- Email: [email protected]
CYSTECTOMY IN A DIABETIC
1048
during the first 3 weeks there appeared to be an upward trend over a fortnight or so; this was followed by a rapid fall over 48 hours, and then a further gradual decline, until the initial values were reached about 5 weeks after the start of the observations. The surgical trauma of the muscle biopsy may have been partly responsible for this peak in serum enzyme activity; but even if this possibility is admitted, the remarkably sudden fall to near-normal values remains to be explained. Transaminase levels were raised slightly in all blood samples taken. Lactic dehydrogenase activity, measured on two occasions (when the serum aldolase was at its highest and lowest levels respectively) was within normal
lactic acid; and it would therefore not be surprising to find other enzyme defects, at several intermediate sites, all giving a picture essentially similar to that of the McArdle syndrome-pain and stiffness after moderate exertion, and failure to form lactic acid after exercise. Oliver et al. (1961) have reported such a syndrome in a 50-year-old man, in whom the other enzyme of glycogen degradation-the debrancher enzyme-was absent. McArdle’s first case has now been followed up for more than ten years, and the condition appears to be essentially benign. It is therefore reasonable to reassure the patient and the relatives that no gross disability is likely. Fructose seems to produce an improvement in exercise performance, and we suggest that fructose 30-45 g. be given by mouth two or three times a day, or before any sub. Fructose can enter the stantial muscular exertion. the stage requiring phosphorylase, glycolytic cycle beyond and this probably explains the benefit derived from its administration. The enzymatic defect appears to be inherited as an autosomal recessive gene (Schmid and Hamaker 1961). There is therefore little chance of offspring being clinically affected unless there is a consanguineous marriage. The rather small rise in the father’s blood-lactate after ischxmic exercise shows that some heterozygous individuals may have low levels of muscle phosphorylase and, therefore, a reduced capacity to mobilise muscle glycogen.
found
limits. Discussion
In McArdle’s syndrome muscle pain with stiffness is the most constant symptoms, and it is particularly suggestive of this syndrome if it dates from childhood or adolescence. As in the present case, the pain and stiffness are usually provoked by more than moderate exercise. Exercise tolerance varies from patient to patient, and, in addition, it may vary in the same patient from day to day. This day-to-day variability, and the apparent decrease in tolerance associated with infection or depression of mood, were also noted by McArdle (1951) in the first recorded case.
While a typical clinical history affords a strong lead the diagnosis, proof rests on the demonstration of a defect in anaerobic glycolysis by measuring bloodlactic-acid levels before and after ischaemic exercise; finally, the diagnosis is confirmed when biochemical and histochemical methods show the absence of phosphorylase to
(fig. 4). Muscle wasting has been present in only one case (Schmid and Mahler 1959), where it affected the proximal muscles of the upper and lower limbs equally on both The sternomastoids were also involved, and sides. pseudohypertrophy of the calf muscles was present. In two respects our findings appear to differ from those in previously reported cases: firstly, in the unexpected behaviour of the serum enzymes; and secondly, in the finding of a normal amount of muscle glycogen. The variation in serum enzyme levels could be a general feature of the syndrome, not previously detected. It could well have been overlooked if, for most of the time, the levels are more or less normal, and are only raised for fairly short periods or in response to some stimulus; observations over a considerable period would then be needed to detect any abnormality. We may just have been lucky by chancing to make the estimations at a favourable time. In all cases of McArdle’s syndrome so far observed, excessive storage of glycogen in the muscle accompanies the defect in anaerobic glycolysis. But in our case muscleglycogen content was normal. This suggests that an additional enzyme deficiency may have been presentone which would tend to reduce the rate of glycogen synthesis from glucose. Such a partial block might well occur at the conversion of glucose 6-phosphate to glucoseI-phosphate-a reaction catalysed by the enzyme phosphoglucomutase. Our observation that the formation of lactic acid from glucose-1-phosphate may be less than normal would accord with this possibility. Unfortunately, the biopsy specimen was too small to allow any further investigation of this point. Many enzymes are concerned in the breakdown of glycogen to pyruvate and
Summary A
case
of
McArdle’s
syndrome-phosphorylase-
deficient myopathy-is described, with the diagnostic clinical and biochemical findings. Certain unexpected biochemical results-notably, the absence of excessive glycogen stores-suggest that this case is a variant of the syndrome. It may be helpful to give fructose by mouth before any moderate or severe muscular exertion. Dr. Rowland Hill first saw and provisionally diagnosed the disorder in this patient. We thank him for his assistance, and for permission to publish the case. We are also grateful to Mr, R. L. Bassett and Miss G. E. Adams for their assistance with biochemical
estimations, and to Mr. James Mills for the photomicrography. One of us (B. P. H.) is indebted to the Muscle Dystrophy Group for financial support. REFERENCES
Friedman, M. M., Laplan, B. (1958) J. lab. clin. Med. 51, 745. McArdle, B. (1951) Clin. Sci. 10, 13. Oliver, L., Schulman, M., Larner, J. (1961) Clin. Res. 9, 243. Pearson, C. M., Rimmer, D. G., Mommaerts, W. F. H. M. (1961) Amer. J. Med. 30, 502. Schmid, R., Hamaker, L. (1961) New Engl. J. Med. 264, Mahler, R. (1959) J. clin. Invest. 38, 2044.
