Veins in plaques of multiple sclerosis patients - a longitudinal magnetic resonance imaging study at 7 Tesla.

OBJECTIVE: To monitor the venous volumes in plaques of patients with multiple sclerosis (MS) compared to an age-matched control group over a period of 3.5 years. METHODS: Ten MS patients underwent an annual neurological examination and MRI. Susceptibility-weighted imaging (SWI) combined with fluid-attenuated inversion recovery (FLAIR) or FLAIR-like contrast at 7 Tesla (7 T) magnetic resonance imaging (MRI) was used for manual segmentation of veins in plaques, in the normal-appearing white matter (NAWM) and in location-matched white matter of 9 age-matched controls. Venous volume to tissue volume ratio was assessed for each time point in order to describe the dynamics of venous volumes in MS plaques over time. RESULTS: MS plaques, which were newly detected during the study period, showed significantly higher venous volumes compared to the preplaque area 1 year before plaque detection and the corresponding NAWM regions. Venous volumes in established MS plaques, which were present already in the first scans, were significantly higher compared to the NAWM and controls. CONCLUSIONS: Our data underpin a relation of veins and plaque development in MS and reflect increased apparent venous calibers due to increased venous diameters or increased oxygen consumption in early MS plaques. KEY POINTS: • Longitudinal 7 T Magnetic Resonance Imaging study of intralesional veins in MS patients. • Venous volumes are significantly increased in newly detected and established MS plaques. • Venous volumes in established MS plaques show a trend to decrease with time.

Replication study of multiple sclerosis (MS) susceptibility alleles and correlation of DNA-variants with disease features in a cohort of Austrian MS patients.

We performed a replication study in 883 Austrian multiple sclerosis (MS) patients and 972 control individuals for 25 previously risk-associated loci (39 SNPs). Two loci, rs1109670 (DDEF2/MBOAT2, p < 0.02) and rs16914086 (TBC1D2, p < 0.05), are replicated here for the first time. Furthermore, we tested all 39 SNPs for association with age at disease onset and measures of disease severity. We observed a trend for association of rs3135388 (HLA-DRB1*1501, p < 0.01), rs7090530 (IL2RA, p < 0.026) and rs1841770 (ZIC1, p < 0.017) with a younger age at MS onset and of rs12044852 (CD58, p < 0.035) with shorter time to reach EDSS6.

Evaluation of the 2010 McDonald multiple sclerosis criteria in children with a clinically isolated syndrome.

BACKGROUND: Magnetic resonance imaging diagnostic criteria for paediatric multiple sclerosis have been established on the basis of brain imaging findings alone. The 2010 McDonald criteria for the diagnosis of multiple sclerosis, however, include spinal cord imaging for detection of lesion dissemination in space. The new criteria have been recommended in paediatric multiple sclerosis. OBJECTIVE: (1) To evaluate the 2010 McDonald multiple sclerosis criteria in children with a clinically isolated syndrome and to compare them with recently proposed magnetic resonance criteria for children; (2) to assess whether the inclusion of spinal cord imaging provided additional value to the 2010 McDonald criteria. METHODS: We performed a retrospective analysis of brain and spinal cord magnetic resonance imaging scans from 52 children with a clinically isolated syndrome. Sensitivity, specificity and accuracy of the magnetic resonance criteria were assessed. RESULTS AND CONCLUSION: The 2010 McDonald dissemination in space criteria were more sensitive (85% versus 74%) but less specific (80% versus 100%) compared to the 2005 McDonald criteria. The Callen criteria were more accurate (89%) compared to the 2010 McDonald (85%), the 2005 McDonald criteria for dissemination in space (81%), the KIDMUS criteria (46%) and the Canadian Pediatric Demyelinating Disease Network criteria (76%). The 2010 McDonald criteria for dissemination in time were more accurate (93%) than the dissemination in space criteria (85%). Inclusion of the spinal cord did not increase the accuracy of the McDonald criteria.

Fingolimod in the treatment algorithm of relapsing remitting multiple sclerosis: a statement of the Central and East European (CEE) MS Expert Group.

