Douglas Chyatte

Recommendations for the management of patients with unruptured intracranial aneurysms: A statement for healthcare professionals from the Stroke Council of the American Heart Association.

Aneurysmal subarachnoid hemorrhage (SAH) has a 30-day mortality rate of 45%, with approximately half the survivors sustaining irreversible brain damage.1 On the basis of an annual incidence of 6 per 100 000, ≈15 000 Americans will have an aneurysmal SAH each year. Population-based incidence rates vary considerably from 6 to 16 per 100 000, with the highest rates reported from Japan and Finland.2 3 4 5 Approximately 5% to 15% of stroke cases are secondary to ruptured saccular aneurysms. Although the prevention of hemorrhage has been advocated as the most effective strategy aimed at lowering mortality rates,6 the optimal management of patients with unruptured intracranial aneurysms (UIAs) remains controversial. Management decisions require an accurate assessment of the risks of various treatment options compared with the natural history of the condition. The natural history of UIAs and treatment outcomes are influenced by (1) patient factors, such as previous aneurysmal SAH, age, and coexisting medical conditions; (2) aneurysm characteristics, such as size, location, and morphology; and (3) factors in management, such as the experience of the surgical team and the treating hospital. These many influences have contributed to considerable variability in the reported risks for aneurysmal SAH and the treatment of UIAs. There are no prospective randomized trials of treatment interventions versus conservative management to date, and it is possible that no such studies will be carried out in the future. According to a classification system suggested by Cook et al,7 randomized clinical trials with low likelihoods of false-positive and false-negative errors provide the highest level of evidence (level I) that can be applied to a clinical recommendation. Randomized trials with high likelihoods of false-negative and positive errors provide level II evidence. Level III evidence is generated with nonrandomized concurrent cohort comparisons between contemporaneous patients who did and …

Recommendations for the Management of Patients With Unruptured Intracranial Aneurysms A Statement for Healthcare Professionals From the Stroke Council of the American Heart Association

Aneurysmal subarachnoid hemorrhage (SAH) has a 30-day mortality rate of 45%, with approximately half the survivors sustaining irreversible brain damage.1 On the basis of an annual incidence of 6 per 100 000, ≈15 000 Americans will have an aneurysmal SAH each year. Population-based incidence rates vary considerably from 6 to 16 per 100 000, with the highest rates reported from Japan and Finland.2 3 4 5 Approximately 5% to 15% of stroke cases are secondary to ruptured saccular aneurysms. Although the prevention of hemorrhage has been advocated as the most effective strategy aimed at lowering mortality rates,6 the optimal management of patients with unruptured intracranial aneurysms (UIAs) remains controversial. Management decisions require an accurate assessment of the risks of various treatment options compared with the natural history of the condition. The natural history of UIAs and treatment outcomes are influenced by (1) patient factors, such as previous aneurysmal SAH, age, and coexisting medical conditions; (2) aneurysm characteristics, such as size, location, and morphology; and (3) factors in management, such as the experience of the surgical team and the treating hospital. These many influences have contributed to considerable variability in the reported risks for aneurysmal SAH and the treatment of UIAs. There are no prospective randomized trials of treatment interventions versus conservative management to date, and it is possible that no such studies will be carried out in the future. According to a classification system suggested by Cook et al,7 randomized clinical trials with low likelihoods of false-positive and false-negative errors provide the highest level of evidence (level I) that can be applied to a clinical recommendation. Randomized trials with high likelihoods of false-negative and positive errors provide level II evidence. Level III evidence is generated with nonrandomized concurrent cohort comparisons between contemporaneous patients who did and …

Preliminary report: effects of high dose methylprednisolone on delayed cerebral ischemia in patients at high risk for vasospasm after aneurysmal subarachnoid hemorrhage.

Mounting evidence suggests that chronic cerebral vasospasm may be linked to the inflammatory response that follows subarachnoid hemorrhage. Twenty-one patients judged to be at high risk for vasospasm because of either poor admitting grade or a large amount of subarachnoid blood shown by computed tomography were treated with a course of high dose methylprednisolone, and management results were compared to those of a cohort of contemporary control patients matched for grade, number of hemorrhages, time from hemorrhage to admission, time from hemorrhage to operation, aneurysm location, age, and sex. Patients treated with high dose methylprednisolone were twice as likely to have an excellent result and half as likely to die as those who were not treated. The incidence and severity of delayed cerebral ischemia were reduced in treated patients when compared to control patients. None of the treated patients developed a serious side effect that could be attributed to steroid treatment. These findings are consistent with the conclusion that chronic vasospasm is an inflammatory vasculopathy and suggest that early treatment with high dose methylprednisolone may benefit this high risk group of patients.

