Drug Refractory Epilepsy – A Series of Lesions with Triple Pathology
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.266289
Source of Support: None, Conflict of Interest: None
Keywords: Cortical dysplasia, dysembryoplastic neuroepithelial tumors, gangliogliomas, triple pathology
Daumas-Duport et al. first described dysembryoplastic neuroepithelial tumors (DNETs) in 1988. These are considered benign tumors of developmental malformations and consist of a mixture of glial cell components. Gangliogliomas are low-grade tumors comprising atypical ganglion or neuronal cells and an atypical glial cell component. Cortical dysplasias can result from (i) abnormal proliferation of undifferentiated cells in the neuroepithelium; (ii) migration abnormality of neuroblasts; and (iii) anomaly of cell differentiation. Blümcke et al. classified focal cortical dysplasias (FCDs) in 2011 and defined the category 3b which includes FCDs associated with tumors such as DNETs and gangliomas. These were termed as acquired processes, rather than double pathologies. Many authors have also found such associations, including few reports of triple pathology like hippocampal sclerosis, FCD, and tumors.
In an extensive search, we did not find any reports of coexisting FCD, a gangliogliomas, and a DNETs in a single patient. In this series, we highlight five cases where these three pathological entities coexisted in a single epileptogenic focal lesion of the temporal lobe. Their coexistence strengthens the acquired process concept. We also present our management strategy for these lesions along with a review of world literature on cases with a similar constellation of pathologies.
This study is a retrospective review of all patients with drug refractive epilepsy who have undergone surgery at our institute between January 2000 and December 2015. Cases were reviewed to confirm a diagnosis of DNETs and gangliogliomas, using criteria outlined by the World Health Organization classification of tumors. Of the possible cases, five patients had coexistent DNETs, gangliogliomas, and FCD which were excised concurrently. FCDs were classified as described by Palmini et al. Medical records from the hospital were reviewed and patients were followed-up with telephonically.
Histopathological examinations of the five patients revealed the coexistence of a gangliogliomas, a DNETs and type I cortical dysplasia, the details of which are summarized in [Table 1]. The mean age of the patients at presentation was 26.6 years [standard deviation (SD) 10.73 years] with a mean symptom duration of 12.2 years (SD 6.94 years). The identifed semniology was of mesial temporal lobe onset. Magnetic resonance imaging (MRI) confirmed the lesions's location in the right temporal lobe in all five patients. The patients underwent right temporal corticoamygdalohippocampectomy (CAH), along with excision of these tumors. None of the patients had a recurrence of seizures during a mean follow-up period of 7 years (ranging from 2 to 15 years).
A 19-year-old man had presented with a history of sudden-onset generalized tonic clonic seizures for the past 6 years. He had no focal neurological deficit. His electroencephalogram was suggestive of few transient sharp wave activities in the right frontotemporal region leads. Contrast-enhanced MRI [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d showed a 4.5 cm × 4cm space-occupying lesion in the right temporal cortex which was of heterogeneous intensity on T1- and T2-weighted images with few areas of nodular contrast enhancement. He underwent right temporal craniotomy with electrocorticographic (ECOG)-guided gross total resection of the tumor and CAH. The tumor was intraxial (solid cystic), greyish pink and moderately vascular. The patient had an uneventful postoperative period with no recurrence of seizure.
A histo exam revealed grossly few greyish pink brain tissues which were subjected to microscopic examination. Routine hematoxylin–eosin-stained sections showed lesion comprising areas resembling gangliogliomas. These areas consisted of an admixture of atypical-appearing astrocytic cells and focally increased numbers of atypical-appearing neuronal cells [Figure 2]a. The cells were characterized by nuclear irregularities, an abnormal distribution and amount of Nissl substance, and binucleate forms. The associated astrocytic component of the tumor was characterized by a proliferation of cells showing mild to moderate nuclear atypia, characterized by nuclear enlargement, hyperchromasia, and angularity. Mitotic figures were not identified. Vascular endothelial hyperplasia or necrosis was not seen. Numerous eosinophilic granular bodies were distributed throughout this portion of the tumor. Rare, scant perivascular lymphocytes were also identified. Calcifications were not seen.
