Neurologic disease

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1. Seizures require the use of anticonvulsant drugs. Initial therapy is 300 to 400 mg of phenytoin daily, with monitoring of serum drug levels. If needed to achieve seizure control, 20 to 60 mg of phenobarbital three times daily is added.

2. Psychosis may be secondary to either steroid therapy or SLE.

a. Steroid-induced psychosis will improve with tapering of systemic corticosteroids. Major tranquilizers, such as 1 mg of haloperidol twice daily, initially will assist in control of psychotic manifestations.

b. Systemic lupus erythematosus-related psychosis. The occurrence of SLE-related psychosis does not necessarily require an increase in steroid therapy. If adequate behavioral control is achieved with major tranquilizers and no organic signs are present on either physical examination or cerebrospinal fluid analysis, corticosteroids are not initiated or increased.

3. Parenchymal central nervous system disease. In the presence of new focal neurologic findings, 20 mg of prednisone is given three times daily until either improvement or toxicity is observed. Some neurologic lesions are not responsive to steroids. If no improvement is evident after about 3 to 4 weeks of high-dose therapy, prednisone is tapered to avoid complications. Dosages of prednisone above 60 to 80 mg daily rarely produce additional therapeutic benefit but markedly increase the risk for serious side effects. Any trial of very high-dose prednisone in severe disease should continue only for a predetermined, limited period of time. Pulse methylprednisolone therapy may be helpful for patients who do not respond to standard therapy. Cytotoxic agents such as IV cyclophosphamide have been used in steroid-unresponsive SLE patients with severe central nervous system disease.

4. Peripheral nerve disease. Peripheral neuropathy is common. Mononeuritis multiplex usually represents small-vessel vasculitis. If the patient is unresponsive to 60 mg of prednisone daily in three divided doses, then 1 to 3 mg of azathioprine per kilogram or 1 to 2 mg of cyclophosphamide per kilogram may be initiated.

I. Renal disease. For the initial management of active renal disease, as defined by active urinary sediment including red blood cells and red cell casts, proteinuria, and a decrease in creatinine clearance, the intensity of therapy is often defined by the severity of presentation and extra-renal manifestations of disease. Response to a chosen treatment is assessed by serial urinalyses, 24-hour urine testing, and determination of levels of serum complement and anti-DNA antibodies. Although renal biopsy is helpful in characterizing the type of renal lesion and extent of acute and chronic change, it is not mandatory. Patients with diffuse proliferative or membranoproliferative glomerulonephritis have the worst prognosis, but the natural history of clinically silent, diffuse proliferative disease with normal renal function has not been determined. Chronic changes of fibrosis and atrophy suggest little reversible disease and a poor prognosis. Any therapeutic regimen must consider both short-term and long-term effects encountered during the management of chronic nephritis.

Infection and drug-related causes of renal abnormalities must be sought and corrected. Vigorous control of blood pressure and avoidance of nephrotoxins is mandatory.

1. Corticosteroid therapy is the mainstay of treatment for active nephritis. The dosage, route of administration, and duration of therapy vary depending on the initial presentation, presence of comorbidities, and prior treatment modalities. Two approaches have been employed for the management of active nephritis.

Prednisone (60 mg daily in divided doses) for 1 to 2 months: Resolution of signs of active disease commonly permits tapering of prednisone. A recurrence of active urinary sediment, increased proteinuria, and decreased kidney function may prompt an increase in steroid dosage, a switch to "pulse" steroids, or a decision to perform a kidney biopsy in preparation for consideration of cyclophosphamide therapy.

High-dose, "pulse" methylprednisolone: This regimen is defined by courses of 1,000 mg/d for 3 days monthly for 6 months, with 0.5 mg of oral prednisone per kilogram between pulses, to control both renal and extra-renal manifestations. It is used as (a) initial therapy for active nephritis, (b) sole therapy to avoid cumulative side effects of long-term daily steroids, or (c) therapy for exacerbations of severe disease that do not respond to daily oral steroids.

Although prednisone clearly helps to relieve acute exacerbations of disease, long-term corticosteroid therapy is associated with serious side effects.

a. Physical appearance is altered by weight gain that produces truncal fat deposition (moon facies, buffalo hump), hirsutism, acne, easy bruising, and purple striae. Although individual patients differ in their susceptibility to these changes, reduction of the steroid dosage will eventually reduce the severity of these manifestations.

b. Infection occurs with greater frequency in corticosteroid-treated patients. Corticosteroids may mask both local and systemic signs of infection. Minor infections have a greater potential to become systemic. Latent infections, especially mycobacterial varieties, may become activated, and opportunistic agents such as fungi, Nocardia, and Pneumocystis carinii may cause serious clinical problems. Skin testing for delayed hypersensitivity to Mycobacterium tuberculosis should be performed before the initiation of corticosteroid therapy. However, a negative reaction may reflect the altered immunity of active SLE rather than lack of previous exposure to M. tuberculosis.

c. Mental function may be altered. Minor reactions include irritability, insomnia, euphoria, and inability to concentrate. Major reactions may include severe depression, mania, and paranoid psychoses.

