INTRODUCTION

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease that can affect virtually every organ system and has protean clinical manifestations. It is characterized by mild to severe episodic relapses most often affecting the skin and joints, but visceral organ involvement, including kidney, lung, and central nervous system (CNS) disease, also occurs.¹ Neuropsychiatric events in patients with SLE can be primary manifestations of the disease, complications of treatment, or comorbid conditions, and distinguishing among these can be challenging in practice. Although many patients with SLE experience neuropsychiatric events, the proportion of these events attributable to SLE ranges from 17% to 38%.^2-7 Neuropsychiatric manifestations attributable to SLE (NPSLE) are a significant cause of morbidity and mortality, with both focal (eg, stroke) and diffuse (eg, cognitive dysfunction) manifestations.

EPIDEMIOLOGY

The incidence and prevalence of SLE are increasing, likely because of improved diagnosis of mild cases and better approaches to treatment.⁸ In the United States, the reported prevalence is 20 to 150 cases per 100,000, with women much more frequently affected than men (9:1).⁹ SLE is more common among African, Asian, and Hispanic Americans as compared with Caucasians, and is more common in urban than rural areas.¹⁰ Women of reproductive age are most often affected, and the female predilection is less pronounced in older adults and children. Although SLE is more common in women, men are more likely to experience renal, cardiovascular, neurologic, and vasculitic manifestations, and mortality rates are likely higher in men.¹¹ Contemporary data suggest that mortality in SLE has decreased significantly in recent decades,¹² but the disease remains a leading cause of death in young women.¹³ Internal organ involvement and infections are associated with increased mortality risk.¹⁴ Therapeutic interventions such as immunotherapy and vaccinations have contributed to reduced mortality.

The reported prevalence of NPSLE is highly variable, ranging from 21% to 95%; reported clinical outcomes are likewise varied.^3-5,7,15 Some studies have found increased mortality associated with NPSLE,¹⁶ while others have not.¹⁷ Such variation in the literature may be related to a lack of standardized definitions and misattribution of neuropsychiatric events to SLE, as well as limitations in validated outcome measures in NPSLE. Neuropsychiatric events of any etiology have been observed in 6% to 12% of all patients within the first year of SLE diagnosis, but only about one third or less (17%-38%) of those events can be attributed to NPSLE.^2-7 Although the cumulative occurrence of neuropsychiatric events of any cause increases over time, the proportion of neuropsychiatric events attributable to NSPLE remains relatively stable.^18,19

PATHOPHYSIOLOGY

The pathogenesis of SLE is likely a combination of genetic susceptibility, environmental exposures, and hormonal factors.²⁰ SLE is associated with defects in apoptotic clearance, which leads to intracellular antigen exposure.²¹ Disturbances in immunity associated with SLE include hyperactivation of B and T lymphocytes, overproduction of autoantibodies, and tissue deposition of immune complexes.²²

Current evidence supports 2 complementary pathogenic pathways associated with neurologic damage in SLE: vascular and inflammatory.²³ Large- and small-vessel ischemic injuries can result from antiphospholipid antibodies (aPLs), immune complexes, and/or complement activation (Figure 1). Inflammatory mechanisms include increased permeability of the blood-brain barrier, production of immune complexes and intrathecal antibodies, and production of inflammatory mediators such as interferon-α, interleukin (IL) -1, IL-6, and tumor necrosis factor.²⁴ More than 116 autoantibodies have been identified in SLE, although most are not assessed in clinical practice.²⁵ In addition to the effects of aPLs, a subset of double-stranded DNA (dsDNA) antibodies cross-reacts with the NR2 subunit of the N-methyl-D-aspartate receptor (NMDAR) and is associated with NPSLE (in contrast, NMDAR encephalitis is associated with antibodies to the NR1 subunit).^26,27

A seminal neuropathology study of SLE revealed that microinfarction was the most common manifestation of NPSLE.²⁸ Microinfarcts did not correlate with the presence of Libman-Sacks endocarditis or systemic embolism and there was no evidence of generalized arteritis in the brain. Another autopsy study also found no evidence of CNS arteritis, but identified mitral valvulitis in 46% of patients with embolic infarcts as the primary neuropathology.²⁹ aPLs produce a hypercoagulable state that contributes to small-vessel vasculopathy and large-vessel thrombosis.³⁰ Such studies support vascular damage from embolic and microvascular disease as a prominent cause of neuropathology in SLE.

Question 1

A 68-year-old woman with systemic lupus erythematosus (SLE) treated with prednisone and azathioprine presents with hemiballistic movements in the right arm and leg for the past 3 weeks. It is summertime, and she reports that she had a mild upper respiratory tract infection a month ago; she has not been exposed to antipsychotics.