JLC020403 Cognitive Impairment Associated with Multiple Sclerosis Jonathan L. Carter, MD Director...

JLC020403

Cognitive Impairment Cognitive Impairment Associated with Associated with

Multiple SclerosisMultiple Sclerosis

Cognitive Impairment Cognitive Impairment Associated with Associated with

Multiple SclerosisMultiple Sclerosis

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

Prevalence of Cognitive Impairment in MSPrevalence of Cognitive Impairment in MS

Patterns of Cognitive Impairment in MSPatterns of Cognitive Impairment in MS

Correlation with Disability ProgressionCorrelation with Disability Progression

Correlation with MRI FindingsCorrelation with MRI Findings

Diagnosis of Cognitive ImpairmentDiagnosis of Cognitive Impairment

Treatment of Cognitive ImpairmentTreatment of Cognitive Impairment

Prevalence of Cognitive Impairment in MSPrevalence of Cognitive Impairment in MS

Patterns of Cognitive Impairment in MSPatterns of Cognitive Impairment in MS

Correlation with Disability ProgressionCorrelation with Disability Progression

Correlation with MRI FindingsCorrelation with MRI Findings

Diagnosis of Cognitive ImpairmentDiagnosis of Cognitive Impairment

Treatment of Cognitive ImpairmentTreatment of Cognitive Impairment

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MS Cognitive Impairment: PrevalenceMS Cognitive Impairment: PrevalenceMS Cognitive Impairment: PrevalenceMS Cognitive Impairment: Prevalence

• Population-based studies: Estimated Population-based studies: Estimated prevalence of 43-46% in unselected prevalence of 43-46% in unselected MS patientsMS patients

• MS specialty clinic or hospitalized MS specialty clinic or hospitalized patients: Estimated prevalence of 50-60%patients: Estimated prevalence of 50-60%

• Prevalence depends on how CI is defined Prevalence depends on how CI is defined and how rigorously it is looked forand how rigorously it is looked for

• Population-based studies: Estimated Population-based studies: Estimated prevalence of 43-46% in unselected prevalence of 43-46% in unselected MS patientsMS patients

• MS specialty clinic or hospitalized MS specialty clinic or hospitalized patients: Estimated prevalence of 50-60%patients: Estimated prevalence of 50-60%

• Prevalence depends on how CI is defined Prevalence depends on how CI is defined and how rigorously it is looked forand how rigorously it is looked for

Rao et al. Neurology 1991JLC020403

MS Cognitive Impairment: PrevalenceMS Cognitive Impairment: PrevalenceMS Cognitive Impairment: PrevalenceMS Cognitive Impairment: Prevalence

Prevalence of Impairment by DomainPrevalence of Impairment by Domain

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

Prevalence of Impairment by DomainPrevalence of Impairment by Domain

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 % MS patients scoring Defined as % 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 domains frequently affected:Cognitive domains frequently affected:– Recent memory Recent memory – Abstract reasoningAbstract reasoning– Verbal fluencyVerbal fluency– Sustained attention Sustained attention

(especially with multiple-tasks)(especially with multiple-tasks)– Visuospatial perception Visuospatial perception

• Cognitive domains frequently affected:Cognitive domains frequently affected:– Recent memory Recent memory – Abstract reasoningAbstract reasoning– Verbal fluencyVerbal fluency– Sustained attention Sustained attention

(especially with multiple-tasks)(especially with multiple-tasks)– Visuospatial perception Visuospatial perception

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

learn when presented with multiple learn when presented with multiple trials of same materialtrials of same material

– Unlike Alzheimer’s, MS patients perform Unlike Alzheimer’s, MS patients perform better on recognition tests than free recall better on recognition tests than free recall tests; suggesting information is encoded tests; suggesting information is encoded and stored but inaccurately retrieved and stored but inaccurately retrieved without cueswithout cues

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

learn when presented with multiple learn when presented with multiple trials of same materialtrials of same material

