570 dominant
simply because, at the time of its inception, it was easier to purify and label the substance (e.g., insulin, thyroxine) than the reagent (anti-insulin antibody, thyroxine-binding globulin).
...
Labels other than radioactive isotopes can be used in either approach, but technical problems associated with nonradioactive labels such as enzymes and fluorophors deterred all but the most ardent methodologists. ELISA is one such method, exactly analogous to immunoradiometric assay, in which the specific reagent is labelled with a selected enzyme rather than with radioactivity. In comparing ELISA with R.I.A. it is important to distinguish between attributes of the labelled (or excess) reagent methods of the immunoradiometric genre and attributes of enzyme labels per se. The use of an enzyme label confers no specific analytical advantage. All the substances you referred to can be measured with equal (if not greater) sensitivity and precision, and with equal ease, by immunoradiometric assay. Immunoradiometric assays may ultimately replace many R.I.A.S, but your suggestion that enzyme labelling will replace radioisotopic techniques (particularly in assays demanding highest sensitivity) is much more questionable. In making this prediction you present a distorted picture of the logistic and financial disadvantages of radioactive techniques. For example, a simple but adequate manual radioisotope counter costs about 200; the major cost of conventional counting equipment is associated with the sample-changing and data-recording mechanisms-mechanisms which would be required in any automatic device whatever the signal detection system used. Moreover, the isotopes used for labelling represent a tiny part of the total cost of an assay, and the whole cost of radioactivity measurement (including equipment) is undoubtedly less than that of an enzyme assay technique, bearing in mind the additional chemical manipulations required. Although the radioactive reagents used in R.I.A. are often chemically unstable those used in immunoradiometric techniques are not. Thus, for example, we happily use a single preparation of 1251-labelled anti-rabbit y-globulin for six months or more (in an assay for T.s.H.). Finally, the hazards of radioactivity should not be exaggerated; they are much less (in this context) than those associated with the possible presence of hepatitis virus in samples under test. Enzyme labels entail increased sample manipulation, increased liability to extraneous, non-specific, chemical effects and to technical error, and represent an altogether more vulnerable and difficult end-point determination than the placing of a tube into a radioactive counter. For these reasons enzyme methods have not proved generally successful in the measurement of those substances which, because of their low concentration in biological fluids, demand the highest sensitivity and for which radioimmunoassay methods were originally and spe-
cifically designed. It would be foolish to
predict that radioactive techniques superseded or to suggest that non-radioactive immunological assay methods do not possess certain advantages that may make them logistically preferable in the measurement of certain substances or in certain special situations. But it would be quite wrong for your readers to be stampeded into selling their radioanalytical equipment or to anticipate the dawn of a new age in the measurement of biologically important substances merely in consequence of the birth of ELISA. will
never
be
Department of Nuclear Medicine, Middlesex Hospital Medical School, London W1N 8AA
ROGER EKINS
SIR,-Many readers experienced in laboratory medicine will to accept your prediction (Aug. 21, p. 406): "Enzyme immunoassays are expected to overtake radioimmunoassays within a few years". The time required to establish change in clinical laboratory practice is almost always underestimated. The transition from bioassays to colorimetric be unable
analysis for oestrogens took more than six years. Almost two years ago, another editorial’ stated "we shall see the rapid arplication [of cytochemistry] to the measurement of many hor mones for which radioimmunoassays do not exist or are unsatisfactory". The cytochemical assays referred to are not yet available even at national (special assay service) level. I believe that radioimmunoassay (R.I.A.) will continue as a useful and powerful tool for very many years to come--on account of its own potential which has not yet been fully realised. R.I.A. is not more expensive than enzyme-linked immunosorbent assay (ELISA) or enzyme-modified immunoassay technique (EMIT). In the rich developed world, radioisotopic immuno-type assays have already made a greater contribution to health delivery than has, for example, gas chromatography, Most types of enzyme-linked immunoassay, including ELISA, are not in competition with but are complementary to R.I.A. is well suited
