In-Depth Characterization of Somatic and Orofacial Sensitive Dysfunctions and Interfering-Symptoms in a Relapsing-Remitting Experimental Autoimmune Encephalomyelitis Mouse Model

Among the many symptoms (motor, sensory, and cognitive) associated with multiple sclerosis (MS), chronic pain is a common disabling condition. In particular, neuropathic pain symptoms are very prevalent and debilitating, even in early stages of the disease. Unfortunately, chronic pain still lacks efficient therapeutic agents. Progress is needed (i) clinically by better characterizing pain symptoms in MS and understanding the underlying mechanisms, and (ii) preclinically by developing a more closely dedicated model to identify new therapeutic targets and evaluate new drugs. In this setting, new variants of experimental autoimmune encephalomyelitis (EAE) are currently developed in mice to exhibit less severe motor impairments, thereby avoiding confounding factors in assessing pain behaviors over the disease course. Among these, the optimized relapsing-remitting EAE (QuilA-EAE) mouse model, induced using myelin oligodendrocyte glycoprotein peptide fragment (35–55), pertussis toxin, and quillaja bark saponin, seems very promising. Our study sought (i) to better define sensitive dysfunctions and (ii) to extend behavioral characterization to interfering symptoms often associated with pain during MS, such as mood disturbances, fatigue, and cognitive impairment, in this optimized QuilA-EAE model. We made an in-depth characterization of this optimized QuilA-EAE model, describing for the first time somatic thermal hyperalgesia associated with mechanical and cold allodynia. Evaluation of orofacial pain sensitivity showed no mechanical or thermal allodynia. Detailed evaluation of motor behaviors highlighted slight defects in fine motor coordination in the QuilA-EAE mice but without impact on pain evaluation. Finally, no anxiety-related or cognitive impairment was observed during the peak of sensitive symptoms. Pharmacologically, as previously described, we found that pregabalin, a treatment commonly used in neuropathic pain patients, induced an analgesic effect on mechanical allodynia. In addition, we showed an anti-hyperalgesic thermal effect on this model. Our results demonstrate that this QuilA-EAE model is clearly of interest for studying pain symptom development and so could be used to identify and evaluate new therapeutic targets. The presence of interfering symptoms still needs to be further characterized.

Single-nucleus RNA-seq of normal-appearing brain regions in relapsing-remitting vs. secondary progressive multiple sclerosis

Multiple sclerosis (MS) is an immune-mediated demyelinating disease that alters central nervous system (CNS) functions. Relapsing-remitting MS (RRMS) is the most common form, which can transform into secondary-progressive MS (SPMS) that is associated with progressive neurodegeneration. Single-nucleus RNA sequencing (snRNA-seq) of MS lesions identified disease-related transcriptomic alterations; however, their relationship to non-lesioned MS brain regions has not been reported and which could identify prodromal or other disease susceptibility signatures. Here, snRNA-seq was used to generate high-quality RRMS vs. SPMS datasets of 33,197 nuclei from 8 normal-appearing MS brains, which revealed divergent cell type-specific changes. Notably, SPMS brains downregulated astrocytic sphingosine kinases (SPHK1/2), the enzymes required to phosphorylate and activate the MS drug, fingolimod. This reduction was modeled with astrocyte-specific Sphk1/2 null mice in which fingolimod lost activity, supporting functionality of observed transcriptomic changes. These data provide an initial resource for studies of single cells from non-lesioned RRMS and SPMS brains.

Reliability of televisits for patients with mild relapsing–remitting multiple sclerosis in the COVID-19 era

