Brain Tumor and Epilepsy: Effect of Tumor Typeaz9194.vo.msecnd.net/pdfs/121201/301.03A.pdf ·...
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Brain Tumor and Epilepsy: Effect of Tumor Type
December 2, 2012
Lara Jehi, MD
Cleveland Clinic
American Epilepsy Society | Annual Meeting
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Disclosure
None
American Epilepsy Society | Annual Meeting 2012
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Learning Objectives
• Summarize most essential facts relating tumor type to the clinical manifestations of epilepsy.
• Summarize the most critical implications of tumor type on epilepsy treatment.
American Epilepsy Society | Annual Meeting 2012
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Learning Objectives
• Summarize most essential facts relating tumor type to the clinical manifestations of epilepsy.
• Summarize the most critical implications of tumor type on epilepsy treatment.
American Epilepsy Society | Annual Meeting 2012
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Fact 1:
American Epilepsy Society | Annual Meeting 2012
Tumor type is one of the main determinants of the risk of epilepsy (Jehi, 2010)
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Fact 2:
Timing of seizures in relation to diagnosis- rather than tumor type- determines seizure characteristics (Hildebrand,
2005)
American Epilepsy Society | Annual Meeting 2012
40% Focal 50% GTC 75% Focal 20% GTC
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Fact 3:
American Epilepsy Society | Annual Meeting 2012
Tumor type is one of the main determinants of the risk of associated epileptic pathology
Dual Pathology
Developmental brain tumors: DNET and gangliogliomas
25%-70%
Malformation of
cortical development (Frater, 2000; Morris, 1996;
Jehi, 2008)
Hippocampal
sclerosis (Prayson, 2008)
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What is behind the “facts”?
American Epilepsy Society | Annual Meeting 2012
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Tumor type: (Lyons, 2007)
• Necrosis
• Endothelial proliferation
• Mitosis
• Tissue infiltration
American Epilepsy Society | Annual Meeting 2012
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Low grade High grade
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Tumor type: (Lyons, 2007)
• Necrosis
• Endothelial proliferation
• Mitosis
• Tissue infiltration
American Epilepsy Society | Annual Meeting 2012
Mechanisms of Epilepsy!
• cell death
• hemosiderin deposition
• disruption of local anatomy
• disruption of networks
Determinants of excitability
Tumor type: (Lyons, 2007)
Mechanisms of Epilepsy!
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Fact 1:
American Epilepsy Society | Annual Meeting 2012
Tumor type is one of the main determinants of the risk of epilepsy (Jehi, 2010)
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Fact 1:
Tumor type is one of the main determinants
of the risk of epilepsy (Jehi, 2010)
Low grade High grade
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Fact 2:
Timing of seizures in relation to diagnosis- rather than tumor type- determines seizure characteristics (Hildebrand,
2005)
American Epilepsy Society | Annual Meeting 2012
40% Focal 50% GTC 75% Focal 20% GTC
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Fact 3:
American Epilepsy Society | Annual Meeting 2012
Tumor type is one of the main determinants of the risk of associated epileptic pathology
Dual Pathology
Developmental brain tumors: DNET and gangliogliomas
25%-70%
Malformation of
cortical development (Frater, 2000; Morris, 1996;
Jehi, 2008)
Hippocampal
sclerosis (Prayson, 2008)
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Association with hippocampal sclerosis
Consideration particularly with long standing epilepsy
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Association with MCD (Jehi, 2010, from Wyllie’s textbook of the Treatment of the epilepsies)
Ictal onset 1
Ictal onset 2
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Fact 4:
American Epilepsy Society | Annual Meeting 2012
•In general, risk of developing intractability is
at least 50% when tumor is the etiology.
•Twice as high as the risk of intractability with
other causes of epilepsy.
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Impact on Clinical Care and Practice
• Recognize high risk of seizures in all patients with brain tumors.
• Recognize that adequate epilepsy control requires adequate treatment of the tumor.
• Consider early surgery
•Tumor surgery is NOT the same as epilepsy surgery.
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Thank you!
American Epilepsy Society | Annual Meeting 2012
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Peritumoral Changes and
Epileptogenesis
December 2, 1012
Steve Chung, MD
Professor of Neurology
Barrow Neurological Institute
American Epilepsy Society | Annual Meeting
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Disclosure
American Epilepsy Society | Annual Meeting 2012
• Received research grants: Barrow foundation, Esai,
GSK, Lundbeck, Medtronics, Neuronex, SK Life
Science, Supernus, Sunovion, UCB Pharma, Upsher-
Smith, Valeant
• Member of speaker’s bureau: GSK, Lundbeck, UCB
Pharma
• Consulting/Advisory Board: Esai, Lundbeck, UCB
Pharma, Upsher-Smith
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Learning Objectives
• What causes seizures in brain tumor patients?
• Understand the various peritumoral changes that contribute to seizures
American Epilepsy Society | Annual Meeting 2012 24
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Does size, grade, or location matter?
• High-grade gliomas are less often associated with seizures (30-40%), and smaller tumors are more likely present with seizures1
• Low grade glioneuronal tumors (i.e. gangliogliomas and DNETs) are more often assoiated with seizures (80-100%)2
• Seizures are more likely to occur if tumors are in mesial temporal and insular structures
Are tumor-related seizures due to peritumoral changes
rather than the tumor itself?
