Current Epilepsy Treatment Options

Seizure Disorders in Children: New Treatment Options Agust í n Legido, MD, PhD, MBA Chief, Section of Neurology St. Christopher’s Hospital for Children Professor of Pediatrics and Neurology Drexel University College of Medicine Philadelphia, PA

Early Pharmaceutical Prescription for the Treatment of Childhood Epilepsy R x : Powdered cranium of a human philosopher Oak Hazelwood Portions of precious stones from red rubies Emeralds 5 grains of oriental crocodile Johann Victor Jägerschmidt (1684)

New Antiepileptic Drugs (AEDs)
Why are they needed ?
What do they offer ?
How do they work?

Anticonvulsant Drugs Approved in the U.S. 1912 Phenobarbital Winthrop 1935 Mephobarbital Winthrop 1938 Phenytoin Parke-Davis 1947 Mephenytoin Sandoz 1954 Primidone Ayerst 1957 Methsuximide Parke-Davis 1957 Ethotoin Abbott 1960 Ethosuximide Parke-Davis 1968 Diazepam Roche 1974 Carbamazepine Ciba-Geigy 1975 Clonazepam Roche 1978 Valproate Abbott 1981 Chlorazepate Abbott 1993 Felbamate Carter-Wallace 1993 Gabapentin Pfizer 1994 Lamotrigine Glaxo-Smith-Kline 1996 Topiramate Ortho-McNeil 1997 Tiagabine Abbott 2000 2000 2000 Zonisamide Levetiracetam Oxcarbazepine Elan Pharma UCB Pharma Novartis

Individualized Responses to AEDs in Adults Mattson RH et al., 1986, 1987
Failure 53%
Toxicity 20%
Toxicity +
inadequate
sz control 30%
Inadequate
sz control 3%
Success 47% Initial AED (N=421) Alternate AED (N=89)
Failure 54%
Toxicity 16%
Toxicity +
inadequate
sz control 38%
Inadequate
sz control 0%
Success 46%

Alternate AED (N=72) ) Success 42% Failure 58% Camfield P et al. J Pediatr 131:794, 1997 Success 61% Initial AED (N=345) Failure 21%
Intractable 4%
2 nd Drug 17%
Individualized Responses to AEDs in Children

Success with Antiepileptic Drug (AED) Regimens 13% 4% 36% 47% Seizure free with 1st drug Seizure free with 2nd drug Seizure free with 3rd or multiple drugs Not seizure free Kwan P, Brodie MJ. N Engl J Med 2000;342(5):314-319 Previously Untreated Epilepsy Patients (N=470)

Newly Diagnosed Epilepsy: Two Populations Kwan P, Brodie MJ. N Engl J Med 342:314, 2000 Respond to monotherapy ~60% Difficult-to-treat de novo ~40%

“ Epilepsy proves intractable in a number of patients for reasons that have little to do with actual failure of the medication.” O’Donohue, 1985 Medical Intractability of Epilepsy

Reasons for Apparent Drug Resistance in Epilepsy
Wrong diagnosis
Noncompliance
Change in drug formulation
Pharmacokinetic/dynamic interactions
Developmental pharmacokinetics

Mechanisms of Drug Resistance in Epilepsy
Genome variability
– Gene polymorphisms
Disease-related mechanisms
– Etiology of seizures
– Disease progression
– Structural abnormalities
– Alterations in drug target/s or in brain drug uptake

Löscher W, Potschka H., Nat Rev Neurosci:591-602,2005

Mechanisms of Drug Resistance
Medication-related mechanisms
– Loss of therapeutic efficacy (functional tolerance)
– Induction of drug-metabolizing enzymes (metabolic tolerance)
– Induction of drug tansporters
– Ineffective mechanism of drug action

L öscher W, Potschka H., Nat Rev Neurosci:591-602,2005

Drug Efflux Transporters and Multidrug Resistance Proteins (MDR)
Initially detected in cancer cells resistent to chemotherapy
• Glycoprotein P (P-gp) regulated by the MDR1 gene
• Multidrug resistance protein (MRPs)
• Breast cancer resistance protein (BCRP)
Also located in normal cell membranes
Stimulate cell and tissue efflux of lipophilic drugs
Protect tissue intoxication by lipophilic drugs
Highly expressed in BBB capillary endothelial cells
L öscher W, Potschka H., Nat Rev Neurosci:591-602,2005

Immunological Basis for Refractory Epilepsy
Anti brain Abs in Landau-Kleffner
Anti GM1 Abs in partial cryptogenic epilepsy
Anti glutamate R3 Abs in Rasmussen’s encephalitis
Anti GAD Abs in refractory epilepsy

Factors Associated with Increased Risk for Intractable Epilepsy
Prospective, population-based study in CT
Newly diagnosed epilepsy (N=613)
Intractable Epilepsy
Failure of >2 AEDs, >1 sz/month, over 18 months
Median age at onset of 5.3 years; M=F
Median follow-up 4.8 years; 98% followed for > 18 months
Berg et al. Neurology 56:1445-1452, 2001 .

