Neonatal Epilepsy Research Articles

Familial neonatal seizures caused by the Kv7.3 selectivity filter mutation T313I.

ObjectiveA spectrum of seizure disorders is linked to mutations in Kv7.2 and Kv7.3 channels. Linking functional effects of identified mutations to their clinical presentation requires ongoing characterization of newly identified variants. In this study, we identified and functionally characterized a previously unreported mutation in the selectivity filter of Kv7.3.MethodsNext‐generation sequencing was used to identify the Kv7.3[T313I] mutation in a family affected by neonatal seizures. Electrophysiological approaches were used to characterize the functional effects of this mutation on ion channels expressed in Xenopus laevis oocytes.ResultsSubstitution of residue 313 from threonine to isoleucine (Kv7.3[T313I]) likely disrupts a critical intersubunit hydrogen bond. Characterization of the mutation in homomeric Kv7.3 channels demonstrated a total loss of channel function. Assembly in heteromeric channels (with Kv7.2) leads to modest suppression of total current when expressed in Xenopus laevis oocytes. Using a Kv7 activator with distinct effects on homomeric Kv7.2 vs heteromeric Kv7.2/Kv7.3 channels, we demonstrated that assembly of Kv7.2 and Kv7.3[T313I] generates functional channels.SignificanceBiophysical and clinical effects of the T313I mutation are consistent with Kv7.3 mutations previously identified in cases of pharmacoresponsive self‐limiting neonatal epilepsy. These findings expand our description of functionally characterized Kv7 channel variants and report new methods to distinguish molecular mechanisms of channel mutations.

Neonatal developmental and epileptic encephalopathy due to autosomal recessive variants in SLC13A5 gene.

Autosomal recessive pathogenic variants of the SLC13A5 gene are associated with severe neonatal epilepsy, developmental delay, and tooth hypoplasia/hypodontia. We report on 14 additional patients and compare their phenotypic features to previously published patients to identify the clinical hallmarks of this disorder. We collected clinical features of 14 patients carrying biallelic variants in SLC13A5 and performed a PubMed search to identify previously published patients. All patients presented clonic or tonic seizures in the first days of life, evolving into status epilepticus in 57%. Analysis of seizure frequency and developmental milestones divided into five epochs showed an evolutionary trajectory of both items. In the first 3years of life, 72% of patients had weekly/monthly seizures, often triggered by fever; 14% were seizure-free. Between the ages of 3 and 12years, 60% become seizure-free; in the following years, up to age 18years, 57% were seizure-free. After the age of 18years, all three patients reaching this age were seizure-free. Similarly, 86% of patients at onset presented mild to moderate developmental impairment and diffuse hypotonia. In late childhood, all had developmental delay that was severe in most. Benzodiazepines, phenobarbital, phenytoin, and carbamazepine were the most effective drugs. Eight probands carried heterozygous compound variants, and homozygous pathogenic variants occurred in six. Literature review identified 45 patients carrying SLC13A5 gene pathogenic variants whose clinical features overlapped with our cohort. A peculiar and distinguishing sign is the presence of tooth hypoplasia and/or hypodontia in most patients. Autosomal recessive pathogenic variants in SLC13A5 are associated with a distinct neonatal epileptic encephalopathy evolving into severe cognitive and motor impairment, yet with seizures that settle down in late childhood. Tooth hypoplasia or hypodontia remains the peculiar feature. The SLC13A5 gene should be screened in neonatal epileptic encephalopathies; its recessive inheritance has relevance for genetic counseling.

Functional Distinction between Human and Mouse Sodium-Coupled Citrate Transporters and Its Biologic Significance: An Attempt for Structural Basis Using a Homology Modeling Approach.

NaCT (SLC13A5; mINDY), a sodium-coupled citrate transporter, is the mammalian ortholog of Drosophila INDY. Loss-of-function mutations in human NaCT cause severe complications with neonatal epilepsy and encephalopathy (EIEE25). Surprisingly, mice lacking this transporter do not have this detrimental brain phenotype. The marked differences in transport kinetics between mouse and human NaCTs provide at least a partial explanation for this conundrum, but a structural basis for the differences is lacking. Neither human nor mouse NaCT has been crystallized, and any information known on their structures is based entirely on what was inferred from the structure of VcINDY, a related transporter in bacteria. Here, we highlight the functional features of human and mouse NaCTs and provide a plausible molecular basis for the differences based on a full-length homology modeling approach. The transport characteristics of human NaCT markedly differ from those of VcINDY. Therefore, the modeling with VcINDY as the template is flawed, but this is the best available option at this time. With the newly deduced model, we determined the likely locations of the disease-causing mutations and propose a new classification for the mutations based on their location and potential impact on transport function. This new information should pave the way for future design and development of novel therapeutics to restore the lost function of the mutant transporters as a treatment strategy for patients with EIEE25.