1 Lee JW. Arch Neurol. 2010; 67(3) 2 Prayson RA . Am J Surg Pathol 2010; 34
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Are seizures caused by the tumor or peritumoral tissue?
• Intrinsic epileptogenicity of brain tumors is supported by the presence of hyperexcitable neuronal components within the tumor1
• i.e. Dysplastic neurons and giant cells of cortical tubers (Alteration of glutamate and GABA receptor expressions)2
• Also, the dysplastic and disorganized peritumoral region may
cause epileptogensis via Distorsion and Infiltration.
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1Ferrier et al. Epilepsia. 2006 2White et al. Ann. Neurol. 2001
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Changes in peritumoral tissue by high-grade tumors
• Rapid growth causes tissue damage (Distortion)1
• Necrosis • Hemosiderin deposition • Peritumoral edema
• High-grade tumors present less frequently with seizures • i.e. in GBM, 30-50%2
1Riva et al. Neurol Sci. 2005 2Moots et al. Arch Neurol. 1995
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Changes in peritumoral tissue Initial thoughts
• Penfield in 1940: Seizures are due to impaired vascularization and peritumoral ischemic changes1
• Echlin in 1959 proposed partial isolation or denervation hypersensitivty theory2
1Penfield . Arch Neurol Psych 1940 2Echlin. Clin Neurophysiol 1959
1,2Beaumont. Acta Neurochir 2000 28
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Changes in peritumoral tissue Altered living environment
• Peritumoral regions face altered biochemical and hormonal profile, vascular organization, axonal collaterals and neosynaptogensis.
• May explain why low-grade tumors cause seizures more frequently
1 Lee JW. Arch Neurol. 2010; 67(3) 2 Prayson RA . Am J Surg Pathol 2010; 34
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Changes in peritumoral tissue Altered living environment (1)
• Ion chnages may cause hyperexcitability1
• Decreased extracellular Mg2+
• Increased extracellular Fe3+
• pH changes may cause hyperexcitability2, 3
• Peritumoral cortex is significantly alkaline • Altered carbonic acid levels • Alkalinity blocks membrane K+ conductance • pH increase causes reduced GABA levels and activates
NMDA receptors
1Singh R. Epilepsia 1990
2Okada Y. J Neurosurg 1992 3 Tang C. Proc Natl Acad Sci 1990
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Changes in peritumoral tissue Altered living environment (2)
• Changes in amino acid concentration • Inhibition of glutamate transporters (GLAST, GLT1,
EAAC1) extra cellular glutamate level increase1
• Altered GABA level and GABAnergic transmission2
• Increased level of polyamines (Spermine, spermidine, putrescine) 3
• Enzymatic changes (i.e Glutamine synthetase)
• These changes may be a cause or a consequence of seizures
1Rothstein J. Neuron 1996 2Haglund N. J Neurosurg 1992
3 Sessa A. Cancer Lett 1994 31
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Changes in peritumoral tissue Altered living environment (3): IL-1
• Immune mediated changes occur in peritumoral region1
• Elevated IL-1 level in brain tumor2 • Elevated IL-1 in acute/chronic seizure models • Proconvulsive effects of IL-1 3
• Augments nitric oxide formation • Directly inhibits GABAA
• Increases NMDA receptor function • Inhibits K+ efflux
1Soliven B. J Neurochem 1992 2Nowak M. Epilepsia 2009
3Li G. Seizure 2011 32
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Changes in peritumoral tissue Altered living environment (4): TNF, BBB
• Up-regulation of TNF mRNA after seizures and in sujects with CNS tumors (in animal)1
• TNF may play a dichotomous role2
• TNF activates p55: proconvulsant effect
activates p75: antionvulsant effect
1Godlevsky L. Pol J Pharmacol 2002 2Li G. Seizure 2011
3Marchi N. Epilepsia 2007
• Cytokines cause enhanced BBB permeability3
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Summary: Peritumoral tissue and Epileptogenesis
• Aberrant neuronal/glial neosynapses
• Disturbed balance of excitatory/inhibitory inputs
• Membrane instability and altered neurotransmitter concentrations
• Cytokine/TNF mediated membrane exctitability
• Disruption of the blood-brain-barrier
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Panel Flash Session:
How genetic & biochemical alterations in brain tumors
contribute to epileptogenesis
Joon H. Uhm, MD FRCPC
Departments of Neurology & Oncology
Mayo Clinic, Rochester, MN
American Epilepsy Society | Annual Meeting
December 2nd, 2012
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Disclosures
Name of Commercial Interests
NONE
American Epilepsy Society | Annual Meeting 2012
Type of Financial Relationship
N/A
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Learning Objectives
Snapshot of
• The key genetic alterations in gliomas
• The mechanisms by which these genetic alterations lead to epileptogenic changes in the peritumoral microenvironment
American Epilepsy Society | Annual Meeting 2012
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38
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39 39
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Epilepsy
40
DNA
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40
Proteases Angiogenic
factors
Glutamate
2HG (IDH1)
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How do tumor-derived ‘pollutants’
promote epileptogenesis?
Proteases
Angiogenic
factors
Glutamate
2HG (IDH1)
Infiltration, BDNF
Infiltration
Inflammatory
cytokines Excitotoxic
More detailed discussion in session to follow…