Neurodevelopmental Outcomes of a Cohort of Children with Tuberous Sclerosis Complex with Epileptic Spasms.

The neurodevelopmental outcomes in children with tuberous sclerosis complex (TSC) with epileptic spasms remain underdiagnosed and might be responsible for significant morbidity and mortality burdens, even after spasms abate. The study was a cross-sectional study over 18 months at a tertiary care pediatric hospital, involving 30 children with TSC who had epileptic spasms. They were assessed with Diagnostic and Statistical Manual of Mental Disorders-5 criteria for autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and intellectual disability (ID), and childhood psychopathology measurement schedule (CPMS) for behavioral disorders. The median age at onset of epileptic spasms was 6.5 (1-12) months, and the age at enrolment was 5 (1-15) years. Of 30 children, 2 (6.7%) had only ADHD, 15 (50%) had only ID/GDD (global developmental delay), 4 (13.3%) had ASD and ID/GDD, 3 (10%) had ADHD and ID/GDD, and 6 (20%) had none. The median intelligence quotient/development quotient (IQ/DQ) score was 60.5 (20-105). CPMS assessment revealed significant behavioral abnormalities in almost half the children. Eight (26.7%) patients were completely seizure-free for at least 2 years, 8 (26.7%) had generalized tonic-clonic seizures, 11 (36.6%) had focal epilepsy, and 3 (10%) had evolved into Lennox-Gastaut syndrome. A high proportion of neurodevelopment disorders, including ASD, ADHD, ID/GDD, and behavioral disorders were seen in this pilot study with a small cohort of children with TSC with epileptic spasms.

Knowledge and experiences of healthcare workers in managing children with neurometabolic disorders in a developing country: a cross-sectional study.

OBJECTIVE: To evaluate the knowledge and experiences of healthcare workers in the management of neurometabolic disorders. METHODS: A cross-sectional study was carried out among the 132 participants of a continued medical education program conducted in the Department of Pediatrics at a tertiary-care teaching hospital. A questionnaire-based feedback form was circulated among the participants, and their responses were analyzed. RESULTS: Ninety-three responses were analyzed. The most common pediatric illnesses identified were infections (91%), nutritional (91%), birth-related injuries (44.4%) and metabolic disorders (44.4%). Consanguinity (81.5%) and genetic heterogeneity (42.4%) were recognized as most important causes of neurometabolic disorders. Important steps identified for prevention were prenatal testing (65.6%) and newborn screening at birth (61%); while for improving the diagnosis were routine availability of metabolic investigations (65.3%) and screening at birth (46.6%). Most respondents (58.7%) expressed discomfort in managing a case with inherited metabolic defect due to a lack of knowledge (46.8%) and diagnostic facilities (44.6%). Despite access to testing in the majority, a high cost of testing was noticed for biochemical and genetic investigations. The majority of participants (73%) considered some of the inherited metabolic disorders as treatable. Dietary substitution (89.3%), enzyme replacement (69%), cofactor replacement (53.6%), gene therapy (35.7%) and regular dialysis (16.7%) were considered the treatment options. CONCLUSION: In spite of growing awareness of inherited metabolic disorders, there are still gaps in knowledge among healthcare workers. It is challenging to diagnose and manage these disorders. Cost-reduction of diagnostic tests, routine newborn screening and increased educational activities are key challenges to be addressed.

Neurodegeneration and Early Infantile Epilepsy Associated with ITPA Variants: A Case Series and Review of Literature.

BACKGROUND: Inosine triphosphate pyrophosphohydrolase (ITPase) deficiency associated with mutations in the ITPA gene is a recently characterized purine pathway defect that presents with early infantile epileptic encephalopathy and lethal course. This disorder is rare, and only 12 cases are reported worldwide. METHODS: We report two additional cases of ITPA-associated neurodegeneration and two pathogenic compound heterozygous variants. We also reviewed the previously published cases of ITPA-associated encephalopathy. RESULTS: Both cases presented with progressive infantile-onset encephalopathy, severe developmental delay, microcephaly, facial dysmorphism, and epilepsy. Together with the presented two cases, 14 cases were available for analysis. The mean age of presentation was 16.7 ± 12.4 months (range 3-48 m). The most common clinical features at presentation were developmental delay, seizures, microcephaly, and hypotonia, seen in all 14 (100%) patients. The mean age of seizure onset was 4.75 months (range 2-14 m). Cardiomyopathy was noted in 42% of patients where it was explicitly evaluated (n = 5/12). Consanguinity was reported in 77% of the cases. The cardinal neuroradiological features are T2-signal abnormalities and diffusion restriction in the long tracts, especially the posterior limb of the internal capsule and the optic radiation. The majority of the patients died before 4 years of age (85.7%). CONCLUSION: ITPA-related encephalopathy presents with infantile-onset neurodegeneration, progressive microcephaly, and epilepsy. Progressive brain atrophy and diffusion restriction in the white matter tracts are important radiological clues.

