ENDOCRINE ACTIVITY IN MULTIPLE SCLEROSIS

64

normal. Therefore, in hypertensive patients on benzothiadiazine diuretics, with 120-minute blood-sugar levels of above 200 mg. per 100 ml., it would seem possible that the diuretic contributes to an inhibition of insulin release. Potassium will decrease the acute hyperglycasmic effects of the benzothiadiazines (Wolff and Parmley 1964) and carbohydrate intolerance is common in patients with

hypertension and hypokalxmia (Conn 1965). The serumpotassium was measured within 8 months before the detection of diabetes in all twelve patients. The lowest value was 3-6 mEq. per litre and the average was 4-1mEq. per litre. We realise that the serum-potassium may not reflect the total exchangeable potassium, and that a considerable total potassium deficit may exist in the presence of a normal serum-potassium. Five of the twelve patients were receiving supplementary potassium by mouth, but Rapoport and Hurd (1964) suggested that potassium supplements seemed to improve carbohydrate tolerance that had deteriorated on benzothiadiazines. The finding that frusemide caused a slight further impairment of glucose tolerance and a rise in seruminsulin contrasts with the findings of Jackson and Nellen (1966), who found no such deterioration in nineteen moderately hypertensive patients treated with frusemide for 3 months. But these workers found that the levels of serum-insulin did not rise when measured during a G.T.T. This observation does not yield evidence about the diabetogenic activity of frusemide in previously untreated patienxs but does suggest that it is not a suitable alternative for patients who have developed diabetes while on

hydrochlorothiazide. We thank Dr. Ruth Haslam of the department of chemical pathology for estimation of blood-sugars and Dr. Harry Keen and Miss M. Whichelow of Guy’s Hospital for making available glucose-tolerancetest data from the random sample of the Bedford population.

ENDOCRINE ACTIVITY IN MULTIPLE SCLEROSIS GRAHAM M. TEASDALE M.B. Durh., M.R.C.P. RESEARCH ASSISTANT

Ph.D. Durh.

M.B. Durh.

SENIOR HOSPITAL BIOCHEMIST

SENIOR HOUSE-OFFICER

A. L. LATNER M.D., D.Sc. Lpool, F.R.C.P., F.C.Path. PROFESSOR OF CLINICAL BIOCHEMISTRY

HENRY MILLER Durh., F.R.C.P.

M.D.

PROFESSOR OF NEUROLOGY

From the

Departments of Neurology and Clinical Biochemistry, Royal Victoria Infirmary, Newcastle upon Tyne 1

THERE is clinical evidence of a role for stress in the initiation of exacerbations of multiple sclerosis and for the beneficial therapeutic effects of corticotrophin in acute lesions. We have investigated aspects of endocrinological activity in twenty-one patients with multiple sclerosis, none of whom was severely disabled. Spontaneous adrenal activity, as assessed by urinary steroid estimations and plasma-hydrocortisone levels, was normal in the whole group, and patients with recent acute deterioration had normal values for plasmahydrocortisone and hydrocortisone-secretion rate. Adrenal reserve, as assessed by the response of plasma-hydrocortisone to corticotrophin, was adequate. The stress of insulin-induced hypoglycæmia was followed by a rise in plasma-hydrocortisone, although the magnitude of the rise was lower than that observed in healthy controls. Summary

Introduction

REFERENCES

Conn, J. W. (1965) New Engl. J. Med. 273, 1135. Dollery, C. T., Pentecost, B. L., Samaan, N. A. (1962) Lancet, ii, 735. Finnerty, F. A. (1959) in Symposium on Hypertensive Disease (edited by J. F. Moyer). Philadelphia. Freis, E. D. (1959) ibid. Goldner, M. G., Zarowitz, H., Akgun, S. (1960) New Engl. J. Med. 262, 403. Jackson, W. P. U., Nellen, M. (1966) Br. med. J. ii, 333. Kemsley, W. F. F. (1951) Ann. Eugen. 16, 316. Ostrander, L. D., Francis, T., Hayner, N. S., Kjelsburg, M. D., Epstein, F. H. (1965) Ann. intern. Med. 62, 1188. Rapoport, M. I., Hurd, F. H. (1964) Archs intern. Med. 113, 405. Rubenstein, A. H., Lowy, C., Welborn, T. A., Fraser, R. (1967) Metabolism (in the press). Samaan, N. A., Dollery, C. T., Fraser, R. (1963) Lancet, ii, 1244. Sharp, C. L., Butterfield, W. J. H., Keen, H. (1964) Proc. R. Soc. Med. 57, 193. Vallance-Owen, J., Ashton, W. L. (1963) Lancet. i, 1226. Welborn, T. A., Fraser, R. (1966) Diabetologia, 1, 211. Breckenridge, A., Rubenstein, A. H., Dollery, C. T., Fraser, R. (1966) Lancet. i, 1336. Rubenstein, A. H., Haslam, R., Fraser, T. R. (1966) ibid. p. 280. Wilkins, R. W. (1959) Ann. intern. Med. 50, 1. Wolff, F. W., Parmley, W. W. (1964) Diabetes, 13, 115. —