d. Glucose intolerance may be induced or exacerbated by corticosteroids. Insulin may be required to control hyperglycemia and should be adjusted as the corticosteroid dosage is changed.

e. Hypokalemia may be caused by preparations with mineralocorticoid activity. Serum potassium should be checked frequently, especially if congestive heart failure, nephrosis, or peripheral edema producing secondary hyperaldosteronism is present.

f. Sodium retention, edema, and hypertension may be induced by all corticosteroid drugs. When these effects become clinically significant, agents with fewer salt-retaining properties can be used. Alternative steroid preparations are listed in Appendix E. Because steroids should be given only for major SLE manifestations, it is usually not feasible to control hypertension by a reduction in dosage; therefore, blood pressure must be controlled by appropriate antihypertensive therapy.

g. Myopathy may occur in patients receiving long-term, high-dose steroids. The muscles are not tender, and unlike inflammatory myositis, steroid-induced myopathy is usually not characterized by elevated serum muscle enzymes. Proximal weakness is the most common symptom. Weakness of the pelvic girdle is more common than shoulder-girdle symptoms. Biopsy may be useful in distinguishing inflammatory, SLE-related myositis from non-inflammatory, corticosteroid-induced myopathy. Drug-induced myopathy will gradually improve with a reduction of corticosteroid dosage.

h. Skeletal abnormalities include osteopenia and osteonecrosis. Corticosteroids may reduce gastrointestinal calcium absorption, induce secondary hyperparathyroidism, and also reduce collagen matrix synthesis by osteoblasts. Compression fractures in the vertebral spine represent a major secondary complication, especially in older patients. They occur in about 15% of steroid-treated patients. Prophylactic vitamin D 3 (400 U twice daily) and calcium (1,500 mg/d from dietary and supplemental sources) are recommended. Patients receiving long-term corticosteroid therapy (for more than 1 month) should undergo baseline and yearly bone density evaluations and treatment with suitable bisphosphonates if necessary (see Chapter.46). Osteonecrosis occurs most frequently in weight-bearing joints, especially the femoral heads. The mechanism is unknown (therapy is discussed in Chapter45). Reduction in corticosteroid dosage is desirable whenever possible, although it is unlikely to affect established osteonecrosis.

i. Hypoadrenalism may occur during periods of physiologic stress in patients with suppression of the hypothalamic-pituitary-adrenal axis resulting from exogenous steroid administration. During episodes of surgery or major intercurrent illness, it is advisable to provide supplemental steroid therapy to patients who are receiving corticosteroid therapy or who have discontinued such therapy within the previous year. Hydrocortisone (300 mg/d or equivalent dosage in three divided doses) may be given IV or IM during the period of maximum stress and subsequently tapered during 5 days. The stress of major nonsurgical illness may be managed with an increase in daily steroid dosage to at least the equivalent of 30 mg of prednisone.

j. Other side effects of corticosteroids include increased intraocular pressure, which may precipitate glaucoma, and the occurrence of posterior subcapsular cataracts. Although dyspepsia may accompany the use of steroids, it usually responds to antacids or histamine 2 blockers and administration of medication with meals. Enhancement of peptic ulcer disease probably does not occur. Menstrual irregularities, night sweats, and pancreatitis have been associated with corticosteroid therapy. Pseudotumor cerebri, associated with rapid steroid dosage reduction, is a rare complication.

2. Cytotoxic drugs are used in either severe corticosteroid-resistant disease or in the context of unacceptable steroid side effects. In patients with diffuse proliferative glomerulonephritis, cyclophosphamide has shown to retard progression of scarring in the kidney and reduce the risk for end-stage renal failure. Monthly infusions of IV "pulse" cyclophosphamide (0.5 to 1.0 g/m2 of body surface area) preserve renal function more effectively than do corticosteroids alone, but the rate of relapse following a 6-month course is high. Most patients require extended therapy. Potential toxicities are substantial: nausea and vomiting (often requiring treatment with antiemetic drugs); alopecia (reversible); ovarian failure (nearly universal in patients more than 30 years old) or azoospermia; and hemorrhagic cystitis, bladder fibrosis, and bladder transitional cell or squamous carcinoma. Intermittent IV cyclophosphamide may decrease the incidence of bladder complications associated with daily oral therapy. Azathioprine (1 to 3 mg/kg daily) is a far less toxic drug that avoids the potential complications of alopecia, sterility, and hemorrhagic cystitis associated with cyclophosphamide, but it is considered less effective. Each agent requires careful monitoring of complete blood cell counts. Allopurinol should not be used with azathioprine because it inhibits azathioprine catabolism. The long-term toxicity of these agents may include both hematopoietic malignancy and solid tumors (lymphomas with azathioprine, bladder carcinoma with cyclophosphamide).

3. Other regimens. Controlled trials of plasmapheresis have not shown benefit in most cases. Currently, clinical experience is being gathered with methotrexate and mycophenolate mofetil, but no controlled studies are available. Clinical experience with cyclosporin A (3 to 6 mg/kg daily) suggests that it might be useful in membranous glomerulonephritis. Side effects, particularly hypertension and renal toxicity, appear to be infrequent.

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