Treatment Strategies in Epilepsy

History of Epilepsy Treatment

200 BC
Horse lichen Crocodile feces Rabbit heart and genitals Boar, Ram, Rooster testicles Turtle blood

History of Epilepsy Treatment

Middle Ages
Trepanation Ingesting silver nitrate Rubbing the head with oil Wearing bracelet with nail of wrecked ship Exorcism

History of Epilepsy Treatment

1857

K+ Bromide: Sir Charles Locock

Caused temporary impotency in man

1881

Castration, Circumcision

Thought epilepsy was due to masturbation

Treatment Options
Established AEDs (antiepilepsy drugs)
Phenobarbital - 1912 Phenytoin - 1938 Ethosuximide - 1962 Carbamazepine - 1974 Valproic acid - 1978

Treatment Options
New AEDs : 1993 on

Felbamate (Felbatol) Gabapentin (Neurontin) Lamotrigine (Lamictal) Topiramate (Topamax) Tiagabine (Gabitril) Oxcarbazepine (Trileptal) Levetiracetam (Keppra) Zonisamide (Zonegran)

AEDs: Mechanisms of Action

Drug Sodium GABA T-Ca++ Excit. Currents Currents Currents Currents CBZ ++ + PHT ++ + VPA ++ ?/+ ?/Barbit + + BZD + ++ Ethosux ++ -

AEDs: Mechanisms of Action

Drugs GPT LTG TPM TGB OXC LVT ZNM Sodium GABA T-Ca++ Excit. Currents Currents Currents Currents +/? +/? ++ -/? -/? + ++ + + ++ ++ ? ? ++ ? ++ -

Treatment Options

Case 1
A 22 y.o. female presents to your office with recurrent spells. She describes a strange feeling followed by a loss of time. Witnesses describe her as staring with associated lip smacking movements and picking at her clothes. Following this she is confused and tired.

Case 1
Issues to consider
Seizure type Drug side effects Drug interactions Womens issues

Pregnancy Oral contraceptive use / hormones

Case 1
Seizure Type

All drugs except ethosuximide shown to be effective in partial onset seizures Drugs with most use in monotherapy

Pb, PHT, CBZ, VPA, LTG, OXC CBZ became the gold standard

Drugs with studies showing effectiveness in monotherapy use

Pb, PHT, CBZ, VPA, GPN, LTG, TPM, OXC, LEV, ZNS

Case 1
Adverse events

Many side effects common among all the AEDS

Neurologic

Headache, tiredness, asthenia, dizziness Nausea, constipation, diarrhea

GI

Case 1
Adverse Events

Unique to individual drugs

Pb: memory, drowsiness, Dupuytren's PHT: gingival hyperplasia CBZ: hyponatremia, weight gain VPA: weight gain, tremor, alopecia ESM: GI

Case 1
Adverse Events

Unique to individual drugs

FBM: liver failure, aplastic anemia, HA, weight loss GPN: weight gain LTG: rash if increase too quickly TPM: weight loss, cognitive, renal stones TGB: tremor OXC: hyponatremia LEV: behavior ZNS: weight loss, renal stones

Pharmacokinetics
AED
PB/Prim PHT CBZ VPA ESM

Metabolism
50% liver, 50% renal Liver Liver Liver Liver

Protein binding
Low High Moderate High Low

Effects on liver enzymes

Potent inducer Potent inducer Potent inducer inhibitor none

Pharmacokinetics
AED
GBP

Metabolism
Renal

Protein binding
Low

Effects on liver enzymes

None

LTG
TPM TGB OXC LEV

Liver
80% renal if uninduced Liver Liver Renal

Low
Low High, but low conc. Low Low

None
Mild induction (OC) None known Mild induction (OC) None

ZNS

50% liver

Low

None

AED interactions
Pb Initial AED Pb CBZ PHT VPA GPN LTG TPM OXC ZNS LEV * At higher doses * * CBZ PHT VPA GPN LTG TPM OXC ZNS LEV

