Description of health problem
Status epilepticus is the most severe form of epilepsy; it is a life-threatening neurological condition that requires urgent treatment.1–3 Status epilepticus can be convulsive (i.e. with limb stiffness, abnormal posturing and jerking, so-called tonic–clonic seizures, often with impaired awareness/consciousness) or non-convulsive (i.e. altered consciousness with little or no limb movements) and can be of focal or generalised onset.2,4,5 The focus of the present study is generalised convulsive status epilepticus. Generalised convulsive status epilepticus is defined as ‘≥ 5 min of (a) continuous seizures or (b) two or more discrete seizures between which there is incomplete recovery of consciousness’.6
Status epilepticus arises because of the failure of mechanisms that abort seizure activity, that is either the breakdown of the mechanisms that terminate seizures or the instigation of mechanisms responsible for abnormally sustained seizures.3,7,8 There are various causes of status epilepticus. In adults, the most common causes of status epilepticus are low levels of antiepileptic drugs in people with existing epilepsy, cerebrovascular disease, metabolic abnormalities, alcohol-related causes and hypoxia.9 Status epilepticus can also occur in people with no history of epilepsy or in people with established epilepsy.10
The incidence of status epilepticus has been reported as 10–60 per 100,000 population per year, with half of these people having convulsive status epilepticus.11–14 Mortality has been reported as 10–20% and is generally related to the underlying condition.10–13 Those at the highest risk of seizures are children and people aged > 60 years.10 The incidence of status epilepticus is equal in males and females.3
Status epilepticus is a medical emergency with significant morbidity and mortality, which can worsen with suboptimal or delayed treatment.15–19 The likelihood of status epilepticus spontaneously resolving is negatively related to its persistence, and treatment should be given as quickly as possible.1,20 It has been shown that early treatment of status epilepticus is associated with better outcomes in terms of seizures terminated on arrival at the hospital emergency department (ED) and reduced morbidity and mortality.21–23 Therefore, the main goal of treatment of status epilepticus is to promptly stop both clinical and electroencephalographic seizure activity.4,24
First-line treatment of status epilepticus is currently benzodiazepines, a class of drugs that bind the gamma-aminobutyric acid (GABA) receptor complex that modulates GABA release in the central nervous system and causes down-regulation of neuronal excitation (i.e. neurons become less excitable).25,26 In the community, buccal midazolam is recommended as first-line treatment in children, young people and adults with prolonged or repeated seizures. Rectal diazepam can be administered if preferred or if buccal midazolam is not available. Intravenous (i.v.) lorazepam can be administered if i.v. access is already established and resuscitation can be facilitated. In addition, care plans outlining the home use of buccal midazolam or rectal diazepam are recommended for children, young people and adults who have had a previous episode of prolonged or serial convulsive seizures.25
The purpose of this assessment is to conduct a synthesis of the current evidence on the clinical effectiveness and cost-effectiveness of treatments for convulsive status epilepticus in pre-hospital settings (i.e. the community and ED) and to inform the design and conduct of any future randomised controlled trials (RCTs) in this clinical context.
Current service provision
Variation in services and/or uncertainty about best practice
There is considerable uncertainty and a limited evidence base on the effectiveness of the first-line treatment options available for treating status epilepticus. As a result, treatment guidelines do not recommend any specific treatment over another and treatment decisions are frequently based on expert opinion.4,24,27
A recent retrospective chart review conducted for patients in the USA diagnosed with status epilepticus within the last 10 years concluded that treatment for status epilepticus does not consistently follow guidelines or recommendations. In particular, underdosing of first-line benzodiazepines (i.e. lorazepam and midazolam) was identified.28
Relevant national guidelines
The National Institute for Health and Care Excellence (NICE) guideline on the diagnosis and management of epilepsies, which was published in 2012 and subsequently updated (last updated 12 May 2020),25 provides recommendations on first-line treatment for convulsive status epilepticus in people of all ages.25
In particular, the NICE clinical guidance25 supports the following recommendations:
- Give immediate emergency care and treatment to children, young people and adults who have prolonged (lasting ≥ 5 minutes) or repeated (three or more in an hour) convulsive seizures in the community.
- Prescribe buccal midazolam or rectal diazepam for use in the community only for children, young people and adults who have had a previous episode of prolonged or serial convulsive seizures.
- Administer buccal midazolam as first-line treatment in children, young people and adults with prolonged or repeated seizures in the community. Administer rectal diazepam if preferred or if buccal midazolam is not available. If i.v. access is already established and resuscitation facilities are available, administer i.v. lorazepam.
- Care must be taken to secure the child, young person or adult’s airway and assess their respiratory and cardiac function.
- Depending on response to treatment, the person’s situation and any personalised care plan, call an ambulance, particularly if:
- the seizure is continuing 5 minutes after the emergency medication has been administered
- the person has a history of frequent episodes of serial seizures or has convulsive status epilepticus, or this is the first episode requiring emergency treatment
- there are concerns or difficulties monitoring the person’s airway, breathing, circulation or other vital signs.
