Neurologic Disease in Women.Pdf

Neurologic Disease in Women

Second Edition

Neurologic Disease in Women

Second Edition

EDITED BY PETER W. K APLAN, MB, FRCP Professor of Neurology Johns Hopkins University School of Medicine and Chairman, Department of Neurology Johns Hopkins Bayview Medical Center Baltimore, Maryland

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Library of Congress Cataloging-in-Publication Data Neurologic disease in women / edited by Peter W. Kaplan. p. ; cm. Includes bibliographical references and index. ISBN 1-888799-85-4 (hardcover : alk. paper) 1. Nervous system—Diseases. 2. Women—Diseases. 3. Sex factors in disease. I. Kaplan, Peter W., 1951– . [DNLM: 1. Nervous System Diseases. 2. Sex Factors. 3. Women’s Health. WL 140 N49157 2006] RC361.N465 2006 616.8'082—dc22

2005016608

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Copyeditor: Joann Woy, Freelance Editorial Services Production/Typesetter: Patricia Wallenburg, TypeWriting Printer: The Maple-Vail Book Manufacturing Group Indexer: Joann Woy, Freelance Editorial Services Dedication

To Nora, Emma, and Alexander, Lenna and Martin, Alexa and Jeffrey, who have been a limitless source of support and inspiration

Contents

Preface xi Acknowledgments xiii Contributors xv

I GENERAL ISSUES IN WOMEN

1. Gender Differences in Diseases of the Nervous System Joan C. Amatniek, Lauren C. Frey, and W. Allen Hauser 3 2. Sex Differences in Regional Brain Structure and Function Susan M. Resnick 15 3. Women’s Lives and Their Experiences with Health Care Aileen MacLaren and Nancy Fugate Woods 27 4. Drug Treatments and Trials in Women Stephen D. Silberstein 41 5. Reproductive and Metabolic Disorders with AED Use Martha Morrell 63 6. Effect of Ovarian Hormones on the Nervous System Pavel Klein and Donald L. Schomer 75 7. Genetic Neurologic Disorders in Females Orest Hurko 91 8. Women, Law, and Neurologic Disease H. Richard Beresford 115

vii viii CONTENTS

II LIFE STAGES AND NEUROLOGIC DISEASE EXPRESSION IN WOMEN

9. Neurologic Disease in Girls S. Lane Rutledge and Holly Mussell 127 10. Menstruation and Pregnancy: Interactions with Neurologic Disease James O. Donaldson III 147 11. Obstetric Issues in Women with Neurologic Diseases Errol R. Norwitz and John T. Repke 151 12. The Menopausal Transition: Changing Physiology, Symptoms, and Hormone Therapy Nancy Fugate Woods 169 13. Frailty in Elderly Women E. Jeffrey Metter 185

III NEUROLOGIC DISORDERS IN WOMEN

14. Migraine Ramesh Khurana 201 15. Seizures and Epilepsy in Women Martha Morrell 219 16. Eclampsia Peter W. Kaplan 235 17. Cerebrovascular Disease in Women Rafael S. Llinas and Carla J. Weisman 247 18. Multiple Sclerosis P. K. Coyle and Mustafa Hammad 265 19. Optic Neuritis Neil R. Miller 283 20. Peripheral Nerve Disease in Women Alan R. Moore, E. Wayne Massey, and Janice M. Massey 297 21. Muscle Disease in Women James M. Gilchrist 315 22. Neurologic Presentations of Autoimmune Disorders in Women Michelle Petri 335 23. Gender Differences in Movement Disorders Yvette M. Bordelon and Stanley Fahn 349 24. Chorea Gravidarum Gretchen L. Birbeck 355 CONTENTS ix

25. Giant Cell Arteritis David B. Hellmann 359 26. The Neurologic Basis of Common Pelvic Floor Disorders Linda Brubaker and J. Thomas Benson 367 27. Infections of the Nervous System in Women David N. Irani 379 28. Neuro-oncological Diseases in Women Alessandro Olivi and John J. Laterra 387 29. Pseudomotor Cerebri Neil R. Miller 393 30. Alzheimer Disease in Women Julene K. Johnson and Kristine Yaffe 411 31. Psychiatric Disorders in Women Angela S. Guarda and Karen L. Swartz 419 32. Nonepileptic, Psychogenic, and Hysterical Seizures Allan Krumholz and Tricia Ting 445

Index 455

Preface

Although a general understanding persists that the important medical issues relating to these populations. Of human brain functions similarly in women and in men, particular concern is the situation of the pregnant woman, an increasing body of knowledge indicates that neuronal for whom the treating physician is often uncertain about connectivity, recruitment, and disease patterns exhibit how to proceed and is in need of information regarding gender differences. Imaging techniques such as positron conditions, diseases, and their treatment—as, for exam- emission computerized tomography (PET) and single ple, in migraine, epilepsy, depression, autoimmune dis- photon emission computerized tomography (SPECT) ease, and other neurologic disorders. Finally, there is the have highlighted some gender-based differences in human elderly woman, whose longer life expectancy now renders brain function. her more vulnerable to dementia and many other medical Clear gender differences are present in genetic problems that may give rise to a condition of physical expression, physiologic function, metabolism, hormonal and/or mental “frailty.” The need for special attention is makeup, and psychosocial profile, which often modify the intensified by the aging of this population and the atten- clinical expression of neurologic and other diseases. In dant problems such as increasing instability of gait, mul- addition, ethnic, cultural, and economic factors are fre- tiple falls, and reliance on supportive care. Much new quently overlooked in dealing with the health problems data have appeared on the risks and benefits of hormone of women, even though they undoubtedly have a strong replacement therapy (HRT) in postmenopausal women. influence on the clinical course of the illness. The World This second edition of Neurologic Disease in Health Organization (WHO) has highlighted a number Women was designed to help physicians and other med- of relevant factors, including women’s lower social and ical personnel seeking information relevant to patient economic status that adversely affect health in early child- care, and to this end is divided into three sections. The hood; in many countries girls receive less food, education, first addresses general anatomic, hormonal, epidemio- and health care than do boys. Each year, half a million logic, and drug aspects of women’s health. The second women die from causes related to pregnancy and child- relates to neurologic conditions that arise during child- birth; 90% of them are in poorer countries. Women carry hood, pregnancy, adulthood, and old age. The third cov- the burden of care within the family, and their health has ers specific neurologic conditions that present differently a strong generational impact on the children they bear or predominantly in females. Because this book is orga- and rear, and hence on society. nized by subject, with the authors’ particular viewpoints, We now have many clinical studies demonstrating some overlap occurs in areas common to several chapters. gender differences in disease prevalence, clinical features, For example, each chapter may discuss medications use- and response to treatment, yet many studies propose sim- ful in particular disorders, but will also address these ilar management and medication guidelines for both issues in chapters on pregnancy and drug treatment tri- sexes. Furthermore, for various reasons, drug trials have als in women. Similarly, particular diseases or gender often avoided including women and children and, in so issues may arise in several chapters, but are further doing, have generated data that fail to enlighten us on focused in the chapter on genetics. I believe that this cross-

xi xii PREFACE

referencing of subject and chapter will permit the reader chapters include reproductive and metabolic disorders to pursue the breadth and depth of neurologic issues in with antiepileptic drug use and movement disorders. Other women. chapters remain relatively unchanged, for example, regard- Important advances in several areas led to the inclu- ing women, law, and neurologic disease, and the effects sion of new chapters, new approaches, and additional of menstruation and pregnancy on neurologic disease. information provided in the chapters on hormonal effects The authors and I hope that this reference text will in women and the use of HRT; the adverse effects of help in a more directed approach to understanding and antiepileptic drugs on hormonal homeostasis, weight, and treating neurologic diseases in women. bone health; and cardiovascular diseases in women. New Acknowledgments

This is a multiauthored and multidisciplinary work. I am grateful to all the contributors for their efforts and patience throughout the rather prolonged revisions of the manuscripts. I would especially like to thank Joyce Caplan, who performed expert secretarial assistance and editing functions on the draft manuscript.

xiii

Contributors

Joan C. Amatniek, MD Yvette M. Bordelon, MD, PhD Visiting Research Associate Assistant Professor Columbia University Department of Neurology G. H. Sergievsky Center and Department of Neurology UCLA Medical Center College of Physicians and Surgeons Los Angeles, California New York, New York and Linda Brubaker, MD Director, Clinical Development Professor and Fellowship Director Alzheimer’s Disease Department of Obstetrics and Gynecology Ortho-McNeil Neurologics, Inc. Female Pelvic Medicine and Reconstructive Surgery Titusville, New Jersey Loyola University Medical Center Maywood, Illinois J. Thomas Benson, MD Clinical Professor, Obstetrics and Gynecology P. K. Coyle, MD Indiana University School of Medicine Professor of Neurology and Acting Chair Director, Female Pelvic Medicine and Reconstructive Department of Neurology Surgery Fellowship SUNY at Stony Brook Indianapolis, Indiana and Director of Stony Brook MS Comprehensive Care Center H. Richard Beresford, MD SUNY at Stony Brook Adjunct Professor of Law Stony Brook, New York Cornell Law School Myron Taylor Hall James O. Donaldson III, MD Ithaca, New York Professor of Neurology and University of Connecticut Health Center Professor of Neurology Farmington, Connecticut University of Rochester School of Medicine Rochester, New York Stanley Fahn, MD H. Houston Merritt Professor of Neurology Gretchen L. Birbeck, MD, MPH Director, Center for Parkinson’s Disease and Other Associate Professor Movement Disorders Departments of Neurology and Epidemiology Columbia University Medical Center Michigan State University Neurological Institute African Studies Center Core Faculty New York, New York East Lansing, Michigan xv xvi CONTRIBUTORS

Lauren C. Frey, MD David N. Irani, MD Instructor Assistant Professor of Neurology Department of Neurology Department of Neurology Anschutz Outpatient Pavilion Johns Hopkins University School of Medicine University of Colorado Health Sciences Center and Denver, Colorado Assistant Professor of Molecular Microbiology and Immunology James M. Gilchrist, MD Johns Hopkins University Bloomberg School of Public Professor of Neurology Health Department of Clinical Neuroscience Johns Hopkins Hospital Brown Medical School Baltimore, Maryland Rhode Island Hospital Providence, Rhode Island Julene K. Johnson, PhD Assistant Professor of Medicine Angela S. Guarda, MD Department of Neurology Assistant Professor of Psychiatry Memory and Aging Center Johns Hopkins University School of Medicine University of California San Francisco and San Francisco, California Director, Eating Disorders Program The Johns Hopkins Hospital Peter W. Kaplan, MB, FRCP Baltimore, Maryland Professor of Neurology Johns Hopkins University School of Medicine Mustafa Hammad, MD and Attending Physician Chairman, Department of Neurology The Brain and Spine Center Johns Hopkins Bayview Medical Center Panama City, Florida Baltimore, Maryland

W. Allen Hauser, MD Ramesh Khurana, MD Professor of Neurology and Public Health– Assistant Professor of Neurology Epidemiology Johns Hopkins University School of Medicine Columbia University Clinical Associate Professor of Neurology G. H. Sergievsky Center University of Maryland and and Department of Neurology Chief, Division of Neurology College of Physicians and Surgeons Union Memorial Hospital Mailman School of Public Health Baltimore, Maryland New York, New York Pavel Klein, MB, BChir David B. Hellmann, MD, MACP Mid-Atlantic Epilepsy and Sleep Center Mary Betty Stevens Professor of Medicine Champlain Building Department of Medicine Bethesda, Maryland Johns Hopkins University School of Medicine and Allan Krumholz, MD Chairman, Department of Medicine Professor of Neurology Johns Hopkins Bayview Medical Center Department of Neurology Baltimore, Maryland University of Maryland Baltimore, Maryland Orest Hurko, MD Assistant Vice President John J. Laterra, MD, PhD AVP Discovery Medicine Professor of Neurology, Oncology & Neuroscience Wyeth Research Johns Hopkins University School of Medicine Collegeville, Pennyslvania and The Kennedy Krieger Research Institute Baltimore, Maryland CONTRIBUTORS xvii

Rafael H. Llinas, MD Martha Morrell, MD Assistant Professor Clinical Professor of Neurology Department of Neurology Stanford University Johns Hopkins University School of Medicine and and Chief Medical Officer Johns Hopkins Bayview Medical Center NeuroPace, Inc. Baltimore, Maryland Mountain View, CA

Aileen MacLaren Loranger, CNM, PhD Holly Mussell, MD Clinical Assistant Professor, Family & Child Nursing Birmingham, Alabama University of Washington School of Nursing Seattle, Washington Errol R. Norwitz, MD, PhD Associate Professor E. Wayne Massey, MD Yale University School of Medicine Clinical Associate Professor of Neurology and and Director of Perinatal Research Clinical Director, MDA Clinics Co-Director, Division of Maternal-Fetal Medicine Duke University Medical Center Department of Obstetrics, Gynecology and Reproductive Durham, North Carolina Sciences Yale–New Haven Hospital Janice M. Massey, MD New Haven, Connecticut Professor of Medicine Division of Neurology Alessandro Olivi, MD Duke University Medical Center Professor and Vice Chairman and Department of Neurosurgery Director, EMG Laboratory Johns Hopkins University School of Medicine Durham, North Carolina Chairman, Department of Neurosurgery Johns Hopkins Bayview Medical Center E. Jeffrey Metter, MD and Medical Officer Director of Neurosurgical Oncology National Institutes on Aging Johns Hopkins Hospital Clinical Research Branch Baltimore, Maryland NIA-ASTRA Harbor Hospital Michelle Petri, MD, MPH and Professor of Medicine Associate Professor Department of Medicine Department of Neurology Johns Hopkins University School of Medicine Johns Hopkins University School of Medicine Baltimore, Maryland Baltimore, Maryland John T. Repke, MD Neil R. Miller, MD Professor and Chairman Professor Neuro-Ophthalmology and Orbital Disease Department of Obstetrics and Gynecology Johns Hopkins University School of Medicine Penn State University, College of Medicine and and Johns Hopkins Hospital Obstetrician-Gynecologist-in-Chief Baltimore, Maryland Milton S. Hershey Medical Center Hershey, Pennsylvania Alan R. Moore, MD Clinical Assistant Professor Susan M. Resnick, PhD Department of Neurology Senior Investigator University of Mississippi Medical Center Laboratory of Personality and Cognition Jackson, Mississippi National Institute on Aging Gerontology Research Center Baltimore, Maryland xviii CONTRIBUTORS

S. Lane Rutledge, MD Tricia Ting, MD Associate Professor of Pediatrics, Neurology, and Assistant Professor Genetics Department of Neurology University of Alabama at Birmingham University of Maryland School of Medicine and Baltimore, Maryland The Children’s Hospital Birmingham, Alabama Carla J. Weisman, MD Faculty Practice Attending Donald L. Schomer, MD Department of Obstetrics and Gynecology Professor of Neurology Sinai Hospital Harvard University Baltimore, Maryland Director Laboratory of Clinical Neurophysiology Nancy Fugate Woods, PhD, RN, FAAN Chief, Comprehensive Epilepsy Program Dean and Professor Beth Israel Deaconess Medical Center University of Washington School of Nursing Boston, Massachusetts Seattle, Washington

Stephen D. Silberstein, MD Kristine Yaffe, MD Professor of Neurology Associate Professor of Psychiatry, Neurology, and Thomas Jefferson University Epidemiology School of Medicine University of California San Francisco Director, Jefferson Headache Center and Thomas Jefferson University Hospital Chief, Geriatric Psychiatry Philadelphia, Pennsylvania University of California San Francisco and San Francisco Veterans Association Medical Center Karen L. Swartz, MD San Francisco, California Assistant Professor of Psychiatry Johns Hopkins University School of Medicine and Co-director, Mood Disorders Program Johns Hopkins Hospital Baltimore, Maryland

GENERAL ISSUES IN WOMEN

Gender Differences in Disease of the 1 Nervous System

Joan Amatniek, Lauren Frey, and W. Allen Hauser

he emphasis on women’s issues in SPECIFICITY FOR WOMEN’S ISSUES neurology and other health fields represents a trend that reflects the The identification of conditions that differentially affect T awareness that a particular disease one gender can alert the provider to altered risk and thus may affect women in a way different from men and that earlier intervention or therapy. This identification not diseases predominantly affecting women have been only allows for the development of gender-specific pre- understudied. Although the management of conditions ventive strategies, but also the development of gender- may vary by gender for biologic and sociologic reasons, specific therapeutic interventions. Although recent more basic questions of epidemiologic interest arise. Are emphasis in this area has been on the uniqueness of the there conditions that are differentially distributed in pop- female gender, the better understanding of factors such ulations by gender, and how do we interpret the differ- as hormonal influences on the disease process will be of ences in distribution to develop meaningful interventions universal benefit. that might be gender-specific? A number of strategies have been used to identify differential disease frequency by gender. None is perfect, and all are open to some criticism. Various levels of cer- CLUES TO OVERALL ETIOLOGY tainty of difference are based upon data source.

Despite the difficulties in interpretation, basic descriptive epidemiologic data are important in hypothesis devel- CLINICAL IMPRESSION opment, both to understand disease processes and develop interventions. Conditions that universally affect We all have impressions of the differential frequency of one gender with greater or lesser frequency suggest that disease based upon our clinical perceptions. This may be some universal biologic factor associated with gender driven by the most recent cases that have been evaluated, functions as a modifier of disease susceptibility or expres- or, for specialists, may be driven by referral patterns. sion. A variation in frequency by gender across studies Although such data are important for hypothesis gener- suggests that gender-specific environmental factors are ation, such data must be considered anecdotal unless con- important in the underlying disease mechanisms. firmed by other strategies.

3 4 NEUROLOGIC DISEASE IN WOMEN

CLINICAL SERIES for medical care than the elderly. For example, the age distribution of patients with Parkinson disease reported Collections of cases from individual clinicians, referral from clinical series from referral centers underenumerates centers, or hospitals may provide somewhat better infor- the proportion in the oldest age groups. This is related mation regarding gender specificity. Despite substantial to referral patterns and the tendency in the elderly not to numbers, conclusions regarding the ratio of male to seek specialized medical care (1). In this same situation, female cases from such collections of cases can be con- in many societies, elderly men are more likely to be siderably flawed. One seldom is aware of the general referred than women. referral base, much less its distribution by gender. Other Many studies of people with epilepsy depend upon important considerations may bias the impressions the identification of cases through clinical neurophysiol- derived from such series. ogy laboratories. The elderly are much less frequently referred for such testing (2). Failure to take these referral patterns into account may in part explain differences in Problems of Referral Bias in the the frequency and gender distribution of epilepsy cases Interpretation of Clinical Series in some studies within the same region (3,4). Thus, an Several examples exist of neurologic conditions for which inappropriate perception of both age and gender distrib- specific patterns of referral are influenced by gender. Table ution may occur in clinical series or epidemiologic stud- 1.1 lists the studies reviewed in this chapter. ies if incomplete methods of ascertainment are used.

Referral Bias: Parkinson Disease or Self-Selection for Medical Care: Epilepsy in the Elderly The Young with Headache A difference clearly exists in health-seeking behavior in Studies of headache identifying differences in health-seek- terms of referral between the elderly and the young. ing behavior between men and women. Women are more Younger individuals are much more likely to be referred likely to seek medical care for this condition than men (5).

TABLE 1.1 Age/Gender Adjusted Incidence (per 100,000 Population) Age Adjusted to the 1990 U.S. Population Unless Otherwise States

LOCATION DURATION MALE FEMALE AGE COMMENTS

STROKE: TOTAL Shiga, Japan (15) 1989–93 189.9 94.1 35 to 85+ *1980 Japanese population Southern Greece (16) 1994–95 362.4 276.1 18 to 85+ *European population Lund–Orup, Sweden (17) 1993–95 194.2 126.2 15 to 85+ *European population Melbourne, Australia (18) 1996–97 153 117 0 to 85+ *“World” population of Segi Hisayama, Japan (19) 1961–93 640 340 40+ *Unidentified “standard” population Bavaria, Germany (20) 1994–98 129.6 101.4 0 to 85+ *WHO standard European population Vittoria, Italy (21) 1991 200.9 194.7 0 to 85+ No. Manhattan, N.Y. (22) 1993–96 204.5 143.8 20 to 85+ No. Manhattan, N.Y. (22) 1993–96 259 222 20 to 85+ Black *1990 US census for No. Manhattan No. Manhattan, N.Y. (22) 1993–96 118 80 20 to 85+ White *1990 US census for No. Manhattan No. Manhattan, N.Y. (22) 1993–96 232 172 20 to 85+ Hispanic *1990 US census for No. Manhattan Belluno, Italy (23) 1992–93 208.2 166.2 <35 to 85+ Shibata, Japan (24) 1977–92 849.3 680.3 40 to 70+ Warsaw, Poland (25) 1991–92 169.2 125.1 <30 to 85+ Malmo, Sweden (26) 1989 165.3 110.8 <45 to 85+ Valle d’Asota (27) 1989 228.6 180.2 <55 to 85+ Fredericksburg, Denmark (28) 1989–90 224.5 132.2 <55 to 85+ Fredericksburg, Denmark (28) 1972–74 164.5 121.4 <55 to 85+ (continued on next page) GENDER DIFFERENCES IN DISEASE OF THE NERVOUS SYSTEM 5

TABLE 1.1 Age/Gender Adjusted Incidence (per 100,000 Population) Age Adjusted to the 1990 U.S. Population Unless Otherwise States (continued)

LOCATION DURATION MALE FEMALE AGE COMMENTS

Umbria, Italy (29) 1986–89 193.2 147.8 <55 to 85+ Dijon, France (30) 1985–86 188.5 101.7 <15 to 85+ Perth, Australia (31) 1986 349.8 164.4 30 to 85+ Soderham, Sweden (32) 1983–86 429.7 395.3 25 to 85+ Soderham, Sweden (32) 1975–78 392.8 285.9 25 to 85+ Auckland, New Zealand (33) 1981–82 204.3 178.7 15 to 85+ Oxfordshire, England (34) 1981–82 177 162 <55 to 75+ STROKE: SUBARACHNOID HEMORRHAGE Shiga, Japan (15) 1989–93 18.0 22.6 35 to 85+ *1980 Japanese population Sweden (35) 1996 6.4 13.5 0 to 85+ ICH and *Swedish population SAH No. Manhattan, N.Y. (22) 1993–96 26.2 3.2 20 to 85+ Black *1990 US census for No. Manhattan No. Manhattan, N.Y. (22) 1993–96 4.9 11.9 20 to 85+ White *1990 US census for No. Manhattan No. Manhattan, N.Y. (22) 1993–96 6.3 15.6 20 to 85+ Hispanic *1990 US census for No. Manhattan Belluno, Italy (23) 1992–93 5.5 4.7 <35 to 85+ Shibata, Japan (24) 1977–92 34.7 42.7 40 to 70+ Valle d’Asota (27) 1989 5.0 5.0 <55 to 85+ *1988 Italian working population STROKE: INTRACEREBRAL HEMORRHAGE Shiga, Japan (15) 1989–93 58.0 47.5 35 to 85+ *1980 Japanese population No. Manhattan, N.Y. (22) 1993–96 37.2 34.9 20 to 85+ Black *1990 US census for No. Manhattan No. Manhattan, N.Y. (22) 1993–96 15.3 10.8 20 to 85+ White *1990 US census for No. Manhattan No. Manhattan, N.Y. (22) 1993–96 44.2 22.0 20 to 85+ Hispanic *1990 US census for No. Manhattan Belluno, Italy (23) 1992–93 33.9 34.8 <35 to 85+ Shibata, Japan (24) 1977–92 94.1 15.9 40 to 70+ Valle d’Asota (27) 1989 22.0 36.0 <55 to 85+ *1988 Italian working population EPILEPSY AND SEIZURES Martinique (36) 1994–95 109.2 57.6 0 to 70+ Provoked and unprovoked seizures Houston, Texas (37) 1988–1994 30.0 30.3 0 to 75+ Epilepsy Umea, Sweden (4) 1992–94 54.1 51.3 17 to 80+ Unprovoked seizures Umea, Sweden (38) 1985–87 67.7 89.7 0 to 15 Unprovoked seizures Rural Iceland (39) 1993 55.2 35 0 to 85+ Epilepsy Geneva, Switzerland (40) 1990–91 90.2 51.9 0 to 80+ Provoked and unprovoked seizures Rural central Ethiopia (41) 1986–90 54.5 41 0 to 70+ Epilepsy El Salvador, Chile (42) 1984–88 101.4 89.7 0 to 60+ Epilepsy Rochester, Minn. (43) 1935–84 49.6 41.5 0 to 85+ Eepilepsy Rochester, Minn. (43) 1975–84 53.3 45.2 0 to 85+ Epilepsy Rochester, Minn. (43) 1935–44 46.9 40.3 0 to 85+ Epilepsy Rochester, Minn. (43) 1935–84 30.4 26.5 0 to 85+ Epilepsy of unknown cause Rochester, Minn. (43) 1935–84 68.6 56.2 0 to 85+ All unprovoked seizures Rochester, Minn. (44) 1935–84 45 27 0 to 75+ Acute *1970 US population Symptomatic seizures Rochester, Minn. (43) 1955–84 53.8 30 0 to 75+ (continued on next page) 6 NEUROLOGIC DISEASE IN WOMEN

TABLE 1.1 Age/Gender Adjusted Incidence (per 100,000 Population) Age Adjusted to the 1990 U.S. Population Unless Otherwise States (continued)

LOCATION DURATION MALE FEMALE AGE COMMENTS

STATUS EPILEPTICUS Rochester, Minn. (45) 1965–84 23.2 13.1 0 to 80+ *1980 US population Western Switzerland (46) 1997–98 12.1 7.8 0 to 75+ *1980 US population Hessen, Germany (47) 1997–99 26.1 13.7 18 to 60+ * German census data SUDEP Midwestern US (48) 1991–96 79.5 108 0 to 80+ * Compared to full cohort population VASCULAR DEMENTIA Canada (49) 1991–96 331.6 111.7 *Compared to undemented cohort population Rochester, Minn. (50) 1985–89 21.7 34.1 50 to 85+ EURODEM (51) 1992–97 31.0 37.4 65–85+ ALZHEIMER DISEASE EURODEM (51) 1992–97 60.7 189.7 65–85+ Rochester, Minn. (52) 1985–89 77.1 155.1 50–85+ Seattle, WA (53) 1994–2002 89.6 193.8 65–85+ Baltimore, MD (54) 1985–98 1000 2200 55–85+ Rural India (55) 1991–99 41.0 86.4 55 to 85+ Stockholm, Sweden (56) 1990–92 912 1943.2 75 to 84 Rochester, Minn. (57) 1980–84 95.7 103.5 0 to 85+ Rochester, Minn. (57) 1975–79 85.3 96.6 0 to 85+ Rochester, Minn. (57) 1970–74 60.6 91.2 0 to 85+ Rochester, Minn. (57) 1965–69 66.8 60 0 to 85+ Rochester, Minn. (57) 1960–64 76.7 78.5 0 to 85+ Cambridge, England (58) Unspecified 1483 3134.9 75 to 85+ Mild + Alzheimer disease Cambridge, England (58) Unspecified 6139 9039.1 75 to 85+ Minimal + Alzheimer disease MILD COGNITIVE IMPAIRMENT Southwest France (59) 1988–98 57.9 37.4 70–85+ MULTIPLE SCLEROSIS Bagheria City, Sicily (60) 1985–94 3.55 5.85 0 to 45+ Catania, Sicily (61) 1975–94 2.31 2.73 0 to 75+ Enna, Italy (62) 1986–95 5.46 6.25 0 to 45+ Sassari, Sardinia, Italy (63) 1965–85 3.6 7.3 10 to 54 Olmsted County, Minn (13) 1905–84 2.8 6.8 0 to 65+ *1950 US white population Rochester, Minn (13) 1905–84 3.4 7.7 0 to 65+ *1950 US white population Perth, Australia (64) 1961–81 0.6 2.2 0 to 85+ New Castle, Australia (64) 1961–81 2.2 2.6 0 to 85+ Hobart, Australia (64) 1961–81 3.5 4.1 0 to 85+ Barbagia, Sardinia, Italy (65) 1961–80 5.4 6.6 10 to 49 PARKINSON DISEASE Ilan County, Taiwan (66) 1993–95 11.1 9.8 40 to 80+ *1970 US census population Washington Heights, N.Y. (67) 1989–91 31.9 10.3 45 to 85+ Black *1990 US census for Washington Heights Washington Heights, N.Y. (67) 1989–91 13.3 11.8 45 to 85+ White *1990 US census for Washington Heights Washington Heights, N.Y. (67) 1989–91 12.2 11.3 45 to 85+ Other *1990 US census for Washington Heights

(continued on next page) GENDER DIFFERENCES IN DISEASE OF THE NERVOUS SYSTEM 7

TABLE 1.1 Age/Gender Adjusted Incidence (per 100,000 Population) Age Adjusted to the 1990 U.S. Population Unless Otherwise States (continued)

LOCATION DURATION MALE FEMALE AGE COMMENTS

Ferrara, Italy (68) 1962–87 9.3 10.7 *Italian standard working population Pozan, Poland (69,70) 1985–86 13 10 0 to 85+ *1970 US population Rochester, Minn. (68,71) 1967–79 25 16 0 to 85+ *1970 US population Turku, Finland (68,72) 1968–70 13 12 0 to 895+ *1970 US population Yonago, Japan (73) 1975–79 159.1 181.3 30 to 80+ MIGRAINE Olmsted County, Minn. (74) 1989–90 192.1 466.9 0 to 85+ Washington County, Md. (75) 1986–87 285.9 1047.6 10 to 21 Migraine with aura Washington County, Md. (75) 1986–87 782.4 1659.5 10 to 21 Migraine without aura Olmsted County, Minn. (76) 1979–81 137.3 284.6 0 to 60+ Migraine PRIMARY INTRACRANIAL TUMORS New York state (77) 1976–1995 0.28 0.18 AA *1970 US census population New York state (77) 1976–1995 1.48 1.05 ANOS *1970 US census population New York state (77) 1976–1995 3.49 2.27 GBM *1970 US census population Valle d’Aosta, Italy (78) 1992–99 17.3 18.5 0 to 85+ Valle d’Aosta, Italy (79) 1986–91 21.62 28.09 0 to 75+ *1988 Italian population AMYOTROPHIC LATERAL SCLEROSIS Western Washington state (80) 1990–95 2.1 1.9 0 to 85+ Parma, Italy (81) 1960–90 0.9 0.6 0 to 70+ Sardinnia, Italy (82) 1971–80 0.6 0.4 0 to 80 + Sardinnia, Italy (82) 1981–90 0.9 0.5 0 to 80+ Harris County, Texas (10) 1985–88 1.8 1.5 15 to 75+ Messina, Italy (10,83) 1976–85 0.9 0.22 0 to 85+ *1970 US population Palermo, Italy (84) 1973–84 0.7 0.4 20 to 79 Minnesota (10,85) 1925–84 2.9 1.9 0 to 85+ *1970 US population Ferrara (110,86) 1964–82 0.6 0.3 0 to 85+ *1970 US population Middle Finland (87) 1976–81 5.7 6.4 40 to 79 Florence, Italy (10,88) 1967–76 0.7 0.5 0 to 85+ *1970 US population Israel (10,89) 1959–74 0.9 0.6 0 to 85+ *1970 US population Mexico (10,90) 1962–69 0.3 0.5 0 to 85+ *1970 US population GUILLAIN–BARRE SYNDROME Harbin, China (91) 1997–98 0.74 0.57 0 to 60+ Emilia–Romagna, Italy (92) 1992–93 1.4 0.7 0 to 70+ Ferrara, Italy (93) 1981–93 2 1.3 0 to 70+ Stockholm County, Sweden (94) 1973–91 1.6 1.4 0 to 80+ Benghazi, Libya (95) 1983–85 2.2 2.5 0 to 60+ PSEUDOTUMOR CEREBRI Rochester, Minn. (96) 1976–90 0.2 1.6 0 to 45+ Benghazi, Libya (97) 1982–89 0.2 6.3 0 to 60+ BELL PALSY Laredo, Texas (98) 1974–82 31.5 37.7 0 to 70+ Rochester, Minn. (99) 1968–82 26.3 28.1 0 to 70+ Rochester, Minn. (100) 1955–67 25 27.6 0 to 70+

Supported in part by NINDS grants. 8 NEUROLOGIC DISEASE IN WOMEN

Thus, if one bases perceptions on data based upon med- headache or movement disorders, population surveys ical contact alone, an erroneous perception of frequency may be necessary. The use of these strategies must be and conceivably age distribution may occur. taken into account when interpreting studies. Unfortu- nately, because of considerations of the expense and time required, few incidence studies of neurologic conditions EPIDEMIOLOGIC CONSIDERATIONS exist. Those that do exist have been done predominately in developed countries. This may lead to some bias in All the potential biases associated with clinical series can interpretation if the age or gender distributions underly- also influence epidemiologic studies. Hopefully, some of ing developed populations in some way differ systemati- these factors are considered in the study design by the epi- cally from those underlying other populations. demiologic investigator. The availability of a denomina- Several design strategies are used in those incidence tor based upon population surveys may provide some studies providing gender-specific data. Each has advan- reassurance of the validity of gender-specific comparisons, tages and disadvantages. but this may not be the case for all comparisons. Historical Cohort Studies Gender and Prevalence The determination of incidence through the retrospec- Prevalence studies exist for most neurologic conditions, tive review of medical records for a defined community but for several reasons, these studies may provide inap- has represented a successful strategy for the determina- propriate conclusions if one wishes to compare gender- tion of incidence. This strategy has been used successfully specific disease frequency. Despite the obvious problems in studies of neurologic disease from Rochester, Min- of need for age adjustment (seldom performed even in the nesota. These studies require medical records from the most sophisticated studies), many other problems arise in entire population at risk, preferably both inpatient and the interpretation of gender-specific prevalence. outpatient. They provide reliable data for conditions likely to require medical attention. Thus, conditions such as stroke or epilepsy can be successfully studied in such Differential Mortality populations, whereas data may be unreliable for condi- Prevalence is a complex measure driven by the influence tions such as migraine. The advantage of these studies is of incidence and duration of illness. If there is differen- the ability to document occurrence and associated factors. tial survivorship by gender [as may exist for amyotrophic The disadvantage is the lack of ability to ask contempo- lateral sclerosis (6) or for epilepsy (7,8), for example], one rary questions. The influence of these studies on changes may come to erroneous conclusions about gender-specific in diagnostic criteria and in disease perception may need frequency. to be taken into account if the data cover a long interval. The possibility of time trends in disease frequency unrelated to technology advancement is also important. This Differential Remission could be gender specific. Not all diseases are life-long. An example of this is epilepsy, in which 65% to 70% of all cases go into remis- Reconstructed Cohorts sion (9). Differential remission by gender could again provide misleading perceptions of the true frequency of the A variation on the historical cohort study is the recon- condition in the sexes. struction of incidence through interview of prevalence cases. For nonfatal conditions, this could be a successful strategy, although one is also at the mercy of recall bias Incidence and inability to verify the condition. These strategies have A much better perception of gender-specific frequency is been used in the study of migraine incidence. provided through the study of newly identified (or incidence) cases. These cases eliminate the potential biases Cross-Sectional Surveys that Provide Incidence associated with differential mortality or disease duration, although they are subject to the same problems of patient Incidence has been determined in cross-sectional studies identification that can cause difficulty in the interpreta- associated with community-based prevalence surveys. Inci- tion of clinical series. For conditions that would invari- dent cases are those with “recent” onset of symptoms. ably require medical attention (amyotrophic lateral scle- These surveys offer the advantage of case verification and rosis, for example), identification through hospital or can be successful in conditions not rapidly fatal, but most medical referrals may be adequate (10). For conditions neurologic conditions require huge populations to provide for which medical care may not be sought, such as useful information, thus making these studies expensive. GENDER DIFFERENCES IN DISEASE OF THE NERVOUS SYSTEM 9

Prospective Studies der-specific incidence must be provided to allow age adjustment to a standard population, or the authors must Prospectively followed cohorts can provide detailed infor- have done such an adjustment. If not specified, age adjust- mation not only on incidence but also on factors associ- ment to the 1990 U.S. population has been performed by ated with onset, which may modify interpretation of inci- us using only the age groups presented by the author. For dence, because targeted data can be collected at the time studies that have provided an age-adjusted incidence, we of onset or of diagnosis of the disease in question. Exam- have tried to designate the standard population and the ples of these studies include the Framingham studies, lim- age groups used for adjustment. All comparisons should ited by a small population, and studies by health main- be made across gender within studies. Comparisons tenance organizations. The latter studies may cause across studies may be made, but the varying age groups difficulties in interpretation because of the selection of included in different studies make such comparisons dif- those included. Data are, in all likelihood, reliable for con- ficult, and these are not the purpose of this paper. Further, ditions affecting healthy young individuals, but unreliable definitions of the disease of interest may vary across stud- for disease associated with poverty or with highest fre- ies and require more interpolation. We do not include quency in the elderly. conditions that are determined through modification of the X or Y chromosomes. Need for Age Adjustment

Regardless of the method of incidence determination, the Stroke need for age adjustment should be obvious, but it is seldom done. If wide variation occurs in the age distribution The age-adjusted incidence of all cerebrovascular disease by gender, crude incidence may be misleading. An exam- is substantially higher in men compared with women ple is the frequency of Parkinson disease in Rochester, across all studies. This finding holds true across racial Minnesota (11). Crude incidence was equal for males and lines in the one study that examined age, sex, and race females, but age-adjusted incidence was 60% higher in together. A review of gender-specific incidence within age males compared with females. Age adjustment is also strata, however, suggests a substantially higher incidence needed to compare disease frequency across populations, in women in the oldest age group (85+). This is true for although this is not the objective of this chapter. many but not all studies. The comparatively small population of that age makes the contribution to the overall age-adjusted figure low. Cumulative Incidence For stroke subtypes other than ischemic, the case for Cumulative incidence may also be used to compare gen- gender specificity is less clear. For both intracerebral and der differences. This may offer some statistical advan- subarachnoid hemorrhage, studies vary in regard to gen- tages, but may also be more difficult to interpret, and may der predominance. For the Northern Manhattan study, be misleading if applied to restricted age groups. which examined age, race, and sex, a male excess of intracerebral hemorrhage existed for each racial group, while a female excess of subarachnoid hemorrhage Gender as a Risk Factor in existed for whites and Hispanics only. Case Control and Cohort Studies Gender may be assessed as a variable in either case con- Convulsive Disorders and Epilepsy trol studies or in cohort studies. The advantage of using gender in this fashion is the ability to control for other Regardless of the definitions used, seizures occur more factors to establish an idea about the independent con- frequently in men than women. This is true for epilepsy, tribution of gender, if any. For example, the age-adjusted status epilepticus, all unprovoked seizures, and sympto- incidence of stroke was 10% higher for men compared matic seizures. The higher incidence of acute symptomatic with women in the Cardiovascular Health Study (12). In seizures in men is not surprising, since most of the con- proportional hazards analysis, the adjusted risk for male ditions associated with this class of seizure are more fre- sex was 0.97, suggesting that other factors measured were quent in men. The male predominance persists after an responsible for differences in incidence. exclusion of cases of epilepsy of presumed cause. A single study has been done to determine the gender-specific incidence of sudden unexplained death in GENDER-SPECIFIC FREQUENCY OF epilepsy patients (SUDEP). This study showed a female SELECTED NEUROLOGIC DISEASES predominance, a finding that should be confirmed with additional studies. For reasons discussed above, we limit our discussion to The cumulative incidence of epilepsy through age 85 data provided by incidence studies. Further, age- and gen- in Rochester, Minnesota was 5% in men compared to 4% 10 NEUROLOGIC DISEASE IN WOMEN

in women. A reversal in epilepsy risk by gender may occur Parkinson Disease in the oldest age groups (over age 75). Incidence studies of Parkinson disease generally suggest a slight male excess, but this is by no means consistent across Alzheimer Disease all studies. In Italy, a slight female excess occurs, and in The age-adjusted incidence of Alzheimer disease is sub- Japan, the female preponderance is substantial. Differences stantially higher in women compared with men across in Washington Heights are mainly attributable to the sub- all studies. A review of gender-specific incidence within stantially greater incidence in black men. The substantial age strata in some studies suggests a slightly higher inci- male excess for “parkinsonism” noted in Rochester, Min- dence in men in the younger age groups (65 to 70). The nesota may be misleading, because it includes cases with overall differences are, therefore, likely driven by a dra- “arteriosclerotic” and “postencephalitic” features. matically higher female incidence with advancing age. Pseudotumor Cerebri Other Dementias Studies of the incidence of pseudotumor cerebri are few Increasing clinical attention has been focused on two other but show a consistent female excess. subtypes of cognitive dysfunction: vascular dementia and mild cognitive impairment. Two studies have now sug- Guillain-Barré Syndrome gested that the incidence of vascular dementia may be higher in women, an unexpected finding given the male Several studies of Guillain-Barré syndrome provide gen- predominance of cerebrovascular disease. One additional der-specific incidence. There seems to be a slight male study from Canada showed a clear male excess in the inci- excess in these studies. dence of vascular dementia, although, in multivariate analysis, gender was not a significant predictor of disease. Bell Palsy The one study that has been done on mild cognitive impairment suggests a male predominance, although, clearly, Few incidence studies of peripheral nerve dysfunction additional studies are needed to confirm this finding. exist. Bell palsy is the only condition for which incidence has been systematically studied and for which gender-specific incidence is available. A slight but consistent female Multiple Sclerosis excess is noted. The difference may be greater in younger Data on the gender-specific incidence of multiple sclero- age groups. sis (MS) are consistent with clinical series and with prevalence studies. A consistently higher incidence of MS Brain Tumor occurs in women than men. This is consistent across age groups. A number of studies of brain tumor incidence using national registries have suggested that brain tumor incidence may be increasing, although this may be a reflec- Migraine tion of the greater use of imaging procedures. Detailed sta- Migraine is a condition that is universally believed to have tistical evaluation fails to confirm this observation—at a female excess. The incidence studies seem to confirm least in the United States (13). In studies in Rochester, Min- this perception. In addition to the studies cited, an inci- nesota, almost 35% of brain tumors are noted incidentally dence study in an HMO reported the cumulative inci- at autopsy. The majority of these incidental tumors were dence between the third and fourth decades of life to be meningiomas (14). No statistically significant increase in 10% in women and 3% in men. When age-specific inci- total incidence over time has occurred in Rochester, Min- dence is evaluated however, incidence is higher in men nesota. The gender-specific differences in incidence of pri- than women in the youngest age groups. The female mary brain tumors varies by tumor type, with a slightly excess is not evident until the teenage years. higher incidence of gliomas and astrocytomas in men. The incidence of mengiomas is consistently higher in women. The age-adjusted incidence of symptomatic brain tumors Amyotrophic Lateral Sclerosis was higher in women in this community. Studies are consistent in showing a male excess; this is true for age-adjusted incidence and for incidence within Other Conditions age groups. The sole exception is a study from Mexico, performed some 30 years ago, in which incidence was Other conditions seem to have a definite gender pre- substantially lower in men than in the other studies. ponderance, such as myasthenia gravis (female excess), GENDER DIFFERENCES IN DISEASE OF THE NERVOUS SYSTEM 11 although there are no studies that allow age adjustment. 12. Manolio TA, Kronmal RA, Burke GL, et al. Short term There may be an increased risk for females in the predictors of incident stroke in older adults. The Car- younger age groups and a male excess in older age diovascular Health Study. Stroke 1996;27:1479–1486. 13. Ahsan H, Neugut AI, Bruce JN. Trends in incidence of groups. primary malignant brain tumors in USA, 1981–1990. Int J Epidemiol 1995;24:1078–1085. 14. Radhakrishnan K, Mokri B, Parisi JE, O’Fallon WM, SUMMARY Sunku J, Kurland LT. The trends in incidence of primary brain tumors in the population of Rochester, Minnesota. Ann Neurology 1995;37:67–73. Women clearly are more frequently affected by MS, 15. Kita Y, Okayama A, Ueshima H, Wada M, Nozaki A, migraine, meningioma, Alzheimer disease, pseudotumor Choudhury SR, Bonita R, Inamoto Y, Kasamatsu T. cerebri, and possibly some conditions of the peripheral Stroke incidence and case fatality in Shiga, Japan nervous system (such as Bell palsy). For cerebrovascular 1989–1993. Int J Epidemiol 1999;28:1059–1065. 16. Vemmos KN, Bots ML, Tsibouris PK, Zis VP, Grobbee disease, generally a male excess exists, although this is DE, Stranjalis GS, Stamatelopoulos S. Stroke incidence not consistent for subarachnoid or intracerebral hemor- and case fatality in southern Greece: the Arcadia stroke rhage. For Parkinson disease, there is a slight but con- registry. Stroke 1999;30:363–370. sistent male excess. For epilepsy, amyotrophic lateral scle- 17. Johansson B, Norrving B, Lindgren A. Increased stroke rosis, and Guillain-Barré syndrome, a definite male excess incidence in Kund-Orup, Sweden, between 1983 to 1985 and 1993 to 1995. Stroke 2000;31:481–486. occurs. These gender-specific differences must be further 18. Thrift AG, Dewey HM, Macdonell RA, McNeil JJ, Don- explored to better understand the underlying patho- nan GA. Stroke incidence on the east coast of Australia: physiologic mechanisms associated with gender and its the North East Melbourne Stroke Incidence Study effect on disease susceptibility or expression. (NEMESIS). Stroke 2000;31:2087–2092. 19. Tanizaki Y, Kiyohara Y, Kato I, et al. Incidence and risk factors for subtypes of cerebral infarction in a general population: the Hisayama study. Stroke 2000;31: References 2616–2622. 20. Kolominsky-Rabas PL, Weber M, Gefeller O, Neundo- 1. Kurland LT, Hauser WA, Okazaki H, Nobrega FT. Epi- erfer B, Heuschmann PU. Epidemiology of ischemic stroke demiologic studies of Parkinsonism with special refer- subtypes according to TOAST criteria: incidence, recur- ence to the cohort hypothesis. Proc Sympos Parkinson’s rence, and long-term survival in ischemic stroke subtypes: Dis. E&S Livingstone, 1970. a population-based study. Stroke 2001;32:2735–2740. 2. Ólafsson E, Hauser WA, Luovigsson P, Gudmundsson 21. Lemolo F, Beghi E, Cavestro C, Micheli A, Giordano A, G. Incidence of epilepsy in rural Iceland. Epilepsia Caggia E. Incidence, risk factors and short-term mortal- 1996:37(10):951–955. ity of stroke in Vittoria, southern Italy. Neurol Sci 3. Forsgren L. Prospective incidence study and clinical char- 2002;23:15–21. acterization of seizures in newly referred adults. Epilep- 22. Sacco RL, Boden-Albala B, Gan R, Chen X, Kargman sia 1990;31:292–301. DE, Shea S, Myunghee CP, Hauser WA and the North- 4. Forsgren L, Bucht G, Eriksson S, Bergmark L. Incidence ern Manhattan Stroke Study Collaborators. Stroke inci- and clinical characterization of unprovoked seizures in dence anong white, black and hispanic residents of an adults: a prospective population-based study. Epilepsia urban community. Am J Epidemiology 1998;147:1–10. 1996;37:224–229. 23. Lauria G, Gentile M, Fassetta G, et al. Incidence and 5. Lipton RB, Stewart WF, Celentano DD, Reed ML. Undi- prognosis of stroke in the Belluno province, Italy. First- agnosed migraine headaches. A comparison of symptom- year results of a community-based study. Stroke based and reported physician diagnosis. Arch Intern Med 1995;6:1787–1793. 1992;152:1273–1278. 24. Nakayama T, Date C, Yokoyama T, Yoshiike N, Yam- 6. Grundman M, Donnenfeld H, Masdeu JC, Hauser WA. aguchi M, Tanaka H. A 15.5-year follow-up study of Do women with ALS present with more severe disease? stroke in a Japanese provincial city. The Shibata Study. Neurology 1992;42:3–16. Stroke 1997;28:45–52. 7. Hauser WA, Annegers JF, Elveback LR. Mortality in 25. Czlonkowska A, Ryglewicz D, Weissbein T, Baranska- patients with epilepsy. Epilepsia 1980;21:399–412. Gieruszak M, Hier DB. A prospective community based 8. Ólafsson E, Hauser WA, Luovigsson P, Gudmundsson study of stroke in Warsaw, Poland. Stroke 1994;25: G. Incidence of epilepsy in rural Iceland. Epilepsia 547–551. 1996:37(10):951–955. 26. Jerntorp P, Berglund Goran. Stroke registry in Malmo, 9. Annegers JF, Hauser WA, Elveback LR. Remission of Sweden. Stroke 1992; 23:356–361. seizures and relapse in patients with epilepsy. Epilepsia 27. D’Alessandro G, Di Giovanni M, Roveyaz L, Ianizzi L, 1979;20:729–737. Compagnoni MP, Blanc S, Bottacchi E. Incidence and 10. Annegers JF, Appel S, Lee RJ, Perkins P. Incidence and prognosis of stroke in the Valle d’Aosta, Italy: first year prevalence of amyotrophic lateral sclerosis in Harris results of a community-based study. Stroke 1992;23: County, Texas, 1985–1988. Arch Neurol 1991;48: 1712–1715. 590–594. 28. Jorgensen HS, Plesner AM, Hubbe P, Larsen K. Marked 11. Rajput AH, Offord KP, Beard CM, Kurland LT. Epi- increase of stroke incidence in men between 1972 and demiology of Parkinsonism: incidence, classification, and 1990 in Frederiksberg, Denmark. Stroke 1992;23: mortality. Ann Neurol 1984;16:278–282. 1701–1704. 12 NEUROLOGIC DISEASE IN WOMEN

29. Ricci S, Celani MG, La Rosa F, et al. SEPIVAC: a com- tors in the Canadian Study of Health and Aging. Stroke munity-based study of stroke incidence in Umbria, Italy. 2000;31:1487–1493. J Neurol Neurosurg Psychiatry 1991;54:695–698. 50. Knopman DS, Rocca WA, Cha RH, Edland SD, Kokmen 30. Giroud M, Gras P, Chadan N, Beuriat P, Milan C, E. Incidence of vascular dementia in Rochester, Min- Arveux P, Dumas R. Cerebral haemorrhage in a French nesota: 1985–1989. Arch Neurol 2002;59:1605–1610. prospective population study. J Neurol Neurosurg Psy- 51. Andersen K, Launer LJ, Dewey ME, et al. Gender dif- chiatry. 1991;54:595–598. ferences in the incidence of AD and vascular dementia: 31. Ward G, Jamrozik K, Stewart-Wynne E. Incidence and The EURODEM studies. EURODEM Incidence outcome of cerebrovascular disease in Perth, Western Research Group. Neurology 1999;53:1992–1997. Australia. Stroke 1988;19:1501–1506. 52. Edland SD, Rocca WA, Petersen RC, Cha RH, Kokmen 32. Terent A. Increasing incidence of stroke among Swedish E. Dementia and Alzheimer disease rates do not vary by women. Stroke 1988;19:598–603. sex in Rochester, Minnesota. Arch Neurol 2002;59: 33. Bonita R, Beaglehole R, North JDK. Event, incidence and 1589–1593. case fatality rates of cerebrovascular disease in Aukland, 53. Kukull WA, Higdon R, Bowen JD, et al. Dementia and New Zealand. Am J Epidemiol 1984;120:236–243. Alzheimer disease incidence: a prospective cohort study. 34. Oxfordshire Community Stroke Project. Incidence of Arch Neurol 2002;59:1737–1746. stroke in Oxfordshire: first years experience of a com- 54. Kawas C, Gray S, Brookmeyer R, Fozard J, Zonderman munity stroke register. British Med J 1983;287:713–717. A. Age-specific incidence rates of Alzheimer’s disease: the 35. Nilsson OG, Lindgren A, Stahl N, Brandt L, Saveland H. Baltimore Longitudinal Study of Aging. Neurology Incidence of intracerebral and subarachnoid hemorrhage 2000;54:2072–2077. in southern Sweden. J Neurol Neurosurg Psychiatry 55. Chandra V, Pandav R, Dodge HH, et al. Incidence of 2000;69:601–607. Alzheimer’s disease in a rural community in India: the 36. Jallon P, Smadja D, Cabre P, Le Mab G, Bazin M. EPI- Indo-US study. Neurology 2001;57:985–989. MART: prospective incidence study of epileptic seizures 56. Lavados J, Germain L, Morales A, Campero M, Lava- in newly-referred patients in a French Carribean island dos P. A descriptive study of epilepsy in the district of El (Martinique). Epilepsia 1999;40:1103–1109. Salvador, Chile, 1984–1988. Acta Neurologica Scand 37. Annegers JF, Dubinsky S, Coan SP, Newmark ME, Roht 1992;85:249–256. L. The incidence of epilepsy and unprovoked seizures in 57. Kokmen E, Beard CM, O’Brien PC, Offord KP, Kurland multiethnic, urban health maintenance organizations. LT. Is the incidence of dementing illness changing? A 25- Epilepsia 1999;40:502–506. year time trend study in Rochester, Minnesota: (1960- 38. Sidenvall R, Forsgren L, Blomquist HK, Heijbel J. A 1984). Neurology 1993;43:1887–1892. community-based prospective incidence study of epilep- 58. Brayne C, Gill C, Huppert FA, et al. Incidence of clini- tic seizures in children. Acta Paediatrica 1993;82:60–65. cally diagnosed subtypes of dementia in an elderly pop- 39. Ólafsson E, Hauser WA, Luovigsson P, Gudmundsson ulation. Cambridge Project for Later Life. Brit J Psychiat G. Incidence of epilepsy in rural Iceland. Epilepsia 1996; 1995;167:255–262. 37(10):951–955. 59. Larrieu S, Letenneur L, Orgogozo JM, et al. Incidence 40. Jallon P, Goumaz M, Haenggeli C, Morabia A. Incidence and outcome of mild cognitive impairment in a popula- of first epilepstic seizures in the canton of Geneva, tion-based prospective cohort. Neurology 2002;59: Switzerland. Epilepsia 1997;38:547–552. 1594–1599. 41. Tekle-Haimamot R, Forsgren L, Ekstedt J. Incidence of 60. Salemi G, Ragonese P, Aridon P, et al. Incidence of mul- epilepsy in rural central Ethiopia. Epilepsia 1997;38: tiple sclerosis in Bagheria City, Sicily, Italy. Neurol Sci 541–546. 2000;21:361–365. 42. Lavados J, Germain L, Morales A, Campero M, Lava- 61. Nicoletti A, Lo Bartolo ML, Lo Fermo S, et al. Preva- dos P. A descriptive study of epilepsy in the district of El lence and incidence of multiple sclerosis in Catania, Salvador, Chile, 1984–1988. Acta Neurologica Scand Sicily. Neurology 2001;56:62–66. 1992;85:249–256. 62. Grimaldi LM, Salemi G, Grimaldi G, et al. High inci- 43. Hauser WA, Annegers John F, Kurland LT. Incidence of dence and increasing prevalence of MS in Enna (Sicily), epilepsy and unprovoked seizures in Rochester, Min- southern Italy. Neurology 2001;57:1891–1893. nesota: 1935–1984. Epilepsia 1993;34(3):453–468. 63. Rosati G, Aieloo I, Mannu L, et al. Incidence of multi- 44. Annegers JF, Hauser WA, Lee JR-J, Rocca WA. Incidence ple sclerosis in the town of Sassari, Sardinia, 1965 to of acute symptomatic seizures in Rochester, Minnesota: 1985: evidence for increasing occurrence of the disease. 1935–1984. Epilepsia 1995;36(4):327–333. Neurology 1988;38:384–388. 45. Hesdorffer DC, Logroscino G, Cascino G, Annegers JF, 64. Hammond SR, McLeod JG, Millingen KS, et al. The epi- Hauser WA. Incidence of status epilepticus in Rochester, demiology of multiple sclerosis in three Australian cities: Minnesota: 1965–1984. Neurology 1998;50:735–741. Perth, Newcastle and Hobart. Brain 1988;111:1–25. 46. Coeytaux A, Jallon P, Galobardes B, Morabia A. Inci- 65. Granieri E, Rosati G, Tola R, et al. The frequency of mul- dence of status epilepticus in French-speaking Switzer- tiple sclerosis in Mediterranean Europe. An incidence land: (EPISTAR). Neurology 2000;55:693–697. and prevalence study in Barbagia, Sardinia, insular Italy. 47. Knake S, Rosenow F, Vescovi M, et al. Incidence of sta- Acta Neurologica Scand 1983;28:84–89. tus epilepticus in adults in Germany: a prospective, pop- 66. Chen RC, Chang SF, Su CL, et al. Prevalence, incidence, ulation-based study. Epilepsia 2001;42:714–718. and mortality of PD: a door-to-door survey in Ilan 48. Walczak TS, Leppik IE, D’Amelio M, et al. Incidence and county, Taiwan. Neurology 2001;57:1679–1686. risk factors in sudden unexpected death in epilepsy: a 67. Mayeux R, Marder K, Cote LJ, et al. The frequency of prospective cohort study. Neurology 2001;56:519–525. idiopathic Parkinson’s disease among middle-aged and 49. Hebert R, Lindsay J, Verreault R, Rockwood K, Hill G, elderly Black, Hispanic and White men and women in Dubois M-F. Vascular dementia: incidence and risk fac- New York City. Am J Epidemiol 1995;142:820–827. GENDER DIFFERENCES IN DISEASE OF THE NERVOUS SYSTEM 13

