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.

Acute simultaneous development of brain tumour-like lesion and demyelinating polyneuropathy in a patient with chronic relapsing myelitis.

Combined central and peripheral demyelination (CCPD) is a rare chronic inflammatory disorder of the nervous system. We describe the case of a patient with a history of recurrent myelitis that acutely and simultaneously developed a brain tumour-like lesion and a sensitive-motor demyelinating polyneuropathy. The diagnosis of CCPD was supported by a detailed diagnostic workup. Up to date, no similar cases have been reported in the literature.

Tübingen model study: large-scale introduction of rapid antigen testing in the population and the viral dynamics of SARS-CoV-2.

Despite of contact restrictions, population mobility remains the main reason for the spread of SARS-CoV-2. The state of Baden-Württemberg (BW), Germany, approved a model study in Tübingen (TÜMOD) to evaluate how mandatory rapid diagnostic tests (RDT) could reduce transmission. Between 16 March and 24 April 2021, approximately 165,000 residents and visitors to the city were screened for SARS CoV-2 infection using Abbott Panbio™ COVID-19 Antigen rapid test device. We assessed incidences and recorded epidemiological characteristics in a subset of 4,118 participants recruited at three of the nine testing stations. PCR tests were performed in RDT-positives to determine the positive predictive value (PPV), and circulating variants of SARS-CoV-2 were identified by whole-genome sequencing. 2,282 RDT-negative samples were tested by pooled PCR to calculate the false negative rate (FNR). Viral load was compared between variants. 116 (3%) participants were positive by RDT, and of these, 57 (49%) were positive by PCR, 55 (47%) were negative. This resulted in a PPV of 51%. Of the 57 positives, 52 SARS-CoV-2 genomes were successfully sequenced. Of these, 50 belonged to the B.1.1.7 lineage, which had a high viral load (average Ct = 19). Of the 2,282 RDT negatives tested, all were PCR negative (FNR 0%). At the end of TÜMOD, the incidence in Tübingen, which was initially lower, had reached the incidence in the state of BW. While it is difficult to assess the impact of TÜMOD on incidence independent of confounding factors, further studies are needed to identify the effect of close-meshed testing on infection rates.

The association of intrathecal immunoglobulin synthesis and cortical lesions predicts disease activity in clinically isolated syndrome and early relapsing-remitting multiple sclerosis.

BACKGROUND: The intrathecal production of immunoglobulin (Ig) is a major biological feature of multiple sclerosis (MS), and immunopathological studies have suggested a primary role of the humoral immune response in causing irreversible brain damage. OBJECTIVE: To evaluate whether, in the early phases of MS, intrathecal Ig synthesis correlates with the presence of cortical lesions (CLs), and if their association could predict the clinical course of the disease. METHODS: Eighty-six patients presenting with symptoms and signs suggestive of MS underwent a diagnostic work-up that included magnetic resonance imaging and cerebrospinal fluid examination. The risk ratios (RR) for conversion to MS and for a new disease activity were calculated. RESULTS: Patients with clinically isolated syndromes (CIS) having CLs and intrathecal synthesis of Ig had the highest risk of conversion to MS (RR = 3.4; Wald 95% CI = 1.7-7.0, p < 0.001) whereas CIS patients without CLs and intrathecal synthesis of Ig had the lowest risk of conversion to MS (RR = 0.1, Wald 95% CI = 0.02-0.7, p < 0.001). The highest risk of having disease-related activity during the follow-up was observed in CIS and relapsing-remitting MS patients showing CLs and intrathecal Ig synthesis (RR = 2.1; Wald 95% CI = 1.5-3.1, p < 0.001) while the lowest in CIS and relapsing-remitting MS patients without CLs and intrathecal Ig synthesis (RR = 0.3; Wald 95% CI = 0.1-0.7, p < 0.001). CONCLUSION: We observed that the association of intrathecal immunoglobulin synthesis and CLs was highly predictive of an earlier CIS conversion to MS as well as of a higher disease activity.

Wide Cytokine Analysis in Cerebrospinal Fluid at Diagnosis Identified CCL-3 as a Possible Prognostic Factor for Multiple Sclerosis.

