EFFECT OF ADRENERGIC RECEPTOR BLOCKADE ON THE TACHYCARDIA OF THYROTOXICOSIS AND ANXIETY STATE

1316 but their frequency of occurrence is lower than in the diabetics. Abnormal physical signs become more common with age in both series. It is suggested that impaired vibration and position sense and a reduced ankle-jerk are indicative of vascular degeneration whereas severe neuropathic pain with or without muscular wasting and weakness is associated with uncontrolled diabetes. Under the general term of diabetic neuropathy there appear to be at least two types which are of different astiology. This work was done while I was employed by the United Birmingham Hospitals as a research fellow. I thank Dr. J. M. Malins and Dr. M. G. FitzGerald, who helped me throughout. The control

patients came from the practices of Dr. L. Pike and Dr. D. L. Crombie, who were most cooperative. Miss Mary Wall of the Regional Hospital Board interpreted the statistical significance of the data obtained.

TABLE I-CLINICAL AND LABORATORY DATA ON

amylobarbitone sodium 62.5mg. A determined by electrocardiogram for 5 minutes before and 10 minutes after each injection and from the radial pulse at hourly intervals for 6 hours.

phentolamine

5 mg., and

resting-heart-rate

REFERENCES

Bouchardat, A. (1883) De la Glycosurie ou Diabète Sucré; vol. 2. Paris. College of General Practitioners (1962) Br. med. J. i, 1497. Critchley, M. (1931) Lancet, i, 1119. Jordan, W. R. (1936) Archs intern. Med. 57, 307. Matthews, J. D. (1955) Lancet, i, 474. Melander, R. (1931) Acta med. scand. 74, 396. Rundles, R. W. (1945) Medicine, Baltimore, 24, 111. Sevringhaus, E. L. (1931) Am. J. med. Sci. 182, 311.

EFFECT OF ADRENERGIC RECEPTOR BLOCKADE ON THE TACHYCARDIA OF THYROTOXICOSIS AND ANXIETY STATE PAUL TURNER M.D., B.Sc. Lond., M.R.C.P. WELLCOME

SENIOR

RESEARCH

FELLOW

IN

CLINICAL

SCIENCE

AND

LECTURER IN PSYCHIATRY

ST.

MEDICAL PROFESSORIAL UNIT, BARTHOLOMEW’S HOSPITAL, E.C.1

J. V. SMART OF

B.Sc. St. And., F.S.S. THE DEPARTMENT OF STATISTICS, RESEARCH AND DEVELOPMENT DIVISION, SMITH KLINE AND FRENCH LABORATORIES,

was

Results

The results

are shown graphically in the accompanying were subjected to an analysis of variance They figure. which demonstrated that there were no differ(table ill) ences between patients with thyrotoxicosis and anxiety but that a significant difference existed between patients within each group. There was a significant difference as expected, between drugs, but not between days. Applying the t test to these results, there was no significant difference between the effect of amylobarbitone sodium and physiological saline solution in either condition. There was a significant fall in pulse-rate after propranolol and rise after phentolamine in both conditions, but no significant difference in these responses as measured by the interaction-conditions x times x drugs.

Discussion

LECTURER IN CLINICAL PHARMACOLOGY

K. L. GRANVILLE-GROSSMAN * M.D. Lond., M.R.C.P., D.P.M.

8 THYROTOXIC PATIENTS

These results demonstrate that beta-adrenergicreceptor blockade by propranolol produced a significant fall in heart-rate of patients with thyrotoxicosis. This is at variance with the observations of Wilson et al. (1964) but the reason for this is obscure. There is little doubt that they achieved effective blockade with pronethalol as demonstrated by inhibition or notable attenuation of the TABLE

