POVZETEK

V zadnjih letih se je zanimanje za možganske mikrokrvavitve bistveno povečalo. Danes je znana povezanost možganskih mikrokrvavitev z znotrajmožganskimi krvavitvami, arterijsko hipertenzijo in boleznijo malih žil. Meni se, da bi lahko bile dober označevalec h krvavitvam nagnjenim mikroangiopatij. Možganske mikrokrvavitve so majhnim pikam podobne poškodbe, ki se kot hipointenziven signal prikažejo na eho T2 sekvencah magnetnorezonančne tomografije. Prvič so bile opisane leta 1994 kot elipsoidna področja signalne nepravilnosti s premerom 2-5 mm brez okoliškega edema (3). Radiološka opredelitev izključuje vse signalne nepravilnosti znotrajžilnih prostorov, podkožne kalcifikacije in leptomeningealna žarišča hemosiderinskih odlogov. Vedno večja uporaba MRI je opozorila na njihovo prisotnost in postavila številne klinične dileme: Ali so lahko označevalci grozeče znotrajmožganske krvavitve? Ali lahko bolnik z znanimi možganskimi mikrokrvavitvami prejme trombolizo, protikoagulacijsko terapijo ali celo Aspirin? In kaj o bolnikih, ki lahko imajo možganske mikrokrvavitve, vendar brez MRI tega ne moremo vedeti? Očitno te črne pike vzbujajo veliko negotovosti in postavljajo številna vprašanja. V tem preglednem članku avtorji poskušajo poročati o do sedaj znanih dejstvih glede možganskih mikrokrvavitev.

ABSTRACT

The interest in cerebral microbleeds (CMBs) has increased substantially over the last few years. Supported by a growing body of literature, it is now widely accepted that the presence of CMBs is associated with intracerebral haemorrhage, hypertension, and SVD. Most notably, CMBs are a subject of interest as markers of a bleeding-prone microangiopathy. Brain microbleeds are small dot-like lesions appearing as hyposignal (black) on gradient echo T2* MR sequences. CMBs were first described in 1994, based on gradient echo sequences, as ellipsoid areas of signal abnormality with a diameter of 2–5 mm without peripheral edema (3). The definition of CMBs excludes any signal abnormalities within the vascular space, subcutaneous calcified lesions or leptomeningeal foci of hemosiderin deposition. The increasing use of MRI in clinical practice and in research has brought them to our attention, raising many clinical dilemmas. Are they markers of future intracerebral haemorrhage (ICH)? Should a patient with known CMBs be thromolysed, given anticoagulant therapy, or even aspirin? And what about patients who might have microbleeds but without an MR scan it is impossible to know? Obviously these black dots raise many uncertainties and questions for the clinician. In this review article the authors tried to report on what has been known about CMBs so far.

INTRODUCTION

Cerebral microbleeds (CMBs) are increasingly being recognized as another manifestation of cerebral small vessel disease (SVD) (1). Actually white matter hyperintensities (WMH), lacunes and microbleeds are regarded as MRI expressions of SVD and are commonly found on brain MRI of elderly subjects. White matter hyperintensities visible as hyperintense areas on T2 weighted MRI scans (including FLAIR), while lacunes are identified on MRI as small cavities with a diameter of 3 mm to 10e15 mm, and signal intensities comparable with CSF. Lacunes are located in the white matter or subcortical grey matter and often have a surrounding hyperintense halo. Microbleeds are small, round, hypointense foci on gradient echo T2* weighted MRI and are mostly located in the basal ganglia or corticale-subcortical areas (Gregoire SM, Chaudhary UJ, Brown MM, et al. 2009, cit in 11). Examples of these abnormalities are given in figure 1, 2 and 3. Unfortunately, definition and quantification of these MRI expressions of SVD vary between studies. This warrants a standardisation of SVD rating on MRI, as extrapolation of results from different studies to more general conclusions may be severely hampered otherwise. Figure 1, Figure 4, Figure 5.

