ESO FAQ - Frequently Asked Questions on Stroke

Stroke Prevention by the Practitioner – Introduction to the Management of Stroke

  1. Introduction to the Management of Stroke
  2. Epidemiology of Stroke
  3. High Blood Pressure
  4. Diabetes and Stroke
  5. Lipids and Stroke
  6. Other Risk Factors for Stroke
  7. Carotid Surgery
  8. Antiplatelets, Therapy for Stroke Prevention
  9. Anticoagulant Therapy and Stroke Prevention
  10. Prevention in Atrial Fibrillation and Other Cardiac Sources of Embolism
  11. Stroke Services

Introduction to the Management of Stroke

What Is a Stroke?

Stroke is a type of cerebrovascular disease that involves the vessels of the central nervous system. It usually occurs with sudden onset due to a burst of cerebral arteries, hemorrhage or occlusion by a thrombus or other particles ischemia, leading to focal brain dysfunction. Immediately, nerve cells depleted of oxygen in the involved vascular territory will be functionally disturbed and die if the circulation is not promptly restored. Two main mechanisms may lead to ischemic stroke: occlusive or hemodynamic. These two situations decrease the cerebral perfusion pressure and eventually lead to cellular death. But within certain limits, the brain blood flow can be maintained by autoregulation of cerebral arteries and collateral circulation. When occlusion of an artery develops, blood flow in the periphery of the infarct core is usually reduced but still sufficient to avoid structural damage, so that the functional modifications of cells may be reversible if circulation is restored. This ring-like area of reduced blood flow around the ischemic center of infarct has been termed penumbra as an analogy of the half-shaded part around the center of a solar eclipse. It may largely explain the functional improvement occurring after stroke. Indeed, the neurons surviving in this critical area of infarct at reduced blood flow may again function as soon as blood flow and oxygen delivery is restored.

How Many Types of Stroke Are There?

Cerebral infarction is not a single disease and there are two main types of stroke: ischemic or hemorrhagic. Embolism is the most frequent cause of ischemic stroke. Embolism may originate from the heart, aortic arch or cervico-cephalic arteries. 70-80 of ischemic strokes are due to embolic migration. Intracerebral and subarachnoid hemorrhages are usually related to the rupture of an artery or arterioles. Their morbidity and mortality rates are higher than for ischemic stroke. Artery-to-artery embolism is the main cause of ischemic stroke. Rupture of atheromatous plaques is a potent cause of thrombosis. Indeed, the progression of atheromatous plaques leads to arterial stenosis, formation of wall thrombus, and finally occlusion with high probability of thrombi (e.g. embolism). The size and composition of emboli, and the collateral system may determine the size of infarcts. Usually, small platelet emboli are rapidly disaggregated and lead only to transient ischemic attacks by temporary occlusion of distal cerebral arteries. On the other hand, large thrombotic embolism, rich in fibrin, is therefore less friable and may cause more persisting and severe ischemia. The internal carotid artery at its origin (bifurcation) is the main site of atherosclerotic plaques, followed by the carotid siphon, the proximal and distal vertebral arteries and the mid-basilar artery. The onset of ischemic stroke is thus related to the onset of embolism, which is linked to vascular territories, dynamic changes in atherosclerotic plaques, and degree of stenosis. When atherosclerosis involves small cerebral arteries in the deep perforative network, especially in patients with hypertension or diabetes, small deep ‘lacunar’ infarcts may occur because, at this level, the arteries are terminal branches and have no collaterals. Microatheromatous or lipohyalinotic occlusion is the main cause of lacunar infarction. Intraparenchymal and subarachnoid hemorrhages are due to the rupture of the brain vessel wall. Spontaneous, intracerebral hemorrhage accounts for 10-15% of all strokes. The main mechanisms underlying hemorrhage include hypertensive arteriolopathy. arteriovcnous malformations, amyloid angiopathy, drugs (anticoagulants, thrombolytics) and inflammatory vasculitides.

How Frequent Are Strokes?

Stroke is the third main cause of death after heart disease and cancer, and the first cause of severe disability. One third of fatal strokes occur before age 65 years. For all stroke types combined, the mortality varies from country to country between 20 and 250 per 100,000 per year. In the USA strokes are the cause of 150,000 deaths per annum. Between 1969 and 1987, stroke mortality has significantly decreased in some developed countries: 40% for men and 45% for women in the USA. This fall is related with the introduction of effective treatment of risk factors (lowering hypertension, lifestyle management), and with the improvement of diagnostic accuracy and better management of the acute phase of stroke. Data obtained from 25 countries allow to conclude that a decrease in mortality of 3-5%} per annum had occurred in western European countries between 1970 and 1985. The incidence of stroke is estimated to be about 150 per 100,000 population per year in industrial countries. It has also decreased by about 20% during the 1980s. In the very first days, transtentorial herniation due to cerebral edema and brain compression represent the main cause of death. The first or second week after stroke onset, one of the causes of mortality after stroke is due to secondary complications of hospitalization immobility, e.g. chest infection (bronchopneumonia), venous thromboembolism.

Which Are the Warning Symptoms of Stroke?

Warning symptoms of stroke (‘brain attack’) include: Sudden weakness or numbness of the face, arm or leg on one side of the body. Sudden dimness or loss of vision, particularly in one eye, or Loss of speech, or trouble talking or understanding speech. Sudden, severe headaches with no known or apparent cause. Unexplained dizziness, unsteadiness or sudden falls, especially along with any of the previous symptoms. Sudden difficulty swallowing. If a patient feels any of these symptoms, even for a few seconds or minutes, he must consult a physician as soon as possible. When one of these warning signs is temporary and lasts less than 24 h. it corresponds to what has been called a transient ischemic attack or TIA. Up to 30% of strokes are preceded by TIA. A patient who has experienced one or more TIAs is 10 times more likely to develop a stroke than someone who has not. TIAs are an extremely important warning symptom and they must never be ignored.

Which Are the Effects of Stroke?

The heterogeneity of stroke pathogenesis and difference between stroke subtypes may hamper diagnosis and management. But usually, the neurological findings help to identify the location of lesions and to predict the stroke mechanism, which is fundamental for determining the initial investigations and treatment. Different patterns of weakness may be found in lesions of the middle cerebral artery (MCA) territory. Hemiplegia is related to large or deep MCA infarcts. Lesions in the upper branch of MCA produces hemiparesis with facio-brachial predominance. On the other hand. weakness predominates in the contralateral lower limb with lesions in the anterior cerebral artery territory. Sensory deficit is also common in MCA stroke, resulting from lesions affecting the territory of the posterior parietal artery. Usually, complete contralateral sensory loss is produced by lesions in the ventroposterolateral part of the thalamus. However, a pseudothalamic pattern may be found in infarcts involving the anterior parietal artery territory. Visual symptoms predominate in the posterior cerebral artery territory. Homonymous hemianopia or quadrantanopia may occur and pertubate walking or driving. They are sometimes associated with alexia or apraxia. Ocular disturbances, such as diplopia, are produced by lesions in the brainstem. They are often associated with hemiparesis or ataxia. Many patients can develop speech disorders, called aphasia, related to infarcts in the dominant hemisphere. It affects the capacity of speaking, listening, reading or writing. Neurobehavioral manifestations are also prominent in stroke and can involve the capacity of thinking and planning activities. Hemineglect is usually found in lesions of the nondominant hemisphere. After stroke, many patients develop a depression which can affect motor improvement. Deglutition or swallowing can also be affected by stroke, usually with medullary infarctions or bilateral lesions. Bronchoaspiration can occur in such cases.

Which Are the Risk Factors of Stroke?

There are two main groups of ‘cardio-cerebrovascular’ risk factors. The first group is genetically determined or related with natural body functions. On the contrary, the second is the result of lifestyle and can be modified. The risk factors may interact more than just by summation, so that the risk of stroke markedly increases as the number of risk factors increases. The unmodifiable risk factors are: age, sex, race, family history, and previous T1A or stroke. Age is the most powerful risk factor. Indeed, the risk of stroke doubles or triples with every decade after 50 years of age. Many studies have demonstrated a higher incidence of stroke in men than in women and the general decline in stroke in western countries also seems to have been particularly marked in women. According to risk factors and stroke etiology, the recurrence rate of stroke varies between less than 1% and more than 10% in the first year, with the first 6 months being the period of highest risk. Hypertension, diabetes, and smoking increase this risk. The main modifiable risk factors, which must be controlled to decrease the risk of stroke, include hypertension, smoking, high lipids, diabetes and alcohol intoxication. Hypertension is the most important risk factor for brain infarction. The relationships between blood pressure and the relative risk of stroke is nearly log linear. The effect of hypertension decreases in the very elderly, and the relative risk for stroke falls from 3.5 in people aged 50-59 years to 1.7 in those aged over 80. This risk factor is associated with large-artery atheroma, small-artery disease and intracerebral hematoma. Smoking, despite controversial data, is clearly a risk factor, dose-responsive. Diabetes is a major risk factor particularly when associated with hypertension. The metabolism of cholesterol is directly implicated in the development of atherosclerosis and plaques and high cholesterol is a stroke risk factor. The modifications of blood levels of lipids are related not only with eating habits but also with genetic factors.

How to Make the Diagnosis of Stroke?

An early and correct diagnosis of stroke is made by evaluating symptoms, reviewing the patient’s medical history and risk factors, and performing routine tests. The clinical examination is crucial for the choice and timing of investigations. ECG and blood tests are usually the first laboratory investigations carried out in the emergency room. They must include sedimentation rate, red and white cell count, platelet count, hematocrit, blood ionogram, glucose, serum enzymes, cholesterol and lipids levels, and routine coagulation profile, including serum fibrinogen, prothrombin time and partial thromboplastin time. Brain CT scan is the most useful radiological investigation in the acute phase. Within about 20 min. it allows to distinguish between ischemic and hemorrhagic lesions and also to rule out nonstroke brain conditions. In the first hours after an ischemic stroke, a CT scan can be normal. But often indirect signs of stroke can be visualized: focal brain edema, obliteration of cortical sulcus, spontaneous hyperdense artery. The main limitations of CT are the detection of brainstem and cerebellar infarcts. Magnetic resonance imaging (MRI) is a technique which offers different possibilities to detect ischemic lesions in the acute phase of stroke. It is especially useful for brainstem infarcts. Compared with CT scan, MRI is more sensitive in the detection of recent and old strokes. MRI can improve stroke localization and detect small infarcts. It may also better allow to define the age of an ischemic lesion. MI has not replaced CT in the emergency phase of stroke, because of its availability and difficulty in differentiating recent hemorrhage from ischemia. With this technique, angiographic pictures (MR angiography or MRA) can also be obtained noninvasively. But a longer time and good collaboration of patients (no claustrophobia) are necessary to obtain good images. However, with reduction of examination time and costs, it is likely that more and more patients will have MRI in the acute phase, since it may give data on viable vs. irreversibly damaged tissue and underlying vascular lesions at the same time. Other investigations, such as Doppler ultrasounds, echocardiography, catheter angiography and other tests are usually made to determine the etiology of a diagnosed stroke, often in selected patients.

Which Tests Can Help in the Search of Stroke Etiology?

Doppler ultrasounds easily allow evaluation of the blood flow at the precerebral level in the carotid and vertebral artery systems. It can provide information on a potential arterial source of emboli and on arterial occlusion and is currently performed as a screening procedure before more invasive investigations. It can be made and repeated at the bedside and it can be completed by echotomography and transcranial Doppler. It is very useful to detect carotid stenosis or dissection. With good practice it can even avoid conventional angiography in many instances. Actually, conventional angiography is reserved for special situations with suspicion of multiple or intracranial stenosis, floating thrombus, arteritis, or uncommon angiopathies. Electroencephalogram is usually not performed in stroke patients, although it can sometimes be useful. It can provide information on stroke localization, whether deep or superficial, when CT is inconclusive. It may make it possible to differentiate stroke from migraine or epileptic seizure, although not always. In a comatose patient, it gives information on the depth of coma, functional asymmetry and may exclude associated epileptic seizures. In suspected cardioembolism, the investigations must include at least 24 h one- to three-lead electrocardiogram monitoring. Noninvasive studies also include echocardiography to look at the heart in selected patients. Indeed, cardioembolism is the cause of 25-30% of ischemic strokes. Transthoracic two-dimensional echocardiography gives reliable information on the ventricular wall and the aortic and mitral valves. It can exclude a left-ventricular thrombus and demonstrate intracardiac shunts when used with a contrast microbubble test. Transesophageal echocardiography represents an advantage for the assessment of the posterior part of the heart, particularly the left atrium and appendage. If provides information on atheromatosis and ulcerated plaques in the aortic arch. Its disadvantage is the endoscopic procedure, which necessitates a good cooperation of the patient. Cerebrospinal fluid examination is rarely required in acute stroke, but it can provide information on specific conditions, including cerebral venous thrombosis and vasculitis.

