Current Medications for

Seizure Control

Nabil J. Azar, M.D. Assistant Professor of Neurology

Director, Clinical Neurophysiology Training Program

Medical Director, Intra-operative Neuromonitoring

Vanderbilt University Medical Center

Nashville, TN

Outline • General principles of antiepileptic (AED) drugs use • AED selection: a. Depends on type of seizures and epilepsy

syndrome b. Old vs. new AEDs c. Safety and ease of use d. Presence of other medical conditions e. Titration rate and dosing f. Special populations: - Children - Women of child bearing age - elderly • Limitations of AED drug therapy

Goal of epilepsy treatment

Seizure freedom and no side effects

Efficacy and tolerability

Initiation of AED therapy • Diagnosis: seizure type (s), epilepsy syndrome and

etiology (if possible). • Selection of best (or ideal) AED: - Efficacy: one AED (monotherapy) is the goal - Safety - Tolerability - Pharmacokinetic advantages - Titration rate - Dosing - Comorbidities

Newly treated epilepsy- outcome of AED treatment

470 patients with epilepsy who had never received AED treatment: 64% were seizure-free at follow-up

Kwan & Brodie, Epilepsia 2001

Antiepileptic drugs (AEDs) old new

• Phenobarbital (Luminal) 1912 • Primidone (Mysoline) • Phenytoin (Dilantin) • Methsuximide (Celontin) • Ethosuximide (Zarontin) • Clonazepam (Klonopin) • Carbamazepine (Tegretol,

Carbatrol) • Valproate (Depakote) 1978

• Felbamate (Felbatol) 1993 • Gabapentin (Neurontin) • Lamotrigine (Lamictal) • Topiramate (Topamax) • Tiagabine (Gabitril) • Levetiracetam (Keppra) • Oxcarbazepine (Trileptal) • Zonisamide (Zonegran) • Pregabalin (Lyrica) • Vigabatrin (Sabril) • Lacosamide (Vimpat) • Clobazam (Onfi) • Rufinamide (Banzel) • Ezogabine (Potiga) 2012

Coming soon: Eslicarbazepine, brivaracetam…

Azar & Abou-Khalil; Sem in Neurol 2008

Azar & Abou-Khalil; Sem in Neurol 2008

Failed therapy due to lack of efficacy

• Option 1: substitution therapy- best if first AED has failed completely

• Option 2: add-on therapy- best if there has been some benefit • all new AEDs

Questions to be answered when AEDs fail

Some questions have to be asked: Is the diagnosis correct?

Are we dealing with a different seizure type than we thought? are seizures non-epileptic?

Are seizure medications used optimally? Is the patient taking the medication consistently? Are there other factors such as stress, sleep deprivation,

alcohol, drug abuse, another medication that worsens seizures?

Epilepsy may be truly resistant to medication treatment

Epilepsy surgery, VNS, ketogenic diet, new drug trials

Advantageous combinations

• Advantages can be based on lack of interaction • no significant interaction in either direction:

gabapentin, levetiracetam, pregabalin • do not significantly affect others, but have

shorter half-life when added to an enzyme-inducing AED:

lamotrigine, topiramate, tiagabine, oxcarbazepine, zonisamide

• Combinations with synergistic effects: • Lamotrigine + valproate • Levetiracetam + lamotrigine

Pharmacokinetic overview of old AEDs

PHT

bioavailability

Protein binding

T1/2

Autoinduction

>90% 75-85% >90% >90%

90% 75% 90% 45%

7-42 6-20 5-15 65-110

no yes no no

CBZ VPA PHB PMD

>90%

<20%

8-15

no

ESX

>90%

<10%

30-60

no

CZP

>80%

86%

30-40

no

% Metabolism 95% >95% >96% <80%

Metabolism site Liver Liver Liver Liver Liver Liver Liver

65-90% ~80%

Enz. induction yes yes yes yes no no no

Enz. Inhibition yes

Pharmacokinetic overview

of new AEDs

FBM

Absorption

dose dependent

bioavailability

Tmax (hrs)

