The Journal of the Royal Medico-Chirurgical Society of Glasgow, the Scottish Society for Experimental Medicine and the Aberdeen Medico-Chirurgical Society.
iSSN: 0036-9330
Volume 36
ACUTE STROKE CARE - OPPORTUNITIES FOR LIMITING BRAIN DAMAGE ACUTE STROKE remains one of the commonest causes of admission to hospitals in the developed nations of the West and consumes more resources from healthcare budgets than any other disease. 1,2,3,4 In addition there is a significant mortality both before and after admission to hospital. Despite all the major advances in medical practice mortality has remained unchanged at about 50 per cent. 5,6,7,8 Of the 50 per cent of hospital admissions who survive about half will manage to return to their own homes and lead independent lives or even return to work, the other half will need continuing care to a greater or lesser extent. The clinical picture of acute stroke has remained unchanged over many years. 9 There is now increasing evidence that in the long term, control of hypertension, cholesterol and cessation of smoking will reduce stroke incidence just as it has reduced that of acute myocardial . f . 1011 12 However nationa . I programmes to change popuIn arction. " lation lifestyle and hence reduce stroke incidence will take many years to be effective and physicians are currently required to deal with a vascular legacy from the past. About 90 per cent of all strokes are due to ischaemia resulting from thrombus formation in nutrient arteries with a small number resulting from emboli originating in the heart and associated . "1314 Abo ut 10 per cent result from cerebral haemorrhage. artenes.' The outcome from acute ischaemic stroke is related to the volume of brain which has been damaged and the site affected. 15It is likely that surrounding the area of damage is an "ischaemic penumbra" in which brain tissue may be potentially viable if some flow can be restored quickly.16Therepeutic strategies to increase oxygenation of the anoxic area are still experimental but could limit the extent of ischaemic damage and hence reduce the resulting physical and mental impairment. A variety of different approaches are now under trial and initial studies give some reasons for hope. Thrombolytics have been available for over thirty years and their use in dissolution of coronary artery thrombi has been validated in a large series of clinical trials using both mortality and mor. . 171819 A range of first and second generation bidi 1 ity cntena. " agents is now available for clinical use and these include streptokinase (SK), urokinase (UK), tissue plasminogen activator al teplase (tPA) and acylated streptokinase (APSAC, anistreplase) and single chain urokinase plasminogen activator (SCUPA). In coronary artery disease all these agents are effective when given early after the thrombotic event, all have a similar profile of adverse events and as a result the clinicians choice is now dictated by cost. Thus streptokinase is now widely used as the first line drug after proven myocardial infarction with rtPA being reserved for patients who have recently received streptokinase. Thrombolytic agents are all activators of plasminogen which has been intimately bound to fibrin as it forms to produce the occluding thrombus. Streptokinase requires a pro-activator but the rest act directly. The result of plasminogen activation is rapid breakdown of the fibrin thrombus and re-establishment of blood flow. Unfortunately all these agents may also act on circulating plasminogen and on plasminogen adsorbed to haemostatic plugs in the arterial and venous systems and as a result may be associated with bleeding
Number 6
Scottish Medical Journal
Decemberl991
