Genetic and phenotypic landscape of pediatric-onset epilepsy in 142 Indian families: Counseling and therapeutic implications.

The application of genomic technologies has led to unraveling of the complex genetic landscape of disorders of epilepsy, gaining insights into their underlying disease mechanisms, aiding precision medicine, and providing informed genetic counseling. We herein present the phenotypic and genotypic insights from 142 Indian families with epilepsy with or without comorbidities. Based on the electroclinical findings, epilepsy syndrome diagnosis could be made in 44% (63/142) of the families adopting the latest proposal for the classification by the ILAE task force (2022). Of these, 95% (60/63) of the families exhibited syndromes with developmental epileptic encephalopathy or progressive neurological deterioration. A definitive molecular diagnosis was achieved in 74 of 142 (52%) families. Infantile-onset epilepsy was noted in 81% of these families (61/74). Fifty-five monogenic, four chromosomal, and one imprinting disorder were identified in 74 families. The genetic variants included 65 (96%) single-nucleotide variants/small insertion-deletions, 1 (2%) copy-number variant, and 1 (2%) triplet-repeat expansion in 53 epilepsy-associated genes causing monogenic disorders. Of these, 35 (52%) variants were novel. Therapeutic implications were noted in 51% of families (38/74) with definitive diagnosis. Forty-one out of 66 families with monogenic disorders exhibited autosomal recessive and inherited autosomal dominant disorders with high risk of recurrence.

Neurodegeneration with brain iron accumulation: a case series highlighting phenotypic and genotypic diversity in 20 Indian families.

Neurodegeneration with brain iron accumulation (NBIA) is an umbrella term encompassing various inherited neurological disorders characterised by abnormal iron accumulation in basal ganglia. We aimed to study the clinical, radiological and molecular spectrum of disorders with NBIA. All molecular-proven cases of NBIA presented in the last 5 years at 2 tertiary care genetic centres were compiled. Demographic details and clinical and neuroimaging findings were collated. We describe 27 individuals from 20 unrelated Indian families with causative variants in 5 NBIA-associated genes. PLA2G6-associated neurodegeneration (PLAN) was the most common, observed in 13 individuals from 9 families. They mainly presented in infancy with neuroregression and hypotonia. A recurrent pathogenic variant in COASY was observed in two neonates with prenatal-onset severe neurodegeneration. Pathogenic bi-allelic variants in PANK2, FA2H and C19ORF12 genes were observed in the rest, and these individuals presented in late childhood and adolescence with gait abnormalities and extrapyramidal symptoms. No intrafamilial and interfamilial variability were observed. Iron deposition on neuroimaging was seen in only 6/17 (35.3%) patients. A total of 22 causative variants across 5 genes were detected including a multiexonic duplication in PLA2G6. The variants c.1799G > A and c.2370 T > G in PLA2G6 were observed in three unrelated families. In silico assessments of 8 amongst 9 novel variants were also performed. We present a comprehensive compilation of the phenotypic and genotypic spectrum of various subtypes of NBIA from the Indian subcontinent. Clinical presentation of NBIAs is varied and not restricted to extrapyramidal symptoms or iron accumulation on neuroimaging.

Does the ketogenic ratio matter when using ketogenic diet therapy in pediatric epilepsy?

The ketogenic diet (KD) is a widely used therapeutic option for individuals with medically refractory epilepsy. As the diet's name implies, ketosis is a historically important component of the diet, but it is not well understood how important ketosis is for seizure control. The ketogenic ratio is defined as the ratio of fat to carbohydrate plus protein by weight in the diet (grams). Traditionally, the classic KD contains a 4:1 ratio, and a very high proportion of fat in the diet. The classic KD, with its high proportion of fat and limited carbohydrate intake can be restrictive for patients with epilepsy. Recently, there is experience with use of lower ketogenic ratios and less-restrictive diets such as the modified Atkins diet and the low glycemic index treatment. In this narrative review, we examine the role of ketosis and ketogenic ratios in determining the efficacy of the KD in children with epilepsy.

SUDEP counseling: Where do we stand?

