To explore which modifiable lifestyle behaviors contribute to illness intrusiveness in persons with multiple sclerosis (MS).
Cohort study.
Community-based comprehensive MS center.
Adults with MS ...(N=154) who completed an online battery of self-report questionnaires.
Not applicable.
Illness intrusiveness was measured with the 13-item Illness Intrusiveness Ratings Scale. Lifestyle behaviors were measured using the respective components of the Simple Lifestyle Indicator Questionnaire (ie, Diet, Physical Activity, Alcohol, Smoking, and Life Stress) and self-reported body mass index (BMI).
After controlling for age, race, sex, disease duration, and level of physical disability ("disability"), life stress was associated with greater illness intrusiveness (b=4.65, P<.001), and physical activity was associated with less illness intrusiveness (b=-0.67, P=.009). Exploratory mediation analyses revealed physical activity had an indirect effect on illness intrusiveness through disability (b=-0.39, 95% CI: -0.68, -0.16). Conversely, disability also displayed an indirect effect on illness intrusiveness through physical activity (b=0.57, 95% CI: 0.12, 1.16).
Life stress and physical activity are 2 modifiable lifestyle behaviors that contribute to illness intrusiveness, with the latter also having an indirect effect through disability. These findings may help inform future behavioral interventions for improving health-related quality of life in persons with MS.
Role of VEPS and OCT in demyelinating diseases Leocani, Letizia; Guerrieri, Simone; Costa, Gloria Dalla ...
Journal of the neurological sciences,
October 2021, 2021-10-00, Letnik:
429
Journal Article
Spinal cord pathology is a major determinant of irreversible disability in progressive multiple sclerosis. The demyelinated lesion is a cardinal feature. The well-characterised anatomy of the spinal ...cord and new analytic approaches allows the systematic study of lesion topography and its extent of inflammatory activity unveiling new insights into disease pathogenesis. We studied cervical, thoracic, and lumbar spinal cord tissue from 119 pathologically confirmed multiple sclerosis cases. Immunohistochemistry was used to detect demyelination (PLP) and classify lesional inflammatory activity (CD68). Prevalence and distribution of demyelination, staged by lesion activity, was determined and topographical maps were created to identify patterns of lesion prevalence and distribution using mixed models and permutation-based voxelwise analysis. 460 lesions were observed throughout the spinal cord with 76.5% of cases demonstrating at least 1 lesion. The cervical level was preferentially affected by lesions. 58.3% of lesions were inflammatory with 87.9% of cases harbouring at least 1 inflammatory lesion. Topographically, lesions consistently affected the dorsal and lateral columns with relative sparing of subpial areas in a distribution mirroring the vascular network. The presence of spinal cord lesions and the proportion of active lesions related strongly with clinical disease milestones, including time from onset to wheelchair and onset to death. We demonstrate that spinal cord demyelination is common, highly inflammatory, has a predilection for the cervical level, and relates to clinical disability. The topography of lesions in the dorsal and lateral columns and relative sparing of subpial areas points to a role of the vasculature in lesion pathogenesis, suggesting short-range cell infiltration from the blood and signaling molecules circulating in the perivascular space incite lesion development. These findings challenge the notion that end-stage progressive multiple sclerosis is ‘burnt out’ and an outside-in lesional gradient predominates in the spinal cord. Taken together, this study provides support for long-term targeting of inflammatory demyelination in the spinal cord and nominates vascular dysfunction as a potential target for new therapeutic approaches to limit irreversible disability.
The anterior optic pathway is one of the preferential sites of involvement in CNS inflammatory demyelinating diseases, such as multiple sclerosis and neuromyelitis optica, with optic neuritis being a ...common presenting symptom. What is more, optic nerve involvement in these diseases is often subclinical, with optical coherence tomography demonstrating progressive neuroretinal thinning in the absence of optic neuritis. The pathological substrate for these findings is poorly understood and requires investigation. We had access to post-mortem tissue samples of optic nerves, chiasms and tracts from 29 multiple sclerosis (mean age 59.5, range 25-84 years; 73 samples), six neuromyelitis optica spectrum disorders (mean age 56, range 18-84 years; 22 samples), six acute disseminated encephalomyelitis (mean age 25, range 10-39 years; 12 samples) cases and five non-neurological controls (mean age 55.2, range 44-64 years; 16 samples). Formalin-fixed paraffin-embedded samples were immunolabelled for myelin, inflammation (microglial/macrophage, T- and B-cells, complement), acute axonal injury and astrocytes. We assessed the extent and distribution of these markers along the anterior optic pathway for each case in all compartments (i.e. parenchymal, perivascular and meningeal), where relevant. Demyelinated plaques were classified as active based on established criteria. In multiple sclerosis, demyelination was present in 82.8% of cases, of which 75% showed activity. Microglia/macrophage and lymphocyte inflammation were frequently found both in the parenchymal and meningeal compartments in non-demyelinated regions. Acute axonal injury affected 41.4% of cases and correlated with extent of inflammatory activity in each compartment, even in cases that died at advanced age with over 20 years of disease duration. An antero-posterior gradient of anterior optic pathway involvement was observed with optic nerves being most severely affected by inflammation and acute axonal injury compared with the optic tract, where a higher proportion of remyelinated plaques were seen. In neuromyelitis optica spectrum disorder, cases with a history of optic neuritis had extensive demyelination and lost aquaporin-4 reactivity. In contrast, those without prior optic neuritis did not have demyelination but rather diffuse microglial/macrophage, T- and B-lymphocyte inflammation in both parenchymal and meningeal compartments, and acute axonal injury was present in 75% of cases. Acute demyelinating encephalomyelitis featured intense inflammation, and perivenular demyelination in 33% of cases. Our findings suggest that chronic inflammation is frequent and leads to neurodegeneration in multiple sclerosis and neuromyelitis optica, regardless of disease stage. The chronic inflammation and subsequent neurodegeneration occurring along the optic pathway broadens the plaque-centred view of these diseases and partly explains the progressive neuroretinal changes observed in optic coherence tomography studies.
