- Email: [email protected]
ALPHA-TOCOPHEROL IN TARDIVE DYSKINESIA
913
print-out data, were sent to the central organising laboratory (Glasgow) for analysis. Problems in the familiarisation phase were soon overcome and ease of use was established before specificity and sensitivity were evaluated. In the screening phase 6001 random donor samples were examined. 21 samples were positive but only 2 were repeat positive (and these were found to have anti-mouse or anti-calf activity). This frequency (035%) of initial false screen positivity is acceptable. Pools of 20 samples known to be HBsAg negative by ’Ausria II’ (Abbott Laboratories) were clearly negative by the Wellcome test, and when 10 HBsAg negative, anti-HBc positive, anti-HBs positive samples were tested all laboratories obtained the correct result (ie, negative for HBsAg by the Wellcome test). 8 donor sera whose only marker was anti-HBc positivity gave HBsAg negative results, as expected. 30 known HBsAg positive samples were examined and all were identified without difficulty, and no problem was found in detecting 8 subtypes ay and 10 subtypes ad taken as representative of 18 known strongly reactive HBsAg positive sera. When we examined in duplicate 8 samples known to react weakly HBsAg positive in the Abbott test, 2, from the same donor, failed to give uniform results; three centres recorded a positive result with the Wellcome test on one occasion only and one laboratory recorded a negative result on both occasions. As in-house method two centres used the BPL radioimmunoassay (BPL, Elstree) and encountered difficulty with a further 2 donor samples; the other two centres, which used the Abbott assay in house, obtained the correct result with all samples. Further examination of sensitivity, using the Glasgow sensitivity panel, indicated that the Abbott assay detected to at least 0.3 ng/ml and the Wellcome test to at least 0.6 ng/ml. Comparison with the British reference preparation of HBsAg (National Institute for Biological Standards and Control, London NW3) diluted to 2, 1, and 05 BSU/ml showed that the Wellcome test could detect down to 0-5 BSU/ml without difficulty, which is well below the 2 BSU/ml or less required for plasma destined for fractionation in the UK.1 In Scotland, this standard has been reviewed and has been set at 05 BSU/ml or less. For practical purposes, therefore, the Wellcome HBsAg test system is robust and reliable and has an acceptable specificity; its sensitivity is sufficient to meet UK requirements for donations for plasma fractionation. Glasgow & West of Scotland Regional Blood Transfusion Service, Law Hospital, Carluke ML8 5ES
A. BARR R. MITCHELL
at the vault; the growth was histologically consistent with a clear cell carcinoma. Case 3.-A 39-year-old nulliparous woman presented with intermenstrual and postcoital bleeding. Until the past 2 years, her periods had been regular. She subsequently had polymenorrhagia. Examination at that time revealed vaginal polyps which were reported histologically to be vaginal adenosis. She was treated with danazol for 1 year until she had postcoital bleeding. Re-examination revealed a friable tumour along the anterior wall of the vagina; histology of the tumour was typical of a clear cell adenocarcinoma with adjacent adenosis. She had no prenatal history of stilboestrol exposure. These cases belong to an older age group than those exposed to prenatal stilboestrol. The development of a clear cell carcinoma was preceded by administration of a hormone therapy which interacts pharmacologically with oestrogens. In case 3, there was apparent transition of vaginal adenosis to clear cell carcinoma. Vaginal adenosis represents persisting mullerian columnar epithelium which has not undergone squamous metaplasia and glycogenation.3 Aetiologically, prenatal exposure to stilboestrol is documented in the development of this benign condition, but the transition to clear cell carcinoma is less known.4,5 Modulation of oestrogenic effects on the vaginal mucosa by pharmacological agents may contribute to the development of clear cell carcinoma. The short time between exposure and development of the neoplasm suggests a role as promoters of carcinogenesis rather than as initiators. Animal studies indicate that tamoxifen can act as a tumour promoter after initiation with a carcinogen,6,7 and tamoxifen may be a partial agonist on vaginal mucosa of postmenopausal women.8 The major pharmacological effect of danazol is to inhibit pituitary gonadotropins, but danazol also has partial
exophytic growth
agonist activity on oestrogen receptors.9 Tamoxifen is invaluable in the management of breast cancer, and any risk in developing clear cell carcinoma of the vagina is negligible in this context. However, the possible widespread use of tamoxifen in benign medical conditions, particularly fibrocystic mastopathy, is controversial.10-12 If tamoxifen or danazol are administered for benign breast disease, caution must be exercised and regular, appropriate gynaecological examinations done along the lines that are
routine for postmenopausal oestrogen therapy.
