Cognition in multiple sclerosis

Dawn W. Langdon
Royal Holloway, University of London, Egham, Surrey,
UK
Correspondence to Dr Dawn W. Langdon, Reader in
Neuropsychology, Royal Holloway, University of
London, Egham, Surrey TW20 0EX, UK
Tel: +44 1784 443956; e-mail: d.langdon@rhul.ac.uk
Current Opinion in Neurology 2011, 24:244249

Purpose of review
A broad overview of cognition in multiple sclerosis (MS) is provided, taking account of
its impact on the lives of patients, how cognitive impairment relates to disease and
magnetic resonance variables, which cognitive domains are most vulnerable, the
influence of depression and fatigue and what treatment options are available.
Recent findings
The current focus is on cognitive reserve, which seems to offer some protection from the
cognitive impact of MS. There is also considerable momentum with new MRI techniques
and growing interest in PET studies.
Summary
Cognition in MS is a priority for patients. Although understanding of the natural history of
MS cognitive deficits is reasonably well understood, treatment options require further
work before precise recommendations can be made on an individual basis.
Keywords
cognition, information processing, memory, multiple sclerosis
Curr Opin Neurol 24:244249
2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
1350-7540

Introduction
Cognitive impairment is an important predictor of healthrelated quality of life at all stages of multiple sclerosis
(MS) [1]. It reduces physical independence [2], competence in daily activities [3], coping [4], symptom management [5], medication adherence [6] and rehabilitation
potential [7]. It also reduces driving safety. Cognitive
function is the strongest predictor of poor lane positioning
during high cognitive load and also slower response times
to other car movements [8]. Information processing speed
is the best predictor of overall driving performance, with
spatial learning and recall the best predictors of driving
accidents [9]. Unemployed MS patients are more likely to
have cognitive impairments than MS patients in employment [10]. In addition, declining performance over time
on tests of attention and verbal memory has been shown
to predict reduced employment status [11].

Disease subtypes and stages, pattern of

deficits
Studies of large, unselected samples of MS patients have
reported cognitive impairment prevalence rates between
40 and 70% [12]. Cognitive impairments have been
demonstrated at all stages and in all subtypes of the
disease. This includes the clinically isolated syndrome
(CIS), relapsingremitting multiple sclerosis (RRMS),
secondary progressive multiple sclerosis (SPMS), primary
progressive multiple sclerosis (PPMS) and even benign
multiple sclerosis (BMS) [13,14]. Interest has now
extended to the boundaries of the disease, with studies
1350-7540 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

of cognition at both the CIS stage [15] and very late stage
of MS [16]. Although longitudinal studies over a few years
often fail to show significant cognitive decline, it seems
that if observations are made over a sufficiently long timescale, cognitive impairment will emerge and progress
[17]. The more severe levels of cognitive impairment
tend to occur in the progressive phase [13,18] and decline
is most pronounced in progressive patients [19]. Although
almost any configuration of cognitive deficits can be
observed in MS [20], the typical profile is of impairments
in information processing speed, memory and often
executive skills, with relative preservation of language
[12].

Measurement and self-report

The measurement of an MS patients cognitive abilities
requires expertise, because the cluster of physical and
cognitive symptoms they have may well confound performance on cognitive tests (e.g. visual or other sensory
impairments) [21]. Two cognitive batteries are particularly widely used in clinical and research settings, both
having good psychometric properties and having been
constructed to be relatively robust to the effects of other
MS symptoms. They are Brief Repeatable Battery of
Neuropsychological tests (BRB-N) [22] and Minimal
Assessment of Cognitive Function in MS (MACFIMS)
[21]. MS patients self-report of cognitive impairments,
although important clinically, is unlikely to be related to
objective cognitive test performance, but rather linked to
depression. Relatives reports of patients cognitive function are more likely to be reliable [23].
DOI:10.1097/WCO.0b013e328346a43b

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Cognition in multiple sclerosis Langdon

Information processing speed

For several decades, it has been established that MS

patients are most likely to fail tests of information
processing speed [24]. Cognitive tests of information
processing speed often involve working memory, the
system which maintains and manipulates information for
brief periods. Over several years, MS patients performance on tests of information processing speed declines
more rapidly than on other cognitive tasks [25]. Detailed
methodological investigations of performance on a range of
cognitive tests point towards speed of processing as the
unitary underlying deficit [26]. Information processing
speed is reduced in MS patients, and the slowness is more
pronounced on tasks that are explicitly timed, compared
with normal participants [27]. When cognitive load is
varied, increasing the interval between stimuli presentations allows more processing time and improves the
accuracy of MS patients performance [28].
There are two widely used tests of processing efficiency
and speed in MS: the Paced Auditory Serial Addition
Task (PASAT) [29] and the Symbol Digit Modalities
Test (SDMT, oral form) [30]. The PASAT requires the
patient to listen to a string of auditory digits and continuously add up the last two heard. In the SDMT, the
patient is presented with nine graphical symbols, each
paired with a single digit, serving as a key. Below are rows
of the symbols, randomly ordered, and the patient must
say the numbers that go with each digit. The tests have
similar psychometric properties [24]. Unsurprisingly,
there is evidence that the two tasks utilize slightly
different cerebral networks, with the PASAT activating
more frontal areas [31].

