Assessing upper limb function in multiple sclerosis using an engineered glove.

BACKGROUND AND PURPOSE: The importance of upper limb function in multiple sclerosis (MS) is increasingly recognized, especially for the evaluation of patients with progressive MS with reduced mobility. Two sensor-engineered gloves, able to measure quantitatively the timing of finger opposition movements, were previously used to assess upper limb disability in MS. The aims of the present study were: (1) to confirm the association between glove-derived variables and standard measures of MS disability in a larger cohort; (2) to assess the correlation with quantitative magnetic resonance imaging (MRI) and quality of life (QoL) measures; and (3) to determine if the glove-derived variables offer advantages over the standard measure for assessing upper limb function in MS, namely, the Nine-Hole Peg Test (9HPT). METHODS: Sixty-five patients with MS, stable on disease-modifying treatment, were evaluated at baseline using the glove, and through clinical examination (Expanded Disability Status Scale, Symbol Digit Modalities Test, Timed 25-Foot Walk Test and 9HPT), MRI evaluation and QoL questionnaires. Correlations between the glove-derived variables and clinical, MRI and QoL variables were assessed using Spearman's rank correlation coefficient analysis. RESULTS: Glove-derived variables significantly differed between patients with relapsing-remitting and those with progressive MS, with similar or slightly higher correlations of the 9HPT with clinical variables. We found greater correlations of the QoL physical component with glove-derived variables than with the 9HPT, and a significant correlation of its mental component with the glove-derived variables but not with the 9HPT. CONCLUSION: The study results, confirming previous findings and showing advantages over the 9HPT, encourage the investigation of sensitivity to change in glove-derived variables in a longitudinal setting.

Aggressive multiple sclerosis: a single-centre, real-world treatment experience with autologous haematopoietic stem cell transplantation and alemtuzumab.

BACKGROUND AND PURPOSE: The best therapeutic approach for aggressive relapsing-remitting multiple sclerosis remains unknown. The objective was to compare the efficacy and safety of autologous haematopoietic stem cell transplantation (aHSCT) and alemtuzumab in aggressive relapsing-remitting multiple sclerosis. METHODS: The time to first relapse, time to confirmed disability worsening, time to first evidence of magnetic resonance imaging (MRI) activity and time to first evidence of disease activity were compared between the two treatment groups. Secondary outcomes included the 12, 24 and 36 month annualized relapse rate (ARR) and the 6-month confirmed Expanded Disability Status Scale (EDSS) changes at months 12 and 24. RESULTS: Fifty-seven patients treated with aHSCT (n = 25) or alemtuzumab (n = 32) were included. At baseline, aHSCT patients had a higher EDSS (median score 6 vs. 3; P < 0.001), higher ARR (mean ARR 3.2 vs. 1.7; P = 0.001) and a higher number of baseline T1 gadolinium-enhancing lesions on MRI (mean number 15.5 vs. 1.6; P < 0.001). NEDA-3 (no evidence of disease activity) status was more frequently achieved in aHSCT-treated patients than in alemtuzumab-treated patients [75% vs. 56% of patients at the end of the observation period; hazard ratio (HR) 0.27, 95% confidence interval (CI) 0.08-0.84; P = 0.023]. aHSCT significantly reduced the risk of relapse (relapse-free survival 84% vs. 69%; HR 0.13, 95% CI 0.02-0.63; P = 0.012) and MRI activity (MRI-activity-free survival 85% vs. 59%; HR 0.13, 95% CI 0.03-0.59; P = 0.009). The ARR at 36 months was significantly lower in the aHSCT group (0.05 vs. 0.35, P = 0.02). A significant effect of aHSCT in promoting EDSS improvement compared with alemtuzumab was noted (P = 0.035). CONCLUSIONS: Alemtuzumab and aHSCT are effective treatment choices for aggressive multiple sclerosis. aHSCT seems to be superior to alemtuzumab in inducing complete disease control and in promoting short-term disability improvement.

PDGF-BB regulates splitting angiogenesis in skeletal muscle by limiting VEGF-induced endothelial proliferation.

