Hideaki Kanemura

Development of the prefrontal lobe in infants and children: a three-dimensional magnetic resonance volumetric study

Relatively little is known about normal prefrontal lobe development. We used three-dimensional magnetic resonance imaging (MRI)-based brain volumetry to characterize developmental changes in prefrontal lobe volumes in infants and children. Prefrontal volumes were determined in 30 subjects aged 5 months to 18 years (221 months) and 3 adults aged 28-39 years (324-468 months). Images were acquired on a 1.5-T MRI system using T1-weighted gradient-echo sequences. Volumes of the frontal and prefrontal lobes were determined using a workstation, and the prefrontal-to-frontal volume ratio was calculated. Prefrontal lobe volume increased slowly until 8 years (96 months) of age, contrasting sharply with rapid growth between 8 and 14 years (96 and 168 months). The prefrontal-to-frontal volume ratio increased with age as a sigmoid growth curve. A prefrontal growth spurt occurs in late childhood. Knowledge of prefrontal lobe development is essential for understanding cognitive development and dysfunction.

Serial changes of prefrontal lobe growth in the patients with benign childhood epilepsy with centrotemporal spikes presenting with cognitive impairments/behavioral problems

Several studies have reported a higher incidence of learning and behavioral difficulties in association with frontal lobe dysfunctions in children with benign childhood epilepsy with centrotemporal spikes (BCECTS). We studied serial changes in frontal and prefrontal lobe volumes using three-dimensional magnetic resonance imaging in BCECTS with or without cognitive impairments and behavioral problems and evaluated correlations between prefrontal lobe growth and active seizure period. Serial changes in regional cerebral volumes were measured in two patients with cognitive impairments and behavioral problems (BCECTS(+)) and five patients without neuropsychiatric deficits (BCECTS(-)). Eleven normal subjects (4-13years old) served as controls. Volumes of the frontal and prefrontal lobes were determined using a workstation, and the prefrontal-to-frontal lobe volume ratio was calculated. Frontal and prefrontal lobe volumes revealed growth disturbance in BCECTS(+) compared with BCECTS(-) and control subjects. In addition, prefrontal-to-frontal lobe volume ratio increased serially in BCECTS(-) similarly to controls, but was stagnant or decreased in BCECTS(+). Prefrontal growth also revealed more rapid recovery in a BCECTS(+) patient with shorter active seizure period. These findings suggest that longer active seizure period as frequent spike-waves coupled with the occurrence of frequent seizures may be associated with prefrontal lobe growth disturbance, which relates to neuropsychological problems.

EEG characteristics predict subsequent epilepsy in children with febrile seizure.

The role of electroencephalography (EEG) in the work-up of febrile seizure (FS) remains controversial. We investigated the importance of EEG characteristics, especially the localizations of paroxysmal discharges, as predictors for subsequent epilepsy. Patients were referred from the outpatient department for EEG within 7-20 days after the seizure. EEGs were classified as paroxysmally abnormal based on the presence of spikes, sharp waves, or spike-wave complexes, whether focal or generalized, that were considered abnormal for age and state. Of 119 patients with FS, 26 (21.8%) revealed paroxysmal abnormality on EEG and 9 (7.6%) developed epilepsy. Of nine patients with later epilepsy, 6 (66.7%) revealed paroxysmal EEG abnormality. Of 26 patients with paroxysmal abnormality, 6 (23.1%) developed epilepsy. Of 10 patients with generalized paroxysmal spike and wave activity, one (10%) developed epilepsy. Of seven patients with rolandic discharge (RD), two (28.5%) developed epilepsy. Of four patients with paroxysms in the frontal region, three (75%) developed epilepsy. Of five patients with paroxysms in the occipital region, none developed epilepsy. Compared with generalized EEG foci, the relative risk (RR) for patients with frontal EEG foci was 27.0. Patients with frontal EEG paroxysms had a significantly higher risk of developing epilepsy than those with paroxysms in other regions of EEG foci (p=0.035). These findings suggest that patients with FS presenting with frontal paroxysmal EEG abnormalities may be at risk for epilepsy. In patients with frontal paroxysmal EEG abnormalities, serial EEG should be performed, even though it does not contribute to treatment.