Background: Apart from IgG oligoclonal bands, no other biomarker has, to date, been validated for diagnostic and/or prognostic purposes in multiple sclerosis (MS). Aim: To investigate a wide panel of cytokines and chemokines in the cerebrospinal fluid (CSF) of relapsing-remitting MS (RRMS) patients and evaluate their association with clinical and magnetic resonance imaging (MRI) parameters, as well as their predictive clinical value. Methods: Fifty-one RRMS at clinical onset and 17 other not inflammatory neurological disorders (ONINDs) underwent brain MRI (including 3D-T1, 3D-FLAIR, and 3-DIR sequences) and CSF examination. Eighty-seven cytokines and chemokines were analyzed in CSF by Multiplex technology. Results: Compared to ONIND, CXCL-10, CXCL-11, CXCL-13, CCL-1, CCL-2, CCL-3, CCL-22, IL-16, and BAFF were significantly (p < 0.05) increased in RRMS CSF. However, only CCL-3 was associated with both MS diagnosis and IgGOB detection. Based on a 95%CI in ONIND (cut-off value: 0.798 pg/ml) and ROC analysis (cut-off value: 0.495 pg/ml), RRMS patients were stratified in CCL-3high (>0.736 pg/mL), CCL-3medium, and CCL-3low (<0.495 pg/ml). Survival analysis disclosed a strong association between high CCL-3 values and disease reactivation (OR = 4.9, 95%CI: 1.8-13.3, p < 0.005) in the following 2 years. Conclusions: CCL-3 deserves further investigation as a candidate prognostic biomarker for RRMS.

Alemtuzumab as rescue therapy in case of multiple sclerosis rebound following Natalizumab break: Clinical case and literature review.

INTRODUCTION: Natalizumab break exposes multiple sclerosis (MS) patients to a high risk of disease reactivation or rebound, whose prevention and treatment constitute a clinical challenge. CASE PRESENTATION: We describe a dramatic case of MS rebound, characterized by the development of severe neurological and psychiatric symptoms, following natalizumab break. Alemtuzumab rapidly and completely suppressed brain inflammation as demonstrated by clinical and radiological findings. CONCLUSIONS: Our case further adds to the available literature evidence on Alemtuzumab as first-choice rescue therapy following Natalizumab discontinuation.

Decreased platelet number in multiple sclerosis during alemtuzumab infusion: a common, transient and clinically silent phenomenon.

BACKGROUND: The cause and clinical significance of the transient decrease in platelet (PLT) count observed in relapsing remitting multiple sclerosis (RRMS) during alemtuzumab administration remain undefined. The aim of this study was to analyse the kinetics and clinical relevance of early onset thrombocytopaenia in alemtuzumab-treated RRMS. METHODS: A total of 26 patients with RRMS were included in a longitudinal study. Blood samples were collected immediately before the first alemtuzumab infusion (D0), and after 3 days (D3), 28 days (D28) and 49 days (D49). PLT, red blood cell (RC), leucocyte and lymphocyte counts, haemoglobin (Hb) concentration and haematocrit (Htc) were measured. Patients with MS were clinically evaluated every day of drug infusion and then at D28 and D49 to verify the presence of signs or symptoms suggestive of thrombocytopaenia. RESULTS: PLT number significantly decreased at D3 (p < 0.005) and was associated with a decrease in RC count (r: 0.53, p < 0.01), Hb (r: 0.42, p = 0.05) and Htc (r: 0.53, p < 0.01). A progressive reversion of PLT number to normal values was observed at D28 and D49. A mild thrombocytopaenia was observed in 12 patients (46.2%), 8 of which (66.6%) had PLT nadir values at D3, and 4 (33.3%) at D28. No sign or symptom suggestive of thrombocytopaenia was observed. A strong correlation between pretreatment and nadir PTL counts (r: 0.59, p < 0.005) was observed; indeed, mild thrombocytopaenia was observed more frequently in these patients with a baseline PTL count lower than 230 × 109/L (83.3% versus 42.9%, p < 0.05). CONCLUSIONS: The early PLT decrease in alemtuzumab-treated patients is transient, mild, not associated with clinically relevant events and is probably related to the cytokine-released syndrome. Notwithstanding this, our findings suggest the opportunity for PLT monitoring during infusion and in the following 2 months, since a decrease in PLT count may occur.

NEDA-3 status including cortical lesions in the comparative evaluation of natalizumab versus fingolimod efficacy in multiple sclerosis.

