Glioneuronal tumors are an increasingly recognized cause of partial seizures that occur primarily in children and young adults. Focal epilepsy associated with glioneuronal tumors is often resistant to pharmacological treatment. The cellular mechanisms underlying the epileptogenicity of glioneuronal tumors remain largely unknown. The involved mechanisms are certain to be multifactorial and depend on specific tumor histology, integrity of the blood-brain barrier, characteristics of the peritumoral environment, circuit abnormalities, or cellular and molecular defects. Glioneuronal tumors presenting with epilepsy were observed to have relatively benign biological behavior. The completeness of the tumor resection is of paramount importance in avoiding tumor progression and malignant transformation, which are rare in cases of epileptogenic glioneuronal tumors. An evolving understanding of the various mechanisms of tumor-related epileptogenicity may also lead to a more defined surgical objective and effective therapeutic strategies, including antiepileptogenic treatments, to prevent epilepsy in at-risk patients. 1. Introduction Glioneuronal tumors are an increasingly recognized cause of partial seizures that occur primarily in children and young adults [1, 2]. These are tumors with an admixture of glial and neuronal components. Both cell types are thought to be part of the same neoplastic process. Entrapment of preexisting neurons by an infiltrating glioma therefore has to be distinguished from glioneuronal tumors. More well-established examples of glioneuronal tumors include dysembryoplastic neuroepithelial tumors (DNTs) ganglioglioma and desmoplastic infantile ganglioglioma. More recently recognized entities partly included in the latest version of the WHO classification include the rosette-forming tumor of the fourth ventricle the papillary glioneuronal tumor and rosetted glioneuronal tumor/glioneuronal tumor with neuropil-like islands. The glial component in these tumors varies but often resembles either a pilocytic astrocytoma or an infiltrating glioma with astrocytic or oligodendroglial features [3]. Gangliogliomas and DNTs arise most commonly in the temporal lobe and appear to be associated with an increased incidence of cortical dysplasia or neuronal migration abnormalities [1, 4, 5]. Focal epilepsy that is often resistant to pharmacological treatment is a common presenting symptom of glioneuronal tumors [1, 2]. Even though the biological behavior of these tumors is usually benign, especially when patients present only with epilepsy, cases of tumor
References
[1]
E. Aronica, S. Leenstra, C. W. van Veelen et al., “Glioneuronal tumors and medically intractable epilepsy: a clinical study with long-term follow-up of seizure outcome after surgery,” Epilepsy Research, vol. 43, no. 3, pp. 179–191, 2001.
[2]
I. Blümcke and O. D. Wiestler, “Gangliogliomas: an intriguing tumor entity associated with focal epilepsies,” Journal of Neuropathology and Experimental Neurology, vol. 61, no. 7, pp. 575–584, 2002.
[3]
P. Pytel and R. V. Lukas, “Update on diagnostic practice: tumors of the nervous system,” Archives of Pathology and Laboratory Medicine, vol. 133, no. 7, pp. 1062–1077, 2009.
[4]
M. A. Nolan, R. Sakuta, N. Chuang et al., “Dysembryoplastic neuroepithelial tumors in childhood: long-term outcome and prognostic features,” Neurology, vol. 62, no. 12, pp. 2270–2276, 2004.
[5]
S. H. Im, C. K. Chung, B. K. Cho, and S. K. Lee, “Supratentorial ganglioglioma and epilepsy: postoperative seizure outcome,” Journal of Neuro-Oncology, vol. 57, no. 1, pp. 59–66, 2002.
[6]
N. R. Kim, K. C. Wang, J. S. Bang et al., “Glioblastomatous transformation of ganglioglioma: case report with reference to molecular genetic and flow cytometric analysis,” Pathology International, vol. 53, no. 12, pp. 874–882, 2003.
[7]
F. F. Lang, F. J. Epstein, J. Ransohoff et al., “Central nervous system gangliogliomas. Part 2: clinical outcome,” Journal of Neurosurgery, vol. 79, no. 6, pp. 867–873, 1993.
[8]
E. Aronica, J. A. Gorter, G. H. Jansen, S. Leenstra, B. Yankaya, and D. Troost, “Expression of connexin 43 and connexin 32 gap-junction proteins in epilepsy-associated brain tumors and in the perilesional epileptic cortex,” Acta Neuropathologica, vol. 101, no. 5, pp. 449–459, 2001.
[9]
L. Tassi, N. Colombo, R. Garbelli et al., “Focal cortical dysplasia: neuropathological subtypes, EEG, neuroimaging and surgical outcome,” Brain, vol. 125, no. 8, pp. 1719–1732, 2002.
[10]
H. L. Weiner, C. Carlson, E. B. Ridgway et al., “Epilepsy surgery in young children with tuberous sclerosis: results of a novel approach,” Pediatrics, vol. 117, no. 5, pp. 1494–1502, 2006.
