Effectiveness of first generation disease-modifying therapy to prevent conversion to secondary progressive multiple sclerosis.

BACKGROUND: The use of disease-modifying therapies (DMTs) in multiple sclerosis (MS) has been associated with reduced relapse rates and accumulation of disability. However, studies examining impact of DMT on risk of transition to secondary progressive MS (SPMS) leveraging population-based nationwide data are still rare. Here, we determine the population incidence of conversion to SPMS using two consecutive nation-wide cohorts, one immediately before and one after the introduction of DMT in Sweden. METHODS: We included two consecutive population cohorts of relapsing-remitting MS (RRMS) from the Swedish national MS register for the periods 1975-1994 (n = 2161), before DMT availability, and 1995-2011 (n = 3510), in which DMTs, mainly first generation DMT (injectables), became available and eventually were used by 70% of patients. We explored the risk of transition to SPMS as a calendar year function encompassing the two cohorts. In addition, we determined the incidence of transition to SPMS through age strata below and above 50 years in untreated and treated patient subgroups. RESULTS: The risk of conversion to SPMS (adjusted for current age, current time since onset, calendar year and sex) was significantly lower in the second compared with the first population cohort (hazard ratio 0.58; CI 0.48, 0.70). The risk of SPMS conversion per calendar year decreased by 2.6% annually (p < 0.001) after 1995. The risk of SPMS conversion increased with age until age 50. Thereafter, it was unchanged or decreased among those with early MS onset age (<35 years), but continued to increase with onset at higher age, with similar trends in treated and untreated subgroups. CONCLUSION: The incidence of SPMS conversion significantly decreased at the population level after introduction of first generation DMTs by 1995. DMT efficiency was confirmed by a downward turn of the annual trajectory of the risk of SPMS conversion after 1995. An onset age determined pattern of variable SPMS incidence in higher age appeared in both treated and untreated strata. While first generation DMT delayed conversion to SPMS, their long-term effect was only moderate.

The Swedish MS registry ­ clinical support tool and scientific resource.

The Swedish MS registry (SMSreg) is designed to assure quality health care for patients with multiple sclerosis (MS). It has been active since 2001 and web-based since 2004. It runs on government funding only and is used in all Swedish neurology departments. The SMSreg currently includes data on 14,500 of Sweden's estimated 17,500 prevalent patients with MS. One important function of SMSreg, to which participation is voluntary, is to serve as a tool for decision support and to provide an easy overview of the patient information needed at clinical visits. This is its core feature and explains why the majority of Swedish MS specialists contribute data. Another success factor for SMSreg is that entered data can be readily accessed, either through a query function into Excel format or through a set of predesigned tables and diagrams in which parameters can be selected. Recent development includes a portal allowing patients to view a summary of their registered data and to report a set of patient-reported outcomes. SMSreg data have been used in close to 100 published scientific reports. Current projects include an incidence cohort (EIMS), post-marketing cohorts of patients on novel disease-modifying drugs (IMSE), and a prevalence cohort (GEMS). As these studies combine physical sampling and questionnaire data with clinical documentation and possible linkage to other public registries, together they provide an excellent platform for integrated MS research.

Time to secondary progression in patients with multiple sclerosis who were treated with first generation immunomodulating drugs.

BACKGROUND: It is currently unknown whether early immunomodulatory treatment in relapsing-remitting MS (RRMS) can delay the transition to secondary progression (SP). OBJECTIVE: To compare the time interval from onset to SP in patients with RRMS between a contemporary cohort, treated with first generation disease modifying drugs (DMDs), and a historical control cohort. METHODS: We included a cohort of contemporary RRMS patients treated with DMDs, obtained from the Swedish National MS Registry (disease onset between 1995-2004, n = 730) and a historical population-based incidence cohort (onset 1950-64, n = 186). We retrospectively analyzed the difference in time to SP, termed the "period effect" within a 12-year survival analysis, using Kaplan-Meier and Cox regression analysis. RESULTS: We found that the "period" affected the entire severity spectrum. After adjusting for onset features, which were weaker in the contemporary material, as well as the therapy initiation time, the DMD-treated patients still exhibited a longer time to SP than the controls (hazard ratios: men, 0.32; women, 0.53). CONCLUSION: Our results showed there was a longer time to SP in the contemporary subjects given DMD. Our analyses suggested that this effect was not solely driven by the inclusion of benign cases, and it was at least partly due to the long-term immunomodulating therapy given.

