724
Aspiration About 28% of unilateral hemispheric stroke patients22 and 67% of those with brainstem involvement23 have dysphagia or silent aspiration. Pneumonia can lead to secondary deterioration from hypoxia and pyrexia. For prevention, patients should be fed in an upright position with food of appropriate consistency and small boluses; they should be encouraged to cough gently after each swallow and to swallow several times after each bolus.
Complications of treatment Complications of therapy are common. Examples include (a) sedation and depression induced by tranquillisers; (b) fever with adverse drug reactions; (c) inappropriate antidiuretic hormone secretion caused by carbamazepine or chlorpropamide; (d) effects of hypotensive agents in patients whose cerebral autoregulation has been impaired by stroke; and (e) haemorrhage from anticoagulants. Cardiac complications Stroke and coronary heart disease often coexist. However, stroke can affect the heart independently of an ischaemic mechanism. Non-ischaemic cardiac myofibre damage (myocytolysis) and increased cardiac enzymes (indicating cardiac damage) are common after stroke,1 although necropsy often fails to show acute coronary or cardiac ischaemic lesions. on changes Repolarisation in occur of 60-70% cerebral electrocardiography haemorrhages and in 5-17% of ischaemic strokes 24 Such changes can be induced in man and animals by administration of catecholamines, and catecholamine concentrations are often raised after a stroke.1.14 The insular cortex is involved in blood pressure regulation and contains a site of cardiac representation; stimulation of this area can induce cardiac arrhythmias .21 Insular stroke might therefore induce uncontrolled hypotension from cardiac dysfunction. Such patients and those showing acute electrocardiographic changes might be especially vulnerable to stroke extension and should be monitored closely. REFERENCES 1. Hachinski VC, Norris JW. The acute stroke. Philadelphia: FA Davis, 1985. 2. Bruce DA, Hurtig HI. Incidence, course, and significance of cerebral edema associated with cerebral infarction. In: Price TR, Nelson E, eds. Cerebrovascular diseases. New York: Raven, 1979: 191-98. 3. Norris JW, Hachinski VC. High dose steroid treatment in cerebral infarction. Br Med J 1986; 292: 21-23. 4. Poungvarin N, Bhoopat W, Viriyavejakal A, et al. Effects of dexamethasone in primary supratentorial intracerebral hemorrhage. N Engl J Med 1987; 316: 1229-33. 5. Lodder J. Hemorrhagic transformation in cardioembolic stroke. Stroke 1988; 19: 1482-84. 6. Hart RG, Easton JD. Hemorrhagic infarcts. Stroke 1986; 17: 586-89. 7. Cerebral Embolism Study Group. Immediate anticoagulation of embolic stroke: brain hemorrhage and management options. Stroke 1984; 5: 779-89. 8. Black SE, Hachinski VC, Norris JW. Seizures after stroke. Can J Neurol Sci 1982; 9: 291. 9. Gupta SR, Naheedy MH, Elias D, Rubino FA. Post-infarction seizures: a clinical study. Stroke 1988; 19: 1477-81. 10. Starkstein SE, Robinson RG, Price TR. Comparison of spontaneously recovered vs non-recovered patients with post-stroke depression. Stroke 1988; 19: 1491-96. 11. House A, Dennis M, Warlow C, Hawton K, Molyneux A. Mood disorders after stroke and their relation to lesion location: a CT study. Brain 1990; 113: 1113-24 12. Reding MJ, Orto LA, Winter SW, Fortuna IM, Di Ponte P, McDowell FH. Antidepressant therapy after stroke: a double blind trial. Arch Neurol 1986; 43: 763-65.
13. Melamed E. Reactive hyperglycemia m patients with acute stroke. J Neurol Sci 1976; 29: 267-75. 14. Myers MG, Norris JW, Hachinski VC, Sole MJ. Plasma norepinephrine in stroke. Stroke 1981; 12: 200-04. 15. Oppenheimer SM, Hoffbrand BI, Oswald GA, Yudkin JS. Diabetes mellitus and early mortality from stroke. Br Med J 1985; 291: 1015-16. 16. Helgason CM. Blood glucose and stroke. Stroke 1988; 19: 1049-53. 17. Ghandhavadi B. Hypertension after brainstem stroke. Arch Phys Med Rehabil 1988; 69: 130-37. 18. Dutha AJ, Hallenbeck JM, Kochanek P. A brief episode of severe arterial hypertension induces delayed deterioration of brain function and worsens blood flow after transient multifocal cerebral ischemia. Stroke 1987; 18: 386-95. 19. Hindfelt B. The prognostic significance of subfebrility and fever in ischemic cerebral infarction. Acta Neurol Scand 1976; 53: 72-79. 20. Busto R, Dietrich WD, Globus M, Ginsberg M. The importance of brain temperature in cerebral ischemic injury. Stroke 1989; 20: 1113-14. 21. Warlow C, Ogston D, Douglas AS. Deep vein thrombosis in legs after stroke. Part 1: incidence and predisposing factors. Br Med J 1976; i: 1178-81. 22. Barer D. The natural history and functional consequences of dysphagia after hemisphere stroke. J Neurol Neurosurg Psychiatry 1989; 52: 236-41. 23. Homer J, Massey EW, Rishi JE, Lathrop DL, Chase KN. Aspiration following stroke: clinical correlates and outcome. Neurology 1988; 38: 1359-62. 24. Oppenheimer SM, Cechetto DF, Hachinski VC. Cerebrogenic cardiac arrhythmias. Arch Neurol 1990; 47: 513-19. 25. Oppenheimer SM, Wilson JX, Guiraudon C, Cechetto DF. Insular cortex stimulation produces lethal cardiac arrhythmias: a mechanism of sudden death. Brain Res 1991; 550: 115-21.
