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Background: An earlier follow-up study from the CogEx rehabilitation trial showed little change in symptoms of depression, anxiety and psychological distress during the first COVID-19 lockdown compared to pre-pandemic measurements. Objective(s): Here we provide a second follow-up set of behavioral data on the CogEx sample. Method(s): Data were obtained from the CogEx study, a randomized controlled trial of exercise and cognitive rehabilitation in people with progressive MS involving 11 centres in North America and Europe. Participants completed the same COVID Impact Survey and self-report measures of depression, anxiety and MS symptoms that had been obtained during the first pandemic lockdown period. Result(s): The average time between measurements was 11.4 (SD=5.56) months. Sample size declined from 131 to 72 largely because pandemic restrictions prevented data collection from sites in Denmark and England. There were no significant differences in age, sex, EDSS, disease course and duration between those who participated in the current follow-up study (n=74) and the group that could not (n=57). One participant caught Covid in the time between assessments. Participants now took a more negative view of their mental/psychological wellbeing (p=.0001), physical wellbeing (p=.0009) and disease course (p=.005) compared to their last assessment. Depression scores increased on the HADS-depression scale (p = .01) and now exceeded the clinically significant threshold of >= 8.0 for the first time. Anxiety scores on the HADS remained unchanged. Poorer mental wellbeing was predicted by HADS depression scores (p=.012) and a secondary-progressive disease course (p=.0004). Conclusions and Relevance: A longer follow-up period revealed the later onset of clinically significant depressive symptoms on the HADS and a decline in self-perceptions of mental and physical wellbeing associated with the COVID-19 pandemic.
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Introduction: Concerns have emerged during Covid-19 pandemic about management of Disease Modifying Therapies (DMTs) in patients with Multiple Sclerosis (pwMS). In particular, Ocrelizumab (OCR)-treated pwMS faced possible delays of scheduled infusions due to disruption of MS Centers activities as well as safety worries during lockdown periods. Objective(s): To assess changes of OCR infusion schedule in Italian pwMS during the first wave of COVID-19 pandemic (observation period: February-June 2020) and to investigate predictive factors determining delaying of OCR infusions. Material(s) and Method(s): Data were extracted from the Italian MS Register database. pwMS with an OCR infusion scheduled during the observation period and at least two previous OCR infusions were selected. Demographics (age, gender), disease characteristics (MS phenotype, disease duration, Expanded Disability Status Scale score, number of previous OCR infusions) and location of MS Centers among three Italian macro-regions (North, Center, South) were tested as potential predictors for treatment delay using univariable and multivariable linear model analyses. Result(s): Five-hundred ninety-nine pwMS (343 F/256 M;411 Relapsing MS/188 Progressive MS) from 65 MS centers were included in the analysis. Mean interval between two OCR infusions was 28.1 weeks (SD 2.72) before the observation period compared to 30.8 weeks (SD 5.45) during the observation period, with a mean delay of 2.7 weeks (p <0.001). No clinico-demographic factors emerged as predictors of infusion postponement, except for location of MS centers in the North of Italy (4.7 weeks vs 1.5 in the Center and 1.6 in the South). Such a difference was confirmed in multivariate analysis (p < 0.001) adjusting for prelockdown mean OCR infusion schedule. Conclusion(s): This large registry-based study shows that OCR infusions were significantly delayed during the first wave of COVID-19 pandemic in Italy. The location of the MS Centers in Northern Italy was the only predictor of OCR infusion postponement. This geographical area corresponds to the region in Italy that was hit first and more strongly by Covid-19 pandemic. The observed delay in OCR infusions disruptions of MS centers activities due to a drastic reduction of healthcare workers availability (because of infection/quarantine and/or reallocation in Covid Units) and concerns about using an immunosuppressive DMT like OCR during a new virus pandemic with many uncertainties.
