Hunmin Kim

Clinical and EEG risk factors for subsequent epilepsy in patients with complex febrile seizures

PURPOSE To identify the risk factors for subsequent epilepsy in patients with complex febrile seizures from a single-center retrospective cohort. METHODS The medical records of 1091 patients discharged with a diagnosis of febrile seizures from the Seoul National University Bundang Hospital from February 2004 to October 2009 were reviewed. One hundred eighty-three patients (107 boys and 76 girls) with complex febrile seizures who showed normal neurocognitive development were included in the analysis. Clinical characteristics, including features of complex febrile seizure, initial interictal electroencephalographic findings, and subsequent epilepsy, were reviewed and the odds ratio of subsequent epilepsy was estimated. The mean follow-up duration for subsequent epilepsy was 6.1 years (range, 2.5-8.0 years). RESULTS Complex febrile seizures were observed in 22.6% of all patients with febrile seizures. Among 183 patients with complex febrile seizures, 22 patients (12.0%) developed subsequent epilepsy. Prolonged (>10 min) seizure (p=0.031; odds ratio, 3.04; 95% confidence interval, 1.11-8.32) or the presence of multiple seizures for 24 h (p=0.032; odds ratio, 3.63; 95% confidence interval, 1.12-11.8) was significantly more frequent in patients with subsequent epilepsy, whereas the presence of focal seizure was not significantly different. Epileptiform discharges (focal in all cases) were significantly more frequent in patients with subsequent epilepsy (50% vs. 13%, p=0.002), with an odds ratio of 5.15 (95% confidence interval, 1.84-14.5). CONCLUSION The presence of epileptiform discharges is a significant risk factor for subsequent epilepsy in patients with complex febrile seizures. Electroencephalography should be considered in all patients with complex febrile seizures especially those who had multiple or prolonged seizures.

Paroxysmal nonepileptic events in pediatric patients confirmed by long-term video-EEG monitoring — Single tertiary center review of 143 patients

The purpose of the study was to evaluate the clinical characteristics of paroxysmal nonepileptic events (PNEs) in pediatric patients. Reports of 1108 patients who underwent long-term video-EEG monitoring at Seoul National University Childrens Hospital were reviewed retrospectively. One hundred forty-three (12.9%) patients were diagnosed as having PNEs. The most common type of PNE was staring. Staring, tonic posturing, sleep myoclonus, and sleep-related disorders were more common in patients younger than 6 years old. Psychogenic nonepileptic seizure was the most common PNE in patients older than 6 years. Patients who were younger than 6 years old showed shorter disease duration and more varied types of PNEs when compared to older patients (6 years old or older). Presence of epilepsy was not significantly related to clinical difference in PNEs. In patients with developmental delay, staring and tonic posture were significantly more frequent than patients without developmental delay. Thirty-two patients without concurrent epilepsy were misdiagnosed with epilepsy, and AEDs were discontinued after the correct diagnosis of PNEs. Whenever the diagnosis of paroxysmal abnormal behavior is uncertain, correct diagnosis should be made using long-term video-EEG monitoring, especially in younger pediatric patients and patients with developmental delay.

Comparison of flunarizine and topiramate for the prophylaxis of pediatric migraines

The purpose of this study was to compare the efficacy and tolerability of topiramate and flunarizine for the prophylaxis of pediatric migraines. A retrospective medical-record review of patients who underwent prophylaxis after receiving a diagnosis of migraine with aura and without aura was performed. Only patients who completed at least 3 months of treatment were included in the analysis. Response to treatment was assessed as the total number of headache days/month. Patients with more than 50% reduction in headache days/month were classified as responders. Responder rate, retention rate, and adverse-event rates were also calculated from all patients who started on the prophylaxis. Further analyses were performed using different patient groups with a cut-off age of 12 years. The responder rate was 80% (89/111 patients) for flunarizine and 81% (122/150 patients) for topiramate, based on a comparison among 261 patients. The retention rate was 67% for flunarizine and 63% for topiramate and the adverse-event rate was 6% for flunarizine and 10% for topiramate. The responder rate, the retention rate, and the adverse-event rate were not significantly different between flunarizine and topiramate. These findings were concordant between the preadolescent (6-12 years old) and adolescent (13-18 years old) groups. The efficacy and tolerability of topiramate were not inferior to those of flunarizine for the prophylaxis of pediatric migraines. These findings were observed in preadolescent and adolescent patients.

Clinical and mutational spectrum in Korean patients with Rubinstein-Taybi syndrome: the spectrum of brain MRI abnormalities.

