NEUROLOGIC DISEASE IN WOMEN 232 Breast-feeding is, in general, encouraged for women with epilepsy taking AEDs. The benefits of breast-feed- ing are believed to outweigh the risks associated with fur- ther exposure of the neonate to AEDs (96,98). Exceptions to this recommendation are made when the infant appears lethargic or irritable, or if there is feeding diffi- culty or poor weight gain. Further discussion regarding the concentrations of individual AEDs in breast milk is provided in Chapter 5. Concerns are mounting that exposure to AEDs in utero may confer long-lasting neurodevelopmental or neurocognitive deficits. Fetal head growth retardation and low intelligence (89,99) has been associated with the maternal use of AEDs. Although prospective trials are lacking, retrospective studies show that children exposed in utero to valproate in monotherapy or polytherapy are more likely to require special educational resources (100). Prospective studies are under way to better define the neu- rodevelopmental risks of AED exposure to the develop- ing brain. Recent efforts by the American Academy of Neu- rology (96) and the American College of Obstetric and Gynecologic Physicians (97) to highlight those issues rel- evant to the care of women with epilepsy will enhance clinician familiarity with these diverse health concerns. These professional efforts, as well as a large-scale pro- fessional and public initiative by the Epilepsy Foundation of America, provide the medical professional with infor- mation and educational resources to enhance the com- prehensive care of women with epilepsy. RESOURCES AVAILABLE FOR HEALTH CARE PROVIDERS AND WOMEN WITH EPILEPSY Epilepsy Foundation of America 4351 Garden City Drive Landover, MD 20785-2267 Telephone: 800-EFA-1000 Web site: www.efa.org The Antiepileptic Drug Pregnancy Registry Genetics and Teratology Unit 14CNY-MGH East Room 5022A Charlestown, MA 02129-2000 Telephone: 888-233-2334 Web site: neuro-www2.mgh.harvard.edu/aed/ registry.nclk The American Epilepsy Society 638 Prospect Avenue Hartford, CT 06105-4240 Telephone: 860-586-7505 Web site: www.aesnet.com References 1. Morrell MJ, Guidice L, Seale C, et al. Ovulatory dys- function in women with epilepsy receiving antiepileptic drug monotherapy: an interaction of syndrome and treatment. Ann Neurol 2002;52(6):704–711. 2. Fisher RS, Vickrey BG, Gibson P, et al. The impact of epilepsy from the patient’s perspective I. Descriptions and subjective perceptions. Epilepsy Res 2000;41:39–51. 3. Morrell MJ, Sarto GE, Osborne-Shafer P, Borda EA, Herzog A, Callanan M. Health issues for women with epilepsy: a descriptive survey to assess knowledge and awareness among healthcare providers. J Womens Health Gend Based Med 2000;9:959–965. 4. Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Min- nesota: 1935–1984. Epilepsia 1993;34(3):453–468. 5. Hauser WA, Rich SS, Annegers JF, Anderson VE. Seizure recurrence after a first unprovoked seizure: an extended follow-up. Neurology 1990;40:1163–1170. 6. Hopkins A, Garman A, Clarke C. The first seizure in adult life: value of clinical features, electroencephalog- raphy, and computerized tomographic scanning in pre- diction of seizure recurrence. Lancet 1988;1:721–726. 7. Annegers JF, Hauser WA, Elveback LR. Remission of seizures and relapse in patients with epilepsy. Epilepsia 1979;20:729–737. 8. Nelson KB, Ellenberg JH. Epidemiology of cerebral palsy. Adv Neurology 1978;19:421–435. 9. Hauser WA, Hesdorffer DC. Risk factors. In: Hauser WA, Hesdorffer DC, (eds.) Epilepsy: frequency, causes and consequences. New York, NY: Demos, 1990; 53–100. 10. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classifica- tion of epileptic seizures. Epilepsia 1981:22:489–501. 11. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syn- dromes. Epilepsia 1989:30(4):389–399. 12. Pearl PL, Holmes GL. Absence seizures. In: Dodson WE, Pellock JM, (eds.) Pediatric epilepsy: diagnosis and ther- apy. New York: Demos, 1993;157–169. 13. Panayiotopoulos CP, Obeid T, Waheed G. Differentia- tion of typical absence seizures in epileptic syndromes: a video-EEG study of 224 seizures in 20 patients. Brain 1989;112:1039–1056. 14. Sato S, Dreifuss FE, Penry JK. Prognostic factors in absence seizures. Neurology 1976;26:788–796. 15. Harding GFA, Jeavons PM. Photosensitive epilepsy. London: MacKeith Press, 1994. 16. Zifkin BG, Andermann F. Epilepsy with reflex seizures. In: Wyllie E, (ed.) The treatment of epilepsy: principles and practice, 2nd ed . Baltimore, Md: Williams and Wilkins, 1996;573–583. 17. Janz and Christian, 1957. 18. Wallace H, Shorvon S, Tallis R. Age-specific incidence and prevalence rates of treated epilepsy in an unselected population of 2,052,922 and age-specific fertility rates of women with epilepsy. Lancet 1998;352:1970–1973. 19. Aicardi J, (ed.) Infantile spasms and related syndromes. In: Aicardi J. Epilepsy in children. New York, NY: Raven Press; 1986;17–38. 20. Morrell MJ. Differential diagnosis of seizures. Neurol Clin 1993;11(4):737–754. SEIZURES AND EPILEPSY IN WOMEN 233 21. Lesser RP. Psychogenic seizures. Neurology 1996;46: 1499–1507. 22. Gumnit RJ, Gates JR: Psychogenic seizures. Epilepsia 1986; 27(S2):S124–S129. 23. Gates JR, Ramani V, Whalen SM, Loewenson RB. Ictal characteristics of pseudoseizures. Arch Neurol 1985; 42:1183–1187. 24. Leis AA, Ross MA, Summers AK. Psychogenic seizures: ictal characteristics and diagnostic pitfalls. Neurology 1992;42:95–99. 25. Feldhaus KM, Koziol-McLain J, Amsbury HL, Norton IM, Lowenstein SR, Abbott JT. Accuracy of three brief screening questions for detecting partner violence in the emergency department. JAMA 1997;277:1357–1361. 26. Betts T, Boden S. Diagnosis, management and progno- sis of a group of 128 patients with non-epileptic attack disorder. Part II. Previous childhood sexual abuse in the aetiology of these disorders. Seizure 1992;1(1):27–32. 27. Smith S, Woolley CS. Cellular and molecular effects of steroid hormones on CNS excitability. Cleve Clinic J Med , 2004;71(Suppl 2):S4–S10. 