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FIG. 2

FIG. 1.-Flat mucosa with mosaic pattern from the jejunum of a patient (J. S.) aged 30 and symptom-free for 20 years. (x 35.)

FIG. 2.-Histological section of mucosa shown in Fig. 1. (H. and E. X85.)

FIG. 1 http://www.bmj.com/ RICHARD C. R. CONNOR: HEART DAMAGE ASSOCIATED WITH INTRACRANIAL LESIONS on 24 September 2021 by guest. Protected copyright.

- W - W~ or FIG. 1.-Myocardium. There is normal muscle above and FIG. 2.-Myocardium. Marked area of lesion in Fig. 1 CK78/ below an area showing myocytolysis. Empty sarcolemmal 65) at higher magnification. In the upper part of the picture sheaths and bare nuclei can be seen. (Haemalum and eosin. there is a damaged vacuolated muscle fibre. Scattered remnants x 160.) of fibres are seen in the lesion. Sarcolemmal sheaths with and without nuclei are shown. Polymorphs are not present. (Haemalum and eosin. X400.)

* 6 July 1968 Penicillin-induced Anaemia-White et al. DBRMSHAL 29 no alternative if the penicillin has to be stopped because of concentrations, and Professor J. V. Dacie for his helpful criticism haemolysis. Though no reports exist regarding in-vivo survival of this paper. of cells sensitized with ampicillin, methicillin, and cephalori- dine, Nesmith and Davis (1968) reported that 51Cr-labelled red REFERENCES Br Med J: first published as 10.1136/bmj.3.5609.8 on 6 July 1968. Downloaded from cells sensitized with cephalothin had a TJ of 135 minutes when Beardwell, C. G. (1964). Proc. roy. Soc. Med., 57, 332. injected into a patient with penicillin-induced haemolytic Bird, G. W. G. (1960). 7. clin. Path., 13, 51. Clayton, E. M., Altshuler, J., and Bove, J. R. (1965). Amer. 7. clm. anaemia. Path., 44, 648. We found, as did Bird (1960), that the antibody had no de Weck, A. L. (1964). Nature (Lond.), 202, 975. Dawson, R. B., jun., and Segal, B. L. (1966). Arch. intern. Med., 118, effect on the in-vitro bactericidal activity of penicillin. 575. Incidence of Haemolytic Anaemia after High-Dose Penicillin Fujii, R., Grossman, M., and Ticknor, W. (1961). Pediatrics, 28, 662. Josephson, A. S., and Kaplan, A. P. (1967). 7. Immunol., 98, 293. Therapy.-The incidence of penicillin immune haemolytic Kochwa, S., and Rosenfield, R. E. (1964). 7. Immunol., 92, 682. anaemia in patients receiving high doses of penicillin is not Lai, M., Rosner, F., and Ritz, N. D. (1966). 7. Amer. med. Ass., 198, 483. known, but it is probably not common. We have observed four Landsteiner, K., and Miller, C. P., jun. (1925). 7. exp. Med., 42, 853. other patients who were receiving 20 mega units a day for Levine, B. B. (1965). Fed. Proc., 24, 45. up to six weeks. All gave negative direct antiglobulin tests, Levine, B. B., Fellner, M. J., Levytska, V., Franklin, E. C., and Alisberg, N. (1966a). 7. Immunol., 96, 719. and no antipenicillin antibodies were detected in their sera, Levine, B. B., and Redmond, A. (1966). Information Exchange Group, even though penicillin was easily detectable on the red cells. No. 5. Levine, B. B., Redmond, A. P., Fellner, M. J., Voss, H. E., and Levytska, None of the patients developed signs of haemolysis during V. (1966b). 7. clin. Invest., 45, 1895. therapy. Petz and Fudenberg (1966) briefly mentioned a Ley, A. B., Caham, A., and Mayer, K. (1959). In Proceedings of the patient with a positive direct antiglobulin test and Seventh Congress of the International Society of Blood Transfusion, penicillin p. 539. Basel. antibodies in the serum, in whom there was no evidence of Mollison, P. L. (1967). Blood Transfusion in Clinical Medicine, 4th ed. increased destruction of the red cells. Oxford. Nesmith, L. W., and Davis, J. W. (1968). 7. Amer. med. Ass., 203, 27. Petz, L. D., and Fudenberg, H. H. (1966). New Engl. 7. Med. 274, 171. Strumia, P. V., and Raymond, F. D. (1962). Arch. intern. Aked., 109, We thank Professor C. C. Booth and Professor J. P. Shillingford 603. for permission to publish case histories of the two patients, Mrs. Swanson M. A., Chanmougan, D., and Schwartz, R. S. (1966). -New Engi. 7. Med., 274, 178. Jane Farndon and Mrs. Pamela Lisamore for skilled technical Van Arsdel, P. P., jun., and Gilliland, B. C. (1965). 7. Lab. clin. Med., assistance, Mrs. Ruth Mitcheson for measuring the penicillin serum 65, 277.