Which Tests Can Help in the Search of Stroke Etiology?

Doppler ultrasounds easily allow evaluation of the blood flow at the precerebral level in the carotid and vertebral artery systems. It can provide information on a potential arterial source of emboli and on arterial occlusion and is currently performed as a screening procedure before more invasive investigations. It can be made and repeated at the bedside and it can be completed by echotomography and transcranial Doppler. It is very useful to detect carotid stenosis or dissection. With good practice it can even avoid conventional angiography in many instances. Actually, conventional angiography is reserved for special situations with suspicion of multiple or intracranial stenosis, floating thrombus, arteritis, or uncommon angiopathies. Electroencephalogram is usually not performed in stroke patients, although it can sometimes be useful. It can provide information on stroke localization, whether deep or superficial, when CT is inconclusive. It may make it possible to differentiate stroke from migraine or epileptic seizure, although not always. In a comatose patient, it gives information on the depth of coma, functional asymmetry and may exclude associated epileptic seizures. In suspected cardioembolism, the investigations must include at least 24 h one- to three-lead electrocardiogram monitoring. Noninvasive studies also include echocardiography to look at the heart in selected patients. Indeed, cardioembolism is the cause of 25-30% of ischemic strokes. Transthoracic two-dimensional echocardiography gives reliable information on the ventricular wall and the aortic and mitral valves. It can exclude a left-ventricular thrombus and demonstrate intracardiac shunts when used with a contrast microbubble test. Transesophageal echocardiography represents an advantage for the assessment of the posterior part of the heart, particularly the left atrium and appendage. If provides information on atheromatosis and ulcerated plaques in the aortic arch. Its disadvantage is the endoscopic procedure, which necessitates a good cooperation of the patient. Cerebrospinal fluid examination is rarely required in acute stroke, but it can provide information on specific conditions, including cerebral venous thrombosis and vasculitis.

How to Treat a Patient with Acute Stroke?

Management of the acute phase of stroke is not the target of this brochure. In short, treatment must begin as soon as possible to ensure that no further damage to brain cells develops. Stroke is an emergency, like myocardial infarction. In the acute phase of stroke, it is critical that patients get adequate management for the prevention of early complications, such as elevated intracranial pressure and broncho-aspiration or infection, fever, deep venous thrombosis, pulmonary embolism, bed sores, and metabolic and hydroionic disorders. General and medical treatments aim at preserving the integrity of cells in the periphery of the infarct core (penumbra). As an example, patients should be maintained in a supine position to avoid a sudden decrease of brain perfusion pressure in the ischemic area, where autoregulation is lost. However, this position may be contradictory to the prevention of bronchoaspiration, so that management must be adopted to individual situations. Treatment of arterial hypertension is commonly considered when mean arterial pressure is above 160 mm Hg. Hyperthermia must also be avoided because the cerebral metabolic rate is proportional to body temperature and increases 5-17%/°C. Elevated glucose levels increase brain damage, and must be controlled. Encouraging findings have been demonstrated for hyperacute therapy of ischemic stroke with thrombolytic agents, mainly recombinant tissue plasminogen activator (rtPA). One multicentre study has shown significant and sustained neurological improvement when thrombolytic treatment is initiated within the first 3 h of stroke onset. Ongoing studies will allow to specify if therapy can be applied with a prolonged delay after onset of stroke. Neuroprotection with drugs acting on the ischemic cascade might be an extremely promising therapy in acute stroke, but it is still being evaluated with clinical trials. The early prevention of stroke recurrence, immediately after stroke, is a critical facet of stroke management. Recent data from the International Stroke Trial (1ST) and the Chinese Acute Stroke Trial (CAST) suggest that aspirin when administered as soon as possible in an acute stroke patient, mainly decreases the rate of early stroke recurrence. Even though low-dose heparin (or low-mo-lecular-weight heparin) is more controversial but is currently given in many centers in order to decrease the risk of venous thromboembolism and PE, high-dose heparin carries a higher risk of hemorrhage and should be avoided, except in selected indications (floating thrombus, minal thrombus. extracranial dissection, venous thrombosis) and with careful aPTT monitoring.

What to Do to Prevent Stroke?

The great majority of strokes are a consequence of atherosclerosis, with the development of atherosclerotic plaques in multiple arteries. Therefore, primary prevention, e.g. risk factors’ management including anti-platelet agents, aims to slow down the formation of atherosclerosis. Regarding secondary prevention measures, a number of prospective studies have established that antiplatelet agents are effective in the secondary prevention of stroke, myocardial infarction and vascular death with a mean reduction of 25%. The ideal dosage of aspirin for stroke prevention is still debated. No study has been made to assess a potential difference between high-dose aspirin (950-1,300 mg a day) and very low dose, 30-50 mg a day. Meta-analysis of available data from clinical trials suggests that the best clinical effect is obtained with intermediate doses (200-325 mg a day). Other specific treatments for stroke prevention include other platelet aggregation inhibitors (possibly in combination with aspirin), anticoagulant therapy and specific surgical procedures (such as carotid endarterectomy). In addition, major risk factors must be considered, the most important one being hypertension: high blood pressure explains up to 25% of all strokes and a reduction of diastolic blood pressure of 6 mm Hg is associated with a reduction of 40%i of first strokes. Another one is atrial fibrillation for subjects over 65 years of age. Conventional oral anticoagulation is effective in patients with nonrheumatic atrial fibrillation. Lifestyle management is also essential (stop smoking, lose weight). The aim of this brochure is to address the main questions related to the issue of stroke prevention.

Epidemiology of Stroke

What Is the Mortality due to Stroke?

Stroke is the second most common cause of mortality, after cardiovascular disease. The crude death rates range from 63.5/100.000 (males Switzerland 1992) to 273.4/ 100.000 (females Russia 1991). The underlying stroke etiology influences the 30-day mortality: 8-15% for cerebral infarction, 42 46% for subarachnoid hemorrhage and 48-82% for intracerebral hemorrhage. The causes of 180-day mortality following acute stroke are mainly due to comorbid diseases: heart disease in 35% of the cases, acute and recurrent stroke in 25%, pneumonia in 15%, pulmonary embolism in 10% and other causes in 15%. The age-specific mortality rates increase exponentially with age. doubling every 5 years after 45 years.

A trend of reduction in death rate is observed in many European countries as well as North America. This de-crease is probably multifactorial. The detection and more effective treatment for hypertension may play an important factor, as well as improved acute medical care and improvement in diagnostic procedures.

What Are the New Features of Epidemiology of Stroke in 1998?

Stroke is a huge public health concern because of its high morbidity and disability, partly as a consequence of its decreased mortality. Recent data have shown that about 72-86% of strokes are ischemic, 9-18% are due to hemorrhage (intracerebral or subarachnoid) and the rest are undefined. For hemorrhagic strokes, the main risk factors are hypertension and excessive alcohol consumption. Smoking is an important risk factor with an overall relative risk (RR) of 3.5 for stroke. In women smoking is a dominant risk factor for subarachnoid hemorrhage with a dose-response relationship. Heavy alcohol consumption is clearly associated with an increase risk in stroke but this association is less clear for moderate and light dose (see question 2). Risk factors for ischemic strokes are multiple and combined (age, hypertension, hyperlipidemia, diabetes mellitus, atrial fibrillation, valvular disorders, coagulation disorders, smoking). Whereas hypertension (RR 4.0) and age (RR per decade 1.6) are other important risk factors for stroke, new data have shown that a family history of stroke might also increase the risk of stroke. However, further studies are needed to confirm this. Other risk factors recently related to stroke include high cholesterol, use of oral contraceptives, physical inactivity, obesity, hypercysteinemia, increased fibrinogen, coagulation disturbance (protein C or protein S deficiency, antiphospholipid anti-bodies). Chronic atrial fibrillation, transient ischemic at-tacks, carotid bruits, patent foramen ovale, aortic arch atheroma are cardiovascular conditions associated with an increased risk of stroke. The risk of stroke is increased in patients with diabetes mellitus (RR 1.5-3.0) [but there is still no evidence that treatment reduces the risk of stroke]. Another novelty is that stroke is no more considered as unavoidable and untreatlable. It is now a clear consensus that stroke is an emergency and that specialized units and teams improve outcome and may lower costs.

Which Are the Common Types of Stroke?

The usual mode of expression of cerebrovascular diseases is the stroke, denned as a sudden, nonconvulsive and focal neurological deficit. Strokes are generally classified into two groups. The most frequent type of stroke results from cerebral infarction (ischemic stroke) whereas in 15-20% of cases, stroke is due to intracranial parenchymatous hemorrhage. Approximately 30% of cerebral infarctions result from atherothrombosis in the aortic arch and in extracranial arteries [Bogousslavsky ct al., 1988]. Strokes resulting from embolism of cardiac origin (cardioembolic stroke) account for 20 25% of ischemic strokes. In these cases, the most common causes of intracardiac thrombus are a myocardial infarction or atrial fibrillation. Another cardiac condition frequently associated with stroke is valvular disease, whether it is due to a defect in native valves or associated with prosthetic valves. The so-called lacunar strokes account for 15-20%i of cerebral infarctions. Lacunar strokes are usually associated with hypertension of long duration and result from changes in small intracerebral arteries. The remaining 30% of ischemic strokes are due to less common conditions (vasculitis, paradoxical embolism through a patent foramen ovale) or of unknown origin (fig.).

Reference
Bogousslavsky J, Van Melle G, Regli F: The Lausanne Stroke Registry: Analysis of 1,000 consecutive patients with first stroke. Stroke 1988,19:1083–1092.

Which Are the Risk Factors for Stroke?

A large number of risk factors for stroke have been described, a reflection of the heterogeneity of the disease. Generally, risk factors for stroke can be classified as modifiable, potentially modifiable and nonmodifiable [Sacco et al., 1977]. Nonmodifiable risk factors for stroke are important to detect, even if no measure can be taken to eliminate them, because their presence helps identify individuals at higher risk and thus justifies the implementation of vigorous treatments to reduce modifiable risk factors.

Well-documented nonmodifiable risk factors for stroke include age, gender, family history and ethnicity (table). Age is the single most important risk factor for stroke. Indeed, for each 10 years after age 55, the stroke rate more than doubles for both men and women [Brown et al., 1966: Wolf et al., 1992]. In the Framingham study, parental history of stroke or coronary artery disease constituted a risk factor for stroke [Kiely et al., 1993]. Gener-ally, the incidence of stroke appears to be higher in non-Caucasians than in Caucasians [Sacco ct al., 1997].

Modifiable risk factors are discussed in question 4.

Table. Major nonmodifiable risk factors for stroke

  1. Age
  2. Gender
  3. Ethnicity
  4. Positive family history

References
Brown RD. Whisnant JP. Sicks RD. O’Fallon WM. Wieber.s DO: Stroke incidence. prevalence, and survival: Secular trends in Rochester, Minnesota, through 1989. Stroke 1996:27:373–380.
Kiely DK. Wolf PA. Cupples LA. Reiser AS, Myers RH: Familial aggregation of stroke; The Framingham Study. Stroke 1993:24:1366–1371.
Sacco RL. Benjamin h.l. Broderick .IP. Dykcn M. Easton JD. Feinberg WM, Goluslein LB. Gordick Pli. Howard G. Kitlner SJ. Manolio TA, Whisnant JP. Woll PA: American Heart Association Prevention Conference. IV. Prevention and Rehabilitation of Stroke. Risk factors. Stroke 1997:28:1366–1371.
Wolf PA. D’Agostino RB. O’Ncal MA. Sytkowski P. Kase CS. Belanger AJ, Kannel WB: Secular trends in stroke incidence and mortality: The Framingham Study. Stroke 1992,23:1551–1555.

Which Are the Modifiable Risk Factors for Stroke?

