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C OGNITION AND MS

C OGNITION AND MS. 2019 REGIONAL MS SUMMIT Elizabeth Morrison-Banks, MD, MSED Clinical Professor of Neurology Director , Multiple Sclerosis Program University of California, Riverside School of Medicine. O BJECTIVES. After participating in this session, attendees will be able to:

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C OGNITION AND MS

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  1. COGNITION AND MS 2019 REGIONAL MS SUMMIT Elizabeth Morrison-Banks, MD, MSED Clinical Professor of Neurology Director, Multiple Sclerosis Program University of California, Riverside School of Medicine

  2. OBJECTIVES After participating in this session, attendees will be able to: Describe the epidemiology and clinical presentation of cognitive impairment in multiple sclerosis. List evidence-based methods for assessing cognition in people with MS. Discuss strategies for managing cognitive challenges including counseling people with MS and their families, offering interventions, and addressing controversies in clinical care.

  3. COGNITION AND MS: EPIDEMIOLOGY

  4. COGNITION AND MS: EPIDEMIOLOGY • Prevalence estimates vary. • Some degree of cognitive dysfunction likely occurs in 40-60% of people living with MS. • Protecting cognitive function is a patient-centered priority for people living with MS and their loved ones.

  5. COGNITION AND MS: EPIDEMIOLOGY • Cognitive dysfunction can occur in every subtype of MS, including clinically isolated demyelinating syndromes.1 • Modeling cognitive impairment by disease duration:2 • Year 5 after disease onset: 20.9% mild, 6% severe • Year 10 after disease onset: 29.3% mild, 9% severe 1Brochet B, Ruet A. Front Neurol. 2019; Mar 20;10:261. doi: 10.3389/fneur.2019.00261.  2Achiron A. et al. PLoS One. 2013 Aug 1;8(8):e71058. doi: 10.1371/journal.pone.0071058. 

  6. COGNITION AND MS: EPIDEMIOLOGY • Systematic review and meta-analysis of cognitive impairment by MS disease subtype: • More cognitive impairment in primary progressive MS (PPMS) than in relapsing MS (g = -0.37)1 • No evidence of subtype-specific patterns in cognitive deficits • No differences in anxiety, depression or fatigue 1Johnen A. et al. NeurosciBiobehav Rev. 2017; 83: 568-578.

  7. COGNITION AND MS: EPIDEMIOLOGY • In another systematic review,1 even so-called “benign MS” (disease duration ≥10 years with EDSS ≤2) did not exclude the possibility of cognitive impairment. • Accelerated brain volume loss at all disease stages: 0.6-1% per year in MS, vs. 0.1-0.3% in normal aging2 1Ton AMM. et al. ArqNeuropsiquiatr. 2017; 75: 394-401. 2Miller DH. et al. Brain. 2002; 125: 1676-1695.

  8. COGNITIVE PERFORMANCE AND PHYSICAL DISABILITY • After mean disease duration of 19.6 years:1 • Low cognitive performance: 50.6% have severe disability. • High cognitive performance (cognitive resilience): 64.4% have mild disability. 1Harel Y. et al. PLoS One. 2019; Aug 29;14(8):e0221784.

  9. COMORBIDITIES CAN WORSEN COGNITION • Comorbidities associated with cognitive impairment: • Hypertension, heart disease1 • Diabetes, anxiety disorders2 • Mood disorders3…(among other examples…) 1Jakimovski D. et al. Eur J Neurol. 2019; 26: 87-e8. 2Marrie RA. et al. for Comorbidity and Cognition in MS (CCOMS) Study Group. MultSclerRelatDisord. 2019; 27: 164-170. 3Gill S. et al. J NeuropschiatryClinNeurosci. 2019; 31: 37-42.

