Comment
were identified in 72 individuals (16%, 95% CI 13–19), with a total of 114 aneurysms recorded. The clearest modifiable risk factors for aneurysms at first screening were smoking (multivariable analysis OR 2·7, 95% CI 1·2–5·9), history of aneurysms (3·9, 1·2–12·7), and high familial burden of aneurysms (3·5, 1·6–8·1). Almost 40% of patients who had a known previous aneurysm had further aneurysms on follow-up. The frequency of aneurysms increased with age, although five (8%) of 59 individuals with an aneurysm at first screening (including those retrospectively identified) were younger than 30 years. Most relatives with a close family member who has had aSAH and who find that they have aneurysm are likely to seek treatment. Therefore, it is interesting that only 35 (49%) of the 72 individuals in whom aneurysms were identified sought treatment in Bor and colleagues’ study.4 The aneurysms which were not treated, but were managed conservatively and followed up, were small aneurysms; no aneurysms smaller than 2 mm were treated and they were fewer than half of those of 2–5 mm. Most of these aneurysms were stable in size at follow-up imaging. Rupture of an aneurysm was recorded in three individuals in the cohort: one woman had a de-novo aneurysm that ruptured 3 years after first screening, one woman had aSAH 14 years after first screening, and another woman had aSAH from a preexisting but small aneurysm.4 Information about the total number of observational person-years for this cohort is unavailable, so the risk of aSAH cannot be put into an overall temporal risk context. One of the key questions that this paper does not address is the potential number of aSAH and the associated morbidity and mortality that might have been prevented by the strategy adopted. Future studies from this cohort of relatives might include some estimates of the expected number of aSAH events in the
population screened, compared with the actual number, and further refinement of a cost-effectiveness modeling of the strategy.5 This paper provides very helpful data for those advising families of patients with SAH. The data are unique in their completeness and duration of followup. A randomised study will never be done in this area so, as with many aspects of medicine, only imperfect data will be available. However, the findings of Bor and colleagues4 provide a good guide about how to advise relatives of patients with aSAH. The key message that can be taken from this study is that it is reasonable to offer screening to the relatives of patients in whom two first-degree family members who have had an aSAH, or have been shown to have a cerebral aneurysm, provided proper prescreening counseling is done and relatives fully understand the consequences and effect that the discovery of an aneurysm might have on their life.6 Andrew J Molyneux Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, UK [email protected] I am a paid consultant for Sequent Medical and have received fees for expert medical evidence in cases related to cerebral aneurysms and SAH. 1
2
3 4
5
6
Bor AS, Rinkel GJ, Adami J, et al. Risk of subarachnoid haemorrhage according to number of affected relatives: a population based case-control study. Brain 2008; 131: 2662–65. Okamoto K, Horisawa R, Kawamura T, et al. Family history and risk of subarachnoid hemorrhage: a case-control study in Nagoya, Japan. Stroke 2003; 34: 422–26. Struycken PM, Pals G, Limburg M, at al. Anticipation in familial intracranial aneurysms in consecutive generations. Eur J Hum Genet 2003; 11: 737–43. Bor ASE, Rinkel GJE, van Norden J, Wermer MJH. Long-term, serial screening for intracranial aneurysms in individuals with a family history of aneurysmal subarachnoid haemorrhage: a cohort study. Lancet Neurol 2014; published online March 5. http://dx.doi.org/10.1016/S14744422(14)70021-3. Bor AS, Koffijberg H, Wermer MJ, Rinkel GJ. Optimal screening strategy for familial intracranial aneurysms: a cost-effectiveness analysis. Neurology 2010; 74: 1671–79. Wermer MJ, van der Schaaf IC, Van Nunen P, et al. Psychosocial impact of screening for intracranial aneurysms in relatives with familial subarachnoid hemorrhage. Stroke 2005; 36: 836–40.
