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Peripheral demyelinating polyneuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung’s disease is a rare genetic disorder caused by de novo variants in the SOX10 gene. The SOX10 gene is expressed in the neural crest cells during early embryonic development and in the glial cells of the peripheral and central nervous systems during late embryonic development, as well as in adults. Here, we describe our findings in a 9-month-old male infant presenting with failure to thrive, global developmental delay, seizures, hypotonia, heterochromia iridis, hypopigmented skin macules, pendular nystagmus, Hirschsprung’s disease, and hearing impairment. Nerve conduction studies were suggestive of sensorimotor demyelinating polyneuropathy. Brain magnetic resonance imaging showed diffuse hypomyelination. Targeted genetic testing revealed a novel stop-loss variant in the SOX10 gene (NM_006941.4). This case highlights the importance of clinical phenotyping that can aid in targeted genetic testing.

Subacute sclerosing panencephalitis (SSPE) is a neurodegenerative disorder because of the persistence of mutated measles virus in the central nervous system. Till date, no curative therapy has been established for SSPE. Multiple drugs have been tried to modify the disease process but have shown mild to moderate benefit at best. It is also challenging to attribute the relative success of some strategies described in single case reports because of the known phenomenon of spontaneous improvement in 5% of patients with SSPE. Critical gaps in understanding the pathophysiological processes involved exist. Current therapies such as interferon alfa require invasive strategies for administration by the intraventricular or intrathecal route, with varying dosage regimens. Oral therapies such as isoprinosine and ribavirin are expensive and not readily available in resource-constrained settings. Most of the evidence so far favors the use of combinational regimens. In this viewpoint, we critically summarize the current evidence on disease-modifying strategies in the context of our region.

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.

Background: Syndromes in which some manifestations occur later in life are difficult to diagnose in childhood. A systematic clinical approach may prove to be extremely useful. Gorlin syndrome (GS) is characterized by jaw keratocysts and/or basal cell carcinomas usually appearing in the second decade of life. Clinical Description: A 9-month-old girl, second born to a nonconsanguineous couple, presented with delay in attaining milestones and spinal deformities. There was no significant antenatal, perinatal, neonatal, or family history. She had no neck control, vocalization, or social smile. Fixation and tracking of objects and startle response to sound was present. Salient examination findings were macrocephaly, frontoparietal bossing, flat occiput, hypertelorism, broad nasal bridge, right preauricular pit, palmar pitting, and kyphoscoliosis. X-ray chest revealed bifid vertebra, hemivertebrae, and bifid ribs. Echocardiogram, ultrasound abdomen, magnetic resonance imaging brain, and brainstem-evoked response audiometry were normal. Management: A systematic clinical approach was used that included the following steps: (1) history, examination, and identification of overt anomalies; (2) searching for concealed anomalies; (3) synthesizing information; (4) literature/database search using good search handles; (5) critically analyzing the differential diagnoses; and (6) surveillance for associated morbidities of established diagnosis. We arrived at a clinical diagnosis of GS after applying diagnostic criteria and excluding differential diagnoses. Appropriate intervention was started. The child is under annual follow-up. Conclusion: A systematic clinical approach including an effective search strategy with good handles helps in arriving at a clinical diagnosis in children with dysmorphism.

Although acquired manganese neurotoxicity has been widely reported since its first description in 1837 and is popularly referred to as “manganism,” inherited disorders of manganese homeostasis have received the first genetic signature as recently as 2012. These disorders, predominantly described in children and adolescents, involve mutations in three manganese transporter genes, i.e., SLC30A10 and SLC39A14 which lead to manganese overload, and SLC39A8, which leads to manganese deficiency. Both disorders of inherited hypermanganesemia typically exhibit dystonia and parkinsonism with relatively preserved cognition and are differentiated by the occurrence of polycythemia and liver involvement in the SLC30A10-associated condition. Mutations in SLC39A8 lead to a congenital disorder of glycosylation which presents with developmental delay, failure to thrive, intellectual impairment, and seizures due to manganese deficiency. Chelation with iron supplementation is the treatment of choice in inherited hypermanganesemia. In this review, we highlight the pathognomonic clinical, laboratory, imaging features and treatment modalities for these rare disorders.

