Abstracts

Rationale:
Super-refractory status epilepticus (SE) is SE that continues or recurs 24 hours or more after initiation of anesthetic therapy, including instances in which SE recurs on the reduction or withdrawal of anesthesia and is associated with high morbidity and mortality. Studies suggest that during prolonged seizures, the rate of GABAA receptor internalization is regulated by neuronal activity and this acceleration of receptor internalization contributes to the reduction of inhibitory transmission.
Method:
We discuss a 17-year-old female who had been hospitalized for 8 months with recurrent refractory SE who relapsed while in our inpatient rehabilitation unit. She was treated under an emergency investigational new drug (E-IND) application to the FDA with IV ganaxolone (GNX) (Marinus Pharmaceuticals).
Results:
A 17-year-old female with a history of sporadic primarily febrile and rare afebrile convulsive seizures in early childhood had been seizure-free for 10 years off medication until she began to have focal seizures with generalization. Seizure semiology was characterized by eye fluttering with rapid bilateral involvement at times with leftward head/eye deviation as clusters prior to generalization. She had recurrent seizures over the first three weeks and was admitted to an outside hospital for SE requiring intubation. Over the course of 7 months at the initial tertiary hospital she had 6 episodes of SE and required intubation 4 times with medically induced coma for seizure suppression. She was transferred to our inpatient pediatric rehabilitation unit after being seizure-free for one month on 5 antiseizure medications (cannabidiol, perampanel, phenobarbital, lacosamide, lorazepam), pyridoxine, ketogenic diet, anakinra, and menstrual suppression. A thorough infectious, metabolic, genetic, vascular and autoimmune evaluation was non-diagnostic. While in the inpatient rehabilitation unit she developed a fever of 41.7oC and respiratory viral panel was positive for parainfluenza. SE returned requiring transfer to the ICU for midazolam and pentobarbital infusions. vEEG monitoring throughout her course demonstrated multifocal seizure onset. She was seizure-free for two days after drips were weaned before seizures returned prompting VNS placement and a prolonged 2-week course of IV pentobarbital titrated to EEG burst suppression. As pentobarbital was weaned off, convulsive seizures returned (Figure 1). She was granted E-IND approval for a trial of IV to enteric GNX. GNX was administered using an IV bolus followed by infusion over 4 days: on day 1 pentobarbital was discontinued; by day 3 clinical and electrographic seizures stopped. On Day 5 she was transitioned from IV to enteric GNX and has remained seizure-free (Figure 2).
Conclusion:
GNX is a positive allosteric modulator of the GABAA receptor. It is a 3β-methylated synthetic analog of the endogenous progesterone metabolite, allopregnanolone. GNX differs from other GABA agents by interacting with both synaptic and extrasynaptic GABAA receptors and at binding sites distinct from benzodiazepines or barbiturates. In this patient, GNX was effective in cessation of super-refractory SE. Additional studies of GNX for super-refractory SE are warranted.
Funding:
:Marinus Pharmaceuticals provided IV and oral ganaxolone. No monetary support was provided.