- Email: [email protected]
ACQUIRED THROMBOCYTOPATHY IN PATIENTS WITH PERNICIOUS ANÆMIA
400 later emerge from a comparison of the age-distribution of patients with X-chromosome abnormalities and the age structure of the hospital population as a whole.
patients found in the first year of our hospital study (cases 3 and 8) had diseases which may be particularly associated with their chromosomal abnormalities. Mental defect in case 3 was not directly responsible for his admission to hospital. The diagnosis of paranoid schizophrenia in case 8 is of particular interest in view of the findings of Court Brown et al. (1964). Of 25 adult XXX females, most of them patients in psychiatric hospitals or institutions for the mentally retarded, schizophrenia or paranoia is mentioned in the diagnosis of 7. In contrast, in the other 2 XXX females (cases 9 and 10) there was no reason to suspect chromosomal abnormality until a buccal smear was examined. It now seems likely from our observations and those of Close (1963) that most
THROMBOCYTOPATHY IN PATIENTS WITH PERNICIOUS ANÆMIA
ACQUIRED
Reversion of Biochemical Abnormalities after Treatment with Vitamin B12
2 of the 10
XXX
females
have
neither
mental
nor
menstrual
abnormality and that many are fertile, in spite of their liability to mental retardation and disease. Our results in the 1830 members of a general population call for little comment. Both this investigation and the community health survey of which it was a part are to be regarded as pilot studies, undertaken to provide essential experience for larger studies. Our experience suggests that the inclusion of a buccal smear study in a community health survey offers the best opportunity of determining the frequency of abnormalities of sex-chromatin in a general population. The finding of 6 chromatin-positive males in 942 males seems surprising but is statistically significant (=6-46, 0-02 >p> 0’01). This result must be accepted with reserve, however, because of the size of the population studied. Other features of this population and the results of the health survey will be described elsewhere.
Summary 8600 consecutive admissions to a general hospital were examined for sex-chromatin. Less than 1 % of admissions was lost to the survey and there were 1204 readmissions within the first year of study. Of 7310 patients, 7 were chromatin-positive males of sex-chromosome constitution XXY and 3 were abnormally chromatin-positive females of sex-chromosome constitution XXX. The frequencies of numerical abnormalities of the X chromosome in this population do not differ significantly from their frequencies at birth.
No new disease associations of X-chromosome abnormalities have yet been discerned. In a pilot study of a section of the general population 942 males and 888 females were examined. There were 6 chromatin-positive males (6-36 per 1000) and no abnormal females. These studies are supported by a grant from the Anti-Cancer Council of Victoria. The hospital survey is made possible by the active cooperation of the administration of St. Vincent’s Hospital and by the sustained good-will of its medical staff. The study of the general population was carried out as part of a community health survey in association with the Mental Health Research Institute of Victoria and supported by the Melbourne Rotary Club. We are grateful to Miss Jennifer E. Kalve, Miss Gillian A. Lake, and Miss Patricia Walsh, S.R.N., for their admirable assistance.
Requests for reprints should be University Department of Medicine, N.6, Victoria, Australia.
References
at
addressed to A. G. B. at the St. Vincent’s Hospital, Fitzroy,
foot of next
column
MUSTAFA KARACA *
MARIO STEFANINI
M.D. Istanbul
M.D. Rome
From St. Elizabeth Hospital, Brighton, Massachusetts, and St. Joseph Hospital, Chicago, Illinois
QUALITATIVE deficiencies of platelets are characterised by haemorrhagic tendency of variable severity, especially after accidents or during and after surgical procedures. The number of platelets may be normal or only slightly subnormal but conventional, phase contrast, and electron microscopy show morphological abnormalities of various types. The bleeding-time is often prolonged. Clot retraction and/or utilisation of prothrombin during clotting are abnormal. The qualitative platelet deficiencies associated with defective retraction of the clot
are
defined
thrombocytoasthenias (thromboasthenias), while those associated with abnormal generation of thromboplastin and poor utilisation of prothrombin during clotting are defined as thrombocytopathies. Thrombocytopathies may be or the congenital acquired, acquired type having been described in a variety of clinical disorders (Karaca and Stefanini 1966). Platelets from patients with acquired thrombocytopathy show a biochemical abnormality consisting of decreased content of lipids, phospholipids, lecithin, and phosphatidyl serine (Karaca and Stefanini 1966). In a series of 14 cases of pernicious anaemia, 3 showed features of thrombocytopathy with abnormally decreased content of lipids and phospholipids in platelets. After parenteral administration of vitamin B12 two findings were noted: (1) improvement in the hxmatological picture and in the haemostatic activity of platelets, and (2) return to normal of the content and composition of lipids and phospholipids of platelets. as
Materials and Methods Standard
techniques
were
used for blood studies
(Wintrobe
1961). Reported in detail are the results of the following tests, performed with the procedures indicated by the reference in parenthesis after each one: platelet count (Bjorkman 1959), bleeding-time (Ivy et al. 1935), prothrombin consumption (Stefanini and Crosby 1950), thromboplastin-generation test (Biggs and Douglas 1953). Analysis of content and activity of individual clotting factors, using the techniques described by Stefanini and Dameshek (1962), showed np significant deficiency. Anticoagulants and increased fibrinelytic activity were not *
detected. Clot retraction
Present address:
was
normal in all instances.
