NEWS & VIEWS STROKE
The worldwide burden of stroke—a blurred photograph Blanca Fuentes and Exuperio Díez Tejedor
Assessing the burden of stroke is essential to improve stroke care. Two recent systematic reviews provide a picture of the worldwide stroke burden. However, poor-quality data sources in low-income and middle-income countries make this a blurred photograph, and set a challenge to expand stroke registries. Fuentes, B. & Tejedor, E. D. Nat. Rev. Neurol. 10, 127–128 (2014); published online 11 February 2014; corrected online 25 March 2014; doi:10.1038/nrneurol.2014.17
countries, as well as the limited quality of the patient registries. Two accompanying editorials in The Lancet and The Lancet Global Health have highlighted the worldwide coverage as one of the major strength of these studies. 3,4 Data from registries in 21 high-income, middle-income and low-income regions were included in both systematic reviews. However, this strength is also the Achilles heel of both these studies, as data sources from low-income and medium-income countries are limited and of questionable quality, as acknowledged by the authors of both the systematic reviews and the editorials. Surprisingly, data from the 191 low-income and middle-income countries included in the analysis was based on 61 articles, only 14 (23%) of which were rated as high-quality studies according to guidelines in the STROBE statement for assessing the quality of observational studies.5,6 Moreover, the majority (88.3%) of the studies selected for analysis in these two systematic reviews were carried out in 1990–2004, and only 14 were carried out in 2005–2010 (11.7%). Data for 2010, therefore, seem to be based on less than 12% of the total included studies. The small and nonsignificant increase in the prevalence of stroke in low-income and middle-income countries could also be explained by the limitations of the quality of the stroke registries, as has been previously suggested.3 The increases in the incidence of stroke and stroke-related mortality in these countries over the past two decades could be due to so-called epidemiological transition, caused by an increase in the incidence of vascular risk factors. Other possibilities that have so far been ignored, however, are increasing recognition of stroke symptoms
NATURE REVIEWS | NEUROLOGY
in these countries, and the possible development of improved registries that, on the surface, might contribute to the increased incidence of stroke. The incidence of stroke in low-income and middle-income countries is still underestimated, possibly owing to the competition with other diseases with a higher burden of disease than stroke, such as infectious diseases.7 Moreover, stroke is classifixed among noncommunicable diseases by the WHO. This classification is another potential reason for the underestimation of stroke incidence: it is not feasible to obtain data on the incidence of stroke or stroke-related mortality from official registries, as they do not provide enough data on noncommunicable diseases. The development of improved stroke registries should become a priority for future actions of the World Stroke Organization. The data from both of the new studies1,2 are of great importance in terms of setting a challenge to improve stroke registries in low-income and middle-income countries. Previous studies such as the WHO MONICA Project show that multinational comparisons of stroke incidence present considerable problems, the most important
Thinkstock
Two recently published systematic reviews have raised great interest in the global burden of stroke, which has increased over the past two decades. The first article focuses on the global and regional burdens of stroke, the main findings of which are increases in the absolute numbers of people with stroke and stroke-related deaths, as well as an increase in the global burden of stroke in terms of disability-adjusted life years (DALYs) in middle-income and low-income countries.1 The second study, which addresses the global and regional burden of first-ever ischaemic or haemorrhagic stroke, shows the burden of both of these types of stroke has increased in the past two decades in terms of the absolute number of people with stroke, stroke-related deaths, and DALYs, despite a decrease in age-s tandardized mortality. 2 Compared with ischaemic stroke, haemorrhagic stroke has a lower incidence, is responsible for a higher burden of disease, and is the cause of more stroke-related deaths and DALYs in middle-income and low-income countries.2 The good news from these studies is a decrease in age-standardized mortality over the past two decades in high-income countries, which could reflect an improvement in acute stroke management.1,2 The decrease in age-standardized incidence of stroke, also in high-income countries, probably relates to the success of preventative health-care policies. The reduction in agestandardized mortality over the past 20 years is less in low-income and middle-income countries than in high-income countries. This small reduction is probably due to the greater heterogeneity in reporting and case ascertainment among low-income to middleincome countries than among high-income
