Wasterlain, Claude Guy, Gezalian, Michael Mkrtich
Department of Neurology, VA Greater Los Angeles Health Care System, David Geffen School of Medicine at UCLA, California (USA).
Email: mgezalian@yahoo.com No Disclosure to declare.
STATUS EPILEPTICUS: AN UPDATE État de mal épileptique: UNE MISE À JOUR
associated with poor outcomes [2]. Despite treatment, mortality remains unacceptably high, and many sufferers from SE end up with permanent brain damage, especially in the limbic system, resulting in memory loss, cognitive dysfunction, epilepsy and other neurological conditions [3S5]. Rapid control of seizures is fundamental in decreasing longSterm sequellae [6] and neurological injury. Implementing SE protocols in emergency rooms and intensive care units may help speed up initiation of therapy, improve effectiveness and decrease the widespread problem of treatment being “too low, too slow” [7].
Definition
The International League Against Epilepsy [8] defines status epilepticus as continuous seizure activity or intermittent seizures without recovery of consciousness between seizures, lasting 30minutes or longer. However, in practice we cannot wait until we are 100% certain that the patient is in fullSblown SE to treat. As a result, many authors have used an “operational” definition of SE, a time which the likelihood of developing SE is high enough to justify the risks of treatment. We call it “impending SE” [7]. Since about 60% of patients are in SE, and we cannot tell which ones will stop spontaneously, the risk is high enough to justify treating as SE. For generalized convulsive SE (GCSE), there is a broad consensus on duration of 5 minutes [9, 3, 10] of continuous seizures, or of intermittent seizures without recovery of consciousness between seizures, as defining impending SE.
SE lasting 30 minutes or longer without full recovery to consciousness between seizures is defined as
“established SE” [3]. “Refractory SE” is defined as SE that persists despite treatment with adequate amounts of two antiepileptic drugs (AEDs). Some have also defined Refractory SE as SE requiring general anesthesia [11].
SE that continues for at least 24 hours since the onset of anesthesia is defined as “SuperSrefractory SE” [11].
Etiology, Epidemiology & Mortality
The annual incidence of SE in the United States is 18S41 cases per 100,000 [4, 12], which equates to about 152,000 cases of SE per year [4]. Half of all cases report no history of epilepsy and SE. Of all SE cases within the United States, an estimated 22S42,000 result in death [4]. Others report a case fatality rate ranging from 15%S22% [13]. SE In children, is often caused by or associated with infections whereas in adults, major causes of SE are stroke, trauma, Abstract
Status epilepticus is a neurological emergency associated with significant morbidity and mortality.
Delays in treatment are associated with poor outcomes.
Experimental models show that, within 30 minutes, SE becomes selfSsustaining, develops pharmacoresistance and cell damage can be detected. Clinical experience confirms that rapid control of seizures is fundamental in decreasing longSterm sequellae and neurological injury.
Implementing SE protocols and highlighting initiation of treatment in the preShospital setting may improve outcome. This review will discuss recent clinical trials and the role in the treatment of status epilepticus of new drugs which have recently become available in injectable preparations. It will be limited to the approach and management of generalized convulsive status epilepticus in adults.
Keywords: Status epilepticusS TreatmentS Treatment algorithmS PreShospitalS Emergency departmentS Intensive care unit.
Résumé
L’état de mal épileptique (EME) est une urgence neurologique associée à une morbidité et une mortalité importantes. Les retards de traitement sont associés à de mauvais résultats. Les modèles expérimentaux montrent que, en 30 minutes, l’EME devient autonome et développe la pharmacorésistance et les dommages cellulaires.
L’expérience clinique confirme que le contrôle rapide des crises est fondamental dans la réduction des séquelles à long terme et des lésions neurologiques. La mise en œuvre des protocoles EME et l’utilité de l’initiation du traitement dans le milieu pré hospitalier peut améliorer les résultats. Cette revue de la littérature discute de récents essais cliniques et le rôle dans le traitement de l’EME de nouveaux médicaments qui sont récemment devenus disponibles dans les préparations injectables.
Elle sera limitée à l’approche et la gestion des étatsde mal épileptique convulsifs chez les adultes.
MotsSclés: Etat de mal épileptiqueS TraitementS Algorithme de traitementS Pré cliniqueS Service d’urgenceS Unité de soins intensifs.