Scottish Intercollegiate Guidelines Network (SIGN) 143 guideline for the diagnosis and management of epilepsy in adults, which was originally published in 2015 and subsequently revised in 2018,16 states that many status epilepticus seizures resolve themselves without treatment; emergency treatment is necessary if there are continuous seizures or serial seizures lasting for ≥ 5 minutes. The current recommended treatments are:
- 10 mg of midazolam administered either buccally or intranasally
- 4 mg of i.v. lorazepam if midazolam is unavailable
- 10 mg of diazepam administered either intravenously or rectally if both midazolam and lorazepam are not available.
The guidance further points out the need to treat status epilepticus as soon as possible as it can worsen if treatment is delayed.
In 2016, the American Epilepsy Society published an algorithm for the treatment of convulsive status epilepticus.29 The use of a benzodiazepine is recommended for initial therapy, specifically intramuscular (i.m.) midazolam, i.v. lorazepam or i.v. diazepam. If none of these is available, then i.v. phenobarbital, rectal diazepam or intranasal midazolam is recommended as first-line treatment. Recommended second-line options are i.v. fosphenytoin, i.v. valproic acid or i.v. levetiracetam, with i.v. phenobarbital recommended if these are not available.
An older set of guidelines, published by the European Federation of Neurologists in 2010, recommends i.v. administration of 4–8 mg of lorazepam or 10 mg of diazepam directly followed by 18 mg/kg phenytoin.30
Description of technologies under assessment
Benzodiazepines
Benzodiazepines are currently the first treatment for status epilepticus.25 In UK clinical practice, the most common benzodiazepines used as first-line treatment for status epilepticus are midazolam, diazepam and lorazepam. Benzodiazepines vary in their potency, onset and duration of effect, uptake, distribution, metabolism and presence or absence of active metabolites.31,32 Lorazepam is more potent than midazolam, which in turn is more potent than diazepam. Midazolam and diazepam are more lipid soluble than lorazepam and are quicker in crossing the blood–brain barrier, resulting in a more rapid onset of action (2–10 minutes) than lorazepam (5–20 minutes).26,33 The half-life of midazolam is 3–11 hours, compared with 8–15 hours for lorazepam and 20–120 hours for diazepam.33,34 Midazolam and diazepam metabolites are active and they tend to accumulate with prolonged administration, especially in patients with renal dysfunction.26,35 Lorazepam metabolites are not active and, for this reason, it is the preferred benzodiazepine in patients with renal failure.26 Clonazepam has been investigated in the treatment of status epilepticus but is rarely used in the USA, as it is not available as an i.v. formulation.36,37 Adverse effects of benzodiazepines include hypotension, respiratory depression, paradoxical agitation and delirium.31,33,38
Midazolam
Midazolam is a short-acting, water-soluble benzodiazepine that is available as 2.5-mg, 5-mg, 7.5-mg and 10-mg oromucosal solutions for buccal administration. Oromucosal midazolam is indicated for treatment of prolonged, active, convulsive seizures in infants, toddlers, children and adolescents (from 3 months to < 18 years). The NICE guideline25 on diagnosis and management of epilepsy notes the lack of a UK marketing authorisation for this indication and/or population (i.e. adults) and stipulates that informed consent should be obtained and documented in line with normal standards in emergency care.25 In the community, a single dose of midazolam can be administered by a carer. If the seizure has not stopped within 10 minutes of administration of midazolam, emergency medical assistance must be sought. A second or repeat dose when seizures re-occur after an initial response should not be given without prior medical advice.39 Midazolam is also occasionally given as an intranasal preparation, although this is not available in the UK. Buccal preparation can be given intranasally (5 mg in each nostril, 10 mg total dose) as unlicensed use.
Diazepam
Diazepam is a benzodiazepine available for rectal, i.v. and i.m. administration. The therapeutic indications for rectal administration (5 mg or 10 mg of rectal solution) include epileptic and febrile convulsions, and it may be used in circumstances where i.v. administration is not available but rapid effects are required.40 Rectal administration may be particularly suitable for infants and children.40 The posology for adults is specified as 0.5 mg/kg body weight.40 Similarly, the therapeutic indications for i.v. and i.m. administration (5-mg/ml emulsion for injection) include control of convulsions and status epilepticus, with posology specified as an initial dose of 0.15–0.25 mg/kg body weight by i.v. injection repeated in 30–60 minutes if required and followed, if necessary, by infusion of up to 3 mg/kg body weight over 24 hours. The emulsion can also be administered by slow i.v. injection (1 ml/minute).41
Lorazepam
Lorazepam is a benzodiazepine that is available as a 4-mg/ml solution for injection. Therapeutic indications include the control of status epilepticus. Lorazepam injections can be administered intravenously or intramuscularly, but the i.v. route is preferred. The dosage for adults in status epilepticus is 4 mg intravenously.42
Inclusion in this assessment was not limited to specific benzodiazepines; all of those used as first-line pre-hospital treatment of status epilepticus were eligible.
