Julio H. Garcia

Pathogenesis of Leukoaraiosis A Review

BACKGROUND Changes in the cerebral hemispheric white matter, detectable with increasing frequency by modern neuroimaging methods, are associated with aging and conceivably may contribute to the development of specific cognitive deficits. The pathogenesis of these cerebral white matter abnormalities (sometimes described as leukoaraiosis) is unknown. This review evaluates the available evidence in support of the hypothesis that the etiology of leukoaraiosis is related to a specific type of cerebral ischemia and highlights mechanisms by which ischemic injury to the brain may induce selected structural alterations limited to the cerebral white matter. SUMMARY OF REVIEW The review is based on the critical analysis of over 100 publications (most appearing in the last decade) dealing with the anatomy and physiology of the arterial circulation to the cerebral white matter and with the pathogenesis of leukoaraiosis. CONCLUSIONS A significant number of clues support the hypothesis that some types of leukoaraiosis may be the result of ischemic injury to the brain. Structural changes affecting the small intraparenchymal cerebral arteries and arterioles that are associated with aging and with stroke risk factors, altered cerebral blood flow autoregulation, and the conditions created by the unique arterial blood supply of the hemispheric white matter each seem to contribute to the development of leukoaraiosis. To the best of our ability to interpret current information, the type of ischemic injury that is most likely responsible for these white matter changes involves transient repeated events characterized by moderate drops in regional cerebral blood flow that induce an incomplete form of infarction. This hypothesis could be tested in appropriate experimental models.

Neurological Deficit and Extent of Neuronal Necrosis Attributable to Middle Cerebral Artery Occlusion in Rats Statistical Validation

BACKGROUND AND PURPOSE Occluding a large intracranial artery in rats produces a brain lesion that grows in terms of an increase in both surface area and number of necrotic neurons. The present study investigated whether reperfusing the ischemic territory 30 to 60 minutes after the arterial occlusion would have a beneficial effect on either the clinical or the histological outcome of the lesion. METHODS One hundred four adult rats (including appropriate controls) were used; 97 had a middle cerebral artery occluded by inserting a nylon monofilament via the right external carotid artery. The arterial occlusion was transient in two groups and permanent in another; survival times were comparable for all groups. Control animals were subjected to a sham operation during which the artery was occluded for less than 1 minute. The outcome was evaluated by measuring the extent of the neurological deficit and the severity of the histological injury. RESULTS Mean neurological score and mean number of necrotic neurons in the cortex were more favorable after transient (30- to 60-minute) compared with permanent arterial occlusion (P < .005). Moreover, the correlation between mean neurological score and mean number of necrotic neurons was highly significant: r = .951; P < .001. CONCLUSIONS The histological effects of an intracranial arterial occlusion in the adult rat can be predicted on day 1 by the neurological score described in this report. Significant improvement can be obtained in these animals by reestablishing arterial flow 60 minutes or sooner after the ictus. The pattern of cortical pannecrosis observed after permanent occlusion (> or = 72 hours) was transformed into incomplete ischemic injury in most instances of transient occlusion.

Cerebral White Matter Is Highly Vulnerable to Ischemia

BACKGROUND AND PURPOSE The effects of ischemia on the cerebral white matter structure seldom have been studied possibly because white matter is generally considered less vulnerable to ischemia than gray matter. The objective of this study was to evaluate the early (< or = 24 hours) structural effects of experimental focal ischemia on the cerebral white matter of the rat as a preliminary step to investigating human conditions of unknown pathogenesis that are characterized by selective damage to the white matter. METHODS Twenty-eight rats, including four controls, had a middle cerebral artery occluded with an intravascular filament for periods ranging between 0.5 and 24 hours. Brain samples from the subcortical white matter were examined with light and electron microscopic methods, and the abnormalities were quantified with an image-analysis system. RESULTS As early as 30 minutes after the arterial occlusion, there was conspicuous swelling of oligodendrocytes and astrocytes; after 3 hours, large numbers of oligodendrocytes were lethally injured. These changes preceded by several hours the appearance of necrotic neurons in the cortex and basal ganglia. Vacuolation and pallor of the white matter were very marked after 24 hours and reflected the segmental swelling of myelinated axons, the formation of spaces between myelin sheaths and axolemma and astrocyte swelling. CONCLUSIONS These results suggest that the cerebral white matter is highly vulnerable to the effects of focal ischemia. Pathological changes in oligodendrocytes and myelinated axons appear early and seem to be concomitant with, but independent of neuronal perikaryal injury. Modifications of this experimental model of focal ischemia could provide the means to test the hypothesis that selected types of human leukoencephalopathies have an ischemic origin.

