Correlation of brain cell glucose metabolism and patient's condition in children with epileptic encephalopathy An assessment using fluorine-18-fluoro-2-deoxy-D-glucose positron emission computed tomography

We examined a total of 16 children with epileptic encephalopathy using fluorine-18-fluoro-2-deoxy-D-glucose （18F-FDG） positron emission computed tomography （PET）, magnetic resonance imaging （MRI） and electroencephalography. Children with infantile spasms showed significant mental retardation, severely abnormal electroencephalogram recordings, and bilateral diffuse cerebral cortex hypometabolism with I^F-FDG PET imaging. MRI in these cases showed brain atrophy, multi-micropolygyria, macrogyria, and porencephalia. In cases with Lennox-Gastaut syndrome, 18F-FDG PET showed bilateral diffuse glucose hypometabolism, while MRI showed cortical atrophy, heterotopic gray matter and tuberous sclerosis. MRI in cases with myoclonic encephalopathy demonstrated bilateral frontal and temporal cortical and white matter atrophy and 18F-FDG PET imaging showed bilateral frontal lobe atrophy with reduced bilateral frontal cortex, occipital cortex, temporal cortex and cerebellar glucose uptake. In children who could not be clearly classified, MRI demonstrated cerebral cortical atrophy and ~aF-FDG PET exhibited multifocal glucose hypometabolism. Overall, this study demonstrated that the degree of brain metabolic abnormality was consistent with clinical seizure severity. In addition, ~SF-FDG PET imaging after treatment was consistent with clinical outcomes. These findings indicate that ~SF-FDG PET can be used to assess the severity of brain injury and prognosis in children with epileptic encephalopathy.

Developmental and epileptic encephalopathy 44 due to compound heterozygous variants in the UBA5 gene:a case report

Background Developmental and epileptic encephalopathy(DEE)is a group of rare inherited disorders characterized by intellectual disability,delayed development,epileptic seizures,and other related symptoms.DEE44 is caused by mutations in the UBA5 gene,which encodes a ubiquitin-like protein involved in protein degradation and cell signaling.However,there is limited information on the genotype–phenotype correlation of DEE44,and its clinical features remain to be fully characterized.Case presentation We report a 12-month-old infant who presented with epileptic spastic seizures beginning at 4 months of age,accompanied by overall developmental delay,short stature,microcephaly,inability to hold his head upright,chasing vision,and high muscle tone in the extremities.Genetic findings showed compound heterozygous mutations of the UBA5 gene:NM_024818 c.562C>T(p.R188X)from the mother and NM_024818 c.214C>T(p.R72C)from the father.Conclusions This case report expands the clinical spectrum of DEE44 and highlights the importance of considering DEE44 in the differential diagnosis of developmental delay and epilepsy,even in the absence of classical symptoms suggestive of the condition.We hope that this case report will advance the understanding of DEE44 and improve the expertise of clinicians and early diagnose of this disease.

Clinical Manifestations and Amplitude-integrated Encephalogram in Neonates with Early-onset Epileptic Encephalopathy

Background： The patients with early-onset epileptic encephalopathy （EOEE） suffer from neurodevelopmental delay. The aim of this study was to analyze the clinical manifestations and amplitude-integrated encephalogram （aEEG） characteristics of infants with EOEE with onset within the neonatal period, to make early diagnosis to improve the prognosis. Methods： One-hundred and twenty-eight patients with neonatal seizure were enrolled and followed up till 1 year old. Sixty-six neonates evolved into EOEE were as the EOEE group, the other 62 were as the non-EOEE （nEOEE） group. Then we compared the clinical and aEEG characteristics between the two groups to analyze the manifestations in neonates with EOEE. Results： Compared to the nEOEE group, the incidence of daily seizure attacks, more than two types of convulsions, more than two antiepileptic drugs （AEDs） application, severely abnormal aEEG background, absence of cyclicity, and more than two seizures detection were significantly higher in the EOEE group （P 〈 0.05） （97% vs. 54.8%; 30.3% vs. 14.5%; 97.0% vs. 25.4%; 39.4% vs. 3.2%; 57.6% vs. 9.7%; and 56% vs. 3.2%, respectively）. Severely abnormal background pattern （odds ratio [OR] = 0.081, 95% confidence interval [CI]：0.009-0.729, P = 0.025） and more than two seizures detection by aEEG （OR = 0.158, 95% CI： 0.043-0.576, P = 0.005） were the independent risk factors for the evolvement into EOEE. The upper and lower margins of active sleep （AS） and quiet sleep （QS） were significantly higher in EOEE group than those of the control group （P 〈 0.05） （34.3 ± 13.6 vs. 21.3 ± 6.4; 9.9 ± 3.7 vs. 6.7 ± 2.2; 41.2 ± 15.1 vs. 30.4 ± 11.4;and 11.9 ± 4.4 vs. 9.4 ± 4.0; unit： μV, respectively）. AS upper margin was demonstrated a higher diagnostic specificity and sensitivity for EOEE than another three parameters according to the receiver operating characteristic curves; the area under the curve was 0.827. Conclusions： The clinical characteristics of the neonatal seizure which will evolve into EOEE were more than two AEDs application, high seizure frequency （daily attack）, and more than two types of the seizure. Significant high voltage, severely abnormal background, absence of cyclicity, and more than two seizures detected on aEEG were the meaningful indicators to the prediction of EOEE.

