1 Department of Neurology, University Hospital of Tromsø, Departments of
2 Psychology and
3 Clinical Medicine, University of Tromsø and
4 Department of Rheumatology, The National University Hospital, Oslo, Norway
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Abstract |
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Methods. Twenty-eight patients with SLE were examined at baseline and after a mean follow-up of 60.7±5.0 months using standardized neuropsychological tests. Group changes in performance over time were measured and the effects of baseline values for subsequent changes in individual variables after 5 yr were evaluated.
Results. When all SLE patients were considered as a group, seven out of nine (78%) neuropsychological variables remained unchanged and two (22%) improved significantly during the observation period, possibly due to methodological bias. Analysis of the importance of the level of initial cognitive performance for subsequent changes during the observation period, demonstrated that cognitive changes were not significantly influenced by baseline levels, except for a trend in three of nine variables. Neither demographic nor disease-associated quantitative factors were associated with cognitive changes over time.
Conclusion. Cognitive dysfunction seems to be a relatively stable feature of central nervous system involvement in SLE. A decrease in performance over time was not demonstrated consistently in the majority of domains.
KEY WORDS: SLE, Neuropsychiatric SLE, Cognitive dysfunction, Longitudinal.
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Introduction |
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The pathogenesis of CNS dysfunction in SLE is not well understood. The observation of both diffuse and focal CNS involvement in SLE has led to the hypothesis that there are several pathogenic mechanisms in NPSLE, such as microvascular damage, small-vessel vasculopathy and autoantibody-mediated neuronal cell injury [912]. It has been proposed that antineuronal and antiphospholipid antibodies are related to NPSLE features, such as cognitive dysfunction, but their pathogenic role in the induction of cognitive deficits remains uncertain. Some studies [1215] have suggested a relationship between anticardiolipin (aCL) antibody, lupus anticoagulant and cognitive function, while one study found no such association [16]. We have not previously seen any association between lupus anticoagulant or aCL antibody and cognitive abnormalities [17], although we have demonstrated that patients with SLE have significant cognitive abnormalities compared with patients with a chronic, non-immunological illness [18]. Furthermore, there were no associations between cognitive dysfunction and depression, indicating that cognitive dysfunction in SLE reflects CNS involvement and is not related to coexisting depressive disturbances [18]. Two recently published longitudinal studies demonstrated an association between persistently elevated aCL titres and cognitive dysfunction, suggesting that aCL may serve as an immunological marker [19, 20]. Most studies have found no associations between cognitive dysfunction and clinical or laboratory markers of disease activity, severity or corticosteroid medication [16, 21, 22].
Most studies on cognitive dysfunction in SLE have been cross-sectional in design. However, it is important to know whether these abnormalities are static or progressive or if they resolve over time. Furthermore, it is important to elucidate the long-term implications of cognitive dysfunction in SLE patients and to determine whether such patients require aggressive medication, including prophylactic anticoagulation, to prevent cerebral infarction [17]. Few longitudinal studies have been reported [2325], only one being a long-term (5 yr) follow-up study [26]. We therefore performed a longitudinal study, also focusing on factors of possible importance in the development of cognitive dysfunction in SLE patients over time.
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Patients and methods |
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Demographic and clinical data at inclusion in 1991
Twenty-six females (93%) and two males (7%) were included. The mean age was 41.0±12.2 yr (range 2067 yr), mean education level 10.6±3.4 yr (range 519 yr), and mean disease duration 13.8±6.4 yr (range 6.031.0 yr). Disease duration was defined as the interval between the time of assessment and the onset of symptoms or signs attributable to SLE. Nineteen patients (68%) were on medication for SLE with a single drug or a combinations of drugs. Thirteen patients (46%) used corticosteroids, 12 (43%) antimalarials and nine (32%) azathioprine, while nine patients (32%) were not on medication for SLE. None used antidepressive drugs. The most frequent disease complication was glomerulonephritis, in five patients (18%), while stroke and lung fibrosis occurred in one patient each. Concomitant diseases were arterial hypertension in five patients (19%), coronary heart disease in two (7%) and aseptic osteonecrosis in two (7%). The mean number of American Rheumatism Association criteria met was 5.6±1.4 (range 48). Disease activity in 1991 was quantified using the scoring system of Valentijn et al. [28], which was the method employed by our group when our studies on SLE started in 1985. The Valentijn scoring system evaluates SLE activity as inactive, moderate or highly active. The mean Valentijn score was 4.4±2.8 (range 09), higher numbers indicating greater disease activity.
