1255
EDITORIALS
Operating to prevent stroke "A mild attack of apoplexy may be called death’s
retaining
fee"--Gilles Menage (1613-1692).
In this issue (p 1235) we publish the interim results of a major trial of surgery for carotid stenosis. The findings will have a profound impact on the management of patients who have sustained a transient ischaemic attack (TIA) or other minor ischaemic event as a result of carotid disease. Each year in the UK about 50 people per 100 000 have a TIA1 and 200 per 100 000 have a completed stroke; the figures are similar for other western countries. At least 10% of those with a completed stroke report a preceding transient event.2 A TIA confers a thirteenfold increased risk of stroke in the first year after the event and a seven-fold excess risk for the seven years thereafter. Occurrence of a TIA also indicates that these patients are more likely to have coronary artery disease, so their overall risk of death, stroke, or myocardial infarction is about 10 % annually.3What can be done to delay payment of death’s retainer and prevent these strokes for which there is advanced
warning? About 80% of TIAs are in the carotid artery territory. The longstanding view that transient strokes were due to "vasospasm" was discredited by in the late 1940s.4 In the next decade, as a Pickering result of Miller Fisher’s observation that extracranial artery atheroma was associated with ischaemic stroke, transient attacks were attributed to flow reduction by carotid stenosis or embolism from atheromatous carotid plaques. The successful reconstruction of the stenosed carotid artery of a patient with TIAs by Eastcott, Pickering, and Rob in 19545 heralded the development of carotid endarterectomy for extracranial carotid artery disease. This operation has now become one of the commonest surgical procedures in the USA. In the UK, carotid endarterectomies are done twenty-seven times less frequently per head of population than in the USA and seven times less frequently than in Canada.66 Within the USA there are wide variations in the frequency with which this operation is carried out, and doubt has been expressed about the need for many of the procedures. In the UK confusion about the appropriate
management of TIAs is reflected in the wide variation in the rate with which carotid angiography (a prerequisite for endarterectomy) is conducted in such patients. In the UK-TIA Aspirin Trial the neurologists’ angiography rate varied from 3% to 100%.7 Of the 41 patients in this trial who had carotid surgery, 10 (24%) sustained a perioperative stroke, of whom 4 died, so in these patients endarterectomy was a dangerous procedure. Other reports up to the early 1980s revealed a risk of perioperative stroke or death of 2-5-21-9%. Of these, only one-the Joint Study of Extracranial Arterial Occlusion published in 19778 -was a randomised prospective study. In this small trial a perioperative risk of 11% (stroke or death) negated the statistically insignificant improved outcome with respect to stroke or death in the operated group. Subsequent non-randomised uncontrolled series showed a reduction in the stroke rate after endarterectomy of 2% per year at an initial perioperative stroke risk of 3%. That this outcome is an improvement on the natural history previously reported was said to be justification for the procedure.9 Nevertheless, in the early 1980s it was perceived that full-scale controlled trials were needed to assess the benefit of endarterectomy and to determine the level of perioperative risk at which the procedure becomes acceptable. Several very large trials are now underway, including the European Carotid Surgery Trial (ECST), which started in 1981, and the North American Symptomatic Carotid Endarterectomy Trial (NASCET), which began in 1988. A "clinical alert" from NASCET indicated that carotid endarterectomy is very effective in preventing stroke following TIA in patients with a severe stenosis (greater than 70%).10 The interim results reported this week from ECST-already the largest randomised trial of any
surgical procedure-show a striking preventive effect endarterectomy in patients with TIA or minor (non-disabling) stroke who have a severe stenosis. Despite a 7-5% perioperative risk of significant stroke (symptoms lasting more than 7 days) or death, patients randomised for endarterectomy had a six-fold reduction in the rate of stroke on that side compared with unoperated patients. Disabling or fatal strokes were reduced at least eight-fold. For those with mild carotid stenosis (less than 30%) any benefits of surgery are outweighed by the risks of the procedure; endarterectomy is therefore not recommended as first-line treatment in these patients, who should be treated with aspirin." For patients with an intermediate degree of stenosis (30-69%) the trial has not produced an answer and randomisation for this of
group continues.
