Abstracts

Rationale: Super-refractory status epilepticus (SRSE) is status epilepticus (SE) that continues or recurs after 24 hours or more of anesthetic therapy, including instances in which SE recurs during the reduction or withdrawal of anesthesia. SRSE is associated with high morbidity and mortality. Synaptic GABA_A receptor (GABA_AR) internalization contributes to the intractable nature of SRSE. Ganaxolone is a 3β-methylated synthetic analog of the endogenous neuroactive steroid, allopregnanolone, that has positive allosteric modulatory activity on synaptic and extrasynaptic GABA_A receptors. It binds to unique neurosteroid sites distinct from benzodiazepines or barbiturates. Ganaxolone is currently in clinical trials to treat rare pediatric seizure disorders and refractory SE.

Methods: Two pediatric patients with SRSE were treated under emergency investigational new drug (E-IND) applications with intravenous (IV) ganaxolone administered as an initial bolus and a maintenance infusion for up to 6 days, with as-needed, intermittent IV boluses. Treatment with IV ganaxolone was followed by a transition to chronic treatment using an enteral formulation.

Results: Patient 1: A 17-year-old female with a remote history of sporadic seizures in early childhood was transferred to Levine Children’s for inpatient rehabilitation after having recurrent refractory SE over a 7-month outside hospitalization. She was on 5 antiseizure medications (ASMs): cannabidiol, perampanel, phenobarbital, lacosamide, and lorazepam along with pyridoxine, ketogenic diet, anakinra, and menstrual suppression. She developed SE in association with a febrile URI. SE persisted, requiring midazolam and pentobarbital infusions. After multiple failed attempts to wean pentobarbital, IV ganaxolone was initiated. On day 1 pentobarbital was discontinued and, by day 3, all seizures stopped. On day 5, IV ganaxolone was tapered while transitioning to the enteric formulation without recurrence of seizures (Figure 1).

Patient 2: A 7-year-old, previously healthy female presented with encephalopathy and fever, who developed SRSE concordant with FIRES (fever-induced refractory epilepsy syndrome). SE persisted despite 5 ASMs (levetiracetam, valproic acid, perampanel, lacosamide, and zonisamide) and midazolam, pentobarbital and subsequent ketamine infusions. IV ganaxolone was initiated and transitioned to the enteric formulation by day 6. Midazolam was discontinued by day 2; ketamine was discontinued by day 8 with the assistance of phenobarbital (Figure 2).

In both patients, video EEG monitoring demonstrated multifocal seizure onset. Thorough infectious, metabolic, genetic, vascular, and autoimmune evaluations were non-diagnostic in both patients. Seizure control remains sustained in the outpatient setting with maintenance ganaxolone in combination with other ASMs.

Conclusions: Ganaxolone was effective in terminating SRSE in two pediatric patients, permitting IV anesthetics to be weaned. Seizure control was maintained after transitioning to enteric ganaxolone. Further investigation of ganaxolone as a treatment for SRSE is warranted.

Funding: Please list any funding that was received in support of this abstract.: Marinus Pharmaceuticals provided IV and oral ganaxolone. No monetary support was provided.