Practical management of multiple sclerosis

Patients with multiple sclerosis often require high levels of medical input from their GP and treating neurologist. GPs are often their first point of contact regarding symptoms or complications of their disease or its treatment

Narrowband UVB phototherapy for clinically isolated syndrome: A trial to deliver the benefits of Vitamin D and other UVB-Induced molecules

Low vitamin D and insufficient sun exposure are additive independent risk factors for the development of multiple sclerosis (MS). The usual measure of vitamin D status, serum 25-hydroxy vitamin D [25(OH)D], is also a marker of recent exposure to the UVB rays of sunshine. The main evidence for a protective effect for MS development of higher 25(OH)D comes from observational studies, but this study design cannot separate out whether 25(OH)D is acting as a marker of vitamin D status, sun exposure, or both. In light of a lack of definitive outcomes in MS patients after trials of vitamin D supplementation and the ability of narrowband UVB to induce vitamin D, as well as other immune-regulatory molecules in skin, the Phototherapy for Clinically Isolated Syndrome (PhoCIS) trial was established to investigate the benefits of narrowband UVB, in addition to supplemented vitamin D, on MS development in individuals with Clinically Isolated Syndrome. We propose that the PhoCIS trial provides a fresh approach to re-defining the reported associations of 25(OH)D levels with MS development and progression

Zero retinal vein pulsation amplitude extrapolated model in non-invasive intracranial pressure estimation

Intracranial pressure (ICP) includes the brain, optic nerve, and spinal cord pressures; it influences blood flow to those structures. Pathological elevation in ICP results in structural damage through various mechanisms, which adversely affects outcomes in traumatic brain injury and stroke. Currently, invasive procedures which tap directly into the cerebrospinal fluid are required to measure this pressure. Recent fluidic engineering modelling analogous to the ocular vascular flow suggests that retinal venous pulse amplitudes are predictably influenced by downstream pressures, suggesting that ICP could be estimated by analysing this pulse signal. We used this modelling theory and our photoplethysmographic (PPG) retinal venous pulse amplitude measurement system to measure amplitudes in 30 subjects undergoing invasive ICP measurements by lumbar puncture (LP) or external ventricular drain (EVD). We estimated ICP from these amplitudes using this modelling and found it to be accurate with a mean absolute error of 3.0 mmHg and a slope of 1.00 (r = 0.91). Ninety-four percent of differences between the PPG and invasive method were between − 5.5 and + 4.0 mmHg, which compares favourably to comparisons between LP and EVD. This type of modelling may be useful for understanding retinal vessel pulsatile fluid dynamics and may provide a method for non-invasive ICP measurement

Evolving Identification of Blood Cells Associated with Clinically Isolated Syndrome: Importance of Time since Clinical Presentation and Diagnostic MRI

It is not clear how the profile of immune cells in peripheral blood differs between patients with clinically isolated syndrome (CIS) and healthy controls (HC). This study aimed to identify a CIS peripheral blood signature that may provide clues for potential immunomodulatory approaches early in disease. Peripheral blood mononuclear cells (PBMCs) were collected from 18 people with CIS, 19 HC and 13 individuals with other demyelinating conditions (ODC) including multiple sclerosis (MS). Individuals with CIS separated into two groups, namely those with early (≤14 days post-diagnostic magnetic resonance imaging (MRI); n = 6) and late (≥27 days; n = 12) blood sampling. Transitional B cells were increased in the blood of CIS patients independently of when blood was taken. However, there were two time-dependent effects found in the late CIS group relative to HC, including decreased CD56bright NK cells, which correlated significantly with time since MRI, and increased CD141+ myeloid dendritic cell (mDC2) frequencies. Higher CD1c+ B cells and lower non-classical monocyte frequencies were characteristic of more recent demyelinating disease activity (ODC and early CIS). Analysing cell populations by time since symptoms (subjective) and diagnostic MRI (objective) may contribute to understanding CIS

Changes in serum neurofilament light chain levels following narrowband ultraviolet B phototherapy in clinically isolated syndrome