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death in children and adults living with epilepsy. Several recent clinical practice guidelines have recommended that all individuals living with epilepsy and their caregivers be informed about SUDEP as a part of routine epilepsy counseling. Furthermore, several studies over the last two decades have explored the state of SUDEP counseling. Patients with epilepsy and their families want to be informed about the risk of SUDEP at or near the time of diagnosis, and preferably in person. Despite guideline recommendations, many pediatric and adult neurologists do not routinely inform individuals with epilepsy and their families about SUDEP. Some neurologists discuss SUDEP with only a subset of patients with epilepsy, such as those with risk factors like frequent generalized or focal to bilateral tonic-clonic seizures, nocturnal seizures, noncompliance, or medically refractory epilepsy. Proponents of routine SUDEP counseling argue that patients with epilepsy and their families have a "right to know" and that counseling may positively impact epilepsy self-management (i.e., behavioral modification and risk reduction). Some neurologists still believe that SUDEP counseling may cause unnecessary stress and anxiety for patients and their families (although this is erroneous) and that they also have a "right not to know." This narrative review explores the current gaps in SUDEP counseling, patients' and caregivers' perspectives of SUDEP counseling, and SUDEP prevention.

Neurologic Complications in Patients With Lymphoreticular Malignancy: A Descriptive Cohort Study.

OBJECTIVES: The objectives of this study were to study the spectrum of neurologic complications in children with lymphoreticular malignancy (acute lymphoblastic leukemia, Hodgkin, and non-Hodgkin lymphoma) at diagnosis and during treatment and to determine the etiology of these complications. MATERIALS AND METHODS: In this descriptive cohort study, conducted between November 2018 and March 2020, 204 children with a diagnosis of lymphoreticular malignancy were enrolled. The baseline investigations were done in all the cases. Those who developed neurological symptoms were evaluated with cerebrospinal fluid examination and radiologic and electrophysiologic studies as per indication and were managed according to standard management guidelines. RESULTS: Of the 204 patients, 30 (14.7%) developed neurological complications. The majority of these complications (n=20/30; 87%) occurred during the intensive chemotherapy period. Common complications included acute methotrexate neurotoxicity (n=7), vincristine-induced neurotoxicity (n=7), central nervous system (CNS) relapse (n=4), and posterior reversible encephalopathy syndrome (n=2). L-asparaginase-induced thrombosis (n=1), intramedullary compression syndrome (n=1), CNS infection (n=2), CNS hemophagocytic lymphohistiocytosis (n=1), and steroid-induced myopathy (n=1) were also observed. The complications resolved in 21/30 (70%) patients after receiving appropriate treatment while the neurological complication persisted in 2/30 (6.7%) patients. Three patients (10%) abandoned the treatment, and 4 (13.3%) patients expired. CONCLUSIONS: Neurologic complications in patients with lymphoreticular malignancy are quite variable, having common presenting symptoms but varying imaging abnormalities. By close follow-up and effective treatment, the morbidity and mortality of these complications can be minimized.

Sudden unexpected death in epilepsy in children.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality in children and adults living with epilepsy. The incidence of SUDEP is comparable in both children and adults; it is approximately 1.2 per 1000 person years. The pathophysiology of SUDEP is not well understood but may involve mechanisms such as cerebral shutdown, autonomic dysfunction, altered brainstem function, and cardiorespiratory demise. Risk factors for SUDEP include the presence of generalized tonic-clonic seizures, nocturnal seizures, possible genetic predisposition, and non-adherence to antiseizure medications. Pediatric-specific risk factors are not fully elucidated. Despite recommendations from consensus guidelines, many clinicians still do not follow the practice of counseling their patients about SUDEP. SUDEP prevention has been an area of important research focus and includes several strategies, such as obtaining seizure control, optimizing treatment regimens, nocturnal supervision, and seizure detection devices. This review discusses what is currently known about SUDEP risk factors and reviews current and future preventive strategies for SUDEP.

Further evidence of muscle involvement in neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy.

TRAPPC4-related neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy (MIM# 618741) is a recently described TRAPPopathy with clinical findings of developmental delay, seizures, postnatal microcephaly, spasticity, facial dysmorphism, and cerebral and cerebellar atrophy. Muscle involvement, a frequent finding in TRAPPopathies, was observed in one individual with TRAPPC4-related disorder previously. Only a single variant, an in-frame deletion in one family has been reported outside a recurrent disease-causing variant. We report three individuals from two Indian families harboring novel bi-allelic missense variants c.191T>C and c.278C>T (NM_016146.6) in TRAPPC4 with classic clinical presentation in one and milder and later onset in the other family. We provide further evidence for muscle involvement and review the detailed phenotypic findings in individuals reported with this disorder till date.

