Identifying Multiple Sclerosis Patients Research Articles

Methylation of Interleukin-1 receptor-associated kinase-3 and the risk of multiple sclerosis relapse/activity

This study retrospectively investigated the impact of interleukin-1 receptor-associated kinase-3 (IRAK-3/IRAK-M) silencing by methylation on the likelihood of multiple sclerosis (MS) activity. This cross-sectional study included 90 patients with MS: 45 with active disease (Group 1), 45 in remission (Group 2), and 45 healthy controls. The study included quantitation of IRAK-3 methylation index (MI%), IRAK-3 mRNA, and myeloid differentiation factor88 (MyD88) and assessment of NF-κB activity.IRAK-3 MI% was significantly higher in group 1 compared to group 2, accompanied by lower IRAK-3 mRNA expression, elevated circulating MyD88, and increased NF-κB activity. IRAK-3 MI% correlated negatively with its transcript and positively with MyD88 and NF-κB activity. A logistic regression model was created to predict active demyelination. The C-index was 0.924, which indicates a very strong prediction model. Within the limitations of current work, IRAK-3 methylation level seems to be a promising candidate biomarker for identifying MS patients at risk of relapse.

Should autologous hematopoietic stem cell transplantation be offered as a first-line disease modifying therapy to patients with multiple sclerosis?

In multiple sclerosis (MS), progression independent of new focal inflammation may commence shortly after disease onset, and it is increasingly revealed that the risk of disability accrual is reduced by early use of high-efficacy disease-modifying therapies (HE-DMTs). People with aggressive MS may therefore benefit from early treatment with autologous haematopoietic stem cell transplantation (AHSCT), a procedure inducing maximal immunosuppression followed by immune reconstitution, demonstrated to be superior to DMTs in one randomized clinical trial. However, in current practice prior failure to HE-DMTs is typically required to establish the indication for AHSCT. In the present article, the available evidence on the potential role of AHSCT as first-line treatment in aggressive MS and the rationale for its early use will be summarized. Proposed definitions of aggressive MS that could help identifying MS patients eligible for early treatment with AHSCT will also be discussed.

Blood CD8+ Naïve T-Cells Identify MS Patients with High Probability of Optimal Cellular Response to SARS-CoV-2 Vaccine.

This single-center study included 68 multiple sclerosis (MS) patients who received the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination from one of several approved vaccine preparations in Spain. Blood samples were collected one to three months after the second dose of the vaccine had been administered. Cellular immune responses to the vaccine were assessed using QuantiFERON analysis, and peripheral blood mononuclear cell subsets were assayed using flow cytometry. Response associated with higher percentages of total lymphocytes, naïve CD4+ T-cells (p = 0.028), CD8+ T-cells (p = 0.013), and, mostly, naïve CD8+ T-cells (p = 0.0003). These results were confirmed by analyzing absolute numbers (p = 0.019; p = 0.002, and p = 0.0003, respectively). Naïve CD8 T-cell numbers higher than 17 cells/μL were closely associated with an optimal cellular response to SARS-CoV-2 vaccination (odds ratio: 24.0, confidence interval: 4.8-460.3; p = 0.0001). This finding clearly shows that independent of the treatment received, higher numbers of naïve CD8+ T-cells yield a strong cellular response to SARS-CoV-2 vaccines in MS patients. If this finding is validated with other viruses/vaccines, it could provide a good tool for identifying MS patients undergoing treatment who will develop strong cellular responses to anti-virus vaccines.

Discontinuation of disease-modifying therapy in MS patients over 60 years old and its impact on relapse rate and disease progression

