Neurologic Disease in Women - part 9 pot

NEUROLOGIC DISEASE IN WOMEN 382 system and the pathogen itself are responsible for the spread of infection during pregnancy (1–7,23). Coccid- ioidal meningitis is subtle in its presentation with lethargy, confusion, headache, low-grade fever, and generalized weight loss developing gradually. Diagnosis may be further delayed when meningitis occurs without any appar- ent pulmonary disease, a pattern of presentation that occurs in almost two-thirds of cases involving the CNS (24). The CSF is always abnormal in patients with coccidioidal meningitis, and the diagnosis is made either by detecting anticoccidioidal complement fixing (CF) antibodies or by growing C. immitis from the CSF. Because it is invariably fatal when left untreated, aggressive therapy for all patients is indicated (Table 27.2). The main therapeutic regimen requires intravenous followed by intraventricular amphotericin B at least until the CSF anticoccidioidal CF antibody titers remain negative for 6 to 12 months, and sometimes for life (Table 27.3) (25). Although pregnant mothers usually survive, the fetus often succumbs (21,25). Malaria Only one of the four species of plasmodia that infect humans, Plasmodium falciparum, is capable of causing severe cerebral disease. Falciparum malaria is especially common in pregnancy during which the level of para- sitemia is increased and both fetal and maternal morbidity are high. In Thailand, malaria is the most common cause of mortality during pregnancy (26). Patients with cerebral malaria present with headache, increasing drowsiness, confusion, delirium, seizures, and finally coma; the fever, anemia, and jaundice that accompany these findings serve as clues to the diagnosis. An important feature of falciparum malaria in pregnancy is the frequent development of hypoglycemia that becomes particularly severe during the intravenous administration of quinine (27). This derangement, along with a high sequestration of parasites in the placenta, thereby impeding oxygen and nutrient sup- ply to the fetus, are believed to result in the fetal mortality (27,28). Serum glucoses should therefore be carefully monitored and hypoglycemia managed aggressively. Because untreated cerebral malaria is commonly fatal, it requires prompt intervention. Many strains of P. falciparum in Africa, Asia, and South America are now chloro- quine-resistant, and because high doses of quinine may rarely cause stillbirths and fetal anomalies (28), it is now advisable to treat pregnant patients with intravenous quinidine gluconate (Table 27.2) (29). The combination of artesunate and mefloquine has also recently been tested in pregnancy and shown to have comparable efficacy to quinine in a small study (30). Antimalarial drugs can appear in breast milk, but not in quantities that can treat infant malaria (31). The use of antimalarials is not a con- traindication to breast-feeding (31). Viruses Despite the fact that cell-mediated immunity is suppressed during pregnancy, viral meningitis and viral encephalitis TABLE 27.2 Treatment Considerations for Common Neurologic Infections during and Immediately after Pregnancy Drug of Breast-feeding Disease Choice Teratogenicity* Ok? † Recommendations Tuberculous meningitis Isoniazid + No Treat with multidrug regimen at Rifampicin + No all stages of pregnancy Pyrazinamide + No and/or Ethambutol + No Listerial meningitis Ampicillin – Yes Treat with standard antibiotic doses as soon as possible Coccidioidal meningitis Amphotericin B – Unknown Begin antifungal therapy as soon as pathogen is identified Cerebral malaria Quinidine gluconate – Yes Treat as indicated as soon as possible Disseminated HSV Acyclovir – Yes Use IV dosing for all forms of disseminated infection (including encephalitis) * – = No adverse effects demonstrated or no adverse effects known (Class A or B), + = adverse effects in animals and no studies in women (Class C), ++ = significant fetal risk (Class D or X). † Yes = absent or low concentrations of the drug excreted into breast milk, No = systemic or concentrated levels found in milk, proceed with caution, or avoid breast-feeding altogether. INFECTIONS OF THE NERVOUS SYSTEM IN WOMEN 383 are not increased in frequency or severity during pregnancy (32). Paralytic poliomyelitis is slightly more common in pregnant women (33), and some nonneurologic viral infections, including smallpox, influenza, and vari- cella-zoster, can be more severe in these patients (32). Her- pes simplex virus (HSV) infections of the genital tract can lead to intrauterine fetal infection or neonatal disease when contracted during vaginal birth (34,35). Although these may have devastating effects on the infant, no data show that pregnancy itself increases the rate with which latent genital HSV infections reactivate. Likewise, whereas reactivated genital HSV infections can rarely dis- seminate to the CNS, this does not occur more commonly in pregnant women (35,36). In a small number of cases, however, disseminated HSV infection during pregnancy (either with or without obvious CNS involvement) was associated with a maternal mortality of greater than 50% (35). As a result, despite its potential for causing chro- mosome breaks at very high concentrations (37), acyclovir should be given to all pregnant women with disseminated HSV infection in doses that are standard for the treatment of encephalitis (Table 27.3). Isolated genital HSV infections typically should not be treated since acyclovir simply decreases the duration of viral shedding and has no beneficial effect on preventing subsequent reactivations (36). Active genital HSV infection during labor, however, may be