VOLUME 10 | MARCH 2014 | 127 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS being incomplete case ascertainment.8 To facilitate the standardization of the datacollection process and improve the quality of stroke registers, the WHO, in collaboration with the World Stroke Organization, developed a manual of basic methods to establish a stepwise approach to set up stroke registries (STEPS Stroke) that has become a useful tool in low-income and middle-income countries.9 Moreover, it has been suggested that the involvement of national stroke associations in collaboration with the World Stroke Organization or regional institutions is crucial to ensuring the quality of stroke registers in low-income and middle-income countries. 9 In this context, we would like to highlight the Safe Implementation of Treatments in Stroke from the Iberoamerican Cerebrovascular Diseases Society as an example of a noninterventional monitored register for patients with acute stroke. This register was developed in the Iberoamerican region—in collaboration with the Karolinska Institute, Stockholm, Sweden—and could improve the knowledge of stroke burden in this g eographical area.10 In conclusion, these two systematic reviews are welcome as they report for the first time the global burden of stroke in terms of incidence, prevalence, mortality, DALYs lost, and age-stratified mortality to stroke incidence ratios. The global and regional data coverage shows differences in stroke burden between high-income and low-income or middle-income countries. Moreover, the studies report for the first time the differences in the global burden of two types of stroke—ischaemic and haemor rhagic. It is clear, however, that clinicians and researchers should make an effort to improve the quality of stroke registries, particularly in low-income and middle-income countries. Such an effort could ensure a clearer picture of the worldwide stroke burden, and could also aid promotion of acute care and stroke prevention measures in these countries. Department of Neurology and Stroke Centre, La Paz University Hospital, IdiPAZ Health Research Institute, Autonomous University of Madrid, Paseo de la Castellana 261, 28046 Madrid, Spain (B.F., E.D.T.). Correspondence to: E.D.T. [email protected] Competing interests The authors declare no competing interests. 1.
2.
Feigin, V. L. et al. Global and regional burden of stroke during 1990–2010: findings from the Global Burden of Disease Study 2010. Lancet 383, 245–255 (2014). Krishnamurthi, R. V. et al. Global and regional burden of first-ever ischaemic and
128 | MARCH 2014 | VOLUME 10
3.
4.
5.
6.
7.
haemorrhagic stroke during 1990–2010: findings from the Global Burden of Disease Study 2010. Lancet Glob. Heal. 1, e259–e281 (2013). Hankey, G. J. The global and regional burden of stroke. Lancet Glob. Heal. 1, e239–e240 (2013). Giroud, M., Jacquin, A. & Béjot, Y. The worldwide landscape of stroke in the 21st century. Lancet 383 195–197 (2013). Von Elm, E. et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting of observational studies. Internist (Berl.) 49, 688–693 (2008). Global Burden of Disease Expert Group & Bennett, D. A. Methodology of the global and regional burden of stroke study. Neuroepidemiology 38, 30–40 (2012). The global burden of disease 2004 update. World Health Organization [online], http://
www.who.int/healthinfo/global_burden_ disease/GBD_report_2004update_full.pdf (2004). 8. Asplund, K. et al. Multinational comparisons of stroke epidemiology. Evaluation of case ascertainment in the WHO MONICA Stroke Study. World Health Organization monitoring trends and determinants in cardiovascular disease. Stroke 26, 355–360 (1995). 9. Truelsen, T. et al. Standard method for developing stroke registers in low-income and middle-income countries: experiences from a feasibility study of a stepwise approach to stroke surveillance (STEPS Stroke). Lancet Neurol. 6, 134–139 (2007). 10. SIECV SITS Iberoamerican Stroke register to be implemented in 2009. Safe Implementation of Treatments in Stroke [online], https:// sitsinternational.org/news/siecv-sitsiberoamerican-stroke-register-to-beimplemented-in-2009 (2009).
