Masao Aihara

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.

Quantitative Analysis of Benzodiazepine Receptor in Temporal Lobe Epilepsy: [125I]Iomazenil Autoradiographic Study of Surgically Resected Specimens

Summary:  Purpose: To evaluate the changes of the inhibitory neurotransmitter receptor system related to epileptogenesis by measuring central benzodiazepine receptors (BZDRs) in surgically resected specimens of temporal lobe epilepsy by using [125I]iomazenil autoradiography.

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.

Effectiveness of lidocaine infusion for status epilepticus in childhood: A retrospective multi-institutional study in Japan

We evaluated the usefulness of intravenous lidocaine therapy for managing of status epilepticus (SE) during childhood in a retrospective multi-institutional study. Questionnaires were sent to 28 hospitals concerning patients admitted for SE who were managed with lidocaine, assessing patient characteristics, treatment protocols and efficacy. In 279 treated patients, 261 SE occurrences at ages between 1 month and 15 years were analyzed. SE was classified as showing continuous, clustered, or frequently repeated seizures. Considering efficacy and side effects in combination, the usefulness of lidocaine was classified into six categories: extremely useful, useful, slightly useful, not useful, associated with deterioration, or unevaluated. In 148 SE cases (56.7%), lidocaine was rated as useful or extremely useful. Multivariate analysis indicated lidocaine was to be useful in SE with clustered and frequently repeated seizures, and SE attributable to certain acute illnesses, such as convulsions with mild gastroenteritis. Efficacy was poor when SE caused by central nervous system (CNS) infectious disease. Standard doses (approximately 2mg/kg as a bolus, 2mg/kg/h as maintenance) produced better outcomes than lower or higher doses. Poor responders to the initial bolus injection of lidocaine were less likely to respond to subsequent continuous infusion than good initial responders. We recommend lidocaine for use in SE with clustered or frequently repeated seizures, and in SE associated with benign infantile convulsion and convulsions with mild gastroenteritis. Lidocaine should be initiated with a bolus of 2mg/kg. If SE is arrested by the bolus, continuous maintenance infusion should follow; treatment should proceed to different measures when SE shows a poor response to the initial bolus of lidocaine.

Treatments with midazolam and lidocaine for status epilepticus in neonates

Status epilepticus (SE) occurs in children of all ages. Recent epidemiologic investigations of SE show heightened morbidity and mortality in newborns and young infants. However, the existing definition of SE in newborns is not precise and not easily applied in clinical investigations or in clinical practice. To evaluate the underlying conditions, clinical features and treatment of SE in neonates in Japan, a retrospective multi-center study was performed. In the initial investigation, questionnaires were sent to pediatric neurologists in 194 neonatal intensive care units of university hospitals, childrens hospitals, and general hospitals throughout in Japan. The questionnaires sought information on the background of each case, types of seizures, etiology of SE, treatments, results and adverse effects of treatment for patients less than 1 week old who had prolonged or frequently repeated seizures lasting more than 15 min and who are refractory to treatment with conventional anticonvulsants, such as diazepam (DZP), phenobarbital (PB) or phenytoin (PHT). As a secondary investigation, 65 cases from nine institutes, which completely fulfilled these criteria and were treated with midazolam (MDL) or lidocaine (Lid) to stop seizures were examined more fully. Subtle seizure and generalized tonic-clonic seizure were the most frequent seizure types. Neonatal SE was most frequently associated with hypoxic-ischemic encephalopathy, followed by intraventricular hemorrhage, central nervous system infections, and cerebral infarction. The final treatment outcome was available for 72.7% and 81.3% of MDL- and Lid-treated patients, respectively. Adverse effects of MDL and Lid were identified in 7.3% and 6.3% of patients, respectively. To reveal electroclinical seizures, clinical seizures without ictal discharge or other non-epileptic movements in neonates was important for appropriate treatment. MDL and Lid were useful drugs for the treatment of neonatal SE.

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.

Age shifts frontal cortical control in a cognitive bias task from right to left: part I. Neuropsychological study

Two functionally and neurally distinct cognitive selection mechanisms involve the prefrontal lobes: those based on internal representations (context dependent) and those involving exploratory processing of novel situations (context independent). We used a cognitive bias task (CBT) representing contextual reasoning to correlate lateralization with age in the frontal lobes. Subjects included 37 healthy right-handed male children and adolescents (age range, 5-18 years). Controls were 19 right-handed men from 20 to 30 years old. A computer-presented version of the original card-choice task simplified, modified for children was used (modified CBT; mCBT). Simple visual stimuli differed dichotomously in shape, color, number, and shading. A target object presented alone was followed by two choices from which subjects selected according to preference. Considering all four characteristics, similarity between target and subject choice was scored for 30 trials. A high score implied a context-dependent response selection bias and a low score, a context-independent bias. Similarity increased significantly with age. The youngest children (5-7 years) scored lower than ages from 11 years to adulthood. Between 7 and 9 years, scores began to increase with age to reach an adult level by age 13-16. Young children showed context-independent responses representing right frontal lobe function, while adolescents and adults showed context-dependent responses implicating left frontal lobe function. The locus of frontal cortical control in right-handed male subjects thus shifts from right to left as cognitive contextual reasoning develops.

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.