Progressive Forms Of Multiple Sclerosis Research Articles

037 Treating secondary progressive multiple sclerosis in the UK: use of guidelines and stopping criteria

BackgroundAs new treatment approaches emerge for progressive forms of multiple sclerosis (MS), it is important to understand the factors underlying current practice.MethodsWe used a structured questionnaire to interview 59 healthcare professionals (HCPs) from geo- graphically-dispersed UK MS centres about current disease modifying therapy (DMT) management of patients with suspected/confirmed secondary progressive MS (SPMS).ResultsOf 43 HCPs (73%) who follow guidelines for DMT management of patients transitioning from relapsing-remitting multiple sclerosis (RRMS) to SPMS, most (n=37/43, 86%) use the NHS England (NHSE) algorithm; 7/43 (16%) use ABN guidance. Fifty-eight (98%) HCPs use DMTs to treat patients with RRMS whom they suspect may be transitioning to SPMS and 30 (51%) for (a minority of) patients with newly- diagnosed SPMS. Expanded Disability Status Scale (EDSS) 7.0 was the most frequently-reported criterion used for stopping DMTs (n=29, 49%), however, a variety of other criteria were used and a small majority of HCPs reported continuing DMTs beyond EDSS 7.0 in certain circumstances (most commonly recent relapse activity [n=32, 54%] or in younger patients [n=20, 34%]).ConclusionsAlthough most HCPs follow NHSE guidelines, a range of DMT stopping criteria are employed in clinical practice and treatment decisions may be based on individual patient circumstances.katherine.rhys@novartis.com

Current and Future Biomarkers in Multiple Sclerosis.

Multiple sclerosis (MS) is a debilitating autoimmune disorder. Currently, there is a lack of effective treatment for the progressive form of MS, partly due to insensitive readout for neurodegeneration. The recent development of sensitive assays for neurofilament light chain (NfL) has made it a potential new biomarker in predicting MS disease activity and progression, providing an additional readout in clinical trials. However, NfL is elevated in other neurodegenerative disorders besides MS, and, furthermore, it is also confounded by age, body mass index (BMI), and blood volume. Additionally, there is considerable overlap in the range of serum NfL (sNfL) levels compared to healthy controls. These confounders demonstrate the limitations of using solely NfL as a marker to monitor disease activity in MS patients. Other blood and cerebrospinal fluid (CSF) biomarkers of axonal damage, neuronal damage, glial dysfunction, demyelination, and inflammation have been studied as actionable biomarkers for MS and have provided insight into the pathology underlying the disease process of MS. However, these other biomarkers may be plagued with similar issues as NfL. Using biomarkers of a bioinformatic approach that includes cellular studies, micro-RNAs (miRNAs), extracellular vesicles (EVs), metabolomics, metabolites and the microbiome may prove to be useful in developing a more comprehensive panel that addresses the limitations of using a single biomarker. Therefore, more research with recent technological and statistical approaches is needed to identify novel and useful diagnostic and prognostic biomarker tools in MS.

Systematic Review and Meta-Analysis Comparing the Safety of Natalizumab, Ocrelizumab, and Alemtuzumab in Treating Relapsing–Remitting, Primary Progressive, and Secondary Progressive Multiple Sclerosis

Three monoclonal antibodies—natalizumab (NTZ), ocrelizumab (OCR), and alemtuzumab (ALM)—are the mainstays for the treatment of both relapsing and progressive forms of multiple sclerosis (MS). Here, their safety in patients with MS is analyzed and compared for rational use, especially during the COVID-19 pandemic. All clinical studies published between 2016 and 2020 with the primary outcome of the occurrence of adverse events (AEs) with the use of NTZ, OCR, and ALM in the treatment of MS were systematically searched in the PubMed database. In this review, the percentage of patients reporting AEs was calculated and compared. The most common AEs associated with the use of NTZ, OCR, and ALM were infection and infestation. The percentage of patients reporting urinary tract infection, upper respiratory tract infection, and herpes was 16% using natalizumab, 7% using natalizumab and ocrelizumab, and 2% with ocrelizumab, respectively. The most common AEs, such as rashes, pyrexia, and influenza, were reported with ocrelizumab and alemtuzumab. Additionally, alemtuzumab was associated with immune thrombocytopenia (2%), respiratory infections (7%), and thyroid dysfunction (43%). All these data outcomes show that of the three monoclonal antibodies, natalizumab and ocrelizumab were associated with a reduced incidence of adverse events, making them a safer choice for MS.

