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FAMILIAL HYPOKALAEMIC PERIODIC PARALYSIS
1140 altered vascular reactivity which normally escape clinical notice. Before these findings are accepted as denoting a generalised change in vascular reactivity in variant angina, the studies need to be repeated in other groups. One possibility is that they relate particularly to patients living in areas with cold climates such as Canada (where Miller et al. did their work). Two other points arise. Firstly, there are dangers in drawing inferences from correlations between frequency of vasospastic angina, which seems to represent a syndrome caused by different mechanisms,’6and Raynauds’ phenomenon and migraine (or their subclinical equivalents), which certainly represent clinical syndromes of diverse causes. A study relating coronary spasm to clearly established idiopathic Raynaud’s disease (with its typical triphasic colour response and with bilateral involvement) and to unequivocal migraine would seem a more appropriate starting-point. Secondly, it is puzzling that vasospastic myocardial ischaemia, Raynaud’s phenomenon, and migraine do not occur at the same time and that the anatomical and functional characteristics of the vessels in which vasoconstriction occurs in these three syndromes may be quite different. Coronary spasm seems to be a complex phenomenon, and attempts to understand it should start with rigorous characterisation of homogeneous subsets of patients. Only then can appropriate working hypotheses be adequately explored.
FAMILIAL HYPOKALAEMIC PERIODIC PARALYSIS ONE disadvantage of rare diseases is that an individual clinician’s experience is likely to be small. As a result, abnormalities that are peculiar to one patient or family are liable to be attributed to the disease with the proliferation of contradictory reports and conclusions. Nowhere is this unsatisfactory state of affairs more apparent than in the published work on familial periodic paralysis with hypokalaemia, where few basic observations have gone unchallenged. Particular value therefore attaches to a review from Johnsen,’ in Denmark, where careful registration has yielded 94 patients from twelve affected families together with 12 additional patients in whom no family history could be discovered. One encouraging feature is immediately apparent. When patients in this series were reviewed in 1959 there was a substantial number of deaths associated with paralytic attacks in patients aged 14-31. By 1978 only 1 additional patient had died during a paralytic attack (after the administration of digitalis) and mean life expectancy was no different from that of the normal Danish population. This change is not due to a final unravelling of the mysteries of the disease, which remains as perplexing as ever. The clinical manifestations, in their classic form, are unmistakable. Total paralysis may come on gradually over a few hours and may last for up to 72 hours. Alternatively there may be short episodes of weakness in one limb lasting an hour or so. Paralysis tends to occur in periods of rest, usually after vigorous exercise-in one case a blacksmith had his first attack of paralysis soon after going on strike.
16. Maseri A, Chierchia S, L’Abbate A. Pathogenetic mechanisms underlying the clinical events associated with atherosclerotic heart disease. Circulation 1980, 62: suppl V3-13. 1. Johnsen T. Familial periodic paralysis with hypokalaemia. Dan Med Bull 1981; 28: 1-27.
