Venkata R. Challa

Longer Duration of Cardiopulmonary Bypass Is Associated With Greater Numbers of Cerebral Microemboli

BACKGROUND AND PURPOSE Many patients who undergo cardiac surgery assisted with cardiopulmonary bypass (CPB) experience cerebral injury, and microemboli are thought to play a role. Because an increased duration of CPB is associated with an increased risk of subsequent cerebral dysfunction, we investigated whether cerebral microemboli were also more numerous with a longer duration of CPB. METHODS Brain specimens were obtained from 36 patients who died within 3 weeks after CPB. Specimens were embedded in celloidin, sectioned 100 microm thick, and stained for endogenous alkaline phosphatase, which outlines arterioles and capillaries. In such preparations, emboli can be seen as swellings in the vessels. Cerebral microemboli were counted in equal areas and scored as small, medium, or large to estimate the embolic load (volume of emboli). RESULTS With increasing survival time after CPB, the embolic load declined (P<0.0001). (Lipid emboli are known to pump slowly through the brain.) Also with increasing time after CPB, the percentage of large and medium emboli became lower (P=0.0034). This decline is consistent with the concept that the emboli break into smaller globules as they pass through the capillary network. A longer duration of CPB was associated with increased embolic load (P=0. 0026). For each 1-hour increase in the duration of CPB, the embolic load increased by 90.5%. CONCLUSIONS Thousands of microemboli were found in the brains of patients soon after CPB, and an increasing duration of CPB was associated with an increasing embolic load.

Brain microemboli associated with cardiopulmonary bypass: A histologic and magnetic resonance imaging study

Emboli in brain tissue after cardiopulmonary bypass were reported in the literature 30 years ago, but there is little objective evidence confirming the presence of emboli in the brain after cardiopulmonary bypass with more modern equipment and techniques. Recently, with alkaline phosphatase vascular staining, we found an acellular fatty material in brain microvasculature from autopsy material of patients who died shortly after cardiopulmonary bypass. These fatty intravascular collections range in diameter from 10 to 70 microns, a size that lodges in the smallest vessels of the microvasculature. They have been found in numbers sufficient to cause detectable neurologic dysfunction and are believed, but not proved, to be emboli. By sequentially injecting colored microspheres, we can determine when emboli occur during experimental cardiopulmonary bypass. In ongoing related studies, magnetic resonance imaging was performed before cardiac valve replacement in 39 patients for whom preoperative and postoperative neurologic and neuropsychologic testing was available. Preliminary results suggest that magnetic resonance imaging evidence of prior stroke is not a significant risk factor for cognitive or motor decrement after cardiopulmonary bypass.

Cerebral Microvascular Alterations in Aging, Leukoaraiosis, and Alzheimer's Disease

ABSTRACT: We have been using alkaline phosphatase (AP) histochemical staining, formerly a research tool for the study of cerebral cortical vascular morphology, to examine pathological changes in the cortex and deep cerebral structures. Deep structures stain similarly to the cortex. The AP stain is found in the afferent vessels (small arteries, arterioles, and capillaries), but not in venules and veins. The stain is also present in leaky vessels, such as those in the area postrema. The vascular supply to the cerebrum is not homogeneous. Supply to the deep white matter, for instance, derives from the leptomeningeal border zone, and then medullary arterioles must wind their way for up to 4 cm before arriving at their ultimate destination. Adding to the difficulties, tortuosities develop in some of these vessels with aging. According to some calculations, hypertensive levels of blood pressure would be required to maintain irrigation through some of these vessels. We have identified a venous alteration that attends aging: periventricular venous collagenosis (PVC). PVC is a previously unrecognized, noninflammatory, mural disease of the periventricular veins. In severe cases, examples can be found of veins that are completely occluded by this process. PVC is found in 65% of subjects over 60 years old, and it strongly correlates with leukoaraiosis. In addition to previously mentioned aging‐related changes, we have found extreme tortuosity, multiplications, and aneurysms of the smallest arterioles and lumpy‐bumpy capillaries in the deep structures of patients with Alzheimers disease.

