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CALCIUM AND MAGNESIUM ADMINISTRATION IN MYASTHENIA GRAVIS
561
RITTER’S DISEASE (TOXIC EPIDERMAL NECROLYSIS) SIR,-Ithink that Dr. Potter (Sept. 1) is right in supposing that the extensive peeling of the skin in Ritter’s disease described and illustrated by Dr. Benson and others could be included under the heading of toxic epidermal necrolysis. Anyone interested in this intriguing but potentially serious type of skin reaction should read the very excellent review1 by Dr. Jean Walker. She seeks, however, to " " " substitute acute for toxic ", with which view I do not agree. It happened that the cases which I saw originally suffered from toxaemia ", and so have many of the cases reported
causing activation of acetylcholinesterase in vitro,2 an opposite effect of these divalent cations on muscle strength in myasthenia gravis is understandable if one assumes that calcium and magnesium ions compete for the activation of this enzyme, and that calcium ions tend to produce a relative anticholinesterase effect by blocking the more effective mag-
subsequently. I thought that it was not possible to blame any recognised pathological process to explain the apparent scalding of the skin but, because it was likely that what had damaged the skin had also damaged the patient, it seemed reasonable to attribute both effects to a poison or poisons unknown, or, being grand, a toxin. By a toxin I meant any mechanism harmful to the wellbeing of the organism, and certainly did not intend to restrict my meaning to specific poisons such as hemlock or diphtheria toxin. It still seems to me that toxic is the best word to cover damage that can result from the external action of paraffin or petrol, from coal gas or barbiturate poisoning, from staphylococcal infection, as a reaction to certain drugs, as an agonal phenomenon, or for no obvious reason, particularly as a profound, sometimes fatal, illness accompanies the skin reaction in severe cases. To substitute acute for toxic would, I believe, detract from the meaning which I had intended as well as suggest, incorrectly, that a chronic form of the disease exists.
to
"
"
Department of Dermatology, Aberdeen Royal Infirmary.
"
ALAN LYELL.
CALCIUM AND MAGNESIUM ADMINISTRATION IN MYASTHENIA GRAVIS SIR,-In-vitro studies have shown that magnesium, calcium, and potassium ions influence the activity of acetylcholineacetylase and acetylcholinesterase, the en-
help to regulate acetylcholine balance.23 Since magnesium is said to possess a curare-like activity and patients with myasthenia gravis are extremely sensitive to curare, we surmised that patients with myasthenia gravis might also be unduly sensitive to magnesium, possibly from the effect of magnesium ions on these enzymes. Gottlieb and Laurenthave reported benefit from treatment with spironolactone in patients with myasthenia gravis similar to that obtained with potassium. Perhaps this, too, is due in part to an effect of potassium on the enzymes concerned with acetylcholine levels.
zymes which
We studied a patient with thyrotoxicosis who had myasthenia gravis of moderate degree and short duration. The prostigmine test was positive. We gave 1 g. of calcium gluconate by vein, and observed an immediate and definite but transient increase in skeletal-muscle strength. This was shown by the ability of the patient to flex her thigh the full distance while supine, and to squeeze the hand strongly as well, after the giving of calcium glucomate. She was then given a saturated solution of magnesium sulphate, 20 drops a day. After only 45 drops she had grown so much weaker that she could no longer stand without falling, and we were afraid to give any
magnesium. She was then given calcium lactate 2-4 g. daily by mouth. After 5 days she was as strong as before the giving of magnesium. The calcium lactate was continued, and the progressive gain in strength persisted. No other treatment for myasthenia was needed, if one discounts the subsequent treatment for thyrotoxicosis. Since calcium ions are less effective than magnesium ions
more
1. Med. Proc. 1962, 8, 208. 2. Feldberg, W., Mann, T. J. Physiol. 1945, 104, 8. 3. Nachmansohn, D. Nature, Lond. 1940, 145, 513. 4. Gottlieb, B., Laurent, L. P. E. Lancet, 1961, ii, 528.
in
nesium ions. Department of Medicine, University of Texas, Medical Branch, Galveston, Texas.
WILLIAM K. GEORGE CHU LAI HAAN.