Callosal atrophy in multiple sclerosis is related to cognitive speed.

BACKGROUND: Long-term changes regarding corpus callosum area (CCA) and information processing speed in cognitive and sensory-motor tasks have rarely been studied in multiple sclerosis (MS). OBJECTIVE AND METHODS: Information processing speed in cognitive (Symbol Digit Modalities Test, SDMT), sensory (visual and auditory reaction time) and motor (finger-tapping speed, FT; right and left hand) tasks as well as auditory inter-hemispheric transfer (verbal dichotic listening, VDL) was related to CCA, measured by MRI at baseline and at follow-up after nine years in 22 patients with MS. Possible confounding by demographic (age, gender and education), clinical (symptom onset, duration, severity of disease) and relative brain volume (RBV) as well as T2 lesion load was taken into account. RESULTS: The smaller the CCA at baseline, the slower was SDMT performance at baseline. In a similar way, CCA at follow-up was associated with poor SDMT result at follow-up. Furthermore, the higher the annual rate of change in CCA, the poorer was performance in VDL on the left ear and the more pronounced was the right ear advantage. A positive relationship between performance in VDL right ear and annual rate of change in RBV was also seen. Sensory-motor tests were not significantly associated with CCA. T2 lesion load at baseline was associated with FT performance at baseline. Demographic, clinical and radiological (RBV and T2 lesion load) characteristics did not confound the significant relation between CCA and SDMT. CONCLUSIONS: CCA unlike RBV and T2 lesion load was associated with SDMT, which indicated a marked cognitive rather than perceptual-motor component.

One-dimensional-ratio measures of atrophy progression in multiple sclerosis as evaluated by longitudinal magnetic resonance imaging.

BACKGROUND: For decades, normalized one-dimensional (1D) measures have been used in the evaluation of brain atrophy. In multiple sclerosis (MS), the use of normalized linear measures over longitudinal follow-up remains insufficiently documented. PURPOSE: To evaluate the association between different regional atrophy measures and disability in MS patients over four decades in a longitudinal cross-sectional study. MATERIAL AND METHODS: 37 consecutively selected MS patients were included. At baseline, patients had a range of disease duration (1-33 years) and age (24-65 years). Each patient was followed by magnetic resonance imaging (MRI) for a mean of 9.25 years (range 7.3-10 years). Four 1D measures were applied at three time points on axial 5-mm T1-weighted images. Three clinical MS subgroups were represented: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS). RESULTS: There were significant changes in all 1D ratios during follow-up. The Evans ratio (ER) and the bifrontal ratio (BFR) were associated with the development of disability. Changes of ER and BFR reflected more aggressive disease progression, as expressed by MS severity score (MSSS). CONCLUSION: All four normalized ratios showed uniform atrophy progression, suggesting a consistent rate of atrophy over long-term disease duration independent of MS course. Disability status correlated with 1D measures, suggesting that serial evaluation of Evans and bifrontal ratios might contribute to the radiological evaluation of MS patients.

Rate of ventricular enlargement in multiple sclerosis: a nine-year magnetic resonance imaging follow-up study.

