Resting-state functional connectivity in multiple sclerosis patients receiving nabiximols for spasticity.

BACKGROUND: Nabiximols (Sativex®) is a cannabinoid approved for multiple sclerosis (MS)-related spasticity. Its mechanism of action is partially understood, and efficacy is variable. OBJECTIVE: To conduct an exploratory analysis of brain networks connectivity changes on resting state (RS) functional MRI (fMRI) of MS patients treated with nabiximols. METHODS: We identified a group of MS patients treated with Sativex® at Verona University Hospital, who underwent RS brain fMRI in the 4 weeks before (T0) and 4-8 weeks after (T1) treatment start. Sativex® response was defined as ≥ 20% spasticity Numerical Rating Scale score reduction at T1 vs. T0. Connectivity changes on fMRI were compared between T0 and T1 in the whole group and according to response status. ROI-to-ROI and seed-to-voxel connectivity were evaluated. RESULTS: Twelve MS patients (7 males) were eligible for the study. Seven patients (58.3%) resulted Sativex® responders at T1. On fMRI analysis, Sativex® exposure was associated with global brain connectivity increase (particularly in responders), decreased connectivity of motor areas, and bidirectional connectivity changes of the left cerebellum with a number of cortical areas. CONCLUSIONS: Nabiximols administration is associated with brain connectivity increase of MS patients with spasticity. Modulation of sensorimotor cortical areas and cerebellum connectivity could play a role in nabiximols effect.

Adverse effects of immunotherapies for multiple sclerosis: a network meta-analysis.

