Studies of effects of kainic acid lesions in the dorsal lateral geniculate nucleus of rat.

Kainic acid has been described as a highly specific neurotoxin that when injected locally into the nervous system destroys neuronal perikarya but spares axons of passage and terminals in the vicinity of the injection site. The effects of injection of this agent into the rat dorsal lateral geniculate nucleus on geniculocortical and corticofugal pathways have been examined. Neuronal perikarya were absent from injected geniculates, and products of neuronal degeneration were observed in the external stratum of the optic radiation and in layer IV of striate cortex. Furthermore, no visually driven units could be found in physiological recordings from ipsilateral visual cortex, and no orthograde axonal transport of radioactivity to cortex was detectable by autoradiography. These observations are consistent with the complete destruction of the geniculocortical pathway. On the other hand orthograde axonal transport appeared normal in corticogeniculate and corticotectal neurons on the injected side. In addition to silver grains appearing over the geniculate and superior colliculus label was observed over corticofugal axons in the internal stratum of the optic radiation. It is noteworthy that axons of the corticofugal pathways are clearly segregated from geniculocortical axons over a part of their course through white matter. Corticogeniculate neurons on the injected side were able to transport D-aspartate but not nuclear yellow retrogradely to cell bodies in layer VI. These results are consistent with the notion that cortical neurons terminating in and passing through the kainate lesion site survive but suggests, however, that corticogeniculate neurons may be functionally altered by these lesions.

Microalbuminuria in ischemic stroke.

OBJECTIVES: To determine (1) the incidence of microalbuminuria in patients with recent ischemic stroke, (2) its relationship to risk factors for stroke, (3) its prevalence in the major subtypes of ischemic stroke, and (4) its potential for identifying patients at increased risk for recurrent stroke, myocardial infarction, or vascular death. DESIGN: Prospective case-control study. SETTING: Outpatient clinics at the medical centers affiliated with the Department of Veterans Affairs and Oregon Health Sciences University in Portland, Ore. PATIENTS: A total of 186 older men and women (median age, 65 years) who were enrolled in a prospective study of risk factors for recurrent stroke, including 97 patients with recent (6-8 weeks) ischemic stroke, 51 with similar clinical risk factors for stroke, including 24 with a history of remote stroke or transient ischemic attack, and 38 community-dwelling volunteers. RESULTS: Microalbuminuria was 3 times more prevalent in patients with recent stroke (29%) than in those with clinical risk factors for stroke (10%), and was undetectable in healthy elderly controls (P<.001). The presence of microalbuminuria in recent stroke as well as in the combined recent and remote stroke or transient ischemic attack group (n = 121) was predicted by diabetes (odds ratio [OR], 8.4; 95% confidence interval [CI], 2.6-27.0; P<.001; serum albumin levels (OR, 0.12; 95% CI, 0.03-0.50; P<.005); age (OR, 1.1; 95% CI, 1.0-1.2; P<.01), and ischemic heart disease (OR, 3.0; 95% CI, 1.0-9.1; P<.05). Among patients with recent stroke the prevalence of microalbuminuria did not differ among major ischemic stroke subtypes, ie, atheroembolic, 23%; cardioembolic, 30%; and lacunar, 33%. During a mean +/- SD of 1.5 +/- 0.9 years of follow-up, 20% of patients with recent stroke, 14% with risk factors for stroke, and 0% of healthy elderly volunteers had vascular end points (P<.004), with events being as frequent in patients with microalbuminuria (32%) as in patients with macroalbuminuria (33%). After controlling for major clinical risk factors, microalbuminuria remained an independently significant predictor of future stroke in the combined recent stroke and remote stroke or transient ischemic attack group (Cox proportional hazard ratio, 4.9; 95% CI, 1.4-17.6; P<.01). CONCLUSIONS: Microalbuminuria is a common finding in patients with cerebrovascular disease and is associated with increased risk for stroke even after correction for the presence of confounding clinical risk factors. These data suggest that microalbuminuria merits further examination as a potentially inexpensive and easily measured marker of increased risk for stroke.

