Early-onset autosomal dominant GTP-cyclohydrolase I deficiency: Diagnostic delay and residual motor signs.

OBJECTIVE: Autosomal dominant (AD) guanosine triphosphate cyclohydrolase 1 (GCH1) deficiency is the most common cause of dopa-responsive dystonia (DRD). Patients with GCH1 deficiency are likely to experience diagnostic delay, but its consequences have not been described thoroughly in patients with early-onset disease. We describe the diagnostic delay and residual motor signs (RMS) observed in patients with early-onset (before 15 years of age) disease. METHODS: Twelve patients with early-onset AD GCH1 deficiency from a single center were included in the case series analysis. For the meta-analysis, the PubMed database was searched for articles on early-onset AD GCH1 deficiency published from 1995 to 2019. RESULTS: In the case series, the mean duration of diagnostic delay was 5.6 years. Two patients exhibited RMS, and four patients underwent orthopedic surgery. The literature search yielded 137 AD GCH1 deficiency cases for review; gait disturbance was reported in 92.7% of patients, diurnal fluctuation of symptoms in 91.9%, and RMS in 39%. The mean duration of diagnostic delay was 14.6 years overall: 12.0 years in RMS-negative patients and 21.2 years in RMS-positive patients. CONCLUSIONS: Diagnostic delay in early-onset AD GCH1 deficiency is more closely associated with later RMS. Early clinical suspicion, timely diagnosis, and levodopa treatment may reduce the occurrence of RMS in patients with early-onset AD GCH1 deficiency.

Deep Convolutional Neural Network Based Interictal-Preictal Electroencephalography Prediction: Application to Focal Cortical Dysplasia Type-II.

We aimed to differentiate between the interictal and preictal states in epilepsy patients with focal cortical dysplasia (FCD) type-II using deep learning-based classifiers based on intracranial electroencephalography (EEG). We also investigated the practical conditions for high interictal-preictal discriminability in terms of spatiotemporal EEG characteristics and data size efficiency. Intracranial EEG recordings of nine epilepsy patients with FCD type-II (four female, five male; mean age: 10.7 years) were analyzed. Seizure onset and channel ranking were annotated by two epileptologists. We performed three consecutive interictal-preictal classification steps by varying the preictal length, number of electrodes, and sampling frequency with convolutional neural networks (CNN) using 30 s time-frequency data matrices. Classification performances were evaluated based on accuracy, F1 score, precision, and recall with respect to the above-mentioned three parameters. We found that (1) a 5 min preictal length provided the best classification performance, showing a remarkable enhancement of >13% on average compared to that with the 120 min preictal length; (2) four electrodes provided considerably high classification performance with a decrease of only approximately 1% on average compared to that with all channels; and (3) there was minimal performance change when quadrupling the sampling frequency from 128 Hz. Patient-specific performance variations were noticeable with respect to the preictal length, and three patients showed above-average performance enhancements of >28%. However, performance enhancements were low with respect to both the number of electrodes and sampling frequencies, and some patients showed at most 1-2% performance change. CNN-based classifiers from intracranial EEG recordings using a small number of electrodes and efficient sampling frequency are feasible for predicting the interictal-preictal state transition preceding seizures in epilepsy patients with FCD type-II. Preictal lengths affect the predictability in a patient-specific manner; therefore, pre-examinations for optimal preictal length will be helpful in seizure prediction.

Chronic inflammatory demyelinating polyneuropathy: Plasmapheresis or cyclosporine can be good treatment options in refractory cases.

Childhood chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare condition, and the optimal treatment strategy is not well established, especially in refractory cases. We analyzed the clinical features and treatment outcomes of 14 cases of childhood CIDP with more than 12 months of follow-up. Of the 14 cases, 10 cases were considered refractory to the conventional first-line treatment. In the monophasic group (n = 6), plasmapheresis resulted in a better treatment response than did IVIG. Monophasic refractory cases (n = 4) were especially responsive to plasmapheresis. In the polyphasic group (n = 8), IVIG and plasmapheresis had comparable effects. Among them six polyphasic patients were refractory to the first-line treatment options and received additional immunosuppressants. Four treatment-refractory polyphasic patients received cyclosporine and achieved successful disease control. With regard to the long-term outcomes, six patients showed minimal symptoms and no relapse within 6 months. Our results suggest that early administration of plasmapheresis in a monophasic course and cyclosporine in a polyphasic course may be effective treatment options for refractory childhood CIDP.

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.

The Korean undiagnosed diseases program: lessons from a one-year pilot project.

