Biomedical subjects
Publications and source records attributed to V C Hachinski.
Cardiac disorders associated with cerebral embolism including cardiac surgery, myocardial infarction, endocarditis and non-valvular atrial fibrillation (NVAF) are reviewed along with methods to detect cardioembolic sources. Warfarin and aspirin are effective in the primary prevention of stroke in NVAF but the relative efficacy remains to be determined.
OBJECTIVE: To highlight the mechanisms, common causes and management of stroke in the elderly. DATA SOURCES: MEDLINE was searched for articles published from 1967 to 1990. The following key words were used: "stroke," "cerebrovascular disease," "elderly," "aging," "hypertension," "drug interactions," "etiology," "evaluation," "management" and "recovery of function." Original articles with large series of patients were reviewed in detail. STUDY SELECTION: Of about 750 original articles reviewed 116 were finally selected for detailed analysis. Those that dealt with cause, pathophysiologic features and management of stroke with emphasis on the elderly were chosen. DATA SYNTHESIS: With increasing age the incidence of stroke increases, cardiovascular reserve decreases, catecholamine responsiveness diminishes and cardiac arrhythmias become more common. Blood pressure, especially systolic, rises, and the benefits of its treatment become both more difficult to assess and less certain. In the elderly population embolic stroke, particularly that due to nonvalvular atrial fibrillation, is seen with increasing frequency. Because of postural hypotension, cardiac arrhythmias and overmedication, watershed infarction occurs more frequently with increasing age. Amyloid angiopathy now represents the most common cause of spontaneous intracerebral hemorrhage. CONCLUSIONS: Because of the altered drug metabolism and pharmacodynamics in the elderly the therapeutic armamentarium is growing, and so are the risks of such treatments. Stroke in the elderly poses unique problems that deserve distinctive solutions. Further research is needed to study the effect of cerebral ischemia to understand better how the older brain handles the stress of the ischemic insult.
BACKGROUND: Without strong evidence of benefit, the use of carotid endarterectomy for prophylaxis against stroke rose dramatically until the mid-1980s, then declined. Our investigation sought to determine whether carotid endarterectomy reduces the risk of stroke among patients with a recent adverse cerebrovascular event and ipsilateral carotid stenosis. METHODS: We conducted a randomized trial at 50 clinical centers throughout the United States and Canada, in patients in two predetermined strata based on the severity of carotid stenosis--30 to 69 percent and 70 to 99 percent. We report here the results in the 659 patients in the latter stratum, who had had a hemispheric or retinal transient ischemic attack or a nondisabling stroke within the 120 days before entry and had stenosis of 70 to 99 percent in the symptomatic carotid artery. All patients received optimal medical care, including antiplatelet therapy. Those assigned to surgical treatment underwent carotid endarterectomy performed by neurosurgeons or vascular surgeons. All patients were examined by neurologists 1, 3, 6, 9, and 12 months after entry and then every 4 months. End points were assessed by blinded, independent case review. No patient was lost to follow-up. RESULTS: Life-table estimates of the cumulative risk of any ipsilateral stroke at two years were 26 percent in the 331 medical patients and 9 percent in the 328 surgical patients--an absolute risk reduction (+/- SE) 17 +/- 3.5 percent (P less than 0.001). For a major or fatal ipsilateral stroke, the corresponding estimates were 13.1 percent and 2.5 percent--an absolute risk reduction of 10.6 +/- 2.6 percent (P less than 0.001). Carotid endarterectomy was still found to be beneficial when all strokes and deaths were included in the analysis (P less than 0.001). CONCLUSIONS: Carotid endarterectomy is highly beneficial to patients with recent hemispheric and retinal transient ischemic attacks or nondisabling strokes and ipsilateral high-grade stenosis (70 to 99 percent) of the internal carotid artery.
