Background:
Neuroretinal atrophy is associated with whole-brain atrophy and disease activity in multiple sclerosis (MS). Recent findings support that subclinical visual pathway involvement might also ...occur in neuromyelitis optica spectrum disorders (NMOSDs).
Objective:
The objective of this study is to assess retinal thinning in MS and NMOSD and its association with disease activity.
Methods:
In total, 27 NMOSD and 54 propensity-score-matched MS patients underwent optical coherence tomography, visual acuity, and visual-evoked potentials at 2.4 years apart, in addition to routine clinical and magnetic resonance imaging (MRI) assessment. We excluded eyes with acute optic neuritis.
Results:
In NMOSD, we detected peripapillary retinal nerve fiber layer (pRNFL) thinning in patients with disease activity during follow-up (−0.494 µm/year), but not in stable patients (−0.012 µm/year). Macular ganglion cell-inner plexiform layer (GCIPL) thinning occurred instead in all patients (−0.279 µm/year). Relapsing–remitting multiple sclerosis (RRMS) meeting NEDA-3 criteria had no pRNFL or GCIPL thinning during follow-up. Active-disease RRMS and progressive MS, both active and stable, displayed pRNFL (−0.724, −0.586, −0.556 µm/year, respectively) and GCIPL loss.
Conclusion:
In MS, neuroretinal atrophy was associated with disease activity but occurred in progressive MS even when achieving NEDA-3 criteria. In NMOSD, pRNFL thinning was associated with non-ocular relapses due to a spreading of inflammatory activity. GCIPL thinning was found in all patients, supporting a primary retinal pathology targeting AQP4-rich structures.
Objective:
To investigate resting state (RS) functional connectivity (FC) abnormalities within the principal brain networks in a large cohort of multiple sclerosis (MS) patients, to define the ...trajectory of FC changes over disease stages and their relation with clinical and structural magnetic resonance imaging (MRI) measures.
Methods:
RS functional magnetic resonance imaging (fMRI), clinical, and neuropsychological evaluation were obtained from 215 MS patients and 98 healthy controls. Connectivity abnormalities and correlations with clinical/neuropsychological/imaging measures were evaluated. We analyzed seed-voxel FC with seven major hubs, producing one visual/sensory, one motor, two cognitive, one cerebellar, and two subcortical networks.
Results:
MS patients showed reduced network average RS FC versus controls in the default-mode network. At regional level, a complex pattern of decreased and increased RS FC was found. Reduced RS FC mainly involved sensorimotor, cognitive, thalamic, and cerebellar networks, whereas increased RS FC involved visual/sensory and subcortical networks. Reduced RS FC correlated with T2 lesions. Reduced thalamic RS FC correlated with better neuropsychological performance, whereas for all remaining networks reduced FC correlated with more severe clinical/cognitive impairment.
Conclusion:
Increased and decreased RS FC occurs in MS and contributes to a wide spectrum of clinical manifestations. RS FC reduction is related to T2 lesions. Such a paradigm is inverted for the thalamic network.
Objective
Astrocytes outline the perivascular space (PVS) and regulate fluid exchange through the aquaporin‐4 water channel. As neuromyelitis optica is an autoimmune astrocytopathy targeting ...aquaporin‐4, we hypothesized that it could be associatied with PVS abnormalities.
Methods
A total of 34 patients, and 46 age‐ and sex‐matched healthy controls from two independent cohorts (exploratory and validation dataset) underwent a standardized 3.0‐T magnetic resonance imaging protocol including conventional and diffusion tensor imaging. Susceptibility‐weighted imaging was also acquired in the exploratory dataset. We evaluated macroscopic and microstructural abnormalities of PVS in terms of enlargement and water diffusivity (DTI‐ALPS index). In the exploration dataset, a susceptibility‐weighted sequence was used to draw the regions of interest for the DTI‐ALPS index calculation in areas having veins perpendicular to lateral ventricles. Between‐group comparisons, correlations, and regression models were run to assess associations between PVS abnormalities, and clinical and magnetic resonance imaging variables.
