The latest medical research on Neurology

The research magnet gathers the latest research from around the web, based on your specialty area. Below you will find a sample of some of the most recent articles from reputable medical journals about neurology gathered by our medical AI research bot.

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Ecotropic viral integration site 1 regulates EGFR transcription in glioblastoma cells.

Journal of Neuro-Oncology

Ecotropic viral integration site-1 (EVI1) is a transcription factor that contributes to the unfavorable prognosis of leukemia, some epithelial cancers, and glial tumors. However, the biological function of EVI1 in glioblastoma multiforme (GBM) remains unclear. Based on microarray experiments, EVI1 has been reported to regulate epidermal growth factor receptor (EGFR) transcription. Signal transduction via EGFR plays an essential role in glioblastoma. Therefore, we performed this study to clarify the importance of EVI1 in GBM by focusing on the regulatory mechanism between EVI1 and EGFR transcription.

We performed immunohistochemical staining and analyzed the EVI1-expression in glioma tissue. To determine the relationship between EVI1 and EGFR, we induced siRNA-mediated knockdown of EVI1 in GBM cell lines. To investigate the region that was essential for the EVI1 regulation of EGFR expression, we conducted promoter reporter assays. We performed WST-8 assay to investigate whether EVI1 affected on the proliferation of GBM cells or not.

It was observed that 22% of GBM tissues had over 33% of tumor cells expressing EVI1, whereas no lower-grade glioma tissue had over 33% by immunohistochemistry. In A172 and YKG1 cells, the expression levels of EGFR and EVI1 correlated. Analysis of the EGFR promoter region revealed that the EGFR promoter (from - 377 to - 266 bp) was essential for the EVI regulation of EGFR expression. We showed that EVI1 influenced the proliferation of A172 and YKG1 cells.

This is the first study reporting the regulation of EGFR transcription by EVI1 in GBM cells.

Communicating hydrocephalus after radiosurgery for vestibular schwannomas: does technique matter? A systematic review and meta-analysis.

Journal of Neuro-Oncology

Communicating hydrocephalus (cHCP) after radiosurgery (RS) for vestibular schwannomas (VS) has been reported. Many hypothetical mechanisms for this pathology have been proposed without consensus. The aim of this study is to determine if the platform used to treat the disease, Gamma Knife (GK) versus linear accelerator (LINAC)-based RS, makes a difference in outcome.

We conducted a meta-analysis of databases PubMed and Cochrane to identify all articles for the period January 2000-August 2018 with the following inclusion criteria: (1) VS treated with single fraction SRS (2) > 10 patients (3) original reports only (4) hydrocephalus reported as complication (5) human study.

A total of 7039 and 988 VS patients reported in 35 and 10 papers were treated with GK or LINAC RS, respectively. Demographic baseline characteristics not reported in aggregate did not differ between the two groups. The incidence of cHCP was 3% [95% CI 2-4] and 2% [95% CI 1-3] for GK and LINAC RS patients, respectively. Surgical CSF diversion was performed in 88% and 68% of patients evaluated for cHPC in the GK and LINAC group, respectively. Follow-up range was 30-150 and 29-92 months for GK and LINAC, respectively.

The incidence of cHCP following RS for VS is very low in both GK and LINAC treated patients, albeit not identical. The higher reported surgical intervention rate for VS patients treated with GK RS might be multi-factorial, including longer follow-up in the GK group.

White matter changes in primary central nervous system lymphoma patients treated with high-dose methotrexate with or without rituximab.

Journal of Neuro-Oncology

White matter changes (WMCs) can develop following systemic chemotherapy in patients with primary central nervous system lymphomas (PCNSLs), but the frequency and extent of these changes is not well characterized. This single center retrospective semi-quantitative study was performed to determine the rate, timing and grade of WMC on MRI in adult patients with newly-diagnosed radiotherapy-naïve PCNSL undergoing treatment with high-dose methotrexate (HD-MTX) with or without the addition of rituximab (-R).

Serial MRI scans of consecutive adult PCNSL patients treated with HD-MTX ± R were assessed for WMC comparing the pre-treatment to post-treatment scans utilizing a 0-to-8-point severity scoring system.

Forty-seven PCNSL patients treated with either HD-MTX-R (n = 34; median age 66, 50% male) or HD-MTX (n = 13; median age 53, 54% male) were included in the analysis. WMC were detected in 62% (95% CI 46-76%) overall, in 68% of the HD-MTX-R, and in 46% of the HD-MTX group. Among patients with WMC (n = 29), WMC were first detected at an average of 2.8 months from beginning of therapy in the HD-MTX-R versus at 10.7 months in the HD-MTX group. Average WMC non-zero scores when first detected following the start of treatment were 2.5 (± 1.1) in HD-MTX-R and 1.5 (± 0.6) in HD-MTX.