Secondary prevention of stroke
Secondary prevention of stroke—ie, reducing stroke risk a stroke or transient ischaemic attack (TIA)—is one component of the general strategy to decrease the number of strokes in the community and their associated mortality and disability (see figure). In community studies, the risk of after
stroke after TIA is about 12% in the first year and then 7% per annum, which is seven times the risk of stroke in a
population of the same age.1 The risk in TIA patients referred to hospital is lower, probably because normal
referral bias results in a lower mean age; another factor is that a delay in being seen in hospital will exclude stroke patients during the early high-risk period when an extracranial atheromatous plaque or cardiac source of embolism may still be active and releasing emboli to the brain.2 Although about one-third of TIA patients report recurrent TIAs,2 the main aim of treatment is not to prevent these transient abnormalities but to reduce the risk of more serious vascular events, especially strokes. The risk of serious cardiac events (ie, fatal and non-fatal myocardial infarction, sudden presumed cardiac death, &c) is about the same as the risk of stroke,2 so it is logical to consider the risk of all serious vascular events—stroke, myocardial infarction, vascular death—together. These conditions have similar vascular risk factors; almost all are potentially preventable by antithrombotic drugs (except the occasional ruptured aortic aneurysm and haemorrhagic stroke); and the composite outcome of "stroke, myocardial infarction, vascular death" provides the largest number of events for precise statistical estimates. The risk of these
ADDRESS: Department of Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU, UK (Prof C. Warlow,
FRCP).
725
serious vascular events is about 9% per annum in the community, which is higher than in hospital-referred
populations.2 It is difficult to predict individual risk. People at high risk in 2 years) have most to gain from undergoing procedures such as carotid angiography and endarterectomy that may be associated with complications. These individuals should also be prescribed low-risk but effective treatments such as aspirin. In addition, low-risk therapy should be offered to moderate and lower risk patients.3 Although stroke risk can partly be predicted by the extent of carotid stenosismuch if not all of this risk is more easily predicted from a combination of age, frequency of TIAs, peripheral vascular disease, left ventricular
PERCENTAGE OF TIA AND ISCHAEMIC STROKE PATIENTS WITH VASCULAR RISK FACTORS AND DISEASES IN THE SAME COMMUNITY*
of stroke ( > 20%
hypertrophy, &c.3
Strategies for improving health by reducing the incidence of stroke and recurrent stroke and the associated mortality and disability. Modified with permission from Dennis M, Warlow CP. stroke. Br Med] 1991; 303: 636-38.
*Unpublished data from the Oxfordshire Community Stroke Project.
secondary than in primary prevention because, if the relative or proportional risk reductions attributable to treatment are the same, symptomatic patients have a much higher absolute risk of stroke than the normal population. Symptomatic vascular disease (eg, angina, claudication) should be treated on its merits. Occasionally there are specific treatable causes of TIA such as giant cell arteritis. Management of cardiogenic embolism has already been reviewed in this series (see Hart, March 7, p 589). In about 80% of patients the TIA or ischaemic stroke is due to the thrombotic and embolic complications of atheroma, or to small vessel disease of the perforating arteries of the brain (known as lipohyalinosis or microatheroma) ; for these individuals there are antithrombotic drugs and, sometimes, vascular surgery. However, the public health impact of treating TIA should not be exaggerated. Only 10-15% of stroke patients have had earlier TIAs and only about half report these events to a doctor.’ Consequently, treatment of TIA, even if it were completely successful in abolishing stroke, could not prevent
more
than about 5% of all strokes in the
community.
Strategy for
Survivors of mild ischaemic stroke have much the same risk of stroke as patients with transient cerebral ischaemia (patients with transient monocular ischaemic attacks [amaurosis fugax] have a lower risk).3.4This similarity is not surprising because TIA and stroke are distinguished according to an arbitrary 24-hour limit and not because there are any differences in underlying vascular lesions. Within stroke populations the presumed vascular abnormality, which can be partly predicted from simple clinical features, affects the risk of recurrent stroked Thus patients with restricted cortical infarcts have a high risk of recurrence (17% in the first year), perhaps because an embolic source is still active, whereas those with infarction of the entire middle cerebral artery territory, which was probably caused by occlusion of the middle cerebral artery trunk, have only a 6% risk, perhaps because further emboli to that hemisphere cannot make matters worse. Lacunar infarct patients have a 9% risk, presumably because any recurrence requires thrombotic occlusion of another small perforating artery.
General management There are no good randomised trials of risk factor modification in TIA and stroke patients. However, we can draw inferences from primary prevention studies and, at the very least, advocate control of hypertension and discourage cigarette smoking,6 both factors being common in stroke patients (see table). Absolute risk reductions are greater in
Antiplatelet drugs Numerous randomised trials have been conducted; fortunately, the investigators collaborated in a meta-analysis of all their published and some of their unpublished data.8 Long-term antiplatelet drugs reduce the risk of stroke and of other serious vascular events by about one quarter. This effect is much the same in males and females, in young and old, after TIA or ischaemic stroke, in diabetics and non-diabetics, and in patients with or without hypertension. No antiplatelet agent is clearly better than aspirin, and there is nothing as cheap or less toxic. Ticlopidine can be prescribed for patients who cannot tolerate aspirin.9 Theoretically, a daily dose of 50 mg of aspirin will inhibit platelet function after a few days, but this effect can be achieved by a single dose of 150 mg.1o Indirect trial evidence has not shown any difference in efficacy between 75 mg, 300 mg, and 1200 mg of aspirin daily.8.ll The few direct comparisons have not shown any difference between 300 and 1200 mg daily12 or between 30 and 283 mg,13 although a
small difference one way or the other may have been missed. The lower doses cause less gastric irritation.12,13 There is some concern that aspirin may cause intracranial but not in enough patients to negate the haemorrhage, of effect positive preventing thrombotic vascular events. The recommended dose is 300 mg for almost instant inhibition of platelet aggregation, followed by 75-150 mg a day, presumably indefinitely. Over 2 years, this strategy will prevent or delay a serious vascular event in about 3 of every 100
patients.9
726
Anticoagulants good evidence that the risks of oral anticoagulation outweigh any possible benefits. The There is
no
randomised trials that have been conducted were too small to be informative.14 This approach may be more promising in cardiogenic embolism (see Hart, March 7, p 589).