Department of Medicine, University of Ege, Izmir,
Turkey.
DR. BAIKIE AND OTHERS: REFERENCES
H. G.
(1963) Lancet, ii, 1358. Court Brown, W. M., Harnden, D. G., Jacobs, P. A., Maclean, N., Mantle, D. J. (1964) Spec. Rep. Ser. Med. Res. Coun. no. 305. Ferguson, J. (1962) Med. J. Austr. i, 40. Ferguson-Smith, M. A., Lennox, B., Mack, W. S., Stewart, J. S. S. (1957) Lancet, ii, 167. Israelsohn, W. J., Taylor, A. I. (1961) Br. med. J. i, 633. Jacobs, P. A., Harnden, D. G., Buckton, K. E., Court Brown, W. M., King, M. J., McBride, J. A., MacGregor, T. N., Maclean, N. (1961) Lancet, i, 1183. Maclean, N., Harnden, D. G., Court Brown, W. M., Bond, J., Mantle, D. J. (1964) ibid. i, 286. Mitchell, J. M., Harnden, D. G., Williams, J., Jacobs, P. A., Buckton, K. E., Baikie, A. G., Court Brown, W. M., McBride, J. A., Strong, J. A., Close, H. G., Jones, D. C. (1962) ibid. i, 293. Moorhead, P. S., Nowell, P. C., Mellman, W. J., Battips, D. M., Hungerford, D. A. (1960) Exp. Cell Res. 20, 613. Ross, A. (1960) J. med. Lab. Technol. 17, 178.
Close,
—
401 VALUES BEFORE AND AFTER THREE WEEKS OF TREATMENT WITH VITAMIN
TABLE I-H&MATOLOGICAL
B12
IN
3 CASES
OF PERNICIOUS
ANaeMIA
M.C.H.C. =mean corpuscular hoemoglobin concentration M.c.v.=mean corpuscular volume. corpuscular haemoglobin. E. = eosinophils. B. = basophils. R. =reticulocytes M. =monocytes. N. =neutrophils. L. =lymphocytes. * "Co-labelled without and with intrinsic factor. administered (B) vitamin-B12 (A)
m.c.H. =mean
TABLE II—HAEMOSTATIC FUNCTION OF PLATELETS AND THEIR CONTENT AND COMPOSITION OF PHOSPHOLIPIDS IN
3
PATIENTS WITH
PERNICIOUS ANEMIA, BEFORE AND THREE WEEKS AFTER TREATMENT WITH VITAMIN B122
*
At 7 minutes with
t Values for
a
system of
platelets from
a
plasma and serum reagents from healthy individuals and platelet reagent from patients (200,000 per ml.). series of 4 healthy individuals.
