Microfibrillar-associated protein 4 as a potential marker of acute relapse in inflammatory demyelinating diseases of the central nervous system: Pathological and clinical aspects.

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.

Efficacy of surgical treatment in patients with trigeminal neuralgia secondary to multiple sclerosis: A prospective study of 18 cases with evaluation of outcome and complications by independent evaluators.

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.

Predictive value of optical coherence tomography, multifocal visual evoked potentials, and full-field visual evoked potentials of the fellow, non-symptomatic eye for subsequent multiple sclerosis development in patients with acute optic neuritis.

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.

Multifocal visual evoked potential evaluation for diagnosis of acute optic neuritis and for prediction of visual outcome and ganglion cell layer thinning following optic neuritis.

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.

Neurovascular contact plays no role in trigeminal neuralgia secondary to multiple sclerosis.

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).

Functional-structural assessment of the optic pathways in patients with optic neuritis.

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.

Sensitive Assessment of Acute Optic Neuritis by a New, Digital Flicker Test.

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.

A free and simple computerized screening test for visual field defects.

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.

Detection of capillary abnormalities in early diabetic retinopathy using scanning laser ophthalmoscopy and optical coherence tomography combined with adaptive optics.

This study tested if a high-resolution, multi-modal, multi-scale retinal imaging instrument can provide novel information about structural abnormalities in vivo. The study examined 11 patients with very mild to moderate non-proliferative diabetic retinopathy (NPDR) and 10 healthy subjects using fundus photography, optical coherence tomography (OCT), OCT angiography (OCTA), adaptive optics scanning laser ophthalmoscopy (AO-SLO), adaptive optics OCT and OCTA (AO-OCT(A)). Of 21 eyes of 11 patients, 11 had very mild NPDR, 8 had mild NPDR, 2 had moderate NPDR, and 1 had no retinopathy. Using AO-SLO, capillary looping, inflections and dilations were detected in 8 patients with very mild or mild NPDR, and microaneurysms containing hyperreflective granular elements were visible in 9 patients with mild or moderate NPDR. Most of the abnormalities were seen to be perfused in the corresponding OCTA scans while a few capillary loops appeared to be occluded or perfused at a non-detectable flow rate, possibly because of hypoperfusion. In one patient with moderate NPDR, non-perfused capillaries, also called ghost vessels, were identified by alignment of corresponding en face AO-OCT and AO-OCTA images. The combination of multiple non-invasive imaging methods could identify prominent microscopic abnormalities in diabetic retinopathy earlier and more detailed than conventional fundus imaging devices.

Detection of antibodies to the 20s proteasome by ELISA.

The presence of antibodies against the 20S proteasome has been correlated with diseases like multiple sclerosis (MS) and systemic lupus erythematosus (SLE) but no definite association has been established. In order to investigate this further, we optimized an ELISA for proteasome antibodies and applied it to test a total of 324 serum and plasma samples from MS patients, SLE patients, and healthy controls. Our results yield a functional and reliable assay but no correlation between the amount of proteasome antibodies present and the development of MS or SLE could be established.

Automated detection of hyperreflective foci in the outer nuclear layer of the retina.

PURPOSE: Hyperreflective foci are poorly understood transient elements seen on optical coherence tomography (OCT) of the retina in both healthy and diseased eyes. Systematic studies may benefit from the development of automated tools that can map and track such foci. The outer nuclear layer (ONL) of the retina is an attractive layer in which to study hyperreflective foci as it has no fixed hyperreflective elements in healthy eyes. In this study, we intended to evaluate whether automated image analysis can identify, quantify and visualize hyperreflective foci in the ONL of the retina. METHODS: This longitudinal exploratory study investigated 14 eyes of seven patients including six patients with optic neuropathy and one with mild non-proliferative diabetic retinopathy. In total, 2596 OCT B-scan were obtained. An image analysis blob detector algorithm was used to detect candidate foci, and a convolutional neural network (CNN) trained on a manually labelled subset of data was then used to select those candidate foci in the ONL that fitted the characteristics of the reference foci best. RESULTS: In the manually labelled data set, the blob detector found 2548 candidate foci, correctly detecting 350 (89%) out of 391 manually labelled reference foci. The accuracy of CNN classifier was assessed by manually splitting the 2548 candidate foci into a training and validation set. On the validation set, the classifier obtained an accuracy of 96.3%, a sensitivity of 88.4% and a specificity of 97.5% (AUC 0.989). CONCLUSION: This study demonstrated that automated image analysis and machine learning methods can be used to successfully identify, quantify and visualize hyperreflective foci in the ONL of the retina on OCT scans.

Hyperreflective dots in the avascular outer retina in relapsing-remitting multiple sclerosis.

BACKGROUND: Hyperreflective granular elements with a transient presence in the retina can be detected non-invasively by optical coherence tomography (OCT). Such foci or dots may represent aggregates of activated microglia. However, in multiple sclerosis an increased number of hyperreflective foci has so far not been demonstrated in the intrinsically hyporeflective and avascular outer nuclear layer of the retina where there are no fixed elements in healthy eyes. Therefore, the present study intended to investigate the presence of hyperreflective foci in the outer nuclear layer in patients with relapsing- remitting multiple sclerosis (RRMS) by using a high-resolution OCT scanning protocol. METHODS: This cross-sectional exploratory study examined 88 eyes in 44 RRMS patients and 106 eyes in 53 age- and sex-matched healthy subjects. None of the patients had any sign of retinal disease. All patients and healthy subjects each underwent one session of spectral domain OCT imaging. A total of 23,200 B-scans extracted from 8 × 8 mm blocks of linear B-scans at 60 µm intervals were analysed for hyperreflective foci in the outer nuclear layer of the retina. Analyses were made of the total block scan and a circular 6-mm diameter fovea-centered field in each eye. Multivariate logistic regression analysis was used to assess associations between parameters. RESULTS: Hyperreflective foci were observed in 31 out of 44 (70.5 %) multiple sclerosis patients compared to 1 out of 53 (1.8%) healthy subjects (p < 0.0001). From analyses of the total block scans, the median number of hyperreflective foci in the outer nuclear layer was 1 (range 0-13) in patients and 0 (range 0-2) in healthy subjects (p < 0.0001). In total, 66.2% of all hyperreflective foci were located within 6 mm of the center of the macula. There was no detectable association between the presence of hyperreflective foci and retinal nerve fiber layer or ganglion cell layer thickness. CONCLUSION: Hyperreflective granular foci in the avascular outer nuclear layer of the retina seen by OCT were almost completely absent in healthy subjects, whereas they were found, albeit at low density, in the majority of patients with RRMS. Hyperreflective foci can be repeatedly examined by non-invasive means and without pupil dilation, which opens a new field of investigation of infiltrating elements in an unmyelinated part of the central nervous system.

Scanner agnostic large-scale evaluation of MS lesion delineation tool for clinical MRI.

Introduction: Patients with MS are MRI scanned continuously throughout their disease course resulting in a large manual workload for radiologists which includes lesion detection and size estimation. Though many models for automatic lesion segmentation have been published, few are used broadly in clinic today, as there is a lack of testing on clinical datasets. By collecting a large, heterogeneous training dataset directly from our MS clinic we aim to present a model which is robust to different scanner protocols and artefacts and which only uses MRI modalities present in routine clinical examinations. Methods: We retrospectively included 746 patients from routine examinations at our MS clinic. The inclusion criteria included acquisition at one of seven different scanners and an MRI protocol including 2D or 3D T2-w FLAIR, T2-w and T1-w images. Reference lesion masks on the training (n = 571) and validation (n = 70) datasets were generated using a preliminary segmentation model and subsequent manual correction. The test dataset (n = 100) was manually delineated. Our segmentation model https://github.com/CAAI/AIMS/ was based on the popular nnU-Net, which has won several biomedical segmentation challenges. We tested our model against the published segmentation models HD-MS-Lesions, which is also based on nnU-Net, trained with a more homogenous patient cohort. We furthermore tested model robustness to data from unseen scanners by performing a leave-one-scanner-out experiment. Results: We found that our model was able to segment MS white matter lesions with a performance comparable to literature: DSC = 0.68, precision = 0.90, recall = 0.70, f1 = 0.78. Furthermore, the model outperformed HD-MS-Lesions in all metrics except precision = 0.96. In the leave-one-scanner-out experiment there was no significant change in performance (p < 0.05) between any of the models which were only trained on part of the dataset and the full segmentation model. Conclusion: In conclusion we have seen, that by including a large, heterogeneous dataset emulating clinical reality, we have trained a segmentation model which maintains a high segmentation performance while being robust to data from unseen scanners. This broadens the applicability of the model in clinic and paves the way for clinical implementation.

Reactivity of Rheumatoid Arthritis-Associated Citrulline-Dependent Antibodies to Epstein-Barr Virus Nuclear Antigen1-3.

Rheumatoid arthritis (RA) is a chronic disease which causes joint inflammation and, ultimately, erosion of the underlying bone. Diagnosis of RA is based on the presence of biomarkers, such as anti-citrullinated protein antibodies (ACPA) and rheumatoid factors, along with clinical symptoms. Much evidence points to a link between the Epstein-Barr virus and RA. In this study, we analyzed ACPA reactivity to citrullinated peptides originating from Epstein-Barr nuclear antigens (EBNA1, EBNA2, and EBNA3) in order to elaborate the diagnostic potential of citrullinated EBNA peptides. Moreover, ACPA cross-reactivity to citrullinated peptides from myelin basic protein (MBP) was analyzed, as citrullinated MBP recently was described to be associated with multiple sclerosis, and some degree of sequence homology between MBP and citrullinated EBNA exists. A peptide from EBNA2, (EBNA2-A, GQGRGRWRG-Cit-GSKGRGRMH) reacted with approximately 70% of all RA sera, whereas only limited reactivity was detected to EBNA1 and EBNA3 peptides. Moreover, screening of ACPA reactivity to hybrid peptides of EBNA3-A (EPDSRDQQS-Cit-GQRRGDENRG) and EBNA2-A and peptides containing citrulline close to the N-terminal confirmed that ACPA sera contain different populations of ACPAs. No notable ACPA reactivity to MBP peptides was found, confirming that ACPAs are specific for RA, and that other factors than the presence of a central Cit-Gly motif are crucial for antibody binding. Collectively, these findings illustrate that citrullinated EBNA2 is an optimal candidate for ACPA detection, supporting current evidence that EBV is linked to RA onset.

Assessment of Artificial Intelligence Automatic Multiple Sclerosis Lesion Delineation Tool for Clinical Use.

PURPOSE: To implement and validate an existing algorithm for automatic delineation of white matter lesions on magnetic resonance imaging (MRI) in patients with multiple sclerosis (MS) on a local single-center dataset. METHODS: We implemented a white matter hyperintensity segmentation model, based on a 2D convolutional neural network, using the conventional T2-weighted fluid attenuated inversion recovery (FLAIR) MRI sequence as input. The model was adapted for delineation of MS lesions by further training on a local dataset of 93 MS patients with a total of 3040 lesions. A quantitative evaluation was performed on ten test patients, in which model-generated masks were compared to manually delineated masks from two expert delineators. A subsequent qualitative evaluation of the implemented model was performed by two expert delineators, in which generated delineation masks on a clinical dataset of 53 patients were rated acceptable (< 10% errors) or unacceptable (> 10% errors) based on the total number of true lesions. RESULTS: The quantitative evaluation resulted in an average accuracy score (F1) of 0.71, recall of 0.77 and dice similarity coefficient of 0.62. Our implemented model obtained the highest scores in all three metrics, when compared to three out of the box lesion segmentation models. In the clinical evaluation an average of 94% of our 53 model-generated masks were rated acceptable. CONCLUSION: After adaptation to our local dataset, the implemented segmentation model was able to delineate MS lesions with a high clinical value as rated by delineation experts while outperforming popular out of the box applications. This serves as a promising step towards implementation of automatic lesion delineation in our MS clinic.

Real-world study of relapsing-remitting multiple sclerosis patients treated with Teriflunomide in Nordic countries: Quality-Of-Life, efficacy, safety and adherence outcomes.

BACKGROUND: Teriflunomide 14 mg (Aubagio®) is a once-daily, oral drug approved for the treatment of relapsing forms of multiple sclerosis (MS). While the efficacy and safety of teriflunomide have been thoroughly characterised across an extensive clinical program, we were interested in studying performance of the drug with respect to quality-of-life (QoL) outcomes in persons with MS in a real-world setting. METHODS: Teri-LIFE was a prospective, open label, non-interventional, observational, multi-centre study that enrolled 200 teriflunomide-treated patients from three Nordic countries. The primary outcome measure changes in patient-reported QoL over 24 months as measured by the Short Form-36 (SF-36) questionnaire. Secondary endpoints included clinical efficacy, fatigue, safety, treatment satisfaction (Treatment Satisfaction Questionnaire for Medication version 1.4 (TSQM-1.4)), treatment adherence, and health economic outcomes. Most assessments were made at baseline and then at 6-monthly intervals. RESULTS: Overall, changes in SF-36 scores from baseline to last visit indicated a stable QoL during treatment with teriflunomide for up to 24 months. Relapse activity decreased during the study compared to the pre-baseline period (p<0.001), patient-reported disability increased marginally, and no substantial change was seen in fatigue scores. The mean scores for TSQM domains increased nominally though not significantly from Month 6 to Month 24. The convenience and side effects TSQM domains recorded the highest median scores, indicating the acceptability of oral teriflunomide in this cohort. This was reflected in a generally high treatment adherence and decreased healthcare utilization during the study period. Some differences were seen between treatment-naïve and previously treated patients, likely reflecting different patient demographics and disease status at study entry, along with different treatment expectations. CONCLUSION: Teri-LIFE offers a reliable snapshot of QoL, efficacy, safety, and health economic outcomes in persons with relapsing MS treated with teriflunomide in routine clinical practice in Nordic countries The results were consistent with previous clinical trials and real-world studies.

Blood-brain barrier permeability changes in the first year after alemtuzumab treatment predict 2-year outcomes in relapsing-remitting multiple sclerosis.

BACKGROUND: In relapsing-remitting multiple sclerosis (RRMS), early disease control reduces the risk of permanent disability. The blood-brain barrier (BBB) is compromised in MS, and its permeability is a potential biomarker. OBJECTIVE: To investigate BBB permeability measured by MRI as a marker of alemtuzumab efficacy. METHODS: Patients with RRMS initiating alemtuzumab treatment were recruited prospectively. BBB permeability was assessed as the Patlak-derived influx constant (Ki) by dynamic contrast-enhanced MRI before and 6, 12, and 18 months after the first course of alemtuzumab. No Evidence of Disease Activity-3 (NEDA-3) status was ascertained two years after treatment initiation. RESULTS: Patients who maintained NEDA-3 status at two years (n = 7) had a larger decrease in Ki between baseline and six months (-0.029 ml/100 g/min [CI -0.005 - -0.053]) and between baseline and 12 months in normal appearing white matter (0.043 [CI 0.022 - -0.065]), than those who experienced disease activity (n = 8). ROC curve analysis of the Ki change between baseline and 12 months in NAWM predicted a loss of NEDA status at 2 years with 86% sensitivity and 86% specificity (AUC 0.98, p = 0.002). CONCLUSION: BBB permeability predicted alemtuzumab efficacy at two years, indicating that BBB permeability is a biomarker of treatment response in RRMS.

