Skip to main content
SpringerLink
Log in

Treatment of Super-Refractory Status Epilepticus

  • Epilepsy (CW Bazil, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Super-refractory status epilepticus (SRSE) is a devastating neurological condition with limited treatment options. We conducted an extensive literature search to identify and summarize the therapeutic options for SRSE. The search mainly resulted in case reports of various pharmacologic and non-pharmacologic treatments. The success rate of each of the following agents, ketamine, inhaled anesthetics, intravenous immunoglobulin G (IVIG), IV steroids, ketogenic diet, hypothermia, electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), and vagal nerve stimulation (VNS), are discussed in greater detail. The choice of appropriate treatment options for a given patient is based on clinical presentation. This review focuses on evidence-based, pharmacotherapeutic strategies for patients in SRSE.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Trends in status epilepticus-related hospitalizations and mortality: redefined in US practice over time. - PubMed - NCBI [Internet]. [cited 6/9/2015]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25915004.

  2. Brophy GM, Bell R, Claassen J, Alldredge B, Bleck TP, Glauser T, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17(1):3–23. This reference is important as it is the most recent guidelines from the neurocritical care society that describe status epilepticus definitions and classification, etiology, diagnostic evaluation, prognosis, monitoring, and management in critically ill patients.

    Article  PubMed  Google Scholar 

  3. Kossoff EH. A shot in the arm for prehospital status epilepticus: the RAMPART study. Epilepsy Curr. 2012;12(3):103–4.

    Article  PubMed Central  PubMed  Google Scholar 

  4. Mnatsakanyan L, Chung JM, Tsimerinov EI, Eliashiv DS. Intravenous lacosamide in refractory nonconvulsive status epilepticus. Seizure. 2012;21(3):198–201.

    Article  CAS  PubMed  Google Scholar 

  5. Miro J, Toledo M, Santamarina E, Ricciardi AC, Villanueva V, Pato A, et al. Efficacy of intravenous lacosamide as an add-on treatment in refractory status epilepticus: a multicentric prospective study. Seizure. 2013;22(1):77–9.

    Article  CAS  PubMed  Google Scholar 

  6. Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain. 2011;134(Pt 10):2802–18.

    Article  PubMed  Google Scholar 

  7. Smith KR, Kittler JT. The cell biology of synaptic inhibition in health and disease. Curr Opin Neurobiol. 2010;20(5):550–6.

    Article  CAS  PubMed  Google Scholar 

  8. Goodkin HP, Yeh JL, Kapur J. Status epilepticus increases the intracellular accumulation of GABAA receptors. J Neurosci. 2005;25(23):5511–20.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Kapur J, Lothman EW. NMDA receptor activation mediates the loss of GABAergic inhibition induced by recurrent seizures. Epilepsy Res. 1990;5(2):103–11.

    Article  CAS  PubMed  Google Scholar 

  10. Mazarati AM, Wasterlain CG. N-methyl-D-asparate receptor antagonists abolish the maintenance phase of self-sustaining status epilepticus in rat. Neurosci Lett. 1999;265(3):187–90.

    Article  CAS  PubMed  Google Scholar 

  11. Bramstedt KA, Morris HH, Tanner A. Now we lay them down to sleep: ethical issues with the use of pharmacologic coma for adult status epilepticus. Epilepsy Behav. 2004;5(5):752–5.

    Article  PubMed  Google Scholar 

  12. Dara SI, Tungpalan LA, Manno EM, Lee VH, Moder KG, Keegan MT, et al. Prolonged coma from refractory status epilepticus. Neurocrit Care. 2006;4(2):140–2.

    Article  PubMed  Google Scholar 

  13. The effects of ketamine on cardiovascular dynamics during ha… : Anesthesia & Analgesia [Internet]. [cited 4/28/2015]. Available from: http://journals.lww.com/anesthesia-analgesia/Abstract/1975/09000/The_Effects_of_Ketamine_on_Cardiovascular_Dynamics.5.aspx.

  14. Kofke WA, Bloom MJ, Van Cott A, Brenner RP. Electrographic tachyphylaxis to etomidate and ketamine used for refractory status epilepticus controlled with isoflurane. J Neurosurg Anesthesiol. 1997;9(3):269–72.

    Article  CAS  PubMed  Google Scholar 

  15. Kramer AH. Early ketamine to treat refractory status epilepticus. Neurocrit Care. 2012;16(2):299–305.

    Article  PubMed  Google Scholar 

  16. Rossetti AO. Novel anesthetics and other treatment strategies for refractory status epilepticus. Epilepsia. 2009;50 Suppl 12:51–3.

    Article  PubMed  Google Scholar 

  17. Rosati A, L’Erario M, Ilvento L, Cecchi C, Pisano T, Mirabile L, et al. Efficacy and safety of ketamine in refractory status epilepticus in children. Neurology. 2012;79(24):2355–8.

