Edison Manrique-Garcia

MD Anna Sidorchuk
email: anna.sidorchuk@ki.se

Johan Hallqvist Ad

Tahereh Moradi

Socioeconomic Position and Incidence of Acute Myocardial Infarction: a Meta-Analysis

Keywords: Acute Myocardial Infarction, socioeconomic position, meta-analysis

Background: Negative socioeconomic gradient is established for coronary heart disease (CHD) mortality and survival, while socioeconomic pattering of disease incidence is less investigated. To study socioeconomic inequalities in incidence of acute myocardial infarction (AMI), the major component of CHD, we undertook meta-analysis to summarize existing evidence on the issue. Methods: A systematic search was performed in PubMed and EMBASE databases for observational studies on AMI incidence and socioeconomic position (SEP), published in English through April 2009. Random-effects model was used to pool the risks estimates from the individual studies. Results: Among 1,181 references, 70 studies fulfilled inclusion criteria. An overall increased risk of AMI among the lowest SEP was found for all three indicators: income (pooled RR=1.71, 95% CI 1.43 to 2.05), occupation (pooled RR=1.35, 95% CI 1.19 to 1.53) and education (pooled RR=1.34, 95% CI 1.22 to 1.47). The strongest associations were seen in high-income countries such us US/Canada and Europe, while the results were inconsistent for middle-and low-income regions. Conclusion: AMI incidence is associated with low SEP. The nature of social stratification at the level of economic development of a country could be involved in the differences of risk of AMI between social groups.

INTRODUCTION

Acute Myocardial Infarction (AMI) is a major cause of death and disability worldwide. [START_REF] Thygesen | Universal definition of myocardial infarction[END_REF] According to an estimate from the WHO, about 40% of all deaths will be related to cardiovascular diseases (CVD) in 2020, with AMI being the main single cause. [START_REF] Murray | The global burden of disease: a comprehensive assessment of mortality and disability from disease, injuries and risk factors in 1990 and projected to 2020[END_REF] Projection of global mortality and burden of disease for 2030 presented that despite the decline in mortality due to coronary heart disease (CHD) in high-income countries during the last decades, it will remain the leading cause of mortality in low-and middle-income countries. [START_REF] Okrainec | Coronary artery disease in the developing world[END_REF][START_REF] Pais | Early intervention and prevention of myocardial infarction[END_REF][START_REF] Mathers | Projections of global mortality and burden of disease from 2002 to 2030[END_REF] Due to high mortality rate, severe damage to physical and mental health, long rehabilitation periods and a high rate of disability, the burden of AMI is a highly significant social issue. [START_REF] Hoit | Myocardial infarction in young patients: an analysis by age subsets[END_REF] There is a considerable body of evidence linking socioeconomic position (SEP) with the conventional risk factors for CHD, including AMI as the major component of CHD. [START_REF] Levenson | Reducing the global burden of cardiovascular disease: the role of risk factors[END_REF][START_REF] Tyroler | The influence of socioeconomic factors on cardiovascular disease risk factor development[END_REF][START_REF] Lynch | Explaining the social gradient in coronary heart disease: comparing relative and absolute risk approaches[END_REF] Lower SEP is often associated with health-damaging lifestyle resulting in the development of poor dietary habits as well as influencing behaviours related to smoking and physical activity. [START_REF] Kaplan | Socioeconomic factors and cardiovascular disease: a review of the literature[END_REF] Individuals with low SEP are prone to be exposed to multiple risk factors and, therefore, seem to suffer dramatically from excess burden of disease. [START_REF] Ruberman | Psychosocial influences on mortality after myocardial infarction[END_REF] Associations between SEP and CVD mortality and survival have been well discussed in a number of reviews. [START_REF] Krantz | Effects of psychological and social factors on organic disease: a critical assessment of research on coronary heart disease[END_REF][START_REF] Gonzalez | Relationship between socioeconomic status and ischaemic heart disease in cohort and case-control studies: 1960-1993[END_REF][START_REF] Brezinka | Psychosocial factors of coronary heart disease in women: a review[END_REF][START_REF] Strike | Psychosocial factors in the development of coronary artery disease[END_REF][START_REF] Alboni | In industrialized nations, a low socioeconomic status represents an independent predictor of mortality in patients with acute myocardial infarction[END_REF] However, quantitative assessment of socioeconomic pattering of CVD incidence and AMI incidence is presented to a lower extent. Use of incidence data generally avoids problems with post-diagnosis SEP changes as well as with different survival by socioeconomic groups. [START_REF] Devesa | Socioeconomic and racial differences in lung cancer incidence[END_REF] Addressing the issue of social inequality in AMI further, it is important to estimate the individual contribution of each SEP indicator rather than interchangeable SEP measures as they affect health through different pathways and causal mechanisms. [START_REF] Geyer | Education, income, and occupational class cannot be used interchangeably in social epidemiology. Empirical evidence against a common practice[END_REF] We undertook meta-analysis as a quantitative approach to summarize the existing evidence on the issue [START_REF] Stroup | Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group[END_REF][START_REF] Zwahlen | Meta-analysis in medical research: potentials and limitations[END_REF] to investigate the association between AMI incidence and various SEP measures including educational attainment, income, and occupation categories.

SUBJECTS AND METHODS

Search strategy

To identify eligible studies of associations between socioeconomic determinants and AMI incidence, we conducted a systematic search in PubMed and EMBASE databases for articles published in English-speaking, peer-reviewed journals from 1966 to April 01, 2009. For this search, we used the relevant medical subject heading (MeSH) terms and key words related to socioeconomic determinants combined with specific outcome defined as "acute myocardial infarction". The details of electronic search are reported on-line in Appendix 1. The reference lists were scrutinized to identify additional studies.

Study selection

To be included in this meta-analysis, studies had to 1) use original data; 2) be designed as case-control or cohort studies; 3) consider AMI incidence as an outcome; 4) present risk estimates with 95% confidence intervals (CIs) on the association between incident cases of AMI and at least one measure of SEP, or report sufficient information to compute these for men, women or both.

The articles were selected for inclusion if the study event was originally defined as AMI either nonfatal or in combination with fatal or reported as a composite outcome of AMI and death attributed to CHD / ischemic heart disease (IHD), including sudden death. We also considered studies where the outcome definition composed AMI with congestive heart failure [START_REF] Bosma | Low control beliefs, classical coronary risk factors, and socio-economic differences in heart disease in older persons[END_REF][START_REF] Pell | Retrospective study of influence of deprivation on uptake of cardiac rehabilitation[END_REF] or unstable angina (UA). [START_REF] Kontogianni | The impact of olive oil consumption pattern on the risk of acute coronary syndromes: The CARDIO2000 case-control study[END_REF] In order to avoid the inclusion of chronic ischemic disease, we did not include studies if the outcome of interest was presented as CHD event corresponding to codes 410-414 in ICD-9 or I21-I25 in ICD-10 with no further specification. Neither did we include studies if AMI was combined with angina pectoris, coronary atherosclerosis or stroke with no possibility to extract data on AMI alone. We sought data on the first AMI event to assess the impact of social inequality on development of the disease in people apparently free from acute ischemic disease. Studies focusing exclusively on mortality and survival were not included. SEP indicators were included only if they were based on income, educational attainment or occupational categories. Studies utilizing a social indicator constructed as a combination of two or more standard socioeconomic indicators were not included. Neither did we include studies where the SEP measure was based on ownership of car/houses/health insurance or presented as categories of deprivation. Only the studies with adult individuallevel measure of SEP were included. No restrictions were made by the type of SEP, personal or household.

When overlap was identified from various studies, the original data were included only once, prioritizing datasets providing maximally-adjusted risk estimates. If not, we used the most up-to-date information or studies with greater number of participants. Two co-authors (EM, AS) independently extracted relevant studies following the inclusion criteria. In case of missing data we contacted the corresponding authors. All authors [START_REF] Ahlbom | Occupational magnetic field exposure and myocardial infarction incidence[END_REF][START_REF] Falger | Exhaustion, psychological stressors in the work environment, and acute myocardial infarction in adult men[END_REF][START_REF] Hallqvist | Can we disentangle life course processes of accumulation, critical period and social mobility? An analysis of disadvantaged socioeconomic positions and myocardial infarction in the Stockholm Heart Epidemiology Program[END_REF][START_REF] Mattila | Association between dental health and acute myocardial infarction[END_REF][START_REF] Pais | Risk factors for acute myocardial infarction in Indians: a case-control study[END_REF][START_REF] Vogels | Sex differences in cardiovascular disease: are women with low socioeconomic status at high risk?[END_REF] from whom the additional information was requested provided us with data we asked for. Discrepancies were resolved by consensus in a panel meeting (TM, EM, AS).

