Magnetic Resonance Imaging Activity Research Articles

Evaluation of frequency, severity, and independent risk factors for recurrence of disease activity after fingolimod discontinuation in a large real-world cohort of patients with multiple sclerosis.

Clinical and radiological signs of recurring disease activity (RDA) have been described in patients with multiple sclerosis (pwMS) after discontinuation of fingolimod (FGL). To describe frequency, severity and potential risk factors for RDA after FGL discontinuation in a large real-world cohort of pwMS. Post-FGL RDA was defined as evidence of clinical and/or radiological activity within 6 months after FGL discontinuation. Relapses with Expanded Disability Status Scale increase ⩾2 points and/or magnetic resonance imaging (MRI) activity with at least five cerebral gadolinium-enhancing lesions and/or ⩾6 cerebral new T2 lesions were defined as severe recurring disease activity (sRDA). Using a multivariate logistic model, we explored the influence of age, disease duration, sex, clinical, and MRI activity under FGL on the occurrence of RDA. We identified 110 pwMS who discontinued FGL. Thirty-seven (33.6%) developed post-FGL RDA and 13 (11.8%) also fulfilled criteria for sRDA. Younger age at diagnosis [odds ratio (OR) = 1.10, p < 0.01], shorter disease duration (OR = 1.17, p < 0.01), and MRI activity under FGL (OR = 2.92, p = 0.046) were independent risk factors for the occurrence of post-FGL RDA. Individual risk assessment and optimal treatment sequencing can help to minimize the risk of post-FGL RDA. Early switch to highly effective disease-modifying therapy might reduce occurrence of post-FGL RDA.

Relapsing-remitting and primary progressive multiple sclerosis treated with ocrelizumab: A comparative study.

To compare the clinical and radiological effectiveness of ocrelizumab in primary progressive multiple sclerosis (PPMS) and relapsing-remitting multiple sclerosis (RRMS) in a clinical practice setting and describe its tolerability and adverse events. A retrospective observational cohort study was conducted comparing clinical and magnetic resonance imaging (MRI) data of all patients with (pw)PPMS and RRMS who had received treatment with ocrelizumab at least one cycle and have been followed up for one year at minimum. 42 patients (27 women) were treated with ocrelizumab: 30 had RRMS and 13 PPMS. The follow-up period was 26.4±8.4 months. The proportion of pwRRMS with no evidence of disease activity (NEDA) in the first year was 69.2% and in the second was 80%. In the first year, radiological activity was reduced by 80.0% in pwRRMS and 91.7% in pwPPMS. In the second year, radiological activity was completely reduced in both groups. A statistically significant difference (p<0.05) was observed between the pre-ocrelizumab rate of disability progression vs. the first year rate of progression for pwRRMS and pwPPMS. However, an increase in the disability progression rate in the second year of treatment was found in pwPPMS. Ocrelizumab was mostly well tolerated and some adverse effects were reported: infusion-related reactions (IRRs) were the most frequent adverse event, followed by infections and hematological side effects. Discontinuations were due to infections, hematological complications, and perception of ineffectiveness. Ocrelizumab was very effective in reducing relapses and MRI activity. The rate of progression was slowed down; however, the effect was more evident for pwRRMS than for pwPPMS over time.

Disease activity 4.5 years after starting cladribine: experience in 264 patients with multiple sclerosis.

Cladribine is an effective immunotherapy for people with multiple sclerosis (pwMS). Whilst most pwMS do not require re-treatment following standard dosing (two treatment courses), disease activity re-emerges in others. The characteristics of pwMS developing re-emerging disease activity remain incompletely understood. To explore whether clinical and/or paraclinical baseline characteristics, including the degree of lymphocyte reduction, drug dose and lesions on magnetic resonance imaging (MRI) are associated with re-emerging disease activity. Service evaluation in pwMS undergoing subcutaneous cladribine (SClad) treatment. Demographics, clinical, laboratory and MRI data of pwMS receiving two courses of SClad were extracted from health records. To assess associations of predictor variables with re-emerging disease activity, a series of Cox proportional hazards models was fitted (one for each predictor variable). Of n = 264 pwMS 236 received two courses of SClad and were included in the analysis. Median follow-up was 4.5 years (3.9, 5.3) from the first, and 3.5 years (2.9, 4.3) from the last SClad administration. Re-emerging disease activity occurred in 57/236 pwMS (24%); 22/236 received further cladribine doses (SClad or cladribine tablets) at 36.7 months [median; interquartile range (IQR): 31.7, 42.1], and 22/236 other immunotherapies 18.9 months (13.0, 30.2) after their second course of SClad, respectively. Eligibility was based on MRI activity in 29, relapse in 5, both in 13, elevated cerebrospinal fluid neurofilament light chain level in 3, deterioration unrelated to relapse in 4 and other in 3. Only 36/57 of those eligible for additional immunotherapy had received a reduced dose of SClad for their second treatment course. Association was detected between re-emerging disease activity and (i) high baseline MRI activity and (ii) low second dose of SClad. Re-emerging disease activity was associated with baseline MRI activity and low dose second course of SClad.

