KCTD7-related progressive myoclonic epilepsy: Report of 42 cases and review of literature.

OBJECTIVE: KCTD7-related progressive myoclonic epilepsy (PME) is a rare autosomal-recessive disorder. This study aimed to describe the clinical details and genetic variants in a large international cohort. METHODS: Families with molecularly confirmed diagnoses of KCTD7-related PME were identified through international collaboration. Furthermore, a systematic review was done to identify previously reported cases. Salient demographic, epilepsy, treatment, genetic testing, electroencephalographic (EEG), and imaging-related variables were collected and summarized. RESULTS: Forty-two patients (36 families) were included. The median age at first seizure was 14 months (interquartile range = 11.75-22.5). Myoclonic seizures were frequently the first seizure type noted (n = 18, 43.9%). EEG and brain magnetic resonance imaging findings were variable. Many patients exhibited delayed development with subsequent progressive regression (n = 16, 38.1%). Twenty-one cases with genetic testing available (55%) had previously reported variants in KCTD7, and 17 cases (45%) had novel variants in KCTD7 gene. Six patients died in the cohort (age range = 1.5-21 years). The systematic review identified 23 eligible studies and further identified 59 previously reported cases of KCTD7-related disorders from the literature. The phenotype for the majority of the reported cases was consistent with a PME (n = 52, 88%). Other reported phenotypes in the literature included opsoclonus myoclonus ataxia syndrome (n = 2), myoclonus dystonia (n = 2), and neuronal ceroid lipofuscinosis (n = 3). Eight published cases died over time (14%, age range = 3-18 years). SIGNIFICANCE: This study cohort and systematic review consolidated the phenotypic spectrum and natural history of KCTD7-related disorders. Early onset drug-resistant epilepsy, relentless neuroregression, and severe neurological sequalae were common. Better understanding of the natural history may help future clinical trials.

Cryptogenic posterior circulation stroke in children.

We aimed to evaluate the percentage of posterior circulation arterial ischaemic stroke (PCAIS) caused by craniovertebral junction (CVJ) anomalies and describe their clinical course. Children admitted to a tertiary care paediatric hospital with PCAIS between July 2017 and December 2020 were assessed retrospectively for disease aetiology. We reviewed the clinical, radiological, and surgical details of children with evidence of CVJ anomalies. Fourteen (24.1%) of 58 children admitted with arterial ischaemic stroke had posterior circulation involvement. The mean age of patients presenting with posterior circulation stroke was 6 years 6 months (range 3 months-15 years), 11 were male. Six of 14 cases with PCAIS were due to CVJ anomaly, their ages ranged from 4 months to 15 years (two age ranges were noted, 4 months-4 years and 11-15 years), four were male. Two children had atlantoaxial dislocation with basilar invagination, two had Bow Hunter syndrome with Chiari malformation type 1 (one with completed stroke), one had Chiari malformation type 1 alone, and one presented with Farber disease with proatlas segmentation anomaly in CVJ. The time lag to stroke and CVJ diagnosis ranged from 2 weeks to 24 months. A dynamic angiogram was required to evaluate biomechanical changes on scans with inconclusive findings on standard stroke imaging. CVJ anomalies are an important treatable cause of paediatric posterior circulation stroke. Cervical spine x-ray in flexion and extension should be done in all patients with posterior circulation stroke beyond the acute period. In cryptogenic aetiology, provocative angiography with guarded neck rotation should be considered to evaluate possible dynamic vertebral artery compression. WHAT THIS PAPER ADDS: Craniovertebral junction anomalies are an important cause of posterior circulation stroke in children. Evidence of flat occiput, short neck, and short stature in children with posterior circulation stroke should be assessed. Dynamic imaging helps identify dynamic vertebral artery compression.

Impact of COVID lockdown: Increased prevalence of symptomatic Vitamin D deficiency in adolescents.

