Postgrad Med J: first published as 10.1136/pgmj.31.360.516 on 1 October 1955. Downloaded from

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ARENAL IMPAIRMENT IN WITH SPECIAL REFERENCE TO NEPHROCALCINOSIS By K. M. CITRON, M.D.(Lond.), M.R.C.P. Senior Medical Registrar, Brompton Hospital

Introduction Case Record* Although impaired renal function is uncommon Miss I.E., aged 23, had in 1948 commenced in sarcoidosis the recognition of this complication work in a factory where she was engaged in coating is of importance since it may cause death and be- the inside of fluorescent tubes with a mixture con- cause prompt treatment may result in recovery of taining beryllium phosphor. This exposure to renal function. beryllium lasted one year. A chest radiograph at The kidney is a common site for sarcoid lesions. the end of this time was stated to be normal. Thus, in a combined series of 45 autopsies the However, ten months later, in April 1953, she kidneys showed macroscopic or microscopic in- attended the Brompton Hospital complaining of volvement in 20 per cent. (Ricker and Clark, I949; dry cough and dyspnoea on exertion. Physical Longcope and Freiman, I952). In view of the examination at this time showed no abnormalityby copyright. known tendency of sarcoid lesions to infiltrate but the chest radiograph showed miliary mottling organs extensively and impair function, it was in both lungs and enlarged hilar shadows (Fig. i). assumed by earlier authors that renal impairment The Mantoux reaction was negative i :ioo O.T. was due to massive invasion of the kidneys (Kline- and the E.S.R. was 75 mm. in one hour (Wester- felter and Salley, 1940). However, sarcoid lesions gren). in the kidney are in fact usually small and relatively The following month she developed erythema few in number and would be unlikely to produce nodosum on both legs. Soon after this raised renal insufficiency (Longcope and Freiman, I952). nodules appeared on the skin of the hands and Evidence has accumulated pointing to another some of these were situated over old scars. of these nodules revealed the mechanism of renal damage. In 1939 Horton, of one histologicalhttp://pmj.bmj.com/ Lincoln and Pinner recorded a case of sarcoidosis features of sarcoidosis (Fig. 2). Histochemical associated with renal impairment in which the tests using Denz's napthachrome technique (Denz, kidneys at autopsy were contracted and showed I949) failed to demonstrate the presence of marked calcification and degeneration of the beryllium in the lesions. By September 1950 the tubules. The serum was not estimated in liver had become palpable and she had lost one this case, but in the same year Harrell and Fisher stone in weight. (1939) noted the occurrence of in In I952 a painless bulbous swelling gradually some cases of sarcoidosis. Van Creveld in I941 appeared on the right fourth toe (Fig. 3). Radio- on October 2, 2021 by guest. Protected recorded the case of a child with sarcoidosis graphy of this showed a calcified excrescence on associated with hypercalcaemia, renal stone and the terminal phalanx (Fig. 4). This swelling impaired kidney function and in 1948 Albright and occasioned discomfort during walking and the toe Reifenstein pointed out that nephrocalcinosis and was therefore amputated. The specimen revealed nephrolithiasis might occur in sarcoidosis in a granulomatous reaction around deposits of cal- association with hypercalcaemia. Finally this con- cium in the soft tissues (Fig. 5). cept was confirmed by Longcope and Freiman In I953 frequency of micturition and nocturia (1952) who described a case of sarcoidosis where developed. In July I953 she noted discomfort in death was due to uraemia; hypercalcaemia was the eyes and conjunctival abnormalities were present and at post-mortem there was extensive found. She was admitted to hospital in October calcification in and around the renal tubules. 1953. The case of sarcoidosis to be described offered *This case was shown at the Clinical Section of the the opportunity of studying this condition and also Royal Society of and is briefly described in of following the response to cortisone . Proc. Roy. Soc. Med. (1954), 47, 507. Postgrad Med J: first published as 10.1136/pgmj.31.360.516 on 1 October 1955. Downloaded from October I955 CITRON: Renal Impairment in Sarcoidosis with Special Reference to Nephrocalcinosis 517

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FIG. i.-Chest radiograph, October 1950, showing FIG. 2.-Biopsy of skin nodule showing sarcoid in- miliary shadowing in lungs. filtration (magnification x I Io). http://pmj.bmj.com/ on October 2, 2021 by guest. Protected