Background / AimsThe benefit of disease-modifying therapy (DMT) is unclear for older patients with multiple sclerosis (MS), namely those who have not experienced clinical disease activity for a prolonged time. We aimed to compare baseline differences and clinical outcomes between DMT discontinuers and continuers in a cohort of MS patients older than 60 years. MethodsRetrospective, observational study identifying MS patients aged over 60 years, stable on DMT> 24 months. Additional inclusion criteria were a previous diagnosis of relapsing MS and a minimum follow-up period of 24 months. Differences between groups (continuers/discontinuers) were assessed. For risk of relapse and of confirmed disability worsening at follow up, a time to outcome survival model was constructed using Cox proportional hazards regression, testing for possible risk predictors. ResultsThirty-five patients were included (68.6% female), with a mean age at diagnosis of 42.1 ( ± 9.5) years and a median EDSS score of 3 (IQR 2) at the age of 60 years (baseline). Thirteen patients discontinued DMT after baseline, in a mean follow-up time of 77.1 months ( ± 40.2). No differences were found between DMT continuers vs discontinuers. DMT discontinuation did not predict risk to relapse (HR 0.38, 95%CI 0.04–3.80, p = 0.408) or disability worsening at follow-up (HR 0.83, 95%CI 0.31–2.22, p = 0.712). MRI gadolinium-enhancing lesions and EDSS score > 3 at baseline were found to be independent predictors of risk to relapse and disability worsening at follow-up, respectively. ConclusionDMT discontinuation did not seem to influence clinical outcome, equating with the perceived limited effect of continued immunomodulation on older stable and/or progressive patients.

Reduced clinical connectome fingerprinting in multiple sclerosis predicts fatigue severity

BackgroundBrain connectome fingerprinting is progressively gaining ground in the field of brain network analysis. It represents a valid approach in assessing the subject-specific connectivity and, according to recent studies, in predicting clinical impairment in some neurodegenerative diseases. Nevertheless, its performance, and clinical utility, in the Multiple Sclerosis (MS) field has not yet been investigated. MethodsWe conducted the Clinical Connectome Fingerprint (CCF) analysis on source-reconstructed magnetoencephalography signals in a cohort of 50 subjects: twenty-five MS patients and twenty-five healthy controls. ResultsAll the parameters of identifiability, in the alpha band, were reduced in patients as compared to controls. These results implied a lower similarity between functional connectomes (FCs) of the same patient and a reduced homogeneity among FCs in the MS group. We also demonstrated that in MS patients, reduced identifiability was able to predict, fatigue level (assessed by the Fatigue Severity Scale). ConclusionThese results confirm the clinical usefulness of the CCF in both identifying MS patients and predicting clinical impairment. We hope that the present study provides future prospects for treatment personalization on the basis of individual brain connectome.

A novel prognostic score to assess the risk of progression in relapsing-remitting multiple sclerosis patients.

BackgroundAt the patient level, the prognostic value of several features that are known to be associated with an increased risk of converting from relapsing−remitting (RR) to secondary phase (SP) multiple sclerosis (MS) remains limited.MethodsAmong 262 RRMS patients followed up for 10 years, we assessed the probability of developing the SP course based on clinical and conventional and non‐conventional magnetic resonance imaging (MRI) parameters at diagnosis and after 2 years. We used a machine learning method, the random survival forests, to identify, according to their minimal depth (MD), the most predictive factors associated with the risk of SP conversion, which were then combined to compute the secondary progressive risk score (SP‐RiSc).ResultsDuring the observation period, 69 (26%) patients converted to SPMS. The number of cortical lesions (MD = 2.47) and age (MD = 3.30) at diagnosis, the global cortical thinning (MD = 1.65), the cerebellar cortical volume loss (MD = 2.15) and the cortical lesion load increase (MD = 3.15) over the first 2 years exerted the greatest predictive effect. Three patients’ risk groups were identified; in the high‐risk group, 85% (46/55) of patients entered the SP phase in 7 median years. The SP‐RiSc optimal cut‐off estimated was 17.7 showing specificity and sensitivity of 87% and 92%, respectively, and overall accuracy of 88%.ConclusionsThe SP‐RiSc yielded a high performance in identifying MS patients with high probability to develop SPMS, which can help improve management strategies. These findings are the premise of further larger prospective studies to assess its use in clinical settings.

Optimal Intereye Difference Thresholds in Retinal Nerve Fiber Layer Thickness for Predicting a Unilateral Optic Nerve Lesion in Multiple Sclerosis.

