Acetylcholinesterase inhibitors are ineffective in MuSK-antibody positive myasthenia gravis: Results of a study on 202 patients.

BACKGROUND: Myasthenia gravis (MG) with MuSK antibodies (MuSK-MG) represents a distinct subtype with different responses to treatments compared to patients with AChR antibodies, especially in terms of tolerance to acetylcholinesterase inhibitors (AChEI). However, AChEI are often used as first line symptomatic treatment in MuSK-MG, despite reports that they are poorly tolerated, seldom effective or even deleterious. METHODS: We analyzed demographic, clinical and therapeutic responses and side-effects in the large cohort of 202 MuSK-MG patients cared for at the MG Clinic of Azienda Ospedaliero-Universitaria Pisana. RESULTS: 165 patients had received AChEI at first evaluation. Only 7/165 patients (4.2%) reported an initial clinical benefit. Conversely, 76.9% of patients reported at least one side effect, most commonly neuromuscular hyperexcitability (68.4%), gastrointestinal (53.9%) and neurovegetative (35.8%) disturbances. 56 (33.9%) patients reported a concomitant worsening of muscle weakness and twelve patients (7.3%) suffered a cholinergic crisis. According to these patients, the severity of cholinergic side effects was greater at higher doses of AChEI, but side effects occurred regardless of the dose administered and ceased once the drug was discontinued. CONCLUSIONS: This is the largest population of MuSK-MG patients reported for perceived responsiveness and tolerance to AChEI treatment. Our obervations strongly suggest avoiding this treatment in MuSK-MG.

Gender differences in microRNA expression in levodopa-naive PD patients.

Gender is an important factor influencing epidemiological and clinical features of Parkinson's disease (PD). We aimed to evaluate gender differences in the expression of a panel of miRNAs (miR-34a-5p, miR-146a, miR-155, miR-29a, miR-106a) possibly involved in the pathophysiology or progression of disease. Serum samples were obtained from 104 PD patients (58 men and 46 women) never treated with levodopa. We measured levels of miRNAs using quantitative PCR. Correlations between miRNA expression and clinical data were assessed using the Spearman's correlation test. We used STRING to evaluate co-expression relationship among target genes. MiR-34a-5p was significantly upregulated in PD male patients compared to PD female patients (fc: 1.62; p < 0.0001). No correlation was found with age, BMI, and disease severity, assessed by UPDRS III scale, in male and female patients. MiR-146a-5p was significantly upregulated in female as compared to male patients (fc: 3.44; p < 0.0001) and a significant correlation was also observed between disease duration and mir-146a-5p. No differences were found in the expression of miR-29a, miR-106a-5p and miR-155 between genders. Predicted target genes for miR-34a-5p and miR-146-5p and protein interactions in biological processes were reported. Our study supports the hypothesis that there are gender-specific differences in serum miRNAs expression in PD patients. Follow-up of this cohort is needed to understand if these differences may affect disease progression and response to treatment.

Evaluation of Intraoperative End-Tidal Carbon Dioxide Change Relates to Length Hospitalisation in Peridiaphragmatic Surgery: A Pilot Study.

Intraoperative evaluation is deeply changed using many new tools, both invasive and non-invasive. Peripheral oxygen saturation percentage (SpO2) is the more reliable method for a non-invasive monitoring of patient's blood oxygen concentration. Capnography (using end-tidal CO2 (EtCO2)) evaluation is an immediate and continuous non-invasive monitoring of carbon dioxide (CO2) in the breathing that provides important information on circulatory status and ventilation.Aim of this study is to perform a preliminary analysis of oxygen change during surgery exploring its possible influence on post-operative evolution. METHODS AND RESULTS: Intraoperative evaluation of SpO2 and EtCO2 was performed. Change in each parameter was categorised as 1 point for each five-point variation from baseline value (∆SpO2 as 1 point for each 5%, ∆EtCO2 as 1 point for each 5 mmHg). For each patient, the length of stay (LOS) in the intensive care unit (ICU), total hospitalisation, duration of intervention, surgical risk and complications were recorded. RESULTS: We analysed 93 consecutive patients (43 males and 40 females, aged 66.35 ± 9.79 years) that underwent peridiaphragmatic surgery. Forty patients (48.19%) presented complications after surgery. There was no statistically significant difference in age, duration of intervention and length of stay in ICU between complicated and non-complicated patients. As expected, patients with complications present an increased hospitalisation time compared to uncomplicated cases (14.69 ± 11.41 days vs 10.70 ± 6.28 days; p < 0.05). ∆EtCO2 was significantly increased (p < 0.05) in complicated compared to non-complicated. No differences were found in ∆SpO2 between the two groups. Considering the whole population, ∆EtCO2 presents a significant direct correlation to surgical risk, hospitalisation and duration of intervention. CONCLUSION: ∆EtCO2 may be related to possible complications after surgery and hospitalisation. An important comparison between SpO2 and EtCO2 and strict monitoring with an intraoperative arterial blood gas (ABG) sample during the main steps of surgery could bring some essential information to understand oxygen changes in intra- and post-operative evolution. However, a further validation analysis is needed before the approach can be used extensively in daily clinical settings.