  10. COGNITION AND MS: EPIDEMIOLOGY • Ethnic and racial disparities in cognition have been documented.1 • Unclear if disparities reflect differences in disease course, vs. discrepancies in performance on neuropsychological testing seen in general population2 1Rivas-Rodriguez R, Amezcua L. NeurolClin. 2018; 36: 151-162. 2Mascialino G. et al. NeuroRehabil. 2019; 44: 445-449.

  11. PEDIATRIC-ONSETMS IS ASSOCIATED WITH: • Decreased brain volume from symptom onset and brain growth failure1 • Impaired performance in school and on neuropsychological testing2 • Deficits persist into adulthood.3 1Bartels F. et al. MultScler. 2019; 25: 927-936. 2Cardoso M. et al. Pediatr Neurol. 2015; 53: 287—292. 3Fenu G. et al. MultSclerRelat Dis. 2018; 21: 103-107.

  12. COGNITION AND MS: CLINICAL SIGNIFICANCE • Systematic review of 13 published studies:1 • Cognitive impairment limits employment. • Unemployed adults with MS had deficits in information processing speed, executive function, immediate recall and delayed recall. • Employment is only one example of many ways ↓ cognition harms people with MS. 1Clemons C and Langdon D. MultSclerRelat Dis. 2018; 26: 183-191.

  13. COGNITION AND MS: CLINICAL SIGNIFICANCE Abuse and Neglect of People with Multiple Sclerosis: A Survey with the North American Research Committee on Multiple Sclerosis (NARCOMS) Funded by the National Multiple Sclerosis Society, Health Care Delivery and Policy Research Program, Contract HC0099 Elizabeth H. Morrison, M.D., M.S.Ed. Dara Sorkin, Ph.D. Laura Mosqueda, M.D. Napatkamon Ayutyanont, Ph.D. Cognitive dysfunction correlates with risk of abuse and/or neglect among people with MS.

  14. COGNITION AND MS: ASSESSMENT

  15. COGNITION: ASSESSMENT1 Your results may vary • Clinical measures: • 45 minutes: Brief Repeatable Battery of Neuropsychological Tests (BRB-N) • 90 minutes: Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) • MRI: ?Consensus on best measures? 1Rocca MA et al for the MAGNIMS Study Group. Lancet Neurol. 2015; 14: 302-317.

  16. COGNITION AND MS: ASSESSMENT • Methods for evaluating MRI indices of brain volume remain controversial.1-2 • However measured, brain volume loss strongly correlates with clinical measures of cognition (SDMT, PASAT, MSFC).3 1Azevedo CJ and Pelletier D. CurrOpin Neurol. 2016; 29: 237-242. 2Marciniewicz E. et al. AdvClinExp Med. 2019; 28: 893-903. 3Vollmer T. et al. Neurol Sci. 2016; 37: 165-179.

  17. COGNITION AND MS: ASSESSMENT • Phenomenon of pseudoatrophy: • Disease-modifying therapy decreases inflammation and edema.1 • Can be a factor when evaluating clinical studies of MS disease-modifying therapies and their effects on brain volume and cognition 1Rudick RA et al. and MS Collaborative Research Group. Neurol. 1999; 53: 1698–1704.

  18. COGNITION AND MS: SCREENING • National MS Society screening guidelines:1 • Minimum: Baseline screening with SDMT or similarly validated test, then repeat annually • Adults >18 years: ↑ neuropsychological testing if +cognitive symptoms or applying for disability • Children <18 years: ↑ neuropsychological testing if unexplained problems in school 1Kalb R et al. MultScler J. 2018; 24: 1665-1680.

  19. COGNITIVE SCREENING: WHICH TESTS? • Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) guidelines:1 • If only 5 minutes available, information processing speed: Symbol Digit Modalities Test (SDMT) • If have 10 more minutes, immediate recall tests: • California Verbal Learning Test, 2nd Ed. – verbal • Brief Visuospatial Memory Test – visuospatial 1Langdon DW et al. MultScler. 2012; 18: 891-898.

