1. Generalized Convulsive Status Epilepticus Zohair A. Al Aseri MD, FRCPC EM & CCM Chairman and Associte Professor, DEM College of Medicine King Saud University Consultant Emergency Medicine and Intensivist King Khalid University Hospital Zohair Al Aseri MD,FRCPC EM & CCM

2. Introduction  Generalized convulsive status epilepticus (GCSE) has a high morbidity and mortality.  GCSE is not a specific disease but is a manifestation of a disease. Zohair Al Aseri MD,FRCPC EM & CCM DeLorenzo R.J., Hauser W.A., Towne A.R., et al: A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology 46. (4): 1029-1035.1996;

3.  It is mandatory to look for an underlying cause.  First-line include the use of a benzodiazepine, followed by an infusion of a phenytoin with a possible role for intravenous valproate or phenobarbital.  If these fail go to continuous infusion of midazolam, pentobarbital, or propofol. Zohair Al Aseri MD,FRCPC EM & CCM

4.  Timing for intervention is critical, as prolonged seizure duration is associated with a greater number of complications and a higher likelihood of permanent neuronal damage. Zohair Al Aseri MD,FRCPC EM & CCM

5.  SE constitutes prolonged seizure activity that overwhelms the body’s compensatory mechanisms required to maintain homeostasis.  The Epilepsy Foundation of America’s Working Group on Status Epilepticus used the definition of SE as a seizure lasting 30 minutes or 2 or more seizures without full recovery of consciousness between episodes. Zohair Al Aseri MD,FRCPC EM & CCM Defining Status Epilepticus

6. Zohair Al Aseri MD,FRCPC EM & CCM Causes of status Epilepticus Infectious Meningitis Encephalitis Brain abscess Vascular Ischemic stroke Subarachnoid hemorrhage Subdural hematoma Epidural hematoma Vasculitis Metabolic Hyponatremia Hypoglycemia Hypocalcemia Hypomagnesemia Toxic Cocaine, crack Tricyclics Anticholinergics Isoniazid Alcohol withdrawal Tumors Eclampsia

7.  GCSE mortality rate in adults of 10% to 40%. Zohair Al Aseri MD,FRCPC EM & CCM Knake S., Rosenow F., Vescovi M., et al: Incidence of status epilepticus in adults in Germany: a prospective, population-based study. Epilepsia 42. (6): 714-718.2001; Vignatelli L., Tonon C., D’Alessandro R.: Incidence and short-term prognosis of status epilepticus in adults in Bologna, Italy. Epilepsia 44. (7): 964-968.2003; Morbidity and Mortality

8.  The 10-year mortality after a first episode of SE is 2.8 times greater than the general population. Zohair Al Aseri MD,FRCPC EM & CCM Logroscino G., Hesdorffer D.C., Cascino G.D., et al: Long-term mortality after a first episode of status epilepticus. Neurology 58. (4): 537-541.2002;

9.  Morbidity and mortality increase as the duration of the GCSE episode increases Morbidity related to  cerebral hypoxia  direct neuronal death  systemic effects such as Zohair Al Aseri MD,FRCPC EM & CCM Lowenstein D.H., Alldredge B.K.: Status epilepticus. N Engl J Med 338. (14): 970-976.1998;  Hypoxia  Hypotension  Hypoperfusion  metabolic acidosis  Hyperthermia  Rhabdomyolysis  hypoglycemia

10.  ensure adequate oxygenation and ventilation  secure intravenous access  initiate pharmacologic interventions  bedside serum glucose determination  obtain diagnostic studies once the seizure episode has been terminated. Zohair Al Aseri MD,FRCPC EM & CCM Initial stabilization

11.  If the airway is secured using rapid sequence intubation, paralytic agents will stop the motor activity but not the abnormal neuronal firing associated with GCSE. Zohair Al Aseri MD,FRCPC EM & CCM Initial stabilization

12.  Thiamine, 100 mg is recommended with dextrose boluses in adult patients who appear malnourished or could have concomitant chronic alcohol abuse. Zohair Al Aseri MD,FRCPC EM & CCM Initial stabilization

13.  If a CNS infection is suspected, empiric antibiotic therapy with ceftriaxone, 1 to 2 g IV and vancomycin, 1 g IV should be given pending head computed tomography (CT) and lumbar puncture. Zohair Al Aseri MD,FRCPC EM & CCM Initial stabilization

14.  Serum electrolytes  Calcium  Magnesium  Glucose  Blood urea nitrogen (BUN), creatinine  Liver function testing  Hypomagnesemia should be suspected in seizing patients who are hypokalemic. Zohair Al Aseri MD,FRCPC EM & CCM Laboratory Studies Diagnostic testing

