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The Effects of Levetiracetam on Neuropsychological Functioning
in Relation to “Subclinical” Spike Production
Mark Mintz,1 Daniel LeGoff,1 Jean Scornaienchi,1 Sarah Levin,2 Pnina Mintz,1 and Cathy Smith1
1 Clinical Research Center of New Jersey and The Center for Neurological and Neurodevelopmental Health, Voorhees, New Jersey, USA;
2 Department of Psychology, Drexel University, Philadelphia, Pennsylvania, USA
Figure 1. Clinical Global Impression Scale Scoring*
Neurodevelopmental history was noteworthy for early
Table 2. Clinical Global Impression Scale Results
articulation difficulties resolved by age 5 years, early inter-
vention and preschool disabilities services (but the subject
CGI-Severity of Illness†
attended mainstream kindergarten), and, currently while
The objective is to determine if levetiracetam (LEV, Keppra®)
in third grade, difficulty following directions, poor focus
Three subjects were enrolled, 2 females and 1 male (mean
can improve neuropsychological functioning in children
and attention, and slowness in completing work. His neuro-
age, 9.5 years). Results of psychometric testing were as fol ows:
manifesting evidence of “subclinical” spike production.
logical examination was within normal limits.
Analysis of pretreatment and posttreatment scores
Subject A became irritable and had difficulty falling asleep
for the 3 participants indicated a significant improvement on
on LEV 30 mg/kg/day, so he was maintained on 20 mg/kg/day.
all indexes for 2 subjects and on 2 indexes for the third
He experienced only 1 clinical event during the study, consisting
† CGI-Improvement; done at the end of the study.
‡ CGI-Efficacy; done at the end of the study.
of garbled speech for 10 seconds; this event occurred after
There has been concern that interictal spikes, particularly
Table 1. WRAML2 Results*
rolandic spikes, with or without clinical seizures, can be
The subject was a 10-year-old female with a history of inat-
associated with attention deficit hyperactivity disorder and
tentiveness and episodes of staring. Baseline EEG revealed
deficits in visual perception, short-term memory, and overall
frequent spike- and slow-wave discharges that had electrical
• Overall, the results strongly support the hypothesis that
cognitive functioning (Deonna et al, 2000; Holtmann et al,
source localization to the right central region; there were
posttreatment scores are significantly higher than would
2003; Weglage et al, 1997). In children with benign epilepsy
no clinical phenomena noted during EEG. MRI was unre-
be predicted based on the combined effects of error and
with centrotemporal spikes (BECTS), LEV has been shown
markable except for a 5-mm pineal cyst. Her medical history
practice effects for the WRAML2, which assesses memory
to reduce seizure frequency and cause normalization of
was significant for a previous diagnosis of central auditory
and attention, but not for the WIAT-II-Abbreviated, which
electroencephalography (EEG) (Bello-Espinosa and Roberts,
processing disorder, poor social skills, anxiety, obsessive-
assesses academic achievement. Thus, this cohort of 2
2003). LEV is a novel antiepileptic drug that is indicated
compulsive behaviors, sensory issues, dyspraxia, constipation,
children with spike activity who did not have identifiable
for use as adjunctive treatment of partial onset seizures in
and myopia corrected with glasses. She achieved her neuro-
clinical seizure manifestations (subjects B and C) and
adults and children 4 years of age and older with epilepsy.
developmental milestones at age-appropriate times. She is
1 child with interictal spike activity and a history of ictal
Thus, we hypothesized that children with attentional/learn-
maintained in a mainstream classroom with supplemental
phenomenology suggestive of BECTS (subject A) had
ing difficulties and “subclinical” spikes would have improve-
educational support. Her educational profile is noteworthy
demonstrable deficits in memory and attentional function
ment of neuropsychological functioning if treated with LEV.
for poor reading comprehension, difficulty with mathematics,
at baseline that significantly improved after 10 weeks
and poor writing skills. A trial of atomoxetine in 2004 was
discontinued because of lack of efficacy. Her neurological
• Academic achievement scores did not change significantly
examination had brisk deep tendon reflexes but was other-
from baseline, but academic achievement will lag by
months after improvement in memory and attention.
† In reference to attention/learning abilities.
Subject B was titrated to LEV 40 mg/kg/day. No clinical
Follow-up testing is being planned to determine if initial
seizure phenomena were reported during the study.
improvements in attention and memory may predict later
Subjects with learning difficulties, EEG findings of focal
Her teacher reported improvement in organizational
improvements in academic achievement.
spike discharges, and Leiter International Performance
Pretreatment and posttreatment test scores were compared
Scale-Revised (Leiter-R) scores >70 were enrolled. Neuropsy-
by calculating the difference (ie, posttreatment minus
• This study adds to the literature that suggests “subclinical”
pretreatment) and comparing it with both the standard
chological testing (Wide Range Assessment of Memory and
interictal spikes might not be benign but rather might be
Learning, Second Edition [WRAML2; Sheslow and Adams,
error of measurement (SEM) for each index and the standard
The subject was a 10-year-old female with a history of
responsible for memory and attentional deficits, and thus
2003] and Wechsler Individual Achievement Test
retest gain for each subtest (based on the published stan-
inattentiveness. Her medical history was significant for
could adversely affect a child’s ability to learn. Further-
Edition [WIAT-II]-Abbreviated [Psychological Corporation,
dardization data for each test). The hypothesis that test
word-finding and memory difficulties and a previous
more, this study suggests that the antiepileptic drug LEV
2001]) was completed at baseline and after 10 weeks of LEV
scores would be higher in the posttreatment administration
diagnosis of central auditory processing disorder. Early
can ameliorate these memory and attention deficits.