considered an indication to deliver the baby by caesarean section to prevent neonatal infection (35). VACCINATION DURING PREGNANCY Because of the theoretical risk of transplacental trans- mission, immunizing pregnant women with live virus vaccines is generally avoided. The Centers for Disease Con- trol (CDC) have stated that inactivated vaccines are officially safe during pregnancy, however (38). Circum- stances can arise during pregnancy when there is a need to immunize a woman against an infection that might potentially involve the nervous system. For example, it is important to ensure that pregnant women are immunized against tetanus because the transplacental transfer of maternal antibodies is important in preventing this disease in neonates. Pregnant women can safely be given a combination of tetanus and diphtheria toxoids (38). Sim- ilarly, in pregnant women potentially exposed to rabies virus, post-exposure rabies vaccine can be given (38). The live vaccine of greatest concern is the attenuated oral polio vaccine (OPV), because recently immunized children can TABLE 27.3 Antimicrobial Regimens Commonly Used to Treat Neurologic Infections during Pregnancy Drug Dose Frequency Duration Antimycobacterials Isoniazid 5 mg/kg PO Daily 9 mo. to 1 yr. Rifampin 10 mg/kg PO Daily 9 mo. to 1 yr. Pyrazinamide 15–30 mg/kg PO Daily 2 months Ethambutol 15–25 mg/kg PO Daily 2 months Antibacterials Ampicillin 2 g IV Every 4 hours 2–3 weeks Antifungals Amphotericin B* 0.5 mg/kg IV Daily Total dose of 30–40 mg/kg, plus: 0.2–0.5 mg Every other day at least until CSF intraventricular** titer (–) for 6–12 mo. Antimalarials Quinidine 10 mg base/kg IV load, TID Until oral Rx gluconate*** then 0.02 mg/kg/h can be started, then: 648 mg PO 7 days plus: Sulfadoxine-pyrimethamine 3 tablets all at once at the end of quinidine therapy Antivirals Acyclovir 10 mg/kg IV Every 8 hours 2–3 weeks * Adverse effects are common; requires an initial test dose of 1 mg under close observation (see reference 25). ** Duration of therapy typically necessitates the placement of an intraventricular reservoir. *** Cardiac monitoring is indicated during infusion. Slow or stop if QRS lengthens >25% of baseline or if QTc interval >500 msec. NEUROLOGIC DISEASE IN WOMEN 384 spread these fecally excreted viruses to pregnant mothers through close household contact. OPV was recently given to pregnant women during a poliomyelitis outbreak in Finland. No vaccine-related cases of paralysis occurred, and no harmful effects on fetal development were noted (39). Nevertheless, the CDC does not recommend its rou- tine use in the United States during pregnancy (38). GENDER-BASED DIFFERENCES IN THE FREQUENCY, MANIFESTATIONS, AND OUTCOMES OF SPECIFIC NEUROLOGIC INFECTIONS In a few examples, apart from pregnancy, neurologic infections differ in their frequency, manifestations, and/or clinical outcomes between men and women. Sex differences in the susceptibility to viral infection of the CNS have also been documented in experimental animals (40,41). These animal studies are helpful because they begin to address the mechanisms underlying gender-based differences in outcome. In these reports, both groups of investigators showed that female animals generated more robust immune responses to infection than males (40,41). This led to an improved overall outcome for females with one infection (40). In the other case, however, where symptoms of the infection were predominantly immune-mediated, the enhanced immune response in female animals resulted in more severe disease and greater mortality (41). In humans, examples in which differences between the sexes have been identified typically show that women either do better or less commonly have the disease than men. Mumps Mumps is a systemic infection caused by a paramyxovirus. Although salivary gland enlargement, especially parotitis, is the most easily recognized clinical manifestation of mumps, CNS involvement frequently occurs (42). This ranges from a mild aseptic meningitis to a fulminant and potentially fatal encephalitis. The disease has largely been controlled by vaccination over the last three decades, but cases in unvaccinated individuals still occur (42). This is most common in urban populations, where school-aged children are typically affected. Although boys and girls have the same incidence of mumps parotitis (43), a distinct male predominance (up to 80%) of CNS disease exists. In most series, the ratio of males to females is between 3:1 and 4:1 (42,44–46). The peak incidence of CNS involvement in mumps occurs at about age 7 in both sexes (44–46). Brain Abscess Brain abscesses are focal areas of infection within the brain parenchyma itself. They occur as single or multiple lesions, commonly in association with three clinical situations: (i) a contiguous focus of infection such as a sinusitis or otitis media, (ii) hematogenous spread from a distant source, such as pneumonia or bacterial endo- carditis, or (iii) following cranial trauma. Several large series report a male predominance among patients with brain abscesses, as high as 3:1 (47–50). The reason for this difference between men and women is unknown, and the disease is otherwise the same for both sexes. Subdural Empyema A subdural empyema is an infection that occupies the space between the dura mater and the arachnoid mater. It is most often a complication of ear, nose, and throat infection, but may also occur following head trauma, neurosurgery, osteomyelitis of the skull, bacteremic spread from a distant source, or leptomeningitis in infants (51). As with brain abscesses, males with subdural empyemas outnumber females by 3:1 (52). Nearly 70% are in their