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.

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.

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.

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.

Retinal layer thinning as a biomarker of long-term disability progression in multiple sclerosis.

BACKGROUND: Peripapillary retinal nerve fibre layer and macular ganglion cell plus inner plexiform layer thinning are markers of neuroaxonal degeneration in multiple sclerosis. OBJECTIVE: We aimed to investigate the value of peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer thinning for prediction of long-term disability. METHODS: This is a 6-year prospective longitudinal study on 93 multiple sclerosis patients. Optical coherence tomography scans were performed at baseline, after 1, 2 and 6 years. Primary endpoint was disability progression after 6 years, defined as expanded disability status scale worsening and/or cognitive deterioration. Univariate and multivariate analysis was used to investigate the value of peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer to predict the primary endpoint. RESULTS: A total of 57 (61.3%) patients had disability worsening, 40 (43.0%) expanded disability status scale worsening and 34 (36.6%) cognitive deterioration. Mean peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer baseline thickness were 93.0 and 75.2 µm, and mean annualised peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer thinning rates over 6 years were 1.3 and 1.6 µm, respectively. Univariate and multivariate analysis revealed lower peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer baseline thickness and higher annualised thinning rates in patients with disability progression after 6 years. Effects were more pronounced for ganglion cell plus inner plexiform layer and expanded disability status scale worsening than for peripapillary retinal nerve fibre layer models and cognitive deterioration. CONCLUSION: Ganglion cell plus inner plexiform layer and peripapillary retinal nerve fibre layer measurements depict neurodegeneration and predict disability progression in multiple sclerosis.

Olfactory threshold predicts treatment response in relapsing multiple sclerosis.

BACKGROUND: Olfactory threshold (OT) is associated with short-term inflammatory activity in relapsing multiple sclerosis (RMS). OBJECTIVE: We aimed to investigate OT for prediction of treatment response in RMS. METHODS: In this 5-year prospective study on 123 RMS patients, OT was measured at disease-modifying treatment (DMT) initiation (M0), after 3 months (M3), and 12 months (M12) by Sniffin' Sticks test. Primary endpoint was defined as an absence of relapse during the observation period, with Expanded Disability Status Scale (EDSS) progression and magnetic resonance imaging (MRI) activity being the secondary endpoints. Optimal cutoff values were determined by receiver operating characteristic analyses and their predictive value assessed by multivariable Cox regression models. RESULTS: Higher OT scores at M0, M3, and M12 were independently associated with decreased relapse probability with the strongest risk reduction at M3 (hazard ratio (HR) = 0.44, p < 0.001). Improvement of OT scores from M0 to M3 (ΔOTM3) was also associated with reduced relapse risk (HR = 0.12, p < 0.001). OT score > 6.5 at M3 was the strongest predictor of relapse freedom (HR = 0.10, p < 0.001) with high diagnostic accuracy (positive predictive value (PPV) = 87%), closely followed by ΔOTM3 ⩾ 0.5 (HR = 0.12, p < 0.001, PPV = 86%). CONCLUSIONS: OT is an independent predictor of freedom of disease activity upon DMT initiation within 5 years and may be a useful biomarker of treatment response.

Macular ganglion cell-inner plexiform layer thinning as a biomarker of disability progression in relapsing multiple sclerosis.

BACKGROUND: Macular ganglion cell-inner plexiform layer (mGCIPL) is an emerging biomarker of neuroaxonal degeneration in multiple sclerosis (MS). OBJECTIVE: We aimed to determine cut-off values of mGCIPL thinning for discriminating between progressing and stable patients in relapsing multiple sclerosis (RMS). METHODS: This is a 3-year prospective longitudinal study on 183 RMS patients with annual optical coherence tomography. Best possible cut-off values of baseline mGCIPL and annual loss of macular ganglion cell-inner plexiform layer (aLmGCIPL) for discriminating clinically progressing (physical progression or cognitive decline) from stable patients were defined by receiver operating characteristics analysis and tested using multivariate regression models. RESULTS: Baseline mGCIPL thickness <77 µm was associated with an increased risk (hazard ratio: 2.7, 95% confidence interval (CI): 1.5-4.7, p < 0.001) of disability progression. An aLmGCIPL cut-off ⩾1 µm accurately identified clinically progressing patients (87% sensitivity at 90% specificity) and was a strong predictor of clinical progression (odds ratio: 18.3, 95% CI: 8.8-50.3). CONCLUSION: We present evidence that cross-sectionally measured mGCIPL thickness and annualized thinning rates of mGCIPL are able to identify clinically progressing RMS with high accuracy.