In middle and late adult life, hypertension is undoubtedly the strongest modifiable risk factor for both ischemic and hemorrhagic stroke. Hypertension is present in approximately 70% of stroke cases. The risk of stroke rises in proportion to blood pressure, for males as well as for females, and almost doubles for every 7.5 mm Hg increment in diastolic blood pressure (DBP) [Collins and McMahon, 1994]. However, the strength of the associ-ation between DBP and the risk of stroke is attenuated when age increases. In a recent meta-analysis [Prospective Studies Collaboration, 1995] the relative risk for developing stroke between the highest and the lowest quintiles in DBP was tenfold, fivefold and twofold for individuals aged at the time of screening <45, 45-64 and > 65 years, respectively. The relationship between systolic blood pres-sure, including ‘isolated’ systolic hypertension, may be even stronger than for DBP [Shaper et al., 1991; Keli et al., 1992].

Cigarette smoking also represents a major cause of ischemic and hemorrhagic stroke. In their meta-analysis, Shinton and Beevcrs [1989] estimated that the relative risk of stroke for smokers and former smokers, as compared to nonsmokers, was 1.5 and 1.17, respectively. The risk of stroke increased in proportion to the number of cigarettes smoked per day and was higher for women as compared to men. As is the case for blood pressure, the risk of developing stroke attributable to smoking decreased with advancing age.

Diabetes is associated with stroke, independently of the various cardiovascular risk factors which usually ac-company this disease (hypertension, dyslipidemia and obesity). Indeed, the relative risk of stroke of all types was 1.8 for diabetic men and 3.0 for diabetic women [Shinton and Beevers, 1989; Burchfield et al., 1994].

Whether hypercholesterolemia, a major risk factor for coronary heart disease, is associated with stroke is controversial, for reasons discussed in questions 5-8. In a large meta-analysis of 45 prospective cohorts including 13,000 strokes [Prospective Studies Collaboration. 1995], plasma total cholesterol levels were highly significantly associated with the risk of developing stroke, but only in the subset of individuals aged <45 at the time of screening. In contrast, no association was observed for older groups. Other modifiable well-documented risk factors for stroke include heart disease like atrial fibrillation, a recent large myocardial infarction and valvular defects. A causative treatment, if available, is obviously the therapy of choice, but their discussion extends beyond the limits of this question [Warlow et al., 1996; Sacco et al., 1997; Mohr et al., 1997]. Other potentially modifiable risk factors, whose value is still controversial, include the use of oral contraceptives (containing large doses of estrogen). consumption of large amounts of alcohol, use of illicit drugs, physical inactivity, obesity, elevated hematocrit, insulin resistance, migraine hypercoagulable states and others [Warlow et al., 1996; Sacco et al., 1997; Mohr et al., 1997]. In conclusion, the major modifiable risk factors for stroke include hypertension, cigarette smoking and hypercholeslerolemia. For these three factors, the strength of their association to the risk of developing stroke declines when age increases. References Burchfiel CM. Curb JD. Rodriguz. BL. Abbott RD. Chin D. Yano K: Glucose intolerance and 22-year stroke incidence: The Honolulu Heart Program. Stroke 1994:25:951–957. Collins R. McMahon S: Blood pressure, antihypertensive drug treatment and risks of stroke and of coronary heart disease. Br Mod Bull 1994:50:272–298. Keli S. Bloemberg B, Kromhout D: Predictive value of repeated syslolic blood pressure measurements for stroke risk: The Zutphen Study. Stroke 1992; 23:347–351. Mohr JP, Albers GW. Amarenco P. Babikian VL, Billcr J. Brcy RL. Coull B, Easton JD. Gomez CR. Helgason CM. Kase CS. Pullicino PM. Turpie AG: American Heart Association Prevention Conference. IV Prevention and Rehabilitation of Stroke. Etiology of Stroke. Stroke 1997,28:1501–1506. Prospective Studies Collaboration: Cholesterol, diastolic blood pressure, and stroke: 13.000 strokes in 450.000 people in 45 prospective cohorts. Lancet 1995:346:1647–1653. Sacco RL. Benjamin EJ. Broderick JP. Dyken M, Easton JD. Feinberg WM. Goldstein LB. Gorelick PB, Howard G. Kittner SJ, Manolio TA, Whisnant JP. Wolf PA: American Heart Association Prevention Conference. IV. Pre-vention and Rehabilitation of Stroke. Risk factors. Stroke 1997,28:1507–1517. Shaper AG. Phillips AN. Pocock SJ. Walker M. Macfarlane PW: Risk factors for stroke in middle aged British men. Br Mod J 1991:302:1111-1115. Shinton R. Becvcrs G: Meta-analysis of relation between cigarette smoking and stroke. BMJ 1989:298:789–94. Warlow CP. Dennis MS. Van Gijn .1, Sandercock PAG, Bamford JM. Wardlaw J: Stroke: A Practical Guide to Management. Oxford. Blackwell, 1996, pp 190–203.

Is the Risk Factor Profile Similar for Ischemic and Hemorrhagic Stroke?

Stroke is the common manifestation of pathophysiological processes as different as intraparenchymatous hemor-rhage or thromboembolism from cardiac origin. The clinical heterogeneity of the disease is reflected by the different risk factor profiles associated with each stroke subtype [Mohret al., 1997; Sacco et al., 1997; Warlow et al.. 1996].

As it contributes to the development of both hemorrhages and atherosclerosis, hypertension is a common risk factor for both hemorrhagic and ischemic strokes (fig.), and this has been confirmed in numerous epidemiological studies [Mohr et al., 1997; Sacco et al., 1997; Warlow et al., 1996]. Conversely, treatment of hypertension has led to a substantial decline in the incidence of both hemorrhagic and ischemic strokes [McMahon and Rodgers, 1994].

Other factors which participate in the occurrence of hemorrhagic stroke include rupture or malformation of intracerebral vessels, as well as certain deficiencies in the hemostatic processes including the use of anticoagulants, antiplatelet therapy or thrombolytic agents. In addition, heavy alcohol consumption has been shown to be an important contributor to hemorrhagic strokes [Mohr et al., 1996]. Some earlier studies have reported an association between low or reduced plasma cholesterol levels and an increased risk of hemorrhagic stroke [Rossouw et al., 1993; Law et al., 1994]. The validity of this association has been recently challenged, as discussed in question 6.

During these last years, atherosclerosis has emerged as a major player in the pathogenesis of ischemic stroke. Atherosclerosis may promote the development of ischemic stroke in two ways [Mohr ct al., 1997]. The deposition of plaques within the aortic arch and extracerebral arteries may lead to an impairment in blood flow to cerebral tissues by narrowing of these vessels or by embolism of plaque material into cerebral arteries. Atherosclerosis may also promote the development of coronary artery disease, thus leading to myocardial infarction or atrial fibrillation, two major causes of cardioembolic strokes. Indeed, numerous risk factors for atherosclerosis have also been associated with stroke: hypertension, cigarette smoking, diabetes mellitus and increased fibrinogen concentrations are established risk factors for stroke [Sacco et al., 1997]. Moreover, the role of lipids in the develop-ment of stroke has recently been (unexpectedly and surprisingly enough) demonstrated by the dramatic reduction in the incidence of stroke in hyperlipidemic subjects given statins, a powerful cholesterol-lowering agent [Crouse et al.. 1997].

In conclusion, hypertension is clearly associated with an increased risk of strokes, irrespective of the subtypes. Anatomic and hemostatic abnormalities are main contributors to hemorrhagic strokes, whereas ischemic strokes are much more related to the major risk factors of atherosclerosis.

References
Crouse JR. Byington RP, Hoen HM, Furberg CD: Reductase inhibitor mono-therapy and stroke prevention. Arch Intern Med 1997.157:305 1310.
Law MR. Thompson SG. Wald N.I: Assessing possible hazards of reducing serum cholesterol. Bi Mcd ,1 1994:308:373–379.
McMahon S. Rodgers A: The epidemiologic association between blood pressure and stroke: Implication for primary and secondary prevention. Hypertens Res 1994:17(suppl 1 “:S23–S32.
Mohr JP. Albers GW. Ainarcnco P. Babikian VL. Billcr J. Brcy RL. Coull B, Easton .11). Gome/ CR. Helpason CM. Kase C’S, Pullicino PM. Turpie AG; American Heart Association Prevention Conference. IV. Prevention and Rehabilitation ol’Stroke. Etiology ol’Strokc. Stroke 1997;28:1501–1506.
Rossouw JE. Gotto AM Jr: Docs low cholesterol cause death? Cardiovase Drugs Ther 1993:7:789–793.
Sacco RL. Benjamin EJ. Broderick .IP. Dyken M. F.aston JD. Fcinbcrg WM, Goldslein l.B. Gorelick PB. Howard G. Kitlncr S.I, Manolio ‘I’A. Whisnant JP. Woll’PA: American Heart Association Prevention Conference. IV. Pre-vention and Rehabilitation of Stroke. Risk factors. Stroke 1997;28:1507–1517.
WarlowCP. Dennis MS. Van Gijn J. Sandcrcock PAG. Bamtbrd JM. Wardlaw J: A Practical Guide to Management. Oxford.
Blackwell. 1996. pp 190–203.

Is the Risk Factor Profile Similar for Stroke and Coronary Artery Disease?

While one considers the prominent role that atherosclerosis plays in the development of both coronary artery disease (CAD) and ischemic stroke, one would anticipate the risk factor profiles to be similar for both diseases. Indeed, epidemiological studies support this view with regards to three major risk factors: hypertension, cigarette smoking and diabetes which all predispose to stroke and CAD [Collinsand McMahon, 1994; Prospective Studies Collaboration 1995; Sacco et al., 1997; Neaton et al., 1992].

There is one major exception, however, Hypercholesterolemia [Prospective Studies Collaboration, 1995] (table). Hyperrcholesterolemia, particularly elevated levels of low-density lipoprotein (LDL)-cholesterol has been unambiguously associated with the development of coronary artery disease, but not with stroke (fig.), at least in subjects aged 45 or older.

Does this mean that high cholesterol levels do not contribute to the development of stroke? Certainly not. Indeed, prospective studies and interventional studies [Crouse et al., 1997] using highly effective lipid-lowering agents show that reducing cholesterol levels in plasma significantly decreases the risk of stroke (see question 7). Numerous explanations can be provided to account for the lack of association in cross-sectional epidemiological studies between hypercholesterolemia and stroke, at least in the elderly:

  1. Stroke is a more heterogeneous condition than CAD. Obviously, CAD is mainly the result of the development of atherosclerotic lesions within the coronary arteries, whereas stroke is the common manifestation of various pathophysiological processes affecting the heart as well as extracranial or intracerebral vessels.
  2. Cholesterol may have divergent effects on hemorrhagic and ischemic stroke. Low cholesterol levels have been associated with an increased risk of hemorrhagic stroke (discussed in question 8) whereas on the other hand high cholesterol levels may promote the development of ischemic stroke.
  3. Plasma concentrations of cholesterol decline with advancing age, partly due to poor nutrition, changes in diet or associated diseases. The majority of strokes occur in the elderly, but the disease may have developed over decades and the hypercholesterolemic state which has contributed to the development of the disease in earlier years may no longer be noticeable when the disease be-comes clinically manifest.

In conclusion, the most striking difference between the risk factors profile for stroke of all types and coronary heart disease is characterized by a weaker predictive value of cholesterol levels, particularly when this lipid parameter is assessed in the elderly.

References
Collins R. McMahon S: Blood pressure, antihypertensive drug treatment and risks of stroke and of coronary heart disease. Br Mod Bull 1994.50:272–298.
Crouse JR. Byington RP. Hoen HM, Furberg CD: Reductase inhibitor monotherapy and stroke. Arch Intern Mod 1997;157:1305–1310.
Neaton JD. Blackburn H. Jacobs D. Kuller 1.. Lee DJ. Sherwin R. Shih J, Stamler J. Wenlworth I.: Serum cholesterol level and mortality findings for men screened in the Multiple Risk Factor Intervention Trial. Arch Intern Mod 1992:152:1490–1500.
Prospective Studies Collaboration: Cholesterol, diastolic blood pressure, and stroke: 13.000 strokes in 450,000 people in 45 prospective cohorts. Lancet 1995:346:1647–1653.
Sacco RL. Benjamin F., Broderick .IP, Dyken M. Easton JD, Feinherg WM, Goldslein LB.Gorelick PB. Howard G. KitlnerSJ. ManolioTA.Whisnant.IP, Wolf’ PA: American Heart Association Prevention CoriCcrence. IV. Prevention and Rehabilitation of Stroke. Risk factors. Stroke 1997:28:1507–1517.