The ECST results are a further vindication of the value of large cooperative randomised trials to answer important clinical questions. This trial also illustrates the value of applying the uncertainty principle in clinical medicine. Thus clinicians were encouraged to randomise only patients about whom they
1256
experienced "uncertainty" as to whether an endarterectomy was indicated. In this way all were at liberty to heed their intuitive convictions but these were, as it transpired, sufficiently variable to produce a heterogeneous mixture of severity of carotid disease for analysis. So clinicians now know that if a patient with a carotid territory TIA (there is a differential diagnosis12) has severe stenosis of the artery they should recommend endarterectomy. The procedure should be carried out, within the next few weeks, by a surgical team whose operative risks are known to be at least as low as those in the ECST. In the ECST, although patients who underwent surgery within an hour of the TIA did badly, there was a suggestion that the benefits of surgery would wane if operation was delayed by even a few months. How can the patients with severe stenosis be identified? Should those with a TIA who are fit for and consent to operation undergo carotid angiography? In the UK, this investigation costs the health service about c520, and in 1 patient in 100 it will lead to a disabling stroke.13 Nationally about 17 000 people will have a carotid TIA (more if minor completed strokes are included) each year. If 10 000 are candidates for surgery, a policy of angiography in all to identify the 20% with a severe stenosis would cost 1000 people a stroke and the health service 520 000 (plus the capital costs of extra angiography facilities). A screening process is clearly required. To detect severe carotid disease, auscultation over the artery is helpful but insufficiently sensitive. Duplex ultrasonography13 is most cost effective; this investigation would exclude the 80% of patients with TIA who do not have severe stenosis and reduce angiography costs but would not deny the benefits of surgery to those in whom an operation is likely to be effective. In the UK the frequency of carotid endarterectomies is likely to increase (perhaps three to five fold) whereas in some areas of North America it will probably decline. Most UK districts will not have the duplex ultrasonography and angiography facilities or the surgical resources to cope with the likely demand. Surgeons carrying out endarterectomies will be expected to audit their performance to ensure that low complication rates are maintained. Waiting times will have to be very short for assessment and for surgery if adequate prevention of strokes is to be achieved. The new health service management structure will be sorely tested.
There are some unanswered questions, apart from the efficacy of surgery in moderate symptomatic carotid stenosis. For example, what should one do about symptom-free individuals in whom carotid stenosis is picked up incidentally? The ECST trialists comment that the size of the surgical effect on the outcome of carotid stenosis in those with symptoms is such that the question of surgery for symptomless
stenosis is worth examining; several underway in North America.
large trials
are
1. Dennis MS, Bamford JM, Sandercock PAG, Warlow CP. Incidence of transient ischaemic attacks in Oxfordshire, England. Stroke 1989; 20: 333-39. 2. Mohr JP, Pessin MS. Extracranial carotid artery disease. In: Barnett HJM, Stein BM, Mohr JP, Yatsu FM, eds. Stroke: pathophysiology, diagnosis and management. New York: Churchill Livingstone, 1986: 293-336. 3. Dennis MS, Bamford JM, Sandercock PAG, Warlow CP. The prognosis of transient ischaemic attacks in the Oxford Community Stroke Project. Stroke 1990; 21: 848-53. 4. Pickering GW. Transient cerebral paralysis with hypertension and cerebral embolism. JAMA 1948; 137: 848-53. 5. Eastcott HHG, Pickering GW, Rob CG. Reconstruction of the internal carotid artery in a patient with intermittent attacks of hemiplegia. Lancet 1954; ii: 994-96. 6. Barnett HJM. Symptomatic carotid endarterectomy trials. Stroke 1990; 21 (suppl III): III-2-III-5. 7. UK-TIA Study group. Variation in the use of angiography and carotid endarterectomy by neurologists in the UK-TIA Aspirin trial. Br Med J 1983; 286: 514-17. 8. Warlow CP. Carotid endarterectomy: does it work? Stroke 1984; 15: 1068-76. 9. Sundt TM, Dyken ML Surgical treatment for ischaemic vascular disease. In: Harrison MJG, Dyken ML, eds. Cerebral vascular disease. London Butterworths; 1983: 284-308. 10. National Institute of Neurological Disorder and Stroke. Clinical alert: Benefit of carotid endarterectomy for patients with high grade stenosis of the internal carotid artery. February, 1991. 11. UK-TIA Study Group. United Kingdom transient ischaemic attack (UK-TIA) Aspirin Trial: interim results. Br Med J 1988; 296: 316-20. 12. Allen CMC, Harrison MJG, Wade DT. The management of acute stroke. Tunbridge Wells: Castle House, 1988: 85-95. 13. Hankey GJ, Warlow CP. Symptomatic carotid ischaemic events: safest and most cost effective way of selecting patients for angiography before carotid endarterectomy. Br Med J 1990; 300: 1485-91.
