Epidemiology and Semiology of Tumor-based Epilepsy December 2, 2012

Transcription

1 Epidemiology and Semiology of Tumor-based Epilepsy December 2, 2012 Charles J. Vecht, MD, PhD Medical Center The Hague SEIN Epilepsy Foundation, The Netherlands CHU Pitié-Salpêtrière, Paris, France American Epilepsy Society Annual Meeting

2 Disclosure Dr. Vecht has received Consultancy fees from UCB Pharma; Research Grants from UCB Pharma, Eisai and GlaxoSmithKline; Travel Funding from UCB Pharma. American Epilepsy Society Annual Meeting 2012

3 Published Papers on Epilepsy & Brain Tumors Epilepsy ,1 % Cancer ,7 % Brain Tumors Epilepsy & Br.Tumors + 20,9 % + 17,2 % ,4 % ,6 % ,0 % ,0 %

4 Epilepsy in Brain Tumours Epidemiology & Semiology Type of Seizures Type of Tumor Localization of Tumor Hereditary Tumors Systemic Cancer Prognostic Factors Underlying Mechanisms

5 Epilepsy in Brain Tumours Treatment Medical Management Prophylaxis of Seizures & Peri-operative Period Seizure Control with AEDs Treatment-Resistance Drug-Drug Interactions Anti-Tumor Therapy Surgery Radiation Therapy & Systemic Chemotherapy Interaction of AEDs with Tumor Control Toxicity Issues Side-Effects Quality of Life / Cognitive Changes

6 In General Population with New Onset Epilepsy Overall Frequency of Brain Tumors is 4 % Over 25 years of age 15 % Surgery for Intractable Epilepsy % In Brain Tumors: Frequency of Epilepsy is > 40 % In Low-grade Brain Tumors Frequency of Epilepsy > 75 % Van Breemen 2007

7 In > 4 % Epilepsy in Systemic Cancer Metabolic Encephalopathies - Organ Dysfunction Toxic Encephalopathies - Iatrogenic Antibiotics, Interferons Systemic Chemotherapy (and Intrathecal & I.A.) Antidepressant & Neuroleptic Agents Often of Cumulative Nature (Co-Morbidities) Opportunistic CNS Infections Radionecrosis

8 100 Seizure Frequency in Brain Tumours DNET GG LGA MG GBM MT PL LM DNET GG LGA MG GBM MT PL LM DYSEMBRYOBLASTIC NEURO-EPITHELIAL TUMOUR (DNET) GANGLIOGLIOMA LOW-GRADE ASTROCYTOMA (LOW-GRADE GLIOMA; LGG) MENINGIOMA GLIOBLASTOMA MULTIFORME (GBM) BRAIN METASTASIS PRIMARY CNS LYMPHOMA Van Breemen 2007 LEPTOMENINGEAL METASTASIS

9 Underlying Mechanisms Imbalance Adjacent Cortical Inhib. / Excit. Mechanisms Tumour Type: Developmental Tumors assoc. with Cortical Dysplasia and Well-diff. Cells, Time-course Aberrant Neuronal Migration, Synaptic Vesicles Glutamate, Glutamate-Decarboxylase, Gaba-Receptor Changes in Micro-environment: Angiogenesis, Perfusion, Hypoxia, ph Hypoxia: Lower Stability of DNA-Repair, Mutations Secondary Epileptogenesis: Temporal Location & Time Course

10 Disturbed Small Networks Patterns of connectivity loss in the gamma band in three patients (14, 10, and 2). Synchronization likelihood (SL) graphs were built at a threshold of 0.05 in the gamma band (30 60Hz). In the last column, the regions (dashed areas) showing a increase in missing connective points in comparison with control subjects (Z-score 1.96) are indicated. Bartolomei & Stam, 2006

11 Proportion of Drug-Resistant Epilepsies Gilioli 2012

12 Miller 2009

13 Calatozollo 2012

14 Association between MDR Protein Expression and Treatment-Response Calatozollo 2012

15 Seizure History in Low-Grade Glioma Sz. as Presenting Symptom is Favorable Prognostic Factor for Survival Van Veelen 1998; Smits 2011

