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Precision medicine for Mendelian epilepsy is rapidly developing. We describe an early infant with severely pharmacoresistant multifocal epilepsy. Exome sequencing revealed the de novo variant p.(Leu296Phe) in the gene KCNA1, encoding the voltage‐gated K+ channel subunit KV1.1. So far, loss‐of‐function variants in KCNA1 have been associated with episodic ataxia type 1 or epilepsy. Functional studies of the mutated subunit in oocytes revealed a gain‐of‐function caused by a hyperpolarizing shift of voltage dependence. Leu296Phe channels are sensitive to block by 4‐aminopyridine. Clinical use of 4‐aminopyridine was associated with reduced seizure burden, enabled simplification of co‐medication and prevented rehospitalization. [ABSTRACT FROM AUTHOR]

In a retrospective case series of 10 children with cryptogenic FIRES, we sought to describe the early clinical course and potential biomarkers following anakinra initiation. Six children achieved anesthetic withdrawal within 3 weeks of therapy and one in week four. Of the available cEEG (six children), CRP (10 children), and serum cytokine (six children) studies, there were temporal changes in highly epileptiform bursts (observed in three children), CRP, IL‐6, and IL‐10 levels that might parallel clinical progression. These observations may represent candidate biomarkers for monitoring clinical progression and therapeutic interventions including anakinra, which merits further investigation in future studies. [ABSTRACT FROM AUTHOR]

Febrile infection‐related epilepsy syndrome (FIRES) is a rare catastrophic epileptic encephalopathy that presents suddenly in otherwise normal children and young adults causing significant neurological disability, chronic epilepsy, and high rates of mortality. To suggest a therapy protocol to improve outcome of FIRES, workshops were held in conjunction with American Epilepsy Society annual meeting between 2017 and 2019. An international group of pediatric epileptologists, pediatric neurointensivists, rheumatologists and basic scientists with interest and expertise in FIRES convened to propose an algorithm for a standardized approach to the diagnosis and treatment of FIRES. The broad differential for refractory status epilepticus (RSE) should include FIRES, to allow empiric therapies to be started early in the clinical course. FIRES should be considered in all previously healthy patients older than two years of age who present with explosive onset of seizures rapidly progressing to RSE, following a febrile illness in the preceding two weeks. Once FIRES is suspected, early administrations of ketogenic diet and anakinra (the IL‐1 receptor antagonist that blocks biologic activity of IL‐1β) are recommended. [ABSTRACT FROM AUTHOR]

Summary: Objective: Phenobarbital is frequently used in pediatric patients for treatment and prophylaxis of seizures. Pharmacokinetic data for this patient population is lacking and would assist in dosing decisions. Methods: A retrospective population pharmacokinetic analysis was designed for all pediatric patients <19 years of age initiated on phenobarbital at our institution from January 2011 to June 2017. Patients were included if they were initiated on intravenous or enteral phenobarbital for treatment or prophylaxis of seizures and had a serum phenobarbital concentration monitored while an inpatient. Data collection included the following: age, weight, height, gestational age, core body temperature, serum creatinine, blood urea nitrogen, aspartase aminotransferase, alanine aminotransferase, urine output over the prior 12 hours, phenobarbital doses and serum concentrations, and potential drug–drug interactions. Descriptive statistical methods were used to summarize the data. Pharmacokinetic analysis was performed with NONMEM and simulation was performed for doses of 10, 20, 30, and 40 mg kg−1 dose−1, iv, followed by enteral doses of 3, 4, 5, and 6 mg kg−1 d−1. Results: A total of 355 patients (50.3% male, median gestational age 39 weeks (interquartile range [IQR] 35, 40), median age 0.28 years (IQR 0.06, 0.82). Median phenobarbital dose was enteral = 2.6 (IQR 1.9, 3.9) mg kg−1 dose−1; intravenous = 2.6 (IQR 2.2, 4.9) mg kg−1 dose−1) and mean serum concentration was 41.1 ± 23.9 mg/L at median 6.5 (IQR 2.9, 11.1) hours after a dose. A one‐compartment proportional error model best fit the data where clearance and volume of distribution were allometrically scaled using fat‐free mass. Significant covariates included serum creatinine, postmenstrual age, and drug–drug interactions on clearance, and age in years on volume of distribution. Significance: Phenobarbital dosing of 30 mg kg−1 dose−1,iv, followed by 4 mg kg−1 d−1 had the highest probability of attaining a therapeutic concentration at 7 days. Postmenstrual age and drug–drug interactions should be incorporated into dosing decisions. [ABSTRACT FROM AUTHOR]