223.
—
CYSTECTOMY IN A DIABETIC P. D. HUGHES M.B. Sydney, F.R.C.S. SENIOR
REGISTRAR,
DEPARTMENT OF
UROLOGY, GENERAL HOSPITAL,
NEWCASTLE UPON TYNE *
THIS report concerns a diabetic in whom carcinoma of the bladder recurred after radiotherapy had apparently been successful. Total cystectomy was necessary; but, because transplanting of the ureters into the colon would render urine testing of the faecal-urine mixture not only difficult and distasteful but probably inaccurate, it was decided to provide an ileal bladder.
Case-report A.B., a male security officer, was aged 59 when first seen in December, 1959. He had been a known diabetic for 11 years *
Present
appointment: honorary urologist, Canberra Community Hospital, Canberra, Australia.
1049
patient whose functioning kidneys were already inade-
from
a
two
quate. The Operation It was decided to remove the bladder, together with the left kidney and ureter, and to form an ileal bladder for receiving the urine from the right kidney. Routine bowel preparation was carried out. At 6 A.M. on the morning of the operation the patient was given his usual dose of insulin, and his usual breakfast carbohydrate z200 calories-as 500 ml. of 10% glucose mouth. An intraby Pyelograms showing (left) normal appearance in December, 1959, and (right) a tumour of the renal pelvis in venous drip of 5 % May, 1961. dextrose was started. and was maintained on an 1800-calorie diet containing 150 g. Blood-sugar estimation at 9 A.M. was 222 mg. per 100 ml. It was planned to keep the patient hyperglycxrnic for the next of carbohydrate, with 38 units of insulin each morning (18 units of soluble insulin and 20 units of protamine zinc insulin). He twenty-four hours. The abdomen was opened through a long left paramedian complained of painless hw-maturia of six weeks’ duration. At that time excretory pyelograms demonstrated good funcincision. The bladder tumour could be felt in the posterior wall and roof of the bladder, but it did not appear to have tion in both kidneys and no abnormality. His blood-urea the overlying peritoneum, and there was no attachchest invaded was 32 mg. per 100 ml. of showed some old X-ray ment to surrounding structures. No enlarged pelvic or parapneumoconiosis. aortic could be felt, and the liver appeared to be lymph-nodes demonstrated scattered solid 0,5 to tumours, Cystoscopy normal. The descending colon was reflected medially, and the 2 cm. in diameter on the base, posterior wall, and left lateral left kidney mobilised. Soft tumour could be felt distending wall of the bladder with areas of reddened thickened mucosa the renal pelvis. The renal vessels were ligated and divided, and between them. No thickening, infiltration, or fixation could be the ureter mobilised down to the bladder. Radical cysto-prostafelt on bimanual examination. Deep biopsy specimens were tectomy, with block dissection of the pelvic lymph-nodes in taken from the tumours with the Thompson resectoscope. continuity with the left ureter and kidney, was carried out. examination all a of the tumours showed wellHistological An 8 in. segment of ileum was isolated to form an ileal bladder, differentiated transitional-cell carcinoma of the bladder, with and the right ureter was implanted into the proximal end, the no evidence of infiltration of muscle (Dr. B. E. Tomlinson). distal end being brought out on to the abdominal surface, to Because of the dispersion and the malignancy of the lesions, the the of the umbilicus. 2160 ml. of whole blood were given right patient was treated with supervoltage X-ray therapy from a the during operation, and there was no period of hypotension. 4-million-volt linear accelerator. This was carried out by At the end of the operation the blood-sugar was 384 mg. Mr. R. Finney, who gave a total dose of 6448r in six weeks, ml. The 100 patient was given 3 litres of 5% dextrose finishing in February, 1960. The patient had some frequency per in next twenty-four hours. From the time the intravenously of micturition during and after the course of radiotherapy, but of there a steady output of urine from the was operation Furadantin ’. this cleared up with urine tests showed heavy glycosuria, ileostomy. Two-hourly Cystoscopy in May, August, and November, 1960, showed no but tests for acetone were The glycosuria gradually negative. of bladder tumour. sign and the blood-sugar the next morning was 128 mg. decreased, In May, 1961, cystoscopy disclosed recurrence of tumour, per 100 ml. 2 x 2 cm., on the posterior wall of the bladder and extending on Postoperative Course to the fundus. Deep biopsy specimens were taken with bitingThe patient was given 3 litres of fluid intravenously each day, forceps, through a Braasch cystoscope. The tumour could with salt and potassium as required. Each bottle was made up just be felt on bimanual examination. There was no fixity. to dextrose by adding 50% dextrose when necessary, thus and differentiated 5% examination. Cellular Histological poorly transitional-cell carcinoma of the bladder. providing 600 calories as carbohydrate each day. Insulin The