sign in sign up
<<
Home , Zonisamide

Role of Newer Antiepileptic DISCLOSURE

COMMERCIAL INTEREST: LUNDBECK Lara Jehi, MD RELATIONSHIP: CONSULTING

“Mr. Davis” Treatment

• onset at 34 years of age • for 5 years • “Strange feeling in his head” then - persisted, 1 to 2 per month difficulty concentrating, pallor, chewing • Phenytoin + movements, unresponsiveness • Topiramate + • Rare evolution to generalized tonic- • Topiramate + clonic convulsion - Seizures decreased, 1 to 2 per year • EEG and MRI - normal

Question #1 Question #1

Mr. Davis should not be considered to Mr. Davis should not be considered to have drug resistant , as he only have drug resistant epilepsy, as he only has 1 to 2 seizures per year. has 1 to 2 seizures per year. 1. True 1. True 2. False 2. False

1 “Failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom”

Definitions “Sustained Seizure Remission”

• “Appropriately chosen” intervention • No seizures (including auras) for - Previously shown to be effective, whichever is longer – preferably in randomized controlled - 12 months, or studies - A minimum of 3 times the longest • “Adequate” trials pre-intervention inter-seizure interval - Application of the intervention in (determined from seizures occurring adequate strength / dosage for a within the past 12 months) sufficient length of time

Success of Antiepileptic Drug Regimens in Mr Davis – 45 to 49 years 470 Patients with New-Onset Epilepsy

Response to AED • On the 5th drug (zonisamide) + 50 lamotrigine at high doses 40 • Seizures gradually worsened back to 1 30 to 2 per month 20 10 • Evaluated for epilepsy surgery 0 1st 2nd 3rd AED AED 47% AED 13% 4%

Kwan and Brodie, NEJM, 2000

2 Results Ictal SPECT

• Video EEG - No interictal spikes - Non-localizable seizures (8 recorded) • MRI – normal • PET – bilateral temporal hypometabolism Injection at 23 sec Right mid posterior superior insula hyperperfusion

MEG Overall Localization is Challenging…

CS • Right hemispheric: - SPECT - insula Right dorsolateral, - MEG - mesial parietal mesial central, and superior parietal • Discordant: lobule dipoles - PET - bilateral temporal (L>R)

RIGHT RIGHT • Non-localizing: - MRI - normal - EEG – non-localized

Options Question #2

• Discussed invasive EEG versus After trying 5 seizure medications so far, ongoing medical therapy what is the chance of controlling David’s • Mr. Davis elected seizures with a new antiepileptic drug? adjustment 1. <10% 2. 10%-30% 3. About 50%

3 Question #2 Natural Course of Drug Resistant Epilepsy

Cumulative After trying 5 seizure medications so far, probability of 12- what is the chance of controlling David’s month seizure seizures with a new antiepileptic drug? remission - 33.4% 1. <10% 2. 10%-30% 3. About 50%

Callaghan, 2011

Natural Course of Drug Natural Course of Drug Resistant Epilepsy Resistant Epilepsy

Cumulative Cumulative probability of 12- probability of 12- month seizure month seizure remission - 33.4% remission - 33.4%

Risk of relapse Risk of relapse after 12-month after 12-month period of seizure period of seizure remission – 71.2% remission – 71.2% at 5 years at 5 years Overall chance of sustained seizure-freedom is <10% Callaghan, 2011 Callaghan, 2011

Many New AEDs to Choose From Suggested or Proven Efficacy in Class 1 Trials

Focal Gen Tonic Gen Gen Lennox Infantile Seizures Clonic Absence Myoclonic Gastaut Spasms

Clobazam + + + + + Zonisamide + + + + + + + + + + + Ezogabine +

Seizure: European Journal of Epilepsy 2011 Continuum, Feb 2016

4 FDA Approval and Place in Therapy

Focal Sz – Focal Sz – Monotherapy Adjunctive Special Features Time to choose a new or Adjunctive Only antiepileptic drug for Mr. Eslicarbazepine + Similar efficacy to with possibly better tolerability Davis.. Lacosamide + Better tolerated and more effective with non- blockers Perampanel + Novel mechanism of action Long half-life (once daily dosing) Ezogabine + Potential long-term toxicity (bluish skin pigmentation) Approved for adjunctive therapy of “LGS-like” seizures

Question #3 Question #3

Which antiepileptic drug regimen Which antiepileptic drug regimen combines drugs with different combines drugs with different mechanisms of action? mechanisms of action? 1.Lamotrigine + 1.Lamotrigine + Carbamazepine 2.Lamotrigine + Eslicarbazepine 2.Lamotrigine + Eslicarbazepine 3.Ezogabine + Zonisamide 3.Ezogabine + Zonisamide 4.Lamotrigine + Clobazam 4.Lamotrigine + Clobazam

Mechanisms of Action of Key Question #4 Antiepileptic Medications

Sodium Gamma- Synaptic Multiple AMPA Combining antiepileptic medications with Channel aminobutyric Vesicle Mechanisms Antagonist Blockers Acid Analog Protein 2A the same mechanisms of action increases Binding efficacy without increasing side effects. Carbamazepine Levetiracetam Valproic acid Perampanel Phenytoin Vigabatrin 1.True Lacosamide Topiramat e 2.False Lamotrigine Zonisamide Oxcarbazepine

Continuum, Feb 2016

5 Question #4 JAMA Neurology 2014

Combining antiepileptic medications with the same mechanisms of action increases efficacy without increasing side effects. • Commercial Claims Database 1.True • 96 million covered lives • July 1, 2004, through March 31, 2011 2.False • Adults with concomitant use of 2 different AEDs and a recent partial-onset seizure diagnosis • AEDs classified by mechanisms of action

Same Mechanisms of Action Different Mechanisms of Combinations Action Combinations

• Shortest continuation • Lower risk for inpatient admission • Greatest risk of discontinuation due to (odds ratio, 0.716) side effects • Lower risk for emergency department visits (odds ratio, 0.853)

Most Commonly Used AEDs Mr. Davis - Outcome Drug Main issues “Added Benefits” Levetiracetam Irritability No drug-drug interactions Minimal cognitive side effects ?Anti-epileptogenic • Changed from zonisamide + lamotrigine Lamotrigine Rash Minimal teratogenic potential Slow titration Mood stabilizer to zonisamide + lacosamide Oxcarbazepine, Hyponatremia Rapid titration Carbamazepine Osteoporosis Mood stabilizer - Continued with 1-2 seizures / month Drug-drug interactions • Clobazam added Topiramat e Weight loss Weight loss Nephrolithiasis prophylaxis - Seizure-free since July 2014 Cognitive slowing Neuropathic pain Slow titration Valproic acid Weight gain Migraine prophylaxis Thrombocytopenia Mood stabilizer Hepatotoxicity, pancreatitis Polycystic ovarian syndrome Teratogenicity

6 Case Highlights

• It is important to recognize drug- resistance and investigate non-medical treatment options • Investigating surgical treatment and optimizing medical therapy are NOT mutually exclusive • Important - but not absolutely necessary- to optimize seizure medications by mechanism of action

7