FIGl3.-photograph of right foot showing bulbous FIG. 4.-Radiograph of right foot showing calcification swelling of -fourth toe. in soft tissues of fourth toe. Postgrad Med J: first published as 10.1136/pgmj.31.360.516 on 1 October 1955. Downloaded from

5I8 POSTGRADUATE MEDICAL JOURNAL October I955 (I9 mg. per ioo ml.) and serum phosphorus was also raised (5.6 mg. per ioo ml.). Alkaline phos- phatase, 6.5 King-Armstrong units. Serum pro- s.. tein; total 8.5 g., albumen 4.3 g., globulin 4.2 g. A&I per ioo ml. Blood urea 50 mg. per ioo ml. The urea clearance was 50 per cent. of normal. Marked hypercalcuria was present (o.8 g. calcium per 24 y .0fr5VF;,? hours). Treatment. She was given isoniazid and strepto- Ii/I'I mycin. The dose of the latter had to be reduced to only I g. on alternate days on account of high blood streptomycin levels due to renal impairment. No significant change in biochemistry or renal fl'Es function occurred during one month of this treatment. Cortisone was then given in dosage of ISo mg. daily by mouth for ten days and thereafter ioo mg. daily. Fig. 9 shows the rapid fall in serum calcium and phosphorus which took place as a result of this treatment. Urinary calcium excretion also diminished. Eleven weeks later the urea clearance FIG. 5.-Section of soft tissues of right fourth toe was 96 per cent. of normal and the blood urea 25 showing granulomatous reaction around deposits of mg. per ioo ml. Cortisone dosage was scaled calcium (magnification X 95). down to a maintenance dose of 25 mg. daily. Therapy was terminated after eight months at On examination she was thin. No abnormal which time serum calcium and phosphorus wereby copyright. physical signs were found in the respiratory or normal. She felt much better in herself and had cardiovascular systems and the blood pressure was gained one stone in weight. Frequency of 12o/8o. No rash was present. No lymph nodes micturition was absent. Dyspnoea on exertion she were palpable, but the liver was palpable three claimed was less, though lung function tests fingers breadth below the costal margin. showed no significant change nor was the chest In the conjunctivae of both eyes there were many radiograph altered. The conjunctival deposits were small raised nodules, ocular appearances similar to no longer evident and deposits on the tympanic those described by Walsh and Howard (I947) in membranes were less extensive. hypercalcaemic states and attributed to deposits of In summary, investigations of this case of sar- calcium phosphate in the conjunctiva. (Fig. 6.) coidosis revealed hypercalcaemia with metastatic Both tympanic membranes showed white cal- calcification in the conjunctivae, tympanic mem-http://pmj.bmj.com/ careous areas. There was no previous history of branes, the soft tissues of the fingers and toes and ear disease and the audiogram was normal. kidney, and renal impairment thought to be due Investigations. Review of the chest films to nephrocalcinosis. Treatment with cortisone re- showed no change in the miliary mottling over sulted in correction of the hypercalcaemia and three and a half years. Tomography confirmed renal impairment. The relationship of the sar- hilar node enlargement. Mantoux negative, I/I000 coidosis to exposure to beryllium is not established

T.U. P.P.D. E.S.R., 28 mm. in one hour (Wester- since beryllium was not demonstrated in the skin on October 2, 2021 by guest. Protected gren). No tubercle bacilli found on culture of lesions and erythema nodosum is not recorded as a gastric lavage. feature of beryllium sarcoidosis. It seems likely Radiograph of the hands in 1952 showed trans- that the case is one of non-industrial sarcoidosis lucencies in the tips of the terminal phalanges and with an incidental history of possible beryllium opaque deposits in the soft tissues of the fingers, hazard. especially the left fifth and the right middle (Fig. 7). The film in 1953 was similar except that the Review of the Literature deposits in the soft tissues were absent. Many hundreds of cases of sarcoidosis are re- A radiograph showed two calcified areas in the corded in the voluminous literature on the subject left kidney (Fig. 8). Urine contained a trace of yet only 37 with renal impairment have been albumen, casts and calcium oxalate crystals. Cul- found. However, it is likely that more frequent ture was sterile. investigation of renal function and serum calcium The biochemical findings are demonstrated in would reveal more cases. Fig. 9. The serum calcium was remarkably high Analysis of these 37 cases indicates clearly that Postgrad Med J: first published as 10.1136/pgmj.31.360.516 on 1 October 1955. Downloaded from