Heart Damage Associated with Intracranial Lesions

RICHARD C. R. CONNOR,* M.B., B.S. http://www.bmj.com/

[ WITH SPECIAL PLATE FACING PAGE 8]

Brit. med. J., 1968, 3, 29-31

Summary: Focal myocytolysis, a form of myocardial Material and Methods on 24 September 2021 by guest. Protected copyright. damage, has been found to occur in about 8% of patients dying of intracranial lesions. Electrocardio- From September 1964 until April 1966 231 necropsies were graphic abnormalities in patients with brain damage may performed in the West of Scotland Neurosurgical Unit. The be due to this. The cause of focal myocytolysis remains four main causes of death were intracranial haemorrhage 35%, unknown, but if it could be prevented it might avert the intracranial tumours 25%, head injuries 20%, and intracranial patient's death from cardiac arrest or arrhythmia. More- 15%. over, more than a minimal degree of this type of damage Blocks of ventricular myocardium were fixed in neutral to the heart might make it unsuitable for transplantation. formol saline (10%) and double-embedded by the method of Russell (1956). During the period of this study two transverse slices of most hearts were taken across both ventricles, one Introduction about 3 cm. from the apex and the other near the atrioventri- It has been known for at least 30 years (Aschenbrenner and cular junction. These slices were then divided into multiple Bodechtel, 1938) that brain lesions may be accompanied by blocks. From 18 cases with myocytolysis 170 blocks of myo- abnormalities in the electrocardiogram (E.C.G.). Post-mortem cardium were examined. Paraffin sections were stained with examination of hearts from such patients has not usually shown haemalum and eosin and Masson's trichrome method. any appreciable abnormality, and a vague impression has arisen Correlation of the findings with E.C.G. changes is unfortun- that E.C.G. changes are due to neural influences rather than ately impossible. As the neurosurgical unit is not part of a to actual myocardial changes (Cropp and Manning, 1960). It general hospital, E.C.G.s are not performed routinely. is therefore important to record that myocardial damage does occur in patients with brain lesions. One type of this damage is focal myocytolysis (Schlesinger and Reiner, 1955), which is the subject of this paper. If such damage is more than minimal Results it might render the heart unsuitable for transplantation. Examination of the 231 hearts showed that 18 had foci of *Assistant Pathologist, Department, Western Infirmary, myocytolysis though significant abnormality bad not been seen Glasgow. on naked-eye inspection. Of the 170 blocks from these 18 cases BurrSH 30 6 July 1968 Intracranial Lesions-Connor MEDICAL JOURNAL 101 showed this lesion; some of the sections contained only 1964), U.K. (Srivastava and Robson, 1964), and Japan one or two small foci. Most of the foci were found in the left (Tomomatsu et al., 1964). ventricle rather than the right, but the distribution of damage Focal myocytolysis may cause changes in the E.C.G.; the Br Med J: first published as 10.1136/bmj.3.5609.8 on 6 July 1968. Downloaded from in the muscle was random. There seemed to be no predilection two patients in the present series on whom E.C.G.s were per- for the subendocardial zone; indeed, many of the lesions were formed had considerable changes. One was reported as showing subepicardial. The atrial muscle was not examined. "anterior ," but this was not confirmed when the Thirteen of the patients died from intracranial haemorrhage, heart was examined at necropsy, and focal myocytolysis was two from intracranial infection, and one each of trauma, the only evidence of myocardial damage. It is possible that tumour, and cerebral infarction. Nine of the patients were this lesion could account for some of the reported E.C.G. under 50 years of age, seven were in the sixth decade, and two abnormalities. were older. Cases occurred in every decade. Only two of the The cause of the myocardial damage is not known. Four cases were without evidence of raised intracranial pressure or possible explanations are vagal overactivity, sympathetic over- midline shift at necropsy. Details of the cases are shown in activity, a combination of these two, or an excessive release of the Table. catecholamines. There is clinical or experimental evidence in favour of all these theories as applied to E.C.G. changes. Summary of Cases of Focal Myocytolysis Clinically there is good evidence of vagal overactivity, since Raised Survival patients with brain damage often have bradycardia, pulmonary Case Sex Age Intra- After Coronary Cause of Death oedema, and peptic ulceration, and Cropp and Manning (1960) Agscranial Ictus Stenosis Pressure (Days)I thought that such vagal action might cause the known E.C.G. the E.C.G. in man 121/64 F 61 + 7 + Ruptured vertebral changes. Atropine may improve picture aneurysm 1960; Connor, 1965) and prevent abnormalities 192/64 F 38 5 Hypertensive cerebral (Shuster, + haemorrhage appearing in mice subjected to head injury (Jacobson and 70/65 M 11 2 Severe brain lacerations Section of the cervical cord above the 78/65 M 60 + 4 Ruptured aneurysm Danufsky, 1954). 