Status epilepticus

Status epilepticus is a seizure lasting over 5 minutes, or two or more seizures without return to baseline between them. It is a medical emergency with mortality of about 10 to 20%, and neuronal injury begins after 30 to 60 minutes. Response to benzodiazepines falls with time, so the first drug is given within minutes.

Stages.

• Early: 5 to 20 minutes, first line benzodiazepine.
• Established: persists after adequate benzodiazepine, at about 20 to 40 minutes, second line antiseizure drug.
• Refractory: persists after a first line and an adequate second line drug, usually over 40 to 60 minutes, anaesthetic treatment.
• Super-refractory: continues or recurs 24 hours or more after anaesthetic therapy starts.

Types. Convulsive (generalised tonic-clonic), focal motor (including epilepsia partialis continua), myoclonic, and non-convulsive (with coma, or without coma such as absence status or focal impaired awareness status).

Mechanisms. Failure of seizure termination and development of receptor changes (internalisation of GABA-A receptors) that make benzodiazepines less effective with time.

Key distinctions. Persistent coma after convulsions stop may be non-convulsive status. Functional (psychogenic) seizures can mimic status and can occur in a patient with epilepsy, so avoid anaesthesia without EEG when features are doubtful.

History.

• Known epilepsy: missed drugs, recent changes, alcohol, intercurrent infection, sleep loss.
• New onset: head injury, stroke, fever, headache, HIV infection, malignancy, travel and malaria exposure, pregnancy, drug and alcohol use, ingestions (tramadol, bupropion, tricyclic antidepressants, theophylline, isoniazid, organophosphates), and withdrawal from alcohol or benzodiazepines.
• Duration, semiology, and whether recovery occurred between seizures.

Examination.

• Airway, breathing, circulation, temperature, capillary glucose, tongue bite, injuries, incontinence, and signs of alcohol use or injection.
• Focal deficit, meningism, papilloedema, rash, and signs of raised intracranial pressure.
• Subtle signs of non-convulsive status when consciousness does not return: eyelid or facial twitching, nystagmus, gaze deviation, automatisms, fluctuating responsiveness.
• Features favouring functional seizures: eyes closed throughout, side to side head movement, asynchronous or waxing and waning movements, preserved responsiveness, and recall.

Red flags.

• Seizure over 5 minutes or repeated without recovery, hypoxia, glucose under 4.0 mmol/L, sodium under 120 mmol/L.
• Fever with neck stiffness or immunosuppression, head injury, new focal deficit, pregnancy or recent delivery, ingestion or poisoning, and temperature over 40 °C.

Special groups.

• Children: febrile seizures and glucose first, weight based doses, and consider pyridoxine dependency in infants.
• Pregnancy: eclampsia until proven otherwise, left lateral tilt, and avoid valproate.
• Older adults: stroke and non-convulsive status.
• Region specific: cerebral malaria, neurocysticercosis, tuberculous meningitis, HIV opportunistic infections, hypoglycaemia in children, and organophosphate exposure.

Provoked (acute symptomatic) causes.

• Central nervous system infection: bacterial meningitis, herpes simplex encephalitis, cerebral malaria, neurocysticercosis, tuberculous meningitis, cerebral toxoplasmosis, cryptococcal meningitis, brain abscess.
• Cerebrovascular: ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, cerebral venous thrombosis, hypoxic ischaemic brain injury after cardiac arrest.
• Structural: brain tumour, traumatic brain injury.
• Metabolic: hypoglycaemia, hyponatraemia, hypocalcaemia, hypomagnesaemia, hyperosmolar hyperglycaemic state, uraemia, hepatic encephalopathy, hypoxia, vitamin B6 and thiamine deficiency.
• Toxic and withdrawal: alcohol withdrawal, benzodiazepine and barbiturate withdrawal, tramadol toxicity, tricyclic antidepressant poisoning, bupropion toxicity, isoniazid poisoning, theophylline toxicity, organophosphate poisoning, cocaine and amphetamine toxicity, lithium toxicity.
• Other: eclampsia, posterior reversible encephalopathy syndrome, autoimmune encephalitis, central nervous system vasculitis.

Epilepsy related. Breakthrough in known epilepsy (non-adherence, drug withdrawal, intercurrent illness), first presentation of epilepsy, and cryptogenic status epilepticus.

Mimics. Functional (psychogenic non-epileptic) seizures, convulsive syncope, tetanus, strychnine poisoning, dystonic reactions, serotonin syndrome and neuroleptic malignant syndrome, rigors, post-hypoxic myoclonus, and decerebrate posturing.

Treatment starts before tests.

Concurrent tests.