[11]
M. Wong, “Mechanisms of epileptogenesis in tuberous sclerosis complex and related malformations of cortical development with abnormal glioneuronal proliferation,” Epilepsia, vol. 49, no. 1, pp. 8–21, 2008.
[12]
M. F. Shamji, E. C. Fric-Shamji, and B. G. Benoit, “Brain tumors and epilepsy: pathophysiology of peritumoral changes,” Neurosurgical Review, vol. 32, no. 3, pp. 274–284, 2009.
[13]
I. Najm, Z. Ying, T. Babb et al., “Mechanisms of epileptogenicity in cortical dysplasias,” Neurology, vol. 62, no. 6, supplement 3, pp. S9–S13, 2004.
[14]
M. Thom, “Recent advances in the neuropathology of focal lesions in epilepsy,” Expert Review of Neurotherapeutics, vol. 4, no. 6, pp. 973–984, 2004.
[15]
E. Aronica, F. ？zbas-Ger？eker, S. Redeker et al., “Expression and cellular distribution of high- and low-affinity neurotrophin receptors in malformations of cortical development,” Acta Neuropathologica, vol. 108, no. 5, pp. 422–434, 2004.
[16]
T. Ravizza, K. Boer, S. Redeker et al., “The IL-1β system in epilepsy-associated malformations of cortical development,” Neurobiology of Disease, vol. 24, no. 1, pp. 128–143, 2006.
[17]
A. Vezzani and T. Granata, “Brain inflammation in epilepsy: experimental and clinical evidence,” Epilepsia, vol. 46, no. 11, pp. 1724–1743, 2005.
[18]
A. Vezzani, D. Moneta, C. Richichi, C. Perego, and M. G. De Simoni, “Functional role of proinflammatory and anti-inflammatory cytokines in seizures,” Advances in Experimental Medicine and Biology, vol. 548, pp. 123–133, 2004.
[19]
A. Vezzani, M. Conti, A. De Luigi et al., “Interleukin-1β immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: functional evidence for enhancement of electrographic seizures,” Journal of Neuroscience, vol. 19, no. 12, pp. 5054–5065, 1999.
[20]
T. Ravizza and A. Vezzani, “Status epilepticus induces time-dependent neuronal and astrocytic expression of interleukin-1 receptor type I in the rat limbic system,” Neuroscience, vol. 137, no. 1, pp. 301–308, 2006.
[21]
J. G. Heida and Q. J. Pittman, “Causal links between brain cytokines and experimental febrile convulsions in the rat,” Epilepsia, vol. 46, no. 12, pp. 1906–1913, 2005.
[22]
E. Aronica, J. A. Gorter, S. Redeker et al., “Distribution, characterization and clinical significance of microglia in glioneuronal tumours from patients with chronic intractable epilepsy,” Neuropathology and Applied Neurobiology, vol. 31, no. 3, pp. 280–291, 2005.
[23]
K. Boer, W. G. Spliet, P. C. van Rijen, S. Redeker, D. Troost, and E. Aronica, “Evidence of activated microglia in focal cortical dysplasia,” Journal of Neuroimmunology, vol. 173, no. 1-2, pp. 188–195, 2006.
[24]
N. C. Tan, J. C. Mulley, and S. F. Berkovic, “Genetic association studies in epilepsy: "the truth is out there",” Epilepsia, vol. 45, no. 11, pp. 1429–1442, 2004.
[25]
E. Aronica, B. Yankaya, G. H. Jansen et al., “Ionotropic and metabotropic glutamate receptor protein expression in glioneuronal tumours from patients with intractable epilepsy,” Neuropathology and Applied Neurobiology, vol. 27, no. 3, pp. 223–237, 2001.
[26]
M. Avoli, J. Louvel, R. Pumain, and R. K？hling, “Cellular and molecular mechanisms of epilepsy in the human brain,” Progress in Neurobiology, vol. 77, no. 3, pp. 166–200, 2005.
[27]
M. E. Calcagnotto, M. F. Paredes, T. Tihan, N. M. Barbaro, and S. C. Baraban, “Dysfunction of synaptic inhibition in epilepsy associated with focal cortical dysplasia,” Journal of Neuroscience, vol. 25, no. 42, pp. 9649–9657, 2005.
[28]
R. Spreafico, L. Tassi, N. Colombo et al., “Inhibitory circuits in human dysplastic tissue,” Epilepsia, vol. 41, supplement 6, pp. S168–S173, 2000.
[29]
C. Cepeda, V. M. André, J. Flores-Hernández et al., “Pediatric cortical dysplasia: correlations between neuroimaging, electrophysiology and location of cytomegalic neurons and balloon cells and glutamate/GABA synaptic circuits,” Developmental Neuroscience, vol. 27, no. 1, pp. 59–76, 2005.
