Neurite Orientation Dispersion and Density Imaging for Assessing Acute Inflammation and Lesion Evolution in MS.

BACKGROUND AND PURPOSE: MR imaging is essential for MS diagnosis and management, yet it has limitations in assessing axonal damage and remyelination. Gadolinium-based contrast agents add value by pinpointing acute inflammation and blood-brain barrier leakage, but with drawbacks in safety and cost. Neurite orientation dispersion and density imaging (NODDI) assesses microstructural features of neurites contributing to diffusion imaging signals. This approach may resolve the components of MS pathology, overcoming conventional MR imaging limitations. MATERIALS AND METHODS: Twenty-one subjects with MS underwent serial enhanced MRIs (12.6 ± 9 months apart) including NODDI, whose key metrics are the neurite density and orientation dispersion index. Twenty-one age- and sex-matched healthy controls underwent unenhanced MR imaging with the same protocol. Fifty-eight gadolinium-enhancing and non-gadolinium-enhancing lesions were semiautomatically segmented at baseline and follow-up. Normal-appearing WM masks were generated by subtracting lesions and dirty-appearing WM from the whole WM. RESULTS: The orientation dispersion index was higher in gadolinium-enhancing compared with non-gadolinium-enhancing lesions; logistic regression indicated discrimination, with an area under the curve of 0.73. At follow-up, in the 58 previously enhancing lesions, we identified 2 subgroups based on the neurite density index change across time: Type 1 lesions showed increased neurite density values, whereas type 2 lesions showed decreased values. Type 1 lesions showed greater reduction in size with time compared with type 2 lesions. CONCLUSIONS: NODDI is a promising tool with the potential to detect acute MS inflammation. The observed heterogeneity among lesions may correspond to gradients in severity and clinical recovery after the acute phase.

Effect of pregnancy loss on MS disease activity.

OBJECTIVE: To evaluate the effect of pregnancy loss (PL) on MS disease activity. METHODS: Eleven women with first-trimester PLs were identified through a reproductive questionnaire. MS activity (MRI lesions and/or clinical relapses) was compared for the 12 months before conception and after PL. RESULTS: There was MS activity in 7/11 participants after, compared with 3/11 before PL (McNemar's test, p = .29), including MRI activity in 7/11 after, compared with 2/11 before PL (McNemar's test, p = .13). CONCLUSION: Larger studies are needed to confirm this observed trend of increased MS activity following PL.

Continuous daily assessment of multiple sclerosis disability using remote step count monitoring.

Disability measures in multiple sclerosis (MS) rely heavily on ambulatory function, and current metrics fail to capture potentially important variability in walking behavior. We sought to determine whether remote step count monitoring using a consumer-friendly accelerometer (Fitbit Flex) can enhance MS disability assessment. 99 adults with relapsing or progressive MS able to walk ≥2-min were prospectively recruited. At 4 weeks, study retention was 97% and median Fitbit use was 97% of days. Substudy validation resulted in high interclass correlations between Fitbit, ActiGraph and manual step count tally during a 2-minute walk test, and between Fitbit and ActiGraph (ICC = 0.76) during 7-day home monitoring. Over 4 weeks of continuous monitoring, daily steps were lower in progressive versus relapsing MS (mean difference 2546 steps, p < 0.01). Lower average daily step count was associated with greater disability on the Expanded Disability Status Scale (EDSS) (p < 0.001). Within each EDSS category, substantial variability in step count was apparent (i.e., EDSS = 6.0 range 1097-7152). Step count demonstrated moderate-strong correlations with other walking measures. Lower average daily step count is associated with greater MS disability and captures important variability in real-world walking activity otherwise masked by standard disability scales, including the EDSS. These results support remote step count monitoring as an exploratory outcome in MS trials.

Women's experiences of menopause in an online MS cohort: A case series.

