Cerebrovascular reserve in patients with carotid occlusive disease assessed by stable xenon-enhanced ct cerebral blood flow and transcranial Doppler.

BACKGROUND AND PURPOSE: Cerebrovascular reserve (CVR) by both transcranial Doppler ultrasonography (TCD) and quantitative cerebral blood flow (CBF) can identify subgroups of patients at increased risk for stroke. A direct comparison of CVR measurements obtained with both technologies in patients with cerebrovascular occlusive disease is lacking. METHODS: CVRs before and after acetazolamide administration (1 g IV) were measured by TCD insonation of the middle cerebral artery (MCA) and CBF obtained with stable xenon CT (Xe/CT) in 38 patients with carotid occlusive disease. Sensitivity/specificity calculations were based on 2 Xe/CT MCA values: an average over 4 levels and the level with the lowest percent change in CBF. Compromised CVR was defined as no reactivity or a decrease in reactivity. RESULTS: Using the analysis of the systolic TCD, we found that velocity changes compared with the average Xe/CT MCA CVR showed a sensitivity of 33%, specificity of 90.6%, positive predictive value of 54.5%, and negative predictive value of 80%. The sensitivity of TCD compared with the lowest Xe/CT CBF CVR was 35.5%, specificity and positive predictive values were 100%, and negative predictive value was 66.7%. The index of validity was between 72% and 76%. CONCLUSIONS: TCD is much less sensitive than Xe/CT CBF in identifying patients with compromised CVR. This may be a result of the inability of TCD to identify patients with compromised reserves when their MCA blood flow comes from collateral sources. The lack of correlation between TCD and Xe/CT CBF for identifying patients with compromised CVR should be considered when stroke risk assessments are made by TCD.

Relationship between cerebral blood flow and clinical outcome in acute stroke.

OBJECTIVE: The purpose of this study was to determine the relationship between cerebral blood flow (CBF) measurements in acute stroke and early clinical outcome. MATERIAL AND METHODS: The xenon-enhanced computed tomography (XeCT) CBF studies performed in 50 patients in the acute stage (within 8 h) of a hemispheric stroke were retrospectively analyzed. The mean CBF of the symptomatic vascular territory was compared to the corresponding territory in the contralateral hemisphere. Clinical assessment on admission and discharge was performed using the National Institutes of Health stroke scale (NIHSS). RESULTS: Three groups were defined according to the degree of CBF asymmetry between the symptomatic and the contralateral asymptomatic vascular region. The CBF asymmetry was mild in group A (< or =20%), moderate in group B (>20% and <60%) and severe in group C (> or =60%). Patients in group A (n = 18) had a good outcome with a mean NIHSS score of 2 +/- 2 at discharge. In group B, the patients (n = 22) had intermediate but variable outcomes: 2 patients died and the mean NIHSS score for the survivors was variable (mean NIHSS score: 9 +/- 6). The patients in group C (n = 10) had a very poor outcome: 4 patients died and the survivors had a mean NIHSS score of 15 +/- 1. CONCLUSIONS: Quantitative XeCT CBF measurements may be useful for selecting subgroups of stroke patients with different clinical outcomes. The possibility of predicting patient prognosis as early as in the first hours after the ischemic event may help to identify the appropriate target population that will benefit from aggressive stroke therapy.

Clinical application of cerebrovascular reserve assessment as a strategy for stroke prevention.

Patients diagnosed as having symptomatic carotid occlusion, who are at increased risk for stroke, can be readily identified by methods designed to measure cerebrovascular reserves. This paper reviews the use of xenon-enhanced computed tomography (Xe/CT) cerebral blood flow (CBF) methods for quantitatively assessing cerebrovascular reserves.

The effect of reperfusion therapy on cerebral blood flow in acute stroke.

