Unprescribed cannabinoids and multiple sclerosis: a multicenter, cross-sectional, epidemiological study in Lombardy, Italy.

INTRODUCTION: Cannabinoids are approved for spasticity and pain in multiple sclerosis (MS). In 2017 the prevalence of current users in the Italian general population was 10.2%, while data on Italian MS patients are limited. METHODS: From March 2022 to February 2023, we conducted a multicenter, cross-sectional study. Adult MS patients completed an anonymous online survey. The primary outcome was the estimated prevalence of unprescribed cannabis current use. Cannabis use patterns and associations with clinical and socio-demographical variables were investigated. The binomial method was used to estimate 95% confidence interval (95% CI) for primary outcome. RESULTS: 5620 patients were invited and 2024 (36.0%) were included (mean age 45.2 years, females 64.5%). Relapsing remitting form was the most frequent (77.3%). Median expanded disability status scale (EDSS) was 2.0. The proportion of current users was 15.5% (95% CI 13.9-17.1) and 36.4% of them disclosed to their physician their unprescribed cannabis use. 15.0% patients were former users while 69.5% never used cannabis. Current users more frequently reported a medical use (i.e., current medical users) compared to former users (p < 0.001). 41.1% of never users would use cannabis if it was legal. Young age, being male, and a free marital status were associated with current use. Current medical users had higher disability, spasticity and pain, reduced quality of life, concomitant neurological/psychiatric drugs and analgesics use. Unprescribed cannabis appeared relatively safe, with limited addiction risk, and reported clinical benefits, including concomitant medications reduction. CONCLUSION: Unprescribed cannabis use is common in patients with MS in Italy, with observed prevalence seemingly superior to the general population, often intended for medical use and without the disclosure to the treating physician, although with potential clinical benefits.

Reducing the Impact of Headache and Allodynia Score in Chronic Migraine: An Exploratory Analysis from the Real-World Effectiveness of Anti-CGRP Monoclonal Antibodies Compared to Onabotulinum Toxin A (RAMO) Study.

BACKGROUND: Chronic migraine (CM) is a disabling and hard-to-treat condition, associated with high disability and high cost. Among the preventive treatments, botulinum toxin A (BoNT-a) and monoclonal antibodies against the calcitonin gene-related protein (anti-CGRP mAbs) are the only disease-specific ones. The assessment of the disease burden is complex, and among others, tools such as the allodynia symptoms checklist (ASC-12) and headache impact test (HIT-6) are very useful. This exploratory study analysed the impact of these two therapies on migraine burden. METHODS: The RAMO study was a multicentre, observational, retrospective investigation conducted in two headache centres: the Fondazione IRCCS Istituto Neurologico Carlo Besta (Milan) and the Fondazione Policlinico Campus Bio-Medico (Rome). This study involved patients with chronic migraine treated with mAbs or BoNT-A. We conducted a subgroup exploratory analysis on HIT-6 and ASC-12 scores in the two groups. The Wilcoxon rank-sum test, Fisher's exact test, and ANOVA were performed. RESULTS: Of 126 patients, 36 on mAbs and 90 on BoNT-A had at least one available follow-up. mAbs resulted in a mean reduction of -11.1 and -11.4 points, respectively, in the HIT-6 at 6 and 12 months, while BoNT-A was reduced -3.2 and -3.6 points, respectively; the mAbs arm resulted in mean reductions in ASC-12 at 6 and 12 months of follow-up of -5.2 and -6.0 points, respectively, while BoNT-A showed lesser mean changes of -0.5 and -0.9 points, respectively. The adjusted analysis confirmed our results. CONCLUSIONS: In this exploratory analysis, anti-CGRP mAbs showed superior effectiveness for HIT-6 and ASC12 compared to BoNT-A. Reductions in terms of month headache days (MHD), migraine disability assessment test (MIDAS), and migraine acute medications (MAM) were clinically relevant for both treatments.

COVID-Vaccines in Pregnancy: Maternal and Neonatal Response over the First 9 Months after Delivery.