Data extraction

The following information was extracted from each publication: the first author's last name, the year of publication, the country where the study was performed, study design, years of data collection and type of controls (population-based / hospital-based) in casecontrol studies, duration of follow-up in cohort studies, the sample size, indicators of SEP, source and type of SEP data, definition and status of the outcome, status of event, sex and age along with the risk estimates for AMI associated with SEP with corresponding 95% CIs, and the variables controlled for. The information on country where the study was performed was then classified both according to the geographical area (US/Canada, Europe, Asia, Latin America, Middle East) and country's income level (high-, middle-, or low-income countries). [START_REF] Mathers | Projections of global mortality and burden of disease from 2002 to 2030[END_REF] From each study, we extracted the risk estimate both minimally-and maximally-adjusted for the potential confounders. Unless otherwise stated, we included in the analysis the maximally-adjusted estimates in order to overcome inconsistency in handling confounding and mediating variables. We considered the study risk estimates to be minimally-adjusted if unadjusted or adjusted for age, sex and residence, either one or all, by matching, restriction, stratification or statistical adjustment, and to be maximally-adjusted if in addition adjusted for any of the classical well-recognised AMI-specific risk factors. If the original study reported risk estimates in association with more than one measure of SEP, each estimate was extracted and then analysed as its own association with the specific SEP.

Statistical analysis

Relative risk (RR) was used as the measure for summary statistic of associations between SEP and AMI incidence. To simplify the procedure, RRs represented all reported study-specific results derived from cohort studies and odds ratios (ORs) from case-control studies. [START_REF] Greenland | Quantitative methods in the review of epidemiologic literature[END_REF] Due to the initial assumption of between-study heterogeneity, a random-effects model of DerSimonian-Laird, [START_REF] Dersimonian | Meta-analysis in clinical trials[END_REF] which incorporates both within-and between-study variability, was applied to combine log RRs across the studies. To augment comparability between the studies using different SEP categories, we compared the lowest versus the highest SEP category. If the original study reported the risk estimates not in this order, we back-calculated the point estimate and 95% CIs. For the articles that did not report estimates in form of RRs or ORs, the risk estimates and 95% CIs were recalculated from the presented raw data by using standard equations. If the original study reported separate RRs for different sexes [START_REF] Baigi | Birthplace and social characteristics as risk factors for acute myocardial infarction in the province of Halland, Sweden[END_REF][START_REF] Ciruzzi | Diabetes and risk of acute myocardial infarction[END_REF][START_REF] Roux | Neighborhood of residence and incidence of coronary heart disease[END_REF][START_REF] Ljung | Accumulation of adverse socioeconomic position over the entire life course and the risk of myocardial infarction among men and women: results from the Stockholm Heart Epidemiology Program (SHEEP)[END_REF][START_REF] Rayce | Economic consequences of incident disease: the effect on loss of annual income[END_REF][START_REF] Salomaa | Relationship of socioeconomic status to the incidence and prehospital, 28-day, and 1-year mortality rates of acute coronary events in the FINMONICA myocardial infarction register study[END_REF] or different races [START_REF] Roux | Neighborhood of residence and incidence of coronary heart disease[END_REF] or if RRs were reported separately for two subcohorts with rheumatoid arthritis and non-inflammatory rheumatoid disorders within same cohort, [START_REF] Wolfe | The risk of myocardial infarction and pharmacologic and nonpharmacologic myocardial infarction predictors in rheumatoid arthritis: A cohort and nested case-control analysis[END_REF] the risk estimates were pooled (weighted by inverse of their variance) to obtain a single estimate per SEP from each study.

To evaluate the statistical heterogeneity among studies we used the Cochran's Q test. [START_REF] Cochran | The combination of estimates from different experiments[END_REF] This test examines the null hypothesis that heterogeneity across the study estimates of RRs is due to chance by using a chi-square test with degrees of freedom equal to the number of studies minus one. For Q statistic we considered P<0.1 as a representative of statistically significant heterogeneity. To describe the proportion of total variance in study estimates explained by heterogeneity between study variation rather than chance, we calculated the I 2 statistic. [START_REF] Higgins | Measuring inconsistency in meta-analyses[END_REF] Random-effect meta-regression analyses were performed to identify study-level factors contributing to heterogeneity between studies. The explanatory variables included study design, geographical area, country's income level, publication year (before 2000 / 2000 and after), type of adjustment with respect to AMI-specific risk factors, type of controls in casecontrol studies, personal or household SEP, and status of the event and the natural logarithm of RR was the dependent variable. [START_REF] Baker | Understanding heterogeneity in meta-analysis: the role of meta-regression[END_REF][START_REF] Thompson | Explaining heterogeneity in meta-analysis: a comparison of methods[END_REF][START_REF] Van Houwelingen | Advanced methods in meta-analysis: multivariate approach and meta-regression[END_REF] An univariate meta-regression was performed for each study-level factors for studies on income, education and occupation. A backward stepwise approach was used to select the significant variables to be included in a multivariate analysis. In addition, a series of subgroup analyses were conducted by stratifying the original studies by sex, country's income level and geographical region, study design, adjustment strategy, publication period, personal or household SEP and type of study event. The stability of the results was also evaluated in leave-one-out sensitivity analysis in which the influence of the individual study on the overall pooled RR was estimated by omitting one study at a time. [START_REF] Tobias | Assessing the influence of a single study in meta-analysis[END_REF] We assessed publication bias by constructing funnel plots and using the Egger's regression asymmetry test and the Begg-Mazumdar adjusted rank correlation test. [START_REF] Begg | Operating characteristics of a rank correlation test for publication bias[END_REF][START_REF] Egger | Bias in meta-analysis detected by a simple, graphical test[END_REF]. All statistical analyses were performed using STATA version 10 (StataCorp, College Station, TX). P-values that were less than 0.05 were considered statistically significant. All statistical tests were two-sided.

RESULTS

Study characteristics

Total search in the electronic databases revealed 2,539 references and among those 1,358 were overlapping between different search categories. The search strategy for the 1,181 unique references is presented on Figure 1 as the QUOROM statement [START_REF] Moher | Improving the quality of reports of metaanalyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses[END_REF] flowchart where the detailed procedure of the reference identification along with the information on exclusion criteria applied on different stages of the selection is described. Briefly, 855 articles did not address the issue of interest and were excluded after the screening the abstracts leaving us with 326 full-text articles for further examination. Of these, only 64 articles fulfilled the predefined inclusion criteria and were selected to be included in the analysis. The reference lists of the selected articles were scrutinized and 19 articles were additionally identified fulfilling the inclusion criteria. To mitigate overlapping in study populations, several studies being initially considered relevant for the analysis [START_REF] Ahlbom | Occupational magnetic field exposure and myocardial infarction incidence[END_REF][START_REF] Hallqvist | Can we disentangle life course processes of accumulation, critical period and social mobility? An analysis of disadvantaged socioeconomic positions and myocardial infarction in the Stockholm Heart Epidemiology Program[END_REF][START_REF] Andersen | Do factors in the psychosocial work environment mediate the effect of socioeconomic position on the risk of myocardial infarction? Study from the Copenhagen Centre for Prospective Population Studies[END_REF][START_REF] Appels | Vital exhaustion as risk indicator for myocardial infarction in women[END_REF][START_REF] Bobak | Association between psychosocial factors at work and nonfatal myocardial infarction in a population-based case-control study in Czech men[END_REF][START_REF] Chang | The influence of economic development on the association between education and the risk of acute myocardial infarction and stroke[END_REF][START_REF] Ciruzzi | Case-control study of passive smoking at home and risk of acute myocardial infarction[END_REF][START_REF] Ciruzzi | Hypertension and the risk of acute myocardial infarction in Argentina[END_REF][START_REF] Ciruzzi | Frequency of family history of acute myocardial infarction in patients with acute myocardial infarction[END_REF][START_REF] Gustavsson | A population-based case-referent study of myocardial infarction and occupational exposure to motor exhaust, other combustion products, organic solvents, lead, and dynamite[END_REF][START_REF] Hallqvist | Does heavy physical exertion trigger myocardial infarction? A case-crossover analysis nested in a population-based casereferent study[END_REF][START_REF] Nyboe | Risk factors for acute myocardial infarction in Copenhagen. I: Hereditary, educational and socioeconomic factors. Copenhagen City Heart Study[END_REF][START_REF] Panagiotakos | Risk stratification of coronary heart disease in Greece: final results from the CARDIO2000 Epidemiological Study[END_REF][START_REF] Peter | Socioeconomic status, status inconsistency and risk of ischaemic heart disease: a prospective study among members of a statutory health insurance company[END_REF][START_REF] Rosengren | Coronary heart disease and mortality in middle aged men from different occupational classes in Sweden[END_REF][START_REF] Rosenlund | Environmental tobacco smoke and myocardial infarction among never-smokers in the Stockholm Heart Epidemiology Program (SHEEP)[END_REF][START_REF] Van Lenthe | Material and behavioral factors in the explanation of educational differences in incidence of acute myocardial infarction: the Globe study[END_REF][START_REF] Weinehall | Perceived health modifies the effect of biomedical risk factors in the prediction of acute myocardial infarction. An incident case-control study from northern Sweden[END_REF] were excluded and substituted by more recent ones, providing maximally-adjusted risk estimates or with greater number of participants [START_REF] Geyer | Education, income, and occupational class cannot be used interchangeably in social epidemiology. Empirical evidence against a common practice[END_REF][START_REF] Kontogianni | The impact of olive oil consumption pattern on the risk of acute coronary syndromes: The CARDIO2000 case-control study[END_REF][START_REF] Ciruzzi | Diabetes and risk of acute myocardial infarction[END_REF][START_REF] Ljung | Accumulation of adverse socioeconomic position over the entire life course and the risk of myocardial infarction among men and women: results from the Stockholm Heart Epidemiology Program (SHEEP)[END_REF][START_REF] Andersen | Income as mediator of the effect of occupation on the risk of myocardial infarction: does the income measurement matter?[END_REF][START_REF] Bobak | Own education, current conditions, parental material circumstances, and risk of myocardial infarction in a former communist country[END_REF][START_REF] Chang | Can cardiovascular risk factors explain the association between education and cardiovascular disease in young women?[END_REF][START_REF] Collijn | Psychosocial risk factors for cardiovascular disease in women: the role of social support[END_REF][START_REF] Hippe | Familial predisposition and susceptibility to the effect of other risk factors for myocardial infarction[END_REF][START_REF] Huisman | The contribution of job characteristics to socioeconomic inequalities in incidence of myocardial infarction[END_REF][START_REF] Schaufelberger | Heart failure in different occupational classes in Sweden[END_REF][START_REF] Wennberg | The effects of commuting activity and occupational and leisure time physical activity on risk of myocardial infarction[END_REF].