• Capillary glucose.
• Blood gas with lactate (a high lactate and low pH are expected and settle in 60 minutes; persisting acidosis points to a metabolic cause).
• Sodium, potassium, calcium, magnesium, creatinine, liver tests.
• Creatine kinase (rhabdomyolysis).
• Full blood count, coagulation, ammonia.
• Alcohol level, paracetamol and salicylate levels, toxicology.
• Antiseizure drug levels (phenytoin, valproate, carbamazepine).
• Pregnancy test.
• Blood cultures, malaria test and HIV test as relevant.
• ECG.

Imaging and puncture.

• Non-contrast CT head after stabilisation for first seizure, trauma, focal signs, fever, persistent altered mental state, anticoagulation or immunosuppression. MRI later.
• Lumbar puncture for fever, meningism or immunosuppression after CT; start antimicrobials without waiting.

EEG.

• Urgent EEG when consciousness does not return within 30 to 60 minutes after convulsions stop, as non-convulsive status is common after treated convulsive status.
• All refractory cases need continuous EEG, aiming for seizure suppression or burst suppression.

Limitations. EEG access is limited in many settings, so treat clinically and consider non-convulsive status for persistent coma. Prolactin has limited value. A normal CT does not exclude encephalitis or early infarction.

0 to 5 minutes: stabilise. Note the time of onset. Position on the side, suction, high flow oxygen titrated to saturation 94 to 98%, nothing in the mouth, IV access, monitoring (ECG, pressure, saturation, capnography if available), capillary glucose, and left lateral tilt in pregnancy.

Treat the cause at once.

• Hypoglycaemia (under 4.0 mmol/L): glucose 10% 150 to 200 mL IV over 15 minutes (or glucose 20% 75 to 100 mL), recheck at 10 to 15 minutes and every 15 minutes; children glucose 10% 2 mL/kg; sulphonylurea hypoglycaemia recurs, so observe at least 24 hours.
• Alcohol misuse or malnutrition: thiamine 500 mg IV over 30 minutes, given before or with glucose, then 500 mg IV three times daily for 2 to 3 days if Wernicke encephalopathy is possible.
• Eclampsia: magnesium sulphate 4 g IV over 5 to 15 minutes, then 1 g/hour for 24 hours after the last seizure; monitor reflexes, respiratory rate over 12 breaths/min and urine output over 100 mL in 4 hours; reduce in kidney impairment.
• Severe hyponatraemia: 3% sodium chloride 150 mL IV over 20 minutes, repeated once if seizures persist; monitor sodium every 20 minutes to 1 hour; limit the rise to 8 to 10 mmol/L in 24 hours.
• Isoniazid poisoning: pyridoxine IV matched gram for gram to the ingested isoniazid (5 g if the amount is unknown), infused over 30 to 60 minutes; benzodiazepines in addition.
• Cerebral malaria: artesunate 2.4 mg/kg IV at 0, 12 and 24 hours, then once daily until oral therapy is tolerated; monitor glucose hourly.
• Bacterial meningitis or encephalitis: ceftriaxone 2 g IV every 12 hours (maximum 4 g daily), dexamethasone 10 mg IV every 6 hours for 4 days started with the first antibiotic dose.
• Add amoxicillin 2 g IV every 4 hours if over 60 or immunocompromised.
• Aciclovir 10 mg/kg IV every 8 hours (every 12 hours for CrCl 25 to 50 mL/min and every 24 hours for CrCl 10 to 25 mL/min).
• Alcohol or benzodiazepine withdrawal: diazepam 10 to 20 mg IV, repeated as needed with monitoring.
• Tricyclic antidepressant poisoning with QRS over 100 ms: sodium bicarbonate 8.4% 50 to 100 mmol IV.

5 to 20 minutes: first line (give one benzodiazepine, then no more than one repeat).

• Lorazepam 4 mg IV over 1 to 2 minutes (0.1 mg/kg, maximum 4 mg a dose), repeated once after 10 minutes if seizures continue; maximum 8 mg in total.
• Monitor respiration and blood pressure, with bag mask support ready; reduce the dose in frail older adults and respiratory disease.
• Without IV access: midazolam 10 mg IM (over 40 kg; 5 mg for 13 to 40 kg), single dose, or buccal midazolam 10 mg, or rectal diazepam 10 to 20 mg.
• Diazepam IV 10 mg (0.15 to 0.25 mg/kg, maximum 10 mg a dose) at up to 5 mg/min, repeated once after 5 minutes; effect lasts 15 to 30 minutes, so follow with a second line drug; monitor respiration.
• Children: lorazepam 0.1 mg/kg IV (maximum 4 mg).
• Children, buccal midazolam: 2.5 mg (3 months to under 1 year), 5 mg (1 to under 5 years), 7.5 mg (5 to under 10 years), 10 mg (10 to under 18 years).
• Children, rectal diazepam: 0.5 mg/kg (2 to 5 years), 0.3 mg/kg (6 to 11 years), 0.2 mg/kg (12 years and over), maximum 20 mg.
• Benzodiazepines given before arrival count toward the total.

