Eun-Hee Kim

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.

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.

Risk factors for neurological complications and their correlation with survival following pediatric liver transplantation.

Despite the improved outcomes of LT, post‐operative NCs remain a significant cause of morbidity and mortality. The aim of the study was to identify the incidence of and risk factors for NCs in children who underwent LT. The medical records of pediatric patients who underwent LT at Asan Medical Center Childrens Hospital between January 1994 and December 2010 were retrospectively analyzed. The onset and types of NC and pretransplant variables associated with NC were evaluated. We identified 190 children (85 boys [44.7%], 105 girls [55.3%]) of mean age 4.1 ± 4.7 yr, who underwent LT. Forty‐six NCs occurred in 41 (21.6%) patients after LT, the most common being seizures (n = 13, 28.3%) and encephalopathy (n = 10, 21.7%). Of the 46 NCs, 24 (52.2%) occurred within three months after LT. Multivariate analysis showed that primary liver disease, preoperative neurological problems, preoperatively higher serum creatinine concentration, and graft failure were significant risk factors for NCs. The survival rate was significantly lower for patients with NCs than for those without (p < 0.001). NCs after pediatric LTs were common and associated with a higher mortality rate in our study. Close monitoring and appropriate risk management may improve the long‐term outcomes of pediatric patients who undergo LT.

Attention profiles in childhood absence epilepsy compared with attention-deficit/hyperactivity disorder

OBJECTIVEnThis study aimed to compare the attention profiles of subjects with childhood absence epilepsy (CAE) to those of children with attention-deficit/hyperactivity disorder (ADHD) and controls.nnnMETHODnWe retrospectively reviewed the medical records of 20 children (age 7.2u202f±u202f1.6u202fyears, 5 boys) in whom CAE was diagnosed at the Department of Pediatric Neurology of Asan Medical Center, Seoul, Korea. ADHD and control subjects were selected from children who visited the Department of Pediatric Psychiatry and were confirmed as having or not having ADHD based on Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (K-SADS-PL). The 20 children with CAE, 20 with ADHD and 20 controls completed the Advanced Test of Attention (ATA), which is a computerized continuous performance task.nnnRESULTSnThe CAE subjects without ADHD showed increased Omission errors (p=.013) on the visual ATA and Response time (p=0.044) on the auditory ATA than the controls, although these differences did not remain significant after multiple comparison correction. The CAE subjects without ADHD had significantly decreased Response time variability on the visual ATA than the ADHD group (p<0.001). The CAE subjects with comorbid ADHD showed increased Commission errors (p=0.020) and Response time variability (p=0.016) on the visual ATA and increased Commission errors (p=0.022) on the auditory ATA than the CAE subjects without ADHD, although statistical significance disappeared after multiple comparison adjustments.nnnCONCLUSIONnThese findings suggest that selective attention is impaired in children with CAE and comorbid ADHD contributes to further impairment of sustained attention and response inhibition.

Neurovascular Manifestation of Loeys-Dietz Syndrome: A Case Report

A 5-year-old boy was referred to our hospital for evaluation of headache, tortuous intracranial arteries and vertebral arteries found up on brain magnetic resonance angiography. The patient’s family history was unremarkable for any genetic disease. He was born at 39 weeks of gestation by spontaneous vaginal delivery without complications. His birth weight was 3,580 gm. At 3 years Neurovascular Manifestation of Loeys-Dietz Syndrome: A Case Report

Genotype-Phenotype Correlation of SMN1 and NAIP Deletions in Korean Patients with Spinal Muscular Atrophy