Effectiveness of Anti-Cluster of Differentiation 20 as a Disease-Modifying Therapy in Multiple Sclerosis Across Its Different Phenotypes at the University Hospital of Caen.

BackgroundMultiple sclerosis is a chronic, demyelinating disorder occurring primarily as two main forms of relapsing-remitting multiple sclerosis (RRMS) found predominantly in women, and primary progressive multiple sclerosis (PPMS) occurring predominantly in men. In this retrospective single-center study, we aimed to explore the effects of anti-cluster of differentiation (CD)20 treatment for both relapsing-remitting and primary progressive forms of multiple sclerosis (MS) in a population-based cohort treated at the university hospital. MethodologyThe diagnostic factors being assessed were forms of multiple sclerosis (MS), age at first relapse, whereas therapeutic factors were age at first disease-modifying therapy (DMT), age at starting anti-CD20, reason to switch to anti-CD20 and the duration of anti-CD20 treatment. Primary outcomes measured were number of relapses and progression in disability as measured by the Expanded Disability Status Scale, while secondary outcomes measures being assessed number of cerebral lesions on MRI and level of IgG at the beginning and end of the 12-month treatment.ResultsTreatment with anti-CD20 demonstrated a reduction in number of relapses 12 months after treatment, no change in the progression of disability in RRMS type, but an increase in PPMS type. No change was observed in cerebral MRI lesions at the end of treatment after 12 months. A statistically significant reduction in serum IgG value was observed after 12 months from the start of treatment, where only one out of 26 (3.8%) patients developed hypogammaglobulinemia with IgG less than 6 g/L but none developed hypogammaglobulinemia of less than 5 g/L.ConclusionAnti-CD20 antibodies as disease-modifying therapy can profoundly impact the course and progression of MS in both its forms if utilized at an earlier stage in patients and therefore greatly improve the quality of life in patients living with multiple sclerosis.

DNA methylation changes in glial cells of the normal-appearing white matter in Multiple Sclerosis patients

ABSTRACT Multiple Sclerosis (MS), the leading cause of non-traumatic neurological disability in young adults, is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS). Due to the poor accessibility to the target organ, CNS-confined processes underpinning the later progressive form of MS remain elusive thereby limiting treatment options. We aimed to examine DNA methylation, a stable epigenetic mark of genome activity, in glial cells to capture relevant molecular changes underlying MS neuropathology. We profiled DNA methylation in nuclei of non-neuronal cells, isolated from 38 post-mortem normal-appearing white matter (NAWM) specimens of MS patients (n = 8) in comparison to white matter of control individuals (n = 14), using Infinium MethylationEPIC BeadChip. We identified 1,226 significant (genome-wide adjusted P-value < 0.05) differentially methylated positions (DMPs) between MS patients and controls. Functional annotation of the altered DMP-genes uncovered alterations of processes related to cellular motility, cytoskeleton dynamics, metabolic processes, synaptic support, neuroinflammation and signaling, such as Wnt and TGF-β pathways. A fraction of the affected genes displayed transcriptional differences in the brain of MS patients, as reported by publically available transcriptomic data. Cell type-restricted annotation of DMP-genes attributed alterations of cytoskeleton rearrangement and extracellular matrix remodelling to all glial cell types, while some processes, including ion transport, Wnt/TGF-β signaling and immune processes were more specifically linked to oligodendrocytes, astrocytes and microglial cells, respectively. Our findings strongly suggest that NAWM glial cells are highly altered, even in the absence of lesional insult, collectively exhibiting a multicellular reaction in response to diffuse inflammation.

Cognitive Impairment in Secondary Progressive Multiple Sclerosis: Effect of Disease Duration, Age, and Progressive Phenotype.