Carotid endarterectomy
nearly 40 years of confusion following the first carotid endarterectomy, and a near epidemic in its use, the interim results from the European Carotid Surgery Trial (ECST)is and the North American Symptomatic Carotid Endarterectomy Trial (NASCET)16 published in 1991 led to the same conclusions. For patients with a recent mild carotid-distribution ischaemic event and severe (70-99% luminal diameter) stenosis of the origin of the symptomatic internal carotid artery, the operation carries a significant risk of stroke or death, in addition to the small risk of the preceding angiography: 75% in ECST and 58% in NASCET. However, these figures cannot be generalised because the risk of surgery depend on who does the operation and where it is done. The second conclusion is generally applicable-ie, if the patient survives surgery without a stroke, the risk of ipsilateral ischaemic stroke over the next few years is almost completely abolished (16-8% in 3 years in ECST and 26% in 2 years in NASCET). Depending on local surgical risk and risk of stroke in unoperated patients, between 5 and 10 patients must be operated on to prevent 1 from having a stroke. Stroke during surgery is either due to low cerebral blood After
flow as a consequence of clamping the internal carotid artery without using a shunt in a patient with inadequate collateral blood flow, or to embolism of atherothrombotic debris or air from the operation site. Stroke hours or days later is most probably the result of a technical error at the operation site, where a loose distal intimal flap can be a source of dissection, thrombosis, or embolism. 17 18 Bleeding or oedema in the cerebral hemisphere ipsilateral to the operation is rare. Other complications include operative damage to the
hypoglossal, superior laryngeal, recurrent laryngeal, vagus, and facial nerves, which will cause difficulty in speaking or swallowing for a few weeks; ipsilateral vascular-type headache; neck haematoma; aneurysmal dilatation at the endarterectomy site; venous thromboembolism; and myocardial infarction. Early and late restenosis is increasingly recognised but seldom leads to symptoms;19we do not know whether use of a patch rather than simple closure during endarterectomy will prevent restenosis. For patients with mild stenosis (0-29%) the risk of surgery never becomes worthwhile because there are almost no strokes to be prevented (therefore, even ulceration in a non-stenosing plaque cannot be of any great importance).15 Patients with moderate stenosis (30-69%) are still being randomised in both trials because the balance of risk and benefit of carotid endarterectomy remains unclear. All patients in both trials are being followed up to assess the long-term results of sugery.
Other invasive approaches to prevention of ischaemic stroke
Theoretically, anastomosis of a branch of the external carotid artery to a cortical branch of the middle cerebral artery distal to an occlusion or stenosis of that artery, or distal to an occlusion or inaccessible stenosis of the internal
carotid artery, might reduce the risk of ipsilateral ischaemic stroke. The one large randomised trial20 did not show a reduction. Various direct and indirect surgical approaches to vertebral artery disease have been proposed, and there is some anecdotal experience of angioplasty of the extracranial arteries; these techniques have not been tested in randomised trials.
Frequent TIAs TIAs are not usually so frequent-ie, several a weekthat treatment must be prescribed to stop them and not merely to prevent stroke. Such patients should be treated quickly with aspirin. If the attacks are carotid in distribution and non-invasive ultrasound imaging shows severe stenosis of the ipsilateral internal carotid artery, angiography and possibly endarterectomy are indicated. If there is less severe stenosis, or if the attacks are vertebrobasilar in distribution, heparinisation may be helpful; heparin can be followed by warfarin for a few weeks and then lifelong aspirin. In patients with carotid occlusion or severe inoperable stenosis any antihypertensive treatment should be reviewed in case the pressure is too low and the continuing TIAs are due to low cerebral blood flow. If the attacks persist, the diagnosis of TIA should be reconsidered.
Intracerebral haemorrhage Little is known about the risk of recurrent strokes and whether they are again haemorrhagic or due to cerebral infarction. Any cause should be removed if safe and feasible (eg, excessive anticoagulation) and vascular risk factors should be vigorously treated (eg, hypertension). REFERENCES 1. Dennis
M, Bamford J, Sandercock P, Warlow C. Prognosis of transient ischemic attacks in the Oxfordshire Community Stroke Project. Stroke 1990; 21: 848-53.
2.
Hankey GJ, Slattery JM, Warlow CP. The prognosis ofhospital-referred transient ischaemic attacks. J Neurol Neurosurg Psychiatry 1991; 54: 793-802.
