Problems and Controversies in Status Epilepticus

A Review and Recommendations

Hussam Seif-Eddeine; David M Treiman

Expert Rev Neurother. 2011;11(12):1747-1758.

Abstract and Introduction

Abstract

Status epilepticus (SE) is a neurologic emergency that require immediate vigorous treatment in order to prevent serious morbidity or even death. Several investigators have suggested that the underlying etiology is the primary determinant of outcome. We believe that this may be true in aggressively treated SE, but not when the treatment is less than optimal. In this article, we will discuss the factors that have been implicated in affecting SE outcomes, and argue, on the basis of both human and experimental animal data, that aggressive treatment is necessary and appropriate for all presentations of SE in order to maximize the probability of a successful outcome even when the etiology suggests a poor prognosis.

Introduction

Status epilepticus (SE) is a neurologic emergency that, when it presents as repeated generalized convulsions without full recovery of consciousness between convulsions, has been generally thought to require immediate vigorous treatment in order to prevent serious morbidity or even death.^[1–5]

Although several studies have investigated and established the first line of treatment, the subsequent treatment steps remain controversial as, to date, there have been no class I studies that have investigated such a treatment. This is in part owing to the difficulty of conducting such trials on human patients. Furthermore, the necessity for urgent treatment in the case of subtle or nonconvulsive SE has been less widely accepted, and some have suggested that the underlying etiology is the primary determinant of outcome. This may be true in aggressively treated SE, but is not necessarily true when treatment is less than optimal. In this article we discuss the role of etiology and other factors on the outcome of generalized convulsive SE, but we argue, on the basis of both human and experimental animal data, that aggressive appropriate treatment for all presentations of SE will maximize the probability of successful outcome even when the etiology suggests a poor prognosis.

SE is defined as a single seizure lasting longer than 30 min or a series of epileptic seizures during which full function is not regained between ictal events.^[6] More recently others have suggested that continuous ictal activity without evolution lasting more than 10 min^[7] or even 5 min^[8] should be considered SE. Thus, any seizure type of sufficient duration or frequency can be considered SE.^[9] This allows the use of the International Classification of Epileptic Seizures^[10] to classify SE. However, advances in understanding of generalized convulsive SE require that we expand the classification of at least secondarily generalized SE to include overt, subtle and electrical presentations of this type of SE (Box 1).

The occurrence of frequent seizures without fulfilling the criteria for SE in the International Classification of Epileptic Seizures has been described by several authors utilizing different terms, such as seizures cluster, serial seizures or acute repetitive seizures. However, this concept of frequent seizures and its relationship to SE remains controversial. Some authors have suggested that seizure clusters can evolve into SE,^[11] or at least create a higher risk for developing convulsive SE,^[12] while others observed a decrease in the risk of developing SE after seizure clusters.^[13]

Physiologically, SE is a condition where the effects of a single seizure still persist when the next seizure begins or where seizure terminating mechanisms have failed, so that epileptic activity continues longer than the usual seconds-to-minutes duration of single seizures.^[14] These two scenarios result in a cumulative effect of seizure-induced pathophysiological changes, with the result that untreated or undertreated SE is a dynamic state. The dynamic nature of generalized convulsive SE, first recognized by Clark and Prout,^[15–17] has been again appreciated in the last several decades.^[5,18,19] We now recognize that untreated generalized convulsive SE can evolve from repeated overt convulsion without complete recovery of consciousness between the seizures, to more subtle, more-or-less continuous motor twitches of the face, abdomen or extremities, to complete cessation of motor activity even though ictal discharges continue on the EEG. This evolution is hypothesized to be due to an increasingly encephalopathic state that results in attenuation of transmission of messages from the motor cortex down the neuroaxis to the extremities to produce convulsions of the extremities. However, when the brain insult that induces generalized convulsive SE is sufficiently severe to induce an encephalopathic state from the beginning, patients may present in subtle or electrical generalized convulsive SE, without ever exhibiting overt convulsions.

Sometimes the term 'nonconvulsive SE' is used to apply to cases of subtle or electrical generalized convulsive SE. However, the concept of nonconvulsive SE is not well defined. Several investigators agree that nonconvulsive SE can be defined as a prolonged state of impaired consciousness or altered sensorium associated with continuous paroxysmal activity or electrographic discharges on the EEG. However, the term 'nonconvulsive SE' is also used to refer to complex partial SE and also to absence SE, so the terminology in this field is confusing. Furthermore, refractory SE is a term used by several investigators to define SE that has failed to respond to initial treatment (benzodiazepines and phenytoin), but again there is no general agreement regarding a precise definition of this term.

