Status epilepticus (SE) is a rare but potentially life-threatening condition that may present to the emergency room.  Anywhere between 50,000 and 150,000 American’s are diagnosed with SE annually¹.  Presentation can generally be classified as either convulsive or non-convulsive. Previous definitions have listed SE as 30 minutes of either 1) continuous seizure activity or 2) two or more sequential seizures without full recovery of consciousness¹.  The 30-minute definition has fallen out of favor diagnostically for obvious reasons, as this mark is where permanent neuronal injury is likely to occur¹.   The more favorable definition revolves around a 5-minute window without cessation of seizures, which is the mark where a seizure is less likely to self-abort¹.  With either definition, prompt emergent therapy is warranted as the goal is cease seizure activity as soon as possible.

Therapy for SE consists of emergent and urgent therapy. Emergent therapy primarily includes the administration of benzodiazepines either intravenously or intramuscularly¹.  The RAMPART trial proved this point by comparing pre-hospital administration of intramuscular midazolam to intravenous lorazepam and finding similar safety and efficacy of the two treatments².

The next phase of therapy, should emergent treatment fail, is referred to as urgent therapy. This involves the administration of anti-epileptic drugs (AEDs).  The evidence to support which agent is preferred in this phase is equivocal with no agent really standing out above the rest as no studies have really compared them all head to head.  The majority of the evidence lies with phenytoin and valproic acid with valproic acid showing higher efficacy in seizure cessation in one study and comparable results between the two agents in the others¹.  Levetiracetem has also been considered as an urgent therapy agent given its ease of administration and lack of drug interactions.  In the American Epilepsy Society guidelines for status epilepticus, levetiracetam is listed as a second line agent next to phenytoin and valproic acid¹.  Recent evidence in the pediatric arena may show more promise for this agent as it was compared to phenytoin and found similar efficacy in time to cessation of SE³.  Currently, there is an active study being referred to as the ESETT (Established Status Epilepticus Treatment Trial) trial that is setting out to help clarify this phase in therapy by comparing phenytoin, valproic acid and levetiracetam (NCT01960075).

If seizure activity continues, the guidance for the next decision point falls off greatly as no evidence currently exists for these therapies.  The American Epilepsy Society guidelines jump to the administration of anesthetic type agents, generally in the form of a continuous infusion. This can be with either Propofol, midazolam or pentobarbital¹.  The patient will need an airway at this point, given the nature of the drugs being administered as well as the duration of seizures they have been experiencing.  Another agent that is starting to come into favor is ketamine.  The data is limited to mostly retrospective case reports and case series, but the mechanism of its benefit makes sense.  The leading theory is that as benzodiazepines are administered in large quantities and seizure activity continues, GABA receptors undergo maladaptive change and NMDA receptors begin to upregulate, increasing excitatory tone⁴.  By adding an NMDA-antagonist like ketamine, the push-pull effect of those two receptors can be mitigated.  Other recent publications have pushed for earlier administration of ketamine in status epilepticus⁵.

Once all these steps have been completed, the “kitchen-sink” phase begins.  Adding more AEDs of differing mechanisms coupled with up titrations of anesthetic type agents should be considered.  At this phase the guidance should be driven by a neurologist in concert with the intensivist and clinical pharmacist.

This discussion probably goes beyond the scope of the emergency room, but the information is relevant and pertinent.  The treatment of status epilepticus is not as black and white as the phases may seem, but more of a continuum of care with the ultimate goal being cessation of seizure activity and optimization of AEDs to prevent further potential of SE.  Appropriate and timely administration of medications as well as optimization of pharmacokinetic properties is vital for these patients.  The American Epilepsy Society guidelines from 2016 are an excellent resource to refer to for stepwise medication administration as well as dosing¹.

Benjamin Jagow PharmD

References

1. Glauser T, Shinnar S, Gloss D, et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016;16(1):48-61
2. Hirsch LJ. Intramuscular versus intravenous benzodiazepines for prehospital treatment of status epilepticus. N Engl J Med. 2012;366(7):659-60
3. Lyttle MD, Rainford NEA, Gamble C, et al. Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial. Lancet. 2019
4. Fang Y, Wang X. Ketamine for the treatment of refractory status epilepticus. Seizure. 2015;30:14-20
5. Zeiler FA. Early Use of the NMDA Receptor Antagonist Ketamine in Refractory and Superrefractory Status Epilepticus. Crit Care Res Pract. 2015;2015:831260