BRITISH MEDICAL JOURNAL
pilot studies in breast screening is acknowledged, but the group suggests that there is need for a limited extension of this service. This should be within a co-ordinated programme of research designed to answer certain fundamental questions about cost effectiveness, risks, and the identification of women most likely to benefit. Screening clinics will need to be backed up by expert diagnostic and biopsy services, so that methods can be standardized and information of importance not lost. Screening clinics apart, the group emphasizes the reduction in mortality which could come from the development of efficient services for the diagnosis and treatment of breast cancer, particularly if associated with an attempt to encourage women to seek treatment early. In times of fixed resources the cost and effect of all medical services must be considered, and large programmes of screening should not have priority over the establishment of an efficient service for the management of patients with established disease. The recent statement by the Minister of State that joint committees will be set up with the Medical Research Council to plan how these problems might be investigated indicates that the Health Departments are fully aware of the needs.3 1
2
3
339
9 AUGUST 1975
Fisher, B., et al., New England3Journal of Medicine, 1975, 292, 117. Shapiro, S., Strax, P., and Venet, L., in Seventh National Cancer Conference Proceedings, 1973, 663. Hansard, House of Commons, 28 April, 1975, col. 9.
Neuropharmacol ogical Aspects of Migraine Our understanding of migraine is hampered by lack of knowledge of its cause and by lack of precision in defining the condition. The pathophysiology of the attack is, perhaps, a simpler problem than that of aetiology and is increasingly agreed to be based on vasoconstriction followed by vasodilatation in cranial blood vessels, but even so the question of definition remains a stumbling block. Where does the simple vascular headache end and the entity migraine begin; and in particular are our pharmacological models of migraine simply those of any vascular headache ? In the past few years there has been no lack of biochemical and pharmacological candidates for a causative role. Any assessment of their claims to explain the condition should be made within the defined context of classical migraine-an aura of focal cerebral signs, commonly visual, leading to hemicrania often with nausea and vomiting-since it is from this that the accepted pathophysiology has been derived. Of the substances proposed as an initiator of the migraine attack serotonin has proved the most enduring. It is a vasoactive amine causing an increase in pulse rate and variable blood pressure changes, and it has vasoconstrictor, antidiuretic, and emetic effects. A number of observations link it with migraine. Increased urinary excretion of its main catabolites is found early in many migraine attacks.' A slight rise in plasma serotonin levels has been found at the start of the migraine attack, but more convincingly a marked fall has been noted at the onset of the headache phase.2 These changes seem specific for migraine and are not found in other equally severe headaches. Serotonin appears to be released from platelets, its main carrier cells in the blood, and a serotonin-releasing factor has been found in the plasma during a migraine attack.3 Reserpine, which is known to lower the plasma serotonin concentration,
commonly causes an attack in those liable to migraine; while phenelzine, a monoamine oxidase inhibitor, increases endogenous serotonin production and is claimed to reduce the frequency and severity of attacks. Serotonin itself, given intravenously, may also relieve an attack.4 Methysergide, which remains one of the most effective prophylactics in migraine, may act by competing for certain serotonin receptor sites, thus allowing more to be available at others-and accounting for both the serotonin antagonist and simulating effects noted. The picture is, however, less simple than at first appears. The potentiation of some adrenaline effects by serotonin, and the possible role of prostaglandins as a release factor, add complexity and widen the range of interpretation. While these observations, and the emetic and antidiuretic properties of serotonin, may seem to make a strong case and perhaps justify the phrase "low serotonin syndrome" for migraine, there are difficulties, cogently argued recently by Sjaastad.5 Migraine attacks begin with vasoconstriction; serotonin is only a mild vasoconstrictor and the rise in its level at the start of an attack is only slight. Reserpine, besides reducing blood serotonin, also affects noradrenaline and dopamine activity. Methysergide, with large antiserotonin properties nevertheless appears to prevent and in some cases abort migraine attacks. Monoamine oxidase inhibitors are also effective, though there is some evidence that monoamine oxidase activity is already reduced in migraine sufferers. Moreover the serotonin levels are variable within a group of migraine patients in attacks, and in individual cases these may not be correlated with headache. These difficulties can be overcome by calling on the complexities of pharmacokinetics, but the place of serotonin as a main mediator ofthe migraine attack must still be regarded as sub judice. Sicuteri, F., Testi, A., and Anselmi, B., International Archives of Allergy
and Applied Immunology, 1961, 19, 55. Curran, D. A., Hinterberger, H., and Lance, J. W., Brain, 1965, 88, 997. 3 Anthony, M., Hinterberger, H., and Lance, J. W., Research and Clinical Studies in Headache, 1968, 2, 29. 4 Kimball, R. W., Friedman, A. P., and Vallejo, E., Neurology, 1960, 10, 107. 5 Sjaastad, O., Acta Neurologica Scandinavica, 1975, 51, 200. 2
Braille Anniversary Louis Braille, born in 1809 the son of a village cobbler near Paris, was blinded at the age of 3 years. He received some education in the village school, and at the age of 10 he was admitted to the National Institute for the Young Blind in Paris. Letters used for reading by the blind at this time were those of the ordinary Roman alphabet and made of lead or wood, so that they protruded above the surface. During the year that Louis Braille enrolled at the institute a French artillery officer, Charles Barbien de la Serre, began to interest the Paris Academy of Sciences in a system of raised dots and dashes which he had invented to enable soldiers to communicate with each other while on night operations. Louis Braille worked on this system and at the age of 16, 150 years ago, produced his system of reading based on six raised dots used in mathematical variation to express letters, punctuation signs, and mathematical signs. The system has been revised to some extent but basically remains the same as when it was introduced. He enlarged the system later to cover musical notation. Braille writers enable blind people to communicate by writing letters. Braille died in 1851 aged 42, and nine years passed before his raised type came into general use.
