WONOEP appraisal: The role of glial cells in focal malformations associated with early onset epilepsies.

Epilepsy represents a common neurological disorder in patients with developmental brain lesions, particularly in association with malformations of cortical development and low-grade glioneuronal tumors. In these diseases, genetic and molecular alterations in neurons are increasingly discovered that can trigger abnormalities in the neuronal network, leading to higher neuronal excitability levels. However, the mechanisms underlying epilepsy cannot rely solely on assessing the neuronal component. Growing evidence has revealed the high degree of complexity underlying epileptogenic processes, in which glial cells emerge as potential modulators of neuronal activity. Understanding the role of glial cells in developmental brain lesions such as malformations of cortical development and low-grade glioneuronal tumors is crucial due to the high degree of pharmacoresistance characteristic of these lesions. This has prompted research to investigate the role of glial and immune cells in epileptiform activity to find new therapeutic targets that could be used as combinatorial drug therapy. In a special session of the XVI Workshop of the Neurobiology of Epilepsy (WONOEP, Talloires, France, July 2022) organized by the Neurobiology Commission of the International League Against Epilepsy, we discussed the evidence exploring the genetic and molecular mechanisms of glial cells and immune response and their implications in the pathogenesis of neurodevelopmental pathologies associated with early life epilepsies.

Seizure outcome in surgically treated pediatric gangliogliomas and dysembryoplastic neuroepitheliomas according to imaging and resection strategies.

PURPOSE: Imaging and resection strategies for pediatric gangliogliomas (GG) and dysembryoplastic neuroepitheliomas (DNET) presenting with epilepsy were retrospectively analyzed in a consecutive institutional series of surgically treated patients. METHODS: Twenty-two children (median 8 years, 3-18 years) presented with seizures for 30 months median (14-55.2 months) due to a histologically verified GG/DNET. RESULTS: There were 20 GG and 2 DNT, 68 % located temporal, 32 % extra-temporal. Seizure history was significantly longer in temporal cases (38 versus 14 months median, p < 0.01). MRI contrast enhancement was present in 50 % and methionine (MET) positron emission tomography (PET) uptake in 70 % (standard uptake values (SUVs) 2.92 mean, from 1.6 to 6.4). 27 % had glucose PET hypometabolism. Primarily, in temporal GG, ECoG (electrocorticography) -guided lesionectomies were performed in 87 % and antero-mesial temporal lobe resections (AMTLR) in 13 %, whereas in extra-temporal GG/DNETs, lesionectomies were performed in 100 %. ILAE Class 1 seizure outcome was primarily achieved in 73 % of the temporal cases, and was increased to 93 % by performing six repeat surgeries using AMTLR. Extratemporal patients experienced ILAE Class 1 seizure outcomes in 86 % without additional surgeries, although harboring significantly more residual tumor (p < 0.005, mean follow-up 28 months). CONCLUSION: In children, MET PET imaging for suspected GG is proposed preoperatively showing a high diagnostic sensitivity and an option to delineate the lesions for navigated resection, whereas MRI contrast behavior was of no differential diagnostic use. As a surgical strategy we propose primarily lesionectomies for extratemporal but AMTLR for temporal GG respecting eloquent brain areas.

Contralateral transcallosal transfalcine approach for bilateral intra-extraventricular anaplastic ganglioglioma via 'the trans-tumoral route': a technical case instruction.

