Loading…

Flash Player 9 (or above) is needed to view presentations.
We have detected that you do not have it on your computer. To install it, go here.

Like this document? Why not share!

ACEP ACEP Scientific Assembly Scientific Assembly New Orleans ...

on

  • 477 views

 

Statistics

Views

Total Views
477
Views on SlideShare
477
Embed Views
0

Actions

Likes
0
Downloads
3
Comments
0

0 Embeds 0

No embeds

Accessibility

Categories

Upload Details

Uploaded via as Adobe PDF

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

ACEP ACEP Scientific Assembly Scientific Assembly New Orleans ... ACEP ACEP Scientific Assembly Scientific Assembly New Orleans ... Document Transcript

  • A Neurologist’s Perspective on Rx Objectives & AED Use 1Gregory Bergey, MD, FAAN ACEP ED Seizure and SE Patient Management: Scientific Assembly A Neurologist’s Perspective on Rx Objectives & AED Use New Orleans, LA October 16-18, 2006 Gregory Bergey, MD, FAAN Gregory Bergey, MD, FAAN Gregory Bergey, MD, FAAN Disclosures • Consultant: Pfizer, UCB, Professor of Neurology GlaxoSmithKline, Ortho McNeil • Speakers’ Bureau: Abbott, Eisai, GSK, Speakers’ Director, Johns Hopkins Epilepsy Center Novartis, Pfizer, UCB Vice-Chair for Neurological Laboratories • Grant support: Neuropace, NIH Neuropace, • No stock Johns Hopkins University School of Medicine and Hospital Baltimore, MD Gregory Bergey, MD, FAAN Gregory Bergey, MD, FAAN AAN Guidelines Key Clinical Questions on Seizures and Epilepsy • What are the priorities of the • Of 94 practice parameters or guidelines of neurologist or epileptologist who treats AAN only 3 deal with initiation of AED the seizure and epilepsy patients who therapy AED prophylaxis in brain tumors (2000) are seen in follow-up after hospital follow- • AED prophylaxis in severe brain injury (2003) admission or ED discharge? • • Treatment of the child with a first unprovoked • How can the neurologists’ priorities be neurologists’ seizure (2003) optimally met as emergency physicians • No AAN guidelines for prophylaxis with diagnose, treat, and document the care craniotomy of ED seizure and epilepsy patients? • No AAN guidelines for status epilepticus Gregory Bergey, MD, FAAN Gregory Bergey, MD, FAAN
  • A Neurologist’s Perspective on Rx Objectives & AED Use 2Gregory Bergey, MD, FAAN Treatment of the Child With a First AED Prophylaxis in Severe Unprovoked Seizure Traumatic Brain Injury AAN Practice Parameter AAN Practice Parameter • Treatment with AED is not indicated for the prevention of epilepsy (Level B) • Post-traumatic seizures Post- • Treatment with AED may be considered • Prophylaxis with phenytoin warranted in in circumstances where the benefits of high risk pts to decrease risk of seizures reducing the risk of a second seizure in first 7 days (Level A) outweigh the risks of pharmacologic • Prophylaxis with PHT, CBZ, VPA should and psychosocial side effects (Level B) not be routinely used beyond the first 7 • The decision to treat should be days to decrease risk of seizures individualized and take into account beyond that time (Level B) both medical issues and the patient and family preference Chang and Lowenstein, Neurology 2003; 60:10-16 Hirtz et al. Neurology 60:166-175, 2003 Gregory Bergey, MD, FAAN Gregory Bergey, MD, FAAN AED Prophylaxis in Patients with 2004 AAN Guideline Summaries Newly Diagnosed Brain Tumors for New AEDS AAN Practice Parameter • Released Spring, 2004 • In patients with newly diagnosed brain tumors, • Assessment of new AEDs anticonvulsant medications are not effective in preventing first seizures. Because of their lack of • Newly diagnosed epilepsy efficacy and their potential side effects, prophylactic anticonvulsants should not be used routinely in • Refractory epilepsy patients with newly diagnosed brain tumors (standard) • Guideline is evidence based (Class I - IV) • In patients with brain tumors who have not had a • Translation of evidence to recommendations seizure, tapering and discontinuing anticonvulsants after the first postoperative week is appropriate, – Level A – C particularly in those patients who are medically stable and who are experiencing side effects • No comparative data between AEDs (guideline) French et al. Neurology 2004; 62:1252-1260, 1261-1273 Gregory Bergey, MD, FAAN Gregory Bergey, MD, FAAN Glantz et al. Neurology 2000; 54:1886-1893 Treatment of Epilepsy: Treatment of Epilepsy: Lessons from Pivotal Trials Lessons from Pivotal Trials • Initial VA cooperative trials • VA cooperative trial in elderly demonstrated carbamazepine and demonstrated lamotrigine better phenytoin more successful than tolerated than gabapentin and valproate, phenobarbital, or primidone gabapentin better than carbamazepine for partial seizures (Mattson et al. NEJM in new onset seizures 1985; 313:145-151) 313:145- • Sustained release carbamazepine not • No comparable trials with 2nd generation used; trial begun before levetiracetam AEDs approved • Other factors (e.g. pharmakokinetics, pharmakokinetics, enzyme inducion) may guide selection inducion) (Rowan AJ et al. Neurology 2005; 64:1868-1873) Gregory Bergey, MD, FAAN Gregory Bergey, MD, FAAN