—

"... If a lack of belief in themselves is the misapprehension of social workers, society’s is an assumption that ideas of dedication and vocation are independent of such mundane matters as salaries and conditions ... Some kind of commitment is probably essential to good social work, but committed people have to live and work much as any other members of the community, and should not be penalised simply because they have chosen a particular form of career which happens to have certain additional and incidental non-monetary satisfactions. To take a cynical view, if society wants to employ social workers to salve its conscience by sweeping dirt under the carpet, it might at least have the decency to provide its cleaners with good brushes and pay them well."-JoHN HAINES, New Society, Jan. 5, 1967, p. 17.

R. WILKINSON

P. A. SMITH

IN most exacerbations of multiple sclerosis no external factor can be identified. In about a third, recent infection probably plays a part (Miller et al. 1961) while very occasionally painful trauma (Miller 1964) or emotional disturbance are so closely related to the onset of an acute episode of the disease as to raise the question of possible triggering mechanisms. The facts in these connections are certain but their interpretation-if indeed they are more than coincidental-is difficult. It has been suggested that infection may activate multiple sclerosis either by stimulating the activity of a latent chronic virus infection, or by augmenting an antigen-antibody reaction in the way that an adjuvant contributes to the production of experimental allergic encephalitis. The occasional effects of trauma or emotional disturbance may be mediated through circulatory changes, just as the symptoms of the disease may be transiently increased by a hot bath or by smoking a

provoking

cigarette. There is considerable evidence (Fog 1951, Miller et al. 1961, Alexander et al. 1961) of a marginally beneficial but inconstant effect of corticotrophin in shortening the course of acute exacerbations of multiple sclerosis. But this effect is usually conspicuous only in acute, spontaneously reversible, and almost certainly pre-demyelinative lesions such as acute retrobulbar neuritis (Rawson et al. 1966) or acute transverse myelitis. The effect may well be non-specific and merely antiphlogistic, encouraging the

inflammatory oedema, as in experimental allergic cerebral lesions (Field and Miller 1961). The results of controlled trials of long-term treatment with resolution of

65

corticotrophin are awaited with interest, but clinicall experience suggests that the hormone given in this way .

probably

exerts

little effect

on

the natural

course

of the

,

disease. The activation of multiple sclerosis by a variety of external stresses and the effect of corticotrophin on acute episodes of the disease also raise the possibility that some failure of adrenal function might be concerned, either in the form of a continuing inadequacy or a failure of response to stress. It was in pursuit of this that we

. .

’

decided

investigate the activity of the hypothalamic/ pituitary/adrenal system in patients with multiple sclerosis. Previous work in this field has relied extensively estimation of urinary excretion of steroid on the metabolites, and findings were conflicting. We have been concerned in the main with techniques that measure the level of hydrocortisone itself, hoping in this way to avoid the inaccuracies and difficulties of interpretation inherent in less specific methods. to