PARKINSON DISEASE
Intestinal levodopa infusion in PD —the first randomized trial Regina Katzenschlager and Werner Poewe
The first randomized, placebo-controlled trial of intrajejunal levodopa provides support for the benefits of continuous dopaminergic drug delivery. Motor fluctuations in patients with advanced Parkinson disease were markedly improved. In clinical practice, the symptomatic benefits of this treatment need to be weighed carefully against its adverse effect profile. Katzenschlager, R. & Poewe, W. Nat. Rev. Neurol. 10, 128–129 (2014); published online 18 February 2014; doi:1038/nrneurol.2014.26
Dopaminergic replacement therapies significantly improve motor function in most patients with Parkinson disease (PD); however, long-term levodopa therapy is frequently associated with troublesome motor fluctuations and drug-induced involuntary movements (dyskinesias). Results from the first placebo-controlled study assessing the benefits of continuous levodopa delivery support previous evidence for continuous delivery of dopaminergic drugs in PD:1 the daily ‘off ’-time in the continuous delivery group was almost 2 h shorter than in the immediate-release group. Although our understanding of the mechanisms that underlie the motor complications in PD remains incomplete, discontinuous drug delivery is thought to be involved. Under normal physiological conditions, striatal dopamine release is relatively stable. Pharmacotherapy with short-half-life drugs, such as levodopa, is associated with oscillating plasma levels of the drug and subsequent fluctuations in synaptic dopamine concentrations. Over time, this variability is
believed to induce maladaptive changes in basal ganglia motor circuits.2,3 Amelioration of motor response oscillations and, to some extent, dyskinesias in patients receiving continuous subcutaneous infusions of the dopamine agonist apomorphine or intra intestinal infusions of a gel formulation of levodopa has been repeatedly observed in uncontrolled, open-label case series. The trial by Olanow and colleagues, published recently in The Lancet Neurology,1 is the first ever randomized, placebocontrolled study comparing continuous pump delivery and oral immediate-release dopaminergic pharmacotherapy. In this 12-week multicentre study, all 71 patients underwent initial gastrostomy and were randomly assigned to either intrajejunal or oral immediate-release levodopa, receiving the alternative drug as a dummy, with all dose changes performed in both modalities during the titration phase.1 The mean baseline duration of daily ‘off ’ time was typical for patients enrolled into studies of advanced PD. The degree of improvement with www.nature.com/nrneurol
© 2014 Macmillan Publishers Limited. All rights reserved
ADDENDUM The worldwide burden of stroke—a blurred photograph Blanca Fuentes and Exuperio Díez Tejedor Nat. Rev. Neurol. 10, 127–128 (2014); doi:10.1038/nrneurol.2014.17 The correspondence details for this article have changed: the authors wish to update the email address to [email protected]. The details have been amended in the HTML and PDF versions of the article.
NATURE REVIEWS | NEUROLOGY
VOLUME 10 | MARCH 2014 © 2014 Macmillan Publishers Limited. All rights reserved
The worldwide burden of stroke—a blurred photograph Blanca Fuentes and Exuperio Díez Tejedor
Assessing the burden of stroke is essential to improve stroke care. Two recent systematic reviews provide a picture of the worldwide stroke burden. However, poor-quality data sources in low-income and middle-income countries make this a blurred photograph, and set a challenge to expand stroke registries. Fuentes, B. & Tejedor, E. D. Nat. Rev. Neurol. 10, 127–128 (2014); published online 11 February 2014; corrected online 25 March 2014; doi:10.1038/nrneurol.2014.17
countries, as well as the limited quality of the patient registries. Two accompanying editorials in The Lancet and The Lancet Global Health have highlighted the worldwide coverage as one of the major strength of these studies. 3,4 Data from registries in 21 high-income, middle-income and low-income regions were included in both systematic reviews. However, this strength is also the Achilles heel of both these studies, as data sources from low-income and medium-income countries are limited and of questionable quality, as acknowledged by the authors of both the systematic reviews and the editorials. Surprisingly, data from the 191 low-income and middle-income countries included in the analysis was based on 61 articles, only 14 (23%) of which were rated as high-quality studies according to guidelines in the STROBE statement for assessing the quality of observational studies.5,6 Moreover, the majority (88.3%) of the studies selected for analysis in these two systematic reviews were carried out in 1990–2004, and only 14 were carried out in 2005–2010 (11.7%). Data for 2010, therefore, seem to be based on less than 12% of the total included studies. The small and nonsignificant increase in the prevalence of stroke in low-income and middle-income countries could also be explained by the limitations of the quality of the stroke registries, as has been previously suggested.3 The increases in the incidence of stroke and stroke-related mortality in these countries over the past two decades could be due to so-called epidemiological transition, caused by an increase in the incidence of vascular risk factors. Other possibilities that have so far been ignored, however, are increasing recognition of stroke symptoms
