Keywords

FormalPara Critical Points

  • Seizures occur on a continuum. Most seizures stop within 1 minute. The longer a seizure lasts, the more difficult it is to terminate.

  • Status epilepticus (SE) leads to death from a combination of hyperpyrexia, acidosis, hypoxemia, and ultimately cerebral ischemia. Halting seizure activity, protecting the airway, and administering adequate supplemental oxygen are the cornerstones of therapy.

  • The goal is to treat early with an aggressive, multireceptor approach. Simultaneous first-line and second-line therapies are the best approaches.

  • First-line antiepileptic drug (AED) for SE is midazolam (0.2 mg/kg up to 10 mg) given intramuscularly (IM) or lorazepam (0.1 mg/kg up to 4 mg) given intravenously (IV).

  • Second-line AEDs for SE include phenytoin (20 mg/kg), fosphenytoin (20 mg PE/kg), and valproate sodium (20–40 mg/kg).

  • Consider nonconvulsive SE (NCSE) in patients who remain persistently altered or comatose after overt motor activity stops.

  • Refractory SE (RSE) is defined as patients who are in either convulsive or NCSE, despite adequate therapy with first -and second-line AEDs.

  • Patients with RSE should be endotracheally intubated and placed on continuous midazolam (0.05–2 mg/kg/h) or propofol (30–200 μg/kg/min) infusions.

  • All of these patients will need continuous EEG (cEEG) monitoring in the intensive care unit (ICU).

Introduction

Seizures are defined as sudden abnormal electrical activity involving cortical, subcortical, and thalamic neuronal networks, which may cause a change in mental status and possible convulsive motor activity. They are categorized as generalized or focal, convulsive (involving rhythmic muscle contraction and relaxation) or nonconvulsive, provoked or unprovoked and based on duration. They are common, with 11% of the population having a seizure at some point in life and resulting in 1 million ED visits annually [30]. The terminology used to categorize seizures is not standardized. In this chapter, status epilepticus (SE) refers to generalized convulsions lasting greater than 5 minutes or repeated seizures without a return to baseline cognitive state. Refractory SE (RSE) refers to generalized convulsions that do not resolve after administration of two or more antiepileptic drugs (AEDs). Nonconvulsive SE (NCSE) refers to seizure activity in the absence of motor findings, usually confirmed by EEG.

Most seizures are brief and self-limited. Among patients who present to the ED with seizures, most do not have SE and are discharged home. The objective of this chapter is to provide an evidence-based review of the pathophysiology and current therapeutic approaches to manage SE. In the past 35 years, results of critical trials have allowed us to establish our current standards of practice; however, the current body of work pertaining to seizures and SE is inadequate to definitively answer many clinical questions. Part of this chapter will provide an in-depth review of the pathophysiology of SE to help guide the clinician when first-line therapies are ineffective. We feel this is important, as an early aggressive multireceptor approach should be taken when it comes to treating patients with SE [2, 3].

Status Epilepticus – An Evolving Definition

Status epilepticus (SE) is either witnessed seizure activity lasting greater than 5 minutes or repeated seizures without a return to baseline cognitive state. The seizure duration that defines SE has evolved throughout the years and remains controversial. Classically, the America’s Working Group on Status Epilepticus in 1993 defined SE as seizure activity lasting for 30 minutes [6]. Seizure duration was reduced to 10 minutes in the 1998 Veterans Affairs Status Epilepticus Cooperative Study. [7] The timeline changed again to 5 minutes in 2001 when Alldredge and colleagues published their landmark study comparing the efficacy of halting seizures with lorazepam vs. diazepam vs. placebo.

The past 35 years of basic science research has attempted to shed light on SE and its underlying neurophysiology. Although still incomplete, we now have more insight into what makes patients prone to have seizures, how AEDs function, and why certain patients develop refractory SE. The theory of pharmacoresistance, first described by Wasterlain and colleagues [11, 12], is the most practical explanation of the importance of early aggressive multireceptor approach to treating SE. This theory will be discussed in detail below and helps us understand why delayed treatment of SE can lead to decreased efficacy of benzodiazepines and ultimately lead to increased morbidity and mortality [1, 8,9,10].