The optic nerve is a frequent site for involvement in multiple sclerosis (MS). Optical coherence tomography (OCT) detects thinning of the retinal nerve fiber layer (RNFL) in eyes of patients with MS and in those meeting criteria for clinically or radiologically isolated demyelinating syndromes. Current international diagnostic criteria for MS do not include the optic nerve as an imaging lesion site despite the high prevalence of acute optic neuritis (ON), or occult optic neuropathy, among early MS and clinically isolated syndrome patients; as well as most MS patients over the course of the disease. We sought to determine optimal thresholds for intereye difference in peripapillary RNFL thickness that are most predictive of a unilateral optic nerve lesion. We analyzed spectral domain OCT data of 31 healthy volunteers and 124 patients with MS at a single center as part of an ongoing collaborative investigation of visual outcomes. Intereye differences in peripapillary (360°) RNFL thickness were calculated as the absolute value of the difference. First, we determined the 95th percentile value of intereye difference for the healthy volunteers. This value was applied to the convenience sample group of MS patients as a validation cohort determining how well this threshold could distinguish patients with vs without a history of unilateral ON. The relation of intereye differences in peripapillary RNFL thickness to binocular low-contrast letter acuity scores was also examined. Among healthy volunteer participants (n = 31), the 95th percentile value for intereye difference (upper boundary of expected for normal controls) was 6.0 μm. This value was applied to the convenience sample group of MS patients (n = 124, validation cohort). Positive predictive value, negative predictive value, sensitivity, and specificity for identifying MS patients with a history of unilateral ON were calculated for the 6-μm threshold value in a 2 × 2 table analysis with the application of χ tests (P < 0.0001). The 6-μm threshold was predictive of worse binocular low-contrast acuity scores at 2.5% (P = 0.03) and 1.25% (P = 0.002 by linear regression analyses). A receiver operating characteristic curve analysis demonstrated an optimal intereye difference threshold of 5 μm for identifying unilateral ON in the MS cohort. An intereye difference of 5-6 μm in RNFL thickness is a robust structural threshold for identifying the presence of a unilateral optic nerve lesion in MS.

Validation of the brief international cognitive assessment for multiple sclerosis (BICAMS) in the Portuguese population with multiple sclerosis

BackgroundThe validation of international cognitive batteries in different multiple sclerosis (MS) populations is essential. Our objective was to obtain normative data for the Portuguese population of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) and assess its reliability.MethodsThe BICAMS was applied to 105 MS patients and 60 age, gender and education matched healthy controls (HC). In order to test its reliability, BICAMS was re-administered in a subset of 25 patients after a 7-month interval.ResultsMost participants were women, with a mean age of 37, 21 years and a mean of 14,08 years of education. The vast majority of the MS patients (92.4%) had the relapsing remitting type, 58.1% were professionally active, mean disease duration was 6.52 years, median EDSS score was 1.5 (range: 0–6.0) and the median MSSS score was 2.01 (IQR range: 3.83). The MS group presented significantly higher scores of anxiety and depression than HC and 47,4% had fatigue. The MS group performed significantly worse than the control group across the three neuropsychological tests, yielding the following values: SDMT: t(165) = 3.77, p = .000; CVLT-II: t(165) = 2.98, p = .003; and BVMT-R: t(165) = 2.94, p = .004. The mean raw scores for Portuguese normative data were as follows: SDMT: 58.68 ± 10.02; CVLT-II: 60.47 ± 10.12; and BVMT-R: 24.68 ± 5.52. Finally, test–retest reliability coefficients for each test were as follows: SDMT: r = .90; CVLT-II: r = .71; and BVMT-R: r = .84.ConclusionsThe Portuguese version of BICAMS here in described is a reliable monitoring instrument for identifying MS patients with cognitive impairment.

Prevalence, treatments and medical cost of multiple sclerosis in Japan based on analysis of a health insurance claims database.

ObjectiveTo understand, through an analysis of health insurance claims data, the current treatment status and medical cost of multiple sclerosis (MS) in Japan.MethodsWe analyzed claims data (January 2005–January 2016) from the Japan Medical Data Center Co., Ltd., identifying MS patients, except those with neuromyelitis optica, using an algorithm based on diagnosis codes. Prescription drug usage and medical costs for MS patients were analyzed.ResultsA total of 713 MS patients were identified in the database. Between 2011 and 2015, the age‐adjusted prevalence of MS in the database increased from 0.015% to 0.019%, and the female‐to‐male ratio increased from 1.70 to 2.03. The prescription rate for disease‐modifying therapy drugs was higher in larger care settings. Prescriptions for fingolimod increased from 2011, with a concomitant decrease in prescriptions for interferon. The per patient per month cost for MS was ¥124 337 (US$1190 or €1084, as of October 2016). This was higher than the costs for Parkinson's disease (¥84 410), myasthenia gravis (¥82 944) and rheumatoid arthritis (¥53 843). However, the total per member per month cost for MS, which represents the population‐based economic impact, was ¥25.2, which was lower than the parallel costs for Parkinson's disease (¥123.0) and rheumatoid arthritis (¥311.6) because of the low prevalence of MS in Japan.ConclusionsUsing real‐world data, we obtained up‐to‐date prevalence, treatment status and medical cost information for MS in Japan. The present results showed the efficacy of a real‐world database to obtain the latest national trends for rare diseases, such as MS; this could have important implications for clinicians and policymakers.

