Current Epilepsy Treatment Options

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  • LAMICTAL ® (lamotrigine) is indicated as adjunctive therapy for the treatment of difficult-to-treat generalized seizures of Lennox-Gastaut syndrome in patients 2 or more years of age. In 2003, LAMICTAL was approved by the FDA as adjunctive therapy for partial seizures in patients 2 or more years of age. The safety and effectiveness of LAMICTAL in patients younger than 16 years, other than those with partial seizures and the generalized seizures of Lennox-Gastaut syndrome, have not been established.
  • ZNS: En 4 pacientes zonisamida fué retirada debido a pérdida de peso (1) o falta de eficacia (3)
  • ZNS: En 4 pacientes zonisamida fué retirada debido a pérdida de peso (1) o falta de eficacia (3)
  • Diagnosis of the epilepsy syndrome or at least the seizure type is the first step in AED selection. The universe of available AEDs has generally been divided into “broad spectrum” and “narrow spectrum” agents. Broad spectrum agents can be loosely defined as agents that are effective against partial seizures, PGTCS, and one or more other generalized seizures. While these agents may not be effective against all generalized seizures, they have a lower risk than narrow spectrum agents of aggravating generalized seizures. One exception may well be LTG since it appears to aggravate myoclonic seizures. In contrast, narrow spectrum agents are typically effective against partial seizures and both SGTCS and PGTCS. However, these agents have a higher risk of aggravating nonconvulsive seizures such as absence and/or myoclonic seizures. While this classification would appear to simplify decision-making, the data from the National General Practice Study of Epilepsy showed that more than one-third of epilepsies could not be definitively classified as either partial or generalized.
  • Current Epilepsy Treatment Options

    1. 1. 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
    2. 3. 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)
    3. 4. New Antiepileptic Drugs (AEDs) <ul><li>Why are they needed ? </li></ul><ul><li>What do they offer ? </li></ul><ul><li>How do they work? </li></ul>
    4. 5. 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
    5. 6. Individualized Responses to AEDs in Adults Mattson RH et al., 1986, 1987 <ul><li>Failure 53% </li></ul><ul><li>Toxicity 20% </li></ul><ul><li>Toxicity + </li></ul><ul><li>inadequate </li></ul><ul><li>sz control 30% </li></ul><ul><li>Inadequate </li></ul><ul><li>sz control 3% </li></ul>Success 47% Initial AED (N=421) Alternate AED (N=89) <ul><li>Failure 54% </li></ul><ul><li>Toxicity 16% </li></ul><ul><li>Toxicity + </li></ul><ul><li>inadequate </li></ul><ul><li>sz control 38% </li></ul><ul><li>Inadequate </li></ul><ul><li>sz control 0% </li></ul>Success 46%
    6. 7. 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% <ul><li>Intractable 4% </li></ul><ul><li>2 nd Drug 17% </li></ul>Individualized Responses to AEDs in Children
    7. 8. 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)
    8. 9. 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%
    9. 10. “ 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
    10. 11. Reasons for Apparent Drug Resistance in Epilepsy <ul><li>Wrong diagnosis </li></ul><ul><li>Noncompliance </li></ul><ul><li>Change in drug formulation </li></ul><ul><li>Pharmacokinetic/dynamic interactions </li></ul><ul><li>Developmental pharmacokinetics </li></ul>
    11. 12. Mechanisms of Drug Resistance in Epilepsy <ul><li>Genome variability </li></ul><ul><li>– Gene polymorphisms </li></ul><ul><li>Disease-related mechanisms </li></ul><ul><li>– Etiology of seizures </li></ul><ul><li>– Disease progression </li></ul><ul><li>– Structural abnormalities </li></ul><ul><li>– Alterations in drug target/s or in brain drug uptake </li></ul><ul><li> </li></ul><ul><li> Löscher W, Potschka H., Nat Rev Neurosci:591-602,2005 </li></ul>
