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Neuropsychological
Test
Cognitive Abilities
Required
Description
Spatial Recall Test
(SPART)
Visual
learning and
memory
Spatial
awareness
Patients are shown a visual pattern
of shapes on a square board and
must then reproduce the
arrangement from memory,
immediately and again after a
delay.
Controlled Oral
Word Association
Test (COWAT)
Wordfinding using
phonetic
cues
Behavioral
initiation and
fluency
Processing
speed
Patients are asked to rapidly
generate words beginning with
specified letters. This test can be
administered with one trial using a
single letter or by combining the
total score across multiple letter
trials.
Word List
Generation (WLG)
Wordfinding using
semantic
cues
Ability to
sustain
performance
Processing
speed
Patients are asked to quickly name
as many items as possible within a
specified category, such as types of
animals. Normative data are
available for numerous semantic
categories, and for various
demographic populations.
Table 18.3
Cognitive Screeners and Neuropsychological Test Batteries Used in
Multiple Sclerosis (MS) Evaluation
Length of
Administration
Clinical Notes
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Length of
Administration
Clinical Notes
Minimal
Assessment of
Cognitive Function
in MS (MACFIMS)
90 min
(<10 min for
abbreviated
version)
Comprehensive standardized
assessment of cognition in MS,
including processing speed,
attention, working memory,
executive functioning, memory,
language, and visuospatial
processing
Tests function extensively in both
verbal and nonverbal modalities
Abbreviated form (aMACFIMS)
has been validated as a screening
measure and allows for
intraindividual comparison over
time against shortened or full
battery
Brief Repeatable
Battery of
Neuropsychological
Tests (BRB-N)
30 min
Short neuropsychological battery
containing measures of attention
and working memory, memory,
and verbal fluency
Alternate form available to allow
retesting of patients
Brief International
Cognitive
Assessment for MS
(BICAMS)
15 min
Three-test screening battery
validated in MS cross-culturally
Assessment of processing speed
and memory
Indicated for screening and
monitoring
Montreal Cognitive
Assessment
(MoCA)
10 min
Short evaluation of executive
functions, attention, memory,
language, and construction
Demonstrates some use in MS as
a screener, but not valid as a
formal diagnostic instrument
Mini-Mental State
Examination
(MMSE)
10–15 min
Brief screening of memory,
language, and construction
Poor sensitivity due to inadequate
assessment of cognitive functions
typically affected by MS
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While many individuals with MS will endorse reduced speed
of thinking when it is presented as an option, few will consider
this independently as an explanation for changes they have
noticed or volunteer it in discussions with a clinician. More
often, patients may report the functional cognitive symptoms
that exist secondary to slowed processing, including the
following: difficulty sustaining attention, as patients can no
longer keep pace with externally presented information at their
prior level of ability; memory problems, which can occur in
the context of diminished attention and learning of
information; difficulty understanding others, as normal rate of
speech is now faster than they can adequately process and
comprehend; or trouble finding words, as the formation of a
thought process representing an idea is no longer occurring in
lockstep with the retrieval of words and formation of language
output. This loss of synchronization is of particular relevance
in MS given the presence of focal white matter changes, which
can manifest such that cognitive slowing does not occur
evenly throughout the brain.
42
Attention
Simple attention can be disrupted in MS, with some patients
endorsing changes in their ability to focus either in short bursts
or for extended periods of time. Patients also may complain
that they have become easily distractible. More typical and
specific to MS, however, are changes in complex attention and
working memory, defined as the ability to mentally hold and
interact with information. Patients may also report difficulty
with multitasking that becomes noticeable when engaging in
complicated multistep activities, such as driving or cooking.
Diminished ability to multitask has been specifically related to
patients experiencing difficulties at work.
