Neurologic Disease in Women - part 8 ppt

NEUROLOGIC DISEASE IN WOMEN 332 148. Beeson PB. Age and sex associations of 40 autoimmune diseases. Am J Med 1994;96:457–462. 149. Buchbinder R, Hill CL. Malignancy in patients with inflammatory myopathy. Curr Rheum Rep 2002;4: 415–426. 150. Callen JP. Relationship of cancer to inflammatory muscle diseases. Dermatomyositis, polymyositis, and inclu- sion body myositis. Rheum Dis Clin North Am 1994;20: 943–953. 151. Cormio G, DiVagno G, Loverro G, Selvaggi L. Polymyositis and vaginal carcinoma. Arch Gynecol Obstet 1993;253:145–147. 152. Kubo M, Sato S, Kitahara H, Tsuchida T, Tamaki K. Vesicle formation in dermatomyositis associated with gynecologic malignancies. J Am Acad Dermatol 1996; 34:391–394. 153. Whitmore SE, Rosenshein NB, Provost TT. Ovarian cancer in patients with dermatomyositis. Medicine (Balti- more) 1994;73:153–160. 154. Cherin R, Piette JC, Herson S, et al. Dermatomyositis and ovarian cancer: a report of 7 cases and literature review. J Rheumatol 1993;20:1897–1899. 155. 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Induction of neurasthenic musculoskeletal pain syndrome by selective sleep stage deprivation. Psychosom Med 1976;38:35–41. onnective tissue diseases and some types of vasculitis disproportion- ately affect women. The rheumato- logic diseases in women that most frequently have neurologic manifestations are Takayasu arteritis, giant cell arteritis, systemic lupus erythematosus (SLE), Sjögren’s syndrome, rheumatoid arthritis (RA), and scleroderma. Medium-vessel vasculitides, including Wegener granulomatosis and polyarteritis nodosa, do not have a special female predominance and are not covered in this chapter. The neurologic manifestations of rheumatic diseases often require long-term corticosteroid therapy, leading to corticosteroid complications (such as cataracts and osteoporosis) in many patients. The treatment of women during pregnancy presents particular problems in management, both because the diseases (and their activity) can be difficult to diagnose and follow and because many of the effective medications are either contraindicated during pregnancy or, as is the case with corticosteroids, aggravate hyperglycemia, osteoporosis, and preeclampsia. Antiphospholipid antibody syndrome (APS) is a hypercoagulable state that occurs equally in patients with connective tissue diseases, usually lupus, and in a primary form, without known autoimmune disease. Many of these patients are women. APS has many neurologic presentations, including transient ischemic attack (TIA), stroke, chorea, and transverse myelopathy (see also Chapters 17 and 24). The neurologic manifestations of connective tissue diseases, vasculitis, and APS are reviewed in this chapter. TAKAYASU ARTERITIS Takayasu arteritis is a large-vessel vasculitis that predominantly affects young women, with a sex ratio of 9:1. Most patients present between 15 and 25 years of age. In the United States, the incidence is very low, at 2.6 per million per year (1); it is more common in Asia (2,3). It is a vasculitis of the aorta and major branches, typically presenting as a two-stage illness. In the first stage, systemic phase (“pre-pulseless”), symptoms include fever, malaise, night sweats, arthralgias, myalgias, and tender arteries (4). In the late “pulseless” phase, there are symptoms of ischemia, with claudication, headache, syncope, paresthesia, and visual disturbance (5,6). Many patients do not follow the two-stage pattern, however. On physical examination, the classic findings are those of decreased pulses (especially carotid, radial, ulnar, and brachial), blood pressure differential between the arms, and bruits over vessels, especially the subclavian arteries or aorta. Laboratory abnormalities include an elevated erythrocyte sedimentation rate (ESR) in most patients. Arteriography is the usual mode of diagnosis, 335 Neurologic Presentations of Autoimmune Disorders in Women Michelle Petri, MD, MPH 22 C NEUROLOGIC DISEASE IN WOMEN 336 revealing one of three patterns: type I, with aortic arch and branch involvement; type II, with involvement of the descending thoracic and abdominal aorta; and type III, a combination of type I and type II (7,8). Neurologic presentations include syncope, stroke, or TIA; limb weakness from vascular insufficiency; dizziness; and multiple ocular manifestations (diplopia, amaurosis, and retinal changes) (Table 22.1) (1,3,9,10). Treatment is often delayed because most patients are not diagnosed in the early phase, in which most