BRITISH MEDICAL JOURNAL
340
Now the Royal National Institute for the Blind in London prints 100 000 books, 395 000 newspapers, and 130 000 magazines a year in Braille. Skill in reading it comes more easily to the young than the elderly, but there is no reason why blind patients of any age should not be encouraged to use Braille. Sensitivity in the tips of the fingers and an ability to concentrate are essential. The Moon system, developed after the Braille system and also consisting of raised marks, does not require so much sensitivity but is not so widely used and the libraries are not so comprehensive. A "blind" person is not necessarily a person without sight. To be registered as blind a person must have insufficient sight to do work for which sight is essential. Many persons registered as blind can walk about by themselves and, with care, can cross busy roads. Some of them if they do not wish to study Braille are helped to do some reading by the use of visual aids. These take various forms, but the simplest is the ordinary magnifying glass; others are compound lenses, similar to opera glasses, in various strengths and combinations. Macular degeneration, common in later life, is a typical example of an ocular disease which causes difficulty in reading but whose effects can be mitigated by the use of a low-vision aid. Reading is not so easy as with normal eyes, because lowvision aids do not have a big field of vision. The reader has to some extent to read along a line word by word in contrast to the ordinary reading, when the meaning is taken in line by line. Reading with a low-vision aid tends, therefore, to be slow. Many elderly people find this difficult to accept and do not persevere enough, though it would undoubtedly help them to do some reading. Some of the new low-vision aids include a screen, like a television screen, on which reading matter is shown in magnified form, and this does give a bigger field, but unfortunately they are expensive. It is certain, however, that much can be done to help registered blind persons to read, whether by the use of Braille or by other means, and everyone with defective reading vision should be given the opportunity of employing one of these methods.
Extracorporeal Oxygenation for Acute Respiratory Failure The commonest torm of acute respiratory failure in Britain is that associated with chronic airways obstruction; characteristically there is a fall in arterial Po2 and a rise in arterial PcO2. Though arguments persist about the optimum level of arterial Po2 in such patients, it is not difficult to improve arterial oxygenation, often with relatively modest increases in inspired oxygen concentration.' The major therapeutic problem is that as the inspired oxygen is raised there may be an accompanying rise in arterial Pco2 and increasing drowsiness. For such patients mechanical ventilation may be necessary; this will almost always correct carbon dioxide retention-indeed care has to be taken to avoid too drastic a reduction2 in arterial Pco2. But there is another type of respiratory failure seen in
9 AUGUST 1975
acutely ill patients, often without preceding lung disease, in which there is extremely severe hypoxaemia without CO2 retention. Its causes include severe pneumonia, trauma to the lung, fat or amniotic fluid embolism, and "shock lung" associated with severe non-thoracic trauma or septicaemia. The first step in such patients is to increase the inspired oxygen concentration. If an adequate level of arterial Po2 (which should be higher in these patients than in patients adapted to chronic hypoxia) cannot be achieved with an inspired oxygen concentration of 50-60%, this implies that much of the pulmonary blood flow is passing through the lung without coming into contact with alveolar gas. Further increases in inspired oxygen concentration are unlikely to produce much improvement in arterial Po2 and carry the potential hazard of increasing the lung injury.3 In this situation mechanical ventilation with positive end-expiratory pressure usually improves