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1.
Neurol Neuroimmunol Neuroinflamm ; 11(3): e200230, 2024 May.
Article in English | MEDLINE | ID: mdl-38669615

ABSTRACT

BACKGROUND AND OBJECTIVES: The aim of this study was to identify novel biomarkers for multiple sclerosis (MS) diagnosis and prognosis, addressing the critical need for specific and prognostically valuable markers in the field. METHODS: We conducted an extensive proteomic investigation, combining analysis of (1) CSF proteome from symptomatic controls, fast and slow converters after clinically isolated syndromes, and patients with relapsing-remitting MS (n = 10 per group) using label-free quantitative proteomics and (2) oligodendrocyte secretome changes under proinflammatory or proapoptotic conditions using stable isotope labeling by amino acids in cell culture. Proteins exhibiting differential abundance in both proteomic analyses were combined with other putative MS biomarkers, yielding a comprehensive list of 87 proteins that underwent quantification through parallel reaction monitoring (PRM) in a novel cohort, comprising symptomatic controls, inflammatory neurologic disease controls, and patients with MS at various disease stages (n = 10 per group). The 11 proteins that passed this qualification step were subjected to a new PRM assay within an expanded cohort comprising 158 patients with either MS at different disease stages or other inflammatory or noninflammatory neurologic disease controls. RESULTS: This study unveiled a promising biomarker signature for MS, including previously established candidates, such as chitinase 3-like protein 1, chitinase 3-like protein 2, chitotriosidase, immunoglobulin kappa chain region C, neutrophil gelatinase-associated lipocalin, and CD27. In addition, we identified novel markers, namely cat eye syndrome critical region protein 1 (adenosine deaminase 2, a therapeutic target in multiple sclerosis) and syndecan-1, a proteoglycan, also known as plasma cell surface marker CD138 and acting as chitinase 3-like protein 1 receptor implicated in inflammation and cancer signaling. CD138 exhibited good diagnostic accuracy in distinguishing MS from inflammatory neurologic disorders (area under the curve [AUC] = 0.85, CI 0.75-0.95). CD138 immunostaining was also observed in the brains of patients with MS and cultured oligodendrocyte precursor cells but was absent in astrocytes. DISCUSSION: These findings identify CD138 as a specific CSF biomarker for MS and suggest the selective activation of the chitinase 3-like protein 1/CD138 pathway within the oligodendrocyte lineage in MS. They offer promising prospects for improving MS diagnosis and prognosis by providing much-needed specificity and clinical utility. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that CD138 distinguishes multiple sclerosis from other inflammatory neurologic disorders with an AUC of 0.85 (95% CI 0.75-0.95).


Subject(s)
Biomarkers , Multiple Sclerosis, Relapsing-Remitting , Syndecan-1 , Humans , Biomarkers/cerebrospinal fluid , Adult , Female , Male , Multiple Sclerosis, Relapsing-Remitting/cerebrospinal fluid , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Middle Aged , Syndecan-1/cerebrospinal fluid , Cohort Studies , Proteomics , Multiple Sclerosis/cerebrospinal fluid , Multiple Sclerosis/diagnosis , Oligodendroglia/metabolism
2.
Mult Scler Relat Disord ; 86: 105595, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38598952

ABSTRACT

INTRODUCTION: Continuously acquired smartphone keyboard interactions may be useful to monitor progression in multiple sclerosis (MS). We aimed to study the correlation between tapping speed (TS), measured as keys/s, and baseline disability scales in patients with MS. METHODS: Single-center prospective study in patients with MS. We passively assessed TS during first week, measured by an "in house" smartphone application. Reliability was assessed by intraclass correlation coefficient (ICC). Correlations between median and maximum keys/s of first week of assessment and baseline disability measures were explored. RESULTS: One-hundred three patients were included: 62.1 % women, with a median (IQR) age of 47 (40.4-54.8) years-old and an EDSS score of 3.0 (2.0-4.0). Distribution by MS subtypes was: 77.7 % relapsing-remitting MS (RRMS), 17.5 % secondary-progressive MS (SPMS) and 4.9 % primary-progressive MS (PPMS). ICC during first week was 0.714 (p < 0.00001). Both median and maximum keys/s showed a negative correlation with Expanded Disability Status Score, 9-hole peg test and timed 25-foot walk and a positive correlation with Processing Speed Test CogEval® raw and Z-score. Median and maximum keys/s were lower in patients diagnosed with SPMS than in RRMS. Both measures of tapping speed were associated with MS phenotype independently of age. CONCLUSION: TS measured through our application is reliable and correlates with baseline disability scales.