BACKGROUND: Bilateral, biventricular lesions present a challenging scenario in neurosurgery, often requiring complex surgical techniques for management. Gangliogliomas (GG), while typically indolent, can manifest as anaplastic variants (AGG), necessitating comprehensive treatment strategies. This case study explores a unique surgical approach for a patient with bilateral, intra-extraventricular lesions infiltrating the corpus callosum, highlighting the complexities of managing such cases. METHODS: A 63-year-old female presented with a progressive intraventricular lesion infiltrating the left frontal lobe, diagnosed initially as a ganglioglioma. Following resection and histological examination, the lesion was confirmed as a WHO Grade 1 ganglioglioma. Subsequently, a contralateral lesion emerged, necessitating a novel surgical approach to achieve maximal safe resection while minimising neurological deficits. The technique involved extending the surgical corridor contralaterally along the tumour route, guided by neuronavigation and fluorescence imaging. RESULTS: The surgical approach enabled maximal safe resection of the lesion, with postoperative imaging confirming complete resection in most sites except for a known infiltration in the right posterior lateral ventricle. Histological examination revealed AGG, prompting subsequent adjuvant radiotherapy due to its aggressive nature. CONCLUSION: The management of bilateral, biventricular lesions such as AGG requires innovative surgical approaches tailored to individual patient characteristics. The case highlights the efficacy of a transtumoral approach in achieving maximal safe resection while minimising neurological sequelae. Moreover, it underscores the importance of comprehensive treatment strategies, including adjuvant therapies, in addressing aggressive histological variants of gangliogliomas.

Desmoplastic infantile astrocytoma/ ganglioglioma in a pediatric onset multiple sclerosis patient: A case report.

Here we present a co-occurrence of a non-typical presentation of DIG/DIA and multiple sclerosis in a 13-year-old female. Our case highlights how a thorough investigation prior to treatment is needed in patients with such condition to choose proper management for better prognosis.

Intra-axial Cortical-Based Tumour Presented as Homonymous Hemianopia in a Young Patient: A Diagnostic Dilemma.

Intra-axial cortical-based tumours are rare tumours affecting children and young adults. These tumours can be classified as either low-grade or high-grade, depending on their aggressiveness and rate of growth. We report a case of homonymous hemianopia secondary to an intra-axial cortical-based tumour in a young patient. A 26-year-old lady presented with bilateral blurring of vision for three weeks associated with a headache. Visual acuity was 6/6 in both eyes. Bilateral optic nerve functions were normal. The Humphrey visual field test showed left-homonymous hemianopia. A CT scan and MRI of the brain revealed an intra-axial cortical-based tumor. Differential diagnoses include pleomorphic xanthoastrocytoma (PXA), ganglioglioma, oligodendroglioma, and dysembryoplastic neuroepithelial tumour (DNET). The patient was treated conservatively and closely monitored through clinic follow-up.

Imaging of pediatric glioneuronal and neuronal tumors.

Glioneuronal tumors (GNTs) are an expanding group of primary CNS neoplasms, commonly affecting children, adolescents and young adults. Most GNTs are relatively indolent, low-grade, WHO grade I lesions. In the pediatric age group, GNTs have their epicenter in the cerebral cortex and present with seizures. Alterations in the mitogen-activated protein kinase (MAPK) pathway, which regulates cell growth, are implicated in tumorigenesis. Imaging not only plays a key role in the characterization and pre-surgical evaluation of GNTs but is also crucial role in follow-up, especially with the increasing use of targeted inhibitors and immunotherapies. In this chapter, we review the clinical and imaging perspectives of common pediatric GNTs.

Diffuse leptomeningeal glioneuronal tumor with distinct neuronal and glial components but identical diagnostic molecular and genetic features.

The 2021 World Health Organization (WHO) classification of the central nervous system (CNS) tumors has classified diffuse leptomeningeal glioneuronal tumor (DLGNT) as a mixed neuronal and glial tumor. Here, we report a DLGNT with two distinct morphological tumor components but identical molecular features. A four-year-old female child presented with progressive right upper extremity weakness. Magnetic resonance imaging (MRI) revealed the leptomeningeal enhancement over the brain stem and cervicothoracic spine. The histological examination of surgical specimens revealed two distinct tumor components: approximately half of the tumor is composed of oligodendroglioma-like tumor intermingled with nodules of ganglioglioma-like tumor. Immunohistochemistry confirmed the oligodendroglioma and ganglioglioma features. The molecular genetic studies demonstrated the features of DLGNT, including fusion of KIAA1549::BRAF, deletion of chromosome 1p, and absence of isocitrate dehydrogenase 1/2 (IDH1/2) mutation in both tumor components. Interestingly, the genetic studies also revealed the distinct chromosomal abnormalities of the loss of chromosome 4 only in oligodendroglioma-like tumor and copy neutral loss of heterozygosity of 7Q34Q36.3 in the ganglioglioma-like tumor component. This case highlights the critical role of molecular testing in the diagnosis of rare cases of DLGNT with diverse morphological components as well as in the identification of unique molecular alternations responsible for morphological phenotypes of the distinct tumors in DLGNT.