elsewhere in the body.17,18,20 Throm bolytic agents have already been used in acute thrombotic and embolic stroke21 with evidence of partial opening of thrombosed vessels, eg in 29 of94 patients (31 per cent) partial opening and complete opening in four patients (4 per cent) within 60 minutes of starting treatment. There was good clinical evidence of return of neurological function with 34 of74 (46 per cent) given t-PA within 90 minutes of the acute event showing significant improvement.v' The concern is that uncontrolled lysis may initiate bleeding at the ischaemic edges of the infarct or in other sites. Properly controlled clinical trials are in hand to answer these important questions - especially the safety aspect. Oxygen deprivation as a result of ischaemia prevents oxidative phosphorylation which inhibits ATP production which in tum produces major downstream defects in ion and neurotransmitter transport in cell membranes especially in the control of calcium channels. The result is the generation of hi~hly toxic free-radical species which produce local cell necrosis 3 a process which is compounded by the associated acidosis. Scavengers of these free radicals have a potential role in therapy following stroke. In animals administration of superoxide dismutase, a synthetic scavenger, has been shown to reduce oedema and improve survival24 and compounds of the 21-aminosteroids class have also been shown to decrease the amount of ischaemic damage.2 5 Trials of these and related compounds are in progress. Excessive release of the neurotransmitter glutamate from brain cells during the ischaemic process probably plays a major role in injuring adjacent brain cells.2 6 On the postsynaptic membrane there are three sub-types of glutamate receptors which may be specifically activated by N-methyl-D-asparate (NMDA), kainate (K) and quisqualate (Q) respectively. The K and Q receptors are involved in channels which exchange sodium ions for potassium, and the NMDA receptor operates a calcium ion channel which, when ischaemic, allows calcium entry which in turn exacerbates the ischaemic process. Agents that block glutamate receptors and prevent the uRtake of glutamate by normal cells appears to limit this damage. In animals given dextromethorphan (a glutamate antagonist) damage from experimental stroke was reduced significantly. To date syntheti~ inhibitors of the NMDA channel (e.g, MK801) look promising 8,29,30 but may have serious side ef31 fects and newer agents are currently being developed. Interest has also centred on existing calcium channel blocking drugs such as nimodipine which has been shown to be of clinical value in reducing the ischaemic sequellae in subarachnoid haemorrhage. 32 In patients with ischaemic stroke nimodipine increased blood supply by up to 30 per cent. 33,34 However in a well conducted randomised trial no significant clinical benefit was obtained.:J5,36 After the onset of ischaemia the affected tissue swells due to leakage ofplasma constituents through the damaged endothelium. This swelling has the effect of reducing blood flow in the adjacent brain. Studies of agents which would have an osmotic effect on the swelling have been disappointing; these have included glucose, glycerol and steroids. Indeed there is some evidence that steroids may enhanf~ the ischaemic process and produce a larger area of infarction? ' 8 Changes also occur in both the plasma and cellular components of blood (rise in fibrinogen and white cell counts) as a reaction to 163
Comment
the acute tissue damage. These produce elevation of blood viscosity and accentuate the reduction in flow. Clinical trials to redu~e blood viscosity and enhance rheology have been unsuccessful. 9 Failure of all these current acute strategies underlines our lack of knowledge about the basic mechanisms of both the ischaemic process and cell damage which results. Some of these approaches have potential for the future but in the meantime leave the clinical doctor very little to offer except for care of symptoms and signs, active rehabilitation and psycho-social support. Lack of effective intervention strategies underlines the importance of both primary and secondary r.revention by lifestyle modification of the known risk factors 40 ,4 ,42 and a parallel pharmalogical intervention. 43
CD Forbes Professor of Medicine Ninewells Hospital and Medical School Dundee DD19SY REFERENCES
2
3 4 5 6 7 8 9 10 11 12
13 14 15 16 17