Factors Associated with Increased Risk for Intractable Epilepsy
Initial seizure frequency (p<0.0001)
Focal EEG slowing (p=0.02)
Status epilepticus (p=0.001)
Acute symptomatic
Neonatal
Not significantly associated factors:
Absolute number of seizures
Unprovoked or febrile status epilepticus
Berg et al. Neurology 56:1445-1452, 2001

Potential Advantages of Newer AEDs
Fewer drug interactions
Better therapeutic ratio
Fewer adverse effects
Better tolerability
Better pharmaco-kinetics
No need for therapeutic drug monitoring
Multiple mechanisms of action

Potential Advantages of Newer AEDs: Multiple Mechanisms of Action

New Anticonvulsant Drugs Approved in the U.S. 1993 Felbamate Carter-Wallace 1993 Gabapentin Pfizer 1994 Lamotrigine Glaxo-Smith-Kline 1996 Topiramate Ortho-McNeil 1997 Tiagabine Abbott 2000 2000 2000 Zonisamide Levetiracetam Oxcarbazepine Elan Pharma UCB Pharma Novartis

Lamotrigine
Mechanism:  repetitive discharges (Na++)  excitotoxicity (glutamate)
Adjunctive use in patients  2 years of age
Partial seizures
Generalized seizures of Lennox-Gastaut syndrome
Primary generalized epilepsy
Conversion to monotherapy from VPA for age >12 years

Lamotrigine
Dosage:
1 mg/kg/day with increments every two weeks till 10-15 mg/kg/day
0.3 mg/k/day with increments every two weeks in presence of VPA till maximum 5 mg/kg/day
Available: 2, 5, 25, 50, 100, 150 mg tablets
Side effects: Skin rash (0.8%), anorexia, GI sx, insomnia, agitation, ataxia, headache, dizziness

Topiramate
Mechanism:  repetitive discharges (Na++)  excitotoxicity (kainate/AMPA)  GABA (Cl-)
Class 1 evidence as add-on in:
partial and primary generalized epilepsy, 2-12 yrs
LGS, and infantile spasms

Topiramate
Dosage: 1 mg/kg/day increments every 2 weeks until 6-9 mg/kg/day in bid or tid dose
Available: 15, 25, 50, 100 mg tablets/sprinkles.
Side effects: word finding difficulty, sedation, fatigue, ataxia, concentration difficulty, confusion, dizziness, anorexia, urolithiasis, GI, cognitive, weight loss, metabolic acidosis, fever, glaucoma.

Zonisamide
Mechanism:  repetitive discharges (Na++)  excitotoxicity (glutamate, Ca T channels)  GABA (Cl-)
Add-on in partial seizures and primary generalized epilepsy including absences, JME, LGS, IS

Zonisamide
Dosage: 1 mg/kg increments,6-9 mg/kg/day, once or twice a day because of long half life (63 hrs)
Available: 25, 50, 100 mg capsules
Side effects: Somnolence, ataxia, anorexia, renal calculi, metabolic acidosis, neuro-cognitive, fever

Levetiracetam
Mechanism: Glutamatergic? (AMPA?)  Ca influx through N voltage channels? Binding to SV2A?
Add-on in partial seizures and primary generalized including SLG and JME

Levetiracetam
Dosage: 10 mg/kg/day increments every week until 30-50 mg/kg/day in bid doses
Available: 250, 500 mg tablets, 500 mg/5ml elixir
Side effects: Sedation, nausea, behavioral, personality changes, worsening of seizures

Oxcarbazepine
Mechanism:  repetitive discharges (Na++) (10-hydroxycarbamazepine)
Add-on for partial seizures in children > 2 yrs.
Monotherapy for partial seizures in children > 2 yrs.

Oxcarbazepine
Dosage: 10 mg/kg/day increment every week to 30 mg/kg/day in bid doses
Available: 150, 300, 600 mg tablets, 300 mg/5ml elixir
Side effects: Similar to CBZ but of lesser magnitude, higher incidence of hyponatremia

Double-Blind Equivalence Studies: Efficacy Compared with Standard AED
Superior efficacy
None
Equal efficacy
LTG = CBZ, PHT
OXC = CBZ, PHT, VPA
TPM = CBZ and VPA
Inferior efficacy
VPA < CBZ (CPS)
RMC < CBZ
TGB<CBZ
VGB<CBZ

Efficacy Comparison of New AED’s Monotherapy: Section of Neurology - SCHC
209 patients
92 M
117 F
Type of epilepsy:
Partial 130
Generalized 79
Mean age 10.7 yrs. (range 0.5-21)
Mean F/U 23 mos. (range 10.4-40)