Epileptic Encephalopathies in Infants and Children: Study of Clinico-Electroencephalographic Spectrum in a Tertiary Hospital in Bangladesh

Background: The epileptic encephalopathies collectively exact an immense personal, medical, and financial toll on the affected children, their families, and the healthcare system. Objective: This study was aimed to delineate the clinical spectrum of patients with Epileptic encephalopathies (EEs) and classify them under various epileptic syndromes. Methods: This was a cross-sectional study that was carried out in the department of Neurophysiology of the National Institute of Neurosciences and Hospital, Bangladesh from July 2016 to June 2019. Children with recurrent seizures which were difficult to control and associated with developmental arrest or regression in absence of a progressive brain pathology were considered to be suffering from EE. Children under 12 years of age fulfilling the inclusion criteria were enrolled in the study. These patients were evaluated clinically and Electroencephalography (EEG) was done in all children at presentation. Based on the clinical profile and EEG findings the patients were categorized under various epileptic syndromes according to International League Against Epilepsy (ILAE) classification 2010. Results: A total of 1256 children under 12 years of age were referred to the Neurophysiology Department. Among them, 162 (12.90%) fulfilled the inclusion criteria. Most of the patients were male (64.2%) and below 1 year (37.7%) of age. The majority (56.8%) were delivered at the hospital and 40.1% had a history of perinatal asphyxia. Development was age-appropriate before the onset of a seizure in 38.9% of cases. Most (53.7%) of the patients had seizure onset within 3 months of age. Categorization of Epileptic syndromes found that majority had West Syndrome (WS) (37.65%) followed by Lennox-Gastaut syndrome (LGS) (22.22%), Otahara syndrome (11.73%), Continuous spike-and-wave during sleep (CSWS) (5.66%), Myoclonic astatic epilepsy (MAE) (4.94%), Early myoclonic encephalopathy (EME) (3.7%), Dravet syndrome (3.7%) and Landau-Kleffner syndrome (LKS) (1.23%). 9.26% of syndromes were unclassified. Conclusion: EEG was found to be a useful tool in the evaluation of Epileptic encephalopathies. The clinico-electroencephalographic features are age-related. Their recognition and appropriate management are critical.

Ion channels in neurodevelopment:lessons from the Integrin-KCNB1 channel complex

Ion channels modulate cellular excitability by regulating ionic fluxes across biological membranes.Pathogenic mutations in ion channel genes give rise to epileptic disorders that are among the most frequent neurological diseases affecting millions of individuals worldwide.Epilepsies are trigge red by an imbalance between excitatory and inhibitory conductances.However,pathogenic mutations in the same allele can give rise to loss-of-function and/or gain-of-function va riants,all able to trigger epilepsy.Furthermore,certain alleles are associated with brain malformations even in the absence of a clear electrical phenotype.This body of evidence argues that the underlying epileptogenic mechanisms of ion channels are more diverse than originally thought.Studies focusing on ion channels in prenatal cortical development have shed light on this apparent paradox.The picture that emerges is that ion channels play crucial roles in landmark neurodevelopmental processes,including neuronal migration,neurite outgrowth,and synapse formation.Thus,pathogenic channel mutants can not only cause epileptic disorders by alte ring excitability,but further,by inducing morphological and synaptic abnormalities that are initiated during neocortex formation and may persist into the adult brain.

Is tuberous sclerosis complex-associated autism a preventable andtreatabledisorder?

