endovascular embolotherapy (69) Testing new embolic agents (70) Development of new embolization techniques (47) Study of temporal histopathologic changes in chronic AVM models (71) Study of changes in hemodynamics (46,72–75)

Linking hemodynamics to patient outcome (46,76,77)

Human Studies Best for well-developed methods after safety and efficacy documented Best for well-developed methods after safety and efficacy documented Best for well-developed methods after safety and efficacy documented Definitive information

Best information, but limited access

Direct comparison possible

Abbreviation: AVM, arteriovenous malformation.

Animal Models Ideal for initial studies

Ideal for initial studies

Ideal for initial studies

Provides some useful information but indirect/ uncertain relationship of model to human disease Good information, better access, but incomplete applicability to human disease due to relatively simplistic models Indirect at best

Computational Models Possibly good for making predictions and design of study Theoretical advantages and drawbacks can be described Theoretical advantages and drawbacks can be described Never attempted

Ideal for generating hypothesis to test in human studies that are limited by sample size or measurement abilities Never attempted

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The normal swine carotid rete mirabile was proposed as a morphological replica of an AVM nidus (53–55). The carotid rete mirabile of swine is a fine network of vessels ranging in size from 70 mm to 275 mm (mean of 154 mm) (53) with connections across the midline, situated at the termination of both ascending pharyngeal arteries as they perforate the skull base. The complex plexus of microarteries that make up each rete extensively anastomose to give the appearance of a single structure on gross examination. Bilateral retia and their midline connections measure about 2.5 cm x 2.5 cm x 1.5 cm in size. To combine high flow shunting with a reasonable model of AVM nidal structures, an experimental porcine model of an AVM was attempted previously by iatrogenic traumatic shunting from the rete into the surrounding cavernous sinus (56). Drawbacks of this model are that (a) it requires the relatively invasive insertion of a long spinal needle through the animal’s orbit, with consequent post-procedural orbital hemorrhages and proptosis; (b) it involves iatrogenic puncture/transection of the rete vessels, i.e., trauma to the ‘‘nidus’’ of the ‘‘AVM’’; and (c) ensuing spontaneous thrombosis readily occurs because arteriovenous shunting is at the level of the normal rete microvessels, thus essentially limiting this model to an acute-phase one. To address some of these shortcomings, Massoud et al. developed an animal model of an AVM with closer resemblance to human lesions (57). The model still makes use of the carotid rete mirabile of swine, but with the added experimentally induced feature of faster blood flow and unidirectional shunting through bilateral retia. Briefly, following surgical right-sided common carotid to external jugular fistula formation and selective occlusion of various neck arteries ipsilateral to the fistula (which has been omitted in more recent uses of our model), left carotid and ascending pharyngeal arteriography demonstrates an angiographic simulation of an AVM, with rapid circulatory diversion from the left ascending pharyngeal artery (simulated ‘‘main or terminal feeder’’) across both retia mirabilia (simulated ‘‘nidus’’), and fast retrograde flow into the right ascending pharyngeal and common carotid artery (simulated ‘‘draining vein’’) toward the fistula. Recruitment of surrounding arteries (branches from the left external carotid system: ramus anastomoticus and arteria anastomotica) results in these smaller arteries simulating ‘‘en passage’’ feeders. The advantages and disadvantages of this swine AVM model are outlined in Table 3. SUMMARY Table 4 summarizes key concepts discussed in our review. The computer-modeling approach may be useful to better characterize both the pathophysiology and the clinical course of cerebral AVMs. Estimating risk of hemorrhage might be an enormous aid in the construction of rational clinical trials. Overall, interdisciplinary modeling studies of the cerebral circulation can be an important adjunct to experimental studies for increasing the knowledge of cerebral pathophysiology and devising treatment strategies, either by screening proposed theories or by testing existing ones. APPENDIX 1. DESCRIPTION OF A COMPUTATIONAL AVM MODEL In this appendix, we describe one system for constructing a model of AVM hemodynamics and risk of rupture. For further details and results of the application of this model, the reader is referred to the published report of this work (36). Model Construction On the basis of the intranidal model previously developed by the UCLA group (30,41,42) and the whole-brain (extranidal) model described by the Columbia group (31,39), a new hybrid model was constructed to maximize the advantages of both (36). This new hybrid model of an AVM embedded in a normal brain is shown in Figure 4A and 4B. The basic element used to construct the model is a compartment. A compartment has one or more vessels arranged in parallel. The geometric parameters of the vessel (or compartment) network of this model, the position of its two ends within the model, are demonstrated by representative compartments in Table 2. A complete list of vascular parameters has been previously published (31).

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Embedded in the extranidal model, the vessels of a previously developed intranidal model (41,42) were substituted by corresponding compartments. The number of the vessels in one intranidal compartment is the same as in others, which is assumed to be proportional (the proportionality was chosen to be one) to the calculated AVM volume. The effects of AVM size for a specific patient can be considered easily by changing the number of the vessels in the compartments without changing the network structure. The nodes in the intranidal structures are shown in Figure 4B. There were two kinds of intranidal compartments: plexiform and fistulous. The distribution of plexiform vessel numbers vs radius (frequency) follow the distribution suggested by histopathologic examinations and neuroradiologists’ observation to determine the number of fistulous connections. The fistulas were the compartments collecting nodes 90 and 108 vs nodes 93, 99, and 105. The radii of plexiform and fistula were 0.05 and 0.01 mm, respectively. To simulate the arteriolar resistance beds and brain tissue, we constructed ‘‘microvessel groups’’ (MVGs) as special compartments. The model contains 20 MVGs, each of them consisting of 5,000 parallel small vessels, which are 0.1 mm in diameter. As shown in Figure 4A, six of the 20 MVGs are perfused by the anterior cerebral artery (ACA), ten are perfused by the middle cerebral artery (MCA), and four are perfused by the posterior cerebral artery (PCA). They are symmetrically distributed in left and right hemispheres. Assuming a brain weight of 1500 g, each MVG represents a brain tissue weight of 75 g. The MVG also incorporates autoregulatory function into the normal (non-AVM) vasculature. Model of Physiological Simulations Poiseuille’s formula was used for single vessel hemodynamics (30): Q¼

pR4 DP 8Lg

ðA1:1Þ

where Q is the flow rate through the vessel, DP is the pressure drop across the vessel, R is the inner radius, L is length, and g is the blood viscosity (g ¼ 3.5 centipoise). If the transmural pressure of the vessel is P, the relationship between R and P can be approximated as R ¼ R0 ðI þ mPÞ

ðA1:2Þ

where R0 is the vessel radius at P ¼ 0 and m is the elastic coefficient of the vessel (29). m can be calculated from elastic modulus, E(e), and wall thickness, h0 (31), as m ¼ R0 =EðeÞh0

ðA1:3Þ

where e is the strain defined as e ¼(R
R0)/R0. For the inclusion of autoregulation, the precapillary arterioles (embedded in the MVGs) are assumed to regulate flow constant between pressures of 50 and 150 mmHg; flow becomes pressure-passive above and below these boundaries (31). The number of the vessels in plexiform and fistulous compartments is inversely proportional to the AVM resistance: AVM Resistance ¼

DP 8Lg ¼ 4 Q pR

/ ðAVM dimensionÞ
3 / 1=AVM volume

ðA1:4Þ

where L and R are assumed to be approximately proportional to AVM dimension. Therefore, the number of the vessels in each compartment is approximately proportional to the AVM volume. Clinically, conductance blood vessels dilate if there is a chronic increase in blood flow. Although the mechanisms of vessel dilation remain unclear, shear stress on the vessel wall is one possible effector of dilation (58,59). In this model, whenever the mean shear stress is greater than 10 times normal, the vessel dilates to adjust so that shear stress is equal to 10 times the normal value. We have found that this adjustment is necessary to make modeled predictions agree with experimental ones (31). By using Poiseuille’s Law to calculate the flow, turbulence of the blood flow was ignored in our model.

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APPENDIX 2. MATHEMATICAL AND COMPUTATIONAL APPROACH The pressures at all N nodes are used as N-independent variables. The continuity condition, the flow to a node equals the flow from the node, is used to build N-independent equations. Numeral iterations are used to solve these equations. A detailed description can be found in Gao et al. (31). Determination of Riskmodel Gao et al. used this model to estimate AVM rupture risk with clinical data from 12 patients (36). Clinical data included the largest AVM size in any dimension, venous drainage pattern, number of draining veins reaching a sinus, and measurements of feeding artery and systemic arterial mean pressures. For the purpose of this feasibility study, the number of feeders was fixed at 3 for all patient-specific models. AVM feeding supply was set at anterior/middle/posterior cerebral artery (ACA/MCA/PCA). Feeder radii were set: 0.5 mm for ACA feeders, 1 mm for MCA feeders, and 0.5 mm for PCA feeders. The radius of the draining vein (DV) was fixed at 1 mm for large DVs and 0.5–0.7 mm for small DVs. After each patient-specific model was built, it was simulated. The intranidal pressure and radius were calculated for Riskmodel of both hemodynamic- and structural-weighted estimates. Model Risk (Riskmodel) Calculated for Hemodynamic-weighted Estimate The method to calculate Riskmodel for hemodynamic-weighted estimates is based on our previous risk calculation (42). The critical radius (Rc) represents the theoretical radius of the cylindrical blood vessel just prior to rupture and a. depends on the elastic modulus, wall thickness (h), and transmural pressure (P); b. describes the theoretical radius prior to rupture of a single, isolated blood vessel. The objective is to apply the expression for the Rc to nidus vessels within an AVM. In addressing the first point, because the Rc is dependent on three variables, there can be an almost infinite number of possible combinations of these three variables that would yield the same Rc. It thus becomes reasonable to assert that the elastic modulus and h for all nidus vessels within a given AVM are uniform, based on the fact that biomechanical data pertaining to the elastic modulus and h of nidus vessels are virtually non-existent. This simplifies the expression of the Rc to only one variable (P), with elastic modulus and h now constant. Because the AVM nidus consists of a large and random distribution of interconnected vessels, the expression for the Rc cannot be directly applied to a single nidus vessel. Since we are dealing with a number of interconnected nidus vessels in an AVM, the individual pressure value of a nidus vessel becomes dependent not only on surrounding nidus vessels, but also on the number and individual pressure measurements of arterial feeders. To accommodate the wide range of possible pressure values through the entire nidus, we must look at the theoretical distribution of pressures experienced by the nidus. However, because in vivo hemodynamic measurements cannot be accessed to any degree inside nidus vessels, we can only hypothesize about the possible limits of pressure experienced by a nidus vessel. We hypothesized that the lower limit of pressure (Pmin) experienced by the nidus microvessels is equivalent to a cerebral venous pressure (CVP) of approximately 5 mmHg. The upper limit of pressure experienced by the nidus microvessels before rupture is likely to occur during considerable systemic hypertension (i.e., blood pressure that is then transmitted to the arterial feeders and the nidus). We have assumed that the normally low pressure arterial feeders may reach a maximum value of 74 mmHg during mean systemic (SMAP) hypertensive levels of 118 mmHg (derived by assuming a linear relationship between these two parameters). Therefore, 74 mmHg was chosen (somewhat conservatively) as the upper limit of blood pressure (Pmax) possibly encountered by nidus vessels before rupture. Risk of rupture is lowest at values closest to those of CVP and increases in an exponential fashion to a maximum value at pressures equal to or greater than the Pmax. The theoretical distribution of the Rc for the nidus vessel over the range from Pmin and Pmax serves as a baseline value for the RC of all vessels within the nidus. This in turn serves as

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a normalization factor for the assessment of RC of any nidus vessel. The same calculation of an experimental factor is performed for a particular nidus vessel using the same lower limit of pressure (CVP) as that for the normalization factor. The upper limit of pressure is the pressure for each nidus vessel, determined at simulation. The risk of rupture can be determined by the ratio of the experimental factor to the normalization factor multiplied by 100% and is represented mathematically (42): Riskmodel ¼ lnðPi =Pmin Þ=lnðPmax =Pmin Þ

ðA2:1Þ

where Pi is the transmural pressure of vessel i. If the experimental factor (numerator) is greater than the normalization factor (denominator) (which occurs when the experimental pressure (Pi) approaches Pmax), then the risk of rupture approaches 100%, implying that rupture has occurred. It is shown in Eq. (A2.1) that the contribution of the vessel to AVM rupture risk depends on pressures Pi, Pmax, and Pmin. Because Pmax and Pmin are the same for all vessels, intranidal transmural pressure, Pi, determines the risk. The risk is hemodynamically dominated (so-called hemodynamic-weighted risk). Since the intranidal pressure changes minimally from vessel to vessel, every vessel has almost the same risk as other vessels. The risk is distributed within the AVM uniformly. As the denominator is constant, the hemodynamic-weighted estimate of Riskmodel is proportional to the natural logarithm function of intranidal transmural pressure. Model Risk (Riskmodel) Calculated for Structural-Weighted Estimate To describe the uncertainty of vessel rupture, a random distribution function can be used. There are several frequently used functions, such as Gaussian, Rayleigh, Beta, Gamma, and v2. We used the Rayleigh (60) distribution function. Although the Gaussian distribution is the most frequently used distribution function due to its simplicity, it is not suitable for our model because it has a finite value in the negative range. A Rayleigh distribution function has a form similar to the Gaussian function, but it approaches zero when the parameter (radius) goes to zero. Critical Radius The Rc of a vessel can be calculated by vessel critical strain and unloaded vessel radius. However, there is no theory to precisely predict the rupture of a vessel, because of the many unknowns and the uncertainty of parameters. As described previously (42), the critical radius of a vessel can be written as Rc ¼ Eh0 =Pc

ðA2:2Þ

where E and h0 are elastic modulus and thickness of the vessel wall, respectively, and Pc is the critical pressure (the maximal pressure the vessel can support). Equation (A2.2) indicates that for the same material properties of the vessel wall, E and h0 being constant, Rc is inversely proportional to Pc: a vessel ruptured at high pressure has small critical radius. In a vessel ruptured at the same pressure, Pc being constant, Rc is positively proportional to either E or h0. The relationship between vessel radius and pressure depends on the material properties of the vessel wall and geometry of the vessel. The description of the elastic properties of arterial vessel wall is available (61,62). The experimental data represented in this literature indicate that the dependence of the radius on the pressure is nonlinear, which usually makes the calculation very complicated. Using Eq. (A2.2) and linear elastic approximation R ¼ R0 (I þ mP), one can eliminate the pressure and obtain an equation for critical radius of the vessel (36): Rc ¼ R0 ð1 þ mEh0 =Rc Þ

ðA2:3Þ

where m ¼ R0/E(e)h0 is the elastic coefficient of the vessel. Reforming Eq. (A2.3), we have R2c
Rc R0
mEh0 R0 ¼ 0

ðA2:4Þ

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Substituting Eq. (A2.3) into (A2.4), we have: R2c
Rc R0
RR0 2 ¼ 0

ðA2:5Þ

Solving Eq. (A2.5) and dropping the negative root, we have Rc ¼ 1:62R0

ðA2:6Þ

Eq. (A2.6) states that the vessel will rupture when its radius increases by a factor of about 1.62. Strain is defined as the relative change of radius: e ¼ ðRc
R0 Þ=R0 ¼ 0:62

ðA2:7Þ

Eq. (A2.7) shows that the same rupture strain is predicted for any vessel under the linear approximation. This result is not very precise because the material is assumed to be linear and the thickness of the vessel wall is constant. Actually, the vessel wall is non-linear and the thickness decreases if the radius increases. The elastic increases with the pressure, or the elastic coefficient decreases with the pressure and also depends on E and h0. However, Eq. (A2.7) still gives a first-order approximation of critical radius. Based in part on previous experimental data (63), we feel it is reasonable to assume that the degree of elongation just before the vessel rupture is about 30%, that is Rc ¼ 1:3R0

ðA2:8Þ

The detailed analysis of the force exerted by blood on the vessel wall is provided in Appendix 3. AVM Rupture Risk Even though the parameters of vessels are the same, unknown factors or fluctuations may cause some to rupture, while others do not. Thus it cannot be predicted with absolute certainty whether a vessel will rupture. Instead, the probability or statistical risk of rupture may be determined. The derivation of the formulas of risk is given as follows: The rupture risk of a single vessel is described by a probability distribution function as Z R qi ðRÞdR ðA2:9Þ Ui ðRÞ ¼ 0

where Ui ðRÞ is the probability that a vessel ruptures at any value of radius smaller than R, and qi(R) is the probability distribution function, which equals the rupture probability of the vessel if it ruptures when the radius is in a unit interval around R. Rayleigh Distribution Function If the Rayleigh distribution function is used, the risk of rupture of a single vessel is
 R2 Ui ðRi Þ ¼ 1
exp
i2 2Ric The AVM rupture risk is the probability sum over all intranidal vessels, such that
 ! 1 X Ri0 Pi 2 1þ Riskmodel ¼ 1
exp
3:38 i EðeÞhi0

ðA2:10Þ

ðA2:11Þ

Equation (A2.11) shows that the contribution of the vessel to AVM rupture risk depends on P and R0 to h0 ratio exponentially. The vessel with lowest h0/R0 has the most risk of rupture, or is the most dangerous to the AVM. Since the intranidal vessel thickness-to-radius ratio varies significantly, and intranidal transmural pressure changes minimally from vessel to vessel in the

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AVM, Riskmodel mainly depends on the vessel structures of the few weakest vessels. Hence, Riskmodel is vessel-structure dominated. Because the intranidal structure of the AVM was not described for each patient before preliminary calculations, the vessel thickness-to-radius ratio was assumed to be 0.60%. In Table A2-1, the key assumptions for the model risk calculations and their limitations as compared to their usefulness are presented. Morphologic, Hemodynamic, and Clinical Criteria Predicting Spontaneous Hemorrhagic Presentation (Riskexp) We used an experimentally derived estimate of relative hemorrhagic risk in AVM patients (Riskexp) (64). Briefly, we examined data from a large cohort of patients studied prospectively. Because of the strong evidence of our group and of others that future hemorrhage in the natural course of the disease is related to the initial mode of presentation (65–67), risk factors that are associated with initial hemorrhagic presentation can be used as a surrogate estimate of the propensity for hemorrhage in the natural course (Note that not all authors agree that initial hemorrhage is related to subsequent hemorrhage) (68). A stepwise variable selection procedure considered all significant univariate predictors that were selected from a large dataset that included factors such as anatomic (eloquent location, AVM side, AVM border), vascular (aneurysms, pial-to-pial collateral to nidus, venous drainage patterns) and clinical (cerebral arterial and systemic pressures, sex, age). The variables that were independently associated with increased hemorrhagic risk were identified using a standard multivariate logistic model. The stepwise variable selection procedure considered all significant univariate predictors. We found that two factors were the most powerful associative risk factors for initial hemorrhagic presentation of an AVM: (a) higher feeding mean arterial pressure (FMAP) at the point where embolic agents are injected, and (b) the presence of deep-only venous drainage (DVD-only, i.e., venous outflow into the internal cerebral vein or Galenic system, not into the major superficial sinuses). For a dataset of 129 cases, the risk (hazard ratio) per 10 mmHg increment in FMAP was 1.40 (95% confidence interval (CI) 1.08, 1.80; P < 0.01). For DVD only, the hazard ratio was 3.69 (95% CI 1.39, 9.75; P < 0.01), which is a dichotomous variable. We used a multivariate logistic regression procedure in which the probability, Riskexp, of an event is the same as the relative experimental risk and is expressed as: Riskexp ¼

1 1 þ eW

ðA2:12Þ

Table A2-1 Assumptions and Limitations of the Circulatory Model Assumption

Description

Improvement/Advantage

Curvature of vessels

Normal vessels, and especially AVM-related vessels, have significant curvatures

Network intranidal structure

Intranidal structure is Simplifies complicated assumed to be a network vascular structure and of plexiform and/or combination of plexiform fistulous compartments and fistulous nidus Linear elasticity is assumed Simple but good for vessel wall approximation Shunt flow is assumed to be Simple to calculate and consistent with our steady and non-turbulent flow in the intranidal estimates vessels

Linear vessel wall distensibility Steady and non-turbulent flow

Simplified as straight vessels

Abbreviations: AVM, arteriovenous malformation; MRA, magnetic resonance angiography. Source: From Ref. 36.