OBJECTIVE Rubinstein-Taybi syndrome (RSTS) is one of the neurodevelopmental disorders caused by mutations of epigenetic genes. The CREBBP gene is the most common causative gene, encoding the CREB-binding protein with histone acetyltransferase (HAT) activity, an epigenetic modulator. To date, there have been few reports on the structural abnormalities of the brain in RSTS patients. In addition, there are no reports on the analysis of CREBBP mutations in Korean RSTS patients. PATIENTS AND METHODS We performed mutational analyses on 16 unrelated patients with RSTS, with diagnosis based on the typical clinical features. Their medical records and brain MRI images were reviewed retrospectively. RESULTS Ten of 16 patients (62.5%) had mutations in the CREBBP gene. The mutations included five frameshift mutations (31.2%), two nonsense mutations (12.5%), and three multiexon deletions (18.8%). There were no remarkable significant differences in the clinical features between those with and without a CREBBP mutation, although brain MRI abnormalities were more frequently observed in those with a CREBBP mutation. Seven of 10 patients in whom brain imaging was performed had structural abnormalities, including Chiari malformation type 1, thinning of the corpus callosum, and delayed myelination. There were no differences in delayed development or cognitive impairment between those with and without abnormal brain images, while epilepsy was involved in two patients who had abnormalities on brain MRI images. CONCLUSIONS We investigated the spectrum of CREBBP mutations in Korean patients with RSTS for the first time. Eight novel mutations extended the genetic spectrum of CREBBP mutations in RSTS patients. This is also the first study showing the prevalence and spectrum of abnormalities on brain MRI in RSTS patients.

Effectiveness of Intravenous Levetiracetam as an Adjunctive Treatment in Pediatric Refractory Status Epilepticus

Objectives Intravenous levetiracetam (LEV) has been shown to be effective and safe in treating adults with refractory status epilepticus (SE). We sought to investigate the efficacy and safety of intravenous LEV for pediatric patients with refractory SE. Methods We performed a retrospective medical-record review of pediatric patients who were treated with intravenous LEV for refractory SE. Clinical information regarding age, sex, seizure type, and underlying neurological status was collected. We evaluated other anticonvulsants that were used prior to administration of intravenous LEV and assessed loading dose, response to treatment, and any adverse events from intravenous LEV administration. Results Fourteen patients (8 boys and 6 girls) received intravenous LEV for the treatment of refractory SE. The mean age of the patients was 4.4 ± 5.5 years (range, 4 days to 14.6 years). Ten of the patients were neurologically healthy prior to the refractory SE, and the other 4 had been previously diagnosed with epilepsy. The mean loading dose of intravenous LEV was 26 ± 4.6 mg/kg (range, 20–30 mg/kg). Seizure termination occurred in 6 (43%) of the 14 patients. In particular, 4 (57%) of the 7 patients younger than 2 years showed seizure termination. No immediate adverse events occurred during or after infusions. Conclusions The current study demonstrated that the adjunctive use of intravenous LEV was effective and well tolerated in pediatric patients with refractory SE, even in patients younger than 2 years. Intravenous LEV should be considered as an effective and safe treatment option for refractory SE in pediatric patients.

FARS2 mutation and epilepsy: Possible link with early-onset epileptic encephalopathy

Early-onset epileptic encephalopathy (EOEE) consists of a heterogeneous group of epilepsy phenotypes. Recent technological advances in molecular biology have also rapidly expanded the genotype of EOEE. Genes involved in diverse molecular pathways, including ion channels, synaptic structure, transcription regulation, and cellular growth, have been implicated in EOEE. Mitochondrial aminoacyl tRNA synthetase, which plays a key role in mitochondrial protein synthesis by attaching 20 different amino acids to the tRNA tail, has been recently linked with the epilepsy phenotype. Here, we report a novel homozygous c.925G>A (G309S) missense mutation in the gene that encodes the human mitochondrial phenylalanyl-tRNA synthetase (FARS2) in four patients from two nonconsanguineous Korean families. All four patients suffered from intractable seizures that started at the age of 3 and 4 months. Seizure types were variable, including infantile spasms and myoclonic seizures, and often prolonged. Although their initial development seemed to be normal, relentless regression after seizure onset occurred in all patients. An etiologic investigation, including brain imaging and metabolic studies, did not reveal a specific etiology. We reviewed the epilepsy phenotypes of six additional FARS2 mutation-positive patients and suggest that FARS2 can be considered one of the genetic causes of EOEE.

Magnetoencephalography in Pediatric Lesional Epilepsy Surgery

This study was performed to assess the usefulness of magnetoencephalography (MEG) as a presurgical evaluation modality in Korean pediatric patients with lesional localization-related epilepsy. The medical records and MEG findings of 13 pediatric patients (6 boys and 7 girls) with localization-related epilepsy, who underwent epilepsy surgery at Seoul National University Childrens Hospital, were retrospectively reviewed. The hemispheric concordance rate was 100% (13/13 patients). The lobar or regional concordance rate was 77% (10/13 patients). In most cases, the MEG spike sources were clustered in the proximity of the lesion, either at one side of the margin (nine patients) or around the lesion (one patient); clustered spike sources were distant from the lesion in one patient. Among the patients with clustered spike sources near the lesion, further extensions (three patients) and distal scatters (three patients) were also observed. MEG spike sources were well lateralized and localized even in two patients without focal epileptiform discharges in the interictal scalp electroencephalography. Ten patients (77%) achieved Engel class I postsurgical seizure outcome. It is suggested that MEG is a safe and useful presurgical evaluation modality in pediatric patients with lesion localization-related epilepsy.

