Turning When Using Smartphone in Persons With and Those Without Neurologic Conditions: Observational Study.

BACKGROUND: Turning during walking is a relevant and common everyday movement and it depends on a correct top-down intersegmental coordination. This could be reduced in several conditions (en bloc turning), and an altered turning kinematics has been linked to increased risk of falls. Smartphone use has been associated with poorer balance and gait; however, its effect on turning-while-walking has not been investigated yet. This study explores turning intersegmental coordination during smartphone use in different age groups and neurologic conditions. OBJECTIVE: This study aims to evaluate the effect of smartphone use on turning behavior in healthy individuals of different ages and those with various neurological diseases. METHODS: Younger (aged 18-60 years) and older (aged >60 years) healthy individuals and those with Parkinson disease, multiple sclerosis, subacute stroke (<4 weeks), or lower-back pain performed turning-while-walking alone (single task [ST]) and while performing 2 different cognitive tasks of increasing complexity (dual task [DT]). The mobility task consisted of walking up and down a 5-m walkway at self-selected speed, thus including 180° turns. Cognitive tasks consisted of a simple reaction time test (simple DT [SDT]) and a numerical Stroop test (complex DT [CDT]). General (turn duration and the number of steps while turning), segmental (peak angular velocity), and intersegmental turning parameters (intersegmental turning onset latency and maximum intersegmental angle) were extracted for head, sternum, and pelvis using a motion capture system and a turning detection algorithm. RESULTS: In total, 121 participants were enrolled. All participants, irrespective of age and neurologic disease, showed a reduced intersegmental turning onset latency and a reduced maximum intersegmental angle of both pelvis and sternum relative to head, thus indicating an en bloc turning behavior when using a smartphone. With regard to change from the ST to turning when using a smartphone, participants with Parkinson disease reduced their peak angular velocity the most, which was significantly different from lower-back pain relative to the head (P<.01). Participants with stroke showed en bloc turning already without smartphone use. CONCLUSIONS: Smartphone use during turning-while-walking may lead to en bloc turning and thus increase fall risk across age and neurologic disease groups. This behavior is probably particularly dangerous for those groups with the most pronounced changes in turning parameters during smartphone use and the highest fall risk, such as individuals with Parkinson disease. Moreover, the experimental paradigm presented here might be useful in differentiating individuals with lower-back pain without and those with early or prodromal Parkinson disease. In individuals with subacute stroke, en bloc turning could represent a compensative strategy to overcome the newly occurring mobility deficit. Considering the ubiquitous smartphone use in daily life, this study should stimulate future studies in the area of fall risk and neurological and orthopedic diseases. TRIAL REGISTRATION: German Clinical Trials Register DRKS00022998; https://drks.de/search/en/trial/DRKS00022998.

Severe meningo-/encephalitis after daclizumab therapy for multiple sclerosis.

BACKGROUND: Daclizumab is a monoclonal antibody that binds the high-affinity interleukin-2 receptor and was approved for the treatment of relapsing multiple sclerosis. Due to severe inflammatory brain disorders, the approval was suspended in March 2018. OBJECTIVE AND METHODS: This retrospective cohort study summarizes clinical, laboratory, radiological, and histological findings of seven patients who developed meningo-/encephalitis after daclizumab therapy. RESULTS: Patients presented with encephalitis and/or meningitis and suffered from systemic symptoms such as fever (5/7), exanthema (5/7), or gastrointestinal symptoms (4/7). Secondary autoimmune diseases developed. Blood analysis revealed an increase in eosinophils (5/7). Six patients fulfilled the diagnostic criteria for a drug reaction with eosinophilia and systemic symptoms (DRESS). Magnetic resonance imaging (MRI) showed multiple contrast-enhancing lesions, and enhancement of the ependyma (6/7), meninges (5/7), cranial or spinal nerves (2/7), and a vasculitic pattern (3/7). Histology revealed a pronounced inflammatory infiltrate consisting of lymphocytes, plasma cells and eosinophils, and densely infiltrated vessels. Most patients showed an insufficient therapeutic response and a high disability at last follow-up (median Expanded Disability Status Scale (EDSS) 8). Two patients died. CONCLUSION: Meningoencephalitis and DRESS may occur with daclizumab therapy. This potential lethal side effect is characterized by a dysregulated immune response. Our findings underline the importance of postmarketing drug surveillance.

