Ischaemic stroke : new frontiers.
Lot of advancement has taken place, not only in the management but also in the pathophysiology and imaging modalities in patients of stroke. Indolent chronic infections, particularly those due to H. pylori, have been identified as one of the risk factors. The mechanism of inflammation in inducing a precoagulant state has also been worked out. SPECT studies have detected ischaemic areas before appearance of CT abnormalities. CT angiography identifies abnormalities in the 'circle of willis' in posterior circulation strokes much better, and helps weigh the risk versus benefit of thrombolysis. With experiance in use of r-TPA, the list of contra indications and precautions has become longer than its indications. Newer drugs like lubeluzole and edselen have also been recommended. Various other drugs e.g. aptiganel hydrochloride, MDL 28170, 'basic fibroblast growth factor' and 'superoxide dismutase' are at an experimental stage. The concept of a 'stroke cocktail' may be in vogue soon. Controversies still exit regarding the exact indication of prophylactic anticoagulant and the 'international normalized ratio' (INR) to be achieved. Guidelines have been laid down for the approach to patients with asymptomatic carotid artery stenosis. However, the paramount message in stroke care is dissipation of the concept of 'brain attack', amongst the primary care medical and para-medical personnel.
It is well known that prior to occurrence of irreversible neuronal damage, an infarct passes through a `window period' of 3-6 hrs during which it is salvageable if circulation is restored. Delayed reperfusion however results in the release of inflammatory mediators, which accentuate neuronal death. Recent advances have implicated leukocytes and bacterial infection in contributing and aggravating the ischaemic insult. Strategies are underway to increase the window period, limit reperfusion injury and reduce the infarct size. The survival time of tissue after ischaemia depends mainly on the residual cerebral blood flow (CBF) through collaterals and on selective neuronal vulnerability to ischaemia. The electrical neuronal function of brain in the penumbra region is abolished but the neurons themselves are viable until the amount of ATP produced falls below 50% of normal values and the breakdown of energy producing metabolites causes lactic acidosis, ion pump failure and eventually irreversible membrane injury. Secondary to ischaemia there occurs a rise in intracellular sodium, calcium and free radicals resulting in cytotoxic oedema. Microcirculatory disturbance results in breach in blood brain barrier and increased expression of intercellular adhesion molecule (ICAM), producing vasogenic oedema [Figure 1]. On return of blood flow, together with resumption of oxygen delivery and provision of substrates for metabolism, interaction between blood and the already damaged tissue can be responsible for further tissue damage, which has been termed reperfusion injury. More sophisticated investigations are needed to complement early CT images to improve selection of patients for thrombolysis, who are at risk of reperfusion injury, and to use agents that increase the window period.
There is increasing evidence that the inflammatory response potentiates central nervous system (CNS) ischaemic injury. Tumour necrosis factor-alpha (TNF-ę) normally produced by macrophages, monocytes and astrocytes in the brain is increased during ischaemia and anti-TNF-ę monoclonal antibodies have been shown to decrease infarct size. TNF-ę alongwith other cytokines e.g. the interleukines (IL-6) increases the expression of adhesion receptors on the leukocytes (ICAM-1) and on endothelial cells (CD-18). Cytokines facilitate expression of E-selectin on endothelial cells which activate the neutrophils resulting in release of proteases (tissue injury) and recruiting platelet for thrombus formation [Figure 2]. Adhesion molecules namely intercellular adhesion molecule-1 (ICAM-1) expressed on leukocytes, fibroblasts, endothelial cells, and vascular cell adhesion molecule-1 (VCAM-1) are expressed on endothelial cells. These alongwith selectins (P-selectin and E-selectin), found on platelets and endothelial cells respectively, not only cause fissuring of atherosclerotic plaques but also peak during acute ischaemia. Accumulation of free radicals, ionic imbalances, anaerobic glycosis that follow an ischaemic insult result in activation of endothelial cells/platelets and upregulation of the cell surface glycoproteins mentioned above, causing a sludging of neutrophils with transendothelial migration. Once infiltrated into tissues, neutrophils are capable of releasing various proteases, lipid derived mediators and reactive oxygen species that can injure potentially salvageable cells. Currently pre-clinical trials have been completed combining antileukocyte adhesion therapy (anti CD-18, anti ICAM-1) with thrombolysis, as a part of a `stroke cocktail'. Similarly monoclonal antibodies to TNF-ę have been shown to limit infarct size.
