Radiological pathology of microvascular brain disease
INDEX www.yassermetwally.com INTRODUCTION CENTRAL/CORTICAL ATROPHY LEUKOARAIOSIS LACUNAR INFARCTIONS GRANULAR ATROPHY BASAL GANGLIONIC CALCIFICATIONS DILATED VIRCHOW RUBIN SPACESINTRODUCTION & PATHOGENESIS :Microcirculatory brain disease is a collective terminology that comprises vasculararteriolar pathology, metabolic endocrinal abnormalities and haemorheologicalabnormalities. Clinically it is characterized by the existence of cerebral ischaemic eventsthat have a peculiar tendency for recurrence and progression to multi-infarct dementia.These ischaemic events are commonly associated with increased incidence of depression,parkinsonian manifestations, essential hypertension and blood hyperviscosity. Theassociates of the microvascular brain disease are collectively called the metabolicsyndrome. See table 1
Table 1. Microvascular brain disease associates (the metabolic syndrome)Microvascular associate DescriptionClinical picture Stroke, TIAs, multi-infarct dementia, essential hypertension, depression, parkinsonismMetabolic, endocrinal changes Type VI hyperlipidaemia (Hypertriglyceridemia), hyperuricemia, type 2 diabetes, Insuline resistance, truncal obesity (The metabolic syndrome)Vascular pathology Lipohyalinosis, astrogliosis and interstitial edema, etc Increased whole blood viscosity and hypercoagulabilityHaemorheological changes characterized by an increased plasminogen activator inhibitor-1 (PAI-1) level.The endocrinal and metabolic abnormalities characteristic of the microvascular braindisease include non-insulin dependent diabetes mellitus, Type IV hyperlipidaemia(increased triglyceride and reduced HDL), truncal obesity, and hyperuricemia (Themetabolic syndrome)Although the association between parkinsonian manifestations (vascular parkinsonism)and microvascular brain disease can be attributed to the pathologic findings of multiplebasal ganglia cavitations (etat crible) and infarcts (etat lacunaris) that are encountered inthe ischemic microvascular brain disease, however a link between the idiopathic parkinsondisease and type 2 diabetes was demonstrated by Hu, et al, . Hu, G, et al, 122 foundthat individuals who developed type 2 diabetes have an 83% increased risk for PDcompared with the general population. The mechanism of the association between type 2diabetes and PD is, however, poorly understood. Insulin might play a role in the regulationof central dopaminergic transmission. 122 According to the study of Hu, et al, 122 Theassociation between type 2 diabetes and PD is independent of sex, smoking, alcohol andcoffee intake, and body weight. The demonstrated link between the idiopathic parkinsondisease and type 2 diabetes could result in increased incidence of the idiopathic parkinsondisease in the microvascular brain disease that is independent of any structural ischemiccerebral pathology. Insuline resistance, the metabolic syndrome and the ischemic microvascular brain diseaseThe mechanisms that are responsible for the insulin resistance syndromes (IRS) includegenetic or primary target cell defects, autoantibodies to insulin, and accelerated insulindegradation. Obesity, the most common cause of insulin resistance, is associated with adecreased number of receptors and postreceptor failure to activate the tyrosine kinase.Insulin resistance plays a major pathogenic role in the development of the metabolicsyndrome that may include any or all of the following: hyperinsulinemia; type 2 diabetes orglucose intolerance; central obesity; hypertension; dyslipidemia that includes hightriglycerides (TG); low high-density lipoprotein cholesterol (HDL-C) and small, dense low-
density lipoprotein (LDL) particles; and hypercoagulability characterized by an increasedplasminogen activator inhibitor-1 (PAI-1) level. Figure 1. Diabetes, hyperlipidaemia, truncal obesity depression, parkinson disease, hyperuricaemia hypertension, etc all stem from one and the same root (the genetic root)THE ISCHEMIC MICROVASCULAR BRAIN DISEASEAs a point of departure a quick over view on the cerebral microcirculation will be given.Two microvascular systems were described. The centrifugal subependymal system and thecentripetal pial system. The centrifugal subependymal microvascular system originatesfrom the subependymal arteries which are terminal branches of the choroidal arteries,then extends centrifugally outward into the periventricular gray matter (Basal ganglia andthalamus) and the immediate periventricular white matter.The centripetal pial vascular system originate from the pial arteries then extendscentripetally inwards towards the ventricular system. This system supply the cortical graymatter and the immediate subcortical white matter. Accordingly the microcirculation isheavily concentrated in the cortical and the immediate periventricular regions. Figure 2. The cerebral microcirculationThe microvascular pathology includes initially vascular smooth muscle cell (VSMC)proliferation associated with increased sensitivity of the VSMCs resulting in increasedcontractibility of the microvascular smooth muscle cells. This is reflected in increasedtendency of the fine penetrating intracerebral arterioles for vasospasm. At an advanced
