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Background: The genetic component of multiple sclerosis (MS) is now set to 200 autosomal common variants. However, it is unclear how genetic knowledge be clinically used in the differential diagnosis between MS and other inflammatory conditions like adult-onset postinfectious neurological syndromes (PINS). The aim of this study was to investigate whether PINS and MS have a shared genetic background using an updated polygenic risk scores., Methods: Eighty-eight PINS patients have been consecutively recruited between 1996 and 2016 at Mondino Foundation of Pavia, diagnosed according to clinical, MRI and CSF findings and followed-up for several years. Patients were typed using Illumina array, and genotypes imputed using the 1000 Genomes Project reference panel. A weighted genetic risk score (wGRS) has been calculated based on autosomal MS risk loci derived from large-scale studies, and an HLA genetic burden (HLAGB) was also calculated on loci associated to MS., Results: PINS occurred as an episode of myelitis in 44% of patients, encephalomyelitis in 44%, and encephalitis in remaining cases, with an involvement of peripheral nervous system in 41% of patients. Mean age of onset was 50.1 years, and female:male ratio was 1.4. Patients were followed-up for a mean of 7.2 years, and at last visit 55% had a low disability grade (mRS 0-1). Disease was monophasic in 67% of patients, relapsing in 18% and chronic-progressive in 15%. The wGRS of PINS cases was comparable to 370 healthy controls, while significantly lower compared to 907 bout-onset MS (BOMS) cases (wGRS= 20.9 vs 21.2; p<0.0001). The difference was even larger for PINS with peripheral nervous system involvement (wGRS=20.6) vs BOMS., Conclusion: The distinction between MS and PINS is not easy to make in clinical practice. However, our study shows that the new set of MS risk alleles does not confer increased susceptibility to PINS. These data support the importance to discriminate these cases from MS with pathophysiological and therapeutic implications., (Copyright © 2020. Published by Elsevier B.V.)

Background: Transverse myelitis (TM) is an inflammatory disorder that can be idiopathic or associated with central nervous system autoimmune/dysimmune inflammatory diseases, connective tissue autoimmune diseases, or post-infectious neurological syndromes. Prognosis of initial TM presentations is uncertain., Objective: To identify outcome predictors in TM., Methods: Retrospective study on isolated TM at onset. Scores ⩾3 on the modified Rankin scale (mRS) marked high disability., Results: A total of 159 patients were identified. TM was classified as follows: idiopathic (I-TM, n = 53), post-infectious (PI-TM, n = 48), associated with multiple sclerosis (MS-TM, n = 51), or neuromyelitis optica spectrum disorders/connective tissue autoimmune diseases/neurosarcoidosis ( n = 7). At follow-up (median, 55 months; interquartile range, 32-80), 42 patients were severely disabled, and patients with I-TM or PI-TM showed the worst outcomes. Predictors of disability were infectious antecedents, sphincter and pyramidal symptoms, high mRS scores, blood-cerebrospinal fluid barrier damage, lumbar magnetic resonance imaging (MRI) lesions on univariate analysis, and older age (odds ratio (OR), 1.1; 95% confidence interval (CI), 1.0-1.1), overt/subclinical involvement of the peripheral nervous system (PNS) (OR, 9.4; 95% CI, 2.2-41.0), complete TM (OR, 10.8; 95% CI, 3.4-34.5) on multivariate analysis., Conclusion: Our findings help define prognosis and therapies in TM at onset. Infectious antecedents and PNS involvement associate with severe prognosis. Nerve conduction studies and lumbar MRI could improve the prognostic assessment of this condition.

