The cyclin-dependent kinase-like 5 deficiency disorder (CDD) is an ultrarare X-linked disorder causing early-onset epileptic encephalopathy and severe developmental deficits. Few studies exist on its electroclinical features, outcomes, sex differences, and neuroimaging, particularly from India. This study aims to describe the electroclinical syndrome, developmental profile, radiological findings, and outcomes in patients with CDD and to compare these factors between males and females. This is a hospital-based observational study of patients diagnosed with CDD identified from a prospectively maintained registry of children with developmental and epileptic encephalopathy. Data on demographics, seizure types, epilepsy syndromes, antiseizure medications, electroencephalography findings, developmental assessments, genetic characteristics, brain magnetic resonance imaging, and outcomes were collected. We included 12 patients with pathogenic (9) and likely pathogenic (3) variants in cyclin-dependent kinase-like 5 (CDKL5), among whom seven were female. The mean age at onset of seizures was 5.95 ± 5.56 months and was higher for males than females (8.6 ± 7.23 vs 3.19 ± 2.47). The most common seizure types at onset were tonic seizures in 6 (50%) children and epileptic spasms in 4 (33.3%). Lennox-Gastaut syndrome and West syndrome were the most frequent epilepsy syndromes. The median number of seizures per person was 2.9, and the median number of antiseizure medications used was 6 during their lifetime. Magnetic resonance imaging revealed cerebral volume loss in 7 children and white matter lesions in 6. Severe developmental deficits, a Rett-like phenotype, and cortical visual impairment were observed in three-fourths of the children, and regression of milestones occurred in two-thirds. Repetitive motor behavior (P 0.0455) and regression (P 0.0101) were more common in females. CDD causes refractory epilepsy and severe developmental deficits irrespective of the sex of the patient, variant type, and treatment.

Infantile epileptic spasms syndrome (IESS) is a devastating developmental epileptic encephalopathy (DEE) and patients exhibit diffuse white matter alterations and structural remodeling. However, the correlation between these structural changes and brain network properties, or their effect on the efficacy of treatment outcomes in MRI non-lesional IESS patients is not clear. This retrospective study was conducted on IESS patients using fixel-based analysis (FBA) of diffusion MRI and graph theory analysis of structural connectivity, involving 26 non-lesional IESS patients aged 2 to 12 months and 120 age-matched controls. We further examined the differences between antiseizure medication (ASM) responders and non-responders within the IESS cohort. FBA was performed across three age groups (2-5, 6-7, and 8-12 months) to evaluate white matter integrity at the micro- and macroscale using fiber density (FD), fiber cross-section (FC), and combined fiber density and cross-section (FDC). Graph theory analysis was used to assess global and local network properties. When compared to the control group, IESS patients exhibited significantly lower FD, FC, and FDC across major white matter tracts, including the corticospinal tract, corpus callosum, superior longitudinal fasciculus, optic radiations, and thalamic radiations (family-wise error-corrected, p < 0.05). Graph theory analysis revealed significant alterations in brain network properties, particularly in the age group of 2-5 months, where IESS patients exhibited a significantly lower mean clustering coefficient (p < 0.001, d = -0.74) and global efficiency (p = 0.001, d = -0.69. Small-world network analysis demonstrated a shift toward a more randomized network structure in IESS patients, particularly in the age group of 6-7 months (p = 0.001, d = -0.6182). In the secondary analysis, ASM treatment responders showed higher FD values in regions critical for seizure control, such as the hippocampus. Meanwhile, the ASM treatment non-responders exhibited increased FC in areas such as the pons and brainstem. Although subgroup differences did not achieve statistical significance, trends suggest that white matter integrity and network organization may influence treatment outcomes. The results highlight widespread changes in white matter integrity and network connectivity in non-lesional IESS patients, with preliminary evidence suggesting a relationship between structural brain differences and treatment responsiveness. These findings underscore the potential of advanced neuroimaging analyses to guide personalized interventions in IESS. TBCK-related neurodevelopmental disorder (TBCK-NDD) is typically a progressive condition in which individuals have significant developmental and respiratory issues. A majority of affected individuals do not achieve independent ambulation or spoken language. Most affected individuals also have congenital and severe hypotonia, which can also lead to feeding issues and dysphagia, with many affected individuals requiring gastrostomy tube placement. Neuromuscular weakness usually affects the distal muscles first, leading to distal muscle wasting, and then the proximal muscles become involved. Electrophysiologic studies suggest that weakness is secondary to a motor neuronopathy. Respiratory issues are also progressive, with most affected individuals requiring noninvasive nocturnal respiratory support by age five years and about 75% of teenagers requiring a tracheostomy. Seizures are also common, and brain MRI imaging may show white matter lesions and progressive cortical atrophy over time. Most affected individuals exhibit some degree of developmental