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2012
MSJ19710.1177/1352458512466606Multiple Sclerosis JournalHarder et al.

MULTIPLE
SCLEROSISMSJ
Research Paper JOURNAL

Multiple Sclerosis Journal

Cognitive functioning in 19(7) 947952


The Author(s) 2012
Reprints and permissions:
pediatric transverse myelitis sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/1352458512466606
msj.sagepub.com

Lana L Harder1,2,3, Alice Ann Holland1,2, Elliot Frohman1,3,


Donna Graves1,3 and Benjamin M Greenberg1,3

Abstract
Background: Transverse myelitis (TM) is an inflammatory disease of the spinal cord. In pediatric TM patients, cognitive
and psychological problems have been described only anecdotally.
Objectives: Study aims include describing cognitive dysfunction among a cohort of pediatric TM patients as well as
qualitatively exploring the impact of depression, medication, and fatigue on cognitive functioning.
Methods: Twenty-four consecutive TM patients referred to a pediatric demyelinating diseases clinic completed
neuropsychological screening. Means, standard deviations (SD), and percentages of patients performing at or below 1.0,
1.5, and 2.0 SD from the mean on tests administered are presented.
Results: Means were generally average across domains; however, scores ranged widely across subjects within each
domain. The highest rate of deficits was observed in fine-motor speed/dexterity. Slightly higher frequencies of impairment
were observed in attention and memory as compared to processing speed and verbal fluency. Results did not suggest a
clear association between cognitive problems and depression or medication use but did suggest that fatigue may impact
cognitive functioning.
Conclusions: This study is the first to document cognitive deficits in pediatric TM and raises questions regarding our
understanding of the central nervous system (CNS) injury associated with TM. Findings warrant further exploration of
neuropsychological outcomes in TM to inform appropriate intervention.

Keywords
Neuropsychology, transverse myelitis, pediatric demyelinating disease
Date received: 30th May 2012; revised: 12th September 2012; accepted: 7th October 2012

Introduction
Idiopathic transverse myelitis (TM) is diagnosed based on investigation of cognitive functioning likely derives from
evidence of inflammation within the spinal cord and the the perceived restricted anatomic localization of TM.6 In
absence of cerebral involvement, generally differentiating our multi-disciplinary TM center, we routinely assess all
it from acute disseminated encephalomyelitis (ADEM) and central nervous system (CNS) demyelinating disease
multiple sclerosis (MS). Estimates suggest that up to 20% patients with neuropsychological screening. The objec-
of TM cases emerge prior to age 18 years.1 Previous tive of the present study was to describe cognitive dys-
research has not systematically characterized this highly function among pediatric TM patients.
disabling disorder among pediatric patients; however,
research has begun to elucidate the unique experiences of
pediatric patients with TM.2,3
1Childrens Medical Center Dallas, USA.
Cognitive impairment is commonly associated with 2University of Texas Southwestern Medical Center, Department of
brain-based demyelinating diseases including MS and Psychiatry, USA.
ADEM, conditions that target both the brain and spinal 3University of Texas Southwestern Medical Center, Department of

cord.4 Further, pediatric demyelinating disorders are Neurology and Neurotherapeutics, USA.
commonly associated with a constellation of highly com-
Corresponding author:
plex psychosocial manifestations.5 Problems with cogni- Lana L Harder, Childrens Medical Center Dallas, 6300 Harry Hines
tive and psychological functioning in pediatric TM have Blvd, Suite 900, Dallas, Texas 75235, USA.
been described anecdotally.3 The paucity of systematic Email: lana.harder@childrens.com
948 Multiple Sclerosis Journal 19(7)