A standardised frankincense extract reduces disease activity in relapsing-remitting multiple sclerosis (the SABA phase IIa trial).

OBJECTIVE: To investigate whether oral administration of a standardised frankincense extract (SFE) is safe and reduces disease activity in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: We performed an investigator-initiated, bicentric phase IIa, open-label, baseline-to-treatment pilot study with an oral SFE in patients with RRMS (NCT01450124). After a 4-month baseline observation phase, patients were treated for 8 months with an option to extend treatment for up to 36 months. The primary outcome measures were the number and volume of contrast-enhancing lesions (CEL) measured in MRI during the 4-month treatment period compared with the 4-month baseline period. Eighty patients were screened at two centres, 38 patients were included in the trial, 28 completed the 8-month treatment period and 18 of these participated in the extension period. RESULTS: The SFE significantly reduced the median number of monthly CELs from 1.00 (IQR 0.75-3.38) to 0.50 (IQR 0.00-1.13; difference -0.625, 95% CI -1.25 to -0.50; P<0.0001) at months 5-8. We observed significantly less brain atrophy as assessed by parenchymal brain volume change (P=0.0081). Adverse events were generally mild (57.7%) or moderate (38.6%) and comprised mainly gastrointestinal symptoms and minor infections. Mechanistic studies showed a significant increase in regulatory CD4+ T cell markers and a significant decrease in interleukin-17A-producing CD8+ T cells indicating a distinct mechanism of action of the study drug. INTERPRETATION: The oral SFE was safe, tolerated well and exhibited beneficial effects on RRMS disease activity warranting further investigation in a controlled phase IIb or III trial. CLINICAL TRIAL REGISTRATION: NCT01450124; Results.

Successful Replication of GWAS Hits for Multiple Sclerosis in 10,000 Germans Using the Exome Array.

Genome-wide association studies (GWAS) successfully identified various chromosomal regions to be associated with multiple sclerosis (MS). The primary aim of this study was to replicate reported associations from GWAS using an exome array in a large German study. German MS cases (n = 4,476) and German controls (n = 5,714) were genotyped using the Illumina HumanExome v1-Chip. Genotype calling was performed with the Illumina Genome Studio(TM) Genotyping Module, followed by zCall. Single-nucleotide polymorphisms (SNPs) in seven regions outside the human leukocyte antigen (HLA) region showed genome-wide significant associations with MS (P values < 5 × 10(-8) ). These associations have been reported previously. In addition, SNPs in three previously reported regions outside the HLA region yielded P values < 10(-5) . The effect of nine SNPs in the HLA region remained (P < 10(-5) ) after adjustment for other significant SNPs in the HLA region. All of these findings have been reported before or are driven by known risk loci. In summary, findings from previous GWAS for MS could be successfully replicated. We conclude that the regions identified in previous GWAS are also associated in the German population. This reassures the need for detailed investigations of the functional mechanisms underlying the replicated associations.

Distinct functionality of neutrophils in multiple sclerosis and neuromyelitis optica.

BACKGROUND: In contrast to multiple sclerosis (MS), lesions in neuromyelitis optica (NMO) frequently contain neutrophils. However, the phenotypic profile of neutrophils in these two distinct pathologies remains unknown. OBJECTIVE: Our aim is to better understand the potential contribution of neutrophils to NMO and MS pathology. METHODS: We performed the first functional analysis of blood neutrophils in NMO and MS, including evaluation of neutrophil immune response (fMLP receptor, TLR2), chemotaxis and migration (CXCR1, CD62L, CD43), regulation of complement (CD46, CD55, CD59), respiratory burst, phagocytosis and degranulation. RESULTS: Compared with healthy controls (HC), neutrophils in NMO and MS show an activated phenotype characterized by an increased surface expression of TLR2 and fMLP receptor. However, contrary to MS neutrophils, NMO neutrophils show reduced adhesion and migratory capacity as well as decreased reduced production of reactive oxygen species (respiratory burst) and degranulation. CONCLUSION: Although NMO and MS neutrophils display an activated phenotype in comparison with HC, NMO neutrophils show a compromised functionality when compared with MS patients. These results suggest a distinct functional profile of neutrophils in MS and NMO.

A multiple sclerosis-associated variant of CBLB links genetic risk with type I IFN function.

