Neues aus der Epileptologie

Zusammenfassung

In den letzten Jahren wurden von der Internationalen Liga gegen Epilepsie die Definition einer pharmakoresistenten Epilepsie sowie eine revidierte Terminologie und neue Konzepte zur Einteilung epileptischer Anfälle und Epilepsien vorgestellt. Derzeit viel diskutiert wird das Konzept der sog. rationalen Polytherapie, nachdem Medikamente mit unterschiedlichem Nebenwirkungsspektrum und verschiedenen Wirkmechanismen besser zu kombinieren seien als solche mit ähnlichen oder gleichen Mechanismen. In diesem Zusammenhang ist die Einführung neuer antikonvulsiv wirkender Medikamente zu begrüßen, von denen die zugelassenen Substanzen Lacosamid (Blockade von Natriumkanälen durch selektive Verstärkung der langsamen Inaktivierung) und Retigabin (als erster Kaliumkanalaktivator) sowie das wahrscheinlich bald verfügbare Perampanel (als erster selektiver AMPA-Rezeptor-Antagonist) neue Wirkprinzipien aufweisen. Weiterhin wurde die Tiefenhirnstimulation im anterioren Thalamus als neue, nichtmedikamentöse Therapiemöglichkeit zugelassen. Hinsichtlich der genetischen Untersuchungen bei Epilepsien sind neue, pathophysiologisch interessante Gene beschrieben worden. Die Sequenziertechniken der neuen Generation sind sowohl für die Wissenschaft als auch bereits für die Diagnostik von großem Nutzen. Bei einigen Epilepsien ist die Kenntnis der genetischen Befunde auch im Alltag wichtig, da Zusatzdiagnostik vermieden und spezifische Therapien zeitnah begonnen werden können. Im Bereich der Bildgebung gibt es neue computerunterstützte Nachbearbeitungsmethoden, die besonders bei bislang MRT-negativen Patienten eine unmittelbare Bedeutung haben können. Ein vielversprechendes Potenzial haben zudem kombinierte Techniken wie EEG-fMRT oder auch Konnektivitätsanalysen, beide bedürfen jedoch noch weiterer Validierung.

Abstract

In the last years, the International League against Epilepsy has introduced the definition of a pharmacoresistant epilepsy and a proposal for a revised terminology and concepts to classify epileptic seizures and epilepsies. Under current discussion is the concept of the so-called “rational polytherapy” according to which drugs with different mechanisms of action and distinct side effects should rather be combined instead of drugs with similar or identical mechanisms. In this context, the recent introduction of new antiepileptic drugs which exhibit novel mechanisms of action is welcome, such as lacosamide (blockage of sodium channels by selective enhancement of slow inactivation) and retigabine (the first potassium channel enhancer), and perampanel (the first selective AMPA-receptor antagonist) which will be hopefully available soon. Also deep brain stimulation within the anterior thalamic nucleus has been approved as an alternative non-pharmacological treatment. In the genetic field, novel genes were described pointing to new pathophysiological pathways. The development of next generation sequencing techniques significantly improves both research and diagnostic genetic investigations. In special types of epilepsy, the underlying genetic defect helps to avoid additional diagnostic steps and may support the early start of specific therapies. Novel concepts of neuroimaging, in particular computer-assisted post-processing, may improve the diagnostic work-up for previously MRI-negative patients. Combined imaging methods like EEG-fMRI or connectivity analyses have shown potential but will need further evaluation.

