Early Myoclonic Encephalopathy Research Articles

Metabolic causes of pediatric developmental & epileptic encephalopathies (DEE)- genetic variant analysis in a south Indian cohort

PurposeDrug-resistant epilepsy is seen in patients with inborn errors of metabolism and metabolic dysfunction in neurons is crucial to brain disorders associated with psychomotor impairment. Diagnostic rates of metabolic causes of developmental and epileptic encephalopathy (DEE) using next generation sequencing have been rarely studied in literature. MethodsA prospective hospital study was carried out in 384 children with DEE, who underwent genetic testing. Metabolic disorders were evaluated with biochemical blood/urine assays and when required CSF estimations performed. ResultsA total of 154 pathogenic/likely pathogenic variants in 384 children were identified. Out of 384 children, 89 were clinically suspected to have probable or possible metabolic disorders. Pathogenic/likely pathogenic variants in metabolic genes were identified in 39 out of 89 (43.8 %) and promising VUS in 28 (31.4 %). These included variants for progressive myoclonus epilepsies (21; 53.8 %), DEE with focal/multifocal seizures (8; 20.5 %), generalized epilepsy (5;12.8 %), early myoclonic encephalopathy (2; 5.1 %), LGS (1; 2.6 %) and West syndrome (2; 5.1 %). ConclusionOur cohort demonstrates for the first time from the Indian subcontinent that identification of metabolic variants can guide investigations and has therapeutic implications in patients with variable DEE phenotypes. A high utility is noted with regard to diagnosis and prognostication, given the low yield of available biochemical tests, indicating cost-effectiveness of this approach.

Comment: Amenable Treatable Severe Pediatric Epilepsies

Phillip L. Pearl Seminars in Pediatric Neurology Volume 23, Issue 2, May 2016, Pages 158-166 Vitamin-dependent epilepsies and multiple metabolic epilepsies are amenable to treatment that markedly improves the disease course. Knowledge of these amenably treatable severe pediatric epilepsies allows for early identification, testing, and treatment. These disorders present with various phenotypes, including early onset epileptic encephalopathy (refractory neonatal seizures, early myoclonic encephalopathy, and early infantile epileptic encephalop athy), infantile spasms, or mixed generalized seizure types in infancy, childhood, or even adolescence and adulthood. The disorders are presented as vitamin responsive epilepsies such as pyridoxine, pyridoxal-5-phosphate, folinic acid, and biotin; transportopathies like GLUT-1, cerebral folate deficiency, and biotin thiamine responsive disorder; amino and organic acidopathies including serine synthesis defects, creatine synthesis disorders, molybdenum cofactor deficiency, and cobalamin deficiencies; mitochondrial disorders; urea cycle disorders; neurotransmitter defects; and disorders of glucose homeostasis. In each case, targeted intervention directed toward the underlying metabolic pathophysiology affords for the opportunity to significantly effect the outcome and prognosis of an otherwise severe pediatric epilepsy.

Early Myoclonic Infantile Encephalopathy in Neonate Caused by 5-Oxoprolinuria, a Rare Metabolic Entity: A Case Report

Neonatal encephalopathy is a common entity encountered by treating physicians in any neonatal intensive care unit. Though hypoxic ischaemic encephalopathy is the most frequent cause in developing countries, metabolic causes should also be looked for in refractory neonatal seizures with sibling death and parental consanguinity. Early myoclonic infantile encephalopathy, considered under the broad spectrum of infantile encephalopathy, is a rare syndrome in infants with onset within 3 months of age. It is characterized by myoclonic seizures, features of encephalopathy and caused by underlying metabolic diseases, nonketotic hyperglycinemia being the most common cause. On contrary its close mimicker, Ohtahara syndrome or early infantile epileptic encephalopathy is most likely associated with structural neurological lesions. We report a 12-day term Indian male neonate, born of second degree consanguinity with multiple sibling death history, presented with refractory myoclonic seizures in spite of uneventful birth history. Myoclonic seizures, refractory to intravenous phenobarbitone, phenytoin and infusion Midazolam, persisted after ruling out hypoglycemia, dyselectrolytemia, and neonatal sepsis. EEG showed typical burst suppression pattern pointing towards diagnosis of early myoclonic infantile encephalopathy. Further metabolic causes were looked for but tandem mass spectrometry for dried blood sample was normal. Lastly, urinary GCMS revealed 5-oxoprolinuria, an autosomal recessive condition, characterized by acidosis, jaundice, and severe hemolytic anemia among neonates, primarily due to glutathione synthetase enzyme deficiency. In severe form of 5-oxoprolinuria, neurological complications in form of seizures, ataxia have been documented in earlier studies; however, its association with myoclonic encephalopathy is yet to be reported in the literature and this report may be the first of its kind.