BACKGROUND: Many women with multiple sclerosis (MS) are postmenopausal. Previously reported findings from an online MS cohort suggested that earlier, surgical menopause may be associated with higher patient-reported MS severity scores. OBJECTIVE: To explore experiences of menopause in a series of MS women responding to a reproductive survey from an online research platform, PatientsLikeMe (PLM). METHODS: The free-text responses from a detailed reproductive history survey deployed to PLM members were analyzed using grounded theory approach. RESULTS: Of the 208 free text responses, 127 responses related to menopause. Five themes emerged: (1) perimenopausal onset of MS symptoms, (2) overlap of MS and menopausal symptoms, (3) MS exacerbations and pseudo-exacerbations triggered by hot flashes, (4) escalation of disease course after menopause, including increasing fatigue, cognitive disturbance, and other symptoms; and (5) effect of HRT on MS symptoms. Some women reported no effects of menopause or HRT. CONCLUSION: Given an aging population and a median age of individuals currently living with MS very close to menopausal age in many cohorts, there is a pressing need to understand the impact of menopause on MS course. Qualitative responses in this study illustrated several specific themes that require quantitative testing in clinic-based cohorts.

Longitudinal BMI trajectories in multiple sclerosis: Sex differences in association with disease severity.

BACKGROUND: Adolescent obesity is a risk factor for multiple sclerosis (MS), but little is known about changes in body mass index (BMI) after MS onset. OBJECTIVE: To assess the relationship between MS and longitudinal changes in BMI. METHODS: We analyzed prospectively collected BMIs in a cohort of patients with adult-onset MS and matched adult healthy controls (HC) gathered from the same hospital network central clinical data registry. RESULTS: We made three main observations. First, at baseline MS patients had a significantly higher BMI than HC (age- and sex- adjusted mean difference=0.57; 95% CI: 0.15, 0.99; p=0.008). Second, a significant age by MS status interaction was observed (p<0.0001), such that in MS, BMIs did not increase significantly higher in older individuals, whereas BMIs in HCs were higher with increasing age. Third, we observed sex-specific associations with disease severity: higher BMI was associated with higher cross-sectional EDSS in women, but with lower EDSS in men (p=0.003, N=758). There were no longitudinal associations between BMI and EDSS in either sex or in the entire cohort (p=0.65, N=772). CONCLUSION: After MS onset, patients may not experience age-expected increases in BMI. BMI may have sex-specific associations with MS disability scores. More refined measures of body composition are warranted in future studies to distinguish adiposity from muscle mass.

Patients report worse MS symptoms after menopause: findings from an online cohort.

BACKGROUND: Many women with multiple sclerosis (MS) are postmenopausal, yet the impact of menopause on MS symptoms is unknown. OBJECTIVE: To investigate patient-reported impact of menopause in a large online research platform, PatientsLikeMe (PLM). METHODS: A detailed reproductive history survey was deployed to PLM members, and responses were linked to PLM׳s prospectively collected patient-reported severity score (MS Rating Scale, MSRS). The MSRS has previously shown good correlation with physician-derived EDSS scores. RESULTS: Of the 513 respondents, 55% were postmenopausal; 54% of these reported induced menopause. Median age at natural menopause was 51. Surgical menopause occurred at an earlier age (p<0.001) and was associated with more hormone replacement therapy use (p=0.02) than natural menopause. Postmenopausal status, surgical menopause, and earlier age at menopause were all associated with worse MSRS scores (p≤0.01) in regressions adjusting for age, disease type and duration. CONCLUSION: Postmenopausal patients in this study reported worse MS disease severity. Further, this study highlights a utility for online research platforms, which allow for rapid generation of hypotheses that then require validation in clinical settings.

Low testosterone is associated with disability in men with multiple sclerosis.

