The document summarizes guidelines for the management of status epilepticus from the American Epilepsy Society. It defines status epilepticus and provides timelines. Common causes are listed. Five key questions are addressed through evidence-based conclusions about effective anticonvulsants for initial and subsequent treatment, associated adverse events, the most effective benzodiazepines, efficacy of fosphenytoin vs phenytoin, and when efficacy drops significantly. Recommendations are made for first-line treatments including benzodiazepines, second-line treatments, and refractory status epilepticus treatments.

1. STATUS EPILEPTICUS
Time for a New Guideline for
Management
Prof Ashraf Abdou
NEUROPSYCHIATRY DEPARTMENT
FACULTY OF MEDICINE
ALEXANDRIA UNIVERSITY
Member AAN - SfN

2. Definition
 Conventional “textbook” definition of status epilepticus:
 Single seizure > 30 minutes
 Series of seizures > 30 minutes without full recovery
 Why 30 min?
Animal experiments in the 1970s and 1980s had shown that ...
 … neuronal injury could be demonstrated after 30 min of seizure activity, even while
maintaining respiration and circulation.
 Operational definition
 Generalized, convulsive status epilepticus in children and
adults refers to > 5 minutes of continuous seizure or >2
discrete seizures with incomplete recovery of consciousness
 Patients with generalized seizure activity at arrival in the ER are treated promptly regardless of prior
duration

3. Status epilepticus timeline
Grover EH, et al. Curr Treat Options Neurol 2016

6. Status epilepticus –common etiology
1. Low AED levels ------------ 35%
2. Stroke, including hemorrhagic ------------- 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%

7. Starting in 2012 supported by American Epilepsy Society
The goal of this current guideline is to provide evidence-based
answers to efficacy, safety, and tolerability questions regarding the
treatment of convulsive status epilepticus and to synthesize these
answers into a treatment algorithm

8. Grading of recommendations

9. QUESTION TO BE ANSWERED
Q1. Which Anticonvulsants Are Efficacious as Initial and Subsequent
Therapy?
Q2. What Adverse Events Are Associated With Anticonvulsant
Administration?
Q3. Which Is the Most Effective Benzodiazepine?
Q4. Is IV Fosphenytoin More Effective Than IV Phenytoin?
Q5. When Does Anticonvulsant Efficacy Drop Significantly (i.e., After How
Many Different Anticonvulsants Does Status Epilepticus Become Refractory)?

10. Q1. Which Anticonvulsants Are Efficacious as Initial and Subsequent
Therapy?
The following conclusions were drawn. In ADULTS,
 IM midazolam, IV lorazepam, IV diazepam (with or without
phenytoin), and IV phenobarbital are established as efficacious at
stopping seizures lasting at least 5 minutes (level A).
 Intramuscular midazolam has superior effectiveness compared
with IV lorazepam in adults with convulsive status epilepticus
without established IV access (level A).
 Intravenous lorazepam is more effective than IV phenytoin in
stopping seizures lasting at least 10 minutes (level A).

11. Q1. Which Anticonvulsants Are Efficacious as Initial and
Subsequent Therapy?
The following conclusions were drawn. In ADULTS,
 There is no difference in efficacy between IV lorazepam followed by IV
phenytoin, IV diazepam plus phenytoin followed by IV lorazepam, and
IV phenobarbital followed by IV phenytoin (level A).
 Intravenous valproic acid has similar efficacy to IV phenytoin or
continuous IV diazepam as second therapy after failure of a
benzodiazepine (level C).
 Insufficient data exist in adults about the efficacy of Levetiracetam as
either initial or second therapy (level U).

12. Q1. Which Anticonvulsants Are Efficacious as
Initial and Subsequent Therapy?
The following conclusions were drawn. In PEDIATRICS
 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 at stopping seizures lasting at least
5 minutes (level B).
 Insufficient data exist in children about the efficacy of intranasal
lorazepam, sublingual lorazepam, rectal lorazepam, valproic acid,
Levetiracetam, phenobarbital, and phenytoin as initial therapy (level
U).

13. Q1. Which Anticonvulsants Are Efficacious as
Initial and Subsequent Therapy?
The following conclusions were drawn. In PEDIATRICS
 Intravenous valproic acid has similar efficacy but better
tolerability than IV phenobarbital as second therapy after
failure of a benzodiazepine. (level B)
 Insufficient data exist in children regarding the efficacy of
phenytoin or Levetiracetam as second therapy after
failure of a benzodiazepine (level U).