Long-term seizure outcome after epilepsy surgery of neuroglial tumors.

Purpose: Neuroglial tumors are frequently associated with pharmacorefractory epilepsies. However, comprehensive knowledge about long-term outcomes after epilepsy surgery and the main prognostic factors for outcome is still limited. We sought to evaluate long-term outcomes and potential influencing factors in a large cohort of patients who underwent surgery for neuroglial tumors in a single-center setting. Methods: The study analyzed the outcomes of 107 patients who underwent epilepsy surgery for neuroglial tumors between 2001 and 2020 at the Department of Epileptology, University Hospital Bonn, in Germany. The outcomes were evaluated using Engel classification. Differences in outcome related to potential prognostic factors were examined using the Chi2-test, Fisher's exact test and sign test. Additionally, stepwise logistic regression analysis was employed to identify independent prognostic factors. Results: Complete seizure freedom (Engel Class IA) was achieved in 75% of the operated patients at 12 months, and 56% at the last follow-up visit (70.4 ± 6.2 months, median: 40 months). Completeness of resection was a crucial factor for both 12-month follow-up outcomes and the longest available outcomes, whereas lobar tumor localization, histology (ganglioglioma vs. dysembryoplastic neuroepithelial tumor), history of bilateral tonic-clonic seizures prior to surgery, invasive diagnostics, side of surgery (dominant vs. non-dominant hemisphere), age at epilepsy onset, age at surgery, and epilepsy duration did not consistently impact postsurgical outcomes. Among temporal lobe surgeries, patients who underwent lesionectomy and lesionectomy, including hippocampal resection, demonstrated similar outcomes. Conclusion: Neuroglial tumors present as excellent surgical substrates in treating structural epilepsy. To achieve an optimal postsurgical outcome, a complete lesion resection should be pursued whenever possible.

Incidence and survival characteristics of pediatric ganglioglioma from 2004 to 2018, with focus on infratentorial sites.

Background: Ganglioglioma (GG) is a slow-growing glioneuronal neoplasm, most frequently seen in the supratentorial location in older children and associated with epilepsy syndromes. GG is rare in the infratentorial location, hence we embarked upon analyzing the National Cancer Institute's (NCI) Survival, Epidemiology, and End Results (SEER) database to better evaluate GG outcomes by location in comparison to the broader pediatric low-grade glioma (pLGG) population. Methods: Pediatric patients diagnosed with GG and pLGG from 2004 to 2018 were included in the study. Their demographic, clinical, and survival characteristics were analyzed using SEER*Stat. Results: This study describes the largest cohort of pediatric GG, including 852 cases from year 2004 to 2018, with focus on infratentorial sites. Patients with brainstem GG or those with subtotally resected disease were identified as having higher risk of death. Conclusions: Our analysis highlights brainstem GG as a high-risk, poor-prognostic subgroup and elaborates on the incidence and survival characteristic of this lesser-known subgroup.

Low-grade glioma of the temporal lobe and tumor-related epilepsy in children.