Multiple sclerosis (MS) is an autoimmune disease of the CNS, and autoreactive CD4(+) T cells are considered important for its pathogenesis. The etiology of MS involves a complex genetic trait and environmental triggers that include viral infections, particularly the EBV. Among the risk alleles that have repeatedly been identified by genome-wide association studies, three are located near the Casitas B-lineage lymphoma proto-oncogene b gene (CBLB). The CBLB protein (CBL-B) is a key regulator of peripheral immune tolerance by limiting T cell activation and expansion and hence T cell-mediated autoimmunity through its ubiquitin E3-ligase activity. In this study, we show that CBL-B expression is reduced in CD4(+) T cells from relapsing-remitting MS (RR-MS) patients during relapse. The MS risk-related single nucleotide polymorphism of CBLB rs12487066 is associated with diminished CBL-B expression levels and alters the effects of type I IFNs on human CD4(+) T cell proliferation. Mechanistically, the CBLB rs12487066 risk allele mediates increased binding of the transcription factor C/EBPß and reduced CBL-B expression in human CD4(+) T cells. Our data suggest a role of the CBLB rs12487066 variant in the interactions of a genetic risk factor and IFN function during viral infections in MS.

Boswellic acids reduce Th17 differentiation via blockade of IL-1ß-mediated IRAK1 signaling.

Interferon-gamma producing CD4(+) T (Th1) cells and IL-17-producing CD4(+) T (Th17) cells are involved in the pathogenesis of several autoimmune diseases including multiple sclerosis. Therefore, the development of treatment strategies controlling the generation and expansion of these effector cells is of high interest. Frankincense, the resin from trees of the genus Boswellia, and particularly its prominent bioactive compound acetyl-11-keto-ß-boswellic acid (AKBA), have potent anti-inflammatory properties. Here, we demonstrate that AKBA is able to reduce the differentiation of human CD4(+) T cells to Th17 cells, while slightly increasing Th2- and Treg-cell differentiation. Furthermore, AKBA reduces the IL-1ß-triggered IL-17A release of memory Th17 cells. AKBA may affect IL-1ß signaling by preventing IL-1 receptor-associated kinase 1 phosphorylation and subsequently decreasing STAT3 phosphorylation at Ser727, which is required for Th17-cell differentiation. The effects of AKBA on Th17 differentiation and IL-17A release make the compound a good candidate for potential treatment of Th17-driven diseases.

Detection of Spinal Cord Multiple Sclerosis Lesions Using a 3D-PSIR Sequence at 1.5 T.

PURPOSE: Multiple sclerosis (MS) is a prevalent autoimmune inflammatory disease. Besides cerebral manifestations, an affection of the spinal cord is typical; however, imaging of the spinal cord is difficult due to its anatomy. The aim of this study was to assess the diagnostic value of a 3D PSIR pulse sequencing at a 1.5 T magnetic field strength for both the cervical and thoracic spinal cord. METHODS: Phase sensitive inversion recovery (PSIR), short tau inversion recovery (STIR) and T2-weighted (T2-w) images of the spinal cord of 50 patients were separately evaluated by three radiologists concerning the number and location of MS lesions. Furthermore, lesion to cord contrast ratios were determined for the cervical and thoracic spinal cord. RESULTS: Of the lesions 54.81% were located in the cervical spinal cord, 42.26% in the thoracic spinal cord and 2.93% in the conus medullaris. The PSIR images showed a higher sensitivity for lesion detection in the cervical and thoracic spinal cord (77.10% and 72.61%, respectively) compared to the STIR images (58.63% and 59.10%, respectively) and the T2-w images (59.95% and 59.52%, respectively). The average lesion to cord contrast ratio was significantly higher in the PSIR images compared to the STIR images (p < 0.001) and the T2-w images (p < 0.001). CONCLUSION: Evaluation of the spinal cord with a 3D PSIR sequence at a magnetic field strength of 1.5 T is feasible with a high sensitivity for the detection of spinal MS lesions for the cervical as well as the thoracic segments. In combination with other pulse sequences it might become a valuable addition in an advanced imaging protocol.

Automatic lesion detection at Multiple Sclerosis patients - Comparison of 2D- and 3D-FLAIR-datasets.

