Distinctive Amplitude-Integrated EEG Ictal Pattern and Targeted Therapy with Carbamazepine in KCNQ2 and KCNQ3 Neonatal Epilepsy: A Case Series.

BACKGROUND: Carbamazepine (CBZ) is effective in treating KCNQ2/3-related seizures, which may present with a distinctive amplitude-integrated electroencephalography (aEEG) pattern. OBJECTIVE: To assess how improved recognition of the distinctive aEEG ictal pattern associated with KCNQ2/3 variants has enabled early and effective targeted therapy with CBZ. METHODS: Retrospective descriptive study of five neonates with KCNQ2/3 pathogenic gene variants admitted at a level 3 neonatal intensive care unit (NICU) over an 8-year period. RESULTS: The distinctive ictal aEEG pattern was recognized in four neonates after an average of 61.5 hours (minimum 12 hours, maximum 120 hours) from the first electroclinical seizure and prompted the use of CBZ that was effective in all. The two most recently diagnosed patients could avoid polytherapy as they received CBZ as the first and second antiseizure medication, respectively. Three out of five patients with continuous normal voltage (CNV), sleep-wake cycling (SWC), and shorter postictal suppression had normal neurodevelopmental outcome. Regarding the remaining two infants, one was not trialed with CBZ and had a high seizure burden, both presented with a prolonged postictal suppression, no SWC, and had moderate-to-severe developmental delay. Genetic results became available after the neonatal period in all but one of the infants, who had a prenatal diagnosis. CONCLUSION: Recognition of the distinctive ictal aEEG pattern in the NICU allowed early and effective targeted therapy with CBZ in four neonates, well before genetic results became available. Furthermore, a CNV background pattern with SWC and short postictal suppression were associated with normal developmental outcomes.

Treatment of seizures in the neonate: Guidelines and consensus-based recommendations-Special report from the ILAE Task Force on Neonatal Seizures.

Seizures are common in neonates, but there is substantial management variability. The Neonatal Task Force of the International League Against Epilepsy (ILAE) developed evidence-based recommendations about antiseizure medication (ASM) management in neonates in accordance with ILAE standards. Six priority questions were formulated, a systematic literature review and meta-analysis were performed, and results were reported following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 standards. Bias was evaluated using the Cochrane tool and risk of Bias in non-randomised studies - of interventions (ROBINS-I), and quality of evidence was evaluated using grading of recommendations, assessment, development and evaluation (GRADE). If insufficient evidence was available, then expert opinion was sought using Delphi consensus methodology. The strength of recommendations was defined according to the ILAE Clinical Practice Guidelines development tool. There were six main recommendations. First, phenobarbital should be the first-line ASM (evidence-based recommendation) regardless of etiology (expert agreement), unless channelopathy is likely the cause for seizures (e.g., due to family history), in which case phenytoin or carbamazepine should be used. Second, among neonates with seizures not responding to first-line ASM, phenytoin, levetiracetam, midazolam, or lidocaine may be used as a second-line ASM (expert agreement). In neonates with cardiac disorders, levetiracetam may be the preferred second-line ASM (expert agreement). Third, following cessation of acute provoked seizures without evidence for neonatal-onset epilepsy, ASMs should be discontinued before discharge home, regardless of magnetic resonance imaging or electroencephalographic findings (expert agreement). Fourth, therapeutic hypothermia may reduce seizure burden in neonates with hypoxic-ischemic encephalopathy (evidence-based recommendation). Fifth, treating neonatal seizures (including electrographic-only seizures) to achieve a lower seizure burden may be associated with improved outcome (expert agreement). Sixth, a trial of pyridoxine may be attempted in neonates presenting with clinical features of vitamin B6-dependent epilepsy and seizures unresponsive to second-line ASM (expert agreement). Additional considerations include a standardized pathway for the management of neonatal seizures in each neonatal unit and informing parents/guardians about the diagnosis of seizures and initial treatment options.

A novel approach to seizures in neonates.

