RESUMO
Hedgehog signaling mediates embryologic development of the central nervous system and other tissues and is frequently hijacked by neoplasia to facilitate uncontrolled cellular proliferation. Meningiomas, the most common primary brain tumor, exhibit Hedgehog signaling activation in 6.5% of cases, triggered by recurrent mutations in pathway mediators such as SMO. In this study, we find 35.6% of meningiomas that lack previously known drivers acquired various types of somatic structural variations affecting chromosomes 2q35 and 7q36.3. These cases exhibit ectopic expression of Hedgehog ligands, IHH and SHH, respectively, resulting in Hedgehog signaling activation. Recurrent tandem duplications involving IHH permit de novo chromatin interactions between super-enhancers within DIRC3 and a locus containing IHH. Our work expands the landscape of meningioma molecular drivers and demonstrates enhancer hijacking of Hedgehog ligands as a route to activate this pathway in neoplasia.
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Neoplasias Meníngeas , Meningioma , Humanos , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Meningioma/genética , Ligantes , Transdução de Sinais , Neoplasias Meníngeas/genéticaRESUMO
Drug-resistant mesial-temporal lobe epilepsy is a devastating disease with seizure onset in the hippocampal formation. A fraction of hippocampi samples from epilepsy-surgical procedures reveals a peculiar histological pattern referred to as 'gliosis only' with unresolved pathogenesis and enigmatic sequelae. Here, we hypothesize that 'gliosis only' represents a particular syndrome defined by distinct clinical and molecular characteristics. We curated an in-depth multiparameter integration of systematic clinical, neuropsychological as well as neuropathological analysis from a consecutive cohort of 627 patients, who underwent hippocampectomy for drug-resistant temporal lobe epilepsy. All patients underwent either classic anterior temporal lobectomy or selective amygdalohippocampectomy. On the basis of their neuropathological exam, patients with hippocampus sclerosis and 'gliosis only' were characterized and compared within the whole cohort and within a subset of matched pairs. Integrated transcriptional analysis was performed to address molecular differences between both groups. 'Gliosis only' revealed demographics, clinical and neuropsychological outcome fundamentally different from hippocampus sclerosis. 'Gliosis only' patients had a significantly later seizure onset (16.3 versus 12.2 years, P = 0.005) and worse neuropsychological outcome after surgery compared to patients with hippocampus sclerosis. Epilepsy was less amendable by surgery in 'gliosis only' patients, resulting in a significantly worse rate of seizure freedom after surgery in this subgroup (43% versus 68%, P = 0.0001, odds ratio = 2.8, confidence interval 1.7-4.7). This finding remained significant after multivariate and matched-pairs analysis. The 'gliosis only' group demonstrated pronounced astrogliosis and lack of significant neuronal degeneration in contrast to characteristic segmental neuron loss and fibrillary astrogliosis in hippocampus sclerosis. RNA-sequencing of gliosis only patients deciphered a distinct transcriptional programme that resembles an innate inflammatory response of reactive astrocytes. Our data indicate a new temporal lobe epilepsy syndrome for which we suggest the term 'Innate inflammatory gliosis only'. 'Innate inflammatory gliosis only' is characterized by a diffuse gliosis pattern lacking restricted hippocampal focality and is poorly controllable by surgery. Thus, 'innate inflammatory gliosis only' patients need to be clearly identified by presurgical examination paradigms of pharmacoresistant temporal lobe epilepsy patients; surgical treatment of this subgroup should be considered with great precaution. 'Innate inflammatory gliosis only' requires innovative pharmacotreatment strategies.