VEGF induces normal or aberrant angiogenesis depending on its dose in the microenvironment around each producing cell in vivo. This transition depends on the balance between VEGF-induced endothelial stimulation and PDGF-BB-mediated pericyte recruitment, and co-expression of PDGF-BB normalizes aberrant angiogenesis despite high VEGF doses. We recently found that VEGF over-expression induces angiogenesis in skeletal muscle through an initial circumferential vascular enlargement followed by longitudinal splitting, rather than sprouting. Here we investigated the cellular mechanism by which PDGF-BB co-expression normalizes VEGF-induced aberrant angiogenesis. Monoclonal populations of transduced myoblasts, expressing similarly high levels of VEGF alone or with PDGF-BB, were implanted in mouse skeletal muscles. PDGF-BB co-expression did not promote sprouting and angiogenesis that occurred through vascular enlargement and splitting. However, enlargements were significantly smaller in diameter, due to a significant reduction in endothelial proliferation, and retained pericytes, which were otherwise lost with high VEGF alone. A time-course of histological analyses and repetitive intravital imaging showed that PDGF-BB co-expression anticipated the initiation of vascular enlargement and markedly accelerated the splitting process. Interestingly, quantification during in vivo imaging suggested that a global reduction in shear stress favored the initiation of transluminal pillar formation during VEGF-induced splitting angiogenesis. Quantification of target gene expression showed that VEGF-R2 signaling output was significantly reduced by PDGF-BB co-expression compared to VEGF alone. In conclusion, PDGF-BB co-expression prevents VEGF-induced aberrant angiogenesis by modulating VEGF-R2 signaling and endothelial proliferation, thereby limiting the degree of circumferential enlargement and enabling efficient completion of vascular splitting into normal capillary networks despite high VEGF doses.

Effect of radial shock wave therapy on pain and muscle hypertonia: a double-blind study in patients with multiple sclerosis.

BACKGROUND: Radial shock wave therapy (RSWT) has been extensively used in rehabilitative medicine to treat pain, and more recently muscle hypertonia, in patients with cerebral palsy and stroke. OBJECTIVES: To assess the long-term effects of RSWT in a cohort of subjects affected by multiple sclerosis (MS) who were suffering from painful hypertonia of ankle extensor muscles. METHODS: In this randomised, double blind, placebo-controlled study, we treated 34 patients with four sessions of RSWT (once weekly) and treated 34 patients with placebo. Participants were assessed at baseline, 1 week after the first session, and 1 week and 4 weeks after the last session. We measured pain using the visual analogue scale for pain, while we assessed muscle tone using the modified Ashworth scale and evaluated spinal excitability using the H-reflex. RESULTS: After RSWT, muscle tone decreased 1 week after the last session and pain decreased at all the follow-up evaluations, while spinal excitability was unaffected. No significant changes were found after the placebo treatment. CONCLUSIONS: RSWT can reduce pain and muscle tone in MS patients without adverse effects. The lack of RSWT effects on spinal excitability supports the idea that RSWT is likely to act on non-reflex hypertonia, for example reducing muscle fibrosis.

Autologous haematopoietic stem cell transplantation with an intermediate intensity conditioning regimen in multiple sclerosis: the Italian multi-centre experience.

BACKGROUND: Over recent years numerous patients with severe forms of multiple sclerosis (MS) refractory to conventional therapies have been treated with intense immunosuppression followed by autologous haematopoietic stem cell transplantation (AHSCT). The clinical outcome and the toxicity of AHSCT can be diverse, depending on the various types of conditioning protocols and on the disease phase. OBJECTIVES: To report the Italian experience on all the consecutive patients with MS treated with AHSCT with an intermediate intensity conditioning regimen, named BEAM/ATG, in the period from 1996 to 2008. METHODS: Clinical and magnetic resonance imaging outcomes of 74 patients were collected after a median follow-up period of 48.3 (range = 0.8-126) months. RESULTS: Two patients (2.7%) died from transplant-related causes. After 5 years, 66% of patients remained stable or improved. Among patients with a follow-up longer than 1 year, eight out of 25 subjects with a relapsing-remitting course (31%) had a 6-12 months confirmed Expanded Disability Status Scale improvement > 1 point after AHSCT as compared with one out of 36 (3%) patients with a secondary progressive disease course (p = 0.009). Among the 18 cases with a follow-up longer than 7 years, eight (44%) remained stable or had a sustained improvement while 10 (56%), after an initial period of stabilization or improvement with median duration of 3.5 years, showed a slow disability progression. CONCLUSIONS: This study shows that AHSCT with a BEAM/ATG conditioning regimen has a sustained effect in suppressing disease progression in aggressive MS cases unresponsive to conventional therapies. It can also cause a sustained clinical improvement, especially if treated subjects are still in the relapsing-remitting phase of the disease.

Association of melanoma and natalizumab therapy in the Italian MS population: a second case report.

There is debate about a possible association between natalizumab treatment and higher risk of melanoma. Here we report a case of melanoma in a patient who developed melanoma after 77 infusions of natalizumab, without known risk factors. Pharmacovigilance programs of new drugs can help to monitor adverse events in patients at risk.

