Dravet-like syndrome with PCDH19 mutations in Taiwan - A multicenter study.

OBJECTIVE: Protocadherin-19 (PCDH19) epilepsy is a rare female restricted epilepsy syndrome with early onset seizures and developmental delay caused by a change or mutation of the PCDH19 gene on the X chromosome. SCN1A-negative patients with a Dravet-like phenotype may have a gene mutation in PCDH19. The aim of this case series was to characterize the phenotype of epileptic patients according to PCDH19 mutations, antiseizure medications, brain images and mutation types in Taiwan. METHODS: We retrospectively reviewed the medical records of patients with PCDH19 epilepsy from July 2017 to December 2021 from multiple centers in Taiwan. We analyzed the patients' clinical data and genetic reports. RESULTS: Fifteen female patients (age 3-23 years) were enrolled. Seizure onset was at 4 months to 2 years 7 months of age with generalized tonic-clonic or focal seizures. Seizure frequency tended to be in clusters rather than single longer seizures. The patients had varying degrees of intellectual disability, however 3 had no impairment. Two patients had abnormal brain images including mesial temporal sclerosis, subcortical and periventricular white matter lesions. On average, the patients received 4 antiseizure medications (range 3-6), including 9 patients who were seizure free, and 3 who received sodium channel blockers without aggravation. Missense and truncating variants (frameshift and nonsense variants) accounted for 40% and 46.7% of all mutations. The mutations of 13 patients were located on EC1 to EC4, and EC5 to cytoplasmic domain in 2 patients. SIGNIFICANCE: PCDH19 epilepsy has distinct phenotypes and an unusual X-linked pattern of expression in which females manifest core symptoms. Psychiatric and behavioral problems are frequently part of the clinical picture. Patients are usually treated with a wide array of standard antiseizure medications, with no preferred antiseizure medication class. No strong correlations between phenotype and location of variant mutations were found in our patients.

Prediction of seizure recurrence using electroencephalogram analysis with multiscale deep neural networks before withdrawal of antiepileptic drugs.

BACKGROUND: The decision to continue or discontinue antiepileptic drug (AED) treatment in patients who are seizure free for a prolonged time is critical. Studies have used certain risk factors or electroencephalogram (EEG) findings to predict seizure recurrence after the withdrawal of AEDs. However, applicable biomarkers to guide the withdrawal of AEDs are lacking. METHODS: In this study, we used EEG analysis based on multiscale deep neural networks (MSDNN) to establish a method for predicting seizure recurrence after the withdrawal of AEDs. A total of 60 patients with epilepsy were divided into two groups (30 in the recurrence group and 30 in the non-recurrence group). All patients were seizure free for at least 2 years. Before AED withdrawal, an EEG was performed for each patient, which showed no epileptiform discharges. These EEG recordings were classified using MSDNN. RESULTS: We found that the performance indices of classification between recurrence and non-recurrence groups had a mean sensitivity, mean specificity, mean accuracy, and mean area under the receiver operating characteristic curve of 74.23%, 75.83%, 74.66%, and 82.66%, respectively. CONCLUSION: Our proposed method is a promising tool to help physicians to predict seizure recurrence after AED withdrawal among seizure-free patients.

Ictal and interictal electroencephalographic findings can contribute to early diagnosis and prompt treatment in KCNQ2-associated epileptic encephalopathy.

BACKGROUND: KCNQ2-associated epilepsy is most common in neonatal genetic epilepsy. A prompt diagnosis to initialize early treatment is important. METHODS: We studied the electroencephalographic (EEG) changes including automated EEGs and conventional EEGs monitoring of 10 nonconsanguineous cases with KCNQ2 mutations, identified among 162 (6%) childhood epilepsy. We compared 11 (25%) non-KCNQ2 seizures videoed from 44 automated EEG and EEG monitoring. RESULTS: Patients with KCNQ2 seizures had received more antiepileptic treatments than patients in non-KCNQ2 group. Seizures were detected in all patients with KCNQ2 epileptic encephalopathy (EE); the detection rate in KCNQ2 group was more than in patients with non-KCNQ2. The ictal recordings showed 3 newborns presented with initial lower amplitudes (<15 µV) and fast activity (>20 Hz), evolving into higher-amplitude theta-delta waves. Two patient's ictal seizures showed recurrent focal tonic movements of the unilateral limbs associated with slowly continuous spikes in the contralateral hemisphere. The interictal EEGs in 5 KCNQ2 EE were burst-suppression. In 5 patients with familial KCNQ2 mutations, the interictal EEGs showed focal paroxysmal activity. Compared with 11 non-KCNQ2 EEG of ictal seizures, the differences are ictal EEGs initially appeared manifesting theta-delta waves without fast activities. In KCNQ2 seizures, patients with mutations locating in the selectivity filter controlling K+ permeability had severe EEG patterns and poor neurodevelopmental outcomes. CONCLUSION: Ictal EEGs in KCNQ2 seizures are unique and different from the EEGs of seizures with other etiologies. An EEG monitoring can be a valuable tool for early diagnosing KCNQ2-associated seizures and for supporting prompt treatments.

