Zahedan Journal of Research in Medical Sciences
Journal homepage: www.zjrms.ir
Cognitive Impairment in Multiple Sclerosis
Mohammad Ali Sahraian,1 Farnaz Etesam*2
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1. Department of Neurology, Sina MS Research Center, Tehran University of Medical Sciences, Tehran, Iran
2. Department of Psychiatry, Sina MS Research Center, Tehran University of Medical Sciences, Tehran, Iran
Article information
Abstract
Article history:
Received: 27 May 2012
Accepted: 12 Aug 2012
Available online: 12 Mar 2013
ZJRMS 2014; 16(1): 1-7
Keywords:
Multiple sclerosis
Cognitive impairment
Cognitive
Neuropsychological test
Cognitive impairment can emerge in the earliest phases of multiple sclerosis. It strongly
impacts different aspects of Multiple Sclerosis (MS) patients' lives, like employment,
social relationships and the overall quality of life; thus, its on-time recognition and
treatment is mandatory. This paper discusses issues, diagnostic methods and treatment
options for cognitive dysfunctions in MS.
This paper is a descriptive review of the related studies in the recent 10 years, performing
a keyword search in the main databases.
Cognitive impairment mostly involves aspects of information processing, memory and
executive functioning in MS. Neuropsychological tests like MACFIMS and BRB-N are
recommended for its assessment. Still, there is no fully efficient treatment for cognitive
impairment. Researchers have shown some positive effects, using disease-modifying
therapies and cognitive rehabilitation. Depression, pain, fatigue and other factors
influencing cognitive functions must be paid attention to.
Recognizing cognitive impairment as a major symptom for MS, makes studying this
subject one of the priorities in dealing with the disease. Therefore, a consecutive research
for identification and management of this part of quality of life in MS patients is
obligatory.
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*Corresponding author at:
Department of Psychiatry, Sina
MS Research Center, Tehran
University of Medical
Sciences, Tehran, Iran.
E-mail:
fa.etesam@gmail.com
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Copyright © 2014 Zahedan University of Medical Sciences. All rights reserved.
Introduction
M
ultiple Sclerosis (MS) is a chronic immune
system disease that is characterized with
demyelination and axonal destruction. The
disease may emerge at any age; however, it is usually
diagnosed at 20-40 years of age. Since neurons of any
part of the brain or spinal cord may be involved, a wide
range of symptoms in form of eye and sensory motor
problems, bladder and bowel dysfunction, pain in
different parts of the body, sexual problems, vertigo and
imbalance can be observed in MS patients [1]. The
disease is classified into four major subtypes based on its
clinical course (Table 1) [2].
Since the identification of MS as a disease, physical
disabilities accompanying the disease have mostly been
the focus of attention for patients and physicians.
However, in the past decade, impairment in different
cognitive areas has been significantly considered.
Cognitive impairment with the occurrence of 40-70% is
observed in all subtypes and stages of the disease, even its
milder forms like clinically isolated syndrome (CIS)
(incidence of the first clinical MS symptoms like
inflammation of the optic nerve or sensory motor signs
with/without MRI findings) and benign MS [3, 4].
Clinical presentations of the said impairment are diverse
and range from milder forms like short term memory
problems to rare severe impairments like dementia.
According to longitudinal studies, cognitive impairment
gradually progresses through time and more severe
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degrees are seen in advanced phases of the disease and
patients with progressive disease.
Cognitive impairment in a patient with stable physical
condition predicts the future progress of the disease;
likewise, cognitive deficits can predict benign MS
progress and it can also demonstrate the increase in the
probability of turning the disorder into MS in CIS [5].
Causes of cognitive impairment are different in patients.
Various factors such as sensory problems, disruption of
the connections between parts of the brain (corticocortical and cortico-thalamic) following brain lesions,
involvement of seemingly normal white and gray matter
of the brain and the direct effect of inflammation
byproducts are considered effective in the emergence of
the impairment in MS patients [6, 7].
