status epilepticus...

1. Dr. RAHI KIRAN
SR I NEUROLOGY
GOVT MEDICAL COLLEGE, KOTA

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.
 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.
J K Murthy Convulsive status epilepticus API India 2013

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

5. 1. Low AED levels - 35%
2. Stroke - 20%
3. Alcohol withdrawal - 15%
4. Anoxic brain injury - 15%
5. Metabolic disturbances - 15%
6. Remote brain injury/ cong. malformations - 20%
7. Infections - 5%
8. Brain neoplasms - 5%
9. Idiopathic - 5%

6.  According to an Indian study, the etiology of SE 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.  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 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.  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
 complex partial status epilepticus- 10 minutes

9. 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 blood lactate levels

10.  Decompensation –homeostatic faliure
1. Cardiorespiratory collapse
2. Electrolyte imbalance
3. Rhabdomyolysis & delayed tubular necrosis
4. Hyperthermia
5. Multi organ Failure
6. Raised ICP & cerebral oedema

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 (RSE)
 defined as SE persisting despite sufficient dose of
benzodiazepines and at least one antiepileptic drug (AED),
irrespective of time.
 Nearly 23 to 48% of status epilepticus are refractory.

13. Malignant / Super- refractory status epilepticus (SRSE)
 defined as SE that continues for 24 hours or more after the use
of anesthetic therapy, including cases that recur on weaning of
the anesthestic agent.
 22% of the patients with SE.
 Needs combination therapy (AED & Anesthetic drugs) .

14. MANAGEMENT OF STATUS EPILEPTICUS

15. 1. Termination of Status Epilepticus
2. Prevention of Seizure Recurrence
3. Management of Precipitating cause
4. Management of complications

16. 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

17. •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. 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

20.  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)

21.  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

22. Diazepam
 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)

23. Lorazepam
 Has emerged as preferred BZD for treatment of SE
• 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.

24.  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 .
 Another longer-acting AED is needed if the underlying etiology is not
rapidly reversible.

25.  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.

26. Phenytoin Fosphenytoin
• 15-20 mg/kg i.v.
@50mg/min
• 100 mg phenytoin =
• 20 mg PE/kg i.v @
150mg/min
Fosphenytoin 150 mg
Extravasation causes
severe tissue injury
Extravasation well
tolerated
• Onset 5-10 min • Onset 10-30 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

27.  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.

28.  Used in SE when BZD and Phenytoin have failed.
 Loading dose – 15-20 mg/kg, 20 mg/kg, at a rate of less than 100 mg/min.
 If the EEG continues to show ictal activity, anesthesia has to be deepened
to a burst-suppression pattern and even to complete suppression in some
cases
 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.

29.  Most troublesome S/E- hypotension (may require pressor therapy)
 Tendency to accumulate
 Caution advised in elderly or in cardiac, hepatic or renal diseases.
 Aqueous solution is unstable if exposed to air.

30.  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.  Is used as an alternative to Diazepam in early SE where IV administration
is difficult or conventional AED are contraindicated or proved 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 decomposed drug is highly toxic.
 Given at a dose of 0.4 mg/kg PR, Diluted in NS or olive oil for rectal or I/M
route.(10ml of 10% sol.) Epilepsy; draft full guideline, Appendix C: December 2003

32.  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.

33.  S-enantiomer of Piracetam
 Was introduced for treatment of SE in 2006
 Insufficient data exist in adults about the efficacy of levetiracetam
as either initial or second therapy (level U).
 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)

34.  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 Lorazepam group.

35.  In addition to anticonvulsant property, it has shown potential to retard
kindling induced epileptogensis.
 There have been several small studies which have shown the efficacy of
intravenous lacosamide in SE.
 A randomized controlled trial has shown a comparable efficacy and side
effect profile in controlling lorazepam resistant SE
(Misra et al. 2017 – LCM vs VPA comparable in LOR resistant SE).

36. Dubey D, Kalita J, Misra UK. Status epilepticus: Refractory and super-refractory. Neurol India 2017;65, Suppl S1:12-7
•The treatment of RSE and SRSE is not evidence based.
•Refractory SE therapy recommendations should consist of continuous infusion AEDs, but vary
by the patient’s underlying condition
•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

37.  Propofol, midazolam, and thiopental are commonly used first-line
anesthetics for RSE
 thiopental often being reserved for use as a second-line anesthetic
for those patients still refractory after these initial medications.
 A systematic review comparing pentobarbital, midazolam, and
propofol found no significant difference in overall mortality
 In the absence of randomized data to guide management
decisions, selection of an anesthetic should be individualized

