Neurol Sci
DOI 10.1007/s10072-016-2775-7
ORIGINAL ARTICLE
Cognitive dysfunction in patients with multiple sclerosis treated
with first-line disease-modifying therapy: a multi-center,
controlled study using the BICAMS battery
Bilge Piri Cinar1 • Görkem Kösehasanoğulları2 • Pinar Yigit3 • Serkan Ozakbas3
Received: 2 May 2016 / Accepted: 18 November 2016
Ó Springer-Verlag Italia 2016
Abstract Multiple sclerosis (MS) can impair cognitive
functions even in the early stages. The Brief International
Cognitive Assessment for Multiple Sclerosis (BICAMS)
battery is very short and highly sensitive and can be used to
evaluate cognitive status in the disease. Several clinical
trials have shown beneficial effects of disease-modifying
drugs (DMDs) on long-term cognitive measures which may
even reduce cognitive deficits in MS patients. Relapsing
remitting MS patients using DMDs were enrolled in the
study and monitored for 12 months. BICAMS and the
Expanded Disability Status Scale were applied to the study
group. We evaluated and monitored 161 newly diagnosed
cases of definite MS by the end of the trial. 110 patients
(68.2%) were female. One hundred and two healthy sub-
jects (female to male ratio 68:34) were enrolled into the
study. MS patients were categorized into three DMT
groups: IFNB1-a SC, IFNB1-b, and GA. Mean scores of all
three cognitive tests (SDMT, BVMT-R, and CVLT-II)
were significantly higher in the control group than in the
MS patients. The number of cognitively impaired patients
decreased from 31.7 to 21.7% on the basis of CVLT
(p = 0.024), and 42 (26.1%) to 30 (18.6%) on the basis of
BVMT-R at month 12. A significant difference was
determined in terms of cognitive status between MS
patients using both IFNB and GA and the healthy control
& Bilge Piri Cinar
bilge.cinarpiri@gmail.com
1
Department of Neurology, Samsun Training and Research
Hospital, Samsun, Turkey
2
Department of Neurology, Usak State Hosapital, Usak,
Turkey
3
Department of Neurology, Dokuz Eylul University, Izmir,
Turkey
group. Ours is the first study to compare IFNB and GA in
terms of evaluating cognitive involvement and to use the
BICAMS battery in monitoring treatment.
Keywords Multiple sclerosis
Cognition
Disease-
modifying drugs
BICAMS battery
Introduction
Multiple sclerosis (MS) is a chronic autoimmune disease
that affects at least 2.5 million people worldwide [1].
Relapsing remitting (RR) MS is defined as recurrent
exacerbations due to central nervous system (CNS)
involvement which may lead to physical disability. How-
ever, MS can also impair cognitive functions, even in the
early stages [2, 3]. Once present, cognitive symptoms are
unlikely to resolve, and the level of some aspects of
impairment is believed to increase, particularly disease
duration [4, 5], worsening of physical disability [6], and the
onset of progressive disease [4, 5]. The prevalence of
cognitive dysfunction was previously underestimated.
Recent studies have shown that at least half of MS patients
will develop cognitive dysfunction, which can significantly
influence their daily functional abilities [7, 8]. Mild and
early changes in cognitive functions in MS can now be
identified, as well as specific aspects of these functions,
such as memory, attention, visual–spatial abilities, execu-
tive functions, and processing speed [9, 10]. Deficits in
these areas may reflect damage to specific regions of the
brain, which do not affect physical functioning. Cognitive
decline can, therefore, indicate disease progression in
patients with stable physical functions [4, 9]. Several dif-
ferent neuropsychological batteries have been proposed for
use. Among the most frequently used, instruments are the
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Brief Repeatable Battery of Neuropsychological tests
(BRB-N) [11] and the Minimal Assessment of Cognitive
Function in MS (MACFIMS) [12, 13]. While both batteries
are known to be highly specific for the evaluation of cog-
nitive impairment (CI) in MS patients, their implementa-
tion in everyday clinical practice remains limited due to
their high time demands and the need for surveillance and
interpretation by certified neuropsychologists [11, 13].