Valproate sodium enhances body weight gain in patients with childhood epilepsy: A pathogenic mechanisms and open-label clinical trial of behavior therapy

OBJECTIVES Excessive weight gain associated with valproate sodium (VPA) may predispose patients with epilepsy to other health problems such as insulin resistance. The purpose of this study was to examine the changes in body weight and several biochemical parameters in children receiving VPA treatment. The effects of behavior therapy for epileptic children with VPA-induced weight gain are discussed. METHODS Fifteen patients newly diagnosed with epilepsy were included in the study. The following parameters were measured: body weight, body mass index (BMI), serum glucose, serum insulin, serum VPA concentration and serum free carnitine. In addition, behavior therapy was introduced at the initiation of VPA therapy, and lasted at least for 2 years. RESULTS After 6 months of follow-up, there were eight (53%) patients in whom weight gain was demonstrated. Significant increases in the serum insulin level and the insulin/glucose ratio were observed in the weight gain group (p<0.01). All patients with significant weight gain showed increased appetite. However, BMI stopped increasing with intensive behavior therapy. CONCLUSIONS These findings suggest that an increase in serum insulin and insulin/glucose levels may cause weight gain, possibly by stimulating appetite, and that weight changes seem to be reversible with intensive behavior therapy without discontinuation of VPA.

Growth disturbance of frontal lobe in BCECTS presenting with frontal dysfunction

A considerable proportion of children with benign childhood epilepsy with centrotemporal spikes (BCECTS) have increasingly been found to show neuropsychiatric deficits such as cognitive impairment and impulsivity, possibly associated with frontal lobe dysfunctions. We performed 3-dimensional magnetic resonance imaging (MRI)-based brain volumetry to characterize serial changes in frontal and prefrontal lobe volumes and compare volumetric changes with clinical symptoms. Serial changes in regional cerebral volumes were measured in a 5-year-old boy with BCECTS. Seizures were not easily controlled, and he demonstrated oromotor deficits, cognitive impairments and behavioral problems. Cognitive and behavioral deficits persisted even after remission of seizure disorder and oromotor deficits. Two BCECTS patients (5-6 years old) without neuropsychological disorders served as typical BCECTS, and nine normal subjects (4-10 years old) served as controls. Volumes of the frontal and prefrontal lobes were determined using a workstation, and prefrontal to frontal lobe volume ratio was calculated. Frontal and prefrontal lobe volumes showed no growth even after remission of seizure disorders. Prefrontal to frontal lobe volume ratio reduced slightly even after remission of both seizure disorders and EEG abnormalities. The result suggests that BCECTS presenting with atypical course may be associated with frontal lobe dysfunction resulting in cognitive and behavioral deficits.

EEG improvements with antiepileptic drug treatment can show a high correlation with behavioral recovery in children with ADHD

We investigated the relationship between neuropsychological disturbance, assessed using the global assessment of functioning (GAF) and the ADHD-rating scale (ADHD-RS), paroxysmal EEG abnormalities, and treatment with valproate sodium (VPA) in children with both attention deficit hyperactivity disorder (ADHD) and paroxysmal abnormality (PA). Participants with ADHD but without obvious epilepsy were recruited between April 1, 2003 and March 31, 2008. Paroxysmal abnormality was scored by measuring the spike frequency. Of 46 children, 16 showed PA; 3 of the 16 were excluded because no follow-up EEG was available. The EEG improved with VPA treatment in 5 of 8 patients with frontal PA and 3 of 5 patients with rolandic PA. While 83.3% of the patients with improvements in both assessments had frontal PA, only 16.7% had rolandic PA. The patients with frontal PA showed a significantly higher correlation between PA frequency and improvement in ADHD-RS compared with those with rolandic PA. In this study of children with ADHD, EEG improvement with antiepileptic drug treatment showed a high correlation with behavioral improvements as shown by ADHD-RS and GAF scores. However, this was not a population-based study, and the relative importance of detecting and treating PA in ADHD has yet to be determined.