Severe inflammatory myopathy in a pulmonary carcinoma patient treated with Pembrolizumab: An alert for myologists.

Immune-related adverse events (irAE) during the administration of immune-checkpoint inhibitors (ICIs) become more evident due to the increased use of these therapies. To remind the importance of early recognition of this phenomenon, we report a paradigmatic case characterized by severe systemic inflammatory myopathy and severe cardiac involvement that abruptly precipitated in an untoward ending after one single dose of Pembrolizumab.

Combination of photodynamic therapy with 5-aminolaevulinic acid and microneedling in the treatment of alopecia areata resistant to conventional therapies: our experience with 41 patients.

Alopecia areata (AA) is a complex immune-mediated disorder, which is difficult to treat. The available treatment options seem to have limited benefit, help only some patients and have a high relapse rate. We evaluated a new therapeutic option for moderate to severe AA based on the combination of photodynamic therapy (PDT) with 5-aminolaevulinic acid (ALA) and microneedling (MN). In total, 14 patients were enrolled, and these were randomly divided into 3 groups: Group A (MN alone; n = 9), Group B (ALA-PDT alone; n = 15) and Group C (combination of MN and ALA-PDT; n = 17). All patients were treated once every 3 weeks for a total of six treatments. The best clinical outcome was achieved in Group C, with complete hair regrowth observed in three patients, and an improvement of ≥ 50% and < 50% of the treated areas obtained in seven and six patients, respectively. Our report suggests that combination of ALA-PDT with MN could be an additional therapeutic option in moderate to severe AA, as MN allows better skin penetration of ALA and subsequent indirect immunosuppression.

Clinical predictors of Dimethyl Fumarate response in multiple sclerosis: a real life multicentre study.

BACKGROUND: Dimethyl-fumarate (DMF) was effective and safe in relapsing-remitting multiple sclerosis (MS) in randomized clinical trials. We aimed to evaluate the efficacy and safety of DMF and factors related to drug response in real-life setting. METHODS: We analysed prospectively collected demographic and clinical data for patients treated with DMF in six multiple sclerosis (MS) centers from 2015 to 2017 in Campania region, Italy. We performed univariate and multivariate analyses to assess relationships between baseline parameters and DMF efficacy outcomes, Annualized Relapse Rate (ARR), Expanded Disability Status Scale (EDSS) progression and No Evidence of Disease Activity (NEDA-3) status. RESULTS: we analyzed data of 456 patients (67% female subjects, mean age 40 ± 12 years, mean disease duration 9 ± 9 years, mean treatment duration 18 ± 11 months, median EDSS 2.5, 0-8). Proportion of Naïve versus pretreated with other DMTs patients was 149/307 (32.7%), with 122 patients switching to DMF for disease activity (26.7%) and 185 for safety and tolerability issues (40.6%). During treatment with DMF, the annualized relapse rate was reduced by 75% respect to the pre-treatment ARR [incidence-rate-ratio (IRR) = 0.25, p < 0.001, CI 0.18-0.33]. Factors influencing ARR rate while on DMF were relapsing remitting (RR) MS course (IRR = 2.0, p = <0.001, CI 1.51-2.73) and previous DMTs status: de-escalating from second-line therapies was associated to higher risk of relapsing (IRR = 1.8, p < 0.001, CI 1.39-2.31). At multivariable Cox proportional hazard model, only age of onset was related with rate or relapses, with younger age being protective (HR 0.96, p = 0,02). EDSS remained stable in 88% of patients. Disease duration was associated with higher rate of NEDA-3 failure, that was instead maintained in 65% of patients at 24 months. 109 patients (22%) discontinued therapy after a mean of 1.1 ±+ 0.7 years. Reasons for DMF discontinuation over time were lack of efficacy (50%), safety issues (30%), tolerability (7%), poor compliance (7%), and pregnancy (4%). Higher pre-treatment EDSS was associated with DMF discontinuation (p = 0.009). Only 33 patients dropped out due to safety reasons (7%), the most frequent safety issues driving to drop out being lymphopenia, liver/pancreatic enzymes increase, gatrointestinal severe tolerability issues. We recorded 95 cases (24%) of lymphopenia: 60 grade I (13%), 31 grade II (7%) and 4 grade III (1%). CONCLUSIONS: We confirm that DMF shows a good efficacy in both naïve patients and patients switching from other first-line DMTs, especially in patients with early onset of disease. Higher baseline EDSS was a risk factor for discontinuing DMF therapy, while shorter disease duration was protective for both EDSS progression and NEDA-3 status maintenance.

