Mi-Sun Yum

Validation of the rat model of cryptogenic infantile spasms

Purpose:  To determine whether a new model of cryptogenic infantile spasms consisting of prenatal priming with betamethasone and postnatal trigger of spasms by N‐methyl‐d‐aspartate (NMDA) responds to chronic adrenocorticotropic hormone (ACTH) treatment, and has electroencephalography (EEG) signature, efficacy of treatments, and behavioral impairments similar to those in human infantile spasms.

Prenatal stress promotes development of spasms in infant rats

We have developed a new model of cryptogenic infantile spasms with prenatal betamethasone brain priming to increase susceptibility to development‐specific spasms triggered by N‐methyl‐d‐aspartate (NMDA). A recent clinical study linked severe prenatal stress to increased risk for development of infantile spasms. Here, we determined whether prenatal restraint stress (2 × 45 min) in rats on gestational day 15 would increase susceptibility to develop spasms on postnatal day 15. Prenatal stress significantly accelerated onset and increased number of NMDA‐triggered spasms compared to handled controls. A single adrenocorticotropic hormone (ACTH or corticotropin) dose delivered acutely had no effects, whereas long‐term (3 day) ACTH pretreatment significantly increased latency to onset and decreased number of spasms (an effect similar to that in the human condition). Our data support the notion that extra care should be provided during pregnancy to minimize stress.

Central nervous system (CNS) involvement is a critical prognostic factor for hemophagocytic lymphohistiocytosis.

Background Hemophagocytic lymphohistiocytosis (HLH) is a rare multisystem disorder that frequently involves the central nervous system (CNS). We compared the clinical characteristics, treatment, and prognosis of patients with HLH according to the degree of CNS involvement. Methods The clinical manifestations, initial laboratory data, treatment, and outcomes for 50 patients diagnosed with HLH and treated at Asan Medical Center between January 1995 and August 2011 were retrospectively reviewed and analyzed. CNS involvement was defined as the presence of neurological symptoms or an elevated white blood cell (WBC) count in the cerebrospinal fluid (CSF). Results Among these 50 patients, 23 (46%) developed CNS disease. Among patients with CNS disease, 19 had neurological symptoms, including seizures, altered consciousness, facial palsy, dysarthria, and dysphagia. Four patients had elevated CSF WBC counts without neurological symptoms. Twelve patients had abnormal brain imaging results, including high signal intensity lesions on T2-weighted magnetic resonance imaging (MRI) findings, ventriculomegaly, hemorrhage, atrophy, and leptomeningeal enhancement. Patients with CNS disease had lower ferritin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels as well as reduced 5-year survival as compared to those without CNS disease. Conclusion CNS involvement is common among patients with HLH. Overall, patients with CNS disease achieve poorer outcomes than patients without CNS involvement. To improve outcomes, physicians must carefully monitor the neurological manifestations in patients with HLH and administer the appropriate course of intensified chemotherapy to patients with CNS disease.

Effect of methylphenidate on the quality of life in children with epilepsy and attention deficit hyperactivity disorder

This open study explored whether methylphenidate could be tolerated and effective in improving the quality of life (QOL) and attention deficit hyperactivity disorder (ADHD) symptoms of children with epilepsy and ADHD. Twenty-five subjects (aged 10.1 +/- 3.0 years) with ADHD and epilepsy were recruited at an outpatient clinic in Seoul, Korea. We used the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE), ADHD rating scale (ARS) and clinical global impression (CGI) in this study. Osmotic-controlled release oral delivery system (OROS) methylphenidate, 1.0 +/- 0.4 mg/kg/day, was administered for 55.2 +/- 7.5 days. The QOL subscales including physical restriction (p = 0.005), self-esteem (p = 0.002), memory (p < 0.001), language (p = 0.005), other cognition (p < 0.001), social interaction (p = 0.002), behaviour (p < 0.001), general health (p = 0.002) and QOL (p < 0.001) were significantly increased and the ARS (p < 0.001) and CGI-Severity of illness scores (p < 0.001) were significantly reduced after medication. Although 60% of subjects had experienced adverse effects, most were tolerable and only two subjects withdrew from the study owing to unbearable adverse effects (anorexia and insomnia). Two subjects had seizure attacks during the study period without having to discontinue the trial drug. Despite limitations related to the small sample size and the open design of the present pilot study, our results suggest that OROS methylphenidate may be well tolerated and effective in reducing ADHD symptoms and improving QOL in this patient population.

