Sex Differences in the Preventive Effect of Cardiovascular and Metabolic Therapeutics on Dementia

Dementia is a clinical syndrome characterized by progressive impairment of cognitive and functional abilities. As currently applied treatments for dementia can only delay the progression of dementia and cannot fundamentally cure it, much attention is being paid to reducing its incidence by preventing the associated risk factors. Cardiovascular and metabolic diseases are well-known risk factors for dementia, and many studies have attempted to prevent dementia by treating these risk factors. Growing evidence suggests that sex-based factors may play an important role in the pathogenesis of dementia. Therefore, a deeper understanding of the differences in the effects of drugs based on sex may help improve their effectiveness. In this study, we reviewed sex differences in the impact of therapeutics targeting risk factors for dementia, such as cardiovascular and metabolic diseases, to prevent the incidence and/or progression of dementia.

First Successful Application of Preimplantation Genetic Diagnosis for Lethal Neonatal Rigidity and Multifocal Seizure Syndrome in Korea: A Case Report

Lethal neonatal rigidity and multifocal seizure syndrome (RMFSL) is a severe autosomal recessive epileptic encephalopathy characterized by rigidity, intractable multifocal seizures, microcephaly, apnea, and bradycardia immediately after birth. RMFSL is related to a mutation in breast cancer 1-associated ataxia telangiectasia mutated activation-1 protein (BRAT1). We report a case of a female infant born to non-consanguineous Korean parents who developed hypertonia, dysmorphic features, progressive encephalopathy with refractory seizures at birth, and worsening intermittent apnea, leading to intubation and death at 137 days of age. The initial repeated electroencephalographic findings were normal; however, a pattern of focal seizures emerged at 35 days of life. Rapid trio whole-exome sequencing revealed heterozygous mutations c.1313_1314delAG p.(Gln438Argfs*51) and c.1276C>T p. (Gln426*) in BRAT1. After genetic counseling for pregnancy planning, a preimplantation genetic diagnosis for targeted BRAT1 mutations was successfully performed, and a healthy baby was born. To our knowledge, this is the first reported case of a Korean patient with compound heterozygous mutations in BRAT1. An early and accurate genetic diagnosis can help provide timely treatment to patients and indicate the need for reproductive counseling for parents for family planning.

Clinical Spectrum of Myelin Oligodendrocyte Glycoprotein-Immunoglobulin G-Associated Disease in Korean Children

Background@#and Purpose: The myelin oligodendrocyte glycoprotein (MOG) antibody is detected at a high rate in childhood acquired demyelinating syndrome (ADS). This study aimed to determine the diagnostic value of the MOG antibody in ADS and the spectrum of MOGantibody-positive demyelinating diseases in children. @*Methods@#This study included 128 patients diagnosed with ADS (n=94) or unexplained encephalitis (n=34). The MOG antibody in serum was tested using an in-house live-cell-based immunofluorescence assay. @*Results@#The MOG antibody was detected in 48 patients (46 ADS patients and 2 encephalitis patients, comprising 23 males and 25 females). Acute disseminated encephalomyelitis (ADEM) (35.4%) was the most-common diagnosis, followed by the unclassified form (17.4%), isolated optic neuritis (ON) (15.2%), neuromyelitis optica spectrum disorder (13.0%), multiple sclerosis (MS) (10.8%), other clinically isolated syndromes [monophasic event except ADEM, isolated ON, or transverse myelitis (TM)] (8.7%), and unexplained encephalitis (4.3%). At the initial presentation, 35 out of the 46 patients with ADS had brain lesions detected in magnetic resonance imaging, and 54% of these 35 patients had encephalopathy. Nine of the 11 patients without brain lesions exhibited only ON. Thirty-nine percent of the patients experienced a multiphasic event during the mean follow-up period of 34.9 months (range 1.4–169.0 months). Encephalopathy at the initial presentation was frequently confirmed in the monophasic group (p= 0.011). @*Conclusions@#MOG antibodies were identified in all pediatric ADS phenotypes except for monophasic TM. Therefore, the MOG antibody test is recommended for all pediatric patients with ADS, especially before a diagnosis of MS and for patients without a clear diagnosis.