stage microvascular remodelling occurs resulting in VSMCs degeneration coupled withexcessive deposition of the ground substance (collagen fibres and Lipohyaline material) inthe arteriolar walls resulting in what is termed pathologically lipohyalinosis. VSMCsdegeneration coupled with lipohyalinosis ultimately result in loss of the physiologicalautoregulatory process. Figure 3. Lipohyalinosis is seen in the smaller penetrating arteries (<200 micrometers in diameter) and occurs almost exclusively in patients with hypertension. It has features of both atheroma formation and fibrinoid necrosis with lipid and eosinophilic fibrinoid deposition in the media.The haemorheological changes associated with microvascular brain disease includeincrease in the whole blood viscosity and thrombotic tendency of the blood. In general asignificant increase of blood, plasma and serum viscosity and a decrease of whole bloodfilterability are observed in the metabolic syndrome, and this significantly impair flow inthe microcirculation and contribute to the development of the ischemic microvascularbrain disease. 118,119,120,121A negative relationship is observed between directly measured whole-blood viscosity andinsulin sensitivity as a part of the insulin-resistance syndrome (The metabolic syndrome),and a positive relationship is observed between insulin resistance and whole blood viscosity.In general, obesity and insulin resistance both impair blood rheology by acting on red cellrigidity and plasma viscosity. Whole blood viscosity reflects rather obesity than insulinresistance. 118,119,120,121 Whole blood viscosity is a collective terminology that include blood viscosity and plasma viscosity. Blood viscosity is determined by the haematocrit value and plasma viscosity is determined by serum fibrinogen. Increase of the haematocrit value and serum fibrinogen - even within the normal range - increases the whole blood viscosity. Increase of the platelet aggregation also increases whole blood viscosity. Figure 4. PLATELETS AGGREGATIONReduced RBCs deformability and increased RBCs aggregability also increase whole bloodviscosity. Normally the RBCs must be deformed (they usually become parachuted) in orderto pass through the microcirculation. Reduction of the RBCs deformability results in poorRBCs flow through the microcirculation and subsequently poor tissue oxygenation.
Figure 5. RBCs deformability [left] and rigidity [right]It should also be noted that increased fibrinogen level, especially when associated withincrease of the RBCs and platelet aggregability, reflects a hypercoagulable state thatselectively affects the microcirculation of the brain. Microvascular occlusion can occureither by Local aggregation of hyperaggragable platelets or by red cell aggregation withimpaction of rigid red cell in the microcirculation.Increase of the blood viscosity results in global reduction of brain perfusion, however, thisis normally compensated for by the physiological process of autoregulation. In response tocritical reduction of brain perfusion, the brain microvascular bed dilates thus increasingbrain perfusion. Normally the autoregulatory process keeps the brain perfusion at aconstant level despite the normal daily fluctuation of the whole blood viscosity.Loss of the autoregulatory physiological process, secondary to microvascular arteriolarpathology, will simply mean that brain perfusion will fluctuate with fluctuation of thewhole blood viscosity. The micro vascular brain disease is the end result of a vicious circlethat starts at one end of the circle with loss of the autoregulatory process and restarts at theother end of the circle by increase of the whole blood viscosity. This vicious circle shouldmean that in microcirculatory brain disease there is critical and chronic reduction of wholebrain perfusion that is interrupted by frequent microvascular thrombo-occlusive episodesof sudden onset and regressive course. These episodes are secondary to thehypercoagulable state and increased thrombotic tendency of the blood. The metabolicsyndrome, which is commonly associated with the microvascular brain disease, are socommonly associated with increased blood viscosity to the point that it can be called theblood hyperviscosity syndrome.In general hypertension, an elevated hematocrit value above 45, increased fibrinogen level,old age, cigarette smoking and the metabolic syndrome are significantly linked with silentand symptomatic lacunar infarctions and the microvascular brain disease. Cigarettesmoking is significantly linked with the metabolic syndrome (The insulin resistancesyndrome). Smoking increases insulin resistance and is associated with central fataccumulation.CEREBRAL PARENCHYMAL CONSEQUENCES OF MICROVASCULAR BRAINDISEASE Central and cortical atrophyThis is secondary to chronic global reduction of brain perfusion.
Figure 6. Central and cortical atrophy secondary to chronic global reduction of brain perfusion, Notice the associated lacunar infarctions LeukoaraiosisLeukoaraiosis is an ischaemic demyelination of the immediate periventricular white matterassociated with astrogliosis, enlarged extracellular spaces and white mattermicrocavitations. It is secondary to chronic global reduction of brain perfusion.Leukoaraiosis, which appears as an area of hyperintense signal in the white matter on MRimages, is an age-related neurodegenerative condition that, when severe, correlates withdementia. It is characterized histologically by demyelination, loss of glial cells, andspongiosis. The pathogenesis of leukoaraiosis is not yet established, but it is thought to berelated to ischemia. Periventricular venous collagenosis, thickening of the vessel wall bymultiple layers of collagen, has been reported to occur in aging brains and to be moresevere in brains with leukoaraiosis. In postcapillary venules and small veins, the stenosisthat results from severe periventricular venous collagenosis may be one contributing factorin chronic localized ischemia, with consequent cell injury and death.