PURPOSE: Low-grade glioma is the most common brain tumor among children and adolescents. When these tumors arise in the temporal lobe, patients frequently present with seizures that are poorly controlled with antiepileptic drugs. Here we summarize the clinical features, pathophysiology, preoperative evaluation, surgical treatment, and outcomes of pediatric patients with low-grade gliomas in the temporal lobe. METHODS: We reviewed the literature on pediatric low-grade gliomas in the temporal lobe, focusing on cohort studies and systematic reviews that described surgical treatment strategies and reported both oncologic and epilepsy outcomes. RESULTS: The differential diagnoses of pediatric low-grade gliomas in the temporal lobe include ganglioglioma, dysembryoplastic neuroepithelial tumor, desmoplastic infantile ganglioglioma, papillary glioneuronal tumor, pilocytic astrocytoma, pleomorphic xanthoastrocytoma, angiocentric glioma, and polymorphous low-grade neuroepithelial tumor of the young. There is no consensus on the optimal surgical approach for these tumors: lesionectomy alone, or extended lesionectomy with anterior temporal lobectomy, with or without removal of mesial temporal structures. Gross total resection and shorter preoperative duration of epilepsy are strongly associated with favorable seizure outcomes, defined as Engel Class I or Class II, approaching 90% in most series. The risk of surgical complications ranges from 4 to 17%, outweighing the lifetime risks of medically refractory epilepsy. CONCLUSION: Pediatric patients with temporal low-grade glioma and tumor-related epilepsy are best managed by a multidisciplinary epilepsy surgery team. Early and appropriate surgery leads to prolonged survival and a greater likelihood of seizure freedom, improving their overall quality of life.

Diffuse Gliomas with FGFR3::TACC3 Fusion: Morphological and Molecular Features and Classification Challenges.

FGFR3::TACC3 fusion is a driver, potentially targetable, genetic alteration identified in approximately 4% of high-grade diffuse gliomas and rare cases with low-grade histology. Herein, we review the genetic and epigenetic features of these tumors and highlight the challenges in their classification and grading. Diffuse gliomas with FGFR3::TACC3 fusion display unique histopathological and molecular features, including an oligodendroglioma-like appearance, calcifications, and CD34 extravascular immunoreactivity. High-grade tumors exhibit molecular alterations and a DNA methylation profile typical of glioblastoma, suggesting that they may represent a subtype clinically characterized by a slightly better prognosis. Tumors with low-grade morphology are genetically and epigenetically heterogeneous. Some, exclusive to adults, have molecular alterations typical of glioblastoma, although most do not match any methylation classes, using version 12.5 of the Heidelberg classifier. Another group, which mostly affects children or adolescents, lacks the molecular features of glioblastoma and has a DNA methylation profile similar to that of low-grade glioneuronal tumors. In conclusion, diffuse gliomas with FGFR3::TACC3 fusion do not constitute a distinct nosological entity, owing to their genetic and epigenetic diversity. Further studies are warranted to clarify the biological aggressiveness of tumors with low-grade histology to refine the grading and determine the optimal treatment strategy.

Ganglioglioma with anaplastic/high-grade transformation: Histopathologic, molecular, and epigenetic characterization of 3 cases.

Ganglioglioma (GG) with anaplasia (anaplastic ganglioglioma) is a rare and controversial diagnosis. When present, anaplasia involves the glial component of the tumor, either at presentation or at recurrence. To date, most published cases lack molecular characterization. We describe the histologic and molecular features of 3 patients presenting with BRAF p. V600E-mutant GG (CNS WHO grade 1) with high-grade glial transformation at recurrence. The tumors occurred in pediatric patients (age 9-16 years) with time to recurrence from 20 months to 7 years. At presentation, each tumor was low-grade, with a BRAFV600E-positive ganglion cell component and a glial component resembling pleomorphic xanthoastrocytoma (PXA) or fibrillary astrocytoma. At recurrence, tumors resembled anaplastic PXA or high-grade astrocytomas without neuronal differentiation. CDKN2A homozygous deletion (HD) was absent in all primary tumors. At recurrence, 2 cases acquired CDKN2A HD; the third case showed loss of p16 and MTAP immunoexpression, but no CDKN2A/B HD or mutation was identified. By DNA methylation profiling, all primary and recurrent tumors either grouped or definitely matched to different methylation classes. Our findings indicate that malignant progression of the glial component can occur in GG and suggest that CDKN2A/B inactivation plays a significant role in this process.

