Navigating the landscape of COVID-19 for Multiple Sclerosis patients and clinicians

The purpose of this literature review was to summarise relevant findings regarding the clinical management of multiple sclerosis (MS) in the COVID-19 pandemic, with the focus on patient risks, and the implications of disease-modifying treatment, both on COVID-19 severity and on the response to the SARS-CoV-2 vaccinations. Although MS per se does not seem to put patients at risk for more severe COVID-19, alongside the risk factors known to apply to the general population, progressive disease course, higher disability status, and B-cell depleting therapies may all negatively affect infection severity. The question of COVID-19 sequelae in patients with MS (pwMS) remains unresolved, challenging researchers to further explore this area. The safety profile of COVID-19 vaccinations in pwMS is similar to that of the general population. The efficacy of the vaccination might be affected by B-cell depletion, as well as by S1PR-modulating medications that attenuate humoral responses to the COVID-19 vaccination. Future research should focus on gathering evidence regarding the clinical course of MS following COVID-19 infection and vaccination in larger studies, as well as on establishing the safest and most efficient schedule of COVID-19 vaccination in pwMS on cell-depleting therapies

Zagadkowe objawy kliniczne: zespół wizji Picka oraz choroba Marchiafava-Bignamiego — opis dwóch przypadków

W pracy omówiono 2 przypadki rzadkich zespołów chorobowych o symptomatologii neuropsychiatrycznej: zespołu wizji Picka oraz metaalkoholowego zespołu/choroby Marchiafava-Bignamiego. W komentarzu dotyczącym historii oraz patomechanizmu tych zespołów podkreślono rolę badań neuroobrazowych, w szczególności tomografii rezonansu magnetycznego mózgowia, w adekwatnym rozpoznaniu tych rzadkich schorzeń o niezwykłej różnorodności występujących objawów

Update on pathology of central nervous system inflammatory demyelinating diseases

Multiple sclerosis (MS) is by far the most common central nervous system inflammatory demyelinating disease (CNS-IDD). It is diagnosed according to detailed criteria based on clinical definitions, magnetic resonance imaging (MRI) and cerebrospinal fluid findings. However, in rare instances, atypical syndromes associated with CNS demyelination, such as unusual MRI findings or poor response to standard treatment, may eventually necessitate a CNS biopsy with neuropathological examination.Pathology remains the gold standard in the differentiation of atypical CNS-IDDs, the recognition of which is essential for establishing the correct prognosis and optimal therapy. However, one must bear in mind that between different CNS-IDDs there are still overlapping features, even in the pathology.In this review, we compare and highlight contrasts within a spectrum of CNS-IDDs from the neuropathological perspective. We characterise pathological hallmarks of active vs chronic multiple sclerosis. Also, we define differences in the pathology of MS, acute disseminated encephalomyelitis (ADEM), aquaporin 4-IgG positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOsd), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD).Detailed description of the particular CNS-IDD pathology is crucial on an individual patient level (when clinically justified in atypical cases) but also from a broader perspective i.e. to advance our understanding of the complex disease mechanisms. Recent immunobiological and pathological discoveries have led to the description of novel inflammatory CNS disorders that were previously classified as rare MS variants, such as NMOsd and MOGAD. Multiple sclerosis remains an umbrella diagnosis, as there is profound heterogeneity between patients. Advances in neuropathology research are likely to disentangle and define further CNS-IDDs that used to be categorised as multiple sclerosis

Evaluation of clinical prognostic factors in Polish interferon beta-1b treated multiple sclerosis patients

