JLC020303 Multiple Sclerosis and the Mind: Memory Loss and Cognitive Impairment Jonathan L. Carter MD Director Mayo Clinic Scottsdale MS Center Jonathan.

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Multiple Sclerosis Multiple Sclerosis and the Mind:and the Mind:

Memory Loss and Memory Loss and Cognitive ImpairmentCognitive Impairment

Multiple Sclerosis Multiple Sclerosis and the Mind:and the Mind:

Memory Loss and Memory Loss and Cognitive ImpairmentCognitive Impairment

Jonathan L. Carter MDJonathan L. Carter MD

DirectorDirector

Mayo Clinic Scottsdale MS CenterMayo Clinic Scottsdale MS Center

Jonathan L. Carter MDJonathan L. Carter MD

DirectorDirector

Mayo Clinic Scottsdale MS CenterMayo Clinic Scottsdale MS Center

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OutlineOutlineOutlineOutline

Frequency of Memory Impairment in MSFrequency of Memory Impairment in MS

Patterns of Memory Impairment in MSPatterns of Memory Impairment in MS

Correlation with Progression of Physical DisabilityCorrelation with Progression of Physical Disability

Correlation with MRI FindingsCorrelation with MRI Findings

Diagnosis and Treatment of Memory ImpairmentDiagnosis and Treatment of Memory Impairment

Memory Impairment and Family/CaregiverMemory Impairment and Family/Caregiver

Frequency of Memory Impairment in MSFrequency of Memory Impairment in MS

Patterns of Memory Impairment in MSPatterns of Memory Impairment in MS

Correlation with Progression of Physical DisabilityCorrelation with Progression of Physical Disability

Correlation with MRI FindingsCorrelation with MRI Findings

Diagnosis and Treatment of Memory ImpairmentDiagnosis and Treatment of Memory Impairment

Memory Impairment and Family/CaregiverMemory Impairment and Family/Caregiver

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MS Cognitive Impairment: FrequencyMS Cognitive Impairment: FrequencyMS Cognitive Impairment: FrequencyMS Cognitive Impairment: Frequency

• Community-based studies: Estimated Community-based studies: Estimated frequency of 43-46% in unselected frequency of 43-46% in unselected MS patientsMS patients

• MS specialty clinic or hospitalized MS specialty clinic or hospitalized patients: estimated frequency of 50-60%patients: estimated frequency of 50-60%

• Frequency depends on how cognitive Frequency depends on how cognitive impairment is defined and how carefully impairment is defined and how carefully it is looked forit is looked for

• Community-based studies: Estimated Community-based studies: Estimated frequency of 43-46% in unselected frequency of 43-46% in unselected MS patientsMS patients

• MS specialty clinic or hospitalized MS specialty clinic or hospitalized patients: estimated frequency of 50-60%patients: estimated frequency of 50-60%

• Frequency depends on how cognitive Frequency depends on how cognitive impairment is defined and how carefully impairment is defined and how carefully it is looked forit is looked for

Rao et al. Neurology 1991JLC020303

MS Cognitive Impairment: FrequencyMS Cognitive Impairment: FrequencyMS Cognitive Impairment: FrequencyMS Cognitive Impairment: Frequency

Frequency of Impairment in Specific AreasFrequency of Impairment in Specific Areas

LanguageLanguage 8-9%8-9%

Visuospatial abilitiesVisuospatial abilities 12-19%12-19%

Attention spanAttention span 7-8%7-8%

Information processingInformation processing 22-25%22-25%

MemoryMemory 22-31%22-31%

Problem solvingProblem solving 13-19% 13-19%

Defined as % of MS patients scoring Defined as % of MS patients scoring <5th percentile for normal population<5th percentile for normal population

Frequency of Impairment in Specific AreasFrequency of Impairment in Specific Areas

LanguageLanguage 8-9%8-9%

Visuospatial abilitiesVisuospatial abilities 12-19%12-19%

Attention spanAttention span 7-8%7-8%

Information processingInformation processing 22-25%22-25%

MemoryMemory 22-31%22-31%

Problem solvingProblem solving 13-19% 13-19%

Defined as % of MS patients scoring Defined as % of MS patients scoring <5th percentile for normal population<5th percentile for normal population

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MS Cognitive Impairment: PatternsMS Cognitive Impairment: PatternsMS Cognitive Impairment: PatternsMS Cognitive Impairment: Patterns

• Cognitive areas frequently affected in MS:Cognitive areas frequently affected in MS:

– Recent memory (short-term memory)Recent memory (short-term memory)

– Abstract reasoningAbstract reasoning

– Verbal fluencyVerbal fluency

– Sustained attention (especially with Sustained attention (especially with multiple-tasks)multiple-tasks)

