Methodological Quality of Clinical Trials in Amyotrophic Lateral Sclerosis: A systematic Review.

Background: More than 200 clinical trials have been performed worldwide in ALS so far, but no agents with substantial efficacy on disease progression have been found. Objective: To describe the methodological quality of all clinical trials performed in ALS and published before December 31, 2022. Methods: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta Analyses. Results: 213 trials were included. 47.4% manuscripts described preclinical study evaluation, with a positive effect in all. 67.6% of trials were conducted with a parallel-arm design, while 12.7% were cross-over studies; 77% were randomized, while in 5.6% historical-controls were used for comparison. 70% of trials were double blind. Participant inclusion allowed forced vital capacity (or corresponding slow vital capacity)<50% in 15% cases, between 55-65% in 21.6%, between 70-80% in 14.1% reports, and 49.3% of the evaluated manuscripts did not provide a minimum value for respiratory capacity at inclusion. Disease duration was <  6-months in 6 studies, 7-36 months in 68, 37-60 months in 24, 8 trials requested more than 1-month of disease duration, while in 107 reports a disease duration was not described. Dropout rate was ≥20% in 30.5% trials, while it was not reported for 8.5% . Conclusion: The methodological quality of the included studies was highly variable. Major issues to be addressed in future ALS clinical trials include: the requirement for standard animal toxicology and phase I studies, the resource-intensive nature of phase II-III studies, adequate study methodology and design, a good results reporting.

Comparison of Baseline and Post-Nitrate Exercise Testing in Patients with Angina but Non-Obstructed Coronary Arteries with Different Acetylcholine Test Results.

Background: Intracoronary acetylcholine testing may induce epicardial coronary artery spasm (CAS) or coronary microvascular spasm (CMVS) in patients with angina syndromes but non-obstructive coronary artery disease, but their causal role in individual patients is not always clear. In this prospective, observational single-center study, we aimed to assess whether (1) the induction of myocardial ischemia/angina by electrocardiogram (ECG) exercise stress test (EST) differs between patients showing different results in response to acetylcholine testing (i.e., CAS, CMVS, or no spasm); (2) the preventive administration of short-acting nitrates has any different effects on the EST of those patients who showed a positive basal EST. We expected that if exercise-induced angina and/or ischemic ECG changes are related to CAS, they should improve after nitrates administration, whereas they should not significantly improve if they are caused by CMVS. Methods: We enrolled 81 patients with angina syndromes and non-obstructive coronary artery disease, who were divided into three groups according to acetylcholine testing: 40 patients with CAS (CAS-group), 14 with CMVS (CMVS-groups), and 27 with a negative test (NEG-group). All patients underwent a basal EST (B-EST). Patients with a positive B-EST repeated the test 24-48 h later, 5 min after the administration of short-acting nitrates (N-EST). Results: There were no significant differences among the groups in terms of the B-EST results. B-EST was positive in eight (20%) patients in the CAS-group, seven (50%) in the CMVS-group, and six (22%) in the NEG-group (p = 0.076). N-EST, performed in eight, six, and five of these patients, also showed similar results in the three groups. Furthermore, the N-EST results also did not significantly differ compared to B-EST in any group, remaining positive in seven (87.5%), four (66.7%), and four (80%) patients in the CAS-group, CMVS-group, and NEG-group, respectively (p = 0.78). Conclusions: Our data show that patients with angina and non-obstructive coronary artery disease show largely comparable results of the ECG exercise stress test and similar poor effects of short-acting nitrates on abnormal ECG exercise stress test results. On the whole, our findings suggest caution in attributing to the results of Ach testing a definite causal role for the clinical syndrome in individual patients.

Inflammation and acute cardiotoxicity in adult hematological patients treated with CAR-T cells: results from a pilot proof-of-concept study.

