ABSTRACT
BACKGROUND: AQP4-antibody seropositive (AQP4-Ab+) neuromyelitis optica spectrum disorder (NMOSD) may cause reduced work capability due to disability. Here, we evaluated the socioeconomic status of patients with AQP4-Ab+NMOSD in off-label therapy era compared with the general population. METHODS: A longitudinal nationwide population-based study including all Danish patients with AQP4-Ab+NMOSD and matched controls from the general population. The cohort was linked to other Danish nationwide population-based databases. The study period was from 1992 to 2021. The main outcomes were loss of income from salary, limited work capability, disability pension and civil status. The longitudinal risks of outcomes were presented in cumulative incidence curves. Fisher's exact test, χ2 test or Wilcoxon test were applied for comparison. RESULTS: We included 65 patients with a median follow-up of 8.6 years. Annual income declined significantly after disease onset (index year) compared with the general population. One year after the index year, the median annual income in 2015-indexed Euro for patients averaged 13 285 (IQR: 139 to 36 336) versus controls 33 035 (IQR: 6870 to 45 978); p=0.04. Five years postindex year, the average income for patients further dropped to 276 (IQR: 0 to 23 691) versus controls 22 141 (IQR: 0 to 42 986); p=0.03. At the end of follow-up, significantly higher proportion of patients were either in 'flexjob' (36.9% patients vs 14% controls, p<0.00) or receiving disability pension (16.9% patients vs 4.3% controls, p<0.00). CONCLUSIONS: The socioeconomic status of patients with AQP4-Ab+NMOSD deteriorates rapidly following disease onset. A substantial proportion of these patients lose their work capacity leading to increased financial burden on both their families and society.
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BACKGROUND: Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein not previously described in the human central nervous system (CNS). OBJECTIVES: We determined MFAP4 CNS expression and measured cerebrospinal fluid (CSF) and serum levels. METHODS: Tissue was sampled at autopsy from patients with acute multiple sclerosis (MS) (n = 3), progressive MS (n = 3), neuromyelitis optica spectrum disorder (NMOSD) (n = 2), and controls (n = 9), including 6 healthy controls (HC). MFAP4 levels were measured in 152 patients: 49 MS, 62 NMOSD, 22 myelin oligodendrocyte glycoprotein-associated disease (MOGAD), and 19 isolated optic neuritis (ION). RESULTS: MFAP4 localized to meninges and vascular/perivascular spaces, intense in the optic nerve. At sites of active inflammation, MFAP4 reactivity was reduced in NMOSD and acute MS and less in progressive MS. CSF MFAP4 levels were reduced during relapse and at the onset of diseases (mean U/mL: MS 14.3, MOGAD 9.7, and ION 14.6 relative to HC 17.9. (p = 0.013, p = 0.000, and p = 0.019, respectively). Patients with acute ON (n = 68) had reduced CSF MFAP4 (mean U/mL: 14.5, p = 0.006). CSF MFAP4 levels correlated negatively with relapse severity (rho = -0.41, p = 0.017). CONCLUSION: MFAP4 immunoreactivity was reduced at sites of active inflammation. CSF levels of MFAP4 were reduced following relapse and may reflect disease activity.
Subject(s)
Multiple Sclerosis, Chronic Progressive , Multiple Sclerosis , Neuromyelitis Optica , Humans , Myelin-Oligodendrocyte Glycoprotein , Neuromyelitis Optica/cerebrospinal fluid , Central Nervous System , Inflammation , Autoantibodies , Aquaporin 4/cerebrospinal fluid , Carrier Proteins , Glycoproteins , Extracellular Matrix ProteinsABSTRACT
INTRODUCTION: Medical treatments for trigeminal neuralgia secondary to multiple sclerosis have low efficacy and tolerability and scientific evidence regarding efficacy of neurosurgery is scarce. We aimed to assess neurosurgical outcome and complications in trigeminal neuralgia secondary to multiple sclerosis. METHODS: Patients with trigeminal neuralgia secondary to multiple sclerosis who underwent microvascular decompression, glycerol rhizolysis or balloon compression were prospectively and consecutively included from 2012 to 2019. Preoperatively, we systematically obtained clinical characteristics and performed a 3.0 Tesla MRI. Follow-up at three, six and 12 months was performed by independent assessors. RESULTS: We included 18 patients. Of the seven patients treated with microvascular decompression, two patients (29%) had an excellent outcome (both had neurovascular contact with morphological changes), three patients (43%) had a good outcome, one patient (14%) had treatment failure and one patient (14%) had a fatal outcome. Three patients (43%) had major complications. Of 11 patients treated with percutaneous procedures, seven patients (64%) had an excellent or good outcome with major complications in three patients (27%). CONCLUSION: Percutaneous procedures provided acceptable outcome and complication rates and should be offered to the majority of patients with trigeminal neuralgia secondary to multiple sclerosis who need surgery. Microvascular decompression is less effective and has a higher complication rate in trigeminal neuralgia secondary to multiple sclerosis compared to microvascular decompression in classical and idiopathic trigeminal neuralgia. Microvascular decompression should only be considered in patients with trigeminal neuralgia secondary to multiple sclerosis when they have neurovascular contact with morphological changes.
