227LEADING ARTICLES

Hypertensive Encephalopathy and ArterialSpasm

THE LANCETLONDON: SATURDAY, JULY 31, 1954

THE term hypertensive encephalopathy "

was

applied by OPPENHEIMER and FISHBERG 1 to a groupof acute and usually transient cerebral symptomsoccurring in patients with high blood-pressure. The

symptoms are headache, disorientation, convulsions,blindness, transient pareses, and coma, and they mayappear in acute nephritis, chronic nephritis, malignantessential hypertension, and hypertension arisingduring pregnancy. VOLHARD had observed that inacute nephritis these attacks were not due to renalinsufficiency, and had called them " pseudo-uræmia ":he believed that cerebral vasoconstriction was

primarily responsible for them, and OPPENHEIMERand FISHBEBG agreed with him. The fact that theattacks may be promptly and dramatically relievedby venesection or hypotensive drugs is a strongargument in favour of this explanation. There is

evidence, however, that the cerebral vessels reactbut feebly to sympathetic stimulation and vaso-

constrictor agents. Moreover, during the past twentyyears hypertension has been increasingly attributedto generalised vasoconstriction of a humoral nature,and the idea that it may in turn give rise to excessivefocal vasoconstriction, particularly in the brain, hasseemed somewhat illogical. Some authorities have

preferred to suppose that the symptoms of hyper-tensive encephalopathy are caused by œdema.

Knowledge of the actual mechanism of hypertensiveencephalopathy is important both in itself andbecause of its bearing on the basic problem of vasculartone in hypertension ; but clinical research has beenhindered by the difficulty of direct experiment, whichhas been possible only in animals. In 1939 WILSONand BYROM 2 were able to describe acute cerebralattacks in rats with induced hypertension and showedthat the symptoms appeared in the absence of uraemiaand disappeared promptly when the blood-pressurewas restored to normal. Since these early experimentsBYROM has made a remarkably detailed and compre-hensive investigation of encephalopathy in hyper-tensive rats, a full account of which appears at thefront of our present issue. He describes how hyper-tension was induced by excising one kidney andconstricting the opposite renal artery. Of 250 animalsthus treated which developed encephalopathy, 34%had generalised epileptiform convulsions, other mani-festations being myoclonic contractions, muscularweakness, hemiplegia, paraplegia, and coma. Cervical

sympathectomy neither relieved nor prevented theattacks; but abolition of hypertension in 142 rats by1. Oppenheimer, B. S., Fishberg, A. M. Arch. intern. Med. 1928,

41, 264.2. Wilson, C., Byrom, F. B. Lancet, 1939, i, 136.

removal of the clip from the renal artery broughtabout dramatic and permanent remission in 129which survived this operation. Post-mortem examina-tion of the brain showed organic lesions in 55%,including focal necrosis of small or medium arteries,small infarcts in various stages of healing, and arterialor capillary hemorrhages : the remaining 45% hadeither no organic changes or patchy cerebral oedema.There was no correlation between the clinical mani-festations and the presence or absence of organiclesions. In a control series of rats with " simplehypertension

"

(i.e., without encephalopathy) the

only abnormalities found were 2 healed infarcts.BYROM then proceeded to a detailed study of

cerebral oedema in the hypertensive animals. Whereasin simple hypertension no increase in the watercontent of the brain was found, encephalopathy wasassociated with a slight increase which becamesubstantial in the later stages, sometimes leading tothe formation of a pressure cone. The pressure of the

cerebrospinal fluid, measured in the cisterna magna,was occasionally normal in early encephalopathybut was greatly raised in the later stages. The mech-anism and distribution of cerebral oedema in encephalo-pathy was investigated by intra-vitam injection oftrypan-blue, which does not pass the blood-brainbarrier unless the capillary endothelium is damaged.In rats with normal blood-pressure or simple hyper-tension no staining of the brain was found, whereas in87% of 145 rats with cerebral symptoms multiplescattered foci of staining appeared in the grey matterof the cerebrum, the cerebellum being almostunaffected. Examination of the choroid plexuses withthe dissecting microscope yielded no evidence of