    Article  CAS  PubMed  Google Scholar 

  18. Gaspard N, Foreman B, Judd LM, Brenton JN, Nathan BR, McCoy BM, et al. Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study. Epilepsia. 2013;54(8):1498–503. This reference is important as it is one of the largest studies for ketamine use in SE. It is a retrospective multi-center study and included 58 subjects. Ketamine was felt to have contributed to permanent control (“possible” or “likely” responses) in about one third of the cases.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Yan J, Jiang H. Dual effects of ketamine: neurotoxicity versus neuroprotection in anesthesia for the developing brain. J Neurosurg Anesthesiol. 2014;26(2):155–60.

    Article  PubMed  Google Scholar 

  20. Kofke WA, Young RS, Davis P, Woelfel SK, Gray L, Johnson D, et al. Isoflurane for refractory status epilepticus: a clinical series. Anesthesiology. 1989;71(5):653–9.

    Article  CAS  PubMed  Google Scholar 

  21. Mirsattari SM, Sharpe MD, Young GB. Treatment of refractory status epilepticus with inhalational anesthetic agents isoflurane and desflurane. Arch Neurol. 2004;61(8):1254–9.

    Article  PubMed  Google Scholar 

  22. Vezzani A, French J, Bartfai T, Baram TZ. The role of inflammation in epilepsy. Nat Rev Neurol. 2011;7(1):31–40.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Gall CR, Jumma O, Mohanraj R. Five cases of new onset refractory status epilepticus (NORSE) syndrome: outcomes with early immunotherapy. Seizure. 2013;22(3):217–20. This paper is one of the larger, more recent case series of the potential efficacy immunotherapy for the treatment of new onset refractory status epilepticus without known cause. This data adds guidance to the support of using steroids in combination with IVIG for SRSE in adult patients.

    Article  PubMed  Google Scholar 

  24. Wilder-Smith EP, Lim EC, Teoh HL, Sharma VK, Tan JJ, Chan BP, et al. The NORSE (new-onset refractory status epilepticus) syndrome: defining a disease entity. Ann Acad Med Singap. 2005;34(7):417–20.

    CAS  PubMed  Google Scholar 

  25. Ferlisi M, Shorvon S. The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy. Brain. 2012;135(Pt 8):2314–28.

    PubMed  Google Scholar 

  26. Costello DJ, Kilbride RD, Cole AJ. Cryptogenic new onset refractory status epilepticus (NORSE) in adults—infectious or not? J Neurol Sci. 2009;277(1–2):26–31.

    Article  PubMed  Google Scholar 

  27. Plasma exchange in cryptogenic new onset refractory status epilepticus. - PubMed - NCBI [Internet]. [cited 5/14/2015]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23068971. This article is of importance because the use of plasma exchange for SRSE is much less reported when compared to other treatment modalities. These authors provide data on 3 adult patients who responded well to plasma exchange after failing several other standard therapies.

  28. Autoimmune status epilepticus. - PubMed - NCBI [Internet]. [cited 5/14/2015]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23852708.

  29. Nabbout R, Mazzuca M, Hubert P, Peudennier S, Allaire C, Flurin V, et al. Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES). Epilepsia. 2010;51(10):2033–7.

  30. Ye F, Li XJ, Jiang WL, Sun HB, Liu J. Efficacy of and patient compliance with a ketogenic diet in adults with intractable epilepsy: a meta-analysis. J Clin Neurol. 2015;11(1):26–31.

    Article  PubMed Central  PubMed  Google Scholar 

  31. Thakur KT, Probasco JC, Hocker SE, Roehl K, Henry B, Kossoff EH, et al. Ketogenic diet for adults in super-refractory status epilepticus. Neurology. 2014;82(8):665–70.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Cervenka MC, Henry B, Nathan J, Wood S, Volek JS. Worldwide dietary therapies for adults with epilepsy and other disorders. J Child Neurol. 2013;28(8):1034–40.

    Article  PubMed  Google Scholar 

  33. Wusthoff CJ, Kranick SM, Morley JF, Christina Bergqvist AG. The ketogenic diet in treatment of two adults with prolonged nonconvulsive status epilepticus. Epilepsia. 2010;51(6):1083–5.

    Article  CAS  PubMed  Google Scholar 

  34. Kumada T, Miyajima T, Kimura N, Saito K, Shimomura H, Oda N, et al. Modified Atkins diet for the treatment of nonconvulsive status epilepticus in children. J Child Neurol. 2010;25(4):485–9.

    Article  PubMed  Google Scholar 

  35. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002 02/21; 2015/04;346(8):549–56.

  36. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons. Guidelines for the management of severe traumatic brain injury. J Neurotrauma. 2007;24 Suppl 1:S1–106.

