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BACKGROUND: Juvenile pilocytic astrocytoma (JPA) is the most common primary brain tumor of childhood and is rarely seen in adults. Neurofibromatosis type 1 (NF1), a common tumor predisposition syndrome, demonstrates a strong association with low-grade gliomas, most notably pilocytic astrocytoma, which are relatively indolent. Unlike its juvenile counterpart, reports of adult pilocytic astrocytoma (APA) vary widely in terms of disease progression from benign to much more malignant courses. Moreover, current studies discussing APA report different treatment approaches and outcomes (e.g., malignant transformation of JPA and APA with or without radiation), as little is known regarding the management of recurrent tumors and how adjuvant therapies may alter disease progression. OBSERVATIONS: The authors report the unique case of an adult male with NF1 and APA who underwent rapid malignant conversion after intensity-modulated radiation therapy. LESSONS: The authors demonstrate that caution should be taken in utilizing radiotherapy instead of resection in cases of APA and NF1, with close monitoring for posttreatment recurrence. https://thejns.org/doi/10.3171/CASE24241.
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PURPOSE: Primary treatment of spinal ependymomas involves surgical resection, however recurrence ranges between 50 and 70%. While the association of survival outcomes with lesion extent of resection (EOR) has been studied, existing analyses are limited by small samples and archaic data resulting in an inhomogeneous population. We investigated the relationship between EOR and survival outcomes, chiefly overall survival (OS) and progression-free survival (PFS), in a large contemporary cohort of spinal ependymoma patients. METHODS: Adult patients diagnosed with a spinal ependymoma from 2006 to 2021 were identified from an institutional registry. Patients undergoing primary surgical resection at our institution, ≥ 1 routine follow-up MRI, and pathologic diagnosis of ependymoma were included. Records were reviewed for demographic information, EOR, lesion characteristics, and pre-/post-operative neurologic symptoms. EOR was divided into 2 classifications: gross total resection (GTR) and subtotal resection (STR). Log-rank test was used to compare OS and PFS between patient groups. RESULTS: Sixty-nine patients satisfied inclusion criteria, with 79.7% benefitting from GTR. The population was 56.2% male with average age of 45.7 years, and median follow-up duration of 58 months. Cox multivariate model demonstrated significant improvement in PFS when a GTR was attained (p <.001). Independently ambulatory patients prior to surgery had superior PFS (p <.001) and OS (p =.05). In univariate analyses, patients with a syrinx had improved PFS (p =.03) and were more likely to benefit from GTR (p =.01). Alternatively, OS was not affected by EOR (p =.78). CONCLUSIONS: In this large, contemporary series of adult spinal ependymoma patients, we demonstrated improvements in PFS when GTR was achieved.
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Ependimoma , Procedimentos Neurocirúrgicos , Intervalo Livre de Progressão , Neoplasias da Medula Espinal , Humanos , Masculino , Ependimoma/cirurgia , Ependimoma/mortalidade , Ependimoma/patologia , Feminino , Pessoa de Meia-Idade , Adulto , Neoplasias da Medula Espinal/cirurgia , Neoplasias da Medula Espinal/mortalidade , Neoplasias da Medula Espinal/patologia , Procedimentos Neurocirúrgicos/mortalidade , Seguimentos , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem , Idoso , Prognóstico , AdolescenteRESUMO
BACKGROUND: Hypoxia is associated with poor prognosis in many cancers including glioblastoma (GBM). Glioma stem-like cells (GSCs) often reside in hypoxic regions and serve as reservoirs for disease progression. Long non-coding RNAs (lncRNAs) have been implicated in GBM. However, the lncRNAs that modulate GSC adaptations to hypoxia are poorly understood. Identification of these lncRNAs may provide new therapeutic strategies to target GSCs under hypoxia. METHODS: lncRNAs induced by hypoxia in GSCs were identified by RNA-seq. Lung cancer-associated transcript-1 (LUCAT1) expression was assessed by qPCR, RNA-seq, Northern blot, single molecule FISH in GSCs, and interrogated in IvyGAP, The Cancer Genome Atlas, and CGGA databases. LUCAT1 was depleted by shRNA, CRISPR/Cas9, and CRISPR/Cas13d. RNA-seq, Western blot, immunohistochemistry, co-IP, ChIP, ChIP-seq, RNA immunoprecipitation, and proximity ligation assay were performed to investigate mechanisms of action of LUCAT1. GSC viability, limiting dilution assay, and tumorigenic potential in orthotopic GBM xenograft models were performed to assess the functional consequences of depleting LUCAT1. RESULTS: A new isoform of Lucat1 is induced by Hypoxia inducible factor 1 alpha (HIF1α) and Nuclear factor erythroid 2-related factor 2 (NRF2) in GSCs under hypoxia. LUCAT1 is highly expressed in hypoxic regions in GBM. Mechanistically, LUCAT1 formed a complex with HIF1α and its co-activator CBP to regulate HIF1α target gene expression and GSC adaptation to hypoxia. Depletion of LUCAT1 impaired GSC self-renewal. Silencing LUCAT1 decreased tumor growth and prolonged mouse survival in GBM xenograft models. CONCLUSIONS: A HIF1α-LUCAT1 axis forms a positive feedback loop to amplify HIF1α signaling in GSCs under hypoxia. LUCAT1 promotes GSC self-renewal and GBM tumor growth. LUCAT1 is a potential therapeutic target in GBM.