The effect of reperfusion therapy on cerebral blood flow (CBF) in acute cerebral ischemia was studied using xenon-enhanced computed tomography (XeCT). The XeCT CBF studies of 10 patients were evaluated before and after thrombolytic therapy. CBF evidence of reperfusion was evaluated in relation to the angiographic results and the clinical outcomes. Six patients had occlusions of the middle cerebral artery and four of the internal carotid artery. The mean CBF of the ischemic areas before attempted reperfusion was 9 +/- 3 mL/100g/min compared with 34 +/- 9 mL/100g/min in the contralateral asymptomatic region (P<.001). Intra-arterial-thrombolysis was performed in nine patients, and in one patient the intravenous route was used. Reperfusion of the ischemic region was shown in 9 of 10 patients, both angiographically and with the XeCT CBF studies (the mean CBF increased from 9 +/- 3 mL/100g/min to 32 +/- 10 mL/100g/min, P<.001). Among the nine successfully reperfused patients, seven were neurologically improved, one was unchanged, and one died. The mean National Institutes of Health stroke scale in the eight reperfused survivors was 12 on admission and decreased to 6 on discharge. XeCT CBF measurements are correlated with the angiographic results and can assist in the understanding of the effects of thrombolytic therapy on CBF in acute stroke. Re-establishment of CBF is associated with an improved clinical outcome but exceptions can be found. Reperfusion can occur in ischemic brain regions even with very low CBF (approaching 0 mL/100g/min) although it is not associated with prevention of infarction.

Xenon-enhanced computed tomography cerebral blood flow measurements in acute cerebral ischemia: Review of 56 cases.

OBJECTIVE: Ischemic stroke must be diagnosed promptly if patients are to be treated with thrombolytic therapy. The diagnosis of acute cerebral ischemia, however, is usually based on clinical and computed tomography (CT) scan findings. CT scans are often normal in the first few hours after stroke. The purpose of this study was to determine whether Xenon-enhanced CT (XeCT) cerebral blood flow (CBF) studies could increase the sensitivity of stroke detection in the acute stage. METHODS: CBF studies performed within 8 hours of symptom onset were evaluated in 56 patients who presented with hemispheric stroke symptoms. Mean CBF in the symptomatic vascular territory was calculated and compared with the corresponding contralateral area. CBF values below 18 mL/100g/min on 2 adjacent regions of interest were considered ischemic lesions. CT scans and angiograms were compared with the XeCt findings. Neurological condition on admission and discharge was evaluated by using National Institutes of Health Stroke Scale (NIHSS) scores. RESULTS: The mean NIHSS score on admission was 12+/-5. Early CT scans were abnormal in 28 (50%) patients. There were 9 (16%) patients who had normal XeCT scans because of spontaneous reperfusion of the ischemic area. XeCT studies showed an ischemic lesion in 47 (84%) patients. In these patients, the mean CBF in the affected vascular territory was 16+/-8 mL/100g/min compared with 35+/-13 mL/100g/min in the contralateral specular territory (P<0.001). There were no false positive or negative XeCT studies, and the location of the perfusion defect corresponded with the CT and/or angiographic findings in all cases. Eight patients died (14%), and the 48 survivors (86%) had a mean NIHSS score of 9+/-6 on discharge. CONCLUSIONS: CBF measurements were correlated with the CT and angiographic results and greatly assisted in the diagnosis of acute ischemic stroke. XeCT studies used for estimating the location and extent of cerebral ischemia may be important in the triage of patients for acute stroke therapy.

Qualitative versus quantitative assessment of cerebrovascular reserves.