Clinical and Genetic Spectrum of ATP1A3-Related Disorders in a Korean Pediatric Population

BACKGROUND@#AND PURPOSE: The aim of this study was to expand the understanding of the genotype-phenotype spectrum of ATP1A3-related disorders and to evaluate the therapeutic effect of a ketogenic diet in patients with alternating hemiplegia of childhood (AHC).@*METHODS@#The clinical information of 13 patients with ATP1A3 mutations was analyzed by performing retrospective chart reviews. Patients with the AHC phenotype who consented to ketogenic diet were included in the trial.@*RESULTS@#Ten patients presented with the clinical phenotype of AHC, two patients presented with rapid-onset dystonia parkinsonism, and one patient presented with cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss. Two novel mutations of the AHC phenotype were identified: p.Ile363Thr and p.Asn743Ser. The clinical phenotypes of three mutations differed from those in previous reports: p.Arg597Pro, p.Thr769Pro, and p.Arg756Cys. One of the two patients who started a ketogenic diet experienced seizure provocation and so immediate stopped consuming the diet, while the other patient continued the ketogenic diet for 1 year, but this produced no clear benefit such as reduction of paroxysmal symptoms.@*CONCLUSIONS@#Our study is the first case series of ATP1A3-related disorders to be described in Korea and which further expands the understanding of its genotype-phenotype spectrum. A ketogenic diet showed no clear benefit for the patients with AHC.

Antiepileptic Drug Withdrawal after Surgery in Children with Focal Cortical Dysplasia: Seizure Recurrence and Its Predictors

BACKGROUND AND PURPOSE: This study investigated the seizure recurrence rate and potential predictors of seizure recurrence following antiepileptic drug (AED) withdrawal after resective epilepsy surgery in children with focal cortical dysplasia (FCD). METHODS: We retrospectively analyzed the records of 70 children and adolescents with FCD types I, II, and IIIa who underwent resective epilepsy surgery between 2004 and 2015 and were followed for at least 2 years after surgery. RESULTS: We attempted AED withdrawal in 40 patients. The median time of starting the AED reduction was 10.8 months after surgery. Of these 40 patients, 14 patients (35%) experienced seizure recurrence during AED reduction or after AED withdrawal. Half of the 14 patients who experienced recurrence regained seizure freedom after AED reintroduction and optimization. Compared with their preoperative status, the AED dose or number was decreased in 57.1% of patients, and remained unchanged in 14.3% after surgery. A multivariate analysis found that incomplete resection (p=0.004) and epileptic discharges on the postoperative EEG (p=0.025) were important predictors of seizure recurrence after AED withdrawal. Over the mean follow-up duration of 4.5 years after surgery, 34 patients (48.6% of the entire cohort) were seizure-free with and without AEDs. CONCLUSIONS: Children with incomplete resection and epileptic discharges on postoperative EEG are at a high risk of seizure recurrence after drug withdrawal. Complete resection of FCD may lead to a favorable surgical outcome and successful AED withdrawal after surgery.

Association of Tumor Necrosis Factor-α Gene Promotor Variant, Not Interleukin-10, with Febrile Seizures and Genetic Epilepsy with Febrile Seizure Plus / 대한소아신경학회지

PURPOSE@#Cytokines demonstrate active roles in the occurrence of febrile seizures (FS). However, whether a genetic predisposition to inflammation is implicated in FS, febrile seizure plus (FS+) or genetic epilepsy with febrile seizure plus (GEFS+) are still unclear. Therefore we perform this study to find the association of promotor variants in pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) genes and anti-inflammatory cytokine interleukin 10 (IL-10) genes either with FS, FS+, and GEFS+ in Korean children.@*METHODS@#Fifty-seven children with FS, 32 FS+, and 12 GEFS+ patients were compared with 108 controls. The allelic and genotypic distributions were compared for TNF-α-238 (rs361525), −308 (rs1800629), −857 (rs1799724), −863 (rs1800630), and IL-10-592 (rs1800872), −819 (rs1800871), −1082 (rs1800896), and −1352 (rs1800893).@*RESULTS@#Allelic and genotypic frequencies of TNF-α and IL-10 promotor variants showed no significant differences between FS, FS+, and GEFS+ versus controls. However, AA genotypes at TNF-α-863 were present only in controls. TNF-α-863 (rs1800630) promoter variants showed an association with FS, FS+, and GEFS+ in a recessive mode of inheritance pattern (P<0.05).@*CONCLUSION@#Our results suggest that AA genotypes at TNF-α-863 may be associated with FS, FS+, and GEFS+, implicating protective roles against to development of FS, FS+, and GEFS+.