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Introduction: MS centers (MSc) activities related to OCR management were strongly and diffusely hit during the first wave of COVID-19 pandemic. Concerns were mainly related to its immunosuppressive effects and the need for in-hospital administration. Objective(s): To investigate changes in OCR schedule among Italian MS centers participating to the Italian MS Register during the first wave of COVID-19 pandemic and to identify factors determining such changes. Material(s) and Method(s): A quick online survey was sent to 65 Italian MSc in order to collect from them the following data: macro-region (North, Center, South) location, number of OCRtreated patients, modifications of OCR schedule and a list of factors potentially influencing the postponement of OCR infusions (i.e. age, co-morbidity, MS phenotype, number of previous OCR cycles, disease severity/activity, CD-20 lymphocytes count, distance to MS center, fear of infection, inclusion in a research trial, infections trend, shortage of medical/paramedical staff for reallocation/ infection). Result(s): Among 55 MSc who answered the survey, 50 (91%) declared to have suspended or extended OCR interval dosing for at least one patient. The MSc that didn't modify OCR schedule were all from the South of Italy (33% of all South MSc). Main factors influencing OCR schedule delay were advanced age/comorbidity (70%) and pandemic trend in the area (72%), while recent MS-disease activity hindered OCR schedule modifications (65%). Conclusion(s): This study shows that most Italian MSc decided either to delay or suspend OCR treatment during the first wave of COVID-19 pandemic. Advanced age and co-morbidity and no evidence of recent MS-disease activity were the most relevant patient-dependent predictors of OCR postponement. Among patient-independent factors the most relevant factor was the local trend of infections. Contrary to what expected, the shortage of medical and/or paramedical staff in MSc did not come out as relevant. The disruption of OCR schedule during the first COVID-19 pandemic wave in Italy mostly reflected the geographical distribution and the impact on the National Health System of COVID- 19 pandemic.
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Background: During COVID-19 pandemic second line disease modifying therapies (DMTs) for multiple sclerosis (MS), have been frequently postponed because of the epidemiological situation and the lack of safety information. Objective(s): To evaluate clinical implications of delaying ocrelizumab dosing in MS. Aim(s): To assess the occurrence of clinical relapses, disability worsening and neuroradiological disease activity in MS patients receiving extended interval dosing ocrelizumab in a real-world setting. Method(s): Data from 90 MS patients (65 RRMS, 25 PPMS) who underwent ocrelizumab dose delay have been retrospectively obtained: in particular MS history, neurological examinations, white blood cells count (particularly lymphocyte subsets) and neuroradiological data have been collected. Result(s): Enrolled patients have been followed up for a mean of 9.5+/-2.8 months after ocrelizumab dose delay (mean dosing interval 7.67+/-0.79 months). None of our 65 RRMS patients had clinical relapses, nor rapid disability worsening has been experienced by the PPMS cohort. Pre-infusion CD19+/CD20+ lymphocyte subset was available in 75/90 patients, with 18/75 patients showing significant B cells repopulation (defined as CD19+/CD20+ >= 1.0%). MRI data were available in 47/90 patients, with 5/47 patients showing evidence of neuroradiological disease activity (mild in all reported cases and in the absence of any correlation with B cells repopulation). Conclusion(s): Our data suggest ocrelizumab dose delay is generally safe in MS patients. Experiences during COVID-19 pandemic could be a starting point towards a more personalized scheduling of ocrelizumab therapy.
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COVID-19 patients require early treatment and admission to an appropriate care setting, considering possible rapid and unpredictable to Severe Acute Respiratory Syndrome. A flow-chart was developed by a multidisciplinary team of Emergency Department (ED) clinicians, intensivists and radiologists aiming to provide tools for disease severity stratification, appropriate ventilation strategy and hospitalization setting identification. We conducted a retrospective application of our model on 313 hospitalized patients at Pisa University Hospital including 222 patients admitted to ED for respiratory failure between March and April 2020. Risk stratification score was based on respiratory and chest imaging parameters, while management strategy on comorbidities and age. Age, comorbidities, clinical respiratory and arterial blood gas parameters, semi-quantitative chest computed tomography score were significant predictors of mortality (p<0.05). Mortality rate was higher in patients treated in intensive care units (26.5%) and undergoing endo-tracheal intubation (32.7%), compared to medical area (21.3%). We verified a good concordance (81.7%) between the proposed model and actual evaluation in ED. Outcomes analysis of subgroups of patients homogeneous for baseline features allowed to verify safety of our model: in non-elderly and/or non-comorbid patients (15% mortality) our scheme overestimates the risk in 30% of cases, but it suggests non-intensive management in patients with reduced functional reserve, elderly and with comorbidities (50% mortality). Correct management of respiratory failure COVID-19 patients is crucial in this unexpected pandemic. Our flow-chart, despite retrospectively application in small sample, could represents a valid and safe proposal for evaluation in ED.
