- Status epilepticus has a worldwide incidence of 3.8 to 38 per 100,000 people per year, with peaks in children and the elderly. Around 31-44% of cases are refractory to initial treatment.
- Initial treatment involves benzodiazepines like lorazepam or diazepam. If seizures continue, second-line drugs like phenytoin, fosphenytoin, or valproate are used.
- Refractory status epilepticus is defined as failure to control seizures with benzodiazepines and other antiepileptics. It requires general anesthesia with drugs like propofol, thiopental, or midazolam along with
2. • Worldwide incidence of Convulsive Status Epilepticus
- 3.8 to 38 per lakh per year in children.
- 6 to 27 per lakh per year in adults.
• Bimodal peak distribution, with peaks in children and
elderly.
• Frequency of refractory status epilepticus in status
epilepticus patients = 31-44%
• No community based incidence studies in India but is
expected to be high because of high prevalence of
epilepsy, CNS infections and treatment gap.
J K Murthy Convulsive status epilepticus API India 2013
3. • In approximately 50% cases, there is no prior
history of epilepsy.
• Males are affected more compared to females
partly attributed to lower seizure threshold in
males.
• Mortality rates range between 10.5-28%.
• Neurological or cognitive sequelae in convulsive
SE occur in 11- 16 % patients.
4. • Factors associated with poor outcome after
generalised SE :
– Underlying etiology
– De novo development in hospitalised patients
– Older age
– Associated medical complication
– Duration of seizures
– Focal neurological signs at onset
6. • According to an Indian study, the etiology of Status Epilepticus
was Infection in 53.8%, drug default in 7.9%, metabolic in
14.5%, Stroke in 12.8% and miscellaneous in 11% of patients.
• Infection as an etiology was more common in children, drug
default and metabolic causes in adult and stroke in elderly.
• Mortality = 29% (elderly >> children)
(A clinical, radiological and outcome study of status
epilepticus, India J Neurology (2010) 257:224-229)
7. Definition
• The first definition of Status Epilepticus came from
Clark and Prout as “ maximal development of
epilepsy in which seizures are so frequent that coma
and exhaustion are continuous between seizures.”
• The first official definition of SE was the product of
10th Marseilles Colloquium (1962) which was
accepted by International League Against Epilepsy
(ILAE) in 1964 and modified in 1971 as “a seizure
that persists for sufficient length of time or repeated
frequently enough that recovery between attacks
does not occur.”
8. Operational Definition
• Status Epilepticus is defined as 5 minutes or
more of :
1.continuous clinical and/or electrographic
seizure activity or
2. recurrent seizure activity without
recovery (returning to baseline) between
seizures
9. Clinical features
• Genaralized convulsive status epileptics-
• Self-perpetuating generalized tonic-clonic seizure or of
a series of generalized tonic-clonic seizures without
return to consciousness in between seizures.
• Initial compensatory phase-sympathetic overdrive
a. increased C.O.
b. increased BP
c. increased BS
d. increased blood lactate levels
11. • Nonconvulsive status epilepticus
• Diverse - severe impairment of consciousness to
subtle phenomena.
• Motor manifestations if any –needs careful CNS
exam.
• Often mistaken for psychiatric disorders.
12. • Refractory status epilepticus
• Do not repond to standard treatment regimen
for status epilepticus (adequate doses of intial
BZD followed by a second acceptable
antiepileptic drug )
• Nearly 40% of status epilepticus are refractory.
• Predictors- encephalitis / nonstructural
causes(HIE) / delayed diagnosis & treatment .
13. • Malignant / Super- refractory status
epilepticus
• Status epilepticus that does not respond to a
course of anesthetic drug.
• 20% of refractory status epilepticus patients.
• Needs combination therapy (AED & Anesthetic
drugs) .
15. Aims of management of Status Epilepticus are as
follows :-
1. Termination of Status Epilepticus
2. Prevention of Seizure Recurrence
3. Management of Precipitating cause
4. Management of complications
16. Approach: Diagnostic workup
All patients
• Obtain IV access
• Monitor vital signs (ABC).
• Head CT (appropriate for most cases)
• Labs: blood glucose, CBC, renal function tests, Calcium,
Magnesium, electrolytes, AED levels.