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Epilepsia Resistente a Medicamentos , Epilepsia do Lobo Temporal , Esclerose Hipocampal , Humanos , Epilepsia do Lobo Temporal/patologia , Gliose/patologia , Esclerose/patologia , Hipocampo/patologia , Lobo Temporal/patologia , Epilepsia Resistente a Medicamentos/complicações , Resultado do TratamentoRESUMO
BACKGROUND: Resection of cerebral arteriovenous malformations (AVM) is technically demanding because of size, eloquent location or diffuse nidus. Controlled arterial hypotension (CAH) could facilitate haemostasis. We performed a study to characterize the duration and degree of CAH and to investigate its association with blood loss and outcome. METHODS: We retrospectively analysed intraoperative arterial blood pressure of 56 patients that underwent AVM-resection performed by the same neurosurgeon between 2003 and 2012. Degree of CAH, AVM size, grading and neurological outcome were studied. Patients were divided into two groups, depending on whether CAH was performed (hypotension group) or not (control group). RESULTS: The hypotension group consisted of 28 patients, which presented with riskier to treat AVMs and a higher Spetzler-Martin grading. CAH was achieved by application of urapidil, increasing anaesthetic depth or a combination thereof. Systolic and mean arterial blood pressure were lowered to 82 ± 7 and 57 ± 7 mmHg, respectively, for a median duration of 58 min [25% percentile: 26 min.; 75% percentile: 107 min]. In the hypotension group, duration of surgery (4.4 ± 1.3 h) was significantly (p < 0.001) longer, and median blood loss (500 ml) was significantly (p = 0.002) higher than in the control group (3.3 ± 0.9 h and 200 ml, respectively). No case fatalities occurred. CAH was associated with a higher amount of postoperative neurological deficits. CONCLUSIONS: Whether CAH caused neurological deficits or prevented worse outcomes could be clarified by a prospective randomised study, which is regarded as ethically problematic in the context of bleeding. CAH should only be used after strict indication and should be applied as mild and short as possible.
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Hipotensão , Malformações Arteriovenosas Intracranianas , Seguimentos , Humanos , Hipotensão/etiologia , Malformações Arteriovenosas Intracranianas/complicações , Malformações Arteriovenosas Intracranianas/cirurgia , Estudos Prospectivos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: Using multimodal imaging, we tested the hypothesis that patients after hemispherotomy recruit non-primary motor areas and non-pyramidal descending motor fibers to restore motor function of the impaired limb. METHODS: Functional and structural MRI data were acquired in a group of 25 patients who had undergone hemispherotomy and in a matched group of healthy controls. Patients' motor impairment was measured using the Fugl-Meyer Motor Assessment. Cortical areas governing upper extremity motor-control were identified by task-based functional MRI. The resulting areas were used as nodes for functional and structural connectivity analyses. RESULTS: In hemispherotomy patients, movement of the impaired upper extremity was associated to widespread activation of non-primary premotor areas, whereas movement of the unimpaired one and of the control group related to activations prevalently located in the primary motor cortex (all p ≤ 0.05, FWE-corrected). Non-pyramidal tracts originating in premotor/supplementary motor areas and descending through the pontine tegmentum showed relatively higher structural connectivity in patients (p < 0.001, FWE-corrected). Significant correlations between structural connectivity and motor impairment were found for non-pyramidal (p = 0.023, FWE-corrected), but not for pyramidal connections. INTERPRETATION: A premotor/supplementary motor network and non-pyramidal fibers seem to mediate motor function in patients after hemispherotomy. In case of hemispheric lesion, the homologous regions in the contralesional hemisphere may not compensate the resulting motor deficit, but the functionally redundant premotor network.
