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Brain tumors and epilepsy: pathophysiology of peritumoral changes

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Abstract

Epilepsy commonly develops among patients with brain tumors, frequently even as the presenting symptom, and such patients consequently experience substantial morbidity from both the seizures and the underlying disease. At clinical presentation, these seizures are most commonly focal with secondary generalization and conventional medical management is often met with less efficacy. The molecular pathophysiology of these seizures is being elucidated with findings that both the tumoral and peritumoral microenvironments may exhibit epileptogenic phenotypes owing to disordered neuronal connectivity and regulation, impaired glial cell function, and the presence of altered vascular supply and permeability. Neoplastic tissue can itself be the initiation site of seizure activity, particularly for tumors arising from neuronal cell lines, such as gangliogliomas or dysembryoblastic neuroepithelial tumors. Conversely, a growing intracranial lesion can both structurally and functionally alter the surrounding brain tissue with edema, vascular insufficiency, inflammation, and release of metabolically active molecules, hence also promoting seizure activity. The involved mechanisms are certain to be multifactorial and depend on specific tumor histology, integrity of the blood brain barrier, and characteristics of the peritumoral environment. Understanding these changes that underlie tumor-related epilepsy may have roles in both optimal medical management for the seizure symptom and optimal surgical objective and management of the underlying disease.

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Authors and Affiliations

  1. Division of Neurosurgery, The Ottawa Hospital, Civic Campus, C2, 1053 Carling Avenue, Ottawa, ON, K1Y 4E9, Canada

    Mohammed F. Shamji & Brien G. Benoit

  2. Department of Biomedical Engineering, Duke University, Durham, NC, USA

    Mohammed F. Shamji

  3. Department of Public Policy, Duke University, Durham, NC, USA

    Elana C. Fric-Shamji

Authors
  1. Mohammed F. Shamji
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  2. Elana C. Fric-Shamji
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  3. Brien G. Benoit
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Correspondence to Mohammed F. Shamji.

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Comments

Thomas Grunwald, Zurich, Switzerland

This review by Shamji et al. gives a comprehensive overview of intralesional and perilesional mechanisms contributing to epileptogenicity and clearly shows that both neoplastic brain tissue and the perilesional cortex can exhibit pathophysiological characteristics that can initiate and maintain seizure activity. Thus, this review may help, first, to reconcile seemingly irreconcilable views of suitable strategies for epilepsy surgery and, second, to call for ongoing research activity in epilepsy surgery programs.

1. Epilepsy surgery aims at the removal of the epileptogenic zone, which may or may not include an epileptogenic lesion. Whether lesionectomy alone or lesionectomy plus corticectomy is a more suitable approach has been debated since the observation that resection of a structural lesion can lead to seizure freedom [1]. Epileptogenic characteristics of neoplastic brain tissue as summarized in the present review may explain why pure lesionectomies may be successful with regard to postoperative seizure control. This may also hold true for cavernomas—at least in patients with oligoepilepsies of extramesial temporal seizure origin (e.g., [2]). However, meanwhile, a majority of studies agrees that extended tailored resections of cavernomas including perilesional epileptogenic areas have a better outcome (e.g., [3, 4]). For low-grade gliomas, the most important predictor of a favorable outcome is complete resection of the lesion [5]. However, defining the borders of the lesion may not always be easy: For example, “satellite” tumor clusters can frequently be found histologically in brain regions adjacent to gangliogliomas [6], and a recent study found signs of cortical dysplasia near dysembryoplastic neuroepithelial tumors in eight of ten patients in whom additional corticectomies were performed according to the results of intraoperative electrocorticography [7]. Thus, the data reviewed by Shamji et al. can help explain why some lesionectomies do not lead to seizure freedom.

2. However, the data presented here cannot adjudicate the question of when additional corticectomies are necessary and when are they not. At least for patients with low-grade tumors who present with chronic epilepsies, this decision necessitates thorough presurgical evaluations using both noninvasive and—if necessary—invasive electrophysiological techniques. It remains an open question for future research whether not only the results of presurgical evaluations but also findings from histological and physiological studies as reviewed here can predict the course of postoperative seizure control and thus whether continuous antiepileptic medication is mandatory or dispensable.

Moreover, resections of epileptogenic tissue offer the unique opportunity to perform functional in vitro experiments in living human brain specimen which, together with genetic studies, can both enhance our understanding of pharmacoresistance [8] and contribute to the development of novel medical therapies.

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6. Blümcke I, Wiestler OD (2002) Gangliogliomas: an intriguing tumor entity associated with focal epilepsies. J Neuropathol Exp Neurol 61:575–584

7. Lee J, Lee BL, Joo EY et al (2008) Dysembryoplastic neuroepithelial tumors in pediatric patients. Brain Dev, Dec 4. [Epub ahead of print]

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Riccardo Soffietti, Turin, Italy

The problem of epilepsy in brain tumors, notably in gliomas, has in recent years gained particular attention for several reasons: seizures may represent a medically intractable condition, diminishing quality of life in patients with otherwise good prognosis; with modern advances, surgery, radiation therapy, and chemotherapy allow a control of both tumor growth and seizures in an increasing number of patients; the interactions between antiepileptic and antineoplastic (including the new targeted agents) drugs are an emerging challenge. Thus, this review on the pathophysiology of brain tumor epilepsy, written by Dr. Shamji and coworkers, is timely. The manuscript provides an excellent in-depth update of the biochemical and molecular mechanisms related to the development and maintenance of epileptic seizures in the different tumor types. What is intriguing for future research is the existence of common factors underlying both tumor progression/invasion and epileptogenicity that hopefully could be modulated by new treatment approaches.