Evidence of an endocrine factor in the evolution of multiple sclerosis can be sought in two ways: spontaneous adrenal activity might be abnormal, either permanently depressed during the disease or declining at times of clinical activity, although the interpretation of deviations of adrenal activity near the normal range is difficult; or we might test the ability of the adrenal to increase production of hydrocortisone in response to artificial challenge, which is a more efficient means of detecting impaired function (Landon et al. 1966)-the stimulus may be applied directly with exogenous corticotrophin, or indirectly via the hypothalamic-pituitary system. Patients and Methods Twenty-one patients with presumed multiple sclerosis were investigated-eighteen women and three men. The diagnosis was based on the usual clinical criteria and on biochemical examination of the spinal fluid. Eleven patients were judged to have had an exacerbation within the previous 14 days, five were in a static phase, and the remainder were pursuing a chronic progressive deterioration. Their ages ranged from 17 to 55 years (mean 37-1 years, S.D. 5-7) and the duration of the disease at the time of study was from 1 week to 15 years (mean 6-9 years, S.D. 5-7). Although permanent disability was present in some cases, all patients were ambulant and none had clinical evidence of decubitus ulceration or infection. No patient had previously received adrenal steroids, although one had been given a short course of corticotrophin in an acute exacerbation 2 years previously. Preliminary routine erythrocyte-sedimentation rate, haemoglobin, and white-blood-cell counts were normal in all cases, though .routine mid-stream urine culture disclosed three cases of asymptomatic bacteriuria. We assessed spontaneous adrenal activity by measuring: (1) the urinary excretion of 17-ketosteroids (Medical Research Council Committee on Clinical Endocrinology 1951) and total 17-hydroxycorticosteroids (Nabarro et al. 1957) were measured over a 24-hour period; (2) on the same specimen, free 11-hydroxycorticosteroids as hydrocortisone (Mattingly et al. 1964); and (3) in a small number of patients in an acute phase of the disease, the hydrocortisone-secretion rate was determined for us by Dr. J. L. Gibbons using an isotope-dilution method (Gibbons 1964). In fifteen patients the capacity of the adrenal cortex to respond to corticotrophin was determined by the response of the plasma-hydrocortisone to an 8-hour infusion of porcine corticotrophin (Organon Ltd.) at a rate sufficient to deliver at least 25 units in that time. Plasma-hydrocortisone was determined on samples taken at 0, 6, and 8 hours (Stewart et al. 1961). Experience has been gained in this hospital using this technique in healthy people (Cameron and Kilborn 1964) and asthmatics (Robson and Kilborn 1965) and we are indebted to

Dr. A. O. Robson for providing figures for the response in ten healthy individuals (Robson 1966). Hypothalamic-pituitary response was initially assessed by blocking 11-p-hydroxylation of 11-desoxyhydrocortisone with metopirone, 750 mg. 6-hourly in three patients and observing the rise in urinary excretion of hydrocortisone precursors. In all three patients there was a normal rise of 17-hydroxycorticosteroids. We then observed the response of plasma-hydrocortisone to the stress of insulin-induced hypoglycxmia in thirteen patients (Landon et al. 1963, Greenwood et al. 1966). Patients fasted overnight and were given 0-15 units of insulin per kg. body-weight intravenously at 9.30 A.M. The blood-sugar was estimated on samples taken at 10-minute intervals during the first hour and every 15 minutes during the second hour. Plasma-hydrocortisone was determined every half-hour.

Figures for the response in nine of our twelve controls provided by Dr. A. O. Robson (Robson 1966).

were

Results

Urinary Steroid Production We must consider males and females separately since in females 17-hydroxycorticosteroid and 17-ketosteroid output is derived almost entirely from the adrenal, while in the male a considerable proportion of the 17-ketosteroids is derived from testicular hormones. In twelve female patients the average daily production of 17-ketosteroids was 9-4 mg. (S.E.M., 1-26) and of hydroxycorticosteroids, 7-4 mg. (S.E.M., 0-87). These values lie within the normal range of 5-15 mg. per 24 hours, as do those for mean 24-hour production of 17-hydroxycorticosteroids 5-1 mg. (S.E.M., 0-86) and 17-ketosteroids 10-7 mg. (S.E.M., 1-10) (four samples) from three male patients.

Urinary 11-Hydroxycorticosteroids (as Hydrocortisone) Thirteen estimations were performed, the mean value being 117-3 ug. per 24 hours (S.E.M., 16-45) comparing with the normal range of 70-370 tg. per 24 hours (Mattingly et al. 1964).

Hydrocortisone-secretion

Rate

In four patients with the disease in an acute phase hydrocortisone production averaged 17-2 mg. per 24 hours (s.D. 5-41) which corresponds closely with that found in healthy people-16-2 mg. per 24 hours (s.D., 5-7) (Cope and Pearson 1965).