  • A Neurologist’s Perspective on Rx Objectives & AED Use 3Gregory Bergey, MD, FAAN Treatment of Epilepsy: Lessons from Pivotal Trials Seizure ER Presentation • VA status epilepticus trial • New onset seizures demonstrated that in convulsive • Provoked status phenytoin alone not as good as • Unprovoked lorazepam or diazepam + phenytoin • Single or multiple seizures (Treiman DM et al. N Engl J Med. 1998;339:792-798). • Status trials with valproate difficult to • Seizures in patient with known seizure do due to interaction with phenytoin history • No status trials with levetiracetam • Single or multiple seizures • Animal studies and anectodal evidence suggest possible efficacy Gregory Bergey, MD, FAAN Gregory Bergey, MD, FAAN Seizure ER Questions: Important Epileptic New Onset Seizures Syndromes • Provoked seizures often do not require • Absence epilepsy (childhood or juvenile) treatment unless multiple • May have associated GTCS • Assess seizure type • Localization related childhood epilepsies • Primary generalized typically have onset in childhood or teenage years • Idiopathic partial (e.g. benign rolandic) • Almost all unprovoked seizures in • Juvenile myoclonic epilepsy (JME) adults or elderly are partial onset • Myoclonic seizures, rare GTCS, ± absence reflecting symptomatic (or cryptogenic) etiology • Idiopathic Gregory Bergey, MD, FAAN Gregory Bergey, MD, FAAN AED Use: AED Use: General Considerations Initial Monotherapy • All AEDs (except ethosuximide) ethosuximide) • AEDs typically initially approved as useful for partial seizures (with or adjunctive therapy for partial seizures • FDA requires superiority trials in without GTCS) epilepsy (not in many other disorders) • Broad spectrum AEDs useful for • European union accepts noninferiority partial and primary generalized trials • Superiority trials difficult to do; ethical seizures concerns in refractory patients • Some AEDs can exacerbate • All AEDs probably effective as primary generalized seizures monotherapy Gregory Bergey, MD, FAAN Gregory Bergey, MD, FAAN
  • A Neurologist’s Perspective on Rx Objectives & AED Use 4Gregory Bergey, MD, FAAN Potential AED Exacerbation of Seizures Broad Spectrum AEDs Typical Absence Myoclonic • First generation • Second generation • Carbamazepine • Carbamazepine • Valproate* • Lamotrigine • Gabapentin • Gabapentin • Oxcarbazepine • Lamotrigine • Levetiracetam* • Phenytoin • Oxcarbazepine • Topiramate • Pregabalin • Phenytoin • Zonisamide • Tiagabine • Pregabalin • Tiagabine * Available as parenteral formulations Gregory Bergey, MD, FAAN Gregory Bergey, MD, FAAN Evidence Based Treatment of Idiopathic Generalized Epilepsies Valproate Use in Young Women (Class I or II Data Supporting Use) • Valproate should not be first choice • Typical absence agent for treatment of seizures in • Valproate (FDA approved) women of childbearing age • Lamotrigine (AAN Guidelines) • Major malformation rate of ~10% • Myoclonic* • North American AED registry has identified valproate and phenobarbital • Levetiracetam (FDA approved) as having significantly higher risk to • Generalized tonic-clonic* fetus • Topiramate (FDA approved) • Growing concern about increased risk *No class I or II data for valproate in primary GTCS myoclonic seizures for learning disabilities Gregory Bergey, MD, FAAN Gregory Bergey, MD, FAAN Bergey GK, Epilepsia 2005; 46 Suppl 9:161-168 Treatment Considerations for New Onset Seizures AED Titration • Is AED therapy indicated? • AEDs that can be rapidly introduced • Risk of seizure recurrence without respiratory or systemic • Is AED loading indicated? support • Oral vs parenteral • Gabapentin • Levetiracetam* • Are benzodiazepines indicated? • Phenytoin / Fosphenytoin* • Reserve for status epilepticus or • Pregabalin seizure clusters, not just recurrent • Valproate* seizures *Agents with approved parenteral formulations Gregory Bergey, MD, FAAN Gregory Bergey, MD, FAAN
