386 able to the inhibitory action of cyclic A.M.P. Cyclic A.M.P. is considered to be inhibitory, particularly to suppressor T cells,1O so increased sensitivity to cyclic A.M.P. should result in an imbalance between suppressor and helper T cells. A failing regulatory T-cell function might first affect the synthesis of IgE antibodies since this synthesis seems to be more dependent on T-cell regulation than is the formation of other immunoglobulins." The end-result will thus be overproduction of IgE (reaginic) antibodies and atopic disease. A vicious circle might be established because the manifestation of allergy is accompanied by histamine liberation and hence production of intracellular cyclic A.M.P. Atopic allergy is not invariably accompanied by hyperproduction of IgE. Atopic disease is really ultimately a consequence of the action of vasoactive amines, and it would be surprising if the chain of events described above were the only pathway for the development of atopic disease. However, our hypothesis would explain the features of the most usual forms of hereditarily determined, atopic hypersensitivity to common
allergens. Department of Virology, Institute of Medical Microbiology, University of Umeå; and Pædiatric Clinics, Universities of Göteborg and Umeå, Sweden
Ö. STRANNEGÅRD I.-L. STRANNEGÅRD
P. JUTO
TYRAMINE AND M.A.O. INHIBITORS IN POSTURAL HYPOTENSION
SIR,--The conclusions drawn by Dr Davies and his colleagues (Jan. 28, p. 172) concerning the use of tyramine and monoamine-oxidase inhibitors in the management of postural hypotension are unduly pessimistic, and may discourage a trial of this treatment in severely disabled patients. In the past two years four patients with severe orthostatic hypotension have been referred to this unit for consideration of treatment with the combination. All four patients were unable to stand without fainting. Three .patients had already been treated with fludrocortisone, postural training, and elastic stockings for several years without persistent benefit. After detailed tests of autonomic function the patients were given tranylcypromine, and the dose of tyramine was gradually adjusted to that which enabled each patient to remain standing for at least 5 min.’ Our practice was to keep each patient in bed in the morning until 15-30 min after the first dose of tyramine and to adjust the frequency of dosage depending on return of symptoms of postural hypotension. The last dose of tyramine was taken so that symptoms were again apparent before the patient went to bed at night. The three patients receiving the combination treatment have all been able to resume an upright posture at home, and two now leave their homes without fear of fainting. All are aware, and were warned before treatment, of the dangers of lying down after taking tyramine. Treatment has been continued for 5, 10, and 12 months, in the three patients and all continue to wear elastic stockings and take fludrocortisone. Mean sitting blood-pressure has risen from a pre-treatment level of 125/87 to 143/93 mm Hg, and mean standing blood-pressure is now 86/52 mm
Hg. The fourth patient responded to postural training and elastic support stockings, and this should always be tried before therapy with tyramine and monoamine-oxidase inhibitors. However, a trial of this drug therapy should not be denied patients with intolerable postural hypotension. M.R.C. Blood Pressure Unit, Western Infirmary, Glasgow G11 6NT 10. 1.
PATRICK M. TRUST
Teh, H.-S., Paetkau, V. Cell. Immun, 1976, 24, 220. Nanda, R. N., Johnson, R. H., Keogh, H. J.Lancet, 1976, ii, 1164.
CARDIORESPIRATORY ARREST IN DIABETIC NEUROPATHY
SIR,-The paper by Dr Page and Dr Watkins (Jan. 7, p. 14) prompts us to report a case. A 31-year old insulin-requiring diabetic female was admitted for nausea, vomiting, and dehydration. 5 years earlier she had had a hypophysectomy in an unsuccessful attempt to halt severe diabetic retinopathy. She was taking adequate amounts of thyroid and hydrocortisone. Her history showed no clear cause for the emesis, but was positive for both peripheral parsesthesia and diabetic autonomic neuropathy (orthostatic hypotension and abnormal sweating). She had hypotension (blood-pressure 80/40 mm Hg), normal heart and lungs, no evidence of gastrointestinal obstruction, much decreased sensation in the lower extremities with no peripheral reflexes, and a gag reflex. The intial diagnosis was either "’flu-like illness" or "gastroparesis diabeticorum". She was given large amounts of cortisol, and hydrated. She did very well; the emesis stopped, and she was about to be transferred from intensive care when she suddenly became apnceic while maintaining a palpable carotid pulse which subsequently disappeared. Her mouth and trachea were found to contain large amounts of stomach contents upon emergency endotracheal intubation. (Blood-sugar 30 min before the arrest had been 156 mg/dl.) She was easily resuscitated, but had moderately severe aspiration pneumonitis. She was vigorously treated with antibiotics and steroids with resolution of the aspiration pneumonitis. Electrocardiograms remained normal. 13 days after the "arrest" she was transferred from intensive care. We were unsure whether the "arrest" had been caused by or had caused the aspiration. Throughout the 13-days of inten-
sive-care, vomiting was not a problem.
