Role of Perampanel in the Management of Pediatric Epilepsies in Asia: Expert Opinion.

Management of pediatric epilepsies poses unique challenges around diagnosis, treatment options, comorbidities, and the potential for these factors to interact with processes in the developing brain. In pediatric patients, broad-spectrum antiseizure medications (ASMs) with minimal potential for adverse events (AEs) and limited impact on cognition and behavior are preferred. Perampanel is a first-in-class ASM with broad-spectrum efficacy, a tolerable safety profile, minimal negative impact on cognitive function, and other features that make it a viable treatment option in this patient population. However, evidence and experience of its use in pediatric patients are less extensive than in adult patients. Experts in pediatric epilepsy across the region convened at a series of meetings to discuss the use of perampanel in pediatric patients, including dose optimization, AE prevention and management, and considerations in particular groups. This article summarizes key evidence for perampanel in the pediatric population and consolidates the experts' recommendations for using the ASM in managing pediatric epilepsies.

Utilisation of exome sequencing for muscular disorders in Thai paediatric patients: diagnostic yield and mutational spectrum.

Muscular dystrophies and congenital myopathies are heterogeneous groups of inherited muscular disorders. An accurate diagnosis is challenging due to their complex clinical presentations and genetic heterogeneity. This study aimed to determine the utilisation of exome sequencing (ES) for Thai paediatric patients with muscular disorders. Of 176 paediatric patients suspected of genetic/inherited myopathies, 133 patients received a molecular diagnosis after performing conventional investigations, single gene testing, and gene panels. The remaining 43 patients from 42 families could be classified into three groups: Group 1, MLPA-negative Duchenne muscular dystrophy (DMD) with 9 patients (9/43; 21%), Group 2, other muscular dystrophies (MD) with 18 patients (18/43; 42%) and Group 3, congenital myopathies (CM) with 16 patients (16/43; 37%). All underwent exome sequencing which could identify pathogenic variants in 8/9 (89%), 14/18 (78%), and 8/16 (50%), for each Group, respectively. Overall, the diagnostic yield of ES was 70% (30/43) and 36 pathogenic/likely pathogenic variants in 14 genes were identified. 18 variants have never been previously reported. Molecular diagnoses provided by ES changed management in 22/30 (73%) of the patients. Our study demonstrates the clinical utility and implications of ES in inherited myopathies.

Neuronal Ceroid Lipofuscinoses Presenting as Rett-like Phenotype: A Two-Case Report From Thailand.

BACKGROUND: Neuronal ceroid lipofuscinoses (NCLs) (hereafter described as CLN disease) comprise a rare and life-limiting set of genetically inherited neurodegenerative disorders that are characterized by abnormal lysosomal storage. The NCL disorders are, collectively, the most common group of degenerative brain disorders in children. PATIENT DESCRIPTIONS: We report two cases of CLN disease that were diagnosed and treated at the Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Both cases of CLN disease (CLN1 and CLN6 diagnosed in 2016 and 2017, respectively) profiled in this report presented with clinical features of Rett syndrome. In the first case, a 2-year-old girl presented with Rett-like clinical features, including global developmental regression and hand-wringing action. Single-gene analysis of the MECP2 gene was negative. However, PPT1 gene sequencing revealed a novel homozygous frameshift mutation, c.629_630dupGT (p.Ile211Valfs∗10). In the second case, a 7.5-year-old girl presented with ataxia, progressive myoclonic epilepsy, and Rett-like hand-wringing. A c.794_796delCCT variant in the CLN6 gene was identified by whole-exome sequencing. Fingerprint bodies from electron microscopy of the skin also supported a diagnosis of CLN disease in our second case. DISCUSSION: Presentation with clinical features of Rett syndrome has only been reported in patients diagnosed with CLN1 and CLN7 disease, and never in those with CLN6. CONCLUSIONS: Physicians should suspect and investigate for CLN disease in patients with Rett-like phenotype who are negative for MECP2 mutation, especially in patients with visual impairment and early prominent brain atrophy.

Juvenile dermatomyositis in Thai children: Retrospective review of 30 cases from a tertiary care center.

