Cognitive Impairment
Associated with
Multiple Sclerosis
Jonathan L. Carter, MD
Director
Mayo Clinic Scottsdale MS Center
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Outline
Prevalence of Cognitive Impairment in MS
Patterns of Cognitive Impairment in MS
Correlation with Disability Progression
Correlation with MRI Findings
Diagnosis of Cognitive Impairment
Treatment of Cognitive Impairment
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MS Cognitive Impairment: Prevalence
• Population-based studies: Estimated
prevalence of 43-46% in unselected
MS patients
• MS specialty clinic or hospitalized
patients: Estimated prevalence of 50-60%
• Prevalence depends on how CI is defined
and how rigorously it is looked for
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MS Cognitive Impairment: Prevalence
Prevalence of Impairment by Domain
Language
8-9%
Visuospatial abilities
12-19%
Attention span
7-8%
Information Processing
22-25%
Memory
22-31%
Problem Solving
13-19%
Defined as % MS patients scoring
<5th percentile for normal population
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Rao et al. Neurology 1991
MS Cognitive Impairment: Patterns
• Cognitive domains frequently affected:
– Recent memory
– Abstract reasoning
– Verbal fluency
– Sustained attention
(especially with multiple-tasks)
– Visuospatial perception
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MS Cognitive Impairment: Patterns
• MS memory impairment:
– Unlike Alzheimer’s, MS patients
learn when presented with multiple
trials of same material
– Unlike Alzheimer’s, MS patients perform
better on recognition tests than free
recall tests; suggesting information is
encoded and stored but inaccurately
retrieved without cues
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MS Cognitive Impairment: Patterns
• Cognitive domains not
frequently affected:
– Language (receptive
and expressive)
– Attention span (digit span)
– Femote memory
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MS Cognitive Impairment: Case Study
• Cognitive impairment as early sign of MS:
– 54 year old woman was referred to our Clinic for
evaluation of memory problems over several
months, including disorientation while driving
and forgetting appointments
– Had to make lists to keep track of daily activities
and appointments
– Also reported unsteady gait, left hand and foot
numbness, and urinary stress incontinence
– Score on the Mayo STMS was 34/38 (normal >29)
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MS Cognitive Impairment: Case Study
• Cognitive testing showed severe deficits in
short-term recall and new verbal learning, and
moderate deficits in visuospatial perception
– All other cognitive domains were normal.
• Brain MRI showed multiple lesions involving
periventricular white matter, internal capsule,
corpus callosum, and brainstem
– Moderate generalized atrophy was present
• Cervical spine MRI showed lesions in medulla,
C1, C6, and T2 levels
• CSF was abnormal, consistent with MS
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MS Cognitive Impairment: Case Study
• Patient was diagnosed with primary progressive
MS and has been followed for last 4 years in a
clinical trial
• Cognitive impairment has slowly progressed
during trial
– She still functions independently, but husband
has looked into hiring a caregiver when he is
away during business trips
• Brain MRIs have shown progressive atrophy during
course of the clinical trial
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MS Cognitive Impairment: Correlation with Disability
• Most MS rating scales do not adequately
assess cognitive function:
– Kurtzke EDSS scale includes cognition
as one of 7 subscales; does not require
quantitative assessment of cognitive function
– Kurtzke EDSS scale is dependent solely
on ambulation at range where cognitive
impairment often becomes evident
(EDSS 4.0 and above)
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MS Cognitive Impairment: Correlation with Disability
– MS Functional Composite (MSFC) includes
cognition as one of 3 independent variables:
» Uses PASAT 3 test which is quantitative and is
converted into a “Z” score
» Provides better assessment of cognitive
function than Kurtzke scale
» Increases “weight” of cognitive dysfunction in
determining disability
» Major drawback is lack of “intuitive” nature of
score and lack of uniform acceptance
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MS Cognitive Impairment: Correlation with Disability
• Frequency and severity of cognitive dysfunction
does increase with increasing physical
disability; but correlation is poor:
– Patients with progressive MS and
predominantly spinal cord disease may have
advanced disability but normal cognition
– Patients with minimal physical disability but
extensive white matter disease on brain MRI
may have severe cognitive impairment
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MS Cognitive Impairment: Correlation with Disability
• Presence of CI is single most important
determinant of employability in MS patients
• Presence of CI correlates with decreased
social functioning, greater caregiver stress
and “burnout”
• Presence of CI may also interfere with health
care decisions including poor compliance
with treatments, unrealistic expectations of
treatments, and irrational reliance on
“alternative” treatments
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“Red Flags” for Presence of Cognitive Impairment*
• Difficulty relaying coherent medical history
• Caregiver gives most of medical history
• Frequently misses appointments
• Appears depressed/withdrawn but fails to
respond to antidepressants
• Large burden of T2 lesions on MRI
• Significant cerebral atrophy on MRI
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*Adapted from Bourdette; "Cognitive
Dysfunction in MS", 2001
MS Cognitive Impairment: MRI Correlation
• Cognitive impairment correlates with:
– T2 cerebral lesion volume
– Cerebral atrophy measures:
» Brain Parenchymal Fraction (BPF)
» Lateral ventricular and
3rd ventricular volumes
» Thickness of corpus callosum
– T1 “black hole” lesion volume
