Status epilepticus

• Status epilepticus (SE) is prolonged or repeated seizure activity without recovery of consciousness or baseline function. It is a neurological emergency in the same class as stroke and cardiac arrest.
• The practical treatment cut-off is 5 minutes: most seizures stop within 5 minutes, and once a seizure passes 5 minutes it is unlikely to stop on its own, so treatment should begin at that point. ^[2]
• Timed treatment has four phases: stabilise (0 to 5 minutes), initial therapy with a benzodiazepine (5 to 20 minutes), second therapy with fosphenytoin, valproate or levetiracetam (20 to 40 minutes), and refractory treatment from 40 minutes onward. ^{[2] [1]}
• It occurs in people with and without pre-existing epilepsy. In an adult the common causes are stroke, brain injury, alcohol or drug problems, infection, tumour, metabolic disturbance, and withdrawal of antiseizure medication. ^[4]
• Outcome depends on speed of treatment. Respiratory failure accounts for as many as 30% of deaths, and inadequate doses or delayed dosing make the outcome worse. ^[4]

By the end of this page you should be able to:

1. Define status epilepticus and distinguish convulsive from non-convulsive forms, and early from established, refractory and super-refractory disease.
2. Explain the 5-minute and 30-minute time points and why treatment starts at 5 minutes. ^[4]
3. List the common causes in adults and children and recognise the ones that need specific treatment.
4. Plan the initial assessment and investigations, including when continuous EEG is needed.
5. State the timed treatment algorithm with drug, dose, route and rate for the first-line, second-line and refractory phases, and the recommendations of the NCS (2012), AES (2016) and NICE (NG217) guidelines. ^[1]
6. Describe the complications, prognosis, and prevention of status epilepticus, and how to manage it in pregnancy, in children and in older adults.
7. Tell the difference between status epilepticus and its common mimics.

On the evidence used here, that first time point (t1) is 5 minutes and the second (t2) is 30 minutes for convulsive status epilepticus. ^[4] A seizure that lasts more than 5 minutes is unlikely to stop on its own, which is why every major protocol treats at 5 minutes. Damage is not fixed: if a seizure lasts beyond 30 minutes it can produce neuronal injury by itself, as shown by hippocampal injury after prolonged febrile seizures. ^[4]

Guidelines phrase this differently, and you should know both:

• The Neurocritical Care Society (NCS) 2012 guidelines define status epilepticus as 5 minutes or more of continuous clinical or electrographic seizure activity, or recurrent seizure activity without return to baseline in between. ^[1]
• The American Epilepsy Society (AES) 2016 guideline uses an older convention: status epilepticus is more than 30 minutes of continuous seizure activity, or two or more sequential seizures without full recovery of consciousness. For treatment it follows the 5-minute convention, on the same reasoning that prolonged seizures become unlikely to stop once they pass 5 minutes. ^[2]
• The National Institute for Health and Care Excellence (NICE) guideline NG217 (section 7) treats convulsive status epilepticus as seizures lasting 5 minutes or more. ^[3]

• Convulsive (generalised convulsive) status epilepticus: repeated generalised tonic-clonic seizures with depression of consciousness between them. This is the most common form and the one with the highest mortality. ^[2]
• Non-convulsive status epilepticus: continuous or fluctuating seizure activity on the EEG without the clinical signs of convulsive status epilepticus. It can appear as confusion, reduced responsiveness, or a fluctuating "epileptic twilight" state, and it is easily missed. ^[2]
• Focal or partial status epilepticus: repeated focal seizures producing focal motor signs, focal sensory symptoms or a focal deficit such as aphasia without altered awareness (epilepsia partialis continua). ^[2]
• Absence status epilepticus: a continuous absence state, often in a person with a known absence epilepsy.

