Elsevier

The Lancet Neurology

Volume 5, Issue 3, March 2006, Pages 246-256
The Lancet Neurology

Review
Status epilepticus: pathophysiology and management in adults

https://doi.org/10.1016/S1474-4422(06)70374-XGet rights and content

Summary

As in Clark and Prout's classic work, we identify three phases of generalised convulsive status epilepticus, which we call impending, established, and subtle. We review physiological and subcellular changes that might play a part in the transition from single seizures to status epilepticus and in the development of time-dependent pharmacoresistance. We review the principles underlying the treatment of status epilepticus and suggest that prehospital treatment is beneficial, that therapeutic drugs should be used in rapid sequence according to a defined protocol, and that refractory status epilepticus should be treated with general anaesthesia. We comment on our preference for drugs with a short elimination half-life and discuss some therapeutic choices.

Introduction

In this review we will focus exclusively on major motor (convulsive) status epilepticus in adults. Complex partial and other forms of status epilepticus are well covered in Simon Shorvon's Status Epilepticus,1 in several recent reviews,2, 3, 4, 5, 6, 7, 8, 9 and in an upcoming volume edited by one of us.10

The earliest known description of status epilepticus was in the 25th and 26th tablets of the Sakikku cuneiform of the Neo-Babylonian era, written during 718–612 BC.1 Status epilepticus is Bazire's latin translation of “Etat de mal”,11 a term coined by the patients of Bicetre and the Salpêtrière, and introduced in published medical work in Louis Calmeil's doctoral thesis.12

In 1876, Bourneville defined status epilepticus as more or less incessant seizures.13 Clark and Prout14 described the natural course of status epilepticus in 38 patients unaffected by anticonvulsants. They recognised three phases: an early pseudostatus phase (described as aborted, imperfect, or incomplete); convulsive status; and stuporous status. Data15, 16 support Clark and Prout's concept, and we propose calling the three phases impending, established, and subtle status epilepticus.

Gastaut17 stated that “there are as many types of status as there are types of epileptic seizures” and defined status epilepticus as “a term used whenever a seizure persists for a sufficient length of time or is repeated frequently enough to produce a fixed or enduring epileptic condition”.18 However, status epilepticus is never truly “fixed”, and this definition is not easily translated into clinical trials or into everyday practice. Furthermore, research with animals shows that repetitive seizures become self-sustaining and pharmacoresistant within 15–30 min15, 19 and can lead to neuronal injury at about the same time.20 The duration of what is accepted as status epilepticus has been shrinking progressively from 30 min in the guidelines of the Epilepsy Foundation of America's Working Group on Status Epilepticus21 to 20 min,22 to 10 min in the Veterans Affairs Status Epilepticus Cooperation Study,16 and most recently, a length of 5 min was proposed.23, 24, 25 This trend indicates the need to find an “operational” definition of status epilepticus—eg, a time when the patient should be treated as having status epilepticus, even if not all such patients are in established status epilepticus.

Section snippets

Early or impending status epilepticus

The operational definition of status epilepticus is an empirical compromise dictated by therapeutic needs, because treatment should not be delayed until patients are in established status epilepticus, when neuronal injury and time-dependent development of pharmacoresistance have occurred. However, a better name would recognise that treatment is needed even though not all patients are in established status epilepticus. We propose the term “impending status epilepticus”, defined as continuous or

Epidemiology

Three important population-based prospective studies were done to investigate the epidemiology of status epilepticus. The incidence of status epilepticus around Richmond (VA, USA) was 41 per 100 000 individuals per year;36 however, it was 27 per 100 000 per year for young adults and 86 per 100 000 per year in the elderly. This askew distribution of incidence suggests that in an ageing society, such as in the USA as the baby-boom generation ages, status epilepticus will become more frequently

Aetiology

The main causes of status epilepticus are low blood concentrations of antiepileptic drugs in patients with chronic epilepsy (34%), remote symptomatic causes (24%), cerebrovascular accidents (22%), anoxia or hypoxia (∼10%), metabolic causes (∼10%), and alcohol and drug withdrawal (∼10%).36

Several prognostic factors are important in predicting outcome of status epilepticus: cause, age, seizure duration, and response to treatment. The high mortality groups are patients with anoxia or multiple

