Effect of acetazolamide on cerebral blood flow and cerebral metabolic rate for oxygen.

The aim of this study was to evaluate the effect of acetazolamide on cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2). CBF, arterial and jugular venous partial O2 pressure, partial CO2 pressure, pH, and O2 saturation percentage were measured in six patients before and 3 and 20 minutes after intravenous administration of 1 g of acetazolamide. CBF was measured by the intracarotid 133xenon injection technique. In addition, changes in CBF were estimated from the arteriovenous oxygen content difference. CBF increased in all patients after acetazolamide, by approximately 55 and 70% after 3 and 20 min, respectively. The CBF changes were of the same order whether calculated from the 133Xe clearance or from the arteriovenous oxygen differences (A-V)O2. CMRO2, calculated from (A-V)O2 differences and CBF, remained constant. Except for an increase in the venous oxygen saturation, the blood gases remained constant. Acetazolamide, in a dose sufficient to inhibit the erythrocyte carbonic anhydrase (EC 4.2.1.1), thus induced a rapid and marked increase in CBF, leaving CMRO2 unchanged. This effect of acetazolamide on CBF is probably explained by a decrease in brain pH rather than by brain tissue hypoxia due to inhibition of oxygen unloading in the brain capillaries.

Ultrasonic echolucent carotid plaques predict future strokes.

BACKGROUND: We tested prospectively the hypothesis that stroke development can be predicted by echolucency of carotid atherosclerotic plaques in previously symptomatic and asymptomatic patients. METHODS AND RESULTS: We followed incidence of ipsilateral ischemic strokes for 4.4 years in 111 asymptomatic and 135 symptomatic patients with >/=50% relevant carotid artery stenosis. At inclusion, echogenicity of carotid plaques and degree of stenosis were evaluated with high-resolution B-mode ultrasound with computer-assisted image processing and Doppler ultrasound, respectively. We observed 44 ipsilateral ischemic strokes. In symptomatic patients, relative risk of ipsilateral ischemic stroke for echolucent versus echorich plaques was 3.1 (95% CI, 1.3 to 7.3), whereas for 80% to 99% versus 50% to 79% stenosis, the relative risk was 1.4 (95% CI, 0.7 to 3.0). Relative to symptomatic patients with echorich 50% to 79% stenotic plaques, those with echorich 80% to 99% stenotic plaques, echolucent 50% to 79% stenotic plaques, and echolucent 80% to 99% stenotic plaques had relative risks of ipsilateral ischemic strokes of 3.1 (95%CI, 0.7 to 14), 4.2 (95% CI, 1.2 to 15), and 7.9 (95% CI, 2.1 to 30), equivalent to absolute risk increases of 11%, 18%, and 28%. This was not observed in previously asymptomatic patients. CONCLUSIONS: Echolucent plaques causing >/=50% diameter stenosis by Doppler ultrasound are associated with risk of future stroke in symptomatic but not asymptomatic individuals. This suggests that measurement of echolucency, together with degree of stenosis, may improve selection of patients for carotid endarterectomy.

Multiple autoimmune manifestations in monoclonal gammopathy of undetermined significance and chronic lymphocytic leukemia.

In 18 cases of monoclonal gammopathy of undetermined significance, MGUS (monoclonal gammopathy of undetermined significance), admitted for diagnosed or suspected peripheral neuropathy, 11 patients showed other co-existing autoimmune manifestations. Two had POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-component, and skin symptoms), the others mainly endocrinopathy and polyclonal pseudolymphoma. There were 13 cases of sensorimotor neuropathy, two cases of neuritis, while neuropathy could not be confirmed in three cases. Compared with a retrospective review of autoimmunity in a randomly selected CLL (chronic lymphocytic leukemia) cohort of 115 patients, 13 out of 42 patients with clinical and/or laboratory features of autoimmunity showed co-expression of autoimmune signs, the dominating traits being Coombs positive AIHA (auto-immune hemolytic anemia), platelet autoantibodies, endocrinopathy mainly associated with the thyroid gland, serological and/or rheumatological symptoms, but only one case of sensorimotor neuropathy. Viewed from a current model of acquired autoimmunity it is perhaps not surprising that such autoimmunity is seen predominantly in patients with monoclonal gammopathy. Thus, a high concentration of cross-reacting polyreactive autoantibodies related to the M-component might be present in these patients. Furthermore, quantitative defects of the immunoglobulins including the hypogammaglobulinemia associated with M-components can presumably give rise to a defect of the anti-idiotypic network's regulation of natural autoantibodies and autoimmune manifestations in vivo. Such autoimmune manifestations, which are easily overlooked in CLL may call for additional treatment with immunosuppression and/or intravenous, polyclonal IgG.