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Conectoma , Epilepsia Resistente a Medicamentos/cirurgia , Hemisferectomia , Córtex Motor/fisiopatologia , Rede Nervosa/fisiopatologia , Extremidade Superior/fisiopatologia , Adolescente , Adulto , Criança , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Motor/diagnóstico por imagem , Rede Nervosa/diagnóstico por imagem , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Adulto JovemRESUMO
Selective amygdalohippocampectomy is an effective treatment for patients with therapy-refractory temporal lobe epilepsy but may cause visual field defect (VFD). Here, we aimed to describe tissue-specific pre- and postoperative imaging correlates of the VFD severity using whole-brain analyses from voxel- to network-level. Twenty-eight patients with temporal lobe epilepsy underwent pre- and postoperative MRI (T1-MPRAGE and Diffusion Tensor Imaging) as well as kinetic perimetry according to Goldmann standard. We probed for whole-brain gray matter (GM) and white matter (WM) correlates of VFD using voxel-based morphometry and tract-based spatial statistics, respectively. We furthermore reconstructed individual structural connectomes and conducted local and global network analyses. Two clusters in the bihemispheric middle temporal gyri indicated a postsurgical GM volume decrease with increasing VFD severity (FWE-corrected p < 0.05). A single WM cluster showed a fractional anisotropy decrease with increasing severity of VFD in the ipsilesional optic radiation (FWE-corrected p < 0.05). Furthermore, patients with (vs. without) VFD showed a higher number of postoperative local connectivity changes. Neither in the GM, WM, nor in network metrics we found preoperative correlates of VFD severity. Still, in an explorative analysis, an artificial neural network meta-classifier could predict the occurrence of VFD based on presurgical connectomes above chance level.
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Epilepsia do Lobo Temporal , Procedimentos Neurocirúrgicos/efeitos adversos , Complicações Pós-Operatórias , Lobo Temporal , Transtornos da Visão , Adulto , Imagem de Tensor de Difusão , Epilepsia do Lobo Temporal/diagnóstico por imagem , Epilepsia do Lobo Temporal/fisiopatologia , Epilepsia do Lobo Temporal/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/fisiopatologia , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/cirurgia , Transtornos da Visão/diagnóstico por imagem , Transtornos da Visão/etiologia , Transtornos da Visão/fisiopatologia , Testes de Campo VisualRESUMO
Motor function after hemispheric lesions has been associated with the structural integrity of either the pyramidal tract (PT) or alternate motor fibers (aMF). In this study, we aimed to differentially characterize the roles of PT and aMF in motor compensation by relating diffusion-tensor-imaging-derived parameters of white matter microstructure to measures of proximal and distal motor function in patients after hemispherotomy. Twenty-five patients (13 women; mean age: 21.1 years) after hemispherotomy (at mean age: 12.4 years) underwent Diffusion Tensor Imaging and evaluation of motor function using the Fugl-Meyer Assessment and the index finger tapping test. Regression analyses revealed that fractional anisotropy of the PT explained (p = 0.050) distal motor function including finger tapping rate (p = 0.027), whereas fractional anisotropy of aMF originating in the contralesional cortex and crossing to the ipsilesional hemisphere in the pons explained proximal motor function (p = 0.001). Age at surgery was found to be the only clinical variable to explain motor function (p < 0.001). Our results are indicative of complementary roles of the PT and of aMF in motor compensation of hemispherotomy mediating distal and proximal motor compensation of the upper limb, respectively.
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Hemisferectomia , Atividade Motora/fisiologia , Córtex Motor/fisiologia , Tratos Piramidais/cirurgia , Substância Branca/cirurgia , Adolescente , Lesões Encefálicas/patologia , Lesões Encefálicas/cirurgia , Criança , Imagem de Tensor de Difusão , Feminino , Humanos , Masculino , Tratos Piramidais/patologia , Substância Branca/patologia , Adulto JovemRESUMO
OBJECTIVE: Recent large-cohort sequencing studies have investigated the genomic landscape of meningiomas, identifying somatic coding alterations in NF2, SMARCB1, SMARCE1, TRAF7, KLF4, POLR2A, BAP1, and members of the PI3K and Hedgehog signaling pathways. Initial associations between clinical features and genomic subgroups have been described, including location, grade, and histology. However, further investigation using an expanded collection of samples is needed to confirm previous findings, as well as elucidate relationships not evident in smaller discovery cohorts. METHODS: Targeted sequencing of established meningioma driver genes was performed on a multiinstitution cohort of 3016 meningiomas for classification into mutually exclusive subgroups. Relevant clinical information was collected for all available cases and correlated with genomic subgroup. Nominal variables were analyzed using Fisher's exact tests, while ordinal and continuous variables were assessed using Kruskal-Wallis and 1-way ANOVA tests, respectively. Machine-learning approaches were used to predict genomic subgroup based on noninvasive clinical features. RESULTS: Genomic subgroups were strongly associated with tumor locations, including correlation of HH tumors with midline location, and non-NF2 tumors in anterior skull base regions. NF2 meningiomas were significantly enriched in male patients, while KLF4 and POLR2A mutations were associated with female sex. Among histologies, the results confirmed previously identified relationships, and observed enrichment of microcystic features among "mutation unknown" samples. Additionally, KLF4-mutant meningiomas were associated with larger peritumoral brain edema, while SMARCB1 cases exhibited elevated Ki-67 index. Machine-learning methods revealed that observable, noninvasive patient features were largely predictive of each tumor's underlying driver mutation. CONCLUSIONS: Using a rigorous and comprehensive approach, this study expands previously described correlations between genomic drivers and clinical features, enhancing our understanding of meningioma pathogenesis, and laying further groundwork for the use of targeted therapies. Importantly, the authors found that noninvasive patient variables exhibited a moderate predictive value of underlying genomic subgroup, which could improve with additional training data. With continued development, this framework may enable selection of appropriate precision medications without the need for invasive sampling procedures.