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Neoplasias Encefálicas , Regulação Neoplásica da Expressão Gênica , Glioblastoma , Subunidade alfa do Fator 1 Induzível por Hipóxia , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioblastoma/genética , Animais , Camundongos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Progressão da Doença , Ensaios Antitumorais Modelo de Xenoenxerto , Proliferação de Células , Células Tumorais Cultivadas , Camundongos Nus , Linhagem Celular Tumoral , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Prognóstico , ApoptoseRESUMO
INTRODUCTION: Rasmussen's encephalitis (RE) is a rare, predominantly pediatric epilepsy disorder of unknown etiology. It classically affects one of the cerebral hemispheres and histologically shows cortical chronic inflammation, gliosis, and neuronal loss. The etiopathogenesis of RE remains unknown, with genetic, infectious, and autoimmune factors all speculated to play a role. Although the histologic findings in RE are well described, few studies have investigated a large cohort of cases looking for the coexistence of RE with focal cortical dysplasia (FCD). DESIGN: The study is a retrospective review of RE patients who underwent surgical resection of brain tissue between 1979 and 2021. Relevant patient history was retrieved, and available histologic slides were reviewed. The histologic severity of RE was described according to the Pardo criteria. In cases where FCD was present, the observed patterns of FCD (namely Ia, Ib, IIa, IIb, etc.) were described using the International League Against Epilepsy (ILAE) classification. RESULTS: Thirty-eight resection specimens from 31 patients formed the study cohort. Seventeen patients (54.8 %) were male; average age at surgery was 8 years (range: 2-28 years). Twenty-seven resection specimens (71.1 %) from 23 patients (74 %) showed evidence of coexistent FCD. Most cases with FCD resembled the ILAE type Ib (n = 23) pattern. Cases of RE that did not show FCD were either Pardo stage 1 (n = 5) or 4 (n = 6), with all Pardo stage 2 and 3 cases demonstrating FCD. CONCLUSIONS: FCD was found in most patients with RE (74 %). The most observed pattern of FCD was ILAE Ib.
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Encefalite , Epilepsia , Displasia Cortical Focal , Malformações do Desenvolvimento Cortical , Criança , Humanos , Masculino , Pré-Escolar , Adolescente , Adulto Jovem , Adulto , Feminino , Epilepsia/complicações , Epilepsia/patologia , Encefalite/complicações , Estudos Retrospectivos , Inflamação , Malformações do Desenvolvimento Cortical/complicações , Malformações do Desenvolvimento Cortical/patologia , Malformações do Desenvolvimento Cortical/cirurgia , Imageamento por Ressonância MagnéticaRESUMO
Tumor-to-tumor metastasis (TTM) is a process where one tumor metastasizes to another tumor. It is an exceedingly rare phenomenon, particularly in the central nervous system, where it most commonly occurs with meningiomas as the recipient. Herein, we present a case of tumor-to-tumor metastasis of an adenocarcinoma to a glioblastoma in a 75-year-old female. The patient had a history of high-grade ductal carcinoma in situ of the breast 8 years prior, treated with lumpectomy and radiation. She presented with a left fronto-parietal mass. Histologically, the lesion showed a glioblastoma, IDH-wildtype, WHO grade 4, associated with a metastatic adenocarcinoma (positive for estrogen receptor, progesterone receptor, and mammaglobin), suggesting a breast primary. The patient passed away 5 months after surgery. Involvement of glioblastoma by TTM is especially rare; only 1 case of TTM to glioblastoma is thus far reported in the English literature. The mechanism by which TTM occurs is poorly understood. TTM may be the first presentation of an occult malignancy and warrants thorough clinical, laboratory, and imaging investigation.