Is It Time for Ocrelizumab Extended Interval Dosing in Relapsing Remitting MS? Evidence from An Italian Multicenter Experience During the COVID-19 Pandemic

In the COVID-19 pandemic era, safety concerns have been raised regarding the risk of severe infection following administration of ocrelizumab (OCR), a B-cell-depleting therapy. We enrolled all relapsing remitting multiple sclerosis (RRMS) patients who received maintenance doses of OCR from January 2020 to June 2021. Data were extracted in December 2021. Standard interval dosing (SID) was defined as a regular maintenance interval of OCR infusion every 6 months, whereas extended interval dosing (EID) was defined as an OCR infusion delay of at least 4 weeks. Three infusions were considered in defining SID vs. EID (infusions A, B, and C). Infusion A was the last infusion before January 2020. The primary study outcome was a comparison of disease activity during the A-C interval, which was defined as either clinical (new relapses) or radiological (new lesions on T1-gadolinium or T2-weighted magnetic resonance imaging (MRI) sequences). Second, we aimed to assess confirmed disability progression (CDP). A total cohort of 278 patients (174 on SID and 104 on EID) was enrolled. Patients who received OCR on EID had a longer disease duration and a higher rate of vaccination against severe acute respiratory syndrome-coronavirus 2 (p < 0.05). EID was associated with an increased risk of MRI activity during the A-C interval (OR 5.373, 95% CI 1.203–24.001, p = 0.028). Being on SID or EID did not influence CDP (V-Cramer 0.47, p = 0.342). EID seemed to be associated with a higher risk of MRI activity in our cohort. EID needs to be carefully considered for OCR-treated patients.

Putamen Structure and Function in Familial Risk for Depression: A Multimodal Imaging Study

BackgroundThe putamen has been implicated in depressive disorders, but how its structure and function increase depression risk is not clearly understood. Here, we examined how putamen volume, neuronal density, and mood-modulated functional activity relate to family history and prospective course of depression. MethodsThe study includes 115 second- and third-generation offspring at high or low risk for depression based on the presence or absence of major depressive disorder in the first generation. Offspring were followed longitudinally using semistructured clinical interviews blinded to their familial risk; putamen structure, neuronal integrity, and functional activation were indexed by structural magnetic resonance imaging (MRI), proton magnetic resonance spectroscopy (N-acetylaspartate/creatine ratio), and functional MRI activity modulated by valence and arousal components of a mood induction task, respectively. ResultsAfter adjusting for covariates, the high-risk individuals had lower putamen volume (standardized betas, β-left = −0.17, β-right = −0.15, ps = .002), N-acetylaspartate/creatine ratio (β-left= −0.40, β-right= −0.37, ps < .0001), and activation modulated by valence (β-left = −0.22, β-right = −0.27, ps < .05) than low-risk individuals. Volume differences were greater at younger ages, and N-acetylaspartate/creatine ratio differences were greater at older ages. Lower putamen volume also predicted major depressive disorder episodes up to 8 years after the scan (β-left = −0.72, p = .013; β-right = −0.83, p = .037). Magnetic resonance spectroscopy and task functional MRI measures were modestly correlated (0.27 ≤ r ≤ 0.33). ConclusionsFindings demonstrate abnormalities in putamen structure and function in individuals at high risk for major depressive disorder. Future studies should focus on this region as a potential biomarker for depressive illness, noting meanwhile that differences attributable to family history may peak at different ages based on which MRI modality is being used to assay them.

Fast and functionally specific cortical thickness changes induced by visual stimulation.

