NDUFV1-Related Mitochondrial Complex-1 Disorders: A Retrospective Case Series and Literature Review.

BACKGROUND: Pathogenic variants in the NDUFV1 gene disrupt mitochondrial complex I, leading to neuroregression with leukoencephalopathy and basal ganglia involvement on neuroimaging. This study aims to provide a concise review on NDUFV1-related disorders while adding the largest cohort from a single center to the existing literature. METHODS: We retrospectively collected genetically proven cases of NDUFV1 pathogenic variants from our center over the last decade and explored reported instances in existing literature. Magnetic resonance imaging (MRI) patterns observed in these patients were split into three types-Leigh (putamen, basal ganglia, thalamus, and brainstem involvement), mitochondrial leukodystrophy (ML) (cerebral white matter involvement with cystic cavitations), and mixed (both). RESULTS: Analysis included 44 children (seven from our center and 37 from literature). The most prevalent comorbidities were hypertonia, ocular abnormalities, feeding issues, and hypotonia at onset. Children with the Leigh-type MRI pattern exhibited significantly higher rates of breathing difficulties, whereas those with a mixed phenotype had a higher prevalence of dystonia. The c.1156C>T variant in exon 8 of the NDUFV1 gene was the most common variant among individuals of Asian ethnicity and is predominantly associated with irritability and dystonia. Seizures and Leigh pattern of MRI of the brain was found to be less commonly associated with this variant. Higher rate of mortality was observed in children with Leigh-type pattern on brain MRI and those who did not receive mitochondrial cocktail. CONCLUSIONS: MRI phenotyping might help predict outcome. Appropriate and timely treatment with mitochondrial cocktail may reduce the probability of death and may positively impact the long-term outcomes, regardless of the genetic variant or age of onset.

Disseminated phaeohyphomycosis due to Cladophialophora bantiana in an immunocompetent child.

A 3-year-old boy presented with acute headache, vomiting and right focal clonic seizures without history of fever, joint pain or altered sensorium. Neuroimaging showed multifocal contrast enhancing lesions with significant perilesional edema. CECT chest and abdomen showed multiple variable sized nodules in the lungs and hypodense lesion in liver with mesenteric lymphadenopathy. There was persistent eosinophilia with maximum upto 35 %. Liver biopsy and brain biopsy revealed Cladophialophora bantiana. He was treated with IV liposomal amphotericin and voriconazole for 6 weeks with repeat neuroimaging showing more than 50 % resolution of the intracranial lesions. He was transitioned to oral combination of flucytosine and voriconazole. At 14 months follow-up, he remained symptom free with complete radiological resolution of the lesions and no eosinophilia. High suspicion, an aggressive approach in obtaining microbiological diagnosis and timely combination antifungal therapy may give satisfactory outcome without surgery.

Efficacy of daily versus intermittent low glycemic index therapy diet in children with drug-resistant epilepsy: A randomized controlled trial.

INTRODUCTION: The predominant reason for the discontinuation of low glycemic index therapy (LGIT) in children with epilepsy is the dietary restrictions imposed therein. This trial intended to compare the efficacy of daily and intermittent LGIT in children with drug-resistant epilepsy (DRE). METHODS: This study was performed between February 2018 and January 2019 to compare the efficacy of daily and intermittent LGIT in children aged 1-15 years with DRE following 24 weeks of dietary therapy. Compliance, the difficulty faced by caregivers, adverse effects, impact on behaviour, and social quotient in both arms were compared. Children in the intermittent LGIT arm received a liberalized diet for two days every week (Saturday and Sunday), which also allowed medium glycemic index foods. Carbohydrate calories were allowed up to 20% of the total caloric requirement in the liberalized diet, as compared to only 10% in standard LGIT. RESULTS: Out of 132 children randomized (66 in each group), 122 completed 24 weeks follow up. Mean weekly seizure frequency reduction at 24 weeks in the intermittent LGIT group was comparable with that of the daily LGIT group in both intention-to-treat (ITT) and per-protocol analysis (-50.95%± 22.34% vs -47.16%± 23.41%, p=0.36 in ITT and -53.88%±20.54% vs -49.20%±21.87%, p=0.23) in per-protocol analysis for intermittent and daily LGIT group respectively). The proportion with ≥50% reduction in seizure frequency was also comparable between both groups (p=0.73 and 0.56 in ITT and per protocol analysis respectively). The proportion of patients with adverse events and satisfactory compliance rate also had a trend towards favoring intermittent LGIT (p=0.06 and 0.51, respectively), while caregiver difficulty was lower with intermittent LGIT (p=0.001). CONCLUSIONS: Intermittent LGIT is comparable to daily LGIT in terms of seizure frequency reduction after 24 weeks of dietary therapy. TRIAL REGISTRATION: ClinicalTrials.gov (Registration number- NCT03464487, https://clinicaltrials.gov/ct2/show/NCT03464487).