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Adenocarcinoma , Glioblastoma , Segunda Neoplasia Primária , Feminino , Humanos , Idoso , Adenocarcinoma/patologia , Adenocarcinoma/secundário , Adenocarcinoma/terapiaRESUMO
Programmatic assessment is a systematic approach used to document and assess learner performance. It offers learners frequent formative feedback from a variety of contexts and uses both high- and low-stakes assessments to determine student progress. Existing research has explored learner and faculty perceptions of programmatic assessment, reporting favorable impact on faculty understanding of the importance of assessment stakes and feedback to learners while students report the ability to establish and navigate towards goals and reflect on their performance. The Cleveland Clinic Lerner College of Medicine (CCLCM) of Case Western Reserve University adopted programmatic assessment methods at its inception. With more than 18 years' experience with programmatic assessment and a portfolio-based assessment system, CCLCM is well-positioned to explore its graduates' perceptions of their programmatic assessment experiences during and after medical school. In 2020, the investigators interviewed 26 of the 339 physician graduates. Participants were purposefully sampled to represent multiple class cohorts (2009-2019), clinical specialties, and practice locations. The investigators analyzed interview transcripts using thematic analysis informed by the frameworks of self-determination theory and professional identity formation. The authors identified themes and support each with participant quotes from the interviews. Based on findings, the investigators compiled a series of recommendations for other institutions who have already or plan to incorporate elements of programmatic assessment into their curricula. The authors concluded by discussing future directions for research and additional avenues of inquiry.
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Several microglia-expressed genes have emerged as top risk variants for Alzheimer's disease (AD). Impaired microglial phagocytosis is one of the main proposed outcomes by which these AD-risk genes may contribute to neurodegeneration, but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here we show that microglia form lipid droplets (LDs) upon exposure to amyloid-beta (Aß), and that their LD load increases with proximity to amyloid plaques in brains from human patients and the AD mouse model 5xFAD. LD formation is dependent upon age and disease progression and is more prominent in the hippocampus in mice and humans. Despite variability in LD load between microglia from male versus female animals and between cells from different brain regions, LD-laden microglia exhibited a deficit in Aß phagocytosis. Unbiased lipidomic analysis identified a substantial decrease in free fatty acids (FFAs) and a parallel increase in triacylglycerols (TAGs) as the key metabolic transition underlying LD formation. We demonstrate that DGAT2, a key enzyme for the conversion of FFAs to TAGs, promotes microglial LD formation, is increased in microglia from 5xFAD and human AD brains, and that inhibiting DGAT2 improved microglial uptake of Aß. These findings identify a new lipid-mediated mechanism underlying microglial dysfunction that could become a novel therapeutic target for AD.
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The Wnt pathway is frequently dysregulated in many cancers, underscoring it as a therapeutic target. Wnt inhibitors have uniformly failed in clinical trials. Here, we report a mechanism of WNT pathway activation through the Semaphorin 3 C neurodevelopmental program in glioma stem-like cells. Sema3C directs ß-catenin nuclear accumulation in a Rac1-dependent process, leading to transactivation of Wnt target genes. Sema3C-driven Wnt signaling occurred despite suppression of Wnt ligand secretion, suggesting that Sema3C drives canonical Wnt signaling independent of Wnt ligand binding. In a mouse model of glioblastoma, combined depletion of Sema3C and ß-catenin partner TCF1 extended animal survival more than single target inhibition alone. In human glioblastoma, Sema3C expression and Wnt pathway activation were highly concordant. Since Sema3C is frequently overexpressed in glioblastoma, Sema3C signaling may be a significant mechanism of resistance to upstream Wnt pathway inhibitors. Dual targeting of Sema3C and Wnt pathways may achieve clinically significant Wnt pathway inhibition.
