CNS Drugs

, Volume 19, Issue 9, pp 759–768 | Cite as

Refractory Generalised Convulsive Status Epilepticus

A Guide to Treatment
  • Reetta KälviäinenEmail author
  • Kai Eriksson
  • Ilkka Parviainen
Therapy in Practice


The patient with status epilepticus has continuous or rapidly repeating seizures. Generalised convulsive status epilepticus (GCSE) is the most common form of the disorder and is a life-threatening condition that requires prompt medical management. Status epilepticus that does not respond to first-line benzodiazepines (lorazepam or diazepam) or to second-line antiepileptic drugs (phenytoin/fosphenytoin, phenobarbital or valproate) is usually considered refractory and requires more aggressive treatment.

The optimal treatment of refractory GCSE has not been defined, but patients should be treated in an intensive care unit, as artificial ventilation and haemodynamic support are required. Invasive haemodynamic monitoring is often necessary and EEG monitoring is essential.

The drug treatment of refractory GCSE involves general anaesthesia with continuous intravenous anaesthetics given in doses that abolish all clinical and electrographic epileptic activity, often requiring sedation to the point of burst suppression on the EEG. Barbiturate anaesthetics, pentobarbital in the US and thiopental sodium in Europe and Australia, are the most frequently used agents and are highly effective for refractory GCSE both in children and adults. Indeed, they remain the only way to stop seizure activity with certainty in severely refractory cases. Other options are midazolam for adults and children and propofol for adults only.

Regardless of the drug selected, intravenous fluids and vasopressors are usually required to treat hypotension. Once seizures have been controlled for 12–24 hours, continuous intravenous therapy should be gradually tapered off if the drug being administered is midazolam or propofol. Gradual tapering is probably not necessary with pentobarbital or thiopental sodium. Continuous EEG monitoring is required during high-dose treatment and while therapy is gradually withdrawn. During withdrawal of anaesthetic therapy, intravenous phenytoin/fosphenytoin or valproate should be continued (these agents having been administered during earlier phases of GCSE) to ensure an adequate baseline of antiepileptic medication so as to prevent the recurrence of status epilepticus. If additional medication is needed, the most appropriate antiepileptic drugs are gabapentin for focal seizures and levetiracetam and topiramate for all seizure types, as these drugs can be started at high doses with a low risk of idiosyncratic reactions.

Even with current best practice, mortality in patients who experience refractory GCSE is about 50% and only the minority return to their premorbid functional baseline. Therefore, new treatment options are urgently needed. The ideal new drug for refractory GCSE would be one that has the ability to stop seizures more effectively and safely than current drugs, and that has neuroprotective properties to prevent the brain damage and neurological morbidity caused by GCSE.


Valproate Status Epilepticus Fosphenytoin Burst Suppression Rectal Diazepam 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The preparation of this manuscript was supported by internal departmental funds from the Department of Neurology, Kuopio University Hospital and Pediatric Research Centre, University of Tampere, Finland. The authors have no conflicts of interest that are directly relevant to the content of this review.