Limitation/Disadvantage Less accurate prediction; unknown effect; large conductance vessel image perhaps available from MRA in the future Increases the amount of computer calculations; exact structure not known Vessel wall may have nonlinear elasticity The details of flow in large intranidal vessels and at nodes have not been well described: therefore, the validation of this assumption is not available

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where W ¼ a0 þ a1 x1 þ a2 x2 , x1 ¼ deep-drainage only, and x2 ¼ FMAP. The coefficients are a0 ¼ 1.9157, a1 ¼ 1.3043, and a2 ¼ 0.0335. This calculation was used on a case-by-case basis to derive the values for mean Riskexp. Statistical Procedures A chi-square statistic was used to assess goodness of fit as follows:  2 N X Riskexp
Riskmodel 2 v ¼ Riskexp i¼1

ðA2:13Þ

The significance of differences in model estimates of risk was assessed using McNemar’s test comparing the deviations of each of the two model risks for hemodynamic- and structuralweighted estimates from Riskexp. The relationship between measured pressure in the feeding artery and model-predicted pressure was tested by linear regression. APPENDIX 3. VASCULAR STRESS The force exerted by blood on a unit area of vessel wall can be separated into two components: the component perpendicular to (transmural pressure, P) and the component tangential to (shear stress, s) the inner surface of the vessel wall (both of which can be expressed in units of dyne/cm2). A vessel wall is an elastic material. The transmural pressure on the vessel wall tends to expand the vessel. Expansion is counteracted by the elastic forces within the vessel wall. These opposing forces applied to the vessel wall per unit area are defined as biomechanical stress (S, dyne/cm2). During normal stable conditions in the vessel wall, the transmural pressure is always balanced by biomechanical stress. The biomechanical stress inside the vessel wall can be separated into two components: circumferential stress (SC): SC ¼ Pr=h

ðA3:1Þ

Figure A3.1. Schematic representation of a thin-walled cylindrical vessel with blood flow. The stresses and pressures (forces per unit area) exerted on the vascular wall are indicated: transmural pressure (P); shear stress (s); biomechanical stress consisting of circumferential (Sc) and longitudinal (SL) stresses. See Appendix 3 for explanation. Source: From Ref. 39.

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and longitudinal stress (SL): SL ¼ Pr=2h

ðA3:2Þ

where r is the radius of the vessel and h is the thickness of the vessel wall. These stresses are shown diagrammatically in Fig. A3.1. Readers who are interested in the balance conditions or derivation of these formulae are referred to Chandran (61). According to the above formulae, the circumferential stress is greater than longitudinal stress (SC > SL). Therefore, circumferential stress will result in rupture before longitudinal stress will, and for the purpose of the model only circumferential stress was simulated and discussed (note that this assumes that the structural integrity of the vessel wall is similar in all directions). From S ¼ Pr/h, it can be seen that biomechanical stress is high with high pressure, large radius, and thin vessel wall. Shear stress is produced by blood flow and is always in the direction of flow, as shown in Fig. A3.1. Shear stress can be estimated as s ¼ 4gQ=Pr

ðA3:3Þ

where g and Q are the viscosity and flow of blood, respectively (30). The importance of shear stress for a modeling study was reported in one of our previous papers where it exerted an influence on the endothelial surface and was a control factor of flow-induced vasodilation (31). The direction of shear stress is parallel to longitudinal biomechanical stress. However, the relative contribution of shear stress to biomechanical stress is probably negligible.

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The natural history of symptomatic arteriovenous malformations of the brain: a 24-year follow-up assessment [comments in J Neurosurg 1991 (Aug); 75(2):338–339]. J Neurosurg 1990; 73:387–391. 69. Massoud TF, Ji C, Vinueia F, et al. Laboratory simulations and training in endovascular embolotherapy with a swine arteriovenous malformation model. AJNR 1996; 17:271–279. 70. Massoud TF, Ji C, Guglielmi G, Vinuela F. Endovascular treatment of arteriovenous malformations with selective intranidal occlusion by detachable platinum electrodes: technical feasibility in a swine model. Am J Neuroradiol 1996; 17:1459–1466. 71. Massoud TF, Vinters HH, Chao K, Vinuela F, Jahan R. Histopathology of a chronic arteriovenous malformation in a swine model: Preliminary study. AJNR 2000; 21:1268–1276. 72. Murayama Y, Massoud TF, Vinuela F. Transvenous hemodynamic assessment of experimental arteriovenous malformations. Doppler guidewire monitoring of embolotherapy in a swine model. 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[see comments by Lo, Eng H: J Neurosurg 1993 (Jan); 78(l): 156–158; Chaloupka, John C, et al. J Neurosurg 1993 (May); 78(5):850–853]. J Neurosurg 1992; 76:918–923. Kader A, Young WL, Pile-Spellman J, et al. The Columbia University AVM Study Project. The influence of hemodynamic and anatomic factors on hemorrhage from cerebral arteriovenous malformations. Neurosurgery 1994; 34:801–807 [discussion 807–808]. Hartmann A, Mast H, Mohr JP, et al. Morbidity of intracranial hemorrhage in patients with cerebral arteriovenous malformation. Stroke 1998; 29:931–934. DeMeritt JS, Pile-Spellman J, Mast H, et al. Outcome analysis of preoperative embolization with N-butyl cyanoacrylate in cerebral arteriovenous malformations. Am J Neuroradiol 1995; 16:1801–1807. Fogarty-Mack P, Pile-Spellman J, Hacein-Bey L, et al. Superselective intraarterial papaverine administration: effect on regional cerebral blood flow in patients with arteriovenous malformations. J Neurosurg 1996; 85:395–402.

Section II

CLINICAL PRESENTATION AND DIAGNOSTIC EVALUATION

5

Natural History Bernard R. Bendok, Christopher Eddleman, Joseph G. Adel, M. Jafer Ali, H. Hunt Batjer, and Stephen L. Ondra Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, U.S.A.

INTRODUCTION Arteriovenous malformations (AVMs) are lesions composed of arteries and veins without intervening capillary beds. A high flow profile leads to vascular recruitment and arterialization of venous structures (1). It is believed that these lesions are most often congenital, arising at approximately the third week of gestation. At that point, an arrest in development results in the formation of direct arteriolar to venous communications without an intervening capillary bed (2). AVMs comprise 1.5% to 4% of intracranial masses and are thought to occur approximately one-tenth as often as intracranial aneurysms (3). Although only 2000 new cases are reported per year in the United States (2), it is estimated that over 300,000 Americans harbor these lesions at any given time (4). Stapf et al. reported on an ongoing, prospective, population-based incidence and case-control study designed to determine AVM detection rates and the incidence and prevalence of AVM-associated morbidity, mortality, and case fatality rates. Those authors in their New York Islands’ population found an average annual AVM detection rate of 1.34 per 100,000 person-years (5). Approximately 65% of all intracranial AVMs are hemispheric. An additional 15% occur in the deep midline structures, and 20% are found in the posterior fossa (6). Multifocal AVMs of the brain have been reported (6). Intracranial AVMs occur in men slightly more often than in women (3). A review of 545 cases of intracranial AVMs by Perret and Nishioka revealed a 1.1:1 male to female ratio (3). The most common presentations of intracranial AVMs include hemorrhage, convulsions, headaches, progressive neurologic deficits, and mental deterioration (3). Most patients with AVMs develop symptoms between the ages of 20 and 40; peak incidence appears to be in the late second or early third decade of life with no age differences between women and men (5). A number of studies have tried to elucidate the natural history of these vascular lesions. However, most reports have been limited by small sample size, short inconsistent follow-up, and selection bias of the available study population. When different databases are compared, significant differences are noted between the many features of this kind of lesion. In this chapter, we review this literature and attempt to provide some conclusions about the fate of the untreated intracranial AVM. PRESENTING SYMPTOMS Hemorrhage Most intracranial AVMs present with symptoms related to hemorrhage (7,8). A multicenter prospective analysis has estimated this figure at approximately 53% (9). In their study of 284 patients with AVMs, Stapf et al. found a crude incidence rate of first-ever AVM hemorrhage (n ¼ 108) of 0.51 per 100,000 person-years and an estimated prevalence of AVM hemorrhage among detected cases (n ¼ 144) of 0.68 per 100,000 (5). This study, however, is limited by short follow-up (27 months) as of this report. Numerous studies have speculated on the incidence of hemorrhage in patients suffering from these lesions. Graf et al. estimated the risk of rebleeding after hemorrhage from such lesions to be 6% during the first year and 2%

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per year for up to 20 years after the initial hemorrhage. In this study, mean follow-up in patients with ruptured AVMs was two years (maximum of 37) (10). In a study of 168 patients with unruptured AVMs at the Mayo Clinic, 18% experienced hemorrhage during a mean follow-up period of 8.2 years, with an average risk of hemorrhage from previously unruptured AVM estimated at 2.2% per year. Among the survivors, a significant risk of hemorrhage persisted for at least 20 years (11). In their retrospective survey of 217 patients who did not undergo any form of surgery or irradiation, Crawford et al. reported that the yearly risk of hemorrhage was 2.6% for unruptured AVMs and 1.7% for ruptured lesions. This study had a mean follow-up period of 10.4 years (7). In 1985, Wilkins prepared a review of 1500 patients compiled from earlier clinical studies. He reported that unruptured AVMs carry an annual risk of hemorrhage of 2% to 3%. The rate of hemorrhage after an initial bleed was 6% in the first year and the same as for unruptured lesions thereafter (12). The literature on this topic often focuses on attempts to somehow stratify risk according to presentation. Graf et al., using life survival statistics, reported a rebleed rate of 42% by 20 years in patients presenting with hemorrhage but only a 37% risk for patients presenting with epilepsy. In this series, patients who presented without hemorrhage or epilepsy had a risk of hemorrhage of 45% (10). Fults and Kelly reported a 67% incidence of repeat hemorrhage over 15 years in those presenting with hemorrhage and a 27% incidence of hemorrhage in patients presenting with seizure (13). Some authors have also attempted to stratify the risk of hemorrhage according to the age of the patient. While some of these reports suggest a higher risk of hemorrhage in older patients (7,10), others suggest a relatively higher rate of bleeding in children with AVMs (13). The fact that most studies relating to the natural history of AVMs of the brain have been limited by small sample size, short inconsistent follow-up studies, and selection bias of the available study population presumably accounts for the great variability in statistics reported in the literature. In 1990, Ondra and colleagues updated a Finnish series of 166 prospectively followed, unoperated, symptomatic patients with AVMs of the brain (8). Follow-up data were obtained for 96% of the original study population with a mean follow-up period of 23.7 years. The relative geographic and linguistic isolation of the Finnish population combined with the centralization of medical care and meticulous record keeping allowed for a unique level of reliability for the study. Patients were divided into three groups: those who presented with hemorrhage, those who presented with seizure without history or evidence of seizure, and those who had headaches, asymptomatic bruits, or other vague neurological complaints but no evidence of hemorrhage. The annual bleeding rate in these patients was found to be 4%, and there was, in contrast to other reports, no significant difference in the rate of hemorrhage between these groups. The incidence of bleeding remained constant over 20 years of follow-up. The overall relatively higher rates of bleeding than those reported in earlier studies were attributed to the length and overall completeness of follow-up review in a well-defined, centrally cared-for population. In addition, the average interval between bleeding events was reported at 7.7 years, which was as long as or longer than the average follow-up intervals reported in previous studies. The authors suggested that this might also have contributed to the apparent underestimation of the rebleeding incidence in prior studies (8). Although the findings of studies addressing the issue of bleeding with intracranial AVMs are variable, some conclusions can be drawn from a review of the literature on this topic. It appears that unruptured AVMs are probably more harmful than earlier investigators had thought and that they appear to bleed with similar frequency to AVMs that initially present with hemorrhage. The incidence of hemorrhage appears to be between 2% to 4% per year. Finally, according to the most rigorous study available, the incidence of bleeding in these patients remains constant over the life of the patient. Although it is important for neurosurgeons to understand the risk of bleeding in patients with intracranial AVMs, it is equally important that these statistics be interpreted correctly and presented to patients so that they may put them in the proper perspective when they make decisions on treatment. Kondziolka et al. (14) demonstrated that, within the neurosurgical community, knowledge varied about the use of such statistics to predict long-term risks of hemorrhage. At two different national meetings in 1988 and 1994, the authors asked 119 neurosurgeons (36 residents, 80 attending neurosurgeons, and 3 nonspecified) to assess the risk of bleeding from an untreated AVM in a young adult over a 20- to 30-year period given

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a 3% to 4% annual risk of hemorrhage. Answers ranged from 1% to 100%, and were arrived at by many different means of calculation. To simplify the use of these statistics in clinical practice, the authors suggested the following formula based on the multiplicative law of probability to estimate the lifetime risk of hemorrhage in a patient not treated for an AVM: Risk of hemorrhage ¼ 1
ðAnnual risk of no hemorrhageÞexpected years of remaining life Clearly, a number of assumptions are made when the formula is applied to individual patients. First, it is assumed that there exists some degree of population homogeneity. This assumption is reasonable on the basis of results reported by investigators in the United States (11), Japan (15), Sweden (16), France (17), Great Britain (7), and Finland (8). Second, the formula assumes some degree of uniformity in the natural history of AVMs. Given that the study with the longest follow-up showed a constant bleeding rate over 20 years regardless of presentation (8), this assumption seems reasonable as well. Although a number of other variables exist that may apply to a particular patient, this formula provides a quick means of estimating lifetime risk of hemorrhage in patients that can easily be used in a clinical setting.

MORBIDITY AND MORTALITY RELATED TO HEMORRHAGE Estimations of morbidity and mortality rates in patients with intracranial AVMs have been reported. Graf et al. reported a morbidity rate of 81% of 191 patients after hemorrhage between 1946 and 1980 (10). Perret and Nishioka observed a 58% neurologic morbidity rate associated with AVM hemorrhage (18). Crawford et al., in their retrospective chart review, reported that of the patients who suffered AVM hemorrhage, 62% showed no neurologic handicap, 25% had minor disability, and 6% had major deficits. Crawford et al. (7) estimated the risk of a neurological deficit from AVM hemorrhage to be 27% over 20 years. This study also reported a mortality rate from all causes in patients harboring AVMs of 29% during this projected time period. Sixty-five percent of the deaths were thought to be a direct result of the AVM, most often due to hemorrhage (7). Svien and McRae reported ‘‘good survival quality’’ in 85% of the patients with AVMs who suffered incident hemorrhages, and 86% in those with subsequent hemorrhages (19). Brown et al. (11) reported that 29% of the patients who bled from AVMs died from the hemorrhage and that 23% had long-term morbidity. Overall, however, the authors described functional independence in at least 86% of the patients with AVMassociated hemorrhages. Wilkins et al. reported the annual mortality rate from ruptured AVMs as approximately 1% (12). In the study by Ondra et al. of 166 unoperated patients with AVMs, 40% suffered at least one major hemorrhage during the follow-up period (mean ¼ 23.7 years) (8). Of those patients who had hemorrhages after enrollment in the study, 85% suffered a major morbidity or died. An overall annual mortality rate in patients with AVMs was reported at 1%, was not affected by mode of presentation, and stayed constant throughout the length of the study. This conclusion that the rate of death in symptomatic patients with AVMs remains constant for their entire lives contradicts the conclusions of other AVM studies with fewer subjects and shorter follow-up (7,13). In total, 23% of the patients who enrolled in this study died as a direct result of hemorrhage. A conservative estimate of the combined annual major morbidity and mortality rates in patients harboring AVMs was reported at 2.7% per year and was constant throughout the follow-up period. Of note, the morbidity rate was higher in patients who initially presented with hemorrhage than in those who presented otherwise. The authors attributed this phenomenon to ‘‘additive injury’’ that was superimposed on neurological impairment from the earlier bleeding episodes and the resultant depletion of reserves to accommodate subsequent hemorrhages (8). A study conducted by Hartman et al. with data from the Columbia-Presbyterian AVM Study Project focused on neurological impairments secondary to bleeding from cerebral AVMs (20). These authors argued that most of the studies of morbidity secondary to AVM hemorrhages were based on retrospective analyses of hospital charts, often before the availability of modern brain imaging, and frequently did not specify the degree of impairment or the time interval between hemorrhages and follow-up assessment. Their study, in which hemorrhages were defined by computed tomography (CT) and magnetic resonance imaging

