Comparison of two high doses of oral methylprednisolone for multiple sclerosis relapses: a pilot, multicentre, randomized, double-blind, non-inferiority trial.

BACKGROUND AND PURPOSE: Oral or intravenous methylprednisolone (≥500 mg/day for 5 days) is recommended for multiple sclerosis (MS) relapses. Nonetheless, the optimal dose remains uncertain. We compared clinical and radiological effectiveness, safety and quality of life (QoL) of oral methylprednisolone [1250 mg/day (standard high dose)] versus 625 mg/day (lesser high dose), both for 3 days] in MS relapses. METHODS: A total of 49 patients with moderate to severe MS relapse within the previous 15 days were randomized in a pilot, double-blind, multicentre, non-inferiority trial (ClinicalTrial.gov, NCT01986998). The primary endpoint was non-inferiority of the lesser high dose by Expanded Disability Status Scale (EDSS) score improvement on day 30 (non-inferiority margin, 1 point). The secondary endpoints were EDSS score change on days 7 and 90, changes in T1 gadolinium-enhanced and new/enlarged T2 lesions on days 7 and 30, and safety and QoL results. RESULTS: The primary outcome was achieved [mean (95% confidence interval) EDSS score difference, -0.26 (-0.7 to 0.18) at 30 days (P = 0.246)]. The standard high dose yielded a superior EDSS score improvement on day 7 (P = 0.028). No differences were observed in EDSS score on day 90 (P = 0.352) or in the number of T1 gadolinium-enhanced or new/enlarged T2 lesions on day 7 (P = 0.401, 0.347) or day 30 (P = 0.349, 0.529). Safety and QoL were good at both doses. CONCLUSIONS: A lesser high-dose oral methylprednisolone regimen may not be inferior to the standard high dose in terms of clinical and radiological response.

Anti-inflammatory disease-modifying treatment and disability progression in primary progressive multiple sclerosis: a cohort study.

BACKGROUND AND PURPOSE: Treatment options in primary progressive multiple sclerosis (PPMS) are scarce and, with the exception of ocrelizumab, anti-inflammatory agents have failed to show efficacy in ameliorating disability progression. The aim of this study was to investigate a potential effect of anti-inflammatory disease-modifying treatment on disability outcomes in PPMS. METHODS: Using MSBase, a large, international, observational database, we identified patients with PPMS who were either never treated or treated with a disease-modifying agent. Propensity score matching was used to select subpopulations with similar baseline characteristics. Expanded Disability Status Scale (EDSS) outcomes were compared with an intention-to-treat and an as-treated approach in paired, pairwise-censored analyses. RESULTS: Of the 1284 included patients, 533 were matched (treated, n = 195; untreated n = 338). Median on-study pairwise-censored follow-up was 3.4 years (quartiles 1.2-5.5). No difference in the hazard of experiencing 3-month confirmed EDSS progression events was observed between the groups [hazard ratio (HR), 1.0; 95% confidence interval (CI), 0.6-1.7, P = 0.87]. We did not find significant differences in the hazards of confirmed EDSS improvement (HR, 1.0; 95% CI, 0.6-1.6, P = 0.91) or reaching a confirmed EDSS step ≥7 (HR, 1.1; 95% CI, 0.7-1.6, P = 0.69). CONCLUSION: Our pooled analysis of disease-modifying agents suggests that these therapies have no substantial effect on short- to medium-term disability outcomes in PPMS.

On the complexity of clinical and molecular bases of neurodegeneration with brain iron accumulation.

Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited heterogeneous neurodegenerative rare disorders. These patients present with dystonia, spasticity, parkinsonism and neuropsychiatric disturbances, along with brain magnetic resonance imaging (MRI) evidence of iron accumulation. In sum, they are devastating disorders and to date, there is no specific treatment. Ten NBIA genes are accepted: PANK2, PLA2G6, C19orf12, COASY, FA2H, ATP13A2, WDR45, FTL, CP, and DCAF17; and nonetheless, a relevant percentage of patients remain without genetic diagnosis, suggesting that other novel NBIA genes remain to be discovered. Overlapping complex clinical pictures render an accurate differential diagnosis difficult. Little is known about the pathophysiology of NBIAs. The reported NBIA genes take part in a variety of pathways: CoA synthesis, lipid and iron metabolism, autophagy, and membrane remodeling. The next-generation sequencing revolution has achieved relevant advances in genetics of Mendelian diseases and provide new genes for NBIAs, which are investigated according to 2 main strategies: genes involved in disorders with similar phenotype and genes that play a role in a pathway of interest. To achieve an effective therapy for NBIA patients, a better understanding of the biological process underlying disease is crucial, moving toward a new age of precision medicine.