Considerable efforts have, therefore, been made over the
past decade to create a simpler but specialized neuropsy-
chological instrument for the assessment of CI in MS
patients. The Brief International Cognitive Assessment for
Multiple Sclerosis (BICAMS) has recently been proposed
[14]. The BICAMS battery is very short and highly sen-
sitive. It is also easily administered and does not require
any special equipment or training, and may be conve-
niently used in everyday clinical practice [14, 15].
During the past decade, several disease-modifying drugs
(DMDs) have become available for the treatment of MS
and have altered the long-term course of the disease [16].
These agents are generally safe and well tolerated, can
reduce the risk of physical disability, and can reduce the
number of active brain lesions visible at magnetic reso-
nance imaging [17]. Several clinical trials have shown
beneficial effects of DMDs on long-term cognitive mea-
sures, which may even reduce cognitive deficits in MS
patients [18, 19]. However, as the pivotal trials of DMDs
did not, in general, include cognitive assessments, their
cognitive benefits in patients with MS have yet to be
confirmed. Given the high incidence and the importance of
cognitive dysfunction in MS, we designed this clinical trial
to the level of effect of various DMDs on the cognitive
status of patients with MS using BICAMS.
Materials and methods
Methods
This was a multi-center, examiner-blinded, prospective
study.
Patients and controls
Eligible patients had been diagnosed with MS on the basis
of the McDonald criteria [20]. All patients were newly
diagnosed (within the previous 2 years), had sufficiently
high cognitive levels to provide anamnesis, and were able
to sign informed consent forms. Further inclusion criteria
were age above 18, being treatment-naı̈ve or receiving
ongoing beta-interferon or GA for less than six months, and
Expanded Disability Status Scale (EDSS) [21] scores of 5.5
or less. We also required patients to be prepared and able to
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Neurol Sci
adhere to the study protocol for the entire study period.
Patients were excluded if they had previously been treated
with other than ongoing DMT, lymphoid irradiation,
mitoxantrone, natalizumab, cyclophosphamide, or long-
term systemic glucocorticoids. Patients who had received
corticosteroid therapy within 30 days before baseline, with
a history of drug or alcohol abuse within 1 year before
screening, with psychiatric disorders that might affect
cognitive tests or with any clinically significant medical
condition that might interfere with trial participation,
patients who had converted to secondary progressive MS,
and patients who showed any signs of depression were also
excluded. The patient group was compared against age-,
sex-, and education-matched healthy controls. Healthy
volunteers have been comprised of patients’ relatives,
people who attended to our Neurology clinic suffered from
headache, and healthy employees of the hospital.
Outcome measures
Participants and all those assessing the outcomes were
blinded to the treatment groups during initial neurological
and psychiatric assessment, as well as during administration
of the BICAMS. Demographic data, including age and
gender, were extracted from the study questionnaires. Cog-
nition status was defined as the primary outcome measure.
The study psychologist was blinded to the treatment groups
and evaluated cognitive function before treatment and
12 months after treatment. Three tests included in the
BICAMS were used for this purpose. Validated BICAMS
(unpublished data) was used in accordance with the pro-
posed standards. Tests were administered by means of a
standard protocol. The BICAMS includes the SDMT [11],
the California Verbal Learning Test, second edition (CVLT-
II) for assessing verbal memory [22], and the Brief Visu-
ospatial Memory Test Revised (BVMT-R) for visual-spatial
memory [23]. In the SDMT, the patient is asked to look at
specific geometric figures paired with specific numbers and
then to cite the number given for each figure as quickly as
possible in 90 s. The patient is told how the test is to be
performed before commencement. The patient is asked to
find the numbers responding to the first ten figures with no
time limit involved to facilitate comprehension of the per-
formance of the test. These responses are recorded in the
relevant section in the guideline, but they are not considered
when calculating scores. The number of correct and
responses is recorded at the end of 90 s. The CVLT-II
begins with the administrator reading a list of 16 words, out
loud at 1-s intervals. The patent then repeats the words he
remembers from that list, and these are recorded by the test
administrator. However, the patient is given no clues con-
cerning recall. This procedure is performed five times, and
the words recalled are recorded on each occasion. No time
Neurol Sci
limit is applied in the test. At the evaluation stage, the total
correct number, repeat number, and false number are
recorded. In the BVMT-R, the patient is shown six shapes
on a piece of paper and asked to examine this for 10 s. The
piece of paper is then taken away, and the patient is asked to
reproduce the shapes on a blank piece of paper. Each shape
is given a score of 0, 1, or 2. If the patient reproduces the
shape correctly and in the correct place, a score of 2 is
awarded. A shape similar to the original and in the correct
location is awarded a score of 1. The total score is calculated
by adding the scores from each of three consecutive
attempts.