15.  Antiepileptic drug levels for which a laboratory assay is available  A serum toxicologic screen for ethanol, aspirin, acetaminophen, and tricyclic antidepressants. Zohair Al Aseri MD,FRCPC EM & CCM Laboratory Studies Diagnostic testing

16.  If you suspect CNS infection when treating GCSE patients it is most important to begin empiric antibiotic or antiviral therapy, obtain neuroimaging, and defer the lumbar puncture until which time it can be done safely. Zohair Al Aseri MD,FRCPC EM & CCM Lumbar Puncture Diagnostic testing

17.  A noncontrast head CT scan should be considered for all GCSE patients once they have been stabilized. Zohair Al Aseri MD,FRCPC EM & CCM NeuroImaging Diagnostic testing

18.  Not essential in the acute  Should be considered when electrical (subtle) SE or generalized nonconvulsive SE are in the differential diagnosis.  Subtle SE is a consideration whenever a GCSE patient remains comatose after the termination of the generalized seizure, whenever paralytics render the neurologic examination impossible, Zohair Al Aseri MD,FRCPC EM & CCM Electroencephalographic Monitoring Diagnostic testing

19.  48% of patients in one series continued to have electrical seizures (subtle SE) on EEG monitoring during the 24-hour period after treatment for GCSE, despite having no clinical signs of ongoing convulsions. Zohair Al Aseri MD,FRCPC EM & CCM Electroencephalographic Monitoring DeLorenzo R.J., Waterhouse E.J., Towne A.R., et al: Persistent nonconvulsive status epilepticus after the control of convulsive status epilepticus. Epilepsia 39. (8): 833-840.1998;

20.  Few randomized clinical trials that demonstrate superiority of one agent over another. Zohair Al Aseri MD,FRCPC EM & CCM Status epilepticus treatment protocols and guidelines

21.  Studies have shown that a GCSE treatment protocol proactively established can facilitate quality care when the medical emergency actually occurs. Zohair Al Aseri MD,FRCPC EM & CCM Status epilepticus treatment protocols and guidelines Shepherd S.M.: Management of status epilepticus. Emerg Med Clin North Am 12. 941-961.1994; Appleton R., Choonara I., Martland T., et al: The treatment of convulsive status epilepticus in children. The Status Epilepticus Working Party, Members of the Status Epilepticus Working Party. Arch Dis Child 83. (5): 415-419.2000;

22. Intravenous benzodiazepines remain the first drugs of choice for SE.  Diazepam (0.2 mg/kg given at 5 mg/min)  Lorazepam (0.1 mg/kg given at 2-4 mg/min) Zohair Al Aseri MD,FRCPC EM & CCM Benzodiazepines

23. Lorazepam has a smaller volume of distribution, thus the CNS levels remain constant for a longer period of time. Zohair Al Aseri MD,FRCPC EM & CCM Benzodiazepines

24.  A San Francisco study of out-of-hospital treatment of seizures compared the use of lorazepam, diazepam.  Seizure activity terminated in 60% of the lorazepam-treated patients, 43% of diazepam- treated patients, and 21% of patients who received placebo Zohair Al Aseri MD,FRCPC EM & CCM Benzodiazepines Alldredge B.K., Gelb A.M., Isaacs S.M., et al: A comparison of lorazepam, diazepam, and placebo for the treatment of out-of- hospital status epilepticus. N Engl J Med 345. (9): 631-637.2001;

25.  When intravenous access is not available in a patient with SE, alternative routes of drug delivery must be considered.  Both diazepam and lorazepam can be given rectally Zohair Al Aseri MD,FRCPC EM & CCM Benzodiazepines 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 37. (8): 682-688.1995; Chamberlain J.M., Altieri M.A., Futterman C., et al: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Pediatr Emerg Care 13. (2): 92-94.1997; Towne A.R., DeLorenzo R.J.: Use of intramuscular midazolam for status epilepticus. J Emerg Med 17. (2): 323-328.1999;

26.  Phenytoin is very effective--------- but  limitation is the rate at which it can be delivered.  The dose is 20 mg/kg in a nonglucose solution, with a second dose of 10 mg/kg given if needed. Zohair Al Aseri MD,FRCPC EM & CCM Phenytoin Browne T.R.: The pharmacokinetics of agents used to treat status epilepticus. Neurology 40. (5 Suppl 2): 28-32.1990;

27.  The infusion rate is limited to 50 mg/min (25 mg/min in the elderly and patients with cardiovascular disease)  hypotension may occur primarily due to the propylene glycol diluent. Zohair Al Aseri MD,FRCPC EM & CCM Phenytoin

