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BMC Medical Research Methodology Jun 2024Individualizing and optimizing treatment of relapsing-remitting multiple sclerosis patients is a challenging problem, which would benefit from a clinically valid...
BACKGROUND
Individualizing and optimizing treatment of relapsing-remitting multiple sclerosis patients is a challenging problem, which would benefit from a clinically valid decision support. Stühler et al. presented black box models for this aim which were developed and internally evaluated in a German registry but lacked external validation.
METHODS
In patients from the French OFSEP registry, we independently built and validated models predicting being free of relapse and free of confirmed disability progression (CDP), following the methodological roadmap and predictors reported by Stühler. Hierarchical Bayesian models were fit to predict the outcomes under 6 disease-modifying treatments given the individual disease course up to the moment of treatment change. Data was temporally split on 2017, and models were developed in patients treated earlier (n = 5517). Calibration curves, discrimination, mean squared error (MSE) and relative percentage of root MSE (RMSE%) were assessed by external validation of models in more-recent patients (n = 3768). Non-Bayesian fixed-effects GLMs were also applied and their outcomes were compared to these of the Bayesian ones. For both, we modelled the number of on-therapy relapses with a negative binomial distribution, and CDP occurrence with a binomial distribution.
RESULTS
The performance of our temporally-validated relapse model (MSE: 0.326, C-Index: 0.639) is potentially superior to that of Stühler's (MSE: 0.784, C-index: 0.608). Calibration plots revealed miscalibration. Our CDP model (MSE: 0.072, C-Index: 0.777) was also better than its counterpart (MSE: 0.131, C-index: 0.554). Results from non-Bayesian fixed-effects GLM models were similar to the Bayesian ones.
CONCLUSIONS
The relapse and CDP models rebuilt and externally validated in independent data could compare and strengthen the credibility of the Stühler models. Their model-building strategy was replicable.
Topics: Humans; Multiple Sclerosis, Relapsing-Remitting; Bayes Theorem; Female; Adult; Male; Precision Medicine; Treatment Outcome; Middle Aged; Registries; Recurrence; Disease Progression
PubMed: 38914938
DOI: 10.1186/s12874-024-02264-9 -
Neurology(R) Neuroimmunology &... Jul 2024The complement system is known to play a role in multiple sclerosis (MS) pathogenesis. However, its contribution to disease progression remains elusive. The study...
BACKGROUND AND OBJECTIVES
The complement system is known to play a role in multiple sclerosis (MS) pathogenesis. However, its contribution to disease progression remains elusive. The study investigated the role of the complement system in disability progression of patients with primary progressive MS (PPMS).
METHODS
Sixty-eight patients with PPMS from 12 European MS centers were included in the study. Serum and CSF levels of a panel of complement components (CCs) were measured by multiplex enzyme-linked immunosorbent assay at a baseline time point (i.e., sampling). Mean (SD) follow-up time from baseline was 9.6 (4.8) years. Only one patient (1.5%) was treated during follow-up. Univariable and multivariable logistic regressions adjusted for age, sex, and albumin quotient were performed to assess the association between baseline CC levels and disability progression in short term (2 years), medium term (6 years), and long term (at the time of the last follow-up).
RESULTS
In short term, CC played little or no role in disability progression. In medium term, an elevated serum C3a/C3 ratio was associated with a higher risk of disability progression (adjusted OR 2.30; 95% CI 1.17-6.03; = 0.040). By contrast, increased CSF C1q levels were associated with a trend toward reduced risk of disability progression (adjusted OR 0.43; 95% CI 0.17-0.98; = 0.054). Similarly, in long term, an elevated serum C3a/C3 ratio was associated with higher risk of disability progression (adjusted OR 1.81; 95% CI 1.09-3.40; = 0.037), and increased CSF C1q levels predicted lower disability progression (adjusted OR 0.41; 95% CI 0.17-0.86; = 0.025).
DISCUSSION
Proteins involved in the activation of early complement cascades play a role in disability progression as risk (elevated serum C3a/C3 ratio) or protective (elevated CSF C1q) factors after 6 or more years of follow-up in patients with PPMS. The protective effects associated with C1q levels in CSF may be related to its neuroprotective and anti-inflammatory properties.
Topics: Humans; Male; Female; Disease Progression; Multiple Sclerosis, Chronic Progressive; Middle Aged; Adult; Follow-Up Studies; Complement C3; Complement C3a; Disability Evaluation; Complement System Proteins
PubMed: 38912898
DOI: 10.1212/NXI.0000000000200270 -
JCI Insight Jun 2024The diffuse axonal damage in white matter and neuronal loss, along with excessive neuroinflammation, hinder long-term functional recovery after traumatic brain injury...