patient had another cardiorespira(Blood-sugar 1 h earlier had been 180 mg/dl.) Again, aspiration occurred. She was successfully resuscitated; 1
tory
day
after transfer the
arrest.
however, the aspiration pneumonitis resulted in
severe
hypoxia, necessitating the use of a respirator with high oxygen concentration. Adult respiratory-distress syndrome developed and the patient died 26 days after her original admission. not clear what caused these cardiorespiratory The patient was in metabolic balance and had no evidence of significant cardiac or respiratory disease beforehand. At first we thought that the earlier episode was secondary to aspiration of gastric contents. Diabetics may have gastric retention’ and abnormal motor. oesophageal function,2 and the combination of these two disorders could have resulted in vomiting, though we knew of no reports of aspiration in diabetics. Diabetics can have vocal-cord paralysis.3 We could find no reports of aberrant epiglottal function. Dudley’ has shown that vagal denervation of the oesophagus in pigs can result in aspiration pneumonia. We therefore felt that perhaps aspiration had been the problem, and that we could explain the aspiration on the basis of diabetic autonomic neuropathy. We similarly explained the second cardiorespiratory arrest, although we were unsure whether the patient had vomited before or after the "arrest". This report provides an additional case of sudden death in a patient with diabetic autonomic neuropathy. As in the cases of Ewing et aJ.3 and Page and Watkins, we are unsure what caused the catastrophe. We agree that impairment of respiratory reflexes is an interesting possibility. What role might aspiration have played in the twelve cardiorespiratory arrests reported by these workers? Diabetics may have abnormal sweating patterns; might they also have an abnormal reflex response to small amounts of aspirated stomach contents?
We
are
arrests.
1. Kassandar, P. Ann. intern. Med. 1958, 48, 797. 2. Silber,W. Br. med J., 1969, iii, 688. 3 Rucente, E. F Ann Otolar. 1973, 82, 131. 4 Dudley, N. E. Aust.pœdiat. J. 1973, 9, 289. 5 Ewing, D. J., Campbell, I. W., Burt, A. A., Clarke, B. F. 1354
Lancet, 1973, ii,
387 Diabetic autonomic neuropathy remains a mysterious and bothersome complication of diabetes, which may be lethal. Division of Endocrinology and Metabolism, Santa Clara Valley Medical Center, San Jose, California 95128, U.S.A. and Division of Endocrinology,
A. PONT J. L. RUSHING T. KELSEY
Stanford University
L. JACOBS
INTESTINAL LYMPHOMA ASSOCIATED WITH MALABSORPTION
SiR.—The important paper by Dr Isaacson and Professor 14, p. 67) raises two questions--the identity of
Wright (Jan.
