Neuropsychological functioning and its relationship to antiphospholipid antibodies in patients with systemic lupus erythematosus

While it is clear that central nervous system (CNS) lesions in systemic lupus erythematosus (SLE) adversely affect cognitive functioning, it is also evident that patients without visible lesions (non-CNS SLE) may also exhibit subtle cognitive impairment. The presence of antiphospholipid antibodies (aPLs) has been proposed as a marker of disease severity and hence should be correlated with neuropsychological dysfunction in this population. The current study compared groups of non-CNS lupus patients who were positive (LA+) or negative (LA-) for aPLs on selected measures of neuropsychological functioning. In addition, we attempted to characterize the pattern of cognitive impairment that is associated with LA status in these patients. No coherent neuropsychological pattern emerged, but LA+ patients performed worse than LA- patients on measures assessing attention, concentration, and visual search, as well as spatial learning and memory.     

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.     

Positron emission tomography and magnetic resonance imaging for cerebral involvement in patients with systemic lupus erythematosus

Central nervous system (CNS) involvement in systemic lupus erythematosus (SLE) remains difficult to diagnose, particularly since structural abnormalities may not be revealed by magnetic resonance imaging (MRI). Glucose utilisation was measured by positron emission tomography (PET) in 35 SLE patients to detect signs of CNS involvement. The patients were examined by a standardised neurological examination, a battery of tests to evaluate neuropsychological performance and MRI. Antineuronal antibodies were determined to investigate their putative role in CNS involvement in SLE. Twenty patients had distinct neurological (17) and/or psychiatric (3) symptoms. Ten patients had pronounced cognitive impairment. Neurological and cognitive deficits were thus found to be unrelated disorders in SLE. Global glucose utilisation of SLE patients did not differ significantly from that of normal controls, nor were differences found between SLE patients with or without neurological or cognitive abnormalities. On MRI of the brain, the number and size of white matter lesions correlated with the presence of neurological deficits but were unrelated to the severity of cognitive impairment. Within the normal range, lower global glucose utilisation tended towards lower values with increasing number and size of white matter lesions. Patients with lesions larger than 8 mm also showed distinctly increased IgG anticardiolipin antibody titres, whereas measuring antineuronal antibodies did not reveal any relation to the variables investigated. We conclude that the demonstration of CNS lesions by MRI can contribute confirmatory evidence for CNS involvement in SLE, but PET or the presence of antineuronal antibodies adds little if any information beyond that obtained by clinical examination, neuropsychological testing, and MRI. Received: 22 May 1996 Received in revised form: 15 October 1996 Accepted: 2 November 1996     

Antiphospholipid antibodies and stroke

Antiphospholipid antibodies (aPLs) have been associated with recurrent thromboembolic events, thrombocytopenia, and cardiac valvular disease. Although these antibodies were originally described as a complication of systemic lupus erythematosus (SLE) and other connective tissue diseases, it is now recognized that aPLs can develop in the absence of other autoimmune disorders. Cross-sectional and prospective studies have suggested that aPLs are an independent risk factor for stroke, particularly when cerebral ischemia develops in young persons or in the setting of SLE. We will examine the present state of research on aPLs as a risk factor for thrombotic and embolic stroke and cerebral venous thrombosis. We will also review the current state of management strategies for patients with the antiphospholipid antibodies and stroke.     

Neuropsychological functions in systemic lupus erythematosus: a comparison with chronic whiplash patients

A comprehensive battery of neuropsychological tests sampling a wide range of cognitive functions was administrated to 36 patients with systemic lupus erythematosus (SLE), and a control group consisting of 31 patients with persistent symptoms after whiplash injury. Our results demonstrated significant group differences and suggest that cognitive dysfunction is common in SLE and that there are significant abnormalities in the SLE group compared to chronic illness of non-immunological nature. Considerable variability occurred in the neuropsychological profiles for SLE patients. No significant association was found between cognitive dysfunction and use of corticosteroids, except for the two neuropsychological tests Digit span and Seashore rhythm test. Associations were not found between cognitive dysfunction and depression either, except for the Seashore rhythm test. These findings indicate that cognitive dysfunction in SLE reflects CNS involvement, rather than coexisting emotional disturbance. No significant cognitive impairment was found in the whiplash group. However, our results indicate depressed mood among the whiplash group.     

