ANTIBODIES AGAINST ACETYLCHOLINE RECEPTOR IN TARDIVE DYSKINESIA

320 theoretical problems which are obstacles to routine use in clinical laboratories. For instance, since a Lancet editorial three years agoZ hardly any improvements have been published with respect to the solid phase used, and the problem of inconstant3 selective adsorption of antigens and antibodies remains to be solved. Furthermore, there is a clear need for standardisation of materials and methods, as demonstrated by the different methods for determining end-points and cut-off values or for expressing antibody levels.4-9 A. M. VAN LOON Laboratory of Medical Microbiology, J. TH. M. VAN DER LOGT University of Nijmegen, 6500 HB Nijmegen, Netherlands J. VAN DER VEEN

EFFECT OF GLUCOCORTICOID ON FETAL LECITHIN AND SPHINGOMYELIN

CONCENTRATIONS

SIR,-A single intramuscular injection of prednisolone sodium succinate (’Di-Adreson F’) given to the mother before premature delivery increases surfactant production and lowers the incidence of respiratory-distress syndrome in the newborn." Corticosteroids complex with a glucocorticoid receptor on the fetal lungs which is responsible for the synthesis of pulmonary sufactant.11Glucocorticoid receptors have been demonstrated in fetal lungs as early as 9-12 weeks of gestation. 12 According to Iacobelli et al.11 the concentration of the receptors does not change between the 15th and 28th weeks. We wondered if surfactant synthesis could be enhanced by corticosteroids given at 16-25 weeks’ gestation-i.e., at a time when receptors are present in the fetal lungs. Prednisolone sodium succinate was administered to mothers with threatened abortion when the process has been progressing despite conservative therapy. A single dose of 2 mg/kg was given intramuscularly. The lungs of the fetuses who died in consequence of abortion were analysed for lecithin (L) and sphingomyelin (S) content and the ratio L/S was determined for the tracheal and amniotic fluid. The data refer to cases where at least 48 h had elapsed between steroid administration and delivery. Values for non-treated aborted fetuses of the same gestational age served as control. Prednisolone sodium succinate treatment did not significantly alter either the lecithin concentration in the lungs or the L/S ratio in the amniotic fluid (table). These findings can be explained in one of two ways:-either, a sufficient number of 2. Editorial ELISA: a replacement for radioimmunoassay? Lancet 1976; ii: 406. 3. Chessum BS, Denmark JR. Inconstant ELISA. Lancet 1978; i: 161. 4. Voller A, Bidwell DE. A simple method for detecting antibodies to rubella.

Br J Exp pathol 1975; 56: 338-39. 5. Booth JC, Hannington G, Aziz TAG, Stern H. Comparison of enzymelinked immunosorbent assay (ELISA) technique and complement-fixation for estimation of cytomegalovirus IgG antibody. J Clin Pathol 1979; 32: 122-27. 6. Morgan-Capner D, Pullen HJM, Pattison JR, Bidwell DE, Bartlett A, Voller A. A comparison of three tests for rubella antibody screening. J Clin Pathol 1979; 32: 542-45. 7. Leinikki P, Pässilä S. Solid phase antibody assay by means of enzyme conjugated to anti-immunoglobulin. J Clin Pathol 1976; 29: 1116-20. 8. Leinikki PO, Shekorchi I, Dorsett P. Sever JL. Enzyme-linked immunosorbent assay determination of specific rubella antibody levels in micrograms of immunoglobulin G per milliliter of serum in clinical samples. J Clin Microbiol 1978; 8: 419-23. 9. Felgner P. Stepless antibody determination with the stick-ELISA technique: Results expressed as multiple of normal activity (MONA). Zbl Bakt Hyg

I Abt Orig A 1978; 242: 100-05. 10. Szabó I, Csaba I, Novák P, Drozgyik I. Single-dose glucocorticoid for prevention of respiratory-distress syndrome. Lancet 1977; ii: 243. 11. Ballard LP, Baxter JD, Higgins SJ, Rousseau GG. Mechanism of glucocorticoid action: generality of the cytoplasmic receptor system. Clin Res 1973; 21: 289. 12. Giannopoulos G. Variations in the levels of cytoplasmic glucocorticoid receptors in lungs of various species at different developmental stages. Endoc-

rinology 1974; 94: 450. 13. Iacobelli S, Ranelletti SF, Sica human fetal lung. J Endocrinol

G, Barile G. Glucocorticoid receptors in

Invest 1978; 1: 209.