Biotin-thiamine-responsive basal ganglia disease is a rare, autosomal recessive, treatable, neurometabolic disorder associated with biallelic pathogenic variations in the SLC19A3 gene. The condition may present as an early-childhood encephalopathy, an early-infantile lethal encephalopathy with lactic acidosis, with or without infantile spasms, or a late-onset Wernicke-like encephalopathy. The key radiological features are bilateral, symmetrical lesions in the caudate, putamen, and medial thalamus, with variable extension into the brain stem, cerebral cortex, and cerebellum. Treatment is life long and includes initiation of high dose biotin and thiamine. Genetic testing confirms the diagnosis. The prognosis depends on the time from diagnosis to the time of vitamin supplementation. The genotype-phenotype correlations are not clear yet, but the early infantile phenotype portends a poorer prognosis. We provide a brief overview of the disorder and emphasize the initiation of high-dose biotin and thiamine in infants and children with unexplained encephalopathy and basal ganglia involvement.

Psychogenic non-epileptic seizure (PNES) is a common disorder that imitates epileptic seizures and has its etiological roots in psychological distress. Due to its “epileptic” similarity, it is often dealt with not only by mental health professionals but also by physicians, pediatricians and neurologists. There is a growing consensus towards the psychotherapeutic treatment of the disorder, albeit a lack of clarity in choosing a gold-standard approach. This paper seeks to serve as a compendium of different psychotherapeutic approaches and their efficacy in the management of PNES. The paper employed the search strategy by selecting the keywords: “Psychogenic Non-Epileptic Seizures (PNES) and psychosocial management”, “PNES Treatment approach”, “PNES and psychotherapy” in PUBMED, EBSCO host, PsycINFO, and SCOPUS database. Eventually, specific therapies were cross-searched with PNES for an exhaustive review. Several studies were found employing various psychotherapeutic approaches for the treatment of PNES in pilot studies, randomized controlled, or open uncontrolled trials. Cognitive Behavior Therapy was demonstrated as an efficacious treatment for PNES in a randomized controlled trial (RCT). Other approaches that were effective in ameliorating the symptoms were psychodynamic therapies or psychoeducation based group therapies. Some therapies like Novel Integrative psychotherapy, Eye Movement Desensitisation Therapy and Mindfulness-based therapies require further exploration in larger clinical trials. The findings demonstrate that psychological intervention for PNES is a promising alternative treatment approach with a need for more RCTs with a larger sample and robust methodology for better generalization.

Introduction: Scoring systems to predict outcomes in pediatric status epilepticus (SE) are limited. We sought to assess usefulness of the END-IT score in pediatric SE. Methodology: We conducted a retrospective study at a tertiary hospital in New Delhi, India. Children aged 1 month–18 years who presented with seizure for ≥5 min/actively convulsing to emergency were enrolled. END-IT score was calculated and correlated with outcome at discharge using Pediatric Overall Performance Category (POPC) scale, in-hospital mortality, and progression to refractory and super-refractory SE (SRSE). Results: We enrolled 140 children (mean age 5.8 years; 67.1% males). Seven children died and 15 had unfavorable outcomes. The predictive accuracy of END-IT at a cutoff of > 2: for unfavorable outcome (POPC score ≥3) was: sensitivity 0.73 (95% CI: 0.45–0.92), specificity 0.94 (95% CI: 0.89–0.98), PPV 0.61 (95% CI: 0.36–0.83), NPV 0.97 (95% CI: 0.92–0.99), positive likelihood ratio (13.09), F1 score (0.666); for death: sensitivity 0.86 (95% CI: 0.42–0.99), specificity 0.91 (95% CI: 0.85–0.95), PPV 0.33 (95% CI: 0.13–0.59), NPV 0.99 (95% CI: 0.96–1.00), F1 score (0.48); for RSE: sensitivity 0.80 (95%CI: 0.28–0.99), specificity 0.90 (95% CI: 0.83–0.94), PPV 0.22 (95% CI: 0.06–0.48) NPV 0.99 (95% CI: 0.96–1.00), F1 score (0.35); for SRSE: sensitivity 0.67 (95% CI: 0.22–0.96) specificity 0.75 (95% CI: 0.66–0.82), PPV 0.22 (95% CI: 0.06–0.48) NPV 0.98 (95% CI: 0.94–0.99), F1 score (0.33). Conclusion: We demonstrate utility of the END-IT score to predict short-term outcomes as well as progression to refractory and SRSE for the first time among children with SE.

