Low glycemic index therapy in children with sub-acute sclerosing panencephalitis (SSPE): an experience from a measles-endemic country.

Introduction: Sub-acute sclerosing panencephalitis (SSPE) is a chronic, progressive neurodegenerative disorder, commonly seen in measles-endemic countries leading to progressive neuronal loss and death. Currently, there is no proven cure for this devastating disease. We started a low glycemic index therapy (LGIT) in children with SSPE using the same principle as per its role in intractable epilepsy. Methodology: Low glycemic index diet was started in children with a confirmed diagnosis of SSPE based on Dyken's criteria. All children were then classified into four stages according to disease progression. The response to diet was evaluated by improvement in their myoclonic jerks, motor activities, and changes in their stage of the disease. Results: A total of 12 children were enrolled. The mean age was 6.65 years (range 3.3-10 years), with a male-to-female ratio of 2:1. Five children were at stage IV, five were at stage III, and two were at stage II at the start of the diet. Nine (75%) children showed improvement in their stage of illness. Of three children who were at stage IV at the initiation of the diet, one improved to stage II and two to stage III. Four children at stage III reverted to stage II. Two children initiated at stage II went into total remission. Seven (58.3%) children showed a >50% reduction in myoclonic jerks with three (25%) having a 100% reduction. Three (25%) children died due to pneumonia. Conclusion: LGIT may play an effective role in the management of SSPE and gives hope to families having children with this potentially life-threatening disease.

Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders.

Genetic variants in chromatin regulators are frequently found in neurodevelopmental disorders, but their effect in disease etiology is rarely determined. Here, we uncover and functionally define pathogenic variants in the chromatin modifier EZH1 as the cause of dominant and recessive neurodevelopmental disorders in 19 individuals. EZH1 encodes one of the two alternative histone H3 lysine 27 methyltransferases of the PRC2 complex. Unlike the other PRC2 subunits, which are involved in cancers and developmental syndromes, the implication of EZH1 in human development and disease is largely unknown. Using cellular and biochemical studies, we demonstrate that recessive variants impair EZH1 expression causing loss of function effects, while dominant variants are missense mutations that affect evolutionarily conserved aminoacids, likely impacting EZH1 structure or function. Accordingly, we found increased methyltransferase activity leading to gain of function of two EZH1 missense variants. Furthermore, we show that EZH1 is necessary and sufficient for differentiation of neural progenitor cells in the developing chick embryo neural tube. Finally, using human pluripotent stem cell-derived neural cultures and forebrain organoids, we demonstrate that EZH1 variants perturb cortical neuron differentiation. Overall, our work reveals a critical role of EZH1 in neurogenesis regulation and provides molecular diagnosis for previously undefined neurodevelopmental disorders.

Paediatric posterior reversible encephalopathy syndrome: is there an association of blood pressure with imaging severity and atypical magnetic resonance characteristics?

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is relatively uncommon in paediatric patients; however, its pathophysiology remains obscure. OBJECTIVE: The aims of this study were to find an association or correlation between (1) blood pressures and (2) imaging severity and the presence of atypical imaging features in children with PRES. MATERIALS AND METHODS: We performed a retrospective cross-sectional evaluation in children diagnosed with PRES. We reviewed radiologic findings along with each patient's clinical profile and outcome. We categorised imaging severity into mild, moderate and severe, and assessed the MR imaging pattern, enhancement and diffusion restriction for each child. We assessed both associations and correlations between variables using the chi-square test, Cramer V and Kendall tau b. RESULTS: A total of 63 children met the inclusion criteria (31 boys; mean age 9.7 years). A total of 42 children (67%) had an elevated blood pressure. Imaging showed parieto-occipital lobe involvement pattern in 24 (38%) children, frontal lobe pattern in 25 (40%) and cerebellar involvement in 12 (19%). Three (5%) had haemorrhage, 15 (24%) had contrast enhancement and 19 (30%) had positive diffusion restriction (cytotoxic oedema). We found no statistically significant association between imaging severity and blood pressures (P=0.11), nor any association between blood pressure and atypical imaging findings such as diffusion restriction (P=0.1), enhancement (P=0.11) or haemorrhage (P=0.33). CONCLUSION: According to our results, there is no statistically significant association or correlation between blood pressure and either imaging severity or atypical imaging features in children with PRES. Further prospective studies are warranted.

Concentrations of Lead, Mercury, Arsenic, Cadmium, Manganese, and Aluminum in the Blood of Pakistani Children with and without Autism Spectrum Disorder and Their Associated Factors.