The Effect of Hypothermia on Transient Middle Cerebral Artery Occlusion in the Rat

We investigated the effect of moderate whole body hypothermia (30°C) on transient middle cerebral artery occlusion (MCAO) in the rat. Male Wistar rats were subjected to 2 h of ischemia by inserting a suture into the lumen of the internal carotid artery and occluding the origin of the MCA. Experimental groups were (a) MCAO induced at 37°C body temperature (n = 15); (b) 30°C body temperature induced prior to ischemia and maintained for 2 h of MCAO and 1 h of reperfusion (n = 12); and (c) MCAO with regional brain and body temperatures measured in normothermic (n = 3) and hypothermic MCAO rats (n = 2). Histopathological evaluation was performed 96 h after reperfusion. All normothermic MCAO animals exhibited ischemic infarct involving the ipsilateral cortex and basal ganglia with infiltration of neutrophils, macrophages, and microvascular proliferation. Hypothermic MCAO animals exhibited minor ischemic damage ranging from selective neuronal injury to small focal areas of infarct with minimal inflammatory response. Our data demonstrate that transient ischemia induced by using the intra-arterial suture method to occlude the MCA results in a reproducible brain lesion and that moderate hypothermia has a profound protective effect on the brain injury after transient MCAO.

Cerebral infarction. Evolution of histopathological changes after occlusion of a middle cerebral artery in primates.

Occlusion of a middle cerebral artery is performed with a surgical clip which is placed through a transorbital approach. This results in a reproducible cerebral lesion (infarction) which was analyzed sequentially in a group of primates at intervals ranging from 2 1/2 hours to 16 days. The earliest cytological alterations, involving neurons, neuropil and astrocytes, can be demonstrated convincingly 2 1/2 hours after the arterial occlusion in paraffin-embedded sections, stained with hematoxylin and eosin. A detailed description of the topographic-cytologic abnormalities and the sequence of inflammatory changes elicited by this form of cerebral ischemia, as well as a delineation of the beginning of the post-ischemic healing processes are provided. A three-zone separation of the histological features is suggested. In addition, we illustrate the cellular alterations in the hemisphere opposite to the arterial occlusion and discuss the axonal changes observed in the different zones of the evolving ischemic encephalomalacia. Abnormalities in the microcirculation are also discussed.

Ischemic Stroke and Incomplete Infarction

BACKGROUND The concept of selective vulnerability or selective loss o f individual neurons, with survival of glial and vascular elements as one of the consequences of a systemic ischemic-hypoxic insult (eg, transient cardiac arrest or severe hypotension), has been recognized for decades. In contrast, selective neuronal death as one of the lesions that may develop in the brain after occluding an intracranial artery is an idea not readily acknowledged in the current medical literature dealing with human stroke. SUMMARY OF REVIEW A review of pertinent publications reveals that selective neuronal injury after middle cerebral artery occlusion was observed in autopsy specimens over 40 years ago, although its pathogenesis remains unclear. Recent observations in both humans and animals suggest that selective neuronal necrosis (rather than infarct) is the consequence of either a short-term arterial occlusion or permanent occlusion accompanied by ischemia of moderate severity. During the acute and subacute states of an ischemic stroke, the loss of a limited number of neurons (ie, incomplete infarction) does not result in structural changes discernible by either CT or conventional MRI. However, the loss of a selected number of neurons may be demonstrable in vivo by calculating the corresponding loss of benzodiazepine receptors. The use of specific radiotracers in combination with single-photon emission CT or positron emission tomography allows demonstration of a decrease in gamma-aminobutyric acid-ergic receptor sites at places where many neurons have been lethally injured. CONCLUSIONS We aim to alert physicians to the potential development of incomplete brain infarctions in patients with intracranial arterial occlusions. Recognizing incomplete infarcts is particularly important in the context of stroke therapy with thrombolytic and neuroprotective agents. This brain lesion is likely to be the consequence of an arterial occlusion with a resultant ischemia of moderate severity (eg, regional blood flows in the range of 15 to 20 mL x 100 g-1 x min-1).

Mild hypothermic intervention after graded ischemic stress in rats.

We investigated the effect of mild (34 degrees C) postischemic hypothermia on hippocampal neuronal damage in 43 rats as a function of the duration of forebrain ischemia. Two temperatures and two durations were investigated. In two normothermic groups ischemia lasted 8 (n = 15) and 12 (n = 10) minutes, respectively. In two hypothermic groups ischemia lasted 8 (n = 9) and 12 (n = 9) minutes, respectively, and was followed immediately by the lowering and maintenance of rectal temperature to 34 degrees C for 2 hours. Seven days after the ischemic insult, the rats were sacrificed and the brains were prepared for histologic analysis; the percentage of necrotic neurons among the total neuronal population in selected CA1/2 sectors of the hippocampus was determined. There was a significant decrease in the percentage of necrotic neurons in the central (77.5% versus 55.5%, p = 0.006) and lateral (62.5% versus 38.9%, p=0.005) areas and in the overall CA1/2 sector of the hippocampus (71.8% versus 52.2%, p = 0.008) for the 8-minute hypothermic group compared with the 8-minute normothermic group. In contrast, no differences were detected in any area of the hippocampus between the 12-minute normothermic and the 12-minute hypothermic groups (p = 0.29-0.49). Our data indicate that mild postischemic whole-body hypothermia ameliorates neuronal survival when ischemia lasts 8 minutes but not 12 minutes.