Background: Cognitive deficits are common in multiple sclerosis (MS) and affect patients at all stages of the disease, regardless of phenotype. Aims: This literature review focuses the cognitive deficits observed in secondary progressive MS (SPMS). It is mainly based on studies that compared the frequency and main characteristics of cognitive deficits in SPMS with other phenotypes. Methods: A bibliographic search was carried out using the PubMed database with the following keywords: multiple sclerosis, secondary-progressive, cognition. Results: Thirteen studies were initially selected that were published in English, reporting the neuropsychological data of a sample of at least 30 patients with SPMS, comparing them with patients with other phenotypes. Studies suggest that there is an association between the duration of the disease and the frequency and extent of the cognitive disorders. Studies also showed that the SP form is associated with an increased frequency of cognitive impairment and with an increased severity as compared to relapsing-remitting MS (RRMS). Compared to RRMS, progressive forms of MS are associated with more severe impairment in certain cognitive areas, such as episodic verbal memory, information processing speed, working memory, or verbal fluency. Two studies showed that cognitive performances decline overtime in SPMS. Conclusion: Cognitive disorders are more frequent and more severe in the SP form than in relapsing course of MS. The profile of cognitive impairment encountered in the SP form also appears to be different from those found in the other phenotypes.

Medical cannabis use in Canadians with multiple sclerosis

Background: The extent of medical cannabis use by people with multiple sclerosis (MS) in Canada has not been evaluated for more than a decade since recreational cannabis was legalized. Legalization provided an avenue for those to whom legal cannabis was previously inaccessible to access it as an alternative therapy. Our objective was to evaluate the prevalence of medical cannabis use by Canadians with MS, the reasons it is used, adverse effects, as well as the context surrounding how it is obtained and where users learned about it. Methods: An anonymous questionnaire was distributed to prospective participants through various channels. The questionnaire included questions about participant characteristics and quality of life, their MS, and their medical cannabis use. It also employed two validated patient-reported outcome measures, the PDDS and the MSQOL-54. Results: Completed questionnaires were submitted by 344 individuals. Among respondents, 215/344 (64.5%) reported having used medical cannabis at least once, and 180 (52.3%) reported still currently using it. Based on disease and quality of life data, we found that respondents with more severe or progressive forms of MS were more likely to have tried medical cannabis. Medical cannabis was used most by current and former users to treat sleep problems (84.2%), pain (80.0%), and spasticity (68.4%), while the most reported adverse effects were drowsiness (57.2%), feeling quiet/subdued (48.8%), and difficulty concentrating (28.4%). Most current and former users obtained their cannabis from a legal, reliable source (76.1%) and many (74%) learned about medical cannabis from someone other than a healthcare provider. Conclusions: This study showed that nearly two-thirds of survey respondents, comprised of Canadians living with MS, have tried medical cannabis at least once and that those with a greater disease burden were more likely to have tried it. Users reported that cannabis is moderately to highly effective in treating several symptoms and that adverse effects are not generally severe, nor are they the main factor driving medical cannabis cessation. Our results support the need for more research examining medical cannabis use in MS and for evidence-based resources to be publicly available for those exploring it as a potential therapy.

Colony-stimulating factor-1 receptor inhibition attenuates microgliosis and myelin loss but exacerbates neurodegeneration in the chronic cuprizone model.

Multiple sclerosis (MS), especially in its progressive phase, involves early axonal and neuronal damage resulting from a combination of inflammatory mediators, demyelination, and loss of trophic support. During progressive disease stages, a microenvironment is created within the central nervous system (CNS) favoring the arrival and retention of inflammatory cells. Active demyelination and neurodegeneration have also been linked to microglia (MG) and astrocyte (AST)-activation in early lesions. While reactive MG can damage tissue, exacerbate deleterious effects, and contribute to neurodegeneration, it should be noted that activated MG possess neuroprotective functions as well, including debris phagocytosis and growth factor secretion. The progressive form of MS can be modeled by the prolonged administration to cuprizone (CPZ) in adult mice, as CPZ induces highly reproducible demyelination of different brain regions through oligodendrocyte (OLG) apoptosis, accompanied by MG and AST activation and axonal damage. Therefore, our goal was to evaluate the effects of a reduction in microglial activation through orally administered brain-penetrant colony-stimulating factor-1 receptor (CSF-1R) inhibitor BLZ945 (BLZ) on neurodegeneration and its correlation with demyelination, astroglial activation, and behavior in a chronic CPZ-induced demyelination model. Our results show that BLZ treatment successfully reduced the microglial population and myelin loss. However, no correlation was found between myelin preservation and neurodegeneration, as axonal degeneration was more prominent upon BLZ treatment. Concomitantly, BLZ failed to significantly offset CPZ-induced astroglial activation and behavioral alterations. These results should be taken into account when proposing the modulation of microglial activation in the design of therapies relevant for demyelinating diseases. Cover Image for this issue: https://doi.org/10.1111/jnc.15394.

