Cerebral microbleeds as a predictor of macrobleeds: what is the evidence?
Corresponding Author
Andreas Charidimou
Stroke Research Group, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
Correspondence: Andreas Charidimou, National Hospital for Neurology and Neurosurgery, Box 6, Queen Square, London WC1N 3BG, UK.
E-mail: [email protected]
Search for more papers by this authorDavid J. Werring
Stroke Research Group, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
Search for more papers by this authorCorresponding Author
Andreas Charidimou
Stroke Research Group, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
Correspondence: Andreas Charidimou, National Hospital for Neurology and Neurosurgery, Box 6, Queen Square, London WC1N 3BG, UK.
E-mail: [email protected]
Search for more papers by this authorDavid J. Werring
Stroke Research Group, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
Search for more papers by this authorAbstract
Cerebral microbleeds on blood-sensitive magnetic resonance imaging sequences have emerged as a common and important marker of small vessel disease. Cerebral microbleeds differ from other imaging manifestations of small vessel disease (e.g. lacunes and leukoaraiosis), as they seem to provide more direct evidence of microvascular leakiness from bleeding-prone arteriopathies, namely hypertensive arteriopathy and cerebral amyloid angiopathy, the two leading causes of spontaneous intracerebral haemorrhage. Thus, cerebral microbleeds in specific sub-populations might provide evidence of an ongoing active small vessel arteriopathy with increased future risk of symptomatic intracerebral haemorrhage (‘macrobleeding’). If this hypothesis is correct, it raises clinical dilemmas especially regarding the safety of antithrombotic drug use. Although data so far are limited, the relationship of microbleeds to future macrobleeding (and cerebral ischemia) seems to critically depend on the specific patient population and cerebral microbleeds location and burden, which may reflect the nature and severity of the underlying arteriopathies.
References
- 1 Fazekas F, Kleinert R, Roob G et al. Histopathologic analysis of foci of signal loss on gradient-echo T2*-weighted MR images in patients with spontaneous intracerebral hemorrhage: evidence of microangiopathy-related microbleeds. AJNR Am J Neuroradiol 1999; 20: 637–642.
- 2 Shoamanesh A, Kwok CS, Benavente O. Cerebral microbleeds: histopathological correlation of neuroimaging. Cerebrovasc Dise 2011; 32: 528–534.
- 3
Charidimou A, Werring DJ. Cerebral microbleeds: detection, mechanisms and clinical challenges. Future Neurol 2011; 6: 587–611.
10.2217/fnl.11.42 Google Scholar
- 4
Werring D. Cerebral Microbleeds: Pathophysiology to Clinical Practice. Cambridge, Cambridge University Press, 2011.
10.1017/CBO9780511974892 Google Scholar
- 5 Kakar P, Charidimou A, Werring D. Cerebral microbleeds: a new dilemma in stroke medicine. JRSM Cardiovasc Dis 2012; 1:2048004012474754. eCollection 2012.
- 6 Cordonnier C, Al-Shahi Salman R, Wardlaw J. Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting. Brain 2007; 130(Pt 8): 1988–2003.
- 7 Poels MM, Vernooij MW, Ikram MA et al. Prevalence and risk factors of cerebral microbleeds: an update of the Rotterdam scan study. Stroke 2010; 41(10 Suppl.): S103–106.
- 8 Sveinbjornsdottir S, Sigurdsson S, Aspelund T et al. Cerebral microbleeds in the population based AGES-Reykjavik study: prevalence and location. J Neurol Neurosurg Psychiatry 2008; 79: 1002–1006.
- 9 Lee SH, Bae HJ, Kwon SJ et al. Cerebral microbleeds are regionally associated with intracerebral hemorrhage. Neurology 2004; 62: 72–76.
- 10 Roob G, Lechner A, Schmidt R, Flooh E, Hartung HP, Fazekas F. Frequency and location of microbleeds in patients with primary intracerebral hemorrhage. Stroke 2000; 31: 2665–2669.
- 11 Smith EE, Nandigam KR, Chen YW et al. MRI markers of small vessel disease in lobar and deep hemispheric intracerebral hemorrhage. Stroke 2010; 41: 1933–1938.
- 12 Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 2010; 9: 689–701.
- 13 Greenberg SM, Vernooij MW, Cordonnier C et al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol 2009; 8: 165–174.
- 14 Vinters HV. Cerebral amyloid angiopathy. A critical review. Stroke 1987; 18: 311–324.