jejunal mucosa with lymphoma (only five of their eighteen patients had evidence of coeliac disease) and the possible relationship of their malignant histiocytosis to the abdominal lymphoma which is so common in the Middle East. In our review (unpublished) of twenty-seven patients with lymphoma and coeliac disease from one unit and under the care of one physician (W.T.C.) seventeen lymphomas developed in long-diagnosed coeliac disease. In contrast, the other ten had a flat jejunal mucosa demonstrated less than a year before the definitive diagnosis of malignant lymphoma was made and might well be classified by Isaacson and Wright as primary lymphoma with "malabsorption". However, two had had a the flat
significant clinical response to a gluten-free diet; three, including one with a sister whose coeliac jejunal mucosa responded morphologically to a gluten-free diet, had histories of a macrocytic anxmia and recurrent diarrhoea extending back 10 years or more; one had been diagnosed in childhood at the Birmingham Children’s Hospital before the advent of jejunal biopsy but had been well from adolescence to presentation with lymphoma at the age of 39; and one had had recurrent diarrhoea and failure to thrive in childhood although he had been well since adolescence. Three patients had no such evidence of codiac disease. Family studies’ have shown that asymptomatic codiac disease is not uncommon, and these three may well have had their symptoms unmasked by the onset of lymphoma. In our experience patients with lymphoma, malabsorption, and a flat jejunal mucosa often have pointers in their histories to long-standing but previously unrecognised coeliac disease. Thus, careful history taking is of paramount importance if such patients are to be properly identified. Isaacson and Wright offer few clinical data, so it is impossible to exclude codiac disease in any of their patients with lymphoma and a flat jejunal mucosa. Furthermore, their conclusion that all their patients had a characteristic malignant histiocytosis makes it more likely that their patients also had underlying codiac disease. The very low incidence of flat jejunal biopsies amongst patients with all types of malignancy would be in favour of this hypothesis. We agree with Isaacson and Wright that patients with flat jejunal mucosa, malabsorption, and lymphoma need careful study to determine whether there is pre-existing cceliac disease present, with careful histories from the patient and his relatives, HLA typing, family studies, and a trial of a gluten-free diet. However, in our experience by the time a lymphoma becomes clinically manifest, it is usually too late for a response to a
SLOWING OF CONDUCTION IN VISUAL PATHWAY IN HYPOTHYROIDISM
SIR,-In patients with hypothyroidism conduction in the peripheral nervous system is slowed’ but little is known about conduction in central-nervous-system pathways.2.3We have studied conduction in the visual pathway in hypothyroid patients before and after replacement therapy by measuring cortical-evoked potentials generated by pattern reversal.4 Eleven patients, seven females and four males aged 24-65, were studied. Patients with severe uncorrected refractive errors or other ocular disorders were not included. Hypothyroidism was diagnosed by clinical criteria and biochemistry (including serum-thyroxine, effective thyroxine ratio, and serum thyroid-stimulating hormone) and was due to Hashimoto’s disease (nine cases), hypophysectomy, or iodine -131 therapy. Evoked potentials were studied before or shortly after the start of thyroxine or triiodothyronine supplements. In five patients studies were repeated up to 6 months later when they were clinically and biochemically euthyroid. The technique is described elsewhere.5,6 The response is recorded from an active midline occipital electrode during bilateral monocular stimulation with a reversing black-andwhite chequerboard pattern. Data are collected and averaged over 125 cycles using a PDP 11/40 computer and subsequently analysed on a ’Tektronix 4010’ display terminal. Particular attention is given to the latency and amplitude of the major surface-positive component of the response (P2). The normal range for P2 latency in fifty controls aged 17-65 was 85-113 ms
(mean+2-5s.D.).
The P2 latency was initially at -the upper limit of or above of the normal range in seven cases (see figure). In four of these patients who were studied again after treatment with thyrox-
Scarpalezos, S., Lygidakis, C., Papageorgiou, C., Maliara, S., Koukoulommati, A. S., Koutras, D. A. Archs Neurol. 1973, 29, 140. 2. Vitová, Z., Kopecky, A., Faladová, L. Electroenceph. clin. Neurophysiol. 1.
1976, 41, 554 (abstr.). Cooper, R., Scarratt, D., Tallis, R., van’t Hoff, W. ibid. 1977, 43, 464 (abstr.). 4. Cobb, W. A., Morton, H. B., Ettlinger, G. Nature, 1967, 216, 1123. 5. Mastaglia, F. L., Black, J. L., Collins, D. W. K. Proc. Aust. Ass. Neurol. 1976, 13, 15. 6. Collins, D. W. K., Black, J. L., Mastaglia, F. L. J. neurol. Sci. (in the press). 3.
gluten-free diet.
Department of Medicine, Hammersmith Hospital, London W12
B. T. COOPER
Department of Medicine, Selly Oak Hospital, Birmingham 29
G. K. T. HOLMES
Latency of major positive component of V.E.P. (P2) in relation
W. T. COOKE
Each point represents the mean P2 value for the two eyes of one patient. The points joined by lines represent P2 values in patients studied before and after correction of hypothyroidism. The stippled area shows the normal limits for P2 latency and the vertical line the lower limit of the normal range for serum-thyroxine (55-104 nmol/1).