Importance of RNF213 polymorphism on clinical features and long-term outcome in moyamoya disease

OBJECT Moyamoya disease (MMD) is an idiopathic cerebrovascular occlusive disorder prevalent in East Asia. In the pathogenesis of MMD, the important role of genetic factors is being elucidated, and RNF213 has recently been identified as a susceptibility gene for MMD. The aim of this retrospective study was to investigate the RNF213 genotype in patients with MMD and to determine their genotype-phenotype associations. METHODS The study involved 165 Korean MMD patients from 155 unrelated families who were diagnosed with MMD at a single center from 1995 to 2013. Their demographic, radiological, and clinical findings were evaluated. Direct sequencing of the major RNF213 single nucleotide polymorphisms was performed. The association of the common RNF213 variant with MMD risk was evaluated using historical controls for comparison. Correlations between RNF213 genotype and phenotype were statistically analyzed. RESULTS The c.14429G>A (p.R4810K) variant was identified in 125 (75.8%) of 165 MMD patients. Most patients (112) were heterozygous, and 13 patients had 2 copies of the c.14429G>A variant. A novel heterozygous variant, c.12086A>G (p.Q4029R), was found in 1 additional patient. The minor allele frequency of the c.14429G>A variant was significantly higher in the MMD group (138 [41.8%] of 330 patients) than in the control group (8 [1.36%] of 588 subjects; p < 0.001). The c.14429G>A (p.R4810K) variant significantly increased the risk of MMD in Korean patients, with an OR of 52.11 (p < 0.001) compared with controls. Moreover, c.14429G>A (p.R4810K) genotypes occurred more frequently in patients with a family history of MMD. The homozygous variant was highly associated with early-onset MMD (age at onset < 5 years), cerebral infarction at diagnosis, and cognitive impairment in long-term outcome. CONCLUSIONS The findings indicate that the c.14429G>A (p.R4810K) allele of RNF213 is strongly associated with Korean patients with MMD. The homozygous c.14429G>A (p.R4810K) variant is particularly related to early-onset MMD, severe symptomatic manifestations at diagnosis, and poor prognosis. This genotypic variant may be a useful biomarker for early-onset MMD or unstable MMD with cerebral infarction, which requires early diagnosis and revascularization treatment.

The Efficacy of the COMFORT Scale in Assessing Optimal Sedation in Critically Ill Children Requiring Mechanical Ventilation

Sedation is often necessary to optimize care for critically ill children requiring mechanical ventilation. If too light or too deep, however, sedation can cause significant adverse reactions, making it important to assess the degree of sedation and maintain its optimal level. We evaluated the efficacy of the COMFORT scale in assessing optimal sedation in critically ill children requiring mechanical ventilation. We compared 12 month data in 21 patients (intervention group), for whom we used the pediatric intensive care unit (PICU) sedation protocol of Asan Medical Center (Seoul, Korea) and the COMFORT scale to maintain optimal sedation, with the data in 20 patients (control group) assessed before using the sedation protocol and the COMPORT scale. Compared with the control group, the intervention group showed significant decreases in the total usage of sedatives and analgesics, the duration of mechanical ventilation (11.0 days vs. 12.5 days) and PICU stay (15.0 days vs. 19.5 days), and the development of withdrawal symptoms (1 case vs. 7 cases). The total duration of sedation (8.0 days vs. 11.5 days) also tended to decrease. These findings suggest that application of protocol-based sedation with the COMPORT scale may benefit children requiring mechanical ventilation.

Attention-deficit/hyperactivity disorder and attention impairment in children with benign childhood epilepsy with centrotemporal spikes