Development of WMC in PCNSL patients treated with MTX and MTX-R is common. WMC changes appear to be more frequent, occur earlier and are more extensive in patients treated with HD-MTX-R compared to HD-MTX. Prospective studies are required to determine whether WMC correlate with survival or neurocognitive outcomes.

Association between extent of resection on survival in adult brainstem high-grade glioma patients.

Journal of Neuro-Oncology

Brainstem high-grade gliomas (HGG) are rare lesions with aggressive behavior that pose significant treatment challenges. The operative use of brainstem safe entry zones has made such lesions surgically accessible, though the benefits of aggressive resection have been unclear. This study aimed to clarify the survival in adult patients.

We utilized the SEER database (1973-2015) to analyze the association between survival and demographic data, tumor characteristics, and treatment factors in adult patients with brainstem HGGs. Patients without surgical intervention were excluded. Overall survival (OS) was analyzed using univariable and multivariable Cox regression.

Our dataset included a total of 502 brainstem HGG patients of which only those who had undergone surgical intervention were included in the analysis, totaling 103. Mean age was 42.4 ± 14.1 years with 57.2% (n = 59) male. Median OS of the entire cohort was 11.0 months. Median OS for patients receiving biopsy, subtotal resection, and gross total resection were 8, 11, and 16 months, respectively. Age, extent of resection, and radiation therapy were selected into the multivariable model. A significant decrease in survival was seen in older patients, 50-60 years (HR = 2.77, p = 0.002) and ≥ 60 years (HR = 5.30, p < 0.001), compared to younger patients (18-30 years). Partial resection (HR = 0.32, p = 0.006) and GTR (HR = 0.24, p < 0.001) sustained survival benefits compared to patients with biopsy only. Patients receiving postoperative radiation demonstrated no survival benefit (HR = 1.57, p = 0.161) in multivariable regression.

While survival of brainstem HGG patients remains poor, for surgically accessible HGGs, STR and GTR were associated with a three and fourfold increase in overall survival when compared to biopsy only.

Prognostic significance of molecular subgroups of medulloblastoma in young children receiving irradiation-sparing regimens.

Journal of Neuro-Oncology

Irradiation-avoiding strategies have been used with relative success in the treatment of infants and young children with medulloblastoma. While advances in cancer genomics have significantly improved our understanding of the tumor biology of medulloblastoma allowing for improved prognostication and risk-stratification, the molecular subgroup-specific outcomes of infants and young children with medulloblastoma treated with irradiation-avoiding strategies remains unknown.

Molecular and clinical features of children with medulloblastoma treated with irradiation-avoiding strategies at Children's Hospital Los Angeles were analyzed. Molecular subgrouping of these patients was determined using a 31-gene TaqMan Low Density Array signature. Survival analyses were conducted based on 3 molecular subgroups (SHH, Group 3, and Group 4).

Twenty-eight patients with medulloblastoma received irradiation-sparing regimens and were included in this analysis. Patients were divided into SHH (n = 16), Group 3 (n = 3) and Group 4 subgroups (n = 9). Subgroup specific 5-year progression-free and overall survival was 81.2% (95% CI 52.5-93.5) and 93.7% (95% CI 63.2-99.1) for SHH, 0% and 0% for Group 3 and 0% and 44.4% (95% CI 13.6-71.9) for Group 4.

The majority of young children with SHH-subgroup medulloblastoma can be treated effectively with irradiation-sparing regimens. Our results support the use of chemotherapy-only strategies for upfront treatment of young children with SHH medulloblastoma, while demonstrating the urgent need for intensification/augmentation of treatment for patients with group 3/4 medulloblastoma.

Observation after surgery for low grade glioma: long-term outcome in the light of the 2016 WHO classification.

Journal of Neuro-Oncology

To provide detailed long-term data after initial observation for patients after histological confirmation of low grade (WHO II) gliomas according to molecular stratification.

A series of 110 patients with watchful waiting strategy after initial surgery for LGG and re-surgery at tumor progression were analyzed. Progression-free survival, time to malignant transformation, post-recurrence survival, and overall survival were estimated with the Kaplan-Meier method. Prognostic factors were identified by the Log Rank test and Cox multivariate proportional hazards model.

The cohort comprised 18 IDH wild type (IDHwt) and 53 IDH mutated (IDHmut) astrocytomas, and 39 IDH mutated and 1p 19q co-deleted (IDHmut/codel) patients. The median follow-up was 126 (95% CI 109-143) months. Surgery was gross total resection in 58, subtotal resection in 28, and biopsy in 24 patients. Progression-free survival rates at 5, 10 and 15 years was 38% 18% and 1%. The corresponding malignant transformation rates were 17%, 39% and 71%. The initial extent of resection influenced progression-free survival, time to malignant transformation and overall survival. Molecular subtype IDHmut/codel was the strongest prognostic factor for overall survival and for time to malignant transformation.

