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Meningiomas E-Book

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1271 pages
English

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Description

Meningiomas, by M. Necmettin Pamir, MD, Peter M. Black, MD, PhD, and Rudolf Fahlbusch, MD, presents current and comprehensive guidance on this most common, yet clinically challenging type of brain tumor. Written and edited by the world’s most prominent brain tumor neurosurgeons, it helps you to not only determine the type and location of the tumor, but also the most ideal surgical approach to provide your patients with the best outcomes. An extensive collection of surgical photographs covers unique and original cases, while discussions of pre-surgical techniques and approaches emphasize decision making with the help of all imaging modalities and analysis of symptoms and patient history. Expert Consult functionality enhances your reference power with convenient online access to the complete text and illustrations from the book, along with videos that depict surgical techniques in real time.

  • Provides access to the complete text online—fully searchable, along with all of the illustrations downloadable for your personal presentations, and real-time surgical videos covering microscopic extended endonasal approach to suprasellar meningioma, and more, at expertconsult.com.
  • Covers today’s full range of management methods, including adjuvant therapies, providing you with the best strategies for obtaining optimal outcomes.
  • Features the work of the world’s most prominent brain tumor neurosurgeons—a completely international authorship—bringing you the best procedures globally.
  • Offers an in-depth section on surgical methods and approaches based upon tumor location, to help you in the decision-making process.
  • Includes coverage of spinal meningiomas including pre-diagnosis symptoms and outcomes.

Sujets

Ebooks
Savoirs
Medecine
Vascular endothelial growth factor C
Surgical suture
Therapy
Benignity
Ascend
Biology
Diaphragma sellae
Sphenoid wing meningioma
Meningeal arteries
Ligation
Vitality
Perioperative
Superior sagittal sinus
Pulmonary valve stenosis
Neurofibromatosis type II
Biologic
Visual impairment
Neuro-ophthalmology
Neuropathology
Cell adhesion molecule
Microsurgery
Neoplasm
Craniotomy
Cadherin
Radiosurgery
Proton therapy
Traumatic brain injury
Meningioma
Platelet-derived growth factor
Vestibular schwannoma
Pituitary adenoma
Fractionation
Intracranial hemorrhage
Hypopituitarism
Biological agent
Subarachnoid hemorrhage
Melanoma
Anesthetic
Stroke
Optic Nerve
Daughter
Renal cell carcinoma
Meninges
Cerebral edema
Pleural effusion
Cauterization
Osteosarcoma
Wild Turkey
Medical imaging
Pulmonary embolism
Hydrocephalus
Natural history
Trepanning
Tinnitus
Cataract
Edema
Headache
Epidemiology
Angiogenesis
Neurofibromatosis
Ophthalmology
X-ray computed tomography
Multiple sclerosis
Philadelphia
Hearing impairment
Phenytoin
Brain tumor
Artery
Syringomyelia
Data storage device
Epileptic seizure
Radiation therapy
Paranasal sinuses
Positron emission tomography
Optic neuritis
Neurosurgery
Neurologist
Neurology
Mechanics
Molecule
Magnetic resonance imaging
Growth factor
Gene therapy
General surgery
Epilepsy
Major depressive disorder
Chemotherapy
Monitoring
Headache (EP)
Blindness
Keith Tucker
Pathology
Bypass
Multiple
Dindon sauvage
Gene
Turkey
Vascular endothelial growth factor
Genetics
Dissection
Intensive Care
Planning
Phénobarbital
Carbamazépine
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Fatigue
Electronic
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Syringomyélie
Vertigo
Acouphène
Philadelphie
Surface
Son
Boston
Copyright
Photon
Virus
thérapies
Factor de crecimiento endotelial vascular
Meleagris gallopavo
Derecho de autor
Vértigo (desambiguación)
Acúfeno
Angiogénesis
Múltiple
Turquía
Surgical incision
Oncology
Meningitis
Circulatory collapse
CDH1 (gene)
Vascular endothelial growth factor B

Informations

Publié par
Date de parution 25 janvier 2010
Nombre de lectures 0
EAN13 9781455708994
Langue English
Poids de l'ouvrage 23 Mo

Informations légales : prix de location à la page 0,0885€. Cette information est donnée uniquement à titre indicatif conformément à la législation en vigueur.

Exrait

Meningiomas
A Comprehensive Text

M. Necmettin Pamir, MD
Professor of Neurosurgery, Chairman, Department of Neurosurgery, Acibadem University School of Medicine, Istanbul, Turkey

Peter M. Black, MD, PhD, FACS
Franc D. Ingraham Professor of Neurosurgery, Harvard Medical School
Founding Chair, Department of Neurosurgery, Brigham and Women's Hospital, Chair Emeritus
Department of Neurosurgery, Children's Hospital Boston, Boston, Massachusetts

Rudolf Fahlbusch, MD, PhD
Professor of Neurosurgery, Director, Endocrine Neurosurgery and Intraoperative MRI, International Neuroscience Institute, Hannover, Germany
Saunders
Front matter
Meningiomas: A Comprehensive Text
M. Necmettin Pamir, MD
Professor of Neurosurgery, Chairman, Department of Neurosurgery, Acibadem University School of Medicine, Istanbul, Turkey
Peter M. Black, MD, PhD, FACS
Franc D. Ingraham Professor of Neurosurgery, Harvard Medical School, Founding Chair, Department of Neurosurgery, Brigham and Women’s Hospital, Chair Emeritus, Department of Neurosurgery, Children’s Hospital Boston, Boston, Massachusetts
Rudolf Fahlbusch, MD, PhD
Professor of Neurosurgery, Director, Endocrine Neurosurgery and Intraoperative MRI, International Neuroscience Institute, Hannover, Germany

Meningiomas: A Comprehensive Text
Copyright
Saunders Elservier
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, Pennsylvania 19103-2899
MENINGIOMAS: A COMPREHENSIVE TEXT
ISBN: 978-1-4160-5654-6
Copyright © 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies, and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.
This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notice
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.
With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.
Library of Congress Cataloging-in-Publication Data
Meningiomas: a comprehensive text/[edited by]
M. Necmettin Pamir, Peter Black, Rudolf Fahlbusch. - 1st ed.
p. ; cm.
Includes bibliographical references.
ISBN 978-1-4160-5654-6
1. Meningioma. I. Pamir, M. Necmettin. II. Black, Peter McL. III. Fahlbusch, Rudolf.
[DNLM: 1. Meningioma. QZ 380 M5448 2009]
RC280.M4M46 2009
616.99′4--dc22
2009014345
Acquisitions Editor: Adrianne Brigido
Developmental Editor: Lisa Barnes
Design Direction: Ellen Zanolle
Printed in China
Last digit is the print number: 9 8 7 6 5 4 3 2 1
Dedication
To my mother, my wife and my daughter.
MNP
To my families: my wife Katharine and our wonderful children, and the family of co-workers, students, and friends who have made academic life so fulfilling.
PMB
To my wonderful sons Fabian and Marius
RF
Contributors

John R. Adler, Jr., MD, Dorothy & TK Chan Professor of Neurosurgery, Department of Neurosurgery & Radiation Oncology, Stanford University School of Medicine, Stanford, California

Linda S. Aglio, MD, MS, Director of Neuroanesthesia, Department of Anesthesia, Perioperative and Pain Medicine, Associate Director of Neurophysiologic Monitoring, Brigham and Women's Hospital, Boston, Massachusetts

Nejat Akalan, MD, PhD, Professor of Neurosurgery, Department of Neurosurgery, Hacettepe University School of Medicine, Ankara, Turkey

Serdar Baki Albayrak, MD, Assistant Professor of Neurosurgery, Department of Neurosurgery, Suleyman Demirel University, Medical Faculty Hospital, Isparta, Turkey, Brain Tumor Fellow, Department of Neurosurgery, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts

Ossama Al-Mefty, MD, Professor and Chairman, Department of Neurosurgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas

Jorge E. Alvernia, MD, Senior Resident, Neurological Surgery Department, Tulane University, New Orleans, Louisiana

Danielle Baleriaux, MD, Neuroradiologist and Department Head, Department of Neuroradiology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium

Feyyaz Baltacioğlu, MD, Associate Professor of Radiology, Department of Radiology, Marmara University School of Medicine, Istanbul, Turkey

Hiriam Basiouni, MD, Department of Neurosurgery, University of Essen, Essen, Germany

Muhittin Belirgen, MD, Clinical Fellow, Department of Neurosurgery, University of Texas Southwestern Children’s Medical Center, Dallas, Texas

Jacqueline A. Bello, MD, FACR, Professor of Clinical Radiology, Department of Radiology, Albert Einstein College of Medicine of Yeshiva University, Director of Neuroradiology, Department of Radiology, Montefiore Medical Center, Bronx, New York

Amaresh S. Bhaganagare, Mch, Department of Neurosurgery, King Edward Memorial Hospital, Seth G. S. Medical College, Parel, Mumbai, India

Peter M. Black, MD, PhD, FACS, Franc D. Ingraham Professor of Neurosurgery, Harvard Medical School, Founding Chair, Department of Neurosurgery, Brigham and Women’s Hospital, Chair Emeritus, Department of Neurosurgery, Children’s Hospital Boston, Boston, Massachusetts

Alp Özgün Börcek, MD, Neurosurgeon, Department of Neurosurgery, Division of Pediatric Neurosurgery, Gazi University Faculty of Medicine, Ankara, Turkey

John Borchers, III, MD † , Neurosurgeon, Department of Neurosurgery, Stanford University School of Medicine, Stanford, California

Michael Brada, MB ChB, FRCR, FRCP, Professor of Radiation Oncology, Academic Unit of Radiotherapy and Oncology, The Institute of Cancer Research and Neuro-oncology Unit The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom

Jacques Brotchi, MD, Emeritus Professor and Honorary Chairman, Department of Neurosurgery, Hôpital Erasme, Brussels, Belgium

Michael Bruneau, MD, Neurosurgeon, Université Libre de Bruxelles, Associate Attending Neurosurgeon, Department of Neuroradiology, Hôpital Erasme, Brussels, Belgium

Lisa Calvocoressi, PhD, Associate Research Scientist, Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticuit

Giorgio Carrabba, MD, Neuro-oncology Fellow, Department of Neurosurgery, Neurosurgery Fellow, Department of Neurosurgery, Toronto Western Hospital, Toronto, Ontario, Canada

Rona S. Carroll, PhD, Assistant Professor of Surgery, Department of Surgery, Harvard Medical School, Assistant Professor of Neurosurgery, Department of Neurosurgery, Brigham and Women’s Hospital, Boston, Massachusetts

Elizabeth B. Claus, MD, PhD, Professor of Epidemiology and Public Health, Department of Epidemiology and Public Health, Yale School of Medicine, New Haven, Connecticut, Attending Neurosurgeon, Department of Neurosurgery, Brigham and Women’s Hospital, Boston, Massachusetts

V. Peter Collins, MD, PhD, Professor of Histopathology and Morbid Anatomy, Pathology Division of Molecular Histopathology, University of Cambridge, Honorary Consultant Histopathologist, Department of Histopathology, Addenbrooke’s Hospital, Cambridge, United Kingdom, Foreign Adjunct Professor, Histopathology, The Karolinska Institute, Stockholm, Sweden

Jeroen R. Coppens, MD, Fellow, Department of Neurosurgery, University of Utah, Salt Lake City, Utah

William T. Couldwell, MD, PhD, Professor and Joseph J. Yager Chairman, Department of Neurosurgery, Attending Physician, Department of Neurosurgery, University of Utah, Salt Lake City, Utah

Chris Couser, MD, Department of Neurosurgery, Brigham and Women’s Hospital, Boston, Massachusetts

Manoel A. de Paiva Neto, MD, Research Fellow, Division of Neurosurgery, University of California at Los Angeles, David Geffen School of Medicine, Los Angeles, California, Clinical Instructor, Disciplina de Neurocirurgia, Universidade Federal de Sao Paulo, Sao Paulo, Brazil

Ketan I. Desai, Mch, Consultant Neurosurgeon, Department of Neurosurgery, P.D. Hinduja National Hospital and Medical Research Center, Mumbai, Maharashtra, India

Alp Dinçer, MD, Assistant Professor of Radiology, Department of Radiology, Acibadem University School of Medicine, Istanbul, Turkey

Francesco Doglietto, MD, Clinical Fellow, Department of Neurosurgery, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada, Neurosurgeon, Department of Neuroscience, Institute of Neurosurgery, Catholic University School of Medicine, Rome, Italy

Joshua R. Dusick, MD, Assistant Researcher, Division of Neurosurgery, University of California at Los Angeles, David Geffen School of Medicine, Los Angeles, California

Canan Erzen, MD, Professor of Radiology, Department of Radiology, Marmara University School of Medicine, Istanbul, Turkey

Rudolf Fahlbusch, MD, PhD, Professor of Neurosurgery, Director, Endocrine Neurosurgery and Intraoperative MRI, International Neuroscience Institute, Hannover, Germany

Joaquim M. Farinhas, MD, Assistant Professor, Department of Radiology, Albert Einstein College of Medicine, Bronx, New York

Nasrin Fatemi, MD, Neuroendocrine Research Fellow, Division of Neurosurgery, University of California at Los Angeles, David Geffen School of Medicine, UCLA Pituitary Tumor and Neuroendocrine Program, Los Angeles, California

Shifra Fraifeld, MBA, Research Associate, Department of Neurosurgery, Hadassah – Hebrew University Medical Center, Jerusalem, Israel

Fred Gentili, MD, MSc, FRCSC, FACS, Professor, Deputy Chief, Department of Surgery, Division of Neurosurgery, University of Toronto, Professor, Department of Otolaryngology and Head and Neck, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada

Venelin M. Gerganov, MD, PhD, Associate Neurosurgeon, International Neuroscience Institute, Hannover, Germany

Atul Goel, Mch, Professor and Head, Department of Neurosurgery, King Edward Memorial Hospital, Seth G. S. Medical College, Parel, Mumbai, India

Alexandra J. Golby, MD, Assistant Professor of Surgery, Assistant Professor of Radiology, Harvard Medical School, Associate Surgeon, Department of Neurosurgery, Brigham and Women’s Hospital, Boston, Massachusetts

Menachem M. Gold, MD, Clinical Instructor, Department of Radiology, Albert Einstein College of Medicine, Neuroradiology Fellow, Department of Radiology, Montefiore Medical Center, Bronx, New York

William B. Gormley, MD, Director, Neurosurgical Critical Care, Department of Neurosurgery, Harvard Medical School, Boston, Massachusetts

Lance S. Governale, MD, Resident, Department of Neurosurgery, Brigham and Women’s Hospital, Boston, Massachusetts

Abhijit Guha, MD, Professor, Department of Surgery - Neurosurgery, University of Toronto, Attending Neurosurgeon, Department of Neurosurgery, Toronto Western Hospital, Senior Scientist and Co-Director, Brain Tumor Center, Department of Cell Biology, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada

Wendy Hara, MD, Clinical Instructor, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California

Toshinori Hasegawa, MD, Chief Neurosurgeon, Department of Neurosurgery, Komaki City Hospital, Gamma Knife Center, Komaki, Japan

Werner Hassler, MD, PhD, Chief, Department of Neurosurgery, Wedau Kliniken, Duisburg, Germany

Stanley Hoang, BS, Department of Neurosurgery, Stanford University School of Medicine, Stanford, California

Bernd M. Hofmann, MD, Neurosurgeon, Healthcare Sector, Workflow & Solutions Division, Siemens AG, Erlangen, Germany

Liz L. Holzemer, MA Journalism, Founder, Meningioma Mammas, Highlands Ranch, Colorado

Mark Hornyak, MD, Fellow, Department of Neurosurgery, University of Utah, Salt Lake City, Utah

John A. Jayne, Jr., MD, PhD, FRCS(C), Assistant Professor of Neurosurgery and Pediatrics, Department of Neurosurgery, University of Virginia Health System, Charlottesville, Virginia

Michel Kalamarides, MD, PhD, Professor of Neurosurgery, Universite de Paris, Paris, France, Department of Neurosurgery, Hospital Beaujon, AP-HP, Clichy, France

Hideyuki Kano, MD, PhD, Research Assistant Professor, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania

Tulay Kansu, MD, FAAN, Professor of Neurology, Department of Neurology, Professor of Neuroophthalmology, Department of Neuro-Ophthalmology, Hacettepe University School of Medicine, Ankara, Turkey

Takeshi Kawase, MD, Professor and Chairman, Department of Neurosurgery, Keio University School of Medicine, Tokyo, Japan

Dilaver Kaya, MD, Assistant Professor of Neurology, Department of Neurology, Acibadem University School of Medicine, >Attending Neurologist, Department of Neurology, Adibadem Kozyatagi Hospital, Istanbul, Turkey

Andrew H. Kaye, MBBS, MD, FRACS, James Stewart Professor of Surgery, Head, Department of Surgery, The University of Melbourne, Director, Department of Neurosurgery, Director, The Melbourne Comprehensive Cancer Centre, The Royal Melbourne Hospital, Melbourne, Australia

Daniel F. Kelly, MD, Director, Brain Tumor Center, John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, California

Ron Kikinis, MD, Professor, Department of Radiology, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts

Türker Kiliç, MD, Associate Professor of Neurosurgery, Department of Neurosurgery, Marmara University School of Medicine, Istanbul, Turkey

James A.J. King, MBBS, PhD, FRACS, Senior Lecturer, Department of Surgery, University of Melbourne, Neurosurgeon, Department of Neurosurgery, Royal Melbourne Hospital, Melbourne, Australia

Saeed Kohan, MD, Clinical Fellow of Pediatric Neurosurgery, Department of Neurosurgery, Marmara University Medical Center, Istanbul, Turkey, Instructor, Department of Neurosurgery, Concord Hospital, University of Sydney, Sydney, Australia

Douglas Kondziolka, MD, FACS, FRCS, Peter J. Jannetta Professor and Vice-Chairman of Neurological Surgery and Radiation Oncology, Department of Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania

Ender Konukoglu, PhD, PhD Candidate, Asclepios Research Project, INRIA Sophia Antipolis, Sophia Antipolis, France

Deniz Konya, MD, Assistant Professor, Department of Neurosurgery, Marmara University School of Medicine, Istanbul, Turkey

Niklaus Krayenbühl, MD, Neurosurgeon, Department of Neurosurgery, University Hospital Zürich, Zürich, Switzerland

Osami Kubo, MD, PhD, Professor, Department of Neurosurgery, Institute of the Advanced Biomedical Sciences, Tokyo Women’s Medical University, Tokyo, Japan

Edward R. Laws, Jr., MD, FACS, Director, Pituitary/Neuroendocrine Center, Department of Neurosurgery, Brigham and Women’s Hospital, Neurosurgeon, Department of Neurosurgery, Children’s Hospital Boston, Neurosurgeon, Dana-Farber Cancer Institute, Boston, Massachusetts

Gordon Li, M.D., Resident, Department of Neurosurgery, Stanford University School of Medicine, Stanford, California

Jay S. Loeffler, MD, FACR, Herman and Joan Suit Professor of Radiation Oncology, Harvard Medical School, >Chief, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts

L. Dade Lunsford, MD, FACS, Professor, Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

Dennis Malkasian, MD, PhD, Associate Clinical Professor of Neurosurgery, Division of Neurosurgery, University of California at Los Angeles, David Geffen School of Medicine, UCLA Pituitary Tumor and Neuroendocrine Program, Los Angeles, California

Carolina Martins, MD, PhD, Anatomy Professor, Medical School of Pernambuco – IMIP, >Neurosurgeon, IMIP Recife, Brazil, Visiting Professor, University of Florida, Gainesville, Florida

Tiit Mathiesen, MD, Associate Professor, Department of Neurosurgery, Karolinska University, Department of Neurosurgery, Karolinska University Hospital Solna, Stockholm, Sweden

Giuseppe Minniti, MD, PhD, Assistant Professor of Radiation Oncology, Department of Radioterapia Oncologica, Ospedale Sant’Andrea, Rome, Italy

Debabrata Mukhopadhyay, MBBS, DNB (Neurosurgery), Neuro-oncology Fellow, Department of Neurosurgery, Neurosurgery Fellow, Department of Neurosurgery, Toronto Western Hospital, Toronto, Ontario, Canada

Ajay Niranjan, MBBS, MS, MCh, Associate Professor, Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania

Andrew D. Norden, MD, Instructor of Neurology, Harvard Medical School, Associate Neurologist, Division of Neuro-oncology, Department of Neurology, Brigham and Women’s Hospital, Attending Neuro-oncologist, Department of Medical Oncology, Center for Neuro-oncology, Dana-Farber Cancer Institute, Boston, Massachusetts

Y. Ono, MD, PhD, Professor, Department of Neuroradiology, Tokyo Women’s Medical University, Tokyo, Japan

Koray Özduman, MD, Assistant Professor of Neurosurgery, Department of Neurosurgery, Acibadem University School of Medicine, Attending Neurosurgeon, Department of Neurosurgery, Acibadem Kozyatagi Hospital, Istanbul, Turkey

M. Memet Özek, MD, Professor of Neurosurgery, Chairman, Department of Neurosurgery, Marmara University School of Medicine, >Chief, Division of Pediatric Neurosurgery, Department of Neurosurgery, Acibadem University, Istanbul, Turkey

Serdar Özgen, M.D., Associate Professor of Neurosurgery, Department of Neurosurgery, Marmara University School of Medicine, Istanbul, Turkey

Tuncalp Özgen, MD, Professor and Chairman, Department of Neurosurgery, Hacettepe University School of Medicine, Ankara, Turkey

M. Necmettin Pamir, MD, Professor of Neurosurgery, Chairman, Department of Neurosurgery, Acibadem University School of Medicine, Istanbul, Turkey

Chirag G. Patil, MD, MS, Chief Resident, Department of Neurosurgery, Stanford University, Stanford, California

Selçuk Peker, MD, Associate Professor, Department of Neurosurgery, Acibadem University School of Medicine, Istanbul, Turkey

Annette M. Pham, MD, Private Practice, ENT Specialists of Shady Grove, PC, Rockville, Maryland

Joseph M. Piepmeier, MD, Professor of Neurosurgery, Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut

Killian M. Pohl, PhD, Research Associate, Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, Researcher, IBM Almaden, San Jose, California

Ivan Radovanovic, MD, PhD, Clinical Fellow, Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada

Naren Raj Ramakrishna, MD, PhD, Director, Neurologic and Pediatric Oncology, MD Anderson Cancer Center, Orlando, Florida

Albert L. Rhoton, Jr., MD, R.D. Keene Family Professor and Chairman Emeritus, Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida

Guy Rosenthal, MD, Attending Neurosurgeon, Department of Neurosurgery, Hadassah – Hebrew University Medical Center, Jerusalem, Israel, Assistant Adjunct Professor, Department of Neurosurgery, San Francisco General Hospital, University of California at San Francisco, San Francisco, California

James T. Rutka, MD, PhD, FRCSC, FACS, FAAP, Chair, Division of Neurosurgery, University of Toronto, The Hospital for Sick Children, Department of Otolaryngology, University of Toronto, University Health Network, Toronto, Ontario, Canada

John A. Rutka, MD, FRCSC, Professor, Department of Otolaryngology, University of Toronto, Staff Neurotologist, Department of Otolaryngology, University of Toronto, University Health Network, Toronto, Ontario, Canada

Siegal Sadetzki, MD, MPH, Senior Lecturer, Department of Epidemiology and Preventive Medicine, Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel, Head, The Cancer & Radiation Epidemiology Unit, The Gertner Institute for Epidemiology & Health Policy Research, Chaim Sheba Medical Center, Tel Hashomer, Israel

Gordon T. Sakamoto, MD, Chief Resident, Department of Neurosurgery, Stanford University School of Medicine, Stanford, California

Katsumi Sakata, MD, Associate Professor and Director, Department of Neurosurgery, Yokohama City University School of Medicine, Yokohama, Japan

Madjid Samii, MD, PhD, Professor of Neurosurgery, International Neuroscience Institute, Hannover, Germany

Aydin Sav, MD, Professor, Director, Department of Pathology, Acibadem University, >Professor, Head, Pathology Laboratory, Neuropathology Unit, Marmara University Istanbul, Turkey

Bernd Scheithauer, MD, Professor of Pathology, Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota

Uta Schick, MD, PhD, Assistant Professor of the Clinic of Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany

Johannes Schramm, MD, Professor and Chairman, Department of Neurosurgery, Rheinische Friedrich Wilhelms University, Bonn, Germany

Patrick Schweder, MD, Department of Neurosurgery, The Royal Melbourne Hospital, Parkville, Victoria, Australia

Volker Seifert, MD, PhD, Professor and Chairman, Department of Neurosurgery, >Director, Center of Clinical Neurosciences, Johann Wolfgang Goethe University, Frankfurt am Main, Germany

Askin Seker, MD, International Research Fellow, Department of Neurosurgery, University of Florida, Gainesville, Florida

Keivan Shifteh, MD, Assistant Professor of Radiology, Department of Radiology, Albert Einstein College of Medicine, Montefiore Hospital, Bronx, New York

Helen A. Shih, MD, MS, MPH, Assistant Professor, Harvard Medical School, Radiation Oncologist, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts

Yigal Shoshan, MD, Associate Professor, Department of Neurosurgery, Hebrew University – Hadassah School of Medicine, Attending Neurosurgeon, Department of Neurosurgery, Hadassah – Hebrew University Medical Center, Jerusalem, Israel

Matthias Simon, MD, Assistant Professor of Neurosurgery, Department of Neurosurgery, Rheinische Friedrich Wilhelms University, Bonn, Germany

Robert L. Simons, MD, FACS, Clinical Professor, Department of Otolaryngology – Head and Neck Surgery, Division of Facial Plastic and Reconstructive Surgery, University of Miami, Medical Board Chairman, The Miami Institute for Age Management and Intervention, Miami, Florida

Marc P. Sindou, MD, PhD, Chairman, Professor of Neurosurgery, Hospital Neurologique Pierre Wertheimer, Universite de Lyon, Lyon, France

Sergey Spektor, MD, PhD, Clinical Senior Lecturer, Department of Neurosurgery, Hebrew University – Hadassah School of Medicine, Attending Neurosurgeon, Department of Neurosurgery, Hadassah – Hebrew University Medical Center, Jerusalem, Israel

K. Takakura, MD, Professor Emeritus, Department of Neurosurgery, Institute of the Advanced Biomedical Sciences, Tokyo Women’s Medical University, Tokyo, Japan

Farzana Tariq, MD, Research Fellow, Department of Neurosurgery, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts

A. Teramoto, MD, PhD, Professor of Neurosurgery, Department of Neurosurgery, Tokyo Women’s Medical University, Tokyo, Japan

Felix Umansky, MD, Chair, Department of Neurosurgery, Hebrew University – Hadassah School of Medicine, Chairman, Department of Neurosurgery, Hadassah – Hebrew University Medical Center, Jerusalem, Israel, Attending Neurosurgeon, Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan

Onder Us, MD, Chairman and Professor, Department of Neurology, Marmara University School of Medicine, Istanbul, Turkey

Marcus L. Ware, MD, PhD, Assistant Professor in Neurosurgery, Department of Neurosurgery, Tulane University School of Medicine, New Orleans, Louisiana

Damien C. Weber, MD, Vice Chairman, Radiation Oncology Department, Geneva University Hospital ,Geneva, Switzerland

Patrick Y. Wen, MD, Clinical Director, The Dana-Farber/Brigham and Women’s Cancer Center, Associate Professor of Neurology, Harvard Medical School, Boston, Massachusetts

Guido Wollmann, MD, Associate Research Scientist, Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut

Isao Yamamoto, MD, Professor and Chairman, Department of Neurosurgery, Yokohama City University, Yokahama, Japan

Jun Yoshida, MD, PhD, Professor and Chairman, Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan

Jacob Zauberman, MD, Trauma Unit, Chaim Sheba Medical Center, Tel Hashomer, Israel

† Deceased.
Preface

M. Necmettin Pamir, Peter M. Black, Rudolf Fahlbusch
Meningiomas are fascinating tumors because of their surgical challenge, their biological complexity, the possibility of achieving surgical remission and the increasing recognition that they are very common. The classic monograph of Cushing and Eisenhart on meningiomas was published in 1938; this monumental book established the fundamental principles of meningioma treatment, and since then there have been several other books devoted to them.
In the last decade, advances in the field of molecular biology and other experimental work have improved our understanding of the clinical behavior of meningiomas. Progress in the field of neurosurgery has also resulted in clinical advances in meningioma treatment. These developments led us to the project of collecting the new knowledge on scientific and clinical progress in meningiomas with a comprehensive book. The first section on the “neurobiology of meningiomas” is composed of ten chapters. In addition to the history, anatomy and embryology, this section provides advanced knowledge on molecular biology of meningiomas. The second section, in seven chapters, summarizes the classical and advanced diagnosis of meningiomas including new imaging techniques and the latest pathological classification. The third section is dedicated to general issues on the surgical treatment of meningiomas. The fourth section covers the surgical management of meningiomas by their site of origin. In this section, each chapter is aimed to provide a detailed summary of surgical techniques, potential pitfalls, and complication avoidance specific to each location of meningioma. Accompanying illustrative videos are also provided for some of the chapters. The fifth section focuses on adjuvant treatment alternatives including radiosurgical and fractionated radiation treatment modality, chemotherapy and biological treatment. The last section presents special topics on meningiomas. We also have included a chapter on the patient’s point of view, which is quite uncommon in the present literature. Each chapter is written by experts on each field from all over the world.
With such comprehensive content the book is intended not only to bring the extensive understanding of each topic to the reader’s attention, but also to convey each author’s personal experience. Repetitions were avoided but different points of view were encouraged. This comprehensive book is therefore intended for use by neurosurgeons, neurologists and oncologists but also by physicians from other disciplines, internists and nurses.
We hope that this book will boost the readers contemporary understanding of meningiomas, promote refinement of meningioma treatment and contribute to the care of meningioma patients.
Videos

1. Convexity Meningioma 339
Jacques Brotchi, MD, Michael Bruneau, MD, and Danielle Baleriaux, MD
CHAPTER 23
2. Falcine Meningioma 349
Jacques Brotchi, MD, Michael Bruneau, MD, and Danielle Baleriaux, MD
CHAPTER 24
3. Superior Sagittal Sinus Invasion and Its Repair 355
Marc P. Sindou, MD, PhD and Jorge E. Alvernia, MD
CHAPTER 25
4. Olfactory Groove Meningiomas 373
William T. Couldwell, MD, PhD and Jeroen R. Coppens, MD
CHAPTER 27
5. Anterior Clinoidal Meningioma 395
M. Necmettin Pamir, MD
CHAPTER 29
6. Suprasellar Meningioma 407
Edward R. Laws, Jr, MD, FACS,
Chirag G. Patil, MD, MS, and John A. Jayne, Jr, MD, PhD, FRCS(C)
CHAPTER 30
7. Suprasellar Meningioma 407
Edward R. Laws, Jr, MD, FACS,
Chirag G. Patil, MD, MS, and John A. Jayne, Jr, MD, PhD, FRCS(C)
CHAPTER 30
8. Microscopic Extended Endonasal
Approach to Suprasellar Meningioma 413
Daniel F. Kelly, MD, Dennis Malkasian, MD, PhD,
Nasrin Fatemi, MD, Joshua R. Dusick, MD, and Manoel A. de Paiva Neto, MD
CHAPTER 31
9. Supra-Orbital Removal of an Olfactory
Groove Meningioma 413
Daniel F. Kelly, MD, Dennis Malkasian, MD, PhD,
Nasrin Fatemi, MD, Joshua R. Dusick, MD, and Manoel A. de Paiva Neto, MD
CHAPTER 31
10. Sylvian Meningioma 427
M. Necmettin Pamir, MD
CHAPTER 32
11. The Retrosigmoid Suprameatal
Approach in a Case of a Petroclival
Meningioma 503
Rudolf Fahlbusch, MD, PhD and Venelin M. Gerganov, MD, PhD
CHAPTER 39
12. Cerebello-Pontine Angle
Meningioma 529
Peter M. Black, MD, PhD, FACS and James A. J. King, MBBS, PhD, FRACS
CHAPTER 42
13. Cerebellopontine Angle Meningiomas 529
M. Necmettin Pamir, MD
CHAPTER 42
Table of Contents
Instructions for online access
Front matter
Copyright
Dedication
Contributors
Preface
Videos
Neurobiology of Meningiomas
Chapter 1: Meningioma: History of the Tumor and Its Management
Chapter 2: Meningeal Anatomy
Chapter 3: The Origin of Meningiomas
Chapter 4: Epidemiology and Natural History of Meningiomas
Chapter 5: Radiation-Induced Meningiomas
Chapter 6: Neuropathology of Meningiomas
Chapter 7: Biology of Meningiomas
Chapter 8: Molecular Biology and Genetics of Meningiomas
Chapter 9: Meningiomas and Brain Edema
Chapter 10: Angiogenesis in Meningiomas
Diagnosis of Meningiomas
Chapter 11: Clinical Presentation of Meningiomas
Chapter 12: Neuro-ophthalmology of Meningiomas
Chapter 13: CT Evaluation of Meningiomas
Chapter 14: MRI Evaluation of Meningiomas
Chapter 15: Advanced MRI and PET Imaging of Meningiomas
Chapter 16: Angiographic Evaluation of Meningiomas
Chapter 17: Automatic Tumor Growth Detection
Surgery of Meningiomas
Chapter 18: Decision Making in Meningiomas
Chapter 19: Perioperative Management of Patients with Meningiomas
Chapter 20: Anesthetic and Intensive Care Management of the Patient with a Meningioma
Chapter 21: Indications and Technology of Neurophysiologic Monitoring in Meningioma Surgery
Chapter 22: The Cerebral Venous System in Meningioma Surgery
Surgery of Meningiomas by Site of Origin
Chapter 23: Surgery of Convexity Meningiomas
Chapter 24: Parasagittal and Falx Meningiomas
Chapter 25: Dural Sinus Invasion in Meningiomas and Repair
Chapter 26: Management of Superior Sagittal Sinus Invasion in Parasagittal Meningiomas: Resection Versus Irradiation
Chapter 27: Olfactory Groove Meningiomas
Chapter 28: Suprasellar Meningiomas
Chapter 29: Anterior Clinoidal Meningiomas
Chapter 30: Intrasellar and Diaphragma Sellae Meningiomas
Chapter 31: Minimally Invasive Approach to Frontal Fossa and Suprasellar Meningiomas
Chapter 32: Sphenoid Wing Meningiomas
Chapter 33: Primary Optic Nerve Sheath Meningiomas
Chapter 34: Cavernous Sinus Meningiomas
Chapter 35: Middle Fossa Meningiomas
Chapter 36: Overview of Petroclival Meningiomas
Chapter 37: The Posterior Petrosal Approach for the Treatment of Petroclival Meningiomas
Chapter 38: Petroclival Meningiomas: Middle Fossa Anterior Transpetrosal Approach
Chapter 39: Petroclival Meningiomas: Suboccipital Retrosigmoid Approach
Chapter 40: Presigmoid Keyhole Approach for Petroclival Meningiomas
Chapter 41: Tentorial and Falcotentorial Meningiomas
Chapter 42: The Surgical Management of Cerebellopontine Angle Meningiomas
Chapter 43: Cerebellar Convexity Meningiomas
Chapter 44: Foramen Magnum Meningiomas
Chapter 45: Intraventricular Meningiomas
Chapter 46: Spinal Meningiomas
Chapter 47: Pediatric Meningiomas
Chapter 48: Meningiomas and Neurofibromatosis Type 2
Chapter 49: Multiple Meningiomas
Radiation and Chemotherapy for Meningiomas
Chapter 50: Fractionated Radiation for Meningiomas
Chapter 51: Gamma Knife® Radiosurgery for Convexity and Parasagittal Meningiomas
Chapter 52: Radiosurgery for Meningiomas (With Special Emphasis on Skull-Base Meningiomas)
Chapter 53: LINAC-Based Stereotactic Radiosurgery and Stereotactic Radiotherapy for Parasagittal, Skull-Base, and Convexity Meningiomas
Chapter 54: Proton Radiation Therapy for Meningiomas
Chapter 55: Cyberknife® Radiosurgical Ablation of Meningiomas
Chapter 56: Chemotherapy and Experimental Medical Therapies for Meningiomas
Chapter 57: Gene Therapy for Meningiomas
Special Topics
Chapter 58: Recurrence of Meningiomas and Its Management
Chapter 59: Management of Atypical and Anaplastic Meningiomas
Chapter 60: Meningioma Metastasis
Chapter 61: Meningiomas: A Patient's View
Chapter 62: Emerging Surgical Techniques for the Treatment of Meningiomas
Chapter 63: Experimental Meningioma Models
Chapter 64: Challenges and Opportunities in Future Meningioma Research and Care
Index
Neurobiology of Meningiomas
CHAPTER 1 Meningioma
History of the Tumor and Its Management

Chirag G. Patil, Edward R. Laws, Jr.
Meningioma/s has attracted the attention of surgeons, anatomists, pathologists, and physicians for many centuries. Given the tendency of these neoplasms to cause thickening of the overlying calvarium, meningiomas have left an unmistakable mark on human skulls dated as far back as prehistoric times. 1 - 4 Most of this evidence has come from the well-preserved skulls of the Incas in the Peruvian Andes that show classic hyperostosis indicating the presence of an underlying meningioma ( Fig. 1-1 ).

FIGURE 1-1 Prehistoric Peruvian skull, showing hyperostosis from an underlying meningioma.
(From al-Rodhan NR, Laws ER Jr. Meningiomas: a historical study of the tumor and its surgical management. Neurosurgery 1990:26(5):832–46; discussion 846–7.)
Felix Plater ( Fig. 1–2 ) was probably the first to describe a meningioma in more recent times. Born in 1536 in Sion, Switzerland, he was educated at Montpellier, where he received his doctorate in 1557. Caspar Bonecurtius, a nobleman, was Plater’s patient with a meningioma who presented with gradual physical and mental deterioration. On autopsy, Plater described a round fleshy tumor, like an acorn. 5, 6 It was as large as a medium-sized apple, hard and full of holes. It was covered with a membrane and entwined with veins. Plater described it as having no connections with the matter of the brain, so much so that when it was removed by hand, it left behind a remarkable cavity. This first clear description of a meningioma is most consistent with an encapsulated meningioma. 7, 8 Felix Plater continued to practice as a distinguished Professor of Medicine at the University of Basel and died in Basel at the age of 78.

FIGURE 1-2 Felix Plater (1536–1614) of Switzerland, the first to describe a meningioma.
(From al-Rodhan NR, Laws ER Jr. Meningiomas: a historical study of the tumor and its surgical management. Neurosurgery 1990:26(5):832–46; discussion 846–7.)