SCN1B Genetic Variants: A Review of the Spectrum of Clinical Phenotypes and a Report of Early Myoclonic Encephalopathy.

Background: Pathogenic variants in SCN1B, the gene encoding voltage-gated sodium channel b1/b1B subunits are associated with a spectrum of epileptic disorders. This study describes a child with early myoclonic encephalopathy and a compound heterozygous variant in the SCN1B gene (p.Arg85Cys and c.3G>C/p.Met1), along with the child’s clinical response to anti-seizure medications (ASMs) and the ketogenic diet. We reviewed the current clinical literature pertinent to SCN1B-related epilepsy. Methods: We described the evaluation and management of a patient with SCN1B-related developmental and epileptic encephalopathy (DEE). We used the Medline and Pubmed databases to review the various neurological manifestations associated with SCN1B genetic variants, and summarize the functional studies performed on SCN1B variants. Results: We identified 20 families and six individuals (including the index case described herein) reported to have SCN1B-related epilepsy. Individuals with monoallelic pathogenic variants in SCN1B often present with genetic epilepsy with febrile seizures plus (GEFS+), while those with biallelic pathogenic variants may present with developmental and epileptic encephalopathy (DEE). Individuals with DEE present with seizures of various semiologies (commonly myoclonic seizures) and status epilepticus at early infancy and are treated with various antiseizure medications. In our index case, adjunctive fenfluramine was started at 8 months of age at 0.2 mg/kg/day with gradual incremental increases to the final dose of 0.7 mg/kg/day over 5 weeks. Fenfluramine was effective in the treatment of seizures, resulting in a 50% reduction in myoclonic seizures, status epilepticus, and generalized tonic-clonic seizures, as well as a 70–90% reduction in focal seizures, with no significant adverse effects. Following the initiation of fenfluramine at eight months of age, there was also a 50% reduction in the rate of hospitalizations. Conclusions: SCN1B pathogenic variants cause epilepsy and neurodevelopmental impairment with variable expressivity and incomplete penetrance. The severity of disease is associated with the zygosity of the pathogenic variants. Biallelic variants in SCN1B can result in early myoclonic encephalopathy, and adjunctive treatment with fenfluramine may be an effective treatment for SCN1B-related DEE. Further research on the efficacy and safety of using newer ASMs, such as fenfluramine in patients under the age of 2 years is needed.

Monoamine neurotransmitters in early epileptic encephalopathies: New insights into pathophysiology and therapy

AimTo study neurotransmitter status in children with early epileptic and developmental and epileptic encephalopathy (DEE) and to explore the clinical response to dopaminergic and serotoninergic therapies in a group of patients.MethodTwo hundred and five patients (111 males [54.1.%] and 94 females [45.9%], mean age 10 months at the onset of epilepsy [SD 1 year 1 month], range 0–3 year) with epileptic encephalopathy/DEE were recruited, including those with West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, myoclonic encephalopathy in non‐progressive disorders, infantile spasms, Doose syndrome, Lennox–Gastaut syndrome, Landau–Kleffner syndrome, and those unclassified. Cerebrospinal fluid (CSF) neurotransmitter studies and patients' medical records were reviewed. Additionally, we present clinical data of 10 patients with low CSF neurotransmitter levels who received dopaminergic/serotoninergic treatments.ResultsAbnormal neurotransmitter values were identified in 68 (33%) patients. 5‐Hydroxyindoleacetic acid (5‐HIAA) deficit was the most prevalent alteration (91%). Low CSF 5‐HIAA levels were significantly higher in 1‐ to 3‐year‐old children. A negative significant correlation was found between 5‐HIAA levels and epilepsy duration before CSF study (Spearman's ρ=−0.191, p=0.007). Abnormalities in deep grey matter were associated with low levels of CSF homovanillic acid and 5‐HIAA. Ten patients with low CSF neurotransmitter levels received dopamine and/or serotonin therapies. Six of them showed initial decrease of seizure frequency and severity and maintained improvement in some neurodevelopmental skills.InterpretationA considerable number of patients showed neurotransmitter abnormalities. Age at seizure onset and duration of epilepsy before CSF study were the principal factors related to neurotransmitter depletion. Early monoamine supplementation would seem advisable as a neuroprotective strategy.What this paper adds 5‐Hydroxyindoleacetic acid homeostasis is especially vulnerable in patients with epileptic encephalopathy/developmental and epileptic encephalopathy. Age of seizure onset and duration of epilepsy are determinants of neurotransmitter depletion.

