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Background: Serum neurofilament light (sNfL) chain is a promising biomarker reflecting neuro-axonal injury in multiple sclerosis (MS). However, the ability of sNfL to predict outcomes in real-world MS cohorts requires further validation., Objective: The aim of the study is to investigate the associations of sNfL concentration, magnetic resonance imaging (MRI) and retinal optical coherence tomography (OCT) markers with disease worsening in a longitudinal European multicentre MS cohort., Methods: MS patients ( n  = 309) were prospectively enrolled at four centres and re-examined after 2 years ( n  = 226). NfL concentration was measured by single molecule array assay in serum. The patients' phenotypes were thoroughly characterized with clinical examination, retinal OCT and MRI brain scans. The primary outcome was disease worsening at median 2-year follow-up., Results: Patients with high sNfL concentrations (⩾8 pg/mL) at baseline had increased risk of disease worsening at median 2-year follow-up (odds ratio (95% confidence interval) = 2.8 (1.5-5.3), p  = 0.001). We found no significant associations of MRI or OCT measures at baseline with risk of disease worsening., Conclusion: Serum NfL concentration was the only factor associated with disease worsening, indicating that sNfL is a useful biomarker in MS that might be relevant in a clinical setting.

Background: Decreased motion perception has been suggested as a marker for visual pathway demyelination in optic neuritis (ON) and/or multiple sclerosis (MS)., Objectives: To examine the influence of neuro-axonal damage on motion perception in MS and neuromyelitis optica spectrum disorders (NMOSD)., Methods: We analysed motion perception with numbers-from-motion (NFM), visual acuity, (multifocal (mf)) VEP, optical coherence tomography in patients with MS ( n = 38, confirmatory cohort n = 43), NMOSD ( n = 13) and healthy controls ( n = 33)., Results: NFM was lower compared with controls in MS ( B = -12.37, p < 0.001) and NMOSD ( B = -34.5, p < 0.001). NFM was lower in ON than in non-ON eyes ( B = -30.95, p = 0.041) in NMOSD, but not MS. In MS and NMOSD, lower NFM was associated with worse visual acuity ( B = -139.4, p < 0.001/ B = -77.2, p < 0.001) and low contrast letter acuity ( B = 0.99, p = 0.002/ B = 1.6, p < 0.001), thinner peripapillary retinal nerve fibre layer ( B = 1.0, p < 0.001/ B = 0.92, p = 0.016) and ganglion cell/inner plexiform layer ( B = 64.8, p < 0.001/ B = 79.5, p = 0.006), but not with VEP P100 latencies. In the confirmatory MS cohort, lower NFM was associated with thinner retinal nerve fibre layer ( B = 1.351, p < 0.001) and increased mfVEP P100 latencies ( B = -1.159, p < 0.001)., Conclusions: Structural neuro-axonal visual pathway damage is an important driver of motion perception impairment in MS and NMOSD.

Background: Cross-sectional studies suggest normal appearing white matter (NAWM) integrity loss may lead to cortical atrophy in late-stage relapsing-remitting multiple sclerosis (MS)., Objective: To investigate the relationship between NAWM integrity and cortical thickness from first clinical presentation longitudinally., Methods: NAWM integrity and cortical thickness were assessed with 3T magnetic resonance imaging (MRI) in 102 patients with clinically isolated syndrome or early MS (33.2 (20.1-60.1) years old, 68% female) from first clinical presentation over 2.8 ± 1.6 years. Fifty healthy controls (HCs) matched for age and sex were included. NAWM integrity was evaluated using the standardized T1w/T2w ratio (sT1w/T2w). The association between sT1w/T2w and cortical thickness was assessed using linear mixed models. The effect of disease activity was investigated using the No Evidence of Disease Activity (NEDA-3) criteria., Results: At baseline, sT1w/T2w ( p  = 0.152) and cortical thickness ( p  = 0.489) did not differ from HCs. Longitudinally, decreasing sT1w/T2w was associated with cortical thickness and increasing lesion burden (marginal R 2  = 0.061). The association was modulated by failing NEDA-3 (marginal R 2  = 0.097)., Conclusion: sT1w/T2w may be a useful MRI biomarker for early MS, detecting relevant NAWM damage over time using conventional MRI scans, although with less sensitivity compared to quantitative measures.

Background: Spinal cord (SC) affection is a hallmark symptom of neuromyelitis optica spectrum disorders (NMOSD). Patients with aquaporin-4 (AQP4-IgG+) or myelin oligodendrocyte glycoprotein (MOG-IgG+) antibody seropositivity show this overlapping clinical phenotype., Objective: Quantitative comparison of SC lesions and atrophy in AQP4-IgG+ and MOG-IgG+ NMOSD., Methods: AQP4-IgG+ ( n  = 38), MOG-IgG+ ( n  = 15) NMOSD patients and healthy controls (HC, n  = 24) were analysed for SC lesion (prevalence, length, location), atrophy as mean upper cervical cord area (MUCCA), Expanded Disability Status Scale (EDSS), timed 25-foot walk speed (T25FWS) and 9-hole peg test (9HPT) measures., Results: In total, 92% (35/38) of AQP4-IgG+ and 53% (8/15) of MOG-IgG+ patients had myelitis attacks (χ 2  = 6.47, p  = 0.011). 65.8%/26.7% of AQP4-/MOG-IgG+ patients had chronic SC lesions (χ 2  = 5.16, p  = 0.023), with similar proportions in cervical, upper thoracic and lower thoracic cord, and no length differences. MUCCA was decreased in AQP4-IgG+ ( t  = -2.27, p  = 0.028), but not MOG-IgG+ patients ( t  = 0.58, p  = 0.57) compared to HC. MUCCA associated with myelitis attacks (rho = -0.33, p  = 0.016), EDSS (rho = -0.31, p  = 0.030), pyramidal functional score (rho = -0.42, p  = 0.003), T25FWS ( r  = 0.43, p  = 0.010) and 9HPT Z-score ( r  = 0.32, p  = 0.037), regardless of antibody status., Conclusion: AQP4-IgG+ patients had more myelitis attacks, SC lesions and SC atrophy was more pronounced than in MOG-IgG+ patients. MUCCA is associated with clinical myelitis attacks and disability in all NMOSD patients.

Objective: Since recent studies suggested a role of the striatum and prefrontal cortex for multiple sclerosis (MS)-related fatigue, we investigated resting-state functional connectivity alterations of striatal subdivisions and the dorsolateral prefrontal cortex (dlPFC)., Methods: Resting-state functional magnetic resonance imaging was acquired in 77 relapsing-remitting MS patients (38 fatigued (F-MS), 39 non-fatigued (NF-MS)) and 41 matched healthy controls (HC). Fatigue severity was assessed using the fatigue severity scale. Seed-based connectivity analyses were performed using subregions of the striatum and the dlPFC as regions of interest applying non-parametric permutation testing., Results: Compared to HC and NF-MS patients, F-MS patients showed reduced caudate nucleus and ventral striatum functional connectivity with the sensorimotor cortex (SMC) and frontal, parietal, and temporal cortex regions. Fatigue severity correlated negatively with functional connectivity of the caudate nucleus and ventral striatum with the SMC and positively with functional connectivity of the dlPFC with the rostral inferior parietal gyrus and SMC., Conclusion: MS-related fatigue is associated with reduced functional connectivity between the striatum and sensorimotor as well as attention and reward networks, in which the ventral striatum might be a key integration hub. Together with increased connectivity between the dlPFC and sensory cortical areas, these connectivity alterations shed light on the mechanisms of MS-related fatigue.

Background: Decision-making (DM) abilities deteriorate with multiple sclerosis (MS) disease progression which impairs everyday life and is thus clinically important., Objective: To investigate the underlying neurocognitive processes and their relation to regional gray matter (GM) loss induced by MS., Methods: We used a functional magnetic resonance imaging (fMRI) Iowa Gambling Task to measure DM-related brain activity in 36 MS patients and 21 healthy controls (HC). From this activity, we determined neural parameters of two cognitive stages, a deliberation ("choice") period preceding a choice and a post-choice ("feedback") stage reporting decision outcomes. These measures were related to DM separately in intact and damaged GM areas as determined by a voxel-based morphometry analysis., Results: Severely affected patients (with high lesion burden) showed worse DM-learning than HC ( t = -1.75, p = 0.045), moderately affected (low lesion burden) did not. Activity in the choice stage in intact insular ( t = 4.60, p Family-Wise Error [FWE] corrected  = 0.034), anterior cingulate ( t = 4.50, p FWE  = 0.044), and dorsolateral prefrontal areas ( t = 4.43, p FWE  = 0.049) and in insular areas with GM loss ( t = 3.78, p FWE  = 0.011) was positively linked to DM performance across patients with severe tissue damage and HC. Furthermore, activity in intact orbitofrontal areas was positively linked to DM-learning during the feedback stage across these participants ( t = 4.49, p FWE  = 0.032). During none of the stages, moderately affected patients showed higher activity than HC, which might have indicated preserved DM due to compensatory activity., Conclusion: We identified dysregulated activity linked to impairment in specific cognitive stages of reward-related DM. The link of brain activity and impaired DM in areas with MS-induced GM loss suggests that this deficit might be tightly coupled to MS neuropathology.

Background: Many studies in multiple sclerosis (MS) have investigated the retina. Little, however, is known about the effect of MS on the cornea, which is innervated by the trigeminal nerve. It is the site of neural-immune interaction with local dendritic cells reacting in response to environmental stimuli., Objective: This study aims to investigate the effect of MS on corneal nerve fibres and dendritic cells in the subbasal nerve plexus using in vivo confocal microscopy (IVCM)., Methods: We measured the corneal nerve fibre and dendritic cell density in 26 MS patients and matched healthy controls using a Heidelberg Retina Tomograph with cornea module. Disease severity was assessed with the Multiple Sclerosis Functional Composite, Expanded Disability Status Scale, visual acuity and retinal optical coherence tomography., Results: We observed significant reduction in total corneal nerve fibre density in MS patients compared to controls. Dendritic cell density was similar in both groups. Reduced total nerve fibre density was associated with worse clinical severity but not with previous clinical trigeminal symptoms, retinal neuro-axonal damage, visual acuity or disease duration., Conclusion: Corneal nerve fibre density is a promising new imaging marker for the assessment of disease severity in MS and should be investigated further.

Background: Previous studies have postulated an association between dentate nucleus T1 hyperintensity and multiple sclerosis (MS)-related progressive neurodegeneration. Therefore, MS patients have been excluded from most studies investigating brain deposition of gadolinium-based contrast agents (GBCAs)., Objective: To study the hypothesis that dentate nucleus T1 hyperintensity in MS patients is associated with GBCA administration., Methods: In a cohort of 97 MS patients, the dentate-to-pons signal intensity ratio (DPSIR) was calculated for 265 consecutive T1-weighted magnetic resonance (MR) scans (including sessions with and without the administration of GBCA). Patients exclusively received either gadopentetate dimeglumine (Gd-DTPA, linear) or gadobutrol (Gd-BT-DO3A, macrocyclic)., Results: In patients receiving Gd-DTPA, DPSIR increased significantly between the first and the last scan (+0.009, p < 0.001), and following magnetic resonance imaging (MRI) with Gd-DTPA administration as compared to following an MRI without Gd-DTPA administration (+0.005 vs -0.001; p = 0.022). Additionally, there was a positive linear relationship between the number of Gd-DTPA administrations and the increase in DPSIR ( p = 0.017). No DPSIR increase was observed after Gd-BT-DO3A administration., Conclusion: Dentate nucleus T1 hyperintensity in MS patients is associated with Gd-DTPA (but not Gd-BT-DO3A) administration, suggesting an alternative explanation for the association of T1 hyperintensity with disease duration and severity.

Background: Multiple sclerosis (MS) patients frequently have postural control impairment but quantitative posturography is difficult to perform in clinical care. Recent technology facilitates new posturography approaches., Objective: To evaluate construct validity of visual perceptive computing (VPC) for static posturography to study postural control in MS patients., Methods: A total of 90 MS patients and 59 healthy controls (HCs) performed three stance tests: open, closed and tandem stance. Static posturography was performed using a VPC system with Microsoft Kinect. Clinical assessments included Expanded Disability Status Scale (EDSS), Timed-25-Foot-Walk, Short-Maximum-Speed-Walk and 12-item MS Walking Scale (MSWS-12) questionnaire. Reliability was assessed with intra-class correlation coefficients at retest., Results: As a group, MS patients performed worse than HCs in all tests. The closed stance test showed best applicability and reliability. With closed eyes, in 36.7% of patients, the three-dimensional mean angular sway velocity (MSV-3D) was above HCs' 95th percentile. Higher MSV-3D was associated with decreased walking speed (p < 0.001); worse clinical scores, mainly attributable to the cerebellar functional system score (p < 0.001); and reflected in self-reported walking disability (MSWS-12, p < 0.001)., Conclusion: Postural control can be reliably assessed by VPC-based static posturography in patients with MS. Abnormal postural control seems to predominantly reflect involvement of cerebellar circuits with impact on gait and walking disability., (© The Author(s), 2016.)

Background: Depression is a common co-morbidity in patients with multiple sclerosis (MS). While somatic symptoms of MS correlate with depression levels, it is unclear whether the clinical presentation of MS-associated depression differs from patients with "idiopathic" major depressive disorder (MDD)., Objective: To compare the clinical phenotype of depression among MS and idiopathic MDD patients., Methods: Mean relative contribution of individual Beck Depression Inventory-II (BDI-II) items was evaluated among n = 139 patients with relapsing-remitting MS and n = 85 MDD patients without somatic illness. Next, comparisons were repeated in n = 38 MS with clinically relevant depressive symptoms (BDI-II > 19) and n = 38 MDD patients matched for sex, age, and depression severity. Finally, the underlying construct of depression was compared across groups using confirmatory factor analysis (CFA)., Results: Comparisons on a whole-group level produced the expected differences along somatic/non-somatic symptoms. However, when appropriately controlling for depression severity, age, and sex, only four items contributed differentially to BDI-II total scores in MS versus MDD. CFA suggested that the underlying depression construct is essentially identical in both groups., Conclusion: The clinical phenotype of "idiopathic" MDD and MS-associated depression appears similar when adequately examined. The relevance of these findings for psychotherapeutic approaches for MS-associated depression should be explored in future studies., (© The Author(s), 2016.)

We investigated the association of retinal nerve fibre layer thickness (RNFL) with white matter damage assessed by diffusion tensor imaging (DTI). Forty-four MS patients and 30 healthy subjects underwent optical coherence tomography. DTI was analysed with a voxel-based whole brain and region-based analysis of optic radiation, corpus callosum and further white matter. Correlations between RNFL, fractional anisotropy (FA) and other DTI-based parameters were assessed in patients and controls. RNFL correlated with optic radiation FA, but also with corpus callosum and remaining white matter FA. Our findings demonstrate that RNFL changes indicate white matter damage exceeding the visual pathway., (© The Author(s), 2014.)

Background: Axonal and neuronal damage are widely accepted as key events in the disease course of multiple sclerosis. However, it has been unclear to date at which stage in disease evolution neurodegeneration begins and whether neuronal damage can occur even in the absence of acute inflammatory attacks., Objective: To characterize inner retinal layer changes in patients with clinically isolated syndrome (CIS)., Method: 45 patients with CIS and age- and sex-matched healthy controls were investigated using spectral domain optical coherence tomography. Patients' eyes were stratified into the following categories according to history of optic neuritis (ON): eyes with clinically-diagnosed ON (CIS-ON), eyes with suspected subclinical ON (CIS-SON) as indicated by a visual evoked potential latency of >115 ms and eyes unaffected by ON (CIS-NON)., Results: CIS-NON eyes showed significant reduction of ganglion cell- and inner plexiform layer and a topography similar to that of CIS-ON eyes. Seven eyes were characterized as CIS-SON and likewise showed significant retinal layer thinning. The most pronounced thinning was present in CIS-ON eyes., Conclusion: Our findings indicate that retinal pathology does occur already in CIS. Intraretinal layer segmentation may be an easily applicable, non-invasive method for early detection of retinal pathology in patients unaffected by ON.