28.  Phenytoin slows the recovery of voltage- activated sodium channels, thus decreasing repetitive action potentials in neurons.  This effect can lead to QT prolongation and arrhythmias.  cardiac monitoring is recommended during the infusion. Zohair Al Aseri MD,FRCPC EM & CCM Phenytoin Manno E.M.: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 78. (4): 508-518.2003;

29.  It is formulated at a pH of approximately 12, thus it is extremely toxic to the vascular walls and should be given through a large vein.  Extravasation can be disastrous for the patient, resulting in extensive necrosis, namely the “purple glove syndrome.” Zohair Al Aseri MD,FRCPC EM & CCM Phenytoin Kilarski D.J., Buchanan C., Von Behren L.: Soft-tissue damage associated with intravenous phenytoin. N Engl J Med 311. (18): 1186-1187.1984; O’Brien T.J., Cascino G.D., So E.L., et al: Incidence and clinical consequence of the purple glove syndrome in patients receiving intravenous phenytoin. Neurology 51. (4): 1034-1039.1998; Burneo J.G., Anandan J.V., Barkley G.L.: A prospective study of the incidence of the purple glove syndrome. Epilepsia 42. (9): 1156-1159.2001;

30.  a prodrug of phenytoin with an added phosphoryl group that makes it water soluble and allows a lower pH (the solution is buffered to pH 8.6–9).  Without the propylene glycol, fosphenytoin can be infused at rates faster than phenytoin, though hypotension can still rarely occur. Zohair Al Aseri MD,FRCPC EM & CCM Fosphenytoin Rosenow F., Arzimanoglou A., Baulac M.: Recent developments in treatment of status epilepticus: a review. Epileptic Disord 4. (Suppl 2): S41-S51.2002;

31.  The lower pH decreases vascular irritation and decreases tissue toxicity, allowing for intramuscular administration.  The conversion half-life is 8 to 15 minutes.  For simplicity, fosphenytoin is measured in phenytoin equivalents (PE) and can be given at up to 150 mg PE/min.  No controlled studies of the use of fosphenytoin in SE have been published. Zohair Al Aseri MD,FRCPC EM & CCM Browne T.R., Kugler A.R., Eldon M.A.: Pharmacology and pharmacokinetics of fosphenytoin. Neurology 46. (6 Suppl 1): S3-S7.1996; Fosphenytoin

32.  Phenytoin cannot be given intramuscularly; fosphenytoin can, with rapid achievement of therapeutic serum drug levels within 1 hour (within 30 minutes in 40% of patients).  Fosphenytoin is prepared as 500 PE/10 mL, that is, an intramuscular loading dose of 1000 PE would be a 20-mL injection. Zohair Al Aseri MD,FRCPC EM & CCM Fischer J.H., Patel T.V., Fischer P.A.: Fosphenytoin: clinical pharmacokinetics and comparative advantages in the acute treatment of seizures. Clin Pharmacokinet 42. (1): 33-58.2003; Fosphenytoin

33.  This volume can be safely given in the buttocks; however, many nursing protocols preclude use of this volume and defaults to physician administration. Zohair Al Aseri MD,FRCPC EM & CCM Fosphenytoin

34.  Potential advantage is its excellent safety profile. Zohair Al Aseri MD,FRCPC EM & CCM Valproate Other First-Line Therapies: Valproate and Phenobarbital

35.  Recommended loading dose of 15 to 20 mg/kg in dextrose-containing solutions at a rate of 3 to 6 mg/kg/min Zohair Al Aseri MD,FRCPC EM & CCM Valproate Other First-Line Therapies: Valproate and Phenobarbital

36.  In small studies on the use of IV valproate for GCSE it has been reported to terminate seizure activity in 42% to 80% of patients. Zohair Al Aseri MD,FRCPC EM & CCM Valproate Other First-Line Therapies: Valproate and Phenobarbital Giroud M., Gras D., Escousse A., et al: Use of injectable valproic acid in status epilepticus. Drug Investigation 5. (3): 154-159.1993;

37.  Further study is needed, but one would expect valproate to be useful in cases where benzodiazepine use is limited by hypotension and where there is a known hypersensitivity to phenytoin, or status resulting from noncompliance in patients on valproic acid. Zohair Al Aseri MD,FRCPC EM & CCM Valproate Other First-Line Therapies: Valproate and Phenobarbital