Schlüsselwörter

Epileptologie - Behandlung - Terminologie

Keywords

epileptology - treatment - terminology

• Literatur

• 1 Hauser WA, Annegers JF, Rocca WA. Descriptive epidemiology of epilepsy: contributions of population-based studies from Rochester, Minnesota. Mayo Clin Proc 1996; 71: 576-586
• 2 Berg AT, Berkovic SF, Brodie MJ et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 2010; 51: 676-685
• 3 Krämer G, Bast T, Baumgartner C et al. The new ILAE-proposal for a revised terminology and concepts for an organization of seizures and epilepsies: comments of the Königstein Working Group of Epileptology. International Epilepsy Congress 2011
• 4 Berg AT, Berkovic SF, Brodie M et al. Revidierte Terminologie und Konzepte zur Einteilung von epileptischen Anfällen und Epilepsien: Bericht der Klassifikations- und Terminologiekommission der Internationalen Liga gegen Epilepsie, 2005-2009. Akt Neurol 2010; 37: 120-130
• 5 Fisher RS, van Emde Boas W, Blume W et al. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 2005; 46: 470-472
• 6 Fisher RS, van Emde Boas W, Blume W et al. Epileptische Anfälle und Epilepsie: von der Internationalen Liga gegen Epilepsie (International League Against Epilepsy; ILAE) und dem Internationalen Büro für Epilepsie (International Bureau for Epilepsy; IBE) vorgeschlagene Definitionen. Akt Neurol 2005; 32: 249-252
• 7 Deckers CL, Czuczwar SJ, Hekster YA et al. Selection of antiepileptic drug polytherapy based on mechanisms of action: the evidence reviewed. Epilepsia 2000; 41: 1364-1374
• 8 Brodie MJ, Yuen AW. Lamotrigine substitution study: evidence for synergism with sodium valproate? 105 Study Group. Epilepsy Res 1997; 26: 423-432
• 9 Pisani F, Oteri G, Russo MF et al. The efficacy of valproate-lamotrigine comedication in refractory complex partial seizures: evidence for a pharmacodynamic interaction. Epilepsia 1999; 40: 1141-1146
• 10 Poolos NP, Warner LN, Humphreys SZ et al. Comparative efficacy of combination drug therapy in refractory epilepsy. Neurology 2012; 78: 62-68
• 11 Sake JK, Hebert D, Isojarvi J et al. A pooled analysis of lacosamide clinical trial data grouped by mechanism of action of concomitant antiepileptic drugs. CNS Drugs 2010; 24: 1055-1068
• 12 Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000; 342: 314-319
• 13 Callaghan BC, Anand K, Hesdorffer D et al. Likelihood of seizure remission in an adult population with refractory epilepsy. Ann Neurol 2007; 62: 382-389
• 14 Luciano AL, Shorvon SD. Results of treatment changes in patients with apparently drug-resistant chronic epilepsy. Ann Neurol 2007; 62: 375-381
• 15 Miceli F, Soldovieri MV, Martire M et al. Molecular pharmacology and therapeutic potential of neuronal Kv7-modulating drugs. Curr Opin Pharmacol 2008; 8: 65-74
• 16 Jentsch TJ. Neuronal KCNQ potassium channels: physiology and role in disease. Nat Rev Neurosci 2000; 1: 21-30
• 17 Maljevic S, Wuttke TV, Seebohm G et al. KV7 channelopathies. Pflugers Arch 2010; 460: 277-288
• 18 Delmas P, Brown DA. Pathways modulating neural KCNQ/M (Kv7) potassium channels. Nat Rev Neurosci 2005; 6: 850-862
• 19 Lange W, Geissendorfer J, Schenzer A et al. Refinement of the binding site and mode of action of the anticonvulsant Retigabine on KCNQ K+ channels. Mol Pharmacol 2009; 75: 272-280
• 20 Schenzer A, Friedrich T, Pusch M et al. Molecular determinants of KCNQ (Kv7) K+ channel sensitivity to the anticonvulsant retigabine. J Neurosci 2005; 25: 5051-5060
• 21 Wuttke TV, Seebohm G, Bail S et al. The new anticonvulsant retigabine favors voltage-dependent opening of the Kv7.2 (KCNQ2) channel by binding to its activation gate. Mol Pharmacol 2005; 67: 1009-1017
• 22 Hermann R, Knebel NG, Niebch G et al. Pharmacokinetic interaction between retigabine and lamotrigine in healthy subjects. Eur J Clin Pharmacol 2003; 58: 795-802
• 23 Ferron GM, Paul J, Fruncillo R et al. Multiple-dose, linear, dose-proportional pharmacokinetics of retigabine in healthy volunteers. J Clin Pharmacol 2002; 42: 175-182
• 24 Ferron GM, Patat A, Parks V et al. Lack of pharmacokinetic interaction between retigabine and phenobarbitone at steady-state in healthy subjects. Br J Clin Pharmacol 2003; 56: 39-45