Repeated seizures induce prefrontal growth disturbance in frontal lobe epilepsy

BACKGROUND The possible consequences of seizures in the immature brain have been the subject of much conjecture. We prospectively measured frontal and prefrontal lobe volumes using three-dimensional (3D) magnetic resonance imaging (MRI)-based volumetry in patients with frontal lobe epilepsy (FLE) presenting with the same seizure semiology. The pathogenesis of repeated seizure-induced brain damage is discussed herein. METHODS Serial changes in regional cerebral volumes were measured in two patients with FLE presenting with intractable clinical courses and cognitive impairments/behavioral problems (FLE(+)) and four FLE patients without cognitive impairments/behavioral problems (FLE(-)). Eleven normal subjects (4-13 years old) served as controls. Volumes of the frontal and prefrontal lobes were determined using a workstation, and the prefrontal-to-frontal lobe volume ratio was calculated. RESULTS Frontal and prefrontal lobe volumes revealed growth disturbance in FLE(+) compared with those of FLE(-) and control subjects. In addition, prefrontal-to-frontal lobe volume ratio increased serially in FLE(-) similarly to controls, but was stagnant or decreased in FLE(+). Prefrontal growth also revealed more rapid recovery in a FLE(+) patient with shorter active seizure period. CONCLUSION These findings suggest that repeated seizures may lead to prefrontal growth disturbance. The occurrence of frequent seizures in patients with FLE may be associated with prefrontal lobe growth retardation, which relates to neuropsychological problems and ultimate neuropsychological outcome.

Efficacy and safety of add-on levetiracetam in refractory childhood epilepsy

PURPOSE The purpose of the present study was to evaluate the efficacy and safety of levetiracetam (LEV) in refractory epileptic children. METHODS The study group included 61 outpatients (7 generalized, 48 localization-related, 3 undetermined, 3 unclassified) aged between 16 months and 18 years. LEV was given twice daily at a total dose of 10 mg/kg/day. The final mean dose was 50.7 mg/kg/day. The mean number of prior anti-epileptic drugs was 5.2. The entire treatment period was more than 6 months after LEV administration. RESULTS Fifteen children (24.6%) became seizure-free for 6 months after starting LEV, and 18 (29.5%) had a seizure reduction of more than 50% for the entire 6 months. The response rate was 33/61 (54.1%). Responders included 2/3 of patients (66.7%) with epilepsy with continuous spikes and waves during slow sleep and 13/19 (68.4%) with frontal lobe epilepsy. The effective dosage of LEV in the responders demonstrated a wide range (mean, 46.1 mg/kg/day; range, 19.4-59.1 mg/kg/day), and showed bimodal distribution. Adverse events occurred in only two patients who did not require LEV discontinuation. CONCLUSION LEV represents an important addition to the treatments available for refractory epileptic children.

Do sequential EEG changes predict atypical clinical features in rolandic epilepsy

Aim  Although the prognosis for rolandic epilepsy is regarded to be favourable, a small proportion of cases that initially present as rolandic epilepsy evolve into atypical benign partial epilepsy (ABPE) of childhood. The purpose of our study was to determine electroencephalogram (EEG) criteria in relation to atypical seizure manifestations, and cognitive and behavioural problems in rolandic epilepsy.

Prefrontal Lobe Growth in a Patient with Continuous Spike-Waves during Slow Sleep

Epilepsy with continuous spike-waves during slow sleep (CSWS) is characterized by impairment of neuropsychological abilities, frequently associated with behavioral d isorders. These manifestations strongly correlate with frontal lobe dysfunctions. In the present case, an 11-year-old girl presented with progressive behavioral deteriorations after the appearance of electrical status epilepticus in sleep. The duration of CSWS period was 5 months. Serial measurements (at the appearance of the EEG pattern, and 6 months and 1, 2, 3 and 4 years thereafter) of frontal and prefrontal lobe volumes by 3-dimensional magnetic resonance imaging-based volumetry showed growth disturbance of prefrontal lobe volume, particularly prefrontal-to-frontal lobe volume ratio, after the appearance of the EEG pattern when compared with two frontal lobe epilepsy subjects without neuropsychological disorders and 13 control subjects. However, the ratio was restored to the growth ratio and seen to reach control levels, after improvement of the clinical manifestations of CSWS. These results suggest that children with CSWS may be prone to frontal lobe dysfunctions, and that the duration of CSWS period seems to be a significant prognostic factor. The urgent suppression of this EEG abnormality may be necessary to prevent the progression of neuropsychological impairments.