EDITORIAL
Rating total cerebral small-vessel disease Does it add up?
Glen C. Jickling, MD Christopher Chen, MD
Correspondence to Dr. Jickling: [email protected] Neurology® 2014;83:1224–1225
Cerebral small-vessel disease (SVD) causes ischemic stroke, cognitive impairment, and gait dysfunction.1 Although very prevalent, early detection presents a challenge, and severity is often underestimated because of insidious onset. Lacunar infarction, age-related white matter hyperintensities (WMH), perivascular spaces (PVS), and microhemorrhages all serve as MRI markers of cerebral SVD. A combined assessment of total cerebral SVD may improve our understanding of the epidemiology, pathogenesis, and genetics and ultimately develop novel therapies to reduce its clinical consequences. In this issue of Neurology®, Staals et al.2 evaluate a 4-point composite SVD scale to measure the overall burden of cerebral SVD. One point was assigned for each MRI marker of SVD (lacunar infarct, WMH, PVS, and microhemorrhages). Each measure was determined using previously defined rating criteria dichotomized as present or absent. In 461 patients with ischemic stroke, a higher SVD score was associated with lacunar stroke subtype (odds ratio [OR] 2.45), hypertension (OR 1.50), smoking (2.81), male sex (OR 1.58), and age (1.10). The authors suggest that the scale is useful to comprehensively assess cerebral SVD. An assessment of total SVD has several potential advantages over individual measures. It provides a more complete assessment of the total burden of SVD, which may be important to understand the impact of SVD on clinical outcomes such as disability and cognition. For example, in CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a genetic disorder of cerebral small vessels, multiple MRI features of cerebral SVD are present including WMH and lacunar infarction that together are used in the diagnosis and evaluation of disease severity.3 Likewise, in patients with a mutation in the COL4A1 gene, several features of cerebral SVD are present including WMH, microhemorrhages, PVS, and lacunar infarction.4 Having a tool to comprehensively summarize total cerebral SVD advances the assessment of disease severity and is likely to improve interrater reliability among investigators of SVD.
The proposed scale provides a practical framework to gauge total cerebral SVD. Several questions raised by the proposed scale will require further study. Consensus among cerebral SVD investigators is required to determine how to best assess each SVD measure.5 The study by Staals et al. dichotomized established rating systems for each measure. Whether increasing the detail at which each SVD feature is measured would improve the scale remains unclear. Certainly, a simple scale improves interrater reliability. However, scale complexity may depend on the intended use. In WMH, simple rating scales are better at separating cognitive subgroups whereas more complex scales correlate better with cognitive measures.6 Volumetric assessment of WMH may offer advantages over the visual scoring used in the study by Staals et al. Automated methods to calculate WMH volume are being developed that may make volumetric assessment of WMH feasible.7 The definition of lacunar stroke also requires consensus. In the report, a distinction between lacunar stroke and lacunes is made based on clinical symptoms. Small deep infarcts often labeled as lacunar may also arise from arterial disease of the parent vessel or from distal embolus, and thus do not represent lipohyalinosis or microatheroma of the small penetrating vessels. Improving the methods to distinguish different causes of small deep infarcts will better define SVD and enhance the study of cerebral SVD.8 The proposed SVD scale may have utility as a composite endpoint in clinical trials of cerebral SVD. Composite endpoints are frequently used in trials as the primary outcome measure to increase statistical precision and efficiency.9 In SVD treatment trials, the total SVD scale may be an attractive primary outcome but could introduce problems that warrant consideration. Use of the total SVD scale as an endpoint assumes that the therapy under evaluation has a similar effect on each SVD measure. However, this assumption is not always correct. For example, in a trial comparing losartan with atenolol, the significance of the composite endpoint was reduced because myocardial infarction was increased despite a reduction of stroke.10 This
See page 1228 From the Department of Neurology and the MIND Institute (G.C.J.), University of California at Davis, Sacramento, CA; and Department of Pharmacology (C.C.), National University of Singapore. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. 1224
© 2014 American Academy of Neurology
highlights that therapies targeting cerebral SVD may have different effects on lacunar stroke, WMH, PVS, or microhemorrhages. It will also be important to consider whether each measure of SVD included in the proposed scale carries the same importance to patients. Preventing a lacunar stroke causing weakness may have greater meaning than preventing a microhemorrhage or PVS enlargement. Hence, future studies should investigate whether differential weighting of each MRI feature is needed to optimally predict outcomes of clinical importance. An integrated method to quantify cerebral SVD is of great interest and holds promise for assessing the burden of SVD. The proposed scale provides an excellent framework to assess total cerebral SVD. Whether modifying aspects of the rating system might improve the assessment of SVD burden will require further study. The proposed SVD scale, or modifications, will need to be evaluated in larger cohorts of patients to better determine its construct validity. Of interest will be the relationship between total SVD score and clinical measures such as cognitive impairment and disability in the variety of conditions in which SVD affects patients. It also will be important to evaluate the role of the total SVD score as a composite endpoint in clinical trials targeting cerebral SVD. As the scale is refined, the hope is that a comprehensive evaluation of cerebral SVD will improve our understanding and treatment of SVD, and ultimately improve brain health. STUDY FUNDING No targeted funding reported.
