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The article discusses research on the presence of anti-AQP4 antibodies in a series of 11 Leber's hereditary optic neuropathy (LHON) patients whose diagnoses were confirmed by direct sequencing. The 11 patients had severe bilateral optic neuropathy but had no symptoms or signs of myelopathy. It suggests an association between LHON mtDNA mutations with AQP4-autoimmunity and indicates that autoimmunity could potentially modulate clinical expression in LHON mutation carriers.

Neuromyelitis optica spectrum disorders (NMOSD) are rare, debilitating autoimmune diseases of the central nervous system. Many NMOSD patients have antibodies to Aquaporin-4 (AQP4). Prior studies show associations of NMOSD with individual Human Leukocyte Antigen (HLA) alleles and with mutations in the complement pathway and potassium channels. HLA allele associations with NMOSD are inconsistent between populations, suggesting complex relationships between the identified alleles and risk of disease. We used a retrospective case-control approach to identify contributing genetic variants in patients who met the diagnostic criteria for NMOSD and their unaffected family members. Potentially deleterious variants identified in NMOSD patients were compared to members of their families who do not have the disease and to existing databases of human genetic variation. HLA sequences from patients from Belgrade, Serbia, were compared to the frequency of HLA haplotypes in the general population in Belgrade. We analyzed exome sequencing on 40 NMOSD patients and identified rare inherited variants in the complement pathway and potassium channel genes. Haplotype analysis further detected two haplotypes, HLA-A*01, B*08, DRB1*03 and HLA-A*01, B*08, C*07, DRB1*03, DQB1*02, which were more prevalent in NMOSD patients than in unaffected individuals. In silico modeling indicates that HLA molecules within these haplotypes are predicted to bind AQP4 at several sites, potentially contributing to the development of autoimmunity. Our results point to possible autoimmune and neurodegenerative mechanisms that cause NMOSD, and can be used to investigate potential NMOSD drug targets., Competing Interests: The members of the Regeneron Genetics Center and AK were employed by Regeneron. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tabansky, Tanaka, Wang, Zhang, Dujmovic, Mader, Jeganathan, DeAngelis, Funaro, Harel, Messina, Shabbir, Nursey, DeGouvia, Laurent, Blitz, Jindra, Gudesblatt, Regeneron Genetics Center, King, Drulovic, Yunis, Brusic, Shen, Keskin, Najjar and Stern.)

The fetal brain is constantly exposed to maternal IgG before the formation of an effective blood-brain barrier (BBB). Here, we studied the consequences of fetal brain exposure to an antibody to the astrocytic protein aquaporin-4 (AQP4-IgG) in mice. AQP4-IgG was cloned from a patient with neuromyelitis optica spectrum disorder (NMOSD), an autoimmune disease that can affect women of childbearing age. We found that embryonic radial glia cells in neocortex express AQP4. These cells are critical for blood vessel and BBB formation through modulation of the WNT signaling pathway. Male fetuses exposed to AQP4-IgG had abnormal cortical vasculature and lower expression of WNT signaling molecules Wnt 5a and Wnt 7a. Positron emission tomography of adult male mice exposed in utero to AQP4-IgG revealed increased blood flow and BBB leakiness in the entorhinal cortex. Adult male mice exposed in utero to AQP4-IgG had abnormal cortical vessels, fewer dendritic spines in pyramidal and stellate neurons, and more S100β + astrocytes in the entorhinal cortex. Behaviorally, they showed impairments in the object-place memory task. Neural recordings indicated that their grid cell system, within the medial entorhinal cortex, did not map the local environment appropriately. Collectively, these data implicate in utero binding of AQP4-IgG to radial glia cells as a mechanism for alterations of the developing male brain and adds NMOSD to the conditions in which maternal IgG may cause persistent brain dysfunction in offspring.