Status Epilepticus – Etiology

Status epilepticus is a heterogeneous disease process that encompasses not only people with underlying epilepsy, but also those with acute neurologic and systemic illnesses. The average duration of generalized tonic–clonic seizures is only 1 minute in humans based on video EEG studies; thus, convulsions lasting longer than 5 minutes are a clear marker of abnormal seizure activity [5]. From a practical standpoint, the majority of SE cases are due to subtherapeutic AED levels or due to a known trigger. Other etiologies of SE include alcohol use and withdrawal, metabolic encephalopathy, trauma, cerebrovascular accident (CVA), hypoxemia, and anoxia. There have been a handful of both prospective and retrospective US-based population studies that describe the underlying cause and associated mortality in patients with SE. The results of four of these studies are summarized in Fig. 22.1 [23,24,25,26].

Fig. 22.1
figure 1

Associated underlying etiology of SE and its corresponding mortality based on the studies of US population [23,24,25,26]. (∗Remote symptomatic is a classification described in the Richmond Study by DeLorenzo et al., in which an acute cause of SE could not be found; however the patient has a history of prior stroke, meningitis, congenital malformation, hydrocephalus, arteriovenous malformation (AVM), or genetic disease)

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Status Epilepticus – Pathophysiology and Current Concepts

Seizures involve abnormally synchronized electrical activity involving cortical, subcortical, and thalamic neuronal networks . The start of a generalized tonic–clonic seizure begins with excitation of susceptible epileptic cerebral neurons, which leads to synchronous discharges that can progressively recruit larger cortical networks and ultimately lead to the clinical manifestation of seizure activity. Why seizures don’t stop (known as self-sustaining SE), when the stimulus is withdrawn, is central to the theory of why SE develops.

In a series of studies with a rodent model designed to mimic SE, Mazarati and colleagues used bipolar stimulating electrodes to directly induce SE [11, 31]. When brain stimulation was withdrawn in as little as 15 minutes, the rodents continued to seize. They demonstrated that benzodiazepines lose efficacy in prolonged SE and are most effective when given prior to seizure onset. Similarly, Kapur and McDonald showed that the potency of diazepam decreases >20-fold within 30 minutes of self-sustaining SE in a rat model [13]. These data suggest that seizure mechanisms evolve as seizures continue.

Naylor and colleagues used a similar rat model where self-sustaining SE (SSE) was induced chemically and immunocytochemical studies were performed on hippocampal slices. They demonstrated that after approximately 1 hour of SSE, there was a 50% decrease in the number of physiologically active gamma-aminobutyric acid type A (GABAA) receptors, with subsequent increase of gamma-aminobutyric acid (GABA) receptor subunit uptake from the synaptic membrane to the cytoplasm by endocytosis [12]. Interestingly, glutamate receptors appear to be upregulated in SE. Mathern and colleagues found that patients with autopsy evidence of temporal lobe epilepsy (hippocampal sclerosis) have a significantly higher level of glutamate receptor density per dentate granule cell [17]. Other studies have also shown a significant increase in gene transcription of N-methyl-d-aspartate (NMDA) glutamate receptor subunits in hippocampal tissue from humans with chronic temporal lobe epilepsy compared to nonepilepsy humans [18, 19]. These studies have shed light on the concept of the plasticity of GABA receptors and development of pharmacoresistance, which is the underlying biochemical explanation for what causes refractory SE in humans (Fig. 22.2) [14,15,16].