• cEEG monitoring (preferably)
Consider based on clinical presentation
• Brain MRI
• Lumbar puncture
• Toxicology panel (i.e. isoniazid, TCAs, theophylline, cocaine,
sympathomimetics, organophosphates, cyclosporine)
• Other relevant investigations as per the need
Brophy, et al NCC 2012
17. Continuous EEG Monitoring
Brophy, et al NCC 2012
•The use of cEEG is usually required for the treatment of SE.
•Continuous EEG monitoring should be initiated within 1 h of SE
onset if ongoing seizures are suspected.
•The duration of cEEG monitoring should be at least 48 h in
comatose patients to evaluate for non-convulsive seizures.
18. Indications for cEEG in SE
Brophy, et al NCC 2012
• Recent clinical seizure or SE without return to
baseline >10 min
• Coma, including post-cardiac arrest
• Epileptiform activity or periodic discharges on initial
30 min EEG
• Suspected non-convulsive seizures in patients with
altered mental status
19. Continuous EEG treatment endpoints
Brophy, et al NeuroCritical Care 2012
• Cessation of non-convulsive seizures
• Diffuse beta activity
• Burst suppression 8–20 s intervals
• Complete suppression of EEG
21. BENZODIAZEPINES
• Drug of choice for out of hospital as well as in-
hospital treatment.
• Effective in terminating seizures in 59-78 % cases.
• Lorazepam is the DOC for IV administration.
• Midazolam is the DOC for IM administration.
• Rectal Diazepam is effective in children.
• Other routes are buccal Midazolam and intranasal
Midazolam (not commonly used)
22. • Benzodiazepines
– Diazepam
- 10mg IV push over 30-60 seconds
- repeat after 10-15mins, upto 40mg (5mg/min)
-Repeat after 2-4hrs. (max 100mg/day)
- bolus dose should be given in undiluted form
at rate not exceeding 2-5 mg/min.
– Lorazepam
0.1- 0.15 mg/kg i.v, upto 4-6 mg over 1-2 minutes
If SE persists, repeat every 5-10 minutes
23. • Diazepam
One of the drug of choice for first line management of SE
• Good results, easy to administer. (fast acting, short lasting)
• More lipid soluble, hence short distribution half-life.
• Anti-seizure effect 15-30min.
• Sufficient cerebral levels are achieved within 1 min of IV
administration and about 20 mins after rectal
administration.
• Elimination half life abt 24 hrs (may accumulate)
• Side effects -- hypotension, bradycardia,
respiratory depression, cardiac arrest,
tolerance, depresses mental status.
• In children and elderly :
Rectal Diazepam 0.5 mg / kg in children and 10 mg
in elderly are also good alternatives.
24. • Lorazepam
• Has emerged as preferred BZD for treatment of SE
• The veteran affairs (VA) co-operative study demonstrated
advantage of IV Lorazepam over Phenytoin.
• Less lipid distribution with distribution half life of 2-3
hours
• So Fast acting, longer lasting compared to Diazepam
– Longer therapeutic half-life. Anti-seizure effect for
6-12hrs.
– 2mg dose, upto a max dose of 8mg in total
• Main disadvantage is rapid devlopment of tolerance,
hence repeated doses are less effective and has no role
in long term therapy.
25. • - If Benzodiazepines are successful in stopping
• GCSE, the decision to add another agent
• depends on the underlying etiology.
• - If the etiology is reversible (e.g. metabolic or
• toxic factors), BZDs may be the only treatment
• necessary.
• - Another longer-acting AED is needed if the
• underlying etiology is not rapidly reversible.
26. Seizures continuing / Stage of Established Seizure
• In patients taking Sodium Valproate -25mg/kg iv
sodium valproate can be tried who may be sub
therapeutic.
• Phenytoin:- 20mg/kg Bolus dose IV at the rate of
50mg/min.
• Fosphenytoin:- 20mg PE/kg Bolus dose IV at the rate
of 150mg/min
• Above drugs have advantage that they lack sedative
effects.
27. Phenytoin Fosphenytoin
• 15-20 mg/kg i.v.