– Unlike Alzheimer’s, MS patients perform Unlike Alzheimer’s, MS patients perform better on recognition tests than free recall better on recognition tests than free recall tests; suggesting information is encoded tests; suggesting information is encoded and stored but inaccurately retrieved and stored but inaccurately retrieved without cueswithout cues

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• Cognitive domains not Cognitive domains not frequently affected:frequently affected:

– Language (receptive Language (receptive and expressive)and expressive)

– Attention span (digit span)Attention span (digit span)

– Femote memoryFemote memory

• Cognitive domains not Cognitive domains not frequently affected:frequently affected:

– Language (receptive Language (receptive and expressive)and expressive)

– Attention span (digit span)Attention span (digit span)

– Femote memoryFemote memory

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

• Cognitive impairment as early sign of MS:Cognitive impairment 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 months, including disorientation while driving and forgetting appointmentsand forgetting appointments

– Had to make lists to keep track of daily activities Had to make lists to keep track of daily activities and appointmentsand appointments

– Also reported unsteady gait, left hand and foot Also reported unsteady gait, left hand and foot numbness, and urinary stress incontinencenumbness, and urinary stress incontinence

– Score on the Mayo STMS was 34/38 (normal >29) Score on the Mayo STMS was 34/38 (normal >29)

• Cognitive impairment as early sign of MS:Cognitive impairment 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 months, including disorientation while driving and forgetting appointmentsand forgetting appointments

– Had to make lists to keep track of daily activities Had to make lists to keep track of daily activities and appointmentsand appointments

– Also reported unsteady gait, left hand and foot Also reported unsteady gait, left hand and foot numbness, and urinary stress incontinencenumbness, and urinary stress incontinence

– Score on the Mayo STMS was 34/38 (normal >29) Score on the Mayo STMS was 34/38 (normal >29)

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• Cognitive testing showed severe deficits in Cognitive testing showed severe deficits in short-term recall and new verbal learning, and short-term recall and new verbal learning, and moderate deficits in visuospatial perceptionmoderate deficits in visuospatial perception– All other cognitive domains were normal.All other cognitive domains were normal.

• Brain MRI showed multiple lesions involving Brain MRI showed multiple lesions involving periventricular white matter, internal capsule, periventricular white matter, internal capsule, corpus callosum, and brainstemcorpus callosum, and brainstem– Moderate generalized atrophy was present Moderate generalized atrophy was present

• Cervical spine MRI showed lesions in medulla, Cervical spine MRI showed lesions in medulla, C1, C6, and T2 levelsC1, C6, and T2 levels

• CSF was abnormal, consistent with MSCSF was abnormal, consistent with MS

• Cognitive testing showed severe deficits in Cognitive testing showed severe deficits in short-term recall and new verbal learning, and short-term recall and new verbal learning, and moderate deficits in visuospatial perceptionmoderate deficits in visuospatial perception– All other cognitive domains were normal.All other cognitive domains were normal.

• Brain MRI showed multiple lesions involving Brain MRI showed multiple lesions involving periventricular white matter, internal capsule, periventricular white matter, internal capsule, corpus callosum, and brainstemcorpus callosum, and brainstem– Moderate generalized atrophy was present Moderate generalized atrophy was present

• Cervical spine MRI showed lesions in medulla, Cervical spine MRI showed lesions in medulla, C1, C6, and T2 levelsC1, C6, and T2 levels

• CSF was abnormal, consistent with MSCSF was abnormal, consistent with MS

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• Patient was diagnosed with primary progressive Patient was diagnosed with primary progressive MS and has been followed for last 4 years in a clinical MS and has been followed for last 4 years in a clinical trialtrial

• Cognitive impairment has slowly progressed Cognitive impairment has slowly progressed during trialduring trial

– She still functions independently, but husband She still functions independently, but husband has looked into hiring a caregiver when he is has looked into hiring a caregiver when he is away during business tripsaway during business trips