Persistent inflammatory response in stroke survivors.

OBJECTIVE: Goals were to determine how long acute-phase markers remain elevated after ischemic stroke and how marker levels relate to stroke risk factors, stroke mechanism, and subsequent vascular events. METHODS: Fibrinogen (FIB), C-reactive protein (CRP), leukocytes (WBC), neutrophils (PMN), interleukin-6, and interleukin-1 receptor antagonist were measured at stroke onset and at 6 weeks, 6 months, and 1 year after enrollment, or until a vascular event occurred in 136 acute ischemic stroke patients, 76 patients with comparable risk factors for stroke, and 48 age-balanced healthy subjects. RESULTS: Multivariate logistic analysis showed that prior stroke and FIB level predicted new events in stroke patients (p < 0.04 for both), whereas congestive heart failure (p < 0.02) and creatinine level (p < 0.006) were predictive in at-risk patients. After controlling for infection, FIB, CRP, and PMN levels at baseline were higher in at-risk but not in stroke patients with recurrent events (p < 0.05 for all). At 1 year, FIB levels remained elevated in event-free stroke survivors compared with levels in the risk and control groups (p < 0.001 for both). FIB also remained higher in stroke survivors who had atheroembolism (AE) compared with non-AE stroke survivors (381+/-72 versus 342+/-78 mg/dL, p < 0.02). Peripheral vascular disease was an independent predictor (p < 0.0001) of longitudinal FIB in stroke survivors. Of note, both WBC and PMN levels were chronically elevated in patients with stroke risk factors and in stroke survivors (p < 0.0001 for both) compared with healthy elderly subjects. CONCLUSIONS: Most acute-phase markers decline gradually after stroke, but FIB remains significantly elevated and is associated with increased risk for recurrent vascular events.

Anterior operculum syndrome.

The anterior operculum syndrome (AOS) is a well-defined clinical entity that has received little attention in the English literature. We report the clinical and CT findings in 3 cases of AOS; 2 were caused by bilateral cerebral infarctions secondary to bilateral internal carotid occlusion and 1 by the residual effects of viral encephalitis. Although there was variability in the range of deficits found in our cases, each of these patients presented with characteristic facio-pharyngo-glosso-masticatory diplegia with a dramatic automatic-voluntary movement dissociation. This syndrome deserves attention for its characteristic anatomic and prognostic implications.

Prostacyclin infusion in acute cerebral infarction.

We gave prostacyclin infusions to seven patients with acute cerebral infarction. Patients without CT evidence of infarction improved, but those who already had hypodensities on CT did not benefit. Increased platelet activity, measured by plasma beta-thromboglobulin, decreased significantly (p less than 0.01) during prostacyclin administration to normal levels, but rose again after the infusion. These results indicate that prostacyclin can be given safely in doses adequate to suppress platelet function. Our findings encouraged us to proceed with a controlled trial of its clinical efficacy.

Circulating intercellular adhesion molecule-1 levels and neutrophil adhesion in stroke.

To examine whether changes in leukocyte adhesion properties occur during stroke, we measured circulating serum intercellular adhesion molecule 1 (cICAM-1) levels and neutrophil adhesion in acute stroke, patients at high risk of stroke, and in matched controls. Levels of cICAM-1 were significantly lower in the stroke group (186.2 +/- 15.6 ng ml-1) compared to controls (257.7 +/- 24.8) and risks (257.7 +/- 16.5). Neutrophil adhesion was significantly higher in the stroke group (23.6 +/- 4.3%; n = 14) compared to controls (9.7 +/- 2.3%; n = 12) and risks (12.7 +/- 2.5%; n = 13). These data suggest that changes in leukocyte adhesion dynamics are occurring in acute stroke.

Localization and organization of geniculocortical and corticofugal fiber tracts within the subcortical white matter.