I thank Professor R. J. Berry and Dr M. F. their patients.
Meyerstein Institute of Radiotherapy and Oncology, Middlesex Hospital, London W1N 8AA
1. Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen and its Antibody. Third report. London: DHSS, 1981.
OESTROGEN MODULATORS AND CLEAR CELL CARCINOMA OF VAGINA
SIR,--Clear cell carcinoma of the vagina is a rare neoplasm which has merited increasing attention over the past two decades because of its association in young women with prenatal exposure to stilboestrol.’,’ The unusual presentation of a 74-year-old woman with such a carcinoma prompted me to investigate the case-records of patients with primary vaginal adenocarcinomas who presented to this department since 1950. Of 95 cases of malignant vaginal
neoplasms, 75 were squamous carcinomas, 14 were secondary adenocarcinomas, and 3 were anaplastic carcinomas. Only 3 cases, which are described here, were primary adenocarcinomas. Case 1.-A 74-year-old nulliparous woman presented with vaginal bleeding. She had been taking tamoxifen, 10 mg twice daily for 1 year, after
a
local excision for carcinoma of the breast.
Examination revealed a mass involving the anterior vaginal wall; the mass was
histologically a clear cell adenocarcinoma distinct from her
breast carcinoma. Case 2.-A
73-year-old nulliparous woman presented with vaginal bleeding. She had been on oestrogen replacement therapy to prevent osteoporosis for 20 years. 8 years ago, she had had a hysterectomy and bilateral salpingo-oophorectomy to manage postmenopausal bleeding. Histology revealed fibroids and ovarian endometriosis only. Current vaginal examination revealed an
Spittle for allowing me to report
STEPHEN M. SAGAR
1. Herbst AL, Norusis MJ, Rosenow PJ, Welch WR, Scully RE. Analysis of 346 cases of clear cell adenocarcinoma of the vagina and cervix with emphasis on recurrence and survival. Gynecol Oncol 1979; 7: 111-22. 2. Monaghan JM, Sirisena LAW. Stilboestrol and vaginal clear cell adenocarcinoma syndrome. Br Med J 1978; i: 1588-90. 3. Emens M. Vaginal adenosis and diethylsilboestrol. Br J Hosp Med 1984; 31: 42-48. 4. Ghosh TK, Cera PJ. Transition of benign vaginal adenosis to clear cell carcinoma. Obstet Gynecol 1983; 61: 126-30. 5. Kaufman RH, Korhonen MO, Strama T, Adam E, Kaplan A. Development of clear cell adenocarcinoma in DES-exposed offspring under observation. Obstet Gynecol 1982; 59: 68s-72s. 6. Sheehan DM, Frederick CB, Branham S, Heath JE. Evidence for estradiol promotion of neoplastic lesions in the rat vagina after initiation with N-methyl-N-nitrosourea.
Carcinogenesis 1982; 3: 957-59. Taguchi O, Nishizuka Y. Reproductive tract abnormalities in female mice treated neonatally with tamoxifen. Am J Obstet Gynecol 1985; 151: 675-78. 8. Furr BJA, Jordan VC. The pharmacology and clinical uses of tamoxifen. Pharmacol Ther 1984; 25: 127-205. 9. Musich JR, Behrman SJ, Menon KMJ. Estrogenic and antiestrogenic effects of danazol administration m studies of estradiol receptor binding. Am J Obstet Gynecol 1981; 140: 62-69. 10. Smallwood JA, Taylor I. Tamoxifen for mastalgia. Lancet 1986; i: 680-81. 1 1. Editorial. Tamoxifen for benign breast disease. Lancet 1986; i: 305. 12. Diver JMJ, Jackson IM, Fitzgerald JD. Tamoxifen and non-malignant indications. 7.