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Glioblastoma , Semaforinas , Animais , Humanos , Camundongos , beta Catenina/genética , beta Catenina/metabolismo , Linhagem Celular Tumoral , Glioblastoma/genética , Glioblastoma/metabolismo , Ligantes , Semaforinas/genética , Via de Sinalização Wnt/genéticaRESUMO
Memory dysfunction is prevalent in temporal lobe epilepsy, but little is known about the underlying pathophysiological etiologies. Here, we use spatial quantitation to examine differential expression of targeted proteins and transcripts in four brain regions essential for episodic memory (dentate gyrus, CA3, CA1, neocortex) between temporal lobe epilepsy patients with and without episodic memory impairment. Brain tissues were obtained from dominant temporal lobectomies in 16 adults with pharmacoresistant temporal lobe epilepsy associated with hippocampal sclerosis. Verbal memory tests from routine pre-operative clinical care were used to classify episodic memory as impaired or intact. Digital spatial profiling of a targeted protein panel and the whole transcriptome was performed using tissue sections from the temporal neocortex and hippocampus. We performed differential expression and pathway enrichment analysis between the memory groups within each temporal lobe region. Several proteins associated with neurodegenerative disease were overexpressed in the neocortex of patients with impaired memory, corroborating our prior findings using bulk transcriptomics. Spatial transcriptomics identified numerous differentially expressed transcripts in both neocortical and hippocampal subregions between memory groups, with little overlap across subregions. The strongest molecular signal was observed in the CA3 hippocampal subregion, known to play an essential role in memory encoding. Enrichment analyses revealed BDNF as a central hub in CA3-related networks regulating phenotype-relevant processes such as cognition, memory, long-term potentiation and neuritogenesis (Padj < 0.05). Results suggest memory impairment in temporal lobe epilepsy with hippocampal sclerosis is associated with molecular alterations within temporal lobe subregions that are independent from hippocampal cell loss, demographic variables and disease characteristics. Importantly, each temporal subregion shows a unique molecular signature associated with memory impairment. While many differentially expressed transcripts and proteins in the neocortex have been associated with neurodegenerative disorders/processes, differentially expressed transcripts in hippocampal subregions involve genes associated with neuritogenesis and long-term potentiation, processes essential for new memory formation.
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ABSTRACT: Patients with HIV have a higher incidence of rhabdomyolysis compared with the HIV negative population because of medication-related myotoxicity and drug-drug interactions. Statins and antiretroviral therapy have been previously reported to cause myopathy in patients with HIV when used alone or in combination. In this study, we describe a case of biopsy-proven noninflammatory and nonautoimmune myopathy associated with the use of simvastatin and Genvoya (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate) and review 3 previously reported similar cases. Our patient presented with acute proximal limb weakness and significantly elevated serum creatine kinase. Muscle biopsy revealed scattered degenerating and regenerating muscle fibers without evidence for an inflammatory process. She did not respond to empiric treatment with high-dose intravenous steroids and intravenous immunoglobulin. Her creatine kinase only began to downtrend after discontinuation of both simvastatin and Genvoya, and she returned to baseline function at 2-month follow-up. Our case highlights the importance of recognizing drug-drug interactions between HIV and statin medications in causing significant noninflammatory myopathy. In these patients, both categories of medications need to be discontinued for recovery.
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Infecções por HIV , Doenças Musculares , Feminino , Humanos , Combinação Elvitegravir, Cobicistat, Emtricitabina e Fumarato de Tenofovir Desoproxila/uso terapêutico , Sinvastatina/efeitos adversos , Doenças Musculares/induzido quimicamente , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Creatina QuinaseRESUMO
BACKGROUND: Xanthomatous lesions of the pituitary have been linked to ruptured or hemorrhagic Rathke's cleft cysts. Most cases are reported to resolve following radical resection. When recurrence does occur, there is no established treatment regimen. High-dose glucocorticoids have been reported to be beneficial in several published cases; however, their effects are often not sustained once therapy is discontinued. OBSERVATIONS: The authors report the case of an adolescent male who developed recurrent xanthogranulomatous hypophysitis associated with a Rathke's cleft cyst despite two surgical interventions. He was treated with a short course of dexamethasone followed by a maintenance course of celecoxib and mycophenolate mofetil. This regimen proved to be safe and well-tolerated, and it successfully prevented another recurrence of his xanthogranulomatous hypophysitis. LESSONS: This case demonstrates a novel nonsurgical approach to the management of recurrent xanthogranulomatous hypophysitis. It suggests a potential application of a combined corticosteroid-sparing immunosuppressive and anti-inflammatory regimen in other cases of refractory xanthogranulomatous hypophysitis.