Recommendations for the management of urinary disorders in multiple sclerosis: a consensus of the Italian Multiple Sclerosis Study Group.

Urinary disorders are uncommon in the initial phases of multiple sclerosis, but increase in frequency as the disease progresses, with a negative impact on quality of life. The goal of this study was to propose a protocol for the diagnosis and treatment of urinary disorders in multiple sclerosis, based on data from the scientific literature and the experience of Italian clinical centres. In particular, the following clinical aspects were considered: what to do with patients with asymptomatic multiple sclerosis; what to do with symptomatic patients; how and when to perform a second-level diagnostic evaluation; and how to treat urinary disorders. A diagnostic-therapeutic algorithm is proposed, that can be applied in Italian clinical centres.

Autologous haematopoietic stem-cell transplantation in multiple sclerosis: benefits and risks.

Autologous haematopoietic stem-cell transplantation has been evaluated over the last years as a possible new therapeutic strategy in severe forms of multiple sclerosis unresponsive to the approved therapies. Up to now, more than 400 patients have been treated and numerous are the phase I and phase II studies which addressed the feasibility of this treatment, the efficacy, side effects and transplant-related mortality. The clinical response is strongly related to the intensity of the conditioning regimen utilized as well as to the phase of the disease course in which the therapy is carried out. Rapidly evolving multiple sclerosis with a relapsing-remitting clinical course and MRI signs of activity are the cases that can take more advantage. The risk of mortality, which dropped in the last years to 2-3%, is still the main problem of this powerful therapy.

Tocilizumab in MOG-antibody spectrum disorder: a case report.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-related spectrum disorders (MOG-SD) are a heterogeneous group of inflammatory demyelinating diseases of the central nervous system, usually responsive to conventional immunosuppressive therapies. However, knowledge about treatment of non-responder patients is scarce. METHODS: We report on a 20-year-old MOG-SD patient who experienced clinical deterioration despite rituximab-induced B-cell depletion. RESULTS: Rescue therapy with tocilizumab (TCZ) prevented further relapses, with reduction of spinal-cord load on MRI, and a remarkable reduction of disability at the two-year follow-up. CONCLUSION: Our observations suggest that TCZ could induce clinico-radiologic improvements, which make it as an option for the treatment of MOG-SD.

Serum sickness (Like Reaction) in a patient treated with alemtuzumab for multiple sclerosis: A case report.

BACKGROUND: Alemtuzumab is a monoclonal antibody approved for relapsing-remitting multiple sclerosis (RRMS). The only report of Serum Sickness (SS) in a MS patient occurred during treatment with natalizumab. Non-protein drugs, such as some antibiotics, may induce "SS-like" reactions (SSLR), whose clinical and laboratory features may partially overlap with the traditional SS. OBJECTIVE: To report a case of SS/SSLR in a RRMS patient treated with alemtuzumab. CASE REPORT: A 42-year-old-woman with RRMS developed SS/SSLR in the first week after the first alemtuzumab treatment. Concomitant medications included trimethoprim-sulfamethoxazole at low dose. Intravenous methylprednisolone therapy led to clinical resolution and normalization of serum inflammatory markers. CONCLUSION: SS/SSLR should be considered in patients treated with alemtuzumab developing delayed fever, rash and arthralgia and differentiated with Infusion Associated Reactions (IARs) and infections.

Autologous stem cell transplantation for severe autoimmune diseases: a 10-year experience.

The first autologous hematopoietic stem cell transplantation in Europe for a patient with severe refractory systemic lupus erythematosus (SLE) was performed in Genoa in 1996. Since then, 32 patients with a wide spectrum of autoimmune diseases (ADs) received autologous transplants, 22 of them with multiple sclerosis (MS). There were no fatal adverse events. All patients had complete or very good partial remissions, but relapses were frequent, especially in SLE, though never as aggressive as pretransplant. The mechanism of action of this intervention remains not completely understood, as briefly discussed here.

Quantitative 3D investigation of Neuronal network in mouse spinal cord model.

The investigation of the neuronal network in mouse spinal cord models represents the basis for the research on neurodegenerative diseases. In this framework, the quantitative analysis of the single elements in different districts is a crucial task. However, conventional 3D imaging techniques do not have enough spatial resolution and contrast to allow for a quantitative investigation of the neuronal network. Exploiting the high coherence and the high flux of synchrotron sources, X-ray Phase-Contrast multiscale-Tomography allows for the 3D investigation of the neuronal microanatomy without any aggressive sample preparation or sectioning. We investigated healthy-mouse neuronal architecture by imaging the 3D distribution of the neuronal-network with a spatial resolution of 640 nm. The high quality of the obtained images enables a quantitative study of the neuronal structure on a subject-by-subject basis. We developed and applied a spatial statistical analysis on the motor neurons to obtain quantitative information on their 3D arrangement in the healthy-mice spinal cord. Then, we compared the obtained results with a mouse model of multiple sclerosis. Our approach paves the way to the creation of a "database" for the characterization of the neuronal network main features for a comparative investigation of neurodegenerative diseases and therapies.

