Radiological pathology of cerebral microbleeds

INDEX

INTRODUCTION

INTRODUCTION

In the last decade or so, cerebral microbleeds (CMBs) – tiny perivascular hemorrhagesseen as small, well-demarcated, hypointense, rounded lesions on MRI sequences that aresensitive to magnetic susceptibility – have generated increasing interest among neurologistsand clinical stroke researchers. As MRI techniques become more sophisticated, Cerebralmicrobleeds are increasingly detected in various patient populations (including all types ofstroke, Alzheimer’s disease and vascular cognitive impairment) and healthy community-dwelling older people. Their presence raises many clinical dilemmas and intriguingpathophysiological questions. Cerebral microbleeds are emerging as an important newmanifestation and diagnostic marker of cerebral small-vessel disease.

Professor Yasser Metwallywww.yassermetwally.com

www.yassermetwally.com

Box 1. Cerebral microbleeds are a potential predictor of

1- Future intracerebral hemorrhagic risk.

2- A possible contributor to cognitive impairment anddementia.

3- A potential key link between vascular anddegenerative pathologies.

Cerebral microbleeds are defined radiologically as small, rounded, homogeneous,hypointense lesions on T2*-weighed gradient-recalled echo (T2*-GRE) and related MRIsequences that are sensitive to magnetic susceptibility.[2] Scharf et al. were the first toreport on small, intracerebral black dots of signal loss on T2-weighted spin-echo MRI inpatients with hypertensive cerebrovascular disease and intracerebral hemorrhage (ICH)associated with ischemic white matter disease and lacunar infarcts.[3] They called theselesions ‘hemorrhagic lacunes’, and their further characterization using T2*-GRE MRIsequences led to the current radiologic definition of ‘microbleeds’, a term coined byOffenbacher and colleagues in 1996.[4] A key feature of Cerebral microbleeds is that theyare not seen well on conventional computed tomography or MRI scans. Availablehistopathological studies suggest that Cerebral microbleeds radiological lesions are due totiny bleeds adjacent to abnormal small vessels, being mainly affected by hypertensiveangiopathy (arteriolosclerosis – usually lipohyaline degeneration related to hypertension)or cerebral amyloid angiopathy (CAA).[5]

Cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA), also known as congophilic angiopathy, affectsexclusively the cerebral vasculature, without involvement of other areas of the body. Theamyloid substance is deposited in the media and adventitia of small and medium diameterarteries, as well as in veins, of the cortical surface and leptomeninges. The histologicaldiagnosis is made by showing areas of the vessel wall that stain with Congo red and show acharacteristic apple green birefringence under polarized light.

Cerebral amyloid angiopathy characteristically affects the elderly, with a linear increase infrequency with age. In routine autopsy studies, the frequency of Cerebral amyloidangiopathy has been 5-13% in those patients aged 60-69, 20-40% in patients aged 70-79,35-45% in patients aged 80-89, and 45-58% in individuals older than 90 years of age. Themain clinical manifestation of Cerebral amyloid angiopathy is Intracerebral hemorrhage,but an association with Alzheimer's disease and with a leukoencephalopathy are now wellrecognized as well.



Figure 1. Lobar hemorrhage due to amyloid angiopathy, B Microscopic section of the braincortex, section has been stained with Congo Red for amyloid viewed with polarized light.The section shows relatively preserved cortical neurons and the blood vessels showsbirefringence with polarized light. In some areas the walls of the blood vessels are yellow-green (arrow). Diagnosis: Amyloid angiopathy, also known as congophilic angiopathy.

Table 1. The Intracerebral hemorrhages that occur in the setting of Cerebral amyloidangiopathy have several characteristic features. These include:

CCA

CCA

CCA

CCA

CCA

CCA

CCA

A lobar location, due to the cortical and leptomeningealdistribution of the angiopathy.

A frequently irregular, variegated appearance on acomputed tomography (CT) scan, which results fromextension of the superficially-located haemorrhage into theadjacent subarachnoid space.

