The Egyptian Rheumatologist (2012) 34, 67–73

Egyptian Society for Joint Diseases and Arthritis

The Egyptian Rheumatologist

www.rheumatology.eg.net
www.sciencedirect.com

ORIGINAL ARTICLE

Cognitive impairment in non-neuropsychiatric

systemic lupus erythematosus
a,*
Abeer Mohamed El-Shafey , Sahar Mahfouz Abd-El-Geleel a,
Eman Soliman Soliman b

a
Rheumatology & Rehabilitation Department, Faculty of Medicine, Zagazig University, Egypt
b
Psychiatry Department, Faculty of Medicine, Zagazig University, Egypt

Received 1 January 2012; accepted 25 February 2012

Available online 9 April 2012

KEYWORDS Abstract Introduction: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease
Systemic lupus which can cause prominent central nervous system (CNS) involvement. Cognitive dysfunction is
erythematosus; one of the major neuropsychiatric syndromes of SLE.
Neuropsychiatric lupus; Aim of the work: To evaluate cognitive functions in SLE patients without evident neuropsychi-
Cognitive functions; atric manifestations and to find out if it is correlated with disease activity and with treatment.
Montréal cognitive assess- Patients & methods: Thirty SLE patients without evident neuropsychiatric manifestations were
ment (MoCA) scale; evaluated. The evaluation included full clinical examination, assessment of SLE disease activity
Trail making test
index-2k (SLEDAI-2k), routine laboratory investigations, autoantibodies assessment and cognitive
function assessment using Montréal cognitive assessment (MoCA) scale and trail making test
(TMT) (part A and part B). Twenty apparently healthy individuals were taken as control.
Results: Cognitive dysfunction is present in all SLE patients included in our study. During
assessment of cognitive functions, a highly statistically significant difference was observed between
patients and control subjects, even with equal levels of education. While patients with higher

* Corresponding author. Mobile: +20 1144704146.

E-mail addresses: abeerelshafey@hotmail.com (A.M. El-Shafey),
Dr_saharmahfouz@yahoo.com (S.M. Abd-El-Geleel), Dr_eman_alex
@yahoo.com (E.S. Soliman).

1110-1164 Ó 2012 Egyptian Society for Joint Diseases and Arthritis.

Production and hosting by Elsevier B.V. All rights reserved.

Peer review under responsibility of Egyptian Society for Joint Diseases

and Arthritis.
doi:10.1016/j.ejr.2012.02.002

Production and hosting by Elsevier

68 A.M. El-Shafey et al.

educational levels were as impaired as those with lower levels of education. Cognitive dysfunction
was not correlated with disease activity or with the doses of drugs used for treatment. But a statis-
tically significant positive correlation was noted between deterioration of cognitive functions and
the disease duration.
Conclusion: Cognitive dysfunction is a prominent feature in SLE patients without symptoms of
CNS involvement. Psychological evaluation should be performed for each SLE patient to detect
cognitive dysfunctions. Psychological intervention is recommended to prevent further deterioration.
Correlation with disease duration should pay attention to the chronicity of disease.
Ó 2012 Egyptian Society for Joint Diseases and Arthritis. Production and hosting by Elsevier B.V.
All rights reserved.