Background: During the COVID lockdown in India, which lasted for more than a year, all schools were closed and children were homebound. When the lockdown was lifted, we observed an increased prevalence of Vitamin D deficiency(VDD) in adolescents. We want to highlight the effect of home lockdown on adolescents, which can predispose such children to VDD. Aim: To document the increased prevalence of symptomatic VDD in adolescents after COVID lockdown and to study the symptoms, biochemical abnormalities, and response to therapy in this subset. Methods: This prospective observational study was done from November 2021 to May 2022 with a minimum follow-up of six months. Inclusions: Consecutive children presenting with gait abnormalities, proximal myopathy, and pains, with documented VDD. Exclusion: Genetic, neuromuscular disorders, juvenile rheumatoid arthritis, chronic renal failure, thyroid disorders and those on anti-epileptic medications and vitamin D supplementation in the past 6 months were excluded from the study. We recorded the symptomatology, biochemical abnormalities, and muscle weakness and followed their improvement after Vitamin D and Calcium supplementation. Results: A statistically significant increase in symptomatic VDD in adolescents, in six months post-lockdown was noted. Thirty-one adolescents between 9 to 14 years were studied. All cases were relieved of pain and muscle power normalized in 12 weeks. Conclusion: Prolonged house arrest may cause VDD in adolescents. Physicians should consider VDD in adolescents with myopathy and pain after pandemic lockdowns. Supplementation of Vitamin D and calcium resolves most symptoms except deformities. Follow-up is needed until growth spurt completion for recurrence of symptoms.

Diagnostic and Therapeutic Roles of the "Omics" in Hypoxic-Ischemic Encephalopathy in Neonates.

Perinatal asphyxia and neonatal encephalopathy remain major causes of neonatal mortality, despite the improved availability of diagnostic and therapeutic tools, contributing to neurological and intellectual disabilities worldwide. An approach using a combination of clinical data, neuroimaging, and biochemical parameters is the current strategy towards the improved diagnosis and prognosis of the outcome in neonatal hypoxic-ischemic encephalopathy (HIE) using bioengineering methods. Traditional biomarkers are of little use in this multifactorial and variable phenotype-presenting clinical condition. Novel systems of biology-based "omics" approaches (genomics, transcriptome proteomics, and metabolomics) may help to identify biomarkers associated with brain and other tissue injuries, predicting the disease severity in HIE. Biomarker studies using omics technologies will likely be a key feature of future neuroprotective treatment methods and will help to assess the successful treatment and long-term efficacy of the intervention. This article reviews the roles of different omics as biomarkers of HIE and outlines the existing knowledge of our current understanding of the clinical use of different omics molecules as novel neonatal brain injury biomarkers, which may lead to improved interventions related to the diagnostic and therapeutic aspects of HIE.

Fever, Seizures and Encephalopathy: From Bush Fires to Firestorms.

Fever-associated seizures and febrile encephalopathy are common neurological problems in children. Infections of the nervous system are responsible for the majority of cases. However, there is a spectrum of infection-associated and inflammatory conditions associated with the triad of fever, seizures, and encephalopathy. Apart from complex febrile seizures and febrile status epilepticus, fever infection-related epilepsy syndrome of childhood (FIRES), infantile hemiconvulsion hemiplegia epilepsy syndrome (IHHE), acute encephalopathy with delayed diffusion restriction (AESD), acute necrotizing encephalopathy of childhood (ANE), and reversible splenial lesion syndrome (RESLES) are age-related clinical phenotypes of fever-related epilepsy and encephalopathy. Awareness of these entities is important for appropriate diagnosis and the prompt use of immunomodulatory/immunosuppressive therapies. In this review, we discuss the pathophysiology, clinical phenotypes, and management approaches of these fever-related seizure and encephalopathy states.

