JLC Cognitive Impairment Associated with Multiple Sclerosis Jonathan L. Carter, MD Director Mayo Clinic Scottsdale MS Center Jonathan L. Carter, MD Director Mayo Clinic Scottsdale MS Center

JLC OutlineOutline Prevalence of Cognitive Impairment in MS Patterns of Cognitive Impairment in MS Correlation with Disability Progression Correlation with MRI Findings Diagnosis of Cognitive Impairment Treatment of Cognitive Impairment Prevalence of Cognitive Impairment in MS Patterns of Cognitive Impairment in MS Correlation with Disability Progression Correlation with MRI Findings Diagnosis of Cognitive Impairment Treatment of Cognitive Impairment

JLC MS Cognitive Impairment: Prevalence Population-based studies: Estimated prevalence of 43-46% in unselected MS patientsPopulation-based studies: Estimated prevalence of 43-46% in unselected MS patients MS specialty clinic or hospitalized patients: Estimated prevalence of 50-60%MS specialty clinic or hospitalized patients: Estimated prevalence of 50-60% Prevalence depends on how CI is defined and how rigorously it is looked forPrevalence depends on how CI is defined and how rigorously it is looked for Population-based studies: Estimated prevalence of 43-46% in unselected MS patientsPopulation-based studies: Estimated prevalence of 43-46% in unselected MS patients MS specialty clinic or hospitalized patients: Estimated prevalence of 50-60%MS specialty clinic or hospitalized patients: Estimated prevalence of 50-60% Prevalence depends on how CI is defined and how rigorously it is looked forPrevalence depends on how CI is defined and how rigorously it is looked for

JLC Rao et al. Neurology 1991 MS Cognitive Impairment: Prevalence Prevalence of Impairment by Domain Language8-9% Visuospatial abilities12-19% Attention span7-8% Information Processing22-25% Memory22-31% Problem Solving13-19% Defined as % MS patients scoring <5th percentile for normal population Prevalence of Impairment by Domain Language8-9% Visuospatial abilities12-19% Attention span7-8% Information Processing22-25% Memory22-31% Problem Solving13-19% Defined as % MS patients scoring <5th percentile for normal population

JLC MS Cognitive Impairment: Patterns Cognitive domains frequently affected:Cognitive domains frequently affected: –Recent memory –Abstract reasoning –Verbal fluency –Sustained attention (especially with multiple-tasks) –Visuospatial perception Cognitive domains frequently affected:Cognitive domains frequently affected: –Recent memory –Abstract reasoning –Verbal fluency –Sustained attention (especially with multiple-tasks) –Visuospatial perception

JLC MS Cognitive Impairment: Patterns MS memory impairment:MS memory impairment: –Unlike Alzheimer’s, MS patients learn when presented with multiple trials of same material –Unlike Alzheimer’s, MS patients perform better on recognition tests than free recall tests; suggesting information is encoded and stored but inaccurately retrieved without cues MS memory impairment:MS memory impairment: –Unlike Alzheimer’s, MS patients learn when presented with multiple trials of same material –Unlike Alzheimer’s, MS patients perform better on recognition tests than free recall tests; suggesting information is encoded and stored but inaccurately retrieved without cues

JLC MS Cognitive Impairment: Patterns Cognitive domains not frequently affected:Cognitive domains not frequently affected: –Language (receptive and expressive) –Attention span (digit span) –Femote memory Cognitive domains not frequently affected:Cognitive domains not frequently affected: –Language (receptive and expressive) –Attention span (digit span) –Femote memory

JLC MS 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 evaluation of memory problems over several months, including disorientation while driving and forgetting appointments –Had to make lists to keep track of daily activities and appointments –Also reported unsteady gait, left hand and foot numbness, and urinary stress incontinence –Score on the Mayo STMS was 34/38 (normal >29) Cognitive impairment as early sign of MS:Cognitive impairment as early sign of MS: –54 year old woman was referred to our Clinic for evaluation of memory problems over several months, including disorientation while driving and forgetting appointments –Had to make lists to keep track of daily activities and appointments –Also reported unsteady gait, left hand and foot numbness, and urinary stress incontinence –Score on the Mayo STMS was 34/38 (normal >29)