14. ‫الرمل‬ ‫محطة‬1930

15. QUESTION TO BE ANSWERED
Q1. Which Anticonvulsants Are Efficacious as Initial and Subsequent
Therapy?
Q2. What Adverse Events Are Associated With Anticonvulsant
Administration?
Q3. Which Is the Most Effective Benzodiazepine?
Q4. Is IV Fosphenytoin More Effective Than IV Phenytoin?
Q5. When Does Anticonvulsant Efficacy Drop Significantly (i.e., After How
Many Different Anticonvulsants Does Status Epilepticus Become Refractory)?

16. Q2. What Adverse Events Are Associated With
Anticonvulsant Administration?
The following conclusions were drawn. In ADULTS
 Respiratory and cardiac symptoms are the most common encountered
treatment-emergent adverse events associated with IV anticonvulsant
administration in adults with status epilepticus. (level A).
 The rate of respiratory depression in patients with status epilepticus treated
with benzodiazepines is lower than in patients with status epilepticus treated
with placebo (level A), indicating that respiratory problems are an important
consequence of untreated status epilepticus.
 No substantial difference exists between benzodiazepines and phenobarbital
in the occurrence of cardiorespiratory adverse events in adults with status
epilepticus (level A).

17. Q2. What Adverse Events Are Associated With
Anticonvulsant Administration?
The following conclusions were drawn. In PEDIATRICS
 Respiratory depression is the most common clinically significant treatment-
emergent adverse event associated with anticonvulsant drug treatment in
status epilepticus in children (level A).
 No substantial difference probably exists between midazolam, lorazepam,
and diazepam administration by any route in children with respect to rates of
respiratory depression (level B).
 Adverse events, including respiratory depression, with benzodiazepine
administration for status epilepticus have been reported less frequently in
children than in adults (level B).

18. QUESTION TO BE ANSWERED
Q1. Which Anticonvulsants Are Efficacious as Initial and Subsequent
Therapy?
Q2. What Adverse Events Are Associated With Anticonvulsant
Administration?
Q3. Which Is the Most Effective Benzodiazepine?
Q4. Is IV Fosphenytoin More Effective Than IV Phenytoin?
Q5. When Does Anticonvulsant Efficacy Drop Significantly (i.e., After How
Many Different Anticonvulsants Does Status Epilepticus Become Refractory)?

19. Q3. Which Is the Most Effective Benzodiazepine?
The following conclusions were drawn. In ADULTS
 In adults with status epilepticus without established IV access,
IM midazolam is established as more effective compared with IV
lorazepam (level A).
 No significant difference in effectiveness has been demonstrated
between lorazepam and diazepam in adults with status
epilepticus (level A).

20. Q3. Which Is the Most Effective Benzodiazepine?
The following conclusions were drawn. In PEDIATRICS
 In children with status epilepticus, no significant difference in
effectivenesshas been established between IV lorazepam and IV
diazepam (level A).
 In children with status epilepticus, non-IV midazolam
(IM/intranasal/buccal) is probably more effective than diazepam
(IV/rectal) (level B).

21. ‫قير‬ ‫أبو‬ ‫شارع‬1930

22. QUESTION TO BE ANSWERED
Q1. Which Anticonvulsants Are Efficacious as Initial and Subsequent
Therapy?
Q2. What Adverse Events Are Associated With Anticonvulsant
Administration?
Q3. Which Is the Most Effective Benzodiazepine?
Q4. Is IV Fosphenytoin More Effective Than IV Phenytoin?
Q5. When Does Anticonvulsant Efficacy Drop Significantly (i.e., After How
Many Different Anticonvulsants Does Status Epilepticus Become Refractory)?

23. Q4. Is IV Fosphenytoin More Effective Than IV Phenytoin?
The following conclusions were drawn:
 Insufficient data exist about the comparative efficacy of
phenytoin and fosphenytoin (level U).
 Fosphenytoin is better tolerated compared with
phenytoin (level B).
 When both are available, fosphenytoin is preferred based
on tolerability, but phenytoin is an acceptable alternative
(level B).

24. 10 $ 150 $

25. QUESTION TO BE ANSWERED
Q1. Which Anticonvulsants Are Efficacious as Initial and Subsequent
Therapy?
Q2. What Adverse Events Are Associated With Anticonvulsant
Administration?
Q3. Which Is the Most Effective Benzodiazepine?
Q4. Is IV Fosphenytoin More Effective Than IV Phenytoin?
Q5. When Does Anticonvulsant Efficacy Drop Significantly (i.e.,
After How Many Different Anticonvulsants Does Status Epilepticus
Become Refractory)?