Reciprocal connections are formed between the dorsal lateral geniculate nucleus and the striate cortex in the mammalian visual system. The question of whether fibers of these corticopetal and corticofugal pathways are segregated or intermingled within the white matter is still open. In order to examine the organization of these fiber tracts within the white matter, we have used orthograde axonal transport of radiolabelled proteins and neuronal degeneration following kainic acid lesions in the geniculocortical and corticofugal pathways of the rat. Within the white matter the two pathways reside in different layers and are segregated from one another over a significant portion of their course, geniculocortical fibers lying in the external sagittal stratum and corticofugal fibers lying in the internal sagittal stratum of the white matter. In addition, the corticofugal pathways projecting to subcortical structures appear fasciculated in both the transport and the degeneration studies suggesting that axons of cortical output neurons are organized into fiber bundles. The separation of fibers within the white matter may be of potential use for selectively stimulating afferent and efferent pathways in electrophysiological studies in situ and in cortical slice preparations. In addition, the corticofugal fiber bundles may play an important role in guiding axons therein to appropriate targets during axonogeneis and may carry the output of columnar units within visual cortex.

Organization of cortical afferent and efferent pathways in the white matter of the rat visual system.

Fibers forming reciprocal connections between the dorsal lateral geniculate nucleus and primary visual cortex run in separate tracts in the white matter. The corticofugal fibers are organized into bundles which project through the coronal plane at an oblique angle. We have examined the organization of corticofugal fiber tracts within the white matter of the rat using cortical slices which encompassed the predicted trajectory of these fiber bundles. Field potentials were evoked in layer VI of visual cortex by focal stimulation of subcortical white matter using microbipolar electrodes. Two major responses were elicited: a short-latency and a longer-latency response. The short-latency response was elicited in the superficial strata of white matter with proximal stimulation sites and was obtained in deeper strata for more distant, lateral sites. The longer-latency response was associated with superficial strata in white matter at both proximal and distant stimulation sites. Based on the electrophysiological properties and the white matter location for eliciting these responses, it is likely that the short-latency response is due to antidromic activation of corticogeniculate fibers, whereas the longer-latency response probably arises from orthodromic activation of geniculocortical fibers. These findings provide an electrophysiological demonstration that cortical afferent and efferent pathways are segregated within the white matter and that they can be selectively activated by focal stimulation. The fact that the fiber bundle model successfully predicted the trajectory of corticofugal fibers provides additional support for this model of white matter organization. A double labeling technique which combined orthograde axonal transport and neuronal degeneration was used to examine the topographic arrangement of corticofugal fibers in the white matter.(ABSTRACT TRUNCATED AT 250 WORDS)

Light-evoked release of endogenous glycine into the perfused vitreous of the intact rat eye.

Glycine, a putative neurotransmitter, is released into the perfused vitreous of anesthetized pigmented rats when the eye is stimulated by intermittent flashes of bright light. Other amino acids do not show stimulated release. This result provides further evidence for the role of glycine as a neural transmitter in the retina.

Lazaroids. CNS pharmacology and current research.

The 21-aminosteroids (lazaroids) are inhibitors of lipid membrane peroxidation and appear to function as oxygen free radical scavengers. The therapeutic potential of the lazaroid tirilazad mesylate has been extensively studied in several CNS disorders. Tirilazad and related compounds have been found to be highly beneficial in spinal cord trauma. Spinal cord injury studies utilising tirilazad are currently underway to determine the optimal combination of medications. Tirilazad has also been found to be beneficial in experimental head injury models, however current clinical studies have failed to confirm this efficacy, due in part to difficulties in obtaining therapeutic drug concentrations. Clinical studies using tirilazad in subarachnoid haemorrhage have been more promising. It has been shown to be beneficial in terms of reducing vasospasm and cerebral infarction associated with subarachnoid haemorrhage, and has now been approved in several European countries in this indication. Results from US studies are expected shortly. Finally, tirilazad has also been extensively tested in a variety of stroke models. Although it appears to be highly beneficial in experimental models, the clinical studies to date have failed to confirm this efficacy. Again, this failure appears to be due largely to inadequate drug concentrations having so far been tested.

The influence of antiadhesion therapies on leukocyte subset accumulation in central nervous system ischemia in rats.