Multiple sclerosis usually involves people during their
first vocational years. Cognitive impairment can be fully
disabling and impose heavy personal and social costs [8].
It is well recognized that cognitive impairment does not
only have potential effects on decreasing the quality of
life in patients, but also can influence their daily functions
like the ability to make the required decisions on disease
treatment, acceptance and following up treatment
instructions, keeping social relations and the ability to
drive. It can also play an important role in losing jobs;
therefore, early diagnosis of the impairment, starting
clinical interventions and preventing its progress is
necessary.
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Zahedan J Res Med Sci 2014 Jan; 16(1): 1-7
Table 1. Clinical course classification of MS
Disease course
Relapsing-remitting MS (RRMS)
Secondary-progressive MS (SPMS)
Primary-progressive MS (PPMS)
Progressive-relapsing MS (PRMS)
Key characteristics
Acute attacks with deteriorating neurologic signs followed by variable courses of symptom
remission and disease stability.
The clinical course of initial RRMS continues with progressive deterioration of basic
conditions with/without additional attacks.
The disease course is primarily a progressive and gradual worsening of basic conditions
with little fluctuations and without clear attacks.
Progression of disability with clear acute relapses, with or without full recovery.
Deterioration continues throughout attacks.
According to recent studies, the incidence of MS is
increasingly spreading in Iran and our country is being
located among regions with moderate-to-high incidence
rate for MS in the world [9, 10]. Thus, continuous studies
for determining useful strategies to prevent, manage and
treat different aspects of the disease including the
resulting cognitive impairments would be required. The
present study evaluates different cognitive problems,
diagnostic procedures and presently available treatments
for patients at risk of developing the impairment.
Materials and Methods
This is a descriptive review article resulting from
studying relevant articles on major databases like Scopus,
Google Scholar and PubMed. Using keywords including
multiple sclerosis, cognitive impairment, cognitive and
neuropsychological tests, pertinent studies published in
the recent 10 years with acceptable study design, research
methods and assessment tools were selected and review
articles of scholars in the field of cognitive impairments
in MS were also used. Moreover, it was attempted to
include the most recent valid data in the related fields.
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Results
Although almost all types of cognitive deficits can be
seen in MS [11], the common view includes impairment
in sustained attention, information processing, memory
and executive functions [12] that are described below.
Information processing speed: The most prevalent
area of cognitive impairment in MS patients is
information processing speed which refers to the speed
with which a person can process any kind of information
including verbal or visual [13]. Information processing
speed decreases in MS patients and compared to normal
people, more slowness is highlighted in performing tasks
with a time limit [14]. Decrease in processing can occur,
independent of other impairment areas; however, this
affects the development of impairment in cognitive areas
like working memory, executive functions and other
aspects of memory [13].
Attention: Attention is a complicated cognitive function
and includes different aspects like alertness, vigilance,
selective, sustained and divided attention [15].
Impairment in sustained attention is more common in MS
and there have been reports on divided attention
2
impairment (tasks that require the patient to execute more
than one action at a time) [16].
Memory: Memory is usually classified based on time
and content aspects. In case of time, memory is divided
into short-term and long-term memory. Immediate
memory and working memory are within the short-term
memory group. Explicit memory and implicit memory are
content-based memory classifications ad they are divided
into episode memory and semantic memory subgroups
[15]. Working memory, a system with which information
is saved and manipulated for a short time, is frequently
impaired in MS patients and it is closely followed by
verbal and visual memory impairments and is known as
the most prevalent areas of impairment in MS [5].
Semantic memory impairment is also seen in MS. The
said impairments claim that the prevalence of memory
impairment in MS patients is 40-60% [13].
Executive functions and other areas in cognition:
Executive functions are a series of complicated cognitive
abilities including logical thinking, planning, organizing,
goal-directed behaviors, evaluating and solving problems
in addition to beginning, controlling and inhibiting
behaviors. About 19% of the MS patients have
impairment in this area. There is a significant relationship
between executive function impairment and damage in
pre-frontal cortex [15].