LECITHIN AND SPHINGOMYELIN CONCENTRATIONS IN FETAL LUNG TISSUE AND TRACHEAL AND AMNIOTIC FLUID Lis RATIOS IN TREATED FETUSES AND IN UNTREATED CONTROLS:

MEAN±SD

receptors must be present in the fetal lungs for effective corticosteroid treatment or the degree of sensitivity to corticosteroids is of prime importance. Our results suggest that glucocorticoids will affect the functional matority of fetal lungs for only a short period ofluns development. I. SZABÓ I. CSABA

J. BÓDIS

Department of Obstetrics

P. NOVÁK

and Gynæcology, University Medical School, 7624 Pécs, Hungary

J. DROZGYIK J. SCHWARTZ

ANTIBODIES AGAINST ACETYLCHOLINE RECEPTOR IN TARDIVE DYSKINESIA

SIR,-A variety of membrane-active drugs, including phenothiazines, can cause a lupus erythematosus syndrome.’ Furthermore, long-term D-penicillamine can produce myasthenia gravis complete with serum autoantibodies against the acetylcholine receptor (AChR).2-4 These findings support the contention that certain drugs can induce autoimmune disease by altering the function of the immune system or by altering the structure of membranes, so rendering them antigenic.5 Membrane-active drugs could directly bind to membrane components or change the lipid environment, thus indirectly modifying their conformation and antigenicity. These changes could result in the production of autoantibodies. We report here a patient with tardive dyskinesia (TD) after long-term fluphenazine who had antibodies against the AChR but no symptoms of myasthenia gravis. This 26-year-old woman had an unremitting psychiatric illness, beginning about 7 years earlier. The diagnosis is hebephrenic schizophrenia. She had been treated with phenothiazines from the first. Fluphenazine decanoate 25 mg intramuscularly every 2 weeks with benzotropine mesylate 2 mg and fluphenazine 10 mg orally every day had been her regimen for the previous 3 years. The patient dated the onset of her movement disorder to at least 2 years previously. Posture was disturbed by extreme lumber lordosis. Gait was impaired and it exacerbated her other movements, especially truncal athetosis and neck movements. The neck was nearly tonically hyperextended and turned to the left. Arms displayed frequent athetotic and occasional choreic movements. Fingers and hands showed sporadic choreic and athetotic movement. The upper facial musculature was beset with grimaces. The mouth and tongue were affected and speech was thickened and slurred. Muscle strength was normal. There was no family history of

unusual movements. There was

no

evidence of dementia.

1. Tan EM. Drug-induced autoimmune disease. Fed Proc 1974; 33: 1894-97 2. Masters CL, Dawkins RL, Zildo PJ, Simpson JA, Leedman RJ, Lindstrom J. Penicillamine-associated myasthenia gravis, anti-acetylcholine receptor and antistriational antibodies. Am J Med 1977; 63: 689-93.

3. Russell AS, Lindstrom JM. Penicillamine-induced myasthenia gravis associated with antibodies to acetylcholine receptor. Neurology (Minneap) 1978; 28: 847-49. 4. Vincent A, Newson-Davis J, Martin V. Anti-acetylcholine receptor antibodies in D-penicillamine-associated myasthenia gravis. Lancet 1978; i: 1254. 5. Bluestein HG, Zvaifler NJ, Weisman MH, Shapiro RF. Lymphocyte alteration by procainamide: Relation to drug-induced lupus erythematosus. Lancet 1979; i: 816-19.