68. Granieri E, Carreras M, Casetta I, et al. Parkinson’s dis- Rochester, Minnesota: 1925 through 1984. Neuroepi- ease in Ferrera, Italy 1967 through 1987. Arch Neurol demiology 1986;5:61–70. (As cited in Annegers JF, 1991;48:854–857. 1990.) 69. Zhang Z-X, Roman GC. Worldwide occurrence of 86. Granieri E, Carreras M, Tola R, et al. Motor neuron dis- Parkinson’s disease: An updated review. Neuroepidemi- ease in the province of Ferrara, Italy, in 1964–1982. Neu- ology 1993;12:195–208. rology 1988;38:1604–1608. (As cited in Annegers JF, 70. Wender M, Pruchink D, Kowal P, Florezak J, Zalejski 1990.) T. The epidemiology of parkinsonism in the Poznan 87. Murros R, Fogelholm R. Amyotrophic lateral sclerosis region. Przegal Epidemiol 1989;43:150–155. (As cited in middle Finland: an epidemiological study. Acta Neu- in Zhang Z-X.) rol Scand 1983;67:41–47. (As cited in Annegers JF, 71. Rajput AH, Offorf KP, Beard CM, Kurland LT. Epi- 1990.) demiology of parkinsonism: incidence, classification, and 88. Bracco L, Antuono P, Amaducci L. Study of epidemio- mortality. Ann Neurol 1984;16:278–282. (As cited in logical and etiological factors of amyotrophic lateral scle- Zhang Z-X.) rosis in the province of Florence, Italy. Acta Neurol 72. Marttila RJ, Rinne UK. Epidemiology of Parkinson’s dis- Scand 1979;60:112–124. (As cited in Annegers JF, ease in Finland. Acta Neurol Scand 1976;53:81–102. (As 1990.) cited in Zhang Z-X.) 89. Kahana E, Zilber N. Changes in the incidence of amy- 73. Harada H, Nishikawa S, Takahashi K. Epidemiology of otrophic lateral sclerosis in Israel. Arch Neurol Parkinson’s disease in a Japanese city. Arch Neurol 1984;41:157–160. (As cited in Annegers JF, 1990.) 1983;40:151–154. 90. Olivares L, San Estaban E, Alter M. Mexican ‘resistance’ 74. Rozen TD, Swanson JW, Stang PE, McDonnell SK, to amyotrophic lateral sclerosis. Arch Neurol Rocca WA. Incidence of medically recognized migraine: 1972;27:397–402. (As cited in Annegers JF, 1990.) a 1989-1990 study in Olmsted County, Minnesota. 91. Cheng Q, Wang DS, Jiang GX, et al. Distinct pattern of Headache 2000;40:216–223. age-specific incidence of Guillain-Barre syndrome in 75. Stewart WF, Linet MS, Celentano DD, Van Natta M, Harbin, China. J Neurol 2002;249:25–32. Ziegler D. Age and sex-specific incidence rates of 92. Emilia-Romagna Study Group on Clinical and Epi- migaine with and without visual aura. Amer J Epidemiol demiological Problems in Neurology. A prospective 1991;134:1111–1120. study in the incidence and prognosis of Guillain-Barré 76. Stang PE, Yanagihara PA, Swanson JW, et al. Incidence syndrome in Emilia-Romagna region, Italy 1992–1993. of migraine headache, a population based study in Olm- Neurology 1997;48:214–221. sted County, Minnesota. Neurology 1992;42:1657–1662. 93. Govoni V, Granieri E, Casetta I, et al. The incidence of 77. McKinley BP, Michalek AM, Fenstermaker RA, Plunkett Guillain-Barré syndrome in Ferrara, Italy: is the disease RJ. The impact of age and sex on the incidence of glial really increasing? J Neurol Sci 1996;137(1):62–68. tumors in New York state from 1976 to 1995. J Neuro- 94. Jiang GX, de Pedro-Cuesta J, Fredrikson S. Guillain- surg 2000;93:932–939. Barré syndrome in south-west Stockholm, 1973–1991. 78. Cordera S, Bottacchi E, D’Alessandro G, Machado D, Quality of registered hospital diagnoses and incidence. De Gonda F, Corso G. Epidemiology of primary intracra- Acta Neurologica Scand 1995;91:109–117. nial tumours in NW Italy, a population based study: sta- 95. Radhakrishnan K, El-Manghoush A, Gerryo SE. ble incidence in the last two decades. J Neurol Descriptive epidemiology of selected neuromuscular dis- 2002;249:281–284. orders in Benghazi, Libya. Acta Neurol Scand 1987; 79. D’Alessandro G, Di Giovanni M, Iannizzi L, Guidetti E, 75:95–100. Bottachi E. Epidemiology of primary intracranial tumors 96. Radhakrishnan K, Ahlskog E, Shelley A, Kurland LT, in the Valle d’Aosta (Italy) during the 6-year period O’Fallon WM. Idiopathic intracranial hypertension 1986–1991. Neuroepidemiology 1995;14:139–146. (pseudotumor cerebri). Descriptive epidemiology in 80. McGuire V, Longstreth WT Jr, Koepsell TD, van Belle G. Rochester, Minnesota: 1976–1990. Arch Neurol 1993; Incidence of amyotrophic lateral sclerosis in three counties 50:78–80. in western Washington state. Neurology 1996;47:571–573. 97. Radhakrishnan K, Thacker AK, Bohlaga NH, Maloo JC, 81. Bettoni L, Bazzani M, Bortone E, Dascola I, Pisani E, Gerryo SE. Epidemiology of idiopathic intracranial Mancia D. Steadiness of amytrophic lateral sclerosis in hypertension: a prospective and case-control study. J the province of Parma, Italy, 1960–1990. Acta Neurol Neurol Sci 1993;116:18–28. Scand 1994;90:276–280. 98. Brandenberg N, Annegers JF. Incidence and risk factors 82. Giagheddu M, Mascia V, Cannas A, et al. Stroke in a for Bell’s palsy in Laredo, Texas. 1974–1982. Neuro- French prospective populaton study. Neuroepidemiol- epidemiology 1993;12:313–325. ogy 1989;8:97–104. 99. Katusic SK, Beard M, Wiederholt WC, Bergstralh EJ, 83. DeDomenico P, Malara CE, Marabello L, Puglisi RM, et Kurland LT. Incidence, clinical features and prognosis al. Amyotrophic lateral sclerosis: an epidemiological in Bell’s palsy, Rochester, Minnesota: 1968–1982. Annals study in the province of Messina, Italy 1976–1985. Neu- of Neurology 1986;20:622–627. roepidemiology 1988;7:152–158. 100. Hauser WA, Karnes WE, Annis J, Kurland LT. Incidence 84. Salemi G, Fierro B, Arcara A, Cassata M, Castiglione and prognosis of Bell’s palsy in the population of MG, Savettieri G. Amyotrophic lateral sclerosis in Rochester, Minnesota: Mayo Clinic Proc 1971;46: Palermo, Italy: an epidemiological study. Ital J Neurolog 258–264. Sci 1989;10:505–509. 85. Yoshida S, Mulder DW, Kurland LT, Chu CP, Okazaki H. Follow-up study on amyotrophic lateral sclerosis in

Sex Differences in Regional Brain Structure 2 and Function

Susan M. Resnick, PhD

ex differences in human behavior promise of elucidating the neuroanatomic and neurophys- have led to the hypothesis that sex iologic correlates of behavioral differences. A greater under- differences in brain anatomy and standing of sex differences in brain structure and function S physiology contribute to these is important in defining brain–behavior associations and behavioral differences. Behavioral measures for which sex how they are affected by normal aging and disease. In this differences have been reported include some aspects of cog- chapter, we examine the evidence for morphologic and nition and memory (1). For example, men, on average, physiologic sex differences in animal models and in the achieve higher scores on some tests of mathematical rea- brains of neurologically normal individuals to provide a soning ability (2,3) and spatial ability, particularly spatial foundation for understanding the impact of neurologic dis- rotation, the ability to mentally rotate an object in two- ease on brain and behavior in women. or three-dimensional space (4). Conversely, average scores for women are higher on some language tests, such as verbal fluency (1), on some measures of verbal memory (5,6), NEUROANATOMIC SEX DIFFERENCES on tests of verbal articulation (1), and on tests that assess Songbirds and Rodents attention to detail or perceptual speed and accuracy (1,7). Sex differences in hemispheric specialization have also From songbirds to humans, morphologic sex differences been reported, with men showing greater asymmetry for exist in the brain. In songbirds, the sex difference in the both verbal and nonverbal material (8–10). Early studies brain is lateralized and has been linked to a specific behav- suggest that sex differences in brain lateralization become ior: the capacity of males to learn a species-specific song manifest in certain neurologic disorders, particularly (15). The anatomic sex difference and the singing behav- stroke, with men exhibiting more frequent and severe ior are influenced by both hormonal factors, as shown by aphasias following left hemisphere stroke (8,11). However, experimental studies in which hormones are manipulated more recent studies using these indirect approaches to (16), and by seasonal factors, as indicated by cyclical sea- examine brain sex differences offer no consistent evidence sonal variation in brain morphology and singing behav- of sex differences in the incidence, severity, or type of lan- ior (17). Interestingly, recent studies have demonstrated guage disturbance following stroke (12–14). that testosterone implants in the brain can actually induce By offering a direct approach to the study of sex dif- the seasonal-like growth in the neural circuitry underly- ferences in the brain, neuroimaging technology holds the ing singing behavior (18). 15 16 NEUROLOGIC DISEASE IN WOMEN

Similarly, a number of sex differences have been doc- months of age (28,29). Developmental sex differences in umented in rodent brains, most often in regions thought learning abilities (30) and in the effects of selective tem- to be directly involved in rodent sexual behavior and neu- poral lobe lesions on visual discrimination tasks have also roendocrine regulation, such as the preoptic area of the been reported in the rhesus monkey (27). Three-month- hypothalamus. Morphologic and behavioral sex differ- old female monkeys with neonatal lesions show greater ences in rats, mice, guinea pigs, and other rodents are deficits on these tasks than males. This sex difference in highly influenced by neonatal hormones (19–21). The 3-month-old monkeys is influenced by neonatal andro- neonatal administration of testosterone to female rats gen exposure (31). The same lesions in adult monkeys masculinizes brain morphology and increases the proba- produce severe deficits in both males and females (27). bility that females will display male-typical sexual behav- These results are consistent with sex differences in the rate ior as adults (19). Gonadal steroids also influence a num- of maturation and vulnerability to damage of cortical ber of nonsexual behaviors, including maternal behavior, regions associated with specific behaviors. In addition to activity levels, aggression, juvenile play, and learning and sex differences in cortical regions, one MRI-based study memory. For example, early androgen treatment increases of rhesus monkeys showed a larger splenial area in female aggression and activity levels in female rodents. Con- compared to male animals (32), but another postmortem versely, neonatal castration of male rats demasculinizes study found no consistent evidence of sex differences for behavior (21). the corpus callosum in New and Old World monkeys In addition to morphologic sex differences in brain (33). regions mediating sexual behavior, rodent studies of the corpus callosum indicate differences between male and Humans female rats that are influenced by early hormonal manipulation (22,23). Subtle sex differences in the hippocam- Given the frequency with which morphologic sex differ- pus have also been reported that may influence spatial ences are observed in the brains of many species, it is not learning and memory [see McEwen and Alves for more surprising that morphologic sex differences in the human detailed review (24)]. Male rats have a larger dentate brain have also been reported. Early studies of neu- gyrus than females and a greater number of mossy fiber roanatomic sex differences in humans were based on synapses from granule neurons in the dentate gyrus. Sex postmortem examination of gross anatomic differences. differences are apparent also in the density and branch- Men were reported to have a larger preoptic area of the ing of dendrites of CA3 pyramidal neurons, with male hypothalamus (34,35). Men were also more likely to be rats having more excrescences for CA3 mossy fiber con- missing the massa intermedia, a midline structure tacts and females having greater branching of CA3 api- between the right and left thalamus that is not present cal dendrites. Some of these anatomic differences can be in all individuals (36). Table 2.1 lists general sex-related modulated by neonatal hormonal manipulation or differences between men and women, in brain structure changes in the rearing environment. In addition, hor- and function. monal manipulations influence sex differences in spatial More recently, advances in neuroimaging techniques learning ability using a Morris water maze. Neonatal have allowed the noninvasive study of the human brain testosterone administration to female rats improved spa- in vivo, initially using computed tomography (CT) and tial learning performance, whereas neonatal castration of later magnetic resonance imaging (MRI). MRI provides male rats produced female typical spatial learning. excellent resolution and high contrast among gray mat- Because testosterone is aromatized to estradiol in the ter, white matter, and cerebrospinal fluid (CSF), thus per- brain, testosterone’s effects on behavior may reflect either mitting the quantification of increasing numbers of brain androgen or estrogen effects on spatial learning. regions as both image acquisition and processing techniques advance. In fact, current advances in automated image analysis provide the capability for quantitative Nonhuman Primates MRI studies in large epidemiologic investigations. Sex differences have been demonstrated in the brains of To date, a number of sex differences in brain struc- nonhuman primates. Sex differences exist in the dendritic ture have been reported through the quantification of a structure of the preoptic area of juvenile macaque mon- limited number of brain areas, although several recent keys (25) and in the maturation of the orbital frontal cor- studies have examined differences throughout the brain. tex (26) and temporal lobe of rhesus monkeys (27). At 75 In this section, we focus primarily on sex differences in days of age, males, but not females, with orbital frontal the adult brain [see Durston (37) for a comprehensive lesions showed deficits on an object discrimination rever- review of sex differences earlier in development]. Earlier sal task, sensitive to damage in this region. These sex dif- studies of structural differences between the male and ferences were dependent on perinatal androgen exposure female brain focused on more global regions or specific (26) and were not evident in monkeys tested after 18 brain structures through the manual or semiautomated SEX DIFFERENCES IN REGIONAL BRAIN STRUCTURE AND FUNCTION 17

TABLE 2.1 Sex Differences in Brain Structure and Function: Selected Findings in Humans*

Brain structure: Cerebrum Larger in males Cerebellum Larger in males* Preoptic area of hypothalamus Larger in males Massa intermedia More likely to be missing in males Corpus callosum Splenium larger in females* Corpus callosum Isthmus larger in females* Planum temporale Greater asymmetry in males* Ventricular volume Relative size larger in men, particularly in elderly* Sulcal volume Relative size larger in men, particularly in elderly Brain Function: EEG: Beta and theta activity Higher in females Alpha activity Higher in males ERP: P300 Shorter latency and greater amplitude in females PET, SPECT, and 133Xenon techniques: Global cerebral blood flow Higher in females Global cerebral glucose metabolism Higher in females* Regional distribution of glucose Higher relative activity in males in lateral and ventro-medial temporal metabolism and CBF lobe, hippocampus, inferior frontal regions, and cerebellum Higher relative activity in females in posterior and middle cingulate and parietal regions Higher absolute glucose metabolic rates in males in hippocampus but lower absolute rates in thalamus# Functional MRI (most based on single study): Phonological processing Greater left hemisphere lateralization in males and more symmetric activation in females Passive listening Greater asymmetric activation of anterior and posterior temporal regions in men Lexical visual field task Greater left-lateralized activation in inferior frontal and fusiform gyrus in men and more symmetric activation in language areas in women Working memory Women show greater left lateralization and men more bilateral or right- lateralized Odor identification Greater activation of frontal and perisylvian regions in women Mood induction negative affect Right-lateralized amygdala activation in men but not women Neuroreceptor systems (most findings based on single study): Dopamine Greater decline of striatal D2-dopamine receptors with age in women Greater striatal uptake of 18F-fluorodopa in women Greater striatal dopamine transporter availability in women Higher binding potentials for D2-like receptors in the frontal cortex for women Serotonin Greater 5HT2 receptor binding in men than women, most pronounced for frontal and cingulate cortex Greater binding in women for the 5HT1A receptor in the dorsal raphe, amygdala, cingulate gyrus and prefrontal cortex Higher rates of serotonin synthesis in men than women Mu opioid system Men had greater activation in anterior thalamus, ventral striatum, and amygdala in response to sustained pain

*Findings are often inconsistent, but summary statement reflects the direction of effect in studies reporting sex differences #Results of a single study 18 NEUROLOGIC DISEASE IN WOMEN

definition of specific regions of interest (ROIs). Evidence replicate these results in post-mortem investigations of exists that both younger (38) and older men (39) have adults (48,49) and children (50). larger brains than women of comparable ages, even after The capacity for detailed in vivo visualization of the adjusting for variability in height. Although Nopoulous corpus callosum has led to many more recent studies of and colleagues reported similar sex differences for frontal, sex differences in size of the corpus callosum, with incon- parietal, temporal, and occipital lobes in younger indi- sistent findings across studies (46,51). For example, a viduals, Resnick and colleagues found that sex differences larger callosal isthmus in females but no sex difference in older adults were greater for frontal and temporal than in splenial area was reported in autopsy (52) and MRI parietal and occipital regions. Sex differences in brain vol- (53) studies. Similarly, findings from studies of the effects ume are apparent for the cerebrum, but are inconsistent of sex on the association between age and callosal size are for the cerebellum (38,40). inconsistent. In an autopsy sample, Witelson (54) Sex differences have also been reported for more reported significant negative correlations between age and specific regions. Gur and colleagues (41) found larger vol- total callosal area in 23 men aged between 26 and 69 umes of orbital frontal regions in young women com- years old but no significant association in 39 women aged pared with men, but similar volumes of hippocampus, 35 to 68 years. In contrast, other investigators have not amygdala, and dorsal frontal prefrontal cortex. Pujol and found sex differences in the association between age and colleagues (42) reported that young men had a larger MRI-assessed callosal size in adults (51,55–57). In an anterior but not posterior cingulate cortex on the right. MRI study of children aged 4 to 18 years, callosal size Several recent studies have used voxel-based analy- increased with age, but there were no differences between sis to investigate sex differences throughout the brain. In males and females (58). this approach, each individual MRI is elastically It has been suggested that the varied findings across deformed (through expansion and contraction) to a stan- studies may reflect the way in which sections of the cal- dard template MRI or average MRI, transforming all losum are divided for measurement (36,59) and that there brains to a standard stereotaxic coordinate space. Using may be sex differences in the shape but not size of the cor- software, such as Statistical Parametric Mapping (43), dif- pus callosum (36). Another issue is that some authors ferences between groups of subjects can be investigated examine sex differences in callosal regions, adjusted for for each voxel in the standardized space. In a large study brain volume. Because males have larger brains than of 465 normal adults, ranging from 18 to 79 years of age, females, it is important to investigate whether sex differ- Good and colleagues (44) used voxel-based morphome- ences occur in the relative size of callosal subunits after try (VBM) to examine sex differences throughout the adjusting for variability in total brain or callosal volume. brain. Adjusting for global volumes, they found greater Davatzikos and colleagues (60) applied an earlier gray matter volumes for women compared with men in version of voxel-based morphometry to the analysis of the regions adjacent to the banks of the central sulci, in sex differences in corpus callosum morphology. This the right Heschl’s gyrus and planum temporale, in right deformation-based method avoids many of the draw- inferior frontal and frontomarginal gyrus and in the cin- backs of previous methods and allows the examination gulate gyrus, and greater white matter volumes bilater- of size and shape differences, separately. Using an elastic ally in the posterior frontal regions and in the right tem- deformation, each point on an individual’s corpus callo- poral stem. Conversely, men had increased gray matter sum is mapped with reference to a standard atlas of the volumes bilaterally in the mesial temporal lobes, entorhi- callosum, and a coefficient—the deformation function— nal and perirhinal regions, and in the anterior lobes of the is calculated for each point. The deformation function for cerebellum, and greater white matter volumes bilaterally each point describes the relative shrinkage or expansion in the anterior temporal white matter extending into the of the structure for that point; that is, how much each internal capsules. individual’s corpus callosum must be warped to move into One region that has received much attention in spatial registration with the corpus callosum of the atlas. investigations of morphologic sex differences in the The deformation functions can then be averaged for human brain is the corpus callosum, perhaps due to impli- groups of subjects, and differences between groups can cations of callosal size for interhemispheric transfer of be calculated to reflect average differences in the shrink- information and hemispheric specialization. In 1982, age or expansion at each point of the structure. Illustrat- DeLacoste-Utamsing and Holloway (45) reported that ing this technique on MRIs from eight men and eight adult women had a more bulbous splenium—the poste- women, who are participants aged 60 to 85 years in the rior portion of the corpus callosum—in a study based on Baltimore Longitudinal Study of Aging (BLSA), we found post-mortem samples of 14 brains. While the finding of significantly larger splenial size in women as well as sex a larger splenial area in females was replicated (46) and differences in average callosal shape. This finding was extended to the fetal corpus callosum (47) by the same extended and confirmed in a larger sample of 114 right- research group, other investigators have been unable to handed participants in the longitudinal neuroimaging SEX DIFFERENCES IN REGIONAL BRAIN STRUCTURE AND FUNCTION 19 study of the BLSA (61). In the larger sample, we also longitudinal investigation of brain changes in the BLSA. found significant positive associations between cognitive Sex differences in brain aging have been reported performance and splenial size in women, but no such throughout the lifespan. In an MRI study of children and associations for men (Figure 2.1). Greater interhemi- adolescents aged 4 to 18 years, Giedd and colleagues (69) spheric connectivity may be more essential to perfor- reported larger cerebral and cerebellar volumes, even after mance in women than men due to their greater reliance adjusting for height and weight, in males compared with on the bilateral processing of information. females. In addition, after adjusting for cerebral volume, Sex differences have also been reported in other the putamen and globus pallidus were larger in males than types of MRI-based measures. A greater percentage of females, whereas the volume of the caudate nucleus was gray matter compared with white matter was found in larger in females. In males only, the regression of brain one study of young women compared with men (using volumes on age revealed a significant positive slope for proton density/T2-weighted images) (62), but higher con- the lateral ventricles, suggesting increases with age, and trast volumetric images did not support this finding in negative slopes for the caudate and putamen, suggesting other samples (39,63). Sex differences have also been decreases with age. found in tissue contrast and signal intensities on MRI Early cross-sectional CT (70) and MRI (71,72) stud- (64), thus reflecting qualitative differences in tissue com- ies of adults aged 20 to 80 years indicated greater brain position. In two large samples of older adults, women had atrophy, as indexed by increased CSF volumes, in older more extensive evidence of white matter signal abnor- compared with younger individuals. Although these early malities (65) and nonsignificant trends toward more fre- studies suggested the possibility of greater and earlier quent subcortical and periventricular white matter lesions increases in atrophy in men compared with women, sex (66). A study of chemical shift imaging in a large sample differences in age-associated increases in ventricular of elderly individuals revealed sex differences in levels of and/or sulcal volumes were not significant. More recent creatine, N-acetylaspartate, and choline in some brain MRI and CT studies have shown significant sex differ- regions (67). ences in the effects of age on brain atrophy. Gur and col- CT and MRI have also allowed the investigation of leagues (73) reported a significant influence of sex on age sex differences in age-associated brain changes (68). The differences in MRI-assessed CSF volumes. Older individ- majority of studies of the influence of sex on brain aging uals (aged 55–80 years) had more CSF than younger indi- have been cross-sectional, although as noted above, our viduals (aged 18–54 years), and this difference was group at the National Institute on Aging is conducting a greater for men, particularly for sulcal CSF. In a CT study

FIGURE 2.1

A. Sex differences in corpus callosum morphology. Regions in white depict areas of the corpus callosum that are larger in women than men, p<0.0001. B. Correlations between the deformation functions and five neuropsychologic tests for women (top row) and men (bottom row). White regions show points of significant positive correlations, p<0.05. The five tests are: Card Rotations (CR), Figural Recognition Memory (FRM), Verbal Recognition Memory (VRM), Boston Naming Test (BNT), and Let- ter Fluency (LF). Greater callosal size, particularly in the splenial region, is associated with better cognitive performance in women only. Effects are adjusted for sex differences in total callosal size. Adapted from Davatzikos and Resnick (61). 20 NEUROLOGIC DISEASE IN WOMEN

of ventricular volumes, sex differences in lateral ventric- for the planum temporale, whereas women showed a ular volume, adjusted for cranial volume, were demon- more symmetric and less consistent pattern (85). This strated for each decade from the 20s to the 80s (74). MRI- finding was not replicated in one study of 40 post-mortem based ratings of ventricular and sulcal atrophy on 3,660 brains (20 men, 20 women) (86), which reported sex dif- community-dwelling individuals aged 65 years and older ferences in the bifurcation patterns of the sylvian fissure. (65) in the Cardiovascular Health Study are consistent The availability of high-resolution MRI and new image with greater atrophy in older men compared with women. processing techniques has facilitated the investigation of Greater age differences for men compared with women larger samples to clarify sex differences in brain asym- were also reported for quantitative volumes of sulcal and metries. Applying voxel-based analysis to a large sample Sylvian fissure CSF in a subgroup of this elderly sample of subjects (described above), Good and colleagues (44) (68). In summary, most CT and MRI studies examining replicated the greater leftward asymmetry of tissue vol- CSF as an index of brain atrophy have found greater age ume in the region of Heschl’s gyrus and the planum tem- effects on CSF volumes in men than women. porale for men versus women. Sex differences in the effects of age on other brain regions have also been explored. Cowell and colleagues (75) quantified frontal and temporal volumes from MRI SEX DIFFERENCES IN REGIONAL images of 96 younger (aged 18–40 years) and 34 older BRAIN PHYSIOLOGY (aged 41–80 years) adults. These investigators reported greater differences between age groups for men than A number of physiologic techniques have been employed women, with older individuals having lower volumes in to assess sex differences in brain function. These include both regions. Murphy and colleagues (76) reported sex electroencephalography (EEG) and evoked potentials, effects on age differences in frontal, parietal, temporal, 133Xenon inhalation and single photon emission com- and hippocampal volumes. Consistent with the findings puted tomography (SPECT) measures of regional cerebral of Cowell and colleagues, decreases in frontal and tem- blood flow (rCBF), and positron emission tomography poral volumes in older, compared with younger, subjects (PET) to measure regional cerebral glucose metabolism, were greater in men than women. Conversely, decreases rCBF, and neuroreceptor distribution, and functional in parietal and hippocampal volumes in older subjects MRI (fMRI) to measure blood volume and oxygenation were greater in women. However, it is important to note changes. that hippocampal volumes were actually greater in younger women than younger men and were not signifi- EEG cantly different among older men and women. In a large sample of Japanese subjects, men showed greater age- Sex differences in some EEG parameters have been related decreases in tissue volume than women in the pos- described in young (87) and elderly (88) individuals. The terior right frontal lobe, right temporal lobe, left basal most consistent findings in the literature are greater spec- ganglia, and bilaterally in the parietal lobe and the cere- tral power and increased beta and theta activity in bellum (77). More recently, Gur and colleagues (78) women, and increased alpha activity in men (88,89). In showed that sex differences in age effects on some brain studies of healthy elderly adults, these sex differences are regions may emerge early in adulthood. In a sample rang- consistent across different age groups (88). Sex differing in age from 18 to 49 years, they found greater age ences are commonly found in sensory evoked potentials effects in men than women for cortical gray matter, most (ERPs), with women showing shorter latencies (90–92). pronounced for dorsolateral prefrontal regions. Further Similar findings have been reported in event-related delineation of sex differences in age effects on specific potential studies involving simple attentional activation regional brain volumes awaits further investigation in tasks. Although sex effects are not commonly analyzed, larger samples with more sophisticated image processing a number of studies reported sex differences in the ampli- methods. tude and latency of the P300, with women showing In addition to the investigation of morphologic sex greater amplitude and shorter latency than men (93,94). differences in specific brain volumes, sex differences in It has been argued that sex differences in skull thickness neural asymmetry have also been reported in animals and or myogenic activity (95), head size or core body tem- humans (79,80). For example, the planum temporale, a perature (91), and limb and trunk size could account for superior temporal brain region involved in language func- these sex-related effects in evoked potentials. tion, is thought to be greater on the left than right side Sex differences in EEG activity elicited by more com- of the human brain in right-handed individuals (81,82). plex activational tasks have also been reported. In a study It has been reported that this asymmetry may depend on of continuous recognition performance, Erwin and col- sex (83,84). In one MRI study of 24 adults (12 men, 12 leagues found that women showed greater hemispheric women), men typically had greater left than right areas asymmetry of activation than men did, in both verbal and SEX DIFFERENCES IN REGIONAL BRAIN STRUCTURE AND FUNCTION 21 spatial tasks (95). Interestingly, these results paralleled perfusion. In a sample of adults ranging in age from 20 findings of sex differences in rCBF in a study involving a to 81 years, voxel-based analysis demonstrated signifi- similar activation task (96). Others, however, have failed cantly greater perfusion for women in the right parietal to find hemispheric differences in similar activation tasks, lobe and for men in anterior temporal, inferior frontal, and instead have found sex differences in the effects of and cerebellar regions (106). Using a different approach test material (i.e., figural or spatial) on the spatial topog- to image analysis in a study of individuals between the raphy of brain activity (94). Overall, sex differences in ages of 50 and 92 years, women were found to have EEG during the performance of complex cognitive tasks higher regional perfusion in the mid-cingulate/corpus cal- are less consistent than those focusing on baseline sex dif- losum, inferior temporal, and inferior parietal areas ferences. (107). In addition to sex differences in regional metabolism, sex differences in interregional correlations have also Global Cerebral Blood Flow and been reported (104), suggesting different patterns of Glucose Metabolism neural connectivity during a resting state for men and Higher CBF throughout the gray matter in females com- women. pared with males has been a consistent finding in 133Xenon topographic studies (96,97) and SPECT (98,99) Brain Activation in Response to studies of rCBF. Findings of increased levels of global Cognitive Challenge brain activity in females also received support from two studies examining gender differences in regional cerebral The examination of sex differences in regional brain activ- glucose metabolism, using 18F-fluorodeoxyglucose (FDG) ity during the performance of specific cognitive tasks has and PET. Baxter et al. (100) and Yoshii et al. (101) found been facilitated by PET studies using oxygen-15-labeled higher cerebral metabolic rates for glucose in females water to measure rCBF and developments in fMRI imag- compared with males, although the latter authors argued ing, which allow the measurement of changes in blood that differences in brain volume accounted for the sex dif- oxygenation as an index of changes in brain activity. In ferences in metabolism. Other investigators have reported an early study using the 133Xenon clearance technique to no significant sex differences in global cerebral glucose measure cortical blood flow, Gur and colleagues found metabolism (76,102–104) or nonsignificant trends to sex differences in hemispheric activation patterns during higher metabolism in women (105). the performance of verbal analogies and spatial judgment of line orientation tasks (96). Applying an adapted version of these tasks for use in an fMRI paradigm, this PET/SPECT Studies of Regional Distribution of group reported sex differences in hemispheric lateraliza- Brain Activity during a Resting Condition tion in response to the spatial but not verbal task (108). Gur and colleagues (103) reported sex differences in the The expected left hemispheric lateralization for the ver- regional distribution of cerebral metabolic activity dur- bal task was found in the inferior parietal and planum ing a resting state in a sample of 61 younger individuals temporale regions in both men and women, but only men (mean ages: 27.3 Ϯ 6.5 and 27.7 Ϯ 7.4 years for 37 men showed the right lateralized increase for these regions dur- and 24 women, respectively). Relative metabolism ing the spatial task. These findings contrasted somewhat (regional radioactivity count rates divided by counts for with an earlier fMRI study demonstrating greater hemi- the whole brain) did not differ between men and women spheric specialization for language in a group of young for nonlimbic frontal, parietal, and occipital regions. In men compared with women (109). Although men showed contrast, men had higher relative metabolism in tempo- highly lateralized increases in activity in the left inferior ral cortex, hippocampus, parahippocampal gyrus, insula, frontal gyrus during phonologic processing, women inferior frontal regions, the putamen, and the cerebellum, showed bilateral activation of this region during task per- whereas women had higher relative metabolism in the formance. The phonologic processing and verbal analo- middle and posterior cingulate gyrus. Conversely, in a gies tasks employed in the two studies, however, involved sample of 55 men and 65 women over a broader age different task demands and brain regions responsive to range (mean 54 Ϯ 22 years for men and 52 Ϯ 23 years these tasks. for women), Murphy and colleagues (76) found greater Other sex differences in the aspects of language hippocampal metabolism in old but not young men com- processing include more asymmetric activation of the pared with women, suggesting sex differences in the effect anterior and posterior temporal region (110,111) in men of age on hippocampal glucose metabolism. versus women during passive listening tasks, greater left- Studies using SPECT and 99mTc-ECD or 99mTc- lateralized activation in inferior frontal and fusiform HMPAO to measure regional perfusion have also demon- gyrus in men, and more symmetric patterns in language- strated sex differences in the regional pattern of cerebral related areas in women during a lexical visual field task 22 NEUROLOGIC DISEASE IN WOMEN

(112). Sex differences have also been reported in the func- the luteal phase. Nordstrom and colleagues, however, tional organization of the brain for working memory found no differences in raclopride binding to striatal D2- (women show left lateralization across a number of tasks dopamine receptors across the menstrual cycle (124). and men show more bilateral or right-sided activation) Menstrual cycle variation in neurotransmitter receptor (113); spatial navigation (activation of the left hip- binding characteristics, an area that has received little pocampus in males and right parietal and prefrontal cor- attention, has important implications for the efficacy of tex in females) (114); odor identification (greater spatial pharmacotherapies in women. extent of activation of frontal and perisylvian regions in More recently, additional sex differences in the women) (115), and primary visual cortex response to red dopamine system have been described. In a PET study and blue light (116). using 18F-fluorodopa as a radiotracer, women had sig- The use of neuroimaging techniques to investigate nificantly higher striatal uptake of fluorodopa than men, sex differences in brain activation patterns has yielded a with the difference more pronounced in the caudate than variety of often conflicting findings. The results of these putamen (125). Using SPECT and a technetium99m studies must be interpreted within the context of the spe- labeled analog of cocaine (TRODAT-1) to measure the cific samples studied (e.g., young versus older) and the availability of the dopamine transporter, women had particular task demands of the activation and control higher availability than men in the caudate nucleus (126). tasks employed in each paradigm. Because the statistical Furthermore, dopamine transporter availability was asso- analysis of these studies is typically based on image sub- ciated with executive and motor functioning in women traction or another form of direct comparison between but not men. In another study of the dopamine trans- activation and control tasks, the demands of the latter are porter (using 123IB-CIT and SPECT), women had higher as critical in determining the result as the particular acti- uptake than men in the striatum, diencephalon, and vation task. brainstem (127). New radiotracers also allow the investigation of extrastriatal dopamine receptor activity. Using 11C-FLB475, women had higher D2-like receptor bind- Brain Activation in Response to ing potentials than men in the frontal cortex, most pro- Emotional Stimuli nounced in bilateral anterior cingulate cortex (128). Thus, Sex differences have also been reported in neural activity a number of studies support greater dopaminergic activ- during receptive and expressive emotion. Using a mood ity in both striatal and extrastriatal cortical regions in induction paradigm and fMRI, Schneider and colleagues women, and these sex differences in neurotransmitter (117) found increased right amygdala activity in men but activity in healthy individuals may have important impli- not women during negative affect. Different patterns of cations for the pathophysiology and treatment of neu- brain activation for men and women have also been ropsychiatric diseases involving the dopamine system. reported for tasks tapping receptive emotions, with sex Although sex differences in dopaminergic activity differences in activation during the discrimination of have been the most widely studied in humans, several happy, sad, and neutral faces (118,119). Sex differences recent studies suggest that there may also be sex differ- in activation patterns have also been observed during the ences in other neurotransmitter systems. Using PET and retrieval of emotional words (120) and during the encod- 18F-altanserin, Biver and colleagues found greater 5HT2 ing of emotional pictures (121). receptor binding in men than women in a number of cortical regions, most pronounced in frontal and cingulate cortex. However, using PET and 11C-WAY-100635 to Neurotransmission measure serotonin 5-HT1A binding potential, Parsey and Few in vivo studies have been done of sex differences in colleagues reported greater binding in women compared brain neurotransmitter levels and receptor binding dis- with men in the dorsal raphe, amygdala, cingulate gyrus, tributions. In an early study using PET and 11CN-methyl- and prefrontal cortex (129). The rates of serotonin syn- spiperone (11C-NMSP) as a radiotracer, Wong and col- thesis, measured with PET and alpha-11C-methyl-trypot- leagues (122) reported sex differences in the rate of phan, were higher in men than women (130). Sex differ- decline with age in D2-dopamine receptor binding. Males ences in the regional activation of the mu opioid system had a steeper slope or decline with age than females for in response to sustained pain have also been observed D2 dopamine receptor binding, but no sex differences (131). Men had greater activation than women (during occurred in association with age for serotonin binding follicular phase) in the anterior thalamus, ventral basal using this tracer. Preliminary PET 11C-NMSP studies of ganglia, and amygdala, whereas women showed reduced D2 dopamine receptor binding in women over the men- activation in the nucleus accumbens in a basal state dur- strual cycle suggested cyclic variation in dopamine binding pain. For comparable levels of pain intensity, men and ing (123). In a small sample of six women, dopamine women differed in the response of the mu opioid system receptor binding tended to increase from the follicular to in specific brain regions. The majority of in vivo studies SEX DIFFERENCES IN REGIONAL BRAIN STRUCTURE AND FUNCTION 23 of neurotransmission have been performed in younger eferences individuals and do not address sex differences in neuro- R transmitter systems in older adults or differential aging 1. Maccoby EE, Jacklin CN. The Psychology of Sex Dif- for men and women. ferences. Stanford: Stanford University Press, 1974. 2. Benbow CP, Stanley JC. Sex differences in mathematical reasoning ability: more facts. Science 1983; 222(4627):1029–1031. CONCLUSION 3. Benbow CP, et al. Sex differences in mathematical reasoning ability at age 13: their status 20 years later. Psy- The present overview of sex differences in brain neu- chol Sci 2000;11(6):474–480. roanatomy and neurophysiology highlights recent find- 4. Voyer D, Voyer S, Bryden MP. Magnitude of sex differences in spatial abilities: a meta-analysis and considera- ings from the nascent field of neuroimaging. Although we tion of critical variables. Psychol Bull 1995;117: have only begun to appreciate the effects of sex, age, and 250–270. individual differences on brain structure, this direct 5. Bleecker ML, et al. Age-related sex differences in verbal approach to the investigation of brain sex differences pro- memory. J Clin Psychol 1988;44:403–411. vides a useful method for testing those hypotheses gen- 6. Kramer JH, et al. Age and gender interactions on verbal memory performance. J Int Neuropsychol Soc 2003; erated from more indirect approaches and from studies 9(1):97–102. on animals. Advances in image acquisition and process- 7. Wilson JR, Vandenberg SG. Sex differences in cognition: ing now allow a more detailed investigation of morpho- evidence from the Hawaii Family Study. In: McGill TE, metric and functional differences in the human brain. It Dewsbury DA, Sachs BD, (eds.) Sex and Behavior. New is critical to consider potential sex effects on brain and York, NY: Plenum, 1978;317–335. 8. McGlone J. Sex differences in human brain asymmetry: cognitive aging throughout the lifespan, because different a critical survey. Behavioral Brain Sci 1980;3:215–263. maturational rates for men and women may lead to age- 9. Kimura D, Harshman RA. Sex differences in brain orga- specific findings of sex differences in brain structure and nization for verbal and non-verbal functions. In: DeVries function. As we advance our understanding of sex dif- GJ, (eds.) Sex Differences in Primates. New York, NY: ferences in the human brain across the lifespan, the poten- Elsevier 1984;423–441. 10. Harshman RA, Hampson E, Berenbaum SA. Individual tial contributions of organizational hormones early in differences in cognitive abilities and brain organization, development and activational hormones throughout mat- part I: sex and handedness differences in ability. Can J uration should also be investigated. Psychol 1983; 37(1):144–192. It is important to emphasize that sex differences in 11. Lansdell H. A sex difference in effect of temporal lobe brain and behavior refer to average differences between neurosurgery on design preference. Nature 1962;194: 842–854. men and women and that differences between individu- 12. Hier B, et al. Gender and aphasia in the Stroke Data als within each sex are much greater than the average dif- Bank. Brain Language 1994;47(1):155–167. ferences between sexes. Given that scores for men and 13. Kertesz A, Benke T. Sex equality in intrahemispheric lan- women largely overlap, one cannot predict an individual’s guage organization. Brain Language 1989;37:401–408. score on a cognitive test or the volume of a particular 14. Kimura D. Sex differences in cerebral organization for speech and praxic functions. Can J Psychol 1983;37: brain structure on the basis of her sex any more than one 19–35. can predict a particular blood assay level from group 15. Nottebohm F, Arnold AP. Sexual dimorphism in vocal averages. Nonetheless, just as normative values for labo- control areas of the songbird brain. Science 1976;194: ratory tests provide useful clinical guidelines for evaluat- 211–213. ing patients, sex- and age-specific normative values for 16. Gurney ME, Konishi M. Homone-induced sexual differentiation of brain and behavior in zebra finches. Sci- brain imaging measures may be indicated. As neuro- ence 1980;208:1380–1383. physiologic techniques assume an increasingly important 17. Nottebohm F. A brain for all seasons: cyclical anatomi- role in neuroscience and clinical investigations, it is crit- cal changes in song control nuclei of the canary brain. ical to understand the effects of sex on these measures as Science 1981;214:1368–1370. they relate to the correct interpretation and application 18. Brenowitz EA, Lent K. Act locally and think globally: intracerebral testosterone implants induce seasonal-like to clinical practice. growth of adult avian song control circuits. Proc Natl Acad Sci USA, 2002;99(19):12421–12426. Acknowledgments 19. Beatty WW. Gonadal hormones and sex differences in non-reproductive behaviors in rodents: organizational and activational influences. Hormones Behavior 1979; Wendy Elkins, BA provided assistance in updating this chapter, 12:112–163. and Pauline Maki, PhD provided helpful input into the origi- 20. Reinisch JM. Fetal hormones, the brain and human sex nal chapter. Their contributions are gratefully acknowledged. differences: a heuristic, integrative, review of the recent literature. Arch Sexual Behavior 1974;3:51–90. 21. Goy RW, McEwen BS. Sexual Differentiation of the Brain. Cambridge, Mass: MIT Press, 1980. 24 NEUROLOGIC DISEASE IN WOMEN

22. Fitch RH, et al. Corpus callosum: effects of neonatal hor- 43. Frackowiak RSJ, et al. Human Brain Function. San mones on sexual dimorphism in the rat. Brain Res Diego, Calif: Academic Press, 1997. 1990;515:111–116. 44. Good CD, et al. Cerebral asymmetry and the effects of 23. Mack CM, et al. Ovarian estrogen acts to feminize the sex and handedness on brain structure: a voxel-based female rat’s corpus callosum. Develop Brain Res morphometric analysis of 465 normal adult human 1993;71:115–119. brains. Neuroimage 2001;14(3):685–700. 24. McEwen BS, Alves SE. Estrogen actions in the central 45. DeLacoste-Utamsing C, Holloway RL. Sexual dimor- nervous system. Endocr Rev 1999;20(3):279–307. phism in the human corpus callosum. Science 1982; 25. Ayoub DM, Greenough WT, Juraska JM. Sex differences 216:1431–1432. in dendritic structure in the preoptic area of the juvenile 46. Holloway RL, et al. Sexual dimorphism of the human macaque monkey brain. Science 1983;219:197–198. corpus callosum from three independent samples: rela- 26. Clark AS, Goldman-Rakic PS. Gonadal hormones influ- tive size of the corpus callosum. Amer J Physical Anthro- ence the emergence of cortical function in nonhuman pology 1993;92:481–498. primates. Behavioral Neuroscience 1989;103(6): 47. DeLacoste MC, Holloway RL, Woodward D. Sex dif- 1287–1295. ferences in the fetal corpus callosum. Human Neurobi- 27. Bachevalier J, et al. Age and sex differences in the effects ology 1986;5:93–96. of selective temporal lobe lesion on the formation of 48. Witelson SF, The brain connection: the corpus callosum visual discrimination habits in rhesus monkeys (Macaca is larger in left-handers. Science 1985;229:665–668. mulatta). Behavioral Neuroscience 1990;104(6): 49. Demeter S, Ringo JL, Doty RW. Morphometric analysis 885–899. of the human corpus callosum and anterior commissure. 28. Goldman PS, et al. Sex-dependent behavioral effects of Human Neurobiology 1988;6:219–226. cerebral cortical lesions in the developing rhesus mon- 50. Bell AD, Variend S. Failure to demonstrate sexual dimor- key. Science 1974;186:540–542. phism of the corpus callosum in childhood. J Anatomy 29. Goldman PS. Age, sex, and experience as related to the 1985;143:143–147. neural basis of cognitive development. In: Buchwald NA, 51. Parashos IA, Wilkinson WE, Coffey CE. Magnetic res- Brazier MAB, (eds.) Brain Mechanisms in Mental Retar- onance imaging of the corpus callosum: predictors of size dation. New York, NY: Academic Press, 1975;379–392. in normal adults. J Neuropsychiatry 1995;7:35–41. 30. Bachevalier J, Hagger C. Sex differences in the develop- 52. Witelson SF. Hand and sex differences in the isthmus and ment of learning abilities in primates. Psychoneuroen- genu of the human corpus callosum: a postmortem mor- docrinology 1991;16(1-3):177–188. phological study. Brain 1989;112:799–835. 31. Hagger C, Bachevalier J. Visual habit formation in 3- 53. Steinmetz H, et al. Sex but no hand difference in the isth- month-old monkeys (Macaca mulatta): reversal of sex mus of the corpus callosum. Neurology 1992;42: difference following neonatal manipulations of andro- 749–752. gens. Behav Brain Res 1991;45(1):57–63. 54. Witelson SF. Sex differences in neuroanatomical changes 32. Franklin MS, et al. Gender differences in brain volume with aging. N Engl J Med 1991;325:211–212. and size of corpus callosum and amygdala of rhesus 55. Johnson SC, et al. Corpus callosum surface area across monkey measured from MRI images. Brain Res the human adult life span: effect of age and gender. Brain 2000;852(2):263–267. Res Bull 1994;35(4):373–377. 33. Holloway RL, Heilbroner P. Corpus callosum in sexu- 56. Pozilli C, et al. No differences in corpus callosum size ally dimorphic and nondimorphic primates. Am J Phys by sex and aging. J Neuroimaging 1994;4:218–221. Anthropol 1992;87(3):349–357. 57. Sullivan EV, et al. Sex differences in corpus callosum size: 34. Swaab DF, Fliers E. A sexually dimorphic nucleus in the relationship to age and intracranial size. Neurobiol human brain. Science 1985;228:1112–1115. Aging 2001;22(4):603–611. 35. Allen LS, et al. Two sexually dimorphic cell groups in the 58. Giedd J, et al. A quantitative MRI study of the corpus human brain. J Neurosci 1989;9(2):497–506. callosum in children and adolescents. Brain Res Dev 36. Allen LS, et al. Sex differences in the corpus callosum of Brain Res 1996;91(2):274–280. the living human being. J Neurosci 1991;11(4):933–942. 59. Constant D, Ruther H. Sexual dimorphism in the human 37. Durston S, et al. Anatomical MRI of the developing corpus callosum? A comparison of methodologies. Brain human brain: what have we learned? J Am Acad Child Res 1996;727:99–106. Adolesc Psychiatry 2001;40(9):1012–1020. 60. Davatzikos C, et al. A computerized approach for mor- 38. Nopoulos P, et al. Sexual dimorphism in the human phological analysis of the corpus callosum. J Comput brain: evaluation of tissue volume, tissue composition Assist Tomog 1996;20(1):88–97. and surface anatomy using magnetic resonance imaging. 61. Davatzikos C, Resnick SM. Sex differences in anatomic Psychiatry Res 2000;98(1):1–13. measures of interhemispheric connectivity: correlations 39. Resnick SM, et al. One-year age changes in MRI brain with cognition in women but not men. Cereb Cortex volumes in older adults. Cereb Cortex 2000;10(5): 1998;8(7):635–640. 464–472. 62. Gur RC, et al. Sex differences in brain gray and 40. Raz N, et al. Age and sex differences in the cerebellum white matter in healthy young adults: correlations with and the ventral pons: a prospective MR study of healthy cognitive performance. J Neurosci 1999;19(10): adults. AJNR Am J Neuroradiol 2001;22(6):1161–1167. 4065–4072. 41. Gur RC, et al. Sex differences in temporo-limbic and 63. Nopoulos PC, et al. Sex differences in the absence of frontal brain volumes of healthy adults. Cereb Cortex massa intermedia in patients with schizophrenia versus 2002;12(9):998–1003. healthy controls. Schizophr Res 2001;48(2-3):177–185. 42. Pujol J, et al. Anatomical variability of the anterior cin- 64. Kim DM, et al. MR signal intensity of gray matter/white gulate gyrus and basic dimensions of human personality. matter contrast and intracranial fat: effects of age and Neuroimage 2002;15(4):847–855. sex. Psychiatry Res 2002;114(3):149–161. SEX DIFFERENCES IN REGIONAL BRAIN STRUCTURE AND FUNCTION 25

65. Yue NC, et al. Sulcal, ventricular, and white matter 84. Shapleske J, et al. The planum temporale: a systematic, changes at MR imaging in the aging brain: data from the quantitative review of its structural, functional and clin- Cardiovascular Health Study. Radiology 1997;202: ical significance. Brain Res Brain Res Rev 1999;29(1): 33–39. 26–49. 66. de Leeuw FE, et al. Prevalence of cerebral white matter 85. Kulynych JJ, et al. Gender differences in the normal lat- lesions in elderly people: a population based magnetic eralization of the supratemporal cortex: MRI surface- resonance imaging study. The Rotterdam Scan Study. J rendering morphometry of Heschl’s gyrus and the Neurol Neurosurg Psychiatry 2001;70(1):9–14. planum temporale. Cerebr Cortex 1994;4:107–118. 67. Sijens PE, et al. Human brain chemical shift imaging at 86. Ide A, et al. Bifurcation patterns in the human sylvian age 60 to 90: analysis of the causes of the observed sex fissure: hemispheric and sex differences. Cerebr Cortex differences in brain metabolites. Invest Radiol 2001; 1996;6:717–725. 36(10):597–603. 87. Matsura M, et al. Age development and sex differences 68. Coffey CE, et al. Sex differences in brain aging: a quan- of various EEG elements in healthy children and adults titative magnetic resonance imaging study. Arch Neurol —quantification by a computerized wave form recogni- 1998;55:169–179. tion method. Electroencephalo Clin Neurophysiol 1985; 69. Giedd JN, et al. Quantitative magnetic resonance imag- 60:394–406. ing of human brain development: ages 4–18. Cereb Cor- 88. Brenner RP, Ulrich RF, Reynolds CFI. EEG spectral find- tex 1996;6:551–560. ings in healthy, elderly men and women—sex differences. 70. Takeda S, Matsuzawa T. Age-related brain atrophy: a Electroencephalo Clin Neurophysiol 1995;94:1–5. study with computed tomography. J Gerontol 1985;40: 89. Veldhuizen RJ, Jonkman EJ, Poortvliet DCJ. Sex differ- 159–163. ences in age regression parameters of healthy adults— 71. Grant R, et al. Human cranial CSF volumes measured normative data and practical implications. Electroen- by MRI: sex and age influences. Magn Res Imag cephalo Clin Neurophysiol 1993;86:377–384. 1987;5:465–468. 90. Allison T, Wood CC, Brainstem GWR. Auditory, pat- 72. Condon B, et al. Brain and intracranial cavity volumes: tern-reversal visual, and short-latency somatosensory in vivo determination by MRI. Acta Neurol Scand evoked potentials: latencies in relation to age, sex and 1988;78:387–393. brain and body size. Electroencephalo Clin Neurophys- 73. Gur RC, et al. Gender differences in age effect on brain iol 1983;55: 619–636. atrophy measured by magnetic resonance imaging. Proc 91. Stockard JJ, Hughes JF, Sharbrough FW. Visually evoked Nat Acad Sci USA 1991;88:2845–2849. potentials to electronic pattern reversal: latency varia- 74. Kaye JA, et al. The significance of age-related enlarge- tions with gender, age and technical factors. Am J EEG ment of the cerebral ventricles in healthy men and Technol 1979;19:171–204. women measured by quantitative computed x-ray 92. Emerson RG, et al. Effects of click polarity on brainstem tomography. J Amer Geriatr Soc 1992;40:225–231. auditory evoked potentials in normal subjects and 75. Cowell PE, et al. Sex differences in aging of the human patients: unexpected sensitivity of wave V. Ann NY Acad frontal and temporal lobes. J Neurosci 1994;14(8): Sci 1982;388:710–721. 4748–4755. 93. Polich J, Martin S. P300, cognitive capability, and per- 76. Murphy DGM, et al. Sex differences in human brain sonality: a correlational study of university undergrad- morphometry and metabolism: an in vivo quantitative uates. Personality and Individual Differences 1992;13: magnetic resonance imaging and positron emission 533–543. tomography study on the effect of aging. Arch Gen Psy- 94. Taylor MJ, Smith ML, Iron KS. Event-related potential chiatry 1996;53:585–594. evidence of sex differences in verbal and nonverbal mem- 77. Xu J, et al. Gender effects on age-related changes in brain ory tasks. Neuropsychologia 1990;28:691–705. structure. AJNR Am J Neuroradiol 2000;21(1): 95. Erwin RJ, et al. Effects of task and gender on EEG indices 112–118. of hemispheric activation: Similarities to previous rCBF 78. Gur RC, et al. Brain region and sex differences in age findings. Neuropsychi, Neuropsychol, Behav Neurol association with brain volume: a quantitative MRI study 1989;2:248–260. of healthy young adults. Am J Geriatr Psychiatry 96. Gur RC, et al. Sex and handedness differences in cere- 2002;10(1):72–80. bral blood flow during rest and cognitive activity. Sci- 79. Hines M, Gorski RA. Hormonal influences on the devel- ence 1982;217:659–661. opment of neural asymmetries. In: Benson DF, Zaidel E, 97. Mathew RJ, et al. Abnormal resting regional cerebral (eds.) The Dual Brain. New York, NY: The Guilford blood flow patterns and their correlates in schizophre- Press, 1985;75–96. nia. Arch Gen Psychiatry 1988;45(6):542–549. 80. Hines M, Green R. Human hormonal and neural corre- 98. DeVoogd T, Nottebohm F. Gonadal hormones induce lates of sex-typed behaviors, in Review of Psychiatry. dendritic growth in the adult avian brain. Science Washington, D.C.: American Psychiatry Press, 1991; 1981;214:202–204. 536–555. 99. Jones K, et al. Use of singular value decomposition to 81. Geschwind N, Levitsky W. Human brain: left-right characterize age and gender differences in SPECT cere- asymmetries in the temporal speech region. Science bral perfusion. J Nucl Med 1998;39(6):965–973. 1968;161:186–187. 100. Baxter LR, et al. Cerebral glucose metabolic rates in nor- 82. Galaburda AM, et al. Right-left asymmetries in the mal human females versus normal males. Psychiatry Res brain. Science 1978;199:852–856. 1987;21:237–245. 83. Wada JA, Clarke R, Hamm A. Cerebral hemispheric 101. Yoshii F, et al. Sensitivity of cerebral glucose metabolism asymmetry in humans. Cortical speech zones in 100 to age, gender, brain volume, brain atrophy, and cere- adult and 100 infant brains. Arch Neurol 1976;32: brovascular risk factors. J Cerebr Blood Flow Metabo- 239–246. lism 1988;8:654–661. 26 NEUROLOGIC DISEASE IN WOMEN

102. Miura SA, et al. Effect of gender on glucose utilization activity during sadness. Hum Brain Mapp 2000;9(4): rates in healthy humans: a positron emission tomogra- 226–238. phy study. J Neurosci Res 1990;27:500–504. 118. George MS, et al. Gender differences in regional cerebral 103. Gur RC, et al. Sex differences in regional cerebral glu- blood flow during transient self-induced sadness or hap- cose metabolism during a resting state. Science 1995; piness. Biol Psychiatry 1996;40(9):859–871. 267:528–531. 119. Lee TM, et al. Gender differences in neural correlates 104. Azari NP, et al. Gender differences in correlations of cere- of recognition of happy and sad faces in humans assessed bral glucose metabolism rates in young normal adults. by functional magnetic resonance imaging. Neurosci Lett Brain Res 1992;574:198–208. 2002;333(1):13–16. 105. Andreason PJ, et al. Gender-related differences in 120. Bremner JD, et al. Gender differences in cognitive and regional cerebral glucose metabolism in normal volun- neural correlates of remembrance of emotional words. teers. Psychiatry Res 1994;51:175–183. Psychopharmacol Bull 2001;35(3):55–78. 106. Van Laere K, et al. 99mTc-ECD brain perfusion SPECT: 121. Canli T, et al. Sex differences in the neural basis of emo- variability, asymmetry and effects of age and gender in tional memories. Proc Natl Acad Sci USA 2002;99(16): healthy adults. Eur J Nucl Med 2001;28(7):873–887. 10789–10794. 107. Pagani M, et al. Regional cerebral blood flow as assessed 122. Wong DF, et al. Effects of age on dopamine and serotonin by principal component analysis and (99m)Tc-HMPAO receptors measured by positron emission tomography in SPET in healthy subjects at rest: normal distribution and the living human brain. Science 1984;226:1393–1396. effect of age and gender. Eur J Nucl Med Mol Imaging 123. Wong DF, et al. D2 dopamine receptor density measured 2002;29(1):67–75. in human brain in vivo by positron emission tomogra- 108. Gur RC, et al. An fMRI study of sex differences in phy: age and sex differences. Ann NY Acad Sci 1988; regional activation to a verbal and a spatial task. Brain 203–214. Lang 2000;74(2):157–170. 124. Nordstrom AL, Olsson H, Halldin C. A PET study of D2 109. Shaywitz BA, et al. Sex differences in the functional orga- dopamine receptor density at different phases of the nization of the brain for language. Nature 1995;373: menstrual cycle. Psychiatry Res 1998;83(1):1–6. 607–609. 125. Laakso A, et al. Sex differences in striatal presynaptic 110. Phillips MD, et al. Temporal lobe activation demon- dopamine synthesis capacity in healthy subjects. Biol strates sex-based differences during passive listening. Psychiatry 2002;52(7):759–763. Radiology 2001;220(1):202–207. 126. Mozley LH, et al. Striatal dopamine transporters and 111. Kansaku K, Yamaura A, Kitazawa S. Sex differences in cognitive functioning in healthy men and women. Am J lateralization revealed in the posterior language areas. Psychiatry 2001;158(9):1492–1499. Cereb Cortex 2000;10(9):866–872. 127. Staley JK, et al. Sex differences in [123I]beta-CIT SPECT 112. Rossell SL, et al. Sex differences in functional brain acti- measures of dopamine and serotonin transporter avail- vation during a lexical visual field task. Brain Lang ability in healthy smokers and nonsmokers. Synapse 2002;80(1):97–105. 2001;41(4):275–284. 113. Speck O, et al. Gender differences in the functional orga- 128. Kaasinen V, et al. Sex differences in extrastriatal nization of the brain for working memory. Neuroreport dopamine d(2)-like receptors in the human brain. Am J 2000;11(11):2581–2585. Psychiatry 2001;158(2):308–311. 114. Gron G, et al. Brain activation during human navigation: 129. Parsey RV, et al. Effects of sex, age, and aggressive traits gender-different neural networks as substrate of perfor- in man on brain serotonin 5-HT1A receptor binding mance. Nat Neurosci 2000;3(4):404–408. potential measured by PET using [C-11]WAY-100635. 115. Yousem DM, et al. Gender effects on odor-stimulated Brain Res 2002;954(2):173–182. functional magnetic resonance imaging. Brain Res 130. Nishizawa S, et al. Differences between males and 1999;818(2):480–487. females in rates of serotonin synthesis in human brain. 116. Cowan RL, et al. Sex differences in response to red and Proc Natl Acad Sci USA 1997; 94(10):5308–5313. blue light in human primary visual cortex: a bold fMRI 131. Zubieta JK, et al. Mu-opioid receptor-mediated antinoci- study. Psychiatry Res 2000;100(3):129–138. ceptive responses differ in men and women. J Neurosci 117. Schneider F, et al. Gender differences in regional cerebral 2002;22(12):5100–5107.