Background: While John Cunningham virus (JCV) is known to cause neuronal damage in progressive multifocal leukoencephalopathy (PML) among natalizumab-treated MS patients, its association with axonal ...loss in non-PML conditions remains unclear. Methods: In a cohort of 128 natalizumab-treated MS patients, serum neurofilament (sNfL) levels and JCV antibody titres were measured. Results: Among 128 patients (mean age = 38.4 years, 71.9% female), 51 (40%) were JCV positive. NfL levels increased by 15.3% for JCV index <0.7 (95% confidence interval CI = 0.963–1.381), by 18.6% for index 0.7–1.5 (95% CI = 1.009–1.394) and by 21.1% for index >1.5 (95% CI = 1.040–1.409) compared to JCV negative patients. Conclusion: These findings indicate a potential link between JCV burden and neuroaxonal degeneration in natalizumab-treated MS patients.
Objective
In vivo measures of myeloid activity are promising biomarkers in multiple sclerosis. We previously demonstrated that cerebrospinal fluid (CSF) myeloid microvesicles are markers of ...microglial/macrophage activity and neuroinflammation in multiple sclerosis. Here, we aimed at investigating the diagnostic and prognostic value of myeloid microvesicles in a clinical setting.
Methods
Six hundred one patients discharged with a diagnosis of neuroinflammatory, neurodegenerative, or no neurological disease were enrolled. Myeloid microvesicles were measured with flow cytometry as isolectin B4–positive events in fresh CSF. Clinical, demographical, and magnetic resonance imaging (MRI) data were collected at diagnosis (all patients) and during follow‐up (n = 176).
Results
CSF myeloid microvesicles were elevated in neuroinflammatory patients compared to the neurodegenerative and control groups. In multiple sclerosis, microvesicles were higher in patients with MRI disease activity and their concentration increased along with the number of enhancing lesions (
p
< 0.0001, Jonckheere–Terpstra test). CSF myeloid microvesicles were also higher in patients with higher disease activity in the month and year preceding diagnosis. Microvesicles excellently discriminated between the relapsing–remitting and control groups (receiver operator characteristic curve, area under the curve = 0.939,
p
< 0.0001) and between radiologically isolated syndrome and unspecific brain lesions (0.942,
p
< 0.0001). Furthermore, microvesicles were independent predictors of prognosis for both the relapsing–remitting and progressive groups. Microvesicles independently predicted future disease activity in relapsing–remitting patients (hazard ratio HR = 1.967, 95% confidence interval CI = 1.147–3.372), correcting for prognostic factors of standard clinical use. In the progressive group, microvesicles were independent predictors of disability accrual (HR = 10.767, 95% CI = 1.335–86.812).
Interpretation
Our results confirm that CSF myeloid microvesicles are a clinically meaningful biomarker of neuroinflammation and microglial/macrophage activity in vivo. These findings may support a possible use in clinical practice during diagnostic workup and prognostic assessment. ANN NEUROL 2021;90:253–265
Objective
To determine the optimal thresholds for intereye differences in retinal nerve fiber and ganglion cell + inner plexiform layer thicknesses for identifying unilateral optic nerve lesions in ...multiple sclerosis. Current international diagnostic criteria for multiple sclerosis do not include the optic nerve as a lesion site despite frequent involvement. Optical coherence tomography detects retinal thinning associated with optic nerve lesions.
Methods
In this multicenter international study at 11 sites, optical coherence tomography was measured for patients and healthy controls as part of the International Multiple Sclerosis Visual System Consortium. High‐ and low‐contrast acuity were also collected in a subset of participants. Presence of an optic nerve lesion for this study was defined as history of acute unilateral optic neuritis.