permeability to trypan-blue, and no dye was visiblein the ventricular system. Though organic vascularlesions of the brain were associated with blue staining,125 out of 161 stained areas appeared histologicallynormal or showed indefinite focal oedema. By carefulsampling, the water content of the stained areas wasnow compared with that of corresponding areas ofunstained brain tissue, and a considerable excess ofwater was demonstrated in the former. From theseobservations BYROM deduced that in encephalopathymultiple foci of increased capillary permeabilityregularly occur and give rise to focal oedema ; inthese areas organic arterial lesions may be present orabsent.The nature of the local circulatory disturbance was

next investigated. Studies of blood-flow in theexternal and internal carotid arteries of animals withand without encephalopathy suggested a considerableincrease of cerebral vascular resistance in those with

encephalopathy. But obviously it was necessary tohave more reliable evidence of cerebral arterial

behaviour, and this has now been provided by a re-

markable series of direct observations of the cerebralarteries through windows inserted in the rat’s skull :the surface of the brain was photographed by electronicflashlight, using a 35 mm. camera attached to thedissecting microscope. In 190 observations on 160rats with simple hypertension the cerebral arteriesremained normal in appearance even after manymonths, and spasm was recorded on only 7 occasions.But in 135 rats with encephalopathy the picture wasvery different. Pallor of the brain was conspicuous,small arteries appeared diffusely narrowed, and in

228

larger arteries both diffuse and localised spasm wasseen : these changes were absent in only 16 of 150observations. When (in 76 rats) hypertension wasabolished by removal of the clip from the renal artery,symptoms of encephalopathy disappeared and controlphotographs two weeks later always showed a returnof the cerebral arteries to normal. By careful analysisof his material, BYROM excluded the possibility thatthe abnormal appearances might be due to distortionof vessels by cerebral oedema. He holds that thevascular spasm is a direct response to the strain ofincreased intra-arterial pressure. In a smaller seriesof rats with severe hypertension-and especially inthose with encephalopathy-the arteries of theintestine and mesentery showed similar widespreadfocal arterial spasm.

Relating these findings to his previous observationson the production of arterial spasm and arterialnecrosis in the kidney by injection of pitressin 3 andby forcible distension of the arterial system by salineinjection,4 BYROM reaches the conclusion that bothencephalopathy and the acute arterial necrosis whichis the essential lesion of malignant hypertension arethe result of focal arterial spasm. The fact that inthe hypertensive rat a clamp on the renal arteryprotects the kidney against arterial necrosis is con-firmatory evidence that high blood-pressure is thestimulus which provokes the excessive vasoconstric-tion and leads to the arterial necrosis. He suggeststhat, in human malignant hypertension, papilloedemaand raised intracranial tension may be the expressionof sustained cerebral oedema resulting from chronicencephalopathy. Against this is the fact that, thoughcerebral oedema is occasionally observed in the latestages of malignant hypertension, this is unusual,whereas papilloedema and raised intracranial tensionare early manifestations which appear long before- and indeed in the absence of-attacks of encephalo-pathy. The mechanism of papilloedema in malignanthypertension needs further clarification.BYROM’s work proves the existence, in severe hyper-

tension, of focal arterial spasm ; and, according tothe intensity, duration, and distribution of theanoxia it induces, this might cause capillary damage(leading to focal oedema), tissue damage (leading todisorder of function), and damage to the arterialwall (leading to necrosis). He asks two very pertinentquestions. First, if it is accepted that big increases inintra-arterial pressure cause excessive local vasocon-

striction, may not smaller increases (as in " simplehypertension ") contribute directly and progressivelyto the generalised vasoconstriction ? Secondly, maynot the increase in arteriolar tone which initiallycauses the blood-pressure to rise be a response ofabnormally irritable arterioles to the normal blood-

pressure ? In posing these questions he recalls thatover fifty years ago W. M. BAYLISS postulated thatthe tension within an artery is a normal and directstimulus to contraction of its muscle coat. These

speculations are timely because. in discussions ofarteriolar tone, more emphasis is now being placedon electrolyte distribution than on circulating pressorsubstances. It may well be that study of whatBYROM terms the " uncontrolled focal vascular spasm"