Corticotrophin Stimulation The results shown in tableI and fig. 1 are from fifteen infusions performed on fourteen patients. Compared with ten controls the slightly higher mean level reached at 8 hours in the patients is not significant. Basal

Plasma-hydrocortisone

in Acute Cases

Seven of the patients given corticotrophin had recently had an acute exacerbation. The mean of their basal plasma-hydrocortisone was 8’7 g. per 100 ml. (s.E.M., 1-44) which does not differ significantly from the mean basal level (11-4 g. per 100 ml., S.E.M., 0-81) of the controls (t=1-74; 15 degrees of freedom, P=0-3). TABLE I-PLASMA-HYDROCORTISONE AFTER CORTICOTROPHIN STIMULATION IN FIFTEEN PATIENTS WITH MULTIPLE SCLEROSIS COMPARED WITH TEN HEALTHY CONTROLS

66

Fig. to

I-Plasma-hydrocortisone corticotrophin.

lvfetopirone

Fig. 3-Plasma-hydrocortisone response to

response

Fig. 2-Blood-sugar

Test

response to insulin.

relative value

The results of urinary-steroid estimations before and after metopirone administration to three patients are shown in table 11. There was a three-to-four fold increase in urinary 17-hydroxycorticosteroid excretion. Insulin-stress Test Before insulin the mean basal blood-sugar in the TABLE II-RESULTS OF METOPIRONE TEST IN THREE PATIENTS

insulin.

seems to us more

truly indicative of the

in adrenal cortical activity during the test and its use cancels out a slight, statistically insignificant difference between the basal plasma-hydrocortisone of the thirteen patients and the twelve controls. In the control series the variance of the values for maximum increment of plasma-hydrocortisone is less than that for the maximum absolute level of plasma-hydrocortisone, indicating that the relative value is a more uniform and therefore more reliable indication of change in adrenal cortical activity, After insulin-induced hypoglycxmia the mean plasmahydrocortisone level of the patients rose to a significant

change

TABLE IV-PLASMA-HYDROCORTISONE FOLLOWING INTRAVENOUS INSULIN IN THIRTEEN PATIENTS WITH MULTIPLE SCLEROSIS AND TWELVE

CONTROLS

patients, 71-2 mg. per 100 ml., was significantly lower than in the controls, 86-8 mg. per 100 ml. This difference was maintained during the hypoglycaemia after intravenous insulin (table ill, fig. 2) and the mean of the lowest of the patients’ blood-sugars, 19-6 mg. per 100 ml. (S.E.M., 181), was significantly lower than the corresponding value for the controls, 25-3 mg. per 100 ml. (s.E.M., The 205) (t=2-066; 23 degrees of freedom; P<0-05). sugar-recovery index (S.R.I.) is an artificial value relating degree and duration of hypoglycxmia to the initial bloodsugar level. Although lower in the patient-group, the difference was not significant. Response to hypoglycxmia may be measured by the highest absolute level of plasma-hydrocortisone reached, or by the increment of this over the basal reading. The TABLE III-BLOOD-SUGARS AFTER

0-15 UNITS INSULIN PER

over the basal (t= 15-57; 12 degrees of freedom; 0’001) but the magnitude of the rise was reduced when compared with that observed in healthy controls (table iv, fig. 3). The mean maximum increment in patients was 9-4 g. per 100 ml., and this is significantly

level p <

less than that of the controls-11 9 jg. per 100 ml. The

kg. IN THIRTEEN PATIENTS WITH MULTIPLE SCLEROSIS AND TWELVE HEALTHY CONTROLS

67

bolites, and is also inaccurate at low levels (Norymberski 1960). Although steroid-metabolite estimation may be adequate as a guide to gross abnormality in hyperadrenal or hypoadrenal cortical states, it is not related to the production of hydrocortisone in the normal range as measured by isotope methods (Cope and Pearson 1965). It is evident that in multiple sclerosis no such gross abnormality exists and it is doubtful whether urinary

value for the highest plasma-hydrocortisone achieved by the patients 20-3 g. per 100 ml. was lower than that for the controls (22-5 g. per 100 ml.), but was

mean

not

significantly

different.