Efficacy Comparison of New AED’s Monotherapy: Section of Neurology - SCHC
AEDs:
Lamotrigine 20
Topiramate 42
Zonisamide 69
Levetiracetam 18
Oxcarbazepine 60

Efficacy Comparison of New AED’s Monotherapy: Section of Neurology – SCHC Global Seizure Reduction 52 24 74 62 15 85 60 Lamotrigine < 25% > 50% 100% AEDs Zonisamide 76 15 Levetiracetam Topiramate 61 67 33 Trileptal (only partial szs) 40 85 12

Lamotrigine: (5%), increase in myoclonic seizures Topiramate: (7%), weight loss, somnolence, memory difficulties Zonisamide: (26%), weight loss, somnolence, cognitive deficit, dizziness, decreased appetite Efficacy Comparison of New AED’s Monotherapy: Section of Neurology – SCHC Adverse Effects

Levetiracetam: (22%), somnolence, irritability, behavioral and cognitive problems Oxcarbazepine: (18%), somnolence, aggressive behavior, ataxia, dizziness, cramps Efficacy Comparison of New AED’s Monotherapy: Section of Neurology – SCHC Adverse Effects

Efficacy Comparison of New AED’s Monotherapy: One Center Practical Experience: Conclusions
The 5 new AEDs studied showed high efficacy (mean 77%) as monotherapy in the treatment of pediatric epilepsy
Efficacy ranking:
Lamotrigine and Trileptal (80s)
Topiramate and Zonisamide (70s)
Levetiracetam (60s)
Adverse effects were mild and transient in the majority of cases

Factors Influencing the Choice of AEDs
Seizure type
Specific epileptic syndrome
Side effect profile
Age and duration of epilepsy
Personal training and experience
Formulation / compliance
Titration schedule
Mechanism of action

Prospective study of 248 patients failing to respond to first AED
Considered seizure-free if no seizures > 1 yr
Similar seizure-free rates
Substituted monotherapy
Combination (add-on) treatment
Factors Influencing the Choice of AEDs Kwan P, Brodie MJ. Seizure 9:464, 2000

Patients, N Na + channel blocker + multiple actions 28 Two Na + channel blockers 5 Na + channel blocker + GABAergic drug 5 Two drugs with multiple actions 2 GABAergic + multiple actions 1 Na + channel blocker + glutamate antagonist 1 Kwan P, Brodie MJ. Seizure 9:464, 2000 Factors Influencing the Choice of AEDs

Factors Influencing the Choice of AEDs Seizure-Free Patients, % Na + channel blocker + multiple mechanisms 36% Other combinations 7% P=0.05 Kwan P, Brodie MJ. Seizure 9:464, 2000

AED Treatment Options by Seizure Type Secondarily generalized LTG PB, TPM VPA, FBM, ZNS Partial-Onset Generalized Onset Simple Complex CBZ, OXC, PHT, GBP, TGB, LEV, ZNS Absence ESM Tonic- clonic Tonic Atonic Myoclonic CZP

Rufinamide (Banzel)
Lacosamide (Vimpat)
Vigabatrin (Sabril)
Newer AEDs

High fat, low carbohydrate (CB) diet
CB:Protein = 3:1 or 4:1
MCT: Medium chain triglyceride
Atkins
Alternative Tx for Epilepsy: Ketogenic Diet

Open label studies
>90% reduction in 20-40%
>50% reduction in further 20-60%
Cochrane review, 2004: No reliable evidence of efficacy
Lancet Neurology, 2008:
>50% reduction in 38%
>90% reduction in 7%

Alternative Tx for Epilepsy Vagus Nerve Stimulator

26 children, 16 M and 10 F, 3-17 yrs
Refractory epilepsy, symptomatic in 77%
Duration tx: 1 mo-8 yrs (mean 3.5 yrs)
>50% seizure reduction in 54%
<50% reduction in 23%
4 patients responded to magnet stimulation
Childs Nerv Syst 2007;23:1309-12
Alternative Tx for Epilepsy: Vagus Nerve Stimulator Vagus nerve stimulation in children with refractory epilepsy: unusual complications and relationship to sleep-disordered Breathing.

Focal
Resection of lesion
Resection of epileptic focus
Generalized
Corpus callosotomy
Alternative Tx for Epilepsy Surgery

Epilepsy Surgery Evaluation
1 . Video EEG monitoring
2. MRI, CT
3. SPECT (Interictal, Ictal), PET
4. Neuropsychology
5. Wada Test: Sodium Amobarbital test
6. Magnetoencephalography
7. Epilepsy conference

Invasive Monitoring for Epilepsy Surgery
Intraoperative electrocorticography
Long-term invasive monitoring:
Subdural grids
Epidural grids
Depth electrodes
Cortical stimulation (brain mapping), EP’s

Intra-operative electrocorticography
Navigation

Alternative Tx for Epilepsy Surgery: Corpus Callosotomy

Thank you very much!

Current Epilepsy Treatment Options

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