Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment.

BACKGROUND: The management of unruptured intracranial aneurysms is controversial. Investigators from the International Study of Unruptured Intracranial Aneurysms aimed to assess the natural history of unruptured intracranial aneurysms and to measure the risk associated with their repair. METHODS: Centres in the USA, Canada, and Europe enrolled patients for prospective assessment of unruptured aneurysms. Investigators recorded the natural history in patients who did not have surgery, and assessed morbidity and mortality associated with repair of unruptured aneurysms by either open surgery or endovascular procedures. FINDINGS: 4060 patients were assessed-1692 did not have aneurysmal repair, 1917 had open surgery, and 451 had endovascular procedures. 5-year cumulative rupture rates for patients who did not have a history of subarachnoid haemorrhage with aneurysms located in internal carotid artery, anterior communicating or anterior cerebral artery, or middle cerebral artery were 0%, 2. 6%, 14 5%, and 40% for aneurysms less than 7 mm, 7-12 mm, 13-24 mm, and 25 mm or greater, respectively, compared with rates of 2 5%, 14 5%, 18 4%, and 50%, respectively, for the same size categories involving posterior circulation and posterior communicating artery aneurysms. These rates were often equalled or exceeded by the risks associated with surgical or endovascular repair of comparable lesions. Patients' age was a strong predictor of surgical outcome, and the size and location of an aneurysm predict both surgical and endovascular outcomes. INTERPRETATION: Many factors are involved in management of patients with unruptured intracranial aneurysms. Site, size, and group specific risks of the natural history should be compared with site, size, and age-specific risks of repair for each patient.

Thermal sensitivity of hypoxic responses in neocortical brain slices.

Electrophysiological responses to transient hypoxia were studied in neocortical brain slices from adult gerbils. Evoked responses and direct current (DC) potentials were recorded in layer III of the parietal cortex under normoxic and hypoxic conditions. The excitatory synaptic component of the evoked waveform was identified by its sensitivity to calcium and 6,7-dinitroquinoxaline-2,3-dione (DNQX). Under normoxic conditions, hypothermia reduced excitatory synaptic responses in a temperature-dependent manner. Under hypoxic conditions, hypothermia prolonged the delays to synaptic loss and hypoxic depolarization in a temperature-dependent manner. Synaptic recovery following a fixed period under hypoxic depolarization was greatly enhanced when hypoxia was administered at reduced temperature. The findings demonstrate that evoked responses are reduced under hypothermic conditions, but that these responses are sustained for a longer period of time during hypoxia. The data suggest that hypothermia protects against hypoxic damage to excitatory synaptic mechanisms in the neocortex both by prolonging the delay to hypoxic depolarization, and by extending the period of hypoxic depolarization that can be tolerated.

Effect of subarachnoid hemorrhage on serotonin uptake and metabolism in rabbit basilar artery.

The effects of subarachnoid hemorrhage (SAH) on neuronal uptake and metabolism of serotonin (5-HT) in the rabbit basilar artery were examined. Extracted 3H-amines from the isolated arteries after incubation with [3H]5-HT were separated by column chromatography. Radioactivity of 5-HT and 5-hydroxyindoleacetic acid was, respectively, 52.7 +/- 13.9 and 22.9 +/- 5.4 x 10(2) dpm/mg tissue in the control group (n = 8); 32 and 18% of control after denervation (n = 6); 99 and 12% of control after treatment with pargyline (n = 7); and 65 and 76% of control after SAH (n = 7). These results suggest that the neuronal uptake of 5-HT is impaired by SAH, although monoamine oxidase activity is relatively preserved.

Muscarinic cholinergic receptors on the endothelium of human cerebral arteries.

To characterize the muscarinic cholinergic receptors on the endothelium of human cerebral arteries, isometric tension measurement and receptor autoradiographic studies were performed. Acetylcholine (ACh) induced dose-dependent relaxation of human cerebral arteries precontracted by 10(-5) M serotonin, with an EC50 of 1.9 +/- 0.6 X 10(-6) M (n = 7). The relaxation was abolished by 10(-5) M hemoglobin. Autoradiography, using the muscarinic antagonist [3H]propylbenzilycholine mustard, demonstrated the high density of muscarinic cholinergic receptors on the endothelial cells of human cerebral arteries, especially on the luminal surface of the endothelium. These findings suggest that ACh-induced relaxation mediated by muscarinic cholinergic receptors on the endothelium has a physiological function in human cerebral arteries.