Structural characteristics of the human brain serve as important markers of brain development, aging, disease progression, and neural plasticity. They are considered stable properties, changing slowly over time. Multiple recent studies reported that structural brain changes measured with magnetic resonance imaging (MRI) may occur much faster than previously thought, within hours or even minutes. The mechanisms behind such fast changes remain unclear, with hemodynamics as one possible explanation. Here we investigated the functional specificity of cortical thickness changes induced by a flickering checkerboard and compared them to blood oxygenation level-dependent (BOLD) functional MRI activity. We found that checkerboard stimulation led to a significant thickness increase, which was driven by an expansion at the gray-white matter boundary, functionally specific to V1, confined to the retinotopic representation of the checkerboard stimulus, and amounted to 1.3% or 0.022mm. Although functional specificity and the effect size of these changes were comparable to those of the BOLD signal in V1, thickness effects were substantially weaker in V3. Furthermore, a comparison of predicted and measured thickness changes for different stimulus timings suggested a slow increase of thickness over time, speaking against a hemodynamic explanation. Altogether, our findings suggest that visual stimulation can induce structural gray matter enlargement measurable with MRI.

The relationship of cerebrospinal fluid neurofilament levels with magnetic resonance imaging lesion location and disease activity in multiple sclerosis.

Background and purposeNeurofilament light chain (NfL) is an accepted biomarker of disease activity in multiple sclerosis (MS), but its relationship with magnetic resonance imaging (MRI) activity particularly in reference to lesion location and recurrent activity is not well understood.MethodsIn 139 MS patients who underwent lumbar punctures with follow‐up in 25, the relationship between cerebrospinal fluid (CSF) NfL and cranial MRI based on lesion location and lesion number was evaluated. Spearman rank correlation was used to assess the association between CSF NfL and MRI lesion location and lesion counts at baseline and follow‐up at 1 year. Multiple linear regression analysis was performed to assess which lesion location was most strongly associated with CSF NfL values.ResultsThe associations between baseline CSF NfL and lesion location and follow‐up lesions were modest, whilst those between baseline MRI and follow‐up CSF NfL were greater: periventricular (r = 0.31, p = 0.141), juxtacortical (r = 0.47, p = 0.022), infratentorial (r = 0.71, p ≤ 0.001) and cord lesions (r = 0.60, p = 0.002). All associations, however, improved following adjustment for disease duration and type of MS. Modelling revealed 53% of (log) CSF NfL could be explained by variance in baseline MRI lesion location.ConclusionsBaseline CSF NfL did not correlate with current or future MRI activity and lesion location. However, baseline MRI activity explained around 53% of the variation in the follow‐up CSF NfL, suggesting that the relationship between MRI and CSF NfL is mainly precedent rather than an association, that is one occurring before the other.

Predictors of Cladribine Effectiveness and Safety in Multiple Sclerosis: A Real-World, Multicenter, 2-Year Follow-Up Study.

IntroductionCladribine administration has been approved for the treatment of relapsing–remitting multiple sclerosis (MS) in 2017; thus, data on cladribine in a real-world setting are still emerging.MethodsWe report on cladribine effectiveness, safety profile, and treatment response predictors in 243 patients with MS followed at eight tertiary MS centers. Study outcomes were: (1) No Evidence of Disease Activity-3 (NEDA-3) status and its components (absence of clinical relapses, MRI activity, and sustained disability worsening); (2) development of grade III/IV lymphopenia. The relationship between baseline features and the selected outcomes was tested via multivariate logistic models.ResultsOf the 243 subjects included in the study (66.5% female, age 34.2 ± 10 years, disease duration 6.6 ± 9.6 years), 64% showed NEDA-3 at median follow-up (22 months). Patients with higher number of previous treatments had lower probability to retain NEDA-3 [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.41–0.98, p = 0.04] and were more prone to experience clinical relapses (OR 1.6, 95% CI 1–2.6, p = 0.04). The presence of active lesions at baseline was associated with follow-up magnetic resonance imaging (MRI) activity (OR 1.92, 95% CI 1.04–3.55, p = 0.04). Patients with higher rate of relapses in the year prior to cladribine start were at higher risk of developing sustained disability worsening (OR 2.95% CI 1–4.2, p = 0.04). Lymphopenia grade III/IV over the follow-up was associated with baseline lymphocyte count (OR 0.998, 95% CI 0.997–0.999, p = 0.01).ConclusionIn this large cohort, we confirm previous data about cladribine effectiveness on disease activity and disability worsening and provide information on response predictors that might inform therapeutic choices.