AIMS: Chimeric Antigen Receptor-T (CAR-T) cell infusion is a rapidly evolving antitumor therapy; however, cardiovascular (CV) complications, likely associated with cytokine release syndrome (CRS) and systemic inflammation, have been reported to occur. The CARdio-Tox study aimed at elucidating incidence and determinants of cardiotoxicity related to CAR-T cell therapy. METHODS: Patients with blood malignancies candidate to CAR-T cells were prospectively evaluated by echocardiography at baseline and 7 and 30 days after infusion. The study endpoints were i) incidence of cancer therapy-related cardiac dysfunction (CTRCD), CTRCD were also balanced for any grade CRS, but CTRCD occurred of Cardiology Guidelines on Cardio-Oncology (decrements of left ventricular ejection fraction (LVEF) or global longitudinal strain (GLS) and/or elevations of cardiac biomarkers (high sensitivity troponin I, natriuretic peptides) and ii), correlations of echocardiographic metrics with inflammatory biomarkers. RESULTS: Incidence of CTRCD was high at 7 days (59,3%), particularly in subjects with CRS. The integrated definition of CTRCD allowed the identification of the majority of cases (50%). Moreover, early LVEF and GLS decrements were inversely correlated with fibrinogen and interleukin-2 receptor levels (p always ≤ 0.01). CONCLUSIONS: There is a high incidence of early CTRCD in patients treated with CAR-T cells, and a link between CTRCD and inflammation can be demonstrated. Dedicated patient monitoring protocols are advised.

A Delphi consensus to identify the key screening tests/questions for a digital neurological examination for epidemiological research.

BACKGROUND: Most neurological diseases have no curative treatment; therefore, focusing on prevention is key. Continuous research to uncover the protective and risk factors associated with different neurological diseases is crucial to successfully inform prevention strategies. eHealth has been showing promising advantages in healthcare and public health and may therefore be relevant to facilitate epidemiological studies. OBJECTIVE: In this study, we performed a Delphi consensus exercise to identify the key screening tests to inform the development of a digital neurological examination tool for epidemiological research. METHODS: Twelve panellists (six experts in neurological examination, five experts in data collection-two were also experts in the neurological examination, and three experts in participant experience) of different nationalities joined the Delphi exercise. Experts in the neurological examination provided a selection of items that allow ruling out neurological impairment and can be performed by trained health workers. The items were then rated by them and other experts in terms of their feasibility and acceptability. RESULTS: Ten tests and seven anamnestic questions were included in the final set of screening items for the digital neurological examination. Three tests and five anamnestic questions were excluded from the final selection due to their low ratings on feasibility. CONCLUSION: This work identifies the key feasible and acceptable screening tests and anamnestic questions to build an electronic tool for performing the neurological examination, in the absence of a neurologist.

Impact on clinical outcome of ventricular arrhythmias in patients undergoing transcatheter aortic valve implantation.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) has become a largely used treatment for severe aortic stenosis. There are limited data, however, about predictors of long-term prognosis in this population. In this study, we assessed whether ventricular arrhythmias may predict clinical outcomes in patients undergoing TAVI. METHODS AND RESULTS: We performed a 24 h ECG Holter monitoring in 267 patients who underwent TAVI for severe aortic stenosis within 30 days from a successful procedure. The occurrence of frequent premature ventricular complexes (PVCs; ≥30/h), polymorphic PVCs and nonsustained ventricular tachycardia (NSVT) was obtained for each patient. Clinical outcome was obtained for 228 patients (85%), for an average follow-up of 3.5 years (range 1.0-8.6). Cardiovascular events (CVEs; cardiovascular death or resuscitated cardiac arrest) occurred in 26 patients (11.4%) and 63 patients died (27.6%). Frequent PVCs but not polymorphic PVCs and NSVT were found to be associated with CVEs at univariate analysis. Frequent PVCs were indeed found in 12 patients with (46.2%) and 35 without (17.3%) CVEs [hazard ratio 2.30; 95% confidence interval (CI) 1.03-5.09; P  = 0.04], whereas polymorphic PVCs were found in 11 (42.3%) and 54 (26.7%) patients of the two groups, respectively (hazard ratio 1.44; 95% CI 0.64-3.25; P  = 0.38), and NSVT in 9 (34.6%) and 43 patients of the two groups, respectively (hazard ratio 1.18; 95% CI 0.48-2.87; P  = 0.72). Frequent PVCs, however, were not significantly associated with CVEs at multivariate Cox regression analysis (hazard ratio 1.53; 95% CI 0.37-6.30; P  = 0.56). Both frequent PVCs, polymorphic PVCs and NSVT showed no significant association with mortality. CONCLUSION: In our study, the detection of frequent PVCs at Holter monitoring after TAVI was a predictor of CVEs (cardiovascular death/cardiac arrest), but this association was lost in multivariable analysis.