Background Evidence of the cost-effectiveness of telemedicine (TM) for the management of Multiple Sclerosis (MS) has been provided recently. However, some doubts persist about the accuracy of neurological examinations performed remotely. Objectives This study investigated the reliability of neurological evaluations performed through TM in mild MS patients as compared with standard in-person visits. Methods In total, 76 patients with relapsing–remitting MS and Expanded Disability Status Scale (EDSS) ≤ 3.5 were consecutively recruited. Of them, 40 patients (52.6%) accepted to undergo both in-person and TM evaluations with independent examiners within 48 h. We alternatively asked patients to assure or not the presence of a caregiver during TM visits. A satisfaction questionnaire was administered to all participants. Results The inter-rater agreement attributed by two independent neurologists during TM visit was high (κ > 0.80) for EDSS and Functional Systems (FS) scores. Moderate agreement between TM and in-person evaluations emerged for pyramidal (κ = 0.57; p < 0.001), brainstem (κ = 0.57; p < 0.001), bowel and bladder (κ = 0.54; p < 0.001) and sensory (κ = 0.51; p < 0.001) FS scores, higher in patients providing the support of a caregiver. A good reliability was reported for EDSS scores computed during remote and in-person visits (ICC = 0.83; 95% CI 0.70–0.91; p < 0.001). Conclusions Despite the complexity of neurological examination, TM could be useful in monitoring MS patients with low disability.

Physiotherapists perceived role in managing anxiety in patients with relapsing-remitting multiple sclerosis: a mixed-methods study

Background Anxiety is common for people with Multiple Sclerosis (PwMS) and is higher in those with relapsing-remitting MS (RRMS) and in community-based samples. Anxiety can impact self-efficacy, pain, fatigue, engagement in physical activity and treatment adherence, all of which influence the rehabilitation process. Little is known about how physiotherapists manage anxiety in PwMS and the challenges associated with anxiety throughout the rehabilitation process, in community and outpatient settings. Methods A mixed-methods design, combining a cross-sectional survey and semi-structured interviews with UK-physiotherapists, was used to answer the research question. To inform the qualitative study, a cross-sectional survey collected data from physiotherapists working in neurology to understand the impact and management of anxiety in people with MS (PwMS) during rehabilitation. Analysis used descriptive statistics and the findings formed the interview guide. Semi-structured interviews with specialist physiotherapists explored barriers and facilitators to managing anxiety in PwMS in community and outpatient settings, identified perceived physiotherapy training needs and offered suggestions to develop physiotherapy research and practice. Themes were derived inductively. Results The survey suggested how PwMS present with anxiety, its impact during rehabilitation, physiotherapy management practices, and physiotherapist skills and training needs. Five semi-structured interviews with specialist physiotherapists expanded on the survey findings and identified five main themes: Understanding the MS journey, modifying assessment and treatment, anxiety management toolbox, lagging behind Musculoskeletal Physiotherapy, and gaining knowledge and skills. Conclusion Physiotherapists encounter anxiety in PwMS in community and outpatient rehabilitation and perceive they have a role in managing it as it presents. Facilitators included communication, listening skills and opportunities to develop strong therapeutic relationships. Poor training and support, lack of clinical guidelines and limited research evidence were considered barriers. Clinically relevant learning opportunities, interprofessional working, and greater support through clinical supervision is recommended to better develop physiotherapy practice.

Thrombotic Thrombocytopenic Purpura in Interferon Beta-1a-Treated Patient Diagnosed with Relapsing-Remitting Multiple Sclerosis: A Case Report

Background: Secondary thrombotic thrombocytopenic purpura (TTP) due to interferon beta-1a intramuscular (im) treatment is an uncommon adverse effect with only a few cases in multiple sclerosis patients reported worldwide. TTP together with haemolytic uremic syndrome (HUS) are classic forms of thrombotic microangiopathy, characterized by small-vessel platelet micro-thrombi that manifest clinically in a similar manner. Most common signs and symptoms include bruises and ecchymosis, neurologic symptoms and renal impairment. Interferon beta-1a represents one of the first-line therapies for relapsing-remitting multiple sclerosis due to its accessibility and efficacy. Case presentation: A 36-year-old woman who was previously diagnosed with relapsing-remitting multiple sclerosis had received weekly intramuscular injections with beta-interferon-1a (Avonex 30 mcg). After 9 months of treatment, she presented bruises and ecchymosis on her limbs and torso, epistaxis, gingival bleeding aggravated within 48 h and a persistent headache that was non-responsive to common analgesics. Haematology tests revealed typical results for thrombotic microangiopathy, including severe thrombocytopenia (4000/mm3) and microangiopathic haemolytic anaemia with frequent schistocytes on the peripheral blood smear. Once the beta-interferon administration was ceased and upon the initiation of methylprednisolone, the symptoms remitted. Conclusions: In this case study, we portrayed the particular association between the remission phase of multiple sclerosis and the violent onset of interferon-induced thrombotic thrombocytopenic purpura.