Hankey GJ, Slattery JM, Warlow CP. Transient ischaemic attacks: which patients are at high (and low) risk of serious vascular events? J Neurol Neurosurg Psychiatry (in press). 4. Dennis MS, Bamford JM, Sandercock PAG, Warlow CP. A comparison of risk factors and prognosis for transient ischemic attacks and minor ischemic strokes: the Oxfordshire Community Stroke Project. Stroke 1989; 20: 1494-99. 5. Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. Classification and natural history of clinically identifiable subtypes of cerebral 3.
infarction. Lancet 1991; 337: 1521-26. 6. Dunbabin D, Sandercock P. Preventing stroke by the modification of risk factors. Stroke 1990; 21 (suppl IV): 36-39. 7. Dennis MS, Bamford JM, Sandercock PAG, Warlow CP. Incidence of transient ischemic attacks in Oxfordshire, England. Stroke 1989; 20: 333-39. 8. Antiplatelet Trialists’ Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br Med J 1988; 296: 320-31. 9. Warlow CP. Ticlopidine, a new antithrombotic drug: but is it better than 185-87. 10. Patrono C. Aspirin and human platelets: from clinical trials to acetylation of cyclooxygenase and back. Trends Pharmacol Sci 1989; 10: 453-58. 11. The SALT Collaborative Group. Swedish Aspirin Low-dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet 1991; 338: 1345-49. 12. UK-TIA Study Group. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry 1991; 54: 1044-54. 13. Dutch TIA Trial Study Group. A comparison of two doses of aspirin (30 mg vs 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. N Engl J Med 1991; 325: 1261-66. 14. Warlow C. Transient ischaemic attacks. In: Matthews WB, Glaser GH, eds. Recent advances in clinical neurology 3. Edinburgh: Churchill Livingstone, 1982: 191-214. 15. European Carotid Surgery Trialists’ Collaborative Group. MRC
727
European Carotid Surgery Trial: interim results for symptomatic patients with severe (70-99%) or with mild (0-29%) carotid stenosis. Lancet 1991; 337: 1235-43.
16. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991; 325: 445-53. 17. Loftus CM, Quest DO. Technical controversies in carotid artery surgery.
Neurosurgery 1987; 20: 490-95.
18. Krul JMJ, van Gijn J, Ackerstaff RGA, Eikelboom BC, Theodorides T, Vermeulen FEE. Site and pathogenesis of infarcts associated with carotid endarterectomy. Stroke 1989; 20: 324-28. 19. Hunter GC, Palmaz JC, Hayashi HH, Raviola CA, Vogt PJ, Guernsey JM. The etiology of symptoms in patients with recurrent carotid stenosis. Arch Surg 1987; 122: 311-15. 20. EC-IC Bypass Study Group. Failure of extracranial-intracranial arterial bypass to reduce the risk of ischemic stroke: results of an international randomised trial. N Engl J Med 1985; 313: 1191-200.
HYPOTHESIS Low serum cholesterol and suicide
Primary prevention trials which have shown that the lowering of serum cholesterol concentrations in middle-aged subjects by diet, drugs, or both leads to a decrease in coronary heart disease have also reported an increase in deaths due to suicide or violence. There has been no adequate explanation for this association. I have reviewed the relevant published work and describe a physiological mechanism that might account for this curious finding. One of the functions of serotonin in the central nervous system is the suppression of harmful behavioural impulses. When mouse brain synaptosomal membrane cholesterol is increased there is a pronounced increase in the number of serotonin receptors. Low membrane cholesterol decreases the number of serotonin receptors. Since membrane cholesterol exchanges freely with cholesterol in the surrounding medium, a lowered serum cholesterol concentration may contribute to a decrease in brain serotonin, with poorer suppression of aggressive behaviour. Introduction review of six randomised, controlled, primary prevention trials, Muldoon et all found that lowering of raised serum cholesterol in middle-aged subjects by diet, drugs, or both was associated with a significant decrease in the number of deaths from coronary heart disease (CHD) but not in total deaths. There was a significant increase in mortality due to suicides or violence: compared with control groups, the treated groups had 28 fewer deaths from CHD and 29 more deaths from suicide, homicide, and accident. Muldoon and colleagues recommended a more cautious approach to population-based interventions for the control oflipids-ie, only those individuals at especially high risk of death from ischaemic heart disease should be targeted. However, neither the original review nor subsequent correspondence gave an adequate explanation for a causal relation between lowered serum cholesterol and increased suicidal tendencies. Since results were similar in all six trials, I thought it unlikely that these findings were merely due to chance alone, and I decided to look into published work that might throw light on this curious finding. In
a
Cerebral serotonin and behaviour Various lines of evidence suggest that abnormalities in cerebral serotonin systems are associated with poor impulse control, which may manifest either as suicidal behaviour or as aggression towards others.2 When serotonin transmission is low, there is an increase in the types of behaviour that are usually suppressed.3 The brains of suicide victims have low concentrations of serotonin, and among patients with of concentrations cerebrospinal-fluid depression acetic acid serotonin (a metabolite) major 5-hydroxyindole are lower in those who attempt suicide than in those who do not*—findings which suggest that brain serotonin affects behaviour. Vikkunen found that subjects with antisocial personalities and aggressive conduct disorders had lower blood cholesterol than did control groups. For example, criminals with an antisocial personality had a mean serum cholesterol of 5 04 mmol/1 compared with 6.02 mmol/1 in criminals with other personality disorders, and adolescent boys with attention deficit and aggressive conduct disorders had significantly lower mean serum cholesterol than did those without the aggression.’ Additionally, among homicidal offenders with an antisocial personality or intermittent explosive disorder, those who were habitually violent when intoxicated by alcohol had a significantly lower mean serum cholesterol than did those not so influenced by alcohol.8 In the antisocial personality group, lower serum cholesterol was found only in those younger than 30 years, whereas in patients with intermittent explosive disorder the serum cholesterol was significantly lower in all age groups; there was no difference in concentrations of triglycerides.8 Monkeys on a diet low in saturated fat and cholesterol diet were significantly more aggressive than were control animals on a normal diet.9 Several older studies accord with these observations. For example, patients in a mental-health hospital who had higher cholesterol concentrations (mean 7-55 mmol/1) were less regressed and withdrawn than were those with lower concentrations (mean 4-80 mmol/1), although nutritional status was no different.1o Significantly higher serum cholesterol concentrations were also found in ADDRESS Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA (H. Engelberg, MD). Correspondence to Dr Hyman Engelberg, California Arteriosclerosis Research Foundation, 465 North Roxbury Drive, Beverly Hills, California
90210, USA.
