Smouldering multiple sclerosis: the ‘real MS’ Giovannoni, Gavin; Popescu, Veronica; Wuerfel, Jens ...
Therapeutic Advances in Neurological Disorders,
01/2022, Volume:
15
Book Review, Journal Article
Peer reviewed
Open access
Using a philosophical approach or deductive reasoning, we challenge the dominant clinico-radiological worldview that defines multiple sclerosis (MS) as a focal inflammatory disease of the central ...nervous system (CNS). We provide a range of evidence to argue that the ‘real MS’ is in fact driven primarily by a smouldering pathological disease process. In natural history studies and clinical trials, relapses and focal activity revealed by magnetic resonance imaging (MRI) in MS patients on placebo or on disease-modifying therapies (DMTs) were found to be poor predictors of long-term disease evolution and were dissociated from disability outcomes. In addition, the progressive accumulation of disability in MS can occur independently of relapse activity from early in the disease course. This scenario is underpinned by a more diffuse smouldering pathological process that may affect the entire CNS. Many putative pathological drivers of smouldering MS can be potentially modified by specific therapeutic strategies, an approach that may have major implications for the management of MS patients. We hypothesise that therapeutically targeting a state of ‘no evident inflammatory disease activity’ (NEIDA) cannot sufficiently prevent disability accumulation in MS, meaning that treatment should also focus on other brain and spinal cord pathological processes contributing to the slow loss of neurological function. This should also be complemented with a holistic approach to the management of other systemic disease processes that have been shown to worsen MS outcomes.
Background:
Patients with multiple sclerosis (MS) frequently reveal social behavior disturbance. Nevertheless, little is known regarding the impact of MS on social cognition, particularly theory of ...mind (ToM), and its neural basis.
Objectives:
To explore how ToM is affected in MS and its neural correlates.
Methods:
Enrolled 60 consecutive MS patients and 60 healthy controls (HC) matched on age, sex, and education. Participants underwent ToM testing (Eyes Test, Videos Test) and 3 T brain magnetic resonance imaging (MRI). Using Freesurfer software, cortical and subcortical gray matter (GM) volumes were calculated.
Results:
MS patients performed worse on Eyes Test (58.7% ± 13.8% vs 81.9% ± 10.4%, p < 0.001) and Videos Test (75.3% ± 9.3% vs 88.1% ± 7.1%, p < 0.001). Eyes Test performance in MS was positively correlated with the volume of subcortical structures (amygdala, putamen) and cortical regions (entorhinal cortex, fusiform gyrus, superior temporal gyrus, superior parietal gyrus, supramarginal gyrus, medial orbitofrontal cortex, anterior and posterior cingulate gyrus). In regression analysis, amygdala volume was the single predictor of performance (R2 change = 0.064, p = 0.031), and a mediation analysis indicated that it contributes for the differences observed between MS and HC.
Conclusion:
Patients with MS have impairment on social cognition. Amygdala atrophy was the main predictor probably due to its central position within the “social brain” network.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Up to two thirds of patients with multiple sclerosis (MS) under natalizumab report a resurgence of symptoms at the end of the natalizumab cycle (wearing-off (WO) effect). At the outbreak of COVID-19, ...in line with the international recommendations for MS management, our centre switched all clinically stable patients on natalizumab therapy for more than one year from standard interval dosing (SID) to extended interval dosing (EID) with every six weeks infusions. This study aimed to evaluate the impact of EID in WO in MS patients under natalizumab.
An observational retrospective study in patients with MS under natalizumab on EID was conducted. A questionnaire regarding current (on EID) and past (on SID) experience of WO effect was applied.
Seventy-six patients were included. No significant differences were found in the annual relapse rate after the switch to EID (p = 0.083). However, there was a significant increase in the proportion of patients complaining of WO from 38.2% to 56.6% (p = 0.001). Moreover, patients with WO on SID, referred a significant increase in severity (p = 0.019) and duration of WO symptoms (p = 0.029), due to an anticipation of the symptoms relative to the day of natalizumab infusion (p = 0.019), when switching to EID. Symptoms improved with treatment maintenance in 23.3% of patients; instead, a reduction in interval dosing was needed in 54.8% with symptom improvement.
WO affects a significant proportion of MS patients under natalizumab. Its prevalence, severity, and duration increase on EID, therefore despite clinical effectiveness maintenance of this posology should be individualized.
•Wearing-off is prevalent among multiple sclerosis patients under natalizumab.•Wearing-off prevalence, severity and duration increase on natalizumab extended interval dosing.•Switching natalizumab from standard to extended interval dosing should be an individualized decision.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
OBJECTIVE:To assess the contribution of microstructural normal-appearing white matter (NAWM) damage to social cognition impairment, specifically in the theory of mind (ToM), in multiple sclerosis ...(MS).
METHODS:We enrolled consecutively 60 patients with MS and 60 healthy controls (HC) matched on age, sex, and education level. All participants underwent ToM testing (Eyes Test, Videos Test) and 3T brain MRI including conventional and diffusion tensor imaging sequences. Tract-based spatial statistics (TBSS) were applied for whole-brain voxel-wise analysis of fractional anisotropy (FA) and mean diffusivity (MD) on NAWM.