THE CHALLENGE OF SEIZURE RECOGNITION: Recognition of seizures in neonates remains the foremost challenge to overcome. All neonates at risk for seizures, especially the critically ill, should undergo video-EEG monitoring. The initial step toward an accurate diagnosis is the accurate description and interpretation of the electro-clinical phenotype. THE IMPORTANCE OF SEIZURE SEMIOLOGY AND ASSOCIATION WITH ETIOLOGY: The early distinction between acute provoked seizures and neonatal-onset epilepsies serves as the primary determinant for guiding management, treatment choices, and duration. Seizures in neonates should be seen as a symptom, not a disease, and their semiology may suggest the etiology. TREATMENT OF ACUTE PROVOKED SEIZURES: Neonates with hypoxic-ischemic encephalopathy respond best to phenobarbital, while levetiracetam is a better choice for neonates with congenital heart diseases. Anti-seizure medication can be discontinued after 72 h of seizure freedom, before discharge from the hospital. TREATMENT OF NEONATAL EPILEPSIES: Neonates with epilepsy usually require a personalized, etiology-based approach in terms of choice and duration of treatment. Neonates with channelopathies tend to respond to sodium channel blockers such as carbamazepine, oxcarbazepine, or phenytoin. The surgical option should be considered early in cases of large brain malformations, such as hemimegalencephaly.

Early recognition of characteristic conventional and amplitude-integrated EEG patterns of seizures in SCN2A and KCNQ3-related epilepsy in neonates.

PURPOSE: Early recognition of seizures in neonates secondary to pathogenic variants in potassium or sodium channel coding genes is crucial, as these seizures are often resistant to commonly used anti-seizure medications but respond well to sodium channel blockers. Recently, a characteristic ictal amplitude-integrated electroencephalogram (aEEG) pattern was described in neonates with KCNQ2-related epilepsy. We report a similar aEEG pattern in seizures caused by SCN2A- and KCNQ3-pathogenic variants, as well as conventional EEG (cEEG) descriptions. METHODS: International multicentre descriptive study, reporting clinical characteristics, aEEG and cEEG findings of 13 neonates with seizures due to pathogenic SCN2A- and KCNQ3-variants. As a comparison group, aEEGs and cEEGs of neonates with seizures due to hypoxic-ischemic encephalopathy (n = 117) and other confirmed genetic causes affecting channel function (n = 55) were reviewed. RESULTS: In 12 out of 13 patients, the aEEG showed a characteristic sequence of brief onset with a decrease, followed by a quick rise, and then postictal amplitude attenuation. This pattern correlated with bilateral EEG onset attenuation, followed by rhythmic discharges ending in several seconds of post-ictal amplitude suppression. Apart from patients with KCNQ2-related epilepsy, none of the patients in the comparison groups had a similar aEEG or cEEG pattern. DISCUSSION: Seizures in SCN2A- and KCNQ3-related epilepsy in neonates can usually be recognized by a characteristic ictal aEEG pattern, previously reported only in KCNQ2-related epilepsy, extending this unique feature to other channelopathies. Awareness of this pattern facilitates the prompt initiation of precision treatment with sodium channel blockers even before genetic results are available.

BRAT1-related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients.

BRAT1 biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations. Fifty-nine individuals presented with BRAT1-related RMFSL phenotype. Most of them had no psychomotor acquisition (100%), epilepsy (100%), microcephaly (91%), limb rigidity (93%), and died prematurely (93%). Thirty-eight individuals presented a non-lethal phenotype of BRAT1-related NEDCAS phenotype. Seventy-six percent of the patients in this group were able to walk and 68% were able to say at least a few words. Most of them had cerebellar ataxia (82%), axial hypotonia (79%) and cerebellar atrophy (100%). Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46; 100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS (28/34; 82%). The phenotype of patients carrying splice variants was variable: 41% presented with RMFSL (7/17) and 59% with NEDCAS (10/17).

Relationship Between Epileptic Activity and Developmental Outcome in KCNQ2-Related Epilepsy.