Subject(s)
Multiple Sclerosis , Smartphone , Humans , Female , Male , Middle Aged , Adult , Prospective Studies , Multiple Sclerosis/physiopathology , Multiple Sclerosis/diagnosis , Disability Evaluation , Reproducibility of Results , Disease Progression , Mobile Applications , Multiple Sclerosis, Chronic Progressive/physiopathology , Multiple Sclerosis, Chronic Progressive/diagnosis , Multiple Sclerosis, Relapsing-Remitting/physiopathology , Multiple Sclerosis, Relapsing-Remitting/diagnosis
3.
Autoimmunity ; 57(1): 2332340, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38545756

ABSTRACT

Interferon-beta (IFN-ß) is one of the classical drugs for immunomodulatory therapy in relapsing-remitting multiple sclerosis (RRMS) patients, but the drug responsiveness of different patients varies. Currently, there is no valid model to predict IFN-ß responsiveness. This research attempted to develop an IFN-ß responsiveness prediction model based on mRNA expression in RRMS patient peripheral blood mononuclear cells. Peripheral blood mononuclear cell mRNA expression datasets including 50 RRMS patients receiving IFN-ß treatment were obtained from GEO. Among the datasets, 24 cases from GSE24427 were included in a training set, and 18 and 9 cases from GSE19285 and GSE33464, respectively, were adopted as two independent test sets. In the training set, blood samples were collected immediately before first, second, month 1, 12, and 24 IFN-ß injection, and the mRNA expression data at four time points, namely, two days, one month, one year and two years after the onset of IFN-ß treatment, were compared with pre-treatment data to identify IFN-stimulated genes (ISGs). The ISGs at the one-month time point were used to construct the drug responsiveness prediction model. Next, the drug responsiveness model was verified in the two independent test sets to examine the performance of the model in predicting drug responsiveness. Finally, we used CIBERSORTx to estimate the content of cell subtypes in samples and evaluated whether differences in the proportions of cell subtypes were related to differences in IFN-ß responsiveness. Among the four time points, one month was the time point when the training set GSE24427 and test set GSE33464 had the highest number of ISGs. Functional analysis showed that these one-month ISGs were enriched in biological functions such as the innate immune response, type-I interferon signalling pathway, and other IFN-ß-associated functions. Based on these ISGs, we obtained a four-factor prediction model for IFN-ß responsiveness including MX1, MX2, XAF1, and LAMP3. In addition, the model demonstrated favourable predictive performance within the training set and two external test sets. A higher proportion of activated NK cells and lower naive CD4/total CD4 ratio might indicate better drug responsiveness. This research developed a polygene-based biomarker model that could predict RRMS patient IFN-ß responsiveness in the early treatment period. This model could probably help doctors screen out patients who would not benefit from IFN-ß treatment early and determine whether a current treatment plan should be continued.


Subject(s)
Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Humans , RNA, Messenger/genetics , Leukocytes, Mononuclear , Interferon-beta/therapeutic use , Interferon-beta/genetics , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Multiple Sclerosis, Relapsing-Remitting/genetics
4.
J Mol Diagn ; 26(6): 520-529, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38522839

ABSTRACT

This study aims to identify RNA biomarkers distinguishing neuromyelitis optica (NMO) from relapsing-remitting multiple sclerosis (RRMS) and explore potential therapeutic applications leveraging machine learning (ML). An ensemble approach was developed using differential gene expression analysis and competitive ML methods, interrogating total RNA-sequencing data sets from peripheral whole blood of treatment-naïve patients with RRMS and NMO and healthy individuals. Pathway analysis of candidate biomarkers informed the biological context of disease, transcription factor activity, and small-molecule therapeutic potential. ML models differentiated between patients with NMO and RRMS, with the performance of certain models exceeding 90% accuracy. RNA biomarkers driving model performance were associated with ribosomal dysfunction and viral infection. Regulatory networks of kinases and transcription factors identified biological associations and identified potential therapeutic targets. Small-molecule candidates capable of reversing perturbed gene expression were uncovered. Mitoxantrone and vorinostat-two identified small molecules with previously reported use in patients with NMO and experimental autoimmune encephalomyelitis-reinforced discovered expression signatures and highlighted the potential to identify new therapeutic candidates. Putative RNA biomarkers were identified that accurately distinguish NMO from RRMS and healthy individuals. The application of multivariate approaches in analysis of RNA-sequencing data further enhances the discovery of unique RNA biomarkers, accelerating the development of new methods for disease detection, monitoring, and therapeutics. Integrating biological understanding further enhances detection of disease-specific signatures and possible therapeutic targets.


