Leptomeningeal inflammation is associated with the development of global cortical gray matter atrophy in multiple sclerosis. However, its association with localized loss of tissue remains unclear. ...The purpose of this study was to evaluate the relationship between leptomeningeal contrast enhancement, a putative marker of leptomeningeal inflammation, and focal cortical thinning in MS.
Forty-three patients with relapsing-remitting MS and 15 with secondary-progressive MS were imaged on a 3T scanner. Cortical reconstruction was performed with FreeSurfer. Leptomeningeal contrast-enhancement foci were visually identified on 3D-FLAIR postcontrast images and confirmed using subtraction imaging. Leptomeningeal contrast-enhancement foci were mapped onto the cortex, and ROIs were obtained by dilating along the surface multiple times (
= 5, 10, 15, 20, 25, 30, 35, 40). Resulting ROIs were then mapped onto the homologous region of the contralateral hemisphere. Paired
tests compared the thickness of the cortex surrounding individual leptomeningeal contrast-enhancement foci and the corresponding contralateral region. Results were corrected for the false discovery rate.
Differences between ipsilateral and contralateral ROIs progressively decreased with larger ROIs, but no significant effects were detected when considering the entire MS sample. In patients with relapsing-remitting MS only, significantly reduced cortical thickness was found for 5 dilations (-8.53%, corrected
= .04) and 10 dilations (-5.20%, corrected
= .044).
Focal leptomeningeal contrast enhancement is associated with reduced thickness of the surrounding cortex in patients with relapsing-remitting MS, but not in those with secondary-progressive MS. Our results suggest that pathology associated with the presence of leptomeningeal contrast-enhancement foci has a stronger, localized effect on cortical tissue loss earlier in the disease.
Immune checkpoint inhibitors (ICIs) have revolutionised cancer therapy but frequently cause immune-related adverse events (irAEs). Description of late-onset and duration of irAEs in the literature is ...often incomplete.
To investigate reporting and incidence of late-onset and long-lasting irAEs, we reviewed all registration trials leading to ICI’s approval by the US FDA and/or EMA up to December 2019. We analysed real-world data from all lung cancer (LC) and melanoma (Mel) patients treated with approved ICIs at the University Hospital of Lausanne (CHUV) from 2011 to 2019. To account for the immortal time bias, we used a time-dependent analysis to assess the potential association between irAEs and overall survival (OS).
Duration of irAEs and proportion of patients with ongoing toxicities at data cut-off were not specified in 56/62 (90%) publications of ICIs registration trials. In our real-world analysis, including 437 patients (217 LC, 220 Mel), 229 (52.4%) experienced at least one grade ≥2 toxicity, for a total of 318 reported irAEs, of which 112 (35.2%) were long-lasting (≥6 months) and about 40% were ongoing at a median follow-up of 369 days 194–695 or patient death. The cumulative probability of irAE onset from treatment initiation was 42.8%, 51.0% and 57.3% at 6, 12 and 24 months, respectively. The rate of ongoing toxicity from the time of first toxicity onset was 42.8%, 38.4% and 35.7% at 6, 12 and 24 months. Time-dependent analysis showed no significant association between the incidence of irAEs and OS in both cohorts (log Rank p = 0.67 and 0.19 for LC and Mel, respectively).
Late-onset and long-lasting irAEs are underreported but common events during ICIs therapy. Time-dependent survival analysis is advocated to assess their impact on OS. Real-world evidence is warranted to fully capture and characterise late-onset and long-lasting irAEs in order to implement appropriate strategies for patient surveillance and follow-up.
•Late-onset and long-lasting irAEs are underreported in immunotherapy clinical trials.•RWD is of paramount importance to complement data from ICI’s clinical trials.•Long-lasting irAEs are common events during ICI’s therapy.•Time-dependent survival analysis is advocated to assess the impact of irAEs on OS.
•Selected studies are heterogeneous in terms of patient characteristics as well as type, duration and frequency of rehabilitative approach.•Neuromotor rehabilitation promotes neuroplasticity, as ...measured with MRI.•Advanced MRI techniques provide reliable markers of structural and functional connectivity that may potentially aid in helping to implement the most appropriate rehabilitation intervention.
Stroke-related disability is a major problem at individual and socio-economic levels. Neuromotor rehabilitation has a key role for its dual action on affected body segment and brain reorganization. Despite its known efficacy in clinical practice, the extent and type of effect at a brain level, mediated by neuroplasticity, are still under question.
To analyze studies applying MRI markers of functional and structural connectivity in patients affected with stroke undergoing motor rehabilitation, and to evaluate the effect of rehabilitation on brain reorganization.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria were applied to select studies applying quantitative non-conventional MRI techniques on patients undergoing motor rehabilitation, both physical and virtual (virtual reality, mental imagery). Literature search was conducted using MEDLINE (via PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), and EMBASE from inception to 30th June 2020.