  20. Symbol Digit Modalities Test (SDMT), oral version: • Validated measure of information processing speed • Requires examinee to use key to substitute numbers for abstract symbols • 82% sensitivity, 60% specificity

  21. Systematic review and meta-analysis of six studies of the SDMT using functional MRI:1 • Adults aged 18-50 years • fMRI maps SDMT to frontoparietal attentional network, occipital cortex, cuneus, precuneus and cerebellum • SDMT has been validated in the pediatric MS population.2 • 1Silva PHR et al. MultSclerRelat Dis. 2018; 20: 136-143. • 2Charvet LE et al. J Neurol Sci. 2014; 341: 79-84.

  22. SCREENING EXAMINATION FOR COGNITIVE IMPAIRMENT(SEFCI)1-3 • Validated battery of three cognitive screening tests: • SHORT D word list (immediate recall) • Shipley-2 Institute of Living Scale (vocabulary and verbal reasoning) • Symbol Digit Modalities Test (processing speed) 1Beatty WW et al. Neurol. 1995; 45: 718-723. 2Aupperle RL et al. MultScler. 2002; 8: 382-389. 3Solari A et al. MultScler. 2002; 8: 169-176.

  23. COGNITION AND MS: MANAGEMENT

  24. COGNITION AND MS: DISEASE-MODIFYING THERAPIES • Meta-analysis of 4 randomized trials of DMT in RRMS:1 DMT ↓ed brain atrophy ~19% at 24 months • Trials included: • IMPROVE (beta IFN-1a 44 mcg 3x/week vs. placebo) • FREEDOMS (FGM vs. placebo) • E/C GASG (GA vs. placebo) • MSCRG (beta IFN-1a 30 mcg weekly vs. placebo) 1Tsivgoulis G et al. PLoS One. 2015; 10: e0116511.

  25. COGNITION AND MS: DISEASE-MODIFYING THERAPIES • Branger P et al. meta-analysis of 35 randomized trials of DMTs in relapsing MS1: Use of “1st-line DMTs” (GA, IFN, TFN, LAQ, DMF) -> 86% ↑ brain atrophy at 24 months vs. use of “2nd-line DMTs” (NTZ, ALM, DAC) • A separate linear regression analysis of the 12-48 month post-pseudoatrophy window showed robust continued superiority of NTZ, ALM and DAC. 1Branger P et al. PLoS One. 2016; 11: e0149685.

  26. INTERFERONS (IFN) • IFN trials: modest ↓ in MS-related cognitive changes (GOLDEN,1 SKORE,2 Mokhber N et al3) • Pegylated IFN did not show statistically significant effects on brain volume loss at 96 weeks.4 1Comi G. et al. JNeurol. 2017; 264: 2436-2449. 2Benesova Y, Tvaroh A. TherAdvNeurolDisord. 2017; 10: 18-32. 3Mokhber N. et al. JNeurol Sci. 2014; 32: 16-20. 4Arnold DA. et al. BMC Neurol. 2017; 17: 29.

  27. DISEASE-MODIFYING THERAPIES: GLATIRAMER ACETATE (GA) • GA vs. placebo: No significant differences in neuropsychological testing scores over 24 months in a prospective observational study1 • GA does mitigate grey matter loss2 and whole-brain volume loss.3 1Ehling R et al. JNeuroimmunol. 2015; 287: 98-105. 2Crescenzo F et al. MultSclerRelat Dis. 2019; 27: 305-311. 3Zivadinov R et al. J Neurol Sci. 2018; 387: 152-156.

  28. DISEASE-MODIFYING THERAPIES: TERIFLUNOMIDE (TFM) • TEMSO trial: TFM showed 30.6% relative reduction in brain volume loss at 24 months, vs. placebo.1 • Teri-RADAR study: 25.9% of patients on TFM vs. 58.6% on DMF (p=0.0135) had annualized %age whole-brain volume change (PBVC) < -0.04%.2 1Radue EH. et al. NeurolNeuroimmunolNeuroinflamm. 2017; 4: e390. 2Zivadinov R. et al. J Comp Eff Res. 2019; 8: 305-316.