regression and/or neurologic decompensation in the setting of illness, which often raises clinical concerns for mitochondrial disorders. Other features include vision issues (including optic atrophy), the development of contractures and neuromuscular scoliosis, coarsening of facial features over time, recurrent nephrolithiasis and/or urinary tract infections, dyslipidemia without clear adverse cardiovascular events, and the development of left ventricular hypertrophy. The diagnosis of TBCK-NDD is established in a proband with suggestive findings and biallelic pathogenic variants in TBCK identified by molecular genetic testing. Treatment of manifestations: Gastrostomy tube placement may be required for ongoing feeding issues and/or dysphagia. Nocturnal ventilatory support and/or tracheostomy may be required for those who have apnea and/or progressive neuromuscular weakness. Standard treatment for developmental delay / intellectual disability / neurobehavioral issues, epilepsy, neuromuscular weakness, spasticity/contractures, growth deficiency, bowel dysfunction, pancreatitis, osteopenia / frequent fractures, eye/vision issues, left ventricular hypertrophy, recurrent urinary tract infections, nephrolithiasis, and neurogenic bladder. No treatment is typically necessary for macroglossia. It remains unclear if treatment of dyslipidemia has a clinically meaningful impact. Surveillance: At each visit: measure growth parameters and evaluate nutritional status and safety of oral intake; monitor for constipation and signs/symptoms of pancreatitis; monitor for signs/symptoms of chronic respiratory insufficiency, nocturnal hypoventilation, and apnea; assess for new manifestations, such as seizures, changes in tone, and weakness; monitor those with seizures as clinically indicated; assess for developmental progress and educational needs; assess for neurobehavioral concerns; and assess for progressive contractures and bony fractures. Annually or as clinically indicated: ophthalmology evaluation. Every one to two years: complete lipid panel; echocardiogram to assess for left ventricular hypertrophy (if symptomatic; or starting in adolescence). Every two to three years: DXA scan to evaluate for osteopenia. Based on clinical concern: sleep study; evaluation for urinary tract infections, neurogenic bladder, and nephrolithiasis. Agents/circumstances to avoid: Some affected individuals have been reported to have adverse effects to bisphosphonate infusions for management of osteoporosis. The frequency and mechanism of this observation in the TBCK-NDD population remain unclear, so close monitoring is advised if bisphosphonates are clinically indicated. TBCK-NDD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a TBCK pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the TBCK pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Seizures occur in approximately one-third of children with cerebral palsy. This study aimed to determine epilepsy syndromes in children with seizures and cerebral palsy due to vascular injury, anticipating that this would inform treatment and prognosis. We studied a population-based cohort of children with cerebral palsy due to prenatal or perinatal vascular injuries, born 1999-2006. Each child's MRI was reviewed to characterize patterns of grey and white matter injury. Children with syndromic or likely genetic causes of cerebral palsy were excluded, given their inherent association with epilepsy and our aim to study a homogeneous cohort of classical cerebral palsy. Chart review, parent interview and EEGs were used to determine epilepsy syndromes and seizure outcomes. Of 256 children, 93 (36%) had one or more febrile or afebrile seizures beyond the neonatal period and 87 (34%) had epilepsy. Children with seizures were more likely to have had neonatal seizures, have spastic quadriplegic cerebral palsy and function within Gross Motor Function Classification System level IV or V. Fifty-six (60%) children with seizures had electroclinical features of a self-limited focal epilepsy of childhood; we diagnosed these children with a self-limited focal epilepsy-variant given the current International League Against Epilepsy classification precludes a diagnosis of self-limited focal epilepsy in children with a brain lesion. Other epilepsy syndromes were focal epilepsy-not otherwise specified in 28, infantile spasms syndrome in 11, Lennox-Gastaut syndrome in three, genetic generalized epilepsies in two and febrile seizures in nine. No epilepsy syndrome could be assigned in seven children with no EEG. Twenty-one changed syndrome classification during childhood. Self-limited focal epilepsy-variant usually manifested with a mix of autonomic and brachio-facial motor features, and occipital and/or centro-temporal spikes on EEG. Of those with self-limited focal epilepsy-variant, 42/56 (75%) had not had a seizure for >2 years. Favourable seizure outcomes were also seen in some children with infantile spasms syndrome and focal epilepsy-not otherwise specified. Of the 93 children with seizures, at last follow-up (mean age 15 years), 61/91 (67%) had not had a seizure in >2 years. Children with cerebral palsy and seizures can be assigned specific epilepsy syndrome diagnoses typically reserved for normally developing children, those syndromes commonly being age-dependent and self-limited. Compared to typically developing children with epilepsy, self-limited focal epilepsy-variant occurs much more commonly in children with cerebral palsy and epilepsy. These findings have important implications for treatment and prognosis of epilepsy in cerebral palsy, and research into pathogenesis of self-limited focal epilepsy.