The strongest determinant of the patients' course after initial watchful waiting was the molecular tumor status. Extensive resection may increase time to progression and malignant transformation. Observation may be justified in selected patients.

Cerebrospinal fluid VEGF levels and angiogenic capacity as potential prognostic markers in patients with gliomas: a pilot study.

Journal of Neuro-Oncology

Gliomas are tumors of the central nervous system. Despite new classifications, they are still divided in low and high-grade gliomas, being the latter of greater malignancy. The degree of malignancy is directly related with the angiogenic activity in tumoral tissues. We measured VEGF concentrations and angiogenic capacity in cerebrospinal fluid (CSF) from patients with high and low-grade gliomas. The purpose of this study was to find a biomarker that contributes in the differential diagnosis and prognosis of gliomas.

CSF was obtained from 19 individuals: 8 with low-grade gliomas, 6 with high-grade gliomas and 5 controls. VEGF concentration in CSF was measured by ELISA and the angiogenic capacity was measured by chick chorioallantoic membrane (CAM) test.

The VEGF concentration was higher in patients with high-grade gliomas, compared to patients with low-grade gliomas and controls (2860 pg/mL ± 975 vs. 182.6 ± 37.1 and 47.4 ± 0.4, respectively). On the other hand, CSF from patients with high-grade gliomas generated a higher microvascular density (MVD) than patients with low-grade gliomas and controls (13.23 ± 0.6 vessels/9000μm2 vs. 9.3 ± 0.3 and 7.92 ± 0.2, respectively). Interestingly, there was not statistical differences in both VEGF levels and angiogenic capacity in patients with low-grade gliomas and controls.

Together VEGF levels and angiogenic capacity in CSF can be used as a biological marker of gliomas malignancy.

Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model.

Molecular Neurodegeneration

The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease (AD). ApoE is produced by both astrocytes and microglia in the brain, whereas hepatocytes produce the majority of apoE found in the periphery. Studies using APOE knock-in and transgenic mice have demonstrated a strong isoform-dependent effect of apoE on the accumulation of amyloid-β (Aβ) deposition in the brain in the form of both Aβ-containing amyloid plaques and cerebral amyloid angiopathy. However, the specific contributions of different apoE pools to AD pathogenesis remain unknown.

We have begun to address these questions by generating new lines of APOE knock-in (APOE-KI) mice (ε2/ε2, ε3/ε3, and ε4/ε4) where the exons in the coding region of APOE are flanked by loxP sites, allowing for cell type-specific manipulation of gene expression. We assessed these mice both alone and after crossing them with mice with amyloid deposition in the brain. Using biochemical and histological methods. We also investigated how removal of APOE expression from hepatocytes affected cerebral amyloid deposition.

As in other APOE knock-in mice, apoE protein was present predominantly in astrocytes in the brain under basal conditions and was also detected in reactive microglia surrounding amyloid plaques. Primary cultured astrocytes and microglia from the APOE-KI mice secreted apoE in lipoprotein particles of distinct size distribution upon native gel analysis with microglial particles being substantially smaller than the HDL-like particles secreted by astrocytes. Crossing of APP/PS1 transgenic mice to the different APOE-KI mice recapitulated the previously described isoform-specific effect (ε4 > ε3) on amyloid plaque and Aβ accumulation. Deletion of APOE in hepatocytes did not alter brain apoE levels but did lead to a marked decrease in plasma apoE levels and changes in plasma lipid profile. Despite these changes in peripheral apoE and on plasma lipids, cerebral accumulation of amyloid plaques in APP/PS1 mice was not affected.

Altogether, these new knock-in strains offer a novel and dynamic tool to study the role of APOE in AD pathogenesis in a spatially and temporally controlled manner.

Quantitative analysis of phenotypic elements augments traditional electroclinical classification of common familial epilepsies.

Epilepsia

Classification of epilepsy into types and subtypes is important for both clinical care and research into underlying disease mechanisms. A quantitative, data-driven approach may augment traditional electroclinical classification and shed new light on existing classification frameworks.

We used latent class analysis, a statistical method that assigns subjects into groups called latent classes based on phenotypic elements, to classify individuals with common familial epilepsies from the Epi4K Multiplex Families study. Phenotypic elements included seizure types, seizure symptoms, and other elements of the medical history. We compared class assignments to traditional electroclinical classifications and assessed familial aggregation of latent classes.