Infection and stroke
Acute bacterial infection, mainly of the respiratory tract, has been identified as an independent risk factors for ischaemic stroke., This was found to be true particularly in young patients with stroke. It was also noted that the neurological deficit (assessed by the Scandanavian Stroke Scale) at admission, was more severe than in those without infection. Recurrent or chronic bronchial infection and chronic dental infection, as also chronic infection with Chlamydia pneumoniae and Helicobacter pylori has also been shown to increase the risk of cerebral ischaemia., Any long standing smouldring infection (dental, bronchial, gut) results in raised fibrinogen and C-reactive protein (CRP) levels which tilt the coagulation cascade in favour of thrombosis. Release of inflammatory cytokines (TNF, IL) and elastase (from activated granulocytes) also induce a procoagulant state. Besides, there occurs a fall in blood levels of protein C, Protein S, and antithrombin III which are promoters of anticoagulation pathway. Hence the internal milieu is set towards thrombus formation. The various pathogenetic processes involved are summarized in [Table I]. Till date, Indian literature is silent regarding conclusive data of the role of chronic infection in stroke, although currently trials are underway in some centres especially involving H. pylori infection.
Carotid Atherosclerosis and Other Risk Factors
Degree and progression of carotid atherosclerosis are directly related to cholesterol and LDL and inversely related to HDL and cessation of smoking. Amongst individuals with asymptomatic carotid disease the annual stroke risk has been reported as 1.3% in those with less than 75% stenosis and 3.3% in those with more than 75% stenosis. Control of modest elevations of LDL, limits the progression of asymptomatic carotid atherosclerotic plaque and reduces the number of stroke events. Long term exposure to arsenic has been postulated to accelerate carotid atherosclerosis and is now considered an independent risk factor of ischaemic stroke. Hypertension, diabetes mellitus, tobacco use and low haemoglobin concentration rather than level of cholesterol have been shown as important risk factors in our country. Advancing age, male sex, family history of stroke, hypertension, diabetes, smoking, hypercholesterolaemia and atrial fibrillation are well known risk factors for stroke. In younger patients studies are underway to assess the role of mitral annular calcification, patent foramen ovale, aortic arch atherosclerotic disease, atrial septal aneurysms, valvular strands and use of echocardiography contrast. Ongoing investigations are evaluating hypercoagulation factors such as antiphospholipid antibodies, protein C, protein S and factor V deficiencies, and hyperhomocysteinaemia. An analysis of various causes of stroke reveals that cerebral thrombosis related to pregnancy and puerperium and cardiogenic embolism are most common causes of stroke in young in India. Cerebral venous thrombosis is peculiar to the Indian sub-continent and is not a common cause of stroke in the west.
Brain and Vascular Imaging
An ideal imaging modality besides identifying the underlying disease should assess the pathophysiologic state of the cerebral circulation, and differentiate normal from dying and dead tissue, so as to choose the appropriate treatment. Ischaemic cytotoxic cerebral oedema does not develop above the critical flow level of 10-15 ml/100g/min. CT scan detects a 1% increase in tissue water content as a decrease in attenuation by 2.5 Hounsfield units (HU), i.e. affected tissue becomes darker or `hypodense' in relation to normal brain parenchyma, appearing as early as 3-6 hours. Such early parenchymal hypodensities delineate a volume of tissue that will later be necrotic. The increased tissue water content compromises local microcirculation and microcirculation and metabolism, setting up a vicious cycle. A retrospective analysis showed that an initial hypodense tissue volume exceeding 50% of the MCA territory is associated with a 85% mortality. Recently the prognosis (death or severe disability) has been shown to progressively worsen as per the initial CT findings. Patients without any parenchymal hypodensity fare better than those with small hypodensities of less than 33% of MCA territory. Those having larger hypodensities, with or without treatment using recombinant tissue plasminogen activator (r-tpa), have the poorest outcome.
CT angiography (CTA) has evolved as a recent tool, particularly in the assessment of collaterals where the ischaemic oedema is small in relation to the occluded artery, so as to evaluate the risk/benefit ratio of thrombolytic therapy. If the entire territory is involved, the likelihood of irreversible damage is high and thrombolysis would not be indicated. For CTA, 130ml of a non ionic contrast agent is infused into an antecubital vein at a rate of 4-5ml/sec using an injection pump. Twenty seconds later a spiral CT scan with 1.5-2.0mm section thickness is performed covering the circle of Willis.
