Brain tumor is a common cause of epilepsy. About 5% of new epilepsy patients have brain tumor, and about 10% of epilepsy with focal seizures are caused by brain tumor [8]. BTRE is a multi-factorial condition with unclear physiological mechanisms. Current studies have indicated that epilepsy is associated with many factors, such as the histological type of intracranial tumor, the severity and location of tumor, genetic factors, the integrity of the blood-brain barrier, peritumoral morphological changes, changes in neurotransmitters, abnormal ion concentrations, and tissue hypoxia [9].
Although seizures may develop from almost all types of intracranial tumors (including primary and secondary brain tumors), the incidence of epilepsy varies among different histological types. For example, the incidence of epilepsy is 100% in dysembryoblastic neuroepithelial tumors, 25% in meningiomas, 10% in primary central nervous system lymphoma, and 20–35% in intracranial metastases [2]. About 20–45% of patients with glioma present with epilepsy as the first symptom at disease onset, and the other 15–30% of glioma patients develop epilepsy during the course of disease progression [10]. The incidence of epilepsy in glioma varies according to the grade of the tumor, with the WHO grade I–II gliomas more prone to epilepsy than WHO grade III–IV gliomas. The incidence of epilepsy is 70–80% in glioneuronal tumor, 60–75% in low-grade glioma (WHO grade I–II), and 25–60% in high-grade glioma (WHO grade III–IV) [11]. In general, the slowly-growing low-grade tumors and intracranial multi-focal tumors have a higher propensity to develop epilepsy than the higher-grade tumors and focal tumors, respectively [12]. Regardless of the type of intracranial tumor, patients with epilepsy as the first symptom at disease onset have a significantly increased risk of drug-refractory epilepsy [13]. In this study, 78 of the 153 BTRE patients were patients with primary tumor, and the other 75 patients had tumor from extracranial tumor metastases. A majority (57 cases, 73.1%) of the primary tumors were gliomas, suggesting that patients with glioma are more likely to develop tumor-related epilepsy, which is consistent with previous reports. There is also a clear relationship between the location of the tumor and the occurrence of epilepsy. Studies have shown that the frontal lobe, temporal lobe, and parietal lobe are closely associated with language, cognition, and motor function [14, 15]. Lesions in these areas can cause abnormal firing in these regions and thus seizures, and the occurrence of seizures may be further increased by glioma invasion into the cortex. Therefore, the incidence of epilepsy would be extremely high with a tumor location in the cortex, and the rate of seizures may be higher with locations of brain tumor in the frontal lobe, temporal lobe, and parietal lobe than in the occipital lobe. In contrast, patients with tumor lesions in the infratentorial or sellar region are less likely to develop epilepsy, except in the condition of hemispherical involvement [16]. Currently, few studies have focused on BTRE epilepsy. In this study, 60.1% of the patients had generalized seizures, while only 39.9% had focal seizures, including 23 patients having symptoms of automatisms with lesions all located in the supratentorial lobe. This suggests that a major proportion of BTRE may have a generalized origin. In addition, we found that the type of epilepsy did not have histological correlation, nor was it correlated with the location of the lesion (in the brain parenchyma or meninges), but it was related to the lobular localization of lesions. The lesions can be located in different lobes of the brain, accompanied by different types of epilepsy. Lesions in the frontal lobe tend to cause generalized seizure, while lesions in the temporal and parietal lobe are more likely to cause focal seizure.
Most cases of EAT have benign tumors that grow slowly with a long clinical history, with epilepsy (mostly drug-refractory epilepsy) as the main or the only clinical manifestation. The lesions of EAT are mostly located in or near the cortex, usually with no significant mass effect but accompanied by cystic changes and calcification, and most are WHO grade I–II tumors, which are curable after surgical resection. The common types of EAT include glioneuronal tumor and low-grade glioma [17]. EAT accounts for about 2–5% of central nervous system tumors, and is the second most common cause of epilepsy surgery in adults (next to hippocampal sclerosis) and children (next to focal cortical dysplasia) [18]. In 2003, Luyken et al. proposed the concept of “long-term epilepsy-associated tumor”, where “long-term” indicates having a long history of drug-resistant epilepsy of more than 2 years [4]. In this study, 2 cases of LEAT were included, 1 with dysembryoblastic neuroepithelial tumor found after a 17-year history of epilepsy, and 1 with gemistocytic astrocytoma after a 4-year history of epilepsy. As the development of imaging technology enables early discovery of some “secret” tumor lesions, the classification of LEAT alone has limited significance in clinical practice. However, brain imaging of EAT at early stage may not necessarily show the presence of tumor lesions, which can cause failure to diagnose and misdiagnose, therefore, it is of great significance to study the clinical characteristics of EAT.
