Cerebrospinal fluid mitochondrial DNA levels in patients with multiple sclerosis.

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.

Long-term disability outcomes in relapsing-remitting multiple sclerosis: a 10-year follow-up study.

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.

Validation and cross-cultural adaptation of the COMPASS-31 in Croatian and Serbian patients with multiple sclerosis.

AIM: To validate and cross-culturally adapt Croatian and Serbian versions of composite autonomic symptom score-31 (COMPASS-31) for the detection of dysautonomia in patients with multiple sclerosis (MS). METHODS: A total of 179 patients, 67 with clinically isolated syndrome (CIS) and 112 with MS, completed the COMPASS-31 at two MS centers in Zagreb and Belgrade between April 1 and October 31, 2016. Demographic and clinical data including age, gender, MS phenotypes, and the Expanded Disability Status Scale (EDSS) score were collected. RESULTS: The Cronbach's alpha coefficient of COMPASS-31 total score was 0.844 for the Croatian MS sample and 0.779 for the Serbian MS sample. A joint analysis yielded Cronbach's alpha coefficients ranging from 0.394 to 0.796, with values in four domains higher than 0.700. In Croatian and Serbian samples and the total study sample, the Cronbach's alpha coefficient of COMPASS-31 was 0.785. Reproducibility measured by intra-class correlation coefficient (ICC) was acceptable (ICC=0.795). With regard to the clinical validity, significant correlation was found between EDSS and the COMPASS-31 total score (P<0.001). Furthermore, significant differences between MS phenotypes were detected for bladder and gastrointestinal domains and for the COMPASS-31 total score (PP<0.001, P=0.005, and P=0.027, respectively). Finally, significant differences between MS phenotypes in patients with score >0, which implies the existence of at least one of the symptoms investigated in each domain, were detected for secretomotor and bladder domains (P=0.015 and PP<0.001, respectively). CONCLUSION: COMPASS-31 represents a valid and acceptable self-assessment instrument for the detection of dysautonomia in MS patients.

The Rao's Brief Repeatable Battery in the study of cognition in different multiple sclerosis phenotypes: application of normative data in a Serbian population.

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_lts, SRT_cltr, SDMT, SRT_D, SPART_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.

The Prevalence of Pain in Adults with Multiple Sclerosis: A Multicenter Cross-Sectional Survey.

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.

Relapsing inappropriate antidiuretic hormone secretion in an anti-aquaporin-4 antibody positive paediatric patient.

Paediatric patients with the syndrome of an inappropriate antidiuretic hormone secretion (SIADH), as a manifestation of inflammatory demyelinating disorders of the central nervous system, have been rarely described until now, in only a few cases of neuromyelitis optica spectrum disorders (NMOSDs). We present a case of relapsing SIADH associated with NMOSD, in an anti-aquaporin-4 antibody positive 14-year-old girl, who is, to our best knowledge, the first reported paediatric patient with relapsing SIADH and NMOSD. Additionally, our case further supports the notion that paediatric encephalomyelitis associated with SIADH should suggest the diagnosis of NMOSD.

Consensus definitions and application guidelines for control groups in cerebrospinal fluid biomarker studies in multiple sclerosis.

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.

Serial cerebrospinal fluid neurofilament heavy chain levels in severe Guillain-Barré syndrome.

INTRODUCTION: Proximal axonotmesis results in the release of neurofilament (Nf) proteins into the cerebrospinal fluid (CSF) in patients with Guillain-Barré syndrome (GBS). High CSF levels of the phosphorylated form of Nf-heavy chain (NfH(SMI35) ) at GBS onset have been reported to be a poor prognostic marker, but routine measurement of CSF NfH(SMI35) levels has not been done and the longitudinal profile of CSF NfH(SMI35) levels in GBS is not known. METHODS: This prospective case series describes the clinical, neurophysiological, and biomarker characteristics of 3 patients with severe GBS. RESULTS: High and increasing levels of CSF NfH(SMI35) in serial CSF samples were associated with poor clinical and electrophysiological outcome. CONCLUSIONS: These data further suggest that CSF NfH(SMI35) could be a prognostic biomarker which might indicate the development of retrograde axonal degeneration or additional proximal axonal damage during the course of GBS.

