721

colon adenocarcinoma cell lines that express c-myb. Cancer Res 1991; 51: 2897-901.

33.

YS, Clair T, Tortora G, Yokozaki H, Pepi S. Suppression of malignancy targeting the intracellular signal transducing proteins of cAMP: the use of site selective cAMP analogs antisense strategy and gene transfer. Life Sci 1991; 48: 1123-32. 20. Szczylik C, Skorski T, Nicolaides NC, et al. Selective inhibition of BCR-ABL antisense cell leukemia proliferation by oligodeoxynucleotides. Science 1991; 253: 562-68. 21. Kolch W, Heidecker G, Lloyd P, Rapp UR. Raf-1 protein kinase is required for growth of induced NIH/313 cells. Nature 1991; 349: 19. Cho-Chung

426-28.

22. Vleminck K, Vakaet L, Mareel M, Fiers W, Van Roy F. Genetic of E-Cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 1991; 66: 107-19. 23. James RF, Edwards S, Hui KM, et al. The effect of Class II gene transfection on the tumorigenicity of the H-2K negative mouse leukemia cell line. Immunology 1991; 72: 213-18. 24.Rosenberg SA, Albersold P, Cornetta K, et al. Gene transfer into humans: immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med 1990; 323: 570-78. 25. Aebersold P, Hyatt C, Johnson S, et al. Lysis of autologous melanoma cells by tumor-infiltrating lymphocytes: association with cLnical response. J Natl Cancer Inst 1991; 83: 932-37. 26. Chen L, Thomas EK, Hu SL, Hellstrom I, Hellstrom KE. Human papilloma virus type 16 nucleoprotein E7 is a tumour rejection antigen. Proc Natl Acad Sci USA 1991; 88: 110-14. 27. Corey CA, Desilva AD, Holland CA, Williams DA. Serial transplantation of methotrexate-resistance bone marrow: protection of murine recipients from drug toxicity by progeny of transduced stem cells. Blood 1990; 75: 337-43. 28. Galski H, Sullivan M, Willingham M, et al. Expression of a human multidrug resistance CDNA(MDRI) in the bone marrow of transgenic mice. Mol Cell Biol 1989; 9: 4357-63. 29. Keith WN, Brown R, Pragnell IB. Retrovirus mediated transfer and expression of GM-CSF in haematopoietic cells. Br J Cancer 1990; 62: 388-94. 30. Huber BE, Richards CA, Krenitsky TA. Retroviral-mediated gene therapy for the treatment of hepatocellular carcinoma: an innovative approach for cancer therapy. Proc Natl Acad Sci 1991; 88: 8039-43. 31. Leone A, Flatow U, King CR, et al. Reduced tumor incidence, metastatic potential and cytokine responsiveness of nm23-transfected melanoma cells. Cell 1991; 65: 25-35. 32. Mercer WE, Shields MT, Lin D, Appella E, Ulrich SJ. Growth suppression induced by wild-type p53 protein is accompanied by selective down-regulation of proliferating-cell nuclear antigen

manipulation

expression. Proc Natl Acad Sci USA 1991; 88: 1958-62. Huang HJS, Yee JK, Shew JY, et al. Suppression of the neoplastic phenotype by replacement of the RB gene in human cancer cells. Science 1988; 242: 1563-66.

Johnson A, Kageyama R, Popescu NC, Pastan I. Expression and chromosomal localisation of the human transcriptional repressor GCF. J Biol Chem (in press). 35. Weissman BE, Saxon PJ, Pasquale SR, et al. Introduction of a normal

34.