Women’s Lives and Their Experiences 3 with Health Care

Aileen MacLaren Loranger, CNM, PhD and Nancy Fugate Woods, PhD, RN

omen’s health is inextricably health and disease through social structures that encom- related to women’s lives. What pass socially assigned life roles, access to resources such women do in everyday life, the as money and power, and the society’s image of what it is W resources available to them, and to be female or male (2,3). Indeed, gender and sex differ- notions of what a woman “should be” converge to cre- ences have been increasingly incorporated into research ate the social context in which women experience health design, public policy, and clinical practice as the impetus and illness. A woman’s own personal development is to improve the health of and health care services for shaped not only by that social context, but also by her women has gained momentum over the past 15 years. personal development, which contributes to the context Understanding gender influences attributed to economic, in which she lives her life. “Social causation” is an impor- social, cultural, geographic, and behavioral factors, as tant determinant of how biology interacts with sociocul- well as unique sex-based biologic differences, will better tural factors to produce differences in women’s health (1). shape health care and health care services in the future (4). It is unlikely that a health care clinician can understand Economically, a gender-based division of labor is fully how women experience health or illness without reflected in the allocation of work both outside and inside understanding the context of their lives. This chapter the home. Segregation within the labor market is preva- examines how the context of women’s lives and their per- lent in the United States despite laws to the contrary, sonal development influence their health and their expe- resulting in inequality of wages for men and women. In riences with health care. 2002, the median income for women was 75 percent of the median income of men (5). Women are over-represented in the lower paying occupations, such as clerical GENDER or service workers. In addition, subtle (and not so subtle) discrimination remains in skills training that influ- Gender influences people’s lives in multiple, complex ences who gets trained for better paying jobs and who ways. Gender refers to the social experience and self- experiences discrimination in promotions—the so-called expression of being a woman or man, whereas sex refers “glass ceiling” for women. The appropriation of gender- to the biological dimensions of being female or male, based work is further reflected in the design of work and based on chromosomal assignment. Gender, as a social tools to perform work. For example, household appli- category, organizes people’s lives and ultimately influences ances are sized to women’s hands, whereas most tools 27 28 NEUROLOGIC DISEASE IN WOMEN

used in certain types of manufacturing have been sized tem; women are up to five times more likely to report no to fit men’s hands. usual source of care and twice as likely to report no recent Women disproportionately assume the allocation of physician visit. A lack of coverage limits access to essen- childrearing responsibilities, with few men undertaking tial preventive care, reproductive health care, and both primary parental responsibility. Approximately 40% of acute and chronic care needs. Without adequate insur- women in the U.S. workforce have children younger than ance, women are five times more likely to report unmet 18 years of age (6). In addition, some working women health needs and nearly six times more likely to use the also have caregiving responsibilities for mentally or phys- emergency room as their only source of health care. Unin- ically disabled or aging family members (7). In 1998, 9% sured women experience higher mortality and nearly of women were caring for a sick or disabled relative. Of twice the risk of avoidable hospitalizations for conditions those women, 43% provided more than 20 hours of care that could have been treated as outpatient care or pre- per week, and a majority (53%) had annual household vented altogether (14). incomes of $35,000 or less (8). Caregivers also report that Power is also allocated according to gender. This they are in poorer health than noncaregivers. gender-related disparity is reflected in the dynamics of As a result of the allocation of labor market oppor- domestic relationships, including the control of money tunities and women’s disproportionate responsibility for and other resources and the tacit approval of violence childrearing and/or caregiving in the United States, against women, in particular, domestic violence. In the women are more frequently poor than men. Not surpris- United States, one woman is beaten in her home by some- ingly, poverty is one of the major social issues affecting one she knows every 14 seconds (15). Nearly 45% of women’s lives and their health. In 2000, 11.9 million women aged 18 to 64 years report having experienced women aged 18 and older were living with incomes below one or more forms of violence, including child abuse the federal poverty level, when compared with 7.6 mil- (17.8%), physical assault (19.1%), rape (20.4%), and lion men of similar age (9). Single women with young chil- intimate partner violence (34.6%) during the course of dren or who are elderly are most likely to live in poverty, their lifetime (16). Hierarchies of state and business reflect and they remain poor for longer periods than do men. the gender order of the society; therefore, the subordina- Indeed, 29% more women than men live in poverty (10). tion of women to men is assured through rules that make Women heads of households are five times more likely change difficult. to be poor than men; teen mothers and residents of rural Cathexis refers to ideas about gender, including the areas are especially at risk of being poor (11,12).Recently, ideology governing the social patterning of relationships 26.4% of all female-headed families were poor compared or links to one another. The image of a woman as a repro- to 4.9% of families in which males were present (13). ductive or sexual object constrains what women can Poverty is particularly acute among older women, and aspire to be in a society. Sexism pervades Western soci- health care costs are often responsible for older women’s eties in subtle as well as overt ways (17). Sexual harass- poverty. ment of women in the workplace, sexual discrimination Acute care health services are supported through in hiring and promotion practices, and differential access entitlement programs such as Medicare, but the services to education persist despite changes in the law. Incest, sex- women need as they age without a spouse or children to ual abuse, unwanted sex or “date rape,” homicide, and care for them, such as home care services and nursing violent acts against women such as rape and battery, are home care, have limited coverage through Medicare. increasingly recognized and reflect both the image of Thus, women must spend down their savings and apply women as objects and gender differences in power. Taken for Medicaid to finance caregiving for themselves. together, the division of labor, power, and imagery about A substantial decrease in health insurance coverage women shape contemporary women’s lives. for American women occurred during the last decade of the twentieth century. The proportion of uninsured women increased by 16.8%, whereas the total uninsured CONTEMPORARY WOMEN’S LIVES population rose by 11.5%, and the proportion of men who were uninsured rose by 7.1%. Approximately one The lives of women from different birth cohorts vary in five working-age women (17.7%) is uninsured. considerably. The unique experiences of different birth Between 1990 and 1999, the number of uninsured Amer- cohorts are exemplified by comparing the lives of women icans reached 43 million, including over 20 million unin- born in the two decades following World War II (1946 sured women, despite a national focus on the uninsured to 1964), referred to as the Baby Boomers, with their and the unparalled economic prosperity over the previ- mothers. The large postwar population surge that pro- ous nine years (14). duced the Baby Boomers has had a dramatic impact on As a result of this inequity, uninsured women are U.S. society as a whole. The mothers of the Baby more likely to be disenfranchised from the health care sys- Boomers were unusual in that they had larger families, WOMEN’S LIVES AND THEIR EXPERIENCES WITH HEALTH CARE 29 less formal education, and married at younger ages than Women have worked throughout U.S. history, but their own mothers. The Baby Boomer generation of much of women’s work has been unpaid work performed women has differentiated itself from women of previ- in the home and invisible to the larger society. Contem- ous generations in that many have fashioned their lives porary women have experienced an increase in their paid as individuals. Whereas past generations of women orga- work without a compensatory decrease in the responsi- nized their life roles and goals around their family’s bilities for the unpaid work benefiting their families. As objectives, women now spend more of their lives as sin- a result, many experience conflicts among their complex gle, independent adults, organizing their lives to meet multiple roles and report feeling overloaded. their personal and work objectives. The Baby Boomer woman is better educated, lives alone longer than her Adult Partnerships mother’s generation, and participates in the labor force throughout her life regardless of her marital status and Although over 51% of U.S. women are married (21), the the ages of her children. She experiences greater finan- proportion of women who are single heads of households, cial independence and fertility control than her mother. assuming responsibility for their children, has grown dra- Marriage and family are no longer the single control- matically since the 1950s. This change is largely attrib- ling institutions around which the Baby Boomer gener- utable to U.S. divorce rates escalating, but to some extent ation of women organized their lives. Moreover, it is women choosing not to marry but live with a male part- likely that daughters of the Baby Boomers will be pro- ner or a series of partners. As women have been able to foundly influenced by these changing norms and that provide financial support for themselves, the financial their lives will be more similar to their mothers’ lives necessity to marry has been reduced. Estimates are that than those of their grandmothers (18). 12% of 25- to 29-year-old women may never marry. Median age at first marriage is now approximately 25 years (23) and duration of marriages is about 23 years. Employment About half of all divorces occur within the first seven Since the late 1960s a profound shift has occurred in the years of marriage (18). relationship of women to the family and economic system, most evident in the integration of work and family Parenting roles. The next generation of women is a product of the transition made by Baby Boomer women who entered As women’s labor market participation has increased dra- adulthood with work and family attitudes similar to those matically, their childbearing and childrearing activities of their mothers, but who underwent dramatic transi- have slowed somewhat. Currently, women have an aver- tions. These changes have been reflected in women’s roles, age of 1.9 children, but estimates are that now one of particularly those of educational attainment and paid five women will have no children during her lifetime. employment, along with parenting, partnerships, and Median age at first birth is 23 years, but 11% of women caregiving, which remain significant components of have their first birth after age 30. Both education and women’s work. employment opportunities for women have slowed the Data from the U.S. Bureau of Labor (19) reveal that birth rate in the United States. Indeed, only 30% of col- 58% of all women aged 16 and older are employed out- lege educated women have had their first child by age 25 side of their homes for pay. Motherhood is an important years (18). component of many—but not all—women’s work lives. Estimates are that employed women work another Nearly three-quarters (71%) of married women with chil- 11 or more hours more each week at home than employed dren under age 18 were employed in 1997, whereas the men. Employed women with young children are among rate of labor participation of single mothers was 68% the most overloaded. In the United States, on-site child (20). In 1998, among women with infants under the age care for employed women has begun to be available, but of one year, 36% were working full-time, 17% were it is not the norm. When child care is available, child care working part-time, and 6% were actively seeking employ- workers (most of whom are women) are not well remu- ment—representing a record high of almost 60% of new nerated. Indeed, most child care workers (94%) in the mothers participating in the labor force (21). An esti- United States earn wages below the poverty level (24). mated two-thirds of preschool children in the United Some women with children have pursued employ- States have mothers who are employed. Only 20% of ment by working at home. Over 11.2 million women in mothers of preschoolers in the United States are full-time the United States are self-employed, working in their homemakers. Most women are employed because their homes (8). Although it would seem that women with incomes are essential to their family’s well-being. This is young children might welcome some assistance by cutting so for over 70% of black married women and 50% of back on employment, the concept of a “mommy track,” white married women in the United States (22). a slower career progression than that typifying men, has 30 NEUROLOGIC DISEASE IN WOMEN

met with criticism from women in the United States. Per- ties for child care and home maintenance, may have neg- haps more assistance with work at home and with child ative health effects. Moreover, the combination of long care would be the preferable solution for many women. stressful hours at poorly paid, unrewarding, physically exhausting work that includes exposure to toxic substances or illnesses may combine to produce health prob- Caregiving lems. In addition to caring for their children, women in the The Framingham Heart study (29) revealed some United States contribute disproportionately to caring for interesting findings about women who did not seem to their elderly parents and other family members during benefit from employment. Data from a birth cohort a gen- times of sickness. Informal or unpaid family care is often eration older than the Baby Boomers indicated that an overlooked yet essential component of the U.S. health women who worked at home had the lowest incidence care system for the nation’s sick, disabled, frail, and ter- of heart disease, whereas women who were currently minally ill (25). The fastest growing portion of the pop- employed and those who had been employed previously ulation in the United States is the group between 75 and had higher rates of disease. The incidence of heart disease 85 years of age. U.S. estimates are that women consti- was highest among women who were clerical workers, tute 72% of the 2.2 million people caring for 1.2 million who were married to blue collar (working class) hus- elderly living at home (26). Often these women are elderly bands, and who had three or more children. Clerical themselves, but many are midlife women who also have workers with blue collar husbands were likely to be work- children at home. This situation is so common in the ing due to economic necessity and were likely to receive United States that women with responsibilities to multi- little spousal support for their employment. Moreover, ple generations are described as the “sandwich genera- aspects of their work situation also influenced women’s tion.” Women are sandwiched into caregiving roles by health. Clerical workers who had remained in jobs with their children and adolescents on one hand and by care- a nonsupportive boss and who were unable to express giving responsibilities for their elderly parents and their anger experience a higher incidence of heart disease spouses’ parents. These responsibilities add about 20 to than do other women (29). 28 hours to women’s work weeks, in some cases causing Later studies show that employment has the most then to leave employed positions, reduce hours in the beneficial health effects for women without an alterna- workplace, and lose benefits such as health insurance and tive source of social integration and self-esteem. Women pensions. A growing body of scientific evidence exists who were not married, did not have children, and were about these financial, emotional, physical, or familial not well educated, benefited the most from being threats that face caregivers (both women and men) (25). employed (30). U.S. women have an estimated average lifespan of More recent research has focused on the conse- nearly 80 years. This fact should alert us to an increas- quences of combining work and family responsibilities. ing number of elderly in our society who will need care. Workplace exposure to stressors was studied among As the lifespan increases, so does the necessity for family women employed as managers in a Swedish manufactur- caregiving by future generations. Indeed, Baby Boomer ing industry using norepinephrine levels as an indicator women will soon require the supportive caregiving of of stress. During the day, women’s norepinephrine levels their children, who will also be involved in paid labor, resembled those of male managers. When women went childrearing, and their own life partnerships. home from work, however, their norepinephrine levels rose. Their male counterparts’ norepinephrine levels fell; suggesting that going home was a relaxing part of their Multiple Roles daily experiences, unlike women’s experiences of going The challenges of balancing multiple roles have become home (31). A study of U.S. partnered women and men commonplace for the Baby Boomer generation of women. who were both employed documented that women work Although work generally has been shown to have posi- a second shift when they come home from their paid tive effects on women’s health, and studies of women per- employment (32). Women, more than men, continue to forming multiple roles reveal health benefits (27), other participate in unpaid work as well as their paid labor. situations may be health-damaging for women. In the U.S. studies show that young adult women who United States, an estimated 55% of women return to were employed and had children and who received both work within 1 year of the birth of their children (28). This emotional support and help with the work from their hus- fact may reflect women’s satisfaction with their work as bands had better mental health than those who did not well as concern about continuing their employment due receive this type of support. Moreover, when women jug- to economic necessity, because health care benefits are gling multiple responsibilities were convinced that it was linked to employment in the United States. Work that is appropriate for women to be involved in nontraditional physically demanding, coupled with heavy responsibili- roles, their mental health was better than for those with WOMEN’S LIVES AND THEIR EXPERIENCES WITH HEALTH CARE 31 more traditional norms (33). When women had partners expectation of mutuality in this regard” (37, p. 59). One who did not assume an equitable load of the work at comes to know oneself and others in the context of home, they became depressed. This was most pronounced mutual relational interaction and in the continuity of when the women felt overloaded (34). For women who emotional-cognitive dialog. Communication is interac- were working at home, emotional support and positive tion rather than debate. affirmation from their spouses were most important (33). Power, in the context of self-in-relation theory, is the The profile of a woman’s life course is shaped in capacity to move or produce changes. This definition is large part by the constellation of her roles. The shape of in contrast to power as dominion, control, or mastery. the Baby Boomer’s life course differs from that of her Power is not seen as “power over” but “power with” mother’s in two significant ways: the continuity of (37). The contrast to empowerment is disempowerment, employment throughout her reproductive years and the which makes it difficult to create or sustain a healthy rela- discontinuities in adult life partnerships due to divorce tional context. As one develops “power with,” one has a and remarriage. What remains similar in the life course sense of being part of the growth and empowerment of of Baby Boomers and their mothers is parenting. Those others. One develops while seeing another become more women who become parents remain parents—usually of who she is as one does the same. The “power over” developing adult relationships with their children that model limits growth because it limits the relational con- persist throughout the life course (35). As the nature of text (37). work is changing in U.S. society, another dimension of women’s lives is also changing—education. Women once Female Friendships completed their formal education before entering the labor force, but now increasingly punctuate their lives Women have overlapping relational networks that span with educational episodes geared toward re-training, as many domains of life, including their personal, educa- the labor market requires it. tional, work, and political involvements (38). Although women’s networks provide a great deal of support, particularly in times of crisis, little is known about these WOMEN’S ADULT DEVELOPMENT structures and their development across a woman’s lifespan. Female friendship provides a unique context in The current concepts of women’s adult development which women can experience happiness in relation to emphasize women’s relational nexus and interdependence women’s lives, not defined in relation to men’s lives. in contrast to accounts of men’s lives that emphasize indi- Importantly, female friendship makes women visible to viduation and independence. The use of the concept “self- one another. The dual vision of what is and what can be in-relation” has revolutionized the concepts of women’s includes making women visible to themselves and to one adult development. Seeking an identity as being in a rela- another in a world that frequently keeps women and tionship with others implies developing all aspects of one- women’s doings invisible by design (39). self in increasingly complex ways, in the context of increasingly intricate relationships. When the nature of Cognitive Development and Moral Reasoning those relationships is suppressive or oppressive, women’s development is thwarted (36). Instead of emphasizing sep- The new accounts of women’s development have also aration-individuation, the self-in-relation theorists pro- examined women’s cognitive development and women’s posed that relationship-differentiation is central to moral reasoning. Relational experiences may contribute women’s development. to a special style of knowing for women. Belenky and col- The basic elements of women’s core self, then, are: leagues (40) have proposed that connected learning, tak- i) interest in and attention to the other person, forming ing the views of others and connecting them to one’s own the basis for emotional connection and empathy; ii) the knowledge, contributes to a larger understanding of expectation of a mutual empathic process in which the human experience. This approach discourages a split sharing of experience enhances development of oneself between thinking and feeling. In addition, their work and another; and iii) the expectation of interaction and illustrates how differential access to social resources and relationships as a process of mutual sensitivity and definitions of self have kept some women silent rather responsibility that stimulates the growth of empowerment than promoted their ability to construct knowledge. and self knowledge (37). Carol Gilligan’s works (41) illustrate how women’s In the context of self-in-relation theory, relationship ethical development differs from men’s by evolving has a specific meaning. Relationship means the “experi- around an ethic of caring versus an orientation of enti- ence of emotional and cognitive intersubjectivity: the tlement. Gilligan found that women live in networks or ongoing, intrinsic inner awareness and responsiveness to webs of attraction, a fact that influences the development the continuous existence of the other or others and the of an ethic of caring. Women make decisions about moral 32 NEUROLOGIC DISEASE IN WOMEN

acts using the criterion of caring or responsibility versus women, and 75% of nursing home residents over 75 years an orientation of rights or privilege. of age are women (46). Increasingly savvy regarding their One important caveat in considering adult develop- health and well-being, women want to be taken seriously ment and research on women’s roles and their health is during visits with their health care clinicians and yet, fre- that most work has involved white women who have quently find themselves frustrated and dissatisfied when above-average economic resources. Studies often do not they feel they are not being listened to (47–49). reflect the reality of poor women’s lives, and women of Women regularly express a longing to be more com- color are disproportionately poor. fortable asking questions and getting clearer answers from their physicians, despite the pressures of today’s managed care environment, in which time efficiency is WOMEN’S EXPERIENCES at a premium during the medical encounter (47). The OF HEALTH CARE advent of IHC holds great promise for enhancing women’s focused interactions with their clinicians, and Women have well established themselves as expert con- results in better informed decision-making and greater sumers of health care services in the United States and as patient satisfaction. a primary resource for their family’s health care decisions (1,42). Recent innovations in the field of information The Influence of Telecommunications technology are greatly increasing the access to knowledge on Health Care of health maintenance and health care, including the expanding interactive capacities of the Internet, electronic In 2002, the adoption of Internet use in the United States mail (e-mail), handheld computers, and cellular tele- was at a rate of 2 million new Internet users per month. phones. The Science Panel on Interactive Communication Over half the nation is now online, and overall Internet and Health (43) defines these tools of communication use is steadily increasing, regardless of income, education, technology or interactive health communications (IHC) age, race, ethnicity, or gender. Low family incomes, low as “the interaction of individuals—consumer, patient, levels of overall education, and English as a second lan- caregiver, or professionals—with or through an electronic guage are still the strongest predictors of those within the device or communication technology to access or trans- “unconnected” population (50). Yet, the exponential mit health information or to receive guidance and sup- growth rate in the Internet’s user base, with the greatest port on a health related issue” (43, p. 1264). The con- increase occurring among younger, school-aged user vergence of rapidly developing scientific advances and groups, is rapidly narrowing the “digital divide” (44,51). IHC is changing the nature of contemporary health care Women and men demonstrate equal rates of com- experiences and health care communications. The acces- puter utilization. Not surprising, women go online to find sibility of up-to-date medical information through the information on health services or practices more fre- Internet adds another dimension to the consumer power quently than men (39.8% of female computer users con- held by women, one which potentially fosters more active trasted with 29.6% of male computer users). Regular e- participation in health, health care decisions, and confi- mail use was reported by 85.1% of female users versus dence in obtaining appropriate health care for themselves 82.8% of male users. Routine computer use and Inter- and their families (44). net access at work, school, or libraries is substantially nar- Equally important to an understanding of women’s rowing the “unconnected population” in computer appli- experiences of health care are the effects that sociocul- cations nationwide, which subsequently influences tural influences have. Acknowledging and sensitively increased household usage (50). addressing the cultural characteristics and needs of As the Internet becomes a more conventional infor- diverse groups during the provision of health care will mation tool, expectations have increased about the reli- reduce existing socioeconomic, ethnic, and racial dispar- ability of health or medical information found online. ities, stereotyping, and gender bias. According to the Pew Internet & American Life Project (52), 67% of Americans believe that health care information found online is reliable, which explains why such Women as Health Care Consumers information plays an increasing role in people’s interac- Women represent the largest proportion of health services tions with their health care providers and in their more consumers at all ages in the United States (even after active participation in decision-making. adjusting for childbearing) (45). American women make Most Internet “health seekers” are women, who say three-fourths of the health care decisions in their house- that they are still careful to consult with a medical pro- holds and spend nearly two of every three health care dol- fessional before acting on online medical advice. Fifty- lars. More than 61% of physician visits are made by eight percent of Internet health seekers predict that they women, 59% of prescription drugs are purchased by will first go online when next they need reliable health WOMEN’S LIVES AND THEIR EXPERIENCES WITH HEALTH CARE 33 care information versus 35% who say that their first ical care. For the professional, unsuccessful calls are min- move will be to contact a health care professional (52). imized, messages can be read and responded to at more In an exploratory study to determine the motiva- convenient times, medical advice can be carefully worded tions of women who use the Internet to obtain health before it is provided, communications can be saved in information, health consciousness as well as health needs print form for the patient’s record, and easy references and cost-effectiveness were each significant (44). In par- to other sources of information can be provided either in ticular, the efficiency of Internet searching was premium hand-outs or web-links (53,54). for women whose full daily schedules included manag- As with any new technology, potential problems ing child care, elder care, and/or personal health issues. exist with “digital doctoring” through electronic com- Advances in telecommunications and interactive munications, including concerns over privacy issues; media offer both advantages and potential risks in health uncertainty as to the reception of the message; nonuni- communication. The Science Panel on Interactive Com- versal access, especially for those more vulnerable and munication and Health (43) found that the benefits of already underserved populations (55,56); the potential IHC include enhanced opportunities for the provision of for managing staggering e-mail volume; or an inability information “tailored” to the specific needs or charac- to respond in an efficient manner, which could create teristics of those searching the Web; increased access to increasing patient dissatisfaction or enhance the imper- information and support at the user’s convenience; greater sonal nature of medical encounters (56,53). Specific rec- opportunities for interaction with clinical experts as well ommendations for clinical e-mail and medicolegal and as obtaining support from others with similar conditions administrative e-mail guidelines have been developed to through e-mail or chat rooms; and enhanced abilities for enhance the use of this technology in positive and pro- the widespread dissemination and currency of content. ductive ways (54). Potential problems with direct Internet access also These technologies can have a democratizing effect exist, including the lack of regulation on the quality of the on access to and control of information between health health information presented, which potentially com- care professionals and laypersons. These types of inter- promises the accuracy and appropriateness of the mate- actions have the potential for increased availability, a bet- rial online. This can result in patients obtaining inappro- ter understanding of various aspects of the diagnosis or priate treatment or delay in seeking necessary medical management of a health condition, and better prepara- care. Further, greater reliance on IHC can erode people’s tion for health care visits (44). trust in their health care professionals and prescribed ther- Despite all its potential, it is equally important to apies if there are substantial differences of opinion. Pri- recognize that these newest information technologies con- vacy and confidentiality may be violated (43). tinue to emphasize the gaps between the privileged and E-mail is also becoming a useful adjunct to the less fortunate of our society (55). Whether the issues patient–clinician communications, replacing the tele- are access to obtaining health care, health insurance, or phone in efficiency and provider accessibility. Typically, health information, the largest barrier for a substantial important aspects of health care take place via tele- portion of women remains the acquisition of adequate phone—patients call to ask advice, get prescription refills, education and income to afford these essentials. A major and give feedback on previously prescribed therapies, challenge of the future will include finding solutions to whereas providers call to discuss lab results or follow a bridge the “digital divide” to improve health care services patient’s progress. Problems encountered with this tech- for all. nology include missed telephone calls in either direction, lines that are often busy, or interruptions to the recipient’s Traditional Communication within Health Care activity. Misunderstanding or misinterpretation is common over the phone and can lead to poor compliance A fundamental component of effective health care is the with medical advice. The documentation of these calls is dialog that occurs between patients and their clinicians. often incomplete, which makes the subsequent decision- The communication that is exchanged between women making process challenging and increases the clinician’s and their physicians is central to the quality of the ther- legal liability (53). apeutic alliance that they establish. It is through talk that For nonemergent medical issues, e-mail has the unique interpersonal relationships are shaped, essential potential to improve patient–clinician communications. medical information is exchanged, health problems or For the patient, e-mail can reduce the inconvenience of risks are identified, health education and counseling is dis- waiting for call-backs; questions can be formulated more cussed, and decisions about treatment options or pre- purposefully; the clinician’s instructions can be read, vention measures are negotiated and carried out. saved, and later reread; sensitive questions may be easier Widely studied, the significant benefits of proficient to ask electronically; and the ability to ask quick ques- communication between patients and clinicians include tions between visits gives a sense of greater access to med- reduced patient anxiety, enhanced patient understanding 34 NEUROLOGIC DISEASE IN WOMEN

and recall, increased perceptions of personal control over talk differently as a result. Girls and boys grow up in dif- one’s health, satisfaction with medical care, adherence to ferent worlds, even when they grow up in the same house- medical therapeutics, and subsequent improved health holds. These differences continue into adulthood and status (57–65). reinforce communication patterns established in child- Yet, women’s experiences of the health care system hood (72, p. 133). Recognizing these gender differences, often reflect a less than courteous climate. Women which include differing expectations about the role of talk patients may encounter a physician’s inappropriate use of in relationships, is essential to the provision of quality familiar forms of address (i.e., using the patient’s first health care to women. name), disparagement of their abilities to use medical In studies of patient–provider communication, information rationally, a condescending manner, or with- women are more likely to recognize and report symptoms holding technical information, such as the benefits and as well as be more articulate and knowledgeable when risks of informed consent. These kinds of exchanges have talking with their physicians during annual medical vis- been described and interpreted as ways in which the its (73). Perhaps because they are more familiar and com- physician controls the medical visit and the patient’s fortable with health system utilization, women talk more behavior (66–68). and offer more complaints during medical visits The consequences of communication problems, (74,61,62); ask more questions (756–77); receive more based on a review of studies on physician and patient rela- information and a greater number of explanations from tions by Stewart (69), include inaccurate medical diag- both male and female physicians (78–80), and generally noses, lack of patient participation in medical care dis- have longer medical visits than men (61,77,62) (as cussions, or inadequate provision of information to the reviewed in 70,81). Among patients with chronic disease, patient. women are more likely to prefer an active role in decision- Ineffective communication most commonly results making that males (82). in patient dissatisfaction with a physician’s care and con- Hooper and colleagues (78) determined that female sequently, the patient’s termination of their professional patients got more information and empathy from their relationship (57). From the Commonwealth Fund doctors as well as fewer physician-initiated disruptions women’s health survey data, women were approximately during their visits. Findings by Stewart (83) revealed that twice as likely as men to have changed physicians due to physicians demonstrated more tension release (e.g., laugh- dissatisfaction. Women were also more likely to report ter) with female patients and were more likely to solicit communication problems with their physicians, and this their feelings and opinions (81). issue was cited as the most important contributing factor for switching health care providers for both men and Power women (70). Ineffective communication is also a major source of stress and anxiety for the patient during the Studies of interactions between physicians and patients, medical encounter (71). however, have also described the constrained structure of typical medical encounters and the use of power or domination to limit and control medical dialog. The use Social Context of interruption and the amount of talk or words, ques- The social context of the medical encounter also influ- tion-asking, information-giving, and adversativeness are ences patient–provider interaction. The dialog between examples of methods that physicians employ to control women and their physicians occurs in a variety of clini- the course of the medical interview (84–88). One study cal settings, between individuals of unequal power, (89) revealed that physicians interrupt patients an aver- involving issues of vital importance that are both cultur- age of 18 seconds into the patient’s opening remarks. The ally and emotionally laden and thus, necessitate joint patient was only able to complete her primary complaint cooperation. The ideal patient–provider relationship in or concern 23% of the time. But, as Allen and colleagues which mutual trust exists, communication is reciprocal, (90) suggest, perhaps it is not the interruption, but the and therapeutic goals and decisions are agreed upon, is missed opportunity to disclose information about them- not easily achieved (64). selves and their situation that leaves patients feeling that they have not been taken seriously. Communication Styles Meaning Communication style differences between genders account for the distinct ways in which men and women Patients must be able to tell their stories, but may be con- use questions, volume and pitch, indirectness, interrup- fronted with their clinicians’ incompatible frame of ref- tions, silence, or polite refusals. From birth, women and erence as to what information should be shared during men are treated differently, related to differently, and they medical visits (91). Physicians may not be aware of or WOMEN’S LIVES AND THEIR EXPERIENCES WITH HEALTH CARE 35 understand women’s “explanatory models” of their Clinicians are challenged to examine the part they health concerns or their attitudes, values, and beliefs as play in creating these disparities: their expressions of bias related to illness and health care (92,93). These models (or discrimination), greater clinical uncertainty when inter- are the patient’s underlying assumptions about their med- acting with minority patients, and the beliefs (or stereo- ical condition and its related therapies, which often types) held by professionals about the behavior or health explain the types of questions that the patient asks about of minorities. In response, patients may contribute to these their condition’s etiology, symptoms, the degree of sever- dynamics through mistrust, treatment refusal, or poor ity, the type of sick role (chronic or acute) they assume, compliance with prescribed therapies. Additional barri- and various treatment options (94). These beliefs are ers to health care access for minorities can include lan- directly influenced by one’s cultural groups and social guage, geography, and cultural familiarity. Health systems class (93,95). may also contribute to these inequities because of heavy In analyzing medical discourse, Mischler (96) iden- time pressures, cognitive complexities within the clinical tifies two opposing voices: the voice of medicine (reflect- encounter, and the push for cost containment (103). ing a scientific, detached attitude) and the voice of the As one example, a study by Rivadeneyra and col- “lifeworld” (patient’s meaning of illness and how this dis- leagues (107) revealed that Spanish-speaking patients rupts the achievement of personal goals). He sees the med- experience a double disadvantage when receiving medical ical encounter as a situation of conflict between two dis- care from English-speaking physicians. Primary care tinct efforts to construct meaning (97, p. 81). As patients who spoke through an interpreter made markedly Kleinman (92) suggests, the effectiveness of professional fewer comments than did patients speaking directly with communication and health care outcomes is a function of clinicians. Due to time consumed by the interpretation the agreement between the patient’s and clinician’s process, these patients had fewer opportunities to explain explanatory models. their symptoms or raise concerns. Further, when they did Understanding the patient’s perspective of her con- offer comments, they were more likely to be ignored than dition is a prerequisite for successful clinician–patient dia- the English-speaking patients. These findings illustrate that logue. It is also important to recognize how frequently this non-English speaking patients have communication bar- perspective differs (93). Studies that have explored issues riers beyond just difficulties with translation. Rivadeneyra of potential patient–provider conflict include the degree and associates suggest that both physician and patient may to which physicians meet patient expectations (98), how change their behavior in subtle ways that may compromise often physicians are aware of patients’ concerns (99,100), the development of mutual trust, increase the likelihood of the rate of agreement between patients and physicians physician misunderstanding of the complexity associated about those problems that require follow-up visits (101), with the patient’s symptoms, and decrease the possibility and levels of agreement between patients and their physi- of patient compliance with medical advice (107). cians regarding the patient’s health status (102). Other studies have also found that clinicians deliver less information, less supportive remarks, and less proficient clinical performance to black and Hispanic patients Implications of Cultural Diversity and patients from lower economic status than they do to Racial, ethnic and social disparities exist in U.S. health more advantaged patients, even in the same setting care and have become the focus of a recent Institute of (78,80,108). Medicine report uncovering “unequal treatment” (103). The ability to establish effective interpersonal and Even after controlling for age, insurance status, income, working relationships that transcend cultural differences comorbid conditions, and symptom expression, racial defines “cultural competence.” Within health care, cul- and ethnic groups are more likely to experience a sub- tural competence describes the process by which a clini- standard quality of health care. Explanations for this dis- cian continuously attempts to be effective within the cul- parity in health care, embedded in historic and contem- tural context of a patient, who may be an individual, porary socioeconomic inequalities, are complex. family, or community (109,106). Accountabilities exist on many levels: health systems, Strategies to bridge the sociocultural inequities in administrative and bureaucratic policies, utilization man- health care include providing interpreters as well as lin- agers, and clinicians and patients (103). guistic competency to health education materials, the As the growth of ethnic populations currently incorporation of clinical staff who share similar cultural referred to as minorities continues, they will comprise backgrounds in addition to the inclusion of family or 40% of the U.S. population by 2035, and 47% by 2050 community health workers, and clinic accommodations (104). The health care needs of an increasingly diverse that adjust hours of operation and physical environment, U.S. population are now established as a goal of public and increasing the ability of professionals to interact effec- health, thus cultural, linguistic, and literacy differences tively within the culture of the patient population through must addressed (105,106). regular continuing education (110,106). 36 NEUROLOGIC DISEASE IN WOMEN

Gender Bias with better health outcomes (116). Patients are also most satisfied by interactions with physicians who encourage Research has also investigated gender bias in the deliv- them to talk about psychosocial issues in an atmosphere ery of health care—that is, if and how female patients that is characterized by the absence of domination by the are treated and perceived in a way different from male physician (118). patients by physicians. Twenty years ago, McCranie, In summary, women’s experiences of health care ser- Horowitz, and Martin (111) reported no evidence that vices and physician interactions are different from those physicians attribute psychogenic illness more frequently of their male patient counterparts. The role of commu- to women than men or recommend psychological treat- nication is paramount to ensuring maximal health out- ments more to women. Verbrugge and Steiner (112) also comes. As information technology becomes more acces- failed to identify any significant gender differences in tests sible and more widely utilized, the nature of this and procedures in their analyses of National Ambulatory communication will change. Yet, interpersonal interac- Medical Care Survey data. tions are essential to health care provision. A mutual More recent research in coronary artery disease, kid- appreciation and respect for the expertise that each indi- ney dialysis and transplantation, and the diagnosis of lung vidual (patient or clinician) brings to the medical cancer (113–115) provides convincing evidence that dif- encounter will facilitate more substantive dialog. Assim- ferences in the quality of the technical care received by ilating the principles of cultural competence enhances the women cannot be explained by other factors, such as interactions and significantly influences the outcomes of poorer health status (116). care. Just as physicians are technical experts in medical Bernstein and Kane (117) investigated the relative science and therapeutic options, so women are experts impact of patient gender and expressivity on attitudes of in how they feel, both physically and emotionally. Women primary care physicians toward patients. Their research can usually talk about how their health or illness affects determined that physicians believed that women were the complexity of their lives, their careers, and families or more likely to make excessive demands as compared to relationships. Women must be listened to without inter- men, women’s health complaints were assessed as more ruption and believed by their care providers. Physicians likely to be influenced by emotional factors, and women must attempt to integrate the complex, contextual aspects were identified more frequently with psychosomatic com- of women’s health or illness and not focus solely on the plaints than men. Their results supported their hypothe- pathology of their medical condition and its treatment. ses that physicians have preconceptions about female patients. They also argue, however, that differences in References physicians’ responses are not simply due to bias against women, but may be a complex response to the open and 1. Weisman CS. Women’s health care: activist traditions expressive behavioral style more frequently identified in and institutional change. Baltimore, Md: The Johns Hopkins University Press, 1998;10–36. women. They suggest that their findings underline the 2. Wizemann TM, Pardue M-L (eds). Exploring the Bio- necessity for physicians to rise above stereotypes and treat logical contributions to human health: does sex matter? each patient as an individual, instead of a member of a Washington, DC: National Academy Press, 2001. group (118, p. 607). 3. Connell R. Gender and power. Stanford, Calif: Stanford University Press, 1987. 4. Pinn VW. Sex and gender factors in medical studies: Collaboration implications for health and clinical practice. JAMA 2003;289(4):397–399. Increasing evidence exists for the value of a collabora- 5. U.S. Department of Labor, Bureau of Labor Statistics, tive model of communication that promotes mutual inter- August 2001. Highlights of women’s earnings in 2000 action between patients and providers. Roter and Hall (Report 952). http://www.bls.gov/cps/cpswom2000.pdf. Accessed 1/12/03. (87) offer a framework for understanding patient– 6. U.S. Department of Health and Human Services. provider communication as a partnership, each having Women, work and health. DHHS Pub No. (PHS) 98- certain responsibilities to contribute to the quality of their 1791. Washington, DC: USDHHS, 1997. exchange. This model suggests associations between the 7. Messing K. Multiple roles and complex exposures: hard- patient’s question-asking (and the information that is sub- to-pin down risks for working women. In: Goldman MB, Hatch MC, (eds.) Women & Health. San Diego, Calif: sequently offered by the provider) with the patient’s over- Academic Press, 2000;455–462. all comprehension, agreement with treatment, and con- 8. Collins KS, Schoen C, Joseph S, et al. Health concerns tinuance with prescribed therapies. across the lifespan: 1998 Survey of Women’s Health. The value of patient involvement during the medical New York, NY: The Commonwealth Fund, 1999. encounter is revealed through enhanced patient satisfac- 9. U.S. Census Bureau and Bureau of Labor Statistics, Cur- rent Population Survey, Annual Demographic Survey, tion and loyalty to the clinician (70); among patients with March 2000 (Table 1). http://ferret.bls.census.gov/ chronic diseases, active patient participation is associated macro/032001/pov/toc.htm. Accessed 1/12/03. WOMEN’S LIVES AND THEIR EXPERIENCES WITH HEALTH CARE 37

10. U.S. Bureau of the Census. Poverty in the United States 30. Nathanson C. Social roles and health status among 1998: current population reports. Washington, DC: U.S. women: the significance of employment. Soc Sci Med Bureau of the Census. 1980;14a:463–471. 11. Wilson J. Women and poverty: a demographic overview. 31. Frankenhauser M. The psychophysiology of sex differ- Women’s Health 1987;12(3/4):21–40. ences as related to occupation. In: Frankenhauser M, 12. Richardson H. The health plight of rural women. Lundberg U, Chesney M, (eds.) Women, work and Women’s Health 1987;12(3/4):41–54. health: stress and opportunities. New York, NY: Plenum, 13. Institute for Research on Poverty (IRP). Who was poor 1991;35–64. in 2001? http://www.ssc.wisc.edu/irp/faqx/faq3.htm. 32. Hochschild A, Machung A. The second shift. New York, Accessed 1/13/03. NY: Avon Books, 1990. 14. American College of Physicians-American Society of 33. Woods N. Employment, family roles, and mental ill Internal Medicine. White paper: No health insurance? health in young adult married women. Nursing Research It’s enough to make you sick. Philadelphia, Pa: Ameri- 1985;34(1):4–9. can College of Physicians-American Society of Internal 34. Van Fossen B. Sex differences in the mental health effects Medicine, 2000. of spouse support and equity. J Health Soc Behav 15. Campbell J, Landenberger K. Violence against women. 1981;22:130–143. In: Fogel C, Woods N, (eds.) Women’s health care: A 35. McBride A. Multiple roles. Am Psych 1990;45:381–384. comprehensive handbook. Thousand Oaks, Calif: Sage, 36. Miller J. The development of a woman’s sense of self. In: 1995. Jordan J, Kaplan A, Miler J, Stiver I, Surrey J, (eds.) 16. Plichta SB, Falik M. Prevalence of violence and its impli- Women’s growth in connection: writings from the Stone cations for women’s health. Women’s Health Issues Center. New York, NY: Guilford, 1991;11–26. 2001;11(3):244–258. 37. Surrey J. The “self-in-relation”: A theory of women’s 17. Faludi S. Backlash. New York, NY: Crown Books, 1991. development. In: Jordan, op cit. 1991;51–66. 18. McLaughlin S, Melber B. The changing lifecourse of 38. Jordan J. Empathy and self boundaries. In Jordan, op cit. American women: Life-style and attitude changes, draft. 1991;67–80. Seattle, Wash: Battelle Human Affairs Research Centers, 39. Raymond J. A Passion for friends: toward a philosophy 1986. of female affection. Boston, Mass: Beacon, 1986. 19. U.S. Department of Commerce News. US Census Bureau 40. Belenky M, et al. Women’s ways of knowing: the devel- releases profile of nation’s women, 2001. Washington, opment of self, voice, and mind. New York, NY: Basic DC: http://www.census.gov/Press-Release/www/2001/ Books, 1986. cb01-49.html. 41. Gilligan C. In a different voice: psychological theory and 20. Bernstein AB. Motherhood, health status, and health women’s development. Cambridge, Mass: Harvard Uni- care. Women’s Health Issues 2001;11(3):173–184. versity Press, 1982. 21. U.S. Department of Commerce News. U.S. Census 42. Nussbaum R. Studies of women’s health care: selected Bureau releases record share of new mothers in labor results. Permanente Journal 2000;4(3):62–67. force, Census Bureau Reports. Washington, DC: 2000. 43. Robinson TN, Patrick K, Eng TR, Gustafson D, for the http://www.census.gov/Press-Release/www/2000/cb00- Science Panel on Interactive Communication and Health. 175.html. Accessed 1/12/03. An evidence-based approach to interactive health com- 22. Collins K, Rowland D, Salganicoff A, Chait E. Assessing munication: a challenge to medicine in the information and improving women’s health. In: Costello C, Stone A, age. JAMA 1998;280(14):1264–1269. (eds.) The American woman: 1994–: Where We Stand. 44. Pandey SK, Hart JJ, Tiwary S. Women’s health and the New York, NY: Norton, 1994;154–196. Internet: understanding emerging trends and implica- 23. U.S. Census Bureau Public Affairs Information Office. tions. Soc Sci Med 2003;56:179–191. U.S. Census Bureau facts for features: women’s history 45. Weisman CS. Women’s use of health care. In: Falik MM, month: March 1-31. Washington, DC: 2001. Collins KS, (eds.) Women’s Health: the Commonwealth http://www.census.gov/Press-Release/www/2001/ Fund survey. Baltimore, Md: Johns Hopkins University cb01ff03.html. Accessed 1/12/03. Press, 1996;19–48. 24. McGovern P, Gjerdingen D, Froberg D. The parental 46. Society for Women’s Health Research. Women’s Health- leave debate: implications for policy relevant research. links. http://www.womens-health-org/healthfactsheet2. Women’s Health 1992;18:97–118. html. Accessed 5/18/01. 25. Donelan K, Falik M, DesRoches CM. Caregiving: chal- 47. Healy BP. Editorial: listening to America’s women. J lenges and implications for women’s health. Women’s Wom Health 1995;4(6):589–590. Health Issues 2001;11(5):185. 48. Rothert M, Padonu G, Holmes-Rovner M, et al. 26. Russo N. Overview: forging research priorities for Menopausal women as decision makers in health care. women’s mental health. Am Psych 1990;45(3): Exp Gerontol 1994;29:(3/4):463–468. 368–373. 49. Rothert M, Rovner D, Holmes M, et al. Women’s use 27. Verbrugge L. Role burdens and physical health of of information regarding hormone replacement therapy. women and men. Women’s Health 1986;11(1):47–77. Res Nurs Health 1990;13(6):355–366. 28. U.S. Census Bureau Public Affairs Information Office. 50. U.S. Department of Commerce. A nation online: how U.S. Census Bureau facts for features: mother’s day Americans are expanding their use of the Internet. Wash- 1999: May 9. Washington, DC: 1999. http://www. ington, DC: 2/2002. http://www.nti.doc.gov/ntia- census.gov/Press-Release/www/1999/cb99ff07.html. home/dn/html. Accessed 12/15/02. Accessed 1/12/03. 51. Hoffman D, Novak T. Bridging the racial divide on the 29. Haynes S, Feinleib M. Women, work, and coronary heart Internet. Science 1998;390–391. disease: prospective findings from the Framingham 52. Pew Internet & American Life Project http://pewinter Heart Study. Am J Public Health 1980;70(2):133–141. net.org/reports/reports.asp. Accessed 12/2/02. 38 NEUROLOGIC DISEASE IN WOMEN

53. Leber S, Mack K. The Internet and clinical practice of 75. Wallen J, Waitzkin H, Stoeckle J. Physician stereotypes child neurology. Curr Op Neurol 2000;13:147–153. about female health and illness: a study of patient’s sex 54. Kane B, Sands DZ and the American Medical Informat- and the informative process during medical interviews. ics Association Task Force on Guidelines for the Use of Wom Health 1979;4:135. Clinic-Patient Electronic Mail. Guidelines for the clini- 76. Kaplan SH, Greenfield S. Gender differences in physical use of electronic mail with patients. J American cian-patient communication for patients seeing the same Inform Assoc 1998;5:104–111. and opposite gender physicians [Abstract]. Soc Gen 55. Eng TR, Maxfield A, Patrick K, Deering MJ, Ratzan SC, Intern Med 1991. Gustafson DH. Access to health information and sup- 77. Roter DL, Lipkin M, Korsgaard A. Sex differences in port: a public highway or a private road? JAMA patients’ and physicians’ communication during primary 1998;280:1371–1375. care visits. Med Care 1991;29(11):1083–1093. 56. Mandl DK, Kohane IS, Brandt AM. Electronic patient- 78. Hooper EM, Comstock LM, Goodwin JM, Goodwin JS. physician communication: problems and promises. Ann Patient characteristics that influence physician behav- Intern Med 1998;129:495–500. ior. Med Care 1982;20(6):630–638. 57. Hall J, Roter D, Katz NR. Correlates of provider behav- 79. Pendleton DA, Bochner S. The communication of med- ior: a meta-analysis. Med Care 1988;26(7):657–675. ical information in general practice consultations as a 58. Kaplan SH, Greenfield S, Ware JE Jr. Assessing the effects function of patients’ social class. Soc Sci Med of physician-patient interactions: the outcomes of 1980;14A(6):669–673. chronic disease. Med Care 1989;27(suppl 3):S110–S127. 80. Waitzkin H. Information giving in medical care. J Health 59. Brody DS, Miller SM, Lerman CE, Smith DG, Caputo Soc Behav 1985;26(2):81–101. GC. Patient perception of involvement in medical care: 81. Hall JA, Irish JT, Roter DL, Ehrlich CM, Miller LH. relationship to illness attitudes and outcomes. J Gen Gender in medical encounters: an analysis of physician Intern Med 1989;4(Nov/Dec):506–511. and patient communication in a primary care setting. 60. Anderson LA, Sharpe PA. Improving patient and Health Psych 1994;13(5):384–392. provider communication: a synthesis and review of com- 82. Arora NK, McHorney CA. Patient preferences for med- munication interventions. Patient Education Counseling ical decision making: who really wants to participate? 1991;17:99–134. Med Care 2000;38(3):335–341. 61. Meeuwesen L, Schaap C, Van der Staak C. Verbal analy- 83. Stewart M. Patient characteristics which are related to sis of doctor-patient communication. Soc Sci Med the doctor-patient interaction. Fam Prac 1983;1:30–36. 1991;32(10):1143–1150. 84. Svarstad BL. The doctor-patient encounter: an observa- 62. Bensing J, van der Brink-Muinen A, de Bakker D. Gen- tional study of communication and outcome. Doctoral der differences in practice style: a Dutch study of general dissertation, University of Wisconsin, Madison, 1974. practitioners. Medical Care 1993;31(3):219–229. 85. West C, Zimmerman DH. Small insults: a study of inter- 63. Hodne CJ, Reiter RC. Decision-making in women’s ruptions in cross-sex conversations between unac- health care. Clin Obstet Gynecol 1994;37(1):162–178. quainted persons. In: Thorne B, Kramarer C, Henley N 64. Ong LML, DeHaes JCJM, Hoos AM, Lammes FB. Doc- (eds.) Language, gender and society. Rowley, Mass: tor-patient communication: a review of the literature. Newbury House, 1983;103–117. Socl Sci Med 1995;40(7):903–918. 86. West C, Zimmerman DH. Doing gender. Gender in Soci- 65. Lin CT, Albertson GA, Schilling LM, et al. Is patients’ ety 1987;1:125–151. perception of time spent with the physician a determi- 87. Roter DL, Hall JA. Health education theory: an appli- nant of ambulatory patient satisfaction? Arch Intern cation to the process of patient-provider communication. Med 2001;161:1437–1442. Health Ed 1991;6:1301–1306. 66. Fisher S. In the patient’s best interest: women and the 88. Tannen D. You just don’t understand: women and men politics of medical decisions. New Brunswick, NJ: Rut- in conversation. New York, NY: William Morris, 1990. gers University Press, 1986. 89. Beckman HB, Frankel RM. The effect of physician 67. Ruzek S. The women’s health movement. New York, behavior on the collection of data. Ann Intern Med NY: Praeger, 1979. 1984;101(5):692–696. 68. Weisman C, Teitelbaum M. Women and health care com- 90. Allen D, Gilchrist V, Levinson W, Roter D. Caring for munication. Patient Ed Counse 1989;13:183–189. women: is it different? Schroeder H, ed. Patient Care 69. Stewart MA. Effective physician-patient communication Nov 1993;183–196. and health outcomes: a review. Canadian Med Assoc J 91. Mathews JJ. The communication process in clinical set- 1995;152(9):1423–1433. tings. Soc Sci Med 1983;17(18):1371–1378. 70. Kaplan SH, Sullivan LM, Spetter D, Dukes KA, Khan 92. Kleinman AM. Patients and healers in the context of cul- A, Greenfield S. Gender and patterns of physician- ture. Los Angeles, Calif: University of California Press, patient communication. In: Falik MM, Collins KS, (eds.) 1987. Women’s health: The commonwealth fund survey. Bal- 93. Helman CG. Communication in primary care: the role timore, Md: Johns Hopkins University Press, 1996; of patient and practitioner explanatory models. Soc Sci 76–95. Med 1985;20(9):923–931. 71. Roter DL. Patient question asking in physician-patient 94. Joos SK, Hickam DH. How health professionals influ- interaction. Health Psych 1984;3(5):395–409. ence health behavior: Patient-provider interaction and 72. Tannen D. Gender and discourse. New York, NY: health care outcomes. In: Glanz K, Lewis FM, Rimer BK, Oxford University Press, 1994. (eds.) Health behavior and health education. San Fran- 73. Weisman C, Teitelbaum M. Women and health care com- cisco, Calif: Jossey-Bass, 1990;216–241. munication. Patient Ed Counse 1989;13:183–189. 95. Kleinman A, Eisenberg L, Good B. Culture, illness, and 74. Verbrugge L. Sex differences in complaints and diag- care: clinical lessons from anthropologic and cross-cul- noses. J Behav Med 1980;3:327–355. tural research. Ann Intern Med 1978;88(2):251–258. WOMEN’S LIVES AND THEIR EXPERIENCES WITH HEALTH CARE 39

96. Mischler EG. The discourse of medicine: dialectics of 107. Rivadeneyra R, Elderkin-Thompson V, Cohen Silver R, medical interviews. Norwood, NY: Ablex, 1984. Waitzkin H. Patient centeredness in medical encounters 97. Weston WW, Brown JB. The importance of patients’ requiring an interpreter. Am J Med 2000;108:470–474. beliefs. In: Stewart M, Roter D, (eds.) Communicating 108. Wasserman RC, Inui TS, Barriatua RD, Carter WB, Lip- with medical patients. Newbury Park, Calif: Sage Pub- pincott P. Pediatric clinicians’ support for parents makes lications, 1989;77–85. a difference: an outcome-based analysis of clinician-par- 98. Bell RA, Kravitz RL, Thorn D, Krupat E, Azari R. Unmet ent interaction. Pediatrics 1984;74:1047–1053. expectations for care and the patient-physician relation- 109. Camphina-Bacote J. A model and instrument for ship. J Gen Intern Med 2002;17:817–824. addressing cultural competence in health care. J Nurs Ed 99. Krupat E, Rosenkranz SL, Yeager CM, Barnard K, Put- 1999;38:203–220. nam SM, Inui TS. The practice orientations of physicians 110. Brach C, Fraser I. Can cultural competency reduce racial and patients: the effect of doctor-patient congruence on and ethnic disparities? A review and conceptual model. satisfaction. Patient Ed Counsel 2000;39:49–59. Med Care Res Rev 2000;57(suppl 1):181–210. 100. Levinson W, Gorawar-Bhat, Lamb J. A study of patient 111. McCranie EW, Horowitz AJ, Martin RM. Alleged sex- clues and physician responses in primary care and sur- role stereotyping in the assessment of women’s physical gical settings. JAMA 2000;284:1021–1027. complaints: a study of general practitioners. Soc Sci Med 101. Starfield B, Steinwachs D, Morris I, Bause G, Siebert S, 1978;12(2A):111–116. Westin C. Patient-doctor agreement about problems 112. Verbrugge LM, Steiner RP. Physician treatment of men needing follow-up visit. JAMA 1979;242(4):344–346. and women patients: sex bias or appropriate care? Med 102. Rakowski W, Hickey T, Dengiz A. Congruence of health Care 1981;19(6):609–632. and treatment perceptions among older patients and 113. Wenger NK, Speroff L, Packard B. Cardiovascular health providers of primary care. Int J Aging Hum Devel and disease in women. N Engl J Med 1993;329(4): 1987;25:67–81. 247–256. 103. Smedley BD, Stith AY, Nelson AR, (eds.) Unequal treat- 114. Ayanian JZ, Epstein AM. Differences in the use of pro- ment: confronting racial and ethnic disparities in health cedures between men and women hospitalized for coro- care. Washington, DC: The National Academies Press, nary artery disease. N Engl J Med 1991;325:221–225. 2002. 115. Council on Ethical and Judicial Affairs, American Med- 104. U.S. Bureau of the Census. Current population reports, ical Association. Gender disparities in clinical decision- series P25-1130: population projections for the U.S. by making. JAMA 1991;266(4):559–562. sex, race and Hispanic origin, 1995-2050. Washington, 116. Kaplan SH, Gandek B, Greenfield S, Rogers WH, Ware DC: U.S. Bureau of the Census, 1996. JE Jr. Patient and visit characteristics related to physi- 105. Agency for Health Care Policy and Research. Under- cians’ participatory decision-making style: results from standing and eliminating minority health disparities the medical outcomes study. Med Care 1995;33(12): (RFA: HS-00-003). Rockville, Md: Agency for Health 1176–1187. Care Policy and Research, 1999. 117. Bernstein B, Kane R. Physicians’ attitudes toward female 106. Cooper LA, Roter DL. Patient-provider communication: patients. Med Care 1981;19(6):600–608. the effect of race and ethnicity on process and outcomes 118. Bertakis KD, Helms LJ, Callahan EJ, Azari R, Robbins of health care. In: Smedley BD, Stith AY, Nelson AR, JA. The influence of gender of physician practice style. (eds.) Unequal treatment: confronting racial and ethnic Med Care 1995;33(4):407–416. disparities in health care. Washington, DC: The National Academies Press, 2002;330–354.