Myelitis: Differences between multiple sclerosis and other aetiologies.

BACKGROUND: Myelitis can appear as an initial symptom in the context of demyelinating diseases, systemic inflammatory diseases, and infectious diseases. We aim to analyse the differences between myelitis associated with multiple sclerosis (MS) and myelitis resulting from other aetiologies. METHODS: Single-centre, retrospective analysis of patients with initial myelitis (2000-2013). Demographic, aetiological, clinical, radiological and prognostic variables were analysed and compared between patients with myelitis from MS and those with myelitis due to other aetiologies. RESULTS: We included 91 patients; mean follow-up was 7 years. Diagnoses were as follows: MS 57 (63%), idiopathic transverse myelitis 22 (24%), associated systemic diseases 6 (7%), and other diagnoses (6%). Myelitis due to MS was associated with younger age of onset (35 ± 11 vs. 41 ± 13; P = .02), more pronounced sphincter involvement (40.4 vs. 27.3%; P=.05), greater multifocal involvement in spinal MRI (77.2 vs. 26.5%; P=.001), shorter lesion extension (2.4 vs. 1.4 vertebral segments; P=.001), cervical location (82.5 vs. 64.7%; P=.05) and posterior location (89.5 vs. 41.2%; P=.001). Myelitis due to other aetiologies more frequently showed anterior location (47.1 vs. 24.6%; P=.02), and central cord involvement (47.1 vs. 14.1%; P=.001), with better recovery at one year of follow up (EDSS 2.0 vs. 1.5; P=.01). Multivariate analysis showed that multifocal spinal cord involvement (OR 9.38, 95% CI: 2.04-43.1) and posterior cord involvement (OR 2.16, 95% CI: 2.04-2.67) were independently associated with the diagnosis of MS. CONCLUSIONS: A high percentage of patients with an initial myelitis event will be diagnosed with MS. The presence of multifocal and posterior spinal cord lesions was significantly associated with the diagnosis of MS.

Similar biological effect of high-dose oral versus intravenous methylprednisolone in multiple sclerosis relapses.

UNLABELLED: Our aim was to investigate differences in immune mechanisms in multiple sclerosis (MS) relapse, after high-dose oral methylprednisolone (oMP) or intravenous methylprednisolone (ivMP). We measured serum cytokines (IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α and IFN-γ) in 39 of 49 MS patients with moderate-severe relapse, whom were treated with ivMP or oMP in a placebo-controlled, non-inferiority clinical trial. We assessed these cytokine levels at baseline and at 1 and 4 weeks post-treatment. The cytokine levels between oMP and ivMP were similar at any time. Proinflammatory cytokines (IL-6 and IFN-γ) were significantly decreased in both groups at week 1 (p = 0.05 / p = 0.03) and at week 4 (p = 0.04 / p = 0.05). This study provides further confirmatory evidence that oMP is not inferior to ivMP. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00753792.

A randomized clinical trial of oral versus intravenous methylprednisolone for relapse of MS.