Infratentorial Relapsing Neuroglial Tumors in Adults: Management and Unsolved Issues-A Systematic Review.

(1) Background: Gangliogliomas are rare tumors accounting for about 0.4% of all central nervous system tumors. They are usually located in the temporal lobes of children and young adults, though such tumors in the infratentorial region and adult-age patients rarely reported. (2) Methods: A systematic review on ganglioglioma with infratentorial location in the adult population was conducted in accordance with the PRISMA guidelines. A total of 275 articles were found, and 23 were included. Demographic data, the location and histology of the lesion, pre-operative neurological status, the type of surgery, recurrence, radiotherapy/chemotherapy adjuvant treatments, neurological outcomes and follow-up information were collected. We also presented an illustrative case. (3) Results: A total of 27 patients were included. In 51%, the location was the cerebellum; in 40%, it was the fourth ventricle; in 11%, it was brainstem; and in 4%, it was the cerebellopontine angle. STR was performed in 44%, GTR in 26% and biopsy in 15% of the cases. Adjuvant radiotherapy was found in 22% of cases. Disease recurrence occurred in 15% of patients between 1 and 12 months after surgery with a diagnosis of high-grade ganglioglioma, while in six cases, no disease recurrence was documented. (4) Conclusions: Infratentorial glioneuronal tumors are rare findings in the adult population. Histopathological characterization does not seem to fully reflect their true behavior. Future studies are warranted for better characterizing histopathological findings and treatment.

Extremely slow-growing cerebellar ganglioglioma in an elderly patient.

Background: Gangliogliomas account for 0.4% of primary brain tumors. They mainly occur in the supratentorial compartment and typically affect only children and young adults. We present an especially rare case of cerebellar ganglioglioma in an elderly patient. Case Description: A 76-year-old Japanese woman presented with headache and nausea from 1 month previously. She had been diagnosed with a cerebellar tumor in her childhood, but the lesion was asymptomatic at that time, and there was no evidence of an increase in size, so it had been monitored without surgery. At the time of presentation, she had not been examined for approximately ten years. On admission, magnetic resonance imaging indicated a T2 hypertense cyst in the cerebellar vermis. Post-contrast T1 imaging showed an enhanced mural nodule in the cyst. Cerebral angiography showed that none of the vertebral arteries were significant feeders. The tumor was removed through posterior fossa craniotomy. The histopathological diagnosis was ganglioglioma. The patient's headache and nausea improved after surgery. Conclusion: Our patient presented a very rare case of extremely slow-growing elderly ganglioglioma in the cerebellum. In patients with gangliogliomas, long-term follow-up is important because the disease may become symptomatic at an older age.

Cerebellar anaplastic ganglioglioma in a septuagenarian.

Ganglioglioma is a rare neoplasm most common in children and adolescents. It is typically located in the supratentorial compartment, with the temporal lobe being the most common tumor location. Anaplastic ganglioglioma is a WHO grade III ganglioglioma, a rare subtype accounting for a small minority of ganglioglioma cases. Posterior fossa anaplastic ganglioglioma in an adult is incredibly rare; only 3 prior cases have been reported. Only 1 adult anaplastic ganglioglioma in the cerebellum has been reported. We present the second reported adult cerebellar anaplastic ganglioglioma.

Natural history and neuro-oncological approach in spinal gangliogliomas: a systematic review.