What Is the Best Evidence for Stroke Prevention?

The aim of primary prevention is to anticipate major adverse events to health. Risk of stroke is clearly influenced by lifestyle.

The aim of primary prevention could be reached first by population education, i.e. by attempting to suppress the development of risk factors. Modification of lifestyle is the first line of work, and the targets to modify are poor diet, alcohol drinking, smoking and lack of physical activity. Clear recommendations must be given for weight reduction, decreased salt and animal fat intake, smoking cessation, increased exercise and how to drink alcohol in a ‘safe’ way. The second step is an individual approach and aim to detect hypertension and atrial fibrillation and introduce specific treatment. Aspirin has not been shown to be beneficial in the primary prevention of stroke.

Secondary stroke prevention concerns patients with risk of stroke or transient ischemic attacks. Aspirin, ticlopidine, dipyridamole, and clopidogrel are the drugs which have proven efficacious for reducing stroke recurrence. Anticoagulation for atrial fibrillation with a therapeutic range of INR 2-3 has proven its efficiency with very low acceptable level of intracerebral hemorrhage (less than 1% per year). Carotid endarterectomy is beneficial to patients with recent transient ischemic attack or nondisabling stroke and ipsilateral high-grade stenosis (70-99%) of the internal carotid artery.

Tertiary prevention consists in patient rehabilitation after stroke, in order to recover partial or complete independence and to improve quality of life. Recovery from stroke is seldom complete and it is estimated that 40% of patients living at home after stroke need help in daily living. Probably it will be a challenge in the future to improve hospital and community rehabilitation programs in the way to give to patients a maximum independence and diminish the cost of hospitalization and disability.

What Is the Morbidity due to Stroke?

Two weeks after stroke up to 60% of patients require some assistance in daily activity. The frequency of deficits are hemiparesis (70-80%), ambulation problems (70-80%), visual perception deficits (60-75%), dysarthria (55%), depression (40%), aphasia (20 35%), dysphagia (15-35%), alteration of recent memory (10-20%).

The prognosis for functional recovery after a stroke is influenced by various clinical and medical factors.

The main predictors of stroke evolution or localization and type of stroke as well as the time from the onset of its first manifestations to the arrival at hospital, and the type of medical care, including stroke unit, stroke team, stroke pathway. It has been shown that a well-determined clinical pathway for patients with nonhemorrhagic stroke improved the quality of care and functional recovery.

Social support also seems to be associated with faster and more extensive recovery of functional disability after stroke. Socially isolated patients may be at a particular risk for poor outcome. The other factors which determine functional recovery and duration of hospital are age, sex, severity of the initial deficit, etiology and localization of stroke. A majority of first ischemic stroke survivors having access to a rehabilitation service return home (84%), but only a few return to work.

Is There Any Secular Trend in Stroke and in Death-Related Stroke?

The annual overall incidence of stroke is estimated at 127,000 in Germany, 112,000 in Italy, 101,000 in UK, 89,000 in Spain and 78,000 in France.

In Japan which had the highest stroke rate in the 1970s, there has been a dramatic decline in stroke incidence during these last years (7%/year).

Death related to stroke is declining in many countries (Finland, Sweden, France, Spain) and in both sexes. The Scandinavian countries (Norway, Sweden, Denmark).

The Netherlands and Switzerland have the lowest rates (38/100.000/year to 47/100.000/year). However, in eastern European countries (Russia, Bulgaria, Hungary, etc.) the rate of stroke mortality is still high (176/100,000/year to 249/1,000,000/year) and may even be currently increasing.

What Are the Costs of Stroke?

Stroke is mainly a disease of the elderly, although 15% of the patients may be younger than 45-50 years. With an aging population, the costs of stroke will increase in the future. It has been estimated that approximately 50% of the costs of the first years are due to hospital stay. Two studies have estimated the costs of the first stroke. A Swedish study showed that the lifetime costs directly related from first stroke to death in 1991 were USD 30,000 per patient. The indirect annual costs were estimated to USD 405 million, which represented 24% of the costs of stroke. It should be pointed out that the indirect costs are difficult to evaluate, so this result must be interpreted with caution. A Dutch study showed that the direct lifetime cost per patient, from first stroke to death, was USD 43,990 for women and USD 37,630 for men in 1991. The difference between women and men was due to the higher risk for women to be discharged to a nursing home, which was the major cost component for the lifetime costs. Stroke accounted for 4% of the total healthcare in the Netherlands.

High Blood Pressure

Aphasia, Left Hemiparesis and High Blood Pressure

A 64-year-old patient is found aphasic in his bed at home. Physical examination shows a left hemiparesis and a blood pressure at 210/125 mm Hg. What would you do?

  1. Inject slowly dihydralazine, 6.25 mg i.v., and then hospitalize the patient?
  2. Hospitalize the patient immediately?

Blood pressure is abnormally elevated in some 70-80% of patients with acute stroke [Cruickshank et al., 1987]. Several mechanisms may be responsible for this phenomenon. They include activation of the sympathetic nervous system secondary to the brain damage and the ensuing impaired autoregulatory vasodilatation, and decreased perfusion in the ischemic border zone of the cerebral lesion [Powers, 1993]. Preexisting hypertension is a strong predictor of elevated blood pressure during the acute phase of stroke. Patients with increased blood pressure after stroke are at higher risk for early mortality, but the severity of hypertension on admission and the clinical outcome are not related. In most cases, the occurrence of hypertension after stroke does not allow correlation of the elevated blood pressure to a well-defined localization of the brain damage. In patients with ischemic stroke, worsening of neurological deficits may occur if blood pressure is lowered too drastically during the first few days after the event. This is mainly because cerebral autoregulation in the border zone of the cerebral infarct is impaired. Cerebral blood flow can therefore become insufficient if blood pressure is lowered below a critical level. Blood pressure often reaches very high levels immediately following intracerebral hemorrhage. It is tempting to try to restore blood pressure to previous levels in this condition, to avoid early rebleeding, but, as with acute ischemic stroke, it is recommended that cautious lowering of blood pressure be carried out only in patients with extreme hypertension. The natural tendency is for elevated blood pressure to decline within a few days after stroke. Therefore the risk of causing harm by pharmacological lowering of blood pressure, together with the lack of evidence ofassociative benefit, suggests that it is wise not to treat high blood pressure during the acute phase of stroke, unless there an comorbid conditions that could require antihypertensive treatment.

References
Cruickshank JM. Thorp JM. Zacharias FJ: Benefits and potential harm o: lowering high blood pressure. Lancet 1987;i:581–583.
Powers WJ: Acute hypertension after stroke: The scientific basis for treatment decisions. Neurology 1993,43:461–467.

High Blood Pressure, Otherwise Symptomless

A symptomless 75-year-old woman is seen on several visits with a blood pressure of 170 to 190 mm Hg for systolic and 70 to 85 mm Hg for diastolic. The patient is not overweight and there is no evidence of target organ damage. Routine laboratory tests including plasma cholesterol and glucose levels are normal. What would you do?

  1. Leave the patient untreated?
  2. Initiate antihypertensive treatment?

With aging central arteries progressively stiffen. This is reflected by an age-related disproportionate increase in systolic over diastolic blood pressure and, consequently, by a rise in pulse pressure [Safar et al., 1996]. Isolated systolic hypertension, as defined in the elderly by a systolic blood pressure > 160 mm Hg and a diastolic blood pres-sure < 95 mm Hg, has a high prevalence among aged people (more than 25% among patients aged 80 years or, older) [Staessen et al., 1990]. Noteworthy, the pulsatile component of blood pressure is an important predictor of cardiovascular risk, particularly for left-ventricular hypertrophy and ischemic heart disease [Darne et al., 1985 Madhavan et al., 1994]. It is now well established that elderly patients with isolated systolic hypertension benefit from antihypertensive therapy. Thus, in the SHEP trial (Systolic Hypertension in the Elderly Program), active treatment for 5 years with a diuretic and/or a betablocker reduced the total rate of stroke and myocardial infarction by 35% and 27% (p<0.05 vs. placebo), respectively [SHEP Cooperative Research Group, 1991]. This double-blind trial included 4,736 patients aged 60 years or more with a systolic blood pressure ranging from 160 to 219 mm Hg and a diastolic blood pressure below 90 mm Hg. Very recently, another placebo-controlled trial involving 4,695 patients (>60 years) with isolated systolic hypertension (systolic blood pressure comprised between 160 and 219 mm Hg with a diastolic blood pressure lower than 95 mm Hg) confirmed the preventing effect of a calcium antagonist-based treatment (nitrendipine, with the possible addition of an ACE inhibitor and a diuretic if needed) [Staessen et al., 1997]. The active treatment reduced the total rate of stroke by 42% (p< 0.003) and that of myocardial infarction by 26% (n.s.). This trial was interrupted prematurely because an interim analysis showed a significant benefit for the prevention of stroke. References Dame B, Gired X, Safar M, Cambien F, Guise L: Pulsatile versus steady component of blood pressure: A cross-sectional analysis and a prospective analysis on cardiovascular mortality. Hypertension 1989:13:392 400. Madhavan S. Ooi WL. Cohen H, Alderman MH: Relation of pulse pressure and blood pressure reduction to the incidence ol' myocardial infarction. Hypertension 1994:23:395 401. Safar ME. Cloarec-Blanchard L, London GM: Arterial alterations in hypertension with a disproportionate increase in systolic over diastolic pressure. J Hypertens 1996:14(suppl 2):103–110. SHEP Cooperative Research Group: Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991:265:3255–3264. Staessen J, Amery A. Fagard R: Isolated systolic hypertension in the elderly. J Hypertens 1990:8:3255–3264. Staessen JA. Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, Bulpitt C. de Leeuw PW. Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C. O'Brien ET. Rosenfeld J. Rodicio JL. Tuomilento G, Zanchetti A. for the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators: Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997,350:757–764.

Progressive Decline in Cognitive Function

A progressive decline in cognitive function has been observed in a 72-year-old man. The patient still lives with his wife at home, his capacity for independent activity being sufficiently preserved. The patient has no complaint. His blood pressure is found repeatedly at around 170/lOOmmHg. What would you do?

  1. Leave the patient untreated?
  2. Initiate antihypertensive treatment?

A relation between hypertension and low cognitive function has been shown in case-control studies involving elderly patients [Battersby et al. 1993; Kaira et al. 1993], but it is still unknown whether antihypertensive treatment slows down the progression of cognitive decline. One might have the concern that lowering blood pressure may cause insufficient cerebral perfusion. thereby impairing cerebral perfusion and possibly deteriorating cognitive function. This concern seems, however, not justified since antihypertensive treatment in elderly patients with isolated systolic hypertension does not increase the incidence of dementia while having a marked beneficial effect in terms of stroke and myocardial infarction prevention. During the course of the SHEP trial. 1.6% of patients allocated to the active treatment had a diagnosis of dementia, as compared with 1.9% in patients allocated to placebo [SHEP Cooperative Research Group, 1991].

References
Battersby C. Hartley K, Fletcher AE, Markowe HJL, Brown RG. Styles W: Cognitive function in hypertension: A community based study. J Hum Hypertens 1993;7:117–123. Kaira L. Jackson SHD. Swift CG: Psychomotor performance in elderly hyper-tensive patients. J Hum Hyperlens 1993:7:279-284.
SHEP Cooperative Research Group: Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: Final results of’ the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991;265:3255–3264.

Stenosis at the Left Carotid Artery

A 68-year-old man is seen repeatedly with a systolic blood pressure comprised between 170 and 185 mmHg and a diastolic blood pressure between 90 and 100 mmHg on both arms. His heart rate is regular, at 70 beats/min. The cardiac auscultation is normal, but there is a systolic murmur on the left carotid artery. A Duplex ultrasonography displays an 80%i stenosis at the level of the left common carotid artery. What would you do?

  1. Initiate antihypertensive therapy and prescribe aspirin?
  2. Initiate antihypertensive therapy and consider a carotid endarterectomy?