Enteral lorazepam is a promising weaning strategy for midazolam-responsive febrile infection-related epilepsy syndrome (FIRES): a case series

OBJECTIVE: Prolonged and repetitive cycles of pharmacological coma, with midazolam or other general anaesthetics, is often the mainstay for seizure control in febrile infection-related epilepsy syndrome (FIRES). Here we present our experience of enteral lorazepam as an effective weaning substitute in midazolam-dependent patients. METHODS: This was a retrospective study based on a review of medical records of all FIRES patients who had received enteral lorazepam as a weaning substitute for midazolam, between January 2020 and July 2021. The patients were divided into an early group (lorazepam initiated after one failed attempt to wean off midazolam) and late group (lorazepam initiated after two or more failed attempts). The conversion from intravenous midazolam to enteral lorazepam was also calculated, and epilepsy outcome at follow-up was also assessed. RESULTS: Seven patients (five males) were eligible. The median age at onset of FIRES was seven years (range: 4-14). A median of six (range: 6-8) anti-seizure medications (ASMs) had failed (including clobazam in two and clonazepam in one) to control seizures. The early and late lorazepam groups were comparable regarding the maximum midazolam dose for seizure control, total ASMs tried and days to wean off midazolam. The median (range) duration of hospital stay was 27 days (22-46) in the early group, compared to 51 days (40-78) in the late group. The early group patients were also on fewer ASMs (median: 3;range: 3-5) compared to the late group (median: 5; range: 4-6) at discharge. Five patients were sedated with initial lorazepam dose, but this side effect resolved on dosage reduction. On follow-up, all seven patients had seizure recurrence. In four, seizures recurred on reducing lorazepam, however, in three of these patients, this was resolved by escalating the dose. SIGNIFICANCE: Enteral lorazepam can be an effective weaning substitute for midazolam-dependent children with FIRES. Early introduction of enteral lorazepam was associated with reduced duration of hospital stay.

Cerebral creatine deficiency disorders - A clinical, genetic and follow up study from India.

INTRODUCTION: Cerebral creatine deficiency syndromes (CCDS) are a group of potentially treatable neurometabolic disorders. The clinical, genetic profile and follow up outcome of Indian CCDS patients is presented. MATERIALS AND METHODS: This was a retrospective cohort of CCDS patients seen over six-years. Diagnosis was based either on low creatine peak on proton magnetic resonance spectroscopy (MRS) and/or genetic evaluation. RESULTS: Thirteen patients were eligible [8 creatine transporter deficiency (CTD), 4 guanidinoacetate methyltransferase (GAMT) deficiency and 1 could not be classified]. The mean (±SD) age at diagnosis was 7.2(±5.0) years. Clinical manifestations included intellectual disability (ID) with significant expressive speech delay in all. Most had significant behavior issues (8/13) and/or autism (8/13). All had history of convulsive seizures (11/13 had epilepsy; 2 patients only had febrile seizures) and 2/13 had movement disorder. Constipation was the commonest non-neurological manifestation (5/13 patients). Cranial MRI was normal in all CTD patients but showed globus pallidus hyperintensity in all four with GAMT deficiency. MRS performed in 11/13 patients, revealed abnormally low creatine peak. A causative genetic variant (novel mutation in nine) was identified in 12 patients. Three GAMT deficiency and one CTD patient reported neurodevelopmental improvement and good seizure control after creatine supplementation. CONCLUSION: Intellectual disability, disproportionate speech delay, autism, and epilepsy, were common in our CCDS patients. A normal structural neuroimaging with easily controlled febrile and/or afebrile seizures differentiated CTD from GAMT deficiency patients who had abnormal neuroimaging and often difficult to control epilepsy and movement disorder.

Thiamine-responsive, life-threatening, pulmonary hypertensive crisis with encephalopathy in young infants: A case series.