Results
Patients had a higher frequency of severe PVS enlargement in the centrum semiovale (29.4% vs 8.7%), which correlated with brain atrophy, deep grey matter atrophy, and poorer cognitive performance (r‐values range: −0.44, −0.36; p values: 0.01–0.046).
In both datasets, patients had reduced DTI‐ALPS index compared with controls (p values 0.004–0.038). Lower DTI‐ALPS index, deep gray matter volume, and cortical volume could discriminate between patients and controls (R2 = 0.62), whereas lower DTI‐ALPS index, higher number of myelitis, and higher T2‐lesion volume were associated with worse disability (R2 = 0.55).
Interpretation
Patients with neuromyelitis optica spectrum disorder are characterized by abnormal enlargement and impaired water diffusion along the PVS, whose clinical implications suggest a direct correlation with disease pathogenesis and severity. ANN NEUROL 2022;92:173–183
Objectives
In multiple sclerosis (MS), magnetic resonance imaging (MRI) is a sensitive tool for detecting white matter lesions, but its diagnostic specificity is still suboptimal; ambiguous cases are ...frequent in clinical practice. Detection of perivenular lesions in the brain (the “central vein sign”) improves the pathological specificity of MS diagnosis, but comprehensive evaluation of this MRI biomarker in MS‐mimicking inflammatory and/or autoimmune diseases, such as central nervous system (CNS) inflammatory vasculopathies, is lacking. In a multicenter study, we assessed the frequency of perivenular lesions in MS versus systemic autoimmune diseases with CNS involvement and primary angiitis of the CNS (PACNS).
Methods
In 31 patients with inflammatory CNS vasculopathies and 52 with relapsing–remitting MS, 3‐dimensional T2*‐weighted and T2–fluid‐attenuated inversion recovery images were obtained during a single MRI acquisition after gadolinium injection. For each lesion, the central vein sign was evaluated according to consensus guidelines. For each patient, lesion count, volume, and brain location, as well as fulfillment of dissemination in space MRI criteria, were assessed.
Results
MS showed higher frequency of perivenular lesions (median = 88%) than did inflammatory CNS vasculopathies (14%), without overlap between groups or differences between 3T and 1.5T MRI. Among inflammatory vasculopathies, Behçet disease showed the highest median frequency of perivenular lesions (34%), followed by PACNS (14%), antiphospholipid syndromes (12%), Sjögren syndrome (11%), and systemic lupus erythematosus (0%). When a threshold of 50% perivenular lesions was applied, central vein sign discriminated MS from inflammatory vasculopathies with a diagnostic accuracy of 100%.
Interpretation
The central vein sign differentiates inflammatory CNS vasculopathies from MS at standard clinical magnetic field strengths. Ann Neurol 2018;83:283–294
Background:
The precuneus is involved in cognition and depression; static functional connectivity (SFC) abnormalities of this region have been observed in neuromyelitis optica spectrum disorders ...(NMOSD). Time-varying functional connectivity (TVC) underpins dynamic variations of brain connectivity.
Objective:
The aim of this study was to explore precuneus SFC and TVC in NMOSD patients and their associations with neuropsychological features.
Methods:
This retrospective study includes 27 NMOSD patients and 30 matched healthy controls undergoing resting state functional magnetic resonance imaging (MRI) and a neuropsychological evaluation of cognitive performance and depressive symptoms. A sliding-window correlation analysis using bilateral precuneus as seed region assessed TVC, which was quantified by the standard deviation of connectivity across windows. Mean connectivity indicated SFC.
Results:
Compared to controls, patients had reduced SFC between precuneus, temporal lobe, putamen and cerebellum, and reduced TVC between precuneus and prefronto-parietal-temporo-occipital cortices and caudate. Patients also had increased intra-precuneal TVC and increased TVC between the precuneus and the temporal cortex. More severe depressive symptoms correlated with increased TVC between the precuneus and the temporal lobe; worse cognitive performance mainly correlated with higher TVC between the precuneus and the parietal lobe.
