Time is myelin: early cortical myelin repair prevents atrophy and clinical progression in multiple sclerosis.

Cortical myelin loss and repair in multiple sclerosis (MS) have been explored in neuropathological studies, but the impact of these processes on neurodegeneration and the irreversible clinical progression of the disease remains unknown. Here, we evaluated in vivo cortical demyelination and remyelination in a large cohort of people with all clinical phenotypes of MS followed up for 5 years using magnetization transfer imaging (MTI), a technique that has been shown to be sensitive to myelin content changes in the cortex. We investigated 140 people with MS (37 clinically isolated syndrome, 71 relapsing-MS, 32 progressive-MS), who were clinically assessed at baseline and after 5 years and, along with 84 healthy controls, underwent a 3 T-MRI protocol including MTI at baseline and after 1 year. Changes in cortical volume over the radiological follow-up were computed with a Jacobian integration method. Magnetization transfer ratio was employed to calculate for each patient an index of cortical demyelination at baseline and of dynamic cortical demyelination and remyelination over the follow-up period. The three indices of cortical myelin content change were heterogeneous across patients but did not significantly differ across clinical phenotypes or treatment groups. Cortical remyelination, which tended to fail in the regions closer to CSF (-11%, P < 0.001), was extensive in half of the cohort and occurred independently of age, disease duration and clinical phenotype. Higher indices of cortical dynamic demyelination (ß = 0.23, P = 0.024) and lower indices of cortical remyelination (ß = -0.18, P = 0.03) were significantly associated with greater cortical atrophy after 1 year, independently of age and MS phenotype. While the extent of cortical demyelination predicted a higher probability of clinical progression after 5 years in the entire cohort [odds ratio (OR) = 1.2; P = 0.043], the impact of cortical remyelination in reducing the risk of accumulating clinical disability after 5 years was significant only in the subgroup of patients with shorter disease duration and limited extent of demyelination in cortical regions (OR = 0.86, P = 0.015, area under the curve = 0.93). In this subgroup, a 30% increase in cortical remyelination nearly halved the risk of clinical progression at 5 years, independently of clinical relapses. Overall, our results highlight the critical role of cortical myelin dynamics in the cascade of events leading to neurodegeneration and to the subsequent accumulation of irreversible disability in MS. Our findings suggest that early-stage myelin repair compensating for cortical myelin loss has the potential to prevent neuro-axonal loss and its long-term irreversible clinical consequences in people with MS.

Non-invasive assessment of hepatic steatosis by ultrasound-derived fat fraction in individuals at high-risk for metabolic dysfunction-associated steatotic liver disease.

AIMS: Given the increasing number of individuals developing metabolic dysfunction-associated steatotic liver disease (MASLD) and the low rate of those with progressive liver disease, there is a pressing need to conceive affordable biomarkers to assess MASLD in general population settings. Herein, we aimed to investigate the performance of the ultrasound-derived fat fraction (UDFF) for hepatic steatosis in high-risk individuals. METHODS: A total of 302 Europeans with obesity, type 2 diabetes, or a clinical history of hepatic steatosis were included in the analyses. Clinical, laboratory, and imaging data were collected using standardized procedures during a single screening visit in Rome, Italy. Hepatic steatosis was defined by controlled attenuation parameter (CAP) or ultrasound-based Hamaguchi's score. UDFF performance for hepatic steatosis was estimated by the area under the receiver operating characteristic curve (AUC). RESULTS: Overall, median (IQR) UDFF was 12% (7-20). UDFF was positively correlated with CAP (ρ = 0.73, p < 0.0001) and Hamaguchi's score (ρ = 0.79, p < 0.0001). Independent predictors of UDFF were circulating triglycerides, alanine aminotransferase (ALT), and ultrasound-measured visceral adipose tissue (VAT). UDFF AUC was 0.89 (0.85-0.93) and 0.92 (0.88-0.95) for CAP- and ultrasound-diagnosed hepatic steatosis, respectively. UDFF AUC for hepatic steatosis was higher than those of fatty liver index (FLI), hepatic steatosis index (HSI), CAP-score (CAPS), and ALT (p < 0.0001). Lower age, ALT, and VAT were associated with discordance between UDFF and ultrasound. CONCLUSIONS: UDFF may be a simple and accurate imaging biomarker to assess hepatic steatosis and monitor changes in hepatic fat content over time or in response to therapeutic interventions beyond clinical trials.

