On the track of neuropsychiatric lupus (2003)

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 destructive and proliferative changes in large vessels, or in small vessels with multiple small infarctions, occurred in 66 patients; vasculitis occurred rarely, in only 11 patients (10, 14-16). Ischemic or hemorrhagic brain injury may underlie the nonreversible cognitive disorder in SLE, and, when progressive or cumulative, may cause atrophy and multiinfarct dementia; nonetheless, many patients with cognitive impairment have no demonstrable vascular lesion. Neuroimaging studies have offered new opportunities to explore brain metabolism and structural lesions in vivo and can be informative even in individuals with subtle neurologic disorders. Recent imaging studies in SLE confirm that stroke correlates with the presence of antiphospholipid antibodies. Many abnormalities have been noted with magnetic resonance imaging, magnetic resonance spectroscopy, and positron emission tomographic techniques. However, imaging studies have not revealed a structural or metabolic abnormality that is consistently correlated with cognitive impairment (17-24). A recent study using the American College of Rheumatology case definitions for NPSLE syndromes (1) and a reliable battery of neuropsychological examinations demonstrated the presence of NPSLE in 80% of the subjects studied (25). Consistent with previous studies, those investigators showed that nearly 50% of patients had mild to severe cognitive impairment, and that this impairment was particularly significant in the areas of motor performance speed, and visual and verbal memory. This observation suggests that a major component of cognitive impairment may occur initially with regional brain injury, and that impairment might continue to accrue over time as a result of the cumulative, more general vasculopathic or toxic brain damage. It is reasonable, therefore, to speculate that a longitudinal (in addition to a cross-sectional) approach might efficiently reveal mechanisms that underlie cognitive impairment. The formal assessment of behavior, along with concomitant neuroimaging of metabolic and structural brain damage, in the context of measurement of disease activity and serum autoantibody levels, may provide new insights into disease mechanisms. In this issue of Arthritis & Rheumatism, Trysberg et al describe a study in which they used immunochemical analysis to identify the light subunit of the neurofilament triplet protein (NFL) and the glial fibrillary acidic protein (GFAP) in the cerebrospinal fluid of patients with SLE (26). The authors suggest the need for new, sensitive surrogate markers for NPSLE, the complex but increasingly diagnosed brain disorder that occurs in patients with lupus. The finding of the filamentous components of the cytoskeleton of neurons and astrocytes in the cerebrospinal fluid suggests that neurons are dying and implicates astrocytes in the pathologic process. Although neither NFL nor GFAP can be considered diagnostic for a specific disease, this study by Trysberg et al demonstrates unequivocally that some patients with SLE sustain persistent CNS injury. These authors demonstrate a logarithmic increase in the level of NFL and a significant increase in the GFAP level in SLE patients who have brain dysfunction compared with both SLE patients without evidence of CNS disease and normal subjects. They show that an increase in these markers correlated with the presence of inflammatory cytokines and oligoclonal bands in the cerebrospinal fluid, and with structural changes on magnetic resonance images of the brain. Furthermore, in a smaller group of patients with NPSLE, they show a marked decline of NFL and GFAP levels after cyclophosphamide treatment. A variety of basic and clinical studies that focus on particular syndromes within NPSLE, many of which are currently underway, are needed to elucidate pathogenetic mechanisms. However, the treatment of NPSLE will require more than an understanding of the underlying mechanisms. For these studies to be optimally informative, reliable surrogate markers for ongoing CNS disease will be necessary. Although markers of ongoing cerebral damage, such as the presence of NFL and GFAP in the cerebrospinal fluid, will not alone solve the puzzle of the pathogenesis of brain disease in patients with NPSLE, they may help signal disease activity and progression. It may even become evident that these markers will correlate with certain pathogenetic mechanisms and not with others. Finally, it is clear that markers such as these, obtained from minimally invasive diagnostic procedures, will be necessary to assess the efficacy of therapeutic interventions.