Effects of cognitive impairment on prosodic parameters of speech production planning in multiple sclerosis.

Cognitive impairment (CI) affects 40-65% of patients with multiple sclerosis (MS). CI can have a negative impact on a patient's everyday activities, such as engaging in conversations. Speech production planning ability is crucial for successful verbal interactions and thus for preserving social and occupational skills. This study investigates the effect of cognitive-linguistic demand and CI on speech production planning in MS, as reflected in speech prosody. A secondary aim is to explore the clinical potential of prosodic features for the prediction of an individual's cognitive status in MS. A total of 45 subjects, that is 22 healthy controls (HC) and 23 patients in early stages of relapsing-remitting MS, underwent neuropsychological tests probing specific cognitive processes involved in speech production planning. All subjects also performed a read speech task, in which they had to read isolated sentences manipulated as for phonological length. Results show that the speech of MS patients with CI is mainly affected at the temporal level (articulation and speech rate, pause duration). Regression analyses further indicate that rate measures are correlated with working memory scores. In addition, linear discriminant analysis shows the ROC AUC of identifying MS patients with CI is 0.70 (95% confidence interval: 0.68-0.73). Our findings indicate that prosodic planning is deficient in patients with MS-CI and that the scope of planning depends on patients' cognitive abilities. We discuss how speech-based approaches could be used as an ecological method for the assessment and monitoring of CI in MS.

A new assessment tool for patients with multiple sclerosis from Spanish-speaking countries: validation of the Brief International Cognitive Assessment for MS (BICAMS) in Argentina

Background: The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) is an international assessment tool for monitoring cognitive function in multiple sclerosis (MS) patients. BICAMS comprises the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test – Second Edition (CVLT II) and the Brief Visuospatial Memory Test – Revised (BVMT-R). Our objective was to validate and assess the reliability of BICAMS as applied in Argentina and to obtain normative data in Spanish for this population. Method: The sample composed of 50 MS patients and 100 healthy controls (HC). In order to test its reliability, BICAMS was re-administered in a subset of 25 patients. Results: The sample’s average age was 43.42 ± 10.17 years old, and average years of schooling were 14.86 ± 2.78. About 74% of the participants were women. The groups did not differ in age, years of schooling, or gender. The MS group performed significantly worse than the HC group across the three neuropsychological tests, yielding the following Cohen’s d values: SDMT: .85; CVLT I: .87; and BVMT-R: .40. The mean raw scores for Argentina normative data were as follows: SDMT: 56.71 ± 10.85; CVLT I: 60.88 ± 10.46; and BVMT-R: 23.44 ± 5.84. Finally, test–retest reliability coefficients for each test were as follows: SDMT: r = .95; CVLT I: r = .87; and BVMT-R: r = .82. Conclusion: This BICAMS version is reliable and useful as a monitoring tool for identifying MS patients with cognitive impairment.

Anti-JCV Antibodies Detection and JCV DNA Levels in PBMC, Serum and Urine in a Cohort of Spanish Multiple Sclerosis Patients Treated with Natalizumab

One of the most effective multiple sclerosis (MS) treatment is natalizumab. Nevertheless, it has been associated with an increased risk of progressive multifocal leukoencephalopathy (PML) caused by the JC virus (JCV). Our main objective was to assess the utility of testing JCV-DNA, apart from anti-JCV antibodies, to determine which natalizumab-treated MS patients has been previously in contact with the virus. For this purpose, 138 MS natalizumab/non-natalizumab treated patients participated in several studies. Cross-sectional study (CS): association of several epidemiological variables with anti-JCV antibodies and JCV-DNA levels in PBMC/serum/urine. First longitudinal study (A): evaluation of JCV-DNA prevalence in urine throughout the treatment. Second longitudinal study (B): simultaneous assessment of antibodies and viral DNA levels in PBMC/serum/urine at two time points. CS: The seropositivity rate for anti-JCV antibodies (62.3%) and JCV prevalence in urine (59.4%) were similar; although 26% of our population was positive only using one of the two techniques. A: The viral prevalence in urine seemed to increase between the baseline visit and the others (Baseline-Visit/V18months, p = 0.006). B: Our rate of positive antibody seroconversion was 36%. Nearly all patients with detectable JCV-DNA levels in PBMC excreted the virus intermittently in urine; while our PML case, positive in PBMC and serum samples 2month before the PML, excreted JCV permanently. In conclusion, the determination of JCV DNA levels in urine could be complementary to anti-JCV antibodies for identifying MS patients who has been infected by the JCV. Further research would be necessary to understand the different JCV excretion profiles in urine.