Two risk estimates for educational attainment and AMI incidence presented by Chang C et al. [START_REF] Chang | Can cardiovascular risk factors explain the association between education and cardiovascular disease in young women?[END_REF] for women from Eastern Europe and whose from non-European countries (Latin America, Asia and Africa) were independently included in the analysis, referred as Chang C (A) and Chang C (B), respectively. Similar to that, two substudies on occupational SEP and AMI described in the article by Mattila K et al. [START_REF] Mattila | Association between dental health and acute myocardial infarction[END_REF] (series I and series II), were also analysed separately. The same strategy was applied to data derived from the articles by Eaker E et al. [START_REF] Eaker | Myocardial infarction and coronary death among women: psychosocial predictors from a 20-year follow-up of women in the Framingham Study[END_REF] and Qureshi A et al., [START_REF] Qureshi | Educational attainment and risk of stroke and myocardial infarction[END_REF] where occupational and educational SEP were presented among women at the age of 45-54 years (Eaker E (A)) and 55-64 years (Eaker E (B)) and patients younger 50 years (Qureshi A (A)) and older 50 years (Qureshi A (B)), respectively.

Substudies from the articles by Bosma H et al.[74] originated from Lithuania (Bosma H (A))

and The Netherlands (Bosma H(B)) were included independently. Therefore, 70 original studies from 65 articles, extending back to the year 1968, were finally included in the analysis.

In total, there were 37 case-control studies in 35 articles [START_REF] Kontogianni | The impact of olive oil consumption pattern on the risk of acute coronary syndromes: The CARDIO2000 case-control study[END_REF][START_REF] Falger | Exhaustion, psychological stressors in the work environment, and acute myocardial infarction in adult men[END_REF][START_REF] Mattila | Association between dental health and acute myocardial infarction[END_REF][START_REF] Pais | Risk factors for acute myocardial infarction in Indians: a case-control study[END_REF][START_REF] Baigi | Birthplace and social characteristics as risk factors for acute myocardial infarction in the province of Halland, Sweden[END_REF][START_REF] Ciruzzi | Diabetes and risk of acute myocardial infarction[END_REF][START_REF] Ljung | Accumulation of adverse socioeconomic position over the entire life course and the risk of myocardial infarction among men and women: results from the Stockholm Heart Epidemiology Program (SHEEP)[END_REF][START_REF] Bobak | Own education, current conditions, parental material circumstances, and risk of myocardial infarction in a former communist country[END_REF][START_REF] Chang | Can cardiovascular risk factors explain the association between education and cardiovascular disease in young women?[END_REF][START_REF] Collijn | Psychosocial risk factors for cardiovascular disease in women: the role of social support[END_REF] reporting associations with different SEP among 74,056 AMI cases and 619,652 controls and 33 cohort studies, including 2 studies nested in cohort, in 30 articles [18, 21, 29, 34, 36-38, 64, 68-74, 100-114] where association with SEP was studied for 28,629 incident cases among 3,869,270 participants. Supplementary table S1 presents data on detailed study characteristics of the included studies.

Overall result

The overall results of this meta-analysis provided evidence of a significant increase in risk of AMI among the lowest socioeconomic categories for all three socioeconomic indicators (Fig. 234). Heterogeneity was observed for all three SEP indicators (p<0.001) (Table1). 1).

Further stratification by sex, adjustment strategy, study design, status of event, personal or household type of SEP or publication years did not alter the overall pooled results. No association was seen for the case-control studies utilizing hospital controls, while studies with population controls revealed statistically significant association between the lowest income group and AMI (Table 1).

We observed a 34% increased risk of AMI for the lowest educational group (RR=1.34, 95% CI 1.22 to 1.47) (Table 1). The increase was apparent in subanalyses after stratifying by the main study characteristics, i.e. sex, adjustment strategy, study design, publication period, and status of event, apart from for the case-control studies with hospital controls (Table 1).

Increased incidence of AMI was observed when studies on occupational categories were pooled (RR=1.35, 95% CI 1.19 to 1.53) (Table 1). The increase persisted for the lowest occupational SEP when pooling studies within subgroups with different sex, status of event, and publication years. Non-significant increase was seen in subanalysis for household SEP measure (husband's occupation for women). The results were less consistent among casecontrol studies (Table 1).

Increased incidence of AMI was evident for the lowest income-based, educational and occupational SEP in high-income countries and in regional areas such us US/Canada and Europe (Table 1). No significant associations were, however, apparent between any of the SEP determinants and AMI incidence in studies carried out in the middle-or low income countries, particularly in Asian region. In contrary, for middle-or low income countries an inverse association was observed for the results combined across the studies on occupational SEP.

There was a substantial heterogeneity in overall result among the studies on all SEP determinants (p< 0.001) that remained significant for the results from most of the subanalyses. However, no or low heterogeneity was present when analyses were restricted to studies originated from US/Canada. There was a low heterogeneity among studies on occupation when results were combined for middle-or low-income countries. Similar pattern was seen when studies on income published before the year 2000 were analysed separately.

In random-effect meta-regression analyses the relation between SEP and AMI incidence persisted irrespective to the design of original studies, though in case-control studies multivariate regression indicated the association between type of control (hospital vs.

population controls) and RR of AMI for studies on all SEP indicators (for income ß coefficient (ß) = -2.76, 95% CI -4.77 to -0.76, p= 0.007; for education ß = -0.40, 95% CI -0.75 to -0.05, p= 0.02; for occupation ß = -0.51, 95% CI -1.00 to -0.02, p= 0.04). Pooling together the cohort studies and case-control studies with population controls only had no effect on the overall results (pooled RR for income =1. No publication bias were observed for educational SEP (Egger's test p=0.49) with borderline significant result for occupational SEP (p=0.05), while selection of the studies focusing on income introduced publication bias (p=0.03). The publication bias funnel plots are presented as Supplementary material (Figure S1). No individual studies significantly altered the overall estimates based on the results of the sensitivity analysis.

DISCUSSION

Our results indicated an increased incidence of myocardial infarction among the lowest socioeconomic categories in income (71%), education (34%) and occupation (32%) compared to the highest category of the corresponding SEP. The associations were significant for both males and females and consistent for most of the results from the subgroup analyses.

The increased risk of AMI for the lowest categories of all SEP indicators was most evident in high-income countries, while middle-or low-income countries revealed less consistent associations probably due to a limited number of the studies included in the latter strata.

