Acute Seizure Management

1. Acute Seizure Management Krista L Brown, PharmD PGY1 Pharmacy Resident

2. Objectives Describe the pathophysiology and etiology of status epilepticus List the current guidelines for pharmacological treatment of status epilepticus Examine recently published literature on new treatment options for refractory status epilepticus

3. What is Status Epilepticus (SE)? 5 minutes or more of continuous seizure activity 2 or more discrete seizures without complete recovery of consciousness between them 10 minutes or more of continuous seizure activity 30 minutes or more of continuous seizure activity According to the European federation of neurological societies guidelines, 30 minutes has been the traditional length of time because this is when studies have shown irreversible neuronal damage occurs to cells exposed to continuous epileptic activity. The other definitions have also been used for clinical trials and treatment purposes. Seizures lasting > minutes are unlikely to spontaneously terminate. According to the European federation of neurological societies guidelines, 30 minutes has been the traditional length of time because this is when studies have shown irreversible neuronal damage occurs to cells exposed to continuous epileptic activity. The other definitions have also been used for clinical trials and treatment purposes. Seizures lasting > minutes are unlikely to spontaneously terminate.

4. Epidemiology Incidence of 10-40 persons per 100,000 2nd most common neurological emergency 23-43% develop refractory SE Mortality rates of 10-20% refractory SE is generally considered to be SE that continues after a patient has received an adequate dose of a benzo and at least one AEDrefractory SE is generally considered to be SE that continues after a patient has received an adequate dose of a benzo and at least one AED

5. Pathophysiology Glutamate Most common excitatory neurotransmitter Excess excitation mediated through the N-methyl-D-aspartate (NMDA) receptor Unfortunately at this point we don�t have any medications which work to stop seizure activity through the NMDA receptor, although there is research in rats into the use of memantine. Unfortunately at this point we don�t have any medications which work to stop seizure activity through the NMDA receptor, although there is research in rats into the use of memantine.

6. Pathophysiology Gamma-aminobutyric acid (GABA) Most common inhibitory neurotransmitter GABAA receptor prevents excess excitation Medications which bind GABAA receptor become less effective as SE continues As SE continues, GABA receptors are either taken up from the cell surface or become less responsive. So, need to use meds that have different mechanisms of action.As SE continues, GABA receptors are either taken up from the cell surface or become less responsive. So, need to use meds that have different mechanisms of action.

7. GABA

8. Pathophysiology

9. First line treatment Benzodiazepines 1. Lorazepam 0.1mg/kg IV (max 10mg) May repeat in 10 minutes 2. Diazepam 0.2mg/kg IV (max 30 mg) May repeat in 10 minutes 3. Midazolam* 10 mg IM * Unlabeled use Diazepam is very lipid soluble and redistributes to adipose tissue. Because of this the acute anticonvulsant effect only lasts about 20 minutes. Lorazepam doesn�t undergo extensive redistribution so it�s effective for 4-6 hours. Diazepam is very lipid soluble and redistributes to adipose tissue. Because of this the acute anticonvulsant effect only lasts about 20 minutes. Lorazepam doesn�t undergo extensive redistribution so it�s effective for 4-6 hours.

10. Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) Purpose: To determine if intramuscular midazolam is as effective as intravenous lorazepam in terminating SE seizures prior to hospital arrival Primary outcome: Termination of seizures prior to ED arrival without administration of rescue therapy

11. RAMPART 148 did not receive IV lorazepam148 did not receive IV lorazepam

12. Second line treatment Phenytoin 15-20 mg/kg Maximum infusion rate 50mg/min Highly protein bound Can check serum level 2 hours after infusion Goal level is 10-20 mcg/ml Non-linear kinetics Arnett may be switching to only fosphenytoin useArnett may be switching to only fosphenytoin use

13. Phenytoin

14. Phenytoin Other adverse effects include: Hypotension Arrhythmia Thrombophlebitis Dizziness

15. Second line treatment Fosphenytoin 15-20 phenytoin equivalents (PE)/kg Maximum infusion rate of 150 PE/min 1mg phenytoin = 1 PE fosphenytoin Prodrug of phenytoin

16. Treatment Pathways Diverge Generalized Convulsive Status Epilepticus (GCSE) Pulmonary edema and cardiac arrhythmias can occur rapidly In animal models, brain damage can result in 30 minutes Can also cause temperature disturbances and electrolyte imbalances Anesthetizing anticonvulsants should be next line treatment