The interest in cerebral microbleeds (CMBs) has increased substantially over the last few years. Supported by a growing body of literature, it is now widely accepted that the presence of CMBs is associated with intracerebral haemorrhage, hypertension, and SVD. Most notably, CMBs are a subject of interest as markers of a bleeding-prone microangiopathy. Brain microbleeds are small dot-like lesions appearing as hyposignal (black) on gradient echo T2* MR sequences. Cerebral microbleeds are the principle radiographic findings in patients with sub-clinical neurological impairment (2). CMBs were first described in 1994, based on gradient echo sequences, as ellipsoid areas of signal abnormality with a diameter of 2–5 mm without peripheral edema (3). The definition of CMBs excludes any signal abnormalities within the vascular space, subcutaneous calcified lesions or leptomeningeal foci of hemosiderin deposition. The increasing use of MRI in clinical practice and in research has brought them to our attention, raising many clinical dilemmas. Are they markers of future intracerebral haemorrhage (ICH)? Should a patient with known CMBs be thromolysed, given anticoagulant therapy, or even aspirin? And what about patients who might have microbleeds but without an MR scan it is impossible to know ? Obviously these black dots raise many uncertainties and questions for the clinician.

WHAT ARE CEREBRAL MICROBLEEDS?

Scharf, Brauherr, Forsting and their article ‘Significance of haemorrhagic lacunes on magnetic resonance imaging (MRI) in patients with hypertensive cerebrovascular disease and intracerebral haemorrhage’ (4) were the first to report on small, clinically silent intracerebral black dots detected by T2-weighted MRI (T2w) and announced it to be ‘haemorrhagic lacunes’. These lesions were found more frequently in patients with primary intracerebral haemorrhage in the presence of the same degree of age-related white matter changes and non-haemorrhagic lacunar infarcts (5). The term ‘cerebral microbleeds’ was introduced as a name for focal areas of signal loss in brain parenchyma measuring o5mmon T2_weighted (T2_w) MRI .Most of the following studies adhered to this size limit; however, some authors also number lesions of more than 5mm among the CMBs (6). Even when following these assumptions, it is important to mention that the term ‘cerebral microbleeds’ is controversial.

First, a hypointense spot might represent not only a haemorrhage but also other pathologies and even artefacts (7). Second, even if the aetiology is correct, in most cases, the ‘microbleed’ represents neither an acute nor chronic bleeding but the deposition of blood degradation products like haemosiderin (7).

The increasing use of hem-sensitive gradient echo (GRE-T2) sequences in MRI of the brain during the research and clinical investigation of neurological disorders – especially stroke – has led to the frequent detection of CMBs. .Application of three-dimensional T2_weighted MRI at high spatial resolution was shown to depict more BMBs when compared with conventional two-dimensional GRE at lower resolution: with this technique the prevalence of BMBs in healthy people increased to 35.5% (8). Figure 4.

It is obvious that not only old haemoglobin degradation products can cause susceptibility artefacts; iron without haemorrhage, calcification and air can look similar. The differential diagnosis of black dots in cerebral parenchyma also includes micro cavernomas (Figure 5) and even the release of prosthetic heart valve materials . Multiple CMBs can be observed in patients with disseminated intra vasal coagulation or acutely after head trauma. The most important factor for an assignment of the aetiology of a signal loss is the patient’s history as well as the location, the number and the distribution of the lesions and their associated imaging findings (7).

CEREBRAL MICROBLEDS AND SMALL VESSEL DISEASE

It is presumed that CMBs are strongly associated with SVD, which becomes visible as leukoaraiosis. The occurrence and the number of CMBs are associated with the degree of these cerebral white matter changes (9), which suggests that they share an underlying pathology in patients with cerebral SVD. The anatomic correlations between CMBs and SVD severity add to the existing evidence of a strong pathophysiologic link (10). In patients with white matter disease, CMBs are more frequent when white matter disease occurs at a younger age (Gorner A, Dutilleux C, Schrooten M et al.2005, cit in 7).Most cerebral SVD affect the small penetrating end arteries widely lacking distal collateralisation. They supply the brainstem, the basal ganglia and the corona radiata with the surrounding white matter but not the cortex and its U fibres.

