What is the immediate treatment for a patient with New-Onset Refractory Status Epilepticus (NORSE)?

Immediate Treatment for New-Onset Refractory Status Epilepticus (NORSE)

For NORSE, immediately initiate combination immunotherapy with high-dose corticosteroids plus either IVIG or plasma exchange from the beginning, while simultaneously managing seizures with anesthetic agents for refractory status epilepticus. 1

Initial Seizure Management

First-Line: Benzodiazepines

• Administer IV lorazepam 4 mg slowly (2 mg/min), with a repeat dose of 4 mg after 10-15 minutes if seizures persist 2, 3
• Alternative options include IM midazolam or intranasal midazolam if IV access is delayed 2
• Critical warning: Airway patency must be assured and ventilation equipment immediately available, as respiratory depression is the most important risk 3

Second-Line: Non-Sedating Antiepileptic Drugs

If seizures continue after benzodiazepines, choose one of the following 2:

• Valproate 20-30 mg/kg IV over 5-20 minutes (88% efficacy, 0% hypotension risk) 1, 2
• Levetiracetam 30 mg/kg IV over 5 minutes (68-73% efficacy, minimal adverse effects) 1, 2
• Fosphenytoin 20 mg PE/kg IV at maximum 50 mg/min (84% efficacy but 12% hypotension risk) 2
• Phenobarbital 20 mg/kg IV over 10 minutes (58.2% efficacy but higher respiratory depression risk) 2

Valproate is preferred over phenytoin due to similar efficacy with significantly less hypotension (0% vs 12%) 2

Refractory Status Epilepticus Management

NORSE typically evolves to super-refractory status epilepticus requiring anesthetic agents 4, 5:

Anesthetic Options 2, 5:

• Midazolam: 0.15-0.20 mg/kg IV load, then 1 mg/kg/min continuous infusion, titrate up by 1 mg/kg/min every 15 minutes to maximum 5 mg/kg/min 2
• Pentobarbital: 13 mg/kg bolus, then 2-3 mg/kg/hour infusion (92% efficacy but highest hypotension rate at 77%) 1, 2
• Propofol: 2 mg/kg bolus, then 3-7 mg/kg/hour infusion (requires mechanical ventilation but shorter ventilation time than barbiturates) 2, 5

Pentobarbital shows the highest treatment success rate (92%) compared to midazolam (80%) and propofol (73%), though it requires vasopressor support more frequently 1

Immediate Immunotherapy Initiation

This is the critical distinguishing feature of NORSE management: Unlike typical status epilepticus, NORSE requires immediate immunotherapy even before definitive diagnosis 1, 6:

Combination Therapy from Onset 1:

• High-dose corticosteroids (typically IV methylprednisolone 1 gram daily for 3-5 days) PLUS
• IVIG (2 g/kg divided over 2-5 days) OR Plasma exchange (5-10 sessions every other day)

Start combination immunotherapy immediately in patients with severe presentations like NORSE rather than sequential therapy 1

Choosing Between IVIG vs Plasma Exchange 1:

• Consider IVIG first in agitated patients and those with bleeding disorders
• Consider plasma exchange first in patients with severe hyponatremia, high thromboembolic risk, or if there is associated demyelination

Early immunotherapy (within the first 2 weeks) is associated with significantly better outcomes in NORSE, with some case series showing good neurological recovery when started early 6

Essential Concurrent Management

Continuous Monitoring Requirements 2, 3:

• Continuous EEG monitoring is crucial for detecting ongoing electrical seizures, as 25% of patients have continuing electrical activity without convulsive movements 1, 5
• Continuous vital sign monitoring with particular attention to respiratory status and blood pressure 2
• Maintain unobstructed airway with mechanical ventilation equipment immediately available 3

Search for Underlying Causes 2:

• Immediately check and correct: hypoglycemia, hyponatremia, hypoxia, drug toxicity
• Autoimmune encephalitis is the most frequently identified cause of NORSE 4, 7
• Obtain CSF for cell count, protein, glucose, oligoclonal bands, IgG index, and neuronal autoantibodies 1
• Send serum for neuronal autoantibodies (including GAD65, NMDAR, LGI1, CASPR2) 1, 7

Second-Line Immunotherapy

If no improvement after 2-4 weeks of combined acute immunotherapy 1:

• Rituximab for known or highly suspected antibody-mediated autoimmunity (e.g., NMDAR-antibody encephalitis) 1
• Cyclophosphamide for known or highly suspected cell-mediated autoimmunity 1

Critical Pitfalls to Avoid

• Do not delay immunotherapy while waiting for antibody results—approximately 50% of adult NORSE cases remain of unknown etiology, but early immunotherapy still improves outcomes 4, 6
• Do not undertreate the seizures: NORSE has 12-27% short-term mortality and most cases evolve to super-refractory status epilepticus requiring ICU-level care 4
• Do not assume consciousness impairment is post-ictal: Prolonged altered consciousness may represent nonconvulsive status epilepticus requiring continuous EEG monitoring 1
• Avoid premature withdrawal of anesthetic agents, as seizures frequently recur; this is a major challenge in NORSE management 5, 6