Baum HM, Robins M. National survey of stroke: survival and prevalence. Stroke 1981; 12(Supp 1): 59-68. Bamford J, Sandercock P, Dennis M, et al. A prospective study of acute cerebrovascular disease in the community: The Oxfords hire Community Stroke Project 1981-1986: 1 Methodology, demography and incident cases of first ever stroke. J Neurol, Neurosurg Psychiatry 1988; 51: 1373-1380. Adelman MS. National survey of stroke: Economic impact. Stroke 1981; 12(Suppll): 69-78. WolfPA, D'AgostinoRB, Belanger AJ, etal. Probability ofstroke: A risk profile from the Framingham study. Stroke 1991; 22: 312-318. Melville ID, and Renfrew S. The prognosis of survival from cerebrovascular accidents. J Neurol Neurosurg Psychiatry 1961; 24: 346-349 Thomson JA. Strokes in an acute medical unit. Health Bull 1971; 29: 113-114. Lowe GDO, Jaap AJ, Forbes CD. Relation of atrial fibrillation and high haematocrit to mortality in acute stroke. Lancet 1983; i: 784-786. Dale S. Stroke 1988; Office of Health Economics, No 89, London. Aho K, Harmsen P, Hatano S, Marquardsen J, et al. Cerebrovascular disease in the community: Results of a WHO Collaborative Study. Bull ofthe WHO 1980; 58: 113-130. WhishnantJP. The decline of stroke. Stroke 1984; 15: 160-168. Shinton R, and Beevers G. Meta analysis of relation between cigarette smoking and stroke. Br Med J 1989; 298: 789-794. Collins R, PetoR, MacMahon S, et al. Bloodpressure, stroke and coronary heart disease, Part II: Effects of short term reductions in blood pressure and overview of the unconfounded randomised drug trials in an epidemiological context. Lancet 1990; 335: 827-838. Cerebral Embolism TaskForce: Cardiogenic brain embolism, Arch Neurol1986; 43: 71-84. Sandercock PAG, Warlow CP, Jones LN, et al. Predisposing factors for cerebral infarction: the Oxfordshire community stroke project. Br Med J 1989; 298: 75-80. Allen CMC. Predicting outcome after acute stroke: role of computed tomography. Lancet 1985; ii: 464-465. Astrup J, Siesjo BK, Symon L. The state of penumbra in the ischaemic brain: viable and lethal threshold in cerebral ischaemia. Stroke 1981; 12: 723-725. Gruppo Italiano per10 Studio della Streptokinasi nell' Infarto Miocardio (GISSI). Efectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; i: 297-301.
164
18 Second Interuational Study of Infarct Survival (ISIS-2) Collaborative Group. Randomised trial ofintra venous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; ii: 349-360. 19 The Thrombolysis in Myocardial Infarction (TIMI) Study Group. Comparison of invasive and conservative strategies after treatment with intravenous plasminogen activator in acute myocardial infarction. New EnglJ Med 1989; 320: 618-627. 20 Petch MC. Dangers of thrombolysis (Editorial). Br Med J 1990; 300: 483. 21 The r-tPA/Acute Stroke Study Group. An open safety/efficacy trial of r-tPA in acute thromboembolic stroke: Final report. Stroke 1991; 22: 153 (Abstract). 22 Brott, Haley C, Levy D, et al. Safety and potential efficacy of tissue plasminogen activator (t-PA) for stroke. Stroke 1990; 181(Abstract). 23 McCord JM. Oxygen-derived free radicals in postischaemic tissue injury. NewEnglJMed 1985;312: 159-163. 24 Uyama 0, Shiratsuki N, Matsuyama T, Nakanishi T, Matsumoto Y, Yamada T, et al. Protective effects of recombinant human superoxide dismutase on reperfusion injury of gerbil brain. Stroke 1990; 21: (Suppl 1): 1-32. 25 Hall ED, Pazara KE, Braughler JM. 21-arninosteroid lipid peroxidation inhibitor U74oo6F protects against cerebral ischaemia in gerbils. Stroke 1988; 19:997-1002. 26 Rothman SM, Olney JW. Glutamate and the pathophysiology of hypoxicischemic brain damage. Ann Neurol 1986; 19: 105-111. 27 Steinberg GK, Lo EH, Kunis DM, Grant G. Dextromethorphan prevents post ischemic increase in cerebral blood flow and protects against cerebral injury following focal cerebral ischemia. Stroke 1991; 22: 141(Abstract). 28 Johnson RL, and Koerner JF. Excitatory amino acid neurotransmission. J Med Chern 1988; 31: 2057-2066. 29 Gill R, Foster AC, Woodruff GN. Systemic administration of MK-80l protects aganstischaemia-induced hippocampal neurodegeneration in the gerbil. J Neurosci 1987; 7: 3343-3349. 