The diffuse axonal damage in white matter and neuronal loss, along with excessive neuroinflammation, hinder long-term functional recovery after traumatic brain injury (TBI). MicroRNAs (miRs) are small noncoding RNAs that negatively regulate protein-coding target genes in a posttranscriptional manner. Recent studies have shown that loss of function of the miR-15a/16-1 cluster reduced neurovascular damage and improved functional recovery in ischemic stroke and vascular dementia. However, the role of the miR-15a/16-1 cluster in neurotrauma is poorly explored. Here, we report that genetic deletion of the miR-15a/16-1 cluster facilitated the recovery of sensorimotor and cognitive functions, alleviated white matter/gray matter lesions, reduced cerebral glial cell activation, and inhibited infiltration of peripheral blood immune cells to brain parenchyma in a murine model of TBI when compared with WT controls. Moreover, intranasal delivery of the miR-15a/16-1 antagomir provided similar brain-protective effects conferred by genetic deletion of the miR-15a/16-1 cluster after experimental TBI, as evidenced by showing improved sensorimotor and cognitive outcomes, better white/gray matter integrity, and less inflammatory responses than the control antagomir-treated mice after brain trauma. miR-15a/16-1 genetic deficiency and miR-15a/16-1 antagomir also significantly suppressed inflammatory mediators in posttrauma brains. These results suggest miR-15a/16-1 as a potential therapeutic target for TBI.
Topics: Animals; MicroRNAs; Brain Injuries, Traumatic; Mice; Recovery of Function; Disease Models, Animal; Male; Mice, Knockout; Mice, Inbred C57BL; Brain
PubMed: 38912585
DOI: 10.1172/jci.insight.178650 -
JCI Insight Jun 2024
Topics: Neutrophils; Demyelinating Diseases; Humans; Meninges; Gray Matter; Male; Female; Middle Aged; Adult; Magnetic Resonance Imaging; Aged; Aging; Age Factors
PubMed: 38912582
DOI: 10.1172/jci.insight.183445 -
Cureus Jun 2024Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal plasma cell disorder characterized by monoclonal immunoglobulins and/or an abnormal...
Uncommon Presentation of IgM Monoclonal Gammopathy of Undetermined Significance (MGUS) and Anti-Myelin-Associated Glycoprotein (MAG)-Associated Demyelinating Peripheral Neuropathy as Respiratory Failure: A Case Report.
Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal plasma cell disorder characterized by monoclonal immunoglobulins and/or an abnormal free immunoglobulin light chain ratio. MGUS can be associated with immune-mediated neuropathies, including chronic inflammatory demyelinating neuropathy and its variants. Here, we report the case of a 76-year-old male who presented with progressive weakness, initially in the lower extremities and later including the upper extremities. Serum protein electrophoresis and immunofixation identified an IgM kappa monoclonal protein and further testing confirmed high titers of anti-myelin-associated glycoprotein (MAG) antibodies, leading to a diagnosis of anti-MAG-associated demyelinating peripheral neuropathy. The coexistence of MGUS and anti-MAG antibodies requires meticulous diagnosis and management, especially in patients who present with atypical symptoms of the disease.
PubMed: 38912071
DOI: 10.7759/cureus.62865 -
Frontiers in Immunology 2024Although fingolimod, a sphingosine 1-phosphate receptor agonist, has shown to be an effective treatment reducing relapse rate and also slowing down the disability...
BACKGROUND
Although fingolimod, a sphingosine 1-phosphate receptor agonist, has shown to be an effective treatment reducing relapse rate and also slowing down the disability progression in relapsing-remitting multiple sclerosis (RRMS) patients, it is important to quickly identify those suboptimal responders.
OBJECTIVE
The main objective was to assess different clinical, radiological, genetic and environmental factors as possible early predictors of response in MS patients treated with fingolimod for 24 months. The secondary objective was to analyze the possible contribution of the environmental factors analyzed to the progression and activity of the disease along the 2-years of follow-up.
METHODS
A retrospective study with 151 patients diagnosed with MS, under fingolimod treatment for 24 months, with serum samples at initiation and six months later, and with clinical and radiological data at initiation and 24 months later, were included in the study. Clinical and radiological variables were collected to establish NEDA-3 (no evidence of disease activity: patients without relapses, disability progression and new T2 lesions or Gd+ lesions) and EDA (evidence of disease activity: patients with relapses and/or progression and/or new T2 lesions or gadolinium-positive [Gd+] lesions) conditions. Human leukocyte antigen II (HLA-II), EBNA-1 IgG and VCA IgG from Epstein-Barr virus (EBV) and antibody titers against Human herpesvirus 6A/B (HHV-6A/B) were also analyzed.
