MULTIMODAL THERAPY FOR MS- ASSOCIATED COGNITIVE DYSFUNCTION Michael K. Racke, MD Professor and Chairman in Neurology The Helen C. Kurtz Chair in Neurology Department of Neurology Ohio State University Medical Center Columbus, OH
MICHAEL K. RACKE, MD Disclosures Research/Grants: National Institutes of Health; National Multiple Sclerosis Society Speakers Bureau: None Consultant: Biogen Idec; Eli Lilly and Company; Revalesio Corporation Stockholder: None Other Financial Interest: None Advisory Board: Novartis Pharmaceuticals Corporation Editorial Boards: Archives of Neurology; Journal of Neuroimmunology; The Neurologist
LEARNING OBJECTIVE Review the effects of cognitive dysfunction in MS on QoL, and apply multimodal strategies for the measurement of disease activity and treatment of cognitive dysfunction in MS into improved, individualized therapy for patients.
MEASURES OF DISEASE ACTIVITY Relapse rate MRI Neuro exam/edss Neuropsychological testing Patient s assessment
COGNITIVE IMPAIRMENT IN MS Prevalence of 45% to 65% 1,2 Areas affected 2,3 Episodic memory Working memory Processing speed* Executive function* Visual/spatial processing Language * Can also be related to depression See supplemental bibliography for full references.
COGNITIVE IMPAIRMENT IN MS Most common in SPMS and PPMS course 1-3 Correlation with physical disability is small 4,5 Progresses inconsistently and slowly 6,7 SPMS = Secondary progressive multiple sclerosis PPMS = Primary progressive multiple sclerosis See supplemental bibliography for full references.
DEPRESSION IN MS 1,2 Depression affects up to 60% of MS patients Depression can affect cognitive function, including processing speed and executive function 1. Rao SM, et al. Arch Neurol. 1984;41:625-631. 2. Minden SL, et al. Arch Neurol. 1990;47:98-104.
FATIGUE AND DEPRESSION Pathogenesis uncertain Weakly associated with overall neurologic impairment No anatomic markers of fatigue Temperature Uhthoff s phenomenon Immune factors Cytokines, IL-6, IL-1, and TNF
FATIGUE AND DEPRESSION Pathogenesis uncertain Infection Altered cerebral metabolism fmri shows increased brain activation Disruption in neurotransmitter systems Serotonergic pathway Psychological factors
MRI CORRELATES WITH COGNITION Increased disease burden associated with cognitive dysfunction 1 Evaluate association with cognition 2-4 Atrophy Cortical atrophy Lesion volume Width of third ventricle See supplemental bibliography for full references.
TYPES OF CORTICAL LESIONS IN MS Type I Type II Type III Trapp BD, et al. Ann Rev Neurosci. 2008;31:247-269.
IMAGING CORTICAL LESIONS a b Pitt D, et al. Arch Neurol. 2010;67:812-818.
FATIGUE AND COGNITION IN MS 90% of MS patients experience fatigue 1 Physical and cognitive fatigue 1,2 Poor association with fatigue and cognitive function 1,2 1. Schapiro RT, et al. Int J MS Care. 2002:6-7. 2. DeLuca J. Fatigue: Its Definition, its Study and its Future. In: DeLuca J, editor. Fatigue as a Window to the Brain. Cambridge, MA. MIT Press; 2005: pp. 319-325.
DISEASE MODIFYING THERAPY* Interferon beta-1a 1,2 Showed improvement in processing speed, learning, and memory Interferon beta-1b 3 Showed improvement in cognitive performance * Not FDA approved for the treatment of cognitive impairment in MS 4 See supplemental bibliography for full references.
PHARMACOLOGIC INTERVENTIONS* Donepezil* showed benefit in a small, placebocontrolled study 1 Amantadine* benefited fatigue, but not cognitive function 2 L-amphetamine* helped improve cognitive function in recent study 3 4-AP* trend for improvement in some neuropsychological tests 4 SSRIs* also have shown benefit, but may be related to effects on depression 5 * Not FDA approved for the treatment of cognitive impairment in MS 6 See supplemental bibliography for full references.
NONPHARMACOLOGIC INTERVENTIONS Education and support Exercise (graded, not overexertion) Multidisciplinary rehabilitation program Behavioral therapy Cooling devices Active Cooling suits or liquid-cooled garments Passive Ice or gel packs; cooling a garment
IMPLICATIONS FOR CLINICAL PRACTICE Initial questions Are there signs of an impending relapse? Is there an infection present or has there been increased heat exposure? Have medications been changed or added that could increase fatigue? Anti-spasticity agents, ß-blockers, tricyclic antidepressants, benzodiazepines, antiepileptic drugs ß = beta Chiaravalloti ND, et al. Lancet Neurol. 2008;7:1139-1151.
IMPLICATIONS FOR CLINICAL PRACTICE Questions regarding pain, sleep, and depression Other fatigue-producing conditions Lab screen: TFT, CBC, Lytes/glu, LFT, ESR, UA, vit B-12 Psychiatric referral Overwhelming fatigue with severe depression Refractory to treatment of fatigue TFT = thyroid function test; LFT = liver function test; CBC = complete blood count; ESR = erythrocyte sedimentation rate; UA = urinalysis; Lytes = electrolytes; glu = blood glucose Chiaravalloti ND, et al. Lancet Neurol. 2008;7:1139-1151.
CLINICAL CONNECTIONS Consider MRI correlates of cognitive impairment Atrophy Cortical atrophy Lesion volume Width of third ventricle Utilize measures of disease activity Screen for neuropsychological impairment Correct modifiable causes
CLINICAL CONNECTIONS Exercise Consider pharmacologic and nonpharmacologic modalities Environmental factors (cooling)
QUESTIONS AND ANSWERS