BACKGROUND: In multiple sclerosis (MS), brain atrophy assessed by linear measurements of ventricular widths has been reported to be well correlated with three-dimensional (3D) measurements. Therefore, serial linear measurements with no need for advanced 3D evaluation may be proven to be robust markers of irreversible, destructive changes. PURPOSE: To evaluate the rate of supratentorial ventricular enlargement representing four decades of disease span. MATERIAL AND METHODS: 37 MS patients with disease duration at baseline ranging from 1 to 33 years were included. The mean time of the individual magnetic resonance imaging (MRI) follow-up was 9.25 years (range 7.3-10 years). Enlargement rate of the third and lateral ventricles was studied over time by applying three linear measurements on axial 5-mm T1-weighted MRI images. RESULTS: Progression of supratentorial ventricular widths during 9 years' follow-up was found. The mean annual width increase of the third ventricle was 0.20 mm (P<0.001, 95% confidence interval [CI] 0.15-0.25), for the frontal horn width 0.32 mm (P<0.001, 95% CI 0.23-0.40), and increase of the intercaudate distance was 0.26 mm (P<0.001, 95% CI 0.19-0.33). The association between these three measurements and disability status persisted at the time of follow-up. CONCLUSION: We found uniform ventricular enlargement progression during four decades of disease span, suggesting unchanging total brain atrophy progression over time.

Modeling the cost-effectiveness of a new treatment for MS (natalizumab) compared with current standard practice in Sweden.

OBJECTIVE: To estimate the cost-effectiveness of a new treatment (natalizumab) for multiple sclerosis (MS) compared with current standard therapy with disease-modifying drugs (DMDs) in Sweden. METHODS: A Markov model was constructed to illustrate disease progression based on functional disability (the Expanded Disability Status Scale (EDSS)). The effectiveness of natalizumab was based on a 2-year clinical trial in 942 patients (AFFIRM). The effectiveness of current DMDs was estimated from a matched sample of 512 patients in the Stockholm MS registry. Patients withdrawing from treatment were assumed to follow the disease course of 824 patients with relapsing-remitting disease at onset in the Ontario natural history cohort. Costs and utilities are based on a recent observational study in 1339 patients. All data sets were available at the patient level. Main results are presented from the societal perspective, over a 20-year time frame, in 2005 Euros (euro1 = 9.25 SEK). RESULTS: In the base case, treatment with natalizumab was less expensive and more effective than treatment with current DMDs. When only healthcare costs were considered, the cost per quality-adjusted life year gained with natalizumab was euro38 145. Results are sensitive only to the time horizon of the analysis and assumptions about effectiveness of natalizumab beyond the trial. CONCLUSIONS: This cost-effectiveness analysis used registry data, cohort and observational studies to extrapolate the efficacy findings of natalizumab from the AFFIRM clinical trial to measure effectiveness in clinical practice. The analysis results suggest that for the population considered, natalizumab provides an additional health benefit at a similar cost to current DMDs from a societal perspective.

Multiple sclerosis: a study of chemokine receptors and regulatory T cells in relation to MRI variables.

Magnetic resonance imaging (MRI) remains the most valuable tool for monitoring disease activity and progression in patients with multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system (CNS) with presumably autoimmune etiology. Chemokine receptors have been implicated in MS as key molecules directing inflammatory cells into the CNS. Regulatory (CD4+CD25+) T cells (Tr cells) are important in suppressing autoimmunity, and their absolute or functional deficit could be expected in MS. In the present study, venous blood was obtained from MS patients concurrent with MRI examination of the brain, and expression of chemokine receptors CCR1, CCR2, CCR5, CXCR3 and CXCR4 by CD4 T cells and monocytes, proportions of Tr cells, as well as expression of CD45RO, CD95, CTLA-4, HLA-DR and interleukin (IL)-10 by Tr cells and non-Tr (CD25-) CD4 T cells was analyzed by flow cytometry. Surface expression of CXCR3 by CD4 T cells was downregulated in the group of patients with high lesion load (LL) on T2-weighted images and gadolinium (Gd)-enhancing lesions on T1-weighted images, compared to the group with high LL and no Gd-enhancing lesions, and to the group with low LL, suggesting internalization of CXCR3 due to the release of its chemokine ligand (IP-10/CXCL10) from active MS lesions. Proportions of Tr cells amongst all CD4 T cells, and expression of IL-10 by Tr cells were increased in the patients with high LL and Gd-enhancing lesions. These results suggest that there is correlation between MRI parameters, chemokine receptor expression and the status of circulating Tr cells in MS, but further studies need to discriminate between pathogenetically relevant and bystander phenomena.

