Air Care Series: Status Epilepticus Update
/The Case:
AirCare 3 is dispatched for a patient with a seizure. The seizure was witnessed while the patient was on a retreat and described as full body “convulsions”. The patient is hemodynamically stable with a finger stick blood glucose > 100 mg/dL but has remained unresponsive for thirty minutes prompting the call for transport. While reassessing the patient, he develops full body tonic-clonic seizure activity.
Introduction:
The taxonomy of seizures and epilepsy continues to evolve as clinical observations are aligned with insights from electroencephalography (EEG), neuro anatomy and physiology. A full classification of seizure type is offered by the International League Against Epilepsy (ILAE) where they reaffirm a definition of seizure as “a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain”.[1] The types of seizures that routinely come to the attention of emergency providers include those with impaired or loss of consciousness and abnormal motor activity. Motor activity may vary widely but commonly involves fixed tonic or rhythmic clonic type muscle contractions or a combination of both, the classic generalized tonic-clonic seizure.
Table 1: Selection of status seizure types with proposed time limits at which the seizure is unlikely to terminate spontaneously (t1) and cause permanent neurologic harm (t2). Table adapted from Trinka et al. [2]
The ILAE defines status epilepticus (SE) as “a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms which lead to abnormally prolonged seizures (after time point t1). It is a condition that can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures.”[2] While all seizures, both convulsive and non-convulsive, may fail to terminate spontaneously, the pronouncement of SE and impetus for intervention varies by seizure type. Table 1 lists several status seizure types and proposed time thresholds. Generalized convulsive status epilepticus (GCSE) represents the greatest risk with t1 and t2 at 5 and 30 minutes respectively. It is for this reason that GCSE and the related subtle convulsive status epilepticus (sCSE) represent medical emergencies and demand prompt intervention. The ILAE definition remains well aligned with the long-standing definition of status epilepticus as seizure activity lasting greater than 5 minutes or the presence of two or more seizures between which there is no recovery to baseline mental status.[3]
Regarding sCSE, this is a form of non-convulsive status epilepticus (NSCE) which occurs in the context of inadequately or untreated GCSE wherein the patient is persistently unresponsive and has no prominent motor activity however may demonstrate “discrete (subtle) muscle twitching” [4]. Among other NCSE entities including simple partial status epilepticus (with normal consciousness), complex partial status epilepticus (with impaired consciousness) and absence status epilepticus (with impaired consciousness) there appears to be less risk of permanent neurologic injury and therefore debate continues as to when these must be treated. [5,6] Despite the debate, treatment modalities for NCSE are consistent with those strategies employed for GCSE. However, definitive diagnosis requires an EEG unlike convulsive SE which can be diagnosed clinically.
Outcomes:
Upon return of seizure-like activity the patient is rolled on his side and supplemental oxygen is provided via face mask at 15 Lpm. The patient remains unresponsive with rhythmic clonic motor activity noted throughout his extremities and major muscle groups of his back and neck. The patient is incontinent of urine. IV access previously obtained is lost with return of seizure-like activity.
The mortality rate for adults with GCSE is estimated at 19-22% [7-9]. Recognizing GCSE as a symptom, underlying etiologies may be categorized as either acute or chronic. Acute etiologies include stroke, representing 22% of acute causes, metabolic abnormalities, hypoxia/anoxia, trauma and infection. Chronic etiologies include sub therapeutic levels of anti-epileptic medications in patients with epilepsy representing 34% of chronic causes, sequelae of remote injury (stroke, trauma, mass) and alcohol use. [7,10-12] GCSE resulting from acute causes contributes to greater morbidity and mortality when compared to chronic causes. Sudden Unexpected Death in Epilepsy (SUDEP) is a poorly understood fatal complication of epilepsy without a known toxicologic or anatomic cause. SUDEP does account for a significant number of acute epilepsy-related deaths. One of several mechanisms of neuronal injury in GCSE is depletion of metabolic substrate leading to hypermetabolic neuronal necrosis. This is treated with general supportive care in addition to termination of the seizure.[9] Supportive care includes ensuring airway patency, oxygen supplementation, support for adequate hemodynamics, treating hypoglycemia and fever. [13]
Treatment:
Having lost IV access, the patient is administered 10 mg of midazolam intramuscularly and his seizure activity resolves. New IV access is obtained; monitors are applied including capnography and his vitals remain stable. The patient is packaged and loaded for transport. Shortly after liftoff the patient remains obtunded. A repeat examination finds trace muscle twitching across the right side of his face and a fixed leftward gaze on eye examination.
To operationalize treatment of any high-risk SE namely GCSE and sCSE, goals include early recognition followed by stepwise escalation of care to achieve resolution of seizure activity within 30 minutes. Written protocols should be developed based upon treatment context and available resources. [10,14] Some pharmacologic interventions as well as diagnostic modalities such as EEG are not available in the transport setting however a robust approach to management is possible. Three levels of escalating pharmacologic treatment begin with administration of a benzodiazepine followed by administration of a non-benzodiazepine anti-epileptic drug (AED) and finally the administration of a continuous intravenous anesthetic if necessary.