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.     

Cognitive impairment in systemic lupus erythematosus and neuropsychiatric systemic lupus erythematosus: a population-based neuropsychological study

We present a cross-sectional, population-based neuropsychological study of systemic lupus erythematosus (SLE) patients identified within Tampere University Hospital district, Finland with 440,000 inhabitants. Patients with definite SLE in the age range of 16-65 years (n = 46) and matched controls (n = 46) underwent neurological examination and comprehensive neuropsychological testing. On the basis of medical examination, the SLE patients were divided into neuropsychiatric (NP+; n = 15) and nonneuropsychiatric (NP-; n = 31) cases. The neuropsychological test results revealed more prevalent cognitive impairment in the NP+ patients, indicating that this subgroup mostly accounts for neuropsychological changes in SLE. Most characteristic changes in NP+ were observed in domains of memory, psychomotor speed, and complex attention. This suggests nonspecific CNS involvement, which is in line with neurological manifestations of the disease.     

Cognitive Impairment in Systemic Lupus Erythematosus and Neuropsychiatric Systemic Lupus Erythematosus: A Population-Based Neuropsychological Study

We present a cross-sectional, population-based neuropsychological study of systemic lupus erythematosus (SLE) patients identified within Tampere University Hospital district, Finland with 440,000 inhabitants. Patients with definite SLE in the age range of 16-65 years (n =46) and matched controls (n =46) underwent neurological examination and comprehensive neuropsychological testing. On the basis of medical examination, the SLE patients were divided into neuropsychiatric (NP+; n =15) and nonneuropsychiatric (NP—; n =31) cases. The neuropsychological test results revealed more prevalent cognitive impairment in the NP+ patients, indicating that this subgroup mostly accounts for neuropsychological changes in SLE. Most characteristic changes in NP+ were observed in domains of memory, psychomotor speed, and complex attention. This suggests nonspecific CNS involvement, which is in line with neurological manifestations of the disease.     

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.     

Cognition, MRS neurometabolites, and MRI volumetrics in non-neuropsychiatric systemic lupus erythematosus: preliminary data.

OBJECTIVE: To correlate cognitive dysfunction with structural and neurometabolic brain findings in patients with non-neuropsychiatric systemic lupus erythematosus (non-NPSLE). BACKGROUND: Over 25% of non-NPSLE patients have cognitive dysfunction, but the cerebral basis of this observation is not well understood. METHOD: Seven patients with non-NPSLE and seven control subjects were given a series of neuropsychological tests and neuroimaging with magnetic resonance imaging and magnetic resonance spectroscopy. Analyses of cognitive function and structural and neurometabolic measures of the brain were performed. RESULTS: Compared with controls, the non-NPSLE patients were significantly impaired on a global cognitive impairment index (CII). No significant differences between the groups were found in choline/creatine (Ch/Cr), N-acetylaspartic acid/Cr, or hippocampal volumes. Ch/Cr was highly associated with CII across the sample. CONCLUSIONS: This is the first study to correlate cognitive impairment with an increase in Ch/Cr ratio among patients with SLE. These results, although preliminary, suggest that changes in cerebral white matter may be important in determining the subtle cognitive impairment that may occur in patients with SLE, even in the absence of neuropsychiatric symptoms.     

