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.

HPV-related papillary squamous cell carcinoma of the tonsil during treatment with fingolimod.

Fingolimod is a commonly used treatment for highly active relapsing-remitting multiple sclerosis (MS). We describe the case of a 50-year old man on fingolimod since 2011 who presented, in April 2017, with a voluminous swelling of the left tonsil. A left tonsillectomy was performed, and histological exam disclosed a papillary squamous cell carcinoma of the palatine tonsil, with an in situ hybridization positive for human papillomavirus (HPV)-16 DNA. Neither lymph nodes involvement nor other metastases were detected. Fingolimod was stopped as a precautionary measure in May 2017, and the patient currently continues his follow up at our Department. Immunocompromised patients are at risk for developing HPV-related malignancies probably in light of the suppression of T-cell immunity, therefore an increased risk for HPV activation in MS patients treated with disease modifying therapies (DMTs) characterized by a more pronounced immunosuppressant activity cannot be excluded. Given the absence of studies on larger cohorts of MS patients exposed to DMTs, additional monitoring for HPV infection during fingolimod treatment is not currently recommended. However, vigilance for this possible association is warranted.

A case of multiple sclerosis and necrotizing autoimmune myopathy with anti-SRP antibodies.

Only few reports exist regarding the coexistence of multiple sclerosis (MS) and autoimmune myopathies. We describe the case of a man with a long history of undiagnosed left lower limb motor impairment who was hospitalized for subacute onset of a myopathic syndrome. In addition, neurological examination revealed sensory impairment and pyramidal signs in the left limbs. Muscle biopsy revealed a necrotizing myopathy and serum anti-signal recognition particle (SRP) antibodies were found. Brain and spinal cord MRI displayed several non-enhancing demyelinating lesions, and CSF-restricted oligoclonal bands were detected. Multimodal evoked potentials showed increased latency of central conduction. Total body PET-CT did not reveal malignancies. A final diagnosis of anti-SRP necrotizing autoimmune myopathy (NAM) and MS was made, and subsequent therapy with azathioprine resulted in a complete stability for both diseases during the follow up. To the best of our knowledge this is the first reported case of concomitant NAM and MS.

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.

Anti-N-methyl-d-aspartate receptor encephalitis causing a prolonged depressive disorder evolving to inflammatory brain disease.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a rapidly evolving condition that combines psychiatric and neurologic manifestations. Much remains unclear about its clinical onset and subsequent course. Although successful treatment depends on diagnosing the disorder early and therefore minimizing long-term complications, this is a difficult task owing to the atypical onset of this condition and the prolonged clinical course that has been observed in some patients. This report, illustrating a patient with slowly progressing psychiatric manifestations, unusual imaging and electrophysiological features, extends the information on varied clinical phenotypes. CASE REPORT: A 32-year-old woman suffered from an isolated depressive disorder for 4 months before undergoing psychiatric evaluation. During the following 5 months, she manifested hypersexuality, dysarthria, imbalance, dyskinesias and decreased word output. Brain magnetic resonance imaging (MRI) showed multifocal hyperintense T2/FLAIR lesions, a few contrast-enhanced, involving the corona radiata, the periventricular white matter, the deep gray nuclei, the optic nerves and the brainstem. MRI spectroscopy disclosed confluent bilateral demyelination and focal optic nerve involvement suggesting widespread encephalitis. Visual evoked potential studies indicated a demyelinating disorder. Serological screening and total body positron-emission tomography yielded negative findings for malignancies. Cerebrospinal fluid examination disclosed IgG oligoclonal bands and anti-NMDAR antibodies. Corticosteroids and intravenous immunoglobulin provided only slight improvement, whereas switching to cyclophosphamide markedly improved her neurological status. CONCLUSION: In patients with a prolonged clinical course, including psychiatric and neurological symptoms, the differential diagnosis should be anti-NMDAR encephalitis. This report expands the known disease phenotypes in this emerging condition.

Benign course of tumour-like multiple sclerosis. Report of five cases and literature review.