SEP is a surrogate measure for numerous factors that may affect health. There is an increasing awareness that SEP indicators should not be used interchangeably because they may represent different risk factors [115] and relate to different causal pathways. [START_REF] Geyer | Education, income, and occupational class cannot be used interchangeably in social epidemiology. Empirical evidence against a common practice[END_REF]116] Recent reviews discussed the new approach for health researchers to study the socioeconomic inequalities in health by measuring the respective impact of separate socioeconomic indicators on health outcomes along with the mediating mechanisms and adjustment suggested by each indicator rather than studying an effect of a single composite SEP variable. [START_REF] Geyer | Education, income, and occupational class cannot be used interchangeably in social epidemiology. Empirical evidence against a common practice[END_REF]117,118] In our analysis the attempt was made to identify the independent contribution of each SEP indicator to AMI outcome across regions and over time. The results must be interpreted with cautions because of the observational nature of the data. [START_REF] Stroup | Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group[END_REF]119,120] Several methodological issues are needed to be taken under consideration. One of the limitations in our study was possible differences in the definition and classification of SEP across studies. It was of particular importance for educational and income SEP categories since differences in countries' general economy, educational systems and cultural issues could cause the variability in the scales used to classify the exposure. The methodological limitations for quantitative comparison of studies on SEP due to the substantial dissimilarity in exposure measures used in different studies over time and geographical regions have been discussed previously.

[115] Lack of uniformity in reporting SEP data in original studies have limited our ability to investigate a social gradient in AMI incidence. To reduce the inconsistency in SEP stratification across the original studies and to obtain the meaningful indicator of socioeconomic inequality in health, it has been suggested to measure the difference between the extreme categories of SEP, i.e. to compare the highest and the lowest SEP strata. [117,118,121] Studies selected for our analysis varied significantly in presenting SEP categories that prevented us from collapsing the middle-level SEP categories in one. To overcome the problem and to increase the comparability across the studies, we applied the suggested approach and compared the extreme categories that, however, impaired the possibility of studying the social gradient and could be considered as a limitation of the analysis.

Due to significant heterogeneity observed across the selected studies, the pooled results should be interpreted with cautions. The nature of observational studies introduces design-related heterogeneity that basically reflects the disparity in the study characteristics. selected for the analysis even further.

[124] Socioeconomic inequalities may influence all above mentioned conditions and, thus, be one of the reasons for type of controls to be a source of heterogeneity. For income-based SEP overall results for studies published before 2000 yielded highly significant association with the outcome along with no heterogeneity between studies, though in multivariable meta-regression the publication year was not recognised as a potential source for heterogeneity. We must, however, acknowledge that in meta-analysis of observational studies the results of multivariable meta-regression can also be confounded by unidentified study-level factors. [START_REF] Baker | Understanding heterogeneity in meta-analysis: the role of meta-regression[END_REF] Publication bias is a concern in meta-analysis since it might lead to overestimation of the relative risk. Since our meta-analysis was restricted to English-speaking peer reviewed publications, our estimates may have been affected by missing data from the studies performed in the low-or middle-income countries where SEP may be differently associated with AMI. It may explain the presences of publication bias detected in our analysis for combined estimates for studies on income-based SEP. In our study, publication bias may be partially explained by variability in outcome definitions and SEP measures or if studies with relatively smaller sample size and inconsistent results were lacking in the analysis representing significance bias, size bias and suppression publication bias.

[119]

Our selection criteria, particularly with respect to study definition, were rather tight that resulted in a limited number of studies. We acknowledge the fact that numerous studies potentially relevant for the analysis were, however, excluded if AMI was reported as a study endpoint in combination with chronic heart diseases. In order to control highly heterogeneous outcome and being mostly interested in social pattering of first acute coronary event, we deliberately narrowed the analysis to AMI only.

Another restraint deals with the variety of confounders and/or mediators across the original studies. It might mainly be crucial for the pooled results if the adjustment strategy differs between the studies with respect to risk factors for myocardial infarction. The complicated interplay between socioeconomic factors and risk factors for cardiovascular diseases must be acknowledged while interpreting the results of meta-analysis. It is wellknown that standard risk factors explain more than half of association between SEP and CHD mortality and morbidity and there is a pronounced socioeconomic gradient in CHD-related behavioural and lifestyle factors. influence of various adjustment we, therefore, performed separate subanalyses for studies minimally-and maximally-adjusted that in our analysis yielded the similar results.

Our findings presented the overall increase in risk of AMI incidence among the lowest SEP that has previously been reported for AMI mortality and CHD morbidity. [START_REF] Gonzalez | Relationship between socioeconomic status and ischaemic heart disease in cohort and case-control studies: 1960-1993[END_REF][START_REF] Alboni | In industrialized nations, a low socioeconomic status represents an independent predictor of mortality in patients with acute myocardial infarction[END_REF] The aforementioned results corroborated the strong evidence of the relation between Competing of interest: None declared.

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What is already known?

Adverse socioeconomic position is related to coronary heart disease mortality and survival.

What does this study add?

This meta-analysis reveals an association between low socioeconomic position (SEP) and increased incidence of acute myocardial infarction (AMI). The associations were consistent for both men and women.

People from the lowest strata of income-based SEP have a 71% greater risk to develop myocardial infarction compared to those in the highest strata. An increased risk in AMI incidence of 34% and 35% was found for the lowest compared to the highest categories of educational and occupational SEP, respectively.

The socioeconomic patterns in myocardial infarction incidence were seen to be most pronounced for high-income countries. The nature of social stratification at the level of economic development of a country could be involved in the differences of risk of AMI between social groups.

Policy Implications

Public health policies aiming at reducing the risk of AMI should address socioeconomic position both in the promotion and the evaluation of preventive measures.

The potential for variation in the strength of AMI inequalities between different societies should be acknowledged by national and international policy makers. 416

  [122] In our case the heterogeneity was probably boosted by the initial unevenness in study bases as well as in outcome definitions and status of event used in the original studies along with inconsistency in measures of exposure and variability in handling confounding and mediating factors. The incidental manner of reporting SEP data in descriptive tables in a numerous studies, resulted in using estimates adjusted neither by matching nor by statistical adjustment and, probably influenced the completeness of the search. The result-related heterogeneity[122] may be less pronounced in our meta-analysis due to non-substantial variability between the original point estimates and considerable overlaps of the confidence intervals. Meta-regression analyses indicated type of study controls in case-control studies as potential sources of heterogeneity between studies for all SEP indicators. Several metaanalyses discussed the limitations introduced by pooling the results of studies different in study design or type of control groups as in hospital-based case-control studies the choice of controls may affect the representativeness of exposure.[115, 123] In addition, characteristics of hospital catchment area and presence of Berkson's bias, if study exposure is related to the risk of being hospitalized for the control diseases, may jeopardize comparability of studies

  [125-128] Therefore, the choice of variables in the original study to adjust for can influence the pooled results. Adjustment for risk factors acting as intermediate steps in the causal pathways will result in underestimation of the relation between SEP and the disease, while relation will be overstated if genuine confounders left unadjusted. Evidence from the recent studies and reviews indicate that different SEP measures can simultaneously be included in the multivariable models as they do not act as proxy for each other,[117, 118, 129-131] while biological, behavioural and psychological factors can mediate an association between SEP and AMI.[126-128, 131] To reduce the

  socioeconomic deprivation and incidence of acute ischemic events. Further research providing validated information is required to address public health strategies to reduce the risk of AMI among the most vulnerable groups in different countries and among different societies. It is imperative to emphasise the importance of such studies, particularly for the regions with lower level of economic development, where the epidemic of CHD is becoming a public health issue. Source of financial support: Meta-analysis was supported by grant from the Swedish Council for Working Life and Social Research [FAS, 2006-0230 to Tahereh Moradi]. The study founder had no role in the design, collection, analysis, or interpretation of the data, or in the writing or decision to submit the manuscript.

Figure 1 .Figure 2 .

 12 Figure 1. The QUOROM a statement [47] flowchart for study selection.

Figure 3 .

 3 Figure 3. Relative Risk (RR) and 95% confidence intervals (CIs) for acute myocardial

Figure 4 .

