ADRENERGIC BLOCKADE AND THE EYE SIGNS OF THYROTOXICOSIS

525

ADRENERGIC BLOCKADE AND THE EYE SIGNS OF THYROTOXICOSIS

J. M. SNEDDON B.Sc. Lond. RESEARCH ASSISTANT

PAUL TURNER M.D., B.Sc. Lond., M.R.C.P. SENIOR LECTURER IN CLINICAL PHARMACOLOGY AND WELLCOME SENIOR RESEARCH FELLOW IN CLINICAL SCIENCE

From the Medical Professorial Unit and Department of Pharmacology, St. Bartholomew’s Hospital, London E.C.1

EVIDENCE is accumulating that sympathetic blockade, and 3-adrenergic-receptor blockade in particular, may diminish the peripheral cardiovascular manifestations of thyrotoxicosis (Turner et al. 1965, Howitt and Rowlands 1966). Some uncontrolled observations by Buckfield and

Davis (1966) have suggested that p-adrenergic blockade with oral propranolol may produce improvement in the eye signs of thyrotoxicosis, but it is uncertain whether this involved changes in exophthalmos, besides lid retraction and lid lag. Lee et al. (1961) investigated the relationship between the ocular manifestations of thyroid disease and sympathetic nervous activity, and found that instillation of phentolamine into the conjunctival sac of three patients with thyrotoxic lid retraction produced significant improvement in only one. Conjunctival irritation and inflammation prevented further work with this drug. The availability for clinical investigation of ophthalmic preparations of guanethidine and propranolol has permitted a comparison of these agents in patients with eye involvement associated with thyrotoxicosis; and preliminary results of this study are given here. Patients and Methods Method The patients’ eyes were photographed in a small partitioned room with light-grey walls, and general illumination provided by an overhead light. Patients sat at a small table on which was mounted an ophthalmic head-rest against which they placed their heads to obtain constant and reproducible positions. Full-face illumination was provided by two variable-angle lamps with normal metal reflectors, containing two 40 W opaque-glass bulbs, 65 cm. from the head-rest and at the level of the patient’s eyes. This gave a constant illumination (deflection of 9-3 on a’Weston V’ light meter) which was not painful to the patient yet satisfactory for photography using Ilford’HPS ’ film at 1/60 second and f 5-6. Photographs were taken with a’Nikon F ’ single-lens reflex with 135 mm. lens mounted on a movable stand, 50 cm. from the head-rest. Patients focused on the lens aperture when the photographs were being taken. Measurement of Palpebral Fissure The photographic negatives were projected with anAldis’ projector on to a white wall to a final magnification of x 8. The palpebral fissure was taken as the distance between the upper and lower lid margins in the mid-pupillary plane and was measured from the projected photographs to the nearest millimetre. The mean and standard error of the mean of the palpebral fissure were calculated from the values obtained from all patients at the specific time interval. Patients Fourteen female patients were studied. Evidence of thyrotoxicosis was an elevated protein-bound iodine, raised 1311 uptake and clinical signs of lid lag and lid retraction with or without exophthalmos. During the period reported most patients had not yet received antithyroid therapy. Four were receiving carbimazole at a constant dose throughout the observation period, but the alleviation of the eye signs was

not

considered

primarily due to antithyroid therapy guanethidine drops.

but

as a

consequence of the

Results

Five patients took part in acute studies after application to the conjunctival sac of one drop of 10% guanethidine for 24 hours, and their response is that shown for day 1 in fig. 1. The remaining nine patients all received 10% guanethidine eye drops for 1 week or more, and in addition four of these have also received 1 ° propranolol for 1 week either before or after guanethidine (fig. 3).

Palpebral Fissure All patients exhibited signs of lid lag and lid retraction. Four to twelve photographs were taken of each patient. The appearance of the treated eye improved strikingly within 24 hours, with the development of ptosis and miosis. Subjectively most patients first reported that the treated eye was more " comfortable " with a rapid disappearance of the " grittiness " which was a complaint of all our patients with lid retraction. Within 2

mean decrease in palpebral fissure of one eye compared with pretreatment values in fourteen patients receiving guanethidine 10%, two drops twice daily. Each point represents the mean

Fig. 1- The

(±S.E.M.).