Objective: To identify biomarkers associated with progressive phases of MS and with neuroprotective potential., Methods: Combined analysis of the transcriptional and proteomic profiles obtained in CNS tissue during chronic progressive phases of experimental autoimmune encephalomyelitis (EAE) with the transcriptional profile obtained during the differentiation of murine neural stem cells into neurons. Candidate biomarkers were measured by ELISA in the CSF of 65 patients with MS (29 with relapsing-remitting MS [RRMS], 20 with secondary progressive MS, and 16 with primary progressive MS [PPMS]) and 30 noninflammatory neurologic controls (NINCs)., Results: Integrative analysis of gene and protein expression data identified 2 biomarkers, the serine protease inhibitor Serpina3n and the calcium-binding protein S100A4, which were upregulated in chronic progressive EAE and whose expression was induced during neuronal differentiation. Immunofluorescence studies revealed a primarily neuronal expression of S100A4 and Serpina3n during EAE. CSF levels of SERPINA3, the human ortholog of murine Serpina3n, and S100A4 were increased in patients with MS compared with NINCs (SERPINA3: 1,320 vs 838.6 ng/mL, p = 0.0001; S100A4: 1.6 vs 0.8 ng/mL, p = 0.02). Within the MS group, CSF SERPINA3 levels were significantly elevated in patients with progressive forms, mainly patients with PPMS compared with patients with RRMS (1,617 vs 1,129 ng/mL, p = 0.02) and NINCs (1,617 vs 838.6 ng/mL, p = 0.0001). Of interest, CSF SERPINA3 levels significantly correlated with CSF neurofilament light chain levels only in the PPMS group (r = 0.62, p = 0.01)., Conclusion: These results point to a role of SERPINA3 as a biomarker associated with the progressive forms of MS, particularly PPMS., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

The role of cerebrospinal fluid (CSF) mitochondrial DNA (mtDNA) levels as biomarker in multiple sclerosis (MS) is unknown. We determined CSF mtDNA levels in a cohort of 237 individuals, including patients with MS and clinically isolated syndrome (CIS), inflammatory and non-inflammatory neurological controls, and cognitively healthy controls (HC). mtDNA concentration was measured by droplet digital polymerase chain reaction. CSF mtDNA levels were increased in all pathological conditions compared with HC, though no differences were observed between relapse-onset and progressive MS clinical forms, CIS patients and neurological controls. These findings do not support the determination of CSF mtDNA levels as a useful biomarker in MS clinical practice.

Objective: The aim of this study is to assess the impact of interferon (IFN) beta treatment on the development of worsening disability in relapsing-remitting (RR) multiple sclerosis (MS) patients in the single-center observation cohort., Method: This is a prospective study of 236 IFN-beta-treated and 183 untreated RRMS patients recruited consecutively at the Clinic of Neurology in Belgrade (Serbia). Out of this original cohort, 10-year follow-up data were available for 233 IFN-beta-treated and 131 untreated subjects. The median time since recruitment was 9.7 years., Results: IFN-beta treatment significantly delayed (p < 0.001) the time to reach each of the clinical outcomes (secondary progression-SP, EDSS scores 4 and 6) since recruitment. Time from the first visit to SP was reached after 9.7 years for IFN-beta-treated vs. 7.8 years for untreated patients. The delay for the development of EDSS score ≥ 4 from the first visit was 1.6 years (8.7 years for IFN-beta-treated vs. 7.1 years for untreated patients). Time from the first visit to EDSS score of 6 was reached after 9.8 years for IFN-beta-treated vs. 8.8 years for untreated patients. The IFN-beta-treated group showed significant reduction (p < 0.001) in the risk of conversion to SP when compared with untreated patients (HR = 0.22). There was also a significant difference in reaching EDSS scores 4 and 6 (p < 0.001), in favor of the IFN-beta-treated group (HR = 0.40 and HR = 0.27, respectively)., Conclusion: Comparison of outcomes in our IFN-beta-treated vs. untreated RRMS patients suggests that this treatment may delay development of long-term disability in MS.