Vaccination against SARS-CoV-2 has been demonstrated to be safe during gestation. Nevertheless, there are no robust data investigating the entity of maternal antibodies' transmission through the placenta to the newborn and the persistence of the antibodies in babies' serum. The objective of this study is to assess the maternal antibody transmission and kinetics among newborns in the first months of life. Women having received one or two doses of anti-SARS-CoV-2 mRNA-vaccines during pregnancy at any gestational age, and their newborns, were recruited and followed-up over 9 months. Ninety-eight women and 103 babies were included. At birth, we observed a significant positive correlation between maternal and neonatal serum anti-SARS-CoV-2 antibody levels and a significant negative correlation between the time since last dose and antibody levels in mothers with two doses. Over the follow-up, the birth antibody level significantly decreased in time according to the received doses number at 3, 6, and 9 months. During the follow-up, we registered 34 dyad SARS-CoV-2 infection cases. The decreasing trend was slower in the SARS-CoV-2 infection group and among breastfed non-infected babies. Antibodies from maternal anti-SARS-CoV-2 vaccination are efficiently transferred via the placenta and potentially even through breast milk. Among newborns, antibodies show relevant durability in the first months of life.

Long-Term Globus Pallidus Internus Deep Brain Stimulation in Pediatric Non-Degenerative Dystonia: A Cohort Study and a Meta-Analysis.

BACKGROUND: The evidence in the effectiveness of deep brain stimulation in children with medication-refractory non-degenerative monogenic dystonia is heterogeneous and long-term results are sparse. OBJECTIVES: The objective is to describe long-term outcomes in a single-center cohort and compare our results with a meta-analysis cohort form literature. METHODS: We performed a retrospective single-center cohort study including consecutive pediatric patients with non-degenerative genetic or idiopathic dystonia treated with globus pallidus internus deep brain stimulation at our center and a systematic review and individual-patient data meta-analysis with the same inclusion criteria. The primary outcome was the change from baseline in the Burke-Fahn-Marsden Dystonia Rating Scale-movement (BFMDRS-M) score. RESULTS: The clinical cohort included 25 patients with a mean study follow-up of 11.4 years. The meta-analysis cohort included 224 patients with a mean follow-up of 3 years. Overall, the BFMDRS-M mean improvements at 1 year and at last follow-up were 41% and 33% in the clinical cohort and 58.9% and 57.2% in the meta-analysis cohort, respectively. TOR1A-dystonia showed the greatest and most stable BFMDRS-M improvement in both cohorts at 1 year and at last follow-up (76.3% and 74.3% in the clinical cohort; 69.6% and 67.3% in the meta-analysis cohort), followed by SGCE-dystonia (63% and 63.9% in the meta-analysis cohort). THAP1-dystonia (70.1% and 29.8% in the clinical cohort; 52.3% and 42.0% in the meta-analysis cohort) and KMT2B-dystonia (33.3% and 41.3% in the clinical cohort; 38.0% and 26.7% in the meta-analysis cohort) showed a less pronounced or sustained response. CONCLUSION: Globus pallidus deep brain stimulation long-term treatment seems effective with a possible gene-specific differential effect. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Real-world effectiveness of Anti-CGRP monoclonal antibodies compared to OnabotulinumtoxinA (RAMO) in chronic migraine: a retrospective, observational, multicenter, cohort study.

