Clinical presentation of new onset refractory status epilepticus in children (the pSERG cohort).

OBJECTIVE: We aimed to characterize the clinical profile and outcomes of new onset refractory status epilepticus (NORSE) in children, and investigated the relationship between fever onset and status epilepticus (SE). METHODS: Patients with refractory SE (RSE) between June 1, 2011 and October 1, 2016 were prospectively enrolled in the pSERG (Pediatric Status Epilepticus Research Group) cohort. Cases meeting the definition of NORSE were classified as "NORSE of known etiology" or "NORSE of unknown etiology." Subgroup analysis of NORSE of unknown etiology was completed based on the presence and time of fever occurrence relative to RSE onset: fever at onset (≤24 h), previous fever (2 weeks-24 h), and without fever. RESULTS: Of 279 patients with RSE, 46 patients met the criteria for NORSE. The median age was 2.4 years, and 25 (54%) were female. Forty (87%) patients had NORSE of unknown etiology. Nineteen (48%) presented with fever at SE onset, 16 (40%) had a previous fever, and five (12%) had no fever. The patients with preceding fever had more prolonged SE and worse outcomes, and 25% recovered baseline neurological function. The patients with fever at onset were younger and had shorter SE episodes, and 89% recovered baseline function. SIGNIFICANCE: Among pediatric patients with RSE, 16% met diagnostic criteria for NORSE, including the subcategory of febrile infection-related epilepsy syndrome (FIRES). Pediatric NORSE cases may also overlap with refractory febrile SE (FSE). FIRES occurs more frequently in older children, the course is usually prolonged, and outcomes are worse, as compared to refractory FSE. Fever occurring more than 24 h before the onset of seizures differentiates a subgroup of NORSE patients with distinctive clinical characteristics and worse outcomes.

Factors associated with long-term outcomes in pediatric refractory status epilepticus.

OBJECTIVE: This study was undertaken to describe long-term clinical and developmental outcomes in pediatric refractory status epilepticus (RSE) and identify factors associated with new neurological deficits after RSE. METHODS: We performed retrospective analyses of prospectively collected observational data from June 2011 to March 2020 on pediatric patients with RSE. We analyzed clinical outcomes from at least 30 days after RSE and, in a subanalysis, we assessed developmental outcomes and evaluated risk factors in previously normally developed patients. RESULTS: Follow-up data on outcomes were available in 276 patients (56.5% males). The median (interquartile range [IQR]) follow-up duration was 1.6 (.9-2.7) years. The in-hospital mortality rate was 4% (16/403 patients), and 15 (5.4%) patients had died after hospital discharge. One hundred sixty-six (62.9%) patients had subsequent unprovoked seizures, and 44 (16.9%) patients had a repeated RSE episode. Among 116 patients with normal development before RSE, 42 of 107 (39.3%) patients with available data had new neurological deficits (cognitive, behavioral, or motor). Patients with new deficits had longer median (IQR) electroclinical RSE duration than patients without new deficits (10.3 [2.1-134.5] h vs. 4 [1.6-16] h, p = .011, adjusted odds ratio = 1.003, 95% confidence interval = 1.0008-1.0069, p = .027). The proportion of patients with an unfavorable functional outcome (Glasgow Outcome Scale-Extended score ≥ 4) was 22 of 90 (24.4%), and they were more likely to have received a continuous infusion. SIGNIFICANCE: About one third of patients without prior epilepsy developed recurrent unprovoked seizures after the RSE episode. In previously normally developing patients, 39% presented with new deficits during follow-up, with longer electroclinical RSE duration as a predictor.

Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures.

