Rational Selection of Epilepsy Therapies

Amit Verma, MDHMH Neurological Institute Comprehensive Epilepsy Program

Houston Methodist HospitalHouston, Texas

Disclosures

Lundbeck – Consultant, Speakers Bureau

Sunovion – Consultant, Speakers Bureau

UCB – Consultant, Speakers Bureau

Layout of Presentation

When do we start treatment?

What do we start treatment with and why?

Old and New AEDs

Options for medically refractory patients

Epilepsy

4th most common neurological disorder

2.3 million people are estimated to have epilepsy in the USA (50 million worldwide)

0.8% of the US population

Problems of intractable epilepsy

Social adjustment

Employment- 40%-60% are employed (although these jobs are

often below their potential)- 15%-20% are unemployed- 20% retire early

Driving

Intellectual functioning (seizures vs. drugs)- 56% finish high school and 15% finish college

Problems of intractable epilepsy

Co-Morbidities- Depression and psychiatric disorders- Sleep Apnea, weight gain etc.

Morbidity- Accidents, Injuries

Mortality- Sudden unexpected death in epilepsy- Status epilepticus, Suicide, Accidents, Cancer,

Infections etc.

Prevalence of Psychiatric Disorders in Epilepsy

1Kanner AM. Biol Psychiatry. 2003;54:388-398. 2Ettinger A, et al. Neurology. 2004;63:1008-1014. 3Wrench J, et al. Epilepsia. 2004;45:534-543.4Weissman MM, et al. J Clin Psychiatry. 1986;47(suppl 6)11-17.

5 Blum D, et al. In: Program and abstracts of the 54th Annual Meeting of the AAN; April 13-20, 2002.6Ettinger A, et al. Neurology. 2005;65:535-540.

7Kessler RC, et al. Arch Gen Psychiatry. 1994;51:8-19.

Prevalence, %

Epilepsy Patients General Population

Depression1-3 20-55 2-4

Anxiety/Panic Disorder4 19-45 2.5-6.5

Bipolar Disorder5,6 8-12 1-2

Psychosis7 2-8 0.5-0.7

Sleep Disordered Breathing Common in patients with epilepsy

- ? 2-3 times general population (Malow BA, Vaughn B)

Often related to- Sedentary lifestyle- Weight gain (Lifestyle vs. medications)- Vagus Nerve Stimulation may worsen preexisting

apnea

OSA can be related to poor seizure control

Treatment of OSA can result in seizure control

When do we start treatment?

Treatment is typically started after the second unprovoked seizure if:- Imaging shows findings consistent with high risk of

seizure recurrence- EEG shows findings that suggest high risk of seizure

recurrence Initial EEG positive in 29-55% Repeated EEGs increase yield to 80-90% One video-EEG study, demonstrated that 19% had no

IIEDs (mean of 6.9 days of monitoring (Walczak et al, 1993)

Several studies have demonstrated that IIEDs are rare in individuals without epilepsy

Treatment Goals

Freedom from seizures or substantial reduction in seizures- Use of medications and surgical options appropriate

for patients diagnosis and comorbidities- Minimizing adverse events (short term and long

term) and using medications with simple daily regimens

Freedom to participate and be productive members of society

Important Characteristics of an Anti Epileptic Medication

Needs to be effective

Minimal side effects

Convenient –once daily dosing is best

Rapid-acting

Broad spectrum of activity- Effective for both partial onset and generalized seizures

Not associated with exacerbation of seizures

Multiple mechanisms of action

Linear pharmacokinetics

No drug interactions

Ability to monitor levels

Lacosamide -Proposed mechanism is that it enhances slow inactivation of voltage gated sodium channels-Linear Pharmacokinetics-Twice daily dosing-PO and IV formulation available-Well tolerated (dizziness, headache, nausea, diplopia are most common AEs)

Clobazam -1,5 Benzodiazepine-Broad spectrum of activity in all seizure types associated with LGS-Extensive experience overseas-Long half life-No IV-Tolerance does not appear to be an issue as demonstrated by their pivitol trial and long term data

Highlights of the “Newer AEDs”

Eslicarbazepine Acetate

-Unique molecule as recognized by the FDA-Inhibition of voltage gated sodium channels-Once daily doing-PO formulation-Main Aes are dizziness and somnolence and can be limited by starting at 400 mg per day

Perampanel -AMPA receptor antagonist-Black box warning for behavioral side effects including hostility, aggression and homicidal ideation-Once daily dosing-Indication for both partial and generalized seizures

Other “New AEDs” Extended release preparations-Oxtellar XR-Quedexy XR-Trokendi XR

Highlights of the “Newer AEDs”

N = 194(r = -0.71,P<.0001)

Gilliam F, et al. 2000.