30 McDonald JW, Silverstein FS, Johnston MY. MK-801 protects the neonatal brain from hypoxic-ischaernic damage. Eur J Pharmacol1987; 140: 359-361. 31 Albers GW, Goldberg MP, Choi DW. N-methyl-D-asparate antagonists; ready for clinical trial in brain ischemia? Ann Neurol 1989; 25: 398-403. 32 Greenberg JH, Uematsu D, Araki N, et al. Cytosolic free calcium during focal cerebral ischaemia and the effects of nimodipine on calcium and histologic damage. Stroke 1990; (Suppl): 72-77. 33 Gelmers HJ, Forter K, de Weerdt CJ, et al. A controlled trial of nimodipine in acute ischaemic stroke. New Engl J Med 1988; 318: 203-207. 34 Tomberg T, Magi M. Effect of calcium antagonists on cerebral blood flow in the acute stage of cerebral infarction. J Neuroll990; 237: 138. 35 Trust Study Group. Randomised double-blind, placebo-controlled trial of nimodipine in acute stroke. Lancet 1990; 336: 1205-1209. 36 Martinez- Villa E, Guillen F, Yuillaneuva JA, et al. Placebo-controlled trial of nimodipine in the treatment of acute ischemic cerebral infarction. Stroke 1990; 21: 1023-1028. 37 Norris JW, and Hachinski YC. High dose steroid treatment in cerebral infarction. BrMedJ 1986; 292: 21-23. 38 Sapolsky RM, Pulsinelli WA. Glucocorticoids potentiate ischemic injury to neurons; therapeuticimplications. Science 1985; 229: 1397-1400. 39 Italian Acute Stroke Study Group. Haemodilution in acute stroke: results of the Italian haemodilution trial. Lancet 1988; i: 318-321. 40 Shaper AG, Phillips AN, Pocock SJ, et al. Risk factors for stroke in middle-aged British men. Br Med J 1991; 302: 1111-1115. 41 Medical Research Council Working Party. Stroke and coronary heart disease in mild hypertension: risk factors and the value of treatment. Br Med J 1988; 296: 1565-1570. 42 Donnan GA, McNeil JJ, Adena MA, et al. Smoking as a risk factor for cerebral ischaemia. Lancet 1989; ii: 643-647. 43 Antiplatelet Triallists Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br Med J 1988; 296: 320-331.
iSSN: 0036-9330
Volume 36
ACUTE STROKE CARE - OPPORTUNITIES FOR LIMITING BRAIN DAMAGE ACUTE STROKE remains one of the commonest causes of admission to hospitals in the developed nations of the West and consumes more resources from healthcare budgets than any other disease. 1,2,3,4 In addition there is a significant mortality both before and after admission to hospital. Despite all the major advances in medical practice mortality has remained unchanged at about 50 per cent. 5,6,7,8 Of the 50 per cent of hospital admissions who survive about half will manage to return to their own homes and lead independent lives or even return to work, the other half will need continuing care to a greater or lesser extent. The clinical picture of acute stroke has remained unchanged over many years. 9 There is now increasing evidence that in the long term, control of hypertension, cholesterol and cessation of smoking will reduce stroke incidence just as it has reduced that of acute myocardial . f . 1011 12 However nationa . I programmes to change popuIn arction. " lation lifestyle and hence reduce stroke incidence will take many years to be effective and physicians are currently required to deal with a vascular legacy from the past. About 90 per cent of all strokes are due to ischaemia resulting from thrombus formation in nutrient arteries with a small number resulting from emboli originating in the heart and associated . "1314 Abo ut 10 per cent result from cerebral haemorrhage. artenes.' The outcome from acute ischaemic stroke is related to the volume of brain which has been damaged and the site affected. 15It is likely that surrounding the area of damage is an "ischaemic penumbra" in which brain tissue may be potentially viable if some flow can be restored quickly.16Therepeutic strategies to increase oxygenation of the anoxic area are still experimental but could limit the extent of ischaemic damage and hence reduce the resulting physical and mental impairment. A variety of different approaches are now under trial and initial studies give some reasons for hope. Thrombolytics have been available for over thirty years and their use in dissolution of coronary artery thrombi has been validated in a large series of clinical trials using both mortality and mor. . 