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Introduction: The SARS-CoV-2 pandemic has raised, among others, a particular concern for people taking immune-suppressants. The Italian MS Foundation (FISM), Neuroimmunology Association (AINI), Neurological Society (SIN), and MS Registry have constituted an Alliance to tackle these issues. In the field of multiple sclerosis, several reports have suggested a higher risk of infection and an increased severity of the disease in persons treated with anti-CD20 monoclonal antibody. Serological investigations, showing a blunted production of anti-SARS-CoV-2 antibodies, questioned the usefulness of vaccination in these subjects, without, however, considering T cell responses. Objectives and Aims: To investigate antiviral T cell responses after infection with SARS-CoV-2 in persons with MS (pwMS) treated with Ocrevus.Control groups include pwMS treated with Ocrevus without SARS-CoV-2 infection, persons without MS with SARS-CoV-2 infection, and healthy individuals vaccinated or not with BNT16b2. Methods: Blood samples were collected and processed to isolate PBMCs, that were then stored frozen. PBMCs were stimulated with SARS-CoV-2 peptide pools and T cell reactivity was assessed by ELISPOT for IFNg detection, and by multiparametric FACS analyses for assessment and characterization of T cell activation. Results: ELISPOT assay against the spike and the N protein of SARS-CoV-2 displayed specific T cell reactivity in 80% pwMS treated with Ocrevus and infected by SARS-CoV-2, similar to infected persons without MS. FACS analysis following stimulation with SARS-CoV-2 peptide pools, showed the presence of activation-induced markers (AIM) in both CD4 and CD8 T cell subsets in 96% and 92% of these individuals, respectively. CD4 AIM+ cells were mostly central and effector memory cells, while CD8 cells were largely CD45RA+ terminally differentiated effectors (TEMRA) and poised for cytotoxicity, with a significant fraction of naïve cells. Within naïve AIM+ CD4 and CD8 cells we detected memory stem cells, suggesting the acquisition of long-term memory and protection from reinfection. COVID-19- recovered pwMS treated with Ocrevus had T cell responses comparable to healthy individuals vaccinated with BNT162b2, particularly concerning the ability to produce cytokines. Conclusions: B-cell depletion using Ocrevus does not impair the development of anti-SARS-CoV-2 T cell responses. Multistakeholder initiatives are mandatory to rapidly obtain unbiased clinically crucial information.
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Background: Data collected from several international platforms provided important information about risk factors, including treatment exposure, impacting COVID-19 severity in people with multiple sclerosis (PwMS). However, up to now, factors increasing the risk of getting SARS-CoV2 infection in PwMS are not known. MS registers represent a suitable tool to provide denominators for risks assessment. Objectives: To assess risk factors for SARS-CoV2 infection in PwMS by using data collected in the Italian MS Register (IMSR). Methods: A case-control (1-2) study was set-up. PwMS with (cases) and without (controls) COVID-19 were identified within the IMRS and propensity-score matched by the date of COVID-19 diagnosis (cases) and the date of last visit (controls) and for the region of residence. COVID-19 risk was estimated by multivariable logistic regression models including demographic and clinical covariates. The role of DMTs exposure was assessed in 3 different models including: last recorded DMT or DMT sequences (induction strategy/escalation strategy/only first line DMT exposure/ never treated) or last DMTs grouped according to the place of administration (at hospital or self-administered at home). A minimal treatment exposure for each DMT was defined on the basis of the recognized minimal time required to be potentially effective. Results: A total of 779 [median (IQR) age: 42.40 years (33.00- 50.80);30.17% male] confirmed COVID-19 cases were matched to 1558 controls [46.90 years (37.50-55.70);35.82% male]. In all models, comorbidities, female sex and age were significantly associated (p<0.02) to a higher risk of getting COVID-19. Patients receiving Natalizumab as last DMT (OR (95% CI): 2.38(1.66-3.42), p<0.0001) and those who underwent an escalation treatment strategy (1.57 (1.16-2.13), p=0.003) were at significant higher COVID-19 risk. Moreover, the group of PwMS receiving last DMTs requiring hospital access (1.65(1.34-2.04), p<0.0001) showed a significant higher risk than those taking selfadministered DMTs at home. Conclusions: This case-control study embedded in the IMSR showed that PwMS at higher COVID-19 risk are younger, more frequently female and with comorbidities. Long-lasting escalation approach and last therapies that expose patients to the hospital environment seem to increase significantly the risk SARS-CoV2 infection in PwMS.