Global intellect and language function problems have
been observed in children with MS more [17]; this area
remains intact in adults but some latent comprehension
deficits are shown related to slowed information
processing [3].
Visual perception functions comprise recognizing visual
stimulus and the proper perception of its features and
approximately one fourth of MS patients have problems
in this area. Primary visual processing problems (due to
optic nerve inflammation) can have a destructive effect on
visual perception, though perceptual deficits may occur,
independent of these problems or other cognitive
impairments [18].
Factors affecting cognitive functioning in MS
Disease variables: 1) Atrophy & brain lesions: the
moderate relationship between the overall volume of
brain lesions and the stronger relationship between
cerebral atrophy, and particularly the increase in the third
ventricle size are not only correlated with cognitive
impairment, but also have a predictive value [19].
Thalamus atrophy is also a powerful predictor of
Cognitive impairment in multiple sclerosis
cognitive function problems, though it is not as valid as
cortical atrophy [20].
The increase in cortical lesions was accompanied by
reduction of cognitive functions through time [21]. On the
other hand, studies conducted using fMRI have shown the
increasing use of cortical networks through compensatory
mechanisms; it theoretically preserves the cognitive
function. These improved activities are demonstrated in
patients with normal cognitive function and seemingly
normal cerebral tissue in MRI and is interpreted as a
pathology that is not clinically obvious yet. According to
this method, cognitive impairment in MS does not occur
just because of tissue destruction; however, the cause is
the imbalance between tissue destruction, tissue
restoration as well as re-organization and adaptive
function. When the increase in the activity of cortical
neurons cannot keep cortical activity correlation,
cognitive problems emerge [22]. 2) Genetics: cognitive
impairment genetics is not known in MS; yet, recent
studies have mentioned a relationship between APOEε4
allele and cognitive impairment [23]. 3) Duration of
disease and degree of disability: conflicting results have
been reported on the relationship between cognitive
impairment, duration of disease and level of disability in
MS patients. According to some longitudinal studies,
cognitive
impairment
increases
following
the
deterioration of physical disability, duration of disease
and onset of a progressive disease. On the other hand, a
weak relationship is demonstrated between cognitive
status and level of disability.
It is prevalently observed that there are MS patients who
suffer from cognitive dysfunction despite their low EDSS
score (a method of quantifying disability in multiple
sclerosis). Considering the point that EDSS focuses on
spinal involvement and movement in addition to cognitive
impairments with a drop in cortical activities, the absence
of a relationship between the two areas is not predictable.
Nevertheless, better recognition of such relationships
requires further studies with stronger methodologies [8,
24].
Accompanying clinical and medical factors:
Depression, the other common syndrome accompanying
MS, has a reverse effect on cognitive abilities, particularly
information processing speed and executive function. The
prevalence of lifetime depression in MS is estimated at
approximately 50%; thus, it is more prevalent compared
to the general publication and other neurologic diseases
[25]. There is a complicated, reciprocated relationship
between depression and cognitive impairment. Depression
may lead to some cognitive function impairments like
lack of concentration, attention problems and slowing of
information processing. On the other hand, patients’
awareness of the drop of cognitive ability may lead to an
increase in anxiety and depression. Depressed patients
may also estimate their cognitive problems at a higher
level and this intensifies depression in them [26].
Pain is another effective factor in cognitive function.
Acute and chronic pain influences attention, information
processing speed and encoding and can indirectly affect
mood (like depression). Drugs used in treating pain or
Sahraian MA and Etesam F
other
disease
symptoms
(like
benzodiazepine,
corticosteroids, anticonvulsant and anti-spasm drugs, etc.)
can also have adverse effects on cognitive function [5,
13].
Fatigue is another factor that is frequently complained
about. Patients often state that fatigue impairs cognitive
function while no exact relationship has been found
between the complaints and poor performance on
cognitive tasks. On the other hand, it was demonstrated
that fatigue can reduce the ability of patients in
performing tasks that require time and attention
maintenance. Indeed, the relationship between fatigue and
cognition in MS is not well detected yet and further
investigations are required in this field [27, 28].
