Humoral immune response after COVID-19 in multiple sclerosis: A nation-wide Austrian study.

BACKGROUND: Knowledge on immunity after SARS-CoV-2 infection in patients with multiple sclerosis (pwMS) and the impact of disease-modifying treatment (DMT) is limited. OBJECTIVE: To evaluate degree, duration and potential predictors of specific humoral immune response in pwMS with prior COVID-19. METHODS: Anti-SARS-CoV-2 antibody testing was performed in pwMS with PCR-confirmed diagnosis of symptomatic COVID-19 from a nation-wide registry. Predictors of seropositivity were identified by multivariate regression models. RESULTS: In 125 pwMS (mean age = 42.4 years (SD = 12.3 years), 70% female), anti-SARS-CoV-2 antibodies were detected in 76.0% after a median of 5.2 months from positive PCR. Seropositivity rate was significantly lower in patients on IS-DMT (61.4%, p = 0.001) than without DMT or immunomodulatory DMT (80.6%; 86.0%, respectively). In multivariate analysis, IS-DMT was associated with reduced probability of seropositivity (odds ratio (OR): 0.51; 95% confidence interval (95% CI): 0.17-0.82; p < 0.001). Predefined subgroup analyses showed marked reduction of seropositivity in pwMS on rituximab/ocrelizumab (OR 0.15; 95% CI: 0.05-0.56; p < 0.001). Rate of seropositivity did not change significantly over 6 months. CONCLUSIONS: Humoral immunity is stable after SARS-CoV-2 infection in MS, but is reduced by immunosuppressive DMT, particularly anti-CD20 monoclonal antibodies. This provides important evidence for advising pwMS as well as for planning and prioritizing vaccination.

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.

Late-onset neutropenia in a multiple sclerosis patient after first dose ocrelizumab switched from rituximab.

Ocrelizumab is a humanized monoclonal anti-CD20 antibody approved for treatment of relapsing-remitting and primary progressive multiple sclerosis (MS). Before approval of this drug, the chimeric anti-CD20 antibody rituximab was used off-label for treatment of MS. On treatment with rituximab late-onset neutropenia (LON) was reported as a rare adverse event. Here we report the case of a patient with MS who first received rituximab without experiencing any hematologic abnormalities, but developed grade IV LON after switching to ocrelizumab. This first case of LON in a patient treated with different anti-CD20 antibodies highlights the necessity of regular hemogram examinations during ocrelizumab.

Validation of inter-eye difference thresholds in optical coherence tomography for identification of optic neuritis in multiple sclerosis.

OBJECTIVE: To examine and validate thresholds for inter-eye differences in peripapillary retinal nerve fibre (pRNFL) and ganglion cell + inner plexiform layer (GCIPL) thicknesses for identifying unilateral optic neuritis in MS. METHODS: In this two-centre, cross-sectional study, optical coherence tomography was performed in 340 patients with clinically isolated syndrome (CIS) and MS. Cut-off values of inter-eye difference for identification of eyes with a history of unilateral ON were evaluated by receiver-operating characteristics analysis. RESULTS: For pRNFL ≥5 µm, sensitivity was 69% and specificity 68%, while for GCIPL ≥4 µm sensitivity was 67% and specificity 78%. The areas under the curve (AUC) were 0.72 (95% confidence interval: 0.64 - 0.79) for pRNFL and 0.78 (95%CI: 0.72 - 0.85) for GCIPL, indicating GCIPL as the superior model (p<0.001). When analysing only CIS patients, GCIPL inter-eye difference ≥4 µm also remained significant, while pRNFL inter-eye difference did not. INTERPRETATIONS: Inter-eye differences of ≥4 µm for GCIPL and to a lesser degree ≥5 µm for RNFL are robust thresholds for identifying unilateral optic nerve lesions. These thresholds could be used to demonstrate previous symptomatic and possibly asymptomatic ON and might be included into a new version of the diagnostic criteria.

Retinal layer thinning is reflecting disability progression independent of relapse activity in multiple sclerosis.