This patient exhibits an asymptomatic arteriosclerotic disease of the carotid artery. This is a common finding, particularly in the elderly. Up to 30% of people aged over 50 years show some ultrasonographic evidence of carotid stenosis [Bornstein and Norris 1992]. The degree of stenosis has been estimated at 80%. The probability for this patient to develop an ipsilateral stroke is rather low since an annual rate of stoke of about 2.5%i is expected in patients with at least 75-80% stenosis [Norris et al., 1991; Hennerici el al., 1987]. In a recent study, 1,662 patients with an asymptomatic carotid artery stenosis greater than 60%) were randomized to medical treatment (aspirin, 325 mg/day) or carotid endarterectomy [Executive Committee for the ACAS, 1995]. The relative risk of stroke was reduced by 54%; during the mean observation period of 2.7 years, in patients subjected to endarterectomy [Executive Committee for the ACAS, 1995]. It should be kept in mind that correlations between ultrasonographic and arteriographic measurements re-main imprecise [Riles et al., 1992]. Carotid arteriography is therefore still needed in the preoperative evaluation of patients who could, like the patient presented here, benefit from an endarterectomy. The patient described above is hypertensive and should be treated with blood pressure lowering, drugs. Because of the occlusive carotid disease a concern might be to lower systemic blood pressure too much and, thereby, to increase the risk of ischemic attack on the side of the carotid stenosis [Dobkin. 1989]. It appears therefore wise to avoid overtreatment. In this respect it is important to ensure that the patient will not develop orthostatic hypotension.

References
Bornstein NM. Norris JW: Management of patients with asymptomatic neck bruits and carotid stenosis. Neurol Clin 1992:10:269–280. Dobkin BH: Orthostatic hypotension as a risk factor for symptomatic occlusive ccrcbrovascular disease. Neurology 1989:39:30–34.
Executive Committee for the ACAS: Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995:273:1421–1428.
Hennerici M, Hulsbomer HB. Hefter H. Lammerts D. Rautcnberg W: Natural history of asymptomatic extracranial arterial disease: Results of a long-term prospective study. Brain 1987:110:777–791.
Norris JW. Zhu CZ. Bornstein NM. Chambers BR: Vascular risks of asympto-matic carotid stenosis. Stroke 1991:22:1485–1490.
Riles TS. Eidelman EM, Litt AW. Pinto RS. Oldford F, Schwartzenberg GW: Comparison of magnetic resonance angiography, conventional angiography, and duplex scanning. Stroke 1992,23:314–346.

20-Year-Old History of Hypertension

A 72-year-old survivor is seen 2 weeks after release from the hospital. There is no neurological deficit any-more. Blood pressure is at 170/100 mm Hg in both upright and supine posture. The patient has a past history of hypertension and has been on antihypertensive therapy for the last 20 years. What would you do?

  1. Prescribe a blood pressure lowering drug?
  2. Leave the patient untreated as long as he is asymptomatic?

Antihypertensive drug treatment is very effective in preventing the occurrence of stroke [Collins et al.. 1990]. A major issue remains, however, whether pharmacological treatment of hypertension is beneficial for hypertensive patients who have already suffered from stroke or transient ischemic attack, i.e. patients particularly prone to suffer from a new stroke. This question was addressed in a recent meta-analysis of 9 controlled trials which assessed the effect of antihypertensive treatment on the recurrence of stroke in patients with prior history of stroke or transient ischemic attack [Gueyffier et al.1997]. The occurrence of a new stroke, either fatal or nonfatal, was significantly reduced (p< 0.001) in treated patients compared with untreated controls, with a relative risk of 0.72 (95% confidence interval: 0.61-0.85). It appears therefore justified to normalize blood pressure with anti-hypertensive medications in hypertensive stroke survivors. References Collins R, Peto R, MacMahan S, Hebert P, Fiebach NH, Eberlein KA. Godwin J, Qizilbash N. Taylor JO, Hennekens CH: Blood pressure, stroke and coronary heart disease. 2. Short-term reductions in blood pressure: Overview of randomized drug trials in their epidemiological context. Lancet 1990: 335:827–838. Gueyffier F, Boissel J-P, Boutitie F. Pocock S. Coope J, Cutler J. Ekbom T, Fagard R, Friedman L. Kcrlikowske K. Perry M. Princas R. Schron E: Effect of antihypertensive treatment in patients having suffered from stroke: Gathering the evidence. Stroke 1997:28:2557–2562.

Diabetes and Stroke

Does Diabetes Increase the Risk of Stroke?

Diabetes is a prominent risk factor for ischemic but not hemorrhagic stroke. It is responsible for 7% of deaths in stroke patients. Several large population studies have shown an increase in the prevalence of stroke in the diabetic population and in people with glucose intolerance. There is an increased relative risk in females compared to male diabetics and the greatest relative risk is in the fifth and sixth decades, decreasing thereafter. Females with diabetes lose the ‘protection’ of their sex, and the prevalence of stroke is equally high in male and female diabetics. The relative risk is increased on average by 2-to 4-fold in the diabetic population, but it varies depending on the population studied. The type and distribution of stroke in diabetic patients is not significantly different from that in nondiabetics. Lacunar infarcts caused by small ischemic lesions in the deep regions of the brain and brainstem caused by occlusion of small penetrating branches of major cerebral arteries occur more frequently in patients with diabetes and hypertension, but the role of isolated diabetes is controversial. There is an increased prevalence of diabetes among patients with intracranial vertebral, proximal middle cerebral and intracranial carotid artery atheromatous disease. On the other hand. extracranial carotid artery disease may not be a major cause of cerebral ischemia in diabetics, and only 28% of diabetics with a cerebral ischemic event have significant (> 50%) carotid stenosis.

Is Stroke More Severe in Diabetic Patients?

Several studies have shown an increase in short- and longterm morbidity and mortality in diabetics or glucose-intolerant patients who have had a stroke. The increased morbidity may be related to the admission glucose level (> 6.6 mmol/1); hyperglycemia has been proposed to worsen stroke severity and the effects of hyperglycemia seem to be independent of the degree of atherosclerosis. In animal studies, acute hyperglycemia preceding cerebral ischemia and chronic hyperglycemia increases histological brain damage and leads to a worse outcome. The mechanisms explaining the deleterious effects of hyperglycemia may be the production of lactic acid from glucose under hypoxic conditions resulting in cerebral intra- and extracellular acidosis and damage to neurons, glial cells and vascular tissue; alternatively, hyperglycemia may inhibit the reuptake of the neurotransmitters glutamate and aspartate which are both excitory and neurotoxic and which may eventually cause neuronal death. The development of intracranial atheroma in large, medium and small arteries as well as in arterioles and even capillaries results in poor collateral circulation, which, along with the chronic impairment of cerebral blood flow and autoregulation, contributes to poor outcome of strokes. The long-term outcome may also be less favourable in diabetics. Functional recovery, return to work, and 5-year mortality have all been shown to be negatively influenced by diabetes.

Does Diabetes Lead to an Early Occurrence of Stroke?

Although this question cannot be answered from population studies, available information suggests that it is not the case. Indeed, 90%i of diabetics have noninsulin-dependent type II diabetes, which occurs for the vast majority of them after 50 years of age. As a matter of fact, as in nondiabetic patients, age is the main risk factor for stroke in the diabetic population. In insulin-dependent type I patients, however, it is likely that stroke occurs at an earlier age compared to nondiabetics. In a study of 448 diabetics dying under t age of 50, 7% died of stroke. Furthermore, a Swedish population study suggested that the stroke rate is more frequent in diabetics compared to nondiabetic patients at all ages between 35 and 74; 76% of the patients suffering from strokes in the 35- to 44-year age group had insulin-dependent diabetes. Cerebral blood flow in response to vasodilating stimuli may also play an important role.

Are There Any Differences in the Frequency and Severity of Stroke in Type I and Type II Diabetic Patients?

In patients with type I insulin-dependent diabetes mellitus. the frequency of stroke and death from stroke is lower than in patients with noninsulin-dependent diabetes mellitus. However, few data are available to answer this question precisely. The increased risk in type II diabetics may be related to their higher prevalence of other risk factors, such as hypertension, hyperlipidemia, obesity and lack of exercise.

Is Hyperglycemia Itself a Risk Factor for Stroke?

Most studies have observed an independent association, in both men and women, of diabetes with relative risks of ischemic stroke. There is also evidence to support a positive association between the degree of glucose intolerance and an increased risk of stroke. In the prospective Honolulu Heart Study, the prevalence of thromboembolic stroke was increased in those people with a glycemia > 6.6 mmol/1 1 h after a 50-gram glucose load; in that study, however, the prevalence was just as high in those with 1-hour glucose levels between 6.6 and 8.2 mmol/1 as in those with 1-hour glucose levels > 10.5 mmol/1, suggesting a threshold effect. The postulated mechanisms for the independent association between hyperglycemia and stroke include glycosylation of tissue proteins leading to accelerated atherogenesis and enhanced thrombosis due to decreased fibrinolytic activity, increased platelet aggregation and adhesiveness, elevated levels of fibrinogen, and factors VII and VIII. Although atherosclerosis is the leading cause of cerebral ischemia in diabetics, additional factors such as chronic impairment of cerebral blood flow and cerebral autoregulation, reduced red blood cell deformability. hyperviscosity. endothelial cell dysfunction, impaired prostacyclin synthesis, and failure to increase.

What Is the Role of Other Risk Factors for Stroke Frequently Found in Diabetics in Their Increased Risk?

Patients with diabetes and particularly noninsulin-dependent diabetes have multiple risk factors for ischemic heart disease and stroke, such as hypertension, hyperlipidemia, smoking, obesity and physical inactivity. Hypertension is the strongest risk factor. The incidence of hypertension in diabetics is close to 40%, and this constitutes a major aggravating factor in this population. Hyperlipidemia, obesity and physical inactivity, although showing a more tenuous association with stroke, are even more prevalent than hypertension in the diabetic population, and are likely to further increase the risk substantially.

Can Good Metabolic Control Lead to a Decrease in the Risk of Stroke?

No information is available on this subject. Since diabetes is an independent risk factor for stroke and hyperglycemia may be deleterious, both acutely and chronically, for stroke outcome, it is reasonable to hypothesize that a good control of the blood glucose level is beneficial to decrease the risk of stroke. However, efforts to achieve a good metabolic control should be accompanied by a systematic and aggressive approach towards other risk factors.

How Can We Identify Diabetic Patients at Risk for Stroke?

Type II noninsulin-dependent diabetic patients are at increased risk for stroke compared to type I insulin-de-pendent diabetic patients. The presence of additional risk factors for stroke, such as hypertension, particularly systolic hypertension, smoking, hyperlipidemia, obesity. physical inactivity, and increasing age further increases the risk in diabetic patients. Evidence for atherosclerosis is a risk factor for stroke in diabetic patients. The presence of heart disease in diabetics increases the risk of cerebrovascular events and is a predictor of mortality after stroke. The diabetic population is at risk for carotid stenosis: asymptomatic carotid stenosis is identified in about 10-25% of diabetic patients with symptomatic atherosclerosis in other vascular beds, and in 25-40% of those undergoing contralateral carotid endarterectomy. Progression to high-grade carotid stenosis correlates with cerebrovascular events, with a TIA or stroke rate of 10.5% per year with carotid stenosis greater than 75%. Diabetes is a major risk factor for atheroma progression. TIAs occur 3 times more frequently in noninsulin-dependent diabetic patients compared to the general population. However, the association of stroke with extra-cranial carotid disease is not clear in the diabetic patient. In the only prospective study of diabetic patients, a > 50% carotid stenosis was found in 8.2% of diabetic patients compared with 0.7% of age- and sex-matched control subjects. However, only 28% of the diabetic patients with an ischemic event had significant carotid stenosis, al-though in those cases the infarct usually occurred on the side of the stenosis. Orthostatic hypotension, a common manifestation of autonomic neuropathy can also be accompanied by watershed infarction which occurs in border zones between two main arterial territories.

What Can Decrease the Risk of Stroke in Diabetic Patients?

Although data relating to this issue is lacking in diabetic patients, correction of hyperglycemia and other risk factors seems warranted. In nondiabetics, treatment o systolic and diastolic hypertension in primary prevention leads to a 36-41% reduction in the risk of stroke; cessation of smoking and promotion of a physically active lifestyle have similar effects. It is reasonable to think, although unproven, that treatment of hypertension, cessation o smoking and maintenance of an active lifestyle will also decrease the risk of stroke in diabetics. Recent trials have suggested that treatment of hyperlipidemia with HMG CoA reductase inhibitors might decrease the risk of stroke in secondary prevention trials. Subanalysis of the Scandinavian Simvastatin Survival Study (4S) showed that the relative risk of cerebrovascular events in treated diabetic; was 0.38 compared to nondiabetics, although it did no reach statistical significance. Antiplatelet therapy, although of unproven specific benefit in diabetic patients, would seem indicated in patients who have had TIAs or strokes. No study of primary prevention in the diabetic population is available.