second or third decade of life (52), and the growing posterior wall of the frontal sinus in boys between the ages of 9 and 20 has been offered as a possible explanation for this striking sex and age susceptibility (53). HORMONAL THERAPY AND NEUROLOGIC INFECTIONS IN WOMEN Exogenous female sex hormones are used therapeutically for a number of purposes. Some examples include progesterone, either alone or with estrogen, in contraceptive pills and conjugated estrogens that are used to treat the vasomotor symptoms associated with menopause (“hot flashes”) and to prevent postmenopausal osteoporosis. Although these treatments may increase the susceptibility of women to both cardiovascular and cerebrovascu- lar disease, they have never been directly linked to an increased risk of infection. Some drug interactions, however, may occur between contraceptive pills and certain antibiotics including rifampin, tetracycline, and ampicillin (54). These drugs all decrease the effectiveness of contraceptive pills (54). This effect may be particularly enhanced by the concurrent administration of anticon- vulsants such as phenytoin and carbamazepine. CONCLUSION Infections of the CNS in women present a number of unique situations and challenges that are not applicable to men. Conditions present during menses may predis- pose women to develop TSS, which can involve the CNS. This uncommon disorder requires prompt recognition and appropriate antibiotic therapy. Immune suppression INFECTIONS OF THE NERVOUS SYSTEM IN WOMEN 385 during pregnancy increases the susceptibility of women to certain neurologic infections, and the adverse effects of particular antimicrobial drugs on the fetus may compli- cate the treatment of these disorders. Particular care is likewise required in determining the appropriateness of vaccines against neurologic infections during pregnancy. Women taking contraceptive pills or hormone supple- ments during menopause may find that the effectiveness of these drugs decreases in the presence of certain antibiotics that are used to treat neurologic infections. In contrast to their striking susceptibility during pregnancy, however, women also resist certain neurologic infections such as mumps and brain abscesses compared to men. Whereas studies in experimental animals have begun to elucidate the immunologic underpinnings for these differences in susceptibility to CNS infections, only the in vitro effects of estrogens on cells of the immune system have begun to be delineated. Pregnancy is a critical period during which neurologic infections require prompt iden- tification and careful management, because of the often subtle presenting features, changes in antibiotic metabo- lism, and potentially damaging effects of both infection and treatment on the fetus. References 1. Grossman CJ. Regulation of the immune system by sex steroids. Endocrine Rev 1984;5:435–451. 2. Paavonen T. Hormonal regulation of lymphocyte func- tions. Med Biol 1987;65:229–236. 3. Sarvetnick N, Fox HS. Interferon-gamma and the sexual dimorphism of autoimmunity. Mol Biol Med 1990;7:323–330. 4. Styrt B, Sugarman B. Estrogens and infection. Rev Infect Dis 1991;13:1139–1151. 5. Bhalla AK. Hormones and the immune response. Ann Rheum Dis 1989;48:1–6. 6. Ansar-Ahmed S, Penhale WJ, Talal N. Sex hormones, immune responses, and autoimmune diseases. Am J Path 1985;121:531–551. 7. Paavonen T, Anderson LC, Adlercreutz H. Sex hormone regulation of in vitro immune response. J Exp Med 1981;154:1935–1945. 8. Huber SA, Pfaeffle B. Differential Th1 and Th2 cell responses in male and female BALB/c mice infected with coxsackievirus group B type 3. J Virol 1994;68: 5126–5132. 9. Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidi- rectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a Th2 phenomenon? Immunol Today 1993;14:353–356. 10. Siiteri PK, Stites DP. Immunologic and endocrine inter- relationships in pregnancy. Bil Reprod 1982;26:1–14. 11. Johnson PM. Immunobiology of the human placental trophoblast. Exp Clin Immunogenetics 1993;10: 118–122. 12. Robertson SA, Seamark RF, Guilbert LJ, Wegmann TG. The role of cytokines in gestation. Crit Rev Immunol 1994;14:239–292. 13. Davis JP, Chesney PJ, Wand PJ, La Venture M. Toxic shock syndrome: epidemiologic features, recurrence, risk factors, and prevention. N Engl J Med 1980;303: 1429–1435. 14. Waldvogel FA. Staphylococcus aureus (including toxic shock syndrome). In: Mandell GL, Bennett JE, Dolin R, (eds.) Principles and practice of infectious diseases. New York: Churchill Livingstone, 1995;1754–1777. 15. Bharucha NE, Bhabha SK, Bharucha EP. Bacterial infections of the nervous system. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD, (eds.) Neurology in clinical practice. Boston: Butterworth-Heinemann, 1991; 1049–1084. 16. Hamadeh MA, Glassroth J. Tuberculosis and pregnancy. Chest 1992;101:1114–1120. 17. Kingdom JCP, Kennedy DH. Tuberculous meningitis in pregnancy. Br J Obstet Gynecol 1989;96:233–235. 18. D’Cruz IA, Dandeker AC. Tuberculous meningitis in pregnant and puerperal women. Obstet Gynecol 1968;31:775–779. 19. Armstrong D. Listeria monocytogenes. In: Mandell GL, Bennett JE, Dolin R, (eds.) Principles and practice of infectious diseases . New York: Churchill Livingstone, 1995;1880–1885. 20. McLauchlin J. Human listeriosis in Britain 1967–1985, a summary of 722 cases. 1. Listeriosis during pregnancy and in the newborn. Epidemiol Infect 1990;104:181–190. 21. Ampel NM, Wieden MA, Galgiani JN. Coccidioidomy- cosis: clinical update. Rev Infect Dis 1989;11:897–911. 22. Dodge RR, Lebowitz MD, Barbee R, Burrows B. Esti- mates of Coccidioides immitis infection by skin test reac- tivity in an endemic community. Am J Public Health 1985;75:863–865. 