The Schilling test was performed with the urinary excretion procedure (Schilling 1953), using 6OCo-labelled vitamin Bl2’ After the diagnosis had been established and base line studies completed, each patient received intramuscularly 100 tLg. of vitamin Bl2 daily for three weeks. At the end of this period, most studies were repeated. Techniques for the determination of platelet lipids, phospholipids, and their constituents were minor modifications of the procedures of Marinetti et al. (1958) as described by Karaca and Stefanini (1966). These studies were done before and after three weeks of treatment with vitamin Bi2. Results
Significant hxmatological details of the 3 cases under study are given in table i. Blood glucose and urea nitrogen and serum-creatinine were normal in all cases. Table n summarises the results of tests of haemostatic function before and after treatment. The content of lipids, phospholipids, lecithin, and phosphatidyl serine in platelets was low at the beginning of our study. Treatment with vitamin B12 improved the haematological status (table i). Also, after treatment, the hxmostatic function of platelets and their lipid content and distribution became normal (table 11). Discussion
Thrombocytopenia is not infrequently seen in untreated pernicious anaemia (Paddock and Smith 1939). It is corrected by the parenteral administration of vitamin B12 (Stefanini and Dameshek 1962). Thrombocytopathy in pernicious anaemia, however, has not been reported previously. The biochemical abnormality seen in the platelets in these patients parallels that observed in
thrombocytopathies of different aetiology (Karaca and Stefanini 1966). The pathogenesis of these biochemical abnormalities is not clear. Three possibilities, however, may be considered: (1) faulty synthesis of lipid constituents ; (2) loss of platelets through a defective platelet membrane; and (3) tenuous and insufficient binding of lipids by platelets. The selected depletion of specific phospholipids favours a deficiency in their synthesis as the most significant factor in the pathogenesis of the biochemical defect. In the 3 cases of pernicious anxmia which we studied the xtiology and nature of the defect remain obscure, especially since the defect was found in only 3 of 14 cases which were investigated. It is of interest, however, that these abnormalities regressed with the improvement of the hxmatological picture, suggesting a potential relationship between vitamin-B12 deficiency and status of platelet phospholipids. Summary
Among 14 cases of pernicious anaemia, 3 showed features acquired thrombocytopathy. Chemical and chromatographic analysis of platelets from these patients indicated depletion of lipids, phospholipids, lecithin, and phosphatidyl serine. After parenteral administration of vitamin B12 for three weeks, the haematological picture improved and the haemostatic function of platelets returned to normal. The depletion in content and the abnormality in composition of lipids and phospholipids appeared corrected. These findings suggest a relationship between vitamin B12 and status of lipids and phospholipids in platelets. This work was supported, in part, by grants from the National of
Institutes of Health and the Illinois Division of the American Cancer
402
Society. Requests for reprints should be addressed to Dr. Mario Stefanini, 1104, Rossell Avenue, Oak Park, Illinois 60302, U.S.A. REFERENCES
Biggs, R. G., Douglas, A. S. (1953) J. clin. Path. 6, 23. Bjorkman, S. E. (1959) Acta Hœmatol. 22, 377. Ivy, A. C., Shapiro, P. R., Melnick, P. (1935) Surgery, Gynec. Obstet. 60, 781. Karaca, M., Stefanini, M. (1966) J. Lab. clin. Med. (in the press). Marinetti, G. V., Erbland, J., Kochen, J. (1958) Fedn Proc. Fedn Am. Socs exp. Biol. 16, 837. Paddock, F. K., Smith, K. E. (1939) Am. J. med. Sci. 198, 372. Schilling, R. F. (1953) J. Lab. clin. Med. 42, 860. Stefanini, M., Crosby, W. H. (1950) Blood, 5, 964. Dameshek, W. (1962) The Hemorrhagic Disorders. New York and —
London.
Wintrobe, M. M. (1961) Clinical Hematology. Philadelphia.
USE OF MANNITOL IN PROLONGED COMA DUE TO INSULIN OVERDOSE B. I. HOFFBRAND M.A., B.M. Oxon., M.R.C.P. MEDICAL REGISTRAR *
L. H. SEVITT B.A., M.B. Dubl., M.R.C.P. SENIOR HOUSE-OFFICER
WHITTINGTON
&dag er;
HOSPITAL, LONDON, N.19
in
insulin-treated diabetes usually responds rapidly to the administration of or glycogenolytic agents such as adrenaline or glucose HTTOGLYC.S.MIC
coma
mellitus
glucagon. Occasionally, however, in spite of the return of blood-sugar to normal or even hyperglycxmic levels, consciousness remains impaired for prolonged periods. Such events may lead to variable neurological or psychia-
the
tric deficits or even to death. A young diabetic patient died in this hospital shortly after the onset of hypoglycsemic coma in spite of large quantities of intravenous glucose. At necropsy most of the viscera, including the brain, were found to be extremely cedematous. Although cerebral oedema may represent a response of the brain to virtually any form of damage, it appears to be a prominent feature in both human and experimental hypoglycxmia due to insulin overdose (Terplan 1932, Bowen and Beck 1933, Yannet 1939, Marks and Rose 1965). We therefore decided to use one of the newer hypertonic agents in the treatment of these cases. The results in the two patients treated so far are encouraging and are reported here.