In utero exposure to maternal anti-aquaporin-4 antibodies alters brain vasculature and neural dynamics in male mouse offspring.

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 Wnt5a and Wnt7a. 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 S100ß+ 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.

Rare variants and HLA haplotypes associated in patients with neuromyelitis optica spectrum disorders.

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.

Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders.

BACKGROUND: Serum autoantibodies against the water channel aquaporin-4 (AQP4) are important diagnostic biomarkers and pathogenic factors for neuromyelitis optica (NMO). However, AQP4-IgG are absent in 5-40% of all NMO patients and the target of the autoimmune response in these patients is unknown. Since recent studies indicate that autoimmune responses to myelin oligodendrocyte glycoprotein (MOG) can induce an NMO-like disease in experimental animal models, we speculate that MOG might be an autoantigen in AQP4-IgG seronegative NMO. Although high-titer autoantibodies to human native MOG were mainly detected in a subgroup of pediatric acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) patients, their role in NMO and High-risk NMO (HR-NMO; recurrent optic neuritis-rON or longitudinally extensive transverse myelitis-LETM) remains unresolved. RESULTS: We analyzed patients with definite NMO (n = 45), HR-NMO (n = 53), ADEM (n = 33), clinically isolated syndromes presenting with myelitis or optic neuritis (CIS, n = 32), MS (n = 71) and controls (n = 101; 24 other neurological diseases-OND, 27 systemic lupus erythematosus-SLE and 50 healthy subjects) for serum IgG to MOG and AQP4. Furthermore, we investigated whether these antibodies can mediate complement dependent cytotoxicity (CDC). AQP4-IgG was found in patients with NMO (n = 43, 96%), HR-NMO (n = 32, 60%) and in one CIS patient (3%), but was absent in ADEM, MS and controls. High-titer MOG-IgG was found in patients with ADEM (n = 14, 42%), NMO (n = 3, 7%), HR-NMO (n = 7, 13%, 5 rON and 2 LETM), CIS (n = 2, 6%), MS (n = 2, 3%) and controls (n = 3, 3%, two SLE and one OND). Two of the three MOG-IgG positive NMO patients and all seven MOG-IgG positive HR-NMO patients were negative for AQP4-IgG. Thus, MOG-IgG were found in both AQP4-IgG seronegative NMO patients and seven of 21 (33%) AQP4-IgG negative HR-NMO patients. Antibodies to MOG and AQP4 were predominantly of the IgG1 subtype, and were able to mediate CDC at high-titer levels. CONCLUSIONS: We could show for the first time that a subset of AQP4-IgG seronegative patients with NMO and HR-NMO exhibit a MOG-IgG mediated immune response, whereas MOG is not a target antigen in cases with an AQP4-directed humoral immune response.

CSF SERPINA3 Levels Are Elevated in Patients With Progressive MS.

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.

Stability of cerebrospinal fluid/serum glucose ratio and cerebrospinal fluid lactate concentrations over 24 h: analysis of repeated measurements.

BACKGROUND: The cerebrospinal fluid/serum glucose ratio (CSF/S(glu)) and CSF lactate measurements are part of the routine CSF work-up. The in-vitro stability of both metabolites in CSF has not been formally investigated. METHODS: Following collection, CSF/S(glu) and CSF L-lactate concentrations were measured repeatedly at five time points (baseline, 1 h, 2 h, 4 h and 24 h) in CSF and whole blood specimens stored at 4 degrees C. RESULTS: CSF glucose and lactate concentrations were stable over 24 h in samples with both normal and increased CSF cell counts. The CSF cell count did not influence CSF glucose concentrations, but correlated significantly with CSF lactate concentrations. The CSF/S(glu) increased significantly over time due to glucose consumption. CONCLUSIONS: Glucose and L-lactate are stable in CSF specimens at 4 degrees C over 24 h. The CSF/S(glu) seems to be more reliable than CSF lactate because it is independent of the cell count. Falsely increased CSF/S(glu) may be corrected by the rate of consumption of blood glucose.