Drug Treatments 4 and Trials in Women

Stephen D. Silberstein

rugs are usually developed and example, the belief that reproduction and fetal health are tested in young to middle-aged exclusively women’s health issues has resulted in a lack of adults despite the fact that age and investigation of male-mediated reproductive toxicity (2). D gender differences exist in pharmacokinetics (how individuals handle drugs) and pharmacodynamics (how individuals respond to drugs) (1). GENDER DIFFERENCES Drugs are not usually developed for or specifically evaluated in children, and the adult drug dose cannot always Gender can lead to differences in pharmacokinetics. be safely converted to its pediatric equivalent (1). Phar- Women often have higher plasma drug concentrations macodynamic differences can lead to unexpected out- than men receiving the same dose; for example, lidocaine comes and adverse effects. For example, antihistamines and chlordiazepoxide levels are higher in women because and barbiturates, which generally sedate adults, often of longer elimination half-life (3). Oral contraceptive cause children to become hyperactive. Chronic pheno- (OC) use, sex differences in basal metabolism, and hor- barbital therapy can affect learning and behavior in chil- mone and enzyme levels all influence drug metabolism. dren (1). In infants, pharmacokinetic differences may OCs can prolong the elimination half-life of drugs that affect drug bioavailability. Low gastric acidity, slower are metabolized by hepatic oxidation. Differences in vas- absorption rates, and a difference in gastric emptying time cular resistance, muscle mass, and muscle composition may influence the absorption of orally administered drugs may cause a variation in absorption from intramuscular in the neonate. injections. Differences in gastric motility and secretion Pregnant women are often excluded from drug tri- and metabolic rate may influence plasma levels of orally als, despite the fact that they may metabolize drugs in a administered drugs (3). way different from nonpregnant women. Differences Gender differences may be present in psychotropic between breast-feeding mothers and other women of the drugs. In one study, male schizophrenic patients required same age could cause changes in drug distribution. Fat less medication and had a more favorable outcome than accumulated during pregnancy is still present in the nurs- female patients (3). Findings from a more recent study ing mother and may affect the distribution of fat-soluble by Yonkers and coworkers (4), however, indicate that drugs. Sex bias may result in the perception that women antipsychotic agents have greater efficacy in women as have a higher biologic vulnerability than do men. For well as greater likelihood of adverse reactions. 41 42 NEUROLOGIC DISEASE IN WOMEN

Gender differences depend in part on which sex hor- (increased LH pulse frequency promotes the development mone milestone a woman has passed. Menarche marks of PCOS). the onset of the cyclic ovarian function that spans the time Valproate use in women with epilepsy is associated between puberty and menopause, which themselves are with a higher incidence of PCOS (10,11) than other transitional periods of increasing or decreasing ovarian antiepileptic drugs (AEDs). Isojärvi and coworkers (11) activity. Menses are a peripheral marker of steroid hor- have suggested that this is due to valproate-induced mone withdrawal that bridges smooth changes in hor- weight gain and induced insulin resistance. PCOS, how- mone levels: Follicular growth with rising estrogen lev- ever, is more common in valproate-treated obese women els is followed by ovulation and rising progesterone levels. with epilepsy than in obese normal control subjects. Her- Other sex hormone milestones include pregnancy, OC zog (12) has speculated that the fundamental problem is use, and estrogen replacement therapy. Differences in sex epilepsy itself, which is associated with PCOS, and that hormone levels can influence drug metabolism, and drugs the other AEDS induce cytochrome P450 and accelerate can influence sex hormone levels (5). the biotransformation of testosterone, whereas valproate The phase of the menstrual cycle can affect alcohol does not. This association occurs only in women with metabolism. Decreased elimination times, reduced area epilepsy treated with valproate and has not been shown under the curves (AUCs; a measure of bioavailability), to occur with increased frequency in women with other and faster disappearance rates occur during the midluteal disorders, such as mania or migraine. Women with phase compared with the early follicular and ovulatory epilepsy can be treated with valproate, but they should be phases. The midluteal phase is associated with higher followed up for menstrual irregularities. If irregularities progesterone levels, elevated progesterone-estradiol occur, ultrasound may be indicated. ratios, and lower follicle-stimulating hormone (FSH) levels (6). When postmenopausal women take oral replace- RISK OF DRUG TREATMENT ment estrogen, alcohol ingestion can lead to a threefold increase in circulating estradiol levels, similar to the A teratogen is usually defined as any agent, physical force, changes that occur when women use transdermal estro- or other factor that can induce a congenital anomaly gen. Estrone levels decrease after alcohol ingestion, per- through the alteration of normal development during any haps due to decreased conversion from estradiol. stage of embryogenesis (8). Increased oxidation of sulfated estrogen precursor andro- The recognition of the teratogenicity of aminopterin gens to estradiol occurs in rats in response to alcohol and and thalidomide and the rubella epidemic of 1963–1964, may account in part for higher estradiol levels (7). resulted in extremely conservative drug use during preg- Gender differences can also be caused by nonhor- nancy. In 1977, the Food and Drug Administration (FDA) monal factors, such as (i) poverty and socioeconomic sta- developed a policy against phase I and early phase II test- tus; (ii) nutritional deficits related to poverty or to eating for pregnant women or women of childbearing poten- ing behavior, such as cyclical dieting; and (iii) tial, and many practitioners now avoid drug treatment occupational selection biases that favor women, as in in pregnancy even when it is indicated. More than 2,500 nursing or housecleaning. Each of these factors can affect agents are listed in Shepard’s catalog of teratogenic a woman’s metabolism, and some can increase her expo- agents. About 1,200 can produce congenital anomalies in sure to toxins (2). experimental animals, but only about 40 of these are Gender, disease state, and drugs can interact. Poly- known to cause defects in the human (8). Insufficient cystic ovarian syndrome (PCOS), characterized clinically knowledge exists about the birth defect risks from drug by hirsutism and menstrual irregularities, is frequently (30 exposure, despite the fact that 67% of women take drugs to 50%) associated with obesity. Multiple follicular cysts during pregnancy, and 50% take them during the first and increased stroma in the ovaries may be found on trimester (9). ultrasonography. Hyperandrogenism is caused by ele- Most drugs cross the placenta and have the poten- vated serum levels of testosterone, androstenedione, or tial to adversely affect the fetus, and although studies have dehydroepiandrosterone sulfate. Elevated luteinizing hor- not absolutely established the safety of any medication mone (LH), FSH, and prolactin levels are common. during pregnancy, some drugs are believed to be relatively Menstrual disorders, altered pulsatile secretion of safe (see Tables 4.7 through 4.21) (10–13). LH, and PCOS are common among women with epilepsy. In 1966, the FDA replaced the Multigeneration Herzog and colleagues found a 60% frequency of men- Continuous Feeding Reproductive Study with a three-seg- strual disorders and a 30% frequency of PCOS among 20 ment design, identified as Segment I (Fertility and Gen- women with untreated complex partial seizures (8), eral Reproductive Performance), Segment II (Teratology), whereas another group (9) found higher LH pulse fre- and Segment III (Perinatal and Postnatal Evaluations), for quency in untreated epileptics compared with controls testing drugs. These studies were designed to detect agents DRUG TREATMENTS AND TRIALS IN WOMEN 43 that specifically interrupt reproduction. More than 3,300 percent of the subjects took medication, each receiving an chemicals have been tested; of these, 37% are teratogenic. average of 2.9 prescriptions. Of a total of 37,309 pre- These studies frequently used very high doses of drugs, scriptions, 73% were given by obstetricians, 12% by gen- which then produced maternal toxicity, not fetal terato- eral practitioners, and 5% by midwives (11). In a survey genicity. Currently 19 drugs, or drug groups, and two of pregnant women at Parkland Memorial Hospital in chemicals have been established as human teratogens. Dallas, 40% took some type of medication other than Negative results in other species cannot predict a lack of iron or vitamin supplements, and up to 20% used an illicit teratogenicity in humans, and drugs that are teratogenic drug or alcohol (18). In contrast, in England only 35% at high doses in these species may not be teratogenic in of pregnant women took drugs or medications during humans at lower doses (14). Thalidomide, which has no pregnancy, and only 6% used medications other than vit- teratogenic effect in mice and rats, has profound terato- amin or iron supplements during the first trimester. genic effects in humans (10,15). Among 18,886 Medicaid patients in Michigan, women received an average of 3.1 prescriptions for medications other than vitamins or iron during their pregnancies (19). WOMEN AND DRUG TRIALS Approximately 70% of pregnant women in the United States took prescribed drugs, according to two surveys A negative pregnancy test is often a condition of enroll- (20,21). The National Hospital Discharge Survey found ment in a study, and postenrollment pregnancy can lead a 576% increase in discharges of drug-using parturient to the termination of participation. This poses a prob- women and a 456% increase in discharges of drug- lem for pregnant women who are sick and in need of affected newborns in the United States between 1979 and treatment. If the drug has not been tested in pregnant 1990. women during the research phase, information is lack- ing about the safety and efficacy of the drug for the Adverse Effects woman as well as for the fetus (16). The Institute of Med- icine Committee on Research in Women made the con- Adverse drug effects depend on the dose and route of troversial recommendation that pregnant and lactating administration, concomitant exposures, and timing of the women should be considered eligible for enrollment in exposure relative to the period of development, which clinical studies on a routine basis (16). This report consist of the preimplantation period, embryogenesis, and reversed the existing exclusion of pregnant women and fetal development. The preimplantation period lasts from the severely restricted enrollment of women of “child- conception to 1 week postconception, during which time bearing potential” in most clinical studies. With regard the conceptus is relatively protected from drugs (18). to enrollment, the Committee recommended that women Embryogenesis is the time of organogenesis, which occurs who are or may become pregnant during the course of a from the time of implantation to 58 to 60 days postcon- study should be viewed as any other potential research ception (18). Most congenital malformations arise dur- subject. ing this time. Placental transport is not well established With more women of childbearing age participating until the fifth week after conception. This may protect the in clinical trials, more information will be gained about embryo from maternal drugs. The final phase, fetal devel- the risks of birth defects, but uncertainty will still per- opment, follows embryogenesis. The fetus grows mainly sist. If the medication is associated with a very high level in size, although structural changes such as neuronal of birth defects (e.g., thalidomide), however, very few arrangement also occur. Malformations can develop at exposures need to be followed to detect this risk; if the this time in normally formed organs due to their necro- medication is associated with a slight increase in the over- sis and reabsorption (18). all occurrence of birth defects, approximately 300 Death to the conceptus, teratogenicity, fetal growth exposed pregnancies need to be followed up to detect a abnormalities, perinatal effects, postnatal developmen- doubling of risk; and if the medication is associated with tal abnormalities, delayed oncogenesis, and functional a rare increase of a specific defect (e.g., 1 in 1,000), and behavioral changes can result from drugs or other approximately 10,000 exposed pregnancies need to be agents (Table 4.1) (10). According to the Perinatal Col- followed up to detect a doubling of risk (17). laborative Project, a prospective and concurrent epidemiologic study of more than 50,000 pregnancies, many drugs have little or no human teratogenic risk (10,22). DRUG USE DURING PREGNANCY Spontaneous Abortion The World Health Organization (WHO) completed an international survey of 14,778 pregnant women on pre- Nearly one-half of early pregnancies (0 to 58 days) spon- scription drug utilization during pregnancy. Eighty-six taneously abort, most due to chromosomal abnormalities. 44 NEUROLOGIC DISEASE IN WOMEN

this background rate. TABLE 4.1 Birth defects are more common in the children of Definitions and Drug Effects (10) epileptics, even those who are not taking drugs. The risk is further increased if AEDs are used. Treatment with mul- Spontaneous Death of the conceptus. Most due tiple AEDs increases the teratogenic risk; therefore, abortion: to chromosomal abnormality. monotherapy is advocated (23,24). Overlapping drugs Embryotoxicity: The ability of drugs to kill the during AED change may expose the fetus to higher con- anomalies: developing embryo. centrations of toxic metabolites and is relatively con- Congenital Deviation from normal morphol- traindicated. ogy or function. The classic teratogenic period in the human is a crit- Teratogenicity: The ability of an exogenous agent ical 6 weeks, lasting from approximately 31 days through to produce a permanent abnor- 10 weeks from the last menstrual period. A teratogenic mality of structure or function in effect depends on the timing of the exposure as well as an organism exposed during on the nature of the teratogen. Exposure early in the preg- embryogenesis or fetal life. nancy, when the heart and central nervous system are Fetal effects: Growth retardation, abnormal forming, may result in an anomaly such as congenital histogenesis (also congenital heart disease or neural tube defect, whereas later expo- abnormalities and fetal death). The main outcome of fetal drug sure may result in malformation of the palate or ear (10). toxicity during the second and After the teratogenic period has passed, the major risk third trimesters of pregnancy. of congenital anomaly is gone, but other abnormalities Perinatal effects: Effects on uterine contraction, can occur. These include fetal effects, neonatal effects, and neonatal withdrawal, or postnatal effects. hemostasis. Postnatal effects: Drugs may have delayed long- Fetal Effects term effects: delayed oncogenesis, and functional and behavioral Fetal effects include damage to normally formed organs, abnormalities. damage to systems undergoing histogenesis, growth retardation, or fetal death. Growth retardation is the most common of these. Before the time of organogenesis, exposure to a potential teratogen or toxic drug has an all-or-none effect. An expo- Neonatal and Postnatal Effects sure around the time of conception or implantation may Certain drugs are associated with adverse neonatal kill the conceptus, but if the pregnancy continues, there is effects, such as drug withdrawal and neonatal hypo- no increased risk of congenital anomalies (10). glycemia, or adverse maternal effects, such as hemostasis and uterine contracture disorders. Chronic exposure Developmental Defects to psychoactive medications, such as alcohol, during the second and third trimesters may cause mental retardation, Developmental defects may result from genetic or envi- which may not be recognized until later in life (10). Devel- ronmental causes, or from interactions between them. opmental delay and long-term cognitive dysfunction have Teratogenic drug effects are generally visible anatomic been reported in children born to mothers who took malformations; they are defined as the production of a AEDs during pregnancy. permanent alteration of an organ’s structure or function due to intrauterine exposure. These effects are dose- and time-related, with the fetus at greatest risk during the first Delayed Oncogenesis trimester of pregnancy. Drug exposure accounts for only Exposure to diethylstilbestrol as late as 20 weeks’ gesta- 2 to 3% of birth defects; approximately 25% are genetic, tion may cause reproductive organ anomalies that are not and the causes of the remainder are unknown (10). The recognized until after puberty. incidence of major malformations either incompatible with survival (e.g., anencephaly) or requiring major surgery (e.g., cleft palate or congenital heart disease) is Drug Risk Categories approximately 2 to 3% in the general population. If all The FDA lists five categories of labeling for drug use in minor malformations are included (ear tags or extra dig- pregnancy (Table 4.2) (11,25). These categories are its), the rate may be as high as 7 to 10%. The risk of mal- intended to provide therapeutic guidance, weighing the formation after drug exposure must be compared with risks as well as the benefits of the drug. Although this sys- DRUG TREATMENTS AND TRIALS IN WOMEN 45

were taking phenytoin needed 1 mg of folate supple- TABLE 4.2 mentation a day to maintain a normal serum level (34). FDA Risk Categories Some suggest increasing folic acid intake by 4 mg, which might result in a 48% reduction in neural tube defects Category A: Controlled human studies show no risk (28). Supplementing this by fortifying food with folate Category B: No evidence of risk in humans, but there benefits all women. are no controlled human studies Category C: Risk to humans has not been ruled out Category D: Positive evidence of risk to humans from Drug Exposure human and/or animal studies During pregnancy, the patient’s neurologist and obstetri- Category X: Contraindicated in pregnancy cian should work together. If a woman inadvertently takes a drug when she is pregnant or becomes pregnant while taking a drug, determine the dosage, timing, and duration tem is an improvement over previous labeling, it is not of the exposure(s). Ascertain the patient’s past and pre- ideal. An alternate system is TERIS, an automated ter- sent state of health and the presence of mental retarda- atogen information resource wherein the rating for each tion or chromosomal abnormalities in the family. Using drug or agent is based on a consensus of expert opinion a reliable source of information (such as TERIS), deter- and on the literature (Table 4.3) (26). It was designed to mine whether the drug is a known teratogen (although assess the teratogenic risk to the fetus from a drug expo- for many drugs, this is not possible) (8,10,11,18,26). sure. The FDA categories have little if any correlation to If the drug is teratogenic or the risk is unknown, have the TERIS teratogenic risk. This discrepancy results in the obstetrician confirm the gestational age by ultrasound. part from the fact that the FDA categories were designed If the exposure occurred during embryogenesis, then high- to provide therapeutic guidance, and the TERIS ratings resolution ultrasound can be performed to determine are useful for estimating the teratogenic risks of a drug whether damage to specific organ systems or structures and not vice versa (27). has occurred. If the high-resolution ultrasound is normal, it is reasonable to reassure the patient that the gross fetal TABLE 4.3 structure is normal (within the 90% sensitivity of the TERIS Risk Rating study) (18). Fetal ultrasound, however, cannot exclude minor anomalies or guarantee the birth of a normal child. N — None (A) Delay in achieving developmental milestones, including UN — Unlikely cognitive development, are potential risks, especially for N-Min — None, minimal (A) children born to epileptics, that cannot be predicted or Min — Minimal (B) diagnosed prenatally (35). Maternal serum alpha-feto- Min-S — Minimal-small (D) protein (MSAFP) can be used to screen pregnancies for S — Small open neural tube defects. Amniocentesis can also be used S-Mod — Small-Moderate to assess an abnormal alpha-fetoprotein level (18). Have Mod — Moderate the obstetrician discuss the results of these studies with H — High (X) U — Undetermined (C) the mother and the significant other; formal prenatal counseling may be helpful in uncertain cases (18). Equivalent FDA ratings in parentheses. Maternal Physiology

Prevention Profound structural and physiologic changes occur during pregnancy (Table 4.4) (36). The uterus rapidly A woman’s risk of having a child with a neural tube defect increases in size, transformed from an almost solid struc- is associated with early pregnancy red cell folate levels in ture weighing 70 g into a relatively thin-walled, muscu- a continuous dose–response relationship (28). Low serum lar organ large enough to accommodate the fetus, pla- and red blood cell folate levels are associated with spon- centa, and amniotic fluid (37). Uterine growth depends taneous abortion and fetal malformations in animals and on estrogen and, to a lesser extent, on progesterone dur- in humans (29–32). Treatment with some drugs, including the first few months of pregnancy. After 12 weeks, ing phenytoin, carbamazepine, and barbiturates, can growth results from the pressure exerted by the expand- impair folate absorption. Valproic acid does not produce ing products of conception. Cell and tissue growth is folate deficiency, but it may interfere with the produc- dependent on the increased synthesis of polyamines tion of folinic acid by inhibiting glutamate formyl trans- (including spermidine and spermine and their immediate ferase (33). In a small study, women with epilepsy who precursor, putrescine) (37). 46 NEUROLOGIC DISEASE IN WOMEN

TABLE 4.4 Physiologic Changes during Pregnancy

PARAMETER CHANGE POTENTIAL IMPLICATIONS FOR TOXICOLOGY

Extracellular volume 4–6 L Dilution of substances in circulation Plasma volume by 40% Same Plasma renin/aldosterone Renal retention/excretion Renal blood flow 30–50% Same Glomerular filtration rate 30–50% Same Sodium and calcium retention Retention of other divalent cations Cardiac output by 40% Increased sensitivity to cardiotoxins (?) Increased blood flow to skin Dermal uptake Food intake 70 kcal/day (average) Increased Energy demand* ~300 kcal/day Increased dose and metabolic shift Lipid stores* ~3–4 kg over pregnancy Same

Oxygen consumption* 51 mL O2/min Metabolic shift (?) Basal metabolic rate 13% Metabolic shifts Hepatic triglyceride synthesis Redistribution

*Depends on nutrition, activity levels, and gestational state. Adapted from Metcalfe et al. (36).

Metabolic changes occur in response to the rapidly The kidneys barely increase in size during pregnancy growing fetus and placenta. Weight gain, due to the (38). Early in pregnancy, at the beginning of the second increase in the uterus and its contents, the breasts, the trimester, the glomerular filtration rate and renal plasma blood volume, and the extravascular extracellular fluid, flow increase by approximately 50% (39,40). The elevated averages approximately 11 kg, with approximately 1 kg glomerular filtration rate persists to term, whereas the renal occurring during the first trimester (37). Water retention plasma flow decreases during late pregnancy (40). The (approximately 6.5 L by term) is a normal occurrence, human liver does not increase in size during pregnancy, and mediated in part by a fall in plasma osmolality of 10 we are not certain whether hepatic blood flow increases. mOsm/kg, due to a resetting of the osmoreceptor. The The profound physiologic changes that occur dur- fetus, placenta, and amniotic fluid contain approxi- ing pregnancy can alter drug pharmacokinetics: Plasma mately 3.5 L of water. Another 3.0 L of water results volume increases by half, cardiac output increases by 30 from increased maternal blood volume and the increase to 50%, and renal plasma flow and glomerular filtration in uterine and breast size. Near term, blood volume is rate increase by 40 to 50%. Serum albumin decreases by approximately 45% above baseline. Weight loss during 20 to 30%, resulting in decreased drug binding and the first 10 days postpartum averages approximately 2 increased drug clearance. Increased extracellular fluid and kg (37). adipose tissue increases the volume of drug distribution. Although pregnancy is potentially diabetogenic, in Drug metabolism may also be increased, modulated in healthy pregnant women, the fasting plasma glucose con- part by the high concentration of sex hormones (41). centration may fall due to increased plasma insulin lev- Seizure frequency can increase during pregnancy due els. Progesterone, when administered to a nonpregnant to changes in AED concentration. Total concentrations of adult in an amount similar to that which is produced dur- carbamazepine, phenytoin, phenobarbital, and valproic ing pregnancy, results in an increased basal insulin con- acid fall due to decreased plasma protein binding, whereas centration and response to an oral glucose challenge sim- free or unbound drug concentrations of only phenobarbi- ilar to that of a normal pregnant woman. Additionally, tal fall significantly. Valproate free concentrations actually estradiol induces hyperinsulinism in both control and increase by 25% by the time of delivery (42). ovariectomized rats (37). The placenta is a lipid membrane barrier that sepa- Lipid, lipoprotein, and apolipoprotein plasma con- rates the maternal and fetal circulation. Most drugs cross centrations increase during pregnancy. A positive corre- this barrier by simple diffusion. The rate of transfer is lation exists between lipid concentrations and levels of dependent on the drug’s molecular size, lipid solubility, estradiol, progesterone, and human placental lactogen. and protein binding. Drugs with a very high molecular DRUG TREATMENTS AND TRIALS IN WOMEN 47 weight, such as heparin, do not cross the placenta easily, Classification of Drugs Used during Lactation whereas drugs with a low molecular weight (<6,000 dal- The American Academy of Pediatrics Committee on tons) cross it easily. Most drugs have steady-state levels Drugs has reviewed and categorized drugs for use in lac- at or near maternal levels, although some drugs may be tating women (Table 4.5) (12,45). The following pre- trapped with fetal levels two to three times maternal lev- scribing guidelines should be followed (45): els (43,44). • Is the drug necessary? If so: Breast-Feeding • Use the safest drug (e.g., acetaminophen instead of aspirin). Milk is a suspension of fat and protein in a carbohydrate- • If there is a possibility that a drug may present a risk mineral solution. A nursing mother secretes 600 mL of to the infant (e.g., phenytoin, phenobarbital), con- milk a day that contains sufficient protein, fat, and car- sider measuring the blood level in the nursing infant. bohydrate to meet the nutritional demands of the grow- • Minimize the nursing infant’s drug exposure by having and developing infant (11). The transport of a drug ing the mother take the medication just after com- into breast milk depends on its lipid solubility, molecu- pleting a breast-feeding. lar weight, degree of ionization, protein binding (inversely proportional), and the presence or absence of active secretion (12). Species differences in the composition of milk CONTRACEPTION can result in differences in drug transfer. Because human milk (pH usually Ͼ7.0) has a much higher pH than cow’s Women of reproductive potential who have neurologic milk (pH usually Ͻ6.8), bovine drug transfer data may disease, especially if they are taking medications, require not be accurate in humans (11). contraceptive counseling. Hormonal contraceptive fail- Many drugs can be detected in breast milk at levels ure can occur with drug use, especially with AEDs. More that are not clinically significant to the infant. The con- than one-fourth of the neurologists (27%) and 21% of centration of a drug in breast milk is a variable fraction the obstetricians among 307 responders to a Johns Hop- of the maternal blood level. The infant dose is usually 1 kins survey reported contraceptive failure (46). The AEDs to 2% of the maternal dose, which is usually trivial. How- ever, any exposure to a toxic drug or potential allergen may be inappropriate (12). TABLE 4.5 Drug concentration in breast milk depends on Drug Use during Lactation drug characteristics (pKa, lipid solubility, molecular weight, protein binding) and breast milk characteristics (1) — Contraindicated (composition and volume). Breast milk is given its (2) — Requires temporary cessation of breast-feeding unique physicochemical properties by the active trans- (3) — Effects unknown but may be of concern port of electrolytes and the formation and excretion of (4) — Use with caution lactose and proteins by glandular epithelial cells in the (5) — Usually compatible breast through the passive diffusion of water. The volume produced depends on nutritional factors, the amount of milk removed by the suckling infant, and the TABLE 4.6 increase in mammary blood flow that occurs with Relationship between Antiepileptic Drugs and breast-feeding. Volume production slowly increases Liver Microsomal Cytochrome P450 from an average of 600 mL a day to 800 mL a day by the time the infant is 6 months old, and undergoes a INDUCERS NONINDUCERS diurnal variation, with the greatest quantity occurring in the morning. For the first 10 days of production, Carbamazepine Benzodiazepines milk composition is characterized by a gradual increase Phenobarbital Gabapentin in fat and lactose from a milk that is higher in protein Phenytoin Lamotrigine content (colostrum). Felbamate Levetiracetam Because most drugs are either weak acids or bases, Primidone the transfer across a biologic membrane is greatly influ- PARTIAL INDUCERS INHIBITORS enced by the ionization characteristics (pKa) and pH differences across the membrane. Because the pH of breast Oxcarbazepine Valproic acid milk (7.0) is slightly lower than that of plasma (7.4), Tiagabine there is a tendency toward ion trapping of basic com- Topiramate pounds. 48 NEUROLOGIC DISEASE IN WOMEN

phenobarbital, primidone, phenytoin, and carbamazepine The reduction in lean body mass, serum albumin, and induce the hepatic cytochrome P450 system of mixed total body water, and the increase in body fat percent- function oxidases, resulting in a reduction of exogenous age that occur in the elderly produce changes in drug estradiol and progesterone levels (Table 4.6). Steroid hor- distribution. Cardiac output and kidney blood flow mone binding globulins may also be increased, resulting decrease, whereas cerebral, coronary, and skeletal mus- in a decrease in free hormone levels. cle blood flow are unchanged. Hepatic blood flow is The failure rate of OCs is 0.7 per 100 women reduced. Altered blood flow has a major impact on drug years. This rate is increased to 3.1 per 100 women years elimination by the liver and kidney and may alter tis- in women who use high-dose estrogen-containing OCs sue distribution. Renal function declines to approxi- (50 µg or more) and enzyme-inducing anticonvulsants mately half that of the young adult. Hepatic cytochrome (47). Because the failure rate is higher when more com- P450 enzymes are reduced, whereas conjugation mech- monly used, lower estrogen-dose OCs are used, an OC anisms are relatively well preserved. Other factors that containing 50 µg or more of ethinyl estradiol or mes- affect metabolic activity include (i) enzyme-inducing tranol is recommended (48). In contrast, valproic acid drugs; (ii) disease states, such as hyperthyroidism and inhibits the hepatic microsomal enzyme system, and osteomalacia; and (iii) exogenous factors, such as bed gabapentin, vigabatrin, levetiracetam, and lamotrigine rest, cigarette smoking, and certain diets. The clearance have no effect. Because these AEDs have not been of drugs that undergo hepatic metabolism is often reported to result in hormonal contraceptive failure, reduced in the elderly. they could be used if oral contraception is desired (49). The elderly have a decrease in both lean body mass Topiramate, in high (Ͼ200 mg/day) but not in low and total body water. The total body fat percentage doses, may compromise the efficacy of OCs by decreas- increases with age in both sexes, increasing from 18 to 36% ing estrogen exposure (25). in men and from 33 to 48% in women between 18 and 85 Intramuscular medroxyprogesterone (Depo-Provera®) years of age (55). Drugs that distribute through the total and levonorgestrel implants (Norplant®) are not viable alter- body weight, such as ethanol, have a decreased volume of natives. Both are progestins whose efficacy is reduced by distribution. Drugs that are primarily distributed through AEDs (50). the extracellular fluid show little change in their volume of distribution. In contrast, lipid-soluble drugs (e.g., the benzodiazepines) have larger volumes of distribution due DRUGS AND THE ELDERLY to the greater percentage of fat in elderly persons. The elimination half-life of lipid-soluble drugs is Many elderly patients fail to take their medicine as pre- increased because of a larger volume of distribution. Elim- scribed. More than half make at least one drug error, and ination half-life may decrease because of decreased renal more than 25% make potentially serious medication or metabolic clearance. A low plasma albumin level often errors (51), perhaps because they cannot afford their results in decreased drug binding. The increased free drug medicines, their treatment schedules are too complicated fraction results in (i) an enhanced pharmacologic effect; (52), or they do not understand the need for and uses of (ii) an increase in the volume of distribution; and (iii) an the drug (53). Changes in drug pharmacokinetics and alteration in the elimination rate. pharmacodynamics that occur with age may result in variable drug plasma levels. Pharmacodynamics The effect of a drug depends on the interaction between Pharmacokinetics it and its receptors. Although pharmacokinetic changes The rate of gastric emptying is delayed, gastrointestinal may result in an increased or decreased quantity of drug motility is decreased, gastric pH levels rise, and active drug reaching the receptor, the drug’s action depends on how transport is reduced in the elderly (54). Most drugs are it interacts with its receptors. Central nervous system absorbed by passive diffusion, and xylose absorption, (CNS) depressant drugs are more potent in the elderly. which reflects the passive transport ability, is reduced by This is important because psychotherapeutic drugs are 40 to 50%. When transport is not rate-limiting, absorp- the second most commonly prescribed category of drugs tion is not affected. The rate and extent of acetaminophen, for elderly persons. In one study, 32% of all people aged phenylbutazone, and sulfamethizole absorption are sim- 60 to 70 had used a psychotropic drug within the previ- ilar in elderly and young patients (53), whereas galactose, ous year (56,57). Increased sensitivity to adverse effects, thiamine, calcium, and dextrose absorption, which such as hypotension from psychotropic medications and depends on active transport, is reduced (54). hemorrhage from anticoagulants, can occur even if the Pharmacokinetic changes result from changes in dosage is appropriately adjusted (1). body composition and drug-eliminating organ function. DRUG TREATMENTS AND TRIALS IN WOMEN 49

INDIVIDUAL CLASSES OF DRUGS given at higher doses. There is no evidence that sumatriptan is a human teratogen, but no adequate, well- The use of various medications is reviewed in pregnancy, controlled studies have been done in pregnant women. during lactation, and in the elderly (11). Sumatriptan is excreted in breast milk in animals. No data exist in humans. Use with caution in nursing women. Acute Specific Antimigraine Drugs

NARATRIPTAN. Naratriptan is used for the acute Ergotamine treatment of migraine headaches. It is not an animal The use of ergot alkaloids during pregnancy is con- teratogen, but it does produce dose-related embryo and traindicated (58,59) (Table 4.7). The abortifacient action fetal developmental toxicity. Human pregnancy of uterotonic ergots in humans has been known for years, experience is too limited to assess the safety of the drug but the teratogenic effects of ergotamine and DHE are or its teratogenic potential. It is excreted in the milk of uncertain. Attempted (but failed) abortion has rarely been nursing rats but there are no reports describing the use associated with certain congenital defects. The Collabo- of naratriptan during human lactation. The molecular rative Perinatal Project (22) reported on 25 exposures to weight of the hydrochloride salt (about 372) is low ergotamine and 32 exposures to other ergot derivatives, enough, however, that passage into the milk should be with the relative risk of malformation being 1 in 24 and expected. The effects of this exposure, if any, on a nursing 1 in 45, respectively. infant are unknown (11). Wainscott (60) believed that it was unlikely that ergotamine tartrate posed any teratogenic hazard, but RIZATRIPTAN. Rizatriptan is indicated for the Hughes (61) thought that, because the actual number of treatment of acute migraine attacks with or without aura exposed women and the severity of exposure were in adults. The Merck Pregnancy Registry program has unknown, no definite conclusion could be drawn. Ergot data on 24 pregnancies exposed to rizatriptan. No alkaloids, which are frequently present in medication for adverse outcomes were observed in liveborn offspring, migraine headaches, enter breast milk and have been but the limited number of exposures studied are not reported to cause vomiting, diarrhea, and convulsions in sufficient to detect a risk of rare disorders such as birth nursing infants. defects. No reports describe the use of rizatriptan in

SUMATRIPTAN. This is a selective serotonin agonist that is safe and effective in the treatment of the TABLE 4.8 nonpregnant migraineur. Sumatriptan at very high doses Analgesics (three times higher than human plasma concentration after a recommended 6 mg subcutaneous dose) caused FETAL RISK embryo lethality in rabbits but not in rats, even when FDA TERIS BREAST-FEEDING

Simple Analgesics TABLE 4.7 Aspirin C* N-Min Caution Ergots and Serotonin Agonists Acetaminophen B N Compatible Caffeine B N-Min Compatible FETAL RISK NSAIDs FDA TERIS BREAST-FEEDING Fenoprofen B* U Compatible Ibuprofen B* N-Min Compatible Ergotamine X Min Contraindicated Indomethacin B* N Compatible Dihydroergotamine X U Contraindicated Ketorolac B* U Caution Methylergonovine C U Caution Meclofenamate B* U Compatible Methysergide D U Caution Naproxen B* U Compatible Almotriptan C U Caution Sulindac B* U Compatible Eletriptan C U Caution Tolmetin B* U Compatible Frovatriptan C U Caution COX-2 Naratriptan C U Caution Celecoxib C* U Concern Rizatriptan C U Caution Rofecoxib C* U Concern Sumatriptan C U Caution Zolmitriptan C U Caution *D if third trimester 50 NEUROLOGIC DISEASE IN WOMEN

human lactation. The relatively low molecular weight of pregnancy (65). There is no evidence of any teratogenic free base (about 269) suggests that the drug will be effect. Its use is compatible with breast-feeding (11). excreted into breast milk. The effects of this exposure on a nursing infant are unknown (11). ELDERLY. Acetaminophen metabolism is not affected by age (66). ASPIRIN (11,62). Concerns about the safety of aspirin in pregnancy came from earlier data (63,64), when CAFFEINE (11,62). In moderate amounts (<300 aspirin was used in therapeutic doses for analgesic or mg a day), caffeine consumption in pregnancy does not antipyretic purposes. There is no evidence that aspirin has pose a measurable risk to the fetus. High doses may be any teratogenic effect. Although three retrospective associated with spontaneous abortion, infertility, or low epidemiologic trials looking at aspirin consumption birth weight. Moderate caffeine use is compatible with among mothers of children with malformations have breast-feeding. Accumulation may occur in infants whose found higher consumption in patients than in controls, mothers use excessive amounts of caffeine, however. these studies suffer from memory bias or a possible coincident teratogen for which the aspirin was taken. A Nonsteroidal Antiinflammatory Drugs (11,62) large prospective study of 50,282 pregnancies found no evidence of aspirin teratogenicity in humans (22,62). PREGNANCY. None of the NSAIDs in Table 4.8 Aspirin in analgesic doses does have perinatal effects. It has been shown to have a teratogenic effect. Their use can inhibit uterine contraction and result in narrowing should be limited during the third trimester because they of the ductus arteriosus and increased maternal and inhibit labor, prolong the length of pregnancy, and newborn bleeding. Aspirin users have longer gestations decrease amniotic fluid volume. A combined 2001 and labors than control patients (11). population-based observational cohort study and a case- Increased teratogenic risks, as well as disturbances control study estimated the risk of adverse pregnancy of platelet function with the risk of hemorrhage in the outcome from the use of NSAIDs. The use of NSAIDs mother and infant, have been reported. Based on exten- during pregnancy was not associated with congenital sive clinical experience, none of these side effects has been malformations, preterm delivery, or low birth weight, but seen at low dose; however, it is generally recommended a positive association was discovered with spontaneous not to start treatment before 15 weeks of pregnancy and abortions. NSAID use is compatible with breast-feeding. to stop it 7 to 10 days before delivery. Aspirin has a clear- The use of indomethacin, which successfully sup- cut effect on the hemostasis of the newborn and should presses uterine contractions even after the failure of other not be used in late pregnancy. It can also cause hyper- tocolytics, has been extensively reviewed (67). bilirubinemia. Low-dose aspirin, however, may help pre- Indomethacin crosses the human placenta and has mul- vent preeclampsia or the fetal wastage associated with tiple effects on the fetus, including constriction of the duc- autoimmune diseases. tus arteriosus and reduction of urine production. The risk of ductus arteriosus constriction depends on the gesta- BREAST-FEEDING. Aspirin is excreted in moderate tional age, with a dramatic increase at 32 weeks, when amounts in breast milk. Occasional aspirin use during almost 50% of cases show a significantly increased blood lactation appears to be safe, but studies have not been flow through the ductus. Because of this high incidence, performed on infants of nursing mothers who ingest high indomethacin should not be used beyond 32 weeks. doses of aspirin over long periods of time. It should be used cautiously during breast-feeding. ELDERLY. Adverse reactions in the elderly are similar to those of salicylates, but some are unique to this ELDERLY. Aspirin may produce serious problems group of drugs. Gastrointestinal side effects with in the elderly. Even in small doses, aspirin may prolong dyspepsia, nausea, diarrhea, ulcers, and hemorrhage may bleeding time and cause gastric erosions with bleeding. occur. CNS symptoms of somnolence, dizziness, tinnitus, tremor, and confusion may occur, but these are usually ACETAMINOPHEN. Acetaminophen is the drug mild. Cognitive dysfunction, manifested by memory loss, most commonly taken during pregnancy. Its mean half- inability to concentrate, confusion, and personality life (3.7 hours) is not significantly different from the change, has been reported in patients over age 65 who nonpregnant value. Its absorption, metabolism, and renal have received either naproxen or ibuprofen (68). clearance are unchanged. The decrease in the mean AUC during pregnancy may be due to its increased volume of Second-Generation NSAIDs distribution. Potentially hepatotoxic metabolites were not found in maternal serum. The absorption and Rofecoxib and celecoxib are second-generation NSAIDs disposition of a standard oral dose is not affected by that inhibit prostaglandin synthesis via the inhibition of DRUG TREATMENTS AND TRIALS IN WOMEN 51 cyclooxygenase-2 (COX-2). In animal reproduction stud- sured in plasma. The relatively long adult serum half-life ies with rats and rabbits, rofecoxib caused peri- and of celecoxib (11.2 hours) and the absence of clinical phar- postimplantation losses and reduced embryo and fetal macologic data in infants suggest that this agent should survival at doses approximately nine and two times, be avoided during nursing (11). respectively. No teratogenicity was observed in rats. In All opioids can produce maternal and neonatal rabbits, a slight, nonstatistically significant increase in the addiction. Their use for prolonged periods and in high incidence of vertebral malformations was seen. Data from doses at term is contraindicated. The amount of morphine the Merck Pregnancy Registry for Vioxx® (rofecoxib), and meperidine excreted in breast milk is small, and these as of July 31, 2000, include eleven exposed pregnancies. medications may be used safely in therapeutic doses. The outcomes in these cases were two normal live-born Addicts, however, may excrete significant amounts of infants, one lost to follow-up, and three ongoing preg- morphine and heroin, and symptoms of withdrawal can nancies. Constriction of the ductus arteriosus in utero is be prevented by allowing their infants to breast-feed. Nar- a pharmacologic consequence arising from the use of cotic use is compatible with breast-feeding (11,12,62). prostaglandin synthesis inhibitors during pregnancy. Although animal studies with rofecoxib did not show this CODEINE (11,62). Indiscriminate codeine use effect, it is not known if humans would be similarly unaf- may present a risk to the fetus during the first or second fected. There are no reports describing the use of rofe- trimester. Cleft lip, cleft palate, dislocated hips, inguinal coxib during human lactation. The drug is excreted in the hernia, and cardiac and respiratory system defects have milk of lactating rats at concentrations similar to those been reported. Codeine passes into breast milk in very in the plasma. The relatively long adult serum half-life small amounts. of rofecoxib (about 17 hours) and the absence of clinical pharmacologic data in infants suggest that this agent PROPOXYPHENE (11,62). Three case reports have should be avoided during nursing (11). linked propoxyphene use to congenital abnormalities, Celecoxib is in the same NSAID subclass (COX-2 but because other drugs were also used, the association inhibitors) as rofecoxib. Teratogenicity studies have been may be coincidental. The Collaborative Perinatal Project conducted in rats and rabbits. In pregnant rats, a dose- found no evidence of increased malformations among related increase in diaphragmatic hernias was observed 2,914 exposures (22). in one of two studies at doses of 30 mg/kg/day (about six times the MRHD). No teratogenic effects occurred in OTHER DRUGS. Butorphanol, hydromorphone, pregnant rabbits. The use of first-generation NSAIDs dur- meperidine, methadone, and morphine are probably not ing the latter half of pregnancy has been associated with teratogenic (11,62). oligohydramnios and premature closure of the ductus arteriosus. Similar effects should be expected if celecoxib ELDERLY. The acute analgesic effect of narcotics is is used during the third trimester or close to delivery. No enhanced in the elderly (66). reports describing the use of celecoxib during human lactation have been located. The drug is excreted in the milk Anticoagulants of lactating rats in concentrations similar to those mea- Heparin is a relatively large molecule with a molecular weight of approximately 20,000. It is highly charged and TABLE 4.9 fails to cross the placenta in any detectable amount. Opioids

FETAL RISK TABLE 4.10 FDA TERIS BREAST-FEEDING Anticoagulant and Antiplatelet Drugs

Butorphanol B** N-Min Compatible FETAL RISK Codeine C** N-Min Compatible FDA TERIS BREAST-FEEDING Hydromorphone B** N-Min Compatible Meperidine B** N-Min Compatible Heparin C N-M Safe Methadone B** N-Min Compatible Low molecular C N-M Safe Morphine B** N-Min Compatible weight heparin Propoxyphene C** N-Min Compatible Warfarin X S-M Compatible Pentoxifylline C U Not **D if prolonged or at term recommended 52 NEUROLOGIC DISEASE IN WOMEN

Although the protracted use of heparin may result in trimesters can produce CNS and eye anomalies in approx- osteoporosis and thrombocytopenia in the mother, there imately 3% of children. Warfarin use in late pregnancy has been no evidence that heparin is teratogenic, because causes fetal, placental, or neonatal hemorrhage (69). it does not cross the placenta. Heparin is not excreted in breast milk, and mothers who use heparin may breast- BREAST-FEEDING. Although many review articles feed safely (69). Low-molecular-weight heparin has a state that oral anticoagulants are contraindicated in molecular weight of approximately 4,000 to 6,000 and nursing mothers, recent evidence indicates that warfarin does not cross the placenta. Omri and associates (70) and dicumarol may be used safely. LeOrme and reported on the use of low-molecular-weight heparin in coworkers (73) measured warfarin levels in the breast 17 women without adverse effects, and Gillis and asso- milk of 13 mothers who were receiving therapeutic doses ciates (71) reported on its use in six pregnant women of warfarin. They found a concentration of less than 25 without apparent adverse effects. Dulitzki and associates mg/ml. (72) recently reported their experience with low-molecular-weight heparin in 41 pregnancies from 34 women and ELDERLY. Patients over 70 years of age are more found it to be both safe and efficacious (69). sensitive to the anticoagulation effect of warfarin and Pentoxifylline is a synthetic xanthine derivative used frequently require lower doses. Older persons who are as a vasodilator and to lower blood viscosity in periph- receiving several drugs are at greater risk for drug eral vascular and cerebrovascular disease. No epidemio- interactions that may lead to enhanced or diminished logic studies of pentoxifylline use during either the first effects of warfarin (Table 4.11). trimester or the later stages of pregnancy are available (69). Warfarin is a coumarin derivative that produces its Thrombolytics anticoagulant effect by interfering with clotting factors II, VII, IX, and X. This anticoagulant and its derivatives are The major thrombolytics include streptokinase, uroki- relatively low in molecular weight and cross the placenta nase, and tissue plasminogen activator. There are no large readily, thus resulting in significant fetal levels. The pat- randomized studies regarding their use during pregnancy. tern of anomalies called the warfarin embryopathy or fetal Turrentine and colleagues (74) recently reviewed 36 warfarin syndrome, includes nasal hypoplasia, stippled epi- reports involving 172 pregnant women treated with physes on radiographs, and growth retardation, and occurs thrombolytics for a variety of thromboembolic condi- in approximately 10% of exposed infants. The period of tions. A summary of the results revealed maternal mor- greatest susceptibility is between the sixth and ninth post- tality in 1.2%, hemorrhagic complications in 8.1%, and menstrual weeks of gestation. Adverse outcomes, such as pregnancy loss in 5.8%. Pregnancy is considered to be a fetal effects, neonatal deaths, stillbirths, spontaneous abor- relative contraindication to thrombolytic therapy, but it tions, and premature births, occur in 31% of treated preg- would appear that it may be of benefit in some cases and nancies. Warfarin therapy during the second and third is relatively safe (69,74).

TABLE 4.11 Oral Anticoagulant Drug Interactions

INCREASED EFFECT DECREASED EFFECT

DRUG MECHANISM DRUG MECHANISM

Nortriptyline Absorption Cholestyramine Absorption Allopurinol Metabolism Barbiturates Metabolism Cimetidine Disulfiram Alcohol Sulfonamides Protein-binding Alcohol (chronic) Metabolism Phenylbutazone Salicylates >3g/day Antibiotics Protein-binding, vitamin K synthesis by bacteria DRUG TREATMENTS AND TRIALS IN WOMEN 53

Anticonvulsants (11,75,76) binding and low molecular weight (about 171), however, transfer to the fetus should be expected. A 1996 review Most AEDs (Table 4.12) have teratogenic potential; mech- reported 16 pregnancies exposed to gabapentin from anisms include induced folate deficiency, interference with preclinical trials and postmarketing surveillance. The folate metabolism, and the production of teratogenic inter- outcomes of these pregnancies included five elective mediary metabolites such as free radicals. One biologically abortions, one ongoing pregnancy, seven normal infants, active metabolite, epoxide, is metabolized by the enzyme and three infants with birth defects. No specific epoxide hydrolase. Reduced amniocyte activity correlates information was provided on the defects other than the with the occurrence of congenital anomalies (77). fact that there was no pattern of malformation, and all were receiving polytherapy for epilepsy. The limited human data do not allow an assessment of gabapentin’s TABLE 4.12 safety in pregnancy. No reports describing the use of Antiepileptic Drug Classification gabapentin during human lactation have been located. Because of its low molecular weight (about 171), transfer FETAL RISK into milk should be expected. The effects of this exposure FDA TERIS BREAST-FEEDING on a nursing infant are unknown (11). Carbamazepine C S Compatible Gabapentin C U Uncertain LAMOTRIGINE. Lamotrigine was not teratogenic Lamotrigine C U Not recom- in animal reproductive studies involving mice, rats, and mended rabbits using oral doses that were 1.2, 0.5, and 1.1 times, Levetiracetam C U Caution respectively, the highest usual human maintenance dose. Oxcarbazepine C U Caution Lamotrigine crosses the human placenta. An interim Phenobarbital D M-S Compatible report of the Lamotrigine Pregnancy Registry, an ongoing project conducted by the manufacturer, was Phenytoin D S-Mod Compatible issued in 2000. A total of 362 prospective pregnancies Primidone D S-Mod Caution (reported before the pregnancy outcome was known) Tiagabine C U Caution have been enrolled in the Registry. Of these, 66 outcomes Topiramate C U Uncertain are pending and 52 have been lost to follow-up. Valproic Acid D S-Mod Compatible Outcomes are known for 244 pregnancies. The earliest Vigabatrin — U Uncertain exposure to lamotrigine occurred in the first trimester in 235 pregnancies, three in the second trimester, two in the third trimester, and four with an unspecified time of BREAST-FEEDING. The major AEDs currently in earliest exposure. Lamotrigine monotherapy was used in use are usually compatible with breast-feeding. In 98 outcomes with earliest exposure in the first trimester, women with epilepsy who are taking sedating AEDs, two outcomes with earliest exposure in the second close monitoring of the newborn for sedation is trimester, and five outcomes (one set of triplets) with necessary. Levels of phenytoin, carbamazepine, and unspecified exposure timing. For first trimester valproic acid in breast milk represent a small fraction exposures, the outcomes were nine spontaneous of the dose that would produce therapeutic levels in the pregnancy losses (Ͻ20 weeks gestation), 27 elective infant. Sedating AEDs, such as benzodiazepines, abortions (two with birth defects), one fetal death (р20 primidone, and phenobarbital, should not preclude a weeks), 14 live infants with birth defects, and 186 live trial of breast-feeding, although close monitoring of the infants without birth defects (includes two sets of twins). newborn is necessary. If the infant becomes sedated, it When the earliest exposure was in the second or third is advisable to discontinue breast-feeding (78). trimesters, or the exposure timing was unspecified, the outcomes were three, two, and six live-born infants, CARBAMAZEPINE (13,78). Carbamazepine is respectively, without birth defects. Lamotrigine probably a human teratogen, having a pattern of monotherapy during the first trimester is associated with congenital malformation whose principal features consist esophageal malformation, cleft soft palate, and right club of minor craniofacial defects, fingernail hypoplasia, and foot. The animal and human data do not appear to developmental delay (similar to the fetal hydantoin indicate a major risk for congenital malformations or syndrome). There may also be a ninefold risk of neural fetal loss following first trimester exposure to tube defects (0.6% incidence). lamotrigine. At least two reviews have concluded that this anticonvulsant may be associated with a lower risk GABAPENTIN. It is not known whether gabapentin of teratogenicity. Lamotrigine is excreted into breast crosses the human placenta. Because of its lack of protein milk. No adverse effects have been seen in nursing 54 NEUROLOGIC DISEASE IN WOMEN

infants of mothers taking lamotrigine, but the number of Antidepressants known cases is too small to adequately assess the safety In utero exposure to either tricyclic antidepressant drugs of this drug during lactation. Monitoring infant serum or fluoxetine does not affect global intelligence quota, lan- levels of lamotrigine may be required (11). guage development, or behavioral development in preschool children (82). Antidepressant use may be a con- PHENOBARBITAL (11,12,76). Phenobarbital has cern during breast-feeding. The exception is fluoxetine, been in use since 1912, and phenytoin has been used which should be used with caution. Its specific use dur- since 1938. It was not until the early 1960s that case ing pregnancy is described subsequently. The American reports began to appear suggesting that phenytoin was Academy of Pediatrics classifies all antidepressants as associated with the development of birth defects. In the drugs whose effect on the nursing infant may be of con- late 1960s, phenytoin was demonstrated to be a cern (11) (Table 4.13). teratogen in rodents, with the subsequent recognition of a pattern of abnormalities in infants exposed to the drug in utero. Phenobarbital therapy in the pregnant woman with TABLE 4.13 Antidepressants epilepsy presents to the fetus a risk of minor congenital abnormalities, hemorrhage at birth, and withdrawal. The FETAL RISK pregnant woman with epilepsy who is taking phenobar- FDA TERIS BREAST-FEEDING bital in combination with other AEDs has a two- to threefold increased risk of having a child with a congenital mal- Tricyclics formation. It is not known if this is due to the drug, the Amitriptyline D N-Min Concern disease, or a combination of these factors. Barbiturates Amoxapine C U Concern have been demonstrated in breast milk, but therapeutic Desipramine C U Concern doses appear to have little or no effect on the infant. A Doxepin C U Concern greater amount of phenobarbital was transmitted when Imipramine D N-Min Concern a single dose of 1.5 g was administered than when the Nortriptyline D U Concern same amount was given in divided doses throughout the day (76). Phenobarbital may cause sedation in nursing Protriptyline C U Concern infants, and it should be used with caution in nursing SSRIs mothers. Citalopram C N Concern Fluoxetine B N Concern PHENYTOIN (11,76). The use of phenytoin Paroxetine C U Concern during pregnancy involves significant risk (10%) to the Sertraline B U Concern fetus in terms of major and minor congenital anomalies MAOIs and hemorrhage at birth. Phenelzine C U Concern Others TOPIRAMATE (25). There are no studies of Bupropion B U Concern topiramate use in pregnant women. Topiramate should Venlafaxine C U Concern be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. Topiramate is excreted in the milk of lactating rats. It is not known whether topiramate is excreted in human milk. Because Tricyclics many drugs are excreted in human milk, the potential for serious adverse reactions in nursing infants is unknown. • Amitriptyline (11). Limb reduction anomalies have been reported but not confirmed. Other malforma- VALPROIC ACID (11,76). Valproic acid is a tions have been reported. human teratogen. The absolute risk of producing a child • Amoxapine (11). No case reports of teratogenicity. with a neural tube defect when used between day 17 and • Desipramine (11). No case reports of teratogenicity. day 30 after fertilization is 1 to 2%. A characteristic Neonatal withdrawal symptoms reported. pattern of facial defects is apparently also associated with • Doxepin (11). No case reports of teratogenicity. One valproic acid (79–81). Valproic acid may also result in serious adverse reaction has been reported in a nurs- impaired cognition in children born to mothers with ing infant. epilepsy (35). • Imipramine (11). Malformations have been reported The teratogenic potential of the new AEDs (vigaba- but are rare. Neonatal withdrawal symptoms have trin, felbamate, tiagabine, and topiramate) is uncertain. been reported. DRUG TREATMENTS AND TRIALS IN WOMEN 55

• Nortriptyline (11). See amitriptyline. However, the available human studies lack the sensitivity • Phenelzine (11). Increased risk found. to identify minor anomalies because of the absence of • Protriptyline (11). No data available. standardized examinations. Late-appearing major defects may also have been missed in at least two of the studies ELDERLY. All tricyclic antidepressants exert both because of the short time frame. Withdrawal symptoms central and peripheral anticholinergic activities and block were reported in four infants exposed to paroxetine the histamine H-1 and H-2 receptors (which may be during gestation, but other drug exposures may have responsible for weight gain) (83). Elderly persons are contributed to the conditions. Paroxetine is excreted into especially sensitive to these side effects. The patient’s human breast milk. Its effect on the infant is unknown, tolerance of a tricyclic is often determined by a patient’s thus the mother should be given this information so that ability to tolerate these effects. she can actively participate in any decision (11).