Tomographic cerebral blood flow measurements in patients with ischemic cerebrovascular disease and evaluation of the vasodilatory capacity by the acetazolamide test.

Cerebral blood flow (CBF) was measured in a series of patients with ischemic cerebrovascular disease using xenon-133 inhalation and single photon emission computer tomography. The spontaneous course of CBF changes in a consecutive series of stroke patients was evaluated. A quite heterogeneous pattern of flow changes was observed: In patients with large cortical/subcortical infarcts, extensive hypoperfused areas were observed, often significantly larger than the corresponding hypodense lesion on the CT scan. Smaller CT lesions caused relatively smaller flow changes. Patients with lacunar infarcts showed only a discrete reduction of CBF, but comprising most of the ipsilateral hemisphere. Repeated CBF studies in the chronic phase showed, that the clinical improvement commonly noted in stroke patients is not related to a CBF increase. On the contrary, the CBF lesions tended to become somewhat larger and more demarcated even in cases where the finding of a normal angiogram and a transient state of hyperemia suggested a dissolution of the intracerebral embolus. The pathogenetic mechanisms for these persisting low flow areas in CT intact structures was discussed. One possibility was a selective neuronal cell damage in the peri-infarct areas caused by the ischemic insult. Such lesions would leave the structures macroscopically intact, but decrease both the metabolic demands and CBF. However, this interpretation finds little support in recent microscopic neuropathological studies in man. A more likely possibility was then considered to be disconnection (diaschisis) where the reduced flow is due to a decreased neuronal function caused by undercutting of afferent or efferent nervefibers. A crossed cerebellar diaschisis was observed in all patients with major infarcts in the forebrain. These findings were observed already in the acute phase, but persisted quite unchanged throughout the subacute and chronic phases. The patients with lacunar infarcts showed cerebellar diaschisis in the acute phase only, suggesting that a transient suppression of remote areas is possible too. In order to differentiate between permanent flow changes caused by a functional impairment and a possible hemodynamic component, CBF was measured before and after administration of a potent cerebral vasodilator, acetazolamide (Diamox). In normal cases tested with Diamox, an even CBF increase is noted throughout the hemispheres, while the cerebral metabolic rate for oxygen remains stable. In patients having a severe stenosis or occlusion of the internal carotid artery, this vasodilatory stress test will identify the patients having poor collateral capacity via the circle of Willis.(ABSTRACT TRUNCATED AT 400 WORDS)

Calcium antagonist (PY 108-068) treatment may further decrease flow in ischemic areas in acute stroke.

The effect of the possible influence of a new calcium antagonist, PY 108-068, on regional CBF was studied in patients suffering acute ischemic stroke. The dosage was 1.5 + 2.5 mg intravenously in six patients (series 1) and 2.5 + 5.0 mg intravenously in five other patients (series 2). CBF was measured before and after treatment by xenon-133 inhalation and single-photon emission computed tomography (Tomomatic 64). In the first series, no changes in hemispheric CBF, MABP, or clinical symptoms were noted after treatment, but one patient showed an increase of CBF in part of the periinfarct area. In the second series, slight increases in mean hemispheric flow values were seen, but in three of the five patients CBF decreased even further in the ischemic area. MABP decreased by 13%, and the clinical symptoms were unchanged.

Noninvasive xenon-133 measurements of cerebral blood flow using stationary detectors compared with dynamic emission tomography.