16 Drug Interactions between Anti-Epileptic Drugs (AEDs) and Chemotherapeutic Drugs (CTDs)

17 First-Generation Antiepileptic Drugs Carbamazepine >95% hepatic Inducer Phenobarbital 75% hepatic, 25% renal Inducer Phenytoin >90% hepatic Inducer Valproate >95% hepatic Inhibitor Patsalos & Perucca 2003

18 Major CYP-450 Enzymes CYP 1A2 CYP 2E1 CYP 3A4 50% CYP 2D6 25% CYP 2C9 15% CYP 2C19 5% CYP 2C CYP 2D6 CYP 3A

19 Effect of Enzyme-Inducing AEDs on Pharmacokinetics of Chemotherapeutic Drugs Brodie et al, 2012

20 Survival of Children with B-lineage Leukaemia Relling 2000

21 Van den Bent 2009

22 P450 Drug-Drug Interactions Websites:

23 Prophylactic AEDs Trials in Brain Tumors Forsyth Metast PHT AED 11/46 Placebo 15/54 OR (CI) Glantz Metast Glioma VPA 13/37 9/ Francesch etti Metast Glioma PHT PHB 3/41 4/ North Metast Glioma PHT 9/42 5/

24 Prophylaxis with LEV vs. PHT in 1 st Post- Operative Week LEV vs. PHT Seizures in 1st week Adverse Drug Reactions Sz. after 1 yr Follow-up Retent. Rate after 1 yr 1/ 105 vs. 9/ 210 (NS) 1/ 105 vs. 38/ 210 (p.001) 26 % vs. 36 % (NS) 64 % vs. 26 % (p.<03) Milligan 2008; Lim 2009

25 Spectrum of Low-Grade Epilepsy-Associated Tumors 144 (70 %) Classic Epilepsy-Associated Tumours 82 Ganglioglioma 29 Dysembryoblastic Neuroepithelial Tumour 33 Pilocytic Astrocytoma 5 Pleomorphic Xantho-astrocytoma 59 (27 %) Other Tumours 38 Astrocytomas gr II 17 Oligodendrogliomas gr II 4 (2 %) Grade III tumours 3 Astrocytoma gr III 1 Ganglioglioma gr III Luyken 2003

26 Seizure Characteristics in Low-Grade Glioma (n = 508) Mean Age 38.1 yrs 45 % Astrocytomas, 9 % Oligodendrogliomas, 46 % Oligo-Astrocytomas (LGG) Cortical Location 31 %, Subcortical 69 % Frontal 71 %, Temporal 37 %, Insular 21 %, Parietal 9% Pre-op Seizures 68.9 % Med. Duration of Sz. Onset and Surgery 10 Mos You 2012

27 Seizure Semiology in Gliobastoma Multiforme As Presenting Sign Seizures 123 ( 42.1 % ) 181 ( 62 % ) Secondary Generalized Simple Partial Combined Partial & Sec. Generalized Complex Partial 74 ( 40.8 % ) 59 ( 32.6 % ) 26 ( 14.4 % ) 9 ( 5 % ) De Wit - Kerkhof, 2012

28 Standard Treatment in Glioblastoma Multiforme (GBM) Chemoradiation with Temozolomide particularly effective with methylated MGMT Methylation Status of MGMT Stupp, 2005

29 Effect of Radiation Therapy and of Systemic Chemotherapy EORTC Study on Radiotherapy in LGG Seizure-Freedom with Early RT: 75 % ( n = 314) Late RT: 59 % Temozolomide in Low-grade Gliomas TMZ Cohort n=39; Control group n=30 Median length of F-U: 39 vs. 37 Months > 50 % Decrease in Sz frequency With TMZ : 59 %; Control group: 13 % (p <. 001) Van den Bent 2005; Sherman, 2011

30 Recommendations Refractory Epilepsy Consider Surgery (rather than Wait & See) Consider Radiotherapy & Chemotherapy Luyken, 2003, Soffietti 2005, Englot 2012