@50mg/min
• 100 mg phenytoin =
• 20 mg PE/kg i.v @
150mg/min
Fosphenytoin 150 mg
pH 12
Extravasation causes
severe tissue injury
pH 8.6
Extravasation well
tolerated
• Onset 10-30 min • Onset 5-10 min
•May cause hypotension,
dysrhythmia
(may be because of rapid administration
and propylene glycol which is used as
diluent)
• less cardiac complications as it
is water soluble and propylene
glycol is not used as diluent.
• Cheap • Expensive
28. Fosphenytoin Vs. Phenytoin
• SO Fosphenytoin injection has the following advantages over
phenytoin
100% bioavailability
better tolerated at site of injection.
can be given IV more rapidly .
can be given IM when cardiac monitoring is not necessary
• But has the following disadvantages
– conversion of fosphenytoin to phenytoin takes about 15
minutes. Hence inappropriate for the initial treatment of
status epilepticus (SE).
– transient paraesthesia and pruritus occur more frequently
than with phenytoin.
– the use of phenytoin equivalents may be confusing.
29. PHENOBARBITAL
• Used in SE when BZD and Phenytoin have
failed.
• Loading dose – 15-20 mg/kg
• Causes sedation and hypotension, so airway
protection should be done.
• Diluted in Polyethylene Glycol which results in
complications like renal failure, myocardial
depresion and seizures.
30. SODIUM VALPROATE
• FDA approved use in SE in 1997
• Parenteral loading is done when oral therapy is not
possible.
• Broadspectrum action and is also useful in absence and
myoclonic SE.
• Patients not responding to 2 first line AEDs may be given
parenteral sodium valproate, especially in setting where
intubation and artificial ventilation are not feasible.
31. PARALDEHYDE
• Is used as an alternative to Diazepam in early SE where IV
administration is difficult or conventional AED are
contraindicated or preoved ineffective.
• Given rectally or I/M with fast and complete absorption with
rapid onset of action.
• Seizure tend to recur after initial control.
• Inappropriately diluted or decomposd drug is highly toxic.
• Given at a dose of 10-20ml of 50% solution rectally or I/M.
• Diluted in NS or arachis oil for rectal or I/M route.
• For I/V route, given as a 5 % infusion in 5% dextrose, freshly
prepared up every 3 hours.
32. Refractory Status Epilepticus
Brophy, et al NCC 2012
•Refractory SE therapy recommendations should consist of
continuous infusion AEDs, but vary by the patient’s underlying
condition
•Dosing of continuous infusion AEDs for RSE should be titrated
to cessation of electrographic seizures or burst suppression
•During the transition from continuous infusion AEDs in RSE, it
is suggested to use maintenance AEDs and monitor for
recurrent seizures by cEEG during the titration period.
•A period of 24–48 h of electrographic control is recommended
prior to slow withdrawal of continuous infusion AEDs for RSE
33. Seizures continuing / Stage of Refractory Status
-General anesthesia should be induced
Propofol:- 2mg/kg IV bolus,Repeat if necessary, followed by
infusion (2 – 10 mg/kg/hr)
Thiopental:- 100-250mg IV bolus over 20 sec. with further
50mg bolus every 2-3 min.until seizure control followed by IV
infusion(3-5mg/kg/hr)
Midazolam:- 0.3mg/kg IV bolus dose at the rate of 4mg/min,
rpt every 5 min 3 doses followed by infusion(2 ug/kg/hr)
Neuromuscular Blocking Agents :
If seizures have been controlled for 12hrs., reduce the
dose over further 12hrs.
If seizure recurs again GA agent should be given
34. Lowenstein DH, Status Epilepticus, NEJM (1998)
• No difference has been found in mortality in groups
treated with either of these agents.
• Pentobarbital was associated with lower frequency
of acute treatment failures and breakthrough
seizures.
• Superior pharmacokinetics and adverse effects
profile makes Propofol preferred drug in Refractory
status epilepticus in children as well as adults
35. THIOPENTONE
• Barbiturate anaesthetic given in ICU setting as patient
requires intubation and mechanical ventialtion.
• Most troublesome S/E- hypotension (may require pressor
therapy)
• Tendency to accumulate
• Caution advised in elderly or in cardiac, hepatic or renal
diseases.