JLC MS Cognitive Impairment: Case Study Cognitive testing showed severe deficits in short-term recall and new verbal learning, and moderate deficits in visuospatial perceptionCognitive testing showed severe deficits in short-term recall and new verbal learning, and moderate deficits in visuospatial perception –All other cognitive domains were normal. Brain MRI showed multiple lesions involving periventricular white matter, internal capsule, corpus callosum, and brainstemBrain MRI showed multiple lesions involving periventricular white matter, internal capsule, corpus callosum, and brainstem –Moderate generalized atrophy was present Cervical spine MRI showed lesions in medulla, C1, C6, and T2 levelsCervical spine MRI showed lesions in medulla, C1, C6, and T2 levels CSF was abnormal, consistent with MSCSF was abnormal, consistent with MS Cognitive testing showed severe deficits in short-term recall and new verbal learning, and moderate deficits in visuospatial perceptionCognitive testing showed severe deficits in short-term recall and new verbal learning, and moderate deficits in visuospatial perception –All other cognitive domains were normal. Brain MRI showed multiple lesions involving periventricular white matter, internal capsule, corpus callosum, and brainstemBrain MRI showed multiple lesions involving periventricular white matter, internal capsule, corpus callosum, and brainstem –Moderate generalized atrophy was present Cervical spine MRI showed lesions in medulla, C1, C6, and T2 levelsCervical spine MRI showed lesions in medulla, C1, C6, and T2 levels CSF was abnormal, consistent with MSCSF was abnormal, consistent with MS

JLC MS Cognitive Impairment: Case Study Patient was diagnosed with primary progressive MS and has been followed for last 4 years in a clinical trialPatient was diagnosed with primary progressive MS and has been followed for last 4 years in a clinical trial Cognitive impairment has slowly progressed during trialCognitive impairment has slowly progressed during trial –She still functions independently, but husband has looked into hiring a caregiver when he is away during business trips Brain MRIs have shown progressive atrophy during course of the clinical trialBrain MRIs have shown progressive atrophy during course of the clinical trial Patient was diagnosed with primary progressive MS and has been followed for last 4 years in a clinical trialPatient was diagnosed with primary progressive MS and has been followed for last 4 years in a clinical trial Cognitive impairment has slowly progressed during trialCognitive impairment has slowly progressed during trial –She still functions independently, but husband has looked into hiring a caregiver when he is away during business trips Brain MRIs have shown progressive atrophy during course of the clinical trialBrain MRIs have shown progressive atrophy during course of the clinical trial

JLC020403

MS Cognitive Impairment: Correlation with Disability Most MS rating scales do not adequately assess cognitive function:Most MS rating scales do not adequately assess cognitive function: –Kurtzke EDSS scale includes cognition as one of 7 subscales; does not require quantitative assessment of cognitive function –Kurtzke EDSS scale is dependent solely on ambulation at range where cognitive impairment often becomes evident (EDSS 4.0 and above) Most MS rating scales do not adequately assess cognitive function:Most MS rating scales do not adequately assess cognitive function: –Kurtzke EDSS scale includes cognition as one of 7 subscales; does not require quantitative assessment of cognitive function –Kurtzke EDSS scale is dependent solely on ambulation at range where cognitive impairment often becomes evident (EDSS 4.0 and above)

JLC MS Cognitive Impairment: Correlation with Disability –MS Functional Composite (MSFC) includes cognition as one of 3 independent variables: » Uses PASAT 3 test which is quantitative and is converted into a “Z” score » Provides better assessment of cognitive function than Kurtzke scale » Increases “weight” of cognitive dysfunction in determining disability » Major drawback is lack of “intuitive” nature of score and lack of uniform acceptance –MS Functional Composite (MSFC) includes cognition as one of 3 independent variables: » Uses PASAT 3 test which is quantitative and is converted into a “Z” score » Provides better assessment of cognitive function than Kurtzke scale » Increases “weight” of cognitive dysfunction in determining disability » Major drawback is lack of “intuitive” nature of score and lack of uniform acceptance