Genetic Etiologies of Neonatal Seizures.

Neonates presenting with seizures are frequently assessed and managed by neonatologists in the NICU. Although hypoxic-ischemic encephalopathy and infection are common underlying causes of neonatal seizures, many patients with neonatal epilepsy will have an identifiable genetic etiology. Often these cases will be evaluated in collaboration with a geneticist. The categories of genetic causes of neonatal seizures include 1) structural brain malformations; 2) inborn errors of metabolism; 3) syndromic; and 4) nonsyndromic, single gene. Evaluation of these patients involves a comprehensive history and examination, followed by appropriate investigations and diagnostic genetic testing. Components of the diagnostic process will vary based on the clinical suspicion and differential diagnoses. In certain cases, syndromic surveillance for evaluation of other congenital anomalies may be recommended. Determination of the underlying genetic diagnosis, when present, will have important implications for treatment. Targeted therapies are currently available for specific genetic syndromes, and outcomes may improve with earlier initiation of therapy. Certain genetic diagnoses may also have guideline-based management involving screening for other manifestations of the disorder.

Clinical characteristics of KCNQ2 encephalopathy

PurposeKCNQ2 mutations are associated with benign familial neonatal epilepsy (BFNE) or developmental and epileptic encephalopathy (DEE). In this study, we aimed to delineate the phenotype of KCNQ2 encephalopathy and evaluate the treatment response. MethodsThirteen patients of KCNQ2 encephalopathy were included in the study. Characteristics of KCNQ2 mutations, electroclinical features, clinical course, and response to the treatment were analyzed. ResultsAge range of the thirteen patients was between 3 months and 20.9 years. The onset of seizures in 11 patients ranged from 1 to 3 days of age, while in the other two patients it was 7 and 40 days, respectively. Most common initial seizure types were tonic seizures. Initial EEGs were suppression burst pattern in seven patients and slow and disorganized background with multifocal epileptiform discharges in six patients. Initial epilepsy syndrome was Ohtahara syndrome in seven patients, neonatal focal seizure in five patients, and focal epilepsy beyond neonatal period in one patient. Sodium channel blockers including oxcarbazepine (OXC) (n = 3), lamotrigine (LTG) (n = 3), phenytoin (PHT) (n = 2), topiramate (TPM) (n = 2), and zonisamide (ZNS) (n = 1) were tried and found effective in eleven patients. Ultimately, 12 of 13 patients became seizure-free. However, developmental outcomes were poor. ConclusionsSodium channel blockers are effective in seizure control in these patients with KCNQ2 encephalopathy. Early recognition of KCNQ2 encephalopathy and early use of sodium channel blockers might be helpful in seizure control.

A Novel Kv7.3 Variant in the Voltage-Sensing S4 Segment in a Family With Benign Neonatal Epilepsy: Functional Characterization and in vitro Rescue by β-Hydroxybutyrate.

