Lupus (2011) 20, 11421146

http://lup.sagepub.com

PAPER

Cognitive dysfunction in SLE: development of a screening tool

T Adhikari, A Piatti and M Luggen
Division of Immunology, Allergy, and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

Background. Cognitive dysfunction (CD) is among the most common neuropsychiatric manifestations of systemic lupus erythematosus (SLE). There are two methods which have been
used to detect CD in patients with SLE: traditional neuropsychological tests (NPT) and the
Automated Neuropsychological Assessment Metrics (ANAM). Both are time-consuming and
neither is readily available for screening purposes.
Purpose. The aim of our study was to evaluate the Montreal Cognitive Assessment (MoCA)
test as a screening tool for detection of CD in SLE.
Methods. SLE patients fulfilling ACR criteria were administered the ANAM, a computerized test battery which measures various cognitive domains and the MoCA, a one-page,
performance-based screening test designed to detect mild cognitive impairment in the elderly.
With the ANAM as the gold standard, the performance characteristics of the MoCA were
assessed.
Results. In total, 44 patients were evaluated. Of these, 11 (25%) were identified by the
ANAM as being impaired in comparison with 13 (29.5%) by the MoCA. The scores were
significantly correlated (r 0.57, p < 0.001). Using the standard cutoff of 26, the sensitivity of
MoCA was 83% and specificity 73%.
Conclusion. The MoCA appears to be a promising screening tool for the detection of CD in
SLE both for epidemiologic studies and for routine clinical care. Lupus (2011) 20, 11421146.
Key words: Automated Neuropsychological Assessment Metrics (ANAM); cognitive dysfunction; Montreal Cognitive Assessment (MoCA); SLE

Introduction
Neuropsychiatric manifestations are common in
systemic lupus erythematosus (SLE). Of these, cognitive dysfunction (CD) is among the most
common, being detected to some extent and in
some studies in up to 80% of patients.14 CD has
been linked to increased unemployment rates5,6 and
may adversely aect health-related quality of life.7
An ad hoc multidisciplinary Committee of the
American College of Rheumatology (ACR) proposed a case denition of CD and suggested specic
neuropsychological tests (NPT) to ascertain this.8
In order to make such testing more practical, the
Committee also proposed a modied test battery
which could be administered in approximately 1 h.

Correspondence to: Michael Luggen, MD, Division of Immunology,

Allergy, and Rheumatology, University of Cincinnati College of
Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0563, USA
Email: michael.luggen@uc.edu
Received 28 November 2010; accepted 3 March 2011
! The Author(s), 2011. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav

Subsequently, the validity and reliability of the

brief battery in comparison to more extensive
NPT were suggested.9 However, NPT is not readily
available in all settings and can be costly, even for
limited evaluations. Because of this, alternative
approaches have been sought. One such approach
involves
the
use
of
the
Automated
Neuropsychologic Assessment Metrics (ANAM).
The ANAM is a computerized battery of tests
developed by the United States Military to assess
the eects of combat on cognitive function. This is
a symbol-based test which assesses some of the
same cognitive domains as NPT.10,11 The ANAM
requires approximately 3045 min, is self-administered after a brief training period, and costs
approximately US$400 for a yearly license.
The ANAM has previously been employed as a
test of cognitive function in SLE in a number of
studies.1215 It appears to correlate reasonably well
with traditional NPT.12 Using NPT as the reference
standard, the ANAM has been demonstrated to
have a sensitivity of 76.2% and specicity of
82.5%.16 While arguably more ecient and less
10.1177/0961203311405374

Cognitive dysfunction in SLE

T Adhikari et al.

1143

costly than traditional NPT, the ANAM is not

readily available, nor is it practical for routine
administration in the clinic or for screening larger
study populations. What is needed for both situations is a brief, sensitive, and reliable screening tool.
The Montreal Cognitive Assessment (MoCA) is
a one-page, performance-based questionnaire
which has been developed to identify mild cognitive
impairment (MCI) in the elderly.17 It has been
tested in the elderly in a number of settings and
appears to have acceptable performance characteristics, with a sensitivity of 8590% with a specicity
of 5387%.18,19 The MoCA has also been successfully utilized in a number of other diseases including Parkinsons disease, Huntingtons disease,
cerebrovascular disease, and substance abuse disorders.2023 To the best of the authors knowledge,
the MoCA has never been used to evaluate patients
with SLE.