Phenylketonuria
grows up
It is clear to anyone who has seen untreated patients with phenylketonuria (PKU) that the introduction of a national neonatal screening programme to detect and treat this condition is one of the successes of modern medicine. The defective enzyme in PKU is phenylalanine hydroxylase, which catalyses the conversion of phenylalanine to tyrosine. The incidence of this autosomal recessive disorder in the USA, the UK, and most of Western Europe is between 1 in 11 000 and 1 in 15 000, although in Ireland it is much more common (1 in 4500). Screening is carried out in the UK between days 6 and 14 and, if the diagnosis is confirmed, dietary treatment is started, ideally before day 21. The aim is to lower the blood phenylalanine concentration to between 100 and 400 µmol/1 (the exact upper limit is still controversial and varies between clinics) by the combination of protein restriction and an aminoacid supplement that contains extra tyrosine and all the essential aminoacids except phenylalanine. Tyrosine becomes an essential aminoacid in this disorder. The severe mental retardation and behavioural problems seen in almost all untreated patients with PKU are caused by a combination of hyperphenylalaninaemia and hypotyrosinaemia. For many years it was thought that only the developing brain was susceptible to damage and the diet was stopped, usually at about 8 years of age.
EDITORIALS
Operating to prevent stroke "A mild attack of apoplexy may be called death’s
retaining
fee"--Gilles Menage (1613-1692).
In this issue (p 1235) we publish the interim results of a major trial of surgery for carotid stenosis. The findings will have a profound impact on the management of patients who have sustained a transient ischaemic attack (TIA) or other minor ischaemic event as a result of carotid disease. Each year in the UK about 50 people per 100 000 have a TIA1 and 200 per 100 000 have a completed stroke; the figures are similar for other western countries. At least 10% of those with a completed stroke report a preceding transient event.2 A TIA confers a thirteenfold increased risk of stroke in the first year after the event and a seven-fold excess risk for the seven years thereafter. Occurrence of a TIA also indicates that these patients are more likely to have coronary artery disease, so their overall risk of death, stroke, or myocardial infarction is about 10 % annually.3What can be done to delay payment of death’s retainer and prevent these strokes for which there is advanced
warning? About 80% of TIAs are in the carotid artery territory. The longstanding view that transient strokes were due to "vasospasm" was discredited by in the late 1940s.4 In the next decade, as a Pickering result of Miller Fisher’s observation that extracranial artery atheroma was associated with ischaemic stroke, transient attacks were attributed to flow reduction by carotid stenosis or embolism from atheromatous carotid plaques. The successful reconstruction of the stenosed carotid artery of a patient with TIAs by Eastcott, Pickering, and Rob in 19545 heralded the development of carotid endarterectomy for extracranial carotid artery disease. This operation has now become one of the commonest surgical procedures in the USA. In the UK, carotid endarterectomies are done twenty-seven times less frequently per head of population than in the USA and seven times less frequently than in Canada.66 Within the USA there are wide variations in the frequency with which this operation is carried out, and doubt has been expressed about the need for many of the procedures. In the UK confusion about the appropriate
management of TIAs is reflected in the wide variation in the rate with which carotid angiography (a prerequisite for endarterectomy) is conducted in such patients. In the UK-TIA Aspirin Trial the neurologists’ angiography rate varied from 3% to 100%.7 Of the 41 patients in this trial who had carotid surgery, 10 (24%) sustained a perioperative stroke, of whom 4 died, so in these patients endarterectomy was a dangerous procedure. Other reports up to the early 1980s revealed a risk of perioperative stroke or death of 2-5-21-9%. Of these, only one-the Joint Study of Extracranial Arterial Occlusion published in 19778 -was a randomised prospective study. In this small trial a perioperative risk of 11% (stroke or death) negated the statistically insignificant improved outcome with respect to stroke or death in the operated group. Subsequent non-randomised uncontrolled series showed a reduction in the stroke rate after