1. Andy S. Jagoda, MD 1 Seizure and Status Epilepticus Therapeutics: A 2005 Update

2. Andy S. Jagoda, MD 2 Professor and Vice Chair Residency Program Director Department of Emergency Medicine Mount Sinai School of Medicine New York, NY

3. Andy S. Jagoda, MD 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. Andy S. Jagoda, MD 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. Andy S. Jagoda, MD 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. Andy S. Jagoda, MD 6 Seizure Therapeutics New generation – IV / PO: Levetiracetam – PO: Felbamate, gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, zonisamide, pregabalin

7. Andy S. Jagoda, MD 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. Andy S. Jagoda, MD 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. Andy S. Jagoda, MD 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. Andy S. Jagoda, MD 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. Andy S. Jagoda, MD 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. Andy S. Jagoda, MD 12 Question a)No treatment and discharge for outpatient evaluation b)Load with phenytoin c)Load with valproic acid d)Load with a new generation AED, e.g., levetiracetam or topiramate 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:

13. Andy S. Jagoda, MD 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. Andy S. Jagoda, MD 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. Andy S. Jagoda, MD 15 Question a)Fosphenytoin, 20 PE/kg, IM in the deltoid b)Fosphenytoin, 20 PE/kg, IV at 300 mg/min c)Phenytoin, 20 mg/kg IV at 50 mg/min d)Phenytoin, 20 mg/kg po and discharge after 4 hrs e)Depends 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?

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

18. Andy S. Jagoda, MD 18 Picture

19. Andy S. Jagoda, MD 19 Picture

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

21. Andy S. Jagoda, MD 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. Andy S. Jagoda, MD 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. Andy S. Jagoda, MD 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. Andy S. Jagoda, MD 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. Andy S. Jagoda, MD 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. Andy S. Jagoda, MD 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. Andy S. Jagoda, MD 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. Andy S. Jagoda, MD 28 Questions?? www.ferne.org www.ferne.org ferne@ferne.org Andy S. Jagoda, MD andy.jagoda@mountsinai.org ferne_2005_aaem_france_jagoda_sz_fshow.ppt 8/29/2005 5:13 AM