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Background and aims: Erenumab proved to be safe and well tolerated in a 5-year continuation of a 1-year double-blind, placebo-controlled study. Aim: to assess >48-week erenumab tolerability and safety in a real-world setting. Methods: In this long term (>48-week), multicenter (n = 15), longitudinal cohort real life study, we monitored all the adverse events emerged in consecutive adult patients with high-frequency episodic migraine (HFEM) or chronic migraine (CM) treated with monthly erenumab 70 mg or 140 mg from 20 December 2018 to 15 December 2020. Results: 442 patients (HFEM: 115;CM: 327) were treated with erenumab for >48 weeks: 209 (47.3%) patients were treated for 49–60 weeks, 132 (29.9%) for 61–72 weeks;73 (16.5%) for 73–84 weeks;21 (4.7%) for 85–100 weeks. Overall, >1 treatment emergent adverse event (TEAE) was reported by 136 (30.8%) [HFEM: 43 (37.4%);CM: 93 (28.4%)]. Most common TEAE were constipation (n = 66;14.9%), injection site erythema (n = 15;3.4%), and influenza (n = 7;1.6%). Serious adverse events (SAE) were reported by 8 patients (1.8%) and led to treatment discontinuation: severe constipation (n = 3), abdominal pain (n = 1), NSTEMI (n = 3), Covid-19 infection (n = 1). Only severe constipation was considered treatment-related SAE (0.45%). Conclusions: Conclusion: Erenumab is safe and well tolerated also in long-term treatment (>48 weeks) in real life.
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Objective: To explore cognitive/behavioral features With in two months from hospital discharge in a cohort of patients with COVID-19. Background: Although the epidemiological and clinical features of COVID-19 patients are well characterized, the psychological impact of SARS-CoV-2 has been given little attention. Design/Methods: 49 patients with confirmed COVID-19 underwent neuropsychological assessment With in two months from hospital discharge. The presence of mood alterations and/or features of post-traumatic stress disorder (PTSD) was also investigated. The total sample was split based on age (yC-19, age<50: N=8;mC-19, age range 50-64: N=21;oC-19, age≥65: N=20) and the frequencies of cognitive and behavioral alterations were reported for the total sample and each sub-group. Correlations were tested between neuropsychological scores and the severity of respiratory symptoms at hospital admission. Results: 5 patients (1 yC-19, 4 mC-19) presented with depressive symptoms and 9 (3 yC-19, 4 mC-9, 2 oC-19) reported PTSD features. 45% of the total sample showed executive dysfunctions and difficulties in encoding new verbal material;30% showed visuospatial difficulties, and 25% long-term verbal and nonverbal memory problems. No patients showed language disturbances. Specifically, the yC-19 group showed the worst profile, with 60-75% patients showing executive dysfunctions and encoding difficulties, 50% pure visuospatial dysfunctions and 40% primary long-term memory problems. The mC-19 group showed primary executive (>40%) and visuospatial (25%) dysfunctions. 40% of the oC-19 group showed executive dysfunctions, 30% poor visuospatial abilities, and 25% long-term memory problems. The total sample showed a negative relationship between frontal executive performances and severity of acute-phase respiratory symptoms at hospital admission. Conclusions: With in two months from hospital discharge, cognitive/behavioral alterations are associated with COVID-19 infection, with more severe outcomes in the youngest group. Whether these alterations are linked with the infection itself or with its related consequences has to be determined, as well as whether they are reversible or part of a neurodegenerative process.