Subject(s)
Biomarkers , Machine Learning , Neuromyelitis Optica , Sequence Analysis, RNA , Neuromyelitis Optica/genetics , Neuromyelitis Optica/diagnosis , Neuromyelitis Optica/drug therapy , Humans , Female , Biomarkers/blood , Sequence Analysis, RNA/methods , Male , Mitoxantrone/therapeutic use , Adult , Diagnosis, Differential , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/genetics , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Multiple Sclerosis, Relapsing-Remitting/blood , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Gene Expression Profiling/methods , Multiple Sclerosis/genetics , Multiple Sclerosis/drug therapy , Multiple Sclerosis/diagnosis , Multiple Sclerosis/blood
5.
J Emerg Med ; 66(4): e441-e456, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38472027

ABSTRACT

BACKGROUND: Multiple sclerosis (MS) is a rare but serious condition associated with significant morbidity. OBJECTIVE: This review provides a focused assessment of MS for emergency clinicians, including the presentation, evaluation, and emergency department (ED) management based on current evidence. DISCUSSION: MS is an autoimmune disorder targeting the central nervous system (CNS), characterized by clinical relapses and radiological lesions disseminated in time and location. Patients with MS most commonly present with long tract signs (e.g., myelopathy, asymmetric spastic paraplegia, urinary dysfunction, Lhermitte's sign), optic neuritis, or brainstem syndromes (bilateral internuclear ophthalmoplegia). Cortical syndromes or multifocal presentations are less common. Radiologically isolated syndrome and clinically isolated syndrome (CIS) may or may not progress to chronic forms of MS, including relapsing remitting MS, primary progressive MS, and secondary progressive MS. The foundation of outpatient management involves disease-modifying therapy, which is typically initiated with the first signs of disease onset. Management of CIS and acute flares of MS in the ED includes corticosteroid therapy, ideally after diagnostic testing with imaging and lumbar puncture for cerebrospinal fluid analysis. Emergency clinicians should evaluate whether patients with MS are presenting with new-onset debilitating neurological symptoms to avoid unnecessary testing and admissions, but failure to appropriately diagnose CIS or MS flare is associated with increased morbidity. CONCLUSIONS: An understanding of MS can assist emergency clinicians in better diagnosing and managing this neurologically devastating disease.


Subject(s)
Multiple Sclerosis, Chronic Progressive , Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Optic Neuritis , Humans , Multiple Sclerosis/complications , Multiple Sclerosis/diagnosis , Multiple Sclerosis, Chronic Progressive/complications , Multiple Sclerosis, Chronic Progressive/diagnosis , Multiple Sclerosis, Relapsing-Remitting/complications , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Radiography , Optic Neuritis/diagnosis , Magnetic Resonance Imaging
6.
Clin Neurol Neurosurg ; 239: 108221, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38447483

ABSTRACT

OBJECTIVE: The time to diagnosis of multiple sclerosis (MS) is of great importance for early treatment, thereby reducing the disability and burden of the disease. The purpose of this study was to determine the time from the onset of clinical symptoms to the diagnosis of MS and to evaluate the factors associated with a late diagnosis in Iranian MS patients. METHODS: The present cross-sectional study was conducted on patients with MS who were registered in the National MS Registry System of Iran (NMSRI). RESULTS: Overall, 23291 MS patients registered in 18 provinces of Iran were included in this study. The mean (standard deviation) interval between the onset of the disease and diagnosis of MS was 13.42 (32.40) months, and the median was one month. The diagnostic interval of 41.6% of patients was less than one month, and 14.8% of them had a one-month time to diagnosis. Patients with an age of onset below 18 years and those diagnosed after the age of 50 years had a longer time to diagnosis (P<0.001). Patients with primary progressive MS (PPMS) had the longest time to diagnose and those with relapsing-remitting MS (RRMS) had the shortest time (P<0.001). The results of negative binominal regression showed that the average rate of delay in diagnosis in women was 12% less than that in men. The average delay in diagnosis in patients with a positive family history of MS was 23% more than that in others. The rate of delay in the diagnosis of patients with PPMS and secondary progressive MS was 2.22 and 1.66 times higher, respectively, compared with RRMS. CONCLUSION: The findings of the present study revealed that more than half of the MS patients were diagnosed within a one-month interval from the symptom onset, which is an acceptable period. More attention should be paid to patients' access to medical facilities and MS specialists.


Subject(s)
Multiple Sclerosis, Chronic Progressive , Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Male , Humans , Female , Adolescent , Middle Aged , Multiple Sclerosis/diagnosis , Multiple Sclerosis/epidemiology , Multiple Sclerosis/complications , Cross-Sectional Studies , Iran , Multiple Sclerosis, Chronic Progressive/diagnosis , Multiple Sclerosis, Chronic Progressive/epidemiology , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Multiple Sclerosis, Relapsing-Remitting/epidemiology , Multiple Sclerosis, Relapsing-Remitting/complications , Registries
7.
Mult Scler Relat Disord ; 84: 105501, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38401203