Repeated bedside measurements of CBF have been made possible by the recent development of a mobile unit with 10 stationary detectors using the intravenous xenon-133 method. To evaluate this technique, comparative CBF studies at rest and following the application of a cerebral vasodilatory stimulus (acetazolamide, 1 g i.v.) were performed with the mobile equipment and with xenon-133 single-photon emission inhalation tomography in patients with cerebrovascular disease. The CBF level and the flow response to acetazolamide as determined with the two methods were well correlated, although at low flow levels the stationary detectors yielded somewhat lower CBF values than did emission tomography. Considering the side-to-side asymmetry, an excellent correlation was obtained. Using the initial slope index, the stationary detectors revealed quantitatively 83% of the interhemispheric asymmetry and 63% of the asymmetry in the middle cerebral artery territory shown with the tomograph. As illustrated by a case history, the nontomographic CBF unit used in this study may provide reliable and useful information in patients with occlusive cerebrovascular disease by performing repeated CBF studies and challenging the cerebral circulation with acetazolamide.

Crossed cerebellar diaschisis in ischemic stroke: a study of regional cerebral blood flow by 133Xe inhalation and single photon emission computerized tomography.

Seventy measurements of CBF were performed in 12 stroke patients by 133Xe inhalation and a rapidly rotating single photon emission computerized tomograph. CBF was measured every other day during the acute phase and at 2- and 6-month follow-up visits. A persistent contralateral cerebellar blood flow depression was evident in five patients with severe hemispheric low flow areas, which correlated with large, hypodense lesions on the computerized tomographic scan. In a sixth patient with a small, deep infarct, a transient crossed cerebellar low flow was observed, while the clinical symptoms persisted. It is concluded from this serial study that crossed cerebellar diaschisis is a common finding in completed stroke. It is probably caused by disconnection of the corticopontine pathways, a disconnection that tends to persist. The phenomenon is in fact less variable than the stroke-related CBF changes in the infarcted hemisphere, in which a period of relative hyperemia is frequently seen.

Human regional cerebral blood flow during rapid-eye-movement sleep.

Owing to the coupling between CBF and neuronal activity, regional CBF is a reflection of neural activity in different brain regions. In this study we measured regional CBF during polysomnographically well-defined rapid-eye-movement (REM) sleep by the use of single photon emission computerized tomography and the new tracer 99mTc-dl-hexamethylpropyleneamine. Eleven healthy volunteers aged between 22 and 27 years were studied. CBF was measured on separate nights during REM sleep and during EEG-verified wakefulness. On awakening from REM sleep, all subjects reported visual dreams. During REM sleep CBF increased by 4% (p less than 0.01) in the associative visual area, while it decreased by 9% (p less than 0.01) in the inferior frontal cortex. The CBF increase in the associative visual area suggests that activation of cerebral structures processing complex visual material is correlated to visual dream experiences. On the other hand, the reduced involvement of the inferior frontal cortex observed during REM sleep might explain the poor temporal organization and bizarreness often experienced in dreams.

Increased cerebral blood flow in anemic patients on long-term hemodialytic treatment.

CBF was measured in 15 patients on chronic hemodialytic treatment. CBF was measured with xenon-133 inhalation using single photon emission tomography. In addition, computerized tomography (CT) and a neurological examination were done prior to hemodialysis. Mean CBF was 66.2 +/- 17.3 (SD) ml 100 g-1 min-1, which was significantly higher (t-test, p less than 0.05) than for an age-matched control group (54.7 +/- 10.2 ml 100 g-1 min-1). However, the hematocrit for the patients was considerably lower, 0.30 +/- 0.07, as compared to 0.43 +/- 0.03 in the controls. A significant negative correlation was observed between CBF and the hematocrit (y = -1.79x + 120.7, r = -0.71, p less than 0.01). Calculating CBF from this equation in the dialyzed patients using a hematocrit of 0.43 yielded a mean CBF value of 43.7 ml 100 g-1 min-1, i.e., 20% below the expected. Two patients showed a focal CBF decrease. CT showed central or cortical atrophy in five patients, and two had small hypodense lesions. The neurological examination revealed slight to moderate dementia in seven cases. Although mean CBF was found to be increased by 21% as compared to the control group, an even higher CBF level would have been expected to outweigh the decreased oxygen carrying capacity of the blood. The findings suggest a lowered metabolic demand of the brain tissue, probably due to subtle brain damage.