Predictors of mortality in children admitted with SARS-CoV-2 infection to a tertiary care hospital in North India.

AIM: To compare the demographic, clinical, laboratory and radiological parameters of patients with different clinical outcomes (death or discharge) and analyse them to find out the potential predictors for mortality in children hospitalised with SARS-CoV-2 infection. METHODS: Retrospective chart review of all patients less than 18 years of age with laboratory-confirmed SARS-CoV-2 infection and requiring hospital admission between 16 April 2020 and 31 October 2020. RESULTS: Of 255 children with SARS-CoV-2 infection, 100 patients (median age 62.5 months, 59% males, 70% with moderate to severe disease) were hospitalised, of whom 27 died (median age 72 months, 59% males and 30% severely underweight). The subgroup with comorbidities (n = 14) was older (median age 126 months) and had longer duration of stay (median 10 days). Fever and respiratory symptoms were comparable while gastrointestinal symptoms were more common among non-survivors. Hypoxia at admission (odds ratio (OR) 5.48, P = 0.001), multiorgan dysfunction (OR 75.42, P = 0.001), presence of acute kidney injury (OR 11.66, P = 0.001), thrombocytopenia (OR 4.40, P = 0.003) and raised serum C-reactive protein (CRP) (OR 4.69, P = 0.02) were independently associated with mortality. The median time from hospitalisation to death was 3 days. The deceased group had significantly higher median levels of inflammatory parameters and a higher incidence of complications (myocarditis, encephalitis, acute respiratory distress syndrome and shock). CONCLUSIONS: Hypoxia at admission, involvement of three or more organ systems, presence of acute kidney injury, thrombocytopenia and raised serum C-reactive protein were found to be independently associated with increased odds of in-hospital mortality in children admitted with SARS-CoV-2 infection.

Clinical and genetic spectrum of 104 Indian families with central nervous system white matter abnormalities.

Genetic disorders with predominant central nervous system white matter abnormalities (CNS WMAs), also called leukodystrophies, are heterogeneous entities. We ascertained 117 individuals with CNS WMAs from 104 unrelated families. Targeted genetic testing was carried out in 16 families and 13 of them received a diagnosis. Chromosomal microarray (CMA) was performed for three families and one received a diagnosis. Mendeliome sequencing was used for testing 11 families and all received a diagnosis. Whole exome sequencing (WES) was performed in 80 families and was diagnostic in 52 (65%). Singleton WES was diagnostic for 50/75 (66.67%) families. Overall, genetic diagnoses were obtained in 77 families (74.03%). Twenty-two of 47 distinct disorders observed in this cohort have not been reported in Indian individuals previously. Notably, disorders of nuclear mitochondrial pathology were most frequent (9 disorders in 20 families). Thirty-seven of 75 (49.33%) disease-causing variants are novel. To sum up, the present cohort describes the phenotypic and genotypic spectrum of genetic disorders with CNS WMAs in our population. It demonstrates WES, especially singleton WES, as an efficient tool in the diagnosis of these heterogeneous entities. It also highlights possible founder events and recurrent disease-causing variants in our population and their implications on the testing strategy.

Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities.

OBJECTIVES: The majority of people with suspected genetic dystonia remain undiagnosed after maximal investigation, implying that a number of causative genes have not yet been recognized. We aimed to investigate this paucity of diagnoses. METHODS: We undertook weighted burden analysis of whole-exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case-finding from international databases, first for the gene implicated by the burden analysis (VPS16), and then for other functionally related genes. Electron microscopy was performed on patient-derived cells. RESULTS: Analysis revealed a significant burden for VPS16 (Fisher's exact test p value, 6.9 × 109 ). VPS16 encodes a subunit of the homotypic fusion and vacuole protein sorting (HOPS) complex, which plays a key role in autophagosome-lysosome fusion. A total of 18 individuals harboring heterozygous loss-of-function VPS16 variants, and one with a microdeletion, were identified. These individuals experienced early onset progressive dystonia with predominant cervical, bulbar, orofacial, and upper limb involvement. Some patients had a more complex phenotype with additional neuropsychiatric and/or developmental comorbidities. We also identified biallelic loss-of-function variants in VPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia. Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function. INTERPRETATION: Our study strongly supports a role for HOPS complex dysfunction in the pathogenesis of dystonia, although variants in different subunits display different phenotypic and inheritance characteristics. ANN NEUROL 2020;88:867-877.