Figure 7. A, Central and cortical atrophy, notice the associated leukoaraiosis and lacunarinfarctions, more on the left side. B, leukoaraiosis. The CT scan periventricularhypodensities are mainly due to astrogliosis and interstitial edema. o Histopathology of leukoaraiosisPostmortem studies reveal that leukoaraiosis can be due to a heterogenous assortment oftissue changes that differ in histopathologic severity. In most cases, periventricularleukoaraiosis consists of variable degrees of axonal loss, demyelination, astrocytosis, andfinely porous, spongy, or microcystic changes in the neuropil. 34,79,96 These changes arefrequently associated with arteriosclerotic vasculopathy and, in more severe cases, withfrank lacunae infarction. 54 On MR imaging the mild degree of leukoaraiosis almostalways present adjacent to the angles of the frontal horns is usually due to focal gaps in theependymal epithelium with mild underlying gliosis. 86 This change, known as ependymitisgranularis, increases in frequency with age and is believed to be due to the wear and teareffects of ventricular CSF pulsations on an ependymal lining incapable of self-repair. 82leukoaraiosis may also be related to histologic characteristics of the normal frontal hornsubependymal region (fasiculus subcallosus) where finely textured fibers may havedifferent T2-relaxation properties than the deeper white matters Figure 8. Etat cribe seen in a cognitively and neurologically normal 81-year- old woman. Fast spin echo: A, Proton density image. B, Second echo: dilated perivascular spaces permeate the basal ganglia bilaterally.Subcortical regions of leukoaraiosis seen on MR imaging share many of the histologicfeatures characteristic of the periventricular pattern. Pathologic correlation studies basedon postmortem MR image scanning have demonstrated reduced axonal andoligodendroglial density, astrocytosis, pallor on myelin staining, diffuse neuropilvacuolation, and hyalinotic arteriolar thickening 74,91. In some cases, these diffuse changesare found to surround variably sized foci of cystic infarction. 12, 13, 66 Subcorticalleukoaraiosis, particularly when highly circumscribed or punctate, can often be explainedby dilated Virchow-Robin spaces surrounding ectatic and sclerotic arterioles. 43,55 Suchchanges may occur in 40% of patients with hypertension, 92 and, when severe, correspondsto the phenomenon of etat crible originally described by Durand-Fardel in 1843. 24
Figure 9. Neurologically normal patient with leukoaraiosis affecting the basis pontis and tegmentum.Rarely, patients with extensive leukoaraiosis can be diagnosed as having Binswangersdisease. This condition, sometimes referred to as lacunar dementia, etat lacunaire, orsubcortical arteriosclerotic encephalopathy, 75 is characterized pathologically by extensiveathero and arteriosclerosis, multiple foci of white matter infarction, diffuse white matterdemyelination with sparing of the subcortical "U" fibers, and variable evidence for corticalinfarction. 5,75 These white matter changes are more destructive than those of typicalleukoaraiosis and are clinically associated with combinations of hemiparesis, gaitdysfunction, spasticity, Parkinsonism, dysarthria, incontinence, pseudobulbar palsy, anddementia. These abnormalities generally accumulate over months or years in a nonuniformand sometimes stroke-like fashion. 6, 19, 22, 39, 51, 88 There is a tendency for patients tobe hypertensive but exceptions have been described. 19, 22, 39
Figure 10. Radiographic/histopathologic correlation for a case of diffuse and extensiveperiventricular LE occurring in an 86-year-old patient. A, Antemortem coronal MR imageof left occipital lobe. Note extensive white matter hyperintensity adjacent and superior tothe occipital horn of the lateral ventricle sparing the subcortical arcuate fibers. B,Postmortem coronal MR image of left occipital lobe. Note topographically coextensivewhite matter changes compared with A. C, Bielschowsky-stained postmortem specimen(2X) corresponding to A and B. D, Photomicrograph (hematoxylin-eosin, originalmagnification x 140) from involved white matter demonstrating perivascular parenchymalrarefaction and macrophage infiltration. E, Photomicrograph (GFAP, originalmagnification x 660) from involved white matter demonstrating reactive astrocytes. Noregions of cystic (lacunar) infarction could be identified in this case. Figure 11. Postmortem specimen. Note the topographically extensive periventricular white matter changes in a hypertensive case with evidence of leukoaraiosis on MRI study
In contrast to the severe and necrotizing changes of Binswangers disease, it is apparentthat the histology underlying most other forms of leukoaraiosis is far less destructive. Thisobservation may explain why individuals with radiographically widespread leukoaraiosisare often unimpaired. In MS, extensive demyelinative plaques with relative axonalpreservation can frequently evolve silently while affecting even neurofunctionally criticalregions such as the brain stem and thoracic spinal cord. 37, 38,50, 64, 72 Given thepathology associated with these clinically silent lesions, the dilated perivascular spaces,isomorphic gliosis and low-grade demyelination of leukoaraiosis might be also expected tohave limited clinical consequences.Figure 12. leukoaraiosis, MRI T2 image. The MRI T2 periventricular hyperintensities aremainly due to astrogliosis and interstitial edema. o Pathophysiology