JLC MS Cognitive Impairment: Correlation with Disability Frequency and severity of cognitive dysfunction does increase with increasing physical disability; but correlation is poor:Frequency and severity of cognitive dysfunction does increase with increasing physical disability; but correlation is poor: –Patients with progressive MS and predominantly spinal cord disease may have advanced disability but normal cognition –Patients with minimal physical disability but extensive white matter disease on brain MRI may have severe cognitive impairment Frequency and severity of cognitive dysfunction does increase with increasing physical disability; but correlation is poor:Frequency and severity of cognitive dysfunction does increase with increasing physical disability; but correlation is poor: –Patients with progressive MS and predominantly spinal cord disease may have advanced disability but normal cognition –Patients with minimal physical disability but extensive white matter disease on brain MRI may have severe cognitive impairment

JLC MS Cognitive Impairment: Correlation with Disability Presence of CI is single most important determinant of employability in MS patientsPresence 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 correlates with decreased social functioning, greater caregiver stress and “burnout” Presence of CI may also interfere with health care decisions including poor compliance with treatments, unrealistic expectations of treatments, and irrational reliance on “alternative” treatmentsPresence of CI may also interfere with health care decisions including poor compliance with treatments, unrealistic expectations of treatments, and irrational reliance on “alternative” treatments Presence of CI is single most important determinant of employability in MS patientsPresence 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 correlates with decreased social functioning, greater caregiver stress and “burnout” Presence of CI may also interfere with health care decisions including poor compliance with treatments, unrealistic expectations of treatments, and irrational reliance on “alternative” treatmentsPresence of CI may also interfere with health care decisions including poor compliance with treatments, unrealistic expectations of treatments, and irrational reliance on “alternative” treatments

JLC *Adapted from Bourdette; "Cognitive Dysfunction in MS", 2001 “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 respond to antidepressantsAppears depressed/withdrawn but fails to respond 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 respond to antidepressantsAppears depressed/withdrawn but fails to respond to antidepressants Large burden of T2 lesions on MRILarge burden of T2 lesions on MRI Significant cerebral atrophy on MRISignificant cerebral atrophy on MRI

JLC MS Cognitive Impairment: MRI Correlation Cognitive impairment correlates with:Cognitive impairment correlates with: –T2 cerebral lesion volume –Cerebral atrophy measures: » Brain Parenchymal Fraction (BPF) » Lateral ventricular and 3rd ventricular volumes » Thickness of corpus callosum –T1 “black hole” lesion volume –Juxta-cortical lesion volume Cognitive impairment correlates with:Cognitive impairment correlates with: –T2 cerebral lesion volume –Cerebral atrophy measures: » Brain Parenchymal Fraction (BPF) » Lateral ventricular and 3rd ventricular volumes » Thickness of corpus callosum –T1 “black hole” lesion volume –Juxta-cortical lesion volume

JLC *Zivadinov et al; JNNP; 2001 MS Cognitive Impairment: MRI Correlation Cerebral atrophy and cognitive impairment found in up to 50% of early RRMS patients:*Cerebral atrophy and cognitive impairment found in up to 50% of early RRMS patients:* –Rate of development of cerebral atrophy found to be greatest predictor of cognitive decline –Development of cerebral atrophy also correlated with EDSS progression –Other studies have found rate of T2 lesion volume to be strongest predictor Cerebral atrophy and cognitive impairment found in up to 50% of early RRMS patients:*Cerebral atrophy and cognitive impairment found in up to 50% of early RRMS patients:* –Rate of development of cerebral atrophy found to be greatest predictor of cognitive decline –Development of cerebral atrophy also correlated with EDSS progression –Other studies have found rate of T2 lesion volume to be strongest predictor

JLC MS Cognitive Impairment: MRI Correlation Changes in normal-appearing white matter (NAWM) have correlated strongly with CI: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 Changes in normal-appearing white matter (NAWM) have correlated strongly with CI: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