1. Introduction demonstrated that elevated levels of C-reactive protein

(CRP) are correlated with deficits in information processing
Systemic lupus erythematosus (SLE) is a chronic autoimmune [12].
disease that is characterized by multisystem involvement and Patients with neuropsychiatric systemic lupus erythemato-
diverse manifestations. It can affect almost any organ in the sus (NPSLE), especially those with cognitive impairment were
body; the primary areas affected by SLE include the heart, found to have elevated levels of matrix metalloproteinase-9
lungs, skin, joints, blood-forming organs, kidneys, and the cen- (MMP-9) in the serum [13] and in the cerebrospinal fluid
tral nervous system (CNS) [1]. (CSF) [14].
Over 50% of patients with SLE demonstrate major psychi- The aim of this study was to evaluate the state of cognitive
atric and neurologic disorders indicating CNS involvement. functions in SLE patients without evident neuropsychiatric
Neuropsychiatric (NP) syndromes in SLE may include major manifestations and to find out if it correlated with disease
manifestations, such as stroke syndromes, seizures, and psy- activity and with treatment or not.
chotic episodes. They may also include less severe abnormali-
ties including headaches, minor mood disorders, and
cognitive difficulties [2]. 2. Patients and methods
In the revised criteria for neuropsychiatric lupus, 19 neuro-
psychiatric syndromes were defined including 11 CNS disor- 2.1. Patients
ders and eight peripheral nervous system disorders. In this
revised nomenclature, cognitive dysfunction was identified as Fifty subjects were included in this study. All subjects were re-
one of the major neuropsychiatric syndromes and was defined cruited from the out-patient clinics and follow-up units of the
as ‘‘significant deficits in any or all of the following cognitive Rheumatology and Rehabilitation Departments, Faculty of
functions: complex attention, executive skills (e.g., planning, Medicine, Zagazig University Hospitals. They were divided
organizing, sequencing), memory (e.g., learning, recall), vi- into two groups. The first group (I): included 30 SLE patients
sual-spatial processing, language (e.g., verbal fluency), and suffering from lupus nephritis and treated by corticoste-
psychomotor speed’’ [3]. roids with either pulsed cyclophosphamide therapy or oral
Studies to date suggest that cognitive impairment in SLE is azathioprine. They were diagnosed according to the revised
in part mediated by autoantibody activity and mechanisms American College of Rheumatology (ACR) criteria for classi-
associated with ischemia [4]. Additional mediators of cognitive fication of SLE [15]. The second group (II): included 20
function in SLE patients include health characteristics (disease apparently healthy subjects, matched for age, sex, total years
activity, disease duration, medication use), immune activity of education, and social backgrounds, taken as a control
(autoantibodies, proinflammatory cytokines), and behavioral group.
factors such as depression, pain, and fatigue [5]. In this study, we excluded patients with major psychiatric
It has been claimed that a subset of anti-DNA antibodies disorders, mental retardation or family history of organic men-
cross reacts with a sequence in the extracellular ligand-binding tal disorders. SLE patients with known comorbid neurologic
domain of NR2 receptors [6]. These receptors are subtypes of conditions (traumatic brain injury; degenerative, vascular, or
N-methyl-D-aspartate (NMDA) receptors which bind to the metabolic disorder; neoplasm, or toxic exposure), major sub-
excitatory neurotransmitter glutamate. They are present at stance abuse, or major psychopathology were excluded from
high density in the hippocampus, which is closely linked to the study. An informed consent was taken from all subjects re-
learning and memory [7]. cruited for the study.
Omdal et al. reported an association between anti-NR2
antibodies and decreased short-term memory and learning 2.2. Clinical and laboratory evaluation
[8], and also with depressed mood [9].
Antiphospholipid syndrome is associated with focal mani- All subjects of our study were subjected to full history taking,
festations of NPSLE, such as stroke and seizures [10]. Persis- thorough physical examination and laboratory investigations
tently elevated levels of anti-cardiolipin antibodies (ACL) are such as: complete blood count (CBC), erythrocyte sedimenta-
associated with decline in cognitive dysfunction, possibly due tion rate (ESR), C-reactive protein (CRP), complete urine
to thrombosis within vessels of minute calibers [11]. analysis, 24-h urinary proteins, C3 level, antinuclear antibody
A previous study identified a relationship between serum IL- (ANA) by immunofluorescent assay, anti-double stranded
6 production and learning deficits in SLE. It was also DNA (Anti-Ds. DNA) done by latex agglutination test and
Cognitive impairment in non-neuropsychiatric systemic lupus erythematosus 69