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FIG. 9.-Diagram showing biochemical findings and response to treatment. on October 2, 2021 by guest. Protected nephrocalcinosis is the cause of renal insufficiency serum calcium like the plasma globulin tends to in the great majority of cases. parallel the activity of the sarcoid process and is Table i lists 28 cases of sarcoidosis with renal normal in quiescent phases (Freiman, 1948). The insufficiency in which serum calcium levels are third case (Parker, 1950) at autopsy had a con- recorded. Hypercalcaemia was present in 25. Of genital single fused kidney unrelated to sarcoidosis three cases with normal serum calcium one (Holt and is therefore excluded from further discussion. and Owens, I949) showed nephrocalcinosis radio- Thus in 27 cases hypercalcaemia was present or logically and another (Markoff, 1951) showed can reasonably be presumed to have been present nephrocalcinosis on renal biopsy. In both only at some time during the course of the disease. one estimation of calcium is recorded and it is In , hypervitaminosis D almost certain that the level was high at some time and other conditions causing hypercalcaemia and in the course of the disease. It is recognized that hypercalcuria renal impairment is well recognized Postgrad Med J: first published as 10.1136/pgmj.31.360.516 on 1 October 1955. Downloaded from

October 1955 Renal Impairment in Sarcoidosis with Special Reference to Nephrocalcinosis 521

TABLE I.-SARCOIDOSIS WITH RENAL IMPAIRMENT. SERUM CALCIUM KNOWN. Renal Radiographs Age Blood Serum Serum c be c Author Cal- urea calcium phos- B.P Renal Sex cifica- Cal- (or mg. 0 phorusa : Z|a | histology tion culus N.P.N.) mg.% .9Z

Van Creveld (1941) F. 49 +5.6 3.7 2.9 Raised 12 + (N.P.N.) 10.9 ± Schupbach and Wernly(943) M. I6.3 5.8 4.0 30 -4- j58 1I.2 3.3 2.7 N. -

Esperson (0944) F. x8 N. - 200/? 29 49 i6 + Klinefelter and Salley (1946) M. 70 17.4 43 N. N. 23 (N.P.N.) 13.0 4.0 ± Westra and Vissa (1949) M. 77 14.0 5.0 5.6 20 + + (N.P.N.) I 3.4 4.2 3.9 N. ± (K .A .) Hlolt and Owens (949) 4M. 50 15.3 4.8 3.0 + Autopsy 42 (B.) nephirocalcinoaia F. 195 9.8 -- - + ~~28 + Keech (1951) F. 57 14.2 N. N. 200/ + 3 11.2 I40 Markoff (1951) M. 48 9.8 - - 130/ ± Biopay 23 (N.P.N.) o9 nephrocalcinosis Longcope and Freiman (I952) F. 75 15.5 4.7 5.2 36 + (N.P.N. 9.2 2.5 2.6 + by copyright. (B.)_ M. io8 i6.5 6.~ - Autopay 34 + (N.P.N.) + nephrocalcinosis Schulman et al. (I952) M. 6o I5.8 5.9 9.0 - 33 (N.P.N.) 9.6 3. I 3.7 (B.) M. I92 12.5 N. N. - Autopay 33 (N.P.N.) | nephrocalcinosis M. 56 i6.9 N. N. - | 37 (N.P.N.) Dent et al. (I953) M. 56 14.3 4.2 II.I N. + Biopay 23 ± IO 2.2 (K.A.) pyelonephritia http://pmj.bmj.com/ Klatskin and Gordon (1953) M. 90 15.0 5.2 5.3 N. 68 (N.P.N.) 11.5 4.9 (B.) + M. I14 12.8 4.2 6.8 N. 51 ± (N.P.N.) |1.9 2.3 5.1 ± (B.) Phillips (1953) M. Il 14.6 3.4 4.3 N. 29 (N.P.N.) 13.6 (B.) ± Davidson et al. (1954) F. 42 i6.8 4.0 2.6 -