– Visuospatial perception Visuospatial perception

• Cognitive areas frequently affected in MS:Cognitive areas frequently affected in MS:

– Recent memory (short-term memory)Recent memory (short-term memory)

– Abstract reasoningAbstract reasoning

– Verbal fluencyVerbal fluency

– Sustained attention (especially with Sustained attention (especially with multiple-tasks)multiple-tasks)

– Visuospatial perception Visuospatial perception

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• MS memory impairment:MS memory impairment:– Unlike Alzheimer’s, MS patients learn Unlike Alzheimer’s, MS patients learn

when presented with multiple trials of when presented with multiple trials of same materialsame material

– Unlike Alzheimer’s, MS patients Unlike Alzheimer’s, MS patients perform better on recognition tests perform better on recognition tests than free recall tests; suggesting than free recall tests; suggesting information is learned and stored but information is learned and stored but difficult to retrieve without cuesdifficult to retrieve without cues

• MS memory impairment:MS memory impairment:– Unlike Alzheimer’s, MS patients learn Unlike Alzheimer’s, MS patients learn

when presented with multiple trials of when presented with multiple trials of same materialsame material

– Unlike Alzheimer’s, MS patients Unlike Alzheimer’s, MS patients perform better on recognition tests perform better on recognition tests than free recall tests; suggesting than free recall tests; suggesting information is learned and stored but information is learned and stored but difficult to retrieve without cuesdifficult to retrieve without cues

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• Cognitive areas not frequently Cognitive areas not frequently affected in MS:affected in MS:– Language (receptive Language (receptive

and expressive)and expressive)– Attention span (digit span)Attention span (digit span)– Remote memory Remote memory

(long-term memory)(long-term memory)

• Cognitive areas not frequently Cognitive areas not frequently affected in MS:affected in MS:– Language (receptive Language (receptive

and expressive)and expressive)– Attention span (digit span)Attention span (digit span)– Remote memory Remote memory

(long-term memory)(long-term memory)

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MS Cognitive Impairment: Case StudyMS Cognitive Impairment: Case StudyMS Cognitive Impairment: Case StudyMS Cognitive Impairment: Case Study

• Cognitive symptoms as early sign of MS:Cognitive symptoms as early sign of MS:

– 54 year old woman was referred to our Clinic for 54 year old woman was referred to our Clinic for evaluation of memory problems over several evaluation of memory problems over several months, including disorientation while driving and months, including disorientation while driving and forgetting appointmentsforgetting appointments

– Had to make lists to keep track of daily activities and Had to make lists to keep track of daily activities and appointmentsappointments

– Also reported unsteady walking, left hand andAlso reported unsteady walking, left hand andfoot numbness and urinary incontinencefoot numbness and urinary incontinence

– Score on the Mayo Short Test of Mental Status was Score on the Mayo Short Test of Mental Status was 34/38 (normal >29) 34/38 (normal >29)

• Cognitive symptoms as early sign of MS:Cognitive symptoms as early sign of MS:

– 54 year old woman was referred to our Clinic for 54 year old woman was referred to our Clinic for evaluation of memory problems over several evaluation of memory problems over several months, including disorientation while driving and months, including disorientation while driving and forgetting appointmentsforgetting appointments

– Had to make lists to keep track of daily activities and Had to make lists to keep track of daily activities and appointmentsappointments

– Also reported unsteady walking, left hand andAlso reported unsteady walking, left hand andfoot numbness and urinary incontinencefoot numbness and urinary incontinence

– Score on the Mayo Short Test of Mental Status was Score on the Mayo Short Test of Mental Status was 34/38 (normal >29) 34/38 (normal >29)

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• Cognitive testing showed severe problems with Cognitive testing showed severe problems with short-term memory and new verbal learning and short-term memory and new verbal learning and moderate problems with visuospatial perceptionmoderate problems with visuospatial perception– All other cognitive areas were normalAll other cognitive areas were normal

• Brain MRI showed multiple lesions involving the Brain MRI showed multiple lesions involving the white matter, and moderate generalized atrophy white matter, and moderate generalized atrophy (shrinkage of the brain) (shrinkage of the brain)

• Cervical spine MRI showed lesions at several Cervical spine MRI showed lesions at several levels in the spinal cordlevels in the spinal cord

• Spinal tap was abnormal, consistent with MSSpinal tap was abnormal, consistent with MS

• Cognitive testing showed severe problems with Cognitive testing showed severe problems with short-term memory and new verbal learning and short-term memory and new verbal learning and moderate problems with visuospatial perceptionmoderate problems with visuospatial perception– All other cognitive areas were normalAll other cognitive areas were normal

