epilepsy in patients with
TRANSCRIPT
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Epilepsy in Patients Witha Brain TumourFocal Epilepsy Requires Focused Treatment
Marjolein de Groot; Jaap C. Reijneveld;
Eleonora Aronica; Jan J. Heimans
Posted: 06/06/2012; Brain. 2012;135(4):1002-
1016. 2012 Oxford University Press
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Abstract
Brain tumours frequently cause epilepticseizures
Medical antiepileptic treatment is often metwith limited success it related with
pharmacoresistance, drug interactions andadverse events are common problems duringtreatment with antiepileptic drugs.
The unpredictability of epileptic seizures and
the treatment-related problems deeply affectthe quality of life of patients with a braintumour.
In this review, focus on both clinical and basic
aspects of possible mechanisms ine ile to enesis in atients with a brain
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Introduction
Brain tumours may arise from brain tissue (primary brain tumours, e.g.
astrocytic, oligodendroglial and glioneuronaltumours)
malignancies elsewhere in the body, e.g. lungcancer and melanoma (secondary braintumours).
Seizures are a frequent symptom in
patients with a brain tumour. Understanding the mechanisms that
underlie epileptogenesis in brain tumoursis essential to identify new treatmenttargets and to develop effective treatment.
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Current State: Treatment of
Epilepsy Efficacy of Antiepileptic Drugs in
Patients With a Brain Tumour
Issues Associated With Antiepileptic
Drugs in Patients With a Brain TumourAdverse Events
Drugdrug Interactions
Pharmacoresistance
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Efficacy of Antiepileptic Drugs in
Patients With a Brain Tumour
Currently, the management of epilepsy in patientswith a brain tumour mainly relies on antiepilepticdrug therapy.
Antiepileptic drugs can be divided into two groups:
first generation drugs (e.g. phenytoin, carbamazepine,valproic acid, ethosuximide, benzodiazepines andbarbiturates)
second generation drugs (e.g. levetiracetam,
felbamate, gabapentin, lamotrigine, pregabalin,tiagabin, zonisamide, oxcarbazepine and topiramate).
The vast majority of antiepileptic drugs are thoughtto modulate inhibitory neurotransmission, in most
cases voltage-gated ion channels.
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Issues Associated With
Antiepileptic Drugs in Patients
With a Brain TumourAdverse Events Antiepileptic drugs may cause a broad range of adverse
events, such as liver dysfunction, drowsiness, bone-
marrow suppression and skin rashes, etc. Patients with a brain tumour are more sensitive to the
side-effects of antiepileptic drugs than other patients
with epilepsy. For example, skin rash due to
antiepileptic drugs (carbamazepine, phenobarbital and
phenytoin) appears to occur more frequently in patients
with brain tumours.
It has also been suggested that patients receiving
radiotherapy and concomitant oxcarbazepine have a
higher risk of developing serious skin rashes such as
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Issues Associated With
Antiepileptic Drugs in Patients
With a Brain TumourDrugdrug Interactions In general, the second generation antiepileptic
drugs are less susceptible to pharmacokineticinteractions, a desirable characteristic for
antiepileptic drugs that are prescribed to patientswith glioma who are often subject to other medicaltreatment regimens.
First generation antiepileptic drugs to enhance
chemotherapy due to their enzyme-inducing or -inhibiting properties
Several antiepileptic drugs might have intrinsicanti-tumour properties (Valproic acid inhibitedtumour cell growth in in vitro and in vivosystems
by modulating multiple pathways through itshistone deacet lase inhibitor ro erties
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Issues Associated With
Antiepileptic Drugs in Patients
With a Brain TumourPharmacoresistance The first hypothesis (The Target Hypothesis)
presumes alterations in drug targets; targets
that antiepileptic drugs normally bind to arepossibly altered in tumour and peritumoraltissue.
The second hypothesis (The Transporter
Hypothesis) drugs can enter and leave thebrain through carrier-mediated transport
The third hypothesis (The Intrinsic SeverityHypothesis) suggests that neurobiologicalfactors, which underlie disease severity,contribute pharmacoresistance.
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Current State: Treatment of the
Tumour
Surgery
Surgery focuses on resection of thetumour as radically as possible in order
to delay tumour growth and lengthensurvival.
The extent of resection of the tumour islimited by functional areas of the brain.
Further, removal of the tumour may alsolead to reduction of seizures, and manypatients are seizure free after
oncological surgery.
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Current State: Treatment of the
Tumour
Radiotherapy and Chemotherapy
Radiotherapy and chemotherapy are
frequently applied in the treatment of
patients with a brain tumour in order to
prolong survival or improve quality of
life.
Although seizure reduction is not the
first priority of chemo- and
radiotherapy, these therapies also
have an effect on seizure occurrence.
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Clinical Impact
Pathophysiology of Tumour-related Epilepsy
Epilepsy commonly develops in patients with a brain lesion Tumour-associated epilepsy can be classified under'symptomatic epilepsy', which is defined as 'the developmentof epilepsy caused by an identifiable injury or lesion
Lesions or injuries such as stroke, contusions, abscesses,vascular malformations and malformations of corticaldevelopment, may all trigger a succession of events that setsoff epilepsy.
However, the cellular mechanisms underlying theepileptogenesis of those lesions are not clear.
Given the fact that both intracerebral and extracerebraltumours can cause epilepsy and differences in seizurefrequency exist between tumours of the samehistopathological tumour type, it is likely that in tumour-relatedepilepsy multiple mechanisms are involved, including tumour-related factors (histological type, location), environment-related factors and functional changes
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Clinical Impact
Effect of Brain Tumours on the Whole Brain (BrainNetworks)
Magnetoencephalography studies demonstrate alteredfunctional connectivity in patients with a brain tumourcompared to healthy controls. Loss of functional connectivity
in patients with a brain tumour affects not only the tumourarea, but also other brain areas. The mechanisms underlyingthe alteration of functional connectivity are unclear.
Studies in patients with temporal lobe epilepsy suggest thatthe small-world configuration is more disrupted in patientswith a longer history of seizures. Moreover, in patients with
epilepsy, increased connectivity has been reported, andpatients with a brain tumour with more severe epilepsy(higher number of seizures) display a stronger increase offunctional connectivity in the theta band. This suggests thatalterations in functional connectivity can contribute to tumour-related epilepsy.
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Future Directions
The foremost step is eliminating the tumourand the epileptic focus, combiningoncological and epilepsy surgery techniques,andif appropriatepostoperative chemo-and radiotherapy
Future research should aim at furthercharacterization of the impact of surgicalresection on epileptogenic brain networks.
Further studies assessing the effects of
postoperative anti-tumour therapy on seizurefrequency are also needed beforepostoperative anti-tumour therapy becomes aroutine part of modern antiepileptic treatment.
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Conclusion
Brain tumours often cause epilepsy and therapy is farfrom perfect.
Epileptogenesis is not well understood, but
presumably comprises structural and
cellular/molecular changes induced by the tumourthat leads to changes in the surrounding tissue and at
further distance, eventually resulting in alterations in
functional connectivity.
Therapy should aim at eliminating the epileptic focusand decrease epileptic activity of the focus.
Research is warranted both for optimizing anti-tumour
treatment and its effects on epilepsy and for
elucidation of the underlying pathophysiology oftumour-related epilepsy to provide targets for new
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