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