Is the Correction of Hyperglycemia Beneficial to Decrease Stroke Severity?

Increased blood concentrations at or about the time of a brain ischemic event may worsen outcome; even mild hyperglycemia (>6.6 mmol/1) may result in increased brain damage and delayed recovery. Studies in rat showed that insulin improved functional recovery from brain ischemia, probably through its effects on glucose and lactate levels. It is thus reasonable to aim for normoglycemia by insulin treatment in diabetic patients with increased glucose levels, although there is no information on the benefit of this approach. Hypoglycemia should be avoided.

Lipids and Stroke

Does Hypercholesterolemia Contribute to the Development of Stroke?

Despite the epidemiological studies which failed to detect any relationship between total cholesterol levels in plasma and the risk of stroke in the elderly [Prospective Studies Collaboration, 1995; Neaton et al., 1992; Sacco et al., 1997], two series of evidence support a role for cholesterol in the development of stroke.

The strongest (and unquestionable) evidence that high plasma levels of total and LDL-cholesterol contribute to the development of stroke comes from two large recent interventional studies with statins (discussed in question 6). In these two studies [Scandinavian Simvastatin Survival Study Group, 1994; Sacks et al., 1996]. a statin was administered to more than 5,000 individuals who were followed prospectively for 5 years or more. Reduction in plasma LDL-cholesterol was accompanied by a profound decrease in the incidence of CAD and, unexpectedly, to a decline to the same extent of the incidence of stroke.

The second lines of evidence is provided by long-term prospective studies which have analyzed the relationship between plasma cholesterol levels and the risk of stroke [Prospective Studies Collaboration. 1995; Neaton et al., 1992; Sacco et al.. 1997; Scandinavian Simvastatin Survival Study Group, 1994] or the extension of atherosclerotic lesions in carotid arteries [Wilson et al,, 1997]. Taken together, these data provide strong evidence that an elevated plasma cholesterol level is a risk factor for the subsequent (even decades later) development of stroke.

References
Neaton JD. Blackburn H. Jacobs D, Kuller L, Lee DJ, Sherwin R, Shih J, Stamler J. Wentworth D: Serum cholesterol level and mortality findings for men screened in the Multiple Risk Factor Intervention Trial. Arch Intern Med 1992:152:1490–1500.
Prospective Studies Collaboration: Cholesterol, diastolic blood pressure, and stroke: 13.000 strokes in 450,000 people in 45 prospective cohorts. Lancet 1995.346:1647–1653.
Sacco RL, Benjamin EJ. Broderick IP, Dyken M, Easton JD, Feinhcrg WM, Goldslcin LB. Gorelick PB. Howard G. Kittner SJ. Manolio TA. Whisnant JP. Wolf PA: American Heart Association Prevention Conference. IV. Prevention and Rehabilitation of Stroke. Risk factors. Stroke 1997;28:1507–1517.
Sacks FM.Pfcffer MA. Moye LA. Rouleau JL. Rutherford JD. Cole TG. Brown L. Warnica JW. Arnold JM, Wun CC. Davis BR. Braunwald F.: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N EngI J Med 199;335;1001–1009.
Scandinavian Simvastatin Survival Study Group: Randomised trial of cholesterol lowering in 4.444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994:344:1383–13S9.
Wilson PWF, Hoeg JM. D´Agostino RB. Silhershalz H. Belanger AM, Poehlmann H. O’Leary D. Wolf PA: Cumulative effect of high cholesterol levels, high blood pressure, and cigarette smoking on carotid stenosis. N Engl J Med 1997:337:516–522.

Are Low Plasma Cholesterol Levels Associated with an Increased Risk of Hemorrhagic Stroke?

Epidemiological studies have identified various causes of death as being overrepresented in subjects with low plasma/serum cholesterol levels. One such cause is hemorrhagic stroke [Rossouw and Gotto, 1993]. In the Multiple Risk Factor Intervention Trial [Neaton et al., 1992], crude death rate from intracranial hemorrhage decreased from 0.9 per 10,000 persons/year in men with serum cholesterol levels lower than 4.1 mmol/1 to 0.6 in those with serum cholesterol levels > 6.2 mmol/1 (fig.).

Fig. Crude death rate from ischemic stroke and hemorrhagic stroke for men screened in the Multiple Risk Factor Intervention Trial [Neaton et al. 1992].

These observations have raised the hypothesis that low cholesterol levels may lead to an increased susceptibility of intracerebral arteries to shear stress, particularly in hypertensive subjects. The medical community was so concerned by this issue that the question was even raised as to whether administration of lipid-lowering therapy should be banned until the issue was resolved.

However, detailed analysis of the data indicated that the inverse relationship between low serum cholesterol levels and the risk of hemorrhagic stroke was restricted to individuals with high diastolic blood pressure. In his meta-analysis on the possible hazards of reducing serum cholesterol levels Law et al. [1994] identified an excess of risk associated with serum cholesterol levels < 5 mmol/1. However, adjustment for other risk factors was not performed in this analysis. In contrast, no increased risk of hemorrhagic stroke associated with low cholesterol concentrations in plasma was confirmed in other studies when a multivariate analysis was performed [Reed, 1990; Menotti et al., 1990].

In the prospective studies using several lipid-lowering agents such as fibrates, resins or the highly effective stat-ins, no increased risk of hemorrhagic stroke was associated with a reduction in serum cholesterol levels [Atkins et al., 1993: Hebert et al., 1995. 1997].

In summary, low cholesterol levels in serum are unlikely to lead to a fragilization of intracerebral arteries and thus to be associated with hemorrhagic stroke. Accordingly, there is no reason to limit the lipid-lowering therapy, since the risk, if any, only seems to affect those individuals with very low serum levels of cholesterol. Even in these subjects, the possible increased risk of hemorrhagic stroke will be outweighed by the benefits resulting from reducing the risk of CAD.

References
Atkins D. Psaty BM. Koespell TD, Longstreth WT Jr, Larson EB: Cholesterol reduction and the risk of stroke in men: A meta-analysis of randomized, controlled trials. Ann Intern Med 1993:119:136–145.
Hebert PR. Gaziano M. Hennckens CH: An overview of trials on cholesterol lowering and risk of stroke. Arch Intern Med 1995:155:50–55.
Hebert PR. Gaziano M. Chan KS, Hennekens CH: Cholesterol lowering with statin drugs, risk of stroke, and total mortality. JAMA 1997,278:313–321.
Law MR. Thompson SG. Wald NJ: Assessing possible hazards of reducing scrum cholesterol. Br Med J 1994:308:373–379.
Menotti A. Keys A. Blackburn H. Aravanis C. Dontas A.F’idanza F. Giampaoli S. Karvonen M. Kromhoul D, Nedeljkovic S, el al: Twenty-year stroke-mortality and prediction in twelve cohorts of the Seven Countries Study. Int J Epidemiol 1990:19:309–315.
Neaton JD. Blackburn H. Jacobs D. Kuller L. Lcc DJ. Sherwin R. Shih J. Stamler J. Wentworlh D: Serum cholesterol level and mortality findings in men screened in the Multiple Risk Factor Intervention Trial. Arch Intern Med 1992; 152:1490–1500.
Reed DM: The paradox of high risk of stroke in population with low risk of coronary heart disease. Am .1 Epidemic! 1990:131:579–588.
Rossouw JE, Gotto AM Jr: Does low cholesterol cause death? Cardiovasc Drugs Ther 1993;7:789–793.

Is Lipoprotein(a) Associated with Stroke?

Lipoprotein(a) (Lp(a)) consists of a low-density lipo-protein (LDL) particle to which is attached a unique glycoprotein called apolipoprotein(a) (apo(a)) [Utermann, 1989]. Plasma levels of Lp(a) vary over a 1,000-fold range (from 0.1 to > 100 mg/dl) between individuals and differ significantly between ethnic groups [Albers et al., 1990; Bovet et al., 1994]. Plasma levels of Lp(a) > 20-30 mg/dl have been repeatedly associated with the premature development of atherosclerosis, at least in Caucasians [Bostom et al., 1994]. In both Caucasians and African-Americans plasma levels of Lp(a) arc highly heritable and are mostly determined by sequences at the apo(a) locus [Mooser et al., 1997].

In a large number of cross-sectional studies, plasma levels of Lp(a) have been shown to be higher in subjects with stroke as compared to controls [Stein and Rosenson, 1997]. A link between Lp(a) and atherosclerotic stroke has been confirmed in most if not all studies which have prospectively examined whether subjects with high Lp(a) levels at the time of initiation had a higher risk of developing stroke. However, the link between high plasma levels of Lp(a) and stroke may not be as strong as for CAD [Cremer et al., 1995; Nguyen et al., 1997]. In addition, in a randomly selected cohort of 855 individuals aged 40-79 years, Lp(a) emerged as a strong independent predictor for stenotic as well as nonstenotic carotid atherosclerosis (odds ratio =4.9 and 2.2, respectively) [Willeit et al., 1995].

In conclusion, Lp(a) can be considered as an independent risk factor for carotid atherosclerosis as well as for stroke. Quantification of plasma Lp(a) levels may help identify individuals at higher risk of developing carotid atherosclerosis and thus stimulate the implementation of preventive measures.

References
Albers JJ. Marcovina SM. Lodge MS: The unique lipoprotein(a): Properties and immunochemical measurement. Clin Chem 1990:36::2019–2026.
Bostom AG. Gagnoil DR. Cupples LA. Wilson PW. Jenner JL. Ordovas JM, Schäefer EJ, Castelli WP: A prospective investigation of elevated lipoprotein(a) detected by electrophoresis and cardiovascular disease in women: The Framingham Heart Study. Circulation 1994;90:1688–1695.
Bovet P. Rickenbach M. Wietlisbach V, Riesen W, Shamlaye C. Darioli R, Uurnand B: Comparison of scrum lipoprotein(a) distribution and its correlates among black and white populations. Int J Epidemiol 1994:23:20–27.
Cremer P. Nagel D. Mann H, et al: Ranking of’ Lp(a) as a cardiovascular risk factor: Results from a 10-year prospective study: in Woodford FP, Uavignon J. Sniderman A (eds): Atherosclerosis X. Amsterdam, Elsevier, 1995, pp 903–907.
Mooser V, Scheer D, Marcovina SM, Wang J, Guerra R, Cohen J, Hobbs HH: The apo(a) gene is the major determinant of variation in plasma Lp(a) levels in African-Americans. Am J Hum Genet 1997:61:402–417.
Nguyen TT. Elletson RD. Hodge DO, Bailey K.R. Kottke TE. Abu Lebdeh HS: Predictive value of electrophoretically detected lipoprotein(a) for coronary heart disease and cerebrovascular disease in a commonly-based cohort of 9,936 men and women. Circulation 1997:96:1390–1397.
Stein JH. Rosenson RS: Lipoprotein Lp(a) excess and coronary heart disease. Arch Intern Med 1997:157:1170–1176. Utermann G…: The mysteries of lipoprotein(a). Science 1989:246:904–910.
Willeit J. Kiechi S. Santer P. Oberholleiv.er I-, Egger G. Jarosch E, Mair A: Lipoprotein(a) and asymptomatic carotid artery disease. Evidence of a prominent role in the evolution of advanced carotid plaques: The Bruneck Study Circulation 1995:26:1582–1587.

Are Triglycerides Associated with Stroke?

High serum levels of triglycerides represent an important risk factor for the development of atherosclerosis. The association between serum triglyceride levels and CAD has been demonstrated in univariate analysis in the Framingham Heart Study, in the Münster PROCAM study and in the Helsinki Heart Study [Castelli, 1992; Assmann and Schulte, 1992; Manninen et al., 1992]. The combination between high serum triglyceride levels and atherosclerosis may even be stronger in the presence of reduced serum HDL-cholesterol levels or elevated LDL-cholesterol concentrations, both for men and women.

