Transcript Generalized Convulsive Status Epilepticus

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
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.
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;
Zohair Al Aseri MD,FRCPC EM & CCM
 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
 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
Defining Status Epilepticus
 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
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
Zohair Al Aseri MD,FRCPC EM & CCM
Morbidity and Mortality
 GCSE mortality rate in adults of 10% to 40%.
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;
Zohair Al Aseri MD,FRCPC EM & CCM
 The 10-year mortality after a first episode of
SE is 2.8 times greater than the general
population.
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;
Zohair Al Aseri MD,FRCPC EM & CCM
 Morbidity and mortality increase
as the duration of the GCSE episode increases
Morbidity related to
 cerebral hypoxia
 direct neuronal death
 systemic effects such as
 Hypoxia
 Hypotension
 Hypoperfusion
 metabolic acidosis
 Hyperthermia
 Rhabdomyolysis
 hypoglycemia
Lowenstein D.H., Alldredge B.K.: Status epilepticus. N Engl J Med 338. (14): 970-976.1998;
Zohair Al Aseri MD,FRCPC EM & CCM
Initial stabilization
 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
 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
 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
 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
Diagnostic testing
Laboratory Studies
 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
Diagnostic testing
Laboratory Studies
 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
Diagnostic testing
Lumbar Puncture
 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
Diagnostic testing
NeuroImaging
 A noncontrast head CT scan should be
considered for all GCSE patients once they have
been stabilized.
Zohair Al Aseri MD,FRCPC EM & CCM
Diagnostic testing
Electroencephalographic Monitoring
 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
 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.
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;
Zohair Al Aseri MD,FRCPC EM & CCM
Status epilepticus treatment protocols
and guidelines
 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
 Studies have shown that a GCSE treatment
protocol proactively established can facilitate
quality care when the medical emergency
actually occurs.
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;
Zohair Al Aseri MD,FRCPC EM & CCM
Benzodiazepines
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
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
 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 diazepamtreated patients, and 21% of patients who
received placebo
Alldredge B.K., Gelb A.M., Isaacs S.M., et al: A comparison of lorazepam, diazepam, and placebo for the treatment of out-ofhospital status epilepticus. N Engl J Med 345. (9): 631-637.2001;
Zohair Al Aseri MD,FRCPC EM & CCM
Benzodiazepines
 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
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;
Zohair Al Aseri MD,FRCPC EM & CCM
Phenytoin
 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.
Browne T.R.: The pharmacokinetics of agents used to treat status epilepticus. Neurology 40. (5 Suppl 2): 28-32.1990;
Zohair Al Aseri MD,FRCPC EM & CCM
Phenytoin
 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
 Phenytoin slows the recovery of voltageactivated 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.
Manno E.M.: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 78. (4): 508-518.2003;
Zohair Al Aseri MD,FRCPC EM & CCM
Phenytoin
 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.”
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;
Zohair Al Aseri MD,FRCPC EM & CCM
Fosphenytoin
 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.
Rosenow F., Arzimanoglou A., Baulac M.: Recent developments in treatment of status epilepticus: a review. Epileptic
Disord 4. (Suppl 2): S41-S51.2002;
Zohair Al Aseri MD,FRCPC EM & CCM
Fosphenytoin
 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
fosphenytoin in SE have been published.
of
Browne T.R., Kugler A.R., Eldon M.A.: Pharmacology and pharmacokinetics of fosphenytoin. Neurology 46. (6 Suppl 1):
S3-S7.1996;
Zohair Al Aseri MD,FRCPC EM & CCM
Fosphenytoin
 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.
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;
Zohair Al Aseri MD,FRCPC EM & CCM
Fosphenytoin
 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
Other First-Line Therapies:
Valproate and Phenobarbital
Valproate
 Potential advantage is its excellent safety
profile.
Zohair Al Aseri MD,FRCPC EM & CCM
Other First-Line Therapies:
Valproate and Phenobarbital
Valproate
 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
Other First-Line Therapies:
Valproate and Phenobarbital
Valproate
 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.