23. Drutz DJ, Huppert M. Coccidioidomycosis: factors affecting the host-parasite interaction. J Infect Dis 1983;147:372–390. 24. Bouza E, Dreyer JS, Hewitt WL, Meyer RD. Coccidioidal meningitis. An analysis of thirty-one cases and review of the literature. Medicine (Baltimore) 1981;60:139–172. 25. Dal Pan GJ. Fungal infections of the central nervous system. In: Johnson RT, Griffin JW, (eds.) Current therapy in neurologic disease . St. Louis: Mosby-Year Book, 1997;146–151. 26. Khanavongs M. Maternal mortality rate at Phaholpol- payuhasena from 1977–1979. Thai Med Council Bull 1980;9:877–881. 27. Looareesuwan S, White NJ, Karbwang J, et al. Quinine and severe falciparum malaria in late pregnancy. Lancet 1985;2:4–8. 28. Dilling WJ, Gemmell AA. A preliminary investigation of of fetal deaths following quinine induction. J Obst Gyn 1929;36:352–366. 29. Miller KD, Greenberg AE, Campbell CC. Treatment of severe malaria in the United States with a continuous infusion of quinidine gluconate and exchange transfu- sion. N Engl J Med 1989;321:66–70. 30. Bounyasong S. Randomized trial of artesunate and mefloquine in comparison with quinine sulfate to treat P. falciparum malaria in pregnant women. J Med Assoc Thai 2001;84:1289–1299. 31. Murphy GS, Oldfield EC. Falciparum malaria. In: Lutwick LI, (ed.) Infectious disease clinics of North America . Philadelphia: WB Saunders, 1996;10(4): 747–775. 32. Johnson RT. Infections during pregnancy. In: Devinsky O, Feldmann E, Hainline B, (eds.) Neurological complications of pregnancy . New York: Raven Press, 1994; 153–162. NEUROLOGIC DISEASE IN WOMEN 386 33. Weinstein L, Aycock WL, Feemster RF. The relation of sex, pregnancy, and menstruation to susceptibility in poliomyelitis. N Engl J Med 1951;245:54-58. 34. Whitley RJ, Schlitt M. Encephalitis caused by her- pesviruses, including B virus. In: Scheld WM, Whitley RJ, Durack DT, (eds.) Infections of the central nervous system. New York: Raven Press, 1991;41–86. 35. Whitley RJ, Stagno S. Perinatal viral infections. In: Scheld WM, Whitley RJ, Durack DT, (eds.) Infections of the central nervous system. New York: Raven Press, 1991; 167–200. 36. Corey L, Adams HG, Brown ZA, Holmes KK. Genital herpes simplex virus infections: clinical manifestations, course, and complications. Ann Intern Med 1983;98: 958–972. 37. Stahlmann R, Klug S, Lewandowski C. Teratogenicity of acyclovir in rats. Infection 1987;15:261–262. 38. Centers for Disease Control and Prevention. Recom- mendation of the Immunization Practices Advisory Com- mittee (ACIP): general recommendations on immunization. MMWR 1994;43 (RR-1). 39. Harjulehto T, Hovi T, Aro T, Saxen L. Congenital mal- formations and oral poliovirus vaccination during pregnancy. Lancet 1989;1:771–772. 40. Barna M, Komatsu T, Bi Z, Reiss CS. Sex differences in susceptibility to viral infection of the central nervous system. J Neuroimmunol 1996;67:31–39. 41. Muller D, Chen M, Vikingsson A, Hildeman D, Peder- son K. Estrogen influences CD4+ T lymphocyte activity in vivo and in vitro in ß2-microglobulin-deficient mice. Immunology 1995;86:162–167. 42. Gnann JW. Meningitis and encephalitis caused by mumps virus. In: Scheld WM, Whitley RJ, Durack DT, (eds.) Infections of the central nervous system. New York: Raven Press, 1991;113–125. 43. Levitt LP, Mahoney DH, Casey HL, Bond JO. Mumps in a general population: a sero-epidemiologic study. Am J Dis Child 1970;120:134–138. 44. Levitt LP, Rich TA, Kinde SW, Lewis AL, Gates EH, Bond JO. Central nervous system mumps. Neurology 1970;20: 829–834. 45. Ritter BS. Mumps meningoencephalitis in children. J Pediatr 1958;52:424–432. 46. Murray HGS, Field CMB, McLeod WJ. Mumps meningo-encephalitis. Br Med J 1960;1:1850–1853. 47. Morgan H, Wood M, Murphy F. Experience with 88 con- secutive cases of brain abscess. J Neurosurg 1973;38: 698–704. 48. Chun CH, Johnson JD, Hofstetter M, Raff MJ. Brain abscess. A study of 45 cases. Medicine (Baltimore) 1986;65:415–431. 49. Samson DS, Clark K. A current review of brain abscess. Am J Med 1973;54:201–210. 50. Spires JR, Smith RJH, Catlin FI. Brain abscesses in the young. Otolaryngol Head Neck Surg 1985;93:468–474. 51. Helfgott DC, Weingarten K, Hartman BJ. Subdural empyema. In: Scheld WM, Whitley RJ, Durack DT, (eds.) Infections of the central nervous system. New York: Raven Press, 1991;487–498. 52. Luken MG, Whelan MA. Recent diagnostic experience with subdural empyema. J Neurosurg 1980;52:764–771. 53. Kaufman DM, Litman N, Miller MM. Sinusitis-induced subdural empyema. Neurology 1983;33:123–132. 54. Bartlett JG. Pocket book of infectious disease therapy. Baltimore, Md: Williams & Wilkins; 1998. he goal of this chapter is to provide an overview of the more common intracranial tumors and neurologic complications of cancer that are unique to women, with particular emphasis on the possible relationship between certain conditions and female sex hormones or oral contraceptives, female-specific cancers, and on the special therapeutic considerations regarding women affected by brain tumors during their childbearing years or during pregnancy. In general, females are not more frequently affected by intracranial tumors than are males (1). The sex ratio (SR) for all histologic types as a group is 1:2 (2). The incidence rate per 100,000 population for primary brain tumors is 9.2 for males and 8.7 for females. Some histologic subtypes such as meningioma and pituitary adenoma are more frequently observed in women of childbearing age, however (3). This observation has led to the hypothesis of a link between the female sex hormones and these tumors. Indeed, research studies have shown the presence of estrogen