Introduction
Status epilepticus (SE) is a neurological emergency. It is a prolonged seizure condition associated with significant morbidity and mortality. Delays in initiating treatment [1], delays between treatments [1], and ineffective dosing are
hypoxia, metabolic derangements, alcohol intoxication or drug withdrawal [14]. The incidence of SE is highest within the first year of life and after 60 years of age, with males more frequently affected than females [4, 12]. Both age and etiology are the most consistent determinants of mortality, which is only 3.4% in children [15] vs. 38S67%
in the elderly [16].
Pathophysiology
Within 30 minutes, SE becomes selfSsustaining in experimental animals [17], pharmacoresistance develops [18] and SESinduced damage can be detected [19]. The progression to neuronal injury and death in SE [19] has been correlated with caspaseSinduced apoptosis [20, 21]. The development of selfSsustaining seizures and pharmacoresistance may be in part due to seizureSinduced trafficking of NMDA and GABAA receptors [22]. Evidence shows that the synaptic GABAA receptors migrate from the synaptic membrane into the cell [22] (Refer to figure below).
Figure 1: Top: after repeated seizures, the synaptic membrane of GABAA receptors forms clathrin-coated pits, which internalize as clathrin-coated vesicles (C), inactivating the receptors because they are no longer within reach of the neurotransmitter. These vesicles develop into endosomes (E), which can deliver the receptors to lysosomes (L) where they are destroyed, or to the Golgi apparatus (G) from where they are recycled to the membrane. Bottom: by contrast, in NMDA synapses, subunits are mobilized to the synaptic membrane and assemble into additional receptors.
As a result of this trafficking, the number of functional NMDA receptors per synapse increases whereas the number of functional GABAA receptors decreases [22].
While GABA receptors are endocytosed, NMDA receptor subunits are moved to the synaptic membrane [22] where they form active receptors and contribute to further excitability and pharmacoresistance [18]. This suggests that during SE, the magnesium ion blocking the NMDA subtype of glutamate receptors under physiologic conditions is no longer capable of occluding the channel, allowing for calcium and other ion to accumulate within
the cell. This leads to intracellular havoc and eventual neuronal damage. The damage results in either delayed apoptosis or acute necrosis by activation of caspases and other deleterious mechanisms, [20, 23, 24].
Treatment
1-First-line therapy and management:
Treatment initiated early is more likely to be effective [5]
and is associated with improved outcomes [25]. Studies report that emergency medical services (EMS) may take 15 minutes to get to the emergency department (ED) [25]
but delays in treatment after EMS arrival to the ER may take up to 50 minutes [26]. Hence when EMS arrives, it is crucial to begin treatment to decrease seizure time and recurrence and improve seizure outcome. The initial minutes after seizure onset are likely to offer the best opportunity for pharmacological termination of SE [2].
Several studies have shown that use of Benzodiazepines prior to arrival to the ED is superior to placebo. Alldredge and colleagues [25] have shown that SE was aborted in 59.1% of cases treated with Lorazepam vs. 42.6% in those treated with diazepam vs. 21.1% in those treated with placebo. Respiratory distress was twice as common in the placebo groups compared to either of the groups given a Benzodiazepine.
Controlled studies in children have shown buccal [27] or nasal Midazolam to be quite efficacious in aborting SE, but that formulation is not available in the USA. Rectal Diazepam [17] is as effective as buccal Midazolam (83.3%
in the diazepam group vs. 74.4% in the Midazolam group), but has not been generally accepted for use by EMS in adults.
The RAMPART Study found that preShospital treatment of SE with intramuscular Midazolam is superior to intravenous Lorazepam[11], by successfully terminating seizures in 73.4% of subjects versus 63.4% in the intravenousSLorazepam group (P<0.001). The difference is attributed to the more rapid administration with the intramuscular route (1.2 minutes vs. 4.8 minutes).
Intubation was required in 14% of both groups, hence, treatment should be initiated only if EMS is trained and can support respiration. Rate of hospitalization was lower in the intramuscular Midazolam group (57.8% vs. 65.6%
with intravenous Lorazepam).