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Next Section

Table. Summary of arguments for and against aggressive treatment of status epilepticus.
Summary of our arguments for aggressive treatment of SE	Summary of arguments made by some investigators against aggressive treatment for SE
The longer SE persists the harder it is to stop [20,50,75,77,78,81,82]	Prolonged SE does not result in poor prognosis if the etiology is not severe (we disagree)
The longer SE persists the worse the sequelae [20,47,50,65,75]	IVGA agents may induce hypotension [48]
Untreated or undertreated generalized convulsive SE is nearly always fatal [47,65]	Most SE episodes stop spontaneously, regardless of treatment[136] (we disagree)
Unless seizure activity is completely stopped by treatment it is likely to reoccur when anesthesia is lightened [48,128]	Periodic epileptiform discharges are not ictal patterns, but rather reflections of neuronal damage[137–139] (we disagree[18,88,89])

IVGA: Intravenous general anesthesia; SE: Status epilepticus.

Box 1. Classification of status epilepticus.
Partial onset Secondarily generalized convulsive Overt Subtle Electrical Complex partial Simple partial Primarily generalized Tonic–clonic Tonic Clonic Myoclonic Atonic Absence

Reproduced with permission from [127].

Box 2. Treatment protocol for generalized convulsive status epilepticus.
0 min Establish the diagnosis by observing one additional seizure in a patient with recent seizures or impaired consciousness or by observing continuous behavioral and/or electrical seizure activity for >10 min. Start the EEG as soon as possible, but do not delay treatment unless EEG verification of the diagnosis is necessary.
5 min Establish iv. catheter with normal saline (dextrose solutions may precipitate phenytoin) – with fos-phenytoin either dextrose or saline is acceptable. Draw blood for serum chemistry, hematologic values and AED concentrations. Check for hypoglycemia by finger stick. If hypoglycemia is present, administer 100 mg of thiamine (if indicated) followed by 50 ml of 50% glucose by direct push into the iv. line.
10 min Administer lorazepam (0.1 mg/kg) by iv. push (<2 mg/min).
25 min If status continues, start fos-phenytoin (20 mg/kg PE) by fast iv. push (up to 150 mg PE/min) directly into the iv. port nearest to patient; if only phenytoin is available, give by slow iv. push (<50 mg/min); with either preparation monitor blood pressure and electrocardiogram during infusion. If status continues after 20 mg PE/kg fos-phenytoin (or 20 mg/kg phenytoin), administer an additional 5 mg/kg and, if necessary, another 5 mg/kg, to a maximum dose of 30 mg/kg. Alternatively give valproate (30 mg/kg) iv., at a rate up to 500 mg/min. If SE continues administer an additional 15 mg/kg and, if necessary, another 15 mg/kg.
60 min If status persists, support respiration by endotracheal intubation; give phenobarbital (20 mg/kg) by iv. push (<100 mg/min) or, preferably, start barbiturate coma: give pentobarbital (5–15 mg/kg) slowly as an initial iv. dose to suppress all epileptiform activity and continue 0.5–5 mg/kg/h to maintain suppression; slow infusion rate periodically to determine cessation of seizure activity; monitor blood pressure, electrocardiogram and respiratory function. If unable to suppress all epileptiform activity, change to continuous infusions of propofol (1 mg/kg given over 5 min, then 2–4 mg/kg/h; adjust to 1–15 mg/kg/h) or midazolam (0.2 mg/kg bolus injection, followed by infusion of 0.05–0.5 mg/kg/h). Maintain full suppression of epileptiform activity (not a burst-suppression pattern) for 48–72 h before beginning to the slow the infusion rate. Before beginning withdrawal of iv. anesthesia adjust phenytoin serum concentration to 30 µg/ml; load phenobarbital to achieve 100–150 µg/ml serum concentration. If VPA has been used in the initial treatment adjust VPA serum concentration to 150 µg/ml. Maintain these levels as the anesthetic agent is slowed. Intravenous LEV and/or LCM are alternatives if PHT, VPA and/or PB are contraindicated. Load LEV with 4 g iv., maintain with up to 1000 mg every 6 h; load LCM with 400 mg iv., maintain with 100 m every 6 h. Target 150 µg/ml of VPA; target serum concentrations for LEV and LCM are not known. If epileptiform activity returns during lightening of the induced coma, increase the infusion rate of the anesthetic agent (pentobarbital, propofol or midazolam) to suppress all epileptiform activity for another 48–72 h before attempting anesthesia withdrawal again Repeat as many times as necessary. Do not give up. Patients have recovered consciousness after >2 months of coma.
AED: Antiepileptic drugs; iv.: Intravenous; LCM: Lacosamide; LEV: Levetiracetam; PB: Phenobarbital; PE: Phenytoin equivalent; PHT: Phenytoin; SE: Status epilepticus; VPA: Valproic acid. Modified with permission from [127].

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