Seroprevalence of MOG and AQP4 Antibodies and Outcomes in an Indian Cohort of Pediatric Acquired Demyelinating Syndromes.

This study aimed to determine the seropositivity of myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) and aquaporin-4 antibodies (AQP4-Ab) and outcomes in children with acquired demyelinating syndromes (ADSs). Children (6 months-15 years) with suspected ADS were enrolled and tested for MOG-Ab and AQP4-Ab prospectively over 18 months at a tertiary care hospital in North India. Children with proven nonimmune-mediated neurological disorders were enrolled as controls. Of 79 children with suspected ADS, 66 were enrolled. Among the enrolled children with ADS, acute demyelinating encephalomyelitis (ADEM) (25) was the most common first clinical event followed by optic neuritis (ON) (20) and transverse myelitis (TM) (19; one child had ON and TM simultaneously [neuromyelitis optica spectrum disorders [NMOSDs]]), while two children had clinically isolated syndrome (CIS) apart from ON and TM. Fourteen (21.2%, confidence interval [CI] 11.3-31.1) tested positive for one antibody (12 [18.1%; 95% CI 10.5-25.5%] for MOG-Ab and 2 [3%; 95% CI 0-7.2%] for AQP4-Ab). None of the 62 controls tested positive for any antibody. The final diagnosis in those with the monophasic ADS was ADEM (21), ON (13), TM (16), and other CIS (1) while that in children with recurrent events was multiphasic disseminated encephalomyelitis (MDEM) (2), NMOSD (3), ADEM-ON (4), recurrent ON (4), and MS (2). Among those with the first event, 4/51 (7.8%; 95% CI 0.5-15.2%) were MOG-Ab positive and 2 AQP4-Ab positive, whereas 8/15 (53.3% [95% CI 28.1-78.6%]) with recurrent events (MDEM [2], ADEM-ON [4], recurrent ON [1], and recurrent TM [1]) were MOG-Ab positive. Hence, MOG-Abs are the most common antibodies detected in one in five children with pediatric ADS, especially in relapsing disease. AQP4-Abs are rare in children with ADS.

High-resolution intracranial vessel wall imaging in cerebral viral infections evaluations.

PURPOSE: Vascular complications can be seen in various viral CNS infections. Variable neuro-imaging findings have been described in the literature elucidating the parenchymal changes with vascular involvement. Vessel wall imaging (VWI) can help to detect these vascular involvements. We aimed to describe the role and usefulness of VWI in the evaluation of various viral CNS infections. METHODS: In this prospective study, we included 15 cases of various diagnosed viral CNS infections (varicella, HIV encephalopathy, HSV encephalitis, Japanese encephalitis, dengue, COVID-19). VWI and time-of-flight MR angiography (TOF MRA) were included in imaging protocol. All cases were evaluated for the presence of cerebral parenchymal changes, vascular enhancement, and vascular stenosis. RESULTS: We found infarctions in all 5 cases of varicella, 1 case of HIV encephalopathy, and 1 case of COVID-19 encephalopathy. All these cases also showed vascular enhancement and stenosis on VWI. The rest of the cases, including 1 case of HIV encephalopathy, 3 cases of herpes encephalitis, 2 cases of dengue, and 2 cases of Japanese encephalitis did not have any vascular complication, and also did not show vascular enhancement or stenosis. CONCLUSION: VWI can be useful in the detection of vascular involvement in various viral infections of CNS which show a relatively higher cerebrovascular complication rate like varicella, HIV encephalopathy, and COVID-19. However, VWI may not be useful in the routine evaluation of other viral infections like herpes, dengue, and Japanese encephalitis, which have a very low rate of cerebrovascular complication rate.

A high frequency and geographical distribution of MMACHC R132* mutation in children with cobalamin C defect.