Multipl Sklerozlu Hastalarda Güncel Diyet Yaklaşımları

Multipl Skleroz (MS); nöroinflamatuvar, demiyelinize, otoimmün merkezi sinir sistemi hastalığıdır. MS ile ilişkili hastalık süreci; inflamasyon, sinir liflerini koruyan ve çevreleyen membran yağ bileşeni, miyelin yıkımı ve/veya hasarı ile sonuçlanmaktadır. Beslenme alışkanlıklarının ve yaşam tarzının MS seyrini etkileyip etkilemediği sorusu hala tartışma konusudur. Diyet faktörleri ve bireyin yaşam tarzı alışkanlıkları, hem atak ve iyileşmelerle giden MS (Relapsing-remitting) hem de birincil ilerleyici MS’de (primer progresif) hastalığın inflamatuvar durumunu modüle ederek semptomları iyileştirebilir veya şiddetlendirebilir. Bu durum hücresel düzeyde hem metabolik hem de inflamatuvar yolları ve kommensal bağırsak mikrobiyatasının bileşimini kontrol ederek oluşmaktadır. Sebzeler, meyveler, kurubaklagiller, balık, prebiyotikler ve probiyotiklerden zengin düşük enerjili diyetlerin ve düzenli yapılan egzersizin; nükleer reseptörler ve enzimler üzerinde olumlu etki oluşturduğu, oksidatif metabolizmayı ve proinflamatuvar molekülleri düzenlediği ve sağlıklı simbiyotik bağırsak mikrobiyatasının sürdürülmesi ve restore edilmesine katkı sağladığı gösterilmiştir. Özellikle Akdeniz tipi beslenme modeli gibi diyet müdahalelerinin; bağışıklık düzenleyici ilaçların olası yan etkilerini ve kronik yorgunluk sendromunun semptomlarını hafifletmede, semptomların nüksetmesini ve hastalığın ilerlemesini önlemede yarar sağladığı bildirilmektedir. MS hastalarının diyetlerindeki sağlıklı beslenmeye yönelik değişiklikler hastaların hem yaşam kalitesini artırmakta hem de fiziksel ve mental iyileşme sağlamaktadır. Bu derlemede, farklı diyet modellerinin MS üzerindeki etkisinin değerlendirilmesi amaçlanmıştır.

Long-term real-world effectiveness and safety of fingolimod over 5 years in Germany

Objective To evaluate the 5-year real-world benefit–risk profile of fingolimod in patients with relapsing–remitting MS (RRMS) in Germany. Methods Post-Authorization Non-interventional German sAfety study of GilEnyA (PANGAEA) is a non-interventional real-world study to prospectively assess the effectiveness and safety of fingolimod in routine clinical practice in Germany. The follow-up period comprised 5 years. Patients were included if they had been diagnosed with RRMS and had been prescribed fingolimod as part of clinical routine. There were no exclusion criteria except the contraindications for fingolimod as defined in the European label. The effectiveness and safety analysis set comprised 4032 and 4067 RRMS patients, respectively. Results At the time of the 5-year follow-up of PANGAEA, 66.57% of patients still continued fingolimod therapy. Annualized relapse rates decreased from baseline 1.5 ± 1.15 to 0.42 ± 0.734 at year 1 and 0.21 ± 0.483 at year 5, and the disability status remained stable, as demonstrated by the Expanded Disability Status Scale mean change from baseline (0.1 ± 2.51), the decrease of the Multiple Sclerosis Severity Score from 5.1 ± 2.59 at baseline to 3.9 ± 2.31 at the 60-months follow-up, and the percentage of patients with ‘no change’ in the Clinical Global Impression scale at the 60-months follow-up (78.11%). Adverse events (AE) occurring in 75.04% of patients were in line with the known safety profile of fingolimod and were mostly non-serious AE (33.62%) and non-serious adverse drug reactions (50.59%; serious AE 4.98%; serious ADR 10.82%). Conclusions PANGAEA demonstrated the sustained beneficial effectiveness and safety of fingolimod in the long-term real-world treatment of patients with RRMS.