SERTRALINE. Sertraline is an SSRI. The limited Selective Serotonin Reuptake Inhibitors (SSRIs) animal and human data do not support a major CITALOPRAM. Citalopram does not appear to be teratogenic risk from sertraline use during pregnancy. In a major human teratogen, although the data are still a 1998 study, the mean milk:plasma ratios of sertraline limited. Citalopram is excreted into human milk. In their and the metabolite in eight lactating women (mean dose product information, the manufacturer describes two 1.05 mg/kg/day) were 1.93 and 1.64, respectively. The infants whose mothers were receiving citalopram and estimated infant doses were 0.2% and 0.3%, respectively, who had excessive somnolence, decreased feeding, and of the weight-adjusted maternal dose. No adverse effects weight loss associated with nursing. from the drug exposure were noted in the infants. All had achieved normal development milestones. FLUOXETINE (25). There is no evidence of teratogenicity in animals. Chambers and colleagues (84) Other Antidepressants concluded that women who take fluoxetine during pregnancy do not have an increased risk of spontaneous BUPROPION. Bupropion is a unique antidepressant pregnancy loss or major fetal anomalies, but that they of the aminoketone class. After reviewing the 90 are at increased risk for minor anomalies, indicating a prospectively reported pregnancy outcomes, the teratogenic effect. Women who are exposed during the Bupropion Pregnancy Registry Advisory Committee third trimester are at increased risk for premature concludes that this sample is insufficient to reliably delivery, poor neonatal adaptation, cyanosis on feeding, compute a birth defect risk, and no conclusions can be and jitteriness (84). In contrast to these results, five made regarding the possible teratogenic risk of bupropion. cohort studies, which included approximately 450 Bupropion is excreted into human breast milk. pregnancies and focused on the relationship between fluoxetine and developmental effects, suggested that VENLAFAXINE. Reproduction studies in rats and children exposed in utero, whether early or late in rabbits at doses up to 2.5 and 4 times the maximum gestation, do not have an increased risk of birth defects, recommended human daily dose based on body surface poor perinatal condition, or neurodevelopmental delay area (MRHD), respectively, did not reveal teratogenicity. (85). Maternal age was higher in the fluoxetine group A 1994 review of venlafaxine included citations of data in the study of Chambers and coworkers (84), which may from the clinical trials of this drug involving its use during partly explain the observed excess of poor perinatal gestation in 10 women for periods ranging from 10 to 60 outcomes. Prematurity, admission to a special-care days, apparently during the first trimester. No adverse nursery, and poor neonatal adaptation are also associated effects of the exposure were observed in four of the infants with maternal psychiatric disorders. The comparison (information was not provided for the other six exposed between the early-exposure and late-exposure groups led pregnancies). The FDA has not received any reports of the authors to conclude that exposure to fluoxetine in adverse pregnancy outcomes involving the use of the drug late pregnancy increases the risk of perinatal problems. during gestation. Venlafaxine is excreted into human breast This finding might also be explained by the fact that milk. The American Academy of Pediatrics considers the patients with severe depressive illness need treatment effects of other antidepressants on the nursing infant to throughout pregnancy, whereas those with mild forms of be unknown, although they may be of concern. the illness do not. Antihypertensives PAROXETINE. The animal reproductive data and limited human pregnancy experience does not appear to BETA-BLOCKERS (11,12,86–88). There is no indicate that paroxetine poses a major teratogenic risk. evidence of human teratogenicity of the beta-blockers, 56 NEUROLOGIC DISEASE IN WOMEN

but fetal and neonatal toxicity may occur. A 1988 review • Nadolol (11). One case report of growth retardation of beta-blocker use during pregnancy concluded that and beta-blockade. these drugs are relatively safe. Newborn infants, however, • Propranolol (11,12,86) (Table 4.15). should be observed for bradycardia, hypoglycemia, and other symptoms of beta-blockage (87). A number of fetal and/or neonatal adverse effects have been reported (61,87,88). Whether these are due BREAST-FEEDING. Beta-blocker use is compatible to propranolol, maternal disease, or other drugs is not with breast-feeding. clear. Daily doses of 160 mg or higher seem to produce more serious complications. Most case reports show • Atenolol (11). No fetal malformations have been intrauterine growth retardation, hypoglycemia, brady- reported. Reduced birth weight and perinatal beta- cardia, and respiratory depression. Propranolol is prob- blockade in the newborn have been reported. ably not a teratogen, but fetal and neonatal toxicity may • Metoprolol (11). No fetal malformations reported. occur.

ELDERLY. Propranolol is cleared by the liver; its half-life in plasma lengthens with age, from TABLE 4.14 approximately 3 hours in young adults to 6 to 8 hours Antihypertensives in elderly persons (89). The tissue distribution slows, while an increase in bioavailability secondary to FETAL RISK decreased metabolism occurs. Metoprolol’s first-pass FDA TERIS BREAST-FEEDING metabolism decreases with age, which leads to increased Beta-Blockers bioavailability (90), but this produces no change in its Atenolol C U Compatible half-life or metabolite accumulation (91). There is Metoprolol B U Compatible decreased beta-adrenoceptor sensitivity to both agonists (isoproterenol) and antagonists (propranolol) (92). Nadolol C U Compatible Propranolol C U Compatible Timolol C U Compatible Adrenergic Blockers Adrenergic Blockers • Clonidine (11). There are no reports of teratogenic- Clonidine C U Compatible ity, but experience is limited. Calcium Channel Blockers Diltiazem C U Compatible Nifedipine C U Compatible Calcium Channel Blockers (Table 4.14) Nimodipine C U Uncertain • Cardizem (11). No studies or reports in pregnant Verapamil C U Compatible women. Ace Inhibitors • Nifedipine (11). Experience is limited. Adverse reac- Enalapril D Mod Compatible tions have occurred when the drug is combined with magnesium sulfate.

TABLE 4.15 Beta-Blockers in the Elderly

CARDIO- ACTIVE ROUTE OF DRUG HALF-LIFE SELECTIVE METABOLITES EXCRETION STARTING DOSE

Propranolol 3 hours (young adults) No Yes Hepatic and renal 10 mg bid qid 6 to 8 hours (elderly) Metoprolol 3 to 6 hours Yes No Hepatic 25 mg bid Timolol 3 to 4 hours No No Hepatic 5 mg bid Nadolol 24 hours (young adults) No No Renal 20 mg qd 30 to 72 hours (elderly) Atenolol 6 to 9 hours (young adults) Yes No Renal 25 mg qd 16 to 27 hours (elderly) DRUG TREATMENTS AND TRIALS IN WOMEN 57

• Verapamil (11). There is no evidence of terato- TABLE 4.17 genicity in animals. There are no adequate, well-controlled studies in women. Antiviral Drugs

FETAL RISK ELDERLY. The side effects of calcium channel FDA TERIS BREAST-FEEDING blockers may be particularly troublesome in the elderly. Verapamil may cause headaches, hypotension, flushing, Amantadine C U Not dizziness, constipation, and nausea. High-grade heart recommended block and congestive heart failure occur, but these Acyclovir C U Caution complications are rare. Noncardiogenic pedal edema Zidovudine C U Unknown occurs in approximately 25% of all patients. Famciclovir B U Not recommended Antiparkinsonian Drugs

TABLE 4.16 and varicella zoster virus infections. No placental tissue Antiparkinsonian Drugs metabolism can be shown (93). Cord blood levels are close to maternal blood levels, whereas amniotic fluid FETAL RISK levels are three to six times the corresponding cord FDA TERIS BREAST-FEEDING plasma levels.

Dopaminergic ZIDOVUDINE. When zidovudine was given during Bromocriptine C U Contraindicated the third trimester of pregnancy to HIV-infected Pergolide B U Unknown asymptomatic pregnant women, it was well tolerated and Levodopa C U Unknown appeared safe for both mother and infant (94). Carbidopa C U Unknown Amantadine C U Not recommended Corticosteroids (11)

Cortisone BROMOCRIPTINE (11). Bromocriptine does not pose a significant risk to the fetus. The pattern and Reports of congenital defects reflect greater cortisone use incidence of anomalies is similar to those expected in a and do not necessarily suggest that it is a more potent ter- nonexposed population. Because bromocriptine suppresses atogen than other glucocorticoids. The Collaborative lactation, its use is contraindicated during breast-feeding. Perinatal Project found no relationship between cortisone and congenital malformations (22). Some concern regard- ELDERLY. Levodopa clearance is reduced, and side ing neonatal adrenal hyperplasia or insufficiency from effects such as postural hypotension and confusion are maternal corticosteroid administration has been raised. aggravated. Bromocriptine and pergolide are not better tolerated in patients who become confused. Dexamethasone Anticholinergic agents should be avoided. No reports link the use of dexamethasone to congenital defects. Leukocytosis has been observed in mothers and Antiviral Drugs in newborn infants. Animal studies have been associated Most pediatric HIV cases result from vertical transmission of the virus from the mother to the infant during pregnancy or at the time of labor and delivery. Anti-HIV TABLE 4.18 nucleoside drugs (Table 4.17) are used in pregnancy and Corticosteroids have two objectives: (i) to reduce progression of the disease in the mother, and (ii) to reduce transmission of the FETAL RISK virus from the mother to the infant or modify the sever- FDA TERIS BREAST-FEEDING ity of the transmitted infection. Cortisone D N-Min Compatible Dexamethasone C N-Min Compatible ACYCLOVIR. Acyclovir is the most commonly used antiviral drug for the treatment of herpes simplex virus Prednisone B N-Min Compatible 58 NEUROLOGIC DISEASE IN WOMEN

with toxic effects, including increased fetal liver weight, infant is unknown, but it may cause drowsiness or reduced fetal head circumference, and reduced adrenal, galactorrhea in the infant. thymus, and placental weight. These effects have not been observed in humans. HALOPERIDOL (11,95). Haloperidol has been associated with two case reports of limb malformation. Other investigators have not found these defects. Its effect Prednisone on the nursing infant is unknown, but may be of concern. Along with prednisolone, prednisone poses a very small risk to the developing fetus. The drugs do not cross the METOCLOPRAMIDE (11). No congenital placenta easily, except in large doses. Their use is com- malformations have been reported. Normal infant patible with breast-feeding. development for up to 4 years following the use of metoclopramide has been reported. Despite theoretic concerns, there is no evidence that metoclopramide in Neuroleptics and Antiemetics moderate doses of 45 mg or less presents a risk to the nursing infant. Neuroleptics

CHLORPROMAZINE (11,95). One survey found an PROCHLORPERAZINE (11,95). Despite occasional increased incidence of defects, and there is one report of reports of congenital defects in children exposed to ectromelia (gross hypoplasia or aplasia of one or more prochlorperazine, the majority of evidence indicates that long bones or limbs). Most studies, however, have found the drug and the general class of phenothiazines chlorpromazine to be safe for both mother and fetus if (promethazine, promazine) are safe for mother and fetus used occasionally in low doses. Its effect on the nursing if used occasionally and in low doses.

Antiemetics

TABLE 4.19 DOXYLAMINE (95). Doxylamine alone, or in Neuroleptics/Antiemetics combination with vitamin B6 (Bendectin®), is not associated with an increased risk of congenital malformations. FETAL RISK FDA TERIS BREAST-FEEDING EMETROL (95). Emetrol is a phosphorylated carbohydrate solution that acts locally on the wall of the Other gastrointestinal tract. Emetrol B U Compatible Doxylamine and B N NA TRIMETHOBENZAMIDE (95). Trimethobenzamide Vitamin B6 has been associated with a low risk of congenital Trimethobenzamide C N-Min NA malformations. Neuroleptics Phenothiazines Chlorpromazine C N-Min Concern Sedatives, Hypnotics, and Antihistamines Prochlorperazine C N Compatible Promethazine C N NA Barbiturates Promazine C U NA BUTALBITAL (11). Butalbital is a short-acting Butyrophenones barbiturate that has not been found to be associated with Haloperidol C N-Min Concern malformations. Severe neonatal withdrawal can occur Thioxanthenes from prolonged overuse. Data relating to breast-feeding Thiothixene C UNA are not available. Other Metoclopramide B N-Min Concern Benzodiazepines (11,62) Olanzapine C U Not recommended CHLORDIAZEPOXIDE (11). Chlordiazepoxide has Risperdal C U Not been associated with an increased risk of congenital recommended malformation in some, but not all, studies. Neonatal Quetiapine C U Not withdrawal can occur when chlordiazepoxide is given recommended at term. DRUG TREATMENTS AND TRIALS IN WOMEN 59

that are metabolized by conjugation with glucuronic acid TABLE 4.20 (temazepam, oxazepam, and lorazepam) do not have Sedatives, Hypnotics, and Antihistamines significant metabolic changes in the elderly (96).

FETAL RISK FDA TERIS BREAST-FEEDING Antihistamines (11,12,95)

Antihistamines Meclizine, cyclizine, and dimenhydrinate are probably Cyclizine B U NA not associated with an increased risk of malformations. Cyproheptadine B U Contraindicated CYPROHEPTADINE (11). There is no evidence of Dimenhydrinate B U NA fetal abnormalities. Contraindicated for nursing mothers Meclizine B N-Min NA because of sedation of the infant. Barbiturates Butalbital C N-Min Caution ZOLPIDEM (25). No teratogenic effects have been Phenobarbital D N-Min Caution reported in animals. No studies in humans. Risk for Benzodiazepam withdrawal in neonates exists. Not recommended in Chlordiazepoxide D N-Min Concern nursing mothers because of sedation of the infant. Clonazepam D U Concern Diazepam D N-Min Concern Lorazepam D U Concern Other Drugs OTHER Zolpidem B U Not Diphenoxylate (11) (in combination with atropine) recommended One case of an infant with multiple defects, including Ebstein’s anomaly, has been reported.

DIAZEPAM (11). Diazepam has been associated with congenital abnormalities, including inguinal hernia, Lidocaine (11) cardiac defects, and pyloric stenosis. Small doses during There is no evidence of an association with large cate- labor are not harmful to the mother or her infant. gories of major or minor malformations or individual Diazepam and its active metabolite, desmethyldiazepam, defects. are excreted in breast milk in measurable quantities, even though the drug is highly protein bound. Therefore, there is a risk of accumulation if this drug is used in lactating Lithium (11) women. The effect of diazepam on the nursing infant is Lithium should be avoided during pregnancy if possible, unknown, but it may be of concern because of its especially during the first trimester. Infants with cardio- potential for sedation. vascular defects, including the rare Ebstein’s anomaly, Recently it has been suggested that the high rate of have been reported, but this association may be less fre- teratogenicity after heavy maternal benzodiazepine use quent than previously thought (97). Lithium use near may be a result of coincident alcohol and substance abuse term may produce severe, usually reversible, toxicity in and not due solely to benzodiazepine exposure.

LORAZEPAM (11). No reports linking lorazepam with congenital defects have been located. It is excreted TABLE 4.21 in breast milk and may be of concern because of its Other Drugs potential for sedation.

FETAL RISK ELDERLY. Toxic effects arise from both an FDA TERIS BREAST-FEEDING increased sensitivity to central nervous system effects and alterations in pharmacokinetics. The benzodiazepines Diphenoxylate C U Compatible that rely on hepatic oxidative metabolism (diazepam, Lidocaine C None* NA flurazepam, nitrazepam, and chlordiazepoxide) have an Lithium C Small Contraindicated increased elimination half-life, with higher plasma levels Paregoric B U Compatible of both the drug and its active metabolites. This may produce lethargy, excessive sedation, confusion, *As local anesthetic orthostatic hypotension, and ataxia. Benzodiazepines AU: Do you have the cities for publication for #3, 9, 14, 16, 17, 22, 41, 78.

60 NEUROLOGIC DISEASE IN WOMEN

the newborn. Lithium is excreted in breast milk and Yankowitz J, Niebyl JR, (eds.) Drug therapy in preg- results in serum levels in nursing infants of approxi- nancy. Philadelphia, Pa: Lippincott, 2001:231–254. mately one-third to one-half the maternal serum levels. 16. Ethical conflicts and practical realities. Proceedings from the Food and Drug Administration conference on regu- Several authors (98) have reported toxic effects of lated products and pregnant women. 1994. lithium in neonates born to women who received lithium 17. Use of observational methods to monitor the safety of during pregnancy. Lithium is contraindicated during marketed medications for risks of birth defects. Pro- breast-feeding. ceedings form the Food and Drug Administration conference on regulated products and pregnant women. 1994. Paregoric (11) 18. Little BB, Gilstrap LC. Human teratology principles. In: Gilstrap LC, Little BB, (eds.) Drugs and pregnancy. New Paregoric is a mixture of opium powder, anise oil, ben- York, NY: Chapman & Hall, 1998:7–24. zoic acid, campho, glycerin, and ethanol. No evidence has 19. Piper JM, Baum C, Kennedy DL. Prescription drug use been found to suggest a relationship to any major or before and during pregnancy in a Medicaid population. Am J Obstet Gynecol 1987;157:148. minor malformation or to individual defects. 20. Fitzgerald M. Prescription and over-the-counter drug use during pregnancy. J Am Acad Nurse Practitioners 1995; 7(2):87. References 21. Rubin JD, Ferencz C, Loffredo C. Use of prescription and nonprescription durgs in pregnancy. The Baltimore- 1. Nies AS. Principles of therapeutics. In: Hardman JG, Washington Infant Study Group. J Clin Epidemiol 1993; Limbird LC, (eds.) The pharmacological basis of thera- 46(6):581. peutics. New York, NY: McGraw-Hill, 2001;45–66. 22. Heinonen OP, Sloan S, Shapiro S. Birth defects and drugs 2. Roberts JS, Silbergeld EK. Pregnancy, lactation, and in pregnancy. Littleton: Publishing Sciences Group, 1977. menopause: how physiology and gender affect the toxi- 23. Martin PJ, Millac PA. Pregnancy, epilepsy, management city of chemicals. Mt Sinai J Med 1995;343–355. and outcome: a ten-year perspective. Seizure 1993; 3. Matthews HW. Racial, ethnic and gender differences in 2(suppl 4):277–280. response to medicines. In: Matthews HW, (ed.) Drug 24. Oguni M, Dansky L, Andermann E, Sherwin A, Ander- metabolism and drug interactions. Freund Publishing mann F. Improved pregnancy outcome in epileptic House, 1995:77–91. women in the last decade: relationship to maternal anti- 4. Yonkers KA, Kando JC, Cole JO, Blumenthal S. Gender convulsant therapy. Brain Dev 1993;14(suppl 6): differences in pharmacokinetics and pharmacodynamics 371–380. of psychotropic medication. Am J Psychiatry 1992;149: 25. Thomson Healthcare. Physicians’ Desk Reference, 57th 587–595. ed. Montvale, NJ: Thomson PDR, 2003. 5. Silberstein SD, Merriam GR. Sex hormones and headache. 26. Friedman JM, Polifka JE. Teratogenic effects of drugs: a In: Goadsby PJ, Silberstein SD, (eds.) Headache. Newton: resource for clinicians (TERIS), 2nd ed. Baltimore, Md: Butterworth-Heinemann, 1997:143–173. Johns Hopkins University Press, 2000. 6. Sutker PB, Goist KC, King AR. Acute alcohol intoxica- 27. Friedman JM, Little BB, Brent RL, Cordero JF, Hanson tion in women: relationship to dose and menstrual cycle JW, Shepard TH. Potential human teratogenicity of fre- phase. Alcohol Clin Exp Res 1987;2(1):74–79. quently prescribed drugs. Obstet Gynecol 1990;75: 7. Ginsburg ES, Mello NK, Mendelson JH, et al. Effects of 594–599. alcohol ingestion on estrogens in postmenopausal 28. Daly LE, Kirke PN, Molloy A, Weir Dg, Scott JM. Folate women. JAMA 1996;276(21):1747–1751. levels and neural tube defects: implications for preven- 8. Shepard TH. Catalog of teratogenic agents, 8th ed. Bal- tion. JAMA 1995;274:1698–1702. timore, Md: The Johns Hopkins University Press, 1995. 29. Ogawa Y, Kaneko S, Otani K, Fukushima Y. Serum folic 9. Drug treatment of the pregnant woman: the state of the acid levels in epileptic mothers and their relationship to art. Proceedings from the Food and Drug Administration congenital malformations. Epilepsy Res 1991;8(suppl conference on regulated products and pregnant women. 1):75–78. Virginia, November 1995. 30. Jordan RL, Wilson JG, Shumacher HJ. Embryotoxicity 10. Yankowitz J. Use of medications in pregnancy: general of the folate antagonist methotrexate in rats and rabbits. principles, teratology, and current developments. In: Teratology 1977;15:73–80. Yankowitz J, Niebyl JR, (eds.) Drug therapy in preg- 31. Dansky LV, Andermann E, Rosenblatt D, Sherwin AL, nancy. Philadelphia, Pa: Lippincott, 2001:1–4. Andermann F. Anticonvulsants, folate levels, and preg- 11. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy nancy outcome: a prospective study. Ann Neurol and lactation, 6th ed. Philadelphia, Pa: Lippincott, 2002. 1987;21(suppl 2):176–182. 12. Niebyl JR. Teratology and drugs in pregnancy and lac- 32. Reynolds EH. Anticonvulsants, folic acid and epilepsy. tation. In: Winters R, (ed.) Danforth’s obstetrics and Lancet 1973;1:1376–1378. gynecology. New York, NY: Lippincott, 1990. 33. Wegner C, Nau H. Alteration of embryonic folate metab- 13. Rayburn WF, Lavin JP. Drug prescribing for chronic med- olism by valproic acid during organogenesis: implications ical disorders during pregnancy: An overview. Am J for mechanism of teratogenesis. Neurology 1992; Obstet Gynecol 1986;155(3):565–569. 42(suppl 5):17–24. 14. Traditional reproductive toxicology studies and their pre- 34. Berg MG, Stumbo PJ, Chenard CA, Fincham RW, Schnei- dictive value. FDA conference on regulated products and der PJ, Schottelius DD. Folic acid improves phenytoin pregnant women. Virginia, 1994. pharmacokinetics. J Am Diet Assoc 1995;95(3): 15. Silberstein SD. Headaches, pregnancy, and lactation. In: 352–356. DRUG TREATMENTS AND TRIALS IN WOMEN 61

35. Adab N, Jacoby A, Smith D, Chadwick D. Additional 58. Dalessio DJ. Classification and treatment of headache dur- educational needs in children born to mothers with ing pregnancy. Clin Neuropharmacol 1986;9:121–131. epilepsy. J Neurol Neurosurg Psychiatr 2001;70:15–21. 59. Saameli K. Effects on the uterus. In: Berde B, Schild HO, 36. Metcalfe J, Stock MK, Barron DH. Maternal physiology (eds.) Ergot alkaloids and related compounds. Berlin: during gestation. In: Knobel E, Neill J, (eds.) The physi- Springer-Verlag, 1978:231–319. ology of reproduction. New York, NY: Raven Press, 60. Wainscott G, Volans GN. The outcome of pregnancy in 1988:2145–2174. women suffering from migraine. Postgrad Med J 37. Cunningham FG, MacDonald PC, Leveno KJ, Gant NF, 1978;54:98–102. Gilstrap LC. Maternal adaptations to pregnancy. In: Cun- 61. Hughes HE, Goldstein DA. Birth defects following mater- ningham FG, MacDonald PC, Leveno KJ, Gant NF, nal exposure to ergotamine, beta-blockers, and caffeine. Gilstrap LC, (eds.) Williams obstetrics. Stamford, CT: J Med Genet 1988;25:396–399. Appleton and Lange, 1993:209–246. 62. Norton ME. Analgesic use in pregnancy. In: Yankowitz 38. Bailey RR, Rolleston GL. Kidney length and ureteric J, Niebyl JR, (eds.) Drug therapy in pregnancy. Philadel- dilatation in the puerperium. Br J Obstet Gynecol phia, Pa: Lippincott, 2001:119–126. 1971;78:55. 63. Stuart MJ, Gross SJ, Elrad H, Graeber JE. Effects of 39. Chesley LC. Renal function during pregnancy. In: Carey acetylsalicylic acid ingestion on maternal and neonatal HM, (ed.) Modern trends in human reproductive physi- hemostasis. N Eng J Med 1982;307:909–912. ology. London: Butterworth, 1963. 64. Hertz-Pigiotto C, Hopenhay-Rich C, Golub M, Hooper 40. Dunlop W. Serial changes in renal hemodynamics dur- K. The risks and benefits of taking aspirin during preg- ing normal human pregnancy. Br J Obstet Gynecol nancy. Epidemiology Rev 1990;12:108–148. 1981;88:1. 65. Rayburn W, Shukla U, Stetson P, Piehl E. Acetaminophen 41. Chaudhuri G. Pharmocokinetics in pregnancy. VA, 11- pharmacokinetics: comparison between pregnant and 7-8. 1994 (Abstract). nonpregnant women. Am J Obstet Gynecol 1986;155: 42. Yerby MS, Friel PN, McCormick K. Antiepileptic drug 1353–1356. disposition during pregnancy. Neurology 1992;42(suppl 66. Merck. Clinical pharmacology. 1995:255–276. 5):12–16. 67. VandenVeyver JB, Moise KJ. Prostaglandin synthetase 43. Murray L, Seger D. Drug therapy during pregnancy and inhibitors in pregnancy. Obstet Gynecolog Survey lactation. Emerg Med Clin N Amer 1994;12:129–149. 1993;48:493–502. 44. Szeto HH. Kinetics of drug transfer to the fetus. Clin 68. Goodwin JS, Regan M. Cognitive dysfunction associated Obstet Gynecol 1993;36:246–254. with naproxen and ibuprofen in the elderly. Arthritis 45. American Academy of Pediatrics Committee on Drugs. Rheum 1982;25:1013–1014. The transfer of drugs and other chemicals into human 69. Gilstrapp LC, Little BB. Anticoagulants, thrombolytics milk. Pediatrics 2001;108(3). and hemostatics during pregnancy. In: Gilstrap LC, Lit- 46. Krauss GL, Brandt J, Campbell M, Plate C. Reproduc- tle BB, (eds.) Drugs and pregnancy. New York, NY: tive issues in epilepsy are poorly understood by U.S. neu- Chapman & Hall, 1998:149–160. rologists and obstetricians. Epilepsia 1995 36(suppl 3),12. 70. Omri A, Delaloye JF, Anderson H, Bachmann F. LMW 47. Mattson RH, Cramer JA, Darney PD, Naftolin F. Use of heparin Novo (LHN-1) does not cross the placenta dur- oral contraceptives by women with epilepsy. JAMA ing the second trimester of pregnancy. Thromb Haemost 1986;256(2):238–240. 1989;61:55. 48. So EL. Update on epilepsy. Med Clin N Amer 1993;77(1): 71. Gillis S, Shushan A, Eldor A. Use of low molecular weight 203–214. heparin for prophylaxis and treatment of thromboem- 49. Shuster EA. Epilepsy in women. Mayo Clin Proc 1996; bolism in pregnancy. Int J Gynecol Obstet 1992;39: 71:991–999. 297. 50. Haukkamaa M. Contraception by Norplant subdermal 72. Dulitzki M, Pauzner R, Langevitz P, Pras M, Many A, capsules is not reliable in epileptic patients on anticon- Schiff E. Low molecular weight heparin during pregnancy vulsant therapy. Contraception 1986;33:559–565. and delivery: preliminary experience with 41 pregnan- 51. Schwartz D, Wang M, Geitz L. Medication errors made cies. Obstet Gynecol 1996;87:380. by elderly chronically ill patients. Am J Public Health 73. LeOrme M, Lewis PJ, Deswiet M, et al. May mothers 1962;52:2018–2029. given Warfarin breast feed their infants? Br Med J 52. Brand FN, Smith RT, Brand PA. Effect of economic bar- 1977;1:564. riers to medical area on patients’ noncompliance. Pub 74. Turrentine MA, Braems G, Ramirez MM. Use of throm- Health Rep 1977;92:72–78. bolytics for the treatment of thromboembolic disease dur- 53. Triggs EJ, Nation RL, Long A, et al. Pharmacokinetics ing pregnancy. Obstet Gynecol 1995;50:534. in the elderly. Eur J Clin Pharmacol 1975;8:55–62. 75. Uknis A, Silberstein SD. Review article: migraine and 54. Bender AD. Effect of age on intestinal absorption: impli- pregnancy. Headache 1991;31:372–374. cations for drug absorption in the elderly. J Am Geriatr 76. Wylen M, Yankowitz J. Anticonvulsants in pregnancy. In: Soc 1968;16:1331–1339. Yankowitz J, Niebyl JR, (eds.) Drug therapy in preg- 55. Novak LP. Aging, total body potassium, fat free mass and nancy. Philadelphia, Pa: Lippincott, 2001:221–230. cell mass in males and females between the ages 18 and 77. Buehler BA, Delimont D, VanWaes M, Finnell RH. Pre- 85 years. J Gerontol 1972;27:438–443. natal prediction of risk of the fetal hydantoin syndrome. 56. Stilwell JE. Psychotherapeutic drugs. In: Cassel CK, N Engl J Med 1990;322:1567–1572. Walsh JR, (eds.) Geriatric medicine. New York, NY: 78. Practice parameter: a guideline for discontinuing Springer-Verlag, 1984:637–647. antiepileptic drugs in seizure-free patients (summary 57. Parry JH, Balter MB, Mellinger GD, et al. National pat- statement). 1994. terns of psychotherapeutic drug use. Arch Gen Psychia- 79. Robert E, Biubaud P. Maternal valproic acid and con- try 1973;28:269–283. genital neural tube defects. Lancet 1982;2:937. 62 NEUROLOGIC DISEASE IN WOMEN

80. Lindhout D, Schmidt D. In utero exposure to valproate 91. Fishman WH. Beta-adrenoceptor antagonists: new drugs and neural tube defects. Lancet 1986;1:1392–1393. and new indications. N Engl J Med 1982;306:1456–1462. 81. Omtzigt JG, Los FJ, Grobee DE, et al. The risk of spina 92. Vestal RE, Wood AJ, Shand DG. Reduced beta-adreno- bifida aperta after first trimester exposure to valproate in ceptor sensitivity in the elderly. Clin Pharmacol Ther a prenatal cohort. Neurology 1992;42(S5):119–125. 1979;26:181–186. 82. Nulman I, Rovet J, Stewart DE, et al. Neurodevelopment 93. Henderson GI, Hu ZQ, Johnson RF, Perez AB, Yang Y, of children exposed in utero to antidepressant drugs. N Schenker S. Acyclovir transport by the human placenta. Engl J Med 1997;336:258–262. J Lab Clin Med 1992;120:885–892. 83. Hollister LE. Treatment of depression with drugs. Ann 94. O’Sullivan MJ, Boyer PJ, Scott GB, et al. The pharma- Intern Med 1978;89:78–84. cokinetics and safety of zidovudine in the third trimester 84. Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones of pregnancy for women infected with human immun- KL. Birth outcomes in pregnant women taking fluoxe- odeficiency virus and their infants: Phase I acquired tine. N Engl J Med 1996;335:1010–1015. immunodeficiency syndrome clinical trials group study 85. Robert E. Treating depression in pregnancy. N Engl J (Protocol #082). The Zidovudine Collaborative Working Med 1996;1056–1058. Group. Am J Obstet Gynecol 1993;168:1510–1516. 86. Robinson JN, Norwitz ER, Repke JT. Antihypertensive 95. McMahon MJ. Drug therapy for the treatment of gas- use during pregnancy. In: Yankowitz J, Niebyl JR, (eds.) trointestinal disorders in pregnancy and lactation. In: Drug therapy in pregnancy. Philadelphia, Pa: Lippincott, Yankowitz J, Niebyl JR, (eds.) Drug therapy in preg- 2001:101–118. nancy. Philadelphia, Pa: Lippincott, 2001:77–100. 87. Pruyn SC, Phelan JP, Buchanan GC. Long-term propra- 96. Conrad KA. Antianxiety agents and hypnotics. In: Con- nolol therapy in pregnancy: maternal and fetal outcome. rad KA, Bressler R, (eds.) Drug therapy for the elderly. Am J Obstet Gynecol 1979;135:485–489. Saint Louis: Mosby, 1982:262–276. 88. Featherstone HJ. Fetal demise in a migraine patient on 97. Jacobson SJ, Jones K, Johnson K, et al. Prospective mul- propranolol. Headache 1983;23:213–214. ticenter study of pregnancy outcome after lithium expo- 89. Shand DG. Propranolol. N Engl J Med 1975;293: sure during first trimester. Lancet 1992;339:530–533. 280–285. 98. Wilbanks GC, Bressler B, Peete CH, et al. Toxic effects 90. Koch-Weser J. Metoprolol. N Engl J Med 1979;301: of lithium carbonate in a mother and newborn infant. 698–703. JAMA 1970;213:865.

Reproductive and Metabolic Disorders 5 with AED Use

Martha J. Morrell, MD

ntiepileptic drugs (AEDs) represent rates phenobarbital and primidone, induce CYP450 a rapidly growing pharmaceutical enzymes, increase steroid hormone metabolism, and bind class with efficacy in a number of to sex hormone binding globulin (SHBG) (Table 5.1). A neurological and psychiatric disor- Both mechanisms reduce the bioavailable concentration ders, including epilepsy, pain, migraine, depression, bipo- of steroid hormone. Oxcarbazepine at doses in excess of lar disorder, and social anxiety disorders. Maintaining 1,200 mg per day also induces cytochrome P450 enzymes, familiarity with the efficacy and tolerability profiles of as does topiramate at dosages in excess of 200 mg per day. individual agents, as well as the pharmacokinetics pro- Valproate effectively inhibits this enzyme system, thereby files, is challenging. In addition, the long-term health con- slowing the metabolism of contraceptive hormones. sequences of taking AEDs must be considered for the Gabapentin, lamotrigine, levetiracetam, and zonisamide many patients who must take these agents for years or do not alter steroid hormone metabolism and thus do not even a lifetime. This chapter focuses on AED use in interfere with hormonal contraceptives. women. Relevant information is also contained in Chap- Women taking CYP450 enzyme–inducing AEDs ter 15, Seizures and Epilepsy in Women, including infor- who wish to use oral hormonal contraception should con- mation about the dosing and pharmacokinetics charac- sider using a product containing at least 50 µg of the teristics of each AED. estrogen product (3) to regulate menstrual bleeding, rather than the commonly used minipill, which contains 35 µg of estrogen or less. Other forms of hormonal con- CONTRACEPTION IN WOMEN traception, such as subdermal levonorgestrel (Norplant®), WITH EPILEPSY a slow-release contraceptive containing only progesterone, also carry a higher risk for failure (4,5). Women taking cytochrome P450 (CYP450) enzyme–inducing AEDs have perhaps a fivefold increase in the failure rate of oral contraceptive agents (1,2) EFFECTS OF AEDs ON PHYSIOLOGICAL because the metabolism of the contraceptive steroid is SEX STEROID HORMONES increased. The hormone dosage, particularly with low- dose hormone pills (the minipill), may not be sufficient to Just as the AEDs alter concentrations of sex steroid hor- be effective. Phenytoin, carbamazepine, and the barbitu- mones used for contraception, so they alter concentrations 63 64 NEUROLOGIC DISEASE IN WOMEN

lism (11). AEDs may alter bone mineral metabolism by TABLE 5.1 decreasing calcium and increasing bone turnover. AEDs Antiepileptic Drug Effects on Oral that interfere with intestinal calcium absorption could Hormonal Contraception directly affect bone cell function, possibly through the inhibition of cellular responses to phenytoin (8,12), but AEDs that induce liver enzymes and may compromise OC efficacy this cannot be the only mechanism. Whereas reproduc- Carbamazepine (Tegretol®, Carbatrol®) tive-age women taking carbamazepine, phenytoin, and Phenytoin (Dilantin®) valproate had significantly reduced calcium levels com- Phenobarbital® pared with women receiving lamotrigine, only phenytoin Mysoline (Primidone®) was associated with increased bone turnover (13), as mea- Oxcarbazepine (Trileptal®)1 sured by metabolic markers indicating enhanced Topiramate (Topamax®)2 osteoblast and osteoclast activity. Valproate was associated with impaired osteoblastic differentiation but not AEDs that do not compromise OC efficacy with a change in osteoclast activity. Women receiving lam- ® Gabapentin (Neurontin ) otrigine showed no abnormalities in any marker of bone Levetiracetam (Keppra®) metabolism. Lamotrigine (Lamictal®) Valproate (Depakote®, Depakene®) Given the available data, women with epilepsy Zonisamide (Zonegran®) receiving AEDs should engage in good bone health practices, including adequate daily calcium (1,200 mg/day) 1At dosages above 1,200 mg/day and vitamin D, and gravity-resisting exercise. Bone den- 2At dosages above 200 mg/day sity scans should be obtained after treatment with phenytoin, carbamazepine, or valproate for 5 or more years, although it seems reasonable to consider this after 3 years. of endogenous ovarian and adrenal steroid hormones. This Treatment with bisphosphonates, calcitonin, estrogen, or subject is reviewed in more detail in Chapter 6. In brief, testosterone may be recommended for women with bone CYP450 enzyme–inducing AEDs reduce the concentra- loss. Individuals with bone loss by density scan should tions of ovarian estradiol and testosterone, as well as be monitored with density scans yearly, or until bone loss adrenal androgens such as androstenedione and DHEAS. begins to reverse. Some authors have associated these reductions in androgens with sexual dysfunction in women using AEDs. Val- proate, as a CYP450 enzyme inhibitor, is associated with AEDs AND POLYCYSTIC OVARY SYNDROME elevations in ovarian and adrenal androgens. The clinical implications of this are discussed in the sections on poly- The neurology community has been concerned about the cystic ovary syndrome and carbohydrate metabolism. increased prevalence of polycystic appearing ovaries and AEDs that have no effect of CYP450 enzymes probably do anovulatory menstrual cycles in women with epilepsy not change steroid hormone concentrations. This has been receiving AEDs (see Chapter 15 for detail). One question studied directly for gabapentin and lamotrigine. Women has been whether these observations imply that women receiving either of these AEDs in monotherapy for epilepsy with epilepsy are at greater risk for polycystic ovary syn- had no difference from nonepileptic untreated controls in drome and if such risk applies to women using AEDs for concentrations of any steroid hormone (6). other indications. Polycystic ovary syndrome is a gynecological syndrome affecting 7% of reproductive-aged women. Poly- EFFECTS OF AEDs ON BONE HEALTH cystic ovaries are found in 15% to 20% of reproductive- aged women and are not a component of the diagnostic Some AEDs alter bone mineral metabolism and compro- criteria for polycystic ovary syndrome. The syndrome mise bone health, especially in women who have smaller diagnosis requires frequent anovulatory cycles and phe- bone mass. Women using phenytoin, phenobarbital, and notypic or serologic evidence for hyperandrogenism. This perhaps carbamazepine and valproate, are at higher risk may present as centripetal obesity, hirsuitism with for bone disorders such as osteopenia, osteoporosis, increased facial and body hair and loss of scalp hair over osteomalacia, and fractures (7–9). A prospective study the crown and temporal recession, and acne. Serum evaluating the risk of hip fractures in women older than androgens may be elevated, and there is often an eleva- 65 years found that women taking AEDs were twice as tion in the ratio of luteinizing hormone (LH) to follicle likely to have a hip fracture (10). stimulating hormone (FSH). The metabolic defect under- AED associated bone disease is the consequence of lying the syndrome is believed to be related to insulin a number of biochemical abnormalities of bone metabo- insensitivity, perhaps because of a genetically determined REPRODUCTIVE AND METABOLIC DISORDERS WITH AED USE 65 abnormality in the insulin receptor. The importance of Changes in carbohydrate metabolism induced by diagnosis comes from concerns about the long-term some AEDs are associated with a change in body mass health risks associated with the syndrome. These risks index. Carbamazepine, gabapentin, and valproate are asso- include infertility, carbohydrate intolerance and diabetes, ciated with weight gain in some patients, whereas felba- dyslipedemia with accelerated atherosclerosis, and mate, topiramate, and zonisamide are associated with endometrial carcinoma. Therefore, treatment is advo- weight loss. Levetiracetam, lamotrigine, and oxcarbazepine cated, even for women not actively trying to conceive. are weight neutral and do not change fasting or postpran- Treatment includes dietary alterations, regulation of pitu- dial insulin levels (21,22). Lamotrigine is not associated itary and gonadal hormones with oral contraceptives, and with changes in weight in adults (21) or adolescents (23). even hypoglycemic and lipid-lowering agents (14). Approximately 50% of persons taking valproate for Women with epilepsy and women with bipolar dis- epilepsy experience significant weight gain, defined as ease have a high frequency of menstrual cycles that are more than 4 kg (24–26). Significant weight gain affects abnormally long and thus suggestive of anovulatory cycles children and adolescents, as well as adults (23,27–29), and (see Chapter 15). In studies of women with epilepsy, 25% is usually evident early in therapy (within 3 to 6 months). to 50% of cycles are anovulatory, depending on the The mechanism for weight gain with valproate epilepsy syndrome. A similar prevalence of anovulatory appears related to changes in lipid and carbohydrate cycles is believed to affect women with bipolar disorder. metabolism, so may be relatively resistant to dietary Although epilepsy and bipolar disorder appear to be one manipulations. Valproate inhibits mitochondrial beta- variable associated with this polycystic-ovary-like syn- oxidation and impairs the utilization of free fatty acids, drome, valproate—an AED that is an effective treatment which are then stored as fat (26). Increased free fatty acids for both disorders—seems to promote weight gain, car- increase insulin production and appetite. Valproate also bohydrate intolerance, and elevated androgens in some increases GABA, an inhibitory neurotransmitter that women. Therefore, some women with these disorders increases appetite. Leptin, which also mediates appetite, who are receiving valproate present with a physical is elevated in persons gaining weight on valproate (23,30). appearance, endocrinopathy, and cycle disturbance that Individuals gaining weight on valproate may have very much resembles polycystic ovary syndrome. It is not some degree of underlying insulin resistance. This hypoth- known, however, whether this phenomenon has long-term esis is supported by observations that fasting and post- health consequences similar to polycystic ovary syndrome. prandial insulin and proinsulin levels are elevated in obese Given present knowledge, the strategy is to watch adolescents and in adults taking valproate (19,20,22). Per- closely for weight gain, cycle lengths shorter than 23 days sons who gain weight on valproate have higher insulin lev- or longer than 35 days (which is suggestive of anovula- els than those who do not gain weight (30). tion), and query regarding changes in body or facial hair, Topiramate is associated with weight loss in persons as well as acne. This topic is discussed in detail with rel- with epilepsy and in nonepileptic patients. Persons with evant references in Chapter 15. weight gain associated with use of serotonin reuptake inhibitors lose weight when treated with topiramate (31,32). Glycemic control is improved in persons with AEDs AND LIPID, INSULIN, AND type II diabetes taking topiramate (33). Topiramate is also CARBOHYDRATE METABOLISM associated with a reduction in the number of binge eating episodes and weight loss in persons with eating dis- Changes in lipid metabolism and body weight are asso- orders (34). ciated with use of some AEDs and may cause long-term The mechanism of topiramate associated weight loss adverse health effects. Carbamazepine, phenytoin, and is not known. In rodents, topiramate decreases lipopro- phenobarbital increase high-density lipoproteins (HDLs) tein lipase and inhibits fat deposition, reduces food intake, and may have cholesterol-lowering effects (15–18). Car- and enhances thermogenesis. Weight loss may be medi- bamazepine does not alter trigycerides (19). Counteract- ated through first- and second-messenger systems and ing these favorable lipid trends, carbamazepine and augmentation of serotonin receptors, or through the phenytoin elevate low-density lipoproteins (LDLs). Val- antagonism of glutamate (35). Topiramate may also proate increases triglycerides, LDLs as well as HDLs, increase insulin sensitivity, thus reducing insulin levels. leading to an unfavorable lipid profile (20). Valproate- associated dyslipidemia may be a consequence of valproate-associated obesity and hyperinsulinemia (21). AED USE IN PREGNANCY Until the nature and mechanisms of AED-associated alterations in lipid metabolism are better understood, clini- Women taking AEDs are understandably concerned that cians should monitor cholesterol and lipid profiles in per- these agents will compromise pregnancy and harm the sons receiving AEDs. fetus. Accumulating data allow health care providers to 66 NEUROLOGIC DISEASE IN WOMEN

TABLE 5.2 TABLE 5.3 FDA Use-in-Pregnancy Risk Categories Maternal and Fetal AED Concentrations

Category C FETAL-TO- FETAL-TO- Animal studies have shown no adverse effect on the MATERNAL TOTAL MATERNAL FREE fetus (teratogenic, embryocidal, or other) but there are AED CONCENTRATION CONCENTRATION no adequate studies in humans. The benefit from the use of the drug in pregnant women may be acceptable Phenobarbital 0.86 1.13 despite its potential risks. Phenytoin 0.91 1.10 Gabapentin Carbamazepine 0.73 1.42 Felbamate Valproate 1.59 0.50 Lamotrigine Lamotrigine 1.02 to 1.55 — Levetiracetam Reproduced with permission from Myllyne, et al. Oxcarbazepine Tiagabine Zonisamide bound drug concentration, especially for AEDs that are Category D highly protein bound, such as carbamazepine, phenytoin, Positive evidence of human fetal risk exists, but the and valproate. Dose adjustments should aim to maintain potential benefits of the drug in pregnant women may a stable nonprotein-bound fraction. Significant preg- be acceptable despite its potential risks (e.g., for a life- nancy-related reductions can be anticipated in concen- threatening condition or a serious disease for which trations of carbamazepine, phenytoin, phenobarbital, safer drugs cannot be used or are ineffective). lamotrigine, and sometimes valproate (see Chapter 15 for Carbamazepine more information). Phenobarbital Phenytoin Valproate (valproic acid, divalproex sodium) AED-ASSOCIATED BIRTH DEFECTS

The older AEDs (benzodiazepines, phenytoin, carba- better counsel women receiving AEDs about pregnancy mazepine, phenobarbital, and valproate) are associated and fetal risks. with a higher risk of fetal major malformations, includ- AEDs taken by the mother pass the placenta and ing cleft lip and palate and cardiac defects (atrial septal enter the fetal circulation. Significant concentrations of defect, tetralogy of Fallot, ventricular septal defect, coarc- the total and nonprotein-bound (free) AEDs are detected tation of the aorta, patent ductus arteriosus, and pul- in the newborn (36). As shown in Table 5.2, the individ- monary stenosis) (38–40). Cleft lip and palate are ual fetal-to-maternal total AED concentration is inversely increased by a factor of 4.7 in children of AED treated correlated with the fetal to maternal free fraction ratios mothers with epilepsy compared to the background rate for carbamazepine, phenobarbital, and phenytoin. The (40). Carbamazepine and valproate are also associated maternal free fraction of valproate is much higher in the with neural tube defects (NTDs) such as spina bifida mother than the fetus because the increase in free fatty (41,42). Exposure to AEDs, rather than the maternal trait acids during later pregnancy increases the free fraction of epilepsy, appears to be the cause of malformations. of valproate. Data are not available for all the newer This suggests that women taking AEDs during pregnancy AEDs. for indications other than epilepsy will have similar risks AED concentrations may change during pregnancy. for birth defects. Changes in total AED concentrations are related to an The incidence of major malformations in infants increase in plasma volume of 40% to 50%, and an born to mothers with epilepsy taking carbamazepine or increase in renal clearance and hepatic metabolism. The phenytoin is believed to be 4% to 6%, compared with pharmacokinetics of some AEDs are more profoundly 2% to 4% for the general population. Neural tube defects affected than that of others, probably because of preg- (spina bifida and anencephaly) occur in 0.5% to 1% of nancy-related differential effects on CYP450 enzymes infants exposed to carbamazepine (42) and 1% to 2% (Table 5.3). Although the total concentration falls for of infants exposed to valproate during the first month of many AEDs, there tends to be an increase in the percent- gestation (41). Minor congenital anomalies associated age of the nonprotein bound fraction of drug because of with AED exposure include facial dysmorphism and dig- a reduction in albumin and, thus, in protein binding (37). ital anomalies, which arise in 6% to 20% of infants Therefore, it is necessary to follow the non–protein- exposed in utero to the older AEDs (43). This represents REPRODUCTIVE AND METABOLIC DISORDERS WITH AED USE 67 a twofold increase over the general population. Minor were present in only 1.62% of pregnancies with no AED anomalies in infants of epileptic mothers taking carba- exposure. There was evidence of increased risk of birth mazepine, phenobarbital, phenytoin, or valproate include defects in offspring of women exposed to phenobarbital. ocular hypertelorism, epicanthal folds, nasal growth defi- Major malformations were seen in 7.8% of 65 pregnan- ciency, abnormal ears, low hairline, distal digital hypopla- cies exposed to phenobarbital in monotherapy and sia, nail hypoplasia, and low arched fingertip dermoto- enrolled in the first trimester (48). Major malformations glyphic patterns (44).These dysmorphisms are essentially were heart defects in four and cleft lip and palate in one. identical to those seen with fetal alcohol syndrome and There were 123 completed pregnancies in which the fetus may be outgrown in the first several years of life (38). was exposed during the first trimester to valproate in The risk of teratogenicity is partly related to the monotherapy. Major birth defects were seen in 8.9% of extent of fetal exposure to the AED (45). The risk of birth these pregnancies (49). Anomalies included heart defects defects increases significantly with AED polytherapy in four, NTDs in two, and one each of hypospadias, poly- (38,45) and with higher daily doses (41,46). In one study dactyly, bilateral inguinal hernia, dysplastic kidneys, and in Japan (45), the risk of malformation after exposure to clubfoot. a single AED was 2% to 4%, whereas the risk had Since 1993, a number of new AEDs have been intro- increased to more than 20% after exposure to four or duced. Little information exists regarding the effects of more AEDs. Some investigators have suggested that it is some of these drugs on the developing human fetus. Ani- the peak dose to which the fetus is exposed rather than mal reproductive toxicology studies for AEDs provide the cumulative dose exposure that determines teratogenic some useful information, but may not be specifically pre- risk (Morrell, 1997). This concern has led some clinicians dictive of the human experience. Data from the U.S. Food to divide the total AED dose into more frequent intervals, and Drug Association (FDA) on fetal outcome in animals particularly for women who require a higher daily dose. exposed to the newer AEDs are favorable. Please see Chapter 4 for further review of drug safety. Data are available for lamotrigine through a drug- Children born to women with a history of seizures specific prospective pregnancy registry established by the on and off AEDs, delivering at one of five maternity hos- manufacturer, GlaxoSmithKline (50). As of March 2003, pitals in the Boston area, were examined for birth defects the registry accumulated prospective data on 302 preg- (47). Identified mother–infant pairs were compared with nancies resulting in a live birth, in which the fetus was control pairs of nonepileptic mothers and infants. Con- exposed to lamotrigine during the first trimester in sidering major malformations alone, 4.5% of women monotherapy. Nine pregnancies resulted in a child with with epilepsy taking a single AED gave birth to a child a major malformation (3.0%; 95% confidence interval with a major malformation, whereas 8.6% of women tak- 1.5–5.8%). The 95% confidence interval indicates that ing two or more AEDs had a child with a major malfor- the incidence of major malformations is no more than a mation. No women with a history of seizures not taking twofold increase over the background population, and an AED gave birth to a child with a major malformation. this may be similar to the background malformation rate. Major malformations were detected in 1.8% of infants Data are also available for outcomes after first- born to controls. When major malformations, growth trimester exposure to lamotrigine in polytherapy. Twelve retardation, microcephaly, and hypoplasia of the midface of 215 pregnancies with known outcomes resulted in a and fingers were considered, 20.6% of the infants born child with a major defect (5.6%). There were 67 prospec- to mothers with epilepsy taking AEDs had one or more tively identified pregnancies in which the polytherapy of these birth defects, in contrast to 28% of the infants included valproate. Malformations occurred in seven chil- born to mothers taking two or more AEDs, 6.1% of the dren (10.4%; 95% confidence interval 4.7–20.9%). AED infants born to mothers with a history of seizures but not polytherapy that did not include valproate resulted in taking AEDs, and 8.5% of controls. major malformations in 5 of 148 outcomes (3.4%; 95% Prospective registries have been established to learn CI 1.3–1.8%). No specific patterns of malformation were more about pregnancy and fetal outcome in women using seen in the registry as a whole or in any subgroup. AEDs. The North American Antiepileptic Drug Preg- Although the sample sizes for the individual regi- nancy Registry was established in 1997 to ascertain the mens are too small for small frequencies of major mal- fetal effects of AEDs taken during the first trimester of formations or large frequencies of very rare malformation pregnancy. This is a purely prospective registry with to be ruled out, this experience is thus far reassuring. Con- women identified in the first trimester, before pregnancy firmation of these findings comes from experience in a outcome is known. Although most pregnancies represent registry maintained in the United Kingdom (51). women with epilepsy, the registry is open to pregnant Pregnancy experience with oxcarbazepine has been women using AEDs for any indication. At the time that reported in several single-center studies. A report from this chapter was written, the registry had released data on Argentina on 42 pregnancy exposures to oxcarbazepine only two AEDs. The registry reports that malformations (25 in monotherapy and 17 in combination with other 68 NEUROLOGIC DISEASE IN WOMEN