Neuronal pH regulation: constant normal intracellular pH is maintained in brain during low extracellular pH induced by acetazolamide--31P NMR study.

The intracellular pH in the brain was studied in six healthy volunteers before and immediately after the administration of 2 g of acetazolamide. Phosphorus-31 nuclear magnetic resonance spectroscopy by a 1.5 tesla whole-body scanner was used. The chemical shift between the inorganic phosphate and the phosphocreatine resonance frequencies was used for indirect assessment of the intracellular pH. The mean baseline intracellular pH was 7.05 +/- 0.04 (SD). The mean pH changes obtained at 15-min intervals within the first hour of acetazolamide administration were -0.03 +/- 0.04 (SD), -0.02 +/- 0.03 (SD), and 0.00 +/- 0.04 (SD), i.e., no statistically significant pH decrease was observed during the period where extracellular pH is known to drop markedly. Although several factors contribute to the lack of change of the intraneuronal pH, we will discuss that this observation in addition might suggest a direct intracerebral effect of acetazolamide.

Cerebral blood flow in rats with renal and spontaneous hypertension: resetting of the lower limit of autoregulation.

The effect of chronic hypertension on cerebral blood flow (CBF) was studied in anaesthetised rats. CBF was measured with the intracarotid 133Xe injection method. Rats with spontaneous and renal hypertension were compared with normotensive controls. The lower limit of autoregulation was determined during controlled haemorrhage. In the normotensive rats, CBF remained constant until mean arterial pressure (MAP) had decreased to the range of 50-69 mm Hg. Thereafter, CBF decreased with each further decrease in MAP. In both types of hypertensive rats, CBF remained constant until MAP had decreased to the range of 70-89 mm Hg. Thus, a 20-mm Hg shift of the lower limit of CBF autoregulation was found in both spontaneous and renal hypertensive rats. A neuropathological study revealed ischaemic brains lesions in half of the hypertensive rats following hypotension, whereas only a single lesion was found in one of six normotensive rats. No ischaemic brain lesions were found in a control study in which CBF was shown to be stable over a 21/2-h period. In conclusion, hypertensive rats showed a shift of the lower limit of CBF autoregulation as well as an increased susceptibility to ischaemic brain damage during hypotension. These findings presumably reflect hypertensive structural changes in the cerebral circulation.

Cerebral blood flow during delirium tremens and related clinical states studied with xenon-133 inhalation tomography.

The regional cerebral blood flow of 12 patients with severe alcohol withdrawal reactions (delirium tremens or impending delirium tremens) was measured during the acute state before treatment and after recovery. Greater cerebral blood flow was significantly correlated with visual hallucinations and agitation during the acute withdrawal reaction. The results suggest that delirium tremens and related clinical states represent a type of acute brain syndrome mainly characterized by CNS hyperexcitability.

Cerebral blood flow in patients with congestive heart failure treated with captopril.

The effect of captopril on cerebral blood flow was studied in five patients with severe congestive heart failure and in five control subjects. Cerebral blood flow was measured by inhalation of 133xenon and registration of its uptake and washout from the brain by single photon emission computer tomography. In addition, cerebral (internal jugular) venous oxygen tension was determined in the controls. The measurements were made before and 15, 60, and 180 minutes after a single oral dose of captopril (6.25 mg in patients with congestive heart failure and 25 mg in controls). Despite a marked decrease in blood pressure, cerebral blood flow increased slightly in the patients with severe congestive heart failure. When a correction was applied to take account of a change in arterial carbon dioxide tension, however, cerebral blood flow was unchanged after captopril administration even in patients with the greatest decrease in blood pressure, in whom a decrease in cerebral blood flow might have been expected. In the controls, blood pressure was little affected by captopril, whereas a slight, but not statistically significant, decrease in cerebral blood flow was observed. The cerebral venous oxygen tension decreased concomitantly.