Introduction. Prompt successful control of disease activity in multiple sclerosis (MS) patients improves outcomes. Therefore, tools to aid drug selection and detect non-responders are urgently needed. Although several biochemical markers for predicting response to treatment have been proposed, clinical markers involving relapses, imaging activity and disability progression in the initial years of therapy remain competitive and appear cost-effective in a real-life setting. The aim of this study was to evaluate the prognostic value of select clinical scores in interferon beta-1b (IFNβ-1b) treated MS patients.Materials and methods. Eighty-eight relapsing-remitting MS (RRMS) patients initiating treatment with IFNβ-1b in a Polish outpatient clinic were followed for a median of 5.5 years. Rio, modified Rio and BREMSO scores, as well as two-year no evidence of disease activity (NEDA), were assessed as predictors of disease activity during the observation.Results. A Rio score of 1 had a Positive Predictive Value (PPV) of 83.3% and a Negative Predictive Value (NPV) of 71.4% for the occurrence of relapses in the first five years. A Rio and modified Rio score of 1 was associated with MRI activity after year 3. A loss of NEDA within the first two years was associated with a failure to maintain NEDA in the next three years. The BREMSO score was higher in patients with early relapse activity. Only baseline EDSS and total number of pre-treatment relapses were significantly associated with disability progression.Conclusions. Rio, modified Rio, early NEDA on treatment and BREMSO score are relatively specific, but insensitive, predictors of relapse activity in the first years of IFNβ-1b treatment. Higher pre-treatment EDSS and relapse activity is associated with disability progression, but not overall NEDA, in subsequent observation. While none of the markers is sufficiently sensitive or specific to make a certain prognosis, they may aid treatment decisions in patients with continued early disease activity

The impact of disease modifying therapies on cognitive functions typically impaired in multiple sclerosis patients: a clinician’s review

ObjectiveOver the last few decades clinicians have become aware that cognitive impairment might be a major cause of disability, loss of employment and poor quality of life in patients suffering from multiple sclerosis [MS].The impact of disease modifying therapies [DMTs] on cognition is still a matter of debate. Theoretically, DMTs could exert a substantial beneficial effect by means of reducing neuroinflammation and brain atrophy, which are established correlates of cognitive dysfunction. The aim of the study was to review the evidence concerning the effect of DMTs on cognitive functions.MethodsPubMed, Scopus, and the European Committee for Treatment and Research in Multiple Sclerosis [ECTRIMS] Library were searched for articles concerning the pediatric and adult populations of patients with multiple sclerosis, including clinical trials and RWD, where psychometric results were analyzed as secondary or exploratory endpoints.ResultsWe reviewed a total of 44 studies that were found by our search strategy, analyzed the psychological tests that were applied, the length of the follow-up, and possible limitations. We pointed out the difficulties associated with assessing of DMTs’ effects on cognitive functions, and pitfalls in cognitive tools used for evaluating of MS patients.ConclusionThere is a need to highlight this aspect of MS therapies, and to collect adequate data to make informed therapeutic decisions, to improve our understanding of MS-related cognitive dysfunction and provide new therapeutic targets

Immune-cell BDNF expression in treatment-naïve relapsing-remitting multiple sclerosis patients and following one year of immunomodulation therapy

Although neurons are the main source of neurotrophins in the healthy brain, neurotrophins can also be expressed in the immune system. We have previously shown that in relapsing-remitting multiple sclerosis (RRMS) lower immune-cell neurotrophin levels are associated with brain atrophy and cognitive impairment. The aim of the present study was to assess if immune-cell neurotrophin expression is impaired in MS as compared with the healthy controls, and to describe if these levels change in treatment-naïve RRMS patients, following one year of immunomodulation. Fifty treatment-naïve RRMS patients were assessed at baseline and after one year of immunomodulation (beta-interferons/glatiramer acetate). The control group included 39 healthy subjects matched according to age and gender. Peripheral blood mononuclear cells (PBMCs) were isolated from heparinized blood using Ficoll-Histopaque gradient. The levels of brain-derived-neurotrophic-factor (BDNF), beta-nerve-growth-factor (beta-NGF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) were measured in PBMC lysates with ELISA. BDNF levels were significantly lower in MS than in the healthy controls (median 613 vs. 1657pg/mg protein, p<0.001). After one year of immunomodulation, BDNF expression did not change significantly (p=0.06) on the group level. In 70% of patients there was no increase in BDNF level, and in 30% it increased. We observed no differences between treatment groups. Other neurotrophins were detected in a minority of MS samples (as opposed to the controls). To conclude, we have shown that immune-cell production of neurotrophins is impaired in MS patients. In our MS cohort standard immunomodulation failed to restore normal BDNF levels in PBMCs within one year of therapy

