Longitudinal ventricular cerebrospinal fluid profile in patients with spontaneous subarachnoid hemorrhage

BackgroundSpontaneous 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.ObjectiveThis study aimed to describe the longitudinal profile of routine CSF parameters in patients with SAH and to identify associations with neurological complications.MethodsA 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.ResultsA 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.ConclusionLongitudinal CSF characteristics are associated with SAH-related complications

Impact of Disease-Modifying Treatments on the Longitudinal Evolution of Anti-JCV Antibody Index in Multiple Sclerosis

Background: Risk of natalizumab-related progressive multifocal leukoencephalopathy is associated with the presence of anti-JC-virus (JCV) antibodies.Objective: To investigate the impact of disease-modifying treatments (DMT) on the longitudinal evolution of anti-JCV antibody index.Methods: Patients with multiple sclerosis who had serum sampling at intervals of 6 ± 3 months over up to 6 years and who either started DMT (interferon-β, glatiramer acetate or natalizumab) during the observation period with at least one serum sample available before and after treatment initiation or received no DMT during the observation period were included. Anti-JCV antibody serological status and index were determined by 2-step second-generation anti-JCV antibody assay.Results: A total of 89 patients were followed for a median time of 55.2 months. Of those, 62 (69.7%) started DMT and 27 (30.3%) were without therapy during the observation period. Variation of longitudinal anti-JCV antibody index ranged from 9 to 15% and was similar in patients with and without DMT. Applying a mixed model considering the combined effects of treatment and time as well as individual heterogeneity did not show a significant change of anti-JCV antibody index by the start of treatment with interferon-β, glatiramer acetate, or natalizumab.Conclusion: Evaluated DMTs do not impact longitudinal anti-JCV antibody index evolution

Myeloid cell iron uptake pathways and paramagnetic rim formation in multiple sclerosis

In multiple sclerosis (MS), sustained inflammatory activity can be visualized by iron-sensitive magnetic resonance imaging (MRI) at the edges of chronic lesions. These paramagnetic rim lesions (PRLs) are associated with clinical worsening, although the cell type-specific and molecular pathways of iron uptake and metabolism are not well known. We studied two postmortem cohorts: an exploratory formalin-fixed paraffin-embedded (FFPE) tissue cohort of 18 controls and 24 MS cases and a confirmatory snap-frozen cohort of 6 controls and 14 MS cases. Besides myelin and non-heme iron imaging, the haptoglobin-hemoglobin scavenger receptor CD163, the iron-metabolizing markers HMOX1 and HAMP as well as immune-related markers P2RY12, CD68, C1QA and IL10 were visualized in myeloid cell (MC) subtypes at RNA and protein levels across different MS lesion areas. In addition, we studied PRLs in vivo in a cohort of 98 people with MS (pwMS) via iron-sensitive 3 T MRI and haptoglobin genotyping by PCR. CSF samples were available from 38 pwMS for soluble CD163 (sCD163) protein level measurements by ELISA. In postmortem tissues, we observed that iron uptake was linked to rim-associated C1QA-expressing MC subtypes, characterized by upregulation of CD163, HMOX1, HAMP and, conversely, downregulation of P2RY12. We found that pwMS with [Formula: see text] 4 PRLs had higher sCD163 levels in the CSF than pwMS with [Formula: see text] 3 PRLs with sCD163 correlating with the number of PRLs. The number of PRLs was associated with clinical worsening but not with age, sex or haptoglobin genotype of pwMS. However, pwMS with Hp2-1/Hp2-2 haplotypes had higher clinical disability scores than pwMS with Hp1-1. In summary, we observed upregulation of the CD163-HMOX1-HAMP axis in MC subtypes at chronic active lesion rims, suggesting haptoglobin-bound hemoglobin but not transferrin-bound iron as a critical source for MC-associated iron uptake in MS. The correlation of CSF-associated sCD163 with PRL counts in MS highlights the relevance of CD163-mediated iron uptake via haptoglobin-bound hemoglobin. Also, while Hp haplotypes had no noticeable influence on PRL counts, pwMS carriers of a Hp2 allele might have a higher risk to experience clinical worsening