Complementing the phenotypical spectrum of TUBA1A tubulinopathy and its role in early-onset epilepsies

TUBA1A tubulinopathy is a rare neurodevelopmental disorder associated with brain malformations as well as early-onset and intractable epilepsy. As pathomechanisms and genotype-phenotype correlations are not completely understood, we aimed to provide further insights into the phenotypic and genetic spectrum. We here present a multicenter case series of ten unrelated individuals from four European countries using systematic MRI re-evaluation, protein structure analysis, and prediction score modeling. In two cases, pregnancy was terminated due to brain malformations. Amongst the eight living individuals, the phenotypic range showed various severity. Global developmental delay and severe motor impairment with tetraparesis was present in 63% and 50% of the subjects, respectively. Epilepsy was observed in 75% of the cases, which showed infantile onset in 83% and a refractory course in 50%. One individual presented a novel TUBA1A-associated electroclinical phenotype with evolvement from early myoclonic encephalopathy to continuous spike-and-wave during sleep. Neuroradiological features comprised a heterogeneous spectrum of cortical and extracortical malformations including rare findings such as cobblestone lissencephaly and subcortical band heterotopia. Two individuals developed hydrocephalus with subsequent posterior infarction. We report four novel and five previously published TUBA1A missense variants whose resulting amino acid substitutions likely affect longitudinal, lateral, and motor protein interactions as well as GTP binding. Assessment of pathogenic and benign variant distributions in synopsis with prediction scores revealed sections of variant enrichment and intolerance to missense variation. We here extend the clinical, neuroradiological, and genetic spectrum of TUBA1A tubulinopathy and provide insights into residue-specific pathomechanisms and genotype-phenotype correlations.

Neonatal Seizures: An Overview of Genetic Causes and Treatment Options.

Seizures are the most frequent neurological clinical symptoms of the central nervous system (CNS) during the neonatal period. Neonatal seizures may be ascribed to an acute event or symptomatic conditions determined by genetic, metabolic or structural causes, outlining the so-called ‘Neonatal Epilepsies’. To date, three main groups of neonatal epilepsies are recognised during the neonatal period: benign familial neonatal epilepsy (BFNE), early myoclonic encephalopathy (EME) and ‘Ohtahara syndrome’ (OS). Recent advances showed the role of several genes in the pathogenesis of these conditions, such as KCNQ2, KCNQ3, ARX, STXBP1, SLC25A22, CDKL5, KCNT1, SCN2A and SCN8A. Herein, we reviewed the current knowledge regarding the pathogenic variants most frequently associated with neonatal seizures, which should be considered when approaching newborns affected by these disorders. In addition, we considered the new possible therapeutic strategies reported in these conditions.

