Refractory Status Epilepticus

Refractory status epilepticus is seizure activity, clinical or electrographic, that continues or recurs despite an adequate benzodiazepine dose and an adequate dose of one second line antiseizure medicine. Seizure activity lasting over 5 minutes already counts as status, and refractoriness is usually declared once a second line drug has failed, commonly 20 to 40 minutes after onset.

Epidemiology. Status epilepticus occurs in about 10 to 40 cases in 100,000 people each year, with peaks under 1 year and over 60 years. About one in three cases becomes refractory. Mortality is 20 to 40% in many series and depends mainly on cause, age and duration.

Causes and associations. Acute symptomatic causes dominate: stroke, central nervous system infection (including cerebral malaria and neurocysticercosis in endemic regions), head injury, hypoxic injury, hypoglycaemia, hyponatraemia, hypocalcaemia and uraemia. Toxins include isoniazid, theophylline, tramadol, bupropion and beta lactams in renal failure.

Other causes are missed antiseizure doses, alcohol or benzodiazepine withdrawal, autoimmune encephalitis, tumour, and eclampsia in pregnancy and the puerperium.

Risk factors for refractoriness. Delayed first treatment, an under dosed first line drug, an acute symptomatic cause, encephalitis and focal motor onset.

Stages. Early (5 to 30 minutes), established (benzodiazepine failed), refractory (second line drug failed) and super refractory (24 hours or more of anaesthetic therapy).

Pathophysiology. Seizures become self-sustaining as synaptic GABA-A receptors are internalised, which weakens benzodiazepine action within minutes, while synaptic NMDA and AMPA receptors increase. This explains the falling response to benzodiazepines and the rationale for NMDA antagonism.

Excitotoxic calcium entry injures neurones from about 30 minutes. Systemic effects are hyperthermia, lactic acidosis, rhabdomyolysis, aspiration and neurogenic pulmonary oedema.

Presentation is continuous or recurrent generalised convulsions, or focal motor seizures. With time, motor signs fade to subtle eyelid, facial or finger twitching, nystagmus or nothing, while electrical seizures continue. Failure to regain consciousness within 20 to 30 minutes of convulsions stopping suggests ongoing nonconvulsive status.

Red flags.

• Fever, headache or neck stiffness (meningitis, encephalitis).
• Pregnancy or the puerperium with hypertension (eclampsia).
• Recent head injury, anticoagulant use or a new focal deficit.
• Ingestion of isoniazid, theophylline, tramadol or bupropion.
• Temperature over 38.5 °C, persistent coma or a rising oxygen requirement.

Immediate tests: capillary glucose, blood gas with lactate, sodium, potassium, calcium, magnesium, creatinine, liver tests, creatine kinase, full blood count, blood cultures, antiseizure drug levels, toxicology screen, pregnancy test, ammonia, malaria test in endemic areas, and ECG.

Brain imaging follows stabilisation, then lumbar puncture when safe (cell count, protein, glucose, culture, herpes simplex PCR, autoimmune antibodies in serum and CSF). Continuous EEG is needed as soon as possible in anyone not waking after convulsions and in everyone on an anaesthetic infusion.

Differential diagnosis.

• Psychogenic nonepileptic status (eyes closed and resisting opening, asynchronous movements, preserved reflexes, normal EEG).
• Convulsive syncope, rigors and tetanus.
• Posturing from raised intracranial pressure and post-hypoxic myoclonus.
• Serotonin syndrome and neuroleptic malignant syndrome.

0 to 5 minutes. Secure the airway, give oxygen, position safely, obtain IV or intraosseous access, attach ECG, blood pressure and oximetry monitoring, and check glucose at once.

• Glucose under 3.0 mmol/L: dextrose 25 g IV (50 mL of 50% dextrose) in adults, or 2 mL/kg of 10% dextrose in children.
• Alcohol misuse or malnutrition likely: thiamine 100 mg IV.

5 to 20 minutes, first line (one agent, one repeat only).