28. Woolley CS, Schwartzkroin PA. Hormonal effects on the brain. Epilepsia 1998;39(suppl 8):S2–S8. 29. Woolley et al. 1997. 30. Woolley et al. 1996. 31. Niijima and Wallace 1989. 32. Rosciszewska D. Epilepsy and menstruation. In: Hop- kins A, (ed.) Epilepsy. London: Chapman and Hall, 1987;373–381. 33. Diamantopoulos N, Crumrine P. The effect of puberty on the course of epilepsy. Arch Neurol 1986;43(9): 873–876. 34. Herzog AG, Klein P. Three patterns of catamenial epilepsy. Epilepsia 1996;37:83. 35. Abbasi F, Krumholz A, Kittner SJ, Langenberg P. New onset epilepsy in older women is influenced by menopause. Epilepsia 1996;37(5):97. 36. Harden CL, Pulver MC, Ravdin L, Jacobs AR. The effect of menopause and perimenopause on the course of epilepsy. Epilepsia 1999;40(10):1402–1407. 37. Herzog AG. Progesterone therapy in women with epilepsy: a 3-year follow-up. Neurology 1999;52(9): 1917–1918. 38. Mattson RH, Cramer JA, Collins JF. A comparison of valproate with carbamazepine for the treatment of com- plex partial seizures and secondarily generalized tonic- clonic seizures in adults. The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group. N Engl J Med 1992;10:327(11):765–771. 39. Mattson RH, Cramer JA, Collins JF, et al. Comparison of carbamazepine, phenobarbital, phenytoin and prim- idone in partial and secondarily generalized tonic clonic seizures. N Engl J Med 1985;313:145–151. 40. Merkatz RB, Temple R, Sobel S, Felden K, Working Group on Women in Clinical Trials. Women in clinical trials of new drugs: a change in Food and Drug Admin- istration Policy. N Engl J Med 1993;329:292–296. 41. FDA/DHHS. Guidelines for the study of and evaluation of gender differences in the clinical evaluation of drugs. Federal Register 1993;58(139):39406–39416. 42. Morrell MJ. The new antiepileptic drugs and women: efficacy, reproductive health, pregnancy and fetal out- come. Epilepsia 1996;37(S6):S34–S44. 43. DHHS. Additional DHHS protections pertaining to research, developemnt and related activities involving fetuses, pregnant women and human in vitro fertiliza- tion. Title 45. Code of Federal Regulations. Part 46, Sub- part B. March 15, 1994. 44. Institute of Medicine. Women and health research: eth- ical and legal issues of including women in clinical stud- ies. Washington D.C.: National Academy Press; 1994; 1–25. 45. Mattson RH, Cramer JA, Darney PD, Naftolin F. Use of oral contraceptives by women with epilepsy. JAMA 1986;256:238–240. 46. Pack AM, Morrell MJ. Adverse effects of antiepileptic drugs on bone structure. Epidemiology, mechanisms and therapeutic implications. CNS Drugs 2001;15(8): 633–642. 47. Webber MP, Hauser WA, Ottman R, Annegers JF. Fer- tility in persons with epilepsy:1935–1974. Epilepsia 1986;27:746–752. 48. Morrell MJ. Stigma and epilepsy. Epilepsy Behav 2002;3(6):S21–S25. 49. Schupf N, Ottman R. Reproduction among individuals with idiopathic/cryptogenic epilepsy: risk factors for reduced fertility in marraige. Epilepsia 1996;37: 833–840. 50. Schupf N, Ottman R. Likelihood of pregnancy in indi- viduals with idiopathic/cryptogenic epilepsy: social and biologic influence. Epilepsia 1994;35(4):750–756. 51. Dansky LV, Andermann E, Andermann F. Marriage and fertility in epileptic patients. Epilepsia 1980;21:261–271. 52. Jalava M, Sillanpaa M. Reproductive activity and off- spring health of young adults with childhood-onset epilepsy: a controlled study. Epilepsia 1997;38(5): 532–540. 53. Isojarvi JIT, Laatikainen TJ, Pakarinen AJ, Juntunen KTS, Myllyla VV. Polycystic ovaries and hyperandro- genism in women taking valproate for epilepsy. N Engl J Med 1993;329:1383–1388. 54. Bilo L, Meo R, Valentino R, Buscaino GA, Straino S, Nappi C. Abnormal pattern of luteinizing hormone pul- satility in women with epilepsy. Fertil Steril 1991;55: 705–711. 55. Herzog AG, Seibel MM, Schomer DL, Vaitukaitis JL, Geschwind N. Reproductive endocrine disorders in men with partial seizures of temporal lobe origin. Arch Neurol 1986;43:347–350. 56. Herzog AG, Seibel MM, Schomer DL, Vaitukaitis JL, Geschwind N. Reproductive endocrine disorders in women with partial seizures of temporal lobe origin. Arch Neurol 1986;43:341–346. 57. Drislane FW, Coleman AE, Schomer DL, et al. Altered pulsatile secretion of luteinizing hormone in women with epilepsy. Neurology 1994;44:306–310. 58. Meo R, Bilo L, Nappi C, et al. Derangement of the hypo- thalamic GnRH pulse generator in women with epilepsy. Seizure 1993;2:241–252. 59. Morrell MJ, Flynn KL, Seale CG, et al. Reproductive dysfunction in women with epilepsy: antiepileptic drug effects on sex-steroid hormones. CNS Spectrums 2001;6:771–786. 60. Isojarvi JIT, Parakinen AJ, Rautio A, Pelkoren O, Myl- lyla VV. Serum sex hormone levels after replacing car- bamazepine with oxcarbazepine. Eur Clin Pharmacol 1995;47:461–464. 61. Levesque LA, Herzog AG, Seibel MM. The effect of phenytoin and carbamazepine on serum dehy- droepiandrosterone sulfate in men and women who have partial seizures with temporal lobe involvement. J Clin Endocrinol Metab 1986;63:243–245. NEUROLOGIC DISEASE IN WOMEN 234 62. Stoffel-Wagner B, Bauer J, Flugel D, Brennemann W, Klingmuller D, Elger CE. Serum sex hormones are altered in patients with chronic temporal lobe epilepsy receiving anticonvulsant medication. Epilepsia 1998; 39:1164–1173. 63. Morrell MJ, Isojarvi J, Taylor A, et al. Higher androgens and weight gain with valproate compared with lamot- rigine for epilepsy. Epilepsy Res 2003;54:189–199. 64. Murialdo G, Galimbertu CA, Magri F, et.al. Menstrual cycle and ovary alterations in women with epilepsy on antiepileptic therapy. J Endocrinol Invest 1997;20(9): 519–526. 65. Polson et al. 1988. 66. Farquhar et al. 1994. 67. Clayton et al. 1992. 68. American College of Obstetric and Gynecologic Physi- cians. Polycystic ovary syndrome. Practice Bulletin #41. 2002;100(6):1389–1402. 69. Vainionpaa LK, Rattya J, Knip M, et al. Valproate- induced hyperandrogenism during pubertal maturation in girls with epilepsy. Ann Neurol 1999;45(4):444–450. 