ELISA
as a
positive/negative serological test for
large-scale antigen-antibody screening programmes-especially those of the poor world’s major infectious diseases which desperately need tackling. On the other hand, for the analysis of femtomole (10-15 mol) amounts of steroids, hormones, and so on to aid patient diagnosis and treatment there is only x.i.A. Since the scale of research expansion and application is much greater with R.I.A. than with ELISA, replacement of R.I.A. by ELISA seems unlikely for many years, if at all. Area
Laboratory, King Edward
VII
Hospital,
Windsor, Berkshire
D. WATSON
ISLET-CELL HYPERPLASIA AND SUDDEN INFANT DEATH
SIR,—We wish to present findings on a case of sudden unexdeath in a newborn infant which we believe may be relevant to the wider problem of sudden death in infancy, A female infant of 3360 g weight was born to a 28-year-old Hindu para 1 at 38 weeks’ gestation. The baby required no resuscitation at birth, was breast fed, and seemed well, apart from mild jaundice noted on the third day of life. At 80 h age (6.0 A.M.) the baby was found freshly dead lying face downin her cot, having been observed to be well 1½hpreviously. A coroner’s necropsy performed 3 days after death revealed congestion and oedema of the lungs: other organs including
pected
liver and pancreas appeared normal. Histological study confirmed the presence of congestion and focal alveolar hxmorrhage in the lungs and showed massive fatty infiltration in the liver. The major findings of interest, however, were in the pancreas. An apparent lack of normal islets in routine histological sections of the pancreas prompted further studies using granule stains (Gomori aldehyde fuchsin) and immunocytochemistry. These methods revealed extensive endocrine-cell proliferation with apparent budding off of endocrine cells from the ductule epithelium and widespread infiltration of the acinar tissue by groups and sheets of endocrine cells. The masses of endocrine tissue, which filled the centres of many lobules. superficially resembled normal islets but were characterised b their ill-defined and irregular outline. The extent of endocrine proliferation was only fully revealed by using immunocytochemical techniques. A very large number of beta cells, reacting specifically to antibodies to insulin, was observed in all sections studied, but groups of other cell types reacting to antibodies to glucagon, pancreatic polypeptide, somatostatin, and V.I.P. (vasoactive intestinal polypeptide) were present in all fields Quantitative estimation showed that endocrine tissue occupied 108% of the mean total area of the pancreatic sections. This is within the range (6-3-44-9%) seen in cases of nesidioblastosis2 and well outside that established by Heitz et al.3 for normal infants (1 - 5-3.4%). 1. Br.
med. J. 1974, ii,
128.
2. Polak, J. M., Adrian, T. E., Bryant, M. G., Bloom, S. R., Heitz, P. Pearse, A. G. E. Lancet, 1976, i, 328. 3. Heitz, P. U., Kloppel, G., Hacki, W. H., Polak, J. M., Pearse, A. G. E. Un
published.
571
probable that this child died as a result of an acute episode hypoglycaemia due to pancreatic islet-cell hyperplasia (nesidioblastosis). If our interpretation is correct it would seem that hyperinsulinism can present in the neonatal period as sudden death, without warning symptoms such as cvanotic attacks or convulsions. Studies of the vitreous humour from sudden infant deaths have shown unduly low glucose levels in a proportion of cases.4Furthermore, gross fatty infiltration of the liver, indicating an underlying metabolic abnormality, is found in up to 35% of cases of sudden infant death between the ages of 2 weeks and 2 years.’ Quite apart from hyperinsulinism such changes might be due to abnormalities of a variety of pancreatic and intestinal hormones which are known to cause profound metabolic disturbances.6 It seems
of
We believe that there is sufficient circumstantial evidence
justify urgent investigation of the possible role of pancreatic hormones in cases of sudden infant death.
