Cognition in MS
Dawn Langdon, PhD FBPS
Professor of Neuropsychology
Disclosures
Consultancy from Novartis, Bayer, TEVA, Biogen, Merck, Sanofi; Speaker bureau for Almirall, TEVA, Biogen, Novartis, Bayer, Excemed, Sanofi; Research grants from Novartis, Biogen, Bayer, Merck.
Multiple sclerosisAn immunomodulatory chronic degenerative condition
Prevalence of 50–300 per 100 000 people
About 2·3 million people are estimated to live with multiple sclerosis globally
No cure, but drugs slow down disease progression
Constellation of physical, psychiatric and cognitive symptoms
About half of people with MS experience cognitive difficulties
Thompson et al., Multiple Sclerosis. Lancet. 2018 Mar 22. pii: S0140-6736(18)30481-1
Clinical Course of MS
Filippi M, Bar-Or A, Piehl F, Preziosa P, Solari A, Vukusic S, Rocca MA. Multiple sclerosis.Nat Rev Dis Primers. 2018 Nov 8;4(1):43.
Plan
• Cognition in MS overview
• Assessment options
• MS cognition in clinical trials
Benedict RHB, DeLuca J, Enzinger C, Geurts JJG, Krupp LB, Rao SM. Neuropsychology of Multiple Sclerosis: Looking Back and Moving Forward. J Int Neuropsychol Soc. 2017 Oct;23(9-10):832-842
Negative impact of cognitive deficits in MSParticipation Safety Disease
Employment Driving Medical decisions
Relationships Falls Medication adherence
Social function Rehabilitation benefit
Daily activities Symptom management
Physical independence Coping
Leisure activities
Mood
General
Life satisfaction
Health-related quality of life
Quality of Life
Langdon. Curr Opin Neurol 2011;24:244-249.
Sokolov AA, Grivaz P, Bove R. Cognitive Deficits in Multiple Sclerosis: Recent Advances in Treatment and Neurorehabilitation. Curr Treat Options Neurol. 2018 Oct 22;20(12):53.
Percentage of people with MS in employment
Kobelt et al. (MSCOI Study Group) Mult Scler 2017;23:1123-1136
0
20
40
60
80
90
70
50
30
10
82%77%
68%
54%49%
39%
29%28%
16% 15%
8%
0 5 6.5 7 8 92 3 41 6
% e
mp
loye
d
EDSS
0%
5%
10%
15%
20%
25%
30%
35%
Memory Information
Processing
Speed
Problem
Solving
Visuospatial
Abilities
Language Simple
Attention
Perc
en
tag
e o
f M
S g
rou
p s
co
rin
g
<5th
perc
en
tile
fo
r h
ealt
hy c
on
tro
ls
8–9%
12–19%
22–25%
7–8%
22–31%
13–19%
Adapted from Rao et al. Neurology, 1991;41:685–691.
Cognitive dysfunction in MS:Prevalence of impairment by cognitive domain
8
Why do we need formal assessment of MS cognition?
• Patient report confounded by depression, fatigue, anxiety and other psycho social variables
• Poor correlation with disease variables– Disease duration
– MRI
– EDSS (Disability)
• Neurologists’ detection of cognitive impairment at routine consultation is 50%
Plan
• Cognition in MS overview
• Assessment options
• MS cognition in clinical trials
Benedict RHB, DeLuca J, Enzinger C, Geurts JJG, Krupp LB, Rao SM. Neuropsychology of Multiple Sclerosis: Looking Back and Moving Forward. J Int Neuropsychol Soc. 2017 Oct;23(9-10):832-842
Assessment of Cognition
Comprehensive Batteries
Intermediate length Batteries
Brief Batteries
Screening tests
MSNQ
BRBSEFCI
MACFIMS
Ad hoc
Routine in the office
Routine NP exam.
Differential diagnosisDisability questionsRehabilitation programs
11
12
Truck SpinachGiraffeBookcaseOnionMotorcycleCabinetZebraCoachLampCeleryCowDeskBoatSquirrelCabbage
Langdon et al., Recommendations for a Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). Mult Scler. Jun;18(6):891-8.Benedict et al., Brief International Cognitive Assessment for MS (BICAMS): international standards for validation. BMC Neurol. 2012 Jul 16;12:55.
RelevanceWhat is missed without cognitive assessment
• “our study shows the potential advantages of using the BICAMS ….in everyday clinical practice. If the cognitive status is not properly measured, one out of four patients with an EDSS<=4 has a miscalculated score with an underestimation of disability. More stunning is that two out of three patients have a cognitive impairment that is not recorded during clinical practice in the CFS.”