Autosomal recessive COX4I1 deficiency has been previously reported in a single individual with a homozygous pathogenic variant in COX4I1, who presented with short stature, poor weight gain, dysmorphic features, and features of Fanconi anemia. COX4I1 encodes subunit 4, isoform 1 of cytochrome c oxidase. Cytochrome c oxidase is a respiratory chain enzyme that plays an important role in mitochondrial electron transport and reduces molecular oxygen to water leading to the formation of ATP. Defective production of cytochrome c oxidase leads to a variable phenotypic spectrum ranging from isolated myopathy to Leigh syndrome. Here, we describe two siblings, born to consanguineous parents, who presented with encephalopathy, developmental regression, hypotonia, pathognomonic brain imaging findings resembling Leigh-syndrome, and a novel homozygous variant on COX4I1, expanding the known clinical phenotype associated with pathogenic variants in COX4I1.

A novel CACNA1A variant in a child with early stroke and intractable epilepsy.

BACKGROUND: CACNA1A variants have been described in several disorders that encompass a wide range of neurologic phenotypes, including hemiplegic migraine, ataxia, cognitive delay, and epilepsy. To date, ischemic stroke caused by a CACNA1A variant has only been reported once in the literature. METHODS: We describe a 4-year-old female with recurrent ischemic strokes beginning at 6 weeks of age, intractable epilepsy, and significant global developmental delay. Exome sequencing (ES) was completed for her evaluation. RESULTS: We found a novel de novo, likely pathogenic variant, p.Leu1692Gln in CACNA1A by ES. The substitution affects a leucine residue that is highly conserved in species from fish to primates. CONCLUSION: We present the second case of recurrent ischemic strokes in a patient with CACNA1A mutation. Our findings expand the phenotypic heterogeneity related to Cav 2.1 (P/Q-type) calcium channel dysfunction and suggest consideration of CACNA1A disorder in evaluation of pediatric strokes.

Hospital Emergency Treatment of Convulsive Status Epilepticus: Comparison of Pathways From Ten Pediatric Research Centers.

OBJECTIVE: We aimed to evaluate and compare the status epilepticus treatment pathways used by pediatric status epilepticus research group (pSERG) hospitals in the United States and the American Epilepsy Society (AES) status epilepticus guideline. METHODS: We undertook a descriptive analysis of recommended timing, dosing, and medication choices in 10 pSERG hospitals' status epilepticus treatment pathways. RESULTS: One pathway matched the timeline in the AES guideline; nine pathways described more rapid timings. All pathways matched the guideline's stabilization phase in timing and five suggested that first-line benzodiazepine (BZD) be administered within this period. For second-line therapy timing (initiation of a non-BZD antiepileptic drug within 20 to 40 minutes), one pathway matched the guideline; nine initiated the antiepileptic drug earlier (median 10 [range five to 15] minutes). Third-line therapy timings matched the AES guideline (40 minutes) in two pathways; eight suggested earlier timing (median 20 [range 15 to 30] minutes). The first-line BZD recommended in all hospitals was intravenous lorazepam; alternatives included intramuscular midazolam or rectal diazepam. In second-line therapy, nine pathways recommended fosphenytoin. For third-line therapy, eight pathways recommended additional boluses of second-line medications; most commonly phenobarbital. Two pathways suggested escalation to third-line medication; most commonly midazolam. We found variance in dosing for the following medications: midazolam as first-line therapy, fosphenytoin, and levetiracetam as second-line therapy, and phenobarbital as third-line therapy medications. CONCLUSIONS: The pSERG hospitals status epilepticus pathways are consistent with the AES status epilepticus guideline in regard to the choice of medications, but generally recommend more rapid escalation in therapy than the guideline.

Diagnosis and management of childhood epilepsy.

Epilepsy is a relatively common neurologic disorder in children that has important implications for development, parents, and society. Making the correct diagnosis starts with an accurate and complete history that consequently leads to a directed diagnostic workup. This article outlines a diagnostic and management approach to pediatric seizures and epilepsy syndromes. Making the correct diagnosis of epilepsy or nonepileptic imitators allows the practitioner to prescribe appropriate therapy. Initial management for typical epileptic syndromes and seizures and potential adverse effects are discussed. Alternative treatment options for pharmacologically resistant patients such as ketogenic diet, vagal nerve stimulation, and surgery are also discussed. While most children favorably respond to antiepileptic medications, early identification of medication failure is important to ensure optimal neurodevelopment.