  29. DISEASE-MODIFYING THERAPIES: DIMETHYL FUMARATE • DEFINE trial: DMF showed 30% relative reduction in brain atrophy at 24 months, vs. placebo.1 • CONFIRM trial: DMF showed 32% relative reduction in brain atrophy from years 1->2, vs. glatiramer acetate.2 • DMF ↓ % whole-brain volume change (PBVC) vs. placebo over 12 months in a retrospective study.3 1Arnold DL. et al. J Neurol. 2014; 261: 1794-1802. 2Miller DH. et al. Neurol. 2015; 84: 1145-1152. 3Dupuy SL. et al. NeurolTher. 2016; 5: 215-229.

  30. DISEASE-MODIFYING THERAPIES: FINGOLIMOD (FGM) • FGM: 32-38% relative reduction in brain volume loss at 16-24 months, vs. placebo.1-2 • PREFERMS: FGM superior to injectable interferons and glatiramer acetate for brain volume protection and SDMT scores3 1Khalid F. et al. Int J Neurosci. 2017; 127: 396-403. 2Zivadinov R. et al. J Neuroimag. 2018; 28: 399-405. 3Cree BAC. et al. Neurol. 2018; 11: 1-15.

  31. DISEASE-MODIFYING THERAPIES: NATALIZUMAB (NTZ) • Cerebral grey matter volume remained stable in an uncontrolled study of adults receiving NTZ over 12 months.1 • Effects plateau long-term.2-3 1Khalid F. et al. Int J Neurosci. 2017; 127: 396-403. 2Eisele P. et al. J Neuroimag. 2019; 29: 190-192. 3Koskimaki F. et al. PLoS One. 2018 Dec 21;13(12):e0209326.

  32. OCRELIZUMAB (OCR) • Relapsing MS: % ↓ brain volume week 24 -> 96 was significant in OPERA 1 trial of OCR vs. β-IFN1a (22.8%, p = 0.004) but not in OPERA 2 (14.9%, p = 0.09).1 • ORATORIO trial in primary progressive MS: OCR showed 17.5% relative reduction in brain volume loss vs. placebo at 120 weeks (p = 0.02).2 1Hauser SL. et al. N Engl J Med. 2017;376: 221-234. 2Montalban X. et al. New Engl J Med. 2017; 376: 209-220.

  33. DISEASE-MODIFYING THERAPIES: SIPONIMOD (SPM) • EXPAND trial in SPMS (n = 1342):1 SPM showed 15% relative reduction in % change in brain volume at month 24, vs. placebo • First FDA-approved agent for SPMS 1Kappos L et al. Lancet. 2018; 391: 1263-1273.

  34. DISEASE-MODIFYING THERAPIES: CLADRIBINE (CDB) • Analysis of CLARITY trial data:1 • CDB 3.5 mg/kg over 2 years showed 17% relative reduction in brain atrophy from months 6 to 24 (-0.77% +/- 0.94%), vs. placebo (-0.95% +/- 1.06%, p=0.02). • Pseudoatrophy may still have ↓ed treatment effect. • Two years of follow-up may also have been insufficient to show full treatment effect. 1De Stefano et al. MultScler J. 2018; 24: 222-226.

  35. DISEASE-MODIFYING THERAPIES: ALEMTUZUMAB (ALM) • CARE-MS I and II:119-62% relative reductions in brain volume loss vs. IFN-1a at 24 months, with inter-trial discrepancy likely reflecting pseudoatrophy. • CARE-MS I2 and CARE-MS II3 extension trials:Alemtuzumab (ALM) continued to slow brain volume loss in years 3-5 without retreatment. 1Arnold DL et al. Neurol. 2016; 87: 1464-1472. 2Havrdova E et al. Neurol. 2017; 89: 1107-1116. 3Coles AJ et al. Neurol. 2017; 89: 1117-1126.