Pathogenic variants in KCNQ2 and KCNQ3, paralogous genes encoding Kv7.2 and Kv7.3 voltage-gated K+ channel subunits, are responsible for early−onset developmental/epileptic disorders characterized by heterogeneous clinical phenotypes ranging from benign familial neonatal epilepsy (BFNE) to early−onset developmental and epileptic encephalopathy (DEE). KCNQ2 variants account for the majority of pedigrees with BFNE and KCNQ3 variants are responsible for a much smaller subgroup, but the reasons for this imbalance remain unclear. Analysis of additional pedigrees is needed to further clarify the nature of this genetic heterogeneity and to improve prediction of pathogenicity for novel variants. We identified a BFNE family with two siblings and a parent affected. Exome sequencing on samples from both parents and siblings revealed a novel KCNQ3 variant (c.719T>G; p.M240R), segregating in the three affected individuals. The M240 residue is conserved among human Kv7.2-5 and lies between the two arginines (R5 and R6) closest to the intracellular side of the voltage-sensing S4 transmembrane segment. Whole cell patch-clamp recordings in Chinese hamster ovary (CHO) cells revealed that homomeric Kv7.3 M240R channels were not functional, whereas heteromeric channels incorporating Kv7.3 M240R mutant subunits with Kv7.2 and Kv7.3 displayed a depolarizing shift of about 10 mV in activation gating. Molecular modeling results suggested that the M240R substitution preferentially stabilized the resting state and possibly destabilized the activated state of the Kv7.3 subunits, a result consistent with functional data. Exposure to β-hydroxybutyrate (BHB), a ketone body generated during the ketogenic diet (KD), reversed channel dysfunction induced by the M240R variant. In conclusion, we describe the first missense loss-of-function (LoF) pathogenic variant within the S4 segment of Kv7.3 identified in patients with BFNE. Studied under conditions mimicking heterozygosity, the M240R variant mainly affects the voltage sensitivity, in contrast to previously analyzed BFNE Kv7.3 variants that reduce current density. Our pharmacological results provide a rationale for the use of KD in patients carrying LoF variants in Kv7.2 or Kv7.3 subunits.

Electroencephalography in neonatal epilepsies.

Neonatal epilepsies - neonatal seizures caused by remote symptomatic etiologies - are infrequent compared with those caused by acute symptomatic etiologies. The etiologies of neonatal epilepsies are classified into structural, genetic, and metabolic. Electroencephalography (EEG) and amplitude-integrated EEG (aEEG) are essential for the diagnosis and monitoring of neonatal epilepsies. Electroencephalography / aEEG findings may differ substantially among infants, even within infants with variants in a single gene. Unusual EEG/aEEG findings, such as downward seizure patterns on aEEG, can be found. Neonatal seizures are exclusively of focal onset. An International League Against Epilepsy task force proposed that the seizure type is typically determined by the predominant clinical feature and is classified into motor or non-motor presentations. Ictal EEG usually demonstrates a sudden, repetitive, evolving, and stereotyped activities with a minimum duration of 10s. In epileptic spasms and myoclonic seizures, the cut-off point of 10s cannot be applied. One must always be aware of electro-clinical dissociation in neonates suspected to have seizures. Amplitude-integrated EEG is also useful for the diagnosis and monitoring of neonatal epilepsies but aEEG cannot be recommended as the mainstay because of its relatively low sensitivity and specificity. At present, EEG findings are not pathognomonic, although some characteristic ictal or interictal EEG findings have been reported in several neonatal epilepsies. Deep learning will be expected to be introduced into EEG interpretation in near future. Objective EEG classification derived from deep learning may help to clarify EEG characteristics in some specific cases of neonatal epilepsy.

Ictal and interictal electroencephalographic findings can contribute to early diagnosis and prompt treatment in KCNQ2-associated epileptic encephalopathy

KCNQ2-associated epilepsy is most common in neonatal genetic epilepsy. A prompt diagnosis to initialize early treatment is important. We studied the electroencephalographic (EEG) changes including automated EEGs and conventional EEGs monitoring of 10 nonconsanguineous cases with KCNQ2 mutations, identified among 162 (6%) childhood epilepsy. We compared 11 (25%) non-KCNQ2 seizures videoed from 44 automated EEG and EEG monitoring. Patients with KCNQ2 seizures had received more antiepileptic treatments than patients in non-KCNQ2 group. Seizures were detected in all patients with KCNQ2 epileptic encephalopathy (EE); the detection rate in KCNQ2 group was more than in patients with non-KCNQ2. The ictal recordings showed 3 newborns presented with initial lower amplitudes (<15μV) and fast activity (>20Hz), evolving into higher-amplitude theta-delta waves. Two patient's ictal seizures showed recurrent focal tonic movements of the unilateral limbs associated with slowly continuous spikes in the contralateral hemisphere. The interictal EEGs in 5 KCNQ2 EE were burst-suppression. In 5 patients with familial KCNQ2 mutations, the interictal EEGs showed focal paroxysmal activity. Compared with 11 non-KCNQ2 EEG of ictal seizures, the differences are ictal EEGs initially appeared manifesting theta-delta waves without fast activities. In KCNQ2 seizures, patients with mutations locating in the selectivity filter controlling K+ permeability had severe EEG patterns and poor neurodevelopmental outcomes. Ictal EEGs in KCNQ2 seizures are unique and different from the EEGs of seizures with other etiologies. An EEG monitoring can be a valuable tool for early diagnosing KCNQ2-associated seizures and for supporting prompt treatments.