Embolic stroke of undetermined source: a therapeutic target? See Personal View page 429
344
After a diagnosis of stroke, one of the main purposes of further investigation is to establish the probable underlying cause or causes and thus tailor treatment to reduce the risk of recurrence. This risk is highest initially (at least 10% in the first few weeks) and reduces to perhaps 5% per year within 12 months. The higher early
risk is mainly in individuals with cardiac embolism or large artery disease, and less in those with lacunar stroke due to cerebral small-vessel disease.1 Early brain imaging identifies intracerebral haemorrhage, for which blood pressure reduction is the main intervention to reduce risk of recurrence. However, for www.thelancet.com/neurology Vol 13 April 2014
most people with ischaemic stroke with or without a visible infarct on brain imaging, additional secondary prevention strategies with antiplatelet drugs and cholesterol reduction with statins should be considered. Blood pressure reduction, antiplatelet drugs, and statins each reduce the relative risk of further stroke by 20–25%.2–4 For individuals with minor ischaemic stroke affecting brain tissue supplied by an internal carotid artery with a moderate (50–69%) or severe (>70%) stenosis at its origin, carotid endarterectomy could reduce the risk of further stroke more than could pharmacological treatment alone.5 However, because pharmacological treatment has improved since earlier surgical trials, the ongoing second European Carotid Surgery Trial is assessing carotid endarterectomy in the context of contemporary best medical care. For patients with a definite cardioembolic source— such as atrial fibrillation, prosthetic valves, severe left ventricular dysfunction, or intracardiac thrombus— secondary prevention with vitamin K antagonists or new oral anticoagulants reduces the relative risk of recurrence by 60–70%.6 In patients without a definite cardioembolic source, results of randomised trials have shown that intensive anticoagulation (target INR 3–4·5) causes an excess of bleeding that offsets any reduction in ischaemic stroke recurrence. Further analyses suggest that the risk of bleeding on anticoagulants is higher in patients with small-vessel disease, which underlies lacunar strokes.7,8 In The Lancet Neurology, the Cryptogenic Stroke/ ESUS International Working Group has proposed that a subgroup of patients with ischaemic stroke—which they have called embolic stroke of undetermined source (ESUS)—could gain more benefit from anticoagulation, and specifically new oral anticoagulants, than from antiplatelet medication.9 Although not based on a systematic review of published work, they provide a persuasive, well argued case that most ischaemic strokes that do not have a definite embolic source (eg, atrial fibrillation, arterial stenosis >50%) and are not due to small-vessel disease—ie, are non-lacunar—are probably an embolic stroke from an undefined source. The point on which many will disagree with their proposal is the name given to this new entity. As acknowledged in Hart and colleagues’ Personal View,9 an unknown proportion of patients with ESUS will not www.thelancet.com/neurology Vol 13 April 2014
Jeremy Catry/Science Photo Library
Comment
have had an embolic stroke, but a stroke due to in-situ thrombosis. Although one can see the advantages of the name for gaining support from funders and clinicians for a trial, and for marketing new oral anticoagulants if they prove effective, the name will mislead clinicians, especially in the future when the arguments made by Hart and colleagues have been forgotten. I do not think that the eligibility criteria for a randomised trial need to be summed up in a diagnostic label. Simply referring to “a non-lacunar ischaemic stroke without a defined cause” would be preferable. The group makes a reasonable argument that anticoagulants might be more effective than are antiplatelet drugs in patients with arterial sources of emboli. It is therefore odd that they would not wish to include patients, even those who do not undergo carotid intervention, who have a greater than 50% stenosis in any cerebral artery. Many patients with >50% stenoses do not undergo vascular procedures because they have had a disabling stroke, or the stenosis is at a site for which no reliable evidence supports vascular intervention. The group has defined the investigations needed to label a patient as having an ESUS. Although the label provides more clarity than does the term cryptogenic stroke, for which there are no agreed criteria, application of the criteria described in the Personal View9 will still result in a diagnostic entity with fuzzy edges. For instance, the authors have not defined how much 345
Comment
ECG monitoring is needed to exclude paroxysmal atrial fibrillation. The options for imaging of the brain include CT or MRI and, for the vessels, carotid duplex plus transcranial doppler, CT, or MR angiography. These options have different diagnostic characteristics, so ESUS defined by one imaging set will differ from those defined by another. Additionally, many patients with a non-lacunar stroke will have evidence of small-vessel disease on brain imaging that might increase their risks of cerebral haemorrhage. Hopefully, planned trials will indicate whether anticoagulants should be recommended for patients with non-lacunar ischaemic stroke without a defined cause, and those with stenoses of cerebral arteries.
1
Martin Dennis
8
Western General Hospital, Department of Clinical Neurosciences, Crewe Rd, Edinburgh EH4 2XU, UK [email protected] I declare that I have no competing interests.