Subject(s)
Microvascular Decompression Surgery , Multiple Sclerosis , Trigeminal Neuralgia , Humans , Trigeminal Neuralgia/diagnostic imaging , Trigeminal Neuralgia/etiology , Trigeminal Neuralgia/surgery , Prospective Studies , Multiple Sclerosis/complications , Microvascular Decompression Surgery/methods , Magnetic Resonance Imaging , Treatment OutcomeABSTRACT
BACKGROUND: While damage to the optic nerve following optic neuritis (ON) is readily quantifiable, the evaluation of prognosis for visual function and neuroaxonal loss in the acute ON is challenging. OBJECTIVE: The objective of this study is to investigate the value of multifocal visual evoked potential (mfVEP) in acute ON, diagnostically for acute ON and prognostically for visual outcome and subsequent ganglion cell/inner plexiform layer thickness (GCLIPLt). METHODS: A prospective cohort study of mfVEP and full-field visual evoked potential (ffVEP) in acute, unilateral ON (onset < 31 days) was conducted. Comparisons with healthy controls (n = 30) and association analysis with follow-up optical coherence tomography (OCT) measurements (of the GCLIPLt) and visual function (Sloan low-contrast visual acuity (LCVA)) were conducted. RESULTS: Seventy-nine ON patients were included (mean: 17 days from onset). Excluding measurements with conduction block, ffVEP (n = 54) and mfVEP (n = 44) showed sensitivities of 89% and 84% to a specificity of 97%. 65/79 patients were re-examined (mean: 200 days follow-up). mfVEP amplitude and latency inter-eye asymmetry in acute ON correlated with GCLIPLt (r = 0.587 and Spearman's ρ = 0.597, for both, p < 0.001). mfVEP amplitude correlated with LCVA inter-eye asymmetry at follow-up (r = 0.421, p < 0.001), mfVEP latency did not. CONCLUSION: mfVEP may support the prognostic evaluation of acute ON patients and prove valuable in future neuroprotective and remyelinating trials. In acute ON, the increase in diagnostic value of mfVEP to ffVEP may be limited due to widespread conduction block.
Subject(s)
Evoked Potentials, Visual , Optic Neuritis , Humans , Optic Neuritis/diagnosis , Prospective Studies , Retina , Tomography, Optical CoherenceABSTRACT
BACKGROUND: Diagnosis of multiple sclerosis (MS) may sometimes be ascertained at the time of optic neuritis (ON) but other times require the advent of new disease activity. OBJECTIVES: The aim of this study was to examine the predictive value of optical coherence tomography (OCT) and visual evoked potential (VEP) measurements of the non-symptomatic, fellow eye of ON patients, for conversion to MS. METHODS: This is a prospective cohort study in patients with acute ON. OCT thickness measurements of peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell layer-inner plexiform layer (GCLIPL), and multifocal (mf) VEP and full-field (ff) VEP, were performed. Univariate and multivariate Cox regression examined the value of predictors for the conversion to MS. RESULTS: A total of 79 unilateral, acute ON patients, with no MS diagnosis or prior demyelination, were included. Of which, 28 patients developed MS during follow-up. Inferonasal GCLIPL, mean GCLIPL, and pRNFL thickness significantly predicted MS development in multivariate analysis (hazard ratio (HR) = 0.922-0.939, p = 0.0172-0.021). MfVEP mean latency (HR = 1.052, p = 0.006) only predicted MS conversion in univariate analysis. No significant predictive value was shown for the other parameters (p > 0.2). CONCLUSION: While both mfVEP and OCT are useful tools in the evaluation of acute ON patients, only OCT measurements of fellow eyes may serve as an independent predictor of MS development.