    Google Scholar 

  37. Corry JJ, Dhar R, Murphy T, Diringer MN. Hypothermia for refractory status epilepticus. Neurocrit Care. 2008;9(2):189–97.

    Article  CAS  PubMed  Google Scholar 

  38. Motamedi GK, Lesser RP, Vicini S. Therapeutic brain hypothermia, its mechanisms of action, and its prospects as a treatment for epilepsy. Epilepsia. 2013;54(6):959–70.

    Article  CAS  PubMed  Google Scholar 

  39. Zhumadilov A, Gilman CP, Viderman D. Management of super-refractory status epilepticus with isoflurane and hypothermia. Front Neurol. 2015;5:286.

    Article  PubMed Central  PubMed  Google Scholar 

  40. Therapeutic hypothermia for status epilepticus: a report, historical perspective, and review. - PubMed - NCBI [Internet]. [cited 5/16/2015]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/?term=Therapeutic+hypothermia+for+status+epilepticus:+A+report,+historical++perspective,+and+review.

  41. Potential mechanisms and clinical applications of mild hypothermia and electroconvulsive therapy on refractory status epilepticus. - PubMed - NCBI [Internet]. [cited 5/16/2015]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25495421.

  42. Versiani M, Cheniaux E, Landeira-Fernandez J. Efficacy and safety of electroconvulsive therapy in the treatment of bipolar disorder: a systematic review. J ECT. 2011;27(2):153–64.

    Article  PubMed  Google Scholar 

  43. Sackeim HA. Convulsant and anticonvulsant properties of electroconvulsive therapy: towards a focal form of brain stimulation. Clin Neurosci Res. 2004;4(1–2):39–57.

    Article  Google Scholar 

  44. Shin HW, O’Donovan CA, Boggs JG, Grefe A, Harper A, Bell WL, et al. Successful ECT treatment for medically refractory nonconvulsive status epilepticus in pediatric patient. Seizure. 2011;20(5):433–6.

    Article  PubMed  Google Scholar 

  45. Kamel H, Cornes SB, Hegde M, Hall SE, Josephson SA. Electroconvulsive therapy for refractory status epilepticus: a case series. Neurocrit Care. 2010;12(2):204–10.

    Article  PubMed  Google Scholar 

  46. Morales OG, Henry ME, Nobler MS, Wassermann EM, Lisanby SH. Electroconvulsive therapy and repetitive transcranial magnetic stimulation in children and adolescents: a review and report of two cases of epilepsia partialis continua. Child Adolesc Psychiatr Clin N Am. 2005;14(1):193–210.

    Article  PubMed  Google Scholar 

  47. Cline JS, Roos K. Treatment of status epilepticus with electroconvulsive therapy. J ECT. 2007;23(1):30–2.

    Article  PubMed  Google Scholar 

  48. Lambrecq V, Villega F, Marchal C, Michel V, Guehl D, Rotge JY, et al. Refractory status epilepticus: electroconvulsive therapy as a possible therapeutic strategy. Seizure. 2012;21(9):661–4.

    Article  PubMed  Google Scholar 

  49. UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet. 2003;361(9360):799–808.

    Article  Google Scholar 

  50. Gangadhar BN, Kapur RL, Kalyanasundaram S. Comparison of electroconvulsive therapy with imipramine in endogenous depression: a double blind study. Br J Psychiatry. 1982;141:367–71.

    Article  CAS  PubMed  Google Scholar 

  51. Pascual-Leone A, Valls-Solé J, Wassermann EM, Hallett M. Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain. 1994;117(4):847.

    Article  PubMed  Google Scholar 

  52. Aleman A. Use of repetitive transcranial magnetic stimulation for treatment in psychiatry. Clin Psychopharmacol Neurosci. 2013;11(2):53–9.

    Article  PubMed Central  PubMed  Google Scholar 

  53. Misawa S, Kuwabara S, Shibuya K, Mamada K, Hattori T. Low-frequency transcranial magnetic stimulation for epilepsia partialis continua due to cortical dysplasia. J Neurol Sci. 2005 7/15;234(1–2):37–9.

  54. Fregni F, Otachi PTM, Do Valle A, Boggio PS, Thut G, Rigonatti SP, et al. A randomized clinical trial of repetitive transcranial magnetic stimulation in patients with refractory epilepsy. Ann Neurol. 2006;60(4):447–55.

    Article  PubMed  Google Scholar 

  55. Sun W, Mao W, Meng X, Wang D, Qiao L, Tao W, et al. Low-frequency repetitive transcranial magnetic stimulation for the treatment of refractory partial epilepsy: a controlled clinical study. Epilepsia. 2012;53(10):1782–9.