Prognostic value of intrathecal IgM synthesis determined by various laboratory methods in patients with early multiple sclerosis - a prospective observational study

BackgroundIntrathecal IgM synthesis has been identified as an adverse prognostic factor in patients with multiple sclerosis (MS); however, some studies have not confirmed this association. The objective of this study was to evaluate the clinical utility of intrathecal IgM synthesis for prediction of disease activity and disability in patients after the first demyelinating event of MS. MethodsWe conducted a single-centre prospective observational cohort study at the Department of Neurology, University Hospital Ostrava, Czech Republic. Intrathecal IgM synthesis was demonstrated by the presence of cerebrospinal fluid-restricted oligoclonal IgM bands and calculated using the Reiber, Auer, and Öhman formula and IgM index. ResultsA total of 61 patients with a clinically isolated syndrome or early relapsing-remitting MS were enrolled into the analysis of which 37 (61 %) were women. The median age at the disease onset was 32 years (interquartile range [IQR] 25 – 42), and the median disease duration was 2.8 years (IQR 2.4 – 3.5). Thirty-eight (62 %) patients experienced a second relapse of MS with a median of 312 days (IQR 192 – 424), and 29 (47.5 %) developed magnetic resonance imaging (MRI) activity during the follow-up. Intrathecal IgM synthesis did not affect the risk of a second relapse or evidence of MRI activity in univariate and multivariate Cox regression analysis. There was no significant difference in disability using the Expanded Disability Status Scale and progression index in patients with or without intrathecal IgM synthesis. ConclusionThis prospective cohort study did not demonstrate that intrathecal IgM synthesis is a risk factor for a second relapse or MRI activity. It was not associated with higher disability in patients after the first demyelinating event.

Clinical and radiological effectiveness of natalizumab extended dosage interval in patients with relapsing multiple sclerosis

Natalizumab (NTZ) is a very effective treatment approved for highly active multiple sclerosis. The main risk of treatment with NTZ is the possibility of developing progressive multifocal leukoencephalopathy, which is related to JC virus positivity and the number of NTZ infusions. This risk decreases with the extended dosage interval (EDI), which involves 9 or fewer infusions/year. However, it is a matter of controversy as to whether EDI remains effective in reducing recurrences and the presence of new lesions in magnetic resonance imaging (MRI). A prospective observational study was conducted from 1 April 2019 to 30 June 2021, following up patients on NTZ treatment who switched to EDI. Patients should have at least one MRI six months after the start of EDI. The presence of attacks or MRI activity (new lesions in T2) during the EDI was recorded. Twenty-three patients with a mean age of 43.5 ± 9.4 years were included. The median number of NTZ infusions was 68 (minimum, 25; maximum, 127). The median interval between the start of the EDI and the last MRI was 14 months (minimum, 6; maximum, 25), and 23 months from the last medical follow-up visit (minimum, 7; maximum, 28). Two patients (8.7%) presented with attacks and two others (8.7%) showed MRI activity. EDI with NTZ maintains high clinical and activity effectiveness in MRI.

Efficacy and safety of rituximab in patients with multiple sclerosis: An observational study at a tertiary center in Makkah, Saudi Arabia.

Objectives:To assess the efficacy and safety of rituximab for multiple sclerosis (MS) treatment in terms of reduction in clinical relapses, magnetic resonance imaging (MRI) activity, Expanded Disability Status Scale (EDSS) score and adverse events.Methods:This is a retrospective cross-sectional study conducted at King Abdullah Medical City, from January 2017 to August 2021, involving patients with MS given rituximab, with 1-year follow-up. Clinical parameters were noted pre- and post-treatment to determine efficacy; adverse events were noted to analyze safety. A paired samples t-test was used to compare responses pre- and post-treatment. A p-value<0.05 was considered significant.Results:Among 31 patients, 6 (19.4%) had progressive MS, and 25 (80.6%) had relapsing-remitting MS (mean disease duration=8.12±5.65 years). The annual relapse rate reduced from 1.67±0.97 to 0.06±0.25 (p<0.001), the EDSS score from 3.16±2.14 to 2.80±2.28 (p=0.141) and the MRI activity score from 1.84±1.03 to 1.03±0.18 (p<0.001). Only one patient had enhancing lesion activity post-treatment. The commonest side effect was urinary tract infection (25.8%). Only 2 patients discontinued the drug.Conclusion:Rituximab is an efficient drug in reducing the annual relapse rate and MRI activity of patients with MS, with few tolerable side effects not leading to drug discontinuation or any lethal outcome.