70. Isojarvi JIT, Rattya J, Myllyla VV, et al. Valproate, lam- otrigine, and insulin-mediated risks in women with epilepsy. Ann Neurol 1998;43:446–451. 71. Luef G, Abraham I, Haslinger M, et al. Polycystic ovaries, obesity and insulin resistance in women with epilepsy. A comparative study of carbamazepine and val- proic acid in 105 women. J Neurol 2002;249(7): 835–841. 72. Rasgon NL, Altshuler LL, Gudeman D, et al. Medica- tion status and PCO syndrome in women with bipolar disorder: a preliminary report J Clin Psychiatry. 2000;61(3):173–178. 73. O’Donovan C, Kusumakar V, Graves GR, Bird DC. Menstrual abnormalities and polycystic ovary syndrome in women taking valproate for bipolar mood disorder. J Clin Psychiatry 2002;63:322–330. 74. Akdeniz F, Taneli F, Noyan A, Yuncu Z, Vahip S. Val- proate-associated reproductive and metabolic abnor- malities: are epileptic women at greater risk than bipo- lar women? Prog Neuropsychopharmacol Biol Psychiatry 2003;27(1):115–121. 75. Ferin M, Morrell M, Xiao E, et al. Endocrine and meta- bolic responses to long-term monotherapy with the antiepileptic drug valproate in the normally cycling rhe- sus monkey. J Clin Endocr Metab 2003;88(6): 2908–2915. 76. Demerdash A, Shaalon M, Midori A, Kamel F, Bahri M. Sexual behavior of a sample of females with epilepsy. Epilepsia 1991;32:82–85. 77. Morrell MJ, Guldner GT. Self-reported sexual function and sexual arousability in women with epilepsy. Epilepsia 1996;37:1204–1210. 78. Guldner GT, Morrell MJ. Nocturnal penile tumescence and rigidity evaluation in men with epilepsy. Epilepsia 1996;37:1211–1214. 79. Morrell MJ. Sexuality in epilepsy. In: Engel J, Pedley TA, (eds.) Epilepsy: a comprehensive textbook. New York: Lippincott-Raven, 1997;2021–2026. 80. Morrell MJ, Sperling MR, Stecker M, Dichter MA. Sex- ual dysfunction in partial epilepsy: a deficit in physio- logical sexual arousal. Neurology 1994;44:243–247. 81. Annegers JF, Hauser WA, Anderson VE, Kurland LT. The risks of seizure disorders among relatives of patients with childhood onset epilepsy. Neurology 1982;32:174–179. 82. Ottman R, Annegers JF, Hauser WA, Kurland LT. Higher risk of seizures in offspring of mothers than of fathers with epilepsy. Am J Hum Genet 1988;43:257–264. 83. Ottman R, Hauser WA, Susser M. Genetic and mater- nal influences on susceptibility to seizures. An analytic review. Am J Epidemiol 1985;122:923–939. 84. Annegers JF, Hauser WA, Elveback LR, Anderson VE, Kurland LT. Congenital malformations and seizure dis- orders in the offspring of parents with epilepsy. Int J Epi- demiol 1978;7:241–247. 85. Treiman LJ, Treiman DM. Genetic aspects of epilepsy. In: Wyllie E, (ed.) The Treatment of epilepsy: principles and practice. Baltimore, Md: Williams and Wilkins, 1997;151–164. 86. Swatjes JM, van Geijn HP, Meinardi H, Mantel R. Fetal heart rate patterns and chronic exposure to antiepilep- tic drugs. Epilepsia 1992;33(4):721–728. 87. Teramo K, Hiilesmaa V, Brady A, Saarikoski S. Fetal heart rate during a maternal grand mal epileptic seizure. J Perinatal Med 1979;7:3. 88. Battino D, Granata T, Binelli S, et al. Intrauterine growth in the offspring of epileptic mothers. Acta Neurol Scand. 1992;86:555–557. 89. Hiilesmaa VK, Teramo K, Granstrom ML, Bardy AH. Fetal head growth retardation associated with maternal antiepileptic drugs. Lancet 1981;2:165–167. 90. Schmidt D, Beck-Mannagetta G, Janz D, Koch S. The effect of pregnancy on the course of epilepsy: a prospec- tive study. In: Janz D, Dam M, Richens A, (eds.) Epilepsy, pregnancy and the child . New York: Raven Press, 1982;39–49. 91. Tomson T, Lindbom U, Ekqvist B, Sundqvist A. Dispo- sition of carbamazepine and phenytoin in pregnancy. Epilepsia 1994;35:131–135. 92. Yerby MS, Friel PN, McCormick K. Pharmacokinetics of anticonvulsants in pregnancy: alterations in plasma protein binding. Epilepsy Res 1990;5:223–228. 93. McAuley JW, Anderson GD. Treatment of epilepsy in women of reproductive age: pharmacokinetic consider- ations. Clin Pharmacokinet. 2002;41(8):559-579. 94. Tran TA, Leppik IE, Blesi K, Sathanandan ST, Remmel R. Lamotrigine clearance during pregnancy. Neurology 2002;59(2):251–255. 95. Zahn CA, Morrell MJ, Collins SD, Labiner DM, Yerby MS. Management issues for women with epilepsy: a review of the literature. American Academy of Neurol- ogy Practice Guidelines. Neurology 1998;51:949–956. 96. American Academy of Neurology. Quality Standards Subcommittee. Practice parameter: management issues for women with epilepsy (summary statement). Neurology 1998;51:944–948. 97. American College of Obstetric and Gynecologic Seizure disorders in pregnancy. Physicians Educational Bulletin. 1996;231:1–13. 98. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–150. 99. Gaily E, Kantola-Sorsa E, Granstrom ML. Intelligence of children of epileptic mothers. J Pediatr 1988;113: 677–684 100. Adab N, Jacoby A, Smith D, Chadwick D. Additional educational needs in children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2001;70:15–21. oxemia of pregnancy (preeclampsia, or toxemia gravidarum) is a syn- drome that is characterized by preg- nancy-induced hypertension (PIH), proteinuria, and edema after week 20 of pregnancy. Although this complex disorder can involve a number of organ systems, its clinical presentation varies. Patients may present with multisystem failure that results in oliguria; disseminated intravascular coagulation (DIC); hemor- rhages into the liver; Hemolysis, Elevated Liver enzymes and Low Platelets (HELLP) syndrome; pulmonary edema; and a number of neurologic problems. The neurologic pre- sentation frequently includes confusion, headaches, visual hallucinations (from which the name eclampsia arises), and blindness. With the appearance of seizures or coma, the patient’s condition is that of eclampsia. No constant rela- tionship exists, however, between the various neurologic manifestations and the severity of preeclampsia. Seizures and ischemic events, for example, may appear with few heralding signs of preeclampsia (1). Worldwide, preeclampsia and eclampsia are