Vascular pathology
Two major vascular pathologies underlie brain damage in patients who have important abnormalities involving small size penetrating brain arteries and arterioles; 1) thickening of the arterial media with encroachment on the arterial lumens and 2) obstruction of the origins of penetrating arteries by parent large intracranial artery intimal plaques. Hypertension, diabetes and other as yet undetermined genetic and other factors may promote thickening of the media of penetrating arteries by fibrinoid deposition and hypertrophy of smooth muscle and other connective tissue elements. The arterial media can also contain foreign deposits as in amyloid angiopathy and genetically mediated conditions such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
Miller Fisher, nearly a half century ago, analyzed the arterial pathology that caused small deep infarcts by carefully assessing serial sections of vessels at necropsy.
1 He observed that the penetrating arteries that supplied the territory of lacunar infarcts showed a characteristic vascular pathology. These tiny vessels often contained focal enlargements and small hemorrhagic extravasations through the walls of these arteries. Subintimal foam cells sometimes obliterated the lumens, and pink-staining fibrinoid material was present within the vessel walls. The arteries in some regions were often replaced by whorls, tangles, and wisps of connective tissue that obliterated the usual vascular layers. Fisher called these processes
segmental arterial disorganization,
fibrinoid degeneration, and
lipohyalinosis.
1
Figure 1, given to me by Fisher, shows a severely narrowed penetrating artery in a patient with severe hypertension. The media is hypertrophied and contains fibrinoid material.
When Fisher reviewed the charts of 114 patients who had lacunes at necropsy, all but three patients had hypertension defined by a prior history of high blood pressures, elevated blood pressure recorded on examination, or heart weight exceeding 400 g without another explanation.
2 The onset of the clinical symptoms of brain infarction often developed at the onset or hypertension or during periods of an increase in blood pressure values. Fisher attributed segmental arterial disorganization and lipohyalinosis to hypertension. At the time of his studies, performed nearly a half century ago, there was little effective treatment for hypertension and hypertensive crises and hypertensive encephalopathy were common. Later epidemiological studies of patients with small deep infarcts has shown that the presence of hypertension, although very common, seemed no different than the frequency in patients with large artery extracranial and intracranial occlusive disease, raising doubt about the crucial importance of high blood pressure in causing the vascular changes that caused these small deep infarcts. The role of diabetes, hyperlipidemia, and aging in causing penetrating artery lesions remains uncertain. Curiously, necropsy examination of patients with chronic small disease does not show evidence of thrombosis or past thrombotic occlusion of these diseased arteries.
3
The other major pathology that directly involves the walls of penetrating arteries is infiltration of the coats of these vessels with materials foreign to vessels. The penetrating arteries, arterioles and capillaries in a hereditary condition dubbed CADASIL contain a granular material in the media that extends into the adventitia. This disorder is caused by dominant mutations in the NOTCH3 gene that encodes a transmembrane receptor predominantly expressed in vascular smooth muscle and pericyte cells in adults.
4,
5 This receptor is needed for the structural and functional integrity of small vessels-small arteries, arterioles and capillaries. Periodic acid-Schiff (PAS) staining suggests the presence of glycoproteins, but staining for elastin and amyloid have been negative.
Figure 2 is a PAS stained section that shows glycoprotein material within vessel walls in a CADASIL. The nature of the deposited material within the vessel wall and matrix remains unknown. Smooth muscle cells in the media are swollen and often degenerated. The endothelium may be absent and replaced by collagen fibers. At times abnormalities also found in hypertensive patients are also found, including duplication and splitting of the internal elastic lamina, adventitial fibrosis and hyaline change, and fibrosis and hypertrophy of the arterial media.
Another hereditary angiopathic condition, now known to be associated with mutations in a gene that encodes procollagen type IV alpha 1 (Col4A1), has been identified. This type of collagen is very important in vascular basement membranes. This genetic mutation affects small brain arteries as well as larger retinal and cerebral arteries.
5,
6
Cerebral amyloid angiopathy (CAA) affects small arteries and arterioles in the leptomeninges and cerebral cortex; involved arteries are thickened by a acellular hyaline material that stains positively with periodic acid-Schiff stains, and has an apple-green birefringence with polarized Congo red stain.
7,
8 Arteries and arterioles in the basal ganglia and deep cerebral white matter also show thickened media but these arteries do not contain amyloid. At times, vessel walls that contain amyloid seem to be reduplicated or split. CAA predominantly affects persons older than 65 years and increases in frequency in the eighth and ninth decades.
The other type of pathology that causes small deep infarcts involves the large arteries that give rise to penetrating artery branches rather than intrinsic disease of the branches themselves. The orifices of these penetrating arterery branches could be obstructed by atherosclerotic plaque lesions. Fisher and Caplan,
9 Fisher,
10 and Caplan
11 described the vascular pathology in these branches, and dubbed the condition intracranial branch atheromatous disease.
Figure 3 contain cartoons that illustrate the location and mechanism of the pathology within the parent arteries. The orifices of the penetrating branches could be blocked by atheroma in the parent artery, atheroma could originate in the parent artery and extend into the branch (so-called junctional atheromatous plaques), or microatheromas could arise at the origin of the branch itself. Thrombus was sometimes superimposed on the atheromas and occasionally a microdissection developed in the parent artery and spread into the first millimeters of the branch.
9
It is now possible to image intracerebral branch atheromatous disease using high resolution MRI. Plaques in the middle cerebral artery and basilar artery can be shown to impinge upon or occlude penetrating branches by MRI techniques that show axial sections of the origins of branches from the parent arteries. The location within the parent artery is critical in blocking lenticulostriate, thalamostriate, and basilar artery branches.
12
Brain pathology
The major related pathology in the brain are small deep infarcts and degenerative abnormalities in the cerebral and cerebellar white matter. Lacunar infarcts are small, discrete, often irregular lesions, ranging from 1 to 15 mm in size. Inspection of these small cavities usually shows fine strands of connective tissue resembling cobwebs. The most common locations of these lacunar infarcts are the putamen and the pallidum, followed by the pons, thalamus, caudate nucleus, internal capsule, and corona radiata.
Figure 4 shows a typical bold basal ganglia lacune. Rarer are lacunes in the cerebral peduncles, pyramids, and subcortical white matter. These lesions are not found in the cerebral or cerebellar cortices.
At necropsy patients with chronic penetrating artery disease show extensive changes in white matter variously called leukoariosis and leukoencephalopathy. The combination of multiple small deep infarcts and extensive white matter abnormalities has been referred to as Binswanger disease,
3,
13,
14 and the clinical findings are often classified as vascular dementia of the small artery type. Grossly visible in the cerebral white matter are confluent areas of soft, puckered, and granular tissue. These areas are patchy and emphasize the occipital lobes and periventricular white matter, especially anteriorly and close to the surface of the ventricles.
3,
13,
14
Figure 5 is a myelin stained section from the cerebral hemispheres that shows a large area of myelin loss in the cerebral white matter. The cerebellar white matter is also often involved. The ventricles are enlarged, and the corpus callosum is usually small. The volume of white matter is reduced, but the cortex is generally spared. The ventricles are enlarged as a result of atrophy of the white matter. The white-matter abnormalities surrounding the ventricles may reduce the strength of the supporting tissue and allow mechanically more ventricular distension.
3,
13,
14 The white-matter abnormalities are nearly always accompanied by some lacunes. Microscopic examination shows myelin pallor. Usually, the myelin pallor is not homogeneous, but islands of decreased myelination are surrounded by normal tissue. At times, the white-matter abnormalities are so severe that necrosis and cavitation occur. Gliosis is prominent in zones of myelin pallor.