BACKGROUND: Chronic migraine (CM) is a disabling condition with high prevalence in the general population. Until the recent approval of monoclonal antibodies targeting the calcitonin gene-related peptide (Anti-CGRP mAbs), OnabotulinumtoxinA (BoNT-A) was the only treatment specifically approved for CM prophylaxis. Direct comparisons between the two treatments are not available so far. METHODS: We performed an observational, retrospective, multicenter study in Italy to compare the real-world effectiveness of Anti-CGRP mAbs and BoNT-A. Patients with CM who had received either treatment according to Italian prescribing regulations were extracted from available clinical databases. Efficacy outcomes included the change from baseline in monthly headache days (MHD), MIgraine Disability ASsessment test (MIDAS), and monthly acute medications (MAM) evaluated at 6 and 12 months of follow-up. The primary outcome was MHD change from baseline at 12 months. Safety outcomes included serious adverse events (SAE) and treatment discontinuation. Unadjusted and adjusted models were used for the analyses. RESULTS: Two hundred sixteen potentially eligible patients were screened; 183 (86 Anti-CGRP mAbs; 97 BoNT-A) were included. One hundred seventy-one (80 Anti-CGRP mAbs; 91 BoNT-A) and 154 (69 Anti-CGRP mAbs; 85 BoNT-A) patients were included in the efficacy analysis at 6 and 12 months of follow-up, respectively. Anti-CGRP mAbs and BoNT-A both resulted in a mean MHD reduction at 6 (-11.5 and -7.2 days, respectively; unadjusted mean difference -4.3; 95%CI -6.6 to -2.0; p = 0.0003) and 12 months (-11.9 and -7.6, respectively; unadjusted mean difference -4.4; 95%CI -6.8 to -2.0; p = 0.0002) of follow-up. Similar results were observed after adjusting for baseline confounders. Anti-CGRP mAbs showed a significant MIDAS (-31.7 and -19.2 points, p = 0.0001 and p = 0.0296, respectively) and MAM reduction (-5.1 and -3.1 administrations, p = 0.0023 and p = 0.0574, respectively) compared to BoNT-A at 6 and 12 months. No SAEs were reported. One patient receiving fremanezumab discontinued treatment due to arthralgia. Treatment discontinuations, mainly for inefficacy, were comparable. CONCLUSION: Both Anti-CGRP mAbs and BoNT-A were effective in CM patients with Anti-CGRP mAbs presenting higher effect magnitude, with comparable safety. Still, BoNT-A remains a valuable option for CM patients with contraindications to Anti-CGRP mAbs or for frail categories who are candidates to local therapy with limited risk of systemic administration.

Exploring the risk of infection events in patients with asthma receiving anti-IL-5 monoclonal antibodies: A rapid systematic review and a meta-analysis.

Introduction: Benralizumab, mepolizumab, and reslizumab are novel monoclonal antibodies approved for asthma, targeting eosinophilic inflammation. Benralizumab is directed against IL-5 receptor (IL-5R), while mepolizumab and reslizumab are directed against IL-5. The three drugs cause a reduction in eosinophils, but benralizumab also causes a cytotoxic effect on eosinophils and basophils. Recently, it has been reported that suboptimal responders to benralizumab presented exacerbations associated with concomitant infections and sputum neutrophilia and the incidence of infections was greater in patients receiving benralizumab compared to mepolizumab and reslizumab. For this reason, we wanted to explore potential differences in terms of infectious adverse events between the three different anti-IL-5 antibodies. Methods: We performed a rapid systematic review on PubMed up to April 28, 2022. We included randomized controlled trials (RCTs) evaluating benralizumab, mepolizumab, or reslizumab in patients with asthma. Included outcomes were the reporting of any respiratory tract infection and any emergency department (ED) or hospital admission for infection or asthma exacerbation. A Mantel-Haenszel meta-analysis was performed with Cochrane RevMan 5.4 to estimate pooled odds ratios (OR) with 95 % confidence intervals (CI). A subgroup analysis for the different active treatments was performed. Results: From 163 references we included 21 studies reporting the results of 23 different RCTs for a total population of 9156 patients. All studies compared anti-IL-5 antibodies against placebo. Anti-IL-5 treatment resulted in non-significant differences compared to placebo in the odds for nasopharyngitis (OR = 0.90; 95 % CI from 0.76 to 1.07), pharyngitis (OR = 1.45; 95 % CI from 0.92 to 2.28), upper respiratory tract infection (URTI) (OR = 0.97; 95 % CI from 0.82 to 1.15), rhinitis (OR = 1.01; 95 % CI from 0.71 to 1.44), pneumonia (OR = 0.56; 95 % CI from 0.10 to 2.01), and influenza (OR = 0.84; 95 % CI from 0.65 to 1.09). We observed significant reductions in the reporting of sinusitis (OR = 0.75; 95 % CI from 0.53 to 1.06), bronchitis (OR = 0.71; 95 % CI from 0.59 to 0.86), and ED or hospital admission due to asthma exacerbation for overall anti-IL-5 antibodies compared to placebo (OR = 0.59; 95 % CI from 0.40 to 0.88). We were not able to discriminate whether exacerbations were associated with infections or to increased sputum eosinophilia. From the subgroup analysis, we observed differences in directions and magnitudes of the effect size in the reporting of some events. Benralizumab was associated with increased odds of pharyngitis (OR = 1.56; 95 % CI from 0.97 to 2.52) and a similar trend was observed for mepolizumab in the reporting of rhinitis (OR = 1.85; 95 % CI from 0.72 to 4.78), both non-statistically significant. In terms of effect size, benralizumab also showed higher odds for bronchitis and pneumonia in comparison to mepolizumab and reslizumab (OR = 0.76, OR = 0.69, and OR = 0.60 for bronchitis and OR = 0.80, OR = 0.20, and OR = 0.45, respectively, all non-significant). Conclusion: Anti-IL-5 treatments might have different effects on the reporting of some infection events in patients with asthma. However, the evidence is limited by sample size and far than conclusive and suggest the need of future studies to evaluate the risk of infections in patients with asthma receiving anti-IL-5 treatments.

