Study of Neuropsychiatric Manifestations and Immunological Markers in Systemic Lupus Erythematosus

Transcription

1 Study of Neuropsychiatric Manifestations and Immunological Markers in Systemic Lupus Erythematosus Hafez N 1, Soltan L 1, Abo Ray AA 2, Hamdy M 1 Departments of Neuropsychiatry 1, Internal Medicine 2, Alexandria University ABSTRACT The objective: of this study was to determine the neuropsychiatric manifestations and its correlation with some immunological markers especially the antiribosomal antibody in the Egyptian patients with Systemic Lupus Erythematosus (SLE). atients and Methods: This study included: 30 SLE patients selected randomly and diagnosed according to the 1997 American College of Rheumatology (ACR) criteria. Ten healthy controls of matching age and sex. A standardized medical history, neurologic, rheumatologic and psychiatric examinations, serologic testing were performed. Results: The mean age of the studied sample was years. Twenty eight patients were females while only two were males. The overall frequency of neuropsychiatric (N) involvement in the studied patients was 80%. Central nervous system (CNS) involvement was more common than peripheral nervous system (NS) involvement. sychiatric disorders and headaches were the most common NSLE syndromes (73.3% and 56.7% respectively). Of which major depression and migrainous headache were the most frequently seen (60% and 30% respectively). As regards the NS, peripheral neuropathy was present in 23.3% of patients. Deterioration of cognitive functions was affected significantly by the disease duration rather than the disease activity markers and the antiribsomal antibody levels. On the other hand, Hamilton depression score correlation was significant with the disease activity markers rather than the disease duration. Antiribosomal antibody showed stronger statistical significant relation to the CNS more than NS. No significant relation was acheived between the age, disease duration and the quantitative value of anti antibodies. The titre of the antiribosomal antibodies seemed to be affected significantly positive by the disease activity markers as well as the Hamilton depression scale. The positive predictive value of elevated antiribosomal levels for identifying patients with NSLE was 66.7% while the negative value was 95.8% with accuracy of 90%. These results point out that anti antibody estimation can be assigned for predicting the involvement of the nervous system in SLE even in non-symptomatic cases.. (Egypt J. Neurol. sychiat. Neurosurg., 2007, 44(1): ). INTRODUCTION Survival in SLE has improved dramatically over the past few decades 1, but specific organ damage, the most frequent of which is neuropsychiatric (N) remains a significant cause of morbidity. (2) The recognition that NSLE is a significant cause of morbidity and mortality has led to increased epidemiological as well as basic science research in this disease. The diagnosis of NSLE is largely clinical and there is disagreement whether the American Collage of Rheumatism (ACR) case definitions represent diagnostic criteria or rather classification criteria. 3,4 Central nervous system lupus may be the initial and sometimes the sole manifestation of lupus. In this context, the erythrocyte sedimentation rate is often normal and results of tests for antinuclear, anti-double stranded (anti-ds) DNA, anti-sm, anti-rn, anti- SS-A, anti-ss-b antibodies are often negative. 5 An erroneous diagnosis is likely to occur if the onset is with psychosis or depression and if systemic features of lupus are not present. 6 A class of autoantibodies that have been increasingly implicated in the pathogenesis of NSLE is the group of antibodies against ribosome (anti ). These autoantibodies recognize the ribosomal phosphoproteins 0, 1, 333