For prehospital treatment of impending or established GCSE in adults, we recommend using 10mg of intramuscular Midazolam. Buccal/nasal Midazolam and rectal diazepam are acceptable alternatives. Securing the airway, placing the patient in left lateral decubitus position, and ensuring that the mouth is clear of all foreign objects is essential in the initial phase. Concurrently, the physician must gather information about history of epilepsy and of allergy to AEDs, which obviously is a contraindication to that particular medication [28]. EMS should, as quickly as possible, administer either 10mg of intramuscular/buccal Midazolam or 15S20mg of Diazepam rectal gel. If the SE is not aborted within 20 minutes of giving treatment, therapy may be repeated. Initial administration of 20mg instead of 10 mg of Benzodiazepines has been suggested [29], but
has not been broadly tested and might incur higher risk of respiratory depression.
Upon arrival to the ED, if pre hospital treatment has not been given, we recommend immediate administration of 10mg of Intramuscular Midazolam. If intravenous access has not yet been established by EMS, be sure to do so now. If the patient has not yet received the 20mg dose of Midazolam, then intravenous Benzodiazepines (Midazolam, Lorazepam or Diazepam) should be initiated concurrently with intravenous Fosphenytoin, Levetiracetam or Valproate. If the patient has received a total of 20mg of Midazolam at this point, then Fosphenytoin, Levetiracetam or Valproate should be initiated. Providers must adjust the doses if the patient has received prehospital Benzodiazepine treatment.
In addition to pharmacological management, medical management is essential. Toxicology screen, monitoring of the vital signs, blood glucose levels, electrolytes, complete blood count, liver function tests, arterial blood gasses and other tests as clinically indicated should be obtained to rule out other causes for the seizures [30]. As seizures persist, the patient may experience physiological decompensation, which includes hyperthermia, tachycardia, systemic and pulmonary hypertension, metabolic acidosis, hypoxia, hyperglycemia, hyperkalemia, etc [14]. Addressing these issues may be neuroprotective [31]. Hemodynamic support with intravenous fluid bolus or vasopressors, if necessary, may be needed to maintain systolic blood pressure above 120 mm Hg ideally and no less than 90 mm Hg in the course of SE [32].
Both diazepam and Lorazepam are equally effective in terminating seizures [33]; however, Midazolam is often the preferred Benzodiazepine for continuous infusion because of its short duration of action with an elimination halfSlife of 90S150 minutes compared with 12S24 hours for Lorazepam and 48 hours for Diazepam [34]. Midazolam is metabolized by cytochrome P450 enzymes while Lorazepam is glucuronated, making it less susceptible to drug interactions than Midazolam. All three drugs quickly achieve effective brain concentrations, although Diazepam is slightly quicker. Hypotension and respiratory suppression are common adverse effects of all three Benzodiazepines; hence caution should be taken with dosing and close monitoring of patient.
Phenytoin and Fosphenytoin work to prolong the recovery of voltage gated sodium channels. Fosphenytoin is a more expensive prodrug of Phenytoin requiring 10S15 minutes for dephosphorylation and activation. Fosphenytoin displaces Phenytoin from albumin binding sites, rapidly raising free phenytoin concentration in patients chronically treated with Phenytoin who develop SE. Fewer cases of arrhythmias and hypotension have been reported with Fosphenytoin vs. Phenytoin and soft tissue necrosis is seen in 1.7% of cases with use of Phenytoin (the “purpleS glove” syndrome) [35].
Valproate, which acts on sodium channels and GABA metabolism, may be an acceptable alternative for Phenytoin. In a study by Misra and Colleagues (2006) [36]
found that Valproate is more effective than Phenytoin in
controlling SE as a first line (66% vs. 42%, P=.046) and second line AED (79% vs. 25%, P= .004). Valproate is safer for use in critically ill and elderly [37] as it causes fewer cardiovascular issues [38] or mental status effects, but its liver toxicity remains a potential problem. Levetiracetam is a synaptic vesicle protein ligand and inhibitor of highS voltageSgated calciumSchannel current. Even at higher doses, Levetiracetam has been well tolerated and safe for use in SE [39], but its efficacy has not been fully established.