38.  Propofol:- 2mg/kg IV bolus,Repeat if necessary, followed by infusion (2 – 10
mg/kg/hr)
 Thiopental:- 3-5 mg/kg IV bolus over 20 sec. followed by IV infusion(3-5mg/kg/hr)
 Midazolam:-(0.1-0.2mg/kg bolus, then 0.05-0.5mg/kg/hour) titrated to effect.
 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

39.  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

40.  No definitive data exist to determine what adequate burst-suppression
entails and how long it should be maintained.
 Convention is to aim for 1 to 2 seconds of cerebral activity with 10-
second interburst intervals of background suppression for a total of 24
to 48 hours before attempting to lighten sedation.
 Dosing of continuous infusion AEDs for RSE should be titrated to
cessation of electrographic seizures or burst suppression

41.  IV ketamine infusion
 inhaled anesthetics isoflurane and desflurane
 Magnesium - no significant toxicity ,drawbacks, evidence of
experimental benefit, Recommended use in all cases of super-
refractory status epilepticus, (initial intravenous bolus and then infusion at a dose
that increases the serum level to ~3.5 mmol/l.)

42.  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.

43.  In adults with convulsive status epilepticus, im midazolam, iv
lorazepam, iv diazepam and iv phenobarbital are established
as efficacious as initial therapy (Level A).
 Im midazolam has superior effectiveness compared to iv
lorazepam in adults with convulsive status epilepticus without
iv access (Level A).

44.  In children, iv lorazepam and iv diazepam are established as
efficacious at stopping seizures lasting at least 5 minutes (Level A)
 rectal diazepam, im midazolam, intranasal midazolam and buccal
midazolam are probably effective (Level B).
 No significant difference in effectiveness between iv lorazepam
and iv diazepam in adults or children with convulsive status
epilepticus (Level A).

45.  Respiratory and cardiac symptoms are the most common
treatment-emergent adverse events asso. with iv anticonvulsant
drug administration in adults with convulsive status epilepticus
(Level A).
 The rate of respiratory depression in patients with convulsive
status epilepticus treated with benzodiazepines is lower than in
patients with convulsive status epilepticus treated with placebo
indicating that respiratory problems are an important consequence
of untreated convulsive status epilepticus (Level A).

46.  When both are available, fosphenytoin is preferred over
phenytoin based on tolerability but phenytoin is an acceptable
alternative (Level A).
 In adults, compared to the first line therapy, the second
therapy is less effective while the third therapy is substantially
less effective (Level A).
 In children, the second therapy appears less effective and
there are no data about third therapy efficacy (Level C).

47.  Insufficient data exist in adults about the efficacy o
levetiracetam as either initial therapy (level U).
 The guideline’s treatment algorithm is not age specific as the
pathophysiology of status epilepticus and anticonvulsant drug
effects on neuronal receptors are the same from infants
through adults, permitting a unified approach for all patients
older than neonates.

48.  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

49.  an NMDA receptor antagonist
 Experimental studies have demonstrated synergistic action of diazepam and
ketamine in termination SE. No RCT till now.
 Efficacy in extremely refractory SE has been documented in both children and
adults.
 No cardiac depressant properties, hence doesnot cause hypotension.
 Dose – 50 mg bolus f/b 100 mg/hr
Shorovan M et al,The treatment of refractory status epilepticus Brain 2011

50.  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.
 Conclusive experimental evidence of any such action is lacking.

51.  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.
Steroids and Immunotherapy

52.  Resective surgery
 Vagal nerve stimulation
 Hypothermia- decrease brain metabolism which is
neuroprotective.
 Electroconvulsive therapy – only reports available.

53.  Recurrent transcranial magnetic stimulation (rTMS)
 a continuous train of low frequency (≤1 Hz) pulses results in
cortical suppression
 Several case reports available, no large studies

55.  The current National Institute of Neurological Disorders and
Stroke funded ESETT trial compares IV fosphenytoin,
levetiracetam and valproate in children and adults with status
epilepticus who did not respond to initial benzodiazepine
therapy.
 ESETT is designed to be a class I RCT that will identify the
optimal second therapy for benzodiazepine-resistant status
epilepticus - results awaited

57.  Glauser, Tracy & Shinnar, Shlomoet al. Evidence-Based Guidline: Treatment of Convulsive
Status Epilepticus in Children and Adults: Report of the Guideline Committee of the
American Epilepsy Society. Epilepsy Currents.2016 .16. 48-61. 10.5698/1535-7597-16.1.48.
 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
 J K Murthy Convulsive status epilepticus API India 2013
 Dubey D, Kalita J, Misra UK. Status epilepticus: Refractory and super-refractory. Neurol India
2017;65, Suppl S1:12-7

60. 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.

61. 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.