Lancet 1986; i: 733.
ALPHA-TOCOPHEROL IN TARDIVE DYSKINESIA
SIR,-A major complication of long-term neuroleptic treatment is tardive dyskinesia (TD). We have suggested that the terminals of neurotransmitter systems may show structural changes and that cell membranes may be destabilised by the toxic action of free radicals produced during the chronic use of neuroleptic drugs.’ We have
914
a-tocopherol may be beneficial in the treatment of some patients with TD, but further research is necessary. Furthermore, the involvement of free-radical formation in the aetiology of persistent TD remains to be independently demonstrated. JAMES B. LOHR JEAN LUD CADET Neuropsychiatry Branch, National Institute of Mental Health, Saint Elizabeths Hospital, Washington DC 20032, USA
MELODIE A. LOHR DILIP V. JESTE RICHARD JED WYATT
JL, Lohr JB, Jeste DV. Free radicals and tardive dyskinesia. Trends Neurosci 1986; 9: 107-08. 2. Cadenas E, Ginsberg M, Rabe U, et al. Evaluation of alpha-tocopherol antioxidant activity in microsomal lipid peroxidation as detected by low-level chemiluminescence. Biochem J 1984; 223: 755-59. 1. Cadet
AIMS
scores
.
tardive
=
after trial 1
dyskinesia;
0
(n = 15) and trial 2 (n = 12). tardive dystonia. =
patients with persistent TD-like movements with a-tocopherol (vitamin E) and matched placebo in a randomised crossover design. fx-tocopherol is an antioxidant: it prevents tissue damage and death due to peroxidation reactions, 2,3 has important membrane-stabilising effectsand prevents brain damage secondary to ischaemia.5 Drug studies of TD are complicated by the highly variable nature of TD over time and by the insensitivity of the abnormal involuntary movements scale (AIMS),6 so we decided to administer two active and placebo phases to as many patients as possible. To help us identify any clinical features associated with response to a-tocopherol we chose a 50% reduction in AIMS score as the criterion separating good response from poor response.6 Subjects were chosen from among the consenting inpatients and outpatients at St Elizabeths Hospital. We tried to keep patients on constant doses of neuroleptic and anticholinergic medications throughout the study. 9 patients with chronic schizophrenia and 6 with schizoaffective disorder7 and persistent TD for at least a year completed the study. TD was diagnosed6,8 by two independent raters. The 11 men and 4 women had an average age of 44 (SD 18, range 19-71) and had had movement disorder for 2.6 years (SD 1.9, range 1-6). 3 patients had movements that were primarily dystonic. After 2 weeks of stabilisation patients received a-tocopherol and matched placebo in a randomised crossover design. The dose of (x-tocopherol was raised from 400 IU daily to 400 IU three times daily over 2 weeks and maintained at that level for 2 weeks. 12 patients also completed a second active and placebo period. Patients were evaluated at the end of each treatment phase on an AIMS scale modified by separating and adding left and right limb dyskinesia scores,9 by two independent raters who were "blind" to medication status. In a subgroup of patients serum fx-tocopherol concentration was measured fluorometrically. The initial AIMS score was 13-9 (SD 5-9). AIMS scores fell significantly after treatment with (x-tocopherol but not after placebo (7-5 [4.8] vs 13-5 [6-4] ; two-tailed t test, p < 0-001) (see figure). The mean reduction with (x-tocopherol was 43 %, 7 patients having more than a 50 % reduction in dyskinesia. In the 12 patients who completed a second active and placebo phase, there was again a significant reduction in AIMS after a-tocopherol and there was no significant (6-2 [3’3] vs 11-1 [5-1]; p<0005), difference in AIMS values between the first and second placebo periods. In the 10 patients who had blood drawn the mean serum (x-tocopherol rose from 11to 23-7 Ilgfrnl (normal range 5-20). The 7 patients with more than 50% improvement had a shorter duration of TD (I - 13 [0’3S] vs 3-29 [2’06] years; p < 0-02) and a later age of onset of psychiatric illness (27-1 [7’3] vs 19-7 [1-7] years; p < 0 03) than the 8 patients with less than 50% improvement but
treated
.
did not differ in terms of other clinical variables.