245

Key points
 Cognitive dysfunction is common in multiple
sclerosis (MS) and the typical profile is slowed
information processing and weakened memory.
 Cognitive impairment is only loosely related to
disease variables, but is more closely related to
magnetic resonance variables, especially atrophy.
 Cognitive reserve modulates the adverse effects of
MS pathology on cognitive function.
 Treatment options remain largely at an individualized, clinical stage.
abnormalities of hippocampal functional connectivity
before spatial memory impairment is evident [35].
Executive functions, language and visual perception

Executive functions relate to planning and goal-directed

behaviour. Drew et al. [36] recorded a range of executive
dysfunction, including disinhibition, poor fluency and
failure to shift sets. In total, 17% of their MS sample
demonstrated deficits of this type. Executive abilities
have been implicated in the completion of informationprocessing speeded tasks with high cognitive loading
[37,38]. Language functions are typically intact in MS,
but some subtle comprehension deficits have been
demonstrated. Weakened sentence comprehension has
been linked to slowed information processing [39]. Deficits in semantic memory have also been identified [40].
Studies have also suggested some visual processing
impairments [41,42].

Cognitive reserve
Memory

Long-term memory refers to the learning and recalling of

new information. MS patients are very likely to experience memory problems, with prevalence rates of 4065%
reported [32]. The most usual tests of verbal memory are
list learning tasks. A widely used test of verbal memory in
clinical and research contexts is the California Verbal
Learning Test-II (CVLT-II) [33]. This comprises a 16item shopping list, with four items belonging to each of
four categories, arranged randomly. The list is read aloud
five times in the same order to the patient. Patients are
required to recall as many items as possible, in any order,
after each reading of the list. Delayed recall, recognition
and distracter tasks are also involved. The validity of the
CVLT-II in MS is well established [34]. Visuospatial
memory is also affected in MS. A frequently used test
of visuospatial memory in MS is the 10/36 spatial recall
task [22]. This comprises 10 counters and a 6  6 grid.
The patient is shown a pattern, which must then be
reproduced from memory by placing the counters on
the grid. Tests of this type have been shown to predict
driving accidents [9]. MS patients sustain substantial

There is large interpatient variability in the pattern and

severity of cognitive deficits in MS. Recently, in an effort
to explain this variability, investigators have addressed the
question of cognitive reserve. Could individual differences
at baseline differentially protect MS patients from cognitive decline? Both years of education and reading level
improved predictions of cognitive decline over 5 years
[43]. Strikingly, the SDMT showed no change in the MS
group with more than 14 years of education, but declined in
the MS group with 14 years or less education. Cognitive
reserve has also been shown to moderate the effects of
atrophy on cognitive function in MS [44]. It has been
suggested that cognitive reserve relies on a default
network, involving the anterior and posterior cingulated
cortices [45].

Relation to disease variables

Cognitive status is typically only loosely related to disease duration [16] and physical disability [46], although
larger studies have shown significant relations [47]. Cognition can predict future disease progression. Cognitive

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246 Demyelinating diseases

status at CIS event stage predicts conversion to MS [48]

and cognitive status at MS diagnosis predicts accumulation of physical disability [49]. Cognitive dysfunction
also predicts disease evolution in benign MS [46]. A
modest relation has been reported between cognition
and some immune measures [50]. The genetics of cognitive dysfunction in MS are undetermined, but current
studies suggest a link between apolipoprotein E epsilon4
and cognitive impairment [51].

shown to increase across subtype cohorts from CIS to

SPMS [66]. PET studies of MS cognition are becoming
more numerous. It is suggested that PET measurements
of brain metabolism may serve as better indicators of
axonal loss or dysfunction in MS lesions, normal appearing white matter and grey matter [67]. Measurement of
microglial activation offers particular promise [68].

Relation to depression
Magnetic resonance (MR) variables are significantly
related to cognitive performance, with total cerebral
lesion area typically achieving modest correlations and
atrophy stronger correlations, especially third ventricle
width [52,53]. Cortical lesions and atrophy have been
demonstrated to be independent predictors of cognitive
dysfunction [54], raising the possibility that they may
represent separate processes. An increase in cortical
lesions over time has been related to increased cognitive
impairment [55]. Recent investigations of cortical thinning raise the possibility of identifying more widespread
pathology underlying cognitive deficits [56]. Changes in
gadolinium enhancement have been significantly linked
to changes in PASAT scores in physically stable patients,
suggesting that inflammation interferes with cognitive
processing efficiency [57]. MR is now considered to
contribute to cognitive assessment [58]. In addition
to MR investigations that utilize traditional clinical tests
of cognition, some experimental cognitive tasks are offering new insights into how MS pathology affects awareness of the world. Using a visual mask after stimuli was
presented to calibrate conscious and nonconscious perception, Reuter et al. [59] were able to demonstrate that
conscious access was directly related to white-matter
bundle integrity, especially in prefrontal cortex. Another
interesting recent development has been the validation
of MR variables as predictors of future cognitive outcomes [6062].

