J. Neurol. Neurosurg. Psychiat., 1966, 29, 451

Hypertensive disease and cerebral oedemalMASAZUMI ADACHI, WILLIAM I. ROSENBLUM, AND IRWIN FEIGIN

From the Departments ofPathology, New York University Medical Center, Bellevue Hospital, and the IsaacAlbert Research Institute, New York, U.S.A.

Previous studies have demonstrated the presence inthe brains of some hypertensive individuals ofpathological changes characteristic of the late effectsof cerebral oedema (Feigin and Popoff, 1963;Feigin, 1966). These consist of a degeneration of thedeeper white matter with a relative preservation ofthe arcuate zone and of the overlying cortex. Thedegenerated tissues are softened, retracted, slightlygray in colour, and may be partially destroyed andeven cystic. Microscopically, the affected tissues arepale with most stains. A few hypertrophied astro-cytes may be seen with ordinary stains, but withgold sublimate impregnations, the great majority ofastrocytes appear poorly stained, small and dis-torted in shape, with processes which are shortened,thickened, poorly formed, and decreased in number.The number of myelinated fibres is decreased, attimes markedly so, and rarely, the loss is complete.An axon loss of lesser severity is evident. Thewalls of the smaller blood vessels are often thickenedand hyalinized. The myelin and astrocytes of thearcuate zone are often sharply distinguished fromthose in the deeper white matter by their normalappearance and number.The localization of the changes is like that of acute

oedema, and the astrocytic changes appear torepresent a persistence and extension of those seenin acute oedema (Greenfield, 1939; Feigin andPopoff, 1962). In the acute stages, the astrocyte cellbodies may be well stained, at times somewhatenlarged and rounded; the processes may be frag-mented though well stained, or short, stubby,variably stained, and decreased in number. Themyelin loss is not evident in the acute stage, inwhich a separation of myelinated fibres showingonly modest intrinsic changes, is noted. More severemyelin changes, including evidence of destructionand phagocyte formation, is evident in the subacutestages (Jellinger, 1966).

It was concluded that hypertensive individuals

'This study was supported in part by research grant HE 02872 of theNational Heart Institute of the United States Public Health Service,and forms part of a study of cerebral vascular diseases at BellevueHospital by the Cornell-New York University Study Group oncerebral vascular diseases.

451

differ from normotensive in having a much greatertendency to develop cerebral oedema followingobvious local brain injury, such as infarcts orhaemorrhages, or less obvious, more diffuse injurysuch as is seen in Binswanger's encephalopathy(Feigin and Popoff, 1963). This inference was drawnin a study of cases selected because of the presenceof lesions characteristic of oedema, these forming asmall minority of the total cases of hypertensivedisease. The present study concerns the majority ofhypertensive individuals, those with no grosslyevident abnormality in the tissues. It would appearthat stigmata of antecedent or continuing oedemaare present in these as well.

MATERIALS AND METHODS OF STUDY

A series of human brains from hypertensive individualswas fixed in 20% formalin-l % acetic acid for one to twoweeks. Immediately after coronal section, specimens ofapparently normal tissues were weighed, then dried toconstant weight at 67°C. or 56°C., this taking up to 144hours. The decrement in weight, expressed in relationto the original weight of the sample, was considered torepresent readily volatile water. The water analyses wereperformed by two separate investigators, using materialfrom three different hospitals. One investigator (M.A.)analysed duplicate samples of cortex, arcuate whitematter, deep white matter, and corpus callosum. Onespecimen from each of four tissues was taken before thesecond specimens were obtained. The other investigator(W.R.) examined single samples from the deep whitematter only.

Tissues adjacent to those studied for water contentwere embedded in paraffin for histological study. Thesesections were stained routinely with haematoxylin andeosin, the Luxol blue-periodic-acid-Schiff stain, agold sublimate technique (Naoumenko and Feigin, 1961),and occasionally by other stains.