Relationship of Adverse Events to QOL Scores

20 30 40 50 60 70

100

80

60

40

20

0

QO

LIE

-89

Sum

mar

y S

core

AEP Summary Score

Comparison of Carbamazepine, Phenobarbital, Phenytoin, and Primidone in partial and secondarily generalized tonic-clonic seizuresMattson RH et al., NEJM 1985

Kwan and Brodie, NEJM 2000

60% patients respond to medication Early response to drug therapy confers a

favorable prognosis- Specifically response to the 1st drug

A large number of seizures before treatment is a poor prognostic indicator

No significant differences in efficacy between “old” and “new” drugs

Kwan P, Brodie MJ. 2000

Major Side Effects of Traditional/New Old AEDs

Phenobarbital Sedation, Hyperactivity, Rash, Osteomalacia

Phenytoin Gingival hyperplasia, Hirsutism, Peripheral Neuropathy, Bone marrow suppression, Osteomalacia

Primidone Sedation, Hyperactivity, Rash, Osteomalacia

Ethosuximide GI Upset, Mood changes, Lethargy, Hiccups, Headache

Carbamazepine Hyponatremia, Leucopoenia, Hepatitis, Rash

Valproate Thrombocytopenia, Tremor, Hair loss, Weight gain, Hepatitis, Pancreatitis

Felbamate Hepatic Failure, Aplastic Anemia

Gabapentin Sleepiness, Weight gain

Lamotrigine Rash (increased risk with VPA)

Topiramate Cognitive slowing, Renal stones, Acute Glaucoma, Weight Loss

Tiagibine Dizziness, Somnolence, Spike Wave Stupor

Oxcarbazepine Hyponatremia, Rash (No Leucopoenia)

Zonisamide Rash, Renal stones

Major Side Effects of New AEDs

Leviteracetam Sedation, Irritability

Lacosamide Dizziness, Headaches, Nausea, Diplopia

Eslicarbazepine Acetate

Dizziness and somnolence, Hyponatremia

Clobazam Sleepiness, Irritability in some patients

Perampanel Aggression, Hostility, Homicidal Ideation, Sedation

Risks associated with enzyme inducing AEDs Bone Mineral Density

Sexual function

Effects on levels of antidepressant and antipsychotic medications

Increased clearance of chemotherapeutic agents

Abnormal lipid profiles

Higher risk of statin use

Higher cardiovascular morbidity and mortality

Brodie et al., 2013

0 1 2 3 4 6 9 12 24

Simvastatin Acid

Sim

vast

atin

(n

g/m

L)

PlaceboCarbamazepine

0 1 2 3 4 6 9 12 24

Simvastatin

Sim

vast

atin

(n

g/m

L)

PlaceboCarbamazepine

Cmax: 68% (P<0.001)AUC: 75% (P<0.001)

Cmax: 68% (P<0.001)AUC: 82% (P<0.001)

Reduced Statin Levels: DrugInteraction With Enzyme-Inducing AED

Ucar M, et al. Eur J Clin Pharmacol. 2004;59:879-882.

Take Home Message

Avoid Using “Older” agents – especially enzyme inducing AEDs

“Newer” agents have less complicated pharmacokinetics and seem to be better tolerated

Risk of Malformations

Malformations can be “Major” or “Minor”

Risk increased with- Uncontrolled seizures- Polytherapy- High doses of polytherapy

Focus currently is at looking at longer term data post delivery – cognitive function etc

AED Pregnancy Registry – Fall 2014aedpregnancyregistry.org

Pregnancy Summary

Important to be aware of risk of malformations with different AEDs

Make sure pregnancy is planned and seizure control is best that you can achieve

? Dose of folic acid

Best medication is probably the one that best controls the patients seizures

Avoid Valproic acid and Phenobarbital

What to use????

Evidence-Based Guidelines

Limited high class evidence

Registration designed trials not conforming to clinical use

Fixed dose and titration of medication

Varying outcomes measures among studies

Do not factor in special needs of the individual patient

Challenges in AED Development and Indications for Use

Cost of drug development- Long timeline for development- Narrow Indications result in continued development

of other indications even after approval

Study Designs- Move away from placebo controlled studies- Historical control design- Rising placebo rates

Epilepsia 2010

Seizure Type and Age Range Initial Monotherapy

Felbamate Partial with and without generalization in adultsLSG: Pediatric and Adult

Yes

No

Gabapentin Partial with and without generalization above age 12Partial from 3-12

No

No

Lamotrigine Partial: Adults

LGS: Pediatric and Adult

Approved for Conversion to MonotherapyNo

Topiramate Partial: Pediatric (>2) and adultsPrimary GTCLGS

Yes (Adults and Children>10)

Tiagibine Partial: Adults and Children (>12) No

Levetiracetam Partial: Adults No

Oxcarbazepine Partial: Adults and Children (>2) Yes (Children and Adults >4)

Zonisamide Partial: Adults No

FDA Approved Indications

Seizure Type and Age Range Initial Monotherapy

Lacosamide Partial onset seizures in adults 17 or older

Yes

Clobazam Seizures associated with LGS above the age of 2

No

Eslicarbazepine Acetate Adjunctive treatment for partial onset seizures

No (Expected soon)