major causes of perinatal morbidity and death (2). In the United States, 6 to 8% of pregnancies have preeclamptic complica- tions (3). This affects 5 to 10% of whites, 15 to 20% of black primigravidas, and up to 30% of twin pregnancies (4). The incidence of preeclampsia also has other demographic dif- ferences. It is most frequently seen in poorly nourished, nul- liparous woman, multiparous women over the age of 35 with extrauterine pregnancies, and women with multiple pregnancies or hydatidiform mole. The American College of Obstetricians and Gynecologists proffers criteria for preeclampsia-eclampsia shown in Table 16.1 (5). CLINICAL CHARACTERISTICS Hypertension Preeclampsia is characterized by hypertension. Although blood pressure values may vary, guidelines suggest a sys- tolic pressure of 140 mm Hg or above; or 90 mm Hg or above, diastolic (5). A blood pressure above 160 to 180 mm Hg systolic, or 110 mm Hg diastolic during bed rest signals severe preeclampsia in the presence of proteinuria of (Ͼ5 g/24 h), or 3+ to 4+ by dipstick (5). The diagnosis is usually established by elevation in blood pressure on two occasions separated by 6 hours, but not infrequently, eclamptic seizures supervene over a shorter period and may occur in the absence of edema or proteinuria. Edema Normal pregnancy frequently results in edema of the legs. The edema of preeclampsia, however, is more marked in degree and affects not only the legs but also the hands and face. Eclampsia Peter W. Kaplan, MS, BS, FRCP 16 T 235 NEUROLOGIC DISEASE IN WOMEN 236 Proteinuria Proteinuria in preeclampsia is defined as the accumula- tion of more than 300 mg of protein in a 24-hour urine collection, whereas severe preeclampsia induces >5 g/24h proteinuria (3+ to 4+ by dipstick). Seizures The exact nature of eclamptic seizures remains unclear, but increasing evidence suggests that focal neuronal excitability arises from cortical damage produced by a number of neuropathologic changes in preeclampsia and eclampsia. These include vasospasm with ischemia, hem- orrhages of various sizes, and cerebral edema; these are discussed later. Epileptic seizures usually remit with delivery of the baby, treatment of the hypertension, or the use of magnesium sulfate. Focal seizures from a vari- ety of etiologies may secondarily spread, resulting in a generalized tonic-clonic seizure. Because of the other neurologic abnormalities that may appear during preg- nancy that may also result in seizures, consideration should be given to the differential diagnosis of peripar- tum seizures (Table 16.2). Seizures in eclampsia may be focal or generalized tonic-clonic. Although they usually appear before child- birth, they frequently occur during or shortly after child- birth. In some patients, seizures occur more than a week postpartum, and there are case reports of seizures occur- ring up to 26 days postpartum (6,7). One series noted that 44% of eclampsia cases occurred postpartum; 12% within 48 hours, but 2% more than a week postpartum (8). In another series, late postpartum seizures (those occurring >48 hours postpartum) accounted for up to 16% of cases of eclampsia (9) whereas others reported a 48% incidence for the same period (4). Late onset eclamp- sia may present without the heralding features of preeclampsia such as edema, proteinuria, or even hyper- tension (10,11). If untreated, approximately 10% of women with eclampsia have further seizures (12). Visual Problems Visual symptoms are common. They may involve differ- ent parts of the visual axis from the retina to the occipi- tal cortex. There may be hypertension-induced retinal arteriolar dilatation, papilledema, occlusion of the cen- tral retinal artery, and vasospasm (13). Retinal edema, hemorrhages, and exudates (Figure 16.1) as well as reti- nal detachment can occur. Although some permanent visual changes may occur, most symptoms resolve with control of hypertension or in the postpartum period. In the posterior visual pathway, there may be microinfarc- tions, microhemorrhages, and edema of the visual cor- tex with cortical blindness (14) (Figure 16.2). Other Clinical Features Other problems with severe preeclampsia include a fall in urine output to below 400 mL/day; cyanosis or pulmonary edema and ARDS, upper abdominal quadrant pain, thrombocytopenia, or hemolysis (HELLP syndrome). TABLE 16.1 Clinical Manifestations of Severe Disease in Patients with Pregnancy-Induced Hypertension Blood pressure Ͼ160–180 mm Hg systolic, Ͼ110 mm Hg diastolic Proteinuria Ͼ5/g/24 h (normal Ͻ300 mg/24 h) Elevated serum creatinine Grand mal seizures (eclampsia) Pulmonary edema Oliguria Ͻ500 mL/24 h Microangiopathic hemolysis Thrombocytopenia Hepatocellular dysfunction (elevated alanine aminotransferase, aspartase aminotransferase) Intrauterine growth retardation or oligohydramnios Symptoms suggesting significant end-organ involve- ment: headache, visual disturbances, or epigastric or right-upper quadrant pain Adapted with permission from the Committee on Terminology of the American College of Obstetricians and Gynecologists, ACOG technical bulletin, #219, January 1996, p. 2. TABLE 16.2 Causes of Seizures around Pregnancy Epilepsy Central stimulants (e.g., Toxins amphetamines cocaine); theophylline Metabolic Hyponatremia, hypocalcemia, problems hypoglycemia, hyperglycemia Cerebrovascular Cerebral infarction problems Cerebral edema Cerebral hemorrhage Cerebral venous sinus thrombosis Subarachnoid hemorrhage Infections/ Bacterial infestations Viral Parasitic infestations HIV Space-occupying Benign and malignant tumors lesions Arterovenous vascular malformations Cerebral abscess ECLAMPSIA 237 PATHOPHYSIOLOGY Myriad pathophysiologic mechanisms have been invoked to explain the changes in preeclampsia-eclampsia, and it is probable that a number of these mechanisms contribute to the symptom complex (15–17) (Table 16.3). Some derive from the physiologic changes that occur during pregnancy, with changes in immunologic tolerance between maternal tissues and paternal elements in the