GULF WAR and HEALTH

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Committee on Gulf War and Health: Brain Injury in Veterans and Long-Term Health Outcomes Board on Population Health and Public Health Practice

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by Contract V101(93) P-2136, Task Order 8 between the National Academy of Sciences and Department of Veterans Affairs. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-12408-9 International Standard Book Number-10: 0-309-12408-5 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at www.iom.edu. Copyright 2009 by the National Academy of Sciences. All rights reserved. Printed in the United States of America The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. Suggested citation: IOM (Institute of Medicine). 2009. Gulf War and Health, Volume 7: Long-term Consequences of Traumatic Brain Injury. Washington, DC: The National Academies Press.

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org . iv

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COMMITTEE ON GULF WAR AND HEALTH: BRAIN INJURY IN VETERANS AND LONG-TERM HEALTH OUTCOMES GEORGE W. RUTHERFORD, MD (Chair) Salvatore Pablo Lucia Professor and Vice Chair, Department of Epidemiology and Biostatistics; Director, Prevention and Public Health Group, Global Health Sciences, University of California, San Francisco School of Medicine JEFFREY J. BAZARIAN, MD, MPH, Associate Professor, Departments of Emergency Medicine and Neurology, University of Rochester School of Medicine and Dentistry IBOLJA CERNAK, PhD, MD, Medical Director, Johns Hopkins University, Applied Physics Laboratory JOHN D. CORRIGAN, PhD, Professor, Department of Physical Medicine and Rehabilitation, Ohio State University SUREYYA S. DIKMEN, PhD, Professor, Department of Rehabilitation Medicine and Adjunct Professor of Neurological Surgery and Psychiatry and Behavioral Sciences, University of Washington M. SEAN GRADY, MD, Chairman, Department of Neurosurgery, University of Pennsylvania School of Medicine DALE C. HESDORFFER, PhD, MPH, Associate Professor of Clinical Epidemiology, Gertrude H. Sergievsky Center, Columbia University JESS F. KRAUS, PhD, MPH, Director, Southern California Injury Prevention Research Center, Professor of Epidemiology, University of California, Los Angeles, School of Public Health HARVEY S. LEVIN, PhD, Professor, Director of Research, Cognitive Neuroscience Laboratory, Department of Physical Medicine and Rehabilitation, Baylor College of Medicine LINDA NOBLE, PhD, Professor, Department of Neurological Surgery and Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco SAMUEL J. POTOLICCHIO, MD, Professor, Department of Neurology, George Washington University Medical Center SCOTT L. RAUCH, MD, Chair, Partners Psychiatry and Mental Health; President and Psychiatrist in Chief, McLean Hospital; Professor of Psychiatry, Harvard Medical School WILLIAM STIERS, PhD, ABPP, Assistant Professor, Department of Physical Medicine and Rehabilitation, Johns Hopkins University CAROL A. TAMMINGA, MD, Professor, Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas NANCY TEMKIN, PhD, Professor, Departments of Neurological Surgery and Biostatistics, University of Washington MARC G. WEISSKOPF, PhD, ScD, Mark and Catherine Winkler Assistant Professor, Departments of Environmental Health and Epidemiology, Harvard School of Public Health v

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STAFF CAROLYN FULCO, Senior Program Officer ABIGAIL MITCHELL, Senior Program Officer ROBERTA WEDGE, Senior Program Officer NAOKO ISHIBE, Program Officer JENNIFER SAUNDERS, Senior Program Associate DEEPALI PATEL, Senior Program Associate (until October 2007) RENEE WLODARCZYK, Senior Program Associate JOE GOODMAN, Senior Program Assistant NORMAN GROSSBLATT, Senior Editor CHRISTIE BELL, Financial Officer HOPE HARE, Administrative Assistant ROSE MARIE MARTINEZ, Director, Board on Population Health and Public Health Practice CONSULTANTS MIRIAM DAVIS, Independent Medical Writer, Silver Spring, MD JOAN MACHAMER, Independent Consultant, University of Washington, Seattle, WA vi