Cerebral Vasospasm After Subarachnoid Hemorrhage

Chronic cerebral vasospasm remains the most important cause of subsequent morbidity in patients who survive the first 48 to 72 hours after a subarachnoid hemorrhage. Prolonged arterial narrowing compromises cerebral hemodynamics and results in cerebral ischemia. Among patients in whom symptomatic chronic cerebral vasospasm develops, almost half die or have a serious residual neurologic deficit. Present evidence indicates that sustained vessel narrowing results from structural changes within the arterial wall rather than from active contraction of vascular smooth muscle. The mechanism (or mechanisms) responsible for these changes is unknown, but damage from prolonged active arterial contraction, depression of vessel wall respiration, and an inflammatory response have all been proposed as explanations. Despite more than 30 years of intensive study, an effective treatment program for chronic cerebral vasospasm remains elusive. Recent therapeutic trials, however, based on efforts to interrupt the mechanisms responsible for these structural changes hold some promise.

Prevention of chronic cerebral vasospasm in dogs with ibuprofen and high-dose methylprednisolone.

Severe chronic cerebral vasospasm was produced in dog basilar arteries by two injections, 2 days apart, of autologous blood into the cisterna magna of 25 dogs. Treatment with ibuprofen (n = 8) or high-dose methylprednisolone (n = 8) after the first injection of blood prevented or reduced angiographic vasospasm. Cerebrospinal fluid concentrations of prostaglandin E2, prostaglandin F2 alpha, 6-ketoprostaglandin F1 alpha (a metabolite of prostacyclin), and thromboxane B2 (a metabolite of thromboxane A2) were measured in both treated and untreated (n = 7) dogs. In untreated dogs, the level of prostaglandin E2 increased 94-fold by Day 8 after the first injection of blood and was strongly and positively correlated with the degree of angiographic vasospasm. Treatment with ibuprofen and high-dose methylprednisolone prevented or significantly reduced this increase in prostaglandin E2 concentration. Smaller increases in cerebrospinal fluid concentrations of thromboxane B2 and 6-ketoprostaglandin F1 alpha occurred after experimental subarachnoid hemorrhage; the magnitude of these increases was also reduced by ibuprofen or high-dose methylprednisolone treatment. In contrast, prostaglandin F2 alpha levels were not significantly altered during the study. These data show that enhanced prostaglandin E2 synthesis occurs during experimental subarachnoid hemorrhage, and the by-products generated in its synthesis may play a role in the pathogenesis of cerebral vasospasm.

Hemicraniectomy and Durotomy Upon Deterioration From Infarction-Related Swelling Trial: Randomized Pilot Clinical Trial

Background and Purpose— Hemicraniectomy and Durotomy Upon Deterioration From Infarction-Related Swelling Trial (HeADDFIRST) was a randomized pilot study to obtain information necessary to design a Phase III trial to evaluate the benefit of surgical decompression for brain swelling from large supratentorial cerebral hemispheric infarction. Methods— All patients with stroke were screened for eligibility (age 18–75 years, National Institutes of Health Stroke Scale ≥18 with Item 1a<2 [responsive to minor stimulation], and CT demonstrating unilateral, complete middle cerebral artery territory infarction by specific imaging criteria). All enrolled patients were treated using a standardized medical treatment protocol. Those with both ≥4 mm of pineal shift and deterioration in level of arousal or ≥7.5 mm of anteroseptal shift within 96 hours of stroke onset were randomized to continued medical treatment only or medical treatment plus surgery. Death at 21 days was the primary outcome measure. Results— Among 4909 screened patients, only 66 (1.3%) patients were eligible for HeADDFIRST. Forty patients were enrolled, and 26 patients developed the requisite brain swelling for randomization. All who failed to meet randomization criteria were alive at 21 days. Mortality at 21 and 180 days was 40% (4/10) in the medical treatment only and 21% (3/14) and 36% (5/14) in the medical treatment plus surgery arms, respectively. Conclusions— HeADDFIRST randomization criteria effectively distinguished low from high risk of death from large supratentorial cerebral hemispheric infarction. Lower mortality in the medical treatment only group than in other published trials suggests a possible benefit to standardizing medical management. These results can inform the interpretation of recently completed European trials concerning patient selection and medical management. Clinical Trial Registration— This trial was not registered because enrollment began before July 1, 2005.

