1227
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-
been
needed in future. Cimetidine is a major advance in the therapy of peptic-ulcer diseases. Reports of well-documented side-effects with this
drug
are
welcome, but speculations need be viewed with
cau-
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
He had
a
electrocardiogram at the beginning of days later his heart-rate was 57/min. On the
normal
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
Six,=The
treatment
of metastatic breast
cancer
with
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
R., 1.
Yanagisawa, N., Toyokura, Y., Shiraki, H. Acta neuropath. (Berl.) 1975, 33, 153.
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-
been
needed in future. Cimetidine is a major advance in the therapy of peptic-ulcer diseases. Reports of well-documented side-effects with this
drug
are
welcome, but speculations need be viewed with
cau-
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
He had
a
electrocardiogram at the beginning of days later his heart-rate was 57/min. On the
normal
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
Six,=The
treatment
of metastatic breast
cancer
with
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
R., 1.
Yanagisawa, N., Toyokura, Y., Shiraki, H. Acta neuropath. (Berl.) 1975, 33, 153.
