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Introduction
Systemic lupus erythematosus (SLE) is a chronic and autoimmune inflammatory disease of connective tissue. Of unknown etiology, SLE is linked to genetic, hormonal, environmental factors, and to the use of some medications. This disease mostly affects women in childbearing age, especially between 15 and 50 years. However, approximately 20% of patients are affected during childhood or adolescence (JSLE), being predominantly of female gender.1-3
JSLE patients show a more severe form of the disease and develop neuropsychiatric symptoms at higher frequencies than in adult patients.4 Cognitive disorders are common and affect mainly attention, concentration, learning, memory, information processing and executive functions, even in the apparent absence of disease activity or of other neuropsychiatric events.5-8
Few studies available in the literature suggest that JSLE patients are at risk of poor academic performance,9,10 especially causing difficulties in arithmetic learning, reading comprehension, visual memory and inability to solve complex problems.10 For these reasons, patients with SLE can meet fewer educational milestones, for example, not finishing high school or college graduation – factors associated with a lower probability of employment and of success at work.10-12 In this scenario, the aim of this study was to determine whether there is an association between the profile of cognitive dysfunction and academic outcomes in patients with JSLE.
Materials and methods
Consecutive patients with JSLE seen at the Pediatric Rheumatology Outpatient Clinic, Hospital das Clínicas, Universidade Estadual de Campinas (UNICAMP), whose clinical and laboratory manifestations were routinely studied according to an already established protocol, were selected.13,14 Inclusion criteria were: patients with age of onset of disease ≤18,15 and with fifth grade of elementary school as the minimum level of scholarship. The study was approved by the Research Ethics Committee (CEP No. 920/2007) of UNICAMP and all the participants and legal guardians signed an informed consent form (FICF).
Cognitive assessment was performed by a qualified psychologist through the application of a survey battery lasting about two hours, consisting of tests adapted to the juvenile population and validated for the Portuguese language and selected from the battery recommended by the American College of Rheumatology (ACR).16 The following tests for evaluation of cognitive functions were selected:
Vocabulary Test: evaluates semantic memory, educational background and general intelligence17,18
Rey Complex Figure Test: evaluates perceptual organization, planning, praxis and memory19
Boston Naming Test: evaluates visual recognition and naming capacity20
FAZ Verbal Fluency Test: assesses verbal-phonological fluency21
Trail Making Test: assesses visual tracking, sustained attention and motor dexterity22
Stroop Neuropsychological Screening Test: evaluates selective attention, inhibitory control and mental flexibility23
Each patient had his/her scores counted individually.
Seventy-one controls matched for gender, age and socioeconomic status were included in order to obtain normative data of applied tests. Presence of cognitive impairment has been defined in cases of cognitive function with a mean Z-score ≤−2 SD or two or more functions with a mean Z-score between −1 and −2 SD.24
On the day of the cognitive tests, the school report of the last academic semester of each participant was requested. The participants were grouped by discipline: Portuguese/English/Spanish; Geography/History; Physical/Chemical/Biological Sciences; Mathematics; Physical Education; Arts; and Sociology/Philosophy. School grades ≥7 (70% success) were considered as satisfactory.24-28
Disease activity was assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) questionnaire and the disease was considered active if the sum of SLEDAI points was >3.29 Cumulative damage was assessed by the application of a questionnaire specifically developed for this purpose, the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) (SLICC/ACR-DI).30
To assess the presence of depressive symptoms, the Children's Depression Inventory – CDI31 for subjects between 7 and 17 years32 was applied; this tool is an adaptation of the BDI (Beck Depression Inventory). Anxiety symptoms were assessed using the Beck Anxiety Inventory – BAI.33,34
Lab work-up of autoantibodies was carried out; routine techniques used in the Clinical Pathology Laboratory and in the Allergy and Immunology Research Laboratory at Hospital das Clínicas, UNICAMP were used. Antinuclear antibody (ANA) (by indirect immunofluorescence; positive if title >1:40); anti-DNA antibody (by indirect immunofluorescence with Crithidia luciliae as substrate)35; anti-Smith antibody (by double immunodiffusion); anticardiolipin antibody (by enzyme immunoassay); and lupus anticoagulant (by TTPA and Russell method) were determined.36 Anti-ribosomal P protein antibody (anti-P) was measured by Enzyme Linked Immuno Sorbent Assay (ELISA).