2 Egypt J. Neurol. sychiat. Neurosurg. Vol. 44 (1) Jan , most commonly a 22-amino acid sequence near the carboxyl-terminal of these proteins. A possible pathogenic role for anti- antibodies is suggested by the findings that 0 is expressed not only in the cytoplasm, but also on the cell surface of some cell types, including neuroblastoma and endothelial cells, and can be recognized there by these antibodies. Anti- antibodies have only rarely been detected in CSF. 7 Although it has been hypothesized that this could be attributable to specific binding to, or uptake by, neuronal cells, there is little evidence to support this theory. Thus, a direct neurotoxic effect appears unlikely; however, the expression of their antigenic target on endothelial cells raises the possibility that anti- antibodies play a role in the development of vasculopathy typical of NSLE. 7,8 Anti-ribosomal antibodies are highly specific for lupus, and are found in 10-20% of all patients with lupus. However, there are possibly some ethnic differences in their prevalence, most notably a considerably higher frequency in Chinese and Japanese SLE patients. 9,10 The goal of this study was to determine neuropsychiatric manifestations and its correlation with some immunological markers especially the anti-ribosomal antibody in the Egyptian SLE patients. SUBJECTS AND METHODS The study was conducted on 30 SLE patients diagnosed according to the 1997 ACR criteria. 11 Ten persons matching in age and sex were used as controls. atients were enrolled into the study between October 2005 and April They were unselected patients from the inpatient ward and outpatient clinic of the Rheumatology department in Alexandria University hospital. Exclusion criteria Non SLE causes of CNS involvement including infection, metabolic abnormalities, and medications were excluded in all patients. The presence of co-existing disease or condition known to influence the study as renal failure, hepatic failure, congestive heart failure, diabetes mellitus, nutritional deficiency. Mixed connective tissue disease and overlapping syndromes. All subjects were subjected to: Full history taking. Neurologic & cardiovascular assessments. Risk factor information for assessing the presence of cardiovascular risk factors (hypertension, diabetes, coronary artery disease, cigarette smoking, hypercholesterolemia or hyperlipidemia, thrombotic events), episodes of fetal loss, or neurologic symptoms. Current medications, including corticosteroid dose. A standard complete neurologic examination was performed. The diagnosis of specific N manifestations was made using the American College of Rheumatology consensus criteria. 11 A structured Clinical Interview for sychiatric Diagnosis was administered to all patients Baseline psychiatric diagnosis were assigned according to the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) 12 Depression, anxiety assessment was performed using the Hamilton rating scale. 13 Cognitive assessment using Mini mental state examination. 14 Erythrocyte sedimentation rate (ESR) first hour and second hour were determined. 15 Immunologic testing: Blood, samples were obtained for determination of antinuclear antibody (ANA), the IgG antinuclear antibodies, the IgG/IgM anti-ds DNA were assayed by an indirect enzyme linked immunosorbant assay (ELISA). 16 Antiribosomal protein antibody using antiribosomal kit by Generic assays. Anti-r is an enzyme immunoassay for the quantitative determination of IgG autoantibodies to ribosomal phosphoprotein (r) in human sera. The bound autoantibodies react specifically with antihuman IgG antibodies conjugated to horseradish peroxidase (HR) within the incubation period of 15 minute at room 334

3 temperature. The optical density (OD) of the solution at 450 nm was measured and was directly proportional to the amount of specific antibodies bound. The standard curve is established by plotting the concentrations of the antibodies of the standards (X axis) and the corresponding OD values (Y-axis) measured. The concentration of antibodies of the specimen is directly read off the standard curve. ositive reference value is above 15 Uml. The blood sample was taken by venipuncture. Serum was separated after clotting by centrifugation. Lipaemic, hemolytic and contaminated samples were excluded. Data processing: The standard curve was established by plotting the mean optical density (OD)-values of the standards 1-6 on the ordinate, Y-axis, versus their respective antiribosomal concentrations of the abscissa X-axis. Antiribosomal concentrations of the unknown samples are directly read off in U/ml against the respective OD values. Test validity: The test was considered valid if: The mean OD of the standard 1 is 0.15 The mean OD of the standard 6 is 1.3 Reference values: ositive 15 U/ml. Negative 15 U/ml RESULTS The present work included 30 SLE patients, 28 females (93.3%) and 2 males (6.7%). Their age ranged from 16 to 52 years with a mean of years. Ten healthy control subjects were age and sex matched with patients' group. Their age ranged from 19 to 40 years with a mean of years. The frequency of NSLE in the studied sample was 24 patients (80%). Six patients (20%) only did not show any of the 19 NSLE symptoms tested. sychiatric disorders and headaches were the most common NSLE syndromes (73.3% & 56.7% respectively). Of which major depression and migranious headache were the most frequently seen (60% & 30% respectively). Cognitive deficit measured by MMSE was present in 4 patients. The most common affection was in the areas of calculations and memory. As regards acute confusional states, radiculopathy, Guillain Barré syndrome, mononeuropathy and plexopathy were not documented in any of the studied 30 SLE patients (Table 1). There was statistical significant difference between both group as regards disease activity markers and antiribosomal protein antibody. Hamilton score and MMSE score (Table 2). The antinuclear antibody reference values were 0-9 IU/ml is negative, more than 9-12 IU/ml is borderline, and more than 12 IU/ml is positive. The range in the SLE was between 13.9 to 640 IU/ml with a mean of The range in the control group was between 5.5 to 20 IU/ml with a mean of The difference was statistically significant. The ds DNA was measured to a reference of 20 IU/ml below which is negative and above which is positive. The reference value of antiribosomal protein antibody was 15 IU/ml below which is considered negative and above which is considered positive. The studied patients showed a range between 18.4 to 240 IU/ml with a mean of while, the control group showed a range between 5.5 and 14 IU/ml with a mean of This difference was statistically significant. In the studied group, twenty four patients had neuropsychiatric involvement. Out of this group antiribosomal antibody was positive in 23 patients. On the other hand, only one third of patients who did not have neuropsychiatric involvement had positive antiribosomal antibody. The antiribosomal antibody test showed 80% sensitivity and 92% specificity in detecting and/or confirming absence of neuropsychiatric involvement in SLE. A stronger statistical 335

