Susan D. Denburg

The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes

OBJECTIVE To develop a standardized nomenclature system for the neuropsychiatric syndromes of systemic lupus erythematosus (NPSLE). METHODS An international, multidisciplinary committee representing rheumatology, neurology, psychiatry, neuropsychology, and hematology developed case definitions, reporting standards, and diagnostic testing recommendations. Before and after the meeting, clinician committee members assigned diagnoses to sets of vignettes randomly generated from a pool of 108 NPSLE patients. To assess whether the nomenclature system improved diagnostic agreement, a consensus index was developed and pre- and postmeeting scores were compared by t-tests. RESULTS Case definitions including diagnostic criteria, important exclusions, and methods of ascertainment were developed for 19 NPSLE syndromes. Recommendations for standard reporting requirements, minimum laboratory evaluation, and imaging techniques were formulated. A short neuropsychological test battery for the diagnosis of cognitive deficits was proposed. In the postmeeting exercise, a statistically significant improvement in diagnostic agreement was observed. CONCLUSION The American College of Rheumatology (ACR) Nomenclature for NPSLE provides case definitions for 19 neuropsychiatric syndromes seen in SLE, with reporting standards and recommendations for laboratory and imaging tests. It is intended to facilitate and enhance clinical research, particularly multicenter studies, and reporting. In clinical settings, consultation with other specialists may be required. It should be useful for didactic purposes but should not be used uncritically or as a substitute for a clinical diagnosis. The complete case definitions are available on the ACR World Wide Web site: http://www.rheumatology .org/ar/ar.html.

Prevalence of cognitive impairment in systemic lupus erythematosus

We administered a battery of neuropsychological tests to 62 female patients with systemic lupus erythematosus (SLE), 12 female patients with rheumatoid arthritis (RA), and 35 normal control subjects. By applying objective decision rules to individual test protocols, an overall prevalence of cognitive impairment of 66% was obtained in the SLE patient sample. Independent clinical, radiological, and laboratory data were used to determine neuropsychiatric (NP) symptomatology and to group SLE patients as 1) “active” (N=21), 2) “inactive” (N=15), and 3) “never” (N=26) NP-SLE. More than 80% of the patients in groups 1 and 2 and 42% in group 3 showed significant cognitive impairment as compared with 17% of the RA patients and 14% of the normal control subjects. Neither steroid medication nor psychological distress could account for these findings. The unexpectedly high prevalence of cognitive impairment in SLE patients with either inactive or absent neuropsychiatric symptomatology provides evidence for subclinical nervous system involvement in SLE.

Neuronal antibodies and cognitive function in systemic lupus erythematosus.

The pathogenesis of neuropsychiatric lupus (NP-SLE) is unclear, but may involve vasculopathy, antibodies against nervous system tissue, or both. A major difficulty in determining the significance of antineuronal antibodies in NP-SLE has been lack of consistent clinical diagnostic approaches. By utilizing a new clinical classification of NP-SLE, neuropsychological assessments, and an assay for IgG antineuronal antibodies, we have found a significant association between antibody-positivity and cognitive impairment or nonfocal NP-SLE. These observations indicate that antineuronal antibodies may play a role in NP-SLE and emphasize the clinical importance of cognitive function in patients with SLE.

Cognitive impairment in systemic lupus erythematosus: A neuropsychological study of individual and group deficits

Eighty-six females with systemic lupus erythematosus (SLE) were grouped according to present or past history of neuropsychiatric (NP) symptomatology (Active, Inactive, or Never). Performance of these three groups was compared to that of 35 normal women on an extensive battery of neuropsychological tests sampling a wide range of cognitive functions. In addition to making group comparisons, we also devised a system for identifying individual impairment using decision rules for both quantitative and qualitative data. Our results indicate that a variety of cognitive deficits are present in SLE patients taken together as a group; there is no significant association between cognitive impairment and emotional disturbance; patients with resolved NP symptomatology are as impaired as patients with active NP symptoms, suggesting residual CNS involvement; in spite of no significant difference emerging on direct group comparisons, significantly more Never NP-SLE patients are impaired than are controls on several summary scores, suggesting subclinical CNS involvement in these patients.

Serum lymphocytotoxic antibodies and neurocognitive function in systemic lupus erythematosus.

The hypothesis that lymphocytotoxic antibodies are associated with neuropsychiatric involvement in systemic lupus erythematosus (NP-SLE) is re-evaluated in this study. In an unselected cohort of 98 women with SLE a cross-sectional study has been performed to analyse associations among standardised clinical, neurological, and neuropsychological assessments and lymphocytotoxic antibodies measured by microcytotoxicity assay. Fifty patients showed objective clinical evidence of continuing or past NP-SLE and 54 patients had cognitive impairment. In accordance with previous observations 44% (24/54) of the cognitively impaired group did not have clinically detectable evidence of NP-SLE. Although lymphocytotoxic antibodies were found to be only marginally more prevalent in those patients with a clinical diagnosis of NP-SLE than in those without (32% v 23%), these antibodies were significantly associated with cognitive impairment (chi 2 = 5.42; p less than 0.02). No association was detected between lymphocytotoxic antibodies and either overall systemic disease activity or other organ system involvement, suggesting that the association between lymphocytotoxic antibodies and cognitive dysfunction in SLE is specific.

