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

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

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

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)

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

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

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

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

Special considerations in pediatric onset MS

Disease activity is higher in pediatric-onset MS than in adult-onset MS

Waubant, Arch Neurol, 2009

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

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)

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.

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

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

Case Vignette

Pediatric MS: A Neuropsychological

Perspective

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

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

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

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

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

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

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

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

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

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

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% ---

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

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

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

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

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

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

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

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

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

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

MRI metrics: • Normalized brain volume • Normalized grey matter volume • Lesion volume

• Corpus callosum area • Volume in thalamus

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

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

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

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

Relationship between IQ and thalamic volume in the control and MS group

Till et al., Neuropsychology, 2011

Fuentes et al., JINS, in review

Are medial temporal lobe structures vulnerable in pediatric onset MS?

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?

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

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

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.

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

How does reduced FA impact cognition in pediatric MS?

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

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

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

No significant mean group changes in cognitive function over a 12-16 mo. period

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

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

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

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

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

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

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

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?

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