Risk of acute brain injury related to cerebral microembolism during cardiac catheterization performed by right upper limb arterial access.

BACKGROUND AND PURPOSE: The primary objective of this study was to assess the incidence of new cerebral infarcts related to cardiac catheterization in patients explored through the right transradial approach. METHODS: This prospective study involved 41 consecutive patients with severe aortic valve stenosis. To assess the incidence of cerebral infarction, all patients underwent cerebral diffusion-weighted MRI before and after cardiac catheterization through the right transradial approach. RESULTS: We detected only two patients (4.9%) with new, small, isolated acute cerebral diffusion abnormalities postcatheterization. All patients remained asymptomatic. CONCLUSIONS: New cerebral lesions on diffusion-weighted MRI are infrequent in patients explored through the right transradial approach. Randomized studies are warranted to confirm for potential advantages of transradial approach versus the femoral approach in cardiac catheterization.

Analysis of thrombi retrieved from cerebral arteries of patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: Information regarding the histological structure of thromboemboli that cause acute stroke provides insight into pathogenesis and clinical management. METHODS: This report describes the histological analysis of thromboemboli retrieved by endovascular mechanical extraction from the middle cerebral artery (MCA) and intracranial carotid artery (ICA) of 25 patients with acute ischemic stroke. RESULTS: The large majority (75%) of thromboemboli shared architectural features of random fibrin:platelet deposits interspersed with linear collections of nucleated cells (monocytes and neutrophils) and confined erythrocyte-rich regions. This histology was prevalent with both cardioembolic and atherosclerotic sources of embolism. "Red" clots composed uniquely of erythrocytes were uncommon and observed only with incomplete extractions, and cholesterol crystals were notably absent. The histology of thromboemboli that could not be retrieved from 29 concurrent patients may be different. No thrombus >3 mm wide caused stroke limited to the MCA, and no thrombus >5 mm wide was removed from the ICA. A mycotic embolus was successfully removed in 1 case, and a small atheroma and attached intima were removed without clinical consequence from another. CONCLUSIONS: Thromboemboli retrieved from the MCA or intracranial ICA of patients with acute ischemic stroke have similar histological components, whether derived from cardiac or arterial sources. Embolus size determines ultimate destination, those >5 mm wide likely bypassing the cerebral vessels entirely. The fibrin:platelet pattern that dominates thromboembolic structure provides a foundation for both antiplatelet and anticoagulant treatment strategies in stroke prevention.

Stroke attributable to a calcific embolus from the brachiocephalic trunk.

BACKGROUND AND PURPOSE: Calcific brain embolization is a rare event that is usually secondary to cardiac valve calcification. We present a case of stroke caused by embolization of calcific material from the brachiocephalic trunk, probably induced by radiotherapy. SUMMARY OF CASE: A 56-year-old right-handed female developed left-sided hemiparesis, hemihypesthesia, and sensory inattention. She had a history of right breast carcinoma that was excised 8 years previously followed by radiotherapy. She had no other history of note. Computed tomography of the head and magnetic resonance imaging confirmed a calcific embolus in right middle cerebral artery and an acute infarction in the corresponding territory. Plain chest radiography, carotid ultrasonography, transthoracic and transoesophageal echocardiography failed to demonstrate the source of calcific embolism. Computed tomography of the thorax revealed heavy calcification of the brachiocephalic trunk and the origin of the right common carotid artery. CONCLUSIONS: Undertaking a vigilant systematic search for the source in cases of calcific embolization is necessary. The aorta and its main branches are possible, yet unusual, sources of calcific emboli that merit investigation.

Absence of microemboli on transcranial Doppler identifies low-risk patients with asymptomatic carotid stenosis.