Acquired neuromyotonia in thymoma-associated myasthenia gravis: a clinical and serological study.

BACKGROUND AND PURPOSE: Acquired neuromyotonia can occur in patients with thymoma, alone or in association with myasthenia gravis (MG), but the clinical prognostic significance of such comorbidity is largely unknown. The clinico-pathological features were investigated along with the occurrence of neuromyotonia as predictors of tumour recurrence in patients with thymoma-associated myasthenia. METHODS: A total number of 268 patients with thymomatous MG were studied retrospectively. Patients with symptoms of spontaneous muscle overactivity were selected for autoantibody testing using immunohistology for neuronal cell-surface proteins and cell-based assays for contactin-associated protein 2 (CASPR2), leucine-rich glioma inactivated 1 (LGI1), glycine receptor and Netrin-1 receptor antibodies. Neuromyotonia was diagnosed according to the presence of typical electromyography abnormalities and/or autoantibodies against LGI1/CASPR2. RESULTS: Overall, 33/268 (12%) MG patients had a thymoma recurrence. Five/268 (2%) had neuromyotonia, four with typical autoantibodies, including LGI1 (n = 1), CASPR2 (n = 1) or both (n = 2). Three patients had Netrin-1 receptor antibodies, two with neuromyotonia and concomitant CASPR2+LGI1 antibodies and one with spontaneous muscle overactivity without electromyography evidence of neuromyotonia. Thymoma recurrence was more frequent in those with (4/5, 80%) than in those without (28/263, 10%, P < 0.001) neuromyotonia. Neuromyotonia preceded the recurrence in 4/5 patients. In univariate analysis, predictors of thymoma recurrence were age at thymectomy [odds ratio (OR) 0.95, 95% confidence interval (CI) 0.93-0.97], Masaoka stage ≥IIb (OR 10.73, 95% CI 2.38-48.36) and neuromyotonia (OR 41.78, 95% CI 4.71-370.58). CONCLUSIONS: De novo occurrence of neuromyotonia in MG patients with previous thymomas is a rare event and may herald tumour recurrence. Neuronal autoantibodies can be helpful to assess the diagnosis. These observations provide pragmatic risk stratification for tumour vigilance in patients with thymomatous MG.

Retrospective analysis of HDFN due to ABO incompatibility in a single institution over 6 years.

OBJECTIVES: To study the rate of ABO haemolytic anaemia of fetus and newborn (HDFN) in one institution over 6 years. BACKGROUND: ABO major incompatibility between mothers and their newborns occurs in about 10% of births. So, mothers with an O blood group may form IgG-class antibodies against A and B antigens, which could pass across the placenta and lead to a variable degree of HDFN in the newborn. METHODS: At our institution, we have reviewed data regarding ABO-based HDFN in the last 6 years. RESULTS: We found that, in 28 089 deliveries, an ABO major incompatibility between mothers and newborns occurs in 11% of cases, with 72% of O/A and 28% of O/B incompatibility. In turn, 23% of these newborns had an eluate-confirmed positive direct antiglobulin test [DAT; 74% (511) were due to anti-A and 26% (179) to anti-B], with 1·0% requiring invasive treatments (exchange transfusion or intravenous immunoglobulin). Overall, 2·5% of the total newborns had a positive DAT for an anti-A or anti-B antibody, and 0·11% required invasive treatment in addition to phototherapy for their HDFN. CONCLUSIONS: Serological ABO HDFN is a relatively frequent event when an O-A/O-B incompatibility between mothers and their newborn occurs and, in most cases, translates into a self-limiting disease, with a small number of newborns requiring invasive treatments. The DAT test, although not predictive of disease severity, appears to be a useful tool to monitor babies born from O-A/O-B-incompatible pregnancies and to identify those who may require treatment.

