Christine Till, PhD, C.Psych Clinical Neuropsychology Rounds Dept. of Psychology September 19, 2011

Transcription

1 Clinical & neuroimaging predictors of cognitive dysfunction in pediatric-onset multiple sclerosis Christine Till, PhD, C.Psych Clinical Neuropsychology Rounds Dept. of Psychology September 19, 2011

2 Overview 1. Clinical, demographic and neurological features of MS 2. Case Vignette 3. Research findings - Neuropsychological outcomes in pediatric MS - Clinical and neural correlates of cognitive impairment

3 Background MS is an autoimmune-mediated, inflammatory and neurodegenerative disease of the CNS Onset prior to age 18 occurs in <10% of all MS cases (Simone et al, 02) Annual incidence in Canadian children 0.9/100,000 (Banwell et al., 2007) Cause unknown, but presumed to involve an interplay between susceptibility genes and environmental factors, such as infectious triggers (EBV) and Vitamin D

4 MS is more prevalent in more northern and southern communities Migrating populations acquire the MS risk of the areas they move to (especially if young at time of move)

5 Clinical-demographic features of MS F:M ratio differs with age at disease onset 1:1 pre-puberty 3:1 post-puberty Heritability: 6-8% of children with MS report a positive family history of MS (Banwell et al, 2007) Disease type: Relapsing Remitting MS (RRMS) is most common in patients with MS >96% in pediatric patients vs. 70% in adults

6 Disease course: Clinical and MRI changes ADS RRMS SPMS Clinical Disability MRI Pre-clinical Relapsing-Remitting Secondary Progressive Phase MS MS Time Clinical Threshold T2 lesion burden Axonal loss Brain Volume Gado + Courtesy of Dr. Amit Bar-or

7 Are unpredictable Symptoms of MS Vary from person to person and from time to time in the same person. Symptoms may include: Fatigue, Balance problems, dizziness, incoordination, sensory impairment, cognitive deficits, depression, etc % have poly-symptomatic presentation Depend on what part(s) of the CNS is affected Optic Neuritis

8 Lesion distribution in MS Juxtacortical lesions Periventricular lesions Corpus callosum Temporal lobe involvement Lesion location disconnection of associative areas; can involve both white and grey matter

9 Special considerations in pediatric onset MS Disease activity is higher in pediatric-onset MS than in adult-onset MS Waubant, Arch Neurol, 2009

10 Special considerations in pediatric onset MS Despite higher disease activity, time to develop disability is longer in pediatric onset MS Yeh et al., Brain, 2009

11 Cognitive Dysfunction in MS There is marked enfeeblement of the memory; conceptions are formed slowly; the intellectual and emotional faculties are blunted in their totality. The dominant feeling in the patients appears to be a sort of almost stupid indifference in reference to all things. Jean Martin Charcot (1877)

12 Challenges in the study of MS and cognition Cognitive impairment is not part of case definition in MS MS considered too messy Variability in pathology / disease subtypes Lots of confounds issues of sensory and motor impairment fatigue pain psychiatric comorbidity anti-epileptic therapy side effects, etc.

13 Cognition in adult-onset MS Cognitive impairment is an important feature of MS 1 predicts work status 2 evolves over the long-term is more frequent and severe in SPMS 3 is widespread processing speed, attention, executive function, episodic memory are commonly affected Higher cognitive reserve is a protective factor 4 1 Benedict; 2 Amato 1995; 3 Amato 2001; 4 Sumowski 2010

14 Cognition in adult-onset MS Lesion volume, brain atrophy, and the extent of white matter abnormalities correlate moderately with cognitive deficits Study N MRI metric Correlation with CI r< 0.3 r= r> 0.6 Rao et al Corpus callosal size X Benedict et al Third ventricle width X Benedict et al Brain atrophy X Christodoulou et al Brain atrophy X Edwards et al 01 Sanfilipo et al White matter volume White matter volume X X Lazeron et al T2 lesion volume X Christodoulou et al T2 lesion volume X Camp et al T1 lesion load X Sanfilipo et al T1/T2 lesion volume X

15 Case Vignette Pediatric MS: A Neuropsychological Perspective

16 Background Information John, right-handed, age 11 at referral, Grade 6 Family background: Born in GTA High-school educated parents, both from Jamaica No FH of any neurological condition or learning difficulties Previously healthy boy until age 4

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18 Medical History cont d Feb 02 (age 5) - Tingling in feet & left arm - no new lesions on MRI Feb 04 (age 7) Bilateral optic neuritis (ON) *Diagnosed with MS and started on treatment (Avonex) Sept 04 (age 7) MS relapse bilateral ON vision progressively worsening