Case-reports FIRST CASE
A 73-year-old man was admitted to hospital in March, 1965, with lobar pneumonia. He had had diabetes for 40 years which had previously been well controlled on twice daily soluble insulin (with a total dose of between 40 and 50 units per day). One evening, 2 weeks after admission, he had a typical hypoglycxmic attack, becoming suddenly confused and sweating profusely. He was unable to take oral glucose but responded rapidly to 10 g. of glucose intravenously, after which he had a further 30 g. orally and some bread and butter. 4 hours later, he again became hypoglycxmic and, in spite of swallowing 30 g. of glucose, lost consciousness. A further quantity of glucose was given by nasogastric tube, the bloodsugar level at this point being 118 mg. per 100 ml. There was no response to a further 50 g. of intravenous glucose and, 3 hours after the onset of his second hypoglycaemic attack, the patient was comatose with extensor plantar responses and a blood-sugar of 335 mg. per 100 ml. 5 hours later he was semiconscious and very restless, his blood* Present address: University College Hospital, London, W.C.1. t Present address: Hammersmith Hospital and Postgraduate Medical School, London, W.12.
sugar being 370 mg. per 100 ml. Intravenous hydrocortisone 100 mg. given with more glucose had no effect. His level of consciousness was unchanged when, 12 hours after the onset of the coma, 200 ml. of 20% mannitol was given intravenously over 15 minutes. 30 minutes later the patient sat up and asked for a urinal. Full consciousness was rapidly regained and the neurological signs disappeared though he remained somewhat querulous and anorectic for the next 2 days. SECOND CASE
A 33-year-old man had had diabetes for 11 years treated with a single morning injection of a mixture of soluble insulin and protamine-zinc insulin, about 16 and 24 units respectively. He had been subject to frequent hypoglycaemic attacks. One morning in May, 1965, he awoke nauseated, and took a smaller dose of insulin than usual with only a little breakfast. 3 hours later he was found semiconscious and admitted to hospital. 30 g. of glucose intravenously gave a minimal improvement in his level of consciousness and following this his blood-sugar was found to be only 100 mg. per 100 ml. Further glucose brought the blood-sugar to 440 mg. per 100 ml. 4 hours after being found hypoglycsemic, he was very drowsy and uncooperative. At this stage 200 ml. of 20% mannitol was given intravenously over 15 minutes. 45 minutes later he awoke and walked to the toilet to micturate.
Discussion In reviewing the treatment of cerebral swelling, Matson (1965) advocated the use of 20% mannitol in preference to other hypertonic solutions because it has less rebound effect and a more prolonged action. The return to normal consciousness within 45 minutes of the infusion suggests, especially in case 1 where confusion had lasted no less than 12 hours, that the mannitol had real therapeutic value. Steroids have been reported to be useful in the treatment of prolonged hypoglycxmic coma (Bloom and Wolff 1955, Kay 1961), although hydrocortisone produced no apparent benefit in case 1. It is possible that in successful cases steroids may act not only by affecting glucose metabolism but also by reducing cerebral oedema for which they are now used in neurosurgery (Matson
1965). the treatment of hypowrites " The use of hypertonic solutions glycaemic coma, of sodium chloride, sucrose or sorbitol may be tried to combat cerebral oedema if lumbar puncture indicates its presence ". He gave no indication whether such treatment, now obsolete, has been used with success if at all. We believe, however, that modern hypertonic solutions may have a place in the early stages of the management of insulin overdose, when, after adequate glucose replacement, consciousness remains impaired.
Marble
(1959), discussing
Summary
hypertonic agent, a 20% solution of mannitol, was given in 2 cases where prolonged hypoglycaemic coma had not responded to intravenous glucose. The patients consciousness 30 and 45 minutes respectively regained A
after the infusion. We thank Dr. Arnold Bloom under whose care these patients were admitted for helpful criticism and encouragement. Requests for reprints should be addressed to B. I. H. at University College Hospital, London, W.C.l. REFERENCES
Bloom, A., Wolff, F. (1955) Br. med. J. i, 1460. Bowen, B. D., Beck, G. (1933) Ann. intern. Med. 6, 1412. Kay, W. W. (1961) J. ment. sci. 107, 194. Marble, A. (1959) in Treatment of Diabetes Mellitus (edited by E. P. Joslin, H. F. Root, P. White, and A. Marble; p. 326. London. Marks, V., Rose, F. C. (1965) in Hypoglycæmia; p. 317. Oxford. Matson, D. D. (1965) New Engl.J. Med. 272, 626. Terplan, K. (1932) Archs. Path. 14, 131. Yannet, H. (1939) Archs. neurol. psychiat., Chicago, 42, 237.