Olfactory function and cognition in relapsing-remitting and secondary-progressive multiple sclerosis.

BACKGROUND: Both cognition and olfaction are impaired in multiple sclerosis (MS). However, little is known about the relationship between smell identification ability and measures of cognitive function in this disease. OBJECTIVE: To assess olfactory function in MS and to evaluate its relationship with cognitive and physical disability. METHODS: Fifty-five MS patients and 20 healthy controls (HCs) were tested. The University of Pennsylvania smell identification test (UPSIT) was administered to assess olfactory function. Cognitive function was tested using the symbol digit modalities test (SDMT), California verbal learning test-II (CVLT II), brief visuospatial memory test (BVMT), paced auditory serial addition test (PASAT), and controlled oral word association test (COWAT). Fatigue and depressive symptoms were evaluated using the Modified Fatigue Impact Scale and the Beck Depression Inventory II, respectively. RESULTS: MS patients had lower UPSIT scores than those of the HCs (28.76 ±â€¯5.48 vs 31.7 ±â€¯2.18, p = 0.02), with secondary-progressive and cognitively impaired MS patients showing the greatest impairment. Scores on the SDMT, CVLTII, BVMT and COWAT were related to the olfactory test scores. CONCLUSION: We confirm that olfactory function is impaired in MS, particularly in progressive phenotypes, and show, for the first time, that such dysfunction is related to a broad range of cognitive measures. Our data suggest that olfactory dysfunction might be considered as an indirect measure of MS severity. Longitudinal studies are needed to confirm this possibility.

A longitudinal real-life comparison study of natalizumab and fingolimod.

BACKGROUND: Different retrospective studies compared natalizumab and fingolimod in relapsing-remitting multiple sclerosis (RRMS), with conflicting results. We aimed to explore the prescriptive attitude and the clinical outcome of the two therapies. METHODS: We retrospectively included all RRMS patients treated with natalizumab (n=101) or fingolimod (n=78) as their first second-line therapy with at least 24-month follow-up. Demographic and clinical features were recorded to calculate the propensity score (PS). Outcomes of interest were annualized relapse rate (ARR), risk of relapse, and change in the EDSS RESULTS: At baseline, natalizumab patients were younger and had a shorter disease duration, a higher number of relapse in 1 year (1yR) and 2 years (2yR) and overall (ARR-PT) pretherapy, compared to fingolimod patients. On therapy, the proportion of relapsing patients and the mean RR were similar in the two groups. However, the change in the ARR was higher in natalizumab than in fingolimod group (P<.002), but, using PS as a covariate, it was comparable (P=.960). Similarly, the change in EDSS was significantly different for the two groups (P<.004), but not after adjusting for the PS (P=.321). CONCLUSION: We observed a comparable efficacy on ARR reduction and on EDSS progression with natalizumab and fingolimod correcting through PS, suggesting that the efficacy difference observed before correction might derive from the clinical attitude in prescribing natalizumab in more active MS patients in real life.

Non-motor symptoms and cardiac innervation in SYNJ1-related parkinsonism.