Whether high triglyceride levels in serum constitute a risk factor for stroke is still a controversial issue. No association between serum triglyceride levels and stroke was found in some studies [Wolf and Kannel, 1986; Aronow et al., 1988; Sidharam, 1992], whereas other studies have identified a positive correlation for both total and ischemic stroke [Korn-Lubetzki et al., 1992; Robinson et al., 1963; Lindenstrom et al., 1994]. In the Copenhagen City Heart Study [Robinson et al., 1963], a log linear association was observed between serum triglyceride levels and nonhemorrhagic stroke, irrespective of age and sex. However, whether this association was due to high triglyceride levels per sc or to metabolic abnormalities frequently encountered in the presence of hypertriglyceridemia like diabetes or obesity of heavy alcohol consumption, conditions which promote the development of stroke, is not known.

In conclusion, although high serum triglyceride levels play an important role in the development of atherosclerosis, the evidence is not so strong that hypertriglyceridemia represents an independent risk factor for stroke. However, hypertriglyceridemia may reflect a cluster of other risk factors for stroke.

References
Aronow WS, Gutstein H, Lee NH. Edwards M: Three-year follow-up of risk factors correlated with new atherothrombotic brain infarction in 708 elderly patients. Angiology 1988:39:563–566.
Assmann G. Schulte H: Role of triglycerides in coronary artery disease: Lessons from the Prospective Cardiovascular Münster Study. Am J Cardiol 1992; 70:10H 13H.
Castelli WP: Epidemiology of triglycerides: A view from Framingham. Am J Cardiol 1992:7;3H–9H.
Korn-Lubetzki 1. KIeinman Y, Eliashiv S, Eliakim M: Correlation between serum lipids and stroke in an Israeli population. Neurol Res 1992;14(suppl2): 78–80.
Lindenström E. Royscn G. Nyboe J: Influence of total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease: The Copenhagen City Heart Study BMJ 1994:309:11–15.
Manninen V. Tenkancn L. Koskinen P. IIutlunen JK.. Mänttäri M, Heinonen OP, Frick MH: Joint effect of serum triglycerides and LDL-cholesterol and HDL-cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study Circulation 1992:85:37–45.
Robinson RW. Higano N, Cohen WD: Comparison of serum lipid levels in patients with cerebral thrombosis and in normal subjects. Ann Intern Med 1963:59:180-185. Sidharam R: Risk factors for ischemic stroke: A case control analysis. Neuroepidemiology 1992:11:24–30.
Wolf PA, Kannel WB: Reduction of stroke through risk factor modification. Semin Neurol 1986:6:243–253.

Do Low Serum HDL-Cholesterol Levels Constitute a Risk Factor for Stroke?

HDL particles promote the transport of extrahepatic cholesterol back to the liver. A reduction in the ‘reverse: cholesterol transport’ has been proposed as a mechanism ‘ to account for the strong relationship between low HDL-; cholesterol levels and CAD. However, whether the activity : of the reverse cholesterol transport correlates to HDL-cholesterol levels remains to be established. The predictive power of low HDL-cholesterol concentrations in serum for CAD, independently of other risk factors, has been well demonstrated in numerous epidemiological studies involving various populations [Gordon el al., 1997; Gordon et al., 1986; Assmann and Schulte, 1992; Pocock et al., 1989]. In most case-control studies, HDL-cholesterol level have been found to be inversely correlated with the risk of stroke [Qizibash et al., 1992].

In the prospective Copenhagen City Heart study [Lindenstrom et al., 1994], for instance, a significant negative log linear association was obtained, both for men and women, between serum HDL-cholesterol levels and the risk of nonhemorrhagic stroke (relative risk =0.53). In the recently published 21-year prospective Israeli Ischemic Heart Study involving 8,586 men [Tanne et al., 1997], men at the lower fertile of HDL-cholesterol levels in plasma experienced a 1.3-fold increase in covariate-adjusted mortality due to is-chemic stroke as compared to individuals with HDL-cholesterol at the upper fertile. These data arc in contrast with those from the Framingham Study, in which low HDL-cholesterol levels were not associated with an increased risk of ischemic stroke [Gordon et al., 1981].

To summarize, strong evidence has been accumulated to recognize low HDL-cholesterol levels as a significant and independent risk factor for stroke. Conversely, high serum levels of HDL-cholesterol appear to have a protective effect not only for CAD, but also for ischemic stroke.

References
Assmann G. Schulte H: Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience).
Am J Cardiol 1992:70:733–737. Gordon DJ (for the Lipid Research Clinics Program): High density lipoprotein cholesterol and coronary heart disease in hypercholesterolemic men: The Lipid Research Clinic’s Coronary Primary Prevention Trial.
Circulation 1986:74:1217–1225. Gordon T. Castelli WP. Hjortland MC, Kannel WB. Dawber TR: High density lipoprotein as a protective factor against coronary heart disease: The Framingham Study Am .1 Med 1977:62:707–714.
Gordon T. Kannel WB. Castelli WP, Dawber TR: Lipoproteins, cardiovascular disease and death: The Framingham Study. Arch Intern Med 1981,141: 1128–1131.
Lindenstrom L, Boysen G. Nyboe J: Influence of total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease. The Copenhagen City Heart Study. BMJ 1994:309:11–15.
Pocock SJ. Shaper AG. Phillips AN: Concentrations of high density lipoprotein cholesterol, triglycerides, and total cholesterol in ischaemic heart disease. BrMed J 1989:298:998–1002.
Qizilbash N. Duffy JW. Warlow C, Mann J: Lipids are risk factors for ischemic stroke: Overview and review. Cerebrovasc Dis 1992:2:127–136.
Tanne D. Yaari S. Goldbourt U: High-density lipoprolcin cholesterol and risk of ischemic stroke mortality: A 21-year follow-up of 8,586 men from the Israeli Ischemic Heart Disease Study. Stroke 1997:28:83–87.

Does Diabetes Increase the Risk of Stroke?

Until recently, treatment of elevated serum (LDL)-cholesterol levels was thought to be of minor benefit in reducing the risk of stroke. Indeed, in an overview of randomized trials that included more than 36,000 individuals, no significant reduction in the incidence of fatal and nonfatal strokes was observed (odds ratio = 1.1 and 1.0, respectively), despite a 6-23% decrease in serum total cholesterol levels obtained through dietary modifications or administration of fibratcs or resins [Atkins et al., 1993; Heberl ct al., 1995]. These conclusions have been challenged since the introduction of HMG-CoA reductase inhibitors (statins). Over the last 5 years, 13 different trials [Blauw et al., 1997; Grouse et al., 1997; Hebert et al., 1997], including three major intervention studies have been reported where statins had been administered in primary (WOSCOPS) [Shepherd el al., 1995] or secondary prevention (4S [Scandinavian Simvastatin Survival Study Group, 1994] and CARE [Sacks et al., 1996]). As shown in the figure, administration of statins led to a dramatic 31% reduction in all strokes, an effect which, in relative terms, was similar to the effect on the incidence of CAD.

Fig. Stroke, statins, and cholesterol: A meta-analysis of randomized, placebo-controlled, double-blind trials [Blauw et al., 1997].

The most striking effect was observed in 4S and in CARE studies, whereas the reduction in the incidence of stroke was not significant in the WOSCOPS study. A possible explanation for these discrepancies is that most if not all subjects included in secondary prevention trials suffered from extensive atherosclerotic disease, whereas the proportion of subjects with atherosclerosis was low in the primary prevention trial.

The availability of statins undoubtedly constitutes a major breakthrough in the prevention of CAD and strokes. Statins are more potent and have fewer side effects than the other lipid-lowering agents. Statins appear to lower the incidence of stroke predominantly in subjects with CAD with high, or even moderate serum cholesterol levels (<6.2 mmol/1). These benefits are partly attributed to the effects of statins on the progression and plaque stabilization of coronary as well as extracranial atherosclerosis. However, it must be emphasized that presently there is no available study on lipid-lowering in patients with prior stroke or TIA. While no information is available on the beneficial effect of statins in secondary prevention of stroke, large studies, including the Oxford Cholesterol Study [Keech et al., 1994], are underway to delineate the effect of statins in this indication. In conclusion, interventional trials using statins have clearly demonstrated the beneficial effect of cholesterol-lowering therapy on both cardiac and cerebrovascular ischemic diseases. Furthermore, these studies have shed some new light on the role of cholesterol in the development of stroke. References Atkins D. Psaly BM. Kocspell TD. Longstreth WT Jr, Larson EB: Cholesterol reduction and the risk of stroke in men: A meta-analysis of randomized controlled trials. Ann Intern Med 1993:119:136–145. Blauw G. Lagaay AM. Smelt AHM. Westendorp RG; Stroke, statins and cholesterol. A meta-analysis of randomized, placebo-controlled, double-blind trials with HMG-CoA-reductasc inhibitors. Stroke 1997:28:946–950. Crouse JR, Byington RP, Hoen HM, Furberg CD: Reductase inhibitor mono-therapy and stroke prevention. Arch Intern Med 1997:157:1305–1310. Hebert PR. Gaziano JM. Hennekens CH: An overview of trials on cholesterol lowering and risk of stroke. Arch Intern Med 1995:155:50–55. Hebert PR. Gaziano JM. Chan KS. Hennekens CH: Cholesterol lowering with statin drugs, risk of stroke, and total mortality. JAMA 1997:278:313–321. Keech A. Collins R, McMahon S. for the Oxford Cholesterol Study Group: Three-year follow-up of the Oxford Cholesterol Study: Assessment of the efficacy and safely of simvastatin in preparation for a large mortality study. Eur Heart J 1994:15:255–269. Sacks FM. Pfeffer MA. Moye LA. Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW. Arnold JM. Wun CC, Davis BR. Braunwald E: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N EngI J Med 1996:335:1001–1009. Scandinavian Simvastatin Survival Study Group: Randomized trial of cholesterol lowering in 4.444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994:344:1388–1389. Shepherd J. Cobbe SM. Ford I. Isles CG. Lorimer AR. MacFarlanc PW, McKil-lop JH. Packard CJ: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N EngI J Med 1995,333:1301–1307. [/et_pb_toggle][et_pb_toggle admin_label="Toggle" title="Which Lipid Parameters Should Be Measured in Primary and Secondary Prevention of Stroke?" open="off" use_border_color="off" border_color="#ffffff" border_style="solid" disabled="off"] Since a large proportion of strokes are due to atherosclerotic processes, more attention is needed to identify subjects at high risk of developing cardiovascular events. In Europe and other countries, guidelines recommend a global multifactorial assessment and management of cardiovascular risks [Pyorala et al., 1994]. Estimation of the overall risk of developing a cardiovascular event is based on: (a) the identification of nonmodifiable cardiovascular risk factors: age, sex, ethnicity, family and personal history of CAD and other atherosclerotic vascular disease; (b) the characterization of modifiable cardiovascular risk factors: cigarette smoking, poor dietary habits, physical inactivity; (c) the quantification of risk factor levels: body mass index, blood pressure, plasma lipid levels. Plasma or serum total cholesterol level may be determined on a venous sample drawn in a nonfasting state. However, in many instances, it is advisable to complete the lipid profile and measure HDL-cholesterol and triglyceride levels in a fasting state (plasma LDL-cholesterol is usually calculated using the Friedewald formula). This should be done in priority in: (a) individuals with established CAD or other atherosclerotic vascular disease; (b) asymptomatic subjects with a major cardiovascular risk factor (diabetes, hypertension) and those with a cluster of several risk factors; (c) close relatives of subjects with premature CAD; or other atherosclerotic vascular disease. Currently, the measure of Lp(a) has not been introduced in clinical practice [Pyorala et al., 1994]. Quantification of serum levels of Lp(a) should be reserved for individuals with premature CAD or other atherosclerotic vascular disease, those with familial hypercholesterolemia and those with a very high risk of developing CAD [Rader, and Brewer, 1992; Wilson and Kannel. 1997]. In conclusion, determination of the lipid profile (total cholesterol, triglycerides and HDL-cholesterol levels) is recommended in primary and secondary prevention of stroke as being part of the global assessment of cardiovascular risk. References Pyorala K. De Backer G. Poole-Wilson P. Wood D: Prevention of coronary heart disease in clinical practice: Recommendations of the Task Force of the European Society of Cardiology, European Atherosclerosis Society and European Society of Hypertension. Atherosclerosis 1994,110:121–161. Rader SJ. Brewer HB Jr: Lipoprotein(a): Clinical approach to a unique athero- genic lipoprotein. JAMA 1992:267:1109–1 III. Wilson PW. Kannel WB: Should we measure lipoprotein Lp(a)? Arch Intern Med 1997.157:1161–1162. [/et_pb_toggle][et_pb_toggle admin_label="Toggle" title="Do the Elderly and Women also Benefit from Lipid-Lowering Therapy?" open="off" use_border_color="off" border_color="#ffffff" border_style="solid" disabled="off"] Cardiovascular diseases represent the leading cause of morbidity and mortality in Western countries, for men as well as for women. Despite the fact that 3 of 4 cardiovascular deaths occur in subjects aged 65 or older, only a few clinical trials have focused on the effect of lipidlowering therapy in older subjects or in women [Beaglehole, 1991; Kashyap, 1989]. Fortunately enough, the 4S, CAR E and the PAIP (Pravastatin Atherosclerosis Intervention Program) studies have all included women and subjects aged 60 or more to determine whether statins would reduce the risk of cardiovascular events, including stroke [Scandinavian Simvastatin Survival Study Group, 1994; Sacks et al., 1996; Byington et al.. 1995]. These studies have clearly established that statins are beneficial for both women and elderly. Indeed, the risk reduction for stroke reached 87% in the PAIP study. Based on results from the CARE study, the number of clinical cardiovascular events prevented by treating 1,000 individuals for 5 years is shown in the table. Table. Clinical cardiovascular events prevented by treating 1,000 patients for 5 years