Fingolimod is the first oral treatment of multiple sclerosis. It is the first-in-class sphingosine 1-phosphate receptor modulator that binds to sphingosine 1-phophate receptors on lymphocytes and via downregulation of the receptor prevents lymphocyte egress from lymphoid tissues into the circulation. This mechanism reduces the infiltration of potentially auto-aggressive lymphocytes into the central nervous system. Two large phase III studies with fingolimod have shown superior efficacy of the drug in two dosages compared to placebo and to weekly intramuscular injections of Interferon beta-1a. Among possible side effects of the drug is a transient bradycardia after the first dose of fingolimod including possible AV blockade and therefore monitoring of pulse rate and blood pressure for 6 h following the first application is needed. During treatment, attention has to be given to specific infections, elevated liver enzymes, and ophthalmologic changes. Recommendations on the use of fingolimod including safety aspects are given in this article.

Analysis of multiple sclerosis lesions using a fusion of 3.0 T FLAIR and 7.0 T SWI phase: FLAIR SWI.

PURPOSE: To improve multiple sclerosis (MS) research by introducing a new type of contrast, namely, the combination of fluid-attenuated inversion recovery (FLAIR) data acquired at 3.0 T and 7.0 T susceptibility-weighted imaging (SWI) phase data. The approach of this new contrast is whole-brain coverage with 3.0 T-FLAIR data for lesion detection--currently limited at 7.0 T due to specific absorption rate (SAR) limits--overlaid with high-resolution, small vessel, and iron-related 7.0 T SWI contrast. Lesion analysis in terms of penetrating veins and local iron depositions were performed. MATERIALS AND METHODS: Data from 10 MS patients were acquired at 3.0 T and at 7.0 T. FLAIR data, acquired at 3.0 T, were registered to 7.0 T SWI phase data and SWI image processing was performed using 3.0 T FLAIR data instead of SWI magnitude data. RESULTS: A total of 299 MS plaques were detected in eight MS patients. Penetrating veins were found in 75 MS plaques, iron depositions in 48 MS plaques, and veins accompanied with iron depositions in 44 MS plaques. CONCLUSION: FLAIR-SWI provides radiologically known, hyperintense definition of MS lesions overlaid with high-resolution visualization of iron deposits and venous blood vessels and offers new insights into MS lesions.

Costs and quality of life of multiple sclerosis in Austria.

This cost-of-illness analysis is part of a Europe-wide study on the costs of multiple sclerosis (MS) and is based on information from patients in Austria. The objective was to estimate the costs and quality of life (QOL) related to the level of disease severity and progression. Questionnaires were sent to 2995 patients registered with a nationwide patient organization. Patients were asked to provide details regarding the type of disease, relapses, level of functional disability, resource consumption (medical and non-medical), work absence, sick leave and informal care, as well as QOL. Surveys from a total of 1.019 (34.0%) patients were used in the analysis, of which the mean (standard deviation [SD]) age was 50 (12.2) years; 70% of patients were female. Patients with mild disease (Expanded Disability Status Scale [EDSS] score 0-3) represented 41% of patients, 36% had moderate disease (EDSS score 4-6.5) and 22% had severe disease (EDSS score > or =7). The mean (SD) EDSS score in the sample was 4.4 (2.4), with a mean (SD) utility of 0.55 (0.32). Costs are presented from the societal perspective as well as from the viewpoint of payers of care and invalidity. Mean total annual costs for an average patient in the sample were estimated at euro 40.300 in the societal perspective, whereas payers' costs were estimated at only half of this. Disease-modifying drugs represented a quarter of all costs in the payer perspective, but only 12% of societal costs. For society, the highest cost was the loss of productivity (36%), while payments for this loss (invalidity pensions and sick-leave compensation) accounted for only 21% of total costs to payers. Costs are highly correlated with disease progression, increasing four-fold from early disease to very severe disease (euro 16.000 to euro 63.800). Mean annual costs per patient reported are thus determined by the distribution of disease severity in the sample. Workforce participation decreases from roughly 75% in early disease to less than 10% in the late stages, despite the fact that 70% of patients with an EDSS score of 8 or 9 are still below the official retirement age. Consequently, productivity losses increase over fivefold. In parallel, costs of informal care increase from euro 325 per year at an EDSS score of 0-1 to over euro 20.000 at an EDSS score of 8-9. Hospitalization is very infrequent in early disease, representing less than euro 1.000 for patients with an EDSS score of 0-1, but increases steeply for patients with an EDSS score > or =5. QOL, measured as utility scores, decreases rapidly from almost 0.90 to 0.05 as disability becomes severe. However, the loss of utility is evident at all disease levels. Young patients with an EDSS score of approximately 2 have a utility that is 0.15 lower than matched individuals from the general population. This loss increases to approximately 0.4 for patients over 60 years of age with an average EDSS score of 6.0-6.5. Patients with a recent relapse had lower utility (-0.1) and higher costs (+ euro 4.750).