anti-cardiolipin (ACL) IgM by enzyme-linked immunosorbent 3. Results

assay (ELISA). Assessment of disease activity was done by
using systemic lupus erythematosus disease activity index-2k 3.1. Grouping of subjects included in the study
(SLEDAI-2k) [16].
This study was performed on 50 individuals, divided into two
2.3. Assessment of cognitive functions groups:
Group I: It included 30 SLE patients. Twenty-one patients
Assessment of cognitive functions was done by: were suffering from active lupus nephritis, and are under
pulsed cyclophosphamide therapy combined with steroid
a. Montréal cognitive assessment (MoCA) scale [17]. treatment, and have completed the first 6 monthly doses of
MoCA scale includes several aspects of cognitive treatment course. The remaining nine patients are under Aza-
functions. Actually, it is divided into several subcores thioprine and steroid treatment.
including visuospatial and executive functions, naming, Group II: It included 20 healthy subjects (control group), of
attention, language, abstraction, delayed recall, and ori- nearly the same epidemiological characters.
entation [18]. All patients and control subjects were further classified,
b. Trail making test (TMT) (part A and part B): The TMT according to the number of years of education, into two sub-
assesses mental shifting and consists of two parts. First, groups a and b, less than 12 years and more than 12 years,
the subject is required to draw lines to connect numbers respectively.
in ascending order as quickly as possible. This part
(TMT A) assesses visual perception rapidity and psycho-
motor rapidity. The second part (TMT B) assesses men- 3.2. Comparison between clinical & laboratory variables of the
tal shifting and the subject’s attention ability since s/he is two groups
required to do the same as for TMT A, but alternating
between numbers and letters. The subject is asked to per- The statistical analyses did not show significant differences
form the task as quickly as possible without lifting his/ among SLE patients and control subjects as regards age, years
her pen. If the experimenter sees a mistake, s/he tells of education, CRP levels, ACL levels and TMT A scores, while
the patient. The time in seconds required for the perfor- there were highly statistically significant differences between
mance of part A and part B was used for the analysis. If both groups as regards ESR, C3 levels, ANA and anti-DNA
the time to complete TMT B is longer than 240 s, then the titers. There were highly statistically significant differences be-
test is stopped and the number of figures connected tween patients and control subjects as regards TMT B and
in the allotted time as well as the number of errors is MoCA scales for cognitive assessment (Table 1).
noted [19].

Statistical analysis: The data of the patients were entered on 3.3. Effect of SLE on cognitive function
Statistical Package for Social Science (SPSS) [20]. Results are
presented as mean and standard deviation. The non-paramet- In subjects with less than 12 years of education, there was a
ric un-paired t-test, Mann Whitney U test, is used to assess highly statistically significant difference in MoCA, TMT A
differences of cognitive functions between each group. Spear- and TMT B scores between subgroups I-a and II-a. While in
man’s correlation coefficient analyses were performed to iden- subjects with more than 12 years of education there was a sta-
tify factors associated with cognitive deficits, such as: MoCA, tistically significant difference in MoCA scores and a highly
TMT A, TMT B, total SLEDAI-2k and renal index. The statistically significant difference in TMT B scores between
statistically significant cutoff value was set at p < 0.05. subgroups I-b and II-b (Table 2).

Table 1 Epidemiological and clinical variables of the two studied groups.