Sexual Dimorphism in the Brain Correlates of Adult-Onset Depression: A Pilot Structural and Functional 3T MRI Study.

Major Depressive Disorder (MDD) is a disabling illness affecting more than 5% of the elderly population. Higher female prevalence and sex-specific symptomatology have been observed, suggesting that biologically-determined dimensions might affect the disease onset and outcome. Rumination and executive dysfunction characterize adult-onset MDD, but sex differences in these domains and in the related brain mechanisms are still largely unexplored. The present pilot study aimed to explore any interactions between adult-onset MDD and sex on brain morphology and brain function during a Go/No-Go paradigm. We hypothesized to detect diagnosis by sex effects on brain regions involved in self-referential processes and cognitive control. Twenty-four subjects, 12 healthy (HC) (mean age 68.7 y, 7 females and 5 males) and 12 affected by adult-onset MDD (mean age 66.5 y, 5 females and 7 males), underwent clinical evaluations and a 3T magnetic resonance imaging (MRI) session. Diagnosis and diagnosis by sex effects were assessed on regional gray matter (GM) volumes and task-related functional MRI (fMRI) activations. The GM volume analyses showed diagnosis effects in left mid frontal cortex (p < 0.01), and diagnosis by sex effects in orbitofrontal, olfactory, and calcarine regions (p < 0.05). The Go/No-Go fMRI analyses showed MDD effects on fMRI activations in left precuneus and right lingual gyrus, and diagnosis by sex effects on fMRI activations in right parahippocampal gyrus and right calcarine cortex (p < 0.001, ≥ 40 voxels). Our exploratory results suggest the presence of sex-specific brain correlates of adult-onset MDD–especially in regions involved in attention processing and in the brain default mode–potentially supporting cognitive and symptom differences between sexes.

CSF TNF and osteopontin levels correlate with the response to dimethyl fumarate in early multiple sclerosis.

Background:Disease activity in the first years after a diagnosis of relapsing-remitting multiple sclerosis (RRMS) is a negative prognostic factor for long-term disability. Markers of both clinical and radiological responses to disease-modifying therapies (DMTs) are advocated.Objective:The objective of this study is to estimate the value of cerebrospinal fluid (CSF) inflammatory markers at the time of diagnosis in predicting the disease activity in treatment-naïve multiple sclerosis (MS) patients exposed to dimethyl fumarate (DMF).Methods:In total, 48 RRMS patients (31 females/17 males) treated with DMF after the diagnosis were included in this 2-year longitudinal study. All patients underwent a CSF examination, regular clinical and 3T magnetic resonance imaging (MRI) scans that included the assessment of white matter (WM) lesions, cortical lesions (CLs) and global cortical thickness. CSF levels of 10 pro-inflammatory markers – CXCL13 [chemokine (C-X-C motif) ligand 13 or B lymphocyte chemoattractant], CXCL12 (stromal cell-derived factor or C-X-C motif chemokine 12), tumour necrosis factor (TNF), APRIL (a proliferation-inducing ligand, or tumour necrosis factor ligand superfamily member 13), LIGHT (tumour necrosis factor ligand superfamily member 14 or tumour necrosis factor superfamily member 14), interferon (IFN) gamma, interleukin 12 (IL-12), osteopontin, sCD163 [soluble-CD163 (cluster of differentiation 163)] and Chitinase3-like1 – were assessed using immune-assay multiplex techniques. The combined three-domain status of ‘no evidence of disease activity’ (NEDA-3) was defined by no relapses, no disability worsening and no MRI activity, including CLs.Results:Twenty patients (42%) reached the NEDA-3 status; patients with disease activity showed higher CSF TNF (p = 0.009), osteopontin (p = 0.005), CXCL12 (p = 0.037), CXCL13 (p = 0.040) and IFN gamma levels (p = 0.019) compared with NEDA-3 patients. After applying a random forest approach, TNF and osteopontin revealed the most important variables associated with the NEDA-3 status. Six molecules that emerged at the random forest approach were added in a multivariate regression model with demographic, clinical and MRI measures of WM and grey matter damage as independent variables. TNF levels confirmed to be associated with the absence of disease activity: odds ratio (OR) = 0.25, CI% = 0.04–0.77.Conclusion:CSF inflammatory markers may provide prognostic information in predicting disease activity in the first years after DMF initiation. CSF TNF levels are a possible candidate in predicting treatment response, in addition to clinical, demographic and MRI variables.