BACKGROUND: Juvenile dermatomyositis is a rare condition, but it is the most common idiopathic inflammatory myopathy in pediatric patients. AIM: To study the clinical manifestations, investigations, treatment, clinical course, and outcomes of juvenile dermatomyositis in Thai children. METHOD: This retrospective study included juvenile dermatomyositis patients treated at Siriraj Hospital, a 2,300-bed national tertiary referral center in Bangkok, Thailand, from 1994 to 2019. RESULTS: Thirty patients (22 females and 8 males) were included with a female to male ratio of 2.7:1. Median age at diagnosis was 5.1 years (range, 2.6-14.8 years). Median duration of illness before diagnosis was 6.5 months (range, 0.3-84.0 months). Acute and subacute onset occurred in the majority of patients. Presenting symptoms included muscle weakness in 27/30 (90%), skin rash in 26/30 (86.7%), muscle pain in 17/26 (65.4%), and arthralgia in 4/18 (22.2%) of patients. Dermatologic examination revealed Gottron's rash, heliotrope rash, and periungual telangiectasia in 25/30 (83.3%), 21/30 (70.0%), and 15/24 (62.5%) of patients, respectively. Interestingly, scalp dermatitis was found in 8/21 (38.1%) of patients. The most commonly used treatment regimen in this series was a combination of prednisolone and methotrexate. During the median follow-up of 3.1 years (range, 0.0-18.5 years), only one-third of patients were seen to have monocyclic disease. Extraskeletal osteosarcoma at a previous lesion of calcinosis cutis was observed in one patient at 12 years after juvenile dermatomyositis onset. LIMITATIONS: This was a retrospective single-center study, and our results may not be generalizable to other healthcare settings. Prospective multicenter studies are needed to confirm the findings of this study. CONCLUSION: juvenile dermatomyositis usually poses a diagnostic and therapeutic challenge, which can be compounded by the ethnic variations in the clinical presentation, as observed in this study. Asian patients tend to present with acute or subacute onset of disease, and arthralgia and/or arthritis are less common than in Caucasian patients. Scalp dermatitis is not uncommon in pediatric juvenile dermatomyositis patients. An association between juvenile dermatomyositis and malignancy, though rare, can occur.

Optimal Use of Perampanel in Asian Patients with Epilepsy: Expert Opinion.

Perampanel is a once-daily, first-in-class AMPA receptor antagonist approved for the treatment of epilepsy and exhibits broad-spectrum efficacy in a range of seizure types when used as both monotherapy and adjunctive therapy. Clinical studies and real-world evidence have demonstrated the advantages of initiating perampanel at low doses and utilizing a slow titration strategy. Initiating perampanel at an early stage has also been shown to be associated with better patient outcomes. However, the optimal use and place of perampanel in clinical practice has not yet been clearly defined for the Asian patient population. Use of perampanel in clinical practice varies markedly across the Asia region because of variation in knowledge, attitudes, and practice. There is currently no specific guidance on best practices for prescribing perampanel in Asian patients or how to optimize treatment strategies to maximize adherence. A group of epilepsy experts attended a virtual meeting in September 2020 to discuss their experience with using perampanel in the Asian practice setting, including their views regarding appropriate patient populations, optimal starting and maintenance doses, optimal titration regimens, key barriers to adherence, and prevention and management of adverse events. This article summarizes key clinical and real-world evidence for perampanel and consolidates the experts' opinions on optimization of perampanel prescribing and adherence in real-world practice, providing practical strategies for clinicians to implement to improve outcomes for people with epilepsy in Asia.

Case series: Childhood Charcot-Marie-Tooth: Predominance of axonal subtype.

Case series reports on clinical features of pediatric hereditary neuropathy in Thailand is scarce. Subtype and clinical presentation in childhood-onset CMT differ from adult-onset. The aim of this study is to investigate the CMT phenotype in Thai children. We retrospectively reviewed children diagnosed with CMT who followed up with Pediatric Neurology, Siriraj Hospital from January 1999 to June 2016. CMT subtypes determined by clinical presentation and neurophysiologic studies. Mutation analysis of PMP22 genes was performed in all demyelinating cases. The disease burden was assessed by CMT Neuropathy Score version 2 (CMTNSv2), CMT Examination Score (CMTES) and CMT Pediatric Scale (CMTPedS). 30 patients from 29 families with Hereditary Neuropathies, 25 diagnosed with CMT and 5 with HSAN. 8-year-old was the average age at first medical visit with disease-related problems. Twenty (67%) were male. Twenty-three were sporadic (77%). 16.7% was autosomal dominant and 6.7% was autosomal recessive. Clinical presentations in CMT children were walking difficulty and foot deformities. Nine (36%) CMT patients had demyelinating and sixteen (64%) had axonal. Forty percent had a history of delayed walking after 15-month-old. Foot deformities presented in all CMT patients, and twelve had foot surgery. 2 axonal CMT patients were wheelchair-dependence. Mean (SD) CMTNSv2, CMTES and CMTPedS were 15.44(9), 11.05(7) and 34(4) respectively. Our findings suggest Thai CMT children are predominantly axonal type. Patients with low socioeconomic status and mild symptoms may not seek healthcare. International collaboration in genetic testing is crucial in diagnosis and initiation of clinical trials in future.