All patients were given a standardized clinical examination. Urinary, haematological and immunological tests were performed in the hospital's routine laboratory. aCL IgG and IgM antibodies were analysed with a commercial enzyme-linked immunosorbent assay according to the manufacturer (Shield, Dundee, UK). Values above 30 GPL (IgG phospholipid units) and 30 MPL (IgM phospholipid units) U/ml were considered positive.
As the basis for comparison of neuropsychological performance, we used normative data for healthy subjects matched for age and education [29]. Previous studies have demonstrated no significant differences between American and Norwegian healthy controls and brain-injured patients matched for age and education [30].
Neuropsychological examinations
These were performed at baseline (1991) and 5 yr later. A battery of standardized tests was used to measure different areas of cognition, such as attention, concentration, cognitive speed, executive function/abstract problem-solving and motor function, as shown in Table 1. The patients were tested individually by an experienced and highly trained test technician. The examinations were based on the following tests: Similarities, Digit Span and Block Design subtests from the Wechsler Adult Intelligence Scale (WAIS) [31], parts A and B of the Trail Making Test, the Seashore Rhythm Test, the Category Test from the HalsteadReitan neuropsychological test battery [32] the and Grooved Pegboard Test from the KløveMatthew motor steadiness battery [32]. T scores were calculated using published means and standard deviations for normative samples [29]. Standardized T scores have a mean of 50 and a standard deviation of 10. To reduce the statistical effects of regression to the mean, the difference from the start to the end of the study (change from baseline) was calculated for each individual neuropsychological variable, and the relative change from baseline, calculated as the percentage change, was used instead of the absolute value. This study treated neuropsychological measures as continuous variables and we therefore used raw scores in the calculation of relative changes. The influence of baseline values on subsequent changes in the individual cognitive variables after 5 yr of study were evaluated by regression analysis with baseline as the independent variable and percentage of change from baseline as the dependent variable.
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Statistical analysis
Results are presented as the mean and standard deviation. The two-tailed paired t-test or analysis of variance (ANOVA) was used to test differences between two or more groups of quantitative data. Group changes in test performance between the start and end of the study were examined with paired t-tests. A statistical problem arises with multiple significance testing because the probability of finding a significant difference increases with increasing number of variables analysed (type I error). This can be corrected by the Bonferroni method, although with numbers of variables exceeding 45 this will be a conservative method, erring on the side of safety (non-significance; type II error). In applying this to the extreme case, supposing all variables in this study were independent (n=9), the significance level would be 0.05:90.006. However, within each test battery it may be assumed that the variables are more or less dependent on each other; the number of variables will then be 0.05:2
0.03. There is no exact solution to this problem, but it is reasonable to assume that the significance level will be somewhere between these values. Because of the multiple comparisons, the Bonferroni-corrected significance threshold of P<0.01 was considered appropriate to reduce the risk of type I errors.
Simple and multiple regression were used to analyse quantitative factors associated with change from baseline neuropsychological variables, while repeated measures ANOVA was used for qualitative factors.
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Results |
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Study group at the start and end of the study
The neuropsychological test results using T scores at the start and end of the study (baseline and follow-up assessments) of the 28 SLE patients revealed no significant group changes in seven of nine cognitive variables (78%), while there were significant group improvements in test performance on two variables (22%) after 5 yr. These were the Trail Making Test parts A and B from the HalsteadReitan neuropsychological test battery and a trend for Block Design from the WAIS (P=0.01), with the best test results at follow-up (Table 2). Calculation using raw scores demonstrated no significant improvement except for a trend to improvement in the Grooved Pegboard Test (P=0.01).
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Change from baseline
Using raw scores, the relative changes (as percentages) from the start of the study were calculated for each individual neuropsychological variable. This showed that changes were not dependent on baseline levels for most variables. However, there was a trend to significance for the Category Test, the Seashore Rhythm Test and the Grooved Pegboard Test, non-dominant hand (P<0.05) (Table 3). For these three variables, a negative regression coefficient indicates that variables with high baseline values would have lower values at the end of the study, and variables with low baseline values would have higher values at the end of the study.