NATURE REVIEWS | NEUROLOGY
in these countries, and the possible development of improved registries that, on the surface, might contribute to the increased incidence of stroke. The incidence of stroke in low-income and middle-income countries is still underestimated, possibly owing to the competition with other diseases with a higher burden of disease than stroke, such as infectious diseases.7 Moreover, stroke is classifixed among noncommunicable diseases by the WHO. This classification is another potential reason for the underestimation of stroke incidence: it is not feasible to obtain data on the incidence of stroke or stroke-related mortality from official registries, as they do not provide enough data on noncommunicable diseases. The development of improved stroke registries should become a priority for future actions of the World Stroke Organization. The data from both of the new studies1,2 are of great importance in terms of setting a challenge to improve stroke registries in low-income and middle-income countries. Previous studies such as the WHO MONICA Project show that multinational comparisons of stroke incidence present considerable problems, the most important
Thinkstock
Two recently published systematic reviews have raised great interest in the global burden of stroke, which has increased over the past two decades. The first article focuses on the global and regional burdens of stroke, the main findings of which are increases in the absolute numbers of people with stroke and stroke-related deaths, as well as an increase in the global burden of stroke in terms of disability-adjusted life years (DALYs) in middle-income and low-income countries.1 The second study, which addresses the global and regional burden of first-ever ischaemic or haemorrhagic stroke, shows the burden of both of these types of stroke has increased in the past two decades in terms of the absolute number of people with stroke, stroke-related deaths, and DALYs, despite a decrease in age-s tandardized mortality. 2 Compared with ischaemic stroke, haemorrhagic stroke has a lower incidence, is responsible for a higher burden of disease, and is the cause of more stroke-related deaths and DALYs in middle-income and low-income countries.2 The good news from these studies is a decrease in age-standardized mortality over the past two decades in high-income countries, which could reflect an improvement in acute stroke management.1,2 The decrease in age-standardized incidence of stroke, also in high-income countries, probably relates to the success of preventative health-care policies. The reduction in agestandardized mortality over the past 20 years is less in low-income and middle-income countries than in high-income countries. This small reduction is probably due to the greater heterogeneity in reporting and case ascertainment among low-income to middleincome countries than among high-income
VOLUME 10 | MARCH 2014 | 127 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS being incomplete case ascertainment.8 To facilitate the standardization of the datacollection process and improve the quality of stroke registers, the WHO, in collaboration with the World Stroke Organization, developed a manual of basic methods to establish a stepwise approach to set up stroke registries (STEPS Stroke) that has become a useful tool in low-income and middle-income countries.9 Moreover, it has been suggested that the involvement of national stroke associations in collaboration with the World Stroke Organization or regional institutions is crucial to ensuring the quality of stroke registers in low-income and middle-income countries. 9 In this context, we would like to highlight the Safe Implementation of Treatments in Stroke from the Iberoamerican Cerebrovascular Diseases Society as an example of a noninterventional monitored register for patients with acute stroke. This register was developed in the Iberoamerican region—in collaboration with the Karolinska Institute, Stockholm, Sweden—and could improve the knowledge of stroke burden in this g eographical area.10 In conclusion, these two systematic reviews are welcome as they report for the first time the global burden of stroke in terms of incidence, prevalence, mortality, DALYs lost, and age-stratified mortality to stroke incidence ratios. The global and regional data coverage shows differences in stroke burden between high-income and low-income or middle-income countries. Moreover, the studies report for the first time the differences in the global burden of two types of stroke—ischaemic and haemor rhagic. It is clear, however, that clinicians and researchers should make an effort to improve the quality of stroke registries, particularly in low-income and middle-income countries. Such an effort could ensure a clearer picture of the worldwide stroke burden, and could also aid promotion of acute care and stroke prevention measures in these countries. Department of Neurology and Stroke Centre, La Paz University Hospital, IdiPAZ Health Research Institute, Autonomous University of Madrid, Paseo de la Castellana 261, 28046 Madrid, Spain (B.F., E.D.T.). Correspondence to: E.D.T. [email protected] Competing interests The authors declare no competing interests. 1.
2.
Feigin, V. L. et al. Global and regional burden of stroke during 1990–2010: findings from the Global Burden of Disease Study 2010. Lancet 383, 245–255 (2014). Krishnamurthi, R. V. et al. Global and regional burden of first-ever ischaemic and
128 | MARCH 2014 | VOLUME 10
3.
4.
5.
6.
