In vivo 2-hydroxyglutarate-proton magnetic resonance spectroscopy (3 T, PRESS technique) in treatment-naïve suspect lower-grade gliomas: feasibility and accuracy in a clinical setting.

Isocitrate dehydrogenase 1/2 (IDH1/2) mutations are often detected in lower-grade gliomas (LGG) and result into 2-hydroxyglutarate (2HG) synthesis. Prior studies showed that 2HG can be detected in vivo using magnetic resonance spectroscopy (MRS), but its accuracy and translational impact are still under investigation. PURPOSE: To investigate the clinical feasibility of MRS for in vivo detection and quantification of 2HG on consecutive treatment-naïve suspect LGG patients and to compare MRS accuracy with tissue IDH1/2 analysis. METHODS: MRS spectra at 3 T were acquired with 1H-MRS single-voxel PRESS 2HG-tailored sequences with TE 30 (group 1) or TE 97 (groups 2A and B). Voxel sizes were 1.5 × 1.5 × 1.5 cm3 for group 1 (n = 13) and group 2A (n = 14) and 2 × 2 × 2 cm3 for group 2B (n = 32). Multiple metabolites' concentrations were analyzed with LCModel. Tumors were assessed for IDH status and main molecular markers. 2HG levels in urine/blood were measured by liquid chromatography-mass spectrometry. RESULTS: The larger voxel TE 97 sequence resulted in highest specificity (100%), sensitivity (79%), and accuracy (87%). Urine and blood 2HG did not result predictive. CONCLUSION: Our data confirm that 2 × 2 × 2-cm3 voxel TE 97 MRS shows high accuracy for 2HG detection, with good sensitivity and 100% specificity in distinguishing IDH mutant gliomas. Main limits of the technique are small tumor volume and low cellularity. Integrating 2HG-MRS with other metabolites may help non-invasive diagnosis of glioma, prognostic assessment, and treatment planning in clinical setting.

A comparative study on assessment procedures and metric properties of two scoring systems of the Coma Recovery Scale-Revised items: standard and modified scores.

OBJECTIVE: The study compared the metric characteristics (discriminant capacity and factorial structure) of two different methods for scoring the items of the Coma Recovery Scale-Revised and it analysed scale scores collected using the standard assessment procedure and a new proposed method. DESIGN: Cross sectional design/methodological study. SETTING: Inpatient, neurological unit. PARTICIPANTS: A total of 153 patients with disorders of consciousness were consecutively enrolled between 2011 and 2013. INTERVENTION: All patients were assessed with the Coma Recovery Scale-Revised using standard (rater 1) and inverted (rater 2) procedures. MAIN OUTCOME MEASURES: Coma Recovery Scale-Revised score, number of cognitive and reflex behaviours and diagnosis. RESULTS: Regarding patient assessment, rater 1 using standard and rater 2 using inverted procedures obtained the same best scores for each subscale of the Coma Recovery Scale-Revised for all patients, so no clinical (and statistical) difference was found between the two procedures. In 11 patients (7.7%), rater 2 noted that some Coma Recovery Scale-Revised codified behavioural responses were not found during assessment, although higher response categories were present. A total of 51 (36%) patients presented the same Coma Recovery Scale-Revised scores of 7 or 8 using a standard score, whereas no overlap was found using the modified score. Unidimensionality was confirmed for both score systems. CONCLUSION: The Coma Recovery Scale Modified Score showed a higher discriminant capacity than the standard score and a monofactorial structure was also supported. The inverted assessment procedure could be a useful evaluation method for the assessment of patients with disorder of consciousness diagnosis.

Validation of the Besta Neurological Institute rating scale for myasthenia gravis.