2-Second-Line Treatment and Management:
If SE persists after administering two first line AEDs, which usually consist of a Benzodiazepine and Fosphenytoin, Levetracetam or Valproate, it is now considered refractory SE (RSE). RSE has a high mortality rate and less than oneSthird of patients recover to their preSmorbid level of functioning [40]. At this point, providers have the option to either initiate general anesthesia or initiate a third line AED, which includes intravenous Levetiracetam or Valproate (if not already given) or intravenous Lacosamide. There is now extensive, but anecdotal evidence for the efficacy of Valproate [41] and Levetiracetam [42], and a few studies of Lacosamide. None of the studies are blinded, and they are subject to publication bias (positive results are more likely to be published than negative results). Several controlled but unblended studies, and sizable uncontrolled studies [32, 41], reported excellent results for seizure control, with little respiration or consciousness. However, the potential for hepatoS and hematotoxicity exists, particularly in patients with mitochondrial diseases, liver disease, or Fanconi syndrome, and an increase in HIV viral loads has also been reported [32]. Levetiracetam has also been reported in uncontrolled studies to be both efficacious and nonStoxic, Thrombocytopenia and aggressivity have been reported, but overall Levetiracetam does not depress respiration, blood pressure or consciousness very much, and is quite safe in acute use [32].
The reported efficacy of Lacosamide was high (44% to 78%) when used early in the course of treatment, however, when used as fourth or later line AED, its efficacy was only 20%
[43]. Even in patients with RSE in an intensive care unit (ICU), 59% of cases became seizure free. The response to Lacosamide was significantly better in patients with no prior history of seizures (p <0.001).
The indications for using a third line AED is still under debate and it can be argued that its administration will delay the use of more effective general anesthetics.
In the Veterans Affairs Cooperative Study [5], 55% of patients with generalized convulsive SE did not respond to first line AEDs and if first line AEDs failed, only 7.3%
of cases responded to second line AED and a meager 2%
responded to a third line AED, regardless of the drug used.
Third line AEDs can be preferred where the necessary equipment to administer endotracheal intubation and ventilation is not available, but great caution should be used since depression of respiration and blood pressure is a common sideSeffect of AEDs. If a provider decides to administer general anesthetics [44], the patient should
be admitted to an ICU, for close monitoring.
3-Third-Line Treatment and Management:
The general anesthetic medications recommended for treatment of nonSresponsive RSE are Propofol, Midazolam, and Pentobarbital. Treatment with these medications should not be delayed and is most effectively used and monitored in the ICU [37]. Also, continuous EEG monitoring, while rarely indispensable, is recommended to look for continued electrographic seizures as RSE at this stage is often electrographic only with or without subtle clinical correlates [5].
A systemic review by Claassen and colleagues [45]
compares Midazolam, Propofol and Barbiturates and a small randomized controlled trial of 23 patients by Rossetti and colleagues have compares Propofol and Barbiturates [46], looking at the efficacy and adverse effects of the drugs. Use of Midazolam for RSE is linked to adverse effects that include pressorS requiring hypotension in about 30% of cases vs. 77% of cases treated with Phenobarbital, respiratory suppression and decreased effectiveness. With Midazolam, ‘50% of cases treated experienced breakthrough seizures compared with Proprofol (15%) and Phenobarbital (12%). Both studies concluded that there is no significant difference in mortality between the three medications when used for RSE. Once seizures are suppressed, medication is typically maintained for 24 hours then anesthetics are stopped under continuous EEG monitoring to evaluate for recurrence of seizures.
4-Fourth-Line Treatment and Management:
If SE is not aborted after 24 hours of initiating anesthetic agents, then the patient is considered to be in SRSE.
Shorvon & Ferlisi [47], reported that in 596 cases, 35%
of SRSE resulted in death and 13% in severe neurological deficit. Recovery to baseline was seen in only 35%. These results highlight the seriousness of this stage of SE and the importance of trying all necessary therapy to control the seizures.
Ketamine is a weak NMDA antagonist that is found to be effective in aborting prolonged SE [48]. Although published experience with Ketamine is limited [49], it has two advantages over conventional anesthetics; it does not cause cardiac depression or hypotension and instead, it increases cardiovascular output by inducing tachycardia and hypertension. Older experiments suggesting that it elevates intracranial pressure have been disproved by studies of traumatic brain injury and therefore, it does not require a CT or MRI before use. It is also neuroprotective. Studies by Martin & Kapur [49]
and Wasterlain and colleagues [50] suggest a synergistic effect when ketamine is used with Benzodiazepines in animal models. If Ketamine fails to control seizures, then combinations of drugs or alternative methods of therapy should be utilized.
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