Change in upper limb function in people with multiple sclerosis treated with nabiximols: a quantitative kinematic pilot study.

OBJECTIVES: Nabiximols represents an increasingly employed add-on treatment option for spasticity in people with multiple sclerosis (PwMS) who either were unresponsive or reported excessive adverse reactions to other therapies. While several studies performed in the last decade demonstrated its effectiveness, safety, and tolerability, few quantitative data are available on the impact on motor dysfunctions. In this open-label, not concurrently controlled study, we aimed to assess the impact of a 4-week treatment with nabiximols on upper limb functionality. METHODS: Thirteen PwMS (9 female, 4 male) with moderate-severe spasticity underwent a combination of clinical tests (i.e., Box and Block, BBT and Nine-Hole Peg test, 9HPT) and instrumental kinematic analysis of the "hand to mouth" (HTM) movement by means of optical motion capture system. RESULTS: After the treatment, improvements in gross and fine dexterity were found (BBT + 3 blocks/min, 9HPT - 2.9 s, p < 0.05 for both cases). The kinematic analysis indicated that HTM movement was faster (1.69 vs. 1.83 s, p = 0.05), smoother, and more stable. A significant reduction of the severity of spasticity, as indicated by the 0-10 numerical rating scale (4.2 vs. 6.3, p < 0.001), was also observed. CONCLUSION: The findings from the present pilot study suggest that a 4-week treatment with nabiximols ameliorates the spasticity symptoms and the overall motor function of upper limb in PwMS with moderate-severe spasticity. The use of quantitative techniques for human movement analysis may provide valuable information about changes originated by the treatment in realistic upper limb motor tasks involved in activities of daily living.

Nabiximols discontinuation rate in a large population of patients with multiple sclerosis: a 18-month multicentre study.

INTRODUCTION: Delta-δ-tetrahydrocannabinol and cannabidiol (THC:CBD) oromucosal spray is used as an add-on therapy option for moderate to severe multiple sclerosis (MS) spasticity resistant to other medications. Aims of this study were to provide real-life data on long-term clinical outcomes in a large population of Italian patients treated with THC:CBD and to evaluate predictors of THC:CBD therapy continuation. MATERIALS AND METHODS: This prospective observational multicentre Italian study screened all patients with MS consecutively included in the Agenzia Italiana del Farmaco e-registry at the start of THC:CBD treatment (baseline), after 4 weeks (T1), 12±3 weeks (T2), 24±3 weeks (T3), 48±3 weeks (T4) and 72±3 weeks (T5) from baseline. RESULTS: A total of 1845 patients were recruited from 32 MS Italian centres. At T1, 1502 (81.4%) of patients reached a Numerical Rating Scale (NRS) improvement of ≥20%, with an NRS reduction of 26.9% at T1 and of 34.4% at T5. At T5, 725 patients (48.3% of 1502) discontinued treatment with highest discontinuation rate at T2 and T3. Daily number of puffs was generally stable through the observation period. The multivariate analysis showed that higher NRS scores at baseline (OR 2.28, 95% CI 1.15 to 6.36, p<0.01) and higher differences of NRS between T0 and T1 (OR 2.11, 95% CI 1.08 to 8.26, p<0.05) were associated with an increased probability to continue therapy after 18 months. DISCUSSION: THC:CBD effects were sustained for 18 months with a relatively stable number of puffs per day. About 50% of patients abandoned THC:CBD therapy for loss of efficacy or adverse events.

Effects of THC/CBD oromucosal spray on spasticity-related symptoms in people with multiple sclerosis: results from a retrospective multicenter study.

INTRODUCTION: The approval of 9-δ-tetrahydocannabinol (THC)+cannabidiol (CBD) oromucosal spray (Sativex®) in Italy as an add-on medication for the management of moderate to severe spasticity in multiple sclerosis (MS) has provided a new opportunity for MS patients with drug-resistant spasticity. We aimed to investigate the improvement of MS spasticity-related symptoms in a large cohort of patients with moderate to severe spasticity in daily clinical practice. MATERIALS AND METHODS: MS patients with drug-resistant spasticity were recruited from 30 Italian MS centers. All patients were eligible for THC:CBD treatment according to the approved label: ≥ 18 years of age, at least moderate spasticity (MS spasticity numerical rating scale [NRS] score ≥ 4) and not responding to the common antispastic drugs. Patients were evaluated at baseline (T0) and after 4 weeks of treatment (T1) with the spasticity NRS scale and were also asked about meaningful improvements in 6 key spasticity-related symptoms. RESULTS: Out of 1615 enrolled patients, 1432 reached the end of the first month trial period (T1). Of these, 1010 patients (70.5%) reached a ≥ 20% NRS score reduction compared with baseline (initial responders; IR). We found that 627 (43.8% of 1432) patients showed an improvement in at least one spasticity-related symptom (SRSr group), 543 (86.6%) of them belonging to the IR group and 84 (13.4%) to the spasticity NRS non-responders group. CONCLUSION: Our study confirmed that the therapeutic benefit of cannabinoids may extend beyond spasticity, improving spasticity-related symptoms even in non-NRS responder patients.

Sativex in resistant multiple sclerosis spasticity: Discontinuation study in a large population of Italian patients (SA.FE. study).