Cobalamin C defect is caused by pathogenic variants in the MMACHC gene leading to impaired conversion of dietary vitamin B12 into methylcobalamin and adenosylcobalamin. Variants in the MMACHC gene cause accumulation of methylmalonic acid and homocysteine along with decreased methionine synthesis. The spectrum of MMACHC gene variants differs in various populations. A total of 19 North Indian children (age 0-18 years) with elevated methylmalonic acid and homocysteine were included in the study, and their DNA samples were subjected to Sanger sequencing of coding exons with flanking intronic regions of MMACHC gene. The genetic analysis resulted in the identification of a common pathogenic nonsense mutation, c.394C > T (R132*) in 85.7% of the unrelated cases with suspected cobalamin C defect. Two other known mutations c.347T > C (7%) and c.316G > A were also detected. Plasma homocysteine was significantly elevated (> 100 µmol/L) in 75% of the cases and methionine was decreased in 81% of the cases. Propionyl (C3)-carnitine, the primary marker for cobalamin C defect, was found to be elevated in only 43.75% of cases. However, the secondary markers such as C3/C2 and C3/C16 ratios were elevated in 87.5% and 100% of the cases, respectively. Neurological manifestations were the most common in our cohort. Our findings of the high frequency of a single MMACHC R132* mutation in cases with combined homocystinuria and methylmalonic aciduria may be proven helpful in designing a cost-effective and time-saving diagnostic strategy for resource-constraint settings. Since the R132* mutation is located near the last exon-exon junction, this is a potential target for the read-through therapeutics.

Neuroimaging Spectrum of Severe Hypernatremia in Infants with Neurological Manifestations.

BACKGROUND: Variable neurological manifestations and imaging findings have been described in children with severe hypernatremia. We aimed to describe the spectrum of neuroimaging changes in infants with severe hypernatremia. METHODS: This retrospective study included infants with severe hypernatremia (serum sodium >160 mEq/L), abnormal neurological examination, and an abnormal magnetic resonance imaging (MRI) of the brain over a period of 2 years in a tertiary care hospital. Relevant clinical data, including the feeding practices, clinical features, complications, and biochemical and radiological parameters, were entered in a structured pro forma. MRI findings were classified as vascular (hemorrhages and cerebral sinus venous thrombosis), osmotic demyelination syndrome (pontine and extrapontine myelinolyses), and white matter changes. RESULTS: The common clinical features in the neonates were poor feeding (n = 4) and decreased urine output (n = 4); the older infants presented with gastrointestinal losses (n = 5). All cases had dehydration with encephalopathy. The patterns of radiological injury were vascular (hemorrhages, n = 5 and venous thrombosis, n = 3), osmotic demyelination (n = 8), and white matter changes (n = 7). Coagulopathy was correlated with the vascular complications (r = 0.8, p < 0.0001); the degree of dehydration was correlated with the venous thrombosis (r = 0.7, p < 0.04) and acute kidney injury (r = 0.8, p < 0.001). Neurological sequelae were seen in four cases and correlated with hypernatremia (r = 0.6, p = 0.03) and hyperosmolarity (r = 0.6, p = 0.03). CONCLUSION: Characteristic neuroimaging findings are vascular changes in the form of venous thrombosis and hemorrhages, osmotic demyelination and white matter tract injury, and/or mostly combinations of these findings. Severe hypernatremia and resulting hyperosmolarity frequently cause neurological sequelae in neonates and infants.

MR vessel wall imaging in tubercular meningitis.

PURPOSE: Tubercular meningitis (TBM) has the propensity to cause secondary vasculitis through various mechanisms leading to development of cerebrovascular complications. These vascular involvements can be detected by vessel wall imaging (VWI). In this study, we aimed to study detailed findings of vessel wall imaging in cases of tubercular meningitis. METHODS: All consecutive patients of suspected tubercular meningitis in whom diagnosis of TBM could be made according to diagnostic criteria given by Ahuja et al. were included in the study. High-resolution MR VWI and time of flight (TOF) magnetic resonance angiography (MRA) were done along with routine MRI sequences. Arteries up to second-order branches were studied, and statistical analyses were done with respect to stage of tubercular meningitis, infarctions and TOF MRA findings. RESULTS: Out of all 101 cases of TBM, infarctions were found in 49 cases (48.5%), and vessel wall enhancement was seen in 67 cases (66.3%). With increasing severity of disease, more severe vascular involvement was seen on VWI. There was significant association between enhancement of individual arteries and infarctions in their territories. VWI had better sensitivity than the MRA, while MRA had better specificity than VWI for detection of vascular complications. CONCLUSION: Tubercular vasculitis can be detected by VWI in the form of nodular or smooth segmental enhancement of vessel wall with or without stenosis. Incorporation of VWI in routine MR imaging can play a greater role in early detection and management of cerebrovascular complications which can help to improve prognosis of the disease.

Metabolic epilepsy in hyperprolinemia type II due to a novel nonsense ALDH4A1 gene variant.