A tendency to be recurrent, on occasion with multipleepisodes of lobar Intracerebral hemorrhage over periods ofmonths or years, a feature that is exceptionally rare inIntracerebral hemorrhage due to hypertension.

The occasional presence of multiple simultaneoushaemorrhages, is also a distinct rarity in Intracerebralhemorrhage of hypertensive mechanism.



Figure 2. Precontrast CT scan showing irregular variegated putameno-capsularhaemorrhage [left two images] and a lobar subcortical haemorrhage [right]

The Intracerebral hemorrhage in patients with Cerebral amyloid angiopathy canoccasionally be related to preceding head trauma or a neurosurgical procedure, raising thepossibility that mechanically-induced vascular rupture may be at times involved in itspathogenesis. Similarly, the use of anticoagulant and fibrinolytic agents is beingincreasingly suspected as a potential risk factor in instances of Intracerebral hemorrhagein the elderly, presumed to harbour Cerebral amyloid angiopathy as a local vascular lesionpredisposing to Intracerebral hemorrhage.

The actual mechanism of bleeding in Cerebral amyloid angiopathy has not been elucidated.A factor that may be related to bleeding is the association of this angiopathy with othervascular changes, notably fibrinoid necrosis. Such vascular lesion has been found with highfrequency (71%) in instances of Cerebral amyloid angiopathy associated withIntracerebral hemorrhage, while it is not present in patients with Cerebral amyloidangiopathy but without Intracerebral hemorrhage. These data suggest that despite the highprevalence of Cerebral amyloid angiopathy in the elderly, the relatively low frequency ofIntracerebral hemorrhage may be explained by the need to have the associated changes offibrinoid necrosis in the affected vessels, in order to result in rupture and Intracerebralhemorrhage.

Figure 3. Precontrast CT scan showing lobar subcorticalhaemorrhage



CA with Intracerebral hemorrhage is a sporadic condition, but two rare familial formshave been described only in specific geographical locations in Iceland and in Holland. Thelatter form of familial Cerebral amyloid angiopathy with Intracerebral hemorrhage hasbeen characterized as a biochemical abnormality in the precursor protein of amyloid,which is also present in Alzheimer's disease and Down's syndrome.

Figure 4. Precontrast CT scan showingsimultaneous cerebral and cerebellarhaemorrhage in a single patient

Other associations of Cerebral amyloid angiopathy include Alzheimer's disease and aleukoencephalopathy. The histological features of Alzheimer's disease are present inapproximately 40% of patients with Cerebral amyloid angiopathy-related Intracerebralhemorrhage, and 30-40% of patients with Cerebral amyloid angiopathy have clinicalfeatures of dementia. The leukoencephalopathy of Cerebral amyloid angiopathy affects thewhite matter of the cerebral hemispheres, with preservation of the 'U' fibres, corpuscallosum, internal capsule, optic radiation, and white matter of the temporal lobes. Theimaging diagnosis of this leukoencephalopathy is greatly facilitated by the use of magneticresonance imaging (MRI), which shows hyperintensity of the white matter in T2-weightedsequences.

Box 2. Cerebral microbleeds are increasingly recognized in patients with the followingneurological disorders

1- Cerebrovascular disease (including first-ever and recurrent ischemic or hemorrhagicstroke),[6,7]

2- Alzheimer’s disease,[8,9]

3- Vascular cognitive impairment[10]

4- Normal elderly populations. [11]

Cerebral microbleeds are emerging as a manifestation and diagnostic marker of cerebralsmall-vessel disease (along with lacunar infarcts, leukoaraiosis, ) .[13–17] They are apotential predictor of Intracerebral hemorrhage risk, a possible contributor to cognitive



impairment and dementia and may provide a new imaging tool to understand the linksbetween vascular and degenerative pathologies.[2]