Alemtuzumab-induced autoimmune thyroid events in patients with relapsing-remitting multiple sclerosis: A real-life and monocentric experience at a tertiary-level centre.

OBJECTIVE: Alemtuzumab-induced autoimmune thyroid events (AIATEs) are the most common adverse effects observed in relapsing-remitting multiple sclerosis (RRMS) patients. This study aims to explore the clinical and biochemical characteristics of such AIATEs, and to examine the risk factors for their occurrence, particularly for the worst clinical phenotype of fluctuating Graves' disease (GD). DESIGN, PATIENTS, MEASUREMENTS: We retrospectively analysed a real-life single-centre consecutive series of 57 RRMS patients treated with alemtuzumab whose clinical and biochemical parameters were collected before starting the treatment and then monthly during their follow-up. RESULTS: AIATEs developed in 39% of patients a mean 17 months ± 11 after the first cycle of alemtuzumab. The most common AIATEs were GD (64%), followed by Hashimoto's thyroiditis with hypothyroidism (23%), TSH-receptor-antibody (TRAb)-positive hypothyroidism (9%), and silent thyroiditis (4%). GD showed a fluctuating course in 57% of cases. Baseline positivity for anti-thyroperoxidase antibodies, and higher absolute titers of anti-thyroglobulin and anti-thyroperoxidase antibodies correlated significantly with the risk of developing AIATEs, but TRAb positivity did not. Higher TRAb titers at the time of GD being diagnosed correlated strongly with a greater risk of the fluctuating GD phenotype. On ROC curve analysis, we found that a cut-off of 7.3 IU/L could be used to predict the risk of developing a fluctuating GD, with a positive predictive value of 100%. CONCLUSIONS: TRAb levels measured with commercial automatic methods at the time of a patient being diagnosed with alemtuzumab-induced GD emerged as a novel biomarker for predicting a fluctuating disease phenotype, with an influence on subsequent therapeutic decisions and patients' follow-up.

Natalizumab treatment and pregnancy in multiple sclerosis: A reappraisal of maternal and infant outcomes after 6 years.

OBJECTIVES: To assess the impact of timing of natalizumab cessation/redosing on long-term maternal and infant outcomes in 72 out of the original 74 pregnancies of the Italian Pregnancy Dataset in multiple sclerosis (MS). METHODS: Maternal outcomes in patients who received natalizumab until conception and restarted the drug within 1 month after delivery ("treatment approach," (TA)) and patients who stopped natalizumab before conception and/or restarted the drug later than 1 month after delivery ("conservative approach," (CA)) were compared through multivariable Cox regression analyses. Pediatric outcomes were assessed through a semi-structured questionnaire. RESULTS: After a mean follow-up of 6.1 years, CA (hazard ratio (HR) = 4.1, 95% CI 1.6-10.6, p = 0.003) was the only predictor of relapse occurrence. Worsening on the Expanded Disability Status Scale (EDSS) was associated with higher annualized relapse-rate during the follow-up (HR = 3.3, 95% CI 1.4-7.9 p = 0.007). We found no major development abnormalities in children. DISCUSSION: Our data confirm that TA reduces the risk of disease activity; we did not observe an increase in major development abnormalities in the child.

Leadless pacemaker in Twiddler's syndrome: A case report.

Twiddler's syndrome is a rare cause of pacemaker lead dislodgement. We present the case of a 49-year-old male patient with Down's syndrome implanted with a dual chamber pacemaker showing high ventricular impedance, no sensing, and complete loss of capture for both leads at the 3-month follow-up due to Twiddler Syndrome. The dislocated device was removed, and an endocardial leadless pacing system was implanted.

Long-term follow-up (up to 11 years) of an Italian pediatric MS cohort treated with Natalizumab: a multicenter, observational study.