DICAM promotes TH17 lymphocyte trafficking across the blood-brain barrier during autoimmune neuroinflammation.

The migration of circulating leukocytes into the central nervous system (CNS) is a key driver of multiple sclerosis (MS) pathogenesis. The monoclonal antibody natalizumab proved that pharmaceutically obstructing this process is an effective therapeutic approach for treating relapsing-remitting MS (RRMS). Unfortunately, the clinical efficacy of natalizumab is somewhat offset by its incapacity to control the progressive forms of MS (PMS) and by life-threatening side effects in RRMS rising from the expression of its molecular target, very late antigen 4 (VLA4), on most immune cells and consequent impairment of CNS immunosurveillance. Here, we identified dual immunoglobulin domain containing cell adhesion molecule (DICAM) as a cell trafficking molecule preferentially expressed by T helper 17 (TH17)–polarized CD4+ T lymphocytes. We found that DICAM expression on circulating CD4+ T cells was increased in patients with active RRMS and PMS disease courses, and expression of DICAM ligands was increased on the blood-brain barrier endothelium upon inflammation and in MS lesions. Last, we demonstrated that pharmaceutically neutralizing DICAM reduced murine and human TH17 cell trafficking across the blood-brain barrier in vitro and in vivo, and alleviated disease symptoms in four distinct murine autoimmune encephalomyelitis models, including relapsing-remitting and progressive disease models. Collectively, our data highlight DICAM as a candidate therapeutic target to impede the migration of disease-inducing leukocytes into the CNS in both RRMS and PMS and suggest that blocking DICAM with a monoclonal antibody may be a promising therapeutic approach.

Charting a global research strategy for progressive MS—An international progressive MS Alliance proposal

Background: Progressive forms of multiple sclerosis (MS) affect more than 1 million individuals globally. Recent approvals of ocrelizumab for primary progressive MS and siponimod for active secondary progressive MS have opened the therapeutic door, though results from early trials of neuroprotective agents have been mixed. The recent introduction of the term ‘active’ secondary progressive MS into the therapeutic lexicon has introduced potential confusion to disease description and thereby clinical management. Objective: This paper reviews recent progress, highlights continued knowledge and proposes, on behalf of the International Progressive MS Alliance, a global research strategy for progressive MS. Methods: Literature searches of PubMed between 2015 and May, 2021 were conducted using the search terms “progressive multiple sclerosis”, “primary progressive multiple sclerosis”, “secondary progressive MS”. Proposed strategies were developed through a series of in-person and virtual meetings of the International Progressive MS Alliance Scientific Steering Committee. Results: Sustaining and accelerating progress will require greater understanding of underlying mechanisms, identification of potential therapeutic targets, biomarker discovery and validation, and conduct of clinical trials with improved trial design. Encouraging developments in symptomatic and rehabilitative interventions are starting to address ongoing challenges experienced by people with progressive MS. Conclusion: We need to manage these challenges and realise the opportunities in the context of a global research strategy, which will improve quality of life for people with progressive MS.