Forty-one out of 6983 papers were included in the current review. Selected studies are heterogeneous in terms of patient characteristics as well as type, duration and frequency of rehabilitative approach. Neuromotor rehabilitation promotes neuroplasticity, favoring functional recovery of the ipsilesional hemisphere and activation of anatomically and functionally related brain areas in both hemispheres, to compensate for damaged tissue.
The evidence derived from the analyzed studies supports the positive impact of rehabilitation on brain reorganization, despite the high data heterogeneity. Advanced MRI techniques provide reliable markers of structural and functional connectivity that may potentially aid in helping to implement the most appropriate rehabilitation intervention.
Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disorder of the central nervous system, caused by the reactivation of the ubiquitous JC virus. PML usually occurs during ...severe immunosuppression, and the most common causes are represented by human immunodeficiency virus infection, lymphoproliferative disorders and other forms of cancer. Recently, the introduction of monoclonal antibodies (e.g. natalizumab, rituximab, efalizumab) in the treatment of several dysimmune diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis and systemic lupus erythematosus, has led to an increased incidence of PML. This phenomenon has had severe consequences, leading, for example, to the withdrawal from the market of Efalizumab, and important restrictions in the use of the other compounds, all of which are characterized by high efficacy in improving prognosis and quality of life. In this review we will discuss clinical, laboratory and imaging findings of PML. In addition, proposed pathogenetic mechanisms promoting the reactivation of JC virus in the context of treatment with monoclonal antibodies will be described.
Background and purpose
Dimethyl fumarate (DMF) is an oral treatment for relapsing‐remitting multiple sclerosis (MS) with anti‐inflammatory and possible neuroprotective properties. Its effect on white ...matter and gray matter pathology is still not fully understood. The aim of the study was to characterize the effect of DMF on normal‐appearing white matter (NAWM) and thalamic pathology longitudinally.
Methods
In this observational, longitudinal, 24‐month magnetic resonance imaging study, 75 patients with relapsing‐remitting MS treated with DMF and 40 age‐ and sex‐matched healthy individuals were enrolled. Regional diffusion tensor imaging metrics and tract‐based spatial statistics analyses were used to assess differences between groups. Mean diffusivity, axial diffusivity, radial diffusivity and fractional anisotropy were measured in the thalamus and NAWM. Baseline differences and changes over time were evaluated within and between study groups.
Results
At baseline, patients with MS showed significantly increased diffusivity and decreased fractional anisotropy in the thalamus (P < 0.001 for mean diffusivity, axial diffusivity and radial diffusivity) and NAWM (all P < 0.016) compared with healthy individuals. No significant within‐group difference was found in diffusion tensor imaging measures over 24 months in either group. Healthy individuals showed a significantly greater rate of increased diffusivity parameters in the thalamus and NAWM compared with patients with MS, over 24 months (P < 0.05).
Conclusions
The lack of changes in diffusion tensor imaging metrics in patients with MS over 24 months possibly indicates a neuroprotective role of DMF. These findings provide additional evidence of the beneficial effect of DMF on MS‐related pathology.
Background: Several authors have used advanced magnetic resonance imaging (MRI) techniques to investigate whether patients with neuromyelitis optica (NMO) have occult damage in normal-appearing brain ...tissue, similarly to multiple sclerosis (MS). To date, the literature contains no data derived from the combined use of several advanced MRI techniques in the same NMO subjects.
Objective: We set out to determine whether occult damage could be detected in the normal-appearing brain tissue of a small group of patients with NMO using a multiparametric MRI approach.
Methods: Eight female patients affected by NMO (age range 44–58 years) and seven sex- and age-matched healthy controls were included. The techniques used on a 1.5 T MRI imaging scanner were magnetization transfer imaging, diffusion tensor imaging, tract-based spatial statistics, spectroscopy and voxel-based morphometry in order to analyse normal-appearing white matter and normal-appearing grey matter.
Results: Structural and metabolic parameters showed no abnormalities in normal-appearing white matter of patients with NMO. Conversely, tract-based spatial statistics demonstrated a selective alteration of the optic pathways and the lateral geniculate nuclei. Diffusion tensor imaging values in the normal-appearing grey matter were found to be significantly different in the patients with NMO versus the healthy controls. Moreover, voxel-based morphometry analysis demonstrated a significant density and volume reduction of the sensorimotor cortex and the visual cortex.
Conclusions: Our data disclosed occult structural damage in the brain of patients with NMO, predominantly involving regions connected with motor and visual systems. This damage seems to be the direct consequence of transsynaptic degeneration triggered by lesions of the optic nerve and spine.