 4 Figure 4. Relative Risk (RR) and 95% confidence intervals (CIs) for acute myocardial

Table 1

 1 Pooled estimates for the lowest versus the highest socioeconomic category and incidence of acute myocardial infarction in series of Corresponds to the studies where less than <10% of cases may had had a prior AMI as well as the studies where information on cases' history on AMI was not clarified by the authors The strongest pattern was seen for the lowest income group where the incidence of AMI increased by 71% compared to high income group (RR=1.71, 95% CI 1.43 to 2.05) (Table

	subgroup analyses
	Subgroup analysis	n = Number of studies, Pooled RR (95% CI), p-value for Q test for heterogeneity, I 2 statistic (%)
		n	Income	Q p-value	n	Education	Q p-value	n	Occupation	Q p-value
				I 2 (%)			I 2 (%)			I 2 (%)
	Summary pooled	19 1.71 (1.43 to 2.05)	<0.001	47 1.34 (1.22 to 1.47)	<0.001	33 1.35 (1.19 to 1.53)	<0.001
	estimate			95.9			77.6			81.6
	Sex
	Male	7	1.50 (1.31 to 1.72)	0.039	13 1.24 (1.04 to 1.48)	<0.001	18 1.34 (1.16 to 1.55)	<0.001
				54.8			83.7			77.3
	Female	4	1.87 (1.48 to 2.36)	0.015	15 1.58 (1.25 to 2.00)	<0.001	11 1.87 (1.34 to 2.60)	<0.001

a Data from Chang C et al

[START_REF] Chang | Can cardiovascular risk factors explain the association between education and cardiovascular disease in young women?[END_REF]

are not included due to presenting combined results from Latin American and Asian countries b Corresponds to data from both Western European and Eastern European countries c On this item data from the study by Qureshi A et al.

[START_REF] Qureshi | Educational attainment and risk of stroke and myocardial infarction[END_REF]

are not available d Unadjusted or adjusted for age, sex and residence only (either one or all)

e Adjusted for at least one AMI-specific risk factors such as smoking, diabetes, hypertension, hypercholesterolemia, physical activity and BMI f Corresponds to cohort studies and case-control studies nested in cohort g Corresponds to either population-based controls or relatives/neighbourhood controls h Corresponds to the family income SEP or husband's occupation for women or combination of women's and husband's occupation SEP i

studies are indicated by squares and the size of the squares represents the statistical weight that each study contributed to the random-effect summary estimate. Horizontal lines indicate the study-specific 95% CIs. Diamond represents the overall summary RR and its 95% CIs.


Caroline Andrews

Iciar Aviles-Olmos

Marwan Hariz

Thomas Foltynie
email: t.foltynie@ion.ucl.ac.uk

Thomas Foltynie Box

Which patients with Dystonia benefit from Deep Brain Stimulation?-a meta-regression of individual patient outcomes

Keywords:

Which patients with Dystonia benefit from Deep Brain

Stimulation?-a meta-regression of individual patient outcomes

INTRODUCTION

Dystonia is a common movement disorder, defined as 'a syndrome of sustained muscle contraction usually producing twisting and repetitive movements or abnormal postures. Classification of dystonia is made according to three main features; the age of onset of symptoms, the distribution of the region of the body affected (focal, segmental or generalized) and the underlying etiology (Primary, Secondary, Dystonia-plus conditions, or Heredodegenerative conditions). Patients with primary dystonia will present with no other neurological condition (with the exception of tremor) and will have no structural brain abnormalities or inborn errors of metabolism. About 10% of generalized dystonia starting in childhood or adolescence are linked to genetic mutations, the majority being caused by a GAG deletion in the DYT1 gene.

Secondary dystonia results from other causes such as brain injury, drugs or toxins, or post encephalitis. Dystonia-plus conditions feature other neurological signs such as in the myoclonusdystonia syndrome, but in these patients brain imaging is normal, no secondary cause is found, and genetic causes for these conditions have been identified. Dystonia is also seen in patients with a range of heredo-degenerative conditions in which neurological symptoms and signs such as parkinsonism, ataxia, bulbar failure or neuropathy can give clues to the underlying diagnosis.

Surgical treatment for dystonia dates from the 1950s and 1960s. Irving Cooper reported that 69% of 227 patients with dystonia improved with thalamotomy, with marked improvement seen in 24% and mild to moderate improvement in 45%. [START_REF] Is | 20-year followup study of the neurosurgical treatment of dystonia musculorum deformans[END_REF] Further teams subsequently demonstrated the benefit of lesioning the globus pallidus internus (GPi) for the treatment of dystonia [START_REF] Lozano | Globus pallidus internus pallidotomy for generalized dystonia[END_REF] and subsequently deep brain stimulation (DBS) of the GPi was evaluated for the treatment of dystonia. The original reports of successful outcomes following DBS for dystonia included patients with the primary generalised form that were positive for the DYT1 GAG deletion. [START_REF] Coubes | Treatment of DYT1generalised dystonia by stimulation of the internal globus pallidus[END_REF] Since then, multiple centres have used DBS as a treatment for patients with many other subtypes of dystonia insufficiently helped by oral medications or Botulinum toxin injections. While mean results have generally been encouraging, a wide range of outcomes have been reported.

Predictive factors of long term outcome have been sought in small series with hints that shorter disease duration is a statistically significant predictor of better long term outcome following DBS. [START_REF] Mehrkens | Long-term efficacy and safety of chronic globus pallidus internus stimulation in different types of primary dystonia[END_REF] Whether patients positive for the DYT1 deletion have greater benefit has been unclear with some reports suggesting that the DYT1 mutation is a predictor of better outcome [START_REF] Yianni | Globus pallidus internus deep brain stimulation for dystonic conditions: a prospective audit[END_REF][START_REF] Eltahawy | Primary dystonia is more responsive than secondary dystonia to pallidal interventions: outcome after pallidotomy or pallidal deep brain stimulation[END_REF][START_REF] Tisch | Effect of electrode contact location on clinical efficacy of pallidal deep brain stimulation in primary generalised dystonia[END_REF], whilst others have not found a significant difference between the DYT1+ve or DYT1-ve groups. [START_REF] Kupsch | Pallidal deep-brain stimulation in primary generalized or segmental dystonia[END_REF][START_REF] Vidailhet | Bilateral, pallidal, deep-brain stimulation in primary generalised dystonia: a prospective 3 year follow-up study[END_REF] There is a lack of effective non-surgical treatment for patients with heredodegenerative and secondary dystonias, therefore DBS has been trialled among widely varying subtypes of such patients; however the efficacy of DBS in the treatment of these patients is less clear.

In view of the substantial variability in the responsiveness of dystonia patients to DBS, we have reviewed the published literature and extracted the results of individual patient outcomes following DBS for dystonia. We have used these data in a meta-regression to re-analyse factors predictive of outcome following DBS for all types of dystonia.

METHODS

Search strategy

The PubMed database was searched for articles describing DBS for dystonia. MeSH headings used were "Dystonia" and "Stimulation". Only articles written in English were reviewed and only publications reporting individual clinical outcome data were included in statistical analyses.

Papers that reported summary mean outcomes following DBS for dystonia are reported alongside the combined individual clinical outcome data. Where there were multiple serial publications from the same centre describing the same or overlapping patient groups, great care was taken to include data from any individual only once using their age at onset, age at surgery and baseline dystonia severity to distinguish them as individuals. Reports of patients with dystonia as a feature of Parkinson's disease were excluded. Dystonia subtypes were coded according to etiology-primary, dystonia plus, heredodegenerative or secondary, then by subtype according to body distribution and or identified underlying cause.

Assessing the outcome of DBS for dystonia

The scale most commonly used for rating severity of generalized dystonia is the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). This comprises a clinician rated movement scale (120 point score) and patient rated disability scale (0 -30 point score). For patients with cervical dystonia (an adult onset focal primary dystonia) the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) is most commonly used with sub scores for severity, disability and pain. Whilst most studies have used BFMDRS and TWSTRS for measuring outcome, the Unified Dystonia Rating Scale (UDRS), the Abnormal Involuntary Movement scale, and the Tsui scale have also been utilized.

Statistical analysis

From each paper documenting individual outcome data, the following information was noted: the dystonia subtype, gender, age at surgery, duration of symptoms, rating scale used, DBS target, pre-operative and post operative scores, duration of follow up, and whether assessment was open or blinded. The percentage improvement in dystonia severity was calculated for each patient.

Microsoft Stata version 8 was used for all analyses. Multiple regression was performed to assess whether percentage improvement in dystonia severity was associated with age at surgery, duration of symptoms, baseline severity, and surgical target. The centre, the duration of follow up, the rating scale used and whether the assessment was performed open or blinded were included as covariates in each model.

RESULTS

The original Pubmed search revealed 1010 papers, of which 157 papers reported clinical outcomes of DBS for dystonia. From these papers, individual quantitative outcomes following DBS were available for 466 patients with all forms of dystonia. The sub-classification of these patients included 344 with primary forms of dystonia, 10 with myoclonus dystonia, 19 with heredo-degenerative dystonias and 93 patients that have had DBS for secondary dystonia. The number of patients in each sub-category together with the references from which the patient data was obtained are presented in Tables 123.