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(MRI), showed a lower morbidity rate for AVM-related hemorrhages than the literature suggests. Eighty-four percent of their patients had no neurological deficit or were independent (Rankin 0 or 1) after the first hemorrhage. In addition, functional outcomes in patients with both incident and subsequent hemorrhages were similar to outcomes of patients with single hemorrhages. The authors argued that this finding contradicted the importance of a cumulative effect of recurrent hemorrhages. While this study raises interesting questions, the mean follow-up time was only 16.2 months. To add perspective, the mean interval between hemorrhages reported by Ondra et al. was 7.7 years (8). Although modern imaging techniques would help to better elucidate the nature of the AVM and its bleeding type, the application of these techniques to the issue of the natural history of AVMs is difficult. The advent of such technology has been accompanied by increasingly sophisticated surgical and endovascular techniques that result in few AVMs being left untreated. The imaging used by Hartmann et al., however, does give insight into the pattern of bleeding associated with AVMs. Of the 115 incident hemorrhages they reported, 30% were subarachnoid, 23% were parenchymal, 16% were intraventricular, and 31% were located in combined areas (20). Some generalizations can be made after a review of the literature on the morbidity and mortality rates of AVM-associated hemorrhages. First, the risk of death for a patient suffering an AVM rupture is likely between 10% and 15%. Overall, the combined risk of morbidity and mortality is approximately 15% for each bleeding episode. For both previously ruptured and unruptured AVMs, the likelihood of a subsequent bleed appears to be approximately 2% to 4% per year with an average interval between bleeding events of about seven to eight years. Finally, the annual mortality risk in patients harboring intracranial AVMs is approximately 1%, and the neurologic morbidity risk is likely 2% to 3% per year. Epilepsy/Seizures After hemorrhage, epilepsy is the second most common symptom in patients harboring intracranial AVMs (21). In the study by Ondra et al., 24% of the patients with AVMs presented with seizure (8). In the study by Graf et al., 43 (32.1%) of 134 patients with AVMs who bled suffered convulsions (10). The timing of these convulsions varied. In just under one-half of the patients, the first seizure was believed to have occurred at the time of hemorrhage. However, approximately 19% of the patients suffered seizures some time after a bleeding episode (mean 4.8 years), and an additional one-third of those suffering convulsions did so before their first documented hemorrhage (mean 11.1 years). In another study, the risk of de novo epilepsy was projected as 18% 20 years after diagnosis (7). It is clear that epilepsy can manifest itself in patients with AVM before, during, or after hemorrhage, although it is difficult to estimate the incidence in each of these categories. In a prospective analysis by Hofmeister et al. of 1289 patients with brain AVMs from three independent databases, patients with AVMs presented with focal seizures about 10% of the time and with generalized seizures an additional 30% of the time (9). This analysis, however, did not distinguish between ruptured and unruptured AVMs. A review of the literature suggests that the annual incidence of de novo epilepsy is likely between 1% and 4% (7,10). Signs and Symptoms of AVMs Without Hemorrhage In most cases, AVMs of the brain present with either hemorrhage or seizure. However, other modes of presentation are documented. In a study of 48 patients with AVMs of the cerebral hemispheres, Pool et al. observed that initial symptoms were hemorrhage (42%), epilepsy (33%), hemiparesis (23%), headache (14%), aphasia (8%), or bruit (2%) (22). Brown et al. also found a variety of signs and symptoms on presentation of 146 patients with symptomatic intracranial AVMs. When categorized by ‘‘main indication for work-up,’’ 25 patients presented with headache attributable to an AVM. Of note, only three of these patients had ruptured lesions. Twelve patients presented with focal ischemia spells due to their AVMs, while only one of these patients presented with hemorrhage. Neurological deficits secondary to mass effect resulted in the work-up of five patients, none of whom had ruptured AVMs. An additional three patients presented with cranial or orbital bruits as their main indication for work-up. Of these, only one patient had a ruptured intracranial AVM (11). Thus, AVMs can

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result in a variety of signs and symptoms, and these modes of presentation are often not indicative of the integrity of the lesion itself. Apart from hemorrhage, several mechanisms have been proposed to explain the symptoms in patients with intracranial AVMs, including arterial steal phenomenon, interference with venous drainage, mass effect, hydrocephalus, venous ischemia, and neurological dysfunction secondary to passive congestion of venous outflow (23,24). At present, however, the complexity of the angioarchitecture of AVMs makes it difficult to definitively identify a single nonhemorrhagic mechanism responsible for any given symptom (23). AVMs IN THE GRAVID WOMAN Crawford et al. noted that one in four females between the ages of 20 and 29 who presented with AVM hemorrhage was pregnant (7). Although this report is compelling, the literature regarding the natural history of intracranial AVMs in the gravid woman is limited. Further studies will be required before generalizations can be confidently derived from these data. However, the available literature is sufficiently intriguing to underscore the need to explore this issue further. Reports have suggested that spontaneous subarachnoid hemorrhage secondary to ruptured aneurysms or AVMs may account for approximately 4.4% of all deaths in pregnant women. It has been reported that up to 50% of pregnant women presenting with intracranial hemorrhage have ruptured AVMs and that the course of AVM rupture may actually be more aggressive in these patients when compared to nongravid women. There is also evidence that rupture of AVMs in pregnant women may occur more frequently between week 20 of gestation and six weeks postpartum, and may be attributable to hemodynamic, hormonal, and coagulation changes that occur during this time (25,26). For a more thorough review of this issue, the reader should refer to Chapter 25 entitled ‘‘Arteriovenous Malformations in Pregnancy.’’ ANATOMICAL FACTORS INFLUENCING THE NATURAL HISTORY OF AVMs Several studies have speculated that anatomic variables related to intracranial AVMs may influence their natural history. Graf et al. reported that whereas the risk of rupture for small AVMs was 52% five years after initial diagnosis, the risk of hemorrhage for larger AVMs was only 10% (10). In a larger study, Crawford et al. found a smaller difference at a five-year follow-up, with rupture occurring 21% of the time in smaller AVMs and 18% in larger lesions (7). Guidetti and Delitala found that initial bleeding in smaller AVMs was more common than in larger AVMs, but smaller lesions had a lower frequency of second bleeds (27). Spetzler et al. also reported an increased frequency of bleeding with smaller AVMs and attributed this finding to increased feeding artery pressures in small lesions (28). They suggested that larger AVMs have higher flow and lower feeding artery pressures that may offer some level of protection from hemorrhage. The authors speculated, however, that these same anatomic features of larger AVMs might also predispose them to other phenomena such as cerebral steal and seizures. The notion that patients with larger AVMs are more likely to present with seizures, whereas those with small AVMs more often present with hemorrhage has been speculated on by other authors as well (29,30). In addition to large size, some authors have speculated that certain locations of intracranial AVMs make them more likely to present with seizure. AVMs located in the temporal and parietal lobes have been associated with higher risk of epilepsy when compared to AVMs occurring in the other lobes of the brain (7,31). In addition, seizures associated with parietal AVMs are predominantly focal, whereas those occurring with frontal lesions are more frequently generalized (12). Special anatomical features of AVMs that are thought to be related to major bleeding episodes include associated aneurysms and certain characteristics of AVM angioarchitecture such as venous stenosis and deep venous drainage. Associated aneurysms have been reported in approximately 10% of the patients with cerebral AVMs and can be located on the primary feeding vessels or other vessels (32). The role of aneurysms associated with AVMs is an issue of ongoing controversy. Mansemann et al. distinguished between aneurysms within the AVM nidus and those occurring on the feeding vessels (33). In their study, 191 (54%) of 357 patients

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without associated aneurysms exhibited hemorrhage. Similarly, 67 (54%) of 124 patients with exclusively proximal associated aneurysms suffered hemorrhage. Furthermore, 48 (57%) of 84 patients with exclusively intranidal aneurysms exhibited hemorrhage. Of the 97 patients who had both proximal and intranidal-associated aneurysms, 42 (43%) suffered an intracranial bleed (33). Whereas Mansemann et al. did not find an association between the presence of intranidal aneurysms or feeding artery aneurysms and hemorrhage, others have reported to the contrary. Brown et al. found the risk of hemorrhage when aneurysms and intracranial AVMs coexist to be 7% per year compared with a reported 1.7% per year for patients with intracranial AVMs alone (11). Turjman et al. also found that the presence of AVM-associated aneurysms, including both intranidal and feeding artery aneurysms, correlated significantly with the clinical presentation of hemorrhage (p ¼ 0.001) (34). Thus, symptomatic aneurysms associated with intracranial AVMs should probably be obliterated. The morbidity and mortality rates associated with ruptured aneurysms are significantly higher than those associated with intracranial AVMs (34). The appropriate management of associated asymptomatic aneurysms is less clear. However, until the natural history of these lesions becomes clearer, it seems prudent to proceed with treatment of these aneurysms as well. For a thorough discussion of AVM-associated aneurysms, the reader is directed to Chapter 24. It is has been hypothesized that any variable of AVM angioarchitecture that contributes to venous hypertension increases the risk of hemorrhage (33). The transmission of high arterial pressures may subject venous structures to pressures that they are not suited to tolerate. Nataf et al. (35) showed correlation between incidence of hemorrhage secondary to intracranial AVM and four variables: exclusively deep venous drainage, venous stenosis, venous reflux, and a higher ratio of feeding to draining systems (afferent/efferent ratio). Venous recruitment was reported to be a favorable prognostic indicator. In another study, arterial stenosis, arterial angioectasia, and arteriovenous fistulae were negatively correlated with hemorrhage, while venous stenosis, in most instances, showed a positive correlation. These authors also noted that the location of the AVMs seemed to modify their venous drainage characteristics. Venous stenosis was not positively associated with hemorrhage for cortical AVMs (33). Turjman et al. found that AVMs in certain locations such as the basal ganglia or a midline location are significantly correlated with hemorrhage (34). Possible mechanisms cited for this anatomical propensity for hemorrhage include vein of Galen stenosis, short arteries with high pressure in AVMs that are deeply situated and possess deep venous drainage, and an association of central venous drainage and AVMs in periventricular locations (34). This relationship between deep venous drainage and AVM hemorrhage has been described in other reports as well (36,37). SPONTANEOUS REGRESSION Spontaneous regression of intracranial AVMs is rare. In a review of the literature, Abdulrauf et al. reported 24 cases of spontaneous angiographic obliteration of AVMs (38). The majority of cases occurred in adults at intervals ranging from 6 months to 21 years after diagnosis, and in most cases, regression was acute. Gradual regressions have also been observed (39). Several mechanisms have been postulated to explain spontaneous regression, including arteriosclerosis of feeding vessels (39), embolism from an associated thrombosed aneurysm (40), and the compressive forces of a hematoma or local edema secondary to hemorrhage (41). Lakke hypothesized that frequent microbleedings of an intracranial AVM with consequent organization and gliosis of the clot caused kinking of the feeding vessels, thereby facilitating its thrombosis (42). There is no clear generalizable mechanism involved in spontaneous regression of these lesions. However, the most common feature appears to be compression of the vascular nidus from AVM hemorrhage, although total spontaneous regression has been reported without hemorrhage or thrombotic phenomena (39). Three of the cases reviewed by Abdulrauf et al. involved patients whose AVMs had been partially resected. The interval to angiographic obliteration in these three patients ranged from five months to eight years. All three residual AVMs were classified as small and were associated with one draining vein. Two of the three appeared to have had limited arterial supply (38). This kind of phenomenon raises questions about the management of residual AVMs, especially in cases involving eloquent cortex. In general, we still advocate prompt resection of residual AVMs with persistent shunting. However, the management of small residual AVMs

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in eloquent cortex that are associated with a single draining vein is less clear. Patients with possible residual AVMs should be followed for several years to confirm absence of further natural history risk. Adjuvant therapies such as endovascular treatment or stereotactic radiosurgery need to be considered. REFERENCES 1. Rothbart D, Awad IA, Lee J, Kim J, Harbaugh R, Criscuolo GR. Expression of angiogenic factors and structural proteins in central nervous system vascular malformations. Neurosurgery 1996; 38:915–924. 2. Stein BM, Wolpert SM. Arteriovenous malformations of the brain. I. Current concepts and treatment. Arch Neurol 1980; 37:1–5. 3. Perret G, Nishioka H. Arteriovenous malformations. In: Sahs AL, Perret GE, Locksley HB, Nishioka H, eds. Intracranial Aneurysms and Subarachnoid Hemorrhage: A Cooperative Study. Philadelphia: Springer Publishing, 1969:200–222. 4. Challa VR, Moody DM, Brown WR. Vascular malformations of the central nervous system. J Neuropathol Exp Neurol 1995; 54:609–621. 5. Stapf C, Mast H, Sciacca RR, et al; New York Islands AVM Study Collaborators. The New York Islands AVM Study: design, study progress, and initial results. Stroke 2003; 34:e29–e33. 6. Schlachter LB, Fleischer AS, Faria MA, Tindall GT. Multifocal intracranial arteriovenous malformations. Neurosurgery 1980; 7:440–444. 7. Crawford PM, West CR, Chadwick DW, Shaw MDM. Arteriovenous malformations of the brain: natural history in unoperated patients. J Neurol Neurosurg Psychiatry 1986; 49:1–10. 8. Ondra SO, 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; 73:387–391. 9. Hofmeister C, Stapf C, Hartmann A, et al. Demographic, morphological, and clinical characteristics of 1289 patients with brain arteriovenous malformation. Stroke 2000; 31:1307–1310. 10. Graf CJ, Perret GE, Torner JC. Bleeding from cerebral arteriovenous malformations as part of their natural history. J Neurosurg 1983; 58:331–337. 11. Brown RD, Wiebers DO, Forbes G, et al. The natural history of unruptured intracranial arteriovenous malformations. J Neurosurg 1988; 68:352–357. 12. Wilkins RH. Natural history of intracranial vascular malformations: a review. Neurosurgery 1985; 16:421–430. 13. Fults D, Kelly DL. Natural history of arteriovenous malformations of the brain: a clinical study. Neurosurgery 1984; 15:658–662. 14. Kondziolka D, McLaughlin MR, Kestle JRW. Simple risk predictions for arteriovenous malformation hemorrhage. Neurosurgery 1995; 37:851–855. 15. Itoyama Y, Uemura S, Ushio Y, et al. Natural course of unoperated intracranial arteriovenous malformation: study of 50 cases. J Neurosurg 1989; 71:805–809. 16. Forster DMC, Steiner L, Hakanson S. Arteriovenous malformations of the brain. J Neurosurg 1972; 37:562–570. 17. Jomin M, Lesoin F, Lozes G. Prognosis for arteriovenous malformations of the brain in adults based on 150 cases. Surg Neurol 1985; 23:362–366. 18. Perret G, Nishioka H. Report on the cooperative study of intracranial aneurysms and subarachnoidal hemorrhage. Section VI. Arteriovenous malformations. J Neurosurg 1966; 25:467–490. 19. Svien HJ, McRae JA. Arteriovenous anomalies of the brain: fate of patients not having definitive surgery. J Neurosurg 1965; 23:23–28. 20. Hartman A, Mast H, Mohr JP, et al. Morbidity of intracranial hemorrhage in patients with cerebral arteriovenous malformation. Stroke 1998; 29:931–934. 21. Yeh H-S, Kashiwagi S, Tew JM, Berger TS. Surgical management of epilepsy associated with cerebral arteriovenous malformations. J Neurosurg 1990; 72:216–223. 22. Pool JL. Treatment of arteriovenous malformations of the cerebral hemispheres. J Neurosurg 1962; 19:136–141. 23. Hurst RW, Hackney DB, Goldberg HI, Davis RA. Reversible arteriovenous malformation-induced venous hypertension as a cause of neurological deficits. Neurosurgery 1992; 30:422–425. 24. Lasjaunias P, Chiu M, Brugge KT, Tolia A, Hurth M, Bernstein M. Neurological manifestations of intracranial dural arteriovenous malformations. J Neurosurg 1986; 64:724–730. 25. Sadasivan B, Malik GM, Lee C, Ausman JI. Vascular malformations and pregnancy. Surg Neurol 1990; 33:305–313. 26. Lanzino G, Jensen ME, Cappelletto B, Kassell NF. Arteriovenous malformations that rupture during pregnancy: a management dilemma. Acta Neurochir (Wein) 1994; 126:102–106. 27. Guidetti B, Delitala A. Intracranial arteriovenous malformations: conservative and surgical treatment. J Neurosurg 1980; 53:149–152. 28. 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; 76:918–923.

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29. Norris JS, Valiante TA, Wallace MC, et al. A simple relationship between radiological arteriovenous malformation hemodynamics and clinical presentation: a prospective, blinded analysis of 31 cases. J Neurosurg 1999; 90:673–679. 30. Kader A, Young WL, Pile-Spellman J, et al. The influence of hemodynamic and anatomic factors on hemorrhage from cerebral arteriovenous malformations. Neurosurgery 1994; 34:801–808. 31. Parkinson D, Bachers G. Arteriovenous malformations: summary of 100 consecutive supratentorial cases. J Neurosurg 1980; 53:285–299. 32. Malik GM. Special considerations in treating arteriovenous malformations. In: Welch KMA, Caplan LR, Reis DJ, Siesjo BK, Weir B, eds. Cerebrovascular Diseases. San Diego: Academic Press, 1997: 525–528. 33. 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; 46:272–281. 34. Turjman F, Massoud TF, Vinuela F, Sayre JW, Guglielmi G, Duckwiler G. Correlation of the angioarchitectural features of cerebral arteriovenous malformations with clinical presentation of hemorrhage. Neurosurgery 1995; 37:856–862. 35. Nataf F, Meder JF, Roux FX, et al. Angioarchitecture associated with haemorrhage in cerebral arteriovenous malformations: a prognostic statistical model. Neuroradiology 1997; 39:52–58. 36. Marks MP, Lane B, Steinberg GK, Chang PJ. Hemorrhage in intracerebral arteriovenous malformations: angiographic determinants. Radiology 1990; 176:807–813. 37. Miyasaka Y, Yada K, Ohwada T, Kitahara T, Kurata A, Irikura K. An analysis of the venous drainage system as a factor in hemorrhage from arteriovenous malformations. J Neurosurg 1992; 76:239–243. 38. Abdulrauf SI, Malik GM, Awad IA. Spontaneous angiographic obliteration of cerebral arteriovenous malformations. Neurosurgery 1999; 44:280–288. 39. Marconi F, Parenti G, Puglioli M. Spontaneous regression of intracranial arteriovenous malformation. Surg Neurol 1993; 39:385–391. 40. Omojola MF, Fox AJ, Vinuela FV, Drake CG. Spontaneous regression of intracranial arteriovenous malformations. J Neurosurg 1982; 57:818–822. 41. Eisenman JL, Alekoumbides A, Pribam H. Spontaneous thrombosis of vascular malformations of the brain. Acta Radiol (Diagn) 1972; 13:77–85. 42. Lakke JPWF. Regression of an arteriovenous malformation of the brain. J Neurol Sci 1970; 11:489–496.

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Classification and Grading Systems Kai U. Frerichs Cerebrovascular Center, Department of Neurosurgery, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts, U.S.A.

Philip E. Stieg Department of Neurological Surgery, Weill Medical College of Cornell University, NewYork-Presbyterian Hospital, New York, New York, U.S.A.

Robert M. Friedlander Cerebrovascular Center, Department of Neurosurgery, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts, U.S.A.