BACKGROUND: Gonadal steroids may modulate disease course in multiple sclerosis (MS). OBJECTIVE: To assess the prevalence and clinical associations of hypogonadism in men with MS. METHODS: Male patients, aged 18-65 years, with relapsing-remitting MS (RRMS) or clinically-isolated syndrome (CIS) and their first symptom < 10 years prior were selected from a longitudinal clinical study. We measured their hormones in stored morning blood samples, and collected their Expanded Disability Status Scale (EDSS) scores every 6 months and their Symbol Digit Modalities Test (SDMT) results annually. RESULTS: Our analysis included 96 men with a mean age of 40 years, EDSS of 1.1 and disease duration of 4.6 years. Of these men, 39% were hypogonadal (total testosterone < 288 ng/dL); none showed compensatory elevations in luteinizing hormone. Their low testosterone levels and testosterone:estradiol ratios were negatively correlated with body mass index (BMI) and leptin, and showed no correlation with 25-hydroxy-vitamin D levels. In our primary cross-sectional analyses, there was a negative age-adjusted correlation between total testosterone and EDSS (p = 0.044). In the age-adjusted longitudinal analyses, higher baseline testosterone levels were associated with less decline in SDMT (p = 0.012). CONCLUSIONS: Men with MS may experience hypogonadotropic hypogonadism. Low testosterone levels may be associated with worse clinical outcomes. A potential neuroprotective role for testosterone warrants further investigation.

Polygyny and women's health in rural Mali.

Women's social networks and social power are increasingly seen as important factors modulating their health in sub-Saharan Africa. Polygyny, a common marital structure in many societies, mediates important intra-household relationships by requiring both competition and co-operation among co-wives. Using mixed methods, semi-structured questionnaires were administered to 298 women aged 15-84 living in the Kolondiéba region of rural Mali in 1999, and supplemented by detailed interviews with 40 women. Three categories of outcome were explored: illness experience, therapeutic itinerary and social support received. Quantitative data were analysed using regression analysis and qualitative data using a grounded theory approach. In quantitative analyses, controlling for age and household wealth index, senior wives were less likely to be escorted to a healer by their husbands during illness than were junior wives or monogamous women. Polygynous women were also less likely to obtain a treatment for which there was a monetary fee. Fewer than one-third of polygynous women reported the assistance of a co-wife during illness in any given task. In qualitative analyses, women further related varied mechanisms through which polygyny impacted their health trajectories. These ranged from strongly supportive relationships, to jealousy because of unequal health or fertility, bias in emotional and material support provided by husbands, and accusations of wrong-doing and witchcraft. This study highlights the need for more prospective mixed methods analyses to further clarify the impact of polygyny on women's health-related experiences and behaviours in sub-Saharan Africa.

Metabolic and endocrine correlates of cognitive function in healthy young women.

OBJECTIVE: Obesity has been associated with cognitive decline in longitudinal studies of older individuals. We hypothesized that the cognitive sequelae of obesity may be detectable in the reproductive years. In addition, we explored the hypothesis that these associations may be mediated by the hormonal milieu. DESIGN AND METHODS: Of 49 young healthy lean and overweight women aged 20-45, we investigated the association between performance on a battery of cognitive tests, body composition parameters [body mass index, total fat, abdominal (visceral, subcutaneous, and total) adipose tissue, and muscle], and hormone levels (insulin, adiponectin, leptin, insulin-like growth factor 1 (IGF-1), estrogen, testosterone, and vitamin D). RESULTS: We found a significant negative association between both visceral adiposity and muscle, and performance in the domain of verbal learning and memory, after controlling for age and education. Other body composition parameters showed similar trends (0.05 < P < 0.10). Additionally, the degree of insulin resistance was negatively associated with executive function domain. None of the associations between the other hormones examined (adipokines, IGF-1, gonadal hormones, and vitamin D) and cognitive function were significant. CONCLUSION: These preliminary findings suggest a possible association between obesity and cognitive function in healthy young women of reproductive age. More research is warranted into the potential modulatory effect of insulin resistance on this association.

Multiple myeloma and paget disease with abnormal skull lesions and intracranial hypertension.