Prevalence and pattern of cognitive impairment in systemic lupus erythematosus patients with and without overt neuropsychiatric manifestations

The prevalence and pattern of cognitive impairment in systemic lupus erythematosus (SLE) patients with (NPSLE) and without (nSLE) overt neuropsychiatric manifestations were investigated. Fifty-two nSLE patients, 23 NPSLE patients and 27 healthy controls were evaluated with a battery of standardized neuropsychological and psychological tests. Disease duration, disease activity index, and current corticosteroid therapy were collected. Cognitive impairment was identified in 14 (26.9%) and in 12 (52.2%) of subjects with nSLE and NPSLE, respectively. Both SLE groups showed a significant impairment compared with controls on tasks assessing verbal and non-verbal long-term memory, and visuoconstructional abilities. In addition, NPSLE patients reported worse performances than both nSLE patients and controls on task evaluating short-term visuospatial memory. NPSLE subjects were significantly more anxious and depressed compared to both nSLE subjects and controls. By multivariate analysis, only depression levels, among clinical variables, significantly predicted cognitive performance. This study shows that cognitive impairment occurs frequently in both nSLE and NPSLE subjects. The higher frequency in NPSLE may be related to coexisting depressive disturbances.     

Neuropsychological dysfunction in systemic lupus erythematosus is not associated with changes in cerebral blood flow

Cognitive dysfunction is found in a considerable proportion of patients with systemic lupus erythematosus (SLE). SPECT provides an estimate of regional cerebral blood flow (rCBF) which has been claimed to be sensitive to detect brain involvement in SLE. It is, however, uncertain if these perfusion defects are related to cognitive dysfunction. In the present study we investigated whether cerebral dysfunction assessed by neuropsychological measures was associated with changes in rCBF. Fifty-two SLE patients were examined with a battery of neuropsychological tests and MRI of the brain. For each patient ^99mTC-HMPAO-SPECT was performed with the visual cortex as reference, and a reduction in rCBF of > 15 % was considered abnormal. Regional CBF was performed with an automated computer program quantitatively estimating blood perfusion in 16 symmetrical sectors of the brain. Several sectors of the brain showed varying areas of reduced rCBF with the temporal lobes most frequently involved. There were generally no associations between cognitive level of functioning and reduced rCBF. MRI demonstrated cerebral infarcts in 9 (17 %) patients. In general rCBF was reduced in all sectors of the brain in patients with infarcts, although statistical significant difference in rCBF between patients with and without infarcts was only seen in the parietal lobe. Several neuropsychological functions were influenced by the presence of cerebral infarcts. There was no significant association between immunological measures and SPECT findings or neuropsychological measures. Neuropsychological dysfunction in SLE was associated with the presence of cerebral infarcts detected by MRI, but not by changes in rCBF. SPECT seems to add little if any information to that obtained by clinical examination, neuropsychological testing, and MRI. Since anticoagulation may prevent cerebral infarcts, such prophylactic intervention may be of importance in preventing cognitive deterioration. Received: 3 November 2000 / Received in revised form: 12 January 2001 / Accepted: 24 January 2001     

Cognitive impairment in systemic lupus erythematosus: a follow-up study

We evaluated outcome and the clinical value of cognitive impairment in systemic lupus erythematosus (SLE). Fifty-one consecutive SLE subjects with or without overt nervous system involvement received two comprehensive neuropsychiatric and neuropsychological assessments, including the Mental Deterioration Battery, the Mini Mental State Examination (MMSE), and tests from the Wechsler Adult Intelligence Scale. The two neuropsychological assessments were made when subjects were in stable neurological condition. Twenty-seven patients were found to have neuropsychiatric symptoms (NP-SLE) at the first assessment, and three others developed them during the follow-up. Fifteen patients (10 NP-SLE) had cognitive impairment at the first assessment. At retest the cognitive deficit persisted in all patients but one (non-NP-SLE) and had developed in four others. In the cognitively impaired subjects scores on MMSE approached the cutoff for an overt dementing condition. No progressively decreasing scores were found on any of the tests. No relationships were shown between neuropsychological diagnosis and neuropsychiatric disorder, neuroradiological findings, disease activity, or steroid and nonsteroid immunosuppressive therapy. Cognitive impairment thus seems to be a stable symptom of CNS involvement in SLE. It corresponds to the subjective complaint of intellectual difficulties and marginal performance on the MMSE. Intellectual deterioration may occur in patients without other symptoms of NP-SLE. Standardized neuropsychological testing methods should be used routinely to assess SLE patients. Received: 8 March 1999/Received in revised form: /18 November 1999/Accepted: 30 November 1999     