38.  It works on the ɣ -aminobutyric acid A (GABA A ) receptor, similar to the mechanism of benzodiazepines.  One study demonstrated it to be equal to the combination of diazepam and phenytoin in the control of GCSE. Zohair Al Aseri MD,FRCPC EM & CCM Phenobarbital Other First-Line Therapies: Valproate and Phenobarbital Shaner D.M., McCurdy S.A., Herring M.O., et al: Treatment of status epilepticus: a prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin. Neurology 38. (2): 202-207.1988;

39.  The VA Cooperative Study showed no difference between phenobarbital in controlling SE when compared with lorazepam or the combination of phenytoin plus diazepam. Zohair Al Aseri MD,FRCPC EM & CCM Phenobarbital Other First-Line Therapies: Valproate and Phenobarbital 5 Treiman D.M., Meyers P.D., Walton N.Y., et al: A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med 339. (12): 792-798.1998;

40.  The problem with phenobarbital is its potential to induce profound respiratory depression and hypotension from its vasodilatory and cardiodepressant effects.  It also has a long half-life, which can make complications difficult to manage. Zohair Al Aseri MD,FRCPC EM & CCM Phenobarbital Other First-Line Therapies: Valproate and Phenobarbital Sillanpaa M., Shinnar S.: Status epilepticus in a population-based cohort with childhood-onset epilepsy in Finland. Ann Neurol 52. (3): 303-310.2002;

41.  It must be remembered that the first-line therapy with a benzodiazepine may modulate the motor signs of seizure activity so that it might appear that the seizure has terminated, whereas instead it may be persistent. Zohair Al Aseri MD,FRCPC EM & CCM Therapy for refractory status epilepticus

42.  All patients at this point should have their airway reassessed and intubation considered.  Neurology consultation should be initiated to discuss the indications for emergent monitoring. Zohair Al Aseri MD,FRCPC EM & CCM Therapy for refractory status epilepticus

43.  Current literature supports the use of continuous IV infusion of anesthetic doses of midazolam, a barbiturate, or propofol in the management of refractory SE.  Inhalational anesthetics do not have a well- defined role Zohair Al Aseri MD,FRCPC EM & CCM Therapy for refractory status epilepticus Walker I.A., Slovis C.M.: Lidocaine in the treatment of status epilepticus. Acad Emerg Med 4. (9): 918-922.1997; Pascual J., Sedano M.J., Polo J.M., et al: Intravenous lidocaine for status epilepticus. Epilepsia 29. (5): 584-589.1988; Lampl Y., Eshel Y., Gilad R., et al: Chloral hydrate in intractable status epilepticus. Ann Emerg Med 19. (6): 674-676.1990; Yeoman P., Hutchinson A., Byrne A., et al: Etomidate infusions for the control of refractory status epilepticus. Intensive Care Med 15. (4): 255-259.1989;

44.  Midazolam is often the preferred benzodiazepine for continuous infusion in the management of refractory SE because of its short duration of action and titratability.  A loading dose of 0.2 mg/kg is followed by an infusion of 0.05 to 2.0 mg/kg/h. Zohair Al Aseri MD,FRCPC EM & CCM Midazolam 53 Kumar A., Bleck T.P.: Intravenous midazolam for the treatment of refractory status epilepticus. Crit Care Med 20. (4): 483-488.1992;

45.  A recent systematic review of the literature reported that in 54 patients in refractory SE, intravenous midazolam, though effective in 80% of cases, was less effective than propofol or pentobarbital.  Midazolam produced less hypotension than the other 2 medications. Zohair Al Aseri MD,FRCPC EM & CCM Midazolam Claassen J., Hirsch L.J., Emerson R.G., et al: Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia 43. (2): 146-153.2002;

46.  Propofol is another GABA A agonist along with the benzodiazepines and barbiturates.  There are limited studies of its efficacy in refractory SE, but there is evidence that it provides almost immediate suppression of seizure activity after a bolus infusion. Zohair Al Aseri MD,FRCPC EM & CCM Propofol Brown L.A., Levin G.M.: Role of propofol in refractory status epilepticus. Ann Pharmacother 32. (10): 1053-1059.1998;

47.  It is rapidly metabolized, and studies report rapid recovery from the propofol when the infusion is discontinued.  Propofol is dosed with a bolus of 3 to 5 mg/kg followed by a continuous infusion at 1 to 15 mg/kg/h. Zohair Al Aseri MD,FRCPC EM & CCM Propofol Cannon M.L., Glazier S.S., Bauman L.A.: Metabolic acidosis, rhabdomyolysis, and cardiovascular collapse after prolonged propofol infusion. J Neurosurg 95. (6): 1053-1056.2001; Bray R.J.: Propofol infusion syndrome in children. Paediatr Anaesth 8. (6): 491-499.1998;