symptoms are systemic (fever, malaise). Treatment with corticosteroids is helpful in improving these systemic symptoms and slowing, progression of vascular occlusion (1,11,12). Some patients require additional immunosup- pression, using azathioprine, cyclophosphamide, or methotrexate (13). Those patients who have fixed claudication or major vascular insufficiency may require angioplasty (13–15) or bypass procedures (16). GIANT CELL ARTERITIS Giant cell arteritis (GCA), or temporal arteritis, is more common in women than in men, with similar clinical presentations in both sexes. Most affected patients are over the age of 50. In the United States, it is more common in people of Scandinavian extraction. Giant cell arteritis is one of the most frequent types of vasculitis, with an incidence of 20 to 30 per 100,000 (17). Typical presentations include headache, amaurosis fugax, muscle and joint aches and pains (with a shoulder-hip gir- dle predominance and morning accentuation, i.e., polymyalgia rheumatica), jaw claudication, scalp tenderness, fever, and sometimes cough or sore throat (Table 22.2). Physical examination may reveal enlargement, beading (alternating enlargement and narrowing), and tenderness of the temporal arteries. The laboratory examination may show the classic triad of a greatly elevated ESR, anemia, and elevated alkaline phosphatase. Diagnosis is based on the characteristic large-vessel vasculitis with giant cells on temporal artery biopsy. Because the vasculitis may skip certain regions, a large segment is obtained and bilateral biopsies should be done if the first one is negative. It is extremely unusual to have biopsy-negative GCA or to have a normal ESR before treatment. Treatment is initially high-dose corticosteroids (usually 40 to 60 mg of prednisone daily). The ESR usually falls promptly, with relief of symptoms following shortly thereafter. The high doses of corticosteroids are usually reduced gradually after the first 4 to 6 weeks, with maintenance therapy often required for a year or longer. It is not necessary to normalize the ESR; it is more important to follow the important symptoms and signs of disease, including headache and visual disturbance. Both sexes are at risk for corticosteroid complications, including dia- betes mellitus; infections; increase in cardiovascular risk factors such as weight, hypertension, and hyperlipidemia; and osteoporosis. Because nearly all women who have this disease are postmenopausal, it is extremely important to treat presumptively for corticosteroid-induced osteoporosis using calcium, vitamin D, and bisphosphonates (either daily or weekly alendronate). Because the Women’s Health Initiative study showed an increase in cardiovascular events in women randomized to hormone replacement therapy (HRT), it is no longer recommended for osteoporosis. TABLE 22.1 Presentations of Takayasu Arteritis Typical Presentation – Female patient under 40 years of age – Clinical features include systemic symptoms (malaise, fever) followed by symptoms due to vascular occlusion (arterial bruits and absent pulses) Neurologic Presentations – Brain – Dizziness – Syncope – Stroke/transient ischemic attack – Headache – Ocular – Difficulty with upward gaze – Visual impairment – Hypertensive retinopathy – Limb weakness TABLE 22.2 Presentations of Giant Cell Arteritis Typical Presentation – Patient over 50 years of age – Clinical features include malaise, headache, jaw claudication, visual disturbance, scalp tenderness, and/or polymyalgia rheumatica – Laboratory features include a greatly elevated ESR, anemia, and/or elevated liver function tests (alkaline phosphatase) Neurologic Presentations – Brain – Headache – Amaurosis fugax – Blindness – Diplopia – Focal cerebral ischemia (transient ischemic attacks, strokes) – Peripheral neuropathy NEUROLOGIC PRESENTATIONS OF AUTOIMMUNE DISORDERS IN WOMEN 337 SYSTEMIC LUPUS ERYTHEMATOSUS Systemic lupus erythematosus (SLE) is the classic example of an autoimmune disease, with a 9:1 female-male ratio and a disproportionate predilection for African-Ameri- cans. It usually has its clinical onset post puberty; the sex ratio is equal before puberty. Although the cause is unknown, several predisposing factors have been identi- fied. Genetic factors include HLA-D alleles and null (lack of the gene product for C4 or C3, due to either deletion or mutation) complement alleles. Environmental factors include exposure to ultraviolet light and sulfa antibiotics (18). Hormonal factors include oral contraceptive pills (although this