2
3
4
5
6
7
9
Lovett JK, Coull A, Rothwell PM, on behalf of the Oxford Vascular Study. Early risk of recurrent stroke by aetiological subtype: implications for stroke prevention. Neurology 2004; 62: 569–74. Antithrombotic Trialists’ Collaboration. Collaborative metaanalysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 71–86. Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol 2009; 8: 453–63. Rashid P, Leonardi-Bee J, Bath P. Blood pressure reduction and secondary prevention of stroke and other vascular events: a systematic review. Stroke 2003; 34: 2741–48. Rothwell PM, Eliasziw M, Gutnikov SA, et al, for the Carotid Endarterectomy Trialists’ Collaboration. Analysis of pooled data from the randomised controlled trials of endarterectomy for symptomatic carotid stenosis. Lancet 2003; 361: 107–16. Van Walraven C, Hart RG, Singer DE, et al. Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis. JAMA 2002; 288: 2441–48. Algra A, Francke CL, Koehler PJJ, for the Stroke Prevention in Reversible Ischaemia Trial (SPIRIT) group. A randomized trial of anticoagulants versus aspirin after cerebral ischaemia of presumed arterial origin. Ann Neurol 1997; 42: 857–65. Gorter JW, for the Stroke Prevention in Reversible Ischaemia Trial (SPIRIT) and European Atrial Fibrillation Trial (EAFT) groups. Major bleeding during anticoagulation after cerebral ischaemia: patterns and risk factors. Neurology 1999; 53: 1319–27. Hart RG, Diener H-C, Coutts SB, et al, for the Cryptogenic Stroke/ESUS International Working Group. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014; 13: 429–38.
Corrections Published Online February 18, 2014 http://dx.doi.org/10.1016/ S1474-4422(13)70306-5
346
Wenning GK, Krismer F, Poewe W. Rifampicin for multiple system atrophy. Lancet Neurol 2014; 13: 237–38—In this Comment, WP’s declaration of interests should have read “WP has received personal fees from AbbVie, Astra-Zeneca, Teva, Novartis, GlaxoSmithKline, Boehringer-Ingelheim, UCB, Orion, Merck Serono, and Merz Pharmaceuticals (consultancy and lecture fees for Parkinson’s disease clinical drug development programmes)”. This correction has been made to the online version as of Feb 18, 2014.
www.thelancet.com/neurology Vol 13 April 2014
were identified in 72 individuals (16%, 95% CI 13–19), with a total of 114 aneurysms recorded. The clearest modifiable risk factors for aneurysms at first screening were smoking (multivariable analysis OR 2·7, 95% CI 1·2–5·9), history of aneurysms (3·9, 1·2–12·7), and high familial burden of aneurysms (3·5, 1·6–8·1). Almost 40% of patients who had a known previous aneurysm had further aneurysms on follow-up. The frequency of aneurysms increased with age, although five (8%) of 59 individuals with an aneurysm at first screening (including those retrospectively identified) were younger than 30 years. Most relatives with a close family member who has had aSAH and who find that they have aneurysm are likely to seek treatment. Therefore, it is interesting that only 35 (49%) of the 72 individuals in whom aneurysms were identified sought treatment in Bor and colleagues’ study.4 The aneurysms which were not treated, but were managed conservatively and followed up, were small aneurysms; no aneurysms smaller than 2 mm were treated and they were fewer than half of those of 2–5 mm. Most of these aneurysms were stable in size at follow-up imaging. Rupture of an aneurysm was recorded in three individuals in the cohort: one woman had a de-novo aneurysm that ruptured 3 years after first screening, one woman had aSAH 14 years after first screening, and another woman had aSAH from a preexisting but small aneurysm.4 Information about the total number of observational person-years for this cohort is unavailable, so the risk of aSAH cannot be put into an overall temporal risk context. One of the key questions that this paper does not address is the potential number of aSAH and the associated morbidity and mortality that might have been prevented by the strategy adopted. Future studies from this cohort of relatives might include some estimates of the expected number of aSAH events in the
population screened, compared with the actual number, and further refinement of a cost-effectiveness modeling of the strategy.5 This paper provides very helpful data for those advising families of patients with SAH. The data are unique in their completeness and duration of followup. A randomised study will never be done in this area so, as with many aspects of medicine, only imperfect data will be available. However, the findings of Bor and colleagues4 provide a good guide about how to advise relatives of patients with aSAH. The key message that can be taken from this study is that it is reasonable to offer screening to the relatives of patients in whom two first-degree family members who have had an aSAH, or have been shown to have a cerebral aneurysm, provided proper prescreening counseling is done and relatives fully understand the consequences and effect that the discovery of an aneurysm might have on their life.6 Andrew J Molyneux Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, UK [email protected] I am a paid consultant for Sequent Medical and have received fees for expert medical evidence in cases related to cerebral aneurysms and SAH. 1