patients found in the first year of our hospital study (cases 3 and 8) had diseases which may be particularly associated with their chromosomal abnormalities. Mental defect in case 3 was not directly responsible for his admission to hospital. The diagnosis of paranoid schizophrenia in case 8 is of particular interest in view of the findings of Court Brown et al. (1964). Of 25 adult XXX females, most of them patients in psychiatric hospitals or institutions for the mentally retarded, schizophrenia or paranoia is mentioned in the diagnosis of 7. In contrast, in the other 2 XXX females (cases 9 and 10) there was no reason to suspect chromosomal abnormality until a buccal smear was examined. It now seems likely from our observations and those of Close (1963) that most
THROMBOCYTOPATHY IN PATIENTS WITH PERNICIOUS ANÆMIA
ACQUIRED
Reversion of Biochemical Abnormalities after Treatment with Vitamin B12
2 of the 10
XXX
females
have
neither
mental
nor
menstrual
abnormality and that many are fertile, in spite of their liability to mental retardation and disease. Our results in the 1830 members of a general population call for little comment. Both this investigation and the community health survey of which it was a part are to be regarded as pilot studies, undertaken to provide essential experience for larger studies. Our experience suggests that the inclusion of a buccal smear study in a community health survey offers the best opportunity of determining the frequency of abnormalities of sex-chromatin in a general population. The finding of 6 chromatin-positive males in 942 males seems surprising but is statistically significant (=6-46, 0-02 >p> 0’01). This result must be accepted with reserve, however, because of the size of the population studied. Other features of this population and the results of the health survey will be described elsewhere.
Summary 8600 consecutive admissions to a general hospital were examined for sex-chromatin. Less than 1 % of admissions was lost to the survey and there were 1204 readmissions within the first year of study. Of 7310 patients, 7 were chromatin-positive males of sex-chromosome constitution XXY and 3 were abnormally chromatin-positive females of sex-chromosome constitution XXX. The frequencies of numerical abnormalities of the X chromosome in this population do not differ significantly from their frequencies at birth.
No new disease associations of X-chromosome abnormalities have yet been discerned. In a pilot study of a section of the general population 942 males and 888 females were examined. There were 6 chromatin-positive males (6-36 per 1000) and no abnormal females. These studies are supported by a grant from the Anti-Cancer Council of Victoria. The hospital survey is made possible by the active cooperation of the administration of St. Vincent’s Hospital and by the sustained good-will of its medical staff. The study of the general population was carried out as part of a community health survey in association with the Mental Health Research Institute of Victoria and supported by the Melbourne Rotary Club. We are grateful to Miss Jennifer E. Kalve, Miss Gillian A. Lake, and Miss Patricia Walsh, S.R.N., for their admirable assistance.
Requests for reprints should be University Department of Medicine, N.6, Victoria, Australia.
References
at
addressed to A. G. B. at the St. Vincent’s Hospital, Fitzroy,
foot of next
column
MUSTAFA KARACA *
MARIO STEFANINI
M.D. Istanbul
M.D. Rome
From St. Elizabeth Hospital, Brighton, Massachusetts, and St. Joseph Hospital, Chicago, Illinois
QUALITATIVE deficiencies of platelets are characterised by haemorrhagic tendency of variable severity, especially after accidents or during and after surgical procedures. The number of platelets may be normal or only slightly subnormal but conventional, phase contrast, and electron microscopy show morphological abnormalities of various types. The bleeding-time is often prolonged. Clot retraction and/or utilisation of prothrombin during clotting are abnormal. The qualitative platelet deficiencies associated with defective retraction of the clot
are
defined
thrombocytoasthenias (thromboasthenias), while those associated with abnormal generation of thromboplastin and poor utilisation of prothrombin during clotting are defined as thrombocytopathies. Thrombocytopathies may be or the congenital acquired, acquired type having been described in a variety of clinical disorders (Karaca and Stefanini 1966). Platelets from patients with acquired thrombocytopathy show a biochemical abnormality consisting of decreased content of lipids, phospholipids, lecithin, and phosphatidyl serine (Karaca and Stefanini 1966). In a series of 14 cases of pernicious anaemia, 3 showed features of thrombocytopathy with abnormally decreased content of lipids and phospholipids in platelets. After parenteral administration of vitamin B12 two findings were noted: (1) improvement in the hxmatological picture and in the haemostatic activity of platelets, and (2) return to normal of the content and composition of lipids and phospholipids of platelets. as
Materials and Methods Standard
techniques
were
used for blood studies
(Wintrobe
1961). Reported in detail are the results of the following tests, performed with the procedures indicated by the reference in parenthesis after each one: platelet count (Bjorkman 1959), bleeding-time (Ivy et al. 1935), prothrombin consumption (Stefanini and Crosby 1950), thromboplastin-generation test (Biggs and Douglas 1953). Analysis of content and activity of individual clotting factors, using the techniques described by Stefanini and Dameshek (1962), showed np significant deficiency. Anticoagulants and increased fibrinelytic activity were not *
detected. Clot retraction
Present address:
was
normal in all instances.