48.  The limiting factor in its long-term and high-dose use is the propofol infusion syndrome of hypotension, lipidemia, and metabolic acidosis in both adults and children.  Propofol can cause nonseizure jerking movements and even induce seizures  EEG monitoring should be present. Zohair Al Aseri MD,FRCPC EM & CCM Propofol Cannon M.L., Glazier S.S., Bauman L.A.: Metabolic acidosis, rhabdomyolysis, and cardiovascular collapse after prolonged propofol infusion. J Neurosurg 95. (6): 1053-1056.2001; Bray R.J.: Propofol infusion syndrome in children. Paediatr Anaesth 8. (6): 491-499.1998;

49.  Pentobarbital and thiopental are much shorter acting than phenobarbital.  Thiopental is rapidly metabolized to pentobarbital.  Both agents are highly lipid soluble and will accumulate in fat stores, leading to prolonged elimination. Zohair Al Aseri MD,FRCPC EM & CCM Anesthetic Barbiturates

50.  Thiopental has a less favorable side effect profile than pentobarbital. Zohair Al Aseri MD,FRCPC EM & CCM Anesthetic Barbiturates

51.  It is more lipid soluble and the metabolic pathway can become saturated, leading to an accumulation of thiopental and delays in recovery when stopped.  For these reasons, pentobarbital is preferred when a barbiturate is used to manage refractory status.  Pentobarbital is loaded at 5 to 15 mg/kg over 1 hour. An infusion can be started at 0.5 to 10.0 mg/kg/h. Zohair Al Aseri MD,FRCPC EM & CCM Anesthetic Barbiturates Vignatelli L., Tonon C., D’Alessandro R.: Incidence and short-term prognosis of status epilepticus in adults in Bologna, Italy. Epilepsia 44. (7): 964-968.2003; Manno E.M.: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 78. (4): 508-518.2003;

52.  Although the authors have found less treatment failure with pentobarbital or need to change to other medications compared with the other 2 drugs, there has also been more frequent hypotension with pentobarbital. Zohair Al Aseri MD,FRCPC EM & CCM Algorithm for treating status epilepticus

53.  If diazepam terminates the seizure, it should be followed by phenytoin or fosphenytoin (20 mg/kg).  If a benzodiazepines does not terminate seizure activity, phenytoin or fosphenytoin, 20 mg/kg should be administered.  Intravenous valproic acid might be considered if the patient is known to have been controlled with valproic acid in the past. Zohair Al Aseri MD,FRCPC EM & CCM Algorithm for treating status epilepticus

54.  If seizure activity continues, the patient is considered to be in refractory SE.  Management choices include midazolam, propofol, and pentobarbital. Zohair Al Aseri MD,FRCPC EM & CCM Algorithm for treating status epilepticus

55.  SE continues to have a high morbidity and mortality  GCSE patients are most effectively treated when a protocol is followed.  Clinical data and published guidelines and protocols support the initial use of a benzodiazepine followed by a phenytoin. Zohair Al Aseri MD,FRCPC EM & CCM Summary

56.  In special cases there might be an indication for IV phenobarbital or valproate.  EEG should be performed when a patient remains comatose, is paralyzed, or is being treated with a continuous-infusion antiepileptic drug Zohair Al Aseri MD,FRCPC EM & CCM Summary

57. Zohair Al Aseri MD,FRCPC EM & CCM Key concepts The formal definition of SE using a 30-minute time frame is not an operational definition; seizure treatment should not be delayed more that 5 to 10 minutes. Early seizure management includes checking blood sugar, ensuring oxygenation, and suspecting infection or drug intoxication. First-line therapy for SE includes lorazepam IV (0.1 mg/kg) or diazepam (0.2 mg/kg); if diazepam is used, it should be immediately followed by a loading dose of phenytoin or fosphenytoin.

58. Zohair Al Aseri MD,FRCPC EM & CCM Key concepts Refractory SE is diagnosed after failure of first-line therapy and treatment should be protocol driven: Choice of medication is dependent on availability, ED capability, and hemodynamic status of the patient. Recommended treatments for refractory SE include: midazolam infusion (0.2 mg/kg bolus then 0.05–2.0 mg/kg/h); pentobarbital (3–15 mg/kg slow push [with hemodynamic monitoring] followed by infusion 0.5–10.0 mg/kg/h; or propofol 3–5 mg/kg bolus, infusion at 1–15 mg/kg/h). An EEG should be considered in patients who have been in convulsive SE to ensure that all seizure activity has ceased.