of leukoaraiosisSeveral pathophysiologic mechanisms have been proposed to explain the histology ofleukoaraiosis. In addition to ependymitis granularis and Virchow-Robin space dilatation,more extensive regions of leukoaraiosis have been attributed to the ischemic effects ofchronic oligemia and to perivascular edema and retrograde axonal degeneration. Chronic hypoperfusionIn the severe (Binswangers disease) form of leukoaraiosis, chronic microvascular oligemiaand intermittent thrombotic occlusion appear responsible for the observed pattern ofmultiple lacunar infarcts with interspersed areas of edema, demyelination, and gliosis.Unlike the richly collateralized cerebral cortex, the leukoaraiosis vulnerable white matter isperfused by long penetrating corticofugal endarteries with few side branches, a vasculararchitecture that provides little protection from the ischemic effects of microvascularstenosis. 22, 80
The extent to which the more common and histologically milder forms of leukoaraiosis canalso be explained by ischemic mechanisms is currently unclear. The term "incompletewhite matter infarction" has been proposed to designate regions of mild demyelination,oligodendroglial loss, astrocytosis, and axonal rarefaction that occur in proximity to cysticinfarcts or in association with arteriolar hyaline vasculopathy. 26 These changes, whichcharacterize most forms of diffuse leukoaraiosis and can be seen in association with thecystic lacunes of Binswangers disease, may represent the long-term consequences ofchronic hypoperfusion due to senescence and hypertension-related microvascular stenosis.Direct evidence for hypoperfusion as an explanation of leukoaraiosis pathogenesis isconflicting. Several studies have demonstrated diminished cerebral blood flow (CBF) inwhite matter regions affected by leukoaraiosis, 30, 51, 18 but it is unclear whether suchhypoperfusion is itself causative or occurs as a secondary response to reduced metabolicactivity of the leukoaraiosis tissue. Using, 18 F fluoromethane positron emissiontomography (PET), one study revealed that while severe leukoaraiosis regions wereassociated with ipsilateral cortical hypoperfusion, the hypoperfused regions typicallyspared the anterior and posterior cortical watershed territories. 45 The authors use thisfinding to argue that the blood flow reductions seen in leukoaraiosis cases result from thelower metabolic demands of cortex rendered electrophysiologically isolated by subjacentzones of disrupted white matter tissue. The implication is that chronically inadequatehemispheric perfusion may not play a role in leukoaraiosis pathogenesis. While thisinterpretation gains support from the observation that hemodynamically significantextracranial carotid stenosis does not correlate with the presence of ipsilateralleukoaraiosis, 30 others have seen leukoaraiosis to progress in concert with a severelystenosed ipsilateral carotid that advanced to complete occlusion. 95 In a more recent study,an increased oxygen extraction fraction (OEF) for white matter was found in fournondemented subjects with severe leukoaraiosis. 94 If replicated, this result would supportchronic hypoperfusion as an etiologic mechanism by revealing leukoaraiosis lesions toexperience a metabolic demand out of proportion to the local CBF. Fluid accumulation and edemaThe subependymal accumulation of interstitial fluid has been proposed as an alternativeexplanation for leukoaraiosis. 16, 97 Approximately 10% to 20% of CSF may be producedintraparenchymally and transependymally absorbed 47, 78, 81 into the lateral ventricles.Such a drain age pattern might increase the water content of the periventricular region andresult in leukoaraiosis, particularly if exacerbated by the effects of age-related ependymaldegeneration (ependymitis granularis).Feigin and Budzilovich, 3l,32 observed leukoaraiosis- like white matter changes includingdemyelination, hyalinized microvessels, cystic necrosis, and astrocytosis in the edematousregions surrounding intracerebral tumors. These authors proposed that Binswangersdisease might result from a self-reinforcing cycle of tissue destruction where chronichypertension combined with episodes of local hypoxia and acidosis contribute to theformation of extracellular edema. The edema would then trigger cytotoxicity, gliosis, anddemyelination and potentiate the degenerative microvascular changes. Based on this model,
others have suggested that exudation of serum proteins from arterioles made leaky fromthe effects of hypertensive vasculopathy might explain the milder white matter changes ofsubcortical leukoaraiosis. 74 Axonal degenerationIschemic axonopathy may also account for leukoaraiosis. Ball, 7 described the presence ofleukoaraiosis with cortical layer III laminar necrosis in the postmortem brains of fourelderly patients who experienced episodic systemic hypotension during life. Because theleukoaraiosis regions consisted of rarefied white matter without necrosis or microvascularsclerosis, this author proposed that distal axonopathy secondary to cortical neuronalischemia was the underlying process. Supporting the hypothesis that retrogradedegenerative white matter changes can account for at least some leukoaraiosis lesions is thefinding of MR image hyperintensities within pyramidal tract locations distal and ipsilateralto internal capsule infarcts. 