Disease modification in epilepsy therapy


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  • Epileptologist: There are many answers to the question of whether epilepsy is a curable disease, depending on the point of view. Epilepsy is certainly a very dynamic disease. Each individual seizure results in a number of changes on a cellular level. Status epilepticus, as well as frequent long-lasting seizures, can result in neuronal injury. A series of animal data as well as human evidence suggests, that one might be able to intervene pharmacologically with the natural course of the disease, which we should like to discuss in detail below.
  • Epileptologist: An animal study by Gruenthal et al. shows a linear relationship between the duration of electrically induced status epilepticus and the degree of hippocampal cell death. There is also evidence in humans that seizures cause damage. Electroencephalographic and histological characteristics of a model of limbic status epilepticus permitting direct control over seizure duration. Gruenthal M., Epilepsy Res 1998 Feb;29(3):221-32 Department of Neurology, University of Louisville School of Medicine, KY 40292, USA. Status epilepticus is a neurological emergency associated with substantial morbidity and mortality. Experimental and clinical investigations suggest that prolonged seizure activity is associated with injury to vulnerable neurons. Compounds with neuroprotective properties may minimize such injury. Existing methods of inducing experimental status epilepticus result in seizure activity of variable duration and neuronal injury of variable degree. To minimize such variability, status epilepticus may be stopped with anticonvulsants, but this limits the ability to screen for independent neuroprotective properties. We have developed a simple and reliable non-pharmacological model of limbic status epilepticus in which the duration of status epilepticus is under direct experimental control. Status epilepticus is induced by continuous, unilateral hippocampal stimulation. Using this model, the degree of hippocampal pyramidal cell injury varies in direct proportion to status epilepticus duration across a range of 15-140 min. A progressive sequence of EEG changes unfolds with increasing status epilepticus duration, resembling that seen in other models. This model may serve as a reference against which the effects of potential neuroprotective compounds can be studied.
  • Epileptologist: There is evidence that neuron-specific enolase, a marker of CNS injury, increases in the serum of patients in correlation with the duration of a status epilepticus. This graph illustrates the mean duration and the highest mean serum NSE value in various types of seizure. Serum neuron-specific enolase in the major subtypes of status epilepticus C.M. DeGiorgio, MD; C.N. Heck, MD; A.L. Rabinowicz, MD; P.S. Gott, PhD; T. Smith, REEGT; and J. Correale, MD / NEUROLOGY 1999;52:746–749 Article abstract—Objectives: To determine the relative magnitudes of neuron-specific enolase (NSE) levels after complex partial status epilepticus (SE), absence SE, generalized convulsive SE, and subclinical generalized convulsive SE (frequently referred to as acute symptomatic myoclonic status epilepticus). Background: NSE is a marker of acute brain injury and blood–brain barrier dysfunction, which is elevated in SE. Methods: Serum NSE levels were drawn in 31 patients 1, 2, 3, and 7 days after SE. Patients were classified as acute symptomatic or remote symptomatic, and the duration and outcome of SE were determined and correlated with the peak NSE level. Results: NSE was elevated significantly in all four subtypes of SE, but NSE levels were highest in complex partial and subclinical SE. The mean peak NSE level for the complex partial SE group was 23.88 ng/mL (n = 12), 21.5 ng/mL for absence SE (n = 1), 14.10 ng/mL for the generalized convulsive SE group (n = 12), and 37.83 ng/mL for the subclinical SE group (n = 6), all of which was significantly higher than normal control subjects (5.02 ng/mL). Outcome was significantly different between the three groups ( p = 0.0007), and was significantly worse for subclinical SE ( p = 0.0005, subclinical versus generalized convulsive SE). Conclusion: Serum NSE levels were highest in complex partial and subclinical generalized convulsive SE. The extremely high levels of NSE in subclinical SE reflect the severity of the acute neurologic insults and poor outcome common to subclinical SE. High NSE levels in complex partial SE reflects the long duration of SE in this subgroup, and potential for brain injury.
