drug, though not impossible, is very unlikely. This patient had on metoclopramide "irregularly", up to the time severe neutropenia was found. Metoclopramide, an investigational drug in the U.S.A., is a procainamide derivative.6 Agranulocytosis has been reported after the repeated use of procainamide.7,8 Cautious rechallenge with metoclopramide and other drugs which the patient received should be done if they are
walking. A brain scan was normal. Over the ensuing 8 months the gait problem got worse; she also had memory loss, difficulty with arithmetic, and poor coordination. Neurological evalua-
needed in future. Cimetidine is a major advance in the therapy of peptic-ulcer diseases. Reports of well-documented side-effects with this
welcome, but speculations need be viewed with
tion. Department of Medicine, University of Miami, and Veterans Administration Hospital,
Miami, Florida 33125, U.S.A.
MARCOS S. SOUZA LIMA
BRADYCARDIA AFTER CIMETIDINE
SIR,-A 49-year-old male, cirrhotic and without heart-disgastrointestinal bleeding with cimetidine was also taking lactulose and thiamine. He (1 g/day orally). ease, was treated for
electrocardiogram at the beginning of days later his heart-rate was 57/min. On the
treatment but 10
following day, it was 50/min and an E.c.G. showed atrioventricular dissociation with idioventricular rhythm. Cimetidine was stopped and tincture of belladonna (45 drops/day daily) was given. 2 days later, the heart-rate was 52/min and the E.c.G. was normal. 2 weeks later, the heart-rate was 63/min. There is evidence for Hz-receptors in the heart. Black et al.’ have shown that the chronotropic effect of histamine on isolated guineapig atrium could be selectively blocked by anti-Hz drugs. This case suggests that cimetidine can cause bradycardia and thus atrioventricular dissociation. Service de Médecine Interne,
Hôpital Universitaire St Pierre, B-1000 Bruxelles, Belgium
PIERRE REDING CORINNE DEVROEDE PIERRE BARBIER
tion in June, 1977, confirmed a decline in intellectual functioning, as well as problems with gait, coordination, and use of hands. Clinically her symptoms suggested a diffuse cerebral and cerebellar problem. An electroencephalogram and computer-assisted tomogram of the brain were both normal on June 6, 1977. An electromyogram showed patchy fibrillation and sharp wave potentials in the right and left lumbar paraspinous muscles, but motor-nerve-conduction velocity and motor and sensory distal latency were normal. The patient was referred for detailed psychological testing. She had a generalised memory disorder, momentary confusion, and mental and motor inertia and perseverative responses. She had difficulty keeping instructions in mind long enough to answer questions. Intelligence tests indicated severe intellectual deterioration on subtests measuring visuospatial perception (performance i.Q. in the borderline mentally defective range). She exhibited perseverative motor responses and was unable to tap out simple rhythms according to verbal instructions. Clomiphene was discontinued on Aug. 29. The patient noted rapid improvement in her neurological functioning, and on Oct. 5 she readily understood questions and her performance I.Q. score was average. Her registration of acoustic material had improved. There was great improvement in visuospatial perception and motor control. She was able to tap out rhythms accurately to verbal instructions. Her remote and recent memory improved substantially ; she did not exhibit momentary confusion as she had while taking clomiphene. We conclude that a high dose of clomiphene citrate may cause serious neurological dysfunction. The patient is now on megestrol acetate and will be considered for a different antioestrogen should megestrol prove ineffective. C. M. HASKELL Departments of Medicine and Neurology, C. HERRMANN, JR U.C.L.A. School of Medicine, Los Angeles, California 90024, U.S.A. G. G. MARSH
CLOMIPHENE-INDUCED NEUROLOGICAL DYSFUNCTION
of metastatic breast
