Cerebral microbleeds: Causes, clinical relevance, and imaging approach – A narrative review

CAA

The CAA is a condition in which there is the deposition of protein in the tunica media and adventitia of the vascular layers of small arteries, arterioles, and capillaries in the cerebral cortex, overlying meninges and the gray-white matter junction. The most common protein in the sporadic CAA is amyloid-β, an eosinophilic, insoluble protein of 42 amino acid peptides cleaved from amyloid precursor protein on chromosome 21. This accumulation of proteins results in fibrinoid degeneration in the tunica media and tunica intima leading to microaneurysm formation. Imaging studies and histological staining of the biopsied tissues are used to establish a diagnosis. On computed tomography (CT), this is characterized by lobar pattern parenchymal hematomas. On MRI, the appearance of hemorrhage will vary according to the age of the bleed. The CMBs in a lobar distribution (cortical-subcortical) characterize CAA. To confirm the diagnosis, a biopsy is done with Congo staining, which shows apple-green birefringence when viewed with polarized light. When stained with thioflavin T, it illuminates with ultraviolet light, and the AB deposits emit bright green fluorescence. In older populations, CAA and HA can coexist resulting in a “mixed” lobar and deep distribution of CMBs, which poses a diagnostic challenge.^[10]

Luminal stenosis and fibrinoid necrosis are caused by the deposition of homogeneous eosinophilic deposits in vessels of the cortex and meninges. The vessels become weaker and more susceptible to bleeding. There is no direct connection between CAA and high blood pressure, diabetes or atherosclerosis. On imaging, surface lobar hematomas with subcortical or subarachnoid extension are visible. The 70% of patients have non-hemorrhagic diffuse encephalopathy and focal or patchy/confluent white matter (WM) disease. In CAA patients with multiple lesions, the distribution of CMBs shows a cortical predominance posteriorly, and they often appear to group in the same lobe. Blood-sensitive MRI sequences are also critical for detecting sporadic CAA markers such as superficial cortical siderosis and convexity subarachnoid hemorrhage (SAH) [Figures 6 and 7]. Apart from the already known lobar position in CAA-related intracerebral hemorrhage (ICH), studies have reported that CAA-related parenchymal hemorrhages are more likely to have subarachnoid space extension, an irregular ICH boundary, and multiple recurrent episodes of hemorrhage. A proposal for a classification scheme based on CT and genetic makeup as well as Edinburgh CT and genetic diagnostic criteria was recently developed. The presence of an ApoE 4 genotype and CT findings such as SAH and finger-like projections of the hematoma border were used to make the diagnosis.^[9,10] There are no specific treatment modalities available for CAA. It is seen that antihypertensive medications prevent ICH recurrence whereas antithrombotic may increase hemorrhage risk. There is a huge burden of CAA in elderly patients, which is unrecognized. Therefore, research efforts to develop or discover biomarkers for early detection of CAA can reduce the cases of microbleeds (MCB) and simultaneously give opportunities to develop treatment interventions.^[11,12]

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Figure 6:

(a and b) Axial T2WI and (c) susceptibility-weighted imaging sequences in a 71-year-old male patient who presented with cognitive decline showing classical imaging findings of amyloidangiopathy (white matter changes with subcortical microhemorrhages).

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Figure 7:

(a and b) Axial T2*- and (c) T1-weighted sequences in a 76-year-old male patient with amyloid angiopathy who presented with acute head and weakness due to right parietal hemorrhage.

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HA

High arterial blood pressure is one of the most common causes of vascular diseases. High arterial blood pressure primarily affects the small arteries in the brain, which results in these arteries undergoing segmental constriction in response to persistent high blood pressure. The long-term constriction leads to smooth muscle hypertrophy in the tunica media by collagen fibers. Chronic arterial hypertension brings structural changes in the intraparenchymal arteries and arterioles called arteriolosclerosis including microadenoma, lipohyalinosis, fibroid necrosis, and microaneurysm (Charcot Bouchard aneurysm). The most common sites for HA are basal ganglia, thalamus, cerebellum, and pons, small vessels prone to hypertensive-induced vascular injuries.

Patients who suffered from microhemorrhaging were at the extreme of old age and had an elevated risk of hypertension. A link was established between the number of microhemorrhages and white matter hyperintensity. Hypertension is among the most common causes of diseases of the small vessel most commonly presenting as non-specific white matter signal changes on imaging representing damage to tissue caused by microangiopathy. The classic location for microhemorrhages includes the lentiform nucleus, thalamus, and brainstem, which are all common sites for symptomatic hematomas. An MRI in hypertensive microangiopathy reveals white matter T2 hyperintensities, a variable number of microbleeds seen best on GRE or SWI, in addition to ICH. Treatment in such patients is to keep the blood pressure under control.^[4,13,14]