76 o Neuroimaging of leukoaraiosisRadiographic LA has been correlated with a variety of neuropathological findings.Punctuate hyperintensities are caused by perivascular demyelination and gliosis, dilatedVirchow-Robin spaces, or small lacunae. Diffuse or extensive LA consists of areas of loss ofaxons and glial cells, predominantly oligodendrocytes, and myelin rarefaction (sparing theU fibers) accompanied by spongiosis. 106, 107 Multiple lacunae and multiple sclerosisplaques have also been found in areas of radiological LA. Periventricular rims, thin caps,and halos correlate with subependymal glial accumulation associated with loss of theependymal lining. The consensus is that small vessel disease is associated with LA. 108However, a variety of vasculopathies have been found to produce LA on imaging studies.Lipohyalinosis of the long penetrating arteries originating from the pial network and theventrofugal branches of the choroidal arteries is the most common abnormality in patientswith LA. Other vasculopathies can also lead to the neuropathological abnormalitiesdescribed earlier. 108 Cerebral amyloid angiopathy consisting of amyloid deposition in themedia and adventitia of small and midsized arteries of the cerebral cortex andleptomeninges is believed to lead to LA in patients with Alzheimer disease. 108 InCADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts andleukoencephalopathy) electron-dense, eosinophilic deposits are found in the media of smallvessels; this leads to lumen narrowing. 109The implications of finding LA on computed tomographic scan or magnetic resonanceimaging are varied. Some studies have found that it is a predictor of vascular death inelderly neurological patients; when found in patients with ischemic strokes, it adds extrarisk of future strokes from large and small vessels. While some studies have found that LAis not an independent risk factor for intracerebral hemorrhage, 108 the increased severityof WMCs was found to correlate with a 7-fold increased risk of bleeding fromanticoagulation in the SPIRIT Study. 110
Lacunar infarctionslacunar infarctions are secondary to the microvascular thrombo-occlusive episodes. Theyare most numerous in the periventricular gray matter (thalamus and basal ganglia) and theimmediate periventricular white matter. Spasm of the fine penetrating arterioles(secondary to increased VSMCs sensitivity) can also result in Lacunar infarctions. o BackgroundThe lacunar hypothesis proposes that (1) symptomatic lacunes present with distinctivelacunar syndromes and (2) a lacune is due to occlusion of a single deep penetrating arterygenerated by a specific vascular pathology. This concept is controversial because differentdefinitions of lacunes have been used. Lacunes may be confused with other empty spaces,such as enlarged perivascular (Virchow-Robbins) spaces, in which the specific small vesselpathology occasionally is absent. Originally, lacunes were defined pathologically, butlacunes now are diagnosed on clinical and radiological grounds. This problem iscompounded by the present inability to image a single penetrating artery.Lacunes may be defined as small subcortical infarcts (less than 15 mm in diameter) in theterritory of the deep penetrating arteries and may present with specific lacunar syndromesor may be asymptomatic. Unfortunately, neither the 5 classical lacunar syndromes nor theradiological appearances are specific for lacunes. Lacunes occur most frequently in thebasal ganglia and internal capsule, thalamus, corona radiata, and pons. o PathophysiologyLacunes are caused by occlusion of a single penetrating artery. The deep penetratingarteries are small nonbranching end arteries (usually smaller than 500 micrometers indiameter), which arise directly from much larger arteries (eg, the middle cerebral artery,anterior choroidal artery, anterior cerebral artery, posterior cerebral artery, posteriorcommunicating artery, cerebellar arteries, basilar artery). Their small size and proximalposition predispose them to the development of microatheroma and lipohyalinosis.
Figure 13. lacunar infarctions are secondary to the microvascular thrombo-occlusiveepisodes. They are most numerous in the periventricular gray matter (thalamus and basalganglia) and the immediate periventricular white matter.Initially, lipohyalinosis was thought to be the predominant small vessel pathology oflacunes; however, microatheroma now is thought to be the most common mechanism ofarterial occlusion (or stenosis). Occasionally, atheroma in the parent artery blocks theorifice of the penetrating artery (luminal atheroma), or atheroma involves the origin of thepenetrating artery (junctional atheroma).A hemodynamic (hypoperfusion) mechanism is suggested when there is a stenosis (and notocclusion) of the penetrating artery. When no evidence of small vessel disease is found onhistologic examination, an embolic cause is assumed, either artery-to-artery embolism orcardioembolism. About 25% of patients with clinical radiologically defined lacunes had apotential cardiac cause for their strokes. o Histologic FindingsLacunes are not examined histologically except at necropsy. Histologically, lacunes are nodifferent from other brain infarcts. Cells undergoing necrosis initially are pyknotic, thentheir plasma and nuclear membranes break down. Polymorphonuclear cells appearfollowed by macrophages, and the necrotic tissue is removed by phagocytosis. A cavitysurrounded by a zone of gliosis is the end result. Careful examination may reveal theunderlying small vessel pathology.