to
gut and
Departments of Histochemistry and Pædiatrics,
Royal Postgraduate Medical School and Hammersmith Hospital, London W12
J. M. POLAK J. S. WIGGLESWORTH
DIAGNOSIS OF PYLORIC STENOSIS
SIR,—DR Freund and his colleagues (Aug. 28, p. 473) suggest light general anesthesia to diagnose suspected pyloric stenosis in infants if the tumour is not palpable. 6 out of 20
patients were so diagnosed in one year. In 19527 we reported a comparison between clinical and radiological diagnosis of the condition in a series of 160 vomiting infants, 75 of whom were found to have pyloric stenosis at operation. 73 (96%) were diagnosed clinically, the remaining 2 being confirmed radiologically. There were, however, two false positives amongst the 85 children with other conditions giving a clinical error of 2 3% in that direction. Of 60 babies fluoroscoped over that period 12 were found to have pyloric stenosis which was confirmed at operation. The other 48 had other conditions, and 1 was thought to have the radiological features of pyloric stenosis. Both clinician and radiologist had, at that time, only about five years of psediatric experience behind them, and these figures could well be improved on now. The clinical examination may indeed take twenty minutes and need occasionally to be repeated. The present day radiological examination may take half an hour but with intermittent screening and image intensification it involves no more radiation than an ordinary barium meal and is to a very limited area since attention is coned down strictly to the
pylorus. Our conclusion was then and remains: if a diagnosis cannot be reached after three full examinations during a feed and after a vomit or if the tumour is atypical, experienced radiological help should achieve an accuracy close to 100%. Children’s Hospital, Birmingham B16 8NT
R. ASTLEY B. WOOD
SIR,—The diagnosis of pyloric stenosis does not even require radiology, let alone the anaesthesia Dr Freund and his colleagues advocate. The only instrument required to diagnose this disease is the tip of the middle finger of the left hand others may prefer a different digit). Pyloric stenosis is unique in having a pathognomonic sign, the palpable tumour, which is present in every case, and it is mcorrect to say that it is palpable in only 70-90% of cases. It 4 Emery, J L. Personal communication. 5 Sinclair-Smith, C., Dmsdale, F., Emery, J. Archs Dis. Childh. 1976, 51, 424. 6. Bloom, S. R. Bri. med. Bull. 1974, 30, 62. 7 Astley, R., Wood, B. S. B. Br. J. Radiol. 1952, 25, 342.
is palpable in 100% of cases, not always, I admit, at the first attempt; but certainly in 90% at that stage, and in the remainder at the second or third examination. Broomyfields, Horseshoe Green, Mark Beech, Edenbridge, Kent
N.M. JACOBY
PSYCHOSIS IN PATIENT ON BROMOCRIPTINE AND LEVODOPA WITH CARBIDOPA
SIR,—Dr Kartzinel and his colleagues (Aug. 7, p. 272) reported that the addition of bromocriptine led to a significant reduction in the dose of Sine met’ (levodopa plus carbidopa) and levodopa required for the treatment of patients with idiopathic parkinsonism, with "similar" adverse reactions. I report here the development in one patient of a persistent paranoid schizophreniform psychosis occurring in temporal association with bromocriptine-sinemet treatment. The patient, a 47-year-old woman with a 5-year history of idiopathic parkinsonism and no previous overt psychiatric impairment, had been treated with 4 g/day levodopa (in conjunction with 5 mg of trihexyphenidyl twice a day and 100 mg of amantadine twice a day) before the substitution for levodopa of bromocriptine 25 mg four times a day. Between the sixth and ninth weeks after the institution of bromocriptine, levodopa in doses up to 1 -1g/day was added to the existing drug regimen because of bradykinesia and rigidity. 12 weeks after bromocriptine had been started, 125 mg of sinemet four times a day was substituted for the added levodopa, at which time also the patient’s legs were observed to be erythematous and she reported daily leg swelling and tenderness. 1 week after that bromocriptine was completely discontinued, and the dose of sinemet was increased to 250 mg four times a day. 2 days after this medication change, the patient began periodically to laugh hysterically without provocation, and within a week developed a paranoid psychosis requiring hospital admission. The patient’s psychosis was characterised by a pervasive, systematised paranoid delusional system and, initially, by auditory and possibly visual hallucinations, somatic delusions, inappropriate affect, and Capgras phenomenon’ (delusional belief that familiar persons have "doubles"). Laboratory studies
unremarkable; E.E.G., brain scan, and skull films normal; a search for metastases, because of a 9 kg weight
were
were
loss over the preceding year, was negative. A brief trial of thioridazine 200 mg a day was stopped because of marked exacerbation of parkinsonian symptoms; an adequate trial of amitriptyline 150 mg a day (because of depressive features) proved ineffective; 6 months of psychotherapy produced minimal change; electroconvulsive therapy could not be administered because of legal impediments. Minimisation of dosages of antiparkinsonian drugs (to 2 g of levodopa and 4 mg of trihexyphenidyl a day) resulted in no discernible psychiatric improvement. One year after its onset, the psychosis continues without remission.