Conclusion:
TVC rather than SFC of the precuneus correlates with NMOSD neuropsychological features; different TVC abnormalities underlie depressive symptoms and cognitive impairment.
Objectives
To validate imaging features able to discriminate neuromyelitis optica spectrum disorders from multiple sclerosis with conventional magnetic resonance imaging (MRI).
Methods
In this ...cross‐sectional study, brain and spinal cord scans were evaluated from 116 neuromyelitis optica spectrum disorder patients (98 seropositive and 18 seronegative) in chronic disease phase and 65 age‐, sex‐, and disease duration–matched multiple sclerosis patients. To identify independent predictors of neuromyelitis optica diagnosis, after assessing the prevalence of typical/atypical findings, the original cohort was 2:1 randomized in a training sample (where a multivariate logistic regression analysis was run) and a validation sample (where the performance of the selected variables was tested and validated).
Results
Typical brain lesions occurred in 50.9% of neuromyelitis optica patients (18.1% brainstem periventricular/periaqueductal, 32.7% periependymal along lateral ventricles, 3.4% large hemispheric, 6.0% diencephalic, 4.3% corticospinal tract), 72.2% had spinal cord lesions (46.3% long transverse myelitis, 36.1% short transverse myelitis), 37.1% satisfied 2010 McDonald criteria, and none had cortical lesions. Fulfillment of at least 2 of 5 of absence of juxtacortical/cortical lesions, absence of periventricular lesions, absence of Dawson fingers, presence of long transverse myelitis, and presence of periependymal lesions along lateral ventricles discriminated neuromyelitis optica patients in both training (sensitivity = 0.92, 95% confidence interval CI = 0.84–0.97; specificity = 0.91, 95% CI = 0.78–0.97) and validation samples (sensitivity = 0.82, 95% CI = 0.66–0.92; specificity = 0.91, 95% CI = 0.71–0.99). MRI findings and criteria performance were similar irrespective of serostatus.
Interpretation
Although up to 50% of neuromyelitis optica patients have no typical lesions and a relatively high percentage of them satisfy multiple sclerosis criteria, several easily applicable imaging features can help to distinguish neuromyelitis optica from multiple sclerosis. ANN NEUROL 2019;85:371–384.
Objective:
Microvesicles (MVs) have been indicated as important mediators of intercellular communication and are emerging as new biomarkers of tissue damage. Our previous data indicate that reactive ...microglia/macrophages release MVs in vitro. The aim of the study was to evaluate whether MVs are released by microglia/macrophages in vivo and whether their number varies in brain inflammatory conditions, such as multiple sclerosis (MS).
Methods:
Electron and fluorescence microscopy and flow cytometry were used to detect myeloid MVs in the cerebrospinal fluid (CSF) of healthy controls, MS patients, and rodents affected by experimental autoimmune encephalomyelitis (EAE), the animal model of MS.
Results:
Myeloid MVs were detected in CSF of healthy controls. In relapsing and remitting EAE mice, the concentration of myeloid MVs in the CSF was significantly increased and closely associated with disease course. Analysis of MVs in the CSF of 28 relapsing patients and 28 patients with clinical isolated syndrome from 2 independent cohorts revealed higher levels of myeloid MVs than in 13 age‐matched controls, indicating a clinical value of MVs as a companion tool to capture disease activity. Myeloid MVs were found to spread inflammatory signals both in vitro and in vivo at the site of administration; mice impaired in MV shedding were protected from EAE, suggesting a pathogenic role for MVs in the disease. Finally, FTY720, the first approved oral MS drug, significantly reduced the amount of MVs in the CSF of EAE‐treated mice.
Interpretation:
These findings identify myeloid MVs as a marker and therapeutic target of brain inflammation. ANN NEUROL 2012;72:610–624
Background
The significance of neutrophil-to-lymphocyte ratio (NLR) has been explored in different diseases. Few studies addressed its role in patients with multiple sclerosis (MS), with promising ...results regarding its association with disease activity or disability.