• Brain MRIs have shown progressive atrophy during Brain MRIs have shown progressive atrophy during course of the clinical trialcourse of the clinical trial

• Patient was diagnosed with primary progressive Patient was diagnosed with primary progressive MS and has been followed for last 4 years in a clinical MS and has been followed for last 4 years in a clinical trialtrial

• Cognitive impairment has slowly progressed Cognitive impairment has slowly progressed during trialduring trial

– She still functions independently, but husband She still functions independently, but husband has looked into hiring a caregiver when he is has looked into hiring a caregiver when he is away during business tripsaway during business trips

• Brain MRIs have shown progressive atrophy during Brain MRIs have shown progressive atrophy during course of the clinical trialcourse of the clinical 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:

– Kurtzke EDSS scale includes cognition Kurtzke EDSS scale includes cognition as one of 7 subscales; does not require as one of 7 subscales; does not require quantitative assessment of cognitive functionquantitative assessment of cognitive function

– Kurtzke EDSS scale is dependent solely Kurtzke EDSS scale is dependent solely on ambulation at range where cognitive on ambulation 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:

– Kurtzke EDSS scale includes cognition Kurtzke EDSS scale includes cognition as one of 7 subscales; does not require as one of 7 subscales; does not require quantitative assessment of cognitive functionquantitative assessment of cognitive function

– Kurtzke EDSS scale is dependent solely Kurtzke EDSS scale is dependent solely on ambulation at range where cognitive on ambulation 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 and is Uses PASAT 3 test which is quantitative and is converted into a “Z” scoreconverted into a “Z” score

» Provides better assessment of cognitive Provides better assessment of cognitive function than Kurtzke scalefunction than Kurtzke scale

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

» Major drawback is lack of “intuitive” nature of Major drawback is lack of “intuitive” nature of score and lack of uniform acceptancescore and lack of uniform acceptance

– 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 and is Uses PASAT 3 test which is quantitative and is converted into a “Z” scoreconverted into a “Z” score

» Provides better assessment of cognitive Provides better assessment of cognitive function than Kurtzke scalefunction than Kurtzke scale

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

» Major drawback is lack of “intuitive” nature of Major drawback is lack of “intuitive” nature of score and lack of uniform acceptancescore and lack of uniform acceptance

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

– Patients with progressive MS and Patients with progressive MS and predominantly spinal cord disease may have predominantly spinal cord disease may have advanced disability but normal cognitionadvanced disability but normal cognition

– Patients with minimal physical disability but Patients with minimal physical disability but extensive white matter disease on brain MRI extensive white matter disease 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 does increase with increasing physical disability; but correlation is poor:disability; but correlation is poor:

– Patients with progressive MS and Patients with progressive MS and predominantly spinal cord disease may have predominantly spinal cord disease may have advanced disability but normal cognitionadvanced disability but normal cognition

– Patients with minimal physical disability but Patients with minimal physical disability but extensive white matter disease on brain MRI extensive white matter disease 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 care decisions including poor compliance with treatments, unrealistic expectations of with treatments, unrealistic expectations of treatments, and irrational reliance on treatments, and irrational reliance on “alternative” treatments “alternative” 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 care decisions including poor compliance with treatments, unrealistic expectations of with treatments, unrealistic expectations of treatments, and irrational reliance on treatments, and irrational reliance on “alternative” treatments “alternative” 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 cerebral lesion volumeT2 cerebral lesion volume– Cerebral atrophy measures:Cerebral atrophy measures:

» Brain Parenchymal Fraction (BPF)Brain Parenchymal Fraction (BPF)» Lateral ventricular and Lateral ventricular and

3rd ventricular volumes3rd ventricular volumes» Thickness of corpus callosumThickness of corpus callosum

– T1 “black hole” lesion volumeT1 “black hole” lesion volume– Juxta-cortical lesion volumeJuxta-cortical lesion volume

• Cognitive impairment correlates with:Cognitive impairment correlates with:– T2 cerebral lesion volumeT2 cerebral lesion volume– Cerebral atrophy measures:Cerebral atrophy measures:

» Brain Parenchymal Fraction (BPF)Brain Parenchymal Fraction (BPF)» Lateral ventricular and Lateral ventricular and

3rd ventricular volumes3rd ventricular volumes» Thickness of corpus callosumThickness of corpus callosum

– T1 “black hole” lesion volumeT1 “black hole” lesion volume– Juxta-cortical lesion volumeJuxta-cortical lesion volume

*Zivadinov et al; JNNP; 2001JLC020403


• 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 Rate of development of cerebral

atrophy found to be greatest predictor atrophy found to be greatest predictor of cognitive declineof cognitive decline

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

– Other studies have found rate of T2 Other studies have found rate of T2 lesion volume to be strongest predictorlesion 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 Rate of development of cerebral

atrophy found to be greatest predictor atrophy found to be greatest predictor of cognitive declineof cognitive decline

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

– Other studies have found rate of T2 Other studies have found rate of T2 lesion volume to be strongest predictorlesion 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

*Rao and the Cognitive Function Study Group, NMSS; 1990

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

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

– ““Brief Repeatable Battery”(BRB) by Rao includes:*Brief Repeatable Battery”(BRB) by Rao includes:*» Verbal immediate and delayed recallVerbal immediate and delayed recall» Spatial immediate and delayed recallSpatial immediate and delayed recall» Complex attention, concentration, and speed Complex attention, concentration, and speed

and accuracy in visual search and scanningand accuracy in visual search and scanning» Sustained attention (PASAT)Sustained attention (PASAT)» Verbal associative fluencyVerbal associative fluency

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

– ““Brief Repeatable Battery”(BRB) by Rao includes:*Brief Repeatable Battery”(BRB) by Rao includes:*» Verbal immediate and delayed recallVerbal immediate and delayed recall» Spatial immediate and delayed recallSpatial immediate and delayed recall» Complex attention, concentration, and speed Complex attention, concentration, and speed

and accuracy in visual search and scanningand accuracy in visual search and scanning» Sustained attention (PASAT)Sustained attention (PASAT)» Verbal associative fluencyVerbal associative fluency

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

– Screening instruments designed for Screening instruments designed for dementia such as the Mini-Mental Status dementia such as the Mini-Mental Status Exam are very insensitive to MS Exam are very insensitive to MS cognitive impairmentcognitive impairment

– PASAT-3 has been incorporated into the MS PASAT-3 has been incorporated into the MS Functional Composite now used as outcome Functional Composite now used as outcome measure in some MS Clinical trialsmeasure in some MS Clinical trials

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

– Screening instruments designed for Screening instruments designed for dementia such as the Mini-Mental Status dementia such as the Mini-Mental Status Exam are very insensitive to MS Exam are very insensitive to MS cognitive impairmentcognitive impairment

– PASAT-3 has been incorporated into the MS PASAT-3 has been incorporated into the MS Functional Composite now used as outcome Functional Composite now used as outcome measure in some MS Clinical trialsmeasure in some MS Clinical trials

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• Other confounding variables need to Other confounding variables need to be investigated: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 MS CIcognitive slowing that can mimic MS CI

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

• Other confounding variables need to Other confounding variables need to be investigated: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 MS CIcognitive slowing that can mimic MS CI

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

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

– Other β-IFN clinical trials (Betaseron, Rebif) Other β-IFN clinical trials (Betaseron, Rebif) haven’t addressed cognitive dysfunctionhaven’t addressed cognitive dysfunction

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

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

– Other β-IFN clinical trials (Betaseron, Rebif) Other β-IFN clinical trials (Betaseron, Rebif) haven’t addressed cognitive dysfunctionhaven’t addressed cognitive dysfunction