Speculatively, bromocriptine may act as a partial dopamine agonist,2 the discontinuation of which may be followed by dopamine receptor hypersensitivity, a mechanism postulated for tardive dyskinesia, other movement disorders, levodopa and amphetamine induced psychoses,3 and akin to the "dopaminergic overactivity" hypothesised to be involved in the pathogenesis of schizophrenia.’However, the persistence of the psychosis suggests that more complex mechanisms are involved. The onset of a persistent paranoid psychosis in conjunction with discontinuation of bromocriptine and increased dosage of sinemet is of great concern; alteration of doses needs to be 1. 2. 3. 4. 5.
Merrin, E. L., Silberfarb, P. M. Archs gen. Psychiat. 1976, 33, 965. Dray, A., Oakley, N. R. J. Pharm. Pharmac. 1976, 28, 586. Klawans, H. L., Margolin, D. I. Archs gen. Psychiat. 1975, 32, 725. Horn, A. S., Snyder, S. H. Proc. natn. Acad. Sci. U.S.A. 1971, 68, 2325. Matthysse, S. Fedn Proc., 1973, 32, 200.
simply because, at the time of its inception, it was easier to purify and label the substance (e.g., insulin, thyroxine) than the reagent (anti-insulin antibody, thyroxine-binding globulin).
...
Labels other than radioactive isotopes can be used in either approach, but technical problems associated with nonradioactive labels such as enzymes and fluorophors deterred all but the most ardent methodologists. ELISA is one such method, exactly analogous to immunoradiometric assay, in which the specific reagent is labelled with a selected enzyme rather than with radioactivity. In comparing ELISA with R.I.A. it is important to distinguish between attributes of the labelled (or excess) reagent methods of the immunoradiometric genre and attributes of enzyme labels per se. The use of an enzyme label confers no specific analytical advantage. All the substances you referred to can be measured with equal (if not greater) sensitivity and precision, and with equal ease, by immunoradiometric assay. Immunoradiometric assays may ultimately replace many R.I.A.S, but your suggestion that enzyme labelling will replace radioisotopic techniques (particularly in assays demanding highest sensitivity) is much more questionable. In making this prediction you present a distorted picture of the logistic and financial disadvantages of radioactive techniques. For example, a simple but adequate manual radioisotope counter costs about 200; the major cost of conventional counting equipment is associated with the sample-changing and data-recording mechanisms-mechanisms which would be required in any automatic device whatever the signal detection system used. Moreover, the isotopes used for labelling represent a tiny part of the total cost of an assay, and the whole cost of radioactivity measurement (including equipment) is undoubtedly less than that of an enzyme assay technique, bearing in mind the additional chemical manipulations required. Although the radioactive reagents used in R.I.A. are often chemically unstable those used in immunoradiometric techniques are not. Thus, for example, we happily use a single preparation of 1251-labelled anti-rabbit y-globulin for six months or more (in an assay for T.s.H.). Finally, the hazards of radioactivity should not be exaggerated; they are much less (in this context) than those associated with the possible presence of hepatitis virus in samples under test. Enzyme labels entail increased sample manipulation, increased liability to extraneous, non-specific, chemical effects and to technical error, and represent an altogether more vulnerable and difficult end-point determination than the placing of a tube into a radioactive counter. For these reasons enzyme methods have not proved generally successful in the measurement of those substances which, because of their low concentration in biological fluids, demand the highest sensitivity and for which radioimmunoassay methods were originally and spe-
cifically designed. It would be foolish to
predict that radioactive techniques superseded or to suggest that non-radioactive immunological assay methods do not possess certain advantages that may make them logistically preferable in the measurement of certain substances or in certain special situations. But it would be quite wrong for your readers to be stampeded into selling their radioanalytical equipment or to anticipate the dawn of a new age in the measurement of biologically important substances merely in consequence of the birth of ELISA. will