ABSTRACT

BACKGROUND: Standardizing health outcomes is challenging in clinical management, but it also holds the potential for creating a healthcare system that is both more effective and efficient. The aim of the present study is to define a standardized set of health outcomes for managing Relapsing-Remitting Multiple Sclerosis (RRMS). METHODS: The project was led and coordinated by a multidisciplinary scientific committee (SC), which included a literature review, a patient-focused group, three nominal group meetings, and two SC meetings. RESULTS: 36 outcome variables were included in the standard set: 24 clinical (including weight, smoking habit, comorbidities, disability, mobility, diagnosis of secondary progressive multiple sclerosis, relapsed-related variables, radiological variables, cognitive status and disease-related symptoms), nine treatment-related (pharmacological and non-pharmacological information), and 3 related to the impact of RRMS on the patient's life (quality of life, pregnancy desire, work-related difficulties). In addition, experts also agreed to collect 10 case-mix variables that may affect but cannot be controlled as part of the management of the condition: 4 sociodemographic (age, sex, race, and employment status) and 6 clinical (height, date of diagnosis and first episode, serological status, early symptoms, and number of relapses pre-diagnosis). CONCLUSION: The information provided through the present standard set of outcome variables can improve the management of RRMS and promote patient-centred quality care.


Subject(s)
Multiple Sclerosis, Chronic Progressive , Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Humans , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Multiple Sclerosis, Relapsing-Remitting/therapy , Quality of Life , Outcome Assessment, Health Care
8.
Mult Scler Relat Disord ; 83: 105381, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38308915

ABSTRACT

BACKGROUND: Multiple sclerosis (MS) knowledge is a prerequisite for active patient engagement in medical decision-making. Treatment of relapses in MS is a clinical field with many uncertainties and each acute relapse requires decisions regarding possible options for action, indicating the need for patient involvement. However, there is no validated instrument assessing relapse knowledge in people with MS. Our study aims to develop a valid MS relapse questionnaire for use as an outcome instrument for educational interventions. METHODS: A multidisciplinary panel developed the relapse knowledge questionnaire (RKQ) based on a previously developed questionnaire. We tested the RKQ on MS patients for comprehensibility, usability and acceptance in qualitative think-aloud interviews and conducted a cross-sectional quantitative online survey to validate the questionnaire. People with suspected or confirmed relapsing-remitting MS and a recent relapse experience were eligible for inclusion. We checked normal distribution of the RKQ score and determined the item difficulty. Construct validity was analysed using correlational analysis. RESULTS: The final RKQ consists of 10 items. After minor changes of the RKQ during pre-testing (n = 2), pilot testing (n = 10) confirmed the usability and acceptance of the instrument. The subsequent validation study (n = 203) resulted in a mean item difficulty of 0.44, ranging from 0.18 to 0.83. Seven items were particularly difficult and answered incorrectly by more than 50 % of participants. Construct validity of the RKQ was satisfactory. The RKQ score correlated only weakly with participants' degree of education (|rp|>0.1), years since diagnosis (|rp|>0.1), and the intention to receive corticosteroids (|rp|>0.1). CONCLUSION: This study indicates the validity of the RKQ and proposes that the RKQ is a suitable instrument to assess relapse knowledge in people with MS participating in educational interventions.


Subject(s)
Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Humans , Multiple Sclerosis/diagnosis , Multiple Sclerosis/therapy , Cross-Sectional Studies , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Multiple Sclerosis, Relapsing-Remitting/therapy , Surveys and Questionnaires , Chronic Disease , Recurrence , Reproducibility of Results
9.
J Neurol Sci ; 457: 122888, 2024 Feb 15.
Article in English | MEDLINE | ID: mdl-38278096

ABSTRACT

BACKGROUND: Predictive and prognostic biomarkers for multiple sclerosis (MS) remain a significant gap in MS diagnosis and treatment monitoring. Currently, there are no timely markers to diagnose the transition to secondary progressive MS (SPMS). OBJECTIVE: This study aims to evaluate the discriminatory potential of the High temperature requirement serine protease (HTRA1)/Macrophage migration inhibitory factor (MIF) cerebrospinal fluid (CSF) ratio in distinguishing relapsing-remitting (RRMS) patients from SPMS patients. METHODS: The MIF and HTRA1 CSF levels were determined using ELISA in healthy controls (n = 23), RRMS patients before (n = 22) and after 1 year of dimethyl fumarate treatment (n = 11), as well as in SPMS patients before (n = 11) and after 2 years of mitoxantrone treatment (n = 7). The ability of the HTRA1/MIF ratio to discriminate the different groups was determined using receiver operating curve (ROC) analyses. RESULTS: The ratio was significantly increased in treatment naïve RRMS patients while decreased again in SPMS patients at baseline. Systemic administrated disease modifying treatment (DMT) only significantly affected the ratio in RRMS patients. ROC analysis demonstrated that the ratio could discriminate treatment naïve RRMS patients from SPMS patients with 91% sensitivity and 100% specificity. CONCLUSION: The HTRA1/MIF ratio is a strong candidate as a MS biomarker for SPMS conversion.