Women s Issues
Effects of hormones on seizures

Estrogen shown to lower seizure threshold Progesterone shown to protect against seizures

Effects of seizures on hormones

Decreased birth rate in women with epilepsy

PB, PHT, CBZ, OXC, TPM decrease effectiveness of oral contraceptives (OC) PB, PHT, CBZ also known to increase sex hormone binding globulin (SHBG)

Effects of AED on hormones

Lowers free estrogen concentration

Womens Issues
Pregnancy

All old AEDs known to increase birth defects

CBZ, VPA increase risk of spina bifida Cardiac, craniofacial defects

Little known on newer AEDS

LTG has most data

Approximately 700 monotherapy exposures 3% birth defect rate (same as general population)

Womens Issues
Effects on fetus

Birth defects increased in women on AEDs

Major

CBZ, VPA linked to spina bifida CBZ, VPA, PHT, PB linked to heart defects and cleft lip/palate Low ears, short fingers LTG has most data-appears safe

Minor

Less known about newer AEDs

Case 2
A 14 year old boy is noted by a school teacher to be a frequent daydreamer. He is often noted to be staring and not paying attention for periods of 10-20 seconds and then quickly returns to full attention. He has a C grade average.

Case 2
Description typical for absence (petit-mal) seizures Must rule out other seizure types also

Myoclonic and tonic-clonic may frequently co-exist with absence seizures

JME (Juvenile Myoclonic Epilepsy): myoclonic, absence, tonic-clonic Ethosuximide only effective in absence seizures JME requires life-long treatment

Important in drug choice and treatment length

Case 2
Broad Spectrum Drugs

Cover multiple seizure types

VPA: covers all seizures LTG: covers all, may worsen rare form of myoclonic seizures TPM: covers most, ? Absence LEV: early data suggests broad spectrum ZNS: covers all CBZ, PHT, GPN, TGB can worsen some seizures

Do not worsen other seizure types

Myoclonic, absence

Case 3
A 72 y.o. gentleman with HTN, DM, CAD, afib had a CVA six months ago. His wife now notices episodes of right arm jerking with difficulty speaking and decreased alertness. They last 45 seconds and he is tired after them. He has had 5 identical episodes in the last week.

Case 3
Issues in the Elderly population
Differences in liver and renal function Often on multiple medications Osteoporosis More prone to adverse effects More prone to injury with seizures More prone to status epilepticus complications

Case 3
Differences in metabolism
Liver metabolism is decreased Cr. clearance is decreased

Case 3
Multiple Medications

Better to have AED with low protein binding and no enzyme induction
GBP LTG LEV ZNS OXC (mild induction) TPM (mild induction)

Case 3
Osteoporosis

Pb, PRIM, CBZ, PHT all shown to increase risk of osteoporosis

Possibly due to enzyme inducing effects

VPA: data suggestive, ? If due to VPA alone or when combined with above AEDs New AEDs: little known

Little to no enzyme induction

Case 3
Status Epilepticus

Poorer outcome associated with very young and very old

Suggests more aggressive therapy may be necessary

Case 3
Current VA study

Comparing efficacy, safety, and tolerability in three AEDs

CBZ GBP LTG

All 3 equally effective Difference in tolerability

Ltg>GBP>CBZ

Comparison of old and new AEDS

Efficacy Side Effects Interactions Cost Ease

PB PHT CBZ VPA GBP LTG TPM TGB

+++ +++ +++ +++ ++ +++ +++ ++

----++ +++ ++

------+ +++ ++ + +

+++ +++ ++ ++ ---------

+++ +++ ++ ++ + +

OXC
LVT ZNS

+++
+++ +++

++
++ ++

+
+++ +

-------

++
++ +++

Comparison of old and new AEDS

Partial Partial T-C with gen. Abs. Myoclonic Atonic

PB PHT CBZ VPA

++ ++ ++ ++

++ ++ ++ ++

++ ++ ++ ++

0 0,-++

+ 0,-++

+ 0 0,+

GBP
LTG TPM TGB OXC LVT ZNS

+
++ ++ + ++ ++ ++

+
++ ++ + ++ ++ ++

+
++ ++ + ++ + ++

0,+ 0 0 0 + +

0,+,+ 0 0 + ++

0
+ + 0 0

Starting dose GBP LTG without VPA LTG with VPA TPM 100-300 mg/day 25-50 mg /day 25 mg QOD 25-50 mg/day

