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Seizure and Status Epilepticus Therapeutics: A 2005 Update . Andy S. Jagoda, MD. Professor and Vice Chair Residency Program Director Department of Emergency Medicine Mount Sinai School of Medicine New York, NY . Learning Objectives.

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andy s jagoda md
Andy S. Jagoda, MD

Professor and Vice ChairResidency Program DirectorDepartment of Emergency MedicineMount Sinai School of MedicineNew York, NY

learning objectives
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
seizure epidemiology in emergency medicine
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
seizure therapeutics
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
seizure therapeutics1
Seizure Therapeutics
  • New generation
    • IV / PO: Levetiracetam
    • PO: Felbamate, gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, zonisamide, pregabalin
mechanism of action of aeds
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
old vs new aeds
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
old vs new aeds1
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
considerations in choosing an aed
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
acep clinical policy therapeutics
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?
question
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
treatment of first time seizures
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
treatment of first time seizures1
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
question1
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
aed loading
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

question2
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
question3
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
status epilepticus se working group consensus document
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

va cooperative study
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

refractory status epilepticus
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.

acep clinical policy what agent s should be administered in se
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.
decision making in status epilepticus
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
conclusions
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.
conclusions1
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
questions
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