By: Ivan Zvonar, M.D.

Faculty Editor: James Feldman, M.D.

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Status epilepticus is a well known entity to emergency physicians. Although the definition has undergone revision within the past decade, with the most recent being seizure activity lasting greater than five minutes or without a return to baseline1, it encompasess the broad category of ongoing and treatment refractory seizures. With an annual incidence of 50,000-150,000 per year in the American population2, it carries significant morbidity and mortality. Decrease in baseline status is seen in almost a quarter of cases, with serious neurologic sequelae occurring in 10-15%, and an estimated overall mortality of 25-30%1,2.

The management of status epilepticus has been influenced by several landmark studies over prior decades. The difficult truth however, is that over the past 30 years with all of these advances, we have not seen a resultant decrease in mortality3. This is in part due to the broad etiology of seizures, many of which require their own specific interventions (table 1) and carry varying prognoses4. Yet our current “one-size-fits-all approach” has not yielded improved outcomes. Most recently in 2016, the American Epilepsy Society released its guidelines for the stepwise management of status epilepticus5. This tiered system is an algorithmic approach to acute management. 

Initial steps include traditional ABCs and stabilizing the patient. Prior to heading down the incremental management steps, ruling out and treating reversible causes (table 1) takes precedence. With continuation of seizure activity, treatment revolves around the use of benzodiazepines. Benzodiazepines were solidified as the mainstay of seizure treatment following the 1998 Veteran’s Affairs study. The study was a five year long RCT which looked at the effectiveness of lorazepam, diazepam, phenytoin, and phenobarbital; ultimately concluding that none was more efficacious (one exception being lorazepam being superior to phenytoin)6. Due to its ease of use and timely administration, lorazepam gained traction as the first-line therapy. As status epilepticus requires prompt treatment, subsequent studies attempted to better define agents for use in the prehospital arena. The 2001 PHTSE trial was unable to show any difference between IV lorazepam and diazepam7, and the 2012 RAMPART which compared IM midazolam to the IV lorazepam standard ultimately showed similar efficacy8. As such, all three agents (IV lorazepam 0.1 mg/kg; 4-8 mg standard dose, IV diazepam 0.2 mg/kg; 10 mg standard dose, and IM midazolam 0.2 mg/kg; 5-10 mg standard dose) gained level A evidence for their use as first line therapies5. Of note, although less frequently used, phenobarbital at 15 mg/kg also holds level A evidence due to never having been shown to have inferior efficacy5. Likely physician comfort plays a role in the overwhelming use of benzodiazepines as first line therapy. It is important to note that proper dosing is paramount and that studies have shown that concerns for respiratory depression are higher in untreated status epilepticus than those with appropriately dosed benzodiazepines2. 

There was great anticipation and excitement in 2019 for the results of the ESETT trial, which looked at effectiveness of second line therapies in benzodiazepine refractory status epilepticus. This multicenter RCT which looked at levetiracetam, fosphenytoin, and valproate yet again showed no significant difference among the agents, but did provide information that seizure activity cessation occured in less than 50% in all three groups at the one hour mark9. In the setting of equal efficacy, levetiracetam, with its more appealing side effect profile, emerged as the preferred agent; noting that the dosage of 60 mg/kg is much higher than some providers may be accustomed to using previously. Overall, the relative lack of efficacy has resulted in many experts arguing that although it can’t hurt to load patients with these agents, waiting to see if they will work sequentially in such a time frame is unacceptable.

It is important to note that although the current guidelines provide timeframes for when sequential therapies should be initiated, they also state that the rapidity with which patients move through these escalating treatment stages may vary5. Therefore, in benzodiazepine refractory cases, and with the knowledge that second line agents are relatively ineffective, many have begun to argue that timely administration of anesthetic agents such as propofol and associated intubation should become standard of care and not demonstrate treatment failure. The adage of “time is muscle” has similarly been echoed with “time is brain”. Further strategies in extreme cases include non GABA-ergic agents such as ketamine, as GABA receptors which are the target of the majority of our treatment modalities become internalized with seizure duration10, and the ongoing KETASER01 trial seeks to provide answers to this question11. Additional difficulties arise when trying to differentiate non-convulsive status epilepticus (NCSE) from the postictal state, as a proportion of status epilepticus will continue in this form12, especially as the vast majority of emergency departments are not readily equipped with EEGs. This was further highlighted in secondary analyses of the ESETT trial, which showed that of the subset of patients who received EEG monitoring within the first 24 hours, 13% of patients meeting the primary outcome of seizure cessation at 60 minutes had electrographic evidence of seizure, confirming that clinical seizure cessation does not always correlate with seizure termination13. 