We review our experience with high-dose intravenous levetiracetam (IV-LEV) for acute seizure exacerbations in nine children with medically intractable epilepsy. All children had acute repetitive seizures—while on chronic antiepileptic drugs—that either led to hospitalization (eight) or occurred during hospitalization (one), and received doses of IV-LEV of 150 mg/kg/day or greater, with a mean dose of 228 ± 48 mg/kg/day. Eight of nine children had resolution of the acute repetitive seizures. Seizure frequency was reduced to less than baseline in seven children (seizure-free in two, ≥80% reduction in four, and 50% reduction in one). Except for one child with increased seizures, IV-LEV was well tolerated in all children without complications. [ABSTRACT FROM AUTHOR]

Summary: Sensory symptoms are commonly seen in association with focal epilepsy, but viscerosensory auras, such as pharyngeal dysesthesias, are rarely the main clinical manifestation. With the introduction of vagal nerve stimulation (VNS) for medically refractory epilepsy, viscerosensory symptoms commonly occur as an adverse effect of VNS. Voice alterations (hoarseness or tremulousness), local neck or throat pain, and cough are the most common adverse effects seen during active stimulation (on-time). Numbness of the throat, neck, or chin, as well as a tingling sensation of the neck and throat is directly related to stimulation intensity. We present a case in which recurrent pharyngeal sensations caused a diagnostic dilemma and in which monitoring the VNS artifact during video/EEG and correlating this with clinical symptoms helped determine the etiology of the recurrent sensory symptoms. [ABSTRACT FROM AUTHOR]

Summary: Purpose: Topiramate (TPM) is widely used as add-on therapy for epilepsy. TPM inhibits carbonic anhydrase, which may result in metabolic acidosis from decreased serum bicarbonate. The ketogenic diet (KGD) predisposes patients to metabolic acidosis, especially during induction. In children with refractory epilepsy, cotreatment with TPM and KGD may be considered, but special attention should be paid to the combined risks for metabolic acidosis and nephrolithiasis. We report our experience in 14 children cotreated with TPM and the KGD. Methods: Medical records of 14 children cotreated with the KGD and TPM for medically refractory epilepsy were reviewed retrospectively. Bicarbonate levels were analyzed and correlated with clinical profiles, including duration of cotreatment, TPM dose, KGD ratio, and seizure control. Results: Nine children had a <20% decrease in bicarbonate levels, from 5.3 to 12.3 mEq/L (mean, 7.6 mEq/L). Cotreatment was continued in all patients for duration of 33 to 544 days (seven had remained on cotreatment at the end of the study period), although two children required bicarbonate supplements to continue the KGD. No patient had nephrolithiasis. Conclusions: Although a large decrease in bicarbonate level occurred in the majority of children, the decrease appeared mostly at the time of KGD induction when added to prior TPM therapy. Bicarbonate levels should be monitored carefully with TPM and KGD cotreatment, and bicarbonate supplements given when symptomatic. [ABSTRACT FROM AUTHOR]

Examines the administration of topiramate (TPM) and metabolic acidosis in pediatric epilepsy in Boston, Massachusetts. Mechanisms of action of TPM; Inhibition of carbonic anhydrase; Decrease in serum bicarbonate levels; Development of tachypnea due to acidosis.

A response by Satish Agadi and colleagues to a letter to the editor on grading medically refractory epilepsy (MFR) in a 2010 issue is presented.

Zonisamide is a broad-spectrum antiepileptic drug used to treat various types of seizures. Although visual hallucinations have not been reported as an adverse effect of this agent, we describe three patients who experienced complex visual hallucinations and altered mental status after zonisamide treatment was begun or its dosage increased. All three had been diagnosed earlier with epilepsy, and their electroencephalogram (EEG) findings were abnormal. During monitoring, visual hallucinations did not correlate with EEG readings, nor did video recording capture any of the described events. None of the patients had experienced visual hallucinations before this event. The only recent change in their treatment was the introduction or increased dosage of zonisamide. With either discontinuation or decreased dosage of the drug the symptoms disappeared and did not recur. Further observations and reports will help clarify this adverse effect. Until then, clinicians need to be aware of this possible complication associated with zonisamide.