may have been more true for pills in the past that contained more estrogen) and pregnancy (19). The diagnosis of SLE is made by history, physical examination, and confirmatory laboratory tests. The history reveals symptoms or signs in multiple organ systems. Frequent presenting symptoms and signs include malar (erythematous rash on the cheeks) or discoid (deeper, inflammatory rash healing with scarring, often hyper- or hypopigmentation) rash, photosensitivity, oral ulcers, alopecia, polyarthritis, and fever. Physical examination will confirm the presence of lupus rashes, reveal whether there is serositis (pleural rub or effusion and/or pericar- dial rub), and demonstrate polyarthritis, characteristically involving the proximal interphalangeal (PIP), metacar- pophalangeal (MCP), and wrist joints of both hands. Some manifestations of SLE are only apparent through laboratory testing, including, in some but not all patients, hemolytic anemia, leukopenia, lymphopenia, thrombocytopenia, elevated ESR, elevated creatinine, hematuria and red blood cell casts, and proteinuria. Serologic tests can be helpful in the diagnosis: A positive antinuclear antibody (ANA) is found in 95% of patients with SLE, but a positive ANA is also found in up to 20% of normal young women. Therefore, a diagnosis of lupus can never be based on a positive ANA alone; evidence of a multiorgan (some combination of dermatologic, musculoskeletal, renal, serositis, hematologic, and neurologic manifestations) systemic disease should exist. Other serologic tests are more specific but are not found in all patients. The autoantibodies anti-dsDNA and anti-Smith (anti-Sm) are found only in SLE. Other autoantibodies, including anti-Ro, anti-La, and anti-RNP, can be found in other connective tissue diseases as well as in SLE. Many patients with SLE will also have evidence of complement consumption, with decreased levels of serum complement (C3, C4, or both). Other connective tissue diseases, vasculitis, and cryoglobulinemia can also cause complement consumption. Two neurologic events (seizures—due to lupus, not due to a prior stroke—and psychosis) are part of the neurologic criterion for SLE (four of eleven American Col- lege of Rheumatology criteria must be present to classify patients as having SLE for research purposes) (20). The eleven criteria include malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, serositis, renal disorder, neurologic disorder, hematologic disorder, immunologic disorder, and positive ANA. The neurologic criterion consists of seizures and psychosis. In the Hopkins Lupus Cohort, our longitudinal study of SLE, only 11% of the cohort have had seizures or psychosis due to SLE. Other neurologic events are actually more common (Table 22.3), including other brain involvement and cranial nerve, cord, and peripheral nervous system manifestations. Brain involvement in SLE includes stroke, meningitis, seizure, organic brain syndrome, coma, cognitive function abnormalities, chorea, psychosis, and lupus TABLE 22.3 Presentations of Systemic Lupus Erythematosus Typical Presentations – Female patient, post puberty, and premenopausal – Clinical features include fever, fatigue, photosensitivity, malar rash, discoid lupus, aphthous ulcers, polyarthritis, lupus nephritis (hematuria and proteinuria), serositis (pericarditis and pleurisy), hemolytic anemia, leukopenia, thrombocytopenia, seizures, and/or psychosis – Laboratory features include hematologic abnormalities, renal abnormalities, positive ANA, multiple organ autoantibodies, and/or low serum complement (C3, C4) Neurologic Presentations – Brain – Stroke – Meningitis – Organic brain syndrome/delirium – Coma – Cognitive function deficits – Chorea – Psychosis – Headache – Pseudotumor cerebri (see APS) – Cranial neuropathy – Spinal cord – Transverse myelopathy – Peripheral nerve – Entrapment neuropathy, especially carpal tunnel syndrome – Peripheral neuropathy – Mononeuritis multiplex – Demyelinating neuropathy – Autonomic neuropathy (rare) – Muscle – Polymyositis – Steroid myopathy – Myasthenia gravis NEUROLOGIC DISEASE IN WOMEN 338 headache (21). The American College of Rheumatology has recently codified neuropsychiatric manifestations of SLE (22). Some strokes are not due to active SLE but to other disease processes or to comorbid conditions, including hypertension. For example, some SLE patients have a hypercoagulable state APS, which can present as a TIA or stroke. This syndrome is discussed in detail later in this chapter. Additionally, SLE patients who