Although treatment with agents that block leukocyte function, including anti-ICAM-1 and doxycycline, reduces experimental central nervous system (CNS) ischemic injury, it is not known how leukocyte subset accumulation is affected by these agents. Using the rat two-vessel occlusion model and immunohistochemistry, we investigated granulocyte (PMN) and monocyte/macrophage (M phi) accumulation at 1 and 4 d postischemia. A total of 24 animals were randomized to sham surgery, or to ischemia with saline, anti-ICAM-1, or doxycycline treatments. No leukocytes were observed in sham animals. At 24 h postischemia, there was a moderate infiltration of PMN and M phi in untreated animals that was significantly decreased with either treatment. At 4 d after ischemia no PMN were identified, with extensive M phi accumulation occurring in untreated animals that was only partially reduced with doxycycline treatment. These results confirm that both anti-ICAM-1 and doxycycline treatments reduce PMN and M phi infiltration at 24 h. Delayed M phi accumulation occurs despite treatment, suggesting that some of these cells represent transformed resident microglia.

The community hospital-based stroke programs in North Carolina, Oregon and New York--V. Stroke diagnosis: factors influencing the diagnostic evaluation of patients following acute stroke.

Among the 4129 patients of the Community Hospital-based Stroke Program, 30% had an unspecified stroke diagnosis. Since specific diagnosis and, perhaps, eventual treatment, derives in part from diagnostic testing, we examined the effect of clinical condition, geographic and demographic factors on the incidence of certain diagnostic tests after acute stroke. In this multivariable analysis, race, sex, history of hypertension and history of diabetes did not influence the chance of having any test, but older age strongly reduced the chances of receiving extensive evaluation. When CT scanning was available, the utilization of a CT as well as other diagnostic studies including cerebral angiography, radionuclide brain scan, EEG and EKG was increased. The odds of receiving a CT scan increased if the patient was married, and decreased with a history of previous stroke. A history of previous TIA increased the chance of having a cerebral angiogram while a history of cardiac disease decreased the chance. There were striking regional geographic differences in the use of CT, radionuclide brain scanning and cerebral angiography which may, in part, reflect differences between the availability of these technologies in urban and rural hospitals. These results indicate that evaluation of stroke patients remains heterogenous.

Role of a common mutation in the homocysteine regulatory enzyme methylenetetrahydrofolate reductase in ischemic stroke.

A common mutation in methylenetetrahydrofolate reductase (MTHFR), a homocysteine metabolic pathway enzyme, has been associated with increased homocysteine levels and increased risk for premature cardiovascular disease. The purpose of this study was to assess the association between the prevalence of the MTHFR mutation, hyperhomocysteinemia, and subtypes of ischemic stroke in an elderly population comprised of three age-balanced groups of patients. The presence of the C677T MTHFR mutation was determined by a direct polymerase chain reaction-based assay performed on blood samples from 136 patients with acute ischemic stroke, 95 patients with atherosclerotic risk factors for stroke (including some with a history of previous stroke or transient ischemic attack), and 52 healthy control subjects. The prevalence of the homozygous C677T mutation was not significantly higher in the elderly stroke patients (7%) than in the atherosclerotic risk (8%) or healthy elderly control (2%) groups. Plasma homocysteine levels were higher in the acute stroke patient group (14.5+/-4.5 micromol/L) and atherosclerotic risk patient group (14.6+/-6.2 micromol/L) compared with the control subjects (10.3+/-3.1 micromol/ L, P < 0.03). Homozygotes for the C677T MTHFR mutation did not have significantly higher homocysteine levels than non-homozygotes. Moderate hyperhomocysteinemia, though common in older patients with ischemic cerebrovascular disease, is not attributable, at least in this patient group, to a higher prevalence of the C677T MTHFR mutation.

Effects of kainic acid lesions in lateral geniculate nucleus: activity dependence of retrograde axonal transport of fluorescent dyes.