Subject(s)
Multiple Sclerosis , Optic Neuritis , Evoked Potentials, Visual , Humans , Multiple Sclerosis/diagnostic imaging , Optic Neuritis/diagnostic imaging , Prospective Studies , Tomography, Optical CoherenceABSTRACT
OBJECTIVE: To investigate clinical outcomes in a real-world setting in the complete population-based cohort of alemtuzumab-treated MS patients in Denmark. METHODS: Data were retrieved from The Danish Multiple Sclerosis Registry between 2009 and 2019. Demographic and disease-specific patient parameters related to treatment history, efficacy, and safety outcomes were assessed at baseline and during follow-up visits. RESULTS: A total of 209 patients (78% female) started treatment with alemtuzumab during the study period with 3.1 ± 1.4 years follow-up. After 2 years, 75% of patients were relapse-free compared to 48% the year before alemtuzumab (p < 0.001). The annual number of relapses was reduced by 69% in year 4 compared with the year prior alemtuzumab. More active disease before alemtuzumab increased the annual hazard rate for relapse (HR: 2.88, p < 0.001). The Expanded Disability Status Scale (EDSS) score remained stable or improved in 81% of patients after 2 years. The need for an additional treatment course was associated with higher number of relapses in the year before alemtuzumab (odds ratio (OR) = 1.95, p = 0.001). CONCLUSION: In a country with primarily escalation strategy, relapse rate reduction was maintained for 5 years, and EDSS stabilized/improved in majority of patients. Higher relapse rate 1 year before alemtuzumab increased the odds for additional courses. Novel serious AEs were not observed.
Subject(s)
Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Alemtuzumab/therapeutic use , Denmark , Female , Humans , Male , Multiple Sclerosis/drug therapy , RegistriesABSTRACT
INTRODUCTION: A demyelinating plaque and neurovascular contact with morphological changes have both been suggested to contribute to the etiology of trigeminal neuralgia secondary to multiple sclerosis (TN-MS). The aim of this study was to confirm or refute whether neurovascular contact with morphological changes is involved in the etiology of TN-MS. METHODS: We prospectively enrolled consecutive TN-MS patients from the Danish Headache Center. Clinical characteristics were collected systematically. MRI scans were done using a 3.0 Tesla imager and were evaluated by the same experienced blinded neuroradiologist. RESULTS: Sixty-three patients were included. Fifty-four patients were included in the MRI analysis. There was a low prevalence of neurovascular contact with morphological changes on both the symptomatic side (6 (14%)) and the asymptomatic side (4 (9%)), p = 0.157. Demyelinating brainstem plaques along the trigeminal afferents were more prevalent on the symptomatic side compared to the asymptomatic side (31 (58%) vs. 12 (22%), p < 0.001). A demyelinating plaque was highly associated with the symptomatic side (odds ratio = 10.6, p = 0.002). CONCLUSION: The primary cause of TN-MS is demyelination along the intrapontine trigeminal afferents. As opposed to classical trigeminal neuralgia, neurovascular contact does not play a role in the etiology of TN-MS. Microvascular decompression should generally not be offered to patients with TN-MS.The study was registered at ClinicalTrials.gov (number NCT04371575).
Subject(s)
Microvascular Decompression Surgery/methods , Multiple Sclerosis/complications , Trigeminal Nerve/diagnostic imaging , Trigeminal Neuralgia/surgery , Denmark , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Multiple Sclerosis/diagnostic imaging , Prospective Studies , Treatment Outcome , Trigeminal Neuralgia/complications , Trigeminal Neuralgia/diagnostic imagingABSTRACT
BACKGROUND: The pattern-reversal visual evoked potential (pVEP) is widely used for the diagnosis of Optic Neuritis (ON), but this method has some limitations. The aim of this study was to examine the added value of multifocal visual evoked potentials (mfVEP) and spectral-domain optical coherence tomography (SD-OCT) in the diagnosis of ON in patients that exhibit a normal pVEP. METHOD: Thirty-three patients with a history of having ON and 30 sex- and age-matched healthy controls (HC) were investigated. We included patients who were suspected of having a first-time ON and in whom pVEP showed normal results. Both eyes of the patients and HC were systematically investigated with SD-OCT, visual acuity, pVEP and mfVEP. The ON-affected eyes of the patients were compared with only one randomly selected eye per person in the HC group. The fellow "non-affected" eye of patients was held as a separate group. Statistical analyses were performed (including t test, Spearman's rank-order correlation test) using SPSS Statistics, Version 24.0. RESULTS: A significant difference was found in OCT mean retinal nerve fibre layer thickness (RNFLt) between patients and HC (p = 0.013) (i.e. 84.24 (± 17.00) µm versus 93.48(± 6.44) µm). An association was detected in patients between mean inter-eye asymmetry of the RNFLt and global (averaged) mfVEP amplitude (r = 0.565, p = 0.002). When analysing mfVEP signals from sectors in the upper hemifield, a significant difference was found in mean mfVEP amplitude between patients and HC (p = 0.005). CONCLUSIONS: Abnormality is potentially measurable (via reduced RNFLt and focal analyses with mfVEP amplitude) in patients suspected of having a first episode of ON where pVEP reports no abnormality. The mfVEP and SD-OCT may together be of value as supplementary tools in diagnosing ON in this patient group.
