On the track of neuropsychiatric lupus.

Abstract

Over the past few decades, we have witnessed a decrease in early mortality among patients with systemic lupus erythematosus (SLE), attributable to the improved management of both the disease itself and the complications of therapy. However, this improved outcome in SLE has been accompanied by an increased awareness, and potentially an increased incidence, of late-onset heart and brain disease in lupus patients. Thus, with some degree of urgency, investigators are seeking to understand the pathogenesis of the delayed onset of organ-specific disease and to identify preventive treatments. The possibility that SLE might underlie a general assault on the central nervous system (CNS) is consistent with data from a growing number of clinical, histopathologic, and neuroimaging studies. In 1999, the Committee on Neuropsychiatric Lupus Nomenclature provided case definitions for 19 different neuropsychiatric syndromes seen in patients with SLE (1). For some of the syndromes included in this comprehensive list, there are solid candidate causative mechanisms. For others, especially the psychiatric and cognitive disorders, there is less information about mechanism or pathology. It is no wonder, then, that identification of a single, all-purpose, unifying mechanism for neuropsychiatric SLE (NPSLE) has remained elusive. SLE is characterized by activation of the immune system leading to autoantibody production, engagement of complement cascades, and exuberant cytokine production, all of which, perhaps, are regulated by hormones. It is now well established that autoantibodies can directly damage organs, especially the kidney (2,3), skin (4), and fetal heart (5). Provocative data suggest that autoantibodies may also mediate brain damage in SLE. In fact, there is a long history of efforts to link autoantibodies in SLE directly to CNS manifestations of disease. Several investigators have sought to identify autoantibodies that either bind directly to neurons or, at high titer, are associated with NPSLE. One autoantibody specificity for which there is a plausible mechanistic explanation for a relationship to brain dysfunction is that to phospholipid antigens (6,7). These pathologic autoantibodies impair the rheologic conditions in large and small vessels, allowing generation of emboli and thrombosis that cause ischemic and hemorrhagic brain injury. In some, but not all, studies, anti–ribosomal P protein autoantibodies have been correlated with psychosis (8). Recently, antibodies to the NR2 N-methyl-D-aspartate receptor were demonstrated to be present in the serum and cerebrospinal fluid of patients with lupus and to have the functional capacity to cause excitotoxic neuronal death (9). Some studies of patients with NPSLE have implicated complement (10), and recent studies of cerebrospinal fluid C3 and C4 indices have demonstrated increased values for patients with NPSLE, which is consistent with a potential for antibody-mediated activation of the complement cascade (11). Autoantibodies are not, however, the only potential causative agent of CNS damage. A growing body of literature describing cytokine abnormalities in the cerebrospinal fluid of lupus patients is matched by the complementary findings that cytokines can directly affect neuron survival and function (12,13). Finally, brain function may also be adversely affected by the considerable secondary effects of systemic organ failure and by direct toxicity of the treatments for SLE. There is some consensus that cognitive dysfunction, one of the 19 syndromic neuropsychiatric complexes included in lupus, may be emerging as a frequent and debilitating manifestation of NPSLE. Four major analyses (10,14–16), which included a total of 141 patients with all varieties of NPSLE, have provided some clues to potential mechanisms for the nonreversible cognitive impairment. Cerebrovascular disease with deBetty Diamond, MD: Albert Einstein College of Medicine, Bronx, New York; Bruce Volpe, MD: Weill Medical College of Cornell University, New York, New York, and The Burke Medical Research Institute, White Plains, New York. Address correspondence and reprint requests to Betty Diamond, MD, Departments of Microbiology & Immunology and Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. E-mail: diamond@aecom.yu.edu. Submitted for publication May 14, 2003; accepted June 6, 2003.