Critical illness-associated CMBs

Critical illness associated microbleeds is a newly described term encompassing many underlying etiologies and primarily seen in intensive care unit (ICU) patients. There is diffuse involvement of the juxtacortical white matter and corpus callosum with sparing of the cortex and periventricular regions [Figure 10].^[17-19] Extensive involvement of the corpus callosum is a hallmark of this entity, more commonly seen in the younger age group.^[20] Respiratory failure is a leading cause for this entity, typically in an ICU setting secondary to acute respiratory distress syndrome, lung transplant, and cystic fibrosis. Other common etiologies include leukemia, lymphoma, sickle cell disease encephalitis, and H1N1 influenza infection. Regardless of the underlying etiology, acute respiratory failure is a common feature in all reported patients as well as our patients. The CMBs can develop rapidly over the course of a few days to weeks and usually remain stable over subsequent follow-up scans.^[20,21]

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Figure 10:

(a and b) Susceptibility-weighted imaging images in a patient with respiratory failure, pre- and post-intensive care unit (ICU) admission. Numerous microbleeds noted in the brain, involving the corpus callosum, 2 weeks after admission to ICU. Findings consistent with “critical-illness related microbleeds.”

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Thrombocytopenia

Thrombocytopenia is a condition where the platelet count is <150,000 platelets per microliter of circulating blood. The primary role of platelets is to maintain hemostasis and take part in angiogenesis and innate immunity. A platelet count as low as 80 × 10⁹/L may be appropriate for hemostasis if platelet function is normal. When the platelet count falls below 20 × 10⁹/L, clinically important spontaneous hemorrhage occurs. Anemia, leukemia, disseminated intravascular coagulation (DIC), or drug-induced thrombocytopenia (quinine, quinidine, gold salts, phenytoin, valproic acid, carbamazepine, sulfonamides, and heparin-induced) are all potential causes of thrombocytopenia. Immune thrombocytopenia (ITP) is an autoimmune disorder associated with an aberrant immune response resulting in thrombocytopenia. Spontaneous microbleeds can frequently be seen in patients with platelet counts <30 × 10⁹. CMBs occur more in ITP with longer duration and lower nadir platelet counts.^[22]

DIC

This syndrome is caused by the loss of clotting factors and platelets, faulty and stimulated fibrinolysis, and a deterioration of the coagulation inhibition mechanism. Fibrin-rich thrombi are seen pathologically in arterioles, capillaries, and venules. The cause of mortality in DIC patients is multi-organ dysfunction and severe bleeding. DIC is not a separate condition but a symptom of an underlying disorder or disorder. Infections, malignancies, obstetric diseases, trauma, blood disorders, aneurysms, and liver disease can complicate DIC. DIC symptoms and signs affecting the nervous system are linked to thrombotic and hemorrhagic complications. There are different treatment modalities to treat DIC along with treating the underlying conditions, including blood transfusion in massive bleeding, heparin in non-symptomatic DIC, synthetic proteases inhibitor, and antifibrinolytic in symptomatic DIC, natural proteases inhibitors in organ failure DIC.^[22,23]

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)/cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL)

A mutation in the NOTCH3 gene on chromosome 19q12 causes CADASIL, an inherited disease. Progressive memory decline, migraines with aura, mood swings, and small vessel infarcts are common in patients. MRI features include changes in white matter on T2-weighted images, lacunar infarcts on T1-weighted images, and CMBs. Microbleeds have been reported to occur in 25–70% of cases of CADASIL without lobar preference. White matter differences in a periventricular distribution affect the anterior temporal lobes, corpus callosum, and external capsule. The capsular-striatal zone, the thalami, and the central pons are popular sites for lacunar infarcts. Cognitive function loss is linked to CMB burden and position, lacunar infarcts, and atrophy of the cortex.^[24] CARASIL is a systemic genetic disorder affecting small intracranial vessels, spine, and hair follicles. This usually presents in the second or third decade of life with premature alopecia, relapsing ischemic stroke-like episodes and epilepsy. The exact incidence of microbleeds in CARASIL is poorly documented at present, given the rarity of this condition.^[24,25]

Infective endocarditis

The inflammation of the innermost layer of the endocardium characterizes infective endocarditis. The pathophysiology of endocarditis can be infective (most commonly bacterial in nature) or non-infective. Complications of infective endocarditis include infective intracranial aneurysm, which leads to the dilation of an arterial wall due to the infection. This mycotic aneurysm leads to CMBs in infective endocarditis patients. Mycotic aneurysms are more prone in immune-compromised hosts such as diabetes mellitus, steroid users, HIV or malignancy/chemotherapy. CMBs are not unusual in the case of infective endocarditis acquired from the community, seen in around 57% in the endocarditis group compared with <20% in controls. CMBs can frequently be seen adjacent to the cerebral sulci, representing small bleeds secondary to tiny sulcal or subpial mycotic aneurysms [Figure 11]. There is currently no modality with an adequate spatial resolution to detect sub-millimeter aneurysms. Occasionally, these tiny mycotic aneurysms can mimic microbleeds; however, these are within the sulci instead of being parenchymal and, unlike other aneurysms, can spontaneously regress.^[4,27]

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Figure 11:

(a-c) 41-year-old female patient with infective endocarditis shows areas of microhemorrhages (red arrow) and a small old subarachnoid hemorrhage in the right frontal lobe (green arrows). The patient presented with the right-side weakness due to an acute infarct in the left parietal lobe (teal arrow) with low apparent diffusion coefficient value.

