Neurobehavioral, biochemical and histological assessment of the effects of resveratrol on cuprizone-induced demyelination in mice: role of autophagy modulation.

Resveratrol is known to exhibit neuroprotective effects in many neurological disorders via autophagy modulation. However, controversial results have been reported about the therapeutic potential of resveratrol and the implication of autophagy in demyelinating diseases. This study aimed to evaluate the autophagic changes in cuprizone-intoxicated C57Bl/6 mice and explore the effect of autophagy activation by resveratrol on the demyelination and remyelination processes. Mice were fed with chow containing 0.2% cuprizone for 5 weeks, followed by a cuprizone-free diet for 2 weeks. Resveratrol (250 mg/kg/day) and/or chloroquine (an autophagy inhibitor; 10 mg/kg/day) were given for 5 weeks starting from the third week. At the end of the experiment, animals were tested on rotarod and then sacrificed for biochemical assessment, luxol fast blue (LFB) staining, and transmission electron microscopy (TEM) imaging of the corpus callosum. We observed that cuprizone-induced demyelination was associated with impaired degradation of autophagic cargo, induction of apoptosis, and manifest neurobehavioral disturbances. Oral treatment with resveratrol promoted motor coordination and improved remyelination with regular compacted myelin in most axons without a significant impact on myelin basic protein (MBP) mRNA expression. These effects are mediated, at least in part, via activating autophagic pathways that may involve SIRT1/FoxO1 activation. This study verified that resveratrol dampens cuprizone-induced demyelination, and partially enhances myelin repair through modulation of the autophagic flux, since interruption of the autophagic machinery by chloroquine reversed the therapeutic potential of resveratrol.

[The cost-effectiveness of interferon beta treatment in patients with a clinically isolated syndrome in Colombia]. / Costo-efectividad del tratamiento con interferón beta en pacientes con síndrome clínico aislado de alto riesgo en Colombia.

INTRODUCTION: Approximately 85% of patients with multiple sclerosis have an initial demyelinating event. Treatment with interferon beta delays the progression of multiple sclerosis for nearly two years in patients with a clinically isolated syndrome. In Colombia, interferon is very expensive when compared to other countries. OBJECTIVE: We sought to determine the cost-effectiveness of a two-year interferon beta treatment within Colombia in patients with a clinically isolated syndrome. MATERIALS AND METHODS: Based on patient and society perspectives, a cost-effectiveness analysis was conducted using a decision tree. A variety of probabilities were defined after a systematic review of the available literature. The disease costs were calculated by reviewing medical charts at the Hospital San Ignacio University and surveys completed by multiple sclerosis patients. To control for uncertainty in these data, analysis of approximately one-thousand patients was performed using Monte Carlo methods. RESULTS: The two-year treatment cost per patient exceeds Col$ 95,000,000 (US$ 50,000). Approximately 80 % of this cost corresponds to medications (US$ 40,500). The price of relapse and indirect costs totals Col$ 41,632,149 (US$ 21,744) and Col$ 11,656,389 (US$ 6,088), respectively. Treatment represents an increase of 0.06 quality-adjusted life years (QALY). The incremental cost-effectiveness ratio exceeds the threshold, regardless of the use of Monte Carlo methods for analysis. CONCLUSION: Administering interferon beta over the course of two years to high-risk patients with a clinically isolated syndrome is not cost-effective within Colombia.

Longitudinal MRI and neuropsychological assessment of patients with clinically isolated syndrome.

Cognitive impairment (CI) may occur in clinically isolated syndrome (CIS) patients. While the relationship between CI and magnetic resonance imaging (MRI) has been investigated extensively in multiple sclerosis (MS), MRI correlates of CI in CIS patients are unknown. To investigate the evolution of CI and to determine brain MRI structural correlates associated with CI in CIS patients. This prospective 24-month observational study examined 81 CIS patients treated with 30 µg of intramuscular interferon beta 1a once a week. MRI acquisition and neuropsychological (NP) assessment were performed at baseline, 6, 12 and 24 months. Participants were tested with Czech-validated version of Minimal Assessment of Cognitive Function in MS battery and MRI measures of lesion activity and burden, and global, tissue-specific and regional brain atrophy were performed. Over 24 months, 36 CIS patients developed clinically definite MS (CDMS). CI was observed in 10 (12.3 %) CIS patients at baseline and at the 24 months follow-up. Eight CIS patients changed their CI status over the follow-up (four improved and four worsened). No significant difference in development of CI was detected between stable CIS patients and those who developed CDMS. In multivariate regression and mixed-effect model analyses, no significant relationship was found between NP and MRI parameters. The lack of significant relationship between MRI metrics and cognition in this group of CIS patients could be attributed to several factors including the cognitive reserve, effect of disease-modifying therapy and relatively short follow-up period.