patient was therefore admitted to hospital. He was in requirements were met by testing the urine four-hourly, and giving soluble insulin on a fixed scale proportional to the good physical condition.His insulin requirements had increased to 48 units each morning (16 units of soluble insulin glycosuria. The patient resumed oral feeding on the fifth and 32 units of protamine zinc insulin). He was still taking an postoperative day. 1800-calorie diet, including 150 g. of carbohydrate, each day. Though the urine output was high, rising to 3 litres on some Chest X-ray showed no change from December, 1959. days, the blood-urea rose steadily, reaching a peak of 222 mg. Excretory urography showed that both kidneys were per 100 ml. on the twelfth day. The serum electrolytes remained functioning well, but in the left pyelogram the crenated appear- within normal limits, except for a low bicarbonate reading ance of a tumour of the renal pelvis was seen. Review of the when the urea was at its highest concentration. On the twelfth day the abdominal wound burst, and was pyelograms of December, 1959, yielded no radiological evidence of tumour at that time (see figs.). resutured. The intravenous regime outlined above was necesHsmoglobin was 13-1 g. per 100 ml. Fasting blood-sugar sary for forty-eight hours, but the blood-urea fell steadily was 212 mg. per 100 ml., and repeated blood-urea estimations over the next two weeks to 69 mg. per 100 ml. were consistently in the 40-50 mg. range. This was noted with The operation specimen showed tumour in the left kidney some anxiety, because nephrectomy would remove one kidney covering the inside of the lower half of the renal pelvis, but not
1050
involving renal parenchyma. On microscopy the tumour was a moderately differentiated carcinoma; it had not infiltrated through the pelvic wall, and did not invade the vessels. The left ureter was free of tumour. The tumour of the bladder involved the fundus and posterior wall. Microscopic examination showed transitional-cell carcinoma infiltrating, but not penetrating, the bladder-wall. The kidney and bladder tumours were histologically dissimilar. Readmission The patient was readmitted to hospital on Aug. 14, 1961, 9 days after discharge, because he said that no urine had come from the ileostomy in the previous thirty hours, and that he had had no insulin during this time. He complained of thirst and of mild pain in the right loin. He had not vomited. He was breathing rapidly, and he was slightly confused, but conscious. Acetone was not smelt in his breath. The temperature was 100-5°F, and he was slightly tender over the right kidney. He was not clinically dehydrated, and there was no sacral or ankle oedema. The jugular venous pressure was not raised, and the lung bases were clear on auscultation. Blood-analysis gave the following results: blood-sugar 900 mg. per 100 ml.; blood-urea 189 mg. per 100 ml.; serum bicarbonate 4-4 m.Eq., sodium 107 m.Eq., chloride 86 m.Eq., potassium 5-6 m.Eq. per litre; haemoglobin 94 g. per 100 ml. At this time, the clinical and biochemical picture was attributed to acute pyelonephritis in the solitary right kidney causing anuria which, combined with the withholding of insulin, had precipitated diabetic ketosis. The dehydration expected with diabetic ketosis was absent, we thought, because of retention of fluids by the renal failure. The patient was given 80 units of soluble insulin (60 unitsi intravenously, and 20 units intramuscularly). An intravenousi drip was started, and the jugular venous pressure and lung; bases were kept under close observation. 1500 ml. of M/6, sodium lactate, and 1000 ml. of 0-9% saline solution, was given intravenously in three hours. At the end of this time, urine began to trickle from the ileostomy and dependent oedema appeared. The drip was discontinued. Urine tests showed sugar 2 % and acetone + - . Blood-analysis showed bloodsugar 890 mg. per 100 ml.; urea 196 mg. per 100 ml.; serum‘ sodium 122 m.Eq. per litre., bicarbonate 4-4 m.Eq., potassium 5-3 m.Eq., and chloride 87 m.Eq. Another 40 units of soluble insulin was then given intramuscularly. Eight hours after, commencement of treatment, fresh urine showed sugar 2% and acetone +. The glycosuria steadily diminished on twohourly testing, and the acetonuria disappeared. 16 hours after commencing treatment, the blood-sugar was 175 mg. per 100 ml., blood-urea 204 mg. per 100 ml., serum sodium 122 m.Eq. per litre, bicarbonate 17-2 m.Eq., potassium 4-4 m.Eq., and chloride 86 m.Eq., and haemoglobin 10-3 g. per 100 ml. The next day the blood-urea was 252 mg. per 100 ml., serum sodium 139 m.Eq. per litre, bicarbonate 16-4 m.Eq., potassium 4 m.Eq., and chloride 96 m.Eq. The urinary output gradually increased, and after eleven days the blood-urea was down to 70 mg. per 100 ml. Three weeks after admission, the; blood-urea was 50 mg. per 100 ml. and the serum electrolytes The patient was finally diswere all within normal limits. charged home, nine weeks after the original operation. His blood-urea has since remained at 45-65 mg. per 100 ml. .