Research considerations for prospective studies of patients with coma and disorders of consciousness.

Disorders of consciousness are neurological conditions characterized by impaired arousal and awareness of self and environment. Behavioural responses are absent or are present but fluctuate. Disorders of consciousness are commonly encountered as a consequence of both acute and chronic brain injuries, yet reliable epidemiological estimates would require inclusive, operational definitions of the concept, as well as wider knowledge dissemination among involved professionals. Whereas several manifestations have been described, including coma, vegetative state/unresponsive wakefulness syndrome and minimally conscious state, a comprehensive neurobiological definition for disorders of consciousness is still lacking. The scientific literature is primarily observational, and studies-specific aetiologies lead to disorders of consciousness. Despite advances in these disease-related forms, there remains uncertainty about whether disorders of consciousness are a disease-agnostic unitary entity with a common mechanism, prognosis or treatment response paradigm. Our knowledge of disorders of consciousness has also been hampered by heterogeneity of study designs, variables, and outcomes, leading to results that are not comparable for evidence synthesis. The different backgrounds of professionals caring for patients with disorders of consciousness and the different goals at different stages of care could partly explain this variability. The Prospective Studies working group of the Neurocritical Care Society Curing Coma Campaign was established to create a platform for observational studies and future clinical trials on disorders of consciousness and coma across the continuum of care. In this narrative review, the author panel presents limitations of prior observational clinical research and outlines practical considerations for future investigations. A narrative review format was selected to ensure that the full breadth of study design considerations could be addressed and to facilitate a future consensus-based statement (e.g. via a modified Delphi) and series of recommendations. The panel convened weekly online meetings from October 2021 to December 2022. Research considerations addressed the nosographic status of disorders of consciousness, case ascertainment and verification, selection of dependent variables, choice of covariates and measurement and analysis of outcomes and covariates, aiming to promote more homogeneous designs and practices in future observational studies. The goal of this review is to inform a broad community of professionals with different backgrounds and clinical interests to address the methodological challenges imposed by the transition of care from acute to chronic stages and to streamline data gathering for patients with disorders of consciousness. A coordinated effort will be a key to allow reliable observational data synthesis and epidemiological estimates and ultimately inform condition-modifying clinical trials.

Autoimmune encephalitis during pregnancy: A diagnostic and therapeutic challenge-A systematic review with individual patients' analysis and clinical recommendations.

Several reports have described the autoimmune encephalitis' (AE) possible onset during pregnancy. In this systematic review, we summarize the available data on the diagnostic and therapeutic approach to AE during pregnancy, highlighting the associated maternal and fetal clinical outcomes. A systematic search of the literature was performed. The following databases were used: PubMed, Google Scholar, EMBASE, and CrossRef. The revision was registered on the PROSPERO platform (CRD42022336357). Forty-nine patients were included. AE onset was mainly observed during the first and the second trimester of pregnancy with psychiatric manifestations and seizures as main onset symptoms. CSF analysis showed AE-specific autoantibody positivity in 33 patients (anti-NMDA receptor as the most frequent). EEG generally showed normal findings. MRI revealed pathological findings in less than half of patients. Tumor screening was positive in 14 cases. First-line immunotherapy (single or combined) was generally employed while second line was administered in a minority of patients. Levetiracetam was the most used antiseizure medication. Cesarean section was performed in 18 women. Most of the women had an excellent early outcome after delivery but 22 showed persistent neurological deficits in long-term follow-up. Fetal outcome was positive in 33 cases, whereas 12 cases of fetal death were reported. A logistic regression showed that no variable significantly influenced the odds of good/bad maternal and fetal clinical outcome. Diagnosis and treatment of AE during pregnancy is challenging. The rate of miscarriage in women with AE seems to be higher than the general population. In addition, mothers may show long-term neurological deficits.

