Leptomeningeal enhancement on post-contrast FLAIR images for early diagnosis of Susac syndrome.

BACKGROUND: Leptomeningeal enhancement (LME) is a key feature of Susac syndrome (SuS) but is only occasionally depicted on post-contrast T1-weighted images (T1-WI). OBJECTIVE: As post-contrast fluid-attenuated inversion recovery (FLAIR) may be more sensitive, our aim was to assess LME in SuS on this sequence. METHODS: From 2010 to 2020, 20 patients with definite SuS diagnosis were retrospectively enrolled in this multicentre study. Two radiologists independently assessed the number of LME on post-contrast FLAIR and T1-WI acquisitions performed before any treatment. A chi-square test was used to compare both sequences and the interrater agreement was calculated. RESULTS: Thirty-five magnetic resonance imagings (MRIs) were performed before treatment, including 19 post-contrast FLAIR images in 17 patients and 25 post-contrast T1-WI in 19 patients. In terms of patients, LME was observed on all post-contrast FLAIR, contrary to post-contrast T1-WI (17/17 (100%) vs. 15/19 (79%), p < 0.05). In terms of sequences, LME was observed on all post-contrast FLAIR, contrary to post-contrast T1-WI (19/19 (100%) vs. 16/25 (64%), p < 0.005). LME was disseminated at both supratentorial (19/19) and infratentorial (18/19) levels on post-contrast FLAIR, contrary to post-contrast T1-WI (3/25 and 9/25, respectively). Interrater agreement was excellent for post-contrast FLAIR (κ = 0.95) but only moderate for post-contrast T1-WI (κ = 0.61). CONCLUSION: LME was always observed and easily visible on post-contrast FLAIR images prior to SuS treatment. In association with other MRI features, it is highly indicative of SuS.

Relation of sensorimotor and cognitive cerebellum functional connectivity with brain structural damage in patients with multiple sclerosis and no disability.

BACKGROUND AND PURPOSE: To investigate the relationship between the functional connectivity (FC) of the sensorimotor and cognitive cerebellum and measures of structural damage in patients with multiple sclerosis (MS) and no physical disability. METHODS: We selected 144 relapsing-remitting MS patients with an Expanded Disability Status Scale score of ≤1.5 and 98 healthy controls from the Italian Neuroimaging Network Initiative database. From multimodal 3T magnetic resonance imaging (MRI), including functional MRI at rest, we calculated lesion load, cortical thickness, and white matter, cortical gray matter, and caudate, putamen, thalamic, and cerebellar volumes. Voxel-wise FC of the sensorimotor and cognitive cerebellum was assessed with seed-based analysis, and multiple regression analysis was used to evaluate the relationship between FC and structural damage. RESULTS: Whole brain, white matter, caudate, putamen, and thalamic volumes were reduced in patients compared to controls, whereas cortical gray matter was not significantly different in patients versus controls. Both the sensorimotor and cognitive cerebellum showed a widespread pattern of increased and decreased FC that were negatively associated with structural measures, indicating that the lower the FC, the greater the tissue loss. Lastly, among multiple structural measures, cortical gray matter and white matter volumes were the best predictors of cerebellar FC alterations. CONCLUSIONS: Increased and decreased cerebellar FC with several brain areas coexist in MS patients with no disability. Our data suggest that white matter loss hampers FC, whereas, in the absence of atrophy, cortical volume represents the framework for FC to increase.

[Long-term outcomes of intradetrusor botulinum toxin A in multiple sclerosis patients]. / Efficacité au long terme de la toxine botulique dans l'hyperactivité de vessie chez les patients atteints de sclérose en plaques.

INTRODUCTION: The objective of this study was to analyze the long-term efficiency and tolerance of TB in the management of anticholinergic refractory hyperactive bladder in patients with MS. MATERIAL AND METHOD: Retrospective mono-centric cohort study of all patients with MS who had a TB injection for anticholinergic refractory hyperactivity from 2005 to 2015. The primary endpoint was clinical efficiency based on the frequency of urinary leakage and symptomatic urinary tract infections. RESULTS: One hundred and nineteen patients received the first injection. Median follow-up was 26.5 months. After an injection, there was a significant decrease in the number of leaks, with 69.7% of patients without leaks and 93.3% of patients without urinary tract infections. After 7 injections 44% of the patients were still dry and 62.07% had no symptomatic urinary tract infections. The failure rate was 24.37%, the average duration before discharge was 34.7 months. 19 (66%) patients stop treatment for loss of efficacy, 9 (31%) for disease progression and 1 (3%) for cessation of treatment without cause. Of the 774 injections performed, there were complications for 26 of them (3.35%). CONCLUSION: Botulinum toxin remains the second-line reference treatment for detrusor overactivity of neurological origin. There is, at least in the short term, a good answer in a large number of cases. This response can be maintained for many years, especially if patients use intermittent catheterization, with excellent tolerance. LEVEL OF EVIDENCE: 4.