Independent of the cause, status epilepticus moves through stages that describe whether it still responds to treatment: ^[4]

1. Early status epilepticus: seizures are discrete and respond to benzodiazepines, the first-line treatment.
2. Established status epilepticus: the seizures have become unresponsive to adequate doses of benzodiazepines.
3. Refractory status epilepticus (RSE): seizures continuing despite an adequate initial benzodiazepine dose followed by a second acceptable anticonvulsant drug. ^[1] On one staging used in the Joshi and Kapur review, this means seizures persisting for 60 to 120 minutes despite first- and second-line treatment. ^[4]
4. Super-refractory status epilepticus: uncontrolled seizures lasting more than 24 hours that have not responded to three or more anticonvulsants, including general anaesthetics. ^[4]

This staging matters because the longer a seizure continues, the less likely benzodiazepines are to work: in experimental models the surface expression of the synaptic GABA-A receptors they target falls during prolonged seizures, an example of why speed of treatment decides outcome. ^[4]

Status epilepticus is common and dangerous. The annual incidence ranges from 10 to 41 per 100,000 persons. ^[4] In the United States, between 50,000 and 150,000 Americans have status epilepticus each year. ^[2]

Mortality depends on age, cause and how quickly treatment is given:

• In children, mortality is estimated at less than 3%. ^[2]
• In adults, mortality is estimated at up to 30%. ^[2]
• One prospective population-based study in Richmond, Virginia, found a mortality rate of 26% in adults and 3% in children. ^[4]
• Mortality associated with status epilepticus overall could be up to 20%. ^[4]

As many as 30% to 60% of patients who develop status epilepticus have pre-existing epilepsy; seizure clusters in such a patient are thought to be the first step of status epilepticus. ^[4] Most children who have status epilepticus were neurologically normal before the first episode. ^[4]

Incidence is reported to be higher in men than in women. ^[4]

The most common causes of status epilepticus in adults are brain injury, stroke, alcohol abuse, drug toxicity, metabolic imbalance, brain haemorrhage, cardiac arrest, central nervous system infection, and withdrawal of antiseizure medication in patients with pre-existing seizures. ^[4]

The Neurocritical Care Society groups causes into acute and chronic processes: ^[1]

Acute processes

• Metabolic disturbances: electrolyte abnormalities, hypoglycaemia, renal failure.
• Sepsis.
• Central nervous system infection: meningitis, encephalitis, abscess.
• Stroke: ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, cerebral sinus thrombosis.
• Head trauma, with or without epidural or subdural haematoma.
• Drug issues: drug toxicity; withdrawal from opioid, benzodiazepine, barbiturate or alcohol; non-compliance with antiseizure medicines.
• Hypoxia and cardiac arrest.
• Hypertensive encephalopathy and posterior reversible encephalopathy.
• Autoimmune encephalitis and paraneoplastic syndromes.

Chronic processes

• Pre-existing epilepsy with breakthrough seizures or discontinuation of antiseizure medicines.
• Chronic ethanol abuse in the setting of intoxication or withdrawal.
• Central nervous system tumours.
• Remote central nervous system pathology such as prior stroke, abscess, traumatic brain injury or cortical dysplasia.

Febrile illness is the most common cause of status epilepticus in children. ^[4] It can also follow acute neurological infection (meningitis or encephalitis), head injury, poisoning, hypoglycaemia or an inborn error of metabolism. Pyridoxine-dependent seizures must be considered in young children. ^[1]

• Non-adherence to antiseizure medication: NICE flags this as a common precipitant. ^[3]
• Antiseizure withdrawal: possible causes include hypoglycaemia, eclampsia and alcohol withdrawal, which need specific additional treatment. ^[3]
• A first presentation of epilepsy, especially in the elderly after stroke.
• Infection and fever.

Everything in status epilepticus follows from a failure of the brain's seizure-terminating mechanisms.

Failure of GABAergic inhibition. GABA-A receptors containing the gamma-2 subunit mediate fast synaptic inhibition and are the target of benzodiazepines. During prolonged seizures these receptors are internalised, in part through dephosphorylation, so inhibition weakens and the seizure becomes self-sustaining. This is why benzodiazepines work best early and become less effective with time. ^[4]

Potentiation of glutamatergic transmission. Excitatory NMDA and AMPA receptor currents increase; AMPA receptors can become calcium-permeable, contributing to excitotoxic injury. Glutamatergic plasticity is one reason anti-glutamate strategies are studied for established and refractory disease. ^[4]

Network expansion. Seizure activity spreads from its origin to connected regions, and across the age spectrum the same pathophysiology applies in adults and older children. ^[2]

Consequences for the patient. Generalised convulsive status epilepticus disturbs respiration, and many patients need mechanical ventilation. ^[4] The hippocampus is vulnerable: the FEBSTAT study found that about 11.5% of children with febrile status epilepticus showed acute hippocampal injury on MRI, and those children had a higher risk of cognitive impairment and of developing epilepsy, with a 10-year cumulative incidence of epilepsy of about 30% after febrile status epilepticus. ^[4]

Irrespective of cause, treatment response divides status epilepticus into four stages, described above. ^[4] Experimental and clinical observations together suggest that between 30% and 45% of patients have seizures that remain uncontrolled despite benzodiazepine treatment. ^[4]

The history establishes that an event was a seizure, how long it lasted and why it happened.