BACKGROUND: Multiple Sclerosis (MS) is a common autoimmune inflammatory disease of the central nervous system (CNS). Magnetic Resonance Imaging (MRI) allows a sensitive assessment of the CNS and is established for diagnostic, prognostic and (therapy-) monitoring purposes. Especially lesion counting in T2- or Fluid Attenuated Inversion Recovery (FLAIR)-weighted images plays a decisive role in clinical routine. Software-packages allowing an automatic evaluation of image data are increasingly established aiming a faster and improved workflow. These programs allow e.g. the counting, spatial attribution and volumetry of MS-lesions in FLAIR-weighted images. Research has shown that 3D-FLAIR-sequences are superior to 2D-FLAIR-sequences in visual evaluation of lesion burden in MS. An influence on the automatic analysis is expectable but not yet systematically studied. This work will therefore investigate the influence of 2D- and 3D datasets on the results of an automatic assessment. MATERIAL AND METHODS: In this prospective study, 80 Multiple Sclerosis patients underwent a clinically indicated routine MRI examination. The clinical routine protocol already including a 3D-FLAIR sequence was adapted by an additional 2D-FLAIR sequence also conform to the 2021 MAGNIMS-CMSCNAIMS consensus recommendations. To obtain a quantitative analysis for assessment of amount, dissemination and volume of the lesions, the acquired MR images were post-processed using the CE-certified Software mdbrain (mediaire, Berlin, Germany). The resulting data were statistically analysed using the paired t-test for normally distributed data and the Wilcoxon-signed-rank-test for not normally distributed data respectively. Demographic data and data such as the subtype, duration, severity and therapy of the disease were collected, pseudonymized and evaluated. RESULTS: There is a significant difference concerning the total number and lesion volume with more lesions being detected (2D: 29.7, +/- 20.22 sd; 3D: 40.1 +/- 31.67 sd; p < 0.0001) but lower total volume (2D: 6.24 +/- 6.11 sd; 3D: 5.39 +/- 6.37 sd; p < 0.0001) when using the 3D- sequence. Especially significantly more small lesions in the unspecific white matter and infratentorial region were detected by using the 3D-FLAIR sequence (p < 0.0001) compared to the 2D-FLAIR image. Main reason for the lower total volume in the 3D-FLAIR sequence was the calculated volume for periventricular lesions which was significantly beneath the calculated volume from the 2D-FLAIR sequence (p < 0.0001). CONCLUSION: Automatic lesion counting and volumetry is feasible with both 2D- and 3D-weightend FLAIR images. Still, it leads to partly significant differences even between two sequences that both are conform to the 2021 MAGNIMS-CMSCNAIMS consensus recommendations. This study contributes valuable insights into the impact of using different input data from the same patient for automated MS lesion evaluation.

Objectively assessed sleep quality parameters in Multiple Sclerosis at home: Association to disease, disease severity and physical activity.

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory autoimmune, neurodegenerative disease that affects regular mobility and leads predominantly to physical disability. Poor sleep quality, commonly reported in MS patients, impacts their physical activity (PA). Accelerometers monitor 24-h activity patterns, offering insights into disease progression in daily life. OBJECTIVE: To test if the sleep quality variables of MS patients, as assessed with wrist-worn accelerometers, differ from those of controls and are associated with PA and disease severity variables. METHODS: Seven-day raw accelerometer data collected from 40 MS patients and 24 controls was processed using an open-source GGIR package, from which variables of sleep quality (sleep efficiency, wake after sleep onset (WASO), sleep regularity index (SRI), intradaily variability (IV)) and PA (of different intensities: inactivity, light (LPA), moderate (MPA), vigorous (VPA)) were analyzed. The variables were compared between the two study groups and in MS patients, correlation tested associations among the variables of sleep quality, PA, and disease severity (assessed with the Expanded Disability Status Scale, EDSS). RESULTS: Sleep efficiency was the only variable that differed significantly between MS patients and controls (lower in MS, p = 0.01). Both SRI (positively) and IV (negatively) correlated with the time spent in LPA and MPA. WASO correlated negatively with inactivity. CONCLUSION: This is one of the few studies with a wrist-worn accelerometer that shows a difference in sleep efficiency between MS patients and controls and, in MS, an association of sleep quality variables with PA variables.

Investigating the metabolite signature of an altered oral microbiota as a discriminant factor for multiple sclerosis: a pilot study.

