Status Epilepticus: A Ketamine-Deficient State?

Status epilepticus (SE) is a life threatening emergency associated with high morbidity and mortality rates. The International League Against Epilepsy (ILAE) defined SE more than twenty years ago as a single seizure that that lasts more than 30 minutes. The alternative definition is a series of epileptic seizures during which the patient’s baseline function is not regained between ictal events, within a 30 minute period. Recently, status epilepticus has been re-defined as: ≥5 minutes of continuous seizures OR ≥2 discrete seizures during which there’s an incomplete recovery of consciousness. Refractory status epilepticus (RSE) is defined as generalized or complex partial seizure activity that is refractory to conventional therapies for seizure disorder, such as benzodiazepines and barbiturates, within 30 minutes.  Super-refractory status epilepticus (SRSE) is further defined as SE that remains refractory to therapy with general anesthesia, for 24 hours, using medications such as propofol.  Incidence of refractory epilepsy is surprisingly high despite the development of many anti-epileptic agents and ranges from 20-40% in the literature.  Multi-faceted factors likely contribute to the development of RSE, including: the type of seizure, any underlying health conditions or neurological disorders, patient’s personal seizure history (frequency, duration, medication compliance, etc.), a patient’s genetics impacting drug metabolism (rate of absorption, metabolism, etc), or any prior use of illicit drugs altering brain chemistry (for example recreational MDMA, chronic alcohol or benzodiazepine use), amongst many others.  To prevent cortical disruption and damage, and to prevent morbidity and mortality, early control of SE is desirable.  Patients with development of RSE have high mortality rates (reported to approach 50%), increased hospital stays, poor functional outcomes, and inability to return to pre-admission baseline functional status.

Conventional therapies of acute seizure, SE, refractory and super refractory status epilepticus are heavily reliant on GABA agonist mediated therapies.  GABA_a agonists control excitatory inhibition and spread of excitatory discharge.  Lorazepam and midazolam are listed to have Level A evidence for use as first line anti-seizure medications.  Second line therapies include sodium channel blockers such as phenytoin, fosphenytoin, levetiracetam, lamotrigine, and carbamazepine.  Also studied therapies include barbiturates, valproate, topiramate, and propofol.  Refractory states of SE are theorized to be attributable to alterations in receptors and disruption of molecular transport at the blood-brain barrier.  GABA_a receptors are thought to be down-regulated with prolonged use of GABA_a agonists. GABA_a subunits are thought to undergo structural changes leading to impaired binding of anti-epileptic medications.  In addition, p-glycoprotein molecules are thought to be up-regulated as molecular transporters leading to increased efflux of medications from the brain, in particular phenytoin and phenobarbital.

With prolonged down regulation of GABA_a receptors, an inhibitory function of excitation is lost. With decreased expression of GABA_a receptors, increased expression and mobilization of non-competitive N-methyl-D-aspartate (NMDA) receptors to the cell surface of neurons occurs. Activation of NMDA receptors by glutamate will increase intracellular calcium, cause neuronal excitation, and potentiate refractory seizure physiology. In addition, prolonged treatment of RSE with traditional GABA_a agonists may lead to development of refractory hypotension and other adverse cardiovascular effects. Hypotension in status epilepticus causes further insult to injury as seizures already have potential to cause anoxic damage as cerebral blood flow autoregulation is disrupted during seizures.

For all of these aforementioned reasons, conventional therapies can adversely impact treating SE. Ketamine has been postulated as a novel agent in treatment of RSE and perhaps has a role for early use in SE. Ketamine is a non-competitive NMDA glutamate receptor antagonist. Animal studies have demonstrated that ketamine is effective in control of refractory seizures and is neuroprotective (leading to decreased morbidity and mortality), when compared to control data. A recent systematic review of the literature by Zeiler (2015) summarized data of multiple human case reports and three prospective cohort studies (with an average of 7 patients per study) utilizing ketamine for RSE. Seizure resolution was established in 56% of 110 total adult patients and 63% of pediatrics patients. Most patients were with seizure resolution within 48 hours to 72 hours of start of ketamine. Treatment time ranged from 2 hours to 27 days in adults and 6 hours to 27 days in pediatrics. The literature is low powered and therefore statistically it is difficult to make generalizations to extrapolate its use and benefits for the general patient population. Dosing, duration, and outcomes with use of ketamine in RSE have been reported to vary, as well. Ketamine has sympathomimetic properties preventing hypotension and cardiac depression. It has been found to be especially useful in RSE when other anti-epileptic treatments are causal in cardiac depression or hypotension, eliminating need for pressor support with ketamine infusion. Treatment doses of continuous ketamine infusions range in the literature from 0.12mg/kg/hour to 10mg/kg/hour. At times, patients were initially bolused at doses ranging from 0.3mg/kg to 4.5mg/kg. Ketamine can be administered with low risk to most patients as there are few contraindications or adverse effects. Previous arguments for increased intracranial pressure with use of ketamine have been refuted in the literature, and few population groups exist where ketamine cannot be used safely for RSE. However, the prolonged use of ketamine and its effects have not been studied in the literature.

Prospective studies are required to help establish a role for NMDA antagonists in treatment of routine seizures. In addition, research should consider studying the use of ketamine earlier in treatment of seizure disorder. In one case report by Kramer (2012), ketamine was administered early on in treatment of SE after the patient began to develop worsening hypotension with escalating doses of midazolam and propofol. Ketamine infusion resulted in immediate reduction in prevalence, duration, and amplitude of seizures on EEG. The need for vasopressor support was weaned off and patient's seizures resolved within 12 hours of start of ketamine. Patient was discharged home with return to baseline level of function.

Now we potentially have another reason to use more ketamine!!!

References

Drislane, FW. Convulsive status epilepticus in adults: Classification, clinical features and diagnosis. UptoDate. (2015). http://www.uptodate.com/contents/convulsive-status-epilepticus-in-adults-classification-clinical-features-and-diagnosis?source=search_result&search=status+epilepticus+adult&selectedTitle=2~150

F. A. Zeiler, “Early Use of the NMDA Receptor Antagonist Ketamine in Refractory and

Superrefractory Status Epilepticus,” Critical Care Research and Practice, vol. 2015, Article ID 831260, 5 pages, 2015.

Shorvon S. and Ferlisi M. “The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol.” Brain: A Journal of Neurology. 10. (2011):1-17.

Synoweic, et al. “Use of ketamine in the treatment of refractory status epilepticus.' Epilepsy Research. 105. (2013). 183-188.

Williams, et al. “Use of ketamine for control of refractory seizures during the intraoperative period.” Journal of Neurosurgical Anesthesiology. 26. (2014). 412.

Kramer AH. “Early Ketamine to Treat Refractory Status Epilepticus.” Neurocritical Care Society. 16. (2012): 299-305