Background Tuberous sclerosis complex(TSC)is a genetic disorder caused by inactivating mutations in the TSCl and TSC2 genes,causing overactivation of the mechanistic(previously referred to as mammalian)target of rapamycin(mTOR)signaling pathway in fetal life.The mTOR pathway plays a crucial role in several brain processes leading to TSC-related epilepsy,intellectual disability,and autism spectrum disorder(ASD).Pre-natal or early post-natal diagnosis of TSC is now possible in a growing number of pre-symptomatic infants.Data sources We searched PubMed for peer-reviewed publications published between January 2010 and April 2023 with the terms“tuberous sclerosis",“autism",or“autism spectrum disorder""animal models",“preclinical studies",“neurobiology",and“treatment".Results Prospective studies have highlighted that developmental trajectories in TSC infants who were later diagnosed with ASD already show motor,visual and social communication skills in the first year of life delays.Reliable genetic,cellular,electroencephalography and magnetic resonance imaging biomarkers can identify pre-symptomatic TSC infants at high risk for having autism and epilepsy.Conclusions Preventing epilepsy or improving therapy for seizures associated with prompt and tailored treatment strategies for autism in a sensitive developmental time window could have the potential to mitigate autistic symptoms in infants with TSC.

Revealing the complex role of CDKL5 in developmental epilepsy through a calcium channel related vision

Developmental and epileptic encephalopathies are severe neurological conditions in clinical practice,among which loss-of-function mutations in brain-enriched serine-threonine kinase cyclin dependent kinase like-5(CDKL5)exists as one of the most common types.It is unknown,therefore,how precisely CDKL5 mutations lead to neuronal hyper-excitation.A recent study that looked at the connection between voltage-gated calcium channel Cav2.3 and CDKL5 in an experimental context was published in Nature Communications.This study has revealed that Cav2.3,a physi-ological phosphorylation target of CDKL5,would show delayed inactivation and increased cholinergic stimulation in CDKL5 knock out conditions.This would in turn cause neuronal hyperexcitability and related enhanced seizure susceptibility.This work,in our opinion,provided fresh insight into the epileptic encephalopathies linked to CDKL5 and highlighted Cav2.3 as a possible target for it.

Long-term follow-up of vagus nerve stimulation in drug-resistant KCNT1-related epilepsy: a case presentation

Background The KCNT1 gene encodes a Na+-activated K+channel.Gain-of-function mutations of KCNT1 lead to autosomal dominant sleep-related hypermotor epilepsy,early-onset epileptic encephalopathy,focal epilepsy and other epileptic encephalopathies.In this paper,we report a boy carrying a KCNT1 gene mutation,who presented with drug-resistant focal-onset seizures.He had decreased seizure frequency and improvement of background changes in electroencephalography(EEG)after vagus nerve stimulation(VNS).Case presentation The case was a nonverbal 9-year-old male who presented with drug-resistant focal-onset seizures since age 3 and had underwent VNS therapy for 2 years.He had hypermotor symptoms,automatism and bilateral asymmetric tonic seizures with cognitive decline and aphasis from age 3.The patient had a variety of seizure types that only occurred at night.The most common seizure type was automatisms,and ictal video EEG showed high-amplitude delta waves,followed by a fast rhythmic sharp activity in the mesial frontal and bitemporal regions.The patient was diagnosed with KCNT1-related epilepsy,epileptic encephalopathy and cognitive disorder.He was refractory to multiple anti-seizure medicines(ASM)and ketogenic diet.After VNS treatment at age 7,the frequency of seizures was reduced significantly and EEG was improved in background slowing.Conclusions Children with KCNT1-related epilepsy usually have early onset of disease,are nonverbal,and are refractory to ASM.This boy with drug-resistant KCNT1-related epilepsy showed significantly reduced seizure frequency after VNS.This report may provide reference for management of cases of KCNT1-related epilepsy.

Gene variations of glutamate metabolism pathway and epilepsy

Background Epilepsy is a paroxysmal disorder of the brain,caused by an imbalance of neuronal excitation and inhibition.Glutamate is the most important excitatory neurotransmitter in the brain and plays an important role in epileptogenesis.Mutations in genes at any step/component of the glutamate metabolic pathway may lead to the development of epilepsy or epileptic encephalopathy.Methods Clinical history of 3 epilepsy patients with genetic variations of the glutamate metabolism pathway was collected.Electroencephalogram recording and magnetic resonance imaging were performed in each patient.We also reviewed recent literature for a variety of the genetic variations involved in epilepsy.Results Case 1 was a SLC1A2 mutation-carrier diagnosed with developmental and epileptic encephalopathy(DEE)41,whose seizures decreased after start of the ketogenic diet.Case 2 carried a GRIN2A gene mutation and was seizure-free for three years after taking levetiracetam and vitamin B6.Case 3 was a GRIN2B mutation-carrier diagnosed with DEE 27,who seizures diminished after taking oxcarbazepine.Conclusions Preclinical and clinical evidence supports the therapeutic potential of glutamatergic signaling-targeting treatments for epilepsy.More studies are needed to discover novel DEE-related genetic mutations in the glutamate metabolic pathway.