Disturbi cognitivi e Sclerosi Multipla Emilio Portaccio Fondazione Don Carlo Gnocchi Firenze

1. Disturbi cognitivi e Sclerosi Multipla Emilio Portaccio Fondazione Don Carlo Gnocchi Firenze

2. Outline Prevalence and neuropsychological profile Clinical correlates MRI correlates Assessment Treatment

3. Outline Prevalence and neuropsychologicalprofile Clinicalcorrelates MRI correlates Assessment Treatment

4. Outline Prevalence and neuropsychologicalprofile Clinicalcorrelates MRI correlates Assessment Treatment

5. Variablesthat can influenceprevalencerates • Studysetting • clinic-based versus community-based • Studyepoch • Poser’s versus MacDonald’scriteria • Study sample • demographic and clinicalcharacteristics • Assessmenttools • Single test • Brief /intermediate/extensivebatteries • Computerizedbatteries • Criteria for defining CI

6. Prevalence of CI in the MS Population • Prevalence range: 40-65% • Nearly 40% in community-based studies • > 65% in clinic-based studies Reviewarticle: Chiaravalloti ND, DeLuca J. Lancet Neurol 2008

8. Community-based study: 100 MS pts. versus 100 HCs, extensive NP batteryPrevalence of CI in the MS sample 43%, (weak) correlation with EDSS Prevalence of impairment by cognitive domain 35% 30% 25% Percentage of MS group scoring 20% <5th percentile for healthy controls 22–31% 22–25% 15% 10% 13–19% 12–19% 8–9% 7–8% 5% 0% Episodic Memory Information Processing Speed & Working Memory Verbal fluency Conceptual Reasoning Visual-spatial Abilities Language Simple Attention Adapted from Rao et al. Neurology, 1991

10. The means by whichweperceive, process and interpret social information • Linked to poorquality of life, mentalhealthproblems, unemployment and loneliness

13. Mean age 39,9 years; Median disease duration 8 years; Median EDSS 2,3; RR course 77%

15. 61,7% 52,8%

20. Outline Prevalence and neuropsychologicalprofile Clinicalcorrelates MRI correlates Assessment Treatment

21. Prevalence of CI in different MS subtypes CIS: range 14-57% • 25-30%* • Comparing PP and SPMS, prevalence of CI in PPMS isreported to be inferior, comparable or superior to thatreported in SPMS Early RRMS (< 5 years): range 20-60% • 30-40%* SPMS: range 37-83% • In most of the studies>60%* time PPMS: range 7-87% • In most of the recentstudies>50%* * Criterion for CI : > 2 tests failed,1.5 – 2.0 SDs

22. Cognitive performancewas assessed in 1040 patients using a battery validated for MS, the Rao’s Brief Repeatable Battery: Selective Reminding Test (SRT) 10/36 Spatial Recall Test (SPART) Paced Auditory Serial Addition Test (PASAT) Symbol Digit Modalities Test (SDMT) Word List Generation (WLG) Stroop Test (ST) Test failure was defined as a score ≤ 2 SDs, using Italian normative values adjusted for age, sex and education as reference. Cognitive impairment was defined as impairment in ≥ 2 cognitive domains. MINIMUS: an Italian collaborative study (Ruano et al., MSJ 2017) Verbal and visuo-spatial learning IPS Executive function

23. Clinical and demographic characteristics of the study sample * Student’s t test for independent samples or χ2 test adjusted for multiple comparisons

24. Significant differences: CIS vs. SP, CIS vs. PP, RR vs. SP and RR vs. PP (p<0.001, χ2 test adjusted for multiple comparisons) Prevalence of cognitive impairment by clinical subtype Frequency of Cognitive Impairment

25. Cognitive impairment by age group (all patients) OR=1.75 [1.54; 2.00] p-value<0.001 Frequency of Cognitive Impairment Patient age (years)

26. Cognitive impairment by disability level (all patients) OR=1.99 [1.68; 2.36] p-value<0.001 Frequency of Cognitive Impairment EDSS score

27. Multivariate logistic regression model for cognitive impairment in MS 

28. Multivariate logistic regression model for cognitive impairment and for each cognitive domain   Variable selection was performed using stepwise likelihood ratio method.

