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Objective
To assess longitudinal changes in cognitive
function among individuals with pediatric MS
evaluated within the US Network of Pediatric
MS Centers
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%
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
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
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)
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
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)
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)
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)
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
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%)
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
Change in total number of
impaired tests
Cognitive Change Index (CCI)
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
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)
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,
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

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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
  • 13. Change in total number of impaired tests
  • 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

Editor's Notes

  1. 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
  2. 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
  3. UAB n=4 UCSF n=4 Boston n=10 SUNY Buffalo n=3 SUNY Stony Brook n=39
  4. 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
  5. 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)
  6. 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
  7. Equal distribution- about same amount improve as decline
  8. 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
  9. 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
  10. 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.