microRNA Expression and Its Association With Disability and Brain Atrophy in Multiple Sclerosis Patients Treated With Glatiramer Acetate.

Background: MicroRNAs are small non-coding RNA that regulate gene expression at a post-transcriptional level affecting several cellular processes including inflammation, neurodegeneration and remyelination. Different patterns of miRNAs expression have been demonstrated in multiple sclerosis compared to controls, as well as in different courses of the disease. For these reason they have been postulated as promising biomarkers candidates in multiple sclerosis. Objective: to correlate serum microRNAs profile expression with disability, cognitive functioning and brain volume in patients with remitting-relapsing multiple sclerosis. Methods: cross-sectional study in relapsing-remitting multiple sclerosis patients treated with glatiramer acetate. Disability was measured with Expanded Disability Status Scale (EDSS) and cognitive function was studied with Symbol Digit Modalities Test (SDMT). Brain volume was analyzed with automatic software NeuroQuant®. Results: We found an association between miR.146a.5p (rs:0.434, p=0.03) and miR.9.5p (rs:0.516, p=0.028) with EDSS; and miR-146a.5p (rs:-0.476, p=0.016) and miR-126.3p (rs:-0.528, p=0.007) with SDMT. Regarding to the brain volume, miR.9.5p correlated with thalamus (rs:-0.545, p=0.036); miR.200c.3p with pallidum (rs:-0.68, p=0.002) and cerebellum (rs:-0.472, p=0.048); miR-138.5p with amygdala (rs:0.73, p=0.016) and pallidum (rs:0.64, p=0.048); and miR-223.3p with caudate (rs:0.46, p=0.04). Conclusions: These data support the hypothesis of microRNA as potential biomarkers in this disease. More studies are needed to validate these results and to better understand the role of microRNAs in the pathogenesis, monitoring and therapeutic response of multiple sclerosis.

High-Efficacy Disease-Modifying Therapies in People with Relapsing-Remitting Multiple Sclerosis: The Role of Risk Attitude in Treatment Decisions.

BACKGROUND: Risk attitude is defined as the willingness to tolerate risk to achieve a greater expected return. Limited information is available on how relapsing-remitting multiple sclerosis people's perceptions about disease trajectory and risk attitude may influence treatment choices. METHODS: A non-interventional study applying principles of behavioral economics was conducted to assess willingness to receive unwarranted high-efficacy disease-modifying therapy (DMT) according to best-practice guidelines. People with relapsing-remitting multiple sclerosis (PwRRMS) according to 2010 McDonald criteria completed a survey on symptom severity, risk preferences, and management of simulated case scenarios mimicking the current treatment landscape. PwRRMS's choice for high-efficacy agents was established as the participant's selection of monoclonal antibodies for case scenarios with at least 2 years of clinical and radiological stability. RESULTS: A total of 211 PwRRMS were studied (mean age 39.1 ± 9.5 years, 70.1% female, mean Expanded Disability Status Scale score 1.8 ± 1.1). Almost 50% (n = 96) opted for a high-efficacy DMT despite the lack of evidence of disease activity. Younger age and risk-seeking behavior were associated with an increased likelihood of selecting unwarranted high-efficacy DMT [odds ratio (OR) 2.00, 95% confidence interval (CI) 1.02-3.93, p = 0.043, and OR 2.17, 95% CI 1.09-4.30, p = 0.027, respectively]. Clinical characteristics or subjective perception of symptom severity had no influence on participants' treatment choices. CONCLUSION: Identifying PwRRMS with risk-seeking behavior would be crucial to implementing specific educational strategies to manage information on disease prognosis, treatment expectations, and safety risk knowledge.

Three-Year Effectiveness of Dimethyl Fumarate in Multiple Sclerosis: A Prospective Multicenter Real-World Study.