RESULTS
A total of 151 MS patients fulfilled the inclusion criteria: 27.8% was NEDA-3 (37.5% among those previously treated with high efficacy therapies >24 months). The following early predictors were statistically significantly associated with NEDA-3 condition: sex (male; p=0.002), age at baseline (older; p=0.009), relapses 2-years before fingolimod initiation ≤1 (p=0.010), and absence of Gd+ lesions at baseline (p=0.006). Regarding the possible contribution of the environmental factors included in the study to the activity or the progression of the disease, we only found that EBNA-1 IgG titers decreased in 20.0% of PIRA (progression independent from relapse activity) patients vs. 73.3% of RAW (relapse-associated worsening) patients (p=0.006; O.R. = 11.0).
CONCLUSION
MS patients that are male, older, and with a low clinical and radiological activity at fingolimod initiation have a greater probability to reach NEDA-3 condition after two years with this therapy. An intriguing association of EBV with the progression of the disease has also been described, but it should be further study in a larger cohort to confirm these results.
Topics: Humans; Fingolimod Hydrochloride; Female; Male; Disease Progression; Adult; Epstein-Barr Virus Nuclear Antigens; Retrospective Studies; Immunoglobulin G; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Treatment Outcome; Immunosuppressive Agents; Multiple Sclerosis
PubMed: 38911861
DOI: 10.3389/fimmu.2024.1384411 -
Frontiers in Immunology 2024Bilateral facial palsy with paresthesia (FDP) is a rare variant of GBS, characterized by simultaneous bilateral facial palsy and paresthesia of the distal limbs....
Bilateral facial palsy with paresthesia (FDP) is a rare variant of GBS, characterized by simultaneous bilateral facial palsy and paresthesia of the distal limbs. Mounting evidence indicates that the presence of anti-GT1a IgG has a pathogenic role as an effector molecule in the development of cranial nerve palsies in certain patients with GBS, whereas anti-GT1a antibody is rarely presented positive in FDP. Here, we report the case of a 33-year-old male diagnosed with FDP presented with acute onset of bilateral facial palsy and slight paresthesias at the feet as the only neurological manifestation. An antecedent infection with no identifiable reason for the fever or skin eruptions was noted in the patient. He also exhibited cerebrospinal fluid albuminocytologic dissociation and abnormal nerve conduction studies. Notably, the testing of specific serum anti-gangliosides showed positive anti-GT1a IgG/IgM Ab. The patient responded well to intravenous immunoglobulin therapy. This case brings awareness to a rare variant of GBS, and provides the first indication that anti-GT1a antibodies play a causative role in the development of FDP. The case also suggests that prompt management with IVIG should be implemented if FDP is diagnosed.
Topics: Humans; Male; Adult; Paresthesia; Facial Paralysis; Autoantibodies; Gangliosides; Immunoglobulins, Intravenous; Immunoglobulin G; Guillain-Barre Syndrome
PubMed: 38911860
DOI: 10.3389/fimmu.2024.1410634 -
Frontiers in Immunology 2024Secondary progressive multiple sclerosis (SPMS) is defined by the irreversible accumulation of disability following a relapsing-remitting MS (RRMS) course. Despite...
BACKGROUND
Secondary progressive multiple sclerosis (SPMS) is defined by the irreversible accumulation of disability following a relapsing-remitting MS (RRMS) course. Despite treatments advances, a reliable tool able to capture the transition from RRMS to SPMS is lacking. A T cell chimeric MS model demonstrated that T cells derived from relapsing patients exacerbate excitatory transmission of central neurons, a synaptotoxic event absent during remitting stages. We hypothesized the re-emergence of T cell synaptotoxicity during SPMS and investigated the synaptoprotective effects of siponimod, a sphingosine 1-phosphate receptor (S1PR) modulator, known to reduce grey matter damage in SPMS patients.
METHODS
Data from healthy controls (HC), SPMS patients, and siponimod-treated SPMS patients were collected. Chimeric experiments were performed incubating human T cells on murine cortico-striatal slices, and recording spontaneous glutamatergic activity from striatal neurons. Homologous chimeric experiments were executed incubating EAE mice T cells with siponimod and specific S1PR agonists or antagonists to identify the receptor involved in siponimod-mediated synaptic recovery.
RESULTS
SPMS patient-derived T cells significantly increased the striatal excitatory synaptic transmission (n=40 synapses) compared to HC T cells (n=55 synapses), mimicking the glutamatergic alterations observed in active RRMS-T cells. Siponimod treatment rescued SPMS T cells synaptotoxicity (n=51 synapses). Homologous chimeric experiments highlighted S1P5R involvement in the siponimod's protective effects.