RESULTS:Patients with MS performed worse on both tasks of ToM compared to HC (Eyes Test 58.7 ± 13.8 vs 81.9 ± 10.4, p < 0.001, Hedges g −1.886; Videos Test 75.3 ± 9.3 vs 88.1 ± 7.1, p < 0.001, Hedges g −1.537). Performance on ToM tests was correlated with higher values of FA and lower values of MD across widespread white matter tracts. The largest effects (≥90% of voxels with statistical significance) for the Eyes Test were body and genu of corpus callosum, fornix, tapetum, uncinate fasciculus, and left inferior cerebellar peduncle, and for the Videos Test genu and splenium of corpus callosum, fornix, uncinate fasciculus, left tapetum, and right superior fronto-occipital fasciculus.
CONCLUSIONS:These results indicate that a diffuse pattern of NAWM damage in MS contributes to social cognition impairment in the ToM domain, probably due to a mechanism of disconnection within the social brain network. Gray matter pathology is also expected to have an important role; thus further research is required to clarify the neural basis of social cognition impairment in MS.
Abstract
Objectives
To investigate the relationship of executive functions (EF) and theory of mind (ToM) in multiple sclerosis (MS), clarifing whether ToM impairment in MS is related to EF ...dysfunction or whether they represent dissociable processes which can be independently impaired in MS.
Methods
We enrolled 60 consecutive MS patients and 60 healthy controls (HC) matched on age, gender, and education level. All participants underwent ToM testing using the Eyes Test and the Videos Test and neuropsychological testing tapping different EF subdomains. A correlation analysis and a hierarchical cluster analysis were used to determine the similarity between explained variance between EF measures and ToM tests.
Results
MS patients had lower scores on both tasks of ToM compared to HC, i.e., Eyes Test (21.1 ± 5.0 vs. 29.5 ± 3.8, p < .001; Cohen’s d: 1.9) and Videos Test (19.6 ± 2.4 vs. 22.9 ± 1.8, p < .001; Cohen’s d: 1.6). They also performed significantly worse on different measures of EF. ToM performance was not significantly correlated with EF tests. The hierarchical cluster analysis showed that ToM measures in MS were clustered separately from the EF measures, revealing three executive clusters (Attention/working memory cluster; Inhibitory control/shifting ability cluster; Verbal Initiative/Abstract reasoning cluster) and one ToM cluster.
Conclusion
This study suggests a dissociation of EF and ToM in MS, meaning that the MS-related neurobehavioral symptoms may be associated with a significant impairment in ToM independent of the level of EF performance. Ultimately, this discrimination of ToM deficits in MS may help to identify the appropriate cognitive and behavioral interventions.
Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system in young adults, representing the leading cause of ...nontraumatic disability in this population. The rising prevalence of MS worldwide makes it critical to recognize the absolute number of patients with MS, demanding the execution of a sustainable healthcare policy. In Portugal, only six studies evaluating MS rates were published, disclosing a prevalence of 64 cases per 100,000 persons and an incidence of 3.1 cases per 100,000 persons/year, but the mortality rates have not been reported. Thus, this observational, cross-sectional study aimed to assess MS prevalence, incidence, and mortality in the city of Coimbra, a region in the center of Portugal. Patients who fulfilled McDonald's Diagnosis Criteria (2017) for MS were recruited. Inclusion criteria were defined according to prevalence, incidence, and mortality studies. The baseline demographic and clinical characterization of the prevalence study population was performed. The MS prevalence rate in Coimbra was 143.45 cases per 100,000 inhabitants. Between 2018 and 2021, the cumulative incidence was 8.52 new cases per 100,000 persons/year. The mortality rate between 2018 and 2021 was 2.84 deaths per 100,000 inhabitants. MS prevalence and incidence in Coimbra are higher than reported in previous similar studies and comparable to Europe's mean prevalence and incidence.
Background
Human herpesvirus 2 (HSV-2) is a major cause of sexually transmitted infections (STIs) worldwide and often occurs synergistically with syphilis, and human immunodeficiency virus (HIV) ...infection. Transgender women (TGW) are disproportionately affected by STIs. The aim of this study was to estimate the prevalence of HSV-2 monoinfection, and HSV-2, syphilis, and HIV coinfection (triple infection) among TGW in Central Brazil.
Methods
A seroprevalence survey was conducted among TGW in Central Brazil from 2018 to 2019. Participants were recruited using respondent-driven sampling and interviewed about their sociodemographic characteristics and STI risk behaviors, and were tested for antibodies to HSV-2,
Treponema pallidum
, and HIV. Multivariable logistic regression models were used to identify variables associated with HSV-2 monoinfection and triple infection.