NOMENCLATURE
Harvey Cushing coined the term meningioma in 1922 to describe a benign neoplasm of the meninges of the brain. However, many other surgeons and pathologists described and named this neoplasm as well. In fact, naming of the tumor likely represents one of the most frequently changed nomenclatures in the history of medicine. Antoine Louis, born in Metz, France, in 1723 into a family of surgeons, developed an interest in surgery of dural tumors, which he named tumeurs fongueuses de la dure-mere or fungoid tumors of the dura mater. 9 He included their description in Memoire de l’Académie Royale de Chirurgie in 1774. In 1854, Sir James Paget named the neoplasm myeloid tumor (marrow like), based on its gross appearance and less malignant behavior. In 1863, Virchow was the first to describe the granules in these tumors and named it psammoma (sand-like). As Virchow was uncertain of the origin of these bodies, he gave the neoplasm a descriptive name. Subsequently, he changed the nomenclature from psammoma to Sarkoma der dura mater to describe these tumors. 2, 10
In the mid-1800s, Meyer, Bouchard, and Robin popularized the term epithelioma which was replaced later by the term endothelioma . 2, 10 Golgi believed that because the tumor was of mesenchymal origin, endothelioma was a more suitable term. Despite the myriad terminology, Virchow’s “sarcoma” and “psammoma” and Golgi’s “endothelioma” came into general use in the late 1800s and early 1900s.
Harvey Cushing was troubled by the confusion that resulted from the different nomenclatures and thought that it would be desirable to place this tumor under a single unified designation. Cushing knew that since the cellular composition of the tumor was in dispute, a histogenic name would not be universally accepted. Further, because these tumors arose from many areas of the brain, a location-based tumor name was not possible. Therefore, Cushing decided on a simple, suitable “tissue name,” meningioma , that was “noncommittal and all-embracing.” In his Cavendish lecture in 1922, Harvey Cushing used this designation to discuss 85 patients with these tumors. 10

CLASSIFICATION
In 1863, Virchow was the first to attempt a classification of meningiomas. 2 This was followed by classification schemas by Engert (1900), Cushing (1920), Oberling (1922), Globus (1935), Russell and Rubinstein (1971), and others. 2, 11 The World Health Organization (WHO) classification is widely used today and has been revised regularly. 12 It includes the recent concept of the “atypical meningioma” as an aggressive variant. Table 1-1 lists the various classifications described.
TABLE 1-1 Classification of meningiomas. Year Author Classification 1900 Engert Four types: (1) fibromatous; (2) cellular; (3) sarcomatous; (4) angiomatous 1920 Cushing Five types: (1) frontal; (2) paracentral; (3) parietal; (4) occipital; (5) temporal 1922 Oberling; later endorsed by Roussy Three types: (1) type neuroepithelial; (2) type glial fusiforme; (3) type conjunctif 1928 Cushing and Bailey Four types: (1) meningothelial; (2) fibroblastic; (3) angioblastic; (4) osteoblastic 1930 Bailey and Bucy Nine types: (1) mesenchymatous; (2) angioblastic; (3) meningotheliomatous; (4) psammomatous; (5) osteoblastic; (6) fibroblastic; (7) melanoblastic; (8) lipomatous; (9) generalized sarcomatosis of the meninges. 1935 Globus Five types: (with emphasis on the tumor content of pial vessels: (1) leptomeningioma; (2) pachymeningioma; (3) meningioma omniforme; (4) meningioma indifferentiale; (5) meningioma piale 1938 Cushing and Eisenhardt Nine types with subvariants: (1) non-reticulin or collagen-forming meningothelial tumor; (2) meningothelial tumor pattern with tendency to form reticulin or collagen; (3) reticulin- or collagen-forming fibroblastic tumors of benign type; (4) reticulin-forming angioblastic tumors; (5) non–reticulin- or collagen forming epithelioid tumors; (6) reticulin- or collagen-forming fibroblastic tumors of malignant type; (7) osteoblastic meningiomas; (8) chondroblastic meningiomas; (9) lipoblastic 1971 Russell and Rubinstein Five types: (1) syncytial; (2) transitional; (3) fibroblastic; (4) angioblastic; (5) mixed type 2007 WHO (World Health Organization) (1) meningothelial: (2) fibrous (fibroblastic); (3) transitional (mixed); (4) psammomatous; (5) angiomatous; (6) microcystic; (7) secretory; (8) lymphoplasmacyte-rich; (9) metaplastic; (10) chordoid; (11) clear cell; (12) atypical; (13) papillary; (14) rhabdoid; (15) anaplastic (malignant)
Adapted from Al-Rodhan and Laws 2 (1990).

PATHOGENESIS
Antonius Pacchioni described arachnoidal granulations in 1705 as analogous to lymph glands. 13 It was not until 1846, however, that Rainey suggested that these granulations were leptomeningeal in origin. 14 Luschka, Ludwig Meyer, and Key and Retzius supported this view but the association between the granulations and meningeal tumors went unrecognized. In 1864, John Cleland, a Professor of Anatomy at Glasgow, described two dural tumors. 15 One was an olfactory groove tumor and the other was right frontal in origin. In the dissecting suite, Cleland was able to separate the tumors from the dura, and hence appropriately described them as villous tumors of the arachnoid ( Fig. 1-3 ). He suspected that they must have originated from the pacchionian corpuscles and attributed to them an arachnoidal origin. In 1902, Schmidt, after microscopic examinations of a series of meningeal tumors concluded that the cellular structure of these tumors was similar to the cell clusters capping the arachnoid villi 16 ( Fig. 1-4 ). Many other competing theories on the origin of these tumors were proposed by some of the leading physicians of the time, including Ribbert (connective tissue origin), 17 Oberling (glial origin), 18 and Roussy and Cornil (neuroepithelial origin). 19 It was not until 1915, after Cushing and Weed confirmed that meningeal tumors arose from arachnoid cap cells, that Cleland’s theory gained widespread acceptance. 20

FIGURE 1-3 Cleland’s illustration of a villous tumor of the arachnoid.
(From al-Rodhan NR, Laws ER Jr. Meningiomas: a historical study of the tumor and its surgical management. Neurosurgery 1990:26(5):832–46; discussion 846–7.)

FIGURE 1-4 Schmidt’s illustration of cell clusters capping an arachnoid villus.
(From al-Rodhan NR, Laws ER Jr. Meningiomas: a historical study of the tumor and its surgical management. Neurosurgery 1990:26(5):832–46; discussion 846–7.)

ETIOLOGY
The association between head injury and meningioma development was first proposed by Berlinghieri in 1813. 21 In 1888, Keen published a series of three surgical cases including a meningioma wherein he discussed the potential connection between head injury and meningioma. Cushing agreed with this connection and wrote 2 :

In so many cases in the series has a tumor been found at the exact situation where a stunning blow had been received on the skull years before, that this must represent something more than a mere coincidence. On the circumstantial evidence it is tempting to assume that the injury has bruised the meninges and caused an extravasation to aid in the absorption of which the local cell-clusters have been incited into a state of morbid activity.
In 1986, Barnett and colleagues 22 concluded that the association between meningioma and head trauma was largely anecdotal, but thought that trauma may contribute in the development of meningiomas in some cases. This association was later refuted by a systematic epidemiological analysis. 22
Chronic irritation from abscess, hemorrhage, and tuberculosis were thought to have possible connection with the development of meningioma. Cushing and Eisenhardt, based on their experience in treating patients with von Recklinghausen’s disease, implicated congenital factors in the etiology of meningioma. 2 In 1981, Deen and Laws presented evidence supporting the irritation theory by describing meningiomas that had developed contiguous to other primary brain tumors. 23 Finally, cranial radiation has been shown to induce development of meningioma. 24

RADIOGRAPHY
In 1897, Obici and Bollici were the first to image the cranium, followed by Oppenheim’s announcement in 1889 that imaging of the sella turcica was possible. 2 In 1902, Mills and Pfahler were the first to provide a radiologic account of a meningioma. 25

An exposure of four minutes made with a moderately hard vacuum. A negative was obtained which showed good detail of all the structures. A large shadow lying between the coronal suture and the posterior meningeal artery corresponded to the area in which Dr. Mills located the tumor.
By 1920 may other reports of meningiomas were published and stereo-roentgenoscopy was in widespread use. The technology progressed through a series of improvements such as replacement of the old glass plates with more sensitive films, thus shortening exposure time. 7 However, the largest improvement in the visualization of brain tumors (including meningiomas) came with Dandy’s seminal paper on the use of ventriculograpy in 1918. 26 Later as the utility of ventriculograpy became more apparent, Cushing and Eisenhardt described it as “one of the most dependable contributions to tumor localization and diagnosis ever made.” 2

SURGICAL RESECTION
In 1743, Heister in Helmstead, Germany was the first to treat a meningioma surgically. 2 His patient was a 34-year-old Peruvian soldier who developed a postoperative infection and died after Heister had applied a caustic lime to the tumor. At autopsy, Heister termed the tumor de tumore capitis fungoso . Olaf Acrel ( Fig. 1-5A ), the father of Swedish surgery, operated on a brain tumor in a 30-year-old patient with a history of head injury 18 months earlier 2 ( Fig. 1-5B ). The patient was found to have a pulsatile tumor that was explored by insertion of a finger. Severe bleeding and convulsions ensued and the patient died a few days later.

FIGURE 1-5 A, Olaf Acrel, the father of Swedish surgery (1717–1806). B, Illustration of Olaf Acrel’s case of meningioma in 1768.
(From al-Rodhan NR, Laws ER Jr. Meningiomas: a historical study of the tumor and its surgical management. Neurosurgery 1990:26(5):832–46; discussion 846–7.)
In 1847, Zanobi Pecchioli of Italy performed the first successful meningioma removal. 27 He was a professor of operative medicine and surgery at Siena University and published a series of 1524 operations, 16 of which were neurosurgical procedures. One of his cases involved a large meningioma of the right sinciput. He removed the tumor through a triangular flap made by drilling three widely spaced burr holes. The operative site was covered with sweet almond oil–soaked cambric. The patient survived for more than 30 months, and in 1840, the description of this operation was chosen for the competition for the chair of surgery at the University of Paris.
In 1879, Sir William McEwen carried out a successful meningioma removal in Glasgow, the first in northern Europe ( Fig. 1-6 ). In the 19th century, the most celebrated and well known neurosurgical operation was performed by Franceso Durante ( Fig. 1-7 ) of Italy on June 1, 1885. 21, 28 His patient was a 35-year-old woman with a left olfactory grove meningioma. Durante completely resected the lobular apple size tumor, which weighed 70 grams, in 1 hour. He left a drainage tube that came down to the left nasal fossa through the opening made in the ethmoid sinus by the tumor. On postoperative day 7 the tube was removed and the patient was discharged home. The patient did very well and required a reoperation 11 years later for a recurrence. As a result of the favorable outcome of the patient, this case was published in Lancet in 1887 and presented at the International Medical Congress in Washington, DC, in September of the same year. 28

FIGURE 1-6 Sir William McEwen.
(From al-Rodhan NR, Laws ER Jr. Meningiomas: a historical study of the tumor and its surgical management. Neurosurgery 1990:26(5):832–46; discussion 846–7.)

FIGURE 1-7 Francesco Durante (1844–1934).
(From al-Rodhan NR, Laws ER Jr. Meningiomas: a historical study of the tumor and its surgical management. Neurosurgery 1990:26(5):832–46; discussion 846–7.)
William W. Keen ( Fig. 1-8 ), one of America’s pioneer neurosurgeons, was the first to successfully remove a meningioma in the United States on December 15, 1887. Keen was chair of surgery at the Jefferson Medical College in his home town of Philadelphia. His meningioma patient was a 26-year-old carriage maker with headaches, seizures, and partial blindness ( Fig. 1-9 ). The patient reported a history of head injury as a child and Keen documented an aphasia and a right hemiparesis on physical examination. The operation was performed after intricate antiseptic measures such as removal of the carpet from the operating theater and cleaning of the walls and ceiling. The operation commenced at 1 P.M. to maximize natural light and lasted 2 hours. The tumor, weighing 88 grams, was completely removed via a frontotemporal craniotomy. Although the procedure was complicated by cerebrospinal fluid leakage and poor wound healing for 5 weeks, the patient recovered and was discharged on postoperative day 84. In gratitude, the patient promised Keen his brain for study. Keen, nearly 30 years older than the patient, outlived him. The patient died 30 years and 44 days after the operation, and the promise was kept on January 29, 1918. 7, 29

FIGURE 1-8 William W. Keen (1837–1932) of Philadelphia, Pennsylvania.
(From al-Rodhan NR, Laws ER Jr. Meningiomas: a historical study of the tumor and its surgical management. Neurosurgery 1990:26(5):832–46; discussion 846–7.)

FIGURE 1-9 Keen’s early case of a meningioma.
(From al-Rodhan NR, Laws ER Jr. Meningiomas: a historical study of the tumor and its surgical management. Neurosurgery 1990:26(5):832–46; discussion 846–7.)
Harvey Cushing’s contributions to the surgical resection of meningioma are unequaled. Born in Cleveland, Ohio, Harvey Cushing ( Fig. 1-10 ) graduated Harvard Medical School in 1895 and joined Halsted’s surgical service at the Johns Hopkins Hospital in Baltimore. In 1912, he became Professor of Surgery at Harvard and Surgeon-in-Chief at the Peter Bent Brigham Hospital. Cushing’s most famous meningioma patient was General Leonard Wood, a military surgeon, Chief of Staff of the United States Army. In 1909, he presented to Cushing with frequent left-sided jacksonian attacks. The next year, Cushing, in a two-stage operation, 4 days apart, resected his right parasagittal meningioma. General Wood was discharged in good health and went on to be the Republican favorite to succeed President Woodrow Wilson. He re-consulted Cushing in 1927, complaining of severe left sided spasticity. Unfortunately, hours after this reoperation, Wood suffered an intraventricular hemorrhage and died. 2

FIGURE 1-10 Harvey Cushing (1869–1939).
(From al-Rodhan NR, Laws ER Jr. Meningiomas: a historical study of the tumor and its surgical management. Neurosurgery 1990:26(5):832–46; discussion 846–7.)

COMMENTARY
The improvement in neurosurgical outcomes at the turn of the 20th century was a result of more refined surgical technique, application of Lister’s antiseptic principles, and more precise localization of tumor. 4, 7 Cushing’s contributions were crucial to the advancement of intracranial surgery for meningioma and for that matter, all of neurosurgery in general. In 1922, Cushing concluded his Cavendish lecture by saying 10 :

There is today nothing in the whole realm of surgery more gratifying than the successful removal of a meningioma with subsequent perfect functional recovery, especially should a correct pathological diagnosis have been previously made. The difficulties are admittedly great, sometimes insurmountable and though the disappointments still are many, another generation of neurological surgeons will unquestionably see them largely overcome.
MacCarty, considering the role of meningioma in neurosurgical history, thought that it had the most prominent role on the development of surgery of the central nervous system 30 :

The road toward understanding and managing meningiomas has been long and eventful. Although many problems remain unsolved, the cumulative contributions of many generations of anatomists, pathologists, neurosurgeons, engineers, and, most of all patients have made the most difficult and inaccessible meningiomas within the safe reach of the modern neurosurgeon.

References

[1] Abbott K.H., Courville C.B. Historical notes on the meningiomas. I. A study of hyperostosis in prehistoric skulls. Bull Los Angeles Neurol Soc . 1939;4:101-113.
[2] Cushing H., Eisenhardt L. Meningiomas: Their Classification, Regional Behaviour, Life History and Surgical End Results. Springfield, IL: Charles C Thomas, 1938.
[3] Moodie R.L. Studies inR. XVIII. Tumors of the head among pre-Columbian Peruvians. Ann Med Hist . 1926;8:394-412.
[4] Wang H., Lanzino G., Laws E.R.J. Meningioma: the soul of neurosurgery: historical review. Sem Neurosurg . 2003;14:163-168.
[5] Netsky M.G. The first account of a meningioma. Bull Hist Med . 1956;30:465-468.
[6] Plater F. Observationum in hominis affectibus plerisque, corpori et animo, functionum laesione, dolore, aliave molestia et vitio incommodantibus, libri tres. Basileae: Impensis Ludovici Konig, 1614.
[7] Al-Rodhan N.R., Laws E.R.Jr. Meningioma: a historical study of the tumor and its surgical management. Neurosurgery . 1990;26:832-846. discussion 846–837
[8] Al-Rodhan N.R., Laws E.R.Jr. Meningioma: a historical study of the tumor and its surgical management. In: Al-Mefty O., editor. Meningioma . New York: Raven Press; 1991:1-8.
[9] Louis A. Mémoire sur les Tumeuers Fongueuses de la Dure-mère. Mem Acad R Chir Paris . 1774;5:1-59.
[10] Cushing H. The meningiomas (dural endotheliomas): their source, and favored seats of origin. Brain . 1922;45:282-316.
[11] Russell D.S., Rubenstein L.J. Pathology of Tumors of the Nervous System. London: Edward Arnold, 1971.
[12] Louis D.N., Ohgaki H., Wiestler O.D., Cavanee W.K. WHO Classification of Tumours of the Central Nervous System. Geneva: WHO Press, 2007.
[13] Pacchioni A. Dissertatio epistolaris de gladulis conglobatis durae meningis humanae, 1705. Rome
[14] Rainey G. On the ganglionic character of the arachnoid membrane of the brain and spinal marrow. Med Chir Trans . 1846;29:85-102.
[15] Cleland J. Description of two tumors adherent to the deep surface of the dura mater. Glasgow Med J . 1864;11:148-159.
[16] Schmidt M. Ueber die pachioniischen Granulationen u. ihr Verhaltniss zu den Sarcomen u. Psammomen der Dura Mater. Virchows Arch . 1902;170:429-469.
[17] Ribbert M.W. Uber das Endotheliom der Dura. Virchows Arch . 1910;200:141-151.
[18] Oberling C. Les tumeurs des meninges. Bull Assoc Franc Cancer . 1922;11:365-394.
[19] Learmonth J.R. On leptomeningiomas (edotheliomas) of the spinal cord. Br J Surg . 1927;14:396-476.
[20] Cushing H., Weed L.H. Studies on the cerebrospinal fluid and its pathway. IX. Calcarious and osseous deposits in the arachnoidea. Johns Hopkins Hosp Bull . 1915;26:367-372.
[21] Guidetti B., Giuffre R., Valente V. Italian contribution to the origin of neurosurgery. Surg Neurol . 1983;20:335-346.
[22] Barnett G.H., Chou S.M., Bay J.W. Posttraumatic intracranial meningioma: a case report and review of the literature. Neurosurgery . 1986;18:75-78.
[23] Deen H.G., Laws E.R. Multiple primary brain tumors of different cell types. Neurosurgery . 1981;8:20-25.
[24] Waga S., Handa H. Radiation-induced meningioma: with review of literature. Surg Neurol . 1976;5:215-219.
[25] Mills C.K., Pfaher G.E. Tumors of the brain localized clinically and by roentgen rays, with some observations relating to the use of the roentgen rays in the diagnosis of lesions of the brain. Phil Med J . 1902;9:268-273.
[26] Dandy W.E. Ventriculography following the injection of air into the cerebral ventricles. Ann Surg . 1918;68:5-11.
[27] Giuffre R. Successful radical removal of an intracranial meningioma in 1835 by Professor Pecchioli of Siena. J Neurosurg . 1984;60:47-51.
[28] Durante F. Contribution to endocranial surgery. Lancet . 1887;2:654-655.
[29] Keen W.W., Ellis A.G. Removal of a brain tumor, report of a case in which the patient survived for more than thirty years. JAMA . 1918;70:1905-1909.
[30] MacCarty C.S. The Surgical Treatment of Intracranial Meningiomas. Springfield, IL: Charles C Thomas, 1961.
CHAPTER 2 Meningeal Anatomy

Askin Seker, Carolina Martins, Albert L. Rhoton, Jr.

THE MENINGEAL COVERINGS
The brain and spinal cord are covered by layers of connective tissue called meninges, from the Greek word meninx , which means membrane. In fishes, only a single layer, the primitive meninx, is present. Amphibians and reptiles have two meningeal layers, the outer dura mater (meaning “hard mother”) and an inner, thin layer the secondary meninx. In mammals and birds, three meningeal layers are present. The pia mater (meaning “tender mother”) is thin, vascular, and closest to the brain. The arachnoid membrane, which has a spider web–like appearance, is the middle, avascular layer. The space between the pia mater and arachnoid is the subarachnoid space. The outermost layer is the dura mater, composed of two layers. Therefore, the meningeal coverings consist of three membranous layers, composed primarily of fibroblasts, varying amounts of extracellular connective tissue and one well-organized fluid-containing space. The membranes are the dura mater (pachymeninx) and the leptomeninges (arachnoid and pia mater). The use of the word mater (“mother”) to describe these membranes comes from the ancient notion that they were the origin, or mother, of all membranes in the body. 1

THE LEPTOMENINGES
Leptomeninx is the term used when the pia mater and arachnoid are considered together as a functional unit and contraposed to pachymeninx (from the Greek packys , meaning thick), designates the finer meningeal coverings. 2
The arachnoid is attached to the overlying dura mater. It consists of several layers of translucent cells that follow with the dura and a contingent of cells that form spindly trabeculae that bridge the subjacent space and attach to the pia mater on the surface of the brain. The subarachnoid space is bordered outside by the layer of arachnoid cells attached to the dura and on the inside by pial cells on the surface of the neural tissue. These structural relationships form the basis for the occurrence of the subarachnoid cisterns, which are dilations of the subarachnoid space containing arteries, veins, and neural structures (see Table 2-1 later).

TABLE 2-1 Classification of subarachnoid cisterns.
The arachnoid granulations or villi are specialized segments of the arachnoid and subarachnoid space that invaginate along the dura mater of the sinus and are involved on cerebral spinal fluid resorption. Although present in any major dural sinuses, they are most concentrated along the superior sagittal sinus, where they enter into the sinus cul de sacs (lacunae lateralis). These large arachnoid granulations leave indentations, called the granular fovea, in the inner table of the skull, parallel to the superior sagittal sinus groove.
Pial cells form a delicate membrane intimately attached to the neural surface, surrounding vessels located in the subarachnoid space and interconnecting with the arachnoid trabecular cells. Spinal pial cells contribute to the formation of the denticulate ligaments, located on the lateral surface of the cord, halfway between the dorsal and ventral roots and extending laterally to the inner surface of the spinal dura. In likewise manner, the filum terminale arises from the conus medullaris, has a core of pial cells and an arachnoid cells covering, and transverses the subarachnoid space of the lumbar cistern to attach to the inner surface of the caudal extreme of the dural sac.

GENERAL STRUCTURE OF THE DURA MATER: ENDOSTEAL AND MENINGEAL LAYERS
The cranial dura mater is a thick, collagenous sheath that lines the cranial cavity and is continuous with the spinal dura at the foramen magnum. The dura is adherent to the surrounding bones, especially at the sutures, cranial base, and around the foramen magnum. With increasing age, the dura becomes less pliable and more firmly adherent to the inner surface of the skull, particularly at the calvaria.
The dura is composed of an endosteal layer that faces the bone and a meningeal layer that faces the brain. 3 These layers are distinguished as separate sheaths at the venous sinuses, foramen magnum, and optic canal. The meningeal layer is continuous with the dural covering of the spinal cord and optic nerves, providing tubular sheaths for the cranial nerves as they pass through the cranial foramina. These sheaths fuse with the epineurium as the cranial nerves emerge from the skull, except at the optic nerve, where the dural sheath blends into the sclera. At the vascular foramina, the meningeal layer fuses with the adventitia of the vessel. The meningeal layer folds inwards to form the falx cerebri, the tentorium cerebelli, the falx cerebelli, and the diaphragm sellae, which partially divide the cranial cavity into freely communicating spaces. The endosteal layer of dura is continuous through the cranial sutures and foramina with the pericranium and through the superior orbital fissure and optic canal with the periorbita. 3
The walls of the cavernous sinus are formed by the dura lining the internal surface of the calvaria. In the lateral portion of the middle cranial fossa, the meningeal and endosteal layers are tightly adherent, but at the lateral aspect of the trigeminal nerve they are separated into two layers. At the upper border of the maxillary nerve, which is the most inferior limit of the cavernous sinus, the meningeal layer extends upward to form the outer part of the lateral wall of the cavernous sinus, and it wraps around the anterior petroclinoid fold, extending medially to form the roof of the cavernous sinus and the upper layer of the diaphragm sellae. The endosteal layer, at the upper border of the maxillary nerve and the lower margin of the carotid sulcus, divides into two layers. One layer adheres to the sphenoid bone, covering the carotid sulcus and the floor of the sella, and the other layer extends upward to constitute the internal layer of the lateral wall and roof of the cavernous sinus and diaphragm sellae. The endosteal layer invests the cranial nerves coursing in the lateral wall of the cavernous sinus. The thin layer in the sellar part of the medial wall of the cavernous sinus is thought to represent a continuation of the meningeal dural layer that faces the brain. Thus, two layers line the sellar floor and the lower surface of the pituitary gland, one that is adherent to the sphenoid bone and the other that comes from the diaphragm and wraps around the pituitary gland. Therefore, with the exception of the paired lateral aspects of the sella and pituitary gland that are covered by one layer, two layers cover the other sellar surfaces. The meningeal and endosteal layers of the lateral wall and cavernous sinus roof and diaphragm sellae continue anteriorly to line the anterior cranial fossa and posteriorly as the covering of the dorsum sellae and clivus. The meningeal layer also continues anteriorly to form the upper (distal) dural ring around the carotid artery and the optic sheath, whereas the endosteal layer continues anteriorly and medially to form the lower (proximal) dural ring around the carotid artery. 4

VASCULAR ORGANIZATION OF DURA
The origin of the membranes of the skull starts when the embryo has a crown-to-rump length of 12 to 20 mm, at which time differentiation of the skull, dura mater, arachnoid, and pial membranes begins. The gradual cleavage of the vascular system into external, dural, and cerebral layers also takes place at this stage, which has been referred to as the third stage of cerebrovascular development. 5 As the membranes covering the brain differentiate, the anastomosing channels that connect the deep capillary plexus with the superficial vessels close, thus separating the vessels surrounding the brain from those belonging to the skull and its coverings. 5, 6 The major meningeal arteries originating from this cleavage give rise to a rich anastomotic network that may enlarge after various insults 7 and play a role in the genesis of dural arteriovenous malformations. This anastomotic network divides progressively into primary, secondary, and penetrating vessels.
The primary anastomotic vessels change little in diameter as they course over the dural surface and anastomose frequently with each other. They cross the superior sagittal sinus, connecting the dura over the paired cerebral hemispheres into a single vascular unit. Crossing vessels are particularly large when one middle meningeal artery is hypoplastic. The primary anastomotic arteries have a straight course and measure 100 to 300 μm in diameter, whereas the main meningeal feeders have a diameter of 400 to 800 μm. The primary anastomotic arteries give rise to arteries to the skull, secondary anastomotic arteries, penetrating dural vessels, and arteriovenous shunts. 8
Secondary anastomotic arteries also lie on the outer dural surface. They measure 20 to 40 microns in diameter, are short, and their anastomotic pattern form a regular polygonal network. 8 Penetrating vessels arise from primary and secondary anastomotic arteries, leave the dural surface and extend to within 5 to 15 μm of inner and juxta-arachnoid surface of dura, to end in the capillary network. Capillaries, 8 to 12 μm in diameter, are present throughout dura, including the falx and tentorium, and are especially rich parasagittally, where they may form several layers. The capillary bed is located on the inner or cerebral surface of dura and is separated from arachnoid by only a few microns. 8
The arteries to the skull originated from the primary anastomotic vessels. They are well seen when the dura is stripped from the skull and many small arteries are torn out of the diploe, revealing their tiny foramina on the inner table of the skull. They measure 40 to 80 microns and supply the metabolic needs of the skull and diploic contents. These vessels, which are often enlarged in dural arteriovenous malformations, can be a source of copious bleeding during elevation of the bone flap, during craniotomy.

Overview of Dural Supply
The dural arteries arise from the internal and external carotid, vertebral, and basilar arteries ( Table 2-1 ) and may be the site of formation of saccular aneurysms, pseudoaneurysms, and arteriovenous fistulas and the source of traumatic and spontaneous hemorrhage into the epidural, subdural, and intraparenchymal area, in addition to the well known role in the vascularization of meningiomas, other tumors, and parenchymal arteriovenous malformations (AVMs).
The pattern of arterial supply of the dura covering the skull base is more complex than over the convexity. The internal carotid system supplies the midline dura of the anterior and middle fossae and the anterior limit of posterior fossa; the external carotid system supplies the lateral segment of the three cerebral fossae; and the vertebrobasilar system supplies the midline structures of the posterior fossa and the area of the foramen magnum. Dural territories often have overlapping supply from several sources. Areas supplied from several overlapping sources are the parasellar dura, tentorium, and falx. The tentorium and falx also receive a contribution from the cerebral arteries, making these structures an anastomotic pathway between dural and parenchymal arteries. A reciprocal relationship, in which the territories of one artery expand if the adjacent arteries are small, is common.
The dura covering the anterior fossa floor draws its supply from the anterior and posterior ethmoidal arteries, the superficial recurrent ophthalmic artery, and the middle meningeal artery ( Fig. 2-1 ). The middle meningeal artery will not contribute to the supply of the dura lining the floor of anterior fossa if the artery or its anterior branch arises from the ophthalmic arterial system. The territory of the anterior convexity and parasagittal area is supplied by both the anterior branch of the middle meningeal artery and the anterior meningeal branch from the ophthalmic artery ( Fig. 2-2 ).

FIGURE 2-1 Superior view of the skull base showing the area of supply of the individual meningeal arteries. Dural branches from the internal carotid arterial system are highlighted in shades of green, external carotid system in shades of blue, and the vertebrobasilar system in shades of red. A, Internal carotid system. The dura covering the medial part of the anterior fossa floor is supplied by the anterior and posterior ethmoidal arteries, the superficial recurrent ophthalmic artery, and olfactory branches of the anterior cerebral artery. The internal carotid system, through its inferolateral trunk and dorsal meningeal artery, supplies most of the parasellar dura and part of the anterior wall of the posterior fossa and the sellar dura through its paired capsular, inferior hypophyseal, medial clival, and dorsal meningeal arteries. B, External carotid system. The anterior and posterior divisions of the middle meningeal artery and its petrosal branch supply the dura covering the lateral skull base. The territories of the anterior and posterior branches of the middle meningeal artery extend toward the supra- and infratentorial convexity dura and medially over the falx and tentorium. The accessory meningeal and the ascending pharyngeal artery branches contribute to the supply of the area between the internal carotid and middle meningeal territories on the middle and posterior fossae. The jugular and hypoglossal branches of the ascending pharyngeal arteries supply the inferior portion of the posterior surface of the petrous bone, lateral cerebellar dura, the midclivus, and anterolateral foramen magnum. The mastoid branch of the occipital artery constitutes the main supply to the lateral part of the cerebellar fossae. C, Vertebrobasilar system. The anterior and posterior meningeal branches of the vertebral artery supply the foramen magnum dura. The posterior meningeal artery provides the major supply to the paramedial and medial portions of the dura covering the cerebellar convexity. The subarcuate artery, a branch of the anterior inferior cerebellar artery, supplies the dura of the posterior surface of the petrous bone and adjacent part of the internal acoustic meatus, as well as the bone in the region of the superior semicircular canal. D, Overview. A., artery; Access., accessory; Ant., anterior; Asc., ascending; Br., branch; Brs., branches; Caps., capsular; Car., carotid; Cer., cerebral; Cliv., clival; Div., division; Dors., dorsal; Eth., ethmoidal; For., foramen; Hypogl., hypoglossal; Inf., inferior; Jug., jugular; Lac., lacrimal; Lat., lateral; Med., medial; Men., meningeal; Mid., middle; Occip., occipital; Olf., olfactory; Ophth., ophthalmic; Pharyng., pharyngeal; Pet., petrosal; Post., posterior; Rec., recurrent; Subarc., subarcuate; Tr., trunk.

FIGURE 2-2 Superior view of the convexity showing the area of supply of the individual meningeal arteries. Dural branches from the internal carotid arterial system are highlighted in shades of green, the external carotid system meningeal branches in shades of blue, and vertebrobasilar system in red. A, Internal carotid system. The anterior ethmoidal artery has also been called the anterior meningeal artery, when its territory extends to the dura of the frontal convexity. It gives origin to the anterior falcine artery, also called the artery of the falx cerebri, which supplies the anterior portion of the falx cerebri and adjacent dura covering the frontal pole. B, External carotid system. The convexity dura is supplied predominantly by branches of the middle meningeal arteries, which supply the dura of frontal, temporal, and parietal convexity and the adjacent walls of the transverse and sigmoid sinus. C, Vertebrobasilar system. The posterior meningeal artery may reach the dura of the posterior convexity in the area above the torcula. D, Overview. The dura over the frontal convexity is supplied by the anterior meningeal branch of the anterior ethmoidal artery and branches of the anterior division of the middle meningeal artery that also reach the dura in the anterior parietal region. The parieto-occipital and petrosquamosal branches of the posterior division of the middle meningeal artery supply the dura over the posterior convexity. A., artery; Access., accessory; A., artery; Ant., anterior; Div., division; Men., meningeal; Mid., middle; Post., posterior.
The supply to middle fossa and paracavernous dura derives laterally from the middle meningeal, accessory meningeal, and ascending pharyngeal arteries. In an anterior to posterior direction, it receives contributions from the recurrent branches of the ophthalmic and lacrimal arteries, as well as from the medial tentorial artery ( Figs. 2-1 and 2-3 ). Medially those arteries anastomose with the cavernous branches of the internal carotid artery. In this system, dominance of a particular vessel can lead to unusual anatomic variants. The sellar dura has a bilateral supply from the paired capsular, inferior hypophyseal, medial clival, and dorsal meningeal arteries that anastomose across the midline in front and behind the dorsum sellae 9, 10 ( Figs. 2-1, 2-3, and 2-4 ). The inferior hypophyseal artery can supply pituitary adenomas and tumors of the sphenoid sinus. 11 - 13

FIGURE 2-3 Superior view of the tentorium showing the area of supply of the individual meningeal arteries. Dural branches from the internal carotid arterial system are highlighted in shades of green, external carotid in shades of blue, and the vertebrobasilar system in shades of red. A, Internal carotid system. From medial to lateral, the dorsal meningeal, the medial and lateral tentorial arteries supply the tentorium at its petrosal attachment. B, External carotid system. The branches of the posterior division of the middle meningeal artery contribute to the supply of the anterolateral tentorium and extend superiorly to supply the falcotentorial junction and falx. The posterior branch of the middle meningeal artery gives rise to the petrosquamosal branch at the junction of the skull base and convexity and supplies the insertion of the tentorium along the petrous ridge and groove for the transverse sinus; the dura of the torcula; and the junction of the sigmoid, transverse and superior petrosal sinuses. A., artery; Ant., anterior; Br., branch; Div., division; Dors., dorsal; Lat., lateral; Med., medial; Men., meningeal; Mid., middle; P.C.A., posterior cerebral artery; Post., posterior; Tent., tentorial.

FIGURE 2-4 Enlarged superior view showing the supply of the parasellar area. Dural branches from the internal carotid arterial system have been highlighted in shades of green, the external carotid system meningeal branches in shades of blue, and the vertebrobasilar system in shades of red. A, Internal carotid system. In an anterior to posterior direction, the parasellar dura receives contributions from the recurrent branches of the ophthalmic artery and the meningolacrimal, medial tentorial, medial clival, and dorsal meningeal arteries. The medial clival and dorsal meningeal arteries supply the dura over the posterior roof of the cavernous sinus and posterior diaphragma sellae and anastomoses laterally, with the branches of the inferolateral trunk, the main supplier of the lateral wall of the cavernous sinus. B, External carotid system. The supply to parasellar part of the middle fossa arises from the main divisions of the middle meningeal artery. The accessory meningeal and ascending pharyngeal arteries may provide an alternative supply of the lateral portion of the parasellar area in their reciprocal relationship with the branches of the internal carotid artery that supply the same area. C, Vertebrobasilar system. There are no branches of the vertebrobasilar system to the parasellar dura. The anterior meningeal artery from the vertebral artery supplies the anterolateral portion of the posterior fossa and foramen magnum. D, Overview. The intracavernous carotid branches provide the major supply to the roof and posterior and lateral walls of the cavernous sinus. These branches border laterally with the ascending pharyngeal and accessory meningeal branches. The main divisions of middle meningeal artery supply the middle fossa dura. The branches of the internal carotid artery supplying the posterior wall of the cavernous sinus may anastomose with the branches of the ascending pharyngeal and vertebral artery to supply the clival dura. A., artery; Access., accessory; Ant., anterior; Asc., ascending; Br., branch; Car., carotid; Cliv., clival; Div., division; Dors., dorsal; Eth., ethmoidal; Inf., inferior; Lac., lacrimal; Lat., lateral; Med., medial; Men., meningeal, meningo; Mid., middle; Ophth., ophthalmic; Pharyng., pharyngeal; Post., posterior; Rec., recurrent; Tent., tentorial; Tr., trunk.
The convexity dura is supplied predominantly by branches of the middle meningeal arteries. These branches course toward the superior sagittal sinus, where they are distributed to the sinus walls and give off descending branches to the adjacent falx cerebri. The scalp arteries, through the emissary foramina, also send branches to the convexity dura. The dura over the frontal convexity is supplied by the anterior meningeal branch of the anterior ethmoidal artery and branches of the anterior division of the middle meningeal artery that also distributes to the dura in the anterior parietal region. The dura over the posterior convexity is supplied by the parieto-occipital an petrosquamosal branches of the posterior division of the middle meningeal artery. 9, 10 This area also receives a contribution from the posterior meningeal branch of the vertebral artery, when this vessel extends above the torcular 14 (see Fig. 2-2 ).
The falx cerebri, falx cerebelli, and tentorium are supplied by basal and convexity branches of the meningeal arteries and receive a contribution from the cerebral arteries, making these structures an anastomotic pathway between dural and parenchymal arteries. Most of the vascular supply of the falx cerebri comes through its insertion on the vault, with the anterior basal insertion, the falcotentorial angle, and the free margin receiving independent contributions 15 ( Figs. 2-3 and 2-5 ). The dural walls of the superior sagittal sinus, the site of insertion of the falx on the dura of the convexity, are supplied by the middle meningeal arteries, which form two paramedial arcades, and are reinforced anteriorly, at the level of the insertion of the falx on the crista galli, by the anterior falcine arteries (see Fig. 2-5 ).