Group I (patients) II (control) P
Mean ± SD Range Mean ± SD Range
Age (years) 34.56 ± 6.01 25–46 33.4 ± 5.71 25–44 0.495
Years of Education 8.27 ± 4.51 1–16 9.2 ± 4.49 2–16 0.476
Diseases duration (years) 5.4 ± 2.21 (1.2–6.4) – –
ESR (mm/h) 31.3 ± 12.4 4–55 5.45 ± 1.76 3–9 <0.001
CRP (mg/dl) 4.86 ± 2.21 3–12 4.75 ± 1.48 3–8 0.123
C3 (mg/ml) 65.13 ± 21.07 35–140 145.1 ± 21.28 110–170 <0.001
ANA (EU/ml) 31.46 ± 6.004 15–45 14.6 ± 3.09 10–20 <0.001
Anti-DNA (IU/ml) 26.57 ± 6.37 14–42 14.05 ± 2.89 10–19 <0.001
Anti-cardiolipin (MPL/ml) 5.15 ± 1.51 2.47–7 4.69 ± 1.68 2.13–6.8 0.108
MoCA 14.66 ± 4.05 11–26 27.95 ± 1.19 26–30 <0.001
TMT A (s) 38.3 ± 10.53 28–71 29.75 ± 1.033 28–32 0.088
TMT B (s) 294.1 ± 10.21 275–312 67.6 ± 4.22 60–74 <0.001
* **
Significant at P < 0.05 and Highly significant at P < 0.001.
70 A.M. El-Shafey et al.

Table 2 Difference in cognition assessment scales between patients and control subjects with the same level of education.
Group mean ± SD <12 years education >12 years education
I-a (patients) N = 22 II-a (control) N = 12 P I-b (patients) N = 8 II-b (control) N = 8 P
** *
MoCA 14.29 ± 3.14 28.2 ± 1.16 <0.001 17.0 ± 5.50 26.43 ± 3.10 0.015
TMT A 39.6 ± 11.9** 29.69 ± 1.48 0.008 36.44 ± 6.71 30.17 ± 1.17 0.43
TMT B 293.3 ± 10.70 66.62 ± 4.46** <0.001 294.4 ± 8.03** 69.43 ± 3.36 <0.001
*
Significant at P < 0.05.
**
Significant at P < 0.001.

there was a non-significant correlation between disease dura-

Table 3 Comparison between the two subgroups of patients
tion and TMT A or MoCA scores. There was, also, a non-sig-
as regards cognition assessment scales.
nificant correlation between any of cognitive assessment scores
Group I-a (patients I-b (patients P and SLEDAI-2k or renal activity index (Table 4).
< 12 years education) > 12 years education)
MoCA 14.29 ± 3.14c 17.33 ± 5.24b 0.017 3.6. Effect of treatment on cognitive function
TMT A 39.6 ± 11.9b 36.44 ± 6.71ab 0.396
TMT B 294.19 ± 11.20b 294.4 ± 8.03b 0.95 There was a highly statistically significant negative correlation
*
Significant at P < 0.05. between SLEDAI-2k and cyclophosphamide dose. While there
**Significant at P < 0.001. was a statistically significant negative correlation between
SLEDAI-2k and steroid dose and between renal activity index
and both cyclophosphamide and steroid dose. None of the
3.4. Effect of education on cognitive function of patients cognitive assessment scores was correlated with the doses of
any of the drugs used in treatment (Table 5).
When comparing the two subgroups of patients (> and
<12 years of education) there was a statistically significant 4. Discussion
difference in MoCA scores, at the same time there is no statis-
tically significant difference between two subgroups as regards SLE is an autoimmune disease with predominance among wo-
TMT A or B (Table 3). men of the child-bearing age. It is characterized by chronic tis-
sue/organ inflammation mediated through autoantibodies,
3.5. Relation between disease parameters and cognitive function immune complexes, and complement activation that results
in multiorgan involvement [21].
There was a statistically significant positive correlation be- Neuropsychiatric SLE (NPSLE) occurs in 14% to over
tween disease duration and TMT B scores (p = 0.049). While 80% of patients with SLE and is associated with increased
morbidity and mortality [4].
Table 4 Correlation between cognitive assessment scales and Cognition is the sum of intellectual functions that result
disease duration, SLEDAI-2k and renal activity index in group in thought. It includes reception of external stimuli, informa-
I. tion processing, learning, storage, and expression [22].
Cognitive dysfunction has been identified in 14–54% of
MoCA TMT A TMT B
non-NPSLE patients suggesting the presence of a subtle
r P r P r P CNS disorder, but investigations into biologic mechanisms
Duration 0.164 0.388 0.218 0.251 0.492* 0.049 have yet to clearly demonstrate the mechanisms underlying
SLEDAI-2k 0.148 0.439 0.120 0.532 0.313 0.09 the phenomenon. Thus, continued studies into the pathogen-
Renal index 0.153 0.422 0.227 0.230 0.049 0.799 esis of subtle brain involvement in non-NPSLE patients are
*
Significant at P < 0.05. warranted [23].
**
Significant at P < 0.001. In this study we evaluated 30 SLE patients suffering from
lupus nephritis and evaluated them for the presence of