never
be
Department of Nuclear Medicine, Middlesex Hospital Medical School, London W1N 8AA
ROGER EKINS
SIR,-Many readers experienced in laboratory medicine will to accept your prediction (Aug. 21, p. 406): "Enzyme immunoassays are expected to overtake radioimmunoassays within a few years". The time required to establish change in clinical laboratory practice is almost always underestimated. The transition from bioassays to colorimetric be unable
analysis for oestrogens took more than six years. Almost two years ago, another editorial’ stated "we shall see the rapid arplication [of cytochemistry] to the measurement of many hor mones for which radioimmunoassays do not exist or are unsatisfactory". The cytochemical assays referred to are not yet available even at national (special assay service) level. I believe that radioimmunoassay (R.I.A.) will continue as a useful and powerful tool for very many years to come--on account of its own potential which has not yet been fully realised. R.I.A. is not more expensive than enzyme-linked immunosorbent assay (ELISA) or enzyme-modified immunoassay technique (EMIT). In the rich developed world, radioisotopic immuno-type assays have already made a greater contribution to health delivery than has, for example, gas chromatography, Most types of enzyme-linked immunoassay, including ELISA, are not in competition with but are complementary to R.I.A. is well suited
ELISA
as a
positive/negative serological test for
large-scale antigen-antibody screening programmes-especially those of the poor world’s major infectious diseases which desperately need tackling. On the other hand, for the analysis of femtomole (10-15 mol) amounts of steroids, hormones, and so on to aid patient diagnosis and treatment there is only x.i.A. Since the scale of research expansion and application is much greater with R.I.A. than with ELISA, replacement of R.I.A. by ELISA seems unlikely for many years, if at all. Area
Laboratory, King Edward
VII
Hospital,
Windsor, Berkshire
D. WATSON
ISLET-CELL HYPERPLASIA AND SUDDEN INFANT DEATH
SIR,—We wish to present findings on a case of sudden unexdeath in a newborn infant which we believe may be relevant to the wider problem of sudden death in infancy, A female infant of 3360 g weight was born to a 28-year-old Hindu para 1 at 38 weeks’ gestation. The baby required no resuscitation at birth, was breast fed, and seemed well, apart from mild jaundice noted on the third day of life. At 80 h age (6.0 A.M.) the baby was found freshly dead lying face downin her cot, having been observed to be well 1½hpreviously. A coroner’s necropsy performed 3 days after death revealed congestion and oedema of the lungs: other organs including
pected
liver and pancreas appeared normal. Histological study confirmed the presence of congestion and focal alveolar hxmorrhage in the lungs and showed massive fatty infiltration in the liver. The major findings of interest, however, were in the pancreas. An apparent lack of normal islets in routine histological sections of the pancreas prompted further studies using granule stains (Gomori aldehyde fuchsin) and immunocytochemistry. These methods revealed extensive endocrine-cell proliferation with apparent budding off of endocrine cells from the ductule epithelium and widespread infiltration of the acinar tissue by groups and sheets of endocrine cells. The masses of endocrine tissue, which filled the centres of many lobules. superficially resembled normal islets but were characterised b their ill-defined and irregular outline. The extent of endocrine proliferation was only fully revealed by using immunocytochemical techniques. A very large number of beta cells, reacting specifically to antibodies to insulin, was observed in all sections studied, but groups of other cell types reacting to antibodies to glucagon, pancreatic polypeptide, somatostatin, and V.I.P. (vasoactive intestinal polypeptide) were present in all fields Quantitative estimation showed that endocrine tissue occupied 108% of the mean total area of the pancreatic sections. This is within the range (6-3-44-9%) seen in cases of nesidioblastosis2 and well outside that established by Heitz et al.3 for normal infants (1 - 5-3.4%). 1. Br.
med. J. 1974, ii,
128.