CONCLUSION
Transition from RRMS to SPMS involves the reappearance of T cell-mediated synaptotoxicity. Siponimod counteracts T cell-induced excitotoxicity, emphasizing the significance of inflammatory synaptopathy in progressive MS and its potential as a promising pharmacological target.
Topics: Humans; Animals; Mice; Female; Multiple Sclerosis, Chronic Progressive; T-Lymphocytes; Azetidines; Benzyl Compounds; Male; Adult; Synapses; Middle Aged; Encephalomyelitis, Autoimmune, Experimental; Sphingosine 1 Phosphate Receptor Modulators; Mice, Inbred C57BL; Sphingosine-1-Phosphate Receptors; Synaptic Transmission; Neurons
PubMed: 38911847
DOI: 10.3389/fimmu.2024.1416133 -
ENeurologicalSci Jun 2024Intractable hiccups, persisting beyond 48 h, pose a clinical challenge, particularly in demyelinating diseases like Neuromyelitis Optica (NMO) and Multiple Sclerosis...
BACKGROUND
Intractable hiccups, persisting beyond 48 h, pose a clinical challenge, particularly in demyelinating diseases like Neuromyelitis Optica (NMO) and Multiple Sclerosis (MS). Understanding the complex neural pathways of the hiccup reflex and the impact of high-dose steroid therapy is crucial for managing this rare but distressing symptom. The hiccup reflex involves afferents from the vagus, phrenic, and sympathetic nerves, with the reflex center in the anterior horns at the C3 to 5 level and the medulla oblongata. The potential interplay between demyelination and corticosteroid therapy in triggering persistent hiccups requires exploration.
CASE REPORT
This case report details a 21-year-old male with undiagnosed demyelinating disorder, presenting persistent hiccups following high-dose steroid therapy for an acute disease flare. The patient's history included vertigo and progressive neurological symptoms, leading to an MS diagnosis with significant brain and spinal lesions. Persistent hiccups, initiated by steroid administration, were recurrent but responsive to metoclopramide after other measures failed.
DISCUSSION
The discussion centers on investigating the cause of hiccups in a patient with demyelination following steroid administration. Steroids' impact on neurological systems, including neurotransmitter function, and the potential disruption of neurological pathways due to demyelination may contribute to hiccups. Successful hiccup resolution with metoclopramide suggests a potential pharmacological approach for corticosteroid-induced hiccups in demyelinating diseases. This case emphasizes the need for further research into the intricate relationship between demyelination, steroid therapy, and hiccups to enhance management strategies for this uncommon yet impactful symptom.
PubMed: 38911508
DOI: 10.1016/j.ensci.2024.100509 -
Journal of Rehabilitation Medicine Jun 2024To examine the relationship between perceived and physiological strains of real-time societal participation in people with multiple sclerosis. (Observational Study)
Observational Study
OBJECTIVE
To examine the relationship between perceived and physiological strains of real-time societal participation in people with multiple sclerosis.
DESIGN
Observational study.
SUBJECTS/PATIENTS
70 people with multiple sclerosis.
METHODS
Perceived and physiological strain of societal participation (10 participation-at-location and 9 transport domains) were measured in real time using the Whereabouts smartphone app and Fitbit over 7 consecutive days. Longitudinal relationships between perceived (1 not strenuous to 10 most strenuous) and physiological strains (heart rate reserve) were examined using mixed-model analyses. Type of event (participation-at-location or transport) was added as covariate, with further adjustments for fatigue and walking ability.
RESULTS
Median perceived strain, summarized for all societal participation domains, varied between 3 and 6 (range: 1-10), whereas physiological strain varied between 18.5% and 33.2% heart rate reserve. Perceived strain (outcome) and physiological strain were not associated (β -0.001, 95%CI -0.008; 0.005, with a 7-day longitudinal correlation coefficient of -0.001). Transport domains were perceived as less strenuous (β -0.80, 95%CI -0.92; -0.68). Higher fatigue levels resulted in higher perceived strain (all societal participation domains) (β 0.05, 95%CI 0.02; 0.08).
CONCLUSION
Societal participation resulted in low-to-moderate perceived and physiological strain. Perceived and physiological strain of societal participation were unrelated and should be considered different constructs in multiple sclerosis.
Topics: Humans; Multiple Sclerosis; Male; Female; Middle Aged; Adult; Fatigue; Social Participation; Heart Rate; Perception
PubMed: 38910543
DOI: 10.2340/jrm.v56.40838