Chimeric antigen receptor-T cell therapy-related cardiotoxicity in adults and children cancer patients: A clinical appraisal.

Chimeric antigen receptor-T (CAR-T) cells therapies represent an innovative immunological treatment for patients suffering from advanced and refractory onco-hematological malignancies. The infusion of engineered T-cells, exposing chimeric receptors on the cell surface, leads to an immune response against the tumor cells. However, data from clinical trials and observational studies showed the occurrence of a constellation of adverse events related to CAR-T cells infusion, ranging from mild effects to life-threatening organ-specific complications. In particular, CAR-T cell-related cardiovascular toxicities represent an emerging group of adverse events observed in these patients, correlated with increased morbidity and mortality. Mechanisms involved are still under investigation, although the aberrant inflammatory activation observed in cytokine release syndrome (CRS) seems to play a pivotal role. The most frequently reported cardiac events, observed both in adults and in the pediatric population, are represented by hypotension, arrhythmias and left ventricular systolic dysfunction, sometimes associated with overt heart failure. Therefore, there is an increasing need to understand the pathophysiological basis of cardiotoxicity and risk factors related to its development, in order to identify most vulnerable patients requiring a close cardiological monitoring and long-term follow-up. This review aims at highlighting CAR-T cell-related cardiovascular complications and clarifying the pathogenetic mechanisms coming at play. Moreover, we will shed light on surveillance strategies and cardiotoxicity management protocols, as well as on future research perspectives in this expanding field.

Selective Cerebrospinal Fluid Hypothermia: Bioengineering Development and In Vivo Study of an Intraventricular Cooling Device (V-COOL).

Hypothermia is a promising therapeutic strategy for severe vasospasm and other types of non-thrombotic cerebral ischemia, but its clinical application is limited by significant systemic side effects. We aimed to develop an intraventricular device for the controlled cooling of the cerebrospinal fluid, to produce a targeted hypothermia in the affected cerebral hemisphere with a minimal effect on systemic temperature. An intraventricular cooling device (acronym: V-COOL) was developed by in silico modelling, in vitro testing, and in vivo proof-of-concept application in healthy Wistar rats (n = 42). Cerebral cortical temperature, rectal temperature, and intracranial pressure were monitored at increasing flow rate (0.2 to 0.8 mL/min) and duration of application (10 to 60 min). Survival, neurological outcome, and MRI volumetric analysis of the ventricular system were assessed during the first 24 h. The V-COOL prototyping was designed to minimize extra-cranial heat transfer and intra-cranial pressure load. In vivo application of the V-COOL device produced a flow rate-dependent decrease in cerebral cortical temperature, without affecting systemic temperature. The target degree of cerebral cooling (- 3.0 °C) was obtained in 4.48 min at the flow rate of 0.4 mL/min, without significant changes in intracranial pressure. Survival and neurological outcome at 24 h showed no significant difference compared to sham-treated rats. MRI study showed a transient dilation of the ventricular system (+ 38%) in a subset of animals. The V-COOL technology provides an effective, rapid, selective, and safe cerebral cooling to a clinically relevant degree of - 3.0 °C.

Incidence and prevalence of coma in the UK and the USA.