Twenty-nine unselected hypertensive cases were chosenoriginally, from which 12 were segregated for this study.The other 17 were all cases in which evidence of congestiveright heart failure was present, either at necropsy or inclinical descriptions shortly before death. In the caseswith congestive failure, the water content of the whitematter was significantly higher than in the 12 hypertensivecases being reported in which no congestive failure waspresent, raising the possibility that congestive failure in

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Masazumi Adachi, William I. Rosenblum, and Irwin Feigin

itself may produce cerebral oedema. Since it was ourspecific aim to study the effects of hypertensive disease,it was thought wise to exclude the 17 cases in failure fromthis investigation.The cases being reported all had documented blood

pressure readings above 160 systolic and 100 diastolicexcept for three. Case 1 had a maximal recorded pressureof 180/80 mm.Hg., but there was a history of hypertensionfor 10 years, the heart was hypertrophied (420 g.), andthe kidneys revealed arteriolar nephrosclerosis. Case 8had a maximal recorded pressure of 200/90 mm.Hg.The heart weighed 480 g., and the kidneys revealedKimelstiehl-Wilson lesions. Case 12 had a maximalrecorded pressure of 180/90 mm.Hg. There was a clinicalhistory of hypertension, for which medication had beengiven; the heart weighed 460 g. and the kidney revealedarteriolar nephrosclerosis. All of the cases fulfil thecriteria for hypertension adopted jointly by the AmericanHeart Association and the National Heart Institute, i.e.,systolic above 160 or diastolic above 95 (Doyle, 1960).The pathological changes in heart and kidney in cases1, 8, and 12 lead us to believe that a more completeclinical documentation would have disclosed higherblood pressure readings than those noted.A clinical diagnosis of 'malignant' or 'accelerated'

hypertension was made in cases 9 and 10, but charac-teristic necrotizing vascular lesions in kidney and viscerawere present at necropsy only in the former. 'Hypertensiveencephalopathy' was not diagnosed in any of the cases.The kidney revealed lesions of chronic glomerulone-phritis in cases 10 and 11. All of the other cases are bestcharacterized as benign essential hypertension, and allrevealed arteriolar changes in the kidney. Two of thecases (cases 7 and 10) showed hypertensive fibrinoidarteritis in the brain, a change which was not accompaniedby, and is unrelated to, fibrinoid arterial lesions in otherorgans (Feigin and Prose, 1959).

OBSERVATIONS AND RESULTS

The data for the water content of the brain tissuesare summarized in Table I, which includes in addi-tion, the mean values for the brains of normalindividuals studied earlier (Adachi and Feigin, 1966).The water content of the cortex is essentially identicalto that in the normal cortex, and is like that reportedfor fresh unfixed normal brain (Folch-Pi andLeBaron, 1957). The water content of the arcuatewhite matter is essentially the same as that in thistissue in normal brains, in both the fixed and theunfixed state. The water content of the corpuscallosum is somewhat higher than that in the fixednormal corpus callosum studied in this laboratorythough not higher than in fresh, unfixed corpuscallosum in another study (Stewart-Wallace, 1939).This difference is not statistically significant. Thewater content of the deep white matter of the hyper-tensive brains is significantly higher (P < 0-01)than that in fixed normal brains studied by us, the

TABLE IREADILY VOLATILE WATER (% WET WEIGHT) IN BRAINS OF

HYPERTENSIVE INDIVIDUALSCase Arcuate

White Matter

A E

1 77-2 76-62 79-8 79-234 81-2 81-05 78-1 78-26 81-0 80-67 78-2 78-08 78-5 78-69 80-2 79-610 79-6 79-81112Median' 79 5Mean' 79-2Mean(normal) 79 0

DeepWhite Matter

B F

72-0 71-476-8 76-473 0756 75074 0 73-676-2 76-076-0 75-876-2 76-278-4 78-478-6 78-266-672-7

Corpus CortexCallosum

C G D H

70-8 71-2 84-0 83-676-0 75 8 86-8 87-0

74-6 73-873-0 73-474-8 74-573-6 73-475-8 75 676-5 76 176-8 75 8

83-487-585687-286-085284-2

83-886-785086-285-685 6850

75-6 74-7 85-474-6 74-5 855

71-2 73-3 85-4

'The duplicate values were averaged before calculations.

latter figure being like that reported in unfixedbrains (Folch-Pi and LeBaron, 1957).

