Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by circulating autoantibodies and immune complexes.1 The disorder most commonly affects young, nonwhite women. The overall prevalence is approximately 50 per 100,000, but the prevalence among young women approaches 1 in 1,000.2

The neurologic diagnoses associated with SLE include stroke, seizure, dementia, psychosis, and peripheral neuropathy.3 CNS involvement has been reported in up to 75% of SLE patients,3 with seizures occurring in up to 50% of patients by the time of death.3,4

The systemic effects of SLE are widespread, most commonly involving the joints and the skin:

  • symmetric arthritis in both large and small joints
  • malar "butterfly" rash (considered characteristic)
  • kidney disorders, most often glomerulonephritis (in up to 50% of cases)
  • cardiac effects: pericarditis or myocarditis
  • pulmonary effects: pleurisy, pneumonitis
  • hematologic effects: anemia, leukopenia, or thrombocytopenia
  • constitutional symptoms: fever, fatigue, and myalgia

Pathophysiology

SLE exerts its widespread effects predominantly via immune-mediated mechanisms. Autoantibodies in SLE form immune complexes that activate inflammatory cascades. Activation of complement leukocytes and macrophages yields end products that may damage vasculature, causing tissue damage. Deposition of immune complexes in blood vessels may also cause a vasculopathy with a variety of end-organ effects.2 In the brain, these mechanisms may result in cerebral edema or ischemia.

Antiphospholipid antibody is one of the more common autoantibodies associated with SLE. It frequently has been reported as a potential risk factor for stroke and described as a potentially prothrombotic factor.1

Neurologic manifestations

Despite the relatively common involvement of the CNS in SLE, presentation of this disorder with neurologic signs or symptoms appears to be uncommon.5

The exact frequency of stroke in SLE is not known, but the risk of recurrence may be 50% or higher, and the occurrence of stroke increases the risk of seizures.3 The mechanism for stroke in SLE is also not known, but it is often believed to be related to cardiac involvement (as a source of embolic phenomena) and a prothrombotic state.3 The presence of anticardiolipin antibody and lupus anticoagulant, both procoagulant substances in vivo, may contribute to this risk. Strokes may occur in any distribution and may be related to immune-mediated microvascular disease. Clinical features are variable and can present with focal deficits or a more global syndrome of dysfunction, such as encephalopathy.2

Cognitive changes with SLE are quite variable. Presentation may be acute or subacute, with clinical manifestations of agitation, altered awareness, dementia, or overt psychosis. Although dementia is not considered one of the most common presentations, formal neuropsychological testing has suggested that 66% of SLE patients experience cognitive impairment.6

The true incidence of seizures in SLE is difficult to determine, owing to the multiple potential etiologies in SLE. In one series of 91 patients, 22 (24%) had seizures. Of these patients, two probably had idiopathic epilepsy, one had probable post-traumatic seizures, nine had active systemic infections, and four had significant azotemia. All of these seizures were generalized, with focal onset in five.3 In another series of 161 SLE patients, 16 (10%) had seizures during the entire course of illness. Seven (4.4%) of these patients had onset of their seizures before developing the required diagnostic criteria for SLE.7

Both partial and generalized seizures occur in SLE. They can occur as the only manifestation of CNS involvement or as a complication of the cerebrovascular manifestations. Seizures that occur secondary to strokes usually are focal in onset but may secondarily generalize. Seizures also may result from encephalopathy with a metabolic cause, particularly uremia from liver failure.8

Diagnosis

The diagnosis of SLE is based on a combination of clinical and laboratory data:

The 1982 American College of Rheumatology criteria for the diagnosis of systemic lupus erythematosus*

  • Malar rash
  • Discoid rash
  • Photosensitivity
  • Oral or nasopharyngeal ulcers, or both
  • Nonerosive arthritis
  • Pleuritis or pericarditis
  • Renal dysfunction: proteinuria above 0.5 g/dL or cellular casts
  • Seizures or psychosis
  • Hematologic disorder: hemolytic anemia, leukopenia, or thrombocytopenia
  • Immunologic disorder: anti-double-stranded DNA or anti-Sm antibodies
  • Antinuclear antibodies

The diagnosis of SLE is established when any four of these criteria are met at any point during the disease. Early in the course of illness, the diagnosis may be difficult to make because the patient may not fulfill all the necessary criteria.