Reliability and validity of the Thai version of the Pediatric Quality of Life inventory™ 3.0 Duchenne Muscular Dystrophy module in Thai children with Duchenne Muscular Dystrophy.

BACKGROUND: Duchenne Muscular Dystrophy (DMD) is the most common genetic neuromuscular disorder in children. This chronic illness may impact the physical, family, social and school life of affected children and their families. These impacts can be assessed using a disease-specific measure of health-related quality of life (HRQOL). The Pediatric Quality of Life Inventory™ (PedsQL™) 3.0 DMD Module is designed to assess quality of life in children with DMD. This study aimed to evaluate the reliability and validity of the Thai version of the PedsQL™ 3.0 DMD Module in Thai children aged 5-18 years. METHOD AND MATERIALS: The Thai translation of the PedsQL™ 3.0 Duchenne Muscular Dystrophy Module was performed in accordance with established guidelines using forward-back translation and was approved by the creator of the instrument. The Thai version of the scale was administered to children with DMD and their parents at the neuromuscular clinic at Siriraj Hospital and during the annual DMD Day meeting. Psychometric properties were established, and a re-test was performed within 2-4 weeks. RESULTS: Fifty-six children were enrolled. An acceptable level of internal reliability was achieved, as measured by α > 0.7 (total score: child report α = 0.88, parent report α = 0.92). Test-retest reliability showed good agreement, with the following intraclass correlation coefficients (ICCs) for the total score (calculated using all subscales from the child reports and parent reports): child report ICCs = 0.74 and parent report ICCs = 0.88. The mean total scale score was 66.03 for ambulatory children and 55.87 (P = 0.08) for non-ambulatory children according to child self-reports and 70.01 (ambulatory) and 54.29 (non-ambulatory) (P ≤ 0.01) according to parent proxy reports. The child self-reports were in acceptable agreement with the parent proxy reports for most subscales (ICC range 0.49-0.81). CONCLUSIONS: The PedsQL™ 3.0 DMD Module Thai version is a reliable and valid measure of disease-specific health-related quality of life in Thai children with Duchenne muscular dystrophy.

Efficacy, safety, and tolerability of perampanel in Asian and non-Asian patients with epilepsy.

People of different ethnic or racial backgrounds may experience variations in pharmacokinetic and pharmacodynamic responses to drug therapies. Our post hoc analysis evaluated the efficacy, safety, and tolerability of perampanel in Asian and non-Asian populations with refractory focal seizures with or without focal to bilateral tonic-clonic (FBTC) seizures. This analysis pooled data from 4 randomized, placebo-controlled, phase-3 studies involving patients aged ≥12 years who have focal seizures with or without FBTC seizures. Patients were receiving 2, 4, 8, or 12 mg perampanel (or placebo) by the end of a 6-week titration period and for a further 13 weeks during the maintenance phase. Efficacy endpoints included median percent change in seizure frequency per 28 days, and 50% and seizure-freedom responder rates relative to baseline. The median percent change in seizure frequency per 28 days from baseline was significantly greater than placebo for perampanel 8 and 12 mg (-31.1% and -38.1% change, respectively; each P < 0.0001) in the Asian population, and for perampanel 4, 8, and 12 mg (-21.1% [P = 0.0001], -26.3% [P < 0.0001], and -27.7% [P = 0.0001] change, respectively) in the non-Asian population. The 50% responder rate relative to baseline was significantly greater than placebo for perampanel 8 and 12 mg (40.1% and 43.8%, respectively; each P < 0.0001) in the Asian population, and for perampanel 4, 8, and 12 mg (29.4% [P = 0.0002], 32.8% [P < 0.0001] and 34.5% [P = 0.0001]), respectively, in the non-Asian population. Seizure-freedom rate among all patients was 4.9%-11.7% for perampanel 2, 4, 8, and 12 mg. The most frequently reported treatment-emergent adverse events (TEAEs) across both populations were dizziness, somnolence, irritability, headache, and fatigue. The most common psychiatric TEAEs were aggression and irritability. Perampanel demonstrated a favorable and similar risk-benefit profile in both Asian and non-Asian populations with refractory focal seizures.

Impact of muscle biopsy on diagnosis and management of children with neuromuscular diseases: A 10-year retrospective critical review.