The Surgical and Cognitive Outcomes of Focal Cortical Dysplasia

Focal cortical dysplasia (FCD) is the major cause of intractable focal epilepsy in childhood leading to epilepsy surgery. The overall seizure freedom after surgery ranges between 50–75% at 2 years after surgery and the long-term seizure freedom remain relatively stable. Seizure outcome after surgery depends on a various factors such as pathologic etiologies, extent of lesion, and types of surgery. Therefore, seizure outcome after surgery for FCD should be analyzed carefully considering cohorts' characteristics. Studies of pediatric epilepsy surgery emphasize the early surgical intervention for a better cognition. Early surgical intervention and cessation of seizure activity are important for children with intractable epilepsy. However, there are limited data on the cognitive outcome after surgery in pediatric FCD, requiring further investigation. This paper reviews the seizure and cognitive outcomes of epilepsy surgery for FCD in children. Several prognostic factors influencing seizure outcome after surgery will be discussed in detail.

Association Analysis of Interleukin-1β, Interleukin-6, and HMGB1 Variants with Postictal Serum Cytokine Levels in Children with Febrile Seizure and Generalized Epilepsy with Febrile Seizure Plus

BACKGROUND AND PURPOSE: Febrile seizure (FS) is a unique type of seizure that only occurs during childhood. Genelized epilepsy with febrile seizure plus (GEFS+) is a familial epilepsy syndrome associated with FS and afebrile seizure (AFS). Both seizure types are related to fever, but whether genetic susceptibility to inflammation is implicated in them is still unclear. To analyze the associations between postictal serum cytokine levels and genetic variants in the cytokine genes interleukin (IL)-1β, IL-6, and high mobility group box-1 (HMGB1) in FS and GEFS+. METHODS: Genotyping was performed in 208 subjects (57 patients with FS, 43 patients with GEFS+, and 108 controls) with the SNaPshot assay for IL-1β-31 (rs1143627), IL-1β-511 (rs16944), IL-6-572 (rs1800796), and HMGB1 3814 (rs2249825). Serum IL-1β, IL-6, and HMGB1 levels were analyzed within 2 hours after seizure attacks using the ELISA in only 68 patients (38 FS, 10 GEFS+, and 20 controls). The allele distribution, genotype distribution, and correlations with serum cytokine levels were analyzed. RESULTS: Near-complete linkage disequilibrium exists between IL-1β-31 and IL-1β-511 variants. CT genotypes of these variants were associated with significantly higher postictal serum IL-1β levels than were CC+TT genotypes in FS (both p<0.05). CT genotypes of IL-1β-31 and IL-1β-511 variants were more strongly associated with FS than were CC+TT genotypes (odds ratio=1.691 and 1.731, respectively). For GEFS+, serum IL-1β levels after AFS for CT genotypes of IL-1β-31 and IL-1β-511 were also higher than for CC+TT genotypes. No significant associations were found for IL-6 and HMGB1. CONCLUSIONS: Genetic variants located in IL-1β-31 and IL-1β-511 promotor regions are correlated with higher postictal IL-1β levels in FS. These results suggest that IL-1 gene cluster variants in IL-1β-31 and IL-1β-511 are a host genetic factor for provoking FS in Korean children.