INTRODUCTION Arteriovenous malformations (AVMs) of the brain consist of abnormal primitive connections between the arterial and venous systems, single or multiple. They can occur throughout the brain with a predilection for the cerebral hemispheres supplied by branches of the middle cerebral artery (MCA) (1–4). AVMs are congenital lesions that develop most likely between the fourth and the eighth weeks of embryonic life (5,6). The lesion is characterized by a persistent direct connection of the arterial inflow and venous outflow without an intervening capillary bed. The primordial vascular plexus first differentiates into afferent, efferent, and capillary components. The more superficial plexus forms large vascular channels destined to be arteries and veins, while the deeper part develops into the capillary component associated with the brain surface. Perfusion of the embryonic brain starts at week four. AVMs arise from failure to develop an intervening capillary system. There is no genetic predisposition. Most AVMs are diagnosed initially in individuals between ages 20 and 40 who typically present with seizures, hemorrhages, and progressive deficits. In children, hemorrhage is the presenting symptom in approximately 80% of cases, and is about seven times more likely than seizure (7,8). This proportion is significantly higher than that found in adults. The reasons for the propensity of pediatric AVMs to hemorrhage are not understood. The mortality rate for AVM hemorrhage in children (25%) (9) is higher than that in adults, which approaches 6% to 10% (7). This may be due to the fact that AVMs in children are more prevalent in the posterior fossa (approximately 24%), where the effects of hemorrhage are more catastrophic, as compared with the predominantly supratentorial location in adults (7,9,10). Treatment modalities include surgical resection, stereotactic radiosurgery, embolization, and combinations of all of them. Surgical grading systems have been developed over the decades. Their primary purpose has been to prognosticate surgical outcomes, and their secondary purpose has been to select the appropriate treatment modalities for a specific AVM. This chapter will review the various grading systems and their potential usefulness in optimizing the treatment of AVMs. CLASSIFICATION AND GRADING PARAMETERS The following parameters will introduce the ‘‘raw material’’ from which grading scales and AVM classifications have been derived and used in various combinations. The most important factors are the anatomical features of the AVM. Hemodynamic parameters and general clinical factors also will be discussed. Anatomy Anatomic parameters include AVM size, location, drainage pattern, arterial supply, and associated aneurysms. These parameters form the critical basis for most grading scales as surgical prognosticators.

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Size Size can be determined as a simple diameter or as volume, the latter being more important for the planning of radiosurgery. For most grading scales, the largest diameter of the lesion is the size grading parameter, and this parameter is correlated with surgical outcome (4,10–17). Size estimation would appear to be a straightforward process, but some limitations and sources of error exist. Computed tomography (CT) uses linear projection techniques that do not distort the geometry of the object on its image. Magnetic resonance imaging (MRI) has several sources of potential errors such as the presence of signal voids and field inhomogeneity generated by various flow patterns that can cause errors in size estimation of up to 5 mm (18–20). With digital subtraction angiography, the gold standard technique for the diagnosis and grading of AVMs, magnification errors occur because of the divergent geometry of the incident x-ray beam (21,22). Errors in linear measurements may be up to 13% at a distance of 7 cm from the calibration plane. Accordingly, errors in area and volume measurements increase even more, up to 25% for area estimates and up to 40% for volume determinations. Linear errors increase further if nonspherical objects are inclined in the viewing direction. Such errors may be avoided if stereotactic markers and algorithms are used. This problem may also be overcome by the use of stereotactic digital dynamic angiographic imaging and an interactive volume rendering algorithm. These solutions do not address the added complexity of AVMs with multiple compartments or separating vessels that are part of the lesion and vessels that are en-passage, which may increase interobserver variability. Neither MRI nor angiography can solve these problems alone. It is critical, however, to optimize accuracy as much as possible because it is likely that AVM volume, rather than maximal linear diameter, will be the ideal size parameter for future studies that compare outcomes from surgical resection and from stereotactic radiosurgery. MRI, angiography, and CT angiography in conjunction will continue to be useful methods for estimating size and volume of AVMs, and consensus about a standard measurement technique would be highly desirable to optimize grading. Location The location of the AVM plays a critical role in the treatment plan. A small AVM located in the pons would be considered inoperable but may be amenable to other types of treatment. The same small AVM located in the right frontal pole would be easily amenable to surgical resection. Although AVMs can occur in any location in the brain, approximately 70% to 93% of AVMs are supratentorial, with a predilection for the cerebral hemispheres (9,15,23–25). In general, the location could be subdivided into regions of accessibility and type of neurological function that is subserved by the region in question (26,27), thereby creating the issue of ‘‘eloquent’’ versus ‘‘noneloquent’’ tissue (1). Eloquent areas are viewed as those whose destruction would result in an obvious and (for most) disabling deficit, such as the loss of speech or the use of an extremity. More subtle deficits may arise from damage to so-called noneloquent areas such as parts of the frontal and temporal lobe, which for some might be just as disabling (28). These considerations illustrate a general point: grading scales for AVMs or similar neurosurgical problems are useful only if each individual patient and the clinical circumstances are carefully assessed as well. Most neurosurgeons would agree, however, to divide the brain into regions of eloquence and ‘‘vital’’ importance as follows: &

Cortical (noneloquent) including the cerebellar hemispheres; the frontal, parietal, and temporal lobes with exception of the speech areas; sensory motor cortex, and the occipital lobes, depending on whether or not a visual field cut is viewed as a significant neurological deficit. & Cortical (eloquent) including sensory motor cortex, speech areas, and visual cortex. & Deep (nonvital) including insula, basal ganglia, anterior limb of the internal capsule, corpus callosum, deep medial temporal lobe, intra- and periventricular and deep cerebellar nuclei. & Deep (vital) including the genu and posterior limb of the internal capsule, thalamus, hypothalamus, brain stem, and any lesion extending into these structures. Drainage Pattern The venous drainage pattern is an important determinant of AVM complexity, can best be determined on angiograms, and may be divided into superficial and deep (12,16,17). The AVM drainage is considered deep if any or all of the venous outflow involves deep veins, such

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as the internal cerebral veins, basal veins, or precentral cerebellar vein. Transcerebral veins allow drainage from superficially located AVMs to the deep venous system. Deep venous drainage can pose a significant surgical challenge, as accessibility is poor and veins may retract deep into the parenchyma, thereby precluding bipolar cauterization (16,29). Although this impression is shared by many neurosurgeons, others do not place as much importance on the direction of the venous drainage (30–33). As indicated above, AVM drainage may involve not just a single venous channel but multiple draining veins. Associated venous anomalies such as varicosities that can reach aneurysmal proportions (34), as well as stenoses and occlusions (4) of such draining veins, may also add to the surgical complexity. Agenesis of the straight sinus associated with a venous steal and other venous abnormalities may be related to a worse prognosis (10,35,36). Arterial Supply The arterial supply of AVMs can arise from a single or multiple vascular territories and involve single or multiple feeders. AVMs located at border zones may be supplied by vessels from two or more territories. Feeding arteries have formed abnormal connections with the venous system in an area that would normally be supplied and drained by these vessels. In some cases, the external carotid circulation may participate and even be the sole source of AVM supply (37,38). These circumstances may not add significantly to the level of surgical difficulty (31). Feeding arteries enlarge secondary to the increased flow through the arteriovenous shunt (39,40). This enlargement in itself may increase the surgical risk (11). High venous pressures and high volume flow lead to increased tortuosity and enlargement of the draining veins. The hemispheric circulation can be further subcategorized into epicerebral, transcerebral, and subependymal circulation. Epicerebral arteries are short penetrating branches that are derived from small pial arteries and enter the cortex at a right angle to supply the cortical gray matter. Transcerebral vessels are longer, enter the deep cortical white matter, and terminate in the periventricular plexus. AVMs that involve mainly the transcerebral vessels may not be visible on the cortical surface. High flow shunting may lead to a steal phenomenon in adjacent brain regions, thereby leading to neurological symptoms. A simple terminal feeder may be ligated without consequence. It may be difficult to ligate multiple feeders completely without compromising adequate blood supply to important structures. This consideration is particularly important for the deep arterial system such as the lenticulostriate, choroidal, and deep perforating arteries at skull base (26,32). Therefore, the number and location of arterial feeders may correlate with surgical risk and prognosis. Furthermore, the specific anatomic origin of the feeding artery may invoke specific difficulties and correlate with a higher risk for complications (33). Associated Aneurysms Aneurysms are frequently associated with AVMs (41–47). The incidence of AVM-associated aneurysms is between 10% and 20%, but an incidence of up to 58% has been reported (47). Most of these reported aneurysms were intranidal and were diagnosed on angiograms that may be prone to interobserver variability. Such aneurysms have been suspected to be related to a higher risk of hemorrhage as the presenting symptom. Furthermore, they may influence the natural history and clinical course of the disease. It is estimated that the annual risk of hemorrhage from an AVM with coexisting aneurysms is 7% versus 1.7% for patients with AVMs only (44). AVM-related aneurysms may be categorized as intranidal, flow-related proximal, flowrelated distal, and unrelated (45). So-called venous aneurysms, however, are probably better described as venous pouches or varicosities that arise secondary to increased AVM shunt flow. Such venous pouches may, however, be associated with an increased risk for hemorrhage and represent an ominous feature (34). Proximal flow-related aneurysms occur on major vessels of the circle of Willis, the proximal middle cerebral (M1) and internal carotid (ICA) arteries, or the vertebrobasilar trunk, which eventually supply the AVM. Distal flow-related aneurysms are located more directly on feeding arteries. Intranidal aneurysms fill early during angiography and are located within the AVM nidus. Unrelated aneurysms do not have an apparent relationship with the AVM and may be coincidental. In their series of 632 AVM patients, Redekop et al. (45) found that 15.3% had at least one aneurysm. Of those, 36% had intranidal aneurysms, 73% had flow-related aneurysms, and 5% had unrelated aneurysms. Of all flow-related aneurysms, 68% were proximal and 32% were distal. The great majority of all flow-related aneurysms were small (less than 12 mm) in size (proximal 95% and distal 97%). No convincing correlation

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has been found between features of the AVM and the associated aneurysms, and therefore the aneurysms could be the result of complex interactions of host-specific and hemodynamic factors. More aneurysms appear to occur, however, in association with larger AVMs (43). The concept that AVM-related aneurysms are flow-related is supported by several observations including statistical analysis of the excessive number of aneurysms on high flow feeding vessels related to AVMs (48) and the disappearance of aneurysms after resection of the AVM (49,50). Aneurysms close to the nidus (distal flow-related) have a much higher rate of spontaneous regression after AVM resection than proximal ones. This finding correlates with more profound flow changes close to the nidus after AVM treatment compared with relatively minor changes proximally (45). Most of the evidence indicates that intranidal aneurysms are also true aneurysms rather than pseudoaneurysms that result from a hemorrhagic episode. The bleeding risk from proximal aneurysms may not be increased (42), whereas intranidal aneurysms or aneurysms close to the nidus may have a significantly increased risk of hemorrhage, especially if they are multiple (42,45,47). The management of these aneurysms is somewhat controversial. It may be beneficial to recommend treatment of the associated aneurysm first regardless of the definitive AVM treatment protocol. This paradigm is followed out of concern for the increased risk of hemorrhage in these patients (42,47). It is unclear if the presence of such aneurysms and their intraoperative surgical treatment increases the overall surgical risk. Hemodynamics AVMs have been categorized on the basis of hemodynamic factors (51,52). This scheme is based on the velocity within the AVM (high- and low-flow lesions), the steal phenomenon, and the velocity in vessels outside the AVM on proximal feeders including extracranial vessels. Spetzler and Martin (16) do not consider flow by itself but view it mainly in its relationship to the size of the AVM. Hemodynamic parameters can be determined during angiography or intraoperatively by directly measuring pressures and flow velocities or by transcranial Doppler for measurement of flow velocities. The steal phenomenon, which deprives other brain regions of adequate perfusion, may be related to the volume and level of shunting, which in turn is related to the AVM size. The presence of steal may increase the risk of hyperemic complications after AVM resection (11). Attempts have been made to assess the degree of steal, which was felt to correlate with the surgical risk, through the use of tagged red cell nuclear blood flow scans (51,52). Steal was classified as no steal, steal peripheral to the AVM, steal beyond AVM borders, and massive steal without connection to the AVM. Other factors such as AVM flow velocity and velocity in the cervical vessels were also felt to have an impact on the risks of surgical morbidity. Pasqualin et al. (32) created two prognostic groups on the basis of AVM flow velocities of greater or less than 120 cm/sec. Duong et al. (46) found a strong correlation between both feeding artery pressure and restricted venous outflow and the propensity of AVMs to hemorrhage. Decreased pulsatility (pulsatility index) within arterial feeders as determined by transcranial Doppler ultrasonography correlates with postoperative neurological outcome, and has been used as a predictor (53). The pathophysiologic correlates of such measurements remain to be determined. Clinical Features Clinical features can influence surgical outcomes for all neurosurgical procedures, and AVM surgery is no exception. The presence of neurological deficits and altered consciousness affect prognosis adversely. Likewise, significant comorbidity may be a contraindication for surgery. Age may also be a poor prognostic factor, although the age at which prognosis significantly worsens is disputed (11,15,17,26,52) and some do not consider age an important prognosticator at all (33). Conversely, young age carries the burden of the significant cumulative risk of subsequent hemorrhages and a greater propensity to develop a seizure disorder. Females may have a more favorable prognosis than males (4,15,33). GRADING SCALES Luessenhop and Gennarelli (1977): Number of Arterial Feeders The first AVM grading system, published by Luessenhop and Gennarelli in 1977 (31) was based on anatomic features that were analyzed on 300 angiograms. Excluded were lesions that

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were infratentorial, extended into the brain stem, or involved the vein of Galen. Three components of AVM-related vascular alterations were identified: & & &

Anatomic location of the AVM (specifically, where the shunt occurs); Enlargement of feeding arteries; and Enlargement of draining veins.

The grading scale is based on the number of tertiary named arteries that feed the AVM, with grades I to IV corresponding to the number of feeding arteries from one vascular territory [MCA, anterior cerebral artery (ACA), and posterior cerebral artery (PCA)]. If the number of arteries exceeds four, no additional grade is assigned, and the lesion is deemed inoperable. In cases of multiple territories, the grade is determined by the highest number of arteries from one territory. The scale provides for the following exceptions: &

The number of lenticulostriate arteries supplying an AVM are counted as if they were named arteries. & AVMs of the choroid plexus are considered grade III as they typically involve supply from one anterior and two posterior choroidal arteries. & AVMs of the corpus callosum supplied by branches from the pericallosal arteries are grade II, unless additional supply comes from the PCA (grade III). In addition to these parameters, the clinical status and the functional anatomical location of the lesion are loosely tied to the grading scheme. The clinical grading is supposed to correspond to the grading of patients with subarachnoid hemorrhage (SAH). The importance and impact of these auxiliary parameters increases with the angiographic grade. Grade I AVMs are considered operable with very low risk and hardly any restriction. Decisions about grades II to III AVMs become more complex. A good correlation of surgical morbidity and mortality rates with this grading system was found when it was applied to 49 cases. Grade IV AVMs were not seen in this series. The major weakness of this scale, however, involves the lack of clear guidelines for integrating the clinical and functional anatomical factors. Drake (1979): Preoperative Clinical Condition Drake (1) graded AVMs by size because he felt that large AVMs are more likely to involve eloquent brain, hemorrhage, and be followed by hyperemic complications after resection. In his series of 166 cases that were surgically treated, AVMs were classified in terms of size as (i) small, less than 2.5 cm; (ii) moderate, 2.5 to 5 cm; and (iii) large, greater than 5 cm. In his report, Drake made no formal attempt, however, to correlate this sizing scale to outcome. In fact, size itself was not seen as the critical obstacle to successful surgical resection. Instead, Drake felt that the preoperative clinical and neurological status of the patient was the single most important correlate of postsurgical outcome. Patients were classified preoperatively as either good or poor risk based on a 5-grade clinical scale: good risk, clinical grades 1 to 2; poor risk, clinical grades 3 to 5. An excellent correlation was found between postsurgical outcome and this preoperative risk assessment. In 140 surgically treated patients, 106 were good risk. In this group, 50% had excellent, 39% good, and 5% poor outcomes, and 6% died. In the poor risk group, outcomes were 3% excellent, 33% good, 32% poor, and 12% died. The short-coming of such a grading system is over-simplification, rendering it unhelpful as a grading scale but useful as a general guideline during decision making for preoperative planning. Pelletieri et al. (1980): Risk Profile Including Several Anatomic and Clinical Parameters This scale is based on various parameters that form a risk profile primarily for the purpose of deciding between surgical versus conservative treatment for 166 consecutive patients with AVMs (15). The scale was evaluated retrospectively by assessing the parameters and features of the AVM that had led to the decision regarding operability. The relative impact of each feature was statistically analyzed. Outcomes were divided into good (no or mild neurological deficit)

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and poor. The following variables in descending order of their impact on the decision-making process were included: & & & & & & &

AVM size: small (less than or equal to 3 cm) versus large (greater than 3 cm) Deep versus superficial location Age: less than or equal to 40 years or greater than 40 years Female versus male SAH versus no SAH Presence versus absence of neurological deficit at presentation ‘‘Silent’’ versus ‘‘nonsilent’’ area (nonsilent constituted the motor cortex and the sylvian fissure)

Factors favoring surgery were a small, superficial AVM in a silent region in a younger female presenting with SAH without neurological deficit. The prognostic risk profiles were found to be identical for patients who underwent surgery and those who were conservatively treated. The individual variables were ranked differently, however, in terms of their relative impact. The risk factor constellation that favors good outcomes in both the surgically and conservatively treated groups are listed in descending order of importance in Table 1. The risk constellation that favors surgical treatment is shown as well. Variables with negative impact were summed up with negative polarity, meaning that a patient with only negative variables was
7 on this scale. A patient without risk factors was 0. The statistical analysis was then extended to assign arbitrary numbers to variables based on the overall prognostic impact in both surgically and conservatively treated groups, with the scale extending from
16 to þ16. Overall, patients with (numerically) similar risk profiles fared better with surgery than with conservative treatment. The grading system, however, fails to provide a useful and simple guide on which decisions about operability and surgical risk can be based. In an attempt to equalize the risk factor constellation in both groups of patients, the study may have shown that surgically treated patients did better, but it did not provide reasons. For example, why would SAH be a favorable variable? Overall, the scale proved too complex for bedside use and did not gain broad application. Luessenhop and Rosa (1984): Size In 1984, Luessenhop and Rosa (30) simplified the 1977 grading system (see above) by grading only the size of the lesion on angiograms. In fact, it was suspected that the number of arterial feeders, to some degree, correlated with AVM size. Deep lesions form a notable exception. This new grading system could now also include cerebellar AVMs but continued to exclude brain stem lesions and vein of Galen malformations. AVM size was graded as follows: & & & &

Grade Grade Grade Grade

1: 2: 3: 4:

6 cm

Table 1 Risk Factor Constellations (Ranked) that Favor a Decision for Surgery and Good Outcomes in Both the Surgically Treated and Conservatively Managed Groups Favorable Outcomes Factor Rank

Decision for Surgery

Surgically Treated

Conservatively Managed

1 2 3 4 5 6 7

Small size Superficial Age < 40 years Female SAH No neurological deficit Silent area

No neurological deficit Age < 40 years Female Small size SAH Superficial Silent

Age < 40 years No neurological deficit Superficial Silent area Small size Female SAH

Abbreviation: SAH, subarachnoid hemorrhage. Source: From Ref. 15.