Primary Dystonia

Primary generalised dystonia (PGD)

The search identified 209 patients that received DBS for primary generalised dystonia from 20 centres. The baseline features of these patients are presented in Table 1. The mean percentage improvement of the group as a whole was 60.7%, (inter-quartile range-43.4% to 83.3%). Within this group, the 91 patients with DYT1 positive dystonia had the greatest percentage improvement. Multiple regression analysis (with adjustment for confounding covariates) showed that a shorter duration of symptoms (p=0.008) (See also Figure 1), a lower baseline severity score (p=0.024) and DYT-1 positive status (p=0.002) (See also Figure 2) were all independently associated with a significantly higher percentage improvement from surgery. In a single patient that had DBS of the subthalamic nucleus (STN) for idiopathic PGD, an overall improvement of 72.1% was observed. [START_REF] Kleiner-Fisman | Subthalamic nucleus deep brain stimulation for severe idiopathic dystonia: impact on severity, neuropsychological status, and quality of life[END_REF] Additional patients have been published in other series but could not be included in the current analysis because of lack of individual data in the published manuscripts. Among 24 patients with generalised dystonia that received GPi DBS in a double blinded trial of DBS (the only double blind trial of DBS for primary generalized dystonia), there was a 41.9% mean reduction in dystonia severity. [START_REF] Kupsch | Pallidal deep-brain stimulation in primary generalized or segmental dystonia[END_REF] A further series of 30 patients followed up for 2 years had a mean reduction in motor severity of 82.5%. [START_REF] Isaias | Deep brain stimulation for primary generalized dystonia: long-term outcomes[END_REF] These authors demonstrated that the presence of fixed skeletal deformities and longer disease duration were both predictive of a lower percentage improvement following GPi DBS. A series of 24 primary generalised dystonia cases improved by a mean of 59% if DYT1 positive, and only 43% if DYT1 negative but this difference was not significant. [START_REF] Egidi | A survey of Italian cases of dystonia treated by deep brain stimulation[END_REF] Spasmodic Torticollis Individual outcome data were identified for 67 patients from 14 centres with isolated spasmodic torticollis treated with DBS. The mean improvement was 48% (SD 41%) but none of the variables entered into the regression model were associated with the magnitude of improvement from surgery. Sixty three patients had electrodes inserted in the GPi with a mean percentage improvement of 49.2%, whereas 4 patients had electrodes in the STN with improvement of only 34.9% . [START_REF] Kleiner-Fisman | Subthalamic nucleus deep brain stimulation for severe idiopathic dystonia: impact on severity, neuropsychological status, and quality of life[END_REF] Patients evaluated in a blinded fashion had a mean improvement of 33.3% compared to a mean improvement of 52.3% in those patients assessed in an open label fashion.

Meige Syndrome

All 17 patients included in this analysis had GPi DBS, with a mean improvement of 64.3% (SD 29.5%). Compared with other patients with focal/ segmental dystonias, the patients with Meige syndrome were older, with a shorter duration of symptoms and a higher percentage response to treatment. The regression analysis confirmed that the only variable showing a trend towards association with improved percentage outcome from DBS was a shorter duration of symptoms (p=0.06).

Focal/ Segmental Dystonias

This subgroup of dystonia patients includes a mixture of phenotypes. The majority of published patients have not been tested for DYT-1 status. Patients had a mean improvement of 57.9% with the GPi target (n=37), all with open label assessments. A single patient receiving STN DBS for this condition had a 23% improvement in symptoms [START_REF] Novak | Successful bilateral subthalamic nucleus stimulation for segmental dystonia after unilateral pallidotomy[END_REF] whereas a single report of ViM DBS had a 58.3% improvement. [START_REF] Wohrle | Risperidoneresponsive segmental dystonia and pallidal deep brain stimulation[END_REF] An additional 16 patients with focal/segmental dystonia had GPi DBS as part of a blinded trial and showed a mean 52.6% reduction in dystonia severity but without individual data. [START_REF] Kupsch | Pallidal deep-brain stimulation in primary generalized or segmental dystonia[END_REF] None of the variables entered into the regression model predicted the magnitude of improvement from surgery for patients with focal/segmental phenotypes.

Myoclonus Dystonia

From 10 patients with myoclonus dystonia, a mean improvement of 58% was seen following GPi DBS (Table 1). Two case reports of VIM DBS for myoclonus-dystonia suggested improvement in myoclonus but not dystonia. [START_REF] Kuncel | Myoclonus and tremor response to thalamic deep brain stimulation parameters in a patient with inherited myoclonus-dystonia syndrome[END_REF][START_REF] Trottenberg | Neurostimulation of the ventral intermediate thalamic nucleus in inherited myoclonusdystonia syndrome[END_REF]

Heredodegenerative dystonias

Patients with Pantothenate Kinase-Associated Neurodegeneration (PKAN) had the greatest percentage improvement of the heredo-degenerative subcategory, all operated in the GPi (Table 2). The percentage response was not associated with age at surgery, duration of symptoms, or baseline severity. Some individuals with neuroacanthocytosis manifest both dystonia and chorea.

Reports of GPi DBS in this condition suggest that dystonia may be improved but this may be at the expense of worsening of chorea. [START_REF] Guehl | Deep brain pallidal stimulation for movement disorders in neuroacanthocytosis[END_REF]

Secondary Dystonia conditions

The number of patients with each secondary dystonia subtype is small (Table 3). Patients with tardive dystonia (n=41) had a 69% improvement in dystonia severity following DBS. A lower pre-operative score (p=0.04) and shorter duration of symptoms (p =0.02) both independently predicted improved percentage response. The 39 patients that had GPi DBS improved by 67.4% in comparison to 2 patients that had STN DBS improving by 92%. [START_REF] Zhang | Deep brain stimulation in the treatment of tardive dystonia[END_REF] Patients with post-traumatic dystonia, dystonic cerebral palsy or post-encephalitic dystonia respond less well to DBS with only isolated rare exceptions [START_REF] Pretto | A prospective blinded evaluation of deep brain stimulation for the treatment of secondary dystonia and primary torticollis syndromes[END_REF][START_REF] Katsakiori | Deep brain stimulation for secondary dystonia: results in 8 patients[END_REF]. The small number of patients with post anoxic dystonia have a higher mean percentage improvement but the variance in response is higher and is not related to age, duration of symptoms or baseline severity.

Quality of life

The vast majority of studies measure the change in one of the validated dystonia severity scales to gauge outcome following DBS for dystonia. These scales are objective but the resulting scores do not necessarily reflect the patient's subjective perception of changes in their daily life or their quality of life (QoL). For example a minor improvement in neck posture, hardly detectable on the BFM movement subscale, may nevertheless have major importance in wheelchair comfort or in swallowing, and indeed the converse can also apply. An alternative is therefore to measure quality of life which has been incorporated into several of the larger dystonia series. Among 22 patients with primary generalised dystonia, significant improvements in general health, physical function and body pain were identified using the generic short form 36 (SF-36) scale. Mean scores did not deteriorate in any SF-36 domain and measures of cognition and mood were unchanged. [START_REF] Vidailhet | Bilateral, pallidal, deep-brain stimulation in primary generalised dystonia: a prospective 3 year follow-up study[END_REF] In the double blind trial of DBS for 40 patients with segmental or generalised dystonia, there was a significant improvement in the SF-36 physical composite score at 3 months. [START_REF] Mueller | Pallidal deep brain stimulation improves quality of life in segmental and generalized dystonia: results from a prospective, randomized sham-controlled trial[END_REF] Adverse effects of DBS surgery for dystonia Not all published reports specifically document detailed adverse effects resulting from DBS for dystonia therefore no attempt to quantify their overall frequency is made here. There are multiple reports of lead migration and lead fracture [START_REF] Mehrkens | Long-term efficacy and safety of chronic globus pallidus internus stimulation in different types of primary dystonia[END_REF][START_REF] Yianni | Globus pallidus internus deep brain stimulation for dystonic conditions: a prospective audit[END_REF][START_REF] Kupsch | Pallidal deep-brain stimulation in primary generalized or segmental dystonia[END_REF][START_REF] Vidailhet | Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia[END_REF][START_REF] Loher | Deep brain stimulation for dystonia: outcome at long-term follow-up[END_REF][START_REF] Parr | Deep brain stimulation in childhood: an effective treatment for early onset idiopathic generalised dystonia[END_REF][START_REF] Sensi | Pallidal stimulation for segmental dystonia: long term follow up of 11 consecutive patients[END_REF][START_REF] Starr | Microelectrodeguided implantation of deep brain stimulators into the globus pallidus internus for dystonia: techniques, electrode locations, and outcomes[END_REF] and one group have proposed that this complication is more common among dystonia patients than other patients undergoing DBS [START_REF] Yianni | Increased risk of lead fracture and migration in dystonia compared with other movement disorders following deep brain stimulation[END_REF].