Newer modalities have come up to detect metabolic abnormalities signifying ischaemic injury within the window period of stroke. As cerebral blood flow drops (<18ml/100gm brain tissue) there is a reduction in the high energy phosphates e.g. ATP and phosphocreatinine with concomitant increase in lactate. Diffusion weighted MRI detects the area of lactate accumulation as early as 105 minutes and MR spectroscopy accurately identifies the regions low in high energy phosphate within 2 hours of the ischaemic insult. Positron emission tomography (PET) outlines an increase in oxygen extraction fraction (OEF) within 1 hour of drop in regional blood flow. With the advent thrombolysis, the need arose for prediction of `symptomatic haemorrhagic transformation' (SHT) following use of such therapy. Members of the `brain imaging council' of the `Society of Nuclear Medicine' recommend the use of single-photon emission CT (SPECT) scanning with hexamethyl propyleneamine oxime (HMPAO) in stroke units for identifying patients at risk for haemorrhage on being subjected to rTPA therapy. The normal adult dose of HMPAO is 10-20 mCi given intravenously in a bolus, and the scanning time is 20-30 minutes. SPECT can be done even in severely ill patients and allows visualization of the depth, extent, and location of ischaemia when the CT scan is negative or inconclusive. The predictive factors identifying patients at risk for symptomatic haemorrhage is summarized in [Table II]. Unfortunately there are very few centers in the country today, having facilities for SPECT.
The foremost guideline is to increase the awareness amongst paramedics and residents in emergency services regarding the concept of a `brain attack' and the `window period', so as to dispel the general apathy in handling cases of stroke. Prior to definitive therapy, brief preliminary investigations to be carried out are summarized in [Table III].
Acute stage : The first steps in the emergency room include assessment of vital functions, and ensuring proper tissue oxygenation and circulation. Cautious use of oral antihypertensive agents is indicated only in patients with markedly elevated blood pressure (systolic>220 mm Hg or mean pressure>130 mm Hg). Rapid lowering of blood pressure using intravenous nitroprusside or sublingual nifidepin is to be avoided, unless thrombolysis is contemplated. Ideal agents for use should not have any effect on the already compromised cerebral auto-regulation, e.g. labetolol and enalapril. In the acute stage, except for thrombolysis, judicious use of anti-coagulants, steroids, haemodilution, calcium channel blockers and gangliosides have yielded negative results in randomized placebo controlled trials.
Thrombolysis : Various agents including streptokinase, urokinase and rTPA administered intravenously and/or intra-arterially, with local infusion have been studied, and the superiority of intravenous rTPA has been established. SPECT studies have demonstrated reperfusion after rTPA therapy. Two large trials, National Institute of Neurological Disorders and Stroke (NINDS) trial and the European Cooperative Acute Stroke Study (ECASS), have generated a lot of controversy regarding the use and safety of rTPA. The 4th conference on thrombolytic therapy in acute ischaemic stroke in June 1996 concluded that the NINDS trial used a 3 hour window period and lower dosage (0.9 mg/kg) thereby accounting for better results than the ECASS group. Presently use of rTPA is recommended in cases of stroke aged >18 years with onset of symptom < 3 hours, in a dosage of 0.9mg/kg (maximum of 90 mg) infused over 60 minutes with 10% of the total dose administered as an initial intravenous bolus over 1 minute. The contraindications are listed in [Table IV]. If these recommendations are followed strictly, rate of haemorrhages can be reduced to 10% with fatality occurring in only 3% of cases.
Anticoagulants and anti-platelet drugs : Recently, the International Stroke Trial (IST) addressing the question of aspirin and/or anti-coagulants has been completed. Aspirin (300 mg daily) has clearly been shown to reduce risk of recurrent ischaemia without any change in the degree of disability at 6 months compared to placebo. Any advantages of these parameters in using heparin was offset by the slight increased risk of haemorrhage. The best risk benefit ratio was obtained with the combination of aspirin and low dose heparin (5000 IV twice a day) probably by additionally decreasing the risk of deep vein thrombosis. The IST included all cases of ischaemic stroke. Since only 15-20% are cardioembolic in origin (of which atrial fibrillation is the major contributor), the benefits of anticoagulants in a setting of atrial fibrillation may have been underplayed. Current guidelines suggest that such patients should be given anti-thrombotic therapy. Similarly, there is no controversy regarding the use of heparin in a progressive stroke due to vertebro-basilar ischaemia.