have been receiving maintenance corticosteroids are at risk for premature atherosclerosis. Brain magnetic resonance imaging (MRI) is a more sensitive test than a computed tomographic (CT) scan to detect infarcts and other lesions from SLE (23). Strokes due to active SLE often do not have demon- strable vasculitis on angiogram, although there are excep- tions (24). The vessel pathology is usually a small-vessel vasculopathy (25,26). Organic brain syndrome (encephalopathy) and coma are frightening manifestations of SLE that can sometimes occur very acutely, over days or a few weeks. As with other manifestations of CNS-SLE, other diagnoses need to be considered. Infections, multiple cerebral infarcts, tumor, intracranial bleeding, status epilepticus, metabolic states [syndrome of inappropriate secretion of antidiuretic hormone (SIADH), hepatic encephalopathy, uremia, myxedema], and drug toxicity may be mistaken for SLE flare and must be excluded. Nearly all patients will require a brain MRI scan and lumbar puncture. It is also important to perform an electroencephalogram to rule out the possibility of status epilepticus. Other diseases that can mimic SLE in this situation are thrombotic thrombocy- topenic purpura (TTP) and the catastrophic (i.e., life- threatening multiorgan vasculopathy and/or infarcts) presentation of APS. In TTP, fever, thrombocytopenia, and renal involvement would be additional clues leading to the diagnosis (discussed later in this chapter). An examination of the blood smear for schistocytes is crucial. Treat- ment with plasmapheresis is indicated for TTP and may be helpful in the catastrophic form of APS, when multiple organs fail due to vasculopathy and/or thrombosis. If the organic brain syndrome or coma is due to SLE, it is important to treat early (often while the patient is still in the emergency room) and effectively. Most patients are given intravenous “pulse” methylprednisolone, 1,000 mg daily over 90 minutes, for 3 days. This is the same dosage that is used for the treatment of renal transplant rejection. Many patients begin to show improvement within hours or a day of receiving the methylprednisolone. A patient who is slow to respond, or who is critically ill, may require additional treatment. Several studies have proven the efficacy of intravenous cyclophosphamide for severe CNS-SLE. It is usually given in doses between 750 and 1,000 mg/m 2 body surface area, initially once monthly for up to 6 months, provided that there are no concerns about bone marrow suppression (27,28). Because most SLE patients are young women, it is important that they be protected against some of the major complications of cyclophosphamide, such as hemorrhagic cystitis and bladder carcinoma. For that reason, we and others recom- mend that cyclophosphamide be preceded by prehydra- tion and that it be given with mesna, which binds toxic metabolites. A lupus patient who presents with symptoms or signs of meningitis must have a lumbar puncture. Patients with SLE, especially those who are receiving treatment with prednisone or immunosuppressive drugs, are at risk for both typical (i.e., pneumococcal) and opportunistic infections, including tuberculosis, cryptococcus, and can- didemia, all of which can be complicated by meningitis. Patients who have SLE may be more susceptible to infection by some viruses, such as herpes zoster, that can cause meningitis. Additionally, certain drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), especially ibuprofen, can rarely cause a drug meningitis in SLE patients (29). Lumbar puncture may show a number of different abnormalities in lupus meningitis, or in CNS-SLE in general, none of which are specific for SLE. These abnormalities include elevated protein, decreased glucose, pleocytosis, oligoclonal bands, and elevated IgG index. The measure of autoantibodies or complement in the cerebral spinal fluid (CSF) is not helpful diagnostically. If infection is ruled out, lupus meningitis is treated initially with high- dose corticosteroids. Seizures are less common in SLE patients today than they were decades ago, perhaps reflecting earlier diagnosis and treatment. In most series, SLE seizures are more common early in the disease course (21,30,31). Most seizures due to SLE are generalized tonic-clonic seizures (32–34). SLE seizures can occur as part of a systemic flare (i.e., activity outside the neurologic system) or can be isolated, without non–CNS-SLE activity. The etiology of SLE seizures is not understood. Antiphospholipid and/or anti- neuronal