Other surgical adverse events do not seem to occur particularly more commonly in dystonia with only occasional reports of haemorrhage [START_REF] Starr | Microelectrodeguided implantation of deep brain stimulators into the globus pallidus internus for dystonia: techniques, electrode locations, and outcomes[END_REF], infection [START_REF] Mehrkens | Long-term efficacy and safety of chronic globus pallidus internus stimulation in different types of primary dystonia[END_REF][START_REF] Kupsch | Pallidal deep-brain stimulation in primary generalized or segmental dystonia[END_REF][START_REF] Novak | Successful bilateral subthalamic nucleus stimulation for segmental dystonia after unilateral pallidotomy[END_REF][START_REF] Vidailhet | Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia[END_REF][START_REF] Alterman | Sixty hertz pallidal deep brain stimulation for primary torsion dystonia[END_REF][START_REF] Cersosimo | Pallidal surgery for the treatment of primary generalized dystonia: long-term follow-up[END_REF][START_REF] Hung | Long-term outcome of bilateral pallidal deep brain stimulation for primary cervical dystonia[END_REF][START_REF] Mikati | Deep brain stimulation as a mode of treatment of early onset pantothenate kinase-associated neurodegeneration[END_REF][START_REF] Bittar | Deep brain stimulation for generalised dystonia and spasmodic torticollis[END_REF][START_REF] Borggraefe | Bilateral pallidal stimulation in children and adolescents with primary generalized dystonia -Report of six patients and literature-based analysis of predictive outcomes variables[END_REF], and misplaced electrodes. [START_REF] Starr | Microelectrodeguided implantation of deep brain stimulators into the globus pallidus internus for dystonia: techniques, electrode locations, and outcomes[END_REF][START_REF] Zh | The Canadian multicentre study of deep brain stimulation for cervical dystonia[END_REF] Adverse effects specifically related to chronic GPi stimulation for dystonia include dysarthria [START_REF] Sensi | Pallidal stimulation for segmental dystonia: long term follow up of 11 consecutive patients[END_REF][START_REF] Hung | Long-term outcome of bilateral pallidal deep brain stimulation for primary cervical dystonia[END_REF][START_REF] Borggraefe | Bilateral pallidal stimulation in children and adolescents with primary generalized dystonia -Report of six patients and literature-based analysis of predictive outcomes variables[END_REF][START_REF] Damier | Bilateral deep brain stimulation of the globus pallidus to treat tardive dyskinesia[END_REF][START_REF] Jeong | Pallidal deep brain stimulation in primary cervical dystonia with phasic type : clinical outcome and postoperative course[END_REF][START_REF] Woehrle | Chronic deep brain stimulation for segmental dystonia[END_REF] and parkinsonism [START_REF] Tisch | Effect of electrode contact location on clinical efficacy of pallidal deep brain stimulation in primary generalised dystonia[END_REF][START_REF] Ostrem | Pallidal deep brain stimulation in patients with cranial-cervical dystonia (Meige syndrome)[END_REF][START_REF] Zauber | Stimulation-induced parkinsonism after posteroventral deep brain stimulation of the globus pallidus internus for craniocervical dystonia[END_REF][START_REF] Berman | Induction of bradykinesia with pallidal deep brain stimulation in patients with cranial-cervical dystonia[END_REF] both of which seem to be reversible but sometimes at the expense of inadequate dystonia relief.

DISCUSSION

This review has drawn together the published data describing the outcomes of DBS for the range of subtypes of dystonia, and presents the overall results of the combined dataset. The most impressive and consistent results are among patients with DYT-1 primary generalised dystonia and patients with tardive dystonia. Because of the fairly recent introduction of DBS for dystonia, there is a lack of long term follow up, although four recent studies have reported on outcome at up to 7.5 and 10 years post DBS implantation [START_REF] Mehrkens | Long-term efficacy and safety of chronic globus pallidus internus stimulation in different types of primary dystonia[END_REF][START_REF] Loher | Deep brain stimulation for dystonia: outcome at long-term follow-up[END_REF][START_REF] Vasques | Factors predicting improvement in primary generalized dystonia treated by pallidal deep brain stimulation[END_REF][START_REF] Cif | Long term follow up of DYT1 dystonia patients treated by Deep Brain Stimulation[END_REF] concluding that DBS can maintain a significant long-term benefit in responding patients.

Inevitably there are potential sources of bias in this type of review. Positive results from surgery are more likely to be reported than negative outcomes, and the vast majority of studies present data from open label assessments that are more likely subject to observer bias. Only two studies included in this review had blinded assessments of their patients (spasmodic torticollis [START_REF] Pretto | A prospective blinded evaluation of deep brain stimulation for the treatment of secondary dystonia and primary torticollis syndromes[END_REF][START_REF] Zh | The Canadian multicentre study of deep brain stimulation for cervical dystonia[END_REF] and secondary dystonia. [START_REF] Pretto | A prospective blinded evaluation of deep brain stimulation for the treatment of secondary dystonia and primary torticollis syndromes[END_REF] Indeed the quantitative outcomes following DBS for dystonia are considerably lower when patients are assessed in a blinded fashion. Despite these potential shortcomings, the data presented here represents the most comprehensive review of dystonia outcomes following DBS to date. DBS has been beneficial to the majority of dystonia patients highlighted in the literature although the percentage improvement rate is very variable.

Primary Generalised Dystonia

This dataset confirms that patients with PGD respond well to pallidal DBS. Patients with DYT1 positive dystonia respond better than those that are DYT1 negative or untested, although all PGD groups respond well overall, but with considerable inter-individual variability. Independent of DYT1 status, surgery performed at a younger age and with lower baseline severity is more likely to lead to a higher percentage improvement in symptoms of dystonia. While this trend is a useful guide, individual patients can confound this general trend for example a PGD patient experiencing only a 20% improvement in BFM despite disease duration of only 5 years, and another patient with an 85% improvement despite disease duration of 21 years. [START_REF] Yianni | Globus pallidus internus deep brain stimulation for dystonic conditions: a prospective audit[END_REF] Analysis of further additional factors that might predict response to DBS was possible in a retrospective review of 40 PGD patients (included in this analysis) operated on in Montpellier, France with 2-8 year follow up. These authors created a multivariate model to evaluate which factors predicted response to DBS in PGD [START_REF] Vasques | Factors predicting improvement in primary generalized dystonia treated by pallidal deep brain stimulation[END_REF], and in addition to their data consistent with that presented here, found that increased anatomical and stimulated volumes of the GPi also predicted better outcomes. Several groups have attempted to look specifically at active electrode position within the GPi and relate this to outcome. Postero-ventral GPi stimulation has been found to provide the greatest overall effect, and has been considered superior for the arm and trunk. [START_REF] Tisch | Effect of electrode contact location on clinical efficacy of pallidal deep brain stimulation in primary generalised dystonia[END_REF] However other series have found no correlation between active contact positions and post operative outcome. [START_REF] Vidailhet | Bilateral, pallidal, deep-brain stimulation in primary generalised dystonia: a prospective 3 year follow-up study[END_REF] The optimal programming parameters vary widely between patients and the interactions between the position of electrode contacts, pulse widths and mode of stimulation make comparisons difficult, although it has to be assumed that the optimal parameters have been chosen through an iterative process for each patient.

Further evaluation of factors predicting outcome following DBS for primary generalised dystonia were also performed as part of a 3 year study [START_REF] Vidailhet | Bilateral, pallidal, deep-brain stimulation in primary generalised dystonia: a prospective 3 year follow-up study[END_REF] that followed up 22 patients (included in this analysis), and demonstrated sustained benefit from the pallidal stimulation (58% mean improvement from baseline).Their patients who had little improvement tended to have severe tonic posturing, whereas the patients with the greatest improvements (>75%) had diffuse phasic hyperkinetic involuntary movements pre-operatively. In addition, most groups have found that those patients with fixed skeletal deformities do less well than those patients caught earlier in their disease progression, although may still improve from their baseline state and therefore benefit from treatment. In addition to fixed skeletal deformities, the development of secondary disability from e.g. cervical myelopathy further limits possible improvements. [START_REF] Krauss | Pallidal deep brain stimulation in patients with cervical dystonia and severe cervical dyskinesias with cervical myelopathy[END_REF]

Spasmodic torticollis

The most common of the adult onset, focal primary dystonias is spasmodic torticollis. The sternocleidomastoid muscles are innervated from both hemispheres with most of their supply coming ipsilaterally therefore bilateral surgery is required even for the most asymmetrical patients. The variance in response however is substantial and does not appear to be explained by age at surgery, duration of symptoms or baseline severity. Even at the same centre a range of improvement between 20 to 83% has been seen [START_REF] Hung | Long-term outcome of bilateral pallidal deep brain stimulation for primary cervical dystonia[END_REF], despite post operative MRI confirming electrode positions and no correlation was found between location of electrode and magnitude of response.