therapy. Digital, 128-channel dense-array EEG recordings
was assessed as follows: difference scores that were larger
neurodevelopment was age appropriate. However, it was
• Additionally, this study suggests that “subclinical” spike
(Electrical Geodesics, Inc) were done throughout each
than the combined SEM and retest gain for that index or
noted in preschool that she had difficulty with prereading
activity should be considered in certain subsets of children
testing session. Additional endpoints incorporated scores
subtest were considered to indicate significant improvement
and math skills. Currently, she is in a special education
SEM = Standard error of measurement; SEM and retest gains are from standardization data (Sheslow and Adams, 2003).
with learning and/or attention difficulties.
from Clinical Global Impression (CGI) scales, including
classroom setting. She is described as having difficulties
* Scores are listed for subjects A/B/C, respectively.
• Further research is necessary to determine if the treatment
CGI-Severity of Illness at baseline and CGI-Improvement
with verbal tasks and short-term memory. She is also
findings are sustainable over longer periods of time. Further
and CGI-Efficacy at the end of the study (Figure 1). LEV
described as being disorganized and forgetful. Family history
analysis of EEG findings is planned to determine if the
was started at 10 mg/kg/day and then titrated weekly by
is significant for a maternal second cousin with epilepsy.
None of the WIAT-II subtest pretreat-
neuropsychometric results and response to LEV correlate
10 mg/kg/day up to a tolerable dose, with the goal of a
Baseline EEG was significant for recurrent spike- and slow-
The subject was an 8-year-old male with the first seizure
ment/posttreatment difference scores were larger than the
with spike quantity or localization.
maximum of 40 mg/kg/day. Dosing was divided to twice
wave discharges, which on digital source localization were
event 1 year before the study. Ictal manifestations involve
combined SEM and gain for that subtest for subjects A or B,
daily. After study completion, subjects were offered LEV
topographically mapped to the left occipital region and/or
speech arrest and garbled speech. Events were mostly
but there were 2 significant subtest improvements for
• Bello-Espinosa LE, Roberts SL. Levetiracetam for benign epilepsy of
left medial parietal lobe; there were no associated clinical
childhood with centrotemporal spikes-three cases. Seizure
. 2003;12:157-159. • Deonna
nocturnal and awakened the subject, although some
subject C, who showed significant gains (ie, larger than
phenomena observed during the baseline EEG. MRI was
T, Zesiger P, Davidoff V, Maeder M, Mayor C, Roulet E. Benign partial epilepsy of childhood:
daytime episodes have occurred. The baseline EEG revealed
SEM plus gain) on both Word Reading and Spelling.
a longitudinal neuropsychological and EEG study of cognitive function. Dev Med Child
unremarkable. Neurological examination was within
sharp- and slow-wave discharges maximal over the right
2000;42:595-603. • Guy W. ECDEU Assessment Manual for Psychopharmacology-
Results of clinician-rated CGI scales revealed
Rockville, Md: US Department of Health, Education, and Welfare, Public
parietal region, which on further digital electrical source
that subjects A and B had significant improvement over
Health Service, Alcohol, Drug Abuse, and Mental Health Administration, NIMH
localization were topographically mapped to the right
Subject C was titrated to 40 mg/kg/day of LEV. No clinical
the course of the study and subject C had minimal
Psychopharmacology Research Branch, Division of Extramural Research Programs; 1976.
central region; no clinical phenomena were noted during
episodes of seizure were noted during the study. The
Publication ADM 76-338. • Holtmann M, Becker K, Kentner-Figura B, Schmidt MH.
the baseline EEG. Magnetic resonance imaging (MRI) was
family reported that the subject was “more responsible.”
Increased frequency of rolandic spikes in ADHD children. Epilepsia
. 2003;44:1241-1244. • Psychological Corporation. Wechsler Individual Achievement Test®
, Second Edition,
normal. Other significant medical history included asthma,
San Antonio, Tex: The Psychological Corporation; 2001. • Sheslow D,
tonsillectomy and adenoidectomy at age 2 because of
Adams W. Wide Range Assessment of Memory and Learning, Second Edition, Admin-
recurrent otitis media infections, difficulty settling to sleep,
istration and Technical Manual.
Wilmington, Del: Wide Range, Inc; 2003. • Weglage J, Demsky A, Pietsch M, Kurlemann G. Neuropsychological, intellectual, and behavioral
and nocturnal enuresis. There was no family history of epilepsy.
findings in patients with centrotemporal spikes with and without seizures. Dev Med Child Neurol.
This presentation was supported by UCB, Inc.
1st North American Regional Epilepsy Congress 2006
Revisão da Literatura Evidências de eficácia da terapia cognitiva Evidences from the efficacy of the cognitive behavior therapy on schizophreniaElizA MARtHA dE PAivA bARREto1 , Hélio Elkis2 1 Psiquiatra, mestre em Psiquiatria pela Universidade de São Paulo (USP). Fellow em terapia cognitiva e comportamental pelo Departamento de Psiquiatria do Massachusetts General Hospital (EUA).
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