• Duration and course. Ask exactly when the jerking started; families usually underestimate. Ask whether there was a clear start and stop, whether consciousness recovered between events, and whether there were repeated events over hours or days.
• Triggers and precipitants. Fever in a child, missed antiseizure doses, alcohol withdrawal, recent head injury, headache, fever, focal weakness, visual disturbance, or a previous stroke.
• Medications and illnesses. Antiseizure medicines and doses, recent changes, pregnancy, liver or kidney disease, diabetes, bleeding or clotting disorders.
• Eye-witness account. Most diagnoses of convulsive status epilepticus are made by a witness describing rhythmic jerking, loss of awareness and postictal confusion.

• Airway, breathing and circulation first. Look for cyanosis, irregular or agonal breathing, and signs of aspiration.
• Vital signs. Temperature (fever), blood pressure (hypertension suggests posterior reversible encephalopathy or hypertensive encephalopathy; hypotension suggests sepsis or sedative drug effect), oxygen saturation.
• Neurological. Level of consciousness; focal findings that may point to an acute structural cause (hemiparesis, gaze deviation, unequal pupils, neck stiffness).
• Skin and mucous membranes. Petechiae, rash, injection sites, signs of trauma.
• Investigations at the bedside. Finger-prick glucose should be checked in every patient. ^[1]

The diagnosis is usually clinical: 5 minutes or more of continuous convulsion, or repeated seizures without recovery. ^[1] Tests are used to find the cause, to guide treatment and to detect non-convulsive activity.

• An ECG is useful because cardiorespiratory compromise is common and drugs such as phenytoin and fosphenytoin can affect cardiac conduction.
• Head CT must not delay treatment of a convulsion; it is usually done once the seizure is controlled or when an acute structural cause is suspected.
• Continuous EEG is the only way to diagnose non-convulsive status epilepticus and is essential when a patient receives anaesthetic doses of midazolam, propofol, pentobarbital or thiopental, where the clinical examination can no longer show whether the seizure has stopped.

The best drug is the one given in time. In adults with adequate therapy, mortality may be as low as 8%, while it may be as high as 45% with insufficient therapy: insufficient dose, wrong route, unnecessary delay between treatments, inadequate ventilation, medical complications, or lack of EEG monitoring. ^[1] Definitive control of status epilepticus should be established within 60 minutes of onset. ^[1]

• Put the patient in the recovery position; protect the airway.
• Give high-flow oxygen; assess breathing and circulation.
• Obtain intravenous access; check glucose and treat hypoglycaemia (give glucose; thiamine if alcohol-related).
• Check temperature, blood pressure, oxygen saturation; monitor the ECG.
• Start timing the seizure; note the time of any treatment.

A benzodiazepine is the drug of first choice. ^[1][2]

Adults ^[1][2]

• Midazolam (intramuscular): 0.2 mg/kg, maximum 10 mg. Dose of 10 mg used in the RAMPART trial. ^{[2] [1]}
• Lorazepam (intravenous): 0.1 mg/kg, maximum 4 mg, up to 2 mg per minute; may be repeated in 5 to 10 minutes. ^[1][2]
• Diazepam (intravenous): 0.15 mg/kg, up to 10 mg per dose, up to 5 mg per minute; may be repeated after 5 minutes. ^[1]
• Diazepam (rectal, buccal alternatives): NICE lists buccal midazolam or rectal diazepam as first-line in the community when IV access is not immediately available. ^[3]
• Phenobarbital (intravenous): 20 mg/kg, an alternative initial therapy where benzodiazepines are unavailable; its slower administration makes it second-line in the AES scheme. ^[1][2]

Children ^[1][2]