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Background and aims: SARS-CoV-2 infection is now known to be associated with a wide spectrum of neurological autoimmune syndromes, in some cases responding to immunotherapies, arising during or after the infection. Whether molecular mimicry or other immune stimulation may induce an aberrant delayed autoimmune response is still to be established. Methods: Case report. Results: A 71 year-old man with no previous medical history apart from mild COVID-19 pneumonia three month earlier, sought medical attention for a subacute onset of diplopia in left gaze, general malaise and fatigue. MRI was characterized by bilateral FLAIR hyperintensities with punctate, perivascular and confluent post-gadolinium enhancement in the pons, mesencephalon, hypothalamus, internal capsules and right hippocampus. Repeated cerebrospinal fluid analysis were normal (2 cells/μL), with no evidence of oligoclonal bands or atypical cells. Screening panel for autoimmune and infectious aetiologies was negative. Whole-body contrast-enhanced CT was unremarkable. Stereotactic temporal lobe brain biopsy showed aspecific chronic lymphocytic perivascular inflammation. Partial spontaneous remission of symptoms occurred within few weeks. He was then treated with intravenous high-dose methylprednisolone with almost complete enhancement regression on MRI. Collected data were suggestive of CLIPPERS with diffuse bilateral sovratentorial involvement. The patient started daily oral steroid tapering and monthly cycles of intravenous cyclophosphamide with persistent clinical and neuroradiological stability. Conclusion: CLIPPERS is a rare diagnosis and to the best of our knowledge, this is the first time it was reported after COVID-19 disease. Even though a case report is not enough to suggest a causal link, future reports could support this possibility. (Figure Presented).
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Background and aims: Anton-Babinski syndrome is a rare condition due to occipital injury by different mechanisms, such as vasogenic edema in posterior reversible encephalopathy syndrome (PRES) resulting from bood-brain barrier (BBB) disruption. PRES has been rarely associated with Guillain-Barré syndrome (GBS). It has hypothesized that autonomic dysfunction in GBS might lead to BBB damage with consequent PRES before motor symptom onset. Another possibility is that BBB injury in PRES might trigger immune-mediated reaction leading to GBS. Methods: An 80-year-old woman was admitted to our emergency room (ER) after she developed two partial seizures, successfully treated with 5mg of intravenous midazolam. Her medical history was unremarkable except for previous SARS-CoV-2 disease. Results: After one hour from midazolam administration, the patient was still markedly confused. Examination revealed binocular blindness, without signs of optic neuropathy;despite being obviously blind, she denied any vision disturbance, a phenomenon known as visual anosognosia. Her blood pressure was 180/90mmHg. Brain MRI showed posterior alterations compatible with PRES. She was treated with antihypertensive and vision recovered after 24 hours. On day 3, she developed areflexia and proximal symmetrical weakness to both upper and lower limbs. Electromyography suggested recent motor poliradiculoneuropathy. Clinical picture was compatible with GBS and intravenous immunoglobulins were started, with gradual recovery. A 8-day follow-up MRI showed nearly complete normalization of posterior lesions. Figure 1 Conclusion: Anton syndrome is a possible rare presentation of PRES. Occurrence of unexplained weakness after PRES should raise suspicion of GBS in consideration of their pathophysiologic connection.