FIGURE 2-5 Lateral view showing the supply of the tentorium and falx. The dural branches from the internal carotid arterial system are highlighted in shades of green, the external carotid system in shades of blue, and the vertebrobasilar system in shades of red. A, Internal carotid system. The anterior falcine artery, the distal continuation of the anterior ethmoidal artery, enters the falx at the cribriform plate and supplies the anterior portion of the falx cerebri and adjacent dura covering the frontal pole. The free border of the falx and the walls of the inferior sagittal sinus receive branches from the pericallosal arteries anteriorly and the medial tentorial artery posteriorly. B, External carotid system. The anterior and posterior divisions of the middle meningeal artery supply the walls of the superior sagittal sinus and give rise to descending branches that are the main supply to the falx and the falcotentorial junction. C, Vertebrobasilar system. The posterior meningeal arteries reach the falcotentorial junction and posterior third of the falx cerebri. D, Overview. A., artery; Ant., anterior; Br., branch; Brs., branches; Div., division; Falc., falcine; Lat., lateral; Med., medial; Men., meningeal; Mid., middle; P.C.A., posterior cerebral artery; Perical., pericallosal; Post., posterior; Tent., tentorial.
Posteriorly, at the falcotentorial junction, the paramedial arcades are reinforced from three sources: the posterior meningeal artery from the vertebral artery, medial tentorial artery from the cavernous carotid, and an occasional branch of the posterior cerebral artery. The posterior meningeal artery, the major contributor, extends along the insertion of the falx cerebri after coursing into the insertion of the falx cerebelli. The medial tentorial artery, which supplies the medial third of the tentorium, reaches the straight sinus and torcular and may ascend in the posterior portion of the falx cerebri 9, 10 (see Fig. 2-5 ). The pericallosal branches of the anterior cerebral artery may also pierce the falx at or near its free edge to reinforce the arterial network along the deep edge of the falx.
The tentorium receives supratentorial and infratentorial contributions ( Figs. 2-3, 2-5 , 2-6 ). The supratentorial sources are the marginal and lateral tentorial branches of the cavernous carotid medially and the branches of the middle meningeal artery anterolaterally. The infratentorial components are the superior extensions of the jugular branch of the ascending pharyngeal artery and the tentorial branch of the posterior cerebral artery medially, the occipital artery laterally, and the posterior meningeal artery posteriorly (see Fig. 2-3 ). The lateral two thirds of the tentorium and its edge along the transverse sinus derive their supply mainly from two arterial arcades, petrosal and occipital. The petrosal arcade follows the superior petrosal sinus and is composed of the lateral tentorial artery, branches from the petrous and petrosquamosal trunk of the middle meningeal artery, and the lateral branch of the dorsal meningeal artery. The occipital arcade is composed above the tentorium by the petrosquamosal trunk and occipital branchs of the middle meningeal artery, and the occipital and posterior meningeal arteries form its infratentorial limb 9, 10 (see Fig. 2-6 ). The medial third of the tentorium is supplied by the medial tentorial artery from the internal carotid artery. This artery may receive a contribution from the posterior cerebral artery through the artery of Davidoff and Schechter (see Figs. 2-3 and 2-6 ).

FIGURE 2-6 Posterior fossa and tentorial dura. The view is directed from medially into the left half of a posterior fossa in which the cerebellum was removed. The clivus in on the right and the transverse sinus on the left. Dural branches from the internal carotid arterial system have been highlighted in shades of green, the external carotid system in shades of blue, and the vertebrobasilar system in shades of red. A, Internal carotid system. The medial tentorial artery supplies the medial third of the tentorium and the dorsal meningeal and the lateral tentorial artery contribute to the arcade that supply the attachment of the tentorium to the petrous ridge. The medial clival and dorsal meningeal arteries supplies the dorsum sellae and upper clivus. B, External carotid system. The hypoglossal and jugular branches of the ascending pharyngeal artery and the branches of the occipital artery supply the dura of the lateral part of the cerebellar fossa and the inferior portion of the posterior surface of the petrous temporal bone. The mastoid branch of the occipital artery constitutes the main supply of the lateral part of the cerebellar fossae and has a role on the supply of the lateral tentorial attachment. C, Vertebrobasilar system. The subarcuate artery, a branch of the anterior inferior cerebellar artery, supplies the posterior surface of the petrous bone above the internal acoustic meatus and surrounding the subarcuate fossa. The anterior and posterior meningeal arteries branches of the vertebral artery supply the foramen magnum dura. The posterior meningeal artery supplies the medial and intermediate portions of the cerebellar fossae dura. The vertebrobasilar system may also infrequently supply the medial edge of the tentorium through a branch of the posterior cerebral artery. D, Overview. Branches derived from all three arterial systems supply the dura covering the posterior surface of the petrous bone and clivus. A., artery; Ac., acoustic; Asc., ascending; Ant., anterior; Br., branch; Brs., branches; Cliv., clival; Dors., dorsal; For., foramen; Hypogl., hypoglossal; Int., internal; Jug., jugular; Lat., lateral; Med., medial; Men., meningeal; Occip., occipital; P.C.A., posterior cerebral artery; Pharyng., pharyngeal; Post., posterior; Sig., sigmoid; Subarc., subarcuate; Tent., tentorial; Transv., transverse.
The clival area derives its supply from the medial clival and dorsal meningeal, branches of the internal carotid artery, the anterior meningeal branch of the vertebral artery, and branches of the ascending pharyngeal artery. The dura over the posterior surface of the petrous bone is supplied by the dorsal meningeal and subarcuate arteries and branches of the middle meningeal, occipital, and ascending pharyngeal arteries (see Figs. 2-1 and 2-6 ). The dura of the lateral portion of the cerebellar fossa receives its supply from the ascending pharyngeal, occipital, and vertebral arteries. The posterior meningeal artery is the major supplier of the paramedial and medial portions of the cerebellar dura, but this area also receives contributions from the middle meningeal and occipital branches to the region of the torcular ( Fig. 2-7 ).

FIGURE 2-7 Posterior view of the dura covering the cerebellum and foramen magnum. A suboccipital craniectomy and C2 laminectomy has been performed while preserving the posterior arch of C1. Dural branches from the external carotid system are highlighted in shades of blue and the vertebrobasilar system in shades of red. No branches of the internal carotid system supply the dura covering the posterior cerebellar surface. A, External carotid system. The mastoid branches of the occipital artery constitute the main supply to the lateral part of the cerebellar fossae. The posteromedial division of the mastoid branch anastomoses with the petrosquamous branch of the middle meningeal artery above and below with the hypoglossal branch of the ascending pharyngeal artery. B, Vertebrobasilar system. The posterior meningeal artery supplies the medial and paramedial cerebellar fossae between the transverse sinus and torcula above, and the posterior edge of the foramen magnum below. C, Overview. The dura of the lateral portion of the cerebellar fossa receives its supply from the middle meningeal, occipital, ascending pharyngeal, and vertebral arteries. The walls of the falx cerebelli and enclosed occipital sinus are supplied mainly by the branches of the posterior meningeal artery. The posterior meningeal artery is also the major supplier of the paramedial and medial portions of the cerebellar dura, with lesser contributions from the middle meningeal and occipital arteries. A., artery; Asc., ascending; Br., branch; Brs., branches; Div., division; Hypogl., hypoglossal; Men., meningeal; Mid., middle; Occip., occipital; Pharyng., pharyngeal; Post., posterior.
In this discussion, the dura of the posterior fossa has been subdivided into several areas. The clival dura extends from the dorsum sellae to the anterior border of foramen magnum and is limited laterally by the petroclival fissure. The posterior petrous dura extends from the petroclival fissure to the sigmoid and superior petrosal sinuses. The cerebellar fossa dura is limited laterally by the sigmoid sinuses and extends over the cerebellar surface from the transverse sinus to the foramen magnum. The dura on each side of the midline has been further subdivided into a medial region, adjacent to the falx cerebelli; a lateral region, adjacent to the sigmoid sinus; and a paramedial region between the two. At the level of the foramen magnum, the dural supply arises predominantly from the external carotid and vertebral arteries 16 (see Fig. 2-6 ). The anterior and posterior meningeal arteries, branches of the vertebral artery, anastomose with the jugular and hypoglossal branches of the ascending pharyngeal artery and the mastoid branch of the occipital artery. The cavernous carotid may also contribute through the clival branches of the dorsal meningeal arteries. 12 The dural branches of the vertebral artery are usually small but may enlarge to supply dura-based lesions. Enlargement of the anterior meningeal artery is seen with meningiomas, glomus jugulare tumors, recurrent hemangioblastomas, and metastatic tumors. 17
Dural territories often have overlapping supply from several sources. A reciprocal relationship between the territories of adjacent arteries is common so that when the area supplied from one source is small another artery enlarges to supply the area. This reinforces the need to see all possible sources of supply to a lesion before any surgical or endovascular treatment. Areas supplied from several overlapping sources are the tentorium and adjacent falx, the walls of the cavernous sinus, and the dura around the gasserian ganglion. 18

Dural Arteries

External carotid artery branches
Three posteriorly directed branches of the external carotid artery—the ascending pharyngeal, occipital, and maxillary arteries—give rise to dural branches. The superficial temporal or posterior auricular arteries, or both, or connections over the convexity that pass through the emissary foramina, may occasionally contribute to the dural supply when one of the three external carotid branches is small.

Ascending pharyngeal artery
The ascending pharyngeal artery, the smallest branch of the external carotid artery, usually arises from the proximal portion of the external carotid artery. It has an ascending vertical course, along the posterolateral wall of pharynx, anterior to the longus capitis muscle, and medial to the styloglossus and stylopharyngeus muscles ( Fig. 2-8A, B ). This initial segment of the artery can be seen, in the lateral angiogram, in front of the vertebral column, and medial to the main external carotid trunk on the anteroposterior view.

FIGURE 2-8 A, Lateral view of the left parapharyngeal space and the ascending pharyngeal artery origin and course. The ascending pharyngeal artery makes a sharp anterior turn at the base of the skull, running downward and forward, following the upper border of the superior pharyngeal constrictor muscle to supply the pharynx and auditory tube. B, The segment of the internal carotid artery below the carotid canal has been removed and the stump retracted posteriorly to expose the anterior and posterior divisions of the ascending pharyngeal artery. The anterior division gives off the pharyngeal rami and the posterior, or neuromeningeal division, sends branches to the posterior fossa dura. The ascending ramus of the anterior branch, also called Eustachian branch, supplies the Eustachian tube and gives off a carotid branch, which accompanies the internal carotid artery within the carotid canal, supplying the periosteum, the sympathetic network around the vessel, and the arterial walls. The jugular branches of the ascending pharyngeal and occipital arteries send branches to cranial nerves IX, X, and XI. C, Intracranial view of the left jugular foramen. The jugular branch descends below the jugular foramen. D, Lateral view of a left mastoidectomy. The mastoid air cells have been removed to expose the superior, posterior, and lateral semicircular canals, facial nerve, sigmoid sinus, and jugular bulb. The lateral division of the jugular branch of the ascending pharyngeal artery ascends along the anterior edge of the sigmoid sinus and anastomoses medially with the meningeal branches of the internal carotid artery, superiorly with the subarcuate artery, and laterally with the mastoid branches of the occipital artery. E, Posterior view of the left lower cranial nerves. The cerebellum and accessory nerve have been elevated to expose the hypoglossal nerve. The hypoglossal branch of the ascending pharyngeal artery passes through the hypoglossal canal with the hypoglossal nerve and enters the dura. F, Posterior view of a hypoglossal canal that has been opened to expose the hypoglossal nerve and the hypoglossal branch of the ascending pharyngeal artery. The hypoglossal branch supplies the dura of the lateral portion of the foramen magnum and inferolateral cerebellar fossa. The posterior inferior cerebellar artery arises from the extradural segment of the vertebral artery. G, The right cerebellar tonsil has been elevated to expose a meningeal artery that arises from intradural vertebral artery and supplies the dura on the lateral edge of the lateral foramen magnum. A., artery; Ant., anterior; Asc., ascending; Br., branch; Cap., capitis; Car., carotid; CN, cranial nerve; Constr., constrictor; Div., division; Ext., external; For., foramen; Hypogl., hypoglossal; Int., internal; Jug., jugular; Lat., lateral; Long., longus; M., muscle; Men., meningeal; Occip., occipital; P.I.C.A., Posterior inferior cerebellar artery; Palat., palatini; Pharyng., pharyngeal; Post., posterior; Proc., process; Semicirc., semicircular; Sig., sigmoid; Sup., superior; Tens., tensor; Vert., vertebral.
The meningeal contribution of the ascending pharyngeal artery is via three branches: hypoglossal, jugular, and carotid (see Fig. 2-8A ). The hypoglossal and jugular branches, the more constant, originate from the posterior division, 10 and the carotid branch from the anterior division ( Fig. 2-8C–G ). The hypoglossal branch accompanies the hypoglossal nerve and enters the skull through the hypoglossal (anterior condylar) canal, to be distributed to the dura surrounding the foramen magnum and clivus, where it anastomoses with the branches arising from the ipsilateral cavernous carotid and vertebral arteries, and its mate from the opposite side. The hypoglossal artery may also arise from the vertebral artery (see Fig. 2-8G ). The area of supply of the hypoglossal branch (see Figs. 2-1, 2-6, and 2-7 ) may extend to the dura of the lateral portion of the cerebellar fossae, where it borders and has a reciprocal relationship with the territory supplied by the mastoid branch of the occipital artery and the posterior meningeal artery of the vertebral artery. In the clival area it may anastomose superiorly with the medial clival branch of the inferior hypophyseal artery and the dorsal meningeal artery and inferiorly with the anterior meningeal artery of the vertebral artery. 9, 10
The jugular branch enters the jugular foramen with cranial nerves IX, X, and XI, where it divides into medial and lateral branches. The lateral branch courses along the dural wall of the sigmoid sinus (see Fig. 2-8D ), where it anastomoses with the jugular branch of the occipital artery ( Fig. 2-9 ). The medial branch courses along and supplies the dura bordering the inferior petrosal sinus. Its territory (see Figs. 2-1, 2-6, and 2-7 ) borders the area supplied by the dorsal meningeal artery and medial clival artery from the cavernous carotid. Superiorly, it anastomoses with the subarcuate artery and the petrosquamosal branch of the middle meningeal artery and laterally with the mastoid branches of the occipital artery. The jugular branch distal to the jugular foramen supplies the dura facing the inferior part of the cerebellopontine angle 9, 10 (see Fig. 2-6 ). The hypoglossal and jugular branches also supply of the adjacent segments of cranial nerves IX through XII. 10, 19, 20 On lateral angiograms, the posterior division of the ascending pharyngeal artery ascends besides and overlaps the foramen magnum. On anteroposterior views, the hypoglossal is the most medial of the terminal branches of the posterior division.

FIGURE 2-9 A, Lateral view of a left occipital artery in the area below the mastoid process. The occipital artery originates from the posterior surface of the external carotid artery, courses posteriorly and upward, and passes deep to the posterior belly of digastric muscle in the occipital groove of the temporal bone. B, Posterior view of the retroauricular area. The occipital artery passes between the longissimus capitis and semispinalis capitis muscle and gives rise to a mastoid branch that passes through the mastoid foramen to reach the dura in the area of the junction of sigmoid and transverse sinus. C, A descending branch of the occipital artery arises as the artery passes above the superior oblique muscle and gives rise to deep rami that anastomose with the vertebral artery. D, Enlarged view of C. The mastoid branch of occipital artery enters the cranium, by passing through the mastoid foramina and anastomoses over the junction of sigmoid and transverse sinus with the branches of the middle meningeal artery. E and F, Left ( E ) and right ( F ) retromastoid areas. E, When the occipital artery’s course is low, no occipital groove is present and the artery passes superficial to the longissimus capitis muscle. F, If the artery courses below the skull base in an occipital groove it passes deep to the longissimus capitis muscle. G, Posterior view of the left occipitomastoid area. The mastoid foramen transmits the mastoid emissary vein and the mastoid branch of the occipital artery. H, A meningeal branch of this segment courses toward the midline and passes through the parietal foramen. I, Posterior view of the sagittal and lambdoid sutures. The parietal foramen, which transmits an emissary vein and a meningeal branch of the terminal segment of the occipital artery, is located near the midline, 3–5 cm above the lambda. J, Lateral view. The stylomastoid artery arises from the posterior surface of the external carotid artery and passes through the stylomastoid foramen to reach the facial canal, where it supplies the mastoid portion of the facial nerve and walls of the tympanic cavity. K, The posterior belly of digastric has been removed to expose the jugular branch of the occipital artery, which ascends behind the carotid sheath to supply the dura around the jugular foramen and cranial nerves IX, X, and XI. A., artery; Br., branch; Brs., branches; Cap., capitis; Car., carotid; CN, cranial nerve; Desc., descending; Digast., digastric; Ext., external; For., foramen; Gr., greater; Inf., inferior; Int., internal; Jug., jugular; Longiss., longissimus; M., muscle; Men., meningeal; Mid., middle; N., nerve; Obl., oblique; Occip., occipital; Occipitomast., Occipitomastoid; Par., parietal; Petrosquam., petrosquamosal; Post., posterior; Proc., process; Sag., sagittal; Sup., superior; Superf., superficial; Temp., temporal; Transv., transverse; V., vein; Vert., vertebral.
The carotid ramus originates from the anterior branch of the ascending pharyngeal artery. It courses in the periosteal lining of the carotid canal and anastomoses, at the level of the foramen lacerum, with branches arising from the carotid siphon 9, 10 to form the recurrent artery of the foramen lacerum. This recurrent artery also anastomoses at the lower edge of the trigeminal ganglion with the posterior branch of the inferolateral trunk and the cavernous branch of the middle meningeal artery. The carotid branch usually does not extend to the dura of clivus and cerebellopontine angle as do the other dural branches of the ascending pharyngeal artery. 9, 10 The recurrent artery of foramen lacerum may be involved in the supply of angiomas, lymphoid tumors, angiofibromas of the nasopharynx, and tumors of the cavernous sinus and caroticocavernous fistulas. 9, 10

Occipital artery
The occipital artery originates from the posterior surface of the external carotid artery, at the level of the angle of the mandible, and courses posteriorly and upward, being crossed superficially by the hypoglossal nerve. It passes deep to the posterior belly of the digastric muscle and lateral to the internal jugular vein, vagus nerve, internal carotid artery, and accessory nerve (see Fig. 2-9A ). At the level of a vertical plane crossing the posterior border of the external auditory canal, the occipital artery can be found in a tunnel formed above by the occipital groove of the temporal bone—a prominent sulcus on the undersurface of the temporal bone, medial to the digastric groove—medially by the attachment of the superior oblique muscle on the transverse process of atlas, and laterally by the cranial insertion of the posterior belly of the digastric muscle in the digastric groove (see Fig. 2-9B–F ). The presence of the occipital groove is dependent on whether the artery courses superficial or deep the longissimus capitis muscle. The groove is present if the artery courses deep to the longissimus capitis muscle along the lower surface of the skull base and is absent if the artery courses inferior to the skull base or lateral to the longissimus capitis muscle (see Fig. 2-9E–G ). 12
The occipital artery at the level of the posterior border of the upper insertion of the longissimus capitis muscle courses in the upper part of the space between the occipital bone and C1 and lateral to the rectus capitis posterior major and semispinalis capitis muscle. It is covered by a deeper layer formed by the splenius capitis muscle and a more superficial layer formed, from lateral to medial, by the sternocleidomastoid and trapezius. The occipital artery pierces the fascia between the trapezius and sternocleidomastoid, near the superior nuchal line and ascends in the superficial fascia of the scalp, where it is accompanied by the greater occipital nerve (see Fig. 2-9H ).
The occipital artery gives rise to the auricular branch, which anastomoses with the posterior auricular artery behind the ear; the stylomastoid artery, muscular branches to the sternocleidomastoid, digastric, stylohyoid, splenius, and longissimus capitis muscles; and meningeal branches to the posterior fossa that enter the skull through the jugular foramen and condylar canal and to inconstant branches that runs through the mastoid foramen (see Fig. 2-9B, D, G ).
The occipital artery is divided into three portions: (1) ascending cervical, (2) cervico-occipital or horizontal, and (3) ascending occipital 21 (see Fig. 2-9A ). The meningeal branches most frequently originate from the second and third arterial segments.
The mastoid branch, present in about one half of specimens 21 (see Fig. 2-9B, D, G ), also called the transmastoid branch or the artery of the mastoid foramen, 3, 9, 10 originates from the second segment of occipital artery, at the level of the insertion of the semispinalis capitis muscle, midway between the inferior and superior nuchal lines. From its origin, the mastoid branch courses between the splenius capitis muscle and the junction of the mastoid and occipital bones. It enters the cranial cavity at the level of the superior nuchal line, by passing through the mastoid foramen. Intracranially, the superior nuchal line corresponds to the level of the transverse sinus. The mastoid branch emerges intracranially at the posterior border of the upper end of the sigmoid sinus and divides into three groups of branches: descending, ascending, and posteromedial. 21 The descending branches are directed toward the jugular foramen and border the dural territory supplied by the jugular branch of the ascending pharyngeal artery (see Fig. 2-8D ). The posteromedial branches anastomose with the petrosquamous branch of the middle meningeal artery and constitute the main supply to the lateral part of the cerebellar fossae that borders the territory of the hypoglossal branch of the ascending pharyngeal artery or the posterior meningeal branch of the vertebral artery, or both. The ascending branches, which are directed to the dura covering the superior part of the posterior surface of the temporal bone that faces the cerebellopontine angle, anastomoses with the subarcuate branch of the anterior inferior cerebellar artery (see Figs. 2-1 and 2-6 ), and can supply acoustic neurinomas, meningiomas, and arteriovenous fistulas. The mastoid branches also supply the endolymphatic duct and sac. 22
The third or ascending occipital portion gives rise to the terminal branches of the occipital artery, which supply the musculocutaneous structures of the posterior portion of the cranial vault, and anastomoses with the branches of the superficial temporal artery (see Fig. 2-9H ). The parietal foramen (see Fig. 2-9J ), which is an inconstant opening located near the sagittal suture, about 3 to 5 cm in front of the lambda, 3 transmits a meningeal branch of the ascending occipital segment and a small emissary vein. 21
Variations of the stylomastoid artery and the mastoid branch include their origin from the ascending pharyngeal artery or from the posterior auricular artery. Alternatively, other meningeal arteries that commonly have other sites of origin, like the posterior meningeal and the branch to the falx cerebelli from the posterior meningeal artery, may also arise from the occipital artery.

Maxillary artery
The maxillary artery, through its middle meningeal and accessory meningeal arteries ( Figs. 2-10 and 2-11 ), provides almost all of the supply to the dura over the convexity and important contributions to the supply of the basal dura (see Figs. 2-1, 2-3, and 2-4 ).

FIGURE 2-10 A, Lateral view of the left mandible and infratemporal area. The superficial temporal artery arises from the external carotid artery and courses behind the condylar process of the mandible and the temporomandibular joint. B, The maxillary artery is divided into mandibular, pterygoid, and pterygopalatine segments. The mandibular segment courses deep to the neck of the mandible. The pterygoid segment courses between the temporalis and pterygoid muscles and gives rise to the deep temporal and pterygoid arteries. The pterygopalatine segment passes through the pterygomaxillary fissure to enter the pterygopalatine fossa. The deep temporal arteries and nerves enter the deep surface of the temporalis muscle. C, The middle meningeal veins accompany the divisions of the artery and communicate above with the superior sagittal sinus through the venous lacunae. D, Middle meningeal artery, which arises from the mandibular segment of the maxillary artery, passes upward between the roots of the auriculotemporal nerve and the foramen spinosum to reach the middle fossa dura. E, Enlarged view. The pterygoid venous plexus has been removed to expose the middle meningeal artery arising from the maxillary artery and coursing between the roots of the auriculotemporal nerve. F, The dura has been elevated from the floor of the left middle fossa to expose the bifurcation of the middle meningeal artery into anterior and posterior divisions lateral to the foramen spinosum. The medial branch of the anterior division courses near the sphenoid ridge and anastomoses with the meningolacrimal or sphenoidal branches of the ophthalmic system, or both. The lateral branch ascends toward the superior sagittal sinus. G, The middle meningeal artery gives rise to cavernous and petrous branches before splitting into anterior and posterior divisions just anterior and lateral to the foramen spinosum. H, Enlarged view of G. Immediately after entering the cranial cavity, the middle meningeal artery gives off a short vessel, which divides into the petrosal artery laterally and a cavernous branch to the trigeminal ganglion medially. The cavernous branch anastomoses with the posterior branch of the inferolateral trunk. The petrosquamosal branch arises from the posterior trunk at the junction of the skull base and convexity; supplies the insertion of the tentorium to the petrous ridge, the dura of the torcula, and the junction of the sigmoid, transverse, and superior petrosal sinuses; and extends to the dura of the posterior fossa bordering the area supplied by the external carotid branches. I, Lateral view of the anterior division of the left middle meningeal artery in another specimen. A branch of the anterior division ascends grooving the parietal bone approximately 1.5 cm behind the coronal suture. In this case, the segment encased in a bony canal was removed in elevating the bone. The petrosquamosal branch, described in H , arises from the middle meningeal artery at the junction of the skull base and convexity. J, Posterolateral view of the dura over the right transverse sinus and torcula. The petrosquamosal branch of the middle meningeal artery supplies the insertion of the tentorium; the dura of the torcula; and the junction of the sigmoid, transverse, and superior petrosal sinus and extends to the dura of the posterior fossa bordering the area supplied by the external carotid branches. K, Superior view of the convexity dura. The middle meningeal arteries give rise to a rich anastomotic layer of vessels referred to as the primary anastomotic arteries. These arteries change little in diameter as they course and anastomose over the dural surface. They cross the superior sagittal sinus, connecting the dura over the paired cerebral hemispheres into a single vascular unit. L, Enlarged view of the area of the superior sagittal sinus. Each middle meningeal artery forms a paramedian arcade just lateral to the superior sagittal sinus. The arcades anastomose across the midline connecting the dural arterial network in a single vascular unit. M, Enlarged view of the sagittal sinus. The middle meningeal branches reach and participate in the supply of the walls of the superior sagittal sinus, where they give off descending branches to the adjacent falx cerebri and anastomoses with the other falcine arteries. N, The superior sagittal sinus has been opened and its walls hold laterally with pins to expose the branching pattern of the middle meningeal arteries along the sinus walls. A., artery; Alv., alveolar; Ant., anterior; Auriculotemp., auriculotemporal; Br., branch; Car., carotid; Clin., clinoid; CN, cranial nerve; Div., division; Ext., external; Fiss., fissure; For., foramen; Gr., greater; Inf., inferior; Int., internal; Lat., lateral; M., muscle; Mandib., mandibular; Med., medial; Men., meningeal; Mid., middle; N., nerve; Parieto-Occip., parieto-occipital; Palat., palatini; Pet., petrosal; Petrosquam., petrosquamosal; Plex., plexus; Post., posterior; Proc., process; Pteryg., pterygoid; Pterygomax., pterygomaxillary; Sag., sagittal; Sup., superior; Superf., superficial; Temp., temporal, temporalis; Tens., tensor; Transv., transverse; Tymp., tympani; V., vein; Ven., venous; Zygo., zygomatic.

FIGURE 2-11 A, Inferolateral view of the right foramina ovale and spinosum and the middle and accessory meningeal arteries passing through the skull base. The accessory middle meningeal artery arises from the maxillary artery, and passes through the foramen ovale in this case. B, Anterior view of the right foramen ovale exposing the sharp lateral curve of the middle meningeal artery above foramen spinosum. The intracranial territory of the accessory meningeal artery includes the gasserian ganglion and adjacent middle fossa dura, where it anastomoses with the meningeal branches from the ophthalmic and middle meningeal arteries and the carotid siphon. C, Endocranial surface of the sella and middle fossa. The sphenoidal emissary foramen is present in approximately 40% of the skulls. It is located medial to the foramen ovale. D, The deep temporal nerves and arteries pierce the deep surface of the temporalis muscle. The middle meningeal artery arises from the mandibular segment of the maxillary artery and gives rise to the accessory meningeal artery. E, Enlarged view of D . In this specimen, the accessory meningeal artery ascends superficial to lingual and inferior alveolar nerves. F, The upper segment of the ascending pharyngeal artery makes a sharp anterior turn, superficial to constrictor pharynx muscle and gives rise to a well developed carotid branch that follows the carotid artery into the carotid canal. A., artery; Access., accessory; Alv., alveolar; Ant., anterior; Asc., ascending; Auriculotemp., auriculotemporal; Br., branch; Cap., capitis; Car., carotid, Clin., clinoid; CN, cranial nerve; Emiss., emissary; For., foramen; Inf., inferior; Int., internal; Jug., jugular; Long., longus; M., muscle; Men., meningeal; Mid., middle; N., nerve; Occip., occipital; Pharyng., pharyngeal; Post., posterior; Sphen., sphenoidal; Temp., temporal; Superf., superficial; V., vein.

Middle meningeal artery
The middle meningeal artery normally arises from the first or mandibular segment of the maxillary artery, just behind the condylar process of the mandible, and enters the skull through the foramen spinosum (see Fig. 2-10A–H ). After passing through the foramen spinosum, the main stem courses laterally, grooving the greater sphenoid wing, where it divides in its anterior and posterior divisions, which supply the dura of frontal, temporal, and parietal convexity; the upper surface of the temporal bone; and the adjacent walls of the transverse and sigmoid sinus as well as the middle fossa dura adjacent to the cavernous sinus (see Fig. 2-10F–N ). In its path between the anterosuperior angle of the greater sphenoid wing and the sphenoid angle of the parietal bone, the anterior division, and sometimes the sphenoparietal sinus, can be encased in a bony canal that varies in extension from 1 to greater than 30 mm. 23 The anterior division is usually single but may be composed of two branches (duplicated) in 0.8%, or absent in 0.7% of cases, while the posterior division is duplicated in 8.1%. 23 At the level of the superior sagittal sinus the middle meningeal artery anastomoses with the anterior falcine branch of the ophthalmic artery to supply the dural layers of the falx (see Fig. 2-5 ).
The middle meningeal artery, and the osseous groove in which it courses, begins at the foramen spinosum and divide into anterior and posterior divisions 15 to 30 mm anterolateral to foramen spinosum (see Fig. 2-10F–I ). The anterior division and its groove divide behind the lateral part of the greater wing into a lateral branch, which passes across the pterion to reach the dura of the lateral convexity, and a medial branch, which courses medially along the lower surface of the sphenoid ridge where it anastomoses with the recurrent branch of the lacrimal artery. In 9 out of 10 orbits dissected, Liu and Rhoton 24 reported the presence of anastomotic connections between the recurrent meningeal branch of the lacrimal artery and the medial branch of the anterior division of the middle meningeal artery. Occasionally, the recurrent meningeal branch of the lacrimal artery gives rise to the anterior segment of the middle meningeal artery or more rarely, the ophthalmic artery can give rise to the main stem of the middle meningeal artery itself. In these cases, with an ophthalmic or lacrimal origin of the middle meningeal artery, the grooves marking the course of the main stem of the middle meningeal artery will originate at the lateral edge of the superior orbital fissure 25 and the foramen spinosum will be hypoplastic or absent. 26 Another, less frequent, site of origin of the middle meningeal artery is from the petrous portion of the internal carotid artery, referred to as a stapedial-middle meningeal artery, an anomaly that results from failure of the embryonic stapedial branch of the internal carotid artery to regress and allow the middle meningeal artery to become connected to the external carotid artery. 26
Angiographically, in the anterior view, the middle meningeal artery is easily recognized by a sharp turn along the floor of the middle fossa after passing through the foramen spinosum. Its course along the inner table is characterized by smooth curves, in contrast with the sinuous course of the overlapping superficial temporal artery. This initial intracranial portion of the middle meningeal artery can be elevated and stretched by lesions arising at the skull base (see Fig. 2-5B ). Radiographically, the grooves for the meningeal branches can become tortuous and the foramen spinosum can enlarge in meningiomas and vascular malformations. 27, 28
Immediately adjacent to the foramen spinosum the middle meningeal artery gives off a short branch, which divides into the petrosal artery laterally and a branch to the trigeminal ganglion medially (see Fig. 2-10G, H ). The trigeminal branch has been referred to as the cavernous branch of the middle meningeal artery. The petrosal branch runs with the greater petrosal nerve and penetrates the temporal bone by passing through the facial hiatus and supplies the facial nerve and walls of the tympanic cavity. 29, 30 Damage to the petrosal branch occurring as the dura is elevated in a subtemporal extradural approach to the trigeminal nerve, cavernous sinus, or internal acoustic meatus may result in a facial nerve deficit. Bleeding at this site should be controlled by a method other than coagulation in order to avoid damaging the facial nerve, which may be exposed in the floor of the middle fossa at the level of the hiatus fallopii. 25, 30
The posterior branch of the middle meningeal artery gives rise to the petrosquamosal branch at the junction of the skull base and convexity (see Fig. 2-10I, J ). It supplies the insertion of the tentorium along the petrous ridge and groove for the transverse sinus; the dura of the torcular; and the junction of the sigmoid, transverse, and superior petrosal sinuses, and extends to the dura of the posterior fossa bordering the area supplied by the other branches of the external carotid artery 31 (see Fig. 2-7 ). The petrosquamosal artery may infrequently supply almost all the posterior fossa dura, including the cerebellar fossa and tentorium cerebelli. 31 The parieto-occipital branch of the middle meningeal artery supplies the dura over the posterior convexity (see Fig. 2-10J ).
The middle meningeal artery in the middle fossa has anastomotic connections with the ophthalmic system and the meningeal branches of the cavernous carotid artery (see Fig. 2-1 ). The middle meningeal artery may contribute to the supply of the second and third trigeminal divisions in addition to the facial nerve. 19 It may supply most of the tentorium when giving rise to a medial tentorial branch. The medial tentorial artery may arise from either the main divisions of the middle meningeal artery or from the accessory meningeal artery, 31 described in the next section.
The middle meningeal artery anastomoses over the upper clivus and adjacent posterior surface of the temporal bone with the dorsal meningeal artery and the subarcuate artery. The distal part of the petrosquamosal branch anastomoses, at the level of the junction of the sigmoid, transverse, and superior petrosal sinuses, with the branches of the occipital artery that passes through the mastoid foramen and the meningeal branches of the ascending pharyngeal and vertebral arteries.
The middle meningeal artery may also anastomose with a branch of the basilar artery. 32, 33

Accessory meningeal artery
The accessory meningeal artery, also called the lesser or small meningeal artery 34, 35 (see Table 2-1 ), may arise from either the maxillary or middle meningeal artery depending on the relationship of the maxillary artery to the pterygoid muscles. 10, 34 It arises from the maxillary artery if the maxillary artery courses deep to the pterygoid muscles and from the middle meningeal artery if the maxillary artery passes superficial to the pterygoid muscle. In the cases in which the middle meningeal artery arises from the ophthalmic, internal carotid or basilar artery, the accessory meningeal artery will arise directly from the trunk of the maxillary artery. 36 The caliber of the accessory middle meningeal artery is about one third to one half of the middle meningeal artery (see Fig. 2-11A, B, D–F ) and in 30% to 45% of the cases it is formed by of multiple small arteries, 34, 35 especially if it arises from the maxillary artery. 34
From its origin, the accessory meningeal artery courses toward the angle between the posterosuperior edge of the lateral pterygoid plate and the infratemporal surface of the sphenoid bone. It usually passes posterior to the inferior alveolar and lingual nerves 34 (see Fig. 2-11A, E ). In 78% of the cases, the accessory meningeal artery enters the cranium through the foramen ovale. In the remaining 22%, it passes through the emissary sphenoid foramen (foramen of Vesalius), an opening occasionally found 2 to 3 mm medial to the anterior edge of foramen ovale that also transmits an emissary vein linking the pterygoid plexus and the cavernous sinus 34, 36 (see Fig. 2-11C ).
The extracranial segment of the accessory meningeal artery has anastomoses with the ascending pharyngeal artery and pterygopalatine arteries 9, 10, 36 (see Fig. 2-11A, F ). It supplies the membranous portion of the Eustachian tube and external acoustic meatus, the lateral pharyngeal wall and medial pterygoid muscle, the mandibular nerve below the foramen ovale, and sphenoid periosteum. It has been suggested that it be called the pterygomeningeal artery because the extracranial structures receive the predominance of its flow while the intracranial branch receives only 10%. 36
The intracranial territory of the accessory meningeal artery includes the gasserian ganglion and adjacent middle fossa dura, where it anastomoses with the meningeal branches from the ophthalmic and middle meningeal arteries and the carotid siphon. The accessory meningeal artery has a reciprocal relationship with the inferolateral trunk of the internal carotid artery in the supply of the mandibular nerve and the dura adjacent to the cavernous sinus. It has prominent anastomoses with the posterolateral branch of the inferolateral trunk (see Fig. 2-1 ). Lasjaunias and Theron 36 found that the accessory meningeal artery was small in 25% of the cases that it anastomoses with the inferolateral trunk of the cavernous carotid artery, had a size similar to the inferolateral trunk in 59%, and that it was the only supply to the cavernous sinus area in 16%. In the latter case, the diameter of this accessory meningeal artery approaches that of the middle meningeal artery. 9, 36 Occlusion of this artery during endovascular procedures may result in cranial nerve deficits because of its supply to the oculomotor, trochlear, trigeminal, abducens and facial nerves. 10, 36
Dilenge and Geraud 35 found that the artery could be identified in lateral angiograms throughout its extracranial course in 60% of 100 selective angiographies, but was recognizable intracranially in only six cases because of its small size. It was more easily identified when it was part of an anastomotic network between the carotid siphon and the internal maxillary artery. On the anteroposterior angiographic view, the accessory meningeal artery slants medially, above the skull base, toward the cavernous sinus at the point of arborization of the inferolateral trunk. It may contribute to the vascular pedicle of meningiomas and schwannomas of the gasserian ganglion, 35 and can be involved in paracavernous arteriovenous malformations.