    12. 13. Mechanisms of Drug Resistance <ul><li>Medication-related mechanisms </li></ul><ul><li>– Loss of therapeutic efficacy (functional tolerance) </li></ul><ul><li>– Induction of drug-metabolizing enzymes (metabolic tolerance) </li></ul><ul><li> – Induction of drug tansporters </li></ul><ul><li> – Ineffective mechanism of drug action </li></ul><ul><li> </li></ul><ul><li> L öscher W, Potschka H., Nat Rev Neurosci:591-602,2005 </li></ul>
    13. 14. Drug Efflux Transporters and Multidrug Resistance Proteins (MDR) <ul><li>Initially detected in cancer cells resistent to chemotherapy </li></ul><ul><li>• Glycoprotein P (P-gp) regulated by the MDR1 gene </li></ul><ul><li>• Multidrug resistance protein (MRPs) </li></ul><ul><li>• Breast cancer resistance protein (BCRP) </li></ul><ul><li>Also located in normal cell membranes </li></ul><ul><li>Stimulate cell and tissue efflux of lipophilic drugs </li></ul><ul><li>Protect tissue intoxication by lipophilic drugs </li></ul><ul><li>Highly expressed in BBB capillary endothelial cells </li></ul><ul><li> L öscher W, Potschka H., Nat Rev Neurosci:591-602,2005 </li></ul>
    14. 16. Immunological Basis for Refractory Epilepsy <ul><li>Anti brain Abs in Landau-Kleffner </li></ul><ul><li>Anti GM1 Abs in partial cryptogenic epilepsy </li></ul><ul><li>Anti glutamate R3 Abs in Rasmussen’s encephalitis </li></ul><ul><li>Anti GAD Abs in refractory epilepsy </li></ul>
    15. 17. Factors Associated with Increased Risk for Intractable Epilepsy <ul><li>Prospective, population-based study in CT </li></ul><ul><li>Newly diagnosed epilepsy (N=613) </li></ul><ul><li>Intractable Epilepsy </li></ul><ul><ul><li>Failure of >2 AEDs, >1 sz/month, over 18 months </li></ul></ul><ul><li>Median age at onset of 5.3 years; M=F </li></ul><ul><li>Median follow-up 4.8 years; 98% followed for > 18 months </li></ul>Berg et al. Neurology 56:1445-1452, 2001 .
    16. 18. Factors Associated with Increased Risk for Intractable Epilepsy <ul><li>Initial seizure frequency (p<0.0001) </li></ul><ul><li>Focal EEG slowing (p=0.02) </li></ul><ul><li>Status epilepticus (p=0.001) </li></ul><ul><ul><li>Acute symptomatic </li></ul></ul><ul><ul><li>Neonatal </li></ul></ul><ul><li>Not significantly associated factors: </li></ul><ul><ul><li>Absolute number of seizures </li></ul></ul><ul><ul><li>Unprovoked or febrile status epilepticus </li></ul></ul>Berg et al. Neurology 56:1445-1452, 2001
    17. 19. Potential Advantages of Newer AEDs <ul><li>Fewer drug interactions </li></ul><ul><li>Better therapeutic ratio </li></ul><ul><li>Fewer adverse effects </li></ul><ul><li>Better tolerability </li></ul><ul><li>Better pharmaco-kinetics </li></ul><ul><li>No need for therapeutic drug monitoring </li></ul><ul><li>Multiple mechanisms of action </li></ul>
    18. 20. Potential Advantages of Newer AEDs: Multiple Mechanisms of Action
    19. 21. 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
    20. 22. Lamotrigine <ul><li>Mechanism:  repetitive discharges (Na++)  excitotoxicity (glutamate) </li></ul><ul><li>Adjunctive use in patients  2 years of age </li></ul><ul><ul><li>Partial seizures </li></ul></ul><ul><ul><li>Generalized seizures of Lennox-Gastaut syndrome </li></ul></ul><ul><ul><li>Primary generalized epilepsy </li></ul></ul><ul><li>Conversion to monotherapy from VPA for age >12 years </li></ul>
    21. 23. Lamotrigine <ul><li>Dosage: </li></ul><ul><ul><li>1 mg/kg/day with increments every two weeks till 10-15 mg/kg/day </li></ul></ul><ul><ul><li>0.3 mg/k/day with increments every two weeks in presence of VPA till maximum 5 mg/kg/day </li></ul></ul><ul><li>Available: 2, 5, 25, 50, 100, 150 mg tablets </li></ul><ul><li>Side effects: Skin rash (0.8%), anorexia, GI sx, insomnia, agitation, ataxia, headache, dizziness </li></ul>