and progesterone receptors in meningioma cells (4). This chapter also describes the most recent diagnostic modalities that enable us to obtain more accurate and timely diagnoses in women affected by brain tumors for establishing appropriately individualized treatment plans. GLIAL TUMORS Glial tumors are the most common primary brain tumors of adults, comprising half of all diagnosed brain tumors. The average adult incidence rate is 5.2 per 100,000, and the most common histologic type is the asytrocytoma (5). Among asytrocytomas, glioblastoma multiforme is the most common and the most malignant histologic variant. Other histologic types include oligodendroglioma and ependymoma. The presenting symptoms can be divided into nonfocal, typically the result of increased intracranial pressure, and focal, as the consequence of direct destructive or irritative involvement of the surrounding nervous tissue. Nonfocal symptoms include headache, drowsiness, nausea, and vomiting. When these symptoms appear without any other accompanying symptom or sign, they can be difficult to distinguish from the common disturbances of pregnancy. Conversely, focal symptoms such as motor or sensory deficits, cranial nerve dysfunc- tions, or seizure can be more promptly related to a new pathologic process in the central nervous system (CNS). A direct influence on tumor growth by hormonal changes has been hypothesized for glial tumors, but lit- tle experimental evidence has been demonstrated (6). Glial tumors are often surrounded by brain edema, which is thought to be the result of incompetent neoplastic vessels that lack mature tight junctions between 387 Neuro-oncologic Diseases in Women Alessandro Olivi, MD and John J. Laterra, MD, PhD 28 T NEUROLOGIC DISEASE IN WOMEN 388 endothelial cells and thus allow extracellular fluid to accu- mulate in the vicinity of the brain tumor. The tendency to retain extra- and intracellular fluid during pregnancy is considered a predisposing factor for the development of more extensive perineoplastic edema and, subsequently, more severe symptoms (7). Diagnosis When an intracranial lesion is suspected, the standard diagnostic test is a high-resolution computed tomographic (CT) scan or magnetic resonance imaging (MRI) performed with and without intravenous contrast. The MRI remains the imaging test of choice because it can provide precise information about the configuration of the lesion, its relative vascularity, the presence of a cystic component or obstructive hydrocephalus, and the extent of mass effect on the surrounding structures. It is also a test that does not expose the pregnant woman to ionizing radiation. Rarely, an angiogram is needed to complete the assessment. Special sequences on the MRI or a magnetic resonance angiogram (MRA) can provide enough information about the vascular component of the brain tumor. Treatment When a glial tumor is accessible, and removal does not involve unacceptable loss of essential brain function, a surgical resection is recommended. This treatment allows tissue sampling for accurate diagnosis and a longer survival both in highly malignant and less aggressive glial tumors (8). For deep-seated lesions or tumors in direct proxim- ity to eloquent portions of the brain, stereotactic biop- sies are performed. These procedures allow the clinician to obtain the initial diagnosis of the tumor with a very low rate of morbidity. Conventional external beam radiotherapy plays a very important role in the treatment of aggressive glial tumors as an adjuvant measure after surgery. In addition, chemotherapeutic regimens in selected patients may play a role in prolonging survival in patients affected with malignant gliomas (9). More recently, stereotactic radiosurgery using precisely converging radiation beams (gamma knife and linear accelerators) has been used as an alternative to surgery for the treatment of small, deep- seated lesions (10). In pregnant women with glial tumors, the treatment plan must be individualized. Surgery is usually indicated when the tumor is causing progressive symptoms or con- siderable mass effect and increased intracranial pressure. If the increase in intracranial pressure is the result of obstructive hydrocephalus, a shunting procedure should be performed. Conversely, if the tumor is not producing significant mass effect and the clinical condition is stable, the option to postpone any kind of invasive procedure until after delivery is available. In this situation, however, the patient should be followed up closely with frequent neurologic examinations and neuroimaging studies and, if nec- essary, with medical therapy (e.g., steroids, antiepileptic drugs [AEDs]) throughout the pregnancy. The most common medical therapy for these lesions consists of synthetic corticosteroids, which are very effective in reducing perineoplastic brain edema, and AEDs for seizure control. Both these treatment modalities should be used very cautiously in pregnant women because of their possible consequences to the fetus (see Chapter 4). In particular, the use of prolonged doses of corticosteroids can cause hypoadrenalism in infants, and teratogenicity has been reported with the use of AEDs (11). Therefore, the use of AEDs should be limited to pregnant women with generalized tonic-clonic seizures or multiple seizures that would jeopardize the health of mother and fetus. Special recommendations should be given to women receiving radiotherapy and chemotherapy during childbearing years. In view of the possible effects on the embryo and the fetus, it is recommended that these women adhere to a strict birth control regimen or practice sexual abstinence during the entire time