95/65 M 26 7 Ruptured aneurysm sympathetic outflow will cause abnormal E.C.G.s to become 98/65 M 21 + 5 Cerebral abscess and have been caused stimulation + meningitis normal when the abnormalities by 86/65 F 58 4 Ruptured aneurysm of the brain in cats et Burch et al. 112/65 M 56 + 5 Ruptured aneurysm (Porter al., 1962). (1960) 122/65 F 46 6 + Ruptured aneurysm suggested that the ischaemic changes in the E.C.G. in man 125/65 M 16 7 Craniopharyngioma " 128/65 F 54 4 Hypertensive intra- might be due to intense sympathetic tone." A combination + + cerebral haemorrhage of and was to be the 135/65 M 28 5 + Haemorrhage into vagal sympathetic overactivity thought + choriocarcinoma cause of E.C.G. abnormalities by Visscher et al. (1956). 2/66 M 42 + 4 Ruptured aneurysm 3/66 F 4 16 Postoperative meningitis With to excess catechol activity, Hockman et al. (1966) 7/66 F 58 5 Carotid occlusion and regard cerebral infarction believed that noradrenaline concentration in the heart was the 43/66 F 59 15 Ruptured aneurysm cause of the E.C.G. changes in brain 46/66 F 52 3 Ruptured aneurysm probable dogs following 59/66 F 62 5 Ruptured aneurysm stimulation, and they noted that propranolol caused a return to normal. Shkhvatsabaia and Men'shikov (1962) found the level of catechols to be increased in the heart and decreased in the adrenals of animals after brain stimulation. There are http://www.bmj.com/ rather inconclusive results regarding urinary levels of catechols Discussion in man after cerebrovascular accidents (Tomomatsu et al., 1964). Focal myocytolysis is a distinctive lesion seen most frequently Finally, Melville et al. (1963), as a result of their experi- in association with , from which it must found be distinguished (Schlesinger and Reiner, 1955). Frank infarc- mental stimulation of the hypothalamus in cats, evidence tion was not seen in the 18 cases of this series. The character- suggesting that the vagus, the sympathetic, and noradrenaline istic features of were all responsible in part for the E.C.G. pattern they myocytolysis are loss of sarcoplasm from small on 24 September 2021 by guest. Protected copyright. areas of muscle, with retention of the sarcolemma, stroma, observed. muscle nuclei, and granules; coagulative is The clinical importance of the E.C.G. changes has been not seen and the sarcoplasm seems to have been dissolved underestimated. The original emphasis was on the danger of (Special Plate, Figs. 1 and 2). patients with a subarachnoid haemorrhage being denied the This condition has also been found in patients dying of possible benefits of surgery because of an abnormal E.C.G. The papers by Koskelo et al. (1964) and Hoffbrand and Morgan insulin shock and poliomyelitis (Schlesinger and Reiner, 1955). E.C.G. in The lesion described as " necrosis " by Eichbaum and Bissetti (1965) are alone in suggesting that the abnormal (1966) in patients dying with head injuries may be of the same patients with brain damage may indicate cardiac dysfunction. serum kinase type. Two papers which may describe similar damage are Dubo et al. (1967) found a raised level of creatine those of Neuburger (1933) concerning death in young epileptics in many patients with strokes and head injuries. The enzyme and of Burch et al. (1960), who briefly mention myocardial was always of the type originating in cardiac and skeletal was the damage in a patient dying with subarachnoid haemorrhage. It muscle, and Connor (1967) suggested that the heart most likely source. Patients with intracranial lesions from is surprising that this lesion has not been more frequently die of heart described in cases of intracranial haemorrhage, as the majority which recovery is possible may sometimes damage, of recent papers on E.C.G. abnormalities and brain lesions have and it would be of value to discover a method of prevention. concerned patients with cerebrovascular accidents. The normal This might be the administration of drugs to reduce the activity gross appearance of the myocardium may be a partial explana- of the parasympathetic or sympathetic nervous systems or a could tion, as multiple blocks would not be examined. Some local to block an excess of catecholamines. If such method be found, it should prevent death from cardiac arrest or factor occurring in the West of Scotland (Crawford and broncho- Crawford, 1967) might predispose the population to the arrhythmia, pulmonary oedema and subsequent can the development of heart damage, but E.C.G. changes in similar pneumonia, and cerebral hypoxia, which only make patients have been reported from many countries. Thus Burch original intracranial damage worse. et al. (1954) described E.C.G. changes in patients in the U.S.A. The cause of focal myocytolysis is not clear. As stated above with cerebrovascular accidents, and among many others there it is often associated with larger areas of , are papers from U.S.S.R. (Popov, 1955), China (Kung et al., though this was not found in the present cases. Focal 1958), South Africa (Hersch, 1964), Finland (Koskelo et al., Myocytolysis may owe its distinctive histological features to the 6 July 1968 Intracranial Lesions-Connor MBDICALJnmOuiu 31