X-Ray Phase Contrast Tomography Reveals Early Vascular Alterations and Neuronal Loss in a Multiple Sclerosis Model.

The degenerative effects of multiple sclerosis at the level of the vascular and neuronal networks in the central nervous system are currently the object of intensive investigation. Preclinical studies have demonstrated the efficacy of mesenchymal stem cell (MSC) therapy in experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis, but the neuropathology of specific lesions in EAE and the effects of MSC treatment are under debate. Because conventional imaging techniques entail protocols that alter the tissues, limiting the reliability of the results, we have used non-invasive X-ray phase-contrast tomography to obtain an unprecedented direct 3D characterization of EAE lesions at micro-to-nano scales, with simultaneous imaging of the vascular and neuronal networks. We reveal EAE-mediated alterations down to the capillary network. Our findings shed light on how the disease and MSC treatment affect the tissues, and promote X-ray phase-contrast tomography as a powerful tool for studying neurovascular diseases and monitoring advanced therapies.

Peripheral benzodiazepine receptors on platelets of fibromyalgic patients.

OBJECTIVE: The aim of the present study was to analyze if alterations of peripheral-type benzodiazepine receptor (PBR) characteristics occurred in platelet membranes of patients affected by primary fibromyalgia (FM). DESIGN AND METHODS: Platelets were obtained from 30 patients with FM. Evaluation of kinetic parameters of PBR was performed using [(3)H] PK11195 as specific radioligand compared with 16 healthy volunteers. RESULTS: The results showed a significant increase of PBR binding sites value in platelet membranes from FM patients (B(max) was 5366+/-188 fmol/mg vs. controls, 4193+/-341 fmol/mg, mean+/-SEM) (**p<0.01) but not for affinity value (K(d) was 4.90+/-0.39 nM vs. controls, 4.74+/-0.39 nM, mean+/-SEM) (p>0.05). Symptom severity scores (pain and tiredness) were positively correlated with B(max). CONCLUSIONS: Our results showed an up-regulation of PBR in platelets of FM patients, and this seems to be related to the severity of fibromyalgic symptoms.

Costs and quality of life of multiple sclerosis in Italy.

This cost-of-illness analysis based on information from 921 patients in Italy is part of a Europe-wide cost-of-illness study in multiple sclerosis (MS). The objective was to analyze the costs and quality of life (QOL) related to the level of disease severity and progression. Patients registered with the Italian MS patient organization were asked to participate in a mail survey, and 31% responded. The questionnaire asked for details on the disease (type of disease, relapses, level of functional disability), information on all medical and non-medical resource consumption, and informal care and work capacity (sick leave and early retirement). In addition, patients were asked about their current QOL (in the form of utility) and the level of fatigue. The mean age of respondents was 46 years, and 8.5% were 65 years or older. As many as 20% of patients had severe disease (Expanded Disability Status Scale [EDSS] score of > or =7), 47% had moderate disease (EDSS score of 4-6.5) and only 31% had mild disease (EDSS score of 0-3). Thus, the mean EDSS score in the sample was 4.6 (median 5.0), with a utility of 0.53 (range: 0 = death to 1 = full health) and a fatigue level of 6.4 (range: 1 = not tired to 10 = extremely tired). Costs and utility are highly correlated with disease severity. Workforce participation decreases from approximately 80% in early disease to less than 10% in the very late stages. Total costs increase fivefold between an EDSS score of 0-1 and a score of 7. Health-care costs, however, show a limited increase with worsening disease--hospitalization increases from euro 800 per patient to euro 3200, and ambulatory care increases from euro 900 to euro 1500. Productivity losses, on the other hand, increase by a factor of 12, while informal care increases from euro 500 at an EDSS score of 0-1 to nearly euro 25 000 at an EDSS score of 7, and euro 39 000 at an EDSS score of 8-9. Hence, total mean costs per patient are determined essentially by the distribution of the severity levels in the sample, increasing from euro 12 000 at an EDSS score of 0-1 to euro 57 000 at an EDSS score of 7, and euro 71 000 at an EDSS score of 8-9. The same is true for utility, which decreases from 0.80 to 0.06 as the disease becomes severe. However, the utility loss compared to the age- and gender-matched general population is high at all levels of the disease, leading to an estimated annual loss of 0.3 quality-adjusted life year (QALY) per patient. Relapses for patients with an EDSS score of <5 are associated with a cost of approximately euro 4000 and a utility loss of 0.18 during the quarter in which they occur.