patients noted ptosis and the improved appearance of the treated eye. The results are expressed graphically in fig. 1, each point representing the mean of some sixty individual values obtained from nine patients. A reduction in the value of the average palpebral fissure by approximately 3 cm. represents a 20-25% reduction over the untreated values. Typical values for three patients are represented below (fig. 2). In two of the examples cited above (A and C) the untreated eye also improved. Results of a cross-over test between propranolol and guanethidine are shown in fig. 3. Two patients received propranolol for 1 week before guanethidine, and the other vice-versa. Propranolol produced variable results, and in the patient who received guanethidine first the ptosis gradually decreased during the period of propranolol treatment. Exophthalmos Besides the typical signs of lid lag and lid retraction, three patients exhibited exophthalmos. Striking clinical improvement with guanethidine was noted in all three and this was substantiated by exophthalmometry (Mr. J. H. Dobree). In one patient improvement in exophdays

most

o

526

thahnos and

palpebral fissure was reversed during a thyroid-suppression test involving administration of 30 µg. triiodothyronine four times a day for 6 days. At the end of the test, the improvement in exophthalmos and lid retraction was again noticeable. In one other patient with malignant exophthalmos propranolol produced no noticeable improvement after 1 week’s treatment, but a change to guanethidine was followed by a progressive decrease in the width of the palpebral fissure and decrease in exophthalmos. Side-effects No untoward side-effects were noted. Two patients exhibited conjunctival hyperæmia with guanethidine, but this disappeared with continued application of the drops. Miosis was present in all patients, but no visual disturbance was reported. Discussion These results indicate that local treatment of the thyrotoxic eye with 10% guanethidine is followed by improvement in lid retraction and lid lag, reducing the

fissure by as much as 20%. This accords with the view that these signs are mediated through the sympathetic nervous system, and may be abolished by sympathetic blockade. A similar response has been induced by intramuscular reserpine (Canary et al. 1957), and by oral guanethidine (Waldstein et al. 1964). These workers considered that proptosis was uninfluenced by therapy; our results of local treatment on this are also

palprebral

difficult has

to assess.

more

than

one

Thyrotoxic exophthalmos probably contributory cause and in its early

three patients to treatment with fissure of the treated eye is about 200,,.

Fig. 2-Response of

Fig. 3-Effect of propranolol 1% and guanethidine 10% on the palpebral fissure of one eye in three patients compared with pretreatment values. Patients A and B received propranolol one week before guanethidine, patient C guanethidine before propranolol. Each value represents the mean of ten readings, and S.E.M. is indicated.

sympathetic activity may be partly responsible, possibly through the muscle of Muller. In long-standing cases, however, organic and more permanent changes have taken place in the retro-orbital tissues, making it unlikely that autonomic blockade alone will produce much improvement. Garber (1966) and Werner (1966) have drawn attention to the possible role of local and stages

guanethidine 10%

in

one

eye for one week. The average

reduction in the

patpebrti

527

steroids in this condition. Nevertheless, in three of the patients whom we have investigated, there was a reduction in exophthalmos in the treated eye; and in one this was reversed when tri-iodothyronine was given in a diagnostic procedure. This suggests a close relationship between the thyroid hormone and sympathetic activity in the production of exophthalmos in this

systemic

patient. Although guanethidine eye-drops produce

a

fall in intraocular pressure, and have therefore been used in the treatment of glaucoma (Oosterhuis 1962), it is unlikely that this is the mechanism for improvement in exophthalmos, since raised intraocular pressure does not produce this sign. In healthy people, local guanethidine produces ptosis and miosis but no endophthalmos (Dorian and Schirmer 1964) in contrast to the features of

Homer’s syndrome. The improvement in the untreated eye in two patients is of special interest. This might be due to a direct action of guanethidine absorbed into the systemic circulation from the treated eye, but there was no other evidence for this in postural hypotension or throat irritation. A second possible explanation is that changes in the sympathetic control of one eye are associated with a change in that of the other to maintain an autonomic balance, and this is being investigated further. Similar effects have been noted by other workers. Garber (1966), using subconjunctival injections of methylprednisolone, noticed improvement in the untreated eye and Brain (1959) noticed a similar effect after unilateral orbital

by local treatment with 10% guanethidine eye drops. Local 1 % propranolol eye drops produce variable results. The effects of both treatments on exophthalmos were difficult to assess. No untoward side-effects were noted and it is felt that local guanethidine may have a place in the treatment of thyrotoxic patients who have eye signs. We thank the physicians of St. Bartholomew’s Hospital who allowed us to study their patients; Prof. E. F. Scowen for his guidance; Mr. J. H. Dobree for measuring the exophthalmos in our patients; and the staff of the photographic department. Guanethidine (’ Ismelin’) and propranolol (’Inderal’) eye drops were provided by Ciba Ltd., and Imperial Chemical Industries Ltd.,

respectively. Requests for reprints should be addressed to P. T., Medical Professorial Unit, St. Bartholomew’s Hospital, London E.C.I. REFERENCES