42 + 9.8 2.6 (B.) ± on October 2, 2021 by guest. Protected F. 122 12.8 10.4 - 220/ Autopsy 32 + + 10.0 7.0 110 + nephrocalcinosis Dent et al. (1954) M. I29 I 6.3 3.8 8. i N. 36 10.5 (K.A.)__ M. 58 14.0 - - N. 14 11.5 ± F. 192 15.0 - - N. 5612.0 ± Citron (1954) F. 52 19.0 5.6 6.5 N. 15)23 I+ ___ 8.7 4.6 (K.A.) ±

Zeldenrust (cited by Van Creveld, I941). Renal impairment with hypercalcaemia. No other data. Longcope and Freiman (195i). Two cases with renal impairment and hypercalcaemia. No other data. Parker (ig5o). Autopsy. Congenital single fused kidney. Normal serum calcium. (Also Rotenberg and Guggenheim, 1942). Bodanski or King-Armstrong units. Postgrad Med J: first published as 10.1136/pgmj.31.360.516 on 1 October 1955. Downloaded from

POSTGRADUATE MEDICAL JOURNAL October 1955 and is due to deposits of calcium in the kidney, ably be attributed to massive invasion of the or both (nephrocalcinosis or nephro- kidney hy sarcoid granulomata. lithiasis). Hence one would expect to find similar The case of Rutishauser and Rywlin (1950) in changes in hypercalcaemia with sarcoidosis. which the main lesion was hyalinization of Analysis of Table i shows this to be the case. glomeruli and preglomerular capillaries demon- Thus all four autopsies in this series showed strates a third possible mechanism of renal impair- nephrocalcinosis and of two renal one also ment in sarcoidosis. The changes in this case were showed nephrocalcinosis and the other, taken similar to those described by Teilum (I951) in during pyelolithotomy, showed sarcoidosis and also in diffuse lupus erythematosis secondary to calculous obstruction. Of the 27 and in other collagen diseases associated with cases radiography showed nephrocalcinosis in hyperglobulinaemia. Teilum ascribed these to a seven and nephrolithiasis in six. Histological or common type of mesenchymal reaction, probably radiological evidence of calcium in the kidneys was allergic in nature. obtained in I3 cases out of a total of 24 for whom full clinical details are available. The Clinical Pattern of Renal Impairment in Renal insufficiency when due to hypercalcaemia Sarcoidosis is known to be often reversible if the hyper- Review of the published cases suggests that calcaemia is corrected (Adams, 195I). In six cases renal impairment in sarcoidosis presents a recog- in Table i serum calcium levels fell spontaneously nizable clinical picture. or in response to low calcium diet andin all renal Renal symptoms comprise frequency, , function improved. In seven renal function im- nocturia, sometimes , but there may be proved as a result of control of the hypercalcaemia no symptoms referable to the urinary tract. with cortisone or ACTH. Symptoms resulting from hypercalcaemia are TABLE 2 frequent and include lassitude, weakness, loss of

