Pediatric and elderly polymorphous low-grade neuroepithelial tumor of the young: Typical and unusual case reports and literature review.

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY), one of the pediatric-type diffuse low-grade gliomas, is characterized by a diffuse infiltrating pattern of oligodendroglioma-like tumor cells showing CD34 positivity and harbors mitogen-activated protein kinase (MAPK) alteration, such as vRAF murine sarcoma viral oncogene homolog B1 (BRAF) p.V600E or fibroblast growth factor fusion genetically. It occurs mainly in pediatric and adolescents with seizures due to the dominant location of the temporal lobe. However, there have been a few cases of PLNTY in adult patients, suggesting the wide range of this tumor spectrum. Here, we describe two cases of PLNTY, one in a 14-year-old female and the other in a 66-year-old female. The pediatric tumor showed typical clinical course and histopathology with BRAF p.V600E mutation, whereas the elderly tumor was unusual because of non-epileptic onset clinically and ependymal differentiation histopathologically harboring KIAA1549-BRAF fusion. There might be unusual but possible PLNTY, as in our elderly case. We also compared typical pediatric and unusual elderly tumors by reviewing the literature.

Cognitive features and surgical outcome of patients with long-term epilepsy-associated tumors (LEATs) within the temporal lobe.

OBJECTIVE: The objective of the study was to evaluate cognitive and epilepsy-related features in 166 surgically treated patients with epilepsy with long-term epilepsy-associated tumors (LEATs) located in the temporal lobe. METHOD: Pre- and postsurgical cognitive as well as the one-year seizure outcome of adult patients with histopathologically confirmed LEATs (28 grade-I dysembryoplastic neuroepithelial tumors (DNET), 95 grade-I gangliogliomas (GG), 24 grade-I pilocytic astrocytomas (PA), 9 grade-II pleomorphic xanthoastrocytoma (PXA), 10 grade-II diffuse astrocytoma (DA)) who underwent epilepsy surgery in Bonn/Germany between 1988 and 2012 were evaluated. RESULTS: At baseline, tumor groups differed in regard to age at epilepsy onset and location within the temporal lobe. Postoperative seizure freedom was achieved most frequently (>77.8%) in DNET, GG, and DA, less often in PXA (62.5%) and the least in PA (56.5%). Preoperative memory was impaired in 67.1% of all patients, executive functions in 44.7%, and language in 45.5%. Patients with PA displayed the poorest cognitive performance. Individual significant memory decline that was observed in 27.1% of all patients was predicted by left-sided surgery, a mesial pathology, and extended hippocampal resection. Executive functions depended on antiepileptic drug (AED) load and remained stable (72.0%) or even improved (21.6%) after surgery. Language functions were unchanged in 89.5% of patients. CONCLUSION: Patients with LEATs in the temporal lobe frequently show cognitive impairments. Predictors for pre- and postoperative cognition mostly correspond to what is known for temporal lobe epilepsy and resections in general. However, different tumor types appear to be associated with different cognitive and seizure outcomes with astrocytoma as the least benefitted group.

[Differential diagnosis of epileptogenic substrates of unknown etiology using a modification of the routine MRI protocol]. / Differentsial'naya diagnostika epileptogennykh substratov neyasnoi etiologii s pomoshch'yu modifikatsii protokola standartnoi MRT.

OBJECTIVE: To evaluate the diagnostic capabilities of modifying the standard MRI protocol as part of an interdisciplinary presurgical examination of patients with epileptogenic substrates of unknown etiology. MATERIAL AND METHODS: The results of dynamic MRI of 8 patients with a referral diagnosis of focal cortical dysplasia (FCD) were analyzed. In 7 patients, epilepsy was the reason for a standard MRI of the brain; in another patient with myasthenia, MRI was performed as part of a comprehensive examination. All patients, in addition to standard MRI, underwent a modification of the real-time scanning protocol to include contrast, tractography (DTI), and perfusion techniques (ASL/DSC). In 1 case, with questionable results, the results of a modification of the standard MRI protocol, high-resolution MRI (HR MRI) and hybrid positron emission CT with 11C-methionine (PET/CT with 11C-MET) were combined. RESULTS: Seven patients underwent epileptic surgery and 1 patient was operated on for a tumor. In 4 out of 8 patients, based on the results of a modification of the standard MRI protocol, radiological signs of a neoplastic process were identified, which suggested a low-grade tumor. One of them needed PET/CT to confirm the assumption. The results of pathomorphological examination correlated with the direct diagnosis for surgical treatment. One of the 4 patients was suspected to have dysembryoplastic neuroepithelial tumor (DNET) based on the results of the protocol modification, which was also confirmed by pathological examination. In another 4 patients in whom it was possible to narrow the differential between FCD type II and DNET based on the results of the modification, FCD IIb was pathomorphologically verified. CONCLUSION: The proposed modification of the standard MRI protocol can significantly facilitate the differential diagnosis between the neoplastic and dysplastic origin of an epileptogenic substrate of unknown etiology, which in turn affects the patient's management tactics.

