Elsevier

The Lancet Neurology

Volume 14, Issue 6, June 2015, Pages 615-624
The Lancet Neurology

Review
Status epilepticus in adults

https://doi.org/10.1016/S1474-4422(15)00042-3Get rights and content

Summary

Status epilepticus is a common neurological emergency with considerable associated health-care costs, morbidity, and mortality. The definition of status epilepticus as a prolonged seizure or a series of seizures with incomplete return to baseline is under reconsideration in an effort to establish a more practical definition to guide management. Clinical research has focused on early seizure termination in the prehospital setting. The approach of early escalation to anaesthetic agents for refractory generalised convulsive status epilepticus, rather than additional trials of second-line anti-epileptic drugs, to avoid neuronal injury and pharmaco-resistance associated with prolonged seizures is gaining momentum. Status epilepticus is also increasingly identified in the inpatient setting as the use of extended electroencephalography monitoring becomes more commonplace. Substantial further research to enable early identification of status epilepticus and efficacy of anti-epileptic drugs will be important to improve outcomes.

Introduction

Most seizures are brief and self-limited. Status epilepticus is broadly defined as a prolonged seizure or multiple seizures with incomplete return to baseline and remains a common neurological emergency with an annual incidence of 10–41 per 100 000 population.1, 2, 3, 4, 5 The overall mortality associated with status epilepticus approaches 20%,6, 7 with generalised convulsive status epilepticus representing about 45–74% of all cases.1, 2 In view of the incidence of status epilepticus and its substantial morbidity and mortality, annual direct inpatient costs are estimated at more than €83 million in Germany8 and US$4 billion in the USA.9

Several advances in the study of status epilepticus have been made, and the increased use of extended electroencephalography (EEG) monitoring has shown a high prevalence of seizures and status epilepticus in the hospital setting. An improved understanding of the pathophysiological mechanisms underlying status epilepticus highlights the need for a more practical definition of the disorder and underscores the importance of early seizure cessation to avoid pharmaco-resistance as seizure duration increases. These concepts have contributed to the design of treatment trials in status epilepticus during the past decade.

In this Review, we discuss the current knowledge about status epilepticus and refractory status epilepticus in adults and focus mainly on the definitions, pathophysiology, epidemiology, outcomes, and treatment of generalised convulsive status epilepticus. We then summarise the data on the utility of extended EEG monitoring and emphasise the importance of early termination of status epilepticus, examine the use of new anti-epileptic rescue drugs, and review the major pre-hospital treatment trials for status epilepticus. We also propose an updated, practical treatment algorithm for generalised convulsive status epilepticus, describe plans for upcoming treatment trials, and highlight areas in need of further research.

Section snippets

Definitions

The 1981 International League Against Epilepsy (ILAE) definition of status epilepticus describes a seizure that “persists for a sufficient length of time or is repeated frequently enough that recovery between attacks does not occur”.10 The absence of a definitive timeframe of seizure duration creates ambiguity, which makes it difficult to accurately define and treat status epilepticus. Accordingly, status epilepticus was redefined as a seizure lasting 60 min, then further refined by the

Epidemiology, aetiology, and outcomes

Status epilepticus is relatively common, with estimates of 50 000–60 000 new cases annually in the USA.2, 16 The incidence of status epilepticus in Europe is somewhat lower (10–16 per 100 000 population)4, 5, 17 compared with the USA (18–41 per 100 000 population). Notably, American ethnic minorities have a substantially higher incidence (57 per 100 000) than whites (20 per 100 000).1 Results of trend studies3, 18 show an increase in incidence of status epilepticus in the past few decades in

Pathophysiology and neuronal injury

Much of the pathophysiology of status epilepticus is still poorly understood, but studies using animal models have led to substantial advances in the understanding of the basic mechanisms underlying status epilepticus. Although numerous molecular and cellular processes are almost certainly involved in the development of status epilepticus, the fundamental principle involves a failure of endogenous mechanisms to terminate a seizure. This failure can occur because of excessive abnormal excitation