Leigh Syndrome in Childhood: Neurologic Progression and Functional Outcome

Background and Purpose Few studies have analyzed the clinical course and functional outcome in Leigh syndrome (LS). The aim of this study was to determine the clinical, radiological, biochemical, and genetic features of patients with LS, and identify prognostic indicators of the disease progression and neurological outcome. Methods Thirty-nine patients who had been diagnosed with LS at the Seoul National University Childrens Hospital were included. Their medical records, neuroimaging findings, and histological/biochemical findings of skeletal muscle specimens were reviewed. Targeted sequencing of mitochondrial DNA was performed based on mitochondrial respiratory chain (MRC) enzyme defects. Results Isolated complex I deficiency was the most frequently observed MRC defect (in 42% of 38 investigated patients). Mitochondrial DNA mutations were identified in 11 patients, of which 81.8% were MT-ND genes. The clinical outcome varied widely, from independent daily activity to severe disability. Poor functional outcomes and neurological deterioration were significantly associated with early onset (before an age of 1 year) and the presence of other lesions additional to basal ganglia involvement in the initial neuroimaging. Conclusions The neurological severity and outcome of LS may vary widely and be better than those predicted based on previous studies. We suggest that age at onset and initial neuroimaging findings are prognostic indicators in LS.

Magnetoencephalography in pediatric epilepsy.

Magnetoencephalography (MEG) records the magnetic field generated by electrical activity of cortical neurons. The signal is not distorted or attenuated, and it is contactless recording that can be performed comfortably even for longer than an hour. It has excellent and decent temporal resolution, especially when it is combined with the patients own brain magnetic resonance imaging (magnetic source imaging). Data of MEG and electroencephalography are not mutually exclusive and it is recorded simultaneously and interpreted together. MEG has been shown to be useful in detecting the irritative zone in both lesional and nonlesional epilepsy surgery. It has provided valuable and additive information regarding the lesion that should be resected in epilepsy surgery. Better outcomes in epilepsy surgery were related to the localization of the irritative zone with MEG. The value of MEG in epilepsy surgery is recruiting more patients to epilepsy surgery and providing critical information for surgical planning. MEG cortical mapping is helpful in younger pediatric patients, especially when the epileptogenic zone is close to the eloquent cortex. MEG is also used in both basic and clinical research of epilepsy other than surgery. MEG is a valuable diagnostic modality for diagnosis and treatment, as well as research in epilepsy.

Surgical outcome and predictive factors of epilepsy surgery in pediatric isolated focal cortical dysplasia

OBJECTIVE Focal cortical dysplasia (FCD) is a common cause of medically intractable epilepsy in children. Epilepsy surgery has been a valuable treatment option to achieve seizure freedom in these intractable epilepsy patients. We aimed to present long-term surgical outcome, in relation to pathological severity, and to assess predictive factors of epilepsy surgery in pediatric isolated FCD. METHODS We retrospectively analyzed the data of 58 children and adolescents, with FCD International League Against Epilepsy (ILAE) task force classification types I and II, who underwent resective epilepsy surgery and were followed for at least 2 years after surgery. RESULTS The mean age at epilepsy onset was 4.3 years (0-14.2 years), and mean age at epilepsy surgery was 9.4 years (0.4-17.5 years). The mean duration of postoperative follow-up was 5.1±2.6 years (2-12.4 years). Of 58 patients, 62% of patients achieved Engel class I at 2 years postoperatively, 58% at 5 years postoperatively, and 53% at the last follow up. Forty eight percent of our cohort successfully discontinued antiepileptic medication. Of 30 patients with seizure recurrence, 83% of seizures recurred within 2 years after surgery. We observed that FCD type IIb was significantly associated with a better surgical outcome. At fifth postoperative year, 88% of FCD IIb patients were seizure free compared with 21% of type I and 57% of type IIa patients (P=0.043). By multivariate analysis, lesion on MRI (P=0.02) and complete resection (P<0.01) were the most important predictive factors for a seizure-free outcome. SIGNIFICANCE Epilepsy surgery is highly effective; more than half of medically intractable epilepsy patients achieved seizure freedom after surgery. In addition, we found significant difference in surgical outcomes according to the ILAE task force classification. Lesion on MRI and complete resection were the most important predictive factors for favorable seizure outcome in isolated FCD patients.