Cerebrospinal fluid protein in Guillain-Barré syndrome: Need for age-dependent interpretation.

BACKGROUND AND PURPOSE: Elevated cerebrospinal fluid (CSF) total protein in patients with acute ascending paresis is indicative of Guillain-Barré syndrome (GBS). Recent studies showed that the outdated, but still widely used upper reference limit (URL) for CSF total protein of 0.45 g/L leads to false-positive results, mainly as a result of lack of age-adjustment. The objective of this study was to assess the frequency of increased CSF total protein in adult GBS patients according to a new age-dependent URL. METHODS: Patients with GBS treated at the Medical University of Innsbruck between 2000 and 2018 were included in this study. Demographic, clinical, electrophysiological and CSF data were obtained from patients' medical charts. Frequency of increased CSF total protein depending on disease duration was compared using the conventional URL of 0.45 g/L and the age-dependent URL. RESULTS: Ninety-seven patients with GBS aged 57 ± 18 years, comprising 38% women, underwent CSF sampling within a median of 6 days after symptom onset. The median CSF total protein concentration was 0.65 g/L and correlated with disease duration. Overall, 74% of patients had elevated CSF total protein levels using the conventional URL, as opposed to 52% applying the age-dependent URL. At 0-3, 4-7, 8-14 and >14 days after disease onset, elevated CSF total protein was found in 46%, 84%, 78% and 100% of patients using the conventional URL, and in 32%, 53%, 65% and 64% of patients using the age-dependent URL. In multivariate analysis, significant predictors of elevated CSF total protein were disease duration and the demyelinating GBS variant. Similar results were obtained for CSF/serum albumin quotient (Qalb ). CONCLUSION: Fewer true-positives for CSF total protein and Qalb must be considered in suspected GBS, especially in the early disease course.

Retinal layer thinning predicts treatment failure in relapsing multiple sclerosis.

BACKGROUND AND PURPOSE: Peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell plus inner plexiform layer (GCIPL) thinning are markers of neuroaxonal degeneration in multiple sclerosis (MS), which is reduced by disease-modifying treatment (DMT). We aimed to investigate the potential of pRNFL and GCIPL thinning for prediction of DMT failure in relapsing MS (RMS). METHODS: In this 4-year prospective observational study on 113 RMS patients, pRNFL and GCIPL were measured at DMT initiation and after 12 months (M12) and 24 months (M24). Treatment failure was defined as 6-month confirmed Expanded Disability Status Scale (EDSS) progression and/or Symbol Digit Modalities Test (SDMT) worsening. Optimal cutoff values for predicting treatment failure were determined by receiver operating characteristic analyses and hazard ratios (HRs) by multivariable Cox regression adjusting for age, sex, disease duration, EDSS/SDMT, and DMT class. RESULTS: Thinning of GCIPL >0.5 µm/year at M24 showed superior value for treatment failure prediction (HR: 4.5, 95% confidence interval [CI]: 1.8-7.6, p < 0.001; specificity 91%, sensitivity 81%), followed by GCIPL >0.5 µm at M12 (odds ratio [OR]: 3.9, 95% CI: 1.4-6.9, p < 0.001; specificity 85%, sensitivity 78%), and pRNFL ≥2 µm/year at M24 (OR: 3.7, 95% CI: 1.1-6.5, p = 0.023; specificity 84%, sensitivity 69%), whereas pRNFL at M12 was not predictive. CONCLUSIONS: GCIPL, and to a lesser degree pRNFL, thinning predicts disability progression after DMT initiation and may be a useful and accessible biomarker of treatment failure in RMS.

Quantifying the risk of disease reactivation after interferon and glatiramer acetate discontinuation in multiple sclerosis: The VIAADISC score.

BACKGROUND AND PURPOSE: There is a lack of evidence guiding discontinuation of disease-modifying therapy (DMT) in relapsing multiple sclerosis (RMS). Thus, the objective of this study was to generate and validate a risk score for disease reactivation after DMT discontinuation in RMS. METHODS: We drew a generation and validation dataset from two separate prospectively collected observational databases including RMS patients who received interferon-ß or glatiramer acetate for ≥12 months, then discontinued DMT for ≥6 months and had ≥2 years of follow-up available. In the generation sample (n = 168), regression analysis was performed to identify clinical or magnetic resonance imaging (MRI) variables independently predicting disease reactivation after DMT discontinuation. A predictive score was calculated using the variables included in the multivariable model and applied to the validation sample (n = 98). RESULTS: The variables included in the final model as independent predictors of disease reactivation were age at discontinuation, MRI activity at discontinuation, and duration of clinical stability (all p < 0.001). The resulting score was able to robustly identify patients at high (83%-85%), moderate (36%-38%), and low risk (7%) of disease reactivation within 5 years after DMT discontinuation in both cohorts. CONCLUSIONS: The composite VIAADISC score is a valuable tool to inform and support patients and neurologists in the process of decision making to discontinue injectable DMTs.