INTRODUCTION: PARK20 is a rare autosomal recessive parkinsonism related to the SYNJ1 gene and characterized by early-onset of disease and atypical signs such as supranuclear vertical gaze palsy, dementia, dystonia, and generalized tonic-clonic seizures. OBJECTIVE: Non-motor features and cardiac sympathetic innervation were assessed in two siblings affected by parkinsonism who harboured the homozygous Arg258Gln mutation in the SYNJ1 gene. METHODS: The Non-Motor Symptoms, the SCOPA-AUT, the Mayo Sleep Questionnaires and polysomnography were used to investigate non-motor signs (NMS), autonomic dysfunction and REM Behavioural Disorder (RBD). Cognitive functions were examined by an extensive battery of neuropsychological tests. In addition, motor and sensory nerve conduction studies and evoked laser potentials were performed. Cardiac sympathetic innervation was assessed in the two patients by (123)I-metaiodobenzylguanidine (MIBG) scintigraphy, computing early and late heart-to-mediastinum (H/M) ratios and myocardial washout rates (WR). RESULTS: Among the non-motor symptoms and autonomic signs, case 1 had cold intolerance, drooling and dysphagia, while case 2 had pain and urinary dysfunction. Both cases showed mood and behavioural disorders. RBD were not found, whereas the neuropsychological assessment revealed a progressive cognitive impairment. Neurophysiological studies revealed no abnormalities. Indexes of cardiac sympathetic innervation in the two patients did not differ from those of control subjects. CONCLUSIONS: Our findings expand the phenotypic profile of SYNJ1-related parkinsonism. Preserved cardiac sympathetic function and absence of RBD suggest that PARK20 should be explained by a pathogenic mechanism different from Lewy Body pathology, or that the latter is not as widespread as idiopathic Parkinson's disease.

An international surgical collaboration: humanitarian surgery in Brazil.

PURPOSE: Brazil is the fifth most populous country in the world with widespread regional and social inequalities. Regional disparities in healthcare are unacceptably large, with the remote and poor regions of the north and northeast having reduced life expectancy compared to the south region, where life expectancy approaches that of rich countries. We report our experience of a humanitarian surgery mission to the Amazonas state, in the northwest part of Brazil. METHODS: In August 2014, a team of seven consultant surgeons, and two trainees with the charity 'International Hernia', visited three hospitals in the Amazonas state to provide hernia surgery and training. RESULTS: Eighty-nine hernias were repaired in 74 patients (female = 22, male = 52) with a median age of 44 years (range 2-83 years). Nine patients underwent more than one type of hernia repair, and there were 9 laparoscopic inguinal and ventral incisional hernia repairs. Local doctors were trained in hernia repair techniques, and an International Hernia Symposium was held at the University of the State of Amazonas, Manaus. CONCLUSION: The humanitarian mission provided hernia surgery to an underserved population in Brazil and training to local doctors, building local sustainability. Continued cooperation between host and international surgeons for future missions to Brazil will ensure continuing surgical training and technical assistance.

The Framingham cardiovascular risk score in multiple sclerosis.

BACKGROUND AND PURPOSE: Cardiovascular risk factors can increase the risk of multiple sclerosis (MS) and modify its course. However, such factors possibly interact, determining a global cardiovascular risk. Our aim was to compare the global cardiovascular risk of subjects with and without MS with the simplified 10-year Framingham General Cardiovascular Disease Risk Score (FR) and to evaluate its importance on MS-related outcomes. METHODS: Age, gender, smoking status, body mass index, systolic blood pressure, type II diabetes and use of antihypertensive medications were recorded in subjects with and without MS to estimate the FR, an individualized percentage risk score estimating the 10-year likelihood of cardiovascular events. RESULTS: In total, 265 MS subjects were identified with 530 matched controls. A t test showed similar FR in cases and controls (P = 0.212). Secondary progressive MS presented significantly higher FR compared to relapsing-remitting MS (P < 0.001). Linear regression analysis showed a direct relationship between FR and Expanded Disability Status Scale (P < 0.001) and MS Severity Scale (P < 0.001). CONCLUSION: The FR, evaluating the global cardiovascular health by the interaction amongst different risk factors, relates to MS disability, severity and course.

Carbon nanotubes: Properties, biomedical applications, advantages and risks in patients and occupationally-exposed workers.

Since the beginning of the 21st century, carbon-based nanomaterials (CNTs) have been introduced in pharmacy and medicine for drug delivery system in therapeutics. CNTs have proved able to transport a wide range of molecules across membranes and into living cells; therefore, they have attracted great interest in biomedical applications such as advanced imaging, tissue regeneration, and drug or gene delivery. Although there are many data on the advantages in terms of higher efficacy and less adverse effects, several recent findings have reported unexpected toxicities induced by CNTs. The dose, shape, surface chemistry, exposure route, and purity play important roles in these differential toxicities. Mapping these risks as well as understanding their molecular mechanisms is a crucial step in the development of any CNT-containing nanopharmaceuticals. This paper seeks to provide a comprehensive review of all articles published on cellular response to CNTs, underlining their therapeutic applications and possible toxicity in patients and occupationally exposed workers.