antibodies may, through direct binding to neural tissue, lead to a metabolic change that lowers the seizure threshold. An SLE patient with new-onset seizures needs a complete evaluation for CNS-SLE and non-SLE causes of seizures (35). The first question is whether the patient is having true seizures or pseudoseizures, such as syncope, movement disorders, narcolepsy, or psychogenic seizures (36). Second, potentially reversible conditions that cause seizures should be investigated. These include infections, metabolic derangements, medication toxicity (including phenothiazines, clozapine, radiographic contrast agents, and some SLE medications, such as antimalarial drugs, that are very rarely associated with seizures) and CNS- SLE. SLE patients with renal failure are at risk for seizure if they are given meperidine hydrochloride; we have seen this problem several times in postoperative patients. Third, it is important to ascertain whether a new focal cause of chronic epilepsy exists, such as a stroke or tumor. NEUROLOGIC PRESENTATIONS OF AUTOIMMUNE DISORDERS IN WOMEN 339 The evaluation of an SLE patient with new-onset seizure includes a search for infection, laboratory testing (complete blood count, electrolytes, BUN, creatinine, liver enzymes), medication review, and a search for activity of SLE outside the neurologic system. Lumbar puncture, EEG, and brain MRI with gadolinium are usually performed. If the seizures are due to active SLE, initial treatment consists of both corticosteroids and antiepileptic drugs (AEDs). Most seizures in SLE patients are tonic-clonic seizures, which can be successfully treated with phenytoin. Phenytoin can affect the metabolism of corticosteroids and, on rare occasions, causes a drug fever in SLE patients. Patients whose seizure was due to a reversible precipitant, such as infection or lupus flare (reactive seizures), may not need long-term AEDs. Cognitive function deficits, including problems with memory, concentration, and judgment, are probably the most common manifestations of CNS-SLE (37). They are also, unfortunately, one of the more nonspecific manifestations and are consequently very difficult to attribute to SLE alone (38). SLE, corticosteroids, other drugs (including tricyclic antidepressants and NSAIDs), and comorbid processes such as APS, dementia, and depression can also contribute to cognitive function abnormalities (39). Formal cognitive function tests are important in localizing the deficits, establishing a baseline, and can often suggest processes such as anxiety and/or depression as possible contributing causes. Patients with major cognitive function deficits should have a brain MRI with gadolinium as part of their evaluation. The role of brain single photon emission computerized tomography (SPECT) scan or brain positron emission tomography (PET) is limited because scans can be abnormal in patients without neurologic symptoms or signs (40,41). Treatment with corticosteroids is used if there is evidence of progression and if SLE is thought to be the primary cause (39). Most SLE patients have mild, stable deficits that may not require treatment with corticosteroids or alky- lating drugs. Chorea is a very unusual presentation of CNS-SLE (42). Its presence should always mandate evaluation for APS, especially if infarcts are found in the basal ganglia on brain MRI scan. Psychosis is an unusual manifestation of CNS-SLE. It may be associated with antiribosomal P antibody (43–45). Antiribosomal P does not have sufficient pre- dictive value to warrant testing for it in all SLE patients, however. Psychosis can also occur from steroid psychosis, infection, and very rarely, drugs such as antimalarials (including hydroxychloroquine and chloroquine). Psy- chosis, if due to active SLE, is treated with corticosteroids and major tranquilizers (such as haloperidol). Severe unremitting headache, unresponsive to nar- cotics and other general headache remedies, can occur as a result of SLE, but is unusual. Headache can be the first presenting sign of other SLE neurologic syndromes, including lupus meningitis, organic brain syndrome, pseudotumor cerebri, and stroke, but it can also represent an infection, tumor, or drug toxicity. Thus, a new severe headache, especially with neurologic symptoms or signs, should be evaluated with brain MRI and lumbar puncture to look for evidence of an opportunistic infection. Chronic recurrent headache is usually not due to lupus and should lead to an evaluation for the common causes of headache, especially migraine. SLE