Discussion The assessment of pituitary or adrenal function in a chronic illness such as multiple sclerosis is complicated by the non-specific changes found in any debilitating steroid estimations can be significant. disease. Cook et al. (1964) found depression of 24-hour We have found no abnormality of spontaneous adrenal ketosteroid production and impaired response to corticoas determined several measurements. Such function, trophin, as measured by urinary steroid production, in estimations as were madebyon urinary steroid metabolites malnourished patients and convalescent hospital patients showed a normal mean output of 17-ketosteroids, and of compared with healthy controls. Resting plasma-hydro17-hydroxycorticosteroids per 24 hours. The mean of cortisone and its response to insulin was normal, although urinary 11-hydroxycorticosteroid excretion also fell within there was a delayed clearance of hydrocortisone due to the normal range. In patients who had recently had an reduced hepatic breakdown. Cook et al. (1964) postulated acute exacerbation of the disease, resting plasma-hydroan alteration in adrenal metabolism diverting steroid cortisone did not differ significantly from that of healthy production from the less essential androgens to the controls. Hydrocortisone-secretion rates afford the best glucocorticoid series. Similarly, Fraser, Forbes et al. measurement of adrenal activity available at present. We (1941) found urinary 17-ketosteroid excretion reduced measured this rate only in patients with the disease in an in chronically ill patients. acute phase, since it was in these patients that depression Several workers have encountered difficulty when studyof adrenal function significant in the evolution of multiple ing patients with multiple sclerosis because of this non- sclerosis might be expected, but the observed mean of specific effect of their debilitated general condition. Early 17-1 per 24 hours (S.E.M., 2-74) corresponds closely exceptions were Garcia-Reyes et al. (1952) who were with mg. the normal value. prompted to investigate adrenal function by favourable Elevation of rate has been hydrocortisone-secretion reports of the effects of corticotrophin in multiple observed in conditions of stress, varying pregnancy (Cope sclerosis. They found urinary outputs of 17-ketosteroids and Black 1959), and active medical disease (Cope and and 11-oxysteroids to be normal, as was the ability of the adrenal cortex to respond to corticotrophin, as assessed by Black 1958), and the elevation of plasma-hydrocortisone stress is well documented. It might be expected eosinophil-count reduction and increase in urinary with that the stress of an acute exacerbation of multiple sclersteroid production. They considered this good evidence osis would give rise to an increased production of hydroagainst an abnormality of the pituitary-adrenal system in cortisone from the adrenal demonstrable by an elevation multiple sclerosis. In spite of this, European workers of level and secretion-rate. Failure to demonplasma continued to speculate on the role of the adrenal cortex in these increases may be due in part to the minor multiple sclerosis. Thus Birkmeyer et al. (1955) found strate nature of the stress, since elevation of plasma-hydroreduced urinary 17-ketosteroids in fifty-one chronic cortisone with stress is related to the nature and severity cases. This was more pronounced in severely disabled of the stress (Sandberg et al. 1954), or to delay between patients, and they suggested that clinical deterioration onset of exacerbation and investigation. occurred when the combination of " exogenous and The adrenal may maintain production of hydrocortimultiple sclerosis specific " stresses exceeded the capacity sone sufficient for normal requirements, but may not be of the endocrine system to respond, and improvement able to increase production in response to stress, either resulted from correcting the balance. It seems more because of inadequate stimulus from the central mechanlikely that the changes were a reflection of the severely concerned with mediating the response to stress, or disabled state of their patients. Wender and Gutowski isms (1959) attributed the reduced 17-ketosteroid production because of reduced adrenal reserve. The second explanaobserved in forty-one severely affected cases to their tion does not accord with the results of artificial stimulaIn response to infusion of corticotrophin the debilitated condition, as did van Cauwenberg (1959) in tion. his series. Cendrowski (1960) and Cazzullo et al. (1964) plasma-hydrocortisone of our patients rose to a mean value also observed depression of urinary 17-ketosteroid of 47-3 mg. per 100 ml. at 8 hours, slightly higher than the control series mean but not significantly different. This secretion in multiple sclerosis. confirms the findings of Garcia-Reyes et al. (1952) who We have been careful to include only patients whose: disability was slight; and all our patients were ambulant. used depression of the eosinophil-count and urinary steroidXo patient was malnourished, nor did any have decubitusò metabolite excretion as a measure of adrenal activity. ulceration. The three patients found to have asympto- The integrity of the hypothalamic-pituitary system as matic bacteriuria did not differ from the others in regardassessed by the response to metopirone was normal in the limited number of patients observed. An extensive to erythrocyte-sedimentation rate, white-blood-cell count,I or endocrine-function tests. We hoped by this means to) study using this test was not made since the response to avoid the complication of studies in debilitated patients. metopirone has been shown to be an unreliable indication Other workers have relied extensively on estimations off of ability to respond to stress (Oppenheimer et al. 1961, urinary steroid metabolites. We think that urinary7van Wyk et al. 1960, Gold et al. 1961, Estep et al. 1963). 17-ketosteroids are an unreliable index of adrenal cortical1 The stress of insulin-induced hypoglycxmia has been activity in chronic illness. Furthermore, the estimationi known to induce adrenal cortical activation since Vogt of C21 metabolites-the 17-ketogenic steroids or 17(1951) studied the resulting depletion of ascorbic acid influenced the from rat adrenals. Prolonged hypoglycoemia after insulin, hydroxycorticosteroids-is by drugs, accuracy of urine collection, and deterioration of metaalthough somewhat dangerous, is an index of reduced ,

.