BACKGROUND: Natalizumab (NAT) has a strong impact on disease activity of aggressive pediatric multiple sclerosis (MS), with no difference in safety profile compared to adult MS. However, available data are limited by short follow-up. Our aim was to report long-term follow-up data (up to 11 years) of a large Italian pediatric MS cohort treated with NAT. MATERIALS AND METHODS: We retrospectively collected data of pediatric MS patients treated with NAT included in a previous study and prospectively followed in Italian MS centers. We compared disease activity pre, during, and post-NAT and we performed survival analyses of time to evidence of disease activity (EDA) during NAT, time to reach EDA post-NAT, and time to NAT discontinuation. RESULTS: Ninety-two patients were included from 19 MS centers in Italy. At NAT initiation, cohort's characteristics were as follows: 55 females; 14.7 ± 2.4 (mean ± SD) years of age; 34 naïve to disease modifying therapies; 1-year pre-NAT annualized relapse rate (ARR): 2.2 ± 1.2; EDSS (median [IQR]): 2.5 [2.0-3.0]; gadolinium-enhancing lesions: 2 [1-5]; 41 JCV positives. During NAT treatment (61.9 ± 35.2 mean infusions), ARR lowered to 0.08 ± 0.23 (p < 0.001), EDSS score to 1.5 [1.0-2.5] at last infusion (p < 0.001), and 51% patients had EDA (21% after 6 months of rebaseline). No serious adverse events were reported. Forty-nine patients discontinued NAT, mainly due to PML concern; the majority (29/49) had disease reactivation in the subsequent 12 months, of which three with a clinical rebound. CONCLUSION: NAT treatment maintains its high efficacy for a long time in pediatric MS patients, with no new safety issues.

Prediction of type 4a myocardial infarction with the angiography-derived hemodynamic (ADDED) index.

Percutaneous coronary intervention (PCI) is frequently complicated by type 4a myocardial infarction (MI), which is associated with an increased risk of mortality. We assessed the usefulness of the angiography-derived hemodynamic index (ADDED), which is based on the extent of myocardium at risk and on the anatomical lesion severity, in predicting type 4a MI in patients with chronic coronary syndrome (CCS) undergoing PCI. We enrolled 442 patients treated with single-vessel PCI. The ADDED index was calculated as the ratio of the Duke Jeopardy Score to the minimum lumen diameter assessed with quantitative angiography analysis. Type 4a MI was defined according to the 4th Universal Definition of MI. The overall population was divided into tertiles of ADDED index. Type 4a MI occurred in 5 patients (3.3%) in the ADDED-low tertile, 8 (5.5%) in the ADDED-mid tertile, and 26 (17.7%) in the ADDED-high tertile (p < 0.0001). At ROC curve analysis, the ADDED index could significantly discriminate between patients with and without type 4a MI (area under the curve 0.745). At multivariate analysis, an ADDED index value > 5.25 was the strongest independent predictor type 4a MI. Our results support the role of the ADDED index as a predictor of type 4a MI in patients with CCS treated with elective PCI of a single vessel. Whether a selective use of additional preventive measures in patients considered at high risk based on ADDED index values may improve peri-procedural and long-term outcomes remains to be tested in dedicated investigations.

Sarcopenia in Hepatocellular Carcinoma: Pathogenesis and Management.

BACKGROUND: Sarcopenia is almost constantly observed in patients with cirrhosis and hepatocellular carcinoma (HCC). SUMMARY: Chronic liver disease represents a unique pathophysiological scenario in which sarcopenia develops and all factors involved in the pathogenesis should be taken into account for an appropriate management of the disease. No properly designed intervention studies on this topic are available and, thus, no effective strategies have been developed for clinical practice. Apart from any targeted intervention, treatment, and optimization of liver disease is crucial. KEY MESSAGES: In patients with cirrhosis and HCC, nutritional support to maintain and restore nutrition status, a targeted use of branched-chain amino acids and a guided physical exercise, should all be an integral part of the multidimensional assessment and tailored interventions.

Crowdsourced Reconstruction of Cellular Networks to Serve Outdoor Positioning: Modeling, Validation and Analysis.