43
MS patients with late-onset changes in attention may not
recognize the nature of their deficits and subsequently frame
them as novel memory complaints. An individual given a
request or new piece of information will not have the
opportunity to consolidate that information to memory if
attentional processes fail to engage. The patient may
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subsequently be told by others that they have forgotten
something, when in reality they never learned it. Patients who
begin an activity but lose focus may also feel that they have
forgotten why they intended to do something, although this too
is less a genuine memory deficit than a reflection of impaired
attention.
Executive Functioning
Executive functions are a broad set of complex thinking
abilities, including behavioral initiation, self-monitoring and
control, cognitive flexibility, planning, organization, and
judgment. Because of the intricacy of these functions,
assessing them independent of other MS-related deficits is a
challenge. Patients often complain of the functional
manifestations of executive dysfunction, although depression
and processing speed have been implicated as potential
confounding variables.
44-46
Nonetheless, patients do
demonstrate impairments in objective and subjective executive
measures, particularly at higher levels of overall disability or
in the presence of frontal lobe change.
47-49
As executive
deficits can be reflected prominently in everyday life, they are
an important consideration within the cognitive disability
profile.
Visual-Spatial Processing
The ability to accurately perceive and interpret visual and
spatial information can be disrupted in MS for several reasons.
Patients with visual disturbance originating in the eyes, optic
nerve, or ocular muscles may present with visual deficits.
50,51
Cortical change, particularly in occipital or posterior parietal
regions, can impact navigation, driving ability, visual
recognition, or simple visual-spatial perception. Because of the
reliance on vision for many daily activities, evaluation of
dysfunction in this area is of clear importance.
Memory
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Memory complaints are perhaps the most common subjective
complaint among MS patients concerned about their cognitive
function. This is unsurprising, as there is a strong tendency
among patients with neurological conditions to describe
changes in cognition in terms of practical memory, which may
be most apparent to them and to others. While other cognitive
functions can produce what appears to be changes in memory,
as has been discussed, organic changes in verbal and visual
memory have been observed in MS. Disruption of
hippocampal circuitry is heavily implicated in memory
dysfunction,
52-54
although other limbic and frontal lobe
connections likely play a role as well.
55,56
Language
Many patients describe difficulties with word-finding,
particularly in real time, and trouble keeping up during
conversations. Processing speed and executive control are
thought to be a considerable part of practical language
dysfunction. Significant damage to language cortex is not
especially pervasive among MS patients, and while isolated
cases of aphasic disorders have been observed, they are not
considered typical. 57 Patients who describe difficulties with
speech output should also be evaluated for dysarthria and
speech apraxia, which may impact language production but are
not necessarily suggestive of a language deficit at the
cognitive level.
Deficits in Processing Speed and Executive Functioning
A 44-year-old right-handed man with a 13-year history of
MS was referred for neuropsychological evaluation owing to
progressive cognitive complaints. Specifically, he reported
periods of “brain fog” beginning around the time of his MS
diagnosis, accompanied by a gradual decrease in his speed
of thinking. He also reported difficulty with planning and
adapting to changes; he had become confused and flustered
by minor deviations from his routine at work and had
difficulty navigating even familiar roads if he needed to
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adjust his route due to traffic or road conditions. A series of
significant errors at his job, dating back several years, was
discovered and ultimately resulted in loss of employment.
Before his dismissal, he had been told by coworkers that he
had become more irritable and abrupt, and his wife
reportedly informed him of subtle personality changes and
behavior that seemed uncharacteristic for him.
Neuroimaging had showed gradual progression of MS, with
multiple T2 hyperintensities present in supratentorial white
matter at the time of his latest magnetic resonance imaging
(MRI).
Several months prior to this evaluation, he had been started
on a serotonin and norepinephrine reuptake inhibitor
(SNRI), which he reported was of some benefit to his mood.
Nonetheless, he presented as anxious, and when queried, he
endorsed multiple symptoms of depression and significant
fatigue. Speech was of normal rate, rhythm, and volume, and
he had no difficulty understanding questions or instructions.
