Seizure and Status Epilepticus Therapeutics: A 2005 Update

1. Seizure and Status Epilepticus Therapeutics: A 2005 Update

2. Andy S. Jagoda, MD Professor and Vice ChairResidency Program DirectorDepartment of Emergency MedicineMount Sinai School of MedicineNew York, NY

3. Learning Objectives • Review the available therapeutics available for seizure management in the emergency department • Discuss the 2004 ACEP Clinical Policy as it pertains to therapeutics • Identify the role for second generation anti-epileptic drugs in the management of seizures in the emergency department

4. Seizure Epidemiology in Emergency Medicine • 1% of adult ED visits • 2% of pediatric ED visits • Most common ED etiologies are not epilepsy related: • Alcoholism • Stroke • Trauma • CNS infection • Metabolic / Toxin • Tumor • Fever in children • 50,000 – 100,000 ED cases of status epilepticus annually • 20% mortality

5. Seizure Therapeutics • Old generation AEDs • IV / PO: Benzodiazepine, phenytoin, barbiturates, valproic acid • PO: Carbamazepine, ethosuximide • New formulations of old generation AEDs • Fosphenytoin, valproic acid, rectal diazepam • Other – CNS depressants • Propofol, edomidate

6. Seizure Therapeutics • New generation • IV / PO: Levetiracetam • PO: Felbamate, gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, zonisamide, pregabalin

7. Mechanism of Action of AEDs • Sodium channel blockade • Phenytoins, Carbamazepine, valproic acid, felbamate, lamotrigine, topiramate, oxcarbazepine, zonisamide • Calcium channel blockade • Valproic acid, lamotrigine, topiramate, oxcarbazepine, zonisamide, levetiracetam • Glutamate antagonism • Diazepam, gabapentin, topiramate • GABA potentiation • Diazepam, phenobarbital, valproic acide, felbamate, topiramate, tiagabine, zonisamide • Carbonic anhydrase inhibition • Topiramate, carbonic anhydrase inhibition • Voltage sensitive calcium channel • Gabapentin, pregabalin

8. Old vs New AEDs • Efficacy is the same old vs new AED • 40% - 60% of patients started on an AED will remain seizure free at one year • Unethical to do a placebo controlled study with a new AED • In general, the new AEDs are not FDA approved for monotherapy

9. Old vs New AEDs • New AEDs have fewer side effects • Exceptions: felbamate and lamotrigine • Gabapentin and levetiracetam have no protein binding, are renally excreted, and have no serious side effects reported • Drug levels are not readily available for the new AEDs • Wide safe therapeutic range • Relatively safe in overdose

10. Considerations in Choosing an AED • Effectiveness for type of seizure • Delivery: PO, IM, PR, IV • Onset of action • Protein binding / competition with other drugs • Metabolism: Hepatic vs renal • Duration of action • Side effects: hypotension, respiratory depression, dysrhythmias, sclerosis / necrosis

11. ACEP Clinical Policy: Therapeutics • Which new onset seizure patients who have returned to normal baseline need to be admitted to the hospital and / or started on an AED? • What are effective phenytoin dosing strategies for preventing sz recurrence in patients who present to the ED with a subtherapeutic serum phenytoin level? • What agent(s) should be administered to a patient in status who continues to seize despite a loading dose of a benzodiazepine and a phenytoin?

12. Question A 25 yo man has a witnessed GC tonic clonic sz. When he arrives in the ED, he is alert and has a normal neurologic exam. His lab tests and CT are normal. Which do you recommend: • No treatment and discharge for outpatient evaluation • Load with phenytoin • Load with valproic acid • Load with a new generation AED, e.g., levetiracetam or topiramate

13. Treatment of First Time Seizures • Decision to initiate AED treatment depends on the risk of recurrence, ie, etiology • Etiology, CT and EEG findings are the strongest predictors • Recurrence risk is up to 20% within the first 24 hours • 20% to 70% within 2 years • Patients needing immediate AED treatment can be loaded with oral or IV phenytoin; IM forphenytoin; IV valproic acid

14. Treatment of First Time Seizures • 2004 AAN Guidelines for New Generation AEDs: • Patients with newly diagnosed epilepsy who require treatment can be initiaited on standard AEDs or on the new AEDs – choice will depend on individual patient characteristics • There is no significant difference in rate of seizure recurrence (about 50%) over a one year period • Decision to admit depends on assessed risk of recurrence, patient compliance, and patients social circumstances