4 Egypt J. Neurol. sychiat. Neurosurg. Vol. 44 (1) Jan 2006 significance was found between antiribosomal antibody and the CNS than with NS involvement. The positive predictive value was 66.7% and the negative predictive value was 95.8% with accuracy of 90%. These results points out that the antiribosomal antibody can be assigned for predicting the involvement of the nervous system even in non-symptomatic cases (Tables 3 and 4). There was a positive significant correlation between the antiribosomal antibody compared to ANA, anti ds DNA, ESR 1 st and 2 nd hour. There was a negative non-significant correlation between the antiribosomal antibody and the MMSE. There was a statistically significant correlation between the Hamilton depression score and the disease activity markers as well as antiribosomal antibody. However there was no statistically significant relation between the Hamilton depression score & the MMSE score. The MMSE correlation with disease activity markers, antiribosomal antibody and the Hamilton score failed to prove statistical significance (Table 5). However there was a positive significant correlation between MMSE and duration of the disease indicating a decrease in cognitive function with time (Table 6). No significant correlation was found between the duration of disease and the quantitative value of the antiribosomal protein antibody in SLE patients (Table 6). Table 1. The frequency of the neuropsychiatric manifestations in the studied SLE patient. NSLE diagnosis atients Number ercentage Aseptic meningitis 1 3.3% Cerebrovascular accidents 1 3.3% Headache Migraine with aura Migraine without aura Tension headache Unspecified % 6.7% 23.3% 16.7% 10% Movement disorders Chorea Tremors % 3.3% 10% Myelopathy 1 3.3% Seizures artial Generalised % 6.7% Cognitive disturbances % sychiatric Anxiety disorder Major depressive-like episode sychosis % 10% 60% 3.3% Myasthenia-Gravis 2 6.7% olyneuropathy (sensoimotor) % Neuropathy (cranial) 2 6.7% Autonomic disturbances 2 6.7% 336

5 Table 2. The mean and standard deviation of the disease activity markers, antiribosomal protein antibody, Hamilton score and MMSE values tested in both studied groups. Antinuclear antibody Anti ds-dna ESR 1 st hr. ESR 2 nd hr. Anti ribosomal protein antibody Hamilton score MMSE score atients n=30 Control n= Table 3. The sensitivity, specificity and accuracy of antiribosomal antibody in detection NSLE. Neuropsychiatric Symptoms in SLE Antiribosomal antibody patients Negative ositive Total Absent resent Total Sensitivity = 4/5*100 = 80.0%. Specificity = 23/25*100 = 92.0%. ositive predictive value = 4/6*100 = 66.7%. Negative predictive value = 23/24*100 = 95.8%. Accuracy = 27/30*100 = 90.0%. 337

