ENTEROVIRUS INFECTION IN PERIPARTUM CARDIOMYOPATHY

968 IMPROVEMENT IN HYPERTROPHIC HEPATIC OSTEOARTHROPATHY AFTER LIVER

TRANSPLANTATION

SiR,—Hypertrophic osteoarthropathy, a rare symptom in patients with liver disease, is seen more often in those with chronic cholestasis. It manifests as painful extremities with arthritis1 and digital clubbing. The syndrome has been reported in chronic rejection of the liver following transplantation.2 A growth-factormediated effect is probably involved leading to elevation of the periosteum with oedema and hyperaemia, new bone deposition, and oedema with increased vascularity of the surrounding soft tissues and ligaments. Dickinson and Martin3postulated that the clubbing may be mediated by a paracrine effect of platelet-derived growth factor. We report two patients with chronic liver disease who had disabling limb pain from hypertrophic osteoarthropathy. Symptoms resolved within a week of successful liver transplantation. A 28-year-old woman with biliary obstruction and chronic graft rejection (vanishing bileduct syndrome) after transplantation (the second attempt) 9 months earlier for fulminant viral hepatitis had intense pruritus and a serum bilirubin of 466 )mol/l. Crippling joint pain had immobilised her in the month before her third transplant. The long bones were exquisitely tender to gentle pressure and small bilateral knee effusions were present. Finger clubbing had developed. X-rays confirmed hypertrophic periostitis. The second patient was a 24-year-old woman with cryptogenic cirrhosis, referred for transplantation because of resistant ascites and lethargy. She had pain in the extremities, especially when walking or writing. No arthritis was present but tenderness over the distal radius, ulna, and tibia were elicited. Finger clubbing was present. Radiographs of the wrist and ankle joints showed the changes of hypertrophic periostitis. Post-transplant immunosuppression was with prednisone 20 mg daily, cyclosporin, and azathioprine. The first patient had been on maintenance cyclosporin before surgery. Both patients had rapid resolution of bony tenderness after transplantation, striking improvement occurring by the third post-operative day with complete loss of pressure tenderness after one week. Vagotomy had not been done in either case at the transplant operation. Radiographs after 3 months in both patients, by then well and discharged from hospital, showed that the periosteal new bone had still not resorbed, although the digital clubbing had regressed. Although we cannot rule out immunosuppression as an explanation for the rapid improvement, this seems unlikely because the first patient had symptoms whilst taking cyclosporin, and prednisone is rarely of benefit in patients with osteoarthropathy from other causes. The stimulus to periosteal reaction and new bone formation may have been a factor which accumulated due to impaired hepatic clearance or was produced in excess by the liver as part of its response to disease. Two growth factors, interleukin-1 and transforming growth factor B, have been shown to modulate bone growth in vitro.4,5 Future cases may provide a good clinical model to evaluate such a liver-derived growth factor, both in vivo and in cultured bone cell lines.

Liver Unit, Queen Elizabeth Hospital, Birmingham B15 2TH

C. VICKERS A. HERBERT J. NEUBERGER E. ELIAS

1. Epstein O, Ajdukiewicz AB, Dick R, Sherlock S. Hypertrophic, hepatic osteoarthopathy: clinical, roentgenologic, biochemical, hormonal and cardiorespiratory studies, and review of the literature. Am J Med 1979; 67: 88-97. 2. Wolfe, SM, Aelion JA, Gupta RC. Hepatic osteoarthropathy associated with a rejected liver transplant. J Rheumatol 1987; 14: 147-51. 3. Dickinson CJ, Martin JF. Megakaryocytes and platelet clumps as the cause of finger clubbing. Lancet 1987; ii: 1434-35. 4. Beresford JN, Gallagher JA, Gowen M, et al. The effects of monocyte-conditioned medium and interleukin 1 on the synthesis of collagenous and non-collagenous proteins by mouse bone and human bone cells in vitro Biochim Biophys Acta 1984; 801: 58-65

AH, Voelkel EF, Lazzaro M, et al. Alpha and beta transforming growth factors stimulate prostaglandin production and bone resorption in cultured mouse calvaria. Proc Natl Acad Sci USA 1985; 82: 4535-38.

