Cold-Induced Reflex Epilepsy.

This case report describes a woman cold-induced reflex seizures.

Androgen loss weakens anti-tumor immunity and accelerates brain tumor growth.

Many cancers, including glioblastoma (GBM), have a male-biased sex difference in incidence and outcome. The underlying reasons for this sex bias are unclear but likely involve differences in tumor cell state and immune response. This effect is further amplified by sex hormones, including androgens, which have been shown to inhibit anti-tumor T cell immunity. Here, we show that androgens drive anti-tumor immunity in brain tumors, in contrast to its effect in other tumor types. Upon castration, tumor growth was accelerated with attenuated T cell function in GBM and brain tumor models, but the opposite was observed when tumors were located outside the brain. Activity of the hypothalamus-pituitary-adrenal gland (HPA) axis was increased in castrated mice, particularly in those with brain tumors. Blockade of glucocorticoid receptors reversed the accelerated tumor growth in castrated mice, indicating that the effect of castration was mediated by elevated glucocorticoid signaling. Furthermore, this mechanism was not GBM specific, but brain specific, as hyperactivation of the HPA axis was observed with intracranial implantation of non-GBM tumors in the brain. Together, our findings establish that brain tumors drive distinct endocrine-mediated mechanisms in the androgen-deprived setting and highlight the importance of organ-specific effects on anti-tumor immunity.

Visualizing Hyperhidrosis With Water-Erasable Ink.

This case report describes the use of water-erasable ink to visualize hyperhidrosis in Frey syndrome.

Ophthalmoplegia With Isolated Extraocular Muscle Hypertrophy.

A 60-year-old man is experiencing diplopia but no problems with visual acuity, pain, or other symptoms. A magnetic resonance image of the head shows abnormal thickening and T2 hyperintensity of the right lateral rectus muscle. What is your diagnosis?

Evaluating yield and utilization of ganglioside antibody testing in clinical practice.

BACKGROUND AND OBJECTIVES: Ganglioside antibodies can help diagnose distinct acute and chronic inflammatory neuropathies including axonal variants of Guillain-Barre syndrome, Miller-Fisher syndrome (MFS), multifocal motor neuropathy, and chronic sensory ataxic neuropathies. Because ganglioside antibody testing may be routinely ordered in patients with suspected inflammatory neuropathy, we sought to evaluate its yield and utilization in clinical practice. METHODS: We performed a retrospective chart review of all patients at London Health Sciences Centre who underwent ganglioside antibody testing between April 2019 and August 2023. The disease phenotype was determined for each patient, and the proportion of all tests that yielded a true-positive result was calculated. Ganglioside antibody positivity was classified as a true-positive result if the disease phenotype was robustly associated with the detected ganglioside antibody and there was no other more likely diagnosis. RESULTS: We identified 92 patients who underwent ganglioside antibody testing. One patient (1%) was classified as having a true-positive result; this patient had GQ1b-IgG positivity with MFS. Among 92 patients tested, 20 patients (22%) had a disease phenotype that was considered to be robustly associated with ganglioside antibody positivity. CONCLUSIONS: The yield of ganglioside antibody testing in clinical practice is low. We found that this testing is frequently ordered in patients with disease phenotypes that are not robustly associated with ganglioside antibody positivity, indicating that suboptimal test utilization is a primary contributor to its low yield. Restricting ganglioside antibody testing to patients with characteristic disease phenotypes would be valuable to improving yield and utilization of this testing.

Insights From the Transition to Competency-Based Medical Education in Neurology Programs.

Canadian neurology residency programs recently transitioned to Competency-Based Medical Education (CBME). Iterative evaluation is required to optimize CBME implementation. This study aimed to examine the variability and challenges in uptake of CBME in neurology residency programs and identify its benefits and pitfalls. Neurology residents and faculty participated in respective anonymous surveys. Common barriers to uptake were identified from both perspectives. Orientation to CBME was adequate, but workload was increased and contributed to burnout for faculty and residents. It is premature to draw conclusions regarding benefits of CBME. Future research considerations include standardization of entrustment scales and reduction of stakeholder burden.