Vagus nerve stimulation for patients with refractory epilepsy: Demographic features and neuropsychological outcomes of the VNS Taiwan child neurology society database.

OBJECTIVES: Vagus nerve stimulation (VNS) is an established adjunctive therapy for medically refractory epilepsy, which is commonly associated with cognitive impairment, especially in children in whom seizures may disrupt development that is essential to their intellectual and social maturation. The Taiwan Child Neurology Society intends to expand the use of VNS by reporting the experience in a nationwide population, displaying the demographic features and neuropsychological outcomes of VNS. METHODS: The enrollment included 105 patients of all ages and seizure types who underwent VNS implantation for refractory epilepsy. Basic data included etiology, past history, seizure phenotypes, and epileptiform syndromes. For efficacy analysis, seizure frequencies were recorded at the baseline and at 3, 12, 24, and 36 months after VNS implantation. For psychological assessment, intelligence quotients (IQ) and Parental Stress Index (PSI) scores were evaluated before and after the VNS. RESULTS: During the study period, 95 patients with VNS had followed seizure frequency, IQ and PSI recording. After implantation, there was a decreased frequency at 3 (P < .001), 12 (P < .001), 24 (P = .010), and 36 (P < .01) months. After implantation, the reduction rate (0-50%) of seizure frequency ranged around 26.1-36.1% from 3 to 36 months. For PSI scores, the VNS significantly improved the PSI- total score (P = .001) and PSI-parent domain (P = .001) but not the PSI-children domain (P = .052). No significant improvement in the IQ test performance was observed. CONCLUSIONS: This prospective nationwide database of VNS in Taiwan indicates long-term efficacy of VNS therapy, which has achieved a trend of seizure frequency reduction over a period of up to 36 months. It also shows the trend of decreased parental stress after VNS implantation.

A New Method of Diagnosing Attention-Deficit Hyperactivity Disorder in Male Patients by Quantitative EEG Analysis.

Attention-deficit hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders of childhood. Diagnosis of ADHD is based on core symptoms and checklists. However, these are both subjective, which can lead to the problems of overdiagnosis and underdiagnosis. Elevated theta/beta ratio (TBR) of EEG band has been approved by the US Food and Drug Administration as a tool to assist in the diagnosis of ADHD. However, several recent studies have demonstrated that there are no significant differences in TBR between people with and without ADHD. In this study, we attempted to develop a new method for differentiating between male with and without ADHD by analyzing EEG features. Thirty boys with ADHD combined type (aged 8 years 5 months ± 1 year 11 months) and 30 age-matched controls (aged 8 years 5 months ± 1 year 8 months) were enrolled in this study. A classification analysis-based approach comprising training and classification phases was developed for classifying each subject's EEG features as ADHD or non-ADHD. Eight crucial feature descriptors were selected and ranked based on the t test. Compared with TBR in our study, the developed method had a higher area under the curve (87.78%), sensitivity (80.0%), and specificity (80.0%). Our method is more precise than using TBR in the diagnosis of ADHD. This newly developed method is a useful tool in identifying patients with ADHD and might reduce the possibility of overdiagnosis and underdiagnosis.

Preimplantation Genetic Diagnosis of Neurodegenerative Diseases: Review of Methodologies and Report of Our Experience as a Regional Reference Laboratory.

Preimplantation genetic diagnosis (PGD) has become a crucial approach in helping carriers of inherited disorders to give birth to healthy offspring. In this study, we review PGD methodologies and explore the use of amplification refractory mutation system quantitative polymerase chain reaction (ARMS-qPCR) and/or linkage analysis for PGD in neurodegenerative diseases that are clinically relevant with typical features, such as late onset, and which are severely debilitating. A total of 13 oocyte retrieval cycles were conducted in 10 cases with various neurodegenerative diseases. Among the 59 embryos analyzed, 49.2% (29/59) were unaffected and 50.8% (30/59) were affected. Of the 12 embryo transfer cycles, three resulted in pregnancy, and all pregnancies were delivered. The implantation rate and livebirth rate were 23.1% (3/13) per oocyte retrieval cycle and 25.0% (3/12) per embryo transfer cycle. Allele dropout (ADO) was noted in two embryos that were classified as unaffected by ARMS-qPCR but were evidenced as affected after prenatal diagnosis, rendering the false negative rate as 6.3% (2/32). Four among the 13 cycles underwent PGD by ARMS-qPCR coupled with linkage analysis, and all were correctly diagnosed. We conclude that PGD by ARMS-qPCR and/or linkage analysis is a feasible strategy, whereas ADO is a concern when ARMS-qPCR is used as the sole technology in PGD, especially in autosomal dominant diseases.

Revascularization of Concurrent Renal and Cerebral Artery Stenosis in a 14-Year-Old Girl with Takayasu Arteritis and Moyamoya Syndrome.