• 25 Hermann R, Ferron GM, Erb K et al. Effects of age and sex on the disposition of retigabine. Clin Pharmacol Ther 2003; 73: 61-70
• 26 Hempel R, Schupke H, McNeilly PJ et al. Metabolism of retigabine (D-23129), a novel anticonvulsant. Drug Metab Dispos 1999; 27: 613-622
• 27 McNeilly PJ, Torchin CD, Anderson LW et al. In vitro glucuronidation of D-23129, a new anticonvulsant, by human liver microsomes and liver slices. Xenobiotica 1997; 27: 431-441
• 28 Hermann R, Borlak J, Munzel U et al. The role of Gilbert’s syndrome and frequent NAT2 slow acetylation polymorphisms in the pharmacokinetics of retigabine. Pharmacogenomics J 2006; 6: 211-219
• 29 Luszczki JJ. Third-generation antiepileptic drugs: mechanisms of action, pharmacokinetics and interactions. Pharmacol Rep 2009; 61: 197-216
• 30 Bialer M, Johannessen SI, Kupferberg HJ et al. Progress report on new antiepileptic drugs: a summary of the Seventh Eilat Conference (EILAT VII). Epilepsy Res 2004; 61: 1-48
• 31 Bialer M, Johannessen SI, Kupferberg HJ et al. Progress report on new antiepileptic drugs: a summary of the Eigth Eilat Conference (EILAT VIII). Epilepsy Res 2007; 73: 1-52
• 32 Bialer M, Johannessen SI, Levy RH et al. Progress report on new antiepileptic drugs: a summary of the Ninth Eilat Conference (EILAT IX). Epilepsy Res 2009; 83: 1-43
• 33 GlaxoSmithKline. Trobalt: Prescribing Information. 2011
• 34 Brodie MJ, Lerche H, Gil-Nagel A et al. Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy. Neurology 2010; 75: 1817-1824
• 35 French JA, Abou-Khalil BW, Leroy RF et al. Randomized, double-blind, placebo-controlled trial of ezogabine (retigabine) in partial epilepsy. Neurology 2011; 76: 1555-1563
• 36 Porter RJ, Partiot A, Sachdeo R et al. Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures. Neurology 2007; 68: 1197-1204
• 37 Orhan G, Wuttke TV, Nies AT et al. Der Kaliumkanalblocker Retigabin für die Add-on-Behandlung fokaler Epilepsien. Psychopharmakotherapie 2011; 18: 148-155
• 38 Eggert K, Squillacote D, Barone P et al. Safety and efficacy of perampanel in advanced Parkinson’s disease: a randomized, placebo-controlled study. Mov Disord 2010; 25: 896-905
• 39 Lees A, Fahn S, Eggert KM et al. Perampanel, an AMPA antagonist, found to have no benefit in reducing “Off” time in Parkinson’s disease. Mov Disord 2012; 27: 284-288
• 40 Hanada T, Hashizume Y, Tokuhara N et al. Perampanel: a novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy. Epilepsia 2011; 52: 1331-1340
• 41 Krauss GL, Bar M, Biton V et al. Tolerability and safety of perampanel: two randomized dose-escalation studies. Acta Neurol Scand 2012; 125: 8-15
• 42 Ryvlin P, Lagae L, Unterberger I et al. Perampanel as adjunctive therapy in patients with refractory partial-onset seizures: safety and tolerability analysis from a phase III trial. American Epilepsy Society 2011; Abst. 2.236
• 43 Steinhoff BJ, Krauss GL, Majoie M et al. Efficacy of perampanel in complex partial and secondary generalized seizures: a phase III study in patients with refractory partial seizures. American Epilepsy Society 2011; Abst. 2.235
• 44 Kwan P, Arzimanoglou A, Berg AT et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010; 51: 1069-1077
• 45 Kwan P, Arzimanoglou A, Berg AT et al. Definition der pharmakoresistenten Epilepsie: Konsensusvorschlag der ad hoc-Task Force der ILAE-Kommission für Therapeutische Strategien. Akt Neurol 2010; 37: 372-381
• 46 Schiller Y, Najjar Y. Quantifying the response to antiepileptic drugs: effect of past treatment history. Neurology 2008; 70: 54-65
• 47 Beekwilder JP, Beems T. Overview of the clinical applications of vagus nerve stimulation. J Clin Neurophysiol 2010; 27: 130-138
• 48 Cooper IS, Amin I, Gilman S. The effect of chronic cerebellar stimulation upon epilepsy in man. Trans Am Neurol Assoc 1973; 98: 192-196
• 49 Rahman M, Abd-El-Barr MM, Vedam-Mai V et al. Disrupting abnormal electrical activity with deep brain stimulation: is epilepsy the next frontier?. Neurosurg Focus 2010; 29: E7
• 50 Schulze-Bonhage A. Deep brain stimulation: a new approach to the treatment of epilepsy. Dtsch Arztebl Int 2009; 106: 407-412