Costo-efectividad del tratamiento con interferón beta en pacientes con síndrome clínico aislado de alto riesgo en Colombia / The cost-effectiveness of interferon beta treatment in patients with a clinically isolated syndrome in Colombia

Introducción. En 85 % de los pacientes con esclerosis múltiple se presenta como manifestación inicial un primer evento desmielinizante o síndrome clínico aislado. En estos casos, el tratamiento con interferón beta retrasa hasta dos años la progresión a esclerosis múltiple. Sin embargo, en Colombia este medicamento es costoso. Objetivo. Determinar si el tratamiento del síndrome clínico aislado con interferón beta es costo-efectivo al retrasar la esclerosis múltiple en dos años. Materiales y métodos. Se realizó un análisis de costo-efectividad empleando un árbol de decisiones basado en la perspectiva del paciente y la sociedad. A partir de una revisión sistemática de la literatura y de conceptos de expertos se definieron las diversas probabilidades. Los costos de la enfermedad se calcularon por medio de la revisión de historias y la aplicación de encuestas a los pacientes atendidos en el Hospital Universitario San Ignacio. Para controlar la incertidumbre se realizó un análisis de sensibilidad mediante una simulación de Monte Carlo con mil pacientes. Resultados. El costo del tratamiento con interferón sobrepasa los Col$ 95´000.000 (US$ 50.000) por paciente durante los dos años. Aproximadamente, 80 % corresponde a los costos del medicamento. El costo de la recaída se acerca a Col$ 39´139.200 (US$ 21.744), y los costos indirectos corresponden a Col$ 10´958.400 (US$ 6.088). La tasa representativa del mercado fue de Col$ 1.800. Con el tratamiento se ganan sólo 0,06 años de vida ajustados por discapacidad (AVAD) adicionales. La razón de costo-efectividad ‘incremental´ (sic.) supera el umbral, incluso en el análisis de sensibilidad. Conclusión. La administración de interferón beta en pacientes con síndrome clínico aislado de alto riesgo en los primeros dos años no es costo-efectiva en Colombia.

Introduction: Approximately 85% of patients with multiple sclerosis have an initial demyelinating event. Treatment with interferon beta delays the progression of multiple sclerosis for nearly two years in patients with a clinically isolated syndrome. In Colombia, interferon is very expensive when compared to other countries. Objective: We sought to determine the cost-effectiveness of a two-year interferon beta treatment within Colombia in patients with a clinically isolated syndrome. Materials and methods: Based on patient and society perspectives, a cost-effectiveness analysis was conducted using a decision tree. A variety of probabilities were defined after a systematic review of the available literature. The disease costs were calculated by reviewing medical charts at the Hospital San Ignacio University and surveys completed by multiple sclerosis patients. To control for uncertainty in these data, analysis of approximately one-thousand patients was performed using Monte Carlo methods. Results: The two-year treatment cost per patient exceeds Col$ 95,000,000 (US$ 50,000). Approximately 80 % of this cost corresponds to medications (US$ 40,500). The price of relapse and indirect costs totals Col$ 41,632,149 (US$ 21,744) and Col$ 11,656,389 (US$ 6,088), respectively. Treatment represents an increase of 0.06 quality-adjusted life years (QALY). The incremental cost-effectiveness ratio exceeds the threshold, regardless of the use of Monte Carlo methods for analysis. Conclusion: Administering interferon beta over the course of two years to high-risk patients with a clinically isolated syndrome is not cost-effective within Colombia.

A cost-effectiveness analysis of subcutaneous interferon beta-1a 44mcg 3-times a week vs no treatment for patients with clinically isolated syndrome in Sweden.

OBJECTIVE: To assess the cost-effectiveness of subcutaneous interferon (sc IFN) beta-1a 44 mcg 3-times weekly (tiw) vs no treatment at reducing the risk of conversion to multiple sclerosis (MS) in patients with clinically isolated syndrome (CIS) in Sweden. METHODS: A Markov model was constructed to simulate the clinical course of patients with CIS treated with sc IFN beta-1a 44 mcg tiw or no treatment over a 40-year time horizon. Costs were estimated from a societal perspective in 2012 Swedish kronor (SEK). Treatment efficacy data were derived from the REFLEX trial; resource use and quality-of-life (QoL) data were obtained from the literature. Costs and outcomes were discounted at 3%. Sensitivity analyses explored whether results were robust to changes in input values and use of Poser criteria. RESULTS: Using McDonald criteria sc IFN beta-1a was cost-saving and more effective (i.e., dominant) vs no treatment. Gains in progression free life years (PFLYs) and quality-adjusted life-years (QALYs) were 1.63 and 0.53, respectively. Projected cost savings were 270,263 SEK. For Poser criteria cost savings of 823,459 SEK were estimated, with PFLY and QALY gains of 4.12 and 1.38, respectively. Subcutaneous IFN beta-1a remained dominant from a payer perspective. Results were insensitive to key input variation. Probabilistic sensitivity analysis estimated a 99.9% likelihood of cost-effectiveness at a willingness-to-pay threshold of 500,000 SEK/QALY. CONCLUSION: Subcutaneous IFN beta-1a is a cost-effective option for the treatment of patients at high risk of MS conversion. It is associated with lower costs, greater QALY gains, and more time free of MS. LIMITATIONS: The risk of conversion from CIS to MS was extrapolated from 2-year trial data. Treatment benefit was assumed to persist over the model duration, although long-term data to support this are unavailable. Cost and QoL data from MS patients were assumed applicable to CIS patients.