,

-

-

68

pituitary or adrenal function (Fraser, Albright et al. 1941). Arner et al. (1962) determined the response of plasmacorticosteroids to hypoglycasmia induced by 0-1units of insulin per kg. body-weight and found a mean increase of l8000over the resting values. Amatruda et al. (1960) found that not all patients experienced the expected degree of hypoglycaemia on this dosage of insulin, and recommended the use of 0- 15 units per kg. They also observed an approximately twofold increase in plasma-hydrocortisone. Landon et al. (1963) also used 0-15 units of insulin per kg. and Greenwood et al. (1966), reviewing experience with the test, suggested that the response as measured by highest plasma-hydrocortisone or largest observed increment may be graded as normal, reduced, or

j

i ’

absent. We noted a significant rise in plasma-hydrocortisone in response to hypoglycaemia. But the magnitude of this increase was slightly but significantly reduced compared with that of the control group. Although the two groups differed in relation to age, sex, and weight, these factors do not significantly affect the response to hypoglycxmia and can be disregarded (Greenwood et al. 1966). The degree of response is related to the depth and duration of Hypoglycsemia, and in our study the patients’ blood-sugars fell to lower levels than those of the controls, so that the reduced response cannot be explained by a reduced stimulus. The difference observed in bloodsugars may be due to the differing sex ratio in the two groups. Greenwood et al. (1966) found that their female controls had a significantly lower mean blood-sugar than did the males. In our series, ten of the thirteen patients

SECRETION OF GASTRIC INTRINSIC FACTOR M.B.

J. H. LAWRIE Glasg., F.R.C.S., D.C.H.

LECTURER IN SURGERY

N. M. ANDERSON SENIOR TECHNICIAN

From the Department of Surgery, Welsh National School of Medicine and United Cardiff Hospitals

THE output of gastric intrinsic factor has been determined in eight healthy controls and in forty patients with various gastroduodenal disorders but without pernicious anæmia. The stimulus was a continuous intravenous infusion of histamine at a dose of 40 µg. per kg. per hour. The responses of acid and intrinsic factor (I.F.) to this stimulus were significantly correlated, but the pattern of the two secretions was different. Thus, whereas the output of acid was maintained at a peak level, that of I.F. reached a peak during the 1st histamine hour and fell almost to basal levels during the 2nd hour. Introduction THE underlying principle of methods of estimating the concentration of intrinsic factor (I.F.) in human gastric juice (Ardeman and Chanarin 1963, Jeffries and Sleisenger 1963, Gottlieb et al. 1965) is the same, and is based on the

Summary

DR. TEASDALE AND OTHERS: REFERENCES

Alexander, L., Berkeley, A. W., Alexander, A.