Personalized medicine in Multiple Sclerosis

In der vorliegenden Dissertation werden fünf Originalarbeiten zusammengefasst, in denen klinische und PatientInnen-spezifische Parameter evaluiert werden, die zur Generierung eines individuellen Profils der Multiplen Sklerose (MS) beitragen dem „Innsbruck MS Profil“. In der ersten Arbeit konnten zwei neue Prädiktoren eines ungünstigen Langzeit-Outcomes aufgezeigt werden: chronische Depression und kognitive Dysfunktion. Außerdem konnte gezeigt werden, dass die vollständige Rückbildung der klinischen Symptome der Erstmanifestation einen günstigen Langzeitverlauf vorhersagt. Dagegen ist das Auftreten einer Schwangerschaft im Verlauf nicht mit dem Langzeit-Outcome verknüpft. In zwei weiteren Arbeiten konnte erstmals bewiesen werden, dass eine Erstmanifestation einer Multiplen Sklerose mit einem sogenannten paroxysmalen oder ungewöhnlichen Erstsymptom entgegen der bisher vertretenen Lehrmeinung keinen benignen Langzeitverlauf prädiziert. Daher sollten MS-PatientInnen mit einer solchen Erstmanifestation ebenso wie PatientInnen mit typischen Erstmanifestationen einer möglichst frühen krankheitsmodifizierenden Intervalltherapie zugeführt werden. Eine weitere Originalarbeit zeigte, dass bei MS-PatientInnen, die unter einer Behandlung mit Interferon beta oder Glatirameracetat über zumindest 4 Jahre kein klinisches Anzeichen einer Krankheitsreaktivierung aufweisen, ab dem 45. Lebensjahr die krankheitsmodifizierenden Intervalltherapie mit einem geringen Risiko einer Krankheitsreaktivierung beendet werden kann. Auf Basis dieser Erkenntnis kann die Beratung von MS-PatientInnen hinsichtlich des weiteren therapeutischen Procedere in der beschriebenen Situation erfolgen. Schließlich wurde in einer weiteren Arbeit eine klinische Testbatterie (“PeRiCoMS”) entwickelt, die eine Evaluation von Persönlichkeitsstruktur, Risikowahrnehmung und Coping-Strategien bei MS-PatientInnen ermöglicht. In einer Pilotstudie mit dieser Testbatterie zeigte sich kein systematischer Unterschied in Bezug auf Persönlichkeitsstruktur, Risikowahrnehmung und Coping-Strategien zwischen MS-PatientInnen und gesunden Kontrollen. Die Resultate der vorliegenden Publikationen tragen signifikant zum Erreichen des Fernziels einer personalisierten Medizin in der Behandlung der Multiplen Sklerose bei. Bis zur Realisierung dieses Ziels sind allerdings weitere Untersuchungen zur integrativen Verarbeitung von klinischen und bildgebenden Daten, PatientInnen-spezifischen Charakteristika und Biomarkern notwendig.This thesis comprises five papers evaluating clinical and patient specific personal parameters contributing to the “Innsbruck MS Profile” project in order to create an individual MS profile. As a first result, we were able to identify two new negative predictors for long-term outcome in MS chronic depression and cognitive dysfunction. Additionally, complete remission of symptoms at disease onset revealed to be predictive for a favourable disease course. Also, it was reaffirmed that pregnancy does not have a negative effect on long term outcome in MS. Second, initial presentation with a paroxysmal or unusual symptom, which was long believed to be indicative of a benign disease course, does not indicate a favourable or even benign MS prognosis. Hence, identifying paroxysmal and unusual symptoms as possible first clinical symptoms of MS is paramount. Disease-modifying treatment should be considered early and treatment decisions should be based on the same criteria as in patients with classical onset symptoms. Third, we could show that patients having been treated with interferon beta or glatirameracetate without evidence of clinical disease activity for more than 4 years and aged 45 years have a very high likelihood of remaining relapse free after DMT discontinuation. While we emphasize the importance of regular, close-meshed and thorough clinical evaluation, demographic factors and clinical monitoring allow stratification of risk for disease reactivation after DMT discontinuation and therefore give guidance in daily clinical routine decision making. Fourth, we developed a testing battery (“PeRiCoMS”) evaluating personality, risk attitude and coping strategies in MS patients which is a feasible tool for studies and in routine practice. We did not find relevant systemic differences regarding personality, risk attitude and coping in MS patients, although this will have to be confirmed in future studies. Finally, we believe that the presented research contributes significantly to the goal of personalized medicine in MS. Still, a lot of future research applying an all-encompassing approach including clinical data, neuroimaging, biomarkers and patients characteristics is necessary to enable true individualized medicine in MS.Dr. Gabriel BstehMedical Universität Innsbruck, Dissertation, 2018OeBB(VLID)257097