– Juxta-cortical lesion volume
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MS Cognitive Impairment: MRI Correlation
• Cerebral atrophy and cognitive impairment
found in up to 50% of early RRMS patients:*
– Rate of development of cerebral
atrophy found to be greatest predictor
of cognitive decline
– Development of cerebral atrophy also
correlated with EDSS progression
– Other studies have found rate of T2
lesion volume to be strongest predictor
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*Zivadinov et al; JNNP; 2001
MS Cognitive Impairment: MRI Correlation
• Changes in normal-appearing white matter (NAWM)
have correlated strongly with CI:
– Magnetization transfer (MT) analysis of NAWM
shows abnormalities not visible on conventional MRI
– One study showed that 68% of total variance in CI
was explained by MT abnormalities in NAWM;
making this more important than T1 lesion load,
T2 lesion load, or brain volume in determining CI
– Global and regional cortical metabolism of glucose
also correlates with CI and with total lesion area
on MRI
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MS Cognitive Impairment: Diagnosis
• Screening Neuropsychological test batteries have
been developed for MS:
– “Brief Repeatable Battery”(BRB) by Rao includes:*
»
Verbal immediate and delayed recall
»
Spatial immediate and delayed recall
»
Complex attention, concentration, and speed
and accuracy in visual search and scanning
»
Sustained attention (PASAT)
»
Verbal associative fluency
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*Rao and the Cognitive Function
Study Group, NMSS; 1990
MS Cognitive Impairment: Diagnosis
– More comprehensive Neuropsychological
batteries require 2-4 hours to administer
– Screening instruments designed for
dementia such as the Mini-Mental Status
Exam are very insensitive to MS
cognitive impairment
– PASAT-3 has been incorporated into the MS
Functional Composite now used as outcome
measure in some MS Clinical trials
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MS Cognitive Impairment: Diagnosis
• Other confounding variables need to
be investigated:
– Many symptomatic MS drugs may have
cognitive side effects; including Baclofen,
Zanaflex, Tegretol, Neurontin, Clonazepam
– Untreated depression may produce
cognitive slowing that can mimic MS CI
– Cognitive function may worsen during
relapse and improve following recovery
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MS Therapies and Cognitive Impairment
• Phase III Avonex (Interferon β1a) study:
– Found significant treatment effects on memory
and information processing, and trends in
visuospatial abilities and executive functions
– No significant treatment effects seen in verbal
abilities or attention span
– % of patients improved, stable, or worse
with serial cognitive testing over 2 years
favored Avonex group (40% reduction in
sustained worsening)
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MS Therapies and Cognitive Impairment
– % of patients who showed sustained changes in
PASAT processing speed also favored Avonex
group (47% reduction in sustained worsening)
– Phase III Avonex study showed reduction in rate
of development of cerebral atrophy on MRI during
second year of study in Avonex patients, which
correlated with changes in cognitive function
– Other β-IFN clinical trials (Betaseron, Rebif)
haven’t addressed cognitive dysfunction
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MS Therapies and Cognitive Impairment
• Phase III glatiramer acetate (GA) study:
– Failed to show treatment effect of GA on
cognitive test battery over 2 years
– Placebo group showed no decline in
cognitive function during study
– Therefore opportunity to show treatment
effect may have been missed
– Effects of GA on T2 lesion volume and T1
black holes would suggest positive effect
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Treatment for Cognitive Impairment
• 12-week, open label trial of Donepezil (Aricept) in
MS cognitive impairment:
– 17 patients in long-term care facility with MMSE
scores <25 (moderate to severe impairment)
– MMSE scores improved at weeks 4 and 12
(maximum increase in mean score of 5.7)
– Attention, naming, verbal fluency, visual recognition
memory, and conceptualization also improved
– Major limitations were lack of control group and
likelihood of practice effect with frequent testing
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Treatment of Cognitive Impairment
– Other limitations include small sample size,
selection of nursing home residents, selection
of patients with severe cognitive impairment
– Results of preliminary studies have led to a
multi-center, double blind, placebo-controlled,
randomized clinical trial of Donepezil vs
placebo, which is currently ongoing
– Mechanism of MS CI different enough from AD
that cholinesterase inhibitors may not work
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Treatment of Cognitive Impairment
• Other pilot studies have failed to show
benefit in treatment of MS CI:
– Amantadine
– Pemoline (Cylert)
– 4-Aminopyridine
• These studies based on theory of “cognitive
fatigue” which has been shown by several
authors to be important in MS
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MS Cognitive Impairment: Conclusions
• Measurable cognitive impairment present from
early stages of MS
• Cognitive impairment is not usually disabling
until later in course of MS and is highly variable
• Cognitive impairment in MS is underrecognized by health care professionals
• Early treatment with disease-modifying
therapies is best preventative measure
at present
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MS Cognitive Impairment: Conclusions
• Further treatment trials for therapies
designed for established cognitive
impairment are needed
• Other confounding variables such as
untreated depression and cognitive
side-effects of common MS drugs need
to be recognized and treated
• Family members and caregivers need to
be counseled on the impact of cognitive
impairment on the MS patient and their family
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