Alemtuzumab treatment for multiple sclerosis in Austria: An observational long-term outcome study.

BACKGROUND/OBJECTIVE: Observational real-world study to analyze the clinical effects of alemtuzumab (ALEM) and subsequent disease-modifying therapy (DMT) usage in multiple sclerosis (MS). METHODS: Data retrieved from the Austrian MS treatment registry (AMSTR) included baseline (BL) characteristics (at ALEM start), annualized relapse rate (ARR), 6-month confirmed progression independent of relapse activity (PIRA; ≥ 0.5-point Expanded Disability Status Scale (EDSS) score increase), 6-month confirmed disability improvement (CDI; ≥ 0.5-point EDSS decrease), and safety outcomes until initiation of a subsequent DMT. The EDSS was re-baselined at 30 days from ALEM start (BL EDSS). RESULTS: Eighty-seven ALEM-treated patients (median age: 32 years, 72% female, 14% treatment-naïve) were followed for a median of 55 (interquartile range 31-68) months. We found significant reductions in the ARR from 1.16 before ALEM to 0.15 throughout Years 1-9 (p < 0.001). Subsequent DMTs were initiated in 19 patients (22%, 74% anti-CD20 monoclonal antibodies). At Year 5 (n = 53), more patients achieved CDI (58%, 95% confidence interval (CI) 45%-71%) than had experienced PIRA (14%, CI 7.5%-24%), and 58% remained relapse-free. Shorter MS duration (p < 0.001, hazard ratio (HR) 0.86 (CI 0.80-0.93)) and no previous high-efficacy treatment (p < 0.001, HR 5.16 (CI 2.66-10.0)) were the best predictors of CDI, while PIRA was associated with a higher number of previous DMTs (p = 0.04, HR 3.06, CI 1.05-8.89). We found no new safety signals. INTERPRETATION: ALEM had long-lasting beneficial effects on the ARR and disability improvement, especially when initiated early in the course of the disease. Only a subset of patients received subsequent DMTs.

Sex impacts treatment decisions in multiple sclerosis.

BACKGROUND: Individual disease-modifying treatment (DMT) decisions might differ between female and male people with MS (pwMS). OBJECTIVE: To identify sex-related differences in DMT strategies over the past decades in a real-world setting. METHODS: In this cohort study, data from the Austrian Multiple Sclerosis Treatment Registry (AMSTR), a nationwide prospectively collected registry mandatory for reimbursement, were retrospectively analyzed. Of 4840 pwMS, those with relapsing-remitting MS, aged at least 18 years, who started DMT and had at least two clinical visits, were identified. At baseline, demographics, Expanded Disability Status Scale (EDSS) score, annualized relapse rate (ARR) in the prior 12 months and MRI lesion load were assessed. At follow-up, ARR, EDSS scores, and DMT were determined. RESULTS: A total of 4224 pwMS were included into the study and had a median of 10 (IQR 5-18) clinical visits over an observation period of 3.5 (IQR 1.5-6.1) years. Multivariable Cox regression analysis revealed that the probability of DMT escalation due to relapse activity was lower in female than male pwMS (HR 4.1 vs. 8.3 per ARR). Probability of discontinuing moderate-effective DMT was higher in female pwMS when they were younger (HR 1.03 per year), and lower in male pwMS at higher age (HR 0.92). Similarly, female pwMS were more likely to stop highly effective DMT than male pwMS (HR 1.7). Among others, the most frequent reason for DMT discontinuation was family planning in female pwMS. All sex-related effects were independent of disease activity, such as MRI lesion load, baseline ARR or EDSS. CONCLUSIONS: Real-world treatment decisions are influenced by sex-related aspects. Awareness of these associations should prevent unwarranted differences in MS care.

Body fluid markers for multiple sclerosis and differential diagnosis from atypical demyelinating disorders.