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Table 2 Correlation Between the Luessenhop and Rosa Grade and the Morbidity and Mortality Rates for 90 Surgically Treated Patients AVM Grade I II III

Number of Cases

Morbidity

Mortality

29 45 16

0 3 (6.7%) 7 (44%)

0 0 2 (12.5%)

Abbreviation: AVM, arteriovenous malformation.

This new system was applied to 90 patients, and the operative results are shown in Table 2. The authors found a good correlation between grade and outcome. Unfortunately, the definition of morbidity in this series lacks precision. For example, a ‘‘minor’’ sensorimotor deficit in a previously intact patient was not considered morbidity and additional qualifiers were included. Nevertheless, it appeared that small (grades 1 and 2) AVMs had a very low surgical morbidity rate, and the authors concluded that these malformations should be excised. They suggested that concessions to factors such as a critical location, age, or complicating disease were not necessary because the benefits of surgery appeared to outweigh the risks associated with the natural history of the disease. The commonly quoted rates for AVM hemorrhage are 2% to 3% for a first hemorrhage, 6% for recurrent hemorrhage during the first year, and 2% per year for a recurrent hemorrhage thereafter (54). For higher-grade lesions, a careful comparison of surgical risk versus natural history becomes much more important, and additional features such as a critical AVM location, age, and comorbidity weigh more heavily into the decision-making process. In addition, presentation with seizures alone skewed the authors toward conservative management for higher-grade lesions. In general, the authors concluded that surgical risk probably exceeds natural risk for lesions classified as grade III and higher in most patients beyond the fourth to fifth decades of life. This scale places significant emphasis on individual patient parameters except for all but low-grade lesions. In cases of small, deep-seated lesions in elderly patients with comorbidity, such a simplification may not be applicable. Spetzler and Martin (1986): Size, Pattern of Venous Drainage, Eloquence The grading system developed by Spetzler and Martin (16) is the most widely used scale today. The authors considered the most important factors for determining the difficulty of AVM resection to be size, number of arterial feeders, amount of flow through the AVM, amount of steal from neighboring areas, eloquence of the tissue, and pattern of venous drainage. Spetzler and Martin felt, however, that size, number of arterial feeders, amount of steal, and amount of flow through the AVM correlated well enough to be combined into one single variable, size. The AVM size was graded by the largest diameter of the nidus. Deep venous drainage was considered to be closely associated with surgical difficulty, as the deep veins are friable and have the propensity to retract and bleed. Drainage was considered deep if some or all of the drainage was through the deep veins (e.g., internal cerebral veins, basal veins, and precentral cerebellar vein). Resection of an AVM close to or within an area of eloquence also carried a higher risk for postoperative neurological deficit in this scheme. The following regions were classified as eloquent: sensorimotor cortex, cortical language areas (Broca, Wernicke), visual cortex, hypothalamus, thalamus, brain stem, and cerebellar peduncles. To assign an AVM grade, size, venous drainage pattern, and eloquence were determined on angiogram, CT, and MRI. Care was taken to correct for any angiographic magnification error (see above). The final grade consisted of the summation of points assigned to these parameters, as shown in Table 3. The scale consists of 5 grades with 12 possible combinations. A separate category was considered for very large lesions involving eloquent areas such as the thalamus or brainstem in which surgical resection would invariably lead to death or major deficit (‘‘grade 6’’ or inoperable). The grading scale was tested on 100 consecutive AVMs that were surgically resected. Outcome was graded as no deficit, including deficits lasting less than three days; minor deficits, including temporary worsening of neurological function beyond three days, mild residual ataxia, or ‘‘very mild’’ increase in brainstem deficit; or major deficit, including hemiparesis, aphasia, and hemianopia. No deaths occurred in this group. Outcomes correlated well with this grading scheme, as seen in Table 4.

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Table 3 Spetzler–Martin Scale for Grading Arteriovenous Malformations Variable

Points

Size 6 cm Venous drainage Superficial Deep Brain region Noneloquent Eloquent

1 2 3 0 1 0 1

This grading scale was very reliable owing to the simplicity of the variables and the low interobserver variability. The scale was applied retrospectively to other series of patients and was found to correlate well with surgical outcome (55–57). As with all grading scales, compromises were made between simplicity and practicality of a scale and the true complexity of each patient harboring an AVM. Criticism can be leveled at each point of this scale, and controversies surround all of them. Luessenhop and Rosa, for example, do not believe that deep venous drainage increases the surgical risk (30). Furthermore, controversy exists about the definition of eloquence and the relative impact of such regions on the surgical morbidity risks in each individual case (28,30,58). Malik et al. (58) point out that a large (greater than 6 cm) frontal lobe AVM and a small thalamic AVM with deep drainage would both be classified as grade III lesions, although the frontal lobe AVM should be much easier to resect. This scale does not formally include individual patient parameters. Shi and Chen (1986): Size, Location, Arterial Supply, Drainage Shi and Chen (26) proposed their scale in the same issue of the Journal of Neurosurgery as Spetzler and Martin (16). AVMs were graded according to the following parameters: 1. Size—largest diameter of the nidus on angiogram excluding distal parts of the draining veins. Sizes less than 2.5 cm, 2.5 to 5 cm, 5 to 7.5 cm, and greater than 7.5 cm correspond to grades 1 to 4, respectively. 2. Location and depth—superficial versus deep, ‘‘functional’’ versus ‘‘non-functional,’’ corpus callosum, brain stem, diencephalon. Grades 1 to 4 are assigned on the basis of increasing anatomic complexity and ‘‘functionality.’’ 3. Arterial supply—single superficial feeders (MCA/ACA) (grade 1), multiple superficial feeders (MCA/ACA) (grade 2), branches of PCA or deep MCA/ACA branches or vertebral artery (grade 3), main branches of all three territories or vertebrobasilar system (grade 4). 4. Venous drainage—single superficial (grade 1), multiple superficial (grade 2), deep (vein of Galen, straight sinus, etc.) (grade 3), deep with aneurysmal venous dilatation (grade 4).

Table 4 Correlation Between the Spetzler–Martin Grading Scale and the Morbidity and Mortality of 100 Surgically Treated Patients Degree of Deficit None

Minor

Major

Grade

No. of Patients

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

9 5 12 20 19 10

0 0 1 1 2 4

0 0 4 7 12 4

0 0 0 0 0 0

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Table 5 Correlation Between the Shi and Chen Grading Scale and the Morbidity and Mortality of 100 Surgically Treated Patients Operative Morbidity

Operative Mortality

Grade

No. of Cases

No.

(%)

No.

(%)

I I–II II II–III III III–IV Total

6 13 28 18 30 5 100

0 0 0 3 6 4 13

0 0 0 17 20 80 13

0 0 0 0 0 1 1

0 0 0 0 0 20 1

The final grade is determined by a simple algorithm and matched with the highest grade(s) if at least two criteria are in that grade. If only one criterion falls in the highest grade, the grade falls between two grades, such as grade III to IV. Operative results in 100 consecutive patients were classified by the presence or absence of operative morbidity and mortality. Operative morbidity was somewhat ill-defined as minor (able to live independently), and major (in need of major assistance or institutionalization). No grade IV patient was subjected to surgery. Surgical morbidity and mortality correlated well with the AVM grade, as shown in Table 5. This scale shares common features with the Spetzler–Martin scale, although it is somewhat more complex. The scale does not take any other individual patient factors into consideration. Tamaki et al. (1991): Size, Depth, Arterial Supply The outcomes of 151 patients treated either surgically or conservatively were assessed with a new grading scale (17). Patients in the surgical group had undergone complete resection, partial resection (intended or not intended), or palliative surgery (ventricular catheter, evacuation of hematoma, feeder clipping, and partial embolization). Twenty-nine patients were treated conservatively. AVMs were graded as follows: 1. Size—maximal diameter on angiogram: less than 4 cm (0 points), greater than or equal to 4 cm (2 points). 2. Location—superficial (0 points) versus deep (1 point), including periventricular, basal ganglia, and corpus callosum. Lesions in the thalamus and brain stem were excluded. 3. Feeding arteries—fewer than three arterial systems (0 points) and three or more systems (1 point). Each of the following was considered one system: ACA, MCA, PCA, anterior and posterior choroidals, lenticulostriates, thalamoperforators, AICA, or PICA. By adding points, grades 0 to 4 are possible. Outcome was assessed in five gradations from dead to no deficit and by the Karnofsky scale. Each variable was found to correlate independently with outcome and resectability on the basis of regression analysis. Because size was found to have the strongest correlation, two points were assigned to large AVMs. In Table 6,

Table 6 Correlation Between the Grading Scale of Tamaki et al. and Outcome Including the Karnofsky Scale Grade 0 1 2 3 4 Significance

No. of Surgically Treated Casesa 48 17 17 11 3

Total Excisions No. 45 14 13 7 2 p < 0.005

a Total excision or only a small part of the lesion remaining. Source: From Ref. 17.

(%) 94 82 76 64 67

Satisfactory Outcome No. 43 14 12 7 1 p < 0.001

(%)

Karnofsky Scale

90 82 71 64 33

86.7 14.0 83.5 16.6 76.5 12.7 68.2 19.4 66.7 20.8 p < 0.05

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outcomes are presented for those patients who underwent total resection or in whom only a small part of the lesion remained; outcomes are listed as satisfactory if the patient was at least able to return to work, although with some possible restrictions. This study evaluated the effects of age, venous drainage pattern, and eloquence on outcome. Patients ages 19 and younger were found to have better outcomes than patients ages 50 and older. No correlation was found between venous drainage pattern or eloquence and surgical morbidity. A formula to predict the postoperative Karnofsky scale was also used, in which size was weighed more heavily: Karnofsky scale ¼ 87.1 – 11.5  size
5.4  location
5.1  feeders. It is difficult to compare this scale, however, with the Spetzler–Martin scale because thalamic and brain stem lesions were not excluded and all AVMs were completely resected in the latter study. Furthermore, it was unclear how patients were assigned to the surgical versus conservative groups in Tamaki’s series. Pertuiset et al. (1991): Anatomical, Hemodynamic, Clinical One of the most complex grading systems was developed by Pertuiset et al. (52) on the basis of their experience with 57 cases. A score system was developed for a variety of factors in one of the three categories: anatomy, hemodynamics, and clinical. The final score would allow prediction of surgical outcome and operability. This system, in fact, was the first to incorporate hemodynamic factors by using Doppler flow studies and tagged red cell scans to evaluate the amount of steal. Briefly, anatomical parameters included the following: 1. 2. 3. 4. 5. 6.

Main feeding artery system (carotid, basilar, and combinations); Caliber of feeding arteries; Presence of deep feeders; Straightening of the main feeder; Localization (brainstem, thalamus, insula, hypothalamus get highest score); and Number of vascular territories (sectors). Hemodynamic factors included:

1. Volume (99Tc-tagged red cells scan) and vascular autoregulation; 2. Steal (semiquantitative); and 3. Flow velocity in neck vessels for each carotid and vertebral artery. Clinical factors included: 1. Previous rupture; and 2. Associated diseases, age over 50 years, vital organ malformations. A total score was calculated and was used to determine operability. A special (veto) score was given to a single parameter if, by itself, it should preclude surgery regardless of the other scores (e.g., a lesion in the brain stem). This scoring system correlated well with operative outcome. The mortality in this series was high and reached 14%. This type of scoring system is too complicated to gain wide acceptance and parameters within the scoring system are not always well defined. The prognostic significance of the hemodynamic factors may also be questionable. Ho¨llerhage et al. (1992): Clinical Grade, Origin of Feeders, Shunting Ho¨llerhage et al. (33) used multiple regression analysis in 107 patients to retrospectively determine and weigh the variables best suited for predicting the risk of surgical morbidity. Clinical status at presentation was determined by a 5-grade scale similar to the Hunt and Hess scale for SAH. Outcome was determined by the Glasgow Outcome Scale. The factors listed in Table 7 were identified as having a significant impact on outcome. Similar to the analysis by Shi and Chen (26), deep versus superficial venous drainage had no impact on outcome. Surprisingly, size also did not reach significance as a prognosticator. The authors proposed a grading system based on the marked factors in Table 7, assigning the number 1 or 0 to each, except the clinical grade on admission, which was dichotomized and assigned a 1 or 2 (to avoid a grade of 0) with a maximum overall score of 7. In a deviation from their

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Table 7 Statistical Analysis of the Impact of Various Factors on Outcome Adverse Factors Male sex Eloquent area A1 feedersa M1 feedersa Rolandic feedersa Fronto-orbital feeders Shunt through anterior communicating arterya Poor clinical gradea

Significance (p 20 cm3) are usually followed or treated with palliative embolization. Protocols for fractionated stereotactic radiotherapy or radiosurgery are also being applied.

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7. Kader A, Goodrich J, Sonstein W, et al. Recurrent cerebral arteriovenous malformations after negative postoperative angiograms. J Neurosurg 1996; 85:14–18. 8. Kondziolka D, Humphreys R, Hoffman H, et al. Arteriovenous malformations of the brain in children: a forty year experience. Can J Neurol Sci 1992; 19:40–45. 9. Morioka T, Nishio S, Hikita T, et al. Marked growth of an angiographically occult arteriovenous malformation. Neurosurgery 1988; 23:101–103. 10. Karlsson B, Lindquist C, Johansson A, et al. Annual risk for the first hemorrhage from untreated cerebral arteriovenous malformations. Min Invas Neurosurg 1997; 40:40–46. 11. Mansmann U, Meisel J, Brock M, et al. Factors associated with intracranial hemorrhage in cases of cerebral arteriovenous malformation. Neurosurgery 2000; 46:272–281. 12. Marks MP, Lane B, Steinberg GK, et al. Hemorrhage in intracerebral arteriovenous malformations: angiographic determinants. Radiology 1990; 176:807–813. 13. Nataf F, Meder JF, Roux FX, et al. Angioarchitecture associated with hemorrhage in cerebral arteriovenous malformations, a prognostic statistical model. Neuroradiology 1997; 39:52–58. 14. Crawford P, West C, Chadwick D, et al. Arteriovenous malformations of the brain: natural history in unoperated patients. J Neurol Neurosurg Psychiatry 1986; 49:1–10. 15. Graf JG, Perret GE, Torner JC. Bleeding from cerebral arteriovenous malformations as part of their natural history. J Neurosurg 1983; 58:331–337. 16. Langer DJ, Lasner TM, Hurst RW, et al. Hypertension, small size, and deep venous drainage are associated with risk of hemorrhagic presentation of cerebral arteriovenous malformations. Neurosurgery 1998; 42:481–486. 17. Stapf C, Mohr JP, Pile–Spellman J, et al. Concurrent arterial aneurysms in brain arteriovenous malformations with hemorrhagic presentation. J Neurol Neurosurg Psychiatry 2002; 73:294–298. 18. Willinksy R, Lasjaunias P, TerBrugge K, et al. Brain arteriovenous malformations: analysis of the angioarchitecture in relation to hemorrhage. J Neuroradiol 1988; 15:225–237. 19. Stefani MA, Porter PJ, TerBrugge KG, et al. Angioarchitectural factors present in brain arteriovenous malformations associated with hemorrhagic presentation. Stroke 2002; 33:920–924. 20. Ondra S, Troupp H, George E, et al. The natural history of symptomatic arteriovenous malformations of the brain: a 24-year follow up assessment. J Neurosurg 1990; 73:387–391. 21. Brown R, Wiebers D, Torner J, et al. Frequency of intracranial hemorrhage as a presenting symptom and subtype analysis: a population–based study of intracranial vascular malformations in Olmstead County, Minnesota. J Neurosurg 1996; 85:29–32. 22. Hartmann A, Mast H, Mohr J, et al. Morbidity of intracranial hemorrhage in patients with cerebral arteriovenous malformation. Stroke 1998; 29:931–934. 23. Forster D, Steiner L, Hakansson S. Arteriovenous malformations of the brain. A long–term clinical study. J Neurosurg 1972; 37:562–570. 24. Stapf C, Mast H, Sciacca RR, et al.; New York Islands AVM Study Collaborators. The New York Islands AVM study: design, study progress, and initial results. Stroke 2003; 34:e29–e33. 25. Mast H, Young W, Koennecke H–C, et al. Risk of spontaneous hemorrhage after diagnosis of cerebral arteriovenous malformation. Lancet 1997; 350:1065–1068. 26. Al–Shahi R, Warlow C. A systematic review of the frequency and prognosis of arteriovenous malformations of the brain in adults. Brain 2001; 124:1900–1926. 27. Soderman M, Andersson T, Karlsson B, et al. Management of patients with brain arteriovenous malformations. European J Radiol 2003; 46:195–205. 28. Apsimon HT, Reef H, Phadke RV, et al. A population–based study of brain arteriovenous malformations. Long–term treatment outcomes. Stroke 2002; 33:2794–2800. 29. Kondziolka D, McLaughlin MR, Kestle JR. Simple risk predictions for arteriovenous malformation hemorrhage. Neurosurgery 1995; 37:851–855. 30. Brown RD. Simple risk predictions for arteriovenous malformation hemorrhage [comment]. Neurosurgery 2000; 46:1024. 31. Stapf C, Khaw AV, Sciacca RR, et al. Effect of age on clinical and morphological characteristics in patients with brain arteriovenous malformation. Stroke 2003; 34:2664–2669. 32. 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. Stroke 2001; 32:1458–1471. 33. Maruyama K, Kawahara N, Shin M, et al. The risk of hemorrhage after radiosurgery for cerebral arteriovenous malformations. N Engl J Med 2005; 352:146–153. 34. Valavanis A, Yasargil MG. The endovascular treatment of brain arteriovenous malformation. Adv Tech Stand Neurosurg 1998; 24:131–214. 35. Wikholm G, Lundqvist C, Svendsen P. The Giteborg cohort of embolized cerebral arteriovenous malformations: a 6-year follow-up. Neurosurgery 2001; 49:799–805 [discussion pp. 805–896]. 36. Willinsky R, Goyal M, TerBrugge K, et al. Embolization of small (200 mg/dL) despite subcutaneous insulin, an insulin drip is run. An insulin drip permits very tight control of blood glucose levels, and, after 24 hours, allows calculation of the daily insulin requirement for conversion back to a subcutaneous regimen. INFECTIOUS DISEASE Critical illness, immunosuppressant effects of glucocorticoids, and the presence of numerous catheters and lines all place patients at risk of infection. Mechanically ventilated patients are at particular risk of sinusitis and pneumonia. Infectious disease management begins with efforts to diminish risk. Aggressive pulmonary toilet is important for all ventilated patients. In patients for whom a prolonged ventilator-dependent course is anticipated, tracheostomy should be performed early. Vascular access catheters should be changed every three to five days to avoid progression from bacterial colonization to infection. Patients with ventriculostomy or an ICP monitor should be given a broad-spectrum antibiotic for prophylaxis; the authors prefer cefazolin (1 g IV every eight hours). Infections are relatively common in critical care patients. A fever or elevated white blood cell count should prompt a meticulous workup for a source of infection. Blood, sputum, urine cultures, and a chest X-ray are usual screening tests. The risk of ventriculitis or meningitis ranges as high as 8.9% in patients with ventriculostomy (39); CSF analysis and cultures should be ordered for any patient suspected of having an intracranial infection. A head CT with intravenous contrast is also useful to rule out ventriculitis, brain abscess, and sinusitis. Once an infectious source is identified, the antibiotic regimen should be correlated with the culture sensitivities. Fever of unknown origin is a periodic problem in neurosurgical critical care patients. Elevations in brain temperature exacerbate ischemic injury (40) and should be avoided. Multiple possible causes of fever should be investigated, such as infections, deep venous thrombosis, atelectasis, and drug fever. Patients who continue to be febrile despite a negative fever workup should be treated with acetaminophen (650 mg every four hours) and cooling blankets to maintain the body temperature in the normal range. The fever workup should be repeated daily or every other day, if needed, to ensure that a treatable fever source is not overlooked. SEDATION AND ANALGESIA Sedation is necessary for mental status changes related to neurologic injury and anxiety. Adequate analgesia and sedation are also important to avoid wide fluctuations in blood pressure. The