Dystonia severity should not be the only measure of outcome following DBS. Among a single blind series [START_REF] Zh | The Canadian multicentre study of deep brain stimulation for cervical dystonia[END_REF], even patients with less than 30% improvement on motor score all improved in relation to their pain, disability and QoL. This study also investigated outcome predictors such as electrode location, surgical centre, surgical technique or type of dystonia (phasic, tonic or tremulous), but none appeared related. The only patient who deteriorated after DBS had good electrode placement.

Meige

The current analysis confirms the findings of case reports suggesting that GPi DBS is a useful therapy for patients with Meige syndrome (Idiopathic cranial cervical dystonia). [START_REF] Vercueil | Deep brain stimulation in the treatment of severe dystonia[END_REF][START_REF] Houser | Meige syndrome and pallidal deep brain stimulation[END_REF][START_REF] Blomstedt | Pallidal deep brain stimulation in the treatment of Meige syndrome[END_REF] In a series of patients with Meige syndrome that followed 6 patients for 6 months, most patients had meaningful clinical improvements by 4 to 6 weeks post implantation. Overall improvements were seen in blepharospasm, oromandibular dystonia and cervical dystonia. Speech and swallowing both showed a trend towards improvement. [START_REF] Ostrem | Pallidal deep brain stimulation in patients with cranial-cervical dystonia (Meige syndrome)[END_REF]

Myoclonus dystonia

Although the number of published patients with myoclonus dystonia that have had DBS is small, the reports of good outcomes among these patients are consistent with our own experience. Both myoclonic features and dystonia can improve.

Heredodegenerative dystonia

Patients with heredodegenerative dystonia are distinctive from other individuals with dystonia by the co-existence of other neurological deficits e.g. cognitive decline, seizures etc. There is no evidence that non-motor symptoms or the degenerative process itself are improved by DBS.

However, improvement in pain as a result of DBS can allow lower medication doses which can have secondary beneficial effects. [START_REF] Castelnau | Pallidal stimulation improves pantothenate kinase-associated neurodegeneration[END_REF] Among these patients a vital pre-requisite in the decision regarding surgery is the identification of the degree of disability that they suffer purely due to dystonia.

Secondary dystonia

The experience of GPi DBS in secondary dystonia has been limited, varied and less successful than in the idiopathic group. Conceptually it might be considered that patients with normal brain MRI have a reversible electro-physiological or neurochemical cause for their dystonia, whereas patients with abnormalities visible on conventional structural imaging may have an irreversible anatomical cause for their dystonia. The excellent response of patients with tardive dystonia is consistent with this. This concept is of course too simplistic in view of the diverse structural abnormalities in basal ganglia pathways that can all be associated with onset of dystonia added to the fact that the creation of lesions within basal ganglia structures can lead to resolution of dystonia. [START_REF] Eltahawy | Primary dystonia is more responsive than secondary dystonia to pallidal interventions: outcome after pallidotomy or pallidal deep brain stimulation[END_REF]

DBS of targets other than GPi

Thalamus

Thalamic DBS in dystonia, targeting various nuclei of the ventrolateral (VL) motor thalamus (Vim, ventral oral posterior (Vop), ventral oral anterior (Voa)) was tried initially as a treatment for dystonia based on the improvements in a minority of patients seen after thalamotomy. There has been no randomised comparison of GPi DBS versus Thalamic DBS for dystonia but the majority of centres have adopted the GPi target based on consensus experience. Among 12 patients that had thalamic DBS for a mixture of dystonia subtypes, three subsequently went on to have successful responses to GPi DBS because of insufficient benefit with thalamic DBS. [START_REF] Vercueil | Deep brain stimulation in the treatment of severe dystonia[END_REF] Our view is that DBS of the VL thalamus should be restricted to those patients with marked tremor causing greater disability than dystonia, or in those patients with structural abnormality of the GPi (although the expectation of success in this group is lower).

Subthalamic Nucleus

There is some experience of the STN as a target for dystonia patients especially in patients with damage to the GPi. Unilateral STN DBS in a patient with left hemidystonia secondary to a basal ganglia infarct led to improvement by 54.5% at 3 months. [START_REF] Tagliati | Deep brain stimulation for dystonia[END_REF] Improvements in tardive and post traumatic hemidystonia have also been reported following STN DBS while 6 patients with other forms of secondary dystonia had minimal improvements. [START_REF] Zhang | Deep brain stimulation in the treatment of secondary dystonia[END_REF] The STN is still a novel target for DBS in dystonia patients so further studies will be needed to assess efficacy.

Conclusions

DBS has been shown to be a safe effective surgical treatment for medically refractory dystonia with the postero-ventral sensori-motor GPi being the most favoured target site. Patients with primary forms of dystonia, and tardive dystonia respond well, particularly so when the surgery is performed at an earlier stage and among patients with lesser disability. Patients with DYT-1 positive dystonia respond better than DYT-1 negative cases although the DYT-1 negative group remains very heterogeneous. Patients with other forms of heredodegenerative and secondary dystonia have variable responses making prediction of response in future patients difficult.

Differences in methodological approach, surgical technique, programming regimes and clinical presentation make determining outcome predictors in these subgroups even more challenging. A systematic and thorough approach to reporting all patient and technical variables needs to be implemented so that useful conclusions can be reached with accumulating reports. Additionally, emphasis should be put on in depth evaluation of patients´ own perception of their life following DBS by using validated quality of life measures possibly including a qualitative approach.

Discussion with patients and their carers requires an honest explanation of the uncertainty of the usefulness of DBS, in particular for patients with heredodegenerative and secondary dystonia subtypes. There is undoubtedly a placebo response and/or a clinician bias in evaluation following DBS, as evidenced by the excess benefits documented in open label follow up compared with blinded trials. The safety record of the centre should be an important factor which determines how much a potential improvement may justify the small surgical risks, especially as patients with dystonia frequently do not have alternative treatment options.

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Figure 1

 1 Figure 1 Graph to show univariate relationship between duration of symptoms of dystonia and

Figure 2 .

 2 Figure 2. Mean percentage improvement following DBS for primary generalized dystonia

Figure 1

 1 Figure 1.

Figure 2 .

 2 Figure 2.

Table 1 . Published individual outcome data of patients with Primary forms of dystonia (and Myoclonus Dystonia) operated with DBS. IQR-Interquartile range

 1

	Primary	Subtype	Numbers of	Age at surgery	Duration of	Pre-op	Percentage	References
			Individual	Mean	symptoms	Severity score	improvement
			patient data	(SD)	Mean	Mean	in motor/
					(SD)	(SD)	severity score
							following DBS
							Mean (SD)
							IQR
	Generalised	DYT1 positive	91	22.6	13.4	53.8	67.5 (27.7)	[4-7,9, ,25,27,
				(12.4)	(11.7)	(23.1)	53.3-92.3	29,30,34,42,51-
								62]
	Generalised	DYT1 negative 108	31.3	15.4	54.4	55.8 (26.6)	[4-7,9,25,29,
				(16.2)	(11.1)	(23.6)	38.6-79.3	30,34,42,51,52,
								57-65]
	Generalised	Unknown	10	36.9	17.0	57.5	51.9 (25.3)	[6,10,27,53,66]

Table 2 . Published individual outcome data of patients with Heredodegenerative forms of dystonia operated with DBS. IQR-Interquartile range. PKAN-Pantothenate kinase associated neurodegeneration. XDP-X-linked Dystonia parkinsonism. RDP-Rapid onset dystonia parkinsonism Heredo- degenerative Individual patient data Age at surgery

 2

		Duration of	Pre-op Severity	Percentage	References
	Mean	symptoms	score	improvement in
	(SD)	Mean	Mean	motor/ severity
		(SD)	(SD)	score following
				DBS
				Mean (SD)
				IQR

Table 3 . Published individual outcome data of patients with secondary forms of dystonia operated with DBS. IQR-Interquartile range. Secondary subtype Individual patient data Age at surgery Mean (SD) Duration of symptoms Mean (SD) Pre-op Severity score Mean (SD)

 3

	Percentage	References
	improvement in
	motor/ severity
	score following
	DBS
	Mean (SD)
	IQR

Acknowledgement

This work was supported by the Parkinson's Appeal-registered charity 263064