1112
entry. Investigation of gut permeability in patients with CBMMPseems worthwhile, and a trial of a gluten-free diet may be reasonablein these individuals for whom we have very little else to offer in the
way of therapy.Department of Dermatology,St Mary’s Hospital,London W2 1NY
Moorfields Eye Hospital,London EC1
Department of Oral Medicine,Eastman Dental Hospital,London WC1
Department of Oral Pathologyand MRC Immunology Group,Bone & Joint Unit,The London Hospital,London E1
J. N. LEONARDLIONEL FRY
PETER WRIGHT
J. J. H. GILKES
D. M. WILLIAMSD. J. UNSWORTHE. J. HOLBOROW
TRIMETHOPRIM-ASSOCIATED MARROW TOXICITYNOT PROVEN
SIR,-In concluding that trimethoprim was the marrow toxicagent in his patient, Dr Sheehan (Sept. 26, p. 692) seems to haveignored the possible marrow toxic effects of drugs to which hispatient had been exposed before starting trimethoprim therapy.Leucopenia, thrombocytopenia and even pancytopenia have been
associated with idoxuridine. 1,2 This has only been reported inconnection with systemic therapy with this drug but skin is not asimpenetrable an organ as is often believed. It could allowtransdermal permeation of topically applied creams and ointmentsin quantities sufficient to have a systemic action.3 Indeed, bonemarrow aplasia has been reported in patients takingchloramphenicol containing eye ointments.
Tricyclic antidepressants, of which trimipramine is a member,have been associated with a vast number of side effects. Marrow
toxicity is one of them.4 Chlorpheniramine was used to treat a rash,and chlorpheniramine too has been associated with marrow
toxicity. 5,6Sheehan’s patient had therefore been exposed to four drugs all
with potential marrow toxicity. Any of them, alone or in
combination, could have been the culprit. Trimethoprim folic acidantagonism is said to be 50 000 times more sensitive in bacteria thanin man. This patient had normal serum folate levels, but othermechanisms could be involved in trimethoprim associated marrowtoxicity.Welsh National School of Medicine,Department of Medicine,Heath Park, Cardiff CF4 4XN K. GICHERU
MISLEADING HEPARIN MONITORING LEADING TOPROTAMINE SULPHATE IN PATIENT WITH LUPUS
ANTICOAGULANT
SIR,-A 69-year-old man was admitted with mitral regurgitationand a critical stenosis of the marginal coronary artery. Mitral valuereplacement and coronary artery bypass were planned. Routinepreoperative coagulation testing revealed a prolonged activatedpartial thromboplastin time (APTT), (44 s; normal <36 s) withnormal prothrombin and thrombin times, platelet count,
fibrinogen, and bleeding time. In vitro mixing of equal parts of thepatient’s plasma and normal plasma corrected the APTT to only38 s. A thromboplastin inhibition test revealed a ratio of 2 - 5 at 1:100and 1 - 7 at 1:1000 dilutions. Any value over 1’ 3 in our laboratory isconsidered diagnostic of a lupus inhibitor. 7
1 Geary CG. Haematological complications of therapy with pyrimidine analogues.Postgrad Med J 1973; 49: 413.
2 Boston interhospital virus study group and the NIAID sponsored co-operation antiviralclinical study. N Engl J Med 1975; 292: 599.
3. Scheuplen, RJ, Blank IH. Permeability of the skin. Phystol Rev 1971; 51: 702.4. Ballin JC. Toxicity of tricyclic antidepressants. JAMA 1975; 231: 1369.5. Shenfield G, Spry CJF. Unusual causes of agranulocytosis. Br Med J 1968, ii: 52.6. Deringer PM, Maniatis A. Chlorpheniramine induced bone marrow suppression.
Lancet 1976; i: 432.7. Schleider MA, et al. A clinical study of the lupus anticoagulant. Blood 1976; 48: 499.