Child Neurology: Allgrove Syndrome: An Intriguing Etiology of Motor Neuron Disease in Children

Motor neuron diseases are a rare group of neurodegenerative disorders with considerable phenotypic heterogeneity and a multitude of etiologies in the pediatric population. In this study, we report 2 unrelated adolescents (a boy and a girl) who presented with 4-6 years of progressive difficulty in walking, thinning of limbs, and gradually progressive darkening of the skin. Examination revealed generalized hyperpigmentation of skin and features suggestive of motor neuron involvement such as tongue atrophy, wasting of distal extremities, and brisk deep tendon reflexes. On detailed exploration for systemic involvement, history of dysphagia, inability to produce tears, and Addisonian crises were evident. An etiologic diagnosis of Allgrove syndrome, which is characterized by a triad of achalasia, alacrimia, and adrenal insufficiency was considered. Next-generation sequencing revealed pathogenic variants in the AAAS gene, confirming the diagnosis. Steroid replacement therapy was initiated along with relevant multidisciplinary referrals. The disease stabilized in the boy and a significant improvement was noted in the girl. These cases highlight the value of non-neurologic cues in navigating the etiologic complexities of motor neuron diseases in children and adolescents. It is imperative for neurologists to develop awareness of the diverse neurologic manifestations associated with Allgrove syndrome because they are often the first to be approached. A multidisciplinary team of experts including neurologists, endocrinologists, gastroenterologists, ophthalmologists, and dermatologists is essential for planning comprehensive care for these patients.

Tolvaptan for Treatment of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) in a Child with Corpus Callosum Agenesis.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is one of the common causes of euvolemic hyponatremia (serum Na+ < 135 mEq/L) in hospitalized children. It is characterized by increased serum ADH, leading to water retention via its action on V2 receptors in the distal renal tubules. Various conditions such as pain, the postoperative state, drugs, central nervous system infections, tumors, malformations, and pneumonia can predispose a person to SIADH. The conventional treatment of SIADH includes fluid restriction and salt supplementation. Occasionally, this may fail to control hyponatremia, mandating pharmacological therapy. V2-receptor antagonists are an FDA-approved therapy for adults with euvolemic and hypervolemic hyponatremia. However, there is limited experience with their use in the pediatric population. Here, the authors present a girl with corpus callosum agenesis with severe symptomatic hyponatremia due to SIADH who was successfully managed with the V2-receptor antagonist tolvaptan.

Optimal duration for recording EEG in children and adolescents- a prospective interventional study.

PURPOSE: This study aimed to determine the proportion of EEG recordings yielding diagnostic findings leading to a change in diagnosis beyond a 20-minute recording window, striking a balance between diagnostic yield and clinical practicability. METHODS: At a tertiary care teaching hospital in North India, 225 subjects aged 1 month to 18 years undergoing outpatient EEG were enrolled. Patients with epileptic encephalopathies, nonepileptic phenomena, and breakthrough seizures in the last 24 hours were excluded. Two recording protocols were employed: Category A (n=163, awake recording with activation procedures for 15 minutes followed by an attempt at sleep for 60 minutes) and Category B (n=62, sleep recording for 55 minutes followed by 5 minutes of awake recording for younger children and those with impaired cognition). EEGs were prospectively reported at 20, 30, 40, 50, and 60-minute time points, with no retrospective changes allowed. RESULTS: Among abnormal EEGs, the final diagnosis was changed beyond 20 minutes in 38.9% and 20.4% in categories A and B, respectively. A significant change in the final diagnosis among abnormal EEGs beyond 20 minutes was seen in - those who achieved sleep compared to those who didn't (45% versus 19%, p=0.03) in category A, and - focal compared to generalised seizures (Category A: 26.1% versus 8.3%, p=0.01; Category B: 23.8% versus 0%, p=0.02). CONCLUSION: Forty minutes of awake EEGs with/without sleep and 30 minutes of sleep EEGs achieve a final diagnosis in nearly 90%. Prolonging awake records beyond 20 minutes, incorporating sleep, is particularly beneficial in focal epilepsies.