BACKGROUND: Muscle biopsy facilitates morphologic, biochemical, and ultrastructural analysis of muscle for the purpose of making definitive neuromuscular diagnosis. However, muscle biopsy is an expensive, invasive, time-consuming, and resource-dependent procedure. The need for general anesthesia in children also increases the risks associated with this procedure. The aim of this study was to investigate the benefits of muscle biopsies performed over a 10-year period, with a focus on indications, suspected and histopathologic diagnosis, and impact on diagnosis and management decisions. METHODS: We retrospectively reviewed results of muscle biopsies performed in children at our center during the 2004 to 2014 study period. Clinical presentations, biopsy complications, pathologic results, and changes in management decision were reviewed and analyzed. RESULTS: Biopsies from 92 patients were included. Mean age of patients was 7.1years, and 66.3% were male. There were no perioperative complications, and definitive diagnosis was made in 74 patients. Regardless of whether pathologic changes were found or not, information gained from muscle biopsy significantly impacted prognosis and subsequent genetic counseling. CONCLUSIONS: Muscle biopsy is a safe and useful diagnostic tool in children suspected of having neuromuscular diseases, especially in those with muscle diseases. Definitive pathologic diagnosis helps to optimize treatment, counseling, and surveillance. THE TYPE OF STUDY AND LEVEL OF EVIDENCE: Study of diagnostic test: level 1.

Review of clinical studies of perampanel in adolescent patients.

AIM: To assess the clinical trial and real-world data for adjunctive perampanel in adolescents and develop consensus recommendations to guide the use of perampanel in this population in clinical practice. METHODS: In May 2015, 15 epilepsy experts attended a Consensus Development Meeting to assess the clinical trial data for perampanel, specific to the adolescent age group (12-17 years) and develop consensus treatment recommendations. RESULTS AND DISCUSSION: Analysis of the adolescent subgroup data of three pivotal placebo-controlled, double-blind, phase 3 trials investigating perampanel in patients with ongoing focal epileptic seizures despite receiving one to three antiepileptic drugs found that perampanel 4-12 mg was superior to placebo. The tolerability profile of perampanel was generally acceptable. Adolescent patients receiving long-term treatment with perampanel in an open-label extension study maintained improvements in seizure control compared with baseline, with a favorable risk-benefit profile. A phase 2 study showed that perampanel had no clinically important effects on cognitive function, growth, and development. CONCLUSION: Perampanel is a welcome addition to the armamentarium of existing antiepileptic drugs as it represents a new approach in the management of epilepsy, with a novel mechanism of action, and the potential to have a considerable impact on the treatment of adolescents with epilepsy.

Predictors of Abnormal Neuroimaging of the Brain in Children With Epilepsy Aged 1 Month to 2 Years: Useful Clues in a Resource-Limited Setting.

Neuroimaging should be performed on infants with seizure. However, there are economic limitations in performing neuroimaging in a resource-limited setting. The younger the age, the higher the risk of having abnormal neuroimaging. The aim was to determine frequency and predictors of abnormal neuroimaging in children with epilepsy aged 1 month to 2 years. History, physical examination, electroencephalogram (EEG), and neuroimaging were reviewed. Thirty-seven of 49 (76%) had neuroimaging studies; 19 computed tomography (CT), 14 magnetic resonance imaging (MRI), and 4 had both. Abnormal neuroimaging was found in 19 (51%). Predictors of abnormal neuroimages are developmental delay, abnormal head circumference, and abnormal neurologic examination. Eight children (21%) had lesions on neuroimaging studies that altered or influenced management. Of 8 patients with normal examination and EEG, 1 had a brain tumor and another had arteriovenous malformation. Neuroimaging should be considered as an essential aid in the evaluation of infants with epilepsy, even in a resource-limited setting.

Ophthalmoplegia in congenital neuromuscular disease with uniform type 1 fiber.

Congenital neuromuscular disease with uniform type 1 fiber (CNMDU1) is a rare type of congenital myopathy. It is characterized by early onset of symptoms, mild proximal muscle weakness, hyporeflexia or areflexia, normal serum creatine kinase (CK) levels and myopathic electromyography finding, uniform type 1 fibers, and nonprogression. We report a 2-year-old boy who presented with congenital hypotonia, breathing and feeding difficulty, myopathic facies, proximal muscle weakness, ptosis, total external ophthalmoplegia and delayed motor developmental milestones. Normal serum muscle enzyme and short duration of motor unit potentials on electromyography were noted. Muscle biopsy showed uniformity of type 1 fibers (greater than 99%) and moderate variation in fiber size without specific structural abnormality. Total external ophthalmoplegia may be one of the important clinical manifestations of CNMDU1. It is important to recognize this disorder because it is nonprogressive in nature.

Acute disseminated encephalomyelitis in Siriraj Hospital: clinical manifestations and short-term outcome.