Evaluation of the Neonate with Seizures.

Neonatal seizures are common, occurring in 2 to 5 of 1,000 live births in the United States. The neonatal brain is thought to be predisposed toward seizures due to a combination of excessive excitatory and deficient inhibitory neuronal activity. The seizures tend to be focal or multifocal without secondary generalization, resulting in subtle seizure appearance. There are five main categories of neonatal seizures: focal clonic, focal tonic, myoclonic, subtle, and generalized tonic. An electroencephalogram is recommended to diagnose and treat neonatal seizures due to poor reliability of the clinical examination. Causes of neonatal seizures are broad, including trauma, structural brain anomalies, infections, metabolic disorders, drug withdrawal or intoxication, and neonatal epilepsy syndromes. Treatment of neonatal seizures involves management of cardiorespiratory status, correction of metabolic derangements, and antiepileptics as needed. The most common antiepileptics used in neonates are phenobarbital, levetiracetam, and fosphenytoin. The long-term risk of neurodevelopmental disability varies depending upon the etiology of neonatal seizures. Close attention to developmental milestones and neurology follow-up is recommended for all neonates with seizures. [Pediatr Ann. 2020;49(7):e292-e298.].

Therapy of neonatal seizures: a two-year retrospective study at Almazov National Medical Research Centre

Introduction.Neonatal seizures are the most common pathological neurological symptom of the neonatal period, requiring immediate treatment. There are 2 directions in the treatment of seizures: relief of acute life-threatening seizures and supportive antiepileptic therapy of the chronic process. Worldwide phenobarbital is still the first-line medication for neonatal seizures. However, due to contraindications the doctors have to select and prescribe other antiepileptic therapy for both stopping seizures and supportive therapy.Objective.To introduce an algorithm for standardized phased treatment of neonatal seizures from stopping an acute debut to starting supportive chronic therapy according to clinical and electroencephalographic indications.Characteristics of children and research methods.The authors retrospectively analyzed 449 patients born in 2016 – 2017. The inclusion criteria: full-term term newborns with clinical and/or encephalographic verification of seizures in the neonatal period. The authors studied the time distribution parameters of the primary realization of seizures from the time of birth, the genesis of convulsive activity, the effectiveness of antiepileptic therapy.Results.Out of 449 treated children (full-term infants with somatic, surgical and cardiosurgical pathologies) 36 (8.0%) patients had neonatal seizures, 35 (97.33%) children of them had symptomatic seizures. Neonatal genetic epilepsy was diagnosed in 1 (2.77%) child (Otahar syndrome). The investigators revealed the prevalence of the primary realization of convulsive syndrome in newborns in the first 4 days of life. Occasionally the initial debut of seizures occurred in children older than 7 days with congenital metabolic disorders, represented by aminoaciduria. The seizures were stopped without anticonvulsants (correction of transient metabolic disorders – hypoglycemia, hypocalcemia) in 3 (8.33%) children, with phenobarbital monotherapy in 5 (13.89%) children, diazepam monotherapy in 4 (11.11%) children, monotherapy with sodium thiopental – in 5 children (13.89%), valproic acid preparations – in 8 (22.22%) children, a combination of first and second line drugs (sodium thiopental + diazepam; sodium thiopental + phenobrobital) – in 11 ( 30.56%) children. Supportive antiepileptic therapy was carried out using phenobarbital monotherapy in 16 (44.44%) children, valproic acid preparations in 7 (19.44%) children, levetiracetam in 4 (11.12%) children, oxcarbazepine in 2 (5.56 %) children; 7 (19.44%) children were discharged without supportive antiepileptic therapy.Conclusion.Currently anticonvulsant monotherapy is effective in less than 50% of neonatal seizures cases; phenobarbital or diazepam remain the first-line medications. 1/3 of the patients require a combination of antiepileptic therapy. It is of great importance to diagnose and correct transient metabolic disorders before the prescription of anticonvulsant therapy.