3. Willmore LJ, Rubin JJ. The effect of tocopherol and dimethyl sulfoxide on focal edema and lipid peroxidation induced by isocortical injection of ferrous chloride. Brain Res 1984; 296: 389-92. 4. Diplock AT. The role of vitamin E in biological membranes. In: Biology of vitamin E (Ciba Found Symp 101). London: Pitman, 1983: 45-55. 5. Fujimoto S, Mizoi K, Yoshimoto T, et al. The protective effect of vitamin E on cerebral ischemia. Surg Neurol 1984; 22: 449-54. 6. Jeste DV, Wyatt RJ. Understanding and treating tardive dyskinesia New York: Guilford Press, 1982. 7. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 3rd ed. Washington, DC: American Psychiatric Association, 1980. 8. Schooler NR, Kane JM. Research diagnosis for tardive dyskinesia (RD-TD). Arch Gen Psychiatry 1982; 39: 486-87. 9. National Institute of Mental Health. Abnormal involuntary movement scale. In. Guy W, ed. ECDEU assessment manual. Rockville, Maryland: US Department of Health, Education and Welfare, 1976: 534-37.
MALABSORPTION OF CYCLOSPORIN IN RENAL TRANSPLANT RECIPIENT WITH CROHN’S DISEASE
SIR,-Although oral administration of cyclosporin is routine, little is known of the exact site of absorption, and intestinal disease has been reported to have a detrimental effect on cyclosporin’s bioavailability.l We report a case of long-standing Crohn’s disease which caused malabsorption of cyclosporin in a renal transplant recipient. In 1967, a 28-year-old man was diagnosed at laparotomy as having Crohn’s disease. At various times during the next 10 years, the disease was shown to affect both the small and large intestines with granulomatous inflammation in the absence of acid-fast bacilli. Despite this long history the course of the disease was mild and he did not require regular medication. In 1977, the patient presented in renal failure and radiology revealed two small non-obstructed kidneys. 4 years later, continuous ambulatory peritoneal dialysis (CAPD) was started and, in August, 1984, he received a cadaveric renal transplant. Throughout this time the patient was free of gastrointestinal symptoms and did not require medical therapy. Post-transplantation, cyclosporin at an oral dose of 15 mg/kg was started, reducing to 6 mg/kg after 12 weeks, as the sole immunosuppressive agent. Over the next 9 months the patient had good renal function and cyclosporin absorption was satisfactory with whole blood trough levels in the range 400-600 ng/ml after a dose of 300 mg daily. In March, 1985, he was admitted as an emergency with a 3-week history of severe diarrhoea. At the time of admission no circulating cyclosporin could be detected by whole blood radioimmunoassay. Renal function had deteriorated from a creatinine clearance of 45 to 15 ml/min, and biopsy of his graft revealed severe cellular rejection. Malabsorption was shown by the complete absence of xylose absorption, and jejunal biopsy revealed partial villous atrophy with heavy mucosal mononuclear cell infiltration, ulceration of the surface epithelium, and small granulomas. Rectal biopsy revealed focal mucosal inflammation with a single granuloma. The administration of methylprednisolone, 3 g over 3 days, followed by 20 days of parenteral feeding and intravenous cyclosporin (3 mg/kg), resulted in improved renal function with an increase in creatinine clearance to 38 ml/min. The diarrhoea settled and xylose absorption returned to normal, with a corresponding improvement in cyclosporin absorption and a blood level of 600 ng/ml after an oral dose of 8 mg/kg. Over the next 4 weeks, in the complete absence of bowel symptoms and despite regular increases in the cyclosporin dose to 20 mg/kg, the absorption of cyclosporin once again decreased, such that by the end of this period the blood levels were