Methods of the participant and available age-based normative data for


each measure. Ages of participants for whom normative data
Participants were available are listed by test below. Of note, two patients
Twenty-four consecutive pediatric idiopathic TM patients, had no use of their hands and thus were not administered
aged 5 to 18 years, were evaluated during a visit at the tasks requiring fine-motor skills; in those cases, no hand
Childrens Medical Center Dallas Pediatric Demyelinating preference was indicated. Verbal learning and memory was
Diseases Clinic over a period of 29 months. One patient had assessed with the California Verbal Learning Test, Childrens
experienced recurrent TM. Patients who met criteria for Version (CVLT-C; 516 years)7 and CVLT, Second Edition
ADEM, MS, or neuromyelitis optica (NMO) were excluded. (CVLT-II; 1718 years).8 Auditory attention and working
Age of onset ranged from 1 to 17 years, with a mean of 9.67 memory were assessed with the Digit Span subtest from the
years. All were at least 30 days from acute symptoms and/or Wechsler Intelligence Scale for Children, Fourth Edition
any acute therapeutic intervention (i.e. steroids); however, (WISC-IV; 616 years)9 and Wechsler Adult Intelligence
approximately 46% of participants were prescribed medica- Scale, Third Edition (WAIS-III; 1718 years).10 Motor-based
tion (i.e. selective serotonin reuptake inhibitors (SSRIs), processing speed was assessed with the Symbol Search sub-
GABAergic medications, tricyclic antidepressants, anticho- test from the WISC-IV/WAIS-IV. The Symbol-Digit Modali-
linergic agents). Time since symptom onset ranged from one ties Test (SDMT; 818 years), Oral Version,11 provided a
to 135 months with a mean of 22 months. measure of motor-free processing speed. Visual-motor inte-
All subjects for whom imaging data were available (n = gration and visual perception were assessed with the Beery
20) had normal brain magnetic resonance images (MRIs) Developmental Test of Visual-Motor Integration, Fifth Edi-
except one patient, who had one non-specific T2 hyperin- tion (VMI-5; 518 years).12 The Grooved Pegboard13 (518
tense lesion not characteristic of ADEM or MS. Four years) was used to assess bilateral fine-motor speed and
patients were remote from their diagnosis years earlier at coordination. Measures of simple and complex attention and
outside institutions and thus brain imaging was unavailable sequencing were assessed with the Trail-Making Test (TMT;
for review. MRI scans of the cervical and thoracic spine 918 years).14 Verbal fluency was measured with the Letter
were available for all but one patient. Fifty-four percent of Fluency subtest from the Delis-Kaplan Executive Function
patients had longitudinally extensive lesions defined as a System (DKEFS; 818 years).15
lesion spanning greater than or equal to three vertebral seg-
ments; however, NMO-immunoglobulin G (IgG) testing Assessment of emotional functioning, fatigue, and school perfor-
was negative in these patients. Cervical lesions were pre- mance. At the time of the evaluation, patients and caregiv-
sent in 54% of TM patients. Forty-six percent of patients ers completed the Pediatric Quality of Life (PedsQL; 518
had normal ambulation, 17% had an abnormal gait but years) Multidimensional Fatigue Scale.16 Caregivers com-
ambulated independently, 29% required bilateral support pleted the Behavior Assessment System for Children, Sec-
(i.e. crutches), and 8.3% were wheelchair bound. ond Edition (BASC-2; 518 years)17 and a non-standardized
school history questionnaire, which included a Likert-type
rating of academic functioning that allowed the parent to
Procedure rate their childs performance in reading/language arts, his-
This project was a retrospective study approved by the tory/social studies, math, and science on the following
Institutional Review Board (IRB) at the University of Texas scale: failing, below average, average, above average.
Southwestern Medical Center. Each participant completed
a brief 60-minute neuropsychological screening evaluation Mobility assessment. The Hauser Ambulation Index is an
administered by a trained examiner as part of his or her established rating scale that assesses mobility based on
clinical evaluation. Additionally, parents completed ques- time to walk 25 feet and need for assistance. Ratings range
tionnaires related to their childs functioning in the areas of from 0, indicating normal ambulation, to 9, indicating that
psychological and school functioning. Caregivers as well the patient is restricted to a wheelchair and unable to trans-
as patients completed questionnaires related to the patients fer independently.
experience of fatigue. Clinical information was recorded
including details regarding diagnosis (i.e. age at onset), Statistical analyses
medication use, and ambulation.
Descriptive data was generated using the Statistical Package
for the Social Sciences, version 18.0.
Measures
Neuropsychological evaluation. A brief neuropsychological
battery was administered to assess multiple domains. Multi-
Results
ple qualified examiners administered assessments. There Demographic information and clinical data are presented in
were slight variations in tests administered based on the age Table 1. Age of participants at the time of the evaluation
Harder et al. 949