Seasonal patterns in optic neuritis and multiple sclerosis: a meta-analysis.

To quantify and characterize seasonal variation in monosymptomatic optic neuritis (MON) onsets, multiple sclerosis (MS) onsets and MS exacerbations (MSE), a meta-analysis was performed, using established methods and pooling weighted information obtained from nine reports on MON, six reports on MS onsets and nine reports on MSE, which fulfilled specific criteria for report quality and data homogeneity. The results suggested that MON, MS onsets and MSE in the Northern hemisphere present a similar pattern with highest frequencies in spring and lowest in winter. These differences were highest for MS onsets, 45% with 95% CI 36-55%, and lowest for MSE, 10% with 95% CI 7-13%, statistically significant and robust, insensitive to an alternative seasonal definition, not unduly influenced by any single primary study, and supported by fail-safe N calculations. Random variation, misclassification and publication bias were less likely to account for the reported generalized seasonal patterns.

Regression analysis of metabolite concentrations estimated from localized proton MR spectra of active and chronic multiple sclerosis lesions.

Localized short echo time magnetic resonance (MR) spectra were obtained from patients with multiple sclerosis of relapsing-remitting or secondary chronic-progressive course and from healthy controls. Automated analysis using model spectra, sensitivity correction, and subtraction of partial ventricular volume yielded tissue concentrations of metabolites that were in line with findings of previous studies. Additional findings were increased creatine in chronic lesions and increased myo-inositol in normal-appearing white matter. Regression analysis was performed to reveal concomitant changes of metabolite concentrations. Differences in the correlations between cholines and myo-inositol suggest increased expression of myo-inositol in chronic lesions or of cholines in active, contrast-enhanced lesions. A correlation between N-acetyl-aspartate and creatine, which is probably due to extracellular edema, was observed in active but not in chronic lesions. Creatine and cholines correlated in chronic lesions, which may be the result of gliosis. The consequences of these findings for the interpretation of absolute concentrations and creatine ratios are discussed.

High numbers of perforin mRNA expressing CSF cells in multiple sclerosis patients with gadolinium-enhancing brain MRI lesions.

Enhanced expression of pro- and anti-inflammatory cytokines is a common finding in MS, but attempts to correlate cytokine expression with disease activity have produced conflicting results. In this paper, gadolinium-(Gd-)enhancing lesions on brain MRI were used as markers for active inflammation in patients with MS not treated with any immunomodulatory drugs. In parallel, in situ hybridization was used to detect blood and cerebrospinal fluid (CSF) mononuclear cells (MNC) expressing cytokine mRNA. An association was observed between numbers of perforin mRNA expressing CSF MNC and numbers of Gd-enhancing brain MRI lesions. Perforin mRNA expressing CSF MNC were not detected in any of the patients lacking active lesions on brain MRI. The expression of tumor necrosis factor-alpha, interleukin-10 (IL-10) and IL-12 mRNA in CSF MNC did not differ between MS patients with and without active MRI lesions. Based on the present finding, a role for perforin in the disruption of the blood-brain barrier in MS can be hypothesized.

Epidemiological assessment of levodopa use in Spain, 1990-1995. Persistent, low consumption in the south.