Subject(s)
Macrophage Migration-Inhibitory Factors , Multiple Sclerosis, Chronic Progressive , Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Humans , Multiple Sclerosis, Chronic Progressive/diagnosis , Multiple Sclerosis, Chronic Progressive/drug therapy , Multiple Sclerosis, Chronic Progressive/cerebrospinal fluid , Multiple Sclerosis/diagnosis , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Multiple Sclerosis, Relapsing-Remitting/cerebrospinal fluid , Temperature
10.
Mult Scler Relat Disord ; 83: 105421, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38244525

ABSTRACT

BACKGROUND: Most Multiple Sclerosis (MS) clinical trials fail to assess the long-term effects of disease-modifying therapies (DMT) or disability. METHODS: COLuMbus was a single-visit, cross-sectional study in Argentina in adult patients with ≥10 years of MS since first diagnosis. The primary endpoint was to determine patient disability using the Expanded Disability Status Scale (EDSS). The secondary endpoints were to evaluate the distribution of diagnoses between relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS), patient demographics, disease history, and the risk of disability progression. The relationship between baseline characteristics and the current disability state and the risk of disability progression was assessed. RESULTS: Out of the 210 patients included, 76.7 % had a diagnosis of RRMS and 23.3 % had been diagnosed with SPMS, with a mean disease duration of 17.9 years and 20.5 years, respectively. The mean delay in the initial MS diagnosis was 2.6 years for the RRMS subgroup and 2.8 years for the SPMS subgroups. At the time of cut-off (28May2020), 90.1 % (RRMS) and 75.5 % (SPMS) of patients were receiving a DMT, with a mean of 1.5 and 2.0 prior DMTs, respectively. The median EDSS scores were 2.5 (RRMS) and 6.5 (SPMS). In the RRMS and SPMS subgroups, 23 % and 95.9 % of patients were at high risk of disability, respectively; the time since first diagnosis showed a significant correlation with the degree of disability. CONCLUSIONS: This is the first local real-world study in patients with long-term MS that highlights the importance of recognizing early disease progression to treat the disease on time and delay disability.


Subject(s)
Multiple Sclerosis, Chronic Progressive , Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Adult , Humans , Multiple Sclerosis/diagnosis , Multiple Sclerosis/epidemiology , Multiple Sclerosis/therapy , Cross-Sectional Studies , Argentina/epidemiology , Disease Progression , Multiple Sclerosis, Chronic Progressive/diagnosis , Multiple Sclerosis, Chronic Progressive/epidemiology , Multiple Sclerosis, Chronic Progressive/drug therapy , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Multiple Sclerosis, Relapsing-Remitting/epidemiology , Multiple Sclerosis, Relapsing-Remitting/therapy
11.
Mult Scler Relat Disord ; 83: 105435, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38245998

ABSTRACT

With evolving diagnostic criteria and the advent of new oral and parenteral therapies for Multiple Sclerosis (MS), most current diagnostic and treatment algorithms need revision and updating. The diagnosis of MS relies on incorporating clinical and paraclinical findings to prove dissemination in space and time and exclude alternative diseases that can explain the findings at hand. The differential diagnostic workup should be guided by clinical and laboratory red flags to avoid unnecessary tests. Appropriate selection of MS therapies is critical to maximize patient benefit. The current guidelines review the current diagnostic criteria for MS and the scientific evidence supporting treatment of acute relapses, radiologically isolated syndrome, clinically isolated syndrome, relapsing remitting MS, progressive MS, pediatric cases and pregnant women. The purpose of these guidelines is to provide practical recommendations and algorithms for the diagnosis and treatment of MS based on current scientific evidence and clinical experience.


Subject(s)
Multiple Sclerosis, Chronic Progressive , Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Pregnancy , Female , Humans , Child , Multiple Sclerosis/diagnosis , Multiple Sclerosis/therapy , Consensus , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Recurrence
12.
Mult Scler Relat Disord ; 83: 105418, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38262330