• Lorazepam 0.1 mg/kg IV (maximum 4 mg a dose), repeated once after 5 to 10 minutes. Monitor respiration and blood pressure and be ready to ventilate, especially in older adults.
• Midazolam IM 10 mg if over 40 kg or 5 mg if 13 to 40 kg, single dose, when there is no IV access.
• Diazepam 0.15 to 0.2 mg/kg IV (maximum 10 mg a dose), repeated once. Its active metabolite accumulates in older adults and liver disease.

20 to 40 minutes, second line (choose one).

• Levetiracetam 60 mg/kg IV over 10 minutes (maximum 4500 mg). The loading dose is not reduced in renal impairment. Maintenance is adjusted to eGFR: 500 to 1000 mg every 12 hours for eGFR 50 to 79, 250 to 750 mg every 12 hours for 30 to 49, and 250 to 500 mg every 12 hours under 30. Monitor for agitation and sedation.
• Fosphenytoin 20 mg PE/kg IV at up to 150 mg PE/min (maximum 1500 mg PE) with continuous ECG and blood pressure monitoring. Phenytoin 20 mg/kg IV at no more than 50 mg/min (25 mg/min in older adults or heart disease) is the alternative, with extravasation risk. Avoid in second or third degree heart block and severe bradycardia. Reduce maintenance in liver disease and interpret levels with albumin.
• Valproate 40 mg/kg IV over 10 minutes (maximum 3000 mg). Avoid in liver disease, suspected mitochondrial disease (including POLG variants), urea cycle disorders and pregnancy. Check ammonia, platelets and liver tests.
• Phenobarbital 15 to 20 mg/kg IV at 50 to 100 mg/min when the other three are unavailable or contraindicated. Expect respiratory depression and hypotension.

After 40 minutes or second line failure. Intubate, admit to intensive care, start continuous EEG and give an anaesthetic infusion.

• Midazolam 0.2 mg/kg IV bolus, then 0.05 to 2 mg/kg/h. Expect accumulation and tachyphylaxis.
• Propofol 1 to 2 mg/kg IV bolus (repeat once or twice if needed), then 2 to 5 mg/kg/h with a brief maximum of 10 mg/kg/h. Keep any rate over 5 mg/kg/h to under 48 hours. Monitor creatine kinase, triglycerides, lactate and acid base balance for propofol infusion syndrome. Avoid in children where alternatives exist.
• Thiopental 2 to 7 mg/kg IV bolus, then 0.5 to 5 mg/kg/h. Expect hypotension needing vasopressors, accumulation and prolonged recovery.
• Ketamine 1 to 3 mg/kg IV bolus, then 0.5 to 5 mg/kg/h, useful when other agents fail. Monitor blood pressure and heart rate.

The EEG target is seizure suppression, and some units aim for burst suppression. Maintain for 24 to 48 hours, then wean over 12 to 24 hours. If seizures recur, restart the infusion. Maintenance antiseizure medicines at therapeutic levels continue throughout.

Cause directed treatment.

• Isoniazid toxicity: pyridoxine 5 g IV (or gram for gram with the ingested isoniazid dose) together with benzodiazepines.
• Eclampsia: magnesium sulphate 4 g IV over 5 to 15 minutes, then 1 g/h for 24 hours after the last seizure. Monitor reflexes, respiratory rate and urine output, and reduce the dose in renal impairment.
• Suspected CNS infection: ceftriaxone 2 g IV every 12 hours and aciclovir 10 mg/kg IV every 8 hours (reduce in renal impairment) until infection is excluded.
• Severe malaria: artesunate 2.4 mg/kg IV at 0, 12 and 24 hours, then daily.
• Autoimmune encephalitis once infection is excluded: methylprednisolone 1 g IV daily for 3 to 5 days.

Monitoring. Continuous EEG, temperature, glucose, electrolytes, creatine kinase, lactate and drug levels.

Referral and escalation. Involve neurology and neurocritical care early. Transfer urgently if continuous EEG or anaesthetic care is unavailable.

Special groups. Children need weight based doses with the maximums given. In pregnancy, magnesium is the drug for eclampsia and valproate is avoided. In liver disease, valproate is avoided.