Objective To determine whether serum neurofilament light chain (sNfL) levels are suppressed in patients with the clinically isolated syndrome (CIS) following narrowband ultraviolet B phototherapy (UVB-PT). Methods sNfL levels were measured using a sensitive single-molecule array assay at baseline and up to 12 months in 17 patients with CIS, 10 of whom received UVB-PT, and were compared with healthy control (HC) and early relapsing remitting multiple sclerosis (RRMS) group. sNfL levels were correlated with magnetic resonance imaging total lesion volume (LV) determined using icobrain version 4.4.1 and with clinical outcomes. Results Baseline median sNfL levels were significantly higher in the CIS (20.6 pg/mL, interquartile range [IQR] 13.7–161.4) and RRMS groups (36.6 pg/ml [IQR] 16.2–212.2) than in HC (10.7 pg/ml [IQR] 4.9–21.5) (p = .012 and p = .0002, respectively), and were strongly correlated with T2 and T1 LV at 12 months (r = .800; p = .014 and r = .833; p = .008, respectively) in the CIS group. Analysis of changes in sNfL levels over time in the CIS group showed a significant cumulative suppressive effect of UVB-PT in the first 3 months (UVB-PT −10.6% vs non-UVB-PT +58.3%; p = .04) following which the levels in the two groups converged and continued to fall. Conclusions Our findings provide the basis for further studies to determine the utility of sNfL levels as a marker of neuro-axonal damage in CIS and early MS and for assessing the efficacy of new therapeutic interventions such as UVB-PT

Association of serum gamma-glutamyltransferase and C-reactive proteins with neuromyelitis optica and multiple sclerosis

Background Many studies have demonstrated that serum gamma glutamyltransferase (GGT) within normal range might be an early marker of oxidative stress. However the role of GGT in neuromyelitis optica (NMO) and multiple sclerosis (MS) is unknown. Methods We assessed the correlations among GGT and C-reactive protein (CRP) levels, as well as clinical characteristics of NMO and MS. Serum GGT and CRP levels were measured in 106 NMO patients, 87 MS patients, 79 patients with non-inflammatory neurological diseases (Parkinson disease) and 80 healthy controls (HC). Clinical parameters, blood-brain barrier (BBB) index and Delpech index of MS and NMO were also investigated. Results We found that NMO patients had higher serum GGT and CRP levels within their normal ranges compared to MS, PD, healthy controls. NMO patients exhibited significantly higher EDSS scores than MS patients. The BBB index in NMO patients was significantly higher than that in MS patients. Significant correlations existed between serum GGT and CRP levels and EDSS scores, BBB index in NMO and MS patients. Conclusion Elevated GGT and CRP levels within their normal ranges in NMO and MS may be associated with inflammatory response, oxidative stress and BBB disturbance in the diseases. Further study into the underlying pathophysiology of this relationship is warranted

Autologous stem cell transplantation in multiple sclerosis: Results from a single centre

Background: In the last 2 decades, intensive immunosuppression followed by autologous stem cell transplantation (ASCT) has been proposed as a possible strategy for treatment of severe immune-mediated disorders, including multiple sclerosis (MS). Objective: To review the outcome of ASCT for MS in Western Australia. Methods: Eligibility criteria for ASCT were (1) progression of sustained disability with expanded disability status scale (EDSS) score increase of more than 1/10 over a 12 month period, (2) advanced MS with threatened loss of ambulation and (3) rapidly progressive disease not adequately assessed by EDSS. Stem cell mobilization was with cyclophosphamide (CY) 2g/m 2 and granu - locyte-colony stimulating factor 5ug/kg bd. conditioning chemo - therapy was with CY 50mg/kg and rabbit antithymocyte globulin 1mg/kg days -5 to -2. Patients were assessed at 3, 6, 12 and 24 months post-transplant. Results: Fourteen patients underwent ASCT. Median age was 47 years; median time from diagnosis to transplant was 12 years. Diagnosis at transplant was secondary progressive MS (12), pri - mary progressive MS (1) and neuromyelitis optica (1). About half the cohorts were neurologically stable at 24 months while the remainder had clinically relevant neurological deterioration. Two patients had meaningful improvement in bladder function. Follow-up MRI showed no Gd-enhancing lesions, but two patients developed new cerebral lesions on T2 weighted imaging. Conclusion: In this group of patients with advanced MS, neuro - logical function 24 months post-ASCT was essentially stable in half the cohort while the remainder experienced clinical progres - sion. It is not possible to conclude whether ASCT altered the natu - ral history of the disease