Internal carotid artery branches

Cavernous segment
The cavernous portion of the internal carotid artery gives rise to branches that supply the walls and enclosed structures of sella, cavernous sinus, and the tentorium (see Figs. 2-3 and 2-4 ). The branches can be divided based on the direction of their course into a medial group that includes the inferior hypophyseal, medial clival, and capsular arteries; a lateral group that includes the inferolateral trunk, also called artery of the inferior cavernous sinus, and its branches and the lateral tentorial artery; and a posterior group that includes the dorsal meningeal artery and medial tentorial artery ( Fig. 2-12A–L ). The medial branches, including the inferior hypophyseal and medial clival artery, derive from the primitive maxillary artery, while the dorsal meningeal artery is the adult remnant of the primitive trigeminal artery. When these two embryonic vessels originate in a single trunk, the meningeal, hypophyseal, and neural branches will arise from a single source, referred to as the meningohypophyseal trunk. 9, 10

FIGURE 2-12 A, Superior view of the sella and roof of the cavernous sinus. The right anterior clinoid has been removed. The medial clival artery, usually a branch of the inferior hypophyseal artery and less commonly of the cavernous carotid artery, runs in the dura of the sinus roof and is distributed to the dura over the posterior clinoid and upper dorsum. B, Superolateral view of the left cavernous sinus. The meningohypophyseal trunk gives origin to the dorsal meningeal, medial clival, and tentorial arteries. C, Superolateral view after opening the lateral sinus wall. The first division of the trigeminal nerve has been retracted laterally to expose the inferolateral trunk, which arises from the lateral side of the midportion of the horizontal segment of the cavernous carotid, passes above the abducens nerve, and deep to the first trigeminal segment, supplies the dura of the inferolateral wall of the cavernous sinus and adjacent middle fossa, and anastomoses with the recurrent artery of the foramen lacerum. The dorsal meningeal artery passes posteriorly with the abducens nerve and is distributed to the dura over the dorsum sellae and clivus and anastomoses with its mate from the opposite side. Its territory has a reciprocal relationship with that of the medial clival artery. The medial clival artery arises from the meningohypophyseal trunk in this specimen. Its initial course is anterior to the posterior clinoid, but it also reaches to the dura over the posterior surface of dorsum sellae. The tentorial arteries pass laterally to reach the tentorium. D, Lateral view. The medial edge of the petrolingual ligament marks the beginning of the intracavernous segment of the carotid. E, Enlarged view of D . The meningohypophyseal trunk arises near the apex of the posterior bend of the intracavernous carotid on the medial side of the trochlear nerve. The tentorial artery arises as a branch of the meningohypophyseal trunk and divides into the medial and lateral tentorial arteries at the level of the petrous ridge. The medial tentorial artery supplies the medial edge and medial one third of the tentorium, reaching the area around the straight sinus and posterior attachment of falx. The lateral tentorial artery supplies the lateral two thirds of the tentorium and the attachment of the tentorium to the petrous ridge and anastomoses with the petrosal and petrosquamosal branches of the middle meningeal artery, the lateral branch of the dorsal meningeal artery, and the mastoid branch of the occipital artery. The dorsal meningeal artery runs posteriorly and passes through Dorello’s canal located below the petrosphenoidal ligament. F, The posterior bend of the intracavernous carotid artery has been retracted laterally to expose the inferior hypophyseal artery passing medially across the cavernous sinus to reach the lateral surface of the posterior lobe and capsule of the pituitary gland. G, Lateral view of the posterior part of a right cavernous sinus. The tentorial, inferior hypophyseal, and dorsal meningeal arteries arise from the meningohypophyseal trunk. The petrosphenoidal ligament has been excised to expose the passage of the dorsal meningeal artery to the clival dura. The inferior hypophyseal artery passes to the posterior lobe of pituitary gland and sellar floor. H, Posterior view after removal of the dorsum sellae in another specimen. The tentorial, inferior hypophyseal, and dorsal meningeal arteries arise directly from the cavernous carotid artery. The paired inferior hypophyseal arteries anastomose on the posterior surface of the posterior lobe to form an arterial circle that reaches the dura over the floor and posterior wall of sellae. Dorello’s canal has been unroofed on the right. The dorsal meningeal artery divides into medial and lateral branches. The lateral branch supplies the abducens nerve and the dura around Dorello’s canal and the medial branch supplies the dura over dorsum and upper clivus. The territory supplied by the medial branch of the dorsal meningeal artery has a reciprocal relationship with the territory of the medial clival artery. I, Enlarged view of the right cavernous sinus shown in H . The tentorial, dorsal meningeal, and inferior hypophyseal arteries arise separately from the posterior bend of cavernous carotid artery. J, Lateral view of the left cavernous sinus. The tentorial and the meningohypophyseal arteries arise from the posterior bend of the carotid. The meningohypophyseal trunk gives rise to the inferior hypophyseal, medial clival, and dorsal meningeal arteries. K, Lateral view. The medial tentorial artery runs parallel to the trochlear nerve in the upper portion of Parkinson’s triangle located between the trochlear nerve and first trigeminal division. The anterolateral branch of the inferolateral trunk courses between V1 and V2 and toward the foramen rotundum. L, Superior view of the specimen shown in K. The inferolateral trunk arises from the lateral side of the midportion of the horizontal segment of the intracavernous carotid and passes between the abducens nerve and the first trigeminal division to supply the dura over the inferolateral wall of the cavernous sinus and adjacent middle fossa. The anterior division of the inferolateral trunk gives rise to anterolateral and anteromedial branches. The anteromedial branch passes forward and supplies the oculomotor, trochlear, and abducens nerves and enters the orbit through the superior orbital fissure. The medial tentorial artery has been removed. M, Superior view of the right cavernous sinus. The roof has been opened and the oculomotor, trochlear, and ophthalmic nerves have been retracted laterally to expose the dorsal ophthalmic artery, the segment of the deep recurrent ophthalmic artery that courses inside the cavernous sinus. The deep recurrent ophthalmic artery arises from the initial intraorbital part of the ophthalmic artery and courses backward through the annulus of Zinn and medial portion of the superior orbital fissure to cross the anterior venous space of the cavernous sinus. The deep recurrent ophthalmic artery anastomoses with the anterolateral branch of the inferolateral trunk. N, Anterior view. A right capsular artery arises from the horizontal segment of the intracavernous carotid and runs medially to supply the dura over the floor of the sella. O, Lateral view. The inferolateral trunk arises medial to the first trigeminal division, but its branches can be seen between the trigeminal divisions. The anterolateral branch of the anterior division courses toward and gives a branch to the foramen rotundum. The posterior division is exposed between the second and third trigeminal divisions. P, Posterior–superior. The posterior division of the inferolateral trunk courses above the motor root of the trigeminal ganglion and supplies the gasserian ganglion and adjacent dura. Q, The trigeminal nerve has been removed to expose the inferolateral trunk and its divisions. In this specimen, the superior division of the inferolateral trunk gives rise to the medial tentorial artery, which supplies the medial third of tentorium and posterior attachment of falx cerebri. The anterior division supplies the segment of the oculomotor, trochlear, and abducens nerves near the superior orbital fissure. The posterior division reaches the gasserian ganglion, mandibular nerve, and adjacent dura and anastomoses with the recurrent artery of foramen lacerum. The dorsal meningeal artery arises from the posterior carotid bend and supplies the abducens nerve in the region of Dorello’s canal. A., artery; Ant., anterior; Br., branch; Caps., capsular; Car., carotid; Cav., cavernous; Clin., clinoid, clinoidal; Cliv., clival; CN, cranial nerve; Diaph., diaphragma; Div., division; Dors., dorsal; For., foramen; Gr., greater; Hyp., hypophyseal; Inf., inferior, infero; Int., internal; Lat., lateral; Lig., ligament; Med., medial; Men., meningeal; Meningohyp., meningohypophyseal; N., nerve; Ophth., ophthalmic, P.C.A., posterior cerebral artery; Pet., petrosal, petrous; Petroling., petrolingual; Petrosphen., petrosphenoid; Pit., pituitary; Post., posterior; Rec., recurrent; Seg., segment; Sup., superior; Tent., tentorial; Tr., trunk.
The meningohypophyseal trunk and the inferolateral trunk are the most consistent branches of the cavernous segment of the internal carotid artery. They arise from a single trunk in 6% of the cavernous sinus. 37 These vessels anastomose with their mates of the opposite side and with the meningeal branches of the external carotid, ophthalmic, and vertebral arteries 13 (see Figs. 2-1 and 2-4 ). The communication between the external carotid and internal carotid through the cavernous branches is of significance in the management of carotid cavernous fistulae, which must be based on evaluation of all these communicating channels. Increase in opacification of the cavernous carotid branches may occur with alteration of cerebral dynamics associated with increased intracranial pressure, a distant intracranial lesion, and in cerebrovascular disease in which the cavernous branches act as the rete mirabili. 13

Meningohypophyseal trunk
The meningohypophyseal trunk is the largest intracavernous branch of the internal carotid artery. 38 - 40 It arises lateral to the dorsum sellae at or just proximal to the apex of the first curve of the intracavernous carotid (see Fig. 2-6 ). It is approximately the same size as the ophthalmic artery. 38 In its most complete form it gives rise to the tentorial, inferior hypophyseal, and dorsal meningeal arteries (see Fig. 2-12B–G, I, J ). However, these branches can arise separately from the internal carotid artery or in different combinations, 9, 36, 37 and the origin of some secondary arteries directly from the meningohypophyseal trunk can give the appearance of more than the usual number of branches (see Fig. 2-12H ). The posterior bend of the internal carotid artery and the origin of the meningohypohyseal trunk can be exposed through Parkinson’s triangle, located in the lateral view between the trochlear and ophthalmic nerves, except when the carotid is elongated and tortuous, causing the posterior bend to rise above the trochlear nerve 11, 12 (see Fig. 2-12D–F ). The oculomotor and trochlear nerves enter the dural roof of the cavernous sinus just above or slightly behind the trifurcation of the meningohypophyseal trunk. According to Harris and Rhoton, 11 the meningohypophyseal trunk provides a branch to the tentorium in 100% of 50 cavernous sinuses examined, making the tentorial artery the most constant branch leaving this trunk.

Tentorial arteries
The tentorium has two sources of supply: the medial tentorial and the lateral tentorial arteries. The medial tentorial artery usually arises from the meningohypophyseal trunk, but may also arise from the inferolateral trunk, middle meningeal, accessory meningeal, ophthalmic, and lacrimal arteries (see Fig. 2-12E, F, K, Q ). It ascends to the roof of the cavernous sinus and then posterolaterally, along the free edge of the tentorium, to contribute to the supply of the transdural segment of the oculomotor and trochlear nerves, the walls of the cavernous sinus, and the medial third of the tentorium. 12, 41, 42 It departs from the cavernous sinus just beneath the entrance of the trochlear nerve and initially courses posteriorly about 5 mm from the free margin of the tentorium (see Fig. 2-12D, E ). As it approaches the region of the straight sinus, it curves laterally, ramifying within tentorium and anastomosing along the base of the falx with branches from its mate from the opposite side 12, 38, 41 (see Figs. 2-3 and 2-5 ). It may also anastomose with the meningeal branches of the ophthalmic artery. Although usually described as a branch of the tentorial division of the meningohypophyseal trunk, 37 the medial tentorial artery may also arise directly from the posterior vertical or from the horizontal segment of the cavernous carotid (as a branch of the inferolateral trunk), the accessory meningeal, intraorbital ophthalmic, lacrimal, or middle meningeal arteries. 18, 42
The term Bernasconi’s artery is used as a synonym for the medial tentorial artery 11, 12, 42 (see Table 2-1 ). Bernasconi and Cassinari (1956) were the first to describe an arterial vessel involved in the supply of the tentorium and its lesions. At that time, they thought the vessel originated from the external carotid artery 39, 41, 43, 44 but its true origin from the internal carotid artery later became apparent. 38, 41, 44
When visible during normal angiography, the medial tentorial artery ranges in length from 5 to 35 mm. A pathologic lesion has been considered a possibility if the tentorial artery can be followed, in the angiogram, for a distance longer than 40 mm. 12, 39 Other aspects such as increased diameter, undulating course, and multiple branching also suggest the presence of a lesion. 13 Its presence on angiograms is not diagnostic of a tentorial meningioma as first suggested, because it can be seen in arteriovenous malformations, gliomas with tentorial invasion, trigeminal neuromas, and even in normal patients. 12, 41, 43, 45
The lateral tentorial artery commonly arises as a single trunk with the medial tentorial artery (see Fig. 2-12D, E ). From its origin, it passed backward, upward, and slightly laterally to enter the tentorium along its attachment to the petrous ridge, and continued backward to supply the tentorial area lateral to that supplied by the medial tentorial artery. 28, 42, 45 The lateral tentorial artery anastomoses with the petrosal and petrosquamosal branches of the middle meningeal artery and the lateral branch of the dorsal meningeal artery (see Figs. 2-3 and 2-6 ).

Dorsal meningeal artery
The dorsal meningeal artery, also called lateral clival artery, is the adult remnant of the trigeminal artery. 31, 36 It arises from the meningohypophyseal trunk in most cases and passes posteriorly through the cavernous sinus, to supply the dura of the dorsum sellae and clivus and anastomose with its mate from the opposite side across midline (see Fig. 2-12B–E, G–J ). It arose from the meningohypophyseal trunk in 90% of the 50 cavernous sinus studied by Rhoton and Harris. 11 In 6% of cases, it arises directly from the lateral surface of the posterior ascending portion of the cavernous carotid, just below the meningohypophyseal trunk. 11, 12, 46
The dorsal meningeal artery divides into medial and lateral branches (see Fig. 2-12H, I ). The medial branch passes below the petrosphenoid ligament, which roofs Dorello’s canal, to accompany and supply the abducens nerve into the canal 31, 36, 38 and anastomoses with the clival ramus of the jugular branch of the ascending pharyngeal artery (see Figs. 2-1 and 2-6 ). The medial branch of the dorsal meningeal artery has a reciprocal relationship with the medial clival artery, which arises as a direct or as a secondary branch of the internal carotid artery from the inferior hypophyseal artery. The medial clival arteries initial course is anterior to the posterior clinoid process, but it also distributes to the dura over the posterior surface of dorsum sellae, where it anastomoses, across the midline, with its counterpart from the opposite side and also with the medial branch of the dorsal meningeal artery (see Fig. 2-12A–C ). If no medial clival artery is found, a branch arises directly from the dorsal meningeal artery or its medial branch and courses medially and superiorly, on the posterior aspect to the posterior clinoid process and dorsum sellae, supplying part of the territory of the medial clival artery (see Fig. 2-12H, I ).
The lateral branch of the dorsal meningeal artery passes above the trigeminal cistern (Meckel’s cave) and accompanies the superior petrosal sinus along the petrous ridge, thus participating in the basal arterial arcade of the tentorium cerebelli (see Fig. 2-3 ). This branch anastomoses, lateral to the trigeminal ganglion, with the lateral tentorial artery and branches of the middle meningeal artery running over the superior surface of the temporal bone.

Inferior hypophyseal artery
The inferior hypophyseal artery arises most frequently from the meningohypophyseal trunk (see Fig. 2-12F, G ) or directly from the medial surface of the posterior ascending segment of the cavernous carotid artery (see Fig. 2-12H–J, N ). 11, 31, 36 It passes medially across the cavernous sinus to reach the lateral surface of the posterior lobe and capsule of pituitary gland. The artery divides into superior and inferior branches that anastomose with their mates of the opposite side, forming an arterial circle anterior to the dorsum sellae (see Fig. 2-12H ). The inferior branch of this arterial circle, along with the more anteriorly located capsular arteries, may supply the dura on the sellar floor. 11, 13, 40, 46 The capsular arteries usually arise directly from the medial surface of the horizontal cavernous carotid (see Fig. 2-12N ), but may also be branches of the inferior hypophyseal artery. 38 The dura of the posterior clinoid and cavernous sinus can also be supplied by the inferior hypophyseal branch, through the medial clival artery, which can also arise directly from the cavernous carotid. 36, 42
Luschka, in 1860 38,40 first identified the inferior hypophyseal artery in man. This artery is the adult remnant of the primitive maxillary artery. In the lateral angiogram, the inferior hypophyseal artery is superimposed on the carotid siphon and is therefore impossible to identify even after subtraction studies. 36, 40

Inferolateral trunk
The inferolateral trunk, also called the lateral main stem 39 or the artery of the inferior cavernous sinus, 38 arises from the lateral side of the midportion of the horizontal segment of the intracavernous carotid, approximately 5 to 8 mm distal to the origin of the meningohypophyseal trunk 11, 46 (see Fig. 2-12K, L ). It arises directly from the carotid artery in 84% of the cavernous sinuses and from the meningohypophyseal trunk in another 6%. 11
The inferolateral trunk passes above (96%) or below (4%) the abducens nerve 47 and descends, through or lateral to the ophthalmic nerve, and supplies the dura of the inferolateral wall of the cavernous sinus and adjacent middle fossa up to the gasserian ganglion (see Figs. 2-1, 2-4, and 2-12K–P ). The branches of the inferolateral trunk anastomose with the middle and accessory meningeal arteries. 46 The branches to the gasserian ganglion may run in the dura lateral to the ganglion or pass superior to the motor root to reach the dura on the medial side of the ganglion (see Fig. 2-12P ).
In its most complete form, the inferolateral trunk gives rise to superior, anterior, and posterior branches 9, 48 (see Fig. 2-12Q ). The superior branch supplies the roof of the cavernous sinus. It gives rise to a medial tentorial branch in approximately 40% of cases 48 (see Fig. 2-12K, Q ). The anterior and the posterior divisions divide into a medial and a lateral branch. The medial branch of the anterior division passes forward and supplies the oculomotor, trochlear, and abducens nerves; enters the orbit through the superior orbital fissure; and terminates as the deep recurrent ophthalmic artery (see Fig. 2-12K–M ). The lateral branch passes toward the foramen rotundum and supplies the dura of the adjacent temporal fossa and maxillary nerve (see Fig. 2-12K, O, Q ). The medial branch of the posterior division is distributed to the abducens nerve, medial third of the gasserian ganglion, and the mandibular nerve (see Fig. 2-12P ). The lateral branch of the posterior division supplies the middle and lateral thirds of the gasserian ganglion and adjacent dura 48 (see Fig. 2-12Q ). Because of its reciprocal relationship with the cavernous branch of the middle meningeal artery, the posterior division may also reach the hiatus fallopi to supply the facial nerve. 9, 19 The posterior division of the inferolateral trunk anastomoses with the recurrent artery of foramen lacerum (see Fig. 2-4 ).

McConnell’s capsular arteries
The term McConnell’s capsular arteries refers to the anterior and inferior capsular arteries, tiny branches that arise distal to the origin of the inferolateral trunk. The inferior capsular artery is the more proximal of the capsular arteries. It arises from the inferomedial surface of the horizontal segment of the cavernous carotid, distal to the origin of the inferolateral trunk, or as a secondary branch of the inferior hypophyseal artery. It runs medially in the dural covering of the inferior surface of the anterior lobe, giving branches to the dura of the floor of the sella turcica (see Fig. 2-12N ). The anterior capsular artery arises from the medial aspect of the internal carotid artery just before it pierces the roof of the cavernous sinus and runs medially in the dura of the anterior margin and roof of the sella turcica, anastomosing with its mate of the opposite side.
McConnell’s capsular arteries are frequently absent, 11, 38, 40, 46 being found in 8% to 50% of cavernous sinuses. 37, 38, 40, 46 This variability may be due to difficulty in injecting these arteries 40 or its origin as a branch of the inferior hypophyseal artery. 46 The capsular arteries have been visualized angiographically in patients with sphenoid sinus carcinoma, craniopharyngioma, and parasellar meningiomas. 13

Recurrent artery of foramen lacerum
This tiny artery originates from the posterior ascending portion of the carotid siphon and descends into the foramen lacerum, supplying the pericarotid autonomic nervous plexus and the arterial wall 9, 48 (see Figs. 2-11F and 2-12C, Q ). This artery cannot be seen angiographically after internal carotid artery injections, because of the density of the parent carotid, but is visible after ascending pharyngeal injection because of its anastomoses with the carotid branch of the ascending pharyngeal artery. The recurrent artery of the foramen lacerum also anastomoses along the inferior surface of the trigeminal ganglion with the posterior branch of the inferolateral trunk (see Figs. 2-1 and 2-4 ).

Supraclinoid carotid branches
The ophthalmic and anterior cerebral branches of the supraclinoid carotid may supply the dura.

Ophthalmic artery
Contributions from the ophthalmic artery to the dura derive mainly from its ethmoidal, recurrent ophthalmic and lacrimal branches ( Figs. 2-13 to 2-15 ).

FIGURE 2-13 Superior view. A, The anterior and posterior ethmoidal arteries arise from the ophthalmic artery, and the anterior and posterior ethmoidal nerves arise from the nasociliary nerves and both the arteries and nerves course medially, passing above the optic nerve and between the superior oblique and medial rectus muscles to enter the ethmoidal canals. B, The lacrimal artery arises from the initial segment of the ophthalmic artery, courses laterally, and anastomoses through its recurrent meningeal or the meningolacrimal branch with the middle meningeal artery. C, Superior view of the dura around the cribriform plate after removal of the olfactory bulbs. The anterior ethmoidal arteries emerge from the ethmoidal canal at the lateral edge of the cribriform plate. The anterior ethmoidal arteries runs anterior and medially to reach and ascend in the falx, where they continue as the anterior falcine arteries The anterior falcine artery provides the major supply to the anterior third of falx. D, Superior view. The anterior ethmoidal artery reaches the anterior fossa at the anterolateral edge of the cribriform plate, and the inferior attachment of the falx to the crista galli. E, Superior view of the same specimen. The anterior falcine artery ascends within the falx and anastomoses with the middle meningeal branches that reach the sagittal sinus and descend on the falx and with the falcine branches of pericallosal branch of the anterior cerebral artery. A., artery; Ant., anterior; CN, cranial nerve; Crib., cribriform; Eth., ethmoidal; Front., frontal; Lac., lacrimal; Med., medial; M., muscle; N., nerve; Nasocil., nasociliary; Obl., oblique; Olf., olfactory; Ophth., ophthalmic; Post., posterior; Sup., superior.

FIGURE 2-14 A, Osseous relationships. Anterior view of the right orbit. The recurrent meningeal (sphenoidal) branch of the lacrimal artery courses through the lateral portion of the superior orbital fissure, to anastomose with branches of the middle meningeal arteries. This accessory anastomotic branch between the lacrimal and middle meningeal artery, called the meningolacrimal artery, courses through the lacrimal foramen located just below the lesser sphenoidal wing lateral to the superior orbital fissure. B, Enlarged view of the right orbit. The lacrimal foramen occupies a variable position relative to the superior orbital fissure. It can be located lateral to the superior orbital fissure, confluent with its lateral end or occupy any intermediate position between these extremes. C, Intracranial view of the superior orbital fissure. The surface of the anterior clinoid process exhibits the opening of a tiny bony tunnel that starts inside the optic canal and gives passage to the superficial recurrent ophthalmic artery, which supplies the roof of cavernous sinus and may continue posteriorly along the tentorium as the medial tentorial artery. The lateral portion of the superior orbital fissure is enlarged (arrow) for the passage of the recurrent meningeal (sphenoidal) artery, which anastomoses with the anterior branch of the middle meningeal artery. D, Intracranial view of the right superior orbital fissure and sphenoid ridge. E, Superior view of the right sphenoid ridge. The anterior division of the middle meningeal artery may be encased in a 1- to 30-mm canal, like that shown, in its course along the sphenoidal ridge. After reaching the upper or distal end of the canal, the branches of the artery ascend in bony grooves on the inner table of the skull. F, View of the medial wall of the orbit. The ethmoidal arteries and nerves course through the ethmoidal canals, located in the suture between the orbital plates of the frontal and ethmoid bones. A., artery; Ant., anterior; Br., branch; Clin., clinoid; Eth., ethmoidal; Fiss., fissure; For., foramen; Front., frontal; Gr., greater; Inf., inferior; Infraorb., infraorbital; Lac., lacrimal; Less., lesser; Max., maxillary; Med., medial; Men., meningeal; Mid., middle; Ophth., ophthalmic; Orb., orbital; Post., posterior; Rec., recurrent; Sphen., sphenoidal; Sup., superior; Supraorb., supraorbital.

FIGURE 2-15 Superolateral view. A, Part of the roof and lateral wall of the left orbit have been removed and the intraorbital structures exposed to demonstrate the anastomotic pathways between lacrimal and middle meningeal arteries. The anterior division of the middle meningeal artery gives off a medial branch, which runs medially along the sphenoid ridge and anastomoses with the lacrimal branch of the ophthalmic system. In this specimen, there is a dual connection between the middle meningeal and lacrimal arteries. The most lateral artery is the meningolacrimal branch, a recurrent meningeal branch that pierces the sphenoid wing by passing through the lacrimal foramen. Another vessel, called the recurrent meningeal artery or sphenoid artery (shown in B ), courses through the superior orbital fissure to create a second anastomosis between the anterior division of the middle meningeal and the ophthalmic system. B, Enlarged view of A. The meningolacrimal artery has been depressed to expose the tortuous course of the recurrent meningeal artery, also called the sphenoidal artery, which courses through the lateral edge of the superior orbital fissure to reach the dura of the middle fossa and parasellar area. C, Lateral view of the left frontal dura. A frontal branch that arises from the ophthalmic artery passes through the orbital roof to supply the frontal dura, reaching forward to the dura that covers the frontal pole. A., artery; Ant., anterior; Br., branch; CN, cranial nerve; Div., division; Front., frontal; Lac., lacrimal; Lat., lateral; M., muscle; Men., meningeal, meningo; Mid., middle; Ophth., ophthalmic; Orb., orbital; Post., posterior; Sphen., sphenoidal.

Ethmoidal arteries
The anterior and posterior ethmoidal arteries arise from the ophthalmic artery in the medial third of the orbit (see Fig. 2-13A, B ) and range in diameter between 0.5 and 1 mm in diameter. 49 These arteries enter the anterior and posterior ethmoidal canals with their corresponding ethmoidal nerves and leave the canals to enter the anterior cranial fossa at the anterior and posterior ends of the lateral edge of the cribriform plate (see Fig. 2-13A–D ). The orbital opening of the ethmoidal canals are located at the junction of the roof and medial wall of the orbit, along the frontoethmoid suture formed by the medial edge of the orbital plate of the frontal bone above and the perpendicular plate of the ethmoid below (see Fig. 2-14F ). Intracranially, the ethmoidal canals open on the suture between the orbital part of the frontal bone and the cribriform plate. Before reaching the intracranial cavity, the ethmoidal arteries send branches to the ethmoid sinuses and nasal cavity and septum. The ethmoidal arteries are prominently enlarged in vascular tumors or dural arteriovenous malformations of the anterior fossa.
Intracranially, the anterior ethmoidal artery has been also called the anterior meningeal artery, especially when its territory extends to the dura of the frontal convexity 50 (see Fig. 2-2 ). It gives origin to the artery of the falx cerebri, also called the anterior falcine artery, 50 - 52 which enters the falx at the cribriform plate and supplies the anterior portion of the falx cerebri and adjacent dura covering the frontal pole that borders with the dural territory of the middle meningeal artery (see Fig. 2-13C–E ). The anterior falcine artery may be present on both sides but either the right or left may predominate. 52 It artery is frequently seen, on normal carotid angiograms, ascending in the falx near its attachment to the convexity dura. 52 It may enlarge in falx meningiomas and occlusive cerebrovascular diseases. 51 The anterior meningeal branches of the ethmoidal arteries often supplies meningiomas from the olfactory groove and may be seen on angiography to be displaced in arch along the surface of the tumor. 28 The anterior falcine artery is not shifted laterally by intracranial masses because it courses within the rigid falx. 52
The posterior ethmoidal artery passes through the posterior ethmoidal canal and enters the dura at the posterior margin of the cribriform plate and supplies the dura of the medial third of the floor of the anterior cranial fossa, including the planum sphenoidale, anterior clinoid process, and chiasmatic groove (see Fig. 2-1 ). It anastomoses posteriorly with the branches of the internal carotid artery, laterally with branches of the middle meningeal artery, and anteriorly with the meningeal branches of the anterior ethmoidal artery (see Figs. 2-1 and 2, 4 ).

Recurrent ophthalmic arteries
The ophthalmic arteries may give rise to two recurrent ophthalmic arteries, one superficial and one deep that supply the dura. The superficial recurrent ophthalmic artery generally arises at a sharp angle, from the proximal portion of the ophthalmic artery in the optic canal, and passes backwards, to supply the dura over the anterior clinoid, adjacent lesser sphenoid wing, and the anterior and medial parts of the middle fossa 50 (see Fig. 2-14C ) and anastomoses with branches of the middle meningeal artery and posterior ethmoidal artery (see Figs. 2-1 and 2-4 ). It supplies the dural roof of the cavernous region and may continue as the medial tentorial artery (see Table 2-1 ). In the lateral angiographic view it projects above the C4 portion of the carotid siphon crossing the C3 portion under or on the anterior clinoid process somewhat more cephalad than the deep recurrent ophthalmic artery. 53
The deep recurrent ophthalmic artery arises from the initial intraorbital part of the ophthalmic artery, courses laterally, through the annulus of Zinn and the medial portion of the superior orbital fissure, crossing the anterior venous space in the cavernous sinus to supply the dura adjacent to the wall of cavernous sinus, bordering the territory of the inferolateral trunk (see Fig. 2-12M ). The presence of the deep recurrent ophthalmic artery is closely related to the embryological process that results in the adult form of the ophthalmic artery. Initially the primitive ophthalmic artery arises from two sources, the anterior cerebral artery and the intracavernous carotid artery. The ophthalmic artery, arising from the anterior cerebral artery, undergoes a process of migration to arise from the paraclinoid internal carotid artery. The ophthalmic artery, arising from the cavernous carotid, also undergoes regression to become the deep recurrent ophthalmic artery. 48 A cavernous origin of the ophthalmic artery, either with or without an ophthalmic artery arising in the usual intradural location, has been reported in 6% to 8% of the cases, 11 a finding explained by the persistence of the dorsal primitive ophthalmic artery. When there are two ophthalmic arteries, one passing through the optic canal and one through the superior orbital fissure either may be dominant.

Lacrimal branch
The most important collateral blood supply to the orbit is the middle meningeal artery 54 and, in reverse fashion, the ophthalmic arterial system can provide flow to the territory of the middle meningeal artery and its branches through the anastomoses between the anterior branch of the middle meningeal artery and the lacrimal branch of the ophthalmic artery (see Fig. 2-15 ). The presence of arterial connections between the ophthalmic arterial system and the middle meningeal artery has its origin in the embryonic development of the stapedial artery 55 and involves persistence of anastomoses that are normal at one stage of the development but later regress. 24, 56 In a 20-mm embryo the stapedial artery (a branch of the hyoid artery) divides into maxillomandibular and supraorbital divisions. The maxillo-mandibular division penetrates the foramen spinosum and is eventually annexed by the external carotid artery, to form the maxillary artery and extracranial segment of the middle meningeal artery. The supraorbital division, arises in the middle fossa and reaches the superior orbital fissure, providing retro- and intraorbital branches that will, in the adult, become the site for the anastomose of the lacrimal with the middle meningeal artery. The supraorbital division of the primitive stapedial artery is thus responsible for formation of the intracranial segment of the middle meningeal artery and the extraocular ophthalmic artery. 56, 57 The supraorbital division also gives off a branch near the superior orbital fissure that courses medially along the posterior edge of the lesser wing of the sphenoid to be distributed to the anterior clinoid process and roof of the cavernous sinus, participating in the supply of the oculomotor and trochlear nerves and sometimes coursing posteriorly as the marginal artery of the tentorium. This arterial branch provides the link between the intraorbital vessels (lacrimal or ophthalmic) and the posterior branches of the carotid siphon. 42, 48 In the adult, this artery possibly corresponds to the superficial recurrent ophthalmic artery.
Partial or complete persistence of intraorbital and retro-orbital branches of the supraorbital artery explains both the dependence of the orbital vascularizarion on the middle meningeal artery and the variable participation of the ophthalmic artery in vascularization of the convexity dura 56, 58 (see Fig. 2-15C ). If the proximal portion of the ophthalmic artery regresses, the adult ophthalmic artery originates, not from the internal carotid artery, but from the middle meningeal artery. 24, 54 Unilateral middle meningeal artery origin of the ophthalmic artery was seen in 2 of 170 anatomic specimens and 3 of 3500 cerebral angiograms. Demonstration of this anomaly bilaterally is extremely rare; only 4 cases have been reported. 59 Ophthalmic origin of the middle meningeal artery can be detected in skulls by the absence or reduced size of the foramen spinosum and/or absence, attenuation or interruption of the osseous sulcus for the middle meningeal artery along the floor of the middle fossa, and has been found in 10% of specimens. 44, 54, 60 Elevating the dura from the greater and lesser wings of the sphenoid, removing the sphenoid ridge, or embolization procedures involving the external carotid artery risk blindness in patients with a middle meningeal origin of the ophthalmic artery. 24, 56, 59 If the supraorbital stapedial branch persists, but its embryonic anastomoses with the primitive ophthalmic artery regresses, the resultant anomaly includes an ophthalmic artery that supplies only the globe and remains separated from intraorbital extraocular branches (muscular and lacrimal branches), which are then supplied by the middle meningeal artery.
The ophthalmic artery complex can supply the dura of the convexity and related lesions by three different anomalous meningeal vessels. The commonest found, in 0.5% of angiograms, is the middle meningeal artery that originates from the ophthalmic artery. This results from failure of the proximal intraorbital stapedial branches to involute in association with the involution of the maxillomandibular division of the stapedial artery. The ophthalmic artery may also supply dural lesions through the anterior branch of the middle meningeal, as occurs if there is a partial involution of retro-orbital stapedial branches. The accessory meningeal artery can also arise from the ophthalmic artery. The anatomico–radiologic features of anomalous meningeal branches arising from the ophthalmic artery are typical. These vessels usually arise at the point that the ophthalmic artery passes above the intraorbital optic nerve near the origin of the posterior ethmoidal artery, and pass upward through the superior orbital fissure to reach the cranial dura. Meningeal vessels of ophthalmic origin and related lesions are opacified exclusively by internal carotid artery injection whereas external carotid artery injection fails to visualize them. The anterior branch of the middle meningeal artery and the accessory meningeal artery of ophthalmic origin may be distinguished on angiograms from the anterior meningeal artery or artery of the falx, because this later branch courses near the midline in anteroposterior view and a few millimeters inside the frontal convexity in the lateral view, while the anterior branch of the middle meningeal artery and the accessory meningeal artery of ophthalmic origin have a more lateral course, away from the midline in the AP view and posterior to the frontal convexity in the lateral view. 56
In 30% of the cases 48, 53 in which the orbital branch of the supraorbital artery divides proximally, within the middle cranial fossa, the sphenoid bone, which ossifies later, will allow more than one transosseous route for these vessels. The anastomotic ramus between the lacrimal and the middle meningeal artery usually enter the orbit through the superior orbital fissure; however, in as much as 50% of dissected specimens an additional foramen can be seen in the greater wing of the sphenoid 60 (see Fig. 2-14A–C ). This foramen has been given several names including the lacrimal, Hyrtl, meningorbital, cranio-orbital, sinus canal, or sphenofrontal foramen. 54, 60
The lacrimal foramen is composed of multiple openings in 5% to 15% of the cases and occupies a variable position relative to the superior orbital fissure. 54, 60 The lacrimal foramen can be located lateral to the superior orbital fissure or confluent with its lateral end 54 (see Fig. 2-14A–C ). Two middle meningeal branches can coexist: one penetrating the orbit through the superior orbital fissure and the other, the lacrimal foramen. The branch that passes through the lacrimal foramen is referred to as the meningolacrimal artery, and the one entering the orbit through the superior orbital fissure is called sphenoidal artery or recurrent meningeal artery or orbital branch of the middle meningeal artery (see Fig. 2-15A, B ).
Sometimes the meningolacrimal artery is intact distally but fails to anastomose proximally with the middle meningeal artery and instead breaks up into a fine anastomotic plexus within the dura. 54 The recurrent meningeal artery runs in the sphenoparietal sulcus, on the lower edge of the sphenoid ridge, with the sphenoparietal sinus. This artery is long and tortuous while the meningolacrimal has a short, straight path to the orbit and to its anastomosis with the lacrimal artery (see Fig. 2-15A, B ). The recurrent meningeal artery may be associated with a laterally expanded superior orbital fissure (see Fig. 2-14C ). The meningeal branches of the ophthalmic artery, because of this variable distribution, should be carefully studied in sphenoid ridge, frontobasal, and anterior falcine tumors. A common angiographic finding in these lesions is enlargement of the ophthalmic artery. 50

Anterior cerebral artery
Dural branches can arise at two levels along the anterior cerebral artery. 9 The olfactory branches from the anterior cerebral artery, which course on the olfactory bulb may anastomose with the olfactory branches from the ethmoidal arteries in the region of the cribriform plate; and the pericallosal artery can send branches to the free margin of falx, anastomosing anteriorly with the anterior falcine branch of the ophthalmic artery and posteriorly with the dural branches from the posterior cerebral artery 9 (see Figs. 2-1 and 2-4 ).

Vertebrobasilar system
The vertebral, anterior inferior cerebellar, or posterior cerebral arteries may offer branches to the dura.

Vertebral artery branches
The anterior and posterior meningeal arteries arise from the extracranial segment of the vertebral artery to supply a portion of the posterior fossa dura ( Fig. 2-16 ).

FIGURE 2-16 A, Posterior view. The anterior meningeal artery arises from the anteromedial surface of the extracranial vertebral artery, between the C2 and C3 transverse processes. The anterior meningeal artery anastomoses with the hypoglossal and jugular branches of the ascending pharyngeal artery to supply the dura of the lateral portion of foramen magnum. The second, third, and fourth segments of the vertebral artery are labeled. B, Posterior view. The posterior meningeal artery arising from the third segment of the vertebral artery, which courses in a bony sulcus on the upper edge of C1. C, Enlarged view of B after a suboccipital craniotomy. The third segment of the vertebral artery is located between the transverse process of atlas and the dural entrance and gives rise to the posterior meningeal artery near the dura entrance than the transverse process of C1. A lateral branch of the posterior meningeal artery runs toward the occipital condyle. The posterior condylar vein passes through the condylar canal. D, The posterior meningeal artery ascends, nearly parallel to the internal occipital crest, to reach the dura over the medial cerebellar fossae and falx cerebelli and above the torcula to reach the dura of the falx cerebri. E, Posterior view of the torcula area. The posterior meningeal artery anastomoses with the meningeal branches of the ascending pharyngeal artery and mastoid branch of the occipital artery at the level of the foramen magnum and over the cerebellar fossae. Above the torcula, the posterior meningeal artery anastomoses with the petrosquamosal and parieto-occipital branches of the middle meningeal arteries. F, Posterior view. The left posterior meningeal artery has an anomalous origin from posterior inferior cerebellar artery. At the level of the cisterna magna, the caudal loop of the posterior inferior cerebellar artery gives rise to a meningeal branch, which pierces the arachnoid to supply the territory of the posterior meningeal artery. G, Posterior view of the right cerebellopontine angle. The anterior inferior cerebellar artery gives off the subarcuate and labyrinthine arteries. H, Posterior view of the right petrous bone adjacent to the subarcuate fossa. A., artery; A.I.C.A., anterior inferior cerebellar artery; Ant., anterior; Asc., ascending; Atl., atlas, atlantal; Br., branch, C1, first cervical nerve; C2, second cervical nerve; C3, third cervical nerve; CN, cranial nerve; Cap., capitis; Cond., condylar; Dors., dorsal; Endolimph., endolymphatic; Flocc., flocculus; For., foramen; Gang., ganglion; Int., internal; Intermed., intermedius; Jug., jugular; Labyr., labyrinthine; Lat., lateralis; M., muscle; Maj., major; Men., meningeal; Mid., middle; Min., minor; N., nerve, nervous; Occip., occipital; Pet., petrosal; Pharyng., pharyngeal; P.I.C.A., posterior inferior cerebellar artery; Post., posterior; Subarc., subarcuate; Suboccip., suboccipital; Sup., superior; Transv., transverse; V., vein; V.A.2, vertebral artery second segment; V.A.3, vertebral artery third segment; V.A.4, vertebral artery fourth segment.

Anterior meningeal artery
The anterior meningeal artery arises from the vertebral artery at the level of the C2, passes medially through the C2–C3 foramen in front of the C3 root, and courses upward near the midline, sending several twigs to the anterior dura along its course (see Fig. 2-16A ). These paired arteries join to form an arch in the dura at the level of the apex of the dens, which gives off multiple fine rami to the dura in the atlanto-occipital space. 16, 60 - 62 Intracranially, the anterior meningeal artery anastomoses with the hypoglossal branch of the ascending pharyngeal artery 16, 61, 63, 64 (see Figs. 2-1 and 2-6 ).
The anterior meningeal artery can be identified in approximately 50% of subtraction angiograms. 60 Its small size, results in only the first 1 to 1.5 cm of its course being seen angiographically. 17, 61 In the frontal angiogram, it is seen to arise from the medial aspect of vertebral artery and courses upward toward the foramen magnum. In the lateral angiogram, its initial segment is projected behind the vertebral artery, but it is subsequently seen into the anterior portion of the spinal canal, immediately posterior to the vertebral bodies, and anterior to the anterior spinal artery. 16, 61, 65

Posterior meningeal artery
The posterior meningeal artery usually arises from the segment of the vertebral artery that runs in the groove for the vertebral artery on the upper edge of the posterior arch of atlas (V3 segment) (see Fig. 2-16B–D ). Its origin is usually closer to the dural entrance than to the transverse foramen of the atlas. Its initial course is along the upper posterior aspect of the extradural vertebral artery toward the posterolateral edge of foramen magnum, where it enters the intracranial dura (see Fig. 2-16B ). It ascends posterosuperiorly, nearly parallel to the internal occipital crest, to reach the attachment of the cerebellar falx. Around the level of the external occipital protuberance, the artery bifurcates and anastomoses with the meningeal branches of the occipital and middle meningeal arteries 6 (see Figs. 2-7 and 2-14D ).
The posterior meningeal artery can be divided into an extracranial and an intracranial portion. The extracranial portion is tortuous, probably as a response to the motility of the neck 16 and extends from origin to the atlanto-occipital space. The intracranial portion shows a relatively straight configuration 17 (see Fig. 2-14B–D ). This pattern, on angiography, facilitates differentiation of the posterior meningeal artery from the branches of the posterior inferior cerebellar artery. The posterior meningeal artery, seen on 30% to 40% of angiograms, is easier to identify on lateral films. 16, 17
The posterior meningeal artery may also originate from the occipital artery, the hypoglossal branch of the ascending pharyngeal artery, the cervical internal carotid artery, 66 and the posterior inferior cerebellar artery. 6 Its origin from an artery supplying the brain parenchyma can result from the persistence of the preexisting anastomotic channels between the primitive cerebral and meningeal vessels, and regression of the proximal stem of the posterior meningeal artery (see Fig. 2-14F ).