SLE may be confused with disorders whose manifestations are included in its diagnostic criteria, including

  • rheumatoid arthritis
  • dermatitis (various forms)
  • hematologic disorders (e.g., idiopathic thrombocytopenic purpura)
  • neurologic disorders (e.g., MS)

Several drugs can cause syndromes with some clinical features similar to SLE:

  • procainamide (most common)
  • hydralazine
  • isoniazid
  • chlorpromazine
  • methyldopa
  • quinidine
  • most antiepileptic drugs

The most common symptoms in these cases are arthralgias, dermatitis, and systemic complaints, with rare CNS involvement. Drugs, including antiepileptics, can also cause false-positive serologic tests for SLE. In drug-induced lupus, antibodies to the histone complex of DNA are found, but antibodies to native DNA (anti-double-stranded DNA) are negative, and complement levels are normal.4-6 Discontinuation of the offending drug results in prompt resolution of symptoms, but serologic abnormalities may persist somewhat longer.

The laboratory evaluation of SLE should include a screen for antinuclear antibodies, anti-double-stranded DNA, and anti-Sm antibodies. Hematologic evaluation typically reveals anemia, leukopenia, and thrombocytopenia. Urinalysis typically reveals proteinuria, hematuria, and casts.

MRI should be performed in patients with neurologic manifestations. Abnormalities have been reported in up to 75% of patients with active disease.9 These most commonly include subcortical and periventricular T2 signal abnormalities. Imaging may also demonstrate areas of infarction, new or old.

EEG abnormalities tend to be nonspecific and may occur in up to 50% of SLE patients.10 In one series of 42 SLE patients (11 with seizures), no epileptiform activity was reported on EEG. However, 29% had focal slowing, and 26% had generalized slowing.11 In another series of 120 patients, one-third had epileptiform activity on EEG, but no seizures were reported in the entire group.12

In cerebrospinal fluid (CSF), protein may be elevated and there may be an increase in the number of mononuclear cells. Oligoclonal bands and increased immunoglobin synthesis also may be found.

Treatment

There is no cure for SLE. Patients may be treated symptomatically with nonsteroidal anti- inflammatory drugs (NSAIDs) for the arthralgias, myalgias, fever, and arthritis. Rashes may respond well to antimalarials or topical preparations.

If manifestations are severe or disabling, immunosuppression may be necessary. High-dose glucocorticoids are commonly used with close monitoring for the undesirable side effects. In severe disease states with frequent flares, the use of cytotoxic agents, such as cyclophosphamide or azathioprine, should be considered.

For SLE patients who have had a stroke, anticoagulation is recommended because of the high recurrence rate, associated with anti-cardiolipin antibody and lupus anticoagulant.

Seizures occurring in association with flares in disease may not require treatment with antiepileptic drugs. Treatment of the underlying inflammatory pathology or correction of a metabolic derangement may be adequate to control convulsions. In some instances, seizures may be controlled with pulse steroid treatments alone. Recurrent seizures will typically respond well to most antiepileptic therapies. Long-term treatment is frequently unnecessary once the systemic inflammatory disorder or metabolic derangement is brought under control.

Prognosis

The 5-year survival rate for SLE is between 75% and 98%, but for those patients with CNS involvement such as seizures, the 5-year survival may be as low as 55%.13-14 The presence of CNS involvement may be a marker of more severe disease.

ACR Criteria adapted from EM Tan, AS Cohen, JF Fries, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271-1277.
Adapted from: Seiden L and Krumholz A. Inflammatory noninfectious disorders. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;135-154.
With permission from Elsevier (www.elsevier.com).

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Authored By: 
L Seiden
A Krumholz
Steven C. Schachter, MD
I<
Authored Date: 
03/2004
Reviewed By: 
Steven C. Schachter, MD
on: 
Wednesday, March 31, 2004