Early first-line treatment response and subsequent disability worsening in relapsing-remitting multiple sclerosis.

Treatment success in relapsing-remitting multiple sclerosis (RRMS) is generally determined using relapse frequency and magnetic resonance imaging (MRI) activity in the first 6 or 12months on treatment. The association of these definitions of short-term treatment success with disability worsening and disease activity in the longer term is unclear. In this study, we investigated risk factors associated with early first-line treatment failure in RRMS, and the association of early treatment failure with subsequent disability worsening or "no evidence of disease activity" (NEDA-3) status. We used data from CombiRx (clinicaltrials.gov identifier NCT00211887) to investigate risk factors associated with early treatment failure, and the association of early treatment failure at 6 and 12months with subsequent disability worsening or NEDA-3 at 36months. CombiRx included 1008 treatment-naïve participants with RRMS, who were randomly assigned to treatment with glatiramer acetate, interferon beta, or the combination of both. Early treatment failure at 6 or 12months by several definitions was associated with NEDA-3 failure at 36months, but not with subsequent disability worsening at 36months. Expanded Disability Status Scale (EDSS) was the only baseline characteristic associated with the risk of disability worsening at 36months. Approximately 70% of NEDA-3 failures occurred due to MRI activity, and <10% occurred due to EDSS worsening. Our investigation shows that current definitions of early treatment failure in RRMS are unrelated to patient-relevant disability worsening at 36months of follow-up. Further research into useful definitions of treatment success and failure in RRMS is needed.

Impact of comorbid post traumatic stress disorder on multiple sclerosis in military veterans: A population-based cohort study

Background: Very little is known regarding the impact of post traumatic stress disorder (PTSD) on the course of multiple sclerosis (MS). Objectives: To explore the impact of pre-existing PTSD on MS relapses, magnetic resonance imaging (MRI) activity, and disability in a large population-based cohort. Methods: Military Veterans with MS and PTSD prior to symptom onset (MSPTSD, n = 96) were identified using the Department of Veterans Affairs MS databases. MSPTSD cases were matched to MS controls without PTSD (n = 95). Number of relapses, number of new T2 lesions and new gadolinium lesions on brain MRI, and neurological disability were abstracted between 2015 and 2019. Results: The mean annualized relapse rate was greater in the MSPTSD group versus controls (0.23 vs 0.06, respectively; p < 0.05), as was the annualized mean number of new T2 and gadolinium-enhancing lesions on brain MRI (0.52 vs 0.16 and 0.29 vs 0.08, respectively; p < 0.05). Disability accrual (time to Disability Status Scale 6.0) was more rapid (23.7 vs 29.5 years, p < 0.05) in relapsing MS patients with PTSD. Conclusion: Patients with MSPTSD have higher disease activity and reach disability endpoints more rapidly than controls. This is the first study to show PTSD as a potentially modifiable risk factor for MS relapses, MRI activity, and disability.

Effects of Pregnancy and Breastfeeding on Clinical Outcomes and MRI Measurements of Women with Multiple Sclerosis: An Exploratory Real-World Cohort Study.