• Intravenous lorazepam: 0.1 mg/kg, maximum 4 mg.
• Intravenous diazepam: 0.2 mg/kg, maximum 8 mg. ^[2]
• Midazolam: 0.2 mg/kg intramuscular; intranasal formulations 0.2 mg/kg; buccal 0.5 mg/kg; rectal diazepam 0.3 to 0.5 mg/kg. ^[1]

NICE is more specific for the community setting: if the person does not have an individualised emergency management plan immediately available, give buccal midazolam or rectal diazepam immediately; use intravenous lorazepam if intravenous access and resuscitation facilities are immediately available. ^[3]

Underdosing is a recognised problem: in a review of prehospital records, guideline-adherent administration was found in only 4% for midazolam, 1.4% for lorazepam and 11.8% for diazepam; most patients received lower-than-recommended doses. ^[4] Give the full single dose once, rather than splitting it, and use the correct route. ^[2]

A practical point from NICE: if the seizure does not stop within 5 to 10 minutes after the first benzodiazepine dose, give a second dose. ^[3] If two doses do not work, move to second-line treatment. ^[3]

If benzodiazepines fail, give an intravenous anticonvulsant. There is no clear evidence that one of these three is better than the others. ^[2] The ESETT trial compared them directly and found fosphenytoin, levetiracetam and valproate similarly effective. ^[4]

Fosphenytoin (intravenous) ^[1]

• Loading dose: 20 mg phenytoin-equivalents/kg, with an optional additional 5 mg/kg. May be given up to 150 mg phenytoin-equivalents per minute. ^[1]
• Monitor the ECG and blood pressure during infusion. Purple glove syndrome (skin discoloration, oedema, pain and necrosis) occurs in 1.7% to 5.3% of cases after phenytoin; fosphenytoin, the prodrug, is preferred for tolerability but phenytoin is an acceptable alternative. ^[2][4]
• In children, fosphenytoin was associated with more frequent intubation than levetiracetam or valproate in ESETT. ^[4]

Valproate sodium (intravenous) ^[1][4]

• Loading dose: 20 to 40 mg/kg; an additional 20 mg/kg may be given. Infuse at 3 to 6 mg/kg per minute.
• Particularly good tolerability in children. Concerns apply in women of childbearing potential, and valproate should be used with care in anyone who may become pregnant; a single dose's risk is not established. ^[4]
• Avoid valproate in children under 2 years where possible, because of hepatotoxicity risk, especially with metabolic or mitochondrial disorder. ^[1]

Levetiracetam (intravenous) ^[1][4]

• Dose: 60 mg/kg (maximum 4500 mg) in adults and children aged 2 years and older, infused over 10 minutes, from ESETT; the older NCS 2012 guideline quoted 1000 to 3000 mg in adults and 20 to 60 mg/kg in children. ^{[1] [5]}
• Easy to administer, faster infusion (5 minutes versus 10 minutes for phenytoin), low toxicity, fewer drug interactions. ^[4]

Phenobarbital (intravenous) ^[1]

• 20 mg/kg, with an additional 5 to 10 mg/kg; 50 to 100 mg per minute. Reasonable alternative if none of the above is available; its cardiorespiratory adverse effects are similar to the benzodiazepines. ^[2]

NICE's order ^[3]

NICE lists levetiracetam, phenytoin and sodium valproate as second-line options, noting that levetiracetam may be quicker to administer and have fewer adverse effects. If one option fails, an alternative second-line option may be tried under expert guidance. ^[3]

When seizures continue despite first- and second-line treatment, the patient is in refractory status epilepticus. ^[1]

• From 40 minutes: repeat a second-line agent, or give anaesthetic doses of thiopental, midazolam, pentobarbital or propofol with continuous EEG monitoring. ^[1][2]
• All these patients need airway protection and mechanical ventilation. ^[4]
• The usual practice is to maintain electrographic seizure control for 24 to 48 hours before gradual withdrawal of the continuous infusion. ^[1]
• There is no clear evidence to guide drug choice in this phase. ^[2]

Refractory dosing (continuous infusions) ^[1]

What is known about newer options. Neurosteroids (ganaxolone, allopregnanolone) have been tested in refractory and super-refractory disease; ganaxolone stopped seizures in 80% versus 13% with placebo in the RAISE trial, but did not reduce progression to anaesthesia at 36 hours (63% versus 51%). These remain investigational and are usually given in trial settings. ^[4] The ketogenic diet has stopped super-refractory status epilepticus in one prospective study of 24 patients (73% within a week) and in 77% to 90% of small reported series, but randomised trials are still awaited. ^[4]

Non-convulsive and subtle status epilepticus require the same urgency because of the risk of neuronal injury; benzodiazepines are first-line, but doses and escalation follow the same timed ladder where clinically appropriate.