Perampanel Partial-Onset Seizures with or without secondarily generalized seizures in patients with epilepsy 12 years of age and older

Primary Generalized Tonic-Clonic Seizures in patients with epilepsy 12 years of age and older

No

FDA Approved Indications

What to use?????? Avoid using enzyme inducing AEDs

Use medications with simplified regimens- Extended release- Once daily dosing- Cleaner pharmacokinetic profiles

?Need to rapid onset of action

AEs can sometimes be used in certain comorbidities or should be avoided when certain comorbities present

Focal Epilepsy – All approved meds are indicated

Generalized Epilepsy- VPA, LEV, TPM, LTG, FYC, ZNS

Other Treatment Options

What are the options if medications fail?- Surgical Resection- Neurostimulation

Vagus nerve stimulation (FDA approved) Brain Stimulation

- RNS (FDA Approved)- DBS (Investigational)

- Other Hormonal therapy Immunotherapy Electroconvulsive therapy Gamma knife surgery

Surgical Resection

Seizure focus needs to be identified and be amenable to complete resection- Limited options for

Diffuse onset epilepsies Poorly localized epilepsies Multifocal epilepsies Problematic if near eloquent cortex Language, Motor function, Memory

- Patients with “lesional” epilepsy have significantly better outcomes than “nonlesional” epilepsy

A Randomized, Controlled Trial of Surgery for Temporal-Lobe EpilepsyWiebe S et al., NEJM August 2001

Patient Employment after Epilepsy Surgery Chin et al, 2007

375 adults with refractory epilepsy

Presurgical employment status was full-time (n = 148, 39.5%), part-time (n = 26, 6.9%), disabled and unemployed (n = 100, 26.7%), unemployed (n = 44, 11.7%), and other (n = 57, 15.2%)

Two years after surgery, 42.8% were employed full-time and 12.4%, part-time

Among those unemployed before surgery, better seizure outcome was associated with gaining employment at 2 years (p = 0.03)

Neurostimulation

Advantages- Localization (depends on device)

Best results with precise localization May not need to localize seizures

- Underlying function Does not appear to be disturbed

Disadvantages- Goal is palliation (at present)

Open LoopNeurostimulation

ResponsiveNeurostimulation

VNS

VNS (E01-E05) Outcomes

0

10

20

30

40

50

60

70

80

1 Year 2 Years 3 Years

≥50% Sz reductionMedian Sz reduction

Morris GL 3rd, Mueller WM and The Vagus Nerve Stimulation Study Group E01-E05. Long-term Treatment with Vagus Nerve Stimulation in Patients with Refractory Epilepsy. Neurology 53: 1731-5, 1999

VNS Side Effects

5 clinical trials (E01-E05) for VNS from 1988 to 1995- Side effects of

Hoarseness (29% year one, 2 % year 3) Paresthesia (12% year one, 0% year 3) Cough (7.8% year one, 1.6% year 3) Shortness of breath (8% year one, 3% year 3)

- Good continuation rates 96.7% after one year, 84.7% after 2 years and

72.1% after 3 years

Morris GL 3rd, Mueller WM and The Vagus Nerve Stimulation Study Group E01-E05. Long-term Treatment with Vagus Nerve Stimulation in Patients with Refractory Epilepsy. Neurology 53: 1731-5, 1999

SANTE StudyStimulation of the Anterior Nucleus of the Thalamus for Epilepsy

0

-40.4%

0.0%

-14.5%

-21.3%

-33.9%

-42.1%

-22.2%-25.3% -28.7%

-70.0%

-60.0%

-50.0%

-40.0%

-30.0%

-20.0%

-10.0%

0.0%

10.0%

20.0%

Baseline Operative (1 month)

Month 1-2 (1 month)

Month 2-3 (1 month)

Month 3-4 (1 month)

1-month groupings

Med

ian

sei

zure

fre

qu

ency

per

cen

t ch

ang

e fr

om

bas

elin

e

Active

Control

Blinded Phase(3-month total duration)

p=0.039 for the primary outcome, excluding 1 outlierp=0.002 for final month, including outlier

Primary Study Outcome – Primary Endpoint was NOT Significant

RNS™ Neurostimulator System

RNS™ System Pivotal Trial

Primary Endpoint (Blinded Period)

Primary effectiveness endpoint met- 37.9% reduction in seizure frequency over the entire

Blinded Period in stimulation group vs.17% in sham group (p < 0.012, GEE)

- In final month of blinded period (month 45): 42% vs 9% reduction in seizures (p=0.008)

Nuvasive: Post Ablation, Contrast Enhanced MR Images

Post-contrast

Ablation Fiber

ACA

Conclusions

Treatment of patients requires a great deal of awareness regarding AE profiles of different medications

AEs can sometimes be leveraged to treat comorbidities

Goal is always seizure freedom

Be aware of issues treating women especially during pregnancy

Try to refer patients for surgery evaluation early

Less invasive surgical options now available