INTRODUCTION: Body fluid markers could be helpful to predict the conversion into clinically definite multiple sclerosis (MS) in people with a first demyelinating event of the central nervous system (CNS). Consequently, biomarkers such as oligoclonal bands, which are integrated in the current MS diagnostic criteria, could assist early MS diagnosis. AREAS COVERED: This review examines existing knowledge on a broad spectrum of body fluid markers in people with a first CNS demyelinating event, explores their potential to predict conversion to MS, to assess MS disease activity, as well as their utility to differentiate MS from atypical demyelinating disorders such as neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein associated disease. EXPERT OPINION: This field of research has shown a dramatic increase of evidence, especially in the last decade. Some biomarkers are already established in clinical routine (e.g. oligoclonal bands) while others are currently implemented (e.g. kappa free light chains) or considered as breakthroughs (e.g. neurofilament light). Determination of biomarkers poses challenges for continuous monitoring, especially if exclusively detectable in cerebrospinal fluid. A handful of biomarkers are measurable in blood which holds a significant potential.

Olfactory threshold as a biomarker of long-term relapse activity in multiple sclerosis.

BACKGROUND: Olfactory threshold (OT) is a marker of short-term inflammatory activity in multiple sclerosis (MS). OBJECTIVE: To investigate whether OT predicts long-term MS clinical disease course. METHODS: This was a 6-year prospective longitudinal study on MS patients at the MS clinic Innsbruck. Clinical visits assessing the occurrence of relapses, Expanded Disability Status Scale (EDSS) scores, and disease-modifying treatment (DMT), were conducted biannually. OT testing was performed at baseline (BL), year 1 (Y1), year 2 (Y2) and year 6 (Y6), using the threshold subscore of the "Sniffin' Sticks" test. Cognitive function was assessed by the Symbol Digit Modalities Test. RESULTS: Of 139 MS patients, 92 were eligible for Y6 follow-up. 68% experienced relapses, 53% EDSS worsening, 29% progression independent of relapse activity (PIRA) and 41% cognitive deterioration. OT scores were lower at BL, Y1 and Y2 in patients requiring DMT escalation. In multivariable analysis, higher OT scores at BL, Y1, Y2 and Y6 were associated with lower risk of relapse (hazard ratio, HR: 0.65-0.92) and EDSS worsening (HR: 0.86-0.89), while no associations were found for PIRA and cognitive deterioration. CONCLUSIONS: OT is a potential surrogate marker for long-term inflammatory disease activity and DMT failure in MS.

Serum biomarker levels predict disability progression in patients with primary progressive multiple sclerosis.

BACKGROUND: We aimed to investigate the potential of serum biomarker levels to predict disability progression in a multicentric real-world cohort of patients with primary progressive multiple sclerosis (PPMS). METHODS: A total of 141 patients with PPMS from 18 European MS centres were included. Disability progression was investigated using change in Expanded Disability Status Scale (EDSS) score over three time intervals: baseline to 2 years, 6 years and to the last follow-up. Serum levels of neurofilament light chain (sNfL), glial fibrillar acidic protein (sGFAP) and chitinase 3-like 1 (sCHI3L1) were measured using single-molecule array assays at baseline. Correlations between biomarker levels, and between biomarkers and age were quantified using Spearman's r. Univariable and multivariable linear models were performed to assess associations between biomarker levels and EDSS change over the different time periods. RESULTS: Median (IQR) age of patients was 52.9 (46.4-58.5) years, and 58 (41.1%) were men. Median follow-up time was 9.1 (7.0-12.6) years. Only 8 (5.7%) patients received treatment during follow-up. sNfL and sGFAP levels were moderately correlated (r=0.43) and both weakly correlated with sCHI3L1 levels (r=0.19 and r=0.17, respectively). In multivariable analyses, levels of the three biomarkers were associated with EDSS changes across all time periods. However, when analysis was restricted to non-inflammatory patients according to clinical and radiological parameters (n=64), only sCHI3L1 levels remained associated with future EDSS change. CONCLUSIONS: Levels of sNfL, sGFAP and sCHI3L1 are prognostic biomarkers associated with disability progression in patients with PPMS, being CHI3L1 findings less dependent on the inflammatory component associated with disease progression.

Odour discrimination and identification as a biomarker of long-term disability worsening in multiple sclerosis.