Anterior inferior cerebellar artery
The subarcuate artery usually originates from the lateral pontine segment of the anterior inferior cerebellar artery (AICA), medial to the porus, penetrates the dura covering the subarcuate fossa, and enters the subarcuate canal (see Fig. 2-14G ). It may arise as a branch of the labyrinthine artery, which also arises from AICA or as a single trunk from a cerebellar branch of AICA (cerebellosubarcuate artery). In the few cases in which the artery arises inside the internal acoustic canal, it reaches the subarcuate canal after a short recurrent segment or by piercing the meatal roof. 12 The subarcuate artery anastomoses with the branches of the stylomastoid artery within the petrous bone, the branches of the middle meningeal artery running over the superior surface of the petrous bone and the mastoid branches of the occipital artery. It supplies the dura of the internal acoustic meatus and adjacent posterior surface of the petrous bone as well as the bone in the region of the semicircular canals. Although not seen angiographically, the subarcute artery is involved in the formation of the dural collateral circulation that joins the leptomeningeal collaterals in cases of anterior inferior cerebellar artery occlusion. 48, 58

Posterior cerebral artery
The posterior part of the falx cerebri and the adjacent medial part of tentorium may be supplied in part by a meningeal branch of the posterior cerebral artery. Wollschlaeger and Wollschlaeger 67 first described this meningeal branch during anatomical dissections and named it the artery of Davidoff and Schechter, in honor of their mentors (see Figs. 2-3 and 2-5 ). This artery originates from the peduncular or ambient segment of the posterior cerebral artery, courses around the brainstem to the midline and makes a sharp angulated upward turn to pierce the tentorium and supplies the tentorium and adjacent falx cerebri along the falcotentorial angle. An enlarged meningeal branch of the posterior cerebral artery has been identified angiographically in vascular tumors and arteriovenous malformations involving the falcotentorial junction. 68 A meningeal branch of the posterior cerebral artery could not be identified in this study or in a prior study from this laboratory. 69 However the senior author (ALR) has noted the presence of this variation in studies related to other areas.

Dural Sinuses and Veins
The sinuses are compartments of dura, lined with endothelium, which collect venous blood from the superficial and deep cerebral venous systems. They include the superior and inferior sagittal, straight, transverse, tentorial, cavernous, superior, and inferior petrosal sinuses.

Superior sagittal sinuses
Superior sagittal sinus is attached to the falx cerebri superiorly, to crista galli anteriorly and tentorium, posteriorly. It is triangular in cross section and has right and left lateral angles at its junction with the dura mater covering the convexities and an inferior angle at its junction with the falx. The superior sagittal sinuses courses in the midline in the shallow groove on the inner table of the cranium, and grows larger as it continues posteriorly. In approximately 60% of cases, superior sagittal sinus ends by becoming the right transverse sinus. 70 - 74 At the termination of the superior sagittal sinus is a dilatation, known as confluence of the sinuses or torcular herophili.
The superior sagittal sinus also communicates with veins in the scalp through emissary veins passing through foramina, as the example of the parietal foramen, which transmits venous connections to the superior temporal vein and may serve as a collateral route of venous drainage.
The cortical veins may pass directly to the superior sagittal sinus, or they may first join the meningeal veins. Enlarged venous spaces, called lacunae, are contained in the dura mater adjoining the superior sagittal sinus. The lacunae are largest and most constant in the parietal and posterior frontal regions. Smaller lacunae are found in the occipital and anterior frontal regions. The lacunae receive predominantly the drainage of the meningeal veins, which accompany the meningeal arteries in the dura mater but cortical veins can also pierce its deeper surface 72 - 77 ( Figs. 2-17 , 2-18 , and 2-19 ).

FIGURE 2-17 Dural sinuses and bridging veins. A, Oblique superior view. B, Direct superior view with the falx and superior sagittal sinus removed. A and B, The veins are divided into four groups based on their site of termination: a superior sagittal group (dark blue), which drains into the superior sagittal sinus; a tentorial group (green), which drains into the transverse or lateral tentorial sinus; a sphenoidal group (red), which drains into the sphenoparietal or cavernous sinus; and a falcine group (purple), which drains into the straight or inferior sagittal sinus either directly or through the basal, great, or internal cerebral veins. The carotid arteries pass through the cavernous sinuses. The meningeal sinuses in the floor of the middle cranial fossae course with the middle meningeal arteries. The medial tentorial sinuses receive tributaries from the cerebellum and join the straight sinus. The basilar sinus sits on the clivus. Pacchionian granulations protrude into the venous lacunae.

FIGURE 2-18 A, Superior view. The dura covering the cerebrum has been removed to expose the cortical veins entering the superior sagittal sinus. B, Venous lacunae and bridging veins to the superior sagittal sinus. A large venous lacunae adjoining the sagittal sinus extends above the bridging veins emptying into the superior sagittal sinus. The veins from the right hemisphere emptying into the superior sagittal sinus are the anterior, middle, and posterior frontal, central, postcentral, and anterior parietal veins. C, Posterior view of the cerebral and cerebellar hemispheres. The superior sagittal sinus is connected through the torcula with the transverse sinuses. The right transverse sinus is slightly larger than the left. The veins arising along the posterior part of the hemisphere are directed forward and join the superior sagittal sinus well above the torcula, leaving a void along the medial occipital lobe where there are no bridging veins emptying into the sinus. D, Superior view of the tentorial sinuses. The long vein on the left basal surface empties into the tributary of the left tentorial sinus shown by the red arrow. The temporobasal veins on the right side empty into the right tentorial sinus with multiple tributaries. The vein empties into the tributary of right tentorial sinus shown with a yellow arrow.

FIGURE 2-19 A, Superior view. There is commonly an area devoid of bridging veins entering the superior sagittal sinus just in front of the coronal suture, as shown, that would be a suitable site for a transcallosal approach. B, Posterolateral view. Both hemispheres removed to show falx and tentorial incisura. C, Anterolateral view. D, Falx was removed. Inferior sagittal sinus, superior sagittal sinus, and straight sinus are preserved. E, Medial surface of the right cerebral hemisphere. The falx except for the inferior sagittal sinus and straight sinus is removed.

The inferior sagittal sinus
Inferior sagittal sinus occupies the posterior two thirds of the free inferior edge of the falx cerebri. It ends by joining the great cerebral vein to form straight sinus. It arises from the union of veins from the adjacent part of the falx, corpus callosum, and cingulated gyrus. The largest tributaries of the inferior sagittal sinus are the anterior pericallosal veins. The superior sagittal sinus may communicate through venous channels in the falx with the inferior sagittal sinus 70, 75 (see Figs. 2-17 and 2-19 ).

Straight sinuses
This venous sinus is formed by the union of the inferior sagittal sinus with the great cerebral vein. It is attached to the tentorium cerebelli and drains either into the right or, most commonly, the left transverse sinus. 72 - 74 , 77 (see Figs. 2-17 and 2-19 ).

Transverse sinuses
The right and left transverse sinuses originate at the torcular herophili and course laterally from the internal occipital protuberance in a shallow groove between the attachments of the tentorium to the inner surface of the occipital bone. The right transverse and sigmoid sinus and the right jugular vein are the main effluent route to the superficial venous system, whereas the left transverse and sigmoid sinus and the left internal jugular vein drain the venous blood mainly from the deep venous system of the brain, which comprise the internal cerebral, basal and great veins 77 (see Figs. 2-17 and 2-18 ).

Tentorial sinuses
These sinuses divide into the medial and lateral groups. 76 The medial tentorial sinuses are formed by the convergence of veins from the superior surface of the cerebellum, and the lateral tentorial sinuses are formed by the convergence of veins from the basal and lateral surfaces of the temporal and occipital lobes. The medial group drains into transverse sinuses and the lateral group drains into both straight and transverse sinuses. 77

Cavernous sinuses
These large sinuses are approximately 2 cm long and 1 cm wide. They are located on each side of sella turcica and the body of the sphenoid bone. There are many trabeculae that contain blood channels. Each cavernous sinus receives blood from the superior and inferior ophthalmic veins, the superficial middle cerebral vein in the lateral fissure of the cerebral hemispheres. The cavernous sinus communicates through the superior petrosal sinus with the junction of the transverse and sigmoid sinuses and through the inferior petrosal sinus with the sigmoid sinus 77 (see Fig. 2-17 ).

Superior petrosal sinuses
These venous sinuses are small channels that drain the cavernous sinuses. They run from the posterior ends of the cavernous sinuses to the transverse sinuses. Both of petrosal sinuses lie in the attached margins of the tentorium cerebella to the petrous ridge. The superficial sylvian veins may empty into an infrequent tributary of the superior petrosal sinus called the sphenopetrosal sinus 77 (see Fig. 2-17 ).

Inferior petrosal sinuses
The inferior petrosal sinuses start at the posteroinferior margin of cavernous sinus and drain the cavernous sinuses into the internal jugulae veins. They run in a groove between petrous bone and occipital bone. 78

Meningeal veins
The small venous channels that drain the dura mater covering the cerebrum are called the meningeal veins. They are small sinuses that usually accompany the meningeal arteries. The meningeal veins that accompany the meningeal arteries course between the arteries and the overlying bone. The fact that the artery presses into the veins gives them the appearance ofparallel channels on each side of their respective arteries. The largest meningeal veins accompany the middle meningeal artery. The meningeal veins drain into the large dural sinuses along the cranial base at their lower margin and into the venous lacunae and superior sagittal sinus at their upper margin. The veins accompanying the anterior branch of the middle meningeal artery join the sphenoparietal or cavernous sinus or may pass through the sphenoidal emissary veins. The meningeal veins accompanying the posterior branch of the middle meningeal artery join the transverse sinus. The meningeal veins may course through a superficial tunnel on the inner surface of the bone so that they have both an intradiploic and an intradural course. The meningeal veins receive diploic veins from the calvarium 77 ( Fig. 2-20 ).

FIGURE 2-20 A, The outer table of the skull has been removed, while preserving the sutures, to expose the diploic veins (red arrows) coursing between the inner and outer tables. B, The inner table has been removed to expose the meningeal sinuses coursing along the middle meningeal artery while preserving the large posterior diploic vein in the bone. The upper end of the diploic vein joins the venous sinuses around the middle meningeal artery at the yellow arrow. C, Superior view. The dura covering the cerebral hemispheres contains a plexus of small meningeal sinus veins that follow the branches of the meningeal arteries. The largest meningeal sinuses course along the anterior and posterior branches of the middle meningeal artery and extend up to the superior sagittal sinus and the region of the venous lacunae.

NEURAL SUPPLY TO THE CRANIAL DURA MATER
The neural supply of the cranial dura matter is mainly from the three divisions of the trigeminal nerve, the first three cervical spinal nerves, and cervical sympathetic trunk.
In the anterior cranial fossa, the dura is innervated by meningeal branches of the anterior and posterior ethmoidal nerves and the meningeal branch of the maxillary (nervus meningeus medius) and mandibular (nervus spinosus) divisions of the trigeminal nerve. The trigeminal ganglion also gives off a small branch. Nervus meningeus medius and spinosus are largely distributed to the middle cranial fossa. The nervus spinosus is a branch from the mandibular division, and enters the cranium through the foramen spinosum accompanying the middle meningeal artery. It divides into anterior and posterior branches that accompany the main divisions of the artery and supply the dura mater in the middle cranial fossa.
The tentorium is supplied by recurrent tentorial nerve from the ophthalmic division. The posterior fossa dura is innervated by upper cervical nerves that give off ascending meningeal branches. Meningeal branches from the first and second cranial nerves enter the cranium through the hypoglossal canal and jugular foramen. Meningeal branches from the second and third cervical nerves enter the cranium through anterior part of the foramen magnum. These meningeal rami contain both sensory fibers from the upper cervical nerves and sympathetic fibers from the superior cervical sympathetic ganglion. Involvement of meningeal branches from hypoglossal and and vagus nerve and possibly from facial and glossopharyngeal nerve has been described. The branch from vagus starts from superior ganglion and supply posterior fossa dura. The fibers from the hypoglossal nerve arise inside the hypoglossal canal and supply the occipital dura, the dura covering the anterior walls and floor of the posterior fossa, and the inferior petrosal sinuses dural layers.
The arachnoid and pia matter do not contain nerve fibers. Only dura matter and blood vessels have a neural supply. 78

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CHAPTER 3 The Origin of Meningiomas

Serdar Baki Albayrak, Peter M. Black

INTRODUCTION
Meningiomas account for approximately 30% of all primary brain tumors constituting the largest subset of all intracranial tumors. 1 - 3 They can occur at any age, but most commonly in middle age. Women are more likely to develop intracranial meningiomas, with a female:male ratio of nearly 2:1. Even though it is generally agreed that meningiomas are of neuroectodermal in origin and arise from the arachnoidal (meningothelial, arachnoid cap) cells based on the ultrastructural and histologic similarities between meningiomas and arachnoid cells, the cellular origins of meningiomas still have not been identified clearly. 4 - 21 The histologic expression of diverse meningioma subtypes ranging from meningothelial to fibroblastic patterns matches well with the various non-neoplastic cells in the arachnoid villi in a similar range of meningeal to fibroblastic cells. Thus, the critical question merges at this point: Is there a universal pluripotent cell that gives rise to all different subtypes of meningiomas or does each meningioma subtype takes origin from different tumor initiating cells in various subsets of cells in the arachnoid villi? The answer to this questions still remains obscure because there is no as yet identified subset of meningioma cells with unique molecular signatures that may give rise to all meningioma subtypes.
Even though it was possible to characterize meningiomas well cytogenetically in the past several decades, they are still poorly understood and defined molecularly. Hence histopathologic grading of the tumor does not necessarily predict its clinical course, particularly in atypical meningiomas. 22, 23 Current findings in molecular genetics provide convincing evidence that meningiogenesis is a dynamic process whereas histopathologic grading, which reflects only a snapshot of tumor behavior, falls short in capturing the complexity of the underlying molecular dynamics of the neoplastic process.
Recently, in addition to the well known tumor suppressor NF-2 gene deletion on chromosome 22, several other genetic aberrations including the deletion of the INK4a-ARF locus have been discovered, and altered biological pathways that potentially promote tumor growth have been suggested. 22, 24 - 28
Even though these findings may provide more insight into the ongoing molecular alterations and thus various clinical courses of meningiomagenesis, the ultimate challenge still remains: the origin and evolution of meningiomas.
In this chapter, we report the latest findings regarding the cellular origins of meningiomas. As well known, the classically described “arachnoid-cell derived meningioma” concept is based on histopathologic and electron microscopic studies. In addition, recent molecular and genetic studies in animal models have shown that biallelic inactivation of the NF2 gene has resulted in meningioma formation, which further supports the concept of “arachoid cell-derived meningioma” at the molecular and genetic levels. 29, 30
The further objective of meningioma research in this sense is to identify whether there are any universal meningioma stem cells, and if so, what their molecular signatures would be. Isolating candidate meningioma “stem cells” from human meningioma tissue samples and establishing a novel in vivo meningioma animal model are the first steps in accomplishing this goal. The next step would be to demonstrate that the molecular and genetic profiles of the initial and in vivo formed tumor cells are identical, which would verify the presence of the meningioma stem cells.

HISTOLOGIC AND ULTRASTRUCTURAL SIMILARITIES BETWEEN ARACHNOID CELLS AND MENINGIOMAS
Arachnoid granulations, or arachnoid villi, are small projections of the arachnoid membrane into the superior sagittal sinus and its major tributaries, involved in the absorption process of cerebrospinal fluid (CSF). There is a general agreement that meningiomas take origin from these granulations. In 1831, Bright noticed the histologic similarities between meningioma cells and arachnoid villi cells. Cleland and Robin proposed for the first time that meningiomas derive from arachnoid cells. Soon after, Schmidt observed obvious histologic similarities between meningioma and arachnoid cells at the ultrastructural level, and with respect to cell adhesion mechanisms and the components of extracellular matrix 11, 13 ( Table 3-1 ).
TABLE 3-1 Ultrastructural and histological features of non-neoplastic arachnoid cells and meningioma cells.   Arachnoid cells Meningioma cells Arachnoid cap cell aggregates Psammoma bodies Psammoma bodies Polygonal arachnoid cells Numerous junctional complexes and interdigitations Fewer junctional complexes and interdigitations Phospholipid composition Phosphatidyl choline-multilamellar bodies to lubricate the surfaces of arachnoid cells thus facilitating the flow or absorption of CSF Phosphatidyl serine ribbonlike rings in meningioma whorls are thought to be the precursors of psammoma bodies E-cadherin expression Localized at the intermediate junctions and anchored to cytoskeleton via intracytoplasmic microfilaments in normal arachnoid cells Distributed along the cell borders and variations exist between the expressions of E-cadherin in different meningioma subtypes Prostaglandin D 2 synthase (PGDS) Mainly localized in the rough endoplasmic reticulum of arachnoid cells and detected in higher concentrations in the core arachnoid cells suggesting that it may play role in the absorption process of CSF The exact role of PGDS in meningioma cells is yet to be identified, besides being a candidate as a cell marker for meningiomas

Ultrastructural Similarities
Human arachnoid villi are composed of five layers: endothelial layer, fibrous capsule, arachnoid cell layer, cap cells, and central core. The outermost layer, an endothelial lining has a pivotal role in the absorption process of CSF, and displays a number of micropinocytotic vesicles, intracytoplasmic vacuoles, and villous projections. Endothelial cells are interconnected to each other by tight junctions. The arachnoid cell layer of the villus is the direct continuation of arachnoid membrane itself. This arachnoid cell layer forms cap cell aggregates that contains calcified organelles (psammoma bodies), which are also one of the histopathologic features of meningiomas. The arachnoid cell layer contains numerous extracellular cisterns that may contain granular material and multilamellar phospholipids. These cisterns form channels from the central core into the venous lumen and are involved in the transport of CSF. In addition, polygonal arachnoid cells are tightly attached via junctional complexes that are less frequently seen in meningioma cells. 13 Several studies in the literature revealed that syncytial areas of meningiomas and normal arachnoid villi are similar ultrastructurally; however, the ultrastructure of the meningioma cells are less organized and display fewer interdigitations. 11, 13, 31
Yamashima and colleagues investigated two forms of phospholipids in arachnoid villi and meningiomas: phosphatidyl choline and phosphatidyl serine. Human arachnoid villi display multilamellar bodies that are similar to pulmonary surfactant and are assumed to lubricate the surfaces of arachoid cells thus facilitating the flow or absorption of CSF. Conversely, phosphatidyl serine appeared as ribbonlike rings in meningioma whorls that are thought to be the precursors of psammoma bodies. 32

Cell Adhesion Mechanisms
During formation of a tumor, the tumor cells attach to each other via adhesion molecules. Adhesion molecules are divided into subgroups including cadherins, immunoglobulins, selectins, integrins, and mucins. These molecules have a pivotal role in tumor cell–tumor cell adhesion, tumor cell–endothelial cell adhesion, or tumor cell–extracellular matrix adhesion, all of which are of paramount importance at different stages in primary tumor formation or metastasis. Here, we discuss some of the common adhesion molecules that are expressed in both non-neoplastic arachnoid tissue and meningioma cells.

Cadherins
Cadherins are a group of glycoproteins playing a crucial role in cell adhesion and known to be one of the fundamental elements in embryologic morphogenesis similar to immunoglobulins and integrins. Cadherins are divided into four subtypes based on the tissue distribution: epithelial (E), neuronal (N), placental (P), and vascular (V).
Epithelial (E)-cadherin is a transmembrane glycoprotein and functions in cell–cell adhesion via β-catenin that indirectly binds E-cadherin to actin filaments. This results in strong adhesive forces between the adjacent arachnoid cells in arachnoid villi, thus enabling individual arachnoid cells to undergo conformational changes during CSF absorption. 33, 34
E-cadherin–dependent cell adhesion is a calcium-dependent process and is regulated by a number of cytoplasmic proteins such as alpha-catenin, moesin, exrin, and radixin. Recent evidence has shown that cadherin-mediated cell–cell adhesion is also controlled by NF2 gene–coded merlin protein, which is lost or inactivated in the majority of meningioma cells.
Apart from their involvement in CSF absorption process in arachnoid villi, cadherins have profound roles in embryogenesis, normal tissue growth, and maintenance of the tumor cell nest. Shimoyama and colleagues reported that E-cadherin is expressed in all epithelial tissues and cancer cells, loss of which may contribute to the invasiveness of cancer cells. Interestingly, most meningiomas display en block growth, compressing the surrounding brain without infiltration. This growth pattern can be partly explained by the expression of E-cadherins, particularly in syncytial and transitional types of meningiomas. Several experimental studies reported an inverse correlation between the invasiveness of meningiomas and the expression of E-cadherins. Further, variations exist between the expressions of E-cadherin in different meningioma subtypes: It is expressed diffusely in syncytial type, less in transitional type, and not expressed in the fibroblastic type. This variation in the expression of E-cadherins in meningioma types correlates with the proposed corresponding cell types in arachnoid villi. Tohma and colleagues 33 claimed that meningiomas may derive from arachnoid cells or fibroblasts (fibrous capsule) in the arachnoid villi rather than a single uniform cell based on the expression pattern of E-cadherin in different meningioma types. It is noteworthy that whereas fibrous capsule and the fibroblastic type of meningiomas do not express E-cadherin, the rest of the layers of arachnoid villi (cap cell cluster, arachnoid layer, and core arachnoid cells), and the proposed corresponding meningioma types do express E-cadherins. Tohma and colleagues also demonstrated ultrastructurally that E-cadherins are distributed along the cell borders in meningioma cells whereas they are localized at the intermediate junctions and anchored to cytoskeleton via intracytoplasmic microfilaments in normal arachnoid cells. 33 This change in the distribution of E-cadherin was thought to be at the receptor level, rendering the E-cadherin inactive and thus resulting in more arbitrary architecture and the increased motility of embryonic and meningioma cells.

Prostaglandin D 2 synthase
Prostaglandin D 2 synthase (PGDS or β-trace) is an enzyme playing a role in the synthesis of prostaglandin D 2 in the central nervous system (CNS). 9, 35 The function of PGDS in arachnoid and meningioma cells was reported in detail by Yamashima and colleagues in 1997. This study demonstrated that PGDS is localized mainly in the rough endoplasmic reticulum of arachnoid cells and detected in higher concentrations in the core arachnoid cells, suggesting that it may play role in the CSF absorption process. 9
The authors also showed diffuse expression of PGDS in meningioma cells. However, the exact role of PGDS in meningioma cells is yet to be identified, besides its being a candidate universal cell marker for meningiomas as proposed by Yamashima and colleagues.

Extracellular Matrix
In the literature, there is convincing evidence that meningiomas are derived from arachnoid cells based on the similarities in the composition and the distribution of the components of extracellular matrix in arachnoid cells and meningiomas.
It is also reported that the two basic subtypes—meningothelial and fibroblastic meningiomas—display common ultrastructural features of intermediate filaments such as vimentin, interdigitations, and desmosomes. 11, 36 Bellon and colleagues 37 have shown extracellular deposition of type 4 collagen in the transitional type. Likewise, McComb and Bigner 38 demonstrated the fibrillar distribution of the laminin in the transitional and the fibroblastic types but not in the meningothelial type. Further, Kubota and colleagues 39 found that whereas type I, III, and IV collagens and laminin occurred diffusely in between the tumors cells of fibroblastic types, these extracellular matrix proteins were detected in the fibrous septum of the meningothelial type that separates the clusters of tumor cells. In addition, Rutka and colleagues demonstrated that cultured meningioma cells express type I and III procollagens, type IV collagen, and laminin independent of the histologic subtypes. 40
In short, the components of extracellular matrix in meningioma cells and non-neoplastic arachnoid cells display significant similarities in terms of amount and type of proteins. It is also noteworthy that expressions of extracellular matrix proteins in meningothelial and fibroblastic subtypes of meningiomas show a different distribution pattern, which might suggest that these two basic meningioma subtypes may originate from different cell types.

ORIGINS OF MENINGIOMAS AT THE GENETIC AND MOLECULAR LEVELS
The majority of meningiomas occur spontaneously or in association with the inherited autosomal dominant disorder, neurofibromatosis 2 (NF2). Mutation of the neurofibromatosis 2 ( NF2 ) gene on chromosome 22q12 is an early aberration in meningioma tumorigenesis and individuals with NF2 are at significantly elevated risk for developing meningiomas. 10, 26, 41 - 43 Mutations in the both alleles of NF2 tumor suppressor gene result in the loss of merlin protein, which is thought to play a central role in regulating leptomeningeal cell proliferation. Biallelic inactivation of the NF2 gene is the initial and most common genetic defect present in at least 50% (30% to 70%) of spontaneous meningiomas. 26, 29, 30, 42 In addition, recent studies have identified merlin inactivation through calpain-mediated proteolysis or aberrant methylation in the 5′ region of the NF2 gene in the remaining approximately 50% of meningiomas. 7, 8, 44 Merlin is a radixin-like protein that is localized underneath the cell membrane and is implicated in the control of cell membrane–cytoskeletal interaction. Merlin acts on linking cell membrane proteins and actin filaments, thus leading to contact inhibition of normal cell growth. Notably, meningioma cells exhibit weak immunostaining for merlin compared to non-neoplastic arachnoid cells. Recent studies have reported that merlin-deficient meningioma cells are prone to develop cytoskeletal and cell contact defects, altered cell morphology, and delayed cellular apoptosis. 41, 44, 45
Another protein called 4.1 B belonging to the same protein superfamily as merlin was localized in DAL1 gene locus on chromosome 18p11.32. Although several studies have demonstrated the loss of 4.1 B protein expressions in up to 76% of cases, no genetic or epigenetic change on the DAL1 gene locus itself could be identified. 46 Similarly, no mutations have been identified in the genes coding for ezrin, radixin, and moesin which are structural relatives of merlin. 26, 27, 47
Atypical and malignant meningiomas have more intricate genetic aberrations with losses of the G 1 –S phase cell cycle checkpoint regulators, CDKN2A and CDKN2B, and p14ARF on chromosome 9p contributing to more aggressive meningioma phenotypes. 25, 28 Recently, Kalamarides and colleagues showed that there is a synergy of NF2 and p16 Ink4a mutations in the natural history of meningioma development in mice with biallelic inactivation of NF2 . 30 In this study, authors investigated that additional loss of the p16 Ink4a locus increased the frequency of meningioma and meningothelial proliferation in NF2 knockout mice regardless of the tumor grade. Likewise, Kalamarides and colleagues developed an animal model earlier. In this animal model, they targeted Cre recombinase to the leptomeninges of NF2 knockout mice by adenoviral delivery. 29 Consequently, these mice developed a range of meningioma subtypes mimicking human meningiomas; hence the authors concluded that NF2 biallelic gene activation in arachnoid cells is rate-limiting for meningioma development in the mouse.
However, in contrast to spontaneous meningiomas, radiation-induced meningiomas express fewer NF2 mutations or losses on chromosome 22. Radiation-induced meningiomas arise in fewer than 1% of irradiated patients and tend to be multifocal and more aggressive, possibly due to additional chromosomal losses on 1p, 6q, and 7p. 26, 41
The correlation between the aforementioned genetic aberrations and the corresponding alterations in molecular pathways during meningiomagenesis presents a challenge. Several studies have been investigating the global gene expression profiles of meningiomas with the goal of providing more insight into the molecular biology of these neoplasms. A recent study by Lal and colleagues has demonstrated that meningiomas of all three histopathologic grades can be divided into two main subgroups—low-proliferative and high-proliferative meningiomas—based on the global gene profiles and underlying molecular mechanisms. 11 The results of this study redefined the grade II meningiomas as either grade I or grade III based on their gene-expression patterns. In this study, gains and losses of chromosomes were described, but no gene amplifications were found in 23 meningioma specimens studied. The frequency of chromosome losses in descending order was chromosome 22, 14q, and 1p. Aberrations have also been detected on chromosomes 3p, 6q, 10, 14q, and 18, and gains on chromosome 1q. The study also claimed that alterations in the transforming growth factor-β (TGF-β) pathway may contribute to the anaplasia of grade III meningiomas, as a striking difference in the number of aberrations in genes that regulate TGF-β pathway was observed between the grade I and grade III meningiomas.
The proposed classification of meningiomas in this study also provided significant clinical relevance in that it retrospectively showed longer survival in the atypical low-proliferative group than in the atypical high-proliferative group. However, more studies are needed to bridge the gap between genetic mutations and intracellular signaling pathways in meningiogenesis.

THE MENINGIOMA STEM CELL CONCEPT AND ITS IMPLICATIONS IN THE ORIGIN OF MENINGIOMAS
Stem cells can be described as self-renewing, omnipotent cells that may eventually form various cell types with multilineage differentiation. Likewise, the concept of “cancer stem cells” denotes cancer cells with stem cell–like features that are responsible for tumor initiation, tumor renewal, and resistance to antineoplastic medications. Initially, this concept took its origin from the obvious similarities between the self-renewal mechanisms of stem cells and cancer cells derived from leukemia, multiple myeloma, and breast cancer. More than a decade ago, Singh and colleagues presented striking evidence regarding the existence of cancer stem cells in medulloblastomas and gliomas. 48 This study demonstrated that CD133 + cancer cells had the potential to form clusters of cells resembling neurospheres with self-renewal and differentiation abilities. The authors posted that the origin of cancer initiating cells might be a normal CD133 expressing neural stem cell, because CD133, a neural stem cell surface marker, was also detected in the normal human fetal brain. Several more recent studies have also revealed similar findings suggestive of a linkage between the normal neurogenesis and carcinogenesis.
Currently, there are no known exclusive markers that are unique to cancer stem cells. Even though CD133 appears to be diffusely expressed by glioma and medulloblastoma-initiating stem cells, it is also present on normal brain stem cells and numerous non-stem cells in different tumors and normal tissues. The same applies to the other frequently proposed cancer stem cell markers including CD44, Scal, and Thyl.
Recently, microarray and genomic hybridization techniques enabled the identification of several genes and signaling pathways, including Bmi-1 , Tie-2 , Shh , Notch , and Wnt/β-catenin , that may exert control over stem cells. Nevertheless, these genes also function in other non-neoplastic cell types. In conclusion, there is still no exclusively identified gene, epigenetic signature, or corresponding signaling pathway for cancer stem cells.
The idea of a “meningioma stem cell” is the extension of the cancer stem cell concept in other various solid tumors. 47
The hypothetical approach for the identification of potential meningioma stem cells should include the consecutive steps as follows:
1. Cultivation of meningioma cells from the patient specimens in serum-free neural stem cell (NSC) medium
2. Isolation of the potential meningioma stem cells using histopathologic (e.g., immunostaining), molecular (e.g., Western blot), and genetic tools (e.g., global gene profiling)
3. Establishment of an in vivo meningioma animal model by implanting isolated meningioma “stem cells”
4. Histopathologic, molecular, and genetic comparison of the in vivo formed meningioma cells with the initial meningioma tumor sample for verification.

Preliminary Results Supporting the Concept of Meningioma Stem Cells
Considering the cell surface markers of tumor-initiating cells, or, in other words, “cancer stem cells,” several transmembrane glycoproteins including CD24, CD34, CD44, CD133, and CD166 were studied in cultured meningioma cells in neural stem cell medium and on paraffin-embedded tissue sections obtained from grade I to III meningiomas. In addition, double staining with the proliferation marker Ki-67 was performed with each of the aforementioned cell surface markers to show the co-localization of Ki-67 staining with any of the stem cell markers. We observed consistent co-localization of CD133 and CD44 with the nuclear proliferation marker Ki-67 in vivo and in vitro. These findings suggested that meningioma stem cells may arise from CD133 + CD44 + CD24 – CD166 – meningioma cells. Further, CD133 + CD44 + CD24 – CD166 – meningioma cell populations had significantly longer survival times and increased proliferation rates in vitro. In the literature we reviewed, breast cancer stem cells displayed similar expression of surface markers as CD133 + CD44 + CD24 – ( Table 3-2 ).

TABLE 3-2 Cell surface markers of cancer stem cells in various solid tumors.
It is also noteworthy that breast carcinoma is also predominantly seen in females; thus it may be feasible to investigate further to clarify any common intracellular signaling pathways and genetic aberrations in both meningiomas and breast carcinomas.
Phase-contrast and immunofluorescence (IF) microscopy confirmed the growth of cultured meningioma cells in serum-free (NSC) media.

Expression of epithelial membrane antigen and vimentin
In numerous studies, IF staining has demonstrated strong positivity for epithelial membrane antigen (EMA) and vimentin in cultured meningoma cells in NSC medium.

Expression of prostaglandin D synthase
Prostaglandin D synthase (PGDS) is one of the proposed meningioma cell markers in vivo, and its physiologic role in arachnoid cells was explained earlier. IF staining for PGDS in our cultured meningioma cells was positive, which may be evidence supporting the differentiation of potential meningioma stem cells into meningioma cells.

Expression of CD44
CD44 is a widely distributed cell surface marker and cell adhesion molecule. The insertion of alternatively spliced exons into the CD44 mRNA creates various isoforms of CD44, each involved in diverse biologic functions. Suzuki and colleagues demonstrated the differential expression of CD44 in various meningioma subtypes. 49 In this study, only the secretory meningiomas appeared to express variant forms of CD44, favoring tumor cell differentiation to epithelial type, whereas meningothelial, fibrous, and malignant meningiomas express the standard form of CD44. Further, several other studies in the literature revealed convincing evidence that the overexpression of CD44 was often associated with increased migration ability and anaplasia in meningioma cells. 49, 50 Sainio and colleagues demonstrated the co-localization of NF2 gene–encoded merlin protein with CD44 and noted the interaction of CD44 and cytoskeleton via ezrin, radixin, and moesin proteins which are structurally related to merlin protein. Similarly, Morrison and colleagues presented additional evidence regarding the role of merlin-mediated contact inhibition of cell growth through interactions with CD44 in schwannoma cell lines.
We observed co-localization of CD44 with the proliferation marker Ki-67 in paraffin-embedded slides and in vitro under an IF microscope.

Expression of CD133
CD133 (Prominin I), a cell-surface antigen, is the first in a class of pentaspan membrane proteins. CD133 is a 97-kDa glycoprotein with five transmembrane domains, binds to the cell membrane cholesterol, and is associated with a particular membrane microdomain in a cholesterol-dependent manner. Even though the exact biologic function of CD133 is not known, it has been shown as a marker for stem and progenitor cells including neural and embryonic stem cells as well as hematopoietic stem and progenitor cells in both humans and mice. It was also shown to be expressed in cancers, including some leukemias and brain tumours, mostly in gliomas and medulloblastomas.
Immunostaining of paraffin-embedded slides has revealed the co-localization of CD133 with the nuclear proliferation marker Ki-67.
We also detected the diffuse expression of CD133 in meningioma cell culture plates The double-staining of CD133 with EMA also revealed positive results in some cells. It was particularly noteworthy to observe the co-staining of CD133 and EMA. Because EMA is an important marker in histologic diagnosis of meningiomas, it is conceivable that meningioma cells displaying positive staining for CD133 and EMA simultaneously may be “candidate meningioma stem cells.” The CD133 might serve as a potential “surface marker” for these meningioma “stem cells.”

Expression of CD166
CD166 (ALCAM) is an activated leukocyte cell adhesion molecule that binds to cell surfaces via CD6. It is a glycoprotein belonging to the immunoglobulin superfamily and is localized mostly on epithelial cells at intercellular junctions as part of the adhesive complex that maintains tissue architecture. CD166 has been detected in numerous malignancies, including melanoma, prostate carcinoma, breast cancer, colorectal carcinoma, bladder cancer, and esophageal squamous cell carcinoma. A recent experimental study has revealed CD166 at intercellular junctions in cultured endothelial cells and at the sites of cell–cell contact in the epithelium of several organs. The CD166 expression on meningiomas has not been reported in the literature so far. We detected diffuse positive IF staining for CD166 on our cultured meningioma cells suggesting a potential role for it on the differentiation and proliferation on meningioma “stem cells.” However, we did not detect persistent staining of CD166 on paraffin-embedded slides and did not observe any co-localization with Ki-67.

CONCLUSION
Classical data regarding the origin of meningiomas are mostly based on electron microscopic and immunohistochemical findings showing that meningiomas arise from arachnoid cells. However, arachnoid cells are not uniform and exhibit a wide range of cellular diversity including meningothelial, fibroblastic, endothelial cells, and the cells at the dura–arachnoid border. Recent studies have further supported the idea of “arachnoid-derived meningioma” concept: biallelic NF2 gene inactivation in arachnoid cells in nude mice led to meningioma formation. Taken together, these classical findings and recent evidence strongly suggested that arachnoid cells are the origins of meningiomas. Nevertheless, it is still not clear what particular type of arachnoid cell or cells are the meningioma-initiating cells. At this point, menigioma stem cell research would serve to investigate the meningioma-initiating cell/cells. Further, the concept of a “meningioma stem cell” does not seem too farfetched in light of current exciting findings. The next challenge is to develop a in vivo animal model that would mimic the natural course of meningioma formation.

References

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CHAPTER 4 Epidemiology and Natural History of Meningiomas

Lisa Calvocoressi, Elizabeth B. Claus

INTRODUCTION
In this chapter, we (1) provide descriptive data on the impact of meningiomas; (2) describe the natural history of these tumors; and (3) review risk and protective factors. Throughout, we critically evaluate the literature and identify gaps in knowledge. We identified studies on natural history and risk factors through MEDLINE using the PubMed system to retrieve articles published through February, 2008. We conducted searches, restricted to articles written in English, using the key words “meningioma” or “meningiomas” in conjunction with “biology,” “natural history,” “long-term,” “outcome,” surgery/microsurgery, “radiotherapy,” “radiation (ionizing),” “radiation effects,” cellular/mobile telephone/s, “occupation,” “head trauma,” “head injury,” “allergy,” breast cancer/carcinoma, “oral contraceptives,” hormone/estrogen replacement therapy, “hormone receptors,” genetic/s, and “epidemiology.” We obtained additional references from those articles and from several recent epidemiologic reviews of brain tumors. 1 - 4 We obtained descriptive statistics from articles identified through PubMed key word searches combining meningioma/s with “incidence,” “prevalence,” “survival,” “recurrence,” and “descriptive epidemiology,” and from the most recent report of the Central Brain Tumor Registry of the United States (CBTRUS) that is based on voluntary reporting by 18 registries from 1998 to 2002. 5

DESCRIPTIVE STATISTICS
By histology, meningiomas were the most frequent primary brain and central nervous system (CNS) tumors reported to CBTRUS between 1998 and 2002, accounting for 19,190 (30.1%) of all 63,698 tumors reported ( Fig. 4-1 ). Ninety-three percent of the meningiomas were nonmalignant. 5

FIGURE 4-1 Histologic distribution of primary brain tumors and CNS tumors, CBTRUS 1998–2002, n = 63,698.