A Nanobiosensor Based on Fluorescent DNA-Hosted Silver Nanocluster and HCR Amplification for Detection of MicroRNA Involved in Progression of Multiple Sclerosis.

MicroRNAs (miRNA) are a novel class of small noncoding RNAs with roles in RNA silencing and post transcriptional regulation of gene expression. Due to their roles, miRNA can be considered as new biomarkers for prognosis of diseases such as Multiple sclerosis (MS). Herein, we report a miRNA nanobiosensor based on nucleic acid hybridization chain reaction and highly fluorescent DNA hosted silver nanoclusters (NC). In our method, two types of hairpin oligonucleotide probes, MB1 and MB2, were employed as hybridization chain reaction (HCR) monomers, where MB1 acted as a template for in situ synthesis of fluorescent Ag NC. These monomers were stable in solution but they triggered a cascade of hybridization events once miR-145 (a biomarker of MS in blood) was added to the solution. The process yielded nicked double stranded DNA. The nanobiosensor showed great sensitivity for the detection of target microRNA and excellent limit of detection of about 0.1 nM with high specificity to differentiate sharply between complementary, mismatch, and non-complementary target miRNAs. Alongside the outstanding sensitivity and selectivity, the nanobiosensor exhibited great reproducibility, stability and a decent response in real sample analysis with blood plasma. In conclusion, this simple and highly responsive nanobiosensor can clinically be used for the early detection of MS by direct detection of the plasma miR-145 in real clinical samples, without a need for sample preparation, RNA extraction and/or amplification.

[Genetic variability in the association of multiple sclerosis and Epstein-Barr virus]. / La variabilidad genética en la asociación esclerosis múltiple y el virus Epstein-Barr.

Multiple sclerosis is a neurodegenerative and autoimmune disease of the central nervous system that mainly affects young people, especially women; its origin has been associated with infection caused by the Epstein-Barr virus. However, not all people who have suffered infection by this virus develop multiple sclerosis, so it would be important to know the role of genetic variability, especially the individual allelic variability of the human leukocyte antigen; as well as to determine the molecular mechanisms and the immunological links of the virus when it remains latent inside the B lymphocytes. Based on the above, it could be defined if the virus is a necessary condition to develop the disease or if there are other factors that need to be present, and thus be able to establish specific prevention and treatment strategies. But the most relevant thing is that the virus is a present condition to develop multiple sclerosis and is potentially preventable through the design of the respective vaccine.

La esclerosis múltiple es una enfermedad neurodegenerativa y autoinmune del sistema nervioso central que afecta, principalmente, a personas jóvenes, sobre todo a mujeres; su origen se ha asociado con la infección provocada por el virus Epstein-Barr. Sin embargo, no todas las personas que han padecido la infección por este virus desarrollan esclerosis múltiple, por lo que sería importante conocer el rol de la variabilidad genética, en especial la variabilidad alélica individual del antígeno leucocitario humano; así como determinar los mecanismos moleculares y los vínculos inmunológicos del virus cuando permanece latente al interior de los linfocitos B. Por lo antes expuesto, se podría definir si el virus es una condición necesaria para desarrollar la enfermedad o si existen otros factores que necesitan estar presentes, y de esta manera poder establecer las estrategias específicas de prevención y tratamiento. Pero lo más relevante es que el virus es una condición presente para desarrollar la esclerosis múltiple y es potencialmente prevenible mediante el diseño de la vacuna respectiva.

Gender disparities in health resource utilization in patients with relapsing-remitting multiple sclerosis: a prospective longitudinal real-world study with more than 2000 patients.