Histological study with the Luxol blue-P.A.S.technique was possible in 11 cases, the paraffinblock having been lost in case 6. None of the tissuescontained lakes of oedema fluid, as may be presentin severe instances of acute oedema (Feigin and Pop-off, 1962). With this myelin stain, pallor of thecentral portions of the white matter, contrasting witha normal depth of staining of the arcuate zone, wasevident in two instances (cases 4 and 5). Histologicalstudies with gold sublimate techniques were possiblein only 10 cases, since the impregnation was notsatisfactory in case 9. All of these showed regressivechanges in the deeper portions of the white matterlike those previously described and summarized inthe introduction to this paper. In seven of these 10cases (cases 3, 4, 5, 8, 10, 11, 12), the astrocytes inthe arcuate zone were relatively normal, in contrastto the altered astrocytes in the deeper white matter.In the other three, they showed similar regressivechanges. In four instances (cases 3, 8, 10, 11), thechanges in the deeper astrocytes were thought to beacute.

COMMENT

The data indicate that the deep white matter, thatportion of the brain most specifically affected incerebral oedema, contains a significantly higherwater content in hypertensive individuals than innormotensive individuals. No differences were notedbetween the water contents of cortex or arcuatewhite matter in the two groups, these tissues generally

452

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Hypertensive disease and cerebral oedema

'i45 3Qt ,F72d, ;wI

IF 8 S j

[j-(k. _

FIG. 1. Deep white matter (case 3), showing regressive changes in astrocytes. Paraffin gold sublimate. x 500.FIG. 2. Arcuate white matter (same section illustrated in Figure 1). The astrocytes here are more nearly normal. Paraffingold sublimate. x 500.

being spared in cerebral oedema. There was a slightdifference between the water content of the corpuscallosum in the two groups: this difference is notstatistically significant, but it is in accord with theobservations that the corpus callosum is less com-pletely refractory to cerebral oedema (Greenfield,1939; Adachi and Feigin, 1966).The magnitude of the change in the deep white

matter, if due solely to an increment of water, is moreclearly evident when the increment itself is calculated.For an i,ncrease in water content from 71 2% (meannormal) to 74-6y% (mean hypertensive), 0-134 g. ofwater would have to be added to each 1 gram ofwhite matter (134%). If this were a 1,200 g. brainwith 50% white matter, the water increment wouldbe approximately 80 g. or 80 ml. This is a consider-able increment of volume to be associated with acondition in which no increment of intracranialpressure (Fishberg, 1954) or clinical abnormality isgenerally observed.The water values cited really reflect the relative

proportion of water and solids. Thus, the value71 2% water in normal white matter indicates the

presence of 0 712 g. of water and 0-288 g. of solidsin each 1 g. of tissue. The apparent water contentcould rise to that observed in the hypertensivebrains, 74-6%, if the water were unchanged butsome of the solids had been lost, as is indeed indi-cated by histological studies. Thus, the original0-712 g. of water associated now with only 0-242 g.of solids, would result in the observed water valueof 74-6 %.1 It should be noted that the decrement ofsolids, 0046 g. per gram of white matter (4-6 %),or 27 6 g. in a 1,200 g. brain with 50% white matter,is of lesser magnitude than the increment required

Water 0-7121 Normal: water 1 = 0-712 = 71-2%

Total 1

Hypertensive: Let x = increment of water

Water 0-712 + x _ 0-746 = 74-6°/Total 10 + x

x = 0-134 g./g.or let y = decrement of solids

Water 0-712= 0.746 = 74-6%

Total 10 -y

y = 0-076 g./g.

L c:-.16.--,'.. 4.:.;kir

.

.w 0.0, 1.11 ... ;.

