Cannabis-Based Products in a Neurological Setting: A Clinical and Pharmacokinetic Survey

Background and aim: Limited data are available in clinical settings on the pharmacokinetics of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). We investigated the use of cannabis-based products in neurological practice, monitoring patients' steady-state cannabinoids (CBs) plasma concentrations matched with different preparations. Methods: This was a prospective, single-center, observational study. Patients underwent venous blood withdrawal before the CBs' morning dose and then 2.5 h post-dosing. Spasticity or pain were patient self-assessed by the Numeric Rating Scale (NRS) before the morning CB's administration and 2.5 h post-dosing. Results: Thirty-three patients were enrolled. Main indications for CBs were spasticity and chronic pain. Sixteen patients were treated with oromucosal spray formulation Sativex® and 17 with oil-based solutions. Both CBs trough plasma concentrations were ≤ limit of detection (0.1 ng/ml) in 45% of patients. Intrasubject CB's plasma levels significantly increased over baseline values in patients treated with Bediol® oil (p < 0.05) and Sativex® (p < 0.01). Post-dosing CB's bioavailability did not significantly differ between oral oil and oromucosal spray. NRS scores decreased (p < 0.01), matching the increase (p < 0.01) in CB's plasma concentrations. Conclusion: This is the first study investigating CB's plasma concentrations of oral and oromucosal preparations in real-world neurological practice. Findings of similar bioavailability for both CBD and THC after galenic oil compared with oromucosal spray dosing may be clinically relevant and deserve additional research in larger cohorts

When ‘good’ is not good enough: a retrospective Rasch analysis study of the Berg Balance Scale for persons with Multiple Sclerosis

BackgroundThe Berg Balance Scale (BBS) is one of the most used tools to quantify balance in Persons with Multiple Sclerosis, a population at high risk of falling.AimTo evaluate the measurement characteristics of the BBS in Multiple Sclerosis through Rasch analysis.DesignRetrospective study.SettingOutpatients in three Italian Rehabilitation centers.PopulationEight hundred and fourteen persons with Multiple Sclerosis able to stand independently for more than 3 s.MethodsThe sample (N = 1,220) was split into one validating (B1) and three confirmatory subsamples. Following the Rasch analysis performed on B1, the item estimates were exported and anchored to the three confirmatory subsamples. After obtaining the same final solution across all samples, we studied the convergent and discriminant validity of the final BBS-MS using the EDSS, the ABC scale, and the number of falls.ResultsThe base analysis on the B1 subsample failed the monotonicity, local independence, and unidimensionality requirements and did not fit the Rasch model. After grouping locally dependent items, the BBS-MS fitted the model (χ28 = 23.8; p = 0.003) and satisfied all requirements for adequate internal construct validity (ICV). However, it was mistargeted to the sample, given the striking prevalence of higher scores (targeting index 1.922) with a distribution-independent Person Separation Index sufficient for individual measurements (0.962). The B1 item estimates were anchored to the confirmatory samples with confirmation of adequate fit (χ2 = [19.0, 22.8], value of ps = [0.015, 0.004]) and satisfaction of all ICV requirements for all subsamples. The final BBS-MS directly correlated with the ABC scale (rho = 0.523) and inversely with EDSS (rho = −0.573). The BBS-MS estimates significantly differed across groups according to the pre-specified hypotheses (between the three EDSS groups, between the ABC cut-offs, distinguishing ‘fallers’ vs. ‘non-fallers’, and between the ‘low’ vs. ‘moderate’ vs. ‘high’ levels of physical functioning; and, finally, between ‘no falls’ vs. ‘one or more falls’).ConclusionThis study supports the internal construct validity and reliability of the BBS-MS in an Italian multicentre sample of persons with Multiple Sclerosis. However, as the scale is slightly mistargeted to the sample, it represents a candidate tool to assess balance, mainly in more disabled people with an advanced walking disability

An Internet- and Kinect-Based Multiple Sclerosis Fitness Intervention Training With Pilates Exercises: Development and Usability Study