OBJECTIVE: Quantitative studies of cerebral blood flow (CBF) combined with a vasodilatory challenge have defined a subgroup of patients with symptomatic carotid occlusion who have an increased risk for stroke. These are patients whose CBF paradoxically decreases in response to a vasodilatory challenge. Recent reports suggest that qualitative CBF techniques, such as single photon emission tomography with 99m-hexamethylpropyleneamine oxime, can also define the same high-risk subgroup. To determine whether qualitative measures of CBF are sufficient for predicting the risk of stroke, we converted our quantitative CBF data, obtained with xenon-enhanced computed tomography (Xe/CT), to qualitative ratios in a manner similar to that used with single photon emission tomography data. METHODS: We analyzed CBF values within the territory of the middle cerebral artery for 94 patients with symptomatic carotid occlusion. Values obtained using Xe/CT before and after the intravenous administration of 1 g of acetazolamide were used to derive an asymmetry index: (Coccl - Cnon)/Cavg x 100. The difference between the postacetazolamide asymmetry index and the baseline asymmetry index was used to classify the patients into groups according to CBF values. The threshold for abnormal qualitative CBF reactivity was defined as a percent change in the asymmetry index of less than -10%. Quantitative (Xe/CT) CBF was considered abnormal ("steal" response) when the response to acetazolamide (percent change) on the occluded side was a decrease of 5% or greater. RESULTS: Of 34 patients whose cerebrovascular reserves were considered compromised based on qualitative criteria, 17 (50%) did not have a steal response as defined by quantitative Xe/CT CBF (i.e., false positive). Eleven of 62 (18%) who were not considered compromised by qualitative criteria had a steal response (i.e., false negative). Our data indicate that a qualitative approach has a 61% sensitivity and a 75% specificity for detecting patients with compromised reserves. Further, the positive predictive value of this method is only 50%. Therefore, the two methodologies do not predict the same patients as having compromised reserves. CONCLUSION: Previous studies have shown that patients at high risk for stroke can be identified with quantitative CBF methods. This study shows that the important subgroup cannot be accurately defined with qualitative methodology. The implications of using the more reliable methodology are important for individual patient management and for designing clinical trials.

Physiological determination of cerebrovascular reserves and its use in clinical management.

Cerebrovascular reserve (CVR) can be assessed by measuring the hemodynamic response to a physiological stress such as alteration of blood pressure, increase in tissue acidosis, lowered oxygen supply, increase in metabolic demand, or occlusion of an artery. Failure of the cerebrovascular system to maintain function or normative values of several interrelated hemodynamic variables--cerebral blood flow (CBF), oxygen extraction fraction (OEF), cerebral blood volume (CBV), and cerebral metabolic rate of oxygen (CMRO2),--in response to a stress implies a compromise of the normally robust compensatory mechanisms. The conclusions that are possible from this information depend on the type of stress induced and the technology used to measure the response. Technologies that permit a rapid test-retest format coupled with a physiological stress provide the most direct information about the hemodynamics of cerebrovascular territories. Patients whose cerebral vasculature becomes compromised by any of a broad range of disorders and who, thus, are at increased risk for stroke now can be readily identified based upon evidence of exhausted CVR. Strategies for treating hemodynamically driven disorders also can now be designed based upon such patient-specific CVR information. It is hoped that integration of CVR into the standard clinical assessment of patients with occlusive vascular disorders (OVD) will lead to treatments that focus not only on the previously understood embolic causes of stroke, but also on the often interrelated hemodynamic factors.

Putative inhibitory extracellular matrix molecules at the dorsal root entry zone of the spinal cord during development and after root and sciatic nerve lesions.

The dorsal root entry zone (DREZ) of the spinal cord is the interface between the central and peripheral nervous systems and is the pathway through which sensory afferents enter the central nervous system during development. However, in the rat, the DREZ becomes a boundary to regenerating sensory axons after Postnatal Days 2-3. The cellular and molecular mechanisms that cause regenerative failure at the DREZ after the critical period for regeneration are unknown. Recent studies demonstrate that two extracellular matrix molecules, Cytotactin/tenascin (CT) and chondroitin 6-sulfate-containing proteoglycans (C-6S-PG) are present in normal boundary regions of the brain and spinal cord during development. In the present study we sought to visualize the expression of these two putative inhibitory molecules in the DREZ of normally developing and adult animals, and also in animals after injury. CT and C-6S-PG spread laterally from the midline to the DREZ by Postnatal Day 3, correlating exactly with the end of the critical period. The staining intensity for these two molecules increases further in the DREZ after root lesions, but not sciatic lesions, at ages when axons cannot regenerate into the spinal cord. Following root lesion CT and C-6S-PG were mostly present in association with reactive glia at the DREZ and in white matter, rather than with reactive glia in grey matter of the dorsal horn, suggesting that astroglia are heterogeneous in their response to root lesion. The coexpression of CT and C-6S-PG may create a molecular barrier which might channel or deflect axons at the DREZ during CNS development and inhibit their growth during regeneration.