Serum neurofilament levels correlate with retinal nerve fiber layer thinning in multiple sclerosis.

BACKGROUND: Serum neurofilament light chain (sNfL) levels and peripapillary retinal nerve fiber layer (pRNFL) are both emerging biomarkers of neuro-axonal damage in multiple sclerosis (MS). However, data on the relation between sNfL and pRNFL are scarce. OBJECTIVE: We aimed to determine the relation of sNfL levels with pRNFL thinning in a large cohort of relapsing-remitting (RR) MS patients. METHODS: We identified 80 patients from a prospective, 3-year observational study on retinal changes in RRMS with annual blood samples available. sNfL levels were measured using single-molecule array (SimoaTM) assay. Annualized loss of pRNFL (aLpRNFL) was determined by individual linear regression models. Correlations between single and repeated sNfL levels and aLpRNFL were analyzed using multivariate linear regression and mixed-effect models. RESULTS: After correction for sex, age, and baseline sNfL, an sNfL increase of 10 pg/mL was associated with an aLpRNFL of -0.7 µm (95% confidence interval (CI): (-1.3, -0.2), p < 0.001). Patients with ⩾2 sNfL measurements >75th percentile displayed higher aLpRNFL (2.2 µm, standard deviation (SD) 0.6) compared to patients with no sNfL measure >75th percentile (0.4 µm, SD 0.2, p < 0.001). Between 15% and 20% of the aLpRNFL variance could be predicted from sNfL levels. CONCLUSION: sNfL levels contribute to the prediction of retinal thinning in patients with RRMS, strengthening its value as a biomarker of neuro-axonal damage.

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.

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.

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.

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.

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.

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.

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.

Longitudinal ventricular cerebrospinal fluid profile in patients with spontaneous subarachnoid hemorrhage.

Background: Spontaneous subarachnoid hemorrhage (SAH) is a severe neurological disease that frequently requires placement of external ventricular drainage (EVD). Cerebrospinal fluid (CSF) obtained via the drain is used to detect potential complications of SAH. Objective: This study aimed to describe the longitudinal profile of routine CSF parameters in patients with SAH and to identify associations with neurological complications. Methods: A total of thirty-three patients with spontaneous SAH who required an EVD and had at least three consecutive CSF samples collected over a period of more than 7 days were included in this study. Results: A median of 6 longitudinally collected CSF samples per patient were available within 1-22 days after SAH onset. Overall, red blood cells (RBC) steadily decreased over time, whereas white blood cells (WBC) and total protein (TP) increased until days 6 and 13, respectively, and decreased thereafter. The estimated decay rates of RBC, WBC, and TP were 28, 22, and 6% per day. Distinct CSF patterns over time were linked to known complications after SAH. Patients with rebleeding showed increased RBC, TP, and phagocytosing cells compared to patients without re-bleeding. For ventriculitis, an elevated cell index with a higher proportion of granulocytes was characteristic. CSF of patients with delayed cerebral ischemia showed increased RBC and WBC compared to patients without DCI. Early CSF WBC and cell index were predictive for the occurrence of DCI and ventriculitis later during the disease course. The amount of daily CSF drainage via EVD had no impact on routine CSF parameters. Conclusion: Longitudinal CSF characteristics are associated with SAH-related complications.

Recovery of Chronic Inflammatory Demyelinating Polyneuropathy on Treatment With Ocrelizumab in a Patient With Co-Existing Multiple Sclerosis.

The chimeric anti-CD20 antibody rituximab has demonstrated good efficacy as an off-label treatment in chronic inflammatory demyelinating polyneuropathy (CIDP), while the humanized anti-CD20 antibody ocrelizumab has been approved for treatment of multiple sclerosis (MS), whereas there is no evidence for its use in CIDP so far. We present a patient suffering from CIDP and MS, both refractory to standard treatment and both showing marked improvement on ocrelizumab. To the best of our knowledge, this is a unique report of CIDP with an almost full electrophysiological recovery on ocrelizumab which could be considered as a potential treatment option for refractory CIDP.