BACKGROUND: Multiple sclerosis (MS) is a chronic disease of the central nervous system that affects mainly young adults (two to three times more frequently in women than in men) and causes significant disability after onset. Although it is accepted that immunotherapies for people with MS decrease disease activity, uncertainty regarding their relative safety remains. OBJECTIVES: To compare adverse effects of immunotherapies for people with MS or clinically isolated syndrome (CIS), and to rank these treatments according to their relative risks of adverse effects through network meta-analyses (NMAs). SEARCH METHODS: We searched CENTRAL, PubMed, Embase, two other databases and trials registers up to March 2022, together with reference checking and citation searching to identify additional studies. SELECTION CRITERIA: We included participants 18 years of age or older with a diagnosis of MS or CIS, according to any accepted diagnostic criteria, who were included in randomized controlled trials (RCTs) that examined one or more of the agents used in MS or CIS, and compared them versus placebo or another active agent. We excluded RCTs in which a drug regimen was compared with a different regimen of the same drug without another active agent or placebo as a control arm. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods for data extraction and pairwise meta-analyses. For NMAs, we used the netmeta suite of commands in R to fit random-effects NMAs assuming a common between-study variance. We used the CINeMA platform to GRADE the certainty of the body of evidence in NMAs. We considered a relative risk (RR) of 1.5 as a non-inferiority safety threshold compared to placebo. We assessed the certainty of evidence for primary outcomes within the NMA according to GRADE, as very low, low, moderate or high. MAIN RESULTS: This NMA included 123 trials with 57,682 participants. Serious adverse events (SAEs) Reporting of SAEs was available from 84 studies including 5696 (11%) events in 51,833 (89.9%) participants out of 57,682 participants in all studies. Based on the absolute frequency of SAEs, our non-inferiority threshold (up to a 50% increased risk) meant that no more than 1 in 18 additional people would have a SAE compared to placebo. Low-certainty evidence suggested that three drugs may decrease SAEs compared to placebo (relative risk [RR], 95% confidence interval [CI]): interferon beta-1a (Avonex) (0.78, 0.66 to 0.94); dimethyl fumarate (0.79, 0.67 to 0.93), and glatiramer acetate (0.84, 0.72 to 0.98). Several drugs met our non-inferiority criterion versus placebo: moderate-certainty evidence for teriflunomide (1.08, 0.88 to 1.31); low-certainty evidence for ocrelizumab (0.85, 0.67 to 1.07), ozanimod (0.88, 0.59 to 1.33), interferon beta-1b (0.94, 0.78 to 1.12), interferon beta-1a (Rebif) (0.96, 0.80 to 1.15), natalizumab (0.97, 0.79 to 1.19), fingolimod (1.05, 0.92 to 1.20) and laquinimod (1.06, 0.83 to 1.34); very low-certainty evidence for daclizumab (0.83, 0.68 to 1.02). Non-inferiority with placebo was not met due to imprecision for the other drugs: low-certainty evidence for cladribine (1.10, 0.79 to 1.52), siponimod (1.20, 0.95 to 1.51), ofatumumab (1.26, 0.88 to 1.79) and rituximab (1.01, 0.67 to 1.52); very low-certainty evidence for immunoglobulins (1.05, 0.33 to 3.32), diroximel fumarate (1.05, 0.23 to 4.69), peg-interferon beta-1a (1.07, 0.66 to 1.74), alemtuzumab (1.16, 0.85 to 1.60), interferons (1.62, 0.21 to 12.72) and azathioprine (3.62, 0.76 to 17.19). Withdrawals due to adverse events Reporting of withdrawals due to AEs was available from 105 studies (85.4%) including 3537 (6.39%) events in 55,320 (95.9%) patients out of 57,682 patients in all studies. Based on the absolute frequency of withdrawals, our non-inferiority threshold (up to a 50% increased risk) meant that no more than 1 in 31 additional people would withdraw compared to placebo. No drug reduced withdrawals due to adverse events when compared with placebo. There was very low-certainty evidence (meaning that estimates are not reliable) that two drugs met our non-inferiority criterion versus placebo, assuming an upper 95% CI RR limit of 1.5: diroximel fumarate (0.38, 0.11 to 1.27) and alemtuzumab (0.63, 0.33 to 1.19). Non-inferiority with placebo was not met due to imprecision for the following drugs: low-certainty evidence for ofatumumab (1.50, 0.87 to 2.59); very low-certainty evidence for methotrexate (0.94, 0.02 to 46.70), corticosteroids (1.05, 0.16 to 7.14), ozanimod (1.06, 0.58 to 1.93), natalizumab (1.20, 0.77 to 1.85), ocrelizumab (1.32, 0.81 to 2.14), dimethyl fumarate (1.34, 0.96 to 1.86), siponimod (1.63, 0.96 to 2.79), rituximab (1.63, 0.53 to 5.00), cladribine (1.80, 0.89 to 3.62), mitoxantrone (2.11, 0.50 to 8.87), interferons (3.47, 0.95 to 12.72), and cyclophosphamide (3.86, 0.45 to 33.50). Eleven drugs may have increased withdrawals due to adverse events compared with placebo: low-certainty evidence for teriflunomide (1.37, 1.01 to 1.85), glatiramer acetate (1.76, 1.36 to 2.26), fingolimod (1.79, 1.40 to 2.28), interferon beta-1a (Rebif) (2.15, 1.58 to 2.93), daclizumab (2.19, 1.31 to 3.65) and interferon beta-1b (2.59, 1.87 to 3.77); very low-certainty evidence for laquinimod (1.42, 1.01 to 2.00), interferon beta-1a (Avonex) (1.54, 1.13 to 2.10), immunoglobulins (1.87, 1.01 to 3.45), peg-interferon beta-1a (3.46, 1.44 to 8.33) and azathioprine (6.95, 2.57 to 18.78); however, very low-certainty evidence is unreliable. Sensitivity analyses including only studies with low attrition bias, drug dose above the group median, or only patients with relapsing remitting MS or CIS, and subgroup analyses by prior disease-modifying treatments did not change these figures. Rankings No drug yielded consistent P scores in the upper quartile of the probability of being better than others for primary and secondary outcomes. AUTHORS' CONCLUSIONS: We found mostly low and very low-certainty evidence that drugs used to treat MS may not increase SAEs, but may increase withdrawals compared with placebo. The results suggest that there is no important difference in the occurrence of SAEs between first- and second-line drugs and between oral, injectable, or infused drugs, compared with placebo. Our review, along with other work in the literature, confirms poor-quality reporting of adverse events from RCTs of interventions. At the least, future studies should follow the CONSORT recommendations about reporting harm-related issues. To address adverse effects, future systematic reviews should also include non-randomized studies.