background: balance impairments are common in people with multiple sclerosis (MS), with reduced ability to maintain position and delayed responses to postural adjustments. Pilates is a popular alternative method for balance training that may reduce the rapid worsening of symptoms and the increased risk of secondary conditions (eg, depression) that are frequently associated with physical inactivity.objective: In this paper, we aimed to describe the design, development, and usability testing of MS Fitness Intervention Training (MS-FIT), a Kinect-based tool implementing Pilates exercises customized for MS. methods: MS-FIT has been developed using a user-centered design approach (design, prototype, user feedback, and analysis) to gain the target user's perspective. a team composed of 1 physical therapist, 2 game programmers, and 1 game designer developed the first version of MS-FIT that integrated the knowledge and experience of the team with MS literature findings related to pilates exercises and balance interventions based on exergames. MS-FIT, developed by using the Unity 3D (Unity Technologies) game engine software with kinect Sensor V2 for Windows, implements exercises for breathing, posture, and balance. Feedback from an Italian panel of experts in MS rehabilitation (neurologists, physiatrists, physical therapists, 1 statistician, and 1 bioengineer) and people with MS was collected to customize the tool for use in MS. The context of MS-FIT is traveling around the world to visit some of the most important cities to learn the aspects of their culture through pictures and stories. At each stay of the travel, the avatar of a Pilates teacher shows the user the exercises to be performed. Overall, 9 people with MS (n=4, 44% women; mean age 42.89, SD 11.97 years; mean disease duration 10.19, SD 9.18 years; Expanded Disability Status Scale score 3.17, SD 0.75) were involved in 3 outpatient user test sessions of 30 minutes; MS-FIT's usability was assessed through an ad hoc questionnaire (maximum value=5; higher the score, higher the usability) evaluating easiness to use, playability, enjoyment, satisfaction, and acceptance.Results: A user-centered design approach was used to develop an accessible and challenging tool for balance training. all people with MS (9/9, 100%) completed the user test sessions and answered the ad hoc questionnaire. the average score on each item ranged from 3.78 (SD 0.67) to 4.33 (SD 1.00), which indicated a high usability level. The feedback and suggestions provided by 64% (9/14) of people with MS and 36% (5/14) of therapists involved in the user test were implemented to refine the first prototype to release MS-FIT 2.0. Conclusions: The participants reported that MS-FIT was a usable tool. It is a promising system for enhancing the motivation and engagement of people with MS in performing exercise with the aim of improving their physical status

Conversion to secondary progressive multiple sclerosis: patient awareness and needs. results from an online survey in Italy and Germany

Background: Few studies have investigated the experiences of patients around the conversion to secondary progressive multiple sclerosis (SPMS). ManTra is a mixed-method, co-production research project conducted in Italy and Germany to develop an intervention for newly-diagnosed SPMS patients. In previous project actions, we identified the needs and experiences of patients converting to SPMS via literature review and qualitative research which involved key stakeholders.Aims: The online patient survey aimed to assess, on a larger and independent sample of recently-diagnosed SPMS patients: (a) the characteristics associated to patient awareness of SPMS conversion; (b) the experience of conversion; (c) importance and prioritization of the needs previously identified.Methods: Participants were consenting adults with SPMS since <= 5 years. The survey consisted of three sections: on general and clinical characteristics; on experience of SPMS diagnosis disclosure (aware participants only); and on importance and prioritization of 33 pre-specified needs.Results: Of 215 participants, those aware of their SPMS diagnosis were 57% in Italy vs. 77% in Germany (p = 0.004). In both countries, over 80% of aware participants received a SPMS diagnosis from the neurologist; satisfaction with SPMS disclosure was moderate to high. Nevertheless, 28-35% obtained second opinions, and 48-56% reported they did not receive any information on SPMS. Participants actively seeking further information were 63% in Germany vs. 31% in Italy (p < 0.001).Variables independently associated to patient awareness were geographic area (odds ratio, OR 0.32, 95% CI 0.13-0.78 for Central Italy; OR 0.21, 95% CI 0.08-0.58 for Southern Italy [vs. Germany]) and activity limitations (OR 7.80, 95% CI 1.47-41.37 for dependent vs. autonomous patients).All pre-specified needs were scored a lot or extremely important, and two prioritized needs were shared by Italian and German patients: "physiotherapy" and "active patient care involvement." The other two differed across countries: "an individualized health care plan" and "information on social rights and policies" in Italy, and "psychological support" and "cognitive rehabilitation" in Germany.Conclusions: Around 40% of SPMS patients were not aware of their disease form indicating a need to improve patient-physician communication. Physiotherapy and active patient care involvement were prioritized in both countries