ABSTRACT

BACKGROUND: In multiple sclerosis (MS), dysphagia is an important and common clinical symptom. Although often overlooked and underdiagnosed, it can have a significant impact on a patient's life, including social integration, and it can lead to malnutrition, aspiration pneumonia, and suffocation, i.e., life-threatening complications. Early detection of dysphagia is essential to prevent these risks. However, the optimal screening method and the inter-relationship between different methods used for dysphagia screening are not clear. The aim of this study was to compare the diagnostic performance of a simple question about swallowing problems, the DYsphagia in MUltiple Sclerosis (DYMUS) swallowing questionnaire, and the Timed Water Swallowing Test (TWST) to detect dysphagia in people with relapsing-remitting MS (RRMS). METHODS: Patients with MS were asked about subjective swallowing difficulties and, regardless of their response, completed the DYMUS questionnaire and underwent the TWST at their routine follow-up visit. Patients with at least one positive screening method were offered an objective assessment of swallowing function using the Fiberoptic Endoscopic Evaluation of Swallowing (FEES). The results were statistically analyzed and correlated with demographic and MS-related parameters. RESULTS: Of the 304 people with RRMS enrolled in the study, 46 (15.1 %) reported having subjective difficulty swallowing when asked a simple question. The DYMUS questionnaire was positive in 59 (19.4 %) of the 304 patients; 51 (16.8 %) had an abnormality on the TWST. A clear correlation (r = 0.351, p < 0.01) was found between the DYMUS and TWST results, but a significant proportion of patients (about half) had an abnormality on only one of these tests. The positivity of at least one of the screening methods used (DYMUS or TWST) had a better chance of identifying a patient with dysphagia than a simple question (p < 0.001). Of the patients with a positive result for difficulty swallowing, 37 underwent FEES, which confirmed dysphagia in 94.6% of this subgroup. Patients with higher Expanded Disability Status Scale (EDSS) scores, female gender, and older age were at higher risk of developing dysphagia. CONCLUSION: The DYMUS questionnaire and TWST had a confirmed potential to identify more patients with dysphagia than a simple question about swallowing problems. However, our study found only a partial overlap between DYMUS and TWST; a combination of these two methods was more sensitive in identifying patients with MS at risk of dysphagia. Furthermore, the screening showed excellent specificity: almost 95 % of the positively screened patients had dysphagia confirmed by objective methods. Age, female gender, and a higher EDSS score appear to be potential risk factors for dysphagia in patients with MS.


Subject(s)
Deglutition Disorders , Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Humans , Female , Deglutition Disorders/diagnosis , Deglutition Disorders/etiology , Multiple Sclerosis, Relapsing-Remitting/complications , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Multiple Sclerosis/complications , Deglutition , Surveys and Questionnaires
13.
CNS Neurol Disord Drug Targets ; 23(4): 512-524, 2024.
Article in English | MEDLINE | ID: mdl-37013432

ABSTRACT

BACKGROUND: Alpha calcitonin gene-related peptide (aCGRP), neuropeptide Y (NPY), and substance P (SP) are neuropeptides that have emerged recently as potent immunomodulatory factors with potential as novel biomarkers and therapeutic targets in multiple sclerosis (MS). OBJECTIVE: The study aimed to detect serum levels of aCGRP, NPY, and SP in MS patients versus healthy controls and their association with disease activity and severity. METHODS: Serum levels were measured in MS patients and age and sex-matched healthy controls using ELISA. RESULTS: We included 67 MS patients: 61 relapsing-remitting MS (RR-MS) and 6 progressive MS (PR-MS), and 67 healthy controls. Serum NPY level was found to be lower in MS patients than in healthy controls (p < 0.001). Serum aCGRP level was higher in PR-MS compared to RR-MS (p = 0.007) and healthy controls (p = 0.001), and it positively correlated with EDSS (r = 0.270, p = 0.028). Serum NPY level was significantly higher in RR-MS and PR-MS than in healthy controls (p < 0.001 and p = 0.001, respectively), and it was lower in patients with mild or moderate/severe disease than in healthy controls (p < 0.001). Significant inverse correlations were found between SP level and MS disease duration (r = -0.279, p = 0.022) and duration of current DMT (r = -0.315, p = 0.042). CONCLUSION: Lower serum levels of NPY were revealed in MS patients compared to healthy controls. Since serum levels of aCGRP are significantly associated with disease activity and severity, it is a potential disease progression marker.


Subject(s)
Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Humans , Biomarkers , Calcitonin Gene-Related Peptide , Multiple Sclerosis/diagnosis , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Neuropeptide Y , Substance P
14.
Mult Scler Relat Disord ; 81: 105346, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38091806

ABSTRACT

BACKGROUND: Multiple sclerosis has a broad spectrum of clinical courses. Early identification of patients at greater risk of accumulating disability is essential. OBJECTIVES: Identify groups of patients with similar presentation through a mixture model and predict their trajectories over the years. METHODS: Retrospective study of patients from 1994 to 2019. We performed a latent profile analysis followed by a latent transition analysis based on eight parameters: age, disease duration, EDSS, number of relapses, multi-topographic symptoms, motor impairment, sphincter impairment, and infratentorial lesions. RESULTS: We included 629 patients, regardless of the phenotypical classification. We identified three distinct groups at the beginning and end of the follow-up. The three-classes model disclosed the "No disability regardless disease duration" (NDRDD) class with low EDSS and younger patients, the "Disability within a short disease duration" (DSDD) class with the worse disability besides short illness, and the "Disability within a long disease duration" (DLDD) class that achieved high EDSS over a long disease duration. EDSS, disease duration, and no sphincter impairment had the best entropy to distinguish classes at the initial presentation. Over time, the patients from NDRDD had a 52.1 % probability of changing to DLDD and 7.7 % of changing to DSDD. CONCLUSIONS: We identified three groups of clinical presentations and their evolution over time based on considered prognostic factors. The most likely transition is from NDRDD to DLDD.


