Vincenzo Brescia Morra

Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: I: Fetal risks

Objective To assess fetal risk after pregnancy exposure to natalizumab in women with multiple sclerosis (MS), with a specific focus on spontaneous abortion (SA) and congenital anomalies (CA). Methods Data of all pregnancies occurring between 2009 and 2015 in patients with MS treated with natalizumab and referring to 19 participating sites were collected and compared with those of pregnancies in untreated patients and patients treated with injectable immunomodulatory agents. Rates of SA and CA were also compared with those reported in the Italian population. Multivariable logistic and linear regression models were performed. Results A total of 92 pregnancies were tracked in 83 women. In the multivariable analysis, natalizumab exposure was associated with SA (odds ratio [OR] 3.9, 95% confidence interval [CI] 1.9–8.5, p < 0.001). However, the rate of SA (17.4%) was within the estimates for the general population, as well as the rate of major CA (3.7%). Moreover, exposure to natalizumab and interferon-β (IFN-β) was associated with lower length and weight of the babies (p < 0.001). Conclusion Our results showed that natalizumab exposure to up 12 weeks of gestation is associated with an increased risk of SA, although within the limits expected in the general population, whereas the risk of CA needs further investigation. Taking into account the high risk of disease reactivation after natalizumab suspension, pregnancy could be planned continuing natalizumab while strictly monitoring conception. Classification of evidence This study provides Class III evidence that in women with MS, natalizumab exposure increases the risk of spontaneous abortion as compared to IFN-β-exposed or untreated patients (OR 3.9, 95% CI 1.9–8.5).

Health-Related Coping and Social Interaction in People with Multiple Sclerosis Supported by a Social Network: Pilot Study With a New Methodological Approach

Background Social media are a vital link for people with health concerns who find in Web communities a valid and comforting source for information exchange, debate, and knowledge enrichment. This aspect is important for people affected by chronic diseases like multiple sclerosis (MS), who are very well informed about the disease but are vulnerable to hopes of being cured or saved by therapies whose efficacy is not always scientifically proven. To improve health-related coping and social interaction for people with MS, we created an MS social network (SMsocialnetwork.com) with a medical team constantly online to intervene promptly when false or inappropriate medical information are shared. Objective The goal of this study was to assess the impact of SMsocialnetwork.com on the health-related coping and social interaction of people with MS by analyzing areas of interest through a Web-based survey. Methods Referring to previous marketing studies analyzing the online platform’s role in targeted health care, we conducted a 39-item Web-based survey. We then performed a construct validation procedure using a factorial analysis, gathering together like items of the survey related to different areas of interest such as utility, proximity, sharing, interaction, solving uncertainty, suggestion attitude, and exploration. Results We collected 130 Web-based surveys. The areas of interest analysis demonstrated that the users positively evaluated SMsocialnetwork.com to obtain information, approach and solve problems, and to make decisions (utility: median 4.2); improve feeling of closeness (proximity: median 5); catalyze relationships and text general personal opinions (sharing: median 5.6); get in touch with other users to receive innovative, effective, and practical solutions (interaction, solving uncertainty, and suggestion attitude medians were respectively: 4.1, 3, and 3); and share information about innovative therapeutic approaches and treatment options (suggestion attitude: median: 3.3). Conclusions SMsocialnetwork.com was perceived by users to be a useful tool to support health-related coping and social interaction, and may suggest a new kind of therapeutic alliance between physicians and people with MS.

Dimethyl fumarate mediates Nrf2-dependent mitochondrial biogenesis in mice and humans

The induction of mitochondrial biogenesis could potentially alleviate mitochondrial and muscle disease. We show here that dimethyl fumarate (DMF) dose-dependently induces mitochondrial biogenesis and function dosed to cells in vitro, and also dosed in vivo to mice and humans. The induction of mitochondrial gene expression is more dependent on DMFs target Nrf2 than hydroxycarboxylic acid receptor 2 (HCAR2). Thus, DMF induces mitochondrial biogenesis primarily through its action on Nrf2, and is the first drug demonstrated to increase mitochondrial biogenesis with in vivo human dosing. This is the first demonstration that mitochondrial biogenesis is deficient in Multiple Sclerosis patients, which could have implications for MS pathophysiology and therapy. The observation that DMF stimulates mitochondrial biogenesis, gene expression and function suggests that it could be considered for mitochondrial disease therapy and/or therapy in muscle disease in which mitochondrial function is important.