    22. 24. Topiramate <ul><li>Mechanism:  repetitive discharges (Na++)  excitotoxicity (kainate/AMPA)  GABA (Cl-) </li></ul><ul><li>Class 1 evidence as add-on in: </li></ul><ul><ul><li>partial and primary generalized epilepsy, 2-12 yrs </li></ul></ul><ul><ul><li>LGS, and infantile spasms </li></ul></ul>
    23. 25. Topiramate <ul><li>Dosage: 1 mg/kg/day increments every 2 weeks until 6-9 mg/kg/day in bid or tid dose </li></ul><ul><li>Available: 15, 25, 50, 100 mg tablets/sprinkles. </li></ul><ul><li>Side effects: word finding difficulty, sedation, fatigue, ataxia, concentration difficulty, confusion, dizziness, anorexia, urolithiasis, GI, cognitive, weight loss, metabolic acidosis, fever, glaucoma. </li></ul>
    24. 26. Zonisamide <ul><li>Mechanism:  repetitive discharges (Na++)  excitotoxicity (glutamate, Ca T channels)  GABA (Cl-) </li></ul><ul><li>Add-on in partial seizures and primary generalized epilepsy including absences, JME, LGS, IS </li></ul>
    25. 27. Zonisamide <ul><li>Dosage: 1 mg/kg increments,6-9 mg/kg/day, once or twice a day because of long half life (63 hrs) </li></ul><ul><li>Available: 25, 50, 100 mg capsules </li></ul><ul><li>Side effects: Somnolence, ataxia, anorexia, renal calculi, metabolic acidosis, neuro-cognitive, fever </li></ul>
    26. 28. Levetiracetam <ul><li>Mechanism: Glutamatergic? (AMPA?)  Ca influx through N voltage channels? Binding to SV2A? </li></ul><ul><li>Add-on in partial seizures and primary generalized including SLG and JME </li></ul>
    27. 29. Levetiracetam <ul><li>Dosage: 10 mg/kg/day increments every week until 30-50 mg/kg/day in bid doses </li></ul><ul><li>Available: 250, 500 mg tablets, 500 mg/5ml elixir </li></ul><ul><li>Side effects: Sedation, nausea, behavioral, personality changes, worsening of seizures </li></ul>
    28. 30. Oxcarbazepine <ul><li>Mechanism:  repetitive discharges (Na++) (10-hydroxycarbamazepine) </li></ul><ul><li>Add-on for partial seizures in children > 2 yrs. </li></ul><ul><li>Monotherapy for partial seizures in children > 2 yrs. </li></ul>
    29. 31. Oxcarbazepine <ul><li>Dosage: 10 mg/kg/day increment every week to 30 mg/kg/day in bid doses </li></ul><ul><li>Available: 150, 300, 600 mg tablets, 300 mg/5ml elixir </li></ul><ul><li>Side effects: Similar to CBZ but of lesser magnitude, higher incidence of hyponatremia </li></ul>
    30. 32. Double-Blind Equivalence Studies: Efficacy Compared with Standard AED <ul><li>Superior efficacy </li></ul><ul><ul><li>None </li></ul></ul><ul><li>Equal efficacy </li></ul><ul><ul><li>LTG = CBZ, PHT </li></ul></ul><ul><ul><li>OXC = CBZ, PHT, VPA </li></ul></ul><ul><ul><li>TPM = CBZ and VPA </li></ul></ul><ul><li>Inferior efficacy </li></ul><ul><ul><li>VPA < CBZ (CPS) </li></ul></ul><ul><ul><li>RMC < CBZ </li></ul></ul><ul><ul><li>TGB<CBZ </li></ul></ul><ul><ul><li>VGB<CBZ </li></ul></ul>
    31. 33. Efficacy Comparison of New AED’s Monotherapy: Section of Neurology - SCHC <ul><li>209 patients </li></ul><ul><ul><li>92 M </li></ul></ul><ul><ul><li>117 F </li></ul></ul><ul><li>Type of epilepsy: </li></ul><ul><ul><li>Partial 130 </li></ul></ul><ul><ul><li>Generalized 79 </li></ul></ul><ul><li>Mean age 10.7 yrs. (range 0.5-21) </li></ul><ul><li>Mean F/U 23 mos. (range 10.4-40) </li></ul>
    32. 34. Efficacy Comparison of New AED’s Monotherapy: Section of Neurology - SCHC <ul><li>AEDs: </li></ul><ul><ul><li>Lamotrigine 20 </li></ul></ul><ul><ul><li>Topiramate 42 </li></ul></ul><ul><ul><li>Zonisamide 69 </li></ul></ul><ul><ul><li>Levetiracetam 18 </li></ul></ul><ul><ul><li>Oxcarbazepine 60 </li></ul></ul>
    33. 35. 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
    34. 36. 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
    35. 37. 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