Incidence
CBTRUS rates per 100,000 person years, age-adjusted to the 2000 U.S. standard population, demonstrated an overall meningioma incidence rate of 4.52. Rates differed little by race/ethnicity (4.46 in non-Hispanic whites; 4.58 in non-Hispanic blacks, and 4.61 in Hispanics of any race), but more than twice as many new cases were diagnosed among women than men (6.01 vs. 2.75). 5 Meningiomas are uncommon in children, accounting for approximately 3% of all childhood tumors; their incidence increases linearly with age ( Fig. 4-2 ). Mean age at diagnosis was 64 years. 5

FIGURE 4-2 Age-adjusted incidence rates of meningioma, 1998–2002. Central Brain Tumor Registry of the United States.
In the United States, data collected by CBTRUS between 1985 and 1994 from six population-based registries did not show an increase in incidence of meningioma, 6 nor did a study of the population of Rochester, Minnesota, 1950–1990. 7 However, data from the Danish Cancer Registry (1943–1997) demonstrated an increase in new cases of meningioma from 0.61 to 2.42 per 100,000 population, with an accelerating increase over time. 8 A similar trend was observed across Denmark, Sweden, Norway, and Finland between 1968 and 1997, 9 whereas in Japan, based on 1973–1993 data, an increase in incidence was seen before 1980, followed by stable subsequent rates. 10 Where an increasing trend has been observed, it has been attributed to increased use of advanced imaging techniques, increased exposure to potential risk factors, 9, 10 and differential histologic classification of meningioma over time. 8

Survival, Prevalence, and Recurrence
Data from the Hospital-based National Cancer Data Base collected from 1985 to 1988 and 1990 to 1992 estimated 5-year survival rates for benign, atypical, and malignant meningiomas in the United States at 70.1%, 74.5%, and 54.6%. 11, 12 Population-based data from Finland, Australia, and Sweden have found that 5-year survival rates for all meningioma histologic subtypes combined ranged from 73% to 94%. 13 - 15 This relatively high 5-year survival is reflected in the number of prevalent cases. Registry data from Connecticut and Utah estimated that 138,000 individuals were living with this tumor in the United States in the year 2000, a prevalence rate of 50.4 per 100,000 population. 16 In addition, meningiomas may recur. At 5 years, 19.2% of persons with benign tumors and 32.4% of persons with malignant meningioma had suffered a recurrence of symptoms. 11
These data likely represent a lower limit of the number of persons with meningioma, as many patients presumed to have such a lesion are managed conservatively (i.e., without surgical intervention and pathologic confirmation), and hence may not be included in national databases that produce estimates of tumor incidence and prevalence. The different incident trends across nations reported here may reflect real differences, but are difficult to compare owing to differences in the time periods assessed and in the quality and methods of reporting. The Danish Cancer Registry is considered valid and 95% to 99% complete. 8 In contrast, case reporting in the United States may be hampered by information and selection biases. Although CBTRUS has worked collaboratively with state cancer registries since the 1980s to collect information on all primary brain tumors, including tumors of benign and uncertain behavior, such reporting was voluntary and necessarily incomplete until recently, primarily reflecting patterns for the white population of the northeastern United States. 6 In 2004, the United States Congress passed the Benign Brain Tumor Registry Amendment Act (Public Law 107-206) that mandated all United States cancer registries within the National Program of Cancer Registries (NPCR) to collect data on nonmalignant brain tumors. The accuracy of future population estimates in the United States will improve once these data become available.

NATURAL HISTORY AND LONG-TERM FOLLOW-UP
Some meningiomas may be asymptomatic and found incidentally. Other meningiomas may cause devastating symptoms with relatively abrupt onset. Or, because of the slow growth, some tumors may cause more subtle neurologic symptoms including difficulty concentrating or finding words and weakness or numbness in arms or legs with resultant problems with gait and walking. 1 In addition, whereas more than 90% of meningiomas are benign (WHO Grade I), approximately 5% are atypical/borderline, and 3% to 5% are malignant. 1 In addition, these tumors differ in size, site, and relationship to important vascular and neural structures. 17 These varied presentations require different treatment strategies, each with associated risks and benefits. Case series that examine long-term outcomes of patients who were conservatively managed, and those who received surgery or radiation therapy, or both, may aid decision making regarding treatment options. We reviewed long-term follow-up studies of tumor progression and recurrence, survival, symptoms, and quality of life among patients with meningioma by treatment modality and histologic grade.

Incidental Findings and Conservative Management
With increasing use of magnetic resonance imaging (MRI) and computed tomography (CT) in clinical settings, asymptomatic meningiomas are more often coming to medical attention, 18 with attendant questions about their clinical management. Several studies with fairly small samples ( n = 17–67) have reported on patients with conservatively treated, incidental and asymptomatic tumors across meningioma sites. During mean follow-up times that ranged from 2.7 to 6.2 years, the proportion of patients who became symptomatic was small, ranging from 0% to 16%. 19 - 22 In addition, during mean follow-up of 1.3 to more than 5 years, a majority of patients (between 63% and 100%) demonstrated no or limited (<1 cm 3 per year) tumor growth. 18, 20 - 24 However, there was substantial variability. For example, in a study of 41 patients over a 3.6-year follow-up, the range in growth rate was 0.48% to 72% and calculated tumor doubling time varied from 1.27 to 143.5 years. 18
Whereas the aforementioned studies examined the natural history of meningiomas across tumor locations in asymptomatic individuals, the natural history of skull base tumors, specifically, was examined in cohorts of conservatively managed patients, many of whom were symptomatic but did not undergo more aggressive treatments owing to advanced age, patient preference, medical contraindications, or tumors considered inoperable. These patients presented with symptoms that included headaches, dizziness and vertigo, seizures, hearing and vision loss, facial palsy, trigeminal neuropathy, swallowing problems, and gait disturbance. 25, 26 Of 21 consecutive patients with petroclival tumors followed on average 6.8 years, tumor growth was observed in 76% of cases, 58% experienced functional deterioration, and two succumbed to tumor-related deaths. 26 Among 40 patients with petroclival, cavernous sinus, and anterior clinoid tumors at 10-year radiographic follow-up, 58% of tumors evidenced some growth. After a mean 6.9 years of clinical follow-up, 11 patients (28%) experienced new or worsening neuropathy; 23 (58%) developed paralysis or long tract signs; 2 (5%) had lost sight in one eye; and two became disabled. 25

Surgery and Radiation Treatments

Benign tumors
Among selected case series that included exclusively or predominantly benign meningiomas, a study of 315 patients treated at Karolinski Hospital in Sweden for meningiomas of the cranial base is notable for its long follow-up (mean = 18 years) and historic cohort (1947–1982), against which more recent series can be compared. In that study, at 5 years, 4% of patients who had undergone Simpson Grade I and II surgeries and 25% to 45% of those with Grade III to Grade V surgeries had experienced symptomatic recurrence. By 20-year follow-up, 100% of tumors among those with Grade IV and V surgeries had symptomatic progression. 27 More recently, two relatively large studies, one from the Mayo Clinic ( n = 581; 1978–1988), 28 and one from the University of Florida ( n = 262; 1964–1992) 29 examined outcomes across intracranial tumor sites. In the Mayo Clinic series, gross tumor resection (GTR) was possible in 80% of cases and resulted in estimates of progression-free survival (PFS) of 88% at 5 years and 75% at 10 years. Where only subtotal resection (STR) was possible, 5- and 10-year PFS were far lower: 61% and 38%, respectively. 28 Similarly, among those treated solely with surgery, local control and cause-specific survival in the University of Florida series were higher after GTR than STR. However, STR cases who received adjuvant RT had outcomes as favorable as those with GTR: 87% local control and 86% cause-specific survival at 15 years. 29
Recurrence and progression in GTR and STR were assessed among a number of case series that focused specifically on tumors of the skull base, where surgery can be technically challenging. 30 Twelve studies of petroclival tumors reviewed by Little and colleagues, with mean follow-up of 14 to 67 months, demonstrated recurrence/progression ranging from 0% to 42%, again related to the extent of resection. 31 As reviewed by Sindou and colleagues, studies of recurrence/progression of tumors of the cavernous sinus treated solely with surgery ranged from 10% to 14% with mean follow-up of 24 to 96 months; recurrence/progression among cases treated with surgery and RT ranged from 6.5% to 19% at 40- to 73-month follow-up. 32 The effectiveness of stereotactic radiosurgery as primary or adjuvant treatment for tumors mainly located in the cranial base was reviewed by Goldsmith; 5-year PFS ranged from 86% to 98%. However, as primary treatment, the latter modality is restricted to smaller tumors. 17
In addition to reports of tumor growth and survival, some investigators have undertaken studies of quality of life among meningioma patients overtime. The Karnofsky Performance Scale (KPS), 33 which ranges from 0 (lowest) to 100 (highest), measures physical functioning and was used in several studies. Among surgically treated patients, preoperative mean KPS scores ranged from 70-90. 34, 35 Postoperatively, KPS scores tended to decline or remain at preoperative levels. 34 - 36 However, functioning may improve gradually. In one study, KPS scores 1 year after treatment were higher than preoperative scores, but even in that study, all patients had at least one impairment including diplopia (72%), hearing loss (48%), facial numbness (45%), or balance problems (38%). 36 Also at 1-year follow-up, two small studies that utilized the well-validated SF-36 that encompasses domains of physical functioning, role limitation, bodily pain, vitality, social functioning, and mental health 37 - 39 found that 39% to 75% of meningioma patients were functioning below accepted norms. 40, 41 At mean follow-up of 33 months among 164 patients surgically treated at Brigham and Women’s Hospital, 47% expressed frustration over not being able to do things they used to do, although 87% described themselves as “quite a bit” or “very much” independent; and 77% said they were “quite a bit” or “very much” content with their quality of life. 42 Of 82 individuals who were treated for meningioma in Austria between 1977 and 1993, 60% reported mild to moderate impairment in quality of life, and 20% suffered from moderate to severe physical handicaps or impairment in energy level. 43

Atypical and malignant tumors
We located seven cases series reported since 1995 that assessed long-term outcomes among patients with atypical and/or malignant meningiomas. These were relatively small studies that included from 22 to 119 cases, reflecting the rarity of the more aggressive tumors. Median follow-up time ranged from 3.5 to 8 years. As one might expect, PFS was higher among those with benign than atypical and malignant meningiomas. In addition, as shown in Table 4-1 , PFS among those with atypical meningiomas was higher than PFS among those with malignant tumors at 5 and 10 years. 44 - 47 In addition, across studies, overall 5- and 10-year survival was also higher for those with atypical than malignant meningiomas. 44 - 49

TABLE 4-1 Recurrence/progression-free and overall survival among patients with atypical and malignant meningiomas: Selected case series since 1995. 44 - 49
As with benign tumors, those with more completely resected atypical and malignant tumors had better outcomes. 44, 49 Post-treatment symptoms and quality of life were described in a small series from Thomas Jefferson Hospital where, based on Eastern Cooperative Oncology Group (ECOG) performance status, 18% of patients improved, 77% demonstrated no change, and 6% declined in functioning after adjuvant radiotherapy. In the post-treatment period, 54% of patients complained of limb weakness, 18% each became blind or aphasic, and 24% experienced memory loss. 48
However, the representativeness of published case series is uncertain. The numbers of patients in studies of atypical and malignant meningiomas and of conservatively managed tumors were small and the decision to manage a case conservatively may vary by practice and institution as well as by clinical considerations and patient preferences. In addition, comparisons across case series are hampered by differences in a number of relevant factors including patient characteristics, criteria used for histologic classification of tumors, the proportion of recurrent cases (which tend to have poorer outcomes), the time periods covered, and treatment methods and approaches used. Nonetheless, these studies, in conjunction with population statistics, indicate that patients with benign meningiomas have relatively long survival with the potential for progression and recurrence and the possibility of compromised long-term functioning and quality of life. This speaks to the impact of meningioma on the health care system and to the need not only to provide adequate medical and rehabilitative services for this population, but also to identify potential preventive measures based on known risk and protective factors.

RISK AND PROTECTIVE FACTORS
Epidemiologic investigations, primarily case control and cohort studies, have examined the potential impact of a range of exposures potentially associated with meningioma. We focus on the factors that have received considerable attention and on developing areas of study that show promise. The current state of knowledge of the impact of these exposures is summarized in Table 4-2 .
TABLE 4-2 Impact of exposures on meningioma. Exposure Impact Ionizing Radiation
Radiation treatment (high and low dose) is an established risk, especially in children.
Effect of diagnostic medical and dental radiation is uncertain and needs further study. Cell Phones No evidence of risk, but longer follow-up is needed. Occupational Exposures Lead exposure may elevate risk, but this needs further study. Medical Conditions
Inconsistent findings regarding the association between head trauma and meningioma.
No evidence of protective effect of allergy.
Possible weak association between breast cancer and meningioma. Hormones
Uncertain effect of endogenous steroid hormones as measured by menarche, pregnancy, lactation, and menopause in women, and by obesity in both sexes.
Inconsistent findings among studies of oral contraceptive use and meningioma risk, with most studies showing no effect.
Inconsistent findings among studies of hormone replacement therapy and meningioma risk, but larger and more recent studies suggest increase risk.
Better prognosis among individuals with tumors expressing progesterone receptors (in conjunction with low mitotic index). Genes
Neurofibromatosis 2 (NF2) is a known risk.
Effects of genetic polymorphisms and their interactions with environmental factors are under investigation.

Ionizing Radiation
Ionizing radiation is one of few established risk factors for brain tumors. 1, 3, 4, 50 Evidence supporting a link between this exposure and meningioma has been mounting for more than years, 51 based largely on studies of (1) atomic bomb survivors; (2) the effects of radiation therapy; and (3) the effects of diagnostic radiographs. Radiation may be implicated in neoplastic transformation and tumor development via production of base-pair alterations and disruption of DNA that is not repaired before DNA replication. 52 Radiation in medical and dental settings is typically measured in grays (Gy). Low (<10 Gy); moderate (10–20 Gy); and high (>20 Gy) treatment doses have been studied in relation to meningioma risk. 52 Sieverts (Svs), which are dose-equivalent, are typically used to assess exposure among atomic bomb survivors. In an acute exposure, greater than 4 Svs is considered a lethal dose. 53
Studies that examined meningioma risk among atomic bomb survivors in Nagasaki (1973–1992) 54 and in Hiroshima (1975–1992) 55 found increasing incidence of meningioma with decreasing distance from the hypocenter of the explosion. The Hiroshima study also found increased incidence of meningioma with exposure to higher doses of radiation at the time of the blast. 55 A more recent study by Preston and colleagues, based on data collected between 1958 and 1995 from the Life Span Study (LSS) of 80,160 individuals in Hiroshima and Nagasaki at the time of the explosion, found a significant relationship between radiation dose and risk of all nervous system tumors combined. However, the risk of meningioma examined separately, albeit elevated, was not significant. These investigators estimated that the vast majority of survivors included in the LSS were exposed to radiation doses of less than 1 Sv and that a minority of identified nervous system tumors in that cohort (14%) were related to radiation exposure. 56 In keeping with that conclusion, Yonehara and colleagues found that the clinical characteristics of the central nervous system tumors in the LSS population were more consistent with the characteristics of “spontaneous” than radiation-induced tumors. 53
Harrison and colleagues provided criteria to distinguish spontaneous meningiomas from tumors that were radiation-induced in medical settings ( Table 4-3 ), 52 modified from criteria originally developed by Cahan to identify radiation-induced sarcoma. 57
TABLE 4-3 Diagnostic criteria for radiation-induced meningioma. The meningioma must:
1. Arise in the field of irradiation.
2. Appear after a latency period sufficient to demonstrate that the neoplasm did not exist prior to irradiation (usually years).
3. Differ from any pre-existing neoplasm.
4. Occur with enough frequency to suggest a causal relationship.
5. Have a significantly higher incidence in the irradiated group than an adequate control group. Additional support is found if an animal model exists and a dose–response relationship exists.
Harrison MJ, Wolfe DE, Lau TS, Mitnick RJ, Sachdev VP. Radiation-induced meningiomas:experience at the Mount Sinai Hospital and review of the Literature; J Neurosurgery 1991;75(4):564–74.
Common features that distinguish spontaneous from radiation-induced meningiomas may include younger age at diagnosis, 52, 58 - 60 shorter latency period, 52 multiple lesions, 52, 58 - 60 relatively high recurrence, 52, 60 and greater likelihood of atypical and malignant meningiomas. 52, 58, 59, 61, 62 One might expect that equal proportions of males and females would be diagnosed with these tumors if they were indeed caused by radiation and members of both sexes were equally susceptible. 58 However, the data are inconsistent, with some studies demonstrating a female preponderance, some a male preponderance, and some a difference in male/female ratio based on radiation dose. 52, 58, 63
The data supporting the existence of radiation-induced meningioma among patients who received cranial radiotherapy is compelling. Studies of survivors of childhood cancers, in particular, have demonstrated strong associations between high-dose radiation treatments and development of secondary neoplasms, including meningiomas. 64 - 69 These include a large retrospective study of 2169 children and adolescents treated for acute lymphoblastic leukemia at St. Jude’s Research Hospital between 1962 and 1998 66 and the Childhood Cancer Survivor Study, a cohort of 14,361 individuals with a history of cancer before the age of 22 years, treated at one of 26 collaborating hospitals between 1970 and 1986. 68 In the latter study, the risk of developing meningioma with any dose of radiation therapy was significantly elevated (odds ratio [OR]: 9.94; 95% confidence interval [95% CI]: 1.54–29.7). In addition, the risk increased with radiation dose; at treatment doses of 30 to 49.9 Gy, the OR was 96.3 (CI: 10.32–899.3). 68 Investigators have noted a long latency period for development of meningiomas after the original diagnosis. 65, 66, 68 In the Childhood Cancer Survivor Study, median time to occurrence from original diagnosis was 17 years for meningioma, nearly twice the time to occurrence of glioma, 68 underscoring the need for long-term follow-up to adequately assess risk. Although younger age has been associated with shorter latency 67 and with greater risk, 64 adults who underwent cranial radiotherapy were also at risk. 52, 70, 71 In a study that included 200 cases and 400 controls, those with meningioma were 3.7 times more likely to have had radiation treatments for any condition (CI: 1.5–9.5) and 11.8 times more likely to have radiation treatment for a neoplastic condition CI: 1.5–∞). 70
In the aforementioned studies, many participants were exposed to high doses of radiation, but there is evidence that relatively low doses may also be implicated, particularly among children. Studies of the Tinea Capitis Cohort are among the most well known in the field. This cohort included 10,834 children who received relatively low-dose radiation (mean 1.5 Gy) for treatment of ringworm in Israel over a 5-day period between 1948 and 1960. The comparison groups included matched population and sibling controls. 63 Follow-up studies published in 1988 72 and 2005 63 found an excess relative risk of meningioma of 5.01 (95% CI: 2.66–9.80) 63 and a relative risk of 9.5 (95% CI: 3.5–25.7) 72 in the irradiated group. Moreover, risk increased with increasing dose. 63, 72
In addition to risks posed by radiotherapy, there are potential risks of diagnostic medical and dental radiographs. Several studies conducted by Preston-Martin and colleagues and reported in the 1980s, found increased risk of meningioma with receipt of full-mouth dental radiograph series before 1960 and with frequency of full-mouth dental radiographs. 73 - 76 Subsequent studies conducted in Australia, Germany, and Sweden, however, demonstrated no or equivocal evidence of an association between dental radiographs and meningioma. 77 - 79 The most recent case control studies demonstrated conflicting findings. Among 200 cases diagnosed between 1995 and 1998 in Washington state, having six or more full-mouth radiograph series performed 15 to 40 years before diagnosis was linked with meningioma risk (OR: 2.06, 95% CI: 1.03–4.17), although a dose–response relationship was not evident. 80 However, the German component of the large INTERPHONE Study found no association. 81
With conflicting findings across studies, the impact of dental radiographs on meningioma risk remains uncertain. Because radiation dose from a full-mouth radiograph series has diminished considerably: from 1000 to 3000 mGy in the 1940s and 1950s to less than 40 mGy by the 1990s, 80 future studies must account for potential changes in radiation dose over time. These studies should also have adequate power to detect potential differences in risk among population subgroups by demographic and other characteristics and should explore the impact of newer dental and medical diagnostic procedures (e.g., CT).

Cellular Telephones
Unlike ionizing radiation that is known to damage DNA, the radiation emitted by cell phones that use radiofrequency (RF) energy does not cause ionization of molecules and atoms. 82 RF energy in sufficient amounts can heat and potentially damage tissue, but whether and through which mechanism the low-level RF energy emitted by cell phones poses a health risk is not known. 83 However, given widespread use of cells phones beginning in the mid-1990s, 84 the potential for health risks from this new technology requires investigation.
In a meta-analysis 85 that included 527 meningioma cases from eight studies published by December 1, 2005, 83, 84, 86 - 91 Lahkola and colleagues did not observe an effect of cell phone use on meningioma development (pooled OR: 0.87; 95% CI: 0.72–1.05). Because tumors related to cell phone exposure would likely occur on the side of the head where the phone is most often used, these researchers conducted an additional analysis that examined cell phone use in relation to these ipsilateral meningiomas and found no association. Because cell phone technology has shifted from analogue to digital phone use, these investigators also examined risk of all intracranial tumors combined by cell phone type and again found no association. 85
The meta-analysis of meningioma risk described in the preceding text included two reports from the INTERPHONE study, 83, 86 the largest case-control study conducted to date of the effects of self-reported cell phone use and related exposures on the development of intracranial and other tumors, conducted across 13 countries. 92 Since publication of the meta-analysis, two additional reports from the INTERPHONE study, conducted in Germany 93 and in Norway, 82 have become available. Neither found an increased risk of meningioma with cell phone use. Further, a recent follow-up study on cell phone use in a Danish cohort of 420,095 cell phone subscribers also found no impact of cell phone use on meningioma formation. 94
Although the results of these studies are quite consistent, they have some methodological shortcomings. With the exception of the Danish cohort study, most of the evidence regarding cell phone use is based on case control studies with self-reported exposure measurement. In the INTERPHONE study, for example, random and systematic errors in exposure reporting were found. 95 In addition, even the most recent published INTERPHONE studies included a relatively small proportion of individuals with 10 or more years of cell phone use. 83, 86, 93 We have learned from studies of ionizing radiation that time from exposure to meningioma formation is long relative to some other tumors. Thus, 20 years or more of follow-up may be needed to examine the effect of cell phones. 2, 84, 85 In addition, exposure may vary depending on the type of device used 82 (e.g., hands-free, Bluetooth), which needs to be taken into consideration in future work.

Occupational Exposures
Several hypothesis-generating studies have examined occupation as a proxy for exposure to potential risks of meningioma. As reviewed by Rajaraman and colleagues, these studies found significant associations between this tumor and a number of occupations including carpenters, cooks, chemists, computer specialists, gas station attendants, glassmakers, inspectors, insurance agents, technicians, and toolmakers. In their study, meningioma risk was associated with having ever worked as an autobody painter, designer/decorator, machine operator, motor vehicle driver, industrial production supervisor, teacher or manager, or having served in the military. These investigators suggested that this extensive list might include two categories: (1) individuals exposed to potential carcinogens (benzene, solvents, lead) and (2) individuals in occupations where there is a greater likelihood of diagnosis. 96
There have been few studies that have endeavored to measure specific occupational exposures and meningioma risk. The German INTERPHONE study site recently reported no association between occupational exposure to RF energy and meningioma. 97 A hospital-based case control study conducted in the United States found no relationship between meningioma and occupational exposure to pesticides in men or women, but did find increased risk among women exposed to herbicides. 98 In addition, several studies have detected an elevated risk of meningioma with occupational lead exposure. 99 - 101 The results of all of these occupational studies should be interpreted cautiously, however, owing to the potential for exposure measurement error and other methodological shortcomings. Additional work to examine the effects of lead exposure is warranted.

Other Medical Conditions

Head trauma
Descriptions of and debates about the association between head trauma and meningioma have been occurring for more than 100 years. 80, 102 Proposed biologic mechanisms, reviewed by Inskip and Bondy, to explain how head injury may lead to neoplastic changes include production of oxygen free radicals, increased cell proliferation, and release of autocoids that may contribute to breakdown of the blood–brain barrier, thereby exposing the brain to agents from which it is normally protected. 51, 103
During the past 30 years, several case control and cohort studies were conducted to examine this association. Some case control studies have not found an association, 79, 102 but others have found an increased risk. The latter include several studies that investigated this association among men and women in Los Angeles county, 74 - 76 an international case control study published in 1998 104 and additional case control studies conducted in China and in Washington state. 99, 105 However, because of a common belief among lay persons that head trauma can cause brain tumors, 74 differential recall of head injuries between cases and controls that might artificially inflate meningioma risk is an oft sited concern. 106 A case control study by Preston-Martin and colleagues that examined the effect of head trauma on both meningiomas and gliomas found that only the risk of meningioma was elevated, which argues against the distortion of study results attributable to recall bias. 74 However, one study found a more pronounced effect of mild than severe brain injury on meningioma risk 105 and another found that risk was no longer elevated when only serious injuries were included. 104 These counterintuitive findings have been attributed to recall bias, 106 as cases are more likely than controls to remember and report minor head injuries. Two cohort studies that were not prone to that methodological problem did not find increased risk of meningioma attributable to head trauma. 103, 107 The largest and most recent ascertained head injury via hospital discharge records and included a Danish cohort of 228,055, followed for an average of 8 years. Relative to population incidence rates, these investigators found an excess of brain tumors among patients with head trauma during the first year after those injuries, which they attributed to the detection of preexisting tumors. There was no excess of meningiomas more than 1 year after the injury (standardized incidence ratio [SIR]: 1.2; 95% CI: 0.8–1.7). 106

Allergies
A hyperactive immune state and the anti-inflammatory effects of cytokines characteristic of allergic conditions have been postulated to decrease growth of abnormal cells and protect against the development of brain tumors 2, 108 Indeed, researchers have observed a protective effect against glioma in a number of studies. 3 However, in a meta-analysis of several studies published through 2006, 79, 109 - 117 Linos and colleagues did not find that allergy protected against meningioma. 108 A subsequent paper, published in 2007, that assessed the impact of allergy on more than 1200 meningioma cases from Denmark, Norway, Finland, Sweden, and southeast England also found no effect.

Breast cancer
There are multiple case reports of patients with breast carcinoma and meningioma in the literature, but relatively few studies have endeavored to quantify an association between these tumors. 118 Custer and colleagues identified four studies that provided numeric estimates, 119 - 122 three of which found significant associations. 119, 120, 122 Their own study, based on data from the western Washington State cancer registry, found nonsignificant elevated risks of breast cancer after meningioma diagnosis and of meningioma after breast cancer. 118 Since 2002, when those data were published, a study by Lee and colleagues found no association between breast cancer and subsequent meningioma. 123 The largest study conducted to date, published in 2007, examined nearly 40 years of Swedish cancer registry data. That study identified 12,012 meningioma patients, 926 of whom developed a subsequent primary diagnosis of cancer. The investigators observed elevated risk of several cancers, including brain and thyroid cancers, across age groups. An increased risk of breast cancer was observed only among women ages 50–59 (SIR: 1.61; 95% CI: 1.23–2.08). 124 In two studies of family cancer history, one found no association between these tumors within families, 125 whereas a second found a strong association between family breast cancer history and meningioma in adults younger than 50 years of age (OR: 3.9; 95% CI: 1.4–11.0). 126
Overall, these findings suggest a possible relationship between breast cancer and meningioma within individuals and across families. If these tumors are related, there may be a common genetic pathway. 1, 118 Although mutations in breast cancer susceptibility genes were not found among 60 meningioma brain specimens, 127 exploration of other possible shared genetic factors would be of interest. There may also be common, hormonally-drive factors between these tumors such as HRT use or late age at menopause. 1, 118 Research in this area is detailed in the text that follows.

Hormones
The possible association between breast cancer and meningioma, the higher incidence of meningioma in women than men, 5 reports that meningiomas may increase in size during pregnancy and the luteal phase of the menstrual cycle, 128 - 130 and the presence of hormone receptors on some meningiomas point to a possible link between hormonal factors and meningioma risk. This area of study has generated considerable interest, as it holds promise for prevention and for development of hormonally based treatments to control tumor growth, although results from clinical studies remain uncertain. 131, 132 We review work on endogenous and exogenous steroid hormones and on tumor hormone receptors in meningioma.

Endogenous hormones
It is well established that breast cancer risk increases with higher serum estrogen levels and with menstrual and reproductive factors that may increase exposure to endogenous estrogens, including early age at menarche and late age at menopause. Lactation, which decreases the number of ovulatory cycles, and early age at first birth are protective. 133 To explore the possibility of shared hormonal factors with breast cancer and to assess the potential impact of circulating levels of estrogen, progesterone, and other steroid hormones on meningioma formation and development, some epidemiologic studies have examined hormonally driven indicators in women.
With regard to age at menarche, two case control studies found no association with meningioma risk 123, 134 and older age at menarche was associated with higher risk in the large cohort of the Nurse’s Health Study, a finding contrary to the investigators’ expectations. 135 A significant effect of parity was not observed in that study, nor in several others. 134 - 136 However, researchers who conducted a hospital-based case control study that included 219 cases did find a strong protective effect of lower age at first pregnancy and of having three or more pregnancies. 123 There was a nonsignificant protective trend of duration of breastfeeding in one study, 134 and additional work with larger sample sizes is warranted. The impact of menopause was assessed by the Nurses Health Study, which found an increased risk of meningioma among premenopausal women compared with postmenopausal women who had never used hormone therapy (relative risk [RR], 2.48; 95% CI: 1.29–4.77), adjusted for age and body mass index (BMI). 135
Higher BMI and adiposity have correlated with higher levels of estrogen and other steroid hormones 137 - 139 and the hypothesis that higher BMI may increase risk of meningioma through such hormonal mechanisms 140 has been investigated in both women and men, with conflicting results. In the Nurses Health Study, there was a trend toward increased risk of meningioma with higher BMI, 135 although a retrospective study conducted in Germany found no such association. 141 Among men, this hypothesis was recently investigated in a small retrospective study of patients who had undergone craniotomies. The investigators found that men with meningiomas were more likely to be obese than men with aneurysms or gliomas. 140 Others have not found an association between obesity and meningioma in men, 141, 142 but additional study with larger samples is needed.
Although the potential for an association between endogenous hormonal factors and meningioma is intriguing, epidemiologic evidence is lacking. Inconsistent results across studies may be due to methodological factors such as small samples sizes and the potential for residual confounding. 135 In men, the study of the relationship between meningioma and hormonally driven factors is in an embryonic stage. The impact of age at puberty and of hair loss, among others factors in men, has not to our knowledge been reported and should be assessed. Examination of serum levels in both sexes would help to clarify which steroid hormones may be involved.

Exogenous hormones
There is a modest increased risk of breast cancer among users of combined oral contraceptives (OCs) and hormone replacement therapy (HRT). 143 Among six studies of meningioma that examined the influence of OCs, 118, 123, 134, 135, 144, 145 there was no association in four and two found a protective effect. One of these, a population-based case control study that included only spinal meningioma cases, reported decreased estimated risk for those with greater than 3 years of OC use, compared with those who had never used OCs (OR: 0.2; 95% CI: 0.1–0.7). 144 The second, a hospital-based case control study, included all 219 incident cases of meningioma recruited from three large medical centers. Compared with never-users, this study found a protective effect for those who had ever used OCs (OR: 0.5; 95% CI: 0.4–0.8) and an even greater effect for current users (OR: 0.2; 95% CI: 0.0–0.8). The Swedish site of the INTERPHONE study examined the impact of non-oral contraceptives including progesterone-only subdermal implants, injections, and intrauterine devices. This study found an elevated estimated risk of meningioma that approached significance (OR: 2.7; 95% CI: 0.9–0.5), 145 signaling the need for larger studies that can separately examine the potential effect of estrogen/progestin and progestin-only contraceptives.
We identified seven studies that examined the impact of HRT on meningioma. 118, 123, 134, 135, 144 - 146 Three case control studies found no effect, 118, 123, 134 an early case control study restricted to spinal meningiomas found a decreased risk with current use of estrogen-only HRT, 144 and three studies found increased risk. 135, 145, 147 The latter include the large cohort of the Nurses Health Study that found a RR of 1.86 (95% CI: 1.07–3.24) for current versus never users of HRT. 135 In addition, the Swedish INTERPHONE study showed marginally significant estimates of meningioma risk (in relation to those who had never used HRT), among those who had ever used HRT (OR: 1.7; 95% CI: 1.0–2.8) and among those with 10 or more years of use (OR: 1.9; 95% CI: 1.0–3.8), although a clear dose–response relationship was lacking. 145 In the largest and most recently published study on this topic, a retrospective cohort study based on the Mayo Clinic Jacksonville database that included 1390 confirmed cases, the OR was 2.2 for HRT users versus nonusers (95% CI: 1.9–2.6). 146
Based on current knowledge of exogenous hormones use, there is little evidence of increased risk of meningioma with OCs, although oral and non-oral preparations including only progesterone may be of concern. With HRT use, there is a suggestion of increased risk of meningioma. Most studies, however, had small sample sizes that precluded meaningful analyses of subgroups (e.g., by parity) and limited power to assess exposure measurement with detail and precision (e.g., dosage, timing, duration of use, and hormone[s] used [estrogen-only, estrogen/progestin, progesterone-only]). In addition, there is a lack of studies of other exogenous hormones. We located only one study that examined the effect of hormones used to treat gynecologic problems (e.g., irregular bleeding) where no association with meningioma was found, 145 and we are not aware of any studies that have examined the influence of fertility medications. We were also unable to identify epidemiologic studies of exogenous hormones and meningioma in men. This an important area of inquiry, as widely used prostate cancer treatments such as luteinizing hormone-releasing hormone (LHRH) agonists may contribute to meningioma growth. 148 Moreover, in addition to examining the impact of exogenous hormone use on meningioma occurrence, the impact of these hormones on tumor progression remains to be elucidated. 131

Tumor hormone receptors
In 1979, Donnell described the presence of estrogen receptor (ER) protein in four of six meningioma specimens. 149 Since that seminal work, the prevalence of progesterone, estrogen, and androgen receptors has been quantified by multiple investigators, their potential prognostic value has been explored, some antihormonal treatments have been tried, and epidemiologic research in this area has begun.
In 2004, Wolfsberger reported that 69% (range 10%–100%) of meningiomas were progesterone receptor positive (PR+) across 26 studies published since 1988. 150 Although some investigators have found more PR+ meningiomas among women, 151, 152 others have not corroborated that finding. 150, 153 - 155 PR status does not appear to vary by age. 156 Notwithstanding Donnell’s early work, ER+ meningiomas appear to be less common that PR+ tumors. 157 - 159 Tumors harboring both PR+ and ER+ receptors were detected in 39% of meningiomas in one study. 154 In addition, both identified isoforms of PR have been expressed in meningiomas, 160 as have both isoforms of ER. 157 Inoue and colleagues found PR-A in 40% and 42% of tumors in men and women respectively, while PR-B was observed in 65% and 53% of male and female tumors. 160 Carroll and colleagues detected ER-α in 68% of meningiomas and ER-β in 44%. 157 Though less studied, androgen receptors (ARs) have been detected in 29%-67% of meningiomas. 154, 161 - 163 In two studies, there were no significant differences in the distributions of ER+ and AR+ tumors by gender, 154, 164 but another study found AR+ tumors more common among women.
Nuclear localization of PRs in meningiomas suggests they are functional. 165 In addition, some in vivo and in vitro studies have demonstrated effectiveness of anti-progesterones in reducing tumor growth, as in one study of nude mice implanted with human meningioma. 166 These findings spurred exploration of the potential efficacy of anti-progesterone treatment in clinical settings. However, in long-term (median 35 months) mifepristone treatment of non-resectable meningiomas, only 8 of 28 cases showed minor improvements and adverse effects, including endometrial hyperplasia, were noted. 167 Because PR positivity is more often found in WHO Grade I than higher grade tumors, Wolfsberger suggested that PR expression may decrease with tumor progression, potentially limiting the usefulness of anti-progesterone therapies. 150 Indeed, low or no PR expression correlates with higher MIB-1 cell proliferation indices, 150 apoptosis, 164 higher tumor grade 155 and other adverse prognostic factors. In addition, there is consistent evidence of worse prognosis measured by shorter disease-free interval 158 and greater likelihood of recurrence 153 among patients with PR- meningiomas, either as a single predictor or in combination with high proliferative and mitotic indices, and higher tumor grade. 155, 158 In contrast, ER+ meningiomas, though less prevalent, are evident in higher grade, more aggressive tumors. 168 However, in two phase II trials, tamoxifen treatment of meningioma patients has yielded limited benefit, 169, 170 although a subsequent case report demonstrated effectiveness of the anti-estrogen mepitiostane. 171 ARs are likely to be functional, 161 but we are not aware of any clinical studies of anti-androgen treatments for meningioma.
Further work to identify potential subgroups of patients by receptor isoform, histologic subtype, and other parameters might boost antihormonal treatment efficacy. For example, in breast cancer, ER-β+ patients obtain less benefit from the antiestrogen therapy tamoxifen than ER-α+ patients. It is possible that the effectiveness of antiestrogen therapy in meningioma may also vary depending on ER isoform. 1 The same may apply to the effectiveness of anti-progesterone treatment, given the existence of two PR isoforms. Treatment efficacy may also vary based on endogenous hormonal status, as was the case with mifepristone treatment that was far more effective in men and premenopausal women than in menopausal women. 167
Researchers have just begun to examine associations between steroid hormones and tumor hormone receptors in epidemiologic studies. In exploratory analyses, Custer and colleagues found that women who had used OCs were more likely to have tumors with low progesterone receptor expression (i.e., in <25% of cells) than women who had never used these hormones (OR: 3.2; 95% CI: 1.3–8.0). This is an exciting area of study as identification of hormonal and other factors associated with PR status has implications for treatment and for prevention of tumor progression. The assessment of endogenous hormonal status, exogenous hormone use, tumor hormone receptor status, and clinical outcomes if undertaken in a single epidemiologic study could provide valuable insights regarding the complex interplay of hormonal factors in tumor formation and progression.

Genetic Epidemiology
The study of genetic risks for meningioma in itself, and in combination with other putative risk factors, has the potential to greatly enhance our understanding of this tumor and to provide more potent prevention and treatment options through identification of at-risk population subgroups and classification of meningiomas most responsive to specific treatments. We report on studies of meningioma that examined (1) family aggregation and hereditary syndromes and (2) genetic polymorphisms and gene–environment interactions. In our discussion of genetic polymorphisms, we focus on epidemiologic studies that have received the greatest attention.