We report a 73 years old man with a diagnosis of Paget Disease (PD) and symptomatic Multiple Myeloma (MM). Coexistence of MM and PD has rarely been described. PD mimics many of the features of bone destructive process in MM, making differential diagnosis more complicated. In addition, the presence of serious muscolo-skeletal and metabolic complications in both diseases makes management of patients difficult, worsening the prognosis.The comparison of these two diseases has led to the characterization of a common molecular mechanism represented by the receptor activator of nuclear factor-kB ligand (RANKL)/Osteoprotegerin signaling pathway. The improved comprehension of these mechanisms led to the development of new pharmacologic agents (bisphosphonates, cytokines inhibitors) effective for the treatment of these bone diseases.

20 MHz high frequency ultrasound assessment of scleral and intraocular conjunctival squamous cell carcinoma.

AIM: To assess in a prospective manner, high frequency ultrasound diagnosis of deep invasion by conjunctival squamous cell carcinoma. METHODS: Prospective, non-randomised case series comparing 20 MHz high frequency ultrasonographic and clinicopathological data. RESULTS: 20 MHz high frequency ultrasound delineated the degree of deep involvement of this tumour into the sclera, globe, and orbit. The results of ultrasonography correlated with the clinicopathological results. CONCLUSIONS: High frequency ultrasound is a useful diagnostic adjunctive test in patients with possible deep involvement by a conjunctival squamous cell carcinoma.

Animated images of cardiac membrane voltage during defibrillation.

Optical recording using voltage-sensitive dyes has been used to investigate the mechanisms of defibrillation because it (1) is immune to the artifacts produced by high-voltage shocks, (2) provides the time course of the membrane action potential, and (3) can be used to make simultaneous recordings at many sites. The authors used the laser scanning technique to optically record action potentials from 100 sites with 1-ms resolution on the surface of the isolated, perfused rabbit heart during defibrillation. The data were typically analyzed by constructing maps of impulse propagation and examining individual recordings from sites of interest. Described here is a new analysis method that creates millisecond-by-millisecond images of the spatial distribution of membrane potentials. The experimental protocol applied a test shock to the fibrillating heart, followed by a rescue shock and a paced beat. Optical recordings were calibrated to yield membrane voltage as a percentage of the resting and overshoot levels of the postrescue stimulated action potential. The positions of the recording sites and the membrane voltage levels for all 100 sites during a single 1-ms interval were used to interpolate membrane voltage levels at points within a 128 x 128 pixel frame using the biharmonic interpolation method. The level of membrane potential was encoded by pixel color and surface elevation. Sequential frames were viewed as a face-on two dimensional or as a three-dimensional perspective of the colored surface. Animation of membrane voltage distributions enabled the visualization of the interaction between the shock-induced electrophysiologic response and the propagation of electrical activity preceding and following a defibrillation shock. Successful defibrillation shocks synchronized repolarization across the surface of the heart following the shock.

Results of an open trial of cyclosporine in a group of steroido-dependent myasthenic subjects.

9 subjects with myasthenia gravis, chronically treated with prednisone, underwent an open clinical trial with cyclosporine, an immunosuppressive and immunomodulator drug. Preliminary results after one year of treatment show that cyclosporine induces a further improvement of myasthenic symptoms, and that prednisone may be reduced or discontinued without relapse of clinical symptoms. Side effects of cyclosporine are very frequent and largely influence the treatment.

A double-blind controlled subjective study of a new pharmaceutical preparation of lormetazepam versus placebo in patients with chronic sleep disturbances.

A double-blind crossover trial was carried out on the sleep-inducing activity of a new preparation (oral drops) of lormetazepam versus placebo. Twenty patients were included and requested to subjectively evaluate their sleep, both by analogue scales and semiquantitative ratings, during 2-night administration of the two products. Also, the usual parameters, sleep duration, sleep latency and number of awakenings were evaluated. Lormetazepam drops appeared to exert the same actions as the capsules' preparation, being significantly different from those of the placebo.