19 2005 Psycho-ed Assessment (age 8, Gr. 3) Cognitive results (WISC-IV): Verbal Comprehension SS=104 (61 st %ile) Perceptual Reasoning SS=74 (4 th %ile) Processing Speed SS=91 (27 th %ile) Working Memory SS=83 (13 th %ile) Academic results (WIAT-II): Below Average: Word Reading, Comprehension, Spelling, and Math (Reasoning, Numerical Operations) Average on Listening Comprehension *Diagnosed with Learning Disability

20 2007 Neuropsychological follow-up (age 11, Gr. 6) Relapse free since 2004, however MRI reveals new lesions Physical disability score (EDSS) = 3.0 (moderate disability in vision; fully ambulatory) Severe fatigue Major issues relate to learning Management at school: IEP in place (reduced work load, extended time limits, accommodations provided) Full-time support from an E.A. Tutor for reading Behavior: Withdrawn, quiet, frustrated with school

21 Summary of 2007 Test Results Intellectual skills (WASI) Verbal IQ SS=81 Performance IQ SS=69 Compare to 2005: VCI: SS=104 PRI: SS=74 Academic Achievement (WJ-III) show minimal gains relative to 2005 Letter-word Identification Word Attack Reading Fluency Passage Comprehension Spelling Calculation Applied Problems SS=47 SS=52 SS=54 SS=52 SS=67 SS=69 SS=56

22 Summary of cognitive results cont d Multiple areas of cognitive weakness speed of processing attention (span, sustained attention) working memory visual-perceptual & visuo-motor ability expressive language verbal learning and visual memory fine motor dysfunction Relative strengths: Verbal memory (recall) verbal reasoning and receptive language Profile consistent with diffuse cerebral dysfunction

23 Longitudinal evaluation of global intelligence 110 Standard Score WASI VIQ PIQ (WISC-IV) 2007 (WASI) 2008 (WASI) 2009 (WASI) Year of evaluation Longitudinal results demonstrates the deleterious effect that MS can have on cognitive development

24 Cognitive impairment (CI) in childhood onset MS Prevalence of CI in 30-50% 1-4 CI may be evident in early stages of disease 2,3 Neuropsychological profile is similar to adult-onset MS, with some exceptions: Involvement of linguistic skills, intellectual deficiency Risk factors? Ionger disease duration, high # of relapses, and younger age at MS onset 1 MacAlister 2005; 2 Amato 2008; 3 Till 2011, 4 Banwell 2005

25 Our Research Team s Aims: To examine 1. Cognitive functioning in childhood-onset MS 2. Clinical and neuroimaging correlates of cognitive impairment 3. Cognitive changes over time

26 MS Group: Participants Recruited from the Pediatric MS Clinic at The Hospital for Sick Children Were at least 4 weeks post-steroid treatment / relapse All presented with relapsing remitting course Controls: Age- and sex-matched Yr 1 Yr 2 Yr 3 MS N Controls N Cognitive Evaluation MRI

27 Demographics Characteristic mean (SD) MS Controls Sex, %F 77.1% 79% Age at MS onset 11.9 yrs (3.8) --- Disease duration 4.5 yrs (3.4) --- Age at assessment 16.3 yrs (2.3) 15.7 yrs (2.1) Parental Educ. yrs 16.6 (2.0) 16.1 (1.9) Disability score: EDSS median =1 (0-4) --- Disease modifying tx 82.9% ---

28 Neuropsychological Test Battery Intelligence Domain Attention & Processing Speed Language Visuo-perceptual Memory Executive Function Tests Wechsler Abbreviated Scale of Intelligence Trail Making Test A Symbol Digit Modalities Test (SDMT) WJ-III: Visual Matching; Rapid Picture Naming WJ-III: Picture Vocabulary WASI Vocabulary Beery Visuomotor Integration WASI: Block Design, Matrix Reasoning TOMAL-2 Word Selective Reminding, Stories, Facial Memory, Abstract Visual Memory Wisconsin Card Sorting Test (WCST) DKEFS (Colour Word Interference, Verbal Fluency)

29 Neuropsychological Test Battery cont d Domain Psychomotor Ability Academic Achievement Emotional & Behavioural Functioning Executive Function Behaviours Hand Dynanometer Tests Grooved Pegboard Test WJ-III Achievement: Spelling; Single word reading, Calculation Questionnaires Behavioural Assessment System for Children (BASC-2): Parent & Self-Report Behavioral Rating Inventory of Executive Functioning (BRIEF): Parent & Self-Report Fatigue Interview; Modified Fatigue Impact Scale 5 item version (MFIS-5)

30 Results: Global Intelligence fell within the average range in the MS group 0.5 z-score Full Scale IQ Verbal IQ Performance IQ WASI Composite