-.4 -

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Masazumi Adachi, William L Rosenblum, and Irwin Feigin

if the change in water concentration were dueentirely to added water, and this loss in solids wouldnot produce an increase in intracranial pressure.It is therefore more consistent with the observedabsence of increased pressure than the alternativeinterpretation, and is probably the more importantfactor in the observed elevation of water concen-tration. The slight loss of tissue may not be clinicallymanifest. It may, however, be a factor in the patho-genesis of the dilated perivascular spaces seen sooften in the white matter of hypertensive individuals.It should be recognized that these two factors arenot mutually exclusive, and that both tissue loss andan absolute increase in fluid may be present simul-taneously. Of greater significance is the realizationthat tissue loss is itself the result of an antecedent,transient or continuing episode of fluid increase, i.e.,cerebral oedema, related to the hypertensive disease.Whether some episodes of headache or other tran-sient neurological symptoms, to which hypertensivesare prone, are specifically related to episodes oracute cerebral oedema, is not established.The histological studies suggest that the examina-

tion of astrocyte morphology with gold sublimateimnpregnations is a far more sensitive indicator ofpresent or antecedent cerebral oedema than wassuspected, and shows changes in tissues which ap-peared normal grossly and with other histologicalstains. The use of paraffin sections greatly facilitatesstudies with the gold technique (Naoumenko andFeigin, 1961). In any case, the profound regressivechanges so evident in these hypertensive cases, and inother cases of cerebral oedema, may well result in aloss of solids of sufficient magnitude to account forpart or all of the apparent increment of watercontent. There are, of course, many other conditionsassociated with regressive changes in astrocytes,and oedemamay be implicated onlywhen the changesas a whole suggest oedema. A sparing of the arcuateastrocytes associated with regressive changes in thedeep white matter is strongly suggestive of oedema.The loss of myelin, which has been observed follow-ing episodes of cerebral oedema of great intensity,was minimal or absent in the tissues studied, therebeing central pallor which contrasted with the normalarcuate zone in only two instances. Such pallor isseen in acute oedema, reflecting a separation offibres by oedema fluid, and as a sequal to oedema,reflecting loss of myelin.

This study appears to confirm the impressionreported earlier that individuals with hypertensivedisease tend to develop cerebral oedema with greaterfrequency and severity than do normotensive indi-viduals. It emphasizes the constancy of the process.All but one of the cases being reported had watervalues greater than the mean of the normal popula-

tion. In the one exception, the water content,66-6 %, is considerably below all other values includ-ing those of the normal group, is most probably anerror, but could not be justifiably excluded on suchassumption. It is of interest that the differencebetween the hypertensive and normotensive groups isstatistically significant even when this case is in-cluded. If it were excluded, the hypertensive groupwould contain a mean of 75 3% water in the deepwhite matter, a value close to the median and veryprobably more accurate. In addition to the elevatedwater values, morphological changes in astrocyteslike those of past or present oedema were present inall 10 cases in which such studies were possible. Thesewere acute in four cases, but not in six others. It ispossible that the oedema is episodic, with periodsof acute oedema being followed by periods of quis-cence within which only the sequelae of the ante-cedent oedema may be recognized.The data in the present and in the earlier studies

suggest that the tendency to cerebral oedema ischaracteristic of the broad class of hypertensiveindividuals, and is not limited to those with severehypertension, with 'malignant hypertension', orwith 'hypertensive encephalopathy'. This tendencyis evident in individuals in whom the blood pressureswere only modestly elevated or, in the earlier study,had even returned to normal from documentedhypertensive levels. The basic mechanism, therefore,may be related to an abnormality associated withhypertensive disease other than the hypertensionitself. The same considerations appear to apply tothe arteritic lesions in the brains of hypertensiveindividuals which may be the basis for the grosscerebral haemorrhages seen in such circumstances(Feigin and Prose, 1959).

This study has disclosed no effect of uraemiaitself on the water content of the brains. Indeed,five of the 12 cases being reported (cases 8-12)had a blood urea nitrogen level above 50 mg.%terminally, but these cases do not differ significantlyfrom the other seven. The same was true within thegroup excluded from the present study because ofthe presence of congestive right heart failure. Thelatter cases will be evaluated again, in part by com-parison with a group of normotensive individuals incongestive failure. At this time, we are in a position tosay that the water content of the deep white matterin these cases (mean 77-8 %) is appreciably higherthan in the group being described, and that thepossibility exists that congestive failure in itself mayproduce or contribute to cerebral oedema.