171819 A range of first and second generation bidi 1 ity cntena. " agents is now available for clinical use and these include streptokinase (SK), urokinase (UK), tissue plasminogen activator al teplase (tPA) and acylated streptokinase (APSAC, anistreplase) and single chain urokinase plasminogen activator (SCUPA). In coronary artery disease all these agents are effective when given early after the thrombotic event, all have a similar profile of adverse events and as a result the clinicians choice is now dictated by cost. Thus streptokinase is now widely used as the first line drug after proven myocardial infarction with rtPA being reserved for patients who have recently received streptokinase. Thrombolytic agents are all activators of plasminogen which has been intimately bound to fibrin as it forms to produce the occluding thrombus. Streptokinase requires a pro-activator but the rest act directly. The result of plasminogen activation is rapid breakdown of the fibrin thrombus and re-establishment of blood flow. Unfortunately all these agents may also act on circulating plasminogen and on plasminogen adsorbed to haemostatic plugs in the arterial and venous systems and as a result may be associated with bleeding
Number 6
Scottish Medical Journal
Decemberl991
elsewhere in the body.17,18,20 Throm bolytic agents have already been used in acute thrombotic and embolic stroke21 with evidence of partial opening of thrombosed vessels, eg in 29 of94 patients (31 per cent) partial opening and complete opening in four patients (4 per cent) within 60 minutes of starting treatment. There was good clinical evidence of return of neurological function with 34 of74 (46 per cent) given t-PA within 90 minutes of the acute event showing significant improvement.v' The concern is that uncontrolled lysis may initiate bleeding at the ischaemic edges of the infarct or in other sites. Properly controlled clinical trials are in hand to answer these important questions - especially the safety aspect. Oxygen deprivation as a result of ischaemia prevents oxidative phosphorylation which inhibits ATP production which in tum produces major downstream defects in ion and neurotransmitter transport in cell membranes especially in the control of calcium channels. The result is the generation of hi~hly toxic free-radical species which produce local cell necrosis 3 a process which is compounded by the associated acidosis. Scavengers of these free radicals have a potential role in therapy following stroke. In animals administration of superoxide dismutase, a synthetic scavenger, has been shown to reduce oedema and improve survival24 and compounds of the 21-aminosteroids class have also been shown to decrease the amount of ischaemic damage.2 5 Trials of these and related compounds are in progress. Excessive release of the neurotransmitter glutamate from brain cells during the ischaemic process probably plays a major role in injuring adjacent brain cells.2 6 On the postsynaptic membrane there are three sub-types of glutamate receptors which may be specifically activated by N-methyl-D-asparate (NMDA), kainate (K) and quisqualate (Q) respectively. The K and Q receptors are involved in channels which exchange sodium ions for potassium, and the NMDA receptor operates a calcium ion channel which, when ischaemic, allows calcium entry which in turn exacerbates the ischaemic process. Agents that block glutamate receptors and prevent the uRtake of glutamate by normal cells appears to limit this damage. In animals given dextromethorphan (a glutamate antagonist) damage from experimental stroke was reduced significantly. To date syntheti~ inhibitors of the NMDA channel (e.g, MK801) look promising 8,29,30 but may have serious side ef31 fects and newer agents are currently being developed. Interest has also centred on existing calcium channel blocking drugs such as nimodipine which has been shown to be of clinical value in reducing the ischaemic sequellae in subarachnoid haemorrhage. 