The analysis of IL-1 beta and its naturally occurring inhibitors in multiple sclerosis: The elevation of IL-1 receptor antagonist and IL-1 receptor type II after steroid therapy.

The aim of our investigation was to analyze the pattern of interleukin-1 (IL-1) family compounds: IL-1 beta, IL-1 receptor accessory protein (Acp), IL-1 receptor antagonist (IL-1Ra) and IL-1 receptor type II (IL-1RII) in the serum and cerebrospinal fluid (CSF) from 67 multiple sclerosis (MS) patients and 31 controls. We found significantly elevated CSF levels of IL-1 beta, IL-1Ra and Acp in MS patients compared to controls (p=0.001), while IL-1 beta and Acp were significantly elevated in MS sera (p=0.001). IL-1Ra and/or IL-1 RII increased in sera of all 10 investigated patients after the steroid treatment for relapse. Our findings suggest the important beneficial role of the induction of IL-1 RII and IL-1Ra in MS.

Cerebrospinal fluid and serum uric acid levels in patients with multiple sclerosis.

BACKGROUND: Peroxynitrite was hypothesized to be involved in the pathogenesis of multiple sclerosis (MS) through its various neurotoxic effects. Uric acid (UA) was shown to be a strong peroxynitrite scavenger. METHODS: We analyzed cerebrospinal fluid (CSF) and serum UA concentrations in 30 MS patients and 20 controls with non-inflammatory neurological diseases (NIND) and correlated these findings with demographic and clinical characteristics of MS patients. Disease activity was assessed by brain magnetic resonance imaging (MRI) and the CSF/serum albumin quotient as an indicator of the state of blood-brain-barrier (BBB). RESULTS: Serum UA concentrations were found to be significantly lower in MS patients compared with controls (p=0.019). CSF UA concentrations were lower in MS patients as compared to controls, as well as in patients with active MS (clinical and/or MRI activity) in comparison to patients with inactive MS or controls, but these differences were not statistically significant. Significant correlation was found between CSF and serum UA concentrations (p=0.016) in MS patients, but not in controls; and between CSF UA concentrations and the CSF/serum albumin quotient in MS patients (p=0.043), but not in controls. CONCLUSIONS: Our results support the significance of UA in the pathogenesis of MS. Decreased serum UA concentrations in MS patients might be due to both intrinsically reduced antioxidant capacity and increased UA consumption in MS. CSF UA concentrations may not be a reliable marker of disease activity in MS since its concentration is dependent on leakage of UA molecules from serum through the damaged BBB and the balance between consumption/production within the central nervous system (CNS).

Autophagy-independent increase of ATG5 expression in T cells of multiple sclerosis patients.

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.

Understanding the Antibody Repertoire in Neuropsychiatric Systemic Lupus Erythematosus and Neuromyelitis Optica Spectrum Disorder: Do They Share Common Targets?

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.

Persistency of Neutralizing Anti-Interferon-ß Antibodies in Patients with Multiple Sclerosis Treated with Subcutaneous Interferon-ß Depends on Antibody Titers, IgG Subclasses, and Affinity Maturation.

Neutralizing antibodies may affect interferon (IFN)-ß 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-ß. A total of 94 patients, who had blood sampling at months 6, 12, 24, and 36 during IFN-ß 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 IgG1 and IgG3 subclasses, lower ADA titers, and antibody binding affinity compared with patients having persistent neutralizing ADA, in whom the predominant IgG subclasses were IgG2 and IgG4. Overall, ADA binding affinity positively correlated with IgG4 and neutralizing ADA titers, but negatively with IgG3 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-ß treatment. The humoral immune response to IFN-ß observed in MS patients as a result of IFN-ß therapy is a multifactorial process that is influenced by ADA titers, affinity maturation, and IgG subclass switching.

Gait pattern in patients with different multiple sclerosis phenotypes.

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.