Benefits of inpatient multidisciplinary rehabilitation in multiple sclerosis.

BACKGROUND: Rehabilitation is often recommended to MS-patients but data on its efficacy is limited. OBJECTIVE: To evaluate the benefit of inpatient multidisciplinary rehabilitation. METHODS: A rater-blinded, randomized, waiting list controlled exploratory study. 19 participants completed the study with ten allocated to the intervention and nine to the waiting list group. Assessment of outcome-parameters was done at baseline and after 3 months. Time Walking Tests (TWTs) and 9 Hole Peg Test were used to objectively assess the level of activity, Functional-Assessment-in-MS and MS-Self Efficacy-Scale to assess participation and quality of life and Expanded Disability Status Scale (EDSS) to assess bodily function. Additionally Rivermead Mobility Index, Berg Balance Scale, Tinetti-Test, MS-Functional Composite and a rater-blinded evaluation of a video-analysis on walking performance was done. RESULTS: Mean change scores of Timed 50 meter Walk (p = 0.014), walking speed (p = 0.034), 2- (p = 0.204) and 6-Minute Walk (p = 0.027) indicated an improvement favoring inpatient multidisciplinary rehabilitation. We could not demonstrate a benefit for upper limb function and some improvement was seen in other outcome-parameters without reaching statistical significance. EDSS remained unchanged. CONCLUSION: Inpatient multidisciplinary rehabilitation is effective in MS patients with positive impact on the level of activity as measured by TWTs covering both short and long distance ambulation.

Natalizumab therapy for highly active pediatric multiple sclerosis.

IMPORTANCE: Given the high frequency of failure of first-line therapies, there is an urgent need for second-line treatment strategies for pediatric patients with multiple sclerosis (MS). OBJECTIVE: To report the use of natalizumab in pediatric MS. Natalizumab, a humanized monoclonal antibody targeting α4 integrin, is effective against active relapsing-remitting MS in adults. DESIGN: Retrospective study. SETTING: Eleven centers for neurology and pediatric neurology in Germany and Austria. PARTICIPANTS: A total of 20 pediatric patients with MS who started treatment with natalizumab prior to 18 years of age. These patients underwent magnetic resonance imaging as clinically indicated, despite the fact that 19 of these 20 patients were undergoing first-line disease-modifying therapy. The mean (SD) age at initiation of natalizumab therapy was 16.7 (1.1) years, and the mean (SD) pretreatment period was 18 (10) months. INTERVENTION: Natalizumab, 300 mg every 4 weeks. MAIN OUTCOME MEASURES: Annualized relapse rates, Expanded Disability Status Scale scores, number of new T2/fluid-attenuated inversion recovery lesions and contrast-enhancing lesions on magnetic resonance imaging, number of adverse events, the prevalence of neutralizing antibodies against natalizumab, and serum JC virus-antibody status. RESULTS Treatment with natalizumab was associated with reductions in mean annualized relapse rates (3.7 without treatment vs 0.4 with treatment; P < .001), median Expanded Disability Status Scale scores (2 without treatment vs 1 with treatment; P < .02), and mean number of new T2/fluid-attenuated inversion recovery lesions per year (7.8 without treatment vs 0.5 with treatment; P < .001). Two patients developed high-titer neutralizing antibodies against natalizumab and had to stop therapy. Adverse events included headaches, asthenia, infections, and hypersensitivity. Abnormal laboratory results were found for 8 patients. JC virus antibodies were found in 5 of 13 patients. After the discontinuation of natalizumab therapy, relapse activity occurred in 6 of 8 patients within 6 months. CONCLUSIONS AND RELEVANCE: Our data indicate that natalizumab may be safe and effective against MS in pediatric patients with breakthrough disease.

How does fingolimod (gilenya(®)) fit in the treatment algorithm for highly active relapsing-remitting multiple sclerosis?

