Source of medical information and behavioral seeking patterns in patients affected with Friedreich's ataxia and their caregivers: a survey study.

BACKGROUND: Friedreich's ataxia (FRDA) is an untreatable disease that negatively impacts patients' and caregivers' quality of life. OBJECTIVES: The aims were to improve the quality of the information for FRDA patients and caregivers and suggest a possible tool to spread this information. MATERIAL AND METHODS: Thirty-four FRDA patients and 45 caregivers were interviewed separately using a structured self-administered survey about their information-seeking behavior, their level of expectation and satisfaction for the information received, and the need for further information. RESULTS AND CONCLUSION: For patients and caregivers, the main source of information was the FRDA specialist and the media. The most searched items were "general information"; patients and particularly caregivers desired to get more information on existing and experimental therapies. Adequate information supply is part of good medical care; therefore, a deeper insight of clinicians in information-seeking behavior of FRDA patients and caregivers would provide tailored information and improve therapeutic alliance.

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.

Lower Multiple Sclerosis Severity Score Is Associated with Higher Adherence to Mediterranean Diet in Subjects with Multiple Sclerosis from Northwestern Italy.

The Mediterranean Diet (MD) is described in the literature as a beneficial dietary pattern for neurodegenerative diseases such as Multiple Sclerosis (MS). The objective of this study was to evaluate the dietary habits in people with MS (pwMS) and to test whether adherence to the MD could have an impact on the severity of the disease measured as the MS severity score (MSSS). Adherence to the MD was assessed in 31 PwMS using the Mediterranean Diet Adherence Screener (MEDAS), the Pyramid-based Mediterranean Diet Score (PyrMDS) index, and the Italian Mediterranean Index (IMI), and their eating habits were recorded in a food diary for a one-year follow-up. When data obtained from dietary analysis were compared to the MSSS, results showed that pwMS with lower MSSS adhere more to the MD than the other pwMS groups according to the MEDAS index. Furthermore, a high consumption of fiber in the MS mild severity class was observed. Further studies are needed to clarify which of the nutritional components of the MD may impact the course of MS and if the sensitization of pwMS to MD adherence can be a strategy for mitigating the disease.

Feeding the gut microbiome: impact on multiple sclerosis.

Multiple sclerosis (MS) is a multifactorial neurological disease characterized by chronic inflammation and immune-driven demyelination of the central nervous system (CNS). The rising number of MS cases in the last decade could be partially attributed to environmental changes, among which the alteration of the gut microbiome driven by novel dietary habits is now of particular interest. The intent of this review is to describe how diet can impact the development and course of MS by feeding the gut microbiome. We discuss the role of nutrition and the gut microbiota in MS disease, describing preclinical studies on experimental autoimmune encephalomyelitis (EAE) and clinical studies on dietary interventions in MS, with particular attention to gut metabolites-immune system interactions. Possible tools that target the gut microbiome in MS, such as the use of probiotics, prebiotics and postbiotics, are analyzed as well. Finally, we discuss the open questions and the prospects of these microbiome-targeted therapies for people with MS and for future research.

Long-lasting neutralizing antibodies and T cell response after the third dose of mRNA anti-SARS-CoV-2 vaccine in multiple sclerosis.

Background and objectives: Long lasting immune response to anti-SARS-CoV-2 vaccination in people with Multiple Sclerosis (pwMS) is still largely unexplored. Our study aimed at evaluating the persistence of the elicited amount of neutralizing antibodies (Ab), their activity and T cell response after three doses of anti-SARS-CoV-2 vaccine in pwMS. Methods: We performed a prospective observational study in pwMS undergoing SARS-CoV-2 mRNA vaccinations. Anti-Region Binding Domain (anti-RBD) of the spike (S) protein immunoglobulin G (IgG) titers were measured by ELISA. The neutralization efficacy of collected sera was measured by SARS-CoV-2 pseudovirion-based neutralization assay. The frequency of Spike-specific IFNγ-producing CD4+ and CD8+ T cells was measured by stimulating Peripheral Blood Mononuclear Cells (PBMCs) with a pool of peptides covering the complete protein coding sequence of the SARS-CoV-2 S. Results: Blood samples from 70 pwMS (11 untreated pwMS, 11 under dimethyl fumarate, 9 under interferon-γ, 6 under alemtuzumab, 8 under cladribine, 12 under fingolimod and 13 under ocrelizumab) and 24 healthy donors were collected before and up to six months after three vaccine doses. Overall, anti-SARS-CoV-2 mRNA vaccine elicited comparable levels of anti-RBD IgGs, neutralizing activity and anti-S T cell response both in untreated, treated pwMS and HD that last six months after vaccination. An exception was represented by ocrelizumab-treated pwMS that showed reduced levels of IgGs (p<0.0001) and a neutralizing activity under the limit of detection (p<0.001) compared to untreated pwMS. Considering the occurrence of a SARS-CoV-2 infection after vaccination, the Ab neutralizing efficacy (p=0.04), as well as CD4+ (p=0.016) and CD8+ (p=0.04) S-specific T cells, increased in treated COVID+ pwMS compared to uninfected treated pwMS at 6 months after vaccination. Discussion: Our follow-up provides a detailed evaluation of Ab, especially in terms of neutralizing activity, and T cell responses after anti-SARS-CoV-2 vaccination in MS context, over time, considering a wide number of therapies, and eventually breakthrough infection. Altogether, our observations highlight the vaccine response data to current protocols in pwMS and underline the necessity to carefully follow-up anti-CD20- treated patients for higher risk of breakthrough infections. Our study may provide useful information to refine future vaccination strategies in pwMS.