Cerebral microbleeds are small brain hemorrhages that are presumed to result fromleakage of blood cells from damaged small vessel walls. They were first detected on MRimaging only in the mid-1990s, as MR imaging sequences sensitive to blood-breakdownproducts became available (eg, T2-weighted gradient-echo technique), which are essentialfor microbleed detection. Histologically, these small black dots on MR imaging representhemosiderin-laden macrophages that are clustered around small vessel. The choice of fieldstrength, sequence parameters (particularly echo time), and postprocessing (eg,susceptibility-weighted imaging technique) have all been found to have a major influenceon the detection rate of cerebral microbleeds. With these advances in imaging, theprevalence of microbleeds has been estimated to be more than 20% in persons aged 60years and older, increasing to nearly 40% in those older than 80 years. Microbleeds arealso commonly asscoiated with microvascular brain disease. Microbleed location isgenerally divided into deep (ie, basal ganglia, thalamus) and infratentorial versus lobarbrain regions.

Figure 5. Cerebral Microbleeds. (A) An axial T2-weighted MRI. (B) A T2*-weightedgradient-recalled echo (T2*-GRE) MRI. Note the microbleeds – small, dark dot-like lesions(arrow) visible only on the T2*-weighted gradient-recalled echo (T2*-GRE) MRI.

In the aging population, microbleeds in lobar locations share apolipoprotein E (APOE) e4genotype as a common risk factor with Cerebral amyloid angiopathy (CAA) andAlzheimer's disease (AD), suggestive of a potential link between vascular and amyloidneuropathology. This link has further been corroborated by the finding that topography oflobar microbleeds in community-dwelling elderly individuals follows the same posteriordistribution as is known from amyloid disease in Cerebral amyloid angiopathy (CAA) andAlzheimer's disease (AD). Furthermore, some reports show that presence of microbleeds,



and particularly those in lobar locations, relates to worse cognitive function, both inhealthy elderly individuals and in patients diagnosed with Alzheimer's disease (AD). Incontrast, deep or infratentorial microbleeds in aging individuals are primarily linked toclassic cardiovascular risk factors and are more likely caused by hypertensivevasculopathy. Longitudinal studies indicate that incident microbleeds commonly occurover time: annually, 3% of presumed healthy elderly individuals develop new microbleeds,increasing to more than 7% of those who already have microbleeds at baseline. Incomparison, these rates are doubled in patients attending a memory clinic.

Table 2. Location of cerebral microbleeds and clinical significance

Location Clinical significance

lobar locations In the aging population, microbleeds in lobar locations shareapolipoprotein E (APOE) e4 genotype as a common risk factorwith Cerebral amyloid angiopathy (CAA) and Alzheimer's disease(AD), suggestive of a potential link between vascular and amyloidneuropathology.

Deep or infratentorialmicrobleeds

Deep or infratentorial microbleeds in aging individuals areprimarily linked to classic cardiovascular risk factors and aremore likely caused by hypertensive vasculopathy and small vesseldisease.

The increasing evidence that microbleeds reflect both vascular disease as well as amyloidangiopathy has led to the belief that these may well represent the missing link between thevascular and amyloid hypotheses in the pathogenesis of Alzheimer's disease (AD).



Figure 6. A postmortem section of thebrain showing a cortical microbleed(arrow) in a patient with Alzheimer’sdisease and CAA

Figure 7. Microbleed imaging. T1-weighted (left), T2-weighted (middle), and T2-weighted(right) images. Cerebral microbleeds, depicted by arrows, are visualized only on the T2-weighted image and not on the T1-weighted or T2-weighted images. The T2-weightedimage is susceptible to paramagnetic properties of hemosiderin, causing the microbleeds toappear as black dots of signal loss.



Figure 8 Microbleed location. T2-weighted MR images showing microbleeds (arrows) inlobar (left), deep (middle), and infratentorial (right) locations.

Table 3. Pathology of ischemic microvascular brain disease

Central and corticalatrophy

This is secondary to chronic global reduction of brain perfusion.

Leukoaraiosis (diffuseperiventricular whitematter disease)

Leukoaraiosis is an ischaemic demyelination of the immediateperiventricular white matter with axonal loss, astrogliosis and interstitialedema. It is secondary to chronic global reduction of brain perfusion.