Based on histopathological observations of changes in the wall of small brain vessels, at least two types of SVD may be separated that reveal different patterns on MRI:

CEREBRAL MICROBLEEDS: PREVALENCE AND RISK FACTORS

The frequency and the number of CMBs increases in older patients. Almost no CMBs are found in patients under the age of 40. In a large study of stroke patients, the prevalence of CMBs increased remarkably in the fifth decade and then remaining stable. In patients with leukoaraiosis, CMBs were more frequent when leukoaraiosis occurred at a younger age (7).

Using conventional MR sequences, the prevalence of CMBs is about 5% in healthy people but increases with age, and is about 34% in ischaemic and 60% in haemorrhagic stroke patients (8). The prevalence is less in first ever compared with recurrent ischaemic and haemorrhagic stroke patients, suggesting that CMBs are a marker for the evolution or severity of the underlying vascular pathology (8).

Several studies have reported on the overall prevalence of CMBs in the general population (12, 13). Reported frequencies of CMBs, however, varied largely among studies (3.1% to 23.5%). One explanation for the differences in reported prevalence is the difference in mean age between the studies (mean age, 53 to 76 years)(13). Consistent with the Age, gene/Environment Susceptibility (AGES) Reykjavik Study (13) a significant overrepresentation of APOE _4 carriers among people with presence ofCMBs. Previously, it was thought that this may be explained by the differences in mean age (13) ). However, in Rotterdam study (14) the authors consistently find the association between APOE _4 genotype and lobar CMBs even in this much younger cohort with an average age of 60 years. Furthermore, the same authors robustly confirmed the association between cardiovascular risk factors, ie, systolic blood pressure, hypertension, smoking, and CMBs in a deep or infratentorial region (13).

The major risk factors for CMBs are arterial hypertension and the presence of WMH on MRI suggestive of chronic small vessel ischemia and perivascular demyelination. Hypertension-associated pathologic changes in the brain and its vasculature include vascular remodelling, impaired cerebral autoregulation, white matter lesions, unrecognized lacunar infarcts and probably also the formation of CMBs (7). Reports from Lee et al. (Lee et al. 2002, cit in 7) suggest that CMBs and lacunes tend to occur to a similar extent in long-standing hypertension, but not necessarily in the same locations. In Dutch-type Cerebral Amyloid Angiopathy (CAA), conversely supratentorial CMBs occur without hypertension indicating a different path for development in contrast to infratentorial CMBs, which are hypertension associated (7).

It has also been reported that low serum cholesterol and low-density lipoprotein levels may be closely associated with multiple CMBs (Lee et al. 2002, cit in 7). The presence of diabetes has been described to be another independent predictor of CMBs (7).

PATHOLOGICAL BASIS OF MICROBLEEDS

Frequent evidence of CMBs in the aging brain have been found, often with capillary involvement and with the majority of the microbleeds occurring in putamen. The CMBs occurred in vessels without amyloid deposition and CMBs occurred in presence and in absence of hypertension. Moreover, blood-brain barrier pericytes in addition to brain macrophages appeared to have a role in CMBs (16).

Iron uptake into brain is complex and may occur as a consequence of hemorrhage and by receptor-mediated endocytosis of transferrin-bound iron. The latter occurs at endothelial cells of the blood-brain barrier and results in tissue iron distribution principally in oligodendrocytes. This is a well-described and age-related process that does not, however, include phagocytosis or inflammation. The neurovascular unit of the blood–brain barrier consists of endothelial cells in close approximation to pericytes, separated only by basement membrane (16). In addition, macrophages are known to be found adjacent to neurovascular unit, either in residence or as cells migrating to that site. It is therefore not surprising that both cell types appear to have a role in CMBs (16).

CLINICAL IMPACT OF CEREBRAL MICROBLEEDS

White matter hyperintensities, lacunes and microbleeds are regarded as typical MRI expressions of SVD and they are highly prevalent in the elderly. However, clinical expression of MRI defined SVD is generally moderate and heterogeneous (11).