Electroclinical variability of pyridoxine-dependent epilepsy caused by ALDH7A1 gene mutations in four Taiwanese children

BackgroundThe aim of this study was to describe the electroclinical variability of four Taiwanese patients with pyridoxine-dependent epilepsy (PDE) caused by ALDH7A1 gene mutations. MethodsDemographic data, case histories, clinical seizure patterns, EEG features, neuroimaging findings, ALDH7A1 gene mutations, treatments, and neurodevelopmental outcomes of the four patients were collected and analyzed. ResultsThe four patients exhibited the first symptom between the ages of 6 days and 11 months. The age of diagnosis was between 2 months and 13 years 8 months. Patient 1 exhibited classical phenotype of PDE, neonatal onset epileptic encephalopathy. Patient 2 showed atypical phenotypes of intractable epilepsy with additional neurological and abdominal symptoms. Patients 3 and 4, who had normal neurodevelopment, had familial epilepsy with fever sensitivity. Patients 2, 3, and 4 had atypical phenotypes and showed seizure exacerbation during febrile infections. EEG features of patient 1 revealed alternating rhythmic discharges followed by electrodecremental episodes; while those of patients 2, 3, and 4 disclosed nonspecific findings or normal results. Administration of oral pyridoxine hydrochloride resulted in seizure cessation in patients 1, 3, and 4, and they achieved normal neurodevelopmental outcomes, but intractable epilepsy and profound mental retardation occurred in patient 2 as he was not diagnosed until he was 13 years and 8 months old. ConclusionElectroclinical features of PDE vary widely, including patients with normal neurodevelopment and normal or nonspecific EEG findings. To avoid delay in treatment, a therapeutic trial with pyridoxine hydrochloride should be performed in all cases of neonatal, infantile, and childhood refractory epilepsy until ALDH7A1 gene mutation-related PDE has been excluded. Pyridoxine treatment may show clinical effectiveness even in a relatively late stage, i.e., age older than one year.

The first case of benign familial neonatal epilepsy diagnosed in Serbia

Introduction. The exact prevalence of benign familial neonatal epilepsy (BFNE) is unknown due to the likelihood of overlooking the disease and not diagnosing the affected patients correctly. The rare autosomal dominant inherited disorder usually occurs within a few days after birth of an otherwise healthy newborn, and disappears after one to four months. Most patients develop no psychomotor deficiencies, nor any other forms of seizures. The disorder is most commonly linked to the KCNQ2 gene, with mutations located on the chromosome 20q13.33 which cause voltage-gated potassium channel changes. This clinically rare condition manifests itself in repeated tonic-clonic episodes of focal and generalized convulsions which are effectively treated with antiepileptic therapy. Case report. We presented a five-day old affected male infant, with genetically proven KCNQ2 gene mutation, in addition to a positive familial history of epilepsy. Seizures did not reoccur after several episodes in the fifth day of life and further psychomotor development of the child proved normal. Conclusion. Neonatal seizures have extensive differential diagnosis. However, BFNE should be suspected when the most common neonatal seizure causes have been excluded, and factors, such as the hereditary factor, in addition to the typical clinical course resembling BFNE, can be observed. Genetic identification of BFNE has resulted in easier and more specific diagnosis of this rare disorder and is therefore the gold standard in its diagnostics.

Condensation of delta-1-piperideine-6-carboxylate with ortho-aminobenzaldehyde allows its simple, fast, and inexpensive quantification in the urine of patients with antiquitin deficiency.

Antiquitin (ATQ) deficiency leads to tissue, plasma, and urinary accumulation of alpha‐aminoadipic semialdehyde (AASA) and its Schiff base delta‐1‐piperideine‐6‐carboxylate (P6C). Although genetic testing of ALDH7A1 is the most definitive diagnostic method, quantifications of pathognomonic metabolites are important for the diagnosis and evaluation of therapeutic and dietary interventions. Current metabolite quantification methods use laborious, technically highly complex, and expensive liquid chromatography‐tandem mass spectro‐metry, which is available only in selected laboratories worldwide. Incubation of ortho‐aminobenzaldehyde (oABA) with P6C leads to the formation of a triple aromatic ring structure with characteristic absorption and fluorescence properties. The mean concentration of P6C in nine urine samples from seven ATQ‐deficient patients under standard treatment protocols was statistically highly significantly different (P < .001) compared to the mean of 74 healthy controls aged between 2 months and 57 years. Using this limited data set the specificity and sensitivity is 100% for all tested age groups using a P6C cut‐off of 2.11 μmol/mmol creatinine, which represents the 99% prediction interval of the P6C concentrations in 17 control urine samples from children below 6 years of age. Plasma P6C concentrations were only elevated in one ATQ subject, possibly because P6C is trapped by pyridoxal‐5‐phosphate (PLP) blocking fusing with oABA. Nevertheless, both urine and plasma samples were amenable to the quantification of exogenous P6C with high response rates. The P6C quantification method using fusion of oABA with P6C is fast, simple, and inexpensive and might be readily implemented into routine clinical diagnostic laboratories for the early diagnosis of neonatal pyridoxine‐dependent epilepsy.

