Editor's Choice

Seizure 2022, Vol 102, Editor’s Choice: Treatment of benzodiazepine-resistant status epilepticus: Systematic review and network meta-analyses

Markus Reuber, MD PhD, Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF

Supported by well-established business models, the development of new drug treatments for the ambulatory care of patients with epilepsy continues at a rapid pace. Apart from the novel substances themselves, the research underpinning their development provides insights into ictogenic and epileptogenic mechanisms. While our ability to predict what will work for whom continues to be limited, we gain at least some understanding of modes of action, efficacy and side-effect profiles of new treatments for different types of epilepsy from premarketing studies.

This situation contrasts strongly with the development of new treatments for status epilepticus. Although pretty much every drug ever licenced for the chronic treatment of epilepsy has been tried in this setting, most status epilepticus treatment studies have been carried out independently of the drug development process. The financial rewards of developing new treatments for status epilepticus are much less certain than those that can be hoped for in relation to new drugs likely to be prescribed for months or years – never mind the fact that there is an evident need for the development of better treatments for an epileptological emergency which continues to be associated with substantial mortality or secondary morbidity.

While we are still waiting for genuinely new treatments for status epilepticus to become available several recent, fully powered, publicly funded trials have at least informed us how we should use some of the medications already available to us in the 40 or so % of patients in whom first line treatment with benzodiazepines fail (1-3). These head-to-head randomised studies were much needed, but, by virtue of their design, they had to focus on a limited number of drug options. What is more, they included levetiracetam (a drug not included on the WHO list of essential medications and therefore unavailable in many countries) while they did not include phenobarbitone (given that it’s use has receded in many developed countries because of its potential to cause respiratory suppression).

While we continue to wait for new and better treatments for status epilepticus, my Editor’s Choice from the current volume of Seizure aims to fill some of the knowledge gaps about the choices available for the treatment of status epilepticus when benzodiazepine treatment has failed. The systematic review, conventional and network meta-analysis by Puneet Jain et al. based on 17 RCTs considered outcomes including seizure cessation within 60 minutes, seizure freedom for 24 hours, death, respiratory depression warranting intubation and cardiovascular instability. Phenobarbital and high-dose levetiracetam emerged as significantly superior to phenytoin with respect to seizure cessation within 60 min. Network ranking placed phenobarbital, high-dose levetiracetam and high-dose valproate on places one to three in terms of status cessation. In pairwise comparisons, phenobarbital was associated with a higher risk of need for intubation and cardiovascular instability while levetiracetam had a better safety profile than fosphenytoin. The fact that levetiracetam emerged as the “safest best” medication overall may provide an additional argument for the inclusion of this drug in the WHO list of essential medications. In the meantime, those clinicians only having access to phenobarbitone may console themselves with the fact that, with careful use, this oldest of the antiepileptic drugs still in widespread use remains unsurpassed in terms of controlling status after benzodiazepines have failed.

References

(1) Kapur J, Elm J, Chamberlain JM, Barsan W, Cloyd J, Lowenstein D, Shinnar S, Conwit R, Meinzer C, Cock H, Fountain N, Connor JT, Silbergleit R; NETT and PECARN Investigators. Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus. N Engl J Med 2019; 381:2103-2113.

(2) Appleton RE, Rainford NE, Gamble C, Messahel S, Humphreys A, Hickey H, Woolfall K, Roper L, Noblet J, Lee E, Potter S, Tate P, Al Najjar N, Iyer A, Evans V, Lyttle MD. Levetiracetam as an alternative to phenytoin for second-line emergency treatment of children with convulsive status epilepticus: the EcLiPSE RCT. Health Technol Assess 2020; 24:1-96.

(3) Dalziel SR, Borland ML, Furyk J, Bonisch M, Neutze J, Donath S, Francis KL, Sharpe C, Harvey AS, Davidson A, Craig S, Phillips N, George S, Rao A, Cheng N, Zhang M, Kochar A, Brabyn C, Oakley E, Babl FE; PREDICT research network. Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial. Lancet 2019; 393:2135-2145.

(4) Jain P, Satinder A, Cunningham J, Ravindra A, Sharma S. Treatment of benzodiazepine-resistant status epilepticus: Systematic review and Network Meta-analyses. Seizure 2022, please add bibliographic details.