Table 5 Correlation of doses of different lines of treatment with disease activity and cognitive assessment scores.
Group Cyclophosphamide N = 21 Azathioprine N = 9 Steroids N = 30
r P r P r P
MoCA 0.03 0.89 0.172 0.698 0.261 0.163
TMT A 0.149 0.513 0.573 0.145 0.155 0.415
TMT B 0.257 0.251 0.175 0.691 0.026 0.891
SLEDAI-2k 0.731** <0.001 0.072 0.871 0.413* 0.022
Renal index 0.448* 0.035 0.451 0.277 0.438* 0.015
*
Significant at P < 0.05.
**
Significant at P < 0.001.
Cognitive impairment in non-neuropsychiatric systemic lupus erythematosus 71

cognitive impairment by using MoCA scale and TMT (part A The same study had similar results to ours that cognitive
and part B), and compared them with 20 healthy control sub- dysfunction in SLE patients did not significantly correlate with
jects. We found that all our patients were suffering from differ- indices of disease activity. On the contrary, the Egyptian study
ent aspects of cognitive impairment in comparison with the by Ezzat et al. revealed statistically significant correlations be-
control group. When performing MoCA scale, only one of tween some items of WAIS scale and SLEDAI [28]. At the
our patients scored as normal and the other 29 patients showed same time, Maneeton et al. found that cognitive scores were
impairment. While in TMT B, all of the patients showed not correlated with disease duration or with disease activity
impairment in the form of exceeding 240 s to perform the test. [27].
In fact, none of them was able to complete the test even in As regards the treatment received by the patients, none of the
longer periods. On the contrary, all patients were able to per- three tests was correlated with the dose of Cyclophosphamide,
form TMT A within the normal time as control subjects. Azathioprine or steroid doses. This is in agreement with the re-
There was a highly statistically significant difference be- sults of Maneeton et al. study, in which the cognitive scores did
tween patients and controls in MoCA scores and TMT B, not correlate with glucocorticoids, Chloroquine, Methotrexate
while there was no significant difference as regards TMT A. or Cyclophosphamide medications [27]. At the same time we
TMT A assesses visual perception rapidity and psycho- found that total SLEDAI-2k and renal activity index had a
motor rapidity, while TMT B assesses, in addition, mental highly significant negative correlation with the dose of Cyclo-
shifting and the subject’s attention ability since s/he is re- phosphamide and a significant negative correlation with the
quired to alternate between numbers and letters [19]. So, dose of steroids.
TMT A is much easier than TMT B. Besides, MoCA scale In an older study done by McLaurin et al., regular predni-
measures several aspects of cognitive functions. This is why sone use was associated with decreased cognitive functioning
our patients showed no significant difference with control in middle-aged patients with SLE [30]. While, Bhasin et al.
subjects as regards TMT A, and showed a highly statistically revealed that the presence of cognitive dysfunction in SLE
significant difference with control subjects as regards TMT B patients did not significantly correlate with glucocorticoids,
and MoCA scores. but they found a significant correlation of cognitive dysfunc-
Glanz et al. stated that cognitive dysfunctions occur in 50% tion with use of azathioprine [29].
of their SLE patients [24] and Petri et al. reported measurable We conclude that cognitive dysfunctions in SLE occur by
cognitive impairment in 75% of SLE patients, using the Auto- another mechanism rather than that of nephritis. This is why
mated Neurophysiological Assessment Metrics (ANAM). it is correlated neither with total SLEDAI-2k or with the renal
Their patients scored significantly lower than controls in the activity index nor with doses of any of the medications used for
ANAM [25]. Another study revealed that cognitive dysfunc- treatment of nephritis.
tions occur frequently in SLE patients [26]. Furthermore, When we compared patients and control subjects who re-