patients with antiphospholipid antibodies should be checked for dural sinus thrombosis. Cranial neuropathies, including Bell’s palsy, are rare in SLE, occurring in only 1 to 2% of patients. Some cases of trigeminal sensory neuropathy do not correspond to trigeminal branches and may be caused by medulla oblon- gata lesions (46). Most cranial neuropathies in SLE are due to vasculitis or infarction (47–49), although facial nerve palsy has been reported due to angioedema (50). The presence of a new cranial neuropathy, especially Bell’s palsy, should lead to an evaluation of other causes, including Lyme disease in endemic areas and space-occupying lesions. Cranial neuropathies due to SLE are treated with corticosteroids. Transverse myelitis can occur both from SLE (51) and from the APS (52,53). The differential diagnosis includes vertebral compression fractures (54), cord lipo- mas, infections (herpes zoster) (55), tuberculosis (56), and polyoma JC virus (57). In the case of SLE, lumbar puncture often shows elevated CSF protein, pleocytosis, and/or decreased CSF glucose (58,59). MRI of the cord may show increased signal intensity, edema, or infarct (60). Because of poor long-term function in many cases (61), if infection and compression fracture can be quickly ruled out with an MRI of the affected cord segment, it is important to institute effective treatment, such as intravenous pulse methylprednisolone, within hours of presentation (62). Those patients with relapsing or nonimproving courses can benefit from the addition of “pulse” intravenous cyclophosphamide. SLE is one of the more common causes of mononeuritis multiplex (63,64). Patients usually first present with pain, hypesthesia, and dysesthesia, followed by motor signs (including weakness). Nerve conduction studies confirm mononeuritis multiplex. If nerve-muscle biopsy is performed, vasculitis is usually demonstrated. Corticos- teroids in high doses are the initial therapy, but often it is necessary to add a second drug, such as azathioprine, to allow eventual reduction of the corticosteroid dose. Patients with SLE can also develop peripheral neuropathy (65), entrapment neuropathies (especially carpal tunnel syndrome), demyelinating neuropathy, and autoimmune neuropathy (66,67). Muscle weakness in an SLE patient can be due to polymyositis, typically with proximal accentuation, and NEUROLOGIC DISEASE IN WOMEN 340 with elevated creatinine phosphokinase (CPK) and/or aldolase. The diagnosis can be confirmed through EMG and muscle biopsy. In a corticosteroid-treated patient, the possibility of steroid myopathy must be considered. Elec- tromyography and muscle biopsy are helpful to rule out inflammatory myopathy, but improvement with corticosteroid reduction is the sine qua non. An occasional patient with SLE may also develop myasthenia gravis (68). All SLE patients with muscle weakness and/or elevated CPK should be checked for hypothyroidism. SJÖGREN’S SYNDROME Sjögren’s syndrome is predominantly a disease of middle- aged women, affecting between 2 and 5% of adults over 55 years of age (69–71). The usual presenting symptoms and signs are dry eyes and mouth, with keratoconjunctivitis sicca and decreased salivary pool. Some patients have parotid enlargement or hepatosplenomegaly. The diagnosis can be confirmed by an abnormal Schirmer test or rose bengal staining in the case of keratoconjunctivitis sicca, or minor salivary gland biopsy (showing inflammation and/or fibrosis) in the case of dry mouth. Many patients have anti-Ro (also called anti-SSA) and anti-La (also called anti-SSB) autoantibodies in the serum. The prevalence of severe neurologic disease in Sjö- gren’s syndrome is controversial. Alexander and colleagues reported neurologic complications in as many as 20% of patients (72). Other centers have reported mostly mild neurologic symptoms, which are often explained by the primary autoimmune disease in patients with secondary Sjögren’s syndrome (73,74). Most centers report predominantly cranial (especially trigeminal) neuropathy (75) and mild sensory or mixed peripheral neuropathies (76). Severe CNS-Sjögren’s disease is not common, except perhaps in referral centers where there is likely to be a selection bias (77). Clinically, it can resemble multiple sclerosis, with multifocal events occurring over months to years. Presentations include CNS involvement (spas- ticity, visual loss, ataxia, hemiparesis, cranial neuropathy, dysarthria, nystagmus, and internuclear ophthalmoplegia) and cord involvement (transverse myelopathy and