Cerebellar lobule atrophy and disability in progressive MS

Objective To investigate global and lobular cerebellar volumetries in patients with progressive multiple sclerosis (MS), testing the contribution of cerebellar lobular atrophy to both motor and cognitive performances. Methods Eighty-two patients with progressive MS and 46 healthy controls (HC) were enrolled in this cross-sectional study. Clinical evaluation included motor and cognitive testing: Expanded Disability Status Scale, cerebellar Functional System score, Timed 25-Foot Walk Test, 9-Hole Peg Test (9-HPT), Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test–Revised (BVMT) and California Verbal Learning Test II (CVLT). Cerebellar volumes were automatically obtained using the Spatially Unbiased Infratentorial Toolbox. A hierarchical multiple linear regression analysis was performed to assess the relationship between MRI variables of supratentorial and cerebellar damage (grey matter fraction, T2 lesion volume, metrics of cerebellar atrophy and cerebellar lesion volume) and motor/cognitive scores. Results Patients with MS exhibited lower cerebellar volumes compared with HC. Regression analysis showed that cerebellar metrics accounted for extra variance in both motor and cognitive performances, with cerebellar lesion volume, cerebellar Lobules VI, Crus I and VIIIa atrophy being independent predictors of 9-HPT, SDMT, BVMT and CVLT performances. Conclusions Atrophy of specific cerebellar lobules explains different aspects of motor and cognitive disability in patients with progressive MS. Investigation of cerebellar involvement provides further insight into the pathophysiological basis of clinical disability in progressive MS.

CD4/CD8 ratio during natalizumab treatment in multiple sclerosis patients

Although improved, the risk of progressive multifocal leukoencephalopathy is a constant threat for patient affected by multiple sclerosis treated with natalizumab. We performed a 24months longitudinal study aimed to evaluate the total WBC and lymphocytes subsets modifications and their correlations with anti-JCV antibody index after 1 and 2years of natalizumab treatment. Natalizumab induced an increase of WBC, total and C19+ lymphocytes together with a decrease of CD3+, CD4+ T lymphocytes and CD4/CD8 ratio, which was positively related to anti-JCV antibodies index at month 0, 12 and 24. Our study confirms that lymphocytes subsets are modified under NAT therapy. Implications of lymphocyte subsets alterations in the pathogenesis of PML are under analyses.

Default mode network modifications in Fabry disease: A resting-state fMRI study with structural correlations

Aim of the study was to evaluate the presence of Default Mode Network (DMN) modifications in Fabry Disease (FD), and their possible correlations with structural alterations and neuropsychological scores. Thirty‐two FD patients with a genetically confirmed diagnosis of classical FD (12 males, mean age 43.3u2009±u200912.2) were enrolled, along with 35 healthy controls (HC) of comparable age and sex (14 males, mean age 42.1u2009±u200914.5). Resting‐State fMRI data were analyzed using a seed‐based approach, with six different seeds sampling the main hubs of the DMN. Structural modifications were assessed by means of Voxel‐Based Morphometry (VBM) and Tract‐Based Spatial Statistics analyses. Between‐group differences and correlations with neuropsychological variables were probed voxelwise over the whole brain. Possible correlations between FC modifications and global measures of microstructural alteration were also tested in FD patients with a partial correlation analysis. In the FD group, clusters of increased functional connectivity involving both supratentorial and infratentorial regions emerged, partially correlated to the widespread white matter (WM) damage found in these patients. No gray matter volume differences were found at VBM between the two groups. The connectivity between right inferior frontal gyrus and precuneus was significantly correlated with the Corsi block‐tapping test results (pu2009=u2009.0001). Widespread DMN changes are present in FD patients that correlate with WM alterations and cognitive performance. Our results confirm the current view of a cerebral involvement in FD patients not simply associated to major cerebrovascular events, but also related to significant and diffuse microstructural and functional changes.

Longitudinal assessment of dentate nuclei relaxometry during massive gadobutrol exposure

We report the assessment of Dentate Nuclei (DN) R1 (1/T1) and R2* (1/T2*) values in a patient with relapsing-remitting Multiple Sclerosis, exposed to 22 standard (0.1 mmol/kg) doses of gadobutrol, who underwent eight relaxometric MR measurements within 2 years. DN R1 did not significantly increase nor correlated with cumulative gadobutrol administration, even after a total dose of 130 ml. Likewise, DN R2* relaxometry remained unchanged. In conclusion, massive gadobutrol exposure did not induce significant DN relaxometry changes.