BACKGROUND: The approval of Sativex for the management of multiple sclerosis (MS) spasticity opened a new opportunity to many patients. In Italy, the healthcare payer can be fully reimbursed by the involved pharma company with the cost of treatment for patients not responding after a 4 week (28 days) trial period (Payment by Results, PbR), and 50% reimbursed with the cost of 6 weeks (42 days) treatment for other patients discontinuing (Cost Sharing, CS). The aim of our study was to describe the Sativex discontinuation profile from a large population of spasticity treated Italian MS patients. METHODS: We collected data of patients from 30 MS centres across the country starting Sativex between January 2014 and February 2015. Data were collected from the mandatory Italian Medicines Agency (AIFA) web-registry. Predictors of treatment discontinuation were assessed using a multivariate Cox proportional regression analysis. RESULTS: During the observation period 631 out of 1597 (39.5%) patients discontinued Sativex. The Kaplan-Meier estimates curve showed that 333 patients (20.8%) discontinued treatment at 4 weeks while 422 patients (26.4%) discontinued at 6 weeks. We found after adjusted modeling that a higher NRS score at T1 (adjHR 2.23, 95% 2.07-2.41, p<0.001) and a lower baseline NRS score (adjHR 0.51 95% CI 0.46-0.56, p<0.001) were predictive of treatment discontinuation. CONCLUSION: These data show that the first 6 weeks are useful in identifying those patients in which Sativex could be effective, thus avoiding the cost of longer term evaluation.

Influence of treatments in multiple sclerosis disability: a cohort study.

BACKGROUND AND OBJECTIVE: A critical aspect of multiple sclerosis (MS) treatments is understanding the effect of disease-modifying drugs (DMDs) on the long-term risk of disability and whether the effect is related to disability at start of treatment. METHODS: We performed an observational study on 3060 MS patients. The effect of therapy on progression to Expanded Disability Status Scale (EDSS) 3.0 and 6.0 from onset was analysed in treated vs untreated (UTP) patients using Cox regression analysis adjusted for propensity score and immortal time bias. RESULTS: Compared to UTP, the risks of EDSS 3.0 were 94% and 73% lower in immunomodulant (IMTP-) and immunosuppressant (ISTP-) treated patients, respectively, while the risk of EDSS 6.0 was 86% lower in IMTP. The risk of EDSS 6.0 was, respectively, 91% and 75% lower in 1275 IMTP before and 114 after EDSS 3.0 than in 539 UTP; the risk was higher in IMTP starting therapy after EDSS 3.0 than before (HR = 4.42). CONCLUSIONS: DMDs delayed long-term disability in MS patients treated either in the early or, to a lesser extent, in the later phase of the disease. Thus, the window of therapeutic opportunity is relatively extended, assuming that early is better than late treatment, but late is better than never.

Unusual clinical presentations in subjects carrying novel NOTCH3 gene mutations.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a disease caused by alterations in the NOTCH3 gene. METHODS: We describe the clinical, instrumental, and genetic findings in CADASIL patients who carry novel NOTCH3 gene mutations. RESULTS AND CONCLUSIONS: This study broadens the spectrum of clinical manifestations and genetic alterations associated with this disease.

A case of neurofibromatosis and multiple sclerosis.

Neurofibromatosis 1 (NF1), also called von Recklinghausen disease or peripheral NF, is a common autosomal-dominant neurocutaneous disorder associated with mutations of the NF 1 gene. The pathogenesis is poorly understood and the disease is characterized by cafè-au-lait spots, neurofibromatous tumors of the skin, Lisch nodules of the iris and many pleiotropic manifestations. The gene responsible for the disorder has been isolated on chromosome 17q11.2. The association of multiple sclerosis with NF is rarely reported in literature. We describe a patient with NF1, who subsequently developed relapsing-remitting multiple sclerosis.

Patients with multiple sclerosis and risk of type 1 diabetes mellitus in Sardinia, Italy: a cohort study.

BACKGROUND: Individuals from Sardinia, Italy, are at high risk of developing multiple sclerosis and type 1 diabetes mellitus. We attempted to assess the prevalence in this region of type 1 diabetes mellitus in individuals with multiple sclerosis, and to ascertain disease risk factors. METHODS: We did a cohort study to assess prevalence of type 1 diabetes in 1090 people with multiple sclerosis, and in their parents (n=2180) and siblings (n=3300), all born and living in Sardinia. All participants were patients at the multiple sclerosis clinic in Cagliari, and were judged representative of the total Sardinian outpatients and inpatients. We asked patients whether their parents or siblings had multiple sclerosis or diabetes, confirming replies by examining clinical records. We identified risk factors for diabetes with univariate and multivariate logistic regression analyses. FINDINGS: Diabetes prevalence in people with multiple sclerosis was, respectively, about three-fold and five-fold that in their healthy siblings (p=0.001) and in the general population (p<0.0001). Presence of other relatives with multiple sclerosis conferred increased risk of type 1 diabetes to healthy siblings of individuals with multiple sclerosis (odds ratio=3.41, p=0.0019). Diabetes risk was six-fold higher in patients with relatives having multiple sclerosis than in healthy siblings of multiple sclerosis patients without other relatives with the disease (p=0.0001). INTERPRETATION: In Sardinian families with genetic inheritance of multiple sclerosis type 1 diabetes is prevalent, both in multiple sclerosis patients and in healthy siblings. This finding indicates that common genes contribute to susceptibility to both diseases in this population.