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Background and aims: It is still debated whether Multiple Sclerosis (MS) patients are at high-risk of COVID-19 because of their life style, disease-or treatments-associated immune alterations. We compared features of MS patients with COVID-19 infection (MS-COVID) to those of residency-, age-, sex-and treatment-matched MS controls (MS-NCOVID). Moreover, the severity of COVID-19 infection was assessed in MS-COVID patients and their cohabitants. Methods: So far, we have enrolled 25 MS-COVID and 104 MS-NCOVID patients. Neurological examination, premorbid laboratory tests, anthropometric variables (height, weight and BMI), life-style habits (smoke, alcohol intake, diet), working-activity and living conditions (number of cohabitants, school-aged children) were assessed. COVID-19 severity was evaluated in terms of fever (magnitude, duration), radiological pneumonia and typical symptoms. Results: Clinical and anthropometric features, life-style habits and living conditions were similar between MS-COVID and MS-NCOVID patients. However, they differed in terms of working activity, with lower rate of unemployment (7.1% vs 23.4%) and higher rate of teamworking (61.5% vs 26.5%) in the MS-COVID group (p<0.01). Furthermore, MS-COVID patients had lower premorbid vitamin D levels (31 vs 40ng/ml p=0.048) and higher neutrophils count (3,803 vs 3,182 cells/ul, p=0.046). Disease course was similar between MS-COVID patients and their cohabitants with fever, ageusia and anosmia being the most common symptoms. Fever and radiologic signs of pneumonia were also comparable. Conclusion: Working-activity, lower vitamin D levels and higher neutrophil count seem to be associated with the risk of COVID-19 infection in MS patients. The burden of COVID-19 disease was comparable between MS patients and their cohabitants.
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Background: Telemedicine is a live communication between patients and physicians through different technological tools. It became fundamental during COVID-19 pandemic to keep on taking care of patients in more medical fields than before. Given the chance for telemedicine to become a pivotal part of neurological routine practice, we investigated patients and neurologists satisfaction about this tool. Objectives: This survey aimed to understand satisfactionabout telemedicine during pandemic and its possible use in the future outside pandemic Methods: We administered a brief survey to a cohort of Multiple Sclerosis (MS) patients and their neurologists at MS center of San Raffaele Hospital, Milan. Demographic and clinical data (EDSS, treatment) were collected. Results: 151 patients filled out the survey: 75% females;mean age 42.2yy (18-73);median EDSS 1.5 (0-7). Treatments were almost equally distributed across first and second-line drugs (10% interferon, 10% glatiramer acetate, 14% teriflunomide, 22% dimethylfumarate, 23% fingolimod, 3% cladribine, 8% alemtuzumab, 10% ocrelizumab). 87% of patients appreciated telemedicine during pandemic;10% had a positive opinion but with a need for traditional evaluations, while 3% were not satisfied. Considering the possible routine use of telemedicine outside the pandemic, 82% firmly stated the importance of traditional evaluations. In particular, 44% would alternate in person and remote visits, while 38% strongly preferred traditional ones. Among the latters, the main reasons were the need for human empathy with the neurologist and the feeling that traditional evaluations may lead to better clinical outcomes. The remaining 18% would always use telemedicine except in the case of acute events. Neurologists and residents (n=18) were inquired about telemedicine: no one would use it as the only tool, 33% would alternate it with traditional practice and 67% would use it only in special contexts. Conclusions: In our survey, both patients and neurologists recognized the importance of telemedicine during a pandemic. Patients more than physicians seemed ready to use it in everyday clinical practice. These data may be biased by a still ongoing patients fear and physicians lack of confidence in this multifaceted tool. The pandemic spurred the development of institutional telematic platforms capable of providing legal protection and traceability of visits and communication between patients and physicians. So far, we can conclude that telemedicine is a useful tool to overcome space-time limits, giving the best care to all patients in any condition. However, it cannot replace but only integrate traditional medicine.
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Starting from 1st case in Italy, on February 20th, 2020, CO-rona VI-rus D-isease 2019 (COVID-19) pandemic spread to whole Italian territory, with different regional distribution. Tuscany has been classified as medium diffusion area (40-100 cases/100000 inhabitants). In this context, all healthcare structures reviewed their organization to meet new needs. Our study's objectives were description of organizational model outlined to safely manage Emergency Department (ED) and analysis of patients' flows within Hospital of Pisa during pandemic. The ED has been reorganized with dedicated areas for examination and waiting for tests results. A similar reduction (-62%) of ED accesses comparing to the same period of 2019 and the previous months of 2020 was observed. Hospital Task Force arranged for progressive activation of Units by modules, according to territorial needs. From the beginning of March to the end of April 2020, 315 COVID-19 patients were hospitalized. Overall, a 45% reduction in hospital admissions compared to the same period of 2019 was observed, with increased mortality (4% versus 2%). The University Hospital of Pisa efficiently managed COVID-19 emergency with a logistical reorganization of ED.