Aspiration About 28% of unilateral hemispheric stroke patients22 and 67% of those with brainstem involvement23 have dysphagia or silent aspiration. Pneumonia can lead to secondary deterioration from hypoxia and pyrexia. For prevention, patients should be fed in an upright position with food of appropriate consistency and small boluses; they should be encouraged to cough gently after each swallow and to swallow several times after each bolus.
Complications of treatment Complications of therapy are common. Examples include (a) sedation and depression induced by tranquillisers; (b) fever with adverse drug reactions; (c) inappropriate antidiuretic hormone secretion caused by carbamazepine or chlorpropamide; (d) effects of hypotensive agents in patients whose cerebral autoregulation has been impaired by stroke; and (e) haemorrhage from anticoagulants. Cardiac complications Stroke and coronary heart disease often coexist. However, stroke can affect the heart independently of an ischaemic mechanism. Non-ischaemic cardiac myofibre damage (myocytolysis) and increased cardiac enzymes (indicating cardiac damage) are common after stroke,1 although necropsy often fails to show acute coronary or cardiac ischaemic lesions. on changes Repolarisation in occur of 60-70% cerebral electrocardiography haemorrhages and in 5-17% of ischaemic strokes 24 Such changes can be induced in man and animals by administration of catecholamines, and catecholamine concentrations are often raised after a stroke.1.14 The insular cortex is involved in blood pressure regulation and contains a site of cardiac representation; stimulation of this area can induce cardiac arrhythmias .21 Insular stroke might therefore induce uncontrolled hypotension from cardiac dysfunction. Such patients and those showing acute electrocardiographic changes might be especially vulnerable to stroke extension and should be monitored closely. REFERENCES 1. Hachinski VC, Norris JW. The acute stroke. Philadelphia: FA Davis, 1985. 2. Bruce DA, Hurtig HI. Incidence, course, and significance of cerebral edema associated with cerebral infarction. In: Price TR, Nelson E, eds. Cerebrovascular diseases. New York: Raven, 1979: 191-98. 3. Norris JW, Hachinski VC. High dose steroid treatment in cerebral infarction. Br Med J 1986; 292: 21-23. 4. Poungvarin N, Bhoopat W, Viriyavejakal A, et al. Effects of dexamethasone in primary supratentorial intracerebral hemorrhage. N Engl J Med 1987; 316: 1229-33. 5. Lodder J. Hemorrhagic transformation in cardioembolic stroke. Stroke 1988; 19: 1482-84. 6. Hart RG, Easton JD. Hemorrhagic infarcts. Stroke 1986; 17: 586-89. 7. Cerebral Embolism Study Group. Immediate anticoagulation of embolic stroke: brain hemorrhage and management options. Stroke 1984; 5: 779-89. 8. Black SE, Hachinski VC, Norris JW. Seizures after stroke. Can J Neurol Sci 1982; 9: 291. 9. Gupta SR, Naheedy MH, Elias D, Rubino FA. Post-infarction seizures: a clinical study. Stroke 1988; 19: 1477-81. 10. Starkstein SE, Robinson RG, Price TR. Comparison of spontaneously recovered vs non-recovered patients with post-stroke depression. Stroke 1988; 19: 1491-96. 11. House A, Dennis M, Warlow C, Hawton K, Molyneux A. Mood disorders after stroke and their relation to lesion location: a CT study. Brain 1990; 113: 1113-24 12. Reding MJ, Orto LA, Winter SW, Fortuna IM, Di Ponte P, McDowell FH. Antidepressant therapy after stroke: a double blind trial. Arch Neurol 1986; 43: 763-65.
13. Melamed E. Reactive hyperglycemia m patients with acute stroke. J Neurol Sci 1976; 29: 267-75. 14. Myers MG, Norris JW, Hachinski VC, Sole MJ. Plasma norepinephrine in stroke. Stroke 1981; 12: 200-04. 15. Oppenheimer SM, Hoffbrand BI, Oswald GA, Yudkin JS. Diabetes mellitus and early mortality from stroke. Br Med J 1985; 291: 1015-16. 16. Helgason CM. Blood glucose and stroke. Stroke 1988; 19: 1049-53. 17. Ghandhavadi B. Hypertension after brainstem stroke. Arch Phys Med Rehabil 1988; 69: 130-37. 18. Dutha AJ, Hallenbeck JM, Kochanek P. A brief episode of severe arterial hypertension induces delayed deterioration of brain function and worsens blood flow after transient multifocal cerebral ischemia. Stroke 1987; 18: 386-95. 19. Hindfelt B. The prognostic significance of subfebrility and fever in ischemic cerebral infarction. Acta Neurol Scand 1976; 53: 72-79. 20. Busto R, Dietrich WD, Globus M, Ginsberg M. The importance of brain temperature in cerebral ischemic injury. Stroke 1989; 20: 1113-14. 21. Warlow C, Ogston D, Douglas AS. Deep vein thrombosis in legs after stroke. Part 1: incidence and predisposing factors. Br Med J 1976; i: 1178-81. 22. Barer D. The natural history and functional consequences of dysphagia after hemisphere stroke. J Neurol Neurosurg Psychiatry 1989; 52: 236-41. 23. Homer J, Massey EW, Rishi JE, Lathrop DL, Chase KN. Aspiration following stroke: clinical correlates and outcome. Neurology 1988; 38: 1359-62. 24. Oppenheimer SM, Cechetto DF, Hachinski VC. Cerebrogenic cardiac arrhythmias. Arch Neurol 1990; 47: 513-19. 25. Oppenheimer SM, Wilson JX, Guiraudon C, Cechetto DF. Insular cortex stimulation produces lethal cardiac arrhythmias: a mechanism of sudden death. Brain Res 1991; 550: 115-21.