The epidemiology of coma is unknown because case ascertainment with traditional methods is difficult. Here, we used crowdsourcing methodology to estimate the incidence and prevalence of coma in the UK and the USA. We recruited UK and US laypeople (aged ≥18 years) who were nationally representative (i.e. matched for age, gender and ethnicity according to census data) of the UK and the USA, respectively, utilizing a crowdsourcing platform. We provided a description of coma and asked survey participants if they-'right now' or 'within the last year'-had a family member in coma. These participants (UK n = 994, USA n = 977) provided data on 30 387 family members (UK n = 14 124, USA n = 16 263). We found more coma cases in the USA (n = 47) than in the UK (n = 20; P = 0.009). We identified one coma case in the UK (0.007%, 95% confidence interval 0.00-0.04%) on the day of the survey and 19 new coma cases (0.13%, 95% confidence interval 0.08-0.21%) within the preceding year, resulting in an annual incidence of 135/100 000 (95% confidence interval 81-210) and a point prevalence of 7 cases per 100 000 population (95% confidence interval 0.18-39.44) in the UK. We identified five cases in the USA (0.031%, 95% confidence interval 0.01-0.07%) on the day of the survey and 42 new cases (0.26%, 95% confidence interval 0.19-0.35%) within the preceding year, resulting in an annual incidence of 258/100 000 (95% confidence interval 186-349) and a point prevalence of 31 cases per 100 000 population (95% confidence interval 9.98-71.73) in the USA. The five most common causes were stroke, medically induced coma, COVID-19, traumatic brain injury and cardiac arrest. To summarize, for the first time, we report incidence and prevalence estimates for coma across diagnosis types and settings in the UK and the USA using crowdsourcing methods. Coma may be more prevalent in the USA than in the UK, which requires further investigation. These data are urgently needed to expand the public health perspective on coma and disorders of consciousness.

Comorbidities in patients with epilepsy: Frequency, mechanisms and effects on long-term outcome.

OBJECTIVE: To assess frequency, types, and mechanisms of comorbidities in people with epilepsy and verify their association with disease features and outcome. METHODS: This cohort study was performed in 13 Italian epilepsy centers with nationwide distribution and accurate records. Eligible patients were children and adults diagnosed before December 31, 2005, and followed for a minimum of 10 years. Two pairs of raters independently reviewed patients' records and classified each comorbidity. In case of disagreement, a third reviewer made the final decision. Comorbidities were classified according to type (organ/system) and underlying mechanism (causal, shared risk factors, chance association). Comorbidity types and mechanisms were described in the entire sample and according to epilepsy prognostic patterns (sustained remission, relapsing-remitting course, no remission). RESULTS: Of 1006 included patients, 266 (26.4%) had at least one comorbidity. The most common were developmental/perinatal (7.5% of cases), psychiatric (6.2%), cardiovascular (5.3%), and endocrine/metabolic (3.8%). Among 408 reported comorbidities, the underlying mechanisms were, in decreasing order, chance association (42.2%), shared risk factors (31.1%), and causal (26.7%). Psychiatric diseases were present in 13.3% of patients with no remission, 5.9% of patients with relapsing-remitting course, and 4.8% of patients with sustained remission (p = .016). The corresponding numbers for endocrine/metabolic diseases were respectively, 9.6%, 3.4%, and 2.9% (p = .013); for respiratory diseases were 3.6%, .3%, and .3% (p = .001), and for urogenital diseases were 3.6%, .7%, and 1.6% (p = .048). The association of endocrine/metabolic, psychiatric, and respiratory comorbidities with epilepsy prognosis was confirmed by multivariable analysis adjusted for the main demographic and clinical variables, with patients with these comorbidities showing a lower probability of achieving remission. SIGNIFICANCE: Comorbidities in epilepsy are not uncommon and reflect differing underlying mechanisms. Psychiatric, endocrine/metabolic, and respiratory disorders are associated with a worse long-term epileptological outcome.

Discontinuation of antiseizure medications in seizure-free patients with long-term follow-up: Patients' profile, seizure recurrence, and risk factors.

