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.

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.