Autophagy, a process of controlled self-digestion which regulates cell homeostasis, is involved in innate and adaptive immunity. We investigated the expression of autophagy genes and autophagic activity in distinct lymphocyte populations in treatment-naive MS patients. The mRNA and protein levels of autophagy-related (ATG)5, required for autophagosome formation, were increased in CD4 + and CD4 - T cells, but not B cells of MS patients compared to control subjects. The expression of other investigated autophagy genes, as well as the autophagic activity, did not significantly differ between the two groups. ATG5 mRNA levels in CD4 + T cells from MS patients were positively correlated with those of the proinflammatory cytokine tumor necrosis factor. These data suggest that autophagy-independent increase in ATG5 expression might be associated with the proinflammatory capacity of T cells in multiple sclerosis., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: IgG anti-DWEYS antibodies cross-reactive with DNA and the N-methyl-d-aspartate receptor subunits GluN2A and GluN2B are known to be associated with neuropsychiatric systemic lupus erythematosus (NPSLE). IgG anti-DWEYS have not been investigated in demyelinating NPSLE or in another demyelinating disorder, neuromyelitis optica spectrum disorder (NMOSD), which is a disease also found mainly in young women and associated with aquaporin 4 (AQP-4) or myelin oligodendrocyte glycoprotein (MOG) antibodies. This study was undertaken to investigate the frequency of all of these brain-reactive antibodies in patients with NPSLE, those with demyelinating NPSLE, and those with NMOSD., Methods: Serum samples from patients with NPSLE (n = 108), patients with SLE without neuropsychiatric manifestations (n = 38), patients with NMOSD (n = 33), and healthy controls (n = 106) were assessed for the frequency of IgG anti-brain antibodies as well as IgG antibodies to AQP-4, MOG, GluN2A/GluN2B, and double-stranded DNA (dsDNA)., Results: Sera were positive for IgG anti-AQP-4 antibodies in 27 (82%) of 33 patients with NMOSD and 3 (27%) of 11 patients with demyelinating NPSLE, whereas all sera from patients with non-demyelinating NPSLE, patients with SLE, and healthy controls were negative for IgG anti-AQP-4. IgG anti-MOG were detected at high titers in 3 (50%) of 6 patients with NMOSD who were negative for IgG anti-AQP-4, and at low titers in 2 (18%) of 11 patients with demyelinating NPSLE and 1 (1%) of 97 patients with non-demyelinating NPSLE. IgG antibodies to dsDNA were present in 11 (33%) of 33 patients with NMOSD. Only 4 (12%) of 33 patients with NMOSD were positive for IgG anti-DWEYS, compared to 11 (29%) of 38 patients with SLE and 59 (55%) of 108 patients with NPSLE. IgG anti-DWEYS antibodies were present in 56 (58%) of 97 patients with non-demyelinating NPSLE and 3 (27%) of 11 patients with demyelinating NPSLE. Serum IgG brain-reactive antibodies were present at a similar frequency in patients with non-demyelinating NPSLE (72 [75%] of 96), those with demyelinating NPSLE (9 [82%] of 11), and those with SLE (32 [84%] of 38), but were less frequent in patients with NMOSD (20 [61%] of 33)., Conclusion: Patients with demyelinating NPSLE should be tested for IgG antibodies to AQP-4, MOG, and DWEYS. IgG anti-AQP-4 can be considered diagnostic for NMOSD, whereas none of these antibodies appear to be diagnostic for demyelinating NPSLE. Moreover, IgG anti-dsDNA are present in patients with NMOSD but are not cross-reactive with IgG anti-DWEYS, indicating that the antigenic stimulus and mechanisms of tissue damage are potentially different between demyelinating NPSLE and NMOSD., (© 2017, American College of Rheumatology.)

Neutralizing antibodies may affect interferon (IFN)-β treatment efficacy, but mechanisms of neutralizing anti-drug antibody (ADA) evolution are not fully elucidated. We investigated the relationship between ADA titers, IgG subclass profile, and binding affinity with the development and persistency of neutralizing ADA in relapsing-remitting multiple sclerosis (MS) patients treated with subcutaneous IFN-β. A total of 94 patients, who had blood sampling at months 6, 12, 24, and 36 during IFN-β therapy, were included into this retrospective study and stratified to the following: non-neutralizing, transient, and persistent neutralizing ADA status. Patients without or with transient neutralizing ADA displayed predominantly IgG 1 and IgG 3 subclasses, lower ADA titers, and antibody binding affinity compared with patients having persistent neutralizing ADA, in whom the predominant IgG subclasses were IgG 2 and IgG 4 . Overall, ADA binding affinity positively correlated with IgG 4 and neutralizing ADA titers, but negatively with IgG 3 titers. Persistency of neutralizing ADA was predicted by their titers at month 24 and month 36 of treatment and by an increase of antibody affinity within the second year of IFN-β treatment. The humoral immune response to IFN-β observed in MS patients as a result of IFN-β therapy is a multifactorial process that is influenced by ADA titers, affinity maturation, and IgG subclass switching.