endarterectomy of 2% per year at an initial perioperative stroke risk of 3%. That this outcome is an improvement on the natural history previously reported was said to be justification for the procedure.9 Nevertheless, in the early 1980s it was perceived that full-scale controlled trials were needed to assess the benefit of endarterectomy and to determine the level of perioperative risk at which the procedure becomes acceptable. Several very large trials are now underway, including the European Carotid Surgery Trial (ECST), which started in 1981, and the North American Symptomatic Carotid Endarterectomy Trial (NASCET), which began in 1988. A "clinical alert" from NASCET indicated that carotid endarterectomy is very effective in preventing stroke following TIA in patients with a severe stenosis (greater than 70%).10 The interim results reported this week from ECST-already the largest randomised trial of any
surgical procedure-show a striking preventive effect endarterectomy in patients with TIA or minor (non-disabling) stroke who have a severe stenosis. Despite a 7-5% perioperative risk of significant stroke (symptoms lasting more than 7 days) or death, patients randomised for endarterectomy had a six-fold reduction in the rate of stroke on that side compared with unoperated patients. Disabling or fatal strokes were reduced at least eight-fold. For those with mild carotid stenosis (less than 30%) any benefits of surgery are outweighed by the risks of the procedure; endarterectomy is therefore not recommended as first-line treatment in these patients, who should be treated with aspirin." For patients with an intermediate degree of stenosis (30-69%) the trial has not produced an answer and randomisation for this of
group continues.
The ECST results are a further vindication of the value of large cooperative randomised trials to answer important clinical questions. This trial also illustrates the value of applying the uncertainty principle in clinical medicine. Thus clinicians were encouraged to randomise only patients about whom they
1256
experienced "uncertainty" as to whether an endarterectomy was indicated. In this way all were at liberty to heed their intuitive convictions but these were, as it transpired, sufficiently variable to produce a heterogeneous mixture of severity of carotid disease for analysis. So clinicians now know that if a patient with a carotid territory TIA (there is a differential diagnosis12) has severe stenosis of the artery they should recommend endarterectomy. The procedure should be carried out, within the next few weeks, by a surgical team whose operative risks are known to be at least as low as those in the ECST. In the ECST, although patients who underwent surgery within an hour of the TIA did badly, there was a suggestion that the benefits of surgery would wane if operation was delayed by even a few months. How can the patients with severe stenosis be identified? Should those with a TIA who are fit for and consent to operation undergo carotid angiography? In the UK, this investigation costs the health service about c520, and in 1 patient in 100 it will lead to a disabling stroke.13 Nationally about 17 000 people will have a carotid TIA (more if minor completed strokes are included) each year. If 10 000 are candidates for surgery, a policy of angiography in all to identify the 20% with a severe stenosis would cost 1000 people a stroke and the health service 520 000 (plus the capital costs of extra angiography facilities). A screening process is clearly required. To detect severe carotid disease, auscultation over the artery is helpful but insufficiently sensitive. Duplex ultrasonography13 is most cost effective; this investigation would exclude the 80% of patients with TIA who do not have severe stenosis and reduce angiography costs but would not deny the benefits of surgery to those in whom an operation is likely to be effective. In the UK the frequency of carotid endarterectomies is likely to increase (perhaps three to five fold) whereas in some areas of North America it will probably decline. Most UK districts will not have the duplex ultrasonography and angiography facilities or the surgical resources to cope with the likely demand. Surgeons carrying out endarterectomies will be expected to audit their performance to ensure that low complication rates are maintained. Waiting times will have to be very short for assessment and for surgery if adequate prevention of strokes is to be achieved. The new health service management structure will be sorely tested.