Graph Machine Learning for Improved Imputation of Missing Tropospheric Ozone Data.

Gaps in the measurement series of atmospheric pollutants can impede the reliable assessment of their impacts and trends. We propose a new method for missing data imputation of the air pollutant tropospheric ozone by using the graph machine learning algorithm "correct and smooth". This algorithm uses auxiliary data that characterize the measurement location and, in addition, ozone observations at neighboring sites to improve the imputations of simple statistical and machine learning models. We apply our method to data from 278 stations of the year 2011 of the German Environment Agency (Umweltbundesamt - UBA) monitoring network. The preliminary version of these data exhibits three gap patterns: shorter gaps in the range of hours, longer gaps of up to several months in length, and gaps occurring at multiple stations at once. For short gaps of up to 5 h, linear interpolation is most accurate. Longer gaps at single stations are most effectively imputed by a random forest in connection with the correct and smooth. For longer gaps at multiple stations, the correct and smooth algorithm improved the random forest despite a lack of data in the neighborhood of the missing values. We therefore suggest a hybrid of linear interpolation and graph machine learning for the imputation of tropospheric ozone time series.

Sex-Biased T-cell Exhaustion Drives Differential Immune Responses in Glioblastoma.

Sex differences in glioblastoma (GBM) incidence and outcome are well recognized, and emerging evidence suggests that these extend to genetic/epigenetic and cellular differences, including immune responses. However, the mechanisms driving immunologic sex differences are not fully understood. Here, we demonstrate that T cells play a critical role in driving GBM sex differences. Male mice exhibited accelerated tumor growth, with decreased frequency and increased exhaustion of CD8+ T cells in the tumor. Furthermore, a higher frequency of progenitor exhausted T cells was found in males, with improved responsiveness to anti-PD-1 treatment. Moreover, increased T-cell exhaustion was observed in male GBM patients. Bone marrow chimera and adoptive transfer models indicated that T cell-mediated tumor control was predominantly regulated in a cell-intrinsic manner, partially mediated by the X chromosome inactivation escape gene Kdm6a. These findings demonstrate that sex-biased predetermined behavior of T cells is critical for inducing sex differences in GBM progression and immunotherapy response. SIGNIFICANCE: Immunotherapies in patients with GBM have been unsuccessful due to a variety of factors, including the highly immunosuppressive tumor microenvironment in GBM. This study demonstrates that sex-biased T-cell behaviors are predominantly intrinsically regulated, further suggesting sex-specific approaches can be leveraged to potentially improve the therapeutic efficacy of immunotherapy in GBM. See related commentary by Alspach, p. 1966. This article is featured in Selected Articles from This Issue, p. 1949.

Contamination of tea leaves by anthraquinone: The atmosphere as a possible source.

The detection of anthraquinone in tea leaves has raised concerns due to a potential health risk associated with this species. This led the European Union to impose a maximum residue limit (MRL) of 0.02 mg/kg for anthraquinone in dried tea leaves. As atmospheric contamination has been identified as one of the possible sources of anthraquinone residue, this study investigates the contamination resulting from the deposition of atmospheric anthraquinone using a global chemical transport model that accounts for the emission, atmospheric transport, chemical transformation, and deposition of anthraquinone on the surface. The largest contribution to the global atmospheric budget of anthraquinone is from residential combustion followed by the secondary formation from oxidation of anthracene. Simulations suggest that atmospheric anthraquinone deposition could be a substantial source of the anthraquinone found on tea leaves in several tea-producing regions, especially near highly industrialized and populated areas of southern and eastern Asia. The high level of anthraquinone deposition in these areas may result in residues in tea products exceeding the EU MRL. Additional contamination could also result from local tea production operations.

Neurologic Complications of Patients With COVID-19 Requiring Extracorporeal Membrane Oxygenation: A Systematic Review and Meta-Analysis.