6 Egypt J. Neurol. sychiat. Neurosurg. Vol. 44 (1) Jan 2006 Table 4. The relation between the antiribosomal protein titer and the clinical findings as grouped into central nervous system and peripheral nervous system manifestations. Antiribosomal antibody Central nervous system Central nervous system R ** eripheral nervous system R * ** Correlation is significant at the 0.01 level (high significance) * Correlation is significant at the 0.05 level (low significance). Table 5. Correlation between the disease activity markers and antiribosomal antibody titer, the Hamilton depression score and MMSE score. Test of significant ANA Anti ds- DNA Anti ribosomal antibody ESR 1 st hour r 0.38 Anti ds-dna p 0.04* Anti ribosomal r antibody p 0.032* 0.037* ESR 1 st r hour p 0.04* 0.043* 0.021* ESR 2 nd r hour p * 0.045* 0.001* Hamilton score MMSE scale r= correlation coefficient, = robability, *= Significant correlation r r p p 0.046* 0.027* 0.045* * * ESR 2 nd hour Hamilton score Table 6. The relation between the duration and the Hamilton depression scale, MMSE and the anti ribosomal antibody. 338 Disease duration Antiribosomal antibody R MMSE score R * Hamilton score R *Correlation is significant at the 0.05 level (low significance). **Correlation is significant at the 0.01 level (high significance). Antiribosomal antibody titer * MMSE score

7 DISCUSSION Although SLE-related morbidity remains high, the prognosis for survival has improved in recent years, from a 5-years survival of 15% in the 1950s to > 90% in recent studies. 17 Nervous system dysfunction occurs in 50-90% of patients with SLE depending on the sampling procedures & diagnostic criteria used. Despite its frequency and severity, nervous system involvement is under diagnosed and poorly understood. 18 While there have been conflicting results in the literature, male have generally been reported to have more N symptoms. 19 On the contrary, only two males were present in this study yet N symptoms were present in 80% of patients. The prevalence of neuropsychiatric symptoms in the present study (30 patients) were compared to several studies done by Ainiala et al. 20 (46 patients), Sanna et al. 21 (323 patients), Brey et al. 22 (128 patient) and Afeltra et al. 23 (61 patients). The overall frequency of NSLE in the SLE patients in these studies ranged between 57.3% as in the Sanna et al. 21 and 91% in the Ainiala et al study. 20 In the present study the overall frequency of NSLE was 80% which lie in an average percentage between both studies. sychiatric disorders, headaches, polyneuropathy, cognitive dysfunction & movement disorders were the most common syndromes seen. The frequency of some N manifestations of the present study resembled more or less the results of Ainiala et al. study 20 as headache, meningitis. There are numerous potential reasons why the estimated prevalence showed reasonable variation between studies. These include age, disease duration, disease activity and socioeconomic factors. The large discrepancy in the reported incidence of neuropsychiatric involvement in patients with SLE (14%-75%) proves the need for a single confirmatory diagnostic tool. Optic neuropathy/neuritis represents the most common form of cranial neuropathy in SLE patients, occurring in up to 7% (Ainiala et al) 20 of SLE patients and remains a major cause of blindness in this population. In this respect our results were similar to Ainiala et al. On the contrary Sanna et al. 21, Costallat et al. 21 reported (1.5% each) and 2% in Brey et al. 22. In addition to cranial neuropathies, a sizeable portion of SLE patients are affected by peripheral neuropathies, most commonly a sensory or sensory motor distal poly-neuropathy. In recent cross-sectional studies using the ACR case definitions, clinically evident polyneuropathy was found with prevalence of 3-28%. Costallat et al. 24 study agreed with Sanna et al. 21 study in the low rate of polyneuropathy (4% and 2.8% respectively) compared to higher rates in Brey et al. 22 (23%), Ainiala et al. 20 (28%) and the current study (23.3). Of importance, it must be noted that ACR case definitions do not include electroneuromyography (ENMG) for diagnosing polyneuropathy. These frequencies may be reduced if only ENMG confirmed cases are taken into account For mononeuropathy, the prevalence estimates range between 0% and 7% in recent cross sectional studies. In the current study no Giullain-Barre` syndrome,, mononuropathy or plexopathy were detected. This was similar to the Finnish data (Ainiala et al). 20 Acute confusional state was present in 7% of cases in the latter study. However, the percentages in Brey et al. 22, Afeltra et al. 23 and in the current study were nil. The overall prevalence of cognitive dysfunction as a NSLE manifestation ranged between 81-74% in Ainiala 20, Sanna 21, Brey 22 and Costallat et al. 24 studies. However in the present study it was 13.3%. Interestingly, even in investigations using not only the ACR case definitions but also very similar test batteries for assessing cognitive dysfunction, estimates of the prevalence of cognitive impairment vary widely. While an almost identical percentage of SLE was affected 339