26. Q5. When Does Anticonvulsant Efficacy Drop Significantly
(i.e., After How Many Different Anticonvulsants Does Status
Epilepticus Become Refractory)?
The following conclusions were drawn
 In adults, the second [7%] anticonvulsant administered is
less effective than the first [55 %] “standard” anticonvulsant,
while the third anticonvulsant administered is substantially
less effective than the first “standard” anticonvulsant [2.5%]
(level A).
 In children, the second anticonvulsant appears less effective,
and there are no data about third anticonvulsant efficacy
(level C).

31. Shorvon meta-analysis (2012)
Shorvon S and Ferlisi M. Brain 2012

32. Status Epilepticus: First-line Treatment Options
Benzodiazepine Route Dosing
Maximum
Dose
Class &
Level of
Evidence
LORAZEPAM IV 0.1mg/kg
4mg @
2mg/min
May repeat x1
in 5-10 min
Class I
Level A
MIDAZOLAM
IM
Nasal
Bucca
l
0.2mg/kg 10mg
Class I
Level A
DIAZEPAM PR 0.2mg/kg 20mg
Class IIa,
Level A
Brophy GM et al. Neurocrit. Care 2012; 17:3–23 [PubMed]

33. Status Epilepticus: Second-line Treatment Options
AED Route Dosing
Maximum
Rate of
Infusion
Additional
Dose
Class &
Level of
Evidence
Fosphenytoin IV 20 PE/kg
150
PE/min
5 PE/kg ,
10 min after
loading dose
Class IIa
Level B
Phenytoin IV 20mg/kg 50mg/min
5-10mg/kg,
10 min after
loading dose
Class IIa
Level B
Valproate
Sodium
IV
20-40
mg/kg
3-6
mg/kg/min
20mg/kg,
10 min after
loading dose
Class IIa
Level A
Return to index

34. Refractory Status Epilepticus:
Treatment Options
Infusions Initial Dose
Continuous
Infusion
Class &
Level of
Evidence
Adverse
Effects
Midazolam
0.2mg/kg
@ 2mg/min
0.05-2mg/kg/hr
Class IIa
Level B
Respiratory
depression
Hypotension
Propofol
1-2mg/kg
@ 20mcg/kg/min
30-200
mcg/kg/min
Class IIb
Level B
Respiratory
Depression
Hypotension*
Propofol infusion
syndrome
Renal Failure
Pentobarbital
5-15 mg/kg
@ ≤ 50mg/min
0.5-5mg/kg/hr
Class IIb
Level B
Respiratory
depression
Hypotension
Cardiac depression
Paralytic Ileus
Prolonged mental
status depression
Brophy GM et al. Neurocrit. Care 2012; 17:3–23 [PubMed]

35. RSE basic info
 Etiology broadly assigned
to one of five groups
1. Drug/toxins
Shorvon S and Ferlisi M. Brain 2011
Betjemann JP and Lowenstein DH. Lancet Neurol 2015
Turnbull D and Singatullina N. Minerva Anestesiol 2013

36. RSE basic info
 Etiology broadly assigned to
one of five groups
1. Drug/toxins
2. Infectious
Shorvon S and Ferlisi M. Brain 2011
Betjemann JP and Lowenstein DH. Lancet Neurol 2015
Turnbull D and Singatullina N. Minerva Anestesiol 2013

37. RSE basic info
 Etiology broadly assigned
to one of five groups
1. Drug/toxins
2. Infectious
3. Structural
Shorvon S and Ferlisi M. Brain 2011
Betjemann JP and Lowenstein DH. Lancet Neurol 2015
Turnbull D and Singatullina N. Minerva Anestesiol 2013

38. RSE basic info
 Etiology broadly assigned
to one of five groups
1. Drug/toxins
2. Infectious
3. Structural
4. Metabolic
Shorvon S and Ferlisi M. Brain 2011
Betjemann JP and Lowenstein DH. Lancet Neurol 2015
Turnbull D and Singatullina N. Minerva Anestesiol 2013

39. Status Epilepticus : Think TIME
• Time to treatment needs to be shorter.
• Response to treatment is time dependent.
• Morbidity and mortality are related to etiology
and duration (time) of status epilepticus.
• Subsequent epilepsy may depend on the
duration (length of time) of the status
epilepticus.
• Prolonged seizures predict future prolonged
seizures.

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