In multiple sclerosis (MS), alterations of the gut microbiota lead to inflammation. However, the role of other microbiomes in the body in MS has not been fully elucidated. In a pilot case-controlled study, we carried out simultaneous characterization of faecal and oral microbiota and conducted an in-depth analysis of bacterial alterations associated with MS. Using 16S rRNA sequencing and metabolic inference tools, we compared the oral/faecal microbiota and bacterial metabolism pathways in French MS patients (n = 14) and healthy volunteers (HV, n = 21). A classification model based on metabolite flux balance was established and validated in an independent German cohort (MS n = 12, HV n = 38). Our analysis revealed decreases in diversity indices and oral/faecal compartmentalization, the depletion of commensal bacteria (Aggregatibacter and Streptococcus in saliva and Coprobacter and Roseburia in faeces) and enrichment of inflammation-associated bacteria in MS patients (Leptotrichia and Fusobacterium in saliva and Enterobacteriaceae and Actinomyces in faeces). Several microbial pathways were also altered (the polyamine pathway and remodelling of bacterial surface antigens and energetic metabolism) while flux balance analysis revealed associated alterations in metabolite production in MS (nitrogen and nucleoside). Based on this analysis, we identified a specific oral metabolite signature in MS patients, that could discriminate MS patients from HV and rheumatoid arthritis patients. This signature allowed us to create and validate a discrimination model on an independent cohort, which reached a specificity of 92%. Overall, the oral and faecal microbiomes were altered in MS patients. This pilot study highlights the need to study the oral microbiota and oral health implications in patients with autoimmune diseases on a larger scale and suggests that knowledge of the salivary microbiome could help guide the identification of new pathogenic mechanisms associated with the microbiota in MS patients.

Chronic Enterovirus Meningoencephalitis in Prolonged B-Cell Depletion After Rituximab Therapy: Case Report.

OBJECTIVES: Persistent impaired immunity is possible even years after B-cell depleting therapies. This may favor the occurrence of infections, including infectious meningitis and encephalitis. In this study, we report a case of chronic enterovirus meningoencephalitis in prolonged B-cell depletion years after rituximab therapy. METHODS: This is a case report from a German academic hospital. In addition to repeated clinical examinations, repeated brain MRI and extended CSF and laboratory diagnostics were performed. We used the CARE checklist when writing our report. RESULTS: A 38-year-old man presented with high fever (>40°C), severe headache, and progressive neurologic and cognitive deficits. As result of previous lymphoma therapy with rituximab years ago, prolonged B-cell aplasia was detected. To restore humoral immunity, the patient received repeated infusions of immunoglobulins. In the end, a complete restitution of the physical and mental condition was achieved with the established therapy. DISCUSSION: This case report should emphasize the importance of assessing humoral immunity even years after B-cell depletion therapy, especially in case of opportunistic infections.

Clinical associations and characteristics of the polyspecific intrathecal immune response in elderly patients with non-multiple sclerosis chronic autoimmune-inflammatory neurological diseases - a retrospective cross-sectional study.

Introduction: The polyspecific intrathecal immune response (PSIIR), aka MRZ reaction (M = measles, R = rubella, Z = zoster, optionally Herpes simplex virus, HSV) is defined as intrathecal immunoglobulin synthesis (IIS) for two or more unrelated viruses. Although an established cerebrospinal fluid (CSF) biomarker for multiple sclerosis (MS), a chronic autoimmune-inflammatory neurological disease (CAIND) of the central nervous system (CNS) usually starting in young adulthood, the full spectrum of CAINDs with a positive PSIIR remains ill defined. Methods: In this retrospective, cross-sectional study, patients with CSF-positive oligoclonal bands (OCB) and - to enrich for non-MS diagnoses - aged ≥50 years were enrolled. Results: Of 415 with PSIIR testing results (MRZ, HSV optional), 76 were PSIIR-positive. Of these, 25 (33%) did not meet the diagnostic criteria for MS spectrum diseases (MS-S) comprising clinically or radiologically isolated syndrome (CIS/RIS) or MS. PSIIR-positive non-MS-S phenotypes were heterogenous with CNS, peripheral nerve and motor neuron involvement and often defied unequivocal diagnostic classification. A rating by neuroimmunology experts suggested non-MS CAINDs in 16/25 (64%). Long-term follow-up available in 13 always showed a chronically progressive course. Four of five responded to immunotherapy. Compared to MS-S patients, non-MS CAIND patients showed less frequent CNS regions with demyelination (25% vs. 75%) and quantitative IgG IIS (31% vs. 81%). MRZ-specific IIS did not differ between both groups, while additional HSV-specific IIS was characteristic for non-MS CAIND patients. Discussion: In conclusion, PSIIR positivity occurs frequently in non-MS-S patients ≥50 years. Although sometimes apparently coincidental, the PSIIR seems to represent a suitable biomarker for previously unnoticed chronic neurologic autoimmunities, which require further characterization.

