Franziska Di Pauli

Background: The relationship between intrathecal kappa free light chain (κ‐FLC) synthesis and retinal layer atrophy in multiple sclerosis (MS) is unknown. Objective: To investigate whether the κ‐FLC index is associated with peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell plus inner plexiform layer (GCIPL) thickness. Methods: Patients with newly diagnosed clinically isolated syndrome or relapsing MS and available cerebrospinal fluid (CSF) analysis and optical coherence tomography (OCT) were included. Clinical and magnetic resonance imaging (MRI) data were also assessed. κ‐FLC concentrations were measured by nephelometry, and the κ‐FLC index was calculated as (CSF κ‐FLC/serum κ‐FLC)/albumin quotient. Results: A total of 100 patients at a median age of 33 (25th–75th percentile: 25–39) years and a female predominance (58%) were included. In multivariable linear regression analysis adjusted for age, sex, disease duration, number of T2‐hyperintense and number of contrast‐enhancing MRI lesions, the κ‐FLC index was associated with pRNFL (log‐transformed κ‐FLC index: β : −2.51; 95% confidence interval [CI]: −4.01, −1.01; p = 0.001) and GCIPL thinning (log‐transformed κ‐FLC index: β : −1.24, 95% CI: −2.32, −0.17; p = 0.024). Conclusions: Intrathecal plasma cell activity, as measured by the κ‐FLC index, is associated with neuroaxonal damage, as reflected by pRNFL and GCIPL atrophy.

Background: Distinguishing relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) has reshaped understanding of disability accumulation in relapsing multiple sclerosis (RMS). The influence of differing definitions of disability accrual on event rates and RAW/PIRA proportions remains uncertain. Methods: This observational cohort study used Austrian MS Treatment Registry data (2010–2024). A custom algorithm evaluated 1440 definitional variants of disability accrual with varying confirmation duration, baseline modeling, and RAW/PIRA classification, including recently proposed “standardized” criteria. Results: We included 3273 RMS patients (mean age 37.5 years; 67.8% female) with ⩾24 months follow-up, ⩾3 Expanded Disability Status Scale (EDSS) scores, and ⩾1 EDSS score per year, contributing 3525 follow-up periods. Depending on definition, disability accrual varied between 15.7% and 41.6% of follow-ups. PIRA accounted for 56.1%–86.3% of events across definitions, while up to 8.4% were ambiguously classified, mainly due to post-relapse re-baselining or relapses during the confirmation period. Even under “standardized” criteria, 144 definitional combinations remained, with event rates ranging from 19.1% to 21.7% and PIRA contribution varying widely from 59.8% to 85.8%. Conclusion: PIRA predominantly drives disability accrual, yet definitional variation substantially influenced event rates and RAW/PIRA proportions. Transparent reporting and further optimization of definitions are critical for improving comparability, interpretation, and clinical relevance in MS research and care.

Progression independent of relapse activity (PIRA) is the main driver of disability accumulation in relapsing multiple sclerosis (RMS). Retinal layer atrophy measured by optical coherence tomography (OCT) reflects neuroaxonal damage and is associated with PIRA. However, it remains unclear whether this association is driven by subclinical inflammatory activity or reflects true progression independent of acute inflammation. Here, we aimed to investigate the relationship between retinal layer atrophy and progression independent of relapse and MRI activity (PIRMA) to clarify the impact of subclinical inflammatory activity. From an ongoing prospective observational study, patients with RMS meeting the following criteria were included: an OCT scan conducted 3-6 months after disease-modifying treatment (DMT) initiation (rebaseline) and at least one follow-up OCT after ≥12 months. Disability accrual was defined as a composite measure comprising worsening in either Expanded Disability Status, Timed 25-Foot Walk Test, 9-Hole Peg Test, or Symbol Digit Modalities Test using a roving baseline with a 6-month confirmation interval. PIRA was defined as disability accrual without relapse between roving baseline and confirmation. PIRMA was defined as PIRA that remained radiologically silent. We evaluated associations between PIRMA and thinning of the peripapillary retinal nerve fiber layer (pRNFL) and the macular ganglion cell plus inner plexiform layer (GCIPL) using multivariable mixed-effects linear regression models adjusted for relevant covariables (age, sex, disease duration, GCIPL/pRNFL at rebaseline, and moderate vs high-efficacy DMT). A total of 210 patients with RMS (mean age 30.5 years, SD 7.9; 74.1% female) were analyzed over a median observation period of 2.3 years (range 1-5.9 years). PIRMA was observed in 28 (13.3% overall, 41.8% of all disability accruals, 54.1% of PIRA) patients, while PIRA was encountered in 50 (23.8% overall, 77.2% of all disability accruals). Multivariable models revealed that PIRMA (vs no PIRMA) was associated with significantly more pronounced thinning of both GCIPL (0.72% per year, 95% CI 0.50-0.82, p < 0.001) and pRNFL (1.05% per year, 95% CI 0.89-1.18, p < 0.001). Our findings indicate that retinal atrophy is significantly linked with PIRMA, reinforcing its potential as a biomarker of MS-related neuroaxonal degeneration that occurs independently of acute focal inflammation.