Evaluation:
1)
Neuropsychological
evaluation:
considering the prevalence of cognitive impairment in MS
patients, its incidence in initial stages of the disease and
its effect on patients' functions in different areas, the early
diagnosis is useful and even essential. The clinical
diagnosis of cognitive impairment is not solely possible
and requires tools that can show cognitive function
differences in different areas among patients and normal
people. However, access to centers offering
neuropsychological services and the high costs impose
restrictions and in many cases, the problem remains
undiagnosed [2].
Two cognitive tool batteries (MACFIMS and BRBN)
are often used on research and clinical centers to
comprehensively assess cognitive functions in these
patients; both tools possess appropriate psychometrical
features and are structurally sensitive to other impacts of
MS (Table 2).
MACFIMS (Minimal Assessment of Cognitive Function
in MS) battery was approved as a test for assessing
cognitive impairment in MS patients in a panel consisting
of experienced MS researches in 2001. It comprises 7
tests measuring 5 cognitive areas; assessing each person
takes about 90 minutes [29]. The Persian version of the
test battery with appropriate validity and reliability has
been recently published for Persian speakers [30].
BRB-N
(The
Brief
Repeatable
Battery
of
Neuropsychological Tests) also includes some tools
measuring the most prevalent cognitive impairments like
episodic, verbal and visual memory as well as information
processing speed and working memory. This test battery
is adjusted for use in a few countries and is commonly
used in MS-related neuropsychological studies [31].
The major difference between MACFIMS and BRB is
the method of assessing memory. As it is shown in table
1, these two test batteries use different tools for assessing
auditory-verbal and visuospatial memory. A study
comparing the tools on MS patients and normal control
cases revealed that both are similarly sensitive to disease
conditions. It was mentioned in this study that SDMT has
the highest level of sensitivity. The Selective Reminding
test was more sensitive for assessing auditory-verbal
memory than CVLT-II and in visuospatial assessment;
BVMT-R was more sensitive than 10/36 Spatial Recall
test [32].
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Zahedan J Res Med Sci 2014 Jan; 16(1): 1-7
Table 2. Common tools in MS neuropsychological assessment
Minimal Assessment of Cognitive Function in MS
Paced Auditory Serial Addition Test
Processing speed/Working memory
Symbol Digit Modalities Test
California Verbal Learning Test-II
Learning and Memory
Brief Visuospatial Memory Test-Revised
Visual perception/Spatial processing
Judgment of Line Orientation Test
Executive functions
Delis-Kaplan Card Sorting Test
Language
Controlled Oral Word Association Test
Brief Repeatable Battery of Neuropsychological tests
Paced Auditory Serial Addition Test
Symbol Digit Modalities Test
Selective Reminding Test
10/36 Spatial Recall Test
Controlled Oral Word Association Test
MS
patient
Follow up/re-evaluation
subsequently
Screening
PASAT, SDMT, SRT, MSNQ
not impaired
Assessing consumed drugs,
fatigue, psychiatric disorders &
other factors affecting cognitive
ability
not impaired
Follow up
Impaired
BRB-N, MACFIMS
Impaired
Diagnostic & medical
measures
Figure 1. Diagnostic assessment of cognitive impairment in MS patients
Although the said tools provide us with comprehensive
information on cognitive functions, their time-consuming
nature restricts their daily application. Various tests like
PASAT and SDMT (Table 2) and MMSE (Mini-Mental
State Examination) have been known as useful measures
for primary screening of cognitive impairment; yet, their
application was accompanied with some problems like
low sensitivity or specificity for MS. Some self-reporting
measures like Multiple Sclerosis Neuropsychological
Questionnaire (MSNQ) are designed for quick assessment
of cognitive impairments and can be filled out by patients
and their families within a short time. However, a recent
study showed that personal reports of patients on their
cognitive impairment had a strong relationship with their
depression, anxiety or personal characteristics and were
less associated with their performance in cognitive tests
[33]. Despite these restrictions, the application of the
mentioned tools provides an overall assessment of
patients' perceptions of their cognitive abilities and
comparing the results with performance neuropsychological tests, offer considerable information on the insight
of patients towards their problems [5]. Figure 1 illustrates
a suggestive process for studying and diagnosing
cognitive impairment in MS patients.