Secondary prevention of stroke
Secondary prevention of stroke—ie, reducing stroke risk a stroke or transient ischaemic attack (TIA)—is one component of the general strategy to decrease the number of strokes in the community and their associated mortality and disability (see figure). In community studies, the risk of after
stroke after TIA is about 12% in the first year and then 7% per annum, which is seven times the risk of stroke in a
population of the same age.1 The risk in TIA patients referred to hospital is lower, probably because normal
referral bias results in a lower mean age; another factor is that a delay in being seen in hospital will exclude stroke patients during the early high-risk period when an extracranial atheromatous plaque or cardiac source of embolism may still be active and releasing emboli to the brain.2 Although about one-third of TIA patients report recurrent TIAs,2 the main aim of treatment is not to prevent these transient abnormalities but to reduce the risk of more serious vascular events, especially strokes. The risk of serious cardiac events (ie, fatal and non-fatal myocardial infarction, sudden presumed cardiac death, &c) is about the same as the risk of stroke,2 so it is logical to consider the risk of all serious vascular events—stroke, myocardial infarction, vascular death—together. These conditions have similar vascular risk factors; almost all are potentially preventable by antithrombotic drugs (except the occasional ruptured aortic aneurysm and haemorrhagic stroke); and the composite outcome of "stroke, myocardial infarction, vascular death" provides the largest number of events for precise statistical estimates. The risk of these
ADDRESS: Department of Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU, UK (Prof C. Warlow,
FRCP).
725
serious vascular events is about 9% per annum in the community, which is higher than in hospital-referred
populations.2 It is difficult to predict individual risk. People at high risk in 2 years) have most to gain from undergoing procedures such as carotid angiography and endarterectomy that may be associated with complications. These individuals should also be prescribed low-risk but effective treatments such as aspirin. In addition, low-risk therapy should be offered to moderate and lower risk patients.3 Although stroke risk can partly be predicted by the extent of carotid stenosismuch if not all of this risk is more easily predicted from a combination of age, frequency of TIAs, peripheral vascular disease, left ventricular
PERCENTAGE OF TIA AND ISCHAEMIC STROKE PATIENTS WITH VASCULAR RISK FACTORS AND DISEASES IN THE SAME COMMUNITY*
of stroke ( > 20%
hypertrophy, &c.3
Strategies for improving health by reducing the incidence of stroke and recurrent stroke and the associated mortality and disability. Modified with permission from Dennis M, Warlow CP. stroke. Br Med] 1991; 303: 636-38.
*Unpublished data from the Oxfordshire Community Stroke Project.
secondary than in primary prevention because, if the relative or proportional risk reductions attributable to treatment are the same, symptomatic patients have a much higher absolute risk of stroke than the normal population. Symptomatic vascular disease (eg, angina, claudication) should be treated on its merits. Occasionally there are specific treatable causes of TIA such as giant cell arteritis. Management of cardiogenic embolism has already been reviewed in this series (see Hart, March 7, p 589). In about 80% of patients the TIA or ischaemic stroke is due to the thrombotic and embolic complications of atheroma, or to small vessel disease of the perforating arteries of the brain (known as lipohyalinosis or microatheroma) ; for these individuals there are antithrombotic drugs and, sometimes, vascular surgery. However, the public health impact of treating TIA should not be exaggerated. Only 10-15% of stroke patients have had earlier TIAs and only about half report these events to a doctor.’ Consequently, treatment of TIA, even if it were completely successful in abolishing stroke, could not prevent
more
than about 5% of all strokes in the
community.
Strategy for
Survivors of mild ischaemic stroke have much the same risk of stroke as patients with transient cerebral ischaemia (patients with transient monocular ischaemic attacks [amaurosis fugax] have a lower risk).3.4This similarity is not surprising because TIA and stroke are distinguished according to an arbitrary 24-hour limit and not because there are any differences in underlying vascular lesions. Within stroke populations the presumed vascular abnormality, which can be partly predicted from simple clinical features, affects the risk of recurrent stroked Thus patients with restricted cortical infarcts have a high risk of recurrence (17% in the first year), perhaps because an embolic source is still active, whereas those with infarction of the entire middle cerebral artery territory, which was probably caused by occlusion of the middle cerebral artery trunk, have only a 6% risk, perhaps because further emboli to that hemisphere cannot make matters worse. Lacunar infarct patients have a 9% risk, presumably because any recurrence requires thrombotic occlusion of another small perforating artery.
General management There are no good randomised trials of risk factor modification in TIA and stroke patients. However, we can draw inferences from primary prevention studies and, at the very least, advocate control of hypertension and discourage cigarette smoking,6 both factors being common in stroke patients (see table). Absolute risk reductions are greater in
Antiplatelet drugs Numerous randomised trials have been conducted; fortunately, the investigators collaborated in a meta-analysis of all their published and some of their unpublished data.8 Long-term antiplatelet drugs reduce the risk of stroke and of other serious vascular events by about one quarter. This effect is much the same in males and females, in young and old, after TIA or ischaemic stroke, in diabetics and non-diabetics, and in patients with or without hypertension. No antiplatelet agent is clearly better than aspirin, and there is nothing as cheap or less toxic. Ticlopidine can be prescribed for patients who cannot tolerate aspirin.9 Theoretically, a daily dose of 50 mg of aspirin will inhibit platelet function after a few days, but this effect can be achieved by a single dose of 150 mg.1o Indirect trial evidence has not shown any difference in efficacy between 75 mg, 300 mg, and 1200 mg of aspirin daily.8.ll The few direct comparisons have not shown any difference between 300 and 1200 mg daily12 or between 30 and 283 mg,13 although a
small difference one way or the other may have been missed. The lower doses cause less gastric irritation.12,13 There is some concern that aspirin may cause intracranial but not in enough patients to negate the haemorrhage, of effect positive preventing thrombotic vascular events. The recommended dose is 300 mg for almost instant inhibition of platelet aggregation, followed by 75-150 mg a day, presumably indefinitely. Over 2 years, this strategy will prevent or delay a serious vascular event in about 3 of every 100
patients.9
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Anticoagulants good evidence that the risks of oral anticoagulation outweigh any possible benefits. The There is
no
randomised trials that have been conducted were too small to be informative.14 This approach may be more promising in cardiogenic embolism (see Hart, March 7, p 589).