Spatial distribution of white matter degenerative lesions and cognitive dysfunction in relapsing-remitting multiple sclerosis patients

Aim. The aim of this study was to assess degenerative lesion localisation in the course of relapsing-remitting multiple sclerosis (RRMS) and to identify the association between localisation and the frequency of T1-hypointense lesions (black holes) with cognitive dysfunction. We also searched for neuroradiological predictors of cognitive dysfunction in patients. The clinical rationale for the study was previous research, and our own findings suggest that lesion localisation plays an important role in cognitive performance and neurological disability of MS patients. Material and methods. Forty-two patients were included in the study. All subjects underwent neuropsychological examination using Raven’s Coloured Progressive Matrices, a naming task from the Brief Repeatable Battery of Neuropsychological Tests, and attention to detail tests. Magnetic resonance imaging (MRI) was acquired on 1.5 Tesla scanner and black holes were manually segmented on T1-weighted volumetric images using the FMRIB Software Library. Linear regression was applied to establish a relationship between black hole volume per lobe and cognitive parameters. Bonferroni correction of voxelwise analysis was used to correct for multiple comparisons. Results. The following associations between black hole volume and cognition were identified: frontal lobes black hole volume was associated with phonemic verbal fluency (t = –4.013, p < 0.001), parietal black hole volume was associated with attention (t = –3.776, p < 0.001), and parietal and temporal black hole volumes were associated with nonverbal intelligence (p < 0.001). The volume of parietal black holes was the best predictor of cognitive dysfunction. Conclusions. Our approach, including measurement of focal axonal loss based on T1-volumetric MRI sequence and brief neuropsychological assessment, might improve personalised diagnostic and therapeutic decisions in clinical practice

Anti-interferon-beta antibodies in Polish multiple sclerosis patients: prevalence and clinical significance in a long-term prospective study

Aim of the study. To determine the prevalence of anti-interferon-β binding (BAb) and neutralising antibodies (NAb), and to investigate whether NAb measured by luciferase-based cell assay can predict treatment response in multiple sclerosis (MS) patients treated with interferon-β-1b (IFNβ-1b). Clinical rationale for the study. A subgroup of IFNβ-treated MS patients develop NAb directed against the drug. The clinical significance remains controversial, which could be explained to some extent by technical difficulties in NAb detection and quantification. A simple, specific and reproducible test for NAb might help elucidate these uncertainties. Materials and methods. Sera from 101 consecutive MS patients initiating treatment with IFNβ-1b were collected at baseline and during the first two years, and assessed for BAbNAb with a novel luciferase-based cell assay. Median clinical follow-up lasted 5.1 years. Results. BAb were present in 97% and NAb in 88% of the study cohort. Unexpectedly, 92% of patients tested positive for Bab and 12.5% for NAb at baseline, before drug exposure. Patients with baseline NAb positivity were more likely to remain free of disease activity in the first three years of treatment. When baseline-positive cases were grouped together with those who remained NAb-negative, and the resulting group was compared to those who became positive after drug exposure, NAb positivity was associated with a higher risk of disease activity during the entire follow-up. Direct comparison of BAb/Nab-positive and BAb/Nab-negative patients only revealed an association of BAb positivity with more active disease after four years of treatment, while NAb failed to predict the outcome. Conclusions and clinical implications. Antibodies developed after treatment initiation are associated with a worse outcome. Naturally- occurring antibodies appear to predict more benign disease. Their prevalence and specificity require further investigation

Autoimmune response in lung cancer patients with neurological paraneoplastic syndromes

