Presentation on study to assess longitudinal changes in cognitive function among individuals with pediatric MS evaluated within the US Network of Pediatric MS Centers.
Introduction to Sports Injuries by- Dr. Anjali Rai
US Network Longitudinal Study of Cognitive Functioning in Pediatric MS, AAN, 2014
1. Objective
To assess longitudinal changes in cognitive
function among individuals with pediatric MS
evaluated within the US Network of Pediatric
MS Centers
2. Background
MS onset prior to age18 years has an estimated incidence of:
0.2-0.6/100,000
Cognitive impairment occurs in approximately 1/3 of those with
pediatric MS
McAllister et al. 2005 (n=37) 35%
Amato et al. 2008 (n=63) 31%
Till et al. 2011(n= 35) 29%
Julian et al. 2012, (n=231) 32%
3. Longitudinal studies are few
Amato et al. 2010: Two-year f/u (n=56), compared to controls
75% worsened on a Cognitive Change Index
Till et al. 2013: One-year f/u (n=28) compared to controls
Groups differed in rate of improvement
MS improved on 18% of measures vs Controls on 86%
Using RCI, decline occurred in 23% MS vs 4% of
Controls
4. Methods
The US Network consists of 9 pediatric MS centers
sharing a common database
Baseline and f/u cognitive testing 18 months later
was administered across 6 sites
Participants had MS or CIS and be were 30 or more
days free of a relapse and last steroid dose
5. Cognitive Test Battery
General Intelligence (WASI)
2 subtest IQ
Simple Attention (Digit Span)
Digits Forward
Digits back
Visuo-motor skill Beery (Visual-Motor Integration
Test)
Language (Expressive One-Word Vocabulary)
6. Cognitive Test Battery
WIAT-II Pseudoword decoding
Verbal Memory California Verbal Learning Test (CVLT-
C/CVLT-II )
Total learning across trials
Total long-delay free recall
D-KEFS Trail Making Test
Visual Scanning
Number Sequence
Letter Sequence
Letter-Number Sequence
Motor Speed
7. Study Cohort
53 MS, 7CIS
Age at first evaluation (NP1)
Mean = 14.36±1.95 years
range (8.11 to 17.77 years)
Time between baseline (NP1) and follow-up
testing (NP2)
Mean = 1.54 years ± 0.56 (0.75 to 2.99
years)
8. Cohort Demographic Features
N = 60; 21 male (35%), 39 female (65%)
Race
White n=46 (76.7%)
African-American n=12 (20%)
Asian n=1 (1/7%)
Other n=1 (1.7%)
Ethnicity:
Hispanic=18 (30%)
Non-Hispanic 28 (70%)
Maternal years of education:
Mean =13.8 ±2.2 years (7 - 18 yrs)
9. Cohort Clinical Features
Symptom duration at NP1
Mean =1.36 ± 1.66 years
(.09 to 8.32 years)
EDSS at NP1
Mean=1.48 ±1.21 (0 to 6)
EDSS at NP2
Mean = 1.19 ± 1.40 (0 to 4.5)
EDSS NP1 vs. EDSS NP2 ns (p=0.35)
10. Performances on individual
measures at NP1 and NP2
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
Meanzscore,n=60
Baseline Follow-Up
WASI 2
DSFWD
DSBACK
EOW
PWD
LIST A TOT
LD FREE
VISSCAN
NUM SCAN
LETTER SEQ
LETTER NUMBER
MOTOR SPEED
VMI
11. Average percentage of
impaired tests per subject
Percent of test scores <1 SD
published norm/patient
NP1: 27% ±21% (range 0 - 86%)
NP2: 26% ±21% (range 0-78%)
12. Number of impaired tests
Sum of impaired tests at baseline
Mean 4.23 ±-2.99 (0 to 12
Sum of impaired tests at follow-up
Mean 4.00 ±-3.00 (0 to 11)
Change in sum of impaired tests
-4.00 to 5, mean -.017 ± 1.95
15. Most patients showed no
change
Declined on 2 or more tasks n=8 (13.3%)
Improved on 2 or more tasks n=12 (20%)
No clear pattern of improvement or decline
on any test, in any area
Change was not related to any clinical or
demographic features
16. Comparisons with other
studies
Amato et al. (2010):
Greater proportion of low IQs
28% vs. only 1 patient in this cohort
20-40% had language problems (with
more language measures in battery)
No indication of language impairment
or decline in this cohort
More time between testing (18 months vs.