Figure 14. Pontine lacunar infarctionsMicroatheroma causing occlusion or stenosis of a deep penetrating artery is the mostcommon small vessel pathology, usually involving the artery in the first half of its course.Histologically, microatheroma is identical to large vessel atheroma with subintimaldeposition of lipids and proliferation of fibroblasts, smooth muscle cells, and lipid-ladenmacrophages.Lipohyalinosis is seen in the smaller penetrating arteries (<200 micrometers in diameter)and occurs almost exclusively in patients with hypertension. It has features of bothatheroma formation and fibrinoid necrosis with lipid and eosinophilic fibrinoid depositionin the media.Three types of lacunar infarctions were defined pathologically. Thus, Type I lacunes consisted ofirregular cavities containing parenchymal fragments, lipid- or haemosiderin-laden macrophagesand small patent blood vessels, surrounded by a narrow zone of gliosis. Type II lacunes wereregular cavities filled with haemosiderin- laden macrophages (old small haemorrhages). Type IIIlacunes were defined as dilated perivascular spaces with no, or minimal, surrounding parenchymaldamage. o Neuroimaging of lacunar infarctionsLacunar infarctions are punctate lesions mostly seen in the in the periventricular graymatter (thalamus and basal ganglia) and the immediate periventricular white matter, andare also seen in the brain stem. These lesions are hypodense on CT scan and hypointense ofT1 weighted images and hyperintense on the T2 weighted images. Contrast enhancementmight occur in acute lesions. Marked hypointensities on the T1 weighted images (blackholes) are consistent with extensive tissue damage and axonal loss.
On FLAIR images acute lacunar infarctions are diffusely hyperintense. However with thepassage of time central necrosis and cavitations occur in the lacunar infarction and theinfarction is transformed into a cavity filled with a CSF-like fluid and surrounded by agliotic wall, subsequently very old lacunar infarction is demonstrated by FLAIR images asa markedly hypointense (black) small lesion (representing the nulled CSF signal inside thecentral cavity of the lacunar infarction), this hypointense lesion (black hole) is surroundedby a hyperintense rim representing the gliotic walls of the lacunar infarction. In lacunarinfarctions, FLAIR MRI images are thus very helpful in demonstrating the age of theinfarction.Figure 15. A, lipohyalinosis, B, lacunar infarction Figure 16. Periventricular lacunar infarctions and calcifications
Figure 17. Lacunes. Small cavitary infarcts, resulting from hypertension, most frequentlyinvolving the basal ganglia (caudate nucleus, globus pallidus, putamen, and amygdala) andbasis pontis. Compare right with left. Granular atrophy (Cortical laminar necrosis )Granular atrophy is defined pathologically as infarctions localized to the cerebral cortexand not extending to the subcortical white matter. It is characterized by the presence ofsmall punched- out foci of cavitated cicatricial softening situated entirely in the cortex andaccompanied by focal glial scar and thinning of the cortical ribbon. The lesions arebilateral and situated along the crest of the gyri. The presence of arteriolar pathology overthe cerebral convexity points to its ischemic aetiology.Chronic brain infarcts are typically seen as low-intensity lesions on T1-weighted and high-intensity lesions on T2-weighted MR images due to prolonged T1 and T2 values 111,112. Insome infarcts, high-intensity lesions may be seen on T1-weighted images. High intensitylesions on T1-weighted MR images can be due to methaemoglobin, mucin, high proteinconcentration, lipid or cholesterol, calcification and cortical laminar necrosis. In ischemicstroke, high intensity laminar lesions can be cortical laminar necrosis, hemorrhagicinfarcts, or a combination of the two. Initially thought to be caused by hemorrhagicinfarction, histopathological examination has demonstrated these cortical short T1 lesionsto be cortical laminar necrosis without hemorrhage or calcification. Although, themechanism of T1 shortening in cortical laminar necrosis remains unclear, high corticalintensity on a T1-weighted image is believed to occur by neuronal damage and reactivetissue change of glia and deposition of fat-laden macrophages 113.The gray matter has six layers. The third layer is the most vulnerable to depletion ofoxygen and glucose. Cortical laminar necrosis is a specific type of cortical infarction, whichusually develops as a result of generalized hypoxia rather than a local vascularabnormality. Depletion of oxygen or glucose as in anoxia, hypoglycemia, status epilepticus,and ischemic stroke has been attributed as an underlying cause of cortical laminarnecrosis. Immunosuppressive therapy (cyclosporin A and FK506), and polychemotherapy(vincristine and methotrexate) have been observed to cause laminar necrosis due to
hypoxic-ischemic-insult. Hypoxic insult leads to death of neurons, glia and blood vesselsalong with degradation of proteins 114.The cortical laminar necrosis, seen as a laminar high-signal lesion on T1-weighted MRimages, was first described by Swada et al. in a patient of anoxic encephalopathy 115. Earlycortical changes usually show low signal intensity on T1-weighted, which could be due toacute ischemic changes (tissue edema). Usually, cortical high intensity lesions on both T1-weighted and FLAIR images appear 2 weeks after the ictus indicating short T1 and long T2lesions. Proton-density images are more sensitive than T1-weighted MR images. Onproton-density images, cortical laminar necrosis may be seen as high intensity due toincreased mobile protons in the reactive tissue 116.To conclude, cortical laminar necrosis shows characteristic chronological signal intensitychanges, and T1-weighted, FLAIR and proton-density MR images are especially helpful indepicting these changes.Figure 18. Granular atrophy, notice laminar necrosis with early cavitation. Notepersistence of the outer most gray matter.