OBJECTIVE: Thiamine (Vitamin B1) deficiency (TD), although reduced in incidence, is still seen in infants. We describe a rarely reported form of infantile TD with life-threatening pulmonary hypertensive crisis and severe encephalopathy, with dramatic response to thiamine supplementation. METHODS: Study design: Descriptive case series. Six young infants with mean age 76 days (range 1-3 months), manifesting rapidly progressive encephalopathy and cardio-pulmonary arrest were included. All infants underwent cardiac, neuroimaging and metabolic evaluations. RESULTS: All six infants had similar presentation with severe pulmonary arterial hypertension (PAH), hypotensive shock, metabolic acidosis and severe encephalopathy. All infants were exclusively breast-fed. Thiamine treatmwnt resulted in dramatic improvement in haemodynamic and neurological function in all the infants. There were no major neurological deficits on follow up. CONCLUSION: A high index of suspicion is warranted for this rarely described form of TD, as early identification helps in preventing mortality and morbidity.

The spectrum of acute leukoencephalopathy with restricted diffusion (ALERD): A case series and review of literature.

INTRODUCTION: The clinico-etiological spectrum of Acute leukoencephalopathy with restricted diffusion (ALERD) is not well known in Indian population. This is likely to vary between populations and ethnicities. METHODS: We retrospectively reviewed the clinicoetiological spectrum of ALERD at a tertiary care pediatric center, and described the clinical, imaging, etiological spectrum and short-term outcomes. RESULTS: Eleven out of 78 children with non-traumatic encephalopathy presenting to our center had a final diagnosis of ALERD. The mean age at presentation was 34.9 months (6-80 months) and 63.6% were males. The monophasic course (72.7%) and the diffuse pattern (63.6%) on neuroimaging were predominant in these children. Dengue haemorrhagic fever was the commonest underlying/triggering infection (5 of 11 children). Ten children required mechanical ventilation in view of neurogenic respiratory failure, with mean duration of ventilation of 6.4 days (Range 2-10 days). The duration of hospital stay varied from 11 to 25 days (Mean - 15.3 days). One child (9 %) died, 6 children (54.5 %) had varying degrees of cognitive impairment and 4 (36.3 %) children had a normal outcome. Children with a shorter duration of ventilation seemed to have a better outcome. CONCLUSION: Dengue haemorrhagic fever was the commonest cause, and diffuse imaging pattern with monophasic course was the commonest presentation in Indian children with ALERD. The clinical presentation and factors influencing outcome are possibly different from previously described literature.

Herbal Medicine-Induced Seizures in Children: Single-Center Experience Over 18 Months.

Many common household herbal preparations may have seizurogenic ingredients. We report 15 children with seizures following exposure to such compounds: oral ingestion of liquid preparation in 13, and local application of balm and Eucalyptus oil ingestion in one each. All children, except one, had generalized seizures. This study highlights the need to address this history during evaluation of first seizure, and increase awareness of seizurogenic potential of such preparations.

Persistent Craniopharyngeal Canal: A Rare Cause for Recurrent Meningitis in Pediatric Population.

We present the case of a 5-year-old girl who had six episodes of meningitis. She also had panhypopituitarism and was found to have a persistent craniopharyngeal canal (CPC) as the cause of her recurrent meningitis. Role of neuroradiology and a high index of suspicion by the clinical team are highlighted here. Persistent CPC is a rare cause of recurrent meningitis. We discuss the approach to the child with recurrent meningitis.

Mitochondrial carbonic anhydrase VA deficiency in three Indian infants manifesting early metabolic crisis.

BACKGROUND: Hyperammonemia and hyperlactatemia in neonates and young children with non-specific biochemical markers poses a diagnostic challenge. An accurate diagnosis is essential for effective management. CASE REPORTS: We present three infants from unrelated families, one with infantile and two with neonatal hyperammonemic encephalopathy, hypoglycaemia, and hyperlactatemia. The underlying cause was confirmed following whole exome sequencing as biochemical markers were not conclusive of a definite diagnosis. CONCLUSION: The combination of hyperammonemic encephalopathy, hyperlactatemia and hypoglycemia in neonates and infants should prompt physicians to suspect Carbonic anhydrase VA deficiency. Majority of these children can have a favourable long-term outcome with symptomatic treatment.

KCNT1-related epilepsy: An international multicenter cohort of 27 pediatric cases.