The Expanded Disability Status Scale (EDSS) was the
secondary outcome measure investigated at baseline and
after 12 months. The EDSS is a method of quantifying
disability in MS in eight Functional Systems (FS) and
elicits a functional system score. EDSS steps 1.0–4.5 apply
to subjects with MS who are fully ambulatory, while steps
5.0–9.5 apply to impairment of ambulation [24].
Trial design and protocol
This multi-center, examiner-blinded, prospective study was
performed in the Dokuz Eylul University, Giresun State
Hospital and Usak State Hospital neurology departments,
Turkey, between May 2013 and February 2015. Informed
consent was obtained from all patients and healthy volun-
teers after being briefed concerning the procedures. Neither
group received any remuneration for participating. Eligible
participants were all new cases of definite MS according to
the revised McDonald criteria, which include magnetic
resonance imaging, detailed neurological history and
examination, and paraclinical laboratory tests of cere-
brospinal fluid findings and visual-evoked potential [20].
The cognitive tests were applied to both the MS group and
the control group before 2:00 pm. Subjects with values
below 1.5 SD for BICAMS were regarded as CI.
Statistical analysis
Data were analyzed using the SPSS Windows 16.0 soft-
ware. Descriptive statistical methods (mean, standard
deviation, and frequency) and the Chi-square test were
used to compare categorical variables, and p values were
calculated for the Fisher exact test when necessary. The
Mann–Whitney U test was used to compare the means of
two independent groups not exhibiting normal distribution.
Similarly, the Wilcoxon test was used to compare the
means of two dependent groups. Spearman correlation
analysis was performed to determine the direction and level
of relationships among variables, and significance was set
at p \ 0.05 for all results.
Results
One hundred and seventy-four patients with newly diagnosed
definite MS were screened for eligibility. Eleven patients were
excluded due to positive signs of depression. The remaining
163 patients were included in the study. One patient treated
with glatiramer acetate (GA) and one treated with IFNB1-b
did not attend the follow-up sessions. We were, therefore, able
to evaluate and follow up 161 newly diagnosed cases of def-
inite MS by the end of the trial. One hundred and ten patients
(68.2%) were female. One hundred and two healthy subjects
(female to male ratio 68:34) were also enrolled in this study.
MS patients were categorized into three DMT groups: IFNB1-
a SC, IFNB1-b, and GA (Table 1).
Mean scores for all three cognitive tests (SDMT,
BVMT-R, and CVLT-II) were significantly higher in the
control group than in the MS patients. The mean SDMT
test score was 12.3 points higher in the control group than
in the MS patients. The mean CVLT-II score was 7.1
points higher, and the mean BVMT-R score was 10.2
points higher in the healthy controls (Table 2). Symbol
digit modality test scores improved in all MS groups at
month 12 compared with baseline. BVMT-R and CVLT-2
scores also improved at month 12 (Table 3). No correlation
was determined between performance in any tests and
disease duration.
In each testing session, we defined cognitive impairment
as scores of at least 1.5 SD below those of the healthy
controls. Forty-six patients (28.5%) were found to be
cognitively impaired on entry to the study on the basis of
SDMT. At follow-up, the number of cognitively impaired
patients decreased to 33 (20.5%) (p = 0.009). The num-
bers of cognitively impaired patients decreased from 51
(31.7%) to 35 (21.7%) on the basis of CVLT (p = 0.024)
and from 42 (26.1%) to 30 (18.6%) on the basis of BVMT-
R at month 12 (Fig. 1).