BACKGROUND: Dimethyl fumarate (DMF) has demonstrated efficacy in phase III studies. However, real-world data are still limited. OBJECTIVE: The objective of this study was to describe the profile of patients who receive DMF and to assess the effectiveness of DMF regarding relapses, disability progression, magnetic resonance imaging activity, and NEDA (No Evidence Disease Activity)-3 status in a Spanish population in a real-world setting. METHODS: We conducted a multicenter prospective study of patients who started DMF between 2014 and 2019 in Spain. Three subgroups were considered: naïve, switch to DMF because of inefficacy, and switch to DMF because of adverse effects. The effects of DMF on clinical and radiological measures were evaluated. RESULTS: Among 886 patients, 25.3% were naïve, 28.8% switched because of adverse effects, and 45.9% because of inefficacy. Median follow-up was 38.9 (interquartile range 22.6-41.8) months. Annualized relapse rates were 0.15, 0.10, and 0.10 at 12, 24, and 36 months respectively, and 77.7% of patients were relapse free at month 42. At 12, 24, and 42 months, 96.1%, 87.4%, and 79.7% of patients were progression free, respectively. The number of T1 gadolinium-enhancement (T1Gd+) lesions was 0.19, 0.14, and 0.18 at 12, 24, and 36 months. NEDA-3 status at month 42 was maintained by 49.8% of patients. Relapsing was associated with higher annualized relapse rates the year before (hazard ratio 1.34, p < 0.001) and to the inefficacy switch vs naïve group (hazard ratio 1.76, p = 0.003). A higher baseline Expanded Disability Status Scale score was associated with disability progression (hazard ratio 1.15, p = 0.003) and more T1Gd+ lesions (hazard ratio 1.07, p < 0.001) with radiological progression. A higher baseline Expanded Disability Status Scale score, a larger number of T1Gd+ lesions, and a switch because of inefficacy (vs adverse events) were all risk factors for losing NEDA-3 status. DMF was discontinued in 29.9% of patients, in 13.5% because of inefficacy. CONCLUSIONS: Our findings confirm the sustained effectiveness of DMF on the clinical and radiological activity of multiple sclerosis in a real-world setting, both in naïve patients and in those switching from other multiple sclerosis therapies.

Tolerability and safety of dimethyl fumarate in relapsing multiple sclerosis: a prospective observational multicenter study in a real-life Spanish population.

BACKGROUND: Dimethyl fumarate (DMF) tolerability and safety in multiple sclerosis (MS) has been analyzed in randomized clinical trials. Real-life studies are needed to assess possible harms of this therapy in a wider MS population. OBJECTIVE: To evaluate DMF tolerability, safety and persistence in MS in a real-world setting. METHODS: We conducted a multicenter prospective study of patients who started DMF, attended in 16 public hospitals of Spain. A specific database was elaborated to collect data on most frequent adverse events (AE). Regression models were used to analyze the effect of demographic and clinical characteristics on risk of AEs and DMF discontinuation. RESULTS: We collected data of 886 patients (2681 patients/years-exposition) with median 39.5 (IQR 23, 51.5) months on DMF exposure; 25.3% were treatment naïve and 74.7% switched to DMF from other disease-modifying therapies. DMF was discontinued in 29.9% of patients, in 13.2% due to AEs and in 13.5% to inefficacy. AEs were experienced by 71.2%, being flushing the most frequent (44.1%), 5.4% developed grade III lymphopenia, without cases of grade IV. Females showed a higher risk of flushing and gastroenteric symptoms (OR 1.49, p = 0.011; OR 1.69, p = 0.001, respectively); lymphopenia was associated with older age (OR 1.04, p < 0.001), and a higher EDSS with lymphopenia (OR 1.10, p = 0.035) and DMF withdrawal (HR 1.43, p = 0.012). No safety problems were reported. CONCLUSIONS: Our findings confirm good tolerability and safety of DMF in real-world setting and suggest that women have an increased risk of AEs and higher baseline disability involves greater risk of drug discontinuation.

New Algorithms Improving PML Risk Stratification in MS Patients Treated With Natalizumab.

Overview: We assessed the role of age and disease activity as new factors contributing to establish the risk of progressive multifocal leucoencephalopathy in multiple sclerosis patients treated with natalizumab in 36 University Hospitals in Europe. We performed the study in 1,307 multiple sclerosis patients (70.8% anti-John Cunninghan virus positive antibodies) treated with natalizumab for a median time of 3.28 years. Epidemiological, clinical, and laboratory variables were collected. Lipid-specific IgM oligoclonal band status was available in 277 patients. Factors associated with progressive multifocal leucoencephalopathy onset were explored by uni- and multivariate logistic regression. Results: Thirty-five patients developed progressive multifocal leucoencephalopathy. The multivariate analysis identified anti-John Cunninghan virus antibody indices and relapse rate as the best predictors for the onset of this serious opportunistic infection in the whole cohort. They allowed to stratify progressive multifocal leucoencephalopathy risk before natalizumab initiation in individual patients [area under the curve (AUC) = 0.85]. The risk ranged from <1/3,300 in patients with anti-John Cunninghan virus antibody indices <0.9 and relapse rate >0.5, to 1/50 in the opposite case. In patients with lipid-specific IgM oligoclonal bands assessment, age at natalizumab onset, anti-John Cunninghan virus antibody indices, and lipid-specific IgM oligoclonal band status predicted progressive multifocal leucoencephalopathy risk (AUC = 0.92). The absence of lipid-specific IgM oligoclonal bands was the best individual predictor (OR = 40.94). The individual risk ranged from <1/10,000 in patients younger than 45 years at natalizumab initiation, who showed anti John Cunningham virus antibody indices <0.9 and lipid-specific IgM oligoclonal bands to 1/33 in the opposite case. Conclusions: In a perspective of personalized medicine, disease activity, anti-lipid specific IgM oligoclonal bands, anti Jonh Cunninghan virus antibody levels, and age can help tailor natalizumab therapy in multiple sclerosis patients, as predictors of progressive multifocal leucoencephalopathy.