arterial Po2 and may also allow a lower concentration of inspired oxygen.4 In a few patients these measures fail to achieve adequate arterial oxygenation; in this critical situation prolonged extracorporeal support with a membrane oxygenator has been proposed. Most experience with this technique has been acquired in the United States, and a recent review reported 15 long-term survivors out of 130 patients submitted to the procedure.5 This survival rate is encouraging -the selection criteria were sufficiently severe to ensure that only patients with extremely widespread and intractable lung disorders were treated. The technical problem of maintaining adequate oxygenation for several days seems to be well on the way to solution, but heparinization is required and problems persist with haemorrhage, thrombocytopenia, and infection. As in the early days of other organ support systems a major problem has been to define which overwhelming (and usually rapidly fatal) lung conditions are reversible with time and which are not. So far the best results have been obtained with "shock lung" after trauma or with pulmonary fat emboli.5 6 Disappointingly, the results with severe bacterial and viral pneumonias have been poor. 7 8 It is apparent that a prodigious research effort will be required to establish extracorporeal oxygenation as a practical procedure and to clarify the indications for its use. Probably only a few centres should attempt to acquire the necessary practical experience in the technique; in the United States the National Heart and Lung Institute is supporting research programmes in nine units. Inevitably the procedure will remain costly, but patients with the type of respiratory failure likely to benefit from this treatment are often young and without pre-existing disease. Moreover the technique would be an invaluable adjunct if lung transplantation became a definitive treatment for irreversible respiratory failure. ICampbell, E. J. M., American Review of Respiratory Diseases, 1967, 96, 626. 2 Sykes, M. K., McNicol, M. W., and Campbell, E. J. M., Respiratory Failure. Oxford, Blackwell Scientific Publications, 1968, pp. 128 and 262. Winter, P. M., and Smith, G., Anesthesiology, 1972, 37, 210. 4Ashbaugh, D. G., et al., Lancet, 1967, 2, 319. 5 Hill, J. D., et al., Journal of Thoracic and Cardiovascular Surgery, 1974, 68, 905. 6 Hill, J. D., et al., New England Journal of Medicine, 1972, 286, 629. 7 Lefrak, E. A., et al., Chest, 1974, 66, 385. 8 Bartlett, R. H., et al., Journal of Thoracic and Cardiovascular Surgery, 1974, 68, 918. 3
pilot studies in breast screening is acknowledged, but the group suggests that there is need for a limited extension of this service. This should be within a co-ordinated programme of research designed to answer certain fundamental questions about cost effectiveness, risks, and the identification of women most likely to benefit. Screening clinics will need to be backed up by expert diagnostic and biopsy services, so that methods can be standardized and information of importance not lost. Screening clinics apart, the group emphasizes the reduction in mortality which could come from the development of efficient services for the diagnosis and treatment of breast cancer, particularly if associated with an attempt to encourage women to seek treatment early. In times of fixed resources the cost and effect of all medical services must be considered, and large programmes of screening should not have priority over the establishment of an efficient service for the management of patients with established disease. The recent statement by the Minister of State that joint committees will be set up with the Medical Research Council to plan how these problems might be investigated indicates that the Health Departments are fully aware of the needs.3 1
2
3
339
9 AUGUST 1975
Fisher, B., et al., New England3Journal of Medicine, 1975, 292, 117. Shapiro, S., Strax, P., and Venet, L., in Seventh National Cancer Conference Proceedings, 1973, 663. Hansard, House of Commons, 28 April, 1975, col. 9.