Patients and methods

After approval by the University of Cincinnati
Institutional Review Board, stable patients with
SLE fullling the updated Revised ACR Criteria
for the Classication of SLE were recruited from
the Rheumatology Clinic at the University of
Cincinnati Hospital and from the faculty practices
of members of the Division of Rheumatology.24,25
After obtaining informed consent, patients were
evaluated for disease activity and disease severity
by the SLE Disease Activity Index (SLEDAI-2K)
and the SLE Damage Index (SLICC).26,27
In addition, depression was assessed by the Beck
Depression Inventory (BDI).28 Fatigue, pain, and
overall wellbeing were evaluated on a 10 cm visual
analogue scale, as was patient global assessment of
disease activity. Medications and co-morbid conditions were also recorded. All subjects were administered the ANAM and the MoCA at the same
session according to the test administration instructions provided.
The total throughput score (TTS) has been utilized as a summary measure of cognitive function
of the ANAM. It is the average of the total number
of correct responses divided by the time required
for those responses over the eight subtests. Age,
sex, and raced-matched patients with rheumatoid
arthritis (RA) derived from the same setting were
chosen as controls. Cases were SLE patients with
abnormal ANAM TTS, which was dened as
scores more than 2 standard deviations (SD)
below the mean of the RA control population.

The scores of the MoCA were compared with the

TTS of the ANAM, and the classication of
normal or abnormal by the ANAM was compared
with the classication by the MoCA using various
cutos.
Statistical analysis
Descriptive statistics of the study population were
computed. Correlation of TTS of ANAM with
summary scores of MoCA was done by
Spearmans correlation. Using various cut points
for the MoCA, the sensitivity, specicity, accuracy,
predictive values, and likelihood ratios were also
computed. A kappa statistic was calculated to further evaluate the magnitude of agreement beyond
chance alone between MoCA and ANAM scores.

Results
In total, 44 patients with SLE were recruited. The
sociodemographic data are shown in Table 1. Mean
age was 46.1 (11.2) years with a female preponderance (88.6% vs. 11.4% men). Various ethnic
groups were represented, with African-American
patients predominating (African-American 59.5%,
Caucasian 35.7%, and Hispanic 2.4%). Some 39%
of patients were married, and 71% had less
than 16 years of education. The mean disease duration was 9.8 (7.1) years. Mean SLEDAI scores

Table 1 Demographic and clinical characteristics

Age
Gender
Women
Men
Ethnicity
Caucasian
African-American
Hispanic
Marital status
Married
Divorced
Widowed
Single
Education (years)
>16
16
12 < yrs < 16
12
Disease duration
Duration (yrs)

Mean

SD

46.1

11.2

88.6
11.4
35.7
59.5
2.4
39.5
21.1
5.3
34.2
15.8
13.2
26.3
38.0
9.8

7.1

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Cognitive dysfunction in SLE

T Adhikari et al.

1144

were 5.6 (4.2) and mean SLICC scores were

3.4 (2.6) (Table 2). Of the patients studied, 20%
had moderate or severe depression. Three-quarters
of patients were taking prednisone (74.3%) and
82.1% were on hydroxychloroquine. Nearly half
were taking other immunosuppressive medications
(46.2%) (Table 2).
Of these 44 patients, 11 (25%) were identied by
the ANAM as being impaired in comparison with
RA controls. Using the MoCA, 13 (29.5%) were
categorized as impaired. The scores of the two
tests were signicantly correlated (r 0.57,
p < 0.001). Using the standard cut-o of 26
and with ANAM as the gold standard, the sensitivity of the MoCA was 83%, the specicity
was 73% with overall accuracy of 75%. Positive
and negative predictive values were 50% and
92%, respectively. The kappa statistic was 0.45,
which indicates moderate agreement. Sensitivity,
specicity, accuracy, and positive and negative
predictive values for dierent cut points of the
MoCA are shown in Table 3. All other cut points

Table 2

Clinical characteristics

SLEDAI
SLICC
Patient Global Assessment (10 CM VAS)
PAIN
BDI
Moderatesevere depression
Fatigue
Prednisone (% use)
Plaquenil (% use)
Immunosuppressants (%)
ASA (%)
NSAID (%)
Opioid (% use)
Antidepressant (% use)

Table 3

SD

5.6
3.4
4.6
3.1
14.2

4.2
2.6
2.4
2.1
11.5

25.1

11.9

20.0
74.3
82.1
46.2
37.8
25.6
21.1
29.7

Discussion
CD appears to be a common manifestation of SLE
and, in many cases, CD signicantly aects
employment and health-related quality of life.
Early diagnosis may permit earlier intervention.
Early diagnosis would also focus attention on
even mild CD as an important clinical manifestation which might require specic therapy.
Accepted methods of detection of CD are not
readily available in all clinical settings. Because of
time and expense, only those patients with overt
disease may be tested. This may lead to under-diagnosis and under-treatment. For this reason a
simple, sensitive, screening test is needed for clinical
care.
The pathogenesis of CD and the risk factors for
its development and progression are uncertain.
Studies have yielded conicting results.29 The reasons for this are probably many, but the complexity
of lupus central nervous system involvement and
the number of other potentially important co-factors which could inuence cognition are obvious
considerations. In order to adequately address
these issues, larger patient populations are
required. The evaluation of larger populations
with currently available methods of assessment
would not appear feasible. For such evaluations,
a brief, sensitive, and inexpensive screening test
for CD could prove invaluable. If such a test were
also reasonably specic, then it might also be used
as a survey denition of CD.

