Collagen-vascular disorders, including SLE, rarely present with seizures. Seizures almost always appear later in the course of active disease, especially during flares of systemic and central nervous system (CNS) lupus.⁷⁹ SLE is one of the most common autoimmune diseases, with an annual incidence of 1.8 to 7.6/100,000 and a prevalence of 39 to 51/100,000.⁷⁹ Onset is most common in early adult life, women account for 80% of patients, and non-whites (Asians and African-Americans) are disproportionately affected.^62,81 In addition to the nervous system, SLE affects, in order of frequency, joints, mucous membranes and skin (discoid lupus, malar rash, photosensitivity, alopecia), kidneys, pleura, heart, and bone marrow. Neurologic or neuropsychiatric complications have been reported in all series since Kaposi⁵³ first described them in 14% to 75% of patients >100 years ago.^2,13,46,71 Psychiatric symptoms include depression and psychosis. Neurologic syndromes include dementia, aseptic meningitis, seizures, stroke, movement disorders (especially chorea), myelopathy, and peripheral neuropathy.^2,14,37 Headache can be prominent due to benign intracranial hypertension, aseptic meningitis, and venous thrombosis.^46,61 Even in the absence of dementia or depression, neuropsychological testing reveals high frequencies of cognitive dysfunction.^46,47,71,72 Neurologic complications are a common cause of hospitalization in patients with SLE⁸⁹ and the second leading cause of death.^14,107 Early neurologic involvement, especially stroke, has a worse prognosis, but seizures also contribute to poor outcome when they occur in children with arthritis.⁹⁰ Seizures double the rate of mortality when found with nephritis in adults.¹⁰⁷

Both partial and generalized seizures occur in SLE. Generalized seizures can be the sole evidence of brain involvement in diffuse CNS lupus [the term “cerebritis” is no longer used by the American College of Rheumatology (ACR) due its lack of specific pathologic findings], or they may occur as part of hypertensive or metabolic encephalopathy. Status epilepticus also occurs, especially in critically ill patients, in whom it may be a preterminal event.¹⁰⁹ Partial seizures can be a manifestation of cerebrovascular complications (hemorrhage, ischemic stroke, venous thrombosis), abscess, or meningitis.¹¹⁰ Reflex epilepsy induced by acoustic and patterned visual stimuli has been reported,¹⁶ as has photosensitive myoclonic epilepsy,⁷⁴ both in children with SLE. Psychiatric symptoms, especially psychosis and delirium, commonly coexist with seizures¹⁴ and are reported to occur at some time in up to 50% of patients. Partial complex (nonconvulsive) status epilepticus presents with confusion, delirium, or hallucinations; electroencephalographic
monitoring is often necessary to confirm the diagnosis,^14,86 which suggests that it may have been missed in the past.

Because of the multiple causes of neuropsychiatric symptoms, it is difficult to obtain meaningful incidence figures for seizures occurring in SLE. However, the fact that seizures are listed first on the SLE activity index devised by the ACR,¹² even after this was updated to separate persistent from acute symptoms,⁴⁰ indicates their importance in this condition. In one series of 91patients with SLE, 22% experienced generalized seizures and an additional 5% had partial seizures.³⁷ Multiple factors, including renal failure, coagulopathy, and hypertension, contributed to seizure occurrence, whereas 3 patients had seizures completely unrelated to SLE. Of interest, 2 patients had seizures only during flares of their SLE, and 8 of the 14 patients who had had strokes experienced seizures during the course of their illness. Most series do not provide sufficient detail to conclude whether the reported seizures are due to SLE or to other conditions.

In patients with seizures, brain imaging should be done promptly to look for evidence of intracranial hemorrhage (parenchymal or subarachnoid), cerebral infarction, or other structural pathology. Hemorrhage is associated with vasculitis, which occurs in only a minority of patients with SLE.⁷⁸ Cortical atrophy is a frequent finding^46,49 and may relate to either long-term steroid use or disease duration.⁴¹ Abnormalities detected by brain magnetic resonance imaging (MRI) scans have been reported in up to 75% of patients with active disease, but the findings are frequently nonspecific subcortical and periventricular punctuate areas of increased T2 signal that most likely reflect small-vessel disease or, possibly, demyelination with gliosis.^41,92 In patients with chronic SLE, abnormal MRI scans were found in 57% of cases; many of the findings were clinically silent.⁴¹ SLE patients with neuropsychiatric symptoms have increased cerebral atrophy and more T1- and T2-weighted lesions compared to both controls and SLE patients without such symptoms.³ However, only 4 of 43 patients had seizures in this study. Similar lesions have been reported in neurologically asymptomatic patients.¹³ Acute inflammatory lesions are enhanced with gadolinium, and in symptomatic patients, serial MRI scans can document loss of enhancement or complete resolution as clinical improvement occurs.^71,110 MR venography and computed tomography (CT) angiography are useful in detecting thrombosis, especially given the dangers of invasive angiography in patients with anticardiolipin antibodies. Transcranial Doppler can be used to follow ischemic changes over time.⁵⁷