Fig. 22.2
figure 2

After repeated seizures, the synaptic membrane containing the gamma-aminobutyric acid type A (GABAA) receptors forms clathrin-coated pits, which internalize as clathrin-coated vesicles (C). These vesicles develop into endosomes (E), which can deliver the receptors to lysosomes (L) to be destroyed, or to the Golgi apparatus (G) to be recycled back to the membrane. Bottom: during status epilepticus, N-methyl-d-aspartate (NMDA) receptor subunits are mobilized to the synaptic membrane and assembled into additional receptors. As a result, the number of functional NMDA receptors per synapse increases whereas the number of functional GABAA receptors decreases [12]. (Reprinted from, Chen JW, Wasterlain CG. Status epilepticus: patho-physiology and management in adults. The Lancet Neurology. 2006;5(3):246–256, Copyright 2006, with permission from Elsevier and Dr. Wasterlain.)

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Continuous SE leads to cell injury and neuronal death secondary to excess release of glutamate causing intracellular hypercalcemia and the development of an “excitotoxic” state [20]. This excess presynaptic activity activates glutamate release, which binds to various NMDA and non-NMDA glutamate receptors within the postsynaptic neuron causing intracellular hypercalcemia. On the cellular level, once SE is initiated, it can transition into what is called a maintenance phase of SE, which is believed to be secondary to maladaptive changes by various mechanisms such as receptor trafficking, activation of neuropeptides, and apoptosis signaling pathways, which are beyond the scope of this chapter. Ultimately, prolonged SE causes an excitotoxic state from unopposed glutamate receptor activation in the postsynaptic membrane causing intracellular hypercalcemia, which then activates multiple pathways leading to cellular apoptosis, neuronal injury, release of cytokines, and neuronal death [4, 21].

Status Epilepticus – Diagnostic Studies

The 2012 Neurocritical Care Society clinical guidelines for initial diagnostic workup for patients with SE include checking fingerstick glucose, basic blood work including the complete blood count (CBC) and chemistries, noncontrast computed tomography (CT), and AED levels if appropriate (Fig. 22.3). This diagnostic approach is practical, given the three most prevalent etiologies of SE which are acute stroke, subtherapeutic AED levels, and remote symptomatic causes (i.e., no acute precipitating event but with history of previous central nervous system (CNS) insult, injury, or malformation) [22].

Fig. 22.3
figure 3

Status epilepticus

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Status Epilepticus – Treatment

Benzodiazepines, specifically lorazepam (IV) and most recently midazolam (IM), have always been the cornerstones for treating SE because of their efficacy and safety profile (Table 22.1). Figure 22.4 is a graph showing the results of four landmark randomized controlled trials (RCTs) that were done in both prehospital and in-hospital settings.

Table 22.1 Status epilepticus – treatment
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Fig. 22.4
figure 4

Efficacy of benzodiazepines on the termination of status epilepticus in randomized controlled trials (RCTs). RCT by Alldredge et al. was the first RCT that studied the administration of lorazepam, diazepam, or placebo in the prehospital setting, which found that the number needed to treat (NNT) is 3 to avoid one mortality at discharge. Silbergleit et al. studied the application of midazolam (IM) compared to lorazepam (IV) in the prehospital setting and found a higher efficacy of successful SE termination

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It is important to recognize that although benzodiazepines are first-line therapy, there is a 30–40% failure rate for termination of SE. The Veterans Affairs Epilepticus Cooperative Study by Treiman et al. showed that patients with subtle SE had a higher mortality compared to overt SE (64.7% versus 27%, respectively). They defined subtle SE as comatose patients with ictal discharges on EEG with or without subtle convulsive movements in the arms, legs, trunk, facial muscles, tonic eye deviation, or eye jerking. This brings out the importance of maintaining high suspicion of ongoing seizures if a patient does not return to their baseline mental status and of an early aggressive multireceptor approach to treating SE with the goal of emergently stopping both clinical and electrographic seizure activities. Basic measures should be taken as always to manage airway, breathing, and circulation which should be done simultaneously while treating the patient and screening for the underlying etiology of SE.