BACKGROUND: Odour discrimination and identification (DI) are markers associated with disability worsening and neuroaxonal damage in multiple sclerosis (MS). OBJECTIVE: The main objective of this research is to investigate whether longitudinal change of DI predicts long-term MS disease course. METHODS: This is a 6-year prospective longitudinal study on MS patients at the MS Clinic Innsbruck. Clinical, bi-annual visits assessed patients' history and Expanded Disability Status Scale (EDSS) score. DI and cognitive function were assessed at baseline (BL), Year 1 (Y1), Year 2 (Y2) and Year 6 (Y6) by the 'Sniffin' Sticks'/Symbol Digit Modalities Test. RESULTS: Around 92 of 139 patients were available for Y6 follow-up. Mean DI scores significantly decreased over time (BL = 27.8, Y1 = 27.5, Y2 = 26.3 and Y6 = 26.3; p < 0.001) and negatively correlated with patients' age (rs = -0.120, p = 0.032) and disease duration (rs = -0.103, p = 0.041). Multivariable regression analyses revealed that lower absolute DI scores and larger DI score loss over time were associated with higher probability of EDSS worsening (per -1 point: hazard ratio (HR) = 1.40 (1.16-1.68) and 2.34 (1.27-4.21)), progression independent of relapse activity (PIRA) (HR = 1.49 (1.20-1.85) and 2.22 (1.33-3.31)) and cognitive deterioration (HR = 1.75 (1.35-2.27) and 4.29 (1.26-2.84)) at Y6, but not with time to first relapse. CONCLUSION: Odour DI is an irreversible marker of neuroaxonal damage, associated with PIRA, cognitive deterioration and EDSS worsening.

Multiple sclerosis in the elderly: a retrospective cohort study.

BACKGROUND: There is a lack of knowledge of disease course, prognosis, comorbidities and potential treatments of elderly MS patients. OBJECTIVE: To characterize the disease course including disability progression and relapses, to quantify the use of DMTs and to identify comorbidities and risk factors for progression in elderly multiple sclerosis (MS) patients. METHODS: This is a retrospective study of 1200 Austrian MS patients older than 55 years as of May 1st, 2017 representing roughly one-third of all the MS patients of this age in Austria. Data were collected from 15 MS centers including demographics, first symptom at onset, number of relapses, evolvement of disability, medication, and comorbidities. RESULTS: Median observation time was 17.1 years with 957 (80%) relapsing and 243 (20%) progressive onsets. Average age at diagnosis was 45 years with a female predominance of 71%. Three-hundred and twenty-six (27%) patients were never treated with a DMT, while most treated patients received interferons (496; 41%) at some point. At last follow-up, 420 (35%) patients were still treated with a DMT. No difference was found between treated and never-treated patients in terms of clinical outcome; however, patients with worse disability progression had significantly more DMT switches. Pyramidal onset, number of comorbidities, dementia, epilepsy, and psychiatric conditions as well as a higher number of relapses were associated with worse outcome. The risk of reaching EDSS 6 rose with every additional comorbidity by 22%. In late and very-late-onset MS (LOMS, VLOMS) time to diagnosis took nearly twice the time compared to adult and early onset (AEOMS). The overall annualized relapse rate (ARR) decreased over time and patients with AEOMS had significantly higher ARR compared to LOMS and VLOMS. Four percent of MS patients had five medications or more fulfilling criteria of polypharmacy and 20% of psychiatric drugs were administered without a matching diagnosis. CONCLUSIONS: In this study, we identified number of comorbidities, pyramidal and cerebellar signs, and a higher number of relapses as unfavorable prognostic factors in elderly MS patients filling gaps of knowledge in patients usually underrepresented in clinical trials and may guide future therapeutic studies.

Subarachnoid haemorrhage or traumatic lumbar puncture. Differentiation by cerebrospinal fluid parameters in a multivariable approach.

Lumbar puncture (LP) is recommended in patients with thunderclap headache and negative computed tomography to rule out spontaneous subarachnoid haemorrhage (SAH). Blood contamination of cerebrospinal fluid (CSF) due to traumatic LP poses a diagnostic dilemma. Therefore, routine CSF parameters were investigated to distinguish between SAH and a traumatic LP. CSF red blood cell (RBC), white blood cell (WBC) count, total protein, CSF colour and supernatant were used for group comparisons of patients with SAH and 'symptomatic controls'. Due to variable time intervals between bleeding onset and LP in SAH patients in contrast to patients with traumatic LP, where blood contamination of CSF occurs at the time of LP, CSF variables were adjusted for decay in time to allow comparability. Logistic regression analysis identified bloody CSF [odds ratio (OR) 32.6], xanthochromic supernatant [OR 15.5] and WBCadjusted [OR 4.5 (per increase of 100/µl)] as predictors of SAH, while age, sex and CSF total proteinadjusted were no predictors. Optimal cut-point of RBCadjusted (determined at day 1 after bleeding) was > 3667/µl to identify SAH patients with a 97% sensitivity and 94% specificity. Combination of low RBC and clear CSF supernatant was found in none of SAH patients. Combined CSF RBC count and CSF supernatant reliably distinguished traumatic LP from SAH.

