Whole brain radiation-induced vascular cognitive impairment: mechanisms and implications.

Mild cognitive impairment is a well-documented consequence of whole brain radiation therapy (WBRT) that affects 40-50% of long-term brain tumor survivors. The exact mechanisms for the decline in cognitive function after WBRT remain elusive and no treatment or preventative measures are available for use in the clinic. Here, we review recent findings indicating how changes in the neurovascular unit may contribute to the impairments in learning and memory. In addition to affecting neuronal development, WBRT induces profound capillary rarefaction within the hippocampus - a region of the brain important for learning and memory. Therapeutic strategies such as hypoxia, which restore the capillary density, result in the rescue of cognitive function. In addition to decreasing vascular density, WBRT impairs vasculogenesis and/or angiogenesis, which may also contribute to radiation-induced cognitive decline. Further studies aimed at uncovering the specific mechanisms underlying these WBRT-induced changes in the cerebrovasculature are essential for developing therapies to mitigate the deleterious effects of WBRT on cognitive function.

Development of a rat model of photothrombotic ischemia and infarction within the caudoputamen.

BACKGROUND AND PURPOSE: Basal ganglia infarction is typically caused by the occlusion of deep arteries and the formation of relatively small lesions called lacunes. In the present study, a rat model of lacunar infarction was induced by photothrombotic occlusion of the small vessels within the caudate-putamen and subsequently characterized. METHODS: Male Sprague-Dawley rats (n=143) were anesthetized, and Rose Bengal dye (20 mg/kg) was intravenously injected. The left caudoputamen was exposed to cold white light for 5 to 10 minutes via a stereotaxically implanted polymethylmethacrylate optic fiber (0.5-0.75 mm diameter). Neurological and morphological changes were assessed at various times during the following 6 weeks. Local cerebral blood flow was measured 90 minutes after photothrombosis by [(14)C]-N-isopropyl-p-iodoamphetamine quantitative autoradiography. The time course of blood-brain barrier opening and ischemic brain edema as well as the effects of aspirin and tissue plasminogen activator treatment were also determined. RESULTS: A virtually round infarct with thrombosed parenchymal vessels surrounded by a layer of selective neuronal death was formed within the caudoputamen; it turned into a cystic cavity (lacune) over 6 weeks. A central zone of markedly reduced blood flow and surrounding oligemic zone were observed 90 minutes after light exposure. Lesion size was proportional to light exposure, and the severity and duration of neurological deficits paralleled infarct size. Early blood-brain barrier opening with edema peaked at day 1. After tissue plasminogen activator treatment, infarction volume and neurological deficits were reduced. CONCLUSIONS: This study describes a new rat model of lacunar infarction by photothrombotic occlusion of the microvessels within the caudoputamen. With this model, infarct size correlates with the severity and duration of the neuropathology and can be varied by altering light exposure.

Development of chronic encapsulated intracerebral hematoma after radiosurgery for a cerebral arteriovenous malformation.

BACKGROUND: We report a rare case of chronic encapsulated intracerebral hematoma (CEIH) after radiosurgery for a cerebral arteriovenous malformation (AVM). METHODS: Seven years after radiosurgery, magnetic resonance imaging revealed a high-intensity mass in the right basal ganglia with a peripheral low signal ring and fluid level on both T1- and T2-weighted images, which was compatible with CEIH. RESULTS: Stereotactic evacuation and placement of an Ommaya reservoir were performed. CONCLUSION: The concentration of vascular endothelial growth factor was high in the hematoma, suggesting that CEIH may be similar to chronic subdural hematoma.

Radiation-induced vascular changes in the intracranial irradiation field in medulloblastoma survivors: An MRI study.