Alexander disease (AxD) is classified into AxD type I (infantile) and AxD type II (juvenile and adult form). We aimed to determine the potential genetic cause(s) contributing to the AxD type II manifestations in a 9-year-old male who presented area postrema-like syndrome and his vomiting and weight loss improved after taking prednisolone. A normal cognitive 9-year-old boy with persistent nausea, vomiting, and a significant weight loss at the age of 6 years was noticed. He also experienced an episode of status epilepticus with generalized atonic seizures. He showed non-febrile infrequent multifocal motor seizures at the age of 40 days which were treated with phenobarbital. He exhibited normal physical growth and neurologic developmental milestones by the age of six. Occasionally vomiting unrelated to feeding was reported. Upon examination at 9 years, a weak gag reflex, prominent drooling, exaggerated knee-deep tendon reflexes (3+), and nasal tone speech was detected. All gastroenterological, biochemical, and metabolic assessments were normal. Brain magnetic resonance imaging (MRI) revealed bifrontal confluent deep and periventricular white matter signal changes, fine symmetric frontal white matter and bilateral caudate nucleus involvements with garland changes, and a hyperintense tumefactive-like lesion in the brain stem around the floor of the fourth ventricle and area postrema with contrast uptake in post-contrast T1-W images. Latter MRI at the age of 8 years showed enlarged area postrema lesion and bilateral middle cerebellar peduncles and dentate nuclei involvements. Due to clinical and genetic heterogeneities, whole-exome sequencing was performed and the candidate variant was confirmed by Sanger sequencing. A de novo heterozygous mutation, NM_001242376.1:c.262 C > T;R88C in exon 1 of the GFAP (OMIM: 137,780) was verified. Because of persistent vomiting and weight loss of 6.0 kg, prednisolone was prescribed which brought about ceasing vomiting and led to weight gaining of 3.0 kg over the next 3 months after treatment. Occasional attempts to discontinue prednisolone had been resulting in the reappearance of vomiting. This study broadens the spectrum of symptomatic treatment in leukodystrophies and also shows that R88C mutation may lead to a broad range of phenotypes in AxD type II patients.

Neonatal hypoxic-ischemic encephalopathy is still a significant cause of neonatal death and neurodevelopmental disabilities, such as cerebral palsy, mental delay, and epilepsy. After the introduction of therapeutic hypothermia, the prognosis of hypoxic-ischemic encephalopathy has improved, with reduction of death and disabilities. However, few studies evaluated whether hypothermia affects rate and severity of postneonatal epilepsy. We evaluated rates, characteristics and prognostic markers of postneonatal epilepsy in infants with moderate to severe hypoxic-ischemic encephalopathy treated or not with therapeutic hypothermia. We analyzed clinical data, EEG recordings, cerebral Magnetic Resonance Imaging (MRI) and outcome in 23 cooled and 26 non-cooled asphyxiated neonates (≥36 weeks' gestation), admitted from 2004 to 2012. Among 49 neonates 11 (22%) had postneonatal epilepsy, of which 9 (18%) were non-cooled and 2 (4%) were cooled (P=0.05). Six of 11 infants (55%) had West syndrome, 4 (36%) had focal epilepsy and 1 (9%) had Lennox-Gastaut Syndrome. At multiple logistic regression analysis MRI pattern significantly correlated with postneonatal epilepsy (OR 0.19, 95% CI 0.04-0.88, P=0.03). Extensive lesions in basal ganglia and thalami plus cortical and white matter were associated with postneonatal epilepsy. Only perinatal asphyxia with extensive lesions in basal ganglia and thalami plus cortical and white matter lesion conveys a high risk for early and severe postneonatal epilepsy. Moreover, therapeutic hypothermia is associated with a decrease of the risk of developing postneonatal epilepsy.