Usually the paralysis is associated with a precipitate fall in potassium2 but the serum potassium can be normal. Since hypokalaemia is associated with a reduction in urinary potassium the potassium ion must be moving into an extravascular compartment. Intracellular electrolytes are notoriously hard to measure because of the difficulty in defining the extracellular space and reports have by no means been unanimous’ but it seems likely that potassium4 together with water and perhaps sodium move into the muscle cells.’ ,
serum
This apparent shift is associated with vacuolationand a tendency to destruction of myofibrils. Structural damage of this type may explain the persistence of weakness in some patients. Abnormal electrolyte handling by skeletal muscle cell membranes would suggest that impairment of contractility is associated with a defect in membrane conduction. Unfortunately, studies of the electrical properties of skeletal muscle fibre membranes have yielded inconclusive and contradictory findings.’ The ultimate question as to why these patients become paralysed therefore remains unanswered. An alternative approach is to identify the mechanisms responsible for such a sudden shift in electrolytes. Here there are probably one or two useful clues. The most consistent stimulus to paralysis clinically is an acute carbohydrate load, Oral or intravenous glucose, usually combined with insulin, has proved to be the most consistently effective experimental means of provoking attacks. As a result of such observations it has been suggested that the primary abnormality is one of carbohydrate metabolism resulting in the generation of nondiffusible osmotically active anionic metabolites.3 Partial blocks have been postulated at the hexosephosphate level5 and in the synthesis of glycogen. More recent evidence has incriminated insulin. Thus, when pancreatic insulin release was blocked with diazoxide, attacks of paralysis could not be provoked.’ Other studies have indicated an increased insulin response to intravenous injection of glucose.8 In view of the well-known effect of insulin on potassium handling by various cells (including those of skeletal muscle9) it is difficult to escape the conclusion that insulin is an important factor in paralytic attacks. Oral diazoxide is probably too toxic for long-term use,’and the mainstay of prophylaxis and treatment continues to be potassium.’ Serum potassium has to be monitored carefully: as the paralysis subsides and potassium is released from the cells, serum potassium can rise swiftly to toxic concentrations. Experience with potassium-retaining diuretics is limited but suggests possible benefit.",11 Acidosis, which greatly increases potassium efflux from cells,
2. Biemond A, Daniels P. Familial periodic paralysis and its transition into spinal muscular atrophy. Brain 1934; 37: 91-108 3. MacArdle B. Familial periodic paralysis. Br Med Bull 1956; 12: 226-29. 4. Zierler KL, Andres R. Movement of potassium into skeletal muscle during spontaneous attack in family periodic paralysis. J Clin Invest 1957; 36: 730-37 5. Engel AG, Lambert EH, Rosevear JW, Tauxe WN. Clinical and electromyographic studies in a patient with primary hypokalemic periodic paralysis AmJ Med 1965, 38: 626-40. 6. Shy GM, Wanko T, Rowley PT, Engel AG. Studies in familial periodic paralysis Exp Neurol 1961; 3: 53-121. 7. Johnsen T. Endogenous insulin fluctuations during glucose-induced paralysis in patients with familial periodic hypokalaemia. Metabolism 1977; 26: 1185-91 8. Johnsen T, Beck-Nielsen H. Insulin receptors, insulin secretion and glucose disappearance rate in patients with periodic hypokalaemic paralysis Acta Endocrinol 1979; 90: 272-82. 9. Clausen T, Kohn PG. The effect of insulin on the transport of sodium and potassium in rat soleus muscle. J Physiol 1977; 265: 19-42. 10. Poskanzer DC, Kerr, DNS. Periodic paralysis with response to spironolactone Lancet 1961; ii: 511-13. 11. Talso PJ, Glynn MF, Oester YT, Fudema J. Body composition in hypokalemic familial periodic paralysis. Ann NY Acad Sci 1963; 110: 993-1008.
1141 seems to have a beneficial effect and for this reason acetazolamide has been employed, with substantial but by no means universal success.12 Johnsen’s current view is that acetazolamide and potassium in combination are probably the prophylactic agents of choice. But credit for the good Danish results probably belongs more to careful clinical
monitoring than to therapeutic breakthrough-an important lesson for clinicians who meet this
puzzling syndrome.