BACKGROUND AND PURPOSE: Carotid endarterectomy clearly benefits patients with symptomatic severe stenosis (SCS), but the risk of stroke is so low for asymptomatic patients (ACS) that the number needed to treat is very high. We studied transcranial Doppler (TCD) embolus detection as a method for identifying patients at higher risk who would have a lower number needed to treat. METHODS: Patients with carotid stenosis of > or =60% by Doppler ultrasound who had never been symptomatic (81%) or had been asymptomatic for at least 18 months (19%) were studied with TCD embolus detection for up to 1 hour on 2 occasions a week apart; patients were followed for 2 years. RESULTS: 319 patients were studied, age (standard deviation) 69.68 (9.12) years; 32 (10%) had microemboli at baseline (TCD+). Events were more likely to occur in the first year. Patients with microemboli were much more likely to have microemboli 1 year later (34.4 versus 1.4%; P<0.0001) and were more likely to have a stroke during the first year of follow-up (15.6%, 95% CI, 4.1 to 79; versus 1%, 95% CI, 1.01 to 1.36; P<0.0001). CONCLUSIONS: Our findings indicate that TCD- ACS will not benefit from endarterectomy or stenting unless it can be done with a risk <1%; TCD+ may benefit as much as SCS if their surgical risk is not higher. These findings suggest that ACS should be managed medically with delay of surgery or stenting until the occurrence of symptoms or emboli.

Can transcranial Doppler discriminate between solid and gaseous microemboli? Assessment of a dual-frequency transducer system.

BACKGROUND AND PURPOSE: Transcranial Doppler ultrasound can reliably detect both gaseous and solid cerebral emboli. However, conventional equipment is unable to discriminate between gaseous and solid emboli. This is a major limitation in situations in which the 2 coexist, because they may have very different clinical relevance. Recently, a novel Embo-Dop system, using insonation at 2 ultrasound transducer frequencies, has been developed. An initial study with a small sample size suggested it provided excellent discrimination. We performed a validation study in subjects with embolic signals of known nature. METHODS: Gaseous embolic signals were obtained in 7 patients with known patient foramen ovale by intravenous injection of agitated saline injections. Solid embolic signals were obtained in patients with symptomatic carotid stenosis (N=23). Discrimination of the 2 using the Embo-Dop system dual-frequency system was assessed. It was compared with discrimination using embolic signal maximum intensity with an intensity threshold. RESULTS: One hundred forty-five solid embolic signals were recorded from carotid stenosis patients. Seventy-three were classified as solid and 72 as gaseous by the Embo-Dop system. Six hundred forty-eight gaseous embolic signals were recorded from 7 patients with patent foramen ovale. Six hundred twenty-five were classified as gaseous and 23 as solid. This gave a sensitivity of 50.3% and specificity of 96.5% for detecting solid embolic signals. Discrimination was better than using a simple intensity threshold. CONCLUSIONS: The Embo-Dop dual-frequency system allows better discrimination than a simple intensity threshold but it is not accurate enough for use in clinical or research studies. Further work is needed to develop reliable clinical systems for discrimination of emboli.

Analysis of combined treatment of embolic stroke in rat with r-tPA and a GPIIb/IIIa inhibitor.

Suppression of platelet activation improves the efficacy of thrombolytic therapy for stroke. Thus, combination treatment with recombinant tissue plasminogen activator (r-tPA) and 7E3 F(ab')2, a GPIIb/IIIa inhibitor that binds the platelet to fibrin, may improve the efficacy of thrombolytic therapy in embolic stroke. Magnetic resonance imaging (MRI) was used to monitor treatment response in rats subjected to embolic middle cerebral artery (MCA) occlusion (MCAo). Animals were randomized into treated (n=12) and control (n=10) groups and received intravenous combination therapy or saline, respectively, 4 hours after MCAo. Magnetic resonance imaging (MRI) measurements performed 1 hour after MCAo showed no difference between groups. However, an increased incidence (50%) of MCA recanalization was found in the treated group at 24 hours compared with 20% in the control group. The area of low cerebral blood flow at 24 and 48 hours was significantly smaller in the combination treatment group, and the lesion size, as indicated from the T2 and T1 maps, differed significantly between groups. Fluorescence microscopy measurements of cerebral microvessels perfused with fluorescein isothiocyanate-dextran and measurements of infarct volume revealed that the combination treatment significantly increased microvascular patency and reduced infarct volume, respectively, compared with the control rats. The efficacy of combination treatment 4 hours after ischemia is reflected by MRI indices of tissue perfusion, MCA recanalization, and reduction of lesion volume. The treatment also reduced secondary microvascular perfusion deficits.

Long-term effects of sequential cortical infarcts on scar size, brain volume and cognitive function.