Maternal autoimmunity and inflammation are associated with childhood tics and obsessive-compulsive disorder: Transcriptomic data show common enriched innate immune pathways.

Although genetic variation is a major risk factor of neurodevelopmental disorders, environmental factors during pregnancy and early life are also important in disease expression. Animal models demonstrate that maternal inflammation causes fetal neuroinflammation and neurodevelopmental deficits, and brain transcriptomics of neurodevelopmental disorders in humans show upregulated differentially expressed genes are enriched in immune pathways. We prospectively recruited 200 sequentially referred children with tic disorders/obsessive-compulsive disorder (OCD), 100 autoimmune neurological controls, and 100 age-matched healthy controls. A structured interview captured the maternal and family history of autoimmune disease and other pro-inflammatory states. Maternal blood and published Tourette brain transcriptomes were analysed for overlapping enriched pathways. Mothers of children with tics/OCD had a higher rate of autoimmune disease compared with mothers of children with autoimmune neurological conditions (p = 0.054), and mothers of healthy controls (p = 0.0004). Autoimmunity was similarly elevated in first- and second-degree maternal relatives of children with tics/OCD (p < 0.0001 and p = 0.014 respectively). Other pro-inflammatory states were also more common in mothers of children with tics/OCD than controls (p < 0.0001). Upregulated differentially expressed genes in maternal autoimmune disease and Tourette brain transcriptomes were commonly enriched in innate immune processes. Pro-inflammatory states, including autoimmune disease, are more common in the mothers and families of children with tics/OCD. Exploratory transcriptome analysis indicates innate immune signalling may link maternal inflammation and childhood tics/OCD. Targeting inflammation may represent preventative strategies in pregnancy and treatment opportunities for children with neurodevelopmental disorders.

Can We Prevent Sudden Unexpected Death in Epilepsy (SUDEP)?

Sudden unexpected death in epilepsy (SUDEP) remains an important cause of epilepsy-related mortality, especially in patients with refractory epilepsy. The exact cause is not known, but postictal cardiac, respiratory, and brainstem dysfunctions are implicated. SUDEP prevention remains a big challenge. Except for low-quality evidence of preventive effect of nocturnal supervision for SUDEP, no other evidence-based preventive modality is available. Other potential preventive strategies for SUDEP include reducing the occurrence of generalized tonic-clonic seizures using seizure detection devices, detecting cardiorespiratory distress through respiratory and heart rate monitoring devices, preventing airway obstruction (safety pillows), and reducing central hypoventilation using selective serotonin reuptake inhibitors and adenosine and opiate antagonists. However, none of the above-mentioned modalities has been proven to prevent SUDEP. The present review intends to provide insight into the available SUDEP prevention modalities.

Novel variant p.(Ala102Thr) in SDHB causes mitochondrial complex II deficiency: Case report and review of the literature.

Leigh syndrome is a clinically and radiologically heterogeneous condition with approximately 75 genes, nuclear and mitochondrial, known to be implicated in its pathogenesis. Leigh syndrome due to complex II deficiency constitutes 2% to 7% of these cases. Previously, nine individuals with Leigh syndrome have been reported with pathogenic variants in SDHB, which encodes for the iron-sulfur cluster subunit of mitochondrial respiratory chain complex II. The proband presented with Leigh syndrome. Exome sequencing revealed a homozygous missense variant p.(Ala102Thr) in SDHB. In silico protein modeling of the wild-type and mutant proteins showed potentially decreased protein stability. We hereby report another individual with Leigh syndrome due to SDHB-related mitochondrial complex II deficiency and review the phenotype and genotype associated with this condition.

Encephalopathy due to defective mitochondrial and peroxisomal fission 2 caused by a novel MFF gene mutation in a young child.