Figure 19. Cortical laminarnecrosis. Sagittal T1-weighted MR image (A)depicts the gyriformincreased signal area inright temporal and parietalregion. T2-weighted MRand FLAIR images showthese areas as dark signalareas.
Basal ganglionic calcificationsThese are calcification of the arteriolar walls within the basal ganglia. Figure 20. Basal ganglionic calcification Dilated Virchow-Robin spaces (VRSs)Virchow-Robin spaces (VRSs) are perivascular spaces that surround the perforatingarteries that enter the brain. These are sometimes called Type III lacunar infarctions. Thespaces are normally microscopic, but when dilated, they may be seen on MR images. Evenin the normal brain, some VRSs are usually seen in the area of the substantia innominataat the level of the anterior commissure, and a small number of dilated spaces may also beseen in the basal ganglia (BG) in up to 60% of individuals. Virchow-Robin Spaces can beidentified by a combination of their typical location and their signal intensitycharacteristics. They are classically described as isointense to CSF on images obtained withall pulse sequences, and they are round or linear depending on the imaging plane, althoughtheir characteristics may vary from this pattern for a number of reasons. First, the smallsize of the Virchow-Robin Spaces makes partial-volume effects common; therefore,measured signal intensities seldom equal those seen in pure CSF, although the changes insignal intensity between sequences are closely correlated. In addition, T1-weighted imageswith substantial flow sensitivity may show high signal intensity due to inflow effects. Evenif we allow for these effects, the measured signal intensity in the VRS often slightly differsfrom that of true CSF. This finding has been attributed to the fact that Virchow-RobinSpaces around intracerebral arteries may represent interstitial fluid trapped in the subpialor interpial space.Pathologic dilatation of Virchow-Robin Spaces is most commonly associated with arteriolarabnormalities that arise due to aging, diabetes, hypercholesterolemia, smoking, andhypertension and other vascular risk factors. This dilatation forms part of a histologicspectrum of abnormalities, which include old, small infarcts (type 1 changes); scars fromsmall hematomas (type 2 changes); and dilatations of Virchow-Robin Spaces (type 3
changes) (124). The presence of these abnormalities on histologic examination is believed toresult from moderate-to-severe microangiopathy characterized by sclerosis, hyalinosis, andlipid deposits in the walls of small perforating arteries 50 – 400 `im in diameter (124, 125).As the severity of the microangiopathy increases, microvessels demonstrate increasinglysevere changes, with arterial narrowing, microaneurysms and pseudoaneurysms, onionskinning, mural calcification, and thrombotic and fibrotic luminal occlusions (124–126)Although microvascular disease is common, few reliable surrogate imaging markers of itspresence have been described. The extent and severity of deep white matter (WM) andperiventricular hyperintensity on T2-weighted images have been widely studied aspotential surrogate markers for small-vessel disease. However, the correlation betweenthese abnormalities and clinical characteristics, such as diagnosis, vascular risk factor, orneuropsychological deficit, is often poor (127). Figure 21. MRI T2 (A), MRI FLAIR (B) and precontrast MRI T1 (C) images showing dilated Virchow-Robin Spaces associated with diffuse white matter changes (leukoaraiosis) o More details about etiology and pathogenesis of dilatation of Virchow-Robin SpacesVirchow-Robin Spaces are potential perivascular spaces covered by pia that accompanyarteries and arterioles as they perforate the brain substance. Deep in the brain, theVirchow-Robin Spaces are lined by the basement membrane of the glia limitans
peripherally, while the outer surfaces of the blood vessels lie centrally. These pial layersform the Virchow-Robin Spaces as enclosed spaces filled with interstitial fluid andseparated from the surrounding brain and CSF . Dilatation of Virchow-Robin Spacesresults in fluid filled perivascular spaces along the course of the penetrating arteries.Abnormal dilatation of Virchow-Robin Spaces is clinically associated with aging, dementia,incidental WM lesions, and hypertension and other vascular risk factors (123).Pathologically, this finding is most commonly associated with arterioscleroticmicrovascular disease, which forms a spectrum of severity graded from 1 to 3 on the basisof histologic appearances (124, 126). Grade 1 changes include increased tortuosity andirregularity in small arteries and arterioles (124) Grade 2 changes include progresssclerosis, hyalinosis, lipid deposits, and regional loss of smooth muscle in the vessel wallassociated with lacunar spaces that are histologically seen to consist of three subtypes. Type1 lacunes are small, old cystic infarcts; type 2 are scars of old hematomas; and type 3 aredilated Virchow-Robin Spaces (129). Grade 3 microangiopathy represents