Focal ischemia induces long-term pathophysiological consequences in widespread brain areas. Here we analyzed long-term effects of sequential cortical lesions on brain volume and cognitive function. Rats received either single photothrombotic lesions in the forelimb sensorimotor cortex (SL) or two lesions in sequence either immediately (DL0), 2 days (DL2), 7 days (DL7), or 10 days (DL10) after the first surgery in the homotopic contralateral area. Infarct and global brain volume were measured 7 days (SL and DL2 groups) and one month (all groups) after the last period of ischemia. In the weeks following a stroke, the single lesion shrank considerably. This shrinkage was accentuated by a further lesion received either earlier or later. Thirty-one days after obtaining the second lesion, the lesion scars on both sides had a mean volume of 5.8 +/- 2.3 mm3 in DL2 as compared to 8.5 +/- 3.5 mm3 in SL-animals. In addition, there was a super-additive loss of residual brain volume by 2.2-8.0% in each hemisphere in animals with sequential lesions. In the watermaze, this loss of brain volume corresponded to a slight but significant impairment in performance. The present study revealed a complex interaction of lesions in animals with sequential strokes associated with global reduction of brain volume and cognitive impairment indicating degenerative processes beyond the lesions itself.

Primary amyloidosis with familial vitreous opacities: an unusual case and family.

Peripheral neuropathy was not found even six to ten years after the onset of visual symptoms in a family with primary amyloidosis, except in the propositus at the terminal stage. The propositus had mainly ocular and CNS involvement. An ocular manifestation, the vitreous opacity, was the only involvement in the family members, in spite of the long clinical course. This family may have a different type of familial primary amyloidosis from that previously reported.

Middle cerebral artery thrombosis: acute blood-brain barrier consequences.

The effect of middle cerebral artery (MCA) thrombosis on the integrity of the blood-brain barrier (BBB) was studied in rats using horseradish peroxidase (HRP). Endothelial injury with subsequent platelet thrombosis was produced by means of a rose bengal-sensitized photochemical reaction, facilitated by irradiating the right proximal MCA segment with the focused beam of an argon laser. At 15 minutes following thrombosis formation, diffuse leakage of HRP was observed bilaterally within cortical and subcortical brain areas. Peroxidase extravasation was most dense within the territory of the occluded artery including neocortical areas and dorso-lateral striatum. Contralaterally, a similar distribution was observed but with less intense HRP leakage. Ultrastructural studies demonstrated an increase in permeability to HRP within arterioles, venules and capillaries. At these sites, the vascular endothelium contained HRP-filled pinocytotic vesicles and tubular profiles. Although less intense, bilateral HRP leakage was also observed following MCA stenosis or femoral artery occlusion. Endothelial-platelet interactions at the site of vascular injury may be responsible for releasing substances or neurohumoral factors which contribute to the acute opening of the BBB.

Mechanisms of blood-brain barrier breakdown after microembolization of the cat's brain.

Unilateral microembolization of the cat brain with carbonized microspheres 15 microns in diameter ten minutes (min) before death induced multifocal disruption of the blood-brain barrier (BBB) to horseradish peroxidase (HRP) in nine adult cats. The gross pattern of HRP extravasates was studied: (a) after five min of in vivo circulation, (b) following infusion of HRP immediately before chemical fixation, and (c) following infusion of HRP after 60 min of aldehyde fixation. Examination of the material from the three different experimental groups revealed no qualitative differences at the light microscopic level; specific features such as ring-shaped extravasations of HRP occurred irrespective of the mode of tracer injection. Tracer-filled pinocytotic vesicles and tubular profiles were abundant in the vascular endothelium after in vivo circulation of HRP, but were virtually absent after supravital and postmortem HRP administration. The results suggest that BBB breakdown for proteins after microembolization is not an energy-dependent process mediated by either pinocytosis or tubular-endothelial channel formation.

Ataxia-telangiectasia with a 32 year survival. A clinicopathological report.

The clinicalpathological findings in a 32-year old woman with ataxia-telangiectasia are presented. This is the oldest patient with this disease to be studied thoroughly clinically and at autopsy. Multiple small gliovascular malformations in the brain and spinal cord and telangiectasis of the liver were found. Other advanced lesions of ataxia-telangiectasia are illustrated. The vascular malformations of the central nervous system and liver are unique. The patient died of a malignant lymphoproliferative disorder and had five other malignant and benign neoplasms.