Self-sustaining status epilepticus

The tendency of status epilepticus to become self-perpetuating and the fact that it is more than a series of severe seizures were recognised as early as the 19th century: in the words of Trousseau11 “in the status epilepticus, something happens [in the brain] which requires an explanation”. In most models of status epilepticus in awake, free-running animals, seizures rapidly become self-sustaining and continue long after the withdrawal of the epileptogenic stimulus, whether chemical41, 42, 43

Therapeutic principles: time is brain

Although the optimum treatment of status epilepticus needs to be further defined by controlled clinical trials, several important principles have emerged. Early initiation of intravenous anticonvulsants is crucial to successful treatment of status epilepticus. Clinical data show worsening of outcome with increasing duration of status epilepticus;40, 111 experimental data show time-dependent loss of synaptic GABAA receptors,59 and as a consequence, rapid loss of responsiveness to benzodiazepines

Refractory status epilepticus

This term is defined by the failure of adequate amounts of two intravenous drugs to stop seizures. Because generalised convulsive status epilepticus is a life-threatening disorder with a very poor outcome if it does not respond to the first two drugs,16 a moderate amount of dose-dependent toxicity (eg, sleepiness, ataxia, and confusion) is a small price to pay for stopping the seizures. Therefore, if the initial treatment does not stop the seizures, the first measure should be to add enough

General anaesthesia

Once the patient has reached this stage, prognosis is poor regardless of treatment choice, and all options entail significant risks. Midazolam is an effective drug,143, 144, 145, 146 but we reserve it for patients who have not received adequate benzodiazepine treatment. There is no objective evidence comparing the risks of the propofol infusion syndrome147 to the risks of the prolonged cardiovascular depression caused by barbiturates.148, 149, 150 Propofol151, 152 has a short half-life, so

Neuroprotection

Most anticonvulsants that are active against partial seizures have some neuroprotective and antiepileptogenic properties in animal models, but evidence from human beings is too scarce to recommend their use at present. Some of the more potent experimental drugs43, 158, 159, 160, 161 might find a place in the future treatment of status epilepticus.

Conclusions

This review highlights the progress made in understanding the nature of status epilepticus in animal models and the paucity of reliable evidence in human beings. We propose a simplified nomenclature of status epilepticus and an aggressive approach to its treatment. For established status epilepticus, available treatments fall far short of what an optimal drug should achieve. New therapies and controlled trials of available drugs are urgently needed.

Search strategy and selection criteria

References for this review were identified by searches of PubMed with the term “status epilepticus” or “SSSE” in combination with “epidemiology”, “GABA”, “glutamate”, “NMDA”, “AMPA”, “treatment”, “intravenous AND valproate”, “midazolam”, and “refractory status epilepticus”. The last search was done in October 2005. The following publication types were excluded: case report, non-controlled trials, retrospective studies, editorial and reviews. Clinical trials of paediatric patients are

References (161)

  • EW Lothman et al.

    Self-sustaining limbic status epilepticus induced by ‘continuous’ hippocampal stimulation: electrographic and behavioral characteristics

    Epilepsy Res

    (1989)
  • EW Lothman et al.

    Recurrent spontaneous hippocampal seizures in the rat as a chronic sequela to limbic status epilepticus

    Epilepsy Res

    (1990)
  • DC McIntyre et al.

    A new model of partial status epilepticus based on kindling

    Brain Res

    (1982)
  • NW Milgram et al.

    Establishment of status epilepticus by limbic system stimulation in previously unstimulated rats

    Exp Neurol

    (1985)
  • RA Morrisett et al.

    Effects of drugs on the initiation and maintenance of status epilepticus induced by administration of pilocarpine to lithium-pretreated rats

    Exp Neurol

    (1987)
  • DP Cain et al.

    Rapid and reliable induction of partial status epilepticus in naive rats by low-frequency (3-Hz) stimulation of the amygdala

    Epilepsy Res

    (1992)
  • KH Taber et al.

    Status epilepticus: a new rodent model

    Electroencephalogr Clin Neurophysiol

    (1977)
  • JP Vicedomini et al.

    A model of status epilepticus based on electrical stimulation of hippocampal afferent pathways

    Exp Neurol

    (1987)
  • EA van Vliet et al.

    Progression of temporal lobe epilepsy in the rat is associated with immunocytochemical changes in inhibitory interneurons in specific regions of the hippocampal formation

    Exp Neurol

    (2004)
  • A Pitkanen et al.