Ketogenic dietary therapies (KDTs) have been in use for refractory paediatric epilepsy for a century now. Over time, KDTs themselves have undergone various modifications to improve tolerability and clinical feasibility, including the Modified Atkins diet (MAD), medium chain triglyceride (MCT) diet and the low glycaemic index treatment (LGIT). Animal and observational studies indicate numerous benefits of KDTs in paediatric neurological conditions apart from their evident benefits in childhood intractable epilepsy, including neurodevelopmental disorders such as autism spectrum disorder, rarer neurogenetic conditions such as Rett syndrome, Fragile X syndrome and Kabuki syndrome, neurodegenerative conditions such as Pelizaeus-Merzbacher disease, and other conditions such as stroke and migraine. A large proportion of the evidence is derived from individual case reports, case series and some small clinical trials, emphasising the vast scope for research in this avenue. The term 'neuroketotherapeutics' has been coined recently to encompass the rapid strides in this field. In the 100th year of its use for paediatric epilepsy, this review covers the role of the KDTs in non-epilepsy neurological conditions among children.

Abstract Objectives This cross‐sectional study was designed to test the applicability of the 1989, 2010, and 2017 International League Against Epilepsy (ILAE) classification of epilepsy in children from a resource‐limited setting in India. Methods Classification of seizure types and syndromes was done through parental interviews and review of medical records in children with epilepsy aged one month to 18 years. Available investigations including EEG, MRI, and metabolic/genetic tests were used in classifying patients as per the 1989, 2010, and 2017 ILAE (level II‐epilepsy type) classification. We compared the proportion of children remaining unclassified by each scheme. Results Seven hundred and twenty‐six children (436 males, mean age 6.4 ± 4.6 years) were enrolled. Using the 1989 ILAE classification, we were able to classify 95.7%, and 82.6% children by the 2010 scheme. The 2017 ILAE classification could classify all 726 children at level I (seizure type), 664 (91.0%) children at level II (epilepsy type), and an electroclinical syndrome could be identified in 409 (56.1%) of the children. An etiology could be identified in 75%, perinatal brain injury being the most frequent. West syndrome was the most common electroclinical syndrome, identified in 22.7% patients. The 1989 ILAE classification system was superior to the 2010 system (P = .01) in epilepsy classification. There was no difference between the 1989 and 2017 schemes (P = .31) or the 2010 and 2017 schemes (P = .10). Significance The 2017 ILAE classification, being multidimensional, allowed classification of children who could not undergo extensive evaluation due to economic constraints and also provided room for overlapping etiologies.

Status epilepticus (SE) is a common neurological emergency in childhood associated with high mortality and morbidity. Acute management of seizures along with aggressive evaluation for establishing the underlying cause are crucial determinants of outcome. Neonatal status epilepticus carries the burden of poor neurological outcomes and may lead to global developmental delay as well as persistent seizures. The aetiology and pathophysiological mechanisms of SE in neonates and young infants differ compared to older children and adults. The most common causes of SE in neonates includes hypoxic sequelae, ischemic stroke and intracranial haemorrhage. In infants, febrile status epilepticus and acute symptomatic seizures are more common than remote symptomatic causes. Recent advances in neuroimaging modalities and molecular diagnostic techniques have facilitated better diagnostic precision. There is deplorable lack of evidence evaluating management strategies of SE in this age group. In addition to prompt initiation of antiseizure medications, vitamin supplementation needs to be empirically added. Simultaneously, meticulous evaluation to determine cause must also be conducted. In this review, we discuss challenges and an algorithmic approach to the diagnosis and management of SE in neonates and infants.