of treatment. As to pregnant women, in most instances, these therapies can be postponed until after delivery. However, if the treatment is required during gestation, some important safety precautions should be taken to protect the fetus. Acute radiation of 100 rads or more through the 15th week of gestation represents a substantial risk for either abortion or mental retardation and congenital defects to the surviving embryo (12). Given the relatively long distance from the maternal brain to the developing fetus, however, and the limited scattering of the ionizing radiation through the body, the use of appropriate lead shielding can reduce radiation diffusion and adequately protect the fetus from dangerous radiation levels. Except in extenuating circumstances, chemotherapeutic agents should be avoided during pregnancy (13). Animal studies have identified the teratogenic effects of carmustine (BCNU), the most widely used agent for malignant gliomas, when it is given early in pregnancy (14). Although there is no evidence of increased risk of teratogenicity associated with the administration of cytotoxic drugs in the second and third trimesters (15,16), the general recommendation is to postpone systemic chemotherapy until after delivery, if possible. Interstitial chemotherapy consisting of BCNU-impregnated poly- mers placed directly into the tumor bed at the time of surgical resection has recently been approved by the Food and Drug Administration (FDA) in the form of Gliadel ® . Although this ideal administration of BCNU dramatically reduces drug delivery to system organs, information regarding its safety during pregnancy is lacking. Finally, because of the likelihood for chemotherapeutic agents NEURO-ONCOLOGIC DISEASES IN WOMEN 389 to be secreted in human milk, breast-feeding is not advised while receiving chemotherapy. PITUITARY TUMORS Pituitary adenomas are the most common intrasellar lesions, comprising 5 to 8% of all intracranial tumors. They have a peak incidence in women of childbearing age (17). They manifest with an endocrinopathy and local mass effect. Functional adenomas produce excessive quantities of pituitary hormones, causing characteristic symptoms. Prolactin-secreting tumors cause the amenorrhea-galactorrhea syndrome; growth hormone–secreting adenomas may produce acromegaly; and ACTH- secreting tumors may cause Cushing’s syndrome. Because of these hormonal symptoms, functional adenomas often can be diagnosed while they are still small. Nonfunctional adenomas are usually manifested by direct compression of the surrounding structures. This can result in pituitary stalk compression and subsequent pituitary insufficiency, optic chiasm compression causing bitemporal hemianopsia, and cavernous sinus compression causing oculomotor problems. Headaches usually are associated with pituitary adenomas and probably are caused by stretching of the surrounding sensory inner- vated dural membranes. Because of the frequent infertility associated with this tumor, it is rare to find them in pregnancy. In those cases in which the reproductive cycle is not affected, however, or when medical treatment such as bromocriptine has restored normal ovulatory function, this association can occur. The well-documented increase in size of the normal pituitary gland during pregnancy, plus the reported observation that pituitary adenomas may expand more rapidly in pregnant women (18), warrant close clinical monitoring of this particular population. The effect of pregnancy on the size of pituitary adenomas is reported more frequently in patients with macroadenoma than in those with microadenoma and usually is more accentuated in the second and third trimesters. Thus, such patients should be followed up closely with ophthalmologic testing and labora- tory and imaging studies to monitor disease progression. Pituitary adenomas can rarely present with “pituitary apoplexy.” This event is caused by acute hemorrhage within the pituitary adenoma that causes a rapid increase of the intrasellar pressure. Violent headaches, rapid deterioration of vision, nausea, and vomiting are the common presenting symptoms. Pituitary apoplexy is a condition that requires emergency surgical treatment to avoid progression of the deficit and possible death. Diagnosis Endocrinologic and neuro-ophthalmologic evaluation should be performed in any patient with a suspected pituitary tumor. A general baseline determination of anterior and posterior pituitary function should be completed with the measurements of serum prolactin, early morning cor- tisol, serum gonadotropins, urine volume, serum elec- trolytes and osmolarity, and a thyroid profile. A formal neuro-ophthalmologic evaluation including visual field assessment should be completed. A high-resolution CT scan or MRI remains the test of choice. In particular, MRI scans can allow the detection of even small tumors using special coronal sections following intravenous injection of paramagnetic contrast agents, such as gadolinium. MRI scans also enable the visualization of the details of the vascular structures and may eliminate the need for angiography in the evaluation of these patients. High-resolution CT scans provide detailed definition of the sella and surrounding bony structures. This information is particularly valuable in the preoperative evaluation of the sphenoidal bones when a transsphenoidal resection is planned. Treatment Medical treatment involves controlling the growth of functional adenomas such as prolactin-secreting adenomas. Bromocriptine is particularly effective. Patients with prolactinomas presenting with a classic amenorrhea- galactorrhea syndrome and placed on bromocriptine