Diagnostic Performance of Adding the Optic Nerve Region Assessed by Optical Coherence Tomography to the Diagnostic Criteria for Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: The optic nerve has been recommended as an additional region for demonstrating dissemination in space (DIS) in diagnostic criteria for multiple sclerosis (MS). The aim of this study was to investigate whether adding the optic nerve region as determined by optical coherence tomography (OCT) as part of the DIS criteria improves the 2017 diagnostic criteria. METHODS: From a prospective observational study, we included patients with a first demyelinating event who had complete information to assess DIS and a spectral domain OCT scan obtained within 180 days. Modified DIS criteria (DIS + OCT) were constructed by adding the optic nerve to the current DIS regions based on validated thresholds for OCT intereye differences. Time to second clinical attack was the primary endpoint. RESULTS: We analyzed 267 patients with MS (mean age 31.3 years [SD 8.1], 69% female) during a median observation period of 59 months (range: 13-98). Adding the optic nerve as a fifth region improved the diagnostic performance by increasing accuracy (DIS + OCT 81.2% vs DIS 65.6%) and sensitivity (DIS + OCT 84.2% vs DIS 77.9%) without lowering specificity (DIS + OCT 52.2% vs DIS 52.2%). Fulfilling DIS + OCT criteria (≥2 of 5 DIS + OCT regions involved) indicated a similar risk of a second clinical attack (hazard ratio [HR] 3.6, CI 1.4-14.5) compared with a 2.5-fold increased risk when fulfilling DIS criteria (HR 2.5, CI 1.2-11.8). When the analysis was conducted according to topography of the first demyelinating event, DIS + OCT criteria performed similarly in both optic neuritis and nonoptic neuritis. DISCUSSION: Addition of the optic nerve, assessed by OCT, as a fifth region in the current DIS criteria improves diagnostic performance by increasing sensitivity without lowering specificity. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that adding the optic nerve as determined by OCT as a fifth DIS criterion to the 2017 McDonald criteria improves diagnostic accuracy.

Immune profiling in multiple sclerosis: a single-center study of 65 cytokines, chemokines, and related molecules in cerebrospinal fluid and serum.

Introduction: The understanding of the pathophysiology of multiple sclerosis (MS) has evolved alongside the characterization of cytokines and chemokines in cerebrospinal fluid (CSF) and serum. However, the complex interplay of pro- and anti-inflammatory cytokines and chemokines in different body fluids in people with MS (pwMS) and their association with disease progression is still not well understood and needs further investigation. Therefore, the aim of this study was to profile a total of 65 cytokines, chemokines, and related molecules in paired serum and CSF samples of pwMS at disease onset. Methods: Multiplex bead-based assays were performed and baseline routine laboratory diagnostics, magnetic resonance imaging (MRI), and clinical characteristics were assessed. Of 44 participants included, 40 had a relapsing-remitting disease course and four a primary progressive MS. Results: There were 29 cytokines and chemokines that were significantly higher in CSF and 15 in serum. Statistically significant associations with moderate effect sizes were found for 34 of 65 analytes with sex, age, CSF, and MRI parameters and disease progression. Discussion: In conclusion, this study provides data on the distribution of 65 different cytokines, chemokines, and related molecules in CSF and serum in newly diagnosed pwMS.

Lower initial red blood cell count in cerebrospinal fluid predicts good functional outcome in patients with spontaneous subarachnoid haemorrhage.