  36. COGNITION AND MS: OTHER APPROACHES STEM CELL TRANSPLANT • Brain atrophy accelerates >3% after immune ablation followed by immune reconstitution therapy (IRT) with autologous hematopoietic stem cell transplant,1 especially grey matter atrophy.2 • Effect of pseudoatrophy? Brain volume loss does taper. 1Lee H. et al. MultScler. 2017; 23: 420-431. 2Lee H. et al. MultScler. 2018; 24: 1055-1066.

  37. COGNITION AND MS: OTHER APPROACHES • Systematic review and meta-analysis of the effects of acetylcholinesterase inhibitors and stimulants on cognition in 950 adults with MS (mean age ~44 years):1 • No effect vs. placebo for AChEIs (donepezil, rivastigmine)or stimulants (modafinil, methylphenidate, amphetamine salts) • NB: Not all included trials selectively sampled people with MS who had objective cognitive dysfunction - ↓ effect size? • 1Cotter J et al. NeurosciBiobeh Rev. 2018; 86: 99-107.

  38. COGNITION AND MS: MEDICATIONS • Modafinil 200 mg daily for 2 weeks ↑ scores on the WAIS-III Letter-Number Sequencing Task, vs. placebo.1 • Extended-release mixed amphetamine salts 10 mg: A single dose ↑ SDMT processing speed by >5 points in a randomized trial (n = 52, p = 0.043)!2 • 1Ford-Johnson L et al. Rehabil Psychol. 2016; 61: 82-91. • 2Morrow SA, Rosehart H. Psychopharmacol. 2015; 232: 4253-4259.

  39. COGNITION AND MS: MEDICATIONS • Donepezil modestly improved Selective Reminding Test scores over 24 weeks in 69 adults with MS (p = 0.043).1 • Memantine did not ↑ PASAT scores in a randomized trial2 and can ↑ MS symptoms.3 • 1Krupp LB et al. Neurol. 2004; 63: 1579-1585. • 2Peyro Saint Paul L et al. J Neurol Sci. 2016; 363: 69-76. • 3Villoslada P et al. Neurol. 2009; 72: 1630-1633.

  40. COGNITION AND MS: DALFAMPRIDINE • Prospective trials: • ↑ cognition independent of effect on ambulation1 • ↑ verbal fluency2 • ↑ alertness, psychomotor speed and verbal fluency3 1Korsen M. et al. Brain Behav. 2017; 7: e00559; DOI:10.1002/brb3.559. 2Broicher SD. et al. J Neurol. 2018; 265: 1016-1025. 3Magnin E et al. Eur Neurol. 2015; 74: 243-250.

  41. COGNITION AND MS: OTHER APPROACHES HIGH-DOSE SIMVASTATIN IN SPMS • In MS-STAT trial (n= 40),1 simvastatin 80 mg daily: • Increased Frontal Assessment Battery scores by ~7% at 24 months compared with control group • Did not affect other cognitive endpoints, or frontal atrophy as measured by MRI 1Chan D. et al. Lancet Neurol. 2017; 16: 591-600.

  42. COGNITION AND MS: OTHER MEDICATIONS • Anticholinergic bladder medications worsen cognition in MS.1 • Melatonin did not improve cognitive or other disability.2 • 1Morrow SA et al. J Neurol Sci. 2018; 385: 39-44. • 2Roostaei T et al. Iran J Allergy Asthma Immunol. 2015; 14: 589-595.

  43. COGNITION AND MS: DIETARY FACTORS • Vitamin D: Vitamin D3 replacement for three months targeted to goal serum 25-(OH)D level >35 ng/mL ↑ed scores on Montreal Cognitive Assessment (MoCA) and Brief Visuospatial Memory Test – Delayed Recall (BVMT-DR) but not on SDMT or Stroop test.1 • Dose: High-dose ergocalciferol ↑es serum 25-(OH)D level more than low-dose cholecalciferol.2 1Darwish H et al. Sci Rep. 2017; 7: 45926. doi: 10.1038/srep45926. 2Hiremath GS et al. MultScler. 2009; 15: 735-740.