IgG 3 + B cells are associated with the development of multiple sclerosis

Objectives Disease‐modifying therapies (DMTs) targeting B cells are amongst the most effective for preventing multiple sclerosis (MS) progression. IgG3 antibodies and their uncharacterised B‐cell clones are predicted to play a pathogenic role in MS. Identifying subsets of IgG3+ B cells involved in MS progression could improve diagnosis, could inform timely disease intervention and may lead to new DMTs that target B cells more specifically. Methods We designed a 31‐parameter B‐cell‐focused mass cytometry panel to interrogate the role of peripheral blood IgG3+ B cells in MS progression of two different patient cohorts: one to investigate the B‐cell subsets involved in conversion from clinically isolated syndrome (CIS) to MS; and another to compare MS patients with inactive or active stages of disease. Each independent cohort included a group of non‐MS controls. Results Nine distinct CD20+IgD−IgG3+ B‐cell subsets were identified. Significant changes in the proportion of CD21+CD24+CD27−CD38− and CD27+CD38hiCD71hi memory B‐cell subsets correlated with changes in serum IgG3 levels and time to conversion from CIS to MS. The same CD38− double‐negative B‐cell subset was significantly elevated in MS patients with active forms of the disease. A third CD21+CD24+CD27+CD38− subset was elevated in patients with active MS, whilst narrowband UVB significantly reduced the proportion of this switched‐memory B‐cell subset. Conclusion We have identified previously uncharacterised subsets of IgG3+ B cells and shown them to correlate with autoimmune attacks on the central nervous system (CNS). These results highlight the potential for therapies that specifically target IgG3+ B cells to impact MS progression

Lymphocyte reconstitution following autologous stem cell transplantation for progressive MS

BACKGROUND: Autologous stem cell transplantation (ASCT) for progressive multiple sclerosis (MS) may reset the immune repertoire. OBJECTIVE: The objective of this paper is to analyse lymphocyte recovery in patients with progressive MS treated with ASCT. METHODS: Patients with progressive MS not responding to conventional treatment underwent ASCT following conditioning with high-dose cyclophosphamide and antithymocyte globulin. Lymphocyte subset analysis was performed before ASCT and for two years following ASCT. Neurological function was assessed by the EDSS before ASCT and for three years post-ASCT. RESULTS: CD4+ T-cells fell significantly post-transplant and did not return to baseline levels. Recent thymic emigrants and naïve T-cells fell sharply post-transplant but returned to baseline by nine months and twelve months, respectively. T-regulatory cells declined post-transplant and did not return to baseline levels. Th1 and Th2 cells did not change significantly while Th17 cells fell post-transplant but recovered to baseline by six months. Neurological function remained stable in the majority of patients. Progression-free survival was 69% at three years. CONCLUSION: This study demonstrates major changes in the composition of lymphocyte subsets following ASCT for progressive MS. In particular, ablation and subsequent recovery of thymic output is consistent with the concept that ASCT can reset the immune repertoire in MS patients

Different exosomal microRNA profile in Aquaporin-4 Antibody Positive Neuromyelitis Optica Spectrum Disorders

Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) are inflammatory demyelinating diseases of the central nervous system. Exosomal microRNAs (miRNAs) are emerging biomarkers for demyelinating diseases. In this study, 52 aquaporin-4 antibody serum-positive NMOSD patients, 18 relapsing-remitting multiple sclerosis (RRMS) patients and 17 healthy controls (HCs) were included for the next-generation sequencing (NGS). To validate the NGS results, the valuable miRNAs were selected for validation by real-time quantitative polymerase chain reaction in another cohort of patients, comprising 31 NMOSD patients and 14 HCs. In addition, these miRNAs were also validated in a longitudinal study. NGS data revealed the exosomal miRNAs profile in NMOSD patients was different from HCs. Among those potential exosomal miRNAs which can distinguish NMOSD status, hsa-miR-122-3p and hsa-miR-200a-5p were the most abundant miRNAs. In addition, hsa-miR-122-3p and hsa-miR-200a-5p were significantly upregulated in the serum exosome of relapsing NMOSD compared with that in remitting NMOSD. Hsa-miR-122-3p and hsa-miR-200a-5p had positive correlations with disease severity in NMOSD patients. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the MAPK, Wnt and Ras signaling pathways were enriched. Further biological function analysis demonstrated that these two miRNAs might be involved in the immunoregulation of NMOSD pathogenesis. Our results indicated that miRNAs delivered by exosomes could be applied as potential biomarkers for NMOSD