5. Tashjian

IS CAMPYLOBACTER PYLORI A ZOONOSIS?

SIR,-Dr Vaira and colleagues (Sept 24, p 725) report that antibodies to both Campylobacter pylori and C }ejunz in abattoir workers were higher than in clerical workers, but did endoscopy in only 28 of 78 non-clerical workers. They do not say whether their serological test was validated originally by endoscopy, because many people with low titres have C pylori in the stomach.’ Alternatively, since Cjejuni is a zoonosis, one reason for some of the low titres of C pylori antibodies could have been partial serological crossreactions between C pylori and C jejuni.1 To substantiate that C pylori is a zoonosis, the organism must be cultured from animals slaughtered in abattoirs. Jones and Curry2 reported that Professor Percival isolated a C pylori-like organism (CPLO) from one pig. Others have failed despite repeated attempts. In Perth we have isolated CPLOs from macaque monkeys, baboons, and ferrets. DNA hybridisation showed that there was less than 100% hybridisation between human C pylori and these animal CPLOs, indicating that they are not identical. In Seattle, USA, two types of CPLO have been isolated from Macaca nemestrina with DNA compositions different from that of C pylori, which is 36-37 mol % G + C. The "nemestrina type A" CPLO has 44 mol % G + C, and "nemestrina type B" CPLO has 24 mol % G + C. We have also found differences in their cellular fatty acids, outer membrane proteins, and menaquinones. The ferret CPLO lacks the fatty acid 3-OH-18:0 typical of C pylori and primate CPLOs. However, these animal CPLOs have some serological crossreactivity with C pylori, and they are all urease positive. Besides the one pig isolate, there is no evidence yet that human-type C pylori exists in abattoir animals, so we should not conclude it is a zoonosis. Stomach bacteria will prove to be a complicated story. Apart from CPLOs, we have seen in animal gastric specimens three different types of spiral and "corkscrew" bacteria distinguishable by special staining of their ultrastructure. Departments of Microbiology and Electronmicroscopy, Royal Perth Hospital,

STEWART GOODWIN

Western Australia 6001

JOHN ARMSTRONG

Regional Primate Research Centre, University of Washington, Seattle, USA

MELINDA BRONSDON

University of Queensland, Brisbane, Australia

LINDSAY SLY

1 Goodwin CS, Blincow E, Peterson G, et al. Enzyme-linked immunosorbent assay for Campylobacter pyloridis: correlation with presence of C pyloridis in the gastric mucosa. J Infect Dis 1987; 155: 488-94. 2. Jones EM, Curry A. Ultrastructural study of gastnc Campylobacter-like organisms (GCLO) from man, baboon, pig and ferret. In: Kaijser B, Falsen E, eds. Campylobacter IV. Proceedings of the fourth international workshop on Campylobacter infections, Goteborg, Sweden. Sweden. University of Gothenburg, 1988: 109.

ENTEROVIRUS INFECTION IN PERIPARTUM CARDIOMYOPATHY

SIR,-In peripartum cardiomyopathy (PPCM) congestive heart failure develops during the third trimester of pregnancy or in the first 6 months postpartum. The aetiology is unknown but myocarditis has been histologically proven in a few cases. One hypothesis is a viral infection of cardiac muscle. We have studied epidemiologically the relation between PPCM and enterovirus infection. The diagnosis of PPCM was made on clinical, radiographic, and echographic signs: dilated heart with low ventricular contractility, normal ventricular thickness, and heart failure first developing during the third trimester of pregnancy or in the first 6 months postpartum.3 38 black African women with PPCM (mean age 30-33 [SD 7-7] years) living in western Niger were included in the study. Controls were 37 breastfeeding African women without cardiac disease who presented at a dispensary on behalf of their children. Age, parity, social profile, and geographical and ethnic origin were similar in the two groups. For every woman a sample was taken by venepuncture into a sterile tube with anticoagulant and immediately separated by centrifugation; plasma was frozen at - 20’C.