The Surgical and Cognitive Outcomes of Focal Cortical Dysplasia

Focal cortical dysplasia (FCD) is the major cause of intractable focal epilepsy in childhood leading to epilepsy surgery. The overall seizure freedom after surgery ranges between 50–75% at 2 years after surgery and the long-term seizure freedom remain relatively stable. Seizure outcome after surgery depends on a various factors such as pathologic etiologies, extent of lesion, and types of surgery. Therefore, seizure outcome after surgery for FCD should be analyzed carefully considering cohorts' characteristics. Studies of pediatric epilepsy surgery emphasize the early surgical intervention for a better cognition. Early surgical intervention and cessation of seizure activity are important for children with intractable epilepsy. However, there are limited data on the cognitive outcome after surgery in pediatric FCD, requiring further investigation. This paper reviews the seizure and cognitive outcomes of epilepsy surgery for FCD in children. Several prognostic factors influencing seizure outcome after surgery will be discussed in detail.

Paroxysmal Dyskinesia in Children: from Genes to the Clinic

BACKGROUND AND PURPOSE: Paroxysmal dyskinesia is a genetically and clinically heterogeneous movement disorder. Recent studies have shown that it exhibits both phenotype and genotype overlap with other paroxysmal disorders as well as clinical heterogeneity. We investigated the clinical and genetic characteristics of paroxysmal dyskinesia in children. METHODS: Fifty-five patients (16 from 14 families and 39 sporadic cases) were enrolled. We classified them into three phenotypes: paroxysmal kinesigenic dyskinesia (PKD), paroxysmal nonkinesigenic dyskinesia (PNKD), and paroxysmal exercise-induced dyskinesia (PED). We sequenced PRRT2, SLC2A1, and MR-1 in these patients and reviewed their medical records. RESULTS: Forty patients were categorized as PKD, 14 as PNKD, and 1 as PED. Thirty-eight (69.1%) patients were male, and their age at onset was 8.80±4.53 years (mean±SD). Dystonia was the most common symptom (38 patients, 69.1%). Pathogenic variants were identified in 20 patients (36.4%): 18 with PRRT2 and 2 with SLC2A1. All of the patients with PRRT2 mutations presented with PKD alone. The 2 patients carrying SLC2A1 mutations presented as PNKD and PED, and one of them was treated effectively with a ketogenic diet. Six mutations in PRRT2 (including 2 novel variants) were identified in 9 of the 13 tested families (69.2%) and in 8 patients of the 25 tested sporadic cases (32.0%). There were no significant differences in clinical features or drug response between the PRRT2-positive and PRRT2-negative PKD groups. CONCLUSIONS: This study has summarized the clinical and genetic heterogeneity of paroxysmal dyskinesia in children. We suggest that pediatric paroxysmal dyskinesia should not be diagnosed using clinical features alone, but by combining them with broader genetic testing.

A Unique Mutational Spectrum of MLC1 in Korean Patients With Megalencephalic Leukoencephalopathy With Subcortical Cysts: p.Ala275Asp Founder Mutation and Maternal Uniparental Disomy of Chromosome 22

BACKGROUND: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare inherited disorder characterized by infantile-onset macrocephaly, slow neurologic deterioration, and seizures. Mutations in the causative gene, MLC1, are found in approximately 75% of patients and are inherited in an autosomal recessive manner. We analyzed MLC1 mutations in five unrelated Korean patients with MLC. METHODS: Direct Sanger sequencing was used to identify MLC1 mutations. A founder effect of the p.Ala275Asp variant was demonstrated by haplotype analysis using single-nucleotide polymorphic (SNP) markers. Multiple ligation-dependent probe amplification (MLPA) and comparative genomic hybridization plus SNP array were used to detect exonic deletions or uniparental disomy (UPD). RESULTS: The most prevalent pathogenic variant was c.824C>A (p.Ala275Asp) found in 7/10 (70%) alleles. Two pathogenic frameshift variants were found: c.135delC (p.Cys46Alafs*12) and c.337_353delinsG (p.Ile113Glyfs*4). Haplotype analysis suggested that the Korean patients with MLC harbored a founder mutation in p.Ala275Asp. The p.(Ile113Glyfs*4) was identified in a homozygous state, and a family study revealed that only the mother was heterozygous for this variant. Further analysis of MLPA and SNP arrays for this patient demonstrated loss of heterozygosity of chromosome 22 without any deletion, indicating UPD. The maternal origin of both chromosomes 22 was demonstrated by haplotype analysis. CONCLUSIONS: This study is the first to describe the mutational spectrum of Korean patients with MLC, demonstrating a founder effect of the p.Ala275Asp variant. This study also broadens our understanding of the mutational spectrum of MLC1 by demonstrating a homozygous p.(Ile113Glyfs*4) variant resulting from UPD of chromosome 22.