Department of Medicine, University of Ege, Izmir,
Turkey.
DR. BAIKIE AND OTHERS: REFERENCES
H. G.
(1963) Lancet, ii, 1358. Court Brown, W. M., Harnden, D. G., Jacobs, P. A., Maclean, N., Mantle, D. J. (1964) Spec. Rep. Ser. Med. Res. Coun. no. 305. Ferguson, J. (1962) Med. J. Austr. i, 40. Ferguson-Smith, M. A., Lennox, B., Mack, W. S., Stewart, J. S. S. (1957) Lancet, ii, 167. Israelsohn, W. J., Taylor, A. I. (1961) Br. med. J. i, 633. Jacobs, P. A., Harnden, D. G., Buckton, K. E., Court Brown, W. M., King, M. J., McBride, J. A., MacGregor, T. N., Maclean, N. (1961) Lancet, i, 1183. Maclean, N., Harnden, D. G., Court Brown, W. M., Bond, J., Mantle, D. J. (1964) ibid. i, 286. Mitchell, J. M., Harnden, D. G., Williams, J., Jacobs, P. A., Buckton, K. E., Baikie, A. G., Court Brown, W. M., McBride, J. A., Strong, J. A., Close, H. G., Jones, D. C. (1962) ibid. i, 293. Moorhead, P. S., Nowell, P. C., Mellman, W. J., Battips, D. M., Hungerford, D. A. (1960) Exp. Cell Res. 20, 613. Ross, A. (1960) J. med. Lab. Technol. 17, 178.
Close,
—
401 VALUES BEFORE AND AFTER THREE WEEKS OF TREATMENT WITH VITAMIN
TABLE I-H&MATOLOGICAL
B12
IN
3 CASES
OF PERNICIOUS
ANaeMIA
M.C.H.C. =mean corpuscular hoemoglobin concentration M.c.v.=mean corpuscular volume. corpuscular haemoglobin. E. = eosinophils. B. = basophils. R. =reticulocytes M. =monocytes. N. =neutrophils. L. =lymphocytes. * "Co-labelled without and with intrinsic factor. administered (B) vitamin-B12 (A)
m.c.H. =mean
TABLE II—HAEMOSTATIC FUNCTION OF PLATELETS AND THEIR CONTENT AND COMPOSITION OF PHOSPHOLIPIDS IN
3
PATIENTS WITH
PERNICIOUS ANEMIA, BEFORE AND THREE WEEKS AFTER TREATMENT WITH VITAMIN B122
*
At 7 minutes with
t Values for
a
system of
platelets from
a
plasma and serum reagents from healthy individuals and platelet reagent from patients (200,000 per ml.). series of 4 healthy individuals.