Cancer risk for multiple sclerosis patients treated with azathioprine and disease-modifying therapies: an Italian observational study.

BACKGROUND: The risk of malignancy associated with sequential disease-modifying therapies (DMTs) for patients with multiple sclerosis (MS) is uncertain. The aim of this study was to analyze the risk of cancer in patients with MS treated with azathioprine (AZA) and the influence of sequential DMTs on the risk. METHOD: We retrospectively enrolled a cohort of AZA-treated MS patients followed in two Italian centers from 1987 to 2019. The ratio between observed and expected cancers in the Italian general population was calculated as standardized incidence ratio (SIR). Associations between AZA and DMTs and cancer were estimated by Cox proportional hazards model. RESULTS: We identified 500 AZA-treated MS patients, followed for a median time of 9.7 (0.1-45.7) years: 61.8% of them were treated with DMTs. We found 22 cases of cancer (4.4%). The SIR was 1.14 (95% CI 0.98-1.29), not significantly increased in comparison with the general population. However, the risk was significantly higher in the quintiles of age 32-45, SIR 1.21 (95% CI 1.21-1.42), and 46-51, SIR 1.11 (95% CI 1.11-1.32) than in older cases. Age at AZA treatment onset was the only covariate significantly related to cancer incidence (HR = 1.049, 95% CI 1.007-1.093). The exposure to other DMTs did not modify the risk. CONCLUSION: The risk of malignancy in MS patients after AZA was similar to that of the general population and did not change with other DMTs sequential treatments. The increased risk in the younger ages should be considered in treatment assessment.

Effects of THC/CBD oromucosal spray on spasticity-related symptoms in people with multiple sclerosis: results from a retrospective multicenter study.

INTRODUCTION: The approval of 9-δ-tetrahydocannabinol (THC)+cannabidiol (CBD) oromucosal spray (Sativex®) in Italy as an add-on medication for the management of moderate to severe spasticity in multiple sclerosis (MS) has provided a new opportunity for MS patients with drug-resistant spasticity. We aimed to investigate the improvement of MS spasticity-related symptoms in a large cohort of patients with moderate to severe spasticity in daily clinical practice. MATERIALS AND METHODS: MS patients with drug-resistant spasticity were recruited from 30 Italian MS centers. All patients were eligible for THC:CBD treatment according to the approved label: ≥ 18 years of age, at least moderate spasticity (MS spasticity numerical rating scale [NRS] score ≥ 4) and not responding to the common antispastic drugs. Patients were evaluated at baseline (T0) and after 4 weeks of treatment (T1) with the spasticity NRS scale and were also asked about meaningful improvements in 6 key spasticity-related symptoms. RESULTS: Out of 1615 enrolled patients, 1432 reached the end of the first month trial period (T1). Of these, 1010 patients (70.5%) reached a ≥ 20% NRS score reduction compared with baseline (initial responders; IR). We found that 627 (43.8% of 1432) patients showed an improvement in at least one spasticity-related symptom (SRSr group), 543 (86.6%) of them belonging to the IR group and 84 (13.4%) to the spasticity NRS non-responders group. CONCLUSION: Our study confirmed that the therapeutic benefit of cannabinoids may extend beyond spasticity, improving spasticity-related symptoms even in non-NRS responder patients.

Inflammatory intrathecal profiles and cortical damage in multiple sclerosis.