A total of 1120 subjects with epilepsy were assigned to five latent classes. Classes 1 and 2 contained subjects with generalized epilepsy, largely reflecting the distinction between absence epilepsies and younger onset (class 1) versus myoclonic epilepsies and older onset (class 2). Classes 3 and 4 contained subjects with focal epilepsies, and in contrast to classes 1 and 2, these did not adhere as closely to clinically defined focal epilepsy subtypes. Class 5 contained nearly all subjects with febrile seizures plus or unknown epilepsy type, as well as a few subjects with generalized epilepsy and a few with focal epilepsy. Family concordance of latent classes was similar to or greater than concordance of clinically defined epilepsy types.

Quantitative classification of epilepsy has the potential to augment traditional electroclinical classification by (1) combining some syndromes into a single class, (2) splitting some syndromes into different classes, (3) helping to classify subjects who could not be classified clinically, and (4) defining the boundaries of clinically defined classifications. This approach can guide future research, including molecular genetic studies, by identifying homogeneous sets of individuals that may share underlying disease mechanisms.

Biallelic inherited SCN8A variants, a rare cause of SCN8A-related developmental and epileptic encephalopathy.

Epilepsia

Monoallelic de novo gain-of-function variants in the voltage-gated sodium channel SCN8A are one of the recurrent causes of severe developmental and epileptic encephalopathy (DEE). In addition, a small number of de novo or inherited monoallelic loss-of-function variants have been found in patients with intellectual disability, autism spectrum disorder, or movement disorders. Inherited monoallelic variants causing either gain or loss-of-function are also associated with less severe conditions such as benign familial infantile seizures and isolated movement disorders. In all three categories, the affected individuals are heterozygous for a SCN8A variant in combination with a wild-type allele. In the present study, we describe two unusual families with severely affected individuals who inherited biallelic variants of SCN8A.

We identified two families with biallelic SCN8A variants by diagnostic gene panel sequencing. Functional analysis of the variants was performed using voltage clamp recordings from transfected ND7/23 cells.

We identified three probands from two unrelated families with DEE due to biallelic SCN8A variants. Each parent of an affected individual carried a single heterozygous SCN8A variant and exhibited mild cognitive impairment without seizures. In both families, functional analysis demonstrated segregation of one allele with complete loss-of-function, and one allele with altered biophysical properties consistent with partial loss-of-function.

These studies demonstrate that SCN8A DEE may, in rare cases, result from inheritance of two variants, both of which exhibit reduced channel activity. In these families, heterozygosity for the dominant variants results in less severe disease than biallelic inheritance of two variant alleles. The clinical consequences of variants with partial and complete loss of SCN8A function are variable and likely to be influenced by genetic background.

Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions.

Epilepsia

Cannabidiol (CBD) has been approved by the US Food and Drug Administration (FDA) to treat intractable childhood epilepsies, such as Dravet syndrome and Lennox-Gastaut syndrome. However, the intrinsic anticonvulsant activity of CBD has been questioned due to a pharmacokinetic interaction between CBD and a first-line medication, clobazam. This recognized interaction has led to speculation that the anticonvulsant efficacy of CBD may simply reflect CBD augmenting clobazam exposure. The present study aimed to address the nature of the interaction between CBD and clobazam.

We examined whether CBD inhibits human CYP3A4 and CYP2C19 mediated metabolism of clobazam and N-desmethylclobazam (N-CLB), respectively, and performed studies assessing the effects of CBD on brain and plasma pharmacokinetics of clobazam in mice. We then used the Scn1a+/- mouse model of Dravet syndrome to examine how CBD and clobazam interact. We compared anticonvulsant effects of CBD-clobazam combination therapy to monotherapy against thermally-induced seizures, spontaneous seizures and mortality in Scn1a+/- mice. In addition, we used Xenopus oocytes expressing γ-aminobutyric acid (GABA)A receptors to investigate the activity of GABAA receptors when treated with CBD and clobazam together.

CBD potently inhibited CYP3A4 mediated metabolism of clobazam and CYP2C19 mediated metabolism of N-CLB. Combination CBD-clobazam treatment resulted in greater anticonvulsant efficacy in Scn1a+/- mice, but only when an anticonvulsant dose of CBD was used. It is important to note that a sub-anticonvulsant dose of CBD did not promote greater anticonvulsant effects despite increasing plasma clobazam concentrations. In addition, we delineated a novel pharmacodynamic mechanism where CBD and clobazam together enhanced inhibitory GABAA receptor activation.

Our study highlights the involvement of both pharmacodynamic and pharmacokinetic interactions between CBD and clobazam that may contribute to its efficacy in Dravet syndrome.

Noninferiority Margins in Trials of Thrombectomy Devices for Acute Ischemic Stroke: Is the Bar Being Set Too Low?

Stroke

Background and Purpose- Novel endovascular thrombectomy (EVT) devices for acute ischemic stroke are often cleared by regulatory agencies on the bas...