Parkinson's disease (PD) is considerably underdiagnosed in Spain and its treatment relies mainly on levodopa (LD), a drug enjoying good access country-wide. In order to identify regions with the highest potential for improvement in the quality of life of PD patients, we evaluated total sales of levodopa in Spanish provinces during the period 1990-1995, using a reported method. Total annual crude sales in the country were medium-low and increased with time. When adjusted for age and infant mortality rates (IMRs), taken as an index of socio-sanitary development, annual LD sales become stable and similar to those in the reference population, Sweden 1994. Provincial LD use (LDU) showed a wide variation in annual levels and time trends, with a north-south gradient in evidence. Statistically significant clustering was seen, with the lowest crude age-adjusted and age- and IMR-adjusted LD sales in the south-west and moderately high levels in north-central and north-west provinces. The results show that LDU in Spain is medium-low, and that demographic and social factors may underlie geographical differences in LD sales. The remarkably low LDU in selected provinces in the south-west of the country might reflect deficient PD detection and/or treatment amenable to control.

Incidence of optic neuritis in Stockholm, Sweden 1990-1995: I. Age, sex, birth and ethnic-group related patterns.

We studied the incidence of monosymptomatic optic neuritis (MON) in Stockholm county, Sweden and its variation with person-related factors. Patients with suspected or diagnosed MON between January 1, 1990 and December 31, 1995 were referred from ophthalmologists and neurologists to a research registry. The diagnosis was based on accepted clinical criteria only, and verified by an ophthalmologist who examined all the patients. Data were collected by interview using a structured questionnaire. The crude mean annual incidence, based on 147 patients, 118 females and 29 males, diagnosed with MON, was 1.46 per 100,000 person-years, 2.28 for females and 0.59 for males. The corresponding age-adjusted incidences were 1.40, 2.28 and 0.53. The age-specific incidence curve for both sexes suggested a bimodal distribution with peaks at 30-34 years and 45-49 years. The smoothed cumulative incidences in 1 year birth cohorts showed a notchy profile, related to bimodality. The incidence among residents born out of the Nordic countries was low, 0.28 per 100,000. Patients with onset of MON before 40 years of age had a significantly higher frequency of mononuclear pleocytosis in cerebrospinal fluid and shorter duration to conversion to multiple sclerosis. In summary, MON occurred in Stockholm at a relatively low frequency, particularly among males. The presence of particular birth date and birth place related patterns might be etiologically relevant.

High levodopa use in periodically time-clustered, Icelandic birth cohorts. A vestige of parkinsonism etiology? Europarkinson Preparatory Activity Research Group.

We evaluated levodopa use (LDU) by the Icelandic population focusing on: 1) annual gross levodopa (LD) sales from wholesalers to pharmacies for the period 1978-1990, using a reported method; 2) data from a prescription survey conducted from October 1st, 1990 to March 31st, 1991; and 3)raw and reported data on prevalences of Parkinson's disease (PD) in 1963 in this country. The standard for adjustments and reference population for LDU comparisons was the Swedish in 1984. Crude gross sales of LD in Iceland in 1990 and in Sweden in 1984 amounted to 1.67 and 1.35 DDD/1000 person days respectively. After respective adjustments for age, and for age and the infant mortality rates, taken as an indicator of health care quality, LDU in Iceland in 1990 was found to be 1.82 and 1.63 (95% CI 1.47-1.89) times that for Sweden. Prevalences of LD-prescription recipients in 1990-1991 and of PD in 1963 increased with age; however, those of drug users were higher than those of PD among the elderly. Higher-than-expected prevalences of PD and LD-prescription users (there being a partial overlap between these two categories) were found in periodically-clustered, one-year birth cohorts. These results support the notion that Iceland has a high LDU and suggest that this variation is due to a high prevalence of LD responsive disorders. Cohorts born after registered whooping cough outbreaks in Iceland may account for the magnitude and birth-related pattern of PD prevalences and LDU levels.

Levodopa use in Denmark: high levels in Greenland and the Faroe Islands. Europarkinson Preparatory Activity Research Group.