Complications come from the seizure itself, from its cause, and from treatment.

• Respiratory failure, which accounts for as many as 30% of deaths; generalised convulsive status epilepticus produces respiratory instability and many patients need mechanical ventilation. ^[4]
• Cardiorespiratory adverse effects of treatment. In the 1998 Veterans Affairs study the treatment-emergent adverse events with intravenous lorazepam were hypoventilation 10.3%, hypotension 25.8%, cardiac rhythm disturbance 7.2%; with intravenous diazepam hypoventilation 16.8%, hypotension 31.6%, cardiac rhythm disturbance 2.1%. ^[2]
• Neuronal injury and hippocampal sclerosis, including cognitive impairment and an increased risk of later epilepsy, as in the FEBSTAT febrile cohort. ^[4]
• Neurological sequelae. Severe neurological or cognitive sequelae occur in 11 to 16% of survivors of convulsive status epilepticus, and deterioration in functional status in 23 to 26%. ^[1]
• Mortality. At hospital discharge, mortality for convulsive status epilepticus is 9 to 21%; at 30 days 19 to 27%; at 90 days 19%. For refractory status epilepticus, mortality at discharge is 23 to 61%. ^[1]
• Aspiration, pneumonia, pressure injuries, rhabdomyolysis, acute kidney injury can follow prolonged convulsion or sedation.
• Side effects of specific drugs. Extravasation of phenytoin can produce purple glove syndrome. ^[4]
• Inadequate dosing is itself a complication: benzodiazepine underdosing was found in the ESETT analysis and contributes to treatment failure. ^[4]

Outcome is most strongly linked to three things: the underlying cause, the duration of the seizure, and the age of the patient. ^[2]

• With adequate and timely treatment mortality may be as low as 8%; with insufficient treatment it may be as high as 45%. ^[1]
• Most survivors recover well if the cause is reversible and treatment is prompt; functional decline is more likely with prolonged seizure duration and anoxic brain injury.
• A refractory or super-refractory course, particularly after an acute brain insult or in the New-Onset Refractory Status Epilepticus (NORSE) phenotype, carries the highest mortality. ^[4]
• Children generally do well when the episode is brief and febrile; febrile status epilepticus itself leaves neurological deficits in a minority and increases the risk of later epilepsy.

There is no population screening for status epilepticus. Prevention has three parts.

1. Prevent precipitants. Counsel patients with epilepsy to take antiseizure medicines as prescribed, avoid abrupt alcohol or sedative withdrawal, sleep regularly and avoid known triggers. Non-adherence and withdrawal are common precipitants. ^[3][1]
2. Rescue therapy for people at risk. In patients with pre-existing epilepsy and seizure clusters, which are thought to be the first step of status epilepticus, intranasal benzodiazepines can be used at home or in the ambulance: intranasal diazepam, approved for adults and children older than 6 years, controlled seizures in 87% in one study; intranasal midazolam, approved for adults and children 12 years and older, controlled seizure clusters for 6 hours in 61%. ^[4]
3. Emergency plan after an episode. After an episode, agree an individualised emergency management plan with the patient (and family) if there is concern that status epilepticus may recur. ^[3]

Pregnancy. The NCS recommends lorazepam and fosphenytoin as emergent initial and urgent control therapy, and levetiracetam should be considered for status epilepticus in pregnancy. ^[1] There are known risks of birth defects with first-trimester exposure to antiseizure medicines, particularly valproate, phenobarbital and phenytoin. ^[1] Eclampsia must be considered in any pregnant or postpartum woman with status epilepticus: magnesium sulfate is superior to phenytoin for the seizure disorder of eclampsia. ^[1]

Children. AES concludes that intravenous lorazepam and intravenous diazepam are established as efficacious at stopping seizures lasting at least 5 minutes (level A), and that rectal diazepam, intramuscular midazolam, intranasal midazolam and buccal midazolam are probably effective (level B). ^[2] Young children with epilepsy who develop status epilepticus should receive intravenous pyridoxine in case they have pyridoxine-dependent seizures. ^[1] Concern exists about hepatotoxicity with valproate in children younger than 2 years, especially with a metabolic or mitochondrial disorder. ^[1] Febrile status epilepticus is the commonest paediatric cause and the one with the hippocampal-injury signal above.

