1. STATUS EPILEPTICUS 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. محطة الرمل 1930

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. شارع أبو قير 1930

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 ? 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 BenzodiazepineRouteDosing Maximum Dose Class & Level of Evidence LORAZEPAMIV0.1mg/kg 4mg @ 2mg/min May repeat x1 in 5-10 min Class I Level A MIDAZOLAM IM Nasal Bucca l 0.2mg/kg10mg Class I Level A DIAZEPAMPR0.2mg/kg20mg Class IIa, Level A Brophy GM et al. Neurocrit. Care 2012; 17:3–23 [PubMed]PubMed]

33. Status Epilepticus: Second-line Treatment Options AED Route Dosing Maximum Rate of Infusion Additional Dose Class & Level of Evidence FosphenytoinIV20 PE/kg 150 PE/min 5 PE/kg, 10 min after loading dose Class IIa Level B PhenytoinIV20mg/kg50mg/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 InfusionsInitial 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]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.

40. 40