Safety and Effectiveness of Cladribine in Multiple Sclerosis: Real-World Clinical Experience From 5 Tertiary Hospitals in Portugal.

OBJECTIVES: Cladribine is a selective and oral immunological reconstitution treatment, approved in Europe for very active multiple sclerosis (MS) with relapses. Aims were to assess the safety and effectiveness of cladribine in real-world setting, during treatment follow-up. METHODS: This was a multicentric, longitudinal, observational study with retrospective and prospective data collection of clinical, laboratory, and imaging data. This interim analysis reports data from July 1, 2018 (study onset), to March 31, 2021. RESULTS: A total of 182 patients were enrolled: 68.7% were female; mean age at onset was 30.1 ± 10.0 years, and mean age at first cycle of cladribine treatment was 41.1 ± 12.1; 88.5% were diagnosed with relapse-remitting MS and 11.5% with secondary progressive MS. Mean disease duration at cladribine start was 8.9 ± 7.7 years. Most patients (86.1%) were not naive, and median number of previous disease-modifying therapies was 2 (interquartile range, 1-3). At 12 months, we observed no significant Expanded Disability Status Scale score worsening ( P = 0.843, Mann-Whitney U test) and a significantly lower annualized relapse rate (0.9 at baseline to 0.2; 78% reduction). Cladribine treatment discontinuation was registered in 8% of patients, mainly (69.2%) due to disease activity persistence. Most frequent adverse reactions were lymphocytopenia (55%), infections (25.2%), and fatigue (10.7%). Serious adverse effects were reported in 3.3%. No patient has discontinued cladribine treatment because of adverse effects. CONCLUSION: Our study confirms the clinical efficacy and the safety profile of cladribine for treating MS patients with a long-term active disease in the real-world setting. Our data contribute to the body of knowledge of the clinical management of MS patients and the improvement of related clinical outcomes.

Consensus for the Early Identification of Secondary Progressive Multiple Sclerosis in Portugal: a Delphi Panel.

INTRODUCTION: Multiple sclerosis is a disease with a heterogeneous evolution. The early identification of secondary progressive multiple sclerosis is a clinical challenge, which would benefit from the definition of biomarkers and diagnostic tools applicable in the transition phase from relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis. We aimed to reach a Portuguese national consensus on the monitoring of patients with multiple sclerosis and on the more relevant clinical variables for the early identification of its progression. MATERIAL AND METHODS: A Delphi panel which included eleven Portuguese Neurologists participated in two rounds of questions between July and August of 2021. In the first round, 39 questions which belonged to the functional, cognitive, imaging, biomarkers and additional evaluations were included. Questions for which no consensus was obtained in the first round (less than 80% of agreement), were appraised by the panel during the second round. RESULTS: The response rate was 100% in both rounds and consensus was reached for a total of 33 questions (84.6%). Consensus was reached for monitoring time, evaluation scales and clinical variables such as the degree of brain atrophy and mobility reduction, changes suggestive of secondary progressive multiple sclerosis. Additionally, digital devices were considered tools with potential to identify disease progression. Most questions for which no consensus was obtained referred to the cognitive assessment and the remaining referred to both functional and imaging domains. CONCLUSION: Consensus was obtained for the determination of the monitorization interval and for most of the clinical variables. Most questions that did not reach consensus were related with the confirmation of progression taking into account only one test/domain, reinforcing the multifactorial nature of multiple sclerosis.

Late onset neuromyelitis optica spectrum disorders (LONMOSD) from a nationwide Portuguese study: Anti-AQP4 positive, anti-MOG positive and seronegative subgroups.

INTRODUCTION: Several neuroimmunological disorders have distinct phenotypes according to the age of onset, as in multiple sclerosis or myasthenia gravis. It is also described that late onset NMOSD (LONMOSD) has a different phenotype. OBJECTIVE: To describe the clinical/demographic characteristics of the LONMOSD and distinguish them from those with early onset (EONMOSD). METHODS: From a nationwide Portuguese NMOSD study we analyzed the clinical/demographic characteristics of the LONMOSD. RESULTS: From the 180 Portuguese patients 45 had disease onset after 50 years old, 80% were female. 23 had anti-AQP4 antibodies (51.1%), 13 anti-MOG antibodies (28.9%) and 9 were double seronegative (20.0%). The most common presenting phenotypes in LONMOSD were transverse myelitis (53.3%) and optic neuritis (26.7%), without difference from EONMOSD (p = 0.074). The mean EDSS for LONMOSD was 6.0 (SD=2.8), after a mean follow-up time of 4.58 (SD=4.47) years, which was significantly greater than the mean EDSS of EONMOSD (3.25, SD=1.80)(p = 0.022). Anti-AQP4 antibodies positive LONMOSD patients had increased disability compared to anti-MOG antibodies positive LONMOSD (p = 0.022). The survival analysis showed a reduced time to use a cane for LONMOSD, irrespective of serostatus (p<0.001). CONCLUSIONS: LONMOSD has increased disability and faster progression, despite no differences in the presenting clinical phenotype were seen in our cohort.