INTRODUCTION: We validated the scale for myasthenia gravis (MG) developed at the Neurological Institute Foundation of Milan (INCB-MG scale). METHODS: A total of 174 patients were evaluated with the INCB-MG and compared with the MG Composite (MGC) as the gold standard. Dimensionality, reliability, and validity of the INCB-MG scale were studied by principal component factor analysis, Cronbach alpha, and Pearson correlation coefficients; interobserver reliability was calculated by the weighted Cohen K coefficient. RESULTS: Generalized and bulbar INCB-MG subscales were unidimensional with excellent consistency; the INCB-MG and MGC scales were strongly correlated. Fatigability assessment was correlated with the INCB-MG generalized, bulbar, and respiratory subscales. CONCLUSIONS: The INCB-MG scale is a reliable tool to assess MG and is strongly correlated with the MGC. The INCB-MG scale is a valid tool for every day practice and should be further investigated for its application in clinical trials.

Multiple Sclerosis Questionnaire for Job Difficulties (MSQ-Job): definition of the cut-off score.

Multiple Sclerosis (MS) mainly affects people of working age. The Multiple Sclerosis Questionnaire for Job Difficulties (MSQ-Job) was designed to measure difficulties in work-related tasks. Our aim is to define cut-off score of MSQ-Job to identify potential critical situations that might require specific attention. A sample of patients with MS completed the MSQ-Job, WHODAS 2.0 and MSQOL-54 respectively for work difficulties, disability and health-related quality of life (HRQoL) evaluation. K-means Cluster Analysis was used to divide the sample in three groups on the basis of HRQoL and disability. ANOVA test was performed to compare the response pattern between these groups. The cut-off score was defined using the receiver operating characteristic (ROC) curve analyses for MSQ-Job total and count of MSQ-Job items scores ≥3: a score value corresponding to the maximum of the sensitivity-to-specificity ratio was chosen as the cut-off. Out of 180 patients enrolled, twenty were clustered in the higher severity group. The area under the ROC curve was 0.845 for the MSQ-Job total and 0.859 for the count of MSQ-Job items scores ≥3 while the cut-off score was 15.8 for MSQ-Job total and 8 for count of items scored ≥3. We recommend the use of MSQ-Job with this calculation as cut-off for identifying critical situations, e.g. in vocational rehabilitation services, where work-related difficulties have a significant impact in terms of lower quality of life and higher disability.

In vivo quantitative magnetization transfer imaging correlates with histology during de- and remyelination in cuprizone-treated mice.

The pool size ratio measured by quantitative magnetization transfer MRI is hypothesized to closely reflect myelin density, but their relationship has so far been confirmed mostly in ex vivo conditions. We investigate the correspondence between this parameter measured in vivo at 7.0 T, with Black Gold II staining for myelin fibres, and with myelin basic protein and beta-tubulin immunofluorescence in a hybrid longitudinal study of C57BL/6 and SJL/J mice treated with cuprizone, a neurotoxicant causing relatively selective myelin loss followed by spontaneous remyelination upon treatment suspension. Our results confirm that pool size ratio measurements correlate with myelin content, with the correlation coefficient depending on strain and staining method, and demonstrate the in vivo applicability of this MRI technique to experimental mouse models of multiple sclerosis.

Older age, higher perceived disability and depressive symptoms predict the amount and severity of work-related difficulties in persons with multiple sclerosis.

Purpose: This cross-sectional study aims to identify the predictors of work-related difficulties in a sample of employed persons with multiple sclerosis as addressed with the Multiple Sclerosis Questionnaire for Job Difficulties. Materials and methods: Hierarchical linear regression analysis was conducted to identify predictors of work difficulties: predictors included demographic variables (age, formal education), disease duration and severity, perceived disability and psychological variables (cognitive dysfunction, depression and anxiety). The targets were the questionnaire's overall score and its six subscales. Results: A total of 177 participants (108 females, aged 21-63) were recruited. Age, perceived disability and depression were direct and significant predictors of the questionnaire total score, and the final model explained 43.7% of its variation. The models built on the questionnaire's subscales show that perceived disability and depression were direct and significant predictors of most of its subscales. Conclusions: Our results show that, among patients with multiple sclerosis, those who were older, with higher perceived disability and higher depression symptoms have more and more severe work-related difficulties. The Multiple Sclerosis Questionnaire for Job Difficulties can be fruitfully exploited to plan tailored actions to limit the likelihood of near-future job loss in persons of working age with multiple sclerosis. Implications for rehabilitation Difficulties with work are common among people with multiple sclerosis and are usually addressed in terms of unemployment or job loss. The Multiple Sclerosis Questionnaire for Job Difficulties is a disease-specific questionnaire developed to address the amount and severity of work-related difficulties. We found that work-related difficulties were associated to older age, higher perceived disability and depressive symptoms. Mental health issues and perceived disability should be consistently included in future research targeting work-related difficulties.