Spatial learning during the course of autoimmune disease in MRL mice

The present study examines whether autoimmune MRL-lpr mice develop impairments in learning and memory that correlate with changing severity of lupus-like disease. MRL-lpr mice (n = 20) were tested in the Morris water-maze at 12, 14, 16 and 18 weeks of age. Age-matched controls were congenic MRL +/+ mice (n = 20) that develop the disease much later. Immune status was assessed by the presence of anti-nuclear antibodies (ANA), brain-reactive antibodies, proteinuria, and haematocrit. Learning rates and memory retention did not differ between the substrains, and did not correlate or deteriorate with advancing age and autoimmunity. However, the baseline performance level in autoimmune MRL-lpr mice was shifted, as evidenced by a consistently longer task-solving latencies. Thigmotaxic swimming (along the pool wall) was pronounced in the MRL-lpr group, and was associated with the observed difference in performance. The present study does not support the notion that learning/memory abilities of autoimmune MRL-lpr mice are impaired per se, but may support the hypothesis that the rapid progress of humoral autoimmunity affects the emotionality of lupus-prone mice.

Immunosuppressive treatment prevents behavioral deficit in autoimmune MRL-lpr mice.

MRL-lpr mice, which develop severe autoimmune disease, explore novel objects less well than do their congenic MRL(-)+/+ controls, in which symptoms of the disease are relatively mild. Moreover, diminished exploration in MRL-lpr mice correlates with the elevated titers of antinuclear antibodies (ANA) in their sera, suggesting that this behavioral deficit is caused by the autoimmune process. To test the hypothesis that autoimmunity affects behavior, in this study we examine whether treatment of the autoimmune process will reduce the difference in performance between the two MRL substrains in the novel-object test. Forty mice in each substrain were treated from 4 to 10 wk of age with the immunosuppressive drug, cyclophosphamide (100 mg/kg/wk, IP) or a saline vehicle. The immunosuppressive treatment reduced ANA titers to low levels and eliminated ANA production completely in 55% of MRL-lpr mice, suggesting an attenuation of the autoimmune process. In addition, treatment with cyclophosphamide, but not saline, abolished significant differences in exploration between the MRL-lpr and MRL +/+ groups, as measured by the latency to touch a novel object and the time spent exploring it. Thus, the present results suggest that a treatment which ameliorates autoimmune symptoms can concurrently remove the substrain difference in behavior. The effect of cyclophosphamide in the MRL-lpr group is believed to reflect the suppression of pathogenic immune factor(s) that alter behavior during the onset of autoimmune disease.

Brain-reactive antibodies and behavior of autoimmune MRL-lpr mice

The hypothesis that brain-reactive autoantibodies (BRA) impair behavior was examined in MRL-lpr mice, which develop spontaneous autoimmune disease. Circulating BRA were measured as in vitro serum reactivity to Neuro-2A neuroblastoma cell line, and behavioral competence was assessed in activity monitors, open field, beam walking, and Morris water maze task. Mice with BRA in serum (BRA positive) exhibited slower spontaneous locomotion in a novel environment, shorter grooming episodes, and less exploration of the open field centre when compared to age-matched 7-11-week-old BRA-negative cagemates. Moreover, when initially exposed to the large swimming pool, BRA-positive mice showed increased swimming along the wall, but had no difficulty in learning the water maze task or in traversing a narrow beam. Brain-reactive autoantibodies titre and behavioral measures were not correlated, suggesting that the concentration of serum BRA is not reflective of the magnitude of behavioral impairment. Nevertheless, the present study suggests that the presence of circulating BRA is associated with impaired exploration and/or enhanced emotional reactivity in MRL-lpr mice. It also supports the hypothesis of a pathogenic role of BRA in various mental disorders.

Neuropsychological correlates of serum lymphocytotoxic antibodies in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by frequent neuropsychiatric (NP) manifestations. At least two different pathogenetic mechanisms have been proposed for NP-SLE, including vasculitis and antibodies against neuronal antigens, the latter as expressed by the presence of brain cross-reactive lymphocyte antibodies. We have previously reported a high prevalence of cognitive dysfunction in SLE which can remain subclinical and which cannot be accounted for on the basis of disease activity, general distress, or steroid medication. In the present study, we undertook the same extensive, standardized neuropsychological testing in 98 consecutive female SLE patients in order to evaluate central nervous system functioning in relation to serum lymphocyte antibodies which were measured at the time of neuropsychological testing by a microcytotoxicity test. A significant association was observed between the presence of serum lymphocytotoxic antibodies (LCA) and cognitive impairment in patients with SLE. The pattern of impairment which predominated in the LCA-positive patients involved deficits in anteriorly associated, primarily visuospatial functions. These findings support the hypothesis of localization of a particular antigen-antibody interaction in the brain in SLE, suggesting the existence of immunological control mechanisms for normal brain functioning.

Nervous System Lupus: Pathogenesis and Rationale for Therapy

Several different pathogenic mechanisms appear to be involved in CNS lupus. These include: B-cell/autoantibody-mediated nervous system compromise; immune complex deposition and vasculitis; microthrombosis and vasculopathy; aberrant MHC Class II antigen expression with T-cell mediated disease (multiple-sclerosis model); and, cytokine-induced brain inflammation. These processes are not mutually exclusive: there exist in vitro and in vivo models for each of these. A number of autoantibodies, especially those with specificities for shared neuronal/lymphocyte antigens, are associated with certain forms of cognitive dysfunction or overt nervous system manifestations. In MRL/lpr mice, lymphoid infiltrates in the brain parenchyma are related to a neurobehavioural dysfunction which develops very early in the course of autoimmune disease. Recent results, both in animal models and in human studies on the therapeutic effects of corticosteroids, immunosuppressive drugs or anticoagulants on clinical and subclinical manifestations of CNS lupus are highlighted in an attempt to develop a rationale for intervention based upon presumed pathogenesis.