Artery of Percheron (AOP) stroke is a rare event. We describe an AOP stroke involving both thalami and the midbrain, resulting in a multifunctional clinical impairment. Intensive inpatient ...multidisciplinary rehabilitation favored the recovery of motor deficits, together with the improvement of cognitive dysfunctions. MRI assessment in the chronic post-stroke phase showed structural and functional reorganization in response to the extended thalamic tissue damage and absence of revascularization. Thalamo-cortical networks involving frontal and prefrontal regions, as well as parietal areas were disrupted, whereas increased functional thalamo-occipital connectivity was found. This report sheds light on brain reorganization following AOP stroke after rehabilitation..
Few data are available on adverse events (AE) associated to vaccines in persons with multiple sclerosis (pwMS).
to study the incidence of acute phase AE (AP-AE) related to SARS-CoV-2 mRNA vaccines in ...pwMS compared to a control group, and to analyze the association between AP-AE and disease modifying treatments (DMT).
This was a cross-sectional study on 438 PwMS and 481 age- and sex-matched subjects not affected by dysimmune diseases that underwent two doses of SARS-CoV-2 mRNA BNT162b2 vaccine (Pfizer/BioNtech).
Two hundred and twenty five (51.4%) pwMS complained of ≥1 AP-AE after the first dose, 269 (61.4%) after the second dose. A logistic regression analysis revealed that only pwMS on Fingolimod and Ocrelizumab did not show a higher risk of developing AP-AE. The likelihood to present with ≥1 AP-AE, after correcting for age and sex, was significantly higher in pwMS than controls.
This study reports qualitative and quantitative features of AP-AE associated with the first and second doses of SARS-CoV-2 vaccine in a large sample of pwMS. The only risk factor identified for developing AP-AE is female gender. AntiCD-20 monoclonal antibodies and S1P inhibitors are associated with a lower risk of AP-AE occurrence.
Acute disseminated encephalomyelitis (ADEM) refers to a monophasic acute multifocal inflammatory CNS disease. However, both relapsing and site-restricted variants, possibly associated with peripheral ...nervous system (PNS) involvement, are also observed, and a systematic classification is lacking.
To describe a cohort of postinfectious ADEM patients, to propose a classification based on clinical and instrumental features, and to identify subgroups of patients with different prognostic factors.
Inpatients of a Neurologic and Infectious Disease Clinic affected by postinfectious CNS syndrome consecutively admitted over 5 years were studied.
Of 75 patients enrolled, 60 fulfilled criteria for ADEM after follow-up lasting from 24 months to 7 years. Based on lesion distribution, patients were classified as encephalitis (20%), myelitis (23.3%), encephalomyelitis (13.3%), encephalomyeloradiculoneuritis (26.7%), and myeloradiculoneuritis (16.7%). Thirty patients (50%) had a favorable outcome. Fifteen patients (25%) showed a relapsing course. Poor outcome was related with older age at onset, female gender, elevated CSF proteins, and spinal cord and PNS involvement. All but two patients received high-dose steroids as first-line treatment, with a positive response in 39 (67%). Ten of 19 nonresponders (53%) benefited from high-dose IV immunoglobulin; 9 of 10 had PNS involvement. The data were not controlled.
A high prevalence of "atypical variants" was found in this series, with site-restricted damage or additional peripheral nervous system (PNS) involvement. Prognosis and response to steroids were generally good, except for some patient subgroups. In patients with PNS involvement and steroid failure, a favorable effect of IV immunoglobulin was observed.
Abstract Swallowing problems can be relevant, even if underestimated, in Multiple Sclerosis (MS) patients. However, no specific questionnaire for the assessment of dysphagia in MS is available. We ...built a questionnaire (DYsphagia in MUltiple Sclerosis, DYMUS) that was administered to 226 consecutive MS patients (168 F, 58 M, mean age 40.5 years, mean disease duration 10.1 years, mean EDSS 3.1) during control visits in four Italian MS Centres. DYMUS was abnormal in 80 cases (35%). The patients who claimed to have swallowing problems had a significantly higher mean DYMUS score that the other patients ( p < 0.0001). Mean DYMUS scores were significantly higher in the progressive forms ( p = 0.003). DYMUS values were significantly correlated to EDSS ( p = 0.0007). DYMUS showed a very good internal consistency (Cronbach's alpha 0.877). Factor analysis allowed us to sub-divide DYMUS in two sub-scales, ‘dysphagia for solid’ and ‘dysphagia for liquid’, both of them had a very good internal consistency (Cronbach's alpha 0.852 and 0.870 respectively). DYMUS demonstrated to be an easy and consistent tool to detect dysphagia and its main characteristics in MS. It can be used for preliminary selection of patients to submit to more specific instrumental analyses, and to direct toward programs for prevention of aspiration.
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