christine till, phd, c - york universitybackground ms is an autoimmune-mediated, inflammatory and...
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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
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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
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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
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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)
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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
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Axonal loss
Brain Volume
Gado +
Disease course: Clinical and MRI changes
Time
Clin
ical
Dis
abili
ty
RRMS SPMS ADS
Clinical Threshold
T2 lesion burden
MR
I
Courtesy of Dr. Amit Bar-or
Pre-clinical Relapsing-Remitting Secondary Progressive Phase MS MS
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Symptoms of MS Are unpredictable 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.
50-70% have poly-symptomatic presentation Depend on what part(s) of the CNS is affected
Optic Neuritis
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Lesion distribution in MS
Lesion location – disconnection of associative areas; can involve both white and grey matter
Temporal lobe involvement
Juxtacortical lesions
Corpus callosum
Periventricular lesions
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Special considerations in pediatric onset MS
Disease activity is higher in pediatric-onset MS than in adult-onset MS
Waubant, Arch Neurol, 2009
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Special considerations in pediatric onset MS
Yeh et al., Brain, 2009
Despite higher disease activity, time to develop disability is longer in pediatric onset MS
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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)
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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.
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Cognition in adult-onset MS
Cognitive impairment is an important feature of MS1 predicts work status2
evolves over the long-term is more frequent and severe in SPMS3 is widespread1 --- processing speed, attention, executive
function, episodic memory are commonly affected
Higher “cognitive reserve” is a protective factor4
1Benedict; 2Amato 1995; 3Amato 2001; 4Sumowski 2010
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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= .3- .59 r> 0.6
Rao et al ‘89 53 Corpus callosal size
X
Benedict et al ’04 Benedict et al ’05
Christodoulou et al ’03
37 31 37
Third ventricle width Brain atrophy Brain atrophy
X X X
Edwards et al ’01 Sanfilipo et al ‘06
40 40
White matter volume White matter volume
X X
Lazeron et al ’05 Christodoulou et al ’03
Camp et al ’05 Sanfilipo et al ‘06
82 37 99 40
T2 lesion volume T2 lesion volume
T1 lesion load T1/T2 lesion volume
X X
X X
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Case Vignette
Pediatric MS: A Neuropsychological
Perspective
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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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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
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2005 Psycho-ed Assessment (age 8, Gr. 3)
Cognitive results (WISC-IV): Verbal Comprehension SS=104 (61st %ile) Perceptual Reasoning SS=74 (4th %ile) Processing Speed SS=91 (27th %ile) Working Memory SS=83 (13th %ile)
Academic results (WIAT-II): Below Average: Word Reading, Comprehension,
Spelling, and Math (Reasoning, Numerical Operations) Average on Listening Comprehension
*Diagnosed with Learning Disability
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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
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Summary of 2007 Test Results
Intellectual skills (WASI) Verbal IQ SS=81 Performance IQ SS=69
Academic Achievement (WJ-III) show minimal gains relative to 2005 Letter-word Identification SS=47 Word Attack SS=52 Reading Fluency SS=54 Passage Comprehension SS=52 Spelling SS=67 Calculation SS=69 Applied Problems SS=56
Compare to 2005: VCI: SS=104 PRI: SS=74
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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
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Longitudinal evaluation of global intelligence
WASI
60
70
80
90
100
110
2005 (WISC-IV) 2007 (WASI) 2008 (WASI) 2009 (WASI)
Year of evaluation
Stan
dard
Sco
re
VIQ
PIQ
Longitudinal results demonstrates the deleterious effect that MS can have on cognitive development
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Prevalence of CI in 30-50%1-4
CI may be evident in early stages of disease2,3
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
1MacAlister 2005; 2Amato 2008; 3 Till 2011, 4 Banwell 2005
Cognitive impairment (CI) in childhood onset MS
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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
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Participants MS Group: • 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 MSN 34 30 26