Subject(s)
Evoked Potentials, Visual/physiology , Optic Neuritis/physiopathology , Visual Pathways/physiology , Adult , Electroretinography , Female , Humans , Male , Middle Aged , Retinal Ganglion Cells , Tomography, Optical Coherence/methods , Visual AcuityABSTRACT
BACKGROUND: The Aulhorn flicker test (AFT) previously showed promise in diagnosing acute optic neuritis (ON) albeit with suboptimal sensitivity. A new, digitalized version of the AFT (the DFT) has not previously been examined in acute ON. OBJECTIVES: To examine the sensitivity, specificity and reproducibility of the DFT in acute ON. METHOD: The DFT assesses the subjective brightness of a flickering field (1-60 Hz). In normal subjects, brightness enhancement occurs at intermediate frequencies, whereas in acute ON darkness enhancement (DE) is hypothesized. AFT and DFT measurements were obtained in acute ON patients (≤31 days from first symptom) with DE as a quantitative covariate. Reproducibility of the DFT end point was assessed in the form of an intraclass correlation. RESULTS: 30 untreated first-time acute ON patients and 55 healthy controls were examined. AFT and DFT were performed 12.7 days (range: 4-30) following ON onset. The DFT showed a sensitivity of 0.93 (95% CI = 0.78-0.99) to a specificity of 0.96 (95% CI = 0.87-1.00). The AFT showed a sensitivity of 0.76 (95% CI = 0.56-0.90) to a specificity of 1.00 (95% CI = 0.93-1.00). No significant correlation was shown between DFT and visual acuity. The intraclass correlation of the DFT end point in healthy subjects was 0.84. CONCLUSIONS: We present a new DFT in acute ON displaying a high specificity of 0.96 and a sensitivity of 0.93. Our study indicates the DFT to be an accurate and easy-to-use tool in diagnosing acute ON, which may be especially helpful in atypical cases.
Subject(s)
Optic Neuritis/diagnosis , Vision Tests/methods , Visual Acuity , Acute Disease , Adult , Female , Humans , Male , Photic Stimulation , Prospective Studies , ROC Curve , Reproducibility of ResultsABSTRACT
Mouse models of multiple sclerosis (MS) have shown the importance of interleukin-10 (IL-10) -producing regulatory B (Breg) cells in dampening disease activity and inhibiting disease initiation and progression. In MS and other autoimmune diseases decreased frequency and functionality of Breg cells correlate with disease activity and the percentage of IL-10-producing Breg cells decreases during relapse and normalizes in remission. Optic neuritis (ON) is a common first clinical manifestation of MS and IL-10-producing Breg cells may be crucial in the transition from ON to MS, we therefore investigate the frequency and function of Breg cells in ON as a clinical model of early demyelinating disease. B cells were purified from 27 patients with ON sampled close to symptom onset (median 23 days, range 7-41 days) and 13 healthy controls. The B cells were stimulated and cultured for 48 hr with CD40 ligand and CpG before measurement of intracellular IL-10 and the surface markers CD19, CD1d, CD5, CD24, CD38 and CD27 by flow cytometry. The frequency of B-cell subsets was analysed in peripheral blood and cerebral spinal fluid (CSF) of patients. Sixty-five per cent of the IL-10-producing Breg cells co-expressed CD24 and CD38, and only 14% were CD24high CD27+ , suggesting that the naive B cells are the primary source of IL-10 in the B-cell culture, followed by memory cells in both healthy controls and patients. The frequency of naive CD19+ CD24+ CD38+ Breg cells was higher in patients with ON compared with controls. The ability of Breg cells to produce IL-10 was at normal levels in both ON patients with high risk and those with low risk of progression to MS. We found no correlation between Breg cell function and the presence of brain white matter lesions by magnetic resonance imaging or CSF oligoclonal bands indicative of ON patients carrying a higher risk of conversion to MS. The frequencies of IL-10-producing B cells did not correlate with the conversion to MS at 2-year follow up. Interleukin-10 was primarily produced by naive and memory B cells. The frequency of IL-10-secreting B cells did not correlate with risk factors of MS. Breg cell function at clinical onset of ON is not a determining factor for conversion to MS.