Amifampridine phosphate in the treatment of muscle-specific kinase myasthenia gravis: a phase IIb, randomized, double-blind, placebo-controlled, double crossover study.

OBJECTIVE: The aim of this study is to determine the safety and the efficacy of amifampridine phosphate in muscle-specific kinase antibody-positive myasthenia gravis, in a 1:1 randomized, double-blind, placebo-controlled, switchback, double crossover study. METHODS: Eligible patients had muscle-specific kinase myasthenia gravis, >18 years of age, and Myasthenia Gravis Foundation of America class II-IV with a score of ⩾9 on Myasthenia Gravis Composite scale. After the run-in phase, during which amifampridine phosphate was titrated to a tolerable and effective dosage, patients were randomized to receive placebo-amifampridine-placebo sequence or amifampridine-placebo-amifampridine sequence daily for 7 days. Then, patients switched treatment arms twice, for a total of 21 days of double-blind treatment. Safety was determined by serial assessments of adverse events/serious adverse events, physical examinations, and clinical and laboratory tests. The co-primary outcome measures included changes from baseline of Quantitative Myasthenia Gravis score and Myasthenia Gravis-specific Activities of Daily Living Profile score. The secondary outcome measures comprised changes from baseline of Myasthenia Gravis Composite score, Myasthenia Gravis Quality of Life scale-15 questions, Fatigue Severity Scale, and Carlo Besta Neurological Institute-Myasthenia Gravis scale. Statistical analyses were assessed using a switchback model for three-period, two-treatment crossover design. RESULTS: A total of 10 patients were screened, enrolled, and treated. Transient paresthesias (60%) were the only amifampridine phosphate-related adverse events reported. Four patients were randomized to receive placebo-amifampridine-placebo sequence and three patients to receive amifampridine-placebo-amifampridine sequence. The co-primary objectives were statistically met (Quantitative Myasthenia Gravis score: p = 0.0003 and Myasthenia Gravis-specific Activities of Daily Living Profile score: p = 0.0006), as well as all the secondary endpoints (Myasthenia Gravis Composite score: p < 0.0001, Myasthenia Gravis Quality of Life scale-15 questions: p = 0.0025, Fatigue Severity Scale: p = 0.0061, and Carlo Besta Neurological Institute-Myasthenia Gravis scale: p = 0.0014). CONCLUSION: Despite the low number of patients, MuSK-001 study provided evidence that amifampridine phosphate, in the range of 30-60 mg daily dose, was safe and effective in treating muscle-specific kinase myasthenia gravis, suggesting the need for a large multi-center trial to confirm these results.

A propensity score analysis for comparison of T-3b and VATET in myasthenia gravis.

OBJECTIVE: We performed propensity score (PS) models to compare the outcome of patients with myasthenia gravis (MG) submitted to 2 different surgical approaches: extended transsternal (T-3b) or thoracoscopic extended thymectomy (VATET). METHODS: Patients' clinical data were retrieved from the MG database of the C. Besta Neurologic Institute Foundation. In the PS analysis, a matching ratio of 1:1 of the main clinical variables was obtained for the 2 groups of patients and treatment effect was estimated by comparing their outcome. RESULTS: A total of 210 patients met the inclusion criteria, by having a complete set of clinical data, and were included in the PS model; a matched dataset of 122 participants (61 per group) showed an adequate balance of all the covariates. Our analysis demonstrated that 68.9% of patients who had thymectomy by the VATET technique reached the pharmacologic remission/remission status at 2 years from thymectomy compared to 34.4% of those operated on by the T-3b technique (p < 0.001), had a lower INCB-MG score (p < 0.001), and had less muscle fatigability (p = 0.004). Similar results were found considering only nonthymomatous patients with MG. Results were also confirmed by paired statistical tests. CONCLUSIONS: Our PS matching analysis showed that VATET is a reliable and effective surgical approach alternative to T-3b in patients with MG who are candidates for thymectomy. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with MG, VATET is more effective than T-3b thymectomy.