Objectives: To assess the neurodevelopmental outcome of West syndrome (WS) in Indian children, who differ in their clinical profile from the western population. Materials and Methods: This cross-sectional study enrolled children aged 2--5 years with prior diagnosis of WS between November 2013 and March 2015. They were assessed for epilepsy outcome and developmental outcome using developmental profile 3 (DP3) and vineland adaptive behavioral scale II (VABS II). Results: Sixty-one children were enrolled. Perinatal asphyxia (40.9%), neonatal hypoglycemia (14.8%), and neonatal meningitis (9.8%) were predominant causes among the children with known etiology. Favorable epilepsy outcome (seizure freedom for >6 months) was observed in 29/61 patients (47.5%). Moderate to severe developmental delay was observed in 55/61 children (91.8%). Favorable developmental outcome (GDS by DP3 >70) was observed in just 5/61 (8%) patients. Conclusions: This study highlights the high prevalence of developmental delay in this population of children with WS, with adverse perinatal events being the most common etiology.

Movement disorders are one of the important neurological manifestations of inherited metabolic disorders. Important clues to the presence of an underlying inborn error of metabolism are early onset, presence of neuroregression or degeneration, parental consanguinity, sibling affection, paroxysmal events, waxing and waning course, skin or hair changes, absence of a perinatal insult or any structural cause, and presence of identifiable triggers. It is particularly important to recognize this class of movement disorders as several of them are eminently treatable and may often need disease-specific therapy besides symptomatic treatment. The current review focusses on the movement disorders associated with inherited metabolic defects in children, with emphasis on treatable disorders.

Movement disorders in childhood comprise a heterogeneous group of conditions that lead to impairment of voluntary movement, abnormal postures, or inserted involuntary movements. Movement disorders in children are frequently caused by metabolic disorders, both inherited and acquired. Many of these respond to vitamin supplementation. Examples include infantile tremor syndrome, biotinidase deficiency, biotin-thiamine-responsive basal ganglia disease, pyruvate dehydrogenase deficiency, aromatic amino acid decarboxylase deficiency, ataxia with vitamin E deficiency, abetalipoproteinemia, cerebral folate deficiency, and cobalamin metabolism defects. Recognition of these disorders by pediatricians and neurologists is imperative as they are easily treated by vitamin supplementation. In this review, we discuss vitamin-responsive movement disorders in children.

Pyridox(am)ine- 5- phosphate Oxidase deficiency (PNPO) is a rare cause of neonatal metabolic encephalopathy associated with refractory status epilepticus. We report a case of a premature neonate presenting with drug-resistant seizures beginning at 2 hours of life. The baby showed initial transient response to pyridoxine followed by recurrence. Genetic report confirmed the diagnosis of PNPO deficiency. A literature review on phenotypic variants in terms of response to pyridoxine is also presented along with a proposed algorithm to manage a case of suspected vitamin responsive epilepsy. This case highlights our limited understanding of why variation in response to treatment exists in children with PNPO deficiency.

Biallelic variants in CARS2 (Cysteinyl-tRNA synthetase 2; MIM*612800), are known to cause combined oxidative phosphorylation deficiency 27 (MIM#616672), characterized by severe myoclonic epilepsy, neuroregression and complex movement disorders. To date, six individuals from five families have been reported with variants in CARS2. Herein, we present an 11-year-old boy who presented with neuroregression, dysfluent speech, aggressive behavior and tremors for 2 years. An electroencephalogram (EEG) revealed a highly abnormal background with generalized spike-and-wave discharges suggestive of Electrical Status Epilepticus during Sleep (ESES). A known homozygous c.655G > A(p.Ala219Thr) pathogenic variant in exon 6 of the CARS2(NM_024537.4) was identified on exome sequencing. Our report expands the electro-clinical spectrum of the phenotype with presence of severe behavioral abnormalities, continuous tremors and ESES pattern on EEG, not previously reported.

Children affected by tuberculous meningitis (TBM), as well as their families, have needs that lie at the intersections between the tuberculosis and meningitis clinical, research, and policy spheres. There is therefore a substantial risk that these needs are not fully met by either programme. In this narrative review article, we use the World Health Organization (WHO) “Defeating Meningitis by 2030: global roadmap” as a starting point to consider key goals and activities to specifically defeat TBM in children. We apply the five pillars outlined in the roadmap to describe how this approach can be adapted to serve children affected by TBM. The pillars are (i) prevention; (ii) diagnosis and treatment; (iii) surveillance; (iv) support and care for people affected by meningitis; and (v) advocacy and engagement. We conclude by calling for greater integration between meningitis and TB programmes at WHO and at national levels.