Do we have to continue antiseizure medications post surgery in long-term epilepsy associated tumors (LEATs)?

OBJECTIVE: To identify the rate of successful antiseizure medication (ASM) withdrawal after resective surgery in patients with long-term epilepsy-associated tumors (LEATs). METHODS: A retrospective analysis (from our prospectively archived data) on the post-operative ASM profile of 123 consecutive patients who completed a minimum of 2 years after resection of LEATs for ASM-resistant epilepsy. A comparison between recurred and non-recurred groups in terms of seizure recurrence was used to identify the potential predictors of seizure recurrence whose attributes were further analyzed using univariate and multiple logistic regression analysis. Kaplan-Meier survival curves were used to study the probability of ASM freedom following surgery. RESULTS: We attempted ASM withdrawal in 102 (82.9 %) patients. Forty-eight (47.1 %) had seizure recurrence while reducing ASM, of which 22 (21.6 %) continued to have seizures even after ASM optimisation. On univariate analysis, presence of pre-operative secondary generalized seizure(s) was the only factor associated with seizure recurrence. At a mean follow-up of 6.1 years, 72 (58.5 %) patients were seizure-free and aura-free at terminal follow-up (53 patients were off any ASM). The cumulative probability of achieving complete ASM-free status was 29 % at fourth year, 42 % at sixth year, 55 % at eighth year, and 59 % at 10th year after surgery. CONCLUSIONS: Following resective surgery for LEATs, ASM(s) could be successfully discontinued in half of the patients. About one-third of the patients may have recurrent seizures on follow-up. Presence of secondary generalized seizure(s) prior to surgery predicts seizure recurrence, whereas MRI defined completeness of resection will not. This information will help in rationalising decisions on ASM management post-resection.

Developmental tumors and adjacent cortical dysplasia: single or dual pathology?

Developmental tumors often lead to refractory partial seizures and constitute a well-defined, surgically remediable epilepsy syndrome. Dysplastic features are often associated with these tumors, and their significance carries both practical and conceptual relevance. If associated focal cortical dysplasia (FCD) relates to the extent of the epileptogenic tissue, then presurgical evaluation and surgical strategies should target both the tumor and the surrounding dyslaminated cortex. Furthermore, the association has been included in the recently revised classification of FCD and the epileptogenicity of this associated dysplastic tissue is crucial to validate such revision. In addition to the possibility of representing dual pathology, the association of developmental tumors and adjacent dysplasia may instead represent a single developmental lesion with distinct parts distributed along a histopathologic continuum. Moreover, the possibility that this adjacent dyslamination is of minor epileptogenic relevance should also be entertained. Surgical data show that complete resection of the solid tumors and immediately adjacent tissue harboring satellites may disrupt epileptogenic networks and lead to high rates of seizure freedom, challenging the epileptogenic relevance of more extensive adjacent dyslaminated cortex. Whether the latter is a primary or secondary abnormality and whether dyslaminated cortex in the context of a second lesion may produce seizures after complete resection of the main lesion is still to be proven.

Invasive EEG studies in tumor-related epilepsy: when are they indicated and with what kind of electrodes?

Patients with tumor-related epilepsy (TRE) represent an important proportion of epilepsy surgery cases. Recently established independent negative predictors of postoperative seizure outcome are long duration of epilepsy, presence of generalized tonic-clonic seizures, and incomplete tumor resection. In temporal lobe cases, additional hippocampectomy or corticectomy may further improve outcome. Invasive electroencephalography (EEG) recordings (IEEG) may be indicated to guide the resection by defining eloquent cortex (EC) or to determine the extent of potentially magnetic resonance imaging (MRI)-negative epileptogenic tissue. In fact, invasive recordings are reportedly used in up to 10% of patients who are undergoing epilepsy surgery for TRE. Following careful consideration of the concepts underlying epilepsy surgery, the current use of IEEG, and the predictors of outcome in extratemporal and temporal tumors in TRE, we postulate the following> (1) In patients with extratemporal TRE, IEEG is necessary only if the MRI lesion (and if feasible a rim around it) cannot be completely resected because of adjacent or overlapping EC. In these cases, EC should be mapped to determine its relationships to the lesion, the irritative, and seizure-onset zones in order to maximize the extent of the lesionectomy. (2) In patients with nondominant temporal TRE, data suggest that if epileptogenic tumors (ETs) are encroaching on mesial temporal structures, if epilepsy duration is long, and seizures are frequent and disabling, these structures should be included in the resection. (3) In patients with dominant temporal TRE, we suggest leaving the mesial structures in place if they are functionally and structurally intact and to consider resecting these structures only if they are structurally and functionally abnormal. There is insufficient evidence justifying the use of IEEG to define the extent of the epileptogenic zone in such cases. This should be reserved for cases where an initial lesionectomy has failed.