THE RESULTS OF CARDIAC SURGERY IN INFANCY
THE past two decades have seen remarkable advances in the management of serious congenital heart disease in infancy. Thanks to improved operative hypothermia and cardioplegia, the surgeon can now perform intricate reconstructions within the heart, and one consequence has been a move towards single-stage corrective surgery, rather than palliative surgery, in infancy.’ Mansfield et allfrom Seattle, have reported their experience for the four years 1974-77 in order to evaluate, among other developments, the move towards early total repair for serious congenital heart disease. 370 patients under two years of age were investigated by cardiac catheterisation for congenital heart disease. 124 infants had closed cardiac procedures. 8 of these infants died in hospital after the operation, seven of the deaths occurring among the 87 infants who were operated on under six months of age. Among the 80 patients who had open heart surgery under two years of age, there was no such progressive decline in mortality with postnatal age, two of the seven deaths occurring in infants under six months compared with five among infants aged six to twenty-four months. The Seattle group compare their overall "hospital mortality rate" of 7’5% with a rate of 30% derived from six recent review articles which cumulatively report two hundred and fifty-one deaths among 823 infants undergoing cardiac surgery in infancy. They conclude that it is possible, by the judicious combination of palliative and open cardiac surgery in early infancy, substantially to improve the overall mortality rate. The patient is best served by the selection of procedures which can be performed at a given institution with the least risk. However, this report deals only with hospital mortality rates and takes no account of late outcome, which must be considered in any discussion of changes in policies. The late results of cardiac surgery in infancy have in the past been presented as percentage late mortality-late deaths divided by the number of operations times 100. This method of monitoring surgical outcome is slow and unsuitable for a fast-moving discipline, and is complicated by variations in the period of follow-up after surgery in individual cases which make up a given series. Furthermore, by the very nature of congenital heart disease one is dealing with a collection of rare conditions and even large referral centres will take many years to collect series big enough to look at long-term efficacy of specific surgical techniques. A study of the long-term outcome of surgery for serious congenital heart disease is
2 Griggs RC, Engel WK, Resnick JS. Acetazolamide treatment of hypokalemic periodic paralysis. Ann Intern Med 1970; 73: 39-48. . Castenada AR, Lamberti J, Sade RM, Williams RG, Nadas AS. Open-heart surgery during the first three months of life. J Thorac Cardiovasc Surg 1974; 68: 719-31 2 Mansfield PB, Hall DG, Rittenhouse EA, Sauvage LR, Stamm SJ, Herndon PS, Furman EC. Cardiac surgery under age two years. JThorac Cardiovasc surg 1979; 77: 816-25
et al. from the Hospital for Sick This London. Children, report analyses the fate of 599 infants who survived three weeks or more after operation, between 1955 and 1976, in the first year after birth for heart defect and coarctation of the aorta. Actuarial survival curves are presented which take into account the variations in length of postoperative observation of individual patients and the year-by-year changes in the number of patients available for postoperative follow-up, which must become fewer the longer the postoperative interval under consideration. Furthermore, by using actuarial analysis Macartney and coworkers estimate the probability of late survival for individual cases currently undergoing cardiac surgery in infancy, or whose follow-up has been relatively short, on the basis of the outcome of those who follow-up has been longer. The method is particularly suitable for patients who require subsequent operation, because of the further variability that this introduces in terms of perioperative mortality and the duration of postoperative follow-up. For the whole population of 599 patients there was an initial steep drop in survival to 85’ 407o--t 1 - 5% after the first year, after which the rate of survival fell by about 1%% per year. The number of patients in individual categories, even in a series as large as this, is small. However, actuarial analysis permits individual curves to be constructed for specific congenital heart defects. For example, of the 123 patients who survived the immediate period after operation for coarctation of the aorta, 84% reached four years with no late deaths thereafter. A second operation for recoarctation was done in 16 cases without any mortality. Survival curves are also presented for infants with critical pulmonary stenosis, pulmonary atresia with a ventricular septal defect, tetralogy of Fallot, total anomalous pulmonary venous drainage, tricuspid atresia, ventricular septal defects, and a group of miscellaneous conditions. This information, taken together with the early postoperative survival figures (determined for the years 1972-76 to give a reasonably up to date assessment of immediate operative risk) enables the Great Ormond Street team to develop four useful categories of risk for infants undergoing surgery for congenital heart disease-(1) low initial survival with low late survival (the worst-outcome group), as seen for example in infants undergoing pulmonary artery banding for complete transposition of the great artery; (2) high initial survival with low late survival as in shunts for tetralogy of Fallot; (3) low initial survival with high late survival as in coarctation of the aorta with or without persistent ductus arteriosus; and (4) high initial survival with high late survival (the best group), as in infants having closure of ventricular septal defect. This type of analysis is important at a time when the techniques for managing congenital heart disease are advancing so rapidly, with developments in preoperative
reported by Macartney
diagnostic precision, perioperative care, and surgical manoeuvres including the long-term possibility of heart transplantation. The application of actuarial analysis is particularly important since it lends itself to the evaluation of randomised policies of management. However, no analytical technique can replace careful long-term follow-up in assessing the quality of life that the survivors of surgery for congenital heart disease can expect as they grow through childhood and adolescence into adulthood.