Angiotensin converting enzyme inhibition and cerebral blood flow autoregulation in normotensive and hypertensive man.

The acute effect on the lower limit of cerebral blood flow (CBF) autoregulation of an angiotensin converting enzyme (ACE) inhibitor, captopril, was studied in normotensive volunteers and in hypertensive patients. Baseline CBF was measured using xenon-133 inhalation tomography, and changes in CBF were measured using the arterio-venous oxygen difference method. Cerebral blood flow autoregulation was studied in two separate normotensive groups, one group of 12 volunteers serving as a control, and one group of 12 volunteers studied after the administration of captopril 50 mg. In a group of seven hypertensive patients CBF autoregulation was studied before and 1 h after the administration of captopril 25 mg. In the normotensive volunteers the median lower limit of CBF autoregulation was 83 and 74 mmHg in the untreated and the captopril-treated group, respectively, with no significant difference between the two groups. In five of the hypertensive patients the lower limit of CBF autoregulation was lowered by captopril, in median by 22 mmHg. However, in two patients it was increased, by 3 and 13 mmHg, respectively. It is proposed that the shift in the lower limit of CBF autoregulation seen in some of our cases, and which has previously been documented in experimental studies, may be dependent on the activity of the sympathetic nervous system.

Dynamic SPECT of the brain using a lipophilic technetium-99m complex, PnAO.

The lipophilic 99mTc-labeled oxime propylene amine oxime (PnAO) should, according to recent reports behave like 133Xe in the human brain. This study compares SPECT images of the two tracers in six subjects: four stroke cases, one transitory ischemic attack case and one normal subject. Technetium-99m PnAO was injected i.v. as a bolus of 15 to 25 mCi. The distribution was followed over 10-sec intervals using a highly sensitive, rapidly rotating SPECT (Tomomatic 64) and compared to 133Xe flow maps. Upon arrival of the PnAO bolus to the brain, a high uptake was found in brain tissue with high cerebral blood flow followed by rapid washout. In the stroke cases, low flow areas were equally well visualized by both tracers. Two dissimilarities were seen in the initial pictures: PnAO visualized the cerebral veins and showed a lesser contrast of gray:white matter uptake. The results suggest that PnAO has a high yet incomplete brain extraction yielding a flow dominated initial distribution with limitations mentioned.

Cerebral blood-flow tomography: xenon-133 compared with isopropyl-amphetamine-iodine-123: concise communication.

Tomographic maps of local cerebral blood flow (CBF) were obtained with xenon-133 and with isopropyl-amphetamine-iodine-123 (IMP) in 11 subjects: one normal, two tumor cases, and eight cerebrovascular cases. A highly sensitive four-face, rapidly rotating, single-photon emission tomograph was used. The Xe-133 flow maps are essentially based on the average Xe-133 concentration over the initial 2 min during and after an inhalation of the inert gas lasting 1 min. These maps agreed very well with the early IMP maps obtained over the initial 10 min following an i.v. bolus injection. The subsequent IMP tomograms showed a slight decrease in contrast amounting to appr. five percentage points in the CBF ratio between diseased and contralateral areas. It is concluded that Xe-133 is more practical: low cost, available on a 7-day basis, easily repeatable, quantifiable without the need for arterial sampling, and with low radiation exposure to patient and personnel. On the other hand, IMP gives an image of slightly higher resolution. It also introduces a new class of iodinated brain-seeking compounds allowing, perhaps, imaging of other functions more important than mere blood flow.

Cerebral O2 metabolism and cerebral blood flow in humans during deep and rapid-eye-movement sleep.