59. Zohair Al Aseri MD,FRCPC EM & CCM

60.  status epilepticus (SE) is the second most frequent neurological emergency (acute stroke being the first) with a risk of major morbidity or mortality. Zohair Al Aseri MD,FRCPC EM & CCM Introduction Lowenstein DH, Alldredge BK: Status epilepticus. N Engl J Med 338. 970-976.1998;

61.  Irrespective of the timeframe, SE that persists despite adequate administration of benzodiazepines and at least one antiepileptic drug is labelled refractory SE (RSE). Zohair Al Aseri MD,FRCPC EM & CCM Introduction Holtkamp M: Treatment strategies for refractory status epilepticus. Curr Opin Crit Care 17. 94-100.2011; Novy J, Logroscino G, Rossetti AO: Refractory status epilepticus: a prospective observational study. Epilepsia 51. 251- 256.2010;

62.  The short-term fatality rates for RSE have been estimated to be between 16% and 39%  mortality after RSE is about three times higher than for non-refractory SE. Zohair Al Aseri MD,FRCPC EM & CCM Mortality and Morbidity Novy J, Logroscino G, Rossetti AO: Refractory status epilepticus: a prospective observational study. Epilepsia 51. 251- 256.2010; Holtkamp M, Othman J, Buchheim K, Meierkord H: Predictors and prognosis of refractory status epilepticus treated in a neurological intensive care unit. J Neurol Neurosurg Psychiatry 76. 534-539.2005; Mayer SA, Claassen J, Lokin J, Mendelsohn F, Dennis LJ, Fitzsimmons BF: Refractory status epilepticus: frequency, risk factors, and impact on outcome. Arch Neurol 59. 205-210.2002; Rossetti AO, Logroscino G, Bromfield EB: Refractory status epilepticus: effect of treatment aggressiveness on prognosis. Arch Neurol 62. 1698-1702.2005;

63.  The risk of epilepsy after an incident symptomatic SE event, especially if refractory, is three times higher than after a first symptomatic seizure. Zohair Al Aseri MD,FRCPC EM & CCM Mortality and Morbidity Holtkamp M, Othman J, Buchheim K, Meierkord H: Predictors and prognosis of refractory status epilepticus treated in a neurological intensive care unit. J Neurol Neurosurg Psychiatry 76. 534-539.2005; Hesdorffer DC, Logroscino G, Cascino G, Annegers JF, Hauser WA: Risk of unprovoked seizure after acute symptomatic seizure: effect of status epilepticus. Ann Neurol 44. 908-912.1998;

64.  Data from the Veteran Affairs Cooperative Study showed that SE treatment becomes less effective as the episode becomes more protracted; subtle SE (or non-convulsive SE with coma), a form usually indicative of a longer duration, was controlled by the first medication in 15% of patients compared with 55% in overt, convulsive SE. Furthermore, a second or third agent was effective in less than 10% of patients in either condition. Zohair Al Aseri MD,FRCPC EM & CCM Rationale for early treatment 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 339. 792-798.1998; Treiman DM, Walton NY, Collins JF, Point P: Treatment of status epilepticus if first drug fails. Epilepsia 40. (suppl 7): 243.1999;

65.  One especially challenging group is those with psychogenic non-epileptic seizures (PNES). By contrast with seizures, PNES episodes are suggestion-prone, generally not stereotyped, and can occur with or without subjective consciousness impairment. During the ictus, the eyes are often closed, ventilatory drive is maintained, and the episode can present as uncoordinated, discontinuous, and fluctuating in intensity. Zohair Al Aseri MD,FRCPC EM & CCM Basic principles of SE treatment LaFrance, Jr, JrWC: Psychogenic nonepileptic seizures. Curr Opin Neurol 21. 195-201.2008;

66.  Laboratory studies can be helpful in this setting; by contrast with patients with SE, patients with PNES do not have raised serum lactate, prolactin, or creatine kinase. Zohair Al Aseri MD,FRCPC EM & CCM Basic principles of SE treatment

67.  Benzodiazepines are the only evidence-based treatment, as shown in three trials and a Cochrane review. Zohair Al Aseri MD,FRCPC EM & CCM Basic principles of SE treatment 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 339. 792-798.1998; 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 345. 631-637.2001; Leppik IE, Derivan AT, Homan RW, Walker J, Ramsay RE, Patrick B: Double-blind study of lorazepam and diazepam in status epilepticus. JAMA 249. 1452-1454.1983; Prasad K, Al-Roomi K, Krishnan PR, Sequeira R: Anticonvulsant therapy for status epilepticus. Cochrane Database Syst Rev 4. 2005; CD003723.