Results
Of the 431 participants, 345 (80%) were positive for HSV-2 antibodies, of whom 36 were HSV-2 immunoglobulin M–positive, and 340 were HSV-2 immunoglobulin G–positive. Human herpesvirus 2 and HIV coinfection, HIV and syphilis coinfection, and triple infection were detected in 38 participants (9.0%), 58 participants (13.8%), and 27 participants (6.4%), respectively. Report of a previous STI was associated with a decreased risk of HSV-2 monoinfection (adjusted odds ratio, 0.39), and an increased risk of triple infection (adjusted odds ratio, 4.4). Participants who reported sex not only with men had a 2.42-fold increased risk of triple infection.
Conclusions
The high prevalence of HSV-2, syphilis, and HIV coinfection among TGW is a cause for concern. Transgender women should be screened for HIV and other STIs. Further studies of risk factors for triple infection among TGW are warranted.
Background
Fingolimod is an oral daily treatment for relapsing remitting multiple sclerosis (RRMS). A decrease in lymphocytes count is a common side effect, whereby clinicians occasionally propose a ...reduced dose rather than its discontinuation. However, current data on the effectiveness of these regimens are scarce and contradictory. Our objective was to investigate if the fingolimod effectiveness is maintained with reduction in dosing frequency.
Methods
Retrospective and observational study of RRMS patients taking fingolimod-nondaily (FTY-ND) for at least 6 months. Propensity score–based matching was performed to select patients taking daily dose (FTY-ED) with comparable baseline characteristics: age, sex, disease duration, annualized relapse rate (ARR), and expanded disability status scale (EDSS). Afterwards, clinical and laboratorial assessment was evaluated in both groups.
Results
Thirty-six patients were included in each group (FTY-ED vs. FTY-ND). Decrease in lymphocytes count was the main reason for switching to FTY-ND (88.9%). Previous treatment with natalizumab was inversely associated with risk of reducing dose (OR 0.253, 95%CI = 0.08–0.807,
p
= 0.016). There were no significant differences in clinical disease activity between patients FTY-ED vs. FTY-ND: mean ARR 0.4 vs. 0.3 (
p
= 0.247), median EDSS 2.0 vs. 2.0 (
p
= 0.687), and proportion of patients with EDSS increase 8.3% vs. 13.9% (
p
= 0.453). FTY-ND was overall well tolerated and was associated with an increase in the mean lymphocytes count (362 ± 103 cells/mm
3
to 541 ± 183 cells/mm
3
,
p
< 0.001).
Conclusion
These data suggest that the effectiveness of FTY is maintained despite the reduction of the dose, minimizing the most common adverse events. These findings warrant further confirmation, ideally with randomized clinical trials.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Reconstructing EEG sources involves a complex pipeline, with the inverse problem being the most challenging. Multiple inversion algorithms are being continuously developed, aiming to tackle the ...non-uniqueness of this problem, which has been shown to be partially circumvented by including prior information in the inverse models. Despite a few efforts, there are still current and persistent controversies regarding the inversion algorithm of choice and the optimal set of spatial priors to be included in the inversion models. The use of simultaneous EEG-fMRI data is one approach to tackle this problem. The spatial resolution of fMRI makes fMRI derived spatial priors very convenient for EEG reconstruction, however, only task activation maps and resting-state networks (RSNs) have been explored so far, overlooking the recent, but already accepted, notion that brain networks exhibit dynamic functional connectivity fluctuations. The lack of a systematic comparison between different source reconstruction algorithms, considering potentially more brain-informative priors such as fMRI, motivates the search for better reconstruction models. Using simultaneous EEG-fMRI data, here we compared four different inversion algorithms (minimum norm, MN; low resolution electromagnetic tomography, LORETA; empirical Bayes beamformer, EBB; and multiple sparse priors, MSP) under a Bayesian framework (as implemented in SPM), each with three different sets of priors consisting of: (1) those specific to the algorithm; (2) those specific to the algorithm plus fMRI task activation maps and RSNs; and (3) those specific to the algorithm plus fMRI task activation maps and RSNs and network modules of task-related dFC states estimated from the dFC fluctuations. The quality of the reconstructed EEG sources was quantified in terms of model-based metrics, namely the expectation of the posterior probability
P
(model|data) and variance explained of the inversion models, and the overlap/proportion of brain regions known to be involved in the visual perception tasks that the participants were submitted to, and RSN templates, with/within EEG source components. Model-based metrics suggested that model parsimony is preferred, with the combination MSP and priors specific to this algorithm exhibiting the best performance. However, optimal overlap/proportion values were found using EBB and priors specific to this algorithm and fMRI task activation maps and RSNs or MSP and considering all the priors (algorithm priors, fMRI task activation maps and RSNs and dFC state modules), respectively, indicating that fMRI spatial priors, including dFC state modules, might contain useful information to recover EEG source components reflecting neuronal activity of interest. Our main results show that providing fMRI spatial derived priors that reflect the dynamics of the brain might be useful to map neuronal activity more accurately from EEG-fMRI. Furthermore, this work paves the way towards a more informative selection of the optimal EEG source reconstruction approach, which may be critical in future studies.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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