969

Enterovirus infection was tested by complement fixation assay with

picomavirus antigen (Virion Institute),

an

antigenic preparation

from coxsackievirus (Bl to B6 and A9 types) and echovirus (4, 6, 9-14,24, and 30 types) groups. After defibrination and removal of complement, plasma samples were read, with 50% haemolysis judged visually as positive. The positivity threshold was 1/10 serum dilution. In the PPCM group, 27/38 (71-05%) samples were positive while in the controls 27/37 (72-97%) samples were positive. O’Connell and Sanderson and their colleagues1.2 showed, by endomyocardial biopsy, subacute or chronic myocarditis lesions in PPCM. Coxsackievirus and echovirus are common agents of presumed viral myocarditis.4 Our results indicate the high frequency of coxsackievirus and echovirus infection among women in Niger, but do not show a higher prevalence among cases of PPCM. A study of the course of antibody titres over time is

required. Department of Internal Medicine, Faculté des Sciences de la Santé, Niamey, Niger; Medicine Internal Service, Hôpital National, Niamey; and Immunology Laboratory, Faculté de Médecine Pitié-Salpêtrière, 75013 Pans, France *Present address: 99

rue

Mathieu Donnart, 29200

A. Y. A. R.

CÉNAC* GAULTIER DEVILLECHABROLLE MOULIAS

Brest, France.

1 O’Connell JB, Costanzo-Nordin

MR, Subramanian R, et al. Peripartum cardiomyopathy clinical, hemodynamic, histologic and prognostic characteristics. J Am Coll Cardiol 1986; 8: 52-56.

2 Sanderson

heart disease:

an endomyocardial JE, Olsen EGJ, Gatei D. Peripartum biopsy study. Br Heart J 1986; 56: 285-91. 3 Cénac A, Gaultier Y, Soumana I, Touré IA, Develoux M La myocardiopathie post-partum: evaluations clinique et échographique de la résponse au traitement: trente cas observes en région soudanosahélienne. Presse Méd 1988, 17: 940-44. 4. Wenger NK, Abelmann WH, Roberts WC. Myocardite. In: Hurst JW, ed. Le coeur. Pans: Masson. 1985; 1211-31.

INTRAVENOUS GAMMAGLOBULIN, ANTIPHOSPHOLIPID ANTIBODIES, AND THROMBOCYTOPENIA

complications occurred. After 2 activity (APTT 30-2 s, KCT 102-5 s) and thrombocytopenia (75 x 10/1) reappeared. Following this observation, we used the same schedule to treat two other patients who had antiphospholipid antibodies and thrombocytopenia; a 28-year-old woman with systemic lupus erythematosus and history of recurrent abortion and thrombophlebitis, and a 45-year-old man with epilepsy and previous thrombophlebitis. However, neither showed any significant modification of LAC activity, serum level of anticardiolipin antibodies, or platelet count. The mechanism of action of high-dose intravenous gammaglobulin in the treatment of immune disorders is poorly understood. Many effects of intravenous gammaglobulin on the function of the immune system have been identified, including interference with the binding of immune particles to macrophage Fc receptors, decreased Fc-receptor-mediated phagocytosis, enhancement of suppressor T-cell function, depression of natural killer-cell activity, and lowering of autoantibody titres by an idiotype-anti-idiotype reaction.

haemorrhagic

or

thrombotic

months LAC

To test whether the transient inhibition of LAC seen in our first was due to an idiotype-anti-idiotype effect, the following in-vitro experiment was done.s Patients and control plasmas were incubated (2 h at 37°C and overnight at 4°C) with saline or increasing concentrations of gammaglobulin (from O’l1 to 40 mg/ml final concentration) and KCT and RVVT were measured. No shortening of coagulation times (ie, no inhibition of LAC activity after incubation with gammaglobulin) was seen in the patient’s

patients

plasma. observations indicate that: (1) intravenous can reduce LAC activity and increase platelet number in some but not all patients with antiphospholipid antibodies; (2) this effect can be clinically worthwhile before an operation, as well as in the treatment of LAC-associated recurrent abortion; and (3) the inhibitory effect on LAC activity was observed in vivo but not in vitro, suggesting a cell-mediated immune mechanism rather than an idiotype-anti-idiotype interaction.6 Thus

our

gammaglobulin

Division of Haematology,

SIR,-Dr Carreras and colleagues (Aug 13, p 393) report successful gammaglobulin treatment of a woman with lupus