Efficacy and safety of direct oral anticoagulants in the pediatric population: a systematic review and a meta-analysis.

BACKGROUND: Direct oral anticoagulants (DOACs) represent a cornerstone of adult venous thromboembolism (VTE) treatment. Recently, randomized controlled trials (RCTs) investigating DOACs in pediatrics have been performed. OBJECTIVES: To evaluate the efficacy and safety of DOACs in the pediatric population. METHODS: We systematically searched MEDLINE (PubMed), EMBASE, and ClinicalTrials.gov from initiation up to August 20, 2022, for RCTs comparing DOACs to standard of care (SOC) in patients aged <18 years according to PRISMA guidelines (PROSPERO registration CRD42022353870). The primary analysis was performed according to the anticoagulation intensity and clinical setting (ie, prophylaxis in cardiac disease or treatment in VTE). Efficacy outcomes were all-cause mortality and VTE. Safety outcomes were major bleeding (MB), clinically relevant non-MB, any bleeding, serious adverse events, and discontinuation due to adverse events (AEs). RESULTS: Seven RCTs were included in the systematic review and 6 in the meta-analysis (3 prophylaxis in cardiac disease and 3 treatment in VTE). DOACs showed a significant reduction of VTE recurrence for treatment (odds ratio [OR] = 0.42; 95% CI, 0.19-0.94) and a nonsignificant reduction in VTE occurrence in prophylaxis (OR = 0.22; 95% CI, 0.03-1.55). No differences were observed for any bleeding, serious AEs, and MB in prophylaxis. Nonsignificant trends were observed for clinically relevant non-MB, MB in treatment, and discontinuation due to AE in prophylaxis. We found a significant increase in discontinuation due to AE in treatment. CONCLUSIONS: DOAC treatment seems to reduce VTE compared with SOC without major safety issues in the pediatric population, whereas DOAC prophylaxis seems at least comparable to SOC.

Efficacy and Safety of Fenfluramine in Epilepsy: A Systematic Review and Meta-analysis.

INTRODUCTION: Fenfluramine (FFA) is an amphetamine derivative that promotes the release and blocks the neuronal reuptake of serotonin. Initially introduced as an appetite suppressant, FFA also showed antiseizure properties. This systematic review aimed to assess the efficacy and safety of FFA for the treatment of seizures in patients with epilepsy. METHODS: We systematically searched (in week 3 of June 2022) MEDLINE, the Cochrane Central Register of Controlled Trials, and the US National Institutes of Health Clinical Trials Registry. Randomized, double- or single-blinded, placebo-controlled studies of FFA in patients with epilepsy and uncontrolled seizures were identified. Efficacy outcomes included the proportions of patients with ≥ 50% and 100% reductions in baseline seizure frequency during the treatment period. Tolerability outcomes included the proportions of patients who withdrew from treatment for any reason and suffered adverse events (AEs). The risk of bias in the included studies was assessed according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions. The risk ratio (RR) along with the 95% confidence interval (CI) were estimated for each outcome. RESULTS: Three trials were identified and a total of 469 Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) subjects were randomized. All three trials were judged to be at low risk of biases. In patients with DS, the RRs for ≥ 50% and 100% reductions in convulsive seizure frequency for the FFA group compared to placebo were 5.61 (95% CI 2.73-11.54) and 4.71 (95% CI 0.57-39.30), respectively. In patients with LGS, the corresponding RRs for ≥ 50% and 100% reductions in drop seizure frequency were 2.58 (95% CI 1.33-5.02) and 0.50 (95% CI 0.031-7.81), respectively. The drug was withdrawn for any reason in 10.1% and 5.8% of patients receiving FFA and placebo, respectively (RR 1.79, 95% CI 0.89-3.59). Treatment discontinuation due to AEs occurred in 5.4% and 1.2% of FFA- and placebo-treated patients, respectively (RR 3.63, 95% CI 0.93-14.16). Decreased appetite, diarrhoea, fatigue, and weight loss were AEs associated with FFA treatment. CONCLUSION: Fenfluramine reduces the frequency of seizures in patients with DS and LGS. Decreased appetite, diarrhoea, fatigue, and weight loss are non-cardiovascular AEs associated with FFA.

