Super Refractory Status Epilepticus Improved After Emergency Use of Ganaxolone: Case Report

Abstract

We present a case of a 34-year-old man with epilepsy who developed super refractory status epilepticus in the setting of COVID-19 pneumonia in whom aggressive therapy with multiple parenteral, enteral, and non-pharmacologic interventions were utilized without lasting improvement in clinical examination or electroencephalogram (EEG). The patient presented with multiple recurrences of electrographic status epilepticus throughout a prolonged hospital stay. Emergency use authorization was obtained for intravenous ganaxolone, a neuroactive steroid that is a potent modulator of both synaptic and extrasynaptic GABA_A receptors. Following administration of intravenous ganaxolone according to a novel dosing paradigm, the patient showed sustained clinical and electrographic improvement.

Introduction

Super refractory status epilepticus (SRSE), status epilepticus that continues beyond 24 h despite the use of anesthetic agents or reappears upon their weaning, persists as a challenging clinical problem associated with high morbidity and mortality. ¹ Possible treatment for SRSE includes a combination of anti-seizure medications (ASM) and anesthetic agents, as well as adjunctive therapies including immunotherapy, ketogenic diet, electroconvulsive therapy, stimulation therapies, and surgical intervention. ² Ongoing seizures have been linked with internalization of synaptic GABA_A receptors which may play a role in pharmacoresistance observed in status epilepticus (SE).^3,4

Ganaxolone is a novel synthetic neuroactive steroid which acts as a potent modulator of synaptic and extrasynaptic GABA_A receptors to increase both phasic and tonic inhibitory currents. In a phase II open-label, multicenter dose finding study of refractory status epilepticus (RSE), IV ganaxolone was associated with rapid SE cessation. ⁵ In the study, patients received IV ganaxolone for up to 4 days in 3 dosing cohorts (713 mg/day, 650 mg/day, or 500 mg/day). Median time to seizure cessation was 5 min and 94% of patients had SE cessation at 30 min. A phase III double-blind, placebo-controlled, multinational trial is currently underway to further evaluate the effect of IV ganaxolone in RSE (RAISE, NCT04391569).

Current data on the use of ganaxolone in the treatment of SRSE remains limited to case reports.^6-8 We aim to contribute our experience with ganaxolone in a case of SRSE, highlighting a new dosing approach, time-locked medication administration with continuous electroencephalography (cEEG) tracings, and pharmacokinetic data collection in a patient who ultimately achieved a favorable outcome.

Case Presentation

A 34-year-old man with cerebral palsy and epilepsy (last known seizures occurred in childhood), was admitted with acute hypoxic respiratory failure in the setting of COVID-19 pneumonia for which he was treated with remdesivir and a course of dexamethasone. On hospital day 2, he had a witnessed tonic-clonic seizure without return to baseline followed by cEEG consistent with non-convulsive status epilepticus, for which he was urgently administered benzodiazepines, levetiracetam, and intravenous anesthetics (propofol and midazolam) in rapid succession. On hospital day 4, additional ASMs were administered (lacosamide and phenobarbital) for SRSE upon attempts to wean anesthetics. Between hospital days 5 and 21, he received continued titration of anti-seizure medications (ASMs) and intravenous anesthetics, as well as 3 days of methylprednisolone without lasting benefit. Medications were initiated and discontinued per treating provider discretion; stopped due to lack of benefit noted on EEG recording or due to the emergence of adverse effects (eg, metabolic acidosis with use of topiramate). During this time, multiple MRI of the brain with/without contrast and a lumbar puncture were completed without evidence of underlying infectious or inflammatory etiology.

He was transferred to our neuro-intensive care unit on hospital day 22, following which additional interventions included ketamine infusion, further addition and up-titration of ASMs, ketogenic diet, plasma exchange, and electroconvulsive therapy (Figure 1). Despite these treatments, the patient’s EEG had near continuous 2-4 Hz generalized periodic discharges on the ictal end of the ictal-interictal continuum without improvement in mental status. He rarely opened his eyes to noxious stimuli. He did not attend to examiners or family members and did not follow any commands.

Figure 1.