BACKGROUND: Steroids improve multiple sclerosis (MS) relapses but therapeutic window and dose, frequency and administration route remain uncertain. OBJECTIVE: The objective of this paper is to compare the clinical and radiologic efficacy, tolerability and safety of intravenous methylprednisolone (ivMP) vs oral methylprednisolone (oMP), at equivalent high doses, for MS relapse. METHODS: Forty-nine patients with moderate or severe relapse within the previous 15 days were randomized in a double-blind, noninferiority, multicenter trial to receive ivMP or oMP and their matching placebos. Expanded Disability Status Scale (EDSS) scores were determined at baseline and weeks 1, 4 and 12. Brain MRI were assessed at baseline and at weeks 1 and 4. Primary endpoint was a noninferiority assessment of EDSS improvement at four weeks (noninferiority margin of one point), with further key efficacy assessments of number and volume of T1 gadolinium-enhancing (Gd+), and new or enlarged T2 lesions at four weeks' post-treatment initiation. Secondary outcomes were safety and tolerability. RESULTS: The study achieved the main outcome of noninferiority at four weeks for improved EDSS score. No differences were found between ivMP and oMP in the number of Gd+ lesions (0 (0-1) vs 0 (0-0.5), p = 0.630), volume of Gd+ lesions (0 (0-88.0) vs 0 (0-32.9) mm(3), p = 0.735), or new or enlarged T2 lesions (0 (0-194) vs 0 (0-123), p = 0.769). MP was well tolerated, and no serious adverse events were reported. CONCLUSIONS: This study provides confirmatory evidence that oMP is not inferior to ivMP in reducing EDSS, similar in MRI lesions at four weeks for MS relapses and is equally well tolerated and safe. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00753792.

First detection of SARS-CoV-2 variant B.1.1.529 (Omicron) in Ecuador.

The National Institute of Research and Public Health reported the first local record of the Omicron variant detected in Ecuador. A fully vaccinated subject returned from South Africa with a negative RT-PCR. We present the cumulative frequency of the variants in Ecuador and a phylogenetic analysis of this new Omicron.

Epigenetic regulation by metabolites from the gut microbiome.

The gut microbiome can metabolise food components, such as dietary fibres and various phytochemicals; and the microbiome can also synthesise some nutrients, for example B vitamins. The metabolites produced by bacteria and other micro-organisms in the colon can have implications for health and disease risk. Some of these metabolites are epigenetically active, and can contribute to changes in the chemical modification and structure of chromatin by affecting the activity and expression of epigenetically-active enzymes, for example histone deacetylases and DNA methyltransferases. The epigenetic activity of such gut microbiome metabolites is reviewed herein.

Gadolinium-enhanced brain lesions in multiple sclerosis relapse.

OBJECTIVE: To study the clinico-radiological paradox in multiple sclerosis (MS) relapse by analyzing the number and location of gadolinium-enhanced (Gd+) lesions on brain MRI before methylprednisolone (MP) treatment. METHODS: We analyzed brain MRI from 90 relapsed MS patients in two Phase IV multicenter double-blind randomized clinical trials that showed the noninferiority of different routes and doses of MP administration. A 1.5- or 3-T brain MRI was performed at baseline before MP treatment and within 15 days of symptom onset. The number and location of Gd+ lesions were analyzed. Associations were studied using univariate analysis. RESULTS: Sixty-two percent of patients had at least 1 Gd+ brain lesion; the median number was 1 (interquartile range 0-4), and 41% of patients had 2 or more lesions. The most frequent location of Gd+ lesions was subcortical (41.4%). Gd+ brain lesions were found in 71.4% of patients with brainstem-cerebellum symptoms, 57.1% with spinal cord symptoms and 55.5% with optic neuritis (ON). Thirty percent of patients with brain symptoms did not have Gd+ lesions, and only 43.6% of patients had symptomatic Gd+ lesions. The univariate analysis showed a negative correlation between age and the number of Gd+ lesions (p=0.002). CONCLUSION: Most patients with relapse showed several Gd+ lesions on brain MRI, even when the clinical manifestation was outside of the brain. Our findings illustrate the clinico-radiological paradox in MS relapse and support the value of brain MRI in this scenario.

Comparative study of clinical grade human tolerogenic dendritic cells.