Giroud M., Gras D., Escousse A., et al: Use of injectable valproic acid in status epilepticus. Drug Investigation 5. (3):
154-159.1993;
Zohair Al Aseri MD,FRCPC EM & CCM
Other First-Line Therapies:
Valproate and Phenobarbital
Valproate
 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
Other First-Line Therapies:
Valproate and Phenobarbital
Phenobarbital
 It works on the ɣ-aminobutyric acid A (GABAA)
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.
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;
Zohair Al Aseri MD,FRCPC EM & CCM
Other First-Line Therapies:
Valproate and Phenobarbital
Phenobarbital
 The VA Cooperative Study showed no difference
between phenobarbital in controlling SE when
compared with lorazepam or the combination of
phenytoin plus diazepam.
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;
Zohair Al Aseri MD,FRCPC EM & CCM
Other First-Line Therapies:
Valproate and Phenobarbital
Phenobarbital
 The problem with phenobarbital is its potential to
induce profound respiratory depression and
hypotension
from
its
cardiodepressant effects.
vasodilatory
and
 It also has a long half-life, which can make
complications difficult to manage.
Sillanpaa M., Shinnar S.: Status epilepticus in a population-based cohort with childhood-onset epilepsy in Finland. Ann
Neurol 52. (3): 303-310.2002;
Zohair Al Aseri MD,FRCPC EM & CCM
Therapy for refractory status epilepticus
 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
 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
 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 welldefined role
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;
Zohair Al Aseri MD,FRCPC EM & CCM
Midazolam
 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.
53 Kumar A., Bleck T.P.: Intravenous midazolam for the treatment of refractory status epilepticus. Crit Care Med 20. (4):
483-488.1992;
Zohair Al Aseri MD,FRCPC EM & CCM
Midazolam
 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.
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;
Zohair Al Aseri MD,FRCPC EM & CCM
Propofol
 Propofol is another GABAA 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.
Brown L.A., Levin G.M.: Role of propofol in refractory status epilepticus. Ann Pharmacother 32. (10): 1053-1059.1998;
Zohair Al Aseri MD,FRCPC EM & CCM
Propofol
 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.
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;
Zohair Al Aseri MD,FRCPC EM & CCM
Propofol
 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
movements and even induce seizures
jerking
 EEG monitoring should be present.
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;
Zohair Al Aseri MD,FRCPC EM & CCM
Anesthetic Barbiturates
 Pentobarbital and thiopental are much shorter
acting than phenobarbital.
 Thiopental
is
pentobarbital.
rapidly
metabolized
to
 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
 Thiopental has a less favorable side effect
profile than pentobarbital.
Zohair Al Aseri MD,FRCPC EM & CCM
Anesthetic Barbiturates
 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.
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;
Zohair Al Aseri MD,FRCPC EM & CCM
Algorithm for treating status epilepticus
 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
 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
 If seizure activity continues, the patient is
considered to be in refractory SE.
 Management choices include
propofol, and pentobarbital.
Zohair Al Aseri MD,FRCPC EM & CCM
midazolam,
Summary
 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
 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
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.
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.
Zohair Al Aseri MD,FRCPC EM & CCM
Zohair Al Aseri MD,FRCPC EM & CCM
Introduction
 status epilepticus (SE) is the second most
frequent neurological emergency (acute stroke
being the first) with a risk of major morbidity or
mortality.
Lowenstein DH, Alldredge BK: Status epilepticus. N Engl J Med 338. 970-976.1998;
Zohair Al Aseri MD,FRCPC EM & CCM
Introduction
 Irrespective of the timeframe, SE that persists
despite
adequate
administration
of
benzodiazepines and at least one antiepileptic
drug is labelled refractory SE (RSE).
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. 251256.2010;
Zohair Al Aseri MD,FRCPC EM & CCM
Mortality and Morbidity
 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.
Novy J, Logroscino G, Rossetti AO: Refractory status epilepticus: a prospective observational study. Epilepsia 51. 251256.2010;
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;
Zohair Al Aseri MD,FRCPC EM & CCM
Mortality and Morbidity
 The risk of epilepsy after an incident
symptomatic SE event, especially if refractory, is
three times higher than after a first symptomatic
seizure.
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;
Zohair Al Aseri MD,FRCPC EM & CCM
Rationale for early treatment
 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.
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;
Zohair Al Aseri MD,FRCPC EM & CCM
Basic principles of SE treatment
 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.