BACKGROUND AND PURPOSE: Red blood cell (RBC) degradation after subarachnoid haemorrhage (SAH) negatively affects functional outcome. Although the detection of RBCs in the cerebrospinal fluid (CSF) is a widely available part of neurological routine diagnostics, the prognostic value as a biomarker remains unclear. This study was undertaken to investigate whether CSF RBC count correlates with established radiological markers of SAH volume and whether the CSF RBC count can predict functional outcome in SAH patients. METHODS: A total of 121 consecutive spontaneous SAH patients were retrospectively analyzed. CSF was collected from external ventricular drain as part of routine diagnostic procedures. We used multivariable binary logistic regression to investigate associations between CSF RBC counts and functional outcome 3 months after SAH or hospital survival. Good functional outcome was defined as modified Rankin Scale ≤ 2. RESULTS: Patients' age was 60 ± 14 years, and the median admission Hunt & Hess grade (H&H) was 4. CSF samples were collected 2 days after intensive care unit admission. High CSF RBC counts positively correlated with radiological measurements for SAH volume, for example, modified Fisher score (p = 0.002) and Hijdra ventricle score (p = 0.016). Multivariable regression analysis adjusted for age, H&H grade, modified Fisher and Hijdra scores showed that low CSF RBC counts predicted hospital survival (per 100,000 CSF RBCs: adjusted odds ratio [adjOR] = 0.74, 95% confidence interval [CI] = 0.61-0.89, p = 0.001) and good functional outcome after 3 months (per 100,000 CSF RBC: adjOR = 0.76, 95% CI = 0.60-0.96, p = 0.020). CONCLUSIONS: CSF RBC counts correlate with radiographic scores quantifying SAH volume and may serve as an early independent biomarker for hospital survival and good functional 3-month outcome in patients requiring ventriculostomy after SAH.

Kappa free light chain and neurofilament light independently predict early multiple sclerosis disease activity-a cohort study.

BACKGROUND: Inter-individual courses of multiple sclerosis (MS) are extremely variable. The objective of this study was to investigate whether κ-free light chain (κ-FLC) index and serum neurofilament light (sNfL) have an additive predictive value for MS disease activity. METHODS: Patients with early MS who had cerebrospinal fluid (CSF) and serum sampling at disease onset were followed for four years. At baseline, age, sex, disease duration, number of T2-hyperintense (T2L), and contrast-enhancing T1 lesions (CEL) on MRI were determined. During follow-up, the occurrence of a second clinical attack and start of disease-modifying treatment (DMT) were registered. κ-FLC was measured by nephelometry, and κ-FLC index calculated as [CSF κ-FLC/serum κ-FLC]/albumin quotient. sNfL was determined by single-molecule array, and age- and body-mass-index adjusted Z scores were calculated. FINDINGS: A total of 86 patients at a mean age of 33 ± 10 years and with a female predominance of 67% were included; 36 (42%) patients experienced a second clinical attack during follow-up. Cox regression analysis adjusted for age, sex, T2L, CEL, disease and follow-up duration, and DMT use during follow-up revealed that both κ-FLC index as well as sNfL Z score independently predict time to second clinical attack. The chance for freedom of relapse within 12 months was 2% in patients with high levels of κ-FLC index (>100) and high sNfL Z score (>3), 30% in patients with high κ-FLC index (>100) and lower sNfL Z score (≤3), 70% in patients with lower κ-FLC index (≤100) but high sNfL Z score (>3), and 90% in patients with lower levels of κ-FLC index (≤100) and sNfL Z score (≤3). INTERPRETATION: κ-FLC index and sNfL Z score have an additive predictive value for early MS disease activity that is independent of known predictors. FUNDING: This study was funded by a grant of the charitable foundation of the Austrian Multiple Sclerosis Society.

Screening for osteoporosis in people with MS: A new risk score.

BACKGROUND: Due to the demographic development and improved treatment options, the role of comorbidities is of increasing importance in the medical care of people with MS (pwMS). A higher risk of osteoporosis is well known in chronic autoimmune diseases, and is also described in MS. While there are several screening guidelines in the elderly or in patients with rheumatoid arthritis, there are no generally accepted recommendations when to perform bone mineral testing in pwMS under the age of 65 years. We aimed to determine risk factors of osteoporosis in pwMS and to develop a risk score which can be applied in daily clinical routine. METHODS: Densitometry (hip and lumbar spine) was performed in 159 pwMS aged ≤65 years and in 81 age- and sex-matched healthy controls (HC). Osteoporosis was defined according to WHO criteria as a bone density 2.5 standard deviation or more below the mean of young adults. Risk factors were identified by logistic regression analysis. RESULTS: Osteoporosis occurred more frequently in postmenopausal pwMS and male pwMS as compared to HC. Besides age, sex, menopausal status in females, body-mass-index and smoking, a higher degree of disability - as assessed by the Expanded Disability Status Scale - was identified as MS specific risk factor for osteoporosis, whereas the cumulative glucocorticoid dose was not associated with osteoporosis risk. Based on these risk factors, we developed an MS-specific risk score which allows to estimate the individual probability of osteoporosis. CONCLUSION: This risk score enables individual screening recommendation for pwMS and, subsequently, early prevention of osteoporosis which probably should result in reduction of fractures and morbidity.