Table 1. Medical and demographic information. moderate, and severe deficits were revealed in 40.9%,
Variable Mean SD Range 22.7%, and 13.6% of participants, respectively. In the area
of graphomotor (i.e. paper/pencil) skills, mild, moderate,
Age (years) at onset 9.67 4.84 117 and severe deficits in visual-motor integration were
Age (years) at evaluation 11.46 3.36 518 observed in 28.6%, 19%, and 4.8%, respectively. Across
Time since symptom onset (months) 22.13 39.37 1135 areas assessed, the lowest rate of impairment was observed
Hauser Ambulation Index 2.58 2.90 09 in the area of visual perception, with only 4.5% of the
Variable n %
cohort falling in the mildly impaired range and none falling
On medicationa 11 45.80
into moderate or severe ranges.
Cervical 13 54.20
Longitudinally extensive lesionb 13 54.20
Female 15 62.50 Attention and executive function
Right handed 21 87.5
Race/ethnicity Approximately 18.2% of participants showed moderate
White 15 62.50 impairment in auditory attention and working memory (i.e.
Black or African-American 1 4.20 Digit Span), while 40.9% had at least a mild deficit. Parents
Hispanic or Latino 6 25.00 reported at-risk or subclinical attention problems in
American Indian or Alaska Native 1 4.20 approximately 30% of participants. Interestingly, no
Asian 1 4.20 patients demonstrated severe problems in this area, nor did
aIncluded
participants parents report clinically significant attention
medication known to have potential cognitive impairment
(i.e. selective serotonin reuptake inhibitors (SSRIs), GABAergic problems. While 5.6% of participants showed severe defi-
medications, tricyclic antidepressants, and anticholinergic agents); cits in simple attention (i.e. Trail-Making Test A), 11.1%
bdefined as lesion spanning greater than or equal to three cord segments.
showed severe deficits in complex attention and sequenc-
ing (i.e. Trail-Making Test B). Mild and moderate deficits
were noted in the area of verbal fluency for 25% and 20%
ranged from 5 to 18 years, with a mean of 11 years. Sixty- of the sample, respectively.
three percent were female and approximately 88% were
right handed. Most participants were White (62.5%) fol-
Verbal memory
lowed by 25% who were Hispanic or Latino.
Results of the neuropsychological screening evaluation In the area of verbal memory, deficits in initial free recall
show that all mean scores for the group were within the (i.e. CVLT-C/II Trial 1) were mildly and moderately
average range with the exception of fine-motor speed and impaired at rates of 33.3% and 20.8%, respectively. Rates
dexterity with the non-dominant hand, which was slightly of deficits in free recall generally decreased with opportuni-
below average. Since scores ranged considerably among ties for rehearsal of the information (i.e. CVLT-C/II Trial 5),
this cohort, mean scores as well as ranges and percentages with 12.5% falling in the mildly impaired range and 4.2%
of the sample falling at or below 1.0, 1.5, and 2.0 standard falling in the severely impaired range. Long delay free
deviations (SD) from the mean are presented in Table 2. recall was mildly, moderately, and severely impaired in
Scores are presented as standard scores (mean = 100; SD = 25%, 8.3% and 4.2% of participants, respectively.
15), scaled scores (mean = 10; SD = 3), or T-scores (mean
= 50; SD =10).
Processing speed
For the purposes of describing performance on standard-
ized performance-based measures, scores at or below 1.0 Timed tasks were administered to measure motor-based
SD from the mean, or the 16th percentile, are described as processing speed (i.e. Symbol Search) and non-motor pro-
mildly impaired. Scores at or below 1.5 SD, or at approxi- cessing speed (i.e. SDMT). Mild and moderate deficits in
mately the fifth percentile, are moderately impaired. Scores motor-based processing speed were observed at rates of
falling at or below 2 SD from the mean (second percentile) 20% and 10%, respectively. When the motor component
are considered severely impaired. was removed, moderate and severe impairment were
observed at rates of 10% and 5%, respectively.
Fine-motor and visual-motor skills
Additional clinical and psychosocial factors
Within this cohort, the highest frequency of scores falling
below the mean was in the area of bilateral fine-motor Data regarding parent-report of symptoms of depression
speed and dexterity, with a lower mean score observed for and attention problems, parent and self-report of fatigue,
the non-dominant hand. For the non-dominant hand, mild school performance, and need for further testing are pre-
deficits were observed in 45.5% of subjects, with severe sented in Table 3. According to parent report on the BASC-
deficits noted in 36.4%. For the dominant hand, mild, 2, TM subjects experienced subclinical (21.7%) or clinical
950 Multiple Sclerosis Journal 19(7)

Table 2. Neuropsychological characteristics.