Carotid endarterectomy
nearly 40 years of confusion following the first carotid endarterectomy, and a near epidemic in its use, the interim results from the European Carotid Surgery Trial (ECST)is and the North American Symptomatic Carotid Endarterectomy Trial (NASCET)16 published in 1991 led to the same conclusions. For patients with a recent mild carotid-distribution ischaemic event and severe (70-99% luminal diameter) stenosis of the origin of the symptomatic internal carotid artery, the operation carries a significant risk of stroke or death, in addition to the small risk of the preceding angiography: 75% in ECST and 58% in NASCET. However, these figures cannot be generalised because the risk of surgery depend on who does the operation and where it is done. The second conclusion is generally applicable-ie, if the patient survives surgery without a stroke, the risk of ipsilateral ischaemic stroke over the next few years is almost completely abolished (16-8% in 3 years in ECST and 26% in 2 years in NASCET). Depending on local surgical risk and risk of stroke in unoperated patients, between 5 and 10 patients must be operated on to prevent 1 from having a stroke. Stroke during surgery is either due to low cerebral blood After
flow as a consequence of clamping the internal carotid artery without using a shunt in a patient with inadequate collateral blood flow, or to embolism of atherothrombotic debris or air from the operation site. Stroke hours or days later is most probably the result of a technical error at the operation site, where a loose distal intimal flap can be a source of dissection, thrombosis, or embolism. 17 18 Bleeding or oedema in the cerebral hemisphere ipsilateral to the operation is rare. Other complications include operative damage to the
hypoglossal, superior laryngeal, recurrent laryngeal, vagus, and facial nerves, which will cause difficulty in speaking or swallowing for a few weeks; ipsilateral vascular-type headache; neck haematoma; aneurysmal dilatation at the endarterectomy site; venous thromboembolism; and myocardial infarction. Early and late restenosis is increasingly recognised but seldom leads to symptoms;19we do not know whether use of a patch rather than simple closure during endarterectomy will prevent restenosis. For patients with mild stenosis (0-29%) the risk of surgery never becomes worthwhile because there are almost no strokes to be prevented (therefore, even ulceration in a non-stenosing plaque cannot be of any great importance).15 Patients with moderate stenosis (30-69%) are still being randomised in both trials because the balance of risk and benefit of carotid endarterectomy remains unclear. All patients in both trials are being followed up to assess the long-term results of sugery.
Other invasive approaches to prevention of ischaemic stroke
Theoretically, anastomosis of a branch of the external carotid artery to a cortical branch of the middle cerebral artery distal to an occlusion or stenosis of that artery, or distal to an occlusion or inaccessible stenosis of the internal
carotid artery, might reduce the risk of ipsilateral ischaemic stroke. The one large randomised trial20 did not show a reduction. Various direct and indirect surgical approaches to vertebral artery disease have been proposed, and there is some anecdotal experience of angioplasty of the extracranial arteries; these techniques have not been tested in randomised trials.
Frequent TIAs TIAs are not usually so frequent-ie, several a weekthat treatment must be prescribed to stop them and not merely to prevent stroke. Such patients should be treated quickly with aspirin. If the attacks are carotid in distribution and non-invasive ultrasound imaging shows severe stenosis of the ipsilateral internal carotid artery, angiography and possibly endarterectomy are indicated. If there is less severe stenosis, or if the attacks are vertebrobasilar in distribution, heparinisation may be helpful; heparin can be followed by warfarin for a few weeks and then lifelong aspirin. In patients with carotid occlusion or severe inoperable stenosis any antihypertensive treatment should be reviewed in case the pressure is too low and the continuing TIAs are due to low cerebral blood flow. If the attacks persist, the diagnosis of TIA should be reconsidered.
Intracerebral haemorrhage Little is known about the risk of recurrent strokes and whether they are again haemorrhagic or due to cerebral infarction. Any cause should be removed if safe and feasible (eg, excessive anticoagulation) and vascular risk factors should be vigorously treated (eg, hypertension). REFERENCES 1. Dennis
M, Bamford J, Sandercock P, Warlow C. Prognosis of transient ischemic attacks in the Oxfordshire Community Stroke Project. Stroke 1990; 21: 848-53.
2.
Hankey GJ, Slattery JM, Warlow CP. The prognosis ofhospital-referred transient ischaemic attacks. J Neurol Neurosurg Psychiatry 1991; 54: 793-802.