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• Phase III glatiramer acetate (GA) study:Phase III glatiramer acetate (GA) study:– Failed to show treatment effect of GA on Failed to show treatment effect of GA on

cognitive test battery over 2 yearscognitive test battery over 2 years– Placebo group showed no decline in Placebo group showed no decline in

cognitive function during studycognitive function during study– Therefore opportunity to show treatment Therefore opportunity to show treatment

effect may have been missedeffect may have been missed– Effects of GA on T2 lesion volume and T1 Effects of GA on T2 lesion volume and T1

black holes would suggest positive effectblack holes would suggest positive effect

• Phase III glatiramer acetate (GA) study:Phase III glatiramer acetate (GA) study:– Failed to show treatment effect of GA on Failed to show treatment effect of GA on

cognitive test battery over 2 yearscognitive test battery over 2 years– Placebo group showed no decline in Placebo group showed no decline in

cognitive function during studycognitive function during study– Therefore opportunity to show treatment Therefore opportunity to show treatment

effect may have been missedeffect may have been missed– Effects of GA on T2 lesion volume and T1 Effects of GA on T2 lesion volume and T1

black holes would suggest positive effectblack holes would suggest positive effect

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

• 12-week, open label trial of Donepezil (Aricept) in 12-week, open label trial of Donepezil (Aricept) in MS cognitive impairment:MS cognitive impairment:

– 17 patients in long-term care facility with MMSE 17 patients in long-term care facility with MMSE scores <25 (moderate to severe impairment)scores <25 (moderate to severe impairment)

– MMSE scores improved at weeks 4 and 12 MMSE scores improved at weeks 4 and 12 (maximum increase in mean score of 5.7)(maximum increase in mean score of 5.7)

– Attention, naming, verbal fluency, visual recognition Attention, naming, verbal fluency, visual recognition memory, and conceptualization also improvedmemory, and conceptualization also 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 Donepezil (Aricept) in 12-week, open label trial of Donepezil (Aricept) in MS cognitive impairment:MS cognitive impairment:

– 17 patients in long-term care facility with MMSE 17 patients in long-term care facility with MMSE scores <25 (moderate to severe impairment)scores <25 (moderate to severe impairment)

– MMSE scores improved at weeks 4 and 12 MMSE scores improved at weeks 4 and 12 (maximum increase in mean score of 5.7)(maximum increase in mean score of 5.7)

– Attention, naming, verbal fluency, visual recognition Attention, naming, verbal fluency, visual recognition memory, and conceptualization also improvedmemory, and conceptualization also 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 Donepezil vs randomized clinical trial of Donepezil vs placebo, which is currently ongoingplacebo, which is currently ongoing

– Mechanism of MS CI different enough from Mechanism of MS CI different enough from AD that cholinesterase inhibitors may not workAD that cholinesterase inhibitors 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 Donepezil vs randomized clinical trial of Donepezil vs placebo, which is currently ongoingplacebo, which is currently ongoing

– Mechanism of MS CI different enough from Mechanism of MS CI different enough from AD that cholinesterase inhibitors may not workAD that cholinesterase inhibitors 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:

– AmantadineAmantadine

– Pemoline (Cylert)Pemoline (Cylert)

– 4-Aminopyridine4-Aminopyridine

• These studies based on theory of “cognitive These studies based on theory of “cognitive fatigue” which has been shown by several fatigue” which has been shown by several authors to be important in MSauthors to be important in MS

• 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:

– AmantadineAmantadine

– Pemoline (Cylert)Pemoline (Cylert)

– 4-Aminopyridine4-Aminopyridine

• These studies based on theory of “cognitive These studies based on theory of “cognitive fatigue” which has been shown by several fatigue” which has been shown by several authors to be important in MSauthors to be important in MS

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

• Measurable cognitive impairment present from Measurable cognitive impairment present from early stages of MSearly stages of MS

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

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

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

• Measurable cognitive impairment present from Measurable cognitive impairment present from early stages of MSearly stages of MS

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

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

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

JLC020403

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

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

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

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

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

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

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

JLC020403 Cognitive Impairment Associated with Multiple Sclerosis Jonathan L. Carter, MD Director...

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