Radiosurgery for intracranial meningiomas: A systematic review and meta-analysis.

BACKGROUND: Radiosurgery(RS), both in single and multiple sessions, have been performed for intracranial meningiomas. Different aspects are still controversial on this field. The aim of this systematic review is to summarize the current literature on long-term efficacy and safety of RS for meningiomas. METHODS: Online databases were searched for studies published until April 2015. The primary outcomes were disease control and progression-free-survival(PFS). The secondary outcomes were symptom control and radiation-induced toxicity. RESULTS: The estimate of disease control rate ranged from 87.0% to 100.0% at 5 years and from 67.0% to 100.0% at 10 years. The PFS rate ranged 78.0%-98.9% and 53.1%-97.2% at 5 and 10 years, respectively. The overall symptom control was 92.3%, the overall toxicity was 8.1%. CONCLUSIONS: RS can be considered a safe and effective treatment. Efforts are needed in standardizing the definition of local and symptom control and toxicity in order to properly compare different treatment schedules.

Stance instability in preclinical SCA1 mutation carriers: A 4-year prospective posturography study.

OBJECTIVE: We aimed to study postural balance in preclinical Spinocerebellar ataxia type 1 (SCA1) mutation carriers to identify and observe specific motor functional deficit before evident clinical manifestation. METHODS: Participants were 9 asymptomatic SCA1 mutation carriers (6M/3F), aged 31.8±7years (range 22-44), and 17 age-matched non-carrier controls (5M/12F) (age 18-42). Subjects underwent postural tests on a force platform (Tetrax®-IBS, Sunlight Medical Ltd.) with and without visual feedback. Amount of body sway was represented by stability index (ST). Tests were repeated after 2- and 4-years. Estimated years to onset were calculated. RESULTS: In controls, ST was unchanged from baseline to 4-year evaluations in all standing conditions. SCA1 mutation carriers performed similarly to controls in the postural tasks with open eyes, whereas in conditions without visual feedback SCA1 carriers had significantly higher ST than controls at all longitudinal evaluations. Close-to-disease onset carriers (≤7years) showed more prominent time-dependent stance abnormalities (p<0.0001 for all comparisons). CONCLUSIONS: Traceable and progressive postural abnormalities can be observed in preclinical close-to-onset SCA1 carriers. Quantitative analysis of stance could represent a promising outcome measure in clinical trials including preclinical subjects.

Transcriptional role of androgen receptor in the expression of long non-coding RNA Sox2OT in neurogenesis.

The complex architecture of adult brain derives from tightly regulated migration and differentiation of precursor cells generated during embryonic neurogenesis. Changes at transcriptional level of genes that regulate migration and differentiation may lead to neurodevelopmental disorders. Androgen receptor (AR) is a transcription factor that is already expressed during early embryonic days. However, AR role in the regulation of gene expression at early embryonic stage is yet to be determinate. Long non-coding RNA (lncRNA) Sox2 overlapping transcript (Sox2OT) plays a crucial role in gene expression control during development but its transcriptional regulation is still to be clearly defined. Here, using Bicalutamide in order to pharmacologically inactivated AR, we investigated whether AR participates in the regulation of the transcription of the lncRNASox2OTat early embryonic stage. We identified a new DNA binding region upstream of Sox2 locus containing three androgen response elements (ARE), and found that AR binds such a sequence in embryonic neural stem cells and in mouse embryonic brain. Our data suggest that through this binding, AR can promote the RNA polymerase II dependent transcription of Sox2OT. Our findings also suggest that AR participates in embryonic neurogenesis through transcriptional control of the long non-coding RNA Sox2OT.