7.
haemorrhagic stroke during 1990–2010: findings from the Global Burden of Disease Study 2010. Lancet Glob. Heal. 1, e259–e281 (2013). Hankey, G. J. The global and regional burden of stroke. Lancet Glob. Heal. 1, e239–e240 (2013). Giroud, M., Jacquin, A. & Béjot, Y. The worldwide landscape of stroke in the 21st century. Lancet 383 195–197 (2013). Von Elm, E. et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting of observational studies. Internist (Berl.) 49, 688–693 (2008). Global Burden of Disease Expert Group & Bennett, D. A. Methodology of the global and regional burden of stroke study. Neuroepidemiology 38, 30–40 (2012). The global burden of disease 2004 update. World Health Organization [online], http://
www.who.int/healthinfo/global_burden_ disease/GBD_report_2004update_full.pdf (2004). 8. Asplund, K. et al. Multinational comparisons of stroke epidemiology. Evaluation of case ascertainment in the WHO MONICA Stroke Study. World Health Organization monitoring trends and determinants in cardiovascular disease. Stroke 26, 355–360 (1995). 9. Truelsen, T. et al. Standard method for developing stroke registers in low-income and middle-income countries: experiences from a feasibility study of a stepwise approach to stroke surveillance (STEPS Stroke). Lancet Neurol. 6, 134–139 (2007). 10. SIECV SITS Iberoamerican Stroke register to be implemented in 2009. Safe Implementation of Treatments in Stroke [online], https:// sitsinternational.org/news/siecv-sitsiberoamerican-stroke-register-to-beimplemented-in-2009 (2009).
PARKINSON DISEASE
Intestinal levodopa infusion in PD —the first randomized trial Regina Katzenschlager and Werner Poewe
The first randomized, placebo-controlled trial of intrajejunal levodopa provides support for the benefits of continuous dopaminergic drug delivery. Motor fluctuations in patients with advanced Parkinson disease were markedly improved. In clinical practice, the symptomatic benefits of this treatment need to be weighed carefully against its adverse effect profile. Katzenschlager, R. & Poewe, W. Nat. Rev. Neurol. 10, 128–129 (2014); published online 18 February 2014; doi:1038/nrneurol.2014.26
Dopaminergic replacement therapies significantly improve motor function in most patients with Parkinson disease (PD); however, long-term levodopa therapy is frequently associated with troublesome motor fluctuations and drug-induced involuntary movements (dyskinesias). Results from the first placebo-controlled study assessing the benefits of continuous levodopa delivery support previous evidence for continuous delivery of dopaminergic drugs in PD:1 the daily ‘off ’-time in the continuous delivery group was almost 2 h shorter than in the immediate-release group. Although our understanding of the mechanisms that underlie the motor complications in PD remains incomplete, discontinuous drug delivery is thought to be involved. Under normal physiological conditions, striatal dopamine release is relatively stable. Pharmacotherapy with short-half-life drugs, such as levodopa, is associated with oscillating plasma levels of the drug and subsequent fluctuations in synaptic dopamine concentrations. Over time, this variability is
believed to induce maladaptive changes in basal ganglia motor circuits.2,3 Amelioration of motor response oscillations and, to some extent, dyskinesias in patients receiving continuous subcutaneous infusions of the dopamine agonist apomorphine or intra intestinal infusions of a gel formulation of levodopa has been repeatedly observed in uncontrolled, open-label case series. The trial by Olanow and colleagues, published recently in The Lancet Neurology,1 is the first ever randomized, placebocontrolled study comparing continuous pump delivery and oral immediate-release dopaminergic pharmacotherapy. In this 12-week multicentre study, all 71 patients underwent initial gastrostomy and were randomly assigned to either intrajejunal or oral immediate-release levodopa, receiving the alternative drug as a dummy, with all dose changes performed in both modalities during the titration phase.1 The mean baseline duration of daily ‘off ’ time was typical for patients enrolled into studies of advanced PD. The degree of improvement with www.nature.com/nrneurol
© 2014 Macmillan Publishers Limited. All rights reserved
ADDENDUM The worldwide burden of stroke—a blurred photograph Blanca Fuentes and Exuperio Díez Tejedor Nat. Rev. Neurol. 10, 127–128 (2014); doi:10.1038/nrneurol.2014.17 The correspondence details for this article have changed: the authors wish to update the email address to [email protected]. The details have been amended in the HTML and PDF versions of the article.
NATURE REVIEWS | NEUROLOGY
VOLUME 10 | MARCH 2014 © 2014 Macmillan Publishers Limited. All rights reserved