Effects of naloxone on canine cerebral vascular smooth muscle.

The pharmacological effects of naloxone on cerebral arterial smooth muscle in vitro were examined using canine basilar arterial strips. Naloxone exerted two different effects on canine basilar artery: (1) at a high concentration (3 X 10(-4) M) it produced nonspecific vasodilation, and (2) at lower concentrations (3 X 10(-7), 3 X 10(-6), and 3 X 10(-5) M) it inhibited the vasoconstrictor effects of norepinephrine without altering KCl-, serotonin-, or hemoglobin-induced constriction. Morphine (2 X 10(-5) or 2 X 10(-4) M) did not reverse the specific vasodilating effect of naloxone (3 X 10(-5) M) on norepinephrine-induced constriction. Rather, morphine and naloxone together produced a greater vasodilating effect on norepinephrine-induced constriction than either agent alone. Naloxone (3 X 10(-5) M) failed to alter either phenylephrine-induced constriction or clonidine-induced constriction. The vasodilating effect of naloxone (3 X 10(-5) M) on 10(-3) M norepinephrine-induced constriction was not reduced with 10(-6) M propranolol. These results suggest that the vasodilating effect of naloxone on norepinephrine-induced constriction does not result from an antagonistic action on opiate receptors, direct inhibition of alpha-adrenoreceptors, or direct stimulation of beta-adrenoreceptors in canine cerebral arterial smooth muscle. The vasodilating effect of naloxone on norepinephrine-induced constriction may influence the CBF changes following naloxone administration.

Live computerized videomicroscopy of cerebral microvessels in brain slices.

A model system for studying cerebral microvasculature is presented in which submerged in vitro brain slices are examined by computerized videomicroscopy. Brain slices are superfused continuously with artificial cerebrospinal fluid, while blood vessels are monitored using a transmission light microscope with water immersion objectives. The responses to well-characterized vasoactive compounds indicate that basic physiological characteristics are maintained in this preparation. This model system represents a simple and rapid technique for studying cerebrovascular responses under conditions in which vessels are surrounded by their normal cellular microenvironment. An additional advantage of this technique is the ability to perform simultaneous electrophysiological recordings in identified neurons. This will facilitate the study of interactions between neuronal and vascular elements and may help elucidate mechanisms underlying the local regulation of cerebral microvasculature.

Intracranial operation within seven days of aneurysmal subarachnoid hemorrhage. Results in 150 patients.

We evaluated the results of intracranial operation in 150 consecutive patients surgically treated within seven calendar days of aneurysmal subarachnoid hemorrhage (SAH). Patients in all clinical grades, except those who were moribund, were treated. Those with either anterior or posterior circulation aneurysms were included. On follow-up assessment, favorable outcomes were noted in 107 patients (71%), 17 had major disabilities (11%), and 26 had died (17%). During hospitalization, vasospasm was diagnosed in 63 patients (42%) and rebleeding occurred in 39 (25%). Operations were performed throughout the first week after SAH; results of operation were similar on each day. A lower rate of good recovery was observed among patients operatively treated four to seven days after SAH than among those operated on earlier. The admitting neurologic condition influenced outcome after early operation, but age did not have a major impact. We find that aneurysm surgery can be performed within one week of SAH with acceptable results, although there is room for improvement.

Factors associated with hydrocephalus after subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study.

Hydrocephalus is an important complication of subarachnoid hemorrhage (SAH). We analyzed several factors possibly related to hydrocephalus following SAH in 3521 patients from the International Study on the Timing of Aneurysm Surgery. Hydrocephalus was diagnosed on admission computed tomographic (CT) scans in 15% of patients and was thought to be clinically symptomatic in 13.2% of patients. There was a 5.9% overlap between these groups. Using contingency table analysis, we found the following were significantly related to clinical hydrocephalus: increasing age; preexisting hypertension; admission blood pressure measurements; postoperative hypertension; admission CT findings of intraventricular hemorrhage, a diffuse collection of subarachnoid blood, and a thick focal collection of subarachnoid blood; posterior circulation site of aneurysm; focal ischemic deficits; use of antifibrinolytic drugs preoperatively; hyponatremia; admission level of consciousness; and a low score on the Glasgow outcome scale. Using discriminate factor analysis to predict clinical hydrocephalus, the most important variables in order were the following: CT hydrocephalus, intraventricular hemorrhage, admission level of consciousness, presubarachnoid hypertension, increasing age, subarachnoid blood noted on CT scan, posterior circulation aneurysm site, and hypertension postoperatively (canonical correlation = .399). We conclude that the development of hydrocephalus after SAH is multifactorial. Factors that compromise cerebrospinal fluid circulation acutely (eg, intraventricular hemorrhage, hemorrhage from a posterior circulation site of aneurysm, and diffuse spread of subarachnoid blood) contribute to the development of acute hydrocephalus. These same factors, plus the use of antifibrinolytic drugs preoperatively, are also important in the pathogenesis of clinical hydrocephalus, perhaps by promoting subarachnoid fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevalence of diabetes mellitus among patients with subarachnoid hemorrhage.

