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Disease modification in epilepsy therapy

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Disease modification in epilepsy therapy

  1. 1. Disease Modification in Epilepsy ? Therapy Is epilepsy curable?
  2. 2. Neuronal injury correlated with status duration ipsilateral injury (score) Seizure duration in min. Gruenthal, M., Epilepsy Res., 29 (1998) 221-232.
  3. 3. Elevation of NSE following status epilepticus NSE and status epilepticus durationNSE ng/mlStatusduration inhours Convulsive Complex partial status status = Status duration = NSE in serum DeGiorgio et al. Neurology 1999;52:746–749
  4. 4. Elevation of S-100 and NSE in temporal lobe epilepsy Steinhoff B. et al. (1999) Epilepsy Res 36(1):75-82
  5. 5. Hippocampal sclerosis /Hemicranial asymmetry Briellmann et al. (1998) Epilepsia 39(11):1174-1181
  6. 6. Acute and chronic neuronal injury• Acute injury – Status epilepticus – Stroke (focal cerebral ischemia) – Craniocerebral trauma – Global hypoxia• Chronic injury – Chronic epilepsy – Amyotrophic lateral sclerosis (ALS) – Alzheimers disease – Parkinsons disease – Multiple sclerosis
  7. 7. Postictal cell changes Susceptibility to seizures Neuro- genesis Neuronal cell death Glial activation Sprouting Protein expression Activation of kinases Early gene activation Calcium ion influx1 sec. 1 min. 1h 1 day 1 wk 1 month 1 year Time (logarithmic) modified after Cole A.J. (2000) Epilepsia 41(S2):13-22
  8. 8. Kindling hypothesisInsult Seizure Seizures Cell changes & Increased neuroplasticity: excitability • altered receptors • altered ion channels • neuronal loss • sprouting sprouting • other unknown mechanisms Altered stimulus conduction after Lynch MW et al. Curr Opin Neurol. 1996;9:97-102
  9. 9. Sprouting / Changes of theneuronal feedback mechanism Normal inter- neuronal inhibition loop Epileptogenic loop
  10. 10. Sprouting / Changes in theneuronal feedback mechanism Ben-Ari & Represa, Trends Neurosci (1990) 312-317
  11. 11. Sprouting / Changes in the neuronal feedback mechanism Ben-Ari & Represa, Trends Neurosci (1990) 312-317
  12. 12. Epileptogenesis and chronicity Altered stimulus conduction Seizure frequency and severity Cell injury Lowering of seizure (e.g. neuronal loss) threshold Seizures 1st seizure Epileptogenesis Chronicity Time
  13. 13. Course of epilepsy / A progressive process Living with Chronic epilepsy seizuresSeizure frequency Seizure severityRisk of neurodegeneration Early phase of epilepsy 1st seizure Monotherapy Combination Non-drug therapy therapy after Schmidt & Elger:Seizure-free Kwan & Brodie (2000) N Engl J Med 342:314-9
  14. 14. Clinical evidence of epileptogenesisTypical "pyknoleptic" course of an untreated juvenile absence epilepsy 120 100 80 Absences / Day 60 40 20 0 Week 1 Week 2 Week 3 Week 4 Week 5 Brandl (2001) (data on file)
  15. 15. Example: Juvenile absence epilepsy• Rapid increase in seizure frequency with an untreated disease course• If freedom from seizures is not obtained in most cases, other forms of seizure also occur• Low relapse rate in seizure-free patients• Increase in seizure frequency repeats itself in the same way if therapy is stopped prematurely• This yields the conclusion that the seizure frequency influences the course itself and not a progression in the underlying canalopathy
  16. 16. Possible mechanisms of disease modification• Delay / Prevention of epileptogenesis or disease progress• Sufficient prevention of seizures• Prevention of neuronal injury – seizure-associated – primary• Improvement of neuronal recovery and regeneration
  17. 17. Possibilities for intervention Altered stimulus conduction Seizure frequency and severity Cell injury Lowering of seizure (e.g. neuronal loss) threshold Seizures Seizures 1st seizure Epileptogenesis Chronicity Time
  18. 18. Possibilities for intervention Altered stimulus conduction Seizure frequency and severity Cell injury Cell injury Lowering of seizure (e.g. neuronal loss) (e.g. neuronal loss) threshold Seizures 1st seizure Epileptogenesis Chronicity Time
  19. 19. Neuronal injury cascade Dirnagl et al. Trends Neurosci 22:391-397 Na+ u GlluG u Na+Gl G lu Na C + Ca2+ A Depolari- P AM zation u Gl DACa2+ Na+ Cell NM Ca2+ distension CC VS Mitochondrial Enzyme injury induction DNA injury Free radicals Membrane Apoptosis degradation Inflammatory mediators
  20. 20. Neuronal injury cascade / Action of AEDs Na+ u Gl lu G u Na+ Gl G lu Na C + Ca2+ A Depolari- P AM zation u Gl DA Ca2+ Na+ Cell NM Ca2+ distension CC VS Enzyme Na+ channel blockers: induction Topiramate Free radicals Phenytoin Membrane Carbamazepine degradation Valproic acid Lamotrigine
  21. 21. Neuronal injury cascade / Action of AEDs Na+ u Gl lu G u Na+ Gl G lu Na C + Ca2+ A Depolari- P AM zation u Gl DA Ca2+ Na+ Cell M CN Ca2+ distension C VS Enzyme Ca2+ channel blockers: induction Topiramate Free radicals Lamotrigine Membrane Felbamate degradation Valproic acid Nimodipine