Microvascular and neuronal consequences of common carotid artery thrombosis and platelet embolization in rats.

The microvascular and neuronal consequences of nonocclusive common carotid artery (CCA) thrombosis were documented in rats. Thrombosis of the CCA was produced by a rose bengal-mediated photochemical insult and regional patterns of blood-brain barrier (BBB) disruption were documented by horseradish peroxidase (HRP) histochemistry at 15 min (n = 12), 4 h (n = 3), 1 day (n = 5) or 7 days (n = 5) after vascular injury. At 15 min and 4 h after thrombosis, multiple foci of BBB disruption were present throughout the thrombosed hemisphere; protein leakage was occasionally detected contralaterally. Extravasated HRP was associated with well-perfused arterioles and arterioles containing luminal platelet aggregates at different stages of degranulation. Evidence for local platelet adhesion and aggregation or endothelial disruption at these sites was not detected. However, HRP-containing endothelial plasmalemmal vesicles were present at leaky sites. Variable degrees of parenchymal injury were documented including dendritic and astrocytic swelling with neuronal necrosis. By 1 day after CCA thrombosis, the overall frequency of permeable sites, more commonly associated with luminal leukocytes and parenchymal necrosis, was reduced. At 7 days, vessels permeable to HRP were associated with tissue necrosis, reactive astrocytes and microglial infiltration. Arteriole wall thickening and leukocyte accumulation within arterioles and venules were also detected. Widespread platelet embolization leading to variable degrees of BBB disruption and tissue injury occurs after CCA thrombosis. Acute abnormalities in vascular permeability are thus hypothesized to play an important role in the acute pathogenesis of cerebrovascular thrombosis. Delayed leukocyte accumulation in this model of embolic infarction may represent a secondary insult to the injured brain.

Temporary regional cerebral ischemia in the cat. A model of hemorrhagic and subcortical infarction.

A comparison was made on some of the effects that temporary and permanent occlusion of the middle cerebral artery may have on the circulation to the ipsilateral hemisphere in the cat. Reperfusibility of the corresponding capillary bed was unimpaired for the initial six hours after occluding the vessel, as demonstrated by in vivo intravenous injection of carbon black. Short-term occlusion of the middle cerebral artery, followed by re-opening of the vessel, resulted in either (a) no demonstrable parenchymal lesions (i.e., areas of softening), (b) smaller lesions, or (c) infarctions that were either hemorrhagic or confined to the subcortical white matter of the ipsilateral hemisphere.

Laser microprobe mass spectrometric study of aluminum and silicon in brain emboli related to cardiac surgery.

Recent investigations have shown numerous fatty microemboli, which we previously termed small capillary and arteriolar dilatations (SCADs), in brain microvessels of patients who died after cardiac surgery assisted by cardiopulmonary bypass (CPB). The hypothesis of this study was that extraneous trace elements such as aluminum (Al) and silicon (Si) might be contaminating the blood and causing the formation of SCADs or coating the SCADs already formed in the extracorporeal circulation during CPB. Small capillary and arteriolar dilatations were identified in thick celloidin sections of the brains of 8 patients who died after cardiac surgery supported with a membrane oxygenator, and of 2 dogs that underwent CPB with a bubble oxygenator. The sections were infiltrated with Spurr's embedding medium for electron microscopy. Resin sections 0.5 microm thick were placed on 100-mesh copper grids and analyzed with laser microprobe mass spectrometry. Brain sections without SCADs from 3 patients (controls) whose deaths were not related to cardiac surgery were processed similarly. In SCADs and nearby neuropil sites of the 8 patients who had cardiac surgery, both Al and Si values were higher than in the neuropil, including vessels of the 3 controls. Si values were also high in the 2 dogs, in which a bubble oxygenator was used. Our results indicate that contamination with Al and Si continues to occur during cardiac surgery assisted by CPB. Our data also suggest that switching to membrane oxygenators from bubble oxygenators for CPB may have reduced Si contamination of blood. Further refinements of CPB aimed at eliminating microemboli formation and Al and Si entry into the circulation are warranted.

Experimental embolic stroke in the guinea pig (Cuvis cobaya).