Medications prescribed on the date of the cognitive tests were taken into account in this study. The drugs were corticosteroids, anti-malarials (chloroquine and hydroxychloroquine), and other immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporine, methotrexate and mycophenolate mofetil).
Statistical analysis was performed using the Statistical and Graphical Software (Systat) program. Shapiro–Wilk normality test was applied for obtaining results. For statistical analysis, nonparametric Kruskal–Wallis and Fisher's exact test were performed. The significance level was set at 5%, i.e., p < 0.05.
Results
Forty-one patients with JSLE (mean age, 14.5 ± 2.84 years), of whom 38 (92.68%) were females, were included and assessed for cognitive impairment and academic notes. Twenty-three (56.09%) patients were elementary education level students, three (7.31%) had completed elementary school and did not continue their studies, and 15 (36.58%) were high school students. The mean age of onset of the disease was 12.58 ± 3.24 years; and the disease duration, until the time of testing, was 2.4 ± 2.63 years. Eleven (26.82%) patients had active disease at the time of testing (mean of SLEDAI, 7.27 ± 2.62).
The control group was composed of 71 healthy volunteers (90.14% women) with mean age of 16.37 ± 5.21 years. No statistically significant differences were found between patients and controls regarding gender and age, and socioeconomic status. According to the criteria adopted for the definition of cognitive dysfunction, 17 (41.46%) patients and 26 (36.6%) controls had cognitive impairment (p = 0.08).
JSLE patients were divided into two subgroups according to the presence or absence of cognitive dysfunction. It was observed that the presence of cognitive impairment was associated with younger age at diagnosis of JSLE (p = 0.038) and an association between cognitive impairment and ANA (p = 0.033) was noted. Demographic, clinical and immunological data are listed in Table 1.
Table 1 Demographic, clinical and immunological data of juvenile systemic lupus erythematosus patients with and without cognitive impairment.
| Variables | Patients with cognitive dysfunction | Patients without cognitive dysfunction | p-Value |
|---|---|---|---|
| n = 17 | n = 24 | ||
| Female | 17 (100%) | 21 (87.5%) | 0.128 |
| Age at diagnosis (mean/SD) | 11.47 years (2.47) | 13.37 years (3.53) | 0.038a |
| Disease duration (mean/SD) | 5.11 years (4.21) | 7.58 years (4.93) | 0.102 |
| Active disease | 5 patients (29.41%) | 6 patients (28.57%) | 0.756 |
| Cumulative damage | 3 patients (17.64%) | 5 patients (20.83%) | 0.75 |
| Anxiety | 5 patients (29.41%) | 3 patients (12.5%) | 0.241 |
| Depression | 1 patient (5.88%) | 0 patient (0%) | 0.235 |
| Anti-P | 5 patients (29.41%) | 3 patients (12.5%) | 0.589 |
| ANA | 17 patients (100%) | 18 patients (75%) | 0.033a |
| Anti-DNA | 10 patients (58.82%) | 16 patients (66.66%) | 0.745 |
| Anti-Smith | 7 patients (41.17%) | 7 patients (29.17%) | 0.430 |
| Anticardiolipin | 6 patients (35.29%) | 5 patients (20.83%) | 0.476 |
| Lupus anticoagulant | 6 patients (35.29%) | 13 patients (54.16%) | 0.342 |
ap < 0.05.
Symptoms of anxiety were observed in 8 patients (19.51%) and were associated with visual perception (p = 0.037), but there was no association of these symptoms with presence of cognitive impairment (p = 0.988). Symptoms of depression were observed in 1 (2.43%) patient and again there was no association with cognitive impairment (p = 1.0). No association was observed between symptoms of anxiety and depression, when compared with academic grades.
No association of cognitive impairment with any medication (corticosteroids, p = 0.988; immunosuppressants, p = 0.75 and antimalarials, p = 0.988) was observed.
When comparing patients with versus without cognitive impairment, school performance showed significant difference between groups only for math grades (p = 0.039) (Table 2).