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Cognitive changes and demographic or disease-associated factors
Nine patients (32%) had a positive test result for aCL antibodies. No quantitative demographic or disease-associated factor had a significant influence on the change from baseline of neuropsychological variables, except for months on corticosteroid medication, which was significantly associated with percentage change from baseline in the Grooved Pegboard Test, non-dominant hand (y=-1.23+0.16x; R2=0.26; P=0.006). Inspection of the regression plot from the statistical analysis revealed one outlying extreme value that could have influenced the results of the analysis. When the patient responsible for this value, who had a cortical infarct in right hemisphere, was removed from the statistical analysis, this association disappeared.
Repeated measures ANOVA
No significant effect of demographic or disease-associated parameters, including medication for SLE and aCL antibody, on neuropsychological measures was seen over time.
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Discussion |
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As SLE is a chronic autoimmune disease, one could assume that when NPSLE develops it will persist or lead gradually to more severe CNS manifestations and a decline in cognitive functions. This raises the concern that if cognitive defects evolve into more profound CNS dysfunction over time, the use of aggressive therapy should be considered. The real clinical picture appears to be more complex, however. Our results indicate that, in the majority of SLE patients, cognitive dysfunction is not cumulative over time, as their test performance indicates more or less stable neuropsychological dysfunction. Some of the variables actually changed in the direction of cognitive improvement during the observation period. This is an unexpected finding that can hardly be explained by the natural course of NPSLE. One possible explanation is methodological. The normative data used in this study were grouped into age intervals of 5 yr [29]. The SLE patient group, which had a mean age at baseline of 41.0 yr, was compared with a normal control group aged 4044 yr. At follow-up, the SLE patient group was compared with another normal group (4549 yr). The improvement that was demonstrated may thus have been biased by this change of comparison norm, and the improvement may reflect a scaling effect of the T scores. Indeed, calculation using raw scores showed no significant improvement. Taken together, these results are consistent with stable cognitive dysfunction over time in SLE patients. This is in agreement with a recent study indicating relatively stable cognitive dysfunction [25], but contrasts with another longitudinal study that showed fluctuations in cognitive functions over time [23, 26].
Another approach is to investigate, in the individual patient, whether the level of functioning at the first examination is of importance for the subsequent development of cognitive dysfunction, or whether demographic or disease-associated quantitative factors exert such an effect. We found that such changes over time were not significantly dependent on baseline values.
Most of the patients had a mild cognitive dysfunction and, on a group basis, several neuropsychological variables were within the normal range. However, in the individual patient some disease factors may be related to cognitive abnormalities. We recently reported that cerebral infarcts and cortical atrophy, as detected by cerebral computed tomography and magnetic resonance imaging, are the only features of SLE that are significantly associated with cognitive disturbances [17, 33].
No other demographic or disease-associated factors, including immunological parameters that could predict changes in cognitive variables over time, were found. In particular, no relationship was found between the presence of aCL antibody and cognitive dysfunction. Our results contrast with two recently published longitudinal studies that have demonstrated an association between a persistently elevated aCL antibody titre and cognitive dysfunction in SLE [19, 20]. However, other studies have not been able to demonstrate such an association [16, 17]. More prospective observations are warranted.
One problem with measuring changes in cognitive function over time is to determine if a difference in test performance is real or represents chance variation or practice effects. The latter will vary as a function of testretest intervals and, to a certain extent, variables such as age and education [34, 35]. For example, Hanly et al. [23] observed some improvement in performance on comparable neuropsychological tests in SLE patients and controls due to the practice effect when the interval between assessments was 1 yr, which could have biased the apparent improvement in performance over time, and this was their main finding. In our study, the SLE patients were followed up after more than 60 months, and testretest effects should thus have been avoided.
In summary, cognitive dysfunction seems to be a relatively consistent and stable finding in SLE, possibly reflecting chronic neuronal damage. The present study demonstrates that, in the majority of patients, cognitive function did not deteriorate over a period of 5 yr. No associations with demographic factors, medication or other diseases were found.
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Acknowledgments |
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Notes |
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References |
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