,
.
,
,
,
.
,
.
Discussion
Reviewing 81 patients who had cystectomy performed in this unit during the last ten years, I found that none .
of these was a diabetic. This case illustrated the obvious benefit of the ileal bladder, in the accurate management of diabetes and its complications in such cases. The correct treatment after his readmission on Aug. 14, with anuria and diabetic ketosis, is problematical. In retrospect, I would give smaller volumes of more concentrated fluids intravenously-namely, 500 ml. of 3% saline solution-to improve the very low extracellular .
,
.
sodium (107 m.Eq. per litre), and 500 ml. of M/2 sodium lactate to alleviate the acidosis and hyperpncea. It is difficult to know whether or not there was any pathological connection between the tumour of the left kidney and that in the bladder occurring at the same time. The fact that the left kidney was radiologically normal in December, 1959, and that there was no histological similarity in the excised specimens in July, 1961, suggests that the presence of two tumours of the urinary tract was merely fortuitous.
Summary The management of a diabetic patient who required cystectomy for carcinoma of the bladder is reported. It is suggested that provision of an ileal bladder is essential in such a case for the accurate management of the diabetes after cystectomy. I would like to thank Mr. John Swinney, of the department of urology, Newcastle upon Tyne General Hospital, for permission to
publish this case, and Dr. B. E. Tomlinson for histopathological on the biopsy and operation specimens.
reports
Preliminary Communications TOXICITY OF SOME MONOAMINE-OXIDASE INHIBITORS IN DOGS A SERIES of new hydrazine monoamine-oxidase inhibitors (M.A.o.i.) have been investigated. The experiments were designed to assess chronic toxicity over a period of 3-6 months using pedigree corgi dogs. METHODS
" control animals, additional Apart from the usual " negative " " were administered positive control substances in groups the form of the original parent compounds; iproniazid (’ Marsilid ’) at dose levels of 2, 10, 15, 25, 50, and 100 mg. per kg. per day; phenylisopropyl hydrazine (’JB 516’ or ’ Catron’) at 3, 5, 10, 20, and 40 mg. per kg. per day; and phenelzine (’ Nardil’) at 2, 10, and 12 mg. per kg. per day. The new compounds tested in the first place were heptylhydrazine at levels of 2, 5, 6, and 10 mg. per kg. per day; tetra hydronaphthyl hydrazine (T.N.H.) at 1, 3, 5, 10, and 20 mg. per kg. per day; and indanyl carbethoxy hydrazine (I.C.H.) at 2 and 10 mg. per kg. per day. All drugs were given orally. RESULTS
became apparent that all these compounds (except iproniazid) were producing similar neurological symptoms. When the syndrome was recognised, arrangements were made for detailed histological examination of the brain by one of us (A. C. P.) on the animals which remained. Details of the clinical and histological findings will be reported later in full. The clinical syndrome consisted of: (1) cerebellar ataxia, a progressive condition which led to prostration and death of the dog, common to all the above drugs except iproniazid; (2) cerebral stimulation (most distinct with phenelzine and the new compound (I.C.H.), presenting as increased sensitivity, periods of excitement, and convulsions ; (3) hxmolytic anaemia, reminiscent of that caused by phenyl hydrazine, so severe in the case of iproniazid that, in doses of 25 mg. per kg. per day and over, the animals died of this symptom before neurological abnormalities were apparent. Iproniazid was unique in this respect, the other compounds producing only mild anxmia which was unlikely to have played much part in the causation of nervous signs. All the animals appeared well and alert, and gained weight (although at a slower rate than normal) until a week or so before they died or It
soon
during the first 3 weeks there appeared to be an upward trend over a fortnight or so; this was followed by a rapid fall over 48 hours, and then a further gradual decline, until the initial values were reached about 5 weeks after the start of the observations. The surgical trauma of the muscle biopsy may have been partly responsible for this peak in serum enzyme activity; but even if this possibility is admitted, the remarkably sudden fall to near-normal values remains to be explained. Transaminase levels were raised slightly in all blood samples taken. Lactic dehydrogenase activity, measured on two occasions (when the serum aldolase was at its highest and lowest levels respectively) was within normal