OBJECTIVE: Gray matter (GM) damage and meningeal inflammation have been associated with early disease onset and a more aggressive disease course in multiple sclerosis (MS), but can these changes be identified in the patient early in the disease course? METHODS: To identify possible biomarkers linking meningeal inflammation, GM damage, and disease severity, gene and protein expression were analyzed in meninges and cerebrospinal fluid (CSF) from 27 postmortem secondary progressive MS and 14 control cases. Combined cytokine/chemokine CSF profiling and 3T magnetic resonance imaging (MRI) were performed at diagnosis in 2 independent cohorts of MS patients (35 and 38 subjects) and in 26 non-MS patients. RESULTS: Increased expression of proinflammatory cytokines (IFNγ, TNF, IL2, and IL22) and molecules related to sustained B-cell activity and lymphoid-neogenesis (CXCL13, CXCL10, LTα, IL6, and IL10) was detected in the meninges and CSF of postmortem MS cases with high levels of meningeal inflammation and GM demyelination. Similar proinflammatory patterns, including increased levels of CXCL13, TNF, IFNγ, CXCL12, IL6, IL8, and IL10, together with high levels of BAFF, APRIL, LIGHT, TWEAK, sTNFR1, sCD163, MMP2, and pentraxin III, were detected in the CSF of MS patients with higher levels of GM damage at diagnosis. INTERPRETATION: A common pattern of intrathecal (meninges and CSF) inflammatory profile strongly correlates with increased cortical pathology, both at the time of diagnosis and at death. These results suggest a role for detailed CSF analysis combined with MRI as a prognostic marker for more aggressive MS. Ann Neurol 2018 Ann Neurol 2018;83:739-755.

Increased cortical lesion load and intrathecal inflammation is associated with oligoclonal bands in multiple sclerosis patients: a combined CSF and MRI study.

BACKGROUND: Although IgG oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF) are a frequent phenomenon in multiple sclerosis (MS) patients, their relationship with grey matter lesions, intrathecal/meningeal inflammation and clinical evolution has not been clarified yet. The aim of our study was to assess the relationship between the OCBs, the inflammatory/neurodegenerative CSF profile at diagnosis, the cortical lesion load and the clinical evolution after 10 years. METHODS: This is a 10-year observational, cross-sectional study based on a combined MRI, cognitive and CSF profiling of the examined patients. Forty consecutive OCB-negative (OCB-) and 50 OCB-positive (OCB+) MS patients were included in this study. Both groups had mean disease duration of 10 years and were age and gender matched. Each patient underwent neurological and neuropsychological evaluation and 3-T MRI. Analysis of the presence and levels of 28 inflammatory mediators was performed in the CSF obtained from 10 OCB- MS, 11 OCB+ MS and 10 patients with other neurological conditions. RESULTS: Increased number of CLs was found in OCB+ compared to OCB- patients (p < 0.0001), whereas no difference was found in white matter lesion (WML) load (p = 0.36). The occurrence of OCB was also associated with increased levels of neurofilament light chains and of several inflammatory mediators linked to B lymphocyte activity and lymphoid-neogenesis (CXCL13, CXCL12, CXCL10, TNFSF13, TNFSF13B, IL6, IL10) and other pro-inflammatory molecules, such as IFN-γ, TNF, MMP2, GM-CSF, osteopontin and sCD163. Finally, the occurrence of OCB was found associated with poor prognosis, from both physical and cognitive points of view. CONCLUSIONS: OCB at MS onset are associated with more severe GM pathology and with a more severe physical disability and cognitive impairment after 10 years. Increased levels of cytokines linked to B cell activation, lymphoid-neogenesis, and pro-inflammatory immune response in the CSF of OCB+ patients support the hypothesis of crucial role played by compartmentalized, intrathecal B cell response in the pathogenesis of CLs and OCB production.

Late-onset multiple sclerosis presenting with cognitive dysfunction and severe cortical/infratentorial atrophy.

OBJECTIVE: Although cognitive dysfunction is a relevant aspect of multiple sclerosis (MS) from the earliest disease phase, cognitive onset is unusual thus jeopardizing early and accurate diagnosis. Here we describe 12 patients presenting with cognitive dysfunction as primary manifestation of MS with either mild or no impairment in non-cognitive neurological domains. METHODS: Twelve patients with cognitive onset who were subsequently diagnosed with MS (CI-MS) were included in this retrospective study. Twelve cognitively normal MS patients (CN-MS), 12 healthy controls and four patients having progressive supranuclear palsy (PSP) served as the reference population. RESULTS: Ten CI-MS patients had progressive clinical course and all patients had late disease onset (median age = 49 years; range = 40-58 years). Among cognitive functions, frontal domains were the most involved. Compared to CN-MS and healthy controls, significant cortical and infratentorial atrophy characterized CI-MS patients. Selective atrophy of midbrain tegmentum with relative sparing of pons, known as "The Hummingbird sign," was observed in eight CI-MS and in three PSP patients. DISCUSSION: Our observation suggests that MS diagnosis should be taken into consideration in case of cognitive dysfunction, particularly when associated with slowly progressive disease course and severe cortical, cerebellar and brainstem atrophy even in the absence of other major neurological symptoms and signs.