Kainic acid lesions in the dorsal lateral geniculate nucleus of rats block the retrograde axonal transport of fluorescent dyes in corticogeniculate neurons without affecting the retrograde transport of D-aspartate or the orthograde transport of radiolabelled proteins in these neurons. This blocking of dye transport does not appear to be a consequence of kainic acid-induced damage to axon terminals in the geniculate since retinal ganglion cells are still able to transport dyes retrograde. A more likely explanation for these results is that fluorescent dye transport requires electrical activity in neurons, and elimination of the geniculate afferents to visual cortex reduces impulse traffic in cortical output fibers to a level below that required to support detectable dye transport. This interpretation is supported by the observation that kainic acid lesions also reduce retrograde transport of dyes in cortical neurons which project to the superior colliculus. Electrical stimulation in the subcortical white matter restores the transport of dye compounds in corticogeniculate neurons: evidence consistent with an activity-dependent mechanism of retrograde transport for these substances. These results provide evidence that axon terminals of retinal ganglion cells and corticogeniculate neurons survive in kainate-lesioned geniculates and are capable of normal neuronal function.

Ultrastructural and functional evidence for the survival of corticogeniculate neurons in kainic acid-lesioned lateral geniculate nucleus.

After a kainic acid lesion in the dorsal lateral geniculate nucleus of rat, retrograde axonal transport of fluorescent dyes is blocked in corticogeniculate but not in retinogeniculate neurons. This inhibition, however, can be reversed by electrical stimulation in the subcortical white matter (Woodward and Coull, Brain Research 454 (1988) 106-115). These observations suggest that retrograde axonal transport in corticogeniculate neurons is impulse-dependent and that neuronal activity in this pathway is reduced as a consequence of the lesions. To test this we examined retrograde transport of horseradish peroxidase (HRP) and cytochrome oxidase activity in the cortex of lesioned animals. Unilateral kainic acid lesions in the geniculate inhibit the retrograde transport of HRP, but this inhibition is reversed by electrical stimulation of white matter. Moreover, histochemical staining for cytochrome oxidase activity is less intense over visual cortex on the lesioned side, implying that cortical activity in intrinsic and efferent pathways is reduced as a consequence of removal of geniculate afferents. Inasmuch as the retrograde transport of HRP is dependent upon impulse activity in neurons and is thought to be mediated by synaptic vesicle recycling, these results suggest that terminals of corticogeniculate fibers survive the kainic acid lesions in the geniculate and are capable of releasing synaptic vesicles. Ultrastructural examination of lesioned geniculates strongly supports this conclusion and reveals the presence of axon terminal profiles which are filled with small round synaptic vesicles and have membrane specializations reminiscent of synaptic contacts. These terminal profiles are presumed to be of retinal and cortical origin.

The release of endogenous amino acids into the vitreous of the intact eye of the albino rat: effect of light, potassium, and ouabain.

The vitreal space of the intact eye of albino rats was perfused in vivo. The concentration of several endogenous amino acids in the vitreal effluent was measured by the [3H]microdansylation procedure. GABA was never detected despite a sensitivity of the method of 0.5 pmol. In contrast to previous results obtained in pigmented rats, photic stimulation with flashing white light did not alter the release of glycine or any of the other amino acids. Potassium (60 mM) and ouabain (0.1 mM) evoked a specific release of glycine. The potassium-evoked release was blocked by magnesium suggesting a neuronal site of origin of glycine. Ouabain-evoked release was not blocked by magnesium. The results were contrasted with experiments on radiolabeled amino acid release from retinas preloaded and superfused in vitro, a condition in which glial localization of exogenous amino acids predominates.

Safety and efficacy of delayed intraarterial urokinase therapy with mechanical clot disruption for thromboembolic stroke.