• Brain MRI showed multiple lesions involving the Brain MRI showed multiple lesions involving the white matter, and moderate generalized atrophy white matter, and moderate generalized atrophy (shrinkage of the brain) (shrinkage of the brain)

• Cervical spine MRI showed lesions at several Cervical spine MRI showed lesions at several levels in the spinal cordlevels in the spinal cord

• Spinal tap was abnormal, consistent with MSSpinal tap was abnormal, consistent with MS

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• Diagnosed with primary progressive MS and has Diagnosed with primary progressive MS and has been followed for last 4 years in a clinical trialbeen followed for last 4 years in a clinical trial

• Cognitive impairment has slowly progressed Cognitive impairment has slowly progressed during trialduring trial– Still functions independently, but husband has Still functions independently, but husband has

looked into hiring a caregiver when he is away looked into hiring a caregiver when he is away during business tripsduring business trips

• Brain MRIs have shown progressive atrophy Brain MRIs have shown progressive atrophy (shrinkage of the brain) during course of the (shrinkage of the brain) during course of the clinical trialclinical trial

• Diagnosed with primary progressive MS and has Diagnosed with primary progressive MS and has been followed for last 4 years in a clinical trialbeen followed for last 4 years in a clinical trial

• Cognitive impairment has slowly progressed Cognitive impairment has slowly progressed during trialduring trial– Still functions independently, but husband has Still functions independently, but husband has

looked into hiring a caregiver when he is away looked into hiring a caregiver when he is away during business tripsduring business trips

• Brain MRIs have shown progressive atrophy Brain MRIs have shown progressive atrophy (shrinkage of the brain) during course of the (shrinkage of the brain) during course of the clinical trialclinical trial

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MS Cognitive Impairment: Correlation with DisabilityMS Cognitive Impairment: Correlation with Disability MS Cognitive Impairment: Correlation with DisabilityMS Cognitive Impairment: Correlation with Disability

• Most MS rating scales do not adequately Most MS rating scales do not adequately assess cognitive function:assess cognitive function:– EDSS scale includes cognition as one of EDSS scale includes cognition as one of

7 subscales; does not require quantitative 7 subscales; does not require quantitative assessment of cognitive functionassessment of cognitive function

– EDSS scale is dependent solely on EDSS scale is dependent solely on walking ability at range where cognitive walking ability at range where cognitive impairment often becomes evident impairment often becomes evident (EDSS 4.0 and above)(EDSS 4.0 and above)

• Most MS rating scales do not adequately Most MS rating scales do not adequately assess cognitive function:assess cognitive function:– EDSS scale includes cognition as one of EDSS scale includes cognition as one of

7 subscales; does not require quantitative 7 subscales; does not require quantitative assessment of cognitive functionassessment of cognitive function

– EDSS scale is dependent solely on EDSS scale is dependent solely on walking ability at range where cognitive walking ability at range where cognitive impairment often becomes evident impairment often becomes evident (EDSS 4.0 and above)(EDSS 4.0 and above)

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MS Cognitive Impairment: Correlation with DisabilityMS Cognitive Impairment: Correlation with DisabilityMS Cognitive Impairment: Correlation with DisabilityMS Cognitive Impairment: Correlation with Disability

– MS Functional Composite (MSFC) includes MS Functional Composite (MSFC) includes cognition as one of 3 independent variables:cognition as one of 3 independent variables:

» Uses PASAT 3 test which is quantitative Uses PASAT 3 test which is quantitative

» Provides better assessment of cognitive function Provides better assessment of cognitive function than EDSS scalethan EDSS scale

» Increases “weight” of cognitive dysfunction in Increases “weight” of cognitive dysfunction in determining disabilitydetermining disability

– Major drawback is lack of uniform acceptance of Major drawback is lack of uniform acceptance of MSFC, and greater complexity than single scaleMSFC, and greater complexity than single scale

– MS Functional Composite (MSFC) includes MS Functional Composite (MSFC) includes cognition as one of 3 independent variables:cognition as one of 3 independent variables:

» Uses PASAT 3 test which is quantitative Uses PASAT 3 test which is quantitative

» Provides better assessment of cognitive function Provides better assessment of cognitive function than EDSS scalethan EDSS scale

» Increases “weight” of cognitive dysfunction in Increases “weight” of cognitive dysfunction in determining disabilitydetermining disability

– Major drawback is lack of uniform acceptance of Major drawback is lack of uniform acceptance of MSFC, and greater complexity than single scaleMSFC, and greater complexity than single scale

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• Frequency and severity of cognitive dysfunction Frequency and severity of cognitive dysfunction does increase with increasing physical disability; does increase with increasing physical disability; but correlation is poor:but correlation is poor:

– Patients with progressive MS and Patients with progressive MS and predominantly spinal cord disease may predominantly spinal cord disease may have advanced disability but normal have advanced disability but normal cognitive functioncognitive function

– Patients with minimal physical disability but Patients with minimal physical disability but extensive white matter lesions on brain MRI extensive white matter lesions on brain MRI may have severe cognitive impairment may have severe cognitive impairment

• Frequency and severity of cognitive dysfunction Frequency and severity of cognitive dysfunction does increase with increasing physical disability; does increase with increasing physical disability; but correlation is poor:but correlation is poor:

– Patients with progressive MS and Patients with progressive MS and predominantly spinal cord disease may predominantly spinal cord disease may have advanced disability but normal have advanced disability but normal cognitive functioncognitive function

– Patients with minimal physical disability but Patients with minimal physical disability but extensive white matter lesions on brain MRI extensive white matter lesions on brain MRI may have severe cognitive impairment may have severe cognitive impairment

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• Presence of CI is single most important Presence of CI is single most important determinant of employability in MS patientsdeterminant of employability in MS patients

• Presence of CI correlates with decreased Presence of CI correlates with decreased social functioning, greater caregiver stress social functioning, greater caregiver stress and “burnout”and “burnout”

• Presence of CI may also interfere with health Presence of CI may also interfere with health care decisions including poor compliance with care decisions including poor compliance with treatments, unrealistic expectations of treatments, unrealistic expectations of treatments, and excessive reliance on treatments, and excessive reliance on “alternative” or unproven treatments “alternative” or unproven treatments

• Presence of CI is single most important Presence of CI is single most important determinant of employability in MS patientsdeterminant of employability in MS patients

• Presence of CI correlates with decreased Presence of CI correlates with decreased social functioning, greater caregiver stress social functioning, greater caregiver stress and “burnout”and “burnout”

• Presence of CI may also interfere with health Presence of CI may also interfere with health care decisions including poor compliance with care decisions including poor compliance with treatments, unrealistic expectations of treatments, unrealistic expectations of treatments, and excessive reliance on treatments, and excessive reliance on “alternative” or unproven treatments “alternative” or unproven treatments

*Adapted from Bourdette; "Cognitive Dysfunction in MS", 2001

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““Red Flags” for Presence of Cognitive Impairment*Red Flags” for Presence of Cognitive Impairment*““Red Flags” for Presence of Cognitive Impairment*Red Flags” for Presence of Cognitive Impairment*

• Difficulty relaying coherent medical historyDifficulty relaying coherent medical history

• Caregiver gives most of medical historyCaregiver gives most of medical history

• Frequently misses appointmentsFrequently misses appointments

• Appears depressed/withdrawn but fails to Appears depressed/withdrawn but fails to respond to antidepressantsrespond to antidepressants

• Large burden of T2 lesions on MRILarge burden of T2 lesions on MRI

• Significant cerebral atrophy on MRISignificant cerebral atrophy on MRI

• Difficulty relaying coherent medical historyDifficulty relaying coherent medical history

• Caregiver gives most of medical historyCaregiver gives most of medical history

• Frequently misses appointmentsFrequently misses appointments

• Appears depressed/withdrawn but fails to Appears depressed/withdrawn but fails to respond to antidepressantsrespond to antidepressants

• Large burden of T2 lesions on MRILarge burden of T2 lesions on MRI

• Significant cerebral atrophy on MRISignificant cerebral atrophy on MRI

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MS Cognitive Impairment: MRI CorrelationMS Cognitive Impairment: MRI CorrelationMS Cognitive Impairment: MRI CorrelationMS Cognitive Impairment: MRI Correlation

• Cognitive impairment correlates with:Cognitive impairment correlates with:– T2 lesion volume (total volume T2 lesion volume (total volume

of white matter spots or lesions)of white matter spots or lesions)– Brain atrophy (shrinkage) measuresBrain atrophy (shrinkage) measures– T1 “black hole” lesion volume T1 “black hole” lesion volume

(volume of destructive lesions)(volume of destructive lesions)– Juxta-cortical lesion volume Juxta-cortical lesion volume

(lesions near surface of brain)(lesions near surface of brain)

• Cognitive impairment correlates with:Cognitive impairment correlates with:– T2 lesion volume (total volume T2 lesion volume (total volume

of white matter spots or lesions)of white matter spots or lesions)– Brain atrophy (shrinkage) measuresBrain atrophy (shrinkage) measures– T1 “black hole” lesion volume T1 “black hole” lesion volume

(volume of destructive lesions)(volume of destructive lesions)– Juxta-cortical lesion volume Juxta-cortical lesion volume

(lesions near surface of brain)(lesions near surface of brain)