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Little is known about the causes of meningioma. Obesity and obesity-related traits have been reported in several epidemiological observational studies to be risk factors for meningioma. We performed an analysis of genetic variants associated with obesity-related traits to assess the relationship with meningioma risk using Mendelian randomization (MR), an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. We considered 11 obesity-related traits, identified genetic instruments for these factors, and assessed their association with meningioma risk using data from a genome-wide association study comprising 1,606 meningioma patients and 9,823 controls. To evaluate the causal relationship between the obesity-related traits and meningioma risk, we consider the estimated odds ratio (OR) of meningioma for each genetic instrument. We identified positive associations between body mass index (odds ratio [ORSD] = 1.27, 95% confidence interval [CI] = 1.03-1.56, P = 0.028) and body fat percentage (ORSD = 1.28, 95% CI = 1.01-1.63, P = 0.042) with meningioma risk, albeit non-significant after correction for multiple testing. Associations for basal metabolic rate, diastolic blood pressure, fasting glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, systolic blood pressure, total cholesterol, triglycerides and waist circumference with risk of meningioma were non-significant. Our analysis provides additional support for obesity being associated with an increased risk of meningioma.
Assuntos
Análise da Randomização Mendeliana/métodos , Meningioma/etiologia , Obesidade/complicações , Tecido Adiposo , Índice de Massa Corporal , Estudos de Casos e Controles , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Obesidade/genética , Razão de Chances , Fatores de RiscoRESUMO
BACKGROUND: Epilepsy surgery is well established as safe and successful for children with temporal lobe epilepsy (TLE). Despite evidence from available data, there remains some reluctance to refer children with medically refractory epilepsy for preoperative evaluation and workup for possible surgery. OBJECTIVE: To present the largest case series of pediatric (TLE) patients thus far, in order to better understand the predictability of preoperative evaluation on seizure outcome, and to better understand longitudinal outcomes in a large pediatric cohort. METHODS: One hundred eighty-three pediatric patients with TLE who underwent surgical treatment between 1988 and 2012 were retrospectively reviewed. Preoperative seizure history, noninvasive and invasive preoperative evaluation, surgical results, pathological results, long-term seizure outcomes, and complications were evaluated. A review of pediatric TLE in the literature was also undertaken to better understand reported complications and long-term outcomes. RESULTS: Mean follow-up was 42 mo (range 12-152 mo); 155 patients had good seizure outcomes (Engel I/II; 84.8%) and 28 patients had poor seizure outcomes (Engel III/IV; 15.2%); 145 patients were Engel I (78.8%). Only 10 patients did not have worthwhile improvement (Engel class IV; 5.4%). A review of the literature identified 2089 unique cases of pediatric TLE. Satisfactory seizure outcomes occurred in 1629 patients (79%) with unsatisfactory outcomes in 433 patients (21%). CONCLUSION: Pediatric patients benefit from surgery for medically refractory TLE with an acceptable safety profile regardless of histopathological diagnosis, seizure frequency, or seizure type. Seizure freedom appears to have extensive durability in a significant proportion of surgically treated patients.