BACKGROUND AND PURPOSE: While survival times after treatment of medulloblastoma are increasing, little is known about radiochemotherapy (RCT)-induced cerebrovascular changes. High resolution vessel wall imaging (VWI) sequences are an emerging tool for the evaluation of cerebrovascular diseases. We performed VWI in medulloblastoma long-term survivors to screen for late sequelae of RCT. MATERIAL AND METHODS: Twenty-two pediatric medulloblastoma survivors (mean age 25.8 years (10-53 years); 16.3 years (mean) post primary RCT (range 1-45 years)) underwent 2D VWI-MRI. Vessel wall thickening, contrast enhancement and luminal narrowing were analyzed. The findings were correlated with the patients' radiation protocols. RESULTS: Vessel wall changes were observed the intracranial internal carotid artery (ICA) and the vertebrobasilar circulation (VBC) in 14 of 22 patients (63.6%). In multivariate analysis, time after RCT (OR = 1.38, p < 0.05) was strongest independent predictor for development of vessel wall alterations. The dose of radiation was not a relevant predictor. CONCLUSIONS: With longer follow-up time intracranial vessel wall changes are observed more frequently in medulloblastoma survivors. Thus VWI is a useful tool to monitor vessel wall alterations of cranially irradiated patients, creating the prerequisite for further treatment of late sequelae.

Albumin therapy augments the effect of thrombolysis on local vascular dynamics in a rat model of arteriolar thrombosis: a two-photon laser-scanning microscopy study.

BACKGROUND AND PURPOSE: Results of our recent pilot clinical trial suggest that the efficacy of thrombolytic therapy in acute ischemic stroke may be enhanced by the coadministration of high-dose albumin. Here, we explored the microvascular hemodynamic effects of this combined therapy in a laboratory model of cortical arteriolar thrombosis. METHODS: We studied the cortical microcirculation of physiologically monitored rats in vivo by two-photon laser-scanning microscopy after plasma-labeling with fluorescein-dextran. We induced focal thrombosis in 30- to 50-microm cortical arterioles by laser irradiation and measured arteriolar flow velocity by repeated line-scanning. At 30 minutes post-thrombosis, we treated animals with the thrombolytic agent, reteplase, which was coadministered with either human albumin, 2 g/kg, or with saline control. RESULTS: Baseline arteriolar flow velocity averaged 3.8+/-0.7 mm/s, was immediately reduced by thrombosis to 22% to 25% of control values, and remained unchanged before treatment. Subthrombolytic doses of reteplase combined with saline led to a median increase in flow velocity to 37% of control distal to the thrombus (P=nonsignificant versus pretreatment). By contrast, reteplase combined with albumin therapy resulted in a prompt, highly significant increase of median flow velocity to 58% of control levels (P=0.013 versus reteplase+saline), which remained significantly higher than the reteplase+saline group at multiple time-points over the subsequent hour. CONCLUSIONS: The beneficial effect of subthrombolytic doses of reteplase on microvascular hemodynamics distal to a cortical arteriolar thrombosis is markedly enhanced by the coadministration of high-dose albumin therapy; these results have important clinical implications for the management of patients with acute ischemic stroke.

Radiosurgery of brain arteriovenous malformations in children.

OBJECTIVE: The authors describe their experience in treating 22 children with a single brain arteriovenous malformation (bAVM) using a dedicated LINAC stereotactic radiosurgery unit. METHODS: The findings of 22 consecutive patients < or = 18 years of age who underwent radiosurgery for a single bAVM and with at least 24 months of follow-up, or earlier proven obliteration,were reviewed. The median age at radiosurgery was 13.8 years,with a hemorrhagic presentation in 86%. Median bAVM-volume was 1.8 ml, with a median prescribed marginal dose of 19.0 Gy. RESULTS: The crude complete obliteration-rate was 68% (n = 15) after a median follow-up of 24 months. The actuarial obliteration- rate was 45 % after two years and 64 % after three years. Patients with a radiosurgery-based AVM score < or = 1 more frequently had an excellent outcome than patients with a bAVM score > 1 (71% vs. 20%, P = 0.12), as well as an increased obliteration rate (P = 0.03) One patient died from a bAVM-related hemorrhage 27 months after radiosurgery, representing a postradiosurgery hemorrhage rate of 1.3%/year for the complete followup interval. Overall outcome was good to excellent in 68% (n = 15). Radiation-induced changes on MR imaging were seen in 36% (n = 8) after a median interval of 12.5 months, resulting in deterioration of pre-existing neurological symptoms in one patient. CONCLUSIONS: Radiosurgery is a relatively effective, minimally invasive treatment for small bAVMs in children. The rebleeding rate is low, provided that known predilection places for bleeding had been endovascularly eliminated.Our overall results compare unfavourably to recent pediatric microsurgical series, although comparison between series remains imprecise. Nevertheless, when treatment is indicated in a child with a bAVM that is amenable to both microsurgery or radiosurgery, microsurgery should carefully be advocated over radiosurgery, because of its immediate risk reduction.