LaFrance , Jr , JrWC: Psychogenic nonepileptic seizures. Curr Opin Neurol 21. 195-201.2008;
Zohair Al Aseri MD,FRCPC EM & CCM
Basic principles of SE treatment
 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
 Benzodiazepines are the only evidence-based
treatment, as shown in three trials and a
Cochrane review.
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-ofhospital 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.
Zohair Al Aseri MD,FRCPC EM & CCM
Basic principles of SE treatment
 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)
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;
Zohair Al Aseri MD,FRCPC EM & CCM
Basic principles of SE treatment
 Use of an accepted and available protocol
probably contributes to an improved prognosis.
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;
Zohair Al Aseri MD,FRCPC EM & CCM
Basic principles of SE treatment
 Thus, to proceed straight to third-line, comainducing 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
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;
Zohair Al Aseri MD,FRCPC EM & CCM
Choice of anaesthetic agents
 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.
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;
Zohair Al Aseri MD,FRCPC EM & CCM
Choice of anaesthetic agents
 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
Anaesthetic agents for refractory status epilepticus
Loading
dose
Maintenan Comments
ce dose
Midazolam
0·2 mg/kg
0·2–0·6 mg/kg per Increasing doses
h
needed with time
Propofol
2 mg/kg
2–5 mg/kg per h,
in some cases
can be raised to
10 mg/kg per h
Barbiturates
Thiopental: 1–2
mg/kg
Pentobarbital: 5
mg/kg
Attention to PRIS,
especially in young
children; combine
with
benzodiazepines
Thiopental: 1–5 Both need loading
mg/kg per h
with repetitive
Pentobarbital: 1–5 boluses and have
mg/kg per h
long wash-out
times
Zohair Al Aseri MD,FRCPC EM & CCM
Choice of anaesthetic agents
 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
 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
Other pharmacological approaches
 Inhalational anaesthetics, which act, in part, on
GABAA 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
 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.
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. 653659.1989;
Zohair Al Aseri MD,FRCPC EM & CCM
Other pharmacological approaches
 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
 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
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;
Zohair Al Aseri MD,FRCPC EM & CCM
Other pharmacological approaches
 ketamine should always be combined with
GABAergic drugs because of a possible
synergistic effect.
Martin BS, Kapur J: A combination of ketamine and diazepam synergistically controls refractory status epilepticus induced by
cholinergic stimulation. Epilepsia 49. 248-255.2008;
Zohair Al Aseri MD,FRCPC EM & CCM
Other pharmacological and nutritional treatments for refractory status
epilepticus
Advantages
Disadvantages/comments
Fast acting
Possible neurotoxicity
Needs closed system, ie, gas recovery
Ketamine
NMDA receptor antagonist
Possible neurotoxicity; combine with
benzodiazepines
Lidocaine
Can rescue phenytoinresistant refractory status
epilepticus
Cardiac monitoring needed; possible
seizure induction
Verapamil
Safe
Does not have antiepileptic drug
action; might improve availability of
antiepileptic drugs in CNS
Magnesium
Can enhance NMDA receptor Possible induction of neuromuscular
blockade
blockade
Isoflurane
Ketogenic diet
Immunological
treatments
Safe
Need skilled dietician; check for
ketonuria
Can act causally
Formal exclusion of infection needed
before treatment
Zohair Al Aseri MD,FRCPC EM & CCM
Other pharmacological approaches
 Topiramate
 Pregabalin
 Levetiracetam
 Lacosamide
 levetiracetam and lacosamide are increasingly
prescribed as second-line drugs)
Towne AR, Garnett LK, Waterhouse EJ, Morton LD, DeLorenzo RJ: The use of topiramate in refractory status epilepticus. Neurology 60. 332334.2003;
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;
Zohair Al Aseri MD,FRCPC EM & CCM
Other pharmacological approaches
 The diet can be administered through a
nasogastric tube and should induce ketonuria;
this approach can show its effect within a few
days.
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;
Zohair Al Aseri MD,FRCPC EM & CCM
Summary
 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
Zohair Al Aseri MD,FRCPC EM & CCM
THANK YOU
Zohair Al Aseri MD,FRCPC EM & CCM