Levodopa (LD) sales from wholesalers to pharmacies during the periods, 1977-1989 in Denmark, 1981-1989 in Greenland, and April 1988-May 1989 in Danish counties and the Faroe Islands, were evaluated using a reported method and a procedure expressly developed for assessment of random variation comparative levodopa use (LDU) measurements. The reference population for comparison of LDU was the Swedish from 1984. LDU diffusion had stabilized by 1989 in Denmark, but considerable annual increments of LD sales were still seen in Greenland in 1989. Crude LDU in Denmark and most Danish counties amounted to a level similar to that of Sweden. Adjustments for age and infant mortality rates, taken as an indicator of socioeconomic development, disclosed statistically significant twofold levels of LDU in the Faroe Islands and Greenland, and lowest LDU in urban regions. The social or biological factors underlying such differences in drug use remain unknown.

Stroke rehabilitation in Stockholm. Basis for late intervention in patients living at home.

In order to identify the basis of late-therapy intervention in patients with stroke, we studied a population-based sample of 20 patients. The requests were that they should be living at home 1-3 years after being hospitalized, and that they had declared themselves in need of rehabilitation services. The assessment of abilities and activities of the patients was related to the model of human occupation developed by Kielhofner and co-workers. Most individuals reported a change in activity and interest patterns after stroke, and high motivation in current activities. The cognitive functions were within normal limits for all tested patients. However, the motor abilities and verbal performances were frequently affected and varied considerably. About 3/4 of the patients were not motivated to change their level of dependence in personal and instrumental ADL. Social and leisure activities outside the home were identified as the most promising goals for community-based rehabilitation programmes. Focusing on such activities, potential improvement in quality of life for this population could be achieved by individually-planned rehabilitation programmes using non-professional collaborators and patient organizations.

Stroke rehabilitation: identification of target groups and planning data.

In order to ascertain the need for late stroke rehabilitation in South-West Stockholm (SWS) and explore the conditions for experimental stroke outcome research, we followed a population-based, systematic sample of incident stroke patients, hospitalized during the period 1987-1988, using computer files and a telephone interview. The annual incidence of first-ever or recurrent transitory ischaemic attack (TIA) or acute stroke during the period was 2.83 per 1000. In December 1989, approximately 3% of these incident patients declared subjective residual dysfunction, were living at home and were considered potential candidates for rehabilitation. The estimated prevalence of home-bound individuals with residual dysfunction due to stroke was 0.74 per 1000 (95% CI 0.51-1.04). The average duration of hospitalization for these patients was 95.2 days. Approximately 3/4 of them were interested in further conventional rehabilitation. The group not interested in this therapy were mainly females and were older. They scored lower in personal ADL and mental activity, but similarly in motor function. We concluded that the prevalence need for rehabilitation after stroke in the SWS community amounted to at least 1/1000. Early rehabilitation in the community, linked to post-acute stroke care with reduction of hospital stay would be functionally and socially advantageous and cost-effective for more than 25% of the incident stroke cases. Stroke rehabilitation and clinical follow-up are closely related processes that should be evaluated simultaneously.

Parkinson's disease incidence: magnitude, comparability, time trends.

In this study, we reviewed incidence surveys of Parkinson's Disease (PD) from all over the world, published during the period 1945-1989, using reported quality criteria. In addition, we compared age-specific PD incidences from selected observations by stratified analysis. Crude incidences were described for 11 populations, and age-specific incidences for three of them: Iceland, Rochester (Minn, USA), and Turku (Finland). Effect modification by age was detected: a) by comparing incidences by age at diagnosis with incidence by age at clinical disease onset; and b) when only data on onset of disease was computed. For disease onsets, the incidences in Rochester for the period 1955-1966, and in Turku (Finland) during the interval 1968-1970, were lower than that in Iceland for the period 1958-1960: RR = 0.58 95% CI (0.41, 0.83), and RR = 0.67 95% CI (0.51, 0.87), respectively. For the Rochester population aged 40-69 years, a statistically significant 56% decrease in the incidences of Parkinsonism onsets during the period 1945-1966 was found. Validity problems in comparing PD incidences and the role of PD underdiagnosis were emphasized. We concluded that: a) stratified analysis is more suitable than standardization when comparing incidences for etiological purposes; b) the incidence of PD was highest in Iceland; and c) in Rochester, PD incidence under the age of 70 decreased with time.