OBJECTIVE: Through international collaboration, we evaluated the phenotypic aspects of a multiethnic cohort of KCNT1-related epilepsy and explored genotype-phenotype correlations associated with frequently encountered variants. METHODS: A cross-sectional analysis of children harboring pathogenic or likely pathogenic KCNT1 variants was completed. Children with one of the two more common recurrent KCNT1 variants were compared with the rest of the cohort for the presence of particular characteristics. RESULTS: Twenty-seven children (15 males, mean age = 40.8 months) were included. Seizure onset ranged from 1 day to 6 months, and half (48.1%) exhibited developmental plateauing upon onset. Two-thirds had epilepsy of infancy with migrating focal seizures (EIMFS), and focal tonic seizures were common (48.1%). The most frequent recurrent KCNT1 variants were c.2800G>A; p.Ala934Thr (n = 5) and c.862G>A; p.Gly288Ser (n = 4). De novo variants were found in 96% of tested parents (23/24). Sixty percent had abnormal magnetic resonance imaging (MRI) findings. Delayed myelination, thin corpus callosum, and brain atrophy were the most common. One child had gray-white matter interface indistinctness, suggesting a malformation of cortical development. Several antiepileptic drugs (mean = 7.4/patient) were tried, with no consistent response to any one agent. Eleven tried quinidine; 45% had marked (>50% seizure reduction) or some improvement (25%-50% seizure reduction). Seven used cannabidiol; 71% experienced marked or some improvement. Fourteen tried diet therapies; 57% had marked or some improvement. When comparing the recurrent variants to the rest of the cohort with respect to developmental trajectory, presence of EIMFS, >500 seizures/mo, abnormal MRI, and treatment response, there were no statistically significant differences. Four patients died (15%), none of sudden unexpected death in epilepsy. SIGNIFICANCE: Our cohort reinforces common aspects of this highly pleiotropic entity. EIMFS manifesting with refractory tonic seizures was the most common. Cannabidiol, diet therapy, and quinidine seem to offer the best chances of seizure reduction, although evidence-based practice is still unavailable.

Clinical Profile, Yield of Cartridge-based Nucleic Acid Amplification Test (GeneXpert), and Outcome in Children with Tubercular Meningitis.

BACKGROUND: GeneXpert MTB/RIF is a test for early, rapid diagnosis of tubercular meningitis (TBM). AIM: The aim of this article was to study the clinical profile, radiological features, yield of GeneXpert, neurosurgical interventions, and outcome of TBM in children. SETTINGS AND DESIGN: This was a retrospective and prospective observational study. MATERIALS AND METHODS: Diagnosis was based on the uniform research definition criteria and was staged according to the British Medical Research Council. Mantoux test, analysis of cerebrospinal fluid (CSF), CSF GeneXpert, and radiological investigations were performed. RESULTS: Of 36 patients, 50% were aged 1-5 years. Fever (100%), headache (82%), altered sensorium (80%), and vomiting (66%) were common features. Twelve (33%) had contact with active case of tuberculosis; 32 received Bacille Calmette Guarin vaccination. Neurological features included severe deterioration in sensorium (Glasgow Coma Scale < 8) (38%), mild and moderate deficit in sensorium (31%), hemiparesis (41%), and involvement of sixth (25%) and seventh (22%) cranial nerves. Cerebral vision impairment (25%), papilledema (25%), and dystonia (22%) were other findings. CSF GeneXpert was positive in 37% (12/33) patients. Hydrocephalus and basal exudates (75%) were noted on neuro-imaging. Surgical intervention was performed in children with hydrocephalus (13/27). Omayya reservoir was placed in seven children, of which five needed conversion to ventriculoperitoneal (VP) shunt; direct VP shunt was carried out in six (6/13). Good outcome was noted in 78% at discharge. Stage III TBM (P = 0.0001), cerebral infarcts (P = 0.0006), and motor deficits (P = 0.03) were associated with poor outcome. Sequelae included learning difficulties with poor scholastic performance (31.5%). CONCLUSION: GeneXpert has high diagnostic specificity, but negative results do not rule out TBM. CSF GeneXpert provided quick results. Placement of Ommaya reservoir in TBM stage II and III with hydrocephalus was not successful. Hydrocephalus was managed conservatively with success (53%).