Hyperprolinemia type II (HPII) is a rare autosomal recessive disorder of proline degradation pathway due to deficiency of delta-1-pyrroline-5-carboxylate dehydrogenase. Pathogenic variants in the ALDH4A1 gene are responsible for this disorder. We here describe an 11-month-old infant with recurrent seizures refractory to multiple antiepileptic drugs. She was hospitalized in view of acute-onset encephalopathy, exacerbation of generalized seizures following an upper respiratory infection. Laboratory investigation revealed significantly elevated proline levels in dried blood spots. DNA sample of the child was subjected to a targeted next-generation sequencing gene panel for hyperprolinemias. We detected a novel nonsense homozygous variant in the ALDH4A1 gene in the child and the heterozygous variant of the same in both the parents. Based on the location of the variant i.e. in the last exon, truncated protein is expected to be expressed by skipping nonsense-mediated decay and such point-nonsense variants could be an ideal target for readthrough drugs to correct genetic defects.

Thiamine Status in Children with Septic Shock from a Developing Country: A Prospective Case-Control Study.

OBJECTIVE: Mitochondrial dysfunction is central to sepsis-induced multi-organ dysfunction. Thiamine deficiency may contribute to mitochondrial dysfunction and thus high mortality. Study was planned to assess thiamine status in children with septic shock in comparison to healthy controls from a developing country and to study the effect of thiamine levels on its outcome. METHODS: A prospective case-control study (April 2017 to May 2018) enrolling consecutive children with septic shock as 'cases' (n = 76), their healthy siblings (n = 51) and apparently healthy children from immunization clinic (n = 35) as 'controls'. Whole blood total thiamine (WBTT) level was measured on days 1, 10 and 1-month post-discharge. Outcome parameters were acute care area free days on days 14 and 28, and mortality. RESULTS: WBTT [nMol/l; median (interquartile range, IQR)] was significantly lower on day 1 in cases compared with sibling controls [23.1 (21.8-26.3) vs. 36.9 (33.6-40.5); p < 0.001]. It fell further on day 10 [20.8 (18.1-21.1); p < 0.02]. Levels rose significantly 1-month post-discharge [35.5 (31.2-36.6)] and became comparable to sibling controls (p = 0.4). Immunization clinic controls also had lower WBTT [42.3 (40.1-45.9)], but was significantly higher than sibling controls and cases at 1-month post-discharge (p < 0.001). Survivors and non-survivors of septic shock were similar. WBTT levels did not correlate with any of the severity indicators of septic shock or its outcomes. CONCLUSIONS: WBTT was significantly low in all children, and fell further during septic shock. Observed severe deficiency might have precluded any further association of thiamine levels with severity of septic shock and its outcome. Data obtained may inform trials on metabolic resuscitation in paediatric septic shock in developing countries. Lay summaryThiamine deficiency may contribute to high mortality in paediatric septic shock as thiamine is an essential factor for functioning of mitochondria, the powerhouse of the cells. This prospective case-control study was conducted to assess thiamine status in children with septic shock in comparison with healthy controls in a developing country. Consecutive children with fluid-refractory septic shock were enrolled as 'cases'. Their apparently healthy siblings, and apparently healthy children from immunization clinic, were enrolled as 'controls'. The whole blood total thiamine (WBTT) level was measured on days 1, 10 and 1 month after hospital discharge. Seventy-six children were enrolled as cases, 51 children as sibling controls and 35 children as immunization clinic controls. WBTT was significantly lower on day 1 in cases as compared with their sibling controls. It fell further on day 10. The level rose significantly after a month of discharge and became comparable to sibling controls. Immunization clinic controls also had lower WBTT but was significantly higher compared with sibling controls and cases at 1-month post-discharge. Survivors and non-survivors of septic shock had similar WBTT levels. Observed severe deficiency might have precluded any further association of thiamine levels with septic shock outcome.

Escherichia coli infected scalp abscess with osteomyelitis following a cephalhaematoma in a neonate.

We discuss an illustrative case of Escherichia coli infected scalp abscess with osteomyelitis following a cephalhaematoma in a 19-day-old neonate. Cephalhaematoma is a common occurrence in neonates after prolonged labour, instrument-assisted, and traumatic deliveries and resolves spontaneously in the majority of cases. Infection may follow haematogenous dissemination or direct inoculation via a skin breach. Complications such as scalp abscess, sepsis, and osteomyelitis of the skull present with local signs, including increasing size, local erythema and tenderness, and fluctuant swelling.

Electroclinical Landscape of Infantile Epileptic Spasms Syndrome.