Platelet activation induced by combined effects of anticardiolipin and lupus anticoagulant IgG antibodies in patients with systemic lupus erythematosus--possible association with thrombotic and thrombocytopenic complications

Antiphospholipid antibodies (aPL) are well known to be associated with arterial and venous thrombosis. In a series of 180 patients with systemic lupus erythematosus (SLE), the prevalence of arterial thrombosis was obviously higher in the patients who had both anticardiolipin antibodies (aCL) and lupus anticoagulant (LA) (17/35, 48.6%, p<0.05) (Table 1) than in the other patients bearing aCL or LA alone or neither of them (2/145, 1.4%). Since a substantial fraction of the former group of patients with arterial thrombosis also had thrombocytopenia (12/17, 70.6%), there was a possibility that aCL and LA might have enhanced platelet activation and aggregation. To test this possibility, we studied the in vitro effects of aCL and LA on the enhancement of platelet activation by flow cytometric analysis using anti-CD62P and anti-CD41 monoclonal antibodies directed against platelet activation-dependent granule-external membrane (PADGEM) protein and platelet glycoprotein IIb (GPIIb), respectively. Platelet activation defined by the surface expression of CD62P was not induced by aCL+ x LA+ plasma only, but was significantly augmented by aCL+ x LA+ plasma in combination with adenosine diphosphate (ADP) at a low concentration that had only a modest effect on platelet activation. In contrast, aCL+ x LA-, aCL- x LA+ and aCL- x LA- plasma samples were incapable of enhancing platelet activation in the presence or absence of ADP stimulation. In addition to plasma samples, the purified IgG from aCL+ x LA+ plasma (aCL+ x LA+-IgG) also yielded apparent enhancement of platelet activation induced by ADP. Furthermore, platelet activation was generated by the mixture of aCL+ x LA--IgG and aCL- x LA+-IgG fractions prepared from individual patients, but not by each fraction alone. These results suggest that aCL and LA may cooperate to promote platelet activation, and may be involved, at least partially, in the pathogenesis of arterial thrombosis and thrombocytopenia in patients with SLE.     

Acquired activated protein C resistance is associated with IgG antibodies to protein S in patients with systemic lupus erythematosus

The objective of this study was to clarify the roles of anti-phospholipid antibodies (aPLs) in the pathogenesis of acquired activated protein C resistance (APC-R) in patients with systemic lupus erythematosus (SLE). We examined several aPLs levels (lupus anticoagulant, anti-cardiolipin antibodies, anti-β2-glycoprotein I antibodies, anti-protein C antibodies, and anti-protein S antibodies), the APC-R test, and the factor V Leiden test in 85 SLE patients. Acquired APC-R, which was not found in any patient with the factor V Leiden mutation, was present in 26 (30.6%) of 85 patients, and confirmed that acquired APC-R was a significant risk factor for thromboembolic complications [odd ratio (OR), 3.36; 95% confidence interval (CI), 1.24-9.11]. Multivariate logistic analysis revealed that both LA and anti-PS strongly associated with the presence of APC-R, and that the correlation between anti-PS and APC-R was much stronger (OR, 46.7; 95%CI, 6.99-311) than that between LA and APC-R (OR, 11.3; 95%CI, 2.26-57.0). Furthermore, the mean value of APC sensitivity ratios was significantly lower in SLE patients with anti-PS (mean ± SD, 1.68 ± 0.37, p < 0.0001) than in those without anti-PS (2.23 ± 0.40). These results suggest that acquired APC-R is most strongly attributable to functional interference of the APC pathway by anti-PS, which contribute to risk of thromboembolic complications.     