Vascular dementia in leukoaraiosis may be a consequence of capillary loss not only in the lesions, but in normal-appearing white matter and cortex as well

We investigated capillary density in 12 subjects with leukoaraiosis (LA), in 9 age-matched normal subjects, in 7 cases of Alzheimers disease (AD), and 4 after whole-brain irradiation for brain tumors. In the LA study (which as been published), autopsy brains were evaluated by MRI. The presence of LA was indicated by confluent or patchy areas of hyperintensity in the deep white matter. We employed a stereology method using computerized image processing and analysis to determine microvascular density. Afferent vessels (arterioles and capillaries, but not veins or venules) were stained for alkaline phosphatase in 100 microm thick celloidin sections. Microvascular density in LA lesions in the deep white matter (2.56%) was significantly lower than in the corresponding deep white matter of normal subjects (3.20%, p=0.0180). LA subjects demonstrated decreased vascular density at early ages (55-65 years) when compared to normal subjects. Our findings indicate that LA affects the brain globally, with capillary loss, although the parenchymal damage is found primarily in the deep white matter. In ongoing studies of the deep white matter in AD brains, we found a pattern of decreased vascular density compared to normal, as well as an age-related decline. In the four irradiated brains, we found very low vessel densities, similar to those found in LA, without an additional age-related decline.

Cerebrovascular pathology in Alzheimer's disease and leukoaraiosis.

Abstract: A high percentage of patients with Alzheimers disease (AD) show evidence of white matter degeneration known as leukoaraiosis (LA), which is due to chronic ischemia. We found that the periventricular veins tend to become occluded by multiple layers of collagen in the vessel walls in the elderly. This collagen deposition is particularly excessive in LA lesions. Therefore, it is present in the brains of many AD patients, along with other ischemia‐causing cerebrovascular pathology. We found evidence that there is severe loss of oligodendrocytes in LA, due to extensive apoptosis. No evidence of inflammation was found in the LA lesions. In thick celloidin sections of AD brain, we have obtained detailed 3D views of small (early) deposits of amyloid (stained with β‐amyloid antibody) around capillaries (stained with collagen IV antibody).

Cerebral vasculitis associated with cocaine abuse.

Background: Earlier reports of cocaine-associated cerebral vasculitis have been based primarily on angiographic findings without pathological verification. Case Description: We present a case of acute encephalopathy following intravenous and intranasal administration of cocaine. Brain biopsy revealed vascular changes involving primarily small arteries. Findings included lymphocytic infiltration, endothelial thickening, and deposition of proteinaceous amorphous material within and around vessel walls. Conclusions: These abnormalities are consistent with pathological features of arteritis previously reported in association with amphetamine and multiple-drug abuse. Vasospasm-induced changes are an alternative explanation for the vascular picture seen in this case. The patient made modest improvement with high-dose intravenous steroids.

Biological Features of Meningiomas That Determine the Production of Cerebral Edema

Although meningiomas are known to cause varying degrees of cerebral edema, the relative importance of their location, size, histological subtype, and other histological features in the production of cerebral edema has not been studied adequately. Therefore, we undertook a retrospective analysis of 43 meningiomas excised between 1975 and 1980. The results indicate that histological subtype has no relationship to the production of cerebral edema, with one exception. Meningiomas containing partly or completely a hemangiopericytic component were the only histological subtype associated consistently with cerebral edema. The location of a meningioma per se may not determine the production of cerebral edema. A relationship between size, aggressive histological features, vascular proliferative changes, and the production of cerebral edema was seen. The need for and the nature of further studies required to explain the cerebral edema that may be associated with small meningiomas are discussed.