Adjacent to and focally intermixed with the gangliogliomas component were morphologically distinct areas resembling DNETs. This component of the tumor was characterized by proliferation of oligodendroglial cells arranged against a microcystic background [Figure 2]b. Neurons and astrocytic cells were intermixed with the oligodendroglial component [Figure 2]c. There was no evidence of mitotic activity, vascular proliferation, necrosis, or calcifications associated with the DNETs component. No significant cytologic atypia was associated with any of the cellular components of the DNETs.
Focal areas of cortical dysplasia were seen. These areas were characterized by disorganized cortical lamination with focal neuronal cytomegaly and increased numbers of large-caliber neurons situated within cortical layers [Figure 2]c. The patient has remained free of seizure (International League Against Epilepsy (ILAE) class I) for the the past eight years following his surgery.
A gangliogliomas, a DNETs and cortical dysplasia were identified in a single temporal lobe lesion of our patient. Such distinct occurrence is extremely rare in recent literature. Small areas of cortical dysplasia seen associated with gangliogliomas and DNETs have been described previously by Prayson  and Shimbo et al. These are commonly reported as a “dual pathology”. Other tumors such as desmoplastic infantile gangliogliomas, angiocentric gliomas, and pleomorphic xanthoastrocytoma may occasionally be associated with FCD.,, The frequent association of these three pathological entities DNETs, gangliogliomas, and cortical dysplasia suggests a common pathogenetic mechanism. Only few case reports are available, where three potentially etiological lesions are present in a patient with drug refractory epilepsy [Table 2].,,,
Gangliogliomas and DNETs have many clinical and pathological similarities, but they are differentiated primarily on the phenotypic appearance, the atypical ganglion, or neuronal cell, and an atypical glial cell components in gangliogliomas resemble the fibrillary astrocytoma. In case of a DNETs, the atypical glial cell component resembles cystic oligodendroglioma. Cortical dysplasia and neuronal migration abnormalities occasionally can occur in association with DNETs and gangliogliomas. Coexistence of the gangliogliomas or DNETs in patients with cortical dysplasia suggests that these lesions may be transitional forms. They also signify the tumoral form of cortical dysplasia or can occur due to neoplastic conversion of the dysplastic lesion.
Gangliogliomas have also been classified along with DNETs as dysplastic tumors indicative of the extreme end of the histopathological variety of FCD. Barkovich et al. had classified DNETs as “malformations due to abnormal neuronal and glial proliferation, abnormal cell types, neoplastic, associated with disordered cortex.” These also lend credit to our belief. Preoperative radiological differentiation between these three pathologies can be difficult.
A study to determine whether (11) C-methionine PET compared with (18)F-FDG PET was useful for the evaluation of FCD and mixed glioneural tumors reported that (18)F-FDG does not contribute to the differential diagnosis and that another tracer such as (11) C-methinine is required. (11) C-methinine PET results correlated well with the pathologic spectrum in pediatric lesional epilepsy patients.
In these cases, preoperative planning is very important to ensure all potential epileptogenic tissue is excised. To this end, we prefer to perform ECOG-guided resections under image guidance to achieve complete resection of lesion and epileptogenic foci. The reduction of ECOG grading gives satisfaction to the operating surgeon regarding completion of the resective procedure. The authors have found excellent outcomes if epilepsy surgery approach (complete excision of the epileptogenic zone) is done. All our patients had postoperative ILAE class I outcome.
Only few cases of “triple pathology” have been described. Of the seven cases reported earlier, only three cases describe a tumor (gangliogliomas) coexisting with mesial temporal sclerosis and cortical dysplasia within the same lesion., Yang et al. had a seizure-free outcome for 8 months despite performing a subtotal resection of the gangliogliomas, this suggests that the tumor had only a minor role in the seizure network and and that a complete excision of the hippocampal sclerosis and cortical dysplasia was mandatory.
To the best of our knowledge, this is the first series of cases which involves patients who had a DNETs, gangliogliomas, and FCD coexisting in the same lesion. These cases demonstrate the importance of accurate localization of epileptogenic activity in tumor-associated cortical dysplasias. In such cases, long-term recurrence may be dependent on completeness of the FCD excision rather than the excision of the tumor alone.
Gangliogliomas and DNETs can arise from the conversion of dysplastic lesion like cortical dysplasias. The coexistence of these three lesions as distinct entity in a single temporal lobe lesion is virtually unknown. An ECOG complete resection of the lesion and epileptogenic foci can provide a cure for intractable epilepsy in such patients.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]