BACKGROUND: For the case of multiple sclerosis, research on gender differences from a health economics perspective has not received much attention. However, cost-of-illness analyses can provide valuable information about the diverse impact of the disease and thus help decision-makers to allocate scarce resources. The aim of this study was to describe healthcare resource use and associated societal costs from a gender perspective. In particular, we aimed to identify how resource utilization potentially differs in certain cost components between men and women. METHODS: Clinical and economic data were extracted from two prospective, multicentre, non-interventional, observational studies in Germany. Information on health resource use was obtained from all patients on a quarterly basis using a validated questionnaire.Cost analyses were conducted from the societal perspective including all direct (healthcare-related) and indirect (work-related) costs, regardless of who bears them. Gender-related differences were analysed by a multivariable generalized linear model with a negative binomial distribution and log link function due to the right-skewed distribution pattern of cost data. In addition, costs for men and women were descriptively analysed within subgroups of two-year disease activity. RESULTS: In total, 2095 patients (women-to-men ratio of 2.7:1) presented a mean age of 41.85 years and a median Expanded Disability Status Scale of 2 (interquartile range 1-3.5) (p > 0.30 for gender-related differences). Women and men did not statistically differ in total quarterly costs (€2329 ± €2570 versus €2361 ± €2612). For both, costs were higher with advancing disease severity and indirect costs were the main societal cost driver. Regarding healthcare-related resources, women incurred higher costs for ambulant consultations [incidence rate ratio (IRR) 1.16, confidence interval (CI) 1.04-1.31], complementary medicine (IRR 2.41, CI 1.14-5.06), medical consumables (IRR 2.53, CI 1.69-3.79) and informal care (IRR 2.79, CI 1.56-5.01). Among indirect costs, we found higher costs for men for presenteeism (IRR 0.62; CI 0.53-0.72) and higher costs for women for disability pension (IRR 1.62; CI 1.23-2.13). CONCLUSIONS: Multiple sclerosis poses a significant economic burden on patients, families and society. While the total economic burden did not differ between male and female patients, we found gender differences in specific cost items that are similar to those in the wider non-MS population.

Unfolded protein response in myelin disorders.

Activation of the unfolded protein response in response to endoplasmic reticulum stress preserves cell viability and function under stressful conditions. Nevertheless, persistent, unresolvable activation of the unfolded protein response can trigger apoptosis to eliminate stressed cells. Recent studies show that the unfolded protein response plays an important role in the pathogenesis of various disorders of myelin, including multiples sclerosis, Charcot-Marie-Tooth disease, Pelizaeus-Merzbacher disease, vanishing white matter disease, spinal cord injury, tuberous sclerosis complex, and hypoxia-induced perinatal white matter injury. In this review we summarize the current literature on the unfolded protein response and the evidence for its role in the pathogenesis of myelin disorders.

Feasibility of using a novel non-invasive ambulatory tibial nerve stimulation device for the home-based treatment of overactive bladder symptoms.

BACKGROUND: To evaluate safety, acceptability and pilot efficacy of transcutaneous low-frequency tibial nerve stimulation (TNS) using a novel device as home-based neuromodulation. METHODS: In this single-centre pilot study, 48 patients with overactive bladder (OAB) (24 with neurogenic and 24 with idiopathic OAB) were randomized to use a self-applicating ambulatory skin-adhering device stimulating transcutaneously the tibial nerve at 1 Hz for 30 minutes, either once daily or once weekly, for 12 weeks. Changes in OAB symptoms and QoL were measured at baseline, weeks 4, 8, and 12 using validated scoring instruments (ICIQ-OAB and ICIQ-LUTSqol), 3-day bladder diary and a Global Response Assessment (GRA) at week 12. RESULTS: Thirty-four patients completed the study (idiopathic n=15, neurogenic n=19). No significant adverse effects were noted. Patients found the device acceptable. Eighteen patients (53%) reported a moderate or marked improvement in symptoms from the GRA. Between baseline and week-12, ICIQ-OAB part A sub-scores improved from mean (SD) 9.3 (2.5) to 7.5 (3.1), and from 9.1 (1.9) to 5.9 (1.7) in the daily and the weekly arms, respectively. ICIQ-LUTSqol part A sub-scores improved from mean (SD) 51 (12.8) to 44.2 (13.1) and 44.9 (9.0) to 35.9 (8.8) in the daily and the weekly arms, respectively. Bladder diary mean 24-hour frequency episodes improved from 11.5 to 8.8 at week 12 for both arms. CONCLUSIONS: This novel ambulatory transcutaneous TNS (TTNS) device is safe and acceptable for use in patients reporting OAB symptoms as a form of home-based neuromodulation. A larger study however is required to confirm clinical efficacy.

Glucose 6 phosphatase dehydrogenase (G6PD) and neurodegenerative disorders: Mapping diagnostic and therapeutic opportunities.