Understanding the role of the blood brain barrier and peripheral inflammation on behavior and pathology on ongoing confined cortical lesions

BackgroundInflammation in the Central Nervous System (CNS) is associated with blood brain barrier (BBB) breakdown during the early stages of Multiple Sclerosis (MS), indicating a facilitated entry of waves of inflammatory cells from the circulation to the CNS. In the progressive forms of MS, as the lesion becomes chronic, the inflammation remains trapped within the CNS compartment forming the slow evolving lesion, characterized by low inflammation and microglia activation at the lesions edges. The chronic expression of interleukin 1β (IL-1β) in the cortex induces BBB breakdown, demyelination, neurodegeneration, microglial/macrophage activation and impaired cognitive performance. The latter can be improved, as long as the BBB recovers and the lesion presents low inflammation. Here, we study the effects of peripheral inflammation on cortical central lesions after the restoration of the BBB, in order to elucidate the role of the peripheral inflammation on these lesions with intact BBB, as it occurs in the progressive forms of MS. Materials and methodsCortical lesions and peripheral inflammation were induced by the chronic expression of IL-1β using an adenovector. We performed histological, immunohistochemistry on brain tissue and behavioural analyses. ResultsThe effects of the chronic expression of IL-1β in the cortex resolved within 56 days. However, peripheral and sustained inflammation re-opened the BBB, allowing the reappearance of the neuroinflammatory processes within the cortical lesions, increased demyelination and neurodegeneration, and an increase of the behavioral symptoms, such as cognitive impairment and anxiety-like symptoms. ConclusionsThe early treatment of peripheral inflammatory processes should be considered in order to protect the brain from exacerbation of the ongoing neurodegenerative process.

Might Hydroxychloroquine Treat Primary Progressive Multiple Sclerosis

More-efficacious therapies for progressive forms of multiple sclerosis (MS) remain an unmet need. Hydroxychloroquine (HCQ) is an antimalarial drug that

REVISION OF MULTIPLE SCLEROSIS CASES ACCORDING TO NEW 2017 MCDONALD CRITERIA AMONG DIAGNOSED PATIENTS IN SULAIMANI CITY

Background &#x0D; Multiple sclerosis (MS) is a chronic, immune-mediated inflammatory disorder of the central nervous system. The diagnosis of Multiple sclerosis is challenging, owing to having a comprehensive list of differentials and mimickers.&#x0D; Objectives &#x0D; To determine the frequency of misdiagnosed Multiple Sclerosis cases diagnosed among those patients in Sulaimani city.&#x0D; Patients and and Methods&#x0D; This retrospective observational study was conducted within a period between December 24th. 2019 and June 10th, 2020, on 106 already diagnosed patients. The study included patients diagnosed with the relapse-remitting form of multiple sclerosis. We excluded those patients with progressive forms of multiple sclerosis. We re-evaluated each patient in-depth and stratified the cases according to the diagnosis certainty based on the fulfillment of the 2017 McDonald Criteria. Finally, we returned those suspicious cases to the multiple sclerosis committee of Shar hospital to verify their final diagnosis. &#x0D; Results&#x0D; Sixteen (16.9%) out of 106 patients, there was diagnostic uncertainty in which 6 (5.7%) of them received the confirmatory diagnosis of relapse-remitting multiple sclerosis by the committee, and 1(0.9%) patient considered secondary progressive multiple sclerosis. In the remaining 9 (8.4%) patients, we found the clinically isolated syndrome in 5 (4.7%) patients, solitary sclerosis in 1 (0.9%) patient, stroke with polycythemia rubra vera (PRV) in 1 (0.9%) patient, possible cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in 1 (0.9%) patient, and 1 (0.9 %) patient was undiagnosed. &#x0D; Conclusion&#x0D; To sum up, the frequency of multiple sclerosis misdiagnosis was 8.4% in Sulaimani city, slightly lower than the other reporting centers.

Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial

Tolebrutinib is an oral, CNS-penetrant, irreversible inhibitor of Bruton's tyrosine kinase, an enzyme expressed in B lymphocytes and myeloid cells including microglia, which are major drivers of inflammation in multiple sclerosis. We aimed to determine the dose-response relationship between tolebrutinib and the reduction in new active brain MRI lesions in patients with relapsing multiple sclerosis. We did a 16-week, phase 2b, randomised, double-blind, placebo-controlled, crossover, dose-finding trial at 40 centres (academic sites, specialty clinics, and general neurology centres) in ten countries in Europe and North America. Eligible participants were adults aged 18-55 years with diagnosed relapsing multiple sclerosis (either relapsing-remitting or relapsing secondary progressive multiple sclerosis), and one or more of the following criteria: at least one relapse within the previous year, at least two relapses within the previous 2 years, or at least one active gadolinium-enhancing brain lesion in the 6 months before screening. Exclusion criteria included a diagnosis of primary progressive multiple sclerosis or a diagnosis of secondary progressive multiple sclerosis without relapse. We used a two-step randomisation process to randomly assign eligible participants (1:1) to two cohorts, then further randomly assign participants in each cohort (1:1:1:1) to four tolebrutinib dose groups (5, 15, 30, and 60 mg administered once daily as an oral tablet). Cohort 1 received tolebrutinib for 12 weeks, then matched placebo (ie, identical looking tablets) for 4 weeks; cohort 2 received 4 weeks of placebo followed by 12 weeks of tolebrutinib. Participants and investigators were masked for dose and tolebrutinib-placebo administration sequence; investigators, study team members, and study participants did not have access to unmasked data. MRI scans were done at screening and every 4 weeks over 16 weeks. The primary efficacy endpoint was the number of new gadolinium-enhancing lesions detected on the scan done after 12 weeks of tolebrutinib treatment (assessed at week 12 for cohort 1 and week 16 for cohort 2), relative to the scan done 4 weeks previously, and compared with the lesions accumulated during 4 weeks of placebo run-in period in cohort 2. Efficacy data were analysed in a modified intention-to-treat population, using a two-step multiple comparison procedure with modelling analysis. Safety was assessed for all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03889639), EudraCT (2018-003927-12), and WHO (U1111-1220-0572), and has been completed. Between May 14, 2019, and Jan 2, 2020, we enrolled and randomly assigned 130 participants to tolebrutinib: 33 to 5 mg, 32 to 15 mg, 33 to 30 mg, and 32 to 60 mg. 129 (99%) completed the treatment regimen and 126 were included in the primary analysis. At treatment week 12, there was a dose-dependent reduction in the number of new gadolinium-enhancing lesions (mean [SD] lesions per patient: placebo, 1·03 [2·50]; 5 mg, 1·39 [3·20]; 15 mg, 0·77 [1·48]; 30 mg, 0·76 [3·31]; 60 mg, 0·13 [0·43]; p=0·03). One serious adverse event was reported (one patient in the 60 mg group was admitted to hospital because of a multiple sclerosis relapse). The most common non-serious adverse event during tolebrutinib treatment was headache (in one [3%] of 33 in the 5 mg group; three [9%] of 32 in the 15 mg group; one [3%] of 33 in the 30 mg group; and four [13%] of 32 in the 60 mg group). No safety-related discontinuations or treatment-related deaths occurred. 12 weeks of tolebrutinib treatment led to a dose-dependent reduction in new gadolinium-enhancing lesions, the 60 mg dose being the most efficacious, and the drug was well tolerated. Reduction of acute inflammation, combined with the potential to modulate the immune response within the CNS, provides a scientific rationale to pursue phase 3 clinical trials of tolebrutinib in patients with relapsing and progressive forms of multiple sclerosis. Sanofi.

Possible Markers of Venous Sinus Pressure Elevation in Multiple Sclerosis: Correlations with Gender and Disease Progression

In a previous study, multiple sclerosis (MS) was found to be associated with an increase in intracranial arterial pulsation volume and a reduction in venous sinus compliance, affecting pulsation dampening. There was a suggestion that the reduction in compliance of the sagittal sinus in MS was caused by an increase in venous pressure, secondary to transverse sinus stenosis. Some differences were noted depending on the gender of the patients, however, the original study was relatively underpowered for further sub-classification. The purpose of the current study is to enroll a larger number of patients to allow sub-classification on gender and disease type to further evaluate the markers of possible venous pressure alteration. 103 patients with MS were prospectively recruited from an MS clinic and compared to 50 matched non-MS patients. Using 3DT1 post contrast images, the sagittal sinus cross-sectional area was measured. The narrowest portion of the transverse sinuses was located and the cross sectional areas and wetted circumferences were measured to calculate the minimum hydraulic and effective diameters. The jugular bulb heights were measured. Voxel wise brain morphometry was performed to evaluate atrophy. Statistical analysis was performed using non-parametric methods and was assessed using α≤0.05. Compared to controls, the MS patients' sagittal sinuses were 23% larger in cross-section (p<0.0001), the transverse sinuses had an average effective stenosis of 39% by area (p<0.0001) and there was a 62% increase in jugular bulb height (p=0.0001). The MS patients showed a reduction in normalized grey matter volume of 2.8% (p= 0.0001). Males with MS showed worse outcomes compared to females, with an increased EDSS and grey matter loss and had a 23% larger sagittal sinus area (p=0.02), 22% higher jugular bulb height (p=0.03) but a lower transverse sinus stenosis percentage (19% vs 48%, p<0.0001). Progressive forms of MS also had worse outcomes and had a 19% larger sagittal sinus area (p=0.04) compared to relapsing remitting MS. In this larger cohort, worse outcomes in both males and progressive forms of MS were associated with larger sagittal sinuses. The possible cause of the altered sinus pressure in females was narrower transverse sinuses. In males, higher jugular bulbs may be associated with increased venous sinus pressure.