Background: The diagnosis of Varicella‐zoster virus related neurological disease (VZD) and Lyme neuroborreliosis (LNB) is based on clinical presentation as well as cerebrospinal fluid (CSF) results.Objectives: To evaluate and compare the diagnostic utility of oligoclonal bands (OCB) and the κ‐free light chain (FLC) index in patients with VZD and LNB.Methods: Patients with the diagnosis of VZD or LNB at the Department of Neurology of the Medical University of Innsbruck between 2008 to 2020 were included. OCB were determined by isoelectric focusing followed by immunoblotting, κ‐FLC were measured by immunonephelometry.Results: A total of 82 patients were included in the study comprising 48 patients with VZD and 34 with LNB. LNB patients exhibited higher κ‐FLC indices (29 [14–45] vs. 4 [2–12], p < 0.001) and were more frequently OCB positive (65% vs. 8%, p < 0.001) than VZD patients. The disease duration was longer in OCB‐positive patients (VZD: 21 [18–28] days; LNB: 15 [7–22] days) compared to OCB‐negative patients (VZD: 10 [5–17] days, p = 0.030; LNB: 5 [4–7] days, p = 0.006). No differences in disease duration were observed between patients with positive or negative κ‐FLC index. In multivariable analysis, OCB positivity was associated with disease duration (Odds Ratio [OR]: 1.11, 95% confidence interval: 1.01–1.23, p = 0.028), while κ‐FLC index was not.Conclusions: In both VZD and LNB, the κ‐FLC index was more frequently positive than OCB, particularly in cases with shorter disease duration. This suggests that the κ‐FLC index may be a more sensitive marker of (sub)acute intrathecal inflammation.

Objectives: This study aims to assess the efficacy of de‐escalating from natalizumab (NTZ) to cladribine (CLAD), dimethyl fumarate (DMF), fingolimod (FTY), ponesimod (PONE), siponimod (SIPO) and teriflunomide (TERI).Material and Methods: We analyzed data from 388 patients in the Austrian MS Treatment Registry who initiated NTZ treatment and remained on therapy for at least 3 months before switching to one of the moderately effective therapies within 1 year. Patients were required to remain on the de‐escalation therapy for at least 3 months.Results: Over a mean treatment duration of 42 months, the estimated ARR (annualized relapse rate) was 0.22 for highly effective therapy and 0.36 for de‐escalation therapies over 61 months (p = 0.009). EDSS scores increased significantly from 2.8 to 3.1 during de‐escalation (p < 0.001). Relapse probability during the treatment gap varied by interval: 14 patients (5.2%) in the < 3 months group, 14 patients (15.7%) in the 3–6 months group, and 13 patients (39.4%) in the 6–12 months group (p < 0.001). Male sex, lower baseline ARR (prior to the initiation of hDMT) and during transition, older age, shorter disease duration, and lower EDSS scores at both baseline and post‐transition were significantly associated with a reduced risk of relapse and longer time to first relapse following de‐escalation.Conclusions: Our findings reveal an increased risk of relapses and EDSS worsening following de‐escalation from NTZ. Additionally, relapse probability and EDSS progression were influenced by ARR during transition and EDSS scores at the end of the transition period.