Nutritional and Intestinal Unit, General Hospital,
Birmingham 4
to
1. Stokes, P. L., Ferguson, R., Holmes, G. K. T., Cooke, W. T. Q. Jl Med. 1976, 45, 567.
serum-thyroxine.
allergens. Department of Virology, Institute of Medical Microbiology, University of Umeå; and Pædiatric Clinics, Universities of Göteborg and Umeå, Sweden
Ö. STRANNEGÅRD I.-L. STRANNEGÅRD
P. JUTO
TYRAMINE AND M.A.O. INHIBITORS IN POSTURAL HYPOTENSION
SIR,--The conclusions drawn by Dr Davies and his colleagues (Jan. 28, p. 172) concerning the use of tyramine and monoamine-oxidase inhibitors in the management of postural hypotension are unduly pessimistic, and may discourage a trial of this treatment in severely disabled patients. In the past two years four patients with severe orthostatic hypotension have been referred to this unit for consideration of treatment with the combination. All four patients were unable to stand without fainting. Three .patients had already been treated with fludrocortisone, postural training, and elastic stockings for several years without persistent benefit. After detailed tests of autonomic function the patients were given tranylcypromine, and the dose of tyramine was gradually adjusted to that which enabled each patient to remain standing for at least 5 min.’ Our practice was to keep each patient in bed in the morning until 15-30 min after the first dose of tyramine and to adjust the frequency of dosage depending on return of symptoms of postural hypotension. The last dose of tyramine was taken so that symptoms were again apparent before the patient went to bed at night. The three patients receiving the combination treatment have all been able to resume an upright posture at home, and two now leave their homes without fear of fainting. All are aware, and were warned before treatment, of the dangers of lying down after taking tyramine. Treatment has been continued for 5, 10, and 12 months, in the three patients and all continue to wear elastic stockings and take fludrocortisone. Mean sitting blood-pressure has risen from a pre-treatment level of 125/87 to 143/93 mm Hg, and mean standing blood-pressure is now 86/52 mm
Hg. The fourth patient responded to postural training and elastic support stockings, and this should always be tried before therapy with tyramine and monoamine-oxidase inhibitors. However, a trial of this drug therapy should not be denied patients with intolerable postural hypotension. M.R.C. Blood Pressure Unit, Western Infirmary, Glasgow G11 6NT 10. 1.
PATRICK M. TRUST
Teh, H.-S., Paetkau, V. Cell. Immun, 1976, 24, 220. Nanda, R. N., Johnson, R. H., Keogh, H. J.Lancet, 1976, ii, 1164.
CARDIORESPIRATORY ARREST IN DIABETIC NEUROPATHY
SIR,-The paper by Dr Page and Dr Watkins (Jan. 7, p. 14) prompts us to report a case. A 31-year old insulin-requiring diabetic female was admitted for nausea, vomiting, and dehydration. 5 years earlier she had had a hypophysectomy in an unsuccessful attempt to halt severe diabetic retinopathy. She was taking adequate amounts of thyroid and hydrocortisone. Her history showed no clear cause for the emesis, but was positive for both peripheral parsesthesia and diabetic autonomic neuropathy (orthostatic hypotension and abnormal sweating). She had hypotension (blood-pressure 80/40 mm Hg), normal heart and lungs, no evidence of gastrointestinal obstruction, much decreased sensation in the lower extremities with no peripheral reflexes, and a gag reflex. The intial diagnosis was either "’flu-like illness" or "gastroparesis diabeticorum". She was given large amounts of cortisol, and hydrated. She did very well; the emesis stopped, and she was about to be transferred from intensive care when she suddenly became apnceic while maintaining a palpable carotid pulse which subsequently disappeared. Her mouth and trachea were found to contain large amounts of stomach contents upon emergency endotracheal intubation. (Blood-sugar 30 min before the arrest had been 156 mg/dl.) She was easily resuscitated, but had moderately severe aspiration pneumonitis. She was vigorously treated with antibiotics and steroids with resolution of the aspiration pneumonitis. Electrocardiograms remained normal. 13 days after the "arrest" she was transferred from intensive care. We were unsure whether the "arrest" had been caused by or had caused the aspiration. Throughout the 13-days of inten-
sive-care, vomiting was not a problem.