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
REFERENCES 1. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 2010;9:689–701. 2. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. Neurology 2014;83:1228–1234. 3. Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser MG. CADASIL. Lancet Neurol 2009;8:643–653. 4. Lanfranconi S, Markus HS. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Stroke 2010;41:e513–e518. 5. Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 2013;12:822–838. 6. Gao FQ, Swartz RH, Scheltens P, et al. Complexity of MRI white matter hyperintensity assessments in relation to cognition in aging and dementia from the Sunnybrook Dementia Study. J Alzheimers Dis 2011;26(suppl 3):379–388. 7. van der Lijn F, Verhaaren BF, Ikram MA, et al. Automated measurement of local white matter lesion volume. Neuroimage 2012;59:3901–3908. 8. Jickling GC, Stamova B, Ander BP, et al. Profiles of lacunar and nonlacunar stroke. Ann Neurol 2011;70:477–485. 9. Freemantle N, Calvert M, Wood J, Eastaugh J, Griffin C. Composite outcomes in randomized trials: greater precision but with greater uncertainty? JAMA 2003;289:2554–2559. 10. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint Reduction in Hypertension Study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995–1003.
Neurology 83
September 30, 2014
1225
Rating total cerebral small-vessel disease: Does it add up? Glen C. Jickling and Christopher Chen Neurology 2014;83;1224-1225 Published Online before print August 27, 2014 DOI 10.1212/WNL.0000000000000843 This information is current as of August 27, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/83/14/1224.full.html
References
This article cites 10 articles, 2 of which you can access for free at: http://www.neurology.org/content/83/14/1224.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): Infarction http://www.neurology.org//cgi/collection/infarction MRI http://www.neurology.org//cgi/collection/mri
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Rating total cerebral small-vessel disease Does it add up?
Glen C. Jickling, MD Christopher Chen, MD
Correspondence to Dr. Jickling: [email protected] Neurology® 2014;83:1224–1225
Cerebral small-vessel disease (SVD) causes ischemic stroke, cognitive impairment, and gait dysfunction.1 Although very prevalent, early detection presents a challenge, and severity is often underestimated because of insidious onset. Lacunar infarction, age-related white matter hyperintensities (WMH), perivascular spaces (PVS), and microhemorrhages all serve as MRI markers of cerebral SVD. A combined assessment of total cerebral SVD may improve our understanding of the epidemiology, pathogenesis, and genetics and ultimately develop novel therapies to reduce its clinical consequences. In this issue of Neurology®, Staals et al.2 evaluate a 4-point composite SVD scale to measure the overall burden of cerebral SVD. One point was assigned for each MRI marker of SVD (lacunar infarct, WMH, PVS, and microhemorrhages). Each measure was determined using previously defined rating criteria dichotomized as present or absent. In 461 patients with ischemic stroke, a higher SVD score was associated with lacunar stroke subtype (odds ratio [OR] 2.45), hypertension (OR 1.50), smoking (2.81), male sex (OR 1.58), and age (1.10). The authors suggest that the scale is useful to comprehensively assess cerebral SVD. An assessment of total SVD has several potential advantages over individual measures. It provides a more complete assessment of the total burden of SVD, which may be important to understand the impact of SVD on clinical outcomes such as disability and cognition. For example, in CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a genetic disorder of cerebral small vessels, multiple MRI features of cerebral SVD are present including WMH and lacunar infarction that together are used in the diagnosis and evaluation of disease severity.3 Likewise, in patients with a mutation in the COL4A1 gene, several features of cerebral SVD are present including WMH, microhemorrhages, PVS, and lacunar infarction.4 Having a tool to comprehensively summarize total cerebral SVD advances the assessment of disease severity and is likely to improve interrater reliability among investigators of SVD.