Aim of the study. The aim of this study was to evaluate granzyme B, perforin and FasL expression in peripheral blood mononuclear cells (PBMCs) in lung cancer patients and in paraneoplastic neurological syndromes (PNS). Clinical rationale for the study. Cellular immune response is activated as part of anti-tumour reaction of the malignancy-bearing host. Paraneoplastic neurological syndromes (PNS) are defined as indirect effects of cancer on the nervous system and are considered immune-mediated. Such stimulation of the immune system may limit the aggressiveness of cancer and the development of metastasis, and thereby improve survival. Granzyme B and perforin pathway, and Fas ligand (FasL) – Fas receptor interaction play an important role in cytotoxic response. Materials and Methods. Fifty-two patients were included in the study: 28 subjects with PNS and 24 subjects with lung cancer. PNS cases were diagnosed according to the Graus criteria. The presence of onconeural antibodies (anti-Hu/anti-Ri/anti-Yo/anti-Ma/Ta/anti-CV2/anti-amphiphysin/anti-myelin/anti-neuroendothelium/anti-MAG/anti-GAD) was detected with indirect immunofluorescence and confirmed with Line Blotting. The expression of granzyme B, perforin and FasL was detected in PBMCs with ELISA. Results. PPBMC-FasL expression was increased in lung cancer compared to other patient groups. The granzyme to FasL ratio was significantly higher in lung cancer patients with peripheral than with central PNS involvement. In a multiple regression model, sex was an independent factor influencing PBMC expression of granzyme and perforin. Conclusions. FasL expression in PBMCs is up-regulated in lung cancer patients. The interplay between granzyme B and FasL may be involved in the development of PNS at the level of the peripheral and the central nervous systems in different manners. Gender is associated with PBMC expression of granzyme B and perforin in lung cancer patients. Clinical Implications. The novel findings that we report broaden the current knowledge on PNS pathomechanism, with aspects that have not been previously explored. Our findings provide a rationale for further exploration of the granzyme B/FasL pathway with regards to its potential diagnostic value. However, our study is preliminary and needs further research, especially in the context of the prognostic value of the proposed markers

Different blood-brain-barrier disruption profiles in multiple sclerosis, neuromyelitis optica spectrum disorders, and neuropsychiatric systemic lupus erythematosus

Aim of the study. To assess differences in BBB damage profiles by measuring serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), and S100 calcium-binding protein B (S100B) in relapsing-remitting multiple sclerosis (RRMS), neuromyelitis optica spectrum disorders (NMOsd), and neuropsychiatric systemic lupus erythematosus (NPSLE) patients.Clinical rationale for the study. Blood-brain-barrier (BBB) disruption is one of the key pathological processes involved in various demyelinating diseases of the central nervous system (CNS) and is associated with shedding of cell adhesion molecules and S100B into the serum compartment. Therefore, making an assessment of serum levels of the above-mentioned molecules could provide information about disease pathogenesis, severity of BBB disruption, and disease activity.Material and methods. We recruited 42 RRMS, 19 NMOsd and 35 NPSLE patients. Subjects were treated with beta-interferons or glatiramer acetate (RRMS), oral steroids and/or azathioprine (NMOsd, NPSLE), other immunosuppressants (NPSLE), or antimalarials (NPSLE). The clinical condition of the patients was assessed using the Kurtzke Expanded Disability Status Scale for MS and NMOsd, and the Systemic Lupus Erythematosus Disease Activity Index for NPSLE. Serum levels of sVCAM-1, sPECAM-1, sICAM-1 and S100B were determined using enzyme-linked immunosorbent assay (ELISA).Results. We found the lowest levels of sPECAM-1, sICAM-1 and S100B in sera from NMOsd patients. The highest levels of sPECAM-1 and sICAM-1 were observed in NPSLE, and in NPSLE and MS, respectively. There were no statistically significant differences in sVCAM-1 levels between the examined groups. In MS and NMOsd, there was a negative correlation between the EDSS score and the following molecules: sPECAM-1, sICAM-1 and S100B.Conclusions and clinical implications. We conclude that there is a different profile of blood-brain-barrier disruption reflected by cell adhesion molecules shedding in the spectrum of autoimmune CNS disorders with disseminated white matter lesions. These molecules could become new biomarkers to be used in CNS demyelinating diseases differential diagnoses and monitoring disease activity, but further studies on larger groups of patients are necessary