Positioning via outdoor fingerprinting, which exploits the radio signals emitted by cellular towers, is fundamental in many applications. In most cases, the localization performance is affected by the availability of information about the emitters, such as their coverage. While several projects aim at collecting cellular network data via crowdsourcing observations, none focuses on information about the structure of the networks, which is paramount to correctly model their topology. The difficulty of such a modeling is exacerbated by the inherent differences among cellular technologies, the strong spatio-temporal nature of positioning, and the continuously evolving configuration of the networks. In this paper, we first show how to synthesize a detailed conceptual schema of cellular networks on the basis of the signal fingerprints collected by devices. We turned it into a logical one, and we exploited that to build a relational spatio-temporal database capable of supporting a crowdsourced collection of data. Next, we populated the database with heterogeneous cellular observations originating from multiple sources. In addition, we illustrate how the developed system allows us to properly deal with the evolution of the network configuration, e.g., by detecting cell renaming phenomena and by making it possible to correct inconsistent measurements coming from mobile devices, fostering positioning tasks. Finally, we provide a wide range of basic, spatial, and temporal analyses about the arrangement of the cellular network and its evolution over time, demonstrating how the developed system can be used to reconstruct and maintain a deep knowledge of the cellular network, possibly starting from crowdsourced information only.

Glycaemic Control in Patients Undergoing Percutaneous Coronary Intervention: What Is the Role for the Novel Antidiabetic Agents? A Comprehensive Review of Basic Science and Clinical Data.

Coronary artery disease (CAD) remains one of the most important causes of morbidity and mortality worldwide, and revascularization through percutaneous coronary interventions (PCI) significantly improves survival. In this setting, poor glycaemic control, regardless of diabetes, has been associated with increased incidence of peri-procedural and long-term complications and worse prognosis. Novel antidiabetic agents have represented a paradigm shift in managing patients with diabetes and cardiovascular diseases. However, limited data are reported so far in patients undergoing coronary stenting. This review intends to provide an overview of the biological mechanisms underlying hyperglycaemia-induced vascular damage and the contrasting actions of new antidiabetic drugs. We summarize existing evidence on the effects of these drugs in the setting of PCI, addressing pre-clinical and clinical studies and drug-drug interactions with antiplatelet agents, thus highlighting new opportunities for optimal long-term management of these patients.

Early red nucleus atrophy in relapse-onset multiple sclerosis.

No study has investigated red nucleus (RN) atrophy in multiple sclerosis (MS) despite cerebellum and its connections are elective sites of MS-related pathology. In this study, we explore RN atrophy in early MS phases and its association with cerebellar damage (focal lesions and atrophy) and physical disability. Thirty-seven relapse-onset MS (RMS) patients having mean age of 35.6 ± 8.5 (18-56) years and mean disease duration of 1.1 ± 1.5 (0-5) years, and 36 age- and sex-matched healthy controls (HC) were studied. Cerebellar and RN lesions and volumes were analyzed on 3 T-MRI images. RMS did not differ from HC in cerebellar lobe volumes but significantly differed in both right (107.84 ± 13.95 mm3 vs. 99.37 ± 11.53 mm3 , p = .019) and left (109.71 ± 14.94 mm3 vs. 100.47 ± 15.78 mm3 , p = .020) RN volumes. Cerebellar white matter lesion volume (WMLV) inversely correlated with both right and left RN volumes (r = -.333, p = .004 and r = -.298, p = .010, respectively), while no correlation was detected between RN volumes and mean cortical thickness, cerebellar gray matter lesion volume, and supratentorial WMLV (right RN: r = -.147, p = .216; left RN: r = -.153, p = .196). Right, but not left, RN volume inversely correlated with midbrain WMLV (r = -.310, p = .008), while no correlation was observed between whole brainstem WMLV and either RN volumes (right RN: r = -.164, p = .164; left RN: r = -.64, p = .588). Finally, left RN volume correlated with vermis VIIb (r = .297, p = .011) and right interposed nucleus (r = .249, p = .034) volumes. We observed RN atrophy in early RMS, likely resulting from anterograde axonal degeneration starting in cerebellar and midbrain WML. RN atrophy seems a promising marker of neurodegeneration and/or cerebellar damage in RMS.

Oligoclonal IgG bands in chronic inflammatory polyradiculoneuropathies.