BACKGROUND: The use of tolerogenic DCs is a promising therapeutic strategy for transplantation and autoimmune disorders. Immunomodulatory DCs are primarily generated from monocytes (MDDCs) for in vitro experiments following protocols that fail to fulfil the strict regulatory rules of clinically applicable products. Here, we compared the efficacy of three different tolerance-inducing agents, dexamethasone, rapamycin and vitamin D3, on DC biology using GMP (Good Manufacturing Practice) or clinical grade reagents with the aim of defining their use for human cell therapy. METHODS: Tolerogenic MDDCs were generated by adding tolerogenic agents prior to the induction of maturation using TNF-α, IL-ß and PGE2. We evaluated the effects of each agent on viability, efficiency of differentiation, phenotype, cytokine secretion and stability, the stimulatory capacity of tol-DCs and the T-cell profiles induced. RESULTS: Differences relevant to therapeutic applicability were observed with the cellular products that were obtained. VitD3-induced tol-DCs exhibited a slightly reduced viability and yield compared to Dexa-and Rapa-tol-DCs. Phenotypically, while Dexa-and VitD3-tol-DCs were similar to immature DCs, Rapa-tol-DCs were not distinguishable from mature DCs. In addition, only Dexa-and moderately VitD3-tol-DCs exhibited IL-10 production. Interestingly, in all cases, the cytokine secretion profiles of tol-DCs were not modified by a subsequent TLR stimulation with LPS, indicating that all products had stable phenotypes. Functionally, clearly reduced alloantigen T cell proliferation was induced by tol-DCs obtained using any of these agent. Also, total interferon-gamma (IFN-γ) secretion by T cells stimulated with allogeneic tol-DCs was reduced in all three cases, but only T cells co-cultured with Rapa-tol-DCs showed impaired intracellular IFN-γ production. In addition, Rapa-DCs promoted CD4+ CD127 low/negative CD25high and Foxp3+ T cells. CONCLUSIONS: Our results demonstrate contrasting influences of different clinical-grade pharmacological agents on human tol-DC generation. This should be taken into account for decisions on the use of a specific agent for the appropriate cellular therapy in the context of a particular disease.

Specific T-cell proliferation to myelin peptides in relapsing-remitting multiple sclerosis.

BACKGROUND: The identification of major immunogenic peptides in multiple sclerosis (MS) is of great importance for the development of antigen-specific therapies. Cellular reactivity against a selected mix of seven myelin peptides was evaluated in vitro. The evolution of this reactivity over time and its correlation with clinical variables was also analysed. MATERIAL AND METHODS: Forty-two patients with MS, 15 with other demyelinating diseases and 40 healthy donors (HD) were studied. Cell proliferation was measured by 3[H] thymidine incorporation into samples obtained at 0, 3, 6 and 12months of MS patient follow-up. RESULTS: A positive reaction to the peptide mix was detected in 31 of the 42 patients (74%), 12 of the 40 HD (30%) and 6 of the 15 (40%) patients with other demyelinating diseases. Patients with positive proliferation had greater disability (EDSS score, 3 [1-5.5] vs. 1.0[1-2], P=0.021), higher number of relapses (7±4.1 vs. 3±1.2, P<0.001) and shorter time since the last relapse (9±7.5 vs. 32±12.3months, P=0.036). After 12months of follow-up, cell reactivity was maintained in 33 patients (78%). CONCLUSION: A high percentage of patients exhibit a significant and maintained reactivity to myelin peptides over time. Therefore, this mix may be useful as a source of antigen in the development of protocols aimed at inducing specific tolerance in MS.

The Global Adherence Project (GAP): a multicenter observational study on adherence to disease-modifying therapies in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: most disease-modifying therapies (DMTs) for multiple sclerosis (MS) are self-injectable medications that must be taken on an ongoing basis to reduce disease activity. Thus, adherence to therapy becomes an important challenge that must be addressed to maximize benefits of therapy. This study evaluated rates of adherence to prescribed treatment and explored factors affecting adherence amongst patients with relapsing-remitting MS. METHODS: this was an observational, multicenter, multinational, phase 4 study. Patients and physicians received paper questionnaires regarding adherence to DMTs approved at the time of the study, including intramuscular interferon beta-1a (IFNß-1a), subcutaneous IFNß-1a, IFNß-1b, and glatiramer acetate. Quality of life and cognition data also were collected. Multivariate analysis was conducted to identify factors associated with adherence to long-term DMTs. RESULTS: two thousand six hundred and forty-eight patients were studied, revealing an average treatment duration of 31 months. Seventy-five percent of patients (n = 1923) were adherent to therapy. The most common reasons for non-adherence were forgetting to administer the injection (50.2%) and other injection-related reasons (32.0%). Adherent patients reported better quality of life (P < 0.05) and fewer neuropsychological issues (P < 0.001) than non-adherent patients. Adherent patients had significantly shorter duration of disease (P < 0.001) and shorter duration of therapy (P = 0.005) than non-adherent patients. Women were more likely than men to adhere to treatment. CONCLUSION: identifying factors that affect adherence to prescribed treatments is the first step in improving adherence of patients with MS to therapy, thereby helping maximize the benefits of long-term DMTs.