The Schilling test was performed with the urinary excretion procedure (Schilling 1953), using 6OCo-labelled vitamin Bl2’ After the diagnosis had been established and base line studies completed, each patient received intramuscularly 100 tLg. of vitamin Bl2 daily for three weeks. At the end of this period, most studies were repeated. Techniques for the determination of platelet lipids, phospholipids, and their constituents were minor modifications of the procedures of Marinetti et al. (1958) as described by Karaca and Stefanini (1966). These studies were done before and after three weeks of treatment with vitamin Bi2. Results
Significant hxmatological details of the 3 cases under study are given in table i. Blood glucose and urea nitrogen and serum-creatinine were normal in all cases. Table n summarises the results of tests of haemostatic function before and after treatment. The content of lipids, phospholipids, lecithin, and phosphatidyl serine in platelets was low at the beginning of our study. Treatment with vitamin B12 improved the haematological status (table i). Also, after treatment, the hxmostatic function of platelets and their lipid content and distribution became normal (table 11). Discussion
Thrombocytopenia is not infrequently seen in untreated pernicious anaemia (Paddock and Smith 1939). It is corrected by the parenteral administration of vitamin B12 (Stefanini and Dameshek 1962). Thrombocytopathy in pernicious anaemia, however, has not been reported previously. The biochemical abnormality seen in the platelets in these patients parallels that observed in
thrombocytopathies of different aetiology (Karaca and Stefanini 1966). The pathogenesis of these biochemical abnormalities is not clear. Three possibilities, however, may be considered: (1) faulty synthesis of lipid constituents ; (2) loss of platelets through a defective platelet membrane; and (3) tenuous and insufficient binding of lipids by platelets. The selected depletion of specific phospholipids favours a deficiency in their synthesis as the most significant factor in the pathogenesis of the biochemical defect. In the 3 cases of pernicious anxmia which we studied the xtiology and nature of the defect remain obscure, especially since the defect was found in only 3 of 14 cases which were investigated. It is of interest, however, that these abnormalities regressed with the improvement of the hxmatological picture, suggesting a potential relationship between vitamin-B12 deficiency and status of platelet phospholipids. Summary
Among 14 cases of pernicious anaemia, 3 showed features acquired thrombocytopathy. Chemical and chromatographic analysis of platelets from these patients indicated depletion of lipids, phospholipids, lecithin, and phosphatidyl serine. After parenteral administration of vitamin B12 for three weeks, the haematological picture improved and the haemostatic function of platelets returned to normal. The depletion in content and the abnormality in composition of lipids and phospholipids appeared corrected. These findings suggest a relationship between vitamin B12 and status of lipids and phospholipids in platelets. This work was supported, in part, by grants from the National of
Institutes of Health and the Illinois Division of the American Cancer
402
Society. Requests for reprints should be addressed to Dr. Mario Stefanini, 1104, Rossell Avenue, Oak Park, Illinois 60302, U.S.A. REFERENCES
Biggs, R. G., Douglas, A. S. (1953) J. clin. Path. 6, 23. Bjorkman, S. E. (1959) Acta Hœmatol. 22, 377. Ivy, A. C., Shapiro, P. R., Melnick, P. (1935) Surgery, Gynec. Obstet. 60, 781. Karaca, M., Stefanini, M. (1966) J. Lab. clin. Med. (in the press). Marinetti, G. V., Erbland, J., Kochen, J. (1958) Fedn Proc. Fedn Am. Socs exp. Biol. 16, 837. Paddock, F. K., Smith, K. E. (1939) Am. J. med. Sci. 198, 372. Schilling, R. F. (1953) J. Lab. clin. Med. 42, 860. Stefanini, M., Crosby, W. H. (1950) Blood, 5, 964. Dameshek, W. (1962) The Hemorrhagic Disorders. New York and —
London.
Wintrobe, M. M. (1961) Clinical Hematology. Philadelphia.
USE OF MANNITOL IN PROLONGED COMA DUE TO INSULIN OVERDOSE B. I. HOFFBRAND M.A., B.M. Oxon., M.R.C.P. MEDICAL REGISTRAR *
L. H. SEVITT B.A., M.B. Dubl., M.R.C.P. SENIOR HOUSE-OFFICER
WHITTINGTON
&dag er;
HOSPITAL, LONDON, N.19
in
insulin-treated diabetes usually responds rapidly to the administration of or glycogenolytic agents such as adrenaline or glucose HTTOGLYC.S.MIC
coma
mellitus
glucagon. Occasionally, however, in spite of the return of blood-sugar to normal or even hyperglycxmic levels, consciousness remains impaired for prolonged periods. Such events may lead to variable neurological or psychia-
the
tric deficits or even to death. A young diabetic patient died in this hospital shortly after the onset of hypoglycsemic coma in spite of large quantities of intravenous glucose. At necropsy most of the viscera, including the brain, were found to be extremely cedematous. Although cerebral oedema may represent a response of the brain to virtually any form of damage, it appears to be a prominent feature in both human and experimental hypoglycxmia due to insulin overdose (Terplan 1932, Bowen and Beck 1933, Yannet 1939, Marks and Rose 1965). We therefore decided to use one of the newer hypertonic agents in the treatment of these cases. The results in the two patients treated so far are encouraging and are reported here.