Benzodiazepines are the foundation for acute management of seizure. They are highly effective in their ability to bind GABA-A receptors which are present at 40% of synapses in the CNS resulting in widespread neuroinhibition contributing to termination of seizure activity. [19] Several varieties of benzodiazepine including diazepam, lorazepam and midazolam as well as routes of administration including intravenous, intranasal, intramuscular, and rectal have been examined.[20] IM midazolam is first line; do not delay IV access. NETT showed 73% response for IM midazolam vs 63% for IV lorazepam, statistically significant difference. Subsequent doses can be given IV or IM. [21-23]
Non benzodiazepine anti-epileptic drugs familiar to emergency medicine and the transport environment include levetiracetam, fosphenytoin and valproate. These agents act as adjuncts to the GABA saturation caused by benzodiazepines, but have discrete mechanisms which despite great scrutiny are yet to be fully elucidated.[19] Levetiracetam appears to function in several ways at both the pre and post synaptic membrane to limit excitatory neurotransmission via glutamate. Phenytoin and its pro drug fosphenytoin inhibit voltage gated sodium channels effectively prolonging the refractory period and thereby limiting repetitive neuronal firing terminating the propagation of seizure activity. Valproate appears to influence GABA production and presynaptic release for overall increase in GABAergic tone without directing interacting with the GABA receptor. Equipoise exists regarding the ideal second line AED, however recent evidence suggests that all three of these agents, levetiracetam, fosphenytoin and valproate, have similar efficacy and safety profiles and the decision to administer one over another may be driven by local factors including availability and ease of administration. [15,16]
“Refractory status epilepticus” describes seizure activity not resolved with the use of benzodiazepine and AED. Nearly 50% of patients that receive both benzodiazepine and AED will remain in status epilepticus. [15] As treatment becomes more aggressive, additional supportive therapies will be required. If continuous IV anesthetic is required, definitive airway control with endotracheal intubation and mechanical ventilation must be obtained. Two anesthetic agents for continuous administration in the context of refractory status epilepticus include midazolam and propofol. Both agents, midazolam as previously described and propofol, enhance GABAA receptor function for overall neurosuppression and resolution of seizure activity. [24] EEG is needed to determine if the patient is still experiencing electrical seizure activity once multiple therapies have been added as any outward signs are likely to be fully suppressed. The appropriate receiving facility will be able to initiate this level of monitoring while continuing or escalating treatment. An approach to therapy in the transport setting utilizing commonly available medications is shown in Table 2. One should consider medications that may be available to start in the context of an interfacility transfer which could be continued during the transport, in addition to the anticipating the side effects caused by these medications.
The flight crew recognizes the patient’s facial twitching and forced gaze deviation as continued evidence of seizure activity, likely sCSE and continue treatment with levetiracetam. The crew discusses a plan to start a midazolam infusion and to intubate utilizing succinylcholine should the patient continue to demonstrate evidence of seizure after completion of the levetiracetam infusion. Shortly before landing the patient appears to show resolution of his seizure.
The goal remains to obtain rapid resolution of high-risk convulsive status epilepticus to avoid permanent neurologic injury. Patients suffering from non-convulsive status epilepticus also appear to be at risk of permanent injury and a similar stepwise approach may be utilized beginning with the administration of benzodiazepines followed by anti-epileptic medication. Because the temporality of injury appears to be much longer in NCSE, management should remain with the first- and second-line interventions making use of repeat doses over advancing therapy to include anesthetic agents with their associated risks. [10] Some patients in refractory status epilepticus will continue to have seizure activity identified on EEG even after initiation of continuous anesthetic infusion and these patients are termed “super refractory”. There are several additional levels of intervention which guide the treatment of these patients which are outside the scope of this discussion. It may be noted that ketamine has a proven role in the care of patients with super refractory SE and there is mounting evidence that it may benefit patients at earlier stages, specifically as a third line agent for refractory SE. During status epilepticus there is a simultaneous down regulation of GABA mediated inhibitory mechanisms, effectively a disappearing target for the first and second line interventions and an up regulation of glutamate mediated excitatory mechanisms for which NMDA receptor antagonism via ketamine could offer benefit.[17] Because ketamine has already become well established in the realm of transport medicine for other purposes, it is well positioned to enter the armamentarium for the treatment of status epilepticus in this setting. [18]
The patient is evaluated in the resuscitation bay and a spot EEG is obtained which shows no evidence of ongoing seizure activity. A head CT finds no abnormalities. He requires no further seizure treatment and shortly begins to show improvement. As the patient wakes up, he states that he suffered a head injury as a child which caused him to have epilepsy and he takes Depakote. He realized on the last night of the wilderness retreat that he had miss counted his medication and therefore was unable to a take his usual dose. This was his first seizure in over ten years.
Take Home Points:
Generalized convulsive status epilepticus (GCSE) must be managed emergently as it is unlikely to spontaneously resolve and can result in permanent neurologic injury.
Treatment should begin after 5 minutes of seizure activity with a goal for seizure resolution by 30 minutes.
Subtle convulsive status epilepticus should be identified and treated in similar fashion to GCSE
Treatment should include a stepwise approach beginning with benzodiazepines followed by an anti-epileptic drug (AED). Any one of three AEDs including levetiracetam, fosphenytoin and valproate may be used.
Continuous infusion of anesthetic agents may be necessary and will require additional support including securing the airway.
Ketamine has previously shown benefit in super refractory status epilepticus and may soon become a useful modality in the transport setting as an earlier intervention.
AUTHORED BY Carl Goff, MD
Dr. Goff is a second-year Emergency Medicine resident at the University of Cincinnati.
Figures BY Kate Connelly, MD
Dr. Connelly is a third-year Emergency Medicine resident at the University of Cincinnati.
POSTED BY ADAM GOTTULA, MD (@LAERTEZZ)
Dr. Gottula is a fourth-year Emergency Medicine resident at the University of Cincinnati and future Anesthesia Critical Care Fellow at The University of Michigan with an interest in critical care and HEMS.
FACULTY EDITORS Charles Kircher, md
Dr. Kircher is an attending in the Neuroscience Intensive Care Unit and Emergency Department at the University of Cincinnati.
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