weight, anorexia and nausea suggesting gastritis.by copyright. Author Remarks Davidson et al. (I954) mention finding prominence of gastric rugae on plain X-ray of the abdomen in Salvarsen (I935) Clinically compatible with some cases. nephrocalcinosis. Horton et al. (I939) Autopsy. Nephrocalcinosis Blood pressure is usually but not invariably Ustvedt (I939) two cases Clinically compatible with within normal limits and retinopathy and oedema nephrocalcinosis. are usually absent, thus distinguishing the con- Chanials (cited by Schup- Autopsy. Massive renal dition from Ellis types I and II bach and Wernly, 1943) invasion by sarcoid. . Ricker and Clark (I 949) Autopsy. Renal arteric and The eyes may show punctate calcium deposits periarteric lesions. in the conjunctiva or in the cornea showing as a Rutishauser and Rywlin Autopsy. Hyalinized semilunar opacity near the limbus which has been (I950) glomeruli and pre- described as band keratopathy (Walsh andhttp://pmj.bmj.com/ glomerular capillaries. Longcope and Freiman No data. Howard, 1949; Cogan et al., I948). (1952) Urine shows small amounts of albumen with a Owen and Henneman Autopsy. Occasional cal- few casts and red cells. The daily excretion of (1954) cified tubule. Subacute calcium is usually excessive. glomerulitis. Blood chemistry is characteristic (Table I). Serum calcium is raised and may be very high. Table 2 lists nine cases for which serum calcium Probably calcium like globulin is raised only when is not known. Post-mortem examination was the sarcoid process is active, so that in quiescent on October 2, 2021 by guest. Protected made in five of which two showed nephrocal- phases its level may be normal though some renal cinosis. Renal insufficiency was attributed to impairment remains. Serum phosphorus is normal extensive sarcoid invasion of the kidney in another. or high, but not low, an important distinction from The fourth showed hyalinization of the glomeruli hyperparathyroidism. Alkaline phosphatase is and preglomerular capillaries. In the fifth the usually normal. Globulin is usually increased. lesion was an arterial and periarterial lesion un- Radiologically the kidneys often show scattered related to sarcoidosis. Of the remaining four cases areas of calcification or calculi (calcium oxalate) in three are clinically compatible with nephro- the renal pelvis. Radiographs of the soft tissues or calcinosis and no clinical information is available blood vessels may show metastatic calcinosis. for the other. Bones may reveal localized destruction but ex- Analysis of these cases therefore shows that tensive translucency to X-rays is rare. nephrocalcinosis or nephrolithiasis is the principal The course of the disease untreated is pro- cause of renal impairment in sarcoidosis. In only longed. Death from renal failure may occur one case (Chanials, 1943) can impairment reason- though more often there is a gradual spontaneous Postgrad Med J: first published as 10.1136/pgmj.31.360.516 on 1 October 1955. Downloaded from

October 1955 Renal Impairment in Sarcoidosis with Special Reference to Nephrocalcinosis 523 correction of the hypercalcaemia and sufficient units of daily, occasionally replacing functioning uncalcified kidney may remain to this by halibut liver oil capsules equivalent to maintain life. 2,500 units daily over a period of about two years. The cause of the abnormal sensitivity to vitamin D The Aetiology of Hypercalcaemia in in sarcoidosis remains obscure. Sarcoidosis Hypercalcaemia, which is not uncommon in Treatment sarcoidosis (i.e. 25 per cent. in 44 cases, Longcope Since hypercalcaemia is liable to cause renal and Freiman, 1952), might result from the damage it is advisable to estimate the serum following factors: calcium in all cases of established sarcoidosis. If i. Disturbed plasma proteins. the level is elevated, renal function should be in. 2. Hyperparathyroidism. vestigated. Persistenthypercalcaemia above12mg. 3. Bone destruction by sarcoid granulomata. per ioo ml., with or without renal damage, merits 4. Increased absorption of calcium from the gut. treatment with cortisone. The case described here The extra calcium in the blood is unlikely to be demonstrates the correction of renal insufficiency due to its being bound to protein, for there is no and hypercalcaemia by cortisone, and other equally constant relationship between hyperglobulinaemia satisfactory therapeutic results have been reported. and hypercalcaemia (Longcope and Freiman, Dent (I954b) has shown that cortisone acts by 1952; Harrell and Fisher, 1939), and albumen diminishing the abnormally high absorption of rather than globulin is mainly concerned in bind- calcium from the gut, thus correcting hypercal- ing calcium. Further, hypercalcuria would not caemia, Other evidence which he quotes to show occur if protein were calcium bound. that cortisone has an action antagonistic to vitamin Hyperparathyroidism is also unlikely. Records D is the low absorption of calcium to be found in of the parathyroids on exploration or autopsy in Cushing's disease (Freyberg et al., 1936) and the