3.
Macartney FJ, Taylor JFN, Graham GR, de Leval M, Stark J cardiac surgery in infancy Circulation 1980; 62: 80-91
The fate of survivors of
FAMILIAL HYPOKALAEMIC PERIODIC PARALYSIS ONE disadvantage of rare diseases is that an individual clinician’s experience is likely to be small. As a result, abnormalities that are peculiar to one patient or family are liable to be attributed to the disease with the proliferation of contradictory reports and conclusions. Nowhere is this unsatisfactory state of affairs more apparent than in the published work on familial periodic paralysis with hypokalaemia, where few basic observations have gone unchallenged. Particular value therefore attaches to a review from Johnsen,’ in Denmark, where careful registration has yielded 94 patients from twelve affected families together with 12 additional patients in whom no family history could be discovered. One encouraging feature is immediately apparent. When patients in this series were reviewed in 1959 there was a substantial number of deaths associated with paralytic attacks in patients aged 14-31. By 1978 only 1 additional patient had died during a paralytic attack (after the administration of digitalis) and mean life expectancy was no different from that of the normal Danish population. This change is not due to a final unravelling of the mysteries of the disease, which remains as perplexing as ever. The clinical manifestations, in their classic form, are unmistakable. Total paralysis may come on gradually over a few hours and may last for up to 72 hours. Alternatively there may be short episodes of weakness in one limb lasting an hour or so. Paralysis tends to occur in periods of rest, usually after vigorous exercise-in one case a blacksmith had his first attack of paralysis soon after going on strike.
16. Maseri A, Chierchia S, L’Abbate A. Pathogenetic mechanisms underlying the clinical events associated with atherosclerotic heart disease. Circulation 1980, 62: suppl V3-13. 1. Johnsen T. Familial periodic paralysis with hypokalaemia. Dan Med Bull 1981; 28: 1-27.
Usually the paralysis is associated with a precipitate fall in potassium2 but the serum potassium can be normal. Since hypokalaemia is associated with a reduction in urinary potassium the potassium ion must be moving into an extravascular compartment. Intracellular electrolytes are notoriously hard to measure because of the difficulty in defining the extracellular space and reports have by no means been unanimous’ but it seems likely that potassium4 together with water and perhaps sodium move into the muscle cells.’ ,
serum
This apparent shift is associated with vacuolationand a tendency to destruction of myofibrils. Structural damage of this type may explain the persistence of weakness in some patients. Abnormal electrolyte handling by skeletal muscle cell membranes would suggest that impairment of contractility is associated with a defect in membrane conduction. Unfortunately, studies of the electrical properties of skeletal muscle fibre membranes have yielded inconclusive and contradictory findings.’ The ultimate question as to why these patients become paralysed therefore remains unanswered. An alternative approach is to identify the mechanisms responsible for such a sudden shift in electrolytes. Here there are probably one or two useful clues. The most consistent stimulus to paralysis clinically is an acute carbohydrate load, Oral or intravenous glucose, usually combined with insulin, has proved to be the most consistently effective experimental means of provoking attacks. As a result of such observations it has been suggested that the primary abnormality is one of carbohydrate metabolism resulting in the generation of nondiffusible osmotically active anionic metabolites.3 Partial blocks have been postulated at the hexosephosphate level5 and in the synthesis of glycogen. More recent evidence has incriminated insulin. Thus, when pancreatic insulin release was blocked with diazoxide, attacks of paralysis could not be provoked.’ Other studies have indicated an increased insulin response to intravenous injection of glucose.8 In view of the well-known effect of insulin on potassium handling by various cells (including those of skeletal muscle9) it is difficult to escape the conclusion that insulin is an important factor in paralytic attacks. Oral diazoxide is probably too toxic for long-term use,’and the mainstay of prophylaxis and treatment continues to be potassium.’ Serum potassium has to be monitored carefully: as the paralysis subsides and potassium is released from the cells, serum potassium can rise swiftly to toxic concentrations. Experience with potassium-retaining diuretics is limited but suggests possible benefit.",11 Acidosis, which greatly increases potassium efflux from cells,