BACKGROUND: Cerebrospinal fluid (CSF) albumincytologic dissociation represents a supportive diagnostic criterion of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).Few studies have investigated possible systemic or intrathecal humoral immune response activation in CIDP.Aim of our study was to investigate whether the search of oligoclonal IgG bands (OCBs) might provide additional data helpful in CIDP diagnostic work-up. METHODS: Forty-eight consecutive patients with CIDP (34 men, mean age 59.4, range 16-83) were recruited. CSF analysis included nephelometric measurement of albumin and IgG concentrations, calculation of QALB, QAlbLIM and intrathecal IgG synthesis, and OCBs detection with isoelectric focusing. Data were compared with those from CSF and serum of 32 patients with Guillain-Barré syndrome (GBS), 18 patients with anti-myelin associated glycoprotein (MAG) antibody neuropathy, 4 patients with multifocal motor neuropathy and 32 patients with non-inflammatory neuropathies (NINPs). RESULTS: Patients with CIDP and anti-MAG antibody neuropathy had significantly higher CSF albumin concentrations and QALB values than NINPs (p=0.0003 and p=0.0095, respectively). A total of 9 (19%) patients with CIDP presented identical serum and CSF OCBs ('mirror pattern') versus 3 patients (16.6%) with anti-MAG antibody neuropathy, 13 patients (40.6%) with GBS and 12.5% patients with NINPs. Only one patient with CIDP showed unique-to-CSF OCBs. First-line therapy was effective in 80.4% of patients with CIDP, irrespective of CSF findings. CONCLUSIONS: Compared with NINP, CIDP, GBS and anti-MAG antibody neuropathies had a significantly increased CSF protein and blood-spinal nerve root barrier damage. Intrathecal humoral immune response is rare in our patients with CIDP. Systemic oligoclonal activation is more frequent, but not significantly different from what was detected in the control groups.

Autologous hematopoietic stem cell transplantation following alemtuzumab therapy in aggressive multiple sclerosis: A report of three cases.

The management of multiple sclerosis patients with persistent disease activity under alemtuzumab treatment is not established yet. Concerns have been raised on the safety of autologous haematopoietic stem cell transplantation (aHSCT) after alemtuzumab treatment because of the risk of serious infectious adverse events. We report short-term safety and efficacy data from three patients treated with aHSCT following alemtuzumab treatment. Early adverse events were consistent with expected transplant toxicities. All patients were free of disease activity at the last follow-up. Our data suggest that aHSCT can be considered as a rescue treatment strategy for MS patients with persistent disease activity during alemtuzumab treatment.

Combined evaluation of aminotransferases improves risk stratification for overall and cause-specific mortality in older patients.

BACKGROUND: Recent studies identified low levels of alanine aminotransferase (ALT) as strong predictors of mortality in older people. AIMS: Here we verified if the combined evaluation of aminotransferases may improve risk stratification for adverse outcomes in older patients. METHODS: Data are from 761 participants aged more than 65 years from a prospective population-based database (InCHIANTI study), without known baseline chronic liver disease or malignancies. Associations between aminotransferase levels and the risk of all-cause, cardiovascular- and cancer-death were assessed by Cox-models with time-dependent covariates. RESULTS: The association of ALT and aspartate aminotransferase (AST) with mortality was non-linear, mirroring a J- and a U-shaped curve, respectively. Based on quintiles of transaminase activities and on their association with overall mortality, low, intermediate (reference group) and high levels were defined. Having at least one transaminase in the low range [aHR 1.76 (1.31-2.36), p < 0.001], mainly if both [(aHR 2.39 (1.81-3.15), p < 0.001], increased the risk of overall mortality, as well as having both enzymes in the high range [aHR 2.14 (1.46-3.15), p < 0.001]. While similar trends were confirmed with respect to cardiovascular mortality, subjects with the highest risk of cancer mortality were those with both enzymes in the high range [aHR 3.48 (1.43-8.44), p = 0.006]. Low levels of transaminases were associated with frailty, sarcopenia and disability, while high levels did not capture any known proxy of adverse outcome. Conclusions and discussion The prognostic information is maximized by the combination of the 2 liver enzymes. While both aminotransferases in low range are characteristically found in the most fragile phenotype, both enzymes in high range are more likely to identify new-onset vascular/infiltrative diseases with adverse outcome.