  • Epileptologist: Steinhoff and coworkers were able to show by means of intracisternal measurements of S100 protein and neuron-specific enolase (NSE) that an elevation of these injury markers is also found interictally in the cerebrospinal fluid of patients with temporal lobe epilepsy. Ipsilateral to the seizure focus, this elevation is significant for both NSE and S 100 protein compared to control subjects (patients with trigeminal neuralgia (TN)). Cisternal S100 protein and neuron-specific enolase are elevated and site-specific markers in intractable temporal lobe epilepsy. Epilepsy Res 1999 Aug;36(1):75-82 Steinhoff BJ, Tumani H, Otto M, Mursch K, Wiltfang J, Herrendorf G, Bittermann HJ, Felgenhauer K, Paulus W, Markakis E In the brain, S100 protein and neuron-specific enolase (NSE) are mainly found in glial cells and neurons, respectively. We investigated concentrations of S100 protein and NSE in cisternal cerebrospinal fluid obtained during implantation of foramen ovale electrodes in eight patients with temporal lobe epilepsy (TLE). In addition, the meningeal markers cystatin-C and beta-trace as well as total protein were measured. Patients with trigeminal neuralgia (TN) undergoing glycerol rhizotomy served as controls. S100 protein and NSE levels ipsilateral to the site of seizure onset were significantly higher than in TN. Contralateral NSE values were also markedly but not significantly elevated. The meningeal markers cystatin-C and beta-trace protein as well as total protein did not differ in TLE and TN. We conclude that interictal temporal lobe dysfunction corresponds with neuronal and glial marker elevations in the extracellular space and that site-specific elevations may predict the site of seizure origin biochemically. Fig. 1. Individual and median values of the cisternal S100 protein and neuron-specific enolase levels in TLE ipsi- and contralateral to the site of predominating interictal and ictal epileptiform activity assessed by foramen ovale electrode EEG and in TN. The plot shows the individual S100 protein levels as filled rectangles, the neuron-specific enolase levels as filled rhombs, and the median levels as bars. Note that the differences between TLE ipsilateral to the site of seizure onset and TN were statistically significant for both parameters. The difference between contralateral TLE and TN findings was not significant.
  • Epileptologist: There is also evidence that over a period of many years patients with temporal lobe epilepsy not only exhibit hippocampal sclerosis but also hemicranial neuron loss, as illustrated by this MRI . This can be interpreted as evidence of neuronal degeneration and continuous nerve cell death. "To be able to assess whether and how the course of epilepsy can be altered, it is essential to understand how an epileptic fit occurs, how it is perpetuated and to which underlying mechanisms neuronal injury is due." Hemicranial volume deficits in patients with temporal lobe epilepsy with and without hippocampal sclerosis. Briellmann RS, Jackson GD, Kalnins R, Berkovic SF Epilepsia 1998 Nov;39(11):1174-81 Department of Neurology, and Brain Imaging Research Institute, Austin and Repatriation Medical Centre, University of Melbourne, Australia. PURPOSE: In patients with refractory temporal lobe epilepsy, studies have suggested volume deficits measured by MRI of brain structures outside the epileptogenic hippocampus. Hippocampal sclerosis (HS) is a frequent, but not obligate, finding in such patients. The present study examines the influence of the presence of HS on quantitative magnetic resonance imaging (MRI) measurements. METHODS: We analyzed 47 patients and 30 controls by quantitative MRI, including intracranial volume (ICV), hemicranial volume, hippocampal volume (HCV), and T2 relaxometry. MRI results were compared with histological findings in the resected temporal lobe. RESULTS: Histology documented HS in 35 patients (HS group) and other findings in 12 patients (no-HS group). In both groups, the hemicranial volume ipsilateral to the epileptogenic focus was significantly smaller than on the contralateral side (p < 0.004). The HCV on both sides was smaller in the HS group compared with patients without HS (p < or = 0.004). Unilateral hippocampal atrophy and increased T2 value were found in 71% of patients with HS, and bilaterally normal HCV and T2 value were found in 67% of patients without HS. CONCLUSIONS: The smaller hemicranial volume on the focus side, irrespective of the presence or absence of HS suggests a different pathogenic mechanism for the additional hemicranial volume deficit, compared to HS itself. The contralateral HCV deficit depends on the presence of HS, indicating a pathogenic connection between damage to both hippocampi.
  • Basic scientist: The principle of influencing the course of a disease pharmacologically is also found in other acute and chronic diseases.
  • Basic scientist: A review by Cole from the past year shows which cell changes can occur following status epilepticus or individual seizures.