Gene markers in brain tumors: what the epileptologist should know.

Gene markers or biomarkers can be used for diagnostic or prognostic purposes for all different types of complex disease, including brain tumors. Prognostic markers can be useful to explain differences not only in overall survival but also in response to treatment and for development of targeted therapies. Multiple genes with specific types of alterations have now been identified that are associated with improved response to chemotherapy and radiotherapy, such as O(6)-methylguanine methyltranferase (MGMT) or loss of chromosomes 1p and/or 19q. Other alterations have been identified that are associated with improved overall survival, such as mutations in isocitrate dehydrogenase 1 (IDH1) and/or isocitrate dehydrogenase 2 (IDH2) or having the glioma CpG island DNA methylator phenotype (G-CIMP). There are many biomarkers that may have relevance in brain tumor-associated epilepsy that do not respond to treatment. Given the rapidly changing landscape of high throughput "omics" technologies, there is significant potential for gaining further knowledge via integration of multiple different types of high genome-wide data. This knowledge can be translated into improved therapies and clinical outcomes for patients with brain tumors.

Historical Overview of the "Firing" Liaison between Brain Tumors and Epilepsy.

This review addresses, in a critical historical perspective, the link between seizures and endocranic neoplasms. Folkloric descriptions of epilepsy can be found in writings from ancient cultures. Hippocrates first provided a medical interpretation. In 1770, Tissot published Traité de l'épilepsie, a milestone in epileptology, whereas the 19th century is considered the golden era of epileptic studies. In 1882, the father of modern epileptology, Jackson, in his article Localized Convulsions from Tumour of the Brain, reported a case of a patient affected by typical Jacksonian seizures in the presence of a brain tumor. However, he did not establish a direct correlation between brain tumors and epilepsy, and an explanation for his clinical case was lacking. Before Jackson's article, other authors reported similar cases, but only Gairdner in 1834 published a report suggesting the concept of a direct relationship between epilepsy and a brain tumor. From the beginning until the mid of the 20th century several authors reported seizures attributed to intracranial tumors, and in recent years studies have focused on the pathogenesis of tumor-related seizures. Biochemical and molecular changes in brain tumors and their environment opened unprecedented working hypotheses on epileptogenesis and on treatment of epilepsy associated with brain tumors.

Factors affecting seizure outcome in Long-term epilepsy associated tumors (LEATs) in children and young adolescents.

OBJECTIVE: Tumors with seizures as primary mode of presentation are collectively called Long-term epilepsy associated tumors (LEATs or Epileptomas). The overall survival is good so 'seizure outcome' becomes the primary goal rather than neuro-oncological outcome. METHODS: A retrospective analysis of our surgical database (2015-19) was done to find operated patients of intra-axial brain tumors with age less than 25-years and who had presented with seizures. RESULTS: The mean age at presentation was 16.44 years (SD + 6.82 years). Complex partial seizures/focal unaware seizures were the most common type of seizures encountered (n = 22) with mean duration of seizures was 49.50 months (SD + 31.04 months). The most common pathology was glioneuronal tumors (GNTs) (n = 17). Gross total resection (GTR) group had a significantly better seizure outcome as compared with the Subtotal resection (STR) group (p = 0.006). Presence of focal or partial seizure was a significant factor pointing towards a better seizure control (p = 0.005). CONCLUSION: The shorter duration of symptoms, partial/focal seizures and gross total excision were predictors of a good seizure-outcome. Age of the patient and the histopathology of the tumor does not affect seizure-outcome on comparing GNTs with non GNTs.

Pathology-MRI Correlations in Diffuse Low-Grade Epilepsy Associated Tumors.

