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
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
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 %
Epilepsy in Brain Tumours
Epidemiology & Semiology
• Type of Seizures
• Type of Tumor
• Localization of Tumor
• Hereditary Tumors
• Systemic Cancer
• Prognostic Factors
• Underlying Mechanisms
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
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
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
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
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
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
Proportion of Drug-Resistant Epilepsies
Gilioli 2012
Miller 2009
Calatozollo 2012
Association between MDR Protein Expression
and Treatment-Response
Calatozollo 2012
Van Veelen 1998; Smits 2011
Seizure History
in Low-Grade Glioma
Sz. as Presenting Symptom
is Favorable Prognostic
Factor for Survival
Drug Interactions
between Anti-Epileptic Drugs (AEDs)
and Chemotherapeutic Drugs (CTDs)
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
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
Brodie et al, 2012
Effect of Enzyme-Inducing AEDs
on Pharmacokinetics of Chemotherapeutic Drugs
Survival of Children with B-lineage Leukaemia
Relling 2000
Van den Bent 2009
P450 Drug-Drug Interactions Websites:
• http://medicine.iupui.edu/clinpharm/ddis/
• http://en.wikipedia.org/wki/cytochrome_p450
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
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
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
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
• 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
Standard Treatment in
Glioblastoma Multiforme (GBM)
Chemoradiation
with Temozolomide
particularly effective
with methylated MGMT Stupp, 2005
Methylation
Status of
MGMT
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
Recommendations
Refractory Epilepsy
• Consider Surgery (rather than Wait & See)
• Consider Radiotherapy & Chemotherapy
Luyken, 2003, Soffietti 2005, Englot 2012
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