However, thought process during the evaluation appeared
mildly disorganized, and he was tangential at times.
Estimates of premorbid functioning based on educational
background, vocational history, and crystallized ability
testing suggested cognition had been well above average at
baseline. On neuropsychological testing, aspects of
executive functioning were impaired, including planning,
complex problem-solving, and pattern recognition.
Processing speed was below expectation. Auditory attention
and working memory were mildly weak for age. Memory
was generally intact; while learning of new information was
mildly weak, likely as a consequence of diminished
attentional capacity, he was able to accurately recall most of
what he had initially acquired. Language functions were
broadly normal, but phonemic verbal fluency was
considerably weaker than semantic fluency. Simple
visuospatial processing was normal.
Commentary: Neurocognitive profiles of the pattern seen in
this patient are not uncommon among those suffering from
diseases primarily affecting white matter integrity such as
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MS. In particular, the gradual onset of slowed processing
speed and executive dysfunction, accompanied by mild and
insidious changes in mood and behavior, is frequently seen
in the context of disruption to frontal-subcortical circuitry. A
large discrepancy between phonemic verbal fluency (which
relies heavily on frontal lobe function) and semantic verbal
fluency (which uses many of the same neural pathways, but
with greater dependence on functioning temporal cortex) is
strongly suggestive of abnormalities in efficient frontal lobe
use.
Quite typically, the cognitive changes in this patient were of
the variety not readily noticed by others. General intellect
and language ability were not considerably altered, and the
lack of overt suspicion about his cognitive performance
allowed his mistakes at work to go unnoticed for years. A
relatively young patient with a high level of baseline
functioning such as this could effectively compensate for, or
at least minimize, many cognitive and behavioral changes up
until a point at which they became too disruptive to ignore.
Neurocognitive Assessment
The cognitive and behavioral presentation of MS patients is
defined by many diverse features. This adds a degree of
difficulty to the application of many standard test batteries to
neuropsychological evaluation in MS. 2 In addition to basic
psychometric validity, examination of deficits requires
accounting for confounding variables that may interfere with
the results of neuropsychological testing, such as fatigue,
physical difficulty completing tests requiring fine motor
dexterity, and problems affecting speech or vision. In
consideration of the fact that MS usually worsens over time,
ideal instruments would be relatively short and easy to repeat
so as to enable longitudinal assessment of patients’
functioning. Neuropsychological methodology often uses a
comparison of patients’ level of performance to a normative
sample matched in features such as age and education.
However, intraindividual comparison at multiple time points
allows for the most effective and precise long-term tracking of
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cognition. This can be of great benefit in assessing whether
meaningful change has occurred and in distinguishing normal
age-related alterations in cognitive function from those
suggestive of active disease pathology.
Many brief cognitive assessments such as the Mini-Mental
State Examination (MMSE) 58 have been shown to lack the
necessary sensitivity to cognitive impairment in MS (as low as
28%) and are not recommended.
59-61
The Montreal Cognitive
Assessment (MoCA), 62 which contains measures of attention
and executive functioning, has somewhat more clinical use,
with a recommended cutoff of 26 points in MS, 63 although
there are still questions regarding its advanced diagnostic
value and correlation with lesion volume. 64 Work on
developing computerized tests in MS has begun, although
further research is needed in this area.
65-68
Generally, the best practice in cases of suspected cognitive
impairment is a formal neuropsychological evaluation.
Fortunately, the past several decades have seen an increase in
research and development of neuropsychological batteries
designed to assess and monitor cognition in MS. These include
the Brief Repeatable Battery of Neuropsychological Tests
(BRB-N), 69 the Minimal Assessment of Cognitive Function in
MS (MACFIMS), 70 and the Brief International Cognitive
Assessment for MS (BICAMS). 71 Some of the tests appearing
in these batteries are discussed below, and are further
described in Table 18.2.
The most extensively studied and empirically validated single
measure of cognitive function in MS is the Symbol Digit
Modalities Test (SDMT).