Immunization status in patients with multiple sclerosis: A cross-sectional, monocenter study in Austria.

BACKGROUND AND PURPOSE: Patients with multiple sclerosis (MS) under certain disease-modifying therapies (DMT) show a higher risk of infection and a lower immune response to vaccination. Hence, assessing immunization status prior to DMT start and, where necessary, performing vaccinations is  recommended. We aimed to determine the immunization status in MS patients and to identify factors associated with low vaccination rates. METHODS: Patients with MS who were seen at the MS clinic of the Medical University of Innsbruck throughout a period of 14 months in 2020 and 2021 were eligible for inclusion into this prospective, single-center study. Immunization status against 17 different pathogens was obtained from vaccination certificate and by patient questionnaire. Antibody detection against seven antigens was performed in peripheral blood. RESULTS: Of 424 patients with MS at a mean age of 43 ± 12 years, the vast majority had vaccinations against tetanus (94%), diphtheria (92%), and poliomyelitis (90%), whereas a lower proportion had vaccinations against tick-borne encephalitis (70%), pertussis (69%), hepatitis B (65%), rubella (55%), hepatitis A (50%), measles (49%), mumps (47%), and only a minority against influenza (10%), pneumococcal (6%) and meningococcal disease (4%), human papillomavirus (4%), yellow fever (2%), and varicella zoster virus (1%). A total of 87% received vaccination against SARS-CoV-2. Overall, higher vaccination rates were associated with younger age, relapsing disease course, and education level. Misinformation on infectious diseases and vaccines was associated with lower vaccination rates. CONCLUSIONS: The majority of MS patients did not fulfil vaccination recommendations. Efforts to increase vaccination rates, preferentially before DMT start, should be promoted.

Retinal layer thickness predicts disability accumulation in early relapsing multiple sclerosis.

BACKGROUND AND PURPOSE: This study was undertaken to investigate baseline peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell and inner plexiform layer (GCIPL) thickness for prediction of disability accumulation in early relapsing multiple sclerosis (RMS). METHODS: From a prospective observational study, we included patients with newly diagnosed RMS and obtained spectral-domain optical coherence tomography scan within 90 days after RMS diagnosis. Impact of pRNFL and GCIPL thickness for prediction of disability accumulation (confirmed Expanded Disability Status Scale [EDSS] score ≥ 3.0) was tested by multivariate (adjusted hazard ratio [HR] with 95% confidence interval [CI]) Cox regression models. RESULTS: We analyzed 231 MS patients (mean age = 30.3 years, SD = 8.1, 74% female) during a median observation period of 61 months (range = 12-93). Mean pRNFL thickness was 92.6 µm (SD = 12.1), and mean GCIPL thickness was 81.4 µm (SD = 11.8). EDSS ≥ 3 was reached by 28 patients (12.1%) after a median 49 months (range = 9-92). EDSS ≥ 3 was predicted with GCIPL < 77 µm (HR = 2.7, 95% CI = 1.6-4.2, p < 0.001) and pRNFL thickness ≤ 88 µm (HR = 2.0, 95% CI = 1.4-3.3, p < 0.001). Higher age (HR = 1.4 per 10 years, p < 0.001), incomplete remission of first clinical attack (HR = 2.2, p < 0.001), ≥10 magnetic resonance imaging (MRI) lesions (HR = 2.0, p < 0.001), and infratentorial MRI lesions (HR = 1.9, p < 0.001) were associated with increased risk of disability accumulation, whereas highly effective disease-modifying treatment was protective (HR = 0.6, p < 0.001). Type of first clinical attack and presence of oligoclonal bands were not significantly associated. CONCLUSIONS: Retinal layer thickness (GCIPL more than pRNFL) is a useful predictor of future disability accumulation in RMS, independently adding to established markers.