Cardiopulmonary bypass was achieved without difficulty. Thelevel of heparin anticoagulation was monitored with the ’Hepcon’system. This is reported to be a protamine sulphate titration withactivated whole blood clotting time as the indicator. The coronaryartery bypass was abandoned due to technical difficulties. Themitral valve replacement was completed successfully. However,after weaning from cardiopulmonary bypass, haemostaticdifficulties developed.53 000 units of heparin had been given at this point.
Intraoperative coagulation studies showed an APTT of 150 s and athrombin time of 21 s (control 11 s). Because of the bleeding,multiple doses of protamine sulphate were administered totalling10 900 mg. With each dose, the APTT and thrombin timeshortened until the APTT was 46 s and the thrombin time was 14 s
(control 11 s). Further doses of protamine sulphate shortened theAPTT to 40 s but the thrombin time lengthened to 20 - 5 s. The
hepcon system throughout this procedure continued to indicate that. additional protamine sulphate was necessary.
Because of the continued bleeding, closure of the sternotomy waspostponed and the patient was taken to the intensive care unit.Eventually, with the administration of 9 units offresh frozen plasmaand no further protamine sulphate, the patient stabilised and hislaboratory values returned to normal. A successful closure of thesternum was completed the next day without complications.The prolongation of the thrombin time after initial correction
suggests that the patient received an overdose of protaminesulphate. Excessive protamine sulphate has been associated withincreased postoperative blood loss.s We believe that the excessiveprotamine sulphate this patient received was due to interferencewith the Hepcon system by a lupus-type anticoagulant.Unfortunately the inhibitor was not demonstrable in the
postoperative period and efforts to recreate the experience with thehepcon system using heparinised blood samples from the patientwere unsuccessful. This was probably due to the large amount ofplasma given in the immediate postoperative period.Although further study is necessary to confirm this suggested
interference, intraoperative monitoring of heparin by any wholeblood technique may be unreliable in patients with a lupus typeinhibitor. The lupus inhibitor occurs in a variety of disorders otherthan systemic lupus erythematosus and may be found in otherwisehealthy subjects. The inhibitor rarely, if every, causes clinical
bleeding, and may disappear spontaneously.Department of Pathology,University Hospitals,Ohio State University,Columbus, Ohio 43210, U.S.A.
GREGORY P. WANGERWILLIAM ROBERTS
JOHN BRANDT
SERUM TESTOSTERONE OF BOYS WITHKARYOTYPE 47,XXY (KLINEFELTER’S SYNDROME)
AT BIRTH
SiR,-Since Oct. 1, 1980, chromosome examinations have beendone on 2773 consecutive liveborn children in the Arhus area inDenmark. 3 of the 1390 boys had karyotypes with supernumerary Xchromosomes, corresponding to Klinefelter’s syndrome. Serumtestosterone concentrations have been measured in these 3 boys,none of whom had any clinical abnormalities.Umbilical cord blood samples were taken, and chromosome
examination was made subsequently. The blood samples werestored at +5° C until the karyotypes were available and samplesfrom boys with supernumerary X chromosomes were stored at- 2 ° C until hormone analyses were done. Blood samples chosen atrandom from boys with normal karyotype born within the same 24 hperiod as the XXY cases were treated in the same way. Serumtestosterone was determined without knowledge of the karyotype byradioimmunoassay at the hormone department, StatensSeruminstitut, Copenhagen. The results are shown in the table.Serum testosterone concentrations are often lowered in the adult
male with Klinefelter’s syndrome. To our knowledge it has notpreviously been demonstrated that this is most probably true in
8. Leichtman DA, Friedman BA. The hemorrhagic complications of open-heart surgery.CRC Crit Rev Clin Lab Sci 1977; 7: 239-54.