Background: The modified Atkins diet (MAD) has been used predominantly in older children, adolescents, and adults. There is a paucity of data on the use of the MAD in refractory epilepsy in young children. Objectives: This study was planned to evaluate the efficacy and tolerability of the MAD in refractory epilepsy in young children. Methods: This study recruited children aged 9 months to 3 years with refractory seizures. Children received MAD for 6-month with the on-going anticonvulsant medications being continued unchanged. Reduction in seizure frequency was the primary outcome measure. Adverse effects were also studied. Results: Thirty-one children with daily seizures were studied with a median age of 18-month (range 9-30 months). West syndrome was the most common epilepsy syndrome (26, 86.6%). Twenty-one children remained on diet at 3 months and 13 at 6 months. The children who achieved >50% seizure reduction were 17 (54.8%) at 3 months and 9 (29%) at 6 months. Refusal to eat was a significant problem seen in eight children. Three children discontinued the diet due to adverse effects. Conclusion: The MAD was found to be feasible, effective, and well-tolerated.

Griscelli syndrome type 2 (GS2) is a rare autosomal recessive disease caused by mutations in the RAB27A gene. It is characterized by cutaneous hypopigmentation, immunodeficiency, and hemophagocytic lymphohistiocytosis. We describe 2 brothers who had GS2 with clinically diverse manifestations. The elder brother presented with a purely neurological picture, whereas the younger one presented with fever, pancytopenia, hepatosplenomegaly, and erythema nodosum. Considering that cutaneous hypopigmentation was a common feature between the brothers, genetic analysis for Griscelli syndrome was performed. As the elder sibling had died, mutation analysis was only performed on the younger sibling, which revealed a novel homozygous mutation in the RAB27A gene on chromosome 15 showing a single-base substitution (c.136T>A p.F46I). Both parents were heterozygous for the same mutation. This confirmed the diagnosis of GS2 in the accelerated phase in both siblings. The atypical features of GS2 in these cases are a novel mutation, isolated neurological involvement in one sibling, association with erythema nodosum, and 2 distinct clinical presentations in siblings with the same genetic mutation.

The ketogenic diet is a high-fat, low-carbohydrate, and restricted protein diet that is useful in patients with refractory epilepsy. The efficacy of the ketogenic diet is better than most of the new antiepileptic drugs. Other modifications of the diet are also beneficial, such as the modified Atkins diet and the low glycemic index treatment. There is a lack of awareness of the ketogenic diet as a treatment modality for epilepsy amongst pediatricians and neurologists. In this review, the use of the ketogenic diet and other dietary treatments in refractory epilepsy is discussed. The Indian experience with the use of these dietary treatments is also briefly reviewed.

Inborn errors of metabolism (IEM) are a rare cause of epilepsy, but seizures and epilepsy are frequently encountered in patients with IEM. Since these disorders are related to inherited enzyme deficiencies with resulting effects on metabolic/biochemical pathways, the term “metabolic epilepsy” can be used to include these conditions. These epilepsies can present across the life span, and share features of refractoriness to anti-epileptic drugs, and are often associated with co-morbid developmental delay/regression, intellectual, and behavioral impairments. Some of these disorders are amenable to specific treatment interventions; hence timely and appropriate diagnosis is critical to improve outcomes. In this review, we discuss those disorders in which epilepsy is a dominant feature and present an approach to the clinical recognition, diagnosis, and management of these disorders, with a greater focus on primarily treatable conditions. Finally, we propose a tiered approach that will permit a clinician to systematically investigate, identify, and treat these rare disorders.

The Sturge Weber syndrome is characterized by developmental delay, seizures in infancy, unilateral cutaneous lesions with ipsilateral leptomeningeal enhancement. We report an unusual presentation of Sturge Weber syndrome with bilateral port wine nevus on the trunk and face along with bilateral cortical involvement in a developmentally normal child with progressive megalencephaly.