OBJECTIVE: To compare withdrawal of antiseizure medications (ASM) to continued treatment in newly diagnosed individuals achieving seizure freedom, and assess the risk of relapse and factors associated with relapse. METHODS: This is a multicenter retrospective cohort study with long-term follow-up. Patients with newly diagnosed epilepsy were identified from the medical records of 13 Italian epilepsy centers and followed up until the most recent visit or death. Seizure-free patients discontinuing treatment were compared to patients who maintained treatment for baseline characteristics. Treatment was stopped upon clinical judgment. The probability of relapse was calculated with the Kaplan-Meier method. Demographic, clinical, and instrumental variables associated with relapse were assessed with Cox proportional hazards models. RESULTS: One thousand and six patients aged 1 month to 72 years at diagnosis were enrolled and followed up for 17,892 person-years (median follow-up, 9.9 years). Three hundred and twenty patients (31.8%) underwent one or more treatment discontinuations. Factors associated with ASM withdrawal were younger age at remission and normal psychiatric examination. The probability of relapse after the first withdrawal was 16% at six months, 24% at 12 months, and 36%, 45%, and 53% at three, five, and ten years, respectively. The probability of remission after the first relapse was 59% at one month, 67%, 72, and 76% at three, six, and 12 months, respectively. Variables associated with relapse were age 14+ years, structural etiology, abnormal neuroimaging, ASM initiation after a single seizure, and symptomatic/cryptogenic epilepsy. CONCLUSIONS: About one half of seizure-free patients stopping ASM relapse in 10 years. However, the possibility of remission after relapse is high, particularly in children and patients with idiopathic/cryptogenic epilepsy. Treatment deprescription might be encouraged at least in these patients.

Status epilepticus and COVID-19: A systematic review.

PURPOSE: In March 2020, the World Health Organization declared the SARS-CoV-2 infection-related coronavirus Disease (COVID-19) a pandemic. During the first and second waves of the pandemic spread, there have been several reports of COVID-19-associated neurological manifestations, including acute seizures and status epilepticus (SE). In this systematic review, we summarized the available data on clinical features, diagnosis, and therapy of COVID-19-related SE. METHODS: We performed a systematic search of the literature to identify data on demographics, clinical, neurophysiological, and neuroradiological data of patients with COVID-19-related SE. We used regression models (linear or logistic) with a stepwise forward method to identify features associated with mortality or severity of SE. RESULTS: Thirty-nine articles were included with a total of 47 cases of SE associated with COVID-19. Age, time between the acute respiratory phase of SARS-CoV-2 infection and SE onset, and hospitalization correlated with a higher SE severity as assessed by quantitative validated scales. CONCLUSIONS: SE can be a neurological manifestation of SARS-CoV-2 infection. Although a possible association between SE and COVID-19 has been reported, the exact mechanisms are still not fully understood. Systemic inflammatory syndrome due to cytokine release could play a role in COVID-19-related SE.

Dietary Habits Bursting into the Complex Pathogenesis of Autoimmune Diseases: The Emerging Role of Salt from Experimental and Clinical Studies.

The incidence and prevalence of autoimmune diseases have increased in Western countries over the last years. The pathogenesis of these disorders is multifactorial, with a combination of genetic and environmental factors involved. Since the epidemiological changes cannot be related to genetic background, which did not change significantly in that time, the role of environmental factors has been reconsidered. Among these, dietary habits, and especially an excessive salt, typical of processed foods, has been implicated in the development of autoimmune diseases. In this review, we summarize current evidence, deriving both from experimental models and clinical studies, on the capability of excessive salt intake to exacerbate proinflammatory responses affecting the pathogenesis of immune-mediated diseases. Data on several diseases are presented, including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and Crohn's disease, with many of them supporting a proinflammatory effect of salt. Likewise, a hypertonic microenvironment showed similar effects in experimental models both in vivo and in vitro. However, murine models of spontaneous autoimmune polyneuropathy exposed to high salt diet suggest opposite outcomes. These results dictate the need to further analyse the role of cooking salt in the treatment and prevention of autoimmune diseases, trying to shape a fine tuning between the possible advantages of a restricted salt intake and the changes in circulating metabolites, mediators, and hormones which come along salt consumption and could in turn influence autoimmunity.