Evolving stroke and the ischemic penumbra

Deterioration of the neurologic deficits that occur hours or even days after the initial presentation is a well-recognized feature of ischemic stroke. In several recent series of prospectively evaluated ischemic stroke patients, the frequency of neurologic worsening ranged from 26 to 43%, and the rate of deterioration was similar in patients evaluated either within 6 to 8 hours or within 1 to 2 days after the onset of symptoms. [1-3] These rates of progression were similar to those previously observed by Jones and Millikan [4] and Jones et al. [5] in patients with either carotid or vertebrobasilar arterial occlusions who were evaluated within 36 hours of stroke onset, although a higher percentage of vertebrobasilar system stroke patients deteriorated at a later time. The definition of neurologic worsening after stroke has varied from study to study, making direct comparisons difficult. With the advent of valid, reproducible neurologic scoring scales, such as the NIH Stroke Scale and the Scandinavian Stroke Scale, a more precise perspective on short-term clinical worsening after acute ischemic stroke will be available from the data that the current plethora of acute stroke intervention trials will provide. [6] The factors that make the deficit worsen are not known. The object of this review is to advance the concept that, in some patients with ischemic stroke, the progression of the neurologic deficits shortly after the ictus relates to the deterioration of the local circulation in which an initially ischemic, but functional, region progresses to a non-functional state and ultimately to infarction. The concept of evolving or progressing stroke initially appeared in the 1950s. [7,8] Several mechanisms potentially contribute to the phenomenon of evolving stroke, and early authors emphasized thrombus propagation despite scarce confirmation of this hypothesis. [9] Other potential mechanisms for the increasing clinical deterioration that may occur during the …

Reversal of acute apparent diffusion coefficient abnormalities and delayed neuronal death following transient focal cerebral ischemia in rats

Twenty‐two rats were subjected to 8, 15, 30, or 60 minutes of temporary middle cerebral artery occlusion (n = 5 per group) or sham occlusion (n = 2) in the magnetic resonance imaging unit. Diffusion‐, perfusion‐, and T2‐weighted imaging were acquired before and during occlusion, and after reperfusion. A coregistration method was used to correlate the acute changes of the average apparent diffusion coefficient (ADCav) with the histology after 72 hours at the same topographic sites. The initially reduced ADCav values recovered completely in both the lateral caudoputamen and upper frontoparietal cortex in the 8‐, 15‐, and 30‐minute groups, partially in the cortex, and not at all in the caudoputamen in the 60‐minute group. The histology showed that the caudoputamen was either normal or had mild neuronal injury in the 8‐minute group and invariably had some degree of neuronal death in the 15‐, 30‐, and 60‐minute groups, whereas the cortex was either normal or had varying degrees of neuronal injury in all groups. No histological abnormalities were seen in the sham‐operated rats. Our data suggest that acute ADCav reversal does not always predict tissue recovery from ischemic injury and that temporary focal ischemia for even 8‐minute duration can cause delayed neuronal death that is more severe in the caudoputamen where the initial ADCav decline was greater than in the cortex.

Postischemic (1 hour) hypothermia significantly reduces ischemic cell damage in rats subjected to 2 hours of middle cerebral artery occlusion.

Background and Purpose We investigated the effect of hypothermia induced 1 hour after transient (2-hour) middle cerebral artery occlusion on the extent of ischemic cell damage in the rat. Methods Middle cerebral artery occlusion was induced extracranial by insertion of a nylon filament into the right internal carotid artery. Two groups of rats were investigated: (1) rats (n=10) subjected to normothermic (37°C) ischemia and normothermic reperfusion; and (2) rats (n=10) subjected to normothermic ischemia and 1 hour of normothermic reperfusion followed by 3 hours of hypothermia (30°C). All rats were killed 1 week after the experiment, and brain sections were stained with hematoxylin and eosin for evaluation of ischemic cell damage. Results Infarct volume in normothermic rats involved 20.9±4.6% of the hemisphere, whereas hypothermic rats exhibited a significantly smaller (P<.001) infarct volume of 11.1 ± 2.7%. The numbers of surviving (or structurally intact) neurons within large sections of the cortex and striatum were significantly greater for hypothermic compared with normothermic rats (P< 01). Conclusions Our data suggest that postischemic induction of hypothermia significantly reduces ischemic cell damage after 2 hours of middle cerebral artery occlusion in the rat, and that an interval of time of at least 1 hour after ischemia exists in which hypothermic intervention is effective in either salvaging or postponing irreversible neuronal injury.