Icariin ameliorates the cognitive function in an epilepsy neonatal rat model by blocking the GluR2/ERK I/II pathway.

The present study was performed to evaluate the protective effects of icariin on cognitive function in ahypoxia-induced neonatal epilepsy rat model. Neonatal epilepsy was induced in rat pups on postnatal day (PD) 20 by induction of hypoxia for 15 minutes. Rats were treated intraperitoneally with icariin at 75 mg/kg 1 hour before the induction of hypoxia. The effects of icariin were examined by estimating seizure stage, cognitive function and parameters of electroencephalography (EEG) in this neonatal epilepsy rat model. Parameters of oxidative stress and expression of proteins were examined in the brain tissue of the neonatal epilepsy rat model by histopathological study and Western blotting analysis, respectively. The results of this study suggest that treatment with icariin ameliorates the changes in seizure stage, number of seizures and parameters of EEG in hypoxia-induced neonatal epilepsy rats. Oxidative stress and apoptosis were decreased in the brain tissue of the icariin treatment group compared to the hypoxia group. Moreover, treatment with icariin ameliorated the altered expression of glutamate ionotropic receptor AMPA type subunit 2 (GluR2) and extracellular receptor kinase (ERK I/II) proteins in the brain tissue of hypoxia-induced epilepsy rats. Histopathological study also showed that icariin treatment improved the histopathology of brain tissue of hypoxia-induced epilepsy rats. In conclusion, the results of the present study suggest that icariin protects against neuronal injury and improves cognitive function in hypoxia-induced neonatal epilepsy rats by modulating the GluR2/ERK I/II pathway.

Phenotypic spectrum and genetics of SCN2A-related disorders, treatment options, and outcomes in epilepsy and beyond.

Pathogenic variants in the SCN2A gene are associated with a variety of neurodevelopmental phenotypes, defined in recent years through multicenter collaboration. Phenotypes include benign (self-limited) neonatal and infantile epilepsy and more severe developmental and epileptic encephalopathies also presenting in early infancy. There is increasing evidence that an important phenotype linked to the gene is autism and intellectual disability without epilepsy or with rare seizures in later childhood. Other associations of SCN2A include the movement disorders chorea and episodic ataxia. It is likely that as genetic testing enters mainstream practice that new phenotypic associations will be identified. Some missense, gain of function variants tend to present in early infancy with epilepsy, whereas other missense or truncating, loss of function variants present with later-onset epilepsies or intellectual disability only. Knowledge of both mutation type and functional consequences can guide precision therapy. Sodium channel blockers may be effective antiepileptic medications in gain of function, neonatal and infantile presentations.

Diagnostic and therapeutic experience of child with neonatal epilepsy: from ICU to home (сlinical case)

Ohtahara syndrome is the earliest of age-dependent epileptic encephalopathies, characterized by an early onset at the age of 3 months (most often the first 10 days of life), ‘suppression-burst’ pattern on EEG both in wakefulness and in sleep, resistance to standard AED therapy, a high probability of poor prognosis in the form of severe psychomotor retardation and death in infancy.

Current Perspectives On The Role Of The Ketogenic Diet In Epilepsy Management.