JLC *Rao and the Cognitive Function Study Group, NMSS; 1990 MS Cognitive Impairment: Diagnosis Screening Neuropsychological test batteries have been developed for MS:Screening Neuropsychological test batteries have been developed for MS: –“Brief Repeatable Battery”(BRB) by Rao includes:* » Verbal immediate and delayed recall » Spatial immediate and delayed recall » Complex attention, concentration, and speed and accuracy in visual search and scanning » Sustained attention (PASAT) » Verbal associative fluency Screening Neuropsychological test batteries have been developed for MS:Screening Neuropsychological test batteries have been developed for MS: –“Brief Repeatable Battery”(BRB) by Rao includes:* » Verbal immediate and delayed recall » Spatial immediate and delayed recall » Complex attention, concentration, and speed and accuracy in visual search and scanning » Sustained attention (PASAT) » Verbal associative fluency

JLC MS Cognitive Impairment: Diagnosis –More comprehensive Neuropsychological batteries require 2-4 hours to administer –Screening instruments designed for dementia such as the Mini-Mental Status Exam are very insensitive to MS cognitive impairment –PASAT-3 has been incorporated into the MS Functional Composite now used as outcome measure in some MS Clinical trials –More comprehensive Neuropsychological batteries require 2-4 hours to administer –Screening instruments designed for dementia such as the Mini-Mental Status Exam are very insensitive to MS cognitive impairment –PASAT-3 has been incorporated into the MS Functional Composite now used as outcome measure in some MS Clinical trials

JLC MS Cognitive Impairment: Diagnosis Other confounding variables need to be investigated:Other confounding variables need to be investigated: –Many symptomatic MS drugs may have cognitive side effects; including Baclofen, Zanaflex, Tegretol, Neurontin, Clonazepam –Untreated depression may produce cognitive slowing that can mimic MS CI –Cognitive function may worsen during relapse and improve following recovery Other confounding variables need to be investigated:Other confounding variables need to be investigated: –Many symptomatic MS drugs may have cognitive side effects; including Baclofen, Zanaflex, Tegretol, Neurontin, Clonazepam –Untreated depression may produce cognitive slowing that can mimic MS CI –Cognitive function may worsen during relapse and improve following recovery

JLC MS Therapies and Cognitive Impairment Phase III Avonex (Interferon β1a) study: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) Phase III Avonex (Interferon β1a) study: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)

JLC MS Therapies and Cognitive Impairment –% of patients who showed sustained changes in PASAT processing speed also favored Avonex group (47% reduction in sustained worsening) –Phase III Avonex study showed reduction in rate of development of cerebral atrophy on MRI during second year of study in Avonex patients, which correlated with changes in cognitive function –Other β-IFN clinical trials (Betaseron, Rebif) haven’t addressed cognitive dysfunction –% of patients who showed sustained changes in PASAT processing speed also favored Avonex group (47% reduction in sustained worsening) –Phase III Avonex study showed reduction in rate of development of cerebral atrophy on MRI during second year of study in Avonex patients, which correlated with changes in cognitive function –Other β-IFN clinical trials (Betaseron, Rebif) haven’t addressed cognitive dysfunction

JLC MS Therapies and Cognitive Impairment Phase III glatiramer acetate (GA) study:Phase III glatiramer acetate (GA) study: –Failed to show treatment effect of GA on cognitive test battery over 2 years –Placebo group showed no decline in cognitive function during study –Therefore opportunity to show treatment effect may have been missed –Effects of GA on T2 lesion volume and T1 black holes would suggest positive effect Phase III glatiramer acetate (GA) study:Phase III glatiramer acetate (GA) study: –Failed to show treatment effect of GA on cognitive test battery over 2 years –Placebo group showed no decline in cognitive function during study –Therefore opportunity to show treatment effect may have been missed –Effects of GA on T2 lesion volume and T1 black holes would suggest positive effect