Diabetes mellitus is generally accepted as an important risk factor in cerebrovascular disease. The importance of this condition varies with the type of stroke. Patients with aneurysmal subarachnoid hemorrhages (SAHs) have a lower or equivalent prevalence of diabetes mellitus than the general population. In particular, insulin-dependent diabetes is rarely present prior to aneurysmal rupture. These observations suggest that diabetic patients are not at increased risk for aneurysmal SAH.

Intracranial hemorrhage produced by spontaneous dissecting intracranial aneurysm.

Two patients with intracranial dissecting aneurysms were seen initially because of acute hemorrhage. One patient died, and a false dissecting aneurysm secondary to atherosclerosis was found at autopsy. In the other patient, the appearance of the carotid arteriogram was typical of a dissection. Because of the propensity of these aneurysms to rupture, caution is indicated in the use of anticoagulants or vasopressors in patients with evolving cerebral infarction secondary to intracranial arterial dissection.

Deep cerebral venous thrombosis. Clinical, neuroradiological, and neuropsychological correlates.

Thrombosis of the deep cerebral venous system is usually fatal, and patients are frequently stuporous or comatose at presentation. This report describes serial radiological and neuropsychological observations in an 18-year-old woman who remained alert and survived this disorder. In association with diencephalic edema seen on computed tomographic scan, she demonstrated disorientation, abulia, attentional deficits, memory loss, and dyscalculia and had impaired IQ scores: the performance scores were worse than the verbal scores. Significant aphasia or sensory loss was absent. She recovered full intellectual capacity in the course of follow-up examinations, and the diencephalic edema seen on the computed tomographic scan resolved despite persistent thrombosis of the straight sinus demonstrable on follow-up digital angiography.

Cooperative study of intracranial aneurysms and subarachnoid hemorrhage: a long-term prognostic study. II. Ruptured intracranial aneurysms managed conservatively.

The late natural history of ruptured intracranial aneurysms was studied in 568 cases reported to the Cooperative Study of Intracranial Aneurysms and Subarachnoid Hemorrhage from 1958 to 1965. The patients had been selected for conservative management of their aneurysms at the time of diagnosis. A follow-up search in 1981 and 1982 revealed 378 known deaths; 40% had occurred within six months of hemorrhage. During the next two decades, the patients' survival probabilities were significantly worse than those of a matched US population. Multiple aneurysms did not differ prognostically from single aneurysms, but posterior circle aneurysms carried a better prognosis after ten-year survival. The rate of probable recurrent bleeding after six months was 2.2% per year for the first 9 1/2 years and 0.86% per year for the second decade. Reported rebleeding episodes were fatal in 78%.

Cooperative study of intracranial aneurysms and subarachnoid hemorrhage: a long-term prognostic study. III. Subarachnoid hemorrhage of undetermined etiology.

Among 6,638 cases reported to the Cooperative Study of Intracranial Aneurysms and Subarachnoid Hemorrhage were 477 cases in which the cause of hemorrhage could not be determined after carotid and vertebral angiography. These patients were followed up for up to 24 years after hemorrhage. Twenty patients were subsequently found to have an aneurysm or arteriovenous malformation missed by the first angiographic survey. After six-month survival, the rate of recurrent hemorrhage was a maximum 0.86% per year. Survival was significantly better than that of patients with verified ruptured aneurysms managed conservatively in this cooperative study. For normotensive patients who survived the first six months, the life expectancy for the next 20 years equaled that of an age- and sex-matched US population. Hypertensive patients had a higher mortality than normotensive patients.