To describe the natural history of spinal gangliogliomas (GG) in order to determine the most appropriate neuro-oncological management. A Medline search for relevant publications up to July 2023 using the key phrase "ganglioglioma spinal" and "ganglioglioma posterior fossa" led to the retrieval of 178 studies. This corpus provided the basis for the present review. As an initial selection step, the following inclusion criteria were adopted: (i) series and case reports on spinal GG; (ii) clinical outcomes were reported specifically for GG; (iii) GG was the only pathological diagnosis for the evaluation of the tumor; (iv) papers written only in English was evaluated; and (v) papers describing each case in the series were included. The World Health Organization (WHO) 2021 grading criteria for gangliogliomas were applied. A total of 107 tumors were evaluated (63 from male patients and 44 from female patients; 1.43 male/1.0 female ratio, mean age 18.34 ± 15.84 years). The most common site was the cervical spine, accounting for 43 cases (40.18%); GTR was performed in 35 cases (32.71%) and STR in 71 cases (66.35%), while this information was not reported in 1 case (0.94%). 8 deaths were reported (7.47%) involving 2 males (25%) and 6 females (75%) aged 4-78 years (mean 34.27 ± 18.22) years. GGs located on the spine displayed the same gender ratio as these tumors in general. The most frequent symptom was pain and motor impairment, while the most prevalent location was the cervical spinal cord. GTR of the tumor posed a challenge for neurosurgeons, due to the difficulty of resecting the lesion without damaging the spinal eloquent area, explaining the lower rate of cure for this tumor type.

Germline BRCA2 pathogenic variants in pediatric ganglioglioma: Case report and review of the literature.

BACKGROUND: BRCA1 and BRCA2 are tumor suppressor genes associated with increased risk of breast and ovarian cancer in adulthood. Patients with germline pathogenic variants in these genes have also been reported to develop brain tumors, although it is unclear whether these syndromes are associated with significant increased risk of brain tumor formation. RESULTS: Here, we report a case of a child with germline BRCA2 pathogenic variant presenting with a symptomatic ganglioglioma. To our knowledge, this is the first such patient to be reported. We discuss prior cases of brain tumors in BRCA1/2 patients and evidence for a potential role for BRCA1/2 pathogenic variants in brain tumor formation. CONCLUSION: BRCA2 germline variants may increase the risk of developing some types of pediatric brain tumors, but further study is needed to determine its effect on low-grade glioma formation.

Ganglioglioma cells potentiate neuronal network synchronicity and elicit burst discharges via released factors.

Gangliogliomas (GGs) represent the most frequent glioneuronal tumor entity associated with chronic recurrent seizures; rare anaplastic GGs variants retain the glioneuronal character. So far, key mechanisms triggering chronic hyperexcitability in the peritumoral area are unresolved. Based on a recent mouse model for anaplastic GG (BRAFV600E, mTOR activation and Trp53KO) we here assessed the influence of GG-secreted factors on non-neoplastic cells in-vitro. We generated conditioned medium (CM) from primary GG cell cultures to developing primary cortical neurons cultured on multielectrode-arrays and assessed their electrical activity in comparison to neurons incubated with naïve and neuronal CMs. Our results showed that the GG CM, while not affecting the mean firing rates of networks, strongly accelerated the formation of functional networks as indicated increased synchrony of firing and burst activity. Washing out the GG CM did not reverse these effects indicating an irreversible effect on the neuronal network. Mass spectrometry analysis of GG CM detected several enriched proteins associated with neurogenesis as well as gliogenesis, including Gap43, App, Apoe, S100a8, Tnc and Sod1. Concomitantly, immunocytochemical analysis of the neuronal cultures exposed to GG CM revealed abundant astrocytes suggesting that the GG-secreted factors induce astroglial proliferation. Pharmacological inhibition of astrocyte proliferation only partially reversed the accelerated network maturation in neuronal cultures exposed to GG CM indicating that the GG CM exerts a direct effect on the neuronal component. Taken together, we demonstrate that GG-derived paracrine signaling alone is sufficient to induce accelerated neuronal network development accompanied by astrocytic proliferation. Perspectively, a deeper understanding of factors involved may serve as the basis for future therapeutic approaches.

Metameric pruritus as the sole manifestation of an intramedullary tumor in a toddler.

An 18-month-old child presented with persistent pruritus and excoriation involving the right T9 and T10 dermatomes. She did not exhibit any other dermatological or neurological anomalies. Based on magnetic resonance imaging investigation of the spine, T8 ganglioglioma was diagnosed and surgically removed resulting in resolution of the pruritus within a few days. This observation underlines the importance of neuroimaging in patients presenting with metameric pruritus without specific skin lesions, especially in young children.