AEDs) found no malformations in the monotherapy with epilepsy receiving valproate alone or in combination group and one ventricular septal defect in an infant also had increased levels of retinol (vitamin A) and decreased exposed to phenobarbital (52). A Finnish series that levels of retinoic acid (57). included 740 pregnancies exposed to AEDs during the Folic acid deficiency has been identified as a con- first trimester found that the occurrence of major mal- tributing factor to the development of NTDs and other formations was independently associated with use of nongenetic malformations, and folate supplementation oxcarbazepine [odds ratio (OR) 10.8%; 95% CI has been conclusively shown to have a beneficial effect 1.1–106], as well as with caramazepine [OR 2.5; 95% CI in reducing this risk. Women with epilepsy appear to be 1–6], and valproate (4.1; 95% CI 1.6–11] (53). The wide at especially high risk for folate deficiency (60). Serum confidence intervals indicate that these data should not folate is reduced in up to 90% of patients receiving pheny- be considered conclusive. toin, carbamazepine, or barbiturates (61). Valproate does Presently, the European Registry (EURAP) is not cause a reduction in folate levels but does interfere enrolling actively across the globe, while the North Amer- with folate and methionine metabolism (62). In mice, val- ican Antiepileptic Drug Registry and pharmaceutical proate reduces levels of 5-formyl- and 10-formyl-tetrahy- company registries continue to gather data. A registry drofolates and increases the level of tetrahydrofolate, should be contacted regarding any woman who becomes apparently by inhibiting the transfer of the formyl group pregnant while taking AEDs. via glutamate formyltransferase (63). Lamotrigine, an AED that has weak folate properties in vitro, had no effects on serum or red blood cell folate in a small num- Mechanisms for AED-Mediated Teratogenesis ber of patients (64). Several biochemical and molecular mechanisms are likely Low serum and red blood cell folate levels are asso- for AED mediated teratogenicity, including interference ciated with an increased incidence of spontaneous abor- with the folate and methionine metabolic pathways (54), tions and malformations in animals and in women with alteration of gene expression (55), generation of reactive epilepsy (61,65). Folate supplementation significantly metabolites via epoxidation or the prostaglandin co-oxi- reduces the risk of occurrent and recurrent NTDs in dation pathway (56), and interference with endogenous nonepileptic women (66–71). The presumption has been retinoid metabolism (57). The embryotoxicity associated that folic acid supplementation will also reduce the risk with folate deficiency and exposure to epoxide intermedi- of major malformations after fetal exposure to AEDs. ates can be minimized through simple treatment strategies. There is, however, no proof that this is so. In fact, at least The teratogenicity of some AEDs (carbamazepine, one report exists of a child born with a NTD after in utero phenobarbital, phenytoin) may be mediated in part by exposure to valproate despite folic acid supplementation oxidative (free radical) metabolites generated by the (72). bioactivation of the parent compound by the hepatic The best method to determine folate status has not CYP450 enzymes. These intermediates may be inacti- been established, because serum folate appears to be a rel- vated by one of several biochemical pathways. Free rad- atively insensitive indicator of functional folate status. ical scavenging enzymes, such as glutathione, bind with Red blood cell folate levels more accurately reflect chronic and disable these reactive intermediates and may be cyto- folate status than do serum levels. In one study, women protective. When glutathione is inhibited, phenytoin who had given birth to two or more children with NTDs embryotoxicity is enhanced (56). These intermediates are had lower red cell folate levels than did controls (178 also metabolized by the enzyme epoxide hydrolase to a ng/mL versus 268 ng/mL). Serum folate, however, was nonreactive dihydrodiol. The activity of this enzyme is equivalent between the two groups (73). A vulnerability genetically mediated, and fetuses with low levels of to develop malformations may be associated with defec- enzyme activity appear to be at the highest risk for birth tive folate metabolism rather than folate deficiency (74). defects (55,58,59). The CYP450 enzyme-inducing AEDs Results from one recent study suggest that the neurotoxic accelerate the formation of epoxide derivatives, and val- effects of valproate are mediated by disruption of folate- proate inhibits epoxide metabolism by inhibiting the mediated biochemical processes rather than by causing a enzyme epoxide hydrolase. Polytherapy with an enzyme folate deficiency (63). inducer and valporate may promote epoxide production In addition, vitamin B12 deficiency, either related to and inhibit epoxide metabolism. insufficient dietary intake or abnormalities of the B12 Vitamin A (retinol) and its oxidative metabolite, all- binding proteins (apotranscobalamins), could contribute trans-retinoic acid, mediate embryonic growth, differenti- to AED-mediated teratogenesis by impairing folate ation, and morphological development. Vitamin excess and metabolism. Mills et al. (75) found higher homocysteine deficiency, and low doses of retinoic acid, are associated values in mothers of children born with NTDs than in with birth defects in animals (57). In a study of 75 patients controls. Elevated homocysteine levels are also found in with epilepsy and 29 healthy untreated controls, patients persons taking AEDs, particularly valproate (76,77). This REPRODUCTIVE AND METABOLIC DISORDERS WITH AED USE 69 could be explained by reduced activity of the enzyme folate levels that were lower than optimal (less than 680 methionine synthetase, which requires both folate and nmol/l). Only one in four had red blood cell folate levels B12 as cofactors. One assessment of women who had pre- that exceeded the optimal 906 nmol/l. viously given birth to a child with a NTD found evidence The United States Public Health Service recom- of intolerance to methionine loading that was consistent mends that all women of childbearing age in the United with pathologic homocysteinemia. This response is usu- States who are capable of becoming pregnant consume ally a consequence of heterozygosity for homocysteine- 0.4 mg/day of folic acid for the purpose of reducing their mia (78). Carriers for inborn errors of homocysteine risk of having a child affected with a NTD (83). Women metabolism might be identified antenatally, and when who have already had a child with a NTD are referred possible, exposure to AEDs associated with neural tube to a 1991 CDC guideline suggesting a dosage of 4 mg/day, abnormalities could be avoided. In women receiving based on the Medical Research Council recurrent risk drugs associated with elevated risk for neural tube abnor- study (68). The Canadian College of Medical Geneticists malities, pathological homocysteinemia could be cor- recommend that 0.8 to 5.0 mg/day of folic acid be given rected with high doses of pyridoxine or folic acid. to women who are at increased risk of having offspring with NTDs and who are planning a pregnancy (84). Whether women with epilepsy require a dosage higher PRENATAL CARE AND DIAGNOSTIC TESTING than 0.4 mg/day is not known. To protect against NTDs, folate supplementation The American Academy of Neurology recommends that, must be provided during the first 28 days of fetal gesta- in order to reduce pregnancy risks, treatment consist of tion. In the United States, 40% of pregnancies are not a single AED at the lowest effective dose (79). Of course, planned, and of planned pregnancies, 50% do not con- this is not always possible, but it remains a worthwhile sult a health care provider during the first trimester (85). goal. The wide availability of reliable home pregnancy testing The malformations associated with AED exposure kits may further reduce preconceptional and first-trimester are readily detected by modern diagnostic testing (80). physician contacts. Therefore, folate supplementation Neural tube defects can be detected by week 16 of fetal should be considered in anticipation of conception. gestation with more than 95% sensitivity by obtaining a maternal serum alpha-fetoprotein (elevated with neural Neonatal Hemorrhage tube abnormalities) and a level II ultrasound to detect neural tube or cardiac malformations. In women who Neonates of mothers with epilepsy are at risk for early have independent risk factors for malformation, such as hemorrhage, which is believed to be a consequence of a advanced maternal age, amniocentesis may be indicated. coagulopathy caused by AED interference with vitamin Amniocentesis to obtain fetal alpha feto-protein (elevated K metabolism. Vitamin K–dependent proteins include the with NTDs) is also recommended if maternal serum clotting factors II, VII, IX, and X and the anticoagulant alpha-fetoprotein is elevated or if the spinal cord cannot proteins, protein C and protein S. Two forms of vitamin be adequately visualized by ultrasound. Women with K occur naturally—vitamin K1 (phylloquinone), which is fetuses having significant neural tube abnormalities or found in green plants and is the major dietary form of vit- other major malformations may be given the option of a amin K, and vitamin K2 (menaquinone), which is syn- first-trimester termination. thesized by intestinal bacteria. Although vitamin K nutri- The optimal concentration of folate to prevent tional deficiency is rare in otherwise healthy populations, NTDs has not been established for women with epilepsy vitamin K levels in the cord blood of unsupplemented on AEDs. Data regarding folate dosage comes entirely neonates exposed in utero to AEDs are reported to be from populations of medically well women. In nonepilep- below detection (86,87). In addition, assays for protein tic women, red blood cell folate levels higher than 906 induced by vitamin K absence (PIVKAs), nonfunctional nmol/l (400 ng/mL) may be optimal for the prevention procoagulants that appear in blood when vitamin K is of folate-responsive NTDs (81). In nonepileptic women deficient, are elevated in neonates exposed to AEDs. The who are users of folic acid supplements, dietary folate assay for PIVKAII is the most sensitive assay for vitamin intakes of greater than or equal to 450 µg/day achieved K deficiency. How AEDs cause vitamin K deficiency in levels of red blood cell folate in excess of 906 nmol/l. In the fetus is not known, but may be a consequence of nonepileptic women who did not use folate supplements, maternal and fetal induction of CYP450 liver enzymes by dietary intake of folate needed to exceed 500 µg/day to AEDs, which increases the rate of oxidative degradation attain desirable red blood cell folate levels (82). In one of vitamin K. Therapeutically, this deficiency can be cor- evaluation of nonepileptic, healthy, well-educated, mid- rected by supplying vitamin K1 at a dose of 10 mg/day dle-income women, one in eight had folate levels indica- to the mother during the last month of gestation. Pla- tive of a negative balance and 44% had red blood cell cental transfer of vitamin K to the fetus occurs, although 70 NEUROLOGIC DISEASE IN WOMEN

slowly. Supplying the neonate with vitamin K at birth is length or regularity of the menstrual cycle. Development safe and has been shown to be efficacious in preventing of male pattern hair growth, obesity, or acne is a sign of neonatal hemorrhage. The neonate receives vitamin K at elevated androgens and/or androgen hypersensitivity. a dose of 1 mg, intramuscular. Cord-blood specimens can Lipid abnormalities and glucose intolerance may accom- be submitted for immediate clotting studies. If a reduc- pany hyperandrogenism and confer significant long-term tion in vitamin K-dependent clotting factors is detected, health risks. then fresh frozen plasma can be administered at 20 mL/kg AEDs may also affect bone health. Although mech- over 1 to 2 hours (88). anisms of bone loss and resultant osteopenia and osteoporosis are not elucidated, compelling data implicate the enzyme–inducing AEDs, particularly phenytoin and phe- BREAST-FEEDING nobarbital. Bone density should be monitored, and all women receiving AEDs should be strongly encouraged to Breast-feeding is strongly recommended by most health observe good bone health practices, including gravity- organizations to promote mother–child bonding and resisting exercise, calcium (at least 1,200 mg/day) and vit- reduce the risk of infection and later-life immunologic dis- amin D supplementation, and periodic bone density orders (89). AEDs cross into breast milk to variable scans. extents. Passage is usually through simple diffusion, and The rates of major morphologic abnormalities after the ratio is determined by the drug’s molecular weight, fetal exposure to the older AEDs are presently believed to pKa, lipophilicity, and, most important, the extent of pro- be 4% to 6% for carbamazepine and phenytoin respec- tein binding (36,90,91). For phenytoin, carbamazepine, tively, 8.9% for valproate, and 7.8% for phenobarbital. valproate, and tiggabine, the concentration in breast milk Information regarding lamotrigine suggests a low risk for is negligible because of their high protein binding. Etho- major malformations after monotherapy exposure. Data suximide, phenobarbital, and PRM result in measurable regarding risks for the other new-generation AEDs are concentrations. Lamotrigine reaches approximately 30% pending. In the meantime, limiting exposure to high AED of the maternal serum concentration (92). Topiramate, dosages and AED polytherapy, supplementing with peri- oxcarbazepine, and oxcarbazepine metabolite levels are conceptional folic acid, and ensuring rigorous prenatal similar in maternal serum, cord blood, and placental tis- diagnostic testing with an anatomic ultrasound can sue (93,94), indicating extensive transplacental passage. enhance the odds for a normal pregnancy outcome. However, this does not necessarily indicate the ultimate Health care providers for women receiving AEDs for exposure for breastfed infants. For topiramate, the milk- epilepsy and other indications can benefit from the mass to-maternal-plasma ratio is 0.69 at 3 months, and breast- of new information coming from the work of a number fed infants have concentrations below the limit of quan- of investigators, including those involved in the prospec- tification (93). tive pregnancy registries. The detection of AED-associ- For most women, the best advice is to seriously con- ated reproductive and metabolic health disturbances can sider breast-feeding. Once started, the infant can be be accomplished easily, and reasonably simple and effec- observed for proper weight gain and sleep cycles. The tive interventions can be readily incorporated into clini- mother must also be advised that AED metabolism and cal practice. The sophisticated treatment of the woman clearance will remain elevated as long as breast-feeding receiving AEDs provides treatment for the disease state continues. When breast-feeding stops, the mother may and also optimizes overall health. experience an increase in serum AED concentrations that requires a dosage adjustment. References 1. Mattson RH, Cramer JA, Darney PD, Naftolin F. Use of oral contraceptives by women with epilepsy. JAMA CONCLUSION 1986;256:238–240. 2. Coulam CB, Annegers JF. Do oral anticonvulsants reduce Clinicians selecting an AED should consider its potential the efficacy of oral contraceptives? Epilepsia 1979;20: impact on reproductive and metabolic health. CYP450 519–526. 3. Zahn CA, Morrell MJ, Collins SD, Labiner DM, Yerby enzyme–inducing AEDs reduce concentrations of MS. Management issues for women with epilepsy: a bioavailable sex steroid hormones, thus affecting oral review of the literature. American Academy of Neurol- contraceptive regulation of the menstrual cycle and con- ogy Practice Guidelines. Neurology 1998;51:949–956. traceptive efficacy. These agents also reduce endogenous 4. Haukkamaa M. Contraception by Norplant subdermal sex steroid hormones, which may contribute to sexual capsule is not reliable in epileptic patients on anticonvulsant treatment. Contraception 1986;33(6):559–565. dysfunction. 5. Odlind V, Olsson SE. Enhanced metabolism of lev- AED-related reproductive endocrine disorders and onorgestrel during phenytoin treatment in a woman with ovarian dysfunction may present as an alteration in the Norplant implants. Contraception 1986;33:257–261. REPRODUCTIVE AND METABOLIC DISORDERS WITH AED USE 71

6. Morrell MJ, Flynn KL, Seale CG, et al. Reproductive dys- weight change in adolescents with epilepsy: results from function in women with epilepsy: antiepileptic drug effects a post hoc analysis of a randomized, double-blind clini- on sex-steroid hormones. CNS Spectrums 2001;6:771–786. cal trial. J Child Neurol 2003;18(2):133–139. 7. Sheth R, Wesolowski C, Jacob J, et al. Effect of carba- 24. Corman CL, Leung NM, Guberman AH. Weight gain in mazepine and valproate on bone mineral density. J Pedi- epileptic patients during treatment with valproic acid: a ret- atr 1996;127:256–262. rospective study. Can J Neurol Sci 1997;24(3):240–244. 8. Valimaki M, Tiihonen M, Laitinen K, et al. Bone min- 25. Dinesen H, Gram L, Andersen T, Dam M. Weight gain eral density measured by dual-energy x-ray absorptiom- during treatment with valproate. Arch Neurol Scand etry and novel markers of bone formation and resorption 1984;70(2):65–69. in patients on antiepileptic drugs. J Bone Miner Res 26. Gidal BE, Anderson GD, Spencer NW, Maly MM, et al. 1994;9:631–637. Valproate associated weight gain in persons with 9. Chang S, Ahn C. Effects of antiepileptic drug therapy on epilepsy: potential relationships to energy expensiture bone mineral density in ambulatory epileptic children. and metabolism. J Epilepsy 1996;9:234–241. Brain Dev 1994;16:382–385. 27. Morrell MJ, Isojarvi J, Taylor A, et al. Higher androgens 10. Bogliun G, Beghi E, Crespi V, Delodovick L, d’Amico P. and weight gain with valproate compared with lamot- Anticonvulsant drugs and bone metabolism. Acta Neu- rigine for epilepsy. Epilepsy Res 2003;54:189–199. rol Scand 1986;74:284–288. 28. Rattya J, Vainionpaa L, Knip M, Lanning P, Isojarvi JI. 11. Pack AM, Morrell MJ. Adverse effects of antiepileptic The effects of valproate, carbamazepine and oxcar- drugs on bone structure. Epidemiology, mechanisms and bazepine on growth and sexual maturation in girls with therapeutic implications. CNS Drugs 2001;15(8): epilepsy. Pediatrics 1999;103(3):588–593. 633–642. 29. Novak, GP, Maytal J, Alshansky A, Eviatar L, Sy-Sho R, 12. Gough H, Goggin T, Bissessar A, Baker M, Crowley M, Siddique Q. Risk of excessive weight gain in epileptic chil- Callaghan N. A comparative study of the relative influ- dren treated with valproate. J Child Neurol 1999;14(8): ence of different anticonvulsant drugs, UV exposure and 490–495. diet on vitamin D and calcium metabolism in outpatients 30. Verrotti A, Basciani F, Morresi S, de Martino M, Morgese with epilepsy. QJM, New Series 59. 1986;230:569–577. G, Chiarelli F. Serum leptin changes in epileptic patients 13. Pack AM, Olarte LS, Morrell MJ, Flaster E, Resor SR, who gain weight after therapy with valproic acid. Neu- Shane E. Bone mineral density in an outpatient popula- rology 1999;53(1):230–232. tion receiving enzyme-inducing antiepileptic drugs. 31. Van Amerigen M, Mancini C, Pipe B, et al. Topiramate Epilepsy Behav 2003 Apr;4(2):169–174. treatment for SSRI-induced weight gain in anxiety dis- 14. American College of Obstetric and Gynecologic Physi- orders. J Clin Psychiatry 2002;63:981–984. cians Practice Bulletin #41. Polycystic ovary syndrome. 32. Van Ameringen M, Mancini C, Pipe B, Campbell M, 2002;100(6):1389–1402. Oakman J. Topiramate treatment for SSRI-induced 15. Calandre EP, Rodriguez-Lopez C, Blazquez A, et al. weight gain in anxiety disorders. J Clin Psychiatr Serum lipids, lipoproteins and apolipoproteins A and B 2002;63(11):981–984. in epileptic treated with valproic acid, carbamazepine or 33. Chengappa R, Levine J, Rathore D, Parepally H, Atzert phenobarbital. Acta Neurol Scand 1991;83:250–253. R. Long-term effects of topiramate on bipolar mood 16. Louma PV, Sotaniemi EA, Peklonen RO, et al. Plasma instability, weight change and glycemic control: a case- high density lipoprotein cholesterol and hepatic series. Eur Psychiatry 2001;16(3):186–190. cytochrome P450 concentrations in epileptics undergo- 34. McElroy S, Arnold L, Shapira N, et al. Topiramate in the ing anticonvulsant treatment. Scand J Clin Lab Invest treatment of binge eating disorder associated with obe- 1980;40:163–167. sity: a randomized, placebo-controlled trial. Am J Psy- 17. Eiris JM, Lojo S, Del Rio MC, et al. Effects of long-term chiatry 2003;160:255–261. treatment with antiepileptic drugs on serum lipid levels 35. Richard D, Ferland J, Lalonde J, Samson P, Deshaies Y. in children treated with anticonvulsants. Neurology Influence of topiramate in the regulation of energy bal- 1995;45:1155–1157. ance. Nutrition 2000;16(10):961–966. 18. Verrotti A, Domizio S, Angelozzi B, et al. Changes in 36. Takeda A, Okada H, Tanaka H, Izumi M, Ishikawa S, serum lipids and lipoproteins in epileptic children treated Noro T. Protein binding of four antiepileptic drugs in with anticonvulsants. J Paediatr Child Health 1997;33: maternal and umbilical cord serum. Epilepsy Res 242–245. 1992;13:147–151. 19. Pylvanen V, Knip M, Pakarinen AJ, et al. Fasting serum 37. Yerby MS, Friel PN, McCormick K. Pharmacokinetics of insulin levels and lipid levels in men with epilepsy. Neu- anticonvulsants in pregnancy: alterations in plasma pro- rology 2003;60(4):571–574. tein binding. Epilepsy Res 1990;5:223–228. 20. Luef G, Abraham I, Hoppichler F, Trinka E, Unterberger 38. Koch S, Loesche G, Jager-Roman E, et al. Major birth I, Bauer G, Lechleitner M. Increase in postprandial serum malformations and antiepileptic drugs. Neurology insulin levels in epileptic patients with valproic acid ther- 1992;42(suppl 5):83–88. apy. Metabolism 2002;51(10):1274–1278. 39. Annegers JF, Hauser WA, Elveback LR, Anderson VE, 21. Isojarvi JI, Rattya J, Myllyla VV, et al. Valproate, lam- Kurland LT. Congenital malformations and seizure dis- otrigine, and insulin-mediated risks in women with orders in the offspring of parents with epilepsy. Int J Epi- epilepsy. Ann Neurol 1998;43(4):446–451. demiol 1978;7:241–247. 22. Stephen LJ, Kwan P, Shapiro D, Dominiczak M, Brodie 40. Friis ML. Facial clefts and congenital heart defects in chil- MJ. Hormone profiles in young adults with epilepsy dren of parents with epilepsy: genetic and environmen- treated with sodium valproate or lamotrigine monother- tal etiologic factors. Acta Neurol Scand 1989:79: apy. Epilepsia 2001;42(8):1002–1006. 433–459. 23. Biton V, Levisohn P, Hoyler S, Vuong A, Hammer AE. 41. Omtzigt JGC, Los FJ, Grobee DE, et al. The risk of spina Lamotrigine versus valproate monotherapy-associated bifida aperta after first-trimester exposure to valproate 72 NEUROLOGIC DISEASE IN WOMEN

in a prenatal cohort. Neurology 1992;42(suppl 5): 60. Tomson T, Lindborn U, Sundqvist A, Berg A. Red cell 119–125. folate levels in pregnant epileptic women. Eur J Clin 42. Rosa FW. Spina bifida in infants of women treated with Pharmacol 1995;48:305–308. carbamazepine during pregnancy. N Engl J Med 1991; 61. Ogawa Y, Kaneko S, Otani K, Fukushima Y. Serum folic 324:674–677. acid levels in epileptic mothers and their relationship to 43. Gaily E, Granstrom ML. Minor anomalies in children of congenital malformations. Epilepsy Res 1991;8:75–78. mothers with epilepsy. Neurology 1992;42(S5):128–131. 62. Alonso-Aperte E, Ubeda N, Achon M, Perez-Miguelsanz 44. Gaily E, Kantola-Sorsa E, Granstrom ML. Intelligence of J, Varela-Moreiras G. Impaired methionine synthesis and children of epileptic mothers. J Pediatr 1988;113: hypomethylation in rats exposed to valproate during ges- 677–684. tation. Neurology 1999;52(4):750–756. 45. Kaneko S, Otani K, Fukushima Y, et al. Teratogenecity 63. Elmazar MM, Nau N. Trimethoprim potentiates valproic of antiepilepsy drugs: analysis of possible risk factors. acid-induced neural tube defects (NTDs) in mice. Reprod Epilepsia 1988;29:459–467. Toxicol 1993 May-June;7(3):249–254. 46. Oguni M, Dansky L, Andermann E, Sherwin A, Ander- 64. Sander JW, Patsalos PN. An assessment of serum and red mann F. Improved pregnancy outcome in epileptic blood cell folate concentrations in patients with epilepsy women in the last decade: relationship to maternal anti- on lamotrigine therapy. Epilepsy Res 1992;13(1): 89–92. convulsant therapy. Brain Dev 1992;14:371–380. 65. Dansky L, Andermann E, Roseblatt D, Sherwin AL, 47. Holmes, et al. Evidence of increased risk of birth defects Andermann F. Anticonvulsants, folate levels and and in offspring of women exposed to phenobarbital as a pregnancy outcome. Ann Neurol 1987;21:176–182. monotherapy. Teratology 2001;63:250. 66. Werler MM, Shapiro S, Mitchell AA. Periconceptional 48. Holmes LB, Harvey EA, Coull BA, et al. The terato- folic acid exposure and risk of occurrent neural tube genicity of anticonvulsant drugs. N Engl J Med 2001; defects. JAMA 1993;269:1257–1261. 344:1132–1138. 67. Czeizel AE, Dudas I. Prevention of the first occurrence of 49. Holmes, et al. Evidence of increased risk of birth defects in neural tube defects by periconceptional vitamin suple- offspring of women exposed to valproate (Depakote, Depak- mentation. N Engl J Med 1992;327:1832–1835. ene, Epival). Am J Obstet Gynecol 2002;187(S):S137. 68. Medical Research Council Vitamin Research Group. Pre- 50. Tennis P, Eldridge RR, and the International Lamotrig- vention of neural tube defects: results of the Medical ine Pregnancy Registry Scientific Advisory Committee. Research Council Vitamin Study. Lancet 1991;338: Preliminary results on pregnancy outcomes in women 131–137. using lamotrigine. Epilepsia 2002;43:1161–1167. 69. Mulinare J, Corder JF, Erickson JD, et al. Periconcep- 51. Morrow JI, Russell A, Craig JJ, et al. Major malforma- tional use of multivitamins and the occurrence of neural tions in the offspring of women with epilepsy: a com- tube defects. JAMA 1988;260:3141–3145. prehensive prospective study. Epilepsia 2001;42(suppl 70. Milunsky A, Jick H, Jick SS, et al. Multivitamin/folic acid 2):125. supplementation in early pregnancy reduces the prevalence 52. Rabinowicz AL, Meischenguiser R, D’Giano CH, Ferraro of neural tube defects. JAMA 1988;262:2847–2852. SM, Carrazanna EJ. Report of a single centre pregnancy 71. Laurence KM, James N, Miller MH, Tennant GB, Camp- registry of AEDS: focus on outcomes with oxcarbazepine. bell H. Double-blind, randomized controlled trial of Epilepsia 2002;43(suppl 8):159. folate treatment before conception to prevent the recur- 53. Kaaja E, Kaaja R, Hiilesmaa V. Major malformations in rence of neural-tube defects. BMJ 1981;282:1509–1511. offspring of women with epilepsy. Neurology 2003;60: 72. Craig J, Morrison P, Morrow J, et al. Failure of pericon- 575–579. ceptional folic acid to prevent a neural tube defect in the 54. Wegner C, Nau H. Alteration of embryonic folate metab- offspring of a mother taking sodium valproate. Seizure olism by valproic acid during organogenesis: implications 1999;8:253–254. for mechanism of teratogenesis. Neurology 1992;42 73. Yates JRW, Ferguson-Smith MA, Shenkin A, Guzman- (suppl 5):17–24. Rodriguez R, White M, Clark BJ. Is disordered folate 55. Finnell RH, Buehler BA, Kerr BM, Ager PL, Levy RH. metabolism the basis for the genetic predisposition to Clinical and experimental studies linking oxidative neural tube defects? Clin Genet 1987;31:279–287. metabolism to phenytoin-induced teratogenesis. Neurol- 74. Gordon N. Folate metabolism and neural tube defects. ogy 1992;42:25–31. Brain Dev 1995;17:307–311. 56. Miranda AF, Wiley MJ, Wells PG. Evidence for embry- 75. Mills JL, McPartlin JM, Kirke PN, et al. Homocysteine onic peroxidase-catalyzed bioactivation and glutathione- metabolism in pregnancies complicated by neural tube dependent cytoprotection in phenytoin teratogenicity: defects. Lancet 1995;345:149–151. modulation by eicosatetraynoic acid and buthione sul- 76. Apeland T, Mansoor MA, Strandjord RE. Antiepileptic foximine in murine embryo culture. Toxicol Appl Phar- drugs as independent predictors of plasma total homo- macol 1994;124:230–241. cysteine levels. Epilepsy Res 2001;47(1-2):27–35. 57. Nau H, Tzimas G, Mondry M, Plum C, Spohr HL. 77. Apeland T, Mansoor MA, Strandjord RE, Kristensen O. Antiepileptic drugs alter endogenous retinoid concentra- Homocysteine concentrations and methionine loading in tion: a possible mechanism of teratogenesis of anticon- patients on antiepileptic drugs. Acta Neurol Scand vulsant therapy. Life Sci 1995;57:53–60. 2000;101(4):217–223. 58. Buehler BA, Delimont D, Van Waes M, Finnell RH. Pre- 78. Steegers-Theunissen RPM, Boers GHJ, Trijbels FJM, natal prediction of risk of the fetal hydantoin syndrome. Eskes TKAB. Neural-tube defects and derangement of N Engl J Med 1990;322:1567–1572. homocysteine metabolism. N Engl J Med 1991;324: 59. Strickler SM, Dansky LV, Miller MA, Seni MH, Ander- 199–200. mann E, Spielberg SP. Genetic predisposition to pheny- 79. American Academy of Neurology. Quality Standards toin-induced birth defects. Lancet 1985;2:746–749. Subcommittee. Practice parameter: management issues REPRODUCTIVE AND METABOLIC DISORDERS WITH AED USE 73

for women with epilepsy (summary statement). Neurol- 87. Cornelissen M, Steegers-Theunissen R, Kollee L, et al. ogy 1998;51:944–948. Increased incidence of neonatal vitamin K deficiency 80. American College of Obstetric and Gynecologic Physi- resulting from maternal anticonvulsant therapy. Am J cians Educational Bulletin. Seizure disorders in preg- Obstet Gynecol 1993;168:923–928. nancy. 1996;231:1–13. 88. Thorp JA, Gaston L, Caspers DR, Pal ML. Current con- 81. Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM. Folate cepts and controversies in the use of vitamin K. Drugs levels and neural tube defects: implications for treatment. 1995;49:376–387. JAMA 1995;274:1698–1702. 89. American Academy of Pediatrics. The transfer of drugs 82. Brown JE, Jacobs DR Jr, Hartman TJ, et al. Predictors and other chemicals into human milk. Pediatrics of red cell folate level in women attempting pregnancy. 1994;93:137–150. JAMA 1997;277(7):548–552. 90. Hagg S, Spigset O. Anticonvulsant use during lactation. 83. MMWR. Recommendations for the use of folic acid to Drug Saf 2000;22:425–440. reduce the number of cases of spina bifida and other 91. Bar-Oz B, Nulman I, Koren G, et al. Anticonvulsants and neural tube defects. MMWR 1992;41:1–7. breast-feeding: a critical review. Pediatr Drugs 2000;2: 84. Van Allen M, Fraser FC, Dallaire L, et al. Recommen- 113–126. dations on the use of folic acid supplementation to pre- 92. Ohman I, Vitols S, Tomson T. Lamotrigine in pregnancy: vent the recurrence of neural tube defects. CMAJ pharmacokinetics during delivery, in the neonate and dur- 1993;149:1239–1243. ing lactation. Epilepsia 2000;41:709–713. 85. Grimes DA. Unplanned pregnancies in the U.S. Obstet 93. Ohman I, Viols S, Luef G, Soderfeldt B, Tomson T. Top- Gynecol 1986;67:438–442. iramate pharmacokinetics during delivery, lactation, and 86. Cornelissen M, Steegers-Theunissen R, Kollee L, Eskes T, in the neonate: preliminary observations. Epilepsia Motohara K, Monnens L. Supplementation of vitamin 2002;43:1157–1160. K in pregnant women receiving anticonvulsant therapy 94. Myllynen P, Pienimaki P, Jouppila P, Vahakangas K. prevents neonatal vitamin K deficiency. Am J Obstet Transplacental passage of oxcarbazepine and its metabo- Gynecol 1993;168:884–888. lites in vivo. Epilepsia 2001;42:1482–1485.

Effect of Ovarian Hormones on the 6 Nervous System

Pavel Klein, MB, BChir and Donald L. Schomer, MD

ormones play an important role in couple of well-known genetically based diseases. We also the expression of many neurologic discuss in detail how partial epilepsy, an intermittent conditions. In some of these disor- physiologically based disorder, may be influenced by and, H ders, endocrine abnormalities are an in turn, influence normal cycling behavior. This will serve integral part of the disease process, for example, the as a model for how a disease process can interact in a abnormal insulin response to a glucose load seen in complex way with neuroendocrinologic control mecha- myotonic dystrophy. In other disorders, the endocrino- nisms. logic abnormality produces the neurologic disorder, such as the peripheral neuropathy of chronic diabetes mellitus. In other endocrinologic disorders such as primary ANATOMICAL, DEVELOPMENTAL, AND hypothyroidism, Cushing, or Addison disease, neurologic PHYSIOLOGICAL CONSIDERATIONS dysfunction can be more subtle and manifest itself as an alteration in cognition or a change in personality. In all The cells of the ventromedial and arcuate nuclei and of these conditions, men and women can be similarly the preoptic area of the hypothalamus are responsible for affected. In women, the cyclical alterations of the ovar- the production of the decapeptide hormone ian hormones and related endocrine factors can have very gonadotrophin releasing hormone (GnRH), also known particular effects. These effects are the subjects of this as luteinizing hormone releasing hormone (LHRH) (1,2). chapter. This hormone controls the release of the anterior pitu- To best approach this subject, the development, itary–derived hormones follicle stimulating hormone anatomic substrates, and physiologic function of the (FSH) and luteinizing hormone (LH), collectively referred female endocrine reproductive axis are reviewed. We out- to as gonadotrophins. The cyclical changes in FSH and line how steroid hormones affect nervous system func- LH regulate the ovarian cycle, which includes follicular tion, with brief examples of how ovarian and other development, ovulation, and corpus luteum maturation. steroid hormones affect neurologic diseases. In the last These stages are associated with the variable production section, we illustrate how ovarian and other steroid hor- of estrogen, progesterone, and testosterone which, in mones affect neurologic functioning and diseases. Many turn, have pleuripotent effects on numerous organs and of the neurologic disorders are dealt with in far greater feedback to hypothalamic and cortical areas related to detail in other chapters in this book; here we discuss a their own regulation. 75 76 NEUROLOGIC DISEASE IN WOMEN

The GnRH-containing neurons, estimated at 1,000 Adolescence to 3,000 total, project their axons to the median eminence at the base of the hypothalamus (2). They release GnRH e s

into the hypothalamic-portal circulation, which delivers a e r

it to the LH- and FSH-containing cells (gonadotrophs) c n I in the anterior pituitary. There, GnRH induces the secre-

H Puberty R

tion and release of LH and FSH. The GnRH neurons n release GnRH in rhythmic synchronized bursts, or pulses, G which, in turn, cause pulsatile secretion of LH and FSH. 12 3 1 5 10 15 20 The pulsatile nature of LH and FSH release by the pitu- Trimester itary gland is an essential feature of the gonadotropic con- Age (Years) trol of ovarian function. FIGURE 6.1 LH and FSH are glycoproteins composed of two different carbohydrate-containing protein subunits called a Ontogeny of GnRH secretion from fetal life to adolescence. and b. The a subunit is identical in LH and FSH. The b subunit differs in its protein sequence in the two hormones and confers specific activity on each hormone. A onto the GnRH neurons as well as, more potently, on higher frequency of GnRH pulses induces the preferen- the gonadotrophs. GnRH neurons are also inhibited by tial formation of LH and high LH pulse frequency, which opioidergic neurons from the central gray matter of the leads to ovarian hypersecretion of androgens and poly- pons and by the corticotrophin releasing hormone cystic ovarian syndrome. Slower frequency (e.g., every 2 (CRH)–containing neurons in the paraventricular to 3 hours) increases FSH production, lowers LH/FSH hypothalamic nucleus. Glutamate stimulates GnRH pulse frequency, and causes anovulation or amenorrhea. neurons. The onset of this stimulation occurs at the GnRH secretion begins at 20 to 30 weeks of gesta- beginning of puberty, for which it is critical. GnRH tion, following the migration of GnRH neurons from the release is further stimulated by input from noradren- olfactory placode to the hypothalamus. Fetal FSH and LH ergic (b1-receptor mediated) and dopaminergic (DA 1- secretion is high: Fetal FSH and LH levels reach receptor mediated) brain stem nuclei and from the menopausal concentrations. Their secretion subsides after NPY-containing neurons in the arcuate nucleus. the first postnatal year and stays low until puberty. The Through these inputs, neural factors mediating stress, reason for this is not well understood, but is likely due pain, energy balance, reward, and other functions mod- to the active suppression of GnRH neurons by the central ulate reproductive endocrine function. nervous system (CNS). Puberty is initiated by a resump- The GnRH neurons receive both direct and multi- tion of the pulsatile release of GnRH (Figure 6.1). At first, synaptic modulatory input from limbic structures, most this occurs only at night and causes predominantly FSH notably from the corticomedial amygdaloid nuclei, from secretion. Later, daytime GnRH secretion and LH respon- the bed nucleus of the stria terminalis, and from the hip- siveness occur coincident with the onset of menarche. pocampus (4,5). The input from the amygdala is partic- During the menstrual cycle, the pulsatile secretion ularly important for reproductive endocrine function. The of LH and FSH changes through the cycle (2). During amygdala has reciprocal relationships with the hypo- the first (follicular) half of the menstrual cycle, FSH and thalamus. The amygdala has two distinctive subnuclear LH pulses occur every 1 to 1.5 hours. During the second regions that are, at least partially, distinguished by their (luteal) half of the cycle, LH/FSH pulses occur every 3 to outflow pathway (4). The corticomedial region has as its 6 hours, as a result of the inhibitory effect of progesterone output—the stria terminalis—and the basolateral region and inhibin A. During perimenopause and menopause, a has output through the ventral amygdalofugal pathway. decline in the ovarian secretion of inhibin, progesterone, Both of these projections are reciprocal to and from the and, eventually, estrogen leads to the disinhibition of pitu- hypothalamus, particularly to those regions high in itary production of FSH and LH, resulting in an elevation GnRH-containing cells. Stimulation and ablation stud- of the gonadotropins. ies in the amygdala and in the output pathways have pro- The intrinsic rhythmicity of the GnRH neurons is duced consistent but often species-specific changes in the modulated by gonadal steroids and by the hypothala- output of LH and FSH. The effects produced have mic and extrahypothalamic nervous system, including included the following observations: the limbic system (2,3). GnRH neurons receive inhibitory GABA-ergic input from the estrogen and • Simulation of the corticomedial nuclei induces ovu- progesterone receptor–containing neurons in the pre- lation and uterine contractions. optic area and the ventromedial nucleus of the hypo- • Stimulation of the basolateral nuclei inhibits sexu- thalamus. The steroids thus exert a negative feedback ally orienting behavior in an ovulating female. EFFECT OF OVARIAN HORMONES ON THE NERVOUS SYSTEM 77

• Sectioning of the stria terminalis (corticomedial outflow tract) blocks ovulation. • Sectioning of the ventral amygdalofugal pathway (basolateral nuclei outflow tract) has no effect, but lesions bilaterally in the basolateral nuclei blocks ovulation (4,6).

The pulsatile secretion of LH and FSH from pituicytes controls follicular development, ovulation, luteal development, and the associated hormonal production. The menstrual cycle can be divided into four phases: follicular (early, mid-, and late), ovulatory, luteal (early, mid-, and late), and menstrual (2). The ovarian life cycle is schematically illustrated in Fig- ure 6.2. The associated pattern of hormonal FIGURE 6.2 changes is shown in Figure 6.3. About 2 days before menstruation, the The life cycle of the human ovary. falling ovarian production of progesterone, estradiol, and a glycoprotein secreted by the Reproduced with permission from Yen SC, Jaffe RB, Barbieri RL (eds.) Repro- corpus luteum, inhibin A, disinhibit FSH secre- ductive Endocrinology, 4th ed. Philadelphia, Pa: WB Saunders, 1999. tion and FSH levels rise. This leads to follicular recruitment for the next cycle, which continues during the first 4 to 5 days of the follicular phase. It is followed by the selection of a single dominant follicle from a cohort of follicles (menstrual cycle days 5 to 7), maturation of the follicle (days 8 to 12), ovulation (days 13 to 15), and formation of the corpus luteum. FSH 100 LH secretion is suppressed during the luteal phase by prog- FSH esterone, estradiol, and inhibin A. The demise of corpus luteum at the end of the cycle (days 26–30) results in a 50 decline in levels of progesterone, estradiol, and inhibin A, IU/L and in initiation of a new cycle.

All ovarian steroids are synthesized from serum- 0 derived cholesterol. Cholesterol is converted to preg- 1200 nenolone, then to progesterone or dehydroepiandros- INHIBIN terone (DHEA). These are made into the respective U/L androgens—testosterone or androstenedione—which are 600 aromatized to the estrogens, estradiol, and estrone (Fig- ure 6.4). The steroidogenic enzymes are regulated by LH and 0 FSH. The two rate-limiting enzymes are cholesterol side 1500 100 E chain cleavage enzyme, or CYP450-scc, which catalyzes 2 P4 the conversion of cholesterol to pregnenolone, and the 1000 nmol/L other, aromatase, which catalyzes the conversion (arom- 50 atization) of androgens to estrogens. pmol/L 500 The follicle is composed of three parts: The oocyte in the center is surrounded by granulosa cells which, in turn, are separated by a basement membrane from the 0 0 –12 –8 –4 0 4 8 12 interstitial or thecal cells. The theca cells have LH recep- Days from LH Peak tors that, when activated by LH, induce the synthesis and release of androgens. Androgens diffuse into the neigh- FIGURE 6.3 boring granulosa cells. Granulosa cells have FSH (as well The hormonal pattern in the human menstrual cycle. as LH) receptors. The activation of FSH receptors by FSH induces aromatase, the enzyme that converts androgens E2 = estradiol, P4 = progesterone 78 NEUROLOGIC DISEASE IN WOMEN

Acetate

C-27 Cholesterol

Pregnenolone Progesterone II-Desoxycorticosterone Corticosterone C-21{ 17a-Hydroxypregnenolone 17a-Hydroxyprogesterone II-Desoxycortisol Cortisol

Dehydrospiondrosterone Androstanedrone Estrone C-19{{C-18 Androstenediol Testosterone 17β-Estrodiol

FIGURE 6.4

Biosynthetic pathways of steroid hormone production. Steroids with a double bond between the carbon 5 and 6 positions are shown on the left; those with a double bond between the 4 and 5 positions are shown on the right.

to estrogens. Thus, activation of the granulosa cells in estrogens in response to FSH (the two compartment response to FSH results in estrogen secretion. The folli- hypothesis, Figure 6.5). cle thus consists of two functionally distinct compart- Steroid synthesis differs during different cycle ments, the theca cells, which secrete androgens in phases. During the early follicular phase, pituitary FSH response to LH, and the granulosa cells, which secrete secretion drives the production of estrogen, which grad-

Luteinizing Hormone

LH Receptor Cholesterol + ATP CAMP Theca Cells Androstenedione

(Circulation) Basement Membrane

Androstenedione Estrogen + Granulosa Cells Aromatase ATPATP CAMP + Enzyme

FSH Receptor (Follicular Fluid)

Follicle Stimulating Hormone

FIGURE 6.5

The two cell-two gonadotropin hypothesis of follicular androgen and estrogen production. EFFECT OF OVARIAN HORMONES ON THE NERVOUS SYSTEM 79 ually increases throughout the follicular phase. Just tiates a particular mRNA transcription and protein syn- before ovulation, a negative feedback of estrogen on pitu- thesis. The latency of this action is in hours to days. It itary LH/FSH changes to a positive feedback, with a affects processes related to neuronal survival and growth, resulting LH surge, a surge of estradiol secretion, and a and to neurotransmitter synthesis and receptor function. release of the oocyte from the follicle in the ovary into In addition, certain steroids, including progesterone the fallopian tubes (ovulation). The granulosa cell rem- and estrogen, have a direct, nongenomic effect on neu- nants of the follicle form the corpus luteum, which ronal membrane (7). Latency of this action is within sec- secretes progesterone in large quantities in response to onds to minutes. The main effects are the modulation of LH stimulation (Figure 6.3). Estrogen secretion initially transmission of the two main CNS neurotransmitters, falls after ovulation, but then rises again. The high mid- glutamate and ␥-aminobutyric acid (GABA), and of neu- luteal concentrations of progesterone and estradiol pre- ronal membrane excitability. pare the endometrium for the implantation of the fertil- The effects of the ovarian hormones on the structure ized egg. The secretion of progesterone, estradiol, and of the CNS are sometimes thought of as “organizational”; inhibin A inhibits pituitary FSH and LH production dur- that is, affecting the hard wiring of the CNS during its for- ing the luteal phase of the menstrual cycle. Towards the mation. The effects on the CNS that occur after comple- end of the luteal phase, luteolysis occurs and ovarian tion of the network hard wiring are thought of as “acti- secretion of progesterone fails, followed shortly by fail- vational.” ure of estrogen secretion. Pituitary FSH production is dis- inhibited, new follicles begin to grow again, and the cycle Organizational and Structural Effects repeats itself. During an anovulatory cycle, the periovulatory In most vertebrate species, structural differences are pres- estradiol surge does not occur. Otherwise, estrogen secre- ent in certain parts of the brains of males and females. tion occurs the same as during an ovulatory cycle. Because Structures that show such differences are termed sexually no follicle is released and corpus luteum is not formed, dimorphic (8,9). In rodents, parts of the hypothalamus there is little production of progesterone. The absence of and the limbic system are sexually dimorphic. For progesterone secretion is the endocrine difference between instance, the medial preoptic nucleus of the hypothala- ovulatory and anovulatory cycles. It may contribute to mus has a sexually dimorphic part (SD-MPN) that is four differences in neurologic symptoms in ovulating versus times larger in males than in females. SD-MPN mediates nonovulating women in diseases such as epilepsy or affec- sexual behavior, including mounting and intromission, a tive disorders. male reproductive behavior. Conversely, another hypothalamic area, the anteroventral preoptic nucleus (AVPNv), is several times larger in the female compared EFFECTS OF OVARIAN STEROIDS to the male. The AVPNv regulates the reproductive ON THE NERVOUS SYSTEM endocrine events related to ovulation, a female-specific activity. Examples of other sexually dimorphic areas Ovarian steroids have a wide-ranging influence upon neu- include the corticomedial amygdala and the bed nucleus ronal activity, neuronal survival, and neuronal differen- of the stria terminalis in the limbic system, structures that tiation and growth. During embryogenesis, they regulate modulate reproductive and aggressive behaviors, among the formation of parts of the nervous system. Later dur- others (8,9). (See also Chapter 2 for further information ing life, they alter neuronal response to injury, including on gender-based brain anatomic differences.) trauma and stroke. They affect neuronal excitability by This difference is determined by pre- and perinatal modulating the synthesis, release, and catabolism of neu- exposure to sex steroids. Nature’s default blueprint for rotransmitters and the sensitivity of neurotransmitter the development of both genitalia and the brain appears receptors. They affect neuronal plasticity throughout life to be female. In the absence of perinatal androgens, a by affecting synaptogenesis and neurite growth. These female pattern of sexually dimorphic brain structures and actions affect reproductive endocrine function, but also a female pattern of GnRH secretion and sexual behavior behavior, mood, memory and cognition, and a number of occur. Pre- and perinatal exposure of the brain to andro- major neurologic and psychiatric diseases. gens induces the development of a male pattern of CNS Ovarian steroid effects on the CNS occur by both structure and function. For instance, even a single andro- receptor-mediated (genomic) and membrane-related gen injection to a genetic female rat during the first week (nongenomic) mechanisms (7). In the classic steroid hor- after birth inhibits the development of the ovulatory trig- mone action, the hormone diffuses into the cell, binds to ger mechanism in the preoptic area of the hypothalamus an intracellular receptor, travels in the receptor-bound (POA) and the loss of female reproductive behavior, lor- complex to the nucleus, binds to a specific DNA recog- dosis. This is due to the perinatal induction by andro- nition sequence (the hormone-response element), and ini- gens of an inhibitory neural circuit between the POA and 80 NEUROLOGIC DISEASE IN WOMEN

the septum. If this connection is severed in an adult These effects on the CNS are referred to as organi- genetic male, female sexual behavior, lordosis, occurs zational because they determine the organization or the (8,9). hard wiring of the CNS. Steroids also have an activational The size differences of the sexually dimorphic struc- effect—they modulate which parts of the formed CNS tures are due to differences in the number of neurons and structure will be used, or activated, and how. The admin- of dendritic branches. During the second half of gesta- istration of testosterone to adult women, for instance, can tion, the testis secrete large amounts of androgens (while induce aggression. More subtly, male- and female-specific the ovary is inactive). Androgens are taken up by the cognitive patterns can be induced in adults by the admin- developing neurons and the supporting glia. Paradoxi- istration of androgens and estrogens, respectively. In cally, the masculinizing effects of pre- and perinatal transsexual men receiving estrogens prior to sex-change androgens are in many instances due to their conversion surgery, estrogens enhance verbal skills. In transsexual to estrogens in the CNS. Androgen and estrogen recep- women, treatment with testosterone before sex change tors are expressed in neurons, astrocytes, and oligoden- surgery enhances visuospatial ability. drocytes in different regions of both the developing and It is well known that certain psychiatric and neuro- adult CNS (Figure 6.6) (10). Aromatase is present in neu- logic diseases have different prevalence in men and rons in some areas such as the preoptic-hypothalamic and women. Depression, for instance, is two times more com- the limbic areas, particularly in the developing brain, and mon in women than in men, anxiety four times, anorexia particularly in the male (11). Those neurons convert nervosa nine times, migraine four times, and benign androgens to estrogens, such as testosterone to estradiol. intracranial hypertension between four and eight times Estrogens inhibit apoptosis perinatally in the SD- more common. Aggression and Tourette disease, by con- MPN via estrogen receptor–mediated mechanisms (8,9). trast, are eight to ten times more common in males (16). Estradiol also causes neuronal differentiation and neurite What is striking is that the incidence and prevalence of growth. Perinatal exposure to androgens or estradiol many of these diseases is the same in men and women therefore increases the number of neurons and the den- until puberty, when the difference emerges. The possible sity of dendritic branching in the SD-MPN, thus account- activational effects of gonadal steroids on the CNS at the ing for the greater size of this nucleus in the males com- time of puberty that might underlie these clinical phe- pared to the females. The apoptotic effect is nomena are unknown. region-specific. In the AVPN, by contrast, estradiol (or testosterone) promotes apoptosis. Effects on Neurotransmitter Systems: In humans, the homologous structure of SD-MPN Genomic Effects is the interstitial nucleus of the anterior hypothalamus (INAH). Two subdivisions of this nucleus, INAH-2 and The genomic mechanisms of ovarian steroids are medi- INAH-3, are two to three times larger in men than in ated by cytosolic neuronal estrogen, progesterone, and women. Furthermore, INAH-3 is larger in heterosexual androgen receptors (ER, PR, AR). Estrogen receptors men than in homosexual men (8,9,12,13). Similarly, in (␣,␤) and progesterone receptors are distributed in dif- the limbic structure, bed nucleus of the stria terminalis ferent parts of the brain, including outside of the hypo- (BNST), which is an outflow relay station from the amyg- thalamic areas involved in the regulation of endocrine and dala and regulates both sexual and aggressive behavior, behavioral aspects of reproduction (10,17). is also bigger in men than in women, and in heterosex- These receptors are found in great density in the cor- ual than in homosexual men. Thus, it is possible that pre- tical and medial amygdaloid nuclei, and in lesser numbers or perinatal sex steroid–induced changes in CNS struc- in the hippocampus and neocortex (10,17). Estrogen and tures underlie gender-specific differences in reproductive progesterone receptors are present in similar areas. ER-con- behavior and aggression in humans as well as in nonhu- taining neurons colocalize with other neurotransmitters, man mammals (8). including GABA, acetylcholine (Ach), 5-hydroxytrypta- Sexual dimorphism of brain structures may also mine (5HT), and dopamine (DA) (1,7,18,19). By regulat- underlie gender differences in nonreproductive behavior. ing the expression of genes affecting the activity, release, For instance, women are better than men in verbal flu- and postsynaptic action of different neurotransmitters and ency and other language-related tasks (Chapter X). The neuromodulators, estrogens and progesterone may affect language areas, Broca’s and Wernicke’s areas and the the function of the neurons that take them up. For instance, planum temporale, are 20% to 30% larger in women E2 reduces GABA synthesis in the corticomedial amygdala than in men (14), and neuronal and dendritic density in and in the hippocampus by decreasing the activity of glu- Wernicke’s area is greater in women than in men (14,15). tamic acid decarboxylase (19). This affects the excitability It is not known, however, at what time of development of hippocampal and amygdaloid neurons. the morphologic differences in the language areas become As another instance, ER and PR colocalize with tryp- established. tophan hydroxylase (TH) in the dorsal raphe nucleus, the EFFECT OF OVARIAN HORMONES ON THE NERVOUS SYSTEM 81 source of the ascending serotonergic innervation of the lim- during proestrus, when serum estrogen levels are highest bic and neocortical structures (20). TH is the rate-limit- (27). Estrogens activate spike discharges, lower seizure ing enzyme in the synthesis of 5-hydroxytryptamine. Estro- threshold, and promote epileptogenesis in different ani- gen induces tryptophan hydroxylase activity and 5HT mal models (28,29). Ovariectomy in adult rats, however, synthesis, whereas progesterone counters that effect. In this does not alter the seizure threshold (30). Thus, a lack of way, estrogen contributes to upregulation of mood, while estrogen may not protect against seizures, whereas an progesterone mitigates that effect. This may relate to mood excess of estrogen promotes them. changes during the menstrual cycle, such as late luteal dys- Estrogens affect neuronal excitability by genomi- phoria (premenstrual syndrome), or to depression during cally dependent mechanisms, by nongenomic, direct effect the menopause. Estrogen also inhibits noradrenaline on neuronal membrane, and by affecting neuronal plas- catabolism by inhibiting monoamine oxidase, which ticity and the number of excitatory synapses. As noted catabolizes noradrenaline, and by initiating the competi- earlier, the genomic mechanisms include a reduction of tion of estrogen metabolites (catecholestrogens) for the GABA synthesis through the inhibition of the GABA-syn- other noradrenergic catabolic enzyme, catechol-O-methyl- thesizing enzyme glutamic acid decarboxylase in the transferase. These actions result in fluctuations of nora- estrogen-containing inhibitory interneurons of the hip- drenaline levels through the menstrual cycle that occur pocampus and in the amygdala, structures critical in the inversely with estrogen levels (21,22) and may similarly generation and propagation of temporolimbic seizures contribute to a fluctuation in the levels of arousal and (7,18,19,28). mood during the menstrual cycle and during menopause. Estrogens also exert a direct excitatory effect at the Estradiol also promotes the synthesis of choline- neuronal membrane, where estradiol (E2) augments both acetyl transferase (ChAT), the rate limiting enzyme of the n-methyl-d-aspartate (NMDA) and non-NMDA glu- acetylcholine synthesis (23). Levels of ChAT and acetyl- tamate receptor activity (31,32). This increases neuronal choline synthesis and release from cholinergic nerve ter- excitability, for example of the hippocampal CA1 pyra- minals in the forebrain and in the hippocampus fluctu- midal neurons, thus facilitating seizure generation and ate across the estrous cycle in rats, being highest during spread. proestrus when estrogen secretion is high (24). Ovariec- Finally, estrogens potentiate neuronal excitability by tomy decreases and estrogen replacement increases by regulating neuronal plasticity and synaptogenesis. E2 20% to 80% ChAT activity in the basal forebrain neu- increases the density of the dendritic spines carrying exci- rons and acetylcholine release in target areas of the basal tatory, NMDA-receptor–containing synapses on hip- forebrain’s cholinergic projections, such as the hippocampal CA1 pyramidal neurons (33,34). In rats, the pocampus and the frontal cortex (23,25). This effect is density of the excitatory synapses fluctuates during the magnified when estradiol administration is followed by estrous cycle. It is highest by about one-third during the progesterone. This may explain the clinical findings of proestrus—the equivalent to human ovulatory phase— cognitive fluctuation during the menstrual cycle, when when estrogen levels are highest, compared to diestrus, verbal memory and creativity are highest during the ovu- when they are low. It decreases markedly following latory and midluteal menstrual cycle phases, when estra- oophorectomy (33). This estrogen-driven increase in exci- diol levels are correspondingly highest. It may also tatory synapses results in an enhanced excitatory input to explain the decline in verbal memory seen in post- the CA1 neurons and in the synchronization of neuronal menopausal women and the observation that in surgical outflow that promotes seizure genesis and propagation menopause, such decline is seen in untreated but not in (34). The increase in excitatory synapses may also estrogen-treated women (26). enhance memory and learning.