Glucose 6 phosphate dehydrogenase (G6PD) is a key and rate limiting enzyme in the pentose phosphate pathway (PPP). The physiological significance of enzyme is providing reduced energy to specific cells like erythrocyte by maintaining co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH). There are preponderance research findings that demonstrate the enzyme (G6PD) role in the energy balance, and it is associated with blood-related diseases and disorders, primarily the anemia resulted from G6PD deficiency. The X-linked genetic deficiency of G6PD and associated non-immune hemolytic anemia have been studied widely across the globe. Recent advancement in biology, more precisely neuroscience has revealed that G6PD is centrally involved in many neurological and neurodegenerative disorders. The neuroprotective role of the enzyme (G6PD) has also been established, as well as the potential of G6PD in oxidative damage and the Reactive Oxygen Species (ROS) produced in cerebral ischemia. Though G6PD deficiency remains a global health issue, however, a paradigm shift in research focusing the potential of the enzyme in neurological and neurodegenerative disorders will surely open a new avenue in diagnostics and enzyme therapeutics. Here, in this study, more emphasis was made on exploring the role of G6PD in neurological and inflammatory disorders as well as non-immune hemolytic anemia, thus providing diagnostic and therapeutic opportunities.

Determinación de los niveles séricos de vitamina D en los pacientes diagnosticados con Esclerosis múltiple y su relación con la severidad y el comportamiento de la enfermedad en el "Hospital Metropolitano de Quito" y en el "Hospital Carlos Andrade Marín" / Determination of vitamin D serum levels in patients diagnosed with multiple sclerosis and their relationship with the severity and illness behavior in the Metropolitan Hospital in Quito and Carlos Andrade Marín Hospital

Introducción: El estudio pretende relacionar los niveles séricos de vitamina D, en pacientes con Esclerosis Múltiple (EM), con la severidad y el comportamiento de la enfermedad. Materiales y Métodos: Reclutamos 81 pacientes con EM, de los cuales se obtuvo una muestra de 50 pacientes para compararlos con 50 sujetos sanos, pareados por edad, sexo y color de la piel. La severidad de la enfermedad se evaluó con la escala de Kurtzke, número de recaídas, exposición solar, etc. Resultados: La concentración sérica de vitamina D en pacientes con EM (M=31.9 SD=12.3 ng/ml) fue similar a la de los controles (M=30.3 SD= 8.0 ng/ml; p=0.53). La prevalencia de insuficiencia de vitamina D fue del 42% (n=21) entre los casos y 46% (n=23) entre los controles, p>0.05). Se calculó la relación entre los niveles óptimos de Vitamina D (> 40, ng/ml) con un bajo grado de discapacidad, definida como un valor en la escala de Kurtzke < 3.5 [χ2(1, N=100)= 3.13 p=0.3]. El promedio de vitamina D en los pacientes con más de una recaída fue de 31.0 ng /ml y con menos de una recaída, 32.5 ng/ml fue similar (p=0.66). Discusión: No hubo diferencia significativa en las concentraciones séricas de vitamina D en pacientes con EM y sujetos sanos, pareados por género, edad y color de la piel. No hubo correlación entre el nivel de vitamina D y el grado de discapacidad medido por la escala de Kurtzke ni con el número de recaídas.

Introduction: The study seeks to relate vitamin D serum levels in Multiple Sclerosis (MS) patients with disease severity and its progression. Methods: From eighty one MS patients enrolled, fifty were selected to compare to healthy subjects, paired according to age, gender and skin color. Disease severity was assessed using the Kurtzke severity scale, relapses number, solar exposure. Results: The mean vitamin D serum concentration in MS patients (M= 31.9 SD=12.3 ng/ml) was similar to controls' (M=30.31 SD=8.0 ng/ml; p=0.53). The prevalence of vitamin D insufficiency was 42% (n=22) among cases and 46% (n=23) among controls (p=0.91). The relationship between an optimal vitamin D serum concentration (>40 ng/ml) and a low grade of disability, using a cutoff point in the Kurtzke scale < 3.5, was assessed and a non-significant correlation was found [χ2(1, N=100)= 3.13 p=0.3]. The mean vitamin D level among patients with more than one relapse (M=31.0 ng/ml) was similar to those with less than one relapse (M=32.49, p=0.66). Discusion: There was no difference of vitamin D serum levels between MS patients and the general population. A weak and not significant correlation was found with the degree of disability, measured by the Kurtzke severity scale, and also with the number of relapses.