We measured circulating serum and cerebrospinal fluid (CSF) concentrations of B lymphocyte activating factor of the tumour necrosis factor superfamily (BAFF), and determined total and Epstein-Barr virus (EBV)-specific oligoclonal IgG bands (OCBs) in 43 patients with multiple sclerosis (MS), 23 patients with other inflammatory demyelinating neurological diseases, and 20 patients with non-inflammatory neurological diseases. Serum and CSF BAFF concentrations did not differ in the three studied groups. In MS, the highest BAFF concentrations were found in the CSF samples with more than 6 OCBs (233.1 ± 129.5 vs 79.2 ± 51.6 pg/mL in the samples with less than 7 OCBs, p<0.0001). Irrespectively from BAFF levels, EBV-specific OCBs were detected in MS and in the other non-inflammatory and inflammatory demyelinating neurological diseases, with a similar frequency, and as a 'mirror pattern' in 30 of 33 EBV-specific OCB-positive cases (p<0.0001). These results indicate that circulating CSF BAFF concentrations cannot help differentiate MS from other inflammatory demyelinating neurological diseases, but positively associates with the qualitative expression of elevated intrathecal IgG production in MS, and that the oligoclonal EBV-specific antibody response, when present, is mostly systemic in all the studied neurological patients, and not preferentially restricted to MS., (Copyright © 2010 Elsevier B.V. All rights reserved.)

We evaluated oligoclonal IgG band (OCB) patterns obtained by analyzing paired cerebrospinal fluid (CSF) and serum samples of 77 patients with acute demyelinating encephalomyelitis (ADEM) and 411 patients with multiple sclerosis (MS). OCBs were searched with isoelectric focusing and capillary immunoblotting. CSF-restricted OCBs were found in 89% of MS patients and 10% of ADEM patients (p<0.0001). Identical serum and CSF OCBs ('mirror pattern'), or no OCBs, were detected in 10% of MS patients and 84% of ADEM patients (p<0.0001). OCBs were also analyzed in 27 mice with proteolipid protein-induced experimental autoimmune encephalomyelitis (EAE). In this animal model, the 'mirror pattern' was the most frequently detected pattern (74%), with the immunizing antigen being the main OCB target. These results indicate that CSF analysis can help differentiate between MS and ADEM and that, similarly to EAE, the 'mirror pattern' observed in ADEM accounts for a predominantly systemic immune activation.

Objectives: We compared the clinical, laboratory, and radiological features of different subgroups of acute transverse myelitis (ATM) diagnosed according to the criteria established by the Transverse Myelitis Consortium Working Group (TMCWG) as well as of non-inflammatory acute transverse myelopathies (NIATM) to identify possible short- and long-term prognostic factors.Methods: A multicenter and retrospective study comprising 110 patients with ATM and 15 NIATM admitted to five Italian neurological units between January 2010 and December 2014 was carried out.Results: A significantly higher frequency of isolated sensory disturbances at onset in ATM than in NIATM patients (chi-square = 14. 7; P = 0.005) and a significantly higher frequency of motor symptoms in NIATM than ATM (chi-square = 12.4; P = 0.014) was found. ATM patients with high disability at discharge had more motor-sensory symptoms without (OR = 3.87; P = 0.04) and with sphincter dysfunction at onset (OR = 7.4; P = 0.0009) compared to those with low disability. Higher age (OR = 1.08; P = 0.001) and motor-sensory-sphincter involvement at onset (OR = 9.52; P = 0.002) were significantly associated with a high disability score at discharge and after a median 1-year follow-up.Conclusions: The diagnosis of ATM may prevail respect to that of NIATM when a sensory symptomatology at onset occurs. In ATM, patients older and with motor-sensory involvement with or without sphincter impairment at admission could experience a major risk of poor prognosis both at discharge and at longer time requiring a timely and more appropriate treatment. [ABSTRACT FROM AUTHOR]