Incident Breakthrough Seizures, Serum Matrix Metalloproteinase-9 and Perfusion Magnetic Resonance Imaging Parameters in a Cohort of Children and Adolescents With Neurocysticercosis: A Longitudinal Observational Study.

BACKGROUND: The current study estimated incident breakthrough seizures, serum matrix metalloproteinase-9 (MMP-9), and perfusion magnetic resonance imaging (MRI) parameters in five- to 18-year-olds with neurocysticercosis (NCC) from colloidal or vesicular through calcified stages over at least 24 months' follow-up. METHODS: Single, colloidal, or vesicular parenchymal NCC cases were treated with albendazole and steroids and followed at a tertiary care north Indian hospital. Serum MMP-9 was estimated in colloidal or vesicular treatment-naive state and in a subset of calcified cases at six-month follow-up. The same subset of calcified cases also underwent perfusion MRI of the brain at six-month follow-up. RESULTS: Among 70 cases, 70% calcified at six-month follow-up. Over a median follow-up of 30 months, the incidence of breakthrough seizures was 48.6% (61.2% in calcified and 19.2% in resolved, P = 0.001; 32.9% early [within six months] and 15.7% late [beyond six months], P = 0.02). Serum MMP-9 levels were higher in colloidal and vesicular compared with calcified stage (242.5 vs 159.8 ng/mL, P = 0.007); however, there was no significant association with breakthrough seizures and/or calcification in follow-up. In a subgroup of calcified cases (n = 31), the median relative cerebral blood volume on perfusion MRI in and around the lesion was lower in those with seizures (n = 12) than in those without (n = 19) (10.7 vs 25.2 mL/100 g, P = 0.05). CONCLUSIONS: In post-treatment colloidal or vesicular NCC, incident breakthrough seizures decrease beyond six months. In calcified NCC with remote breakthrough seizures, significant perilesional hypoperfusion is seen compared with those without seizures.

ASAH1 Variants Causing Spinal Muscular Atrophy Phenotype.

Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a rare autosomal recessive disorder due to mutations in the ASAH1 gene. SMA-PME is characterized by progressive muscle weakness from three to seven years of age, drug refractory epilepsy, and variable degree of cognitive decline. Nearly 50 cases have been reported worldwide so far. Here the authors present a case of 9-y-old boy affected by SMA-PME characterized by progressive proximal weakness, and lower motor neuron disease, as proven by muscle biopsy, electro diagnostic studies and whole exome sequencing (WES). WES revealed compound heterozygous missense variant in exon 12 of ASAH1 gene (chr8: g.18059385G>C) and exon 2 of ASAH1 gene (chr8: g.18075542T>C). Patient did not have cognitive decline and epilepsy and EEG record obtained was normal. In addition to reporting a novel variant in the ASAH1 gene causing SMA-PME disease, this paper discusses previous reports and literature of the disease.

Childhood and Adolescent Sleep Awareness in Caregivers and Health Care Providers: A Community- and Hospital-Based Survey.

BACKGROUND: Sleep disorders are common in childhood and adolescence with mental and physical consequences needing appropriate intervention by caregivers and health care providers (HCPs). The objective of the study, conducted at a tertiary teaching hospital and public school in north India, was to develop validated questionnaires to evaluate childhood and adolescent sleep awareness in caregivers and HCPs. METHODS: The study participants (caregivers represented by parents of 2-18 year olds attending a public school and of those attending outpatient services at the study hospital and HCPs represented by medical interns and nursing graduates within 1 year of graduation) were enrolled after appropriate screening. RESULTS: Two separate questionnaires in English for caregivers (also translated in Hindi) and HCPs were applied on 313 caregivers and 175 HCPs (110 medical interns and 65 nursing graduates) and developed and validated with a Cronbach α of 0.73 and 0.74, respectively. The questionnaires covered three domains: sleep hygiene, sleep related health problems, and miscellaneous. Both group of respondents had >50% correct responses in sleep hygiene. The ĸ agreement between knowledge and practice of sleep hygiene in caregivers was 0.2. Poor response (<50% correct responses) was seen in sleep-related health problems in both groups of respondents implying knowledge deficit in various sleep disorders. The HCPs performed poorly on basic theoretical questions in miscellaneous domain. For consultation of sleep problems, most caregivers (48%) chose pediatricians. CONCLUSION: There is a need to strengthen undergraduate medical and nursing curriculum in sleep. Caregivers should be made aware of implications of unhealthy sleep.