Diagnostic yield of extended EEG monitoring

Status epilepticus can present in several forms: convulsive, non-convulsive, and electrographic. The initial presentation of convulsive status epilepticus is typically not subtle, and is characterised by unresponsiveness and tonic, clonic, or tonic-clonic movements of the extremities. Non-convulsive status epilepticus has not been precisely defined, but is characterised by prolonged seizure activity evidenced by epileptiform discharges on EEG. There are various subtypes of non-convulsive status

Pre-hospital management of status epilepticus

In a retrospective review of adults presenting with status epilepticus,79 first-line therapy (typically diazepam followed by phenytoin) effectively aborted status epilepticus in 92 (60%) of 154 patients treated within 30 min of seizure onset. However, the efficacy of first-line treatment decreased as seizure duration increased. Owing to our knowledge of pharmaco-resistance and neuronal injury as status epilepticus duration increases, clinical research has focused on early treatment of status

Hospital management of status epilepticus

Generalised convulsive status epilepticus is managed as a true medical emergency, in which the patient is stabilised, airway and vital signs are assessed and controlled, and intravenous access is obtained. Tonic-clonic seizures can be associated with periods of apnoea, cyanosis, and metabolic acidosis. The metabolic acidosis almost always self-corrects once seizures are adequately controlled. Most patients are able to breathe adequately during a seizure as long as their airway remains patent.

Refractory status epilepticus

A comprehensive review of refractory status epilepticus is beyond the scope of this Review but can be found in reviews by Rossetti and Lowenstein105 and Ferlisi and Shorvon.106 Refractory status epilepticus is commonly defined as status epilepticus that does not terminate with a first-line agent (benzodiazepines) or a second-line anti-epileptic drug (phenytoin, valproic acid, levetiracetam, or phenobarbital).107 The diagnosis of refractory status epilepticus is clinical and often involves the

Conclusion and future directions

Substantial progress has been made in the identification and treatment of status epilepticus, yet the disorder remains a common neurological emergency with substantial morbidity and mortality. Knowledge regarding the process of epileptogenesis and the transition from a single seizure to self-sustaining status epilepticus has improved through basic research largely with animal models. This research has also led to increased recognition that persistent seizures cause further neurological injury,

Search strategy and selection criteria

We searched PubMed and article references for papers in English published between Jan 1, 1969, and Jan 31, 2015, with the terms “status epilepticus”, “status epilepticus mortality”, “refractory status epilepticus”, “status epilepticus and EEG monitoring”, “status epilepticus radiographic findings”, “status epilepticus and MRI”, and “status epilepticus treatment”. The final set of publications was selected based on the quality of each study and its relevance to this Review.

References (117)

  • G Bauer et al.

    Transient and permanent magnetic resonance imaging abnormalities after complex partial status epilepticus

    Epilepsy Behav

    (2006)
  • RC Scott et al.

    Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial

    Lancet

    (1999)
  • J McIntyre et al.

    Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial

    Lancet

    (2005)
  • G Sechi et al.

    Wernicke's encephalopathy: new clinical settings and recent advances in diagnosis and management

    Lancet Neurol

    (2007)
  • P Agarwal et al.

    Randomized study of intravenous valproate and phenytoin in status epilepticus

    Seizure

    (2007)
  • Z Yasiry et al.

    The relative effectiveness of five antiepileptic drugs in treatment of benzodiazepine-resistant convulsive status epilepticus: a meta-analysis of published studies

    Seizure

    (2014)
  • RJ DeLorenzo et al.

    A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia

    Neurology

    (1996)
  • DC Hesdorffer et al.

    Incidence of status epilepticus in Rochester, Minnesota, 1965–1984

    Neurology

    (1998)
  • G Logroscino et al.

    Time trends in incidence, mortality, and case-fatality after first episode of status epilepticus

    Epilepsia

    (2001)
  • S Knake et al.

    Incidence of status epilepticus in adults in Germany: a prospective, population-based study

    Epilepsia

    (2001)
  • A Coeytaux et al.