Background: Transverse myelitis (TM) is an inflammatory disorder that can be idiopathic or associated with central nervous system autoimmune/dysimmune inflammatory diseases, connective tissue autoimmune diseases, or post-infectious neurological syndromes. Prognosis of initial TM presentations is uncertain. Objective: To identify outcome predictors in TM. Methods: Retrospective study on isolated TM at onset. Scores ⩾3 on the modified Rankin scale (mRS) marked high disability. Results: A total of 159 patients were identified. TM was classified as follows: idiopathic (I-TM, n = 53), post-infectious (PI-TM, n = 48), associated with multiple sclerosis (MS-TM, n = 51), or neuromyelitis optica spectrum disorders/connective tissue autoimmune diseases/neurosarcoidosis (n = 7). At follow-up (median, 55 months; interquartile range, 32–80), 42 patients were severely disabled, and patients with I-TM or PI-TM showed the worst outcomes. Predictors of disability were infectious antecedents, sphincter and pyramidal symptoms, high mRS scores, blood–cerebrospinal fluid barrier damage, lumbar magnetic resonance imaging (MRI) lesions on univariate analysis, and older age (odds ratio (OR), 1.1; 95% confidence interval (CI), 1.0–1.1), overt/subclinical involvement of the peripheral nervous system (PNS) (OR, 9.4; 95% CI, 2.2–41.0), complete TM (OR, 10.8; 95% CI, 3.4–34.5) on multivariate analysis. Conclusion: Our findings help define prognosis and therapies in TM at onset. Infectious antecedents and PNS involvement associate with severe prognosis. Nerve conduction studies and lumbar MRI could improve the prognostic assessment of this condition. [ABSTRACT FROM AUTHOR]

Abstract: A dynamic equilibrium between proliferation and programmed cell death (PCD) of auto-reactive T lymphocytes plays a pivotal role in the prevention of autoimmune diseases. We analyzed T lymphocytes myelin basic protein (MBP)-specific PCD and proliferation in demyelinating diseases. Results showed that MBP-specific PCD was significantly decreased in CD4+ and CD8+ T lymphocytes of progressive multifocal leukoencephalopathy (PML), not determined leukoencephalopathy (NDLE), and acute MS (AMS) patients compared to patients with stable MS (SMS) and healthy controls. MBP-specific proliferation/PCD rates were high in CD4+ T lymphocytes of PML, NDLE, and AMS patients, and in CD8+ T cells of PML and AMS individuals alone. Alterations of the balance between MBP-specific proliferation and PCD are present in demyelinating diseases and could play a major role in the pathogenesis of these diseases. [Copyright &y& Elsevier]

Abstract: Cytokines and chemokines contribute to the pathogenesis of acute disseminated encephalomyelitis (ADEM). Using a multiplex immunochemiluminescence ELISA, we measured 8 Th1/Th2 cytokines and 18 chemokines in the cerebrospinal fluid (CSF) and serum of 17 ADEM patients, 14 multiple sclerosis (MS) patients, and 7 healthy controls (HCs). Relative to HCs, ADEM patients had significantly high mean CSF concentrations of chemokines with attractant/activating properties towards neutrophils (CXCL1 and CXCL7), monocytes/T cells (CCL3 and CCL5), Th1 cells (CXCL10), and Th2 cells (CCL1, CCL22, and CCL17). Mean CSF concentrations of CXCL7, CCL1, CCL22, and CCL17 were higher in ADEM than in MS, whereas those of CCL11 were lower in MS than in ADEM and HCs. CSF pleocytosis correlated with CSF concentrations of CXCL1, CXCL10, CCL1, CCL17, and CCL22. Most of the functionally homologous chemokines correlated with each other. CSF Th1/Th2 cytokines were not detectable in most samples. Their mean concentrations did not differ in the three groups, and the same held for serum cytokines and chemokines. Our data suggest that the upregulation of chemokines active on neutrophils and Th2 cells differentiates ADEM from MS inflammation, and that both Th1 and Th2 chemokines might be produced in ADEM. Chemokines upregulated in ADEM could become CSF biomarkers after a posteriori evaluations in unselected case series. [Copyright &y& Elsevier]