[30]
M. D'Antuono, J. Louvel, R. K？hling et al., “GABAA receptor-dependent synchronization leads to ictogenesis in the human dysplastic cortex,” Brain, vol. 127, no. 7, pp. 1626–1640, 2004.
[31]
E. Aronica, S. Redeker, K. Boer et al., “Inhibitory networks in epilepsy-associated gangliogliomas and in the perilesional epileptic cortex,” Epilepsy Research, vol. 74, no. 1, pp. 33–44, 2007.
[32]
I. Blümcke, M. L？bach, H. K. Wolf, and O. D. Wiestler, “Evidence for developmental precursor lesions in epilepsy-associated glioneuronal tumors,” Microscopy Research and Technique, vol. 46, no. 1, pp. 53–58, 1999.
[33]
C. R. Miller and A. Perry, “CD34 and MAP2 immunohistochemistry in the differential diagnosis in the diagnosis of epilepsy associated glioneuronal tumors,” Advances in Anatomic Pathology, vol. 11, no. 6, pp. 326–327, 2004.
[34]
I. Blümcke, K. Giencke, E. Wardelmann et al., “The CD34 epitope is expressed in neoplastic and malformative lesions associated with chronic, focal epilepsies,” Acta Neuropathologica, vol. 97, no. 5, pp. 481–490, 1999.
[35]
G. Lin, E. Finger, and J. C. Gutierrez-Ramos, “Expression of CD34 in endothelial cells, hematopoietic progenitors and nervous cells in fetal and adult mouse tissues,” European Journal of Immunology, vol. 25, no. 6, pp. 1508–1516, 1995.
[36]
D. R. Sutherland, A. K. Stewart, and A. Keating, “CD34 antigen: molecular features and potential clinical applications,” Stem Cells, vol. 11, no. 3, pp. 50–57, 1993.
[37]
M. Asheuer, F. Pflumio, S. Benhamida et al., “Human CD34+ cells differentiate into microglia and express recombinant therapeutic protein,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 10, pp. 3557–3562, 2004.
[38]
P. Deb, M. C. Sharma, M. Tripathi, P. Sarat Chandra, A. Gupta, and C. Sarkar, “Expression of CD34 as a novel marker for glioneuronal lesions associated with chronic intractable epilepsy,” Neuropathology and Applied Neurobiology, vol. 32, no. 5, pp. 461–468, 2006.
[39]
M. Baybis, J. Yu, A. Lee et al., “mTOR cascade activation distinguishes tubers from focal cortical dysplasia,” Annals of Neurology, vol. 56, no. 4, pp. 478–487, 2004.
[40]
H. Miyata, A. C. Chiang, and H. V. Vinters, “Insulin signaling pathways in cortical dysplasia and TSC-tubers: tissue microarray analysis,” Annals of Neurology, vol. 56, no. 4, pp. 510–519, 2004.
[41]
M. van Slegtenhorst, M. Nellist, B. Nagelkerken et al., “Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products,” Human Molecular Genetics, vol. 7, no. 6, pp. 1053–1057, 1998.
[42]
D. J. Kwiatkowski, “Tuberous sclerosis: from tubers to mTOR,” Annals of Human Genetics, vol. 67, no. 1, pp. 87–96, 2003.
[43]
M. Nellist, B. Verhaaf, M. A. Goedbloed, A. J. J. Reuser, A. M. W. van den Ouweland, and D. J. J. Halley, “TSC2 missense mutations inhibit tuberin phosphorylation and prevent formation of the tuberin-hamartin complex,” Human Molecular Genetics, vol. 10, no. 25, pp. 2889–2898, 2001.
[44]
V. Schick, M. Majores, A. Koch et al., “Alterations of phosphatidylinositol 3-kinase pathway components in epilepsy-associated glioneuronal lesions,” Epilepsia, vol. 48, no. 5, pp. 65–73, 2007.
[45]
J. Fassunke, M. Majores, A. Tresch et al., “Array analysis of epilepsy-associated gangliogliomas reveals expression patterns related to aberrant development of neuronal precursors,” Brain, vol. 131, no. 11, pp. 3034–3050, 2008.
[46]
D. Collen, “The plasminogen (fibrinolytic) system,” Thrombosis and Haemostasis, vol. 82, no. 2, pp. 259–270, 1999.
[47]
D. Alfano, P. Franco, I. Vocca et al., “The urokinase plasminogen activator and its receptor. Role in cell growth and apoptosis,” Thrombosis and Haemostasis, vol. 93, no. 2, pp. 205–211, 2005.
[48]
E. E. Benarroch, “Tissue plasminogen activator: beyond thrombolysis,” Neurology, vol. 69, no. 8, pp. 799–802, 2007.
[49]
R. Pawlak and S. Strickland, “Tissue plasminogen activator and seizures: a clot-buster's secret life,” Journal of Clinical Investigation, vol. 109, no. 12, pp. 1529–1531, 2002.