lactic acid; and it would therefore not be surprising to find other enzyme defects, at several intermediate sites, all giving a picture essentially similar to that of the McArdle syndrome-pain and stiffness after moderate exertion, and failure to form lactic acid after exercise. Oliver et al. (1961) have reported such a syndrome in a 50-year-old man, in whom the other enzyme of glycogen degradation-the debrancher enzyme-was absent. McArdle’s first case has now been followed up for more than ten years, and the condition appears to be essentially benign. It is therefore reasonable to reassure the patient and the relatives that no gross disability is likely. Fructose seems to produce an improvement in exercise performance, and we suggest that fructose 30-45 g. be given by mouth two or three times a day, or before any sub. Fructose can enter the stantial muscular exertion. the stage requiring phosphorylase, glycolytic cycle beyond and this probably explains the benefit derived from its administration. The enzymatic defect appears to be inherited as an autosomal recessive gene (Schmid and Hamaker 1961). There is therefore little chance of offspring being clinically affected unless there is a consanguineous marriage. The rather small rise in the father’s blood-lactate after ischxmic exercise shows that some heterozygous individuals may have low levels of muscle phosphorylase and, therefore, a reduced capacity to mobilise muscle glycogen.
found
limits. Discussion
In McArdle’s syndrome muscle pain with stiffness is the most constant symptoms, and it is particularly suggestive of this syndrome if it dates from childhood or adolescence. As in the present case, the pain and stiffness are usually provoked by more than moderate exercise. Exercise tolerance varies from patient to patient, and, in addition, it may vary in the same patient from day to day. This day-to-day variability, and the apparent decrease in tolerance associated with infection or depression of mood, were also noted by McArdle (1951) in the first recorded case.
While a typical clinical history affords a strong lead the diagnosis, proof rests on the demonstration of a defect in anaerobic glycolysis by measuring bloodlactic-acid levels before and after ischaemic exercise; finally, the diagnosis is confirmed when biochemical and histochemical methods show the absence of phosphorylase to
(fig. 4). Muscle wasting has been present in only one case (Schmid and Mahler 1959), where it affected the proximal muscles of the upper and lower limbs equally on both The sternomastoids were also involved, and sides. pseudohypertrophy of the calf muscles was present. In two respects our findings appear to differ from those in previously reported cases: firstly, in the unexpected behaviour of the serum enzymes; and secondly, in the finding of a normal amount of muscle glycogen. The variation in serum enzyme levels could be a general feature of the syndrome, not previously detected. It could well have been overlooked if, for most of the time, the levels are more or less normal, and are only raised for fairly short periods or in response to some stimulus; observations over a considerable period would then be needed to detect any abnormality. We may just have been lucky by chancing to make the estimations at a favourable time. In all cases of McArdle’s syndrome so far observed, excessive storage of glycogen in the muscle accompanies the defect in anaerobic glycolysis. But in our case muscleglycogen content was normal. This suggests that an additional enzyme deficiency may have been presentone which would tend to reduce the rate of glycogen synthesis from glucose. Such a partial block might well occur at the conversion of glucose 6-phosphate to glucoseI-phosphate-a reaction catalysed by the enzyme phosphoglucomutase. Our observation that the formation of lactic acid from glucose-1-phosphate may be less than normal would accord with this possibility. Unfortunately, the biopsy specimen was too small to allow any further investigation of this point. Many enzymes are concerned in the breakdown of glycogen to pyruvate and
Summary A
case
of
McArdle’s
syndrome-phosphorylase-
deficient myopathy-is described, with the diagnostic clinical and biochemical findings. Certain unexpected biochemical results-notably, the absence of excessive glycogen stores-suggest that this case is a variant of the syndrome. It may be helpful to give fructose by mouth before any moderate or severe muscular exertion. Dr. Rowland Hill first saw and provisionally diagnosed the disorder in this patient. We thank him for his assistance, and for permission to publish the case. We are also grateful to Mr, R. L. Bassett and Miss G. E. Adams for their assistance with biochemical
estimations, and to Mr. James Mills for the photomicrography. One of us (B. P. H.) is indebted to the Muscle Dystrophy Group for financial support. REFERENCES
Friedman, M. M., Laplan, B. (1958) J. lab. clin. Med. 51, 745. McArdle, B. (1951) Clin. Sci. 10, 13. Oliver, L., Schulman, M., Larner, J. (1961) Clin. Res. 9, 243. Pearson, C. M., Rimmer, D. G., Mommaerts, W. F. H. M. (1961) Amer. J. Med. 30, 502. Schmid, R., Hamaker, L. (1961) New Engl. J. Med. 264, Mahler, R. (1959) J. clin. Invest. 38, 2044.