We report our observations on the clinical and radiologic correlates of changes in cerebral white matter based on 94 subjects undergoing magnetic resonance imaging in a prospective study of dementia. Periventricular hyperintensity occurred twice as often in patients with Alzheimer's disease as in healthy control subjects. Within the control group, the presence of periventricular hyperintensity correlated significantly with one measure of cerebral atrophy and with the presence of changes in the adjoining deep white matter. The significance of white-matter changes distinct from the ventricles (leuko-araiosis) remains unsettled. Leuko-araiosis on the magnetic resonance imaging scan, unlike its correlate on the computed tomographic scan, was not shown to relate to cognitive decline or to the presence of focal abnormalities on neurologic examination. This is likely to reflect the heterogeneity of the changes detected with magnetic resonance imaging and their limited extent in our subjects.
We identified 85 patients in a longitudinal study of dementia who had uncomplicated Alzheimer's disease and in whom computed tomography of the head and psychometric testing were conducted within a 6-month period following their entry into the study. Thirty-four patients (40%) had leukoaraiosis, which was disproportionately common in female patients (62% vs 15% in male patients). Analysis of covariance demonstrated a relative reduction of scores on the Extended Scale for Dementia in those patients who had leukoaraiosis, after adjusting for the confounding effects of age, sex, educational level, and duration of illness. Leukoaraiosis was also much more common in women, even after adjusting for the possible confounding effects of age, duration of illness, Extended Scale for Dementia score, and hypertension. Multiple regression analysis showed that leukoaraiosis accounted for 11.6% of the variance of the Extended Scale for Dementia scores. Leukoaraiosis, together with duration of illness, accounted for 18.2% of the variance. Leukoaraiosis is associated with a greater degree of cognitive impairment in patients with Alzheimer's disease.
Systolic and diastolic hypertension in both men and women is a well-established risk factor for the development of ischemic and hemorrhagic stroke. Antihypertensive treatment decreases the risk, but questions remain as to the precise level of hypertension to be treated, whether the effects of antihypertensive treatment are blunted with increasing age, and the best type of antihypertensive drug or combination of drugs to be used. Further questions remain concerning the incidence of pseudohypertension and the potentially harmful effects of its treatment on the brain, and the possibility that fluctuations in blood pressure may be worse than elevation alone. A pragmatic approach would be to treat hypertension with vigor in the young, with caution in the mature, and with reluctance in the old.
Multi-infarct dementia (MID) may not be the only or even the most important form of vascular dementia. Vascular factors probably contribute to dementia through cerebral infarcts and white matter changes more often than they cause it. More subtle ischemic insults affecting synapses, cells, or protein synthesis without causing frank infarction remain plausible but unproven postulates. Lest we regress to vague and comforting notions of silting blood vessels and ailing neurons, let us recognize that although MID may not explain all of vascular dementia, it has the virtue of being a firm, testable concept. As such it has not been overthrown or even seriously challenged. But it is time for a reappraisal.
The three fundamental methods of assessing the therapeutic effects in ischemic stroke are measurements of mortality, morbidity and quality of life. Increasingly more sophisticated cerebral blood flow and metabolism determinations are allowing insights into pathophysiology and giving guidance to the most promising therapeutic approaches. Experimental work and pathophysiological studies provide the scientific basis for therapy, but the assessments that ultimately matter to the patient are clinical, and preferably ones derived from controlled clinical trials.
Arteriosclerotic narrowing of cerebral arteries was once viewed as the key to mental decline. As Alzheimer's disease gained recognition and the concept of multi-infarct dementia achieved acceptance, vascular dementia came to be regarded as uncommon. The changing nature of cerebral vascular disease, the aging of the population and the widespread use of brain imaging techniques have brought new prominence to vascular dementia, chiefly in the form of an epidemic of "Binswanger's disease". Growing evidence suggests that not only grey matter lesions but also white matter lesions contribute to dementia, that vascular factors commonly coexist and interact with Alzheimer changes and that Alzheimer's disease has a vascular and potentially treatable component. Vascular dementia needs to be redefined, reappraised and reinvestigated.