The relationship between the characteristics of burst suppression pattern and different etiologies in epilepsy

To analyze the relationship between the characteristics of burst suppression (BS) pattern and different etiologies in epilepsy. Patients with a BS pattern who were younger than 6 months old were screened from our electroencephalogram (EEG) database. The synchronized and symmetric BS patterns under different etiologies in epilepsy were analyzed. A total of 32 patients had a BS pattern on EEG. The etiologies included genetic disorders (37.5%), cortical malformations (28.1%), inborn errors of metabolism (12.5%), and unknown (21.9%). Twenty-five patients were diagnosed with Ohtahara syndrome, one as early myoclonic encephalopathy, and one as epilepsy of infancy with migrating focal seizure. Five cases could not be classified into any epileptic syndrome. Asynchronous BS pattern was identified in 18 cases, of which 13 (72%) patients had genetic and/or metabolic etiologies. Synchronous BS pattern was identified in 14 cases, of which 8 (57%) patients had structural etiologies. Twenty-three patients had symmetric BS patterns, of which 15 (65%) patients had genetic etiologies. Nine patients had asymmetric BS patterns, of which 8 (89%) patients had structural etiologies. Patients with genetic epilepsies tended to have asynchronous and symmetric BS patterns, whereas those with structural epilepsies were more likely to have synchronous and asymmetric BS patterns.

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.

Epilepsy Syndromes in the First Year of Life and Usefulness of Genetic Testing for Precision Therapy.

The high pace of gene discovery has resulted in thrilling advances in the field of epilepsy genetics. Clinical testing with comprehensive gene panels, exomes, or genomes are now increasingly available and have led to a significant higher diagnostic yield in early-onset epilepsies and enabled precision medicine approaches. These have been instrumental in providing insights into the pathophysiology of both early-onset benign and self-limited syndromes and devastating developmental and epileptic encephalopathies (DEEs). Genetic heterogeneity is seen in many epilepsy syndromes such as West syndrome and epilepsy of infancy with migrating focal seizures (EIMFS), indicating that two or more genetic loci produce the same or similar phenotypes. At the same time, some genes such as SCN2A can be associated with a wide range of epilepsy syndromes ranging from self-limited familial neonatal epilepsy at the mild end to Ohtahara syndrome, EIFMS, West syndrome, Lennox–Gastaut syndrome, or unclassifiable DEEs at the severe end of the spectrum. The aim of this study was to review the clinical and genetic heterogeneity associated with epilepsy syndromes starting in the first year of life including: Self-limited familial neonatal, neonatal-infantile or infantile epilepsies, genetic epilepsy with febrile seizures plus spectrum, myoclonic epilepsy in infancy, Ohtahara syndrome, early myoclonic encephalopathy, West syndrome, Dravet syndrome, EIMFS, and unclassifiable DEEs. We also elaborate on the advantages and pitfalls of genetic testing in such conditions. Finally, we describe how a genetic diagnosis can potentially enable precision therapy in monogenic epilepsies and emphasize that early genetic testing is a cornerstone for such therapeutic strategies.

KCNT1-Related Epilepsy: A Review

Abstract KCNT1 gene encodes the sodium-dependent potassium channel reported as a causal factor for several different epileptic disorders. The gene has been also linked with cardiac disorders and in a family to sudden unexpected death in epilepsy. KCNT1 mutations, in most cases, result in a gain of function causing a neuronal hyperpolarization with loss of inhibition. Many early-onset epileptic encephalopathies related to gain of function of KCNT1 gene have been described, most often associated with two phenotypes: malignant migrating focal seizures of infancy and familial autosomal-dominant nocturnal frontal lobe epilepsy; however, there is no clear phenotype–genotype correlation, in fact same mutations have been represented in patients with West syndrome, Ohtahara syndrome, and early myoclonic encephalopathy. Additional neurologic features include intellectual disability, psychiatric disorders, hypotonia, microcephaly, strabismus, and movement disorders. Conventional anticonvulsant, vagal stimulation, and ketogenic diet have been used in the absence of clinical benefit in individuals with KCNT1-related epilepsy; in some patients, quinidine therapy off-label has been practiced successfully. This review aims to describe the characteristics of the gene, the phenotypes related to genetic mutations with the possible genotype–phenotype correlations and the treatments proposed to date, discussing the comorbidities reported in the literature.