Reviewing the Significance of Blood-Brain Barrier Disruption in Multiple Sclerosis Pathology and Treatment.

The disruption of blood–brain barrier (BBB) for multiple sclerosis (MS) pathogenesis has a double effect: early on during the onset of the immune attack and later for the CNS self-sustained ‘inside-out’ demyelination and neurodegeneration processes. This review presents the characteristics of BBB malfunction in MS but mostly highlights current developments regarding the impairment of the neurovascular unit (NVU) and the metabolic and mitochondrial dysfunctions of the BBB’s endothelial cells. The hypoxic hypothesis is largely studied and agreed upon recently in the pathologic processes in MS. Hypoxia in MS might be produced per se by the NVU malfunction or secondary to mitochondria dysfunction. We present three different but related terms that denominate the ongoing neurodegenerative process in progressive forms of MS that are indirectly related to BBB disruption: progression independent of relapses, no evidence of disease activity and smoldering demyelination or silent progression. Dimethyl fumarate (DMF), modulators of S1P receptor, cladribine and laquinimode are DMTs that are able to cross the BBB and exhibit beneficial direct effects in the CNS with very different mechanisms of action, providing hope that a combined therapy might be effective in treating MS. Detailed mechanisms of action of these DMTs are described and also illustrated in dedicated images. With increasing knowledge about the involvement of BBB in MS pathology, BBB might become a therapeutic target in MS not only to make it impenetrable against activated immune cells but also to allow molecules that have a neuroprotective effect in reaching the cell target inside the CNS.

Autologous Hematopoietic Cell Transplant for Patients With Multiple Sclerosis

&#x0D; Evidence from 2 randomized controlled trials and 4 retrospective studies with limited methodological quality suggests that treatment with autologous hematopoietic stem cell transplantation was associated with significant improvement in clinical outcomes (e.g., disease progression, clinical relapse), MRI outcomes, the composite outcome “No Evidence of Disease Activity,” and quality of life compared to disease-modifying therapies.&#x0D; Treatment with autologous hematopoietic stem cell transplantation was associated with no treatment-related mortality or life-threatening complications including progressive multifocal leukoencephalopathy. However, autologous hematopoietic stem cell transplantation was associated with expected short-term adverse events including febrile neutropenia, organ infections, sepsis, and viral reactivations; and long-term adverse events including the development of new autoimmune diseases, mainly thyroid disease.&#x0D; Both identified guidelines recommend the use of autologous hematopoietic stem cell transplantation as standard of care for the treatment of highly active relapsing-remitting multiple sclerosis patients refractory to disease-modifying therapies and suggest that the treatment may be appropriate for progressive forms of multiple sclerosis with an active inflammatory component.&#x0D; No cost-effectiveness studies were identified.&#x0D;

SARS-CoV-2 Infection in Multiple Sclerosis: Results of the Spanish Neurology Society Registry.