fetus, morphologic arte- rial changes in the uteroplacental bed, vasodilatation from prostaglandin secretion, and abnormalities of platelet aggre- gation. Particular fetal or uterine factors are not essential for the appearance of preeclampsia because it may occur fol- lowing extrauterine or molar pregnancies. Data suggest that the vascular damage in the preeclamptic period arises from the interactions of neutrophils and activated macrophages, T-cell lymphocytes, and the interaction between comple- ment, coagulation systems, and platelets. Endothelial dam- FIGURE 16.1 Fluorescein retinal angiography in eclampsia showing sub- retinal leakage. (Reproduced with permission from Oliver M, Uchenk D. Bilateral exudative retinal detachment in eclamp- sia without hypertensive retinopathy. Am J Ophthalmol 1980;90:794. Copyright by Ophthalmic Publishing Company.) FIGURE 16.2 The occipital poles of a brain showing multiple cortical petechial hemorrhages that may cause cortical blindness. (Reproduced with permission from Sheehan HL, Lynch JB. Pathology of tox- aemia of pregnancy . Edinburgh: Churchill Livingston, 1973.) TABLE 16.3 Mechanisms Suggested as Possible Etiologies for Preeclampsia Abnormal Placentation Abnormal trophoblast invasion Increased trophoblast mass Abnormal uteroplacental location Immunologic Dysfunction Primarily a disease of primigravida Immunologic complexes in placenta and various organs Immunologic complexes in maternal serum Multisystem involvement Coagulation Abnormalities Abnormal prostaglandin metabolism Disseminated intravascular coagulopathy Platelet activation and consumption Low antithrombin III Endothelial Damage Cytotoxic factors against endothelial cells Increased capillary permeability Damaged endothelium on electron microscopy Increased fibronectin levels Dietary Factors Protein and caloric intake Magnesium, calcium, zinc deficiency Excessive sodium intake Essential fatty acids deficiency Endocrine Abnormalities Activated renin-angiotensin-aldosterone system Abnormal catecholamines Abnormal progesterone metabolism Genetic Predisposition Increased incidence in daughter and granddaughters Increased incidence in sisters Increased incidence in patients with previous disease Vasospasm Sensitivity to vasoactive substances Reduced plasma volume in severe disease Reproduced with permission from Sibai BM. Eclampsia. In: Gold- stein PJ, Stern BJ, (eds.) Neurological disorders of pregnancy, 2nd ed. Mount Kisco, NY: Futura Publishing Co., Inc., 1992. NEUROLOGIC DISEASE IN WOMEN 238 age may be produced by platelet consumption and increased platelet aggregation (18) and hypertension. Pregnancy-induced hypertension appears to be a multifactorial process. No single mechanism can account completely for the rise in blood pressure; however, multi- organ vasospasm associated with endothelial dysfunction appears to be a significant contributor. Additionally, the increased vascular responsiveness to catecholamines and angiotensin adversely affect renal function, with conse- quent proteinuria, hypoalbuminemia, edema, and hyper- tension. A shrinking intravascular volume may result in decreased cardiac output and renal function, adversely affecting utero-placental profusion. Multi-organ, includ- ing central nervous system (CNS) morbidity, may arise from the HELLP syndrome, consisting of a number of clinical abnormalities, including hemolysis, elevated liver enzymes, and low platelets. With the invasion of the muscular layer of the uterus by the endovascular trophoblast during the first trimester, deactivation of autonomic innervation of the spiral arter- ies occurs; these result in vascular changes in the inner third of the myometrium (19,20). The spiral arteries then trans- form into uteroplacental arteries, which release nitric oxide (NO) (21,22). Nitric oxide produces a low-pressure, low- resistance, uteroplacental circulation. In preeclampsia, however, an impaired transformation of the spiral arter- ies of the nonpregnant uterus to uteroplacental arteries occurs, only the decidual layers of the uteroplacental arter- ies are involved in the transformation, and fewer arteries are produced (23). There is failure of NO production, immunologic maladaptation of nondilating spiral arteries, increasing inactivation of NO, and further vasoconstric- tion from oxygen free radicals and lipid peroxides. The balance is shifted between the vasoconstrictor and platelet- aggregation promoting effects of platelet-derived throm- boxane-A2 (TXA2) (24), and the vasodilator and platelet- aggregation inhibiting effects of prostacyclin (PGI2) elaborated in the maternal vascular walls. Decreases in PGI2 and NO decrease platelet activation and the pro- duction of circulating serotonin. Mild increases in sero- tonin in mild preeclampsia may restore vascular PGI2 and NO release, in turn improving uteroplacental perfusion by increasing perfusion pressure. Thus, an increase in mater- nal blood pressure satisfies the vascular needs of the fetus. Further increases in serotonin result in increased vaso- constriction and platelet aggregation, however, worsen- ing the pathologic process. Other abnormalities include the renin-angiotensin-aldosterone system (25,26) and the prostacyclin-thromboxane-A2 systems (15). Increasing evidence suggests a mitochronidal defect that impairs cytotrophoblastic differentiation and inva- sion (27). This involves the mitochondrial mutation of the nuclear or mitochondrial genomes, resulting in mutant mitochondria in the daughter cells. These impaired mito- chondria in syncytial tissues are subject to high metabolic demands. The mitochondrial defects are thought to impair normal placentation in pregnancy. Higher inci- dences of the disease exist in immediate blood relatives, especially in a line from mother to daughter (28,29). Such lack of concordance could be explained by differing pro- portions of wild-type and mutant DNA segregating to twins or siblings, thus engendering different cytoplasmic phenotypes (30). These genetic differences are