PATHOGENESIS OF URÆMIA IN ACUTE RENAL FAILURE
SIR,-May I be allowed to comment on what purports be an original hypothesis by Professor Finckh (Aug. 18, p. 330). At a meeting of the Royal Society of Medicine in 1949 I postulated that anuria was the result of renal cortical ischaemia.1 Then again, the results of experiments conducted with Prof. K. J. Franklin (in which intermittent sinusoidal stimulation of the renal nerves produced at first cortical ischsemia and subsequently cortical necrosis, including the intermediate changes described by Prof. H. L. Sheehan) have been dealt with in my monograph.22 Earlier Solymoss3 gave full details of a necropsy of a patient who had died from eclampsia and anuria, with complete ischaemia of the renal cortex and extreme hyperaemia of the medulla, confirming Shaw Dunn and Montgomery’s account4 of kidneys in anuric patients. The arguments against back diffusion, against leakage through damaged tubules, against blockage of the tubules had already been set out by me.5I) The hypothesis postulated underlines the fact that when structural lesions are present they are most likely to be caused by ischaemia, and is entirely in agreement with our earlier published data. Professor Finckh appears to accept without comment the views of Bull et al.(also shared by Oliver et al.’) that the reduction in the renal blood-flow is sufficient to discount the Trueta hypothesis of the regulation of the intrarenal circulation, without taking into account the work of Balintwho by direct measurement had shown that this flow is far in excess of hitherto accepted figures; and also that the renal fraction of the cardiac output does not change for 20 minutes, but actually rises after the acute haemorrhagic hypertension preceding anuria. Later, however, he avers that during shock the fall in renal blood-flow is out of proportion to the general circulatory collapse-a very important observation to which I had also drawn attention, discounting some earlier theses imputing the cause of anuria entirely to the fall of systemic blood-pressure. The explanation of the cause of the variation of glomerular filtration-rates he ascribes to alteration in the tone of the preglomerular and the postglomerular vessels. Pappenheimer9 was unable to accept this explanation, indicating that there was a considerable discrepancy in size of afferent and efferent glomerular vessels, that these were not innervated, and that they had not been observed to constrict or to dilate. He therefore postulated a postglomerular circulation together with skimming of the blood to explain the changes in filtration that could not be otherwise accounted for by the anatomical or pathological evidence. The Trueta mechanism explains these changes in filtrationrate. Jirka et al.1O confirmed some degree of vasoconstriction in 1. Sophian, J. Proc. R. Soc. Med. 1949, 42, 387. 2. Sophian, J. Toxæmias of Pregnancy; p. 184. London, 1953. 3. Solymoss, A. Lancet, 1949, i, 957. 4. Shaw Dunn, J., Montgomery, G. L. J. Path. Bact. 1942, 52, 1. 5. Sophian, J. Excerpta med. Sect. X, 1958, 11, 1. 6. Bull, G. M., Joekes, A. M., Lowe, K. G. Clin. Sci. 1950, 9, 379. 7. Oliver, J., Macdowell, M., Tracy, A. J. clin. Invest. 1951, 30, 305. 8. Balint, J. Lecture at University College Hospital, London, 1961. 9. Pappenheimer, J. R., Kinter, W. B. Amer. J. Physiol. 1956, 185, 377. 10. Jirka, J., Ganz, V., Fench, V., Cort, J. H., Trávinícek, R. Lancet, 1961,
ii, 692.
’
RITTER’S DISEASE (TOXIC EPIDERMAL NECROLYSIS) SIR,-Ithink that Dr. Potter (Sept. 1) is right in supposing that the extensive peeling of the skin in Ritter’s disease described and illustrated by Dr. Benson and others could be included under the heading of toxic epidermal necrolysis. Anyone interested in this intriguing but potentially serious type of skin reaction should read the very excellent review1 by Dr. Jean Walker. She seeks, however, to " " " substitute acute for toxic ", with which view I do not agree. It happened that the cases which I saw originally suffered from toxaemia ", and so have many of the cases reported
causing activation of acetylcholinesterase in vitro,2 an opposite effect of these divalent cations on muscle strength in myasthenia gravis is understandable if one assumes that calcium and magnesium ions compete for the activation of this enzyme, and that calcium ions tend to produce a relative anticholinesterase effect by blocking the more effective mag-
subsequently. I thought that it was not possible to blame any recognised pathological process to explain the apparent scalding of the skin but, because it was likely that what had damaged the skin had also damaged the patient, it seemed reasonable to attribute both effects to a poison or poisons unknown, or, being grand, a toxin. By a toxin I meant any mechanism harmful to the wellbeing of the organism, and certainly did not intend to restrict my meaning to specific poisons such as hemlock or diphtheria toxin. It still seems to me that toxic is the best word to cover damage that can result from the external action of paraffin or petrol, from coal gas or barbiturate poisoning, from staphylococcal infection, as a reaction to certain drugs, as an agonal phenomenon, or for no obvious reason, particularly as a profound, sometimes fatal, illness accompanies the skin reaction in severe cases. To substitute acute for toxic would, I believe, detract from the meaning which I had intended as well as suggest, incorrectly, that a chronic form of the disease exists.
to
"
"
Department of Dermatology, Aberdeen Royal Infirmary.
"
ALAN LYELL.