In hindsight, some may view the relative lack of advancement in status epilepticus management as a failure. However, this would be to disregard the numerous knowledge gaps we have filled over the past several decades. Until further research can demonstrate that early intubation and sedation improves neurologic outcomes in benzodiazepine refractory status epilepticus, and until we can obtain early and consistent EEG monitoring to confirm seizure cessation, it would behoove emergency physicians to treat status epilepticus as a time dependent emergency by accepting sedation and intubation as the standard of care. 

EtiologyTreatment 
Hypoglycemia1 amp D50 (25 g) IV
Repeat prn 

If no access consider: 5 mg Glucagon IM
Hyponatremia150 mL 3% Hypertonic Saline IV
Repeat prn after 20 minutes

OR 2 amp 8.4% NaHCO3 (100 mEq) IV
Eclampsia4 g Magnesium IV
Followed by infusion: 2 g IV/hr 
Sodium channel blocker toxicity3 amp 8.4% NaHCO3 (150 mEq) IV
Followed by infusion: 150 mEq NaHCO3/1 L D5W
INH toxicity1 g:1g  of Pyridoxine:INH ingested (maximum 5 g IV)

OR empiric 5 g IV Pyridoxine if unknown amount ingested
Alcohol withdrawal Similar treatment to status epilepticus
MeningoencephalitisAntibiotic and antiviral administration
Note: empiric treatment is age specific
HyperthermiaCooling measures 
Increased intracranial pressure 250 mL 3% Hypertonic saline
1 g/kg Mannitol 
Table 1: Reversible causes of status epilepticus and treatmenta

aAdapted from Morgenstern, J. “Status Epilepticus: Emergency Management”. http://first10em.com/status-epilepticus-update. Published May 31, 2020. 

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References: 

  1. Brophy GM, Bell R, Claassen J, et al. “Guidelines for the Evaluation and Management of Status Epilepticus”. Neurocritical Care. 2012; 17(1):3-23.
  2. 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 Currents. 2016; 16(1):48-61. 
  3. Neligan A, Noyce AJ, Gosavi TD, et al. “Change in Morality of Generalized Convulsive Status Epilepticus in High-Income Countries Over Time”. JAMA Neurology. 2019; 76(8):897-905. 
  4. Neligan A and Shorvon SD. “Frequency and Prognosis of Convulsive Status Epilepticus of Different Causes”. JAMA Neurology. 2010; 67(8): 931-940. 
  5. 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 Currents. 2016; 16(1):48-61. 
  6. Treiman DM, Meyers PD, Walton NY, et al. “A Comparison of Four Treatments for Generalized Convulsive Status Epilepticus.” The New England Journal of Medicine.1998; 339(12):792‐798. 
  7. Alldredge BK, Gelb AM, Isaacs SM, et al. “Comparison of Lorazepam, Diazepam, and Placebo for the Treatment of Out-of-Hospital Status Epilepticus”. The New England Journal of Medicine. 2001; 345:631-637. 
  8. Silbergleit R, Loweinstein DH Durkalski V, et al. “Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus”. The New England Journal of Medicine. 2012; 366(7):591-600.
  9. Kapur J, Elm J, Chamberlain JM, et al. “Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus”. The New England Journal of Medicine. 2019; 381(22):2103-2113.
  10. Goodkin HP, Yeh JL, Kapur J. “Status Epilepticus Increases the Intracellular Accumulation of GABAA receptors”. Journal of Neuroscience. 2005;25(23):5511-5520. 
  11. Rosati A, Ilvento L, L’Erario M. Efficacy of Ketamine in Refractory Convulsive Status Epilepticus in Children: a Protocol for a Sequential Design, Multicenter, Randomized, Controlled, Open-Label, Non-profit Trial”. British Medical Journal. 2016;6(6). 
  12. DeLorenzo RJ, Waterhouse EJ, Towne AR, et al. “Persistent Nonconvulsive Status Epilepticus After the Control of Convulsive Status Epilepticus”. Epilepsia. 1998;39(8):833-840.
  13. Zehtabchi S, Silbergleit R, Chamberlain JM, et al. “Electroencephalographic Seizures in Emergency Department Patients After Treatment for Convulsive Status Epilepticus.” Journal of Clinical Neurophysiology. 2020; Advance Online Publication. 
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