Music therapy and music medicine interventions with adult burn patients: A systematic review and meta-analysis.

BACKGROUND: Pain is one of the most common and most difficult symptoms to manage in adult burn patients in the Intensive Care Unit (ICU). Insufficient or unsuccessful pain management can negatively affect physiological, psychological, and social health in burn patients, both during and after hospitalization. Music therapy and music medicine interventions have been shown to positively affect pain and mental health in this population. This systematic review and meta-analysis provide an update of Randomized Controlled Trials (RCTs) using music therapy or music medicine interventions in adult burn patients. METHODS: A variety of databases were searched from their beginning to June 2020, including PsycINFO and PsycArticles (via APAsycNET), PubMed and MEDLINE (via OvidSP), Scopus, Web of Science, and the Cochrane Library. Data of all articles meeting the inclusion criteria were extracted, organized, and processed according to the PRISMA guidelines. Statistical analysis was performed using Q-test and I2 statistics. RESULTS: 10 RCTs with a total of 1061 participants were included. The results of the meta-analysis showed a statistically significant reduction of pain (I2 = 96.03%, P < 0.001), anxiety (I2 = 98.85%, P < 0.002), and improved relaxation (I2 = 87.19%, P < 0.001) favoring music interventions compared to control groups. CONCLUSIONS: This review provides preliminary evidence for the effectiveness of music interventions for adult burn patients. However, more high-quality RCTs are needed to safely establish guidelines for music therapists and other health care professionals in using music for health purposes with this population.

The Effect of Music Therapy on Perceived Pain, Mental Health, Vital Signs, and Medication Usage of Burn Patients Hospitalized in the Intensive Care Unit: A Randomized Controlled Feasibility Study Protocol.

Background: Burn patients experience major physiological and psychological stressors during treatment and rehabilitation, including elevated levels of pain, anxiety, stress, or depression. Music interventions inclusive of music therapy (MT) have been shown to improve such symptoms, but rigorous clinical trials investigating specific music therapy methods in adult burn patients are scarce. Methods: This is a single center Randomized Controlled Trial (RCT) protocol with two parallel arms. Participants are 81 adult burn patients admitted to the Intensive Care Unit (ICU) of the University Hospital Fundación Santa Fe de Bogotá in Colombia. The intervention consists of a Music Assisted Relaxation (MAR) protocol, a music therapy technique composed of entrained live music combined with a guided relaxation and/or the use of imagery. The effects of the MAR will be compared to a control group (treatment as usual) over a period of maximum 2 weeks or six interventions. The primary outcome measure is perceived background pain, as measured with a Visual Analog Scale (VAS) before and after each intervention. Secondary outcomes are anxiety and depression levels; vital signs; and the use of pain medication. Additionally, some patients in the intervention group will be invited to participate in electroencephalography, electromyography, and electrocardiography recordings during the MAR. Discussion: This study protocol follows the SPIRIT guidelines for defining items of clinical trials and is the first study in Colombia to evaluate the effects of music therapy for adult burn patients. With this RCT it is hoped to gather new knowledge about the potential of music therapy to help critical care patients cope and recover from their injuries during the hospitalization in the ICU. Trial registration: www.clinicaltrials.gov, Identifier: NCT04571255. Protocol version: V1.0, May 24th 2021.

Neuromyelitis optica spectrum disorders: A nationwide Portuguese clinical epidemiological study.