32 In patients with ischaemic stroke nimodipine increased blood supply by up to 30 per cent. 33,34 However in a well conducted randomised trial no significant clinical benefit was obtained.:J5,36 After the onset of ischaemia the affected tissue swells due to leakage ofplasma constituents through the damaged endothelium. This swelling has the effect of reducing blood flow in the adjacent brain. Studies of agents which would have an osmotic effect on the swelling have been disappointing; these have included glucose, glycerol and steroids. Indeed there is some evidence that steroids may enhanf~ the ischaemic process and produce a larger area of infarction? ' 8 Changes also occur in both the plasma and cellular components of blood (rise in fibrinogen and white cell counts) as a reaction to 163
Comment
the acute tissue damage. These produce elevation of blood viscosity and accentuate the reduction in flow. Clinical trials to redu~e blood viscosity and enhance rheology have been unsuccessful. 9 Failure of all these current acute strategies underlines our lack of knowledge about the basic mechanisms of both the ischaemic process and cell damage which results. Some of these approaches have potential for the future but in the meantime leave the clinical doctor very little to offer except for care of symptoms and signs, active rehabilitation and psycho-social support. Lack of effective intervention strategies underlines the importance of both primary and secondary r.revention by lifestyle modification of the known risk factors 40 ,4 ,42 and a parallel pharmalogical intervention. 43
CD Forbes Professor of Medicine Ninewells Hospital and Medical School Dundee DD19SY REFERENCES
2
3 4 5 6 7 8 9 10 11 12
13 14 15 16 17
Baum HM, Robins M. National survey of stroke: survival and prevalence. Stroke 1981; 12(Supp 1): 59-68. Bamford J, Sandercock P, Dennis M, et al. A prospective study of acute cerebrovascular disease in the community: The Oxfords hire Community Stroke Project 1981-1986: 1 Methodology, demography and incident cases of first ever stroke. J Neurol, Neurosurg Psychiatry 1988; 51: 1373-1380. Adelman MS. National survey of stroke: Economic impact. Stroke 1981; 12(Suppll): 69-78. WolfPA, D'AgostinoRB, Belanger AJ, etal. Probability ofstroke: A risk profile from the Framingham study. Stroke 1991; 22: 312-318. Melville ID, and Renfrew S. The prognosis of survival from cerebrovascular accidents. J Neurol Neurosurg Psychiatry 1961; 24: 346-349 Thomson JA. Strokes in an acute medical unit. Health Bull 1971; 29: 113-114. Lowe GDO, Jaap AJ, Forbes CD. Relation of atrial fibrillation and high haematocrit to mortality in acute stroke. Lancet 1983; i: 784-786. Dale S. Stroke 1988; Office of Health Economics, No 89, London. Aho K, Harmsen P, Hatano S, Marquardsen J, et al. Cerebrovascular disease in the community: Results of a WHO Collaborative Study. Bull ofthe WHO 1980; 58: 113-130. WhishnantJP. The decline of stroke. Stroke 1984; 15: 160-168. Shinton R, and Beevers G. Meta analysis of relation between cigarette smoking and stroke. Br Med J 1989; 298: 789-794. Collins R, PetoR, MacMahon S, et al. Bloodpressure, stroke and coronary heart disease, Part II: Effects of short term reductions in blood pressure and overview of the unconfounded randomised drug trials in an epidemiological context. Lancet 1990; 335: 827-838. Cerebral Embolism TaskForce: Cardiogenic brain embolism, Arch Neurol1986; 43: 71-84. Sandercock PAG, Warlow CP, Jones LN, et al. Predisposing factors for cerebral infarction: the Oxfordshire community stroke project. Br Med J 1989; 298: 75-80. Allen CMC. Predicting outcome after acute stroke: role of computed tomography. Lancet 1985; ii: 464-465. Astrup J, Siesjo BK, Symon L. The state of penumbra in the ischaemic brain: viable and lethal threshold in cerebral ischaemia. Stroke 1981; 12: 723-725. Gruppo Italiano per10 Studio della Streptokinasi nell' Infarto Miocardio (GISSI). Efectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; i: 297-301.
