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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
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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
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Published Papers on Epilepsy & Brain Tumors
1992 -2001 2002 -2011
Epilepsy 35.071
+ 20,1 %
50.421
+ 38,4 %
Cancer 691.982
+ 20,7 %
1.081.142
+ 36,6 %
Brain Tumors 35.377
+ 20,9 %
48.478
+ 39,0 %
Epilepsy &
Br.Tumors
1.262
+ 17,2 %
1.780
+ 38,0 %
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Epilepsy in Brain Tumours
Epidemiology & Semiology
• Type of Seizures
• Type of Tumor
• Localization of Tumor
• Hereditary Tumors
• Systemic Cancer
• Prognostic Factors
• Underlying Mechanisms
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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
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In General Population with New Onset Epilepsy
• Overall Frequency of Brain Tumors is 4 %
• Over 25 years of age 15 %
• Surgery for Intractable Epilepsy 12 - 25 %
In Brain Tumors:
• Frequency of Epilepsy is > 40 %
• In Low-grade Brain Tumors
Frequency of Epilepsy > 75 %
Van Breemen 2007
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Epilepsy in Systemic Cancer
• In > 4 %
• 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
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0
20
40
60
80
100
DNET GG LGA MG GBM MT PL LM
seizure frequency %
DNET DYSEMBRYOBLASTIC NEURO-EPITHELIAL TUMOUR (DNET)
GG GANGLIOGLIOMA
LGA LOW-GRADE ASTROCYTOMA (LOW-GRADE GLIOMA; LGG)
MG MENINGIOMA
GBM GLIOBLASTOMA MULTIFORME (GBM)
MT BRAIN METASTASIS
PL PRIMARY CNS LYMPHOMA
LM LEPTOMENINGEAL METASTASIS
Seizure Frequency in Brain Tumours
Van Breemen 2007
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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
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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.
Disturbed Small Networks
Bartolomei & Stam, 2006
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Proportion of Drug-Resistant Epilepsies
Gilioli 2012
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Miller 2009
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Calatozollo 2012
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Association between MDR Protein Expression
and Treatment-Response
Calatozollo 2012
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Van Veelen 1998; Smits 2011
Seizure History
in Low-Grade Glioma
Sz. as Presenting Symptom
is Favorable Prognostic
Factor for Survival
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Drug Interactions
between Anti-Epileptic Drugs (AEDs)
and Chemotherapeutic Drugs (CTDs)
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Carbamazepine >95% hepatic Inducer
Phenobarbital 75% hepatic, 25% renal
Inducer
Phenytoin >90% hepatic Inducer
Valproate >95% hepatic Inhibitor
First-Generation Antiepileptic Drugs
Patsalos & Perucca 2003
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CYP 3A
CYP 2D6
CYP 2C
Major CYP-450 Enzymes CYP 3A4 50%
CYP 2D6 25%
CYP 2C9 15%
CYP 2C19 5%
CYP 1A2 CYP 2E1
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Brodie et al, 2012
Effect of Enzyme-Inducing AEDs
on Pharmacokinetics of Chemotherapeutic Drugs
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Survival of Children with B-lineage Leukaemia
Relling 2000
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Van den Bent 2009
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P450 Drug-Drug Interactions Websites:
• http://medicine.iupui.edu/clinpharm/ddis/
• http://en.wikipedia.org/wki/cytochrome_p450
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Prophylactic AEDs Trials in Brain Tumors
Forsyth Metast PHT
AED
11/46
Placebo
15/54
OR (CI)
0.33- 2.01
Glantz Metast
Glioma
VPA 13/37 9/37 0.61- 4.63
Francesch
etti
Metast
Glioma
PHT
PHB
3/41 4/22 0.07 - 1.76
North Metast
Glioma
PHT 9/42 5/39 0.56 - 6.12
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Prophylaxis with LEV vs. PHT in 1st Post-
Operative Week
• 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)
LEV vs. PHT
Milligan 2008; Lim 2009
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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
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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
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• As Presenting Sign
• Seizures
• Secondary Generalized
• Simple Partial
• Combined Partial & Sec.
Generalized
• Complex Partial
• 123 ( 42.1 % )
• 181 ( 62 % )
• 74 ( 40.8 % )
• 59 ( 32.6 % )
• 26 ( 14.4 % )
• 9 ( 5 % )
Seizure Semiology in Gliobastoma Multiforme
De Wit - Kerkhof, 2012
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Standard Treatment in
Glioblastoma Multiforme (GBM)
Chemoradiation
with Temozolomide
particularly effective
with methylated MGMT Stupp, 2005
Methylation
Status of
MGMT
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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
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Recommendations
Refractory Epilepsy
• Consider Surgery (rather than Wait & See)
• Consider Radiotherapy & Chemotherapy
Luyken, 2003, Soffietti 2005, Englot 2012