Events Number of events prevented
total group age > 60 years women
Fatal CHD 11 27 10
Clinical myocardial infarction 26 46 83
Stroke/TIA 13 25 28
All cardiovascular events 150 207 228

CARE Study: n=4.159 patients (F= 14%) with previous myocardial infarction. total cholesterol <6.2 mmol/1, randomized, double-blind. placebo-controlled trial; follow-up =4.0-6.2 years; therapy = placebo or pravastatin (40 mg/day). In conclusion, despite the restricted number of clinical trials presently available, subjects over 60 years and women may benefit to an even greater extent than the general population to statin therapy, even when their total cholesterol level is below 6.2 mmol/1. References Beaglehole R: Coronary heart disease and elderly people. BM.I 1991:303:69-70. Byington RP, Jukema W. Salonen JT. Pitt B. Bruschke AV. Hoen H. Furberg CD, Mancini GB: Reduction in cardiovascular events during pravastatin therapy: Pooled analysis of clinical events of the pravastatin atherosclerosis intervention program. Circulation 1995:92:2419 2425. Kashyap RL: Cardiovascular disease in the elderly: Current considerations. Am J Cardiol 1989;63(suppl 16):3 4. Sacks KM. PleHcr MA, Moyc LA. Rouleau JL, Rutherford JD. Cole TG. Brown L. Warnica JW. Arnold JM. Wun CC. Davis BR. Braunwald E: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N EngI .1 Med 1996:335:1001 1009. Scandinavian Simvastatin Survival Study Group: Randomized trial of cholesterol lowering in 4.444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994,344:1383-1389. [/et_pb_toggle][/et_pb_column][et_pb_column type="1_2"][et_pb_text admin_label="Text" background_layout="light" text_orientation="left" use_border_color="off" border_style="solid" disabled="off"]

Diabetes and Stroke

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Does Diabetes Increase the Risk of Stroke?

Diabetes is a prominent risk factor for ischemic but not hemorrhagic stroke. It is responsible for 7% of deaths in stroke patients. Several large population studies have shown an increase in the prevalence of stroke in the diabetic population and in people with glucose intolerance. There is an increased relative risk in females compared to male diabetics and the greatest relative risk is in the fifth and sixth decades, decreasing thereafter. Females with diabetes lose the ‘protection’ of their sex, and the prevalence of stroke is equally high in male and female diabetics. The relative risk is increased on average by 2-to 4-fold in the diabetic population, but it varies depending on the population studied. The type and distribution of stroke in diabetic patients is not significantly different from that in nondiabetics. Lacunar infarcts caused by small ischemic lesions in the deep regions of the brain and brainstem caused by occlusion of small penetrating branches of major cerebral arteries occur more frequently in patients with diabetes and hypertension, but the role of isolated diabetes is controversial. There is an increased prevalence of diabetes among patients with intracranial vertebral, proximal middle cerebral and intracranial carotid artery atheromatous disease. On the other hand. extracranial carotid artery disease may not be a major cause of cerebral ischemia in diabetics, and only 28% of diabetics with a cerebral ischemic event have significant (> 50%) carotid stenosis.

Is Stroke More Severe in Diabetic Patients?

Several studies have shown an increase in short- and longterm morbidity and mortality in diabetics or glucose-intolerant patients who have had a stroke. The increased morbidity may be related to the admission glucose level (> 6.6 mmol/1); hyperglycemia has been proposed to worsen stroke severity and the effects of hyperglycemia seem to be independent of the degree of atherosclerosis. In animal studies, acute hyperglycemia preceding cerebral ischemia and chronic hyperglycemia increases histological brain damage and leads to a worse outcome. The mechanisms explaining the deleterious effects of hyperglycemia may be the production of lactic acid from glucose under hypoxic conditions resulting in cerebral intra- and extracellular acidosis and damage to neurons, glial cells and vascular tissue; alternatively, hyperglycemia may inhibit the reuptake of the neurotransmitters glutamate and aspartate which are both excitory and neurotoxic and which may eventually cause neuronal death. The development of intracranial atheroma in large, medium and small arteries as well as in arterioles and even capillaries results in poor collateral circulation, which, along with the chronic impairment of cerebral blood flow and autoregulation, contributes to poor outcome of strokes. The long-term outcome may also be less favourable in diabetics. Functional recovery, return to work, and 5-year mortality have all been shown to be negatively influenced by diabetes.

Does Diabetes Lead to an Early Occurrence of Stroke?

Although this question cannot be answered from population studies, available information suggests that it is not the case. Indeed, 90%i of diabetics have noninsulin-dependent type II diabetes, which occurs for the vast majority of them after 50 years of age. As a matter of fact, as in nondiabetic patients, age is the main risk factor for stroke in the diabetic population. In insulin-dependent type I patients, however, it is likely that stroke occurs at an earlier age compared to nondiabetics. In a study of 448 diabetics dying under t age of 50, 7% died of stroke. Furthermore, a Swedish population study suggested that the stroke rate is more frequent in diabetics compared to nondiabetic patients at all ages between 35 and 74; 76% of the patients suffering from strokes in the 35- to 44-year age group had insulin-dependent diabetes. Cerebral blood flow in response to vasodilating stimuli may also play an important role.

Are There Any Differences in the Frequency and Severity of Stroke in Type I and Type II Diabetic Patients?

In patients with type I insulin-dependent diabetes mellitus. the frequency of stroke and death from stroke is lower than in patients with noninsulin-dependent diabetes mellitus. However, few data are available to answer this question precisely. The increased risk in type II diabetics may be related to their higher prevalence of other risk factors, such as hypertension, hyperlipidemia, obesity and lack of exercise.

Is Hyperglycemia Itself a Risk Factor for Stroke?

Most studies have observed an independent association, in both men and women, of diabetes with relative risks of ischemic stroke. There is also evidence to support a positive association between the degree of glucose intolerance and an increased risk of stroke. In the prospective Honolulu Heart Study, the prevalence of thromboembolic stroke was increased in those people with a glycemia > 6.6 mmol/1 1 h after a 50-gram glucose load; in that study, however, the prevalence was just as high in those with 1-hour glucose levels between 6.6 and 8.2 mmol/1 as in those with 1-hour glucose levels > 10.5 mmol/1, suggesting a threshold effect. The postulated mechanisms for the independent association between hyperglycemia and stroke include glycosylation of tissue proteins leading to accelerated atherogenesis and enhanced thrombosis due to decreased fibrinolytic activity, increased platelet aggregation and adhesiveness, elevated levels of fibrinogen, and factors VII and VIII. Although atherosclerosis is the leading cause of cerebral ischemia in diabetics, additional factors such as chronic impairment of cerebral blood flow and cerebral autoregulation, reduced red blood cell deformability. hyperviscosity. endothelial cell dysfunction, impaired prostacyclin synthesis, and failure to increase.

What Is the Role of Other Risk Factors for Stroke Frequently Found in Diabetics in Their Increased Risk?

Patients with diabetes and particularly noninsulin-dependent diabetes have multiple risk factors for ischemic heart disease and stroke, such as hypertension, hyperlipidemia, smoking, obesity and physical inactivity. Hypertension is the strongest risk factor. The incidence of hypertension in diabetics is close to 40%, and this constitutes a major aggravating factor in this population. Hyperlipidemia, obesity and physical inactivity, although showing a more tenuous association with stroke, are even more prevalent than hypertension in the diabetic population, and are likely to further increase the risk substantially.

Can Good Metabolic Control Lead to a Decrease in the Risk of Stroke?

No information is available on this subject. Since diabetes is an independent risk factor for stroke and hyperglycemia may be deleterious, both acutely and chronically, for stroke outcome, it is reasonable to hypothesize that a good control of the blood glucose level is beneficial to decrease the risk of stroke. However, efforts to achieve a good metabolic control should be accompanied by a systematic and aggressive approach towards other risk factors.

How Can We Identify Diabetic Patients at Risk for Stroke?

Type II noninsulin-dependent diabetic patients are at increased risk for stroke compared to type I insulin-de-pendent diabetic patients. The presence of additional risk factors for stroke, such as hypertension, particularly systolic hypertension, smoking, hyperlipidemia, obesity. physical inactivity, and increasing age further increases the risk in diabetic patients. Evidence for atherosclerosis is a risk factor for stroke in diabetic patients. The presence of heart disease in diabetics increases the risk of cerebrovascular events and is a predictor of mortality after stroke. The diabetic population is at risk for carotid stenosis: asymptomatic carotid stenosis is identified in about 10-25% of diabetic patients with symptomatic atherosclerosis in other vascular beds, and in 25-40% of those undergoing contralateral carotid endarterectomy. Progression to high-grade carotid stenosis correlates with cerebrovascular events, with a TIA or stroke rate of 10.5% per year with carotid stenosis greater than 75%. Diabetes is a major risk factor for atheroma progression. TIAs occur 3 times more frequently in noninsulin-dependent diabetic patients compared to the general population. However, the association of stroke with extra-cranial carotid disease is not clear in the diabetic patient. In the only prospective study of diabetic patients, a > 50% carotid stenosis was found in 8.2% of diabetic patients compared with 0.7% of age- and sex-matched control subjects. However, only 28% of the diabetic patients with an ischemic event had significant carotid stenosis, al-though in those cases the infarct usually occurred on the side of the stenosis. Orthostatic hypotension, a common manifestation of autonomic neuropathy can also be accompanied by watershed infarction which occurs in border zones between two main arterial territories.

What Can Decrease the Risk of Stroke in Diabetic Patients?

Although data relating to this issue is lacking in diabetic patients, correction of hyperglycemia and other risk factors seems warranted. In nondiabetics, treatment o systolic and diastolic hypertension in primary prevention leads to a 36-41% reduction in the risk of stroke; cessation of smoking and promotion of a physically active lifestyle have similar effects. It is reasonable to think, although unproven, that treatment of hypertension, cessation o smoking and maintenance of an active lifestyle will also decrease the risk of stroke in diabetics. Recent trials have suggested that treatment of hyperlipidemia with HMG CoA reductase inhibitors might decrease the risk of stroke in secondary prevention trials. Subanalysis of the Scandinavian Simvastatin Survival Study (4S) showed that the relative risk of cerebrovascular events in treated diabetic; was 0.38 compared to nondiabetics, although it did no reach statistical significance. Antiplatelet therapy, although of unproven specific benefit in diabetic patients, would seem indicated in patients who have had TIAs or strokes. No study of primary prevention in the diabetic population is available.

Is the Correction of Hyperglycemia Beneficial to Decrease Stroke Severity?

Increased blood concentrations at or about the time of a brain ischemic event may worsen outcome; even mild hyperglycemia (>6.6 mmol/1) may result in increased brain damage and delayed recovery. Studies in rat showed that insulin improved functional recovery from brain ischemia, probably through its effects on glucose and lactate levels. It is thus reasonable to aim for normoglycemia by insulin treatment in diabetic patients with increased glucose levels, although there is no information on the benefit of this approach. Hypoglycemia should be avoided.

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