Objectives
We aimed at confirming the role of NLR as a marker of neuro-inflammation in a cohort of newly diagnosed MS and clinically isolated syndrome (CIS) patients. Furthermore, we compared the validity of NLR with established markers of neuro-inflammation, such as serum neurofilament light chain (Nfl), CSF microvesicles (CSF-MVs) and CSF IgG indices.
Methods
We retrospectively selected, from a prospectively collected cohort of newly diagnosed MS/CIS patients hospitalized for diagnostic work-up, 121 patients who underwent CSF examination, brain MRI and blood cell count within the time of hospitalization and did not receive steroid treatment before sample collection. Patients were grouped according to presence of gadolinium enhancement at brain MRI.
Results
No association was found between NLR and disease activity, nor with other clinical measures. Nfl, CSF-MVs, Link and Tourtellotte indices were significantly higher in patients with brain MRI activity.
Conclusions
Our negative results do not support the use of NLR as a marker of disease activity and disability in patients with MS.
Background
Early recognition and treatment of autoimmune encephalitis (AE) are crucial for patients, but diagnosis is often difficult and time-consuming. For this purpose, a syndrome-based diagnostic ...approach was published by Graus et al. (Lancet Neurol 15:391–404, 2016), but very little is known in the literature about its application in clinical practice.
Aim
Our aims are to test the feasibility of such approach in a real-world single-centre setting and to analyse the most relevant factors in criteria fulfilment.
Methods
We retrospectively applied these criteria to our cohort of patients discharged from our hospital with diagnosis of autoimmune encephalitis (
n
= 33, 58% antibody-positive).
Results
All the subjects fulfilled criteria for possible AE (pAE), with EEG and MRI playing a central role in diagnosis, while CSF was useful mainly to rule out other conditions. Three patients respected criteria for probable anti-NMDA-R encephalitis (pNMDA). Definite anti-NMDAR encephalitis was diagnosed in 4 patients with detection of the autoantibody but, surprisingly, none of these subjects had fulfilled criteria for pNMDA. 18 patients were diagnosed with definite limbic AE (15 patients were antibody-positive, three antibody-negative). Need for MRI bilateral involvement in antibody-negative limbic AE limited diagnosis. One patient fulfilled criteria for probable antibody-negative AE, while ten patients remained classified as pAE.
Conclusion
From our retrospective analysis, some suggestions for a better definition of the criteria may emerge. Larger studies on prospective cohorts may be more helpful to explore possible important issues.
Background:
According to the cognitive reserve (CR) theory, enriching experiences protect against cognitive decline.
Objectives:
To investigate the dynamic interaction between CR and global/regional ...measures of brain white matter (WM) and gray matter (GM) damage and their effect on cognitive performance in multiple sclerosis (MS).
Methods:
Baseline and 2 -year three-dimensional (3D) T1-weighted scans were obtained from 54 MS patients and 20 healthy controls. Patients’ cognitive functions were tested and a cognitive reserve index (CRI) was calculated. Baseline regional atrophy and longitudinal volume changes were investigated using voxel-wise methods. Structural damage and CRI effects on cognitive performance were explored with linear models.
Results:
At baseline, MS patients showed atrophy of the deep GM nuclei, GM/WM frontal–temporal–parietal–occipital regions, and left cerebellum. Controlling for atrophy, higher CRI explained significant portions of variance in verbal memory and verbal fluency (∆R2 = 0.07–0.16; p < 0.03). The interaction between thalamic volume and CRI was significant (∆R2 = 0.05; p = 0.03). Longitudinal changes in memory and attention performance were associated with local/global variations of GM/WM and T2 lesions. CRI had no effect on longitudinal cognitive changes.
Conclusion:
In MS, CR may have a protective role in preserving cognitive functions, moderating the effect of structural damage on cognitive performance. This protective role may diminish with disease progression.
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