OBJECTIVE: To describe clinical manifestations, neuroimaging findings, and clinical outcomes in children with acute disseminated encephalomyelitis (ADEM). MATERIAL AND METHOD: Children with a diagnosis of ADEM who were less than 15 years of age at Siriraj Hospital between January 2002 and December 2008 were retrospectively reviewed. Clinical symptoms and signs as well as cerebrospinal fluid analysis, neuroimaging findings and clinical outcomes were extracted from medical records using a standard form. RESULTS: During the present study period, 14 children were diagnosed with ADEM. Median age was 7.2 years (range, 1.25-13 years). The most common presenting symptoms were decreased mental status (93%), weakness (71%), and fever (50%). Cranial MRI was abnormal in all patients. All but one patient received high dose intravenous methylprednisolone and a course of tapered oral prednisolone. After a mean follow-up period of 28.6 +/- 19.8 months, 13 patients were classified as monophasic ADEM and one progressed to have multiple sclerosis. Eleven patients recovered completely while one was left with mild hemiparesis and the other two (one with final diagnosis of MS) with severe psycho-neurological disturbances. CONCLUSION: There are no specific symptoms and signs in children with ADEM. Multifocal neurological deficits along with encephalopathy and abnormal MRI findings lead to correct diagnosis. Treatment with corticosteroid may improve clinical outcomes. Some children may progress to MS. Long-term clinical and neuroimaging studies in these children are needed.

A novel mutation of the CYBB gene resulting in severe form of X-linked chronic granulomatous disease.

We evaluated a boy who had multiple Salmonella septicemia, Aspergillus pneumonia and brain abscesses. His nitroblue tetrazolium (NBT) test was reportedly abnormal. The dihydrorhodamine (DHR) flow cytometry assay was compatible with typical X-linked chronic granulomatous disease (X-CGD). CYBB analysis revealed a novel complex mutation atggacg --> ttca in exon 12 (base pairs 1532-1538). As a result, 3 amino acids Tyr 511, Gly 512 and Arg 513 were deleted and replaced by 2 amino acids, Phe and Gln. The DHR and mutation analysis of his mother showed normal DHR pattern and no mutations in exon 12 of CYBB gene. In conclusion, any children with multiple Salmonella and Aspergillus infection should be suspected of CGD. NBT test, DHR assay and gene analysis are helpful toolsto confirm the diagnosis e v en i n the case of de novo mutation.

Serotonin syndrome: a case report.

Serotonin syndrome is a rare but potentially fatal complication of drugs that have effects on central nervous system serotonin. It is characterized by sudden onset of altered mental status, increased neuromuscular activity and autonomic instability. The author reports a child with suprasellar region tumor who presented with depression and obsessive-compulsive disorder and received a combination of sertaline (selective serotonin reuptake inhibitor) and clomipramine (tricyclic antidepressant). Symptoms of serotonin syndrome occurred within 24 hours after increasing the dose of sertaline. The patient's symptoms resolved rapidly with discontinuation of the offending drugs and supportive care.

Epilepsy with continuous spikes and wave during slow sleep: A case report.

This report presents a 5.5-year-old girl who presented with multiple types of seizure disorder along with behavioral change, cognitive deterioration, and language impairment. Electroencephalography showed nearly continuous spike-wave during slow wave sleep. Both clinical and electrographic findings were consistent with epilepsy with continuous spikes and wave during slow sleep (CSWS). Although the seizures were well controlled with conventional antiepileptic drugs, improvement of behavioral, cognitive, and language functions was observed only after adding corticosteroid as an adjunctive treatment. Corticosteriod may have a role in treatment in children with CSWS.

Cryptococcosis in HIV-infected children.

Between January 1994 and December 2001, 21 HIV-infected children were diagnosed as having cryptococcosis. The 8-year point prevalence of cryptococcosis among hospitalized HIV-infected patients was 2.97%. Medical records of 19 patients were available for review. Sixteen patients had cryptococcal meningitis. Of these patients, cryptococcal antigen in the cerebrospinal fluid and sera were positive in all tested samples. India ink preparations were positive in 94% of cases. However, the routine CSF examination was normal in 50% of cases. All patients but one received antifungal treatment. Six patients died during treatment, the others (13 patients) were successfully treated. Relapse occurred in 2 patients despite secondary prophylaxis. Two patients died later from other causes and nine were lost to follow-up. We conclude that cryptococcal meningitis was the most common clinical presentation of cryptococcosis among HIV-infected children. HIV-infected children who present with fever, with or without central nervous system signs, should have a lumbar puncture and CSF sent for cryptococcal antigen and culture.