Effects of hippotherapy in multiple sclerosis: pilot study on quality of life, spasticity, gait, pelvic floor, depression and fatigue. / Efecto de la hipoterapia en esclerosis múltiple: estudio piloto en calidad de vida, espasticidad, marcha, suelo pélvico, depresión y fatiga.

INTRODUCTION AND OBJECTIVE: Hippotherapy is being used as a promising method in the physical treatment of multiple sclerosis (MS). MATERIAL AND METHOD: Comparative open clinical pre-post study into hippotherapy intervention during a 6-month period in patients with MS (n=6). Not randomised and with control group (n=4). The study was performed by MHG Foundation. RESULTS: A statistically significant improvement was observed in the therapy group in: spasticity pre-post measured by the modified Ashworth scale (P=.01). Statistically significant improvement in fatigue impact (P<.0001) measured with FIS; in general, perception of heath outcome in urinary quality of life scale KHQ (P=.033), and in subscales 2, 3 and 4 of MSQOL-54 (P=.011). Control group showed no improvement in any scale. CONCLUSIONS: This study reinforces current literature that supports hippotherapy as an adequate intervention for MS patients. Further studies with more participants, control groups and blinded research would be logical steps for future research in this field.

Anti-JC virus seroprevalence in a Spanish multiple sclerosis cohort: JC virus seroprevalence in Spain.

OBJECTIVE: To estimate the seroprevalence of anti-JCV antibodies, seroconverting rates and evolution of antibody levels in a multiple sclerosis (MS) Spanish cohort. METHODS: Multicenter, retrospective cross-sectional and longitudinal study. The JCV seroprevalence was analyzed in 711 MS patients by using 1st (STRATIFY-1) and 2nd generation (STRATIFY-2) two-step ELISA over 2.65 (±0.97) years. Seroconversion rate was obtained over 2 samples from 314 patients, and index stability from 301 patients with 3 or more samples available. The effect of each ELISA generation, demographics, clinical characteristics and therapy on seroprevalence was assessed by logistic regression. RESULTS: The overall anti-JCV seroprevalence was 55.3% (51.6-58.9), similar across regions (p=0.073). It increased with age (p<0.000) and when STRATIFY-2 was used (60.5%, p=0.001). Neither sex nor immunosuppressive therapy had any influence. Yearly seroconversion rate was 7% (considering only STRATIFY-2). Serological changes were observed in 24/301 patients, 5.7% initially seropositive reverted to seronegative and 7% initially seronegative changed to seropositive and again to seronegative, all these cases had initial index values around the assay's cut-off. CONCLUSIONS: JCV seroprevalence in Spanish MS patients was similar to that reported in other European populations. Changes in serostatus are not infrequent and should be considered in clinical decisions.

[Lymphocytic hypophysitis and hypertrophic pachymeningitis: description of a possible case associated to IgG4 pathologies]. / Hipofisitis linfocitaria y paquimeningitis hipertrófica: descripción de un posible caso asociado a las patologías IgG4.

INTRODUCTION: Pathologies related to lymphocyte infiltration and inflammatory cells are classified, according to their topography, into idiopathic orbital pathology, idiopathic hypertrophic pachymeningitis, Tolosa-Hunt syndrome and lymphocytic hypophysitis. Here we review the case of a female patient who began with lymphocytic hypophysitis eight years ago and has since presented several episodes of hypertrophic pachymeningitis in a variety of locations. CASE REPORT: Our study involves a 55-year-old female, being monitored owing to a two-month history of headaches, who was admitted to hospital as the result of a deterioration of her clinical signs and symptoms with paralysis of the whole right-side third cranial nerve, watery eyes and rhinorrhea. A magnetic resonance brain scan revealed the presence of a sellar lesion consistent with lymphocytic hypophysitis. Treatment was established with corticoids with an improvement at first, but two years later the patient's clinical features worsened, with headaches and periocular paraesthesias on the right-hand side. Another MRI scan was performed and several extra-axial lesions were observed, the results of the other studies being normal. Idiopathic hypertrophic pachymeningitis was therefore diagnosed and treatment with corticoids was started again. In the ensuing follow-up the patient presented new lesions in different locations and poor pain control, and so immunomodulator treatment was thus added. Given the association between lymphocytic hypophysitis and hypertrophic pachymeningitis, the study was completed with determination of the IgG4 in serum, which was negative. CONCLUSIONS: The association of lymphocytic hypophysitis and hypertrophic pachymeningitis with IgG4-related pathologies have recently been reported. Although the diagnosis has not been confirmed in our patient, this relationship must be taken into account in these idiopathic cases and, above all, if they are associated with other systemic manifestations.