A novel ELISA system for simultaneous detection of six subclasses of anti-phospholipid antibodies for prediction of thrombotic complications among SLE patients

Background

Anti-phospholipid antibodies (aPLs) are frequently associated with arterial and/or venous thromboembolic complications and recurrent fetal loss in patients with systemic lupus erythematosus (SLE). We recently reported that the clinical picture of SLE apparently depends on subclasses of aPLs in the patient’s sera, but the contribution of each subclass remains uncertain.

Methods

We newly developed an ELISA system for simultaneous detection of six specific categories of aPLs: anti-cardiolipin (aCL), anti-β₂-glycoprotein I (aβ₂GPI), anti-cardiolipin/β₂-glycoprotein I (aCL/β₂GPI), anti-phosphatidylserine (aPS), anti-prothrombin (aPT), and anti-phosphatidylserine/prothrombin (aPS/PT). They were measured in 331 patients with SLE including 63 patients with arterial thromboembolic complications, 64 with venous thromboembolic complications, and 43 with recurrent fetal loss. Lupus anticoagulant (LA) activity in their plasma was measured according to the guidelines recommended by the Subcommittee on Lupus Anticoagulant/Phospholipid-Dependent Antibodies.

Results

Multivariate logistic analysis revealed that the concentration of aPS/PT was most closely associated with arterial thrombosis. In contrast, the concentration of aβ₂GPI was most closely related to venous thrombosis. Furthermore, both aCL/β₂GPI and aPS/PT were independently associated with episodes of recurrent fetal loss. Regarding the relation between APLs and LA activity, aPS/PT, followed by aβ₂GPI and aPT, showed the closest association with the presence of LA activity.

Conclusions

Anti-phospholipid syndrome in patients with SLE can be classified by antigenic specificities of their aPLs as to their susceptibility to arterial and/or venous thromboembolic complications or obstetric complications.     

Neuropsychological outcome after unilateral pallidotomy for the treatment of Parkinson's disease

OBJECTIVE: To assess the long term cognitive outcome of unilateral posteroventral pallidotomy (PVP) and the overall efficacy of the surgery. METHODS: Forty two (29 left and 13 right PVP) patients with Parkinson's disease underwent neurological and neuropsychological testing before PVP and at 3 and 12 months after PVP. The neuropsychological testing battery emphasised measures of verbal learning and memory, visuospatial abilities, speed of information processing, executive functioning, and affective functioning. RESULTS: All patients demonstrated motor improvements after surgery during their off state, and 86% of patients also showed improvements in motor functioning in their on state. Repeated measures ANOVA showed significant improvements in confrontational naming, visuospatial organisation, and affective functioning 3 months and 12 months after surgery, with inconsistent improvements in executive functioning 12 months post-PVP. Patients demonstrated a transient impairment in verbal memory, with verbal learning performance returning to baseline 12 months post-PVP after a significant decline 3 months after PVP. When three patients with lesions extending outside of the PVP were excluded from the analysis, a decline in verbal fluency performance after PVP was not found to be significant. Differences due to side of lesion placement were not found on any of the cognitive measures. CONCLUSIONS: In the largest long term follow up study reported to date, the cognitive changes found up to a year after PVP are minimal compared with the robust improvements in motor function. The findings highlight the need to investigate the relation between the specific fibre tracts affected by the lesions and cognitive outcome.     

"Subcortical" cognitive impairment in patients with systemic lupus erythematosus.

Studies of cognitive functioning in patients with systemic lupus erythematosus (SLE) have found deficits even in patients without other evidence of neurologic involvement. The present study used scores on the 11 items of the Mini-Mental State Exam (MMSE) to classify the cognitive impairment of 93 SLE patients as suggestive of "cortical" or "subcortical" dysfunction using a validated statistical algorithm. Ninety-five percent of patients were categorized as having "subcortical" deficits, and 5% were categorized as having "cortical" deficits. When the analysis was limited to only those with total MMSE scores < or = 24, 81% were classified as "subcortical" and 19% as "cortical." These results suggest that SLE patients can have psychomotor and mental tracking deficits of a type seen in patients with subcortical brain disease, even in the absence of gross neurologic involvement.