A metabonomics investigation of multiple sclerosis by nuclear magnetic resonance

Multiple sclerosis (MS) is a nervous system disease that affects the fatty myelin sheaths around the axons of the brain and spinal cord, leading to demyelination and a broad range of signs and symptoms. MS can be difficult to diagnose because its signs and symptoms may be similar to other medical problems. To find out which metabolites in serum are effective for the diagnosis of MS, we utilized metabolic profiling using proton nuclear magnetic resonance spectroscopy ((1)H-NMR). Random forest (RF) was used to classify the MS patients and healthy subjects. Atomic absorption spectroscopy was used to measure the serum levels of selenium. The results showed that the levels of selenium were lower in the MS group, when compared with the control group. RF was used to identify the metabolites that caused selenium changes in people with MS by building a correlation model between these metabolites and serum levels of selenium. For the external test set, the obtained classification model showed a 93% correct classification of MS and healthy subjects. The regression model of levels of selenium and metabolites showed the correlation (R(2)) value of 0.88 for the external test set. The results indicate the suitability of NMR as a screen for identifying MS patients and healthy subjects. A novel model with good prediction outcomes was constructed between serum levels of selenium and NMR data.

Screening for depression among patients with multiple sclerosis: two questions may be enough

Background Depression among patients with multiple sclerosis (MS) is common and has a significant impact on quality of life. As many as two-thirds of depressed MS patients receive no treatment for their depression. While guidelines for depression management suggest screening, the only validated screening tools are questionnaires, which have not been widely implemented in practice. This is the first study on the effectiveness of using two questions assessing mood and anhedonia (loss of interest or pleasure) in screening for major depressive disorder (MDD) in MS. Methods MS patients under the care of neurologists were recruited from a large health maintenance organization (HMO). The MDD module of the Structured Clinical Interview for the DSM-IV and screening questions was administered. Results Of the 260 participants, 26% met the criteria for MDD. Among patients with MDD, 67% received no anti-depressant medication. The MDD screen identified 99% (95% CI: 91–100%) of cases. Discussion A brief, two question screen is reliable in identifying MS patients with MDD. This suggests that asking these two brief questions could identify almost all MS patients meeting MDD criteria, with minimal numbers of false positives. Multiple Sclerosis 2007; 13: 215–219. http://msj.sagepub.com

The INTERMED: a screening instrument to identify multiple sclerosis patients in need of multidisciplinary treatment

Objective: To analyse the value of the INTERMED, a screening instrument to assess case complexity, compared with the Expanded Disability Status Scale (EDSS) and the Guy’s Neurological Disability Scale (GNDS)...

Prevalence of multiple sclerosis in British Columbia.

A province wide prevalence study on multiple sclerosis (MS) was conducted in British Columbia (B.C.). The prevalence date was July 1, 1982. The major portion of this study was a review of all the files of neurologists practicing in B.C. as this was judged to be the most accurate source for identifying MS patients. 239,412 neurologists' files were hand searched by one researcher using modified Schumacher criteria for classification. Other sources used during the study for identifying MS patients were the MS Clinic, general practitioners, ophthalmologists, urologists, specialized facilities such as long term care facilities and rehabilitation centres, and patient self-referrals. A total of 4,620 non-duplicated cases were identified and classified. 4,112 of these (89%) were classified according to information contained in neurologists' records. The prevalence estimate for definite/probable MS in B.C. was 93.3/100,000 population. This increased to 130.5/100,000 population if possible MS and optic neuritis were also included. These rates are among the highest reported in Canada or elsewhere. The cooperation of B.C. neurologists made this study unique in its scope and accuracy of diagnosis.