Neuropharmacol ogical Aspects of Migraine Our understanding of migraine is hampered by lack of knowledge of its cause and by lack of precision in defining the condition. The pathophysiology of the attack is, perhaps, a simpler problem than that of aetiology and is increasingly agreed to be based on vasoconstriction followed by vasodilatation in cranial blood vessels, but even so the question of definition remains a stumbling block. Where does the simple vascular headache end and the entity migraine begin; and in particular are our pharmacological models of migraine simply those of any vascular headache ? In the past few years there has been no lack of biochemical and pharmacological candidates for a causative role. Any assessment of their claims to explain the condition should be made within the defined context of classical migraine-an aura of focal cerebral signs, commonly visual, leading to hemicrania often with nausea and vomiting-since it is from this that the accepted pathophysiology has been derived. Of the substances proposed as an initiator of the migraine attack serotonin has proved the most enduring. It is a vasoactive amine causing an increase in pulse rate and variable blood pressure changes, and it has vasoconstrictor, antidiuretic, and emetic effects. A number of observations link it with migraine. Increased urinary excretion of its main catabolites is found early in many migraine attacks.' A slight rise in plasma serotonin levels has been found at the start of the migraine attack, but more convincingly a marked fall has been noted at the onset of the headache phase.2 These changes seem specific for migraine and are not found in other equally severe headaches. Serotonin appears to be released from platelets, its main carrier cells in the blood, and a serotonin-releasing factor has been found in the plasma during a migraine attack.3 Reserpine, which is known to lower the plasma serotonin concentration,
commonly causes an attack in those liable to migraine; while phenelzine, a monoamine oxidase inhibitor, increases endogenous serotonin production and is claimed to reduce the frequency and severity of attacks. Serotonin itself, given intravenously, may also relieve an attack.4 Methysergide, which remains one of the most effective prophylactics in migraine, may act by competing for certain serotonin receptor sites, thus allowing more to be available at others-and accounting for both the serotonin antagonist and simulating effects noted. The picture is, however, less simple than at first appears. The potentiation of some adrenaline effects by serotonin, and the possible role of prostaglandins as a release factor, add complexity and widen the range of interpretation. While these observations, and the emetic and antidiuretic properties of serotonin, may seem to make a strong case and perhaps justify the phrase "low serotonin syndrome" for migraine, there are difficulties, cogently argued recently by Sjaastad.5 Migraine attacks begin with vasoconstriction; serotonin is only a mild vasoconstrictor and the rise in its level at the start of an attack is only slight. Reserpine, besides reducing blood serotonin, also affects noradrenaline and dopamine activity. Methysergide, with large antiserotonin properties nevertheless appears to prevent and in some cases abort migraine attacks. Monoamine oxidase inhibitors are also effective, though there is some evidence that monoamine oxidase activity is already reduced in migraine sufferers. Moreover the serotonin levels are variable within a group of migraine patients in attacks, and in individual cases these may not be correlated with headache. These difficulties can be overcome by calling on the complexities of pharmacokinetics, but the place of serotonin as a main mediator ofthe migraine attack must still be regarded as sub judice. Sicuteri, F., Testi, A., and Anselmi, B., International Archives of Allergy
and Applied Immunology, 1961, 19, 55. Curran, D. A., Hinterberger, H., and Lance, J. W., Brain, 1965, 88, 997. 3 Anthony, M., Hinterberger, H., and Lance, J. W., Research and Clinical Studies in Headache, 1968, 2, 29. 4 Kimball, R. W., Friedman, A. P., and Vallejo, E., Neurology, 1960, 10, 107. 5 Sjaastad, O., Acta Neurologica Scandinavica, 1975, 51, 200. 2
Braille Anniversary Louis Braille, born in 1809 the son of a village cobbler near Paris, was blinded at the age of 3 years. He received some education in the village school, and at the age of 10 he was admitted to the National Institute for the Young Blind in Paris. Letters used for reading by the blind at this time were those of the ordinary Roman alphabet and made of lead or wood, so that they protruded above the surface. During the year that Louis Braille enrolled at the institute a French artillery officer, Charles Barbien de la Serre, began to interest the Paris Academy of Sciences in a system of raised dots and dashes which he had invented to enable soldiers to communicate with each other while on night operations. Louis Braille worked on this system and at the age of 16, 150 years ago, produced his system of reading based on six raised dots used in mathematical variation to express letters, punctuation signs, and mathematical signs. The system has been revised to some extent but basically remains the same as when it was introduced. He enlarged the system later to cover musical notation. Braille writers enable blind people to communicate by writing letters. Braille died in 1851 aged 42, and nine years passed before his raised type came into general use.
BRITISH MEDICAL JOURNAL
340
Now the Royal National Institute for the Blind in London prints 100 000 books, 395 000 newspapers, and 130 000 magazines a year in Braille. Skill in reading it comes more easily to the young than the elderly, but there is no reason why blind patients of any age should not be encouraged to use Braille. Sensitivity in the tips of the fingers and an ability to concentrate are essential. The Moon system, developed after the Braille system and also consisting of raised marks, does not require so much sensitivity but is not so widely used and the libraries are not so comprehensive. A "blind" person is not necessarily a person without sight. To be registered as blind a person must have insufficient sight to do work for which sight is essential. Many persons registered as blind can walk about by themselves and, with care, can cross busy roads. Some of them if they do not wish to study Braille are helped to do some reading by the use of visual aids. These take various forms, but the simplest is the ordinary magnifying glass; others are compound lenses, similar to opera glasses, in various strengths and combinations. Macular degeneration, common in later life, is a typical example of an ocular disease which causes difficulty in reading but whose effects can be mitigated by the use of a low-vision aid. Reading is not so easy as with normal eyes, because lowvision aids do not have a big field of vision. The reader has to some extent to read along a line word by word in contrast to the ordinary reading, when the meaning is taken in line by line. Reading with a low-vision aid tends, therefore, to be slow. Many elderly people find this difficult to accept and do not persevere enough, though it would undoubtedly help them to do some reading. Some of the new low-vision aids include a screen, like a television screen, on which reading matter is shown in magnified form, and this does give a bigger field, but unfortunately they are expensive. It is certain, however, that much can be done to help registered blind persons to read, whether by the use of Braille or by other means, and everyone with defective reading vision should be given the opportunity of employing one of these methods.