Lacunar infarctions lacunar infarctions are secondary to the micro vascular thrombo-occlusive episodes. They are most numerous in the periventricular graymatter (thalamus and basal ganglia) and the immediate periventricularwhite matter. Spasm of the fine penetrating arterioles (secondary toincreased VSMCs sensitivity) -can also result in Lacunar infarctions.

Granular atrophy Granular atrophy is defined pathologically as infarctions localized to thecerebral cortex and not extending to the subcortical white matter.

Basal ganglioniccalcifications

These are calcification of the the arteriolar wall of the microcirculationwithin the basal ganglia.

Dilated Virchow-RobinSpaces

Dilation of Virchow-Robin Spaces provides a potential alternativebiomarker of microvascular disease (small vessel disease).

Cerebral Microbleeds The increasing evidence that microbleeds reflect both microvascularbrain disease as well as amyloid angiopathy has led to the belief thatthese may well represent the missing link between the vascular andamyloid hypotheses in the pathogenesis of Alzheimer’s disease (AD).



Physical Principles of Microbleed MRI Detection

The available data suggest that Cerebral microbleeds are composed of small collections ofblood-breakdown products (in particular hemosiderin) contained within perivascularmacrophages. Hemosiderin is an extremely paramagnetic material; this property, knownas magnetic susceptibility, describes the degree to which a tissue (or any material) respondsmagnetically when placed in an exogenous magnetic field.[20] Consequently, whenhemosiderin deposits are brought into the magnetic field of an MRI scanner, microscopiclocal magnetic fields develop, which create significant macroscopical inhomogeneities in themagnetic field surrounding Cerebral microbleeds , leading to fast decay of the local MRIsignal, a phenomenon called the ‘susceptibility effect’.[12] Similar distortions of themagnetic field are also caused by the close proximity of tissues with different magneticsusceptibilities (e.g., at the interface of soft tissues, bone and air).

Figure 9. Lobar microbleeds on 3-dimensional T2*-weighted gradient-recalled echo MRI in an 80 years old manwith dementia and cerebral amyloidangiopathy.



Figure 10. Example ofincident microbleeds on 3-dimensional T2*-weightedgradient-recalled echo MRIin an 80 years old man. Themicrobleeds are lobar inlocation

Figure 11. Radiologic-pathologic correlation of cerebral microbleeds on MR imaging (3 T).Postmortem brain MR imaging shows on T2-weighted imaging a hypointense focus on thegray-white matter interface (white arrow). MR image in the middle of the isolated tissueblock containing this hypointense focus. Pathologic analysis of this tissue block(hematoxylin and eosin stain) shows macrophages containing hemosiderin (black arrows),confirming that the hypointense lesion on MR imaging is compatible with a microbleed.



Figure 12. Example of incidentmicrobleeds on 3-dimensional T2*-weighted gradient-recalled echo MRIin an 80 years old man. Themicrobleeds are mainly lobar inlocation. The patient is presentedclinical with the clinical picture ofAlzheimer dementia.

MRI Criteria for Microbleed Identification & Differential Diagnosis

Cerebral microbleeds are defined as small, rounded or ovoid, blooming, homogeneoussignal voids on T2*-GRE and related MRI sequences that are sensitive to susceptibilityeffects. A precise size definition does not appear to substantially influence the detection ofCerebral microbleeds : although the upper size limit is usually taken to be between 5 and10 mm, a recent analysis revealed that the volume of microbleeds and macrobleeds (at leastin a cohort of patients with Cerebral amyloid angiopathy) is not a continuum, but shows abimodal distribution.[32] Blood vessels in the subarachnoid space, calcifications of thebasal ganglia or cavernous malformations can all give rise to small, dot-like, low-signalareas on T2*-GRE MRI. Careful inspection of contiguous slices using different imagingmodalities (CT, T2 MRI, FLAIR or DWI) and lesion geometry and location facilitates theidentification of Cerebral microbleeds .