Sacca et al., The EDSS integration with the Brief International Cognitive Assessment for Multiple Sclerosis and orientation tests. Mult Scler. 2016 Nov 1:1352458516677592.
What BICAMS adds to EDSS alone…
Benedict RH, Drake AS, Irwin LN, Frndak SE, Kunker KA, Khan AL, Kordovski VM, Motl RW, Weinstock-Guttman B. Benchmarks of meaningful impairment on the MSFC and BICAMS. MultScler. 2016 Feb 26. pii: 1352458516633517. [Epub ahead of print]
Validity of BICAMS in employment context
BICAMS sensitive to physical relapses
17
Test MS group during relapseN=60
MS group 1 month
after relapse
MS group 3 month
after relapse
ANOVA
SDMT 40.18(11.42)
46.2(12.28)
46.62(10.96)
F=43.08P<.001
BVMT-R(0-36)
22.57(6.07)
26.30(4.56)
26.93(4.62)
F=34.73P<.001
CVLT-II(0-80)
52.02(9.61)
58.45(8.36)
60.57(2.04)
F=65.87P<.001
Giedraitiene et al., Cognition during and after multiple sclerosis relapses as assessed with the Brief International Cognitive Assessment for Multiple Sclerosis. Scientific Reports. 2018;8:8169
www.BICAMS.net
BICAMS current status
• 17 countries have published peer review BICAMS national validation studies
• Nearly 20 peer review papers recommend BICAMS for routine cognitive assessment
• 11,000 PwMS assessed annually in clinics around the world
• Over 50 peer review scientific studies of MS cognition reporting BICAMS data
https://researchoutreach.org/articles/bicams-cognition-multiple-sclerosis/
Experimenter Participant
Tablet capture of cognitive data
• Requirements– Tablets for centres
– Wi-fi
– Assessment for specific patient profile
– Interface for specific patient profile
• Advantages– Accurate test administration
– Data automatically scored and sent straight to server
Plan
• Cognition in MS overview
• Assessment options
• MS cognition in clinical trials
Benedict RHB, DeLuca J, Enzinger C, Geurts JJG, Krupp LB, Rao SM. Neuropsychology of Multiple Sclerosis: Looking Back and Moving Forward. J Int Neuropsychol Soc. 2017 Oct;23(9-10):832-842
Disability outcome measuresin Phase III RRMS trials
Uitdehaag BMJ. Disability Outcome Measures in Phase III Clinical Trials in Multiple Sclerosis. CNS Drugs. 2018 Jun;32(6):543-558.
• IFNβ-1a: significant effect on information processing and learning / memory1
• Early IFNβ-1b treatment was associated with improved PASAT scores at 5-year follow-up2
Early studies indicating that DMD’s may have a weak effect on cognitive function
IFN, interferon; PASAT, Paced Auditory Serial Addition Test1Fischer JS et al. Ann Neurol 2000, 48: 885-892; 2Kappos L et al. Lancet Neurol 2009, 8:987-997;
IFNβ-1a vs placebo Early vs delayed IFNβ-1b
Mean change from baseline in PASAT-3 scores (number of correct answers) in the pooled FREEDOMS studies
p-values fingolimod vs placebo:
0.035 at Month 6
0.015 at Month 12
0.016 at Month 24
Dawn W. Langdon, Iris-Katharina Penner, Pasquale Calabrese, Gary Cutter, Dieter A. Häring, Frank Dahlke, Davorka Tomic, Ludwig Kappos. Fingolimod effects on PASAT score and baseline determinants of PASAT in a large cohort of RRMS patients. Poster AAN 2016
BICAMS’ trials
• Improving Cognition in People With Progressive Multiple Sclerosis Using Aerobic Exercise and Cognitive Rehabilitation– N=360, 6 centres across Europe and North America, funded by
Canadian MS Society
• CLARIFY QoL and cognition study– Phase IV, n=445, 2-Year Prospective Study to Assess Health-
related Quality of Life In Subjects With Highly-Active Relapsing Multiple Sclerosis Treated With Mavenclad®, Merck
• MS-STAT-2– 2-year phase III trial of simvastatin. N=1,180 PwSPMS. UK MS
Society funded.
MS trial design - challenges
• MS is changing1,2
• 1993–2002 ARRs 0.5 to .87, modern ARRs 0.16 to .373
• Changing diagnostic criteria and their adoption4
• Increasing DMD options, combinations and availability
• Personalised medicine5
• Symptom management improving6
• Improved health and life expectancy, awareness of cognitively harmful medication
• Brain Health
• Recruitment and attrition biases
1Zhang Y, Salter A, Wallström E, Cutter G, Stüve O. Evolution of clinical trials in multiple sclerosis. Ther Adv Neurol Disord. 2019 Feb 21;12:1756286419826547.