Family aggregation and hereditary syndromes
Examining whether a disease affects multiple family members is a frequent starting point for assessing its potential genetic etiology. Researchers have conducted several such studies among families affected with meningioma. The results of case control studies have not been consistent, but the most recent did find that individuals with meningioma were more likely to report a family history of benign brain tumors (OR: 4.5; 95% CI: 1.0–21.0). 126 The potential for errors in case control and other studies that rely on self-reported family history was overcome in two studies by Hemminki and colleagues that found a familial risk of meningioma using medically verified data from the Swedish Family-Cancer Database, a multigenerational registry with near-complete reporting. 125, 172 In their most recent analysis of concordant meningioma, the SIRs were 3.06 (95% CI: 1.84–4.79) for offspring with a parental history and 4.41 (95% CI: 2.10–8.14) among siblings. 172
But whether familial aggregation is a function of genetic susceptibility, shared environmental factors, or both cannot be determined from these studies. In an effort to disentangle these effects, Malmer and co-investigators used Swedish databases to examine risk of primary brain tumors in first-degree relatives (FDRs) and spouses of affected individuals. They found no excess of meningiomas in spouses (SIR: 0.96; 95% CI: 0.35–2.10) but they did find that the observed number of meningiomas in FDRs was twice the expected number (SIR: 2.17; 95% CI: 1.44–3.14). 173
One genetic explanation for family clustering is neurofibromatosis type 2 (NF2), a rare, highly penetrant autosomal dominant disease associated with multiple tumors, including meningiomas. 174 NF2 is caused by mutations that inactivate the NF2 tumor suppressor gene, located on the long arm of chromosome 22. 175 However, investigators have observed meningioma family clustering in the absence of NF2 , 172, 174, 176 which suggests that other genetic factors may be involved. 174

Genetic polymorphisms and gene–environment interactions
Because most meningiomas are sporadic and only a small proportion are attributable to rare, highly penetrant mutations, attention is now directed at identifying the potential effects of variation in more common, less penetrant genes, and to the potential effects of these genetic polymorphisms in combination with environmental and other factors. For example, although ionizing radiation is strongly associated with meningioma, fewer than 1% of exposed individuals develop this tumor, which suggests that some individuals may be more genetically susceptible to this environmental risk. 177 This was well illustrated in a study of the Tinea Capitis Cohort, augmented by data from the Israeli Cancer Registry. Flint-Richter and Sadetski examined 525 families that included an index member who (1) had radiation-associated meningioma; (2) had radiation but did not develop meningioma; (3) had meningioma with no history of radiation; or (4) had no history of radiation and did not develop meningioma. Compared with index cases in other groups, the index cases with radiation-associated meningioma had a much higher proportion of FDRs who also had radiation-associated meningiomas or cancers. None of the cases had NF2. These findings suggest a genetic susceptibility to the adverse effects of ionizing radiation and compel further study to identify specific genes that may be implicated. 176
Likely candidates include DNA repair, cell cycle control, and apoptosis genes. However, three case control studies did not find an association between genetic polymorphisms in tumor suppressor gene TP53 and meningioma in the total samples under investigation. 178 - 180 When the analysis was restricted to individuals with a family history of cancer in one of those studies, the risk of meningioma among those with the CC-CG-CC polymorphism combination was significantly increased (OR: 5.69; 95% CI: 1.81–17.96). 178 In addition, Malmer and colleagues did find that haplotypes in ataxia telangiectasia mutated ( ATM ) were associated with meningioma risk. Specifically, the 1-1-1-2-1 haplotype was increased and the 2-1-2-1-1 haplotype was decreased in meningioma cases relative to controls. 179 Further, Rajaraman and fellow investigators found that two variants in CASP8 , Ex14-271A>T and Ex13+51G>C, were associated with decreased and increased risk of meningioma, respectively. 180 The most recent report included a relatively large subset of subject from the INTERPHONE study (631 cases and 637 population controls) and examined 1127 single-nucleotide polymorphisms (SNPs) in 136 DNA repair genes. 181 That study discovered a significant association between meningioma risk and rs4968451 that held after adjustment for multiple comparisons. This SNP maps to intron 4 of the breast cancer susceptibility gene 1-interacting protein 1, thus supporting epidemiologic observations of shared factors between these tumors. 181
Sadetzki and colleagues conducted the only study to date that specifically examined the potential impact of DNA repair and cell cycle control genes among irradiated and nonirradiated groups. These investigators found an association between meningioma formation and variants in cell cycle control gene Ki -ras and DNA repair gene ERCC2 among all cases and controls in their study. In addition, they found differences between irradiated and nonirradiated groups. Compared with the CC genotype, the homozygote T genotype of cyclin D1 significantly increased risk of meningioma among nonirradiated individuals and nonsignificantly decreased risk among individuals who had received radiation therapy ( P = .005 for interaction). A similar, thou weaker “inverse” effect for the irradiated and nonirradiated groups was shown for the TG compared with the GG genotype of p16 ( P = .005 for interaction). 177
Rajaraman and colleagues have examined the potential for genetic susceptibility to meningioma among those exposed to lead, a potential environmental risk. Their work focused on the ALAD gene that codes for the enzyme δ-aminolevulinic acid dehydratase (ALAD) which is involved in heme synthesis and is inhibited by lead. Their first study found that the ALAD2 allele of the G177C polymorphism increased risk of meningioma in the total sample and particularly among males. 182 A follow-up study included an assessment of occupational lead exposure and found that this exposure increased meningioma risk most notably among those with the ALAD2 allele. They suggest that the association between the ALAD2 variant and meningioma among men observed in their earlier study may relate to greater lead exposure among men than women. 183
Some studies have examined the relationship between meningioma and genes involved in metabolism of xenobiotics, steroids, and products of oxidative stress (e.g., S -transferases [GTS], cytochrome P450 [CYP] and NAD(P)H:quinine oxidoreductase 1 [NQ01]). In a meta-analysis of three of these studies, 184 - 186 Lai and colleagues found that the GTST1 null genotype conferred elevated risk (pooled OR 1.95; 95% CI: 1.02–3.76), whereas GTSM1 did not. 187 A subsequent study found increased risk of meningioma with the GSTM3 ⁎B/⁎B genotype (stronger among smokers than nonsmokers), and a decreased risk with the CYP1B1 V4321 homozygous variant. 188 These findings were not confirmed, however, in the largest study conducted to date. That study, which included 546 meningioma cases, found no association between meningioma and GSTM3, GSTT1, GSTP1, GSTM1, CPY1A1, or NQ01 polymorphisms. 189 In contrast to previous studies that relied on hospital-based controls, the controls in the Schwartzbaum study were population-based. This may, in part, account for the null findings in that study; hospital controls may not represent the general population and studies that use such controls may produce different estimates. 187
As discussed, there is mounting evidence to support a role for progesterone receptors in meningioma. A recent pilot study of 31 meningioma samples reported that gene expression appeared more strongly associated with PR status than with ER status. Genes on the long arm of chromosome 22 and near the NF2 gene (22q12) were most frequently noted to have expression variation, with significant up-regulation in PR+ versus PR– lesions, suggesting a higher rate of 22q loss in PR– lesions. Pathway analyses indicated that genes in collagen and extracellular matrix pathways were most likely to be differentially expressed by PR status. These data, although preliminary, are the first to examine gene expression for meningioma cases by hormone receptor status and indicate a stronger association with progesterone than with estrogen receptors. PR status is related to the expression of genes near the NF2 gene, mutations in which have been identified as the initial event in many meningiomas. These findings suggest that PR status may be a clinical marker for genetic subgroups of meningioma and warrant further examination in a larger data set. 190
As is the case with epidemiologic studies of environmental and other exposures, genetic epidemiology studies are subject to many potential methodological limitations. In the studies reviewed here, several methodological problems may have affected the results. Sample sizes tended to be small, thereby limiting power to detect potentially meaningful associations. In addition, cases that were most ill may have been less likely to participate; some participants were unwilling to donate blood for DNA testing; 179 errors in genotyping may have occurred; 191 and the hospital controls used in some studies may not have represent the source population. These factors may have introduced bias or limited the generalizability of the study findings. Moreover, polymorphisms in certain genes may have been missed as rare variants may not be examined. 179 In addition, the common practice of testing many candidate genes in a given study raises the possibility of detecting a spurious positive association. 178 In many cases, the first genetic epidemiology studies to report an association have not been replicated. 191 Indeed, the findings presented here should be considered preliminary. Multiple, well-designed studies are need to further examine promising associations identified in exploratory work and to examine additional genetic variants, in combination with environmental and other putative risk factors.

SUMMARY AND CONCLUSIONS
Meningioma, a relatively common brain tumor that occurs more frequently in women than in men, may be completely asymptomatic or may cause devastating symptoms. Those with benign tumors and extensive surgical resection are likely to have better outcomes. There is relatively high overall survival among patients with this tumor, but tumor progression and recurrence occur and quality of life may be compromised. This speaks to the importance of identifying risk and protective factors on which to base preventive and treatment strategies. Currently, NF2 and radiation treatment, which account for a small proportion of meningioma cases, are the only established risks. Although evidence for an association between cell phone use and meningioma is currently lacking, additional follow-up time is needed to definitively rule out an effect of that exposure. There is mounting evidence that exogenous hormone use may increase risk, and further study of exogenous and endogenous hormones will clarify their impact on tumor formation and progression. The study of the effect of exposures, such as exogenous hormone use, on tumor hormone receptor expression, is a new and promising area of epidemiologic research. In addition, a small but burgeoning literature is exploring the potential influences of genetic polymorphisms on meningioma. Studies that examine environmental and hormonal risks in conjunction with information on genetic variants have the potential to greatly enhance our understanding of tumorigenesis and to contribute to prevention and treatment. Now is an ideal time to embark on this work as mandatory reporting of benign brain tumors beginning in 2004 permits more complete case ascertainment in population-based studies and new methods in genetics and molecular epidemiology allow for the processing of thousands of genes in large populations with relative ease.

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CHAPTER 5 Radiation-Induced Meningiomas

Felix Umansky, Siegal Sadetzki, Sergey Spektor, Guy Rosenthal, Shifra Fraifeld, Yigal Shoshan

HISTORICAL PERSPECTIVE
One evening in November 1895, Wilhelm Conrad Roentgen was surprised to notice an unexplained glow on a fluorescent screen in his laboratory during cathode-ray tube experiments. For weeks, Roentgen worked intently to explain the mystery, and on December 22 he published his discovery of a new form of energy, 1 which he named x-rays for the mathematical designation for something unknown. During 1896, a tremendous number of scientific and news articles about the new “Roentgen rays” appeared in newspapers and books, as well as leading scientific and medical journals such as Lancet , the British Medical Journal , Nature , and Science . 2 Roentgen's announcement, including the famous x-ray image of his wife's hand, heralded one of the defining scientific discoveries of the modern era, and earned him the first Nobel Prize in Physics in 1901. His was the first of more than 20 Nobel Prizes awarded for research related to radioactivity in the 20th century.
Roentgen's discovery greatly influenced important research in other laboratories. Within months, Henry Becquerel described the radiation-emitting properties of uranium, and in 1898, Marie Curie, as a young scientist conducting research for her doctoral thesis, discovered polonium and radium, two additional radioactive elements. The members of Madame Curie's committee reported that her research possibly represented the most important scientific contribution ever made in a doctoral thesis.
Marie and her husband Pierre Curie isolated small quantities of the new elements from 100 kg of waste pitchblende and characterized their atomic properties. They refused suggestions to patent their isolation process, believing that research should be carried out for its own sake, with no profit motive, even though radium was soon being produced at the very high price of $100,000 per gram. 3 For their work, the Curies shared with Becquerel the 1903 Nobel Prize in Physics. 4 After her husband's death, Marie Curie earned a second Nobel Prize in 1911, in Chemistry, for her work in radioactivity; she conducted active research until her death in 1934 ( Fig. 5-1 ).

FIGURE 5-1 Heavy French casualties motivated Dr. Marie Curie to raise funds to equip ambulances with radiology equipment, and she was elected by the Red Cross as Head of Radiological Services. With her daughter Irene, Dr. Curie devised courses in advanced radiology and taught physicians techniques for locating foreign objects in the soldiers' bodies. Mme. Curie is shown here driving an ambulance during the war.
(Used with permission of Musée Curie, Paris, France.)
Potential diagnostic and therapeutic applications for radiation were quickly proposed. Roentgen's first images so excited physicians around the world with the new ray's ability to see inside the human body that x-rays were used to diagnose bone fractures and locate embedded bullets within weeks of his discovery. 5 During a 1903 lecture and demonstration at the Royal Institution in London, Pierre Curie mentioned the possibility that radium could possibly be used to treat cancer, and described a burn-like skin injury on his forearm resulting from 10 hours of exposure to a sample of radium. Radiation was indeed used routinely for therapeutic purposes by the 1920s. While presenting, his hands trembling from significant cumulative exposure to radioactive materials, Dr. Curie spilled a small amount of radium on the podium; 50 years later some surfaces in the hall required cleaning after radioactivity was detected. 4
Adverse effects of x-rays in the form of slow-healing skin lesions on the hands of radiologists and technicians were noticed early, but the full extent of dangers from exposure to x-rays was poorly understood for decades. Patients, technicians, physicians, and researchers were repeatedly exposed to large doses of ionizing radiation with no shielding. Fluoroscopists calibrated their equipment by placing their hands directly in the x-ray beam; many lost fingers as a result ( Fig. 5-2 ). There were also more serious problems. American inventor Thomas Edison, who designed the first commercially available fluoroscope, suffered damage to his eyesight, while his assistant, Clarence Dally, succumbed to metastatic radiation-induced skin cancer. Edison halted work with x-rays in his laboratory because of their ill effects. 6

FIGURE 5-2 Radiologists calibrated their fluoroscopes by placing their hands directly in the x-ray path. Many suffered severe hand burns, lost fingers, and developed cancer as a result.
(Used with permission of Radiology Centennial, Inc.)
X-rays also captured the public imagination. Radium was widely thought to have curative powers. A radium potion that “bathed the stomach in sunshine” was thought to cure stomach cancer. Radithor, a medical drink, was sold over the counter until 1931. Belts to be strapped onto limbs, hearing aids, toothpaste, face cream, and hair tonic, all containing radium, were sold into the 1930s, 7 and shoe-fitting fluoroscopy was available as a customer service in many shoe stores until after 1950 ( Fig. 5-3 ). 8, 9

FIGURE 5-3 X-ray shoe-fitting fluoroscopes were available in many shoe stores throughout the United States, providing a free service to customers until the 1950s.
(Used with permission of Oak Ridge Associated Universities.)
Broader public awareness of the dangers of radiation exposure began to develop late in 1927, when journalist Walter Lippman, then editor of the New York World newspaper, exposed the fate of young women employed by U.S. Radium Co. to paint watch dials with radioactive materials. The women, who had worked in large rooms with no shielding, and were instructed to point their brushes with their lips, lost their teeth and developed serious bone decay in their mouths, necks, and backs. As the young women were dying, Lippman railed against delays in the courts that blocked settlements against the U.S. Radium company, which had known of the danger from chronic exposure but provided no protection for its workers. 10 The case is a classic, now used to train journalists regarding the role of investigative reporting in societal change. Scholarly articles describing dangers from radiation also appeared before World War II, particularly in German and French medical journals. 11, 12 X-ray exposure guidelines were established in Germany in 1913, 13 the United Kingdom in 1921, 14 and the United States during the 1930s. 13 The trend has been toward more rigorous protection in the decades since early limits were established. 15
Important additional evidence of risk appeared in 1927 when Hermann Joseph Muller, a founding figure in genetic research, published evidence of a 150-fold increase in the natural mutation rate of fruit flies ( Drosophilia melanogaster ) exposed to x-rays. Muller showed that x-rays broke the genes apart and rearranged them. 16 He earned the Nobel Prize in Medicine for his work, but only in 1947, when concern over genetic consequences from exposure to low levels of radiation became widespread after the world saw the devastation wrought from atomic bombings in Hiroshima and Nagasaki in 1945. 17
Research to define the optimal parameters of radiation therapy for the treatment of brain tumors and to assess treatment risk began in the years after World War I. In 1938, Davidoff and colleagues 11 documented profound histologic and morphologic changes, especially marked in glial and nerve tissues, in the brains and spinal cords of monkeys after exposure to 10 to 50 grays (Gy) in a single exposure, or 48 to 72 Gy in two fractions. Davidoff concluded that the intensity of change was determined primarily by x-ray dose, with time from radiation exposure to autopsy contributing to a lesser extent. Wachowski 12 and others 18, 19 also showed that exposure to ionizing radiation had degenerative effects on neural tissue.
In spite of this work, and the mounting evidence of wide-ranging risks from exposure to ionizing radiation, neural tissue was long considered resistant to direct damage. The authors of a case report published in 1953, describing a patient who had received superficial x-ray therapy for a basal cell carcinoma, stated, “Brain and neural tissue are usually resistant to direct damage by x-ray radiation.” 20 The patient had sustained a skin dose of approximately 25 Gy, and a dose to the temporal lobe of 12.87 Gy at a depth of 2 cm. The authors considered her development of an “underlying, expanding intracranial nontumorous mass” to be a rare event, and not the result of a radiation exposure.
Radiation is now known to induce a wide range of changes in neural tissue, including visual deterioration, hearing loss, hormonal disturbances, vasculopathy, brain and bone necrosis, atrophy, demyelination, calcification, fatty replacement of bone marrow, and induction of central nervous system (CNS) neoplasms. 21 Many changes have been shown to be dose dependent. 14, 22 - 26
In the more than 60 years since the atomic bombings, scientific evidence based on extensive research among these survivors and other populations exposed to ionizing radiation supports the hypothesis that there is a linear dose–response relationship between exposure to ionizing radiation and the development of solid cancer in humans. Excess lifetime risk of disease and death for all solid cancers and leukemia has been estimated based on a wide range of doses from 0.005 up to greater than 2 sieverts (Sv). A statistically significant dose–response relationship has also been shown for heart disease, stroke, and diseases of the digestive, respiratory, and hematopoietic systems, although noncancer risks at very low doses are uncertain. 17
Although we have not yet achieved a full understanding of the mechanisms for carcinogenesis after exposure to radiation, research has elucidated some of the diverse responses in complex biologic systems. Ionizing radiation overcomes the binding energy of electrons orbiting atoms and molecules, resulting in a variety of directly and indirectly induced DNA lesions, including DNA base alterations, DNA–DNA and DNA–protein crosslinks, and single- and double-strand DNA breaks. 27 Cellular mechanisms have the capability to repair some radiation-induced damage; however, some damage may overwhelm cells' intrinsic capability for repair. There may also be genetic factors that modify cellular mechanisms for repair and increase susceptibility to the development of tumors after radiation in some individuals. 28 Occasional misrepair can result in point mutations, chromosomal translocations, and gene fusions, all with potential to induce neoplasms. Radiation may also produce more subtle modifications that can alter gene expression, affect the intracellular oxidative state, lead to the formation of free radicals, influence signal transduction systems and transcription factor networks, and directly or indirectly impact upon metabolic pathways. 29
In summary, the diagnostic and therapeutic benefits from effective use of ionizing radiation in the first century after Roentgen's discovery have contributed greatly to a revolution in medical care. However, the potential for long-term damage has been repeatedly underestimated, often by physicians and scientists who were genuinely motivated to provide good care for patients. As protocols for optimum use of both diagnostic and therapeutic procedures continue to evolve, it remains important to carefully consider the power of Roentgen's mysterious rays.

RADIATION-INDUCED MENINGIOMAS
After publication of small case series describing a suspected link between meningioma and exposure to ionizing radiation, 30 - 32 the causal association between irradiation and meningioma was recognized in a 1974 analytical epidemiologic study by Modan and colleagues 33 In this cohort study, elevated incidence of meningiomas and other tumors of the head and neck area was shown in individuals irradiated as children for treatment of tinea capitis compared to matched nonirradiated population and sibling controls. Radiation-induced meningioma (RIM) is now considered the most common brain neoplasm known to be caused by exposure to ionizing radiation. 34 - 36
In 1991, Harrison and colleagues 35 categorized RIM according to level of exposure. Doses of less than 10 Gy, such as those used for treatment of tinea capitis between 1909 and 1960, were defined as low; doses of 10 to 20 Gy, typical of irradiation for the treatment of head and neck tumors or vascular nevi, are termed intermediate; and doses greater than 20 Gy, used for treatment of primary or secondary brain tumors, were termed high. Harrison's categorization is frequently cited in the neurosurgical literature. Others considered exposure levels greater than 10 Gy to be high. 37, 38 However, the National Academy of Sciences defined exposure of 0.1 Gy or lower as low dose, greater than 0.1 to 1 Gy as a medium dose, and 1 Gy or higher as high dose in its seventh report on the Biological Effects of Ionizing Radiation (BEIR VII). 17

RIM After Exposure to High Doses of Therapeutic Radiation
Mann and colleagues, 32 writing in 1953, are generally credited with the first report of a meningioma ascribed to previous irradiation. The patient was a 4-year-old girl who had been treated as an infant with 65 Gy for an optic nerve glioma.
Numerous case reports and small patient series describing meningiomas developing subsequent to high-dose radiation therapy for primary brain tumors have been published since the initial article appeared. Several authors have summarized their own experience together with reviews of up to 126 cases reported in the literature. 35 - 41 Radiation dose ranges from 22 to 87 Gy in these series. The majority of high-dose RIM patients were irradiated as children, adolescents, or young adults; however, meningiomas secondary to irradiation for primary brain neoplasms in middle-aged and older adults have also been described. 37, 39, 41
Latency periods from irradiation to meningioma detection ranging from two 36, 42 to 59, 39 and even 63 years 43 have been reported, with average latency between 10 and 20 years in most series. Latency is shorter with increasing radiation dose and younger patient age at irradiation. 35, 37, 40, 44 Descriptive studies of series of patients who developed RIM, such as the studies cited above, may understate the true mean latency for tumor development. A more accurate value would require a cohort study including a large population of patients irradiated for primary brain tumor, and the maximum follow-up period possible.
In 2006, Neglia and colleagues 23 published a multicenter nested case-control study of new primary CNS neoplasms in 14,361 survivors of childhood cancer, as a part of the Childhood Cancer Survivor Study (CCSS). Individuals were eligible for participation in the cohort if they were diagnosed and treated between January 1, 1970 and December 31, 1986; received a primary diagnosis of leukemia, CNS cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney tumor, neuroblastoma, soft tissue sarcoma, or bone sarcoma; younger than age 21; and survived for at least 5 years. Data analysis for second primary CNS neoplasms closed on December 31, 2001. The study design included analysis of administration of 28 specific chemotherapeutic agents, surgical procedures, imaging reports, and site-specific dosimetry from radiation therapy. Second primary CNS neoplasms, including 40 gliomas and 66 meningiomas, were diagnosed in 116 case patients of the CCSS cohort. Three meningiomas were malignant at first diagnosis. Each case patient was matched with four other cohort members, who had not developed a CNS neoplasm, by age at primary cancer, gender, and time since original cancer diagnosis. New primary CNS tumors were diagnosed from 5 to 28 years after the original primary tumor diagnosis. Gliomas were diagnosed at a median of 9 years after diagnosis of the primary cancer, with 52.5% diagnosed within 5 years from first cancer diagnosis. Meningiomas showed a much longer latency than gliomas, with a median diagnosis at 17 years from first cancer diagnosis, and 71.2% diagnosed 15 years or more later. 23 Follow-up ranged from 15 to 31 years, and therefore no data are available for latency beyond 31 years.
Exposure to therapeutic radiation delivered for treatment of the original cancer was the most important risk factor for occurrence of a secondary CNS neoplasm. Any exposure to radiation therapy was associated with increased risk of glioma (odds ratio [OR]: 6.78; 95% confidence interval [CI]: 1.54–29.7) and meningioma (OR: 9.94; 95% CI: 2.17–45.6). 23 The CCSS study is unique among assessments of high-dose RIM because of the large number of case patients, the detailed review of medical records for chemotherapy treatment and radiotherapy dosimetry, the length of follow-up (15–31 years), and the size and structure of the study. Taken together, the findings provide compelling evidence of increased risk for secondary CNS neoplasms, including meningioma, following exposure to therapeutic radiation for treatment of primary cancer during childhood.
The incidence of high-dose RIM is expected to increase as a larger proportion of patients who receive radiation therapy for primary tumors survive for extended periods. 37, 44, 45 Continued close follow-up is warranted after high-dose cranial irradiation, particularly when it is administered to children. 23, 37, 46, 47

RIM After Exposure to Low to Moderate Doses of Radiation
Increased risk of meningioma has been reported in individuals who were irradiated for tinea capitis during childhood, 30, 31, 33, 48 - 54 irradiated for the treatment of skin hemangioma during infancy, 22 exposed to radiation after the explosions of atomic bombs in Hiroshima and Nagasaki, 24, 25, 55 - 57 and exposed to a series of dental radiographic studies. 58 - 61

RIM After Irradiation for Tinea Capitis
From 1909 to 1960, the international standard for treatment of tinea capitis was scalp irradiation via the Keinbock–Adamson technique, which was designed to irradiate the entire scalp uniformly with exposure to five overlapping treatment areas. 62 In phantom dosimetry studies, conscientious use of the technique resulted in radiation doses of 5 to 8 Gy to the scalp, 1.4 to 1.5 Gy to the surface of the brain, and 0.7 Gy to the skull base. 63, 64 Tinea capitis was epidemic in some areas ( Fig. 5-4 ), and irradiation was considered the standard of care in such situations before the introduction of griseofulvin circa 1960. 65 - 68

FIGURE 5-4 Five children attending a birthday party in Israel during the 1950s wore white stocking caps (red arrows) following irradiation for tinea capitis.
(Photo used with permission.)
The first evidence of negative consequences after treatment using this protocol appeared in 1929 with a report of somnolence lasting 4 to 14 days in 30 of approximately 1100 children (ages 5–12 years) treated for tinea capitis. 69 In 1932 and 1935, new reports describing children irradiated for tinea capitis added atrophic and telangiectatic changes in the scalp, epilepsy, hemiparesis, emotional changes, and dilatation of the ventricles to the list of symptoms and complaints. 70, 71
In 1966, evidence of long-term side effects increased with a report from the New York University Medical Center comparing 1908 tinea capitis patients treated with irradiation between 1940 and 1958 with 1801 patients who were not irradiated. In the irradiated population there were nine neoplasms—three cases of leukemia and six solid tumors, including two brain tumors—compared to one case of Hodgkin lymphoma in the nonirradiated group. 63 A later report on these patients described additional effects, including increased rates of psychiatric hospitalization, long-term electroencephalographic changes, and permanent functional changes to the nervous system. 64
Additional reports of RIM from Israel, the Unites States, Europe, and the former Soviet Union followed. 30, 31, 35, 48, 49, 54, 72 In 1983, Soffer and colleagues 54 described unique histopathological characteristics in a series of 42 Israeli RIM patients. His findings are discussed in detail below. From 1936 to 1960, about 20,000 Jewish children age 1 to 15 years (mean 7 years) and an unknown number of non-Jewish children were irradiated in Israel for treatment of tinea capitis, with an estimated 50,000 additional children irradiated abroad, before immigration (personal communication from S. Sadetzki, April 15, 2008).
In 1974, Modan and colleagues 33 published the first results of the Israeli tinea capitis cohort study, showing that irradiation was associated with significantly increased risk of meningioma and other benign and malignant head and neck tumors in this population. The cohort includes 10,834 irradiated individuals and two nonirradiated control groups, one drawn from the general population ( n = 10,834) and the second from untreated siblings ( n = 5392). The nonexposed groups were matched to the irradiated group by age, gender, country of origin, and immigration period.
Research using the Israeli cohort continues. In 1988, Ron and colleagues 52 showed a 9.5-fold increase in meningioma incidence following mean radiation exposure levels to the brain of 1.5 Gy (range: 1.0–6.0 Gy). More recently, Sadetzki and colleagues 26 reported Excess Relative Risk per Gy (ERR/Gy) of 4.63 (95% CI: 2.43–9.12) and 1.98 (95% CI: 0.73–4.69) for benign meningiomas and malignant brain tumors, respectively, after a median 40-year follow-up of the cohort. The risk for developing both benign and malignant tumors was positively associated with dose. For meningioma a linear quadratic model gave a better fit than the linear model, but the two models were very similar up to 2.6 Gy, a point that encompasses 95% of observations. The ERR of meningioma reached 18.82 (95% CI: 5.45–32.19) when the level of exposure was greater than 2.6 Gy. While the ERR/Gy for malignant brain tumors decreased with increasing age at irradiation, no trend with age was observed for benign meningiomas.
For both malignant and benign brain tumors, risk remained elevated after a latent period of 30 years and more. While the great majority (74.6%) of benign meningiomas were diagnosed 30 years or more after exposure, only 54.8% of malignant brain tumors had latency over 30 years. 26 In a separate, descriptive study comparing demographic and clinical characteristics of 253 RIM and 41 non-RIM cases, Sadetzki and colleagues 53 showed lower age at diagnosis ( P = .0001), higher prevalence of calvarial tumors ( P = .011), higher rates of tumor multiplicity ( P < .05), and higher rates of recurrence (not statistically significant in this study).

RIM After Irradiation for Skin Hemangioma in Infancy
Karlsson and colleagues 22 performed a pooled analysis of the incidence of intracranial tumors in two Swedish cohorts (the Gothenburg and Stockholm cohorts) involving 26,949 individuals irradiated for the treatment of hemangioma during infancy for whom follow-up data were available. Treatment was administered between 1920 and 1965, with some differences between dates for the two cohorts. In individuals who developed meningiomas, the mean dose to the brain was 0.031 Gy (range 0–2.26 Gy) and average age of exposure was 7 months (range 2–30). In individuals who developed gliomas, mean dose to the brain was 1.02 Gy (range 0–10.0 Gy) and mean age at exposure was 4 months (range 1–15). Both cohorts were followed for intracranial tumors reported in the Swedish Tumor Registry from 1958 to 1993, with a 33-year mean time from exposure as the study closed.
There were 83 intracranial tumors in the irradiated group, including 33 gliomas and 20 meningiomas, yielding a standardized incidence ratio (SIR) of 1.43 (95% CI: 1.14–1.78) compared to the general Swedish population. A larger sample would have been required to permit separate calculations of SIR for meningiomas and gliomas. Meningiomas constituted 23% of all tumors, but 43% of tumors among individuals who received 0.10 Gy or more of radiation ( P = .005). The authors found a linear dose–response relationship between absorbed dose in the brain and development of an intracranial tumor, and higher risk of tumor in those exposed at earlier ages.

RIM in Survivors of the 1945 Atomic Bombing of Hiroshima and Nagasaki
An estimated 120,000 individuals survived atomic bombings in Hiroshima and Nagasaki in 1945, and slightly less than half of this population was still alive in 2000. 17
The Life Span Study (LSS), 73 an ongoing cohort study, includes data for approximately 86,500 survivors who were within 2.5 km of a hypocenter, as well as a sample of survivors who were 3 to 10 km from ground zero, and thus had only negligible exposure to radiation. The LSS continues to serve as a major source of information for experts evaluating health risks from exposure to ionizing radiation. The population is large; not selected because of disease or occupation; has a long follow-up period (1950 and ongoing); and includes both sexes and all ages at exposure, allowing many comparisons of risks by these factors. Extensive data regarding illness and mortality are available for survivors who remained in Japan. Radiation doses for survivors resulted from whole-body exposure. Individual doses have been reasonably well characterized, based on consideration of differences in the biological effectiveness of the bombs, distance from hypocenter, and specific location at the time of explosion. For example, exposure for individuals who were inside a typical Japanese home was reduced by nearly 50%. 17 Within 10 years of the bombings, an excess incidence of leukemia was found in survivors and linked to radiation exposure; however, elevated risk for solid tumors and a direct relationship between solid tumor incidence and proximity to hypocenter was shown only in 1960. 74 A Japanese review of postmortem studies of primary brain tumors in Nagasaki survivors for the years 1946–1977 found only five cases of meningioma, and the authors concluded there was no evidence of increased meningioma incidence in this population 32 years after the bombings. 75 The first report demonstrating excess risk of meningioma in atomic bomb survivors was published only in 1994, when Shibata and colleagues 24 reported a significantly higher meningioma incidence among Nagasaki survivors beginning in 1981, 36 years after the bombings, and increasing annually. This report was confirmed by further research in Nagasaki 55 and in Hiroshima. 56, 57 In 1996, Sadamori and colleagues 55 reported meningioma latency ranging from 36 to 47 years in Nagasaki survivors (mean 42.5 years). Shintani and colleagues 56 reported meningioma incidence of 3.0 per 10 5 persons per year in a population that was distant from the hypocenter and thus received very low levels of exposure, versus incidence of 6.3, 7.6, and 20.0 meningiomas per 10 5 persons per year in survivors who had been 1.5 to 2.0, 1.0 to 1.5, and less than 1.0 km from hypocenter, respectively. Overall incidence in survivors of the bombs, as well as incidence in each of the three groups, differed significantly from incidence in the population with very low exposure. The authors assumed this increasing incidence indicated dose dependence, as doses increased with increasing proximity to hypocenter.
Preston and colleagues 25 studied incidence of CNS tumors between 1958 and 1995 among survivors from both cities in relation to radiation dose measured in Sievert (Sv). The authors found a statistically significant, linear dose–response relationship for all CNS tumors combined (ERR/Sv: 1.2; 95% CI: 0.6–2.1), and concluded that incidence of tumors of the nervous system increases with exposure to even moderate doses (<1 Sv) of ionizing radiation. Risk for glioma was increased, although not to a statistically significant level (ERR/Sv: 0.6; 95% CI: –0.2–2.0). A statistically nonsignificant increased risk was also seen for meningioma (ERR/Sv: 0.06; 95% CI: –0.01–1.8). When risk of meningioma was evaluated separately for adults and children (defined as those <20 years of age at exposure), the authors found higher risk for children compared to adults (ERR/Sv: 1.3; 95% CI: –0.05–4.3, and 0.4, 95% CI: not smaller than –0.1–1.7, respectively), although neither relationship reached statistical significance. In general, children represented a relatively small part of the population among survivors, and the aggregation of all survivors exposed at age 20 or younger into a single group limits understanding of risk levels for exposure at younger ages (e.g., 10 or 12 years and younger), when the brain is thought to be more susceptible to damage from ionizing radiation. There were varying combinations of exposure to gamma rays and neutrons in the two cities. The biological effectiveness of ionizing radiation varies, depending on the type of radiation used. While most RIM studies reported dose in grays (Gy), a measure of absorbed dose, doses in the LSS are expressed in sieverts (Sv), which is calculated as the absorbed dose multiplied by a weighting factor that depends on the type of radiation used.

RIM Due to Dental X-ray Examination
In 1953, Nolan and Patterson 76, 77 published evidence that a single full-mouth dental x-ray delivered doses in excess of 75 rads (0.75 Gy) to the lateral surfaces of the face and neck. He also observed that lines of radiation converged at the meninges, resulting in points of high ionization. He reported blood changes in nine patients exposed to 65 to 315 rads (0.65–3.15 Gy). Nolan's work anticipated a 1980 case-control study of women in Los Angeles County diagnosed with meningioma, led by Preston-Martin and colleagues, 59 which showed an association between early exposure (age <20 years) to dental x-rays and meningioma. Tumors were located in the tentorial or infratentorial region in 68% of patients with a history of greater than 10 full-mouth exposures. Risk was elevated in those radiographed as children or teenagers, and in those imaged before 1945, when dental x-ray doses were higher.
Case control studies in Sweden 61 and the United States, 58 published in 1998 and 2004 respectively, showed that dental radiographs performed after age 25 also increase risk of meningioma. However, the extent to which dental x-ray exposure is associated with increased incidence of meningioma remains controversial.
Before 1960, the dose from a full-mouth series was often nearly 2 Gy. Today the dose from dental studies has been drastically reduced. The brain is exposed to about 37 to 55 µGy in a panoramic study performed on standard equipment, 78 and approximately 10 to 86 µGy with digital equipment. 79 Doses vary widely depending on equipment and imaging protocol. Panoramic studies are the highest dose radiographic study of the mouth. The absorbed dose to the frontal lobe for children who undergo digital cephalometric radiography for orthodontic work can range from 2.9 to 30.4 µSv. 80 This very low level of x-rays (86 µGy = 0.000086 Gy) is comparable to exposure from naturally occurring radiation in day-to-day life.

Clinical Presentation
As is the case with sporadic meningioma (SM), RIM is characterized by strong female preponderance, with female:male incidence approaching 2:1 in most studies. 25, 36, 37, 44, 53, 61 The hallmarks of radiation treatment at clinical examination include scanty hair, or alopecia, and scalp atrophy. 35, 50, 72, 81 Based on their experience treating a large number of RIM patients, the authors are also of the impression that microcephaly occurs with some frequency in these patients, most likely as a result of premature closure of the skull sutures after irradiation during early childhood.
Meningiomas occurring secondary to irradiation typically occur in the irradiated field. In patients treated for tinea capitis, the majority of tumors are calvarial. 35, 53, 54, 72 In patients treated with high-dose irradiation for primary brain tumors, 4% to 19% of RIM are found in the cranial base; however, Ghim and colleagues 40 found a high proportion of calvarial tumors in pediatric high-dose RIM patients.
SMs generally arise in the fifth or sixth decades of life. In comparison, mean age at presentation is 45 to 58 years in patients treated with low-dose irradiation, 35, 53 - 55 , 72, 82 and typically 29 to 40 years in those exposed to high-dose treatments, 35, 36, 38, 39, 42, 45, 83 although both older 23, 37, 43 and younger 23, 40 high-dose RIM patients have been reported. Latency varies with radiation dose and age at treatment. The longest average latency for low-dose RIM, 42.5 years, was reported among survivors in Nagasaki. In patients with RIM after treatment for tinea capitis, average latency was reported as 36.3 years. 53 Mean latency was shorter in a series describing 15 pediatric RIM patients who sustained high-dose irradiation for the treatment of primary brain tumors at an average age of 2.5 years. 40 In these patients, meningiomas were diagnosed an average of 10.3 years after initial treatment (range 5–15.5), at a mean age of 13 years. Strojan and colleagues 38 reported mean latency in high-dose RIM patients of 18.7 years in a case series and review of the literature. A 14-month latency was reported in one 14-year-old boy with a history of irradiation for a tumor in the posterior fossa. 84 Mack and colleagues 44 found a significant correlation between age at irradiation, dose, and latency. Others have also reported that younger age at initial treatment is related to shorter latency for RIM. 37, 38 Multiplicity was reported in 15.8% of RIM patients versus 2.4% of those with SM in the Israeli tinea capitis cohort ( Fig. 5-5 ). 53 More aggressive clinical behavior, with high rates of recurrence after surgery and radiation, is characteristic of RIM. 35, 36, 39, 49, 53, 54, 72, 85 Sofer and colleagues 54 found an 18.7% recurrence rate in RIM patients, with multiple recurrences in many, compared with a 3% rate in the control group of 84 SM patients. Recurrences occurred after complete removal in a higher proportion of RIM than in the control group. RIM patients also tended to have earlier recurrences.