In a cohort study conducted on MS patients, a
summarized version of BRB test battery consisting of
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PASAT, SDMT and Selective Reminding test were
assessed for quick cognitive screening. According to the
findings, these tools could detect cognitive impairment in
patients with 94% sensitivity, 84% specificity and 89%
accuracy. Accordingly, cognitive impairment can be
screened in 5-15 minutes using these tests [34]. Also,
BICAMS (Brief International Cognitive Assessment for
MS) is another summarized package, including SDMT,
CVLT-II and BVMT-R, suggested by Benedict et al. for
conditions requiring short-time assessment which can be
used in small clinics and by one staff, even without
formal neuropsychological knowledge [35].
2) Imaging techniques: Recent studies have emphasized
the validity of MRI as a predictor of cognitive impairment
in future and consider this tool as one of the components
of cognitive studies. Beside the high sensitivity of this
technique in clarifying the relationship between cerebral
atrophy and cognitive status, it can be used to achieve
more precise information about the relation between
functional problems and structural defects. For instance,
left frontal atrophy is associated with dysfunction in
verbal memory while right frontal atrophy is accompanied
with some deficits in visual and working memory [36].
Compared to MRI, the application of fMRI in evaluating
brain functions of MS patients is still a new research area.
Achievements associated with this technique have
Cognitive impairment in multiple sclerosis
provided valuable information on brain function in MS
patients and neuroplasticity in the last 10 years. fMRI
with non-invasive mapping of different parts of the brain
show how brain, despite the developed lesions, can
continue its normal function by making changes in the
organization of functions in different parts. Moreover, this
technique offers useful information on the relationship
between different parts of the brain, cognitive activities
and changes made in activating these parts in MS [37].
Diffusion-tensor MRI, also, provides more information on
changes in the apparently normal brain tissue and the
integrity of white matter, compared to common imaging
methods. In some other studies, some relations between
fractional anisotropy and disconnection between different
cortical and subcortical parts due to MS lesions and
cognitive function are demonstrated [12, 38].
Treatment: The two major approaches in treating
cognitive impairment include pharmacological and nonpharmacological treatments that are discussed below.
1) Pharmacological treatments: Using effective treatments
for advancing cognitive function has been studied for
several years. Drugs like: interferon, glatiramer acetate
and natalizumab can be helpful by inhibiting
inflammatory products quickly; preventing the
development of new lesions and some neuroprotective
effects. According to clinically controlled studies, there is
no evidence proving the effect of natalizumab, glatiramer
acetate or fingolimod on improving cognitive function in
multiple sclerosis [39]. Studies conducted on impacts of
interferon ß has shown its positive effects on cognitive
function with 1-3 years stability; it was even revealed that
the early start of interferon treatment in CIS patients can
be effective in preventing cognitive dysfunction [40, 41].
However, it should be considered that such studies are not
often specifically designed for examining the effect of the
drugs on patients' cognition; therefore, there is no
available data on their baseline cognitive level in advance.
Lack of a control group, small sample sizes, high
percentage of excluded patients, absence of frequent and
regular assessments and choosing retrospective study
approach are among the limitations of these studies. There
have been no strong and sufficient clinically controlled
studies on determining the degree and manner of effective
treatments for cognitive impairment status. Cogni MS is a
longitudinal study on the effect of Interferon ß-b 1 on
cognition of 1520 MS patients in 33 countries. The
primary data of the study showed that specifications of
cognitive impairment in MS patients were similar in 61%
of them; however, no information has been published on
the effect of Interferon ß-b 1 on cognitive function [3, 42].
In addition to findings of MS-specific treatments, some
studies have examined the effect of drugs proven to
modify cognitive status in other neurologic diseases.