Results
Among patients (n = 1,530), receiver operating characteristic curve analysis demonstrated an optimal peripapillary retinal nerve fiber layer intereye difference threshold of 5μm and ganglion cell + inner plexiform layer threshold of 4μm for identifying unilateral optic neuritis (n = 477). Greater intereye differences in acuities were associated with greater intereye retinal layer thickness differences (p ≤ 0.001).
Interpretation
Intereye differences of 5μm for retinal nerve fiber layer and 4μm for macular ganglion cell + inner plexiform layer are robust thresholds for identifying unilateral optic nerve lesions. These thresholds may be useful in establishing the presence of asymptomatic and symptomatic optic nerve lesions in multiple sclerosis and could be useful in a new version of the diagnostic criteria. Our findings lend further validation for utilizing the visual system in a multiple sclerosis clinical trial setting. Ann Neurol 2019;85:618–629
Optical coherence tomography (OCT) is gaining increasing relevance in the assessment of patients with multiple sclerosis. Converging evidence point to the view that neuro-retinal changes, in eyes ...without acute optic neuritis, reflect inflammatory and neurodegenerative processes taking place throughout the CNS. The present study aims at exploring the usefulness of OCT as a marker of inflammation and disease burden in the earliest phases of the disease. Thus, a cohort of 150 consecutive patients underwent clinical, neurophysiological and brain MRI assessment as well as lumbar puncture as part of their diagnostic workup for a neurological episode suggestive of inflammatory CNS disorder; among those 32 patients had another previous misdiagnosed episode. For the present study, patients also received a visual pathway assessment (OCT, visual evoked potentials, visual acuity), measurement of CSF inflammatory markers (17 cytokines-chemokines, extracellular vesicles of myeloid origin), and dosage of plasma neurofilaments. Subclinical optic nerve involvement is frequently found in clinically isolated syndromes by visual evoked potentials (19.2%). OCT reveals ganglion cell layer asymmetries in 6.8% of patients; retinal fibre layer asymmetries, despite being more frequent (17.8%), display poor specificity. The presence of subclinical involvement is associated with a greater disease burden. Second, ganglion cell layer thinning reflects the severity of disease involvement even beyond the anterior optic pathway. In fact, the ganglion cell layer in eyes without evidence of subclinical optic involvement is correlated with Expanded Disability Status Scale, low contrast visual acuity, disease duration, brain lesion load, presence of gadolinium enhancing lesions, abnormalities along motor and somatosensory evoked potentials, and frequency of CSF-specific oligoclonal bands. Third, the inner nuclear layer thickens in a post-acute (1.1-3.7 months) phase after a relapse, and this phenomenon is counteracted by steroid treatment. Likewise, a longitudinal analysis on 65 patients shows that this swelling is transient and returns to normal values after 1 year follow-up. Notwithstanding, the clinical, MRI, serological and CSF markers of disease activity considered in the study are strictly associated with one another, but none of them are associated with the inner nuclear layer. Our findings challenge the current hypothesis that the inner nuclear layer is an acute phase marker of inflammatory activity. The present study suggests that instrumental evidence of subclinical optic nerve involvement is associated with a greater disease burden in clinically isolated syndrome. Neuro-retinal changes are present since the earliest phases of the disease and yield important information regarding the neurodegenerative and inflammatory processes occurring in the CNS.
The global tally of neurological disorders is exponentially rising and yet effective therapies for most remain evasive. There is a great deal of research into novel small molecules, immunotherapies ...and gene therapies to fill this therapeutic gap. We believe greater focus on plasma exchange as a research and clinical tool may provide useful insight into pathological mechanisms and effective treatment strategies. Plasma exchange has been traditionally used to treat antibody-mediated neurological diseases, such as myasthenia gravis and neuromyelitis optica, but there could be much wider future potential uses in neurology. Plasma exchange is not antibody specific, as it also removes a variety of other plasma-soluble factors, including age-related and disease-associated neurotoxic proteins, such as fibrinogen and amyloid. As research develops into the role of blood-brain barrier and immunological alterations in diseases not typically regarded as immune-driven, interest in neurotoxic plasma proteins grows. Here, we highlight that plasma exchange may have uses outside of antibody-mediated neurological diseases, by removing neurotoxic proteins from the systemic circulation.
•Systemic inflammation and circulating plasma proteins contribute to the pathogenesis of many neurological diseases•Plasma exchange has focused on autoantibody-mediated diseases, such as neuromyelitis optica and myasthenia gravis•Therapeutic benefit of plasma exchange may go beyond immunoglobulin removal, such as removal of CNS-toxic plasma proteins•Removal of CNS-toxic proteins through plasma exchange could benefit a wider spectrum of neurological diseases•Research into the use of plasma exchange in neurological diseases could unveil novel mechanisms and therapeutic targets
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.