Drug-refractory epilepsy is a commonly prevalent pediatric neurological illness of global significance. Ketogenic diet (KD) is a time-tested therapeutic modality for refractory epilepsy, which has reemerged as a robust alternative to anti-epileptic pharmacotherapy. There is a growing body of evidence which supports the anti-seizure efficacy, safety profile and feasibility of KD use in childhood epilepsy. In addition, this modality has been recognized to reduce anti-epileptic exposure, improve cognition and behavioral profile of patients as well as improve the quality-of-life of care-givers. Current indications of KD include refractory epilepsy syndromes, selected metabolic disorders (such as pyruvate dehydrogenase deficiency) and a host of varied neurological entities. KD research has broadened the knowledge-base about its mechanisms of action. Four types of KD are in vogue currently with varying nutritional constitution, palatability, administration protocols and comparable efficacy. KD initiation and maintenance are the result of concerted effort of a team of pediatric neurologist/epileptologist, nutritionist and patient’s primary care-giver. Consensus is being formulated about various practical aspects of KD such as patient-selection, parental counseling, baseline work-up, dietary prescription, nutritional supplementation, concurrent anti-epileptic drug administration, follow-up and treatment-duration. Novel applications of KD include its use in neonatal epilepsy and super-refractory status epilepticus and tailor-made formulations such as cooking oil-based KD in predominantly rice-fed populations. Increasing body of clinical experience, improved nutritional designs and translational research are promoting KD as a major therapeutic modality. Currently, KD forms a core essence in the armamentarium against refractory epilepsy. In this review, we summarize the recent advances and current perspectives in the use of KD in refractory epilepsy.

Refractory Seizures of Infancy with SCN2A: A Case Review

Neonatal epilepsy occurs for many reasons. Infants may present shortly after birth with seizure activity or seizures may occur later in the neonatal period. Seizures that are refractory to treatment can be difficult to manage and because of different presentations, there may be a delay in diagnosing the exact etiology. Prompt intervention is necessary and developing a plan of care can be done while exploring the etiology. There are several genetic mutations, including the SCN2A sodium ion channelopathy, that can result in a wide array of epileptic conditions, ranging from mild to severe. This case review focuses on diagnosis and management of SCN2A refractory seizures.

Seizures and Outcome One Year After Neonatal and Childhood Cerebral Sinovenous Thrombosis

BackgroundPediatric cerebral sinovenous thrombosis is a treatable cause of brain injury, acute symptomatic seizures, and remote epilepsy. Our objective was to prospectively study epilepsy and outcomes in neonates and children one year after cerebral sinovenous thrombosis diagnosis. MethodsPatients with cerebral sinovenous thrombosis were enrolled prospectively from 21 international sites through the Seizures in Pediatric Stroke Study. Clinical data, including acute symptomatic seizures and cerebral sinovenous thrombosis risk factors, were collected at diagnosis. A neuroradiologist who was unaware of the diagnosis reviewed acute imaging. At one year, outcomes including seizure recurrence, epilepsy diagnosis, antiepileptic drug use, and modified Engel score were collected. Outcomes were assessed using the modified Rankin score and the King's Outcome Scale for Childhood Head Injury. ResultsTwenty-four participants with cerebral sinovenous thrombosis were enrolled (67% male, 21% neonates). Headache was the most common presenting symptom in non-neonates (47%, nine of 19). Nine (37.5%) presented with acute symptomatic seizures. Six (25%; 95% confidence interval, 10% to 47%) developed epilepsy by one-year follow-up. No clinical predictors associated with epilepsy were identified. King's Outcome Scale for Childhood Head Injury and modified Rankin scores at one year were favorable in 71%. Half of the patients who developed epilepsy (three of six) did not have infarcts, hemorrhage, or seizures identified during the acute hospitalization. ConclusionOur study provides a prospective estimate that epilepsy occurs in approximately one-quarter of patients by one year after diagnosis of cerebral sinovenous thrombosis. Later epilepsy can develop in the absence of acute seizures or parenchymal injury associated with the acute presentation.

Etiology of the Neonatal Seizures: An Epidemiological Study

Background: Neonatal seizure is a rare neurologic condition. The current study aimed at determining the etiology of neonatal seizure. Methods: The current study evaluated the data of 100 neonates who were hospitalized at neonatal intensive care unit (NICU) during 2015-2017. A pediatric neurologist made the final diagnosis of seizure. Patients’ medical records were used to review neonatal seizure variables. SPSS (version 16) was used to perform the statistical analyses. Results: The current study enrolled 100 newborns (41% female) admitted to the NICU following the first episode of seizure and the body temperature of 36.8-39.2°C (mean: 37.2°C). Of 100 participants, 94 (94%) had acute symptomatic seizure and 6 (6%) were compatible with neonatal epilepsy syndrome criteria. According to the results, the commonest etiologies were the neonatal encephalopathy and hypoxic-ischemic encephalopathy constituting 82% of participants. Conclusion: The consequences of acute symptomatic seizures in neonates are determined mainly by the etiology of the seizures. Seizure burden and use of anti-seizure drugs may also have some impact, but this has yet to be fully defined.