24 months)
17. Other studies
Till et al. (2013)
Lower rate of decline consistent with
findings from our cohort
Absence of expected age-related gains
Natural history control group is needed,
18. Conclusions
Cognitive impairment remains relatively
stable for most children
Relative cognitive stability is present
over similar intervals in adult MS
Nonetheless, pediatric MS patients may not
be achieving age-expected cognitive gains
Hinweis der Redaktion
McAllister criteria for impairment= 2 scores following 1.5 SDs or more below published norms on at least two tasks (2/10 scores from 6 tasks: Trails A, Trails B, COWA, BNT, Listening to Paragraphs, WRAML Verbal I And R, WRAML Visual I and R, Beery VMI) Ingraham & Aiken, 1996
Amato- comparison to 57 healthy controls
Failure on 3 tests = 31%; Failure on 2 tests – 53%; Failure = below 5th percentile (or above 95%) from HCs
WISC-R IQ, SRT Verbal learning and delayed, Spatial recall visual learnng and delayed, SDMT, TMT A, TMTB, Modified Card Sorting, Semantic and Phnoemic Verbal Fluency Tests, Oral Demonination Test from Aphasia Test, Token Test, Indication f Pictures Test, Phrase Comprehension Test= 20 variables (2/10 for impairment=20%)- bottom 5% = a little more than 1.5 SDs below mean (1.5 sd below is 7.7%)
Julian= defined as 1/3 more scores falling more than 1 SD below published norms
Till et al: Cognitive deterioration defined as clinically signfiicnat decline (RCI ) on 3 or more of the neuropscyh tests (n=22 measures: SDMT, TMT A, TMT B, WJ Visual Match, WJ Rapid Pc Naming, CPT Omission, WASI Vocab, WASI Simlarityies, Verbal Fluency, WJ Pic Vocab, TOMAL-2 WSR, Stores, AVM, FM, Beery VMI, Block Design, Matrix, Grooved Pegobard, WJ Calculation, Spelling, Ltr-Word ID, Passage Comp
At repeat assessment, Amato replaced Modified Card Sorting Test wit TOL = rate of impairment 3 tests below 5%
13.5 (n=7) classified as improving
6 (11.5%) stable
39 (75%) deteriorating
Amato 2.1 years +-.4 years
Age split 10 to 15 and more than 15- group comparison- so age 10 compared to age 15?
CCI- Conitive Change Index= 0 assigned if scored at above control mean, 1 if within 1 sd below, 2 if below sds- a variation in at least two points – improving or deteriorating
UAB n=4
UCSF n=4
Boston n=10
SUNY Buffalo n=3
SUNY Stony Brook n=39
For analysis, narrowed to tests that were most consistently administered across sites:
Participants completed a comprehensive network-wide battery of tests, of which nine tests were consistently administered at each time point. These tests yielded 13 performance scores that were compared to published normative data.
***NOTE ABOUT MISSING DATA
***NOTE ABOUT PEGBOARD
Age at first evaluation (NP1)
Mean = 14.36±1.95 years
range 8.11 to 17.77 years
Time between baseline (NP1) and follow-up testing (NP2)
Mean = 1.54 years ± 0.56 (0.75 to 2.99 years)
No significant change between NP1 and NP2- Paired sample t-tests- all p’s <.004 (bonferroni corrected; Letter-Number scan p=.032)
All group means WNL
Findings consistent with those from other studies that visumotor integration measures (Trails, Beery VMI) and attention (Digit Span) are the lowest performances
Equal distribution- about same amount improve as decline
Using Amato’s CCI – where each score is weighted relative to comparison to norms (1 for -1 to -2 SDs below norms, etc.) and then totaled for one sum at each time point= sum at time 2- sum at time 1= CCI
it is same pattern
Possible earlier treatment in our sample
Predictors? Education?
Note about pegboard
Repeating with and without pegboard and with only MS- results stay generally same
we only had 3/60 (5%) participants with IQs less than 85, none lower than 70
Kappos, L., Freedman, M.S., Polman, C.H., Edan, G., Hartung, H.P., Miller, D.H., et al., Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol, 2009. 8(11): p. 987-97.
69. Weinstein, A., Schwid, S.R., Schiffer, R.B., McDermott, M.P., Giang, D.W., and Goodman, A.D., Neuropsychologic status in multiple sclerosis after treatment with glatiramer. Arch Neurol, 1999. 56(3): p. 319-24.
70. Fischer, J.S., Priore, R.L., Jacobs, L.D., Cookfair, D.L., Rudick, R.A., Herndon, R.M., et al., Neuropsychological effects of interferon beta-1a in relapsing multiple sclerosis. Multiple Sclerosis Collaborative Research Group. Ann Neurol, 2000. 48(6): p. 885-92.
71. Pliskin, N.H., Hamer, D.P., Goldstein, D.S., Towle, V.L., Reder, A.T., Noronha, A., et al., Improved delayed visual reproduction test performance in multiple sclerosis patients receiving interferon beta-1b. Neurology, 1996. 47(6): p. 1463-8.
72. Qu, Z.X., Pliskin, N., Jensen, M.W., White, D., and Arnason, B.G., Etretinate augments interferon beta-1b effects on suppressor cells in multiple sclerosis. Arch Neurol, 2001. 58(1): p. 87-90.