SLC25A22 and Its Related Epileptic Encephalopathies

AbstractEpileptic encephalopathy is a condition in which seizures, electroencephalographic epileptiform abnormalities lead to a progressive deterioration of brain functions causing a significant psychomotor delay. One of the typical features of this heterogeneous and large group of severe disorders is the extremely early onset of seizures. The main causes of the epileptic encephalopathies include structural brain defects, inherited metabolic disorders; in this aspect, more than 100 genetic defects, including mutations in the solute carrier family 25 (SLC25A22) gene which encodes a mitochondrial glutamate carrier. To date, the main clinical phenotypes related to mutations of this gene are Ohtahara syndrome (or early infantile epileptic encephalopathy), early myoclonic encephalopathy and migrating partial seizures in infancy. In all the cases, prognosis is poor and no disease-modifying treatment is available in the present days.

Early Myoclonic Epileptic Encephalopathy in a Newborn: Successfully Control Seizures and Suppression-Burst EEG with Levetiracetam

Early Myoclonic Epileptic Encephalopathy in a Newborn: Successfully Control Seizures and Suppression-Burst EEG with Levetiracetam

Genotype-phenotype correlates of infantile-onset developmental & epileptic encephalopathy syndromes in South India: A single centre experience

IntroductionA paucity of literature exists on genotype- phenotype correlates of ‘unknown-etiology’ infantile-onset developmental-epileptic encephalopathies (DEE) from India. The primary objective was to explore the yield of genetic testing in identifying potential disease causing variants in electro-clinical phenotypes of DEE MethodsAn observational hospital-based study was undertaken on children with unexplained refractory seizure-onset ≤12 months age and developmental delay, whose families consented and underwent genetic testing during a three year time period (2016–2018) by next-generation sequencing (NGS) or multiplex ligand protein amplification. Yield was considered based on demonstration of pathogenic/likely pathogenic variants only and variants of unknown significance (VUS) were documented. ResultsPathogenic/likely pathogenic variants were identified in 26 (31.7 %) out of 82 children with DEE. These included those variants responsible for primarily DEE- 21(76.7 %); neuro-metabolic disorders- 3(18.6 %) and chromosomal deletions- 2(4.7 %). Of these patients, early-infantile epilepsy onset ≤ 6 months age was noted in 22(84.6 %). The DEE studied included Ohtahara syndrome associated with STXBP1 and SCN8A variants with yield of 50 % (2/4 tested); early myoclonic encephalopathy (no yield in 2); West syndrome with CDKL5, yield of 13.3 % (2/15 tested); epilepsy of infancy with migrating partial seizures due to CACNA1A and KCNT1 variants, yield of 67 % (2/3 tested); DEE-unclassified with KCNQ2, AP3B2, ZEB2, metabolic variants (SUOX, ALDH7A1, GLDC) and chromosome deletions (chr 1p36, chr2q24.3); yield of 32 % (8/25 tested). Patients with Dravet syndrome/Dravet-like phenotypes (N = 33) had variants in SCN1A (N = 10), SCN1B, CHD2; yield of 36.4 % (12/33 tested; 57.1 % from NGS). Eighteen patients with potential variants (SCN1A, SCN2A, SCN8A, KCNQ2, ALDH7A1 which also included VUS) could be offered targeted therapy. ConclusionsOur study confirms a good yield of genetic testing in neonatal and infantile-onset DEE provided robust phenotyping of infants is attempted with prognostic and therapeutic implications, particularly relevant to centres with resource constraints.

Spectrum of genetic early onset epileptic encephalopathies in a tertiary pediatric neurology center in Dubai, UAE

Early onset epileptic encephalopathies (EOEE) are severe disorders characterized by several seizure types, frequent epileptiform activity on EEG, and developmental slowing or regression during the neonatal or early infantile periods. They include Ohtahara syndrome, early myoclonic epileptic encephalopathy and malignant migrating partial seizures of infancy and other undetermined syndromes. The causes can include structural, neurometabolic and genetic disorders. Genetic diagnoses are increasingly made in these cases with availability of next generation genetic studies, especially Whole Exome Sequencing (WES). Latifa Women and Children Hospital provides tertiary pediatric neurology service to Dubai and the Northern Emirates of UAE, catering to a population of 8 million. We describe a cohort of 40 cases of genetically proven early onset epileptic encephalopathies, including their age of onset, electro-clinical features, imaging findings, response to therapy and outcome. The aim of this presentation is to highlight the spectrum of genetic diagnoses in early onset epileptic encephalopathies and to describe the genetic mutations in a cohort of patients from the Middle East region.