Functional brain imaging modalities that have been used in patients with SLE include single photon emission computed tomography (SPECT), positron emission tomography (PET), and MR spectroscopy.^27,92,108 SPECT is abnormal in patients with ischemic stroke, showing focally reduced perfusion in areas that correlate well with both CT and clinical findings. At times, SPECT may be an even more sensitive indicator of cerebral ischemia than MRI, with hypoperfusion preceding clinical symptoms in patients undergoing serial scans.^50,111 Loss of the vascular response to acetazolamide detects marginally perfused areas that are at risk for infarction.⁴³ In patients with psychosis, SPECT has revealed decreased perfusion in the frontal lobes.⁵⁶ PET scans using fluorodeoxyglucose (FDG) demonstrate hypometabolic areas in regions of ischemia or infarction.^22,92

Serologic markers have been studied in both generalized and CNS lupus. Positive antinuclear antibody (ANA) is found in 95% of patients with SLE, and anti–double-stranded DNA is found in 30% to 75%.⁷⁶ Although anti-Sm (smith) antibody is found in <30% of patients, it is specific for SLE. Other laboratory abnormalities that are useful in following active disease are elevated CSF complement 3 and 4,⁵² and anti–single- or anti–double-stranded RNA.³³ Serum markers of autoantibodies, especially antiphospholipids (aPL), are increased in SLE patients with neuropsychiatric symptoms compared to those without them.¹¹⁰ The tests most often used to distinguish among the different connective tissue disorders and types of vasculitis are summarized in Table 1. Anticardiolipin antibody levels, especially immunoglobulin G (IgG), correlate with the occurrence of seizures,⁴⁸ whereas antiribosomal P seems to be a marker of psychosis without other neurologic symptoms or signs.^14,33,113 The presence of antibodies to native DNA rather than to the histone complex favors idiopathic rather than drug-induced lupus.^16,21,36,79 Although antineuronal antibodies reflect diffuse pathology and have been reported in 60% of patients with neuropsychiatric SLE, they are also found in patients without neurologic symptoms, raising doubt as to their role in “cerebritis.”^27,71,99

In patients with cerebral ischemia or infarction, the following findings on blood tests can be helpful: The presence of anticardiolipin antibodies, of which IgG is more significant for stroke^79,116 protein S or C deficiency (this is sometimes caused by the nephrotic syndrome⁶¹ when kidney damage is prominent); thrombocytopenia; and lupus anticoagulant using kaolin clotting time or lupus anticoagulant (LAC)-prolonged activated partial thromboplastin time (aPTT). Echocardiography can assist in determining whether there is a cardiac source for cerebral emboli, although marantic (Libman-Sacks) endocarditis is only rarely responsible for stroke in SLE.⁴⁶

Lumbar puncture is required whenever infection is suspected, although significant thrombocytopenia or other clotting abnormalities need to be corrected before it can be performed to avoid producing a lumbar epidural hematoma. Up to one third of patients undergoing a lupus flare with CNS involvement have nonspecific findings in the cerebrospinal fluid (CSF) including increased numbers of white cells (usually lymphocytic) and elevated protein levels.⁴⁶ CSF antiribosomal-P and anticardiolipin antibodies correlate with disease activity,¹¹² but they can also be related to vascular damage that produces breakdown of the blood–brain barrier. Similarly, CSF interleukin-6 (IL-6), a regulator of autoantibody production, can be elevated in patients with infection and is thus best viewed as a nonspecific inflammatory marker.^46,103,112 CSF antineuronal antibody, oligoclonal bands (seen in 25% of one series, produced locally in half),⁷² and IgG levels decline with treatment,¹¹⁰ suggesting that they play a role in the pathogenesis of neuropsychiatric symptoms.

Electroencephalographic abnormalities have been reported in up to 65% of patients with SLE,⁶⁹ including those without symptomatic cerebral involvement.¹¹⁰ The most common finding is generalized slowing, which correlates better with cognitive dysfunction than with the occurrence of seizures.^14,46 For example, in one series of 42 patients, 11 of whom had seizures, EEG recordings did not reveal epileptiform activity in any, although focal slowing was present in 29%, and diffuse slowing was seen in 26%.⁴⁹ In contrast, however, a study of 120 patients with SLE found that epileptiform activity occurred in one third, but none of these patients had seizures.⁶⁹ Monitoring critically ill SLE patients using continuous EEG is useful in discovering reversible causes of altered mental state or coma, including seizures and metabolic encephalopathy.⁸⁶

There are diverse causes of seizures in patients with SLE. Cerebral involvement by lupus itself results in seizures through immune, vascular, and inflammatory mechanisms. Generalized seizures, often accompanied by neuropsychiatric symptoms

and headache, are associated with increased titers of antineuronal antibodies, elevated levels of CSF IgG, and oligoclonal bands,⁷² as well as cytokine production.⁴⁶ Whether these are simply markers of cerebral lupus or are actually pathogenic is not known,¹¹⁰ although loss of self-tolerance leading to increased cytokine and T- and B-cell production undoubtedly plays some role. Antibodies against brain reactive antibodies,⁹⁹ synaptosomes,⁴⁶ and gangliosides^67,88 are also increased, especially in patients with seizures or psychosis.⁹⁹ Anticardiolipin antibodies from patients with SLE reduce γ-aminobutyric acid (GABA)-mediated chloride currents in snail neurons, a finding that may be relevant to development of seizures.⁶⁴