neurogenic bladder) (Table 22.4). Evoked potential and CSF abnormalities are frequently found. In the series of Alexander and colleagues, 16 of 18 patients had one or more oligoclonal bands, and 10 patients had an elevated IgG index (77). CNS-Sjögren’s disease is treated in a similar fashion to CNS-SLE, using high-dose corticosteroids and the addition of cyclophosphamide in severe or refrac- tory cases. The most common neurologic presentation is peripheral neuropathy (72,73,77–81). Mononeuritis multiplex can also occur (82). A pure sensory neuropathy caused by a lymphocytic infiltration of the dorsal root ganglia has been reported, sometimes preceding the diagnosis of Sjögren’s disease itself. Patients who have this disorder present with an asymmetric sensory deficit, initially in the hands, often in association with Adie’s pupil or trigeminal sensory neuropathy (76,83). Progressive major peripheral neuropathy is treated with corticosteroids. RHEUMATOID ARTHRITIS Rheumatoid arthritis (RA) preferentially affects females, with a ratio of 4:1. It is one of the most common autoimmune diseases, affecting 1% of postmenopausal women. The disease may present in the late twenties or thirties, but many patients present in the peri- or postmenopausal years. Although the cause is unknown, genetic factors are important. One of the most important is the “shared epi- tope,” an HLA sequence that confers susceptibility (84). Hormonal factors play a role in the pathogenesis of the disease. Epidemiologic evidence exists that oral contra- TABLE 22.4 Presentations of Sjögren’s Syndrome Typical Presentation – Female patient, postmenopausal – Clinical features include keratoconjunctivitis sicca and dry mouth Neurologic Presentations – Brain – Stroke (72) – Nystagmus – Cerebellar ataxia – Seizures – Hemianopsia – Unilateral internuclear ophthalmoplegia – Optic neuropathy (78) – Vasculitis (79) – Multiple sclerosis–like (77) – Meningitis (80) – Cognitive function deficits (81) – Migraine headache (156) – Cranial neuropathy – Spinal cord – Transverse myelitis/myelopathy (157) – Spinal subarachnoid hemorrhage – Peripheral nerve – Entrapment neuropathy, especially carpal tunnel syndrome – Peripheral neuropathy – Sensory (75,158–160) – Motor – Mononeuritis multiplex (82) – Muscle – Polymyositis NEUROLOGIC PRESENTATIONS OF AUTOIMMUNE DISORDERS IN WOMEN 341 ceptive use may be protective, and the disease often remits during pregnancy (85). Remissions during pregnancy are due to HLA mismatch between the woman and her part- ner (86). There is great interest in the role of the nervous system in the pathophysiology of RA, especially in terms of the symmetric nature of the polyarthritis and the pref- erence for distal joints (87). For example, substance P is able to activate rheumatoid synoviocytes (88). RA presents as a symmetric arthritis of the joints of the hand (MCP and PIP joints) and wrist (carpal joints) (Table 22.5). Pronounced morning stiffness occurs. Even- tually, many joints may be involved, including elbows, shoulders, knees, ankles, and tarsal joints. Severe disease results in joint erosions and deformities. Laboratory abnormalities include anemia (usually the anemia of chronic disease, although an anemia that is responsive to erythropoietin is also found), elevated ESR, thrombocy- tosis, and hypergammaglobulinemia. Some patients have rheumatoid factor, an IgM autoantibody that is directed against IgG. The treatment of RA consists of drugs that help to suppress acute inflammation, such as NSAIDs and prednisone, and drugs that are “disease-modifying,” slowing the progression of erosive changes and deformities. The major oral disease-modifying drugs that are used in the United States are methotrexate and leflunamide (in Europe, azulfidine is also widely used). Neither are allowed during pregnancy. Other disease-modifying drugs that are used include hydroxychloroquine, azathioprine, and cyclosporine. These are continued during pregnancy only if absolutely required for the health of the mother. Because RA often improves during pregnancy, it is usually possible to stop disease-modifying drugs. Gold and penicillamine have fallen into disfavor because of lower efficacy and greater toxicity. They are not used during pregnancy. Over the past few years, biologic agents that block tumor necrosis factor (etanercept, infliximab, adal- imunab) have been shown to be very effective for both the symptoms and signs of RA. These biologics are associated with an increase in extrapulmonary tuberculosis and may cause