31 Results. Diminished Verbal IQ amongst early disease onset patients (controlling for disease duration) 0.5 z-score Full Scale IQ Verbal IQ Performance IQ Verbal IQ Partial correlation r=.33, p<.05 WASI Composite Age at disease onset (years)

32 Proportion impaired (<1.5 SD) on individual cognitive tests Percentage classified as impaired TMT-A Vis Match. Rapid Pic Nam. SDMT List learning Facial Memory List learning - delay 10/34 (29.4%) of sample met criteria for CI Visuomotor Integ. Performance IQ Verbal Fluency Verbal IQ WCST - errors TMT B-A Attention / Speed Memory Visuo- Language Cognitive of Processing Perceptual Flexibility

33 Clinical Predictors of CI Predictors CI non-ci p- n=10 n=24 value Age at MS onset ns Disease Duration Age at assessment ns # relapses ns Parental education ns Depression ns Physical disability (EDSS) ns

34 MRI 1.5T GE TwinSpeed Excite 12.0 Scanner PD- and T2-weighted images Axial dual TSE (TR/TE1/TE2 = 3500/15/63) 256 x 256, FOV 250, 2 mm thick slices T1-weighted images Whole brain, 3D SPGR (TR/TE = 22/8, 30 excitation pulse angle) 256 x 256, FOV 250, sag 1.5 mm partitions Diffusion tensor imaging (DTI) Single shot spin echo with EPI readout of 25 directions, TR/TE 8300/79 ms, 32 contiguous axial slices (5mm), 128x128, and with b = 0 and b=1000 s/ mm2

35 Initial Quality Control Initial Quality Control Acquired MR image sent to MNI Signal to Noise Ratio Ghosting Check MRI Acquisition Parameters Pre Processing Quality Control Database Courtesy of S. Narayanan, PhD

36 Image pre-processing pipeline QC Passed MR Image Correct intensity nonuniformity Normalizing Intensity Anatomical Alignment of T1w -> PD/T2w Removal of Skull and Scalp Tissue classifier Courtesy of S. Narayanan, PhD

37 Clusters of significant tissue loss (blue) in MS patients compared with controls (p >.01) MS patients show significant volume loss in thalamus and corpus callosum and significant expansion of ventricles Aubert-Broche, NeuroImage, 2011

38 MRI metrics: Normalized brain volume Normalized grey matter volume Lesion volume Corpus callosum area Volume in thalamus

39 Till et al., Neuropsychology, 2011 Regional brain measures across group Corpus callosum: -7.0 % difference p <.001 p <.001 Thalamic volume: -14.9% difference Lower brain size correlated with longer disease duration p <.001

40 MRI metrics MRI Predictors of CI CI n=10 non-ci n=24 p- value Corpus callosum area, cm <.001 Thalamic volume, cm Normalized brain volume, ns cm 3 Normalized grey matter ns volume, cm 3 Total brain T2-lesion volume (log) ns

41 Structure-function correlations in MS group Cognitive T2-LV Corpus Thalamic NBV Outcome callosum volume Full Scale IQ -.35*.52***.70***.43** Processing speed SDMT -.39*.47**.67***.53** Rapid Naming -.40*.37*.64***.51** Vocabulary -.44**.31*.64***.33* Visuomotor integration **.26 *p<.05 **p<.01 ***p<.001 (controlling for age) Till et al., Neuropsychology, 2011

42 *p<.05 **p<.01 ***p<.001 (controlling for age) Till et al., Neuropsychology, 2011 Structure-function correlations in MS group Outcome T2-LV Corpus Thalamic NBV callosum volume Full Scale IQ -.35*.52***.70***.43** Processing speed SDMT -.39*.47**.67***.53** Rapid Naming -.40*.37*.64***.51** Vocabulary -.44**.31*.64***.33* Visuomotor integration **.26 EDSS * Depression

43 Till et al., Neuropsychology, 2011 Relationship between IQ and thalamic volume in the control and MS group

44 Are medial temporal lobe structures vulnerable in pediatric onset MS? Fuentes et al., JINS, in review

45 Is hippocampal volume loss demonstrated in our pediatric MS cohort? Why? Maybe not evident in RRMS? Not long enough (pre-)clinical activity compared with adult samples? Fuentes et al., JINS, in review

46 TOMAL-2: Verbal & visual memory function Word Selective Reminding Read entire word list Ask person to repeat as many words as possible Repeat the words that were missed. Continue until all words on list are recalled (up to 6 trials) DV: Total words correctly recalled over 6 trials

47 Memory impairment is not a prominent feature in our pediatric MS cohort

48 Regional and Global brain volumes as predictors of Word List Learning in pediatric MS r =.39, p<.05 r =.51, p<.01 Learning does not rely only on medial temporal lobe structures. Relationship between verbal learning and whole brain volume reflects involvement of more diffuse cerebral regions when learning and storing r =.40. new p<.05 information. r =.48, p<.01