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REVIEWERS This report has been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards of objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We thank the following for their review of this report: Dan G. Blazer, Duke University Medical Center Linda Cowan, Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center Ramon Diaz-Arrastia, Department of Neurology, University of Texas Southwestern Medical School Sandro Galea, Center for Social Epidemiology and Population Health, University of Michigan Tessa Hart, Moss Rehabilitation Research Institute, Albert Einstein Healthcare Network Janice L. Krupnick, Department of Psychiatry, Trauma and Loss Program, Georgetown University Medical Center James L. Levenson, Department of Psychiatry, Virginia Commonwealth School of Medicine Kathryn Saatman, Spinal Cord and Brain Injury Research Center, University of Kentucky Chandler Medical Center Murray B. Stein, Department of Psychiatry, University of California, San Diego Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Dr. Johanna T. Dwyer, Tufts University School of Medicine and Friedman School of Nutrition Science and Policy, Frances Stern Nutrition Center, Tufts-New England Medical Center and Dr. Robert S. Lawrence, Center for a Livable Future, Johns Hopkins Bloomberg School of Public Health. Appointed by the National Research Council and the Institute of Medicine, they were responsible for making certain that an independent examination of the report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of the report rests entirely with the author committee and the institution. vii

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CONTENTS PREFACE .................................................................................................................................... xiii SUMMARY.....................................................................................................................................1 1 INTRODUCTION ....................................................................................................................13 Background ...............................................................................................................................13 Traumatic Brain Injury..............................................................................................................14 Operation Enduring Freedom and Operation Iraqi Freedom ....................................................15 Charge to the Committee ..........................................................................................................15 Scope of the Report...................................................................................................................15 Organization of the Report........................................................................................................16 References .................................................................................................................................17 2 BIOLOGY OF TRAUMATIC BRAIN INJURY .....................................................................19 Pathobiology of Traumatic Brain Injury ...................................................................................19 Traditional Classifications of Traumatic Brain Injury ..............................................................25 Classification According to Extent of Pathology......................................................................25 Classification According to Biomechanics of Injury ................................................................27 Therapeutics and Traumatic Brain Injury .................................................................................28 Summary of Pathobiology of Traumatic Brain Injury ..............................................................29 Traumatic Brain Injuries Relevant to the Military....................................................................30 Basic Mechanisms of Explosive Injuries ..................................................................................31 Severity Scoring of Blast Injuries and Traumatic Brain Injury ................................................41 References .................................................................................................................................46 3 EPIDEMIOLOGY OF ADULT TRAUMATIC BRAIN INJURY ..........................................59 Incidence of Traumatic Brain Injury.........................................................................................61 Brain Injury Severity.................................................................................................................63 Risk Factors for Traumatic Brain Injury...................................................................................64 Recurrent Traumatic Brain Injury.............................................................................................67 Traumatic Brain Injury and Short-Term Outcomes ..................................................................68 Summary ...................................................................................................................................69 References .................................................................................................................................96 4 CONSIDERATIONS IN IDENTIFYING AND EVALUATING THE LITERATURE .......103 Identification of the Literature ................................................................................................103 Types of Evidence...................................................................................................................104 Inclusion Criteria.....................................................................................................................110 Considerations in Assessing the Strength of Evidence ...........................................................112 Limitations of Studies .............................................................................................................113 References ...............................................................................................................................115 ix

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5 MAJOR COHORT STUDIES ................................................................................................117 General Limitations of Cohort Studies ...................................................................................117 Organization of the Chapter ....................................................................................................118 Military Studies.......................................................................................................................118 Population-Based Studies .......................................................................................................127 Other Cohort Studies...............................................................................................................133 Studies of Sports-Related Traumatic Brain Injury..................................................................140 References ...............................................................................................................................166 6 NEUROCOGNITIVE OUTCOMES ......................................................................................173 Penetrating Brain Injury..........................................................................................................173 Closed Head Injury .................................................................................................................181 References ...............................................................................................................................194 7 NEUROLOGIC OUTCOMES................................................................................................197 Seizure Disorders ....................................................................................................................197 Postconcussion Symptoms ......................................................................................................210 Ocular and Visual Motor Deterioration ..................................................................................224 Endocrine Disorders................................................................................................................227 Neurodegenerative Diseases ...................................................................................................237 Dementia of the Alzheimer Type............................................................................................237 Dementia Pugilistica ...............................................................................................................243 Parkinsonism ...........................................................................................................................246 Multiple Sclerosis ...................................................................................................................251 Amyotrophic Lateral Sclerosis................................................................................................254 References ...............................................................................................................................256 8 PSYCHIATRIC OUTCOMES ...............................................................................................265 Mood Disorders.......................................................................................................................266 Suicide.....................................................................................................................................276 Anxiety Disorders ...................................................................................................................281 Other Psychiatric Outcomes....................................................................................................289 Aggressive Behaviors.........................................................................................................289 Drug and Alcohol Abuse Disorders ...................................................................................291 Psychotic Disorders............................................................................................................292 References ...............................................................................................................................297 9 SOCIAL FUNCTIONING ......................................................................................................301 Primary Studies of Military Populations.................................................................................301 Primary Studies of Civilian Populations .................................................................................303 Secondary Studies ...................................................................................................................307 Summary and Conclusions......................................................................................................314 References ...............................................................................................................................328 10 OTHER HEALTH OUTCOMES ...........................................................................................333 Mortality and Traumatic Brain Injury.....................................................................................333 x