In COVID-19 patients requiring extracorporeal membrane oxygenation (ECMO), our primary objective was to determine the frequency of intracranial hemorrhage (ICH). Secondary objectives were to estimate the frequency of ischemic stroke, to explore association between higher anticoagulation targets and ICH, and to estimate the association between neurologic complications and in-hospital mortality. DATA SOURCES: We searched MEDLINE, Embase, PsycINFO, Cochrane, and MedRxiv databases from inception to March 15, 2022. STUDY SELECTION: We identified studies that described acute neurological complications in adult patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection requiring ECMO. DATA EXTRACTION: Two authors independently performed study selection and data extraction. Studies with 95% or more of its patients on venovenous or venoarterial ECMO were pooled for meta-analysis, which was calculated using a random-effects model. DATA SYNTHESIS: Fifty-four studies (n = 3,347) were included in the systematic review. Venovenous ECMO was used in 97% of patients. Meta-analysis of ICH and ischemic stroke on venovenous ECMO included 18 and 11 studies, respectively. The frequency of ICH was 11% (95% CI, 8-15%), with intraparenchymal hemorrhage being the most common subtype (73%), while the frequency of ischemic strokes was 2% (95% CI, 1-3%). Higher anticoagulation targets were not associated with increased frequency of ICH (p = 0.06). In-hospital mortality was 37% (95% CI, 34-40%) and neurologic causes ranked as the third most common cause of death. The risk ratio of mortality in COVID-19 patients with neurologic complications on venovenous ECMO compared with patients without neurologic complications was 2.24 (95% CI, 1.46-3.46). There were insufficient studies for meta-analysis of COVID-19 patients on venoarterial ECMO. CONCLUSIONS: COVID-19 patients requiring venovenous ECMO have a high frequency of ICH, and the development of neurologic complications more than doubled the risk of death. Healthcare providers should be aware of these increased risks and maintain a high index of suspicion for ICH.

Pharmacokinetic and brain distribution study of an anti-glioblastoma agent in mice by HPLC-MS/MS.

Previously compound I showed great anti-glioblastoma activity without toxicity in a mouse xenograft study. In this study, a sensitive and rapid high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed and validated to investigate the pharmacokinetics and brain distribution of compound I in mice. The protein precipitation method was applied to extract the compound from mouse plasma and brain homogenates, and it was then separated using a Kinetex C18 column with a mobile phase consisting of acetonitrile-0.1% formic acid water (50:50, v/v). The analytes were detected with multiple reaction monitoring for the quantitative response of the compounds. The inter- and intra-day precisions were <8.29 and 3.85%, respectively, and the accuracy range was within ±7.33%. The method was successfully applied to evaluate the pharmacokinetics of compound I in mouse plasma and brain tissue. The peak concentration in plasma was achieved within 1 h. The apparent elimination half-life was 4.06 h. The peak concentration of compound I in brain tissue was 0.88 µg/g. The results indicated that compound I was rapidly distributed and could cross the blood-brain barrier. The pharmacokinetic profile summarized provides valuable information for the further investigation of compound I as a potential anti-glioblastoma agent.

Standardizing T1-w/T2-w ratio images in trigeminal neuralgia to estimate the degree of demyelination in vivo.

BACKGROUND: Novel magnetic resonance (MR) imaging techniques have led to the development of T1-w/T2-w ratio images or "myelin-sensitive maps (MMs)" to estimate and compare myelin content in vivo. Currently, raw image intensities in conventional MR images are unstandardized, preventing meaningful quantitative comparisons. We propose an improved workflow to standardize the MMs, which was applied to patients with classic trigeminal neuralgia (CTN) and trigeminal neuralgia secondary to multiple sclerosis (MSTN), to assess the validity and feasibility of this clinical tool. METHODS: T1-w and T2-w images were obtained for 17 CTN patients and 17 MSTN patients using a 3 T scanner. Template images were obtained from ICBM152. Multiple sclerosis (MS) plaques in the pons were labelled in MSTN patients. For each patient image, a Gaussian curve was fitted to the histogram of its intensity distribution, and transformed to match the Gaussian curve of its template image. RESULTS: After standardization, the structural contrast of the patient image and its histogram more closely resembled the ICBM152 template. Moreover, there was reduced variability in the histogram peaks of the gray and white matter between patients after standardization (p < 0.001). MM intensities were decreased within MS plaques, compared to normal-appearing white matter (NAWM) in MSTN patients (p < 0.001) and its corresponding regions in CTN patients (p < 0.001). CONCLUSIONS: Images intensities are calibrated according to a mathematic relationship between the intensities of the patient image and its template. Reduced variability among histogram peaks allows for interpretation of tissue-specific intensity and facilitates quantitative analysis. The resultant MMs facilitate comparisons of myelin content between different regions of the brain and between different patients in vivo. MM analysis revealed reduced myelin content in MS plaques compared to its corresponding regions in CTN patients and its surrounding NAWM in MSTN patients. Thus, the standardized MM serves as a non-invasive, easily-automated tool that can be feasibly applied to clinical populations for quantitative analyses of myelin content.

