Rhombencephalitis: a series of 97 patients.

The term rhombencephalitis refers to inflammatory diseases affecting the hindbrain (brainstem and cerebellum). Rhombencephalitis has a wide variety of etiologies, some of them potentially severe and life threatening without proper early treatment. In this retrospective observational study, we reviewed the records of consecutively hospitalized patients at University Hospital of Bellvitge (Barcelona, Spain) from January 1990 to December 2008. Rhombencephalitis was defined as a brainstem and/or cerebellar condition demonstrated clinically or by neuroimaging, with pleocytosis (>4 cells/mm) in cerebrospinal fluid. Ninety-seven patients (48 female; mean age, 37 yr; range, 14-79 yr) fulfilled these criteria. We reviewed their clinical, cerebrospinal fluid, and radiologic characteristics. The mean follow-up was 5 years (range, 0-20 yr). The etiologies of rhombencephalitis were as follows: unknown cause (n = 31), multiple sclerosis (n = 28), Behçet disease (n = 10), Listeria monocytogenes infection (n = 9), paraneoplastic syndrome (n = 6) (3 cases associated with anti-Yo antibodies and 3 with anti-Tr antibodies), Epstein-Barr virus (n = 4), tuberculosis (n = 2), pneumococcal infection (n = 2), systemic lupus erythematosus (n = 1), lymphoma (n = 1), Brucella species infection (n = 1), JC virus (n = 1), and relapsing polychondritis (n = 1). Certain clinical, cerebrospinal fluid, and radiologic characteristics that are commonly seen in some of these etiologies can guide us in the first approach to the etiologic diagnosis of rhombencephalitis.

Apolipoprotein alleles and the response to interferon-ß-1b in multiple sclerosis.

BACKGROUND: Results for the e4/e2 alleles of the ApoE gene as markers of susceptibility, clinical and radiological progression, and cognitive deterioration in patients with multiple sclerosis (MS) are contradictory. AIM: The usefulness of these markers in predicting the response to interferon-ß-1b (IFNß-1b) was evaluated. MATERIAL AND METHODS: 95 patients with relapsing-remitting MS treated with IFNß-1b (mean follow-up 7.44 years) were studied. We correlated the e4 and e2 alleles with the time to the first relapse or to a 1-point worsening on the Expanded Disability Status Scale, time to moderate disability, progression index, and treatment discontinuation due to inefficacy. RESULTS: We found no association between the e4 allele and any of the variables. The e2 allele was associated with increased time to moderate disability. CONCLUSION: The e4 allele of ApoE has no prognostic value for the response to IFNß-1b. The e2 allele delayed the progression of disability in our MS patient cohort.

Epistasis between HLA-DRB1 parental alleles in a Spanish cohort with multiple sclerosis.

BACKGROUND AND OBJECTIVE: Multiple sclerosis (MS) has been consistently associated with the HLA-DR2 haplotype and particularly with the HLA-DRB1*15 allele. Epistatic interactions between both parental alleles in the DRB1 loci have been shown to modify the MS susceptibility risk. This study investigated the frequencies of various HLA-DRB1 genotypes, their impact on MS susceptibility and their correlation with the clinical severity in a Spanish population. METHODS: A genotype was considered as the combination of the two parental DRB1 alleles. We compared the frequencies of the genotypes in a sporadic MS population (n=380) with those of an unrelated healthy control cohort (n=1088). We correlated the different genotypes with the age at onset, gender distribution, symptoms at onset, course of the disease and progression severity by means of the time to reach the progressive phase and EDSS scores of 3 and 6. RESULTS: We found 81 different genotypes. There were four different MS-predisposing genotypes. Three of them contained the DRB1*15 allele (DRB1*03/15, DRB1*04/15, and DRB1*08/15) and the fourth was homozygote for the DRB1*03 allele. The highest odds ratio was found with the genotype DRB1*08/15 (OR=3.88, 95% CI=1.83-8.26, p<0.01), followed by DRB1*03/03 (OR=3.15, 95% CI=1.93-5.14, p<0.01), DRB1*03/15 (OR=2.72, 95% CI=1.88-3.94, p<0.01) and DRB1*04/15 (OR=2.54, 95% CI=1.64-3.98, p<0.01). The DRB1*01/04 and the DRB1*15/15 genotypes were associated with a shorter time to reach an EDSS score of 6. CONCLUSIONS: Our results show the importance of epistatic interactions among the HLA-DRB1 alleles, modifying the risk for MS as well as its clinical severity.

International development of the patient-reported outcome indices for multiple sclerosis (PRIMUS).

