Silvia Messina

Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity

Background The approval of 9-δ-tetrahydocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex) for the management of treatment-resistant multiple sclerosis (MS) spasticity opened a new opportunity for many patients. The aim of our study was to describe Sativex effectiveness and adverse events profile in a large population of Italian patients with MS in the daily practice setting. Methods We collected data of all patients starting Sativex between January 2014 and February 2015 from the mandatory Italian medicines agency (AIFA) e-registry. Spasticity assessment by the 0–10 numerical rating scale (NRS) scale is available at baseline, after 1 month of treatment (trial period), and at 3 and 6 months. Results A total of 1615 patients were recruited from 30 MS centres across Italy. After one treatment month (trial period), we found 70.5% of patients reaching a ≥20% improvement (initial response, IR) and 28.2% who had already reached a ≥30% improvement (clinically relevant response, CRR), with a mean NRS score reduction of 22.6% (from 7.5 to 5.8). After a multivariate analysis, we found an increased probability to reach IR at the first month among patients with primary and secondary progressive MS, (n=1169, OR 1.4 95% CI 1.04 to 1.9, p=0.025) and among patients with >8 NRS score at baseline (OR 1.8 95% CI 1.3–2.4 p<0.001). During the 6 months observation period, 631(39.5%) patients discontinued treatment. The main reasons for discontinuation were lack of effectiveness (n=375, 26.2%) and/or adverse events (n=268, 18.7%). Conclusions Sativex can be a useful and safe option for patients with MS with moderate to severe spasticity resistant to common antispastic drugs.

Gray Matters in Multiple Sclerosis: Cognitive Impairment and Structural MRI

Multiple sclerosis (MS) is an immune-mediated disease affecting central nervous system (CNS). Although MS is classically considered a white matter (WM) disease, the involvement of gray matter (GM) in the pathogenic process has been confirmed by pathology studies and MRI studies. Impairment of cognitive domains such as memory, mental processing speed, attention, and executive function can occur from the early stage of the disease and tends to worsen over time, despite stable physical symptoms. WM demyelination is moderately correlated with CI, suggesting that probably WM abnormalities alone cannot fully explain the extent of clinical symptoms in MS, including CI. Several MRI techniques have shown the involvement of GM in MS and the association between GM damage, physical disability, and CI. The aim of this review is to provide an overview of CI and GM damage assessed by structural brain MRI.

Clinical presentation and prognosis in MOG-antibody disease: a UK study

See de Seze (doi:10.1093/brain/awx292) for a scientific commentary on this article. A condition associated with an autoantibody against MOG has been recently recognized as a new inflammatory disease of the central nervous system, but the disease course and disability outcomes are largely unknown. In this study we investigated clinical characteristics of MOG-antibody disease on a large cohort of patients from the UK. We obtained demographic and clinical data on 252 UK patients positive for serum immunoglobulin G1 MOG antibodies as tested by the Autoimmune Neurology Group in Oxford. Disability outcomes and disease course were analysed in more detail in a cohort followed in the Neuromyelitis Optica Oxford Service (n = 75), and this included an incident cohort who were diagnosed at disease onset (n = 44). MOG-antibody disease affects females (57%) slightly more often than males, shows no ethnic bias and typically presents with isolated optic neuritis (55%, bilateral in almost half), transverse myelitis (18%) or acute disseminated encephalomyelitis-like presentations (18%). In the total Oxford cohort after a median disease duration of 28 months, 47% of patients were left with permanent disability in at least one of the following: 16% patients had visual acuity ≤6/36 in at least one eye, mobility was limited in 7% (i.e. Expanded Disability Status Scale ≥ 4.0), 5% had Expanded Disability Status Scale ≥ 6.0, 28% had permanent bladder issues, 20% had bowel dysfunction, and 21% of males had erectile dysfunction. Transverse myelitis at onset was a significant predictor of long-term disability. In the incident cohort 36% relapsed after median disease duration of 16 months. The annualized relapse rate was 0.2. Immunosuppression longer than 3 months following the onset attack was associated with a lower risk of a second relapse. MOG-antibody disease has a moderate relapse risk, which might be mitigated by medium term immunosuppression at onset. Permanent disability occurs in about half of patients and more often involves sphincter and erectile functions than vision or mobility.