*Zivadinov et al; JNNP; 2001JLC020303


• Cerebral atrophy and cognitive impairment Cerebral atrophy and cognitive impairment found in up to 50% of early RRMS patients:*found in up to 50% of early RRMS patients:*– Rate of development of cerebral atrophy Rate of development of cerebral atrophy

found to be greatest predictor of found to be greatest predictor of cognitive declinecognitive decline

– Development of cerebral atrophy also Development of cerebral atrophy also correlated with disability progressioncorrelated with disability progression

– Other studies have found rate increase in Other studies have found rate increase in T2 lesion volume to be strongest predictorT2 lesion volume to be strongest predictor

• Cerebral atrophy and cognitive impairment Cerebral atrophy and cognitive impairment found in up to 50% of early RRMS patients:*found in up to 50% of early RRMS patients:*– Rate of development of cerebral atrophy Rate of development of cerebral atrophy

found to be greatest predictor of found to be greatest predictor of cognitive declinecognitive decline

– Development of cerebral atrophy also Development of cerebral atrophy also correlated with disability progressioncorrelated with disability progression

– Other studies have found rate increase in Other studies have found rate increase in T2 lesion volume to be strongest predictorT2 lesion volume to be strongest predictor

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• Changes in normal-appearing white matter (NAWM) Changes in normal-appearing white matter (NAWM) have correlated strongly with CI:have correlated strongly with CI:

– Magnetization transfer (MT) analysis of NAWM Magnetization transfer (MT) analysis of NAWM shows abnormalities not visible on conventional MRIshows abnormalities not visible on conventional MRI

– One study showed that 68% of total variance in CI One study showed that 68% of total variance in CI was explained by MT abnormalities in NAWM; was explained by MT abnormalities in NAWM; making this more important than T1 lesion load, making this more important than T1 lesion load, T2 lesion load, or brain volume in determining CIT2 lesion load, or brain volume in determining CI

– Global and regional cortical metabolism of glucose Global and regional cortical metabolism of glucose also correlates with CI and with total lesion area also correlates with CI and with total lesion area on MRI on MRI

• Changes in normal-appearing white matter (NAWM) Changes in normal-appearing white matter (NAWM) have correlated strongly with CI:have correlated strongly with CI:

– Magnetization transfer (MT) analysis of NAWM Magnetization transfer (MT) analysis of NAWM shows abnormalities not visible on conventional MRIshows abnormalities not visible on conventional MRI

– One study showed that 68% of total variance in CI One study showed that 68% of total variance in CI was explained by MT abnormalities in NAWM; was explained by MT abnormalities in NAWM; making this more important than T1 lesion load, making this more important than T1 lesion load, T2 lesion load, or brain volume in determining CIT2 lesion load, or brain volume in determining CI

– Global and regional cortical metabolism of glucose Global and regional cortical metabolism of glucose also correlates with CI and with total lesion area also correlates with CI and with total lesion area on MRI on MRI

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MS Cognitive Impairment: DiagnosisMS Cognitive Impairment: DiagnosisMS Cognitive Impairment: DiagnosisMS Cognitive Impairment: Diagnosis

• Screening Neuropsychological test Screening Neuropsychological test batteries have been developed for MSbatteries have been developed for MS

• More comprehensive Neuropsychological More comprehensive Neuropsychological batteries require 2-4 hours to administerbatteries require 2-4 hours to administer

• Screening tests designed for Alzheimer’s Screening tests designed for Alzheimer’s such as the Mini-Mental Status Exam are such as the Mini-Mental Status Exam are insensitive to MS cognitive impairmentinsensitive to MS cognitive impairment

• Screening Neuropsychological test Screening Neuropsychological test batteries have been developed for MSbatteries have been developed for MS

• More comprehensive Neuropsychological More comprehensive Neuropsychological batteries require 2-4 hours to administerbatteries require 2-4 hours to administer

• Screening tests designed for Alzheimer’s Screening tests designed for Alzheimer’s such as the Mini-Mental Status Exam are such as the Mini-Mental Status Exam are insensitive to MS cognitive impairmentinsensitive to MS cognitive impairment

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MS Cognitive Impairment: DiagnosisMS Cognitive Impairment: DiagnosisMS Cognitive Impairment: DiagnosisMS Cognitive Impairment: Diagnosis

• Other factors may need to be investigated:Other factors may need to be investigated:– Many symptomatic MS drugs may have Many symptomatic MS drugs may have

cognitive side effects; including Baclofen, cognitive side effects; including Baclofen, Zanaflex, Tegretol, Neurontin, ClonazepamZanaflex, Tegretol, Neurontin, Clonazepam

– Untreated depression may produce Untreated depression may produce cognitive slowing that can mimic cognitive slowing that can mimic cognitive impairmentcognitive impairment