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Primary Studies .......................................................................................................................333 Secondary Studies ...................................................................................................................336 Summary and Conclusions......................................................................................................339 Brain Tumors and Traumatic Brain Injury .............................................................................350 Primary Studies .......................................................................................................................350 Secondary Studies ...................................................................................................................354 Summary and Conclusions......................................................................................................355 References ...............................................................................................................................364 11 CONCLUSIONS AND RECOMMENDATIONS .................................................................367 Quality of the Studies..............................................................................................................367 Overview of Health Outcomes................................................................................................368 Recommendations ...................................................................................................................370 INDEX .........................................................................................................................................373 TABLES AND FIGURES TABLE 2.1 Safety Recommendations for Standoff Distances from Different Types of Exploding Bombs....................................................................................31 TABLE 2.2 Overpressure Effects on Surrounding Materials and Unprotected Persons...............33 TABLE 2.3 Summary of Most Important Body-System Injuries Induced by Concomitant Primary, Secondary, Tertiary, and Quaternary Effects of Blast ............................................34 TABLE 3.1 Glasgow Coma Scales and Glasgow Outcome Scales...............................................70 TABLE 3.2 US TBI Incidence Studies: Case Identification, Data Source, and TBI Severity Scoring ...................................................................................................................................71 TABLE 3.3 Non-US Incidence Studies: Case Identification, Data Source, and TBI Severity Score..........................................................................................................75 TABLE 3.4 US TBI Incidence Studies..........................................................................................79 TABLE 3.5 Non-US TBI Incidence Data......................................................................................81 TABLE 3.6 US TBI Deaths and Mortality Rates ..........................................................................84 TABLE 3.7 Non-US TBI Deaths and Mortality Rates ..................................................................85 TABLE 3.8 Percent Severity Distributions of Hospitalized Patients in US and Non-US Incidence Studies....................................................................................87 TABLE 3.9 Highest Age-Specific TBI Rates and Gender Rate Ratios: US Studies.....................89 TABLE 3.10 Highest Age-Specific TBI Rates and Gender Rate Ratios: Non-US Studies ..........90 TABLE 3.11 Percent Distributions of TBI Incidence Cases by External Cause: US Studies.......91 TABLE 3.12 Percent Distributions of TBI Incidence Cases by External Cause: Non-US Studies .....................................................................................................................92 TABLE 3.13 TBI In-Hospital Case Fatality Rates (CFR) from US Population-Based Studies....93 TABLE 3.14 TBI In-Hospital Case Fatality Rates (CFR) from Non-US Population-Based Studies ......................................................................................................94 TABLE 3.15 Percent Distribution of GOS Outcome Categories at Hospital Discharge Rate for US and Non-US Studies...........................................................................................95 TABLE 5.1 Major Cohort Studies (Shaded) and Derivative Studies ..........................................143 TABLE 6.1 Penetrating Head Injury and Neurocognitive Outcomes .........................................178 TABLE 6.2 Closed Head Injury and Neurocognitive Outcomes ................................................189 TABLE 7.1 Seizure Disorders and TBI.......................................................................................204 xi