Systematic Review and Meta-analysis Seem to Indicate that Cannabinoids for Chronic Primary Pain Treatment Have Limited Benefit.

INTRODUCTION: The IASP ICD-11 chronic primary pain (CPP) definition includes 19 different painful conditions. In recent years, interest in the potential role of cannabinoids in the management of CPP has increased, since they demonstrated a possible efficacy in treating pain, especially in secondary pain conditions. However, limited evidence is available for patients with CPP. The aim of this systematic review and meta-analysis is to evaluate the efficacy and safety of cannabinoid administration in CPP. METHODS: PubMed, EMBASE, and Cochrane Library were searched form the beginning up to 31 October 2021 to retrieve published articles of randomized controlled trials (RCTs) or observational, retrospective or prospective, studies, investigating cannabinoids in CPP. The study screening process was completed during November 2021. The primary outcome was pain reduction by means of the visual analogue scale (VAS). Secondary outcomes were quality of life by means of the fibromyalgia impact questionnaire (FIQ) or other available scales, appetite, anxiety, depression, and sleep by means of any available scales. Safety was assessed with the reporting of serious adverse events (SAE) and discontinuation due to adverse events. Risk of bias was assessed. The weighted generic inverse variance method and Mantel-Haenszel method were used to estimate the mean difference (MD) and odds ratios (OR) with 95% confidence intervals (CI) for continuous and dichotomous outcomes, respectively. For outcome measures reported with different scales (pain, anxiety, depression), we used the standardized MD (SMD) as the effect measure and then converted it into units of the VAS scale for pain, the Beck Anxiety Inventory (BAI) for anxiety, and the Beck Depression Inventory (BDI) for depression. Summary of findings was produced using GRADEproGDT. RESULTS: From 3007 identified records, we included eight articles reporting the results of eight different RCTs (four parallel and four crossover studies; seven compared to placebo and one to amitriptyline), with a total population of 240 patients. VAS pain reduction was non-significant for cannabinoids against placebo (MD = - 0.64; 95% CI - 1.30 to 0.02) or amitriptyline (MD = - 0.19; 95% CI - 0.58 to 0.19). More than 4 weeks cannabinoid treatment significantly reduced pain compared to placebo in parallel studies with more than 4 weeks of treatment duration (MD = - 1.28; 95% CI - 2.33 to - 0.22). Differences for the FIQ (MD = - 21.69; 95% CI - 46.20 to 2.82), BAI (MD = - 2.32; 95% CI - 7.99 to 3.08), and BDI (MD = 2.32; 95% CI - 1.71 to 6.35) were non-significant, likewise for discontinuation due to adverse events (OR = 2.15; 95% CI 0.44-10.65), when comparing cannabinoids to placebo. The quality of the evidence was generally low mainly as a result of imprecision and risk of bias. CONCLUSION: Cannabinoid treatment in patients with CPP had limited benefit on pain relief; however, it might improve pain with long-term administration.

Amifampridine safety and efficacy in spinal muscular atrophy ambulatory patients: a randomized, placebo-controlled, crossover phase 2 trial.