– Cognitive function may worsen during Cognitive function may worsen during relapse and improve following recoveryrelapse and improve following recovery

• Other factors may need to be investigated:Other factors may need to be investigated:– Many symptomatic MS drugs may have Many symptomatic MS drugs may have

cognitive side effects; including Baclofen, cognitive side effects; including Baclofen, Zanaflex, Tegretol, Neurontin, ClonazepamZanaflex, Tegretol, Neurontin, Clonazepam

– Untreated depression may produce Untreated depression may produce cognitive slowing that can mimic cognitive slowing that can mimic cognitive impairmentcognitive impairment

– Cognitive function may worsen during Cognitive function may worsen during relapse and improve following recoveryrelapse and improve following recovery

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MS Therapies and Cognitive ImpairmentMS Therapies and Cognitive ImpairmentMS Therapies and Cognitive ImpairmentMS Therapies and Cognitive Impairment

• Phase III Avonex (Interferon β1a) study:Phase III Avonex (Interferon β1a) study:

– Found significant treatment effects on memory Found significant treatment effects on memory and information processing, and trends in and information processing, and trends in visuospatial abilities and executive functionsvisuospatial abilities and executive functions

– No significant treatment effects seen in verbal No significant treatment effects seen in verbal abilities or attention span abilities or attention span

– % of patients improved, stable, or worse % of patients improved, stable, or worse with serial cognitive testing over 2 years with serial cognitive testing over 2 years favored Avonex group (40% reduction in favored Avonex group (40% reduction in sustained worsening)sustained worsening)

• Phase III Avonex (Interferon β1a) study:Phase III Avonex (Interferon β1a) study:

– Found significant treatment effects on memory Found significant treatment effects on memory and information processing, and trends in and information processing, and trends in visuospatial abilities and executive functionsvisuospatial abilities and executive functions

– No significant treatment effects seen in verbal No significant treatment effects seen in verbal abilities or attention span abilities or attention span

– % of patients improved, stable, or worse % of patients improved, stable, or worse with serial cognitive testing over 2 years with serial cognitive testing over 2 years favored Avonex group (40% reduction in favored Avonex group (40% reduction in sustained worsening)sustained worsening)

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– % of patients who showed sustained changes % of patients who showed sustained changes in cognitive processing speed also favored in cognitive processing speed also favored Avonex group (47% reduction in worsening)Avonex group (47% reduction in worsening)

– Phase III Avonex study showed reduction in Phase III Avonex study showed reduction in rate of development of cerebral atrophy on rate of development of cerebral atrophy on MRI during second yr of study in Avonex MRI during second yr of study in Avonex patients, which correlated with changes in patients, which correlated with changes in cognitive functioncognitive function

– Betaseron and Rebif clinical trials haven’t Betaseron and Rebif clinical trials haven’t addressed cognitive dysfunction adequatelyaddressed cognitive dysfunction adequately

– % of patients who showed sustained changes % of patients who showed sustained changes in cognitive processing speed also favored in cognitive processing speed also favored Avonex group (47% reduction in worsening)Avonex group (47% reduction in worsening)

– Phase III Avonex study showed reduction in Phase III Avonex study showed reduction in rate of development of cerebral atrophy on rate of development of cerebral atrophy on MRI during second yr of study in Avonex MRI during second yr of study in Avonex patients, which correlated with changes in patients, which correlated with changes in cognitive functioncognitive function

– Betaseron and Rebif clinical trials haven’t Betaseron and Rebif clinical trials haven’t addressed cognitive dysfunction adequatelyaddressed cognitive dysfunction adequately

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• Phase III Copaxone studyPhase III Copaxone study

– Failed to show treatment effect of Copaxone Failed to show treatment effect of Copaxone on cognitive tests over 2 years on studyon cognitive tests over 2 years on study

– Placebo group showed no decline in cognitive Placebo group showed no decline in cognitive function during studyfunction during study

– Therefore opportunity to show treatment Therefore opportunity to show treatment effect may have been missedeffect may have been missed

– Effects of Copaxone on MRI measures would Effects of Copaxone on MRI measures would suggest positive effect, but not provensuggest positive effect, but not proven

• Phase III Copaxone studyPhase III Copaxone study

– Failed to show treatment effect of Copaxone Failed to show treatment effect of Copaxone on cognitive tests over 2 years on studyon cognitive tests over 2 years on study

– Placebo group showed no decline in cognitive Placebo group showed no decline in cognitive function during studyfunction during study

– Therefore opportunity to show treatment Therefore opportunity to show treatment effect may have been missedeffect may have been missed

– Effects of Copaxone on MRI measures would Effects of Copaxone on MRI measures would suggest positive effect, but not provensuggest positive effect, but not proven