BACKGROUND: The Korean Undiagnosed Diseases Program (KUDP) was launched in January 2017 as a one-year pilot project to address the increasing global interest in patients with undiagnosed rare diseases. The purpose of this paper is to summarize the project results and emphasize the unmet research needs among patients with undiagnosed rare diseases in Korea. RESULTS: Patient enrollment, assessment, and diagnostic processes were determined by the KUDP clinical expert consortium. Patients followed a diagnostic workflow after being categorized into one of four groups: I) insufficient clinical information or lack of standard diagnostic processes; II) undiagnosed due to low disease awareness; III) clinically diagnosed but unconfirmed genetically due to genetic heterogeneities; or IV) unknown disease due to complex, atypical clinical presentations. After excluding two patients from group I, 97 patients were enrolled, including 10 in group II, 67 in group III, and 20 in group IV. Most of them (92 of 97, 94.8%) were pediatric patients (< 18 years old) and 59 (60.8%) were male. The primary symptoms for 80 patients (82.5%) were neurologic. During the one-year pilot study, 72 patients completed a diagnostic assessment including clinical and molecular genetic analyses; some patients also underwent pathological or biochemical analysis. Twenty-eight of these patients (28/72, 38.9%) achieved molecular genetic diagnosis. Thirteen patients were diagnosed based on traditional tests, including biochemical assay, single or targeted genetic analysis, and chromosomal microarray. We performed whole exome sequencing on 52 patients, among whom 15 (28.8%, 15/52) reached a final diagnosis. One new disorder was identified via international collaboration. CONCLUSIONS: Using an efficient clinical diagnostic workflow, this KUDP pilot study resulted in a fair diagnostic success rate, improving the potential for additional diagnoses and new scientific discovery of complex and rare diseases. KUDP also satisfied unmet needs for rare diseases with multisystem involvement, highlighting the value of emerging genomic technologies for further research into rare and still-undiagnosed conditions.

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.

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.

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.

Screening Autoimmune Anti-neuronal Antibodies in Pediatric Patients with Suspected Autoimmune Encephalitis.

BACKGROUND AND PURPOSE: The aim of this study was to identify and describe the pediatric autoimmune encephalitis cases positive for anti-neuronal antibody tests. METHODS: Screening of six anti-neuronal antibodies in 23 children with suspected autoimmune encephalitis was performed by cell-based indirect immunofluorescence test with patients' serum or cerebrospinal fluid. RESULTS: Among the 23 cases enrolled here, eight patients (35%) were positive for the anti-N-methyl-d-aspartate (NMDA) receptor antibody and one patient (4%) was positive for the anti-contactin-associated protein-like 2 (CASPR2) antibody. In the anti-NMDA receptor antibody-positive group, seizure and movement disorders were the most prominent features and were present in all patients. A tumor was present in only one patient. Three patients with infant- and toddler-onset disease did not exhibit a classic multistage illness. In addition to seizure and dyskinesia, aphasia or mutism without severe consciousness impairment was present in all three patients. These atypical clinical presentations may suggest different pathomechanism of anti-NMDA receptor encephalitis among these age groups. The patient who was positive for the anti-CASPR2 antibody was an 8-year-old girl who presented with fever, encephalopathy, and seizure. Neuromyotonia or other dyskinesia was not present. CONCLUSIONS: Eight anti-NMDA receptor antibody positive patients and one CASPR2 positive patient were identified from the screening of six anti-neuronal antibodies in pediatric patients suspected with autoimmune encephalitis. Developmental regression specifically for language skills was suggested as one of the atypical clinical features in infants and toddler onset anti-NMDA receptor antibody positive patients.

A case of isolated middle cerebral artery stenosis with hemichorea and moyamoya pattern collateralization.

Isolated middle cerebral artery (MCA) stenosis in young patients with no other medical condition may be a unique pathologic entity with a benign long-term course. Generally, moyamoya disease shows a progression of stenosis from internal cerebral artery (ICA) to other intracranial vessel. A 26-year-old woman was admitted for choreic movements of the right arm and leg. Brain magnetic resonance imaging showed no stroke. Conventional angiography revealed 48% stenosis of the left M1 without ICA stenosis. Single photon emission computed tomography revealed perfusion asymmetry after acetazolamide injection, suggesting decreased uptake in the left basal ganglia and the cerebral cortex. Her hemichorea was mildly decreased with risperidone. One year later, follow-up angiography showed complete occlusion of the left M1 with neovascularization suggestive of moyamoya disease. The patient underwent bypass surgery and her hemichorea disappeared. This may be an atypical presentation of moyamoya disease. The bypass surgery was an effective measure for restoring the vascular insufficiency and, resultantly, controlling her hemichorea.