Refractory Status Epilepticus

When patients fail first-line therapy which is a sufficient dose of benzodiazepines and at least one AED as second-line therapy, irrespective of time this is termed refractory status epilepticus. Primary drugs being used for refractory status epilepticus are Midazolam, Propofol, and Ketamine while other interventions include DBS, surgery, VNS, etc. This chapter focuses on the treatment strategies being involved to treat patients with refractory status epilepticus

Refractory Status Epilepticus

Definition

  • Refractory status epilepticus (RSE)
    • Patients who do not respond to standard treatment regimens for SE
    • RSE is considered
      • when patients fail first line therapy which is sufficient dose of benzodiazepines and
      • at least one AED as second line therapy, irrespective of time
    • 26.6% to 36.6% of patients with SE fail to respond to administration of first-line agents
      • Out of all patients who fail first-line agents, 23-48% of the patients fail second line-agents and termed as RSE
  • Super-refractory status epilepticus (SRSE)
    • SRSE is considered when SE continues for 24 hours or more after the use of 3rd line therapies or anesthetic therapy (continuous IV infusions)
      • includes cases that recur on weaning of the anesthetic agent
    • SRSE occurs in 22% of patients with SE
    •  

Treatment of Refractory Status Epilepticus (RSE)

  • There is no clear evidence, according to AES protocol, to guide therapy in RSE
  • Estimates of the frequency of RSE in patients with SE have ranged from 9% to 40%
  • Treatment for RSE should be carried out with continuous EEG monitoring
  • Treatment should be started immediately
  • Main decision lies between repeating bolus of urgent control AED or to immediately initiate additional agents

General Measures

  • Adequate ventilatory and hemodynamic support
  • Intubation
  • Monitoring with continuous electroencephalography(EEG)
  • Continuous pulse oximetry
  • Blood pressure monitoring, often with an arterial catheter
  • Vasopressors should be available at the bedside

Specific Drug Therapy

The primary drugs used for refractory status epilepticus are
  • Midazolam
  • Propofol
  • Ketamine

Table 1 Specific Drug Therapies

Following are RSE dosing recommendations; initial doses and continuous infusion (CI) dosing recommendations-titrated to EEG
Drug Therapies
DRUG
Administration
Consideration
Adverse Effects
•Initial dose: 0.2 mg/kg; administer at an infusion rate of 2 mg/min •CI: 0.05-2 mg/kg/hr •Breakthrough status epilepticus (SE): 0.1-0.2 mg/kg bolus, increase CI rate by 0.05-0.1 mg/kg/hr every 3-4 hours
•Tachyphylaxis occurs after prolonged use •Active metabolite, renally eliminated, rapid redistribution (short duration) •Does not contain propylene glycol
•Respiratory depression •Hypotension
•Initial dose: start at 20 mcg/kg/min, with 1-2 mg/kg loading dose •CI: 30-200 mcg/kg/min •Breakthrough SE: Increase CI rate by 5-10 mcg/kg/min every 5 min or 1 mg/kg bolus plus CI titration
•When administering high doses (>80 mcg/kg/min) for extended periods of time (i.e. >48h) •Peds: with doses >65 mcg/kg/min; contraindicated in young children •Requires mechanical ventilation •Must adjust daily caloric intake (1.1 kcal/ml)
•Hypotension (especially with loading dose in critically ill patients) •Respiratory depression •Cardiac failure •Rhabdomyolysis •Metabolic acidosis •Renal failure (propofol related infusion syndrome)
•Initial dose: 1-2 mg/kg IV slow push •CI: 0.5-7.5 mg/kg/hr •Titrate by 0.5 mg/kg/hr every 10 minutes
•Maximal effect in 1 minute •Hepatic metabolism to active metabolite norketamine •Favorable hemodynamic effects •Minimal respiratory effects
•Agitation with auditory and visual hallucinations •Conscious vivid dreams •Increased intracranial pressure •Tachyarrhythmias •Hypersalivation