Neonatal Developmental and Epileptic Encephalopathies

The new concept of developmental and epileptic encephalopathy is based on the understanding that many genetic epilepsies are associated with developmental impairment as a direct consequence of the genetic mutation, in addition to the effect of the frequent epileptic activity on brain development. As an example, in infants with KCNQ2 or STXBP1 encephalopathy, seizures may be controlled early after onset or cease spontaneously after a few years, but the developmental consequences tend to remain profound. The term "developmental and epileptic encephalopathy" expresses the concept that the genetic defect may be responsible for both the epilepsy and adverse development which is crucial to understanding the disease process for both families and clinicians. The increased use of EEG monitoring, neuroimaging, and metabolic and genetic testing in the Neonatal Intensive Care Unit has greatly improved our understanding of neonatal-onset epilepsies as seen with the syndromes Ohtahara and Early Myoclonic Encephalopathy outlined in the 1970s into distinct etiology-specific electroclinical phenotypes.

Diffic ulties of diagnostics of epilepsy due to mol ybdenum cofactor deficienc y: a case report

The article presents a clinical study of an infant with rare inherited metabolism disorder – molybdenum cofactor deficiency, for the first time in Russian literature. The onset of disorder – in early neonatal period with a suppression syndrome and myoclonic seizures combined with a burstsuppression electroencephalographic patterns, followed by a reveal of psychomotor delay. Сraniofacial dystrophies were present, including craniostenosis and microcephaly. Somatic status was characterized by hepatolienomegaly, dysmetabolic changes of kidneys’ parenchyma (suggested by ultrasound) and crystalluria. Neuroimaging data were contradictory. Neurosonography results allowed diagnosing concomitant inborn brain development defect: true porencephalia of large hemispheres. However, brain magnetic resonance imaging revealed a picture of diffuse leukomalacia with pseudocyst formation, which were considered a consequence of perinatal brain damage. Magnetic resonance imaging revealed a picture of diffuse leukomalacia with pseudocyst formation, which were considered a consequence of perinatal brain damage. Differential diagnosis was held between the early infantile epileptic encephalopathy (Ohtahara syndrome) and early myoclonic encephalopathy (Aicardi syndrome). However, etiology of the disease remained unclear. To eliminate inherited metabolic disease accompanied by epilepsy, Inherited Epilepsy Panel DNA sequencing was used. The results showed a homozygotic mutation on the exon 6 of MOCS2 gene, leading to deletion of amino acid in position 158 of the protein, which was described before in patients with molybdenum cofactor deficiency (OMIM: 252160).

Successful treatment of intractable life-threatening seizures with perampanel in the first case of early myoclonic encephalopathy with a novel de novo SCN1A mutation

PurposeEarly myoclonic encephalopathy (EME) is a form of developmental and epileptic encephalopathy with myoclonic seizures and a suppression burst on electroencephalogram, which occurs during the neonatal or early infantile period and is characterized by highly intractable seizures and severe development impairment. Although multiple genetic aetiologies of EME have been identified, no SCN1A mutation has been reported. MethodsWe described a female patient with EME due to an SCN1A mutation. ResultsShe developed frequent myoclonic and apnoeic seizures during the neonatal period. As her seizures were refractory to many antiepileptic drugs, she underwent a tracheotomy and has since been treated with continuous mechanical ventilation. Eventually, perampanel was added, which resulted in the cessation of the apnoeic seizures. Genetic analysis revealed a heterozygous de novo missense mutation in the SCN1A gene (c.2588 T > C:p.Leu863Ser). ConclusionThis is the first patient with EME due to anSCN1A mutation to be successfully treated with perampanel. Recently, perampanel was reported to be effective in treating Dravet syndrome, including cases with an SCN1A mutation. Perampanel may contribute to seizure reduction in patients with intractable epilepsy carrying the SCN1A mutation.