Attention-deficit/hyperactivity disorder (ADHD) is a common comorbidity in children with epilepsy and has a negative impact on behavior and learning. The purposes of this study were to quantify the prevalence of ADHD in benign childhood epilepsy with centrotemporal spikes (BCECTS) and to identify clinical factors that affect ADHD or attention impairment in patients with BCECTS. The medical records of 74 children (44 males) with neuropsychological examination from a total of 198 children diagnosed with BCECTS at Asan Medical Center were retrospectively reviewed. Electroclinical factors were compared across patients with ADHD and those without ADHD. Mean T-scores of the continuous performance test were compared across patients grouped according to various epilepsy characteristics. Forty-eight (64.9%) patients had ADHD. A history of febrile convulsion was more common in patients with ADHD than in patients without ADHD (p=0.049). Bilateral centrotemporal spikes on electroencephalogram were more common in patients receiving ADHD medication than in patients with untreated ADHD (p=0.004). Male patients, patients with frequent seizures prior to diagnosis, and patients with a high spike index (≥40/min) on sleep EEG at diagnosis had significantly lower visual selective attention (p<0.05). Children with BCECTS had a high prevalence of ADHD, and frequent seizures or interictal epileptiform abnormalities were closely related to impairment of visual selective attention in children with BCECTS, indicating the need for ADHD or attention impairment screening in children with BCECTS.

Rapamycin has age-, treatment paradigm-, and model-specific anticonvulsant effects and modulates neuropeptide Y expression in rats.

Purpose:  Rapamycin (RAP) has certain antiepileptogenic features. However, it is unclear whether these effects can be explained by the anticonvulsant action of RAP, which has not been studied. To address this question, we tested potential anticonvulsant effects of RAP in immature and adult rats using different seizure models and treatment paradigms. In addition, we studied changes in the expression of neuropeptide Y (NPY) induced by RAP, which may serve as an indirect target of the RAP action.

Surgical treatment for localization-related infantile spasms: excellent long-term outcomes.

OBJECTIVE Focal epileptogenic lesions can manifest as infantile spasms, a catastrophic type of epilepsy. Although early surgery for catastrophic epilepsies has shown positive effects, little is known regarding long-term outcomes. The present study examined long-term outcomes in patients with localization-related infantile spasms treated surgically. METHODS Data from localization-related infantile spasm cases treated surgically between 1998 and 2002 at the Asan Medical Center were retrospectively reviewed. Presurgical evaluation, surgery, postoperative seizure frequency and developmental outcome data were analyzed. RESULTS Five patients met the inclusion criteria, and had etiologies of tuberous sclerosis, fetal infection, encephalomalacia, malformation of cortical development and low-grade astrocytoma, respectively. The mean seizure onset age was 5.4 months (range, 3 days to 11 months), and the mean age at surgery was 19 months (range, 9-29 months). Two patients underwent a functional hemispherectomy, and the remaining three underwent lesionectomy or temporal lobectomy. The follow-up duration was 6-9 years. We found that following surgery, 4 of the 5 patients were seizure-free at the final follow-up. The 2 patients with low grade astrocytoma and cortical dysplasia, respectively showed relatively good developmental outcomes. CONCLUSION Surgery may be an excellent option for treating selected patients with infantile spasms due to unilateral or focal congenital or early-acquired cortical lesions. However, developmental outcomes appear to be strongly linked to etiology and the pre-operative developmental level.

Determinants of intelligence in childhood-onset epilepsy: A single-center study

The purpose of this study was to quantify the intelligence of children with epilepsy and to determine the clinical factors associated with intellectual impairment. The medical records of patients diagnosed with childhood-onset epilepsy at a single tertiary medical center in Korea between 2006 and 2011 were retrospectively reviewed. The Korean Education Development Institute-Wechsler Intelligence Scale for Children or Korean Wechsler Intelligence Scale for adults was used to quantify the level of intelligence. Age at seizure onset, etiology, epilepsy duration, number of seizures in the last year, use of antiepileptic drugs, EEG/MRI findings, and epilepsy classification were recorded. The association between clinical factors and the intelligence was determined using logistic regression. Three hundred and twenty-two patients were included in the analysis. One hundred and seventy-six (54.7%) patients had low intelligence (intelligence quotient [IQ]<80) with 18 (5.6%) defined as borderline mental retardation (IQ 70-79), 47 (14.6%) as mild mental retardation (IQ 60-69), and 111 (34.5%) as moderate-to-severe mental retardation (IQ<60). Epilepsy duration, number of seizures in the last year, and epilepsy classification were significantly associated with low intelligence in multivariate logistic regression (p<0.05). However, when analyzed according to etiology, these factors were not associated with low intelligence in children with idiopathic epilepsy. The most important factors associated with low intelligence in childhood-onset epilepsy are the underlying etiology and, in cryptogenic and symptomatic epilepsy, seizure burden. The results of this study underscore the importance of seizure control to alleviate the harmful impact of epilepsy on cognition.