  44. COGNITION AND MS: DIETARY FACTORS • ↑ BMI (but not ↓vitamin D level) was an independent risk factor for ↓ normalized grey matter volume (nGMV).1 • Wahls Protocol (modified paleo diet, exercise, lower limbs e-stim and stress management) feasibility trial: Modest improvements in Cognitive Stability Index, Delis-Kaplan Executive Function System and WAIS scores2 1Mowry EM et al. Neurol. 2018; 91: e2256-e2264. 2Lee JE et al. J Am CollNutr. 2017; 36: 150-168.

  45. COGNITIVE REHABILITATION IN MS • A 2018 systematic review1 yielded only one new practice standard: Modified Story Memory Technique (mSMT).2 • Systematic review of systematic reviews of rehabilitation in MS: inconclusive evidence for cognitive rehabilitation3 • Overall quality of reporting is suboptimal.4 1Goverover Y. et al. Arch Phys Med Rehabil. 2018; 99: 390-407. 2Chiaravallotti ND. et al. Neurol. 2013; 81: 2066-2072. 3Khan F and Amatya B. Arch Phys Med Rehabil. 2017; 98: 353-367. 4Mhizha-Murira JR. et al. ClinRehabil. 2018; 32: 243-254.

  46. COMPUTERIZED COGNITIVETRAINING • Systematic reviews and meta-analyses of randomized trials showed modest gains in: • Memory domain scores (p= 0.04, 95% CI 0.01-0.43)1 • Attention, processing speed, executive function, verbal and visuospatial memory (g = 0.30, 95% CI 0.18-0.43)2 1Dardiotis E et al. MultSclerRelatDisord. 2018; 20: 58-66. 2Lampit A et al. NeurorehabNeural Repair. 2019; 33: 695–706.

  47. OTHER APPROACHES: AEROBIC EXERCISE • Systematic review of 26 studies including 6 randomized trials: positive (but not definitive) evidence that exercise, physical activity and physical fitness protect cognition1 • Meta-analysis of 36 exercise intervention trials in 6 chronic brain disorders (8 trials in MS):2 ↑ attention, memory, executive function, psychomotor speed 1Dardiotis E et al. Neuropsychol Rev. 2016; 26: 271-294. 2Dauwan M et al. J Neurol. 2019; (https://doi.org/10.1007/s00415-019-09493-9).

  48. COGNITION AND MS: OTHER APPROACHES • Active exergames: • Whole-body, moderate-intensity physical exercises performed through active video games • Meta-analysis of 13 trials found a moderate effect on executive function and visual-spatial abilities.1 1Mura G et al. Eur J PhysRehabil Med. 2018; 54: 450-462.

  49. OTHER APPROACHES: TELEREHABILITATION • Randomized controlled trial of active cognitive remediation (ACR) vs. active control condition (ordinary computer games) for 60 hours over 12 weeks (n=135):1 • Modest improvement in composite of PASAT, WAIS-IV, Selective Reminding Test, Brief Visuospatial Memory Test-Revised, and Dellis-Kaplan Executive Function System Trails (My Cohen’s d effect size was ~0.4.) 1Charvet LR et al. PLoS One. 2017 May 11;12(5):e0177177.

  50. COGNITION AND MS: REPETITIVE TRANSCRANIALMAGNETIC STIMULATION • High-frequency rTMS of the right dorsolateral prefrontal cortex ↑ed performance on a working memory task, compared with baseline and with sham rTMS (n = 28).1 • rTMS can even be delivered at home with telehealth supervision.2 1Hulst HE et al. J NeurolNeurosurg Psychiatry. 2017; 88: 386-394. 2Charvet L et al. Neuromodulation. 2018; 21: 383-389.

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