    36. 38. Efficacy Comparison of New AED’s Monotherapy: One Center Practical Experience: Conclusions <ul><li>The 5 new AEDs studied showed high efficacy (mean 77%) as monotherapy in the treatment of pediatric epilepsy </li></ul><ul><li>Efficacy ranking: </li></ul><ul><ul><li>Lamotrigine and Trileptal (80s) </li></ul></ul><ul><ul><li>Topiramate and Zonisamide (70s) </li></ul></ul><ul><ul><li>Levetiracetam (60s) </li></ul></ul><ul><li>Adverse effects were mild and transient in the majority of cases </li></ul>
    37. 39. Factors Influencing the Choice of AEDs <ul><li>Seizure type </li></ul><ul><li>Specific epileptic syndrome </li></ul><ul><li>Side effect profile </li></ul><ul><li>Age and duration of epilepsy </li></ul><ul><li>Personal training and experience </li></ul><ul><li>Formulation / compliance </li></ul><ul><li>Titration schedule </li></ul><ul><li>Mechanism of action </li></ul>
    38. 40. <ul><li>Prospective study of 248 patients failing to respond to first AED </li></ul><ul><li>Considered seizure-free if no seizures > 1 yr </li></ul><ul><li>Similar seizure-free rates </li></ul><ul><ul><li>Substituted monotherapy </li></ul></ul><ul><ul><li>Combination (add-on) treatment </li></ul></ul>Factors Influencing the Choice of AEDs Kwan P, Brodie MJ. Seizure 9:464, 2000
    39. 41. 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
    40. 42. 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
    41. 43. 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
    42. 44. <ul><li>Rufinamide (Banzel) </li></ul><ul><li>Lacosamide (Vimpat) </li></ul><ul><li>Vigabatrin (Sabril) </li></ul>Newer AEDs
    43. 45. <ul><li>High fat, low carbohydrate (CB) diet </li></ul><ul><li>CB:Protein = 3:1 or 4:1 </li></ul><ul><li>MCT: Medium chain triglyceride </li></ul><ul><li>Atkins </li></ul>Alternative Tx for Epilepsy: Ketogenic Diet
    44. 46. <ul><li>Open label studies </li></ul><ul><ul><li>>90% reduction in 20-40% </li></ul></ul><ul><ul><li>>50% reduction in further 20-60% </li></ul></ul><ul><li>Cochrane review, 2004: No reliable evidence of efficacy </li></ul><ul><li>Lancet Neurology, 2008: </li></ul><ul><ul><li>>50% reduction in 38% </li></ul></ul><ul><ul><li>>90% reduction in 7% </li></ul></ul>Alternative Tx for Epilepsy: Ketogenic Diet
    45. 47. Alternative Tx for Epilepsy: Ketogenic Diet
    46. 48. Alternative Tx for Epilepsy Vagus Nerve Stimulator
    47. 49. <ul><li>26 children, 16 M and 10 F, 3-17 yrs </li></ul><ul><li>Refractory epilepsy, symptomatic in 77% </li></ul><ul><li>Duration tx: 1 mo-8 yrs (mean 3.5 yrs) </li></ul><ul><li>>50% seizure reduction in 54% </li></ul><ul><li><50% reduction in 23% </li></ul><ul><li>4 patients responded to magnet stimulation </li></ul><ul><li>Childs Nerv Syst 2007;23:1309-12 </li></ul>Alternative Tx for Epilepsy: Vagus Nerve Stimulator Vagus nerve stimulation in children with refractory epilepsy: unusual complications and relationship to sleep-disordered Breathing.
    48. 50. <ul><li>Focal </li></ul><ul><ul><li>Resection of lesion </li></ul></ul><ul><ul><li>Resection of epileptic focus </li></ul></ul><ul><li>Generalized </li></ul><ul><ul><li>Corpus callosotomy </li></ul></ul>Alternative Tx for Epilepsy Surgery
    49. 51. Epilepsy Surgery Evaluation <ul><li>1 . Video EEG monitoring </li></ul><ul><li>2. MRI, CT </li></ul><ul><li>3. SPECT (Interictal, Ictal), PET </li></ul><ul><li>4. Neuropsychology </li></ul><ul><li>5. Wada Test: Sodium Amobarbital test </li></ul><ul><li>6. Magnetoencephalography </li></ul><ul><li>7. Epilepsy conference </li></ul>
    50. 52. Invasive Monitoring for Epilepsy Surgery <ul><li>Intraoperative electrocorticography </li></ul><ul><li>Long-term invasive monitoring: </li></ul><ul><ul><li>Subdural grids </li></ul></ul><ul><ul><li>Epidural grids </li></ul></ul><ul><ul><li>Depth electrodes </li></ul></ul><ul><li>Cortical stimulation (brain mapping), EP’s </li></ul>
    51. 53. <ul><li>Intra-operative electrocorticography </li></ul><ul><li>Navigation </li></ul>
    52. 56. Alternative Tx for Epilepsy Surgery: Corpus Callosotomy
    53. 57. Thank you very much!

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