BACKGROUND: We aim to describe a cohort of patients with KCNQ2-related epilepsy and evaluate the relationship between epileptic activity and developmental outcome. This topic is relevant for the selection of clinical end points in future clinical trials, since cessation of seizures may or may not be the most important outcome. METHODS: This retrospective cohort study of children with self-limited (familial) neonatal epilepsy and developmental and epileptic encephalopathy due to pathogenic variants in KCNQ2 was conducted between 2019 and 2021. We collected clinical, therapeutic, and genetic information. Available electroencephalographic recordings were reviewed by a neurophysiologist. Gross motor function was determined using the Gross Motor Function Classification System (GMFCS). The Vineland Adaptive Behavior Composite standard score (ABC SS) was used to measure adaptive functioning. RESULTS: Among 44 children (mean age 8.1 ± 4.0 years, 45.5% were male), 15 of 44 had S(F)NE, and 29 of 44 had DEE. Delayed seizure freedom was more frequent in DEE than in S(F)NE (P = 0.025), but no correlation was observed between age at seizure freedom and developmental outcome in patients with DEE. Multifocal interictal epileptiform abnormalities at epilepsy onset were more frequent in DEE than in S(F)NE (P = 0.014), and were associated with higher GMFCS (P = 0.027) and lower ABC SS (P = 0.048) in patients with DEE. Disorganized background activity at follow-up was more frequent in DEE than in S(F)NE (P = 0.001), and was associated with higher GMFCS levels (P = 0.009) and lower ABC SS (P = 0.005) in patients with DEE. CONCLUSIONS: This study shows a partial correlation between epileptic activity and developmental outcome in KCNQ2-related epilepsy.

Clinical and Neurophysiologic Phenotypes in Neonates With BRAT1 Encephalopathy.

BACKGROUND AND OBJECTIVES: BRAT1 encephalopathy is an ultra-rare autosomal recessive neonatal encephalopathy. We delineate the neonatal electroclinical phenotype at presentation and provide insights for early diagnosis. METHODS: Through a multinational collaborative, we studied a cohort of neonates with encephalopathy associated with biallelic pathogenic variants in BRAT1 for whom detailed clinical, neurophysiologic, and neuroimaging information was available from the onset of symptoms. Neuropathologic changes were also analyzed. RESULTS: We included 19 neonates. Most neonates were born at term (16/19) from nonconsanguineous parents. 15/19 (79%) were admitted soon after birth to a neonatal intensive care unit, exhibiting multifocal myoclonus, both spontaneous and exacerbated by stimulation. 7/19 (37%) had arthrogryposis at birth, and all except 1 progressively developed hypertonia in the first week of life. Multifocal myoclonus, which was present in all but 1 infant, was the most prominent manifestation and did not show any EEG correlate in 16/19 (84%). Video-EEG at onset was unremarkable in 14/19 (74%) infants, and 6 (33%) had initially been misdiagnosed with hyperekplexia. Multifocal seizures were observed at a median age of 14 days (range: 1-29). During the first months of life, all infants developed progressive encephalopathy, acquired microcephaly, prolonged bouts of apnea, and bradycardia, leading to cardiac arrest and death at a median age of 3.5 months (range: 20 days to 30 months). Only 7 infants (37%) received a definite diagnosis before death, at a median age of 34 days (range: 25-126), and almost two-thirds (12/19, 63%) were diagnosed 8 days to 12 years postmortem (median: 6.5 years). Neuropathology examination, performed in 3 patients, revealed severely delayed myelination and diffuse astrogliosis, sparing the upper cortical layers. DISCUSSION: BRAT1 encephalopathy is a neonatal-onset, rapidly progressive neurologic disorder. Neonates are often misdiagnosed as having hyperekplexia, and many die undiagnosed. The key phenotypic features are multifocal myoclonus, an organized EEG, progressive, persistent, and diffuse hypertonia, and an evolution into refractory multifocal seizures, prolonged bouts of apnea, bradycardia, and early death. Early recognition of BRAT1 encephalopathy allows for prompt workup, appropriate management, and genetic counseling.

Characteristics of Neonates with Cardiopulmonary Disease Who Experience Seizures: A Multicenter Study.