Figure 13. Deep microbleeds in a patientwith lacunar stroke

Histopathological Correlates of Cerebral microbleeds

Neuroimaging–pathological correlation studies, as well as other histopathological analysesof Cerebral microbleeds ,[38,44–47] show that Cerebral microbleeds are commonlyassociated with two different small-vessel pathologies: hypertensive vasculopathy(Lipohyelinosis) and Cerebral amyloid angiopathy. Moreover, these two microangiopathicdisorders seem to influence Cerebral microbleeds topography. Typically, hypertensivevasculopathy results in Cerebral microbleeds in the basal ganglia, thalamus, brainstem andcerebellum, while Cerebral amyloid angiopathy is characterized by a lobar, cortical–subcortical distribution.[2]

Risk Factors & Associations

Apart from being associated with specific underlying vasculopathies, Cerebral microbleedsare strongly associated with a number of clinical syndromes including ischemic andhemorrhagic stroke, Alzheimer’s disease and vascular cognitive impairment.[12]



Figure 14. Patterns of Cerebral Microbleed Distribution. (A) Axial T2*-weighted gradient-recalled echo of an elderly individual without a history of hypertension, showingmicrobleeds in strictly lobar.

o Pathophysiology of Cerebral microbleeds

Cerebral microbleeds are unique among the MRI manifestations of cerebral small-vesseldisease, in that they seem to provide direct evidence of microvascular leakiness, causingblood-breakdown products to extravasate through the vessel wall. By contrast,Leukoaraiosis -in small vessel disease) lack pathological specificity and may result from awide range of both vascular and inflammatory conditions. In the setting of small-vesseldisease, the vascular endothelium of small arterioles and capillaries seems to becomepermeable to elements such as red blood cells, inflammatory cells and plasma proteins,[66]which are normally excluded by the BBB.[67] Thus, it seems highly plausible thatendothelial/BBB derangement could play a key role in Cerebral microbleeds formation,[68]although direct evidence for this hypothesis is limited so far.

Clinical Implications of Cerebral microbleeds

It is now becoming evident that Cerebral microbleeds can contribute to neurologicdysfunction, long-term disability and cognitive impairment. A population-based study ofelderly people (n = 435) with or at high risk of cardiovascular disease investigated theprognostic value of Cerebral microbleeds regarding overall, cardiovascular-related andstroke-related mortality.[87] Compared with subjects without any Cerebral microbleeds ,subjects with more than one Cerebral microbleed had a sixfold risk of stroke-related death(hazard ratio: 5.97; 95% CI: 1.60–22.26; p = 0.01).[87] However, the most striking findingswere that deep Cerebral microbleeds were found to be significantly and independently



associated with cardiovascular mortality (hazard ratio: 2.67; 95% CI: 1.23–5.81; p = 0.01),whereas strictly lobar Cerebral microbleeds were significantly associated with stroke-related mortality (hazard ratio: 7.20; 95% CI: 1.44–36.10; p = 0.02).[87] Also in a previousstudy, the presence of Cerebral microbleeds (especially multiple Cerebral microbleeds )was the strongest predictor of mortality (among other MRI markers of vascular damage,such as WMCs) in a memory clinic population of 1138 patients.[88]

As well as affecting mortality and stroke risk, the accumulation of multiple Cerebralmicrobleeds could have a cumulative effect on brain functions subserved by distributednetworks, such as gait or cognition. It is important to note that there are many potentialconfounders in the study of how Cerebral microbleeds could affect brain function andcause clinical impairment. Their close relationship and overlap with other imagingcorrelates of cerebral small vessel disease such as lacunes and white matter damage, as wellas all types of clinical stroke syndromes, makes it challenging to dissect their independenteffects.

Cerebral microbleeds & Neurological Functiono Gait.