eight cases (Albright and Reifenstein, 1948; fact that cortisone increases the requirement ofby copyright. Westra and Vissa, I949; Longcope and Freiman, vitamin D (Moehlig and Steinbach, I954). 1952; Klatskin and Gordon, I953; Davidson et Initially doses of I50 to ioo mg. of cortisone al., 1954 (two cases); Dent et al., I954b) shows daily by mouth causes rapid control of the hyper- some hyperplasia in two and normality in six. calcaemia (Fig. 9). Thereafter the dosage is gradu- Further, the characteristic low phosphorus of ally reduced according to serum calcium levels, but hyperparathyroidism is not found (Table i). usually small doses are found to be required for Liberation of calcium from bone invaded by prolonged periods to control the metabolic defect. sarcoid granulomata is unlikely, for radiological The patient should-be warned against supplement- changes are usually minimal and, moreover, the fall ing the normal diet with preparations containing of serum calcium which occurs in response to low vitamin D. calcium diet in these cases is against this hypothesis http://pmj.bmj.com/ (Dent, et al., I954b). Summary Dent (I954a, b) has recently shown convincingly i. A case of sarcoidosis with renal impairment by means of calcium balance studies that hyper- due to nephrocalcinosis secondary to hypercal- calcaemia in sarcoidosis is due to excessive absorp- caemia is described. tion of calcium from the gastrointestinal tract. 2. The literature on renal insufficiency in sar- Increased absorption of calcium may result from coidosis is reviewed and it is found that nephro- giving large doses of vitamin D. It might also calcinosis is the principal cause. on October 2, 2021 by guest. Protected result from increased sensitivity to normal amounts 3. The aetiolog&y of hypercalcaemia. in sar- of vitamin D, and this is the probable explanation coidosis is discussed. for the increased absorption of calcium in sar- coidosis, for there is abundant evidence that many 4. Cortisone treatment is discussed. patients with sarcoidosis are abnormally sensitive and rapidlv develop hypercalcaemia when given Acknowledgments vitamin D therapeutically (Scadding, 1950; Curtis, I am indebted to Dr. J. G. Scadding and Dr. Taylor and Grekin, I947). This is in contrast with F. H. Young for permission to publish this case experience with patients suffering from other con- and to Dr. C. E. Dent for advice. I also wish to ditions. For instance Steck et al. (Iy937) found thank Mr. H. B. Stallard, Mr. Max Pemberton, toxicity in only 8 per cent. of 773 patients given Dr. R. J. R. Cureton and Dr. J. T. Prendiville for more than ioo,ooo units of vitamin D for up to illustrations and the editors of the Proceedings of five years. The patient described in this paper the Royal Society of Medicne for permission to had taken doses of cod liver oil equivalent to 8oo reproduce this case. Postgrad Med J: first published as 10.1136/pgmj.31.360.516 on 1 October 1955. Downloaded from 524 POSTGRADUATE MEDICAL JOURNAL October 1955