2. Polak, J. M., Adrian, T. E., Bryant, M. G., Bloom, S. R., Heitz, P. Pearse, A. G. E. Lancet, 1976, i, 328. 3. Heitz, P. U., Kloppel, G., Hacki, W. H., Polak, J. M., Pearse, A. G. E. Un
published.
571
probable that this child died as a result of an acute episode hypoglycaemia due to pancreatic islet-cell hyperplasia (nesidioblastosis). If our interpretation is correct it would seem that hyperinsulinism can present in the neonatal period as sudden death, without warning symptoms such as cvanotic attacks or convulsions. Studies of the vitreous humour from sudden infant deaths have shown unduly low glucose levels in a proportion of cases.4Furthermore, gross fatty infiltration of the liver, indicating an underlying metabolic abnormality, is found in up to 35% of cases of sudden infant death between the ages of 2 weeks and 2 years.’ Quite apart from hyperinsulinism such changes might be due to abnormalities of a variety of pancreatic and intestinal hormones which are known to cause profound metabolic disturbances.6 It seems
of
We believe that there is sufficient circumstantial evidence
justify urgent investigation of the possible role of pancreatic hormones in cases of sudden infant death.
to
gut and
Departments of Histochemistry and Pædiatrics,
Royal Postgraduate Medical School and Hammersmith Hospital, London W12
J. M. POLAK J. S. WIGGLESWORTH
DIAGNOSIS OF PYLORIC STENOSIS
SIR,—DR Freund and his colleagues (Aug. 28, p. 473) suggest light general anesthesia to diagnose suspected pyloric stenosis in infants if the tumour is not palpable. 6 out of 20
patients were so diagnosed in one year. In 19527 we reported a comparison between clinical and radiological diagnosis of the condition in a series of 160 vomiting infants, 75 of whom were found to have pyloric stenosis at operation. 73 (96%) were diagnosed clinically, the remaining 2 being confirmed radiologically. There were, however, two false positives amongst the 85 children with other conditions giving a clinical error of 2 3% in that direction. Of 60 babies fluoroscoped over that period 12 were found to have pyloric stenosis which was confirmed at operation. The other 48 had other conditions, and 1 was thought to have the radiological features of pyloric stenosis. Both clinician and radiologist had, at that time, only about five years of psediatric experience behind them, and these figures could well be improved on now. The clinical examination may indeed take twenty minutes and need occasionally to be repeated. The present day radiological examination may take half an hour but with intermittent screening and image intensification it involves no more radiation than an ordinary barium meal and is to a very limited area since attention is coned down strictly to the
pylorus. Our conclusion was then and remains: if a diagnosis cannot be reached after three full examinations during a feed and after a vomit or if the tumour is atypical, experienced radiological help should achieve an accuracy close to 100%. Children’s Hospital, Birmingham B16 8NT
R. ASTLEY B. WOOD
SIR,—The diagnosis of pyloric stenosis does not even require radiology, let alone the anaesthesia Dr Freund and his colleagues advocate. The only instrument required to diagnose this disease is the tip of the middle finger of the left hand others may prefer a different digit). Pyloric stenosis is unique in having a pathognomonic sign, the palpable tumour, which is present in every case, and it is mcorrect to say that it is palpable in only 70-90% of cases. It 4 Emery, J L. Personal communication. 5 Sinclair-Smith, C., Dmsdale, F., Emery, J. Archs Dis. Childh. 1976, 51, 424. 6. Bloom, S. R. Bri. med. Bull. 1974, 30, 62. 7 Astley, R., Wood, B. S. B. Br. J. Radiol. 1952, 25, 342.