Background: Reduced bone mass and increased osteoporosis risk are common in people with multiple sclerosis (pwMS). The aim of the study was to identify risk factors for short‐term bone loss in MS.Methods: This prospective study included 139 pwMS (ages 18–65). Baseline data included demographics, body‐mass index, physical activity, smoking, menopause status, 25‐hydroxy vitamin D levels, and history of glucocorticoid use. Bone mineral density (BMD) was measured at baseline and after 2 years using dual‐energy X‐ray absorptiometry (DXA) for the lumbar spine and hip. Disability worsening was assessed by the Expanded Disability Status Scale (EDSS). Additionally, a literature review was conducted on longitudinal data regarding BMD in MS.Results: Over the 2‐year follow‐up period, significant BMD loss was observed in the hip (baseline g/cm²: median 0.898; IQR 0.808–1.014; 2‐year follow‐up: 0.882; 0.784–1.01; p < 0.001), but not in the lumbar spine. Overall, 101 (73.1%) experienced hip BMD loss, with a median decrease of 3.5%. Patients with disability worsening had an approximately 7‐times higher risk of bone loss compared to those without disability worsening (p = 0.013). PwMS with fractures during the follow‐up period had significantly lower hip BMD (0.760, 0.546–0.890 vs. 0.909, 0.828–1.015; p = 0.024), a higher EDSS score (4.4, 2.8–5.8 vs. 2.0, 1.0–4.0 vs. p = 0.026), and were older (59, 46–62 vs. 47, 37–54; p = 0.030) compared to those without fractures.Conclusion: Disability worsening was identified as a risk factor for BMD loss. These findings underscore the need for active monitoring of pwMS with disability worsening to prevent bone loss and, thus, to reduce fracture risk.

Introduction: Lumbar puncture (LP) is a routine clinical procedure and, in some cases, is repeatedly performed for diagnostic or therapeutic reasons. The impact of repeated LP on cerebrospinal fluid (CSF) findings is not clear.Objective: To investigate whether repeated LP is associated with reactive pleocytosis and disruption of blood–CSF barrier function and to determine the role of interval between repeated LP.Methods: Patients with non‐inflammatory neurological disease (NIND) and at least two consecutive LP were included. Longitudinal changes in CSF white blood cell count (WBC), CSF total protein (TP), and CSF/serum albumin quotient (Q_alb) were assessed depending on the time interval between the LP.Results: A total of 73 patients with a median age of 35 years (25th–75th percentile: 25–45) and a female predominance of 75% had second LP after 6 (3–19) days. Twenty (27%) patients developed pleocytosis with an increase of WBC count to 8/μl (6–15) with a maximum of 30/μl. Patients with pleocytosis had the follow‐up LP significantly earlier than patients without pleocytosis, 3.5 (3–7) versus 7 (3–28) days. The majority of patients (90%) with CSF pleocytosis had the second LP within 10 days. Further repeated LP in a subgroup of patients revealed similar findings. CSF TP and Q_alb slightly increased in patients with pleocytosis.Conclusion: Mild “reactive” CSF pleocytosis occurred in approximately one‐third of patients after repeated LP, mostly when performed within 10 days.

Objective: To investigate the impact of transition interval length when switching from natalizumab (NTZ) to anti‐CD20 monoclonal antibodies (antiCD20) on recurrent disease activity and safety in relapsing multiple sclerosis (RMS).Methods: Aggregating data from 8 MS centres in Austria, Switzerland, and Germany, we included RMS patients who (i) continuously received NTZ for ≥3 months, (ii) were switched to antiCD20, and (iii) had ≥12 months follow‐up after switch. The primary endpoint was occurrence of relapse after switch, secondary endpoints included severe infections (CTCAE grade ≥3).Results: Overall, 139 RMS patients were included (70.5% females, mean age at switch 38.8 years [SD 9.7], mean disease duration at switch 11.3 years [SD 6.2], median duration on NTZ 4.4 years [range: 0.3–16.4], median transition interval 58 days [0–180]). Relapse occurred in 18 patients (12.9%) after NTZ discontinuation. Of those, 11 (61.1%) patients relapsed during the transition interval. No patient with a transition interval below 30 days experienced a relapse, compared to 11.1% and 16.1% with transition intervals of 30–44 days and ≥ 45 days, respectively. In multivariable Cox regression, a transition interval ≥ 45 days predicted a 4.73‐fold increased risk of relapse. Over approximately 4 years of follow‐up, six severe infections were reported without any noticeable effect of transition interval length. No PML occurred.Conclusions: Switching from NTZ to antiCD20 is generally both effective and safe. Keeping the transition interval below 30 days provides the optimal balance between preventing recurrent disease activity and ensuring safety.