20 to 40 minutes: second line (choose one; do not wait for an effect before preparing it).

• Levetiracetam 60 mg/kg IV (maximum 4500 mg) over 10 minutes; maintenance 500 to 1500 mg twice daily, maximum 3000 mg daily; monitor mood and agitation.
• The levetiracetam loading dose is not reduced for kidney impairment.
• Levetiracetam maintenance is reduced (CrCl 50 to 80 mL/min: 500 to 1000 mg every 12 hours; 30 to 50 mL/min: 250 to 750 mg every 12 hours; under 30 mL/min: 250 to 500 mg every 12 hours).
• Fosphenytoin 20 mg phenytoin equivalents/kg IV (maximum 1500 mg phenytoin equivalents) at up to 150 mg phenytoin equivalents/min.
• Or phenytoin 20 mg/kg IV (usual maximum 2000 mg) at no more than 50 mg/min (no more than 25 mg/min in older adults and cardiac disease).
• Give phenytoin only in isotonic saline through a large vein with continuous ECG and blood pressure monitoring; slow or stop for hypotension, bradycardia or QRS widening.
• Avoid phenytoin in heart block, severe bradycardia, and seizures from toxic causes.
• Then 5 mg/kg/day in 2 to 3 doses; target total level 10 to 20 mg/L; use free levels in hypoalbuminaemia, kidney or liver disease.
• Valproate 40 mg/kg IV (maximum 3000 mg) over 10 minutes; monitor liver tests, ammonia, platelets and coagulation; avoid in women of childbearing potential, pregnancy, liver disease, mitochondrial disorders and urea cycle disorders; avoid with meropenem.
• Phenobarbital 15 to 20 mg/kg IV at up to 100 mg/min where other drugs are unavailable; monitor respiration and blood pressure; reduce in older adults and liver disease.
• Lacosamide 200 to 400 mg IV over 15 minutes (evidence is limited); avoid with heart block or PR prolongation.
• Children: levetiracetam 40 to 60 mg/kg (maximum 4500 mg), phenytoin 20 mg/kg, or phenobarbital 20 mg/kg IV over 20 minutes.

After 40 minutes: refractory. Intubate, ventilate and start an anaesthetic agent with continuous EEG and critical care support.

• Midazolam 0.2 mg/kg IV bolus, then 0.05 to 0.4 mg/kg/hour.
• Propofol 1 to 2 mg/kg IV bolus (repeat as needed), then 2 to 5 mg/kg/hour; maximum 5 mg/kg/hour; limit to under 48 hours and monitor lactate, triglycerides, creatine kinase and acid base for propofol infusion syndrome; avoid prolonged infusion in children.
• Thiopental 3 to 5 mg/kg IV bolus, then 1 to 5 mg/kg/hour, with accumulation, hypotension and immunosuppression; vasopressors should be ready.
• Ketamine 1 to 3 mg/kg IV bolus, then 0.3 to 5 mg/kg/hour for super-refractory cases (evidence is limited).
• Aim for seizure suppression or burst suppression for 24 to 48 hours, then withdraw over 12 to 24 hours while continuing a second line drug. Super-refractory cases need specialist input: immunotherapy (methylprednisolone 1 g IV daily for 3 to 5 days, immunoglobulin 0.4 g/kg daily for 5 days) when autoimmune encephalitis is possible, and a search for cause.

Complications. Aspiration, rhabdomyolysis (aggressive isotonic fluid if creatine kinase is markedly raised), hyperthermia, acidosis, injury, raised intracranial pressure.

Monitoring. Continuous ECG, saturation, capnography and blood pressure. Glucose hourly initially. Temperature, electrolytes, creatinine and creatine kinase every 4 to 6 hours. EEG, drug levels (phenytoin level at 24 hours), and neurological status.

Referral and escalation. Critical care for refractory status, airway compromise, respiratory depression or haemodynamic instability. Neurology for all patients. Neurosurgery for mass lesion. Infectious diseases for central nervous system infection. Obstetrics for pregnancy.

Admission criteria. All patients with status epilepticus are admitted. A single brief seizure in known epilepsy with full recovery and a clear trigger may be discharged after review.

Discharge and safety netting. Discharge when seizure free, at baseline, with a maintenance antiseizure plan and neurology follow up. Patients and families are told:

• The first aid steps for a seizure (time it, place on the side, nothing in the mouth, rescue medicine such as buccal midazolam if prescribed, call emergency services at 5 minutes).
• Seizure precautions around water and heights.
• Legal driving restrictions.