Increasing frequency of multiple sclerosis in Catania, Sicily: a 30-year survey

Background and Objective: The objective of this study was to determine the prevalence and incidence of multiple sclerosis (MS) and its temporal profiles from 1975 to 2005 in the city of Catania. Methods: The incidence of MS from 1975 to 31 December 1999 had been previously investigated by the same group. The frequency of MS in the community of Catania from 1 January 2000 to 31 December 2004 was studied in a population of 313,110 inhabitants (2001 census). All patients who satisfied Poser’s criteria were considered as prevalent and incident cases. Results: Three hundred and ninety-eight patients with MS who had experienced the clinical onset of the disease before 31 December 2004 were found in a population of 313,110 inhabitants. The prevalence rate was 127.1/100,000 [95% confidence interval (CI) 115.1–140.4]. From 2000 to 2004, 108 patients with MS had clinical onset of the disease. The mean annual incidence was 7.0/100,000 (95% CI 5.7–13.7) and was higher in women (8.4/100,000; 95% CI 6.4–10.5) than in men (5.3/100,000; 95% CI 3.7–7.2). The mean length of time between the date of clinical onset and the date of the diagnosis was 1.4 ± 1.7 years. During the last 30 years the incidence of MS in this population increased from 1.3/100,000 during the first quinquennium (1975–9) to 7.0/100,000 during 2000–4. Conclusions: Incidence rates have further increased in this population, suggesting that the risk of MS is still increasing.

Multiple Sclerosis and CCSVI: A Population-Based Case Control Study

Background Chronic cerebrospinal venous insufficiency (CCSVI) has been associated to multiple sclerosis (MS). Objective To evaluate the possible association between CCSVI and MS, using a population-based control design. Methods A random cohort of 148 incident MS patients were enrolled in the study. We have also studied 20 patients with clinically isolated syndrome (CIS), 40 patients with other neurological diseases (OND), and 172 healthy controls. Transcranial (TCC) and Echo Color Doppler (ECD) were carried out in 380 subjects. A subject was considered CCSVI positive if ≥2 venous hemodynamic criteria were fulfilled. Results CCSVI was present in 28 (18.9%) of the MS patients, in 2 (10%) of CIS patients, in 11 (6.4%) of the controls, and in 2 (5%) of the OND patients. A significant association between MS and CCSVI was found with an odds ratio of 3.41 (95% confidence interval 1.63–7.13; p = 0.001). CCSVI was significantly more frequent among MS subjects with a disease duration longer than 144 months (26.1% versus 12.6% of patients with duration shorter than 144 months; p = 0.03) and among patients with secondary progressive (SP) and primary progressive (PP) forms (30.2% and 29.4, respectively) than in patients with relapsing remitting (RR) MS (14.3%). A stronger association was found considering SP and PP forms (age adjusted OR = 4.7; 95% CI 1.83–12.0, p = 0.001); the association was weaker with the RR patients (age adjusted OR = 2.58; 95%CI 1.12–5.92; p = 0.02) or not significant in CIS group (age adjusted OR = 2.04; 95%CI 0.40–10.3; p = 0.4). Conclusions A higher frequency of CCSVI has been found in MS patients; it was more evident in patients with advanced MS, suggesting that CCSVI could be related to MS disability.

Lesion Load May Predict Long-Term Cognitive Dysfunction in Multiple Sclerosis Patients

Background Magnetic Resonance Imaging (MRI) techniques provided evidences into the understanding of cognitive impairment (CIm) in Multiple Sclerosis (MS). Objectives To investigate the role of white matter (WM) and gray matter (GM) in predicting long-term CIm in a cohort of MS patients. Methods 303 out of 597 patients participating in a previous multicenter clinical-MRI study were enrolled (49.4% were lost at follow-up). The following MRI parameters, expressed as fraction (f) of intracranial volume, were evaluated: cerebrospinal fluid (CSF-f), WM-f, GM-f and abnormal WM (AWM-f), a measure of lesion load. Nine years later, cognitive status was assessed in 241 patients using the Symbol Digit Modalities Test (SDMT), the Semantically Related Word List Test (SRWL), the Modified Card Sorting Test (MCST), and the Paced Auditory Serial Addition Test (PASAT). In particular, being SRWL a memory test, both immediate recall and delayed recall were evaluated. MCST scoring was calculated based on the number of categories, number of perseverative and non-perseverative errors. Results AWM-f was predictive of an impaired performance 9 years ahead in SDMT (OR 1.49, CI 1.12–1.97 p = 0.006), PASAT (OR 1.43, CI 1.14–1.80 p = 0.002), SRWL-immediate recall (OR 1.72 CI 1.35–2.20 p<0.001), SRWL-delayed recall (OR 1.61 CI 1.28–2.03 p<0.001), MCST-category (OR 1.52, CI 1.2–1.9 p<0.001), MCST-perseverative error(OR 1.51 CI 1.2–1.9 p = 0.001), MCST-non perseverative error (OR 1.26 CI 1.02–1.55 p = 0.032). Conclusion In our large MS cohort, focal WM damage appeared to be the most relevant predictor of the long-term cognitive outcome.