Subject(s)
B-Lymphocytes, Regulatory/immunology , Interleukin-10/immunology , Optic Neuritis/immunology , Adult , Autoimmune Diseases/metabolism , Female , Humans , Immunophenotyping/methods , Male , Multiple Sclerosis/immunologyABSTRACT
OBJECTIVE: To investigate whether blood-brain barrier (BBB) permeability, as measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), can provide early detection of suboptimal treatment response in relapsing-remitting multiple sclerosis (RRMS). METHODS: Thirty-five RRMS patients starting on fingolimod or natalizumab, drugs with a common effect of decreasing lymphocyte influx into the central nervous system, were scanned with DCE-MRI at 3T prior to treatment and at 3 and 6 months posttreatment. We calculated the influx constant Ki , a measure of BBB permeability, using the Patlak model. Suboptimal treatment response was defined as loss of no evidence of disease activity (NEDA) status after 2 years of treatment. RESULTS: Subjects with loss of NEDA status at 2 years had a 51% higher mean Ki in normal-appearing white matter (NAWM) measured after 6 months of treatment, compared to subjects with maintained NEDA status (mean difference = 0.06ml/100g/min, 95% confidence interval [CI] = 0.02-0.09, p = 0.002). Ki in NAWM at 6 months was a good predictor of loss of NEDA status at 2 years (area under the curve = 0.84, 95% CI = 0.70-0.99, p = 0.003), and a value above 0.136ml/100/g/min yielded an odds ratio of 12.4 for suboptimal treatment response at 2 years, with a sensitivity of 73% and a specificity of 82%. INTERPRETATION: Our results suggest that BBB permeability as measured by DCE-MRI reliably predicts suboptimal treatment response and is a surrogate marker of the state of health of the BBB. We find a predictive threshold for disease activity, which is remarkably identical in clinically isolated syndrome as previously reported and established RRMS as investigated here. Ann Neurol 2018;83:902-914.
Subject(s)
Blood-Brain Barrier/drug effects , Fingolimod Hydrochloride/therapeutic use , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Natalizumab/therapeutic use , Permeability/drug effects , Adult , Blood-Brain Barrier/pathology , Female , Humans , Magnetic Resonance Imaging/methods , Male , Middle Aged , White Matter/pathologyABSTRACT
About 30-40% of stroke patients suffer from visual field defects following injury. These can interfere with the standard neuropsychological assessment and complicate the interpretation of tests that use visual materials. However, information about the integrity of a patient's central visual field is often unavailable. We, therefore, designed a screening tool, the computerized visual field test (c-VFT), specifically targeted at providing easily available, but rough, information about patients' central visual field. c-VFT was tested in two samples of stroke patients. Eleven patients were tested on c-VFT and on the Esterman test. Five patients were tested on c-VFT and the Humphrey Visual Field Analyzer (HFA), central 10-2. Criterion validity of the c-VFT was investigated by calculating quadrantwise intraclass correlation for both comparisons. For the HFA comparison, we also calculated point-to-point intraclass correlation, sensitivity, and specificity. Analyses revealed moderately good correspondence between c-VFT and the Esterman test, and between c-VFT and HFA 10-2, respectively. When looking specifically at test points within one degree of visual angle apart in the two tests, intraclass correlation increased. For these points, the sensitivity of c-VFT was 0.89 and specificity was 0.97. While the c-VFT is not designed to be diagnostic nor to replace the detailed visual field analysis, this study shows that it provides a reasonable screening of the central visual field. The test can easily be used and will be made freely available to neuropsychological clinicians and researchers.