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authors prefer intermittent doses of morphine (2–6 mg IV as needed) and midazolam (1–2 mg IV as needed). The minimal dose of each drug should be given so as not to cloud the neurologic examination. Propofol (continuous IV infusion) is a useful alternative, particularly in patients with elevated ICP. Propofol has a very short half-life, which permits fine-tuning of the dose and frequent interruptions of the infusion for neurologic assessment. Propofol is carried in a lipid-based solution with a relatively high caloric content. This should be taken into consideration when nutritional needs are calculated. In addition, with prolonged infusions, the increased lipid metabolic load can lead to a compensatory respiratory alkalosis, as the patient seeks to blow off the added CO2. Propofol infusion should not be used in children for longer than 24 hours; propofol infusion for more than 48 hours in children is associated with fatal myocardial failure (41). GLUCOCORTICOIDS Glucocorticoids inhibit vasogenic cerebral edema and may be helpful for short-term use in patients with AVMs. The authors use dexamethasone (10 mg IV) at the time of surgery, followed by a short course (6 mg IV every six hours) in the ICU, then a taper. Gastrointestinal protection with an H2 blocker is necessary during treatment with glucocorticoids. THROMBOTIC COMPLICATIONS Neurologically impaired patients are at risk of deep venous thrombosis (DVT), primarily because of immobility. Synchronized compression devices, applied continuously to the lower extremities, prevent lower-extremity DVTs in the majority of cases. The lower extremities of patients at risk of DVT should be examined daily; evidence of DVT includes lower-extremity swelling or discoloration, or fever. A patient suspected of having a DVT should undergo Doppler ultrasonography. Patients with intracranial vascular disease and a DVT are at significant risk of pulmonary embolism. Patients in the perioperative period who are unable to undergo systemic anticoagulation should be considered for placement of a vena cava filter. SEIZURE PROPHYLAXIS AND TREATMENT Seizures are a common presenting feature of patients with AVMs. Patients presenting with angiomatous hemorrhage should be treated with anticonvulsants. The authors prefer to give a loading dose of phenytoin (17 mg/kg IV) on admission, followed by a maintenance regimen of 100 mg IV three times a day. Serum phenytoin levels are checked only in the event of seizure or suspected phenytoin toxicity. Patients undergoing elective resection of an AVM are frequently already on an anticonvulsant regimen. For patients not already being treated with an anticonvulsant, the loading dose of phenytoin can be given before treatment. A seizure in a patient with an AVM is a neurologic emergency. Attention to the airway is critical for nonventilated patients. A seizure in progress can be treated with lorazepam, 4 mg IV over two minutes, and repeated every five minutes up to a maximum dose of 9 mg (42). For seizures refractory to lorazepam, phenobarbital (20 mg/kg IV infused 5 liters; two patients died and four had ‘‘rewarding results’’ (24). Residual AVM

Occasionally, a daughter nidus may be ‘‘disconnected’’ from the major nidus during the course of AVM resection. This retained malformation may be the cause of persistent intraoperative bleeding. Although intraoperative angiography is the best way to detect residual nidus, this study is not always available or feasible. Doppler sonography is helpful for identifying retained AVM (29,31). Usually, the daughter nidus is hidden in a sulcus closely related to the main nidus and is connected by one or two vessels. Thorough inspection of the resection cavity after the surgeon feels the AVM has been completely removed occasionally reveals a swollen, tense, or deformed margin that usually represents residual malformation. Routine elevation of the patient’s blood pressure 10–15 mmHg above preoperative levels and inspection for 15 minutes before dural closure may also identify retained AVM and prevent complications or the need for additional AVM therapy. Samson and Batjer advocate immediate postoperative angiography under the same anesthetic and return to the operating room for immediate reexploration if the angiogram reveals evidence of persistent arterial to venous shunting (6). Because the resolution of portable intraoperative angiography is not always sufficient to identify retained elements, careful exploration of the resection cavity before closing will improve results. Brain Swelling Although brain swelling during the course of a neurosurgical operation is by no means unique to surgery performed for AVMs, the specific pathophysiology of these lesions presents additional challenges. General causes such as hypercapnia from obstruction of the endotracheal tube or ventilator disconnection must be ruled out first. Venous drainage compromise must also be ruled out by checking the patient’s head, neck, and body position. Once these causes are ruled out, the specific complications of AVM surgery must be explored, including occult bleeding, intraventricular hemorrhage causing acute obstructive hydrocephalus, and cerebral edema from dysautoregulation. Occult Bleeding Whereas an intraparenchymal hematoma of significant size is unlikely to be completely hidden from the surgeon’s view, a portion of the AVM may become isolated from the surgical exposure and bleed when its venous drainage is disconnected. Significant brain swelling may ensue with no immediately apparent cause. Often, this rapidly expanding hematoma will rupture into the previous plane of resection. The plane of resection must be expanded to include the hematoma cavity, and a circumferential dissection must continue after the hematoma has been evacuated. The potential consequences of such a hemorrhage include parenchymal damage from compression and vascular injury during evacuation and control of bleeding. There is also the potential for rupture into the ventricle (see below). Obstructive Hydrocephalus The ventricle is routinely entered on many AVM resections, and proper precautions can be taken in most instances to prevent the complications of expected bleeding into the ventricular

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system. Effective measures include the placement of cotton sponges to block exposed entry points during resection and removal of all identifiable intraventricular clot with extensive irrigation of the exposed ventricular system before closure. Occasionally, bleeding into the ventricle may be occult, and present only as global or focal brain swelling, accompanied by bradycardia, sudden hypertension, or no change in the vital signs. Premature entry into the ventricle secondary to deep dissection with inadequate circumferential exposure of the AVM is the likely source of such bleeding. When suspected, the ventricle must be immediately exposed through the ependymal wall and the clot evacuated. The site of bleeding must be methodically identified and secured. Normal Perfusion Pressure Breakthrough/Occlusive Hyperemia Once all of the previously mentioned causes of swelling have been ruled out during a period of unexplained intraoperative cerebral edema, NPPB must be considered. This condition, originally described by Spetzler and Wilson, has been reported by several other experienced cerebrovascular neurosurgeons and challenged by others (22,32–37). It is characterized by acute massive brain swelling with a firm, distended, herniating margin of brain around the malformation with multiple bleeding points that are resistant to coagulation. The theory states that the brain around the AVM was subjected to prolonged ischemic steal, resulting in chronic dilatation and loss of autoregulation of the brain’s arteries in an attempt to divert blood from the AVM. These vessels are putatively unable to autoregulate when normal perfusion is reestablished by virtue of resection of the AV shunt. The adjacent brain capillary ‘‘breakthrough’’ results in edema and hemorrhage. Figure 3 demonstrates an AVM that is at high risk for NPPB. When NPPB occurs intraoperatively, it usually appears toward the end of the resection when the high flow shunt has been removed. Treatment consists of immediate brain protection from elevated cerebral perfusion pressure (CPP) by EEG burst-suppressive anesthesia with pentobarbital and systemic arterial blood pressure reduction (systolic 80–90 mmHg) with sodium nitroprusside or nicardipine (33). This approach usually arrests the spread of cerebral edema, allowing for craniotomy closure. Hemorrhagic brain tissue may need to be resected as well as residual AVM. This surgery must be performed with absolute hemostasis. An ICP monitor should be placed, and the patient should be taken for immediate cerebral angiography to verify complete AVM resection. Drake reported the occurrence of NPPB in 4/166 (2%) patients undergoing surgery for AVMs, and all four patients died (38). Heros reported the occurrence of NBBP in only 4/300 (1.3%) patients in his surgical series; good outcomes were achieved in three of them (34). Day et al. successfully treated NPPB that began intraoperatively in three patients with three to five days of the regimen described above, including return to the operating room for evacuation of delayed hematomas (33). The ICP should be lowered by pharmacological means over the next 24 hours under barbiturate coma, and head CT scans should be performed for any unexplained alteration. If the surveillance CT scans demonstrate no progression, the patient can be weaned from the antihypertensive agent over the next 12 to 24 hours provided that the ICP remains controlled and systemic blood pressure does not rise inappopriately. The patient can then be weaned from the barbiturate over the following 24 hours (it may take a few days to metabolize and clear systemically). Prevention of NPPB is the best form of treatment. High fistula flow with a paucity of flow entering the immediately adjacent brain is the angiographic hallmark predicting this condition. Staging AVM treatment with repeat operative approaches and/or endovascular embolization techniques can be effective prophylaxis. This approach theoretically allows autoregulation to be restored at a gradual pace, as the high-flow shunting is methodically reduced.

POSTOPERATIVE CONSIDERATIONS Postoperative Hemorrhage/Cerebral Edema Residual AVM is the most common cause of postoperative hemorrhage, and a daughter nidus is one of the most frequent causes of retained lesion. These are often small remnants of malformation left on the wall or within an adjacent sulcus to the main area of nidus resection. These portions are transected from the bulk of the nidus during the attempt to follow a plane of resection along the vascular coils of the lesion.

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In a series of 414 operations reported by Yasargil for cerebral AVM and vein of Galen aneurysms, reexploration for ICH was required in 29 (7%) instances. Twelve of these 29 patients (41%) had residual AVM, nine of which were completely resected. Of the 12 patients who had residual AVM at the second surgery, six had good outcomes and six died (24). Drake reported that of 105 patients studied with postoperative angiograms, 18 (17%) showed residual AVM. Five of these underwent immediate reresection, although one had an early rehemorrhage. With reoperation, two had a good result, one died, and two did poorly due to large hemorrhages. Fourteen other patients had known incomplete resections and did not undergo immediate reoperation. Five of these had delayed rehemorrhages (38). NPPB is a rare but potential cause of postsurgical bleeding. The Mayo Clinic group uses the term ‘‘occlusive hyperemia’’ to describe the phenomenon of otherwise unexplained brain edema and hemorrhage that occasionally occurs in the postoperative period after resection of a high-flow AVM resection. They analyzed 295 cases of AVM resection over a 20-year period and found the most common cause of postoperative neurological deterioration (15/34 cases) was incomplete AVM resection (36). Of the 19 other patients with deterioration, 13 had hemorrhage and edema, and six had edema alone. Postresection angiography revealed that these 19 patients consistently demonstrated slow flow in former AVM feeders and their parenchymal branches, and impaired venous drainage in the region of resection in 14/19 of these patients. They theorize that stagnant flow in arterial feeders produces hypoperfusion significant enough to cause ischemia, with resultant hemorrhage and/or edema, further complicated by venous outflow obstruction; this leads to hyperemia, engorgement, and worsened arterial stagnation. Early diagnosis and aggressive medical and surgical management of these hemorrhagic complications of AVM surgery are essential to preserve the lowest rates of morbidity and mortality that are possible with the treatment of cerebral AVMs. Vascular Thrombosis Similar to the occlusive hyperemia theory, delayed postoperative neurological deficit can result from parenchymal damage secondary to stasis or true occlusion of veins exposed to arterialized blood before AVM resection. Retrograde thrombosis of major arterial feeders back to the point of a proximal major branch has been reported (39). Old age, larger AVM size, and marked dilatation and elongation of feeders were identified as potential risk factors for this complication. This group treated the complication with intra-arterial urokinase infusion and achieved dramatic clinical and angiographic improvement. Dense hemiplegia and aphasia developed acutely, 30 minutes postoperatively after left frontotemporal AVM surgery, and an angiogram revealed occlusion of the M1 segment of the middle cerebral artery (MCA) The patient had a partially retained microcatheter in the MCA feeding the AVM from a previous embolization procedure that was likely the nidus for postoperative thrombosis. After selective M1 urokinase infusion, the MCA recanalized and the patient recovered to have only a mild expressive aphasia and arm and hand apraxia with normal strength (39). Delayed hemorrhagic venous infarction has been reported after AVM resection, presumed secondary to thrombosis of draining veins, and requiring reoperation and evacuation. The patient in this report had a right temporal lesion and achieved a good outcome, with return to the usual occupation, although suffering from a quadrantanopsia (40). Epilepsy A review of the literature reveals that 27% to 38% of patients with AVMs have epilepsy before treatment, and 4% to 30% develop new seizures after treatment (1,41). Most seizure disorders associated with AVMs are effectively controlled with antiepileptic medications, and patients with malformations in epileptogenic regions should routinely be treated prophylactically with these agents. The reduction or elimination of seizure activity in patients with AVMs and pretreatment epilepsy is a separate issue. Seizures were eliminated in roughly 18% of patients in whom arterial feeders were eliminated by ligation or embolization (8,42). AVM resection increases seizure-free outcome to approximately 56% of patients (43,44). Approximately 50% of 55 patients with preoperative epilepsy in a series of 153 patients operated on for AVM were

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seizure free after AVM surgery (45). Directed seizure surgery with AVM resection can result in as much as a 75% chance of seizure-free outcome (46–48). Cerebrospinal Fluid Absorption Most patients who undergo cerebral AVM surgery do not require permanent CSF diversion. However, temporary ventricular dilatation is a frequent complication of both AVM rupture and surgery due to the presence of blood in the ventricular and subarachnoid spaces after these events. External ventricular drainage usually allows for control of ICP as well as removal of bloody CSF during the time that normal absorption pathways recover. Yasargil found that 8.4% of his 414 patients required shunt operations for hydrocephalus, 4.1% before and 4.3% after AVM resection (24). General Medical Issues Awareness of potential complications, proper monitoring for their development, and prophylactic and therapeutic intervention are basic tenets of postsurgical care. Detailed description and management strategies are beyond the scope of this chapter; however, certain conditions are highlighted briefly. Prolonged immobilization will occasionally follow complicated AVM surgery, and the potential complications of deep venous thrombosis and atelectasis can be reduced with appropriate intermittent compression stockings and pulmonary toilet procedures. Early mobilization, incentive spirometry, and involvement of speech, occupational, and physical therapists will also assist with these potential problems. Residual AVM/Regrowth In Yasargil’s series of 414 surgeries for AVM, residual AVM was the cause of postoperative bleeding in the acute phase in twelve patients (24). Three of these patients had bilateral thalamic AVMs that could not be eliminated, and they died. Three patients whose residual AVMs were completely resected at the second surgery also died. Six others made a good recovery. Yasargil identified 10 other patients whose postoperative angiograms showed incomplete removal. Three of these patients refused surgery, and one of these later died of a rebleed.

Figure 4 Regrowth of an arteriovenous malformation (AVM). Postoperative angiogram after resection of an AVM showing complete resection (A), and repeat angiogram in the same patient after the delayed rebleed demonstrating AVM regrowth (B).

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Of the other seven patients, one had a mesencephalic remnant that was deemed inoperable, one died of a postoperative complication, one died of AVM rebleed, and four were considering radiation versus reexploration at the time of publication (24). Yasargil identified five patients who had complete AVM resection and documented regrowth of the AVM that requires additional surgery one to seven years after the first surgery (24). Four of these suffered rehemorrhage before the regrowth was discovered. Paterson and McKissock reported an additional patient who had a rebleed from a completely excised AVM two years after surgery (49). Forster et al. also reported one case of delayed rebleeding in 49 patients who had complete excision of the AVM (50). We have seen this phenomenon in two patients who presented with rebleeds. Both underwent repeat resection and made good recoveries. Figure 4 demonstrates the initial postoperative angiogram of one of the patients, revealing complete AVM resection, and a repeat angiogram after the delayed rebleed demonstrating AVM regrowth. This patient had abused cocaine and metamphetamines in the interim, and it is possible that this behavior affected her vascular system. SUMMARY The management of cerebral AVMs requires the neurosurgeon to draw from all aspects of his/ her training and skill in terms of proper judgment and microsurgical technique. Perhaps the most difficult decision is to determine which patients and lesions are appropriate for surgical intervention. Systematic analysis of pre-, intra-, and postoperative factors will enable the clinician to recommend appropriate evaluation and intervention for these challenging lesions. With the correct approach, many of these malformations can be safely and completely resected surgically with minimal risk of permanent sequelae. Complications are to be expected, however, even in the hands of the most skilled cerebrovascular surgeons who deal with a large number of cerebral AVMs. Appropriate recognition and management of these complications are essential to achieve the excellent outcomes that are possible with surgical treatment of these lesions. REFERENCES 1. Heros RC. Surgery for arteriovenous malformations of the brain. In: Ojemann RG, Ogilvy CS, Crowell RM, Heros RC, eds. Surgical Mangement of Neurovascular Disease. Baltimore: Williams and Wilkins, 1995:419–474. 2. Graf CJ, Perret GE, Torner JC. Bleeding from cerebral arteriovenous malformations. J Neurosurg 1983; 58:331–337. 3. 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; 73:387–391. 4. Jafar J, Rezai A. Acute surgical management of intracranial arteriovenous malformations. Neurosurgery 1994; 34:8–13. 5. Camarata PJ, Heros RC. Arteriovenous malformations of the brain. In: Youmans, ed. Neurological Surgery. Philadelphia: WB Saunders, 1996:1372–1404. 6. Samson DS, Batjer HH. Surface lesions: lobar arteriovenous malformations. In: Apuzzo MLJ, ed. Brain Surgery. Complication Avoidance and Management. New York: Churchill Livingstone, 1990: 1142–1175. 7. McCormick WF. Pathology of vascular malformations of the brain. In: Wilson CB, Stein BM, eds. Intracranial Arteriovenous Malformations. Baltimore: Williams and Wilkins, 1984:44–65. 8. Kusske JA, Kelly WA. Embolization and reduction of the ‘‘steal’’ syndrome in cerebral arteriovenous malformations. J Neurosurg 1974; 40:313–321. 9. Vinuela F, Nombela L, Roach MR, Fox AJ, Pelz DM. Stenotic and occlusive disease of the venous drainage system of deep brain AVMs. J Neurosurg 1985; 63:180–184. 10. Newton TH, Troost BT, Moseley I. Angiography of arteriovenous malformations and fistulas. In: Wilson CB, Stein BM, eds. Intracranial Arteriovenous Malformations. Baltimore: Williams and Wilkins, 1984:64–104. 11. Nornes H, Grip A. Hemodynamic aspects of cerebral arteriovenous malformation. J Neurosurg 1980; 53:456–464. 12. Spetzler RF, Wilson CB. Enlargement of an arteriovenous malformation documented by angiography. J Neurosurg 1975; 43:767–769. 13. Parkinson D, Bachers G. Arteriovenous malformations. J Neurosurg 1980; 53:285–299. 14. Batjer H, Suss RA, Samson D. Intracranial arteriovenous malformations associated with aneurysms. Neurosurgery 1986; 18:29–35.