Antiepileptic drugs
The NICE guideline25 on diagnosis and management of epilepsy recommends further research into three antiepileptic drugs for the initial treatment of status epilepticus: levetiracetam, sodium valproate and phenytoin.25 This assessment includes any worldwide study assessing the effects of these drugs as a first-line treatment of status epilepticus in adults. At present, in the UK, these drugs are mainly used as a second-line treatment when benzodiazepines have failed to stop seizures.
Levetiracetam
Levetiracetam is an anticonvulsant drug that was the first antiepileptic drug to be licensed in oral and i.v. forms at the same time (in 2006) and has since been used widely to treat status epilepticus.8 The recommended starting dose for non-emergency monotherapy use in adults and adolescents aged ≥ 16 years is 250 mg taken twice daily. This can be increased to an initial therapeutic dose of 500 mg taken twice daily after 2 weeks and further increased by 250 mg taken twice daily every 2 weeks up to the maximum dose of 1500 mg taken twice daily.43 Emergency dosing for status epilepticus is not specified in the summary of product characteristics. The recent Established Status Epilepticus Treatment Trial (ESETT) of second-line treatment of patients with established status epilepticus in the emergency room specified weight-based infusion dosage of 60 mg/kg (maximum 4500 mg) levetiracetam.44 However, first-line dosing is not specified in the literature.
Sodium valproate
Sodium valproate is an anticonvulsant drug that has been extensively used to treat primary generalised and partial-onset seizures; i.v. sodium valproate was approved by the US Food and Drug Administration (FDA) in 1996.45 It is available as a 100-mg/ml solution for injection or infusion and is indicated for people with epilepsy who are normally maintained on oral sodium valproate when oral therapy is temporarily not possible.46 Dosage requirements vary according to age and body weight.46 Similarly, emergency first-line dosing of sodium valproate for status epilepticus is not specified in the summary of product characteristics or the literature in general. ESETT specified a fixed dose of 300 mg over 10 minutes, but first-line treatment may involve slightly lower doses.44
Phenytoin
Phenytoin has long been used for the management of status epilepticus in circumstances when benzodiazepines are ineffective and is recommended as second-line treatment in hospital for ongoing status epilepticus.25 However, there is insufficient evidence to support its efficacy as first-line treatment over other anticonvulsant drugs for status epilepticus in adults and children.47 It is available as a 50-mg/ml solution for injection and is indicated for the control of status epilepticus of the tonic–clonic (grand mal) type and prevention and treatment of seizures occurring during or following neurosurgery and/or severe head injury. For patients showing continuous (rather than serial) seizure activity, i.v. diazepam or a short-acting barbiturate is recommended prior to the administration of phenytoin because of their faster onset of action. For the subsequent treatment of continuous seizures and the initial management of serial epilepsy, a loading dose of 10–15 mg/kg phenytoin should be administered intravenously, followed by a maintenance dose of 100 mg given orally or intravenously every 6–8 hours.48
Phenobarbital
Phenobarbital is also recommended as second-line treatment in hospital for ongoing convulsive status epilepticus.25 Phenobarbital was the first antiepileptic drug available and is still in use today, as it is considered to be both clinically effective and cost-effective.49 Phenobarbital is available as a 30 mg/ml solution for injection and is indicated as an anticonvulsant for the treatment of all forms of epilepsy except absence seizures. A dose of 50–200 mg administered by i.m., subcutaneous or i.v. (after dilution) injection is recommended for the treatment of adults; this can be repeated after 6 hours if necessary.50
Identification of important subgroups
Early treatment of convulsive status epilepticus has been found to be related to reduced morbidity and mortality and improved outcomes, such as shorter duration of seizures.22,23,51 In addition, ongoing seizure activity may also render relevant drugs less effective.52,53 It is common for patients with status epilepticus to be dealt with outside hospital settings, and delays in transfer to hospital may hamper prompt treatment.22 Treatment of status epilepticus in the pre-hospital setting is potentially better than delaying it until arrival at the ED. Therefore, comparing outcomes of patients treated at the ED with those of patients treated in the pre-hospital setting was considered relevant to the scope of this assessment.51
Current use
A recent US-based retrospective chart review of patients diagnosed with status epilepticus showed that lorazepam was the most frequently administered first-line treatment, a finding in accordance with an international survey of clinical experts on the treatment of status epilepticus.27,28 The second-line treatments of choice were fosphenytoin and phenytoin, respectively.27,28 In contrast, UK guidelines25 recommend i.v. phenobarbital or phenytoin as a second-line treatment in hospital for convulsive status epilepticus. The SIGN 143 guideline16 recommendation is for i.v. sodium valproate or i.v. phenytoin to be used as a second-line treatment in hospital (with the warning that sodium valproate is contraindicated in pregnancy and in people of childbearing potential). A further recommendation from the British Medical Journal Best Practice3 for second-line treatment is fosphenytoin/phenytoin, valproic acid or levetiracetam.
Overall aim and objectives of this assessment
The aim of this assessment was to synthesise current evidence on the effects of first-line antiepileptic drugs for the treatment of convulsive status epilepticus in adults either before arriving at the hospital or at arrival at the ED. Information on economic evaluations published in this clinical area was also collected and synthesised.