Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies.

Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies.

Survey of Pediatric Status Epilepticus Treatment Practices and Adherence to Management Guidelines (Pedi-SPECTRUM e-Survey).

Aim: Survey of treatment practices and adherence to pediatric status epilepticus (PSE) management guidelines in India. Methods: This eSurvey was conducted over 35 days (15th October to 20th November 2023) and included questions related to hospital setting; antiseizure medications (ASMs); ancillary treatment; facilities available; etiology; and adherence to PSE management guidelines. Results: A total of 170 respondents participated, majority of them were working in tertiary level hospitals (94.1%) as pediatric intensivists (56.5%) and pediatricians (19.4%), and were in clinical practice for 2-10 years (46.5%). Majority use intravenous (IV) midazolam and levetiracetam as first- and second-line ASMs (67.1 and 51.2%, respectively). In cases with refractory status epilepticus (RSE), the most commonly used ASM is midazolam infusion (92.4%). For super-refractory status epilepticus (SRSE), the commonly used third-line ASMs include midazolam infusion (34.1%), thiopentone infusion (26.5%), high dose phenobarbitone (18.2%), and ketamine infusion (15.3%). Overall, in cases with SRSE, 44.7% respondents use ketamine infusion, 42.5% use add-on oral topiramate, and 34.7% use high-dose phenobarbitone (1-3 mg/kg/hour) infusion. Most respondents targeted both clinical and EEG seizure control (48.8%). Ancillary treatment used for SRSE included IV pyridoxine (57.1%), methylprednisolone (45.3%), IVIG (42.4%), ketogenic diet (40.6%), and second-line immunomodulation (33.5%). Most common causes were febrile SE, viral encephalitis, and febrile illness-related epilepsy syndrome (60.6%, 52.4%, and 37.1%, respectively). Facilities available included pediatric intensive care units (PICU) (97.1%), mechanical ventilation (98.2%), pediatric neurologist (68.8%), MRI brain (86.5%), EEG (69.4%), and viral PCR (58.2%). The compliance with guidelines for timing of initiation of ASM ranged from 63.5 to 88.8%. Conclusion: Intravenous midazolam bolus/es, levetiracetam, and midazolam infusion are commonly used first-, second-, and third-line ASMs, respectively. There were wide variations in use of ASMs for RSE and SRSE, ancillary treatment, and compliance to PSE management guidelines. How to cite this article: Suthar R, Angurana SK, Nallasamy K, Bansal A, Muralidharan J. Survey of Pediatric Status Epilepticus Treatment Practices and Adherence to Management Guidelines (Pedi-SPECTRUM e-Survey). Indian J Crit Care Med 2024;28(5):504-510.

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.

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.

MR vessel wall imaging in cerebral bacterial and fungal infections.

PURPOSE: Central nervous system (CNS) bacterial and fungal infections can cause secondary vasculitis which worsens the prognosis due to development of complications like infarctions or hemorrhages. In this prospective study, we aim to study intracranial vessel wall imaging findings in bacterial and fungal infections. METHODS: We included 12 cases of nontubercular bacterial and fungal CNS infections each, in whom definitive microbiological diagnosis could be made. High-resolution vessel wall imaging (VWI) and time of flight MR angiography (TOF MRA) were incorporated in the routine imaging protocol. All cases were evaluated for the presence of vascular enhancement, pattern of enhancement, and stenosis on VWI. Statistical analysis was done to evaluate association between findings of vessel wall imaging and infarctions. RESULTS: We found infarctions in 5 out of 12 cases (41.7%) of the bacterial group and 7 out of 12 cases (58.3%) of the fungal group. Vessel wall enhancement was seen in 5 cases (41.7%) of the bacterial group and 9 cases (75%) of the fungal group. There was a significant association between infarctions and vessel wall enhancement in the fungal group. However, pattern of enhancement or stenosis on VWI was not significantly associated with presence of infarction. VWI detected more cases of vascular involvement than TOF MRA. CONCLUSION: Secondary infectious vasculitis in bacterial and fungal infections can be detected by VWI, which can play an important role in better patient management as detection of vascular involvement can prompt early treatment to prevent complications like infarctions or hemorrhages.

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.

Aetiological Profile and Short-Term Neurological Outcome of Haemorrhagic Stroke in Children.

BACKGROUND: Haemorrhagic stroke (HS) accounts for nearly half of the paediatric strokes. The aetiology of HS in childhood is not well defined in the Indian context. OBJECTIVES: To study the aetiological profile and short-term neurological outcome of children with HS from North India. METHODS: In a prospective observational study, consecutive patients >28 days to <12 years of age admitted with a diagnosis of HS were enrolled. Demography, clinical, radiological details and investigations were recorded. Short-term outcomes were assessed at three months follow-up with the Paediatric Cerebral Performance Category scale and Paediatric Stroke Outcome Measure (PSOM). RESULTS: A total of 48 children with HS were enrolled. The median age was 6 months (1-58 months), and 33 (69%) were <2 years old. Vitamin K deficiency-related bleeding disorder (VKDB, 44%), central nervous system infections (19%), arteriovenous malformations (13%) and inherited coagulation disorders (8%) were the most common risk factors for HS. VKDB and inherited coagulation disorders were more frequent in children <2 years of age, and arteriovenous malformations were more frequent in children >2 years of age (p = 0.001). During hospitalization, 21 (44%) children died. Older age, low Glasgow coma score (<8) at admission and paediatric intracerebral haemorrhage score ≥2 were associated with mortality at discharge (p = <0.05). Among survivors, 15 (56%) children had neurological deficits (PSOM >0.5) at three month follow-up. CONCLUSION: VKDB, inherited coagulation disorders, central nervous system infections and arteriovenous malformations were the most common risk factors for HS. VKDB is the single most important preventable risk factor for HS in infants.