BACKGROUND: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with early onset in utero or childhood. Environmental exposure to six metals (Pb, Hg, As, Cd, Mn, Al) is believed to be associated with ASD directly or interactively with genes. Objective: To assess the association of ASD among Pakistani children with the six metals and genotype frequencies of three GST genes (GSTP1, GSTM1, GSTT1). METHODS: We enrolled 30 ASD cases, age 2-12 years old, and 30 age- and sex-matched typically developing (TD) controls in Karachi, Pakistan. We assessed associations of ASD status with various factors using Conditional Logistic Regression models. We also used General Linear Models to assess possible interaction of blood Mn and Pb concentrations with the three GST genes in relation to ASD status. RESULTS: The unadjusted difference between ASD and TD groups in terms of geometric mean blood Pb concentrations was marginally significant (p = 0.05), but for Al concentrations, the adjusted difference was marginally significant (p = 0.06). CONCLUSIONS: This is the first study reporting six blood metal concentrations of Pakistani children with ASD. Estimates provided for possible interactions of GST genes with Mn and Pb in relation to ASD status are valuable for designing future similar studies.

Acute Necrotizing Encephalopathy.

OBJECTIVE: To describe the clinical profile of pediatric patients with acute necrotizing encephalopathy (ANE). STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Aga Khan University Hospital, Karachi, Pakistan, from January 2014 to October 2017. METHODOLOGY: Retrospective review of medical records of all children aged 1 month to 16 years admitted with diagnosis of ANE was done. Diagnosis was based on the criteria of ANE described by Mizuguchi et al. the clinical profile, management and outcome were recorded. RESULTS: There were 17 patients. The mean age at presentation was 55.47 ± 59.13 months. The most common presentation was fever with altered consciousness and seizures. The mean length of stay was 11.7 ± 5.6 days. Viral etiology was established in three children. The managements of the patients were symptomatic and supportive; the combination of antibiotics, antivirals and anticonvulsants was the most frequently used regimen. Eleven out of seventeen (65%) patients required intensive care unit admission and mechanical ventilation; while others were managed in the special care unit. Three (17.6%) children died during the stay; while 10 (58.8%) children developed severe morbidity in the form of neurodevelopmental sequelae. CONCLUSION: The devastating outcome of ANE seemed to occur with increasing severity at the time of initial presentation; and the use of antivirals and immunomodulation did not alter the course of disease.

Infantile Spasms: Clinical profile and treatment outcomes.

BACKGROUND AND OBJECTIVE: Infantile spasm (IS) is one of the severe epileptic encephalopathies which affect children in early two years of life. Our objective was to determine the clinical profile, etiology and outcome of treatment in children with infantile spasms attending tertiary care hospital at Karachi, Pakistan. METHODS: This is retrospective study of 36 patients out of 94 registered as IS, aged three months to two years, managed and followed up at Aga Khan University Hospital, Karachi, from 2010 to 2015. Data of all children with IS was collected from case record. Details including clinical observations, lab investigations, anti-epileptic medications and treatment outcome was collected and analyzed. Patients who received treatment for six weeks to document response were included. The treatment response was categorized as complete response, partial response (>50% improvement) and no response. Data was analyzed on SPSS using descriptive statistics. RESULTS: Thirty- six patients (38.29%) with IS fulfilled eligibility criteria. The mean ± SD age at presentation was 4.6±2.1 months. Male to female ratio was 2:1. Consanguinity and developmental motor delay was observed in 66.6% and 89% respectively. Symptomatic etiology was predominant (61%) and hypoxic ischemic insult (32%) was the commonest underlying cause. EEG and MRI were diagnostic tools whereas metabolic studies were not helpful. Multiple antiepileptic drugs were used for seizure control and vigabatrin was the most frequently used (88%) drug. Short term treatment response was not different in idiopathic or symptomatic infantile spasms. CONCLUSION: Majority of patients had symptomatic infantile spasms and generalized tonic clonic along with myoclonic jerks were predominant seizure types. EEG and MRI were diagnostic in most of cases. Multiple AEDs were required to control seizures and VGB was most common drug (88%) used. Treatment outcome was not different in idiopathic and symptomatic groups.

Subacute sclerosing panencephalitis - current perspectives.

Subacute sclerosing panencephalitis is a progressive neurodegenerative disease. It usually occurs 7-10 years after measles infection. The clinical course is characterized by progressive cognitive decline and behavior changes followed by focal or generalized seizures as well as myoclonus, ataxia, visual disturbance, and later vegetative state, eventually leading to death. It is diagnosed on the basis of Dyken's criteria. There is no known cure for subacute sclerosing panencephalitis to date, but it is preventable by ensuring that an effective vaccine program for measles is made compulsory for all children younger than 5 years in endemic countries.

