Biomedical subjects
Publications and source records attributed to R M Carbotte.
Cognitive dysfunction is frequent in SLE, probably related to primary underlying immune/inflammatory mechanisms operating in the brain. Longitudinal studies relating patterns of cognitive impairment to putative pathogenetic factors would provide evidence for this hypothesis. Such studies could also lead to more specific therapeutic interventions to ameliorate or reverse brain compromise in SLE.
Systemic lupus erythematosus (SLE) is a chronic relapsing/remitting autoimmune disorder with both primary and secondary effects on nervous system integrity and psychological functioning. In addition to the occurrence of clinical psychiatric syndromes such as psychosis, depression, and anxiety, other psychological problems documented with increased frequency in SLE include cognitive deficits and emotional distress. We examine issues related to cognitive function, including its assessment and prevalence, and confounding factors in interpreting cognitive problems as reflecting primary central nervous system involvement in SLE. Cognitive data in relation to other facets of the disease such as pain and fatigue, and subjective cognitive complaints are also discussed. Finally, we propose a potential role for cognitive assessment in the identification of SLE related depression.
OBJECTIVE: To examine the relationship between antiphospholipid antibody positivity (expressed as the lupus anticoagulant) and cognitive dysfunction in patients with systemic lupus erythematosus (SLE). METHODS: Cross-sectional comparisons of lupus anticoagulant (LA) positive (N = 39) and negative (N = 79) patients and controls (N = 35) on a cognitive test battery; 22 LA-positive and 53 LA-negative patients who had never experienced neuropsychiatric events (never-NP-SLE) were also compared separately. RESULTS: LA-positive patients were 2 to 3 times more likely than were LA-negative patients to be designated as cognitively impaired. As a group, LA-positive patients, particularly those in the never-NP-SLE group, demonstrated lower performance primarily on tasks of verbal memory, cognitive flexibility, and psychomotor speed. CONCLUSIONS: LA positivity is associated with subclinical nervous system compromise, and a pattern of deficits compatible with subcortical involvement, possibly on the basis of ongoing LA-related microthrombotic events or vasculopathy.
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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.
OBJECTIVE: To determine whether disease activity in organ systems other than the central nervous system (CNS) contributes to impaired neurocognitive functioning in patients with systemic lupus erythematosus (SLE) without current major neuropsychiatric problems. METHODS: A cross sectional study of 90 consecutive female patients with SLE. Neuropsychological status was evaluated with a comprehensive 2.5 h battery of tests. Disease activity was evaluated by the Lupus Activity Criteria Count (LACC) in all patients and the SLE Disease Activity Index (SLEDAI) in a subset of 20. Involvement of particular organ systems was identified with reference to American Rheumatism Association criteria. RESULTS: Sixty-eight of the 90 patients showed no active CNS involvement at the time of testing. Of these 68, 36 (53%) were impaired according to quantitative criteria alone. However, the association between cognitive impairment and disease activity was not significant using either LACC or SLEDAI as the measure of disease activity. Further, the group with active disease did not show generally poorer performance in specific areas of cognitive function than the group with inactive disease at the time of testing. The likelihood of significant cognitive impairment was not increased in the presence of involvement of any of the organ systems reviewed by the LACC. CONCLUSION: These findings substantiate our working hypothesis that cognitive impairment in SLE reflects an immune mediated compromise of an underlying neural substrate, rather than the non-specific effects of chronic illness or its treatment.
OBJECTIVE: To examine the relationships among specific lymphocyte antigenic reactivities of lupus sera and central nervous system complications of systemic lupus erythematosus (SLE), lymphocytotoxic antibody (LCA) positivity, and specific cognitive impairment. METHODS: Sera from 115 patients with SLE were examined for the presence of IgM- and IgG-class autoantibodies binding to surface target antigens on lymphocytes, by immunoblotting and microdroplet lymphocytotoxicity studies. Seventy-three of these patients also underwent detailed neuropsychological testing within the same time period. RESULTS: Significant associations were found between reactivities to several lymphocyte antigenic moieties and neuropsychiatric SLE (NPSLE) or cognitive impairment. Specifically, immunoblot reactivities to 31-32-kd, 50-52-kd, 54-56-kd, and 97-98-kd targets were associated with clinical NPSLE; there was a significant association between reactivity to the 50-52-kd moiety in particular and cognitive impairment. There were also associations between LCA and immunoblot reactivity. Furthermore, the previously reported association between LCA positivity and specific visuospatial cognitive impairment was confirmed with data obtained from 2 different batteries of neuropsychological tests. CONCLUSION: In some cases, specific antigenic targets of LCA-containing sera may be implicated in the pathogenesis of NPSLE:
OBJECTIVE: This study was designed to assess the effects of corticosteroids on select aspects of nervous system functioning, specifically, cognition and mood, as well as disease-related symptoms in individual patients with mild systemic lupus erythematosus (SLE) and mild neuropsychiatric (NP) symptoms. METHODS: Ten women who had not been taking corticosteroids for at least 6 months were selected from a referral-based lupus clinic to participate in an N of 1 double-blind, controlled trial consisting of 3 randomly assigned drug/placebo pairings, with a drug dose of 0.5 mg/kg of prednisone daily. RESULTS: Analysis of variance on the group data yielded significant positive drug effects for cognition (P = 0.02), mood (P = 0.003), and SLE symptom ratings (P = 0.0002). Drug efficacy was also evaluated by an objective decision rule, which yielded evidence of overall drug benefit in 5 of the 8 patients who completed the trial, and a deleterious drug effect in 1 patient. Posttrial clinical results indicated that for the 8 women who completed the trial, "acceptable" decisions, leading to remission of SLE symptoms or appropriate withholding of steroids, were made on the basis of this rule. CONCLUSION: Improvement in cognition, mood, and/or SLE symptom ratings can be observed following brief exposure to relatively low doses of corticosteroids in individual women with mild SLE; these persist over repeated drug exposure. The current application of N of 1 methodology represents the first systematic study of steroid efficacy in central nervous system (CNS)-related problems in SLE. The results can now be applied to the design of randomized, controlled trials of the effects of corticosteroids on CNS function in SLE.
