Phase I clinical trial of intracerebroventricular transplantation of allogeneic neural stem cells in people with progressive multiple sclerosis.

We report the analysis of 1 year of data from the first cohort of 15 patients enrolled in an open-label, first-in-human, dose-escalation phase I study (ClinicalTrials.gov: NCT03282760, EudraCT2015-004855-37) to determine the feasibility, safety, and tolerability of the transplantation of allogeneic human neural stem/progenitor cells (hNSCs) for the treatment of secondary progressive multiple sclerosis. Participants were treated with hNSCs delivered via intracerebroventricular injection in combination with an immunosuppressive regimen. No treatment-related deaths nor serious adverse events (AEs) were observed. All participants displayed stability of clinical and laboratory outcomes, as well as lesion load and brain activity (MRI), compared with the study entry. Longitudinal metabolomics and lipidomics of biological fluids identified time- and dose-dependent responses with increased levels of acyl-carnitines and fatty acids in the cerebrospinal fluid (CSF). The absence of AEs and the stability of functional and structural outcomes are reassuring and represent a milestone for the safe translation of stem cells into regenerative medicines.

Factors Associated with Delirium in COVID-19 Patients and Their Outcome: A Single-Center Cohort Study.

BACKGROUND: A significant proportion of patients with coronavirus disease 2019 (COVID-19) suffer from delirium during hospitalization. This single-center observational study investigates the occurrence of delirium, the associated risk factors and its impact on in-hospital mortality in an Italian cohort of COVID 19 inpatients. METHODS: Data were collected in the COVID units of a general medical hospital in the South of Italy. Socio-demographic, clinical and pharmacological features were collected. Diagnosis of delirium was based on a two-step approach according to 4AT criteria and DSM5 criteria. Outcomes were: dates of hospital discharge, Intensive Care Unit (ICU) admission, or death, whichever came first. Univariable and multivariable proportional hazards Cox regression models were estimated, and risks were reported as hazard ratios (HR) along with their 95% confidence intervals (95% CI). RESULTS: A total of 47/214 patients (22%) were diagnosed with delirium (21 hypoactive, 15 hyperactive, and 11 mixed). In the multivariable model, four independent variables were independently associated with the presence of delirium: dementia, followed by age at admission, C-reactive protein (CRP), and Glasgow Coma Scale. In turn, delirium was the strongest independent predictor of death/admission to ICU (composite outcome), followed by Charlson Index (not including dementia), CRP, and neutrophil-to-lymphocyte ratio. The probability of reaching the composite outcome was higher for patients with the hypoactive subtype than for those with the hyperactive subtype. CONCLUSIONS: Delirium was the strongest predictor of poor outcome in COVID-19 patients, especially in the hypoactive subtype. Several clinical features and inflammatory markers were associated with the increased risk of its occurrence. The early recognition of these factors may help clinicians to select patients who would benefit from both non-pharmacological and pharmacological interventions in order to prevent delirium, and in turn, reduce the risk of admission to ICU or death.

The Impact of Lifetime Alcohol and Cigarette Smoking Loads on Amyotrophic Lateral Sclerosis Progression: A Cross-Sectional Study.

Background-Amyotrophic lateral sclerosis (ALS) is a devastating and untreatable motor neuron disease; smoking and alcohol drinking may impact its progression rate. Objective-To ascertain the influence of smoking and alcohol consumption on ALS progression rates. Methods-Cross-sectional multicenter study, including 241 consecutive patients (145 males); mean age at onset was 59.9 ± 11.8 years. Cigarette smoking and alcohol consumption data were collected at recruitment through a validated questionnaire. Patients were categorized into three groups according to ΔFS (derived from the ALS Functional Rating Scale-Revised and disease duration from onset): slow (n = 81), intermediate (80), and fast progressors (80). Results-Current smokers accounted for 44 (18.3%) of the participants, former smokers accounted for 10 (4.1%), and non-smokers accounted for 187 (77.6%). The age of ALS onset was lower in current smokers than non-smokers, and the ΔFS was slightly, although not significantly, higher for smokers of >14 cigarettes/day. Current alcohol drinkers accounted for 147 (61.0%) of the participants, former drinkers accounted for 5 (2.1%), and non-drinkers accounted for 89 (36.9%). The log(ΔFS) was weakly correlated only with the duration of alcohol consumption (p = 0.028), but not with the mean number of drinks/day or the drink-years. Conclusions: This cross-sectional multicenter study suggested a possible minor role for smoking in worsening disease progression. A possible interaction with alcohol drinking was suggested.