To obviate the risk of haemorrhage, low molecular weight heparin has been designed. When administered subcutaneously within 48 hours in a dosage of 4,100 antifactor Xa IU twice daily, the degree of dependency has been shown to be significantly reduced. The main advantages are lower incidence of heparin induced thrombocytopaenia and no risk of haemorrhagic transformation. The patients do not require monitoring of coagulogram and its efficacy against deep vein thrombosis. The benefits of low molecular weight heparin in presumed posterior circulation strokes have been of doubtful significance. Patients having a clinical setting of ischaemic stroke on arrival in the emergency services should have a non-contrast CT (to rule out haemorrhage), electrocardiogram and if neccessary echocardiography ( to assess the cardiac status), alongwith a baseline coagulogram (for monitoring subsequent anticoagulant therapy). Non-haemorrhagic stroke proved by CT scan (within 3 hours of onset of symptoms) should receive r-TPA therapy provided there is no contraindication [Table V]. Subsequently if this group has a cardiac lesion neccessitating anticoagulants, such therapy should be delayed by 24 hours, after administration of r-TPA. Patients with an infarct size of less than one-third of the hemisphere with atrial fibrillation, and those presenting as `stroke in evolution' should receive anticoagulants. These may need to be continued upto 1 year, except in those aged less than 65 years and harbouring a cardiac lesion with atrial fibrillation wherein life long anticoagulation is required. Patients without a cardiac lesion and those with larger infarcts may be put on a combination of disprin and low molecular weight heparin (prophylactic dose for deep venous thrombosis). Later a carotid doppler would decide between surgical intervention versus medical therapy, as detailed in secondary prevention later. The approach to patient of ischaemic stroke is summarized in [Figure 3].
NMDA receptor and glutamate antagonists : Glutamate antagonism can ameliorate the extant of infarction. Non competitive blockers of the ion channel e.g. aptiganel hydrochloride is currently in phase III trials using 2 dose schedules; (i) 3 mg over 5 minutes followed by 6 mg infusion over 12 hour, or (ii) 5 mg over 5 minutes followed by 9 mg infusion over 12 hours. Competitive blockade using selfotel should not exceed 1.5 mg/kg in conscious stroke patients, to avoid the adverse effects like confusion, agitations or hallucinations. Another agent, lubeluzole (benzothiazole group) inhibits nitric oxide related neurotoxicity in ischaemia. When given within 6 hours of onset of symptoms as an infusion over 1 hour (7.5 mg) followed by 10 mg daily for 5 days, there is a better neurological outcome at 8 weeks.
Membrane stabilizers : For optimal efficacy cytoprotective agents should be administered within the window period although the maximal permissible period varies amongst different agents. Piracetam, when given within 7 hours of onset of symptoms as a 12gm intravenous bolus and then 4.8 gm daily for 4 weeks, has been reported to result in better recovery. It is postulated to decrease hypoxia induced membrane damage, increase ATP production, enhance neurotransmission and second messenger activity. However another agent Ebselen is efficacious even when started upto 48 hours of stroke onset. A lipid soluble seleno organic compound (2 phenyl -1,2 benzisoselenazol - 3[2H]), ebselen inhibits lipid peroxidation through a glutathione peroxidase like action. Available as granules, 150 mg twice a day orally is given for 2 weeks.
Experimental agents awaiting clinical trials : Basic fibroblast growth factor given intravenously has been shown to limit infarct size in focal cerebral ischaemia. Similarly MDL 28170 inhibits intracellular calcium dependent proteases e.g. calpain, when administered in the 6 hour window period. Recently antioxidant enzymes, especially superoxide dismutase (SOD) activity in serum of stroke patients has been shown to inversely correlate with neurological deficit. Hence presently efforts are on to increase SOD enzyme activity in ischaemic stroke, by exogenous administration.