Charles J. Vecht, The Hague, The Netherlands

This clear and succinct review by Shamji, Fric, and Benoit from Duke, NC, and Ottawa, Ontario, concentrates on the multiplicity of causes for seizures in these patients. The authors point out that those factors in the peritumoral microenvironment like hypoxia, Ph abnormalities with altered neurotransmitter activity, changes in receptor density or glial connectivity, and blood brain barrier disruptions may all lead to epileptic activity. A major issue is whether these seizures constitute an inherent part of the tumor with specific elements of tumor cells leading to seizures or are rather secondary phenomena associated with structural lesions of brain tissue. Amino acid changes linked to abnormal neuronal excitability has been encountered both in intra- and extra-axial brain tumors, and similar changes have been associated with focal cortical dysplasia and seizures.

Shamji et al. emphasize that slow-growing lesions may give rise to isolated and thereby deafferentated regions of brain tissue that lead by itself to lower synchronization between cells and to lesser functional connectivity with ensuing greater susceptibility for development of seizures. These observations suggest that many factors point to explanations associated with structural brain lesions independent of the nature of that lesion.

A high frequency of seizures seems inherent to low-grade tumors, particularly in truly benign tumors, like dysembryoplastic neuroepithelial tumors and gangliogliomas which may have true specific features leading to seizures. A stronger glutamate receptor expression may be one such characteristic. Another specific feature is a heightened release of glutamate by glioma cells.

An intriguing question remains why more malignant tumors like glioblastoma multiforme have a lesser frequency of seizures.

The probability that many of the changes in the peritumoral environment associated with seizures are aspecific would not imply that each of these changes have no functional significance. The insight that an acidic Ph more easily leads to calcium channel blocking activity mediated by NMDA receptors, observations of overexpression of kainate receptors, and observations of higher concentrations of glutamate and glycine extracellularly can each be of pathophysiological and of therapeutic relevance.

Over the last 10–15 years, a host of information has become available on the different genetic causes that lead to the development of low- and high-grade gliomas [1]. However, almost none of these genetic changes has had known specific associations with the development of seizures. Indeed, there is possibly one type of low-grade glioma specifically associated with epilepsy [2], and this is in sharp contrast with a host of specific genetic changes associated with various types of brain tumors and the many different and specific genetic abnormalities associated with epilepsy syndromes in nontumor patients [3].

Of course, there are elements of seizures in patients with brain tumors, which seem clearly dictated by genetic characteristics. For example, the drug resistance of seizures for anticonvulsants seems dependent on expression of P-glycoprotein (ABC B1 multidrug resistance protein) and other transporter proteins belonging to the ABC family of transporter proteins [4]. Also, the metabolism of anticonvulsants by the P-450 coenzyme system of the liver and whether or not these coenzymes are being induced or inhibited and would influence the metabolism of other concomitantly administered agents are dependent on specific genetic changes [5].

Likewise, it is uncertain whether medical therapy by anticonvulsants of seizures in patients with brain tumors is different from seizures associated with other structural brain lesions [6]. Circumstantial evidence points rather to aspecific pathophysiological receptor changes which most probably determine the response to therapy. Nevertheless, the treatment of epilepsy in patients with brain tumors does imply specific rules, like the avoiding of enzyme-inducing anticonvulsants and a preference for antiepileptic agents that show no interactions with other drugs.

References

1. Louis DN (2006) Molecular pathology of malignant gliomas. Annu Rev Pathol 1:97–117

2. Gu W, Brodtkorb E, Piepoli T, Finocchiaro G, Steinlein OK (2005) LGI1: a gene involved in epileptogenesis and glioma progression? Neurogenetics 6(2):59–66

3. Steinlein OK (2008) Genetics and epilepsy. Dialogues Clin Neurosci 10(1):29–38

4. Aronica E, Gorter JA, Jansen GH, van Veelen CW, van Rijen PC, Leenstra S et al (2003) Expression and cellular distribution of multidrug transporter proteins in two major causes of medically intractable epilepsy: focal cortical dysplasia and glioneuronal tumors. Neuroscience 118(2):417–429

5. Eichelbaum M, Fromm MF, Schwab M (2004) Clinical aspects of the MDR1 (ABCB1) gene polymorphism. Ther Drug Monit 26(2):180–185

6. van Breemen MS, Wilms EB, Vecht CJ (2007) Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management. Lancet Neurol 6(5):421–430

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Shamji, M.F., Fric-Shamji, E.C. & Benoit, B.G. Brain tumors and epilepsy: pathophysiology of peritumoral changes. Neurosurg Rev 32, 275–285 (2009). https://doi.org/10.1007/s10143-009-0191-7

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