Use of intravenous immunoglobulin in the treatment of immune-mediated demyelinating diseases of the nervous system.

Intravenous immunoglobulins (IVIg) are used in treatment of a broad spectrum of diseases. Immunoglobulin replacement therapy is the standard treatment for immunodeficiencies with compromised humoural immunity. Use of this method as an immunomodulating therapy ranges from transplantation and treatment of autoimmune-haematological diseases to treatment of various neuroimmunological clinical entities. Limited quantitative availability due to dependence on human donors as a source of IVIg, coupled with high treatment costs, make necessary a highly responsible and evidence-based approach with these agents. Discussion of the indications and currently valid recommendations on use of IVIg in treatment of immunomediated demyelinating diseases of the nervous system is based on existing clinical studies. We describe further neurological indications for use of IVIg as well as mechanisms of action and adverse effects of its use.

Paediatric UK demyelinating disease longitudinal study (PUDDLS).

BACKGROUND: There is evidence that at least 5% of Multiple sclerosis (MS) cases manifest in childhood. Children with MS present with a demyelinating episode involving single or multiple symptoms prior to developing a second event (usually within two years) to then meet criteria for diagnosis. There is evidence from adult cohorts that the incidence and sex ratios of MS are changing and that children of immigrants have a higher risk for developing MS. A paediatric population should reflect the vanguard of such changes and may reflect trends yet to be observed in adult cohorts. Studying a paediatric population from the first demyelinating event will allow us to test these hypotheses, and may offer further valuable insights into the genetic and environmental interactions in the pathogenesis of MS. METHODS/DESIGN: The Paediatric UK Demyelinating Disease Longitudinal Study (PUDDLS) is a prospective longitudinal observational study which aims to determine the natural history, predictors and outcomes of childhood CNS inflammatory demyelinating diseases. PUDDLS will involve centres in the UK, and will establish a cohort of children affected with a first CNS inflammatory demyelinating event for long-term follow up by recruiting for approximately 5 years. PUDDLS will also establish a biological sample archive (CSF, serum, and DNA), allowing future hypothesis driven research. For example, the future discovery of a biomarker will allow validation within this dataset for the evaluation of novel biomarkers. Patients will also be requested to consent to be contacted in the future. A secondary aim is to collaborate internationally with the International Paediatric Multiple Sclerosis Study Group when future collaborative studies are proposed, whilst sharing a minimal anonymised dataset. PUDDLS is the second of two jointly funded studies. The first (UCID-SS) is an epidemiological surveillance study that already received ethical approvals, and started on the 1st September 2009. There is no direct patient involvement, and UCID-SS aims to determine the UK and Ireland incidence of CNS inflammatory demyelinating disorders in children under 16 years. DISCUSSION: A paediatric population should reflect the vanguard of MS epidemiological changes and may reflect trends yet to be observed in adult MS cohorts. The restricted window between clinical expression of disease and exposure to environmental factors in children offers a unique research opportunity. Studying a paediatric population from the first demyelinating event will allow us to investigate the changing epidemiology of MS, and may offer further valuable insights into the genetic and environmental interactions in the pathogenesis of MS.

Can the functional assessment of multiple sclerosis adapt to changing needs? A psychometric validation in patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis.

BACKGROUND: The Functional Assessment of Multiple Sclerosis (FAMS) is widely used in clinical trial programmes; however, it was developed before the rise in trials targeted at early stage multiple sclerosis (MS) and clinically isolated syndrome (CIS). OBJECTIVE: The aim of this study was to assess the psychometric properties of the FAMS within two clinically distinct populations, CIS and early relapsing-remitting MS (RRMS), and discern the appropriateness of the FAMS within these populations. METHODS: Secondary analysis was conducted on FAMS data from two clinical trials assessing interferon beta-1b in early RRMS and CIS. The statistical analysis assessed the scale acceptability, reliability, validity and responsiveness of the FAMS. Item response theory (IRT) was also conducted on the early RRMS sample in order to assess how well the FAMS discriminated amongst individuals with less severe MS. RESULTS: Results from both trials demonstrated an improvement in the FAMS psychometric properties with increased baseline disease severity. However, high ceiling effects were evident amongst less severe patients, and there was an overall lack of responsiveness to improvement and poor construct validity. IRT also demonstrated its lack of discrimination/sensitivity in early RRMS. CONCLUSIONS: In trials involving patients with early stage RRMS and CIS, modifications to the FAMS based on a qualitative assessment of its content validity in these populations would be required in order to potentially improve the FAMS psychometric properties and sensitivity.