2
3 4
5
6
Bor AS, Rinkel GJ, Adami J, et al. Risk of subarachnoid haemorrhage according to number of affected relatives: a population based case-control study. Brain 2008; 131: 2662–65. Okamoto K, Horisawa R, Kawamura T, et al. Family history and risk of subarachnoid hemorrhage: a case-control study in Nagoya, Japan. Stroke 2003; 34: 422–26. Struycken PM, Pals G, Limburg M, at al. Anticipation in familial intracranial aneurysms in consecutive generations. Eur J Hum Genet 2003; 11: 737–43. Bor ASE, Rinkel GJE, van Norden J, Wermer MJH. Long-term, serial screening for intracranial aneurysms in individuals with a family history of aneurysmal subarachnoid haemorrhage: a cohort study. Lancet Neurol 2014; published online March 5. http://dx.doi.org/10.1016/S14744422(14)70021-3. Bor AS, Koffijberg H, Wermer MJ, Rinkel GJ. Optimal screening strategy for familial intracranial aneurysms: a cost-effectiveness analysis. Neurology 2010; 74: 1671–79. Wermer MJ, van der Schaaf IC, Van Nunen P, et al. Psychosocial impact of screening for intracranial aneurysms in relatives with familial subarachnoid hemorrhage. Stroke 2005; 36: 836–40.
Embolic stroke of undetermined source: a therapeutic target? See Personal View page 429
344
After a diagnosis of stroke, one of the main purposes of further investigation is to establish the probable underlying cause or causes and thus tailor treatment to reduce the risk of recurrence. This risk is highest initially (at least 10% in the first few weeks) and reduces to perhaps 5% per year within 12 months. The higher early
risk is mainly in individuals with cardiac embolism or large artery disease, and less in those with lacunar stroke due to cerebral small-vessel disease.1 Early brain imaging identifies intracerebral haemorrhage, for which blood pressure reduction is the main intervention to reduce risk of recurrence. However, for www.thelancet.com/neurology Vol 13 April 2014
most people with ischaemic stroke with or without a visible infarct on brain imaging, additional secondary prevention strategies with antiplatelet drugs and cholesterol reduction with statins should be considered. Blood pressure reduction, antiplatelet drugs, and statins each reduce the relative risk of further stroke by 20–25%.2–4 For individuals with minor ischaemic stroke affecting brain tissue supplied by an internal carotid artery with a moderate (50–69%) or severe (>70%) stenosis at its origin, carotid endarterectomy could reduce the risk of further stroke more than could pharmacological treatment alone.5 However, because pharmacological treatment has improved since earlier surgical trials, the ongoing second European Carotid Surgery Trial is assessing carotid endarterectomy in the context of contemporary best medical care. For patients with a definite cardioembolic source— such as atrial fibrillation, prosthetic valves, severe left ventricular dysfunction, or intracardiac thrombus— secondary prevention with vitamin K antagonists or new oral anticoagulants reduces the relative risk of recurrence by 60–70%.6 In patients without a definite cardioembolic source, results of randomised trials have shown that intensive anticoagulation (target INR 3–4·5) causes an excess of bleeding that offsets any reduction in ischaemic stroke recurrence. Further analyses suggest that the risk of bleeding on anticoagulants is higher in patients with small-vessel disease, which underlies lacunar strokes.7,8 In The Lancet Neurology, the Cryptogenic Stroke/ ESUS International Working Group has proposed that a subgroup of patients with ischaemic stroke—which they have called embolic stroke of undetermined source (ESUS)—could gain more benefit from anticoagulation, and specifically new oral anticoagulants, than from antiplatelet medication.9 Although not based on a systematic review of published work, they provide a persuasive, well argued case that most ischaemic strokes that do not have a definite embolic source (eg, atrial fibrillation, arterial stenosis >50%) and are not due to small-vessel disease—ie, are non-lacunar—are probably an embolic stroke from an undefined source. The point on which many will disagree with their proposal is the name given to this new entity. As acknowledged in Hart and colleagues’ Personal View,9 an unknown proportion of patients with ESUS will not www.thelancet.com/neurology Vol 13 April 2014
Jeremy Catry/Science Photo Library