Selective Cerebellar Atrophy Associates with Depression and Fatigue in the Early Phases of Relapse-Onset Multiple Sclerosis.

Cerebellar dysfunctions have been associated to depressive disorders and cognitive impairment in neurodegenerative diseases. The objective is to analyze the associations between cerebellar atrophy, depression, and fatigue in the early phases of relapse-onset multiple sclerosis (RRMS). Sixty-one RRMS patients and 50 healthy controls (HC) were enrolled and clinically evaluated by means of expanded disability status scale (EDSS), Rao's brief repeatable battery of neuropsychological tests (BRB-NT), Delis-Kaplan executive function system sorting test, beck depression inventory II (BDI-II), and fatigue severity scale (FSS). The relationships between MRI variables and clinical scores were assessed. Depressed RRMS (dRRMS) had significantly lower Vermis Crus I volume compared with not depressed RRMS (ndRRMS) (p = 0.009). Vermis Crus I volume was lower in dRRMS suffering from fatigue than in ndRRMS without fatigue (p = 0.01). The hierarchical regression models which included demographic and clinical data (age, sex, and disease duration, FSS or BDI-II) and cerebellar volumes disclosed that cerebellar lobule right V atrophy explained an increase of 4% of the variability in FSS (p = 0.25) and Vermis Crus I atrophy explained an increase of 6% of variability in BDI-II (p = 0.049). Since clinical onset, atrophy of specific cerebellar lobules associates with important clinical aspects of RRMS. Cerebellar pathology may be one of the determinants of fatigue and depression that contribute to worsen disability in RRMS.

Effects of 2-year treatment with dimethyl fumarate on cognition and functional impairment in patients with relapsing remitting multiple sclerosis.

BACKGROUND: A significant proportion of patients with multiple sclerosis (MS) show cognitive impairment. OBJECTIVE: To evaluate the effect of 2-year treatment with oral dimethyl fumarate (DMF) on cognition in relapsing remitting MS (RRMS). METHODS: In this prospective single-arm study RRMS patients treated with DMF underwent a wide battery of tests, including an extensive neuropsychological evaluation, clinical and patient-reported outcomes (PROs) and quality of life (QoL). Primary endpoints were the proportion of patients with cognitive impairment at baseline and of patients with cognitive worsening over 2 years. RESULTS: Overall, 217 patients (74.2% females, mean age 37.3 years) receiving DMF were recruited, and 156 (67.2%) completed the study. Of the 49 patients with cognitive impairment at baseline, 34 had 2-year data: 15 (44.1%) patients worsened and 19 (55.9%) did not. The cognitive impairment index improved in one third of patients at 2 years. Less than 20% of patients had relapses at 2 years (annualized relapse rate: 0.190). Few patients had disability progression. PROs (fatigue, depression, impairment in work/social activities), QoL, and most of neuropsychological tests significantly improved vs. baseline. CONCLUSION: The 2-year treatment with DMF was associated with slowing of cognitive impairment and with significant improvements in QoL and psychosocial function.

Correction to: Aging with multiple sclerosis: prevalence and profile of cognitive impairment.

The above article was published online with an error in author name's affiliation. The Author Claudia Niccolai has changed her affiliation to IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.

PM2.5 levels strongly associate with multiple sclerosis prevalence in the Province of Padua, Veneto Region, North-East Italy.