anticoagulant and recurrent fetal loss. Another condition in which this therapy can be of benefit is before an operation in patients with antiphospholipid antibodies (ie, lupus anticoagulant [LAC] and anticardiolipin), which are associated with an increased risk of thrombotic complications.1 A 42-year-old man was referred to us because of thrombocytopenia and prolonged activated partial thromboplastin time (APTT) before an operation for a discal hernia. Physical examination, routine blood biochemistry, and urine analysis were normal. Blood counts showed: haemoglobin 13-7 g/dl, red cell count 4 81 x 10/1, reticulocytes 0-9%, white cell count 5-08 x 109(1 with normal differential count, and thrombocytopenia (platelets 45 x 109/1). Bone marrow, including megakaryocytes, was normal. Coagulation studies showed that prolongation of APTT was due to LAC since: (1) APTT was not corrected in a 1:1 mixture with normal plasma (patient 36-5 s, normal 28-2s, mixture 34-9 s); (2) kaolin clotting time (KCT)Z was prolonged and not corrected by mixture (patient 117 s, normal 64 s, mixture 98 s); and (3) dilute Russell viper venom test (RVVT)3 was positive (patient 38 s, normal 28-7 s). IgG anticardiolipin antibodies, assayed by ELISA,4 were increased (30 U, normal below 10). A direct Coombs test was positive. Serology for sytemic lupus erythematosus was negative. The patient was considered at increased postoperative risk for bleeding because of thrombocytopenia, and for thrombosis because of antiphospholipid antibodies. Therefore we decided to administer intravenous gammaglobulin (Sandoz) 0-4 g/kg daily for 5 After this treatment, LAC activity disappeared (APTT 27-6 s, KCT 72 s) and platelets increased to 150 x 109/1. anticardiolipin antibodies remained unchanged. The patient was operated on under routine calcium heparin prophylaxis and no

days.

However,

Ospedali Riuniti, 24100 Bergamo, Italy 1.

TIZIANO BARBUI GUIDO FINAZZI ANNA FALANGA SERGIO CORTELAZZO

Vermylen J, Blockmans D, Spitz B, Deckmyn H. Thrombosis and immune disorders.

Clin Haematol 1986; 15: 393-412. 2. Exner T, Rickard A, Kronenberg H. A sensitive test demonstrating lupus anticoagulant and its behavioural pattern. Br J Haematol 1978; 40: 143-51. 3. Thiagarajan P, Pengo V, Shapiro SS. The use of the dilute Russell viper venom time for the diagnosis of lupus anticoagulant Blood 1986; 68: 869-74. 4. Loizou S, Mc Crea JD, Rudge AC, Reynolds R, Bolyle CC, Harris EN. Measurement of anti-cardiolipin antibodies by an enzyme-linked immunosorbent assay (ELISA): standardization and quantitation of results Clin Exp Immunol 1985; 62: 738-45 5. Sultan Y, Kazathkine M, Maisonneuve P, Nydegger U. Anti-idiotypic suppression of autoantibodies to factor VIII (antihaemophilic factor) by high dose intravenous gammaglobulin. Lancet 1984 ii: 765-68. 6 Gris JC, Schved JF, Tousch D, Hereil S, Feugeras O Anti-idiotypic antibodies against anti-phospholipid autoantibodies which suppress lupus-like anticoagulant activity. Nouv Rev Fr Hematol 1988, 30: 143-47.

CLINICAL SPECTRUM OF NEUROLEPTIC MALIGNANT SYNDROME

SIR,-Severe parkinsonism, hyperthermia, and autonomic dysfunction in a patient on a neuroleptic drug suggests neuroleptic malignant syndrome (NMS).1 Failure to recognise and promptly treat the condition by neuroleptic withdrawal and dopaminomimetic agents, with or without the muscle relaxant dantrolene, can lead to myonecrosis and acute myoglobinuric renal failure. 20-30% of cases are fatal. The development of NMS in patients receiving dopamine antagonists1 or dopamine depleting agents2 and in parkinsonian patients on levodopa "drug holidays"3‘ suggests that central dopamine deficiency is responsible. The extrapyramidal effects and hyperpyrexia point to involvement of the terminal fields of dopamine neurons in the striatum and hypothalamus. We report a patient with early NMS, before the