• 100-250mg bolus over 20 secs, with further 50mg
boluses every 2-3 mins till seizures are controlled with
maintainence dose as 3-5mg/kg/hr.
• Aqueous solution is unstable if exposed to air.
36. PROPOFOL
• Nonbarbiturate anesthetic
• Highly lipid soluble with high volume of
distribution resulting in rapid and short lived
action.
• Causes profound respiratory and cerebral
depression requiring assisted ventilation.
• May cause involuntary movements which are not
to be confused with seizures
• 2 mg/kg bolus dose followed by 5-10 mg/kg/hr
infusion.
37. LEVITIRACETAM
• S-enantiomer of Piracetam
• Was introduced for treatment of SE in 2006
• Insufficient data on safety and efficacy of this
drug in status epilepticus.
• Several case reports its use in SE.
• European federation of neurological societies
proposes its usefulness in refractory complex
partial SE. (Meiekord H et al, EFNS guideline on the management of
status epilepticus in adults, Eur Journal 2010)
38. Levetiracetam
• Levetiracetam has been used to control SE, typically
as second line drug.
• Levels peak within 2 hrs. Steady state in 2 days. No
significant interactions.
• Mishra et al (2012) used LEV 20 mg./kg over 15 min.
and compared with Lorezepam 0.1 mg./kg over 2 to
4 min. in 79 patients. Control was comparable (76.3%
and 75.6%). 24 Hour seizure control was also similar.
But hypotension and requirement of mechanical
ventilation was significantly higher in Lorezepam
group.
39. LACOSAMIDE
• In addition to anticonvulsant property, it has shown
potential to retard kindling induced epileptogensis.
• One report shows efficacy in Nonconvulsive
SE.(Kellinghaus C et al, Epilepsy Behav 2009)
• One report showed efficacy of oral Lacosamide in
refractory convulsive SE.(Tilz C et al, Epilepsia 2010)
40. Lacosamide
• Christian et al (2010) reported successful termination
of refractory SE given 22.5 mg. diazepam, 12.5 mg.
etomidate & 5 mg. midazolam, 4 mg. lorazepam &
1500 mg. levetiracetam. Lacosamide 300 mg via per
cutaneous gastric fistula resulted in cessation of SE in
30 min.
• Kellinghaus (2009) reported successful termination
of SE with IV Lacosamide.
• However furthere large RCT are required to prove
the efficacy and safety of this drug in SE.
41. IMPORTANT POINT
• Along with emergency control of SE, maintenance
therapy should be started to prevent recurrence
of seizures.
• In patients known to have epilepsy, their usual
AED can be continued depending on serum AED
levels.
• In patients presenting for the first time as SE,
drugs like Phenytoin or Sodium Vaproate used to
control the status can be continued as
maintenance therapy.
42. EMERGING THERAPIES
• Inhalational Anaesthetic agents
(isoflurane and desflurane )
• Attractive features include efficacy, rapid onset of action,
ability to titrate according to EEG.
• Both drugs in endtidal concentrations of 1.2-5%achieved an
EEG burst suppression and termination of seizure activity
within minutes.
• However further studies are needed in this field.
Mirasattari et al, treatment of refractory status epilepticus with inhalational
anaesthetic agents : Isoflurane & Desflurane , Arch Neurology 2004
43. Shorovan M et al,The treatment of refractory status epilepticus Brain
2011
KETAMINE
• an NMDA receptor antagonist
• Experimental studies have demonstrated synergistic action of
diazepam and ketamine in termination SE.
• Efficacy in extremely refractory SE has been documented in
both children and adults.
• No cardiac depressant properties, hence doesnot cause
hypotension.
44. KETOGENIC DIET
• Diet high in fat and low in carbohydrates
• Induces ketosis in body and thought to suppress
seizures by release of Leptin.
• Exact mechanism remains unknown.
45. Steroids and Immunotherapy
• Rationale that refractory SE may be due to antibodies
directed against neural elements.
• Increasing recognition the role of inflammation in
epileptogenesis.
• SE may be the initial presenting feature of some
immune mediated encephalopathies.