FIGURE 5-5 Meningiomatosis with multiple tumor nodules in a 65-year-old man irradiated for treatment of tinea capitis as a child. After his initial diagnosis at age 57, he underwent three surgeries, conventional radiotherapy, and radiosurgery, for the treatment of recurrent atypical meningiomas.
A differential diagnosis between RIM and SM cannot be made based on imaging studies, as meningiomas of spontaneous origin and those after exposure to radiation have the same appearance on magnetic resonance imaging (MRI) and computed tomography (CT). The presence of multiple meningiomas in a patient with a history of radiation to the head, and typical skin changes, raises the suspicion of RIM. Protocols for MRI and CT imaging of RIM and SM are comparable. In some patients, angiography may be important for visualization of the tumor's vascular anatomy.
Histologic subtypes in RIM resemble those for SM, with meningotheliomatous, syncytial, transitional, and fibroblastic being the most common; 53, 54, 85 however, histologic features are distinctive. Soffer and colleagues 54 found higher rates of cellularity, nuclear pleomorphism, an increased mitotic rate, focal necrosis, bone invasion, and tumor infiltration of the brain in a series of 42 low-dose RIM patients, compared with histological findings in 84 SMs. Rubinstein and colleagues 72 similarly reported a high degree of cellularity; pleomorphic nuclei with great variation in nuclear size, shape, and chromatin density; numerous multi-nucleated and giant cells; and nuclei with vacuolated inclusions. Frequent mitoses, psammoma bodies, foam cells, and thickened blood vessels that did not stain for amyloid were also noted. In various reports, other authors have also reported higher proliferation indices, 86 and higher rates of atypia or malignancy. 35 - 38 , 40, 44, 45, 54, 85, 86
The authors found evidence of tumor multiplicity rates resembling those reported elsewhere, but have had higher rates of recurrence and a higher proportion of atypical (WHO grade II) and anaplastic (WHO grade III) histopathology in RIM versus SM patients (unpublished data).

Management of Radiation-Induced Meningiomas

Surgery
The standard of care for RIM is total surgical resection when possible. However, complete resection may not be feasible without creation of unacceptable neurologic deficit in some patients, particularly those with tumors involving the skull base. Surgery of RIM is complicated by the frequent multiplicity, aggressive nature and high recurrence rates, and involvement of bony structures and vessels of these tumors. In spite of the radiation-related etiology of RIM, it is paradoxical that stereotactic radiosurgery or fractionated stereotactic radiosurgery may be appropriate adjuncts to surgery, or may even be performed instead of surgery, in some patients. Assessment of the superior sagittal sinus is a critical step in surgical planning for the large proportion of RIMs that are located in the calvaria. In our experience, MRI or MR venography are the optimal methods for assessing patency, with rare exceptions, when angiography may be required. Preoperative embolization may be helpful in some patients with highly vascular tumors.
Scalp atrophy is the first consideration when planning the surgical approach in many RIM patients; multiplicity and high recurrence rates are also important issues to consider when planning the surgical procedure ( Fig. 5-6 and Case Report ). The scalp may be slightly or severely atrophic and poorly vascularized, depending on the radiation dose received. The thickness of the galeal/skin flap may be only 1.5 to 2 mm in some patients, necessitating careful planning and precise technique in order to avoid cerebrospinal fluid (CSF) leak and skin flap dehiscence. The risk of these complications increases in patients with atrophic scalp who require multiple craniotomies, as do a large proportion of RIM patients. When scalp atrophy is a significant factor, it may be appropriate to include a plastic surgeon on the team.

FIGURE 5-6 A, Wound dehiscence in a 60-year-old RIM patient treated with surgery and stereotactic radiotherapy for recurrent meningiomas. B, Delayed rotational flap with surgical vacuum to promote granulation in the dehiscent wound. C, Right latissimus dorsi muscle free flap was performed following failure of the delayed rotational flap. D, MRI with gadolinium, sagittal view, showing the recurrent atypical WHO II parasagittal RIM.
E, Intraoperative view following removal of the parasagittal RIM together with the invaded superior sagittal sinus and falx. F, Immediate postoperative view of skin closure around the free flap.
In some patients with severe scalp atrophy, healthy skin is available at the periphery of the radiated area. Often damage to the skin is less severe in the low forehead, or the low temporal or occipital areas, as opposed to the convexity and vertex. In these patients, we prefer to use this skin, which is healthier and better vascularized; hence we place the incision lower than usual. It is important to avoid use of homeostatic clamps or coagulation, which can cause drying or shrinkage of the skin edges and further damage fragile skin. Flap size should be held to the minimum, and linear or slightly curved incisions are preferable to horseshoe contours.
Wide resection margins, always important in surgery for meningioma, 87 - 90 are especially vital given the aggressive nature and higher recurrence rates for RIM. 39 Bony invasion has been linked to higher rates of tumor occurrence, hence the osseous portion of involved bone should be removed radically. 35, 54, 72, 91, 92 In cases where we suspect or find clear evidence of bone flap invasion, we either autoclave the flap or replace it with acrylic cranioplasty. When tumors involve the skull base or a major cranial sinus, wide resection margins may be impossible to achieve. Recurrence rates are higher in these patients, 39, 90, 93 and adjunct radiosurgery should be considered. 82, 94 - 97 Wound closure also frequently requires special consideration of fragile skin conditions. Multilayer closure may not be feasible, especially in convexity meningiomas, where atrophic scalp may not accept additional sutures. The authors close the skin and galea aponeurosis using a single layer of nylon 3/0 sutures, with or without locking, in patients with a very thin scalp, avoiding use of Vicryl. Meticulous stitches, capable of providing a single, watertight layer that can prevent CSF leak, are required. However, skin necrosis, with potential serious sequelae, can result when stitches are spaced too closely. Staples are not suitable for closure in these patients because they provide poor approximation, without hermetic closure, and can easily damage a fragile atrophic scalp.

CASE REPORT
This 60-year-old woman, who was irradiated for the treatment of tinea capitis during childhood, presented in 1989 at age 41 with two small meningiomas in the left frontal and right pterional regions. She was followed with routine imaging until 1995, when the pterional tumor was radically removed. Histopathology was benign WHO grade I meningioma.
In 2003, MRI revealed a large left frontal/parasagittal meningioma crossing the midline and invading the anterior portion of the superior sagittal sinus, as well as a relatively small recurrence of the right pterional lesion resected 8 years earlier. The parasagittal lesion was radically removed together with the invaded portion of the sagittal sinus and the falx. Histopathology revealed an atypical WHO grade II meningioma. There were no new neurologic deficits after surgery. Wound CSF leak was successfully treated with lumbar drain. The patient also underwent surgical removal of three basal cell carcinomas on her scalp and neck at this time.
Less than 2 years later, in March 2005, MRI showed enlargement of both lesions. The frontal/parasagittal lesion removed in 2003 had recurred and was now 2 × 2 cm. Two additional small bifrontal convexity meningiomas were seen, and the pterional tumor operated in 1995 had grown to 4 cm in maximal diameter. Radical resection was performed for removal of the pterional tumor, which was again found to be a benign WHO grade I meningioma. In April 2005, MRI and CT-guided stereotactic LINAC-based radiosurgery was performed for the bifrontal lesions, followed by fractionated stereotactic radiotherapy for the parasagittal meningioma.
Two weeks after radiosurgery, the patient presented with a dehiscent wound in the right frontal radiated scalp area, exposing the skull and Craniofix device ( Fig. 5-6A ). CSF leak was managed with lumbar drainage and the Craniofix was removed; however, the patient's scalp wound became chronically infected and failed to heal. In July 2006, the plastic surgery department performed a delayed rotational flap to cover the skin defect ( Fig. 5-6B ). The underlying bacterial infection was not controlled in spite of focal and intravenous treatment with antibiotics. The rotational flap developed necrotic foci and was removed. In September 2006, a large right latissimus dorsi muscle free flap was grafted onto the surgical site. The underlying infection was resolved, and the free flap remained well vascularized and viable ( Fig. 5-6C ).
In late 2007, the patient presented with neurologic deterioration due to recurrence of the previously operated and irradiated bifrontal parasagittal meningioma ( Fig. 5-6D ). Small bilateral frontal convexity meningiomas were stable, and a new small left anterior clinoid meningioma was also noted. In January 2008, a gross total resection of the parasagittal meningioma was again performed and three additional small convexity tumors were removed from the area of exposure ( Fig. 5-6E ). Histopathology from the primary lesion was WHO grade II meningioma. Focal brain invasion was noted, with an MIB-1 labeling index of 15%. The postoperative course was uneventful and the free flap healed well ( Fig. 5-6F ).
The patient remains under close follow-up.


Stereotactic Radiosurgery and Fractionated Stereotactic Radiotherapy
Adjuvant or primary stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSR) treatment may be necessary in RIM patients when radical excision is not possible, which is not uncommon, or for elderly, infirm patients and others who are not eligible for surgery. When the data are available, treatment planning and dose prescription and delivery should be carried out with careful consideration of the original doses and treatment fields in RIM patients. Adjuvant conventional conformal irradiation is generally recommended after surgery and/or radiosurgery to address tumor cells that may remain viable in the brain parenchyma and along the dura, especially in patients with WHO grade II or WHO grade III meningiomas. 87, 88, 92 Conventional radiotherapy, however, is not an option in some RIM patients, who may have already received maximum tolerable doses of ionizing irradiation. In these patients, fractionated stereotactic radiotherapy FSR or SRS may be advised. 98, 99
A recent study of gamma knife radiosurgery in 16 patients with 20 radiation-induced tumors (17 typical meningiomas, 1 atypical meningioma, and 1 schwannoma), with median follow-up of 40 months, 100 found outcomes resembling results in previously published studies involving patients with SM. 98, 99 Using the m 3 ® high-resolution micro-multileaf collimater (BrainLAB, Heimstetten, Germany) mounted on a linear accelerator for stereotactic radiosurgery, we have found tumor control rates in RIM patients with WHO grade I meningiomas comparable to reported outcomes treating WHO grade I SM (unpublished data). Evidence-based data in this regard remains limited.
Unfortunately, there is a reduced response to stereotactic radiosurgery for both RIM and SM with WHO II or WHO grade III pathology (50% and 17%, respectively). 99 These higher grade tumors are associated with poor outcome. 99, 101, 102

Systemic Therapy
In patients with recurrent, nonresectable SM, systemic adjuvant treatment with tamoxifen 103 or hydroxyurea 104 - 106 has been reported. Both agents have been used in our department for selected RIM patients with recurrent meningioma that was not controlled with surgery and radiotherapy, but with no measurable response.

GENETICS OF RADIATION-INDUCED MENINGIOMA

Genetic Predisposition
Despite the strong established association between exposure to ionizing radiation and risk of meningioma, only a small subset of exposed individuals actually develops this tumor. This observation supports the hypothesis that there are genetic factors that modify the risk of meningioma following exposure to ionizing radiation, and thereby cause personal variability in radiosensitivity.
The classic design for assessing interaction between environmental and genetic factors requires four samples defined by disease and exposure status. In this particular case, the four groups required include irradiated cases, nonirradiated cases, irradiated controls, and nonirradiated controls.
The tinea capitis cohort provided an ideal basis for an investigation of this hypothesis. 26, 33 To enlarge the sample size, additional irradiated and nonirradiated cases were ascertained through the Israel Cancer Registry and through the use of compensation files, submitted in the framework of the Israeli tinea capitis compensation law. This law, established in 1994 by the Israeli Parliament, was designed to compensate irradiated individuals for specific diseases that were proven to be causally associated with irradiation. 107
Based on this nested case-control study, Sadetzki and colleagues 108 published results of an assessment of the possible role of 12 candidate genes involved in DNA repair and cell cycle control, as well as the NF2 gene, which is known to be responsible for familial meningioma in RIM and SM formation. Intragenic single nucleotide polymorphisms (SNPs) in the Ki- ras and ERCC2 genes were associated with increased risk of meningioma (OR: 1.76; 95% CI: 1.07–2.92 and OR: 1.68; 95% CI: 1.00–2.84, respectively), and a significant interaction was found between radiation and cyclin D1 and p16 SNPs ( P for interaction: .005 and .057), suggesting an inverse effect in RIM compared with SM.
Variation in radiosensitivity across the human population is an accepted concept. 17, 109 Direct evidence of radiation sensitivity was demonstrated recently in the tinea capitis study based on a data set of families that included irradiated and nonirradiated members, and members with and without RIM. 28 The fact that tinea capitis is a contagious disease, and that the cohort included a high proportion of individuals from North Africa, generally characterized as having large families (i.e., mean of five to six children), led to a unique situation in which several family members were exposed to radiation and others were not. A natural experiment was therefore created, enabling simultaneous assessment of the effect of exposure and inheritance shown by familial aggregation of the disease among irradiated individuals within the same family ( Fig. 5-7 ).

FIGURE 5-7 Family tree of two families with four RIM in first-degree relatives. Family 1 includes seven siblings, of whom four sisters and one brother were irradiated for tinea capitis. All four irradiated sisters developed meningiomas. Family 2 includes an irradiated mother and eight siblings, of whom five were irradiated. The mother and three of the irradiated siblings (two brothers, one sister) developed meningiomas. Two irradiated siblings were also diagnosed with leukemia (#) or breast cancer (§).
(From Flint-Ritcher and Sadetzki, 28 with permission of Elsevier Science, Ltd.)
As familial clustering of meningiomas is extremely rare, we assumed that in families with no index cases of RIM, the risk of meningioma would be approximately 1%, whereas in families with index cases with RIM (indicating genetic sensitivity), there would be a higher proportion of RIM. Examination of the study group led to the identification of 17 families (11%), in which two to four first-degree relatives developed meningioma. All of the familial cases occurred in irradiated siblings. These findings indicate that the occurrence of meningioma after exposure to radiation is not a random event, and most probably has a genetic component.
Based on the knowledge of increased risk of meningioma with exposure to ionizing radiation, and of genetic susceptibility to meningioma, the contribution of variants in DNA repair genes to disease susceptibility was recently explored. 110 The analysis was based on data from five case-control series, including 631 cases and 637 controls that contributed to multinational studies assessing whether mobile telephone use increases the risk of cancer (the Interphone Study). 111 Genetic analysis included the genotyping of 136 DNA repair genes, as well as 388 putative functional SNPs. Statistically significant associations with meningioma were found for 12 SNPs. Of these, three mapped to breast cancer susceptibility gene 1 ( BRCA1 )-interacting protein 1 (BRIP1), and four to ataxia telangiectasia-mutated. The most statistically significant association was observed for SNP rs4968451 of the BRIP1, for which statistical significance was maintained after adjustment for multiple testing ( P = .009), and for which there was no evidence of heterogeneity among the risks observed in the five case-control data sets. It is believed that this SNP may contribute significantly to meningioma development, as approximately 28% of the European population carries at-risk genotypes for this variant.

Somatic Alterations of RIM
Sporadic meningioma was one of the first solid tumors studied for somatic alterations. The first studies focused on chromosomal aberrations using cytogenetic techniques, including Giemsa staining, spectral karyotyping (SKY), and comparative genomic hybridization (CGH). A number of cytogenetic alterations have been reported; the most frequent abnormalities, seen in 54% to 78% of SM, were located in chromosome 22 and were monosomy or deletion of 22q. Another common chromosomal aberration that was found to correlate with tumor behavior was loss of 1p. Other chromosomal aberrations reported in anaplastic and atypical meningioma have been found at 3p, 6q, 10p, 10q, and 14q, suggesting candidate regions for tumor suppressor genes. 112, 113
Using loss of heterozygosity (LOH) studies, researchers were able to locate smaller regions that were deleted in meningioma. Further studies have tried to identify specific genes and proteins involved in meningioma formation. The gene NF2 , which causes neurofibromatosis II syndrome and has been mapped to chromosome 22q12.2, 114, 115 was deleted in up to 50% of SM. 116, 117 Several observations led to the hypothesis that other tumor suppressor genes located on 22q (e.g., BAM22 , LARGE , and MN1 ) may be involved in meningioma formation. 112
Recent studies have identified additional genes involved in early and advanced meningioma. Inactivation of the 4.1B gene was found in 60% of meningiomas, regardless of histological grade, suggesting that this is an early event in the carcinogenesis process. 118 In atypical and malignant meningioma, genetic changes were found in several genes, i.e., hTERT and K4A/INK4B. 119
Recent studies have used microarray or gene expression data to analyze sporadic meningiomas, but these studies are characterized by small sample sizes and small numbers of genes, which limit their conclusiveness.
Only a few investigators have assessed the somatic characteristics of RIM and even fewer compared genetic alteration in RIM to non-RIM. The first three publications on RIM were case reports, each reporting on one patient who developed meningioma after exposure to therapeutic radiation for a first tumor (skin carcinoma, pituitary adenoma, and glioma). The karyotype for all three meningiomas showed deletions of chromosome 22, and two of them showed additional chromosomal aberrations in chromosome 1, 6, 8, and 9. 120 - 122
Zattara-Cannoni and colleagues 123 used cytogenic techniques to study six meningiomas (four benign and two atypical) from patients previously treated with radiation for first cancer ( Fig. 5-8 ); all showed the same chromosomal abnormality rearrangements between chromosomes 1 and 22. Their hypothesis was that since the rearrangement between chromosomes 1 and 22 was in the 1q11 region, a tumor suppressor gene with possible involvement in RIM formation might be localized in this region.

FIGURE 5-8 Note partial rearrangement between chromosome 1 and chromosome 22, terminal deletion on one chromosome 7, and rearrangement between parts of chromosomes 7 and 17.
(From Zattara-Cannoni, et al., 123 with permission of Elsevier Science, Ltd.)
Al-Mefty and colleagues 39 studied serial tumor samples of 16 RIM cases. The authors found deletions, loss, or additions in chromosome 1p in 89% of cases, and loss or deletion in 6q in 67%.
Studies comparing molecular genetic changes in RIM and SM are limited, mainly due to small sample sizes that preclude significant results. In the first study analyzing a group of radiation-induced solid tumors using molecular genetic tools, 124 investigators studied seven RIM (five grade I, two grade II), and eight SM cases (seven grade I, one grade III). The study assessed chromosomal changes, LOH, mutations in NF2 , and level of NF2 gene product (schwannomin/merlin protein). Allelic loss in 1p was found in 57% of RIM samples and loss of 22q was found in 29% of cases, whereas these changes were found in 30% and 60% to 70%, respectively, in the sporadic cases ( Fig. 5-9A ). Although no mutations were detected in the NF2 gene in RIM cases, 50% of SM showed mutations in this gene. NF2 protein levels were normal in four of four RIM cases tested, whereas 50% activity or less was seen in the non-RIM tumors ( Fig. 5-9B ). The authors concluded that NF2 gene inactivation does not play a role in the pathogenesis of meningioma formation in RIM cases, and that chromosomal deletion in 22q is less frequent in RIM compared to non-RIM. They suggested that other regions, such as 1p, may be important for RIM formation.

FIGURE 5-9 A, LOH is demonstrated on chromosomes 1p (marker D1S551) and 9q (marker D9S171) for case # 12 (arrows). N = blood DNA, T = tumor DNA. The faint signals in the tumor lanes might be due to contaminating normal cells or tumor heterogeneity. Note homozygous alleles are present on loci D1S551 and D9S171 for case #11. Retained heterozygosity is detected for both loci in cases # 13 and 14. B, Western blotting for NF2 protein 66-kDa band expression, indicated by an arrow at right. Note high expression level of NF2 protein in radiation induced meningioma samples (i.e., in human brain [HB] sample), and marked reduction only in NF2-derived meningioma.
(From Shoshan et al., 124 with permission of the authors.)
Rienstein and colleagues 125 made cytogenetic comparisons between 16 RIM (14 benign, two atypical) and 17 sporadic meningioma (16 benign, 1 atypical), and found that the most common losses were in chromosomes 22 and 1 (56.2% and 37.5% compared to 47% and 35.3% in RIM and SM, respectively). In RIM cases, gains of DNA copy numbers of chromosomes 8 and 12 were detected in 2 of 16 cases. The authors concluded that the RIM and SM have the same tumorigenic pathway.
Joachim and colleagues 126 analyzed 25 RIM (9 WHO grade I, 5 WHO grade II, 11 WHO grade III) and 36 SM (21 grade WHO II, 15 WHO grade III) for six genes ( NF2 , p53 , PTEN , K- ras , N- ras , and H- ras ). Although no differences in mutation rates were found between groups for the ras (no mutations were found in either group), p53 , or PTEN genes, there were differences in the frequency of NF2 mutations between RIM and SM (23% and 56%, respectively, P < .02). The authors concluded that with the exception of NF2 , there is a certain overlap in the mutation spectrum in RIM and SM.
Rajcan-Separovic and colleagues 127 analyzed six RIM cases (two benign and four malignant), and one atypical SM. They found loss of 1p and 7p in four of five RIMs with abnormal karyotype and loss of 6q in three of five RIM cases, in comparison with losses in the SM case at 1p, 6q, 14q, 18q, and 22q.

Summary
The current data on somatic alterations in RIM are limited; most sample sizes that were assessed were small and included a mixture of histologic types that might have different genetic alterations regardless of irradiation status.
Some of the investigators did not find significant differences in the genetic characteristics of RIM compared to non-RIM tumors. Four studies, however, have suggested that losses of 1p, 6q, and 7p may play a role in RIM formation.

CONCLUSIONS
Risks associated with the indiscriminate use of ionizing radiation were poorly understood for more than 50 years, and the sensitivity of neural tissue to damage from ionizing radiation was not widely accepted until much later. Today ionizing radiation is considered the only established environmental risk factor in the causation of meningioma. Generally, there is a consensus in the literature for a linear dose–response relationship, and there is evidence that exposure to even low doses of ionizing radiation, on the order of 1 Gy and less, can increase the risk for meningioma as well as other benign and malignant neoplasms of the brain. This relationship has been demonstrated most clearly in children.
The Israeli experience with adults who were irradiated as children for treatment of tinea capitis between the ages of 1 and 15 years, shows that exposure to ionizing radiation during childhood significantly increases risk for meningioma. Other studies also describe significantly increased incidence of meningioma among individuals irradiated during infancy for skin hemangioma, and those irradiated for treatment of childhood cancer. From the studies in Hiroshima and Nagasaki, there is evidence that adults exposed to radiation have increased risk for meningioma, with a linear dose–response relationship, although not at a statistically significant level. Cases of meningioma after irradiation for primary brain tumor during adulthood have also been reported.
The hallmarks of radiation-induced meningioma after treatment for tinea capitis are alopecia and scalp atrophy, although a history of irradiation cannot be ruled out in patients presenting without these clear signs. Many patients also present with multiple tumors. Age at diagnosis for RIM is lower than that for sporadic meningioma. There is evidence that latency is shorter in patients exposed to high therapeutic doses of radiation. Histologic subtypes in RIM resemble those for SM; however, histologic features of RIM include higher rates of cellularity, nuclear pleomorphism, an increased mitotic rate, focal necrosis, bone invasion, and tumor infiltration of the brain. Atypical (WHO grade II) and anaplastic (WHO grade III) findings are more common in RIM. Not surprisingly, recurrence rates in RIM are higher than those for SM.
Direct evidence of genetic susceptibility for developing meningioma after exposure to ionizing radiation has been shown, however, the specific genes contributing to radiosensitivity have not yet been discovered. Although some potential differences in genetic alterations involved in the tumorigenic process in RIM and SM have been suggested, no unique genetic characteristics of RIM have been clearly identified.
The medical benefits of appropriate use of radiation for diagnostic and therapeutic purposes are clear: the discovery of x-rays revolutionized modern medicine. However, taken together, the historical record and research findings suggest that special consideration is indicated before radiation is used for the treatment of benign diseases, especially in young people with a long life expectancy. Routine imaging examinations during childhood and adolescence should also be performed without use of ionizing radiation whenever reasonable alternatives are available.

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[118] Lusis E., Gutmann D.H. Meningioma: an update. Curr Opin Neurol . 2004;17(6):687-692.
[119] Simon M., Bostrom J.P., Hartmann C. Molecular genetics of meningiomas: from basic research to potential clinical applications. Neurosurgery . 2007;60(5):787-798. discussion 787–798
[120] Chauveinc L., Dutrillaux A.M., Validire P., et al. Cytogenetic study of eight new cases of radiation-induced solid tumors. Cancer Genet Cytogenet . 1999;114(1):1-8.
[121] Chauveinc L., Ricoul M., Sabatier L., et al. Dosimetric and cytogenetic studies of multiple radiation-induced meningiomas for a single patient. Radiother Oncol . 1997;43(3):285-288.
[122] Pagni C.A., Canavero S., Fiocchi F., Ponzio G. Chromosome 22 monosomy in a radiation-induced meningioma. Ital J Neurol Sci . 1993;14(5):377-379.
[123] Zattara-Cannoni H., Roll P., Figarella-Branger D., et al. Cytogenetic study of six cases of radiation-induced meningiomas. Cancer Genet Cytogenet . 2001;126(2):81-84.
[124] Shoshan Y., Chernova O., Juen S.S., et al. Radiation-induced meningioma: a distinct molecular genetic pattern?. J Neuropathol Exp Neurol . 2000;59(7):614-620.
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CHAPTER 6 Neuropathology of Meningiomas

Aydin Sav, Bernd W. Scheithauer

DEFINITION
Cushing first coined the term “meningioma” to denote a primary tumor originating from cellular constituents of the meninges, thereby encompassing all primary, meningeal-based neoplasms. 1 Over time, the term became limited to tumors arising from arachnoidal cap or meningothelial cells. Morphologically, the category covers a wide range of neoplasms, ones varying in grade from benign (WHO grade I) through atypical (WHO grade II) to malignant (WHO grade III). A lengthy list of descriptive terms has been appended to subtypes of meningioma, including, among others, meningothelial, fibroblastic, transitional, psammomatous, secretory, and microcystic. Only a handful is associated with characteristic laboratory findings or clinical behavior. 2 - 4
Meningiomas are typically dura-based, often originating in areas where arachnoidal granulations reside. The majority occur in adults and are idiopathic in origin. Children are only occasionally affected. 5, 6 Only rare meningiomas occur after cranial radiation 7 - 11 or arise in the setting of neurofibromatosis type 2 (NF2). The latter disorder should be suspected when meningioma, particularly multiple lesions, occur in childhood and adolescence. 12 Rare meningiomas are accompanied by other estrogen-dependent tumors, such as carcinomas of breast or endometrium. 2

DEMOGRAPHICS
Meningiomas are the most common primary, intracranial, nonglial tumors as well as the most frequently occurring extraaxial neoplasms. 13 Collectively, they comprise 20% of intracranial neoplasms, 13 including 15% of symptomatic and 33% of asymptomatic lesions. 13 Most meningiomas affect adults in middle and older age. In the pediatric population, they account for only 1.4% to 4% of intracranial tumors. 13 Gender predilection typifies meningiomas. The 2:1 female-to-male ratio generally noted diminishes with age. Thus, in malignant meningiomas, the genders are also equally represented. 13 The same is true of meningiomas encountered incidentally at autopsy study.
The reported annual incidence of meningiomas is approximately 2.3 to 3.1 per 100,000. 13 In comparison, the annual incidence of meningiomas detected at autopsy is 3.9 to 5.3 per 100,000. 14 The incidence of both symptomatic and asymptomatic meningiomas rises with age. 13 One recent study showed 38.9% of meningiomas were asymptomatic 15 ; this is particularly true in women and in individuals older than 70 years of age. 14
The proportion of multiple meningiomas, a condition known as “meningiomatosis” when pronounced, is approximately 1% to 5% in surgical series. 16 Such tumors occur more frequently in women and the elderly. 13 On computed tomography (CT), they comprise 8% of meningiomas; the figure is 8% to 16% in autopsy studies of meningiomas. 13 Although multiple meningiomas occur at relatively high frequency in the setting of NF2, it is of note that such patients may not have other characteristic features of the disease, such as multiple schwannomas. 13 Nearly half of the patients with NF2 have a meningioma and that almost 30% have multiple lesions. 13 Among the 5% of patients with meningiomatosis in one series, only 19% fulfilled the diagnostic criteria for NF2. 16 Familial meningiomatosis unassociated with NF2 is extremely rare; only one case has been reported. 16

SPECIFIC SITES
The majority of meningiomas are intradural and arise at intracranial, intraspinal, or orbital locations. Intracranial examples favor sites of arachnoidal granulations and produce increased intracranial pressure, including such symptoms of mass effect and focal neurologic deficits. In contrast to intraparenchymal tumors, such as gliomas and metastases, seizures are relatively uncommon in meningiomas. 2
Neuroimaging usually demonstrates a globular, highly vascular, contrast-enhancing, dura-based tumor. A practical radiologic clue to the diagnosis is the “dural tail sign” due to a wedge-shaped, contrast-enhancing tongue of neoplastic or granulation tissue situated at the angle between tumor and underlying dura. Although an uncommon pattern, some meningiomas, particularly ones involving the sphenoid ridge form a carpet-like or “en plaque” lesion. One histologic subtype, the microcystic variant, is often associated with an intratumoral or peritumoral cyst formation. 2 In some instances, meningiomas are almost entirely embedded within the brain and are associated with peritumoral edema. 2
Neuroimaging is invaluable in the diagnosis of meningiomas. On nonenhanced CT images meningiomas are often isodense to gray matter, making them difficult to visualize. Calcifications are common and bright on CT scans. 17 On MRI scan, most are isointense but may be partly hypointense when densely fibrotic and/or heavily calcified. 18 As a rule, the higher the histologic grade of the tumor, the more frequent and extensive is peritumoral edema. For example, atypical and anaplastic meningiomas that attach themselves to the pia often provoke considerable cerebral edema. 19, 20 It is not surprising, therefore, that edema is more common in association with meningiomas having increased MIB-1 labeling indices. 21 Brain invasive meningiomas show an irregular tumor–brain interface and often impressive edema ( Fig. 6-1A ), a reaction far less evident in grade I or II lesions.

FIGURE 6-1 A , Meningioma with irregular surface. B, Meningioma infiltrating the skull. C, Meningioma showing smooth and lobulated surface.
Histologically, meningiomas often infiltrate the dura and may involve mesenchymal tissue, including the skull, galea, and subcutaneous tissue ( Fig. 6-1B ).
Bone infiltration induces cranial hyperostosis, which consists of bony spicules that radiate from the outer and inner tables. The scalp masses associated with hyperostotic meningiomas may be associated with either galea elevation or penetration and can be the presenting sign of disease. 2
Histologically, choroid plexus owes its configuration to invagination of vessels, mesenchyme, and leptomeninges along the choroidal fissure. Thus, it is not surprising that meningiomas are encountered within choroid plexus stroma. Although infrequent, they involve the lateral, 22 third, 2 and even the fourth 23 ventricles. Meningiomas involving the pineal region are rare. 2
Orbital meningiomas originating from the optic nerve sheath are uncommon. Anatomically, only a small proportion of orbital meningiomas originate as intradural masses; others lie free within orbital soft tissues. 2 Understandably, patients are presented with strabismus, ptosis, and visual disturbance.
Almost all spinal meningiomas are intradural and extramedullary. Many expand at the expense of the adjacent spinal cord and produce segmental neurologic deficits. 2 The cervicothoracic level is most often affected. Nearly all tumors arise either ventral or lateral to the nerve root exit zone, areas wherein meningothelial cells are normally concentrated. Spinal meningiomas are rarely intramedullary. In contrast to intracranial meningiomas, spinal meningiomas rarely involve surrounding bone. The female predilection is much higher than that of intracranial lesions, the ratio being almost 10 to 1. 2 Histologic meningioma subtypes with a clear proclivity for the spinal axis include the psammomatous and clear cell variants.
Another subset of meningiomas, either intracranial or intraspinal, is epidural in location. Although dura-based, their bulk lies outside the dura. Lastly, rare meningiomas arise within bone. Such intraosseous meningiomas usually affect the skull (diploic meningioma) where they presumably originate from meningothelial rests. 2 Also among these are meningiomas of the ear (petrous bone) and temporal bone. 24
Rare sites of occurrence of meningiomas include the sinonasal tract, 25 skin, lungs, 26 mediastinum and peripheral nerves. 2 Such ectopic meningiomas are thought to originate in part by direct extension along soft tissue planes, whereas others are truly ectopic. For example, meningiomas in lungs and/or mediastinum presumably take their origin from discrete, microscopic nests of cells with histologic, immunohistochemical, and ultrastructural characteristics of meningothelium. Molecular studies of microdissection specimens suggest that isolated pulmonary lesions may not be neoplasms, whereas multifocal examples may be true tumors or intermediate, precursor lesions. 2, 27, 28

GROSS FINDINGS
Most meningiomas are well delineated, soft to rubbery in consistency, and discrete with smooth or lobulated surfaces ( Fig. 6-1C ).
The attachment of meningiomas to dura is typically by a broad base. 3, 13, 29 - 31 The majority are soft in texture, but fibrous meningiomas are decidedly more firm. The microcystic subtype may, in part, be grossly cystic and often shows intimate attachment to the brain surface. Invasion of underlying dura is a common finding. In contrast, meningiomas envelope but almost never invade blood vessels other than venous sinuses. Perivascular space involvement may, to some extent, facilitate extradural extension and soft tissue involvement. In addition, extension through bony foramina or fissures permits involvement of adjacent extracranial compartments, such as the orbit or skull base. 2
Occasional meningiomas are coarse and grainy in consistency due to the presence of abundant microcalcifications termed “psammoma bodies.” Such tumors often occur in spinal dura or in the olfactory groove. In contrast, metaplastic bone formation is very uncommon, being most frequent in spinal examples. As noted in the preceding text, meningiomas infiltrating or penetrating bone stimulate remarkable hyperostosis. As previously noted at sites such as over the sphenoid wing, meningiomas grow carpet-like as “en plaque” meningioma. 32, 33 Such tumors pose an operative challenge. On occasion, heavy lipidization renders a tumor bright yellow. In contrast, rare metaplastic tumors with myxomatous features are gray and translucent. 2
Meningiomas often compress adjacent brain but only infrequently show parenchymal invasion. As a rule, they push the leptomeninges before them, creating a margin that serves as a cleavage plane. Microcystic variants are somewhat of an exception, often being broadly attached to the pial surface. Atypical and anaplastic meningiomas, being larger than benign examples, 34 often have a more extensive and irregular tumor–brain interface. Such tumors may not be cleanly removed, particularly if perivascular (Virchow–Robin) space involvement or cortical invasion is present. Recurrent tumors are also less well defined and are more likely to be adherent to the brain or to encase nerves and vessels. 2

HISTOLOGIC SUBTYPING OF MENINGIOMAS
Although all meningiomas are derived from meningothelial cells, they exhibit a wide variety of histologic appearances. 3, 29 - 33 According to the 2007 WHO classification, meningothelial, fibrous and transitional subtypes are most common. On balance, the majority of meningioma subtypes are grade I and follow an uneventful clinical course. Grade II (atypical) and grade III (malignant) examples are far more likely to behave in an aggressive manner. Nonetheless, metastases are rare. Histologically, grades II (atypical, chordoid and clear cell tumors), as well as grade II (anaplastic, papillary, and rhabdoid tumors) comprise the groups of intermediate and high-grade meningiomas. Compared to grade I tumors, those of grade II are 8-fold more likely to recur after gross total removal. Grade III lesions behave in a frankly malignant manner ( Table 6-1 ). 2, 32, 33 The issue of meningioma grading according to various histologic parameters is discussed in the text that follows.
TABLE 6-1 Histologic subtypes of meningiomas according to WHO Grade. Subtypes with low risk of recurrence and aggressive growth     ICD-O code Meningothelial meningioma WHO grade I 9531/0 Fibrous (fibroblastic) meningioma WHO grade I 9532/0 Transitional (mixed) meningioma WHO grade I 9537/0 Psammomatous meningioma WHO grade I 9533/0 Angiomatous meningioma WHO grade I 9534/0 Microcystic meningioma WHO grade I 9530/0 Secretory meningioma WHO grade I 9530/0 Lymphoplasmacyte-rich meningioma WHO grade I 9530/0 Metaplastic meningioma WHO grade I 9530/0 Subtypes with greater likelihood of recurrence and/or aggressive behavior: Meningiomas of any subtype or grade with high proliferation index (4 mitoses/10 high-power fields) and/or brain invasion Chordoid meningioma WHO grade II 9538/1 Clear cell meningioma (intracranial) WHO grade II 9538/1 Papillary meningioma WHO grade III 9538/3 Rhabdoid meningioma WHO grade III 9538/3
Meningiomas show a wide variety of histologic appearances. Many are of no prognostic significance. Histologic features of grade II lesions vary and include both histologic patterns and tumors featuring specific parameters (see later). Simply finding occasional mitoses and pleomorphic nuclei does not indicate aggressive clinical behavior. Histologic parameters used to diagnose atypical meningiomas (see later) are applied independently of tumor subtype, although some patterns are, by definition, grade II or III. Although most meningiomas demonstrate features of at least one of the categories described below, mixed patterns are common. The recent 2007 World Health Organization (WHO) classification of meningiomas is based largely upon the expression of relatively specific morphologic features. 32, 33

Histologic Meningioma Subtypes

Meningothelial meningioma
Once termed “syncytial meningioma,” the meningothelial variant is the most common and archetypic form of meningioma. It consists of varying sized lobules of neoplastic cells with indistinct borders ( Fig. 6-2A ).

FIGURE 6-2 A, Meningothelial meningioma demonstrating its typical “syncytial appearance.” B, Partial clearing of nucleus due to glycogen deposition known as pseudoinclusion. C, Nuclear inclusions (pseudoinclusion) are glycogen containing demonstrated by PAS with diastase.
The intricate manner in which tumor cell membranes are ultrastructurally seen to be interwoven explains why cell border may not be discernible at the light microscopic level. Fibrous tissue is typically lacking in meningothelial tumors. Whorls and psammoma bodies are relatively uncommon in meningothelial tumors.
The cells demonstrate classic cytologic features of meningothelium including round to oval nuclei, delicate chromatin, small solitary nucleoli, and variable numbers of nuclear-cytoplasmic inclusions surrounded by marginated chromatin. Glycogen containing, such inclusions can be found in many meningioma variants ( Fig. 6-2B, C ).
The frequently generous size of some lobules should not be confused with the “sheeting” or loss of architectural pattern often seen in atypical meningioma.
In small biopsy specimens, reactive meningothelial hyperplasia accompanying other processes may simulate meningioma. Florid examples are seen in association with optic nerve glioma, adjacent to tumors such as schwannoma, chronic renal disease, “arachnoiditis ossificans,” advanced patient age, and occasionally in association with diffuse dural thickening (“pachymeningitis”). 35

Fibrous meningioma
Fibrous meningiomas are relatively uncommon, particularly in pure form. The pattern is often partly represented in transitional meningiomas (see later). The fibrous variant consists of elongate, spindle cells forming parallel or storiform arrangements in association with variably collagen-rich matrix ( Fig. 6-3 ).

FIGURE 6-3 Fibrous meningiomas consist of elongated cells in a collagen-rich matrix.
The designation “fibrous” is also loosely applied when cellular elongation is pronounced, despite relative lack of collagen.
Nuclei are often somewhat hyperchromatic and more elongated than those of the transitional meningiomas. Nuclear pseudoinclusions, whorls, and psammoma bodies are less frequent, but calcification of collagen bundles or of vasculature may be seen. 2

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