the most severestage and is especially related to severe chronic hypertension. Typical changes described inlower grades are accompanied by fibrotic thickening vessel wall with onion skinning, lossof muscularis and elastic lamina, and regional necrosis in the vessel walls. The brainparenchyma contains multiple lacunae, and diffuse abnormality of myelin is present in thedeep hemispheric white matter.Several mechanisms for abnormal dilatation of Virchow-Robin Spaces have been suggested(130,131). These include mechanical trauma due to CSF pulsation or vascular ectasia (123),fluid exudation due to abnormalities of the vessel wall permeability (132), and ischemicinjury to perivascular tissue causing a secondary ex vacuo effect (133).In the Western world, ischemic vascular dementia is seen in 8 –10% of cognitivelyimpaired elderly subjects (134) and commonly associated with widespread small ischemicor vascular lesions throughout the brain, with predominant involvement of the basalganglia, white matter, and hippocampus (134). Several groups have shown that a severelacunar state and microinfarction due to arteriolosclerosis and hypertensivemicroangiopathy are more common in individuals with IVD than in healthy controlsubjects, and they have emphasized the importance of small vascular lesions in thedevelopment of dementia (134, 135). On CT or MR imaging, white matter lesions arecommonly used as potential biomarkers of vascular abnormality. Many groups havesuggested that simple scoring schemes for white matter lesion load and distribution areuseful in the diagnosis of vascular dementia (136). Although white matter lesions are moresevere in patients with vascular dementia (136), they are more prevalent in all groups withdementia than in healthy control subjects.Dilation of Virchow-Robin Spaces provides a potential alternative biomarker ofmicrovascular disease (small vessel disease). Virchow-Robin Spaces in the centrumsemiovale were significantly more frequent in patients with fronto-temporal dementia(FTD) than in control subjects (P .01). This finding is not associated with increases in basalganglionic Virchow-Robin Spaces and is closely correlated with measures of forebrain
atrophy, suggesting that these changes are probably representative of atrophy, which ismore marked in this patient group than in those with other dementing conditions (128).The ischaemic microvascular brain disease is the interaction between the haemorheologicalchanges, the vascular arteriolar pathology and the neuronal diminished glucose and oxygen entryTable 2. Pathology of ischemic microvascular brain diseaseCentral and cortical This is secondary to chronic global reduction of brain perfusion.atrophyLeukoaraiosis Leukoaraiosis is an ischaemic demyelination of the immediate periventricular white matter with axonal loss, astrogliosis and interstitial edema. 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 gray matter (thalamus and basal ganglia) and the immediate periventricular white matter. Spasm of the fine penetrating arterioles (secondary to increased VSMCs sensitivity) -can also result in Lacunar infarctions.Granular atrophy Granular atrophy is defined pathologically as infarctions localized to the cerebral cortex and not extending to the subcortical white matter.Basal ganglionic These are calcification of the the arteriolar wall of thecalcifications microcirculation within the basal ganglia.Dilated Virchow- Dilation of Virchow-Robin Spaces provides a potential alternativeRobin Spaces biomarker of microvascular disease (small vessel disease).In general all the pathological consequences of the microvascular brain disease arerestricted to either the cortical zone (cortical atrophy. granular atrophy) or theperiventricular zone (central atrophy, leukoaraiosis and lacunar infarctions, dilatedVirchow-Robin Spaces). i.e. All the ischemic events occurred in the distribution of eitherthe pial or the subependymal microvascular systems. This should mean that hypoperfusion,in microvascular brain disease, is restricted to either the cortical or the periventricularbrain regions. The left cerebral hemisphere is more often and more severely affected thanthe right cerebral hemisphere.It must be noted that in microvascular brain disease one always see a mix of pathology, i.e.in the same patient lacunar infarctions with leukoaraiosis and central and cortical atrophymight coexist.
Finally it should be noted that microvascular brain disease is invariablyassociated with hypertensive concentric left ventricular hypertrophywith unfailing 1-1 relationship.Figure 22. Left ventricular hypertrophy with strain patternTable 3. MICROVASCULAR BRAIN DISEASE & CARDIOVASCULAR ASSOCIATES LACUNAR INFARCTION LEUKOARAIOSIS CENTRAL & CORTICAL ATROPHY GRANULAR ATROPHY SPONTANEOUS HYPERTENSIVE CEREBRAL HAEMORRHAGE BASAL GANGLIONIC CALCIFICATION DUPLEX SCANNING OF CAROTID ARTERIES SHOWS NORMAL FINDINGS OR NON SIGNIFICANT CHANGES LEFT VENTRICULAR HYPERTROPHY WITH STRAIN PATTERN
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