Background: Neurological symptoms are common in acute mountain sickness (AMS); however, the extent of neuroaxonal damage remains unclear. Neurofilament light chain (NfL) is an established blood biomarker for neuroaxonal damage.Objective: To investigate whether plasma (p) NfL levels increase after simulated altitude exposure, correlate with the occurrence of AMS, and might be mitigated by preacclimatization.Methods: Healthy subjects were exposed to simulated high altitude (4500 m) by the use of a normobaric hypoxic chamber at the University of Innsbruck two times, that is, within Cycle 1 (C1) over 12 h, and within Cycle 2 (C2) for another 12 h but with a random assignment to prior acclimatization or sham acclimatization. Before each cycle (measurement [M] 1 and 3) and after each cycle (M2 and M4), clinical data (arterial oxygen saturation [SaO₂], heart rate, and Lake Louise AMS score [LLS]) and plasma samples were collected. pNfL was measured using single‐molecule array (Simoa) technique.Results: pNfL levels did not significantly change within each study cycle, but increased over the total study period (M1: 4.57 [3.34–6.39], M2: 4.58 [3.74–6.0], M3: 5.64, and M4: 6.53 [4.65–7.92] pg/mL, p < 0.001). Subjects suffering from AMS during the study procedures showed higher pNfL levels at M4 (6.80 [6.19–8.13] vs. 5.75 [4.17–7.35], p = 0.048), a higher total pNfL increase (2.88 [1.21–3.48] vs. 0.91 [0.53–1.48], p = 0.022) compared to subjects without AMS. An effect of preacclimatization on pNfL levels could not be observed.Conclusions: pNfL increases alongside exposure to simulated altitude and is associated with AMS.

Background and Purpose: Prognostication in patients with spontaneous subarachnoid hemorrhage (SAH) can be challenging. The aim of this study was to assess whether cerebrospinal fluid (CSF) red blood cell (RBC) count and total protein (TP) concentration are associated with SAH prognosis.Methods: Patients with SAH treated at the neurological intensive care unit (ICU) in Innsbruck were included in this real‐world, observational study. Longitudinal CSF samples were collected as part of routine diagnostics. RBC count and CSF TP at the time of admission (RBC_first, TP_first), in Week 1 (RBC_Days1–7, TP_Days1–7), Week 2 (RBC_Days8–14, TP_Days8–14), and Week 3 or thereafter (RBC_Day>14, TP_Day>14), the highest detected value (RBC_highest, TP_highest), as well as the RBC count adjusted for disease duration (RBC_adjusted) were assessed. Primary outcomes were good functional outcome after 3 months, defined as modified Rankin scale score ≤2 and ICU survival.Results: A total of 183 SAH patients with a female predominance (69%), a median (interquartile range [IQR]) age of 60 (50–70) years and median (IQR) Hunt and Hess score of 4 (3–5) were included. Multivariable analyses revealed that lower values of RBC_first, RBC_adjusted, RBC_highest, TP_first and TP_highest were associated with good functional outcome and hospital survival. Lower TP concentrations in Weeks 1, 2 and 3 were associated with good functional outcome, and in Weeks 1 and 2 with ICU survival. Early RBC measurements (Week 1) were associated with good functional outcome and ICU survival.Conclusions: Low CSF RBC counts and TP concentrations were associated with good functional outcome and ICU survival in a real‐world cohort of SAH patients requiring external ventricular drainage.