The pharmacokinetics of glatiramer acetate for multiple sclerosis treatment

Introduction: Multiple sclerosis (MS) is a T-cell-mediated disease affecting the central nervous system (CNS), characterized by demyelination and axonal degeneration. INF-β1b was the first drug approved for MS patients in 1993. In 1996, glatiramer acetate (GA), a synthetic copolymer, was approved in the USA for the treatment of relapsing-remitting MS (RRMS) and clinically isolated syndrome (CIS). Although the immunological action of GA has been fully investigated, the exact mechanisms of action of GA are still not completely elucidated. Several in vitro studies on mice and human antigen-presenting cells (APCs) have shown that GA is able to bind to the major histocompatibility complex (MHC), on the surface of APCs, recognizing myelin basic protein (MBP). Areas covered: This review explores the pharmacological characteristics of GA, its mechanism of action and its pharmacokinetics properties. The article also provides information on the efficacy, tolerability and an overview of the most important clinical data on GA. Expert opinion: Despite the development of novel compounds, it is not surprising that GA is, to date, one of the most prescribed drugs for RRMS patients and CIS patients. The proven efficacy and the mild adverse events, makes GA a good therapeutic option in the early stage of the disease. This is particularly useful for patients who suffer flu-like symptoms from other RRMS therapies as an alternative.

Increased leptin and A-FABP levels in relapsing and progressive forms of MS.

BackgroundLeptin and adipocyte-fatty acid binding protein (A-FABP) are produced by white adipose tissue and may play a role in chronic inflammation in Multiple Sclerosis (MS). To assess leptin and A-FABP in relapsing and progressive forms of MS.MethodsAdipokine levels were measured in untreated adult relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS) and Healthy control (HC). Pediatric-onset MS (POMS) and pediatric healthy controls (PHC) were also assessed. Leptin and A-FABP levels were measured in serum by ELISA. Groups were compared using linear mixed-effects model.ResultsExcluding two patients with Body Mass Index (BMI) > 50, a significant difference in leptin level was found between RRMS and HC controlling for age (p = 0.007), SPMS and HC controlling for age alone (p = 0.002), or age and BMI (p = 0.007). A-FABP levels were higher in SPMS than HC (p = 0.007), controlling for age and BMI. Differences in A-FABP levels between POMS and PHC was observed after controlling for age (p = 0.019), but not when BMI was added to the model (p = 0.081).ConclusionLeptin and A-FABP levels are highest in SPMS compared to HC, suggesting a role in pathogenesis of this disease subtype. A-FABP levels are increased in POMS patients and may play a role in the early stages of disease.

Frequency and severity of headache is worsened by Interferon‐β therapy in patients with multiple sclerosis

Patti F, Nicoletti A, Pappalardo A, Castiglione A, Lo Fermo S, Messina S, D’Amico E, Cimino V, Zappia M. Frequency and severity of headache is worsened by Interferon‐β therapy in patients with multiple sclerosis. 
Acta Neurol Scand: 2012: 125: 91–95. 
© 2011 John Wiley & Sons A/S.

Longitudinal BMI trajectories in multiple sclerosis: Sex differences in association with disease severity.

BACKGROUND Adolescent obesity is a risk factor for multiple sclerosis (MS), but little is known about changes in body mass index (BMI) after MS onset. OBJECTIVE To assess the relationship between MS and longitudinal changes in BMI. METHODS We analyzed prospectively collected BMIs in a cohort of patients with adult-onset MS and matched adult healthy controls (HC) gathered from the same hospital network central clinical data registry. RESULTS We made three main observations. First, at baseline MS patients had a significantly higher BMI than HC (age- and sex- adjusted mean difference=0.57; 95% CI: 0.15, 0.99; p=0.008). Second, a significant age by MS status interaction was observed (p<0.0001), such that in MS, BMIs did not increase significantly higher in older individuals, whereas BMIs in HCs were higher with increasing age. Third, we observed sex-specific associations with disease severity: higher BMI was associated with higher cross-sectional EDSS in women, but with lower EDSS in men (p=0.003, N=758). There were no longitudinal associations between BMI and EDSS in either sex or in the entire cohort (p=0.65, N=772). CONCLUSION After MS onset, patients may not experience age-expected increases in BMI. BMI may have sex-specific associations with MS disability scores. More refined measures of body composition are warranted in future studies to distinguish adiposity from muscle mass.