Timeline of treatment during hospitalization.

On hospital day 52, ganaxolone was administered after an emergency investigational new drug (E-IND) application was approved by the FDA. Ganaxolone was dosed as an IV bolus of 20 mg then initiated as a continuous infusion at 60 mg/hr for the first hour, followed by 42 mg/hr. The infusion was weaned starting on day 3 and was off by day 7. On day 7, oral ganaxolone was initiated at a dose of 600 mg 3 times daily. The ganaxolone dosing regimen was established by prior clinical experience of the authors; serum concentration levels were not available in real time. Our patient tolerated the administration well without significant adverse events. Patient-specific stimulated and measured pharmacokinetic data are provided in Figure 2. Prior to initiation of IV ganaxolone, the EEG showed stimulus-induced, fluctuating 2-4 Hz spiky, generalized periodic discharges (GPDs), at times meeting criteria for electrographic SE. During the time of ganaxolone infusion, a marked improvement in the EEG pattern was recorded and in subsequent days, additional EEG data revealed an overall decrease in the frequency of generalized discharges though abundant GPDs remained, up to 1 Hz (Figure 3). Simultaneously, his mental status returned to his premorbid baseline (eye opening, attending, communicating with gestures and facial expressions) and we were able to lower the dose of clonazepam and wean off phenobarbital.

Figure 2.

Predicted and observed plasma ganaxolone concentrations.

Figure 3.

Time-locked dosing of ganaxolone with pre- and post-EEG tracings. (A) Prior to GNX infusion, bipolar montage EEG, abundant 2-4 Hz generalized periodic discharges (GPDs), meeting criteria for ictal activity; (B) Time-marked at GNX infusion, quantitative EEG, visual reduction in seizure probability and spike detection, rhythmicity spectrogram and FFT spectrogram tracings after infusion; (C) 1 h post-GNX infusion, bipolar montage EEG, occasional, at times poorly formed GPDs with periods of background suppression; (D) 12 h post-GNX infusion, bipolar montage EEG, abundant fluctuating 2-4 Hz GPDs on ictal-interictal spectrum; (E) 5 days post-GNX infusion, bipolar montage EEG, less frequent stimulus induced GPDs, 2 Hz, with periods of suppression; (F) 5 days post-GNX infusion, quantitative EEG, near absent seizure probability with further reductions in spike detection, rhythmicity spectrogram and FFT spectrogram tracings.

Our patient was discharged to a vent weaning facility on hospital day 88 (36 days after ganaxolone was initiated). At follow-up approximately one month after discharge from the hospital, he remained fully dependent for activities of daily living with persistent need for tracheostomy and gastrostomy. He was awake, alert, and at times able to track and attend, remaining non-verbal without command following, and he regained a social smile with family, who reported him to be near his cognitive baseline. Enteral ganaxolone 600 mg TID was gradually weaned off from week 9 to week 12 post-initiation. He had no further clinical seizures and was discharged home on levetiracetam, lacosamide, clonazepam, and perampanel, 12 weeks after starting ganaxolone.

Discussion

Despite late initiation of IV ganaxolone in the SRSE treatment, this patient showed electrographic and clinical improvement with return to his premorbid baseline mental status. This is the first case to show administration of modified IV ganaxolone dosing in SRSE with patient-specific pharmacokinetic data, and to our knowledge, this is the latest documented initiation of ganaxolone in an adult with SRSE with clinical benefit.

Prior rodent models showed broad-spectrum anticonvulsant activity of ganaxolone, including when benzodiazepine resistance develops in SE.^9,10 While a phase 3 study of allopregnanolone, a similar neurosteroid, failed to demonstrate efficacy for treatment of patients with SRSE (STATUS, NCT02477618), we used a novel dosing paradigm and substantially higher serum ganaxolone levels were achieved during the treatment of our patient. Ganaxolone is a neuroactive steroid with high affinity for both synaptic and extra-synaptic GABA_A receptors. ¹¹ The ability to modulate extra-synaptic GABA_A receptors, in addition to synaptic activity, may provide a mechanistic benefit of ganaxolone in prolonged seizures given the reduction of synaptic GABA_A receptors over time. ¹² For this reason and as in the specific case presented here, it is possible that even late high-dose administration of ganaxolone in SE may be beneficial.