BACKGROUND: The Patient-Reported Indices for Multiple Sclerosis (PRIMUS) comprises a suite of three scales for assessing symptoms, activity limitations, and quality of life in multiple sclerosis (MS). It was developed in the UK and has been shown to have excellent psychometric properties. This study describes the adaptation of eight language versions for Canadian English, Canadian French, French, German, Italian, Spanish, Swedish, and US English. METHODS: The PRIMUS was translated using the dual-panel process. Cognitive debriefing interviews conducted with MS patients assessed face and content validity. Psychometric and scaling properties were assessed via a two-administration postal survey conducted in each country involving the PRIMUS, the Nottingham Health Profile (NHP), the Unidimensional Fatigue Impact Scale (U-FIS), and demographic questions. RESULTS: Cognitive debriefing interviews demonstrated the acceptability of the new language versions. Analysis of survey data showed that the new language versions of the three PRIMUS scales were unidimensional (as indicated by fit to the Rasch model) and that they had good internal consistency and reproducibility. PRIMUS scale scores correlated as expected with those on the NHP and the U-FIS. The scales in all countries were able to discriminate between groups of patients on the basis of their self-reported MS severity, general health, and employment status. CONCLUSIONS: The PRIMUS was successfully adapted into eight new languages. Most of the tests showed the PRIMUS to have good unidimensionality and to have good internal consistency, reproducibility, and construct validity. The measure is now available for use in clinical studies and trials involving these countries and the UK. Further work is required to assess the measure's responsiveness.

Patient-rated suitability of a novel electronic device for self-injection of subcutaneous interferon beta-1a in relapsing multiple sclerosis: an international, single-arm, multicentre, Phase IIIb study.

BACKGROUND: Multiple sclerosis (MS) currently requires long-term treatment with disease-modifying drugs, administered parenterally up to once daily. The need for regular self-injection can be a barrier to treatment for many patients. Autoinjectors can help patients overcome problems or concerns with self-injection and could, therefore, improve treatment adherence. This study was performed to assess the suitability of a new electronic device for the subcutaneous (sc) administration of interferon (IFN) beta-1a, 44 mcg three times weekly, for relapsing MS. METHODS: In this Phase IIIb, multicentre, single-arm study, patients with relapsing MS who had been consistently self-injecting sc IFN beta-1a using an autoinjector for at least 6 weeks were taught to use the new device and self-administered treatment for 12 weeks thereafter. Patient-rated suitability of the device was assessed at the end of Week 12 using the Patient User Trial Questionnaire. Patient satisfaction with, and evaluation of, the injection process was assessed using the MS Treatment Concern Questionnaire. Trainers evaluated the device using the Trainer User Trial Questionnaire. RESULTS: At Week 12, 71.6% (73/102) of patients considered the device 'very suitable' or 'suitable' for self-injection; 92.2% (94/102) reported some degree of suitability and only 7.8% (8/102) found the device 'not at all suitable'. At Weeks 4, 8 and 12, most patients reported that injection preparation and clean-up, performing injections and ease of device use in the previous 4 weeks compared favourably with, or was equivalent to, their previous experience of self-injection. Injection-related pain, injection reactions and 'flu-like' symptoms remained stable over the 12 weeks. Each device feature was rated 'very useful' or 'useful' by at least 80% of patients. All trainers and 95.2% (99/104) of patients found device functions 'very easy' or 'easy' to use. Overall convenience was considered the most important benefit of the device. CONCLUSIONS: Most patients considered the new electronic injection device suitable for the sc injection of IFN beta-1a. They found the device easy to use with useful features, and reported benefits such as overall convenience. The device may, therefore, increase treatment adherence in patients with MS, particularly those with injection-related issues. TRIAL REGISTRATION: NCT00735007.

International development of the Unidimensional Fatigue Impact Scale (U-FIS).

OBJECTIVE: The 22-item Unidimensional Fatigue Impact Scale (U-FIS) provides an index of the impact of fatigue on patients with multiple sclerosis (MS). The objective is to produce eight new language versions of the U-FIS: Canadian-English, Canadian-French, French, German, Italian, Spanish, Swedish, and US-English. METHODS: The U-FIS was translated via two translation panels. Cognitive debriefing interviews conducted with patients in each country assessed face and content validity. Scaling and psychometric properties were assessed via survey data with patients in each country completing the U-FIS, Nottingham Health Profile (NHP), and demographic questions. RESULTS: Cognitive debriefing interviews demonstrated U-FIS acceptability. Analysis of postal survey data showed all new language versions to be unidimensional. Reliability was high, with test-retest correlations and internal-consistency coefficients exceeding 0.85. Initial evidence of validity was provided by moderate to high correlations with NHP scales. The U-FIS was able to discriminate between groups based on employment status, perceived MS severity, and general health. CONCLUSION: The U-FIS is a practical new measure of the impact of fatigue. It was successfully adapted into eight new languages to broaden availability for researchers. Psychometric analyses indicated that the new language versions were unidimensional and reproducible with promising construct validity.