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Epilepsia do Lobo Temporal , Procedimentos Neurocirúrgicos , Criança , Pré-Escolar , Epilepsia do Lobo Temporal/epidemiologia , Epilepsia do Lobo Temporal/cirurgia , Feminino , Alemanha , Humanos , Lactente , Masculino , Procedimentos Neurocirúrgicos/efeitos adversos , Procedimentos Neurocirúrgicos/métodos , Procedimentos Neurocirúrgicos/estatística & dados numéricos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
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.
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Astrocitoma , Neoplasias Encefálicas , Cognição/fisiologia , Epilepsia do Lobo Temporal/psicologia , Epilepsia do Lobo Temporal/cirurgia , Ganglioglioma , Adolescente , Adulto , Análise de Variância , Astrocitoma/complicações , Astrocitoma/cirurgia , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/cirurgia , Função Executiva/fisiologia , Feminino , Ganglioglioma/complicações , Ganglioglioma/cirurgia , Alemanha , Hipocampo/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Convulsões/psicologia , Convulsões/cirurgia , Lobo Temporal/cirurgia , Adulto JovemRESUMO
Background: Meningiomas are adult brain tumors originating in the meningeal coverings of the brain and spinal cord, with significant heritable basis. Genome-wide association studies (GWAS) have previously identified only a single risk locus for meningioma, at 10p12.31. Methods: To identify a susceptibility locus for meningioma, we conducted a meta-analysis of 2 GWAS, imputed using a merged reference panel from the 1000 Genomes Project and UK10K data, with validation in 2 independent sample series totaling 2138 cases and 12081 controls. Results: We identified a new susceptibility locus for meningioma at 11p15.5 (rs2686876, odds ratio = 1.44, P = 9.86 × 10-9). A number of genes localize to the region of linkage disequilibrium encompassing rs2686876, including RIC8A, which plays a central role in the development of neural crest-derived structures, such as the meninges. Conclusions: This finding advances our understanding of the genetic basis of meningioma development and provides additional support for a polygenic model of meningioma.
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Biomarcadores Tumorais/genética , Cromossomos Humanos Par 11/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Neoplasias Meníngeas/genética , Meningioma/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Neoplasias Meníngeas/patologia , Meningioma/patologia , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Adulto JovemRESUMO
This corrects the article DOI: 10.1038/ncomms14433.
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BACKGROUND: Selective amygdalohippocampectomy is an effective treatment option for mesial temporal lobe epilepsy associated with hippocampal sclerosis. METHODS: To describe and emphasize potential pitfalls during selective amygdalohippocampectomy via a modified navigated temporobasal approach, in cases, where temporal basal veins hinder the required elevation of the temporal lobe. CONCLUSIONS: Selective amygdalohippocampectomy via navigated temporobasal approach is a safe procedure that can reduce the rate of visual field deficits by avoiding damage of optic radiation. The option of a small subpial corticotomy of the inferior temporal gyrus allows sufficient elevation of the temporal lobe in cases with difficult basal venous anatomy.