linked to changes in function and morphology, with loss of cristae in the mitochondria, indicating a systemic metabolic dys- function associated with a decrease in cytochrome oxi- dase (31). The same chromosomal locus for pregnancy- induced hypertension is found for the mitochondrial production of endothelial NO synthetase (32). More recent work by Redman and colleagues underscores the probable contribution of an intravas- cular inflammatory response to the preeclamptic process (33). Excessive inflammatory stimulation proportional to placental size (in keeping with the finding that preeclampsia is more frequently seen in multiple gesta- tions and increasing placental size near term), is thought to activate leukocytes and stimulate proinflammatory cytokine production. In this fashion, the increasing pla- cental size, with its concomitant proinflammatory role, generates signals that may stimulate a more generalized inflammatory response in the mother. This balance may decompensate possibly from excessive placental stimu- lus or excessive maternal response. As part of the nor- mal pregnancy process, inflammatory response is shared in the states of normal pregnancy and preeclampsia, and the pathophysiologic processes are thought to reflect exaggerated responses in an otherwise normal preg- nancy. The problem lies, therefore, not with pre-eclamp- sia per se, but the physiology of pregnancy itself. Inter- current toxic, genetic, septic, or other factors may impair the normal downregulation of particular components of the immune activation system that normally keep the inflammatory reactions in check. This dynamic repre- sents the normal maternal-fetal “genetic conflict” (34). Hypertension, which accounts for many of the neu- rologic features seen with the resulting hypertensive encephalopathy and vasospasm, however, is not univer- sally present in all patients with eclampsia. Hence, the reliance placed by a clinician on hypertension to make the diagnosis might result in a delay in management, even with patients manifesting other signs of preeclampsia, but with- out significant increase in blood pressure. HELLP syn- drome, with its associated coagulopathy, may result in major neurologic sequelae and intracranial hemorrhage without hypertension (35) or indeed, proteinuria or edema. Cerebral Pathology A major contributing factor to the cerebral pathology in preeclampsia-eclampsia is cerebral edema supervening ECLAMPSIA 239 when the cerebral blood pressure exceeds the limits of cerebral autoregulation. Cerebral autoregulation is main- tained by the modulation of cerebral arteriolar resistance in the face of the arterial pressure of the blood supply to the brain. This mechanism maintains the independence of cerebral perfusion pressure from the systemic arterial blood pressure. With the relative hypertension seen in preeclampsia, the autoregulation of the cerebral circula- tion is impaired, resulting at one extreme in hyperten- sion and encephalopathy and at the other extreme in cere- bral hypoperfusion (36,37). The ensuing damage to precapillaries and capillaries, disruption of the “tight junctions,” and the extravasation of red cells and proteins in the perivascular spaces contribute to the blood–brain barrier disruption at particular areas of risk, which are the border zones between the larger cerebral arteries. There is local vulnerability to cortical petechiae, microin- farctions, and pericapillary brain hemorrhages. Some of these changes are due to the regional differences in the control of cerebral blood flow (38), with regions of alter- nating arteriolar dilatation and constriction resulting in capillary breakdown, extravasation of blood elements, increased platelet consumption, and the triggering of coagulation with fibrin deposition (39). When the pro- tective precapillary arteriolar vasoconstriction fails, the increase in blood pressure exerts a direct effect on the cap- illary bed, resulting in hemorrhages. The neurologic manifestations of preeclampsia- eclampsia, although sudden, may be transient. Progressively severe headache lasting days may occur with visual distur- bances, hallucinations, or even the perception of “flashing lights” (from whence the name eclampsia is derived). Even the occipital blindness can be reversible. The pathologic processes may progress, presenting clinically with focal neu- rologic deficit, confusion, seizures, or even coma. The visual system may be affected by retinal arteriolar dilatation or spasm, retinal hemorrhages and exudates, or even retinal detachment. Papilledema may result from raised intracere- bral pressure. The posterior cortical watershed zones, less protected by sympathetic vasoconstrictor tone, are partic- ularly subject to microhemorrhages and infarctions, as well as to subcortical gray–white zone edema. Any part of the cerebral hemisphere can be involved, however, resulting, for example, in aphasia or pareses. Eclampsia is a significant risk factor for stroke dur- ing pregnancy in the first 6 weeks postpartum (40) and accounts for about half of the case-related strokes (41). PATHOLOGY Pathologic changes affect various parts of the neuraxis (14). Aside from cerebral edema, hemorrhaging may occur in the subarachnoid, subcortical, and intraparenchymal areas. Small- to medium-sized infarctions can occur in the cerebral cortex, corona radiata, basal ganglia, and brain- stem. Metabolic and hypertensive encephalopathy are also seen. Although damage predominantly affects the water- shed zones in the parieto-occipital regions, vascular changes may also affect the parietal and frontal lobes. Many of these processes may be a source of seizures. Subarachnoid hemorrhages may occur in circum- scribed areas of cerebral cortex, whereas larger hemor- rhages can be seen in the hemispheres, basal ganglia, and pons (14,42). Hemorrhages in the gray matter may then erupt into the ventricles or subarachnoid spaces (14). Smaller hemorrhagic areas, in the form of sulcal petechiae and microinfarctions appear in the