Erratum to: The KMDS-NATION Study: Korean Movement Disorders Society Multicenter Assessment of Non-Motor Symptoms and Quality of Life in Parkinson's Disease NATION Study Group

The original version of this article contained wrong informations of some authors which should be changed.

The KMDS-NATION Study: Korean Movement Disorders Society Multicenter Assessment of Non-Motor Symptoms and Quality of Life in Parkinson's Disease NATION Study Group

BACKGROUND AND PURPOSE: Nonmotor symptoms (NMS) in Parkinson's disease (PD) have multisystem origins with heterogeneous manifestations that develop throughout the course of PD. NMS are increasingly recognized as having a significant impact on the health-related quality of life (HrQoL). We aimed to determine the NMS presentation according to PD status, and the associations of NMS with other clinical variables and the HrQoL of Korean PD patients. METHODS: We surveyed patients in 37 movement-disorders clinics throughout Korea. In total, 323 PD patients were recruited for assessment of disease severity and duration, NMS, HrQoL, and other clinical variables including demographics, cognition, sleep scale, fatigability, and symptoms. RESULTS: In total, 98.1% of enrolled PD subjects suffered from various kinds of NMS. The prevalence of NMS and scores in each NMS domain were significantly higher in the PD group, and the NMS worsened as the disease progressed. Among clinical variables, disease duration and depressive mood showed significant correlations with all NMS domains (p<0.001). NMS status impacted HrQoL in PD (rS=0.329, p<0.01), and the association patterns differed with the disease stage. CONCLUSIONS: The results of our survey suggest that NMS in PD are not simply isolated symptoms of degenerative disease, but rather exert significant influences throughout the disease course. A novel clinical approach focused on NMS to develop tailored management strategies is warranted to improve the HrQoL in PD patients.

Analysis of Lumbar Puncture Test in 5 Patients with Good Prognosis of Shunt Operation for Normal Pressure Hydrocephalus

Five patients with favorable outcomes after a shunt operation in normal pressure hydrocephalus were analyzed with the aim of identifying consistent findings in a lumbar puncture (LP) test. The cases commonly showed improvement in at least one cognition and two gait LP parameters. We suggest that when judging the effects of LP on a shunt operation, the gait parameters need to be tailored to the gait status and the analyzed LP parameters should be evaluated at least twice at different times.

Spot Sign on Initial Brain Computed Tomography Angiography Source Image to Predict Large Hemorrhagic Transformation after Middle Cerebral Artery Infarction

The spot sign refers to tiny enhanced foci within the hematoma on a brain computed tomography angiography image. A spot sign is usually considered to be associated with hematoma progression in patients with acute intracerebral hemorrhage. We describe a patient with infarction of the left middle cerebral artery where a spot sign was observed. A spot sign may also have significant predictive value for large hemorrhagic transformation in patients with ischemic stroke.

Takotsubo Cardiomyopathy Associated With Status Epilepticus

Takotsubo cardiomyopathy is a reversible cardiac syndrome that occurs subsequently to other medical illnesses such as cerebral hemorrhage, shock, or seizure disorders that are presumed to disturb autonomic regulation. This syndrome is characterized by chest pain, dyspnea, and electrocardiographic changes mimicking an acute coronary syndrome. Mild elevation of cardiac enzymes and transient wall-motion abnormalities of apical akinesia can appear. However, takotsubo cardiomyopathy following epilepsy is not well recognized. We report two cases of takotsubo-cardiomyopathy-related idiopathic status epilepticus presenting with cardiogenic shock.