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Tonsila do Cerebelo/cirurgia , Epilepsia do Lobo Temporal/cirurgia , Hipocampo/cirurgia , Procedimentos Neurocirúrgicos/métodos , Tonsila do Cerebelo/diagnóstico por imagem , Veias Cerebrais/diagnóstico por imagem , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Humanos , Complicações Pós-Operatórias/prevenção & controle , Esclerose , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/cirurgia , Resultado do Tratamento , Transtornos da Visão/prevenção & controle , Campos VisuaisRESUMO
OBJECTIVE: To compare the effects of different surgical approaches for selective amygdalohippocampectomy in patients with pharmacoresistant mesial temporal lobe epilepsy with regard to the neuropsychological outcome and to replicate an earlier study employing a matched-pair design. METHOD: 47 patients were randomised to subtemporal versus transsylvian approaches. Memory, language, attentional and executive functions were assessed before and 1 year after surgery. Multivariate analyses of variance (MANOVAs) with presurgical and postsurgical assessments as within-subject variables and approach and side of surgery as between-subject factors were calculated. Additionally, the frequencies of individual performance changes based on reliable change indices were analysed. RESULTS: Seizure freedom International League Against Epilepsy (ILAE) 1a, was achieved in 62% of all patients without group difference. MANOVAs revealed no significant effects of approach on cognition. Tested separately for each parameter, verbal recognition memory declined irrespective of approach. Post hoc tests revealed that on group level, the subtemporal approach was associated with a worse outcome for verbal learning and delayed free recall as well as for semantic fluency. Accordingly, on individual level, more patients in the subtemporal group declined in verbal learning. Left side of surgery was associated with decline in naming regardless of approach. CONCLUSION: The main analysis did not confirm the effects of approach on memory outcome seen in our previous study. Post hoc testing, however, showed greater memory losses with the subtemporal approach. Previous findings were replicated for semantic fluency. The discrepant results are discussed on the background of the different study designs.
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Tonsila do Cerebelo/cirurgia , Cognição/fisiologia , Epilepsia do Lobo Temporal/cirurgia , Hipocampo/cirurgia , Procedimentos Neurocirúrgicos/métodos , Lobo Temporal/cirurgia , Adulto , Atenção/fisiologia , Função Executiva/fisiologia , Feminino , Humanos , Masculino , Memória/fisiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Período Pós-Operatório , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Detailed neuropathological information on the structural brain lesions underlying seizures is valuable for understanding drug-resistant focal epilepsy. METHODS: We report the diagnoses made on the basis of resected brain specimens from 9523 patients who underwent epilepsy surgery for drug-resistant seizures in 36 centers from 12 European countries over 25 years. Histopathological diagnoses were determined through examination of the specimens in local hospitals (41%) or at the German Neuropathology Reference Center for Epilepsy Surgery (59%). RESULTS: The onset of seizures occurred before 18 years of age in 75.9% of patients overall, and 72.5% of the patients underwent surgery as adults. The mean duration of epilepsy before surgical resection was 20.1 years among adults and 5.3 years among children. The temporal lobe was involved in 71.9% of operations. There were 36 histopathological diagnoses in seven major disease categories. The most common categories were hippocampal sclerosis, found in 36.4% of the patients (88.7% of cases were in adults), tumors (mainly ganglioglioma) in 23.6%, and malformations of cortical development in 19.8% (focal cortical dysplasia was the most common type, 52.7% of cases of which were in children). No histopathological diagnosis could be established for 7.7% of the patients. CONCLUSIONS: In patients with drug-resistant focal epilepsy requiring surgery, hippocampal sclerosis was the most common histopathological diagnosis among adults, and focal cortical dysplasia was the most common diagnosis among children. Tumors were the second most common lesion in both groups. (Funded by the European Union and others.).
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Neoplasias Encefálicas/patologia , Encéfalo/patologia , Epilepsia/patologia , Hipocampo/patologia , Malformações do Desenvolvimento Cortical/patologia , Adulto , Fatores Etários , Idade de Início , Neoplasias Encefálicas/complicações , Criança , Bases de Dados como Assunto , Epilepsia/etiologia , Epilepsia/cirurgia , Europa (Continente) , Feminino , Humanos , Masculino , Malformações do Desenvolvimento Cortical/complicações , Lobo Temporal/patologiaRESUMO
Various types of seizures and epilepsy are associated with 20-45% of cerebral arteriovenous malformations (AVMs). The necessity to differentiate between occasional seizures, epilepsy with repetitive seizures, and the much rarer drug-resistant epilepsy (DRE) is underlined. It is clear that where there is frequent seizures or DRE, vascular surgeons should take epilepsy surgery aspects into account. The epidemiology of AVM-associated seizures, assumed pathophysiologic mechanisms, most frequent seizures types, and medical treatment are described. Depending on the severity of the epilepsy, the diagnostic workup, including electroencephalogram (EEG), video-EEG, and, rarely, invasive evaluation, is explained. An invasive presurgical workup is only necessary in rare cases of DRE. The indication to extend the resection to more than just removal of the AVM is defined and the various specific resection techniques for this rare form are outlined. In the vast majority of AVM cases removal of the AVM with some adjoining gliotic or hemosiderotic rim of cortex will be sufficient, however. In the majority of cases with preoperative epilepsy, patients will be seizure-free after surgery. Patients who never had a seizure before AVM removal may develop de novo epilepsy postoperatively (5-15%). Rates of seizure freedom after different treatments (microsurgery, radiosurgery, endovascular) vary.