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive disease where a deficient amount of SMN protein leads to progressive lower motor neuron degeneration. SMN-enhancing therapies are now available. Yet, fatigue and signs of impaired neuromuscular junction (NMJ) transmission could contribute to SMA phenotype. Amifampridine prolongs presynaptic NMJ terminal depolarization, enhancing neuromuscular transmission. METHODS: SMA-001 was a phase 2, 1:1 randomized, double-blind, placebo-controlled crossover study. Ambulatory (walking unaided at least 30 m) SMA Type 3 patients, untreated with SMN-enhancing medications, entered a run-in phase where amifampridine was titrated up to an optimized stable dose. Patients achieving at least three points improvement in Hammersmith Functional Motor Score Expanded (HFMSE) were randomized to amifampridine or placebo, alternatively, in the 28-day double-blind crossover phase. Safety was evaluated by adverse events (AE) collection. Primary efficacy measure was the HFMSE change from randomization. Secondary outcomes included timed tests and quality of life assessment. Descriptive analyses and a mixed effects linear model were used for statistics. RESULTS: From 14 January 2019, 13 patients, mean age 34.5 years (range 18-53), with 5/13 (38.5%) females, were included. No serious AE were reported. Transient paresthesia (33.3%) was the only amifampridine-related AE. Six patients for each treatment sequence were randomized. Amifampridine treatment led to a statistically significant improvement in HFMSE (mean difference 0.792; 95% CI from 0.22 to 1.37; p = 0.0083), compared to placebo, but not in secondary outcomes. DISCUSSION: SMA-001 study provided Class II evidence that amifampridine was safe and effective in treating ambulatory SMA type 3 patients. CLINICAL TRIAL REGISTRATION: NCT03781479; EUDRACT 2017-004,600-22.

Anti-Spike IgG in multiple sclerosis patients after BNT162b2 vaccine: An exploratory case-control study in Italy.

BACKGROUND: Patients with neuroimmunological conditions such as multiple sclerosis (MS) often receive disease-modifying therapies (DMTs) or immunosuppressants which may reduce the response to vaccines. BNT162b2 (Pfizer-BioNTech) is the first COVID-19 vaccine authorized in Italy. Its clinical efficacy and serological response were not evaluated in MS patients receiving DMTs or immunosuppressants. This early multicenter study evaluated serological response to BNT162b2 and safety in these patients. METHODS: From February 2021 we enrolled consecutive MS patients, treated with at least one DMT and all healthcare workers (HCWs), having received or being scheduled to receive the first dose of BNT162b2. Blood samples were collected after the second vaccine dose and analyzed to quantitatively detect the presence of anti-Spike antibodies. Serological response was compared to the one from a control population of HCWs, with neither neuroimmunological conditions nor receiving immunosuppressants. Patients receiving treatments associated with a possible reduced response (Under-scrutiny treatment group) were also compared to those undergoing other treatments. Anti-Spike levels were described as median and interquartile range (IQR). Comparisons were performed with Wilcoxon-Mann-Whitney test. Solicited and unsolicited adverse events (AEs) were collected. RESULTS: 39 MS patients and a control population of 273 HCWs were included. One patient, under treatment with ocrelizumab, did not respond to BNT162b2, while all the remaining patients and all controls developed a serological response to the vaccine. Median anti-Spike levels were similar between patients (1471.0 BAU/ml; IQR 779.7 to 2357.0) and controls (1479.0 BAU/ml; IQR 813.1 to 2528.0) (p = 0.53). Patients included in the Under-scrutiny treatments group showed reduced anti-Spike levels (156.4 BAU/ml; IQR 33.4 to 559.1) compared to those receiving other treatments (1582.4 BAU/ml; IQR 1296.5 to 2219.0) (p = 0.001). Solicited AEs were all mild to moderate in severity, generally reported in the first days after vaccination, and resolved in the following days. Two MS patients reported a clinical relapse after the second vaccine dose. CONCLUSION: BNT162b2 induced a serological response in MS patients treated with DMTs similar to controls not receiving DMTs or immunosuppressants. Some treatments were associated with reduced levels of anti-Spike antibodies in patients. These observations have relevant implications for treated patients receiving BNT162b2 and the community.

A Systematic Review and a Meta-Analysis Comparing Prophylactic and Therapeutic Low Molecular Weight Heparins for Mortality Reduction in 32,688 COVID-19 Patients.