Capillary loss precedes the cognitive impairment induced by fractionated whole-brain irradiation: a potential rat model of vascular dementia.

Brain tumor patients who are long-term survivors after whole-brain irradiation (WBI) often suffer cognitive impairment, including dementia. Although the pathogenic mechanisms remain poorly understood, our studies suggest that radiation-induced cognitive impairment may be a form of vascular dementia. We used a fractionated dose of gamma-rays that is biologically similar to that given to brain tumor patients. The brains of adult rats were irradiated with 40 Gy, in eight 5 Gy fractions over 4 weeks. Cognitive function was assessed prior to WBI and up to 9 months post-irradiation using a partially-baited radial arm maze. A significant increase in working memory errors was found in the irradiated rats by two-way ANOVA (p=0.0042). The increased errors occurred primarily at 6 and 9 months (p < 0.05, student's t-test). Vessel density was quantified using a stereology method with computerized image processing and analysis. Vessel density was unchanged 24 h after the last dose, but significantly decreased (p=0.002), by approximately 30%, from 10 weeks to 52 weeks. Thus, cognitive impairment arose after brain capillary loss in irradiated rats that show no other gross brain pathology. Capillary loss may play an important role in radiation-induced dementia and this may be a model of vascular dementia.

Vascular complications after radiosurgery for meningiomas.

During the past 25 years, radiosurgery has evolved as a primary treatment modality for certain meningiomas when resection would be associated with high patient morbidity. In addition, radiosurgery is now routinely used as an adjunctive therapy for residual or recurrent meningiomas after surgical removal. In this review the authors summarize the vascular complications that occur after radiosurgery for meningiomas as well as experimental study data that give insight into the pathogenesis of this complication. These data may be useful when discussing with patients the risk/benefit ratio of choosing among conservative management, radiosurgery, and surgery.

Thrombotic molecule expression in cerebral vascular malformations.

Thrombosis is an important end-point in the obliteration of vascular malformations after radiosurgery. The aim of this study was to investigate the expression of thrombotic molecules in arteriovenous malformations (AVMs) and cavernous malformations (CMs), and in AVMs after radiosurgery. Fresh-frozen surgical specimens from 18 AVMs (including three that had previously been treated with radiosurgery), seven CMs, and three control specimens were studied. The expression of tissue factor, thrombomodulin and von Willebrand factor (vWF) were examined using immunofluorescence. Thrombomodulin and vWF were expressed in the endothelium of all specimens, while tissue factor was predominately found in the perivascular region and vascular adventitia. Previous treatment of AVMs with either radiation or embolisation did not significantly alter the intensity of expression. In some irradiated lesions, vessels were found with absent endothelial vWF staining and exposed tissue factor. This study has demonstrated that loss of the endothelium and exposure of underlying tissue factor occurs in irradiated AVMs. There were no significant differences in the expression of these thrombotic molecules in vascular malformations when compared to control vessels. While no long-term alterations in antigen expression were observed after radiosurgery, further work may elucidate the nature of the immediate response to irradiation.

[Cerebral infarction related to intracranial radiation arteritis twenty-four years after encephalic radiation therapy]. / Infarctus cérébral secondaire à une artériopathie radique intracrânienne, vingt-quatre ans après une irradiation encéphalique.