68.  However, only one trial has been done to compare them with other medications; lorazepam had statistically better results than phenytoin (but not phenobarbital or diazepam combined with phenytoin) Zohair Al Aseri MD,FRCPC EM & CCM Basic principles of SE treatment 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 339. 792-798.1998;

69.  Use of an accepted and available protocol probably contributes to an improved prognosis. Zohair Al Aseri MD,FRCPC EM & CCM Basic principles of SE treatment Aranda A, Foucart G, Ducassé JL, Grolleau S, McGonigal A, Valton L: Generalized convulsive status epilepticus management in adults: a cohort study with evaluation of professional practice. Epilepsia 51. 2159-2167.2010;

70.  Thus, to proceed straight to third-line, coma- inducing treatment seems reasonable if the second-line treatment with intravenous antiepileptic agents (which take at least 20–30 min to be effective) has failed in patients with generalised convulsive SE Zohair Al Aseri MD,FRCPC EM & CCM Basic principles of SE treatment Lowenstein DH, Alldredge BK: Status epilepticus. N Engl J Med 338. 970-976.1998; Holtkamp M: The anaesthetic and intensive care of status epilepticus. Curr Opin Neurol 20. 188-193.2007;

71.  Midazolam is a benzodiazepine that is already being used as a first-line treatment. Its half-life, which is short after a single bolus, increases to 6–50 h after prolonged administration. However, tachyphylaxis often develops within 24–48 h so the perfusion dose needs to be constantly increased to maintain a constant pharmacological action. Zohair Al Aseri MD,FRCPC EM & CCM Choice of anaesthetic agents Claassen J, Hirsch LJ, Emerson RG, Bates JE, Thompson TB, Mayer SA: Continuous EEG monitoring and midazolam infusion for refractory nonconvulsive status epilepticus. Neurology 57. 1036-1042.2001;

72.  Midazolam is therefore mostly used initially, or in combination with propofol.  availability of an antidote (flumazenil) is a theoretical advantage over the other two groups. Zohair Al Aseri MD,FRCPC EM & CCM Choice of anaesthetic agents

73. Zohair Al Aseri MD,FRCPC EM & CCM Loading dose Maintenan ce dose Comments Midazolam0·2 mg/kg0·2–0·6 mg/kg per h Increasing doses needed with time Propofol2 mg/kg2–5 mg/kg per h, in some cases can be raised to 10 mg/kg per h Attention to PRIS, especially in young children; combine with benzodiazepines BarbituratesThiopental: 1–2 mg/kg Pentobarbital: 5 mg/kg Thiopental: 1–5 mg/kg per h Pentobarbital: 1–5 mg/kg per h Both need loading with repetitive boluses and have long wash-out times Anaesthetic agents for refractory status epilepticus

74.  Despite the increasing elimination half-life of midazolam after protracted infusion, this compound rarely induces a complete suppression of cerebral activity for several days, whereas barbiturates do.  Thus, despite absence of strong evidence (and in view of the availability of the pharmacological antidote flumazenil), midazolam seems to be the safest compound in this setting, but often needs to be combined with propofol to obtain seizure control. Zohair Al Aseri MD,FRCPC EM & CCM Choice of anaesthetic agents

75.  Propofol has the advantage of a short half-life, which allows for a rapid clinical assessment on weaning.  Risk of propofol infusion syndrome needs very careful metabolic monitoring, and the drug should not be used in young children.  Barbiturates should probably be reserved for RSE cases refractory to the other anaesthetics because of their long elimination time. Zohair Al Aseri MD,FRCPC EM & CCM Choice of anaesthetic agents

76.  Inhalational anaesthetics, which act, in part, on GABA A receptors, might be effective in aborting RSE, but the effects seem to be transient, and their administration requires the use of appropriate gas recovery systems (not typically found outside the operating theatre). Zohair Al Aseri MD,FRCPC EM & CCM Other pharmacological approaches

77.  Two small case series describe the use of isoflurane with an end-tidal concentration of 1·2–5% for up to 55 days.  Several patients needed vasopressors, paralytic ileus occurred in some, and the high fatality rates (43–67%) were indicative of the difficult long-term control and the effect of the underlying disease. Zohair Al Aseri MD,FRCPC EM & CCM Other pharmacological approaches Mirsattari SM, Sharpe MD, Young GB: Treatment of refractory status epilepticus with inhalational anesthetic agents isoflurane and desflurane. Arch Neurol 61. 1254-1259.2004; Kofke WA, Young RS, Davis P, et al: Isoflurane for refractory status epilepticus: a clinical series. Anesthesiology 71. 653- 659.1989;

78.  The intravenous anaesthetic agent ketamine has been tried in RSE, because of its properties as an NMDA receptor antagonist and favourable hemodynamic profiles. Zohair Al Aseri MD,FRCPC EM & CCM Other pharmacological approaches

