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.
1257
However, in 1987 Smith and colleagues1 reported 47 patients from London who, having been put on a that age, showed a significant fall of in about 6 points their mean IQ. They compared these patients with 22 patients from Heidelberg who were placed on a relaxed diet and whose phenylalanine concentration remained below 1200 lunol/1 (unlike the London groups). In the German patients the fall in IQ was smaller and non-significant. These researchers suggested that the diet should be relaxed rather than stopped and that aminoacid supplements should be continued. Over the intervening years, preliminary data from the Medical Research Council funded PKU register in the UK and the National Collaborative PKU Study (PKUCS) in the USA have guided those who look after PKU patients to aim for longer strict dietary control. Publication of a French study in 1986,2 which suggested that the diet could be stopped as early as 5 years of age with no fall in IQ, did not alter this policy. This year the UK and US groups have published data that support their guidelines. The PKUCS reported 95 12-year-olds, 25 of whom still had good dietary control (less than 900 µmol/1) and 70 who did not.3Of the 72, control was lost in 25 under 6 years of age and in 47 between 6 and 10 years. The latter group are of most interest because the revised Wechsler intelligence scale for children (WISC-R) and WRAT (wide range achievement tests) scores were 4-5 IQ points lower than those that they had achieved at age 6. Although some of the decrease may be due to differences in content of the test, the 25 patients who remained on the diet showed no fall in IQ. The MRC-funded PKU register published data on follow-up of 599 children and divided them into two cohorts-224 children born between 1964 and 1971 and 375 born between 1972 and 1978.4 They found an inverse and linear relation between IQ (Stanford Binet, WISC [cohort 1], WISC-R [cohort 2]) up to 8 years of age and average phenylalanine concentration in both cohorts. This relation, although less noticeable, continued up to 10 years in cohort 2. It stopped at 8 in cohort 1 patients, who had lower IQs at all ages, possibly because treatment was started later and the period of hyperphenylalaninaemia was longer. Thus the results show that at 8 years, even after allowing for IQ standard deviation score at 4 years as well as for other variables,4 the IQ standard deviation score was still independently and inversely associated with the average phenylalanine control between 5 and 8 years of age. It is not altogether clear why the French study2 showed no effect of discontinuation of diet on IQ; IQ was measured at 5 years by the new metric scale of intelligence and at 11 years by WISC, and at both ages scores were "normal". Mean IQ scores in the USA and Europe have risen in the general population from standardisation onwards,6 and it is possible that a fall in IQ was masked by failure to take this fact into account. Despite their normal IQ scores, 50% of the
normal diet
at
French
patients repeated one or more school years. This work clearly shows the value of carefully collected national data, and funding of both the PKU register and the PKUCS should be continued. It also shows that the diet should be maintained as long as possible, despite difficulties with compliance. Even if the intellectual state becomes stable, other neurological manifestations may develop,5 and with PKU must return to become pregnant.7
women
they
a
strict diet before
1. Smith I, Lobascher ME, Stevenson JE, et al. Effect of stopping low phenylalanine diet on intellectual progress of children with phenylketonuria. Br Med J 1978; ii: 723-26. 2. Saudubray JM, Rey F, Ogier H, et al. Intellectual and school performance in early treated classical PKU patients. The French Collaborative Study. Eur J Pediatr 1987; 146: (suppl 1): 20-22. 3. Azen CG, Koch R, Friedman EG, et al. Intellectual development in 12 year old children treated for phenylketonuria. Am J Dis Child 1991; 145: 35-39. 4. Smith I, Beasley MG, Ades AE. Effect on intelligence of relaxing the low phenylalanine diet in phenylketonuria. Arch Dis Child 1991; 66: 311-16. 5. Smith I, Beasley MG, Ades AE. Intelligence and quality of dietary treatment in phenylketonuria. Arch Dis Child 1990; 65: 472-78. 6. Flynn JR. The mean IQ of Americans: massive gains 1932-1978. Psychol Bull 1984; 95: 29-51. 7. Lenke RR, Levy HL. Maternal phenylketonuria and hyperphenylalaninemia: an international survey of the outcome of untreated and treated pregnancies. N Engl J Med 1980; 303: 1202-08.
Recoverin The mechanism by which light is converted into electrical energy has been studied intensively since Wald and co-workers1 discovered the role of rhodopsin. These researchers showed that the photochemical events were initiated by conversion of the 11-cis form of retinal to the all-trans form within the rhodopsin molecule by light. The consequent electrical changes occur at the plasma membrane. In the dark-adapted state, sodium ions readily enter the rod outer segment through the Na+ channels.2 Sodium ion flux is reduced by light, causing graded hyperpolarisaton of the cell.How are the Na+ channels opened and closed? The first suggestion was that photoexcitation caused a rise in cytosol calcium concentration in the photoreceptor cell, and that calcium blocked the channels.4 However, it was subsequently shown that cytosol calcium falls rather than rises during photoexcitation5 and that calcium chelators do not abolish the light response.66 By 1985, it had become clear that cyclic guanosine monophosphate (c-GMP) regulates the Na channel and keeps the channel open.7 The sequence of events during phototransduction is now generally agreed, and many of the proteins involved in the biochemical cascade have been identified. Photons cause isomerisation of rhodopsin. The cytosol portions of photolysed rhodopsin combine with transducin, which in turn activates phosphodiesterase. Phosphodiesterase converts c-GMP to 5’-GMP, and the resultant fall in cytosol c-GMP concentration causes dissociation of c-GMP from the Na channel,
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.
