Despite the best efforts of experts in the field, NPSLE remains vaguely defined. In 1999, an ad hoc committee assembled by the ACR produced formal definitions of 19 NPSLE syndromes, ranging from headache to cerebrovascular disease.1 Unfortunately, although these definitions have been important for providing uniform nomenclature among researchers, numerous other diseases can cause presentations identical to each NPSLE syndrome. Many complications of SLE, such as uremia caused by lupus nephritis, and medications used to treat SLE can themselves cause neurological disease, which could be considered forms of secondary NPSLE. All in all, CNS symptoms in a patient with SLE are often a diagnostic conundrum with a very broad differential diagnosis.
Primary NPSLE is thought to occur via one of two possible types of mechanisms.2 The better understood of these is vascular insult, in which antiphospholipid antibodies or other risk factors for hypercoagulation lead to thrombi and focal regions of ischemia, causing clinical presentations, such as stroke or seizure. There may also be additional small vessel injury in chronic disease resulting in vasculopathy.
The second mechanism, inflammatory NPSLE, is poorly understood. Autopsy studies on patients with SLE have shown that CNS vasculitis is very, very rare. Instead, it is thought that inflammation may be mediated through antineuronal antibodies or cytokine injury (Note: Elevated levels of interleukin 6 in SLE correlate with increased risk of seizures).2
So far, no particular serological marker has proved to be predictive of NPSLE. Presence of antiribosomal P was proposed to be such a marker. Subsequent studies, however, estimate its sensitivity at 26% and specificity at 80%, limiting the utility of this test.3 With the diverse pathogenic mechanisms causing NPSLE, there may not be a single predictive marker. Elucidating the pathophysiology of the many NPSLE syndromes will be crucial in developing a better framework for its diagnosis and treatment.
Because the possible neuropsychological effects of lupus are broad and can affect both the central and peripheral nervous systems, the diagnostic workup is guided by anatomic localization and clinical suspicion. The workup will uniformly require basic labs—especially because metabolic derangements are a common cause of neurological disease—as well as imaging.
For acute presentations, such as seizures, an immediate head CT without contrast is necessary to rule out hemorrhage or other severe structural disease. For most cases of neuropsychiatric disease in the SLE population, a magnetic resonance imaging (MRI) of the brain will also be indicated. Functional imaging (e.g., positron emission tomography [PET] or functional MRI [fMRI]) has shown promise in recent studies, particularly for cognitive dysfunction, but the findings are not specific for NPSLE.