223.
—
CYSTECTOMY IN A DIABETIC P. D. HUGHES M.B. Sydney, F.R.C.S. SENIOR
REGISTRAR,
DEPARTMENT OF
UROLOGY, GENERAL HOSPITAL,
NEWCASTLE UPON TYNE *
THIS report concerns a diabetic in whom carcinoma of the bladder recurred after radiotherapy had apparently been successful. Total cystectomy was necessary; but, because transplanting of the ureters into the colon would render urine testing of the faecal-urine mixture not only difficult and distasteful but probably inaccurate, it was decided to provide an ileal bladder.
Case-report A.B., a male security officer, was aged 59 when first seen in December, 1959. He had been a known diabetic for 11 years *
Present
appointment: honorary urologist, Canberra Community Hospital, Canberra, Australia.
1049
patient whose functioning kidneys were already inade-
from
a
two
quate. The Operation It was decided to remove the bladder, together with the left kidney and ureter, and to form an ileal bladder for receiving the urine from the right kidney. Routine bowel preparation was carried out. At 6 A.M. on the morning of the operation the patient was given his usual dose of insulin, and his usual breakfast carbohydrate z200 calories-as 500 ml. of 10% glucose mouth. An intraby Pyelograms showing (left) normal appearance in December, 1959, and (right) a tumour of the renal pelvis in venous drip of 5 % May, 1961. dextrose was started. and was maintained on an 1800-calorie diet containing 150 g. Blood-sugar estimation at 9 A.M. was 222 mg. per 100 ml. It was planned to keep the patient hyperglycxrnic for the next of carbohydrate, with 38 units of insulin each morning (18 units of soluble insulin and 20 units of protamine zinc insulin). He twenty-four hours. The abdomen was opened through a long left paramedian complained of painless hw-maturia of six weeks’ duration. At that time excretory pyelograms demonstrated good funcincision. The bladder tumour could be felt in the posterior wall and roof of the bladder, but it did not appear to have tion in both kidneys and no abnormality. His blood-urea the overlying peritoneum, and there was no attachchest invaded was 32 mg. per 100 ml. of showed some old X-ray ment to surrounding structures. No enlarged pelvic or parapneumoconiosis. aortic could be felt, and the liver appeared to be lymph-nodes demonstrated scattered solid 0,5 to tumours, Cystoscopy normal. The descending colon was reflected medially, and the 2 cm. in diameter on the base, posterior wall, and left lateral left kidney mobilised. Soft tumour could be felt distending wall of the bladder with areas of reddened thickened mucosa the renal pelvis. The renal vessels were ligated and divided, and between them. No thickening, infiltration, or fixation could be the ureter mobilised down to the bladder. Radical cysto-prostafelt on bimanual examination. Deep biopsy specimens were tectomy, with block dissection of the pelvic lymph-nodes in taken from the tumours with the Thompson resectoscope. continuity with the left ureter and kidney, was carried out. examination all a of the tumours showed wellHistological An 8 in. segment of ileum was isolated to form an ileal bladder, differentiated transitional-cell carcinoma of the bladder, with and the right ureter was implanted into the proximal end, the no evidence of infiltration of muscle (Dr. B. E. Tomlinson). distal end being brought out on to the abdominal surface, to Because of the dispersion and the malignancy of the lesions, the the of the umbilicus. 2160 ml. of whole blood were given right patient was treated with supervoltage X-ray therapy from a the during operation, and there was no period of hypotension. 4-million-volt linear accelerator. This was carried out by At the end of the operation the blood-sugar was 384 mg. Mr. R. Finney, who gave a total dose of 6448r in six weeks, ml. The 100 patient was given 3 litres of 5% dextrose finishing in February, 1960. The patient had some frequency per in next twenty-four hours. From the time the intravenously of micturition during and after the course of radiotherapy, but of there a steady output of urine from the was operation Furadantin ’. this cleared up with urine tests showed heavy glycosuria, ileostomy. Two-hourly Cystoscopy in May, August, and November, 1960, showed no but tests for acetone were The glycosuria gradually negative. of bladder tumour. sign and the blood-sugar the next morning was 128 mg. decreased, In May, 1961, cystoscopy disclosed recurrence of tumour, per 100 ml. 2 x 2 cm., on the posterior wall of the bladder and extending on Postoperative Course to the fundus. Deep biopsy specimens were taken with bitingThe patient was given 3 litres of fluid intravenously each day, forceps, through a Braasch cystoscope. The tumour could with salt and potassium as required. Each bottle was made up just be felt on bimanual examination. There was no fixity. to dextrose by adding 50% dextrose when necessary, thus and differentiated 5% examination. Cellular Histological poorly transitional-cell carcinoma of the bladder. providing 600 calories as carbohydrate each day. Insulin The