epilepsy in patients with

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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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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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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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