  • A Neurologist’s Perspective on Rx Objectives & AED Use 5Gregory Bergey, MD, FAAN Levetiracetam: AED Initiation IV and Oral Loading Single 1500 mg dose • Steady state is reached after 5 half- of tablet formulation compared with 15 lives minute infusion of • Agents with short half-lives (e.g. 1500 mg of IV formulation. pregabalin, levetiracetam t ½ ~ 7 hrs) reach steady state in < 48 hrs Tmax of IV formulation was 0.25 h; for oral • Agents with long half lives (e.g. formulation was Oral Loading phenbarbital, zonisamide) may take 0.75 h. weeks to reach steady state After initial difference • Oral loading possible with some in time to peak, plasma concentration vs time AEDs (phenytoin, levetiracetam) curves were comparable for IV and tablet Gregory Bergey, MD, FAAN Ramael S et al. Clin Ther 2006;28:734-744 Gregory Bergey, MD, FAAN Serum Levels and Dose Serum Levels and Dose Adjustments Adjustments: Phenytoin • Therapeutic levels even for first generation agents are somewhat • Range of 10 – 20 µg/ml reasonable arbitrary target • Levels slightly above range provide • Therapeutic levels not established for additional seizure control, but may not second generation agents be tolerated • Typically sent to outside labs • High levels (~ 40 µg/ml) may • Useful when patient is at upper dose range or exacerbate seizures noncompliant • Nonlinear kinetics influence titration • Adjustments in dose of 2nd generation AEDs can appropriately be made without levels • Elderly may not tolerate high “therapeutic” levels therapeutic” Gregory Bergey, MD, FAAN Gregory Bergey, MD, FAAN Serum Levels and Dose Serum Levels and Dose Adjustments Adjustments: 2nd Generation AEDs • Carbamazepine range 4 – 12 µg/ml • Lamotrigine 3 – 18 µg/ml • Most patients will not tolerate levels • Well tolerated much above this • After slow introduction to minimize • With initiation must go slowly due to risk of rash, adjustments well tolerated autoinduction • Enzyme inducers, OCPs, pregnancy OCPs, • Valproate range 50 - 125 µg/ml dramatically lower levels of LTG • Patients can tolerate levels above this • Dose range 150 – 800 mg/day as • Dose dependent action tremor monotherapy • Dose dependent thrombocytopenia (platelets functional) Gregory Bergey, MD, FAAN Gregory Bergey, MD, FAAN
  • A Neurologist’s Perspective on Rx Objectives & AED Use 6Gregory Bergey, MD, FAAN Serum Levels and Dose Serum Levels and Dose Adjustments: 2nd Generation AEDs Adjustments: 2nd Generation AEDs • Levetiracetam 10 – 60 µg/ml • Oxcarbazepine 15 – 50 µg/ml (MHD) • Adjustments of 500 or 1000 mg well • Typical daily doses of 600 – 2400 mg, tolerated rarely tolerated above this range • No induction, no drug interactions • Less induction and drug reactions than carbamazepine • Typical dose 1000 – 3000 mg/d; can go higher if benefit • Topiramate 3- 20 µg/ml • Typical daily doses for epilepsy 100 – 800 mg • Titrate slowly at higher doses (> 200 mg) Gregory Bergey, MD, FAAN Gregory Bergey, MD, FAAN Serum Levels and Dose Approach to the ER Patient with Adjustments: 2nd Generation AEDs Established Seizure Disorder • Pregabalin – no drug levels • Repeat imaging rarely indicated if established seizure type/pattern unchanged • Typical daily dose 150 – 600 mg • If compliance good dose adjustment • Little benefit with higher dosing of AED appropriate • No hepatic induction, no drug • Based on serum levels of 1st interactions generation agents • Based on daily dose of 2nd generation agents Gregory Bergey, MD, FAAN Gregory Bergey, MD, FAAN ER Treatment of Epilepsy: ER Treatment of Epilepsy: Adding a Second AED Adding a Second AED • If patient dose not (or would not be • Avoid combinations of phenytoin and expected to) tolerate higher dose of carbamazepine (both hepatic established agent inducers) • Chose agent based on seizure type • Avoid adding carbamazepine to • Partial or primary generalized seizures lamotrigine or zonisamide (will reduce • Partial seizure AED or broad spectrum AED levels) • Minimize drug interactions • Avoid adding valproate to lamotrigine • Choose agent based on patient and (will double levels) side effect profile Gregory Bergey, MD, FAAN Gregory Bergey, MD, FAAN
  • A Neurologist’s Perspective on Rx Objectives & AED Use 7Gregory Bergey, MD, FAAN ER Treatment of Epilepsy: Status Epilepticus Conclusions • Phenytoin/fosphenytoin + • Seizure classification (partial vs benzodiazepine still first line therapy primary generalized) important in AED selection • Do not delay general anesthesia in refractory SE • 2nd generation AEDs can be • Levetiracetam may be useful, but good adjusted in the ED without serum studies in humans are lacking levels • Comparative trials between 2nd generation AEDs are needed to guide therapy Gregory Bergey, MD, FAAN Gregory Bergey, MD, FAAN Questions? www.FERNE.org gbergey@jhmi.edu 410 955 7338 ferne_acep_2006_bergey_neuropriorities_101406_finalcd 2/2/2007 4:08 PM Gregory Bergey, MD, FAAN