Humoral response after the booster dose of anti-SARS-CoV-2 vaccine in multiple sclerosis patients treated with high-efficacy therapies.

Anti-SARS-CoV2 mRNA vaccines showed a blunted antibody (Ab) response in people with MS (pwMS) on high efficacy therapies, suggesting the need for a booster dose. We evaluated the kinetics of the production of anti-receptor binding domain (RBD) Immunoglobulins G (IgG) after the vaccination cycle and the booster in pwMS receiving ocrelizumab, fingolimod and cladribine. A significant increase of anti-RBD IgG seroconversion was observed after booster respect to the vaccination cycle. Results obtained from this study will be useful for the management of pwMS in relation to their disease modifying therapy (DMT) and for any future vaccination campaign.

Atypical Multiple Sclerosis Lesions or Progressive Multifocal Leukoencephalopathy Lesions: That Is the Question.

Progressive multifocal leukoencephalopathy (PML) is a serious infective disease of the central nervous system that may occur in case of severe immunosuppression or after some treatment for multiple sclerosis (MS) with natalizumab, dimethyl fumarate, and fingolimod. In these case reports, we highlight the importance of differential diagnosis between PML and MS lesions in order to provide rapidly the best treatment option, by discussing the finding of brain (magnetic resonance imaging) MRI suggestive for PML in 2 MS patients, one treated with dimethyl fumarate and the other during natalizumab withdrawal. In both cases, although brain MRI was highly suggestive for PML, the detection of John Cunningham virus-DNA copies in cerebrospinal fluid resulted in negative result. These case reports illustrate the diagnostic process in case of suspected PML, as both patients were diagnosed with suspected PML during a routine brain MRI control, and highlights the importance of providing a strict brain MRI follow-up during dimethyl fumarate treatment, although only a few cases of PML during this therapy have been detected, and during natalizumab suspension phase. In clinical practice, in case of a radiologically suspected case of PML, although not confirmed by the cerebrospinal fluid analysis, the best approach could be to perform a close radiological and clinical monitoring before starting a new MS therapy.

Eye Movement Abnormalities in Multiple Sclerosis: Pathogenesis, Modeling, and Treatment.

Multiple sclerosis (MS) commonly causes eye movement abnormalities that may have a significant impact on patients' disability. Inflammatory demyelinating lesions, especially occurring in the posterior fossa, result in a wide range of disorders, spanning from acquired pendular nystagmus (APN) to internuclear ophthalmoplegia (INO), among the most common. As the control of eye movements is well understood in terms of anatomical substrate and underlying physiological network, studying ocular motor abnormalities in MS provides a unique opportunity to gain insights into mechanisms of disease. Quantitative measurement and modeling of eye movement disorders, such as INO, may lead to a better understanding of common symptoms encountered in MS, such as Uhthoff's phenomenon and fatigue. In turn, the pathophysiology of a range of eye movement abnormalities, such as APN, has been clarified based on correlation of experimental model with lesion localization by neuroimaging in MS. Eye movement disorders have the potential of being utilized as structural and functional biomarkers of early cognitive deficit, and possibly help in assessing disease status and progression, and to serve as platform and functional outcome to test novel therapeutic agents for MS. Knowledge of neuropharmacology applied to eye movement dysfunction has guided testing and use of a number of pharmacological agents to treat some eye movement disorders found in MS, such as APN and other forms of central nystagmus.

No evidence of disease activity (NEDA-3) and disability improvement after alemtuzumab treatment for multiple sclerosis: a 36-month real-world study.

In this retrospective, multicenter, real-world study we collected clinical and magnetic resonance imaging (MRI) data of all patients (n = 40) with relapsing-remitting multiple sclerosis (RRMS) treated with alemtuzumab according to a "free-of-charge" protocol available before the drug marketing approval in Italy. Almost all (39/40) started alemtuzumab after discontinuing multiple disease-modifying treatments (DMTs) because of either lack of response or safety concerns. We considered the proportion of alemtuzumab-treated patients who had no evidence of disease activity (NEDA-3) and disability improvement over a 36-month follow-up period. NEDA-3 was defined as absence of relapses, disability worsening, and MRI activity. Disability improvement was defined as a sustained reduction of ≥ 1-point in Expanded Disability Status Scale (EDSS) score. At follow-up, 18 (45%) patients achieved NEDA-3, 30 (75%) were relapse-free, 33 (82.5%) were EDSS worsening-free, and 25 (62.5%) were MRI activity-free. Eleven (27.5%) patients had a sustained disability improvement. We found no predictor for the NEDA-3 status, while the interaction of higher EDSS score by higher number of pre-alemtuzumab relapses was associated with a greater chance of disability improvement (odds ratio 1.10, p = 0.049). Our study provides real-world evidence that alemtuzumab can promote clinical and MRI disease remission, as well as disability improvement, in a significant proportion of patients with RRMS despite prior multiple DMT failures. The drug safety profile was consistent with data available from clinical trials.