Diagnosis of COVID-19 in Patients with Negative Nasopharyngeal Swabs: Reliability of Radiological and Clinical Diagnosis and Accuracy Versus Serology.

BACKGROUND: The diagnosis of Coronavirus disease 2019 (COVID-19) relies on the positivity of nasopharyngeal swab. However, a significant percentage of symptomatic patients may test negative. We evaluated the reliability of COVID-19 diagnosis made by radiologists and clinicians and its accuracy versus serology in a sample of patients hospitalized for suspected COVID-19 with multiple negative swabs. METHODS: Admission chest CT-scans and clinical records of swab-negative patients, treated according to the COVID-19 protocol or deceased during hospitalization, were retrospectively evaluated by two radiologists and two clinicians, respectively. RESULTS: Of 254 patients, 169 swab-confirmed cases and one patient without chest CT-scan were excluded. A total of 84 patients were eligible for the reliability study. Of these, 21 patients died during hospitalization; the remaining 63 underwent serological testing and were eligible for the accuracy evaluation. Of the 63, 26 patients showed anti-Sars-Cov-2 antibodies, while 37 did not. The inter-rater agreement was "substantial" (kappa 0.683) between radiologists, "moderate" (kappa 0.454) between clinicians, and only "fair" (kappa 0.341) between radiologists and clinicians. Both radiologic and clinical evaluations showed good accuracy compared to serology. CONCLUSIONS: The radiologic and clinical diagnosis of COVID-19 for swab-negative patients proved to be sufficiently reliable and accurate to allow a diagnosis of COVID-19, which needs to be confirmed by serology and follow-up.

Quarterly repeat cycles of onabotulinumtoxinA in chronic migraine patients: the benefits of the prolonged treatment on the continuous responders and quality-of-life conversion rate in a real-life setting.

OnabotulinumtoxinA was approved for treatment of chronic migraine (CM) after publication of Phase 3 Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials. However, the PREEMPT trials lasted only up to 1 year. The main aim of our retrospective study was to evaluate whether a prolonged treatment of onabotulinumtoxinA (18 months, six quarterly cycles) will sustain or further improve the efficacy results and the quality of life achieved at 6 and 12 months. Patients were adults with CM with or without overuse of drugs, with at least six regularly repeat onabotulinumtoxinA treatments, administered according to the PREEMPT protocol. The outcomes were investigated after 6, 12, and 18 months of treatment with respect to baseline and with respect to each previous study time point. Headache days and hours, and dosage of headache medication taken with latency period, were collected from the patients daily. Quality of life was evaluated by means of the Migraine Disability Assessment (MIDAS) questionnaire. At each study time point, the proportion of responder patients with respect to baseline was evaluated. For all measures, the baseline data were referred to the previous month before starting. Forty-seven patients were evaluated. Our data show a decrease in the monthly headache days and hours, at each study evaluation, with respect to the previous one. They showed that beyond the first year, a statistically significant difference in the monthly days of headache compared at 18 vs. 12 months is observed. A significantly higher proportion of patients (with a response greater than 75% decrease from baseline in the frequency of headache days and hours) was observed at month 18 compared to month 12. The proportion of patients in MIDAS grade I increased over time, and a statistically significant improvement in MIDAS I score was obtained from month 12 to month 18. A positive modification in the consumption of analgesics over time was observed (p for trend <0.001). The mean acute drug latency strongly decreased over time. Our study confirmed that onabotulinumtoxinA is an effective treatment to reduce headache-related disability and improve patients' quality of life, highlighting that upon repeated administration, the therapy efficacy increases significantly and a progressive trend of "first-time response" is observed for the entire period under consideration.

Reliability of clinical diagnosis of dystonia.