II-SERUM-PROTEIN-BOUND

IODINE

OF

8

PATIENTS

WITH

ANXIETY STATES

WELWYN GARDEN CITY, HERTFORDSHIRE

adrenergic stimulation in producing the haemodynamic changes of thyrotoxicosis is still controversial. Studies of adrenergic and catecholamine blockade in hyperthyroid states (Brewster et al. 1956, Canary et al. 1957, Gaffney et al. 1961, Lee et al. 1962, Goldstein and Killip 1965) suggest that it may The study by Wilson et al. be very important. (1964) does not support this hypothesis, however. The introduction of specific alpha and beta adrenergic receptor blocking drugs has made possible a more detailed study of the part these receptors play both in thyrotoxicosis and in anxiety states. This paper presents the results of such an investigation, which in addition attempted to determine if these conditions could be differentiated by their response to such agents and to amylobarbitone THE role of

sodium. Patients and Methods 16 patients who had a resting-pulse-rate of 96 per minute or greater, were studied. 8 had proven thyrotoxicosis (table i) and 8 had an anxiety state without evidence of an organic basis for their tachycardia (table n). In a latin-square sequence and a double-blind procedure each patient was given, on 4 consecutive days, an intravenous injection over 1 minute of 5 ml. of physiological saline solution, propranolol 5 mg., * Present address: Queen Elizabeth II Hospital, Welwyn Garden City, Hertfordshire.

III-ANALYSIS OF VARIANCE SHOWING EFFECTS DUE TO DIFFERENCES BETWEEN PATIENTS, CONDITIONS, DAYS, TREATMENTS, AND TIMES WITHIN DAYS WITH THEIR RELEVANT INTERACTIONS

TABLE

1317

normal increase in heart-rate and cardiac output during infusions of isoprenaline. Although propranolol may be effective where pronethalol is not, it is more likely that wide differences exist in the extent of adrenergic activity in thyrotoxic patients and that these variations in response result from sampling-error. This is consistent with the fact that in our series of thyrotoxic patients, the response That " hyperto propranolol showed great variation. thyroidism " may represent a continuum of disorders from neurocirculatory asthenia at one extreme to the fully developed syndrome of Graves’ disease at the other has been argued for many years (Moschowitz 1930) and it would seem reasonable to postulate that adrenergic activity varies along this continuum. In clinical studies the hypersensitivity of thyrotoxic patients to adrenaline has been demonstrated (Rosenblum et al. 1933, Peltola 1951, Schneckloth et al. 1953) while in dogs Brewster et al. (1956) abolished both the cardiovascular and metabolic manifestations of experimental hyperthyroidism by interrupting sympathetic activity with a high epidural block. There is still no convincing evidence, however, of increased catecholamine production in thyrotoxicosis, and it may be that the enhancement of sensitivity to catecholamines by thyroxine is as important as an increase in sympathetic activity. Our results, nevertheless, indicate that the tachycardia in this condition can be largely if not completely abolished by beta-adrenergic blocking and thus confirm the observations of Gaffney et al. (1961) that guanethidine, which selectively interrupts adrenergic reflexes and depletes tissue catecholamines, abolished the tachycardia, palpitations, and tremor induced in 4 healthy individuals by tri-iodothyronine. In spontaneous hyperthyroidism, guanethidine has been shown to depress the hyperkinetic circulation similarly (Goldstein and Killip 1965). Canary et al. (1957) achieved similar results using reserpine and demonstrated by means of radio-iodine uptake and serum-protein-bound iodine that the hyper-

thyroid

state

manifestations

persisted, were

even

though

the

peripheral

controlled.

The

changes in heart-rate in anxious patients after propranolol are to be expected on the hypothesis that emotions are expressed through the autonomic nervous system (Cannon 1929) and from the demonstration that affective disturbance is associated with evidence of increased catecholamine output (Elmadjian et al. 1957, Zuidema et al. 1957, Regan and Reilly 1958). The magnitude of the effect suggests that propranolol might have a place in the treatment of anxiety. We are at present investigating its therapeutic effect in outpatients after preliminary studies suggested that several subjective symptoms relating to the cardiovascular system were improved by propranolol. Bollinger (1965) has already demonstrated, with a step test, that a reduced workingcapacity in cases of tachycardia of central nervous origin, became normal after beta-receptor blockade with propranolol, while Besterman and Friedlander (1965) described 4 patients with effort syndrome whose palpitations and tachycardia were notably improved by the

drug. Although not sufficiently notable to be of diagnostic importance, it seems that patients with an anxiety state show a greater response to alpha and beta adrenergic receptor blockade than do thyrotoxic patients in that there is a greater fall in heart-rate after propranolol and rise after phentolamine (see accompanying figure). There are several possible reasons for this. It may be that this simply represents a greater general sympathetic activity in the anxiety state, and that blockade of either alpha or beta This is receptors produces a more striking effect. consistent with the observation that there was a positive correlation (r=0-590) between the anxious patients’ responses to propranolol and to phentolamine which was not found in the thyrotoxic patients (r= — 0-125). Alternatively, it may be argued that thyrotoxic patients are already