    Incidence of status epilepticus in French-speaking Switzerland: (EPISTAR)

    Neurology

    (2000)
  • G Logroscino et al.

    Short-term mortality after a first episode of status epilepticus

    Epilepsia

    (1997)
  • G Logroscino et al.

    Mortality after a first episode of status epilepticus in the United States and Europe

    Epilepsia

    (2005)
  • From the Commission on Classification and Terminology of the International League Against Epilepsy

    Epilepsia

    (1981)
  • Treatment of convulsive status epilepticus

    JAMA

    (1993)
  • S Jenssen et al.

    How long do most seizures last? A systematic comparison of seizures recorded in the epilepsy monitoring unit

    Epilepsia

    (2006)
  • J Kapur et al.

    Rapid seizure-induced reduction of benzodiazepine and Zn2+ sensitivity of hippocampal dentate granule cell GABAA receptors

    J Neurosci

    (1997)
  • DH Lowenstein et al.

    It's time to revise the definition of status epilepticus

    Epilepsia

    (1999)
  • WA Hauser

    Status epilepticus: epidemiologic considerations

    Neurology

    (1990)
  • L Vignatelli et al.

    Incidence and short-term prognosis of status epilepticus in adults in Bologna, Italy

    Epilepsia

    (2003)
  • BS Dham et al.

    The epidemiology of status epilepticus in the United States

    Neurocrit Care

    (2014)
  • DC Hesdorffer et al.

    Risk of unprovoked seizure after acute symptomatic seizure: effect of status epilepticus

    Ann Neurol

    (1998)
  • RJ DeLorenzo et al.

    Epidemiology of status epilepticus

    J Clin Neurophysiol

    (1995)
  • RJ DeLorenzo et al.

    Comparison of status epilepticus with prolonged seizure episodes lasting from 10 to 29 minutes

    Epilepsia

    (1999)
  • AR Towne et al.

    Determinants of mortality in status epilepticus

    Epilepsia

    (1994)
  • YW Wu et al.

    Incidence and mortality of generalized convulsive status epilepticus in California

    Neurology

    (2002)
  • AO Rossetti et al.

    A clinical score for prognosis of status epilepticus in adults

    Neurology

    (2006)
  • R Sutter et al.

    Independent external validation of the status epilepticus severity score

    Crit Care Med

    (2013)
  • AO Rossetti et al.

    Status Epilepticus Severity Score (STESS): a tool to orient early treatment strategy

    J Neurol

    (2008)
  • TM Perl et al.

    An outbreak of toxic encephalopathy caused by eating mussels contaminated with domoic acid

    N Engl J Med

    (1990)
  • JS Teitelbaum et al.

    Neurologic sequelae of domoic acid intoxication due to the ingestion of contaminated mussels

    N Engl J Med

    (1990)
  • JW Chen et al.

    Advances in the pathophysiology of status epilepticus

    Acta Neurol Scand Suppl

    (2007)
  • DE Naylor et al.

    Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus

    J Neurosci

    (2005)
  • HP Goodkin et al.

    GABA(A) receptor internalization during seizures

    Epilepsia

    (2007)
  • H Liu et al.

    Substance P is expressed in hippocampal principal neurons during status epilepticus and plays a critical role in the maintenance of status epilepticus

    Proc Natl Acad Sci USA

    (1999)
  • FA Lado et al.

    How do seizures stop?

    Epilepsia

    (2008)
  • RC Elliott et al.

    Overlapping microarray profiles of dentate gyrus gene expression during development- and epilepsy-associated neurogenesis and axon outgrowth

    J Neurosci

    (2003)
  • A Roopra et al.

    Epigenetics and epilepsy

    Epilepsia

    (2012)
  • SFC Miller-Delaney et al.

    Differential DNA methylation patterns define status epilepticus and epileptic tolerance

    J Neurosci

    (2012)
  • BS Meldrum et al.

    Physiology of status epilepticus in primates

    Arch Neurol

    (1973)
  • Cited by (0)

    View full text