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15. Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg 1986; 65:476–483. 16. Korosue K, Heros RC. Complications of complete surgical resection of AVMs of the brain. In: Barrow DL, ed. Intracranial Vascular Malformations. Neurosurgical Topics. Chicago: AANS Publications, 1990:157–168. 17. Hinke RM, Hu X, Stillman AE. Functional magnetic resonance imaging of Broca’s area during internal speech. Neuroreport 1993; 4:675–678. 18. Tarr RW, Johnson DW, Rutigliano M, et al. Use of acetazolamide-challenge xenon CT in the assessment of cerebral blood flow dynamics in patients with arteriovenous malformations. Am J Neuroradiol 1990; 11:441–448. 19. Batjer HH, Devous MD. The use of acetazolamide-enhanced regional cerebral blood flow measurement to predict risk to arteriovenous malformation patients. Neurosurgery 1992; 31:213–218. 20. Sisti MB, Solomon RA, Stein BM. Stereotactic craniotomy in the resection of small arteriovenous malformations. J Neurosurg 1991; 75:40–44. 21. Golfinos JG, Fitzpatrick BC, Smith LR, Spetzler RF. Clinical use of a frameless stereotactic arm: results of 325 cases. J Neurosurg 1995; 83:197–205. 22. Sugita K, Takayasu M. Arteriovenous malformations: general considerations. In: Apuzzo MLJ, ed. Brain Surgery. Complication Avoidance and Management. New York: Churchill Livingstone, 1990:1114–1117. 23. Martin N, Doberstein C, Bentson J. Intraoperative angiography in cerebrovascular surgery. Clin Neurosurg 1991; 37:312–331. 24. Yasargil MG. Microneurosurgery IIIB: AVM of the Brain. New York: Thieme Medical Publishers, 1988. 25. Yasargil MG. Microneurosurgery IIIA: AVM of the Brain. New York: Thieme Medical Publishers, 1987. 26. Stein BM. Arteriovenous malformations of the cerebral convexities. In: Wilson CB, Stein BM, eds. Intracranial Arteriovenous Malformations. Baltimore: Williams and Wilkins, 1984:156–183. 27. Heros RC. Brain resection for exposure of deep extracerebral and paraventricular lesions. Surg Neurol 1990; 34:188–195. 28. Woodard EJ, Barrow DL. Clinical presentation of intracranial arteriovenous malformations. In: Barrow DL, ed. Intracranial Vascular Malformations. Neurosurgical Topics. Chicago: AANS Publications, 1990:53. 29. Hassler W, Steinmetz H. Cerebral hemodynamics in angioma patients: an intraoperative study. J Neurosurg 1987; 67:822–831. 30. Morgan MK, Johnston IH, Hallinan JM, Weber NC. Complications of surgery for arteriovenous malformations of the brain. J Neurosurg 1993; 78:176–182. 31. Martin N, Doberstein C, Bentson J. Intraoperative angiography in cerebrovascular surgery. Clin Neurosurg 1991; 37:312–331. 32. Spetzler RF, Wilson CB, Weinstein P, Mehdorn M, Townsend J, Telles D. Normal perfusion pressure breakthrough theory. Clin Neurosurg 1978; 25:651–672. 33. Day AL, Friedman WA, Sypert GW. Successful treatment of the normal perfusion pressure breakthrough syndrome. Neurosurgery 1982; 11:625–630. 34. Heros RC, Korosue K. Deep parenchymous lesions. In: Apuzzo MLJ, ed. Brain Surgery. Complication Avoidance and Management. New York: Churchill Livingstone, 1990:1175–1193. 35. Young WL, Kader A, Prohovink I, et al. Pressure autoregulation is intact after arteriovenous malformation resection. Neurosurgery 1993; 32:491–497. 36. Al-Rodan NRF, Sundt TM, 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; 78:167–175. 37. Wilson CB, Hieshima G. Occlusive hyperemia: a new way to think about an old problem. J Neurosurg 1993; 78:165–166. 38. Drake CG. Cerebral arteriovenous malformations: considerations for and experience with surgical treatment in 166 cases. Clin Neurosurg 1979; 26:145–208. 39. Sipos EP, Kirsch MJR, Debrun G, Ulatowski JA, Bell WR. Intra-arterial urokinase for treatment of retrograde thrombosis following resection of an arteriovenous malformation. Case report. J Neurosurg 1992; 76:1004–1007. 40. Miyasaka Y, Yada K, Ohwada T, et al. Hemorrhagic venous infarction after excision of an arteriovenous malformation: case report. Neurosurgery 1991; 29:265–268. 41. Weinand ME. Arteriovenous malformations and epilepsy. In: Carter LP, Spetzler RF, Hamilton MG, eds. New York: McGraw-Hill, 1995:933–956. 42. Lussenhop A, Presper J. Surgical embolization of cerebral arteriovenous malformations through internal carotid and vertebral arteries. J Neurosurg 1975; 42:443–451. 43. Adelt D, Zeumer H, Wolters J. Surgical treatment of cerebral arteriovenous malformations. Follow-up study of 43 cases. Acta Neurochir 1985; 76:45–49. 44. Nornes H, Lundar T, Wikeby P. Cerebral arteriovenous malformations: results of microsurgical management. Acta Neurochir 1979; 50:243–257. 45. Heros RC, Korosue K, Diebold PM. Surgical excision of cerebral arteriovenous malformations: late results. Neurosurgery 1990; 26:570–578.

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46. Yeh H, Kashiwagi S, Tew J, Berger T. Surgical management of epilepsy associated with cerebral arteriovenous malformations. J Neurosurg 1990; 72:216–223. 47. Edgar R, Bladwin M. Vascular malformations associated with temporal lobe epilepsy. J Neurosurg 1960; 17:638–656. 48. Wahren R, Scheithauer B, Lwas E. Thrombosed arteriovenous malformations of the brain. J Neurosurg 1982; 57:520–526. 49. Paterson JH, McKissock W. A clinical survey of intracranial angiomas with special reference to their mode of progression and surgical treatment: a report of 110 cases. Brain 1956; 79:233–266. 50. Forster DMC, Steiner L, Hakanson S. Arteriovenous malformations of the brain. A long term clinical study. J Neurosurg 1972; 37:562–570.

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Endovascular Therapy: Indications, Complications, and Outcome Adnan H. Siddiqui and P. Roc Chen Department of Neurosurgery, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, U.S.A.

Robert H. Rosenwasser Department of Neurosurgery, Division of Cerebrovascular Surgery and Interventional Neuroradiology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, U.S.A.

INTRODUCTION Embolization of arteriovenous malformations (AVMs) has developed over the last four decades from an experimental treatment reported by Lussenhop and Spence in 1960 (1), to a standard component of the multimodal armamentarium used for the treatment of AVMs (2). Initial therapies were developed to embolize feeding arterial pedicles during surgery. Subsequently, plastic microsphere embolics were developed and delivered through a transcervical carotid route. Since then, principles of embolization have evolved in tandem with the development of endovascular technologies. Flow-directed microcatheters provide for routine deployment of embolic material close to or within the nidus. Embolic material science has allowed for a transition from solid and particulate materials to liquid embolics. Embolization is a vital modality either separately or as an adjunct to radiosurgery or microsurgery for treatment and hence obliteration of AVMs. In this chapter we provide an overview of the indications, techniques, complications, and outcomes of endovascular management of AVMs. CEREBROVASCULAR MALFORMATIONS Cerebrovascular malformations are classified as (i) AVMs, (ii) cavernous angiomas (cavernomas, cavernous malformations), (iii) capillary telangiectasias, and (iv) venous angiomas (developmental venous anomalies) (3,4). In an autopsy series of 5743 consecutive patients, venous angiomas were present in 3%, capillary telangiectasias in 0.9%, AVMs in 0.5%, and cavernomas in 0.3% (3). Of this myriad group of essentially congenital vascular anomalies, only AVMs and cavernomas present with hemorrhage, seizures, or other neurological manifestations that require treatment. AVMs are considered congenital, arising from primitive arteriovenous communications that unlike their developmental counterparts fail to regress and hence are present from the very first few weeks of central nervous system (CNS) development. These lesions typically consist of multiple arterial pedicles that feed a dysplastic nidus, which drains without any intervening capillary network through one or more draining veins into major venous sinus systems. Because there is no intervening capillary filter, AVMs are considered high-flow as opposed to cavernomas, which are dilated venous sinusoids and hence low-flow. Although most AVMs are present within pial margins, they do not contain within them functional brain; instead they have dysplastic neuroepithelial rests intertwined between the vascular channels. This neuroepithelial tissue many times provides a compact circumferential plane of dissection around the AVM during surgery distinct from functional neuronal tissue. Angiographically, AVMs are easily identified by the presence of hypertrophied arterial feeders and a compact or diffuse nidus. The hallmark, however, is the identification of an early-draining vein or veins in the arterial phase of the angiogram. The ability to angiographically visualize the AVM enables us to devise endovascular strategies to treat the lesion either as a single modality or as an adjunct to microsurgical resection or stereotactic radiosurgery.

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NATURAL HISTORY OF AVMs Intracerebral and/or subarachnoid hemorrhage is the most common and the most devastating presentation for up to 50% of patients with AVMs (5–7). Seizures are the next most common presentation for supratentorial AVMs (30%) (7). There is a fair amount of uniformity in the results of multiple studies that have been undertaken to estimate the natural history of AVMs. There is consensus that the risk of hemorrhage is between 2% and 4% per year (8–14). The 24-year prospective follow-up study of 166 symptomatic patients by Ondra et al. remains the most quoted, with an annual hemorrhage rate of 4%, mortality rate of 1%, and severe morbidity or mortality rate of 2.7% (13). It is unclear if there is a difference in hemorrhage rates between symptomatic and asymptomatic patients, or between patients presenting with seizures and those presenting with hemorrhage (8,15). It is also controversial whether the risk of subsequent hemorrhages after a hemorrhage increases and whether this risk declines after a latency period. Ondra et al. did not report any such increases, but subsequent reports suggest an increase, which declines to baseline after a year (9–12,14). Regardless, each event of hemorrhage has a well-established 10% risk of mortality and 30% risk of severe morbidity (14,16). A variety of patient characteristics and structural and angiographic features have been investigated to further stratify the risk of hemorrhage. Evidence exists to suggest an inverse relationship between the size of the nidus and the risk of hemorrhage (12,17–23). This inverse relationship is speculated to be related to higher transmittal of arterial pressures onto the draining veins (24,25). However, other evidence suggests that the risk of hemorrhage increases with increasing nidus size (26,27) and still other evidence suggests no relationship (18,28–31). Venous anatomical features that have been suggested to warrant concern for increased risk of hemorrhage are deep venous drainage, venous outflow stricture, and presence of a venous varix (32–37). Location has also been suggested to be a factor, with evidence supporting a higher risk of hemorrhage with deep periventricular and infratentorial lesions (7,15,34,38). The association of aneurysms and AVMs has been reported to be between 2.7% and 14% (18,39–43). Hemodynamic factors play a large role in the development of these aneurysms, often on the feeding arterial pedicles or in the nidus itself. Developmental factors may be at play with aneurysms evident in circulations removed from the AVM. The presence of an associated aneurysm, particularly intranidal, appears to increase the risk of hemorrhage. The management of AVM-associated aneurysms has been the subject of much discussion. The hemodynamic genesis of these aneurysms is supported by the regression of some AVM-associated aneurysms after treatment of the AVM (42); other factors lend support to strategies for early intervention. In particular, in instances of intracranial hemorrhage when both an AVM and an aneurysm are present, the aneurysm is the lesion most likely to have bled (15). This fact, combined with the higher rates of morbidity and mortality associated with an aneurysm hemorrhage, has led many to recommend that the aneurysm be treated first, if at all possible. Patient characteristics that influence the risk of AVM hemorrhage are less well understood. Increasing age may increase risk of hemorrhage (44). However, other patient characteristics such as gender, hypertension, pregnancy, and tobacco use, although associated with aneurysmal hemorrhage, have not been shown to be associated with AVM hemorrhage. Various grading scales for cerebral AVMs have been proposed to aid in the prediction of patient morbidity and/or mortality either with or without treatment. The most commonly employed grading scale is that proposed by Spetzler and Martin in 1986 (see Table 3 in Chapter 6) (45), which was designed to predict the risk of operative treatment. Because this grading scale was based on patients who were treated primarily with surgical resection, its applicability to endovascular therapy is questionable. However, at present there is no widely accepted grading scale for the endovascular treatment of cerebral AVMs. INDICATIONS FOR TREATMENT Based on the established natural history of AVMs, the undertaking of treatment is frequently recommended, particularly in patients who are relatively young, symptomatic, and/or have angiographic or clinical risk factors that predispose to hemorrhage. The rationale for treatment is to reduce the risks of hemorrhage, morbidity, and mortality from those associated with the

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natural history of the disease (14,16). Treatment is also undertaken to improve current neurological status when symptoms can be attributed to venous hypertension or steal phenomenon. The goal of any single treatment modality or combination of modalities is the ultimate obliteration of the AVM. However, each individual treatment modality may have its own specific role in the overall treatment plan. Endovascular embolization as a treatment modality usually assumes one of three roles: (i) adjunctive, (ii) curative, or (iii) palliative. Adjunctive Embolization Before Microsurgery The most common role of endovascular embolization is as an adjunct to either microsurgical resection or stereotactic radiosurgery. For patients with surgically accessible lesions (Spetzler– Martin Grades I and II), microsurgical removal can provide an immediate cure with minimal risk of morbidity and mortality (45,46). However, a large nidus, deep feeding vessels, and high-flow shunts increase the operative risk (45,46). In such patients, the added risks of endovascular treatment may compare favorably to the risks of surgery alone (Figs. 1–4). In a comparison of patients undergoing AVM embolization with N-butyl-cyanoacrylate (NBCA) before surgical resection versus patients undergoing surgery alone, Jafar et al. found that rates of complications and of good or excellent outcomes were similar for both groups despite the fact that the patients undergoing embolization had higher Spetzler–Martin grade lesions (47). Embolization shortened operative time and reduced blood loss. Similar findings have been reported by others (48–55). The degree of preoperative AVM volume reduction necessary to actually effect a difference in surgical resection has been contested. It has been suggested that while elimination of over 75% of the AVM nidus facilitates surgical resection, occlusion of less than 50% does little to aid operative removal (56). The advantage of preoperative embolization is the possible elimination of deep arterial (perforator) feeders, which will not be encountered during surgery until the penultimate phase of resection. Thus, elimination of the superficial arterial supply does nothing to aid surgery, because these are easily addressed during the initial approach. However, embolization of these vessels does expose the patient to the risks of embolization. Therefore, in general, the risks of embolization for surgically accessible small AVMs (Spetzler–Martin Grade I or some Grade II) probably do not outweigh the benefits. An additional benefit of endovascular embolization before surgery is in the management of AVM-associated aneurysms, particularly if they are on deep pedicles or are the source of a recent hemorrhage. In large high-flow AVMs with robust arteriovenous shunting, a gradual reduction of flow through staged embolization may also potentially decrease the risk of postoperative perfusion breakthrough hemorrhage through gradual restoration of vascular reactivity. Some have suggested the use of preoperative embolization of AVMs in eloquent or deep areas to induce either a reduction in flow or elimination of the perforator supply before surgery. If embolization successful, then the decision is made to proceed with surgery; otherwise, the patient is treated with stereotactic radiosurgery (57). Adjunctive Embolization Before Stereotactic Radiosurgery In patients with AVMs located in eloquent cortex or deep structures, stereotactic radiosurgery may be a preferable alternative to microsurgical resection, because the associated risks of morbidity and mortality may be unacceptably high (Fig. 5). In such patients, endovascular embolization may be used to reduce the size of the AVM before radiosurgery or to eliminate certain angiographic features such as intranidal aneurysms, which may provide for elevated risk while the patient awaits AVM obliteration after radiosurgery. The AVM cure rate after stereotactic radiosurgery is inversely proportional to the size of the AVM (58–65). Therefore, the role of endovascular embolization in this setting is to reduce the nidus size so that a cure after radiosurgery will become more likely (59,62,66). This presumption is supported by case series, which have shown an improvement in radiosurgical cure for patients with postembolization reduction in AVM volume to below 10 cm3 (67,68). The volume of an AVM is calculated in similar fashion to that of a sphere (4/3pr3). Therefore, a 2-cm nidus has a volume of 4.18 cm3, while a 3-cm nidus has a volume of 6.3 cm3. The rationale for preradiosurgery embolization is based on the findings that a 1 cm3 AVM has a 100% cure rate, while this drops to 85% for lesions 1 to 4 cm3 in size and further declines to 58% for lesions larger than 4 cm3. In preradiosurgery patients, it is helpful but not essential for the AVM nidus

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to be reduced to a smaller single focus. If this is not possible, a volume-staged approach may be used to treat two or more areas of residual AVM separately (69,70). Alternatively, when stereotactic radiosurgery does not produce complete obliteration, repeated embolization or surgical resection may still be used, often with greater success (71,72).

Figure 1 (Continued on facing page) An axial noncontrast computed tomography scan (A, B) performed on a 27-year-old male who presented with the sudden onset of a severe headache and right hemiparesis shows an acute left intracerebral hemorrhage with associated mass effect and shift. A subsequent angiogram (C, D) demonstrates an arteriovenous malformation (AVM) in the right posterior temporal lobe fed by branches of the right middle cerebral artery (MCA). Note medial and upward displacement of the MCA from the hematoma. (E, F) Emergent embolization resulted in obliteration of AVM. Also note the presence of a distal anterior cerebral artery aneurysm. The patient was taken to the operating room, and the hematoma was evacuated and the AVM resected. (G) The distal anterior cerebral artery aneurysm was clipped. (H, I) Intraoperative angiogram reveals complete excision of the AVM and exclusion of the aneurysm.