Discussion
The most common CI in MS involves recent memory,
attention, information processing speed, executive func-
tions, and visual–spatial perception [2]. Neurological dis-
ability is a poor predictor of CI. It is, therefore, crucially
important to evaluate cognitive functions in MS. Our study
evaluated the effect of interferons and GA on cognitive
functions of patients with MS. Previous controlled trials
investigating DMDs in MS were large pivotal studies,
primarily designed to evaluate the effects of treatment on
clinical outcomes, such as relapse rates, but not on cogni-
tive impairment. Now that the efficacy of DMDs has
become well established, their use is considered the gold
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 Neurol Sci

Table 1 Demographic
MS patients Control group p
characteristics among the
participant groups N 161 102 0.097
Female, n (%) 110 (68.2) 65 (63.7) 0.128
Male, n (%) 51 (31.8) 37 (36.3)
Age, mean ± SD (min–max) 30.4 ± 11.2 (21–39) 31.5 ± 14.3 (20–41) 0.234
Education (years) mean ± SD 13.4 ± 2.4 14.1 ± 3.2 0.176
Disease duration, years ± SD (min–max) 2.02 ± 2.6 (1–5) – –
MS Treatment n (%) – –
Interferon beta 1a (SC) 53 (32.9)
Interferon beta 1b 52 (32.3)
Glatiramer acetate 56 (34.8)

Table 2 Mean BICAMS scores between patients with MS and the One study investigating the effect of IFNB1 on cogni-
control group tion and MRI findings in patients diagnosed with RRMS
MS patients Control group p used the Paced Auditory Serial Addition Test (PASAT) to
assess cognitive status and determined a significant
SDMT 40.3 ± 15.1 52.6 ± 14.2 \0.001 improvement in PASAT scores at the end of 2 years [27].
mean ± SD The COGIMUS study, which assessed cognitive status
BVMT-R 24.5 ± 8.1 31.6 ± 5.7 \0.001 using Rao’s Brief Repeatable Battery (BRB) and the
mean ± SD Stroop Test in patients receiving IFNB1-a over 5 years,
CVLT-II 51.5 ± 13.7 61.7 ± 9.4 \0.001 observed CI even in early stage MS patients and showed
mean ± SD that this was a risk factor for subsequent cognition com-
CG control group, SDMT Symbol Digit Modalities Test, BVMT-R promise. In addition, at the end of the study, IFNB1-a
Brief Visuospatial Memory Test revised, CVLT-II California Verbal therapy was observed not only not to slow impairment in
Learning test, second edition cognition, but also to prevent the development of cognitive
deterioration [28]. Another study used PASAT to assess the
standard in MS treatment. Placebo-controlled trials effect of IFNB1-b therapy initiated at the clinical isolated
assessing cognitive function as the primary endpoint are, syndrome stage on the cognitive sphere. A significant
therefore, unlikely to be conducted. Instead, the effect of improvement was observed at the end of 5 years compared
DMD therapy on cognitive performance is being measured to pre-treatment values in PASAT scores evaluating
in open-label or observational longitudinal studies [25, 26]. attention, concentration, and working memory [29]. In one

Table 3 Mean BICAMS scores in the individual MS subgroups and the control group subgroups at baseline and end of study
SDMT p BVMT-R p CVLT2 p
Baseline End of study Baseline End of study Baseline End of study

HC 52.6 ± 14.2 53.3 ± 12.3 0.12 31.6 ± 5.7 30.9 ± 4.5 0.204 61.7 ± 9.4 62.6 ± 7.1 0.68
IFNB 1b 41.5 ± 11.7 45.1 ± 14.6 0.004 25.3 ± 9.3 27.5 ± 8.4 0.005 53.6 ± 15.5 56.2 ± 11.5 0.006
p2 \0.001 \0.001 \0.001 \0.001 \0.001 \0.001
IFNB1-a 38.9. ± 17.3 41.4. ± 14.2 0.003 22.9 ± 11.5 26.1 ± 10.1 0.003 50.9 ± 11.4 55.2 ± 12.9 0.005
p3 \0.001 \0.001 \0.001 \0.001 \0.001 \0.001
GA 40.8 ± 20.5 44 ± 16.4 0.003 23.9 ± 10.4 26.5 ± 11.6 0.005 52.7 ± 14.8 56.1 ± 14.3 0.006
p4 \0.001 \0.001 \0.001 \0.001 \0.001 \0.001
Total 40.3 ± 15.1 44.7 ± 16.3 0.003 24.5 ± 8.1 2615 ± 10.3 0.004 51.5 ± 13.7 55.7 ± 12.9 0.006