anticestrogens-including nafoxidine, tamoxifen, and clomiphene-has been widely studied in Europe, and, more recently, in the United States.2 These drugs are thought to have very little toxicity, and all three seem to achieve comparable antitumour effects. We report here a reversible neurological complication of high-dose clomiphene citrate. A 66-year-old woman reported back pain in January, 1974, and metastatic breast cancer involving bone was diagnosed in April. Diethylstilboestrol resulted in severe nausea and vomiting and was discontinued. Radiation therapy was given to the lumbar spine in May. The patient was stable on calusterone (’Methosarb’) until she had progressive bone pain treated with radiotherapy in November, 1975. The patient was then put on cyclophosphamide 100 mg orally daily for 14 days, with two intravenous injections of methotrexate and 5-fluorouracil each month. Six courses of this therapy were given, but the disease progressed. Staging studies revealed that the breast cancer was limited to soft tissues and bone, and did not involve the brain, lung, or liver. On June 29, 1976, the patient started taking clomiphene citrate 50 mg four times daily. This was continued for the ensuing 14 months. 6 months after starting clomiphene she had mild disequilibrium, manifested primarily as difficulty in 6. Robinson, O. P. W. Postgrad. med. J. 1973, 49, suppl. 4, p. 77. 7. Konttinin, Y. P., Tuominen, L. Lancet, 1971, ii, 925. 8. Wang, R. I. H., Schuller, G. Am. Heart J. 1969, 78, 282. 1. Black, J. W., Duncan, W. A. M., Durant, G. J., Ganellin, C. Parsons, M. E. Nature, 1972, 236, 385. 2.Legha, S. S., Carter, S. K. Cancer Treatment Rev. 1976, 3, 205.
HERPETIC ENCEPHALITIS WITH ASSOCIATED CYTOMEGALOVIRUS INFECTION AND MYOCLONUS
SIR,-We are aware of only two case-reports of double viral infection of the brain. 1.2 We have seen a patient whose central nervous system may have been infected by both herpesvirus hominis and cytomegalovirus. A 13-month-old, previously healthy female infant was admitted with diarrhoea, vomiting, fever (40°C), and generalised tonic-clonic convulsions. During the following 9 days she showed hypertonia, opisthotonus, and lethargy. She was treated with antibiotics and anticonvulsants, and recovered. After 2 years of complete clinical and electroencephalographic normality, she began to have myoclonic fits and short (2-3 s) periods of loss of consciousness during which there were clonic jerks of the upper limbs. During the acute phase, the cerebrospinal fluid had a slightly lowered glucose content, with 15 lymphocytes/1, and cytomegalovirus was isolated from it on the llth day of illness. In serum, the com-
plement-fixing antibody titre against cytomegalovirus was zero but against herpesvirus hominis it was 1:8. In peripheral blood, the proportion of T lymphocytes (determined by rosetteformation with sheep erythrocytes) was lowered to 8%. We could thus isolate cytomegalovirus without detecting antibodies to it and detect antibodies to herpesvirus without isolating it. Yanagisawa et al.’ have suggested that cytomegalovirus can invade the brainstem and cerebellum through the cerebrospinal fluid. This might explain why our patient had myoclonu.s, which is unusual in herpetic encephalitis. We thus
Yanagisawa, N., Toyokura, Y., Shiraki, H. Acta neuropath. (Berl.) 1975, 33, 153.
our case to be herpetic encephalitis with associated cytomegalovirus infection of brainstem and cerebellum, and consequent myoclonic evolution.2 Alternatively, the low antibody response and the depression of cell-mediated immunity may result from the observed3-’ immunosuppressive activity of cytomegalovirus. PAOLA _ IANNETTI y-
Department I, University of Rome, C.N.R. Centre for Respiratory Viruses Rome 00161, Italy Paediatric
LUCIANO BALDUCCI LUISA BUSINCO MARIO MIDULLA
SUCCESSFUL CHEMOTHERAPY OF PINEALOMA
SIR,-Surgical excision of tumours of the pineal region is usually considered dangerous, and decompression or shunting followed by radiotherapy is usually preferred.l We know of no report of successful chemotherapy. A 27-year-old man was admitted because of headache and visual difficulties. Neurological examination revealed a vertical gaze palsy, small unreactive pupils, bilateral papilloedema, and a tendency to fall backwards on Romberg’s test. Computerised tomography (c.T.) showed a large tumour in the posterior part of the third ventricle with hydrocephalus. Malignant cells were seen
in the lumbar
After Torkildsen ventriculocisternal
IMMUNOTHERAPY FOR ACUTE MYELOGENOUS LEUKÆMIA
SIR,-We read with great interest the letter from Professor Galton and his colleagues (Nov. 5, p. 973) about remissionrates in acute myelogenous leukxmia (A.M.L.). We observed an increased frequency of second and subsequent remissions in patients receiving active immunotherapy6 and this has been confirmed by others as noted by Galton et al. The table shows the situation with regard to second and subsequent remissions IMMUNOTHERAPY IN A.M.L.: RESULTS OF MANCHESTER TRIALS
*Patients still being admitted. tFigures in parentheses show
(not randomised in trial
I). I=immunotherapy. C=chemotherapy. C.T.