Because of the demonstrated suitability of the guinea pig (Cuvis cobaya) for a large variety of laboratory investigations, we sought to develop a stroke model in this animal. Many ingenious stroke models in other animals exist; some depend on anomalous anatomy, others utilize methods of intracranial or extracranial vascular occlusion and yet others combine ischemia and anoxic damage (1-14). As one proposed application for this work was to study immune responses following experimental stroke, survival of several days after cerebral infarction was a requirement. Three to five days elapse before detection of a hymoral and cellular immune response is possible. The guinea pig is especially suited to immunological studies because of the enormous amount of accumulated data on the immunology of this animal. However, the guinea pig has proved relatively invulnerable to existing small animal techniques. Moreover the unacceptably short postoperative survival associated with the use of existing techniques necessitated the development of a new procedure. We have successfully pursued the development of an embolic stroke procedure applicable to this animal.

Primate model of cerebral hematoma.

Using specific anesthetic agents, permanent segmental occlusion of the proximal middle cerebral artery (MCA) causes ischemic infarction limited to the putamen and other deep hemispheral structures in primates. Using this model, 25 rhesus monkeys were subjected to acute arterial hypertension before, during and up to 5 days after onset of MCA occlusion in order to reevaluate the possible role of the ischemic process in pathogenesis of cerebral hemorrhage. Norepinephrine infusion induced prompt rapid rise in mean arterial pressure (MAP) and intracranial pressure (ICP) limited to the duration of infusion. This procedure produced acute ischemic lesions which were totally bland but topographically more extensive than untreated controls; in chronic lesions, however, deep nuclear masses showed hemorrhagic infarction. Animals given 5% CO2 air had slowly progressive elevation in ICP and MAP. Acute specimens showed intact, widely-dilan hypercarbia was induced 5 days after MCA occlusion, animals developed intracerebral hematoma involving putamen, external capsule and claustrum, occasionally dissecting through to ipsilateral ventricle. In acute cerebral ischemia, elevated MAP produced only quantiative changes in lesion size. In the vasoproliferative stages of mature infarction, MAP elevation induced by a cerebral vasoconstrictor caused hemorrhagic infarctions while cerebral vasodilation caused intracerebral hematomas.

Fundamental pathological lesions in vascular dementia.

This review concerns the fundamental cerebral lesions in cases of vascular dementia. Extracerebral vascular alterations are dominated by atherosclerosis with or without thrombosis. In addition, occlusion of extracerebral arteries can be induced by thrombo-embolism and in rare cases by other vascular diseases, chiefly arteritis. Intracerebral microangiopathies are usually of arteriolosclerotic or hyalinotic types in which there is degeneration of smooth muscle cells of the media and deposition of components of extracellular matrix, chiefly collagens. Ageing, chronic hypertension, hyperlipidemias and diabetes are important factors inducing vascular lesions. The vascular lesions, often combined with systemic factors, may produce various ischemic and edematous alterations of the brain parenchyma. Occlusion and obliteration of arteries (macroangiopathy) are associated with large infarcts, whereas microangiopathy may cause lacunar infarcts and some forms of white matter degeneration. Cases of vascular dementia usually present many types of lesions in the brain parenchyma and its arterial supply. The extent and location of the injuries differ considerably from case to case. Location of the lesions, volume of destroyed tissue, multiplicity and bilateral occurrence are most important parameters underlying the clinical manifestations in vascular dementia. A strategic location of a small injury is in some cases of particular importance.

Local cerebral blood flow in a rat cortical vein occlusion model.

The symptoms following sinus and vein occlusion observed in patients and experimental animals display a considerable variability that so far remains largely unexplained. In a rat cortical vein occlusion model using a photochemical thrombotic technique, we examined changes in the cerebral venous flow pattern by fluorescence angiography and regional cerebral blood flow (rCBF) and cerebral blood volume fraction (CBVF) by a modern laser Doppler "scanning" technique. Brain damage was assessed histologically. Fluorescence angiographic findings fell into two groups: group A, rats with an altered venous flow pattern after occlusion (n = 12), and group B, rats with interruption of blood flow and/or a growing venous thrombus (n = 5). In addition, sham-operated animals made up group C (n = 5). Extravasation of fluorescein, a massive decrease in rCBF, a short-lasting increase in CBVF, and regional brain damage were typical for group B. In addition, cortical CBF mapping revealed a transient hyperperfusion zone with hyperemia surrounding a hypoperfused ischemic core in group B. A circulation perturbation following venous occlusion appeared near those occluded cerebral veins without sufficient collateral flow. Furthermore, the venous thrombus continued to grow, accompanied by local critical ischemia and severe brain damage. Conversely, 71% of the animals (12 of 17) tolerated occlusion of a solitary vein without major flow disturbances or histological evidence of damage to the CNS (group A).