patient had another cardiorespira(Blood-sugar 1 h earlier had been 180 mg/dl.) Again, aspiration occurred. She was successfully resuscitated; 1
tory
day
after transfer the
arrest.
however, the aspiration pneumonitis resulted in
severe
hypoxia, necessitating the use of a respirator with high oxygen concentration. Adult respiratory-distress syndrome developed and the patient died 26 days after her original admission. not clear what caused these cardiorespiratory The patient was in metabolic balance and had no evidence of significant cardiac or respiratory disease beforehand. At first we thought that the earlier episode was secondary to aspiration of gastric contents. Diabetics may have gastric retention’ and abnormal motor. oesophageal function,2 and the combination of these two disorders could have resulted in vomiting, though we knew of no reports of aspiration in diabetics. Diabetics can have vocal-cord paralysis.3 We could find no reports of aberrant epiglottal function. Dudley’ has shown that vagal denervation of the oesophagus in pigs can result in aspiration pneumonia. We therefore felt that perhaps aspiration had been the problem, and that we could explain the aspiration on the basis of diabetic autonomic neuropathy. We similarly explained the second cardiorespiratory arrest, although we were unsure whether the patient had vomited before or after the "arrest". This report provides an additional case of sudden death in a patient with diabetic autonomic neuropathy. As in the cases of Ewing et aJ.3 and Page and Watkins, we are unsure what caused the catastrophe. We agree that impairment of respiratory reflexes is an interesting possibility. What role might aspiration have played in the twelve cardiorespiratory arrests reported by these workers? Diabetics may have abnormal sweating patterns; might they also have an abnormal reflex response to small amounts of aspirated stomach contents?
We
are
arrests.
1. Kassandar, P. Ann. intern. Med. 1958, 48, 797. 2. Silber,W. Br. med J., 1969, iii, 688. 3 Rucente, E. F Ann Otolar. 1973, 82, 131. 4 Dudley, N. E. Aust.pœdiat. J. 1973, 9, 289. 5 Ewing, D. J., Campbell, I. W., Burt, A. A., Clarke, B. F. 1354
Lancet, 1973, ii,
387 Diabetic autonomic neuropathy remains a mysterious and bothersome complication of diabetes, which may be lethal. Division of Endocrinology and Metabolism, Santa Clara Valley Medical Center, San Jose, California 95128, U.S.A. and Division of Endocrinology,
A. PONT J. L. RUSHING T. KELSEY
Stanford University
L. JACOBS
INTESTINAL LYMPHOMA ASSOCIATED WITH MALABSORPTION
SiR.—The important paper by Dr Isaacson and Professor 14, p. 67) raises two questions--the identity of
Wright (Jan.
jejunal mucosa with lymphoma (only five of their eighteen patients had evidence of coeliac disease) and the possible relationship of their malignant histiocytosis to the abdominal lymphoma which is so common in the Middle East. In our review (unpublished) of twenty-seven patients with lymphoma and coeliac disease from one unit and under the care of one physician (W.T.C.) seventeen lymphomas developed in long-diagnosed coeliac disease. In contrast, the other ten had a flat jejunal mucosa demonstrated less than a year before the definitive diagnosis of malignant lymphoma was made and might well be classified by Isaacson and Wright as primary lymphoma with "malabsorption". However, two had had a the flat
significant clinical response to a gluten-free diet; three, including one with a sister whose coeliac jejunal mucosa responded morphologically to a gluten-free diet, had histories of a macrocytic anxmia and recurrent diarrhoea extending back 10 years or more; one had been diagnosed in childhood at the Birmingham Children’s Hospital before the advent of jejunal biopsy but had been well from adolescence to presentation with lymphoma at the age of 39; and one had had recurrent diarrhoea and failure to thrive in childhood although he had been well since adolescence. Three patients had no such evidence of codiac disease. Family studies’ have shown that asymptomatic codiac disease is not uncommon, and these three may well have had their symptoms unmasked by the onset of lymphoma. In our experience patients with lymphoma, malabsorption, and