OBJECTIVE: To compare key seizure and outcome characteristics between neonates with and without cardiopulmonary disease. STUDY DESIGN: The Neonatal Seizure Registry is a multicenter, prospectively acquired cohort of neonates with clinical or electroencephalographic (EEG)-confirmed seizures. Cardiopulmonary disease was defined as congenital heart disease, congenital diaphragmatic hernia, and exposure to extracorporeal membrane oxygenation. We assessed continuous EEG monitoring strategy, seizure characteristics, seizure management, and outcomes for neonates with and without cardiopulmonary disease. RESULTS: We evaluated 83 neonates with cardiopulmonary disease and 271 neonates without cardiopulmonary disease. Neonates with cardiopulmonary disease were more likely to have EEG-only seizures (40% vs 21%, P < .001) and experience their first seizure later than those without cardiopulmonary disease (174 vs 21 hours of age, P < .001), but they had similar seizure exposure (many-recurrent electrographic seizures 39% vs 43%, P = .27). Phenobarbital was the primary initial antiseizure medication for both groups (90%), and both groups had similarly high rates of incomplete response to initial antiseizure medication administration (66% vs 68%, P = .75). Neonates with cardiopulmonary disease were discharged from the hospital later (hazard ratio 0.34, 95% CI 0.25-0.45, P < .001), although rates of in-hospital mortality were similar between the groups (hazard ratio 1.13, 95% CI 0.66-1.94, P = .64). CONCLUSION: Neonates with and without cardiopulmonary disease had a similarly high seizure exposure, but neonates with cardiopulmonary disease were more likely to experience EEG-only seizures and had seizure onset later in the clinical course. Phenobarbital was the most common seizure treatment, but seizures were often refractory to initial antiseizure medication. These data support guidelines recommending continuous EEG in neonates with cardiopulmonary disease and indicate a need for optimized therapeutic strategies.

Disorders of Neuronal Migration/Organization Convey the Highest Risk of Neonatal Onset Epilepsy Compared With Other Congenital Brain Malformations.

BACKGROUND: Although seizures in neonates are common and often due to acute brain injury, 10-15% are unprovoked from congenital brain malformations. A better understanding of the risk of neonatal-onset epilepsy by the type of brain malformation is essential for counseling and monitoring. METHODS: In this retrospective cohort study, we evaluated 132 neonates with congenital brain malformations and their risk of neonatal-onset epilepsy. Malformations were classified into one of five categories based on imaging patterns on prenatal or postnatal imaging. Infants were monitored with continuous video EEG (cEEG) for encephalopathy and paroxysmal events in addition to abnormal neuroimaging. RESULTS: Seventy-four of 132 (56%) neonates underwent EEG monitoring, and 18 of 132 (14%) were diagnosed with neonatal-onset epilepsy. The highest prevalence of epilepsy was in neonates with disorders of neuronal migration/organization (9/34, 26%; 95% confidence interval [CI] = 13-44%), followed by disorders of early prosencephalic development (6/38, 16%; 95% CI = 6-31%), complex total brain malformations (2/16, 13%; 95% CI = 2-38%), and disorders of midbrain/hindbrain malformations (1/30, 3%; 95% CI = 0-17%). Of neonates with epilepsy, 5 of 18 (28%) had only electrographic seizures, 13 of 18 (72%) required treatment with two or more antiseizure medicines (ASMs), and 7 of 18 (39%) died within the neonatal period. CONCLUSION: Our results demonstrate that disorders of neuronal migration/organization represent the highest-risk group for early-onset epilepsy. Seizures are frequently electrographic only, require treatment with multiple ASMs, and portend a high mortality rate. These results support American Clinical Neurophysiology Society recommendations for EEG monitoring during the neonatal period for infants with congenital brain malformations.

Neonatal presentation of genetic epilepsies: Early differentiation from acute provoked seizures.