The dosing strategy for ganaxolone in SRSE varies from the STATUS trial. Specifically, the bolus and initial high-rate infusion were targeting to produce loading plasma levels of ganaxolone close to 500 ng/mL followed by maintenance concentrations of approximately the same level over the duration of infusion. For comparison, loading and maintenance plasma levels of allopregnanolone in the STATUS trial were approximately 200 and 50-100 ng/mL, respectively. ¹³ Interestingly, the pharmacokinetics of ganaxolone are such that the peak plasma concentration with IV bolus administration is achieved within minutes and reaches steady state within hours due to continued high dose infusion. Following the initial bolus, the peak concentration correlated with EEG improvement with overall less frequent generalized discharges, after which time there was a rebound worsening in discharge frequency correlating with a drop in ganaxolone concentration due to the decreased infusion rate, which lasted until there was further rise to steady state with continued infusion. While we did not titrate ganaxolone based on serum levels during our patient’s clinical care, the collected serum concentrations show the expected, appropriate rise over time in our patient and further support the benefit of ganaxolone when combined with the EEG data.

In a published case series of two pediatric patients (age 17y and 7y) with SRSE, including one patient with remote epilepsy and the other with fever-induced refractory epilepsy syndrome, ganaxolone was similarly utilized with E-IND approval (Singh, 2022). Interestingly, it is unclear whether ganaxolone was singularly responsible or was in some way additive/synergistic with IV anesthetics or other ASMs to allow control of SRSE as both patients remained on other infusions at the time of ganaxolone initiation. Our patient was comparably on multiple ASMs, though no IV infusions were used at the time of ganaxolone administration. This reality highlights the complexity of multiagent ASM cocktails and potential confounders for comparisons between individual responses.

To date, there is one additional report of high dose ganaxolone administered on hospital day 30 as an adjunctive therapy in an adult (age 60y) with SRSE, who was ultimately diagnosed with new onset refractory status epilepticus. ⁷ Similar to our case, the authors found an initial improvement in EEG (burst suppression lasting 24 h), though in their patient, the overall benefit was not sustained with a return of ictal pattern on EEG. While our patient had persistent GPDs following ganaxolone, the overall frequency was reduced and after the second day of infusion, no additional electrographic seizures were identified.

The outcome for our patient was overall favorable, with an eventual return to near his cognitive baseline. While we are limited in this case by a lengthy inpatient admission with critical illness, ongoing ASMs and ketogenic diet, we did appreciate positive clinical and electrographic changes following treatment with ganaxolone that correlated with expected peak drug concentrations.

While our case provides additional data on the use of ganaxolone in SRSE, it represents one individual response and must be interpreted with caution while we await results of clinical trials, including the ongoing investigational trial of IV ganaxolone in RSE. We did not observe significant hemodynamic changes during the ganaxolone infusion, but given the state of our patient at the time of treatment and baseline cognitive impairment, we were unable to assess for the most common adverse events related to ganaxolone such as somnolence, dizziness, fatigue), all of which are expected based on the mechanism of action of ganaxolone.

Conclusion

We report a case of ganaxolone use in the treatment of SRSE in an adult patient. The treatment in this case came after nearly two months of ongoing epileptic activity which was refractory to maximal multimodal treatment, and which led to an improvement in ictal activity on concurrent EEG recording. In this case, our patient had an eventual positive outcome.

Ethical Statement

Ethical Approval

Emergency administration of ganaxolone was authorized by the US Food and Drug Administration in this case and was authorized by Institutional Review Board at the University of Maryland School of Medicine prior to administration. Patient consent: Consent for sharing and publication of clinical information in this case was provided by the patient’s surrogate decision maker prior to submission.

ORCID iDs

Jody Manners https://orcid.org/0000-0002-5875-3633

Emily Jusuf https://orcid.org/0009-0004-8566-1293

Nicholas A. Morris https://orcid.org/0000-0002-1270-9805