Background and Purpose Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by progressive muscle weakness and atrophy. Most SMA patients have a homozygous deletion in survival of motor neuron 1 (SMN1) gene, and neuronal apoptosis inhibitory protein (NAIP) gene is considered a phenotype modifier. We investigated the genotype-phenotype correlation of SMN1 and NAIP deletions in Korean SMA patients. Methods Thirty-three patients (12 males and 21 females) treated at the Asan Medical Center between 1999 and 2013 were analyzed retrospectively. The polymerase chain reaction (PCR), restriction-fragment-length polymorphism analysis, and multiplex PCR were used to detect deletions in SMN1 (exons 7 and 8) and NAIP (exons 4 and 5). We reviewed clinical presentations and outcomes and categorized the patients into three clinical types. NAIP deletion-driven differences between the two genotypes were analyzed. Results Deletion analysis identified homozygous deletions of SMN1 exons 7 and 8 in 30 patients (90.9%). Among these, compared with patients without an NAIP deletion, those with an NAIP deletion showed a significantly lower age at symptom onset (1.9±1.7 months vs. 18.4±20.4 months, mean±SD; p=0.007), more frequent type 1 phenotype (6/6 vs. 8/24, p=0.005), and worse outcomes, with early death or a requirement for ventilator support (4/4 vs. 2/12, p=0.008). Conclusions Homozygous deletion in SMN1 and a concurrent NAIP deletion were associated with an early onset, severe hypotonia, and worse outcome in SMA patients. Deletion analysis of NAIP and SMN1 can help to accurately predict prognostic outcomes in SMA.

A New Rat Model of Epileptic Spasms Based on Methylazoxymethanol-Induced Malformations of Cortical Development

Malformations of cortical development (MCDs) can cause medically intractable epilepsies and cognitive disabilities in children. We developed a new model of MCD-associated epileptic spasms by treating rats prenatally with methylazoxymethanol acetate (MAM) to induce cortical malformations and postnatally with N-methyl-d-aspartate (NMDA) to induce spasms. To produce cortical malformations to infant rats, two dosages of MAM (15u2009mg/kg, intraperitoneally) were injected to pregnant rats at gestational day 15. In prenatally MAM-exposed rats and the controls, spasms were triggered by single (6u2009mg/kg on postnatal day 12 (P12) or 10u2009mg/kg on P13 or 15u2009mg/kg on P15) or multiple doses (P12, P13, and P15) of NMDA. In prenatally MAM-exposed rats with single NMDA-provoked spasms at P15, we obtain the intracranial electroencephalography and examine the pretreatment response to adrenocorticotropic hormone (ACTH) or vigabatrin. Rat pups prenatally exposed to MAM exhibited a significantly greater number of spasms in response to single and multiple postnatal NMDA doses than vehicle-exposed controls. Vigabatrin treatment prior to a single NMDA dose on P15 significantly suppressed spasms in MAM group rats (pu2009<u20090.05), while ACTH did not. The MAM group also showed significantly higher fast oscillation (25–100u2009Hz) power during NMDA-induced spasms than controls (pu2009=u20090.047). This new model of MCD-based epileptic spasms with corresponding features of human spasms will be valuable for future research of the developmental epilepsy.

An interictal EEG can predict the outcome of vagus nerve stimulation therapy for children with intractable epilepsy

PurposeThis study aimed to evaluate the long-term efficacy of vagus nerve stimulation (VNS) in children and adolescents with intractable epilepsy and identify predictive factors for responsiveness to VNS.MethodsMedical records of pediatric patients who underwent VNS implantation at two Korean tertiary centers were reviewed. At 0.5, 1, 3, and 5xa0years post-VNS implantation, the frequency of the most disabling seizures in each patient was assessed. Responders were defined as showing an overall 50xa0% reduction from baseline seizure frequency during follow-up. The clinical characteristics of responders and non-responders were compared.ResultsAmong 58 patients, approximately half (29/58) were responders. The mean age at implantation was 10.9xa0years (range, 2.7–20.9) and the mean follow-up duration after VNS implantation was 8.4xa0years (range, 1–15.5). At 0.5, 1, 3, and 5xa0years after implantation, 43.1, 50.0, 56.9, and 58.1xa0% of patients exhibited ≥50xa0% seizure frequency reduction disabling seizures. The patients with focal or multifocal epileptiform discharges were more likely to be responders than those with generalized epileptiform activities by video or conventional EEG at the time of VNS implantation (Pearson’s and χ2 test, pxa0=xa00.001). No other clinical variables were found to be associated with seizure outcomes. Wound infections caused VNS removal in two cases. All other adverse events, including cough and hoarseness, were tolerable.ConclusionVNS is a well-tolerated and effective adjuvant therapy in pediatric patients with intractable epilepsy. Notably, patients with focal epileptiform discharges alone rather than those with generalized epileptiform discharges maybe better candidates for VNS.