Sensory integration balance training in patients with multiple sclerosis: A randomized, controlled trial.

BACKGROUND: Impaired sensory integration contributes to balance disorders in patients with multiple sclerosis (MS). OBJECTIVE: The objective of this paper is to compare the effects of sensory integration balance training against conventional rehabilitation on balance disorders, the level of balance confidence perceived, quality of life, fatigue, frequency of falls, and sensory integration processing on a large sample of patients with MS. METHODS: This single-blind, randomized, controlled trial involved 80 outpatients with MS (EDSS: 1.5-6.0) and subjective symptoms of balance disorders. The experimental group (n = 39) received specific training to improve central integration of afferent sensory inputs; the control group (n = 41) received conventional rehabilitation (15 treatment sessions of 50 minutes each). Before, after treatment, and at one month post-treatment, patients were evaluated by a blinded rater using the Berg Balance Scale (BBS), Activities-specific Balance Confidence Scale (ABC), Multiple Sclerosis Quality of Life-54, Fatigue Severity Scale (FSS), number of falls and the Sensory Organization Balance Test (SOT). RESULTS: The experimental training program produced greater improvements than the control group training on the BBS (p < 0.001), the FSS (p < 0.002), number of falls (p = 0.002) and SOT (p < 0.05). CONCLUSIONS: Specific training to improve central integration of afferent sensory inputs may ameliorate balance disorders in patients with MS. Clinical Trial Registration (NCT01040117).

A Multicentric Prospective Incidence Study of Guillain-Barré Syndrome in Italy. The ITANG Study.

BACKGROUND: To assess Guillain-Barré syndrome (GBS) incidence we relied on the Italian Network for the study of GBS (ITANG) established in 2010 in 7 Italian regions to analyse the association between influenza vaccination and GBS. METHODS: All individuals aged ≥18 years, presenting with clinical manifestations that suggested GBS according to the universally accepted Asbury's diagnostic criteria (1990) were prospectively notified to a centralised database by ITANG neurologists over the period October 1, 2010-September 30, 2011. Through a telephone survey, 9 trained interviewers followed up the cases to diagnosis and then for 1 year since hospital discharge. Validation of case reporting was performed with the support of administrative data in 5 regions. RESULTS: We found 365 cases fulfilling the definition for GBS or one of its variants over 19,846,068 population ≥18 years of age, yielding an annual incidence rate of 1.84 per 100,000 (95% CI 1.65-2.03), 2.30 (95% CI 1.99-2.60) in men and 1.41 (95% CI 1.18-1.64) in women. A highly significant peak of incidence was observed in February 2011 as compared to reference month (September 2011, rate ratio 3.3:1, p < 0.01). CONCLUSIONS: In Italy, GBS incidence was among the highest reported in Europe and higher than previously observed in Italian studies.

Are natalizumab and fingolimod analogous second-line options for the treatment of relapsing-remitting multiple sclerosis? A clinical practice observational study.