CALCIUM AND MAGNESIUM ADMINISTRATION IN MYASTHENIA GRAVIS SIR,-In-vitro studies have shown that magnesium, calcium, and potassium ions influence the activity of acetylcholineacetylase and acetylcholinesterase, the en-
help to regulate acetylcholine balance.23 Since magnesium is said to possess a curare-like activity and patients with myasthenia gravis are extremely sensitive to curare, we surmised that patients with myasthenia gravis might also be unduly sensitive to magnesium, possibly from the effect of magnesium ions on these enzymes. Gottlieb and Laurenthave reported benefit from treatment with spironolactone in patients with myasthenia gravis similar to that obtained with potassium. Perhaps this, too, is due in part to an effect of potassium on the enzymes concerned with acetylcholine levels.
zymes which
We studied a patient with thyrotoxicosis who had myasthenia gravis of moderate degree and short duration. The prostigmine test was positive. We gave 1 g. of calcium gluconate by vein, and observed an immediate and definite but transient increase in skeletal-muscle strength. This was shown by the ability of the patient to flex her thigh the full distance while supine, and to squeeze the hand strongly as well, after the giving of calcium glucomate. She was then given a saturated solution of magnesium sulphate, 20 drops a day. After only 45 drops she had grown so much weaker that she could no longer stand without falling, and we were afraid to give any
magnesium. She was then given calcium lactate 2-4 g. daily by mouth. After 5 days she was as strong as before the giving of magnesium. The calcium lactate was continued, and the progressive gain in strength persisted. No other treatment for myasthenia was needed, if one discounts the subsequent treatment for thyrotoxicosis. Since calcium ions are less effective than magnesium ions
more
1. Med. Proc. 1962, 8, 208. 2. Feldberg, W., Mann, T. J. Physiol. 1945, 104, 8. 3. Nachmansohn, D. Nature, Lond. 1940, 145, 513. 4. Gottlieb, B., Laurent, L. P. E. Lancet, 1961, ii, 528.
in
nesium ions. Department of Medicine, University of Texas, Medical Branch, Galveston, Texas.
WILLIAM K. GEORGE CHU LAI HAAN.
PATHOGENESIS OF URÆMIA IN ACUTE RENAL FAILURE
SIR,-May I be allowed to comment on what purports be an original hypothesis by Professor Finckh (Aug. 18, p. 330). At a meeting of the Royal Society of Medicine in 1949 I postulated that anuria was the result of renal cortical ischaemia.1 Then again, the results of experiments conducted with Prof. K. J. Franklin (in which intermittent sinusoidal stimulation of the renal nerves produced at first cortical ischsemia and subsequently cortical necrosis, including the intermediate changes described by Prof. H. L. Sheehan) have been dealt with in my monograph.22 Earlier Solymoss3 gave full details of a necropsy of a patient who had died from eclampsia and anuria, with complete ischaemia of the renal cortex and extreme hyperaemia of the medulla, confirming Shaw Dunn and Montgomery’s account4 of kidneys in anuric patients. The arguments against back diffusion, against leakage through damaged tubules, against blockage of the tubules had already been set out by me.5I) The hypothesis postulated underlines the fact that when structural lesions are present they are most likely to be caused by ischaemia, and is entirely in agreement with our earlier published data. Professor Finckh appears to accept without comment the views of Bull et al.(also shared by Oliver et al.’) that the reduction in the renal blood-flow is sufficient to discount the Trueta hypothesis of the regulation of the intrarenal circulation, without taking into account the work of Balintwho by direct measurement had shown that this flow is far in excess of hitherto accepted figures; and also that the renal fraction of the cardiac output does not change for 20 minutes, but actually rises after the acute haemorrhagic hypertension preceding anuria. Later, however, he avers that during shock the fall in renal blood-flow is out of proportion to the general circulatory collapse-a very important observation to which I had also drawn attention, discounting some earlier theses imputing the cause of anuria entirely to the fall of systemic blood-pressure. The explanation of the cause of the variation of glomerular filtration-rates he ascribes to alteration in the tone of the preglomerular and the postglomerular vessels. Pappenheimer9 was unable to accept this explanation, indicating that there was a considerable discrepancy in size of afferent and efferent glomerular vessels, that these were not innervated, and that they had not been observed to constrict or to dilate. He therefore postulated a postglomerular circulation together with skimming of the blood to explain the changes in filtration that could not be otherwise accounted for by the anatomical or pathological evidence. The Trueta mechanism explains these changes in filtrationrate. Jirka et al.1O confirmed some degree of vasoconstriction in 1. Sophian, J. Proc. R. Soc. Med. 1949, 42, 387. 2. Sophian, J. Toxæmias of Pregnancy; p. 184. London, 1953. 3. Solymoss, A. Lancet, 1949, i, 957. 4. Shaw Dunn, J., Montgomery, G. L. J. Path. Bact. 1942, 52, 1. 5. Sophian, J. Excerpta med. Sect. X, 1958, 11, 1. 6. Bull, G. M., Joekes, A. M., Lowe, K. G. Clin. Sci. 1950, 9, 379. 7. Oliver, J., Macdowell, M., Tracy, A. J. clin. Invest. 1951, 30, 305. 8. Balint, J. Lecture at University College Hospital, London, 1961. 9. Pappenheimer, J. R., Kinter, W. B. Amer. J. Physiol. 1956, 185, 377. 10. Jirka, J., Ganz, V., Fench, V., Cort, J. H., Trávinícek, R. Lancet, 1961,
ii, 692.
’