  22. 22. Neuronal injury cascade / Action of AEDs Na+ u lu Gl G u Na+ Gl G lu Na C + Ca2+ A Depolari- P u AM zation Gl DA Ca2+ Na+ Cell NM Ca2+ distension CC VS Enzyme induction NMDA antagonists Free radicals Membrane Felbamate degradation MK801 Ketamine
  23. 23. Neuronal injury cascade / Action of AEDs Na+ u lu Gl G u Na+ Gl G lu Na C + Ca2+ A Depolari- P u AM zation Gl DA Ca2+ Na+ Cell NM Ca2+ distension CC VS Enzyme induction AMPA antagonists Free radicals Topiramate Membrane degradation Phenobarbital
  24. 24. Mechanisms of action of AEDs 2+ + Glutamate Ca GABA Carbonic anhydrase-AED Na channel receptor channel receptor inhibition +Topiramate + + (L type) + + (AMPA/Kainate) +Phenobarbital - - + - (AMPA/Kainate)Felbamate + NMDA + (L type) + -Lamotrigine + - + (L type) - -Gabapentin + - + (L type) + -Levetiracetam - - - - -Phenytoin + - - - -Carbamazepine + - - - -Valproic acid + - + (L type) + (?) -Ethosuximide - - + (L type) - - Dirnagl U, Wiegand F (2000) Thieme Perspektiven Neurologie: Disease Modification p16
  25. 25. Effect of different receptors onknown neuronal injury models Disease model Status epilepticus Mechanism of Ischemia Cerebrocranial Cerebral palsy ALS induced cell action Hypoxia trauma injury +Na channel ++ ++ ++ ++ -blocker 2+Ca channel + + - - -blockerNMDA receptor ++ ++ - - -antagonistNon- NMDAreceptor +++ ++ +++ +++ +++antagonistGABA receptor + + ? ? -modulator +++ good; ++ moderate; + minimal; - no effect White S. (2000) Symposium: Expanding the Therapeutic Options
  26. 26. Effect of different receptors onknown neuronal injury models Disease model Status epilepticus Mechanism of Ischemia Cerebrocranial Cerebral palsy ALS induced cell action Hypoxia trauma injury +Na channel ++ ++ ++ ++ -blocker 2+Ca channel + + - - -blockerNMDA receptor ++ ++ - - -antagonistNon- NMDAreceptor +++ ++ +++ +++ +++antagonistGABA receptor + + ? ? -modulator +++ good; ++ moderate; + minimal; - no effect  = Study data with topiramate White S. (2000) Symposium: Expanding the Therapeutic Options
  27. 27. TOPIRAMATE Mechanisms of action Glutamate synapse GABA synapse Ca channel Na channel GABAAKainate/AMPA receptorreceptor Cl- Shank R.P. 2000; 2000; 41(Suppl. 1): 3-9
  28. 28. Clinical studies / Outcome parameters Combination therapy Combination therapy Monotherapy studies Monotherapy studies studies studiesSeizure frequency and severity Tolerability and Tolerability and Efficacy Efficacy (broad) efficacy (broad) efficacy Safety in Safety in in early use in early use chronic epilepsy chronic epilepsy Potential for disease modification Potential for disease modification 1st seizure Epileptogenesis Chronicity Time
  29. 29. Comparison of efficacy of new antiepilepticsMeta-analysis of controlled studies Lamotrigine I I Topiramate I I Gabapentin I I Vigabatrin I I Tiagabin I I Zonisamide I I 0 3 6 9 12 15 18 21 Number Needed to Treat (95% confidence interval) Elferink AJA, Van Zwieten-Boot BJ. Brit Med J 314: 603, 1997
  30. 30. TOPAMAX® registration status in Germany* Adjuvant therapy in adults and children of 2 years and over focal seizures primarily generalized tonic-clonic seizures Lennox-Gastaut syndrome * Date of information: 03/2000
  31. 31. TOPAMAX paediatric studies ® Controlled studies with topiramate in children: focal seizures primarily generalized tonic-clonic seizures Lennox-Gastaut syndrome juvenile myoclonic epilepsy
  32. 32. Seizure classification in newly diagnosed epilepsy Adults (N=508)* Children (N=613)** 60 59% 50% 60Patients, % 37% 40 40 29% 20 13% 12% 20 0 0 focal seizures prim. gen. seiz. undetermined *75% ≥15 yrs; Manford M et al. Arch Neurol 49:801, 1992 **Berg AT et al. Epilepsia 41:1269, 2000
  33. 33. TOPAMAX comparative study ® TPM 100 mg Randomization TPM 200 mg CBZ 600 mgInvestigator’s decision:CBZ or VPA TPM 100 mg Randomization TPM 200 mg VPA 1250 mg Decision phase Titration Maintenance therapy <7 days 35 days Privitera et al. Epilepsia, Vol. 41, Suppl. Florence, 2000, P. 138
  34. 34. TOPAMAX® comparative study Design Diagnosis of epilepsy ≤ 3 months before beginning of study Inclusion independent of type of seizure Privitera et al. Epilepsia, Vol. 41, Suppl. Florence, 2000, P. 138
  35. 35. TOPAMAX comparative study ® Patient characteristics Diagnosis of epilepsy or ≥ 2 seizures Age ≥ 6 years Weight > 30 kg Diagnosis of epilepsy ≥ 3 months before beginning of study ≥ 1 unprovoked seizure within the last 3 months Maximum AED treatment < 6 weeks Privitera et al. Epilepsia, Vol. 41, Suppl. Florence, 2000, P. 138
  36. 36. Comparative study / Patient characteristics TPM CBZ VPAN 409 126 78Sex (f/m, %) 45/55 48/52 56/44Age (median) 29 years 34 years 25 yearsTime since 1st seizure 4.0 mths 5.5 mths 5.5 mths(median)Time since diagnosis 4.0 mths 1.0 mth 1.0 mth(median)No AED at beginning 58% 62% 59%of study Poster presentation AES 2000, Los Angeles

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