Sexual dysfunction in female and male people with multiple sclerosis: disability, depression and hormonal status matter.

BACKGROUND AND PURPOSE: Sexual dysfunction (SD) in people with multiple sclerosis (pwMS) is common and an often underestimated issue in the care of pwMS. The objective of the study was to evaluate risk factors for SD in pwMS, correlate its prevalence with patient-reported measures (quality of life and physical activity) and analyse its association with hormonal status. METHODS: Sexual dysfunction was determined in 152 pwMS using the Multiple Sclerosis Intimacy and Sexuality Questionnaire 19. A logistical regression model was used to identify independent risk factors for SD. RESULTS: The prevalence of SD in pwMS was 47%. Independent risk factors for the development of SD were ever-smoking (odds ratio [OR] 3.4, p = 0.023), disability as measured by the Expanded Disability Status Scale (OR 2.0, p < 0.001), depression (OR 4.3, p = 0.047) and bladder and bowel dysfunction (OR 8.8, p < 0.001); the use of disease-modifying treatment was associated with a lower risk for SD (OR 0.32, p = 0.043). SD was associated with worse quality of life (Multiple Sclerosis Impact Scale 29: physical score 6.3 vs. 40.0; psychological score 8.3 vs. 33.3; both p < 0.001) and lower physical activity (Baecke questionnaire, p < 0.001). Laboratory analysis revealed significantly higher luteinizing hormone and follicle-stimulating hormone levels and lower 17-beta oestradiol, androstenedione, dehydroepiandrosterone sulfate, oestrone and anti-Mullerian hormone levels in female pwMS with SD. In male pwMS and SD, there was a significant decrease in inhibin B levels. CONCLUSIONS: Our findings highlight the requirement of a holistic approach to SD in MS including physical, neurourological and psychosocial factors. Active screening for SD, especially in patients with disability, depression or bladder and bowel dysfunction, is recommended.

Chasing shadows: Cytologically detected shadow cells in the cerebrospinal fluid of patients with multiple sclerosis.

BACKGROUND: Pathophysiology of multiple sclerosis (MS) is dominated by both inflammation and neurodegeneration. A correlation between inflammation and regulated cell death has been suggested previously. Shadow cells in the cerebrospinal fluid (CSF) are considered apoptotic cells. OBJECTIVE: To assess the occurrence of shadow cells in MS patients in comparison to other neurological diseases (OND). METHODS: We conducted cytological examination of CSF in 114 MS patients and 125 patients with OND, who had diagnostic lumbar puncture at the Department of Neurology, Medical University of Innsbruck, with time to laboratory processing ≤0.5 h, showed a CSF white blood cell (WBC) count ≤50/µl and a red blood cell (RBC) count ≤500/µl. Shadow cells were counted by two blinded, independent, experienced investigators, using a standardized approach on microscopic slides. RESULTS: The number of shadow cells did not statistically significantly differ between patients with MS (median: 12, IQR: 0-85) and OND (median 6, IQR: 0-94; p = 0.106). Multivariable regression analysis including age, sex, time to laboratory processing, CSF WBC and RBC count, CSF/serum glucose ratio, CSF/serum albumin quotient and disease group as independent variables, identified WBC count as significant predictor of shadow cells (ß [ln WBC count]=0.73, p<10-9), whereas the disease group had no impact (p = 0.466). CONCLUSIONS: Occurrence of shadow cells in the CSF seems to depend on the extent of inflammatory cells rather than MS disease-specific mechanisms.

Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: Intrathecal immunoglobulin-G synthesis is a hallmark of multiple sclerosis (MS), which can be detected by oligoclonal IgG bands (OCB) or by κ-free light chains (κ-FLC) in cerebrospinal fluid. OBJECTIVE: To perform a systematic review and meta-analysis to evaluate whether κ-FLC index has similar diagnostic value to identify patients with clinically isolated syndrome (CIS) or MS compared to OCB, and to determine κ-FLC index cut-off. METHODS: PubMed was searched for studies that assessed diagnostic sensitivity and specificity of κ-FLC index and OCB to discriminate CIS/MS patients from control subjects. Two reviewers following preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines performed study eligibility assessment and data extraction. Findings from studies were analyzed with bivariate mixed models. RESULTS: A total of 32 studies were included in the meta-analysis to evaluate diagnostic value of κ-FLC index. Sensitivity and specificity ranged from 52% to 100% (weighted average: 88%) and 69% to 100% (89%) for κ-FLC index and from 37% to 100% (85%) and 74% to 100% (92%) for OCB. Mean difference of sensitivity and specificity between κ-FLC index and OCB was 2 and -4 percentage points. Diagnostic accuracy determined by mixed models revealed no significant difference between κ-FLC index and OCB. A discriminatory cut-off for κ-FLC index was determined at 6.1. CONCLUSION: The findings indicate that κ-FLC index has similar diagnostic accuracy in MS as OCB.

Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A consensus statement.

Cerebrospinal fluid (CSF) analysis is of utmost importance for diagnosis and differential diagnosis of patients with suspected multiple sclerosis (MS). Evidence of intrathecal immunoglobulin G (IgG) synthesis proves the inflammatory nature of the disease, increases diagnostic certainty and substitutes for dissemination in time according to current diagnostic criteria. The gold standard to determine intrathecal IgG synthesis is the detection of CSF-restricted oligoclonal bands (OCBs). However, advances in laboratory methods brought up κ-free light chains (FLCs) as a new biomarker, which are produced in excess over intact immunoglobulins and accumulate in CSF in the case of central nervous system-derived inflammation. Overwhelming evidence showed a high diagnostic accuracy of intrathecal κ-FLC synthesis in MS with sensitivity and specificity of approximately 90% similar to OCB. κ-FLCs have advantages as its detection is fast, easy, cost-effective, reliable, rater-independent and returning quantitative results which might also improve the value of predicting MS disease activity. An international panel of experts in MS and CSF diagnostics developed a consensus of all participants. Six recommendations are given for establishing standard CSF evaluation in patients suspected of having MS. The panel recommended to include intrathecal κ-FLC synthesis in the next revision of MS diagnostic criteria as an additional tool to measure intrathecal immunoglobulin synthesis.

More Efficient Complement Activation by Anti-Aquaporin-4 Compared With Anti-Myelin Oligodendrocyte Glycoprotein Antibodies.

BACKGROUND AND OBJECTIVES: The objective was to study complement-mediated cytotoxicity induced by immunoglobulin G (IgG) anti-aquaporin-4 antibodies (AQP4-IgG) and anti-myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) in human serum samples from patients suffering from the rare demyelinating diseases of the CNS neuromyelitis optica spectrum disorder (NMOSD) and MOG-IgG-associated disease (MOGAD). METHODS: A cell-based assay with HEK293A cells expressing different MOG isoforms (MOGα1-3ß1-3) or AQP4-M23 was used. Cells were incubated with human MOG-IgG or AQP4-IgG-positive serum samples together with active or heat-inactivated human complement, and complement-dependent cytotoxicity (CDC) was measured with a lactate dehydrogenase assay. To further quantify antibody-mediated cell damage, formation of the terminal complement complex (TCC) was analyzed by flow cytometry. In addition, immunocytochemistry of the TCC and complement component 3 (C3) was performed. RESULTS: AQP4-IgG-positive serum samples induced higher CDC and TCC levels than MOG-IgG-positive sera. Notably, both showed a correlation between antibody titers and CDC and also between titers and TCC levels. In addition, all 6 MOG isoforms tested (MOGα1-3ß1-3) could induce at least some CDC; however, the strongest MOG-IgG-induced CDC levels were found on MOGα1, MOGα3, and MOGß1. Different MOG-IgG binding patterns regarding recognition of different MOG isoforms were investigated, and it was found that MOG-IgG recognizing all 6 isoforms again induced highest CDC levels on MOGα1 and MOGß1. Furthermore, surface staining of TCC and C3 revealed positive staining on all 6 MOG isoforms tested, as well as on AQP4-M23. DISCUSSION: Both MOG-IgG and AQP4-IgG are able to induce CDC in a titer-dependent manner. However, AQP4-IgG showed markedly higher levels of CDC compared with MOG in vitro on target cells. This further highlights the role of complement in AQP4-IgG-mediated disease and diminishes the importance of complement activation in MOG-IgG-mediated autoimmune disease.