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- Rationale
vention and preschool disabilities services (but the subject CGI-I†
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. WRAML2: 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 Subject B
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 Pretreatment
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, CGI-Efficacy‡
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 Memory Index
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 Side Effects
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 Memory Index
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, Therapeutic
processing disorder, poor social skills, anxiety, obsessive- Attention/
assesses academic achievement. Thus, this cohort of 2 2003). LEV is a novel antiepileptic drug that is indicated Interference
compulsive behaviors, sensory issues, dyspraxia, constipation, Concentration
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. Marked: Significant
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 Memory Index
phenomenology suggestive of BECTS (subject A) had ing difficulties and “subclinical” spikes would have improve- Moderate: Partial
educational support. Her educational profile is noteworthy demonstrable deficits in memory and attentional function ment of neuropsychological functioning if treated with LEV.
Minimal: Slight
for poor reading comprehension, difficulty with mathematics, Memory Index
at baseline that significantly improved after 10 weeks Improvement
and poor writing skills. A trial of atomoxetine in 2004 was Unchanged
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 Memory Index
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 Memory Index
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 Subject C
chological testing (Wide Range Assessment of Memory and Concentration
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 Memory Index
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. Screening
therapy. Digital, 128-channel dense-array EEG recordings was assessed as follows: difference scores that were larger neurodevelopment was age appropriate. However, it was Memory Index
• 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 Subject Summaries
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 Subject A
is significant for a maternal second cousin with epilepsy. WIAT-II-Abbreviated: 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 REFERENCES • 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 Neurol. 2000;42:595-603. • Guy W. ECDEU Assessment Manual for Psychopharmacology- CGI Scales: Results of clinician-rated CGI scales revealed
Revised. 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, Abbreviated. 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. 1997;39:646-651. This presentation was supported by UCB, Inc.
1st North American Regional Epilepsy Congress 2006

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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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