It could be expected that the various stages of sleep were reflected in variation of the overall level of cerebral activity and thereby in the magnitude of cerebral metabolic rate of oxygen (CMRO2) and cerebral blood flow (CBF). The elusive nature of sleep imposes major methodological restrictions on examination of this question. We have now measured CBF and CMRO2 in young healthy volunteers using the Kety-Schmidt technique with 133Xe as the inert gas. Measurements were performed during wakefulness, deep sleep (stage 3/4), and rapid-eye-movement (REM) sleep as verified by standard polysomnography. Contrary to the only previous study in humans, which reported an insignificant 3% reduction in CMRO2 during sleep, we found a deep-sleep-associated statistically highly significant 25% decrease in CMRO2, a magnitude of depression according with studies of glucose uptake and reaching levels otherwise associated with light anesthesia. During REM sleep (dream sleep) CMRO2 was practically the same as in the awake state. Changes in CBF paralleled changes in CMRO2 during both deep and REM sleep.

Mental stress and cognitive performance do not increase overall level of cerebral O2 uptake in humans.

We measured cerebral metabolic rate of oxygen (CMRO2), cerebral blood flow (CBF), and cerebral lactate output during rest, during the execution of mental arithmetic, and during mental stress induced by physical and psychological annoyance. Measurements were performed in healthy volunteers by use of the Kety-Schmidt technique with 133Xe as the inert gas. Electroencephalographic desynchronization and highly significant increases in plasma catecholamines and heart rate verified that the test measurements were performed during conditions differing distinctly from the resting state. In accordance with an earlier study (Sokoloff et al. J. Clin. Invest. 34: 1101-1108, 1985), a minimal and nonsignificant 1% reduction of global CMRO2 during mental arithmetic was observed, signifying that this form of mental activation was unassociated with any detectable increase in overall cerebral synaptic activity. Mental stress induced a slight but highly significant (P less than 0.002) 6% reduction in global CMRO2. This finding is in contrast to results from earlier investigations and contradicts the generally accepted notion of an association between mental arousal and a diffuse upregulation of cerebral synaptic activity. During mental arithmetic and mental stress, cerebral lactate output increased by 207 and 344%, respectively, but because of large individual variations in the measured responses, the elevations reached statistical significance only during mental arithmetic.

Cerebral oxygen metabolism and cerebral blood flow in man during light sleep (stage 2).

We measured cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) during light sleep (stage 2) in 8 young healthy volunteers using the Kety-Schmidt technique with 133Xe as the inert gas. Measurements were performed during wakefulness and light sleep as verified by standard polysomnography. Unlike our previous study in man showing a highly significant 25% decrease in CMRO2 during deep sleep (stage 3-4) we found a modest but statistically significant decrease of 5% in CMRO2 during stage 2 sleep. Deep and light sleep are both characterized by an almost complete lack of mental activity. They differ in respect of arousal threshold as a stronger stimulus is required to awaken a subject from deep sleep as compared to light sleep. Our results suggest that during non-rapid eye movement sleep cerebral metabolism and thereby cerebral synaptic activity is correlated to cerebral readiness rather than to mental activity.

Focal reductions of cerebral blood flow in amyotrophic lateral sclerosis: a [99mTc]-d,l-HMPAO SPECT study.

We investigated regional cerebral blood flow (rCBF) using the [99mTc]-d,l-HMPAO technique with brain dedicated high resolution single photon emission computer tomography (SPECT) in 14 consecutive patients with amyotrophic lateral sclerosis (ALS), median age 62 years (45-77). Global CBF, expressed in % relative to the cerebellum, was significantly lower (P less than 0.05) in the ALS group (80.5 +/- 6.7%) than in the control group of 14 age-matched healthy volunteers (87.0 +/- 7.5%). Eight patients (57%) had abnormal rCBF distribution maps with reduced flow, primarily in the frontal lobes. Three of the 8 patients with abnormal rCBF had mild to moderate dementia and another one had mild aphasia. None of the patients with normal rCBF distribution maps had dementia. In the group of ALS patients as a whole rCBF was significantly reduced in the frontal cortex, the hippocampus, and the central white matter. We conclude that reduced rCBF, primarily in the frontal lobes, is a frequent finding in patients with ALS. The decreased rCBF may be associated with cognitive deficits and is most likely caused by neuronal degeneration and reduced metabolic needs.