INTRODUCTION: Neuromyelitis optica spectrum disorder (NMOSD) is a rare disorder in which astrocyte damage and/or demyelination often cause severe neurological deficits. OBJECTIVE: To identify Portuguese patients with NMOSD and assess their epidemiological/clinical characteristics. METHODS: This was a nationwide multicenter study. Twenty-four Portuguese adult and 3 neuropediatric centers following NMOSD patients were included. RESULTS: A total of 180 patients met the 2015 Wingerchuk NMOSD criteria, 77 were AQP4-antibody positive (Abs+), 67 MOG-Abs+, and 36 seronegative. Point prevalence on December 31, 2018 was 1.71/100,000 for NMOSD, 0.71/100,000 for AQP4-Abs+, 0.65/100,000 for MOG-Abs+, and 0.35/100,000 for seronegative NMOSD. A total of 44 new NMOSD cases were identified during the two-year study period (11 AQP4-Abs+, 27 MOG-Abs+, and 6 seronegative). The annual incidence rate in that period was 0.21/100,000 person-years for NMOSD, 0.05/100,000 for AQP4-Abs+, 0.13/100,000 for MOG-Abs+, and 0.03/100,000 for seronegative NMOSD. AQP4-Abs+ predominated in females and was associated with autoimmune disorders. Frequently presented with myelitis. Area postrema syndrome was exclusive of this subtype, and associated with higher morbidity/mortality than other forms of NMOSD. MOG-Ab+ more often presented with optic neuritis, required less immunosuppression, and had better outcome. CONCLUSION: Epidemiological/clinical NMOSD profiles in the Portuguese population are similar to other European countries.

Defining the prodromal phase of multiple sclerosis based on healthcare access in a Portuguese population - ProdMS study.

BACKGROUND: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system. Prodromal symptoms and higher healthcare use have been suggested in patients who later develop MS. OBJECTIVES: Assess the healthcare utilization pattern of relapsing-remitting MS (RRMS) patients in the five years prior to MS diagnosis. METHODS: Retrospective, multicentric study. Demographic and clinical data, drug prescriptions and diagnostic tests were collected from electronic health records five-years previous to MS diagnosis and compared with national data. RESULTS: Included 168 patients, 112 (66.7%) female, median age 34±11 years. The mean number of healthcare use per patient per year was 3.14±2,69, most of them in primary healthcare (47%). Most frequent symptoms were musculoskeletal (22%), gastrointestinal (17%), sensitive (14%) and sensory organs (14%). Median number of diagnostic tests per patient was 6 (IQR 7), and drug prescriptions per patient was 6 (IQR 9). Most frequently prescribed drugs were analgesic/anti-inflammatories, antibiotics and anxiolytics and there was a high request rate of MRIs. CONCLUSION: RRMS patients had a high frequency of healthcare utilization when compared to national data. This supports the current evidence showing a prodromal phase in MS.

Opinions, beliefs and knowledge of people with multiple sclerosis on COVID-19 pandemic and vaccine.

BACKGROUND: Considering the potential COVID-19 impact on pwMS health and the importance of vaccination for this population, we decided to assess: (a) pwMS' beliefs and knowledge on COVID-19 pandemic; (b) their acceptance towards COVID-19 vaccination and (c) pwMS' opinions on general vaccination. METHODS: Observational study, based on a cross-sectional (10-20th September 2020) online survey, conducted in a cohort of pwMS' followed at two Portuguese hospitals. The survey included measures to characterize the sample and a questionnaire designed to assess the topics defined for this study. RESULTS: 270 respondents completed the full survey (response rate 58.2%). pwMS greatest concern during the pandemic was an aggravation of MS, especially by patients older than 50 years old. Almost 40% of the patients older than 50 felt that the pandemic negatively affected their MS related medical assistance. Most patients believed they would recover from COVID-19 infection. More than half of the responders feared a MS aggravation if they got COVID-19; this was more pronounced in patients with progressive MS. About 12% of the participants did not want to be vaccinated and almost 40% was unsure. Regarding vaccines in general, almost a third of the participants feared their side effects or MS related complications. CONCLUSION: Having knowledge of pwMS' opinions on COVID-19 pandemic impact and vaccination is useful to better address these issues. Fears and expectations towards vaccination must be discussed with pwMS.