MIF in the cerebrospinal fluid is decreased during relapsing-remitting while increased in secondary progressive multiple sclerosis.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is involved in the function of both the innate and adaptive immune systems and in neuroprotection and has recently been implicated in multiple sclerosis (MS). OBJECTIVES: Determination of MIF levels in the cerebrospinal fluid (CSF) of patients with distinct subtypes of MS and the cellular localization of MIF in human brain tissue. METHODS: The levels of MIF were investigated in CSF from patients with clinically isolated syndrome (CIS) (n = 26), relapsing-remitting MS (RRMS) (n = 22), secondary progressive MS (SPMS) (n = 19), and healthy controls (HCs) (n = 24), using ELISA. The effect of disease-modifying therapies in the RRMS and SPMS cohorts were examined. Cellular distribution of MIF in the human brain was studied using immunochemistry and the newly available OligoInternode database. RESULTS: MIF was significantly decreased in treatment-naïve CIS and RRMS patients compared to HCs but was elevated in SPMS. Interestingly, MIF levels were sex-dependent and significantly lower in women with CIS and RRMS. MIF expression in the human brain was localized to neurons, astrocytes, pericytes, and oligo5 oligodendrocytes but not in microglia. CONCLUSION: The finding that MIF was decreased in newly diagnosed CIS and RRMS patients but was high in patients with SPMS may suggest that MIF levels in CSF are regulated by local MIF receptor expression that affects the overall MIF signaling in the brain and may represent a protective mechanism that eventually fails.

Anti-myelin oligodendrocyte glycoprotein antibodies in a girl with good recovery after five episodes of prior idiopathic optic neuritis.

PURPOSE: To describe the clinical, radiological, immunological and electrophysiological features of a myelin oligodendrocyte glycoprotein (MOG)-IgG positive girl with five prior episodes of idiopathic bilateral optic neuritis (ON). OBSERVATIONS: We report a Danish girl who has been followed by pediatricians and pediatric neurologists since the age of 10 with recurrent episodes of idiopathic bilateral ON. Since the age of 15 there has been no recurrence of ON, and the patient has been thoroughly investigated for Multiple Sclerosis (MS) several times, but with negative findings. At the age of 19 the patient was referred to the Clinic of Optic Neuritis where she was tested seropositive for antibodies against MOG (MOG- IgG) on a conventionally cell-based assay. Despite 5 previous episodes of ON, the latency and amplitude signals of pattern-reversal visual evoked potentials (pVEP) including multifocal VEP were detected within the normal range. CONCLUSION: The clinical implications of MOG- IgG are not yet clear, but in cases where the diagnosis of MS is less likely and where ON is the main symptom, testing for both IgG antibodies against AQP4 and MOG while having atypical optic neuropathies in mind is important. MOG-IgG positive patients may have a good prognosis with regards to visual function.

APOSTEL 2.0 Recommendations for Reporting Quantitative Optical Coherence Tomography Studies.

OBJECTIVE: To update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations. METHODS: To identify studies reporting quantitative OCT results, we performed a PubMed search for the terms "quantitative" and "optical coherence tomography" from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method. The results were evaluated and discussed by a panel of experts and changes to the initial recommendations were proposed. A final survey was recirculated among the corresponding authors to obtain a majority vote on the proposed changes. RESULTS: A total of 116 authors participated in the surveys, resulting in 15 suggestions, of which 12 were finally accepted and incorporated into an updated 9-point checklist. We harmonized the nomenclature of the outer retinal layers, added the exact area of measurement to the description of volume scans, and suggested reporting device-specific features. We advised to address potential bias in manual segmentation or manual correction of segmentation errors. References to specific reporting guidelines and room light conditions were removed. The participants' consensus with the recommendations increased from 80% for the previous APOSTEL version to greater than 90%. CONCLUSIONS: The modified Delphi method resulted in an expert-led guideline (evidence Class III; Grading of Recommendations, Assessment, Development and Evaluations [GRADE] criteria) concerning study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition analysis, nomenclature and abbreviations, and statistical approach. It will be essential to update these recommendations to new research and practices regularly.