Hanly et al. have confirmed that SLE patients have slower ceived less than 12 years of formal education, we found a
performance on cognitive tasks than that of controls [22]. highly statistically significant difference as regards MoCA
In another study, SLE patients had significantly lower lev- and TMT B, and a statistically significant difference as regards
els than control subjects in the Mini-Mental State score TMT A. The difference was, also, highly statistically signifi-
(MMSE). They showed, also, significantly lower level than cant between patients & control subjects with more than
control subjects in Clock Drawing Test (CDT) [27]. In addi- 12 years of formal education as regards MoCA and TMT B.
tion, Ezzat et al. found statistically significant differences be- When we compared the two subgroups of patients only (i.e.
tween SLE patients and controls in many subsets of patients with different levels of education), we found that there
Wechsler Adult Intelligence Scale (WAIS) [28]. was a statistically significant difference between them in the
By observing these results, we conclude that cognitive dys- MoCA score, while the difference was insignificant as regards
functions are apparent in SLE patients despite using different TMT A and B. Those results can be explained by the fact that
methods of assessment. MoCA scale measures different domains of cognitive func-
It was confirmed that SLE patients with CNS involvement tions. We noted that the visuospatial & executive domains
had a higher degree of cognitive impairment than SLE patients were the most difficult ones. This is why they can be affected
without CNS involvement in the areas of attention/calculation, by the level of education. A non-educated person cannot sim-
auditory comprehension, visuospatial ability, and executive ply draw a cube with accurate measures and cannot draw a
function [27]. clock with accurate numbers and arms on definite time.
In our study, the three tests were not correlated with total Tomietto et al. observed an independent effect of age on the
SLEDAI-2k or with the renal activity index. Neither MoCA development of cognitive impairment and a protective effect of
scale nor TMT A was correlated with disease duration. a high education level on the number of functions impaired
Whereas TMT B scores had a statistically significant positive may be due to a greater functional brain reserve that delays
correlation with the disease duration. the onset of clinical manifestations [31]. In addition, Brey
Trail-Making Test is considered the most difficult and con- et al. identified an association of age and education with some
fusing test in our study. Its correlation with disease duration measures of cognitive impairment [32]. Tomietto et al. also sta-
should pay attention to the occurrence of changes in the brain ted that the presence of chronic damage (long disease dura-
tissue of SLE patients. tion) arose as the main factor affecting the severity of
In another study performed by Bhasin et al., the presence of impairment [31]. In another previous study done by McLaurin
cognitive dysfunction in SLE patients did not significantly cor- et al., consistent prednisone use and less education were signif-
relate with duration of disease [29].This difference can be ex- icantly associated with declining cognitive function especially
plained by the longer disease duration in our patients which in the middle age group and could not be totally explained
ranged from 2 to 9 years, while it was 1 to 2 years in that study. by SLE-associated disease activity [30].
72 A.M. El-Shafey et al.

We did not find other studies that compared between [11] Kozora E, Hanly JG, Lapteva L, Filley CM. Cognitive dysfunc-
cognitive functions of patients and control subjects as tion in systemic lupus erythematosus past, present, and future.
regards their level of education. But our results in this point Arthritis Rheum 2008;58(11):3286–98.
confirm that there is a significant impairment in cognitive func- [12] Shucard JL, Gaines JJ, Ambrus Jr J, Shucard DW. C-reactive
protein and cognitive deficits in systemic lupus erythematosus.
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