print-out data, were sent to the central organising laboratory (Glasgow) for analysis. Problems in the familiarisation phase were soon overcome and ease of use was established before specificity and sensitivity were evaluated. In the screening phase 6001 random donor samples were examined. 21 samples were positive but only 2 were repeat positive (and these were found to have anti-mouse or anti-calf activity). This frequency (035%) of initial false screen positivity is acceptable. Pools of 20 samples known to be HBsAg negative by ’Ausria II’ (Abbott Laboratories) were clearly negative by the Wellcome test, and when 10 HBsAg negative, anti-HBc positive, anti-HBs positive samples were tested all laboratories obtained the correct result (ie, negative for HBsAg by the Wellcome test). 8 donor sera whose only marker was anti-HBc positivity gave HBsAg negative results, as expected. 30 known HBsAg positive samples were examined and all were identified without difficulty, and no problem was found in detecting 8 subtypes ay and 10 subtypes ad taken as representative of 18 known strongly reactive HBsAg positive sera. When we examined in duplicate 8 samples known to react weakly HBsAg positive in the Abbott test, 2, from the same donor, failed to give uniform results; three centres recorded a positive result with the Wellcome test on one occasion only and one laboratory recorded a negative result on both occasions. As in-house method two centres used the BPL radioimmunoassay (BPL, Elstree) and encountered difficulty with a further 2 donor samples; the other two centres, which used the Abbott assay in house, obtained the correct result with all samples. Further examination of sensitivity, using the Glasgow sensitivity panel, indicated that the Abbott assay detected to at least 0.3 ng/ml and the Wellcome test to at least 0.6 ng/ml. Comparison with the British reference preparation of HBsAg (National Institute for Biological Standards and Control, London NW3) diluted to 2, 1, and 05 BSU/ml showed that the Wellcome test could detect down to 0-5 BSU/ml without difficulty, which is well below the 2 BSU/ml or less required for plasma destined for fractionation in the UK.1 In Scotland, this standard has been reviewed and has been set at 05 BSU/ml or less. For practical purposes, therefore, the Wellcome HBsAg test system is robust and reliable and has an acceptable specificity; its sensitivity is sufficient to meet UK requirements for donations for plasma fractionation. Glasgow & West of Scotland Regional Blood Transfusion Service, Law Hospital, Carluke ML8 5ES
A. BARR R. MITCHELL
at the vault; the growth was histologically consistent with a clear cell carcinoma. Case 3.-A 39-year-old nulliparous woman presented with intermenstrual and postcoital bleeding. Until the past 2 years, her periods had been regular. She subsequently had polymenorrhagia. Examination at that time revealed vaginal polyps which were reported histologically to be vaginal adenosis. She was treated with danazol for 1 year until she had postcoital bleeding. Re-examination revealed a friable tumour along the anterior wall of the vagina; histology of the tumour was typical of a clear cell adenocarcinoma with adjacent adenosis. She had no prenatal history of stilboestrol exposure. These cases belong to an older age group than those exposed to prenatal stilboestrol. The development of a clear cell carcinoma was preceded by administration of a hormone therapy which interacts pharmacologically with oestrogens. In case 3, there was apparent transition of vaginal adenosis to clear cell carcinoma. Vaginal adenosis represents persisting mullerian columnar epithelium which has not undergone squamous metaplasia and glycogenation.3 Aetiologically, prenatal exposure to stilboestrol is documented in the development of this benign condition, but the transition to clear cell carcinoma is less known.4,5 Modulation of oestrogenic effects on the vaginal mucosa by pharmacological agents may contribute to the development of clear cell carcinoma. The short time between exposure and development of the neoplasm suggests a role as promoters of carcinogenesis rather than as initiators. Animal studies indicate that tamoxifen can act as a tumour promoter after initiation with a carcinogen,6,7 and tamoxifen may be a partial agonist on vaginal mucosa of postmenopausal women.8 The major pharmacological effect of danazol is to inhibit pituitary gonadotropins, but danazol also has partial
exophytic growth
agonist activity on oestrogen receptors.9 Tamoxifen is invaluable in the management of breast cancer, and any risk in developing clear cell carcinoma of the vagina is negligible in this context. However, the possible widespread use of tamoxifen in benign medical conditions, particularly fibrocystic mastopathy, is controversial.10-12 If tamoxifen or danazol are administered for benign breast disease, caution must be exercised and regular, appropriate gynaecological examinations done along the lines that are
routine for postmenopausal oestrogen therapy.
I thank Professor R. J. Berry and Dr M. F. their patients.
Meyerstein Institute of Radiotherapy and Oncology, Middlesex Hospital, London W1N 8AA
1. Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen and its Antibody. Third report. London: DHSS, 1981.
OESTROGEN MODULATORS AND CLEAR CELL CARCINOMA OF VAGINA
SIR,--Clear cell carcinoma of the vagina is a rare neoplasm which has merited increasing attention over the past two decades because of its association in young women with prenatal exposure to stilboestrol.’,’ The unusual presentation of a 74-year-old woman with such a carcinoma prompted me to investigate the case-records of patients with primary vaginal adenocarcinomas who presented to this department since 1950. Of 95 cases of malignant vaginal
neoplasms, 75 were squamous carcinomas, 14 were secondary adenocarcinomas, and 3 were anaplastic carcinomas. Only 3 cases, which are described here, were primary adenocarcinomas. Case 1.-A 74-year-old nulliparous woman presented with vaginal bleeding. She had been taking tamoxifen, 10 mg twice daily for 1 year, after
a
local excision for carcinoma of the breast.
Examination revealed a mass involving the anterior vaginal wall; the mass was
histologically a clear cell adenocarcinoma distinct from her
breast carcinoma. Case 2.-A
73-year-old nulliparous woman presented with vaginal bleeding. She had been on oestrogen replacement therapy to prevent osteoporosis for 20 years. 8 years ago, she had had a hysterectomy and bilateral salpingo-oophorectomy to manage postmenopausal bleeding. Histology revealed fibroids and ovarian endometriosis only. Current vaginal examination revealed an
Spittle for allowing me to report
STEPHEN M. SAGAR
1. Herbst AL, Norusis MJ, Rosenow PJ, Welch WR, Scully RE. Analysis of 346 cases of clear cell adenocarcinoma of the vagina and cervix with emphasis on recurrence and survival. Gynecol Oncol 1979; 7: 111-22. 2. Monaghan JM, Sirisena LAW. Stilboestrol and vaginal clear cell adenocarcinoma syndrome. Br Med J 1978; i: 1588-90. 3. Emens M. Vaginal adenosis and diethylsilboestrol. Br J Hosp Med 1984; 31: 42-48. 4. Ghosh TK, Cera PJ. Transition of benign vaginal adenosis to clear cell carcinoma. Obstet Gynecol 1983; 61: 126-30. 5. Kaufman RH, Korhonen MO, Strama T, Adam E, Kaplan A. Development of clear cell adenocarcinoma in DES-exposed offspring under observation. Obstet Gynecol 1982; 59: 68s-72s. 6. Sheehan DM, Frederick CB, Branham S, Heath JE. Evidence for estradiol promotion of neoplastic lesions in the rat vagina after initiation with N-methyl-N-nitrosourea.
Carcinogenesis 1982; 3: 957-59. Taguchi O, Nishizuka Y. Reproductive tract abnormalities in female mice treated neonatally with tamoxifen. Am J Obstet Gynecol 1985; 151: 675-78. 8. Furr BJA, Jordan VC. The pharmacology and clinical uses of tamoxifen. Pharmacol Ther 1984; 25: 127-205. 9. Musich JR, Behrman SJ, Menon KMJ. Estrogenic and antiestrogenic effects of danazol administration m studies of estradiol receptor binding. Am J Obstet Gynecol 1981; 140: 62-69. 10. Smallwood JA, Taylor I. Tamoxifen for mastalgia. Lancet 1986; i: 680-81. 1 1. Editorial. Tamoxifen for benign breast disease. Lancet 1986; i: 305. 12. Diver JMJ, Jackson IM, Fitzgerald JD. Tamoxifen and non-malignant indications. 7.
Lancet 1986; i: 733.
ALPHA-TOCOPHEROL IN TARDIVE DYSKINESIA
SIR,-A major complication of long-term neuroleptic treatment is tardive dyskinesia (TD). We have suggested that the terminals of neurotransmitter systems may show structural changes and that cell membranes may be destabilised by the toxic action of free radicals produced during the chronic use of neuroleptic drugs.’ We have
914
a-tocopherol may be beneficial in the treatment of some patients with TD, but further research is necessary. Furthermore, the involvement of free-radical formation in the aetiology of persistent TD remains to be independently demonstrated. JAMES B. LOHR JEAN LUD CADET Neuropsychiatry Branch, National Institute of Mental Health, Saint Elizabeths Hospital, Washington DC 20032, USA
MELODIE A. LOHR DILIP V. JESTE RICHARD JED WYATT
JL, Lohr JB, Jeste DV. Free radicals and tardive dyskinesia. Trends Neurosci 1986; 9: 107-08. 2. Cadenas E, Ginsberg M, Rabe U, et al. Evaluation of alpha-tocopherol antioxidant activity in microsomal lipid peroxidation as detected by low-level chemiluminescence. Biochem J 1984; 223: 755-59. 1. Cadet
AIMS
scores
.
tardive
=
after trial 1
dyskinesia;
0
(n = 15) and trial 2 (n = 12). tardive dystonia. =
patients with persistent TD-like movements with a-tocopherol (vitamin E) and matched placebo in a randomised crossover design. fx-tocopherol is an antioxidant: it prevents tissue damage and death due to peroxidation reactions, 2,3 has important membrane-stabilising effectsand prevents brain damage secondary to ischaemia.5 Drug studies of TD are complicated by the highly variable nature of TD over time and by the insensitivity of the abnormal involuntary movements scale (AIMS),6 so we decided to administer two active and placebo phases to as many patients as possible. To help us identify any clinical features associated with response to a-tocopherol we chose a 50% reduction in AIMS score as the criterion separating good response from poor response.6 Subjects were chosen from among the consenting inpatients and outpatients at St Elizabeths Hospital. We tried to keep patients on constant doses of neuroleptic and anticholinergic medications throughout the study. 9 patients with chronic schizophrenia and 6 with schizoaffective disorder7 and persistent TD for at least a year completed the study. TD was diagnosed6,8 by two independent raters. The 11 men and 4 women had an average age of 44 (SD 18, range 19-71) and had had movement disorder for 2.6 years (SD 1.9, range 1-6). 3 patients had movements that were primarily dystonic. After 2 weeks of stabilisation patients received a-tocopherol and matched placebo in a randomised crossover design. The dose of (x-tocopherol was raised from 400 IU daily to 400 IU three times daily over 2 weeks and maintained at that level for 2 weeks. 12 patients also completed a second active and placebo period. Patients were evaluated at the end of each treatment phase on an AIMS scale modified by separating and adding left and right limb dyskinesia scores,9 by two independent raters who were "blind" to medication status. In a subgroup of patients serum fx-tocopherol concentration was measured fluorometrically. The initial AIMS score was 13-9 (SD 5-9). AIMS scores fell significantly after treatment with (x-tocopherol but not after placebo (7-5 [4.8] vs 13-5 [6-4] ; two-tailed t test, p < 0-001) (see figure). The mean reduction with (x-tocopherol was 43 %, 7 patients having more than a 50 % reduction in dyskinesia. In the 12 patients who completed a second active and placebo phase, there was again a significant reduction in AIMS after a-tocopherol and there was no significant (6-2 [3’3] vs 11-1 [5-1]; p<0005), difference in AIMS values between the first and second placebo periods. In the 10 patients who had blood drawn the mean serum (x-tocopherol rose from 11to 23-7 Ilgfrnl (normal range 5-20). The 7 patients with more than 50% improvement had a shorter duration of TD (I - 13 [0’3S] vs 3-29 [2’06] years; p < 0-02) and a later age of onset of psychiatric illness (27-1 [7’3] vs 19-7 [1-7] years; p < 0 03) than the 8 patients with less than 50% improvement but
treated
.
did not differ in terms of other clinical variables.
3. Willmore LJ, Rubin JJ. The effect of tocopherol and dimethyl sulfoxide on focal edema and lipid peroxidation induced by isocortical injection of ferrous chloride. Brain Res 1984; 296: 389-92. 4. Diplock AT. The role of vitamin E in biological membranes. In: Biology of vitamin E (Ciba Found Symp 101). London: Pitman, 1983: 45-55. 5. Fujimoto S, Mizoi K, Yoshimoto T, et al. The protective effect of vitamin E on cerebral ischemia. Surg Neurol 1984; 22: 449-54. 6. Jeste DV, Wyatt RJ. Understanding and treating tardive dyskinesia New York: Guilford Press, 1982. 7. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 3rd ed. Washington, DC: American Psychiatric Association, 1980. 8. Schooler NR, Kane JM. Research diagnosis for tardive dyskinesia (RD-TD). Arch Gen Psychiatry 1982; 39: 486-87. 9. National Institute of Mental Health. Abnormal involuntary movement scale. In. Guy W, ed. ECDEU assessment manual. Rockville, Maryland: US Department of Health, Education and Welfare, 1976: 534-37.
MALABSORPTION OF CYCLOSPORIN IN RENAL TRANSPLANT RECIPIENT WITH CROHN’S DISEASE
SIR,-Although oral administration of cyclosporin is routine, little is known of the exact site of absorption, and intestinal disease has been reported to have a detrimental effect on cyclosporin’s bioavailability.l We report a case of long-standing Crohn’s disease which caused malabsorption of cyclosporin in a renal transplant recipient. In 1967, a 28-year-old man was diagnosed at laparotomy as having Crohn’s disease. At various times during the next 10 years, the disease was shown to affect both the small and large intestines with granulomatous inflammation in the absence of acid-fast bacilli. Despite this long history the course of the disease was mild and he did not require regular medication. In 1977, the patient presented in renal failure and radiology revealed two small non-obstructed kidneys. 4 years later, continuous ambulatory peritoneal dialysis (CAPD) was started and, in August, 1984, he received a cadaveric renal transplant. Throughout this time the patient was free of gastrointestinal symptoms and did not require medical therapy. Post-transplantation, cyclosporin at an oral dose of 15 mg/kg was started, reducing to 6 mg/kg after 12 weeks, as the sole immunosuppressive agent. Over the next 9 months the patient had good renal function and cyclosporin absorption was satisfactory with whole blood trough levels in the range 400-600 ng/ml after a dose of 300 mg daily. In March, 1985, he was admitted as an emergency with a 3-week history of severe diarrhoea. At the time of admission no circulating cyclosporin could be detected by whole blood radioimmunoassay. Renal function had deteriorated from a creatinine clearance of 45 to 15 ml/min, and biopsy of his graft revealed severe cellular rejection. Malabsorption was shown by the complete absence of xylose absorption, and jejunal biopsy revealed partial villous atrophy with heavy mucosal mononuclear cell infiltration, ulceration of the surface epithelium, and small granulomas. Rectal biopsy revealed focal mucosal inflammation with a single granuloma. The administration of methylprednisolone, 3 g over 3 days, followed by 20 days of parenteral feeding and intravenous cyclosporin (3 mg/kg), resulted in improved renal function with an increase in creatinine clearance to 38 ml/min. The diarrhoea settled and xylose absorption returned to normal, with a corresponding improvement in cyclosporin absorption and a blood level of 600 ng/ml after an oral dose of 8 mg/kg. Over the next 4 weeks, in the complete absence of bowel symptoms and despite regular increases in the cyclosporin dose to 20 mg/kg, the absorption of cyclosporin once again decreased, such that by the end of this period the blood levels were