Table 2 School grades between patients with juvenile systemic lupus erythematosus with and without cognitive impairment.
| Discipline | Patients with cognitive dysfunction (mean ± SD) | Patients without cognitive dysfunction (mean ± SD) | p-Value |
|---|---|---|---|
| Portuguese/English/Spanish | 7.09 ± 1.29 | 6.93 ± 1.08 | 0.302 |
| Geography/History | 7.12 ± 1.51 | 7.38 ± 1.54 | 0.791 |
| Sciences | 6.26 ± 1.52 | 7.04 ± 1.98 | 0.195 |
| Physical Education | 7.55 ± 1.67 | 8.04 ± 1.92 | 0.604 |
| Mathematics | 6.68 ± 2.06 | 7.37 ± 1.65 | 0.039a |
| Arts | 8.14 ± 1.59 | 8.26 ± 0.98 | 0.662 |
| Sociology/Philosophy | 7.62 ± 1.05 | 7.14 ± 1.27 | 0.504 |
ap < 0.05.
Discussion
In our sample, the frequency of cognitive dysfunction was 41.46%; this finding was consistent with other studies reported in the literature.4,6,8,24
The presence of cognitive impairment was associated with poorer performance in mathematics in our patients. Another study found that children with JSLE had poorer academic results versus individuals without this disease.9 It is suggested that deficits in language ability are among the first markers of presence of neurological disorder in patients with JSLE, and that this difficulty may be present even in patients without neuropsychiatric manifestations.6 In this study, there was no significant difference in language-related disciplines.
It is a very difficult task to define school performance, in the face of the multiple variables used to assess this phenomenon.25 Unsatisfactory performance was defined by McCall as the performance of an individual who does not necessarily obtain low grades, but whose grades are below his/her expectations.26 There is greater consensus in considering as unsatisfactory a performance substantially below expectations for the student's own cognitive ability.25,26
It is also difficult to assess school performance, since this parameter depends on different factors, among which are: school physical characteristics, teacher qualifications, education level of parents, and education level of the student.28 In the literature, several measures are available for evaluation of school performance, including: grade repetition, suspension, grades lower than the expected for the student's coefficient of intelligence, and low grades.37 In our study, in the definition of poor school performance we considered the occurrence of unsatisfactory notes, i.e. educational achievement <70% for a certain class content.25-28
It is known that cognitive dysfunction is associated with high morbidity in patients with JSLE.5,12 However, a major obstacle to understanding the neuropsychological functioning of these patients is the lack of a standardized criterion for the identification of this dysfunction.8,24
The cognitive impairment evaluation consisted of tools adapted to juvenile age group and selected from the battery suggested by ACR16 for evaluation of cognitive dysfunction in adults, and also with batteries used in recent studies in patients with JSLE.4,6,8,9,24
In this study, we found no evidence that disease activity plays a role in cognitive function. This finding is supported by two recently published pediatric studies, in which the authors found no association between disease activity and cognitive dysfunction.4,8 On the other hand, when individuals with more severe conditions, e.g., hospitalized patients, were included, we could observe an association between disease activity and cognitive dysfunction.12
Other authors found no association between cognitive deficit and cumulative damage38 or medication,39 which was confirmed in our study.
In children, reports of an association of autoantibodies with cognitive impairment are sparse and inconclusive; moreover, such studies also did not identify in their sample a direct association between the presence of antibodies and cognitive dysfunction.4,8 However, in our study we found an association with ANA and cognitive impairment, suggesting that there is a link between autoimmunity and cognitive functioning.
It is known that living with a chronic disease can cause major adaptive problems associated with emotional distress, such as irritability, insomnia, loss of appetite, emotional instability, and changes in memory and concentration, which may be reflected in school performance.27,28,40 For this reason, some authors point out behavior difficulties as a risk factor for poor academic performance of individuals with JSLE.8,11,41 Behavior difficulties, although being a variable not evaluated in this study, are important in patients with chronic disease, especially in adolescents; these factors may have had some bearing on the results.
Although cognitive disorder frequency has been compared against healthy individuals, unfortunately we did not compute the academic performance of these controls for comparison.
In conclusion, patients suffering from JSLE and with cognitive impairment exhibit a worse academic performance in math, compared to JSLE patients without cognitive impairment.