Validation of the MG-DIS: a disability assessment for myasthenia gravis.

This paper is aimed to present the validation of the myasthenia gravis disability assessment (MG-DIS), a MG-specific patient-reported disability outcome measure. Consecutive MG patients were enrolled, followed-up for 12 months and administered the SF-36, the WHO disability assessment schedule (WHODAS 2.0) and the preliminary 31-item MG-DIS addressing impairments and activity limitations. Factor structure and metric properties were assessed. In total, 109 patients were enrolled: 76 were females, mean age 50, mean MG duration 10.4 years, 86 were AChR-positive. The MG-DIS was reduced to 20 items, explaining 70.6 % of the original questionnaire variance, four subscales (generalized impairment-related problems; bulbar function-related problems; mental health and fatigue-related problems; vision-related problems) and an overall disability index. The MG-DIS has good metric properties (Cronbach's alpha ranging between .808 and .930), is stable, showed to be more sensitive than the WHODAS 2.0 and SF-36 to detect group differences and longitudinal changes and was well correlated with the MG-composite (.642). The MG-DIS includes items representing ocular, generalized, bulbar and respiratory symptoms, and is therefore well-built around MG-specific features. MG-DIS can be used in clinical trials as well as in observational or epidemiological studies to characterize patients' disability level and address the amount of improvement in disability. Further studies are needed to explore the possibility of a shorter disability scale.

Psychosocial difficulties of individuals with multiple sclerosis: the PARADISE-24 questionnaire.

The aim of this study is to identify the most relevant psychosocial difficulties (PSDs) experienced by persons with multiple sclerosis (PwMS); to evaluate the relation between an overall level of PSDs measured with the PARADISE-24 and other variables; to assess which factors may predict PARADISE-24 overall score. Adults PwMS were consecutively enrolled and completed a battery of eight self-reported instruments (i.e. SCQ, EUROHIS-QOL 8, BRS, BFI-10, JSPE, OSS-3, WHODAS-12, PARADISE-24). A clinical evaluation was performed for each patient and the Expanded Disability Status Scale (EDSS) score was determined by neurologists. A total of 80 PwMS, mean age 41.0, 65% women, 62% married, and 76.3% working, 86.3% relapsing-remitting MS, with an EDSS median score of 1.5, took part in the study. The mean disease duration was 7.7 years. The most frequently reported PSDs involved motor and emotional functioning. Free of charge access to medicines; health treatments and family, friends and health professionals' assistance represented the most important facilitators. WHODAS-12 and EUROHIS-QOL 8 were excluded from regression because of their strong correlation with PARADISE-24. EDSS, BRS, OSS-3, and neuroticism were the main predictors of the PARADISE-24 score. Despite MS heterogeneity, a common pattern of PSDs can be observed among PwMS. The level of physical impairment and personal resilience were the main predictors of the overall level of PSDs in PwMS, with a lower but significant additional role played by social support and personality traits. Attention to PSDs and their predictors, using PARADISE-24, can help clinicians to plan tailored and personalized rehabilitation programs.

Is Period3 Genotype Associated With Sleep and Recovery in Patients With Disorders of Consciousness?

Background Sleep evaluation is increasingly being used as prognostic tool in patients with disorders of consciousness, but, surprisingly, the role of Period3 (Per3) gene polymorphism has never been evaluated. Objective The aim of this study was to investigate the contribution of Per3 genotype on sleep quantity and consciousness recovery level in patients with disorders of consciousness (DOC). Methods In this observational study, we evaluated 71 patients with DOC classified as vegetative state/unresponsive wakefulness syndrome or minimally conscious state. Demographic and clinical data were collected and a standardised diagnostic workup, including a polysomnographic record, was applied. After informed consent provided by proxy, genomic DNA was obtained and Per3 polymorphism was analysed by polymerase chain reaction to identify 5/5, 4/5, or 4/4 genotype. Results Per3(5/5) genotype was found in 12.7% of our DOC patients. The median total Coma Recovery Scale-revised score in Per3(5/5) carriers was significantly higher than 4/4 genotype (10, range 5-16 vs 7, range 4-11; post hoc P = .036). Moreover, total sleep time seemed to be higher in 5/5 genotype (5/5, 221 minutes, range 88-515 minutes; 4/4, 151.5 minutes, range 36-477 minutes; and 4/5, 188 minutes, range 44-422 minutes). Conclusion For the first time we have shown a possible association between Per3 polymorphism and consciousness recovery level in DOC patients. Even though the exact molecular mechanism has not been defined, we speculate that its effect is mediated by higher total sleep time and slow wave sleep, which would improve the preservation of main cerebral connections.