Usefulness of computed tomography in predicting outcome after aneurysmal subarachnoid hemorrhage: a preliminary report of the Cooperative Aneurysm Study.

We evaluated the ability of CT performed soon after subarachnoid hemorrhage (SAH) to predict outcome. Generally, the results of CT paralleled level of consciousness in predicting mortality or good recovery. However, CT did detect some groups of patients who were at greater or lesser risk of mortality. If an alert patient had normal CT, 6-month mortality was 2.8%; if blood was detected, mortality rose to 12.3%. Intracerebral hemorrhage or local, thick, or diffuse subarachnoid deposits of blood seen on CT among alert patients were particularly related to increased mortality. CT abnormalities could be used to detect higher mortality rates among drowsy or comatose patients. CT is useful as an adjunct to the clinical examination in predicting outcome after SAH.

Predicting cerebral ischemia after aneurysmal subarachnoid hemorrhage: influences of clinical condition, CT results, and antifibrinolytic therapy. A report of the Cooperative Aneurysm Study.

Cerebral ischemia from vasospasm is a major cause of death and disability following aneurysmal subarachnoid hemorrhage (SAH). This study examines and compares the relative utility of the initial neurologic examination and early CT in predicting cerebral ischemia after SAH. The influence of antifibrinolytic drugs (AFD) in the development of cerebral ischemia was also studied. AFD increased the risk of cerebral ischemia regardless of the admitting neurologic condition or the findings of CT. Among patients given AFD, impaired orientation or alertness was associated with a higher risk of ischemia. Other neurologic signs were not predictive of ischemia. Clinical features were not predictive of ischemia among patients not given AFD. Focal, thick collections of blood on CT were highly predictive of ischemia, whether or not patients received AFD. Admitting CT is the best prognostic indicator for the development of cerebral ischemia after SAH. It should be used to supplement the clinical examination in selecting patients best suited for therapy to prevent vasospasm.

CT and clinical correlations in recent aneurysmal subarachnoid hemorrhage: a preliminary report of the Cooperative Aneurysm Study.

Computed tomography was performed on 1,378 patients admitted within 3 days of subarachnoid hemorrhage (SAH) at 71 centers in a cooperative study. CT on the day of SAH (day 0) was abnormal in 95.8%. Intracranial blood was detected in 95.3% of patients on day 0, 90.5% on the first day after SAH (day 1), and 73.8% on day 3. CT was normal in only 1 of 284 patients in stupor or coma but was normal in 14.6% of 638 alert patients. In the first few days after SAH, CT is highly accurate, often obviating the need of CSF examinations. The interval from SAH until CT and the seriousness of the patient's condition are two factors that influence the results of CT.

Sensitivity and specificity of transcranial Doppler ultrasonography in the diagnosis of vasospasm following subarachnoid hemorrhage.

Vasospasm is the leading cause of death and disability in patients with aneurysmal subarachnoid hemorrhage (SAH). Transcranial Doppler ultrasonography (TCD) can detect the arterial narrowing noninvasively, but the sensitivity and specificity of this technique have not been reported in a population of patients with a high frequency of angiographic vasospasm. In this study, 34 consecutive patients with SAH undergoing angiography during the period of risk for vasospasm had technically adequate TCD examinations within 24 hours of the angiogram. Using a mean flow velocity of 120 cm/sec and above as indicative of vasospasm, TCD correctly detected angiographic vasospasm in 17 patients; there were no false positives. It correctly determined that 5 patients did not have vasospasm, whereas there were 12 false negatives. False negatives were frequently due to angiographic vasospasm involving vessels not assessable by TCD. The correlation between mean flow velocity and the angiographic residual lumen diameter of the middle cerebral artery was statistically significant. These data suggest that TCD is a highly specific (100%), but less sensitive (58.6%) test for the detection of angiographic vasospasm following SAH. Confirmatory angiography may be avoided if the TCD study is positive, but additional studies may be necessary if the clinical picture is suspicious and the TCD study is negative.

Synthesis and biological activity of N6-(p-sulfophenyl)alkyl and N6-sulfoalkyl derivatives of adenosine: water-soluble and peripherally selective adenosine agonists.