Effect of Ovarian Steroids Progestins on Neuronal Excitability Progesterone depresses neuronal firing, lessens epilepti- Gonadal steroid hormones have a profound influence upon form discharges, and inhibits seizures and epileptogene- neuronal excitability. Generally, estrogens increase neu- sis in animal models of epilepsy (28–30,35). The seizure ronal excitability and facilitate seizure occurrence and threshold during the rat estrous cycle is high during epileptogenesis. Progesterone has the opposite effect: It diestrus, when the serum progesterone level is high. The inhibits neuronal excitability, seizures, and epileptogenesis. same occurs in women with epilepsy, in whom seizures are least likely to occur during the lutal phase, when serum progesterone levels are high (36), thus suggesting Estrogens a protective effect of progesterone against seizures. In adult female rats, the seizure threshold fluctuates dur- Like estrogens, progesterone affects neuronal ing the estrous cycle. Susceptibility to seizures is highest excitability by genomic and nongenomic mechanisms. 82 NEUROLOGIC DISEASE IN WOMEN

Progesterone genomically influences the enzymatic activ- tion, some of the sulfated neuroactive steroids have neu- ity controlling the synthesis and release of various neuroexcitatory effects. These include pregnenolone sulfate rotransmitters and neuromodulators (7). Progesterone and DHEAS, the naturally occurring sulfated esters of the decreases the number of dendritic spines and synapses progesterone precursor pregnenolone and of the proges- on hippocampal CA1 pyramidal neurons, thus counter- terone metabolite DHEA (Figure 6.4; 37,44). These acting the stimulatory effects of E2 (33). It has inhibitory steroids increase neuronal firing when directly applied to direct membrane effects, described in the next section. neurons by antagonizing GABA action at the GABA-A receptor and by facilitating glutamate-induced excitation at the NMDA receptor (45). In animals, pregnenolone Neuroactive Steroids sulfate and DHEAS have a proconvulsant effect that is The anticonvulsant effect of progesterone is largely medi- prevented by chronic pretreatment with progesterone ated by its 3␣-hydroxylated metabolite, 3-␣-hydroxy-5-␣- (37,45). pregnan-20-one or allopregnanolone (AP) (37,38). Allo- These neurosteroids may also affect cognition and pregnanolone and the 3␣,5␣-hydroxylated natural memory (46). Pregnenolone sulfate stimulates ACh metabolite of the mineralocorticoid deoxycorticosterone, release as well as glutamatergic activity in adult rat hipp- allotetrahydro-deoxycorticosterone (allo-THDOC), are pocampus. DHEAS and PS improve memory and learn- the two most potent of a number of endogenous neu- ing in aging mice. In humans, DHEA has been reported roactive steroids with a direct membrane effect on neu- to have mood elevating and memory-enhancing effects ronal excitability (37,39). Allopregnanolone is devoid of in middle-aged healthy men and women and in patients hormonal effects. It may be thought of as an endogenous with depression (47,48). regulator of brain excitability with anxiolytic, anticonvulsant, and sedative-hypnotic properties (37). Allopreg- Trophic Effects nanolone and allo-THDOC hyperpolarize hippocampal and other neurons by potentiating GABA-mediated synap- In addition to their neuromodulatory effect on neuronal tic inhibition. They act as positive allosteric modulators of excitability, gonadal steroids also exert a trophic effect the GABA-A receptor, interacting with a steroid-specific on neurons and glial cells. Estrogen is an important site near the receptor to facilitate chloride (Cl) channel neural trophic factor throughout life, with influences on opening and prolong the inhibitory action of GABA on neuronal differentiation, survival, and plasticity (49–51). neurons (7,37,39). Allopregnanolone is one of the most The trophic effects of estrogen may ameliorate the potent ligands of GABA-A receptors in the CNS, with degeneration of neurons in diseases such as Alzheimer affinities similar to the potent benzodiazepines and disease (see also Chapter 30), reduce apoptotic neuronal approximately a thousand times higher than pentobarbi- death in ischemic and traumatic brain injury, and pro- tal (37,39). Progesterone by itself enhances GABA-induced mote neuronal regeneration and growth following such Cl- currents only weakly and only in high concentrations injuries. (37). Plasma and brain levels of allopregnanolone parallel those of progesterone, and plasma levels of AP corre- Trophic Effects and Cholinergic Function late with progesterone levels during the menstrual cycle in Basal Forebrain and Cortex and pregnancy (37). Brain activity of progesterone and AP, however, is not dependent solely on ovarian and adrenal Estrogen plays an important role in the function of the production, because they are both synthesized de novo in basal forebrain cholinergic system involved in memory the brain (40). Their synthesis is region-specific and and cognition. In ovariectomized rats, estradiol replace- includes the cortex and the hippocampus. ment improves spatial memory and maze learning (52). Allopregnanolone and allo-THDOC have potent The basal forebrain cholinergic neurons of the nucleus anticonvulsant effects in animal seizure models and in sta- basalis myenert (NBM) and of the diagonal band of Broca tus epilepticus (37,38,41). Allopregnanolone’s anticon- (DBB) innervate the forebrain and the hippocampus, vulsant properties resemble those of clonazepam, but with areas important in cognition, learning, and memory. lower relative toxicity and with little habituation to its Their degeneration is a key feature of Alzheimer disease. anticonvulsant effect (42). The abrupt withdrawal of allo- Estradiol protects cholinergic neurons against exci- pregnanolone induces seizures, possibly by a modulation totoxic neuronal damage (53). It does so by potentiating of the ␣-4 GABA-A receptor subunit that confers GABA- the endogenous trophic effects of the neurotrophins, insensitivity on the GABA-A receptor. This may be a nerve growth factor (NGF), and brain-derived neu- mechanism of the perimenstrual seizure exacerbation seen rotrophic factor (BDNF). These trophins are produced in some women with epilepsy (43). in the target areas of basal forebrain cholinergic projec- Although the 3- and 5-␣-reduced steroids potentiate tions and exert a trophic effect on cholinergic neurons GABA-A receptor activity and enhance neuronal inhibi- by binding with specific tyrosine kinase receptors, tyro- EFFECT OF OVARIAN HORMONES ON THE NERVOUS SYSTEM 83 sine kinases A and B (trkA and trkB). TrkA and BDNF Myelination mRNA levels in the cholinergic neurons fluctuate across Finally, gonadal steroids may play a hitherto little appre- the estrous cycle in parallel with estrogen levels (54). ciated role in myelination. Estradiol and estradiol with progesterone increase trkA Oligodendrocytes and Schwann cells express estro- and trkB levels in the basal forebrain cholinergic neurons gen and progesterone receptors. Estradiol increases the and BDNF in the hippocampus (55). The protective proliferation of Schwann cells. This finding may relate effects of estrogen on cholinergic neurons may underlie to the exacerbation of neurofibromatosis during perime- the observed protective effect of postmenopausal estro- narche (62). gen replacement therapy against the development of Schwann cell synthesize progesterone from preg- Alzheimer disease (26,56,57). nenolone. Progesterone synthesis may be important in myelin formation. Expression of the synthesizing enzyme, Role in Neuronal Injury and Neuroprotection 3-␤-hydroxysteroid dehydrogenase (3␤HSD) and progesterone synthesis increase in Schwann cells during myelin Estradiol protects neurons against a wide variety of neu- formation. Progesterone, in turn, promotes myelin for- rotoxic stimuli, including ischemic CNS injury, oxidative mation by Schwann cells. Following cryolesion of the sci- stress, excitotoxic insults, and b-amyloid-induced toxic- atic nerve, progesterone concentrations in the regenerat- ity (49,50,58). ing nerve are about sixfold higher than in plasma. In the middle cerebral artery (MCA) occlusion animal Blocking progesterone synthesis or receptor inhibits the model of cerebrovascular accident (CVA), low levels of formation of new myelin. Conversely, local application estradiol replacement reduce infarct size by 50%. The treat- of progesterone or pregnenolone accelerates remyelina- ment must precede ischemia by several days (59). Low-dose tion (61,63). estradiol pretreatment has a similar neuroprotective effect Oligodendrocytes also express progesterone recep- on the pyramidal CA1 neurons of the hippocampus in sta- tors and 3␤HSD, and progesterone may also promote tus epilepticus in rats (60) and protects explant cultures of myelination in the CNS. both neurons and astrocytes against cell death. The mechanism of this neuroprotection may include the estrogen receptor–mediated inhibition of the apop- CLINICAL IMPLICATIONS totic signaling pathways (58), regulation of growth factor genes and their receptors, and modulation of neurite Genetically Based Disorders outgrowth and plasticity (51). In the neocortex, estrogen ␣ receptor (ER-␣) is expressed at high levels only during Disorders that have a genetic basis may encompass an development, when neocortical differentiation occurs, altered ovarian hormonal production, which may affect thus suggesting a developmental role (10). Neocortical neurologic function and may affect those neurologic dis- estrogen ␤ receptor (ER-␤), by contrast, is expressed orders that have a recognized relationship to fluctuations throughout life. In adulthood, ER-␣ is expressed in the in cyclical hormones. Most of these disorders are dealt cortex only after neuronal injury such as CVA. In ER-␣ with in a more detailed fashion in other chapters of this knockout rats, estradiol has no protective effect against book, but a few of these conditions deserve additional CVA (58). Thus, ischemia or injury induces the expres- comments here. sion of ER-␣, the activation of which by estradiol protects Turner syndrome is an example of a chromosomal against ensuing neuronal injury. Recently, another mem- deletion. About 1 in every 5,000 live-born females has 45 brane-associated estrogen receptor (ER-X) has been iden- chromosomes plus a single X chromosome; that is, there tified; ER-X is also expressed perinatally and is only is a deletion of one X chromosome. Girls have ovarian expressed in adulthood following neuronal injury such as dysgenesis, absence of ovarian hormonal secretion, high stroke. Its activation may also be involved in injury- FSH levels, and delayed adolescence as well as a number related neuroprotection (49–51). of associated somatic developmental anomalies. When Pregnenolone also may be important in neuropro- sexual maturation is desired, patients must be treated tection. It reduces the degree of the histopathological with exogenous hormone replacement. Women with injury and increases the recovery of motor function in rats Turner syndrome exhibit male cognitive patterns—they after traumatic spinal cord injury (61). The mechanism perform better on visuospatial tasks than on verbal tasks. is unclear. When untreated with estrogen, patients with Turner syn- Other poorly understood, potentially neuroprotec- drome have memory, attention, and spatial performance tive effects include a reduction of cerebral edema by prog- impairment and hippocampal volume loss on magnetic esterone following cortical contusion, first suggested by resonance imaging (MRI) (64). the observations that males have more edema after simi- Another genetically based disorder is congenital lar degrees of cortical contusion than females (61). adrenal hyperplasia (CAH). This autosomal recessive dis- 84 NEUROLOGIC DISEASE IN WOMEN

order can be caused by a defect in one of six recognized tal childhood period (66). In girls with pre-existing steroid synthesizing enzymes. It affects both men and epilepsy, approximately one-third experience seizure women. In three forms, only the adrenal gland is affected. exacerbation during puberty (66–68). This is more likely In the other three, both the adrenal gland and the ovary to occur in girls with focal epilepsies, refractory seizures, are affected. The enzymatic deficiency (e.g., of the evidence of CNS damage, and delayed menarche. CYP450-c21 hydroxylase) results in impaired adrenal Changes in reproductive hormones may be respon- synthesis of cortisol, reduced inhibitory feedback of sible for these observations. Sexual maturation begins ACTH, and increased adrenal synthesis of the cortisol with adrenarche, which starts between the age of 8 and precursors that can be converted to androgens. Clinically, 10 with a marked increase in the secretion of DHEAS and women with this condition have mild to moderate viril- DHEA (69). This is followed by gonadarche, which starts ization that manifests itself early in life, and that is occa- around the age of 10 with the secretion of estrogen, but sionally associated with a delay in the onset of sexual without the secretion of progesterone. The ovarian secre- development. Two clinical forms of the disease present tion of estrogens gradually rises through menarche neonatally, one in late childhood, adolescence, or adult- (median age 12.8 years) until the onset of ovulation. In hood. In the neonatal forms, there is an increased prena- the majority of girls, menstrual cycles are initially anovu- tal production of androgens. The classic form of CAH latory. Ovulation only starts 12 to 18 months after menar- due to 21-hydroxylase deficiency is a rare disorder of che. It is only at this point that the ovarian secretion of adrenal steroid synthesis that affects approximately 1 in progesterone begins, with a parallel increase in serum 15,000 live births as a result of a gene mutation on the allopregnanolone levels in late puberty (70). Thus, the short arm of chromosome 6. Males or females with CAH secretion of the neuroexcitatory steroids, DHEAS and are exposed to high levels of androgens during gestation, estrogen, precedes the secretion of progesterone, the neu- beginning in the third month of fetal life. As the disease roinhibitory steroid, by several years. Continued expo- is now readily diagnosable and treatable at birth, the hor- sure of the brain during this time to the proconvulsant monal abnormalities are confined to prenatal and early effects of estrogen and DHEAS without the anticonvul- neonatal exposure. CAH has been associated with some sant effect of progesterone may facilitate the development behavioral changes that have been attributed to intrauter- of epilepsy (epileptogenesis) in susceptible girls. ine exposure to increased androgen levels. Women with The cyclical pattern of estradiol and progesterone CAH have an increased risk of gender identity disorder secretion may influence the likelihood of seizures (36). (e.g., of adopting male sexual identity), increased inci- Catamenial seizures broadly refer to an identifiable and dence (33%–45%) of homosexual tendencies, and show predictable occurrence of seizures in relationship to the masculine play behavior in childhood and male-typical menstrual cycle (28,71–73). Herzog et al. described three cognitive performance in adulthood (65). In addition, patterns of catamenial seizure exacerbation (74). The two women with CAH have a higher incidence of polycystic more easily recognized patterns are (i) worsening of ovarian syndrome, which may have neurologic conse- seizures during the mid-cycle and (ii) perimenstrually in quence (2). women with normal ovulation. In the first case, the occurrences of seizures coincide with ovulation, whereas in the second form, the occurrences happen 1 to 2 days before Physiologic Disorders the onset and 1 to 2 days after the onset of menstruation. Changes in the secretion of ovarian hormones associated The third pattern occurs in women who fail to ovulate, with menarche, menstrual cycles, pregnancy, and when seizures occur throughout the entire late stage of menopause may all affect the clinical manifestation of a the cycle, which may vary considerably in duration. It is number of disorders such as epilepsy, migraines, multi- sometimes easier to note that seizures decrease in occur- ple sclerosis, movement disorders, and pseudotumor cere- rence from day 2 through days 8 to 10, and then increase bri during a woman’s life. until menstruation. As mentioned earlier, estradiol has proconvulsant effects on the brain, whereas progesterone has anticon- Partial Epilepsy vulsant effects. In women with ovulatory cycles, the surge Several researchers have noted that epilepsy commonly of ovarian secretion of estrogen before and during ovu- starts around the time of menarche (66,67). In one study, lation may be responsible for the periovulatory seizure seizures began at menarche in 19% of all adult women exacerbation. During the luteal phase, the anticonvulsant with epilepsy. In another study, 35% of epilepsy that effect of progesterone secreted by the corpus luteum may began between the ages of 0.5 and 18 years began within protect against seizures, resulting in lower seizure fre- 2 years of menarche. Epilepsy was much more likely to quency (71,72,74). Perimenstrual seizure exacerbation start within 2 years of menarche (perimenarche) and dur- may be due to the withdrawal of progesterone and its ing the year of menarche than during any other postna- GABA-mediated anticonvulsant effect, similar to the EFFECT OF OVARIAN HORMONES ON THE NERVOUS SYSTEM 85 withdrawal seizures seen with a discontinuation of bar- the amygdala, a mesial temporal lobe structure, has biturates, benzodiazepines, or alcohol (42,43). In women reciprocal relationships with hypothalamic structures that with anovulatory cycles, the ovary secretes essentially influence gonadotrophin secretion. In our study of 50 normal quantities of estrogen during the late follicular women with clinical and electroencephalographic evi- and luteal phases (not the periovulatory phase) but does dence of temporal lobe onset partial epilepsy, 38% had not secrete progesterone. Thus, an elevated estrogen:prog- significant reproductive abnormality (78). Approximately esterone ratio occurs from late follicular phase until men- 20% had polycystic ovarian syndrome (PCOS), and 12% struation. This may explain the unusual pattern of seizure had hypogonadotrophic hypogonadism (HH). Two of the exacerbation, when seizures occur from about menstrual women had premature menopause, and one had hyper- cycle day 8 to 10 until menstruation. In essence, such prolactinemia. An increased risk of premature menopause women are only protected against seizure exacerbation among women with epilepsy was also observed in another when the ovary secretes very little estrogen during the study (79). In humans, it appears that a significant right early and mid-follicular phase of the cycle. temporal lobe versus left temporal lobe differential effect Menopause may also affect epilepsy. The term occurs in the hypothalamic gonadotrophin response to menopause refers to a complex process that encompasses temporal lobe seizure activity. We first observed that the both menopause, cessation of all menstruation, and per- LH levels in women with temporal lobe epilepsy varied imenopause, the preceding decline in reproductive considerably compared to age-matched controls (80). endocrine function. Perimenopause often extends for sev- Women with left temporal seizures had more LH surges eral years. Early in perimenopause ovulatory cycles during an 8-hour period than controls. These women all change to anovulatory, and progesterone secretion had PCOS. In women with hypothalamic hypogonadism declines (75). By contrast, estrogen secretion remains nor- (HH), there was a marked decrease in the number of LH mal through most of perimenopause and may even surges during an 8-hour period compared to controls, and increase episodically when, as a result of erratic follicu- the seizure focus was more often right-sided. A possible lar development, multiple follicles develop during some explanation for these findings may include a differential menstrual cycles. Estrogen levels only drop consistently effect of altered input from the right and left amygdala on late in the perimenopause, during the last few months the hypothalamic GnRH neuronal pulsatile activity (80). before cessation of menses, as the follicle pool becomes In addition to the above observations regarding the exhausted. Thus, for a period of time that may last for complex interactions of seizure type and seizure location several years, there may be a relative excess ratio of estro- on hormonal cyclicity and the hormonal effect on seizure gen to progesterone. Based on the pattern of hormonal frequency, medications play an important and often con- change, an evolving seizure pattern with seizure exacer- founding role. Similarly, pregnancy may have a major bation during the perimenopause might be expected: ini- effect on seizures through its effect on endogenous hor- tial seizure exacerbation when progesterone secretion mone production and its effect on the metabolism of the declines but estrogen secretion continues, followed by sta- antiseizure medication. These effects are discussed in bilization or improvement after menopause, as estrogen more detail in a later chapter. secretion ceases. This pattern did, in fact, occur in a recent study (76). Sixty-four percent of women experienced Migraine seizure exacerbation, and only 13% of women experienced seizure improvement during the perimenopause. By Migraine is equally prevalent in boys and girls until ado- contrast, 43% of women had seizure improvement dur- lescence, when the ratio changes to 3:1 in favor of ing the menopause, with only 31% experiencing seizure women: 17.6% of women suffer from migraines com- exacerbation. Partial epilepsy may also begin during the pared with 5.7% of males (81). In approximately 60% of climacteric, sometime without an apparent cause (77). It women, migraine attacks are linked to the menses, and in is possible that the chronic exposure of the brain to estro- approximately 15% of women with migraines, attacks gen without progesterone during the perimenopausal occur exclusively perimenstrually. The catamenial exac- years could “kindle” an occult nonepileptic CNS lesion erbation of migraines begins at menarche in approxi- into an epileptic one, in a way similar to the suggested mately 33% of women with menstrual migraines. During epileptogenic effect of perimenarche. Estrogen replace- pregnancy, migraines may worsen during the first ment therapy may also be associated with seizure exac- trimester and remit during the last two trimesters, erbation during the perimenopause and menopause (76). although the pattern of improvement or exacerbation is We believe that if there is a clinically significant increase highly variable and individual; approximately 25% of in seizure frequency, hormonal replacement should women with migraines experience no change in their include both estrogen together with natural progesterone. headaches during pregnancy (82). Migraines may worsen In addition, epilepsy, particularly temporal lobe transiently, but at times markedly and for a prolonged epilepsy, can influence the menstrual cycle. As mentioned, time, during perimenopause; migraines may improve after 86 NEUROLOGIC DISEASE IN WOMEN

completion of menopause when the female:male ratio These theories have led to limited therapeutic trials drops to 2:1 (83). with estrogen and, paradoxically, antiestrogen therapy, The pathophysiologic underpinnings of these clini- for example, with tamoxifen, with androgens such as cal phenomena remain essentially obscure. A popular danazol, and with dopamine agonists such as bromocrip- hypothesis is that estrogen withdrawal perimenstrually tine and pergolide to suppress prolactin secretion (91). alters vascular tone, leading to vascular instability and a These studies have been limited in scope and therapeutic greater susceptibility to cerebrovascular dilatation and success, although anecdotal reports of success using all headache. Estrogen receptors are found on the media of these agents abound. medium-size cerebral vessels. Estrogen stimulates the production of nitric oxide and causes cerebrovascular dilata- Multiple Sclerosis tion (84). Blood flow in the internal carotid artery increases by 15% during the ovulatory phase of the men- Multiple sclerosis (MS) is also more common in women strual cycle in normal women (85). However, no differ- than men, with approximately a 2.5:1 ratio. The onset ence has been found in the systemic levels of estrogens, of the disease is also most common during the second and progesterone, androgens, LH, or FSH between women third decades of life, although the incidence rises after with catamenial migraines and controls (86). No blood puberty, during the second half of the second decade. hormone–blood flow correlation studies have been per- Anecdotal reports of MS show perimenstrual exacerba- formed in women with migraines. Progesterone has not tion (92), but also improvement with estrogen contra- been thought to be a significant factor in migraine, but it ceptive treatment (93). One of the most notable features is noteworthy that in an animal model of migraine, pre- of MS, however, is the reduction of relapsing attacks in treatment with both progesterone and the 3,5-a reduced remitting and relapsing MS during the last trimester of metabolites allopregnanolone and tetrahydrodeoxycorti- pregnancy, with a subsequent rebound of attacks during costerone ameliorated plasma extravasation within the the postpartum period (94). meninges (87). This would suggest that progesterone— The relapse decrease of the last trimester may be via allopregnanolone—may play an anti-inflammatory mediated by a shift in immune responses from the inflam- role in the CNS. Perimenstrual withdrawal of proges- matory response promoting T helper 1 lymphocytes (Th1 terone could thus theoretically contribute to an increase cells) to the inflammatory response dampening T helper in the vasogenic inflammation that may be part of the 2 lymphocytes (Th 2 cells). A number of hormones rise pathophysiology of migraine. dramatically during the second half of pregnancy. The Other possible mechanisms that have been sug- serum levels of estradiol, estriol, progesterone, cortisol, gested include a perimenstrual reduction of hypothala- and 1,25-vitamin D, among others, rise tenfold during mic opioid secretion, increased prostacyclin activity, and this time, compared with their preconception levels. All prostacyclin-related vasodilation and modulation of pro- these hormones affect the immune system. Estradiol, lactin secretion (83). Of particular interest is the influ- estriol, cortisol, and 1,25-vitamin D have been shown to ence of estrogen on opioids. Estradiol colocalizes with have an immunosupressant effect and a suppressant effect the opioids endorphins, encephalin, and dynorphin in on experimental allergic encephalomyelitis (EAE), the ani- rat neurons of a number of brain regions, including the mal model of MS (95). Estrogens affect CD4+ T lym- hypothalamus and the dorsal spinal cord sensory neu- phocytes, with differential effects at low versus high dose. rons. It induces the expression and release of the endoge- High levels of estrogen favor T-2 anti-inflammatory nous opioid peptides and activate µ-pioid receptor acti- cytokine and humoral immune response (96). Proges- vation in the hypothalamus and in the amygdala (88). terone also facilitates the T-2 profile, with the induction Expression of endorphin in hypothalamic neurons and of the messenger RNA of the anti-inflammatory inter- the release of opioids into the hypothalamic-portal cir- leukin-4 (97). culation fluctuates during the menstrual cycle. It is high- Clinically, the number and volume of gadolinium- est at the time of ovulation (estrus) and falls as serum enhancing MRI lesions in women with MS do not fluc- estrogen levels fall (89). Thus, estradiol potentiates the tuate between the follicular and the luteal phases of the analgesic effects of endogenous opioids. It may, possibly, menstrual cycle. A positive relationship, however, has by its effect in the amygdala, even alter the subjective been demonstrated between MRI lesion number and vol- perception or “emotional content” of painful stimuli. Its ume and the serum progesterone:estradiol ratio (98). withdrawal perimenstrually may contribute to the men- Attempts at the therapeutic manipulation of repro- strually related migraine. Conversely, its large rise dur- ductive hormones other than in MS have not been system- ing the last two trimesters is associated with an elevation atic and have been largely unsuccessful. Bromocriptine, of the pain threshold during gestation (90). Thus, it may which suppresses the secretion of prolactin, was found to contribute to the alleviation of migraine during this part be very effective in suppressing EAE in animals when of pregnancy. administered both before and after the EAE-inducing agent EFFECT OF OVARIAN HORMONES ON THE NERVOUS SYSTEM 87

(95). Attempts at human studies, however, were not and levels of serum allopregnanolone. promising and have been abandoned (99). 1,25-vitamin D was similarly promising in EAE models and disappointing Movement Disorders in limited human studies (100). Recently, the weak estrogen estriol, a major estrogen product of the second half of Parkinsonian symptoms can worsen perimenstrually in human pregnancy, was found to suppress EAE and to women with Parkinson disease. In one large survey, 75% decrease delayed-type hypersensitivity responses in periph- of women with natural menstrual cycles noted a wors- eral blood mononuclear cells and gadolinium-enhancing ening of symptoms before or during the period (105). The MRI lesion number and volumes in nonpregnant women pathophysiologic mechanisms have not been investigated. with MS compared with pretreatment baseline. The bene- In chorea gravidarum, chorea occurs during preg- ficial MRI effects receded when the treatment was stopped nancy, sometimes in patients with previous post- and re-emerged when it was reinstituted (101). A placebo- rheumatic fever chorea (Sydenham chorea). Its patho- controlled study is being planned. genesis is unclear, but may be related to a pregnancy-associated rise in gonadal hormones, particularly estrogens. This hypothesis is supported by the Neuropsychiatric Diseases observation that estrogen-containing oral contraceptive As already mentioned, most neuropsychiatric diseases are may be a trigger for chorea, sometimes in a patient who “sexually dimorphic,” with a greater predilection for also suffers from chorea gravidarum (106). (See also women (depression, anxiety disorders, anorexia-bulimia) Chapter 24.) or for men (aggression, schizophrenia) (16). The differences in incidence and prevalence of these disorders between men and women emerges during puberty. Menar- CONCLUSION che has been aptly named “the forgotten milestone” of female psychiatric diseases (16). Affective and anxiety dis- The study of the effects of hormones on the nervous sys- orders are commonly affected by the menstrual cycle, and tem, mood, memory, cognition, and behavior in health commonly exacerbate or present de novo during the post- and in disease is beginning to receive the attention that it partum period or during the perimenopause (22). deserves. Hopefully, over the next few years, the complex Both estrogens and progesterone have psychoactive interrelationships between hormonal fluctuations and the properties. Estrogens, via diverse mechanisms that may various neurotransmitter systems and metabolic path- include augmentation of NMDA and non-NMDA gluta- ways, as well as neuronal survival, brain plasticity, neu- matergic activity, serotonergic, noradrenergic, and opiate ronal remodeling, and synaptogenesis will be more fully activity, have an arousing, antidepressant, and potentially understood so that we might predict and treat the normal anxiogenic effect (102). Progesterone and allopreg- and pathologic conditions that arise from the cyclical nanolone, by contrast, have anxiolytic, sedating and, in behavior of ovarian hormones. higher doses, depressive and anesthetic effects similar to On a final note, a word of caution. Although a good those of the benzodiazepines, due to their potentiation of deal is known about the effects of ovarian hormones on GABA-ergic activity. Progesterone withdrawal may there- the nervous system, very little is known about two aspects fore be pathophysiologically important in the perimen- that may be important. The first is the adaptive response strual exacerbation of anxiety disorders, and of rapid of the nervous system to the fluctuation levels of the cycling in bipolar affective disorders, and in premenstrual steroids. Serum steroid levels may change dramatically dysphoric dysfunction (PMDD) or premenstrual syndrome without clinical effects. During the last trimester of the (PMS). PMDD women with greater levels of premenstrual pregnancy, for instance, serum levels of progesterone and anxiety and irritability have significantly reduced allo- estradiol rise to approximately 10 times the level of the pregnanolone levels in the luteal phase relative to less luteal phase of the menstrual cycle and approximately symptomatic PMDD women (103). This suggests that a 40 to 200 times the level of the early follicular phase. dysfunction of metabolism of progesterone to allopreg- Within 24 to 48 hours after delivery, the secretion returns nanolone may be one factor in the causation of PMDD. to the follicular phase level. Yet in the majority of women, The withdrawal of progesterone and low serum allopreg- no neurologic complications occur during the last nanolone levels may also be implicated in postpartum trimester of the pregnancy or the puerperium (2). Thus, depression. Serum allopregnanolone levels were similarly adaptive changes must mitigate the effects of such large decreased after delivery in women with postpartum dys- fluctuations in serum levels on the nervous system. thymia compared to euhymic women (104), with a nega- Second, we know very little about the functional sig- tive correlation between Hamilton Depression Rating nificance of in situ synthesis of neurosteroids in the CNS. score and serum allopregnanolone level. A significant neg- This synthesis is larger than peripheral steroid synthesis ative correlation was observed between the Hamilton score for several major gonadal and adrenal steroids such 88 NEUROLOGIC DISEASE IN WOMEN

DHEA, DHEAS, and pregnenolone (brain levels of which 18. Wallis GJ, Luttge W. Influence of estrogen and proges- are up to 10 times higher than serum levels), as well as for terone on glutamic acid decarboxylase activity in discrete neuroactive progesterone metabolites such as allopreg- regions of rat brain. J Neurochem 1980;34:609–613. 19. Murphy DD, Cole NB, Greenberger V, Segal M. Estra- nanolone and TH-DOC (105). Such knowledge will be diol increases dendritic spine density by reducing GABA important in determining the overall role of steroids, neurotransmission in hippocampal neurons. J Neurosci including ovarian steroids, in the healthy and diseased 1998;18:2550–2559. functioning of the nervous system. 20. Pecins-Thompson M, Brown NA, Kohama SG, et al. Ovarian steroid regulation of tryptophan hydroxylase mRNA expression in rhesus macaques. J Neurosc References 1996;16:7021–7029. 21. Briggs M. The relationship between monoamine oxidase 1. Greenspan FS, Strewler GJ, (eds.) Basic and clinical activity and sex hormone concentrations in human blood endocrinology, 5th ed. Stamford, Conn: Appleton and plasma. J Reprod Fertil 1972;29:447–450. Lange, 1997. 22. Klein P, Versi E, Herzog AG. Mood and the menopause. 2. Yen SSC, Jaffe RB, Barbieri RL, (eds.) Reproductive Br J Obstet Gynaecol 1999;106:1–4. endocrinology, 4th ed. Philadelphia, Pa: WB Saunders, 23. Gibbs RB. Fluctuations of relative levels of choline acetyl 1999. transferase mRNA in different regions of the rat basal 3. Funabashi R, Shinohara K, Kimura F. Neuronal control forebrain across the estrous cycle: effects of estrogen and circuit for the gonadotropin-releasing hormone surge in progesterone. J Neurosci 1996;16:1049. rats. In: Handa RJ, Hayashi S, Terasawa E, Kawata M, 24. Luine VN. Estradiol increases choline acetyltransferase (eds.) Neuroplasticity, development and steroid hormone activity in specific basal forebrain nuclei and projection action. Boca Raton, Fla: CRC Press, 2002;169–177. areas of female rat. Exp Neurol 1985;89:484. 4. Dreifuss JJ, Murphy JT, Gloor P. Contrasting effects of 25. Gibbs RB. Effects of estrogen on potassium-stimulated two identified amygdaloid efferent pathways on single acetylcholine release in the hippocampus and overlying hypothalamic neurons. J Neurophysiol 1986;31:37–248. cortex of adult rats. Brain Res 1997;749:143–146. 5. Canteras NS, Simerly RB, Swanson LW. Organization of 26. Sherwin BB. Estrogen and cognitive aging in women. projections from the medial nucleus of the amygdala: a Trends Pharmacol Sci 2002;23:527–534. PHAL study in the rat. J Comp Neurol 1995;360:213–245. 27. Teresawa E, Timiras P. Electrical activity during the 6. Herzog AG, Russell V, Vaitukaitis J. Neuroendocrine estrous cycle of the rat: cyclic changes in limbic struc- dysfunction in temporal lobe epilepsy. Arch Neurol tures. Endocrinology 1968;83:207. 1982;39:133. 28. Klein P, Herzog AG. Hormonal effects on epilepsy in 7. McEwen BS. How do sex and stress hormones affect women. Epilepsia 1998;39(suppl 8):S9–S16. nerve cells? Ann NY Acad Sci 1994;743:1–16. 29. Edwards HE, Burnham WM, Mendonca A, et al. Steroid 8. Matsumoto A, (ed.) Sexual differentiation of the brain. hormones affect limbic afterdischarge thresholds and Boca Raton, Fla: CRC Press, 1999. kindling rates in adult female rats. Brain Res 1999;838: 9. Breedlove SM. Sexual dimporphism in the vertebrate 136–150. nervous system. J Neurosci 1992;12:4133–4142. 30. Woolley DE, Timiras PS. The gonad-brain relationship: 10. Shughrue PJ, Lane MV, Merchenthaler I. Comparative effects of female sex hormones on electroshock convul- distribution of estrogen receptor-alpha and -beta mRNA sions in the rat. Endocrinol 1962;70:196–209. in the rat central nervous system. J Comp Neurol 1997; 31. Wong M, Moss R. Long-term and short-term electro- 388:507–525. physiological effects of estrogen on the synaptic proper- 11. Roselli CE, Resko JA. Cytochrome P450 aromatase ties of hippocampal CA1 neurons. J Neurosci 1992;12: (CYP19) in the non-human primate brain: distribution, 3217–3225. regulation, and functional significance. J Steroid 32. Foy MR, Xu J, Xie X, et al. 17beta-estradiol enhances Biochem Mol Biol 2001;79:247–253. NMDA receptor-mediated EPSPs and long-term poten- 12. LeVay SA. A difference in hypothalamic structure tiation. J Neurophysiol 1999;81:925–929. between heterosexual and homosexual me. Science 33. Woolley CS, McEwen BS. Role of estradiol and proges- 1991;253:1034–1037. terone in regulation of hippocampal dendritic spine den- 13. Zhou JN, Hofman MA, Gooren LJG, et al. A sex dif- sity during the estrous cycle in the rat. J Comp Neurol ference in the human brain and its relation to transsex- 1993;336:293–306. uality. Nature 1995;378:68–70. 34. Yankova M, Hart SA, Woolley CS. Estrogen increases 14. Harasty J, Double KL, Holliday GM, et al. Language- synaptic connectivity between single presynaptic inputs associated cortical regions are proportionally larger in and multiple postsynaptic CA1 pyramidal cells: a serial the female brain. Arch Neurol 1997;54:171–176. electron-microscopic study. Proc Natl Acad Sci USA 15. Rabinowicz T, MavDonald-Comber Petetot J, Gartside 2001;98:3525–3530. PS, et al. Structure of the cerebral cortex in men and 35. Landgren S, Aasly J, Backstrom T, et al. The effect of women. J Neuropathol and Exp Neurol 2002;61:46– 57. progesterone and its metabolites on the interictal epilep- 16. Angold A, Worthman CW. Puberty onset of gender dif- tiform discharge in the cat’s cerebral cortex. Acta Phys- ferences in rates of depression: a developmental, epi- iol Scand 1987;131:33–42. demiologic and neuroendocrine perspective. J Affect Dis- 36. Backstrom T, Zetterlund B, Blom S, et al. Effects of intra- ord 1993;29:145–158. venous progesterone infusions on the epileptic discharge 17. Simerly RB, Chang M, Muramatsu, et al. Distribution of frequency in women with partial epilepsy. Acta Neurol androgen and estrogen receptor mRNA-containing cells Scand 1984;69:240–248. in the rat brain: an in situ hybridization study. J Comp 37. Paul SM, Purdy RH. Neuroactive steroids. FASEB Neuro 1990;294:76–95. 1992;6:2311–2322. EFFECT OF OVARIAN HORMONES ON THE NERVOUS SYSTEM 89

38. Kokate TG, Banks, MK, Magee T, et al. Finasteride, a 56. Paganini-Hill A, Henderson VW. Estrogen replacement 5a-reductase inhibitor, blocks the anticonvulsant activ- therapy and risk of Alzheimer disease. Arch Intern Med ity of progesterone in mice. J Pharmacol Exp Ther 1996;156:2213–2217. 1999;288:679–684. 57. Lerner AJ. Commentary:women and Alzheimer’s disease. 39. Majewska MD, Harrison NL, Schwartz RD, et al. Steroid J Clin Endocrinol Metab 1999;84:1830. hormone metabolites are barbiturate-like modulators of 58. Wise PM, Wilson M, Dubal DB, Rau SW. In Vitro and the GABA receptor. Science 1986;232:1004–1007. in vivo approaches to the study of the neuroprotective 40. Cheney DL, Uzunov D, Vosta E, et al. Gas chromato- actions of estradiol. In: Handa RJ, Hayashi S, Terasawa graphic-mass fragmentographic quantitation of 3a- E, Kawata M, (eds.) Neuroplasticity, development and hydroxy-5a-pragnan-20-0ne (allopregnanolone) and its steroid hormone action. Boca Raton, Fla: CRC Press precursors in blood and brain of adrenalectomized and 2002;81–91. castrated rats. J Neurosci 1995;15:4641–4650. 59. Wise PM, Dubal DB, Wilson ME, et al. Estradiol is a pro- 41. Reddy DS, Kim HY, Rogawski MA. Neurosteroids with- tective factor in the adult and aging brain: understand- drawal model of perimenstrual catamenial epilepsy. ing of mechanisms derived from in vivo and in vitro stud- Epilepsia 2001;42:328–337. ies. Brain Res Brain Res Rev 2001;37:313–319. 42. Reddy DS, Rogawski MA. Enhanced anticonvulsant 60. Veliskova J, Velisek L, Galanopoulou AS, Sperber EF. activity of neuroactive steroids in a rat model of cata- Neuroprotective effects of estrogens on hippocampal menial epilepsy. Epilepsia 2001;42:337–344. cells in adult female rats after status epilepticus. Epilep- 43. Smith SS, Gong OH, Hsu FC, et al. GABA(A) receptor sia 2000;41(suppl 6):S30–35. alpha-4 subunit suppression prevents withdrawal prop- 61. Beaulieu E, Schumacher M. Progesterone as a neuroac- erties of an endogenous steroid. Nature 1998;30:392: tive neurosteroid, with special reference to the effect of 926–930. progesterone on myelination. Steroids 2000;65:605–612. 44. Reddy DS, Kulkami SK. Proconvulsant effects of neu- 62. Jay JR, MacLaughlin DT, Badger TM, et al. Hormonal rosteroids pregnenolone sulfate and dehydroepiandros- modulation of Schwann cell tumors. I. The effects of terone sulfate in mice. Eur J Pharmacol 1998;345:55–59. estradiol and tamoxifen on methylnitrosourea-induced 45. Kokate TG, Juhng KN, Krkby RD, et al. Convulsant rat Schwann cell tumors. Ann NY Acad Sci 1986;486: actions of the neurosteroid pregnenolone sulfate in mice. 371–382. Br Res 1999;831:119–124. 63. Koenig HL, Ferzaz B, et al. Progesterone synthesis and 46. Flood JF, Morle JE, Roberts E. Pregnenolone sulfate myelin formation by Schwann cells. Science 1995;268: enhances posttraining memory processes when injected 1500–1503. in very low doses into limbic system structures. Proc Natl 64. Murphy DG, DeCarli C, Daly E, et al. X-chromosome Acad Sci USA 1995;92:10806. effects on female brain: a magnetic resonance imaging 47. Morales AJ, Nolan J, Nelson G, et al. Effects of replace- study of Turner’s syndrome. Lancet 1993;342: ment dose of dehydroepiandrosterone (DHEA) in men 1197–1200. and women of advancing age. J Clin Endocrinol Metab 65. Hines M. Gonadal hormones and sexual differentiation 1994;78:1360. of human behavior: effects on psychosexual and cogni- 48. Wolfowitz OM, Reus VI, Roberts E, et al. Dehyepiandros- tive development. In: Matsumoto A, (ed.) Sexual Dif- terone (DHEA) treatment of depression. Biol Psychiatry ferentiation of the Brain. Boca Raton, Fla: CRC Press, 1997;41:311. 1999;257–278. 49. Green PS, Simpkins JW. Neuroprotective effects of estro- 66. Klein P, Van Passell-Clark LM, Pezzullo JC. Onset of gens: potential mechanisms of action. Int J Dev Neurosci epilepsy at the time of menarche. Neurology 2003;60: 2000;18:347–358. 495–497. 50. Garcia-Seguera LLM, Azcoitia I, Don Carlos LL. Neu- 67. Morrell MJ, Hamdy SF, Seale CG, Springer A. Self- roprotection by estradiol. Prog Neurobiol 2001;63: reported reproductive history in women with epilepsy: 29–60. puberty onset and effects of menarche and menstrual 51. Toran-Allerand CD, Guan X, MacLusky NJ, et al. ER-X: cycle on seizures. Neurology 1998;50(suppl 4):A448. a novel, plasma membrane-associated, putative estrogen 68. Rosciszewska D, The course of epilepsy in girls at the age receptor that is regulated during development and after of puberty. Neurol Neurochir Pol 1975;9:597–602. ischemic brain injury. J Neurosci 2002;22:8391–8401. 69. Speroff L, Glass RH, Kase NG, (ed.) Clinical gynecologic 52. Gibbs RB. Estrogen replacement enhances acquisition of endocrinology and infertility, 5th ed. Baltimore, Md: a spatial memory task and reduces deficits associated Willliams & Wilkins, 1994. with hippocampal muscarinic receptor inhibition. Horm 70. Genazzani AR, Bernardi F, Monteleone P, et al. Neu- Behav 1999;36:222–233. ropeptides, neurotransmitters, neurosteroids, and the 53. Horvath KM, Hartig W, Van der Veen R, et al. 17beta- onset of puberty. Ann NY Acad Sci 2000;900:1–9. estradiol enhances cortical cholinergic innervation and 71. Laidlaw J. Catamenial epilepsy. Lancet 1956;217: preserves synaptic density following excitotoxic lesions 1235–1237. to the rat nucleus basalis magnocellularis. Neuroscience 72. Backstrom T. Epileptic seizures in women related to 2002;110:489–504. plasma estrogen and progesterone during the menstrual 54. Gibbs RB. Levels of trkA and BDNF mRNA, but not cycle. Acta Neurol Scand 1976;54:321–347. NGF mRNA, fluctuate across the estrous cycle and 73. Mattson RH, Cramer JA, Caldwell BV. Seizure frequency increase in response to acute hormone replacement. and the menstrual cycle: a clinical study. Epilepsia Brain Res 1998;810:294. 1981;22:242. 55. Gibbs RB. Treatment with estrogen and progesterone 74. Herzog AG, Klein P, Ransill BJ.Three patterns of cata- affects relative levels of brain-derived neurotrophic fac- menial epilepsy. Epilepsia 1997;38:1082–1088. tor mRNA and protein in different regions of the adult 75. Burger HC. The endocrinology of the menopause. Matu- rat brain. Brain Res 1999;844:20–27. ritas 1996;23:129–136. 90 NEUROLOGIC DISEASE IN WOMEN

76. Harden CL, Pulver MC, Ravdin L, Jacobs AR. The effect 93. McFarland HR. The management of multiple sclerosis. of menopause and perimenopause on the course of 3. Apparent suppression of symptoms by an estrogen- epilepsy. Epilepsia 1999;40:1402–1407. progestin compound. Mo Med 1969;66:209–211. 77. Abbasi F, Krumholz A, Kittner SJ, Langenberg P. Effects 94. Confavreux C, Hutchinsoon M, Hours MM, et al. Rate of menopause on seizures in women with epilepsy. of pregnancy-related relapse in multiple sclerosis. N Engl Epilepsia 1999;40:205–210. J Med 1998;339:285–291. 78. Herzog A, Seibel M, Schomer DL, Vaitukaitis JL, 95. Riskind PN, Massacesi L, Doolittle TH, Hauser SL. The Geschwind N. Reproductive endocrine disorders in role of prolactin in autoimmune demyelination: sup- women with partial seizures of temporal lobe origin. pression of experimental allergic encephalomyelitis by Arch Neurol 1986;43:341–346. bromocriptine. Ann Neurol 1991;29:542–547. 79. Klein P, Serje A, Pezzullo JC. Premature ovarian failure 96. Gilmore W, Weiner LP, Correale J. Effects of estradiol on in women with epilepsy. Epilepsia 2001;42:1584–1589. cytokine secretion by proteolipid protein-specific T cell 80. Drislane FW, Coleman AE, Schomer DL, et al. Altered clones isolated from multiple sclerosis patients and nor- pulsatile secretion of luteinizing hormone in women with mal control subjects. J Immunol 1997;158:446–451. epilepsy. Neurology 1994;44:306–310. 97. Piccinni MP, Giudizi MG, Biagiotti R, et al. Progesterone 81. Stewart WF, Lipton RB, Celentano DD, et al. Prevalence favors the development of human T helper cells proof migraine headache in the United States. Relation to ducing Th2-type cytokines and promotes both IL-4 pro- age, income, race, and other sociodemographic factors. duction and membrane CD 30 expression in established JAMA 1992;267:64–69. Th1 cell clones. J Immunol 1995;155:128–133. 82. Ratinahirana H, Darbois Y, Bousser MG. Migraine and 98. Pozzilli C, Falaschi P, Mainero C, et al. MRI in multiple pregnancy: a prospective study in 703 women after deliv- sclerosis during the menstrual cycle: relationship with ery. Neurology 1990;40(suppl 1):437. sex hormone patterns. Neurology 1999;53:622–624. 83. Silberstein SD. Hormone-related headache. Med Clin 99. Bissay V, De Klippel N, Herroelen L, et al. Bromocrip- North Am 2001;85:1017–1035. tine therapy in multiple sclerosis: an open label pilot 84. Geary GG, Krause DN, Duckles SP. Estrogen reduces study. Clin Neuropharmacol 1994;17:473–476. mouse cerebral artery tone through endothelial NOS- 100. Fleming JO, Hummel AL, Beinlich BR, et al. Vitamin D and cyclooxygenase-dependent mechanisms. Am J Phys- treatment of relapsing-remitting multiple sclerosis: a iol Heart Circ Physiol 2000;279:H511–519. MRI-based pilot study. Neurology 2000;50(suppl 85. Krejza J, Mariak Z, et al. ICA flow correlates with serum 3)A:338. estradiol levels during the menstrual cycle. Stroke 101. Sicotte NL, Liva SM, Klutch R, et al. Treatment of mul- 2001;32:30–36. tiple sclerosis with the pregnancy hormone estriol. Ann 86. Epstein MT, Hockaday JM, Hockaday TD. Migraine Neurol 2002;52:421–428. and reproductive hormones throughout the menstrual 102. Bernardi M, Vergoni AV, Sandrini M, et al. Influence of cycle. Lancet 1975;1:543–548. ovariectomy, estradiol and progesterone on the behavior 87. Limmroth V, Lee WS, Koskowitz MA. GABAA-recep- of mice in an experminetal model of depression. Phys- tor-mediated effects of progesterone, its ring-A-reduced iol Behav 1989;45:1067–1068. metabolites and synthetic neuroactive steroids on neu- 103. Girdler SS, Straneva PA, Light KC, Pedersen CA, Mor- rogenic oedema in the rat meninges. Br J Pharmacol row AL. Allopregnanolone levels and reactivity to men- 1996;117:99–104. tal stress in premenstrual dysphoric disorder. Biol Psy- 88. Eckersell CB, Popper P, Micevych PE. Estrogen-induced chiatry 2001;49:788–797. alteration of mu-opioid receptor immunoreactivity in the 104. Nappi RE, Petraglia F, Luisi S, Polatti F, Farina C, Genaz- medial [preoptic nucleus and medial amygdala. J Neu- zani AR. Serum allopregnanolone in women with post- rosci 1998;q8:3967–3976. partum “blues.” Obstet Gynecol 2001;97:77–80. 89. Cheung S, Salinas J, Hammer RP Jr. Gonadal steroid hor- 105. Thulin PC, Carter JH, Nichols MD, et al. Menstrual- mone-dependence of beta-endorphin-like immunoreac- cycle related changed in Parkinson’s Disease. Neurology tivity in the medial preoptic area of the rat. Brain Res 1996;46(suppl)A:376. 1995;675:83–88. 106. Omdal R, Roalso S. Chorea gravidarum and chorea 90. Dawson-Basoa M, Gintzer AR. Gestational and ovar- associated with oral contraceptives—diseases due to ian sex steroid antinociception: synergy between spinal antiphospholipid antibodies? Acta Neurol Scand 1992; kappa and delta opioid systems. Brain Res 1998;794: 86:219–220. 61–67. 107. Baulieu EE. Neurosteroids: of the nervous system, by the 91. Herzog AG. Continuous bromocriptine therapy in men- nervous system, for the nervous system. Recent Prog strual migraine. Neurology 1997;48:101–102. Horm Res 1997;52:1–32. 92. Zorgdrager A, DeKeyser J. Menstrually related worsening of symptoms in multiple sclerosis. J Neurol Sci 1997;149:95–97.

Genetic Disorders 7 in Women

Orest Hurko, MD

or the most part, genetic diseases do but also has a low density of genes (1). Its known con- not discriminate between the sexes, tribution to human neurogenetic disorders appears to be affecting both men and women with limited to a behavioral and mildly dysmorphic phenotype, F equal severity and in a similar man- the XYY syndrome (2). In practice, virtually all sex-linked ner. In a small number of heritable disorders, however, disorders are encoded by genes on the X chromosome. special considerations arise in the clinical management of women that differ considerably from those in men. Sex-Linked Disorders Uniquely, in genetics, the clinician is concerned about manifestations not only in the patient but also in Recognized X-linked disorders are slightly more frequent her relatives, especially actual or potential offspring to than would be predicted by the ratio of one X chromo- whom disease may be transmitted. Some genetic diseases some to 22 autosomes. As of this writing, of the 14,561 are different in women than in men. In others, the only entries in the catalog of human genes and genetic disor- difference is in transmission; the offspring of an affected ders, Online Mendelian Inheritance in Man (OMIM), 810 woman being at different risk than those of an affected (5.56% of the total) are in the X chromosome catalog (1). man. In still others, notably the sex-linked disorders, both Indeed, 101 of the 1,348 phenotype descriptions in the disease and transmission pattern are different in men OMIM are in the X chromosome catalog, representing and women. 7.49% of the total number of all phenotypic descriptions in the entire catalog. This is a higher percentage than would be expected from the relative size of the X chro- EXPRESSION OF GENETIC mosome, the 151,567,156 base pairs (bp) of which rep- DISEASES IN WOMEN resent only 4.67% of the 3,242,415,757 bp that consti- tute the haploid human genome. Indeed, Ensembl, a joint Gender differences in disease phenotype are either sex- project between the European Bioinformatics Institute linked, the underlying gene(s) being located on a sex chro- and the Sanger Institute, currently predicts the existence mosome, or sex-limited autosomal disorders, such as of 24,847 human genes, of which 869 (only 3.49%) are male-pattern baldness. In theory, sex-linked disorders on the X chromosome (3). Thus, there are roughly twice could result from alterations of either the X or the Y chro- as many known human X-linked traits as would be pre- mosome. However, the Y chromosome is not only small dicted by the proportion of human genes that is currently 91 92 NEUROLOGIC DISEASE IN WOMEN

estimated to be located on this chromosome. This dis- is, deficiency of that half of gene product that should have proportion is largely technical and historical. For almost been contributed by the mutant allele. In certain meta- a century it has been known that X-linked inheritance can bolic pathways, such compensation can only occur within be recognized by the simple inspection of a pedigree, the same cell in which a block has occurred. In other dis- whereas a specific autosomal assignment requires linkage eases, a cell that has lyonized (stably inactivated) an X analysis (4,5). Early studies of X-linked genes were also chromosome with a normal gene can be rescued by other facilitated by such useful generalizations as Ohno’s law: cells that have lyonized the X with the mutant gene—so- If a gene were on the X chromosome in one species, it called metabolic cooperation (9). In certain disorders, would be X-linked in others (6). there is selective pressure against those cells that have X-linked disorders might be expected to be more lyonized the normal allele: As the heterozygote ages, common in women, who have two X chromosomes and abnormal cells drop out of the mosaic (10). The strength are thus twice as likely to carry an X-linked mutation, than of this selective pressure can vary from tissue to tissue, in men, who have only one. The opposite is true, how- sometimes influencing the course of the disease and some- ever. Most X-linked disorders are seen more often in men times restricting biopsy choices for diagnostic testing. than in women. This apparent paradox is resolved by con- From these basic considerations we can derive clin- sideration of the protection afforded by having two allelic ically useful generalizations. The effects of X-linked muta- copies of each gene, only one of which is likely to be tions are milder in women than in men, often negligible. mutant. In classic mendelian theory, an individual with one Furthermore, the degree of clinical and biochemical copy of a recessive mutation appears normal because of involvement in heterozygote women can vary in space compensation from the wild-type allele on the other chro- and time, depending on the patch size of lyonized clones mosome. Classic theory also has it that an individual with and the degree of selection against one of the lyonized one copy of a dominant mutation is affected as severely populations. I will refrain from presenting a longer list as is an individual with both copies mutant. That is to say, of dry generalities at this juncture lest we unnecessarily a dominant always completely trumps a recessive. Con- try the patience of the reader. Instead, I will let other trary to classical theory, no completely recessive or com- potentially useful generalizations emerge in the discussion pletely dominant alleles exist: Having a normal allele of specific disorders. always ameliorates the effect of a mutant allele, albeit often very modestly. If phenotypes are examined with sufficient Sex-Linked Disorders Seen (Almost) precision, all mutations are thus semidominant. The only Exclusively in Females known human exception is that of Huntington disease, possibly the only human disorder dominant in Mendel’s Some X-linked disorders are seen only in female het- sense of the word; that is, the phenotype of the homozy- erozygotes because they are lethal to hemizygous males in gote is indistinguishable from that of the heterozygote for utero. Spontaneous abortions of affected male fetuses can the mutant allele (7). This having been said, recessive and occur early enough in pregnancy to be inapparent. A care- dominant remain very useful simplifications for physicians. ful analysis of multiple families segregating such mutations In clinical practice, the term recessive refers to a clinical discloses an excess of female births because of the failure phenotype overtly detectable only when both alleles are of male conceptuses with the mutation to come to term. mutant; the term dominant refers to phenotypes detectable Given the small size of sibships in the industrialized world, when only one allele is mutant. such distorted birth ratios may not be apparent in an indi- Furthermore, although Mendel recognized domi- vidual family. Such disorders are referred to as X-linked nant and recessive phenotypes, X-linked inheritance was dominant or semidominant, male-lethal. not recognized until half a century later, by Thomas Hunt In many of these disorders, affected females show Morgan (5). Later, Mary Lyon discovered that women are severe involvement of the nervous system with mental mosaics: In some cells, the paternal X chromosome is retardation—a useful starting point for the construction active; in others, the maternal (8). This pattern of inacti- of a differential diagnosis, but a virtually worthless tool vation of one of the X chromosomes—named lyonization for its advancement. Specific clinical diagnosis is permit- in her honor—is established approximately 5 to 6 days ted by characteristic systemic findings. A striking exam- after fertilization, when each somatic cell randomly inac- ple is provided by what had been called incontinentia pig- tivates either the maternal or paternal X chromosome, a menti type II, considered by an increasing number of pattern that is stably transmitted by each somatic cell to investigators the classic and only authentic form of incon- its daughters and their progeny (8). Although each cell tentia pigmenti, not deserving the suffix “II” (11). This expresses only one X chromosome or the other, compen- disorder results from mutations of the gene on Xp28 (12) sation is frequently possible. Most recessive mutations encoding NEMO (13), a factor essential for the activa- encode soluble enzymes, normally synthesized in suffi- tion of the transcription factor, NF-kappa-B. Complete cient excess to compensate for haploinsufficiency—that absence of this critical factor in affected males leads to GENETIC DISORDERS IN WOMEN 93 death in utero, presumably because all their cells are vul- berry aneurysm disease, resulting from mutation in either nerable to pro-apoptotic signals. In half of the cells of a the membrane-bound polycystin I (24) or polycystin 2, heterozygous female, however, intact NEMO is expressed with which it heterodimerizes (25) to form an active sig- from the normal X chromosome, permitting her survival. nalling complex. Shortly after birth, heterozygous females develop ery- With rare exceptions, the CHILD syndrome (con- thema, vesicles, and pustules that become verrucous and genital hemidysplasia with ichthyosiform erythroderma hypertrophic. In adolescence, these skin lesions become and limb defects) is seen only in females (26). This is one atrophic, hypopigmented linear streaks. They disappear of a growing list of developmental defects associated with by the age of 20 years, presumably because of selection mutations affecting cholesterol synthesis, resulting from against cells expressing the mutant NEMO allele and sur- mutations in the NSDHL gene at Xq28 (27). The hall- vival of only those cells expressing the normal, wild-type mark of this X-linked disorder is an ichthyotic erythro- allele (14). Alopecia, retinal vascular changes with cica- derma with ipsilateral malformations, particularly trization, peg-shaped teeth, unilateral breast aplasia, and absence or dysplasia of a limb (28). The hemidysplasia dystrophic nails have also been observed accompanying can affect not only the limbs but also parts of the central the mental retardation, spastic tetraparesis, and micro- nervous system (CNS)—brain stem, cerebellum, and cephaly. There are varying degrees of involvement, even spinal cord, with unilateral absence of the trigeminal, within the same pedigree, where all affected individuals facial, auditory, glossopharyngeal, and vagus nerves (29). must have the same allele, presumably because of varia- As indicated by its name, a hallmark of CHILD syndrome tions in the pattern of lyonization. The vast majority of is its extreme lateralization.However, it may exception- cases are in females, although incontinentia pigmenti type ally result in almost symmetric skin lesions (27). In one II was once observed in an XX male (15) and was once reported case, there was also a myelomeningocele (30). transmitted to paternal half sisters by an asymptomatic Another developmental disorder of cholesterol father, presumably a gonadal mosaic (16). metabolism is associated with a deficiency of 3-beta- Other syndromes of pigmentary cutaneous abnor- hydroxysteroid-delta(8), delta(7)-isomerase (31), the X- malities and mental retardation can cause diagnostic con- linked dominant chondrodysplasia punctata 2 (Conradi- fusion. Chief among these are a sporadic Xp11-autoso- Hunermann-Happle syndrome; CDPX2). CDPX2 mal translocation disorder, incorrectly named accounts for about one-quarter of the cases of this group incontinentia pigmenti type I (17), and hypomelanosis of of skeletal dysplasias associated with linear or whorled Ito, a syndrome associated with chromosomal mosaicism, pigmentary skin lesions. It is the only form that is X- in which the hypopigmented skin lesions (best seen under linked dominant, lethal in utero to males (32), with only a Wood lamp) do not undergo a prodromal phase (18). affected females surviving to manifest the syndrome. With rare exceptions, oral-facial-digital dysplasia Unlike the CHILD syndrome, CDPX2 typically shows (OFD) type I (19) has only been observed in females. In mild to moderate assymmetry, but occasionally may be this disorder, malformation of the brain results in a sta- extremely lateralized. Another striking feature of tic encephalopathy with mental retardation, a nonspecific CDPX2 is anticipation, perhaps resulting from skewed neurologic finding. This results from a variety of muta- gene methylation rather than the more widely recognized tions in the previously uncharacterized chromosome X mechanism of triplet repeat expansion (33). Linear skin open reading frame 5 (CXORF5) (20), thereby estab- defects are also seen in microphthalmia with linear skin lishing the important role of this presumed microtubular defects (MIDAS syndrome: microphthalmia, facial der- regulator in human development (21). Diagnosis is made mal hypoplasia, sclerocornea), a male-lethal disorder by recognition of characteristic facial and hand anom- associated with the absence of the Xp22 band, in which alies. There are abnormal oral frenulae, with clefting of is encoded mitochondrial holocytochrome c synthase the jaw and tongue in the area of lateral incisors and (34). In addition to the linear skin defects and microph- canines, as well as irregular, asymmetric clefts of the thalmia with sclerocornea, agenesis of the corpus callo- palate. Hand abnormalities include syndactyly (incom- sum occurs. An exceptional case was reported in two pletely separated fingers), clinodactyly (curved fingers), phenotypically male twins with an XX karyotype. The brachydactyly (short fingers), and occasional postaxial male phenotype was conferred by the abnormal presence polydactyly (extra fingers on the ulnar side). Radiographs of the Sry gene, the result of a subtle XY translocation of hands and feet show irregular mineralization, distin- (35). guishing this disorder from OFD II (22), a disorder that The best known X-linked male-lethal disorder asso- is also associated with heart defects. Later in life, some ciated with agenesis of the corpus callosum is Aicardi syn- individuals develop polycystic kidneys and renal failure drome (36), for which lacunar choreoretinopathy and (23), an important consideration in the management of infantile spasms complete the diagnostic triad. Evidence these patients and a possible source of diagnostic confu- for X-linked inheritance comes from family studies that sion with classic autosomal dominant polycystic kidney— show a high spontaneous abortion rate in mothers of 94 NEUROLOGIC DISEASE IN WOMEN