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Treatment for Cognitive ImpairmentTreatment for Cognitive ImpairmentTreatment for Cognitive ImpairmentTreatment for Cognitive Impairment

• 12-week, open label trial of Aricept in 12-week, open label trial of Aricept in MS cognitive impairment:MS cognitive impairment:– 17 patients in long-term care facility with moderate 17 patients in long-term care facility with moderate

to severe impairment (MMSE score <25)to severe impairment (MMSE score <25)– MMSE scores improved at weeks 4 and 12MMSE scores improved at weeks 4 and 12– Attention, naming, verbal fluency, visual Attention, naming, verbal fluency, visual

recognition memory, and conceptualization recognition memory, and conceptualization also improvedalso improved

– Major limitations were lack of control group and Major limitations were lack of control group and likelihood of practice effect with frequent testinglikelihood of practice effect with frequent testing

• 12-week, open label trial of Aricept in 12-week, open label trial of Aricept in MS cognitive impairment:MS cognitive impairment:– 17 patients in long-term care facility with moderate 17 patients in long-term care facility with moderate

to severe impairment (MMSE score <25)to severe impairment (MMSE score <25)– MMSE scores improved at weeks 4 and 12MMSE scores improved at weeks 4 and 12– Attention, naming, verbal fluency, visual Attention, naming, verbal fluency, visual

recognition memory, and conceptualization recognition memory, and conceptualization also improvedalso improved

– Major limitations were lack of control group and Major limitations were lack of control group and likelihood of practice effect with frequent testinglikelihood of practice effect with frequent testing

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Treatment of Cognitive ImpairmentTreatment of Cognitive ImpairmentTreatment of Cognitive ImpairmentTreatment of Cognitive Impairment

– Other limitations include small sample size, Other limitations include small sample size, selection of nursing home residents, selection selection of nursing home residents, selection of patients with severe cognitive impairmentof patients with severe cognitive impairment

– Results of preliminary studies have led to a Results of preliminary studies have led to a multi-center, double blind, placebo-controlled, multi-center, double blind, placebo-controlled, randomized clinical trial of Ariceptrandomized clinical trial of Aricept

– Mechanism of MS cognitive impairment is Mechanism of MS cognitive impairment is different enough from Alzheimer’s that same different enough from Alzheimer’s that same drugs may not workdrugs may not work

– Other limitations include small sample size, Other limitations include small sample size, selection of nursing home residents, selection selection of nursing home residents, selection of patients with severe cognitive impairmentof patients with severe cognitive impairment

– Results of preliminary studies have led to a Results of preliminary studies have led to a multi-center, double blind, placebo-controlled, multi-center, double blind, placebo-controlled, randomized clinical trial of Ariceptrandomized clinical trial of Aricept

– Mechanism of MS cognitive impairment is Mechanism of MS cognitive impairment is different enough from Alzheimer’s that same different enough from Alzheimer’s that same drugs may not workdrugs may not work

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Treatment of Cognitive ImpairmentTreatment of Cognitive ImpairmentTreatment of Cognitive ImpairmentTreatment of Cognitive Impairment

• Other pilot studies have failed to show Other pilot studies have failed to show benefit in treatment of MS CI:benefit in treatment of MS CI:– Amantadine (Symmetrel)Amantadine (Symmetrel)– Pemoline (Cylert)Pemoline (Cylert)– 4-Aminopyridine (Fampridine)4-Aminopyridine (Fampridine)

• These studies based on the idea that These studies based on the idea that “Cognitive fatigue” is important in MS “Cognitive fatigue” is important in MS cognitive impairment, which has been cognitive impairment, which has been suggested by several studiessuggested by several studies

• Other pilot studies have failed to show Other pilot studies have failed to show benefit in treatment of MS CI:benefit in treatment of MS CI:– Amantadine (Symmetrel)Amantadine (Symmetrel)– Pemoline (Cylert)Pemoline (Cylert)– 4-Aminopyridine (Fampridine)4-Aminopyridine (Fampridine)

• These studies based on the idea that These studies based on the idea that “Cognitive fatigue” is important in MS “Cognitive fatigue” is important in MS cognitive impairment, which has been cognitive impairment, which has been suggested by several studiessuggested by several studies

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MS Cognitive Impairment and the Family/CaregiverMS Cognitive Impairment and the Family/CaregiverMS Cognitive Impairment and the Family/CaregiverMS Cognitive Impairment and the Family/Caregiver

• Cognitive impairment causes increased stress Cognitive impairment causes increased stress on the family or caregiveron the family or caregiver

• MS patients with CI . . .MS patients with CI . . .