IntroductionPregnancy represents an important event for women with multiple sclerosis (MS) and is often accompanied by post-partum disease reactivation. To date, the influence of this reproductive phase on long-term MS outcomes is still largely unexplored. The objective of the study was characterise a large real-world cohort of women with MS to evaluate the effects of pregnancy and breastfeeding on short- and long-term clinical and magnetic resonance imaging (MRI) outcomes while exploring the relationships with MRI measurements of brain atrophy.MethodsMS patients with and without pregnancy were recruited. Clinical relapses and MRI activity of the year before conception versus the year after delivery were evaluated. Regression models were performed to investigate the relationships between long-term MS outcomes (EDSS score and MRI brain measurements obtained by SIENAX software) and pregnancy and breastfeeding duration.ResultsTwo hundred ten women with MS were enrolled; of them, 129 (61.4%) had at least one pregnancy. Of all pregnancies (n = 212), those that occurred after MS onset (90 [42.4%]) were examined to evaluate the short-term outcomes. A higher annualised relapse rate in the post-partum year versus the pre-conception year (0.54 ± 0.84 vs. 0.45 ± 0.71; p = 0.04) was observed. A regression analysis showed that clinical activity after delivery was associated with clinical activity of the year before conception (p = 0.001) as well as duration of breastfeeding (p = 0.022). Similarly, post-partum MRI activity was associated with pre-conception MRI activity (p = 0.026) and shorter breastfeeding duration (p = 0.013). Regarding long-term outcomes, having had at least one pregnancy during MS was associated with a lower EDSS score (p = 0.021), while no relationships were reported with MRI measurements. Conversely, a breastfeeding duration > 6 months was associated with lower white matter volume (p = 0.008).ConclusionsOur study underlines the importance of considering the effects of pregnancy and breastfeeding on short- and long-term MS outcomes. In the current therapeutic landscape, pregnancy planning and treatment optimisation in the post-partum period, in particular for women who choose to breastfeed, are fundamental for the management of these biological phases so central in a woman’s life.

Clinical presentation and course of multiple sclerosis in patients with herpesvirus infection

To date, the features of clinical presentation, course, and the effectiveness of therapy for multiple sclerosis (MS) in the presence of persistent herpesvirus infection (PHVI) remain poorly understood.Objective: to evaluate the features of clinical presentation and course of MS in patients with PHVI to optimize patient management.Patients and methods. We examined 122 patients with a clinically definite diagnosis of MS according to McDonald criteria (2010) (82 women and 40 men, age: 18–50 years, mean age – 37.74±11.04 years). MS duration at the time of examination was from 6 months to 20 years (mean – 8.53±7.47 years), mean Expanded Disability Status Scale (EDSS) score – 2.91±1.67. 86% of patients had relapsing-remitting MS; 14% – secondary progressive MS. 98 (80%) patients received disease modifying therapies (DMTs). All patients underwent a comprehensive clinical and neurological examination, magnetic resonance imaging (MRI). 30 healthy donors (20 women and 10 men, age: 19–62 years, mean age: 39.1±12.1 years) were included in the control group. Serum levels of type-specific IgM and IgG antibodies to herpes simplex virus (HSV) 1, 2, 6, Varicella zoster virus (VVZ), Epstein–Barr virus (EBV), cytomegalovirus (CMV) were detected, in some patients – blood and cerebrospinal fluid (CSF) polymerase chain reaction, serum and CSF oligoclonal IgG.Results and discussion. We identified two sub-groups of MS patients: with PHVI reactivation (main group, n=29) and without it (comparison group, n=93). There were a significantly higher VZV (72%) and EBV infection rate (100%) in MS patients compared to the control group (50% and 83%, respectively). Mixed herpesvirus infection prevailed over mono-infection in MS patients. In contrast to controls, the most common viral pattern in MS group was a combination of 4 herpes viruses: HSV 1, 2 + VZV + EBV + CMV (χ2=3.9; p&lt;0.05). Patients in the main group had an unfavorable disease course: earlier MS onset, predominantly polysymptomatic onset, significantly higher relapse rate, faster disease progression, and higher EDSS and Functional Systems Scale (FSS) scores (p &lt;0.05). MRI activity was also associated with EBV infection: new T1Gd+ and T2 foci were associated with an increase in VCA-IgM to EBV level. We also observed decreased DMTs effectiveness (χ2=4,6; p=0,033) and worse DMTs tolerability (χ2=5,3; p=0,022) in the main group.Conclusion. MS patients with PHVI reactivation, have a more unfavorable course of the demyelinating process and, therefore, a greater degree of disability, compared with age-adjusted patients without a viral infection and the same disease duration.

CD19 Cell Count at Baseline Predicts B Cell Repopulation at 6 and 12 Months in Multiple Sclerosis Patients Treated with Ocrelizumab.