Effect on heart-rate of propranolol 5 mg., phentolamine 5 mg., amylobarbitone sodium 62 mg. and physiological saline solution 5 ml. in patients with thyrotoxicosis and anxiety states. Each point represents the mean of observations in 8 patients.

1318 in a state of peripheral vasodilatation and that phentolamine might not therefore be expected to produce such obvious effect as in other patients. It is of interest, however, that the upper limit of the tachycardia after phentolamine was greater in the anxious than in the thyrotoxic patients, which would not be expected if this were the only factor involved. It may be that the thyrotoxic patients have partially adjusted to their state of peripheral vasodilatation by homeostatic mechanisms, and that the further vasodilatation produced by phentolamine, both directly and indirectly by adrenergic blockade (Taylor et al. 1965a and b) does not elicit such a notable reflex tachycardia as in other patients. This must, be as however, regarded tentative, since analysis of variance did not show that these differences were significant at the 5% level. Amylobarbitone sodium did not produce a significant change in heart-rate of either thyrotoxic or anxious patients. This is suprising since it is known to be effective in relieving at least some of the symptoms of anxiety (Scott 1955, Raymond et al. 1957, Robin 1959, Wing and Lader 1965) and in correcting the associated objective abnormalities of respiration (Coppen and Mezey 1960) and of habituation of the psychogalvanic reflex (Wing and Lader 1965). The mode of administration may be important, however, since these effects were noted on patients who had been taking the drug by mouth for some days. One of our anxious patients showed a response IO amylobarbitone sodium reminiscent of abreaction and it may be that the emotional arousal induced by intravenous administration masks such slowing of the heart as has been reported by Dicker and Steinberg (1957) with oral

barbiturate.

Summary The effects of

adrenergic-receptor-blocking agents and of amylobarbitone sodium on the sinus tachycardia of 8 thyrotoxic patients and of 8 patients with anxiety states are

described.

A sustained fall of heart-rate was noted after propranolol, a transient rise after phentolamine, but the effect of amylobarbitone sodium did not differ from that of physiological saline solution. The response of thyrotoxic patients could not be differentiated from those of patients with anxiety states. The results suggest that in both conditions the stimulation of beta-adrenergic receptors is important in the production of the tachycardia and that blocking agents such as propranolol may be useful in their treatment. We thank Prof. E. F. Scowen and Dr. W. Linford Rees for their continued encouragement and the physicians of St. Bartholomew’s Hospital who allowed us to study their patients. Requests for reprints should be addressed to Dr. Paul Turner, Medical Professorial Unit, St. Bartholomew’s Hospital, London, E.C.!. REFERENCES

Besterman, E. M. M., Friedlander, D. H. (1965) Post-grad. med. J. 41, 526. Bollinger, A. (1965) Schweiz. med. Wschr. 95, 1075. Brewster, W. R., Isaacs, J. P., Osgood, P. A., King, T. L. (1956) Circulation, 13, 1. Canary, J. J., Schaaf, M., Duffy, B. J., Kyle, L. H. (1957) New Engl. J. Med. 257, 435. Cannon, W. B. (1929) Bodily Changes in Pain, Hunger, Fear and Rage. New York.

Coppen, A. J., Mezey, A. G. (1960) J. psychosom. Res. 5, 52. Dicker, S. E., Steinberg, H. (1957) Br. J. Pharmac. Chemother. 12, 479. Elmadjian, F., Hope, J. M., Lawson, E. T. (1957) J. clin. Endocr. Metab. 17, 608. Gaffney, T. E., Braunwald, E., Kahler, R. L. (1961) New Engl. J. Med. 265, 16. Goldstein, S., Killip, T. (1965) Circulation, 31, 219. Lee, W. Y., Bronsky, D., Waldstein, S. S. (1962) J. clin. Endocr., Metab. 22, 879. Moschowitz, E. (1930) Archs intern. Med. 46, 610. Peltola, P. (1951) Acta. med. scand. suppl. 262, 34.