2. Biemond A, Daniels P. Familial periodic paralysis and its transition into spinal muscular atrophy. Brain 1934; 37: 91-108 3. MacArdle B. Familial periodic paralysis. Br Med Bull 1956; 12: 226-29. 4. Zierler KL, Andres R. Movement of potassium into skeletal muscle during spontaneous attack in family periodic paralysis. J Clin Invest 1957; 36: 730-37 5. Engel AG, Lambert EH, Rosevear JW, Tauxe WN. Clinical and electromyographic studies in a patient with primary hypokalemic periodic paralysis AmJ Med 1965, 38: 626-40. 6. Shy GM, Wanko T, Rowley PT, Engel AG. Studies in familial periodic paralysis Exp Neurol 1961; 3: 53-121. 7. Johnsen T. Endogenous insulin fluctuations during glucose-induced paralysis in patients with familial periodic hypokalaemia. Metabolism 1977; 26: 1185-91 8. Johnsen T, Beck-Nielsen H. Insulin receptors, insulin secretion and glucose disappearance rate in patients with periodic hypokalaemic paralysis Acta Endocrinol 1979; 90: 272-82. 9. Clausen T, Kohn PG. The effect of insulin on the transport of sodium and potassium in rat soleus muscle. J Physiol 1977; 265: 19-42. 10. Poskanzer DC, Kerr, DNS. Periodic paralysis with response to spironolactone Lancet 1961; ii: 511-13. 11. Talso PJ, Glynn MF, Oester YT, Fudema J. Body composition in hypokalemic familial periodic paralysis. Ann NY Acad Sci 1963; 110: 993-1008.
1141 seems to have a beneficial effect and for this reason acetazolamide has been employed, with substantial but by no means universal success.12 Johnsen’s current view is that acetazolamide and potassium in combination are probably the prophylactic agents of choice. But credit for the good Danish results probably belongs more to careful clinical
monitoring than to therapeutic breakthrough-an important lesson for clinicians who meet this
puzzling syndrome.
THE RESULTS OF CARDIAC SURGERY IN INFANCY
THE past two decades have seen remarkable advances in the management of serious congenital heart disease in infancy. Thanks to improved operative hypothermia and cardioplegia, the surgeon can now perform intricate reconstructions within the heart, and one consequence has been a move towards single-stage corrective surgery, rather than palliative surgery, in infancy.’ Mansfield et allfrom Seattle, have reported their experience for the four years 1974-77 in order to evaluate, among other developments, the move towards early total repair for serious congenital heart disease. 370 patients under two years of age were investigated by cardiac catheterisation for congenital heart disease. 124 infants had closed cardiac procedures. 8 of these infants died in hospital after the operation, seven of the deaths occurring among the 87 infants who were operated on under six months of age. Among the 80 patients who had open heart surgery under two years of age, there was no such progressive decline in mortality with postnatal age, two of the seven deaths occurring in infants under six months compared with five among infants aged six to twenty-four months. The Seattle group compare their overall "hospital mortality rate" of 7’5% with a rate of 30% derived from six recent review articles which cumulatively report two hundred and fifty-one deaths among 823 infants undergoing cardiac surgery in infancy. They conclude that it is possible, by the judicious combination of palliative and open cardiac surgery in early infancy, substantially to improve the overall mortality rate. The patient is best served by the selection of procedures which can be performed at a given institution with the least risk. However, this report deals only with hospital mortality rates and takes no account of late outcome, which must be considered in any discussion of changes in policies. The late results of cardiac surgery in infancy have in the past been presented as percentage late mortality-late deaths divided by the number of operations times 100. This method of monitoring surgical outcome is slow and unsuitable for a fast-moving discipline, and is complicated by variations in the period of follow-up after surgery in individual cases which make up a given series. Furthermore, by the very nature of congenital heart disease one is dealing with a collection of rare conditions and even large referral centres will take many years to collect series big enough to look at long-term efficacy of specific surgical techniques. A study of the long-term outcome of surgery for serious congenital heart disease is