321 Her TD greatly disabled her. The fluphenazine and benztropine discontinued. Reserpine was started and gradually increased to 3.0 mg daily and maintained. Baclofen was added in doses up to 60 mg per day without benefit. Lithium carbonate was added with achievement of red-blood-cell level of 0.68 mmol/1 and serum level of 1.01 mmol/1 (ratio 0.7) without significant improvement. The lithium was discontinued. Lecithin was added and at 45 mg per day significantly decreased the severity of the dyskinesia; however, prominent movements remained. The baclofen was tapered to 30 mg/day, but dosages below this allowed an increase in movement severity to return.

immune disease. Granulopoietic and erythropoietic progenitor cells were much diminished when bone-marrow mononuclear cells were cultured in agar. The patient required intensive supportive care with red cell and platelet substitution. He did not improve on androgens nor on a 2 week course of high-dose corticosteroids. In November, 1979, the patient died because of

Serum IgG against AChR, measured by immunoprecipitation assay, was 1 -1 nmoVI, which is in the range of titres often found in patients with mild generalised myasthenia

dose,

were

gravis. The presence of this antibody could be some correlate of mental illness, it could be caused by the drug regimen, or it may not be related to either of these variables. Over the past 5 years we have done assays on more than seventy patients with myasthenia gravis and on more than a hundred controls, including healthy controls and patients with other neurological diseases. This is the only non-myasthenic patient we have found with antibody against AChR. If the antibody is drug induced, then many possibilities can be considered. Antibody against AChR may not cause TD but its existence may indicate that a spectrum of autoantibodies have been created. An autoimmune attack against other CNS antigens could be responsible for TD. The antibody against AChR might have further significance in that it could be responsible for the histochemical abnormalities of skeletal muscle which have been reported in some psychotic patients.7 An increased branching and sprouting of terminal motor axons has been observed in both myasthenics8 and psychotic patients.9 We would like to suggest further investigation of the hypothesis that druginduced autoimmunity could cause or contribute to the development of TD associated with the use of neuroleptic drugs. RONALD J. BRADLEY Department of Psychiatry, DONARD S. DWYER and Neurosciences Program, GEORGE E. KEMP University of Alabama in Birmingham, EUGENE L. CREWS Birmingham, Alabama 35294, U.S.A.

APLASTIC ANÆMIA AFTER NAPROXEN?

SIR,-Serious blood dyscrasias have been reported after ingestion of various non-steroid-antirheumatics, such as pyrazole or phenylbutazone derivatives, gold, penicillamine, and indomethacin. Naproxen has been used for several years, predominantly in rheumatoid arthritis, without serious sideon the hxmopoietic system. We have seen a case of aplastic anaemia in a patient taking this drug. A 47-year-old man was given naproxen for recurrent back pain in November, 1975, in January and May, 1976, and then from October, 1978, to February, 1979. The total dose was about 20 g. A multivitamin preparation, triamcinolone, and phenylbutazone (600 mg) were taken in May, 1976. Intake of drugs other than naproxen was repeatedly denied by the patient, his family, and his family physician for the time from October, 1978, to February, 1979. In January, 1979, the patient became ill with a distinct bleeding tendency, pallor, and fatigue. 2 months later, pancytopenia was noticed (erythrocytes 2-5 x 106/µl, reticulocytes 7000/[LI, neutrophils 900/1, platelets 17 000/[1.1). Bone-marrow biopsy showed severe aplasia with only a few erythroid and myeloid cells and no megakaryocytes. There was no evidence of paroxysmal nocturnal hannoglobinuria or auto-

effects severe

6. Dwyer DS, Bradley RJ, Oh SJ, Kemp GE. A modified assay for antibody against the nicotinic acetylcholine receptor in myasthenia gravis. Clin Exp Immunol 1979; 37: 448-51. 7. Meltzer HY, Engel WK. Histochemical abnormalities of skeletal muscle in acutely psychotic patients. II. Arch Gen Psychiat 1970; 23: 492-97. 8. Bickerstaff ER, Woolf AL. The intramuscular nerve endings in myasthenia gravis. Brain 1960; 83: 10-22. 9. Crayton JW, Meltzer HY. Degeneration and regeneration of motor neurons in psychiatric patients. Biol Psychiat 1979; 14: 803-19.

