andy s. jagoda, md 1 seizure and status epilepticus therapeutics: a 2005 update

Andy S. Jagoda, MD1

Seizure and Status Epilepticus Seizure and Status Epilepticus Therapeutics: A 2005 Update Therapeutics: A 2005 Update

Andy S. Jagoda, MD2

Andy S. Jagoda, MD

Professor and Vice ChairResidency Program Director

Department of Emergency MedicineMount Sinai School of Medicine

New York, NY

Andy S. Jagoda, MD3

Learning ObjectivesLearning 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

Andy S. Jagoda, MD4

Seizure Epidemiology in Seizure Epidemiology in Emergency MedicineEmergency 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

Andy S. Jagoda, MD5

Seizure TherapeuticsSeizure 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

Andy S. Jagoda, MD6

Seizure TherapeuticsSeizure Therapeutics

• New generation– IV / PO: Levetiracetam– PO: Felbamate, gabapentin,

lamotrigine, topiramate, tiagabine, oxcarbazepine, zonisamide, pregabalin

Andy S. Jagoda, MD7

Mechanism of Action of AEDsMechanism 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

Andy S. Jagoda, MD8

Old vs New AEDsOld 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

Andy S. Jagoda, MD9

Old vs New AEDsOld 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

Andy S. Jagoda, MD10

Considerations in Choosing an AEDConsiderations 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


ACEP Clinical Policy: TherapeuticsACEP 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?


QuestionQuestion

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. A 25 yo man has a witnessed GC tonic clonic sz. When he arrives in the ED, he is alert and has a When he arrives in the ED, he is alert and has a normal neurologic exam. His lab tests and CT normal neurologic exam. His lab tests and CT are normal. Which do you recommend:are normal. Which do you recommend:


Treatment of First Time SeizuresTreatment 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


Treatment of First Time SeizuresTreatment 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


QuestionQuestion

a) Fosphenytoin, 20 PE/kg, IM in the deltoidb) Fosphenytoin, 20 PE/kg, IV at 300 mg/minc) Phenytoin, 20 mg/kg IV at 50 mg/mind) Phenytoin, 20 mg/kg po and discharge after 4

hrse) Depends

A patient with epilepsy, on phenytoin, 300 mg A patient with epilepsy, on phenytoin, 300 mg qhs is status post a “typical” event but back to qhs is status post a “typical” event but back to baseline. Serum PHT level is 6 ug/ml. Which do baseline. Serum PHT level is 6 ug/ml. Which do you recommend?you recommend?


AED LoadingAED 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; 147:89-92Van der Meyden. Epilepsia 1994; 35:189-194


QuestionQuestion

a) Stop the infusion and administer the rest IMb) Continue infusion but apply warm

compresses to promote absorptionc) Inject HCO3 into the site to buffer the

infiltrationd) Stop the IV, elevate the hand, call risk

management

IV load with phenytoin is ordered. After 50 cc, IV load with phenytoin is ordered. After 50 cc, the nurse notes that the infusion has infiltrated the nurse notes that the infusion has infiltrated into the hand. What do you recommend?into the hand. What do you recommend?


PicturePicture


QuestionQuestion

a. Valium 1 mg IV push q min up to 20 mgb. Ativan 2 mg IV push q min up to 10 mgc. Phenytoin 20 mg / kg IV over 20 mind. Valproic acid 20 mg / kg IV over 5 mine. Phenobarbital 20 mg / kg at 100 mg / min

Patient arrives in status epilepticus. After Patient arrives in status epilepticus. After assessing the ABCs and checking a blood sugar, assessing the ABCs and checking a blood sugar, which of the following would be your next which of the following would be your next intervention:intervention:


STATUS EPILEPTICUS: SE Working GroupSTATUS EPILEPTICUS: SE Working Group(Consensus Document)(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


VA COOPERATIVE STUDYVA 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;339:792-798NEJM 1998;339:792-798


Refractory Status EpilepticusRefractory 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.


ACEP Clinical Policy: What agent(s) ACEP Clinical Policy: What agent(s) should be administered in SE?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.


Decision Making in Status EpilepticusDecision 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


ConclusionsConclusions• 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.


ConclusionsConclusions• 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


Questions??Questions??www.ferne.org

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Andy S. Jagoda, [email protected]

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andy s. jagoda, md 1 seizure and status epilepticus therapeutics: a 2005 update

Documents

old vs new aeds new

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emergency department

new onset seizure patients

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