164
18 Second Interuational Study of Infarct Survival (ISIS-2) Collaborative Group. Randomised trial ofintra venous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; ii: 349-360. 19 The Thrombolysis in Myocardial Infarction (TIMI) Study Group. Comparison of invasive and conservative strategies after treatment with intravenous plasminogen activator in acute myocardial infarction. New EnglJ Med 1989; 320: 618-627. 20 Petch MC. Dangers of thrombolysis (Editorial). Br Med J 1990; 300: 483. 21 The r-tPA/Acute Stroke Study Group. An open safety/efficacy trial of r-tPA in acute thromboembolic stroke: Final report. Stroke 1991; 22: 153 (Abstract). 22 Brott, Haley C, Levy D, et al. Safety and potential efficacy of tissue plasminogen activator (t-PA) for stroke. Stroke 1990; 181(Abstract). 23 McCord JM. Oxygen-derived free radicals in postischaemic tissue injury. NewEnglJMed 1985;312: 159-163. 24 Uyama 0, Shiratsuki N, Matsuyama T, Nakanishi T, Matsumoto Y, Yamada T, et al. Protective effects of recombinant human superoxide dismutase on reperfusion injury of gerbil brain. Stroke 1990; 21: (Suppl 1): 1-32. 25 Hall ED, Pazara KE, Braughler JM. 21-arninosteroid lipid peroxidation inhibitor U74oo6F protects against cerebral ischaemia in gerbils. Stroke 1988; 19:997-1002. 26 Rothman SM, Olney JW. Glutamate and the pathophysiology of hypoxicischemic brain damage. Ann Neurol 1986; 19: 105-111. 27 Steinberg GK, Lo EH, Kunis DM, Grant G. Dextromethorphan prevents post ischemic increase in cerebral blood flow and protects against cerebral injury following focal cerebral ischemia. Stroke 1991; 22: 141(Abstract). 28 Johnson RL, and Koerner JF. Excitatory amino acid neurotransmission. J Med Chern 1988; 31: 2057-2066. 29 Gill R, Foster AC, Woodruff GN. Systemic administration of MK-80l protects aganstischaemia-induced hippocampal neurodegeneration in the gerbil. J Neurosci 1987; 7: 3343-3349. 30 McDonald JW, Silverstein FS, Johnston MY. MK-801 protects the neonatal brain from hypoxic-ischaernic damage. Eur J Pharmacol1987; 140: 359-361. 31 Albers GW, Goldberg MP, Choi DW. N-methyl-D-asparate antagonists; ready for clinical trial in brain ischemia? Ann Neurol 1989; 25: 398-403. 32 Greenberg JH, Uematsu D, Araki N, et al. Cytosolic free calcium during focal cerebral ischaemia and the effects of nimodipine on calcium and histologic damage. Stroke 1990; (Suppl): 72-77. 33 Gelmers HJ, Forter K, de Weerdt CJ, et al. A controlled trial of nimodipine in acute ischaemic stroke. New Engl J Med 1988; 318: 203-207. 34 Tomberg T, Magi M. Effect of calcium antagonists on cerebral blood flow in the acute stage of cerebral infarction. J Neuroll990; 237: 138. 35 Trust Study Group. Randomised double-blind, placebo-controlled trial of nimodipine in acute stroke. Lancet 1990; 336: 1205-1209. 36 Martinez- Villa E, Guillen F, Yuillaneuva JA, et al. Placebo-controlled trial of nimodipine in the treatment of acute ischemic cerebral infarction. Stroke 1990; 21: 1023-1028. 37 Norris JW, and Hachinski YC. High dose steroid treatment in cerebral infarction. BrMedJ 1986; 292: 21-23. 38 Sapolsky RM, Pulsinelli WA. Glucocorticoids potentiate ischemic injury to neurons; therapeuticimplications. Science 1985; 229: 1397-1400. 39 Italian Acute Stroke Study Group. Haemodilution in acute stroke: results of the Italian haemodilution trial. Lancet 1988; i: 318-321. 40 Shaper AG, Phillips AN, Pocock SJ, et al. Risk factors for stroke in middle-aged British men. Br Med J 1991; 302: 1111-1115. 41 Medical Research Council Working Party. Stroke and coronary heart disease in mild hypertension: risk factors and the value of treatment. Br Med J 1988; 296: 1565-1570. 42 Donnan GA, McNeil JJ, Adena MA, et al. Smoking as a risk factor for cerebral ischaemia. Lancet 1989; ii: 643-647. 43 Antiplatelet Triallists Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br Med J 1988; 296: 320-331.