  1. 1.
    Theodore WH, Porter RJ, Albert P. The secondarily generalized tonic-clonic seizure: a videotape analysis. Neurology 1994; 44: 1403–7PubMedCrossRefGoogle Scholar
  2. 2.
    Shinnar S, Berg AT, Moshe SL, et al. How long do new-onset seizures in children last? Ann Neurol 2001; 49: 659–64PubMedCrossRefGoogle Scholar
  3. 3.
    Metsäranta P, Koivikko M, Peltola J, et al. Outcome after prolonged convulsive seizures in 186 children: low morbidity, no mortality. Dev Med Child Neurol 2004; 46(1): 4–8PubMedCrossRefGoogle Scholar
  4. 4.
    Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med 1998; 338(14): 970–6PubMedCrossRefGoogle Scholar
  5. 5.
    DeLorenzo RJ, Garnett LK, Towne AR, et al. Comparison of status epilepticus with prolonged seizure episodes lasting from 10 to 29 minutes. Epilepsia 1999; 40(20): 164–9PubMedCrossRefGoogle Scholar
  6. 6.
    Towne AR, Pellock JM, Ko D, et al. Determinants of mortality in status epilepticus. Epilepsia 1994; 35(1): 27–34PubMedCrossRefGoogle Scholar
  7. 7.
    Logroscino G, Hesdorffer DC, Cascino GD, et al. Long-term mortality after a first episode of status epilepticus. Neurology 2002; 58: 537–41PubMedCrossRefGoogle Scholar
  8. 8.
    Mayer SA, Claassen J, Lokin J, et al. Refractory status epilepticus: frequency, risk factors, and impact on outcome. Arch Neurol 2002; 59(2): 205–10PubMedCrossRefGoogle Scholar
  9. 9.
    Sahin M, Menache C, Holmes G, et al. Prolonged treatment for acute symptomatic refrectory status epilepticus: outcome in children. Neurology 2003; 61: 398–401PubMedCrossRefGoogle Scholar
  10. 10.
    Shorvon SD. Status epilepticus: its clinical features and treatment in children and adults. Cambridge: Cambridge University Press, 1994CrossRefGoogle Scholar
  11. 11.
    Knake S, Rosenow F, Vescovi M, et al., and the Status Epilepticus Group Hessen (SESGH). Incidence of status epilepticus in adults in Germany: a prospective, population-based study. Epilepsia 2001; 42(6): 714–8PubMedCrossRefGoogle Scholar
  12. 12.
    Eriksson K, Koivikko M. Status epilepticus in children; etiology, treatment and outcome. Dev Med Child Neurol 1997; 39: 652–8PubMedCrossRefGoogle Scholar
  13. 13.
    DeLorenzo RJ, Hauser WA, Towne AR, et al. A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology 1996; 46: 1029–35PubMedCrossRefGoogle Scholar
  14. 14.
    Maytal J, Shinnar S, Solomon S, et al. Low morbidity and mortality of status epilepticus in children. Pediatrics 1989; 3: 323–31Google Scholar
  15. 15.
    Claassen J, Hirsch LJ, Emerson RG, et al. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia 2002; 43: 146–53PubMedCrossRefGoogle Scholar
  16. 16.
    Lowenstein DH, Aminoff MJ. Clinical and EEG features of status epilepticus in comatose patients. Neurology 1992; 42: 100–4PubMedCrossRefGoogle Scholar
  17. 17.
    Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med 1998; 339: 792–8Google Scholar
  18. 18.
    Alldredge BK. General principles: treatment of status epilepticus. In: Levy RH, Mattson RH, Meldrum BS, Perucca E, editors. Antiepileptic drugs. 5th ed. Philadelphia (PA): Lippincott Williams and Wilkins, 2002: 159–68Google Scholar
  19. 19.
    Lowenstein DH, Alldredge BK. Status epilepticus at an urban public hospital in the 1980s. Neurology 1993; 43: 483–8PubMedCrossRefGoogle Scholar
  20. 20.
    Cereghino JJ, Cloyd JC, Kuzniecky RI, et al. Rectal diazepam gel for treatment of acute repetitive seizures in adults. Arch Neurol 2002; 59: 1915–20PubMedCrossRefGoogle Scholar
  21. 21.
    Kriel RL, Cloyd JC, Pellock JM, et al., and the North American Diastat Study Group. Rectal diazepam gel for treatment of acute repetitive seizures. Pediatr Neurol 1999; 20: 282–8PubMedCrossRefGoogle Scholar
  22. 22.
    McIntyre J, Robertson S, Norris E, et al. Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial. Lancet 2005; 366: 205–10PubMedCrossRefGoogle Scholar
  23. 23.
    Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam, diazepam and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 2001; 345: 631–7PubMedCrossRefGoogle Scholar
  24. 24.
    Leppik IE, Derivan AT, Homan RW, et al. Double-blind study of lorazepam and diazepam in status epilepticus. JAMA 1983; 249: 1452–4PubMedCrossRefGoogle Scholar
  25. 25.
    Appleton R, Sweeney A, Choonara I, et al. Lorazepam versus Diazepam in the acute treatment of epileptic seizures and status epilepticus. Dev Med Child Neurol 1995; 37: 682–8PubMedCrossRefGoogle Scholar
  26. 26.
    Hirsch LJ, Ciaassen J. The current state of treatment of status epilepticus. Curr Neurol Neurosci Rep 2002; 2: 345–56PubMedCrossRefGoogle Scholar
  27. 27.
    Cranford RE, Leppik IE, Patrick B, et al. Intravenous phenytoin: clinical and pharmacokinetic aspects. Neurology 1978; 28: 874–80PubMedCrossRefGoogle Scholar