2 Griggs RC, Engel WK, Resnick JS. Acetazolamide treatment of hypokalemic periodic paralysis. Ann Intern Med 1970; 73: 39-48. . Castenada AR, Lamberti J, Sade RM, Williams RG, Nadas AS. Open-heart surgery during the first three months of life. J Thorac Cardiovasc Surg 1974; 68: 719-31 2 Mansfield PB, Hall DG, Rittenhouse EA, Sauvage LR, Stamm SJ, Herndon PS, Furman EC. Cardiac surgery under age two years. JThorac Cardiovasc surg 1979; 77: 816-25
et al. from the Hospital for Sick This London. Children, report analyses the fate of 599 infants who survived three weeks or more after operation, between 1955 and 1976, in the first year after birth for heart defect and coarctation of the aorta. Actuarial survival curves are presented which take into account the variations in length of postoperative observation of individual patients and the year-by-year changes in the number of patients available for postoperative follow-up, which must become fewer the longer the postoperative interval under consideration. Furthermore, by using actuarial analysis Macartney and coworkers estimate the probability of late survival for individual cases currently undergoing cardiac surgery in infancy, or whose follow-up has been relatively short, on the basis of the outcome of those who follow-up has been longer. The method is particularly suitable for patients who require subsequent operation, because of the further variability that this introduces in terms of perioperative mortality and the duration of postoperative follow-up. For the whole population of 599 patients there was an initial steep drop in survival to 85’ 407o--t 1 - 5% after the first year, after which the rate of survival fell by about 1%% per year. The number of patients in individual categories, even in a series as large as this, is small. However, actuarial analysis permits individual curves to be constructed for specific congenital heart defects. For example, of the 123 patients who survived the immediate period after operation for coarctation of the aorta, 84% reached four years with no late deaths thereafter. A second operation for recoarctation was done in 16 cases without any mortality. Survival curves are also presented for infants with critical pulmonary stenosis, pulmonary atresia with a ventricular septal defect, tetralogy of Fallot, total anomalous pulmonary venous drainage, tricuspid atresia, ventricular septal defects, and a group of miscellaneous conditions. This information, taken together with the early postoperative survival figures (determined for the years 1972-76 to give a reasonably up to date assessment of immediate operative risk) enables the Great Ormond Street team to develop four useful categories of risk for infants undergoing surgery for congenital heart disease-(1) low initial survival with low late survival (the worst-outcome group), as seen for example in infants undergoing pulmonary artery banding for complete transposition of the great artery; (2) high initial survival with low late survival as in shunts for tetralogy of Fallot; (3) low initial survival with high late survival as in coarctation of the aorta with or without persistent ductus arteriosus; and (4) high initial survival with high late survival (the best group), as in infants having closure of ventricular septal defect. This type of analysis is important at a time when the techniques for managing congenital heart disease are advancing so rapidly, with developments in preoperative
reported by Macartney
diagnostic precision, perioperative care, and surgical manoeuvres including the long-term possibility of heart transplantation. The application of actuarial analysis is particularly important since it lends itself to the evaluation of randomised policies of management. However, no analytical technique can replace careful long-term follow-up in assessing the quality of life that the survivors of surgery for congenital heart disease can expect as they grow through childhood and adolescence into adulthood.
3.
Macartney FJ, Taylor JFN, Graham GR, de Leval M, Stark J cardiac surgery in infancy Circulation 1980; 62: 80-91
The fate of survivors of