MoCA performance characteristics

Cut-off

Sens

Spec

Acca

PPVb

NPVc

LRd

LR-e

24
25
26
27
28

.55
.55
.82
.82
1.00

.82
.76
.73
.52
.36

.68
.70
.75
.59
.53

.50
.43
.50
.36
.34

.84
.83
.92
.92
1.00

3.1
2.3
3.0
1.7
1.6

.6
.6
.20
.3
-

Accuracy.
Positive predictive value.
c
Negative predictive value.
d
Positive likelihood ratio.
e
Negative likelihood ratio.
b

Lupus

Mean

were inferior to the results obtained using a value of

26 with the possible exception of a cut-o of 28,
which increased sensitivity to 100% albeit with a
signicant decrease in specicity (36%) and positive
predictive value (34%).

Cognitive dysfunction in SLE

T Adhikari et al.

1145

The MoCA has been tested in other populations

and found to be useful. In our study, we found that
using the standard cuto of 26 and the ANAM as
the gold standard, the sensitivity of the MoCA
was 83%. The specicity was 73% with positive
predictive valued of 50% and negative predictive
value of 92%. As a screening test, the MoCA compares favorably with other tests commonly used to
evaluate patients suspected of having a rheumatic
disease. For example, anti-SS-A has a sensitivity of
60% for those fullling the joint American
European 2002 consensus criteria for Sjogrens
syndrome,30 and classical rheumatoid factor and
anti-CCP antibodies have sensitivities of 80% and
67%, respectively, for the diagnosis of RA.31,32
Admittedly, each of these tests has higher specicity
and each is used in combination with clinical criteria. Nonetheless, the tests have similar utility as
stand alone screening tools.
An ideal screening test for CD should have a
higher sensitivity than was found in our study.
We attempted to improve the sensitivity of the
test by choosing dierent cutos and were able to
increase sensitivity by increasing the cut point to
28, but at the expense of specicity. In a patient
population similar to ours with a prevalence of
CD of approximately 25%, raising the cutpoint to
28 would identify two additional patients in a
sample size of 100, but would increase the
number of false positives who would need to be
evaluated to 28. Alternatively phrased, 14 patients
would need to be evaluated to identify one additional case of CD. On the other hand, for a population where the prevalence of disease is lower than
the current study population, the number needed to
be screened to identify one additional case of CD
could be even higher. For example, Hanly et al.
recently reported a prevalence of CD of 11% in a
sample of patients with SLE.15 With such prevalence and in a sample of 100 subjects, 29 additional
patients would need to be evaluated to identify one
additional patient with CD. However, neither scenario would be considered by most as an unacceptable utilization of medical resources if the end
result were the early detection and prevention of
potentially signicant cognitive impairment.
There are other brief instruments which have been
used to detect MCI in the elderly. Among these are
the Addenbrookes Cognitive Examination-Revised
(ACE-R), Cambridge Cognitive Examination
(CAMCOG), and the CERAD (Consortium to
Establish a Registry for Alzheimers Disease neuropsychological battery). Each appears to have promising measurement properties, although each has only
been tested in small numbers of patients with MCI.

Nonetheless, it is possible that one or more might also

prove useful in this setting and warrant further
testing.33
The main limitation of our study is the relatively
small number of cases with CD. Additional subjects
will need to be studied in order to verify the reliability of the MoCA and conrm our results. In
addition, our population may not be representative
of the general population of lupus patients as it
is not exactly population based. However, our
patients came from two dierent sources, a
University Hospital Clinic and private faculty practice, which provided some diversity to the population studied. Further eorts should strive to include
a broader range of patients who might be more
representative of the general population of patients
with SLE.
Despite some limitations, this preliminary study
would suggest that the MoCA could be a useful
screening tool for the detection of CD in SLE
both for epidemiological studies and for routine
clinical care.

Funding
Supported by a Lupus Foundation of America,
Neuropsychiatric Lupus Research Grant.

Conflicts of interest
The authors declare that they have no conicts of
interest.

Acknowledgements
We would like to thank Dr Yolanda Farhey, Dr J
Lawrence Houk, and Dr Avis Ware for allowing us
to study their patients. Not only did they graciously
grant us access to their patients, they went out of
their way to encourage their patients to participate.
Without their assistance, this study would not have
been possible.

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