Non-Medicinals for Pediatric Status Epilepticus Lack Clinical Evidence

Ravindra Arya, MD, DM

The evidence supporting dietary, immunological, surgical, and other novel approaches for pediatric status epilepticus is mostly anecdotal, according to part of a recent collection of reviews on the developments in the space.¹

The assessment noted that only about 15% to 35% of pediatric patients with refractory status epilepticus (RSE) achieve desired therapeutic end points with the conventional approaches based on continuous infusion or inhalation of anesthetics or other anti-seizure medications.

It was authored by Ravindra Arya, MD, DM, an associate professor of pediatrics in the Comprehensive Epilepsy Center at the University of Cincinnati College of Medicine, and Alexander Rotenberg, MD, PhD, from the division of Epilepsy and Clinical Neurophysiology at Boston Children's Hospital. Arya told NeurologyLive’s sister publication, MD Magazine, that “RSE and super-RSE [SRSE] present a very challenging situation for the clinical team.”

Arya told MD Mag that the absence of, or sparse evidence for, these non-medicinal approaches, "should be carefully considered and shared with the families of the patients before making treatment decisions."

He and Rotenberg wrote that "these cases represent a desperate situation for the clinical team, and a myriad of approaches are brought upon to control the SRSE, which is frequently based on limited experience,” adding that those who confront this emergent condition—which is associated mortality and long-term neurological morbidity—often "lack of high-quality evidence to formulate a management protocol."

A pair of the modalities assessed, therapeutic hypothermia and brexanolone, a neuro-active steroid, have been tested in randomized controlled studies. According to Arya, they were "found not to be better than placebo in terms of safety and efficacy, as per the end points chosen by the investigators." Although well-documented evidence for anti-seizure and neuroprotective effects of hypothermia has been demonstrated in animal models, the available human trial data has not been encouraging.

Arya and Rotenberg cited the HYBERNATUS trial as the most rigorous of the clinical studies to date. HYBERNATUS included 270 patients with convulsive RSE on assisted ventilation, and although the investigators involved acknowledged that the Glasgow outcome scale may not have recorded subtle neurological deficits, they reported that there was no statistically significant difference between the active and control groups for therapeutic outcomes.²

Brexanolone, a formulation of allopregnanolone and an endogenous progesterone metabolite that appears to modulate gamma-aminobutyric acid (GABA) receptors, has been investigated for the treatment of postpartum depression.³ Ultimately, its potential for RSE has been based solely on experimental evidence suggesting that endogenous steroids can impact altered cortical excitability.

Arya and Rotenberg acknowledged a 37% response rate for patients on brexanolone during an open-label extension trial, despite the phase 3 trial not demonstrating a difference from placebo in the double-blind period.

Another non-medical option explored was a ketogenic diet—a high-fat, low-carbohydrate diet. It has been found useful in certain drug-resistant epilepsies and infantile spasms, and Arya and Rotenberg noted that it is increasingly being investigated for RSE and SRSE.

They also pointed out that it offers several possible modes of interaction with the pathophysiology of RSE. "Of the treatments discussed in this review, [a] ketogenic diet is perhaps the most promising and deserves prompt and rigorous studies to better characterize its place in the management of RSE/SRSE," they wrote.

As for the feasibility of surgery for RSE, the pair of reviewers noted that it is limited by whether or not lesions can be identified as epileptogenic and are accessible. In addition to the uncertainty of a causal site, the imaging procedures themselves can be confounded by ongoing seizure activity, contraindicating medical conditions, and potential hazards associated with transportation, among others.

They also noted that the failure of definitive surgery has led to consideration of vagus nerve stimulation (VNS) and complete corpus callosotomy (CCC). As well, neurostimulation techniques such as transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), and electroconvulsive therapy (ECT) were also reviewed for non-convulsive status epilepticus.

Arya and Rotenberg indicated that "overall, the role of neurostimulation for the treatment of RSE/SRSE remains poorly defined at present. Selection of the candidates who are likely to respond to these modalities, targets of stimulation, dose/regimen, and safety considerations need better evaluation before any recommendations can be formulated."

A version of this article first appeared on MDMag.com.

REFERENCE

1. Arya R, Rotenberg A. Dietary, immunological, surgical, and other emerging treatments for pediatric refractory status epilepticus. Seizure. 2018;S1059-1311(18):30175-4.

doi

: 10.1016/j.seizure.2018.09.002

2. Legriel S, Lemiale V, Schenck M, et al. Hypothermia for neuroprotection in convulsive status epilepticus. N Engl J Med. 2016; 375:2457-2467.

doi

: 10.1056/NEJMoa1608193

3. Meltzer-Brody S, Colquhoun H, Riesenberg R, et al. Brexanolone injection in post-partum depression: two multicentre, double-blind,

randomised

, placebo-controlled, phase 3 trials. Lancet. 2018;392(10152):1058-10170.

doi

: 10.1016/S0140-6736(18)31551-4