  • Basic scientist: The kindling model of epileptogenesis is a generally accepted model for characterizing the changes that can contribute to the occurrence of epilepsy. Many of the cellular mechanisms have still not been elicited unequivocally. There are certainly also types of epilepsy which are difficult to explain by this model.
  • Basic scientist: The sprouting of mossy- fibre axons of the granula cells in the dentate gyrus can generate an excitatory feedback mechanism on their own dendrites in animal studies and hence maintain the kindling process.
  • Basic scientist: The sprouting of mossy- fibre axons of the granula cells in the dentate gyrus can generate an excitatory feedback mechanism on their own dendrites in animal studies and hence maintain the kindling process.
  • Epileptologist: An example of the development of epilepsy is illustrated here. In the early stage of the disease there is an increase in seizure frequency and severity in some patients.
  • Epileptologist: In a study by Kwan & Brodie (N Engl. J. Med. 2000, 342: 314-319) in 470 newly diagnosed epilepsy patients, 47% of patients were seizure-free with the first monotherapy tested and a further 13% with the second. A third monotherapy drug trial resulted in only a further 1% freedom from seizures. In open studies with Topamax in combination therapy, 10% of previously treatment-refractory patients became symptom-free (B. Abou-Khalil et al. Epilepsia, Vol.41, Suppl.l. 1, 2000; at least 6 months observation, focal epilepsy). This shows that freedom from seizures can also be achieved with combination therapy in patients previously classified as treatment-refractory.
  • Epileptologist: The following facts indicate that the model of development of a convulsive disorder as just described can be found in some epilepsy patients at least.
  • Basic scientist: In principle, in order to alter the course of the disease the various paths described above may be considered.
  • Basic scientist: Theoretically there are two different approaches for interfering in the process of kindling and hence in epileptogenesis. These are effective anticonvulsant therapy, which may possibly result in freedom from seizures, and the prevention of neuronal injury.
  • Basic scientist: The ideal drug therapy would naturally be provided by an anticonvulsant which also possessed neuroprotective properties. In order to be able to identify appropriate substances, it is necessary to understand the mechanisms of injury and to know which different receptors are involved in the occurrence of the injury. Stroke can be used as the best characterized model of cerebral injury. The intensive research of the past few years has succeeded in characterizing clearly the pathophysiological injury cascade.
  • Basic scientist: The schematic overview presented here summarizes some of the known mechanisms following focal cerebral ischemia. In addition to the acute energy deficit, neurons are also damaged by the massive activation of a wide variety of neuronal receptors.
  • Basic scientist: An early intervention in the cascade of damaging events is to be found in the inhibition of these channels and receptors. Some of the substances that interact with these receptors in the required way are presented below.
  • Basic scientist: The antiepileptics include some substances that certainly have more than one mechanism of action. On theoretical grounds these substances would have to exhibit the highest protective potential. In particular, pronounced significance is ascribed to the non-NMDA receptor in the pathophysiology of many injuries (cf. following diagram) so that substances which block these receptors are particualrly promising candidates. AEDs that have more than one mechanism of action and at the same time an antiglutamatergic action are topiramate, felbamate and phenobarbital. Because of their tolerability and safety, felbamate and phenobarbital tend however not to be the drugs of 1st or 2nd choice.
  • Basic scientist: The receptors described above play an important role, not only in ischemia and epilepsy, but also in other models of neuronal injury. The figure underlines the observation that the non-NMDA receptor in particular (i.e. AMPA/kainate) exerts a major influence.
  • Basic scientist: Positive study data are available for the models marked in red.
  • Basic scientist: Schematic representation of the different sites of action of topiramate. The inhibition of carbonic anhydrase, which probably contributes to stabilization of the intracellular pH through a modification of the membrane potential, is not illustrated.
  • Epileptologist: In the development of a new antiepileptic agent, the authorities initially insist on studies that prove that, in combination with established drugs, the substance can provide a further improvement in the initial situation or freedom from symptoms in previously treatment-refractory patients. These studies provide conclusions about the efficacy, safety and interactions of the substances. Subsequently studies can be undertaken in monotherapy. The results of these studies allow a better assessment of the tolerability and can confirm the broad efficacy of a drug. In principle, it can very plausibly be assumed that the probability of influencing the course of epilepsy is greatest at the beginning of the disease. However, it is conceivable that nerve tissue can also be protected by suitable neuroprotective substances in the chronic phase.