The origins of descending projections to the lumbar spinal cord at different stages of development in the North American opossum.

We have employed the retrograde transport of fast blue (FB) to identify the origins of descending projections to the lumbar cord of the opossum from postnatal day (PD)1, 12-13 days after conception, to maturity. When FB injections were made into the lumbar cord at PD1, supraspinal labeling was sparse and limited to the hypothalamus, the reticular formation, the coeruleus complex, the caudal raphe, and, in one case, the interstitial nucleus of the medial longitudinal fasciculus and the lateral vestibular nucleus. Only a few propriospinal neurons were labeled at cervical and thoracic levels. By PD3, however, supraspinal and propriospinal labeling was abundant and present in most of the areas labeled in the adult animal. A notable exception was the red nucleus which was not labeled until approximately PD10. Our results have been compared with those described in other species and discussed in light of their relevance to the development of descending control over hindlimb movement and developmental plasticity of descending spinal pathways.

The origin of serotoninergic projections to the lumbosacral spinal cord at different stages of development in the North American opossum.

We have employed immunohistochemistry and the retrograde transport of Fast blue to study the origin of serotoninergic projections to the lumbosacral spinal cord at different stages of development in the North American opossum. A few serotoninergic axons are present in the lumbosacral cord at birth, 12 days after conception, and serotoninergic neurons are numerous in the brainstem where they are present in most, if not all, of the areas which contain them in the adult animals. A few neurons of the caudal raphe and adjacent reticular formation were labeled by lumbar injections of Fast blue on postnatal day 1, and by postnatal day 3, labeled neurons were numerous within all areas which provide serotoninergic projections to the lumbosacral cord in adult animals. By postnatal day 11, it was possible to combine Fast blue labeling with immunofluorescence to show that some of the labeled neurons were serotoninergic. By postnatal day 24, neurons which provide serotoninergic projections to the lumbosacral cord were especially numerous and some of them were found in areas which do not provide comparable projections in adult animals. In developing and adult animals, few, if any, neurons were labeled in the dorsal raphe or superior central nuclei. We have shown previously that serotoninergic axons do not innervate laminae I and II of the lumbosacral cord until approximately postnatal day 50, although they are present in the marginal zone at birth and have grown into laminae III-X by postnatal day 15. Since serotoninergic axons which project to laminae I and II originate within the raphe magnus and adjacent reticular formation, and those areas provide serotoninergic projections to the spinal cord well before postnatal day 50, it is possible that serotoninergic innervation of laminae I and II is provided by late growth of collaterals from axons that have been present in the marginal zone for some time.

Development of catecholaminergic projections to the spinal cord in the North American opossum, Didelphis virginiana.

The intent of our study was to determine when catecholaminergic axons grow into each of their adult targets in the spinal cord of the North American opossum (Didelphis virginiana) and to identify the origin of catecholaminergic axons in the lumbosacral cord at different stages of development. Tyrosine hydroxylase-like immunoreactive axons, presumed to be catecholaminergic, were demonstrated at different stages of development by the indirect antibody peroxidase-antiperoxidase technique of Sternberger. The neurons giving rise to such axons in the lumbosacral cord were identified by using the retrograde transport of Fast Blue and immunofluorescence for tyrosine hydroxylase-like immunoreactive neurons. At birth, 12-13 days after conception, tyrosine hydroxylase-like immunoreactive axons are present in the marginal zone throughout the length of the spinal cord. Such axons are particularly numerous in the dorsolateral marginal zone, the region containing most of them in adult animals. By postnatal day 3, a few immunoreactive axons are present in the intermediate (mantle) zone of the spinal cord; and by postnatal day 8, they are most concentrated in the presumptive intermediolateral cell column. Laminae I and II of the dorsal horn are not innervated by such axons until approximately postnatal day 15. By postnatal day 44, the distribution of tyrosine hydroxylase-like immunoreactive axons in the spinal cord resembles that in adult animals, although some areas may be hyperinnervated. At birth, tyrosine hydroxylase-like immunoreactive cell bodies are present in all of the brainstem areas providing catecholaminergic projections to the spinal cord in adult animals (Pindzola et al.: Brain Behav. Evol. 32:281-292, '88); and by at least postnatal day 5, lumbosacral injections of Fast Blue retrogradely label tyrosine hydroxylase-like immunoreactive neurons in all such areas. Retrogradely labeled immunoreactive neurons were also found in areas that do not contain them in adult animals. Such areas include the dorsal part of the nucleus coeruleus and certain areas of the reticular formation. During development, spinally projecting tyrosine hydroxylase-like immunoreactive neurons are numerous medial to the nucleus ventralis lemnisci lateralis (the paralemniscal region), whereas only a few are present in the same location in adult animals. Our results suggest that catecholaminergic axons grow into the spinal cord prenatally, that they innervate their adult targets postnatally and over an extended time period, and that during some stages of development they originate from areas that do not supply them in the adult animal.