1257
However, in 1987 Smith and colleagues1 reported 47 patients from London who, having been put on a that age, showed a significant fall of in about 6 points their mean IQ. They compared these patients with 22 patients from Heidelberg who were placed on a relaxed diet and whose phenylalanine concentration remained below 1200 lunol/1 (unlike the London groups). In the German patients the fall in IQ was smaller and non-significant. These researchers suggested that the diet should be relaxed rather than stopped and that aminoacid supplements should be continued. Over the intervening years, preliminary data from the Medical Research Council funded PKU register in the UK and the National Collaborative PKU Study (PKUCS) in the USA have guided those who look after PKU patients to aim for longer strict dietary control. Publication of a French study in 1986,2 which suggested that the diet could be stopped as early as 5 years of age with no fall in IQ, did not alter this policy. This year the UK and US groups have published data that support their guidelines. The PKUCS reported 95 12-year-olds, 25 of whom still had good dietary control (less than 900 µmol/1) and 70 who did not.3Of the 72, control was lost in 25 under 6 years of age and in 47 between 6 and 10 years. The latter group are of most interest because the revised Wechsler intelligence scale for children (WISC-R) and WRAT (wide range achievement tests) scores were 4-5 IQ points lower than those that they had achieved at age 6. Although some of the decrease may be due to differences in content of the test, the 25 patients who remained on the diet showed no fall in IQ. The MRC-funded PKU register published data on follow-up of 599 children and divided them into two cohorts-224 children born between 1964 and 1971 and 375 born between 1972 and 1978.4 They found an inverse and linear relation between IQ (Stanford Binet, WISC [cohort 1], WISC-R [cohort 2]) up to 8 years of age and average phenylalanine concentration in both cohorts. This relation, although less noticeable, continued up to 10 years in cohort 2. It stopped at 8 in cohort 1 patients, who had lower IQs at all ages, possibly because treatment was started later and the period of hyperphenylalaninaemia was longer. Thus the results show that at 8 years, even after allowing for IQ standard deviation score at 4 years as well as for other variables,4 the IQ standard deviation score was still independently and inversely associated with the average phenylalanine control between 5 and 8 years of age. It is not altogether clear why the French study2 showed no effect of discontinuation of diet on IQ; IQ was measured at 5 years by the new metric scale of intelligence and at 11 years by WISC, and at both ages scores were "normal". Mean IQ scores in the USA and Europe have risen in the general population from standardisation onwards,6 and it is possible that a fall in IQ was masked by failure to take this fact into account. Despite their normal IQ scores, 50% of the
normal diet
at
French
patients repeated one or more school years. This work clearly shows the value of carefully collected national data, and funding of both the PKU register and the PKUCS should be continued. It also shows that the diet should be maintained as long as possible, despite difficulties with compliance. Even if the intellectual state becomes stable, other neurological manifestations may develop,5 and with PKU must return to become pregnant.7
women
they
a
strict diet before
1. Smith I, Lobascher ME, Stevenson JE, et al. Effect of stopping low phenylalanine diet on intellectual progress of children with phenylketonuria. Br Med J 1978; ii: 723-26. 2. Saudubray JM, Rey F, Ogier H, et al. Intellectual and school performance in early treated classical PKU patients. The French Collaborative Study. Eur J Pediatr 1987; 146: (suppl 1): 20-22. 3. Azen CG, Koch R, Friedman EG, et al. Intellectual development in 12 year old children treated for phenylketonuria. Am J Dis Child 1991; 145: 35-39. 4. Smith I, Beasley MG, Ades AE. Effect on intelligence of relaxing the low phenylalanine diet in phenylketonuria. Arch Dis Child 1991; 66: 311-16. 5. Smith I, Beasley MG, Ades AE. Intelligence and quality of dietary treatment in phenylketonuria. Arch Dis Child 1990; 65: 472-78. 6. Flynn JR. The mean IQ of Americans: massive gains 1932-1978. Psychol Bull 1984; 95: 29-51. 7. Lenke RR, Levy HL. Maternal phenylketonuria and hyperphenylalaninemia: an international survey of the outcome of untreated and treated pregnancies. N Engl J Med 1980; 303: 1202-08.
Recoverin The mechanism by which light is converted into electrical energy has been studied intensively since Wald and co-workers1 discovered the role of rhodopsin. These researchers showed that the photochemical events were initiated by conversion of the 11-cis form of retinal to the all-trans form within the rhodopsin molecule by light. The consequent electrical changes occur at the plasma membrane. In the dark-adapted state, sodium ions readily enter the rod outer segment through the Na+ channels.2 Sodium ion flux is reduced by light, causing graded hyperpolarisaton of the cell.How are the Na+ channels opened and closed? The first suggestion was that photoexcitation caused a rise in cytosol calcium concentration in the photoreceptor cell, and that calcium blocked the channels.4 However, it was subsequently shown that cytosol calcium falls rather than rises during photoexcitation5 and that calcium chelators do not abolish the light response.66 By 1985, it had become clear that cyclic guanosine monophosphate (c-GMP) regulates the Na channel and keeps the channel open.7 The sequence of events during phototransduction is now generally agreed, and many of the proteins involved in the biochemical cascade have been identified. Photons cause isomerisation of rhodopsin. The cytosol portions of photolysed rhodopsin combine with transducin, which in turn activates phosphodiesterase. Phosphodiesterase converts c-GMP to 5’-GMP, and the resultant fall in cytosol c-GMP concentration causes dissociation of c-GMP from the Na channel,