    Article  PubMed  Google Scholar 

  56. Liu A, Pang T, Herman S, Pascual-Leone A, Rotenberg A. Transcranial magnetic stimulation for refractory focal status epilepticus in the intensive care unit. Seizure. 2013;22(10):893–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Gilbert DL, Garvey MA, Bansal AS, Lipps T, Zhang J, Wassermann EM. Should transcranial magnetic stimulation research in children be considered minimal risk? Clin Neurophysiol. 2004;115(8):1730–9.

    Article  PubMed  Google Scholar 

  58. Recently-approved devices > VNS therapy system - P970003s050 [Internet]. [cited 6/9/2015]. Available from: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm078532.htm.

  59. Morris 3rd GL, Gloss D, Buchhalter J, Mack KJ, Nickels K, Harden C. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the guideline development subcommittee of the American Academy of Neurology. Epilepsy Curr. 2013;13(6):297–303.

    Article  PubMed Central  PubMed  Google Scholar 

  60. Vonck K, Van Laere K, Dedeurwaerdere S, Caemaert J, De Reuck J, Boon P. The mechanism of action of vagus nerve stimulation for refractory epilepsy: the current status. J Clin Neurophysiol. 2001;18(5):394–401.

    Article  CAS  PubMed  Google Scholar 

  61. Dorr AE, Debonnel G. Effect of vagus nerve stimulation on serotonergic and noradrenergic transmission. J Pharmacol Exp Ther. 2006;318(2):890–8.

    Article  CAS  PubMed  Google Scholar 

  62. Raedt R, Clinckers R, Mollet L, Vonck K, El Tahry R, Wyckhuys T, et al. Increased hippocampal noradrenaline is a biomarker for efficacy of vagus nerve stimulation in a limbic seizure model. J Neurochem. 2011;117(3):461–9.

    Article  CAS  PubMed  Google Scholar 

  63. Zeiler FA, Zeiler KJ, Teitelbaum J, Gillman LM, West M. VNS for refractory status epilepticus. Epilepsy Res. 2015;112(0):100–13.

    Article  CAS  PubMed  Google Scholar 

  64. VNS for refractory status epilepticus. - PubMed - NCBI [Internet]. [cited 6/9/2015]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25847345.

  65. Urgent, resective surgery for medically refractory, convulsive status epilepticus. - PubMed - NCBI [Internet]. [cited 4/28/2015]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18460420.

  66. Ma X, Liporace J, O’Connor MJ, Sperling MR. Neurosurgical treatment of medically intractable status epilepticus. Epilepsy Res. 2001;46(1):33–8.

    Article  CAS  PubMed  Google Scholar 

  67. Life-saving epilepsy surgery for status epilepticus caused by cortical dysplasia. - PubMed - NCBI [Internet]. [cited 4/28/2015]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12446223.

  68. Rogawski MA, Loya CM, Reddy K, Zolkowska D, Lossin C. Neuroactive steroids for the treatment of status epilepticus. Epilepsia. 2013;54 Suppl 6:93–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy. - PubMed - NCBI [Internet]. [cited 6/2/2015]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25845492.

  70. Progress report on new antiepileptic drugs: a summary of the twelfth Eilat Conference (EILAT XII). - PubMed - NCBI [Internet]. [cited 6/2/2015]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/?term=SAGE-547.

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Ahmad Bayrlee, Nimalya Ganeshalingam, and Lisa Kurczewski declare that they have no conflict of interest.

Gretchen M. Brophy has received consultancy fees from Edge Therapeutics, honoraria payments, and paid travel accommodations from UCB Pharma and payment for development of educational presentations from the American College of Clinical Pharmacy.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Department of Neurology, Virginia Commonwealth University, P.O. Box 980599, Richmond, VA, 23298, USA

    Ahmad Bayrlee

  2. Department of Neurology, Virginia Commonwealth University, P.O. Box 980599, Richmond, VA, 23298-0599, USA

    Nimalya Ganeshalingam

  3. Department of Pharmacy, Virginia Commonwealth University, 401 North 12th Street, P.O. Box 980042, Richmond, VA, 23298-0042, USA

    Lisa Kurczewski

  4. Department of Pharmacy, Virginia Commonwealth University, 410 N. 12th Street, Room 642, Richmond, VA, 23298-0533, USA

    Gretchen M. Brophy

Authors
  1. Ahmad Bayrlee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nimalya Ganeshalingam
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lisa Kurczewski
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gretchen M. Brophy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gretchen M. Brophy.

Additional information

This article is part of the Topical Collection on Epilepsy

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bayrlee, A., Ganeshalingam, N., Kurczewski, L. et al. Treatment of Super-Refractory Status Epilepticus. Curr Neurol Neurosci Rep 15, 66 (2015). https://doi.org/10.1007/s11910-015-0589-2

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11910-015-0589-2

Keywords

Search

Navigation