BACKGROUND: Multiple sclerosis (MS) with initial neuroradiological features suggestive of brain tumour (tumour-like MS) may represent a challenging diagnosis. METHODS: Among the patients seen at the MS centre of our Institution between 2000 and 2010, we identified cases presenting with a large (diameter>2 cm), well-defined lesion, suggestive of brain tumour on initial brain magnetic resonance imaging (MRI). Only patients with at least 10 years follow-up were included. RESULTS: Five young women with MS who presented with a tumour-like lesion on initial brain MRI are described. All cases presented with sudden-onset neurological deficits due to a single large brain lesion compatible with neoplasm at MRI. Two cases underwent brain stereotactic biopsy, both misdiagnosed as astrocytoma. However, the subsequent clinical and MRI follow-up was consistent with MS in all cases. Unnecessary surgery and radiotherapy were responsible for disability in two cases. In three cases, the course of the disease remains benign after more than 13 years from symptoms onset. CONCLUSIONS: Our report of clinical, radiological and pathological features of five tumour-like MS cases confirms that it is mandatory to consider a demyelinating process in the differential diagnosis of tumour-like brain lesions. Many tumour-like MS cases may have a favourable long term prognosis.

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.

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.

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.

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.

Assessment of outcome predictors in first-episode acute myelitis: a retrospective study of 53 cases.

OBJECTIVE: To identify predictors of short- and long-term outcomes in acute myelitis (AM). DESIGN: First episodes of AM were retrospectively identified in a single institution. Information regarding demographics, clinical status, laboratory workup, magnetic resonance imaging of the spine and brain, and electrophysiological assessment was collected. Tau, 14-3-3 protein, and cystatin C levels were assessed de novo in stored cerebrospinal fluid samples. SETTING: A neurological department database. Patients Fifty-three patients with a first episode of AM. MAIN OUTCOME MEASURES: The prognostic value of all variables was analyzed for the following outcomes: recovery from the initial event, symptom recurrence, conversion to multiple sclerosis (MS), and long-term disability. RESULTS: Median follow-up was 6.2 years. Six patients (11%) remained monophasic; 5 (9%) developed recurrent myelitis; and 42 (79%) underwent conversion to MS. Sensory level absence, no sphincter involvement, abnormal magnetic resonance imaging findings in the brain, spinal cord lesions shorter than 3 vertebral segments, and abnormal somatosensory evoked potentials predicted MS conversion. Fifteen of 32 patients with pyramidal dysfunction at onset (47%) and 17 of 43 with relapses during follow-up (40%) had significant disability at the last visit compared with 2 of 21 patients without pyramidal manifestations (10%) and none of the patients without exacerbations (P = .006 and P = .02, respectively). In 11 patients with exacerbations, we observed a significant correlation between cerebrospinal fluid levels of cystatin C and the degree of neurological disability at the last visit (Spearman rho = 0.69; P = .03). CONCLUSIONS: For patients with first-episode AM, the conversion rate to MS is high. Motor dysfunction at onset and relapse occurrence are associated with worse outcome. Cerebrospinal fluid levels of cystatin C may prove useful for predicting the prognosis of such patients.

Cerebrospinal fluid biomarkers in clinically isolated syndromes and multiple sclerosis.

A panel of three cerebrospinal fluid (CSF) markers for clinically isolated syndromes (CIS) and multiple sclerosis (MS), based on SDS-PAGE, 2-D maps, and immunoblot results, is here proposed. No individual marker has any specificity, though, since they appear in a number of other neurological diseases. However the set of three, with the respective modulation sign (up-regulated or maintained at constant level), appears to be unique for MS. These proteins are: tau protein (levels remaining constant and undistinguishable from controls, contrary to up- and downregulation in other neurological disorders); 14-3-3 protein (strong upregulation of distinct isoforms) and cystatin C (changing in accordance to disease stage and progression). As an additional evidence, one can rely in the pattern of isoforms of 14-3-3, as obtained by 2-D maps and Western blot analysis: this pattern further distinguishes the variation of this protein from other neurological syndromes, notably sporadic Creutzfeldt-Jakob disease (sCJD), motor neuron diseases and other dementias. In contrast, a similar qualitative and quantitative upregulation of 14-3-3 is observed in Guillain-Barré syndrome (GBS), a demyelinating condition affecting the peripheral nervous system. To the best of our knowledge, this is the first time in which such a panel of biomarkers is reported in MS.