Interferon-beta1b in multiple sclerosis: effect on progression of disability and clinical markers of treatment response.

There is limited long-term data on the effect of interferon-beta1b (IFN-beta1b) on disability progression in patients with multiple sclerosis (MS). There is also no reliable way of predicting individual responses to IFN-beta1b treatment. This prospective study investigated early clinical prognostic markers of disease activity and progression in 115 patients with relapsing-remitting MS (RRMS) treated with IFN-beta1b for almost 5 years. The study also compared progression of disability in IFN-beta1b-treated patients with a historic untreated cohort of MS patients (n = 44). The number of relapses in the first 2 years of MS and in the 2 years before treatment predicted an early relapse after IFN-beta1b treatment. The IFN-beta1b-treated group experienced a slower progression of disability than the untreated cohort, suggesting that IFN-beta1b treatment delays progression of disability in RRMS.

Direct and indirect costs of Multiple Sclerosis in Baix Llobregat (Catalonia, Spain), according to disability.

BACKGROUND: Multiple sclerosis (MS) is an incurable chronic disease that predominantly affects young adults. It has a high socio-economic impact which increases as disability progresses. An assessment of the real costs of MS may contribute to our knowledge of the disease and to treat it more efficiently. Our objective is to assess the direct and indirect costs of MS from a societal perspective, in patients monitored in our MS Unit (Baix Llobregat, Catalonia) and grouped according to their disability (EDSS). METHODS: We analysed data from 200 MS patients, who answered a questionnaire on resource consumption, employment and economical status. Mean age was 41.6 years, mean EDSS 2.7, 65.5% of patients were female, 79.5% had a relapsing-remitting course, and 67.5% of them were receiving immunomodulatory treatment (IT). Patients were grouped into five EDSS stages. Data from the questionnaires, hospital charts, Catalan Health Service tariffs, and figures from Catalan Institute of Statistics were used to calculate the direct and indirect costs. The cost-of-illness method, and the human capital approach for indirect costs, were applied. Sensitivity analyses were performed to strengthen results. RESULTS: The mean total annual cost of MS per patient results 24,272 euros. This cost varied according to EDSS: 14,327 euros (EDSS = 0), 18,837 euros (EDSS = 1-3), 27,870 euros (EDSS = 3.5-5.5), 41,198 euros (EDSS = 6-7) and 52,841 euros (EDSS>7.5). When the mean total annual costs was adjusted by the mean % of patients on IT in our Unit (31%) the result was 19589 euros. The key-drivers for direct costs were IT in low EDSS stages, and caregiver costs in high stages. Indirect costs were assessed in terms of the loss of productivity when patients stop working. Direct costs accounted for around 60% of total costs in all EDSS groups. IT accounts from 78% to 11% of direct costs, and decreased as disability progressed. CONCLUSION: The total mean social costs of MS in a cohort from Baix Llobregat (Catalonia) were estimated at 24,272 euros per patient/year, and ranged between 14,327 euros (EDSS = 0) and 52,841 euros (EDSS = 7.5-9.5). Total costs, and particularly informal and direct costs, increased as the disability progressed. IT should be able to delay the progression of disability to be efficient and not only effective.

Tau protein in cerebrospinal fluid: a possible marker of poor outcome in patients with early relapsing-remitting multiple sclerosis.

We analyzed the prognostic value of Tau protein, a marker of axonal damage, detected in the cerebrospinal fluid (CSF) of patients with relapsing-remitting multiple sclerosis (RRMS). We sampled the CSF from 32 patients with probable or definite RRMS, having had the disease for less than 5 years. We studied the relationship between Tau protein concentration in the CSF (CSF-TAU) and disability, time to next relapse and time to experience a one point increase on the Expanded Disability Status Scale (EDSS). CSF-TAU was correlated with the Progression Index at the end of follow-up. Patients with higher CSF-TAU experienced a more rapid one point increase in the EDSS. CSF-TAU was the only independent variable to predict the time to next relapse. CSF-TAU, as a marker of axonal loss, may help us to predict short-term outcome in patients with early RRMS.