We report a case of a resolutive late cerebral ischemic event, related to radiation induced vasculopathy of the left posterior cerebral artery, documented by MRI, situated in the irradiated volume 24 years before, for an astrocytome with malignant potential.

Radiation-Induced Large Vessel Cerebral Vasculopathy in Pediatric Patients With Brain Tumors Treated With Proton Radiation Therapy.

PURPOSE: The purpose of this research was to evaluate the incidence, time to development, imaging patterns, risk factors, and clinical significance of large vessel cerebral vasculopathy in pediatric patients with brain tumors treated with proton radiation therapy. METHODS AND MATERIALS: A retrospective study was performed on 75 consecutive pediatric patients with primary brain tumors treated with proton radiation therapy. Radiation-induced large vessel cerebral vasculopathy (RLVCV) was defined as intracranial large vessel arterial stenosis or occlusion confirmed on magnetic resonance angiography, computed tomographic angiography, catheter angiography, or a combination of these within an anatomic region with previous exposure to proton beam therapy and not present before radiation therapy. Clinical records were used to determine the incidence, timing, radiation dose to the large vessels, and clinical significance associated with the development of large vessel vasculopathy in these patients. RESULTS: RLVCV was present in 5 of 75 (6.7%) patients and included tumor pathologic features of craniopharyngioma (n=2), ATRT (n=1), medulloblastoma (n=1), and anaplastic astrocytoma (n=1). The median time from completion of radiation therapy to development was 1.5 years (mean, 3.0 years; range, 1.0-7.5 years). Neither mean age at the time of radiation therapy (5.1 years) nor mean radiation therapy dose to the large vessels (54.5 Gy) was a statistically significant risk factor. Four of the 5 patients with RLVCV presented with acute stroke and demonstrated magnetic resonance imaging evidence of acute infarcts in the expected vascular distributions. Angiography studies demonstrated collateral vessel formation in only 2 of the patients with RLVCV. No patients demonstrated acute hemorrhage or aneurysm. Two patients were treated with pial synangiomatosis surgery. CONCLUSIONS: RLVCV can occur in pediatric patients with brain tumors treated with proton radiation therapy. Further studies are necessary to determine potential risk factors for large vessel vasculopathy with proton radiation therapy in comparison with conventional photon radiation therapy.

Dose to the intracranial arteries in stereotactic and intensity-modulated radiotherapy for skull base tumors.

PURPOSE: To examine retrospectively the maximum dose to the large skull base/intracranial arteries in fractionated stereotactic radiotherapy (FSRT) and intensity-modulated radiotherapy (IMRT), because of the potential risk of perfusion disturbances. METHODS AND MATERIALS: Overall, 56 patients with tumors adjacent to at least one major artery were analyzed. Our strategy was to perform FSRT with these criteria: 1.8 Gy per fraction, planning target volume (PTV) enclosed by the 95% isodose, maximum dose 107%. Dose limits were applied to established organs at risk, but not the vessels. If FSRT planning failed to meet any of these criteria, IMRT was planned with the same objectives. RESULTS: In 31 patients (median PTV, 23 cm3), the FSRT plan fulfilled all criteria. No artery received a dose > or =105%. Twenty-five patients (median PTV, 39 cm3) needed IMRT planning. In 11 of 25 patients (median PTV, 85 cm3), no plan satisfying all our criteria could be calculated. Only in this group, moderately increased maximum vessel doses were observed (106-110%, n = 7, median PTV, 121 cm3). The median PTV dose gradient was 29% (significantly different from the 14 patients with satisfactory IMRT plans). Three of the four patients in this group had paranasal sinus tumors. CONCLUSION: The doses to the major arteries should be calculated in IMRT planning for critical tumor locations if a dose gradient >13% within the PTV can not be avoided because the PTV is large or includes air cavities.

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.

Intracranial atherosclerosis following radiotherapy.