  • Epileptologist: The current registration status of Topamax in Germany: It should be stressed that Topamax is the only one of the more recent antiepileptics to be registered in the area of primarily generalized seizures and is even licensed for children as low as 2 years of age.
  • Epileptologist: Many cases of epilepsy cannot be diagnosed unequivocally at the beginning of the disease (uncertain EEG findings, no clear description of seizures, characteristics of seizures do not occur until a later timepoint). Manford M, Hart YM, Sander JWAS, Shorvon SD. The National General Practice Study of Epilepsy: The syndromic classification of the International League Against Epilepsy applied to epilepsy in a general population. Arch Neurol 1992;49:801-8. Berg AT, Shinnar S, Levy SR, Testa FM, Smith-Rapaport S, Beckerman B. How well can epilepsy syndromes be identified at diagnosis? A reassessment 2 years after initial diagnosis. Epilepsia 2000;41:1269-75.
  • Epileptologist: The multinational, randomized, double-blind controlled study was conducted in 115 centers. The design of this study mimics everyday clinical practice in a unique way: 613 patients with newly diagnosed epilepsy and any type of seizure were allocated by the investigator to standard treatment with either carbamazepine or valproate. Following this allocation, patients of both branches were randomized: into an arm with the chosen therapy and two arms with Topamax at varying dosages. Topamax was thus compared with the doctor's drug of choice. Time course: During the 7-day maximum "decision phase" the seizure process was considered retrospectively over the past 3 months. This was then followed by the doctor's choice of one of the two treatment branches ("CBZ group" or "VPA group"). The titration phase was about 35 days. The double-blind phase ended 6 months after the last randomization of a patient in the study. Titration: TPM 100: Start 25mg; weekly increase of 25mg TPM 200: Start 25mg; weekly increase to 50 mg, 100 mg, 150 mg and 200 mg CBZ: Start 200mg; weekly increase of 200mg every 2 weeks VPA: Start 250mg; weekly increase of 250mg Reasons for exclusion from the study (withdrawal): Ineffective treatment (investigator's decision), adverse events, patient's decision and "Lost to follow up", change of dosage, additional administration of another drug.
  • Epileptologist: Exclusion criteria: Exclusion criteria included non-epileptic seizures, or presence of a treatable cause of seizure, or a progressive or degenerative disorder. Choice of doses: The choice of dosage of CBZ and VPA was based on doses that had proved effective in other studies. It has been shown in other monotherapy studies that CBZ 500-600mg and 800-924mg VPA provided sufficient seizure control. Heller AJ, Chesterman P, Elwes RDC, et al. Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: A randomized comparative monotherapy trial. J Neurol Neurosurg Psychiatry 1995;58:44-50. Richens A, Davidson DLW, Cartlidge NEF, et al. A multicentre comparative trial of sodium valproate and carbamazepine in adult onset epilepsy. J Neurol Neurosurg Psychiatry 1994;57:682-7. Chadwick DW, Anhut H, Greiner MJ, et al. A double-blind trial of gabapentin monotherapy for newly diagnosed partial seizures. Neurology 1998;51:1282-8. Brodie MJ, Richens A, Yuen AWC, UK Lamotrigine/Carbamazepine Monotherapy Trial Group. Lancet 1995;345:476-9. 80%of seizure-free patients with CBZ or VPA as the 1st AED received CBZ 600 mg or less or VPA 1000 mg or less, respectively Brodie MJ, Kwan P. Effectiveness of first ever antiepileptic drug. Epilepsia 2000;41(suppl 7):89. The 100 mg and 200 mg Topiramate doses were chosen since it was to be expected that these doses would achieve the levels obtained with 200-400mg in adjuvant therapy with an enzyme-inducing AED.
  • Epileptologist: Patients had to be at least 6 years old and weigh at least 30 kg. Patients had not previously been treated or, if so, then for less than 6 weeks with an AED. The inclusion of patients who had already received an AED was permitted if there was a self-limiting underlying cause, e.g. infantile spasms. AEDs administered for a maximum of 6 weeks before the study were gradually withdrawn during the titration phase.
  • 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