a flat jejunal mucosa often have pointers in their histories to long-standing but previously unrecognised coeliac disease. Thus, careful history taking is of paramount importance if such patients are to be properly identified. Isaacson and Wright offer few clinical data, so it is impossible to exclude codiac disease in any of their patients with lymphoma and a flat jejunal mucosa. Furthermore, their conclusion that all their patients had a characteristic malignant histiocytosis makes it more likely that their patients also had underlying codiac disease. The very low incidence of flat jejunal biopsies amongst patients with all types of malignancy would be in favour of this hypothesis. We agree with Isaacson and Wright that patients with flat jejunal mucosa, malabsorption, and lymphoma need careful study to determine whether there is pre-existing cceliac disease present, with careful histories from the patient and his relatives, HLA typing, family studies, and a trial of a gluten-free diet. However, in our experience by the time a lymphoma becomes clinically manifest, it is usually too late for a response to a
SLOWING OF CONDUCTION IN VISUAL PATHWAY IN HYPOTHYROIDISM
SIR,-In patients with hypothyroidism conduction in the peripheral nervous system is slowed’ but little is known about conduction in central-nervous-system pathways.2.3We have studied conduction in the visual pathway in hypothyroid patients before and after replacement therapy by measuring cortical-evoked potentials generated by pattern reversal.4 Eleven patients, seven females and four males aged 24-65, were studied. Patients with severe uncorrected refractive errors or other ocular disorders were not included. Hypothyroidism was diagnosed by clinical criteria and biochemistry (including serum-thyroxine, effective thyroxine ratio, and serum thyroid-stimulating hormone) and was due to Hashimoto’s disease (nine cases), hypophysectomy, or iodine -131 therapy. Evoked potentials were studied before or shortly after the start of thyroxine or triiodothyronine supplements. In five patients studies were repeated up to 6 months later when they were clinically and biochemically euthyroid. The technique is described elsewhere.5,6 The response is recorded from an active midline occipital electrode during bilateral monocular stimulation with a reversing black-andwhite chequerboard pattern. Data are collected and averaged over 125 cycles using a PDP 11/40 computer and subsequently analysed on a ’Tektronix 4010’ display terminal. Particular attention is given to the latency and amplitude of the major surface-positive component of the response (P2). The normal range for P2 latency in fifty controls aged 17-65 was 85-113 ms
(mean+2-5s.D.).
The P2 latency was initially at -the upper limit of or above of the normal range in seven cases (see figure). In four of these patients who were studied again after treatment with thyrox-
Scarpalezos, S., Lygidakis, C., Papageorgiou, C., Maliara, S., Koukoulommati, A. S., Koutras, D. A. Archs Neurol. 1973, 29, 140. 2. Vitová, Z., Kopecky, A., Faladová, L. Electroenceph. clin. Neurophysiol. 1.
1976, 41, 554 (abstr.). Cooper, R., Scarratt, D., Tallis, R., van’t Hoff, W. ibid. 1977, 43, 464 (abstr.). 4. Cobb, W. A., Morton, H. B., Ettlinger, G. Nature, 1967, 216, 1123. 5. Mastaglia, F. L., Black, J. L., Collins, D. W. K. Proc. Aust. Ass. Neurol. 1976, 13, 15. 6. Collins, D. W. K., Black, J. L., Mastaglia, F. L. J. neurol. Sci. (in the press). 3.
gluten-free diet.
Department of Medicine, Hammersmith Hospital, London W12
B. T. COOPER
Department of Medicine, Selly Oak Hospital, Birmingham 29
G. K. T. HOLMES
Latency of major positive component of V.E.P. (P2) in relation
W. T. COOKE
Each point represents the mean P2 value for the two eyes of one patient. The points joined by lines represent P2 values in patients studied before and after correction of hypothyroidism. The stippled area shows the normal limits for P2 latency and the vertical line the lower limit of the normal range for serum-thyroxine (55-104 nmol/1).
Nutritional and Intestinal Unit, General Hospital,
Birmingham 4
to
1. Stokes, P. L., Ferguson, R., Holmes, G. K. T., Cooke, W. T. Q. Jl Med. 1976, 45, 567.
serum-thyroxine.
