Super-Refractory Status Epilepticus

Super refractory status epilepticus is status that continues or recurs 24 hours or more after the start of anaesthetic therapy, including recurrence on weaning or reduction of the anaesthetic. It carries high mortality and a high risk of severe disability.

Epidemiology. It develops in about 10 to 15% of patients with status epilepticus overall, and in a larger share of those needing an anaesthetic infusion. Mortality is commonly over 30%, determined mainly by cause and age.

Causes and associations. A large proportion is cryptogenic, including new onset refractory status epilepticus and, in children and young adults, febrile infection related epilepsy syndrome.

Other causes are autoimmune and paraneoplastic encephalitis (anti-NMDA receptor, anti-GAD65, anti-GABA-A receptor), viral encephalitis, mitochondrial disease (POLG variants), Rasmussen encephalitis, cortical malformation and structural lesions, and withdrawal of antiseizure medicines.

Pathophysiology. The mechanisms of refractory status continue, with loss of GABA-A receptors and upregulation of NMDA receptors. In many unexplained cases neuroinflammation with cytokine activation, notably interleukin-1 and interleukin-6, is thought to sustain seizures, which is the basis for early immunotherapy.

Presentation is ongoing electrographic seizures, with or without motor signs, after 24 hours of anaesthesia, or relapse on weaning. A febrile illness precedes many unexplained cases.

Complications include ventilator associated pneumonia, venous thrombosis, pressure injury, critical illness neuropathy and myopathy, ileus, and anaesthetic toxicity (propofol infusion syndrome, thiopental accumulation, hypotension).

Red flags.

• Rising creatine kinase, triglycerides or lactate on propofol.
• Hypotension needing escalating vasopressors.
• Hepatic failure on valproate, especially in a child or when mitochondrial disease is possible.
• Abnormal movements, a psychiatric prodrome or an ovarian teratoma (anti-NMDA receptor encephalitis).

Continuous EEG is mandatory. Extend the cause search:

• MRI brain with contrast
• CSF with a PCR panel (herpes simplex, varicella zoster, enteroviruses) and autoimmune antibodies in serum and CSF
• A paraneoplastic panel
• Pelvic ultrasound or MRI for ovarian teratoma
• CT chest, abdomen and pelvis or whole body PET for malignancy
• A metabolic and mitochondrial screen (lactate, ammonia, amino acids, acylcarnitines)
• Genetic testing including POLG when indicated

Repeat tests when the first set is negative and no cause emerges.

Differential diagnosis.

• Anaesthetic withdrawal phenomena, post-hypoxic myoclonus and critical illness myoclonus.
• Toxic or metabolic encephalopathy with periodic discharges.
• Posterior reversible encephalopathy syndrome and Creutzfeldt-Jakob disease.

Anaesthetic infusion. Continue or re-establish an infusion with an EEG target of seizure suppression or burst suppression for 24 to 48 hours before each weaning attempt, and wean over 12 to 24 hours.

• Midazolam 0.05 to 2 mg/kg/h (maximum about 2 mg/kg/h).
• Propofol 2 to 5 mg/kg/h with a brief maximum of 10 mg/kg/h, and under 48 hours for any rate over 5 mg/kg/h. Monitor creatine kinase, lactate and triglycerides.
• Thiopental 0.5 to 5 mg/kg/h with vasopressor support.
• Ketamine 0.5 to 5 mg/kg/h after a 1 to 3 mg/kg IV bolus. It is often added early here because of the NMDA mechanism.

Maintenance antiseizure medicines at full levels.

• Levetiracetam 60 mg/kg IV load (maximum 4500 mg), then maintenance adjusted to eGFR: 500 to 1000 mg every 12 hours for eGFR 50 to 79. Use 250 to 750 mg every 12 hours for 30 to 49, and 250 to 500 mg every 12 hours under 30.
• Phenobarbital 15 to 20 mg/kg IV loading at 50 to 100 mg/min, then 1 to 3 mg/kg daily.
• Lacosamide 200 to 400 mg IV load, then 200 mg every 12 hours (maximum 600 mg daily). Monitor the PR interval and avoid in second or third degree heart block.
• Topiramate 200 to 400 mg daily in divided doses by nasogastric tube. Monitor for metabolic acidosis and reduce in renal impairment.
• Perampanel 4 to 12 mg once daily by tube.
• Valproate is avoided when mitochondrial disease or POLG variants are possible.

Immunotherapy. Start empirically in the first week when infection is excluded and no cause is found.

• Methylprednisolone 1 g IV daily for 3 to 5 days.
• Immunoglobulin 0.4 g/kg IV daily for 5 days (slow the rate and check renal function in renal impairment), or plasma exchange.
• Rituximab 375 mg/m2 weekly for 4 doses, or cyclophosphamide 750 mg/m2 monthly, when an antibody is found or there is no response by 2 weeks.
• Interleukin-1 or interleukin-6 blockade (anakinra, tocilizumab) is a specialist decision, especially in febrile infection related epilepsy syndrome. Reported doses vary and are not given here.

Other options. Ketogenic diet (4 to 1 ratio) in children and adults, contraindicated in fatty acid oxidation disorders and pyruvate carboxylase deficiency. Hypothermia, magnesium, emergency neurosurgery for a focal lesion and electroconvulsive therapy are specialist decisions with weak evidence.

Monitoring. Continuous EEG, creatine kinase, triglycerides, lactate, liver tests, ammonia, drug levels, sodium and haemodynamics.

Referral and escalation. Transfer to a neurocritical care unit with continuous EEG and immunotherapy access. Involve neurology, immunology and, in children, metabolic specialists early.

Special groups. Children need weight based dosing and an early ketogenic diet. In pregnancy, valproate, topiramate and teratogenic immunosuppressants are avoided where possible. In liver or kidney impairment, levetiracetam, topiramate and lacosamide are adjusted.