Refractory Status Epilepticus – Definition

Refractory status epilepticus is defined as the SE that fails to respond to first- and second-line therapies. Some studies use a time criterion of up to 60 minutes with the requirement of continuous EEG making it a phenomenon that is seen only in the ICU [27]. This is a clinical scenario that is usually seen in the ICU, however, it can also be seen in the ED. An example would be the clinical scenario where a patient is brought to the ED by Emergency Medical Services (EMS) with active seizures in the field that is continuing to have tonic–clonic seizures, despite multiple doses of benzodiazepines and a phosphenytoin load. Less commonly, a comatose patient who was treated adequately and no longer exhibits active convulsions however their mental status cannot be simply explained by a postictal period or somnolence secondary to AED use. Our usual clinical intuition correctly guides us to proceed with orotracheal intubation and deep sedation with either propofol or midazolam infusions.

It is important to remember that patients can continue to have seizure activity without obvious movements of the extremities; thus, continuous EEG monitoring is crucial to determine the efficacy of AEDs in patients who have an altered mental status or who are already intubated. Occasionally however, there are some subtle clinical signs of continued seizure activity that one may pick up if clinically suspecting RSE. The results of the Veterans Affairs Cooperative Study had an overall incidence of subtle SE that ranged between 7.7 and 24.2% in patients with verified diagnosis of SE. [7] Subtle SE was considered present when patients had coma and ictal discharges on EEG, with or without subtle convulsive motor movements such as rhythmic twitching of extremities and face or eye deviation. First-line AEDs were less effective in this subset of patients.

Mayer and colleagues found that 31% of patients admitted to the neuro-ICU who were initially presumed to have SE and were adequately treated with both a benzodiazepine and loaded with a second-line agent such as phenytoin did in fact have RSE which was defined as EEG evidence of seizure activity lasting greater than 60 minutes [27]. These patients were less likely to present with generalized convulsive SE and had a higher incidence of nonconvulsive status epilepticus (NCSE) in the ICU. There are various subtypes of NCSE that are beyond the scope of this chapter, but for all practical purposes, NCSE refers to seizure activity in the absence of motor findings. This would likely manifest as a comatose patient who appears to have an abnormally prolonged postictal period. It is also important to note that nonconvulsive status (NCS) and NCSE are commonly seen in myriad of pathology such as epilepsy-related seizures, subarachnoid hemorrhage, intracerebral hemorrhage (ICH), hypoxic-ischemic encephalopathy, and CNS infections [32, 33].

The majority of emergency departments are unable to have spot EEG or continuous EEG monitoring immediately available for this subgroup of patients and it would be prudent to assume that patients are in RSE if they continue to have an altered mental state and the decision point would be to either proceed with repeat doses of benzodiazepines or continue with more aggressive therapies. The 2012 Neurocritical Care Society Guidelines recommend continued treatment of these patients immediately [22].

Refractory Status Epilepticus – Treatment

There is variable practice among emergency physicians, intensivists, and neurologists when it comes to choosing second- and third-line agents for SE. This is due to a lack of robust evidence evaluating the efficacy of second-line agent antiepileptics such as valproate sodium, levetiracetam, and phenytoin. The 2012 Neurocritical Care Society Guidelines also provided an evidence-based review of the literature along with expert opinion in the management of SE, which was partly incorporated into ACEP 2014 Clinical Policy. Still no enough data are available to support a standardized regimen, and treatment algorithms must be decided based on individual practitioners and the available resources [28].

Basic care should include orotracheal intubation and initiation of a continuous infusion such as midazolam or propofol. In 2002, Claassen et al. showed that barbiturates may be more efficacious compared to propofol and midazolam in a systematic review; however, the use of pentobarbital infusion in the emergency department is not practical, as there is a higher incidence of hypotension leading to the use of vasopressors [29, 34]. An alternative approach would be to load the patient with a second AED, such as valproate sodium or levetiracetam, if there is a high clinical suspicion for RSE. Prior to the escalation of AED, however, it would be necessary to maximize all initial therapies including continuous infusion of either propofol or midazolam. It is important to note that you should anticipate the patient to become hypotensive in such a setting and bring the importance of optimizing preload with adequate crystalloids well in advance (Table 22.2).

Table 22.2 Refractory status epilepticus – treatment
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