affected girls, as well as a skewed ratio of unaffected male pedigree and studies of lyonization, however, had argued to female siblings (37). Presumably, affected females result against a simple X-linked hypothesis (47). from the new onset of an X-linked dominant mutation The X-linked model was finally confirmed by that is lethal to male fetuses. After presentation with demonstrating pathogenic mutations in the gene in Xp28 infantile spasms, affected females continue with lifelong encoding methyl-CpG-binding protein-2, a regulator of mental subnormality and an epilepsy that is quite diffi- chromatin structure. Mutations in the same gene have cult to control. The characteristic anatomic findings are been found responsible for about half the cases of the pre- agenesis (72%) or hypoplasia (28%) of the corpus callo- served speech variant (PSV) of Rett syndrome (48,49). sum (37) and chorioretinal lacunae in a highly specific Further evidence for the importance of the MECP2 gene pattern. Costovertebral defects such as hemivertebrae, is provided by independent reports of severe neurodevel- scoliosis, and malformed or absent ribs are also common. opmental defects, including a case of otherwise typical The degree of psychomotor retardation is variable, appar- Rett syndrome in boys with normal karyotypes and ently reflecting the pattern of lyonization (38), further evi- somatic mosaicism for MECP2 (50,51). dence for X-linked dominant inheritance. In addition to Sex-linked male-lethal inheritance has been pro- brain heterotopias, there have been several reports of posed for the Wildervanck cervicooculoacoustic syn- Aicardi syndrome in association with benign or malig- drome, the juxtaposition of congenital perceptive deaf- nant tumors of the CNS or periphery—choroid plexus ness with bony abnormalities of the inner ear, the papilloma and gastric polyps (39) and scalp lipomas as Klippel-Feil anomaly, and Duane abducens palsy with well as malignant cavernous hemangioma of the leg with retractor bulbi (52). Abducens palsy appears to be the angiosarcomatous metastases (40). most variable part of this syndrome, but Klippel-Feil cer- Unlike the previously described X-linked male-lethal vical vertebral anomalies are more common. Indeed, such disorders, in which characteristic systemic features per- vertebral anomalies occur in 1% of deaf women. Similar mit clinical diagnosis, abnormalities in periventricular inheritance has been proposed for the less common heterotopia are confined to the nervous system (41). Mul- CODAS syndrome (cerebral, ocular, dental, auricular, tiple uncalcified nodules appear on the lateral ventricu- and skeletal anomalies), thus far reported in only two lar walls, sometimes causing diagnostic confusion with unrelated females (53), a segregation pattern for which tuberous sclerosis, which differs from this disorder by the autosomal inheritance is equally plausible. Further, but as presence of depigmented ash-leaf spots, periungual fibro- yet inconclusive, evidence against X-linked inheritance, is mas, and mental retardation. Some females with charac- provided by reports of typically affected males (54). A teristic MRI scans are asymptomatic, whereas others have slowly progressive limb-girdle form of muscular dystro- seizures, sometimes severe (42). phy limited to females has been reported in several fam- Several other disorders of girls appear in which X- ilies (55). The observed pattern of inheritance is compat- linked male-lethal inheritance had long been suggested ible with either X-linked male-lethal or a sex-limited but in which proof of such a mechanism proved elusive. autosomal dominant trait. The best known of these disorders is the Rett syndrome, a distinctive progressive encephalopathy characterized by Sex-Linked Disorders with Milder autism, loss of purposeful hand movements, and an Manifestations in Females acquired microcephaly (43). Characteristically, these girls show normal development until 7 to 18 months of age, Most sex-linked disorders are present in men, with only an essential criterion for clinical diagnosis (44). Deceler- minor if any manifestations in females. In certain circum- ation of linear growth is the first sign of a 1.5-year period stances, however, the clinical phenotype in women can be of illness, during which time the affected girl develops significant, sometimes differing from the classic phenotype microcephaly, severe dementia, truncal ataxia, and pecu- in males and thus causing diagnostic confusion. liar wringing hand movements. After this period of decline, the course stabilizes, resulting in a profound but Duchenne Muscular Dystrophy: subsequently nonprogressive encephalopathy. Other fea- The Best Studied Example tures include seizures, spastic paraparesis, and vasomo- tor abnormalities of the lower limbs. By analogy to the The most common X-linked single gene disorder in Aicardi syndrome, it had been proposed that most girls humans is Duchenne muscular dystrophy (DMD). Boys with Rett syndrome harbor new mutations of an unspec- affected with DMD develop gait difficulty and calf hyper- ified gene on the X-chromosome that is lethal to males trophy as toddlers, need wheelchairs by the end of the first (43). A few instances of affected sisters in which inheri- decade of life, and succumb by the end of the second tance from a germinally mosaic mother could be posited decade. In the allelic disorder, Becker muscular dystrophy (43), and reports exist of two patients with a balanced (BMD), onset and progression of symptoms is signifi- translocation involving the X chromosome (45,46). Other cantly delayed, and affected individuals survive into mid- GENETIC DISORDERS IN WOMEN 95 dle age. The gene encoding dystrophin—mutant in surement of creatine kinase in the serum. Improvement in Duchenne and in Becker muscular dystrophy—enjoys the accuracy of carrier detection is only afforded by the pride of place as the first gene discovered by the now com- clonal analysis of myoblasts cultured from biopsied mus- monplace process of positional cloning, then called cle from putative carriers (61). Although highly accurate, reverse genetics (56). For these two reasons, the expres- this tissue culture procedure is very expensive. sion of this gene in female heterozygotes has been stud- In a small proportion of women, DMD not only poses ied more carefully than has that of any other. Lessons a concern for their offspring, but also affects their own learned from DMD and BMD illuminate our under- health. Approximately 2.5% of DMD heterozygotes have standing of less well characterized X-linked diseases and symptoms, usually a limb-girdle weakness of later onset, are considered in some depth. sometimes asymmetric and usually much milder than that Duchenne muscular dystrophy affects 1 in 3,300 live- of affected boys (62). Although the proportion of mani- born males, most of whom neither have had, nor will have, festing heterozygotes is low, the frequency of DMD muta- another case in their families (57). Because affected males tions in most populations is much higher than that of auto- virtually never survive into reproductive years, the half-life somal recessive limb-girdle dystrophies. Thus, a girl with of a given DMD mutation is only one generation. The dis- a limb-girdle dystrophy is as likely to have DMD as an order remains common in all populations despite this autosomal recessive sarcoglycanopathy. In a large survey strong selection pressure only because of the high rate of of myopathic women with negative family history, elevated new mutations. DMD and BMD carrier females are more levels of serum creatine kinase, and myopathic muscle common than are affected heterozygote males, but most biopsy, 10% were found to have a dystrophinopathy (63). have no detectable muscle weakness. Thus, for women, the Although most manifesting carriers have a mild most common clinical problem posed by DMD or its limb-girdle phenotype, a small proportion have a severe milder allelic variant, BMD, is the birth of an affected son. progressive classic DMD phenotype. In all severely If the son represents a new mutation, the risk to future affected females, there has been a radical departure from pregnancies is negligible. If, however, the woman is an the expected 50–50 pattern of lyonization. Typical DMD unaffected carrier, half of her sons will be affected by this has been described in a phenotypic female with Turner devastating disorder. Determining carrier status is there- syndrome, thus an XO hemizygote (64), and in approx- fore a matter of considerable importance. imately a dozen women with X-autosomal translocations. Approximately 70% of female heterozygotes for These translocations inactivated the dystrophin gene in DMD have an elevated level of creatine kinase in the the Xp21 band of one of the X chromomes, but also stuck serum. The creatine kinase levels tend to be higher in on a piece of autosome that effectively required that the younger carriers and to decrease with age (58). Efforts derivative chromosome be expressed in order for the cell to improve the accuracy of carrier prediction have been to survive. Only the cells that lyonized the normal X chro- only partially successful. The most convenient of these mosome survived in the mosaic. Thus, the only X chro- methods is DNA analysis, which demonstrates a mosome active in these girls was the one that had dis- detectable deletion or insertion in the dystrophin gene in rupted the dystrophin gene. Such translocation females 90% of affected males (59). Once detected in an affected were instrumental in the search for the dystrophin gene hemizygous male, the deletion or insertion can be (65) because the translocation points proved easy targets searched for in female relatives, albeit often with con- for molecular biologists. siderable technical difficulty because of the normal allele More commonly, women with a typical severe DMD present on the other X chromosome. phenotype are one of a pair of discordant monozygotic An alternative method, staining for dystrophin pro- twins. All monozygotic female twins heterozygous for a tein with antibodies in muscle biopsies of many het- DMD mutation are discordant—one twin severely erozygote females, has demonstrated dystrophin-negative affected, the other one completely well. In all reported myofiber segments (60). The majority of myofibers in het- cases, the manifesting twin has disproportionately erozygotes, however, have no detectable deficiency of dys- lyonized the normal X chromosome. The normal twin has trophin. Each myofiber is a multinucleated syncytium had skewed X-inactivation in the opposite direction (66) derived from the fusion of hundreds of mononuclear or a normal pattern of inactivation (67). These findings myoblasts, some of which have lyonized the paternal X suggest that twinning takes place after lyonization, with chromosome, others the maternal. In the majority of a small proportion of the inner cell mass breaking off and myofiber segments, dystrophin produced by normal then catching up with the normal twin, albeit with a skew nuclei is sufficient to compensate for segments served by resulting from small initial sampling (68). Another pat- mutant nuclei. Indeed, a mosaic of dystrophin-negative tern of skewed X-inactivation appears to result not from myofibers has only been detected in those obligate carri- twinning, but from an as yet obscure mechanistic inter- ers who have an elevation of serum creatine kinase. Thus, action between paternal inheritance and the development staining of muscle sections is no more sensitive than mea- of new dystrophin mutations (69). 96 NEUROLOGIC DISEASE IN WOMEN

Another manifestation of DMD in females is car- A different pattern of mildly affected females is seen diomyopathy. Unlike the multinucleated myofibers of in other X-linked muscle diseases. Myotubular or cen- skeletal muscle, cardiac myocytes are mononuclear; a car- tronuclear myopathy exists in several different forms: a diac monocyte expressing mutant dystrophin from its very well documented X-linked recessive neonatal form active X chromosome receives no protection from neigh- that is lethal in infancy, a less well documented mild auto- bors that have lyonized in the opposite direction. From somal dominant form, and an autosomal recessive form 6.6% to 16.4% of DMD carrier females have electro- of intermediate severity that begins in late infancy or early cardiographic abnormalities. A smaller proportion have childhood (79). Males affected with the X-linked type frank cardiomyopathy in the presence or absence of limb [now known to result from a mutation affecting a puta- weakness (70). Similarly, certain mutations affecting the tive tyrosine phosphatase, myotubularin (80)] are born as amino terminal end of the dystrophin molecule result in floppy infants with polyhydramnios, external ophthal- X-linked dilated cardiomyopathy—congestive heart fail- moplegia, weakness of facial and cervical muscles, and ure in teenaged males and older women (71). respiratory insufficiency leading to death in infancy. The clinical presentation is similar to that of neonatal myotonic dystrophy. Unlike mothers with the autosomal Other X-Linked Myopathies dominant myotonic dystrophy, however, mothers of male Similar patterns have been seen in other X-linked infants with X-linked myotubular myopathy do not show myopathies not related to the dystrophin gene. Men facial weakness, cataracts, or myotonia, although they affected with Dreifuss-Emery muscular dystrophy may show mild abnormalities on muscle biopsy (81). An develop a characteristic syndrome of delayed weakness interesting possible exception to the general rule of non- with early contractures of the elbows, Achilles tendons, manifesting carriers was related by Torres, who reported and posterior cervical muscles (72). Additionally, the a mixed brain stem, peripheral nerve, and myopathic dis- men have pectus excavatum and a cardiomyopathy order in a mother of boys with neonatal lethal centronu- beginning with atrioventricular block. In contrast, the clear myopathy (82). only manifestation in females is cardiac disease with In other X-linked myopathies, the only manifesta- atrial arrhythmia, which is sometimes lethal (73). Car- tion in female heterozygotes is minimal nonspecific diac involvement had been thought to result from selec- changes on muscle biopsy. Asymptomatic female carri- tive localization of emerin, the protein primarily affected ers of fingerprint myopathy have such changes rather than in this disorder, in the intercalated discs of cardiomy- the characteristic fingerprint bodies found in the periph- ocytes. Subsequent studies with better antibodies, how- ery of the sarcoplasm in hemizygote boys (83). ever, demonstrated emerin only in the nuclear member of cardiomyocytes (74). X-Linked Peripheral Neuropathies A similar mechanism probably underlies selective cardiac involvement in female carriers of yet another X- Several forms of X-linked neuropathy exist, distinguish- linked disorder, the exceedingly rare syndrome of scapu- able by clinical features, map position, or both. Several of loperoneal muscular dystrophy, mental retardation, and these X-linked forms have been referred to as Charcot- lethal cardiomyopathy reported by Bergia. Affected boys Marie-Tooth disease. Thus, just like myotubular myopa- begin mental deterioration at the age of 5 years, followed thy, spastic paraplegia, and retinitis pigmentosa, Charcot- by humeroperoneal muscular dystrophy and lethal hyper- Marie-Tooth disease(s) can be either autosomal or trophic cardiomyopathy when they are teenagers. In con- X-linked. In X-linked dominant Charcot-Marie-Tooth dis- trast, the female carriers have a cardiomyopathy with- ease (CMTX1), women are affected less severely than are out skeletal muscle involvement (75). men. Careful inspection of pedigrees demonstrates that this Another type of difference between multinucleated is a true sex-linked disorder rather than a sex-limited skeletal myotubes and mononucleated cells is suggested expression of an autosomal dominant Charcot-Marie- by the X-linked deficiency of phosphoglycerate kinase Tooth disease. Affected men transmit the disorder to all (PGK1). Affected men have recurrent myoglobinuria of their daughters but to none of their sons. Affected moth- brought on by exercise-induced rhabdomyolysis, as well ers transmit to half of their sons and to half of their daugh- as mental retardation, epilepsy, and hemolysis (76). In ters, a classic pattern of X-linked transmission. This map contrast, reported women show only hemolytic anemia location has been confirmed and refined to Xq13 by link- (77). Alternatively, these differences may be attributed age studies using DNA markers. This is primarily an to unique properties of individual PGK mutants. No axonal degeneration with secondary changes in peripheral reports appear of clinical abnormalities in females het- myelin, with some affected males showing deafness. erozygous for mutations of the alpha subunit of phos- Affected women show mild clinical signs, including phorylase kinase, responsible for a rare X-linked muscle decreased nerve conduction velocities but no functional glycogenesis in hemizygous males (78). disability (84). In an exceptional family segregating a GENETIC DISORDERS IN WOMEN 97 mutation in the same locus as CMTX1, episodes of tran- can be very severe, including debilitating autonomic neu- sient paraparesis, monoparesis, tetraparesis, dysarthria, ropathy (95), renal failure, cardiomyopathy (96), and aphasia, and cranial nerve palsies occured associated with involvement of the CNS (97). A study of 60 obligate car- reversible white matter lesions on MRI (85). In addition rier females demonstrated painful neuropathy in 70% to this disorder, which is now demonstrated to be caused and other serious systemic manifestations in 30%, includ- by mutations affecting connexin-32 (86), there is also linking renal failure and stroke (98). age evidence for two separate loci—CMTX2 at Xp22.2 In other X-linked disorders, peripheral neuropathy and CMTX3 at Xp26—encoding X-linked recessive forms or sensory ganglionopathy may be the only manifestation of Charcot-Marie-Tooth disease, so called because het- in female heterozygotes of a more complex multisystem erozygous women usually do not show signs of the disease disorder in males. In the myopia-ophthalmoplegia syn- (87). drome, some carrier women have only areflexia, but not Unfortunately, Charcot-Marie-Tooth disease has also the ophthalmoplegia, pupillary abnormalities, chori- been applied to several other more complex neurologic dis- oretinal degeneration, and cardiac and spinal malforma- eases with severe involvement in men and mild involve- tions that are seen in affected male relatives (99). ment in women. In the Cowchock variant of Charcot- Marie-Tooth (CMT2D), male infants are severely weak X-Linked Motor Neuron Disorders and most are either deaf or mentally retarded. Obligate heterozygote females are asymptomatic, although some The first motor neuron disease in which the underlying show minor inconsistent alterations in hearing, on sensory biochemical defect was discovered genetically is X-linked nerve conduction studies, and on electromyography (88). Kennedy spinobulbar atrophy, which is caused by expan- Earlier speculations to the contrary, linkage studies clearly sions of triplet repeats at one end of the gene encoding the demonstrate that the so-called Cowchock variant is not an androgen receptor (100). This was also the first demon- allelic variant of CMTX1 (89) because it maps to Xq24- stration of expansions of triplet repeats as a pathogenic q26. In another so-called X-linked recessive CMT variant, mechanism, now demonstrated in half a dozen other a Schwann-cell form of sensorimotor neuropathy associ- human disorders, all of which affect the nervous system. ated with aplasia cutis congenita of the scalp, with under- Mutations at the other end of the androgen receptor cause lying bony defects of the calvarium in affected males, but the distinct syndrome of testicular feminization—normal only minor distal wasting and denervation in asympto- female secondary sexual characteristics in XY males, who matic female heterozygotes (90). In the Rosenberg-Chutor- are infertile but have no motor neuron disease. Men with ian syndrome, affected males have a sensorimotor neu- Kennedy syndrome develop gynecomastia in their teens ropathy reminiscent of Charcot-Marie-Tooth disease as and are usually impotent, but sometimes are fertile (101). well as sensorineural deafness and optic atrophy (91). In Atrophy and fasciculations of the bulbar muscles begin contrast, heterozygous women show only slowly progres- anywhere from the twenties to forties. We have seen one sive hearing loss (92). phenotypic XY woman with testicular feminization and A small-fiber neuropathy quite distinct from Char- a bulbar spinal muscular atrophy. There is an increased cot-Marie-Tooth disease is a cardinal manifestation of frequency of the Kennedy triplet repeat expansion in Fabry disease, an X-linked multisystem disorder resulting women with polycystic ovary syndrome as well as prefer- from a deficiency of ceramide trihexosidase (also known ential expression of the expanded triplet repeat, compared as alpha-galactosidase) and the resultant vascular depo- with that seen in the general population (102). [However, sition of lipid (93). In addition to a painful small-fiber there has been no report of clinical or subclinical neuro- neuropathy with autonomic involvement and abdominal logic involvement in true female carriers in this disorder or crises, the full syndrome includes a characteristic whorl- in the other X-linked motor neuron disease, lethal infan- like corneal dystrophy, as well as infarctions in the retina tile sex-linked spinal muscular atrophy (SMAX2) (103).] and in the kidney. Whereas renal failure had previously Motor neuron disease may underly some forms of led to death by the third decade, longer survival result- distal infantile arthrogryposis, of which there may be as ing from renal transplantation has permitted survival to many as three distinct X-linked types (104). In one such a later stage manifesting multiple large- and small-vessel family, the disease was transmitted to severely affected infarctions of the CNS. Affected males are easily recog- male infants by female carriers, who themselves had nized by a purpuric skin rash for which the disorder was milder manifestations such as minimal muscle weakness, given its other name, angiokeratoma diffusa. Corneal dys- kyphosis, contractures, and clubfoot (105). trophy is of similar severity in heterozygotes as in hemizygous males (94), but affected women almost never have X-Linked Spastic Parapareses the characteristic skin rash. Without the rash, the diagnosis is frequently overlooked. Although women tend to As in the case of Charcot-Marie-Tooth disease, myotubu- survive longer than do affected men, clinical involvement lar myopathy, and retinitis pigmentosa, hereditary spastic 98 NEUROLOGIC DISEASE IN WOMEN

paraparesis can segregate as either an autosomal domi- erozygous females from one such MASA family ranged nant, autosomal recessive, or X-linked trait. Three well- from adducted thumbs, learning abnormalities, or mild characterized X-linked spastic parapareses exist, all of mental retardation, to hydrocephalus that was lethal which can have significant clinical impact on heterozygous shortly after birth (114). women. Adrenoleukodystrophy (ALD) and the milder In addition to these three well-characterized X- adrenomyeloneuropathy (AMN) are alternate manifesta- linked spastic parapareses, there have been isolated tions of mutations affecting a recently discovered peroxi- reports of possible others. Mild spastic paraparesis was somal transport protein encoded by a gene near the distal the only sign in a girl whose brothers also had Kallman tip of the long arm of the X chromosome. The differences syndrome—hypogonadotrophic hypogonadism and between ALD and AMN—one a leukodystrophy of child- arrhinencephaly (115). The relevance of this isolated hood, the other a neuronopathy of adults—are not man- report is not clear, however. In autosomal Kallman syn- ifestations of different alleles at the same locus (106), but drome, associated with mutations in KAL1 of a secreted of an epistatic interaction from an as yet unidentified auto- protease inhibitor with repeats (116–117), no spastic somal modifier gene. In the presence of one form of this paraparesis occurs, but both transmitting females and putative modifier, affected boys develop rapidly progres- fully affected male heterozygotes have partial or complete sive ALD, which is lethal in mid-childhood, beginning with anosmia. In a study of X-linked Kallman syndrome that markedly inflammatory demyelination, typically beginning was confirmed by a demonstration of mutations in anos- in the occipital corona radiata and advancing frontally. In min, a regulator of migration of GnRH neurons and the absence of this modifier, a more slowly progressive olfactory nerves to the hypothalamus, there was no dis- AMN develops in late adolescence and progresses over a cernible phenotype in female obligate carriers (118). decade. Both disorders can coexist in the same pedigree, indicating that the same allele at Xp28 can give rise to X-Linked Ataxias and Movement Disorders either syndrome (106). In hemizygous males, adrenal insufficiency can occur as part of either syndrome, or as an iso- Gene mutations do not always observe the tidy anatomic lated Addisonism. Approximately 15% of female het- categories favored by neurologists. Nowhere is this mud- erozygotes develop a moderately severe spastic paraparesis dle more evident than in those neurodegenerative disor- (107), sometimes in association with a peripheral neu- ders in which pyramidal, extrapyramidal, and cerebellar ropathy (108) and sphincter disturbance (109). As is the signs coexist, often with spectacularly different degrees of case in all X-linked disorders, heterozygote females are relative severity, even within members of the same sibship. mosaics of cells that have lyonized either the normal or For example, a rare X-linked neurodegenerative disor- mutant gene. Uniquely among X-linked disorders, there der described by Malamud and Cohen begins with cere- is a selective advantage for cells expressing the mutant bellar ataxia and is later characterized by extrapyramidal ALD allele, resulting in their gradual outnumbering of signs (119). Both clincial and anatomic involvement of their normal fellows in the mosaic as she grows older. the cerebellum and basal ganglia are evident in a recently Unlike affected men, heterozygous women are unlikely to reported X-linked disorder with iron deposition in the have severe adrenocortical insufficiency, but they may be basal ganglia and neuroaxonal dystrophy similar to presdisposed to hypoaldosteronism when taking non- Hallervorden-Spatz-Pettigrew syndrome (120). Hemizy- steroidal anti-inflammatory drugs (110). gous boys show a Dandy-Walker malformation of the Certain mutations affecting proteolipid protein give cerebellum as well as choreoathetosis, severe mental retar- rise to a classic Pelizaeus-Merzbacher phenotype with a dation with seizures, and marked hypotonia that evolves leukodystrophy limited to the CNS, resulting in oculo- into spasticity. Although autopsy studies in a female car- motor apraxia, spastic ataxia, and parkinsonian features rier have shown iron deposition and neuroaxonal dys- that can present as early as 8 days of life and progress so trophy, the clinical manifestations were limited to a pre- slowly as to permit survival into middle age (111). Other senile dementia in one woman and mild intellectual mutations of the same X-linked gene give rise to a clas- impairment in others. sic spastic paraparesis (X-linked, type 2, SPPX2) with- Pelizaeus-Merzbacher disease, which was discussed out involvement of eye movements. Some of these segre- in the previous section in relationship to mutations of the gate as strict recessives; others are expressed frequently in proteolipid protein gene and a form of X-linked spastic females (112). paraparesis, would actually fit as nicely into this section Similarly, three disparate syndromes, MASA (men- as the previous one. Although Pelizaeus-Merzbacher distal retardation, aphasia, shuffling gait, adducted thumbs), ease is much more commonly observed in boys, an oth- X-linked aqueductal stenosis with hydrocephalus, and an erwise typical case occurred in a girl with no obvious X-linked spastic paraplegia, can result from different chromosomal abnormality (121). mutations in L1CAM gene, which encodes a neural cell Similarly, Menkes kinky-hair disease typically spares adhesion molecule (113). The clinical phenotype in het- girls but affects hemizygous boys, with severe cerebellar GENETIC DISORDERS IN WOMEN 99 and cerebral degeneration beginning in the first months mouth (134). In some family members, there is only early- of life, with concomitant growth failure, and death by the onset gout, whereas others develop the full syndrome. second year (122). The disease is named because of the Curiously, heterozygous females are on average no less characteristic fragile, microscopically twisted and frac- severely affected than are hemizygous males (135). tured hair shafts of variable diameter—pili torti—present The extent of clinical involvement of female het- in all affected boys and in 43% of carrier women (123), erozygotes differs in a variety of less well characterized usually the only clinical indicator of heterozygosity. A few X-linked cerebellar ataxias. Cerebellar atrophy and self- women, however, have had typical neurologic involve- limited episodes of ataxia were observed in mothers of ment. Among these are girls with a balanced transloca- boys with the ataxia-deafness syndrome: infantile hypo- tion X-autosomal translocation through Xp13 tonia, developmental delay, esotropia, optic atrophy, and (124–126), the site of the gene encoding the alpha ataxia progressing to death in childhood (136). In con- polypeptide of an adenosine triphosphate–dependent cop- trast, clinical manifestations in women heterozygous for per transporter, mutant in this disorder. Otherwise typi- Arts fatal X-linked ataxia and deafness appear to be lim- cal Menkes progressive encephalopathy was described in ited to mild hearing impairment in adulthood (137). Even three additional girls, one a Turner mosaic and the oth- less involvement of women is seen in the more commonly ers without demonstrable chromosomal alterations (127). observed X-linked cerebellar ataxia, for which the only Mild manifestations of the cutis laxa/occipital horn syn- reported manifesting female was an XO Turner hemizy- drome, recently shown to be allellic to Menkes (128), are gote (138). frequently seen in female relatives (129) of males affected It is distinctly unusual for women to be affected by with mild mental retardation, hyperelasticity of the skin, X-linked extrapyramidal disorders. The rare exceptions and characterisitic bony projections of the occipital bone include cytogenetically normal, presumably heterozygote pointing caudally from the foramen magnum. females as well as two women with balanced X-autoso- Two X-linked neurodegenerative disorders are asso- mal translocations (139), variably affected with the ciated with hyperuricemia: Lesch-Nyhan syndrome, a Goeminne TKCR syndrome—torticollis, keloids, cryp- movement and behavioral disorder resulting from inac- torchidism, and renal dysplasia (140). No affected carri- tivation of hypoxanthine-guanine phosphoribosyl trans- ers have been reported in the deafness-dystonia syndrome, ferase (HGPRT), and a less well known ataxia syndrome a progressive dystonia of boys with dysarthria and hyper- due to superactivity of phosphoribosylpyrophosphate activity that leads to severe disability and death in the synthetase-I (PRPS). Some mutations of either enzyme teenage years (141). Only one woman has been affected produce only gout and uric acid kidney stones, whereas with X-linked torsion-dystonia 3 (142), in which parkin- others produce a characteristic neurologic syndrome as sonian features are an early feature of a syndrome that well. The well-known Lesch-Nyhan syndrome—choreoa- begins in the thirties, often with spasmodic eye blinking, thetosis, self-mutilation, mental retardation, and spastic- and evolves into generalized dystonia within seven years. ity—has been reported virtually exclusively in males Two women were mildly affected in a family segregating (130). Clinically unaffected heterozygous girls can be the X-linked Waisman early-onset parkinsonism with shown to have two populations of red blood cells—one mental retardation, a syndrome that includes persistent defective in HGPRT, the other normal—but similar tests frontal release signs as a large neurocranium with frontal of adult heterozygote women demonstrate only one pop- bossing and, in some individuals, strabismus or seizures ulation, with normal HGPRT activity, indicating posi- (143). Variable expression was seen in some female relative selection for those red blood cell precursors that had tives of men affected with congenital hemiparesis and lyonized the mutant X chromosome (9,131). The one athetosis of the paretic upper extremity—hereditary hemi- exceptional case of a girl with a typical Lesch-Nyhan syn- hypotrophy, hemiparesis, and hemiathetosis. It is not clear drome had a deletion of the entire HGPRT gene on the from the single published pedigree if this is an X-linked maternally derived X chromosome and selective lyoniza- trait or a sex-modified expression of an autosomal trait, tion of normal paternal X chromosome (132). as suggested by the authors (144). In contrast, full or partial clinically evident involvement of women is more frequent in families segregating X-Linked Metabolic Encephalopathies an abnormality of PRPS. In addition to hyperuricemia, affected boys in some sibships develop sensorineural high- As a general rule, metabolic disorders segregate as reces- tone deafness, ataxia, peripheral neuropathy with axonal sive genetic traits, whether the gene encoding the relevant and demyelinating features, as well as renal failure (inde- enzyme lies on an autosome or on the X chromosome. pendent of hyperuricemia), sometimes leading to death in The reason for this pattern lies in the large margin of error early childhood (133). In some families, there are dis- built into most metabolic pathways. The flux of metabo- tinctive facial features—hypertelorism (widely spaced lites permitted by the half-normal amount encoded by the eyes) with a prominent forehead, beaked nose, and broad unaffected allele on the other chromosome is usually suf- 100 NEUROLOGIC DISEASE IN WOMEN

ficient for homeostasis. The exceptions to this remarkably (149). Many heterozygous girls are unaffected. Others durable clinical rule of thumb are few: (i) mutations of develop a lifelong habit of avoiding meat and other pro- key regulatory enzymes and/or of enzymes normally tein-rich foods. Some heterozygotes decompensate at working near their maximum velocity; and (ii) allosteric times of fasting, viral infections, or other catabolic stresses mutations affecting components of multisubunit enzyme into intermittent episodes of personality change and assemblies, in which a few mutant protein chains can ataxia that can evolve over hours into stupor or even allosterically poison a disproportionate number of nor- death from increased intracranial pressure. Initial mal subunits. episodes of hyperammonemic coma can occur quite late In addition to the two relentlessly progressive dis- in life, as postpartum coma (150) and after initiation of orders of uric acid metabolism described in the previous valproic acid therapy (151). More commonly, metabolic section, there are two major X-linked enzymopathies with decompensation in heterozygote females is self-limited. profound, but often intermittent, metabolic consequences There appears, however, to be a strong correlation in women—pyruvate dehydrogenase (PDH) deficiency, between long-term decrease in intellectual performance the most common form of primary lactic acidosis in either in heterozygotes and the number of such spells of meta- sex, and ornithine transcarbamylase (OTC) deficiency, bolic decompensation that were left undiagnosed and the most commonly occurring disorder of the urea cycle. untreated (152). In a given sibship, the phenotype of PDH is a massive multimer, visible on electron affected males can be so much more severe than that of micrographs as a particle about the size of a ribosome, affected sisters that neither parents nor physicians appre- containing multiple copies of three subunits, one of ciate that they are suffering from the same disorder. The which, the E1-alpha subunit, is encoded on the X chro- availability of effective dietary and pharmacologic treat- mosome. The majority of cases of PDH deficiency result ment for this disorder makes failure of diagnosis partic- from mutations of this X-linked subunit (145). This ularly tragic (153,154), especially given a heterozygote enzyme is the gatekeeper for partially metabolized prod- frequency of 1:25,000 that makes it at least as common ucts of the cytoplasmic Embden-Meyerhoff pathway as Guillain-Barré syndrome. Metabolic competence of seeking entry into mitochondria for completion of metab- female OTC heterozygotes can be assessed noninvasively, olism through the Krebs tricarboxylic acid cycle and sub- without recourse to a liver biopsy (155). sequently the electron transport chain. In the brain, PDH In other X-linked enzymopathies, female involve- typically is operating at approximately 75% capacity, ment has only been observed in exceptional circum- leaving little margin for error for such a key metabolic stances. Hunter syndrome (MPS II), the only X-linked step. Phenotypes resulting from mutation of the E1-alpha mucopolysaccharidosis, is a dwarfing dysostosis with subunit range from lactic acidosis that is lethal in infancy, atlantoaxial instability and hydrocephalus, coarse facies, to a Leigh’s polioencephalopathy in toddlers, to inter- intimal cardiac defects, and deafness in hemizygous boys. mittent ataxia in adults, depending on the nature of the The full syndrome has been observed in a girl who was mutation and the sex of the patient. Curiously, even one of a pair of discordant identical twins (156) [strongly though PDH deficiency has been reported approximately reminiscent of the assymetric lyonization seen in DMD as often in boys as in girls, almost all reported girls have female twins, as discussed above (68)] and also in a girl had deletions or insertions, whereas most of the presum- with a deletion of band Xq25, resulting in consistent ably milder missense mutations were reported in males. lyonization of that chromosome, with active expression It seems likely that females with mild missense mutations only from the other X chromosome, inherited from her tend to be overlooked, whereas boys with more severe mother, a biochemically proven heterozygote for deletion or insertion mutations die in utero (146). Unlike iduronate 2-sulfatase (157). many metabolic disorders, PDH deficiency can be associated with malformations of the brain, ranging from cor- X-Linked Nonprogressive Encephalopathies tical heterotopias and partial agenesis of the posterior corpus callosum to an olivopontocerebellar atrophy (147). A large number of disorders present with nonprogressive Although ornithine transcarbamylase (OTC) is not mental retardation, either with or without obvious struc- present in the brain (it functions mostly in the liver to con- tural malformations of the nervous system. More males vert waste nitrogen exported from the brain and else- are mentally retarded than are females (158). Although this where into excretable urea), the clinical phenotype asso- disproportion may result in part from sex-limited or sex- ciated with its deficiency is a profound encephalopathy modified expression of well-established autosomal traits, (148). The disease is usually recognized by neonatologists it seems likely that much of it results from mutations of in hemizygous males, who typically present in the first an as yet unspecified number of genes located on the X days of life with an alkalotic hyperammonemia, which, chromosome, which give rise to phenotypes that segregate if left undiagnosed and untreated, leads to coma with for the most part as recessives, with no detectable abnor- massive brain swelling and death over a period of days mality in women. However, in a few of these disorders, GENETIC DISORDERS IN WOMEN 101 phenotypic expression occurs in females, usually quite distinctive facial appearance consisting of ocular hyper- minor compared with that of hemizygous males. telorism with slight upslanting “antimongoloid” palpebral X-linked mental retardation can conveniently be fissures, anteverted nares, a broad upper lip, and a “pecu- divided into two general classes: (i) syndromic mental liar curved linear dimple of the inferior lower lip” (165). retardation, in which associated clinical or anatomic fea- Typically, this dimple is one of the facial stigmata seen tures permit a specific diagnosis; and (ii) nonspecific men- along with other facial and hand abnormalities as the sole tal retardation syndromes, in which mental retardation manifestation in females. The full syndrome, however, was segregates through a pedigree in a sex-linked pattern, but reported in a woman with an X-autosome translocation with no clinical features other than genetic linkage rela- and consistent inactivation of the normal X (166). A sig- tionships to permit distinguishing one from another. There nificant cause of preventable neurologic deficit in this syn- are currently 105 such mental retardation syndromes, drome is atlantoaxial instability resulting from an abnor- which likely will collapse to 10 to 12 loci encoding multi- mal dens and unusual laxity of the cruciate ligament. ple allelic syndromes after all the relevant genes have been The next most frequent syndromic X-linked mental identified and used to classify reported kinships (159). retardation syndrome (representing 20 of Fryns’s 682 cases) The most common of the X-linked mental retarda- is the Coffin-Lowry syndrome, the distinguishing features tion syndromes is the Martin-Bell fragile X-A syndrome, of which are tapering fingers and coarse facial features, with representing 560 cases in a survey of 682 cases of syn- patulous lips, bulbous nose, prominent brow, and dromic X-linked mental retardation made by Fryns (1). downslanting “mongoloid” palpebral fissures (166), result- FRAX-A is a syndrome of mental retardation, mild facial ing from mutation of the RSK2 kinase gene (167), a regu- dysmorphism, and testicular enlargement, associated with lator of chromatin structure, as is the gene product under- expansions of an extragenic triplet repeat that leads to lying Rett syndrome (168). Some affected individuals fragility of the chromosome in folate-deficient tissue cul- develop a compressive myelopathy form of excessive calci- ture medium. This chromosomal fragility previously fication of the ligamentum flavum (169) as well as exten- served as the basis of a diagnostic test before more con- sive diverticular disease from a visceral neuropathy (170). venient and reliable DNA-based tests became available. Unlike in the Aarskog-Scott males, mental deficiency in Cof- Unlike many of the other X-linked mental retardation fin-Lowry males is usually severe, the IQ of affected hem- syndromes, involvement of women is frequent and can be izygote males being 43.2, and of heterozygous females, 65 severe. A large majority of female heterozygotes have an (171). There have also been several reports of mildly affected IQ of less than 85 (160) and a clinically unexpected females with a depressive mood disorder (172) as well as the decrease in the size of the posterior cerebellar vermis distinctive hand, facial, and visceral manifestations. (161). The severity of mental impairment correlates with Facies sufficiently similar to cause diagnostic con- the proportion of active fragile X chromosomes. Other fusion with the Coffin-Lowry syndrome are seen in the features of the fragile X syndrome are seen less frequently nondeletion type of alpha-thalassemia mental retardation in heterozygous women. Approximately 40% of affected syndrome (173), most conveniently diagnosed by demon- adult women show other phenotypic characteristics, stration of hemoglobin H inclusions on a blood smear including the typical square-jawed face, irregular teeth, of affected boys. Similar inclusions were seen in very rare and ligamentous laxity in the fingers (160). Typical facial erythrocytes of female carriers, who were otherwise unaf- characteristics are more noticeable in women than in girls. fected except for some similarity of facial features. Two additional fragile sites appear on the X chromosome Although intellectual impairment of true genotypic (as well as dozens on autosomes), FRAX-E (162) and females has not been described, one can easily be mis- FRAX-F; the former has been implicated by some stud- led. Abnormalities of external genitalia commonly seen ies as another cause of X-linked mental retardation. Cryp- in this syndrome have led to female sex rearing of affected tic deletions at the FRAX-E site appear to be associated XY individuals (174). with premature ovarian failure (163). A disorder of similar frequency to that of Coffin- The next most common form of syndromic X-linked Lowry syndrome, 18 of 682 syndromic mental X-linked mental retardation, albeit mild, is the dysmorphic retardation cases in Fryns’s survey (1), was his own Aarskog-Scott faciogenital dysplasia syndrome, repre- Lujan-Fryns syndrome of mental retardation, psychosis, senting 60 of 682 cases in Fryns’s survey (1). This results marfanoid habitus, as well as a distinctive long, narrow from mutations of a Cdc42 guanine nucleotide exchange face with a high-arched palate and small mandible. Only factor, possibly a regulator of the subcortical actin one manifesting carrier female has been described (175). cytoskeleton and Golgi complex (164). Serious mental Several X-linked static encephalopathies without deficiency is unusual in this syndrome, but mild impair- distinguishing systemic or dysmorphic features can be ment of cognitive function is frequently seen in males. Iden- diagnosed because of characteristic neuroanatomic tifying stigmata in affected boys are a peculiar “shawl scro- abnormalities, recognizable by scanning or at post tum,” moderate short stature with brachydactyly, and a mortem. There have been reports of families segregating 102 NEUROLOGIC DISEASE IN WOMEN

an apparently X-linked migration disorder in which males which is characterized by hypertension, edema, and pro- are lissencephalic and women have band heterotopias teinuria, and the more severe condition of eclampsia, in (176)—failure of migration of neurons comprising lay- which there are superimposed neurologic symptoms of ers 5 and 6, particularly in the frontal and parietal lobes— seizures and coma (see also Chapter 16). Studies of detectable by scanning (177). This has been called the mother-daughter pairs have given evidence of a possible double cortex syndrome. Most affected women are men- genetic susceptibility to this spectrum of disorders (185). tally retarded and all have epilepsy, some severely so. Multiple studies have suggested that eclampsia occurs in Several other rarer syndromic X-linked mental retar- women who are homozygous for a relatively common dation syndromes exist in which karyotypically normal susceptibility gene(s) (186). At least one factor in such sus- female carriers have normal intelligence, but do show some ceptibility appears to be a common variant in the gene of the associated noncerebral manifestations typical of encoding angiotensin (187). affected males. These minor anomalies are usually trivial, of no clinical importance to the affected woman except, of Exacerbations of Preexisting Hereditary course, as sentinel signs warning of carrier status for a dis- Disorders during Pregnancy order that will be devastating to half of her male offspring. With few exceptions, including a woman with a balanced A question that frequently arises in the management of X-autosome translocation (178), the only manifestation in women with genetic disorders is whether pregnancy will female carriers of Lowe oculocerebrorenal syndrome are further jeopardize the affected woman’s health. In some mild “snowflake” lenticular opacities, which are asymp- disorders, this important question has been studied sys- tomatic but provide a sensitive and specific method of car- tematically; in others, answers to this important ques- rier detection (179). Similarly, some female carriers of the tion are anecdotal. In type IV Ehlers-Danlos syndrome, gene for syndromic X-linked mental retardation-type 4 the form associated with fragility of intracerebral and sys- with congenital contractures and low fingertip arches usu- temic blood vessels, there is a 25% mortality rate associ- ally have only a fingerprint pattern of low digital arches ated with each pregnancy. Death occurs from a variety (180); carriers of the Fitzsimmons mental retardation-spas- of causes including rupture of the aorta, vena cava, tic paraplegia-palmoplantar hyperkeratosis syndrome have uterus, or bowel (188). We have observed intracranial only palmoplantar hyperkeratosis (181); female carriers of hemorrhage during pregnancy in women with familial the Christian mental retardation abducens palsy and skele- intracranial cavernous hemangiomas (189). Others have tal dysplasia syndrome may have fusion of cervical verte- observed development of large extracerebral cavernous brae and short middle phalanges (182); female relatives malformations with subsequent high-output cardiac fail- of boys with the FG syndrome of mental retardation, large ure during pregnancy, followed by rapid resolution after head, and imperforate anus, have normal intelligence but delivery (190). Rupture of aortic aneurysms during preg- can have lateral displacement of the inner canthi and ante- nancy has been observed in the Marfan syndrome (191), rior displacement of the anus (183); the only manifesta- with some survivors suffering infarction of the spinal tion in a mother of a boy severely affected with Lenz dys- cord. Epidural anesthesia, which is commonly used in plasia (microphthalmia, mental retardation, and skeletal delivery, poses a significant risk of persistent leakage of anomalies), was a deformity of the fifth finger (184). cerebrospinal fluid in marfanoid women, who have very thin, often ectatic dural sacs. Serious thrombotic disease in either the arterial or venous circulation, systemically or SEX-LIMITED DISEASES in the CNS, has been observed in patients with antithrom- bin III deficiency (192), and this problem is exacerbated A difference in disease expression in men and women does by pregnancy. not imply that the disorder results from a mutation of a A single case has been reported of intraspinal hem- gene located on an X chromosome. A variety of anatomic, orrhage from a hemangioblastoma in a pregnant woman hormonal, and behavioral differences between the sexes with von Hippel Lindau (VHL) syndrome (193). Another can alter the expression of autosomally encoded and non- consideration in managing pregnancies in women with genetic disorders. Indeed, this is the subject matter of this VHL is the presence of pheochromocytomas, which occur entire book. In this section, I confine my comments to in 5.2% of all affected individuals (194). Pheochromo- effects of pregnancy on common autosomal disorders cytomas occur in lower frequency in von Recklinghausen affecting the nervous system. neurofibromatosis (NF I). These are but one of several factors contributing to a higher caesarean section rate (36%) in NF I than in the general population (9.1% to Toxemia of Pregnancy 23.5%). Other contributing factors include kyphoscol- Among the most serious disorders encountered during iosis, pelvic neurofibromata, and spinal cord neurofibro- pregnancy or shortly after delivery are pre-eclampsia, mas. Eighty percent of women reported an increase in GENETIC DISORDERS IN WOMEN 103 number or size of neurofibromata during pregnancy, with tion, characteristic patterns of dysmorphism, and mal- 33% noting a subsequent decrease in size after delivery formation. Complete aneuploidies result from nondis- (195). In contrast, a systematic study of bilateral acoustic junction, or errors of chromosome segregation during neurofibromatosis (NF II) found no adverse effects on meiosis, particularly in the first meiotic division. A dra- acoustic schwannomas or other tumors from either preg- matic increase in the rate of nondisjunction corresponds nancy or the use of contraceptives (196). There have been with advanced maternal age, with a sharp increase at age anecdotal reports of worsening during pregnancy with 35 years. Charcot-Marie-Tooth disease IB (198) and in familial brachial neuritis (198). X-Linked Inheritance Pregnancy can unmask metabolic deficiencies that are otherwise inapparent in female carriers of certain Sexual differences in disease transmission arise by any of autosomal recessive enzymopathies. Infants homozygous several mechanisms, not all of which are genetic. X-linked for mutations of the alpha subunit of trifunctional enzyme inheritance has been extensively considered earlier in this (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thio- chapter. To recapitulate, men transmit their single X chro- lase/Enoyl-CoA hydratase) succumb to a Reye-like meta- mosome to their daughters, and their single Y chromo- bolic encephalopathy, cardiomyopathy, and skeletal some to their sons. Male-to-male transmission of a dis- myopathy. Their heterozygous mothers are at risk for order rules out X-linked inheritance. Mothers transmit acute fatty liver of pregnancy (199,200). Acute fatty liver either their maternal or paternal X chromosome at ran- of pregnancy also has been associated with heterozygos- dom to either their daughters or their sons. ity for the beta subunit of trifunctional enzyme, long chain 3-hydroxyacyl-CoA dehydrogenase (201). Similar Mitochondrial Inheritance mutations more commonly give rise to hyperemesis gravidarum or to the HELLP syndrome, consisting of hyper- Mothers exclusively provide mitochondrial DNA to off- tension or hemolysis, elevated liver enzymes, and low spring of either sex. Not all mitochondrial DNA disor- platelets (202). Pregnancy has been reported to induce ders are maternally transmitted, however (205). The pat- photosensitivity, neurobehavioral manifestations, and tern of transmission relates in part to the severity of the jaundice in hereditary coproporphyria (203). Weakness mitochondrial mutation. Point mutations of protein-cod- of the intrinsic hand muscles recurred in the seventh ing genes that minimally disrupt enzymatic activity under- month of pregnancy and resolved 6 months later in a lie all known forms of Leber’s optic atrophy (206). Such woman affected with a newly described autosomal dom- mutations typically are present in homoplasmic (i.e., iden- inant neuronopathy associated with cataracts and skele- tical mitochondrial DNA in every cell) form in affected tal abnormalities (204). individuals and are transmitted by affected mothers to all their children of either sex, all of whom develop peri- papillary telangiectasias of the retina. For reasons that are TRANSMISSION OF GENETIC not yet understood, however, homoplasmic men are seven DISEASES BY WOMEN times as likely to develop optic atrophy as are women. A hypothesized X-linked modifier gene has recently been disproved (207). Point mutations of intermediate sever- Chromosomal Abnormalities ity, such as those disrupting tRNA genes in MELAS (208) In the general population, the major concern about the or MERRF (209) syndromes, or the ATPase subunit 6 maternal transmission of neurogenetic disease comes gene in one form of Leigh’s disease (210) are only toler- from chromosomal abnormalities—additional or missing ated in heteroplasmic form, with survival only permitted copies of an entire chromosome (aneuploidy). Anywhere by the compensatory presence of at least some normal from 15% to 50% of all pregnancies are lost in the first mitochondrial DNA in each cell. Therefore, mosaic 12 weeks, approximately half of them from chromoso- women transmit these mutations to their children in dif- mal abnormalities. Only a few aneuploidies permit sur- ferent proportions, with resultant differences in pheno- vival of the fetus until birth: (i) aneuploidies of sex chro- typic severity. The deletion mutations of mitochondrial mosomes, including approximately 1% of Turner cases DNA, responsible for the Kearns-Sayre syndrome and the (presumed mosaics); (ii) partial autosomal trisomies or closely related chronic progressive external ophthalmo- monosomies, in which only a part of an autosome is plegia (211), are the most severe. They, too, are present duplicated or missing; and (iii) complete trisomy of the in heteroplasmic form, but with rare exceptions appear smaller autosomes, with 21 causing Down syndrome, 18 as de novo mutations in affected individuals and are not causing Edward syndrome, and 13 causing Patau syn- transmitted from mother to child. Although a specific drome (2). All such autosomal aneuploidies cause pro- mitochondrial DNA deletion mutation has never been found neurologic deficits, intrauterine growth retarda- transmitted from generation to generation, a tendency to 104 NEUROLOGIC DISEASE IN WOMEN

generate new mitochondrial DNA deletions segregates ing spermatogenesis. This inequality explains why the as an autosomal dominant trait, the multiple mitochon- severe childhood-onset Westphal variant of Huntington drial DNA deletion syndrome (212), the result of muta- disease only occurs when the mutation is inherited from tion of an as yet unidentified nuclear-encoded protein that the father (214). In contrast, the severe infantile form of in some way disrupts mitochondrial DNA. Being auto- myotonic dystrophy only occurs when the transmitting somal dominant, this disorder can be transmitted by parent is the mother, but for a different reason. Sperm are either an affected father or mother. sensitive to the genes affected in myotonic dystrophy, with a resultant censoring of extreme expansions of paternal mutations; sperm with large expansions in this region do Genomic Imprinting not keep up with their fellows that have a smaller repeat Other sexual differences in disease transmission result length. By default, extreme expansions of the myotonic from genomic imprinting—the epigenetic inactivation of dystrophy type are only observed when the original muta- certain autosomal regions in a pattern that differs tion is transmitted by the mother (215). between spermatogenesis and oogenesis. As a result of such imprinting, certain autosomal regions inherited from Neural Tube Defects (NTDs) the mother are not equivalent to those inherited from the father. Although well-established in animals, the evidence Both genetic and nongenetic factors contribute to the for- for imprinting in humans is still indirect, coming mostly mation of spina bifida, which ranks with chromosomal from the observations of two neurogenetic syndromes abnormalities as a major cause of neurologic malforma- that result from similar mutations in 15q11-13 (213). tions detectable before birth. The major identified non- The Prader-Willi syndrome of moderate mental genetic factor is maternal deficiency in folic acid at the retardation, hypotonia, and failure to grow in infancy, time of conception. All women of childbearing age at risk followed by hypothalamic hyperphagia and obesity, for pregnancy are advised to take dietary supplements. results either from deletions of 15q11-13 of the paternally The U.S. Department of Agriculture is undertaking a pro- derived chromosome or from isodisomy for maternal gram of folate supplementation of common foodstuffs chromosome 15. Another more profound and easily dis- to ensure that women are not deficient in folate at the time tinguishable neurologic syndrome of profound mental of unplanned conception. Risk from both dietary and retardation and cerebellar ataxia, the Angelman syn- genetic factors can be calculated from the experience in drome, can also result from isodisomy 15 or deletions of previous pregnancies. In the absence of previously 15q11-13. Angelman syndrome cases, however, have affected siblings, the risk of anencephaly and spina bifida paternal isodisomy or deletion of maternal 15q11-13, the is 0.3% to 0.87% (216,217); with one affected sibling, reverse of the Prader-Willi syndrome. the risk is from 4.4% to 5.2%; with two affected siblings, the risk increases to 10%; and with three, to 25% (218). Expansion of Triplet Repeats Nongenetic Transmission An increasing number of neurogenetic disorders result from the instability of those stretches of DNA that contain The transmission of neurologic or psychiatric disorders multiple copies of the same trinucleotide, which are from one generation to another is not always mediated referred to as triplet repeats. A certain amount of repeti- by DNA. A well-studied example of nongenetic mater- tion is tolerable, but beyond a certain length, deleterious nal transmission of neurologic disease is phenylketonuria effects occur. The triplet repeats underlying FRAX-A and (PKU). Irrespective of their own genotype, children whose myotonic dystrophy lie in noncoding regions and appear mothers were not in good metabolic control during their to exert their effects by altering the transcription of the pregnancies have a much higher frequency of hypoplasia neighboring gene(s). In contrast, the triplet repeats in the of the corpus callosum, microcephaly, intrauterine growth olivopontocerebellar atrophies and Huntington disease are retardation, and congenital heart disease than do those intragenic and encode polyglutamine tracts that directly whose mothers were in good control (219). Indeed, all disrupt the function of the protein into which they are children born to PKU mothers, well-controlled or not, inserted. In both cases, the greater the length of the triplet suffer some degree of hyperactivity and other behavioral repeat, the more deleterious its effect. The number of tri- disorders (220). Metabolic abnormalities in mothers nucleotides in a repeat tends to increase each time the DNA affected with other genetic enzymopathies are anecdotally is replicated, particularly during the formation of gametes. reported to be harmful to genetically normal fetuses. For This causes “anticipation”—greater severity and earlier example, maternal hypoglycemia in a woman affected onset of disease in subsequent generations. For reasons not with von Gierke glycogen storage disease was suggested yet understood, the tendency of such triplet repeats to to be responsible for unexpected fetal death at 33 weeks’ increase in length can be different in oogenesis than dur- gestation (221). GENETIC DISORDERS IN WOMEN 105

Sample obtained at 16 to 18 weeks gestation

Elevated AFP Abnormal—at risk for Down syndrome or trisomy 18

Repeat AFP Normal–no further Ultrasound testing

Abnormal—ultrasound Wrong dates Normal 10 days for Down syndrome

4 weeks for trisomy 18

Wrong dates Anomaly Normal Amniocentesis Twins Fetal demise

Obstetric management Amniocentesis Amniocentesis Repeat triple screen for Obstetric management Obstetric management Obstetric management correct gestational age Option for termination Option for termination of pregnancy of pregnancy FIGURE 7.1

Triple screen procedure.

In addition to mitochondrial DNA and small ommendations for repeat testing, sonography, or amnio- metabolites, mothers exclusively provide the developing centesis, according to a protocol such as the one depicted fetus with other important nongenetic, cytoplasmic fac- in Figure 7.1. Such protocols have been devised to offer tors, such as drugs, immunoglobulins, and transmissible a meaningful balance of risk, cost, and provision of mean- pathogens, among them toxoplasmosis, cytomegalovirus, ingful information from which the mother can make an and the AIDS retrovirus. Furthermore, in most societies, informed decision about continuation of the pregnancy. there are significant differences in postnatal interaction Other neurogenetic disorders can be of concern with offspring, many of which have substantial influence either because of a positive family history or if parents on the transmission or expression of disease. These myr- come from ethnic backgrounds in which heterozygosity iad, potentially sex-specific influences range from breast for certain recessive disorders is frequent. In the latter cat- milk and subsequent choice of diet to language, other egory is Tay-Sachs disease, for which approximately 1 of learned behaviors, and socioeconomic status. 30 Ashkenazim and a similar number of French-Canadi- ans are heterozygotes (1). Testing for heterozygosity by biochemical testing has been widely sought by prospec- Genetic Counseling tive spouses to inform their choice of marriage partner Screening for NTDs and chromosomal abnormalities has and other reproductive options. become standard obstetric care. Special testing is advised A positive family history for other neurogenetic dis- in cases of advanced maternal age and in women who had orders can lead to special counseling and testing that previously given birth to children with aneuploidy or would not otherwise be part of routine obstetric care. NTDs. In many states, all pregnant women undergo Central to such endeavors is the accurate diagnosis of “triple screening,” which consists of testing of a venous affected family members. Although some of these disor- blood specimen for alpha-fetoprotein, estriol, and human ders can be detected biochemically or by determination chorionic gonadotropin, at 16 to 18 weeks’ gestational of DNA markers (Table 7.1 and 7.2), for the majority age. Abnormalities in this initial screening lead to rec- the diagnosis must be made clinically. Indeed, given the 106 NEUROLOGIC DISEASE IN WOMEN

current high costs of biochemical and DNA tests, “shot- TABLE 7.1 gun” laboratory testing for neurogenetic disorders is not X-Linked Neurogenetic Disorders Seen (Almost) a viable option; an informed clinician must choose what Exclusively in Females tests are appropriate in a given circumstance. Once the diagnosis of the affected relative(s) is secure, the genetic Definite • Aicardi syndrome counselor uses this information along with a knowledge • CHILD syndrome (congenital hemidysplasia, of the pattern of inheritance to calculate the risk to the ichthyosiform erythroderma, and limb defects) fetus. In many circumstances, the risk may be sufficient • Chondrodysplasia punctata, X-linked dominant form to advise special diagnostic testing by amniocentesis or • Incontinentia pigmenti, type II chorionic villus sampling. • Microphthalmia with linear skin defects The list of disorders for which such testing is avail- • Periventricular heterotopias able is growing monthly (1). Some of these tests are avail- • Rett syndrome able commercially, others only through special arrange- Probable ment with research laboratories. Other changes in this • Wildervanck syndrome (deafness, Klippel-Feil anom- rapidly evolving technology may soon include sampling aly, and Duane syndrome) of rare fetal cells in the maternal circulation, avoiding Possible some of the cost and the 1 in 300 complication rate asso- • CODAS syndrome (cerebral, ocular, dental, auricular, ciated with amniocentesis. However the technology skeletal) changes, certain things will remain constant. As in all • Hemizygous lethal muscular dystrophy branches of medicine, the obligation of the physician is to inform, not to coerce. The recognition of risk for a neu-

TABLE 7.2 X-Linked Neurogenetic Disorders Seen in Males and Females

MUSCLE DISORDERS