Hankey GJ, Slattery JM, Warlow CP. Transient ischaemic attacks: which patients are at high (and low) risk of serious vascular events? J Neurol Neurosurg Psychiatry (in press). 4. Dennis MS, Bamford JM, Sandercock PAG, Warlow CP. A comparison of risk factors and prognosis for transient ischemic attacks and minor ischemic strokes: the Oxfordshire Community Stroke Project. Stroke 1989; 20: 1494-99. 5. Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. Classification and natural history of clinically identifiable subtypes of cerebral 3.
infarction. Lancet 1991; 337: 1521-26. 6. Dunbabin D, Sandercock P. Preventing stroke by the modification of risk factors. Stroke 1990; 21 (suppl IV): 36-39. 7. Dennis MS, Bamford JM, Sandercock PAG, Warlow CP. Incidence of transient ischemic attacks in Oxfordshire, England. Stroke 1989; 20: 333-39. 8. Antiplatelet Trialists’ Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br Med J 1988; 296: 320-31. 9. Warlow CP. Ticlopidine, a new antithrombotic drug: but is it better than 185-87. 10. Patrono C. Aspirin and human platelets: from clinical trials to acetylation of cyclooxygenase and back. Trends Pharmacol Sci 1989; 10: 453-58. 11. The SALT Collaborative Group. Swedish Aspirin Low-dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet 1991; 338: 1345-49. 12. UK-TIA Study Group. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry 1991; 54: 1044-54. 13. Dutch TIA Trial Study Group. A comparison of two doses of aspirin (30 mg vs 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. N Engl J Med 1991; 325: 1261-66. 14. Warlow C. Transient ischaemic attacks. In: Matthews WB, Glaser GH, eds. Recent advances in clinical neurology 3. Edinburgh: Churchill Livingstone, 1982: 191-214. 15. European Carotid Surgery Trialists’ Collaborative Group. MRC
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European Carotid Surgery Trial: interim results for symptomatic patients with severe (70-99%) or with mild (0-29%) carotid stenosis. Lancet 1991; 337: 1235-43.
16. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991; 325: 445-53. 17. Loftus CM, Quest DO. Technical controversies in carotid artery surgery.
Neurosurgery 1987; 20: 490-95.
18. Krul JMJ, van Gijn J, Ackerstaff RGA, Eikelboom BC, Theodorides T, Vermeulen FEE. Site and pathogenesis of infarcts associated with carotid endarterectomy. Stroke 1989; 20: 324-28. 19. Hunter GC, Palmaz JC, Hayashi HH, Raviola CA, Vogt PJ, Guernsey JM. The etiology of symptoms in patients with recurrent carotid stenosis. Arch Surg 1987; 122: 311-15. 20. EC-IC Bypass Study Group. Failure of extracranial-intracranial arterial bypass to reduce the risk of ischemic stroke: results of an international randomised trial. N Engl J Med 1985; 313: 1191-200.
HYPOTHESIS Low serum cholesterol and suicide
Primary prevention trials which have shown that the lowering of serum cholesterol concentrations in middle-aged subjects by diet, drugs, or both leads to a decrease in coronary heart disease have also reported an increase in deaths due to suicide or violence. There has been no adequate explanation for this association. I have reviewed the relevant published work and describe a physiological mechanism that might account for this curious finding. One of the functions of serotonin in the central nervous system is the suppression of harmful behavioural impulses. When mouse brain synaptosomal membrane cholesterol is increased there is a pronounced increase in the number of serotonin receptors. Low membrane cholesterol decreases the number of serotonin receptors. Since membrane cholesterol exchanges freely with cholesterol in the surrounding medium, a lowered serum cholesterol concentration may contribute to a decrease in brain serotonin, with poorer suppression of aggressive behaviour. Introduction review of six randomised, controlled, primary prevention trials, Muldoon et all found that lowering of raised serum cholesterol in middle-aged subjects by diet, drugs, or both was associated with a significant decrease in the number of deaths from coronary heart disease (CHD) but not in total deaths. There was a significant increase in mortality due to suicides or violence: compared with control groups, the treated groups had 28 fewer deaths from CHD and 29 more deaths from suicide, homicide, and accident. Muldoon and colleagues recommended a more cautious approach to population-based interventions for the control oflipids-ie, only those individuals at especially high risk of death from ischaemic heart disease should be targeted. However, neither the original review nor subsequent correspondence gave an adequate explanation for a causal relation between lowered serum cholesterol and increased suicidal tendencies. Since results were similar in all six trials, I thought it unlikely that these findings were merely due to chance alone, and I decided to look into published work that might throw light on this curious finding. In
a
Cerebral serotonin and behaviour Various lines of evidence suggest that abnormalities in cerebral serotonin systems are associated with poor impulse control, which may manifest either as suicidal behaviour or as aggression towards others.2 When serotonin transmission is low, there is an increase in the types of behaviour that are usually suppressed.3 The brains of suicide victims have low concentrations of serotonin, and among patients with of concentrations cerebrospinal-fluid depression acetic acid serotonin (a metabolite) major 5-hydroxyindole are lower in those who attempt suicide than in those who do not*—findings which suggest that brain serotonin affects behaviour. Vikkunen found that subjects with antisocial personalities and aggressive conduct disorders had lower blood cholesterol than did control groups. For example, criminals with an antisocial personality had a mean serum cholesterol of 5 04 mmol/1 compared with 6.02 mmol/1 in criminals with other personality disorders, and adolescent boys with attention deficit and aggressive conduct disorders had significantly lower mean serum cholesterol than did those without the aggression.’ Additionally, among homicidal offenders with an antisocial personality or intermittent explosive disorder, those who were habitually violent when intoxicated by alcohol had a significantly lower mean serum cholesterol than did those not so influenced by alcohol.8 In the antisocial personality group, lower serum cholesterol was found only in those younger than 30 years, whereas in patients with intermittent explosive disorder the serum cholesterol was significantly lower in all age groups; there was no difference in concentrations of triglycerides.8 Monkeys on a diet low in saturated fat and cholesterol diet were significantly more aggressive than were control animals on a normal diet.9 Several older studies accord with these observations. For example, patients in a mental-health hospital who had higher cholesterol concentrations (mean 7-55 mmol/1) were less regressed and withdrawn than were those with lower concentrations (mean 4-80 mmol/1), although nutritional status was no different.1o Significantly higher serum cholesterol concentrations were also found in ADDRESS Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA (H. Engelberg, MD). Correspondence to Dr Hyman Engelberg, California Arteriosclerosis Research Foundation, 465 North Roxbury Drive, Beverly Hills, California
90210, USA.