29. Study design: cross-sectional, mono-centric Assessment through a computerized tool, the Mindstream GAB (NeuroTrax Corp., Bellaire, TX, USA) 1500 MS patients • In a cluster analysis, CIS and RR patients and, respectively, SP and PP patients had a similar cognitive pattern • Predictors of worse cognitive performance (linear regression): • Older age • Higher EDSS score • Longer disease duration • Sharper decline after 5 years from onset Achiron et al., PlosOne 2013

30. Cognitive performance as a function of MS duration Cognitive impairmentwasevidentonlyatfiveyears from onsetsuggesting a therapeuticwindow duringwhichpatientsmay benefit from intervetions to maintain cognitive health Achiron et al., PlosOne 2013

31. JNNP 2011 CI at baseline 29% CI after 5 years 54%

32. A 10-year longitudinal study 10 years Study onset 4.5 years Amato et al. ArchNeurol. 1995, 2001 50 patients with early MS (untreated) compared with 70 HCs CI= 26% CI 56% CI 49% Predictors of a worse cognitive outcomeafter 10 years: • Olderage • Higher EDSS • Shift from RRMS to SPMS No impairment(0-2 failedsubtests) Mildimpairment(3-5 failedsubtests) Moderate impairment(>5 failedsubtests)

33. None of the RIS had a strictlynormal cognitive function and 10/26 failedatleast 1 test (PASAT or DigitSpan) RIS «Itcould be suggestedthatthesepatients are MS patients with an undiagnosedisolated symptompresentingas cognitive dysfunction»

34. CI in Radiologically Isolated Syndrome (RIS) (Amato et al., Neurology 2012) Rao’sbattery

35. Cognitive impairment in “Benign MS” 163 patients with “benign” MS (disease duration >15 years and EDSS <3.0): • 45% cognitive impairment • 49% fatigue • 54% depression In 38% of cases, cognitively impaired patients had reduced their social and work activities measured on the Environmental Status Scale (ESS) A reliabledefinition of BMS should include the preservation of cognitive functioningas an additional requisite (Rovaris et al., Neurology 2008)

36. Cognitive impairment in «benign» MS isassociated with Greater T1 lesionloads in the WM More pronuncedcorticaltissuechanges (reducedvolumes, total and regional MTR values) Higher risk of progression to a no longerbenign status after 5 years Resultsconfirmed in a 12-year follow-up (unpublished data) CI in «BMS» isassociated with MRI metrics and mayhave a prognosticrole Amato et al., 2008, Portaccio et al., 2009

37. In CIS subjects CI predicted more rapid conversion to CDMS after a 3 year follow-up (Zipoli et al. MultScler 2010) In early RRMS patients (meandurationat baseline 23 months) baseline IPS and verbalmemoryimpairmentspredictedhigher EDSS score after 5 and 7 years(Deloire et al., MultScler 2010) In newlydiagnosed MS patients CI predictedfasterprogression to EDSS 4 and shift to SPMS in a 10-year follo-up(Moccia et al., MultScler 2015) Implications for the therapeuticconduct? CI: a factor in prognosis - Longitudinal studies

38. A «cortical variant» of MS? Clinica findings • prominent cognitive and/or psychiatricdisordersatpresentation • mostoften PP course • Positive CSF OB Neuropsychologicalfindings Severe cognitive deficits, sometimes with a «cortical pattern» (aphasia, apraxia) MRI findings • both discrete and confluent, diffuse WM abnormalities • severe brain atrophyatpresentation • higherreduction of GM fractioncompared with WM fraction • high number of CLs with DIR

39. CI in pediatric onset MS (Amato et al, Neurology 2016 Suppl 2)

40. Evolution of CI in pediatric onset MS: five-year follow-up (Amato et al, Neurology 2012) Change in Cognitive Impairment Index CCI Year 0-5 (sameversions of the tests): • 56.3% presenteddeterioration • 25% improvement • 18.7% stability Functions more prone to deteriorate: • visualspatiallearning • verbalfluency • expressivelanguage In the univariateanalysis, CI wasassociated with: • youngerageat MS onset • lowereducation

41. How do cognitive problems affect the lives of people with MS? Review article: Langdon DW, CurrOpin Neurol. 2011 Jun;24(3):244-9.

42. WhataboutPediatric MS? Results of an interview with the parents (30 patients, 25 classifiedashaving CI) • School activities Negative impact in 10 out of 30 cases (33%), all classified as having CI 3 cases had a teacher of support 7 cases had to repeat a year in school • Daily living activities Negative impact on hobbies and sport activities in 16 out of 30 cases (53%) 8 cases had to reduce or change their usual sport activities 8 cases had to quit sport activities altogether • Family and social relationships • Negative impact in 11 out of 30 cases (37%) (behavioural changes, anxiety, aggressiveness, isolation…) Amato et al., Neurology 2012

43. Outline Prevalence and neuropsychologicalprofile Clinicalcorrelates MRI correlates Assessment Treatment

44. MRI correlates of CI • Role of t1 and t2 lesion volumes and location

45. MRI correlates of CI • Role of t1 and t2 lesion volumes and location • Damage in NAWM • Role of grey matter involvement

50. Cognitive impairment in MS: the grey (does) matter – cortical volumes