anti-dsDNA, anticardiolipin, or a drug- induced lupus; they worsen multiple sclerosis and con- gestive heart failure. They are not approved for use in pregnancy. Rheumatoid involvement of the CNS is very rare (89,90). Intracranial lesions include vasculitis (91,92), meningitis (93), and rheumatoid nodules (90,94). Seizures can be due to rheumatoid nodules (95) or to lep- tomeningitis (96). Rheumatoid pachymeningitis can be localized to a discrete location, such as the lumbar cord (97). Finally, normal pressure hydrocephalus has been reported in RA (98). Several of the neurologic complications of RA are directly related to joint swelling and deformity. Carpal tunnel syndrome is the most common nerve entrapment in rheumatoid patients and usually improves as the joint synovitis is controlled. Cock-up wrist splints and carpal tunnel corticosteroid injections are also beneficial treat- ments. Tarsal tunnel syndrome may occur in the foot. Other entrapment neuropathies found in RA include the posterior interosseous nerve, the femoral nerve, the per- oneal nerve, and the interdigital nerve (at the metatar- sophalangeal joint) (99,100). Life-threatening problems can arise from myelopathies due to cervical spine instability (101). C1–2 subluxation, due to destruction of the transverse ligament of C1 or erosion of the odontoid peg, can occur. Atlantoaxial impaction (pseudobasilar invagination or cranial settling) has occurred in 5 to 32% of patients in two series (102,103). Patients present with pain in the occipital area of the neck, retro-orbital area, or temporal area (101). Additionally, there may be upper and lower motor neuron signs, pathologic reflexes, vertebrobasilar insufficiency, and urinary and fecal incontinence (101). Lateral spine films taken in extension and flexion can help to confirm the diagnosis (104), but MRI and somatosen- sory evoked potentials may be needed (105). Neurosur- gical procedures to stabilize the cervical spine are necessary (106). Subluxation of the thoracic or lumbar spine has been reported with RA but is rare (107). Extra-articular neurologic manifestations of RA include mononeuritis multiplex and peripheral neuropathy. Mononeuritis multiplex is caused by rheumatoid vas- TABLE 22.5 Presentations of Rheumatoid Arthritis Typical Presentation – Female patient, peri- or postmenopausal – Clinical features include malaise, symmetric bilateral polyarthritis, especially of the joints of the hands and wrists, and/or rheumatoid arthritis Neurologic Presentations Brain – Meningitis – Vasculitis – Intracranial rheumatoid nodules – Normal-pressure hydrocephalus – Optic atrophy Spinal Cord – Pachymeningitis Cervical Myelopathy – C1–2 subluxation Peripheral Nerve – Entrapment neuropathy – Carpal tunnel syndrome – Tarsal tunnel syndrome – Peripheral neuropathy – Mononeuritis multiplex [...]... 1.2:1.0 to 1.7:1.0 (4) Incidence data for PD are scanty, but the few studies to date have supported the finding of higher rates in males (5) PD estimates in populations in Rochester, Minnesota, and northern California found a higher incidence of PD in men than women, with 13.0 349 NEUROLOGIC DISEASE IN WOMEN 350 and 19.0 per 100,000 in men, compared with 8. 8 and 9.9 per 100,000 in women, respectively... overall This, in addition to the higher incidence of PD in men discussed earlier, has led to investigations into the possible protective effects of estrogen and how hormonal states may influence the disease Animal studies have documented that estrogen increases dopamine concentrations in the brain by increasing tyrosine hydroxylase activity, enhancing dopamine release and inhibiting dopamine reuptake... and Parkinson’s disease Adv Neurol 2003;91:107–114 Quinn NP, Marsden CD Menstrual-related fluctuations in Parkinson’s disease Mov Disord 1 986 ;1(1) :85 87 Sandyk R Estrogens and the pathophysiology of Parkinson’s disease Int J Neurosci 1 989 ;45( 1-2 ):119–122 Saunders-Pullman R, Gordon-Elliott J, Parides M, Fahn S, Saunders HR, Bressman S The effect of estrogen replacement on early Parkinson’s disease Neurology... hallmarks of the disease Most cases of Parkinson disease are idiopathic, but heritable forms of PD have also been found and linked to specific gene mutations, including parkin, alpha-synuclein, DJ-1, PINK1 and LRRK2 (2,3) Onset is typically in the sixth to seventh decades of life Male predominance of idiopathic PD has been found in most population- and clinic-based studies Male to female ratios of disease prevalence... 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