Multiple Sclerosis
and the Mind:
Memory Loss and
Cognitive Impairment
Jonathan L. Carter MD
Director
Mayo Clinic Scottsdale MS Center
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Outline
Frequency of Memory Impairment in MS
Patterns of Memory Impairment in MS
Correlation with Progression of Physical Disability
Correlation with MRI Findings
Diagnosis and Treatment of Memory Impairment
Memory Impairment and Family/Caregiver
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MS Cognitive Impairment: Frequency
• Community-based studies: Estimated
frequency of 43-46% in unselected
MS patients
• MS specialty clinic or hospitalized
patients: estimated frequency of 50-60%
• Frequency depends on how cognitive
impairment is defined and how carefully
it is looked for
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MS Cognitive Impairment: Frequency
Frequency of Impairment in Specific Areas
Language
8-9%
Visuospatial abilities
12-19%
Attention span
7-8%
Information processing
22-25%
Memory
22-31%
Problem solving
13-19%
Defined as % of MS patients scoring
<5th percentile for normal population
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Rao et al. Neurology 1991
MS Cognitive Impairment: Patterns
• Cognitive areas frequently affected in MS:
– Recent memory (short-term 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 learned and stored but
difficult to retrieve without cues
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MS Cognitive Impairment: Patterns
• Cognitive areas not frequently
affected in MS:
– Language (receptive
and expressive)
– Attention span (digit span)
– Remote memory
(long-term memory)
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MS Cognitive Impairment: Case Study
• Cognitive symptoms 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 walking, left hand and
foot numbness and urinary incontinence
– Score on the Mayo Short Test of Mental Status
was 34/38 (normal >29)
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MS Cognitive Impairment: Case Study
• Cognitive testing showed severe problems with
short-term memory and new verbal learning and
moderate problems with visuospatial perception
– All other cognitive areas were normal
• Brain MRI showed multiple lesions involving the
white matter, and moderate generalized atrophy
(shrinkage of the brain)
• Cervical spine MRI showed lesions at several
levels in the spinal cord
• Spinal tap was abnormal, consistent with MS
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MS Cognitive Impairment: Case Study
• Diagnosed with primary progressive MS and has
been followed for last 4 years in a clinical trial
• Cognitive impairment has slowly progressed
during trial
– Still functions independently, but husband has
looked into hiring a caregiver when he is away
during business trips
• Brain MRIs have shown progressive atrophy
(shrinkage of the brain) 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:
– EDSS scale includes cognition as one of
7 subscales; does not require quantitative
assessment of cognitive function
– EDSS scale is dependent solely on
walking ability 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:
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Uses PASAT 3 test which is quantitative
Provides better assessment of cognitive function
than EDSS scale
Increases “weight” of cognitive dysfunction in
determining disability
– Major drawback is lack of uniform acceptance of
MSFC, and greater complexity than single scale
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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
cognitive function
– Patients with minimal physical disability but
extensive white matter lesions 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 excessive reliance on
“alternative” or unproven 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 lesion volume (total volume
of white matter spots or lesions)
– Brain atrophy (shrinkage) measures
– T1 “black hole” lesion volume
(volume of destructive lesions)
– Juxta-cortical lesion volume
(lesions near surface of brain)
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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 disability progression
– Other studies have found rate increase in
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
• More comprehensive Neuropsychological
batteries require 2-4 hours to administer
• Screening tests designed for Alzheimer’s
such as the Mini-Mental Status Exam are
insensitive to MS cognitive impairment
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MS Cognitive Impairment: Diagnosis
• Other factors may 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
cognitive impairment
– 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 cognitive processing speed also favored
Avonex group (47% reduction in worsening)
– Phase III Avonex study showed reduction in
rate of development of cerebral atrophy on
MRI during second yr of study in Avonex
patients, which correlated with changes in
cognitive function
– Betaseron and Rebif clinical trials haven’t
addressed cognitive dysfunction adequately
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MS Therapies and Cognitive Impairment
• Phase III Copaxone study
– Failed to show treatment effect of Copaxone
on cognitive tests over 2 years on study
– Placebo group showed no decline in cognitive
function during study
– Therefore opportunity to show treatment
effect may have been missed
– Effects of Copaxone on MRI measures would
suggest positive effect, but not proven
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Treatment for Cognitive Impairment
• 12-week, open label trial of Aricept in
MS cognitive impairment:
– 17 patients in long-term care facility with moderate
to severe impairment (MMSE score <25)
– MMSE scores improved at weeks 4 and 12
– 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 Aricept
– Mechanism of MS cognitive impairment is
different enough from Alzheimer’s that same
drugs 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 (Symmetrel)
– Pemoline (Cylert)
– 4-Aminopyridine (Fampridine)
• These studies based on the idea that
“Cognitive fatigue” is important in MS
cognitive impairment, which has been
suggested by several studies
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MS Cognitive Impairment and the Family/Caregiver
• Cognitive impairment causes increased stress
on the family or caregiver
• MS patients with CI . . .
– Less likely to be employed
– Need greater assistance in daily activities
and may not be safe to leave alone
– More likely to have mood disturbances
and depression
– More likely to be socially isolated
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MS Cognitive Impairment and the Family/Caregiver
• Family members or caregivers should:
– Discuss issues of cognitive impairment with
health care professionals at appointments
– Accompany patient to appointments to ensure
that instructions are understood and carried out
– Seek respite care where possible if cognitive
impairment is severe
– Seek support or counseling if caregiving duties
become overwhelming
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MS Cognitive Impairment: Conclusions
• Measurable cognitive impairment may be present
from early stages of MS
• Cognitive impairment is not usually disabling until
later in the course of MS and is highly variable
• Cognitive impairment in MS is under-recognized
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 factors 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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