Older adults. Older age is itself a factor associated with poor outcome after convulsive status epilepticus. ^[1] Status in this group often follows stroke or another acute brain lesion, and drug doses and renal or hepatic clearance need attention. No special fixed dose reduction is quoted in the guidelines used here; treat by weight and effect, and involve a clinician early.

Women of childbearing potential. Valproate carries specific warnings because of teratogenic risk; although these warnings apply mainly to chronic use, they should inform the choice of second-line agent whenever a pregnancy is possible. ^[4]

• NICE supports buccal midazolam or rectal diazepam as first-line in the community, which is practical where intravenous access is delayed. ^[3]
• The AES lists rectal diazepam, intranasal midazolam and buccal midazolam as reasonable initial alternatives when intravenous drugs are unavailable. ^[2]
• Intramuscular midazolam is easy to give and works without venous access. ^[1]
• Continuous EEG, MRI and intensive care may be unavailable: stabilisation, a benzodiazepine, a second-line drug and transport remain the minimum standard.

• Epilepsy (seizure disorders); focal and generalised seizures.
• Febrile seizures and febrile status epilepticus in children.
• Alcohol withdrawal and the alcohol withdrawal syndrome.
• Eclampsia and pre-eclampsia.
• Hypoglycaemia and metabolic emergencies.
• Stroke and intracerebral haemorrhage.
• Meningitis and encephalitis.
• Antiseizure drugs: benzodiazepines, levetiracetam, valproate, phenytoin and fosphenytoin.

• Status epilepticus is prolonged or repeated seizure activity without recovery; it is an emergency comparable to stroke.
• Treatment starts at 5 minutes because most seizures stop within 5 minutes and those that do not are unlikely to stop on their own. ^[2]
• Two useful time points: 5 minutes (t1, treatment threshold) and 30 minutes (t2, injury threshold), with long-term consequences including neuronal injury. ^[4]
• The emergency has four phases by responsiveness: early, established, refractory and super-refractory. ^[4]
• Causes differ by age: febrile illness in children; stroke, brain injury, alcohol and drug problems, infection, tumour, metabolic disturbance and antiseizure withdrawal in adults. ^[4]
• Hypoglycaemia, eclampsia, severe electrolyte disturbance, infection and withdrawal are treatable causes that must not be missed. ^[1][3]
• Definitive control should be achieved within 60 minutes. ^[1]
• First-line therapy is a benzodiazepine: intramuscular midazolam 10 mg, intravenous lorazepam 4 mg, or intravenous diazepam 6 to 10 mg; give the full dose once and repeat intravenous lorazepam or diazepam once after 5 to 10 minutes. ^[1][2][3]
• Second line is intravenous fosphenytoin 20 mg phenytoin-equivalents/kg, valproate sodium 20 to 40 mg/kg, or levetiracetam 60 mg/kg (maximum 4500 mg) (the dose used in ESETT); there is no evidence that one is better, but levetiracetam is quicker and better tolerated. ^{[1][2][3][4] [5]}
• Refractory treatment, from 40 minutes, is an anaesthetic infusion (midazolam, propofol, pentobarbital or thiopental) with continuous EEG, with electrographic control maintained for 24 to 48 hours. ^[1][2]
• Outcomes depend on speed: adequate therapy may keep mortality as low as 8%, while inadequate therapy may push it as high as 45%. ^[1]
• Respiratory failure causes up to 30% of deaths. ^[4]
• In pregnancy, consider eclampsia and use magnesium sulfate; lorazepam and fosphenytoin are recommended, levetiracetam should be considered, and valproate is avoided where possible. ^[1]
• Prevention means adherence, avoiding withdrawal, and rescue intranasal benzodiazepines for those with seizure clusters. ^[3][4]