3. Byrom, F. B. J. Path. Bact. 1937, 45, 1.4. Byrom, F. B., Dodson, L. F. Ibid, 1948, 60, 359.

of malignant hypertension will radically alter our

concept of the " orderly diffuse vasoconstriction " ofbenign hypertension.To transfer experimental findings from animals to

man demands the utmost discrimination. Yet, whenevery qualification has been made, this investigationon hypertensive encephalopathy must be regarded asa major contribution to experimental pathology. It is

outstanding in the logic of its argument, the ingenuityof its techniques, and the objectivity of its conclusions,no less than in the magnitude of its achievement.

1. Finney, J. T. M. Bull. Johns Hopk. Hosp. 1893, 4, 53.2. Terrier, F., Hartmann, H. Chirurgie de l’estomac. Paris, 1899.3. Riedel, B. M. C. L. Dtsch. Z. Chir. 1903. 67, 402.4. Finsterer, H. Ibid, 1914, 128, 514.5. Penner, A., Bernheim, A. I. Arch. Path. (Lab. Med.), 1939,

27, 966.6. Williams, M. R., Pullan, J. M. Lancet, 1953, ii, 1013. See Ibid.

p. 1028.7. Pettet, J. D., Bagenstoss, A. H. Dearing, W. H., Judd, E. S.

Surg. Gynec. Obstet. 1954, 98, 546.7A. Kleckner, M. S., Bargen, J. A., Bagenstoss, A. H. Gastro-

enterology, 1952, 21, 212.8. Refiner, L., Sehlesinger, M. J., Miller, G. M. Arch. Path. (Lab.

Med.), 1952, 54, 39.9. Hay, P., McKenzie, P. Lancet, 1954, i, 945.10. Dearing, W. H. Heilman, F. R. Proc. Mayo Clin. 1953, 28, 121.

Pseudomembranous EnterocolitisTHE small bowel is a dark and secret place ; and

many of its disorders are imperfectly understood.One such disorder is pseudomembranous enterocolitis,which is characterised clinically by diarrhœa andsudden severe shock and pathologically by inflamma-tion and eventually mucosal necrosis affecting thesmall bowel more commonly and more intenselythan the large. In 1893 FINNEY 1 described a casein which the patient died after five days of bloodydiarrhoea which began on the tenth day after operationfor pyloric obstruction; " diphtheritic enteritis " wasdiscovered at necropsy. From Paris in 1899 TERRIERand HARTMANN reported 7 similar cases ; RIEDEL 3described 5 more, 1 following hysterectomy; andFINSTERER 4 encountered this disorder in his gastricclinic. It has since been found as a sequel to otheroperations, including thoracotomy 5 ; and last yearWILLIAMS and PULLAN 6 described 10 cases in

patients who had had operations on the stomach. Butnow a study by PETTET et al.,? of the Mayo Clinic, hasrevealed that operations on the colon are by far thecommonest precipitating factor. Pseudomembranousenterocolitis may also arise without any precedingoperation. Between 1940 and 1950 KLECKNER et a1.7Asaw 14 such cases associated with colonic obstructiondue to neoplasm, with cardiac disease, or with infection.Aureomycin and chloramphenicol 8 and oxytetra-cycline (terramycin) 6 9 have also been named as

precipitating factors ; but figures from the MayoClinic 10 suggest that antibiotics do not account formany cases : the number of patients who died of thisdisorder was 42 in 1927-36, compared with 37 in1943-52.

Explanations of the condition have not been lacking.RIEDEL 3 noted the resemblance of the intestinallesions to those of mercury poisoriing and was at painsto point out that his suture material had been thor-oughly washed ; he concluded that long operationswith severe blood-loss made the intestine incapable ofresisting its contents. The views of PENNER andBERNHEIM 5 have carried more weight. They foundsubmucosal dilatation of capillaries and venules.followed by oedema and haemorrhage and ultimately