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PURPOSE: In addition to established prognostic factors in low-grade glioma (LGG), studies suggest a sexual dimorphism with male sex portending worse prognosis. Our objective was to identify the effect of sex on presentation and outcomes in LGG. METHODS AND MATERIALS: We conducted a retrospective cohort study of adults (aged ≥18 years) diagnosed with LGG (World Health Organization 2016 grade 2 glioma). Patients with IDH wild-type tumors were excluded. Patients were matched between male and female sex by age, treatment, and surgery via propensity score matching. Patient, tumor, and treatment characteristics were analyzed by sex. Endpoints included overall survival (OS), next intervention-free survival (NIFS), progression-free survival, and malignant transformation-free survival. Kaplan-Meier analyses and Cox proportional hazards regression multivariable analysis with backward elimination were completed. RESULTS: Of the 532 patients identified, 258 (48%) were men. Men were more likely to present with seizure (69.38% vs 56.57%, P = .002), but no other statistically significant differences between sexes at presentation were identified. Five-year OS was higher in women at 87% (95% confidence interval [CI], 83%-91%) versus 78% (95% CI, 73%-84%) in men (P = .0045). NIFS was significantly higher in female patients at 68% (95% CI, 62%-74%) versus 57% (95% CI, 51%-64%) in men (P = .009). On multivariable analysis, female sex was independently associated with improved OS (hazard ratio [HR], 1.54; 95% CI, 1.16-2.05; P = .002), NIFS (HR, 1.42; 95% CI, 1.42; P = .004), and malignant transformation-free survival (HR, 1.62; 95% CI, 1.24-2.12; P = .0004). In patients with molecularly defined LGG (IDH and 1p19q status; n = 291), female sex remained independently associated with improved OS (HR, 1.79; 95% CI, 1.16-2.77; P = .008) and NIFS (HR, 1.45; 95% CI, 1.07-1.96; P = .016). CONCLUSIONS: In this study, female sex was independently associated with improved outcomes. These findings support intrinsic sex-specific differences in LGG behavior, justifying further studies to optimize management and therapeutics based on sex.
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Neoplasias Encefálicas , Glioma , Adolescente , Adulto , Neoplasias Encefálicas/patologia , Feminino , Glioma/patologia , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Caracteres SexuaisRESUMO
OBJECTIVE: The objectives of this study were to determine the relationship between the severity of pathology and seizure outcomes in patients who underwent hemispherectomy for Rasmussen encephalitis (RE) and to investigate which clinical factors correlated with severity of pathology. METHODS: In this retrospective cohort study, we collected and reviewed pathology and clinical variables. We ascertained seizure outcomes using Engel's classification, and Pardo stages were used to grade pathology. RESULTS: We included 29 unique patients who underwent 34 hemispherectomy procedures for analysis. There was no statistically significant correlation between Pardo stage and seizure outcome (P = 1). Increasing duration of epilepsy (ß = 0.011, P = 0.02) and duration of hemiparesis (ß = 0.024, P = 0.01) were significantly associated with a more severe Pardo stage. In contrast, the presence of epilepsia partialis continua had a negative relationship with Pardo stage (ß = -0.49, P = 0.04). Twenty-six (89.75%) patients were Engel class I at the last follow-up, including all 5 patients who underwent redo hemispherectomy in our cohort. CONCLUSIONS: Consistent with the progressive nature of RE, more severe pathology was associated with a longer duration of epilepsy and longer duration of hemiparesis, while the presence of epilepsia partialis continua was associated with less severe pathology. Results from this series suggest the degree of cortical involvement with RE as assessed on surgical histopathology does not correlate with seizure outcome after hemispherectomy, which appears to be more dependent on surgical technique/complete disconnection.
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Encefalite , Epilepsia Parcial Contínua , Epilepsia , Hemisferectomia , Eletroencefalografia , Encefalite/complicações , Encefalite/patologia , Encefalite/cirurgia , Epilepsia/cirurgia , Hemisferectomia/métodos , Humanos , Inflamação , Paresia/cirurgia , Estudos Retrospectivos , Convulsões/complicações , Convulsões/cirurgia , Resultado do TratamentoRESUMO
Strokes are common among patients with left ventricular devices (LVAD). We hypothesize that there is ongoing cerebral microvascular injury with LVAD support and aim to describe this among LVAD-implanted patients through post-mortem neuropathologic evaluation. We identified and reviewed medical records of LVAD patients who underwent brain autopsy between January 2006 and December 2019 at a tertiary center. Cerebral injury was defined as both gross and microscopic injuries within the intracranial space including cerebral infarct (CI), hypoxic-ischemic brain injury (HIBI), intracranial hemorrhage (ICH), and cerebral microvascular injury. Cerebral microvascular injury was defined as microscopic brain intraparenchymal or perivascular hemorrhage, perivascular hemosiderin deposition, and perivascular inflammation. Twenty-one patients (median age = 57 years, 67% male) had autopsy after LVAD support (median LVAD support = 51 days). The median time from death to autopsy was 19 h. All 21 patients had cerebral injuries and 19 (90%) patients had cerebral microvascular injuries. Fourteen patients (78%) harbored more than one type of cerebral injury. On gross examination, 8 patients (38%) had CI, and 6 patients (29%) had ICH. On microscopic exam, 12 patients (57%) had microscopic intraparenchymal hemorrhage, 3 patients (14%) had perivascular hemorrhage, 11 patients (43%) had perivascular hemosiderin deposition, 5 patients (24%) had meningeal hemorrhage, 13 patients had chronic perivascular inflammation (62%), and 2 patients had diffuse HIBI (10%). Among patients with LVAD, there is a high prevalence of subclinical microvascular injuries and cerebral microbleeds (CMBs), which may provide some insights to the cause of frequent cerebral injury in LVAD population.