patients receiving immunotherapy in Manchester according protocols described elsewhere.’ We still do not know why or to what extent immunotherapy is effective in A.M.L., but one of us has suggested8 that this could be due to a combination of factors including non-specific
stimulation of white-cell function. Our current trial in Manchester is designed to test immunotherapy used as a method for prolonging remission and favouring easy re-induction. This trial randomises patients to immunotherapy (without maintenance chemotherapy) or to no maintenance therapy. The results so far are also shown in the accompanying table. Department of Medical Genetics, University of Manchester, St. Mary’s Hospital Manchester M13 0JH
RODNEY HARRIS S. R. ZUHRIE
Midulla, M., Balducci, L., Iannetti, P., Businco, L., Rezza, E., Fois, A. Lancet, 1976, ii, 377. 3. Groshong, T., Horowitz, S., Lovchik, J., Davis, A., Hong, R. J. Pediat. 1976, 88, 217. 4. Schauf, V., Strelkauskas, A. J., Deveikis, A. Clin. exp. Immun. 1976, 26, 2.
478. P. A., Fiala, M., Schofferman, J., Byfield, P. E., Guze, L. B. Am. J. Med. 1977, 62, 413. 6. Freeman, C. B., Harris, R., Geary, C. G., Leyland, M. J., Maclver, J. E., Delamore, I. W. Br. med. J. 1973, iv, 571. 7. Harris, R., Zuhrie, S. R., Freeman, C. B., Taylor, G. M., Geary, C. G., Maclver, J. E., Delamore, I. W., Hull, P. J., Tooth, J. A. Br. J. Cancer (in the press). 8. Harris, R. Nature, 1973, 241, 95. 5.
patient with pinealoma. (a) Tumour in posterior part of third ventricle, and hydrocephalus. (b) After shunt and radiotherapy. (c) Recurrent tumour. (d) Decrease in size of tumour after one course of chemotherapy. scans
was given with a total of 4960 rad to the tumour area and 3000 rad to the spinal axis, over a period of 6 weeks. After this treatment the neurological signs cleared and follow-up c.T. showed that the tumour had become considerably smaller. 3 months later, the patient presented again with a typical Parinaud’s syndrome, and tumour recurrence was confirmed by C.T. Since germinoma is the predominant histological type in these tumoursz we decided to treat this case with drugs known to be efficient in testicular germ-cell tumours.3 Daunorubicin (’Adriamycin’) 100 mg and vincristine 2 mg intravenously were given on the first day and bleomycin 30 mg intravenously every day from the first to the third day. 7 days after the first course of chemotherapy, neurological examination was again normal. On c.T. the tumour size had decreased remarkably. 3 months later, neurological examination is still normal. Chemotherapy courses are repeated every 3-4 weeks according to haematological tolerance.
1. 2. 3.
De Girolami, U., De Schmidek, H. J. Neurosurg. 1973, 39, 455. Rubinstein, L. J. Tumors of the Central Nervous System. Armed Forces Institute of Pathology, Washington, 1972. Burgess, M. A., Einhorn, 1975, 17, 290.
H., Gottlieb, J. A. Proc. Am. Soc. clin. Oncol.