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Atrial myxoma

Atrial myxoma is the most common primary cardiac tumor accounting for about 50% of cardiac tumors. It occurs 70% of the time in the left atrium, either at the mitral annulus or the fossa ovalis border of the interatrial septum. Myxoma cells are formed from the multipotent mesenchymal cells. A triad of complications, including obstruction, embolic, and constitutional symptoms (such as fever, weight loss, malaise, anorexia, and high erythrocyte sedimentation rate), is associated with atrial myxoma. The villous and friable myxoma has a high potential to cause embolic events, whereas smooth myxoma usually causes obstruction. A quarter of left atrial myxoma patients develop neurological events which most frequently occur due to ischemic stroke, which is secondary to embolization from the heart. The multiple embolizations cause multiple subcortical infarcts that produce dementia over many years. Other causes of neurological manifestations are aneurysms and pseudoaneurysms, formed by the tumor cell infiltrating the cerebral vessel wall, weakening the internal elastic lamina. The embolized particles from the myxoma tumor are believed to be responsible for the microbleed. Echocardiogram is the investigation of choice as it is quick and easily available [Figure 12]. Cardiac MRI is also a diagnostic test to detect cardiac myxoma and provides a fair idea about the microenvironment within the tumor in T1- and T2-weighted sequence. Surgical excision is the treatment of choice for cardiac myxoma.^[28]

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Figure 12:

(a) Cardiac Doppler shows large left atrial myxoma. (b) Computed tomography, and (c and d) magnetic resonance imaging performed for the same patient with complaints of acute severe headache shows acute left frontal bleed with the left frontal subarachnoid hemorrhage.

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Moyamoya syndrome

The intracranial internal carotid arteries and their proximal branches become occluded in Moyamoya syndrome, a chronic progressive occlusive cerebrovascular condition. Reduced blood flow to the corresponding vessels leads to the formation of collateral vasculature. The cause of bleeding is associated with the rupture of fragile collateral vessels. On catheter angiography, the fine tortuous collateral vessels appear as a typical “puff of smoke.” CMBs were mostly found in the paraventricular zone, the subcortical white matter in the temporal lobe, and the basal ganglia [Figure 13]. The existence of multiple CMBs is related to an increased risk of ICH.^[29]

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Figure 13:

(a-c) Computed tomography angiogram of a 41-year-old female patient reveals extensive collateral formation throughout the cerebral parenchyma with severe narrowing of the terminal internal carotid arteries. (d) Susceptibility-weighted imaging revealed multiple tiny chronic hemorrhages. The patient was diagnosed with primary Moyamoya disease.

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Posterior reversible encephalopathy syndrome (PRES)

PRES is a neurologic disorder established when a person presents with visual disturbance, seizure, headaches, and altered mentation. It is believed that PRES syndrome has the following risk factors hypertension, preeclampsia, kidney diseases, autoimmune disorders (thrombotic thrombocytopenia purpura, eosinophilic granulomatosis with polyangiitis, and systemic lupus erythematosus), use of cyclosporine following organ transplantation, and sepsis. Hypertension is believed to be the main triggering factor for PRES syndrome. The PRES can occur acutely or subacutely within hours to days. In acute cases, it is seen that the blood pressure usually ranges from 160 to 190 mmHg. On MRI, fluid attenuation inversion recovery sequences reveal focal areas with symmetric hemispheric hyperintensities, most notably in the parietal and occipital lobes, indicating vasogenic edema. Hemorrhage was once thought to be an atypical characteristic of PRES, but microbleeds can be seen in 15–60% of subjects in whom SWI is acquired. The most accepted theory says that PRES in association with CMBs occurs due to endothelial cell dysfunction. For treatment purposes, removing the underlying causative agent, including controlling the blood pressure will reverse the edematous changes; however, microhemorrhages are irreversible. In acute cases, a sudden reduction of blood pressure can cause cerebral hypoperfusion of the brain and lead to brain ischemia; therefore, blood pressure should not drop more than 10–20 mm, every 10–20 min.^[30]

Renal failure and microhemorrhages

The precise cause of CMBs in patients with renal failure is unclear. It is believed that chronic kidney disease (CKD) patients have an increased prevalence of microbleeds. The uremic toxin affects the blood-brain barrier permeability leading to microbleeds. MRI studies have shown a positive correlation between microbleeds in CKD patients with age-matched non-CKD control. Microhemorrhages have been reported to be more common in hemodialysis patients with chronic renal failure. Cho et al. examined 152 patients with a gradient-echo imaging scan and an acute ischemic stroke. They discovered a clear connection between inadequate kidney function and the existence of microbleeds. According to Ryu et al., CMBs are associated with chronic renal disease in patients who do not have diabetes, but not in diabetic patients with no renal disease. The uremic toxins affect the blood-brain barrier permeability leading to microbleeds. Many MRI studies have shown a positive correlation between microbleeds in CKD patients with age-matched non-CKD control.^[31,32]