Adrenal insufficiency in a child with MELAS syndrome.

Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) are established subgroups of mitochondrial encephalomyopathy. m.3243A>G a common point mutation is detected in tRNA in majority of patients with MELAS phenotype whereas m.8344A>G point mutation in tRNA is observed, in MERRF phenotype. Adrenal insufficiency has not been reported in mitochondrial disease, except in Kearns-Sayre Syndrome (KSS), which is a mitochondrial deletion syndrome. We report an unusual presentation in a five year old boy who presented with clinical phenotype of MELAS and was found to have m.8344A>G mutation in tRNA. Addison disease was identified due to hyperpigmentation of lips and gums present from early childhood. This is the first report describing adrenal insufficiency in a child with MELAS phenotype.

Prevalence of early childhood disability in a rural district of Sind, Pakistan.

AIM: Children born in low- and mid-income countries are at a high risk of developing disabilities, yet estimates of population-based prevalence are sparse. Our aim was to determine the prevalence of early childhood (0-5 year) disability in Sind, a rural area of Pakistan. METHOD: We conducted a cross-sectional household survey in a population of 25,196 households. The Ten Questions screen and the Signs of Disability in Newborn and Infants screen were used. RESULTS: The disability prevalence in a population of 176,364 individuals was 5.5 out of 1000 in children under 2 years and 5.4 out of 1000 in children aged 2-5 years. Fifty-six per cent were males, and 56% had the disability recognized from birth or soon after. The mortality rate of children aged 0-5 years in the area was estimated as 30 out of 1000 live births. Cerebral palsy was the most common disability identified. The Ten Questions screen had better interrater agreement than the Signs of Disability in Newborn and Infants screen. INTERPRETATION: This is the largest reported household screening survey for early childhood disability at a population level from rural Pakistan. The comparatively low prevalence may be due to the younger age studied and high early childhood mortality. Our data highlight the importance of prospective surveillance at a population level and the need for preventive and support services.

Neurodevelopmental outcomes of premature infants at a tertiary care center in Pakistan.

The low gestational ages and morbidities of premature neonates in neonatal intensive care units exert a significant impact on neurodevelopmental outcomes. This longitudinal cohort study assessed the neurodevelopmental status of premature neonates after discharge from neonatal intensive care units in resource-limited countries such as Pakistan. Developmental assessment involved the Denver Development Screening Test II. One hundred and ten infants discharged from our neonatal intensive care unit completed follow-up at age 6 months. Overall developmental delay was evident in 32% of infants. Birth weight and gestational age exerted significant impacts on development. The mean gestational age of developmentally normal infants was 34 weeks, whereas that of delayed infants was 30.7 weeks (P < 0.01). The mean birth weight of developmentally normal infants was 2.17 kg vs 1.27 kg in delayed infants (P < 0.01). Neonates who developed complications such as respiratory distress syndrome, intraventricular hemorrhage, thrombocytopenia, hypoglycemia, hyponatremia, or hypothermia in neonatal intensive care units proved to be delayed at age 6 months (P < 0.05). Prematurity and its associated complications are linked to adverse neurodevelopmental outcomes.

Cerebral venous sinus thrombosis in neonates.

Neonatal Cerebrovenous sinus thrombosis(CVST) is extremely rare, however it is a devastating condition and one needs to be aware of this condition to diagnose it. The risk factors for CVST are still not properly understood. The largest registry for stroke and for neonatal CVST is from the Canadian registry which quotes an incidence of 0.6 per 100,000 population per year. No data is present for the neonatal CVST in this region. One needs to be aware of this devastating condition to manage it timely and appropriately. To date there is no consensus on the role of anticoagulant therapy and therefore therapy is largely supportive, however individual cases have to be evaluated and treated on merit.

A 15-year-old boy with central nervous system vasculopathy presenting with dysarthria-clumsy hand syndrome.

Dysarthria-clumsy hand stroke syndrome has been described frequently in adults but not in children. We report a 15-year-old right-handed boy with sudden onset of dysarthria, dysphagia, right facial weakness, and mild right-hand clumsiness. Computed tomographic scan and magnetic resonance imaging demonstrated infarction in the genu and posterior limb of the left internal capsule. Magnetic resonance angiography and conventional angiography demonstrated stenosis of the supraclinoid portion of the left internal carotid artery and the origin of the left ophthalmic artery. Lacunar infarction in an older adult is not the only mechanism leading to dysarthria-clumsy hand syndrome.