Title : Combination treatment with electroconvulsive therapy and novel neuroactive steroid ganaxolone for cryptogenic new-onset refractory status epilepticus
Abstract:
Rationale:
New-onset refractory status epilepticus (NORSE) is a neurologic emergency and potentially life-threatening syndrome described as continuous seizures in a previously healthy patient. Despite extensive workup, no specific etiology is found in over half of cases of NORSE, a presentation termed Cryptogenic NORSE. Prolonged seizures in NORSE are believed to cause internalization of synaptic GABAA receptors, partly explaining the increased resistance of seizures to treatments targeting neural inhibitory pathways. While intrasynaptic GABAA receptors are internalized in status epilepticus, extrasynaptic GABAA receptors are conserved and can be a target for drug-resistant seizures. Electroconvulsive therapy (ECT) and Ganaxolone have shown efficacy as novel treatments for drug-resistant and cryptogenic NORSE. ECT delivers an electric current through the cerebral cortex, aiming to induce a generalized seizure. ECT is believed to assist with refractory seizures by producing neurotrophic effects, promoting neuroplasticity, increasing cortical GABA transmission, and elevating the seizure threshold. Ganaxolone is a neuroactive steroid that works as a positive allosteric modulator, enhancing inhibitory signaling by affecting both intrasynaptic and extrasynaptic GABAA receptors.
Both ECT and Ganaxolone target these alternative neural pathways and can be used as adjunctive therapies when conventional epilepsy treatments fail to manage seizures. To our knowledge, no research has evaluated the efficacy of combining ECT with Ganaxolone for treatment of cryptogenic NORSE.
Methods:
The patient is a 23-year-old female with no prior history of seizures who presented in status epilepticus following a week of prodromal symptoms of fever, cough, headache, vomiting. Patient developed multiple consecutive seizures that remained refractory to medical management, with an extensive workup that was unrevealing. Seizure activity was effectively suppressed after she was induced into a therapeutic coma using a Pentobarbital infusion. Attempts to wean her off Pentobarbital failed despite multiple anti-epileptic drugs, immunotherapies, and nonpharmacologic treatments. Despite the inadequate response to conventional treatments, a combination therapy involving Ganaxolone and ECT was explored. Starting on day 116 of hospitalization, the patient underwent 12 ECT sessions over 20 days. Each session utilized bitemporal electrode placement with an 800 mAmp stimulus and 120 Hz pulse frequency. A continuous infusion of Ganaxolone was initiated after ECT session 3. After ECT session 8, the patient transitioned from IV to enteric Ganaxolone, which was maintained for the remainder of the ECT course.
Results:
Continuous infusion of Pentobarbital was gradually reduced from a rate of 5.75 mg/kg/hr after the first ECT session. Changes in the electroencephalogram (EEG) were observed after ECT session 3, prior Ganaxolone initiation. After ECT session 9, the patient began experiencing visible tonic-clonic seizures. Following the completion of 12 ECT sessions, significant improvements were detected in the patient's EEG, allowing for complete titration of Pentobarbital.
Conclusions:
In patients with cryptogenic NORSE refractory to multi-epileptic drugs and immunotherapies, a combination therapy consisting of ECT and IV Ganaxolone has demonstrated potential in reducing seizure activity. This combined approach has shown promise in safely tapering patients off anti-epileptic medications. This offers a potential alternative for patients without response to traditional therapies, providing a promising avenue for managing cryptogenic NORSE.
Audience Take Away
- This paper provides data on the effectiveness of combining two novel agents (ECT and Ganaxolone) in treating status epilepticus that was otherwise refractory to conventional drug, immunotherapy, and nonpharmacologic treatments
- Our methods present an ECT protocol that future clinicians can use to guide their own ECT settings, technique, and schedules
- We provide new data on the effectiveness of ECT when initiated after 120 days of continuous status epilepticus. It expands the potential application of ECT to a broader range of patients, offering a fresh perspective on its therapeutic efficacy
- This paper serves as a framework for future investigations, laying the groundwork for further studies on ECT, Ganaxolone, or the combination of multiple novel agents in the treatment of refractory seizures