MRL-lpr mice develop symptoms of autoimmune lupus-like disease early in the life and MRL(-)+/+ mice develop it substantially later. The present study examines our previous suggestion that autoimmune MRL-lpr mice show altered emotional reactivity. In addition, it aims to identify the set of measures which best discriminate the behavior of MRL-lpr mice from their congenic controls (MRL +/+). Behavior of males from these two substrains (n = 40/substrain; 3-4 mo of age) was compared on a battery of tests presumed to be reflective of emotional reactivity. MRL-lpr mice explored the open field less, spent more time at home-base, and defecated less in comparison to congenic MRL +/+ controls. Moreover, MRL-lpr mice hesitated to step down from an elevated platform and to make contact with a novel object. They also visited open-arms of a plus-maze less often and showed extensive floating in the Porsolt's swim test. Discriminant analysis revealed that the performance of the MRL-lpr and MRL +/+ mice differed most profoundly on measures taken in the Porsolt's swim and step-down tests. In addition, in the MRL-lpr group high titers of serum antinuclear antibodies were associated with impaired exploration of a novel object. These results are consistent with the previously proposed notion of increased "timidity" in autoimmune MRL-lpr mice and of an immune factor contribution to altered emotional reactivity. Considering that behavior of autoimmune MRL-lpr mice resembles behavior of stressed animals, it is speculated that disturbed emotional reactivity reflects the effect of autoimmunity on the hypothalamic-pituitary-adrenal axis.
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Several independent studies have now demonstrated the presence of significant cognitive impairment in SLE patients. Such impairment, whether it precedes or follows overt NP events, suggests compromise of the neural substrate, irrespective of overt clinical NP symptomatology. The association between cognitive impairment and brain cross-reactive autoantibodies suggests one mechanism for CNS involvement in SLE that warrants further study; the data relating specific cognitive deficits to the presence of specific antibodies raise the intriguing possibility of system- or structure-specific immune-mediated involvement in the CNS. Whatever the mechanism, cognitive impairment in SLE may have significant implications for daily functioning of some lupus patients and requires the selection of appropriate psychosocial and somatic treatment strategies.
Brain imaging techniques such as MRI and PET have the potential for identifying central nervous system involvement in SLE. They may also help elucidate the mechanisms giving rise to the widely diverging manifestations of CNS involvement in SLE. This report documents an intensive longitudinal study of three women with neuropsychiatric SLE. PET and neuropsychological evaluation were both used to examine the co-occurrence of behavioural/cognitive deficits with alterations in regional brain glucose metabolism. In all three patients, FDG uptake indicated abnormalities which were not identified on CT scan, but corresponded well with localisable cognitive deficits. Changes in each patient's cognitive profile on reassessment paralleled changes on PET. These findings support the suggestion that cognitive deficits in SLE patients reflect primary CNS involvement.
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.
To determine the significance of changes in serum antineuronal antibody levels in systemic lupus erythematosus, 9 patients who had a rise and 11 patients who had a fall in neuronal antibody titre over a mean duration of 2.1 years (range 0.25-5.2) were identified. These changes were examined in the light of concurrent changes in other serological variables, overall disease activity, neuropsychiatric disease and neuropsychological tests. Changes in antineuronal antibodies were frequently associated with concurrent changes in anti-DNA antibodies and overall disease activity. When neuropsychiatric disease or cognitive dysfunction were present, their course showed a close correlation with changes in antineuronal antibody levels. The results support the association between antineuronal antibodies and neuropsychiatric-systemic lupus erythematosus, but suggest that their measurement will provide useful information of disease status in only a subpopulation of patients.
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.
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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.
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.