precapillary and cap- illary areas as well as around arterioles (14,42–43). These result in splitting of the elastic fibers, necrosis of the arte- rial wall, and edema. Deep-seated hemorrhages in the corona radiata, basal ganglia, and brainstem may be seen along with larger cortical hemorrhages (14,43). A recent study of stroke in pregnancy, with eclampsia given as a leading cause, showed the incidence of intraparenchymal hemorrhages and ischemic strokes to be similar (hemor- rhages usually account for approximately 15% of strokes), suggesting that pregnancy increases the risk of cerebral hemorrhage (44). Diffuse cerebral edema is associated with a rise in cerebrospinal fluid pressure and papilledema (45). On postmortem, there may be marked central or trans- verse herniation as well as gyral flattening (14,42). A number of organ systems can be damaged because of the pathologic vascular changes that occur in preeclampsia and eclampsia. Platelet consumption and active coagulopathy may occur in various organs. There is an increasing literature of angiographic and transcra- nial Doppler studies attesting to the vasospastic compo- nent in cerebral pathology (46–48) (Figure 16.3). DIAGNOSIS Preeclampsia is characterized by variable weight gain, pregnancy-induced hypertension, and edema. An exces- sive weight gain is defined as more than 2 pounds per week. Pathologic edema is that which involves the hands and face. However, seizures may appear before the edema, weight gain, or proteinuria (10,11,49). Standard defini- tions of preeclampsia and hypertension are given in Table 16.1. The proteinuria may appear late in the course of preeclampsia. Neurologic features frequently include headache and photophobia, pain in the upper abdomi- nal area, and brisk reflexes (Table 16.4). LABORATORY STUDIES Preeclampsia-eclampsia is a clinical diagnosis. Some accompanying laboratory abnormalities are the raised NEUROLOGIC DISEASE IN WOMEN 240 serum creatinine and uric acid that occur in approxi- mately 60% of patients. In approximately one-third or fewer patients, a fall in platelets below 150,000 per mm 3 may occur; hemolysis from disseminated intravascular coagulation; and elevation of liver enzymes (HELLP syn- drome), an entity that is associated with significant mater- nal morbidity (49,50). IMAGING In most cases of eclampsia, particularly those without focal neurologic findings, computed tomography (CT) head scans are usually normal, but magnetic resonance imaging (MRI) may still show T2-weighted abnormali- ties in watershed zones. Patients with focal neurologic findings and atypical cases warrant investigation to address neurologic complications. Various series of CT head scans have shown abnormalities in 29% to 75% of eclamptic patients (51). These changes include cerebral edema; hemorrhages in the brain stem, subependymal regions, subarachnoid spaces, and parenchymal areas; and infarction (52). Other large series have reported no abnormalities (12,53). MRI scans have documented hypodensities in the basal ganglia, border zone ischemia, and focal cerebral edema, which usually resolve on sub- sequent scanning (49, 54,55) (Figure 16.4). In eclampsia, there may be the characteristic multifocal curvilinear abnormalities at the gray–white junction of the poste- rior watershed zones. Such reversible angiopathy has been further documented using angiography (Figure 16.5), single photon emission computerized tomography (SPECT), and transcranial Doppler ultrasound (TCD) (46,48,54–57). Most patients under obstetric care with eclampsia do not get head MRI or CT scans, and it is only after focal neurologic findings appear that a neurologic consult and imaging are requested. Women with focal neurologic find- ings warrant further investigation, but without it, clinical diagnosis usually leads to treatment with magnesium sul- fate and expeditious delivery of the baby. FIGURE 16.3 Left common carotid artery injection shows spasm of periph- eral branches of left anterior and middle cerebral arteries. Arrows point to beaded appearance of these vessels. Paucity of peripheral branches is shown. (Reproduced with permis- sion from Trommer BL, et al. Cerbral vasospasm and eclamp- sia. Stroke 1988;19:326–329.) TABLE 16.4 Clinical Features Preceding Eclampsia Clinical Features Percent of Patients Headache 83 Hyperreflexia 80 Clonus 46 Visual signs 45 Epigastric pain 20 Adapted with permission from Sibai et al. Obstet Gynecol 1982; 57:199. FIGURE 16.4 MRI scan. Hyperintense areas in the posterior parietal area on a higher section. (Reproduced with permission from Raroque HG, Orrison WW, Rosenberg GA. Neurology 1990;40:167–169.) ECLAMPSIA 241 ELECTROENCEPHALOGRAPHY Electroencephalography is usually abnormal (49). There may be diffuse or focal slowing, and/or focal or general- ized epileptiform activity (58,59). THE MANAGEMENT OF ECLAMPSIA The treatment of mild, moderate, or even severe eclamp- sia is usually handled by obstetricians, and only rarely are neurologists consulted for management. More frequently, neurologists are involved with the appearance of seizures, focal neurologic deficits, or coma. The treatment goal is the rapid delivery of a viable baby, with preservation of maternal health. Therapeutic strategies are directed at decreasing blood pressure to the autoregulatory range, preventing seizures or their recurrence, and preventing or minimizing cerebral edema. Preeclampsia and eclampsia represent a spectrum of neuropathologic change, and management should be directed at the process as a whole. Treatment of Hypertension Cerebral edema may rapidly resolve when hypertension is lowered to within the boundaries of cerebral perfusion autoregulation, usually a fall in 20 to 25% of the mean arterial pressure. Antihypertensive agents used have included diazoxide, sodium nitroprusside, nitroglycerin, and hydralazine (60–62). Nifedipine and labetalol are currently favored agents (61) (Table 16.5). FIGURE 16.5 A cerebral angiogram with injection of contrast into the right (A) and left (B) internal carotid arteries. Diffuse narrowing of anterior cerebral arteries can be seen bilaterally (arrowheads). Focal areas of vasospasm are also seen (arrows). (Reproduced with per- mission from Geraghty JJ, et al. Fatal puerperal cerebral vasospasm and stroke in a young woman. Neurology 1991;41:1146–1147.) AB TABLE 16.5 Pharmacologic Management of Hypertensive Crisis Persistent Blood Pressure—160/110 Drug Administration Hydralazine 5 mg IV; repeat in 10 min- utes; then 10 mg IV every 20 minutes until stable blood pressure (140–150/90–110 mm Hg) achieved Labetalol 5–15 mg IV push; repeat every 10–20 minutes by dou- bling dose to a maximum of 300 mg total Sodium nitroprusside a,b Controlled infusion 0.5–3.0 (best used for refractory mg/kg/min, not to exceed 800 hypertension) mg/min Nifedipine b 10 mg sublingual, repeat in 30 minutes; then 10–20 mg PO every 4–6 hours Nitroglycerine Should be used only by prac- titioners thoroughly familiar with its use in obstetrics a Requires arterial line for continuous blood pressure monitor- ing. b Avoid use in antepartum patients. Profound hypotension may result. Reproduced with permission from Repke JT. A longitudinal approach. In: Moore TR, Reiter RC, Rebar RW, (eds.) Gynecol- ogy and obstetrics. Hypertension and preeclampsia 1993; 29:463–477. [...]... preparations containing у50 mcg of estradiol (57 ,61 ,62 ) In normotensive, nonsmoking women, OCPs containing 35 mcg of estradiol or less do not increase the risk of stroke (63 ,66 ) The majority of studies of secondand third-generation OCPs containing these lower doses of estrogens did not find an increased risk of stroke (61 ,62 ,67 –70) A pooled analysis of two large population case-control studies showed no increased... Gynec Scand 1 961 ;40:127 Sibai BM, Spinnato JA, Watson DL, et al Effect of magnesium sulfate in electroencephalographic findings in preeclampsia-eclampsia Obstet Gynecol 1984b ;64 : 261 – 266 Editorial Management of eclampsia Br Med J 19 76; 2: 1485–14 86 Michael CA Intravenous labetalol and intravenous diazoxide in severe hypertension complicating pregnancy Austral N Z J Obstet Gynaecol 19 86; 26: 26 29 Morris... aspirin for the prevention of pregnancy-induced hypertensive disease JAMA 1991; 266 : 260 – 264 147 CLASP Collaborative Group Low dose aspirin in pregnancy and early childhood development: follow up of the collaborative low-dose aspirin study in pregnancy Br J Obstet Gynecol 1995;102: 861 – 868 148 Ginsberg JS, Kowalchuk G, Hirsh J, et al Heparin therapy during pregnancy Risks to the fetus and mother Arch Intern... Sjöberg HE, Ringertz H Bone mineral density during long-term prophylaxis with heparin in pregnancy Am J Obstet Gynecol 1994;170:1315–1320 152 Warkentin TE, Levine MN, Hirsh J, et al Heparininduced thrombocytopenia in patients treated with lowmolecular-weight heparin or unfractionated heparin N Engl J Med 1995;332:1330–1335 153 Kelton JG The clinical management of heparin-induced thrombocytopenia Semin Hematol... stroke among women receiving HRT versus nonusers (85) None of the other studies detected a large increase in stroke risk, and several reported a slight (but often insignificant) decrease in risk ( 86 92) In the 20-year report from the Nurses’ Health Study, the investigators noted for the first time an increased risk of stroke in women taking estrogen alone (35%) and in women taking combined therapy... Hematol 1999; 36( suppl 1): 17–21 154 Hirsh J, Warkentin TE, Raschke R, et al Heparin and low-molecular-weight heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy and safety Chest 1998;114:4895–5105 155 Bergqvist D Low-molecular-weight heparins J Intern Med 19 96; 240 :63 –72 1 56 Forestier F, Solé Y, Aiach M, et al Absence of transplacental fragmin (Kabi) during second... Haemost 1992 ;67 :180–181 157 Nelson-Piercy C, Letsky, deSwiet M Low-molecularweight heparin for obstetric thromboprophylaxis: experience of sixty-nine pregnancies in sixty-one women at risk Am J Obstet Gynecol 1997;1 76: 1 062 –1 068 158 Dulitzki M, Pauzner R, Langevitz P, et al Low-molecular-weight heparin during pregnancy and delivery: preliminary experience with 41 pregnancies Obstet Gynecol 19 96; 87:380–383... best in preventing eclamptic seizures or their recurrence before the clear underpinnings or rationale for this treatment had been clearly established In part motivated by the controversies regarding magnesium sulfate in eclampsia (63 65 ), a large multicenter trial in 1 ,68 0 women with eclampsia demonstrated that 4 g intravenous (IV) magnesium sulfate over 5 minutes, followed by 5 g intramuscular (IM) in. .. occurring late in pregnancy and during labor and delivery (1 46, 147) AVMs present with hemorrhage about three times more often in pregnant women compared with nonpregnant women (1 46, 148,149) AVMs also result in a larger proportion of SAH during pregnancy—up to 50%—(1 46, 148) compared with about 10% in nonpregnant women and 6% in the general population The reason for the relatively higher incidence of AVM-associated... severe preeclampsia and eclampsia with intravenous diazoxide Obstet Gynecol 1977;49 :67 5 68 0 Donaldson JO The case against magnesium sulfate for eclamptic convulsions Intern J Obstet Anes 1992;1: 159– 166 Kaplan PW, Lesser RP, Fisher RS, et al No, magnesium sulfate should not be used in treating eclamptic seizures Arch Neurol 1988;45:1 361 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 245 Donaldson . Regulations. Part 46, Sub- part B. March 15, 1994. 44. Institute of Medicine. Women and health research: eth- ical and legal issues of including women in clinical stud- ies. Washington D.C.:. dehy- droepiandrosterone sulfate in men and women who have partial seizures with temporal lobe involvement. J Clin Endocrinol Metab 19 86; 63:243–245. NEUROLOGIC DISEASE IN WOMEN 234 62 . Stoffel-Wagner B, Bauer. BS, FRCP 16 T 235 NEUROLOGIC DISEASE IN WOMEN 2 36 Proteinuria Proteinuria in preeclampsia is defined as the accumula- tion of more than 300 mg of protein in a 24-hour urine collection, whereas