We describe a case of severe intracranial atherosclerosis in a young man who had received therapeutic radiation for a presumed brain neoplasm. Since there was no evidence of vascular disease outside the radiation ports, we speculate that accelerated atherosclerosis was induced by radiation and that hyperlipidemia may have predisposed him to this effect.

Large intracranial vessel occlusive vasculopathy after radiation therapy in children: clinical features and usefulness of magnetic resonance imaging.

PURPOSE: To assess the relationship between large intracranial vessel occlusive vasculopathy (vasculopathy) and radiation therapy, and to clarify the clinical efficacy of magnetic resonance (MR) imaging in the diagnosis and screening of the vasculopathy. METHODS AND MATERIALS: We retrospectively evaluated the medical records and serial MR images for 32 pediatric patients, in whom radiation therapy had been given to fields including the circle of Willis and major cerebral arteries. All children had periodically undergone follow-up neurologic assessment and MR imaging examinations at Kanagawa Children's Medical Center for more than one year after radiation therapy (range 1.3-14 years). Patients who had not remained free of tumor progression up to the time of final evaluation were excluded. RESULTS: Vasculopathy developed in 6 of 32 patients 2-13 years after radiation therapy. Three of them presented with transient ischemic attacks (TIA) and the other three showed infarctions without preceding TIA. Steno-occlusive changes of major cerebral arteries were identified by MR imaging in all six patients, but not obtained in the remaining 26 patients. In the patients with TIA, MR imaging demonstrated steno-occlusive changes at the time of TIA, before irreversible infarction. They have been doing well subsequent to encephaloduroarteriosynangiosis. In the three patients who presented infarction without preceding TIA, MR imaging did not demonstrate the vascular change before the onset of infarction, and two of them developed neurologic deficits. The mean exposure dose for the circle of Willis and major cerebral arteries in these six patients was significantly higher than that in the remaining 26 patients without this sequela (61 Gy vs. 50 Gy, p < 0.05). The mean age at radiation therapy of the six patients was lower, but the difference was not significant. CONCLUSION: The incidence of vasculopathy after radiation therapy has a considerable correlation with radiation dose and age at radiation therapy. MR examination is useful for the diagnostic evaluation of vasculopathy, and it is also effective in screening for vasculopathy in patients with TIA, and may be helpful in the prevention of neurologic sequela.

Non-invasive induction of focal cerebral ischemia in mice by photothrombosis of cortical microvessels: characterization of inflammatory responses.

In this study, we adapted the original rat photothrombosis model of Watson et al. (Ann Neurol 17 (1985) 497) for use in mice by refining the application route of the dye, illumination and stereotactic parameters. After intraperitoneal injection of the photosensitive dye Rose bengal, subsequent focal illumination of the brain with a cold light source through the intact skull led to focal cortical infarcts of reproducible size, location and geometry. Cresyl violet histology displayed well-demarcated infarcts that matured with time in a predictable manner. Microglial responses, as assessed by immunocytochemistry, against F4/80 and CD11b antigens were rapid and complete at the infarct site, but delayed and incomplete in degenerating fiber tracts and ipsilateral thalamic nuclei. In contrast to the rat, where the expression of CD4 and CD8 antigens discriminate distinct subpopulations of lesion-associated phagocytes, the expression of both markers was low to absent in the mouse model. In both rats and mice, cerebral photothrombosis shares essential inflammatory responses with focal ischemia induced by middle cerebral artery occlusion. It may provide a useful model to study functional aspects of lesion-associated and remote molecular responses in transgenic mice.

Effects of radiation on cerebral vasculature: a review.

Radiation therapy plays a critical role in the treatment of central nervous system neoplasms and cerebral arteriovenous malformations. The deleterious effects of radiation on cerebral arteries may be the primary limitation to these treatment methods, as radiation may cause a variety of cerebrovascular injuries and hemodynamic changes. Radiation-induced changes in the cerebral arterial wall are determined by a number of cellular processes in endothelium and smooth muscle cells that modulate differences in radiosensitivity and phenotypic expression. The histopathological findings in arterial radiation injury include vessel wall thickening, thrombosis, luminal occlusion, and occasional telangiectases. Mechanisms for radiation injury to blood vessels include phenotypic changes in normal vessel wall cells (especially endothelium) manifested by the expression or suppression of specific gene and protein products that affect cell cycle progression or cellular proliferation or demise via cytotoxic injury or apoptosis. This review describes the molecular and cellular events involved in the systemic and cerebral vascular response to radiation and the potential means by which these responses may be influenced to augment the therapeutic effects of radiation while minimizing the untoward consequences.