Recovery from chronic demyelination by thyroid hormone therapy: myelinogenesis induction and assessment by diffusion tensor magnetic resonance imaging.

The failure of the remyelination processes in multiple sclerosis contributes to the formation of chronic demyelinated plaques that lead to severe neurological deficits. Long-term cuprizone treatment of C57BL/6 mice resulted in pronounced white matter pathology characterized by oligodendrocyte depletion, irreversible demyelination and persistent functional deficits after cuprizone withdrawal. The use of a combination of in vivo diffusion tensor magnetic resonance imaging (DT-MRI) and histological analyses allowed for an accurate longitudinal assessment of demyelination. Injection of triiodothyronine (T(3)) hormone over a 3 week interval after cuprizone withdrawal progressively restored the normal DT-MRI phenotype accompanied by an improvement of clinical signs and remyelination. The effects of T(3) were not restricted to the later stages of remyelination but increased the expression of sonic hedgehog and the numbers of Olig2(+) and PSA-NCAM(+) precursors and proliferative cells. Our findings establish a role for T(3) as an inducer of oligodendrocyte progenitor cells in adult mouse brain following chronic demyelination.

Brain dysmyelination and recovery assessment by noninvasive in vivo diffusion tensor magnetic resonance imaging.

Diffusion tensor magnetic resonance imaging (DT-MRI) was applied for in vivo quantification of myelin loss and regeneration. A transgenic mouse line (Oligo-TTK) expressing a truncated form of the herpes simplex virus 1 thymidine kinase gene (hsv1-tk) in oligodendrocytes was studied along with two induced phenotypes of myelin pathology. Myelin loss and axonal abnormalities differentially affect values of DT-MRI parameters in the brain of transgenic mice. Changes in the anisotropy of the white matter were assessed by calculating and mapping the radial (D perpendicular) and axial (D parallel) water diffusion to axonal tracts and fractional anisotropy (FA). A significant increase in D perpendicular attributed to the lack of myelin was observed in all selected brain white matter tracts in dysmyelinated mice. Lower D parallel values were consistent with the histological observation of axonal modifications, including reduced axonal caliber and overexpression of neurofilaments and III beta-tubulin. We show clearly that myelination and axonal changes play a role in the degree of diffusion anisotropy, because FA was significantly decreased in dysmyelinated brain. Importantly, myelin reparation during brain postnatal development induced a decrease in the magnitude of D( perpendicular) and an increase in FA compared with the same brain before recovery. The progressive increase in D parallel values was attributed to the gain in normal axonal morphology. This regeneration was confirmed by the detection of enlarged oligodendrocyte population, newly formed myelin sheaths around additional axons, and a gradual increase in axonal caliber.

Economic evaluation of Avonex (interferon beta-Ia) in patients following a single demyelinating event.

BACKGROUND: Interferon beta-Ia (Avonex) 30 microg, intramuscular (i.m.), once weekly is efficacious in delaying clinically definite multiple sclerosis (CDMS) following a single demyelinating event (SDE). This study determined the cost effectiveness of Avonex compared to current treatment in delaying the onset of CDMS. METHODS: A cost-effectiveness analysis (CEA) and cost-utility analysis (CUA) were performed from Ministry of Health (MoH) and societal perspectives. For CEA, the outcome of interest was time spent in the pre-CDMS state, termed monosymptomatic life years (MLY) gained. For CUA, the outcome was quality-adjusted monosymptomatic life years (QAMLY) gained. A Markov model was developed with transitional probabilities and utilities derived from the literature. Costs were reported in 2002 Canadian dollars. Costs and outcomes were discounted at 5%. The time horizon was 12 years for the CEA, and 15 years for the CUA. All uncertainties were tested via univariate and multivariate sensitivity analyses. RESULTS: In the CEA, the incremental cost of Avonex per ILYgained was $53110 and $44789 from MoH and societal perspectives, respectively. In the CUA, the incremental cost of Avonex per QAMLY gained was $227586 and $189286 from MoH and societal perspectives, respectively. Both models were sensitive to the probability of progressing to CDMS and the analytical time horizon. The CUA was sensitive to the utilities value. CONCLUSION: Avonex may be considered as a reasonably cost-effective approach to treatment of patients experiencing an SDE In addition, the overall incremental cost-effectiveness profile of Avonex improves if treatment is initiated in pre-CDMS rather than waiting until CDMS.