Extracorporeal Oxygenation for Acute Respiratory Failure The commonest torm of acute respiratory failure in Britain is that associated with chronic airways obstruction; characteristically there is a fall in arterial Po2 and a rise in arterial PcO2. Though arguments persist about the optimum level of arterial Po2 in such patients, it is not difficult to improve arterial oxygenation, often with relatively modest increases in inspired oxygen concentration.' The major therapeutic problem is that as the inspired oxygen is raised there may be an accompanying rise in arterial Pco2 and increasing drowsiness. For such patients mechanical ventilation may be necessary; this will almost always correct carbon dioxide retention-indeed care has to be taken to avoid too drastic a reduction2 in arterial Pco2. But there is another type of respiratory failure seen in
9 AUGUST 1975
acutely ill patients, often without preceding lung disease, in which there is extremely severe hypoxaemia without CO2 retention. Its causes include severe pneumonia, trauma to the lung, fat or amniotic fluid embolism, and "shock lung" associated with severe non-thoracic trauma or septicaemia. The first step in such patients is to increase the inspired oxygen concentration. If an adequate level of arterial Po2 (which should be higher in these patients than in patients adapted to chronic hypoxia) cannot be achieved with an inspired oxygen concentration of 50-60%, this implies that much of the pulmonary blood flow is passing through the lung without coming into contact with alveolar gas. Further increases in inspired oxygen concentration are unlikely to produce much improvement in arterial Po2 and carry the potential hazard of increasing the lung injury.3 In this situation mechanical ventilation with positive end-expiratory pressure usually improves arterial Po2 and may also allow a lower concentration of inspired oxygen.4 In a few patients these measures fail to achieve adequate arterial oxygenation; in this critical situation prolonged extracorporeal support with a membrane oxygenator has been proposed. Most experience with this technique has been acquired in the United States, and a recent review reported 15 long-term survivors out of 130 patients submitted to the procedure.5 This survival rate is encouraging -the selection criteria were sufficiently severe to ensure that only patients with extremely widespread and intractable lung disorders were treated. The technical problem of maintaining adequate oxygenation for several days seems to be well on the way to solution, but heparinization is required and problems persist with haemorrhage, thrombocytopenia, and infection. As in the early days of other organ support systems a major problem has been to define which overwhelming (and usually rapidly fatal) lung conditions are reversible with time and which are not. So far the best results have been obtained with "shock lung" after trauma or with pulmonary fat emboli.5 6 Disappointingly, the results with severe bacterial and viral pneumonias have been poor. 7 8 It is apparent that a prodigious research effort will be required to establish extracorporeal oxygenation as a practical procedure and to clarify the indications for its use. Probably only a few centres should attempt to acquire the necessary practical experience in the technique; in the United States the National Heart and Lung Institute is supporting research programmes in nine units. Inevitably the procedure will remain costly, but patients with the type of respiratory failure likely to benefit from this treatment are often young and without pre-existing disease. Moreover the technique would be an invaluable adjunct if lung transplantation became a definitive treatment for irreversible respiratory failure. ICampbell, E. J. M., American Review of Respiratory Diseases, 1967, 96, 626. 2 Sykes, M. K., McNicol, M. W., and Campbell, E. J. M., Respiratory Failure. Oxford, Blackwell Scientific Publications, 1968, pp. 128 and 262. Winter, P. M., and Smith, G., Anesthesiology, 1972, 37, 210. 4Ashbaugh, D. G., et al., Lancet, 1967, 2, 319. 5 Hill, J. D., et al., Journal of Thoracic and Cardiovascular Surgery, 1974, 68, 905. 6 Hill, J. D., et al., New England Journal of Medicine, 1972, 286, 629. 7 Lefrak, E. A., et al., Chest, 1974, 66, 385. 8 Bartlett, R. H., et al., Journal of Thoracic and Cardiovascular Surgery, 1974, 68, 918. 3