High speed diffusion magnetic resonance imaging of ischemia and spontaneous periinfarct spreading depression after thromboembolic stroke in the rat.

Spontaneous episodes of transient cell membrane depolarization (spreading depression [SD]) occur in the surroundings of experimental stroke lesions and are believed to contribute to infarct growth. Diffusion-weighted imaging (DWI) is capable of detecting the water shifts from extracellular to intracellular space associated with SD waves and ischemia, and can make in vivo measurements of these two features on a pixel-by-pixel basis with good temporal resolution. Using continuous high speed DWI with a temporal resolution of 12 seconds over a period of 3 hours, the in vivo contribution of spontaneous SDs to the development of ischemic tissue injury was examined in 8 rats using a thromboembolic stroke model. During the observation period, the initial lesion volume increased in 4 animals, remained unchanged in 1 animal, and decreased in 3 animals (most likely because of spontaneous clot lysis). Irrespective of the lesion evolution patterns, animals demonstrated 6.5 +/- 2.1 spontaneous SDs outside of the ischemic core. A time-to-peak analysis of apparent diffusion coefficient (ADC) changes for each SD wave demonstrated multidirectional propagation patterns from variable initiation sites. Maps of the time constants of ADC recovery, reflecting the local energy supply and cerebral blood flow, revealed prolonged recovery times in areas close to the ischemic core. However, repetitive SD episodes in the periinfarct tissue did not eventually lead to permanent ADC reductions. These results suggest that spontaneous SD waves do not necessarily contribute to the expansion of the ischemic lesion volume in this model.

Diffusion-, T2-, and perfusion-weighted nuclear magnetic resonance imaging of middle cerebral artery embolic stroke and recombinant tissue plasminogen activator intervention in the rat.

Thrombolysis of embolic stroke in the rat was measured using diffusion (DWI)-, T2 (T2WI)-, and perfusion (PWI)-weighted magnetic resonance imaging (MRI). An embolus was placed at the origin of the middle cerebral artery (MCA) by injection of an autologous single blood clot via an intraluminal catheter placed in the intracranial segment of internal carotid artery. Rats were treated with a recombinant tissue plasminogen activator (rt-PA) 1 hour after embolization (n = 9) or were not treated (n = 15). Diffusion-weighted imaging, T2WI, and PWI were performed before, during, and after embolization from 1 hour to 7 days. After embolization in both rt-PA-treated and control animals, the apparent diffusion coefficient of water (ADCw) and cerebral blood flow (CBF) in the ischemic region significantly declined from the preischemic control values (P < 0.001). However, mean CBF and ADCw in the rt-PA-treated group was elevated early after administration of rt-PA compared with the untreated control group, and significant differences between the two groups were detected in CBF (24 hours after embolization, P < 0.05) and ADCw (3, 4, and 24 hours after embolization, P < 0.05). T2 values maximized at 24 (control group, P < 0.001) or 48 hours (treated group, P < 0.01) after embolization. The increase in T2 in the control group was significantly higher at 24 hours and 168 hours than in the rt-PA-treated group (P < 0.05). Significant correlations (r > or = 0.80, P < 0.05) were found between lesion volume measured 1 week after embolization and CBF and ADCw obtained 1 hour after injection of rt-PA. Within a coronal section of brain, MRI cluster analysis, which combines ADCw and T2 data maps, indicated a significant reduction (P < 0.05) in the lesion 24 hours after thrombolysis compared with nontreated animals. These data demonstrate that the values for CBF and ADCw obtained 1 hour after injection of rt-PA correlate with histologic outcome in the tissue, and that the beneficial effect of thrombolysis of an intracranial embolus by means of rt-PA is reflected in an increase of CBF and ADCw, a reduction in the increase of T2, and a reduction of the ischemic lesion size measured using MRI cluster analysis.