2Magyari M, Sorensen PS. The changing course of multiple sclerosis: rising incidence, change in geographic distribution, disease course, and prognosis. Curr Opin Neurol. 2019 Jun;32(3):320-326. 3Montalban X. Review of methodological issues of clinical trials in multiple sclerosis. J Neurol Sci 2011; 311(Suppl. 1): S35–S42.4Hartung HP, Graf J, Aktas O, Mares J, Barnett MH. Diagnosis of multiple sclerosis: revisions of the McDonald criteria 2017 - continuity and change. Curr Opin Neurol. 2019 Jun;32(3):327-337.5Rotstein D, Montalban X. Reaching an evidence-based prognosis for personalized treatment of multiple sclerosis. Nat Rev Neurol. 2019 May;15(5):287-300.6Miller AE, Cohen BA, Krieger SC, Markowitz CE, Mattson DH, Tselentis HN. Constructing an adaptive care model for the management of disease-related symptoms throughout the course of multiple sclerosis--performance improvement CME. Mult Scler. 2014 Jan;20(1):18-23.
MS trial design - challenges
• MS is changing1,2
• 1993–2002 ARRs 0.5 to .87, modern ARRs 0.16 to .373
• Changing diagnostic criteria and their adoption4
• Increasing DMD options, combinations and availability
• Personalised medicine5
• Symptom management improving6
• Improved health and life expectancy, awareness of cognitively harmful medication
• Brain Health
• Recruitment and attrition biases
1Zhang Y, Salter A, Wallström E, Cutter G, Stüve O. Evolution of clinical trials in multiple sclerosis. Ther Adv Neurol Disord. 2019 Feb 21;12:1756286419826547.
2Magyari M, Sorensen PS. The changing course of multiple sclerosis: rising incidence, change in geographic distribution, disease course, and prognosis. Curr Opin Neurol. 2019 Jun;32(3):320-326. 3Montalban X. Review of methodological issues of clinical trials in multiple sclerosis. J Neurol Sci 2011; 311(Suppl. 1): S35–S42.4Hartung HP, Graf J, Aktas O, Mares J, Barnett MH. Diagnosis of multiple sclerosis: revisions of the McDonald criteria 2017 - continuity and change. Curr Opin Neurol. 2019 Jun;32(3):327-337.5Rotstein D, Montalban X. Reaching an evidence-based prognosis for personalized treatment of multiple sclerosis. Nat Rev Neurol. 2019 May;15(5):287-300.6Miller AE, Cohen BA, Krieger SC, Markowitz CE, Mattson DH, Tselentis HN. Constructing an adaptive care model for the management of disease-related symptoms throughout the course of multiple sclerosis--performance improvement CME. Mult Scler. 2014 Jan;20(1):18-23.
Schwenkenbecher P, Wurster U, Konen FF, Gingele S, Sühs KW, Wattjes MP, Stangel M, Skripuletz T. Impact of the McDonald Criteria 2017 on Early Diagnosis of Relapsing-Remitting Multiple Sclerosis. Front Neurol. 2019 Mar 15;10:188.
Definition of MS endophenotypes based on response to DMT’s
Manouchehri N, Zhang Y, Salter A, Hussain RZ, Hartung HP, Hemmer B, Linker R, Segal BM, Cutter G, Stüve O. Clinical trials in multiple sclerosis: potential future trial designs. Ther Adv Neurol Disord. 2019 May 13;12:1756286419847095.
Endophenotype (EP)-based therapeutic interventions are most effective within their corresponding MS endophenotype.
Manouchehri N, Zhang Y, Salter A, Hussain RZ, Hartung HP, Hemmer B, Linker R, Segal BM, Cutter G, Stüve O. Clinical trials in multiple sclerosis: potential future trial designs. Ther Adv Neurol Disord. 2019 May 13;12:1756286419847095.
New endophenotype (EP)-based multiple sclerosis (MS) trial design versus the status quo
Following an enrichment trial design, new disease-modifying therapies (DMTs) will be assessed against intraendophenotype patient-DMT controls.
Manouchehri N, Zhang Y, Salter A, Hussain RZ, Hartung HP, Hemmer B, Linker R, Segal BM, Cutter G, Stüve O. Clinical trials in multiple sclerosis: potential future trial designs. Ther Adv Neurol Disord. 2019 May 13;12:1756286419847095.
Conclusions
• Cognition in MS is an important outcome for patients
• Increasingly included in major trials
• Changing MS landscape poses challenges for trial design
• Enriched/endophenotype designs?