It is recognized that IDH mutation negative, low-grade epilepsy associated tumors (LEAT) can show diffuse growth patterns and lack the diagnostic hallmarks of either classical dysembryoplastic neuroepithelial tumors (DNT) or typical ganglioglioma. "Nonspecific or diffuse DNT" and more recently "polymorphous low-grade neuroepithelial tumor of the young" have been terms used for these entities. There are few reports on the MRI recognition of these diffuse glioneuronal tumors (dGNT), which is important in planning the extent of surgical resection. In 27 LEATs T1, T2, FLAIR, and postcontrast T1 MRI were evaluated and the pathology reviewed, including immunostaining for NeuN, CD34, MAP2, and IDH1. Each case was then independently classified by pathology or MRI as simple DNT, complex DNT, or dGNT. There was agreement in 23/27 (85%; Kappa score 0.62; p < 0.01). In 4 cases, there was discrepancy in the diagnosis of simple versus complex DNT but 100% agreement achieved for dGNT. DNT showed significantly more expansion of the cortex, cystic change and ventricle extension than dGNT. dGNT showed significantly more subcortical T2w hyperintensity and focal cortical atrophy which correlated on pathology with CD34 expression, cortical neuronal loss and white matter rarefaction. There was no distinct cortical dysplasia component identified by MRI or pathology in any case. This study highlights that dGNT can be reliably discriminated on MRI from DNT.

Early and late epilepsy surgery in focal epilepsies associated with long-term epilepsy-associated tumors.

OBJECTIVE Epilepsy surgery is an effective means of treating focal epilepsy associated with long-term epilepsy-associated tumors. This study evaluated a large population of surgically treated patients with childhood onset of epilepsy and a histologically confirmed diagnosis of long-term epilepsy-associated tumors. The authors analyzed long-term seizure outcomes to establish whether the time of surgery and patients' ages were determinant factors. METHODS The authors separately investigated several presurgical, surgical, and postsurgical variables in patients operated on before (pediatric group) and at or after (adult group) the age of 18 years. Patients with < 24 months of postsurgical follow-up were excluded from the analysis. RESULTS The patients who underwent surgery before 18 years of age showed better seizure outcomes than those after 18 years of age (80% vs 53.3% Engel Class Ia outcome, respectively; p < 0.001). Multivariate analysis showed that the only variables significantly associated with seizure freedom were complete resection of the lesion, a shorter duration of epilepsy, and temporal lobe resection. CONCLUSIONS The findings of this study indicate that pediatric patients are more responsive to epilepsy surgery and that a shorter duration of epilepsy, complete resection, and a temporal lobe localization are determinant factors for a positive seizure outcome.

BRAF V600E mutation is associated with mTOR signaling activation in glioneuronal tumors.

BRAF V600E mutations have been recently reported in glioneuronal tumors (GNTs). To evaluate the expression of the BRAF V600E mutated protein and its association with activation of the mammalian target of rapamycin (mTOR) pathway, immunophenotype and clinical characteristics in GNTs, we investigated a cohort of 174 GNTs. The presence of BRAF V600E mutations was detected by direct DNA sequencing and BRAF V600E immunohistochemical detection. Expression of BRAF-mutated protein was detected in 38/93 (40.8%) gangliogliomas (GGs), 2/4 (50%) desmoplastic infantile gangliogliomas (DIGs) and 23/77 (29.8%) dysembryoplastic neuroepithelial tumors (DNTs) by immunohistochemistry. In both GGs and DNTs, the presence of BRAF V600E mutation was significantly associated with the expression of CD34, phosphorylated ribosomal S6 protein (pS6; marker of mTOR pathway activation) in dysplastic neurons and synaptophysin (P < 0.05). In GGs, the presence of lymphocytic cuffs was more frequent in BRAF-mutated cases (31 vs. 15.8%; P=0.001). The expression of both BRAF V600E and pS6 was associated with a worse postoperative seizure outcome in GNT (P < 0.001). Immunohistochemical detection of BRAF V600E-mutated protein may be valuable in the diagnostic evaluation of these glioneuronal lesions and the observed association with mTOR activation may aid in the development of targeted treatment involving specific pathogenic pathways.

Epilepsy associated tumors: Review article.

Long-term epilepsy associated tumors (LEAT) represent a well known cause of focal epilepsies. Glioneuronal tumors are the most frequent histological type consisting of a mixture of glial and neuronal elements and most commonly arising in the temporal lobe. Cortical dysplasia or other neuronal migration abnormalities often coexist. Epilepsy associated with LEAT is generally poorly controlled by antiepileptic drugs while, on the other hand, it is high responsive to surgical treatment. However the best management strategy of tumor-related focal epilepsies remains controversial representing a contemporary issues in epilepsy surgery. Temporo-mesial LEAT have a widespread epileptic network with complex epileptogenic mechanisms. By using an epilepsy surgery oriented strategy LEAT may have an excellent seizure outcome therefore surgical treatment should be offered early, irrespective of pharmacoresistance, avoiding both the consequences of uncontrolled seizures as well as the side effects of prolonged pharmacological therapy and the rare risk of malignant transformation.