patient was therefore admitted to hospital. He was in requirements were met by testing the urine four-hourly, and giving soluble insulin on a fixed scale proportional to the good physical condition.His insulin requirements had increased to 48 units each morning (16 units of soluble insulin glycosuria. The patient resumed oral feeding on the fifth and 32 units of protamine zinc insulin). He was still taking an postoperative day. 1800-calorie diet, including 150 g. of carbohydrate, each day. Though the urine output was high, rising to 3 litres on some Chest X-ray showed no change from December, 1959. days, the blood-urea rose steadily, reaching a peak of 222 mg. Excretory urography showed that both kidneys were per 100 ml. on the twelfth day. The serum electrolytes remained functioning well, but in the left pyelogram the crenated appear- within normal limits, except for a low bicarbonate reading ance of a tumour of the renal pelvis was seen. Review of the when the urea was at its highest concentration. On the twelfth day the abdominal wound burst, and was pyelograms of December, 1959, yielded no radiological evidence of tumour at that time (see figs.). resutured. The intravenous regime outlined above was necesHsmoglobin was 13-1 g. per 100 ml. Fasting blood-sugar sary for forty-eight hours, but the blood-urea fell steadily was 212 mg. per 100 ml., and repeated blood-urea estimations over the next two weeks to 69 mg. per 100 ml. were consistently in the 40-50 mg. range. This was noted with The operation specimen showed tumour in the left kidney some anxiety, because nephrectomy would remove one kidney covering the inside of the lower half of the renal pelvis, but not
1050
involving renal parenchyma. On microscopy the tumour was a moderately differentiated carcinoma; it had not infiltrated through the pelvic wall, and did not invade the vessels. The left ureter was free of tumour. The tumour of the bladder involved the fundus and posterior wall. Microscopic examination showed transitional-cell carcinoma infiltrating, but not penetrating, the bladder-wall. The kidney and bladder tumours were histologically dissimilar. Readmission The patient was readmitted to hospital on Aug. 14, 1961, 9 days after discharge, because he said that no urine had come from the ileostomy in the previous thirty hours, and that he had had no insulin during this time. He complained of thirst and of mild pain in the right loin. He had not vomited. He was breathing rapidly, and he was slightly confused, but conscious. Acetone was not smelt in his breath. The temperature was 100-5°F, and he was slightly tender over the right kidney. He was not clinically dehydrated, and there was no sacral or ankle oedema. The jugular venous pressure was not raised, and the lung bases were clear on auscultation. Blood-analysis gave the following results: blood-sugar 900 mg. per 100 ml.; blood-urea 189 mg. per 100 ml.; serum bicarbonate 4-4 m.Eq., sodium 107 m.Eq., chloride 86 m.Eq., potassium 5-6 m.Eq. per litre; haemoglobin 94 g. per 100 ml. At this time, the clinical and biochemical picture was attributed to acute pyelonephritis in the solitary right kidney causing anuria which, combined with the withholding of insulin, had precipitated diabetic ketosis. The dehydration expected with diabetic ketosis was absent, we thought, because of retention of fluids by the renal failure. The patient was given 80 units of soluble insulin (60 unitsi intravenously, and 20 units intramuscularly). An intravenousi drip was started, and the jugular venous pressure and lung; bases were kept under close observation. 1500 ml. of M/6, sodium lactate, and 1000 ml. of 0-9% saline solution, was given intravenously in three hours. At the end of this time, urine began to trickle from the ileostomy and dependent oedema appeared. The drip was discontinued. Urine tests showed sugar 2 % and acetone + - . Blood-analysis showed bloodsugar 890 mg. per 100 ml.; urea 196 mg. per 100 ml.; serum‘ sodium 122 m.Eq. per litre., bicarbonate 4-4 m.Eq., potassium 5-3 m.Eq., and chloride 87 m.Eq. Another 40 units of soluble insulin was then given intramuscularly. Eight hours after, commencement of treatment, fresh urine showed sugar 2% and acetone +. The glycosuria steadily diminished on twohourly testing, and the acetonuria disappeared. 16 hours after commencing treatment, the blood-sugar was 175 mg. per 100 ml., blood-urea 204 mg. per 100 ml., serum sodium 122 m.Eq. per litre, bicarbonate 17-2 m.Eq., potassium 4-4 m.Eq., and chloride 86 m.Eq., and haemoglobin 10-3 g. per 100 ml. The next day the blood-urea was 252 mg. per 100 ml., serum sodium 139 m.Eq. per litre, bicarbonate 16-4 m.Eq., potassium 4 m.Eq., and chloride 96 m.Eq. The urinary output gradually increased, and after eleven days the blood-urea was down to 70 mg. per 100 ml. Three weeks after admission, the; blood-urea was 50 mg. per 100 ml. and the serum electrolytes The patient was finally diswere all within normal limits. charged home, nine weeks after the original operation. His blood-urea has since remained at 45-65 mg. per 100 ml. .