Morphometric analysis of arteriolar tortuosity in human cerebral white matter of preterm, young, and aged subjects

Arteriolar tortuousities, consisting of vascular coils, loops, and spirals, appear in white matter in a subset of human cerebral vessels. Computerized morphometry was used to analyze brain sections from a broad age range of subjects to determine whether tortuosity is a phenomenon of aging or is associated with leukoaraiosis (LA) or Alzheimer disease (AD). Autopsy brains were studied from 55 subjects ranging in age from 23 weeks postconception to 102 years. Fourteen aged subjects were diagnosed with LA and 7 with AD. By using computerized morphometry, vascular curl (curvilinear length/straight length) was measured in white matter arterioles in 100-&mgr;m-thick, alkaline phosphatase-stained sections. Aging subjects, compared with young subjects, showed significant increases in both the prevalence and severity of tortuosity. Curl scores in aged subjects with LA or AD were not significantly different from aged controls without LA or AD. We conclude that 1) tortuous vessels are extremely rare in preterm babies, children, or young adults; 2) significant tortuosity, as indicated by elevated curl scores, begins in middle age; 3) tortuosity does not appear in a subset of aged individuals regardless of longevity; and 4) tortuosity does not appear in a subset of individuals with either LA or AD.

Microvascular changes in the white mater in dementia

Our studies of the brain microvascular system have focused on some aspects not commonly studied by other research groups because we use some techniques not often used by others. Our observations tend to add new details to the pathological picture rather than contradict the mainstream findings. We use large, thick celloidin sections which provide a three dimensional view of vascular networks, and alkaline phosphatase (AP) staining which allows one to differentiate between afferent and efferent vessels. We found millions of lipid microemboli in the brains of patients after cardiac surgery, and concluded that they caused vascular dementia in many patients. We previously proposed an animal model of vascular dementia using brain irradiation, which induces capillary loss. Lipid emboli might also be used to create an animal model of vascular dementia. The deep white matter is vulnerable to chronic hypoperfusion because the blood vessels supplying this region arise from the border-zone and have the longest course of all vessels penetrating the cerebrum. In cases with leukoaraiosis (LA), we found periventricular venous collagenosis (PVC), resulting in stenosis. Thirteen of 20 subjects older than 60 years had PVC, and 10 of 13 subjects with severe PVC had LA. Vascular stenosis might induce chronic ischemia and/or edema in the deep white matter, leading to LA. We suggest three mechanisms for a possible genetic predisposition to PVC: i) a predisposition to excessive venous collagenosis; ii) an indirect effect that causes chronic periventricular ischemia with a reactive over-production of collagen; and iii) mechanical damage to small vessels due to increased pulsatile motion. We found tortuous arterioles supplying the deep white matter beginning at about age 50. We also found a trend toward an increase in tortuosity in LA. If tortuosity is a factor in LA, it is probably significant in only a subset of cases. String vessels, remnants of capillaries, occur commonly in the brain, and are increased in ischemia, AD, and irradiation. Capillary injury or shutdown of blood flow can lead to capillary loss and string vessel formation. We found string vessels in brains from preterm babies to the very old. They seem to disappear after some months or years. We found an early loss of capillaries in LA, followed in a few years by the disappearance of string vessels. LA lesions do not progress to cortical cavitating lesions. Our findings raise three questions. 1. Why is the capillary loss arrested before infarction? 2. Why is there a floor below which the vascular density will not fall? 3. Why does the process which initiates string vessels shut down? We explain the vascular changes in LA as follows. LA induces apoptosis with loss of oligodendrocytes. Capillaries and neuropil are lost. Increased oxygen extraction from the blood in the deep white matter in LA implies that there are too many cells for the remaining capillaries. Thus, the capillaries appear to die first. But why do they stop dying? Perhaps a minimum number of capillaries are needed to transport the arterial blood to the venous system. Once the capillaries stop dying, no more string vessels are formed, and the string vessels gradually disappear.

The vascular component in meningiomas associated with severe cerebral edema.

Cerebral edema is usually a complication of the later growth stages of intracranial neoplasms. Three patients with small meningiomas presented with unusually several cerebral edema out of proportion to the size of tumors. All three tumors exhibited benign meningothelial components, the formation of pseudopsammoma bodies, and striking vascular mural proliferation of small dark cells. In two tumors ultrastructural examination of these cells showed features of pericytes. The vascular pericytic component in these tumors may grow more actively than the meningothelial component and thus may cause the production of severe cerebral edema. The clinical, radiological, operative, and light and electron microscopic findings are presented, and the relationship to angioblastic meningiomas is discussed.