BACKGROUND: Cortical lesions (CLs) are typical of multiple sclerosis (MS) and have been recently incorporated in MS diagnostic criteria. Thus, the 'no evidence of disease activity' (NEDA) definition should now include CLs. The aim of this study was to evaluate the NEDA3 + CL status in natalizumab- or fingolimod-treated relapsing remitting MS (RMS) patients. METHODS: Natalizumab- or fingolimod-treated RMS patients were enrolled in a 2-year longitudinal study based on clinical and magnetic resonance imaging (MRI) evaluations performed respectively biannually and annually. CLs were detected by double inversion recovery. The NEDA3 + CL condition was evaluated at baseline (T0) and at the end of the first (T1) and second (T2) year. RESULTS: Of the 137 RMS patients included in the study, 86 were propensity-matched. At T2, the annualized relapse rate was lower on natalizumab (p = 0.021), but the effect on white matter lesions (p = 0.29) and the proportion of NEDA-3 patients (p = 0.14) were similar in the two treatment arms. At T2, 11.6% natalizumab- and 62.8% fingolimod-treated patients had new CLs (p < 0.001) and a higher proportion of natalizumab-treated patients (55.8% versus 11.6%, p < 0.001) achieved the NEDA3 + CL status (hazard ratio 5.2, p < 0.001). CONCLUSION: The incorporation of CLs in the NEDA-3 definition highlighted the higher efficacy of natalizumab versus fingolimod in suppressing disease activity in RMS patients.

Trans-synaptic degeneration in the optic pathway. A study in clinically isolated syndrome and early relapsing-remitting multiple sclerosis with or without optic neuritis.

OBJECTIVE: Increasing evidence suggest that neuronal damage is an early and diffuse feature of Multiple Sclerosis (MS) pathology. Analysis of the optic pathway may help to clarify the mechanisms involved in grey matter damage in MS. Purpose of our study was to investigate the relationship between inflammation and neurodegeneration and to achieve evidence of trans-synaptic degeneration in the optic pathway in MS at clinical onset. METHODS: 50 clinically isolated syndromes/early relapse-onset MS (CIS/eRRMS) with mean disease duration of 4.0±3.5 months, 28 MRI healthy controls (HC) and 31 OCT-HC were studied. Ten patients had optic neuritis at presentation (MSON+), 40 presented with other symptoms (MSON-). MRI examination included 3D-T1, 3D-FLAIR and 3D-DIR sequences. Global cortical thickness (gCTh), pericalcarin CTh (pCTh) and white matter volume (WMV) were analysed by means of Freesurfer on 3D-T1 scans. Optic radiation morphology (OR) and volume (ORV) were reconstructed on the base of the Jülich's Atlas. White matter lesion volume (WMLV), OR-WMLV and percent WM damage (WMLV/WMV = WMLV% and OR-WMLV/ORV = ORWMLV%) were obtained by 3D-FLAIR image segmentation. 3D-DIR sequences were applied to identify inflammatory lesions of the optic nerve. Optic coherence tomography (OCT) protocol included the analysis of global peripapillary retinal nerve fiber layer (g-RNFL) and the 6 fundus oculi's sectors (temporal, T-RNFL; temporal superior, TS-RNFL; nasal superior, NS-RNFL; nasal, N-RNFL; nasal inferior, NI-RNFL, temporal inferior, TI-RNFL). The retina of both eyes was analyzed. The eyes of ON+ were further divided into affected (aON+) or not (naON+). RESULTS: No difference in CTh was found between CIS/eRRMS and HC, and between MSON+ and MSON-. Moreover, MSON+ and MSON- did not differ for any WM lesion load parameter. The most significant correlations between RNFL thickness and optic radiation WM pathology were found in MSON+. In these patients, the temporal RNFL inversely correlated to ipsilateral optic radiation WM lesion load (T-RNFL: r -0.7, p<0.05; TS-RNFL: r -0.7, p<0.05), while nasal RNFL inversely correlated to contralateral optic radiation WM lesion load (NI: r -0.8, p<0.01; NS-RNFL: r -0.8, p<0.01). CONCLUSIONS: Our findings suggest that in MSON+ the optic pathway is site of a diffuse pathological process that involves both directly and via trans-synaptic degeneration the RNFL.

Cerebrospinal fluid IL-1ß correlates with cortical pathology load in multiple sclerosis at clinical onset.

The cerebrospinal fluid levels of interleukin-1 beta and structural magnetic resonance parameters of cortical damage, i.e., cortical lesion number and volume, and global cortical thickness, were analysed in multiple sclerosis patients at clinical onset. Cerebrospinal fluid interleukin-1 beta levels strongly correlated with cortical lesion load and cortical thickness, while correlation with white matter lesion load was modest. Interleukin-1 beta, intrathecally produced by infiltrating lymphocytes and activated microglia, may constitute a possible link between inflammation and neurodegeneration in multiple sclerosis.