BACKGROUND: It is unclear whether natalizumab and fingolimod have analogous efficacy for relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: To compare the outcome of RRMS patients treated with either therapy. METHODS: RRMS patients treated with natalizumab or fingolimod at Verona Hospital, Italy, were included. The study design was retrospective, based on prospectively collected clinical and MRI data. As efficacy outcomes, time to relapse, relapse rate, expanded disability status scale (EDSS) score change, and new T2/gadolinium-enhancing lesions on brain MRI were compared over treatment period between the two groups. Multivariate Cox and logistic regression models were used to control for potential confounders. RESULTS: Fifty-seven subjects receiving natalizumab and 30 receiving fingolimod for a median duration of 23 (1-63) and 22 (2-35) months, respectively (p = 0.22) were included. Patients treated with natalizumab had a more active pre-treatment disease course compared to those treated with fingolimod. In multivariate analysis, the relapse risk was reduced in patients on natalizumab (Hazard Ratio = 0.33; 95% CI = 0.11-1.03; p = 0.056) compared to those on fingolimod. There was no significant difference in EDSS and MRI outcomes. No relevant unexpected adverse events occurred. One patient discontinued natalizumab for progressive multifocal leukoencephalopathy. CONCLUSIONS: RRMS patients receiving natalizumab had higher baseline disease activity and lower relapse risk over 20 months of treatment compared to those receiving fingolimod. Head-to-head randomized clinical trials are needed.

In old anticoagulated patients with mild traumatic brain injury, a 24-h observation period should not be recommended without evidence of a clear benefit: a retrospective study of delayed hemorrhagic versus iatrogenic complications.

Mild traumatic brain injury (mTBI) is a common cause of admission to the Emergency Department (ED). Many patients are elderly on oral anticoagulant therapy (OAT) at increased risk of immediate and delayed intracranial hemorrhage (ICH). To investigate the frequency of delayed ICH (DICH) in old patients with mTBI in OAT and the occurrence of complications related to the ED stay. In this single-center retrospective study, we recruited all patients in OAT aged 65 and over, admitted for mTBI to the ED of our Hospital in Florence from March 2019 to February 2021. Clinical variables were collected and cranial computed tomography (CT) scans reviewed. The primary outcome was the frequency of DICH occurring within 30 days since the trauma after a first negative CT. Secondary outcomes included need of neurosurgical intervention and death for DICH, and hospital-related complications. Statistical analyses were conducted using IBM SPSS Statistics (version 22). Among 363 enrolled patients, there were 31 acute ICH (8.5%) at the first CT scan, while in the 316 negative included patients, 10 DICH (3.2%) were identified. Among the latter, no neurosurgical treatment, or death due to ICH occurred. Overall, 25 cases (6.9%) had iatrogenic complications during the 24-h observation period, often serious, such as respiratory failure after sedation due to restlessness, or COVID-19 infection. The low frequency of DICH and the occurrence of several iatrogenic complications suggest that the risk-benefit ratio of a 24-h ED observation is not advantageous in elderly with mTBI.

Risk of Guillain-Barré syndrome after 2010-2011 influenza vaccination.

Influenza vaccination has been implicated in Guillain Barré Syndrome (GBS) although the evidence for this link is controversial. A case-control study was conducted between October 2010 and May 2011 in seven Italian Regions to explore the relation between influenza vaccination and GBS. The study included 176 GBS incident cases aged ≥18 years from 86 neurological centers. Controls were selected among patients admitted for acute conditions to the Emergency Department of the same hospital as cases. Each control was matched to a case by sex, age, Region and admission date. Two different analyses were conducted: a matched case-control analysis and a self-controlled case series analysis (SCCS). Case-control analysis included 140 cases matched to 308 controls. The adjusted matched odds ratio (OR) for GBS occurrence within 6 weeks after influenza vaccination was 3.8 (95 % CI: 1.3, 10.5). A much stronger association with gastrointestinal infections (OR = 23.8; 95 % CI 7.3, 77.6) and influenza-like illness or upper respiratory tract infections (OR = 11.5; 95 % CI 5.6, 23.5) was highlighted. The SCCS analysis included all 176 GBS cases. Influenza vaccination was associated with GBS, with a relative risk of 2.1 (95 % CI 1.1, 3.9). According to these results the attributable risk in adults ranges from two to five GBS cases per 1,000,000 vaccinations.

Association of the CBLB gene with multiple sclerosis: new evidence from a replication study in an Italian population.

