High prevalence of epileptic seizures have been associated with the presence of tumors in the CNS due to disrupted regulation within neural signal pathways. Rapid growth of tumors damage the structural integrity and interfere with peritumoral homeostasis. Although the mechanism of tumoral epilepsy is not well understood, several studies suggest that potential mechanism may involve altered levels of neurotransmitters and modulators in peritumoral tissue.[1] The pathology of epilepsy in tumor is type dependent. In undifferentiated tumors, seizure is induced directly by tissue damage, mass effect due inflammation and necrosis effect of neurons.[2] Tumor necrosis factor-a (TNF-a) released by microglia plays a neurodegenerative role in epilepsy. In contrast, excessive release of glutamate in the synapse has been implicated in seizure generation and development of seizure focal in differentiated tumors. Animal models show that seizure is a result of high glutamate concentration due to the increased expression of cysteine-glutamate exchanger, system xc−.1 Release of glutamate via system xc− lead to hyperactivity and epileptic activity in tumoral neurons. Glutamate accumulations also lead to excitotoxic neuronal destruction via MK801 mediated NMDA receptor.

1.2.1 Tumor Type, Incidence Rate.


Histological tests showed that prevalence of epilepsy is depended on the tumor type.[1] While any type of tumor can lead to development of seizure foci, low grade glioma was found to be the most epileptogenic. In contrast, high grade tumors have the lowest incident of epilepsy.[2] One of characteristic symptom for low grade tumor is early onset seizures. Tumor tissues itself may not be epileptic. Instead, the formation of epileptic foci may be a result of physical lesion and stimulation to the peri-tumural tissues.

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Figure 1. MRI of a patient with two distinct type of tumors.

Even though epilepsy can be initiated by any type of tumors, low grade tumors (Figure 1) have the highest incident rate. Recent studies showed that 81% percent of patients with low grade gliomas suffered from epilepsy while only 24% in patients with high grade tumor.[2] (Table 1) Dysembryoblastic neuroepithelial tumor is a rare type of tumor with incident rate of 100%. Patients with ganglioglioma and oligodendroglioma are particularly prone to epilepsy with incident rate of 90% and 85%, respectively. Seizure frequency for low-grade astrocytoma and anaplastic astrocytoma are slightly lower, with range between 75% and 67%. One of the possible explanations for the higher incident rate is that patients with slow growing tumors have longer survival time. However, this is explanation is not complete since epileptic seizure start early in the course of disease progression.

Classification_of_Tumors1.jpg
Table 1. Association between tumor type and seizure frequency. [2]

Incident rates are significantly lower in high grade tumors. The seizure frequency for has been reported to be up to 41% for meningioma, 35% for metastasis and 10% for primary CNS lymphoma. Seizure in patients with high grade tumors tended to be less refractory to antiepileptic treatment than patient with low grade tumors.[3] In several studies showed that incidence rate of epilepsy was not directly related to the histological grade of tumor.4 18% of patient with high grade meningioma did not show any improvement after treatment. This result suggested that Epilepsy is the cause of epilepsy is multifactorial. There are other non-tumor related factors contributed to the early onset of seizure. These factor may be involves tissues damage, mass effect due to inflammation and necrosis of the peritumoral neurons.

1.2.3. Peritumoral Homeostasis



Tumor associated epilepsy can be associated with disrupted homeostasis in the Peritumoral region. Alteration in the peritumoral microenvironment commonly involves impaired BBB function, enzymatic change and intercellular connection.[5] The peritumoral chemical imbalance is caused by leakage of BBB. Disruption of the BBB can lead to development of seizure focus. Epilepsy is also linked with abnormal level of enzyme such as lactate dehydrogenase, cAMP phosphodieasterase, enolase and thymidine kinase which also lead to metabolic impairments.[6] In normal tissues, cells are connecting through connexins in gap junction. Abnormal expression of connexin was recorded in epileptic tumors which promote hyperexcitability in the peritumoral tissues.[7]

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Figure 2. Disruption of BBB lead to inflammation response by the immune system.