small size of the lesions or to a slow rate of development and, Hersch, C. (1964). Brit. Heart Y., 26, 785. Hockman, C. H., Mauck, H. P., and Hoff, E. C. (1966). Amer. Heart like myocardial infarction, may be a " pluricausal cardiopathy." 7., 71, 695. Hoffbrand, B. I., and Morgan, B. D. G. (1965). Lancet, 1, 844. Jacobson, S. A., and Danufsky, P. (1954). 7. Neuropath. exp. Neurol., Br Med J: first published as 10.1136/bmj.3.5609.8 on 6 July 1968. Downloaded from I am grateful to Professor J. R. Anderson and Dr. A. T. Sandison 13, 462. for their help and encouragement in preparing this paper. Koskelo, P., Punsar, S., and Sipild, W. (1964). Brit. med. 7., 1, 1479. Kung, L. S., Huang, T. K., Chu, H. Y., and Koang, N. K. (1958). Chin. med. 7., 76, 445. REFERENCES Melville, K. I., Blum, B., Shister, H. E., and Silver, M. D. (1963). Amer. 7. Cardiol., 12, 781. Aschenbrenner, R., and Bodechtel, G. (1938). Klin. Wschr., 17, 298. Neuburger, K. T. (1933). Frankfurt. Z. Path., 46, 14. Burch, G. E., De Pasquale, N., and Malaret, G. (1960). Ann. intern. Popov, V. G. (1955). Ter. Arkh., 27, 45. Med., 52, 587. Porter, R. W., Kamikawa, K., and Greenhoot, J. H. (1962). Amer. Heart Burch, G. E., Meyers, R., and Abildskov, J. A. (1954). Circulation, 9, 7., 64, 815. 719. Russell, N. L. (1956). 7. med. Lab. Technol., 13, 484. Connor, R. C. R. (1965). Personal observations. Schlesinger, M. J., and Reiner, L. (1955). Amer. 7. Path., 31, 443. Connor, R. C. R. (1967). Lancet, 2, 991. Shuster, S. (1960). Brit. Heart 7., 22, 316. Crawford, T., and Crawford, M. D. (1967). Lancet, 1, 229. Shkhvatsabaia, I. K., and Men'shikov, V. V. (1962). Kardiologia Cropp, G. J., and Manning, G. W. (1960). Circulation, 22, 25. (Moscow), 2, No. 6, p. 27. Dubo, H., Park, D. C., Pennington, R. J. T., Kalbag, R. M., and Walton, Srivastava, S. C., and Robson, A. 0. (1964). Lancet, 2, 431. J. N. (1967). Lancet, 2, 743. Tomomatsu, T., et al. (1964). 7ap. Circulat. 7. (Ni.), 28, 905. Eichbaum, F. W., and Bissetti, P. C. (1966). Proceedings of 5th Inter- Visscher, M. B., Haddy, F. J., and Stephens, G. (1956). Pharmacol. national Congress of Neuropathology, p. 1016. Amsterdam. Rev., 8, 389.