• 51 Fisher R, Salanova V, Witt T et al. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 2010; 51: 899-908
• 52 Weber YG, Lerche H. Genetic mechanisms in idiopathic epilepsies. Dev Med Child Neurol 2008; 50: 648-654
• 53 Suls A, Mullen SA, Weber YG et al. Early-onset absence epilepsy caused by mutations in the glucose transporter GLUT1. Ann Neurol 2009; 66: 415-419
• 54 Mullen SA, Marini C, Suls A et al. Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy. Arch Neurol 2011; 68: 1152-1155
• 55 Verrotti A, Agostinelli S, Striano P. Early-onset versus typical childhood absence epilepsy: Are they all the same thing?. Seizure 2012; 21: 409
• 56 Chen WJ, Lin Y, Xiong ZQ et al. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet 2011; 43: 1252-1255
• 57 Schubert J, Paravidino R, Becker F et al. PRRT2 mutations are the major cause of benign familial infantile seizures (BFIS). Hum Mutat 2012; 33: 1339-1343
• 58 Heron SE, Grinton BE, Kivity S et al. PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome. Am J Hum Genet 2012; 90: 152-160
• 59 Weber YG, Lerche H. Indikationen zur genetischen Diagnostik bei Epilepsie. Zeitschrift für Epileptologie 2011; 24: 128-132
• 60 Lemke JR, Riesch E, Scheurenbrand T et al. Targeted Next Generation Sequencing as a Diagnostic Tool in Epileptic Disorders. Epilepsia 2012; 53: 1387-1398
• 61 ILAE Neuroimaging Commission. ILAE Neuroimaging Commission Recommendations for Neuroimaging of Patients with Epilepsy. Epilepsia 1997; 38: 1-2
• 62 Semah F, Picot MC, Adam C et al. Is the underlying cause of epilepsy a major prognostic factor for recurrence?. Neurology 1998; 51: 1256-1262
• 63 Tellez-Zenteno JF, Dhar R, Wiebe S. Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis. Brain 2005; 128: 1188-1198
• 64 Téllez-Zenteno JF, Ronquillo LH, Moien-Afshari F et al. Surgical outcomes in lesional and non-lesional epilepsy: A systematic review and meta-analysis. Epilepsy Research 2010; 89: 310-318
• 65 Focke NK, Bonelli SB, Yogarajah M et al. Automated normalized FLAIR imaging in MRI-negative patients with refractory focal epilepsy. Epilepsia 2009; 50: 1484-1490
• 66 Wagner J, Weber B, Urbach H et al. Morphometric MRI analysis improves detection of focal cortical dysplasia type II. Brain 2011; 134: 2844-2854
• 67 Salmenpera TM, Symms MR, Rugg-Gunn FJ et al. Evaluation of quantitative magnetic resonance imaging contrasts in MRI-negative refractory focal epilepsy. Epilepsia 2007; 48: 229-237
• 68 Focke NK, Symms MR, Burdett JL et al. Voxel-based analysis of whole brain FLAIR at 3T detects focal cortical dysplasia. Epilepsia 2008; 49: 786-793
• 69 Widjaja E, Blaser S, Miller E et al. Evaluation of subcortical white matter and deep white matter tracts in malformations of cortical development. Epilepsia 2007; 48: 1460-1469
• 70 Winston GP, Daga P, Stretton J et al. Optic radiation tractography and vision in anterior temporal lobe resection. Ann Neurol 2012; 71: 334-341
• 71 Focke NK, Yogarajah M, Bonelli SB et al. Voxel-based diffusion tensor imaging in patients with mesial temporal lobe epilepsy and hippocampal sclerosis. Neuroimage 2008; 40: 728-737
• 72 Yogarajah M, Focke NK, Bonelli SB et al. The structural plasticity of white matter networks following anterior temporal lobe resection. Brain 2010; 133: 2348-2364
• 73 Focke NK, Yogarajah M, Symms MR et al. Automated MR image classification in temporal lobe epilepsy. Neuroimage 2012; 59: 356-362
• 74 Baxendale S. The Wada test. Current Opinion in Neurology 2009; 22: 185-189
• 75 Bonelli SB, Powell R, Thompson PJ et al. Hippocampal activation correlates with visual confrontation naming: fMRI findings in controls and patients with temporal lobe epilepsy. Epilepsy Research 2011; 95: 246-254
• 76 Laufs H. Functional imaging of seizures and epilepsy: evolution from zones to networks. Current Opinion in Neurology 2012; 25: 194-200
• 77 Chaudhary UJ, Duncan JS, Lemieux L. Mapping hemodynamic correlates of seizures using fMRI: A review. Hum Brain Mapp 2011; (epub ahead of print)
• 78 Wuttke TV, Lerche H. Novel anticonvulsant drugs targeting voltage-dependent ion channels. Expert Opin Investig Drugs 2006; 15: 1167-1177