human chromosome 11 into

a

Wilms

tumour

cell line controls its

tumorigenic expression. Science 1987; 175: 181. 36. Declue JE, Zhang KE, Redford P, et al. Suppression of transformation by over-expression of full length GTPA activating protein (GAP) or of the GAP C terminus. Mol Cell Biol 1991; 11: 2819-25. 37. Wallich R, Bulbuc N, Hammerling J, et al. Abregation of metastatic properties of tumour cells by de novo expression of H2K antigens following H2 gene transfection. Nature 1985; 315: 301-05. 38. Sadano H, Taniguchi S, Baba T. Newly identified types of &bgr;actin reduces invasiveness of mouse p16 melanoma. FEBS Lett 1990; 271: 23-27. 39. Vleminck K, Vakaet L, Mareel M, et al. Genetic manipulation of E cadherin expression by epithelial tumour cells reveals an invasion suppressor role. Cell 1991; 66: 107-19. 40. Giancotti FG, Ruoslahti E. Elevated levels of the alpha5 beta 1 fibrinectin receptor suppress the transformed phenotype of Chinese Hamster ovary cells. Cell 1990; 60: 849-59. 41. Leone A, Flatow U, King CR, et al. Reduced tumour incidence metastatic potential and cyclokine responsiveness of nn23 transfected melanoma cells. Cell 1991; 65: 25-35. 42. Rollins B, Sunday M. Suppression of tumour formation in vivo by expression of the JE gene in malignant cells. Mol Cell Biol 1991; 11: 3125-31. 43. Kitayama H, Sugimoto Y, Matsuzaki T, Ikawa Y, Noda M. A ras-related gene with transformation suppressor activity. Cell 1989; 63: 77-84. 44. Friedman T, Roblin R. Gene therapy for human genetic disease? Science 1972; 175: 949-55. 45. Friedman T. Progress towards gene therapy. Science 1989; 244: 1275-80. 46. Anderson WF. Prospects for human gene therapy. Science 1984; 226: 401-09. 47. Motulsky AG. Impact of genetic manipulation on society and medicine. Science 1983; 219: 135-40. 48. Recommendations of European Medical Research Councils. Gene therapy in man. Lancet 1988; 1: 1271-72. 49. Murray TH. Ethical issues in human genome research. FASEB J 1991; 5: 55-60. 50. Culver KW, Osborne WRA, Miller AD, et al. Correction of ADA deficiency in human T lymphocytes using retroviral-mediated gene transfer. Transplantation Proc 1991; 23: 170-71.

STROKE OCTET Complications of acute stroke

Acute stroke is remarkable not for the damage it inflicts but for the recovery it allows. Nevertheless, both recovery and survival can be jeopardised by cerebral, systemic, and cardiac complications. The causes vary with time after the stroke (table I). Rigorous attention to general medical factors can attenuate some of these effects (table n).

Cerebral

complications

Overall stroke-related case-fatality is about 20%; the percentage ranges from 15% for supratentorial and brainstem infarcts to 58% for supratentorial haemorrhage.1 Case-fatality from infratentorial haemorrhage is 31 %.1

Transtentorial herniation and cerebral oedema

During the first week,

transtentorial herniation is the of death (table i); the incidence of this peaks within 24 hours for cerebral and at 4-5 days for cerebral infarction.1

commonest cause

complication haemorrhage

Brainstem compression with subsequent haemorrhage and infarction accounts for the serious morbidity and mortality associated with herniation. Herniation is the result of raised intracranial pressure caused by cerebral oedema, and is seen with large strokes.2 Postmortem studies show microscopic cerebral oedema in 93% of stroke patients;2 this high figure may reflect selection bias in necropsy-based investigations. In an antemortem study, 41 % of 22 patients showed computed tomographic (CT) evidence of a mass effect associated with oedema.2There was a good correlation between infarct size, mass effect, midline shift, neurological ADDRESSES: Cerebrovascular Program, Johns Hopkins Hospital and Johns Hopkins University School of Medicine, Baltimore, Maryland, USA (S Oppenheimer, FRCPC), and Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario Canada (Prof V. Hachinski, FRCPC). Correspondence to Dr Stephen Oppenheimer, Johns Hopkins Hospital, Meyer 5-181, 600 N Wolfe Street, Baltimore MD 21205, USA.