The effect of ozagrel sodium on photochemical thrombosis in rat: therapeutic window and combined therapy with heparin sodium.

The therapeutic efficacy of ozagrel sodium (ozagrel), alone and in combination with heparin, and its therapeutic time window were studied in a photochemically induced thrombotic cerebral infarction rat model. Cerebral artery thrombosis was induced by irradiating the brain with green light through intact skull using rose bengal as the photosensitizing dye. One set of animals was treated immediately after thrombosis with (1) vehicle, (2) 10 mg/kg ozagrel in saline, intravenously (i.v.), (3) 150 U/kg unfractioned heparin, subcutaneously (s.c.), or (4) ozagrel, i.v. plus heparin, s.c. Infarct volume was significantly smaller and edema was reduced in the ozagrel-treated groups compared to the vehicle-treated group; heparin did not convey additional benefit. In another set of animals, rats were given either vehicle or 10 mg/kg ozagrel in saline, i.v., 60 min or 120 min after induction of thrombosis. Ozagrel reduced infarct volume, but its effect diminished with delayed administration. The therapeutic window was determined to be less than 60 minutes after induction of thrombosis.

Objectivation of cerebral effects with a new continuous electrical auricular stimulation technique for pain management.

AIMS: The electrical point stimulation system (P-STIM) reflects a new, miniaturized system for pain therapy through ear acupuncture. For this reason, ultrathin needles were applied at the ear. The needles stimulate the acupuncture areas at the ear using electrical impulses, which come from a little generator applied behind the acupunctured ear. METHODS: This study describes continuous, non-invasive measurements of near infrared spectroscopy (NIRS) and multidirectional transcranial Doppler sonography in two healthy females (aged 23 and 27 years) during stimulation with P-STIM, for the first time. RESULTS: The results of the pilot measurements have shown that electrical point stimulation using the new electrical stimulation system on eye acupuncture points is able to modulate the mean blood flow velocity (vm) of the supratrochlear artery. These effects were present using a stimulation frequency of 100 Hz. A lower increase in vm was found in the middle cerebral artery. In addition, stimulus induced, quantifiable and reproducible alterations of the regional cerebral NIRS parameters were be detected. CONCLUSION: For the first time, P-Stim allows intermittent ear acupuncture stimulation for up to several days in combination with complete mobility for the patient.

Pathways of cerebral calcium accumulation in a model of focal ischemia in rats.

Focal cerebral ischemia was produced in anesthetized rats by a minimally invasive photothrombic procedure. Rose bengal was injected into a tail vein and the right middle cerebral artery region irradiated for 5 min through the skull with the right common carotid artery temporarily occluded. This resulted in focal cerebral infarction which was restricted to the cortex as shown by autoradiography and histopathology. Edema and the uptake of 45Ca were determined 1, 3 or 24 hours after ischemia in different regions of the brain, ipsilateral and contralateral to the ischemic injury, the tracer uptake at three time points after administration. The values of 45Ca uptake and edema were the highest at the center of the infarction. Simulation of the 45Ca uptake kinetics in the 24 h post-ischemic group, enabled the determination of the contributions of different physiological pathways to cerebral calcium flux. The results indicated the breakdown of the blood-brain barrier to be primarily responsible for the increased uptake of the tracer by the ischemic cortex. A concomitant, presumably intracellular, sequestration resulted in a ca. 16-fold increase in the tissue pool of exchangeable calcium. Simulation such as proposed here would be of value in predicting the outcome of tracer accumulation in pathological situations.