Case-reports FIRST CASE
A 73-year-old man was admitted to hospital in March, 1965, with lobar pneumonia. He had had diabetes for 40 years which had previously been well controlled on twice daily soluble insulin (with a total dose of between 40 and 50 units per day). One evening, 2 weeks after admission, he had a typical hypoglycxmic attack, becoming suddenly confused and sweating profusely. He was unable to take oral glucose but responded rapidly to 10 g. of glucose intravenously, after which he had a further 30 g. orally and some bread and butter. 4 hours later, he again became hypoglycxmic and, in spite of swallowing 30 g. of glucose, lost consciousness. A further quantity of glucose was given by nasogastric tube, the bloodsugar level at this point being 118 mg. per 100 ml. There was no response to a further 50 g. of intravenous glucose and, 3 hours after the onset of his second hypoglycaemic attack, the patient was comatose with extensor plantar responses and a blood-sugar of 335 mg. per 100 ml. 5 hours later he was semiconscious and very restless, his blood* Present address: University College Hospital, London, W.C.1. t Present address: Hammersmith Hospital and Postgraduate Medical School, London, W.12.
sugar being 370 mg. per 100 ml. Intravenous hydrocortisone 100 mg. given with more glucose had no effect. His level of consciousness was unchanged when, 12 hours after the onset of the coma, 200 ml. of 20% mannitol was given intravenously over 15 minutes. 30 minutes later the patient sat up and asked for a urinal. Full consciousness was rapidly regained and the neurological signs disappeared though he remained somewhat querulous and anorectic for the next 2 days. SECOND CASE
A 33-year-old man had had diabetes for 11 years treated with a single morning injection of a mixture of soluble insulin and protamine-zinc insulin, about 16 and 24 units respectively. He had been subject to frequent hypoglycaemic attacks. One morning in May, 1965, he awoke nauseated, and took a smaller dose of insulin than usual with only a little breakfast. 3 hours later he was found semiconscious and admitted to hospital. 30 g. of glucose intravenously gave a minimal improvement in his level of consciousness and following this his blood-sugar was found to be only 100 mg. per 100 ml. Further glucose brought the blood-sugar to 440 mg. per 100 ml. 4 hours after being found hypoglycsemic, he was very drowsy and uncooperative. At this stage 200 ml. of 20% mannitol was given intravenously over 15 minutes. 45 minutes later he awoke and walked to the toilet to micturate.
Discussion In reviewing the treatment of cerebral swelling, Matson (1965) advocated the use of 20% mannitol in preference to other hypertonic solutions because it has less rebound effect and a more prolonged action. The return to normal consciousness within 45 minutes of the infusion suggests, especially in case 1 where confusion had lasted no less than 12 hours, that the mannitol had real therapeutic value. Steroids have been reported to be useful in the treatment of prolonged hypoglycxmic coma (Bloom and Wolff 1955, Kay 1961), although hydrocortisone produced no apparent benefit in case 1. It is possible that in successful cases steroids may act not only by affecting glucose metabolism but also by reducing cerebral oedema for which they are now used in neurosurgery (Matson
1965). the treatment of hypowrites " The use of hypertonic solutions glycaemic coma, of sodium chloride, sucrose or sorbitol may be tried to combat cerebral oedema if lumbar puncture indicates its presence ". He gave no indication whether such treatment, now obsolete, has been used with success if at all. We believe, however, that modern hypertonic solutions may have a place in the early stages of the management of insulin overdose, when, after adequate glucose replacement, consciousness remains impaired.
Marble
(1959), discussing
Summary
hypertonic agent, a 20% solution of mannitol, was given in 2 cases where prolonged hypoglycaemic coma had not responded to intravenous glucose. The patients consciousness 30 and 45 minutes respectively regained A
after the infusion. We thank Dr. Arnold Bloom under whose care these patients were admitted for helpful criticism and encouragement. Requests for reprints should be addressed to B. I. H. at University College Hospital, London, W.C.l. REFERENCES
Bloom, A., Wolff, F. (1955) Br. med. J. i, 1460. Bowen, B. D., Beck, G. (1933) Ann. intern. Med. 6, 1412. Kay, W. W. (1961) J. ment. sci. 107, 194. Marble, A. (1959) in Treatment of Diabetes Mellitus (edited by E. P. Joslin, H. F. Root, P. White, and A. Marble; p. 326. London. Marks, V., Rose, F. C. (1965) in Hypoglycæmia; p. 317. Oxford. Matson, D. D. (1965) New Engl.J. Med. 272, 626. Terplan, K. (1932) Archs. Path. 14, 131. Yannet, H. (1939) Archs. neurol. psychiat., Chicago, 42, 237.