722

TABLE I-CAUSES OF DEATH AFTER SUPRATENTORIAL STROKE DURING ACUTE AND SUBACUTE PERIODS FOLLOWING ADMISSION TO THE MACLACHLAN ACUTE STROKE UNIT, UNIVERSITY OF TORONTO*

TABLE II-TREATMENT FOR COMPLICATIONS OF ACUTE STROKE

*Modified from reference 1

status, and outcome. Only when associated with a mass effect did any subsequent increase in low-density area on a CT scan correlate with clinical deterioration. Animal studies indicate that oedema begins within hours of stroke onset with maximum volume at 2 days; these observations accord with clinical data.2 By contrast, CT studies suggest that fluid volume after infarction peaks in 7-10 days and oedema remains detectable for 1 month.2 These findings suggest that the peak frequency of herniation in the first week may depend more on the rate of fluid accumulation than on absolute volume. Another explanation is that stroke-induced changes in blood volume and tissue density make CT assessment of oedema

unreliable.2 At the time of maximum fluid accumulation, the blood-brain barrier remains intact according to CT and isotope studies, and endothelial tight junctions are maintained.2 This "cytotoxic" oedema differs in its CT scan appearance from the vasogenic type that accompanies cerebral tumours: it involves the cortex and is well circumscribed without the characteristic finger-like projections of tumour-associated fluid. After several days of ischaemia, breakdown of the blood-brain barrier leads to vasogenic oedema. Controlled trials have shown that steroid treatment of haemorrhagic or infarct-associated oedema does not improve outcome,3,4 so other means of fluid reduction are necessary if patients show clinical deterioration. Mannitol, by decreasing total cerebral volume, may be effective but only temporarily; paralysis and hyperventilation may also help. Decompression may be indicated, especially in patients with cerebellar stroke and signs of progressive brainstem compression.

I

I

*Figure refers to the incidence of silent aspiration and dysphagia m all stroke types 23 i Lower figure (17%) refers to ischaemic stroke and higher figure (70%) to cerebral

haemorrhage.21

fluid.

Haemorrhagic strokes are often cardioembolic in origin (see Hart, March 7, p 589); bleeding occurs when the embolus fragments with reperfusion via distal vessels that have previously been rendered ischaemic or via cortical collateral channels. Apart from a source of cardiogenic embolism, risk factors for haemorrhagic conversion include large infarct volume, midline shift, and increasing age, but not hypertension or anticoagulant therapy. Acute hydrocephalus due to compression of the aqueduct by blood or oedema may complicate cerebral haemorrhage and can lead to deterioration or death. Management includes ventricular shunting, reduction of cerebral oedema (with mannitol or hyperventilation) and haematoma evacuation.

Haemorrhagic transformation Haemorrhagic transformation, which occurs in 74% of cardioembolic strokes within 4 days’ and in 30%6 of all ischaemic strokes, can lead to clinical deterioration and death. At necropsy, cerebral haemorrhage is more commonly seen in association with herniation than are bland infarcts, possibly because of the greater frequency of cerebral oedema.** Neurological accompanying which is seen in 17% of transforming deterioration, haemorrhagic strokes, seldom occurs without a mass effect7 and can usually be explained by stroke size and presence of

Anticoagulation is often considered for patients with cardioembolic strokes because there is a high risk of re-embolisation during the acute staged Anticoagulants should not be prescribed for large infarcts or those with mass effect. When anticoagulation is indicated, it is best to wait until 4 days have elapsed from stroke onset, by which time most haemorrhagic transformations will have occurred. Seizures

Early seizures following stroke are usually single, focal, easily controlled with monotherapy.8,9 Seizures

and

723

of infarcts or haemorrhages8 and their presence correlates with cortical involvement. 33% occur within the first 2 weeks and 90% of these are within the first day.9 Whether seizures are more frequent after cardioembolic stroke than after other types of stroke is controversial.89 Early onset of seizures correlates with a large stroke 9 Seizure activity does not influence morbidity

complicate 11 %

or

mortality significantly. 8,9

Depression stroke patients become depressed10 and with proximity of the lesion to the correlates depression anterior left hemisphere. Observations in the subacute phase at 1 month do not accord with the acute findings, showing no association between depression and location of the lesion.ll The lack of a relation with the extent of physical disability suggests a direct neurophysiological effect, possibly due to involvement of central monoaminergic pathways. 10 Antidepressant therapy can bring about a considerable