Comprehensive Implementation of Shared Decision Making in a Neuromedical Center Using the SHARE TO CARE Program.

Purpose: SHARE TO CARE (S2C) is a comprehensive, multi-module implementation program for shared decision making (SDM). It is currently applied at the University Hospital Schleswig-Holstein in Kiel, Germany, and among general practitioners at the Federal State of Bremen. This study examines the results of the full implementation of S2C in terms of effectiveness within the Kiel Neuromedical Center comprising the departments of neurology and neurosurgery. Method and Design: The S2C program consists of four combined intervention modules: 1) multimodal training of physicians; 2) a patient activation campaign including the ASK-3 method; 3) digital evidence-based patient decision aids; and 4) SDM support by nurses, e.g., as decision coaches. The SDM level before and immediately after implementation was retrospectively assessed in consecutively selected patients on the subscale "Patient Decision Making" of the Perceived Involvement in Care Scale (PICSPDM). Mean scores were compared with t-tests. Results: Eighty-nine percent of all physicians (N = 56) completed the SDM training. We developed a total of 12 evidence-based digital decision aids in the center, educated two decision coaches to support patients' decision processes by using decision aids. Physicians adjusted patients' pathways to incorporate the use of decision aids. Patients (n = 261) reported a significant increase in participation (p<0.001; Hedges' g = 0.49) in medical decision making. Conclusion: The S2C program has been successfully implemented within the entire Neuromedical Center. Patients reported a medium to small increase of perceived involvement in decision making demonstrating the effectiveness of the implementation. For future research, it might be interesting to investigate the sustainability of the effects of S2C. In addition, it seems useful to complement the patient-based evaluation with observer-based data.

Autologous haematopoietic stem cell transplantation for multiple sclerosis: a position paper and registry outline.

Background: While substantial progress has been made in the development of disease-modifying medications for multiple sclerosis (MS), a high percentage of treated patients still show progression and persistent inflammatory activity. Autologous haematopoietic stem cell transplantation (AHSCT) aims at eliminating a pathogenic immune repertoire through intense short-term immunosuppression that enables subsequent regeneration of a new and healthy immune system to re-establish immune tolerance for a long period of time. A number of mostly open-label, uncontrolled studies conducted over the past 20 years collected about 4000 cases. They uniformly reported high efficacy of AHSCT in controlling MS inflammatory disease activity, more markedly beneficial in relapsing-remitting MS. Immunological studies provided evidence for qualitative immune resetting following AHSCT. These data and improved safety profiles of transplantation procedures spurred interest in using AHSCT as a treatment option for MS. Objective: To develop expert consensus recommendations on AHSCT in Germany and outline a registry study project. Methods: An open call among MS neurologists as well as among experts in stem cell transplantation in Germany started in December 2021 to join a series of virtual meetings. Results: We provide a consensus-based opinion paper authored by 25 experts on the up-to-date optimal use of AHSCT in managing MS based on the Swiss criteria. Current data indicate that patients who are most likely to benefit from AHSCT have relapsing-remitting MS and are young, ambulatory and have high disease activity. Treatment data with AHSCT will be collected within the German REgistry Cohort of autologous haematopoietic stem CeLl trAnsplantation In MS (RECLAIM). Conclusion: Further clinical trials, including registry-based analyses, are urgently needed to better define the patient characteristics, efficacy and safety profile of AHSCT compared with other high-efficacy therapies and to optimally position it as a treatment option in different MS disease stages.

Autologous haematopoietic stem cell transplantation for multiple sclerosis Substantial progress has been made in the development of disease-modifying medications for multiple sclerosis (MS) during the last 20 years. However, in a relevant percentage of patients, the disease cannot completely be contained. Autologous haematopoietic stem cell transplantation (AHSCT) enables rebuilding of a new and healthy immune system and to potentially stop the autoimmune disease process for a long time. A number of studies documenting 4000 cases cumulatively over the past 20 years reported high efficacy of AHSCT in controlling MS inflammatory disease activity. These data and improved safety profiles of the treatment procedures spurred interest in using AHSCT as a treatment option for MS. An open call among MS neurologists as well as among experts in stem cell transplantation in Germany started in December 2021 to join a series of video calls to develop recommendations and outline a registry study project. We provide a consensus-based opinion paper authored by 25 experts on the up-to-date optimal use of AHSCT in managing MS. Current data indicate that patients are most likely to benefit from AHSCT if they are young, ambulatory, with high disease activity, that is, relapses or new magnetic resonance imaging (MRI) lesions. Treatment data with AHSCT will be collected within the German REgistry Cohort of autoLogous haematopoietic stem cell transplantation MS (RECLAIM). Further clinical trials including registry-based analyses and systematic follow-up are urgently needed to better define the optimal patient characteristics as well as the efficacy and safety profile of AHSCT compared with other high-efficacy therapies. These will help to position AHSCT as a treatment option in different MS disease stages.