Variable n Mean SD Range 1 SD 1.5 SD 2 SD
VMI SS 21 88.76 10.19 68106 28.60 19.00 4.80
VMI Visual Perception SS 22 98.73 9.87 84117 4.50 0 0
Grooved Pegboard
Dominant SS 22 90.27 18.72 55116 40.90 22.70 13.60
Non-dominant SS 22 82.41 21.18 55116 45.50 36.40 36.40
Digit Span ScS 22 8.55 2.20 513 40.90 18.20 0
Symbol Search ScS 20 9.75 2.79 517 20.00 10.00 0
Letter Fluency ScS 20 9.35 2.74 514 25.00 20.00 0
Trail-Making Test A SS 18 100.39 13.81 55116 5.60 5.60 5.60
Trail-Making Test B SS 18 101.00 17.48 55122 11.10 11.10 11.10
SDMT SS 20 102.05 17.08 61142 10.00 10.00 5.00
CVLT-C/II
Total 15 TS 24 49.17 11.58 2165 29.20 12.50 4.20
Trial 1 SS 24 95.92 13.68 78115 33.30 20.80 0
Trial 5 SS 24 103.71 16.24 55130 12.50 4.20 4.20
Long Delay Free SS 24 99.25 14.44 55115 25.00 8.30 4.20
Recognition SS 24 97.71 14.34 70115 25.00 16.70 12.50

Scores are presented as standard scores (SS) with mean = 100 and SD = 15; scaled scores (ScS) with mean = 10 and SD = 3; or T-scores (TS) with
mean = 50 and SD =10 1, 1.5 and 2 standard deviation (SD) columns indicate percentage of sample at or below those levels;VMI:Visual-Motor Inte-
gration; SDMT: Symbol-Digit Modalities Test; CVLT-C:/II California Verbal Learning Test, Childrens Version, second edition.

Table 3. Clinical and psychosocial characteristics.


Variable n % Mean SD Range
School problems 8 33.30
Referral for further testing 7 29.20
Depression 53.78 11.42 3782
At-risk 5 21.70
Clinically significant 2 8.70
Attention problems 50.13 10.04 3665
At-risk 7 30.40
Clinically significant 0 0
Sleep/rest fatigue Parent 66.86 15.19 4292
Mild 9 42.90
Severe 6 28.60
Self 66.76 17.29 38100
Mild 8 38.10
Severe 0 0
General fatigue Parent 57.81 20.47 488
Mild 7 33.30
Severe 11 52.40
Self 62.29 19.60 2196
Mild 3 14.30
Severe 9 42.90

Depression and attention problems are based on Behavior Assessment System for Children, Second Edition (BASC-2) Parent report; fatigue scores
are derived from the Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale.

(8.7%) levels of depression in a total of 29% of participants. related fatigue (42.9% and 28.6%, respectively). Self-report
Participants and their parents completed rating forms on the of general fatigue indicated rates of 14.3% and 42.9% mild
patients experience of fatigue during the screening evalua- and severe fatigue, respectively. Thirty-eight percent of par-
tion. Parent report indicated mild and severe general fatigue ticipants indicated mild sleep-related fatigue and none
(33.3% and 52.4%, respectively) and mild and severe sleep- reported severe fatigue in this area. Across the sample,
Harder et al. 951