Ecological validity of walking capacity tests following rehabilitation in people with multiple sclerosis.

BackgroundWalking capacity tests are commonly used to evaluate interventions aiming at reducing walking impairment in people with multiple sclerosis (pwMS). However, their ecological validity has recently been questioned. The aim of the present study was to investigate the ecological validity of the 2- and 6-minutes walking tests (2MWT and 6MWT) and the timed 25-foot walk (T25FW) after 28 days of multidisciplinary inpatient rehabilitation (MIR) in pwMS using accelerometry.MethodsPwMS wore an accelerometer on 7 consecutive days within a 14-day period prior to MIR, performed 2/6MWT and T25FW at the beginning and at the end of MIR, followed by another 7 consecutive days of accelerometry.ResultsSignificant improvements in 2/6MWT and T25FW after MIR in a cohort of 76 pwMS (mean age = 47.9, SD 8.3 years) were overall correlated to a significant gain in everyday life mobility (total steps/day). However, the correlation was strongly dependent on pre-existing walking disability defined by EDSS and only pwMS with "mild" walking impairment (EDSS 2-3.5) were able to transfer benefits measurable by walking capacity tests into improved everyday life mobility, while pwMS with "moderate to severe" walking disability (EDSS 4-6.5) were not.ConclusionEcological validity of changes in walking capacity tests following MIR is strongly dependent on pre-existing walking impairment

Immunosenescence in Neurological Diseases—Is There Enough Evidence?

The aging of the immune system has recently attracted a lot of attention. Immune senescence describes changes that the immune system undergoes over time. The importance of immune senescence in neurological diseases is increasingly discussed. For this review, we considered studies that investigated cellular changes in the aging immune system and in neurological disease. Twenty-six studies were included in our analysis (for the following diseases: multiple sclerosis, stroke, Parkinson’s disease, and dementia). The studies differed considerably in terms of the patient groups included and the cell types studied. Evidence for immunosenescence in neurological diseases is currently very limited. Prospective studies in well-defined patient groups with appropriate control groups, as well as comprehensive methodology and reporting, are essential prerequisites to generate clear insights into immunosenescence in neurological diseases

Different lymphocyte counts of multiple sclerosis patients treated with ofatumumab and ocrelizumab: A retrospective observational study.

INTRODUCTION Patients with Multiple Sclerosis (pwMS) treated with anti-CD20 (cluster of differentiation) monoclonal antibodies (mAbs) such as ocrelizumab (OCR) and ofatumumab (OFA) show a reduction mainly of B-lymphocytes, but also other lymphocyte subsets can be affected by these treatments. There is limited data on differences between lymphocyte subset counts of pwMS after treatment initiation with OCR or OFA. OBJECTIVE To compare lymphocyte subset counts after treatment initiation in pwMS treated with OCR and OFA. METHODS We analyzed 22 pwMS initiated on OFA and 56 sex-, age- and MS course matched pwMS initiated on OCR from 2 prospectively collected observational MS databases (Bern [n: OFA 14, OCR 44] and Vienna [n: OFA 8, OCR 12]) statistically comparing lymphocyte subset counts (Mann Whitney Test). RESULTS We found that pwMS treated with OCR showed a stronger reduction of CD20 B-lymphocytes (P = .001), and a trend towards lower counts of CD8+ T cells (P = .056) compared to pwMS treated with OFA, whereas reduction of total lymphocyte, CD4+ lymphocyte and NK cell count was equally distributed between both treatments. CONCLUSION Different effects on lymphocyte subpopulations appear to be present in pwMS after treatment initiation with different anti-CD20 mAbs. Further studies are needed to determine potential effects on anti-CD20 treatment efficacy as well as treatment associated risks such as failed vaccinations and infections

Stability and predictive value of anti-JCV antibody index in multiple sclerosis: A 6-year longitudinal study.