17. Refractory GCSE Midazolam* - 0.2 mg/kg IV bolus - continuous IV infusion at 0.8- 6.5 mcg/kg/min, titrate for seizure suppression Propofol* - 2-3 mg/kg bolus - continuous IV infusion at 66-166 mcg/kg/min, titrate for burst suppression on EEG * Unlabeled Use rates of propofol >5mg/kg/hr for >48 hours can result in propofol related infusion syndrome= arrhythmia in the presence of lipemic plasma, clinically enlarged liver or fatty liver on autopsy, metabolic acidosis, muscular involvement with rhabdomyolysis or myoglobinuriarates of propofol >5mg/kg/hr for >48 hours can result in propofol related infusion syndrome= arrhythmia in the presence of lipemic plasma, clinically enlarged liver or fatty liver on autopsy, metabolic acidosis, muscular involvement with rhabdomyolysis or myoglobinuria

18. Refractory GCSE Pentobarbital - 5-15mg/kg over 1 hour - continuous IV infusion at 0.5-1 mg/kg/hr - may increase to 10 mg/kg/hr, titrate for burst suppression on EEG - Order set available on Downtown Pulse page

19. Which of the following is considered first line treatment in status epilepticus? Phenobarbital Lorazepam Phenytoin Valproic Acid Learning Assessment

20. Non-Convulsive Status Epilepticus Absence Status Epilepticus Complex Partial Status Epilepticus (CPSE) Subtle Status Epilepticus

21. Refractory CPSE Valproic Acid* Loading dose 15-45mg/kg Continuous infusion 1-4 mg/kg/hr OR 500-1000 mg IV q6h Goal level 50-100 mcg/ml Works to increase the amount of GABA available to neurons or enhance the action of GABA Side effects include dizziness, nausea, tremor, nervousness, thrombocytopeniaSide effects include dizziness, nausea, tremor, nervousness, thrombocytopenia

22. Refractory CPSE Phenobarbital 20 mg/kg bolus May give additional 10 mg/kg bolus in 20 minutes if needed Max infusion rate of 50 mg/min Side effects include hypotension and respiratory depression side effects in addition to possible respiratory depression and hypotension from benzos pt received in first line therapyside effects in addition to possible respiratory depression and hypotension from benzos pt received in first line therapy

23. Refractory CPSE Levetiracetam* Loading dose of 1000-3000 mg over 15 min. 500 � 1500mg IV BID Exact mechanism of action unknown May inhibit voltage dependent calcium channels, facilitate GABA�s inhibitory transmissions, or bind to synaptic proteins which modulate neurotransmitter release Side effects are mostly behavioral (agitation, anger, anxiety, depression, emotional lability, nervousness), somnolence, headache, fatigueSide effects are mostly behavioral (agitation, anger, anxiety, depression, emotional lability, nervousness), somnolence, headache, fatigue

24. Efficacy of intravenous levetiracetam as an add-on treatment in status epilepticus: A multicentric observational study Purpose To determine if IV levetiracetam (LEV) is safe and effective in patients in SE Unless contraindicated, all patients received a benzodiazepine + phenytoin or valproic acid as first line treatment Retrospective review of all non- generalized convulsive SE patients at 8 Spanish hospitals in 2008 Efficacy was defined as seizures stopping within 24 hours of starting IV Lev with no further AEDs givenRetrospective review of all non- generalized convulsive SE patients at 8 Spanish hospitals in 2008 Efficacy was defined as seizures stopping within 24 hours of starting IV Lev with no further AEDs given

25. Efficacy of intravenous levetiracetam as an add-on treatment in status epilepticus: A multicentric observational study When administered as early treatment in 14 patients, efficacy was 78.5% When administered as late treatment in 26 patients, efficacy was 46.1% Overall LEV was the last AED used in 23/40 patients Adverse effects: - 5 patients experienced somnolence - 1 patient experienced agitation Early treatment = after BZD because of contraindication to VPA or PHT or as first line tx when BZD was contraindicatedEarly treatment = after BZD because of contraindication to VPA or PHT or as first line tx when BZD was contraindicated

26. Refractory CPSE Lacosamide* IV bolus of 200-400 mg Maintenance dose of 100-200 mg BID Stabilizes hyperexcitable neuronal membranes and inhibits repetitive neuronal firing by enhancing inactivation of sodium channels ADRs are dizziness, headache, NVDADRs are dizziness, headache, NVD