Subject(s)
Hemianopsia/diagnosis , Stroke/complications , Visual Field Tests/methods , Visual Fields/physiology , Hemianopsia/etiology , Humans , Male , Middle Aged , Neuropsychological Tests , Sensitivity and SpecificityABSTRACT
BACKGROUND AND PURPOSE: In vivoidentification of white matter lesions plays a key-role in evaluation of patients with multiple sclerosis (MS). Automated lesion segmentation methods have been developed to substitute manual outlining, but evidence of their performance in multi-center investigations is lacking. In this work, five research-domain automated segmentation methods were evaluated using a multi-center MS dataset. METHODS: 70 MS patients (median EDSS of 2.0 [range 0.0-6.5]) were included from a six-center dataset of the MAGNIMS Study Group (www.magnims.eu) which included 2D FLAIR and 3D T1 images with manual lesion segmentation as a reference. Automated lesion segmentations were produced using five algorithms: Cascade; Lesion Segmentation Toolbox (LST) with both the Lesion growth algorithm (LGA) and the Lesion prediction algorithm (LPA); Lesion-Topology preserving Anatomical Segmentation (Lesion-TOADS); and k-Nearest Neighbor with Tissue Type Priors (kNN-TTP). Main software parameters were optimized using a training set (N = 18), and formal testing was performed on the remaining patients (N = 52). To evaluate volumetric agreement with the reference segmentations, intraclass correlation coefficient (ICC) as well as mean difference in lesion volumes between the automated and reference segmentations were calculated. The Similarity Index (SI), False Positive (FP) volumes and False Negative (FN) volumes were used to examine spatial agreement. All analyses were repeated using a leave-one-center-out design to exclude the center of interest from the training phase to evaluate the performance of the method on 'unseen' center. RESULTS: Compared to the reference mean lesion volume (4.85 ± 7.29 mL), the methods displayed a mean difference of 1.60 ± 4.83 (Cascade), 2.31 ± 7.66 (LGA), 0.44 ± 4.68 (LPA), 1.76 ± 4.17 (Lesion-TOADS) and -1.39 ± 4.10 mL (kNN-TTP). The ICCs were 0.755, 0.713, 0.851, 0.806 and 0.723, respectively. Spatial agreement with reference segmentations was higher for LPA (SI = 0.37 ± 0.23), Lesion-TOADS (SI = 0.35 ± 0.18) and kNN-TTP (SI = 0.44 ± 0.14) than for Cascade (SI = 0.26 ± 0.17) or LGA (SI = 0.31 ± 0.23). All methods showed highly similar results when used on data from a center not used in software parameter optimization. CONCLUSION: The performance of the methods in this multi-center MS dataset was moderate, but appeared to be robust even with new datasets from centers not included in training the automated methods.
Subject(s)
Image Interpretation, Computer-Assisted/methods , Multiple Sclerosis/diagnostic imaging , White Matter/diagnostic imaging , Adult , Female , Humans , Magnetic Resonance Imaging/methods , Male , Multiple Sclerosis/pathology , White Matter/pathologyABSTRACT
BACKGROUND: Inflammatory cytokines produced by cells of the immune system are believed to play a central role in the pathogenesis of multiple sclerosis (MS). Innate lymphoid cells (ILCs) have been shown to produce and secrete a wide range of the cytokines involved in MS pathogenesis; however, a possible implication of ILCs in MS development and disease progression has not been investigated. OBJECTIVE: With this study, we aimed to clarify a potential role of ILCs in the early stages of MS. METHODS AND RESULTS: Using flow cytometry, we analysed the prevalence and phenotype of ILCs in the cerebrospinal fluid (CSF) of patients experiencing their first or second demyelinating event. We found a substantial increase in both frequency and number of ILCs, in particular the LTi subset, as compared to healthy controls. We also found an association between CSF pleocytosis and an increased frequency of LTi cells in the CSF, suggesting a favoured recruitment of blood derived LTi cells. CONCLUSION: Our data suggests a role for ILCs, and in particular the LTi subset, in the early stages of MS. This finding represents an important contribution to the understanding of early inflammation in MS, and adds new knowledge beneficial for future MS therapies.
Subject(s)
Immunity, Innate , Multiple Sclerosis/cerebrospinal fluid , Multiple Sclerosis/immunology , T-Lymphocytes, Helper-Inducer/immunology , Adolescent , Adult , Case-Control Studies , Cerebrospinal Fluid/cytology , Cerebrospinal Fluid/immunology , Disease Progression , Female , Flow Cytometry , Humans , Immunophenotyping/methods , Leukocyte Count , Male , Middle Aged , Multiple Sclerosis/diagnosis , Phenotype , Young AdultABSTRACT
Optic neuritis is an acute inflammatory condition that is highly associated with multiple sclerosis. Currently, the best predictor of future development of multiple sclerosis is the number of T2 lesions visualized by magnetic resonance imaging. Previous research has found abnormalities in the permeability of the blood-brain barrier in normal-appearing white matter of patients with multiple sclerosis and here, for the first time, we present a study on the capability of blood-brain barrier permeability in predicting conversion from optic neuritis to multiple sclerosis and a direct comparison with cerebrospinal fluid markers of inflammation, cellular trafficking and blood-brain barrier breakdown. To this end, we applied dynamic contrast-enhanced magnetic resonance imaging at 3 T to measure blood-brain barrier permeability in 39 patients with monosymptomatic optic neuritis, all referred for imaging as part of the diagnostic work-up at time of diagnosis. Eighteen healthy controls were included for comparison. Patients had magnetic resonance imaging and lumbar puncture performed within 4 weeks of onset of optic neuritis. Information on multiple sclerosis conversion was acquired from hospital records 2 years after optic neuritis onset. Logistic regression analysis showed that baseline permeability in normal-appearing white matter significantly improved prediction of multiple sclerosis conversion (according to the 2010 revised McDonald diagnostic criteria) within 2 years compared to T2 lesion count alone. There was no correlation between permeability and T2 lesion count. An increase in permeability in normal-appearing white matter of 0.1 ml/100 g/min increased the risk of multiple sclerosis 8.5 times whereas having more than nine T2 lesions increased the risk 52.6 times. Receiver operating characteristic curve analysis of permeability in normal-appearing white matter gave a cut-off of 0.13 ml/100 g/min, which predicted conversion to multiple sclerosis with a sensitivity of 88% and specificity of 72%. We found a significant correlation between permeability and the leucocyte count in cerebrospinal fluid as well as levels of CXCL10 and MMP9 in the cerebrospinal fluid. These findings suggest that blood-brain barrier permeability, as measured by magnetic resonance imaging, may provide novel pathological information as a marker of neuroinflammation related to multiple sclerosis, to some extent reflecting cellular permeability of the blood-brain barrier, whereas T2 lesion count may more reflect the length of the subclinical pre-relapse phase.See Naismith and Cross (doi:10.1093/brain/awv196) for a scientific commentary on this article.