Some studies have reported encouraging result of emergency carotid endarterectomy, in patients with mild to moderate neurological deficits. Preliminary data regarding angioplasty in both anterior and posterior circulation strokes are too small to make any recommendations. Anecdotal reports have indicated the benefits of emergency percutaneous carotid stenting in an evolving stroke with significant carotid artery stenosis (>80%). However emergent extracranial-intracranial artery bypass surgery has failed to improve outcome and may be associated with a higher risk of haemorrhage, in strokes involving either the carotid or vertebro-basilar territories. Until randomized trials are available, there is no role of surgery in acute stroke as of date.
Medical complications that follow ischaemic stroke not only increase the mortality but also influence functional outcome. The frequency of severe disability (non ambulatory-totally dependent) of 7% to 19% has been reported. In a recent study of complicated stroke, the mortality at 3 months was 14%. 16% of the patients were left with a severe residual disability. The common medical events were pneumonia, urinary tract congestive cardiac failure, gastrointestinal bleed, deep vein thrombosis, hypoxia, and pulmonary embolism. Serious neurological events included extension of infarct, brain oedema, metabolic, encephalopathy, intraparenchymal haemorrhage and seizures. The medical events were associated with a poorer outcome than neurological events complicating stroke.
Antiplatelet drugs : In 1994 a meta-analysis by the Antiplatelet Trialists' Collaboration concluded that antiplatelet therapy prevents between 20 and 30 strokes for every 1,000 cases treated. The optimal dosage of aspirin has been hotly debated, although in a recent meta-analysis Algra and van Gijan found that any dosage between 30 mg to 1500 mg was efficacious. Most physicians use aspirin in the range of 150-625 mg daily.
Early trials of aspirin plus dipyridamole were unable to detect a significant benefit for combination therapy over aspirin alone. The large ESPS-2 trial has recently provided clear evidence that a combination of low dose aspirin (50mg) plus sustained release dipyridamole (400 mg) daily, more than doubled the risk reduction in stroke risk achieved with aspirin alone.
Episodes of transient ischaemic attack in some patients of ischaemic stroke receiving aspirin are known to occur. Recently the development of `aspirin resistance' has been demonstrated by incomplete inhibition of platelet aggregation on repeat testing at 6 months. Thus, a fixed dose of aspirin does not have a constant antiplatelet effect over time in all the patients. Such cases of `aspirin failures'can be treated with ticlopidine 250mg twice a day. Ticlopidine has also been recommended in patients not tolerating aspirin, diabetics and elderly women.
Oral anticoagulants (Warfarin) have been unequivocally proved to be effective in a setting of atrial fibrillation. The benefits are even greater in symptomatic patients than in primary prevention i.e. those persons without a history of cerebrovascular ischaemia but with risk factors. Comparing aspirin with warfarin in the age groups above and below 65 years with regards to risk/benefit ratios, aspirin is preferred in patients of less than 65 years age having lone atrial fibrillation. Warfarin is indicated in patients above the age of 65 years despite normal cardiac evaluation, and cases with associated valvular heart disease/IHD, immaterial of age. The use of anticoagulants above the 85 years of age needs intensive monitoring as the risk of haemorrhage is very high. However two large studies have shown that ischaemic stroke associated with atrial fibrillation is not only more severe at the onset but also has a poorer outcome., Thus anticoagulants have emerged as the mainstay of secondary prophylaxis against stroke patients having atrial fibrillation so as to maintain a prothrombin time index (PTI) of 1.25-1.5 and international normalized ratio (INR) at approximately 2.5. The Stroke Prevention in Reversible Ischaemia Trial (SPIRIT) study group has shown that anticoagulant therapy with an INR range of 3.0 to 4.5 is associated with an unacceptably high rate of bleeding complications when compared to aspirin.
Carotid Endarterectomy (CEA) and Arterial Stenting (AS)
CEA is three times as effective as medical therapy alone in reducing incidence of stroke in patients with symptomatic stenosis of 70-99%. Various CEA trials in patients with TIAs or minor stroke have shown the following : (i) if the symptoms are referable to a >70% stenosis at the carotid bifurcation, CEA reduces the risk of subsequent ipsilateral stroke from 26% (during the first 2 years with optimal medical management) to 9%, (ii) the benefit assumes a perioperative risk of stroke or death of <50% (iii) surgery is not of benefit for <50% stenosis, (iv) the risk/ benefit of CEA for 50% to 70% stenosis is presently unknown. In another study CEA in patients of asymptomatic stenosis (>60) has shown a 55% relative risk reduction of ipsilateral strokes. However, the perioperative risk and complication rate should be maintaineded at a low rate (<3%), to keep the beneficial effects of carotid endarterectomy over medical therapy. The guidelines for patients with asymptomatic carotid artery disease laid down by the stroke council (American Heart Association) are tabulated in [Table V]. The post operative complications of carotid endarterectomy include wound haematoma, hypertension, hyperperfusion syndrome, intracerebral hemorrhage and seizures. The final decision has to depend on the expertise for the procedure in the concerned hospital versus patient's clinical status.