parent report indicated school problems, as defined by all but one of the patients referred for a full neuropsycho-
below average or failing performance in at least one of four logical evaluation experienced school difficulties.
academic domains, in 33% of participants. This study also begins to qualitatively explore clinical
As a marker of cognitive dysfunction, data were col- factors that may contribute to performance on cognitive
lected indicating which participants were referred for addi- testing such as depression, medication, and fatigue. When
tional testing (i.e. full neuropsychological evaluation) using a referral for further testing based on poor perfor-
based on poor performance on the neuropsychological mance on the screening battery as an indicator of cognitive
screening evaluation. Of the 24 participants, seven (29%) dysfunction, there was no clear relation between cognitive
patients were referred for a full neuropsychological evalua- problems and depression or medication use. In contrast,
tion. School problems were reported in all but one of the parent and self-reported fatigue appeared to be present in
participants referred for further testing (86%). most of the TM participants who were referred for further
To examine the possible role of depression, medica- evaluation, suggesting that fatigue may play an important
tion, and fatigue in cognitive functioning, qualitative role in cognitive dysfunction. This would not be surprising
review of the data was conducted. Of the seven partici- given previous research suggesting that patient report of
pants who showed elevated symptoms of depression fatigue is associated with report of cognitive problems.19
based on parent report, two received referrals for addi- Further exploration of factors such as mood, medication
tional cognitive testing. Likewise, the role of medication use, and fatigue is warranted in this population to better
was examined. Of the 11 participants who were prescribed understand the role they play in cognitive functioning,
medication (i.e. SSRIs, GABAergic medications, tricyclic which will inform targeted interventions.
antidepressants, and anticholinergic agents), only two Previous research has identified unique profiles of CSF
were referred for further cognitive testing. In this cohort, inflammation in patients with TM.20 Given the absence of
results do not suggest a clear association between cogni- obvious cerebral pathology, cognitive deficits were not
tive dysfunction and mood-related factors or adverse expected in TM patients. Yet, in our cohort, varying levels of
medication side effects. In contrast, mild to severe symp- cognitive impairment were observed. Theoretically, circulat-
toms of fatigue were reported in six out of seven partici- ing components of the inflammatory cascade could produce
pants (86%) referred for further cognitive testing. These cerebral damage without obvious lesions on MRI. Previous
results suggest that fatigue may play a meaningful role in research has identified cognitive dysfunction in patients with
performance on cognitive testing. isolated optic neuritis, 24 to 31 years from the demyelinating
event, even in patients with no obvious cerebral demyelina-
tion.21 Studies of MS patients have previously recognized
Discussion the inability of conventional MRI to identify cortical pathol-
The current study describes neuropsychological function- ogy.22 Thus, all TM patients should be screened for cerebral
ing in a cohort of 24 pediatric patients with TM. Although pathology, but even in the absence of MRI changes, neu-
mean scores were largely within the average range, partici- ropsychological testing should be completed.
pant performance varied widely within specific domains. Findings of the current study highlight the need for regu-
Varying rates of impairment were described across areas of lar multi-disciplinary surveillance and treatment of pediat-
fine-motor and visual-motor skills, verbal memory, atten- ric patients with any CNS demyelinating disease.
tion and executive function, and processing speed. The Historically, cognitive testing has been restricted to patients
highest frequency of impairment was noted in the area of with obvious cerebral involvement, but such a paradigm
bilateral fine-motor coordination, which is not surprising would result in missing those TM patients exhibiting
given motor impairment associated with TM. Beyond impairment who would be likely to benefit from academic
motor-based functioning, results showed that attention and and/or therapeutic intervention services. This study is the
memory problems are present in up to 40.9% and 33% of first to describe cognitive functioning in pediatric patients
TM patients, respectively. It should be noted that these with idiopathic TM.
problems did not typically reach the severe range of impair- Limitations of this study include the sample size. Given
ment. Consistent with this finding, 30.4% of parents that pediatric TM is an extremely rare disorder, specialized
endorsed only subclinical attention problems. Difficulties clinics provide an opportunity to study patient outcomes.
occurring at a slightly lower rate included those related to Future studies should involve multiple sites to allow for
processing speed and verbal fluency. Findings are generally larger cohorts to address this limitation. Another limitation
consistent with research on pediatric CNS demyelinating of the study surrounds the understanding of patients pre-
diseases (i.e., MS, ADEM), which has identified cognitive morbid functioning. Given the retrospective nature of the
problems in the areas of attention, memory, and processing current study, information regarding premorbid status was
speed.4,18 Evidence of these cognitive deficits is detected in not available. Of note, capturing this type of information
this cohorts rate of reported school problems. Thirty-three would have been virtually impossible for approximately
percent of patients experienced school problems. Notably, one quarter of the participants in this study given that TM
952 Multiple Sclerosis Journal 19(7)

onset occurred prior to traditional school age and problems, 8. Delis DC, Kramer JH, Kaplan E, et al. California verbal
such as those related to attention and/or learning, may have learning test, second edition. San Antonio, TX: The Psycho-
been difficult to detect at such an early age. Future prospec- logical Corporation, 2000.
tive studies of TM and cognitive functioning should attempt 9. Wechsler D. Wechsler intelligence scale for childrenfourth
edition. San Antonio, TX: Pearson, 2003.
to address this limitation by collecting data to determine
10. Wechsler D. 2008. Wechsler adult intelligence scalethird
whether cognitive dysfunction pre-dated the demyelinating
edition. San Antonio, TX: Pearson, 1997.
event. Such information would help clarify the role of CNS 11. Smith A. Symbol digit modalities test. Los Angeles: Western
inflammation on cognitive outcomes. Psychological Services, 1982.
12. Beery KE and Beery NA. The Beery-Buktenica developmen-
Funding tal test of visual motor integration, fifth edition. San Antonio,
TX: Pearson, 2006.
This research received no specific grant from any funding agency
13. Lafayette Instrument. Grooved pegboard test. Lafayette, IN:
in the public, commercial, or not-for-profit sectors.
Lafayette Instrument, 2002.
14. [United States] Army Individual Test Battery: Manual of

Conflict of interest directions and scoring. Washington, DC: War Department,
The authors declare that there are no conflicts of interest. Adjutant Generals Office, 1944.
15. Delis DC, Kaplan E and Kramer JH. Delis-Kaplan executive
function system. San Antonio, TX: The Psychological Corpo-
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