There are some unanswered questions, apart from the efficacy of surgery in moderate symptomatic carotid stenosis. For example, what should one do about symptom-free individuals in whom carotid stenosis is picked up incidentally? The ECST trialists comment that the size of the surgical effect on the outcome of carotid stenosis in those with symptoms is such that the question of surgery for symptomless
stenosis is worth examining; several underway in North America.
large trials
are
1. Dennis MS, Bamford JM, Sandercock PAG, Warlow CP. Incidence of transient ischaemic attacks in Oxfordshire, England. Stroke 1989; 20: 333-39. 2. Mohr JP, Pessin MS. Extracranial carotid artery disease. In: Barnett HJM, Stein BM, Mohr JP, Yatsu FM, eds. Stroke: pathophysiology, diagnosis and management. New York: Churchill Livingstone, 1986: 293-336. 3. Dennis MS, Bamford JM, Sandercock PAG, Warlow CP. The prognosis of transient ischaemic attacks in the Oxford Community Stroke Project. Stroke 1990; 21: 848-53. 4. Pickering GW. Transient cerebral paralysis with hypertension and cerebral embolism. JAMA 1948; 137: 848-53. 5. Eastcott HHG, Pickering GW, Rob CG. Reconstruction of the internal carotid artery in a patient with intermittent attacks of hemiplegia. Lancet 1954; ii: 994-96. 6. Barnett HJM. Symptomatic carotid endarterectomy trials. Stroke 1990; 21 (suppl III): III-2-III-5. 7. UK-TIA Study group. Variation in the use of angiography and carotid endarterectomy by neurologists in the UK-TIA Aspirin trial. Br Med J 1983; 286: 514-17. 8. Warlow CP. Carotid endarterectomy: does it work? Stroke 1984; 15: 1068-76. 9. Sundt TM, Dyken ML Surgical treatment for ischaemic vascular disease. In: Harrison MJG, Dyken ML, eds. Cerebral vascular disease. London Butterworths; 1983: 284-308. 10. National Institute of Neurological Disorder and Stroke. Clinical alert: Benefit of carotid endarterectomy for patients with high grade stenosis of the internal carotid artery. February, 1991. 11. UK-TIA Study Group. United Kingdom transient ischaemic attack (UK-TIA) Aspirin Trial: interim results. Br Med J 1988; 296: 316-20. 12. Allen CMC, Harrison MJG, Wade DT. The management of acute stroke. Tunbridge Wells: Castle House, 1988: 85-95. 13. Hankey GJ, Warlow CP. Symptomatic carotid ischaemic events: safest and most cost effective way of selecting patients for angiography before carotid endarterectomy. Br Med J 1990; 300: 1485-91.
Phenylketonuria
grows up
It is clear to anyone who has seen untreated patients with phenylketonuria (PKU) that the introduction of a national neonatal screening programme to detect and treat this condition is one of the successes of modern medicine. The defective enzyme in PKU is phenylalanine hydroxylase, which catalyses the conversion of phenylalanine to tyrosine. The incidence of this autosomal recessive disorder in the USA, the UK, and most of Western Europe is between 1 in 11 000 and 1 in 15 000, although in Ireland it is much more common (1 in 4500). Screening is carried out in the UK between days 6 and 14 and, if the diagnosis is confirmed, dietary treatment is started, ideally before day 21. The aim is to lower the blood phenylalanine concentration to between 100 and 400 µmol/1 (the exact upper limit is still controversial and varies between clinics) by the combination of protein restriction and an aminoacid supplement that contains extra tyrosine and all the essential aminoacids except phenylalanine. Tyrosine becomes an essential aminoacid in this disorder. The severe mental retardation and behavioural problems seen in almost all untreated patients with PKU are caused by a combination of hyperphenylalaninaemia and hypotyrosinaemia. For many years it was thought that only the developing brain was susceptible to damage and the diet was stopped, usually at about 8 years of age.