ObjectiveTo understand COVID-19 characteristics in people with multiple sclerosis (MS) and identify high-risk individuals due to their immunocompromised state resulting from the use of disease-modifying treatments.MethodsRetrospective and multicenter registry in patients with MS with suspected or confirmed COVID-19 diagnosis and available disease course (mild = ambulatory; severe = hospitalization; and critical = intensive care unit/death). Cases were analyzed for associations between MS characteristics and COVID-19 course and for identifying risk factors for a fatal outcome.ResultsOf the 326 patients analyzed, 120 were cases confirmed by real-time PCR, 34 by a serologic test, and 205 were suspected. Sixty-nine patients (21.3%) developed severe infection, 10 (3%) critical, and 7 (2.1%) died. Ambulatory patients were higher in relapsing MS forms, treated with injectables and oral first-line agents, whereas more severe cases were observed in patients on pulsed immunosuppressors and critical cases among patients with no therapy. Severe and critical infections were more likely to affect older males with comorbidities, with progressive MS forms, a longer disease course, and higher disability. Fifteen of 33 patients treated with rituximab were hospitalized. Four deceased patients have progressive MS, 5 were not receiving MS therapy, and 2 were treated (natalizumab and rituximab). Multivariate analysis showed age (OR 1.09, 95% CI, 1.04–1.17) as the only independent risk factor for a fatal outcome.ConclusionsThis study has not demonstrated the presumed critical role of MS therapy in the course of COVID-19 but evidenced that people with MS with advanced age and disease, in progressive course, and those who are more disabled have a higher probability of severe and even fatal disease.

Differences in correlates of fatigue between relapsing and progressive forms of multiple sclerosis

BackgroundFatigue is one of the most prevalent and impactful symptoms for people with multiple sclerosis (MS). Yet, fatigue is less understood in progressive forms of MS, and few studies have explored the extent to which MS disease course is associated with fatigue. The current study aimed to (1) describe fatigue severity and fatigue interference (the extent to which fatigue interferes with individuals’ physical, mental, and social activities) in people with progressive MS (primary progressive MS and secondary progressive MS); (2) compare fatigue severity and fatigue interference in people with progressive forms of MS to people with relapsing-remitting MS (RRMS); and (3) identify factors associated with fatigue severity and fatigue interference in people with progressive forms of MS and RRMS. MethodsSecondary analysis of baseline data from participants with MS (N = 573; progressive forms of MS n = 142; RRMS n = 431) in a survey-based longitudinal study on healthy aging in people with a physical disability. Primary outcomes were average fatigue severity (0–10 Numerical Rating Scale), and fatigue interference (PROMIS Fatigue Short Form). Correlates were variables across the demographic and biopsychosocial domains, collected with validated self-reported measures. Statistical methods included t-test and chi-square analyses to compare fatigue severity and fatigue interference in people with progressive MS to those with RRMS, and multiple regression analyses to examine the association of variables with fatigue severity and fatigue interference. ResultsParticipants with progressive forms of MS reported moderate to severe levels of average fatigue severity (5.9 ± 2.8) and elevated levels of fatigue interference (T-Score of 58.2 ± 7.9). There were no group differences between people with progressive MS and RRMS in average fatigue severity or fatigue interference. Common factors associated with greater fatigue severity were lower income, being unemployed, shorter disease duration, greater disability, and greater sleep disturbance. Common factors associated with fatigue interference were younger age, lower income, being unemployed, greater disability, lower alcohol consumption, being a smoker, and greater sleep disturbance. For those with progressive forms of MS, longer MS disease duration was associated with lower average fatigue severity (b = -0.08, t(532) = -3.69, p < .001) and having a college degree or higher was associated with higher fatigue interference (b = 2.84, t(520) = 2.23, p = .026). ConclusionIn this sample, fatigue severity and fatigue interference were similar for progressive forms of MS and RRMS. Future research should consider if interventions that work for fatigue management in people with relapsing forms of MS work similarly for people with progressive forms of MS.

Using Monoclonal Antibody Therapies for Multiple Sclerosis: A Review.

Monoclonal antibody therapies have secured an important role in the therapeutic landscape for the treatment of both relapsing and progressive forms of multiple sclerosis due to their potent efficacy, convenient dosing schedules, and well-defined side effect profiles. Each therapy has unique risks and benefits associated with its specific mechanism of action which ultimately guides clinical decision-making for individual patients. This review will summarize the mechanisms of action, evidence leading to their approval, and clinically relevant considerations for each of the current monoclonal antibody therapies approved for the treatment of multiple sclerosis.