Comment
have had an embolic stroke, but a stroke due to in-situ thrombosis. Although one can see the advantages of the name for gaining support from funders and clinicians for a trial, and for marketing new oral anticoagulants if they prove effective, the name will mislead clinicians, especially in the future when the arguments made by Hart and colleagues have been forgotten. I do not think that the eligibility criteria for a randomised trial need to be summed up in a diagnostic label. Simply referring to “a non-lacunar ischaemic stroke without a defined cause” would be preferable. The group makes a reasonable argument that anticoagulants might be more effective than are antiplatelet drugs in patients with arterial sources of emboli. It is therefore odd that they would not wish to include patients, even those who do not undergo carotid intervention, who have a greater than 50% stenosis in any cerebral artery. Many patients with >50% stenoses do not undergo vascular procedures because they have had a disabling stroke, or the stenosis is at a site for which no reliable evidence supports vascular intervention. The group has defined the investigations needed to label a patient as having an ESUS. Although the label provides more clarity than does the term cryptogenic stroke, for which there are no agreed criteria, application of the criteria described in the Personal View9 will still result in a diagnostic entity with fuzzy edges. For instance, the authors have not defined how much 345
Comment
ECG monitoring is needed to exclude paroxysmal atrial fibrillation. The options for imaging of the brain include CT or MRI and, for the vessels, carotid duplex plus transcranial doppler, CT, or MR angiography. These options have different diagnostic characteristics, so ESUS defined by one imaging set will differ from those defined by another. Additionally, many patients with a non-lacunar stroke will have evidence of small-vessel disease on brain imaging that might increase their risks of cerebral haemorrhage. Hopefully, planned trials will indicate whether anticoagulants should be recommended for patients with non-lacunar ischaemic stroke without a defined cause, and those with stenoses of cerebral arteries.
1
Martin Dennis
8
Western General Hospital, Department of Clinical Neurosciences, Crewe Rd, Edinburgh EH4 2XU, UK [email protected] I declare that I have no competing interests.
2
3
4
5
6
7
9
Lovett JK, Coull A, Rothwell PM, on behalf of the Oxford Vascular Study. Early risk of recurrent stroke by aetiological subtype: implications for stroke prevention. Neurology 2004; 62: 569–74. Antithrombotic Trialists’ Collaboration. Collaborative metaanalysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 71–86. Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol 2009; 8: 453–63. Rashid P, Leonardi-Bee J, Bath P. Blood pressure reduction and secondary prevention of stroke and other vascular events: a systematic review. Stroke 2003; 34: 2741–48. Rothwell PM, Eliasziw M, Gutnikov SA, et al, for the Carotid Endarterectomy Trialists’ Collaboration. Analysis of pooled data from the randomised controlled trials of endarterectomy for symptomatic carotid stenosis. Lancet 2003; 361: 107–16. Van Walraven C, Hart RG, Singer DE, et al. Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis. JAMA 2002; 288: 2441–48. Algra A, Francke CL, Koehler PJJ, for the Stroke Prevention in Reversible Ischaemia Trial (SPIRIT) group. A randomized trial of anticoagulants versus aspirin after cerebral ischaemia of presumed arterial origin. Ann Neurol 1997; 42: 857–65. Gorter JW, for the Stroke Prevention in Reversible Ischaemia Trial (SPIRIT) and European Atrial Fibrillation Trial (EAFT) groups. Major bleeding during anticoagulation after cerebral ischaemia: patterns and risk factors. Neurology 1999; 53: 1319–27. Hart RG, Diener H-C, Coutts SB, et al, for the Cryptogenic Stroke/ESUS International Working Group. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014; 13: 429–38.
Corrections Published Online February 18, 2014 http://dx.doi.org/10.1016/ S1474-4422(13)70306-5
346
Wenning GK, Krismer F, Poewe W. Rifampicin for multiple system atrophy. Lancet Neurol 2014; 13: 237–38—In this Comment, WP’s declaration of interests should have read “WP has received personal fees from AbbVie, Astra-Zeneca, Teva, Novartis, GlaxoSmithKline, Boehringer-Ingelheim, UCB, Orion, Merck Serono, and Merz Pharmaceuticals (consultancy and lecture fees for Parkinson’s disease clinical drug development programmes)”. This correction has been made to the online version as of Feb 18, 2014.
www.thelancet.com/neurology Vol 13 April 2014
![[Does atrial fibrillation cause cryptogenic stroke? - Embolic Stroke of Undetermined Source (ESUS) first requires interdisciplinary diagnostic investigation].](/assets/img/hold.png)