Effect of early withdrawal of phenobarbitone on the recurrence of neonatal seizures: An open-label randomized controlled trial.

BACKGROUND: The long-term administration of phenobarbitone in neonates may be associated with adverse neurological outcome. The timing of stopping phenobarbitone maintenance after acute seizure control in neonates is a matter of debate. OBJECTIVES: To study the effect of early withdrawal of phenobarbitone on recurrence of neonatal seizures. STUDY DESIGN: Open-label randomized controlled trial. PARTICIPANTS: Outborn neonates (≥34 weeks of gestation to <28 days of postnatal period) with seizures (n = 221) admitted to Neonatal unit in Pediatric emergency of a tertiary care hospital in north India over 1 year. INTERVENTION: After a loading dose of phenobarbitone (20 mg/kg), neonates who remained seizure free for at least 12 h were enrolled after written informed consent from parents, and randomized (computer generated block randomization) to 'phenobarbitone withdrawal group' (n = 112) where phenobarbitone maintenance was stopped and 'phenobarbitone continued group' (n = 109) where phenobarbitone maintenance was continued until discharge and further as per clinician's discretion. OUTCOMES: The primary outcome was seizure recurrence until discharge and secondary outcomes were time to reach full enteral feeds, duration of hospital stay, abnormal neurological status at discharge, and mortality in two groups. RESULTS: The baseline variables were comparable in 2 groups. The incidence of seizure recurrence was similar in the phenobarbitone withdrawal and phenobarbitone continued groups (50% vs. 37.6%, respectively, p = 0.078). Among secondary outcomes, the phenobarbitone withdrawal and continued groups had similar time to reach full enteral feeds (4.02 days vs. 4.2 days, p = 0.75), duration of hospital stay (6.3 days vs. 6.5 days, p = 0.23), abnormal neurological status at discharge (45.6% vs. 38%, p = 0.39), and mortality (11.6% vs. 8.3%, p = 0.50). CONCLUSION: Early withdrawal of phenobarbitone in neonatal seizures does not lead to a significant increase in the rate of seizure recurrence.

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.

Efficacy and Safety of Levetiracetam vs. Phenytoin as Second Line Antiseizure Medication for Pediatric Convulsive Status Epilepticus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: To evaluate the efficacy and safety of levetiracetam (LEV) in comparison to phenytoin (PHT) as second line antiseizure medication (ASM) for Pediatric convulsive status epilepticus (SE). DATA SOURCE: PubMed, Embase, Google scholar/Google, Scopus, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials. STUDY SELECTION: Randomized controlled trials (RCTs) assessing LEV and PHT as second line agent for convulsive SE in children <18 years published between 1 January 2000 and 30 November 2020. DATA EXTRACTION: The data were pooled regarding the proportion of children achieving seizure cessation within 5-60 min of completion of study drug infusion (primary outcome); and seizure cessation within 5 min, time to achieve seizure cessation, seizure recurrence between 1 to 24 h, intubation and cardiovascular instability (secondary outcomes). Data were analyzed using RevMan version 5.4 and quality analysis was done using Cochrane risk-of-bias tool. The study protocol was registered with PROSPERO. DATA SYNTHESIS: Twelve RCTs with 2293 children were included. Seizure cessation within 5-60 min was similar with both the drugs [82% in LEV vs. 77.5% in PHT, risk ratio (RR) = 1.04, 95% confidence interval (95% CI) 0.97-1.11, p = 0.30]. Seizure recurrences within 1-24 h was higher with PHT in comparison to LEV (16.6% vs. 9.7%, RR = 0.63, 95% CI 0.44-0.90, p = 0.01). Higher proportion of children in PHT group required intubation and mechanical ventilation (21.4% vs. 14.2%, RR = 0.54, 95% CI 0.30-0.98, p = 0.04). Seizure cessation within 5 min, time to achieve seizure cessation, and cardiovascular instability were similar with both the drugs. Three RCTs were at low risk of bias and nine were at high risk of bias. CONCLUSION: The efficacy of LEV is similar to PHT as second line ASM for Pediatric convulsive SE. Seizure recurrences between 1 to24 h and requirement of intubation and mechanical ventilation were significantly higher with PHT in comparison to LEV.

Managing syndromic congenital ichthyosis at a tertiary care institute-Genotype-phenotype correlations, and novel treatments.

Syndromic congenital ichthyoses (CI) are genetically determined disorders of cornification that are characterized by generalized scaling along with systemic symptoms. Data on congenital syndromic ichthyosis from developing countries are scarce. We aimed to assess the prevalence, phenotype-genotype correlation, and management of syndromic CI patients presenting to our outpatient during the specified period this was a retrospective study of congenital syndromic ichthyosis patients attending a dermatology clinic in a tertiary care center from 2105-2018. We reviewed epidemiological and comorbidities data, phenotype-genotype correlations, and treatments of syndromic congenital ichthyosis patients. Six patients of Syndromic CI were diagnosedamongst 86 patients of CI (8.1%). Amongst these, three patients of Sjogren-Larrson syndrome (SLS), two patients of Netherton syndrome (NS), and one of Chanarin-Dorfman disease (CDD) were reported. Next-generation sequencing (NGS) was performed with novel variants reported in one patient each of SLS, NS, and CDD. An atypical phenotype was observed in a patient with NS with associated growth hormone and adrenocorticotropic hormone deficiency but with favorable clinical response to intravenous immunoglobulin. Our reports point towards the unreported pool of genetic mutations in CI from India. Novel mutations were associated with variable cutaneous and systemic involvement.