8 Egypt J. Neurol. sychiat. Neurosurg. Vol. 44 (1) Jan 2006 in two studies from Finland (Ainiala et al.) 20 and Texas (Brey et al.) 22 81% and 79% respectively, frequencies of 52% and 26% were reported in two groups of Italian patients. 25 Since even the criteria for defining impairment were similar, it is not immediately obvious what accounts for this great variability. A recent hierarchical regression analysis of determinants of cognitive function in SLE patients found that demographic variables accounted for much of the variation in cognitive performance. These findings underscore the importance of using race, age, and educationcorrected norms in the assessment of cognitive functioning, as has been highlighted by other investigators. Ideally, cognitive function should be assessed near the onset of SLE in order to obtain a point of reference from which to measure possible deterioration. 5 Although MMSE and Hamilton depression scale were affected in both SLE patients and non SLE patients it was more affected in the former group. Studies had showed a statistically significant difference in the cognitive performance and mood between SLE patients with no N involvement and NSLE patients. 26 Hanly et al. 25 have argued that coexisting psychiatric disorders could explain the high prevalence of cognitive impairment in SLE patients. This was based on the observation that changes in cognitive function paralleled changes in psychiatric status. In a recent study using the Automated Neuropsychological Assessment Metrics, depression was found to be associated with poor performance on tasks assessing reaction time. 27 In the same study, however, no such association was reported for any areas of cognitive function as measured by traditional neuro-psychological tests. Other investigators have been unable to detect a correlation between cognitive impairment and depression in SLE patients. 28 In the present work there was a significant correlation between the disease activity indices, mood and cognitive functions. There was an inverse relation between the Hamilton score and the MMSE indicating that more depression can cause more cognitive impairment. However, this relation was not statistically significant. This implies a stronger impact of the disease activity markers on the mood and cognition more than the impact that mood and cognition have no each other. Our observation was confirmed by Loukkola et al in his published work. 27 In the present work, the MMSE was not found to fluctuate with all the disease activity markers. On the other hand, the Hamilton score was affected significantly by the titer of the antiribosomal antibody and the disease activity markers rather than by the disease duration. This can be interpreted by the fact that the cognitive function was affected by the disease duration while the depression was more affected by the disease activity. Two neuropsychiatric evaluations, at least one year apart, will be needed with the MMSE and Hamilton score measured to confirm these observations. Clinically, an association between neuropsychiatric manifestations and antiribosomal antibodies have been described but some studies failed to confirm this. 6,9,10,29 Also the frequency of positive test varied greatly in different studies. 29 In the present study, antiribosomal antibodies levels showed significant positive correlation with other disease markers rather than disease duration. In the same prospective was the work done by Walz et al. 30 and Sato et al. 31. Bonfa et al. 32 measured elevated levels in 18 of 20 patients with NSLE. Schneebaum et al. 33 reported that the frequency of elevated anti levels, as detected by ELISA in SLE without N (14%) and with non psychiatric neurologic disease (9%). In current study, elevated anti levels were detected in 25 out of the 30 studied SLE patients. It showed a stronger statistical significant relation with neuropsychiatric CNS than NS. Although some studies fail to proof this. Recent studies have suggested an association of anti- antibodies and lupus psychosis. Studies done by Reichlin et al. 34 and Scheneebaum et al. 33 have confirmed the ability of the antiribosomal 340