High-Risk PML Patients Switching from Natalizumab to Alemtuzumab: an Observational Study.

INTRODUCTION: The choice of therapy in patients withdrawing from natalizumab treatment is still an open question and neurologists need strategies to manage this group of patients. The aim of this study is to evaluate if alemtuzumab is able to control the disease when used in patient who have stopped natalizumab. METHODS: 16 patients stopped natalizumab treatment after a median number of 20 infusions (range 12-114); all the patients were responders to natalizumab (neither clinical nor radiological activity during natalizumab therapy) and the reason for stopping was the risk of PML for all of them. Patients were switched to alemtuzumab after a median wash-out period of 70 days (range 41-99 days); patients underwent brain MRI every three months during natalizumab treatment and then just before starting alemtuzumab in order to exclude signs suggestive of PML; then, contrast-enhanced brain MRI was planned 6 and 12 months after alemtuzumab infusion. RESULTS: At present, 8 out of 16 patients have a follow-up >6 months and 2 out of 8 reached 1-year follow-up; 5 have a follow-up of 3-6 months and 3 have a follow-up <3 months. Brain MRI at 6 months after alemtuzumab is available for 8 out of 16 patients and in all of them, neither signs of disease activity nor new lesions are present; in 2 out of 8 patients, brain MRI at 12 months is also available, showing no sign of disease activity. Clinical evaluation performed at 6 and at 12 months (when available) showed stability, in particular neither relapses nor increase in EDSS were observed. CONCLUSIONS: Alemtuzumab was able to control the disease course in patients who stopped natalizumab; of course, as this is a single-centre study and the number of patients is small, these findings are very preliminary and need further confirmation.

Computerized posturography is more sensitive than clinical Romberg Test in detecting postural control impairment in minimally impaired Multiple Sclerosis patients.

Balance impairment, frequent in Multiple Sclerosis patients (MS), is difficult to detect promptly with routine clinical examination. Computerized platforms can measure subtle deficit but, given the complexity of postural system, multiple tests should be adopted. To evaluate whether platform was more sensitive than Romberg Test (RT) in detecting balance abnormalities, we 1) chose a battery of posturographic tests, 2) collected normative data from 58 healthy subjects 3) applied the tests to Clinically Isolated Syndrome (n=42) and minimally impaired MS (n=76). Subjects underwent 3 trials of quiet standing with eyes open and closed (modified Clinical Test of Sensory Interaction on Balance, mCTSIB) and 4 trials of voluntary anterior and lateral maximal leaning on right and left sides (Limits of Stability, LOS), giving 10 postural indexes. For every subject, the best trials were selected for subsequent analysis. Normative values were established in a range from 1st to 99th percentile, defining balance impairment by the presence of at least 2 indexes out of range. Even adopting the above mentioned strict definition of balance impairment, the forceplate resulted more sensitive than RT, detecting abnormalities in 25% of patients, while RT was abnormal in 7% only. In RT-negative patients with 1-year follow-up (n =67) the detection of a single abnormal index was able to predict a subsequent onset of symptomatic balance impairment. The proposed procedure is quick, easy to perform and can improve the assessment of the clinical course of MS, from a pre-clinical stage up to medium degree of disability.

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.

Diagnosing disconjugate eye movements: phase-plane analysis of horizontal saccades.

BACKGROUND: Saccades are fast eye movements that conjugately shift the point of fixation between distant features of interest in the visual environment. Several disorders, affecting sites from brainstem to extraocular muscle, may cause horizontal saccades to become disconjugate. Prior techniques for detection of saccadic disconjugacy, especially in internuclear ophthalmoparesis (INO), have compared only one point in abducting vs adducting saccades, such as peak velocity. METHODS: We applied a phase-plane technique that compared each eye's velocity as a function of change in position (normalized displacement) in 22 patients with disease variously affecting the brainstem reticular formation, the abducens nucleus, the medial longitudinal fasciculus, the oculomotor nerve, the abducens nerve, the neuromuscular junction, or the extraocular muscles; 10 age-matched subjects served as controls. RESULTS: We found three different patterns of disconjugacy throughout the course of horizontal saccades: early abnormal velocity disconjugacy during the first 10% of the displacement in patients with INO, oculomotor or abducens nerve palsy, and advanced extraocular muscle disease; late disconjugacy in patients with disease affecting the neuromuscular junction; and variable middle-course disconjugacy in patients with pontine lesions. When normal subjects made disconjugate saccades between two targets aligned on one eye, the initial part of the movement remained conjugate. CONCLUSIONS: Along with conventional measures of saccades, such as peak velocity, phase planes provide a useful tool to determine the site, extent, and pathogenesis of disconjugacy. We hypothesize that the pale global extraocular muscle fibers, which drive the high-acceleration component of saccades, receive a neural command that ensures initial ocular conjugacy.