Subject(s)
Disabled Persons , Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Humans , Multiple Sclerosis/diagnosis , Retrospective Studies , Time Factors , Disability Evaluation , Disease Progression , Multiple Sclerosis, Relapsing-Remitting/diagnosis
15.
J Neurol ; 271(1): 125-133, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37650895

ABSTRACT

BACKGROUND: Previous cohort studies evaluating the performances of the McDonald criteria suffered from bias regarding real-life conditions. We aimed to evaluate the probability of diagnosing relapsing-remitting multiple sclerosis (MS) at several timepoints from the first medical evaluation and the gain in time-to-diagnosis with the 2017 McDonald criteria compared with the 2001, 2005 and 2010 versions in real life. METHODS: Patients with a first demyelinating event suggestive of MS between 2002 and 2020 were included in the ReLSEP, an exhaustive and prospectively incremented registry of MS patients in North-Eastern France. We estimated the probability of being positive at the first medical evaluation and at five timepoints according to the four versions of criteria using Kaplan-Meier estimators and Cox models. RESULTS: A total of 2220 patients were followed up for a median of 7.1 years. At baseline, 31.7%, 32.1%, 36.6% and 54.0% of patients, respectively, fulfilled the 2001, 2005, 2010 and 2017 McDonald criteria. Using the 2017 criteria, the gain in time-to-diagnosis was 3.7 months compared with the 2010 criteria. The presence of intrathecal synthesis of immunoglobulin G in the McDonald 2017 criteria led to a 1.8-month reduction in median time-to-diagnosis compared to a version of McDonald 2017 without this criteria. CONCLUSIONS: In real-life, the 2017 McDonald criteria revision undoubtedly shortened time-to-diagnosis.


Subject(s)
Demyelinating Diseases , Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Humans , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Multiple Sclerosis/diagnosis , Cohort Studies , Survival Analysis , Magnetic Resonance Imaging
16.
Eur J Neurol ; 31(1): e16046, 2024 01.
Article in English | MEDLINE | ID: mdl-37584176

ABSTRACT

BACKGROUND AND PURPOSE: The validity, reliability, and longitudinal performance of the Patient-Determined Disease Steps (PDDS) scale is unknown in people with multiple sclerosis (MS) with mild to moderate disability. We aimed to examine the psychometric properties and longitudinal performance of the PDDS. METHODS: We included relapsing-remitting MS patients with an Expanded Disability Status Scale (EDSS) score of less than 4. Validity and test-retest reliability was examined. Longitudinal data were analysed with mixed-effect modelling and Cohen's kappa for concordance in confirmed disability progression (CDP). RESULTS: We recruited a total of 1093 participants, of whom 904 had complete baseline data. The baseline correlation between PDDS and EDSS was weak (ρ = 0.45, p < 0.001). PDDS had stronger correlations with patient-reported outcomes (PROs). Conversely, EDSS had stronger correlations with age, disease duration, Kurtzke's functional systems and processing speed test. PDDS test-retest reliability was good to excellent (concordance correlation coefficient = 0.73-0.89). Longitudinally, PDDS was associated with EDSS, age and depression. A higher EDSS score was associated with greater PDSS progression. The magnitude of these associations was small. There was no concordance in CDP as assessed by PDDS and EDSS. CONCLUSION: The PDDS has greater correlation with other PROs but less correlation with other MS-related outcome measures compared to the EDSS. There was little correlation between PDDS and EDSS longitudinally. Our findings suggest that the PDDS scale is not interchangeable with the EDSS.