B-cell-depletion reverses dysbiosis of the microbiome in multiple sclerosis patients.

To elucidate cross-sectional patterns and longitudinal changes of oral and stool microbiota in multiple sclerosis (MS) patients and the effect of B-cell depletion. We conducted an observational, longitudinal clinical cohort study analysing four timepoints over 12 months in 36 MS patients, of whom 22 initiated B-cell depleting therapy with ocrelizumab and a healthy control group. For microbiota analysis of the oral cavity and the gut, provided stool and oral swab samples underwent 16S rDNA sequencing and subsequent bioinformatic analyses. Oral microbiota-patterns exhibited a reduced alpha-diversity and unique differential microbiota changes compared to stool such as increased levels of Proteobacteria and decreased abundance of Actinobacteria. Following B-cell depletion, we observed increased alpha-diversity in the gut and the oral cavity as well as a long-term sustained reduction of pro-inflammatory Gram-negative bacteria (e.g., Escherichia/Shigella). MS patients have altered stool and oral microbiota diversity patterns compared to healthy controls, which are most pronounced in patients with higher disease activity and disability. Therapeutic B-cell depletion is associated with persisting regression of these changes. Whether these microbial changes are unspecific side-effects of B-cell depletion or indirectly modulate MS disease activity and progression is currently unknown and necessitates further investigations.

Treating sarcoidosis-associated progressive multifocal leukoencephalopathy with infliximab.

Although most of the progressive multifocal leukoencephalopathy cases in sarcoidosis patients are explained by the treatment with immunosuppressive drugs, it is also reported in treatment-naive sarcoidosis patients, which implies a general predisposition of sarcoidosis patients for progressive multifocal leukoencephalopathy. Indeed, it was shown that active sarcoidosis patients have increased regulatory T cell frequencies which could lead to a subsequent systemic immunosuppression. However, if sarcoidosis with systemic changes of T cell subsets frequencies constitute a risk factor for the development of progressive multifocal leukoencephalopathy, which could then be counteracted by sarcoidosis treatment, is not known. In this cohort study, we included, characterized and followed-up six patients with bioptically confirmed definite progressive multifocal leukoencephalopathy and definite or probable sarcoidosis presenting between April 2013 and January 2019, four of them had no immunosuppressive therapy at the time of developing first progressive multifocal leukoencephalopathy symptoms. Analysis of immune cell subsets in these patients revealed significant imbalances of CD4+ T cell and regulatory T cell frequencies. Due to the progression of progressive multifocal leukoencephalopathy in four patients, we decided to treat sarcoidosis anticipating normalization of immune cell subset frequencies and thereby improving progressive multifocal leukoencephalopathy. Notably, by treatment with infliximab, an antibody directed against tumour necrosis factor-α, three patients continuously improved clinically, JC virus was no longer detectable in the cerebrospinal fluid and regulatory T cell frequencies decreased. One patient was initially misdiagnosed as neurosarcoidosis and died 9 weeks after treatment initiation due to aspiration pneumonia. Our study provides insight that sarcoidosis can lead to changes in T cell subset frequencies, which predisposes to progressive multifocal leukoencephalopathy. Although immunosuppressive drugs should be avoided in progressive multifocal leukoencephalopathy, paradoxically in patients with sarcoidosis treatment with the immunosuppressive infliximab might restore normal T cell distribution and thereby halt progressive multifocal leukoencephalopathy progression.

Postural Sway in Parkinson's Disease and Multiple Sclerosis Patients During Tasks With Different Complexity.