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Malformações Arteriovenosas Intracranianas/complicações , Convulsões/etiologia , Convulsões/terapia , Diagnóstico Diferencial , Epilepsia/diagnóstico , Epilepsia/etiologia , Humanos , Microcirurgia , Radiocirurgia , Convulsões/diagnóstico , Resultado do TratamentoRESUMO
Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10-9, odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10-10, OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10-8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10-11, OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10-10, OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10-9, OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10-10, OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10-10, OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10-9, OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10-8, OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10-10, OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10-11, OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10-9, OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.
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Neoplasias Encefálicas/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Glioblastoma/genética , Glioma/genética , Alelos , Neoplasias Encefálicas/classificação , Regulação Neoplásica da Expressão Gênica , Genótipo , Glioblastoma/classificação , Glioma/classificação , Humanos , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genéticaRESUMO
Meningiomas are mostly benign brain tumours, with a potential for becoming atypical or malignant. On the basis of comprehensive genomic, transcriptomic and epigenomic analyses, we compared benign meningiomas to atypical ones. Here, we show that the majority of primary (de novo) atypical meningiomas display loss of NF2, which co-occurs either with genomic instability or recurrent SMARCB1 mutations. These tumours harbour increased H3K27me3 signal and a hypermethylated phenotype, mainly occupying the polycomb repressive complex 2 (PRC2) binding sites in human embryonic stem cells, thereby phenocopying a more primitive cellular state. Consistent with this observation, atypical meningiomas exhibit upregulation of EZH2, the catalytic subunit of the PRC2 complex, as well as the E2F2 and FOXM1 transcriptional networks. Importantly, these primary atypical meningiomas do not harbour TERT promoter mutations, which have been reported in atypical tumours that progressed from benign ones. Our results establish the genomic landscape of primary atypical meningiomas and potential therapeutic targets.
Assuntos
Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/fisiologia , Genoma , Genômica/métodos , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/metabolismo , Meningioma/genética , Meningioma/metabolismo , Sítios de Ligação , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Transformação Celular Neoplásica/genética , Instabilidade Cromossômica , Análise por Conglomerados , Metilação de DNA , Fator de Transcrição E2F2/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Epigenômica/métodos , Exoma/genética , Proteína Forkhead Box M1/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Genes da Neurofibromatose 2 , Técnicas de Genotipagem , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Técnicas de Sonda Molecular , Mutação , Fenótipo , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Proteína SMARCB1/genética , Análise de Sequência , Transdução de Sinais/genética , TranscriptomaRESUMO
OBJECTIVE Arteriovenous malformations (AVMs) of the brain are a frequent and important cause of intracranial hemorrhage in young adults. Little is known about the molecular-genetic pathomechanisms underlying AVM development. Genes of the NOTCH family control the normal development of vessels and proper arteriovenous specification. Transgenic mice with constitutive expression of active NOTCH4 frequently develop AVMs. Here, the authors report a genetic association study investigating possible associations between NOTCH4 gene polymorphisms and formation and clinical presentation of AVMs. METHODS After PCR amplification and direct DNA sequencing or restriction digests, 10 single-nucleotide polymorphisms (SNPs) of the NOTCH4 gene were used for genotyping 153 AVM patients and 192 healthy controls (i.e., blood donors). Pertinent clinical data were available for 129 patients. Uni- and multivariate single-marker and explorative haplotype analyses were performed to identify potential genetic risk factors for AVM development and for hemorrhagic or epileptic presentation. RESULTS Eleven calculated haplotypes consisting of 3-4 SNPs (most of which were located in the epidermal growth factor-like domain of the NOTCH4 gene) were observed significantly more often among AVM patients than among controls. Univariate analysis indicated that rs443198_TT and rs915895_AA genotypes both were significantly associated with hemorrhage and that an rs1109771_GG genotype was associated with epilepsy. The association between rs443198_TT and AVM bleeding remained significant in the multivariate regression analysis. CONCLUSIONS The authors' results suggest NOTCH4 SNPs as possible genetic risk factors for the development and clinical presentation of AVMs and a role of NOTCH4 in the pathogenesis of this disease.
