Objective: Acute encephalopathy may occur in COVID-19-infected patients. We investigated whether medically indicated EEGs performed in acutely ill patients under investigation (PUIs) for COVID-19 report epileptiform abnormalities and whether these are more prevalent in COVID-19 positive than negative patients. Methods: In this retrospective case series, adult COVID-19 inpatient PUIs underwent EEGs for acute encephalopathy and/or seizure-like events. PUIs had 8-channel headband EEGs (Ceribell; 20 COVID-19 positive, 6 COVID-19 negative); 2 more COVID-19 patients had routine EEGs. Overall, 26 Ceribell EEGs, 4 routine and 7 continuous EEG studies were reviewed. EEGs were interpreted by board-certified clinical neurophysiologists (n = 16). EEG findings were correlated with demographic data, clinical presentation and history, and medication usage. Fisher's exact test was used. Results: We included 28 COVID-19 PUIs (30-83 years old), of whom 22 tested positive (63.6% males) and 6 tested negative (33.3% male). The most common indications for EEG, among COVID-19-positive vs COVID-19-negative patients, respectively, were new onset encephalopathy (68.2% vs 33.3%) and seizure-like events (14/22, 63.6%; 2/6, 33.3%), even among patients without prior history of seizures (11/17, 64.7%; 2/6, 33.3%). Sporadic epileptiform discharges (EDs) were present in 40.9% of COVID-19-positive and 16.7% of COVID-19-negative patients; frontal sharp waves were reported in 8/9 (88.9%) of COVID-19-positive patients with EDs and in 1/1 of COVID-19-negative patient with EDs. No electrographic seizures were captured, but 19/22 COVID-19-positive and 6/6 COVID-19-negative patients were given antiseizure medications and/or sedatives before the EEG. | 315GALANOPOULOU et AL. | METHODS | Study design, inclusion and exclusion criteria

Childhood epileptic encephalopathies are age-dependent disorders of the brain whose hallmarks include loss of neurologic function over time, abnormal electroencephalographic findings, and seizures. Ictal and interictal electrographic activity are conjointly thought to be at the root of the often devastating neuropsychological deterioration, which is specific to the maturing brain. The goals of treatment are not only to control seizures, but also to prevent or reverse neurologic loss of function. In general, time is of the essence in diagnosis, and experienced specialists should promptly design a treatment plan. Hormonal and immune therapies are at the forefront of treatment in many cases, with traditional antiepileptic drugs and surgery (when an identifiable lesion is present) playing a limited role. However, gold standard evidence for treatment of epileptic encephalopathies remains limited. Ongoing clinical and basic research may lead to better understanding of these catastrophic conditions and to better and more effective therapies.

The solute carrier (SLC) superfamily encompasses >400 transmembrane transporters involved in the exchange of amino acids, nutrients, ions, metals, neurotransmitters and metabolites across biological membranes. SLCs are highly expressed in the mammalian brain; defects in nearly 100 unique SLC-encoding genes (OMIM: https://www.omim.org) are associated with rare Mendelian disorders including developmental and epileptic encephalopathy (DEE) and severe neurodevelopmental disorders (NDDs). Exome sequencing and family-based rare variant analyses on a cohort with NDD identified two siblings with DEE and a shared deleterious homozygous splicing variant in SLC38A3. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate. Additional subjects with a similar DEE phenotype and biallelic predicted-damaging SLC38A3 variants were ascertained through GeneMatcher and collaborations with research and clinical molecular diagnostic laboratories. Untargeted metabolomic analysis was performed to identify novel metabolic biomarkers. Ten individuals from seven unrelated families from six different countries with deleterious biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability, hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment were present in the majority. Epilepsy was drug-resistant in half. Metabolomic analysis revealed perturbations of glutamate, histidine, and nitrogen metabolism in plasma, urine, and cerebrospinal fluid of selected subjects, potentially representing biomarkers of disease. Our data support the contention that SLC38A3 is a novel disease gene for DEE and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis.