319

and this lymphoma may cause the symptoms of malabsorption. The common presentation of EATCL-with worsening malabsorption, obstruction, perforation, or bleeding-is usually associated with evolution to a high-grade lymphoma. Unless more specialised techniques are used, cases such as the one we presented are likely to be labelled as severe CD or ulcerative jejunitis, since they show no morphological features of malignant disease. Dr Jansen and colleagues from the Netherlands report an increased prevalence of CD diagnosed by at least one biopsy. Biopsy proof requires histological evidence of a response to gluten withdrawal-evidence that cannot be obtained with a single biopsy. They note that this prevalence of CD has not been accompanied by an increase in low-grade lymphomas. Unfortunately, we do not have access to the papers cited in support of this statement but since EATCL almost invariably presents as a high-grade lymphoma, this observation does not appear to be relevant. The argument that the long time-span between the diagnosis of adult onset CD and the development of lymphoma and the reported protective effect of gluten withdrawal is not compatible with a neoplastic process is, in our view, erroneous. We drew an analogy with mycosis fungoides. The case reported by Alfsen et al (our ref 6), in which a clonal T-cell population was demonstrated in the mucosa adjacent to an EATCL that showed only the features of enteropathy, supports our hypothesis that the enteropathy itself may be neoplastic. Also the title of our report did carry a question mark: it is possible that only a proportion of cases of adult-onset CD are neoplastic and if so it would be important to recognise them. University Department of Pathology and Department of Medical Oncology, Southampton General Hospital, Southampton SO9 4XY, UK

Revaccination

D. H. WRIGHT

D. B. JONES G. M. MEAD

against hepatitis

B virus

SiR,-Dr Coursaget and colleagues’ report (May 18, p 1180) raises several points. In our study of about 900 people vaccinated against hepatitis B following the schedule 0,1, 2, 12 months we examined the decrease in anti-HBs titre after the booster dose. We also looked at the distribution of the population by anti-HBs titre and the possibility of predicting the titre in a specific time.1 We agree that the decrease of anti-HBs titre with time is a logarithmic function. However, we showed that women responded much better than men (median 10 000 mIU/ml vs 2500 mIU/1 after the 4th dose), but the titre decreased twice as quickly so that after 5 years the median titres were the same in men and women-about 500 mIU/ml. We found, surprisingly, that the distributions of anti-HBs titre after booster dose and 5 years later are also represented by a logarithmic function, so that "bad responders" cannot truly be distinguished from "good responders". The

implications of this finding are important with respect to values defining bad responders (< 10 mIU/ml). We think prediction of long-term anti-HBs titre in individuals is probably not possible, because various factors modify immunity (sex, smoking habits, hepatitis [icterus] antecedent, hypothyroidism, obesity, age, pregnancy, mononucleosis) and because the titre decreases, following a sinusoidal curve in individuals (figure). We suggest "automatic" revaccination, as proposed previously,2 especially since bad responders in our population of healthy workers did not have bad protection against the illness. Service of Occupational Medicine, Free University of Brussels,

Hôpital Erasme, B-1070 Brussels, Belgium

CH. DE BROUWER A. LECOMTE

1. De Brouwer C, Lecomte A, Liesnard. Vaccination contre l’hépatite B: 5 ans après la 4e dose: étude de distribution et de corrélation. Cahier de Médecine du Travail (in

press). 2. Anon. Immunisation

against hepatitis B. Lancet 1988; i. 875-76.

*** This letter has been shown to Dr Gilks and Dr Coursaget whose reply to it and earlier correspondence follows.-ED. L. SIR,-Dr De Brouwer and Dr Lecomte find that women have a stronger response to vaccination than do men, but lose antibody more quickly subsequently. They also suggest that many other factors affect immune response, and that consequently long-term predictions of anti-HBs titre will not be possible. In Senegalese infants we find no sex differentials. The presence of multiple factors of immune response does not preclude useful prediction: statistical methods have been developed for this; moreover, titre-at-booster is in effect a surrogate control for unobserved factors. We agree with Dr Prince (July 6, p 61) that the need for booster doses of hepatitis B virus vaccine in developing countries requires further surveillance, but if booster doses are eventually found to be required, revaccination at fixed ages would be applied. Our model could be used to best determine those ages. However, the immediate concern in hyperendemic countries is for primary immunisation of infants. With respect to the rate of decay of anti-HBs titre, the results that Professor Scheiermann and Dr Gesemann report (July 6, p 61) broadly support our own. Indeed, the inverse relation between titre and time-since-vaccination seems to be generally applicable. However, Scheiermann and Gesemann find a substantially greater response to boosting, controlling for titre at booster. We agree that response to boosting may depend on study-specific factors: more studies comparing titres at booster with those one month postbooster are required. We like Scheiermann and Gesemann’s simple formula for predicting titres from one-month post-booster titres, but the advantages of avoiding post-booster testing should not be dismissed too readily. Moreover, it is important to express the uncertainty in predictions in a usable way, as we have done in our table in. Medical Research Council Biostatistics Unit, UK

Cambridge CB2 2BW,

W. R. GILKS

Institut de

Virologie de Tours, Facultes de Medecine et de Pharmacie, Tours, France

P. COURSAGET

Oocyte donation and older women

Anti-HBs titres by time after booster dose in 25 individuals. Initial titre after booster=500-1000 mIU/ml.

SIR,-Dr Navot and colleagues’ article (June 8, p 1375) on oocyte donation in older women confirms our report1 that the reproductive potential of such women can be much improved by using donated oocytes from younger women. However, we question whether all infertile women in their 40s need oocyte donation as is implied. The results of in-vitro fertilisation (IVF) in women over 40 are disappointing.2 However, gamete intrafallopian transfer (GIFT) is a preferred treatment, especially in this age group since the "take home baby rate" is higher than the 5% per treatment cycle quoted for assisted conception in the natural cycle for women under 40. We have analysed 349 GIFT cycles over a period of 2zyears in women

320

aged 40-45 in whom the outcome of treatment to delivery is known. No

than four oocytes were transferred and the rates of conception, clinical pregnancy, and delivery per cycle were, respectively, 17-5% (n=61), 13-5% (n=47),and 7-5 % (n = 26). If those responding poorly to ovulation induction were excluded from treatment (ie, one to three oocytes recovered), the respective pregnancy rates would be 21 % (n = 46), 17% (n = 22), and 10% (n = 22). The successful patients would have been denied their own genetic offspring if ovum donation had been implemented for all women aged 40 and over. Navot and colleagues used oocytes from infertile women for their donation programme. However, surveys indicate that infertile patients prefer to have their left-over oocytes fertilised and cryopreserved for their own potential future use rather than used for research or donation.3 There should be a flexible approach to assisted conception treatment, especially in older women. In patients responding well GIFT is preferred to IVF in those with patent tubes, but IVF may still have some place in those with occluded tubes, especially if the resultant embryos are transferred into a hormonally controlled subsequent cycle after cryopreservation, as suggested by Navot and colleagues. Poor responders and those failing GIFT treatment may benefit from oocyte donation. more

London Fertility Centre and Medicraft Services, London W1N 1AF, UK

IAN CRAFT TALHA AL-SHAWAF

1. Serhal PF, Craft IL. Oocyte donation in 61 patients. Lancet 1989; i: 1185-87. 2. Asch RH, Ord T, Stone S, Balmaceda JP, Rotzteju DA. Assisted reproductive techniques in women over 40 years of age: IVF, GIFT, ZIFT, egg donation: is there a best alternative? Fertil Steril 1991 (suppl) (annual meeting of Pacific Coast

Fertility Society, April 10-14, 1991): 0-016:A15. E, Brinsden P, Craft I. Patients’ reponse to a questionnaire reproduction treatment. Ethical Probl Reprod Med 1989; 1: 25-27.

3. Fincham

on

assisted

Spongiform leucoencephalopathy after inhaling heroin SiR,—Spongifbrm leucoencephalopathy is a neurological complication of heroin addiction. 47 cases have been reported from the Netherlands1 and 1 from Germany;2 the cause was thought to be an

unknown toxin factor. There have

not

been any other such

patients recorded since 1983. We report two Spanish patients with this condition after inhalation of heroin. Patient 1-A 43-year-old man presented with a progressive gait disorder which had evolved over one month. He smoked heroin but had never injected it. He had cerebellar ataxia and bilateral pyramidal signs. A cranial computed tomographic (CT) scan revealed symmetrical hypodensity of the cerebral and cerebellar white matter without contrast enhancement. Cerebrospinal fluid was normal. He was negative for HIV-1. Cellular and humoral immunity were normal. The patient regressed neurologically, eventually to coma, and died three weeks after admission. Necropsy showed cerebral swelling with flattening of the gyri, narrowing of sulci, and small bilateral and symmetrical uncal herniations. Extensive white-matter spongiosis and vacuolisation affecting brain and cerebellum were seen microscopically. Oligodendroglia had partly disappeared from the most affected areas whereas axons were easily detectable. Grey matter was normal with the exception of some cromatolytic neurons in the motor cortex and nucleus of the third cranial nerve. Patient 2-A 40-year-old man presented with dysarthria and a progressive lurching gait which had evolved over three months. He smoked heroin and cocaine. He had cerebellar speech and ataxia, with no other abnormalities. A cranial CT scan revealed symmetrical hypodensity of the cerebellar white matter and internal capsules without contrast enhancement. Magnetic resonance imaging of the head showed involvement of cerebellar white matter and internal capsules, hypointense on Tl weighted images and hyperintense on T2 weighted images. Cerebrospinal fluid was normal. He was HIV-1 seronegative. Cellular and humoral immunity were normal. Very-long-chain fatty acids in plasma were normal. A cerebellar biopsy showed striking vacuolisation of the white matter with some hyperplastic astrocytes. Three months later cerebellar function was improving.