Subject(s)
Blood-Brain Barrier/physiopathology , Capillary Permeability/physiology , Multiple Sclerosis/diagnosis , Multiple Sclerosis/physiopathology , Optic Neuritis/physiopathology , Adolescent , Adult , Brain/pathology , Chemokines/metabolism , Female , Humans , Immunoglobulin G/cerebrospinal fluid , Magnetic Resonance Imaging , Male , Middle Aged , Multiple Sclerosis/cerebrospinal fluid , Oligoclonal Bands/cerebrospinal fluid , Optic Neuritis/cerebrospinal fluid , Predictive Value of Tests , ROC Curve , Risk Factors , Statistics, Nonparametric , Young AdultABSTRACT
BACKGROUND: Leber's hereditary optic neuropathy (LHON) and a multiple sclerosis (MS)-like illness appear to coexist 50 times more frequently than would be expected by chance. This association of LHON and MS (LMS) raises an important question about whether there could be a common pathophysiological mechanism involving mitochondrial dysfunction. OBJECTIVE: The primary aim was to define MRI features of LMS and LHON, and to assess the proportions of individuals displaying features typical of MS. Secondarily, we investigated the effect of gender on the risk of developing white matter lesions in the context of LHON. METHODS: A blinded standardised review of conventional brain MRIs of 30 patients with MS, 31 patients with LHON and 11 patients with LMS was conducted by three independent experts in the field. MS-like MRI features were assessed. RESULTS: All patients with LMS and 26% of patients with LHON had white matter lesions. Of these, all patients with LMS and 25% with LHON were found to have an MRI appearance typical of MS. Female patients with LHON had a significantly greater risk of having white matter lesions consistent with MS compared with male patients (relative risk 8.3). CONCLUSIONS: A blinded review of conventional brain MRIs shows that patients with LMS have a scan appearance indistinguishable from MS. Mitochondrial dysfunction could be a common pathophysiological pathway in the formation of white matter lesions. There appears to be a strong female influence on the radiological appearance as well as clinical development of MS in patients with LHON.
Subject(s)
Multiple Sclerosis, Relapsing-Remitting/pathology , Optic Atrophy, Hereditary, Leber/pathology , White Matter/pathology , Adult , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/complications , Neuroimaging , Optic Atrophy, Hereditary, Leber/complications , Sex Factors , Single-Blind Method , Young AdultABSTRACT
PURPOSE: The R2* relaxation rate constant has been suggested as a sensitive measure for iron accumulation. The aim of this multi-center study was to assess the inter-scanner and inter-subject variability of R2* mapping and to investigate the relationship between brain volume and R2* in specific structures. METHODS: R2* mapping was performed in 81 healthy subjects in seven centers using different 3 T systems. R2* was calculated from a dual-echo gradient echo sequence and was assessed in several deep gray matter structures. The inter-scanner and inter-subject variability of R2* was calculated by means of the coefficient of variation before and after correcting for age. RESULTS: Significant center effects were seen in some regions which get lost after age correction. The coefficient of variation for the inter-center variability was much lower (<5.6%) than for the intra-subject variability (6.7%-11.7%). R2* in the putamen and red nucleus scaled with cortical volume while R2* in the globus pallidus and the substantia nigra was negatively associated with white matter volume. CONCLUSION: R2* is a robust and reproducible measure in a multicenter setting provided that a standardized MRI protocol is used. The relationship between iron concentration in deep gray matter and volume of specific brain compartments needs further investigation.