EAT can be further subdivided into tumors of mixed neuronal and glial origin (glioneuronal tumor) and those of the glial origin based on histology. Glioneuronal tumors are composed of neurons and glia with different degrees of differentiation, have a poor proliferative ability and low malignancy, and are almost exclusively WHO grade I benign tumors, with a good prognosis and a low rate of recurrence and malignancy. Glioneuronal tumors commonly include ganglioglioma and embryonic dysplasia neuroepithelial tumors. The incidence of epilepsy in glioneuronal tumor as the first or the only manifestation is ~ 80–100% [19]. Complex partial seizure, which is manifested as stunning, autonomous nervous system or mental symptoms, aura, automatism, etc., is the most common seizure type that occurs in ~ 80% of ganglioglioma cases, followed by partial secondary generalized tonic-clonic seizures (50%) [19]. Only a limited number of patients develop neurological deficits related to the tumor site, such as limb numbness, visual impairment, poor speech, and ataxia, as well as symptoms of elevated intracranial pressure such as headache, dizziness, nausea and vomiting when the tumor affects the cerebrospinal fluid circulation. The epilepsy-related low-grade gliomas originate from different glial cells, mainly belong to the WHO grade II tumors, and exhibit a diffuse infiltrative growth pattern. Although not having a high proliferation capacity, they can recur or become malignant, diagnosed mainly within the age range of 30–45 years [20, 21]. Epilepsy can develop early as the most common major clinical manifestation, and also later in the course of the disease [10]. The seizures usually belong to the type of secondary generalized seizure [21]. Surgical treatment remains the most effective treatment for epilepsy-related low-grade gliomas. Drug resistance to AEDs is present in over 50% of patients before surgery, which may be attributed to insular involvement, delayed diagnosis, and location of tumor in functional areas [20]. In addition to epilepsy, the neurological symptoms of epilepsy-related low-grade gliomas also include headache, dizziness, elevated intracranial pressure, focal neurological deficits, cognitive decline, and mental abnormalities. The diagnosis of EAT mainly depends on clinical symptoms, imaging approaches and pathological examination. Diagnosis of EAT can be considered for refractory epilepsy based on abnormal computed tomography (CT)/magnetic resonance imaging (MRI) findings. More importantly, attentions should be paid to distinguish EAT from cortical dysplasia and intracranial inflammation. There are no clear clinical or imaging boundaries for distinguishing between EAT subtypes, so pathological examination is needed to confirm diagnosis. Immunohistochemical staining has the advantage of distinguishing between neurons and glial cells, and can facilitate histological classification of EAT. Given that the main clinical manifestation of EAT is epilepsy, electroencephalogram (EEG), especially long-term video electroencephalography (VEEG), is an important tool to evaluate EAT. EEG can provide guidance for locating and surgical resection of epileptic foci, evaluating disease severity, predicting the risk of epilepsy recurrence, and making adjustment of epilepsy medications. The interictal EEG signals of EAT patients do not have a specific pattern; they usually appear as spike waves and/or sharp waves, sometimes mixed with slow waves ipsilateral to the tumor. Some EEG activities can even be quite normal [9, 19]. In this study, the EAT patients had an average age of 49.32 ± 16.73 years, and the tumors were mostly gliomas, particularly WHO grade I–II gliomas, which are consistent with the literature. The EAT and non-EAT patients had no significant difference in the type of epilepsy or tumor location. This suggests the need of awareness for low-grade gliomas in epilepsy patients, especially drug-resistant epilepsy patients, who have unknown causes of epilepsy and a disease onset at the middle age. Moreover, follow-up observations, especially follow-up brain imaging, are important for distinguishing EAT from other causes of epilepsy, such as cortical dysplasia and inflammatory pathology. Brain biopsy examination should be performed if necessary.