BACKGROUND: PIRA (progression independent of relapse) has emerged as a term to quantify the proportion of disability worsening due to non-inflammatory neurodegenerative processes in multiple sclerosis (MS). OBJECTIVE: To determine the impact of PIRA on retinal thinning, a biomarker of neuroaxonal degeneration in MS, in comparison to traditional disability worsening and relapse. METHODS: In a 4-year, prospective observational study including 171 relapsing MS (RMS) patients, retinal thinning was determined by annual spectral-domain optical coherence tomography measuring macular ganglion-cell-and-inner-plexiform-layer (GCIPL) and peripapillary-retinal-nerve-fibre-layer (pRNFL). PIRA was defined as an expanded disability status scale (EDSS) or symbol digit modalities test (SDMT) worsening confirmed after 24 weeks with no relapse in the 30 days before or after the disability worsening. RESULTS: Each PIRA event was associated with a mean additional loss of GCIPL (1.8 µm) and pRNFL (1.9 µm), similar to the impact of EDSS and SDMT worsening. Overall relapse and relapse without subsequent EDSS worsening did not influence retinal thinning, while a relapse with EDSS worsening was associated with an additional loss of GCIPL (1.3 µm) and pRNFL (1.4 µm). CONCLUSIONS: PIRA is associated with retinal thinning, likely reflecting neurodegenerative processes, not directly associated with focal inflammation. It might be a clinical measure to identify MS patients with ongoing MS-associated neurodegeneration.

Serum hepcidin levels in multiple sclerosis.

BACKGROUND: Brain iron accumulation is associated with multiple sclerosis (MS). Hepcidin is the master regulator of iron homeostasis and distribution. Dysregulation of hepcidin is a feature of different chronic inflammatory diseases but has not been investigated in MS so far. OBJECTIVE: The aim of this study was to determine serum hepcidin levels of MS patients and healthy volunteers serving as controls and to investigate possible relations between hepcidin levels, disease activity and disease course. METHODS: In a cross-sectional design, we measured serum hepcidin levels in 71 MS patients and 16 healthy controls (HC). MS patients were sub-grouped in active relapsing-remitting MS (aRRMS), inactive (i)RRMS, active progressive MS (aPMS) and inactive (i)PMS. Blood parameters were measured by standard laboratory methods. RESULTS: Median hepcidin levels were 26.9 ng/ml (confidence interval (CI) 22.8; 30.9) in MS and 17.3 ng/ml (CI 12.8; 23.4) in HC with significant age and sex effects. Hepcidin correlates were in line with hepcidin as an indicator of iron stores. After correction for age and sex, hepcidin was neither associated with MS subgroups nor degree of disability and occurrence of relapses. CONCLUSIONS: Serum hepcidin levels are not associated with disease activity and disease course in MS.

Fibrinogen is not elevated in the cerebrospinal fluid of patients with multiple sclerosis.

BACKGROUND: Elevated plasma fibrinogen levels are a well known finding in acute infectious diseases, acute stroke and myocardial infarction. However its role in the cerebrospinal fluid (CSF) of acute and chronic central (CNS) and peripheral nervous system (PNS) diseases is unclear. FINDINGS: We analyzed CSF and plasma fibrinogen levels together with routine parameters in patients with multiple sclerosis (MS), acute inflammatory diseases of the CNS (bacterial and viral meningoencephalitis, BM and VM) and PNS (Guillain-Barré syndrome; GBS), as well as in non-inflammatory neurological controls (OND) in a total of 103 patients. Additionally, MS patients underwent cerebral MRI scans at time of lumbar puncture.CSF and plasma fibrinogen levels were significantly lower in patients with MS and OND patients as compared to patients with BM, VM and GBS. There was a close correlation between fibrinogen levels and albumin quotient (rho = 0.769, p < 0.001) which strongly suggests passive transfer of fibrinogen through the blood-CSF-barrier during acute inflammation. Hence, in MS, the prototype of chronic neuroinflammation, CSF fibrinogen levels were not elevated and could not be correlated to clinical and neuroradiological outcome parameters. CONCLUSIONS: Although previous work has shown clear evidence of the involvement of fibrinogen in MS pathogenesis, this is not accompanied by increased fibrinogen in the CSF compartment.