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Discussion
Reviewing 81 patients who had cystectomy performed in this unit during the last ten years, I found that none .
of these was a diabetic. This case illustrated the obvious benefit of the ileal bladder, in the accurate management of diabetes and its complications in such cases. The correct treatment after his readmission on Aug. 14, with anuria and diabetic ketosis, is problematical. In retrospect, I would give smaller volumes of more concentrated fluids intravenously-namely, 500 ml. of 3% saline solution-to improve the very low extracellular .
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sodium (107 m.Eq. per litre), and 500 ml. of M/2 sodium lactate to alleviate the acidosis and hyperpncea. It is difficult to know whether or not there was any pathological connection between the tumour of the left kidney and that in the bladder occurring at the same time. The fact that the left kidney was radiologically normal in December, 1959, and that there was no histological similarity in the excised specimens in July, 1961, suggests that the presence of two tumours of the urinary tract was merely fortuitous.
Summary The management of a diabetic patient who required cystectomy for carcinoma of the bladder is reported. It is suggested that provision of an ileal bladder is essential in such a case for the accurate management of the diabetes after cystectomy. I would like to thank Mr. John Swinney, of the department of urology, Newcastle upon Tyne General Hospital, for permission to
publish this case, and Dr. B. E. Tomlinson for histopathological on the biopsy and operation specimens.
reports
Preliminary Communications TOXICITY OF SOME MONOAMINE-OXIDASE INHIBITORS IN DOGS A SERIES of new hydrazine monoamine-oxidase inhibitors (M.A.o.i.) have been investigated. The experiments were designed to assess chronic toxicity over a period of 3-6 months using pedigree corgi dogs. METHODS
" control animals, additional Apart from the usual " negative " " were administered positive control substances in groups the form of the original parent compounds; iproniazid (’ Marsilid ’) at dose levels of 2, 10, 15, 25, 50, and 100 mg. per kg. per day; phenylisopropyl hydrazine (’JB 516’ or ’ Catron’) at 3, 5, 10, 20, and 40 mg. per kg. per day; and phenelzine (’ Nardil’) at 2, 10, and 12 mg. per kg. per day. The new compounds tested in the first place were heptylhydrazine at levels of 2, 5, 6, and 10 mg. per kg. per day; tetra hydronaphthyl hydrazine (T.N.H.) at 1, 3, 5, 10, and 20 mg. per kg. per day; and indanyl carbethoxy hydrazine (I.C.H.) at 2 and 10 mg. per kg. per day. All drugs were given orally. RESULTS
became apparent that all these compounds (except iproniazid) were producing similar neurological symptoms. When the syndrome was recognised, arrangements were made for detailed histological examination of the brain by one of us (A. C. P.) on the animals which remained. Details of the clinical and histological findings will be reported later in full. The clinical syndrome consisted of: (1) cerebellar ataxia, a progressive condition which led to prostration and death of the dog, common to all the above drugs except iproniazid; (2) cerebral stimulation (most distinct with phenelzine and the new compound (I.C.H.), presenting as increased sensitivity, periods of excitement, and convulsions ; (3) hxmolytic anaemia, reminiscent of that caused by phenyl hydrazine, so severe in the case of iproniazid that, in doses of 25 mg. per kg. per day and over, the animals died of this symptom before neurological abnormalities were apparent. Iproniazid was unique in this respect, the other compounds producing only mild anxmia which was unlikely to have played much part in the causation of nervous signs. All the animals appeared well and alert, and gained weight (although at a slower rate than normal) until a week or so before they died or It
soon