15. Question A patient with epilepsy, on phenytoin, 300 mg qhs is status post a “typical” event but back to baseline. Serum PHT level is 6 ug/ml. Which do you recommend? • Fosphenytoin, 20 PE/kg, IM in the deltoid • Fosphenytoin, 20 PE/kg, IV at 300 mg/min • Phenytoin, 20 mg/kg IV at 50 mg/min • Phenytoin, 20 mg/kg po and discharge after 4 hrs • Depends

16. AED Loading • IV phenytoin achieves therapeutic serum levels by the end of the infusion • IM fosphenytoin achieves therapeutic serum levels within one hour post injection • PO phenytoin, 19 mg/kg in males and 25 mg/kg in females single dose achieves therapeutic serum levels in 4 hours Ratanakorn. J Neuro Sci 1997; 147:89-92 Van der Meyden. Epilepsia 1994; 35:189-194

17. Question IV load with phenytoin is ordered. After 50 cc, the nurse notes that the infusion has infiltrated into the hand. What do you recommend? • Stop the infusion and administer the rest IM • Continue infusion but apply warm compresses to promote absorption • Inject HCO3 into the site to buffer the infiltration • Stop the IV, elevate the hand, call risk management

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20. Question Patient arrives in status epilepticus. After assessing the ABCs and checking a blood sugar, which of the following would be your next intervention: • Valium 1 mg IV push q min up to 20 mg • Ativan 2 mg IV push q min up to 10 mg • Phenytoin 20 mg / kg IV over 20 min • Valproic acid 20 mg / kg IV over 5 min • Phenobarbital 20 mg / kg at 100 mg / min

21. STATUS EPILEPTICUS: SE Working Group(Consensus Document) • Management must simultaneously address: • Stabilization: ABCs • Diagnostic testing including (including rapid glucose) • Pharmacologic interventions • Drug therapy • Lorazepam .1 mg/kg at 2 mg/min • If diazepam is used, phenytoin must be started simulatneously • Phenytoin 20 mg/kg at 25-50 mg/min (fosphenytoin 20 mg/kg at 150 mg/min) • Repeat phenytoin 5 mg/kg • Phenobarbital 20 mg/kg at 100 mg/min • Valproic acid 20 mg/kg Epilepsy Foundation of America. JAMA 1993;270:854-859

22. VA COOPERATIVE STUDY • Prospective study: 384 patients in CSE • Four treatment regimens • Phenytoin 18 mg/kg • Diazepam plus phenytoin • Phenobarbital 15 mg/kg • Lorazepam .1 mg/kg • No difference among the four groups in recurrance of seizures or mortality at 12 hours or 30 days • Trend in favor of lorazepam; easiest to use NEJM 1998;339:792-798

23. Refractory Status Epilepticus • Systematic review of the literature • 28 studies; 193 patients • 48% mortality • Compared propofol, midazolam, and pentobarbital • Outcome: EEG burst suppression • Pentobarbital (13mg/kg load followed by 2 mg/kg/hr infusion) found to be more effective but associated with higher incidence of hypotension Claassen. Epilepsia 2002; 43:146-153.

24. ACEP Clinical Policy: What agent(s) should be administered in SE? • Level C recommendations: • Administer 1 of the following agents intravenously: “high-dose phenytoin,” phenobarbital, valproic acid, midazolam infusion, pentobarbital infusion, or propofol infusion.

25. Decision Making in Status Epilepticus • Medication history • Is the patient on VA, phenytoin, or phenobarb • Consideration of drug overdose • Avoid phenytoin in managing seizures from drug overdose • Co-morbidities: hypotension, liver disease, renal disease, meningitis, CNS lesion • Caution in using hepatically metabolized drugs in patients with liver disease • Monitoring capablities • Avoid pentabarbital unless prepared to carefully monitor and manage hypotension

26. Conclusions • Fosphenytoin has a better safety profile than phenytoin and can be safely given IM • Consider IV VA in noncompliant patients on VA who seize, and considered in treating status epilepticus refractory to primary therapies. • Most AEDs are metabolized in the liver; attention must be given to avoid inducing drug interactions.

27. Conclusions • Levatiracetam and gabapentin are not protein bound, are renally excreted, and can be used in liver patients. • Pharmacologic management of status epilepticus must be tailored to the clinical environment: Time is brain and interventions should be prioritized to rapidly terminating neuronal discharges

28. Questions?? www.ferne.orgferne@ferne.orgAndy S. Jagoda, MDandy.jagoda@mountsinai.org ferne_2005_aaem_france_jagoda_sz_fshow.ppt 8/29/2005 5:13 AM