BACKGROUND:Risk of natalizumab-related progressive multifocal leukoencephalopathy is associated with the presence of anti-JC-virus (JCV) antibodies. OBJECTIVE:To investigate the longitudinal evolution of anti-JCV antibody index and to determine the predictive value of baseline anti-JCV antibody index for long-term stability of anti-JCV antibody status. METHODS:MS patients from the MS centre of Medical University of Innsbruck, who had serum sampling for a time period of 4-6 years at intervals of 6±3 months, were included in this retrospective, longitudinal study. Anti-JCV antibody serological status and index were determined by 2-step second-generation anti-JCV antibody assay. RESULTS:154 patients were included in this study. Median follow-up time was 63.7 months, with median 11 samples available per patient. At baseline, 111 (72.1%) patients were anti-JCV antibody positive. Baseline anti-JCV antibody index significantly correlated with age (R = 0.22, p = 0.005); there was no difference with respect to sex, disease duration or previously used disease-modifying treatment. During follow-up anti-JCV antibody status changed from negative to positive or vice versa in 17% of patients. In seronegative patients at baseline, baseline anti-JCV antibody index was significantly lower in those remaining seronegative at follow-up compared to those converting to seropositivity (median 0.16 vs. 0.24, p = 0.002). In seropositive patients at baseline, index was higher in those remaining seropositive compared to those reverting to seronegativity (2.6 vs. 0.45, p0.90 predicted stable positive serostatus (sensitivity 88.7%, specificity 96.5%) and <0.20 stable negative serostatus (sensitivity 61.3%, specificity 97.6%). CONCLUSIONS:Anti-JCV antibody index remained relatively stable over 6-year follow-up with annual serostatus change of ~3%. Baseline anti-JCV antibody index predicted stable negative and stable positive JCV serostatus

MRI features of idiopathic intracranial hypertension are not prognostic of visual and headache outcome

Abstract Background In idiopathic intracranial hypertension (IIH), certain MRI features are promising diagnostic markers, but whether these have prognostic value is currently unknown. Methods We included patients from the Vienna-Idiopathic-Intracranial-Hypertension (VIIH) database with IIH according to Friedman criteria and cranial MRI performed at diagnosis. Presence of empty sella (ES), perioptic subarachnoid space distension (POSD) with or without optic nerve tortuosity (ONT), posterior globe flattening (PGF) and transverse sinus stenosis (TSS) was assessed and multivariable regression models regarding visual outcome (persistent visual impairment/visual worsening) and headache outcome (headache improvement/freedom of headache) were fitted. Results We included 84 IIH patients (88.1% female, mean age 33.5 years, median body mass index 33.7). At baseline, visual impairment was present in 70.2% and headache in 84.5% (54.8% chronic). Persistent visual impairment occurred in 58.3%, visual worsening in 13.1%, headache improvement was achieved in 83.8%, freedom of headache in 26.2%. At least one MRI feature was found in 78.6% and 60.0% had ≥3 features with POSD most frequent (64.3%) followed by TSS (60.0%), ONT (46.4%), ES (44.0%) and PGF (23.8%). In multivariable models, there was no association of any single MRI feature or their number with visual impairment, visual worsening, headache improvement or freedom. Visual impairment at baseline predicted persistent visual impairment (odds ratio 6.3, p<0.001), but not visual worsening. Chronic headache at baseline was significantly associated with lower likelihood of headache freedom (odds ratio 0.48, p=0.013), but not with headache improvement. Conclusions MRI features of IIH are neither prognostic of visual nor headache outcome