1113
SERUM TESTOSTERONE OF BOYS WITH KLINEFELTER’S SYNDROME
(AND OF CONTROLS) AT MOMENT OF BIRTH
t=3-24, DF=4, p<O’05 (on the assumption of logarithmic normal distribu-tion, as in normal males). -
perinatal life of Klinefelter boys too. In prepubertal childhood thetestosterone level of boys with supernumerary X chromosomes hasnot been found to differ from that of normal boys.The importance of testicular function during fetal life for the
genital development in the male has been recognised since theclassical study of Lillie in 1916.1 The effects of fetal androgenexposure on the behaviour of animals have been reviewed recently. 2In human studies fetaUy androgenised genetic females have oftenbeen found to have male behaviour traits, although they are rearedas girls.3-4 These traits are often referred to as "tomboyism".In a series of relatively unselected adolescents with Klinefelter’s
syndrome behaviour traits quite opposite to those seen in tomboyswere observed.5 In males with the syndrome insecure genderidentity is a common feature too. 5- 7
It seems that, at least in the last part of fetal life, testicular functionis reduced in males with Klinefelter’s syndrome. The possibilitythat behaviour traits of these males reflect a low androgen level infetal life is intriguing, but more data are needed before any firmconclusions can be drawn.A full report of the study will appear elsewhere.
Cytogenetic Laboratory,Århus Psychiatric Hospital,DK-8240 Risskov, Denmark
Århus Municipal HospitalDepartment of Gynaecologyand Obstetrics
Hormone Department,Statens Seruminstitut,Copenhagen
KURT SØRENSENJOHANNES NIELSEN
MOGENS WOHLERT
PAUL BENNETTSVEND G. JOHNSEN
CEREBROVASCULAR ACCIDENT AS ACOMPLICATION OF LEPTOSPIROSIS
aiR,—in a stuay or cereDrovascuiar acciaents m tne city otSalvador, Bahia, Brazil, we identified three cases of cerebralhaemorrhage in patients with icterohaemorrhagic leptospirosis(Weil’s disease). Diseases accompanied by severe bleeding-such asacute leukaemia, aplastic anaemia, thrombocytopenic purpura, andhepatic cirrhosis-can cause cerebral haemorrhage,8 mainly in theterminal stages. Leptospirosis has been associated with neurologicalproblems, such as aseptic meningitis, meningismus, and more
1. Lillie FR. The theory of the free-martin. Science 1916; 43: 1611.2. Reinisch JM. Effects of prenatal hormone exposure on physical and psychological
development in humans and animals. In: Sachar EJ, ed. Hormones, behaviour, andpsychopathology. New York: Raven Press, 1976: 69-88.
3. Money J, Ehrhardt AA. Man & woman, boy & girl. Baltimore: Johns HopkinsUniversity Press, 1972.
4. Ehrhardt AA, Baker SW. Fetal androgens, human central nervous system differentia-tion and behaviour sex differences. In: Friedman RC, Richart RM, Wiele RLV, eds.Sex differences in behaviour. New York: John Wiley & Sons, 1974: 33-51.
5. Sorensen K, Sorensen AM, Nielsen J. Social and psychological development ofadolescents with Klinefelter’s syndrome. In: Schmid W, Nielsen J, eds. Humanbehaviour and genetics. Amsterdam: Elsevier/North-Holland Biomedical Press,1981: 45-63.
6. Nielsen J, Sorensen A, Theilgaard A, Froland A, Johnsen SG. A psychiatric-psychological study of 50 severely hypogonadal male patients, including 34 withKlinefelter’s syndrome. Copenhagen: Universitetsforlaget i Aarhus/EjnarMunksgaard, 1969.
7. Theilgaard A, Nielsen J, Sorensen A, Froland A, Johnsen SG. A psychological-psychiatric study of patients with Klinefelter’s syndrome Copenhagen:Universitetsforlaget i Aarhus/Ejnar Munksgaard, 1971.
8. Chusid JG. Cerebrovascular accidents (strokes) In: Brained H, Krupp MA, ChaltonMJ, Margen S, eds. Current diagnosis and treatment. Los Altos, California: LangeMedical Publications, 1970:491.