Subject(s)
Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Humans , Multiple Sclerosis/diagnosis , Reproducibility of Results , Disability Evaluation , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Outcome Assessment, Health Care
18.
Georgian Med News ; (340-341): 180-184, 2023.
Article in English | MEDLINE | ID: mdl-37805895

ABSTRACT

Work objective - to study the relationship between the duration of remission after the onset, the severity of relapses against the background of different duration of the relapsing stage (RS) and the nature of the prognosis in the secondary progressive multiple sclerosis (SPMS) using clinical and mathematical analysis. Patients with different prognosis for SPMS; neurological examination using The Expanded Disability Status Scale (EDSS); a survey method. Mathematical methods: 'contingency tables 2x2' (determining the significance of the connection between a pair of two indicators - different duration of remission after the onset and RS in four groups of patients), Yule's Coefficient of Association (determining the magnitude of differences between the group and the studied indicator), a permutation test (defining clinical indicators on RS, which significantly differed in mild and severe relapses). Pairwise comparison in four groups of patients with different duration of remission after the onset and RS in SPMS showed that long-term remission after the onset and prolonged RS delay the transition of RS into secondary progression (SP). Short duration of these indicators revealed the opposite prognostic tendencies, indicating the further progression of the disease. The presence of severe relapses on RS in SPMS is predominantly associated with unfavorable prognostic indicators on RS and indicates the initiation of the transition into SP. Accordingly, the duration of remission after the onset, the severity of relapses against the background of different durations of RS should be regarded as prognostic clinical markers that play a key role in the switch of RS to SPS in SPMS. The results obtained should be used to assess the current clinical situation and timely prescribe an appropriate pathogenetic therapy on RS.


Subject(s)
Multiple Sclerosis, Chronic Progressive , Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Humans , Multiple Sclerosis, Chronic Progressive/diagnosis , Multiple Sclerosis, Chronic Progressive/drug therapy , Multiple Sclerosis/diagnosis , Disease Progression , Neoplasm Recurrence, Local , Prognosis , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Multiple Sclerosis, Relapsing-Remitting/drug therapy
19.
Mult Scler ; 29(11-12): 1437-1451, 2023 10.
Article in English | MEDLINE | ID: mdl-37840276

ABSTRACT

BACKGROUND: Early diagnosis and treatment of patients with multiple sclerosis (MS) are associated with better outcomes; however, diagnostic delays remain a major problem. OBJECTIVE: Describe the prevalence, determinants and consequences of delayed diagnoses. METHODS: This single-centre ambispective study analysed 146 adult relapsing-remitting MS patients (2016-2021) for frequency and determinants of diagnostic delays and their associations with clinical, cognitive, imaging and biochemical measures. RESULTS: Diagnostic delays were identified in 77 patients (52.7%), including 42 (28.7%) physician-dependent cases and 35 (24.0%) patient-dependent cases. Diagnosis was delayed in 22 (15.1%) patients because of misdiagnosis by a neurologist. A longer diagnostic delay was associated with trends towards greater Expanded Disability Status Scale (EDSS) scores (B = 0.03; p = 0.034) and greater z-score of the blood neurofilament light chain (B = 0.35; p = 0.031) at the time of diagnosis. Compared with patients diagnosed at their first clinical relapse, patients with a history of >1 relapse at diagnosis (n = 63; 43.2%) had a trend towards greater EDSS scores (B = 0.06; p = 0.006) and number of total (B = 0.13; p = 0.040) and periventricular (B = 0.06; p = 0.039) brain lesions. CONCLUSION: Diagnostic delays in MS are common, often determined by early misdiagnosis and associated with greater disease burden.


Subject(s)
Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Adult , Humans , Multiple Sclerosis/diagnosis , Multiple Sclerosis/epidemiology , Multiple Sclerosis/pathology , Delayed Diagnosis , Prevalence , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Multiple Sclerosis, Relapsing-Remitting/epidemiology , Multiple Sclerosis, Relapsing-Remitting/pathology , Recurrence , Magnetic Resonance Imaging , Brain/pathology
20.
Clin Immunol ; 256: 109801, 2023 11.
Article in English | MEDLINE | ID: mdl-37816415

ABSTRACT

We recently reported that multiple sclerosis (MS) plasma contains IgG aggregates and induces complement-dependent neuronal cytotoxicity (Zhou et al., 2023). Using ELISA, we report herein that plasma IgG levels in the aggregates can be used as biomarkers for MS. We enriched the IgG aggregates from samples of two cohorts (190 MS and 160 controls) by collecting flow-through after plasma binding to Protein A followed by detection of IgG subclass. We show that there are significantly higher levels of IgG1, IgG3, and total IgG antibodies in MS IgG aggregates, with an AUC >90%; higher levels of IgG1 distinguish secondary progressive MS from relapsing-remitting MS (AUC = 91%). Significantly, we provided the biological rationale for MS plasma IgG biomarkers by demonstrating the strong correlation between IgG antibodies and IgG aggregate-induced neuronal cytotoxicity. These non-invasive, simple IgG-based blood ELISA assays can be adapted into clinical practice for diagnosing MS and SPMS and monitoring treatment responses.


Subject(s)
Multiple Sclerosis, Chronic Progressive , Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Humans , Multiple Sclerosis/diagnosis , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Immunoglobulin G , Biomarkers , Enzyme-Linked Immunosorbent Assay , Multiple Sclerosis, Chronic Progressive/metabolism
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