Donepezil is an approved central cholinesterase inhibitor
for treating dementia and was the first drug studied in MS
cases. Primary clinically controlled studies stated some
positive responses to this drug in neuropsychological tests
and clinical observations of patients; nevertheless, the two
recent studies have not confirmed its impact on improving
cognitive status [43, 44]. Memantine is an NMDA-
Sahraian MA and Etesam F
receptor antagonist confirmed for administering in
alzheimer cases. It is assumed that the drug can facilitate
nerve signal transfer and reduce glutamate - induced
neurotoxicity. Studying the impact of this drug in
improving cognitive impairment in MS patients has not
been promising [45].
2) Non-pharmacological interventions: A series of nonpharmacological approaches like cognitive-behavioral
treatments (CBT), psychotherapies, occupational therapy
and cognitive rehabilitation are used aiming at preventing
the progress of cognitive loss and preserving function in
this area. Making simple changes in patients’ lifestyle like
preventing smoking, sufficient sleep, regular exercise,
balanced diet and reducing the consumption of processed
foods, alcohol and stimulants like coffee and chocolate
are said to be helpful. Considering various results
published in this regard, no non-pharmacological
treatment of choice has been approved for cognitive
impairment in MS.
Cognitive rehabilitation has been the focus of attention
in recent years and consists of specific plans for patients
in order to adjust with cognitive impairments more
effectively or improve some cognitive abilities. Cognitive
rehabilitation is based on two approaches that can be used
in combination, as well:
a) Compensative strategies aiming at reducing the effect
of cognitive impairment on everyday function of the
patient include training time management skills and
determining priorities, memory improvement methods
like using a notebook to record important information,
enclosing reminder notes in front views, carrying a
calendar and computerized pocket memories, etc.
b) Restorative strategies: According to the neuroplasticity
theory, the very approach states that in order to increase
individual ability of the person in processing and
interpreting data, the brain can undergo cortical reorganization following damage. So, training and practice
for developing different cognitive skills like attention and
memory can increase the degree of plasticity and
consequently reinforce the abilities in the patient [2].
Primary studies conducted with the aim of cognitive
rehabilitation have different weak points like lack of
controlled tests, basic differences in groups under study
and focusing on case studies. In a few controlled studies
conducted on the subject, interventions were not made on
all impaired cognitive aspects of the disease, but, memory
and learning were emphasized more. The said studies
mostly used computer programs for cognitive
reinforcement and some positive results are also obtained
[46].
Cognitive rehabilitation can lead to the best results if
specific plans are developed for individuals considering
their needs and personal specifications (age, educational
level, occupational status, mood and degree of fatigue).
However, it should be considered that designing separate
rehabilitation programs for reducing impairment in
different areas like attention, memory and executive skills
is complicated due to complex connections between
neuroanatomical substrates [2].
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Zahedan J Res Med Sci 2014 Jan; 16(1): 1-7
for considering the issue from clinical and research
aspects.
Discussion
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The progressive trend of MS in Iran requires large range
studies for learning more about the disease, its prevention
and treatment. Cognitive impairment is of particular
significance due to its early incidence during the course of
MS, impact on the prognosis of the disease and
destructive effects on patients' quality of life.
Despite promising findings in cognitive rehabilitation
researches, future studies would need larger sample sizes,
longer follow up periods, application of standard
educational tools and examining the effect of clinical
interventions on everyday functioning of the patients.
Offering information in the field of cognitive impairment
in MS is difficult due to lack of sufficient studies carried
out on the subject in Iran; therefore, there is a great need
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Acknowledgements
The authors would like to thank Sina Research and
Development Center for its helpful support. We are also
grateful to Ms. Pourmand for her kind help.
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Authors’ Contributions
All authors had equal role in design, work, and
manuscript writing.
Conflict of Interest
The authors declare no conflict of interest.
Funding/Support
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Please cite this article as: Sahraian MA, Etesam F. Cognitive impairment in multiple sclerosis. Zahedan J Res Med Sci (ZJRMS) 2014; 16(1):
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