BIBLIOGRAHY ADAMS, F. D ( 95') New Eng. Y. Med., 244, 590. LONGCOPE, W. T., and FREIMAN, D. G. (1952), Medicine, 31, I. ALBRIGHT F., REIFENSTEIN, E. C., JUN. (1948), 'The para- MARKOFF, N. (I95I), Helvet. Med. Acta., I8, 389. thyroid glands and metabolic bone disease. Selected studies,' MOEHLIG R. C. and STEINBACHI, A. L. (1954), J Amer. med. Baltimore. Ass., 154, 42. CHANIALS, cited by SCHUPBACH and WERNLY (below). OWEN, K. T., and HENNEMAN, J. (I954), Brit. med.J7., ii, 1141. CITRON, K. M. (I954), Proc. Roy. Soc. Med., 47, 507. PARKER, J. G. (1950), Dis. Chest., I8, 49. COGAN, D. G., ALBRIGHT, F., and BARTTER, F. G. (1948), PHILLIPS, R. W. ('953), New Eng. J. Med., 248, 934. Arch. Opthal., 40, 624. RICKER, W., and CLARK, M. (1949), Amer. J7. Clin. Path., I9, CURTIS, A. C., TAYLOR, H., JUN., and GREKIN, R. H. (I947), 725. Y. invest. Derm., 9, 13 '. ROTENBERG, L., and GUGGENHEIM, A. (1942), Dis. Chest., DAVIDSON, C. N., DENNIS, J. M., McNINCH, E. R., WILL- 8, 392. SON, J. K. V., and BROWN, W. A. (I954), , 62, 203. RUTISHAUSER, E., and RYWLIN, A. (1950), J. Urol. Paris, DENT, C. E., FLYNN, F. V., and NABARRO, J. D. N. (I953), 56, 277. Brit. med. Y., ii, 808. SALVARSEN, H. A. (1935), Acta. Med. Scand., 86, 127. C. E. (1954a), Proc. Roy. Soc. Med., 47, So8. SCADDING, I. G. (1950), Brit. med. J., i, 745. DENT, C. E., ANDERSON, J., HARPER, C., and PHILPOT, SCHUPBACH, A., and WERNLY, M. (I943), Acta. Med. Scand., G. R. (1954b), Lancet, ii, 720. 115, 401. DENZ, F. A. (I949) Quart. Y. micr. Sci., 90, 317. SCHULMAN, L. E., SCHOENRICH, E. H., and HARVEY, ESPERSEN, T. (i9;4), Nord. Med. (Hospitalstid), 22, 894. A. M. (1952), Bull. Johns Hopk. Hosp., 91, 37I. FREIMAN, D. G. (I948), New Eng. J. Med., 239, 709. IREYBERG, R. H., and GRANT, R. L. (1936), Arch. Intern. STECK, I. E., DEUTSCH, H., REED, C. I., and STRUCK, Med., 58, 213. H. C. (1937), Ann. Intern. Med., I0, 951. HARRELL, G. T., and FISHER, S. (I939), J. clin. Invest., I8, 687. TEILUM, G. (I9si), Acta. path. et. Microbiol., Scand., 28, 294. HOLT, J. F., and OWENS, W. I. (1949), Radiology, 53, II. USTVEDT, H. J. (I939), Nord. Med., 2, I677. HORTON, D., LINCOLN, H. S., and PINNER, M. (I939), VAN CREVELD, S. (I94I), Ann. Paediat., 157,I. A.M. Rev. Tuberc., 39, i86. KEECH, M. K. (I95I), Proc. Roy. Soc. Med., 44, 728. WALSH, F. B., and HOWARD, J. E. (I947), Y. Clin. Endocrin., KLATSKIN, G., and GORDON, M. (I953), Amer. Y. Med., I5, 7, 644. 484. WESTRA, S. A., and VISSA, J. F. (1949), Ned. Tid. Geneesk., KLINEFELTER, H. F., and SALLEY, S. M. (1946), Bull. Johns 93, i8. Hopk. Hosp., 79. ZELDENRUST, cited by VAN CREVELD (above). by copyright. OXFORD MEDICAL PUBLICATIONS JUST PUBLISHED PERSONALITY CHANGES FOLLOWING FRONTAL LEUCOTOMY A CLINICAL AND EXPERIMENTAL STUDY OF THE FUNCTIONS OF THE, FRONTAL LOBES IN MAN by P. MACDONALD TOW, Ph.D., M.B., B.S., M.R.C.S. http://pmj.bmj.com/ Sometime Research Psychiatrist in the Nuffield Department of , University of Oxford; Research in the Departmnent of Clinical Research, and Assistant Physician, Runwell Hospital, Essex; Beit Memorial Fellow for Medical Research, and British Medical Association Research Scholar, University of Oxford; Clinical Research Fellow in at the Massachusetts General Hospital, Boston; Teaching Fellow and Milton Research Fellow at Harvard University. With a Foreword by

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Bibliogaraphv continued from page 5xo-Leslie C. Oliver, M.B., B.S., F.R.C.S. METTLER, F. A., COOPER, I., LISS, H., CARPENTER, M., PUTNAM, T. (1940), Arch. Neurol. and Psychiat., 44, 950. and NOBACK, C. (I954), J. Neuropath. and Exper. Neurol., PUTNAM, T., and HERZ, E. (1950), Ibid., 63, 357. 13, 528. SACHS, E. (I942), Trans. Amer. Neurol. Ass., 68, 80. MEYERS, R. (I940), Arch. Neurol. Ps.chiat., 44, 455. MEYERS, R. (I942), N.Y. Statej_. Med., 42, 317. SPIEGEL, E. A., and WYCIS, H. T. (I954), Arch. Neurol. and MEYERS, R. (i955), personal communication. Psychiat., 71, 598. OLIVER, L. C. (I950), Lancet, i, 847. SJOQVIST, 0. (1954), Zbl. Neurochir., I4, i6. OLIVER, L. C. (I953), 'Parkinson's Disease and its Surgical Treatment,' H. K. Lewis & Co., Ltd., London. WALKER, A. E. (I949), Acta Psychiat. kbh., 24, 723. PARKINSON, J. (I817), 'An Essay on the Shaking Palsy,' Sher- WARD, A. H., JUN., McCULLOCH, W. S., and MAGOUN, wood, Neely and Jones, London. H. W. (1948), J. Neurophysiology, II, 317.