CMBs may reflect tiny focal destructive lesions in strategic and nonstrategic subcortical structures and connection fibers relevant to cognitive function (3). In non-demented elderly subjects, WMH, lacunes and CMBs have been associated with cognitive decline, including reduced mental speed and impaired executive functions. WMH have also been related to other potentially disabling symptoms, such as gait disturbances, depression and urinary incontinence (11). Having multiple CMBs or concomitant CMBs and retinopathy is associated with a profile of vascular cognitive impairment. These findings suggest that microvascular damage, as indicated by CMBs and retinopathy lesions, has functional consequences in older men and women living in the community (17).

In a very recent study (18) it was found that the number of CMBs, especially those located in the frontal lobe, temporal lobe, and basal ganglia (and thalamus), interfered with gait independent of coexisting WML and lacunar infarcts. The relation between CMBs in the temporal lobe, which is involved in processing visual and vestibular signals, and gait performance is also in accordance with functional imaging studies of normal gait. This finding is interesting because the temporal lobe is not a predilection site for WML and therefore may indicate much more widespread disruption of neuronal networks in subjects with SVD and gait disturbances than previously thought based on conventional T2-weighted images (18). It is suggested that strictly lobar-located CMBs are attributable to amyloid angiopathy, whereas CMBs in deep/infratentorial regions (with or without lobar CMBs) rather represent hypertensive microangiopathy. These findings therefore are suggestive of hypertensive SVD as the underlying etiology, although it should be noted that these results are supposed to be interpreted with caution (18).

Our results suggest that MBs in the thalamus may play a role in the development of post stroke emotional lability (PSEL). The importance of MBs in PSEL and other psychiatric conditions in stroke survivors warrants further investigation (19).

BRAIN MICROBLEEDS AND ANTITHROMBOTIC TREATMENTS

Some clinicians have raised obvious concerns about the safety of antithrombotic treatments in patients with CMBs—are they at higher than average risk of future intracerebral haemorrhage (ICH) ? But at present there is no clear evidence that they are.

1. Antiplatelet therapy

Antiplatelet agents, especially aspirin, are widely used for the primary and secondary prevention of ischaemic stroke (IS) and cardiovascular diseases. Intracerebral haemorrhage is an uncommon but devastating complication of regular antiplatelet use: identifying high-risk patients before treatment could potentially reduce this hazard. Brain microbleeds on gradient-recalled echo (GRE) T2*- weighted MRI are considered a biomarker for bleeding-prone SVD (20). A clinical decision about the use of antiplatelet treatment must weigh the benefits of treatment against the risks, including ICH. If patients at high risk of ICH could be identified prior to treatment, they could potentially be spared this potentially devastating hazard. This is especially important, since the increasing use of anticoagulants and antiplatelet drugs in an ageing population has led to a dramatic increase in antithrombotic-related ICH in the past two decades (Flaherty ML, Kissela B, Woo D, et al. 2007, cit. in 20).

In a case-control study,it was found that CMBs were more prevalent and numerous in antiplatelet users who developed symptomatic ICH compared with matched antiplatelet users who did not develop ICH (20). The CMBs number was strongly associated with ICH risk, even after controlling for the presence of leucoaraiosis and other potential confounding factors.

Their results suggest that the association of ICH with CMBs may be more powerful than that with leucoaraiosis, although CMBs and leucoaraiosis may reflect similar pathological damage to small vessels (Naka H, Nomura E, Takahashi T, et al.2006, cit. in 20). In separate regression analyses adjusted for the presence of leucoaraiosis, lobar (but not deep) microbleeds were a statistically significant predictor of antiplatelet-related ICH. These data support a potential role for CMBs, particularly in a lobar distribution, as a risk factor for antiplatelet-associated ICH (20).

2. Anticoagulant therapy

Among patients with ICH, 14% occur in patients treated with warfarin (Cordonnier C, Rutgers MP, Dumont F, et al.2009, cit. in 8). Given the rising prevalence of atrial fi brillation and the greater use of warfarin, oral anticoagulant associated ICH incidence is expected to rise. Therefore, any means of better identifying patients at particular risk is vital, and of course it is possible that microbleeds are one risk factor for anticoagulant associated ICH. Microbleeds in a lobar distribution may be a marker for cerebral amyloid angiopathy, an increasingly recognised cause of anticoagulant associated ICH (3).