Introduction: Cerebrospinal fluid collection by lumbar puncture (LP) is performed in the diagnostic workup of several neurological brain diseases. Reluctance to perform the procedure is among others due to a lack of standards and guidelines to minimize the risk of complications, such as post-LP headache or back pain., Methods: We provide consensus guidelines for the LP procedure to minimize the risk of complications. The recommendations are based on (1) data from a large multicenter LP feasibility study (evidence level II-2), (2) systematic literature review on LP needle characteristics and post-LP complications (evidence level II-2), (3) discussion of best practice within the Joint Programme Neurodegenerative Disease Research Biomarkers for Alzheimer's disease and Parkinson's Disease and Biomarkers for Multiple Sclerosis consortia (evidence level III)., Results: Our consensus guidelines address contraindications, as well as patient-related and procedure-related risk factors that can influence the development of post-LP complications., Discussion: When an LP is performed correctly, the procedure is well tolerated and accepted with a low complication rate.

Background: Gait pattern is frequently impaired in multiple sclerosis (MS), however gait characteristics in patients with different MS phenotypes have not been fully elucidated., Methods: We analyzed spatio-temporal gait pattern characteristics in patients with relapsing-remitting (RR, n=52) and primary-progressive (PP, n=18) MS in comparison with age-matched healthy controls (HC, n=40). All subjects performed a standardized simple walking task, a dual motor- motor task, a dual motor-mental task, and a triple combined motor-mental task at a GAITRite electronic walkway of 5.5m active area. We measured: cycle time (CT), stride length (SL), swing time (ST), double support time (DST), gait velocity (GV) and calculated symmetry index (SI) for CT, SL and ST., Results: With each task performed, CT and DST in the total MS group were significantly longer while SL was significantly shorter and GV significantly lower than in HC. ST was similar in the total MS patient group and HC. In both MS patients and HC, CT and DST increased and SL and GV decreased over repeated assessments. Dual and triple tasks while walking influenced walking performance in both MS patients and HC. Although patients with PPMS differed significantly from those with RRMS in the majority of gait parameters, the subgroup analysis in patients matched for age and disability (Expanded Disability Status Scale Score -EDSS, 3.0-5.0) showed similar gait performance in RRMS and PPMS patients having the same level of disability, except for CT and ST- symmetry parameters that were more impaired in the PPMS group. The EDSS score correlated significantly with CT, DST, SL and GV, but no significant correlation was found with ST except at the triple combined motor-mental task., Conclusion: A disturbed gait pattern in MS patients with different MS phenotypes depends on disability and reflects a cognitive-motor interference., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Long-term treatment adherence to disease-modifying drugs (DMDs) may have significant impact on clinical outcomes in multiple sclerosis (MS). It has been recently emphasized that low treatment satisfaction (TS) may be an important factor for achieving high rates of treatment adherence. Interferon (IFN) beta-1b was the first DMD approved for the treatment of MS. The aims of our study were to assess TS in subjects with relapsing-remitting (RR) MS treated with IFN beta-1b in Serbia, Montenegro and the Republika Srpska, Bosnia and Herzegovina (B&H), and additionally, to evaluate the impact of patient support program on TS and adherence., Methods: This is a cross-sectional survey performed in order to examine TS and adherence with IFN beta-1b in seven MS centers across three countries (Serbia, Montenegro and B&H). Included in the study were 296 adult patients with RRMS treated with IFN beta-1b for at least 6 months. They were invited to complete the Treatment Satisfaction Questionnaire for Medication (TSQM). Additional two treatment adherence questions were also asked. Patient support program (Betaplus®) was available exclusively for patients in Serbia and not for those in Montenegro and the Republika Srpska, B&H. In order to assess the potential impact of this program on TSQM, we combined two groups of patients from Montenegro and B&H and compared their results with those from patients in Serbia. Statistical analysis includes multivariable linear regression analysis in order to assess the differences between three MS patients groups in terms of the TSQM scores, adjusted for potential confounders. For the evaluation of the effects of Betaplus® program, multivariable logistic regression was used, controlling for the same confounding factors., Results: Each of the TSQM summary scores in all three countries implicated high level of patients' satisfaction. There was statistically significant group difference on the Effectiveness summary score (p=0.001) and the Side effects summary score (p=0.006) between the group of subjects from Serbia and the combined group of subjects from Montenegro and B&H, in favor of the former cohort. There was statistically significant group difference neither on the Convenience summary score nor on the Overall satisfaction summary score. Results of adjusted logistic regression analysis based on the availability of patient support program (dependent variable) implicate that it had the most significant impact on the Effectiveness summary score (p=0.008). According to the correlation coefficients in the total patient cohort, all TSMQ summary scores except Effectiveness significantly correlated with the decreased adherence (Side effects: p=0.037; Convenience: p=0.016; Overall satisfaction: p=0.046)., Conclusion: TS with IFN beta-1b was high in our MS patients. Additionally, these results have demonstrated that patient support program have significant impact on TS with IFN beta-1b in the Balkan cohort of RRMS patients., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Cognitive impairment is prevalent in multiple sclerosis (MS) occurring in 43-72 % of patients with all MS phenotypes. The aim of our study was to assess cognitive performance in different MS subtypes in Serbian population. Rao's Brief Repeatable Battery of neuropsychological tests (BRB-N) was administered to 168 MS patients [37 patients with clinically isolated syndrome (CIS) suggestive of MS, 65 with relapsing-remitting MS (RRMS), 31 with secondary progressive MS (SPMS) and 35 patients with primary progressive MS (PPMS)]. The percentage of cognitively impaired patients in our total MS cohort was 58.9 %. Prevalence of cognitive dysfunction was 40.5 % in CIS group, 36.9 % in RRMS, 96.8 % in SPMS, and 85.7 % in PPMS group. Patients in CIS and RRMS groups performed consistently better all tests of the Rao's battery than patients in SPMS and PPMS cohort. CIS and RRMS groups performed consistently better in all tests of the Rao's battery than SPMS and PPMS cohort. Additionally, difference in the performance of any of the BRB-N tests was not found between CIS and RRMS. However, there was a significant difference between SPMS and PPMS patients in the performance on five tests of Rao's battery. Statistical significance (p < 0.05) in favor of PPMS patients was demonstrated for the following tasks: SRT&#95;lts, SRT&#95;cltr, SDMT, SRT&#95;D, SPART&#95;D. Our study demonstrates that cognitive impairment is frequent in all MS phenotypes. Furthermore, we have found that cognitive deficit is most severe and most frequent in SPMS patients, followed by PPMS subjects and then CIS and RRMS patients.