M. (1961) Multiple Sclerosis: and Treatment. Springfield. Prognosis controls only one was female. Amatruda, T. T. Jr., Hollingsworth, D. R., D’Esopa, N. D., Upton, G. V, In a diffuse disease of the nervous system pathological Bondy, P. K. (1960) J. clin. Endocr. 20, 339. B., Hedner, P., Karlefors, T. (1962) Acta endocr., Copenh. 40, 421. changes may be present in the areas concerned with Arner, Birkmeyer, W., Iselstöger, H., Seemann, D. (1955) Klin. Med. 10, 550. appreciating hypoglycasmia and mediating the stress Cameron, E. A., Kilborn, J. R. (1964) Clin. Chim. Acta, 10, 308. C. L., Brambilla, F., Mangoni, A., Montaini, R. (1964) Riv. Patol. response. Although at least two additional physiological Cazzullo, nerv. ment. 85, 593. mechanisms influence adrenal activity-diurnal rhythm Cendrowski, W. (1960) Endokr. pol. 11, 271. Cook, J. N. C., James, V. H. T., Landon, J., Wynn, V. (1964) Br. med. J. and steroid feedback-at present the central pathways 662. concerned are not anatomically distinguished. For all Cope,i, C. L., Black, E. G. (1958) ibid. i, 1020. three the ultimate pathway is the formation of a corti(1959) J. Obstet. Gynœc. Br. Emp. 66, 404. Pearson, J. (1965) J. clin. Path. 18, 82. factor in the which hypothalamus cotrophin-releasing Estep, H. L., Island, D. P., Ney, R. L., Liddle, G. W 1963) J. clin. Endocr. reaches the anterior pituitary via a portal-venous plexus 23, 419. Field, E. J., Miller, H. (1961) Arch? intern. Pharmacodyn. 134, 76. and there stimulates the release of corticotrophin into the Fog, T. (1951) Nord. Med. 46, 1742. systemic circulation. Thus Landon et al. (1966) found Fraser, R. W., Albright, F., Smith, P. H. (1941) J. clin. Endocr. 1, 297. Forbes, A. P., Albright, F., Sulkovitch, H., Reifenstein, E. C. (1941) impaired response to the stress of hypoglycsemia in three ibid. p. 234. with disease-due to sarcoid in hypothalamic patients Garcia-Reyes, J. A., Jenkins, D., Forsham, P. H., Thorn, G. W. (1952) Archs Neurol. Psychiat. 68, 776. one to encephalitis in another, and of unknown nature in J. L. (1964) Archs gen. Psychiat. 10, 572. Gibbons, In the third. multiple sclerosis evidence of demyelination Gold, E. M., Kent, J. R., Forsham, P. H. (1961) Ann. intern. Med. 54, 175. involving the hypothalamus in the neighbourhood of the Greenwood, F. C., Landon, J., Stamp, T. C. B. (1966) J. clin. Invest. 45, 429. Landon, J., Greenwood, F. C., Stamp, T. C. B., Wynn, V. (1966) ibid. third ventricle is frequently found at necropsy and our

subjected to insulin stress

were

female while of the twelve

—

—

—

—

findings of reduced

response to stress might be secondary to this. If this is so the change may be more pronounced in cases where the disease is of long duration, and who presumably have more extensive periventricular demyelination. Further work is planned to extend our observations. Although there was a reduced response, our patients were capable of producing a significant rise in plasmahydrocortisone. This would make us hesitant to suggest that our findings are relevant to the setiology of multiple

sclerosis. We thank Dr. A. O. Robson for much practical advice and providing figures for the results of corticotrophin stimulation and insulin stress in controls; Dr. J. L. Gibbons who arranged for the estimation of hydrocortisone-secretion rates; the Multiple Sclerosis Society of Great Britain for financial support. Requests for reprints should be addressed to H. M., Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne 1.

p. 437. Wynn, V., James, V. H. T. (1963) J. Endocr. 27, 183. Mattingly, D., Dennis, P. M., Pearson, J., Cope, C. L. (1964) Lancet, ii, 1046. —

Medical Research Council Committee on Clinical Endocrinology (1951) ibid. ii, 585. Miller, H. (1964) ibid. i, 848. Newall, D. J., Ridley, A. (1961) ibid. ii, 1120. Nabarro, J. D. N., Moxham, A., Walker, G. (1957) Br. med. J. ii, 1018. Norymberski, J. K. (1960) in The Adrenal Cortex (edited by G. K. McGowan and M. Sandler); p. 88. London. Oppenheimer, J. H., Fisher, L. V., Jailer, J. W. (1961) J. clin. Endocr. 21. 1023. Rawson, M. D., Liversedge, L. A., Goldfarb, G. (1966) Lancet, ii, 1044. Robson, A. O. (1966) M.D. thesis, University of London. Kilborn, J. R. (1965) Thorax, 20, 93. Sandberg, A. A., Eik-nes, K., Samuels, L. T., Tyler, F. H. (1954) J. clin. Invest. 33, 1509. Stewart, C. P., Albert-Recht, F., Osman, L. M. (1961) Clin. Chim. Acta. 6, 696. van Cauwenberge, H. (1959) Acta neurol. belg. 59, 772. van Wyk, J. J., Dugger, C. S., Newsome, J. F., Thomas, P. Z. (1960) J. clin. Endocr. 20, 157. Vogt, M. (1951) J. Physiol., Lond. 114, 222. Wender, M., Gutowski, J. (1950) Wien. klin. Wschr. 71, 648. —

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