Management of Super-Refractory Status Epilepticus (MGH SRSE Protocol)

  • Repeat burst suppression for 24-48 hours
  • Add other AEDs like carbamazepine or topiramate
  • IV magnesium (bolus 4g, then infuse 2-6 g/hr)
  • Pentobarbital
    • Initial dose: 5-15 mg/kg, may give additional 5-10 mg/kg; administer at an infusion rate ≤50 mg/min
    • CI: 0.5-5 mg/kg/h
    • Breakthrough SE: 5 mg/kg bolus, increase CI by 0.5-1 mg/kg/h every 12 h
  • Ketamine (a propofol sparing agent)
    • See Above in RSE protocol Table 1
  • IV pyridoxine 200 mg/day
  • Thiopental
    • Initial dose: 2-7 mg/kg, administer at an infusion rate ≤50 mg/min
    • CI: 0.5-5 mg/kg/h
    • Breakthrough SE: 1-2 mg/kg bolus, increase CI rate by 0.5-1 mg/kg/h every 12h
    • Adverse effects
      • Hypotension
      • Respiratory depression
      • Cardiac depression
    • Considerations
      • Requires mechanical ventilation

Box 1: Alternative Therapy Options for Super-Refractory Status Epilepticus

👆
Alternative Therapy Options for Super-Refractory Status Epilepticus
  • Brivacetam
  • Brexanolone
  • Immunomodulatory agents
  • Inhalation anesthetics
  • Clobazam
  • Therapeutic hypothermia
  • Pryidoxine
  • Ketogenic Diet
  • Electoconvulsive therapy
  • Deep brain stimulation
  • Surgical intervention
  • Transcranial magnetic stimulation
  • Vagal nerve stimulation
  • Magnesium

Alternative Therapy Options

  • Brivaracetam
    • 10-30 fold higher affinity than levetiracetam
    • Initial dose range between 50-400 mg/day
    • Titrated to daily dose of 100-400 mg
  • Brexanolone
    • Initial dose: 286.6 μg/kg for 1 hour
    • CI: 86-156 μg/kg/h for four days
  • Immune modulation
    • Methylprednisolone 1 g IV qd x 3-5 days
    • IVIG 0.4 g/kg/day x 5 days
    • Plasma exchange every other day x 5-7 days
  • Isoflurane
    • MAC ranging from 0.5-5.0%
    • Seizure control was seen in 43 out of 47 patients
    • Seizure activity often returned upon discontinuation
  • Emergency neurosurgery
    • Suggested that patients who fail three courses of cerebral suppressant therapy for 2 weeks be considered for surgical treatment
    • Preferred for intractable partial SE with focal electrographic changes
  • Ketogenic diet
    • 4:1 ratio of fat (g) to protein plus carbohydrates (g)
    • Studies show improvements and cessation of seizures in 1-2 weeks
    • Benefits
      • Easy to start, maintain, and monitor in the ICU
      • Synergism with other AEDs
      • Minimal side effects
  • Electroconvulsive therapy
    • There is evidence that cases of SRSE may benefit from ECT
    • ECT consisted of a 504-mC (≈99.4 J)
    • Improvement in seizures in 5 out of 8 patients
    • Need for further research
  • Transcranial magnetic stimulation
    • Had dismal results in epilepsy, although recent promising reports of use in epilepsia partialis continua have been published.
  • Vagal nerve stimulation
    • Four published cases reporting benefit from VNS
  • Therapeutic hypothermia
    • Review of studies include a total of 40 patients
    • Target temperature of 33 degree Celsius, sustained for a median 48 hours
    • 62.5% patients displayed seizure cessation
    • 15% had seizure reduction
    • 22.5% had failure of treatment

Prognosis

The outcome of refractory status epilepticus is often poor
  • Prognosis for RSE treated with prolonged courses of pentobarbital, propofol, or midazolam is poor
  • Outcome of new-onset RSE by Gaspard et al.
    • Retrospective review of patients with RSE etiology within 48 hours of admission
The most important prognostic factors are
  • Age
  • Etiology
  • Medical comorbidities

Mortality

  • Ranging from 19 to 60 percent
  • In-hospital mortality rate is 38 percent
  • From a systemic review on 61 studies by Neligan et al.
    • RSE: Pooled mortality was at 17.3%
  • Case mortality rate in patients with RSE was recorded as 38% by Sutter et al.
 