Apart from meeting the selection criteria mentioned above patients had to be free of major potential cardiac causes of stroke or other medical illness. It is this limitation that prompted the development of carotid arterial stenting (AS), carried out by a percutaneous procedure through the femoral route. Appropriately sized guiding catheters are positioned in the carotid artery just proximal to the segment to the treated. Angular angiographic views are recorded to display the stenosis and tip of the guiding catheter. Quantitative carotid angiography (QCA) facilitates measurement of the diameter of the vessel and sizing of the balloons and stents to be deployed. By this procedure Yadav and colleagues demonstrated encouraging results in a series of 107 patients involving 126 stenosed carotid arteries (mean pre-operative minimal luminal diameter of 1.3.mm). 77% were high risk cases who did not meet the selection criteria for CEA. Mean hospital stay was 1.9 days with low risk (30 days risk of stroke or death was 9.3%), and only a 4.9% incidence of asymptomatic restenosis by 6 months. Ultimately a randomized trial comparing percutaneous stenting with carotid endarerectomy may be indicated. Presently, AS is best-reserved for high-risk patients not suitable for CEA, until further data is available.
Encouraging modalities of treatment have emerged for the care of patients with acute ischaemic stroke. However, in this `decade of the brain' wide disseminatin of these advances amongst primary care physicians is essential to dispel the nihilistic attitude towards patients of stroke. Advance in CEA and AS require a team effort of interventional neurologists, cardiologists, radiologists and neurosurgeons especially in the secondary prevention of stroke.
Major Ongoing Stroke Trials
1. European and Australian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) : Anticoagulants versus combination of aspirin and dipyridamole versus aspirin alone in patients with TIA or nondisabiling stroke. Started July 1997 involving 9 countries and 13 hospitals results expected in July 2003.
2. Alteplase Thrombolysis for Acute Non-interventional Therapy in Ischaemic Stroke (ATLANTIS) : A multicenter placebo-controlled trial using activase- rTPA in U.S. and Canada.
3. Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) : Randomized multicentre study of the benefits/risks of the procedure and comparison of carotid angioplasty with carotid endarterectomy. (Europe, North America. Australia). Started in 1992. Follow up still continuing.
4. European and Australian Cooperative Stroke Study II (ECASS-II) : A placebo controlled trial using alteplase (activase rTPA) in upto 6 hours of onset of symptoms and judging the efficacy at 90 days. 800 patients from 100 centers of 15 countries (October 1996-continuing).
5. Intravenous Magnesium Efficacy in Stroke Trial (IMAGES) : A randomized, double-blind, placebo controlled trial to test the efficacy of magnesium sulfate given within 12 hours of onset of acute stroke. 2700 patients to be recruited from 50 centres over a period from July 1997- July 2000.
6. Patient Foramen Ovale (PFO) in Cryptogenic Stroke Study (PICSS) : To assess the efficacy of warfarin or aspirin in the recurrence of stroke in patients with transoesophageal echocardiographically (TE) defined PFO. Data from 47 centres (July 1994 - June 2000).
7. Triflusat versus Acetylsalicylic Acid in Secondary Prevention of Cerebral Infusion (TACIP study) : A prospective randomized, double-blend trial to compare the efficacy of triflusal (600 mg OD) versus aspirin (325 mg OD) in secondary prevention of cerebral infarction. 2100 patients from 43 centres have been followed up (March 1996-March 1999).
8. Very Early Nimodipine Use in Stroke (VENUS) : A double blind trial to assess the efficacy of nimodipine (30 mg 6 hourly) for 10 days and started within 6 hours of stroke onset, versus placebo. Outcome assessed at 3 months and involves 1000 centres. (started October 1994)