Depression adversely affects cognitive function in MS.

The lifetime prevalence of major depression in MS is
close to 50% [69], making it more common in MS than
the general population or other neurological disorders. An
early meta-analysis demonstrated that depressed MS
patients had more difficulty on the PASAT, reflecting
either reduced information processing speed and/or
weaker working memory [70]. When well matched
groups of depressed MS patients, nondepressed MS
patients and healthy controls completed five cognitive
tasks that made demands on cognitive processing
capacity, the depressed MS group performed less well
than the other two groups on three tasks (PASAT, SDMT
and Visual Elevator Task). There was no difference
among the three groups on two cognitive capacity
demanding tasks (CVLT and 7/24 Spatial Recall test),
or on a reference battery on tasks with low cognitive
capacity demands [71]. In order to distinguish whether
the MS depressed groups poor performance was due to
reduced cognitive capacity or psychomotor slowing, the
same three groupings of MS depressed, MS nondepressed and healthy controls were compared on a word
span task (no working memory involvement) and a reading span task, in which the last word of each sentence had
to be recalled when prompted (working memory capacity
task). The MS-depressed group were worse on the reading span task, but not the word span task [72]. These
elegant and well designed experiments have shown that
depression in MS affects cognitive processing capacity
and, in particular, working memory.

Functional MRI and PET

Relation to fatigue

Functional MRI (fMRI) techniques allow the investigation of activation in real time of the cerebral cortex.
These investigations have demonstrated that there is an
increased recruitment of cortical networks, which are
hypothesized to preserve cognitive performance via a
compensation mechanism. In fact, these increased activations have been demonstrated in MS patients with
normal cognitive performance and interpreted as evidence of pathology that is hardly, or not yet, clinically
eloquent [63,64]. According to this model, when
increased activation can no longer keep pace with the
failing integrity of the cerebral cortex, cognitive performance plummets [65]. Additional activations have been

The effect of fatigue on cognition in MS is not so well

delineated, in part because the construct of fatigue is less
clear cut [73]. Fatigue is one of the most commonly
reported symptoms in MS [74]. MS patients often report
that fatigue impairs their cognitive function [75]. However, the relation between self-reported fatigue and
objective cognitive performance is complex and inconsistent. Processing speed, measured by Digit Symbol
Coding, has been demonstrated to be slower in MS
patients reporting fatigue than those who did not report
fatigue. Processing speed was inversely related to selfreported fatigue, but only in the fatigued MS group [76].
Self-reported fatigue was an independent predictor of

Relation to magnetic resonance

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Cognition in multiple sclerosis Langdon

scores on one of a battery of objective cognitive tests

(Test of Attentional Performance) [77]. Recognition reaction time and accuracy, in a condition which maximized
executive demands, have also been linked to selfreported fatigue [78]. In contrast, several investigations
have failed to find a significant relation between selfreport fatigue and objective cognitive test performance
[79,80,81]. Mental fatigue relates differently to selfreport of cognitive impairment, compared to physical
fatigue [82]. However, a study has reported decline in
sustained task performance over time in MS patients
compared with healthy controls [83] and another reported
decline in performance of MS patients on a variety of
cognitive tests, following a lengthy, cognitively demanding task, again compared with healthy controls [84]. It
appears that MS patients may not be as good at sustaining
cognitive performance over time as healthy people are,
which is most likely the result of fatigue, but they are not
very good at reporting the levels of fatigue they experience that affect their cognitive performance.

Treatment: presentation
Changing the presentation format of information can to
some extent reduce the handicaps that MS cognitive
impairments impose. For example, given that information processing speed is a major factor, it is unsurprising that performance accuracy improves when MS
patients are given more time to process the information
[28]. Simple repetition is often not helpful, but increased
processing (encoding) and more organization of the
information facilitates remembering. Paring down information to the essentials and avoiding unnecessary or
unrelated details are advantageous [85].

positive outcomes [88,89]. The use of symptomatic

agents for cognitive decline is not broadly supported
by convincing studies [90].

Conclusion
Cognition in MS is a priority for patients. Assessment
tools are psychometrically sound and can be used effectively by a specialist neuropsychologist. New and developing MRI techniques offer further insights into how MS
pathology translates to cognitive performance. Understanding of influential related factors, such as depression,
fatigue and cognitive reserve, increase the precision of
evaluation and management. Much further work is
required before a systematic treatment approach can
be recommended.

References and recommended reading

Papers of particular interest, published within the annual period of review, have
been highlighted as:

of special interest
 of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 303304).
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