Background: Antithrombotic treatment, including low molecular weight heparin (LMWH) or unfractionated heparin (UFH), has been proposed as a potential therapy for coronavirus disease 2019 (COVID-19) to lower diffuse intravascular clotting activation. However, it is unclear whether prophylactic or therapeutic doses have similar efficacy in reducing mortality. Methods: We performed a systematic review (PROSPERO registration CRD42020179955) and meta-analysis including observational cohort studies and randomized controlled trials (RCT) evaluating the effectiveness of heparins (either LMWH, UFH, or fondaparinux) in COVID-19 patients. Heparin treatment was compared to no anticoagulation. A subgroup analysis on prophylactic or therapeutic doses compared to no anticoagulation was performed. Prophylactic dose was also compared to full dose anticoagulation. Primary endpoint was all-cause mortality. Secondary endpoints were major bleeding and length of hospital stay (LOS). Results: 33 studies (31 observational, 2 RCT) were included for a total overall population of 32,688 patients. Of these, 21,723 (66.5%) were on heparins. 31 studies reported data on all-cause mortality, showing that both prophylactic and full dose reduced mortality (pooled Hazard Ratio [HR] 0.63, 95% confidence interval [CI] 0.57-0.69 and HR 0.56, 95% CI 0.47-0.66, respectively). However, the full dose was associated with a higher risk of major bleeding (Odds Ratio [OR] 2.01, 95% CI 1.14-3.53) compared to prophylactic dose. Finally, LOS was evaluated in 3 studies; no difference was observed between patients with and without heparins (0.98, -3.87, 5.83 days). Conclusion: Heparin at both full and prophylactic dose is effective in reducing mortality in hospitalized COVID-19 patients, compared to no treatment. However, full dose was associated with an increased risk of bleeding. Systematic Review Registration: https://clinicaltrials.gov/, identifier CRD42020179955.

Deep brain stimulation in Huntington's disease: a literature review.

BACKGROUND: Huntington's disease (HD) is a neurodegenerative disorder characterized by involuntary movements, cognitive decline, and behavioral changes. The complex constellation of clinical symptoms still makes the therapeutic management challenging. In the new era of functional neurosurgery, deep brain stimulation (DBS) may represent a promising therapeutic approach in selected HD patients. METHODS: Articles describing the effect of DBS in patients affected by HD were selected from Medline and PubMed by the association of text words with MeSH terms as follows: "Deep brain stimulation," "DBS," and "HD," "Huntington's disease," and "Huntington." Details on repeat expansion, age at operation, target of operation, duration of follow-up, stimulation parameters, adverse events, and outcome measures were collected. RESULTS: Twenty eligible studies, assessing 42 patients with HD, were identified. The effect of globus pallidus internus (GPi) DBS on Unified Huntington's Disease Rating Scale (UHDRS) total score revealed in 10 studies an improvement of total score from 5.4 to 34.5%, and in 4 studies, an increase of motor score from 3.8 to 97.8%. Bilateral GPi-DBS was reported to be effective in reducing Chorea subscore in all studies, with a mean percentage reduction from 21.4 to 73.6%. CONCLUSIONS: HD patients with predominant choreic symptoms may be the best candidates for surgery, but the role of other clinical features and of disease progression should be elucidated. For this reason, there is a need for more reliable criteria that may guide the selection of HD patients suitable for DBS. Accordingly, further studies including functional outcomes as primary endpoints are needed.

Overall Efficacy and Safety of Safinamide in Parkinson's Disease: A Systematic Review and a Meta-analysis.