ControlsN 33 26 -- Cognitive Evaluation
MRI
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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% ---
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Domain Tests Intelligence Wechsler Abbreviated Scale of Intelligence
Attention & Processing Speed
Trail Making Test – A Symbol Digit Modalities Test (SDMT) WJ-III: Visual Matching; Rapid Picture Naming
Language WJ-III: Picture Vocabulary WASI Vocabulary
Visuo-perceptual Beery Visuomotor Integration WASI: Block Design, Matrix Reasoning
Memory TOMAL-2 Word Selective Reminding, Stories, Facial Memory, Abstract Visual Memory
Executive Function Wisconsin Card Sorting Test (WCST) DKEFS (Colour Word Interference, Verbal Fluency)
Neuropsychological Test Battery
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Domain Tests Psychomotor Ability Hand Dynanometer
Grooved Pegboard Test
Academic Achievement WJ-III Achievement: Spelling; Single word reading, Calculation
Questionnaires Emotional & Behavioural Functioning
Behavioural Assessment System for Children (BASC-2): Parent & Self-Report
Executive Function Behaviours
Behavioral Rating Inventory of Executive Functioning (BRIEF): Parent & Self-Report
Fatigue Interview; Modified Fatigue Impact Scale – 5 item version (MFIS-5)
Neuropsychological Test Battery – cont’d
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Results: Global Intelligence fell within the average range in the MS group
-0.5
0
0.5
Full Scale IQ Verbal IQ Performance IQ
WASI Composite
z-sc
ore
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Results. Diminished Verbal IQ amongst early disease onset patients
(controlling for disease duration)
-0.5
0
0.5
Full Scale IQ Verbal IQ Performance IQ
WASI Composite
z-sc
ore
4 6 8 10 12 14 16 18
Age at disease onset (years)
Verb
al IQ
Partial correlation r= .33, p< .05
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0
10
20
30
40
TMT-A
Vis Matc
h.
Rapid Pic
Nam.
SDMT
List le
arning
List le
arning
- dela
y
Facial
Mem
ory
Visuomotor In
teg.
Perform
ance IQ
Verbal
Fluenc
y
Verbal
IQ
WCST - erro
rs
TMT B-APerc
enta
ge c
lass
ified
as
impa
ired
Attention / Speed Memory Visuo- Language Cognitive of Processing Perceptual Flexibility
Proportion impaired (<1.5 SD) on individual cognitive tests
10/34 (29.4%) of sample met criteria for CI
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Clinical Predictors of CI
Predictors CI n=10
non-CI n=24
p- value
Age at MS onset 11.1 5.1 12.6 2.8 ns
Disease Duration 5.7 4.3 3.6 2.2 .07
Age at assessment 16.8 2.9 16.2 2.0 ns
# relapses 2.6 1.5 3.8 2.6 ns
Parental education 15.9 2.7 15.1 2.5 ns
Depression 50.8 10.6 51.0 11.7 ns
Physical disability (EDSS) 1.3 0.9 1.0 0.7 ns
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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
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Initial Quality Control
Quality Control Database
Initial Quality Control
Pre Process-
ing
MRI Acquisition Parameters Ghosting Check Signal to Noise
Ratio
Acquired MR
image sent to
MNI
Courtesy of S. Narayanan, PhD
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Image pre-processing pipeline
Tissue classifier
Removal of Skull and
Scalp
Anatomical Alignment of T1w -> PD/T2w
Normalizing
Intensity
Correct intensity
non-uniformity
QC Passed
MR Image
Courtesy of S. Narayanan, PhD
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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
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MRI metrics: • Normalized brain volume • Normalized grey matter volume • Lesion volume
• Corpus callosum area • Volume in thalamus
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Regional brain measures across group
p <.001 p <.001 Corpus callosum: -7.0 % difference
Thalamic volume: -14.9% difference Lower brain size correlated with longer disease duration p < .001
Till et al., Neuropsychology, 2011
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MRI Predictors of CI
MRI metrics CI n=10
non-CI n=24
p- value
Corpus callosum area, cm2 419 94 586 55 <.001 Thalamic volume, cm3 9797 985 11352 1616 .01 Normalized brain volume, cm3
1598 131 1647 95 ns
Normalized grey matter volume, cm3
869 90 898 55 ns
Total brain T2-lesion volume (log)
3.7 0.7 3.6 0.4 ns
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Structure-function correlations in MS group Cognitive Outcome
T2-LV Corpus callosum
Thalamic volume
NBV
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
-.13 .25
.44**
.26
*p<.05 **p<.01 ***p<.001 (controlling for age)
Till et al., Neuropsychology, 2011
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Structure-function correlations in MS group Outcome T2-LV Corpus
callosum Thalamic volume
NBV
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
-.13 .25
.44**
.26
EDSS .27 -.31* -.26 -.05
Depression -.01 -.09 .03 .19
*p<.05 **p<.01 ***p<.001 (controlling for age)
Till et al., Neuropsychology, 2011
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Relationship between IQ and thalamic volume in the control and MS group
Till et al., Neuropsychology, 2011
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Fuentes et al., JINS, in review
Are medial temporal lobe structures vulnerable in pediatric onset MS?