Electrocardiographic repolarization changes, comprising QT prolongation, T-wave flattening or inversion, and ST-segment alterations, are most commonly seen after subarachnoid and intracerebral hemorrhage, but may occur in other neurologic conditions. They may presage arrhythmias. The effects likely are mediated by the sympathetic nervous system. Cerebral arrhythmogenesis may underlie sudden death in both normal and epileptic populations. Experimental evidence suggests that the insula has a cardiac chronotropic organization, and may be involved in the genesis of arrhythmias seen in epilepsy or after cerebral hemorrhage or stroke.
The entry characteristics of 1367 patients enrolled into the Extracranial/Intracranial Bypass Study were examined to determine if site differences in intracranial and extracranial arterial lesions among racial groups could be explained by differences in risk factors. Blacks were more often hypertensive, diabetic, or cigarette smokers, while whites had higher systolic blood pressure and hemoglobin values. Orientals had the lowest prevalence of vascular risk factors. Despite these differences in risk factors, multivariate analysis showed race to be an independent and strong predictor of the location of cerebrovascular lesions. To our knowledge, this study is unique in documenting risk factors prospectively and systematically in three racial groups simultaneously. Although generalization is limited by possible biases related to patient selection, the results affirm previous tentative conclusions about the role of race in determining the location of cerebrovascular disease.
We achieved a unique and timely recording of cerebral activity in a 70 year old woman immediately pre- and post-stroke, while studying the effect of acute cerebral infarction on sleep-electroencephalogram (EEG) patterns. Normal patterns, except for increased wakefulness, were recorded during two pre-infarct polysomnograms. Immediately following cerebral infarction increased delta activity was recorded from the infarcted hemisphere only. Initially, REM sleep could not be recorded from either side; however, on the third post infarct day REM sleep returned. Background EEG levels from both hemispheres became progressively slower, flatter and simpler. In addition, sleep spindles and the distinctive saw-tooth wave forms of sleep almost disappeared. At one year post-stroke sleep-EEG rhythm recordings from both hemispheres became more similar except for persisting delta activity from the left hemisphere. Unexpected deterioration of sleep-EEG pattern recordings from the undamaged hemisphere taken during the patient's clinical recovery remains unexplained. Serial sleep recording may facilitate the study of brain recovery, activity and reorganization following stroke.
We report findings on a study of anxiety and depression by questionnaire in 50 patients with mild dementia and 134 control subjects using the Hospital Anxiety and Depression Scale. Thirty-eight percent of patients and 9% of controls had a possible or probable diagnosis of an anxiety disorder. Possible or probable depression was found in 28% of the patients and 3% of the controls. These rates for the patients were above those in normal populations. All patients and control subjects were tested with the Extended Scale for Dementia (ESD). Neither group showed a significant relationship between depression and ESD scores. In the control subjects there was a negative correlation (P less than .006) between anxiety and cognitive scores, one that was not found in the patients.
Reports on the long-term prognosis of patients with transient ischemic attacks and normal angiograms have revealed variable results, some suggesting a good prognosis while others report an outcome no different from that of patients with transient ischemic attacks and atherosclerotic vascular narrowing. Normal cerebral angiograms do not exclude disease in the heart or hematologic disorders. The prognosis for patients with transient ischemic attacks, normal angiograms, and normal results of cardiac and hematologic investigations is not known. We report our experience with 43 patients (26 men and 17 women, mean age 55.6 years) with transient ischemic attacks and normal findings on all investigations (including angiography, cranial computed tomography, echocardiography, and Holter monitoring). The patients were followed for a mean of 4.43 years. Six patients had recurrent transient ischemic attacks and six developed angina pectoris. No patient developed a stroke. In the presence of normal cerebral, cardiac, and hematologic findings, the long-term prognosis of patients with transient ischemic attacks is good. However, the development of cardiac disease during follow-up could not be predicted using the available diagnostic methods.