may resume regular ovulatory cycles and subsequently become pregnant. To minimize any possible effects of bromocriptine on the developing fetus, it is recommended that women discontinue the medication while trying to con- ceive (19). Other medical therapies for less frequent hyperfunctional pituitary adenomas include a somato- statin analog (SMS-201–995) for acromegaly and cypro- heptadine and ketoconazole for Cushing’s disease. A transsphenoidal resection of the tumor is indicated when patients do not respond to the medical therapy, if there is clear progression of the disease with compression of surrounding structures (i.e., optic chiasm causing visual field loss), and if pituitary apoplexy occurs. Radiother- apy can be used as an adjunctive measure after surgery if the residual tumor is particularly large. In rare cases, radiotherapy is the initial form of treatment. Generally, pregnant women affected by pituitary adenomas can be safely followed up clinically with frequent ophthalmologic evaluations and MRI scans. Med- ical management can be quite effective even in pregnant patients. Only a small portion of these patients require further surgical treatment before parturition. MENINGIOMA Meningiomas are tumors that clearly appear more frequently (20) in females than in males, with a ratio of 2:1 to 3:1. Meningiomas originate from the meninges and NEUROLOGIC DISEASE IN WOMEN 390 generally are slow growing. The expression of hormonal receptors in these tumors has been of particular interest. Progesterone receptors are commonly found in these tumors and estrogen receptors occur, although at much lower frequency (4). The clinical presentation of meningioma is determined by their location. Presenting symptoms can include mental status changes, lethargy, and apathy. In tumors that become large enough to increase intracranial pressure, headaches and visual symptoms can occur. Focal irritative signs such as focal motor or com- plex-partial seizures can occur in tumors located next to the motor strip or other areas of the sensitive cortex. Motor or sensory loss also can be the initial manifestation of these tumors. Pregnant women may have a more rapid increase in size of these tumors, presumably because of rapid vascular engorgement as a result of the generalized increase in blood volume during pregnancy (21). There also may be a direct hormonal effect on the rate of tumor growth, presumably via progesterone and estrogen receptor stimulation. The appropriate diagnosis of these tumors is based on CT and MRI studies. An MRA or traditional angiography can be useful in determining the vascularization of these tumors. Treatment Whenever possible, surgical resection remains the only definitive treatment for these benign tumors. Pregnant women affected by meningioma can be followed up very closely in view of the usually slow-growing character- istics. It is therefore generally safe to defer surgery until after pregnancy, unless progression of the disease becomes significant. Repeat surgical resection may be an option in the setting of local recurrence. Radio- surgery or external beam radiotherapy also can be effective therapies following biopsy of a meningioma that is believed to be unresectable due to location or after tumor recurrence. OTHER TUMORS A number of less frequently encountered tumors can occur in women. Acoustic neuroma, ependymoma, hemangioblastoma, medulloblastoma, and choroid plexus papilloma are among them. Again, in general, the incidence of these tumors is not higher in women than in men, and the therapeutic recommendations are simi- lar. Special consideration should be paid to metastatic tumors in general and metastatic choriocarcinoma and breast cancer in particular. The treatment of these tumors is largely palliative and varies according to the nature of the primary tumor and the extent of the systemic and CNS dissemination. Choriocarcinoma can occur during pregnancy and can also metastasize to the brain. This tumor originates from the trophoblast that produces human chorionic gonadotropin and has a known tendency to hemorrhage spontaneously. This can cause rapid deterioration of the neurologic condition, and urgent surgical resection is indicated. In general, when dealing with a solitary brain metastasis, surgical resection followed by whole brain radiotherapy is the treatment of choice (22). More recently, surgical treatment in selected cases has been recommended even in cases in which two or three metastases are present, with the aim of providing the patient with an improved qual- ity of life (23). The radiosensitivity of these tumors and response to radiotherapy should be considered. In women, breast cancer is the most common tumor to metastasize to the brain, followed by lung cancer. This differs from men, in whom the most common metastases to the brain are from primary lung carcinoma. Metastatic breast cancer to the brain usually is approached in the same fashion with surgery, radiotherapy, and in selected cases, chemotherapy. Radiosurgery recently has been used as an alternative or as an adjunctive treatment for metastatic tumors to the brain. The advantages are that it can be given on an outpatient basis, and it is readily applied to deep-seated brain metastases or multiple inoperable tumors. However, it is still unclear whether radiosurgery is more advanta- geous than traditional surgical intervention in prolonging survival. PARANEOPLASTIC SYNDROMES Structures within the central or peripheral nervous sys- tems can be injured as a result of the paraneoplastic effects of cancers that do not directly involve the nervous system. Some of the best-characterized paraneoplastic neurologic