Increment changes 100-300 mg/ 5-7 days 25-50 mg/ 7-14 days 25 mg every 2 weeks 25-50 mg/week

Initial target dose range 1200-1800 mg/day 200-400 mg/day 100-200 mg/day 200 mg/day

Top doses 4800 mg/day 1200 mg/day 200-400 mg/day 1200-1600 mg/day

TGB
OXC

4 mg/day
300-600 mg/day

4-8 mg/week
300-600 mg/week

16-32 mg/day
1200-1800 mg/day

56-72 mg/day
3600 mg/day

LVT
ZNS

500-1000 mg/day
100 mg/day

500-1000 mg/week
100 mg/ 1-2 week

1000-2000 mg/day
200-400 mg/day

5000 mg/day
Up to 600 mg/day

Each AED is bid dosing except GBP (tid or qid): ZNS may be once/day

Comparison of old drugs to new drugs

Medication
Dilantin Tegretol Depakote Neurontin Lamictal Topamax Gabitril Trileptal Keppra Zonegran

Typical Daily Dose

300 - 400 mg 400 800 mg 750 3000 mg 1200 3600 mg 300 800 mg 100 400 mg 12 48 mg 600 2400 mg 2000 3000 mg 200 600 mg

Monthly Cost ($)

24-32 25-58 80-295 140-356 196-300 88-355 106-250 97-360 200-305 100-300

Additional Treatment Options

Only 50% of patients achieve seizurefreedom with first AED

By the use of the third drug, only 11-14% more reach this goal

? If any further reduction with 4 or more drug trials

Other treatments necessary

Additional Treatment Options

Surgery
Temporal lobectomy Lesional Corpus Callosotomy Non-lesional Vagal Nerve Stimulator

VNS Therapy
Mild electrical pulses applied to the left vagus nerve in the neck send signals to the brain Automatic intermittent stimulation Magnet use allows patient/caregiver On-demand stimulation On-demand side effect control Simple in-office programming Assured compliance

VNS Therapy Pulse Duo Generator Model 102R

New Model 102R for use with a dual-pin lead (Model 300) for routine generator battery replacement Same technology as the Model 102 product line

6.9 mm thick (33% thinner than Model 101) Weighs 27 g (29% lighter than Model 101) 6- to 11-year battery life

Conclusions
Older AEDs are well established with years of experience

cheaper

Newer AEDS offer several advantages over older AEDs

Better tolerated Fewer to no drug interactions Several that are broad spectrum ? LTG safer in pregnancy However, more expensive

Conclusions
Be familiar with issues important with drug interactions
Protein binding Enzyme induction or inhibition

Be familiar with which drugs may worsen seizures

Important if not sure of seizure type/s

Conclusions
Be familiar with Womens Issues
Reproduction Pregnancy Interaction of AEDs with OC Relation of seizures to menses

Conclusions
Be familiar with issues in elderly
Changes in metabolism Drug interactions Osteoporosis Injury Tolerability

Key to abbreviations
AEDs: antiepilepsy drugs CBZ: carbamazepine CYP450: cytochrome P450 ESM: ethosuximide GBP: gabapentin JME: juvenile myoclonic epilepsy LTG: lamotrigine LEV: levetiracetam Na: sodium OC: oral contraceptive OXC: oxcarbazepine Pb: phenobarbital PHT: phenytoin Prim: primidone TGB: tiagabine TPM: topiramate VPA: valproic acid VNS: vagal nerve stimulation ZNS: zonisamide