Unfortunately, previous reports have been too limited by small numbers of cases and confounding associations with other risk factors for ICH. Therefore, until further data are available, warfarin should not be withdrawn in patients with microbleeds who have a clear indication for anticoagulation such as atrial fibrillation after ischaemic stroke or transient ischaemic attacks. Whether new oral anticoagulants such as dabigatran have the same risk in the setting of brain microbleeds remains to be seen (8).

ARE BRAIN MICROBLEEDS USEFUL IN THE DIAGNOSIS OF CEREBRAL AMYLOID ANGIOPATHY?

Whether a lobar distribution of CMBs can be used to make the diagnosis of CAA in the absence of macrobleeds remains to be determined but this idea has received indirect support from the correlation between isolated lobar microbleeds and the APOE 4 allele in the population based Rotterdam Scan Study (21). Given the relationship between APOE 4 and cerebral amyloid angiopathy, these results raise the interesting possibility that isolated lobar CMBs might reflect the presence of advanced cerebral angiopathy. But these findings have to be confirmed in other populations.

DO BRAIN MICROBLEEDS AND BRAIN HAEMORRHAGE (MACROBLEEDS) REPRESENT ONE CONTINUUM?

It seems that the volume of small and big hemorrhages has a bimodal distribution (3). The cut-point that best divides the microbleed and macrobleed peaks is a diameter of 5.1 mm, similar to the 5–10mm maximum conventionally used to define CMBs. This suggests that CMBs and macrobleeds may represent two distinct entities, perhaps with different pathophysiology. Unfortunately, these measurements were only performed in patients with probable (CAA) and, therefore, cannot be generalized (for example to deep ICH due to smallvessel disease).

SHOULD A PATIENT WITH PROVEN MICROBLEEDS BE THROMBOLYSED?

Some case reports illustrate haemorrhagic transformation after intravenous thrombolysis at the site of a brain CMBs (22). But of course case reports may be misleading, they tell us that something can happen, not how often it happens. The BRASIL study gathered 570 acute stroke patients treated with intravenous thrombolysis; symptomatic ICH occurred in 3% of patients without versus 6% of patients with CMBs (p=0.17) (23). Even though this study was not big enough to detect a significant increase in bleeding (if one really exists), this risk would still not outweigh the benefit of intravenous thrombolysis shown in the trials where CT rather than MR was used (and so microbleeds were not even known about).

Anyway, at least two questions remain unanswered:

At the moment, these concerns are rather hypothetical as acute stroke patients seldom have an urgent MR but rather a CT scan.

BRAIN MICROBLEEDS AS A PROGNOSTIC MARKER FOR RECURRENT STROKES?

Previous data suggested that stroke patients with CMBs were more likely to suffer from a recurrent stroke during follow-up (8).

Studies showing an increased risk of ICH in patients with CMBs after an ischemic stroke were mainly performed in Asian populations (24). One study performed in Canada suggested that the risk of recurrence mainly concerned ischemic events (25). Thijs et al. (26) found that among 487 patients followed-up for a median of 2.2 years, two patients developed ICH, 32 recurrent ischemic strokes and three an undetermined stroke. Lobar CMBs (alone or in association with deep CMBs) were associated with recurrent strokes. This study highlighted two things: a) first, CMBs are a marker of the severity of the underlying vascular disease, but only lobar CMBs were associated with an increased risk of recurrent stroke; b) second, the risk of future ICH (despite secondary prevention) in a population of ischemic strokes is very low even in the presence of CMBs. The same finding was found in a small prospective study of 21 patients during a mean follow-up for 5.6 years: among eight patients with CMBs, only one ICH occurred versus no ICH in 13 patients without CMBs (27).

