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New Anti-Epileptic Drugs in Pharmacoresistant Epilepsy : Retention Time As Outcome Parameter

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New Anti-Epileptic Drugs in Pharmacoresistant Epilepsy : Retention Time As Outcome Parameter New anti-epileptic drugs in pharmacoresistant epilepsy : retention time as outcome parameter Citation for published version (APA): Bootsma, H. P. (2009). New anti-epileptic drugs in pharmacoresistant epilepsy : retention time as outcome parameter. Datawyse / Universitaire Pers Maastricht. https://doi.org/10.26481/dis.20090604hb Document status and date: Published: 01/01/2009 DOI: 10.26481/dis.20090604hb Document Version: Publisher's PDF, also known as Version of record Please check the document version of this publication: • A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. 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If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, please follow below link for the End User Agreement: www.umlib.nl/taverne-license Take down policy If you believe that this document breaches copyright please contact us at: [email protected] providing details and we will investigate your claim. Download date: 27 Sep. 2021 New anti-epileptic drugs in pharmacoresistant epilepsy: retention time as outcome parameter Thesis_Bootsma_v15.indd 1 9-4-2009 11:30:28 © H.P.R. Bootsma, Maastricht 2009 ISBN: 978 90 5278 829 6 Universitaire Pers Maastricht Layout, cover design & print: Datawyse bv Thesis_Bootsma_v15.indd 2 9-4-2009 11:30:28 Titel ondertitel New anti-epileptic drugs in pharmacoresistantProefschrift epilepsy: retentionter verkrijging time as van outcome de graad van parameter doctor aan de Universiteit Maastricht, op gezag van de Rector Magnificus, PROEFSCHRIFTProf. Dr. A.C. Nieuwenhuijzen Kruseman, volgens het besluit van het College van Decanen ter verkrijging van dein graadhet openbaar van doctor teaan verdedigen de Universiteit Maastricht, op gezag van de Rector Magnificus, Prof. mr. G.P.M.F. Mols volgens hetop besluit vrijdag van het23 College september van Decanen, 1999 om 14.00 uur in het openbaar te verdedigen op donderdag 4 juni 2009 om 14.00 uur door door Hans Peter Ronald Bootsma Auteur geboren 14 maart 1960 te Hoogeveen 15 mm 82,5 mm 35 mm Thesis_Bootsma_v15.indd 3 9-4-2009 11:30:28 Promotores Prof. dr. A.P. Aldenkamp Prof. dr. Y.A. Hekster, Radboud Universiteit Nijmegen Copromotor Dr. ir. J.A.R.J. Hulsman, Epilepsiecentrum Kempenhaeghe Beoordelingscommissie Prof. dr. M. Limburg (voorzitter) Prof. dr. P.A.J.M. Boon, Universiteit van Gent, België Prof. dr. R.P. Koopmans Dr. P.D. Knoester, Ziekenhuisapotheek Rijnland ziekenhuis, Leiderdorp Prof. dr. C. Neef Sponsoring for publication of this thesis was kindly provided by: Department of Research and Development of the Epilepsy Centre Kempenhaeghe St Anna Zorggroep te Geldrop, Stichting KNMP-fondsen te Den Haag, GlaxoSmithKline te Zeist, Janssen-Cilag te Tilburg, Novartis te Arnhem, Pfizer te Capelle a/d IJssel, Roche te Woerden, Sanofi-Aventis te Gouda, UCB te Breda. Thesis_Bootsma_v15.indd 4 9-4-2009 11:30:28 Contents one Introduction 7 two Clinical evaluation of anti-epileptic drugs. 13 Why do we need more than regulatory trials? three Topiramate in clinical practice: long-term experience in patients 31 with refractory epilepsy referred to a tertiary epilepsy center. four Levetiracetam in clinical practice: long-term experience in patients 47 with refractory epilepsy referred to a tertiary epilepsy center. five Lamotrigine in clinical practice: long-term experience in patients 65 with refractory epilepsy referred to a tertiary epilepsy center. six Long-term effects of levetiracetam and topiramate in clinical practice: 79 a head-to-head comparison. seven The effect of anti-epileptic drugs on cognition: patient perceived 95 cognitive problems of topiramate versus levetiracetam in clinical practice. eight Ketter’s hypothesis of the mood effects of anti-epileptic drugs coupled 105 to the mechanism of action of topiramate and levetiracetam. nine The impact of side effects on long-term retention in three new 119 antiepileptic drugs. ten General discussion 135 Summary 143 Samenvatting 147 eleven Dankwoord 155 Curriculum vitae 157 List of publications 158 Thesis_Bootsma_v15.indd 5 9-4-2009 11:30:28 Thesis_Bootsma_v15.indd 6 9-4-2009 11:30:28 one Introduction 7 Thesis_Bootsma_v15.indd 7 9-4-2009 11:30:28 Chapter | one Epilepsy Epilepsy is a neurological disorder characterised by recurrent unprovoked seizures. Epilepsy is not a uniform condition, but comprises many different seizure types and epilepsy syndromes based