Prevention of Chronic Cerebral Vasospasm in Dogs with Milrinone

OBJECTIVE Delayed cerebral ischemia resulting from vasospasm is a major cause of morbidity and death in patients with aneurysmal subarachnoid hemorrhage. Milrinone, because it inhibits Type IV cyclic adenosine monophosphate-specific phosphodiesterase enzyme in both cardiac and vascular smooth muscle, is a powerful inotrope and vasodilator, but it has little effect on heart rate or blood pressure. Because of these properties, milrinone is an attractive potential therapy after subarachnoid hemorrhage. The purpose of the present study was to investigate the effect of milrinone on chronic experimental cerebral vasospasm. METHODS A double-hemorrhage canine model of vasospasm was used to study the efficacy of milrinone. Angiographic vasospasm and systemic hemodynamics were compared in a treatment group of animals that received a loading dose of milrinone (0.05 mg/kg, intravenously) and then slow-release (0.05 microgram/kg/min) milrinone pellets (n = 10) and a control group that received placebo pellets (n = 9), over an 8-day period after the initial subarachnoid hemorrhage. The hemorrhage was created by injection of 4 ml of autologous, nonheparinized, arterial blood into the cisterna magna on Days 1 and 3. Hemodynamic measurements, including cardiac output determinations, were made on Days 0, 1, 3, 6, and 8 with a pulmonary artery catheter, and angiographic vasospasm was assessed on Day 8 by comparison with baseline angiograms. RESULTS Treatment with milrinone caused no significant changes in systemic hemodynamics. Angiographic vasospasm, however, was significantly reduced in the Day 8 angiograms for the treated group, compared with the control group (98.28 +/- 14.06 and 67.89 +/- 13.06% of original vessel cross-sectional area, respectively; P < 0.001). CONCLUSION Milrinone is effective in preventing chronic cerebral vasospasm in a canine model of experimental chronic cerebral vasospasm. This effect is independent of changes in systemic hemodynamics. Milrinone and related drugs warrant further investigation for the treatment of cerebral vasospasm.

Measurement of Prostaglandins in the Cerebrospinal Fluid in Cat, Dog, and Man

Prostaglandins are involved in the modulation of various central functions (neurotransmitters and hypothalamic hormone release, thermoregulation, cerebro‐vascular tone) and their levels increase in pathological situations [subarachnoid hemorrhage (SAH), stroke, convulsive disorders, etc.]. This study, using sensitive and specific antibodies, examined levels of four eicosanoids, Prostaglandins E2 and F2α(PGE2, PGF2α); and the metabolites of PGI2, 6‐keto‐prostaglandin F1α (6‐keto‐PGF1α) and of thromboxane A2, thromboxane B2 (TxB2), in the cerebrospinal fluid (CSF) obtained atraumatically from three species (human, canine, and feline). An assessment of the methodologic procedures (extraction and radioimmunoassay) was carried out. Human lumbar cerebrospinal fluid was shown to contain PGF2α (15–44 pg/ml), 6‐keto‐PGF1α (undetectable to 39 pg/ml), and TxB2 (un‐detectable to 28 pg/ml), whereas PGE2 was undetectable (>18 pg) in all cases. In both animals species the eico‐sanoid concentrations were 3‐to 30‐fold higher than humans for every prostaglandin examined. Although the prostaglandin profile for a given species remained constant (cat, PGE2:6‐keto‐PGF1α:TxB2:PGF2α; dog, TxB2:PGE2:6‐keto‐PGF1α:PGF2α), the absolute levels were found to be lower in the pentobarbital‐anesthetized animals than in conscious cats. The correspondence of the prostaglandin profiles found in cerebrospinal fluid with the profiles reported in the literature in brain homogenates for the same species supports the hypothesis that cerebrospinal fluid levels of prostaglandins reflect the relative rates of synthesis in neural tissue.

Solitary eosinophilic granuloma of the frontal lobe

Solitary intracranial eosinophilic granulomas are rare and most frequently involve the hypothalamus. We report an unusual case of solitary eosinophilic granuloma of the frontal lobe in a patient without evidence of systemic disease. Previously reported cases of solitary intracranial nonhypothalamic lesions are reviewed, and the clinical, radiographic, and histological features of this case are discussed.

5-Hydroxytryptamine: Source of activator calcium in human basilar arteries

We performed experiments in human cerebral arteries to determine the source of activator calcium during contractions induced by 5-hydroxytryptamine. Rings of human basilar artery obtained at autopsy were mounted for isometric tension recording in organ baths filled with a physiological salt solution. Contractile responses to 5-hydroxytryptamine were virtually abolished in Ca++-free solution, and inhibited significantly by nimodipine. In both cases, the depression of the response to 5-hydroxytryptamine was comparable to that seen when KCl was used to contract the vessels. These experiments demonstrate that 5-hydroxytryptamine mediates contraction of the smooth muscle in human basilar artery by increasing membrane permeability to extracellular calcium.