Multiple sclerosis (MS) is a neurological disorder characterized by inflammatory demyelination and neurodegeneration in the central nervous system. Until recently, disease-modifying treatment was based on agents requiring parenteral delivery, thus limiting long-term compliance. Basic treatments such as beta-interferon provide only moderate efficacy, and although therapies for second-line treatment and highly active MS are more effective, they are associated with potentially severe side effects. Fingolimod (Gilenya(®)) is the first oral treatment of MS and has recently been approved as single disease-modifying therapy in highly active relapsing-remitting multiple sclerosis (RRMS) for adult patients with high disease activity despite basic treatment (beta-interferon) and for treatment-naïve patients with rapidly evolving severe RRMS. At a scientific meeting that took place in Vienna on November 18th, 2011, experts from ten Central and Eastern European countries discussed the clinical benefits and potential risks of fingolimod for MS, suggested how the new therapy fits within the current treatment algorithm and provided expert opinion for the selection and management of patients.

Neuromyelitis optica in Austria in 2011: to bridge the gap between neuroepidemiological research and practice in a study population of 8.4 million people.

BACKGROUND: In 2008 the Austrian Task Force for Neuromyelitis Optica (NMO) started a nation-wide network for information exchange and multi-centre collaboration. Their aim was to detect all patients with NMO or NMO spectrum disorders (NMO-SD) in Austria and to analyse their disease courses and response to treatment. METHODS: (1) As of March 2008, 1957 serum samples (of 1557 patients) have been tested with an established cell based immunofluorescence aquaporin-4 antibody (AQP4-ab) assay with a high sensitivity and specificity (both >95%). All tests were performed in a single reference laboratory (Clinical Dept. of Neurology of the Innsbruck Medical University). (2) A nation-wide survey with several calls for participation (via email newsletters, articles in the official journal of the Austrian Society of Neurology, and workshops) was initiated in 2008. All collected data will be presented in a way that allows that every individual patient can be traced back in order to ensure transparency and to avoid any data distortion in future meta-analyses. The careful and detailed presentation allows the visualization and comparison of the different disease courses in real time span. Failure and response to treatment are made visible at one glance. Database closure was 31 December 2011. All co-operators were offered co-authorship. RESULTS: All 71 NMO- or NMO-SD patients with AQP4-ab positivity (age range 12.3 to 79.6 years) were analysed in detail. Sex ratio (m:f = 1:7) and the proportion of patients without oligoclonal bands in cerebrospinal fluid (86.6%) were in line with previously published results. All identified patients were Caucasians. CONCLUSIONS: A nationwide collaboration amongst Austrian neurologists with good network communications made it possible to establish a database of 71 AQP4-ab positive patients with NMO/NMO-SD. This database is presented in detail and provides the basis for further studies and international cooperation in order to investigate this rare disease.

Current immune therapies of autoimmune disease of the nervous system with special emphasis to multiple sclerosis.

Autoimmune diseases of the nervous system such as myasthenia gravis, inflammatory demyelinating polyneuropathies, multiple sclerosis and others are still not curable. Yet the introduction of modern immune therapies could significantly improve the prospects of many patients affected by these disorders. In addition to steroids and immunosuppression i.v. immunoglobulins are used for treatment of myasthenia gravis and chronic inflammatory demyelinating polyneuropathy. Interferons, glatiramer acetate, natalizumab and fingolimod are applied in multiple sclerosis. The ever-improving efficacy of the drugs has to be balanced against the increasing risk of possible severe adverse effects.

Symptomatic therapy in multiple sclerosis: a review for a multimodal approach in clinical practice.

As more investigations into factors affecting the quality of life of patients with multiple sclerosis (MS) are undertaken, it is becoming increasingly apparent that certain comorbidities and associated symptoms commonly found in these patients differ in incidence, pathophysiology and other factors compared with the general population. Many of these MS-related symptoms are frequently ignored in assessments of disease status and are often not considered to be associated with the disease. Research into how such comorbidities and symptoms can be diagnosed and treated within the MS population is lacking. This information gap adds further complexity to disease management and represents an unmet need in MS, particularly as early recognition and treatment of these conditions can improve patient outcomes. In this manuscript, we sought to review the literature on the comorbidities and symptoms of MS and to summarize the evidence for treatments that have been or may be used to alleviate them.

Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring.

Natalizumab, a highly specific α4-integrin antagonist, is approved for treatment of patients with active relapsing-remitting multiple sclerosis (RRMS). It is generally recommended for individuals who have not responded to a currently available first-line disease-modifying therapy or who have very active disease. The expected benefits of natalizumab treatment have to be weighed against risks, especially the rare but serious adverse event of progressive multifocal leukoencephalopathy. In this Review, we revisit and update previous recommendations on natalizumab for treatment of patients with RRMS, based on additional long-term follow-up of clinical studies and post-marketing observations, including appropriate patient selection and management recommendations.