  28. 28.
    Boucher BA, Feler CA, Dean JC, et al. The safety, tolerability and pharmacokinetics of fosphenytoin after intramuscular and intravenous administration in neurosurgery patients. Pharmacotherapy 1996; 16(4): 638–45PubMedGoogle Scholar
  29. 29.
    Swadron SP, Rudis MI, Azimian K, et al. A comparison of phenytoin-loading techniques in the emergency department. Acad Emerg Med 2004; 11(3): 244–52PubMedCrossRefGoogle Scholar
  30. 30.
    Baulac M. Phenobarbital and other barbiturates: clinical efficacy and use in epilepsy In: Levy RH, Mattson RH, Meldrum BS, Perucca E, editors. Antiepileptic drugs. 5th ed. Philadelphia (PA): Lippincott Williams and Wilkins, 2002: 515–21Google Scholar
  31. 31.
    Shaner DM, McCurdy SA, Herring MO, et al. Treatment of status epilepticus: a prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin. Neurology 1988; 38: 202–7PubMedCrossRefGoogle Scholar
  32. 32.
    Lowenstein DH. Treatment options for status epilepticus. Curr Opin Pharmacol 2003; 3: 6–11PubMedCrossRefGoogle Scholar
  33. 33.
    Kokwaro G, Ogutu S, Muchohi S, et al. Pharmacokinetics and clinical effect of phenobarbital in children with severe falciparum malaria and convulsions. J Clin Pharmacol 2003; 56: 453–7Google Scholar
  34. 34.
    Hodges BM, Mazur JE. Intravenous valproate in status epilepticus. Ann Pharmacother 2001; 35: 1465–70PubMedCrossRefGoogle Scholar
  35. 35.
    White JR, Santos CS. Intravenous valproate associated with significant hypotension in the treatment of status epilepticus. J Child Neurol 1999; 14: 822–3PubMedCrossRefGoogle Scholar
  36. 36.
    Ramsay RE, Cantrell D, Collins SD, et al. and The Depacon Rapid Infusion Study Group. Safety and tolerance of rapidly infused Depacon: a randomized trial in subjects with epilepsy. Epilepsy Res 2003; 52: 189–201Google Scholar
  37. 37.
    Yu K-T, Mills S, Thompson N, et al. Safety and efficacy of intravenous valproate in pediatric status epilepticus and acute repetitive seizures. Epilepsia 2003; 44(5): 724–6PubMedCrossRefGoogle Scholar
  38. 38.
    Limdi NA, Faught E. The safety of rapid valproic acid infusion. Epilepsia 2000; 41(10): 1342–5PubMedCrossRefGoogle Scholar
  39. 39.
    Claassen J, Hirsch LJ, Mayer SA. Treatment of status epilepticus: a survey of neurologists. J Neurol Sci 2003; 211(1–2): 37–41PubMedCrossRefGoogle Scholar
  40. 40.
    DeLorenzo RJ, Waterhouse EJ, Towne AR, et al. Persistent nonconvulsive status epilepticus after the control of convulsive status epilepticus. Epilepsia 1998; 39: 833–40PubMedCrossRefGoogle Scholar
  41. 41.
    Shorvon SD. The management of status epilepticus. J Neurol Neurosurg Psychiatry 2001; 70Suppl. II: ii22–7PubMedGoogle Scholar
  42. 42.
    Shorvon S. The use of clobazam, midazolam and nitrazepam in epilepsy. Epilepsia 1998; 38Suppl. 1: S15–23CrossRefGoogle Scholar
  43. 43.
    McBurney JW, Teiken PJ, Moon MR. Propofol for treating status epilepticus. J Epilepsy 1994; 7: 21–2CrossRefGoogle Scholar
  44. 44.
    Cremer OL, Moons KGM, Bouman EAC, et al. Long-term propofol infusion and cardiac failure in adult head-injured patients. Lancet 2001; 357(9250): 117–8PubMedCrossRefGoogle Scholar
  45. 45.
    Walder B, Tramer MR, Seeck M. Seizure-like phenomena and propofol. Neurology 2002; 58: 1327–32PubMedCrossRefGoogle Scholar
  46. 46.
    Eriksson K, Baer M, Kilpinen P, et al. Effects of long barbiturate anaesthesia on eight children with severe epilepsy. Neuropediatrics 1993; 24: 281–5PubMedCrossRefGoogle Scholar
  47. 47.
    Parviainen I, Uusaro A, Kälviäinen R, et al. High-dose thiopental in the treatment of refractory status epilepticus in intensive care unit. Neurology 2002; 59: 1249–51PubMedCrossRefGoogle Scholar
  48. 48.
    Granata T, Fusco L, Gobbi G, et al. Experience with immunomodulatory treatments in Rasmussen’s encephalitis. Neurology 2003; 61: 1807–10PubMedCrossRefGoogle Scholar
  49. 49.
    Ma X, Liporace J, O’Connor MJ, et al. Neurosurgical treatment of medically intractable status epilepticus. Epilepsy Res 2001; 46(1): 33–8PubMedCrossRefGoogle Scholar
  50. 50.
    Deckers CL, Knoester PD, de Haan GJ, et al. Selection criteria for the use of the newer antiepileptic drugs. CNS Drugs 2003; 17(6): 405–21PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  • Reetta Kälviäinen
    • 1
    Email author
  • Kai Eriksson
    • 2
    • 3
  • Ilkka Parviainen
    • 4
  1. 1.Department of NeurologyKuopio University Hospital and University of KuopioKuopioFinland
  2. 2.Pedatric Research Centre, Medical SchoolUniversity of TampereTampereFinland
  3. 3.Department of Pediatric NeurologyTampere University HospitalTampereFinland
  4. 4.Department of Anesthesiology and Intensive CareKuopio University HospitalKuopioFinland

Personalised recommendations