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Fuentes et al., JINS, in review
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?
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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
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Memory impairment is not a prominent feature in our pediatric MS cohort
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Regional and Global brain volumes as predictors of Word List Learning in pediatric MS
r = .39, p<.05 r = .51, p<.01
r = .48, p<.01 r = .40. p<.05
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 new information.
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Region of interest
Normal appearing white matter (FA) MS
Mean (sd) Controls
Mean (sd) P
value %
difference Genu .49 (.08) .55 (.05) .002 -10.3 Ant. Body .32 (.07) .35 (.08) .106 -8.8 Post. Body .28 (.07) .32 (.09) .068 -11.1 Splenium .54 (.06) .61 (.05) <.001 -11.4 L Frontal .30 (.03) .31 (.02) .019 -4.5 R Frontal .29 (.03) .31 (.02) .040 -4.2 L Parietal .28 (.03) .31 (.02) <.001 -9.2 R Parietal .29 (.03) .31 (.02) .001 -7.8 L Temporal .28 (.03) .32 (.02) <.001 -8.6 R Temporal .28 (.03) .31 (.02) <.001 -8.7 L Occipital .20 (.02) .27 (.02) <.001 -10.6 R Occipital .21 (.03) .23 (.02) <.001 -9.9
DTI is sensitive in detecting differences in NAWM between MS and healthy control groups
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How does reduced FA impact cognition in pediatric MS?
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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
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How does reduced FA impact processing speed in pediatric MS?
Bethune et al., J Neurol Sciences, 309;2011
Degree of FA reduction in the MS group correlated with reduced processing speed, confirming a negative functional impact of MS on white matter pathways
r = 0.65
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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
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No significant mean group changes in cognitive function over a 12-16 mo. period
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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
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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
8.42 4.77 12.02 3.47 13.50 3.77 .09
Disease duration (at time 1), yr
4.54 2.19
4.19 3.29 3.96 2.30 .82
T2 lesion volume (at time 1), cm3
13.36 14.34 8.34 9.62 3.24 4.21 .33
∆ T2 Lesion volume†, cm3
1.62 2.3 1.16 3.7 0.16 0.14 .77
*logistic regression comparing decliners vs. stable/improve †change in T2 LV refers to change over a 12-16 mo. period
The majority of the pediatric MS sample (78%) maintained the same level of cognitive function over the 12-16 month interval
Declines were mainly on timed executive function tasks
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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
8.42 4.77 12.02 3.47 13.50 3.77 .09
Disease duration (at time 1), yr
4.54 2.19
4.19 3.29 3.96 2.30 .82
T2 lesion volume (at time 1), cm3
13.36 14.34 8.34 9.62 3.24 4.21 .33
∆ T2 Lesion volume†, cm3
1.62 2.3 1.16 3.7 0.16 0.14 .77
*logistic regression comparing decliners vs. stable/improve †change in T2 LV refers to change over a 12-16 mo. period
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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
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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
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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
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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
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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?
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Acknowledgements SickKids - collaborators SickKids- staff Brenda Banwell, MD Vicentiu Tipu, PhD John Sled, PhD Allison Bethune, MSc Melissa McGowan, MHK Montreal Neurolog. Institute Julie Coleman, MA Sridar Narayanan, PhD Carolyn Darrell, MA Daniel Garcia, PhD Suzanne McGovern, MSc Louis Collins, PhD Douglas Arnold, MD York University Rezwan Ghassemi, MSc Angela Deotto, BSc. Ameeta Dudani, MA MartinaKalahani, BSc Funding Support Bravina Bala, MA The Multiple Sclerosis Society of Canada Amanda Fuentes, MA Faculty of Health, York University Canadian Institutes of Health Research