BACKGROUND: About 12,000 people suffer an ischemic stroke in Norway every year; 20 % of them may be caused by emboli from precerebral arteries. We discuss the epidemiology of carotid artery stenoses and assessment upon suspicion, and provide an overview of medical treatment and indications for surgery. MATERIAL AND METHODS: The article is based on literature identified through non-systematic searches in PubMed, core medical journals and textbooks and the authors' experience from a vascular surgical department and stroke unit. RESULTS: Stroke symptoms or recurrent transient ischemic attacks (TIAs) should lead to direct admission to hospital, while patients with single TIAs should be assessed as out-patients in a hospital within a few days. Risk-factors should be investigated, and the carotid arteries should be examined with duplex ultrasound upon suspicion of stenosis. There is only a weak correlation between a neck bruit and an ipsilateral carotid artery stenosis, but a connection can usually be clarified by use of duplex ultrasound. All patients with a carotid artery stenosis should have medical treatment to prevent complications of atherosclerotic disease; i.e. antithrombotic, and for the majority cholesterol-lowering treatment and possibly antihypertensive medication. Patients with a symptomatic carotid artery stenosis of more than 50 % diameter reduction should be considered for surgical treatment within 14 days. Surgery for asymptomatic carotid artery stenoses seems to have a marginal effect. INTERPRETATION: Patients with stroke-like symptoms should be examined by a doctor as soon as possible. Quick diagnosis and treatment of patients with cerebrovascular events is demanding for the logistics of our hospitals.

In 47 cases of verified ruptured saccular aneurysm, we investigated the relationship of the amount and distribution of subarachnoid blood detected by computerized tomography to the later development of cerebral vasospasm. When the subarachnoid blood was not detected or was distributed diffusely, severe vasospasm was almost never encounters (1 of 18 cases). In the presence of subarachnoid blood clots larger than 5 X 3 mm (measured on the reproduced images) or layers of blood 1 mm or more thick in fissures and vertical cisterns, severe spasm followed almost invariably (23 of 24 cases). There was an almost exact correspondence between the site of the major subarachnoid blood clots and the location of severe vasospasm. Every patient with severe vasospasm manifested delayed symptoms and signs. Excellent correlation existed between the particular artery in vasospasm and the delayed clinical syndrome. Severe vasospasm involved the anterior cerebral artery in 20 cases and the middle cerebral artery in only 14. As the grading system used is partly subjective, the findings should be regarded as preliminary. The results, if confirmed, indicate that blood localized in the subarachnoid space in sufficient amount at specific sites is the only important etiological factor in vasospasm. It should be possible to identify patients in jeopardy from vasospasm and institute early preventive measures.(Neurosurgery, 6: 1--9, 1980)

Nitric oxide (NO) and peroxynitrite, formed from NO and superoxide anion, have been implicated as mediators of neuronal damage following focal ischemia, but their molecular targets have not been defined. One candidate pathway is DNA damage leading to activation of the nuclear enzyme, poly(ADP-ribose) polymerase (PARP), which catalyzes attachment of ADP ribose units from NAD to nuclear proteins following DNA damage. Excessive activation of PARP can deplete NAD and ATP, which is consumed in regeneration of NAD, leading to cell death by energy depletion. We show that genetic disruption of PARP provides profound protection against glutamate-NO-mediated ischemic insults in vitro and major decreases in infarct volume after reversible middle cerebral artery occlusion. These results provide compelling evidence for a primary involvement of PARP activation in neuronal damage following focal ischemia and suggest that therapies designed towards inhibiting PARP may provide benefit in the treatment of cerebrovascular disease.

Adouble-blind trial of aspirin for the treatment of cerebral ischemia was begun in 1972 and continued for 37 months. This was accomplished despite difficulties in controlling a long-term study of a drug which has widespread availability and consumption. The study design, criteria for selection of patients, follow-up surveillance, and methods of data analysis are presented. We report only subjects without carotid surgery before randomization. Patients (178) who had carotid transient ischemic attacks (TIAs) were randomly allocated to aspirin or placebo and followed to determine the incidence of subsequent TIAs,death, cerebral infarction or retinal infarction. Analysis of the first six months of follow-up revealed a statistically significant differential in favar of aspirin when death or cerebral or retinal infarction and the occurrence of TIAs were grouped and considered together as end points. Significance in favor of aspirin treatment was mainly revealed in patients with a history of multiple TIAs and was most evident in those individuals having carotid lesions appropriate to the TIA symptoms. It cannot be inferred from this study that aspirin prevents stroke because when end points were restriced to death or cerebral or retinal infarction, there was no statistically significant differential between the aspirin and placebo treatments.