In a cross-sectional study, De Laat et al. reported the first indications that Cerebralmicrobleeds (especially in the temporal and frontal lobe, basal ganglia and thalamus) maybe associated with gait disturbances, independently of other coexisting markers of cerebralsmall-vessel disease.[89] In addition, in a prospective cohort of elderly patients (n = 94)presenting with spontaneous lobar Intracerebral hemorrhage, Greenberg and colleaguesshowed that a high number of Cerebral microbleeds at baseline was associated with a high3-year cumulative risk of cognitive impairment, functional dependence or death (beingmore than 50% in individuals with more than six Cerebral microbleeds ).[90] Cerebralmicrobleeds have also been associated with clinical disability in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy.[91]

o Cognition.

There has been increasing attention given to Cerebral microbleeds in relation to cognition.Werring and colleagues systematically examined the cognitive impact of Cerebralmicrobleeds [92] in a neurovascular clinic population. Consecutive patients with Cerebralmicrobleeds (n = 25) were compared with a control group without Cerebral microbleeds (n= 30) that was closely matched for age, leukoaraiosis severity, prevalence and location ofcortical infarctions and ischemic stroke subtype (i.e., factors likely to influencecognition).[92] A striking difference in the prevalence of executive dysfunction was foundbetween the two groups: 60% of patients with Cerebral microbleeds were impaired infrontal executive function (i.e., initiation, planning and higher-order problem-solvingbehaviors among others), compared with only 30% of nonmicrobleed patients (p =0.03).[92]



Cerebral microbleeds as Prognostic Markers of Recurrent Stroke

Whether Cerebral microbleeds are a marker of increased future stroke risk (particularlyintracerebral hemorrhage) is one of the most clinically relevant questions at present, yetfew longitudinal data of good quality are available. A previous systematic reviewdemonstrated that Cerebral microbleeds were more prevalent among patients withrecurrent stroke rather than patients with a first-ever stroke.[6] Although this generalconclusion was derived from a small number of patients (n = 1021), it suggests thatCerebral microbleeds may be a useful imaging marker of ongoing cerebrovasculardamage,[6] which can add additional information about stroke recurrence (to that obtainedusing standard MRI sequences).

Overall, the association of Cerebral microbleeds with spontaneous intracerebralhemorrhage raises a clinical dilemma concerning the safety of antithrombotic treatments.Since Cerebral microbleeds provide direct evidence of blood leakage from pathologicallyfragile small vessels, their presence may be a risk factor for antithrombotic-associatedintracerebral hemorrhage, raising the important question of whether Cerebral microbleedsmay shift the risk–benefit balance away from antithrombotic use in some patients.

Cerebral microbleeds & Treatment: Balancing the Riskso Cerebral microbleeds & Antithrombotic Treatment.

Antiplatelet and anticoagulant treatments are widely used in patients at high risk ofcardiovascular or cerebrovascular disease (e.g., ischemic stroke, ischemic heart disease oratrial fibrillation). In our aging population, the lifetime risk for developing atrialfibrillation is one in four people over the age of 40 years.[125] If left untreated, atrialfibrillation increases the risk of ischemic stroke fivefold, with the highest risk seen inelderly patients who have had a previous stroke or transient ischemic attack. In this setting,anticoagulation reduces ischemic stroke risk by approximately 65%. However, this benefithas to be balanced against an increased risk of intracerebral hemorrhage, which is themost feared complication of anticoagulation, causing death or severe disability in up to75% of patients.[126] A recent observational inception cohort study of patients treatedwith anticoagulation (of whom a quarter had a previous history of stroke) reported a 2.5%(95% CI: 1.1–4.7%) risk of Intracerebral hemorrhage in 1 year.[127] Over the last decade,increasing use of warfarin to prevent cardioembolic stroke due to atrial fibrillation has ledto a fivefold increase in the incidence of anticoagulant-related intracerebral hemorrhage,which now accounts for approximately 15% of all intracerebral hemorrhage.[128] Thistrend is set to continue and will be a huge future healthcare, social and economic challenge.With the potential availability of new oral anticoagulants such as dabigatran,[129] it islikely that even more acute cardioembolic stroke patients will be using oral anticoagulationfor secondary stroke prevention. It is a paradox that many of these elderly patients at thehighest risk of cardioembolic stroke are also at the highest risk of Intracerebralhemorrhage. In many patients, this makes it extremely difficult to balance the antiocclusiveand prohemorrhagic effects of antithrombotic drugs; improving this risk–benefitassessment for individual patients remains a major goal of research in cerebrovascularmedicine.