A rare case of dysembryoplastic neuroepithelial tumor combined with encephalocraniocutaneous lipomatosis and intractable seizures

Encephalocraniocutaneous lipomatosis (ECCL) is a rare neurocutaneous syndrome that affects ectomesodermal tissues (skin, eyes, adipose tissue, and brain). The neurologic manifestations associated with ECCL are various including seizures. However, ECCL patients very rarely develop brain tumors that originate from the neuroepithelium. This is the first described case of ECCL in combination with dysembryoplastic neuroepithelial tumor (DNET) that presented with intractable seizures. A 7-year-old girl was admitted to our center because of ECCL and associated uncontrolled seizures. She was born with right anophthalmia and lipomatosis in the right temporal area and endured right temporal lipoma excision at 3 years of age. Seizures began when she was 3 years old, but did not respond to multiple antiepileptic drugs. Brain magnetic resonance (MR) imaging performed at 8 and 10 years of age revealed an interval increase of multifocal hyperintense lesions in the basal ganglia, thalamus, cerebellum, periventricular white matter, and, especially, the right temporal area. A nodular mass near the right hippocampus demonstrated the absence of N-acetylaspartate decrease on brain MR spectroscopy and mildly increased methionine uptake on brain positron emission tomography, suggesting low-grade tumor. Twenty-four-hour video electroencephalographic monitoring also indicated seizures originating from the right temporal area. Right temporal lobectomy was performed without complications, and the nodular lesion was pathologically identified as DNET. The patient has been seizure-free for 14 months since surgery. Although ECCL-associated brain tumors are very rare, careful follow-up imaging and surgical resection is recommended for patients with intractable seizures.

A Rare Case of Childhood Stiff Person Syndrome Associated With Pleuropulmonary Blastoma

INTRODUCTIONnStiff person syndrome is a rare autoimmune, neurological disorder characterized by progressive rigidity and episodic painful spasms, predominantly affecting the proximal limbs and axial muscles, and leading to progressive disability. We report the case of a child who developed symptoms compatible with stiff person syndrome during treatment for pleuropulmonary blastoma.nnnPATIENT DESCRIPTIONnA 3-year, 5-month-old girl was admitted for gradually worsening postural tremor, painful spasms, and generalized stiffness. Since the age of 3 years, she had been on adjuvant chemotherapy for pleuropulmonary blastoma before surgical resection. Brain magnetic resonance imaging and electroencephalographic findings were normal. Although serologic tests for autoimmune disease, including paraneoplastic antibodies and antiglutamic acid decarboxylase antibodies, were unremarkable, her findings were attributed to a paraneoplastic syndrome based on her clinical features and medical history. However, following the planned pulmonary lobectomy, her symptoms were paradoxically aggravated, with continuous motor unit potential at rest on electromyography, which occurs in stiff person syndrome. She gradually improved during postadjuvant chemotherapy with simultaneous immunotherapy including intravenous immunoglobulins and methylprednisolone, and she had recovered completely when evaluated at the 22-month follow-up visit after completion of her treatment for pleuropulmonary blastoma.nnnCONCLUSIONnWe present the first documented child with stiff person syndrome associated with pleuropulmonary blastoma. The marked clinical improvement following chemotherapy for pleuropulmonary blastoma was yet more proof of the pleuropulmonary blastoma-related stiff person syndrome. In children with a malignancy and stiff person syndrome, a paraneoplastic syndrome should be considered and the treatment for the malignancy must be undertaken.