Adherence to disease-modifying therapies in spanish patients with relapsing multiple sclerosis: two-year interim results of the global adherence project.

The post-marketing international Global Adherence Project investigated adherence to disease-modifying therapy for relapsing-remitting multiple sclerosis. We report adherence data from the first 2 years in the Spanish subset of patients (n = 254 at baseline). The overall adherence rate was 85.4%. Patients taking intramuscular (IM) interferon-ß (IFNß)-1a were significantly more adherent (96.4%) compared with patients taking subcutaneous (SC) IFNß-1a 22 µg (79.1%; p = 0.0064), SC IFNß-1a 44 µg (79.6%; p = 0.0064) and glatiramer acetate (82.7%; p = 0.0184). At year 1 (n = 142), the overall adherence rate was 86.6%. Patients on IM IFNß-1a were significantly more adherent than patients on SC IFNß-1a 22 µg (93.9 vs. 66.7%; p = 0.0251). At year 2 (n = 131), the overall adherence rate was 82% (87.5% for IM IFNß-1a, 80.0% for SC IFNß-1a 22 µg, 77.8% for SC IFNß-1a 44 µg, 85.2% for IFNß-1b, and 80.0% for glatiramer acetate). In conclusion, adherence remained high among all disease-modifying therapies over the first 2 years of the study and was significantly higher for IM IFNß-1a, at visit 1, compared with SC IFNß-1a.

Analysis of the pain in multiple sclerosis patients.

INTRODUCTION: Despite pain being a disabling symptom in patients with multiple sclerosis (MS), its prevalence and characteristics are not well established. The aim of this study is to describe the characteristics and prevalence of pain in patients with MS, and to assess the associated clinical variables and radiological findings. METHODS: We prospectively studied patients with MS. A structured questionnaire which evaluated depression symptoms, type of pain, location, intensity (defined according to a visual analogue scale (VAS) as severe (VAS 7-10), moderate (VAS 4-6) and mild (VAS 0-4), and pain therapy was recorded in patients who referred to pain at the time of interview. Protocol variables were demographic data, MS clinical forms (remitting-relapsing, progressive-secondary and progressive-primary), neurological dysfunction (defined according to EDSS scale), symptoms at onset, attack frequency, illness duration, disease modifying treatment, fatigue, spasticity, oligoclonal bands in CSF, visual evoked potentials, depression symptoms (Hamilton test) and presence of lesions in spinal cord MRI. RESULTS: A total of 134 MS patients were included, and MRI was performed on 105 of them. Pain was reported by 74 (55%) patients and was most frequently neuropathic, located in limbs, severe and burning/spiky. Of these 28 (38%) received therapy for their pain, based predominantly in anti-inflammatory drugs. Patients with pain had a worse functional state (EDSS score, 4.5 [3-6] vs 1.5 [1-2], p<0.001), higher number of relapses (7.13±3.4 vs 3.75±2.9, p<0.001), progressive forms of MS (86.7% vs 13.3%, p<0.001), depression (91.9% vs 8.1%, p<0.001), spinal cord involvement at onset (79.2% vs 20.8%, p=0.009), spinal cord lesions by MRI (84.3% vs 15.7%, p<0.001) and longer duration of disease (14.6±7.8 vs 8.43±5.9 months, p<0.001). In a logistic regression model, the presence of lesions in spinal cord MRI (OR 3.5 [1.5-24.5]) and higher EDSS score (OR 1.7 [1.1-2.7]) were independently associated with pain. CONCLUSIONS: Pain is a frequent disabling symptom in MS and is associated with disability and spinal cord lesions.

Aneurysmal bone cyst and osteoblastoma: an extremely rare combination in the pediatric spine.