on heterogeneous etiologies1. An epileptic seizure is the clinical manifestation of epilepsy. These clinical manifestations are sudden and tran- sient and can include a wide variety of movement, feeling or psychic disturbances, with or without alteration in consciousness. Seizures are broadly divided into two categories: partial and generalised. Partial seizures arise in an epileptogenic region in one hemisphere of the cerebral cortex. They are subdivided into simple partial seizures, which occur without alteration of consciousness, and complex partial seizures in which consciousness is impaired or lost. These seizures may generalise into a secondary generalised tonic clonic seizure. Primary generalised seizures are characterised by more diffuse neuronal discharges involving both hemispheres of the brain at once and always result in loss of consciousness. The point prevalence of epilepsy is around 0.5–1% and it is assumed that there are about 100,000 persons with epilepsy in the Netherlands. The incidence rate of epilepsy is age related. The highest incidence rate (ranging from 100 to 233 per 100,000) is observed in children younger than 1 year. Subsequently, this declines in early childhood to around 60 per 100,000. The incidence rate plateaus in adolescents and adults to around 30-40 per 100,000 and rises again in elderly people to 100-170 per 100,000 after the age of 65 years2. Epilepsy and side effects of epilepsy treatment have a great impact on patients’ lives3. The evaluation of side effects should receive more attention in daily practice4. Treatment of epilepsy Drug therapy is the mainstay of epilepsy treatment. In very severe treatment resistant cases, some patients are candidates for brain surgery (in the Netherlands approxi- mately 50/year). For other patients implantation of a nervus vagus stimulator is a treatment option. Finally patients can be treated with a ketogenic diet. However, almost every patient with epilepsy is treated with anti-epileptic drugs (AEDs). The aim of drug treatment is to prevent the occurrence of seizures completely. Approximately 20-30% of the patients do not become seizure free on anti-epileptic drugs. In addition, many patients suffer from side effects. Therefore it is important to find new anti-epileptic drugs and to evaluate them adequately, i.e. with outcomes that clinicians recognize as clinically relevant. If seizure freedom cannot be achieved than the aim of drug therapy should be a good balance between seizure control and optimal quality of life. 8 Thesis_Bootsma_v15.indd 8 9-4-2009 11:30:28 For a good interpretation of the results presented in this thesis it is important to realise that the likelihood to respond to drug therapy is probably a function of the past treatment history. Drug resistance seems to be a graded process that follows a mono-exponential course with a half-decay constant of 1.5–2 antiepileptic drugs. Thus for every two AEDs that proved ineffective in the past, the percentage of patients who responded with a greater than 50% reduction in seizure frequency decreases by twofold5. Organisation of care for epilepsy patients In the Netherlands newly diagnosed epilepsy patients are treated by their neurologists in general hospitals. Patients can be referred to an epilepsy center if their epilepsy does not respond well to drug therapy. These patients suffer from seizures despite drug therapy. Their epilepsy is called refractory. In the Netherlands there are two specialised epilepsy centers. The studies in this thesis were carried out in Epilepsy Center Kempenhaeghe (www.kempenhaeghe.nl). In Kempenhaeghe clinical produc- tion/year for epilepsy patients is 2000 admissions, 33,000 hospital days (short stay), Introduction 106,000 hospital days (long stay) and 12,000 outpatient visits6. Development of new anti-epileptic drugs The European Medicines Agency (EMEA) offers a note for guidance on clinical investigation of medicinal products in the treatment of epileptic disorders7. A new draft guideline on this topic is expected to be released for consultation in the first quarter of 2009. In chapter 2 we discuss the outcome measures which are used in regulatory trials and compare them to guidelines from the FDA and ILAE. Before their market approval new anti-epileptic drugs are tested in patients with refractory epilepsies. The new anti-epileptic drug or a placebo is added to their medication and the patients are followed for 3-6 months. Patients are considered responders if they experience a 50% seizure reduction or more during a predefined period within this 3-6 months trial duration.
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