Among patients suffering from an ICH, no recent studies were published and some data suggest, especially in lobar ICH, that lobar CMBs might predict future risk of symptomatic ICH (28). However, this question still remains open and is supposed to be further studied in large prospective cohorts.

BRAIN MICROBLEEDS IN ALZHEIMER’S DISEASE

Patients with Alzheimer’s disease often have a history of arterial hypertension, and cerebral amyloid angiopathy is frequent at autopsy; both are associated with brain microbleeds (29).

Indeed, microbleeds are frequent in Alzheimer’s disease (one in five patients with the disease) (30). Their anatomical distribution is very close to the distribution of CAA associated ICH; they tend to be lobar with posterior predominance (23). Therefore, it is conceivable that brain microbleeds are a key factor in the pathogenesis of Alzheimer’s disease, connecting the main pathological contributors of amyloid accumulation with cerebrovascular damage. Brain microbleeds may also predict a more aggressive form of the disease, being associated with a more than twofold increased mortality (29). Recently, patients with Alzheimer’s disease with multiple CMBs were compared with those without any (31). The CMBs group had more severe WMH (without any difference in degree of atrophy) and more severe cognitive impairment than could be accounted for by disease duration, degree of atrophy or WMH. Also, they had a lower CSF level of amyloid - suggesting a direct link between CMBs and amyloid - one of the key proteins involved in Alzheimer’s disease.

CONCLUSION

Despite enormous attention cerebral microbleeds recently have attracted, their diagnostic and prognostic values have only received indirect support and remain to be explored. Improvement of imaging techniques will help to better understand how CMBs appears and how they evolve. Unfortunately, MRI will not be sufficient to discuss the histological substrate of those intriguing lesions and we desperately need histological data in this field. To date, CMBs should not contraindicate antithrombotic treatment in settings in which benefits have clearly been demonstrated.

