Research Examines VNS as Treatment for New-Onset Refractory Status Epilepticus

In a recent perspective piece, researchers advocated for consideration of vagal nerve stimulation (VNS) for new-onset refractory status epilepticus (NORSE) in early and late stages of the condition’s presentation.

They also hypothesized a potential additional benefit from implantation in the acute phase, although it should be pursued in the context of a clinical trial.

“A study planned within our UK-wide NORSE-UK network will answer the question if VNS may confer benefits in aborting unremitting status epilepticus, modulate ictogenesis, and reduce long-term chronic seizure burden,” authors wrote in Frontiers in Neurology.

NORSE and its subcategory, febrile infection-related epilepsy syndrome (FIRES), are rare conditions. They are also associated with long-term morbidity while treatment is not supported by controlled studies. Furthermore, resistance to drug therapy poses a major hurdle in managing patients.

Up to two-thirds of NORSE survivors have functional disability, and others experience subsequent chronic epilepsy.

“Whether desynchronizing networks by VNS may improve seizure control remains an unanswered question,” the researchers explained.

In the current piece, they evaluated evidence behind the use of VNS in adult and pediatric patients. One human study shows seizures that were stimulated using VNS had a reduced ictal spread and a reduced impact on cardiovascular function.

Recent developments have also used VNS as an anti-inflammatory treatment. Thus, “application of VNS in NORSE patients may provide an immediate and controllable way to modulate ictogenesis and further brain injury due to unremitting seizures and inflammation,” the authors wrote.

Searches of ClinicalTrials.gov and PubMed databases revealed varied levels of detail in reported cases. The description of VNS stimulation protocols also was not uniform.

Fifteen cases of NORSE were identified. Of these, 10 were in adults, 5 were in pediatric patients, 9 were male and 6 were female. Eight cases fulfilled criteria for FIRES, including the 5 fie pediatric cases. Patients had tried multiple antiseizure medications and anesthetic agents including propofol, ketamine, and midazolam.

In 5 cases, VNS was implanted in the acute phase of NORSE, or within the first 30 days of onset. It was implanted in the chronic phase of treatment-resistant epilepsy in 7 cases. In addition, the most used initial stimulation frequencies were 20 to 30 Hz, the authors wrote.

“VNS resulted in a significant clinical change in 10 cases, an average of 16.3 days after implantation when documented (range, 3-42 days),” they noted.

Observed outcomes included:

• Cessation of super-refractory status was ascribed to VNS in 2 cases implanted in the acute phase and 2 in the chronic phase
• Improvement in seizures but then recurrence was documented in 2 cases, there was no effect in 1 case, and sustained seizure reduction was documented in 3 cases: 30% to 40% in 2 cases and in the third, enabling weaning of anesthetic agents and leaving the intensive care unit
• Long-term outcomes were available for 12 cases and were documented between 1 month and 26 years after implantation: 2 cases implanted in the acute phase died due to multiorgan failure or comorbidities
• Three patients were documented as seizure-free survivors, and 7 have ongoing chronic epilepsy

The only adverse event documented was bradycardia.

The low levels of cases reported in the literature and variable amount of information available means there’s an overall low level of evidence supporting the use of VNS in NORSE, the researchers said.

However, they were able to generally conclude VNS was a well-tolerated intervention without significant adverse effects in the short or long term.

“Whilst it is not possible to determine a stimulation threshold effect leading to seizure cessation, most patients had VNS switched on either immediately or within the first few weeks of implantation at conventional—not high frequency—cycling rates and the output current increased over a short period of time (days to weeks),” they wrote.

Reference

Ritter LM and Selway R. Perspective: vagal nerve stimulation in the treatment of new-onset refractory status epilepticus. Front Neurol. Published online April 20, 2023. doi:10.3389/fneur.2023.1172898