TITLE: Hipofisitis linfocitaria y paquimeningitis hipertrofica: descripcion de un posible caso asociado a las patologias IgG4.Introduccion. Las patologias relacionadas con la infiltracion de linfocitos y celulas inflamatorias se clasifican, segun su topografia, en patologia orbitaria idiopatica, paquimeningitis hipertrofica idiopatica, sindrome de Tolosa-Hunt e hipofisitis linfocitaria. Presentamos a una paciente que comenzo con una hipofisitis linfocitaria hace ocho años y ha presentado varios episodios de paquimeningitis hipertrofica variables en su localizacion. Caso clinico. Mujer de 55 años, en seguimiento por cefalea de dos meses de evolucion, que ingreso por empeoramiento clinico con paralisis del III par derecho completo, lagrimeo y rinorrea. Se realizo una resonancia magnetica cerebral que demostro la presencia de una lesion sellar compatible con hipofisitis linfocitaria. Se inicio tratamiento con corticoides con mejoria inicial, pero, tras dos años, la paciente presento empeoramiento clinico con cefalea y parestesias perioculares derechas. Se repitio la resonancia, donde se observaron varias lesiones extraaxiales, siendo el resto de estudios normales, por lo que se diagnostico paquimeningitis hipertrofica idiopatica y se inicio tratamiento de nuevo con corticoides. En el seguimiento posterior, la paciente presento nuevas lesiones en diferentes localizaciones y mal control algico, por lo que se añadio tratamiento inmunomodulador. Ante la asociacion de hipofisitis linfocitaria y paquimeningitis hipertrofica, se completo el estudio con determinacion de la IgG4 en el suero, que resulto negativa. Conclusiones. La asociacion de hipofisitis linfocitaria y paquimeningitis hipertrofica con las patologias relacionadas con la IgG4 se ha descrito recientemente. A pesar de que en nuestra paciente no se ha confirmado el diagnostico, se debe considerar esta relacion en aquellos casos idiopaticos y, sobre todo, si se asocian otras manifestaciones sistemicas.

Primary continuous unilateral headaches: a nosologic model for hemicrania continua.

BACKGROUND: Hemicrania continua was originally described as a strictly unilateral, continuous headache with an absolute response to indomethacin. Recognition of an increasing number of patients with the same clinical features except for a lack of response to indomethacin has generated controversy about whether the responsive/non-responsive phenotypes belong to the same disorder. DISCUSSION: We suggest that the non-responsive phenotype should be differentiated from the original concept of hemicrania continua, because it probably indicates a separate type of headache of undetermined nature, i.e. hemicrania incerta. However, differentiating hemicrania incerta from hemicrania continua does not imply that the two headaches are unrelated. Both hemicranias may outline a continuum, giving rise to a broader diagnostic field. CONCLUSION: There seems to be a syndrome of 'primary continuous unilateral headache' with at least two distinctive categories: hemicrania continua and hemicrania incerta, which are differentiated by their respective response to indomethacin. This division means plurality but adds precision, and allows a clear-cut diagnosis of some controversial cases.

Bilateral widespread mechanical pain hypersensitivity as sign of central sensitization in patients with cluster headache.

OBJECTIVE: To investigate bilateral widespread pressure pain hyperalgesia in deep tissues over symptomatic (trigemino-cervical) and nonsymptomatic (distant pain-free) regions in patients with cluster headache (CH). BACKGROUND: Central sensitization is claimed to play a relevant role in CH. No study has previously searched for widespread pressure hyperalgesia in deep tissues over both symptomatic (trigemino-cervical) and nonsymptomatic (distant pain-free) regions in patients with CH. METHODS: Sixteen men (mean age: 43 ± 11 years) with CH in a remission phase and 16 matched controls were recruited. Pressure pain thresholds (PPTs) were bilaterally measured over the supra-orbital (V1), infra-orbital (V2), mental (V3), median (C5), radial (C6), and ulnar (C7) nerves, C5-C6 zygapophyseal joint, mastoid process, and tibialis anterior muscle by an assessor blinded to the subjects' condition. RESULTS: The results showed that PPT levels were significantly decreased bilaterally in patients with CH as compared with healthy controls (all sites, P < .001). A greater degree of sensitization over the mastoid process (P < .001) and a lower degree of sensitization over the tibialis anterior muscle (P < .01) was found. CONCLUSIONS: Our findings revealed bilateral widespread pressure pain hypersensitivity in patients with CH confirming the presence of central sensitization mechanisms in this headache condition.