Association of Child Neurology-Indian Epilepsy Society Consensus Document on Parental Counseling of Children with Epilepsy.

When a child is diagnosed with epilepsy, counseling regarding the same is done by the treating doctor. Most parents are frightened and have poor knowledge about epilepsy. Therapeutic advice including drug dosage, administration and side effects takes up the major part of physician's time, thereby neglecting important issues like home seizure management, follow up and others. These lacunae in knowledge require systematic patient and family education. To address these issues, an expert group meeting of pediatric neurologists and epileptologists in India along with social workers/epilepsy educators, legal experts, parents, and teachers was held. The various aspects regarding parental counseling in children with epilepsy were discussed and a consensus document was formulated. Here authors present the group consensus statement on counseling parents and caregivers of children with epilepsy. This document is intended to help physicians and pediatricians counsel the families when a child is diagnosed with epilepsy.

Immunodeficiency, Motor Delay, and Hypouricemia Caused by a Novel Mutation of Purine Nucleoside Phosphorylase Gene in an Indian Infant.

We describe an 11-month-old boy who presented with recurrent respiratory infections from 6 months of age. His elder sister died at 10 months with severe septicemia and meningitis. The boy had a mild motor delay. Investigations revealed T cell deficiency and very low serum uric acid suggestive of purine nucleoside phosphorylase (PNP) deficiency - a rare variant of severe combined immunodeficiency disease. A novel homozygous missense mutation of c.597C>G(p. S199R) of exon 5 on PNP gene confirmed the diagnosis. We suggest that uric acid should be a part of investigation profile for unidentified motor delay, as recurrent infections can be late presentation.

Ictal FDGPET and SPECT in hemifacial seizures due to cerebellar epilepsy-Case report.

The role of cerebellum in seizure generation is debatable. Semiology and electroencephalography (EEG) findings are non-specific and sometimes misleading, posing further difficulty in proving the epileptogenicity in pre-surgical workup. We report two cases of cerebellar lesions who presented with hemifacial seizures since the neonatal period and were refractory to antiepileptic drugs (AEDs). Both inter-ictal and ictal EEGs were non-contributory. Magnetic resonance imaging (MRI) showed a lesion in the cerebellum, in proximity to cerebellar peduncle in both the patients. (18) F-fluorodeoxyglucose-positron emission tomography (FDG-PET) and ictal single photon emission computed tomography (SPECT) showed focal hypermetabolism and hyperperfusion respectively, corresponding to the lesion on MRI in both the cases. Intraoperative electrocorticography showed rhythmic spikes confirming the epileptogenic nature of the lesion. Both patients were operated with a favorable surgical outcome. Histopathology was suggestive of a ganglioglioma in one child and a low-grade glioma in the other. Both cases illustrate that FDG-PET and SPECT can act as surrogate markers for invasive recordings to prove the epileptogenicity of cerebellar lesions, especially in resource limited settings.

Case Reports: Survival from Rabies: Case Series from India.

Rabies, a zoonotic viral encephalitis, continues to be a serious public health problem in India and several other countries in Asia and Africa. Survival is rarely reported in rabies, which is considered to be almost universally fatal. We report the clinical and radiological findings of eight patients with laboratory-confirmed rabies who survived the illness. With the exception of one patient who recovered with mild sequelae, all survivors had poor functional outcomes. The reported survival from rabies in recent years may reflect an increased awareness of the disease and greater access to better critical care facilities in rabies-endemic countries. Nonetheless, there is an urgent need to focus on preventive strategies to reduce the burden of this dreadful disease in rabies-endemic countries.