p5 \0.001 \0.001 \0.001 \0.001 \0.001 \0.001
HC healthy control, SDMT Symbol Digit Modalities Test, BVMT-R Brief Visuospatial Memory Test revised, CVLT-II California Verbal Learning
test, second edition, p2 Comparison of HC and patients treated with IFNB 1b, p3 Comparison of HC and patients treated with IFNB 1a, p4
Comparison of HC and patients treated with GA, p5 Comparison of HC and all patients treated with any disease-modifying drugs

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Neurol Sci
İmpaired
71.5 73.9
69.5
28.5 26.1
20.5
BASELINE END OF BASELINE
STUDY
SDMT
Fig. 1 Comparison of percentages of cognitively impaired patients at baseline and at the end of study
study performed using GA, impairment was observed in
cognitive functions, particularly attention and concentra-
tion, assessed with BRN a mean 10 years after com-
mencement of medication use, while no significant
compromise was observed in memory or semantic recall
[30].
In our study, a significant difference was determined in
terms of cognitive status between MS patients using IFNB
or GA and the healthy control group. No difference was
determined between the patients using the three drugs and
constituting the treatment group. Significant improvement
was observed at the end of 1-year monitoring in SDMT,
BVMT-R, and CVLT-2 values in the control group. No
difference was determined between patients using IFNB-1a
IM, IFNB-1b, or GA. Our findings thus confirm those of
previous studies involving interferons [31, 32]. Similar
findings for GA showed that there is no significant differ-
ence between IFNB and GA in terms of cognitive protec-
tion. Ours is the first case–control study to compare IFNB
and GA in terms of cognitive involvement. The fact that no
difference was observed between the two groups shows
that the two drug groups have similar effects in terms of
cognition. The level of patients in the treatment group with
cognitive involvement with scores 1.5 SD below normal
decreased significantly at the end of 1 year. Combined with
the absence of a significant change in the healthy subjects,
we do not think that the cognitive improvement derived
from a learning effect.
We encountered no problems with the use of the
BICAMS battery in observation in this study. We conclude
that the SDMT, BVMT-R, and CVLT-2 tests that comprise
BICAMS were used in an effective manner in monitoring
Healthy
68.3
81.4 79.3
31.7
18.6 21.7
END OF BASELINE END OF
STUDY STUDY
BVMT-R CVLT-2
cognitive change. One of the limitations of this study is that
although it included a healthy control group, it included no
untreated MS group. This was due to the difficulty in
performing placebo-control studies at the current stage of
MS treatment. Another limitation is that the brief period of
1 year was evaluated. Since this study was planned with
BICAMS for monitoring, the use of the battery that was
described in 2012 was limited to 1 year. We planned to
maintain monitoring. In addition; we did not evaluate the
cognition reserve both patients and healthy groups.
In conclusion, this study of monitoring of cognitive
status using the BICAMS battery determined a cognitive
improvement in patients using DMD. No difference in
terms of cognitive status was observed between IFNB and
GA. The use of BICAMS, which is easily applied and was
used for the first time in the observation of cognitive status,
was approved by patients.
Compliance with ethical standards
Funding The authors received no support for the research, author-
ship, and/or publication of this article.
Conflict of interest The author(s) have no potential conflicts of
interest with respect to the research, authorship, and/or publication of
this article.
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