subtle changes diagnosed by analysis of cerebrospinal fluid.9 Wehave found two reports of CNS bleeding-one of a suspectedsubdural haematoma9 and the other offour cases ofproven subduralhaemorrhage, without involvement of cerebral matter 1°Promptedby these findings we reviewed all cases of leptospirosis coming tonecropsy at the Hospital Professor Edgard Santos (a universityhospital in Salvador) in the period 1950-80.Of-the twenty-one cases gross examination of the brain, alone or
with microscopy, was done in sixteen. Isolated subarachnoidhaemorrhage was described in one case, extensive subarachnoid andcerebral haemorrhage in two, and recent cerebral infarct in one. Thefive cases where brain was not examined included two patients whohad had convulsive seizures immediately before death and onepatient with severe haemorrhagic lesions of skin and mucousmembranes who had died suddenly soon after the admission
physical examination. Sudden death in leptospirosis is usuallyattributed to acute myocarditis! 1,12Cerebral haemorrhage was thus present in 3 out of 16 brains
examined, and was the event leading to death in two of these.patients. None of these diagnoses were made before the patient died.We draw attention to these cases because cerebrovascular accidents
may be missed, being masked by problems more generallyassociated with leptospirosis, such as renal failure and gastro-intestinal haemorrhage.
Faculty of Medicine,Federal University of Bahia,Salvador, 40.000 Bahia, Brazil
INES LESSAELVIRA CORTES
ANOREXIA NERVOSA AND VISUAL EXPERIENCE
SiR,—The many variables which seem to be related to theaetiology of anorexia nervosa include distortion ofbody image in theform of overestimation of body width 1-4 and the cultural valuationof thinness.5 Since it may be presumed that both of these ordinarilydepend upon visual experience, we wondered if anorexia nervosahad been recorded in people with severely impaired vision orblindness.Child psychiatrists, paediatricians, ophthalmologists, neurol-
ogists, and officials associated with institutions serving the
visually handicapped in North America and Britain, including someof the world’s foremost authorities on anorexia nervosa, have beenasked if anorexia nervosa has ever been encountered in a person with
severely impaired sight.All replies to this inquiry have been negative, with one exception.
Hilde Bruch drew our attention to "Olga", a girl with uveitis andiritis who had been almost blind since age 10 although still able todistinguish light and dark. Anorexia nervosa developed at age 12when her mother, who had been acting as the girl’s "seeing eye",began to pursue more of her own interests.Other cases of anorexia nervosa in combination with blindness
might be worth reporting. Of particular significance, if any suchcases are known, would be information on the patient’s previousintact visual experience, and the interpersonal dynamics, as in thecase of the ambivalent and dependent relationship between DrBruch’s patient and her "seeing eye" mother.
Department of Psychiatry,Dalhousie University,Halifax, Nova Scotia, Canada
BEVERLY G. QUIGLEYBENJAMIN K. DOANE
9. Health CW Jr, Alexander AD, Galton MM. Leptospirosis in the United States:Analysis of 483 cases in man 1949-1961. N Engl J Med 1965; 273: 875, 915.
10. Arean VM. The pathologic anatomy and pathogenesis of fatal human leptospirosis(Weil’s disease). Am J Pathol 1962; 40: 393-423.
11. Gonçalves AJR, Neto FDG, Rubens J, Henrique S, Brasil MA, Saldanha LF. Doençade Weil com morte súbita por miocardite. Hospital (Rio de Janeiro) 1970; 77: 83
12. Gonçalves AJR, Santino F, Quagliota R, Suzuki LE. Formas graves do sindrome deWeil. Rev Soc Bras Med Trop 1969; 3: 95-100.
1. Slade PD, Russell GFM. Awareness of body dimensions in anorexia nervosa: Cross-sectional and longitudinal studies. Psychol Med 1973; 3: 188-99.
2. Crisp AH, Kalucy RS. Aspects of the perceptual disorder in anorexia nervosa. Br J MedPsychol 1974; 47: 349-61.
3. Garner DM, et al. Body image disturbances in anorexia nervosa and obesity. PsychosomMed 1976; 38: 327-36.
4. Garfinkle PE, et al. Body awareness in anorexia nervosa: disturbances in body imageand satiety. Psychosom Med 1978; 40: 487-98.
5. Garner DM, et al. Cultural expectations of thinness in women. Psychol Rep 1980; 47:483-91.
6. Bruch H. Eating disorders. New York. Basic Books, 1973.