The proposed scale provides a practical framework to gauge total cerebral SVD. Several questions raised by the proposed scale will require further study. Consensus among cerebral SVD investigators is required to determine how to best assess each SVD measure.5 The study by Staals et al. dichotomized established rating systems for each measure. Whether increasing the detail at which each SVD feature is measured would improve the scale remains unclear. Certainly, a simple scale improves interrater reliability. However, scale complexity may depend on the intended use. In WMH, simple rating scales are better at separating cognitive subgroups whereas more complex scales correlate better with cognitive measures.6 Volumetric assessment of WMH may offer advantages over the visual scoring used in the study by Staals et al. Automated methods to calculate WMH volume are being developed that may make volumetric assessment of WMH feasible.7 The definition of lacunar stroke also requires consensus. In the report, a distinction between lacunar stroke and lacunes is made based on clinical symptoms. Small deep infarcts often labeled as lacunar may also arise from arterial disease of the parent vessel or from distal embolus, and thus do not represent lipohyalinosis or microatheroma of the small penetrating vessels. Improving the methods to distinguish different causes of small deep infarcts will better define SVD and enhance the study of cerebral SVD.8 The proposed SVD scale may have utility as a composite endpoint in clinical trials of cerebral SVD. Composite endpoints are frequently used in trials as the primary outcome measure to increase statistical precision and efficiency.9 In SVD treatment trials, the total SVD scale may be an attractive primary outcome but could introduce problems that warrant consideration. Use of the total SVD scale as an endpoint assumes that the therapy under evaluation has a similar effect on each SVD measure. However, this assumption is not always correct. For example, in a trial comparing losartan with atenolol, the significance of the composite endpoint was reduced because myocardial infarction was increased despite a reduction of stroke.10 This
See page 1228 From the Department of Neurology and the MIND Institute (G.C.J.), University of California at Davis, Sacramento, CA; and Department of Pharmacology (C.C.), National University of Singapore. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. 1224
© 2014 American Academy of Neurology
highlights that therapies targeting cerebral SVD may have different effects on lacunar stroke, WMH, PVS, or microhemorrhages. It will also be important to consider whether each measure of SVD included in the proposed scale carries the same importance to patients. Preventing a lacunar stroke causing weakness may have greater meaning than preventing a microhemorrhage or PVS enlargement. Hence, future studies should investigate whether differential weighting of each MRI feature is needed to optimally predict outcomes of clinical importance. An integrated method to quantify cerebral SVD is of great interest and holds promise for assessing the burden of SVD. The proposed scale provides an excellent framework to assess total cerebral SVD. Whether modifying aspects of the rating system might improve the assessment of SVD burden will require further study. The proposed SVD scale, or modifications, will need to be evaluated in larger cohorts of patients to better determine its construct validity. Of interest will be the relationship between total SVD score and clinical measures such as cognitive impairment and disability in the variety of conditions in which SVD affects patients. It also will be important to evaluate the role of the total SVD score as a composite endpoint in clinical trials targeting cerebral SVD. As the scale is refined, the hope is that a comprehensive evaluation of cerebral SVD will improve our understanding and treatment of SVD, and ultimately improve brain health. STUDY FUNDING No targeted funding reported.
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
REFERENCES 1. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 2010;9:689–701. 2. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. Neurology 2014;83:1228–1234. 3. Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser MG. CADASIL. Lancet Neurol 2009;8:643–653. 4. Lanfranconi S, Markus HS. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Stroke 2010;41:e513–e518. 5. Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 2013;12:822–838. 6. Gao FQ, Swartz RH, Scheltens P, et al. Complexity of MRI white matter hyperintensity assessments in relation to cognition in aging and dementia from the Sunnybrook Dementia Study. J Alzheimers Dis 2011;26(suppl 3):379–388. 7. van der Lijn F, Verhaaren BF, Ikram MA, et al. Automated measurement of local white matter lesion volume. Neuroimage 2012;59:3901–3908. 8. Jickling GC, Stamova B, Ander BP, et al. Profiles of lacunar and nonlacunar stroke. Ann Neurol 2011;70:477–485. 9. Freemantle N, Calvert M, Wood J, Eastaugh J, Griffin C. Composite outcomes in randomized trials: greater precision but with greater uncertainty? JAMA 2003;289:2554–2559. 10. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint Reduction in Hypertension Study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995–1003.
Neurology 83
September 30, 2014
1225
Rating total cerebral small-vessel disease: Does it add up? Glen C. Jickling and Christopher Chen Neurology 2014;83;1224-1225 Published Online before print August 27, 2014 DOI 10.1212/WNL.0000000000000843 This information is current as of August 27, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/83/14/1224.full.html
References
This article cites 10 articles, 2 of which you can access for free at: http://www.neurology.org/content/83/14/1224.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): Infarction http://www.neurology.org//cgi/collection/infarction MRI http://www.neurology.org//cgi/collection/mri
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