Because anticoagulation-related intracerebral hemorrhage is associated with increased ageand previous stroke, and it often occurs with anticoagulation intensity within thetherapeutic range,[130] it is likely that the mechanism underlying this high risk is relatedto individual patient factors (e.g., an age-related disorder of small brain vessels, such asCerebral amyloid angiopathy or hypertensive small-vessel disease). In keeping with thishypothesis, some studies suggest that WMCs (a marker of small-vessel disease) increase therisk of anticoagulant-related Intracerebral hemorrhage.[131,132] Because they providedirect evidence of blood leakage from pathologically fragile small vessels, Cerebralmicrobleeds might be a stronger independent predictor of anticoagulation-associatedIntracerebral hemorrhage. The available studies on Cerebral microbleeds andanticoagulation-associated Intracerebral hemorrhage risk have many limitations, withmost being cross-sectional studies in Asian cohorts, so their findings cannot clearly showcausative relationships and may not be generalizable to other populations.[120,133–146]Nonetheless, existing data support the hypothesis that the presence of Cerebral microbleedsincreases the risk of Intracerebral hemorrhage as a complication of antithromboticmedication.[135,142,145] A prospective study reported Cerebral microbleeds in 87% ofpatients with Intracerebral hemorrhage following warfarin treatment for atrialfibrillation,[142] while a recent case–control study also reported more Cerebralmicrobleeds in warfarin-associated Intracerebral hemorrhage than in matched warfarinusers without Intracerebral hemorrhage.[141]

Cerebral microbleeds in the Setting of Other Treatmentso Thrombolysis

Another relevant question is whether there is an increased risk of intracerebralhemorrhage after thrombolysis of patients with ischemic stroke when Cerebralmicrobleeds are present. Some studies that explored the association between Cerebralmicrobleeds and the risk of hemorrhagic transformation following intravenous tissueplasminogen activator in patients who have had ischemic stroke have indicated possiblelinks,[143,152] while more recent studies have questioned these findings.[153,154] TheBRASIL study (the largest prospective, multicenter study to date), which included 570ischemic stroke patients, found that symptomatic Intracerebral hemorrhage occurred in5.8% of patients with Cerebral microbleeds versus 2.7% of patients without Cerebralmicrobleeds (p = 0.170).[153] However, all of the studies were underpowered to providereliable data of such an effect[6,155] and leave unanswered the questions of the role ofstrictly lobar microbleeds (reflecting underlying Cerebral amyloid angiopathy pathology)and multiple Cerebral microbleeds on the shaping of the risk.[49]

o Statins

Some neurologists have raised concerns over the use of statins in patients with Cerebralmicrobleeds . In the Rotterdam study, low serum cholesterol levels were found to bestrongly associated with the presence of strictly lobar microbleeds.[56] However, thisassociation was not replicated in the recent update of the study.[85] Lee and colleagues alsofound a relationship between low cholesterol concentrations and higher microbleed burdenin the 172 patients they studied.[156] In a more recent retrospective analysis of 349 patients



with acute ischemic stroke or transient ischemic attack, previous statin therapy was notassociated with either the prevalence or the degree of Cerebral microbleeds .[157] The roleof statins and low serum cholesterol in patients with microbleeds needs further exploration,particularly in light of the results of a randomized controlled trial of atorvastatin inpatients with stroke, which showed a small increase in the incidence of Intracerebralhemorrhage among patients receiving high doses of the drug.[158] The increased risk ofIntracerebral hemorrhage may be due to pleiotropic effects of statins other than the lipid-lowering effects.[159]

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Radiological pathology of cerebral microbleeds

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