OBJECTIVE: Although most seizures in neonates are due to acute brain injury, some represent the first sign of neonatal onset genetic epilepsies. Delay in recognition and lack of expert assessment of neonates with epilepsy may result in worse developmental outcomes. As in older children and adults, seizure semiology in neonates is an essential determinant in diagnosis. We aimed to establish whether seizure type at presentation in neonates can suggest a genetic etiology. METHODS: We retrospectively analyzed the clinical and electroencephalographic (EEG) characteristics of seizures in neonates admitted in two Level IV neonatal intensive care units, diagnosed with genetic epilepsy, for whom a video-EEG recording at presentation was available for review, and compared them on a 1:2 ratio with neonates with seizures due to stroke or hypoxic-ischemic encephalopathy. RESULTS: Twenty neonates with genetic epilepsy were identified and compared to 40 neonates with acute provoked seizures. Genetic epilepsies were associated with pathogenic variants in KCNQ2 (n = 12), KCNQ3 (n = 2), SCN2A (n = 2), KCNT1 (n = 1), PRRT2 (n = 1), and BRAT1 (n = 2). All neonates with genetic epilepsy had seizures with clinical correlates that were either tonic (18/20) or myoclonic (2/20). In contrast, 17 of 40 (42%) neonates with acute provoked seizures had electrographic only seizures, and the majority of the remainder had clonic seizures. Time to first seizure was longer in neonates with genetic epilepsies (median = 60 h of life) compared to neonates with acute provoked seizures (median = 15 h of life, p < .001). Sodium channel-blocking antiseizure medications were effective in 13 of 14 (92%) neonates with tonic seizures who were trialed at onset or during the course of the epilepsy. SIGNIFICANCE: Seizure semiology is an easily accessible sign of genetic epilepsies in neonates. Early identification of the seizure type can prompt appropriate workup and treatment. Tonic seizures are associated with channelopathies and are often controlled by sodium channel-blocking antiseizure medications.

Seizure Control in Neonates Undergoing Screening vs Confirmatory EEG Monitoring.

OBJECTIVE: To determine whether screening continuous EEG monitoring (cEEG) is associated with greater odds of treatment success for neonatal seizures. METHODS: We included term neonates with acute symptomatic seizures enrolled in the Neonatal Seizure Registry (NSR), a prospective, multicenter cohort of neonates with seizures. We compared 2 cEEG approaches: (1) screening cEEG, initiated for indications of encephalopathy or paralysis without suspected clinical seizures; and (2) confirmatory cEEG, initiated for the indication of clinical events suspicious for seizures, either alone or in addition to other indications. The primary outcome was successful response to initial seizure treatment, defined as seizures resolved without recurrence within 30 minutes after initial loading dose of antiseizure medicine. Multivariable logistic regression analyses assessed the association between cEEG approach and successful seizure treatment. RESULTS: Among 514 neonates included, 161 (31%) had screening cEEG and 353 (69%) had confirmatory cEEG. Neonates with screening cEEG had a higher proportion of successful initial seizure treatment than neonates with confirmatory cEEG (39% vs 18%; p < 0.0001). After adjusting for covariates, there remained a greater odds ratio (OR) for successful initial seizure treatment in the screening vs confirmatory cEEG groups (adjusted OR 2.44, 95% confidence interval 1.45-4.11, p = 0.0008). CONCLUSIONS: These findings provide evidence from a large, contemporary cohort of neonates that a screening cEEG approach may improve odds of successful treatment of acute seizures. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for neonates a screening cEEG approach, compared to a confirmatory EEG approach, increases the probability of successful treatment of acute seizures.

The ILAE classification of seizures and the epilepsies: Modification for seizures in the neonate. Position paper by the ILAE Task Force on Neonatal Seizures.