Encephalopathy due to defective mitochondrial and peroxisomal fission 2 caused by mitochondrial fission factor (MFF) gene mutation is a rare neurogenetic disorder. Pathogenic MFF mutations have been described in three reports in literature so far. We report a young child of Indian descent who presented to us with global developmental followed by regression of acquired milestones, spasticity, visual and auditory impairment, and was found to harbor a novel pathogenic homozygous MFF truncating variant c.433C>T; p.Arg145Ter. Cellular imaging of patient lymphoblastoid cell line had shown abnormal shapes of mitochondria due to fission defects. The patient has been started on mitochondrial cocktail with some improvement.

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.

Maternal thyroid autoimmunity associated with acute-onset neuropsychiatric disorders and global regression in offspring.

Epidemiological studies, animal models, and case-control studies indicate maternal immune activation may be an important factor involved in disease expression of autism spectrum disorder (ASD), Tourette syndrome, and obsessive-compulsive disorder (OCD). We report eight children (mean age 6y 6mo [range 4-15y]; six males and two females) referred over a 2-year period with at least one of these neurodevelopmental disorders plus a maternal history of thyroid autoimmunity. Seven of eight children presented with an abrupt onset of neuropsychiatric symptoms (OCD [n=6], tics [n=5], and/or psychosis [n=1]), associated with an autistic or global regression. Four children had a pre-existing diagnosis of ASD. Six presentations were preceded by infection, and symptoms followed a relapsing-remitting course in seven children. All children responded to immunomodulatory treatment as indicated by a reduction in psychiatric symptoms, and seven children were also managed with conventional treatment with additional improvement. We propose that maternal autoimmunity can activate fetal microglia or alter transcription of neurodevelopmental vulnerability and/or immune genes in utero, and is an environmental factor that increases the expression and severity of neurodevelopmental problems, and susceptibility to deteriorations after infectious or stress stimuli. WHAT THIS PAPER ADDS: Maternal thyroid autoimmunity may represent a risk factor for neuropsychiatric disorders in offspring. Atypical neuropsychiatric features in these children may be due to maternal immune activation in utero.

AUTOINMUNIDAD MATERNA TIROIDEA ASOCIADA CON TRASTORNOS NEUROPSIQUIÁTRICOS DE INICIO AGUDO Y REGRESIÓN GLOBAL EN LA DESCENDENCIA: Los estudios epidemiológicos, los modelos animales y los estudios de casos y controles indican que la activación inmune materna puede ser un factor importante involucrado en la expresión de la enfermedad del trastorno del espectro autista (TEA), el síndrome de Tourette y el trastorno obsesivo compulsivo (TOC). Informamos ocho niños (edad media 6 años de edad y 6 meses [rango 4-15 años]; 6 varones y 2 mujeres) remitidos durante un período de 2 años con al menos uno de estos trastornos del desarrollo neurológico más un historial materno de autoinmunidad tiroidea. Siete de ocho niños presentaron un inicio brusco de síntomas neuropsiquiátricos (TOC [n = 6], tics [n = 5] y / o psicosis [n = 1]), asociados con una regresión autista o global. Cuatro niños tenían un diagnóstico preexistente de TEA. Seis presentaciones fueron precedidas por infección, y los síntomas siguieron un curso de recaídas y remisiones en siete niños. Todos los niños respondieron al tratamiento inmunomodulador según lo indicado por una reducción en los síntomas psiquiátricos, y siete niños también fueron tratados con tratamiento convencional con una mejora adicional. Proponemos que la autoinmunidad materna puede activar la microglía fetal o alterar la transcripción de la vulnerabilidad del desarrollo neurológico y / o los genes inmunes en el útero, y es un factor ambiental que aumenta la expresión y la gravedad de los problemas del desarrollo neurológico, y la susceptibilidad a deterioros después de estímulos infecciosos o estresantes.