Stroke models in larger animals such as the cat, dog and monkey are becoming increasingly more expensive and less readily available. However, the rat is an excellent model for focal cerebral ischemia. Rats are readily available, inexpensive and their neuroanatomy and brain function have been studied extensively. Increases in plasma catecholamines and myocardial damage have been observed in clinical stroke. We examined autonomic and myocardial changes in two rat stroke models. In one model only the middle cerebral artery was occluded (MCAO) while the other model involved occlusion of both the MCA and the common carotid artery (MCAO/CCAO). Arterial blood pressure and heart rate were monitored continuously in 25 male rats (326-430 g) that underwent one of the following procedures: (1) MCAO only; (2) MCAO/CCAO; (3) CCAO only; and (4) sham occlusions (SHAM). Arterial blood samples (0.5 ml) for radioenzymatic assay of norepinephrine (NE) and epinephrine (E) were taken twice before the occlusions and at 90 and 180 min after the occlusions. The animals were perfused at the end of the experiment and the heart removed and examined histologically. Tetrazolium salts were reacted with oxidative enzymes to delineate the region of inadequate perfusion. The mean blood pressure and pulse pressure of the SHAM, MCAO/CCAO and CCAO groups significantly declined from initial values (from an average of 78 to 53 mm Hg) during the course of the experiment. However, the mean blood pressure and pulse pressure of the MCAO rats did not change during the experiment, so that the final mean blood pressure and pulse pressure were significantly higher than in the other 3 groups. The levels of both NE and E increased significantly (NE, 1443 +/- 285.9 to 4095 +/- 929 pg/ml; E, 2402 +/- 623 to 3741 +/- 1166 pg/ml) following occlusion in the MCAO group only while the other 3 groups did not change. Four of 6 hearts in the MCAO group were abnormal, showing evidence of subendocardial hemorrhage, ischemic damage or subendocardial congestion. MCAO also resulted in a consistent region of the brain with inadequate perfusion including the insular cortex. These autonomic and myocardial changes appear to mimic some of the changes seen clinically in stroke patients and provide the first acute stroke model for studying autonomic dysfunction in the rat.
The Canadian American Ticlopidine Study (CATS) is a randomised, double-blind, placebo-controlled trial to assess the effect of ticlopidine (250 mg twice daily) in reducing the rate of subsequent occurrence of stroke, myocardial infarction, or vascular death in patients who have had a recent thromboembolic stroke. Twenty-five centres entered 1072 patients into the study between 1 week and 4 months after their qualifying stroke. The patients were treated and followed for up to 3 years (mean 24 months). In the efficacy analysis, the event rate per year for stroke, myocardial infarction or vascular death, considered together, was 15.3% in the placebo group and 10.8% in the ticlopidine group, representing a relative risk reduction with ticlopidine of 30.2% (95% confidence interval 7.5-48.3%; p = 0.006). Ticlopidine was beneficial for both men and women (relative risk reductions 28.1%, p = 0.037, and 34.2%, p = 0.045, respectively). Analysis by intention-to-treat gave a smaller estimate of risk reduction (23.3%, p = 0.020) for stroke, myocardial infarction, or vascular death. Adverse experiences associated with ticlopidine included neutropenia (severe in about 1% of cases) and skin rash and diarrhoea (severe in 2% of cases each); all were reversible. This study provides evidence of a beneficial effect of ticlopidine in both men and women with a recent thromboembolic stroke.
We describe the pathologic findings in 17 persons with dementia, 12 of whom exhibited leuko-araiosis on computed tomographic scan. The presence of white matter pallor was confirmed on autopsy in 11 of these 12 cases, 9 with Alzheimer's disease and 2 with multi-infarct dementia. Two further patients, 1 with Alzheimer's disease and 1 with multi-infarct dementia, proved to have white matter changes on pathologic examination. White matter pallor coexisted with cerebral amyloid angiopathy in the brains of the patients with Alzheimer's disease. The presence of severe white matter pallor in patients with Alzheimer's disease correlated with early death, while the presence of cortical scars was associated with prolonged survival. Because early death in patients with Alzheimer's disease has been linked with severe pathologic and chemical changes, the presence of white matter pallor may be further evidence of a particularly severe process in patients with early onset of Alzheimer's disease.
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