Subject(s)
Brain/anatomy & histology , Gray Matter/anatomy & histology , Image Interpretation, Computer-Assisted/methods , Imaging, Three-Dimensional/methods , Magnetic Resonance Imaging/methods , White Matter/anatomy & histology , Adolescent , Adult , Europe , Female , Humans , Male , Middle Aged , Organ Size , Reference Values , Reproducibility of Results , Sensitivity and Specificity , Young AdultABSTRACT
BACKGROUND: Iron accumulation in deep grey matter (GM) structures is a consistent finding in multiple sclerosis (MS) patients. This study focused on the identification of independent determinants of iron accumulation using R2* mapping. SUBJECTS AND METHODS: Ninety-seven MS patients and 81 healthy controls were included in this multicentre study. R2* mapping was performed on 3T MRI systems. R2*in deep GM was corrected for age and was related to disease duration, disability, T2 lesion load and brain volume. RESULTS: Compared to controls, R2* was increased in all deep GM regions of MS patients except the globus pallidus and the substantia nigra. R2* increase was most pronounced in the progressive stage of the disease and independently predicted by disease duration and disability. Reduced cortical volume was not associated with iron accumulation in the deep GM with the exception of the substantia nigra and the red nucleus. In lesions, R2* was inversely correlated with disease duration and higher total lesion load. CONCLUSION: Iron accumulation in deep GM of MS patients is most strongly and independently associated with duration and severity of the disease. Additional associations between cortical GM atrophy and deep GM iron accumulation appear to exist in a region specific manner.
Subject(s)
Brain/metabolism , Gray Matter/metabolism , Iron/analysis , Multiple Sclerosis/metabolism , Adult , Brain/pathology , Female , Gray Matter/pathology , Humans , Image Interpretation, Computer-Assisted , Male , Middle Aged , Multiple Sclerosis/pathology , Young AdultABSTRACT
BACKGROUND: Studies on the capability of cerebrospinal fluid neurofilament light chain (cNfL) to predict multiple sclerosis (MS) conversion in clinically isolated syndromes have yielded varying results. OBJECTIVES: To expand our understanding of cNfL in optic neuritis (ON) and investigate whether incorporating cNfL into the 2017 McDonald criteria could accelerate the diagnosis of MS in patients with ON. METHODS: cNfL was measured in diagnostic samples from 74 patients with verified ON. MS was diagnosed using the 2017 McDonald criteria with a minimum observation time of two years from ON onset. RESULTS: 20.5% of 44 MS-converters did not fulfil the 2017 McDonald criteria at ON onset. A doubling of cNfL was associated with 207% (74%-514%) higher odds of MS (p = 0.00042, adjusted for age). Fulfilment of ≥ 1 MRI criterion for dissemination in space (DIS) and presence of brain contrast-enhancing lesions were associated with higher cNfL. Furthermore, cNfL correlated with inter-eye differences in retinal nerve fiber layer (RNFL) thickness (Spearman's ρ = 0.46, p = 8 × 10-5). Incorporating cNfL ≥ 906 pg/mL as a substitute for either dissemination in time or one MRI criterion for DIS increased the sensitivity (90.9% vs. 79.6%) and accuracy (91.9% vs. 87.8%), but also reduced the specificity (93.3% vs. 100%) of the 2017 McDonald criteria. CONCLUSION: cNfL was related to MS diagnostic parameters and the degree of RNFL swelling. Clinical use of cNfL may aid in identification of ON patients with increased risk of MS until larger studies have elaborated on the potential loss of specificity if used diagnostically.
ABSTRACT
Cerebral oxygen metabolism is altered in relapsing-remitting multiple sclerosis (RRMS), possibly a result of disease related cerebral atrophy with subsequent decreased oxygen demand. However, MS inflammation can also inhibit brain metabolism. Therefore, we measured cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) using MRI phase contrast mapping and susceptibility-based oximetry in 44 patients with early RRMS and 36 healthy controls. Cerebral atrophy and white matter lesion load were assessed from high-resolution structural MRI. Expanded Disability Status Scale (EDSS) scores were collected from medical records. The CMRO2 was significantly lower in patients (-15%, p = 0.002) and decreased significantly with age in patients relative to the controls (-1.35 µmol/100 g/min/year, p = 0.036). The lower CMRO2 in RRMS was primarily driven by a higher venous oxygen saturation in the sagittal sinus (p = 0.007) and not a reduction in CBF (p = 0.69). There was no difference in cerebral atrophy between the groups, and no correlation between CMRO2 and MS lesion volume or EDSS score. Therefore, the progressive CMRO2 decline observed before the occurrence of significant cerebral atrophy and despite adequate CBF supports emerging evidence of dysfunctional cellular respiration as a potential pathogenic mechanism and therapeutic target in RRMS.