Ischemic stroke is the most common life-threatening neurological disease and has limited therapeutic options. One component of ischemic neuronal death is inflammation. Here we show that doxycycline and minocycline, which are broad-spectrum antibiotics and have antiinflammatory effects independent of their antimicrobial activity, protect hippocampal neurons against global ischemia in gerbils. Minocycline increased the survival of CA1 pyramidal neurons from 10.5% to 77% when the treatment was started 12 h before ischemia and to 71% when the treatment was started 30 min after ischemia. The survival with corresponding pre- and posttreatment with doxycycline was 57% and 47%, respectively. Minocycline prevented completely the ischemia-induced activation of microglia and the appearance of NADPH-diaphorase reactive cells, but did not affect induction of glial acidic fibrillary protein, a marker of astrogliosis. Minocycline treatment for 4 days resulted in a 70% reduction in mRNA induction of interleukin-1beta-converting enzyme, a caspase that is induced in microglia after ischemia. Likewise, expression of inducible nitric oxide synthase mRNA was attenuated by 30% in minocycline-treated animals. Our results suggest that lipid-soluble tetracyclines, doxycycline and minocycline, inhibit inflammation and are neuroprotective against ischemic stroke, even when administered after the insult. Tetracycline derivatives may have a potential use also as antiischemic compounds in humans.

OBJECTIVE--To examine the effect of fruit and vegetable intake on risk of stroke among middle-aged men over 20 years of follow-up. DESIGN--Cohort. SETTING--The Framingham Study, a population-based longitudinal study. PARTICIPANTS--All 832 men, aged 45 through 65 years, who were free of cardiovascular disease at baseline (1966 through 1969). MEASUREMENTS AND DATA ANALYSIS--The diet of each subject was assessed at baseline by a single 24-hour recall. The estimated total number of servings per day of fruits and vegetables was the exposure variable for this analysis. Using Kaplan-Meier survival analysis, we examined age-adjusted cumulative incidence of stroke by quintile of servings per day. To adjust for multiple covariates, we used proportional hazards regression to calculate the relative risk (RR) of stroke for each increment of three servings per day. MAIN OUTCOME MEASURE--Incidence of completed strokes and transient ischemic attacks. RESULTS--At baseline, the mean (+/- SD) number of fruit and vegetable servings per day was 5.1 (+/- 2.8). During follow-up there were 97 incident strokes, including 73 completed strokes and 24 transient ischemic attacks. Age-adjusted risk of stroke decreased across increasing quintile of servings per day (log rank P for trend,.01). Age-adjusted RR for all stroke, including transient ischemic attack, was 0.78 (95% confidence interval [Cl], 0.62 to 0.98) for each increase of three servings per day. For completed stroke the RR was 0.74 (95% Cl, 0.57 to 0.96); for completed stroke of ischemic origin the RR was 0.76 (95% Cl, 0.57 to 1.02); and for completed stroke of hemorrhagic origin, 0.49 (95% Cl, 0.25 to 0.95). Adjustment for body mass index, cigarette smoking, glucose intolerance, physical activity, blood pressure, serum cholesterol, and intake of energy, ethanol, and fat did not materially change the results. CONCLUSION--Intake of fruits and vegetables may protect against development of stroke in men.

Global ischemia, in the gerbil, produces profound hippocampal CA1 loss which leads to functional abnormalities (e.g. habituation impairment). In experiment 1, gerbils were subjected to 3 or 5 min of normothermic (brain) ischemia. Hypothermic groups were cooled to 32 degrees C for 12 h beginning 1 h after ischemia, while control groups (no hypothermia) regulated their own temperature. Exploration in a novel open field was assessed on days 3, 7 and 10 following ischemia and CA1 neurons were counted after 10- or 30-day survival. Both ischemia durations produced severe CA1 necrosis which resulted in increased open field activity. Hypothermia attenuated this behavioral pattern and substantially reduced CA1 necrosis against 3 min of ischemia when assessed at 10 and 30 days, but was only partially effective against a 5 min occlusion where, in addition, some cell death appeared to be delayed rather than prevented. In experiment 2, gerbils were occluded for 5 min and survived for 30 days. Twenty-four hours of hypothermia initiated 1 h after ischemia resulted in near total preservation of CA1 neurons. Thus, increasing the duration of post-ischemic hypothermia from 12 to 24 h produced much greater neuroprotection against severe ischemia. Prolonged post-ischemic hypothermia may be a valuable intervention in stroke patients.