79.  Only a few reports describe the use of ketamine in this setting, with doses of up to 7·5 mg/kg per h for several days, and the outcomes have been mixed Zohair Al Aseri MD,FRCPC EM & CCM Other pharmacological approaches Sheth RD, Gidal BE: Refractory status epilepticus: response to ketamine. Neurology 51. 1765-1766.1998; Quigg M, Nathan B, Smith T, Kapur J: Effects of ketamine treatment for refractory status epilepticus. Epilepsia 43. (suppl 1): 282.2002; Prüss H, Holtkamp M: Ketamine successfully terminates malignant status epilepticus. Epilepsy Res 82. 219-222.2008; Hsieh CY, Sung PS, Tsai JJ, Huang CW: Terminating prolonged refractory status epilepticus using ketamine. Clin Neuropharmacol 33. 165-167.2010;

80.  ketamine should always be combined with GABAergic drugs because of a possible synergistic effect. Zohair Al Aseri MD,FRCPC EM & CCM Other pharmacological approaches Martin BS, Kapur J: A combination of ketamine and diazepam synergistically controls refractory status epilepticus induced by cholinergic stimulation. Epilepsia 49. 248-255.2008;

81. Zohair Al Aseri MD,FRCPC EM & CCM Other pharmacological and nutritional treatments for refractory status epilepticus AdvantagesDisadvantages/comments IsofluraneFast acting Possible neurotoxicity Needs closed system, ie, gas recovery KetamineNMDA receptor antagonist Possible neurotoxicity; combine with benzodiazepines Lidocaine Can rescue phenytoin- resistant refractory status epilepticus Cardiac monitoring needed; possible seizure induction VerapamilSafe Does not have antiepileptic drug action; might improve availability of antiepileptic drugs in CNS Magnesium Can enhance NMDA receptor blockade Possible induction of neuromuscular blockade Ketogenic dietSafe Need skilled dietician; check for ketonuria Immunological treatmentsCan act causally Formal exclusion of infection needed before treatment

82.  Topiramate  Pregabalin  Levetiracetam  Lacosamide  levetiracetam and lacosamide are increasingly prescribed as second-line drugs) Zohair Al Aseri MD,FRCPC EM & CCM Other pharmacological approaches Towne AR, Garnett LK, Waterhouse EJ, Morton LD, DeLorenzo RJ: The use of topiramate in refractory status epilepticus. Neurology 60. 332- 334.2003; Stojanova V, Rossetti AO: Oral topiramate as an add-on treatment for refractory status epilepticus. Acta Neurol Scand. 2011;published online June 29. Novy J, Rossetti AO: Oral pregabalin as an add-on treatment for status epilepticus. Epilepsia 51. 2207-2210.2010; Knake S, Gruener J, Hattemer K, et al: Intravenous levetiracetam in the treatment of benzodiazepine refractory status epilepticus. J Neurol Neurosurg Psychiatry 79. 588-589.2008; Kellinghaus C, Berning S, Immisch I, et al: Intravenous lacosamide for treatment of status epilepticus. Acta Neurol Scand 123. 137-141.2011;

83.  The diet can be administered through a nasogastric tube and should induce ketonuria; this approach can show its effect within a few days. Zohair Al Aseri MD,FRCPC EM & CCM Other pharmacological approaches Holtkamp M, Othman J, Buchheim K, Masuhr F, Schielke E, Meierkord H: A malignant variant of status epilepticus. Arch Neurol 62. 1428-1431.2005; Glaser CA, Gilliam S, Honarmand S, Tureen JH, Lowenstein DH, Anderson LJ, et al: Refractory status epilepticus in suspect encephalitis. Neurocrit Care 9. 74-82.2008; Johnson N, Henry C, Fessler AJ, Dalmau J: Anti-NMDA receptor encephalitis causing prolonged nonconvulsive status epilepticus. Neurology 75. 1480-1482.2010; Maeder-Ingvar M, Prior JO, Irani SR, Rey V, Vincent A, Rossetti AO: FDG-PET hyperactivity in basal ganglia correlating with clinical course in anti-NDMA-R antibodies encephalitis. J Neurol Neurosurg Psychiatry 82. 235-236.2010;

84.  Refractory status epilepticus (RSE) is defined as status epilepticus that continues despite treatment with benzodiazepines and one antiepileptic drug. Zohair Al Aseri MD,FRCPC EM & CCM Summary

85. Zohair Al Aseri MD,FRCPC EM & CCM

86. THANK YOU Zohair Al Aseri MD,FRCPC EM & CCM