Cognitive function alone is a poor predictor of health-related quality of life in employed patients with MS: results from a cross-sectional study.

OBJECTIVE: Depression, anxiety, disease severity, and cognitive functions impact on the quality of life of people with MS. However, the majority of studies were not based on multivariate models and did not target employed patients. The aim of this study was to investigate predictors of HRQoL in persons with MS in the workforce considering cognitive, psychological, disease severity, and disability-related variables. METHODS: Cross-sectional study. Hierarchical block regression analyses were conducted to identify predictors of physical and mental components of HRQoL, measured with the MSQOL-54. Candidate predictors included cognitive functioning (a selection of Rao's BRB-NT), sample features (age, education, MS duration), depressive symptoms (BDI-II), anxiety (STAI-Y), disability (WHODAS 2.0), and MS severity (EDSS): those that correlated with PCS and MCS with p < .250 and those that correlated with other predictors with coefficients >.800 were excluded from regression analyses. RESULTS: In total, 181 patients (60.8% females, mean age 39.6, median EDSS 1.5) were included. In both models, cognitive variables had a poor explicative power. The models improved significantly when psychological, as well as, disease severity and disability variables were added. R(2) of complete models was 0.732 for the physical component, 0.697 for the mental one: BDI-II, STAI-State and, some WHODAS 2.0 scales were significant predictors of HRQoL. CONCLUSIONS: Monitoring anxiety, depressive symptoms, and level of disability through self-reported questionnaires may provide useful suggestions to improve the HRQoL of persons with MS in the workforce, permitting to address possible problems in the work context and plan corrective actions.

LMNA-associated myopathies: the Italian experience in a large cohort of patients.

OBJECTIVES: Our aim was to conduct a comparative study in a large cohort of myopathic patients carrying LMNA gene mutations to evaluate clinical and molecular features associated with different phenotypes. METHODS: We performed a retrospective cohort study of 78 myopathic patients with LMNA mutation and 30 familial cases with LMNA mutation without muscle involvement. We analyzed features characterizing the various forms of LMNA-related myopathy through correlation statistics. RESULTS: Of the 78 patients, 37 (47%) had limb-girdle muscular dystrophy 1B (LGMD1B), 18 (23%) congenital muscular dystrophy (MDCL), 17 (22%) autosomal dominant Emery-Dreifuss muscular dystrophy 2 (EDMD2), and 6 (8%) an atypical myopathy. The myopathic phenotypes shared a similar cardiac impairment. Cardioverter defibrillator or pacemaker was implanted in 41 (53%) myopathic patients compared to 7 (23%) familial cases without muscle involvement (p = 0.005). Heart transplantation was performed in 8 (10.3%) myopathic patients and in none of the familial cases. Ten (12.8%) myopathic patients died; there were no deaths among the familial cases (p = 0.032). Missense mutations were found in 14 patients (82%) with EDMD2 and 14 patients (78%) with MDCL compared to 17 patients (45%) with LGMD1B and 4 (67%) atypical patients. Frameshift mutations were detected in 17 (45%) LGMD1B compared to 3 (18%) EDMD2, 1 (6%) MDCL, and 2 (33%) with atypical myopathy (p = 0.021). Furthermore, frameshift mutations were found in 30 of 73 patients (41%) with heart involvement compared to 4 of 35 (11%) without heart involvement (p = 0.004). CONCLUSIONS: Our data provided new insights in LMNA-related myopathies, whose natural history appears to be dominated by cardiac involvement and related complications.