Protein binding

T1/2

Autoinduction

no yes no no

>90% ~60% >98% >80%

1-4 2-3 1.4-4.8 1-4

25% 0% 55% 15%

18-24 5-8 12-70 20-30

no no slight no

GPN LTG TOP TGB

no

>89%

0.9-2.6

96%

2-9

no

LEV

no

~100%

~1

0%

6-8

no

OXC

no

99%

4-6*

40%*

9*

slight

ZNS

no

~100%

2-6

40%

63

no

* applies to monohydroxyderivative (MHD), the main active metabolite

PGB

no

90%

1-2.5

0%

no

5.5-6.7

Pharmacological properties Old AEDs: - Liver induction /

inhibition - Important auto-

induction - High protein binding - Common blood level

monitoring - Prevalent drug-drug

interaction

New AEDs: - No / mild liver

induction / inhibition - No / mild

autoinduction - Low protein binding - Less common blodd

level monitoring - Minimal drug-drug

interaction

Idiosynchratic toxicity of old AEDs

PHT

CBZ

VPA

PHB

PMD

Rash, enlarged lymph nodes, liver failure, blood abn

Rash, other hypersensitivity, liver failure, blood abn

Liver failure, pancreatitis (rare), blood abn

Rash, connective tissue disorders, liver failure, blood

Connective tissue disorders

ESX Blood abnormalitities

CZP Rash

Old AEDs: most problematic adverse effects

PHT

CBZ

VPA

PHB

PMD

Sedation, gum swelling

Sedation, fatigue

Sedation, weight gain, hair loss, hormonal changes

Sedation, slow thinking, lower IQ

Sedation, slow thinking

ESX Gastrointestinal malaise

CZP Sedation, constipation, tolerance

Idiosynchratic toxicity of new AEDs

FBM

GPN

LTG

TPM

TGB

Aplastic anemia, liver failure

-

Skin rash

acute angle-closure glaucoma, oligohydrosis

-

LEV -

OXC Rash

ZNS Rash, oligohydrosis

New AEDs: most problematic adverse effects

FBM

GPN, PGB

LTG

TPM

TGB

GI upset, headache, insomnia

Weight gain, myoclonus

Insomnia

Speech disorder, behavior changes, kidney stones

Confusion, dizziness

LEV Irritability, nightmares

OXC Low sodium (hyponatremia)

ZNS Behavioral changes, kidney stones

Tolerability - cognitive profiles of new AEDs

• Best - Lamotrigine - Gabapentin - Levetiracetam - Oxcarbazepine - Pregabalin - Lacosamide - Ezogabine

• Intermediate - Tiagabine - Zonisamide

• Worst - Topiramate

Prevalence of comorbidity

• Depression (50%) • Bipolar disorder (10%) • Panic attacks 50 % • Migraine: 25 % • Sleep disturbances: >25% • Restless leg syndrome: 10 % • Obesity 30 % • Spasticity: cerebral palsy, multiple sclerosis • Peripheral neuropathy • Chronic pain syndromes

Azar & Abou-Khalil, Sem in Neurol 2008

Nonepileptic indications

How other medical conditions influence our choice

– Migraine: valproate, topiramate(? for levetiracetam, zonisamide)

– Bipolar disease: lamotrigine, valproate( ? gabapentin, topiramate, oxcarbazepine)

– Obesity: topiramate, zonisamide, felbamate – Obesity + migraine: topiramate – Peripheral neuropathy, chronic pain

syndromes: pregabalin, gabapentin

Titration rates: initiation at therapeutic doses

• Rapid titration: - Most of old AEDs - Felbamate - Gabapentin - Zonisamide - Levetiracetam * - Pregabalin - Lacosamide *

• Slow titration: - Lamotrigine - Topiramate - Tiagabine - Vigabatrin - Ezogabine

* Available in intravenous form

Special considerations in Children

• General rules: - Avoid sedating AEDs because of comorbid

disorders (autism, mental retardation…) - Go slower and lower • Specifics: - Rash with lamictal is more serious - Psychosis with keppra is more common - Oligohydrosis with topamax and zonegran

more lethal - Fulminant liver failure with depakote is more

likely (2 years<)

Nadkarni et a; Neurology 2005

Bryant & Dreifuss; Neurology 1996

Pellock & Brodie; Epilepsia 1997

Women of childbearing potential • Infertility: more common than normal population

• Reproductive and sexual dysfunction: • Deapkote causing PCOS reversible with lamotrigine

• Oral contraceptive pills (OCP): - Lowered efficacy by enzyme inducing AEDs; PHB, PHT, CBZ,

PMD, TPM (>200 mg) and OXC (>900 mg) - estradiol (OCP, pregnancy) lowers efficacy of lamotrigine • Developmental abnormalities in exposed fetus: VPA has the highest risk (7- 8 %) especially in polytherapy and high

dosages, followed by CBZ and PHT (5-6 %). Some new AEDs appear safer in event of unexpected pregnancy

(ex: LTG, OXC, ? LEV ?, TPM ?, ZNS ?) Folic acid (1-4 mg daily)

Lofren et al; Epilepsy Res 2007

Artama et al; Neurology 2005

Special considerations in the elderly • General rules: - Avoid sedating AEDs because of comorbid disorders (polytherapy,

dementia…) - Go slower and lower: respond better to low doses - Avoid enzyme-inducing and highly protein-bound AEDs (i.e AEDs) - Anaylze blood levels with caution (ask for free levels) - Use extended release formulation (especially with CBZ, VPA) - Use new AEDs • Specifics: - Hyponatremia with trileptal is common (especially when taking

diuretics) - Reversible Parkinsonism with chronic VPA is not rare - Renal calculi with TPM and ZNS are more likely - Osteopenia and osteaporosis with PB, PHT and CBZ are very

common

Armaon et al; Neurology 1996

Perucca et al; Epilepsy Res 2006

Saetre et al; Epilepsia 2007

New versus old AEDs- summary • Old - Established efficacy - Poor tolerability: more

sedation - Safety issues - Fast titration - Major interactions - Blood level monitoring - Disrupt hormonal milieu - Reduce bone density

• New - Similar efficacy - Better tolerability - Better safety - Slower titration - Less interactions - More expensive - Less teratogenicity - High in breast milk

Limitations of AED therapy

• Treats the symptoms or seizures and not the disease or epilepsy – Does not prevent the development or progression

of epilepsy – Does not cure epilepsy

• We need drugs with: - Better efficacy and tolerability - Prevent epilepsy - Reverse the process of epileptogenesis