LITERATURE

• 1.Kato H, Izumiyama M, Izumiyama K, Takahashi A, Itoyama Y. Silent cerebral microbleeds on T2*-weighted MRI: correlation with stroke subtype, stroke recurrence, and leukoaraiosis. Stroke. 2002;33:1536–1540.
• 2.Viswanathan A, Chabriat H. Cerebral microhemorrhage. Stroke. 2006; 37:550–555.
• 3.Greenberg SM, Vernooij MW, Cordonnier C, et al. Cerebral microbleeds: a guide to detection and interpretation.Lancet Neurol 2009;8:165–174.
• 4.Scharf J, Brauherr E, Forsting M, Sartor K: Significance of haemorrhagic lacunes on MRI in patients with hypertensive Cerebrovascular disease and intracerebral haemorrhage. Neuroradiology 1994; 36:504–8.
• 5.Greenberg SM, Finklestein SP, Schaefer PW: Petechial hemorrhages accompanying lobar hemorrhage: detection by gradient-echo MRI. Neurology 1996; 46:1751–4.
• 6.Jeerakathil T, Wolf PA, Beiser A et al. Cerebral microbleeds: prevalence and associations with cardiovascular risk factors in the Framingham Study. Stroke 2004; 35:1831–5.
• 7.Fiehler |J.Cerebral microbleeds: old leaks and new haemorrhages. Int J of Stroke 2006;1:122-130.
• 8.Cordonnier C Brain microbleeds: more evidence, but still a clinical dilemma. Current Opinion in Neurology 2011;24:69–74.
• 9.JLMJK|Alemany M, Stenborg A, Terent A et al. Co existence of micro hemorrhages and acute spontaneous brain hemorrhage: correlation with signs of microangiopathy and clinical data. Radiology 2006; 238:240–7.
• 10.Werring DJ, Coward LJ, Losseff NA et al. Are cerebral microbleeds in ischemic stroke and TIA clinically important? Stroke 2004; 34:344.ISC:424.
• 11.Gouw AA Seewann A, Van der Flie WMr, et al. Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations. JNNP; 2011;82:126e135.
• 12.Ringelstein EB, Nabavi DG: Cerebral small vessel diseases: cerebral microangiopathies. Curr Opin Neurol 2005; 18:179–88.
• 13.Viswanathan A, Chabriat H. Cerebral microhemorrhage. Stroke. 2006;37:550 –555.
• 14.Sveinbjornsdottir S, Sigurdsson S, Aspelund T, Kjartansson O, Eiriksdottir G, Valtysdottir B, Lopez OL, van Buchem MA, Jonsson PV, Gudnason V, Launer LJ. Cerebral microbleeds in the population based AGES-Reykjavik study: prevalence and location. J Neurol Neurosurg Psychiatry. 2008;79:1002–1006.
• 15.Poels MM,. Vernooi MWj, Ikram MA, Hofman A, Krestin GP, Van der Lug A and Breteler MMB. Prevalence and Risk Factors of Cerebral Microbleeds: An Update of the Rotterdam Scan Study. Stroke 2010;41;S103-S106.
• 16.Fisher M, French S, J Pi and Kim RC. Cerebral Microbleeds in the Elderly: A Pathological Analysis Stroke 2010;41;2782-2785.
• 17.The AGES-Reykjavik Study. Cerebral microbleeds, retinopathy .and dementia. Neurology 2010;75:2221–2228.
• 18.De Laa FK, Van den Berg HAC, Van Norden AGW, Gons AR,. Olde Rikkert MGM and De Leeuw FE. Microbleeds Are Independently Related to Gait Disturbances in Elderly Individuals With Cerebral Small Vessel Disease. Stroke. 2011;42:00-00.
• 19.Tang WK, Chen YK, Lu JU, Mok VCT, Xian YT, Ungvari GS, Ahuja AS, Wong KS. Microbleeds and post-stroke emotional lability. JNNP 2009;80:1082–1086.
• 20.Gregoire SM, Jager HR, Yousry TA, Kallis C, Brown MM, Werring DJ. Brain microbleeds as a potential risk factor for antiplatelet-related intracerebral haemorrhage: hospital-based, case-control study. J NNP 2010;81:679e684.
• 21.Vernooij MW, van der Lugt A, Ikram MA, et al. Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study. Neurology 2008;70:1208–14.
• 22.Kidwell CS, Saver JL, Villablanca JP, et al. Magnetic resonance imaging detection of microbleeds before thrombolysis: an emerging application. Stroke 2002;33:95–8.
• 23.Fiehler J, Albers GW, Boulanger JM, et al. Bleeding Risk Analysis in Stroke Imaging before thromboLysis (BRASIL): pooled analysis of T2*-weighted magnetic resonance imaging data from 570 patients. Stroke 2007;38:2738–44 .
• 24.Soo YO, Yang SR, Lam WW, et al. Risk vs benefit of antithrombotic therapy in ischaemic stroke patients with cerebral microbleeds. J Neurol 2008;255:1679–1686.
• 25.Boulanger J-MMD, Coutts SBMD, Eliasziw MP, et al. Cerebral microhemorrhages predict new disabling or fatal strokes in patients with acute ischemic stroke or transient ischemic attack. Stroke 2006; 37:911–914.
• 26.Thijs V, Lemmens R, Schoofs C, et al. Microbleeds and the risk of recurrentstroke. Stroke 2010; 41:2005–2009.
• 27.Gregoire SM, Brown MM, Kallis C, et al. MRI detection of new microbleeds in patients with ischemic stroke: five-year cohort follow-up study. Stroke 2010;41:184–186.
• 28.Greenberg SM, Eng JA, Ning M, et al. Hemorrhage burden predicts recurrent intracerebral hemorrhage after lobar hemorrhage. Stroke 2004; 35:1415–1420.
• 29.Cordonnier C.Brain Microbleeds Neurological Dilemma. Pract Neurol 2010; 10: 94–100.
• 30.Cordonnier C, van der Flier WM, Sluimer JD, et al. Prevalence and severity of microbleeds in a memory clinic setting. Neurology 2006;66:1356–60.
• 31.Goos JD, Kester MI, Barkhof F, et al. Patients with Alzheimer disease with multiple microbleeds. Relation with cerebrospinal fluid biomarkers and cognition. Stroke 2009;40:3455–60.