Efficacy and Tolerability of Valproic Acid Once Daily Dosing for Juvenile Myoclonic Epilepsy / 대한소아신경학회지

PURPOSE: The purpose of this study was to evaluate the efficacy and tolerability of extended-release valproic acid once daily dosing in juvenile myoclonic epilepsy (JME). METHODS: Medical records of patients who received valproic acid monotherapy for the treatment of JME were retrospectively reviewed. Their clinical information regarding age, gender, seizure types, underlying neurologic status, dosing regimen, response to treatment, and adverse events related to valproic acid, were analyzed. Seizure control, compliance, and adverse events rates were compared between the group of once daily dosing and the group of twice daily dosing. RESULTS: Twenty one patients (11 boys and 10 girls) were included in the study. Twelve patients were taking valproic acid extended-release once daily and nine patients were taking twice a day. More than 50% decrease in myoclonic seizure was achieved in all the patients in both groups. Generalized tonic-clonic seizure was controlled in all the patients who were taking once daily while 3 patients (36%, 3/8 patients) in twice daily group had breakthrough generalized tonic clonic seizures during the 2 year period of treatment. However, there were no statistically significant differences in seizure control, compliance, and adverse event rates between the two groups. CONCLUSION: This study demonstrated that valproic acid extended-release once daily dosing was as effective and tolerable as twice daily in the treatment of JME. Once daily dosing of valproic acid would be convenient which improve patient compliance and consequently bring better outcome in treatment of JME.

Anti-NMDA Receptor Encephalitis Which Has Shown Clinical Symptoms of Schizophrenia

Encephalitis associated with antibodies to the N-methyl-D-aspartate (NMDA) receptor has variable clinical manifestations and treatment responses. Anti-NMDAR encephalitis is often associated with ovarian teratoma, but some cases without tumor have been reported. Here, we describe a patient who has shown psychiatric symptoms, memory impairment and been diagnosed as schizophrenia for one year and had anti-NMDA receptor antibody. The patient showed atypical clinical course compared to previous cases with anti-NMDA receptor encephalitis.

Lacunar Infarctions and the Cognitive Decline in Patients with Parkinson's Disease

BACKGROUND: The cause of dementia in Parkinson's disease (PD) remains incompletely understood. Cerebrovascular lesions (CVLs) are frequently found in the aging brain and may coexist with PD pathology. We hypothesized that lacunar infarction, which is one type of CVL, impacts on cognitive decline in patients with PD. METHODS: The Mini Mental Status Examination (MMSE) and Clinical Dementia Rating (CDR) tools were applied to PD patients with lacunar infarction (<1.5 cm on brain MRI; PD-S) and PD patients with normal brain MRI (PD-NS). RESULTS: Totals of 19 PD-S patients (9 males and 10 females) and 59 PD-NS patients (16 males and 43 females) took part in this study. Univariate analysis revealed that the gender distribution did not differ between the PD-S and PD-NS groups (p=0.1731), whereas age did differ significantly [79.1+/-5.0 years vs 73.0+/-7.8 years (mean+/-SD), respectively; p=0.0002]. There was no difference between the PD-S and PD-NS patients in either PD disease duration (6.9+/-3.2 vs 5.6+/-3.8 years, respectively; p=0.1790) or education duration (5.3+/-5.4 vs 6.4+/-5.3 years, respectively; p=0.4168). After adjustment for age in ANCOVA analysis, the MMSE score was significantly lower (p=0.0128) and the CDR score was significantly higher (p=0.0426) in the PD-S group than in the PD-NS group. Ten of the PD-S patients had a single lesion. The lacunar infarctions appeared in various locations in these patients, but they were most common in the basal ganglia, thalamus, and periventricular white matter. CONCLUSIONS: Lacunar infarction appears to be associated with cognitive decline in patients with PD even after adjustment for age. Analysis of larger age-matched cases for PD-S and PD-NS is required in order to validate these results.

Two Cases of Intracranial Vertebral Artery Dissecting Aneurysm Improved by Antiplatelets Therapy

The clinical course and management of aneurysm by intracranial arterial dissection are not well known. Since intracranial dissecting aneurysm has a higher bleeding risk than an extracranial one, the optimal choice of treatment is controversial. We report two patients who presented with a dissecting aneurysm in the intracranial vertebral artery without subarachnoid hemorrhage. They showed successful responses to antiplatelet treatment without any surgical interventions.