BACKGROUND AND OBJECTIVE: Safinamide is a novel anti-parkinsonian drug with possible anti-dyskinetic properties. Parkinson's disease (PD) is a complex disease. The objective of this systematic review and meta-analysis is to evaluate the efficacy and safety of safinamide administration compared to placebo in PD patients on multiple outcomes. METHODS: PubMed, EMBASE, Cochrane CENTRAL, LILACS, and trial databases were searched up to 23 December 2020 for randomized controlled studies (RCTs) comparing safinamide to placebo, alone or as add-on therapy in PD. Data were extracted from literature and regulatory agencies. Primary outcomes were ON-time without troublesome dyskinesia, OFF-time, and Unified Parkinson's Disease Rating Scale (UPDRS) section III (UPDRS-III). Secondary outcomes included any dyskinesia rating scale (DRS), ON-time with troublesome dyskinesia, UPDRS-II, and Parkinson's Disease Questionnaire 39 (PDQ-39). In order to estimate mean difference (MD) and odds ratios with 95% confidence intervals (CI), generic inverse variance and Mantel-Haenszel methods were used for continuous and dichotomous variables, respectively. Analyses were performed grouping by PD with (PDwMF) or without (PDwoMF) motor fluctuations, safinamide dose, and concomitant dopaminergic treatment. Summary of findings with GRADE were performed. RESULTS: Six studies with a total of 2792 participants were identified. In PDwMF patients, safinamide 100 mg as add-on to levodopa (L-dopa) significantly increased ON-time without troublesome dyskinesia (MD = 0.95 h; 95% CI from 0.41 to 1.49), reduced OFF-time (MD = - 1.06 h; 95% CI from - 1.60 to - 0.51), and improved UPDRS-III (MD = - 2.77; 95% CI from - 4.27 to - 1.28) with moderate quality of evidence. Similar results were observed for the 50 mg dose. However, the quality of evidence was moderate only for ON-time without troublesome dyskinesia, whereas for OFF-time and UPDRS-III was low. In PDwoMF patients taking a single dopamine agonist, safinamide 100 mg resulted in little to no clinically significant improvement in UPDRS-III (MD = - 1.84; 95% CI from - 3.19 to - 0.49), with moderate quality of evidence. Conversely, in PDwoMF patients, the 200 mg and 50 mg doses showed nonsignificant improvement in UPDRS-III, with very low and moderate quality of evidence, respectively. In PDwMF patients taking safinamide 100 mg or 50 mg, nonsignificant differences were observed for ON-time with troublesome dyskinesia and DRS, with high and low quality of evidence, respectively. In the same patients, UPDRS-II was significantly improved at the 100 mg and 50 mg dose, with high and moderate quality of evidence. In PDwoMF, UPDRS-II showed a little yet significant difference only at 100 mg, with low quality of evidence. PDQ-39 resulted significantly improved only with the 100 mg dose in PDwMF, with low quality of evidence. CONCLUSION: Overall, safinamide is effective in PDwMF patients taking L-dopa both at 100 and 50 mg daily. Evidence for efficacy in early PD is limited. Further trials are needed to better evaluate the anti-dyskinetic properties of safinamide.

Iatrogenic Kaposi's sarcoma in myasthenia gravis: learnings from two case reports.

INTRODUCTION: Myasthenia gravis (MG) is an autoimmune neuromuscular disease whose treatment encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants. Kaposi's sarcoma (KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or immunosuppression, mainly corticosteroids. CASE REPORTS: We present two cases of MG patients treated with oral steroids who developed KS. Patient 1 was diagnosed with three oral KS lesions. Prednisone was discontinued with lesion regression and stabilization, while azathioprine and pyridostigmine prompted control of MG. Patient 2 developed KS lesions on the trunk and lower limbs while taking prednisone and azathioprine. Steroid tapering was started but new oral and lymph nodal lesions appeared. Paclitaxel therapy was introduced and the patient experienced pulmonary embolism and developed sensitive neuropathy. Complete remission of KS lesions was achieved and maintained with azathioprine and pyridostigmine as MG medications. CONCLUSIONS: KS is an uncommon but clinically relevant adverse event (AE) often induced by steroid therapy. It can be controlled by steroid withdrawal but could necessitate chemotherapy, which associates with further potential AEs. Skin evaluation should be performed in all patients with chronic steroid therapy. Steroid-sparing strategies, including new drugs, could reduce KS and other steroid-related comorbidities. HHV-8 testing should be considered before starting chronic immunosuppression.

Inositol and Non-Alcoholic Fatty Liver Disease: A Systematic Review on Deficiencies and Supplementation.

Liver lipid accumulation is a hallmark of non-alcoholic fatty liver disease (NAFLD), broadly associated with insulin resistance. Inositols (INS) are ubiquitous polyols implied in many physiological functions. They are produced endogenously, are present in many foods and in dietary supplements. Alterations in INS metabolism seems to play a role in diseases involving insulin resistance such as diabetes and polycystic ovary syndrome. Given its role in other metabolic syndromes, the hypothesis of an INS role as a supplement in NAFLD is intriguing. We performed a systematic review of the literature to find preclinical and clinical evidence of INS supplementation efficacy in NAFLD patients. We retrieved 10 studies on animal models assessing Myoinosiol or Pinitol deficiency or supplementation and one human randomized controlled trial (RCT). Overall, INS deficiency was associated with increased fatty liver in animals. Conversely, INS supplementation in animal models of fatty liver reduced hepatic triglycerides and cholesterol accumulation and maintained a normal ultrastructural liver histopathology. In the one included RCT, Pinitol supplementation obtained similar results. Pinitol significantly reduced liver fat, post-prandial triglycerides, AST levels, lipid peroxidation increasing glutathione peroxidase activity. These results, despite being limited, indicate the need for further evaluation of INS in NAFLD in larger clinical trials.