Assuntos
Epilepsia/genética , Predisposição Genética para Doença/genética , Malformações Arteriovenosas Intracranianas/genética , Hemorragias Intracranianas/genética , Polimorfismo Genético/genética , Receptor Notch4/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
OBJECTIVE The objective of this study was to review the outcomes after microsurgical resection of cerebral arteriovenous malformations (AVMs) from a consecutive single-surgeon series. Clinical and imaging data were analyzed to address the following questions concerning AVM treatment in the post-ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations) era. 1) Are the patients who present with unruptured or ruptured AVMs doing better at long-term follow-up? 2) Is the differentiation between Ponce Class A (Spetzler-Martin Grade I and II) patients versus Ponce Class B and C patients (Spetzler-Martin Grade III and IV) meaningful and applicable to surgical practice? 3) How did the ARUBA-eligible patients of this surgical series compare with the results reported in ARUBA? METHODS Two hundred eighty-eight patients with cerebral AVMs underwent microsurgical resection between 1983 and 2012 performed by the same surgeon (J.S.). This is a prospective case collection study that represents a consecutive series. The results are based on prospectively collected, early-outcome data that were supplemented by retrospectively collected, follow-up data for 94% of those cases. The analyzed data included the initial presentation, Spetzler-Martin grade, obliteration rates, surgical and neurological complications, and frequency of pretreatment with embolization or radiosurgery. The total cohort was compared using "small-AVM," Spetzler-Martin Grade I and II, and ARUBA-eligible AVM subgroups. RESULTS The initial presentation was hemorrhage in 50.0% and seizures in 43.1% of patients. The series included 53 Spetzler-Martin Grade I (18.4%), 114 Spetzler-Martin Grade II (39.6%), 90 Spetzler-Martin Grade III (31.3%), 28 Spetzler-Martin Grade IV (9.7%), and 3 Spetzler-Martin Grade V (1.0%) AVMs. There were 144 unruptured and 104 ARUBA-eligible cases. Preembolization was used in 39 cases (13.5%). The occlusion rates for the total series and small AVM subgroup were 99% and 98.7%, respectively. The mean follow-up duration was 64 months. Early neurological deterioration was seen in 39.2% of patients, of which 12.2% had permanent and 5.6% had permanent significant deficits, and the mortality rate was 1.7% (n = 5). Outcome was better for patients with AVMs smaller than 3 cm (permanent deficit in 7.8% and permanent significant deficit in 3.2% of patients) and Ponce Class A status (permanent deficit in 7.8% and significant deficit in 3.2% of patients). Unruptured AVMs showed slightly higher new deficit rates (but 0 instances of mortality) among all cases, and in the small AVM and Ponce Class A subgroups. Unruptured Spetzler-Martin Grade I and II lesions had the best outcome (1.8% permanent significant deficit), and ARUBA-eligible Spetzler-Martin Grade I and II lesions had a slightly higher rate of permanent significant deficits (3.2%). CONCLUSIONS Microsurgery has a very high cure rate. Focusing microsurgical AVM resection on unruptured lesions smaller than 3 cm or on Spetzler-Martin Grade I and II lesions is a good strategy for minimizing long-term morbidity. Well-selected microsurgical cases lead to better outcomes than with multimodal interventions, as in the ARUBA treatment arm, or conservative treatment alone. Long-term prospective data collection is valuable.