Refractory Status Epilepticus

Authors:

Rizwan Raheem MD,

Filzah Faheem MD,

Junaid Kalia MD

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

• Midazolam

• Propofol

• Ketamine

Table 1 Specific Drug Therapies

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

• 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

• 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

• 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.