Epilepsy surgery as a treatment option for select patients with PCDH19-related epilepsy.

PCDH19 is a common epilepsy gene causing medication resistant epilepsy with fever-related seizures. Traditionally, patients with PCDH19-related epilepsy have not been considered surgical candidates. This retrospective review evaluated three patients with pathogenic variants in PCDH19 who presented with seizures in childhood, had one seizure semiology, became medication resistant, and had concordant imaging, seizure semiology and electrographic findings. All three patients ultimately underwent temporal lobectomy, resulting in seizure freedom. These findings suggest epilepsy surgery can be an effective treatment option for select patients with PCDH19-related epilepsy and a single seizure semiology.

Outcome of Neonates Presenting With Severe Cardiac Failure due to Cerebral Arteriovenous Fistula.

BACKGROUND: Congenital cerebral arteriovenous fistulas (AVFs), including vein of Galen malformations, presenting in infancy carry variable mortality and morbidity. This study aimed to describe the outcome of neonates with cerebral AVFs who present with refractory cardiac failure. METHODS: Retrospective chart review of neonates with refractory cardiac failure due to cerebral AVFs presenting before 28 days of age in a single-center neuro-intensive care nursery over a 12-year period (2008-2020) was conducted. RESULTS: Seventeen neonates were included. Twelve had a vein of Galen malformation, four a non-galenic pial AVF, and one a dural AVF. Seven neonates (41%) died without receiving an embolization procedure. The remaining ten were critically ill. Seven (70%) were mechanically ventilated and on nitric oxide, 5 (50%) were on pressors, and 6 (60%) had renal and/or hepatic dysfunction. Seven (70%) had pre-existing brain injury on imaging. The first embolization procedure occurred at a median age of 4 days (range: 0-8 d). Complications included intracranial hemorrhage in 8 of 10 (80%) and seizures in 5 of 8 (62%). Five (50%) neonates who underwent embolization died. Among the 5 neonates who survived, all have motor impairment. Four (80%) developed hydrocephalus requiring a ventriculoperitoneal shunt, and 2 (40%) developed epilepsy and are nonverbal. CONCLUSION: In this cohort of critically ill neonates with cerebral AVF, all seven who did not receive embolization and half of ten who were treated died. The five survivors all have neurodevelopmental impairment. This information may be helpful to parents and providers who make decisions regarding life-sustaining treatments for neonates with cerebral AVFs and refractory cardiac failure.

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 Encephalopathy: Beyond Hypoxic-Ischemic Encephalopathy.

Neonatal encephalopathy is a clinical syndrome of neurologic dysfunction that encompasses a broad spectrum of symptoms and severity, from mild irritability and feeding difficulties to coma and seizures. It is vital for providers to understand that the term "neonatal encephalopathy" is simply a description of the neonate's neurologic status that is agnostic to the underlying etiology. Unfortunately, hypoxic-ischemic encephalopathy (HIE) has become common vernacular to describe any neonate with encephalopathy, but this can be misleading. The term should not be used unless there is evidence of perinatal asphyxia as the primary cause of encephalopathy. HIE is a common cause of neonatal encephalopathy; the differential diagnosis also includes conditions with infectious, vascular, epileptic, genetic/congenital, metabolic, and toxic causes. Because neonatal encephalopathy is estimated to affect 2 to 6 per 1,000 term births, of which HIE accounts for approximately 1.5 per 1,000 term births, (1)(2)(3)(4)(5)(6) neonatologists and child neurologists should familiarize themselves with the evaluation, diagnosis, and treatment of the diverse causes of neonatal encephalopathy. This review begins by discussing HIE, but also helps practitioners extend the differential to consider the broad array of other causes of neonatal encephalopathy, emphasizing the epidemiology, neurologic presentations, diagnostics, imaging findings, and therapeutic strategies for each potential category.

Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment.

Clinical and genetic features of five unrelated patients with de novo pathogenic variants in the synaptic vesicle-associated membrane protein 2 (VAMP2) reveal common features of global developmental delay, autistic tendencies, behavioral disturbances, and a higher propensity to develop epilepsy. For one patient, a cognitively impaired adolescent with a de novo stop-gain VAMP2 mutation, we tested a potential treatment strategy, enhancing neurotransmission by prolonging action potentials with the aminopyridine family of potassium channel blockers, 4-aminopyridine and 3,4-diaminopyridine, in vitro and in vivo. Synaptic vesicle recycling and neurotransmission were assayed in neurons expressing three VAMP2 variants by live-cell imaging and electrophysiology. In cellular models, two variants decrease both the rate of exocytosis and the number of synaptic vesicles released from the recycling pool, compared with wild-type. Aminopyridine treatment increases the rate and extent of exocytosis and total synaptic charge transfer and desynchronizes GABA release. The clinical response of the patient to 2 years of off-label aminopyridine treatment includes improved emotional and behavioral regulation by parental report, and objective improvement in standardized cognitive measures. Aminopyridine treatment may extend to patients with pathogenic variants in VAMP2 and other genes influencing presynaptic function or GABAergic tone, and tested in vitro before treatment.