JLC Treatment for Cognitive Impairment 12-week, open label trial of Donepezil (Aricept) in MS cognitive impairment:12-week, open label trial of Donepezil (Aricept) in MS cognitive impairment: –17 patients in long-term care facility with MMSE scores <25 (moderate to severe impairment) – MMSE scores improved at weeks 4 and 12 (maximum increase in mean score of 5.7) –Attention, naming, verbal fluency, visual recognition memory, and conceptualization also improved –Major limitations were lack of control group and likelihood of practice effect with frequent testing 12-week, open label trial of Donepezil (Aricept) in MS cognitive impairment:12-week, open label trial of Donepezil (Aricept) in MS cognitive impairment: –17 patients in long-term care facility with MMSE scores <25 (moderate to severe impairment) – MMSE scores improved at weeks 4 and 12 (maximum increase in mean score of 5.7) –Attention, naming, verbal fluency, visual recognition memory, and conceptualization also improved –Major limitations were lack of control group and likelihood of practice effect with frequent testing

JLC Treatment of Cognitive Impairment –Other limitations include small sample size, selection of nursing home residents, selection of patients with severe cognitive impairment –Results of preliminary studies have led to a multi-center, double blind, placebo-controlled, randomized clinical trial of Donepezil vs placebo, which is currently ongoing –Mechanism of MS CI different enough from AD that cholinesterase inhibitors may not work –Other limitations include small sample size, selection of nursing home residents, selection of patients with severe cognitive impairment –Results of preliminary studies have led to a multi-center, double blind, placebo-controlled, randomized clinical trial of Donepezil vs placebo, which is currently ongoing –Mechanism of MS CI different enough from AD that cholinesterase inhibitors may not work

JLC Treatment of Cognitive Impairment Other pilot studies have failed to show benefit in treatment of MS CI:Other pilot studies have failed to show benefit in treatment of MS CI: –Amantadine –Pemoline (Cylert) –4-Aminopyridine These studies based on theory of “cognitive fatigue” which has been shown by several authors to be important in MSThese studies based on theory of “cognitive fatigue” which has been shown by several authors to be important in MS Other pilot studies have failed to show benefit in treatment of MS CI:Other pilot studies have failed to show benefit in treatment of MS CI: –Amantadine –Pemoline (Cylert) –4-Aminopyridine These studies based on theory of “cognitive fatigue” which has been shown by several authors to be important in MSThese studies based on theory of “cognitive fatigue” which has been shown by several authors to be important in MS

JLC MS Cognitive Impairment: Conclusions Measurable cognitive impairment present from early stages of MSMeasurable cognitive impairment present from early stages of MS Cognitive impairment is not usually disabling until later in course of MS and is highly variableCognitive impairment is not usually disabling until later in course of MS and is highly variable Cognitive impairment in MS is under- recognized by health care professionalsCognitive impairment in MS is under- recognized by health care professionals Early treatment with disease-modifying therapies is best preventative measure at presentEarly treatment with disease-modifying therapies is best preventative measure at present Measurable cognitive impairment present from early stages of MSMeasurable cognitive impairment present from early stages of MS Cognitive impairment is not usually disabling until later in course of MS and is highly variableCognitive impairment is not usually disabling until later in course of MS and is highly variable Cognitive impairment in MS is under- recognized by health care professionalsCognitive impairment in MS is under- recognized by health care professionals Early treatment with disease-modifying therapies is best preventative measure at presentEarly treatment with disease-modifying therapies is best preventative measure at present

JLC MS Cognitive Impairment: Conclusions Further treatment trials for therapies designed for established cognitive impairment are neededFurther treatment trials for therapies designed for established cognitive impairment are needed Other confounding variables such as untreated depression and cognitive side-effects of common MS drugs need to be recognized and treatedOther confounding variables such as untreated depression and cognitive side-effects of common MS drugs need to be recognized and treated Family members and caregivers need to be counseled on the impact of cognitive impairment on the MS patient and their familyFamily members and caregivers need to be counseled on the impact of cognitive impairment on the MS patient and their family Further treatment trials for therapies designed for established cognitive impairment are neededFurther treatment trials for therapies designed for established cognitive impairment are needed Other confounding variables such as untreated depression and cognitive side-effects of common MS drugs need to be recognized and treatedOther confounding variables such as untreated depression and cognitive side-effects of common MS drugs need to be recognized and treated Family members and caregivers need to be counseled on the impact of cognitive impairment on the MS patient and their familyFamily members and caregivers need to be counseled on the impact of cognitive impairment on the MS patient and their family