gastrointestinal hxmorrhage. Phenylbutazone has often been indicted as a cause of aplastic anaemia. However, this drug was given, in only a small a

more than two years before the first symptoms of the blood dyscrasia. Hepatitis B surface antigen was not present. In absence of other potentially noxious factors, the possibility that naproxen caused the aplastic ansemia has to be considered, though the coincidence of naproxen therapy and the onset of "idiopathic" aplastic anaemia cannot be excluded.

Department of Internal Medicine, University of Ulm, D7900 Ulm, West Germany

RENATE ARNOLD H. HEIMPEL

NEUROENDOCRINE DISTURBANCES AND THE DIAGNOSIS AND ÆTIOLOGY OF ENDOGENOUS DEPRESSION

SiR,-Several investigators have discussed the possibility that a subgroup of patients with endogenous depression has disinhibited activity of the hypothalamic-pituitary-adrenal (HPA) axis. 40-50% of such patients fail to show normal suppression of plasma cortisol levels during a 24 h overnight dexamethasone suppression test (DST). In four studies,1-4 on a total of 195 depressed patients and 193 comparison patients, an abnormal DST result was found in 43% of the depressives while the specificity was 99% (i.e., only 1% of the comparison patients had an abnormal DST result). Thus the predictive value (or diagnostic confidence) attached to an abnormal DST result is very high (98%),5 and the DST is now being used increasingly as a laboratory test for endogenous depression. The most suitable diagnostic application of the test will be in populations where endogenous depression is suspected and where the prevalence is high. The prevalence rate was 50% in the four studies cited above. We would stress that the test will not eliminate the need for careful clinical judgment in the evaluation of depressed patients. It can, however, be most useful with some difficult clinical problems8 and in evaluating the efficacy of treatment.7 We have found it especially helpful in patients whose endogenous depression was masked by "neurotic" features or by a character disorder, which has led some consultants to advise against somatic antidepressant treatments.

One question is whether psychotropic drugs can interfere with the DST. We have been unable to establish any systematic interfering effect of the common drugs such as lithium, tricyclic antidepressants, neuroleptics, or low-dosage benzodiaze1. Schlesser MA, Winokur G, Sherman BM. Genetic subtypes of unipolar primary depressive illness distinguished by hypothalamic-pituitary-adrenal axis activity. Lancet 1979; i; 739-41. 2. Carroll BJ, Curtis GC, Mendels J. Neuroendocrine regulation in depression. II. Discrimination of depressed from non-depressed patients. Arch Gen Psychiat 1976; 33: 1051-57. 3. Brown WA, Johnston R, Mayfield D. The 24-hour dexamethasone suppression test in a clinical setting: relationship to diagnosis, symptoms and re-

sponse to treatment. Am J Psychiat 1979; 136: 543-47. 4. Carroll BJ, Feinberg M, Steiner M, Haskett R, James NMcI, Tarika J. Diagnostic application of the dexamethasone suppression test in depressed outpatients. In: Mendlewicz J, ed. Advances in biological psychiatry. Amsterdam: Elsevier (in press). 5. Carroll BJ. Implications of biological research for the diagnosis of depression. In: Mendlewicz J, ed. New advances in the diagnosis and treatment of depressive illness. Amsterdam: Elsevier (in press). 6. Greden JF, Carroll BJ. The dexamethasone suppression test as a diagnostic aid in catatonia. Am J Psychiat 1979; 136: 1199-200. 7. Greden JF, Albala AA, Haskett RF, James NMcI, Goodman LI, Carroll BJ. Normalization of dexamethasone suppression tests: a probable index of recovery among endogenous depressives. Biol Psychiat (in press). 8. Langer G, Schonbeck G, Koinig G, Lesch O, Schussler M. Hyperactivity of hypothalamic-pituitary-adrenal axis in endogenous depression. Lancet 1979; ii: 524.