Immunometabolic profiling of patients with multiple sclerosis identifies new biomarkers to predict disease activity during treatment with interferon beta-1a

Reliable immunologic biomarkers able to monitor disease course during multiple sclerosis (MS) are still missing. We aimed at identifying possible immunometabolic biomarkers able to predict the clinical outcome in MS patients during treatment with interferon (IFN)-beta-1a. We measured in 45 relapsing-remitting (RR) MS patients, blood circulating levels of several immunometabolic markers, at enrolment, and correlated their levels to disease activity and progression over time. Higher levels of interleukin (IL)-6, soluble-CD40-ligand (sCD40L) and leptin at baseline associated with a higher relapse rate and a greater risk of experiencing at least one relapse in the following year. Higher values of soluble tumor necrosis factor receptor (sTNF-R) and leptin at baseline were predictive of a higher number of lesions in the following one-year of follow up. In conclusion, our data suggest that an immunometabolic profiling measuring IL-6, sCD40L, leptin and sTNF-R at baseline, could represent a useful tool to predict disease course in RRMS patients during treatment with IFN-beta-1a.

Health-care disparities stemming from sexual orientation of Italian patients with Multiple Sclerosis: A cross-sectional web-based study

Lesbian, gay, bisexual and transgender (LGBT) patients might experience unique difficulties and barriers to treatment of chronic diseases related to their sexual orientation. Thus, we investigated concerns experienced by LGBT patients with multiple sclerosis (MS). We conducted a web-based survey using a multi-choice questionnaire published in an Italian social-network (www.smsocialnetwork.com) for MS patients. The survey investigated: socio-demographic factors, lifestyle habits, MS-related health status and LGBT specific issues (e.g. friendliness to their sexual orientation and eventual homophobic behaviors in the MS Center). Among MS patients willing to use psychological services, LGBT patients were associated with a smaller number of psychological consultations, compared to heterosexuals (Coeff.=-0.449; p<0.001; 95%CI=-0.682 to -0.217). LGBT patients were more likely to change MS Center, compared to heterosexuals (OR=2.064; p=0.046; 95%CI=1.011-4.212). The number of MS Center changes was associated with MS Center friendliness (p=0.037; rho=-0.229) and with the occurrence of homophobic behaviors (p=0.036; rho=0.234). LGBT MS patients more frequently changed MS Center and had a reduced use of psychological services, compared to heterosexuals. The attitude towards LGBT MS patients might affect resource utilizations and LGBTs health status.

Brain Susceptibility Changes in a Patient with Natalizumab-Related Progressive Multifocal Leukoencephalopathy: A Longitudinal Quantitative Susceptibility Mapping and Relaxometry Study

Background Brain MRI plays an essential role in both diagnosis and follow-up of the JC virus infection of the brain. Recently, MR studies with susceptibility-weighted imaging (SWI) sequences have shown hypointensities in U-fibers adjacent to white matter (WM) lesions of progressive multifocal leukoencephalopathy (PML). This finding has been confirmed with the use of quantitative susceptibility mapping (QSM), allowing to hypothesize a paramagnetic effect in these regions. Here, we report the first longitudinal assessment of QSM and R2* maps in natalizumab-associated PML to evaluate serial changes in susceptibility contrast images and their role in PML diagnosis and follow-up. Case presentation We report the case of a 42-year-old woman with multiple sclerosis (MS) who eventually developed, after the 28th natalizumab infusion, subacute cognitive decline and received a laboratory-confirmed diagnosis of PML, leading to immediate drug discontinuation. Three months later, she suffered a new clinical exacerbation, with a brain scan revealing significant inflammatory activity compatible with the radiological diagnosis of an Immune Reconstitution Inflammatory Syndrome (IRIS). She was then treated with corticosteroids until the clinico-radiological spectrum became stable, with the final outcome of a severe functional impairment. Quantitative maps obtained in the early symptomatic stage clearly showed increased QSM and R2* values in the juxtacortical WM adjacent to PML lesions, which persisted during the subsequent disease course. Discussion and conclusion High QSM and R2* values in U-fibers adjacent to WM lesions were early and seemingly time-independent radiological findings in the presented PML case. This, coupled to the known absence of significant paramagnetic effect of new active MS lesions, could support the use of quantitative MRI as an additional tool in the diagnosis and follow-up of natalizumab-related PML in MS.