27. Intravenous lacosamide for treatment of status epilepticus Purpose - To assess the safety and efficacy in SE 39 patients who received IV lacosamide at 3 European hospitals over a two year period were retrospectively analyzed

28. Intravenous lacosamide for treatment of status epilepticus

29. Intravenous lacosamide for treatment of status epilepticus Safety - One allergic skin reaction - Hypotension in 4 patients - Sedation in 25 patients Conclusion - Option for 3rd line treatment in SE - Safe, few drug-drug interactions

30. Second-line status epilepticus treatment: Comparison of phenytoin, valproate, and levetiracetam Retrospectively reviewed 187 cases of SE where either phenytoin, valproate, or levetiracetam was used after benzodiazepine failure Primary outcome was failure of the second-line agent failure of second line agent defined as need to give a different AED within 48 hours offailure of second line agent defined as need to give a different AED within 48 hours of

31. Second-line status epilepticus treatment: Comparison of phenytoin, valproate, and levetiracetam

32. Summary Benzodiazepines Phenytoin/Fosphenytoin

33. Learning Assessment Which medication is not considered as a treatment for CPSE? Pentobarbital Valproic Acid Levetiracetam Lacosamide

34. Questions?

35. References Meierkord H, Boon P, Engelsen B, Gocke K, Shorvon S, Tinuper P, et al. EFNS guideline on the management of status epilepticus in adults. Eur J Neurol 2010;17:348-355. Rosetti AO, Lowenstein DH. Management of refractory status epilepticus in adults: still more questions than answers. Lancet Neurol 2011;10:922-30. Huff JS, Fountain NB. Pathophysiology and Definitions of Seizures and Status Epilepticus. Emerg Med Clin N Am 2011;11:1-13. McGraw-Hill. Antiseizure Drugs. Available at http://basic-clinical-pharmacology.net/chapter%2024_%20antiseizure%20drugs.htm. Accessed March 12, 2012. Silbergleit R, Durkalski V, Lowenstein D Consit R, Pancioli A, Palesch Y, et al. Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus. N Engl J Med 2012;366:591-600. Lorazepam. Lexi-Drugs Online. Lexi-Comp Online. Lexi-Comp, Inc. Hudson, OH. Available at: http://online.lexi.com/crlonline Accessed March 5, 2012. Diazepam. Lexi-Drugs Online. Lexi-Comp Online. Lexi-Comp, Inc. Hudson, OH. Available at: http://online.lexi.com/crlonline Accessed March 5, 2012. Phenytoin. Lexi-Drugs Online. Lexi-Comp Online. Lexi-Comp, Inc. Hudson, OH. Available at: http://online.lexi.com/crlonline Accessed March 5, 2012.

36. References 9. Fosphenytoin. Lexi-Drugs Online. Lexi-Comp Online. Lexi-Comp, Inc. Hudson, OH. Available at: http://online.lexi.com/crlonline Accessed March 5, 2012. 10. Shearer P, Riviello J. Generalized convulsive status epilepticus in adults and children: Treatment guidelines and protocols. Emerg Med Clin N Am 2011;29:51-64. 11. Phenobarbital. Lexi-Drugs Online. Lexi-Comp Online. Lexi-Comp, Inc. Hudson, OH. Available at: http://online.lexi.com/crlonline Accessed March 5, 2012. 12. Levetiracetam. Lexi-Drugs Online. Lexi-Comp Online. Lexi-Comp, Inc. Hudson, OH. Available at: http://online.lexi.com/crlonline Accessed March 5, 2012. Aiguabella M, Falip M, Villaneuva V, de la Pena P, Molins A, Garcia-Morales I, et al. Efficacy of intravenous levetiracetam as an add-on treatment in status epilepticus: A multicentric observational study. Seizure 2011:20;60-64. Lacosamide. Lexi-Drugs Online. Lexi-Comp Online. Lexi-Comp, Inc. Hudson, OH. Available at: http://online.lexi.com/crlonline Accessed March 5, 2012. Kellinghaus C, Berning S, Immisch I, Larch J, Rosenow F Rossetti AO, et al. Intravenous lacosamide for treatment of status epilepticus. Acta Neurol Scand 2011;123:137-141. Alvarez V, Januel J, Burnand B, Rossetti AO. Second-line status epilepticus treatment: Comparison of phenytoin, valproate, and levetiracetam. Epilepsia 2011;52:1292-1296.