OBJECTIVE: To determine the effect of the angiotensin converting enzyme inhibitor ramipril on the secondary prevention of stroke. DESIGN: Randomised controlled trial with 2x2 factorial design. SETTING: 267 hospitals in 19 countries. PARTICIPANTS: 9297 patients with vascular disease or diabetes plus an additional risk factor, followed for 4.5 years as part of the HOPE study. OUTCOME MEASURES: Stroke (confirmed by computed tomography or magnetic resonance imaging when available), transient ischaemic attack, and cognitive function. Blood pressure was recorded at entry to the study, after 2 years, and at the end of the study. RESULTS: Reduction in blood pressure was modest (3.8 mm Hg systolic and 2.8 mm Hg diastolic). The relative risk of any stroke was reduced by 32%(156 v 226) in the ramipril group compared with the placebo group, and the relative risk of fatal stroke was reduced by 61%(17 v 44). Benefits were consistent across baseline blood pressures, drugs used, and subgroups defined by the presence or absence of previous stroke, coronary artery disease, peripheral arterial disease, diabetes, or hypertension. Significantly fewer patients on ramipril had cognitive or functional impairment. CONCLUSION: Ramipril reduces the incidence of stroke in patients at high risk, despite a modest reduction in blood pressure.

BACKGROUND AND PURPOSE: Endoluminal treatment is being increasingly used for carotid artery disease. The aim of this study was to compare the stroke and death risk within 30 days of endovascular treatment or endarterectomy for symptomatic carotid artery disease. METHODS: systematic comparison of the 30-day outcome of angioplasty with or without stenting and endarterectomy for symptomatic carotid artery disease reported in single-center studies, published since 1990, was performed. RESULTS: Thirty-three studies (13 angioplasty and 20 carotid endarterectomy) were included in this analysis. Carotid stents were deployed in 44% of angioplasty patients. Mortality within 30 days of angioplasty was 0.8% compared with 1.2% after endarterectomy (OR 0.68, 95% CI 0.43 to 1.05; P=0.6). The stroke rate was 7.1% for angioplasty and 3.3% for endarterectomy (OR 2.22, CI 1.62 to 3.04; P<0.001), while the risk of fatal or disabling stroke was 3.2% and 1.6%, respectively (OR 2.09, CI 1.3 to 3.33; P<0.01). The risk of stroke or death was 7.8% for angioplasty and 4% for endarterectomy (OR 2.02, CI 1.49 to 2.75; P<0.001), while disabling stroke or death was 3.9% after angioplasty and 2.2% after endarterectomy (OR 1.86, CI 1.22 to 2.84; P<0.01). CONCLUSIONS: In the treatment of symptomatic carotid artery disease, the risk of stroke is significantly greater with angioplasty than carotid endarterectomy. At present, carotid angioplasty is not recommended for the majority of patients with symptomatic carotid artery disease.

With the cooperation of 60 neurosurgical centers in Japan, a prospective randomized placebo-controlled double-blind trial of a new calcium antagonist AT877 (hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride, or fasudil hydrochloride) was undertaken to determine the drug's effect on delayed cerebral vasospasm in patients with a ruptured cerebral aneurysm. A total of 276 patients, who underwent surgery within 3 days after subarachnoid hemorrhage (SAH) of Hunt and Hess Grades I to IV, were entered into the study. Nine patients were excluded because of protocol violation. The remaining 267 patients received either 30 mg AT877 or a placebo (saline) by intravenous injection over 30 minutes, three times a day for 14 days following surgery. Demographic and clinical data were well matched between the two groups. It was found that AT877 reduced angiographically demonstrable vasospasm by 38%(from 61% in the placebo group to 38% in the AT877 group, p = 0.0023), low-density regions on computerized tomography associated with vasospasm by 58%(from 38% to 16%, p = 0.0013), and symptomatic vasospasm by 30%(from 50% to 35%, p = 0.0247). Furthermore, AT877 reduced the number of patients with a poor clinical outcome associated with vasospasm (moderate disability or worse on the Glasgow Outcome Scale at 1 month after SAH) by 54%(from 26% to 12%, p = 0.0152). There were no serious adverse events reported in the AT877 group. This is the first report of a placebo-controlled double-blind trial that has demonstrated a significant reduction in angiographically revealed vasospasm by intravenous drug therapy.