ENCEPHALITIS AFTER THE REDUCTION OF STEROID MAINTENANCE THERAPY M. R. CROMPTON M.D., Ph.D. Lond., M.C.Path. SENIOR LECTURER IN NEUROPATHOLOGY AND HONORARY CONSULTANT NEUROPATHOLOGIST

M.D.

R. D. TEARE Cantab., F.R.C.P., F.C.Path., D.M.J.

READER IN FORENSIC MEDICINE AND CONSULTANT PATHOLOGIST

ST.

GEORGE’S

HOSPITAL MEDICAL

SCHOOL, LONDON, S.W.1

THIS is a short report of the findings in two patients who died from an acute necrotising encephalitis after abrupt and large reduction in steroid maintenance therapy. We emphasise the neuropathological findings which suggest that the herpes-simplex virus was probably the causal agent in both cases.

Case-reports Case 1 A girl, aged 3 years 10 months, in whom Still’s disease had been diagnosed 13 months before her final admission. She had originally been maintained on 10 mg. prednisolone three times a day. Progressive anxmia developed and she was admitted to hospital, 10 months after the original diagnosis, for bloodtransfusion. She was readmitted 1 month later for investigation of proteinuria and was treated with ampicillin. Prednisolone reduced from 30 mg. a day to 4 mg. a day, and 83 mg. chloroquine daily was also given. This new regimen only just kept her joint pains under control. 7 weeks later, she was lethargic, and had a fever. 4 days was

after this her eyes deviated to the left and there was weakness of, at first, the left arm and then of the left leg. On admission to the Atkinson Morley’s Hospital under Mr. A. E. Richardson, 3 days later, she was semiconscious and dysphasic. Lumbar puncture showed no abnormality, but electroencephalography showed enormous slow waves on both sides, especially on the right-a finding which was thought to be compatible with an encephalitis. Her hxmoglobin was 66%, white-blood-cell count 24,000 cells per c.mm., and erythrocytesedimentation rate 95 mm. in the lst hour (Westergren). Ultrasonography and ventriculography were normal. Twitching of the whole of the left side developed, but this responded to 50 mg. hydrocortisone intravenously. The patient was treated with blood-transfusions, antibiotics, and steroids. An X-ray of the chest shortly before death showed pulmonary consolidation on the left. She remained unconscious until death 17 days after the start of her final illness.

Necropsy The general necropsy revealed a lobar type of pneumonia involving most of the left lung, together with a fibrinous pericardial effusion. The brain showed no significant external abnormality. After the brain had been fixed for 2 weeks in 20% formol/saline solution the cut surface showed a rather punctate appearance of a greyish perivascular abnormality in the head of the caudate nuclei and the thalamus on

Raymond, M. J., Lucas, C. J., Beesley, M. L., O’Connell, B. A., FraserRoberts, J. A. (1957) Br. med. J. ii, 63. Regan, P. F., Reilly, J. (1958) J. nerv. ment. Dis. 127, 12. Robin, A. A. (1959) J. ment. Sci. 105, 1064. Rosenblum, M. H., Hahn, R. G., Levine, S. A. (1933) Archs intern. Med.

51, 279. Schneckloth, R. E., Kurland, G. S., Freedberg, A. S. (1953) Metabolism, 2, 546. Scott, P. A. L. (1955) J. ment. Sci. 101, 163. Taylor, S. H., MacKenzie, G. J., M., McDonald, A. (1965a) Br. Heart J. 27, 627. Sutherland, G. R., MacKenzie, G. J., Staunton, H. P., Donald, K. W. (1965b) Clin. Sci. 28, 265. Wilson, W. R., Theilen, E. O., Fletcher, F. W. (1964) J. clin. Invest. 43, 1697. Wing, L., Lader, M. H. (1965) J. Neurol. Neurosurg. Psychiat. 28, 78. Zuidema, G. D., Silverman, A. J., Cohen, S. I., Goodall, M. (1957) New Engl. J. Med. 256, 976. -