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52 DTI is sensitive in detecting differences in NAWM between MS and healthy control groups Region of interest Normal appearing white matter (FA) MS Mean (sd) Controls Mean (sd) P value Genu.49 (.08).55 (.05) Ant. Body.32 (.07).35 (.08) Post. Body.28 (.07).32 (.09) Splenium.54 (.06).61 (.05) < L Frontal.30 (.03).31 (.02) R Frontal.29 (.03).31 (.02) L Parietal.28 (.03).31 (.02) < R Parietal.29 (.03).31 (.02) L Temporal.28 (.03).32 (.02) < R Temporal.28 (.03).31 (.02) < L Occipital.20 (.02).27 (.02) < R Occipital.21 (.03).23 (.02) < % difference

53 How does reduced FA impact cognition in pediatric MS?

54 Symbol Digits Modalities Test (SDMT) Test of Processing Speed Oral administration DV: Total correct in 90 sec. Highly sensitive in detecting cognitive impairment in MS High test-retest reliability

55 How does reduced FA impact processing speed in pediatric MS? r = 0.65 Degree of FA reduction in the MS group correlated with reduced processing speed, confirming a negative functional impact of MS on white matter pathways Bethune et al., J Neurol Sciences, 309;2011

56 Our Research Team s Aims: To examine 1. Cognitive functioning in childhood-onset MS patients 2. Clinical and neuroimaging correlates of cognitive impairment 3. Cognitive changes over time

57 No significant mean group changes in cognitive function over a mo. period

58 Assessment of change over time Reliable change index (RCI) Measurement of clinically significant change Controls for the unreliability of tests RCI = (follow-up baseline) 2(Se ) 2 Reliable change established if it exceeds the 90% C.I. for the predicted score Classify as a decliner if decline shown on 3 or more tests

59 Change in cognitive status on at least 3/8 measures in MS patients determined using Reliable Change Index Decline (n=4) Stable (n=22) Improve (n=2) Age at diagnosis, yr Disease duration (at time 1), yr The majority of the pediatric MS sample (78%) maintained the same level of cognitive function over the month interval T2 lesion volume (at time 1), cm 3 Declines were mainly on timed executive function tasks T2 Lesion volume, cm 3 *logistic regression comparing decliners vs. stable/improve change in T2 LV refers to change over a mo. period

60 Change in cognitive status on at least 3/8 measures in MS patients determined using Reliable Change Index Variable Decline (n=4) Stable (n=22) Improve (n=2) P value* Age at diagnosis, yr Disease duration (at time 1), yr T2 lesion volume (at time 1), cm 3 T2 Lesion volume, cm 3 *logistic regression comparing decliners vs. stable/improve change in T2 LV refers to change over a mo. period

61 What have we learned? 1. Cognitive impairment documented in 29% of pediatric onset MS patients Younger age at onset influences acquisition of verbal knowledge Plasticity of an immature CNS is not sufficient to protect these patients from the deleterious consequences of MS on neural networks important for cognitive function

62 What have we learned? 2. Brain volume loss and abnormalities in both white matter and grey matter structures are observed early in the disease process visible at both the macro- and microscopic level implicate neurodegenerative processes

63 What have we learned? 3. A strong association exists between disease burden visible on MRI and cognitive impairment in children with MS Thalamic volume = top correlate of cognitive outcome White matter integrity strongly associated with mental speed Degree of correlation with cognition is much higher than found with physical disability

64 What have we learned? 4. Changes over time Important to look at changes at the individual level Cognitive deterioration may occur over time, particularly in younger-onset MS patients

65 Future directions What rehabilitative strategies can be developed to prevent cognitive decline in MS? Do youth with MS show cortical reorganization or increased cerebral activation in order to maintain the same level of performance as their peers? Are younger MS-onset patients less able to recruit compensatory mechanisms and hence are at increased risk of cognitive impairment?

66 SickKids - collaborators Brenda Banwell, MD John Sled, PhD Acknowledgements Montreal Neurolog. Institute Sridar Narayanan, PhD Daniel Garcia, PhD Louis Collins, PhD Douglas Arnold, MD Rezwan Ghassemi, MSc Funding Support The Multiple Sclerosis Society of Canada Faculty of Health, York University Canadian Institutes of Health Research SickKids- staff Vicentiu Tipu, PhD Allison Bethune, MSc Melissa McGowan, MHK Julie Coleman, MA Carolyn Darrell, MA Suzanne McGovern, MSc York University Angela Deotto, BSc. Ameeta Dudani, MA MartinaKalahani, BSc Bravina Bala, MA Amanda Fuentes, MA