9 antibody to pointout those who have nervous system involvement due to SLE disease from those who have it as a complication of treatment or just as an associated disease. Their observation points out that SLE patients presenting with neuropsychiatric involvement as a sole manifestation and anti-ribosomal antibody is found positive would benefit from conventional SLE treatment. A possible explanation for the difference seen in studies concerning the correlation between antiribosomal antibody and NSLE can be attributed to variability in diagnostic criteria for psychiatric disease, variance in the temporal relationship between clinical events and serologic testing, differences in assay technique particularly antigen preparation and purity. Lastly but not leastly genetic and ethnic differences can play a role. In conclusion: neuropsychiatric manifestations are common in Egyptian SLE patients. Depression and Headache are the most frequently encountered. Elevated levels of autoantibodies to the C terminal region of ribosomal protein appear to be a specific marker for NSLE. Small sample size limited the statistical power of analysis, therefore rare syndromes as manifestations of NSLE was not assessed in our material. Further multi center studies with larger patient population may further clarify this issue. REFERENCES 1. Blanco FJ, Gomez-Reino JJ, De la Mata J, Corrales A, Rodriguez-Valverde V, Rosa J. Survival analysis of 306 European Spanish patients with systemic lupus erythematosus. Lupus 1998; 7: Mikdashi J, Handwerger B. redictors of neuropsychiatric damage in systemic lupus erythematosus: data from the Maryland lupus cohort. Rheumatology 2004; 43: Ainiala H, Hietaharju A, Loukkola J, et al. Validity of the new American College of Rheumatology criteria for neuropsychiatric lupus syndromes: a population-based evaluation. Arthritis Rheum 2001; 45: Ruggieri A. Neuropsychiatric lupus: nomenclature, classification, criteria, and other confusional states. Arthritis Rheum (Arthritis Care Res) 2001; 45: Weiner SM, Otte A, Uhl M, Brink I, Schumacher M, eter HH. Neuropsychiatric involvement in systemic lupus erythematosus. art 2: diagnostic and therapy. Med Clin. 2003; Feb (15); 98(2): Agius MA, Chan JW, Chung S, Lee EK. Role of antiribosomal protein antibodies in the diagnosis of lupus isolated to the central nervous system. Arch Neurol. 1997; 54(7): Koren E, Reichlin MW, Koscec M, Fugate RD, Reichlin M. Autoantibodies to the ribosomal proteins react with a plasma membrane-related target on human cells, J Clin Invest 1992; 89: Isshi K, Hirohata S. Differential roles of the antiribosomal antibody and antineuronal antibody in the pathogenesis of central nervous system involvement in systemic lupus erythematosus. Arthritis and Rheumatism 1998; 41: Isshi K, Hirohata S. Association of antiribosomal protein antibodies with neuropsychiatric systemic lupus erythematosus. Arthritis Rheum 1996; 39: Yalaoui S, Gorgi Y, Hajri R, Goucha R, Chaabouni L, Kooli C, Ayed K. Autoantibodies to risbosomal proteins in systemic lupus erythematosus. Joint Bone Spine 2002; 69: ACR AD Hoc Committee on Neuropsychiatric Lupus Nomenculture and case definitions for neuropsychiatric syndromes in SLE. Arthritis Rheum 1999; 42: American sychiatric Association: Diagnostic and Statistical manual of mental disorder. Fourth ed. Washington, DC, Am. sych. Ass. 13. Hamilton M, A rating scale for depression, J Neurol Neurosurg sychiatry 23(1960), pp Folstein MF, Folstein SE, Mc Hugh R: Mini Mental State: a practical method for grading the cognitive state of patients for the J. sychiat. Res. 1975, 12, Zolis M. The mystique of the ESR; a reappraisal of one of the oldest laboratory tests still in use. Clin Lab Med 1993; n13: Weinstein A, Bordweel B, Stone B, Tibbetts C, and Rothfield NF. Antibodies to native DNA and serum complement (C3) levels; application to diagnosis and classification of SLE. Am J Med 1983; 74:

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11 الملخصىالعربى درادةىالمظاهرىالعصبوةىوالنفدوةىوالدالئلىالمناعوةىفيىمرضىالذئبةىالحمراءى