Preliminary Communications

Use of Dexamethasone in Cerebral Malaria his destination, the residence of a friend, who immediately called a medical practitioner who had the patient admitted to a nursing- home. There a blood film was examined and malaria parasites Brit. med. J7., 1968, 3, 31-32 were found in it. The patient was given 600 mg. of chloroquine by mouth and managed to swallow the dose; in spite of this, five hours later he was in coma and arrangements were made for his transfer Summary: In a man who had been in a coma for 24 to the Hospital for Tropical . hours with cerebral malaria dexamethasone had a On admission he was comatose, unable to speak, and restless dramatic, and probably life-saving, effect. We believe and at times he was struggling, but he momentarily ceased to do so dexamerhasone should be given routinely, together with when his name was loudly called ; he resisted medical examination. antimalarial therapy, to patients with cerebral malaria. An hour later his coma became deeper and there was no response when his eyelashes were touched. A blood film at this time showed http://www.bmj.com/ that 5% of erythrocytes were parasitized with Plasmodium falci- INTRODUCTION parum. His blood urea on admission was 84 mg./100 ml., plasma sodium 128 mEq/l., and potassium 3.4 mEq/l. An intravenous The mortality rate in cerebral malaria has continued to be drip infusion was set up and through this 200 mg. of chloroquine considerable even though the introduction of haemodialysis in was administered in 45 minutes; a further 100 mg. was given six the treatment of patients with severe malaria who hours later, and three hours later still a blood film showed only develop 0.1 % erythrocytes parasitized. The temperature on admission was uraemia and renal failure has enabled such patients to be kept 104' F. (40' C.), and 18 alive, in most hours later it was still 102' F. (38.9' C.). instances until kidney function recovers (Jackson During these 18 hours he continued to be critically ill, was com- on 24 September 2021 by guest. Protected copyright. and Woodruff, 1962). The principal obstacle to recovery is pletely unconscious, and responded only to painful stimuli. There, usually continued coma and the respiratory infection which were extensor plantar reflexes, and 12 hours after admission-that frequently complicates it. We recently treated a patient in deep is, after he had been unconscious for approximately 16 hours- coma with Cheyne-Stokes breathing whose prognosis appeared there followed a period in which respiration from time 'to time took to be very grave. At this stage dexamethasone was administered on Cheyne-Stokes characteristics with considerable periods of intravenously with the object of reducing the cerebral oedema apnoea. which so often is a major pathological feature in cerebral During the 12 hours following admission he was given 1,500 ml. malaria. The response was so dramatic that we suggest that of fluid intravenously and the urinary output was 1,300 ml., but use of this drug might become standard practice in cases of at the end of this 12-hour period the blood urea remained 84 mg./ this kind. We are not aware of other 100 ml. In view of his critical condition, continuing deep coma, reports on use of dexa- and the possibility that dialysis might become necessary he was methasaone in this regimen for cerebral malaria having so far transferred to the intensive care unit. Here the question of admin- appeared in the literature, and for this reason we consider it istering dexamethasone intravenously was considered, and in view important to draw attention to this case. of the fact that the malarial infection was already satisfactorily controlled and no evidence of respiratory infection was present- CASE HISTORY this possibility having already been covered by the previous admini- stration of tetracycline-it was decided that dexamethasone admini- The patient, a 40-year-old man, had spent a month on a shooting stration could not aggravate any infection and that its effect in expedition approximately 150 miles (240 km.) to the east of Nagpur, diminishing cerebral oedema could be valuable. Twenty hours India; he had never visited any part of Africa. He arrived in after admission-that is, after he had been in coma for approximately Britain by air, having for the previous 7 to 10 days felt unwell 24 hours-10 mg. of dexamethasone was injected intravenously. with headache, aches and pains of the limbs, and attacks of shiver- Four hours later coma had sufficiently lightened for the patient to ing; there is documentary evidence that three days before his arrival ask for a drink, and 12 hours later he was fully conscious and ate he had had a temperature of 1020 F. (38.9° C.); on this day a breakfast. Dexamethasone in doses of 4 mg. was administered blood film had been examined, but no malarial parasites had been intravenously on two occasions during the 24 hours following the noted in it and he had been given treatment with Achromycin V initial dose. in doses of 250 mg. six-hourly; of this it seems he took a total of Progress thereafter continued uninterruptedly. During the suc- 1.5 g. On arrival in Britain he had, with help, managed to reach ceeding four days the plasma urea dropped from 84 to 26 mg./