Catecholaminergic innervation of the spinal cord in the North American opossum, Didelphis virginiana.

Axons presumed to contain catecholamines were visualized in the spinal cord of the spinal cord of the North American opossum using antibodies to tyrosine hydroxylase (TH) by an indirect antibody peroxidase-antiperoxidase (PAP) technique. Axons showing TH-like immunoreactivity (TH-IR) coursed primarily in the dorsal part of the lateral funiculus, although they were also present more ventrally. An occasional TH-IR axon was seen in the dorsal funiculus. Within the gray matter, TH-IR axons were distributed most densely within the intermediolateral cell column (ILC). Such axons were more numerous in the presumptive sacral parasympathetic nucleus than within the adjacent gray matter, but their density was less than that within the ILC. Many TH-IR axons were also found within laminae I-V and X, but the density of innervation in the ventral horn was relatively low. The brainstem origin of TH-IR axons in the spinal cord was studied using a combination of the retrograde transport of fluorescent dyes and immunofluorescence as well as the retrograde transport of horseradish peroxidase and PAP immunohistochemistry. The injections of retrograde markers were made at either cervical, thoracic or lumbar spinal levels. With both techniques, spinally projecting TH-IR neurons were located within the nucleus periventricularis hypothalami, the nucleus paraventricularis hypothalami dorsalis, the area hypothalamica posterior, the ventral part of the nucleus coeruleus, the nucleus coeruleus pars alpha, the lateral part of the nucleus reticularis pontis, and several nuclei of the ventrolateral medulla. Few or no cells within the parabrachial area, the region of the Kölliker-Fuse nucleus or the area adjacent to the superior olivary complex (the location of the A5 group of rats) provided TH-IR projections to the spinal cord. Our results suggest that catecholaminergic projections to the spinal cord of the marsupial opossum are similar in termination and origin to those described for rats and other placental mammals, but differences do exist.

Tangential organization of olfactory, association, and commissural projections to olfactory cortex in a species of reptile (Trionyx spiniferus), bird (Aix sponsa), and mammal (Tupaia glis).

Small amounts of tritiated leucine were injected into the olfactory bulb or anterior olfactory cortex of softshell turtles, wood ducks, and tree shrews in order to compare quantitatively the laminar distribution of olfactory bulb, association, and commissural projections to olfactory cortex. In all three species, a similar colaminar distribution of olfactory and association projections was found: the olfactory projections are restricted to the superficial cortical layer Ia, while the association projections are distributed into the deeper cortical layers Ib, II, and III. Differences among these three species were found in the origin and distribution of commissural projections. Whereas in tree shrews these fibers originate from third-order neurons and project into the deeper layers of the contralateral cortex (with the homolateral olfactory bulb projections), in softshell turtles and wood ducks, they originate from second-order neurons and project into the superficial layer of the contralateral cortex (with the homolateral olfactory bulb projections). These results, in conjunction with those obtained previously in other species, indicate that the basic tangential organization of mammalian olfactory cortex is retained, albeit with some modification, from a remote, reptilian ancestor.