72-75
The SDMT is a 90-second task
that measures processing speed, visual working memory, and
sustained attention. It is a valid longitudinal instrument, 76 and
it can be administered as a traditional paper-and-pencil
measure or orally to accommodate patients with upper motor
dysfunction. Processing speed and working memory in the
auditory modality can be measured with the Paced Auditory
Serial Addition Test (PASAT).
77
Neuropsychological tests of memory are traditionally
dichotomized into verbal and visual modalities. Verbal
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memory can be measured with a list-learning task over
repeated trials, such as the California Verbal Learning Test,
Second Edition (CVLT-II) 78 or Selective Reminding Test
(SRT). 79 Visual memory is assessed with the Brief
Visuospatial Memory Test—Revised (BVMT-R) 80 or Spatial
Recall Test (SPART). 69 These tests allow for distinct
measurement of both short-term learning and long-term
retention of information.
Word retrieval and language production can be measured using
the Controlled Oral Word Association Test (COWAT), in
which patients are tasked with generating words rapidly
according to phonemic cues. In addition to language, this test
also requires behavioral initiation and processing speed,
making it a valuable tool for MS evaluations. 81 Other common
tests measure visual-spatial processing and executive functions
such as concept formation.
Recent efforts to reduce administration time of cognitive
screening measures have revealed that abbreviated versions of
many of these instruments are often sufficient to produce
sensitive and specific conclusions about cognitive functioning.
82
This is a promising finding for future development of
neurocognitive screeners in MS and has already produced an
abbreviated MACFIMS battery (aMACFIMS), which reduces
administration time to under 10 minutes while accurately
screening for dysfunction in processing speed, attention,
memory, language, and executive functioning. 83 A summary
of neurocognitive screening and assessment batteries used
with the MS population is provided in Table 18.3.
Other Etiological Considerations
The complexity of MS is reflected in the many possible
etiologies of cognitive dysfunction. As described previously,
MS-related central nervous system damage can directly
influence cognitive ability,
84,85
but other precipitants should be
considered. Fatigue is highly prevalent and can impact
functional use of cognitive resources. Psychiatric dysfunction
is also common, and the acute effects of stress may prevent an
individual from applying cognition in an optimal manner.
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Additional medical risk factors, including many conditions
that commonly occur alongside MS, also place patients at risk
for cognitive impairment.
Fatigue and Stress
Fatigue is highly prevalent and disabling in MS,
86,87
and it can
result in cognitive performance well below peak ability.
Fatigue has been found to be related to diminished executive
control in MS but not in matched healthy controls. 88 The
phenomenon of cognitive fatigue is an area of ongoing
research, but it is thought that exhaustion of cognitive
resources can occur independently of physical fatigue,
although the two are strongly related.
3,89
Neurophysiological
correlates of cognitive fatigue have also been described.
90-92
Sleep disturbance is known to impact cognition in MS, 93 and
fatigue effects can be exacerbated by commonly prescribed
medications, including MS disease-modifying therapies,
corticosteroids, muscle relaxants, and opioid pain medication.
Life stressors and psychiatric disorders also occur frequently.
Psychological factors play a considerable role in both
performance on cognitive tests and the ability to apply
otherwise intact cognitive abilities in a real-world
environment. The presence of acute and chronic stressors
should be evaluated as a potential causative factor in patients
who report cognitive concerns.
Other Medical Disorders
Patients with MS are certainly not immune to other maladies
that carry cognitive risk factors. White matter change on
neuroimaging in a patient with diagnosed MS is usually
assumed to be a product of the disease, making it easy to
overlook the potential contribution of vascular risk factors to
changes in a patient’s neurocognitive profile. Hypertension,
hyperlipidemia, and diabetes are common among individuals
with MS, and patients are at elevated risk of congestive heart
failure and ischemic heart and cerebrovascular disease.
94
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