BACKGROUND: There is only one small single-center study on the reliability of the diagnosis of focal dystonia. The aim of this study was to assess the inter-rater reliability of dystonia diagnosis among neurologists with different professional experience. METHODS: Twenty-nine adults (18 with dystonia, 9 with other movement disorders, and 2 healthy controls) were videotaped while undergoing neurological examination and during the process of collecting information on the history of their condition. Each case was diagnosed by 35 blind raters (12 general neurologists, 21 neurology residents, and 2 experts in movement disorders) from different hospitals. Sensitivity and specificity were calculated confronting raters with the gold standard (the caring physician). Inter-rater agreement was measured by the Kappa statistic. RESULTS: Specificity and sensitivity were 95.2 and 66.7%, 76.3 and 75.2%, 84.6 and 71.6% for experts, general neurologists, and residents, respectively. Kappa values on dystonia diagnosis ranged from 0.30 to 0.46. The agreement was moderate for experts and residents (0.40-0.60) and fair for general neurologists (0.20-0.40). Kappas were the highest among experts for cranial and laryngeal dystonia (0.61-1), but not for cervical dystonia (0.37). CONCLUSIONS: The diagnosis of dystonia is difficult and only partially mirrors a physician's background.

Functional outcome and health status of injured patients with peripheral nerve lesions.

BACKGROUND: Peripheral nerve lesions (PNLs) can complicate the clinical course and outcome of multiply injured patients. Since this often impedes recovery, it can be a significant burden for both patients and clinicians. The objective of the present study was to investigate the long-term outcome and health status of patients with PNL. SUBJECTS AND METHODS: Multiply injured patients admitted to an intensive rehabilitation setting were identified. The Barthel and modified Rankin scales (mRS) were administered to all patients at admission, discharge and follow-up. The short form (SF)-36 questionnaire was used at follow-up (mean: 25.3+/-6.5 months). RESULTS: Seventy-seven multiply injured patients were identified, and 45 (22 male, 23 female; mean age: 59.7+/-21.7 years; range: 19-83 years) were enrolled. Of the injured patients, 22 subjects (10 male and 12 female) had no PNL, while 23 (12 male, 11 female) did. In the PLN group, the mean Barthel scores at admission, discharge and follow-up, respectively, were 33.4+/-17.9, 85.3+/-3.8 and 93.0+/-6.9 (p<0.001) and the median mRS scores were 4 (interquartile range (IQR): 3-5), 3 (IQR: 1-3) and 1 (IQR: 0-2), respectively. In the group without PLN, the mean Barthel scores at admission, discharge and follow-up, respectively, were 30.4+/-14.5, 86.6+/-9.8 and 96.6+/-4.9 (p<0.001) and the median mRS scores were 4 (IQR: 3-5), 2 (IQR: 1-3) and 0.5 (IQR: 0-2). The mean length of hospital stay was 86.7+/-10.8 and 65.6+/-14.6 days in patients with and without PNL, respectively. The SF-36 did not show significant differences between the groups, but the patients with and without PNL reported significant lower mean scores on all items compared to national population norms. CONCLUSION: Multiply injured patients with and without PNL showed significant improvement and a good long-term outcome after rehabilitation. However, those with PNL had a longer hospital stay and needed more rehabilitation than patients without PNL. Both the groups of patients experienced significant difficulties in the health status.

Prevalence of primary focal or segmental dystonia in adults in the district of foggia, southern Italy: a service-based study.

BACKGROUND: Primary focal or segmental dystonia is a rare clinical condition including early-onset dystonia, which has the tendency to generalize, and late-onset dystonia, which may be focal or segmental. The prevalence of late-onset dystonia ranges from 30 to 7,320 cases per million, but no data are available in Italy. METHODS: A service-based study was conducted in the period 1 January 2001 through 31 December 2002 in the administrative district of Foggia, southern Italy (population 541,653). Cases were traced through hospital discharge diagnosis, botulinum toxin services, day hospital access, ear, nose and throat, ophthalmology and orthopedic surgery specialists, and territorial outpatient services. Inclusion criteria were age 17 years or older, residency in the study area and a diagnosis of primary focal/segmental dystonia. RESULTS: A total of 69 patients were included, giving a crude prevalence of 127.4 per 1,000,000 (women: 146.4; men: 107.0; age 18-34 years: 39.2; 35-54 years: 98.7; 55-74 years: 273.6; 75+ years: 163.3). The standardized rate was 137.5 (95% confidence interval 107.0-174.6). Blepharospasm was the commonest clinical condition (prevalence 68.2), followed by cervical dystonia (prevalence 44.8). CONCLUSION: The prevalence of primary focal or segmental dystonia in Italy is in keeping with several other reports, but is lower than in studies performed in northern Europe, Minnesota, USA, and Japan. The difference in our results may be mostly explained by misdiagnosis, underascertainment of cases and a fairly limited observation period.