Trigeminal neuralgia diffusivities using Gaussian process classification and merged group tractography.

ABSTRACT: Imaging of trigeminal neuralgia (TN) has demonstrated key diffusion tensor imaging-based diffusivity alterations in the trigeminal nerve; however, imaging has primarily focused on the peripheral nerve segment because of previous limitations in reliably segmenting small fiber bundles across multiple subjects. We used Selective Automated Group Integrated Tractography to study 36 subjects with TN (right-sided pain) and 36 sex-matched controls to examine the trigeminal nerve (fifth cranial nerve [CN V]), pontine decussation (TPT), and thalamocortical fibers (S1). Gaussian process classifiers were trained by scrolling a moving window over CN V, TPT, and S1 tractography centroids. Fractional anisotropy (FA), generalized FA, radial diffusivity, axial diffusivity, and mean diffusivity metrics were evaluated for both groups, analyzing TN vs control groups and affected vs unaffected sides. Classifiers that performed at greater-than-or-equal-to 70% accuracy were included. Gaussian process classifier consistently demonstrated bilateral trigeminal changes, differentiating them from controls with an accuracy of 80%. Affected and unaffected sides could be differentiated from each other with 75% accuracy. Bilateral TPT could be distinguished from controls with at least 85% accuracy. TPT left-right classification achieved 98% accuracy. Bilateral S1 could be differentiated from controls, where the affected S1 radial diffusivity classifier achieved 87% accuracy. This is the first TN study that combines group-wise merged tractography, machine learning classification, and analysis of the complete trigeminal pathways from the peripheral fibers to S1 cortex. This analysis demonstrates that TN is characterized by bilateral abnormalities throughout the trigeminal pathway compared with controls and abnormalities between affected and unaffected sides. This full pathway tractography study of TN demonstrates bilateral changes throughout the trigeminal pathway and changes between affected and unaffected sides.

Trigeminal neuralgia associated with multiple sclerosis: A multimodal assessment of brainstem plaques and response to Gamma Knife radiosurgery.

BACKGROUND: Gamma Knife radiosurgery (GKRS) is a minimally invasive procedure for trigeminal neuralgia secondary to multiple sclerosis (MS-TN). Patients with MS-TN experience suboptimal response rates to treatment, and the relationship between trigeminal microstructure and treatment outcome is poorly understood. OBJECTIVE: To characterize imaging features of MS-TN pain and GKRS response. METHODS: 3 T diffusion-weighted imaging (DWI), T1-w, T2-w, and fluid-attenuated inversion recovery (FLAIR) sequences were acquired for 18 MS-TN patients undergoing GKRS. Brainstem plaques were standardized into a common space to determine plaque distribution. Ratio of T1-w/T2-w or "myelin maps (MM)" was generated. Multi-tensor tractography was used to delineate the radiosurgical target (RT), root entry zone (REZ), and proximal pontine segment (PPS) of the trigeminal nerves. RESULTS: Laterality of MS-TN is associated with increased axial diffusivity at the PPS, whereas decreased MM at the PPS correlated with poor GKRS response. Preoperatively, GKRS responders have higher fractional anisotropy at the RT, higher axial diffusivity at the REZ, and higher MM intensities at the PPS. CONCLUSION: This study demonstrates that diffusivities and MM intensities are important correlates of pain and treatment response, respectively. Overall, preoperative multimodal assessment of the central trigeminal pathway is a better indicator of GKRS response than postoperative assessment of the reduction in fractional anisotropy peripherally.