COVID-19 Severity in Multiple Sclerosis: Putting Data Into Context

Background and objectives: It is unclear how multiple sclerosis (MS) affects the severity of COVID-19. The aim of this study is to compare COVID-19-related outcomes collected in an Italian cohort of patients with MS with the outcomes expected in the age- and sex-matched Italian population. Methods: Hospitalization, intensive care unit (ICU) admission, and death after COVID-19 diagnosis of 1,362 patients with MS were compared with the age- and sex-matched Italian population in a retrospective observational case-cohort study with population-based control. The observed vs the expected events were compared in the whole MS cohort and in different subgroups (higher risk: Expanded Disability Status Scale [EDSS] score > 3 or at least 1 comorbidity, lower risk: EDSS score ≤ 3 and no comorbidities) by the χ2 test, and the risk excess was quantified by risk ratios (RRs). Results: The risk of severe events was about twice the risk in the age- and sex-matched Italian population: RR = 2.12 for hospitalization (p < 0.001), RR = 2.19 for ICU admission (p < 0.001), and RR = 2.43 for death (p < 0.001). The excess of risk was confined to the higher-risk group (n = 553). In lower-risk patients (n = 809), the rate of events was close to that of the Italian age- and sex-matched population (RR = 1.12 for hospitalization, RR = 1.52 for ICU admission, and RR = 1.19 for death). In the lower-risk group, an increased hospitalization risk was detected in patients on anti-CD20 (RR = 3.03, p = 0.005), whereas a decrease was detected in patients on interferon (0 observed vs 4 expected events, p = 0.04). Discussion: Overall, the MS cohort had a risk of severe events that is twice the risk than the age- and sex-matched Italian population. This excess of risk is mainly explained by the EDSS score and comorbidities, whereas a residual increase of hospitalization risk was observed in patients on anti-CD20 therapies and a decrease in people on interferon

DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon

Tetrahydrocannabinol/Cannabidiol Oromucosal Spray in Patients With Multiple Sclerosis: A Pilot Study on the Plasma Concentration-Effect Relationship

OBJECTIVES: We aimed to assess the potential relationship between intrasubject 9-tetrahydrocannabinol/cannabidiol (THC/CBD) oromucosal spray plasma profiles and clinical effects elicited by subacute dosing in chronically treated patients with multiple sclerosis (MS). METHODS: The study design was pilot, single center, open, and prospective. The patients were challenged with a morning test dose of 2 THC/CBD sprays at a 15-minute interval. Venous blood samples were collected before the first spray administration and every 30 minutes after the second spray, until 240 minutes postdosing. Patients rated their spasticity by the Numerical Rating Scale (NRS) simultaneously with blood drawings. Postural and motor tests were performed before the first spray and 90 and 180 minutes thereafter. RESULTS: Twelve patients were recruited. Peak plasma concentrations of THC/CBD largely varied among patients, from 0.60 to 13.29 ng/mL for THC and 0.55 to 11.93 ng/mL for CBD. Time to peak plasma concentrations ranged from 150 to 240 minutes for THC and 90 to 240 minutes for CBD. Patients' NRS serial scores decreased after dosing, from a median value of 6 to 3.5 (P < 0.001). A significant inverse correlation was observed between median intrasubject repeated NRS scores and corresponding median values of both THC (P < 0.01) and CBD (P < 0.002) plasma concentrations. No significant effect of cannabinoids dosing could be appreciated according to posturographic and motor tests. CONCLUSIONS: Our kinetic dynamic findings from THC/CBD oromucosal spray are the first obtained in real MS patients. Although preliminary, they suggest that subacute dosing might elicit a subjective clinically significant effect on MS-related spasticity, paralleling cannabinoids measurable plasma concentrations

Lymphocytic Infiltrate and p53 Protein Expression as Predictive Markers of Response and Outcome in Myelodysplastic Syndromes Treated with Azacitidine

High-risk Myelodysplastic syndromes (MDS) represent therapeutical challenges and are usually managed with hypomethylating agents such as azacitidine. Given the lack of data in the literature concerning azacitidine effects on bone marrow, we retrospectively analyzed 57 high-risk MDS cases in order to identify any changes induced by azacitidine therapy or relevant correlations between therapy response and pre- or post-treatment features. Azacitidine treatment had no significant impact on bone marrow cellularity or morphological dysplastic features. On the contrary, although not statistically significant, we observed a slight decrease in CD34+ and CD117+ blasts and p53+ precursors after treatment. Moreover, pre-treatment IPSS-R cytogenetic score (p = 0.004), lymphocytic infiltrate (p = 0.017) and p53+ elements (p = 0.001) correlated with AML progression; pre-treatment lymphocytic infiltrate was also linked to better response to therapy (p = 0.004), suggesting an anti-tumoral role of bone marrow microenvironment. Post-treatment blast count impacted negatively on overall survival (p = 0.035) and risk of leukemic progression (p = 0.04), while both post-treatment lymphocytic infiltrate and p53+ elements showed significant correlation with treatment response (p = 0.004 and p = 0.003 respectively). Higher post-treatment p53+ elements correlated also with risk of leukemic progression (p = 0.013). Our results suggest the possible role of lymphocytic infiltrate and p53+ elements as predictive markers in MDS treated with azacitidine, disclosing new chapters in the understanding of MDS evolution and treatment