 

Further Reading

  • Gaspard, Nicolas et al. “New-onset refractory status epilepticus: Etiology, clinical features, and outcome.” Neurology vol. 85,18 (2015): 1604-13. doi:10.1212/WNL.0000000000001940
  • Rossetti, Andrea O et al. “A randomized trial for the treatment of refractory status epilepticus.” Neurocritical care vol. 14,1 (2011): 4-10. doi:10.1007/s12028-010-9445-z

Bibliography

  • Dubey, D., Kalita, J., & Misra, U. K. (2017). Status epilepticus: Refractory and super-refractory. Neurology India, 65(7), 12.
  • Shaner DM, McCurdy SA, Herring MO, Gabor AJ. Treatment of status epilepticus: a prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin. Neurology 1988; 38: 202–07
  • Mayer, S. A., Claassen, J., Lokin, J., Mendelsohn, F., Dennis, L. J., & Fitzsimmons, B. F. (2002). Refractory status epilepticus: frequency, risk factors, and impact on outcome. Archives of neurology, 59(2), 205-210.
  • Strzelczyk, A., Steinig, I., Willems, L. M., Reif, P. S., Senft, C., Voss, M., ... & Rosenow, F. (2017). Treatment of refractory and super-refractory status epilepticus with brivaracetam: a cohort study from two German university hospitals. Epilepsy & Behavior, 70, 177-181.
  • Rosenthal, E. S., Claassen, J., Wainwright, M. S., Husain, A. M., Vaitkevicius, H., Raines, S., ... & Kanes, S. J. (2017). Brexanolone as adjunctive therapy in super‐refractory status epilepticus. Annals of neurology, 82(3), 342-352.
  • Zeiler, F. A., Zeiler, K. J., Teitelbaum, J., Gillman, L. M., & West, M. (2015). Therapeutic hypothermia for refractory status epilepticus. Canadian Journal of Neurological Sciences, 42(4), 221-229.
  • Ma, X., Liporace, J., O'Connor, M. J., & Sperling, M. R. (2001). Neurosurgical treatment of medically intractable status epilepticus. Epilepsy research, 46(1), 33-38.
  • McDonald, T. J., & Cervenka, M. C. (2017). Ketogenic diets for adults with highly refractory epilepsy. Epilepsy currents, 17(6), 346-350.
  • Ahmed, J., Metrick, M., Gilbert, A., Glasson, A., Singh, R., Ambrous, W., ... & Bobel, K. (2018). Electroconvulsive therapy for super refractory status epilepticus. The journal of ECT, 34(1), e5-e9.
  • Shorvon, S., & Ferlisi, M. (2011). The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain, 134(10), 2802-2818.
  • Hesdorffer, D. C., Logroscino, G., Cascino, G. D., & Hauser, W. A. (2007). Recurrence of afebrile status epilepticus in a population-based study in Rochester, Minnesota. Neurology, 69(1), 73-78.
  • Donaire, A., Carreno, M., Gomez, B., Fossas, P., Bargalló, N., Agudo, R., ... & Obach, V. (2006). Cortical laminar necrosis related to prolonged focal status epilepticus. Journal of Neurology, Neurosurgery & Psychiatry, 77(1), 104-106.
  • Gaspard, N., Foreman, B. P., Alvarez, V., Kang, C. C., Probasco, J. C., Jongeling, A. C., ... & Gerard, E. E. (2015). New-onset refractory status epilepticus: etiology, clinical features, and outcome. Neurology, 85(18), 1604-1613.