STUDY DESIGN: Case report. OBJECTIVE: To report the clinical and imaging findings of a patient with the extremely rare association of aneurysmal bone cyst and osteoblastoma in the cervical spine. To our knowledge, only three cases have been reported in the published literature in children under 16 years of age with this condition in the cervical spine. METHODS: The patient's history, physical examination, imaging findings, and management with a complete 4-year medical history, surgical intervention and radiological follow-up are reported. RESULTS: A 4-year 11-month-old boy was diagnosed with aneurysmal bone cyst in association of osteoblastoma and was treated with CT-guided intralesional injection calcitonin and methylprednisolone. During the course of intralesional therapy, a pathological fracture of C2 was produced. Subsequently, a widened intralesional excision and instrumented fusion from occiput to cervical spine (C0-C4) was performed. CONCLUSION: The association of aneurysmal bone cyst and osteoblastoma in spine is extremely rare. Although both are benign lesions, in the cervical location, complete removal of the tumors is challenging. Wide resection with reconstruction of the segments for stability associated with adjuvant treatment with calcitonin and corticosteroids provides a good option.

Chiari 1: Is decompression always necessary previous to scoliosis surgery?

The association between Chiari 1 malformation and scoliosis is well known in the literature. Prevalence has increased after the advent of magnetic resonance imaging. In children with this association, prophylactic suboccipital decompression prior to scoliosis correction is a common surgical procedure although the rationale for this surgical management and whether not performing it may lead to spinal cord injury has not been clearly elucidated. We conducted a systematic review of the literature with the aim to obtain strong data to support the hypothesis that it is safe to proceed with scoliosis correction without prior prophylactic suboccipital decompression for Chiari 1 in an asymptomatic population. Using the Prisma methodology, we analyzed 3250 studies published between 1972 and 2018. Only four studies met the inclusion criteria. None of the studies had a level of evidence high enough to recommend prophylactic decompression previous to correction of the spinal deformity.

Paving the way towards an effective treatment for multiple sclerosis: advances in cell therapy.

Multiple sclerosis (MS) is a leading cause of chronic neurological disability in young to middle-aged adults, affecting ~2.5 million people worldwide. Currently, most therapeutics for MS are systemic immunosuppressive or immunomodulatory drugs, but these drugs are unable to halt or reverse the disease and have the potential to cause serious adverse events. Hence, there is an urgent need for the development of next-generation treatments that, alone or in combination, stop the undesired autoimmune response and contribute to the restoration of homeostasis. This review analyzes current MS treatments as well as different cell-based therapies that have been proposed to restore homeostasis in MS patients (tolerogenic dendritic cells, regulatory T cells, mesenchymal stem cells, and vaccination with T cells). Data collected from preclinical studies performed in the experimental autoimmune encephalomyelitis (EAE) model of MS in animals, in vitro cultures of cells from MS patients and the initial results of phase I/II clinical trials are analyzed to better understand which parameters are relevant for obtaining an efficient cell-based therapy for MS.

Extended-spectrum beta-lactamase-producing Escherichia coli in common vampire bats Desmodus rotundus and livestock in Peru.

Antibiotic resistance mediated by bacterial production of extended-spectrum beta-lactamase (ESBL) is a global threat to public health. ESBL resistance is most commonly hospital-acquired; however, infections acquired outside of hospital settings have raised concerns over the role of livestock and wildlife in the zoonotic spread of ESBL-producing bacteria. Only limited data are available on the circulation of ESBL-producing bacteria in animals. Here, we report ESBL-producing Escherichia coli in wild common vampire bats Desmodus rotundus and livestock near Lima, Peru. Molecular analyses revealed that most of this resistance resulted from the expression of blaCTX-M-15 genes carried by plasmids, which are disseminating worldwide in hospital settings and have also been observed in healthy children of Peru. Multilocus sequence typing showed a diverse pool of E. coli strains carrying this resistance that were not always host species-specific, suggesting sharing of strains between species or infection from a common source. This study shows widespread ESBL resistance in wild and domestic animals, supporting animal communities as a potential source of resistance. Future work is needed to elucidate the role of bats in the dissemination of antibiotic-resistant strains of public health importance and to understand the origin of the observed resistance.