BACKGROUND: Incidence and prevalence trends of multiple sclerosis (MS) in the Province of Padua, North-East Italy, suggest that environmental factors may be associated with increased MS risk. OBJECTIVE: To investigate the association of PM2.5 with MS prevalence in one of the most polluted geographical area of Italy. METHODS: In total, 1435 Italian MS patients residing in the Province of Padua were enrolled. The province surface was classified into urban areas, isolated villages, industrialized places, and countryside. Satellite-derived dust-free and sea salt-free PM2.5 concentrations (annual average 1998-2015, µg/m3) allowed the identification of 18 classes of territorial sections with statistically evaluable numbers of inhabitants. Possible correlations between residential locality types, PM2.5 concentrations, and MS prevalence were investigated. RESULTS: MS prevalence was significantly (p < 0.0001) higher in urban areas (ranging from 219 in Padua City to 169/100,000 in other urban areas) compared to isolated villages (116/100,000) or rural domains (109/100,000) and strongly correlated with the annual average concentration of PM2.5 (r = 0.81, p < 0.001). Regression analysis further associated MS cases with PM.2.5 average concentration (ß = 0.11, p < 0.001). CONCLUSION: In the Province of Padua, MS prevalence is strongly associated with PM2.5 exposure suggesting that air pollutants may be one of the possible environmental risk factors for MS.

Peripheral imbalanced TFH/TFR ratio correlates with intrathecal IgG synthesis in multiple sclerosis at clinical onset.

BACKGROUND: Alteration of T-follicular helper (TFH) and regulatory (TFR) subpopulations may contribute to the development of auto-reactive B-cell. OBJECTIVE: To investigate whether changes in TFH and TFR subsets are associated with abnormal IgG synthesis in blood and cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients. METHODS: Paired blood and CSF samples were obtained from 31 untreated relapsing-remitting multiple sclerosis (RRMS) patients at diagnosis. Peripheral blood TFH (CD3+CD4+CXCR5+CD25-CD127+), TFR (CD3+CD4+CXCR5+CD25+CD127dim), conventional T-Helper (TH, CD3+CD4+CXCR5-CD25-CD127+), and regulatory T-cells (T-Reg, CD3+CD4+CXCR5-CD25+CD127dim) were analyzed in all RRMS patients and in 13 healthy controls (HCs). Qualitative and quantitative intrathecal IgG synthesis was evaluated in RRMS patients, who were then further subclassified according to the presence of IgG oligoclonal bands in blood and/or CSF. RESULTS: Compared to HC, RRMS had lower TFR percentage ( p < 0.01) and higher TFH/TFR ratio ( p < 0.001). In RRMS, TFH/TFR ratio correlated with both qualitative ( r = 0.56, p < 0.005) and quantitative intrathecal IgG synthesis (IgG Index: r = 0.78; IgGLoc: r = 0.79; IgGIF: r = 0.76, all p < 0.001). Patients with the highest TFH/TFR ratios had higher percentages of circulating B-cells (36.1 ± 35.2%, p < 0.05). CONCLUSION: In RRMS, increased TFH/TFR ratio associates with abnormal IgG production in blood and CSF, suggesting that antibody-producing cells, derived from deregulated peripheral germinal center reaction, colonize the CNS.

Long-term follow-up of pediatric MS patients starting treatment with injectable first-line agents: A multicentre, Italian, retrospective, observational study.

BACKGROUND: Few data are available on very long-term follow-up of pediatric multiple sclerosis (MS) patients treated with disease modifying treatments (DMTs). OBJECTIVES: To present a long-term follow-up of a cohort of Pediatric-MS patients starting injectable first-line agents. METHODS: Data regarding treatments, annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) score, and serious adverse event were collected. Baseline characteristics were tested in multivariate analysis to identify predictors of disease evolution. RESULTS: In total, 97 patients were followed for 12.5 ± 3.3 years. They started therapy at 13.9 ± 2.1 years, 88 with interferons and 9 with copaxone. During the whole follow-up, 82 patients changed therapy, switching to immunosuppressors/second-line treatment in 58% of cases. Compared to pre-treatment phase, the ARR was significantly reduced during the first treatment (from 3.2 ± 2.6 to 0.7 ± 1.5, p < 0.001), and it remained low during the whole follow-up (0.3 ± 0.2, p < 0.001). At last observation, 40% had disability worsening, but EDSS score remained <4 in 89%. One patient died at age of 23 years due to MS. One case of natalizumab-related progressive multifocal encephalopathy (PML) was recorded. Starting therapy before 12 years of age resulted in a better course of disease in multivariate analysis. CONCLUSION: Pediatric-MS patients benefited from interferons/copaxone, but the majority had to switch to more powerful drugs. Starting therapy before 12 years of age could lead to a more favorable outcome.