PURPOSE: To evaluate safety and efficacy of delayed intraarterial urokinase therapy with mechanical disruption of clot to treat thromboembolic stroke. METHODS: Thirteen patients with cerebral thrombolic disease (10 carotid territory, 3 basilar territory) were treated with catheter-directed intraarterial urokinase therapy with mechanical disruption of the clots. All patients were excluded from a 6-hour multicenter thrombolytic trial by either time, recent surgery, age, seizure, or myocardial infarction. Time elapsed before treatment ranged from 3.5 to 48 hours (12 +/- 13 hours), with 200,000 to 900,000 U of urokinase used. RESULTS: Ten patients had successful vessel recanalization, confirmed by repeat angiography. Cases with distal branch vessel occlusions were less likely to recanalize. Asymptomatic hemorrhagic conversion occurred in 2 patients on repeat scans. Both acute neurologic and functional outcomes were assessed with significant improvement occurring in 9 (69%) of 13 patients at 48 hours (greater than four-point change on the National Institutes of Health scale) and in 100% of 3-month survivors. All patients who improved had normal initial CT scans. CONCLUSIONS: Intraarterial cerebral thrombolysis with mechanical disruption of clot seems to be a useful therapy in selected stroke cases even after 6 hours.

Abnormalities of hemostasis in ischemic stroke.

Despite important new diagnostic laboratory and imaging technologies, the cause of brain infarction remains unexplained in 20% to 40% of subjects. Most stroke patients do not require extensive evaluations of coagulation, but hypercoagulability may account for a significant proportion of unexplained strokes. Hemostatic abnormalities associated with stroke may be broadly classified as familial or acquired. Principal among the familial thrombotic coagulopathies are deficiencies in concentration or function in protein-C, protein-S, and antithrombin III, but other hereditary abnormalities include sickle cell disease, homocystinuria, and dysfibrinogenemia. The acquired disorders of hemostasis associated with stroke probably constitute a larger proportion of the important stroke-related coagulopathies. In particular, the aPL antibody syndrome is now strongly associated with thrombotic events including stroke, although neither the mechanism of thrombosis nor effective therapies for this syndrome have been clearly elucidated. Many of the acquired hemostatic abnormalities exist within a special clinical setting such as with malignancy or with myeloproliferative diseases, nephrotic syndrome, and liver disease. Presumably many of these share common pathways of coagulation activation or dysfunction with the inherited disorders. Most of the hemostatic disorders in stroke are associated with dysfunction of vascular endothelium and abnormalities of or interference with the natural anticoagulant proteins: protein-C, protein-S, and antithrombin III. Improved understanding of these relationships should lead to better diagnosis and treatment for people at risk of stroke.

Late stenosis of a superficial temporal-middle cerebral artery bypass: angiographic and histological findings.

The course of a patient with an initially widely patent superficial temporal artery-middle cerebral artery (STA-MCA) bypass and an enlarged donor vessel is presented. Over 17 months, the STA became markedly stenotic. Serial angiography is correlated with autopsy histological findings showing severe atherosclerotic changes throughout the donor vessel. The potential causative factors, both medical and surgical, are discussed and the appropriate literature is reviewed. Parallels are drawn from the cardiac bypass experience. The bypass itself may have precipitated or accelerated intimal hyperplasia, which stenosed (and may have eventually occluded) the vessel. Is this phenomenon more frequent than we realize?

The role of antiphospholipid antibodies in stroke.

Antiphospholipid antibodies may be found in about 10% of all subjects with acute stroke but probably are present in as many as 50% of young persons with stroke and perhaps even in high prevalence in persons who have coexisting rheumatologic diseases such as SLE. In these latter groups, the association may be as high as 50%. Probably the best related syndrome is Sneddon's syndrome, which has a high prediction to dementia. Furthermore, vascular dementia may be a prominent feature of the aPL syndrome in subjects under age 55. The cause and mechanism by which aPL are related to stroke remain unknown. Likewise, there is a dearth of information about prognosis, morbidity, and stroke recurrence in subjects who have these immunoglobulin markers. Thus therapy remains very problematic, but current strategies include the use of antiaggregate therapy, warfarin, and limited implementation with prednisone and plasmaphoresis. Data that demonstrate clear cut benefit of any of these therapies are lacking. Ultimately, unraveling these crucial problems concerning the aPL syndrome may provide great insight into certain stroke mechanisms.