is palpable in 100% of cases, not always, I admit, at the first attempt; but certainly in 90% at that stage, and in the remainder at the second or third examination. Broomyfields, Horseshoe Green, Mark Beech, Edenbridge, Kent
N.M. JACOBY
PSYCHOSIS IN PATIENT ON BROMOCRIPTINE AND LEVODOPA WITH CARBIDOPA
SIR,—Dr Kartzinel and his colleagues (Aug. 7, p. 272) reported that the addition of bromocriptine led to a significant reduction in the dose of Sine met’ (levodopa plus carbidopa) and levodopa required for the treatment of patients with idiopathic parkinsonism, with "similar" adverse reactions. I report here the development in one patient of a persistent paranoid schizophreniform psychosis occurring in temporal association with bromocriptine-sinemet treatment. The patient, a 47-year-old woman with a 5-year history of idiopathic parkinsonism and no previous overt psychiatric impairment, had been treated with 4 g/day levodopa (in conjunction with 5 mg of trihexyphenidyl twice a day and 100 mg of amantadine twice a day) before the substitution for levodopa of bromocriptine 25 mg four times a day. Between the sixth and ninth weeks after the institution of bromocriptine, levodopa in doses up to 1 -1g/day was added to the existing drug regimen because of bradykinesia and rigidity. 12 weeks after bromocriptine had been started, 125 mg of sinemet four times a day was substituted for the added levodopa, at which time also the patient’s legs were observed to be erythematous and she reported daily leg swelling and tenderness. 1 week after that bromocriptine was completely discontinued, and the dose of sinemet was increased to 250 mg four times a day. 2 days after this medication change, the patient began periodically to laugh hysterically without provocation, and within a week developed a paranoid psychosis requiring hospital admission. The patient’s psychosis was characterised by a pervasive, systematised paranoid delusional system and, initially, by auditory and possibly visual hallucinations, somatic delusions, inappropriate affect, and Capgras phenomenon’ (delusional belief that familiar persons have "doubles"). Laboratory studies
unremarkable; E.E.G., brain scan, and skull films normal; a search for metastases, because of a 9 kg weight
were
were
loss over the preceding year, was negative. A brief trial of thioridazine 200 mg a day was stopped because of marked exacerbation of parkinsonian symptoms; an adequate trial of amitriptyline 150 mg a day (because of depressive features) proved ineffective; 6 months of psychotherapy produced minimal change; electroconvulsive therapy could not be administered because of legal impediments. Minimisation of dosages of antiparkinsonian drugs (to 2 g of levodopa and 4 mg of trihexyphenidyl a day) resulted in no discernible psychiatric improvement. One year after its onset, the psychosis continues without remission.
Speculatively, bromocriptine may act as a partial dopamine agonist,2 the discontinuation of which may be followed by dopamine receptor hypersensitivity, a mechanism postulated for tardive dyskinesia, other movement disorders, levodopa and amphetamine induced psychoses,3 and akin to the "dopaminergic overactivity" hypothesised to be involved in the pathogenesis of schizophrenia.’However, the persistence of the psychosis suggests that more complex mechanisms are involved. The onset of a persistent paranoid psychosis in conjunction with discontinuation of bromocriptine and increased dosage of sinemet is of great concern; alteration of doses needs to be 1. 2. 3. 4. 5.
Merrin, E. L., Silberfarb, P. M. Archs gen. Psychiat. 1976, 33, 965. Dray, A., Oakley, N. R. J. Pharm. Pharmac. 1976, 28, 586. Klawans, H. L., Margolin, D. I. Archs gen. Psychiat. 1975, 32, 725. Horn, A. S., Snyder, S. H. Proc. natn. Acad. Sci. U.S.A. 1971, 68, 2325. Matthysse, S. Fedn Proc., 1973, 32, 200.