    Amygdala damage in experimental and human temporal lobe epilepsy

    Epilepsy Res

    (1998)
  • AM Mazarati et al.

    N-methyl-D-asparate receptor antagonists abolish the maintenance phase of self-sustaining status epilepticus in rat

    Neurosci Lett

    (1999)
  • A Vezzani et al.

    Neuropeptide Y: emerging evidence for a functional role in seizure modulation

    Trends Neurosci

    (1999)
  • G Sperk et al.

    Kainic acid induced seizures: changes in somatostatin, substance P and neurotensin

    Neuroscience

    (1986)
  • A Mazarati et al.

    Opioid peptide pharmacology and immunocytochemistry in an animal model of self-sustaining status epilepticus

    Neuroscience

    (1999)
  • A Vezzani et al.

    Brain-derived neurotrophic factor immunoreactivity in the limbic system of rats after acute seizures and during spontaneous convulsions: temporal evolution of changes as compared to neuropeptide Y

    Neuroscience

    (1999)
  • HR Cock et al.

    Mitochondrial dysfunction associated with neuronal death following status epilepticus in rat

    Epilepsy Res

    (2002)
  • H Pollard et al.

    Kainate-induced apoptotic cell death in hippocampal neurons

    Neuroscience

    (1994)
  • ME O'Regan et al.

    Serum neuron specific enolase: a marker for neuronal dysfunction in children with continuous EEG epileptiform activity

    Eur J Paediatr Neurol

    (1998)
  • T Salmenpera et al.

    MRI volumetry of the hippocampus, amygdala, entorhinal cortex, and perirhinal cortex after status epilepticus

    Epilepsy Res

    (2000)
  • J Nixon et al.

    An MRI and neuropathological study of a case of fatal status epilepticus

    Seizure

    (2001)
  • T Morimoto et al.

    Sequential changes of brain CT and MRI after febrile status epilepticus in a 6-year-old girl

    Brain Dev

    (2002)
  • E Tremblay et al.

    Usefulness of parenteral kainic acid as a model of temporal lobe epilepsy

    Rev Electroencephalogr Neurophysiol Clin

    (1984)
  • EA Cavalheiro et al.

    Long-term effects of intrahippocampal kainic acid injection in rats: a method for inducing spontaneous recurrent seizures

    Electroencephalogr Clin Neurophysiol

    (1982)
  • S Shorvon

    Status epilepticus: its clinical features and treatment in children and adults

    (1994)
  • S Shorvon

    The classification of status epilepticus

    Epileptic Disord

    (2005)
  • A Pitkanen et al.

    Antiepileptic drugs in neuroprotection

    Expert Opin Pharmacother

    (2004)
  • S Bassin et al.

    Clinical review: status epilepticus

    Crit Care

    (2002)
  • F Rosenow et al.

    Recent developments in treatment of status epilepticus: a review

    Epileptic Disord

    (2002)
  • R Appleton et al.

    The treatment of convulsive status epilepticus in children

    Arch Dis Child

    (2000)
  • A Trousseau

    Lectures on clinical medicine delivered at the Hotel Dieu, Paris, vol 1. translated by Bazire PV

    (1868)
  • LF Calmeil

    De l'epilepsie, etudiee sous le rapport de son siege et de son influence sur la production de l'alienation mentale

    (1824)
  • DM Bourneville

    L'etat de mal epileptique

  • LP Clark et al.

    Status epilepticus: a clinical and pathological study in epilepsy. [An article in 3 parts]

    Am J Insanity

    (1903)
  • DM Treiman et al.

    A comparison of four treatments for generalized convulsive status epilepticus: Veterans Affairs Status Epilepticus Cooperative Study Group

    N Engl J Med

    (1998)
  • H Gastaut

    Classification of status epilepticus

    Adv Neurol

    (1983)
  • H Gastaut

    A propos d' une classification symptomatologique des etats de mal epileptiques

  • CG Wasterlain

    Mortality and morbidity from serial seizures: an experimental study

    Epilepsia

    (1974)
  • Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of America's Working Group on Status Epilepticus

    JAMA

    (1993)
  • TP Bleck

    Convulsive disorders: status epilepticus

    Clin Neuropharmacol

    (1991)
  • Cited by (0)

    View full text