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TABLE 7.2 Symptoms After Deployment According to Type of Injury During Deployment..........................................................................................................................211 TABLE 7.3 Frequency of Symptoms on RPCS Questionnaire ...................................................214 TABLE 7.4 Prevalence of Subjective Complaints 5 Years After Injury.....................................216 TABLE 7.5 Postconcussive Symptoms and TBI.........................................................................219 TABLE 7.6 Ocular and Visual Motor Deterioration and TBI .....................................................226 TABLE 7.7 Endocrine Disorders and TBI ..................................................................................233 TABLE 7.8 Dementia of the Alzheimer Type and TBI...............................................................242 TABLE 7.9 Parkinsonism and TBI..............................................................................................249 TABLE 7.10 Multiple Sclerosis and TBI ....................................................................................253 TABLE 8.1 Psychologic Outcomes—Mood-Disorder Studies ...................................................270 TABLE 8.2 Psychologic Outcomes—TBI and Suicide...............................................................279 TABLE 8.3 Psychologic Outcomes—Anxiety Disorder Studies ................................................285 TABLE 8.4 Psychologic Outcomes—Personality Disorder Studies ...........................................294 TABLE 9.1 Social Function ........................................................................................................316 TABLE 10.1 TBI and Mortality ..................................................................................................340 TABLE 10.2 TBI and Brain Tumors ...........................................................................................356 FIGURE 2.1 Pathologic classification of TBI ...............................................................................26 FIGURE 2.2 Classification of TBI based on primary insult..........................................................28 FIGURE 2.3 Potential consequences of blast exposure.................................................................30 FIGURE 2.4 Explosion-induced shock waves...............................................................................32 FIGURE 2.5 Examination and diagnosis algorithm for blast injuries ...........................................36 FIGURE 2.6 Complex mechanisms of blast-induced neurotrauma...............................................37 FIGURE 2.7 Brief Traumatic Brain Injury Screen........................................................................45 xii

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PREFACE The Institute of Medicine (IOM) has a long-standing role of providing assistance to the Department of Veterans Affairs (VA) with regard to veterans’ health. The current series of studies on Gulf War and Health, of which this study is one, began in 1998 when Congress passed two laws on Gulf War veterans’ health in response to the recognition that many Gulf War veterans returning from the 1991 Persian Gulf War were suffering from a multisymptom illness of poorly understood pathogenesis that proved difficult to diagnose and treat. The United States is once again engaged in a military conflict in the Middle East. The conflicts in Afghanistan (Operation Enduring Freedom [OEF]) and in Iraq (Operation Iraqi Freedom [OIF]) have been characterized by a type of combat different from that seen in the 1991 war, in that there have been many more deaths, polytrauma, and traumatic brain injury (TBI). The VA, under authorization granted in the 1998 legislation, has asked IOM to determine long- term health outcomes associated with TBI. TBI has been called the signature injury of OEF and OIF primarily due to blast exposure that is characteristic of this conflict. Exposure to blast might cause instant death, injuries with immediate manifestation of symptoms, or injuries with delayed manifestation. Blast-induced neurotrauma, however, has not been studied sufficiently to confirm reports of long-term effects. That many returning veterans have TBI will likely mean long-term challenges for them and their family members. Veterans will need support systems at home and in their communities to assist them in coping with the long-term sequelae of their injuries. Further, many veterans will have undiagnosed brain injury because not all TBIs have immediately recognized effects or are easily diagnosed with neuroimaging techniques. In an effort to detail the long-term consequences of TBI, the committee read and evaluated some 1,900 studies that made up its literature base, and it developed criteria for inclusion of studies to inform its findings. It is clear that brain injury, whether penetrating or closed, has serious consequences. The committee sought to detail those consequences as clearly as possible and to provide a scientific framework to assist the brave men and women who have fought in OEF and OIF as they return home. We are honored to have been of service. I am deeply appreciative of the expert work of our committee members and their extraordinary commitment to the task at hand. The committee extends its appreciation to the many people who presented information at its open meeting and to the IOM staff. In particular we would like to thank Renee Wlodarczyk, Jen Saunders, and Naoko Ishibe who helped with a myriad of tasks including literature searches, retrieving articles, entering data into the numerous tables in the document, and for their contributions in the development of several chapters of the report. We appreciate Joe Goodman’s attention to our meeting and travel needs; and to Carolyn Fulco for her guidance and oversight. George W. Rutherford, MD, AM Chair, Committee on Gulf War and Health: Brain Injury in Veterans and Long-Term Health Outcomes xiii

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