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Issues have been raised with preradiosurgical embolization because of concerns for delayed recanalization of a portion of AVM that was embolized and therefore not included in the radiosurgical plans (63,73). This may be partly related to the embolic materials used because particulate materials are associated with a 15% to 20% recanalization rate as compared to liquid embolics (68). In addition, postradiosurgical follow-up by magnetic resonance imaging (MRI) alone may potentially underreport the persistent presence of an AVM. We therefore follow up patients after radiosurgery with sequential MRI scans, and when there is MRI evidence of obliteration of AVM, we perform cerebral angiograms of all six cranial vessels to confirm complete obliteration. In our experience, this approach has resulted in the identification of AVMs requiring repeat treatments that in some cases would have been considered obliterated based on MRI alone. Curative Embolization The primary goal of AVM treatment is complete obliteration of the lesion and its arteriovenous shunt. Only after complete obliteration is the patient’s future risk of hemorrhage eliminated. For endovascular embolization to be curative, there must be no residual filling of the nidus, and the angiographic shunt or abnormal early venous drainage must be eliminated (Figs. 6–8). For most cerebral AVMs, endovascular embolization alone is unable to provide complete obliteration. Probably the most common reason for this subtotal obliteration is the inability to catheterize and thereby embolize many of the small arterial feeders associated with the majority of brain AVMs. Published endovascular cure rates are difficult to interpret. Because embolization evolved primarily as an adjunctive therapy, many published series suffer from considerable referral bias, whereby only ‘‘large’’ AVMs, which are incapable of being treated with radiosurgery or open microsurgery alone, are the ones referred for embolization, and smaller lesions with only one or two feeding pedicles are treated without endovascular intervention. In addition, the lack of a widely accepted endovascular grading scale makes comparison between various studies problematic. Frizzel and Fisher reviewed 1246 patients who underwent embolization for AVMs in 32 series over a 32-year period and found cure rates between 5% and 18% (74). In a series of 465 patients, Vinuela et al. reported a 9.7% rate of complete AVM occlusion with embolization alone (75). Gobin et al. reported a similar cure rate of 11.2% in a cohort of

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Figure 2 (Continued on facing page) Initial magnetic resonance imaging scan (A, B) from a 20-year-old female who presented with a small intraparenchymal hemorrhage shows an arteriovenous malformation (AVM) in the inferior portion of the left cerebellar hemisphere. (C, D) Preembolization angiogram reveals the AVM supplied primarily by the left PICA. Control angiogram performed after a single session of N-butyl-cyanoacrylate embolization (E, F) shows a considerable reduction in the nidus size. Given the patient’s previous history of hemorrhage, the small size of the residual AVM and the surgically accessible location, the patient underwent microsurgical excision of the lesion. (G, H) The patient was positioned in a lateral decubitus position to allow for an intraoperative angiogram. (I, J) The lateral skull film and intraoperative angiogram reveal no residual nidus and no persistent early venous drainage.

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patients scheduled for radiosurgery who had undergone prior embolization as an ‘‘adjunctive’’ therapy (67). Both series found cure to be more likely in patients with small AVMs. Gobin et al. also found that the rate of cure was inversely related to the number of feeding pedicles. In contrast, other authors have reported much higher rates of cure with endovascular therapy when patients were selected specifically for embolization as a primary modality. After selecting a subgroup of patients based on angiographic features they felt were likely to promote endovascular obliteration, Valavanis and Yasargil noted a cure rate of 74% (or 35% of their overall series) with embolization alone (76). Factors that predisposed to complete occlusion included the presence of dominant feeders without perinidal angiogenesis, a single nidus, and a more fistulous than plexiform nidus. Yu et al. reported on a series of 27 patients from whom 10 were selected for curative embolization on the basis of AVM size less than 3 cm, fewer than three arterial feeders, and the ability to catheterize up to the nidus (77). Their cure rate was 60% for such a select subgroup, with overall cure rate of 22%. Most recently, Haw et al. reported on their embolization experience of 18 years on 306 patients (2). Their cure rate was 9.1% for the entire cohort, but for the subgroup of 55 patients for whom the primary intent was cure through embolization, the rate increased to 31%. Palliative Embolization It is unclear if partial treatment of AVMs alters the natural history of the disease, particularly in regard to the risk of hemorrhage (78,79). Although only complete elimination of the AVM constitutes a true cure, in selected cases palliative treatment may be justified. Specifically, patients who are symptomatic because of large and/or deep-seated AVMs that are unlikely to be cured with any combination of treatments may benefit from subtotal endovascular embolization. Embolization to reduce the arteriovenous shunt and thereby decrease the amount of ‘‘steal’’ and/or venous hypertension associated with a lesion has been reported to cause clinical improvement (80,81). In patients with repeated AVM-related hemorrhages, embolization may be used to eliminate angiographic risk factors for hemorrhage, such as intranidal aneurysms. However, the risk of hemorrhage from the AVM has been suggested to increase after partial treatment as compared to conservative management. Miyamoto et al. reported on 46 patients

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Figure 3 (A) During surgery the glue cast is visible in the nidus on the cortical surface. (B) Post-resection arteriovenous malformation (AVM) filled with glue. (C) Intraoperative angiogram revealing complete absence (excision) of the AVM.

whose AVMs were palliatively treated because of size and/or location (82). They reported an increase in the rate of annual hemorrhage from 2.6% in untreated patients to 14.6% in the partially treated patients. Kwon et al. reported on 27 patients with Spetzler–Martin Grade III AVMs, of which 11 were partially embolized and 16 were managed conservatively (83). Although the incidences of clinical deterioration in the follow-up period were similar, the rate of hemorrhage was 45.5% in the embolized group versus 25% in the conservatively managed group. Evidence to the contrary has been provided by Meisel et al., who reported on the partial embolization of AVMs in 450 patients that were deemed to have angiographically identified high-risk features and be otherwise incurable (84). The annual rate of hemorrhage in the untreated group was 8.9%, and this rate declined to 3.6% after partial targeted embolization to address the angiographic high-risk features. Al-Yamany et al. also reported on patients who presented with progressive neurological decline without evidence of hemorrhage; partial embolization halted the progression of symptoms in over 90% of patients (85). The role of partial embolization remains unclear. However, we believe that there are certain narrow roles by which this modality can help decrease the risk of hemorrhage and effect clinical benefit by addressing specific angiographic attributes or through reduction of flow and correspondent improvement in steal and or venous hypertension. Furthermore, as newer applications of radiosurgery such as volume staging are developed, there may be a shrinking population of AVMs considered to be incurable (70). Modality-Driven Perspectives on the Management of AVMs Controversy exists between neurosurgeons and interventional neuroradiologists in their approach to the indications for AVM treatment (2,67,78,86). As neurosurgeons who perform all three of the major modalities of AVM treatment, we prefer to view indications for treatment from a multidisciplinary perspective with treatment tailored to the individual patient and his/her AVM. The first decision for the treating physician should be whether or not the AVM needs to be treated. This question is answered through analysis of patient factors such as age and symptomatology of the lesion as well as angiographic factors such as size, location, eloquence, venous drainage, and associated high-risk features such as aneurysms and venous outflow obstruction. Once these factors have been assessed, we consider the established natural history of the disease. If intervention provides an improvement in the natural history

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Figure 4 This patient presented with seizures and a right temporal arteriovenous malformation (AVM). (A) Magnetic resonance imaging shows AVM flow void. (B) The angiogram revealed filling principally from the right MCA branches. (C) Microcatheter runs prior to glue embolization reveal the angioarchitecture, flow patterns, and fistulous components of the nidus. (D) Postembolization. Note the absence of the rostrosuperior aspect of the nidus. The patient underwent a surgical excision, and (E) intraoperative angiogram reveals the absence of the AVM.

without exposing the patient to inordinate risk, we proceed to design a tailored treatment plan. This treatment plan usually consists of a multimodal approach to most patients. For patients who have sustained a hemorrhage, every effort is made to eliminate the risk of future bleeding as soon as possible. For such patients this may mean a combination

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Figure 5 Pretreatment angiogram (A) performed on a 56-year-old woman with new onset seizures reveals a left frontal arteriovenous malformation (AVM) fed by branches of the left ACA. (B, C) After the nidus volume was reduced with multiple sessions of glue embolization, an angiogram was performed and the patient underwent volume-staged gamma knife stereotactic radiosurgery. An angiogram performed approximately three years after two stages of radiosurgery (D, E) shows no persistent filling of the AVM. A glue cast is still visible in the left frontal lobe.

of surgical resection and/or endovascular embolization. However, if the risk of morbidity/ mortality associated with these treatments is likely to be greater than that of the natural history of the untreated AVM over the next few years, then a combination of stereotactic radiosurgery and/or embolization may be desirable. Traditionally, surgical resection alone has been favored for patients with mass-effect symptoms from a sizable acute intracerebral hemorrhage. However, even in many of these patients, we have either used emergent aggressive embolization preoperatively to reduce intraoperative blood loss or simply evacuated the hematoma, leaving the AVM for later treatment with any combination of modalities. In general, though, because our institution is a tertiary care referral center, the majority of AVMs that we see are large and arise either within or partially within eloquent brain. As a result, more than 50% of the patients with AVMs treated in the senior author’s series underwent stereotactic radiosurgery and embolization. More recently, we as well as others (70,73) have begun to utilize volume-staged radiosurgery for addressing otherwise incurable or high-interventional-risk AVMs. In the end, success is most likely to be achieved with a multidisciplinary approach tailored to both the individual patient and the characteristics of the lesion itself.

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Figure 6 A high-flow arteriovenous malformation (AVM) fed principally by the left ICA with a prominent fistulous component was embolized. (A, B) Preembolization films reveal the fistulous component. After N-butyl-cyanoacrylate embolization under roadmap (‘‘mask’’) conditions (C), a glue cast can be seen within the AVM nidus. (D, E) Postembolization angiogram reveals complete shutdown of the high-flow fistulous connection and obliteration of the AVM.

Such an approach is best delivered at a tertiary care institution where practitioners experienced in the latest microsurgical, radiosurgical, and endovascular techniques are readily available. MANAGEMENT PRINCIPLES FOR ENDOVASCULAR TREATMENT The first reports of the endovascular treatment of AVMs involved the nonselective use of particles (1). It was not until 1972 that Zanetti and Sherman reported the use of a liquid embolic

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Figure 7 This patient presented with seizures. (A, B) The initial angiogram revealed a medial right frontoparietal arteriovenous malformation (AVM) fed by the right pericallosal artery. (C, D) Postembolization there is minimal flow in the nidus. (E, F) Angiography six weeks postembolization confirms the complete obliteration of AVM.

acrylate polymer to treat cerebral AVMs (87). Today liquid cyanoacrylate glue derivatives delivered through superselective microcatherization are the most commonly used embolic agents for the treatment of cerebral AVMs. At our institution, almost all AVM embolizations are performed under general endotracheal anesthesia with pharmacological paralysis (Fig. 9). This essentially eliminates patient movement and facilitates roadmapping for radiographic intravascular navigation. Rigorous blood pressure control is maintained throughout the procedure and in the postoperative period. To minimize the risk of a neurological deficit in patients treated under general anesthesia, we routinely use intraoperative neurophysiological monitoring in the form of somatosensory evoked potentials and electroencephalography, while brainstem auditoryevoked responses are monitored for lesions requiring access through the posterior circulation. Arterial access is generally achieved through a transfemoral route. In adults, a 7 F sheath is placed in the femoral artery. The use of a 7 F sheath with a 6 F guide catheter allows for continuous blood pressure monitoring through the sheath, thereby eliminating the need for a separate arterial line. In addition, the 6 F guide provides for easy contrast injection such that

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Figure 8 This patient presented with seizures. (A) Magnetic resonance imaging revealed a right temporal arteriovenous malformation (AVM). (B, C) Preembolization angiogram revealed filling principally from the right MCA. Following staged embolization, the AVM nidus was completely occluded. (D, E) Complete occlusion was confirmed through an intraoperative angiogram.

a selective angiogram may be performed even with a microcatheter in place. In addition, a 6 F guide allows for continuous flush through pressurized lines around the microcatheter, eliminating the need for systemic intraprocedural anticoagulation. Flow-directed microcatheters, rather than braided, wire-driven catheters are optimal for accessing distal AVM pedicles and delivering liquid embolic agents. Commonly used brands approved for use in the United States include the Spinnaker Elite (1.5 or 1.8 F) from Boston Scientific (Neurovascular, Fremont,

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Figure 9 The interventional neuroradiology or endovascular suite. (A) Biplane fluoroscopy is critical for intracranial vascular navigation. (B) Electrophysiologic monitoring is utilized for all interventional cases. (C) Sterile technique is used for all procedures. (D) Anesthesia is used for almost all diagnostic angiography with monitored anesthesia care. General anesthesia with pharmacologic paralysis is used for all cases of embolization.

California, U.S.A.) and the Regatta (1.8 F) manufactured by Cordis Neurovascular (Miami, Florida, U.S.A.). Although these catheters are flow-directed, a hydrophilic guidewire (usually 0.10-in. diameter) is still required to facilitate the flow-independent movements often required for selecting a specific arterial pedicle. Aggressive manipulation with the wire, however, should be avoided to minimize the risk of vascular perforation. After the appropriate first- or second-order vessel is selected and catheterized, a pretreatment biplane angiogram including capillary and venous phases should be obtained to serve as a reference for comparison with the postembolization angiogram to quantify the extent of embolization as well as to ensure the patency of all identifiable arterial branches. We attempt to place our guide catheter as distal as is safely possible to provide added support for the microcatheter. This is routinely at the cervicopetrous junction of the internal carotid artery for the anterior circulation and at the V3 segment of the vertebral artery in cases requiring access to the posterior circulation. A digital roadmap is then created and used to navigate the flow-directed microcatheter into an appropriate arterial pedicle. Larger pedicles are usually selected during initial sessions, because smaller pedicles may subsequently dilate as the flow characteristics of the AVM change with treatment. Once a specific pedicle has been selected, contrast injection through the microcatheter is used to judge flow rate through the nidus, assess the proximity of the draining vein(s), and determine whether any normal arterial branches are being supplied distal or adjacent to the nidus, particularly in the case of en passant branches. In some instances, particularly in awake patients, selective barbiturate injections through the microcatheter may be used to assess the eloquence of brain served by the arterial pedicle in question (‘‘amobarbital testing’’) (44,88–90). For patients under general anesthesia, superselective barbiturate injection may lead to changes in neurophysiological parameters. However, the lack of certainty with regard to flow distribution of the barbiturate in the presence of an AVM may limit the usefulness of this method. As a result, a negative amobarbital test does not necessarily guarantee a good outcome. In this regard, newly developed microcatheters allow for catheterization essentially up to the nidus, thus obviating the need for pharmacologic testing in most cases.

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Actual AVM occlusion is achieved with an embolic agent. Over the years, various types of embolic agents have been employed to treat cerebral AVMs. Many earlier treatments were performed with particles, particularly polyvinyl alcohol (PVA). Today, liquid embolic derivatives of cyanoacrylate have largely supplanted PVA as the agent of choice. A prospective, randomized trial comparing NBCA to PVA for the preoperative embolization of cerebral AVMs demonstrated equivalence for both agents, at least in terms of percent nidus reduction and number of pedicles embolized (91). However, PVA particles are unlikely to provide permanent arterial occlusion and should be used only as an adjunct to timely surgical extirpation (92,93). Occasionally, in lesions with fistulous components, the injection of glue may be facilitated by the use of platinum coils that can be pushed to reduce flow (94). Several liquid embolics have been used in the endovascular occlusion of cerebral AVMs. The most popular liquid embolic agents are cyanoacrylate derivatives, including Trufill (Cordis Neurovascular, Miami, Florida, U.S.A.) and Histocryl (Braun-Aesculap, Tuttlingen, Germany). Absolute ethyl alcohol has also been used as an embolic agent for vascular malformations, primarily of the extracranial circulation. The treatment of cerebral AVMs with absolute alcohol has been reported, but its use remains controversial (95). Currently, the only ‘‘glue’’ that the Food and Drug Administration (FDA) approved for use in cerebral AVMs in the United States is Trufill (NBCA). NBCA glue is a clear, colorless, and radiolucent liquid that comes packaged in single concentration 1-ml vials (Fig. 10). The glue begins to polymerize immediately on contact with ionic materials such as blood, saline, and ionic contrast media. To alter the polymerization properties of the glue and make it visible during injection on angiography, NBCA is combined with ethiodol (oil based nonionic contrast), nonionic water-soluble contrast, or tantalum powder.

Figure 10 (A) N-butyl-cyanoacrylate or Trufill is the only Food and Drug Administration-approved liquid embolic material for arteriovenous malformations and comes with provided tantalum powder and nonionic contrast. (B) The glue tray is set up in a stereotypic fashion with compulsory use of specific color-coded syringes, needles, and other equipment.

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Trufill is packaged with ethiodol for dilution, although many have found the behavior of various ethiodol–NBCA concentrations to be inconsistent in terms of viscosity and polymerization. Nevertheless, NBCA concentrations of between 20% and 70% are commonly used depending on the proximity of the microcatheter to the nidus and the rapidity of the arteriovenous shunt. Some authors have advocated the use of glacial acetic acid as the diluting agent for NBCA, feeling that its effects are more reproducible (54). Because acetic acid is also radiolucent, the glue must be combined with tantalum powder (also packaged with Trufill) to make it radioopaque. Tantalum, however, adds to the viscosity of the mixture. With the microcatheter in optimal position, the embolic agent may then be prepared. The appropriate glue concentration should be mixed on a separate table to avoid contamination with blood or other ionic substances that may cause premature polymerization. Determining the appropriate glue concentration is not an exact science. Observation of the AVM’s flow characteristics and angioarchitecture during contrast injection through the microcatheter is critical. In the end, there is no substitute for experience with a specific embolic agent. At our institution moderate hypotension (mean arterial pressure approximately 50 mmHg) is induced before embolization. The microcatheter is repeatedly flushed with 5% dextrose water solution to prevent premature polymerization in the catheter, and the glue is then injected under roadmapping to enhance visualization. After glue administration, the microcatheter must be rapidly pulled from the site of injection to prevent the catheter from being glued in place. The anesthesiologist is forewarned to be prepared to provide a valsalva maneuver to increase venous pressure to prevent or at least retard the progression of embolic material toward the draining vein(s). After glue injection and removal of the microcatheter, the microcatheter should be inspected to ensure that the entire catheter has been removed. Because of the possibility of residual glue in the catheter, we prefer to discard the microcatheter after every glue injection. The guide catheter should be thoroughly flushed before being reused. A postembolization angiogram should be performed to assess the degree and location of AVM obliteration obtained during the embolization as well as to inspect the venous drainage pattern of the residual AVM to ensure there is no venous engorgement and for patency of the arterial tree. Postoperatively, our patients are observed in a monitored intensive care or intermediate care unit. Mild hypotension (MAP