AUTOIMUNIDADE TIREÓIDE MATERNA ASSOCIADA COM DESORDENS NEUROPSIQUIÁTRICAS DE INÍCIO AGUDO E REGRESSÃO GLOBAL NA PROLE: Estudos epidemiológicos, modelos animais, e estudos de caso-controle indicam que a ativação imune materna pode ser um importante fator envolvido na expressão de doenças do transtorno do espectro autista (TEA), síndrome de Tourette, e transtorno obsessivo compulsivo (TOC). Reportamos oito crianças (média de idade 6a 6m [variação 4-15a]; 6 do sexo masculino e 2 do sexo feminino) encaminhadas em um período de 2 anos com pelo menos uma desordem neurodesenvolvimental e história de auto-imunidade tireóide materna. Sete das oito crianças apresentaram início agudo de sintomas neuropsiquiátricos (TOC [n=6], tiques [n=5], e/ou psicose [n=1]), associados com regressão autística ou global. Quatro crianças tinham diagnóstico pré-existente de TEA. Seis apresentações foram precedidas por infecção, e os sintomas seguiram um curso recorrência-remisão em sete crianças. Todas as crianças responderam ao tratamento imunomodulatório, indicado pela redução nos sintomas psiquiátricos, e sete crianças também foram abordadas com tratamento convencional, com melhora adicional. Nós propomos que a autoimunidade maternal pode ativar a microglia fetal ou alterar a transcrição de genes de vulnerabilidade neurodesenvolvimental e/ou imunes, e um fator ambiental pode aumentar a expressão e severidade de problemas neurodesenvolvimentais e suscetibilidade a deterioração após estímulo infeccioso ou estresse.

Incidence of vincristine induced neurotoxicity in children with acute lymphoblastic leukemia and its correlation with nutritional deficiencies.

Injection vincristine is an important component of therapy for acute lymphoblastic leukemia (ALL). An important adverse effect of vincristine is neurotoxicity. The incidence of this adverse effect is well studied. The present was undertaken to determine the incidence of vincristine-induced neurotoxicity in children with ALL after the induction of remission phase of chemotherapy and to ascertain its correlation with undernutrition, vitamin B12, folate and iron deficiency. Thirty children (1-18 years) with ALL were enrolled at the commencement of chemotherapy. The electrophysiological evaluation was done at baseline and repeated after four doses of vincristine (1.5 mg/m2/dose). Clinical evaluation was done regularly. Anthropometry and serum B12, folate and ferritin levels were assessed at baseline. Twelve children over a 4-week period of observation had peripheral neuropathy clinically. The autonomic system was most commonly involved followed by motor and sensory system respectively. On electrophysiological testing, half of the patients had evidence of neuropathy. Micronutrient deficiencies were present in a significant number of patients-63.3% had a B12 deficiency, 20% were deficient in folate and 43.3% in iron. The incidence of vincristine-induced neuropathy in patients with/without these micro-nutrient deficiencies was not statistically significantly different. Vincristine-induced neuropathy is common in Indian children with ALL. The present study did not find any correlation between the occurrences of vincristine-induced neuropathy and nutritional deficiencies. Larger studies are warranted to evaluate the contribution of micronutrient deficiencies to the development of peripheral neuropathy in childhood ALL.

Addition of pyridoxine to prednisolone in the treatment of infantile spasms: A pilot, randomized controlled trial.

BACKGROUND: West syndrome is a catastrophic epilepsy syndrome characterized by infantile spasms, hypsarrhythmia, and developmental arrest or regression. AIM: The aim of this study was to explore the role of pyridoxine in the management of infantile spasms. SETTING AND DESIGN: This was a pilot, randomized, open-label trial conducted at a tertiary level hospital from November 2012 to March 2014. MATERIALS AND METHODS: Children aged 3 months to 3 years presenting with infantile spasms in clusters (at least 1 cluster/day) with hypsarrhythmia or its variants on electroencephalogram (EEG) were enrolled. The study participants were randomized to receive either oral prednisolone (4 mg/kg/day) alone or 30 mg/kg/day of pyridoxine with oral prednisolone. The primary outcome measure was the proportion of children who achieved spasm freedom for 48 h on day-14 after treatment initiation, as per parental reports, in both the groups. The adverse effects were also monitored. The study was registered with clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT01828437). RESULTS: Sixty-two children were randomized into the two groups with comparable baseline characteristics. The proportion of children with spasm cessation on day-14 was similar in the two groups (39 vs. 37%, P = 0.98). The adverse effects were comparable in both the groups. CONCLUSIONS: The combination of pyridoxine with oral prednisolone was not found to be a beneficial therapy as compared to prednisolone alone in the treatment of infantile spasms in this pilot study. However, high dose pyridoxine may be safe in children with infantile spasms.

Inborn Errors of Metabolism and Epilepsy: Current Understanding, Diagnosis, and Treatment Approaches.

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.