Neonatal seizures and neonatal epilepsy: Urgent need for training programs

Neonatal seizures (NS), even short lived, may signify serious underlying problem that occur in immature brain. It may lead to horrible long term adulthood comorbid neurological, behavioral and psychiatric disorders. Experimentally, even single episode of neonatal seizures permanently affects cognition and memory.Neonatal Seizures are considered as a neurological emergency requiring urgent intervention especially in case with potentially treatable etiologies. The prevalence of NS is about 1.5% and overall incidence about 0.3% live births. The incidence is so higher in pre-term infants (57–132 per 1000 live births). About 80% of NS occur in the 1st week of life. From literature, 7:16% of neonates with NS may be died (higher for preterm infants). Among survivors; adverse neurodevelopmental sequelae will take place in 27-55% including cerebral palsy, developmental delay, and postneonatal epilepsy.Neonatal neurology is an emergent sub-specialty area concerning neurologic problems present in the neonatal period. A neurologist with expertise in neonates is becoming more needed. Few neonatologists are interested in neonatal neurology; they considered it as a subject of ambiguity and mystery.Dealing with NS is challenging, especially, for neurologists who aren’t involved in neonatology practice. This may due to dissimilarities and special characteristics of neonates when compared with those of older age groups. In NS; various etiologies should be considered notably hypoxic ischemic encephalopathy, neonatal stroke, kernicterus, traumatic brain injury and metabolic causes. Most NS are subclinical occurring without overt clinical correlate and having the same prognosis as electroclinical seizures. Clinical seizure types in neonates are focal-clonic, focal-tonic, some types of myoclonic, and epileptic spasms. In addition to clinical skills, video EEG monitoring can be used to exclude seizure mimickers including non-seizure behaviors and non-epileptic paroxysmal events as benign neonatal sleep myoclonus, benign non epileptic myoclonus of early infancy (benign non-epileptic infantile spasms) and hyperekplexia. Diagnostic procedures for NS including; biochemical laboratory workup, striking electrophysiological and neuroradiological findings; all have different implication and values in neonates, and lastly; special considerations regarding potentially toxic anti-epileptic medications and other therapeutic modalities should be taken when used in little infants with immature brain, liver and kidneys.Although, most NS are mainly acute, symptomatic and reactive to a specific distinguishable cause, rare distinct early neonatal epilepsy syndromes may occur. Benign familial neonatal epilepsy, early myoclonic encephalopathy, and early infantile epileptic encephalopathy are well known neonatal epileptic syndromes. Understanding genetic heritages for these syndromes are being increasingly acknowledged [7]. Urgent need to understand possible underestimated underlying treatable neurometabolic issues is a matter of necessity in dealing with refractory neonatal epileptic syndromes.So, NS and neonatal epilepsy syndromes may represent a neglected area in medical practice among non- neonatologist primary care providers and adult neurologists in one side and neonatologists not interested in neonatal neurology in the other side. Bridges can cross over barriers and physicians can gain much benefit from comprehensive neonatal neurology training programs.

Different types of suppression-burst patterns in patients with epilepsy of infancy with migrating focal seizures (EIMFS)

PurposeIn rare cases, patients with epilepsy of infancy withmigrating focal seizures (EIMFS) exhibit suppression-burst (SB) patterns on electroencephalography (EEG), similar to the findings observed in patients with Ohtahara syndrome and early myoclonic encephalopathy. In this report, we discuss six cases of EIMFS in which patients exhibited two types of SB patterns. MethodsWe evaluated six patients with EIMFS who had been admitted to the NHO Shizuoka Institute of Epilepsy and Neurological Disorders between 2011 and 2018. We retrospectively examined clinical characteristics and EEG findings for each patient. In all patients, the first EEG was performed within 1 month after seizure onset. Afterwards, EEG examinations were performed at irregular intervals (ranging from 1 to 5 months). ResultsAge at seizure onset ranged from 2 days to 3 months. SB was first detected within 1 month of age in two patients, and within the range of 3–14 months in the remaining four patients. Among the latter four patients, SB patterns persisted at the final EEG recording in three patients (34–54 months). In all patients, SB patterns were observed during sleep only. Interhemispheric asynchrony in SB was observed in the two patients who exhibited SB within 1 month of age, while synchronous SB patterns were observed in the remaining four patients. ConclusionsOur findings indicate that EIMFS may be associated with two types of SB patterns (early-onset and late-onset), which can be distinguished based on the stage of emergence and level of synchrony.