OBJECTIVES: To elucidate the electroclinical characteristics of infantile epileptic spasms syndrome (IESS) and to determine any potential association among these with underlying etiologies and response to therapy. METHODS: Sixty-eight, treatment-naive children with IESS underwent long-term video electroencephalogram (EEG) recording, which was used to characterize the semiology, ictal, and inter-ictal EEG patterns. Children were further followed up to assess electroclinical predictors of etiologies and short-term therapeutic response. RESULTS: Of 68 children enrolled (69% boys), the median age at enrollment was 10.5 mo (IQR-8). Eighty-eight percent of children had flexor spasms, followed by mixed (7%) and extensor (4.4%). Asymmetrical spasms were noted in 17.6% children, and all of them had underlying structural etiology. Two children had the status of epileptic spasms. In the present cohort, authors recognized five distinct ictal EEG correlates of epileptic spasms; the frontocentral dominant slow wave was the most prevalent (32%), followed by the generalized slow-wave complex with superimposed fast rhythm in 29.4%. The occipital dominant slow wave complex was a peculiar pattern in 16%. The major underlying etiologies were hypoxic-ischemic brain injuries (36.7%) and neonatal hypoglycemic brain injuries (22%). Besides asymmetric spasms, authors could not identify any significant association among electroclinical characteristics, underlying etiologies and response to therapy in this study. CONCLUSIONS: The electroclinical landscape of IESS is peculiar and diverse in developing countries. The presence of asymmetrical spasms indicated underlying structural etiology.

Clinical outcomes and Anti-MOG antibodies in pediatric optic neuritis: A prospective observational study.

OBJECTIVES: The objective of this study was to look at the clinical outcomes, and to determine the proportion of children with visual recovery after the first demyelinating event of optic neuritis (ON). METHODOLOGY: In this observational study, children with the first clinical event of optic neuritis at an age less than 18 years were evaluated. High-contrast visual acuity, colour vision, Expanded Disability Status Scale (EDSS), Anti-MOG and AQP-4 antibodies were assessed. RESULTS: Of the 55 screened, 45 children (77 eyes), median age-98 months, 30 (67%) bilateral were enrolled. Fifty of 77 eyes (67%) had Snellen visual acuity less than 6/60. Twelve children (27%) were MOG seropositive and 3 had AQP-4 positivity. At median follow up of 35 months, 10 (22%) children had one or more relapses. At follow up, the median (IQR) visual acuity improved from nadir of 2.1 (1-2.7) logMAR to 0 (0-0.18) logMAR and 64/77 eyes (83%) had visual recovery. The diagnosis at last follow up was isolated ON in 39/45 (86.6%), relapsing ON (5, 11%), AQP-4 positive NMOSD (3, 7%), MOG antibody associated demyelination (12, 27%), dual seronegative ON (30,67%) and Multiple sclerosis (1, 2%). CONCLUSIONS: Most children with first demyelinating event as ON have a monophasic illness. Despite severe acute-phase visual loss, most eyes with ON will recover good visual functions. The risk of AQP-4 disease and multiple sclerosis is low in this group.

The profile of epilepsy and its characteristics in children with neurocutaneous syndromes.

Objectives: The profile of seizures in neurocutaneous syndromes is variable. We aimed to define the characteristics of epilepsy in children with neurocutaneous syndromes. Materials and Methods: Cross-sectional study over 18 months at a tertiary care pediatric hospital, including children with neurocutaneous syndromes aged between 1 and 15 years, using the 2017-International League Against Epilepsy classification. Results: In 119 children with neurocutaneous syndromes, 94 (79%) had epilepsy. In eight children with neurofibromatosis one with epilepsy, 5 (62.5%) had generalized motor tonic-clonic seizures, 1 (12.5%) had generalized motor epileptic spasms, 1 (12.5%) had generalized motor automatism, and 1 (12.5%) had a focal seizure. In 69 children with tuberous sclerosis complex with epilepsy, 30 (43.5%) had generalized motor epileptic spasms, 23 (33.3%) had focal seizures, and nine (13.0%) had generalized motor tonic-clonic seizures. In 14 children with Sturge-Weber syndrome with epilepsy, 13 (92.8%) had focal seizures, and 1 (7.2%) had generalized motor tonic seizures. Statistically significant associations were found between epilepsy and intellectual disability (P = 0.02) and behavioral problems (P = 0.00). Conclusion: Profiling seizures in children with neurocutaneous syndromes are paramount in devising target-specific treatments as the epileptogenesis in each syndrome differs in the molecular pathways leading to the hyperexcitability state. Further multicentric studies are required to unravel better insights into the epilepsy profile of neurocutaneous syndromes.