Black, J. W., Duncan, W. A. M., Shanks, R. G. (1965) Br. J. Pharmac. 25, 577. Brain, R. (1959) Lancet, i, 109. Buckfield, P. M., Davis, J. A. (1966) ibid. i, 1425. Canary, T. J., Schaaf, M., Duffy, B. J., Kyle, L. H. (1957) New Engl. J. Med. 257, 435. Cass, R., Spriggs, T. L. B. (1961) Br. J. Pharmac. 17, 442. Dorian, W., Schirmer, K. E. (1964) Can. med. Ass. J. 90, 932. Garber, M. J. (1966) Lancet, i, 958. Harris, W. S., Schoenfeld, C. D., Brooks, R. H., Weissler, A. M. (1966) Am. J. Cardiol 17, 484. Howitt, G., Rowlands, D. J. (1966) Lancet, i, 628. Lee, W. V., Mosimoto, R. K., Bronsky, D., Waldstein, S. S. (1961) J. clin. Endocr. Metab. 21, 1402. Oosterhuis, J. A. (1962) Archs Ophthal. 67, 802. Turner, P., Granville-Grossman, K. L., Smart, J. V. (1965), Lancet, ii, 1316.

Waldstein, S. S., West, G. M., Lee, W. Y., Bronsky, D. (1964) J. Am. med. Ass. 189, 609. Werner, S. C. (1966) Lancet, i, 1004.

decompression. The effect of propranolol in three patients was variable. one there was a significant effect, but this was small compared with that of guanethidine in the same patient. This may be due to better absorption of guanethidine across the conjunctival membrane, or it may reflect the complexity of x andadrenergic receptor distribution and their activity in the infraorbital and supraorbital muscles. Whereas guanethidine, by depleting the sympathetic neurone of catecholamines, deprives both types of receptor of their humoral transmitter (Cass and Spriggs 1961), propranolol blocks the -receptors alone, allowing a-receptor activity to continue in response to released transmitter (Black et al. 1965)). Probably x-adrenergic activity is increased in man by the absence of ;-activity (Harris et al. 1966). Unfortunately, no x-receptor-blocking drug is available in a preparation suitable for local application to the eye. Phentolamine was used by Lee et al. (1961) in three patients but produced improvement in only one. But since this drug has only a weak oc-blocking action, the significance of this observation is open to doubt. Lid retraction, lid lag, and stare (especially when unilateral) are often the source of considerable embarrassment to thyrotoxic patients, and we suggest that the local application of guanethidine has a place in their treatment. Used at a concentration of 10%, untoward side-effects were not noted, and patients were relieved of the unpleasant gritty " sensation which often accomIn

"

panies early exophthalmos. Further studies of guanethidine and propranolol in thyrotoxicosis may decide whether the eye signs are the result of changes in sympathetic transmitter release, or in the number or sensitivity of the receptors. Their role in the treatment of early exophthalmos is also being investigated.

Summary

Thyrotoxic

lid retraction and lid

lag

may be abolished

ELECTRON MICROSCOPY IN THE RAPID DIAGNOSIS OF SMALLPOX

J. G. CRUICKSHANK M.A.

Cantab., M.B. Lond.

H. S. BEDSON Lond., M.R.C.P.

M.D.

SENIOR LECTURER

LECTURER

D. H. WATSON Glasg., A.R.I.C.

Ph.D.

SENIOR RESEARCH

FELLOW, MEDICAL RESEARCH COUNCIL VIRUS RESEARCH GROUP

From the

Department of Virology

and

Bacteriology,

University of Birmingham IN any outbreak of smallpox there is a clear need for a rapid, simple, and reliable laboratory test to differentiate between smallpox, chickenpox, and rashes due to other The tests in current use are not completely causes. satisfactory and often, especially in cases of chickenpox, the diagnosis is left in doubt until the results of egg culture are known some 48-72 hours later. We have found that electron microscopy has an important role to play and can rapidly provide a correct positive diagnosis in a very high proportion of patients with smallpox or

chickenpox. microscope was first used in the diagnosis of smallpox by van Rooyen and Scott (1948). Although at that time it was shown that virus particles could be identified in specimens from a variety of clinical conditions (Nagler and Rake 1948, Evans and Melnick 1949), it is only comparatively recently that advances in technique have made the electron microscope a satisfactory tool for routine diagnostic use. Osmium-fixation methods were used with success by Peters et al. (1962) in the West German outbreak of variola major. Our own experience in an outbreak of variola minor (Gordon et al. 1966) suggests that negative-staining methods may be even The electron