cognition in ms - isctm · •cognition in ms overview •assessment options •ms cognition in...

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





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

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





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.


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.


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?

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