syndromes result from cancers that occur exclusively in women. Most if not all paraneoplastic neurologic disorders are believed to be immune- mediated by the systemic cancer initiating an anticancer immune response that causes autoimmune neuronal injury (24). This mechanism is supported by the strong association between specific paraneoplastic neurologic syndromes and specific diagnostic antibodies directed against tumor-associated antigens sharing epitopes with macromolecules expressed by the affected neurons. Para- neoplastic neurologic disorders are relatively rare, appearing in approximately 1 in 10,000 patients with systemic cancer. Paraneoplastic syndromes typically develop as the initial sign of underlying cancer (25). Recognizing these unusual syndromes is essential to their rapid diagnosis and treatment. Specific paraneoplastic neuronal syndromes including their most commonly associated malignancies and anti- NEURO-ONCOLOGIC DISEASES IN WOMEN 391 bodies are listed in Table 28.1. The paraneoplastic syndromes specific to women are those associated with gynecologic and mammary cancers. These include anti-Yo+ cerebellar degeneration (25,26), anti-Ri+ opsoclonus- myoclonus (27), anti-amphihysin+ stiff-man syndrome (28,29), and cancer-associated retinopathy (30). The relative incidence of the other syndromes in men versus women is in general determined by the relative incidence of their underlying associated malignancies. Essentially, any part of the nervous system can be affected by paraneoplastic autoimmune mechanisms. The neurologic deficits of paraneoplastic neuronal injury reflect the specific neuronal sites of injury and typically develop subacutely over the course of a few weeks followed by symptom stabi- lization. Spontaneous improvement in the absence of therapy directed at either the neurologic disorder or underlying cancer points strongly to an alternate diagnosis. Diagnosis Because these syndromes develop most commonly in otherwise healthy individuals, a meticulous search for the underlying cancer is mandatory. Evaluations should include CT of the chest, abdomen and pelvis, mammog- raphy, and whole body glucose positron emission tomog- raphy (PET) to locate any occult malignancy. Elec- tromyography and nerve conduction studies should be performed in the setting of neuropathy or suspected neuromuscular junction defect. Cerebrospinal fluid analysis frequently reveals nonspecific abnormalities such as mild pleiocytosis, mildly elevated protein, elevated IgG/albumin ratio, and the presence of oligoclonal bands. The identifi- cation of specific paraneoplastic antibodies in blood can help make a specific diagnosis and can guide the search for occult malignancy (i.e., anti-Yo antibodies and ovarian carcinoma). Treatment Therapy focuses on treating the underlying malignancy. Immune-specific approaches to inhibit humoral and cel- lular autoimmune mechanisms should also be initiated in patients displaying an objective progression of neurologic deficits. The benefits of immune-based therapies remain unpredictable and controversial. Initiating treatment early is critical to preserving neurologic function. Therapy may minimize progression of neurologic deficits but typically will not reverse deficits resulting from paraneoplastic autoimmune neuronal death (e.g., anti-Yo paraneoplastic cerebellar degeneration). In contrast, deficits due to ion channel dysfunction (e.g., Lambert- Eaton syndrome) may improve with treatments that target the blood-borne pathogenic antibodies (31,32). Increasing evidence suggests that cytotoxic T-cell responses play a fundamental role in the pathogenesis of these disorders (33). Patients presenting with paraneoplastic neurologic syndromes tend to have more favorable cancer outcomes than others with the same malignancy. This is likely due to the combination of early cancer diagnosis and the antineoplastic effects of the immune response to tumor-associated antigens. For the majority of the syndromes, generally a small temporal window exists for impacting positively upon neurologic outcome. CONCLUSION Neuro-oncological problems in women are diagnosed and treated by balancing the health risks from the tumor against temporary health issues such as pregnancy. In gen- TABLE 28.1 Paraneoplastic Neurologic Disorders Syndrome Antibody Tissue Target Malignancy Cerebellar degeneration Anti-Yo Purkinje cell Ovarian, breast, lung Ataxia Ϯ opsoclonus-myoclonus Anti-Ri CNS neurons Breast, gynecologic, bladder Stiff-man syndrome, Anti-amphiphysin Presynaptic terminals Breast, lung encephalomyelitis Retinopathy Anti-retinal Ganglia, photoreceptors Gynecologic, lung, melanoma Lambert-Eaton Anti-voltage-gated Presynaptic Small cell lung K + channel neuromuscular junction Encephalomyelitis, sensory Anti-Hu Neurons Lung, prostate Neuronopathy, cerebellar degeneration Encephalitis, cerebellar degeneration Anti-MA1/2 Neurons Lung, testes Peripheral neuropathy Anti-MAG Peripheral nerve Waldenströms macroglobulinemia [...]... 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In: Devinsky O, Feldmann E, Hainline B, (eds.) Neurological complications of pregnancy . New York: Raven Press, 199 4; 153–162. NEUROLOGIC DISEASE IN WOMEN 386 33. Weinstein. Listeriosis during pregnancy and in the newborn. Epidemiol Infect 199 0;104:181– 190 . 21. Ampel NM, Wieden MA, Galgiani JN. Coccidioidomy- cosis: clinical update. Rev Infect Dis 198 9;11: 897 91 1. 22 disorders. Particular care is likewise required in determining the appropriateness of vaccines against neurologic infections during pregnancy. Women taking contraceptive pills or hormone supple- ments

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