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Lesões Encefálicas , Coração Auxiliar , Lesões Encefálicas/etiologia , Feminino , Coração Auxiliar/efeitos adversos , Hemossiderina , Humanos , Inflamação/complicações , Hemorragias Intracranianas/etiologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
We present a patient with positive medium titer MOG-IgG and progressive neurological decline whose clinical and radiological phenotype were not consistent with a MOG-IgG associated disorder and ultimately received a diagnosis of glioblastoma after brain biopsy and died 4 weeks later. This represents an important topic with a high frequency of MOG-IgG testing in clinical practice. Due to this there are increasing reports of MOG-IgG positivity in atypical clinical phenotypes, raising the possibility of false positives, which can have important implications. It is important to highlight that judicious clinical evaluation is needed when interpreting MOG-IgG results in atypical settings.
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Anticorpos Antineoplásicos/sangue , Autoanticorpos/sangue , Autoantígenos/imunologia , Neoplasias Encefálicas/imunologia , Erros de Diagnóstico , Glioblastoma/imunologia , Imunoglobulina G/sangue , Glicoproteína Mielina-Oligodendrócito/imunologia , Adulto , Autoanticorpos/imunologia , Biópsia , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/diagnóstico por imagem , Diagnóstico Tardio , Paralisia Facial/etiologia , Reações Falso-Positivas , Feminino , Transtornos Neurológicos da Marcha/etiologia , Glioblastoma/sangue , Glioblastoma/diagnóstico por imagem , Humanos , Imunoglobulina G/imunologia , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Neuroimagem , Paresia/etiologia , Tomografia por Emissão de Pósitrons , Vertigem/etiologia , Transtornos da Visão/etiologiaRESUMO
OBJECTIVE: Focal cortical dysplasia (FCD) is a major cause of difficult-to-treat epilepsy in children and young adults, and the diagnosis is currently based on microscopic review of surgical brain tissue using the International League Against Epilepsy classification scheme of 2011. We developed an iterative histopathological agreement trial with genetic testing to identify areas of diagnostic challenges in this widely used classification scheme. METHODS: Four web-based digital pathology trials were completed by 20 neuropathologists from 15 countries using a consecutive series of 196 surgical tissue blocks obtained from 22 epilepsy patients at a single center. Five independent genetic laboratories performed screening or validation sequencing of FCD-relevant genes in paired brain and blood samples from the same 22 epilepsy patients. RESULTS: Histopathology agreement based solely on hematoxylin and eosin stainings was low in Round 1, and gradually increased by adding a panel of immunostainings in Round 2 and the Delphi consensus method in Round 3. Interobserver agreement was good in Round 4 (kappa = .65), when the results of genetic tests were disclosed, namely, MTOR, AKT3, and SLC35A2 brain somatic mutations in five cases and germline mutations in DEPDC5 and NPRL3 in two cases. SIGNIFICANCE: The diagnoses of FCD 1 and 3 subtypes remained most challenging and were often difficult to differentiate from a normal homotypic or heterotypic cortical architecture. Immunohistochemistry was helpful, however, to confirm the diagnosis of FCD or no lesion. We observed a genotype-phenotype association for brain somatic mutations in SLC35A2 in two cases with mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy. Our results suggest that the current FCD classification should recognize a panel of immunohistochemical stainings for a better histopathological workup and definition of FCD subtypes. We also propose adding the level of genetic findings to obtain a comprehensive, reliable, and integrative genotype-phenotype diagnosis in the near future.