1.2.3.TNF-a Triggered Immune Response




Research suggested that inflammation played an important role in the progressive nature of the epilepsy.[8] Recurrent seizures increase the production and recruitment of cytokines in the epileptic tissues. Cytokine targets endothelial cells and alter the permeability of the BBB which is crucial for neuronal viability and excitability.[9] Disruption of BBB would further accelerate the transportation of cytokine to the epileptic site. Tumor necrosis factor alpha (TNF-a) is a cytokine that is synthesized by white blood cells in the immune system. TNF-a is expressed at low level in normal cells and rapidly upregulated during physiological conditions such as epilepsy.[10] Research showed seizure induce the rapid release of inflammatory mediators in the epileptic tissues.[11] An inflammation response is initiated by presence of convulsants and electrical stimulation during onset of seizure. Experimental data has showed that the TNF-a directly involved in pro-inflammation signal pathway in epileptogenesis which reduced the threshold of seizure in the cortical area by modulating level of expression of neurotransmitters.

Mechanism for TNF-a pathway involves suppression of neuronal activity by increase the level of expression of GABA, hyperpolarization by inhibition of sodium channel, excitation of neurons by restrict inward flow of potassium current.[12] Animal studies showed in elevation in TNF-a concentration in the brain after electrical stimulation of amygdala. Moreover, increased susceptibility to seizure was observed in rats with TNF-a injection. Blocker of TNF receptor-1 showed antiepileptic effect by reduce the level of inflammation in the peritumoral tissues.[13]


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Figure 3. Transduction patheway involved in cytokines signaling.

1.2.4 Altered Expression of Glutamate Receptor



Epilepsy is caused by uncontrollable hyperexcitability and loses of inhibitory synapse in the neuron. In many epileptic patients, recurrent seizures are caused by abnormal release of neurotransmitter or altered expression of its receptors.[1, 2] Mutations involved both ionotropic and metabotropic glutamate receptors lead epileptogensis.[14] Low grade tumor exhibits elevated level of expression of ionotropic glutamate receptors for AMPA, NMDA and kainite. According to research, mutation in the subunit B of glutamate receptors can result in hyperexcitability.[4] NMDA and kainite receptors are important receptors that involved in the downregulation of inhibitory stimuli. Altered expression or prolong activation of NMDA and kainite receptors are responsible for the development of an epileptic focus. Metabotropic glutamate receptors (mGluRs) is a G-protein coupled receptor that involved in regulation of excitability of cortical neurons.[2] Studies have showed that mGLuRs can lead to intracellular signaling through GTP; it related proteins and protein kinase cascades, resulting calcium release and long-term neuromodulation.[15] Multiple subtypes of metabotropic glutamate receptors have been found to be overexpressed in reactive astrocytes in the peri-lesional zone around tumors compared with normal cortex.

1.2.5 Glutamate Excitotoxicity



Glutamate is a primary transmitter which is excitatory to over 90% of neurons. Glutamate is released by system Xc- cysteine-glutamate exchanger.[16] It binds to both ionotropic and metabotropic receptors on the post synaptic membrane. Glutamate is highly epileptogenic and neurotoxic. Excessive release of glutamate from glioma into peritumoral tissue is associated with narcosis and epileptogenesis. Elevated concentration of glutamate to induce excitotoxic neuronal destruction to create passages for the expansion of tumoral cells that mediated by MK801 sensitive NMDA receptor.[17] Studies have showed that C6 glioma cell line express high level of glutamate has been associated with reduced rate of reuptake.[18] Glutamate also serve as an autocrine trigger which initiate migration of glioma by inducing oscillation of calcium that is required for cellular migration through the activation of GLUR1 and GLUR4. Elevated glutamate release will also lead to local hyperexcitability alone the path of tumoral cell migration.



Reference

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