These

patients had characteristic clinical, laboratory, and neuropathological findings.Heroin was acquired in Madrid. The disease developed in the 2 patients at the end of 1985 and 1989, respectively. An analysis of drug samples by the National Toxicology Institute during 1985-87 (Bulletin on Narcotics, vol 41, p 121) detected heroin adulterants: caffeine, phenobarbital, methaqualone, procaine, piracetam, and lignocaine. None of these substances is known to produce this type of leucoencephalopathy.1 Our findings indicate that this complication may well not have disappeared. Neurology Department and Section of Neuropathology, Hospital Universitario "12 de Octubre", 28041 Madrid, Spain

A. P. SEMPERE I. POSADA

C. RAMO A. CABELLO

1. Wolters ECh, Wijngaarden GK, Stam FC, et al. Leucoencephalopathy after inhaling "heroin" pyrolysate. Lancet 1982; ii: 1233-37. 2. Haan J, Muller E, Gerhard L. Spongiose leukodystrophie nach drogenmissbrauch. Nervenarzt 1983; 54: 489-90. 3. Stam FC. Leukoencephalopathies due to intoxications. In: Koetsier JC, ed. Handbook of clinical neurology, vol 3. Amsterdam: Elsevier, 1985: 551-81.

Chimaeric CD4 monoclonal treatment of

antibody in generalised pustular psoriasis

SIR,-Psoriasis vulgaris may, albeit rarely, progress to a severe

occasionally fatal disease also known as generalised pustular psoriasis and characterised by erythroderma, oedema, pustulation, scarlatiniform peeling, malaise, fever, and leucocytosis. Although the histological hallmarks of the fully expressed psoriatic lesion are hyperproliferation of keratinocytes and epidermal accumulation of granulocytes, the initial phase is dominated by epidermal infiltration of activated CD4 T lymphocytes, suggesting a primary immune trigger for the inflammatory and hyperproliferative process.1,;! Therapeutic efforts aimed selectively at the CD4+ T lymphocyte subpopulation might therefore be warranted. Monoclonal antibodies to the CD4 antigen have proved remarkably effective in the control of experimental autoimmune diseases.3 Here we report on the use of a genetically engineered chimaeric human/mouse CD4 monoclonal antibody (cM-T412), in which the murine constant portions of the immunoglobulin H and L chain have been replaced by the equivalent segments of human IgG1.4 A murine CD4 antibody with similar specificity (M-T151) and

has been effective in rheumatoid arthritis.5 The chimaeric CD4 antibody was used to treat a 63-year-old man with severe generalised pustular psoriasis that had developed following oral administration of steroids. At the time of hospital admission, pustules had been spreading over the back of the feet, lower legs, arms, and groin. There was general desquamation and extensive peripheral lymphoedema, with hypoalbuminaemia and incipient bilateral pleural effusions. With the patient’s informed consent he was given intravenous infusions of alternating doses of 10 and 20 mg CD4 antibody on days 1,2,3,6, and 7. Topical therapy consisted of bland emollients. 2 days after the first infusion the pustules had dried off; by day 11I the erythroderma, desquamation, and oedema had disappeared. The psoriatic plaques on his knees and elbows, present since the age of 19, also disappeared (figure). A slight relapse of erythroderma on day 14 was controlled by an infusion of 20 mg cM-T412. Single guttate lesions developing after day 27 responded well to oral psoralen photochemotherapy and etretinate. The clinical improvement was accompanied by a decline in serum C-reactive protein from 16-4 mg/dl before antibody therapy to 8 mg/dl on day 11 and to 1-6 mg/dl on day 20. The leucocyte count dropped from 19.8 to 5-4 x 109/1, while total serum protein increased from 4-9 to 7-0 g/dl. As observed in the rheumatoid arthritis patientss the CD4 T-cell count decreased rapidly and the CD4/CD8 T cell ratio fell from 1to 0,5. Histological evaluation of the skin revealed a distinct loss of T lymphocytes from the inflammatory infiltrate (a more detailed account will be reported

elsewhere). Our observations suggest that CD4 monoclonal antibody infusion has a therapeutic effect in this severe form of psoriasis and support the hypothesis that CD4 T lymphocytes have a pathogenetic

Oocyte donation and older women.

319 and this lymphoma may cause the symptoms of malabsorption. The common presentation of EATCL-with worsening malabsorption, obstruction, perforatio...
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