Background: Retinal nerve fibre layer (RNFL) thinning is associated with brain atrophy in multiple sclerosis (MS). An influence of optic neuritis is well documented but sparsely investigated. Recently, the retinal ganglion cell layer (GCL) has been shown to provide superior information regarding visual function and retinal neurodegeneration as compared with RNFL., Objective: To investigate the association of white and grey matter brain volume with peripapillary RNFL and macular GCL in MS patients with and without a history of optic neuritis., Methods: 63 patients with relapsing-remitting MS were included in a two-centre cross-sectional prospective study. All patients underwent retinal examination with spectral domain optical coherence tomography and 1.5 T MRI for determination of normalized brain volume (NBV), white matter volume (NWMV) and grey matter volume (NGMV)., Results: Both RNFL and GCL were associated with NBV, NWMV and NGMV in eyes without previous optic neuritis. This association is disrupted in the case of NGMV following optic neuritis., Conclusions: Both RNFL and GCL as parameters of neuro-axonal damage are comparably linked to whole brain as well as white and grey matter atrophy. An event of optic neuritis interferes with this relation, adding further damage to the optic nerve and disrupting especially an association with grey matter.

Background: Damage to venules in multiple sclerosis was first described decades ago. Today, ultrahigh magnetic field strength T2*-weighted magnetic resonance imaging (MRI) techniques depict very small cerebral veins in vivo with great anatomical detail., Objective: We aimed to investigate alterations of periventricular small blood vessel appearance in relation to T2 lesion count and distribution in multiple sclerosis and clinically isolated syndrome in comparison with healthy control subjects at 7 Tesla MRI., Methods: We investigated 38 patients (including 16 with early multiple sclerosis and seven with clinically isolated syndrome) and 22 matched healthy controls at 7 Tesla. The protocol included T2*-weighted Fast Low Angle Shot, and T2-weighted Turbo Inversion Recovery Magnitude sequences. We quantified periventricular venous density by a novel region-of-interest-based algorithm, expressing the ratio of 'veins per region-of-interest' as well as of 'periventricular vascular area'., Results: Our study revealed significantly decreased venous density in multiple sclerosis patients compared with healthy controls. Venous alterations were already detectable in clinically isolated syndrome and early multiple sclerosis, although to a smaller extent. Venous density correlated inversely with periventricular and whole-brain T2 lesion count. Furthermore, we found no indication for cerebral venous congestion in multiple sclerosis., Conclusion: High spatially resolving anatomical T2*-weighted MRI revealed vascular alterations in early stages of multiple sclerosis, presumably as a part of widespread haemodynamic and metabolic alterations.

Background: Fatigue is the most common symptom in multiple sclerosis patients, but is difficult to measure; quantification thus relies on self-assessed questionnaires., Objective: To evaluate a battery of neuropsychological tests regarding their capacity to objectify self-reported fatigue., Methods: We assessed the correlation between age, gender, education, Kurtzke's Expanded Disability Status Scale, depression, fatigue and neuropsychological testing using a cross-sectional approach in 110 multiple sclerosis patients. Fatigue was measured with the Fatigue Severity Scale. Cognition was measured using a series of neuropsychological tests including three subtests of the Test of Attentional Performance, the Brief Repeatable Battery of Neuropsychological Tests and the Faces Symbol Test., Results: According to the Fatigue Severity Scale 51.4% of the cohort were fatigued (scores > or =4). Age, education and depression showed a significant correlation with the Fatigue Severity Scale. Only 5.5% of the cohort exhibited cognitive impairment in the Brief Repeatable Battery of Neuropsychological Tests scores. After correction for age, education, Expanded Disability Status Scale and depression, Fatigue Severity Scale scores were an independent predictor of performance in the alertness subtest of the Test of Attentional Performance (standardized coefficient beta = 0.298, p = 0.014)., Conclusion: The alertness subtest of the Test of Attentional Performance may offer an objective method of evaluating self-reported fatigue, and may therefore - in addition to the Fatigue Severity Scale - be a suitable tool for the assessment of multiple sclerosis patients complaining of fatigue.

Conventional time domain optical coherence tomography has been established for the in vivo assessment of retinal axonal loss in multiple sclerosis. The innovative spectral domain imaging is superior to the conventional technique with respect to data acquisition speed, resolution and reproducibility. However, until now comparability of the two techniques has not been investigated in multiple sclerosis. In this study involving 55 multiple sclerosis patients, data obtained using both techniques (Stratus time domain optical coherence tomography and Cirrus spectral domain optical coherence tomography, Carl Zeiss Meditec) showed an excellent correlation (Pearson's r = 0.926, p < 0.001). However, owing to considerable differences in absolute retinal nerve fibre layer measurements (mean +/- standard deviation 8.1 microm +/- 6.2, range -12 to 23 microm), results from the two devices are not interchangeable.