In-Hospital and Long-Term Prognosis after Spontaneous Intracerebral Hemorrhage among Young Adults Aged 18-65 Years.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) accounts for 10%-15% of all strokes and has an estimated annual incidence of 5/100,000 in young adults. Limited data on prognosis after ICH in young adults are available. We aimed to identify prognostic predictors after ICH among adults aged 18-65 years. METHODS: We retrospectively selected all patients with ICH from a prospective single-center registry of adults with first stroke before 65 years between 1997 and 2002. We recorded in-hospital mortality as well as mortality and recurrent stroke after discharge until December 1, 2018. For in-hospital analysis, we compared patients that died in-hospital versus patients discharged alive. For long-term analysis, we compared patients that died in follow-up versus patients still alive. Independent prognostic predictors were identified using multivariate analyses. RESULTS: Among 161 patients included, 24 (14.9%) died in-hospital. Among in-hospital survivors, 5-year survival was 92.0%, 10-year survival 78.1%, and 15-year survival 62.0%. After median follow-up of 17 years, 47.4% of patients died, 18 patients had ischemic stroke, and 6 recurrent ICH. Regarding in-hospital prognosis, coma at admission (OR .02 [.00-.11]) was independent predictor for mortality whereas alcoholic habits (OR 12.32 [1.82-83.30]) was independent predictor for survival. An increasing age (OR 1.08 [1.03-1.12]), higher blood glucose levels (OR 1.01 [1.00-1.01]), and hypertension (OR 2.21 [1.22-4.00]) were independent predictors of long-term mortality after ICH. CONCLUSIONS: Alcoholic habits may influence in-hospital survival after ICH in young adults. Long-term mortality in young adults seems to be lower than in elderly and was predicted by higher blood glucose levels and hypertension.

A multicenter, non-interventional study to evaluate the disease activity in Multiple Sclerosis after withdrawal of Natalizumab in Portugal.

OBJECTIVES: Natalizumab (NTZ) is very effective for treatment of relapsing-remitting multiple sclerosis (RRMS), its use is mainly limited by safety issues. Discontinuation of NTZ is associated with recurrence of disease activity (reactivation and rebound). The best strategy for subsequent therapy and the predictive factors for recurrence in such patients are areas of active research. We aimed to evaluate predictors of reactivation in a multicentric study. PATIENTS AND METHODS: Multicentric retrospective observational study in five portuguese MS referral centers. Demographic, clinical and imagiological data were collected in the year prior, during and in the year following NTZ discontinuation. Predictors of reactivation and rebound after NTZ suspension were studied using a multivariate Cox model. RESULTS: Sixty-nine patients were included. They were mainly non-naïve patients (97%), with a mean age of 29.1 ±â€¯8.3 years at diagnosis, and a mean age of 37.2 ±â€¯10.3 years at NTZ initiation. The mean annualized relapse rate (ARR) previous, during and after NTZ was 1.6 ±â€¯1.2, 0.2 ±â€¯0.5 and 0.6 ±â€¯1.0, respectively. The median EDSS before, during and after NTZ was 3.5 (IQR 3.3), 3.5 (IQR 3.5) and 4.0 (IQR 3.8), respectively. The median number of infusions was 26.0 (IQR 12.5) and the main reason to NTZ discontinuation was progressive multifocal leukoencephalopathy (PML) risk (70%). After NTZ suspension, reactivation was observed in 25 (36%) patients after a median time of 20.0 (IQR 29.0) weeks. Reactivation predictors in our sample included NTZ suspension for reasons other than PML (adjusted HR = 0.228, 95% CI [0.084- 0.616], p = 0.004), ARR before NTZ (adjusted HR = 1.914 95% [CI 1.330-2.754], p < 0.001) and a longer disease duration at time of NTZ initiation (adjusted HR = 1.154, 95% CI [1.020-1.306], p = 0.023). Rebound occurred in 5 (7%) patients after a median time of 20 (IQR 34.5) weeks. CONCLUSION: Significant predictors of disease reactivation in our cohort were discontinuation of NTZ for reasons other than PML risk, higher disease activity before NTZ treatment, and longer disease duration. Our study provides valuable data of portuguese patients after NTZ withdrawal.

DOK7 myasthenic syndrome with subacute adult onset during pregnancy and partial response to fluoxetine.

DOK7 congenital myasthenic syndrome (DOK7-CMS) generally presents early in life and is treated with salbutamol or ephedrine. This report describes an atypical case of a 39-year-old woman who presented with proximal upper limb weakness in the third trimester of pregnancy and was initially diagnosed with seronegative myasthenia gravis. Dramatic clinical worsening under pyridostigmine and further inefficacy of steroids, intravenous human immunoglobulin (IVIG) and plasma exchange (PLEX) led to the presumptive diagnosis of a CMS. Initially, a slow-channel CMS was regarded as more probable due to prominent finger extension weakness. Accordingly, fluoxetine was started and a lengthy improvement was seen. Clinical deterioration occurred after fluoxetine withdrawal, when a c.1124_1127dup homozygous mutation was detected in DOK7 gene. Afterwards, salbutamol was started and the patient became asymptomatic. This case highlights the importance of considering CMS before an adult-onset myasthenic syndrome and suggests a benefit from fluoxetine not previously reported in DOK7-CMS.