Seizures are the most common neurological emergency in the neonatal period and in contrast to those in infancy and childhood, are often provoked seizures with an acute cause and may be electrographic-only. Hence, neonatal seizures may not fit easily into classification schemes for seizures and epilepsies primarily developed for older children and adults. A Neonatal Seizures Task Force was established by the International League Against Epilepsy (ILAE) to develop a modification of the 2017 ILAE Classification of Seizures and Epilepsies, relevant to neonates. The neonatal classification framework emphasizes the role of electroencephalography (EEG) in the diagnosis of seizures in the neonate and includes a classification of seizure types relevant to this age group. The seizure type is determined by the predominant clinical feature. Many neonatal seizures are electrographic-only with no evident clinical features; therefore, these are included in the proposed classification. Clinical events without an EEG correlate are not included. Because seizures in the neonatal period have been shown to have a focal onset, a division into focal and generalized is unnecessary. Seizures can have a motor (automatisms, clonic, epileptic spasms, myoclonic, tonic), non-motor (autonomic, behavior arrest), or sequential presentation. The classification allows the user to choose the level of detail when classifying seizures in this age group.

Graph theory in paediatric epilepsy: A systematic review.

Graph theoretical studies have been designed to investigate network topologies during life. Network science and graph theory methods may contribute to a better understanding of brain function, both normal and abnormal, throughout developmental stages. The degree to which childhood epilepsies exert a significant effect on brain network organisation and cognition remains unclear. The hypothesis suggests that the formation of abnormal networks associated with epileptogenesis early in life causes a disruption in normal brain network development and cognition, reflecting abnormalities in later life. Neurological diseases with onset during critical stages of brain maturation, including childhood epilepsy, may threaten this orderly neurodevelopmental process. According to the hypothesis that the formation of abnormal networks associated with epileptogenesis in early life causes a disruption in normal brain network development, it is then mandatory to perform a proper examination of children with new-onset epilepsy early in the disease course and a deep study of their brain network organisation over time. In regards, graph theoretical analysis could add more information. In order to facilitate further development of graph theory in childhood, we performed a systematic review to describe its application in functional dynamic connectivity using electroencephalographic (EEG) analysis, focussing on paediatric epilepsy.

Vomiting and retching as presenting signs of focal epilepsy in children.

Ictal vomiting is a rare condition easily misdiagnosed as a common disease. We report two children presenting with retching and vomiting as the main ictal manifestation. Patient 1 was a four-year-old girl with a history of daily nocturnal vomiting for two months, first interpreted as a functional disorder, then as a viral infection. She presented with vomiting accompanied by focal right-sided hemifacial clonic jerking, occurring multiple times per day. Video-EEG demonstrated ictal discharges associated with the retching and vomiting, over a normal background, and occasional interictal focal spikes. MRI was normal. PET demonstrated left-sided opercular hypometabolism. Patient 2 was a girl with a history of focal epilepsy, secondary to a right central dysembryoplastic tumour, first resected with subsequent seizure freedom at the age of three years. At five years of age, she presented with recurrent episodes of retching and vomiting initially diagnosed as migraine. Video-EEG showed ictal discharges, clinically correlating with retching, vomiting and clonic facial jerking, with normal interictal activity. Brain MRI showed a progression of the tumour. A second resection resulted in seizure freedom. Ictal vomiting often goes undiagnosed, especially in children, causing treatment delays. An ictal origin should be considered, particularly when the episodes are recurrent and stereotyped. [Published with video sequences].

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 ß-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 ß-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.

Response to cannabidiol in epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations: An open-label, prospective, interventional study.

Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) is a rare, developmental and epileptic encephalopathy most commonly associated with mutations in KCNT1, a potassium channel. Polymorphous migrating focal seizures begin within 6 months of life and are pharmacoresistant to standard anticonvulsants. Additional therapies are needed to decrease seizure frequency and subsequent developmental deterioration associated with EIMFS. Cannabidiol (CBD) has recently arisen in public interest due to its potential in treatment-resistant epilepsies as demonstrated in randomized controlled trials for Dravet Syndrome and Lennox-Gastaut Syndrome. Here we evaluate the response of three patients, all diagnosed with EIMFS secondary to KCNT1 mutations, to pharmaceutical grade CBD. Two patients showed no benefit and have since voluntarily stopped CBD. One patient showed no overall reduction in seizure frequency, however showed a notable reduction in seizure intensity with possible developmental progression. Further studies are needed to assess the potential benefit of CBD in treatment-resistant epilepsies such as EIMFS, with a focus on early identification and intervention.

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.