BACKGROUND: The T allele of rs9657904 within the CBLB gene was recently found to be significantly associated with multiple sclerosis (MS) in a genome-wide association study in Sardinia. OBJECTIVE: To replicate this association in an independent population with a different genetic background. METHODS: The rs9657904 variant was typed in a sample of 1435 cases and 1466 controls from the Italian mainland. RESULTS: It was found that in this sample also, the common allele T of rs9657904 is significantly positively associated (one-tailed p=7.35 × 10(-5)) and with a comparable effect size with MS (OR=1.31, 95% CI 1.14 to 1.52). CONCLUSION: These data provide further evidence of the association of MS disease with variation within CBLB.

Multiple radiculopathy as the presenting manifestation of primary spinal leptomeningeal B cell lymphoma detected by flow cytometry of cerebrospinal fluid.

Primary leptomeningeal lymphoma is a rare syndrome characterized by lymphomatous meningeal infiltration without identification of systemic lymphoma or parenchymal central nervous system lymphoma. We report a case of a 62-year-old immunocompetent woman with primary spinal leptomeningeal lymphoma presenting as cervical and lumbar radiculopathy who is rare because of particularly unusual onset site of B cell lymphoma. Interestingly, the diagnosis was possible only by cerebrospinal fluid flow cytometry.

Are cerebrospinal fluid biomarkers useful in predicting the prognosis of multiple sclerosis patients?

Multiple sclerosis (MS) is the prototypical inflammatory demyelinating disorder of the central nervous system (CNS). Although many advances have been made in the comprehension of its pathogenesis, the etiology is still unknown. The complexity of MS reflects in the extreme variability of the clinical manifestations and clinical course both between and within patients, in addition to immunopathological mechanisms and response to treatment. Several prognostic factors have been suggested in large scale studies, but predictions in individual cases are difficult to make. Cerebrospinal fluid (CSF) biomarkers, such as 14-3-3, tau, and cystatin C are promising sources of prognostic information with a good potential of quantitative measure, sensitivity, and reliability. However, none has shown sufficient reproducibility to be applied in clinical practice. Here we review the current literature addressing the above mentioned biomarkers as MS severity predictors at an early stage.

Genetic association and altered gene expression of mir-155 in multiple sclerosis patients.

Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system characterized by chronic inflammation, demyelination, and axonal damage. As microRNA (miRNA)-dependent alterations in gene expression in hematopoietic cells are critical for mounting an appropriate immune response, miRNA deregulation may result in defects in immune tolerance. In this frame, we sought to explore the possible involvement of miRNAs in MS pathogenesis by monitoring the differential expression of 22 immunity-related miRNAs in peripheral blood mononuclear cells of MS patients and healthy controls, by using a microbead-based technology. Three miRNAs resulted >2 folds up-regulated in MS vs controls, whereas none resulted down-regulated. Interestingly, the most up-regulated miRNA (mir-155; fold change = 3.30; P = 0.013) was previously reported to be up-regulated also in MS brain lesions. Mir-155 up-regulation was confirmed by qPCR experiments. The role of mir-155 in MS susceptibility was also investigated by genotyping four single nucleotide polymorphisms (SNPs) mapping in the mir-155 genomic region. A haplotype of three SNPs, corresponding to a 12-kb region encompassing the last exon of BIC (the B-cell Integration Cluster non-coding RNA, from which mir-155 is processed), resulted associated with the disease status (P = 0.035; OR = 1.36, 95% CI = 1.05-1.77), suggesting that this locus strongly deserves further investigations.

Long survival and clinical stability in Marburg's variant multiple sclerosis.

Marburg's variant multiple sclerosis (MS) is an acute and aggressive atypical form of MS, leading frequently to death in few months. A 32-year-old man with motor and sensory symptoms suggestive of acute myelopathy, rapidly followed by cerebellar dysfunction and consciousness impairment. Clinical, laboratory and radiological evaluations suggested a central nervous system demyelinating disease. The diagnosis was Marburg's variant MS, usually leading to death in short time. He underwent different treatments, including steroids, cyclophosphamide, plasma exchange and lastly interferon-beta. The patient reached clinical stability with severe residual disability, persistent after 3 years from onset. This observation suggests that subjects with Marburg's MS might reach long clinical stability.