Table of Contents
- Refractory Status Epilepticus
- Definition
- Treatment of Refractory Status Epilepticus (RSE)
- General Measures
- Specific Drug Therapy
- Table 1 Specific Drug Therapies
- Management of Super-Refractory Status Epilepticus (MGH SRSE Protocol)
- Box 1: Alternative Therapy Options for Super-Refractory Status Epilepticus
- Alternative Therapy Options
- Prognosis
- Mortality
- Further Reading
- Bibliography
Primary Category
Epilepsy
P-Category
Secondary Category
Neurocritical Care
S-Category
Authors:
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.
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