SUMMARYObjectives: To describe the antiepileptic drug (AED) treatment of patients with early infantile epileptic encephalopathy due to KCNQ2 mutations during the neonatal phase and the first year of life. Methods: We identified 15 patients and reviewed the electroclinical, neuroimaging, and AED treatment data. Results: Seizure onset was between 1 and 4 days of age with daily tonic asymmetric, focal and clonic seizures in nine patients and status epilepticus in the remaining six. Electroencephalography (EEG) showed multifocal epileptiform abnormalities in nine patients and a burst-suppression pattern in six. All patients were trialed with adequate daily doses of several AEDs before they reached seizure freedom. Six patients (40%) achieved seizure control within 2 weeks of carbamazepine (CBZ) administration and five (33%) were seizure-free with phenytoin (PHT). The last four patients (27%) were successfully treated with topiramate (TPM) (two patients), levetiracetam (LEV) (one), and a combination of LEV with TPM (one). Most patients reached seizure freedom within the first year of life and remained seizure-free thereafter. Twelve patients had moderate-to-severe developmental delay at follow-up. However, the two patients whose seizures ceased within a few days of onset showed only mild cognitive impairment. Significance: Our findings suggest that drugs acting on sodium channels including CBZ and PHT should be considered as first-line treatment in patients with KCNQ2 encephalopathy. Voltage-gated sodium and potassium channels co-localize at the neuronal membrane. Therefore, the efficacy of drugs acting as sodium-channel blockers could be linked to their modulating effect on both channels. The type of KCNQ2 mutation might influence AED response as well as developmental outcome. Early recognition of KCNQ2 encephalopathy followed by the most appropriate and effective treatment may be important for reducing the neurodevelopmental impairment associated with this disorder.

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Objective: This study was undertaken to refine the spectrum of SCN1A epileptic disorders other than Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+) and optimize antiseizure management by correlating phenotype-genotype relationship and functional consequences of SCN1A variants in a cohort of patients.Methods: Sixteen probands carrying SCN1A pathogenic variants were ascertained via a national collaborative network. We also performed a literature review Funding information Investissements d'Avenir-Laboratory of Excellence "Ion Channels Science and Therapeutics", Grant/Award Number: ANR-11-LABX-0015-01; Université Côte d'Azur-IDEX Jedi, Grant/Award Number: ANR-15-IDEX-01; Foundation Famiglie Dravet ONLUS-Italy including individuals with SCN1A variants causing non-DS and non-GEFS+ phenotypes and compared the features of the two cohorts. Whole cell patch clamp experiments were performed for three representative SCN1A pathogenic variants.Results: Nine of the 16 probands (56%) had de novo pathogenic variants causing developmental and epileptic encephalopathy (DEE) with seizure onset at a median age of 2 months and severe intellectual disability. Seven of the 16 probands (54%), five with inherited and two with de novo variants, manifested focal epilepsies with mild or no intellectual disability. Sodium channel blockers never worsened seizures, and 50% of patients experienced long periods of seizure freedom.We found 13 SCN1A missense variants; eight of them were novel and never reported. Functional studies of three representative variants showed a gain of channel function. The literature review led to the identification of 44 individuals with SCN1A variants and non-DS, non-GEFS+ phenotypes. The comparison with our cohort highlighted that DEE phenotypes are a common feature. Significance:The boundaries of SCN1A disorders are wide and still expanding.In our cohort, >50% of patients manifested focal epilepsies, which are thus a frequent feature of SCN1A pathogenic variants beyond DS and GEFS+. SCN1A testing should therefore be included in the diagnostic workup of pediatric, familial and nonfamilial, focal epilepsies. Alternatively, non-DS/non-GEFS+ phenotypes might be associated with gain of channel function, and sodium channel blockers could control seizures by counteracting excessive channel function. Functional analysis evaluating the consequences of pathogenic SCN1A variants is thus relevant to tailor the appropriate antiseizure medication.

We report the management of refractory status epilepticus (SE) by using continuous intravenous infusions of lidocaine in a previously healthy 15-year-old girl with a "catastrophic encephalopathy" in whom a diagnosis of febrile infection-related epilepsy syndrome was supposed. One week after a banal pharyngitis and fever, the patient presented confusion and intractable clusters of seizures. Although she underwent multiple examinations investigating all possible etiologies (intracranial infection, autoimmune disease, or toxic and metabolic illness), all results were negative except a feeble positivity to Mycoplasma pneumoniae serum antibodies. SE was initially treated with benzodiazepine followed by administration of barbiturates and subsequent induction of coma because of refractory SE; different antiepileptic drugs (AEDs) were given at different times in a period of 6 weeks but clinical and electroencephalographic improvements were achieved only after continuous infusion of lidocaine. When she recovered from SE, the patient developed severe psychomotor and cognitive impairment associated with cerebral atrophy. Treatment with lidocaine or other alternative drugs in cases of prolonged SE should be taken into account as soon as it becomes clear that the clinical condition is refractory to common AEDs included in available guidelines for SE treatment, to improve the bad outcome of this severe condition, at least limiting the negative effects of prolonged high metabolic demand due to continuous epileptiform activity and/or the possible negative effects of prolonged burst-suppression coma.

The link between nonverbal learning disorder and right cerebral hemisphere dysfunction due to migraine attack is confirmed. Familial Hemiplegic Migraine can cause transient complex neuropsychological syndromes that can be overlooked if not appropriately investigated.