[50]
L. Lahtinen, K. Lukasiuk, and A. Pitk？nen, “Increased expression and activity of urokinase-type plasminogen activator during epileptogenesis,” European Journal of Neuroscience, vol. 24, no. 7, pp. 1935–1945, 2006.
[51]
A. M. Iyer, E. Zurolo, K. Boer et al., “Tissue plasminogen activator and urokinase plasminogen activator in human epileptogenic pathologies,” Neuroscience, vol. 167, no. 3, pp. 929–945, 2010.
[52]
M. Del Rosso, G. Fibbi, M. Pucci, F. Margheri, and S. Serrati, “The plasminogen activation system in inflammation,” Frontiers in Bioscience, vol. 13, no. 12, pp. 4667–4686, 2008.
[53]
E. Oby and D. Janigro, “The blood-brain barrier and epilepsy,” Epilepsia, vol. 47, no. 11, pp. 1761–1774, 2006.
[54]
A. Dityatev and T. Fellin, “Extracellular matrix in plasticity and epileptogenesis,” Neuron Glia Biology, vol. 4, no. 3, pp. 235–247, 2008.
[55]
E. Aronica, J. A. Gorter, G. H. Jansen et al., “Expression and cellular distribution of multidrug transporter proteins in two major causes of medically intractable epilepsy: focal cortical dysplasia and glioneuronal tumors,” Neuroscience, vol. 118, no. 2, pp. 417–429, 2003.
[56]
H. Potschka and W. L？scher, “Multidrug resistance-associated protein is involved in the regulation of extracellular levels of phenytoin in the brain,” NeuroReport, vol. 12, no. 11, pp. 2387–2389, 2001.
[57]
M. Rizzi, S. Caccia, G. Guiso et al., “Limbic seizures induce P-glycoprotein in rodent brain: functional implications for pharmacoresistance,” Journal of Neuroscience, vol. 22, no. 14, pp. 5833–5839, 2002.
[58]
T. Litman, T. E. Druley, W. D. Stein, and S. E. Bates, “From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance,” Cellular and Molecular Life Sciences, vol. 58, no. 7, pp. 931–959, 2001.
[59]
H. Clusmann, T. Kral, U. Gleissner et al., “Analysis of different types of resection for pediatric patients with temporal lobe epilepsy,” Neurosurgery, vol. 54, no. 4, pp. 847–860, 2004.
[60]
C. S. Rumana and A. B. Valadka, “Radiation therapy and malignant degeneration of benign supratentorial gangliogliomas,” Neurosurgery, vol. 42, no. 5, pp. 1038–1043, 1998.
[61]
S. K. Kim, K. C. Wang, Y. S. Hwang, K. J. Kim, and B. K. Cho, “Intractable epilepsy associated with brain tumors in children: surgical modality and outcome,” Child's Nervous System, vol. 17, no. 8, pp. 445–452, 2001.
[62]
A. Iannelli, F. Guzzetta, D. Battaglia, L. Iuvone, and C. Di Rocco, “Surgical treatment of temporal tumors associated with epilepsy in children,” Pediatric Neurosurgery, vol. 32, no. 5, pp. 248–254, 2000.
[63]
J. H. Johnson Jr., S. Hariharan, J. Berman et al., “Clinical outcome of pediatric gangliogliomas: ninety-nine cases over 20 years,” Pediatric Neurosurgery, vol. 27, no. 4, pp. 203–207, 1997.
[64]
D. B. Sinclair, M. Wheatley, K. Aronyk et al., “Pathology and neuroimaging in pediatric temporal lobectomy for intractable epilepsy,” Pediatric Neurosurgery, vol. 35, no. 5, pp. 239–246, 2001.
[65]
C. Luyken, I. Blümcke, R. Fimmers et al., “The spectrum of long-term epilepsy-associated tumors: long-term seizure and tumor outcome and neurosurgical aspects,” Epilepsia, vol. 44, no. 6, pp. 822–830, 2003.
[66]
M. Giulioni, E. Galassi, M. Zucchelli, and L. Volpi, “Seizure outcome of lesionectomy in glioneuronal tumors associated with epilepsy in children,” Journal of Neurosurgery, vol. 102, no. 3, pp. 288–293, 2005.
[67]
I. Yang, E. F. Chang, S. J. Han et al., “Early surgical intervention in adult patients with ganglioglioma is associated with improved clinical seizure outcomes,” Journal of Clinical Neuroscience, vol. 18, no. 1, pp. 29–33, 2011.
[68]
D. N. Franz, J. Leonard, C. Tudor et al., “Rapamycin causes regression of astrocytomas in tuberous sclerosis complex,” Annals of Neurology, vol. 59, no. 3, pp. 490–498, 2006.