- 15 Passero S, Burgalassi L, D'Andrea P, Battistini N. Recurrence of bleeding in patients with primary intracerebral hemorrhage. Stroke 1995; 26: 1189–1192.
- 16 Janaway BM, Simpson JE, Hoggard N et al. Brain haemosiderin in older people: pathological evidence for an ischaemic origin of MRI microbleeds. Neuropathol Appl Neurobiol 2013; 40: 258–269.
- 17 Gregoire SM, Brown MM, Kallis C, Jager HR, Yousry TA, Werring DJ. MRI detection of new microbleeds in patients with ischemic stroke: five-year cohort follow-up study. Stroke 2010; 41: 184–186.
- 18 Poels MM, Ikram MA, van der Lugt A et al. Incidence of cerebral microbleeds in the general population: the Rotterdam scan study. Stroke 2011; 42: 656–661.
- 19 Goos JD, Henneman WJ, Sluimer JD et al. Incidence of cerebral microbleeds: a longitudinal study in a memory clinic population. Neurology 2010; 74: 1954–1960.
- 20 Lovelock CE, Cordonnier C, Naka H et al. Antithrombotic drug use, cerebral microbleeds, and intracerebral hemorrhage: a systematic review of published and unpublished studies. Stroke 2010; 41: 1222–1228.
- 21 Hart RG, Boop BS, Anderson DC. Oral anticoagulants and intracranial hemorrhage. Facts and hypotheses. Stroke 1995; 26: 1471–1477.
- 22 Biffi A, Halpin A, Towfighi A et al. Aspirin and recurrent intracerebral hemorrhage in cerebral amyloid angiopathy. Neurology 2010; 75: 693–698.
- 23 Charidimou A, Kakar P, Fox Z, Werring DJ. Cerebral microbleeds and recurrent stroke risk: systematic review and meta-analysis of prospective ischemic stroke and transient ischemic attack cohorts. Stroke 2013; 44: 995–1001.
- 24
Charidimou A, Shakeshaft C, Werring DJ. Cerebral microbleeds on magnetic resonance imaging and anticoagulant-associated intracerebral hemorrhage risk. Front Neurol 2012; 3: 1–13.
10.3389/fneur.2012.00133 Google Scholar
- 25 Shoamanesh A, Kwok CS, Lim PA, Benavente OR. Postthrombolysis intracranial hemorrhage risk of cerebral microbleeds in acute stroke patients: a systematic review and meta-analysis. Int J Stroke 2013; 8: 348–356.
- 26 Charidimou A, Kakar P, Fox Z, Werring DJ. Cerebral microbleeds and the risk of intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2013; 84: 277–280.
- 27 Charidimou A, Fox Z, Werring DJ. Do cerebral microbleeds increase the risk of intracerebral hemorrhage after thrombolysis for acute ischemic stroke? Int J Stroke 2013; 8: E1–2.
- 28 Bokura H, Saika R, Yamaguchi T et al. Microbleeds are associated with subsequent hemorrhagic and ischemic stroke in healthy elderly individuals. Stroke 2011; 42: 1867–1871.
- 29 Nishikawa T, Ueba T, Kajiwara M, Fujisawa I, Miyamatsu N, Yamashita K. Cerebral microbleeds predict first-ever symptomatic cerebrovascular events. Clin Neurol Neurosurg 2009; 111: 825–828.
- 30 van Etten E, Auriel E, Haley K et al. Warfarin increases risk of future intracerebral hemorrhage in patients presenting with isolated lobar microbleeds on MRI. Stroke 2013; 44(Abstract TP301).
- 31 Greenberg SM, Nandigam RN, Delgado P et al. Microbleeds versus macrobleeds: evidence for distinct entities. Stroke 2009; 40: 2382–2386.
- 32 Greenberg SM, Briggs ME, Hyman BT et al. Apolipoprotein E epsilon 4 is associated with the presence and earlier onset of hemorrhage in cerebral amyloid angiopathy. Stroke 1996; 27: 1333–1337.
- 33 Biffi A, Sonni A, Anderson CD et al. Variants at APOE influence risk of deep and lobar intracerebral hemorrhage. Ann Neurol 2010; 68: 934–943.
- 34 Rannikmae K, Kalaria RN, Greenberg SM et al. APOE associations with severe CAA-associated vasculopathic changes: collaborative meta-analysis. J Neurol Neurosurg Psychiatry 2014; 85: 300–305.
- 35 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.