Objective: Multiple Sclerosis Spasticity Scale (MSSS)-88 has been developed for self-assessment of spasticity symptoms in patients with multiple sclerosis (MS). The objective of this study was to validate MSSS-88 and evaluate the psychometric properties in patients with MS in Serbia., Methods: The study comprised 65 MS patients with spasticity. MSSS-88 consists of 88 items grouped in eight sections. Internal consistency of the MSSS-88SR subscales was determined using Cronbach's alpha coefficient. Test/retest reliability with an intra-class correlation coefficient (ICC) for each MSSS-88SR subscale was performed. Clinical validity of MSSS-88SR was determined by correlations with the Numeric Rating Scale (NRS) and the Modified Ashworth Scale (MAS)., Results: The range of Cronbach's alpha for all scales and ICC was 0.91-0.96 and 0.84-0.91, respectively. All ICCs were statistically significant (p<0.05). All evaluated subscales of MSSS-88 were significantly correlated with the NRS scale. The highest correlation coefficients were registered between the WL subscale and the EDSS and MAS, while the strongest relationship was observed between the MSS subscale and the NRS., Conclusion: The Serbian translated version of this instrument may be useful as a clinical measure for spasticity and functionality in patients with MS.

Matrix Metalloproteases (MMPs) and cytokines have been involved in the pathogenesis of multiple sclerosis (MS). However, no studies have still explored the possible associations between the two families of molecules. The present study aimed to evaluate the contribution of active MMP-9, active MMP-2, interleukin- (IL-) 17, IL-18, IL-23, and monocyte chemotactic proteins-3 to the pathogenesis of MS and the possible interconnections between MMPs and cytokines. The proteins were determined in the serum and cerebrospinal fluid (CSF) of 89 MS patients and 92 other neurological disorders (OND) controls. Serum active MMP-9 was increased in MS patients and OND controls compared to healthy subjects (p < 0.001 and p < 0.01, resp.), whereas active MMP-2 and ILs did not change. CSF MMP-9, but not MMP-2 or ILs, was selectively elevated in MS compared to OND (p < 0.01). Regarding the MMPs and cytokines intercorrelations, we found a significant association between CSF active MMP-2 and IL-18 (r = 0.3, p < 0.05), while MMP-9 did not show any associations with the cytokines examined. Collectively, our results suggest that active MMP-9, but not ILs, might be a surrogate marker for MS. In addition, interleukins and MMPs might synergistically cooperate in MS, indicating them as potential partners in the disease process.

