Acute Seizure Management

Krista L Brown, PharmD PGY1 Pharmacy Resident

Objectives
1. Describe the pathophysiology and etiology of status epilepticus
2. List the current guidelines for pharmacological treatment of status epilepticus 3. Examine recently published literature on new treatment options for refractory status epilepticus

What is Status Epilepticus (SE)?

A. 5 minutes or more of continuous seizure activity
B. 2 or more discrete seizures without complete recovery of consciousness between them C. 10 minutes or more of continuous seizure activity D. 30 minutes or more of continuous seizure activity

Epidemiology
Incidence of 10-40 persons per 100,000
2nd most common neurological emergency 23-43% develop refractory SE

Mortality rates of 10-20%

Rossetti AO, Lowenstein DH. Lancet neurol 2011;10:922-30.

Pathophysiology
Glutamate
Most common excitatory neurotransmitter Excess excitation mediated through the

N-methyl-D-aspartate (NMDA) receptor

Huff JS, Fountain NB. Emerg Med Clin N Am. 29 (2011) 1-13.

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

Huff JS, Fountain NB. Emerg Med Clin N Am. 29 (2011) 1-13.

GABA

Pathophysiology
Voltage gated Na channels - Phenytoin - Lacosamide Synaptic Vesicle Proteins - Levetiracetam

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

Silbergleit R, Lowenstein D, et al. NEJM 2012;366(7): 591-600

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

RAMPART
IM Midazolam
Seizures had terminated upon arrival to ED, no rescue therapy given % (95% CI)

IV Lorazepam

73.4% (69.377.5)

63.4 (58.967.9)

Hospitalized N (%) RR (95% CI)

ICU admission N (%) RR (95% CI) Did not receive study medication

258 (57.6) 0.88 (0.790.98)

292 (65.6)

128 (28.6) 0.79 (0.650.95)

161 (36.2)

5 due to autoinjector malfunction

42 no IV access obtained 11 other reasons 95 convulsions stopped

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

Phenytoin
Purple Glove Syndrome

Phenytoin
Other adverse effects include:
Hypotension Arrhythmia

Thrombophlebitis
Dizziness

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

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

Meierkord H, Boon P, et al. Eur J Neurol 2010;17:348-355.

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

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

Learning Assessment
Which of the following is considered first line treatment in status epilepticus?
A.Phenobarbital

B.Lorazepam
C.Phenytoin D.Valproic Acid

Non-Convulsive Status Epilepticus

Absence Status Epilepticus
Complex Partial Status Epilepticus (CPSE) Subtle Status Epilepticus

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
* Unlabeled Use Shearer P, Riviello J. Emerg Med Clin N Am 2011;29:51-64.

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

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 GABAs inhibitory transmissions, or bind to synaptic proteins which modulate neurotransmitter release
*Unlabeled use

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

Aiguabella M, Falip M, et al. Seizure 2011;20:60-64.

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

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

* Unlabeled Use

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

Kellinghaus C, Berning S, et al. Acta Neurol Scand 2011: 123; 137-141.

Intravenous lacosamide for treatment of status epilepticus

1st or 2nd line therapy Lacosamide last medication administered 3rd line therapy 4th or later therapy Total

11

17 (44%)

SE terminated

18

11

34 (87%)

SE not terminated

5 (13%)

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

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 secondline agent

Alvarez V, Januel J, Burnand B, Rossetti AO. Epilepsia 2011;52:12921296.

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

Failure of 2nd line agent

Adjusted Odds Ratio (ref is Valproic Acid)

95% CI

p value

Phenytoin

1.88

0.85-4.14

0.119

Levetiracetam

2.69

1.19-6.08

0.017

Summary

Benzodiazepines
Phenytoin/Fosphenytoin

GCSE - AED vs anesthetizing agent

NCSE - Valproic Acid - Levetiracetam - Lacosamide - Phenobarbital

Learning Assessment
Which medication is not considered as a treatment for CPSE?
1. Pentobarbital

2. Valproic Acid
3. Levetiracetam 4. Lacosamide

Questions?

References
1. 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-clinicalpharmacology.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. 2. 3. 4.

5.

6. 7.

8.

Phenytoin. Lexi-Drugs Online. Lexi-Comp Online. Lexi-Comp, Inc. Hudson, OH. Available at: http://online.lexi.com/crlonline Accessed March 5, 2012.

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.
12. 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. 13. Lacosamide. Lexi-Drugs Online. Lexi-Comp Online. Lexi-Comp, Inc. Hudson, OH. Available at: http://online.lexi.com/crlonline Accessed March 5, 2012. 14. 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. 15. Alvarez V, Januel J, Burnand B, Rossetti AO. Second-line status epilepticus treatment: Comparison of phenytoin, valproate, and levetiracetam. Epilepsia 2011;52:1292-1296.