Neurological diseases are associated with static postural instability. Differences in postural sway between neurological diseases could include "conceptual" information about how certain symptoms affect static postural stability. This information might have the potential to become a helpful aid during the process of finding the most appropriate treatment and training program. Therefore, this study investigated static postural sway performance of Parkinson's disease (PD) and multiple sclerosis (MS) patients, as well as of a cohort of healthy adults. Three increasingly difficult static postural tasks were performed, in order to determine whether the postural strategies of the two disease groups differ in response to the increased complexity of the balance task. Participants had to perform three stance tasks (side-by-side, semi-tandem and tandem stance) and maintain these positions for 10 s. Seven static sway parameters were extracted from an inertial measurement unit that participants wore on the lower back. Data of 47 healthy adults, 14 PD patients and 8 MS patients were analyzed. Both healthy adults and MS patients showed a substantial increase in several static sway parameters with increasingly complex stance tasks, whereas PD patients did not. In the MS patients, the observed substantial change was driven by large increases from semi-tandem and tandem stance. This study revealed differences in static sway adaptations between PD and MS patients to increasingly complex stance tasks. Therefore, PD and MS patients might require different training programs to improve their static postural stability. Moreover, this study indicates, at least indirectly, that rigidity/bradykinesia and spasticity lead to different adaptive processes in static sway.

Protective role of natural killer cells in neuropathic pain conditions.

ABSTRACT: During the past few years, the research of chronic neuropathic pain has focused on neuroinflammation within the central nervous system and its impact on pain chronicity. As part of the ERA-Net NEURON consortium, we aimed to identify immune cell patterns in the cerebrospinal fluid (CSF) of patients with herpes zoster neuralgia and patients with polyneuropathy (PNP), which may contribute to pain chronicity in these neuropathic pain conditions. Cerebrospinal fluid of 41 patients (10 herpes zoster and 31 PNP) was analyzed by flow cytometry identifying lymphocyte subsets: CD4+ (T-helper cells), CD8+ (cytotoxic T cells), CD19+ (B cells), and CD56+ (natural killer [NK]) cells. At baseline and at follow-up, the somatosensory phenotype was assessed with quantitative sensory testing. In addition, the patients answered epidemiological questionnaires and the PainDETECT questionnaire. Immune cell profiles and somatosensory profiles, as well as painDETECT questionnaire scores, were analyzed and correlated to determine specific immune cell patterns, which contribute to chronic pain. We found a negative correlation (P = 0.004, r = -0.596) between the frequency of NK cells and mechanical pain sensitivity (MPS), one of the most relevant quantitative sensory testing markers for central sensitization; a high frequency of NK cells correlated with low MPS. The analysis of the individual follow-up showed a worsening of the pain condition if NK-cell frequency was low. Low NK-cell frequency is associated with signs of central sensitization (MPS), whereas high NK-cell frequency might prevent central sensitization. Therefore, NK cells seem to play a protective role within the neuroinflammatory cascade and may be used as a marker for pain chronicity.

Heterogeneity of multiple sclerosis lesions in fast diffusional kurtosis imaging.

BACKGROUND: Mean kurtosis (MK), one of the parameters derived from diffusion kurtosis imaging (DKI), has shown increased sensitivity to tissue microstructure damage in several neurological disorders. METHODS: Thirty-seven patients with relapsing-remitting MS and eleven healthy controls (HC) received brain imaging on a 3T MR scanner, including a fast DKI sequence. MK and mean diffusivity (MD) were measured in the white matter of HC, normal-appearing white matter (NAWM) of MS patients, contrast-enhancing lesions (CE-L), FLAIR lesions (FLAIR-L) and black holes (BH). RESULTS: Overall 1529 lesions were analyzed, including 30 CE-L, 832 FLAIR-L and 667 BH. Highest MK values were obtained in the white matter of HC (0.814 ± 0.129), followed by NAWM (0.724 ± 0.137), CE-L (0.619 ± 0.096), FLAIR-L (0.565 ± 0.123) and BH (0.549 ± 0.12). Lowest MD values were obtained in the white matter of HC (0.747 ± 0.068 10-3mm2/sec), followed by NAWM (0.808 ± 0.163 10-3mm2/sec), CE-L (0.853 ± 0.211 10-3mm2/sec), BH (0.957 ± 0.304 10-3mm2/sec) and FLAIR-L (0.976 ± 0.35 10-3mm2/sec). While MK differed significantly between CE-L and non-enhancing lesions, MD did not. CONCLUSION: MK adds predictive value to differentiate between MS lesions and might provide further information about diffuse white matter injury and lesion microstructure.