Concurrent involvement of bilateral renal and cerebral arteries, usually incurred as stenosis, is rare in childhood-onset Takayasu arteritis (c-TA). We report the case of a 14-year-old girl, with c-TA, presenting with transient ischemic attack after endovascular revascularization for renal artery stenosis and cerebrovascular stroke after surgical revascularization for cerebral artery stenosis associated with childhood-onset moyamoya syndrome. We deem that decrease of blood pressure by endovascular revascularization and improvement of cerebral perfusion by surgical revascularization may have jeopardized the cerebral deep watershed zone to cerebral ischemia followed by cerebral hyperperfusion syndrome and caused transient ischemic attack and cerebrovascular stroke in our patient. Revascularization could be a double-edge sword for c-TA patients presenting with concomitant renal artery stenosis and cerebral artery stenosis, and should be performed with caution. Quantitative analysis of cerebral blood flow by brain magnetic resonance imaging and angiography should be performed within 48 hours after surgical revascularization in c-TA.

Cognitive development in children with language impairment, and correlation between language and intelligence development in kindergarten children with developmental delay.

We performed a retrospective review of 65 children with developmental delay. The male-to-female ratio was 2.25 : 1, and the mean age was 5.8 years; performance IQ was 94.8, verbal IQ was 83, and full-scale IQ was 87.4. Twenty-three (35%) children had normal language development, 13 (20%) had below average language development, and 29 (45%) had developmental language disorder. Performance IQ was significantly better than verbal IQ in all children (P < .001), and there was no difference within the 3 language groups. The performance IQ (P = .007) of children with developmental language disorder and specific language impairment was significantly lower than that of children with normal language development. Performance IQ was found to be correlated with language score (r = .309, P = .012). The children with language impairment were associated with lower IQ scores. The discrepancy between performance IQ and verbal IQ persisted in children with developmental delay, not only in children with language disorder.

Health-related quality of life in fathers of children with or without developmental disability: the mediating effect of parental stress.

PURPOSE: The aims of this study were to compare parental stress and health-related quality of life (HRQOL) between Taiwanese fathers of children with and without developmental disabilities (DDs) and to examine the mediating effect of parental stress on the association between having a child with DD and paternal HRQOL within Chinese culture. METHOD: This cross-sectional, prospective, unmatched case-control study included 206 fathers of children with DDs and 207 fathers of healthy children. HRQOL was assessed by the SF-36 short-form questionnaire, and parental stress was assessed by the Chinese version Parental Stress Scale. RESULTS: Fathers of children with DDs experienced poorer mental and physical HRQOL and higher parental stress than fathers of healthy children. Parental stress acted as a complete mediator for paternal physical HRQOL, while parental stress had a partial mediating effect on the relationship between having a child with DD and paternal mental HRQOL. Having a child with DD also directly affected paternal mental HRQOL. CONCLUSIONS: Fathers of children with DDs should be monitored for parental stress and HRQOL, and interventions should be provided to empower them with the knowledge and skills to reduce their stress and to enhance their HRQOL.

Capillary electrophoresis for analysis of deletion and duplication in exon 44-55 of Duchenne muscular dystrophy gene.

In this study, a genotyping CGE method was established for analysis of Duchenne muscular dystrophy (DMD) gene deletions and duplications in exon 44-55. A total of 12 DMD exons (exon 44-55) and 2 internal standard gene fragments were simultaneously amplified by using a universal multiplex PCR (UMPCR) and determined by CGE. The conditions of UMPCR and CGE were optimized, including the kinds of polymerase, temperatures in UMPCR, separation matrix, separation temperature, and voltage. Finally, the separation was performed by 1.2% poly(ethylene oxide) in 1× TBE buffer at -6 kV and 25°C. After validation, our results showed the peak patterns for differentiation of genetic deletion or duplication in 27 DMD patients and normal subjects, according to the peak height ratios by comparison of two internal standard peaks. Among the 27 subjects, 23 cases are deletion type and four are duplication type. The data of two patients analyzed by this CGE-PCR method were different from that of multiplex ligation dependent probe amplification method, and the sequencing results demonstrated that our results were correct. This UMPCR-CGE method was considered better than the multiplex ligation dependent probe amplification method. Furthermore, this method can be used for eugenics in clinical applications.

Children's deep neck infections in central Taiwan.

BACKGROUND: Deep neck infection (DNI) is an uncommon but severe disease in children. Few study have been reported detailing pediatric deep neck infection. METHODS: A retrospective analysis of 52 cases of deep neck infection at Changhua Christian Hospital over a 10-year period was performed. RESULTS: Thirty-two boys and 20 girls ranged from one month to eighteen years old were collected in the study. The most remarked symptom was neck swelling (83%). There were 48% (23/48) in right side. Two cases (3.8%) yielded a positive blood culture and fifty-three (53%) cases had positive pus culture. The most common pathogen was Streptococcus viridians (33%). There were two cases oxacillin-resistant Staphylococus aureus. CONCLUSIONS: Once a patient exhibited neck swelling, neck pain, fever and signs of airway obstruction, deep neck infection should be considered. When one was highly suspected to have deep neck infection, computed tomography of neck should be arranged for differential diagnosis.