A series of N6-(p-sulfophenyl)alkyl and N6-sulfoalkyl derivatives of adenosine was synthesized, revealing that N6-(p-sulfophenyl)adenosine (10b) is a moderately potent (Ki vs [3H]PIA in rat cortical membranes was 74nM) and A1-selective (120-fold) adenosine agonist, of exceptional aqueous solubility of > 1.5 g/mL (approximately 3 M). Compound 10b was very potent in inhibiting synaptic potentials in gerbil hippocampal slices with an IC50 of 63 nM. At a dose of 0.1 mg/kg ip in rats, 10b inhibited lipolysis (a peripheral A1 effect) by 85% after 1 h. This in vivo effect was reversed using the peripherally selective A1-antagonist 1,3-dipropyl-8-[p-(carboxyethynyl)phenyl]xanthine (BW1433). The same dose of 10b in NIH Swiss mice (ip) was nearly inactive in locomotor depression, an effect that has been shown to be centrally mediated when elicited by lower doses of other potent adenosine agonists, such as N6-cyclohexyladenosine (CHA) (Nikodijevic et al. FEBS Lett. 1990, 261, 67). HPLC studies of biodistribution of a closely related and less potent homologue, N6-[4-(p-sulfophenyl)butyl]adenosine indicated that a 25 mg/kg ip dose in mice resulted in a plasma concentration after 30 min of 0.46 micrograms/mL and no detectable drug in the brain (detection limit < 0.1% of plasma level). Although 10b at doses > 0.1 mg/kg in mice depressed locomotor activity, this depression was unlike the effects of CHA and was reversible by BW1433. These data suggest that 10b is a potent adenosine agonist in vivo and shows poor CNS penetration.

Tonic protein kinase C-mediated vasoconstriction is unmasked when nitric oxide synthase is inhibited in cerebral microvessels.

Recent evidence indicates that nitric oxide participates in the modulation of vascular tone in a variety of vascular beds, including the parenchymal microvasculature of the brain. The present study examined the role of protein kinase activity in the induction and maintenance of the contractile response when endogenous nitric oxide production is inhibited in parenchymal microvessels of the rat hippocampus. Microvessels in in vitro slices of the hippocampus were monitored using computer-assisted video microscopy. The effects of inhibitors of two kinases, protein kinase C and calcium/calmodulin-dependent protein kinase, on the vasoconstrictor response to NG-nitro-L-arginine (L-NNA) were investigated. The resting luminal diameter of the microvessels examined in this study ranged from 9 to 29 microns. Addition of 100 microM L-NNA to the medium superfusing the slice constricted microvessels by 38.8 +/- 0.6%. The addition of protein kinase inhibitors reversed this constriction in a dose-dependent manner. H-7 (50 microM), a relatively non-selective protein kinase C inhibitor, elicited an 81.4 +/- 10.0% reversal of the L-NNA-induced constriction. Bisindolylmaleimide (5 microM), a selective protein kinase C inhibitor, reversed the constriction by 69.1 +/- 13.7%. KN-62, an inhibitor of calcium/calmodulin-dependent protein kinase II, elicited a smaller yet statistically significant reversal of 17.1 +/- 5.1%. Pretreatment with H-7 or bisindolyl-maleimide blocked the LNNA-induced constriction entirely, while KN-62 did not significantly inhibit the response. These findings indicate that the contractile response observed upon removal of endogenous nitric oxidergic vasodilation is mediated by protein kinase activity, and the contribution of protein kinase C to this effect is greater than that of calcium/calmodulin-dependent protein kinase II. The results suggest that a tonic nitric oxidergic influence serves to mask the potential for protein kinase C-mediated vasoconstriction in cerebral microvessels.

Induction of ischemic tolerance and antioxidant activity by brief focal ischemia.

Three forms of non-injurious ischemic preconditioning were tested for their effects on endogenous antioxidant activity and subsequent ischemic injury. Test ischemia alone, consisting of 1 h occlusion of both carotid arteries (BCAs) and one middle cerebral artery (MCA), elicited an average volume of cerebral infarction of 143.4 +/- 15.0 mm3 (mean +/- s.e.m.). Twenty minutes occlusion of the MCA only or MCA and BCAs (but not BCAs only) 24 h before test ischemia significantly increased the activity of the antioxidant enzyme superoxide dismutase and significantly reduced the cerebral infarction volume. These findings demonstrate that brief focal ischemia can attenuate the injurious impact of subsequent ischemia and that an upregulation of endogenous antioxidant activity may play a key role in this neuroprotective effect.