Background: The kinetics of B cell repopulation in MS patients treated with Ocrelizumab is highly variable, suggesting that a fixed dosage and time scheduling might be not optimal. We aimed to investigate whether B cell repopulation kinetics influences clinical and radiological outcomes and whether circulating immune asset at baseline affects B cell repopulation kinetics. Methods: 218 MS patients treated with Ocrelizumab were included. Every six months we collected data on clinical and magnetic resonance imaging (MRI) activity and lymphocyte subsets at baseline. According to B cell counts at six and twelve months, we identified two groups of patients, those with fast repopulation rate (FR) and those with slow repopulation rate (SR). Results: A significant reduction in clinical and radiological activity was found. One hundred fifty-five patients had complete data and received at least three treatment cycles (twelve-month follow-up). After six months, the FR patients were 41/155 (26.45%) and 10/41 (29.27%) remained non-depleted after twelve months. FR patients showed a significantly higher percentage of active MRI scan at twelve months (17.39% vs. 2.53%; p = 0,008). Furthermore, FR patients had a higher baseline B cell count compared to patients with an SR (p = 0.02 and p = 0.002, at the six- and twelve-month follow-ups, respectively). Conclusion: A considerable proportion of MS patients did not achieve a complete CD19 cell depletion and these patients had a higher baseline CD19 cell count. These findings, together with the higher MRI activity found in FR patients, suggest that the Ocrelizumab dosage could be tailored depending on CD19 cell counts at baseline in order to achieve complete disease control in all patients.

Hypothalamic functional MRI activity in the initiation phase of spontaneous and glyceryl trinitrate-induced migraine attacks.

The hypothalamus has been suggested to be important in the initiation cascade of migraine attacks based on clinical and biochemical observations. Previous imaging studies could not disentangle the changes due to the attack and those due to the trigger compound. With a novel approach, we assessed hypothalamic neuronal activity in early premonitory phases of glyceryl‐trinitrate (GTN)‐induced and spontaneous migraine attacks. We measured the hypothalamic blood oxygen level‐dependent (BOLD) response to oral glucose ingestion with 3T‐functional magnetic resonance imaging (MRI) in 27 women, 16 with migraine without aura and 11 controls group matched for age and body mass index (BMI), on 1 day without prior GTN administration and on a second day after GTN administration (to coincide with the premonitory phase of an induced attack). Interestingly, subgroups of patients with and without GTN‐triggered attacks could be compared. Additionally, five migraineurs were investigated in a spontaneous premonitory phase. Linear mixed models were used to study between‐ and within‐group effects. Without prior GTN infusion, the BOLD response to glucose was similar in migraine participants and controls (P = .41). After prior GTN infusion, recovery occurred steeper and faster in migraineurs (versus Day 1; P < .0001) and in those who developed an attack versus those who did not (P < .0001). Prior GTN infusion did not alter the glucose‐induced response in controls (versus baseline; P = .71). Just before spontaneous attacks, the BOLD‐response recovery was also faster (P < .0001). In this study, we found new and direct evidence of altered hypothalamic neuronal function in the immediate preclinical phase of both GTN‐provoked and spontaneous migraine attacks.

Long-Term Effectiveness of Fingolimod for Multiple Sclerosis in a Real-World Clinical Setting

Introduction: The primary aim of the present study was to evaluate the long-term efficacy of fingolimod in patients with multiple sclerosis (MS); secondary aims were to describe the safety of fingolimod with the evaluation of treatment satisfaction and impact on the quality of life in real life. Methods: We collected clinical, demographical, neuroradiological, and treatment data, including pre- and posttreatment status health-related quality of life from 286 MS patients consecutively treated with fingolimod. Clinical assessment was based on the Expanded Disability Status Scale (EDSS), and quality of life assessment was performed with MS-related quality of life inventory (MSQOLI). The data were recorded at baseline and every 6 months for 2 years. Results: One hundred and fourteen males and 172 females were enrolled. The annualized relapse rate and EDSS showed a statistically significant reduction during the observation period (p < 0.001). The patients also demonstrated substantial improvements in magnetic resonance imaging (MRI) outcomes (p < 0.001). Health-related quality of life scores improved significantly between baseline and 24-month visit (p < 0.001). No serious adverse events occurred. Conclusion: In our cohort, fingolimod treatment was associated with reduced relapse, MRI activity, and improved EDSS and MSQOLI scores. Additionally, fingolimod has been able to maintain its effectiveness over a considerable long period of treatment.