50% of

acute

improvement. 12

Fever

Systemic complications tndocrlne aono/vna//es

Acute stroke

stroke in the absence of herniation. This observation has been associated with transient increases of plasma catecholaminesY We do not know whether stroke-induced hypertension correlates with ischaemia in areas of the brain concerned with autonomic control such as the insular cortex or the hypothalamus. In an animal model18 even transient increases in blood pressure adversely affected outcome, the most likely explanation being disruption of the blood-brain barrier and release of endothelium-derived procoagulants which limit the extent of subsequent reperfusion. Treatment of post-stroke hypertension is controversial. Since cerebral autoregulation is impaired in the acute phase, lowering systemic blood pressure could jeopardise cerebral blood flow. Severe increases in blood pressure (> 200 mm Hg systolic, > 120 mm Hg diastolic) should be treated with short-acting agents such as sodium nitroprusside or intravenous labetalol so that the effects can be reversed quickly if necessary; neurological status and blood pressure should be monitored frequently.

can

disturb endocrine

function, which

in

turn affects extension of the stroke, morbidity, and outcome.

Melamed13 noted that blood sugar was increased in 28% of acute stroke patients without a history of diabetes; this increase was thought to be a stress response. Case-fatality in the hyperglycaemic group was three-fold higher than in those with normal blood sugar. This stress response may be related to the increased concentrations of plasma catecholamines and cortisol that have been found after acute stroke, 14 which interfere with peripheral glucose metabolism. Another possibility is that only individuals with latent diabetes manifest a hyperglycaemic response to stroke and have a poor prognosis.’S Moderately raised blood glucose correlates with abnormal HbAlc concentrations; this finding points to disordered blood glucose control for several months preceding the stroke.1s Observations in man and animals show that hyperglycaemia, whether chronic or transitory, is associated with reduced cerebral blood flow, increased cerebral oedema, and larger infarcts.16 Since hyperglycaemia adversely affects outcome, patients with blood glucose in the frankly diabetic range should probably be treated with insulin by infusion in the acute phase and subsequently investigated for latent diabetes on recovery. In those with borderline diabetic glucose concentrations, intravenous glucose should be discontinued and those able to eat should be given a glucose-restricted diet. Inappropriate antidiuretic hormone secretion occurs in 10% of cerebral infarctions and 14% of cerebral haemorrhages1 and may initiate or exacerbate cerebral oedema. Manifestations include clinical deterioration and seizures; plasma sodium concentration and stroke score decline, reaching a nadir at 7-9 days. Treatment is with fluid restriction. However, in most cases hyponatraemia is an incidental finding in stroke patients unassociated with symptoms and no therapy is needed.

Hypertension Hypertension is a risk factor for stroke, and over 80% of acute stroke patients are hypertensive on admission. Stroke can worsen a pre-existing hypertensive state or even initiate hypertension. Patients may become hypertensive after

Fever accompanies about 44% of acute strokes’9 and correlates with stroke severity. In most cases the cause is infection (usually urinary or pulmonary) or deep vein thrombosis. Occasionally, fever is the direct result of stroke, especially with large strokes or those associated with intraventricular or hypothalamic haemorrhage. During the acute phase, even a FC increase is associated with a worse clinical outcome. The longer the fever persists the poorer the prognosis. Animal evidence indicates that increased temperature is associated with changes in blood-brain barrier permeability, with intracerebral acidosis and impaired phosphate metabolism, and with enhanced release of excitatory aminoacids. These effects were reversed by cooling.2O In addition, 2-3°C temperature reductions reduced the severity of ischaemic damage by 80-100%. Studies are underway to ascertain whether cerebral cooling is beneficial in human stroke.

Infection Infections are more common as a cause of death in the subacute phase (table I). Consequently, vigorous attention to infection (pulmonary, urinary, &c) may not only influence mortality but also morbidity in the subacute and chronic stages.

Pressure sores Pressure sores are occasionally encountered in the acute stage, especially in unconscious patients. Resulting skin infection can cause fever and lead to clinical deterioration. For prophylaxis, patients should be turned regularly and use of a ripple mattress is recommended.

Pulmonary embolism Pulmonary embolism is another cause of mortality in the subacute stage. In one study, deep vein thrombosis was detected in 53% of paretic legs after a stroke,21 and 9% of the patients got a pulmonary embolism. There was no correlation with age, obesity, days in bed, or severity of motor impairment. Pulmonary embolism may affect outcome via resultant fever or hypoxia. Prophylaxis with and low-dose anti-thromboembolism stockings subcutaneous heparin (5000 units twice daily) is prudent in all acute stroke patients, although heparin may be withheld if intracerebral haemorrhage is suspected.

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).