Shorovan M et al,The treatment of refractory status epilepticus
Brain 2011
46. NONPHARMACOLOGICAL TREATMENTS
• Resective surgery
• Vagal nerve stimulation
• Hypothermia- decrease brain metabolism
which is neuroprotective.
• Electroconvulsive therapy - ECT-dose-1 session
daily for 3-8 days. Mechanism-not known
47. STATUS EPILEPTICUS
Rapid IV access available
NO
IM Midazolam 0.2mg/kg (max10mg)
OR
Buccal or Intranasal Midazolam
0.5mg/kg (max10mg)
YES
IV LORAZEPAM 0.1mg/kg slow push (max 4mg)
Repeat IV LORAZEPAM 0.1mg/kg
slow push
If Seizure donot
stop in 5 minutes
If Seizure donot
stop in 5 minutes,
Achieve IV access
Shift to 2nd line drugs
If Seizure donot
stop in 5 minutes
IV Phenytoin 20mg/kg @ 50mg/min
OR
IV Fosphenytoin 20mg/kg @ 150 mg/min
If Seizure donot stop in 20 minutes
If possibility of
subttherapeutic levels,
Valproate 40-60 mg/kg @ 6
mg/kg/min can be tried
If Seizure
donot stop in
10 minutes
48. Repeat IV Phenytoin 5mg/kg OR
IV Fosphenytoin 5mg/kg
IV Phenobarbitone 20mg/kg @ 100mg/min f/by 3-5
mg/kg.hr cont infusion
OR
IV Midazolam 0.2 mg/kg loading dose f/by 0.1-0.4
mg/kg/hr cont infusion
OR
IV Propofol 2mg/kg bolus f/by 2-10 mg/kg/hr cont
infusion
OR
IV Pentobarbital 5 mg/kg loading dose f/by
1-3 mg/kg/hr cont infusion
If seizure persists after 24 hrs, try emerging novel therapies: Ketamine bolus 0.5-4.5
mg/kg infusion (upto 5 mg/kg/hr ) ; Immunomodulation IV Methylprednisolone or
IVIg; Resective surgery ; Ketogenic diet ; hypothermia
Alternative
drug
Valproate 40-
60 mg/kg @ 6
mg/kg/min
Alternative
Drug
Levitiracetam
20-30mg/kg
@ 5
mg/kg/min
Seizure not
controlled
Seizure not
controlled
50. References.
• Review article-Status Epilepticus-Lawrence J .Hirsch,MD,FAAN:
Nicolas Gaspard,MD,Phd-2013
• Guidelines for evaluation and management of status
epilepticus Neurocritical Care Society 2012
• article-Status Epilepticus-Lawrence J .Hirsch,MD,FAAN: Nicolas
Gaspard,MD,Phd-2013
51. Levetiracetam IV- Efficacy and Safety
Thongplew and collegues reviewed the clinical use, efficacy, and
outcomes of intravenous levetiracetam in adults with status
epilepticus.
Results:
• 34 prescriptions for intravenous levetiracetam in patients with
status epilepticus were noted.
• All patients had at least one co-morbidity condition
• The seizure control rate was 61.8%
• 41.2% survived and had an improved status at discharge.
Neurology Asia 2013; 18(2) : 167 – 175
Intravenous levetiracetam has good efficacy and may be a good option
for status epilepticus.
52. Levetiracetam IV- Alternative to Lorazepam
Randomized, open labeled pilot study compared the efficacy and safety of
levetiracetam and lorazepam in status epilepticus.
–Patients with convulsive or subtle convulsive SE were randomized to
Levitiracetam 20 mg/kg IV over 15 min or Lorazepam 0.1 mg/kg over 2-4
min.
J Neurol. 2012 Apr;259(4):645-8
Levetiracetam Lorazepam
In first instant,
SE controlled
76.3 75.6
In those resistant,
SE controlled
70.0 88.9
24-h freedom
from seizure
79.3 67.7
Lorazepam
• Significantly higher need
of artificial ventilation
• Insignificantly higher
frequency of hypotension
For the treatment of SE, levetiracetam is an alternative to lorazepam and may
be preferred in patients with respiratory compromise and hypotension.