Purpose: Sexual dysfunction (SD) is a common but often overlooked and undertreated symptom in multiple sclerosis (MS). The purpose of our longitudinal study was to explore the changes in the level of sexual functioning in MS cohort after a period of 3 and 6 years of follow-up, as well as to investigate the predictors of changes in SD during the period of observation., Methods: The study population comprise a cohort of 93 patients with MS (McDonald's criteria, 2001) who were assessed at three time points during the study (baseline, and at the 3- and 6-year follow-up). The presence and severity of SD was quantified by Szasz sexual functioning scale. Independent predictors of the ordinal-scaled measure of sexual problems were identified using a generalized linear mixed regression models., Results: The number of reported SD symptoms increased markedly for both genders during the whole period of observation. Duration of follow-up, age, level of physical disability, depression and fatigue were identified as independent prognostic factors for deterioration of sexual functioning in patients with MS during the 6-year follow-up., Conclusion: Our study provides insight into dynamics of change in sexual function among patients with MS and predictors of change, over the period of 6 years., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Cytokines produced by helper T (Th)1 cells, Th17 and regulatory T cells (Treg) are involved in multiple sclerosis (MS) immunopathogenesis. Interferon (IFN)-β alters the numerous genes' expression, but how this alteration affects the treatment response is still elusive. We assessed relative gene expression of nineteen Th1/Th17/Treg-associated mediators in peripheral blood mononuclear cells and plasma levels of GM-CSF, IL-17A and IL-17F, in relapsing-remitting MS (RRMS) patients before IFN-β1b treatment initiation and at 6, 12, 24 and 36 months of therapy. All mRNA levels changed significantly during the IFN-β1b therapy. Higher IL-12Rβ2 mRNA levels were associated with lower risk of relapse. Despite recent reports regarding role of GM-CSF in MS, our study failed to demonstrate its significance as therapy response biomarker, both on the mRNA and protein level., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: Examination of prevalence, intensity and associations of pain in persons with multiple sclerosis (MS)., Design: Multicenter, international cross-sectional survey., Setting: Patients were recruited from seven MS centers: in Serbia (Clinic of Neurology, Clinical Center of Serbia, Belgrade; Clinic of Neurology, Military Medical Academy, Belgrade; Clinic of Neurology, Clinical Center Kragujevac; Clinic of Neurology, Clinical Center Nis; Department of Neurology, General Hospital-Uzice), in Republic of Srpska-Bosnia and Herzegovina (Clinic of Neurology, Clinical Center Banja Luka) and in Croatia (University Department of Neurology, Sestre Milosrdnice University Hospital Center, Zagreb)., Subjects: Six hundred and fifty consecutive MS patients diagnosed according to the Revised McDonald criteria (2005), from the aforementioned centers, over the period of 6 months., Methods: A semistructured questionnaire was administered during a face-to-face interview with neurologists who also performed Expanded Disability Status Scale (EDSS), the Hamilton Rating Scale for Depression (HDRS) and Hamilton Rating Scale for Anxiety (HARS). To recognize predictive factors for the presence of pain, the linear regression analysis was used., Results: Lifetime prevalence of pain was 66.5% (point prevalence = 44.3%). The prevalence of the comorbidity of pain and depression was 29.1%. Older age (P < 0.001), primary-progressive MS (P = 0.034), higher EDSS score (P = 0.008), higher scores of HDRS (P < 0.001), and HARS (P < 0.001) were significantly associated with pain. Finally, in our multivariate linear regression analysis, anxiety (P < 0.001) was the independent predictor of pain., Conclusions: We confirmed high prevalence of pain, affecting approximately more than half of patients during the course of MS. Pain in MS is associated with disability, depression and, especially with anxiety, which has significant implications for treatment., (Wiley Periodicals, Inc.)

The choice of appropriate control group(s) is critical in cerebrospinal fluid (CSF) biomarker research in multiple sclerosis (MS). There is a lack of definitions and nomenclature of different control groups and a rationalized application of different control groups. We here propose consensus definitions and nomenclature for the following groups: healthy controls (HCs), spinal anesthesia subjects (SASs), inflammatory neurological disease controls (INDCs), peripheral inflammatory neurological disease controls (PINDCs), non-inflammatory neurological controls (NINDCs), symptomatic controls (SCs). Furthermore, we discuss the application of these control groups in specific study designs, such as for diagnostic biomarker studies, prognostic biomarker studies and therapeutic response studies. Application of these uniform definitions will lead to better comparability of biomarker studies and optimal use of available resources. This will lead to improved quality of CSF biomarker research in MS and related disorders.