– Less likely to be employedLess likely to be employed

– Need greater assistance in daily activities Need greater assistance in daily activities and may not be safe to leave aloneand may not be safe to leave alone

– More likely to have mood disturbances More likely to have mood disturbances and depressionand depression

– More likely to be socially isolatedMore likely to be socially isolated

• Cognitive impairment causes increased stress Cognitive impairment causes increased stress on the family or caregiveron the family or caregiver

• MS patients with CI . . .MS patients with CI . . .

– Less likely to be employedLess likely to be employed

– Need greater assistance in daily activities Need greater assistance in daily activities and may not be safe to leave aloneand may not be safe to leave alone

– More likely to have mood disturbances More likely to have mood disturbances and depressionand depression

– More likely to be socially isolatedMore likely to be socially isolated

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MS Cognitive Impairment and the Family/CaregiverMS Cognitive Impairment and the Family/CaregiverMS Cognitive Impairment and the Family/CaregiverMS Cognitive Impairment and the Family/Caregiver

• Family members or caregivers should:Family members or caregivers should:

– Discuss issues of cognitive impairment with Discuss issues of cognitive impairment with health care professionals at appointmentshealth care professionals at appointments

– Accompany patient to appointments to ensure Accompany patient to appointments to ensure that instructions are understood and carried outthat instructions are understood and carried out

– Seek respite care where possible if cognitive Seek respite care where possible if cognitive impairment is severeimpairment is severe

– Seek support or counseling if caregiving duties Seek support or counseling if caregiving duties become overwhelmingbecome overwhelming

• Family members or caregivers should:Family members or caregivers should:

– Discuss issues of cognitive impairment with Discuss issues of cognitive impairment with health care professionals at appointmentshealth care professionals at appointments

– Accompany patient to appointments to ensure Accompany patient to appointments to ensure that instructions are understood and carried outthat instructions are understood and carried out

– Seek respite care where possible if cognitive Seek respite care where possible if cognitive impairment is severeimpairment is severe

– Seek support or counseling if caregiving duties Seek support or counseling if caregiving duties become overwhelmingbecome overwhelming

JLC020303

MS Cognitive Impairment: ConclusionsMS Cognitive Impairment: ConclusionsMS Cognitive Impairment: ConclusionsMS Cognitive Impairment: Conclusions

• Measurable cognitive impairment may be present Measurable cognitive impairment may be present from early stages of MSfrom early stages of MS

• Cognitive impairment is not usually disabling until Cognitive impairment is not usually disabling until later in the course of MS and is highly variable later in the course of MS and is highly variable

• Cognitive impairment in MS is under-recognized Cognitive impairment in MS is under-recognized by health care professionalsby health care professionals

• Early treatment with disease-modifying therapies Early treatment with disease-modifying therapies is best preventative measure at presentis best preventative measure at present

• Measurable cognitive impairment may be present Measurable cognitive impairment may be present from early stages of MSfrom early stages of MS

• Cognitive impairment is not usually disabling until Cognitive impairment is not usually disabling until later in the course of MS and is highly variable later in the course of MS and is highly variable

• Cognitive impairment in MS is under-recognized Cognitive impairment in MS is under-recognized by health care professionalsby health care professionals

• Early treatment with disease-modifying therapies Early treatment with disease-modifying therapies is best preventative measure at presentis best preventative measure at present

JLC020303

MS Cognitive Impairment: ConclusionsMS Cognitive Impairment: ConclusionsMS Cognitive Impairment: ConclusionsMS Cognitive Impairment: Conclusions

• Further treatment trials for therapies designed for Further treatment trials for therapies designed for established cognitive impairment are neededestablished cognitive impairment are needed

• Other confounding factors such as untreated Other confounding factors such as untreated depression and cognitive side-effects of common depression and cognitive side-effects of common MS drugs need to be recognized and treatedMS drugs need to be recognized and treated

• Family members and caregivers need to be Family members and caregivers need to be counseled on the impact of cognitive impairment counseled on the impact of cognitive impairment on the MS patient and their familyon the MS patient and their family

• Further treatment trials for therapies designed for Further treatment trials for therapies designed for established cognitive impairment are neededestablished cognitive impairment are needed

• Other confounding factors such as untreated Other confounding factors such as untreated depression and cognitive side-effects of common depression and cognitive side-effects of common MS drugs need to be recognized and treatedMS drugs need to be recognized and treated

• Family members and caregivers need to be Family members and caregivers need to be counseled on the impact of cognitive impairment counseled on the impact of cognitive impairment on the MS patient and their familyon the MS patient and their family

JLC020303 Multiple Sclerosis and the Mind: Memory Loss and Cognitive Impairment Jonathan L. Carter MD Director Mayo Clinic Scottsdale MS Center Jonathan.

Documents

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