Rituximab in the treatment of Neuromyelitis optica: a multicentre Italian observational study.

Rituximab (RTX) efficacy in NMO is suggested by several case series. No consensus exists on optimal dosing strategies. At present the treatment schedules more frequently used are 375 mg/m2/week iv for 4 weeks (RTX-A) and 1000 mg iv twice, 2 weeks apart (RTX-B). Aim of this study is to confirm RTX efficacy and safety in the treatment of NMO and to evaluate whether a most favourable dosage regimen exists. Data on RTX-treated NMO patients were collected from 13 Italian Hospitals. 73 patients (64 F), were enlisted. RTX-A was administered in 42/73 patients, RTX-B in 31/73. Median follow-up was 27 months (range 7-106). Mean relapse rate in the previous year before RTX start was 2.2 ± 1.3 for RTX-A and 2.3 ± 1.2 for RTX-B. ARR in the first year of treatment was 0.8 ± 0.9 for RTX-A and 0.2 ± 0.4 for RTX-B, in the second year of treatment was 0.9 ± 1.5 for RTX-A and 0.4 ± 0.8 for RTX-B patients (p = 0.001 for the first year, ns (0.09) for the second year). RTX-B was more effective in delaying the occurrence of a relapse (HR 2.2 (95 % IC 1.08-4.53) p = 0.02). Adverse events were described in 19/73 patients (mainly urinary tract and respiratory infections, and infusion reactions). Two deaths were reported in severely disabled patients. Though with the limitations of an observational study, our data support RTX efficacy in NMO and suggest that high dose pulses might be more effective than a more fractioned dose.

Conventional perimetry, short-wavelength automated perimetry, frequency-doubling technology, and visual evoked potentials in the assessment of patients with multiple sclerosis.

PURPOSE: To evaluate the diagnostic power of conventional, achromatic, automated perimetry (CAP), short-wavelength automated perimetry (SWAP), frequency-doubling technology (FDT) perimetry, and visual evoked potentials (VEP) in a group of patients with multiple sclerosis (MS) with or without a history of optic neuritis. METHODS: Thirty eyes of 15 patients (5 male, 10 female, average age 38+/-7 years) with confirmed diagnosis of MS underwent CAP, SWAP (Humphrey 750-II VFA, program central 30-2, full-threshold strategy), FDT perimetry (program N-30), and pattern VEPs. Sixteen eyes (53.3%) had no history of ocular involvement and a negative ophthalmologic examination. They were matched with a control group of 10 healthy volunteers (4 male, 6 female, average age 31+/-10 years). The mean deviation (MD) and the pattern standard deviation (PSD) of the two groups were compared (t-test). Fourteen eyes (46.7%) had, on the contrary, a history of optic neuritis. Inside this group, the MD and the PSD of the three techniques were correlated (Spearman's rank test), in order to investigate whether any significant differences might be revealed by these techniques in pointing out the total amount of visual field damage. RESULTS: When comparing MS patients without signs or symptoms of ocular involvement and a control group, no significant differences were found for CAP MD, CAP PSD, and FDT PSD. Significant differences were found, on the contrary, for SWAP MD (p=0.0014), SWAP PSD (p=0.0001), and FDT MD (p=0.0001). When considering the MD and the PSD of the three techniques in the group of MS patients who had a history of optic neuritis, a significant correlation was found only between CAP MD and SWAP MD (r=0.0057), with a tendency by SWAP to reveal a higher rate of visual field loss. The other correlations were not significant. According to predefined criteria, the group of asymptomatic subjects had abnormal CAP in 1 eye (6.25%), abnormal SWAP in 9 (56.2%), abnormal FDT in 11 (68.7%), and abnormal VEPs in 7 (43.7%). The combined use of all techniques allowed us to identify silent optic nerve impairment in 15 (93.7%) eyes. CONCLUSIONS: Short-wavelength automated perimetry and FDT perimetry are two non-conventional perimetric techniques that were mainly developed for the early detection of glaucomatous damage. The results of this study demonstrate their efficacy also in detecting early visual field deficits in MS patients without clinical signs of optic neuropathy. Frequency doubling perimetry, in particular, proved to be an easy, fast, and sensitive technique in the assessment of patients with MS. Our results also suggest that subclinical visual involvement in MS can be better diagnosed using multiple (neurophysiologic and psychophysical) tests.