In closing, a short comment may be warrantedconcerning the validity of the water analyses ontissues from fixed brains, a subject discussed at lengthin earlier papers (Feigin, 1966; Adachi and Feigin,

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Hypertensive disease and cerebral oedema

1966). We have presented evidence to show that themarked swelling reported in some other studies doesnot occur with the technique employed by us, i.e.,the fixation of the whole human brain in 20%formalin-I % acetic acid. The many normal valuesobtained attest to this conclusion. It is also well tonote that cerebral oedema has been demonstratedin the brains of animals rendered hypertensive byexperimental means (Byrom, 1954; Meyer, Waltz,and Gotoh, 1960; Rosenblum, Donnenfeld, andAleu, 1966).

SUMMARY AND CONCLUSION

The water content and histological appearance oftissues of the brains of hypertensive individualswere compared with those of normal individualspreviously studied. The deep white matter of thehypertensive individuals contained significantly morewater than in normal individuals and showedhistological changes like those of present or ante-cedent cerebral oedema. The cortex, arcuate whitematter, and corpus callosum were essentially similarin the two groups. It is the deep white matter that isspecifically affected in cerebral oedema.

These data suggest that hypertensive individualsin general tend to develop cerebral oedema, as wasinferred from a previous study of isolated cases.This phenomenon is not restricted to cases of'malignant hypertension' or of 'hypertensiveencephalopathy'.

REFERENCES

Adachi, M. and Feigin, 1. (1966). Cerebral oedema and the watercontent of normal white matter. J. Neurol., 29, 446.

Byrom, F. B. (1954). The pathogenesis of hypertensive encephalo-pathy and its relation to the malignant phase of hypertension.Lancet, 2, 201-21 1.

Doyle, J. T. (1960). Report of Subcommittees on clinical evaluation,blood pressure measurement and ECG interpretation. Amer.J. publ. Hlth, 50, no. 10, Suppl., pp. 20-28.

Feigin, I. (1966). The course and sequelae of brain edema. To bepublished in the Transactions of the Workshop on BrainEdema of the World Federation of Neurology.

and Popoff, N. (1962). Neuropathological observations on cere-bral edema: the acute phase. Arch. Neurol. (Chic.), 6, 161-160.

, (1963). Neuropathological changes late in cerebral edema:The relationship to trauma, hypertensive disease and Bins-wanger's encephalopathy. J. Neuropath. exp. Neurol., 22,500-511.

- and Prose P. (1959). Hypertensive fibrinoid arteritis of the brainand gross cerebral hemorrhage; A form of 'hyalinos's'.Arch. Neurol. (Chic.), 1, 98-110.

Fishberg, A. M. (1954). Hypertension and Nephritis. 5th ed., p. 802.Lee and Febiger, Philadelphia.

Folch-Pi, J. and LeBaron, F. N. (1957). Chemical composition of themammalian nervous system. In Metabolism of the NervousSystem, edited by D. Richter. pp. 67-71. Pergamon Press,New York.

Greenfield, J. G. (1939). The histology of cerebral oedema associatedwith intracranial tumours (with special reference to changes inthe nerve fibres of the centrum ovale). Brain, 62, 129-152.

Jellinger, K. (1966). Discussion of paper by Feigin (1965). The dis-cussion will be published in the transactions of the Workshopon Brain Edema of the World Federation of Neurology.

Meyer, J. S., Waltz, A. G., and Gotoh, F. (1960). Pathogenesis ofcerebral vasospasm in hypertensive encephalopathy. II Thenature of increased irritability of smooth muscle of pial arteri-oles in renal hypertension. Neurology (Minneap.) 10, 859-867.

Naoumenko, J. and Feigin, I. (1961). A modification for paraffinsections of the Cajal gold-sublimate stain for astrocytes. J.Neuropath. exp. Neurol., 20, 602-604.

Rosenblum, W., Donnenfeld, H., and Aleu, F. (1966). Effects ofincreased blood pressure on cerebral vessels in micr. Arch.Neuirol. (Chic.), In press.

Stewart-Wallace, A. M. (1939). A biochemical study of cerebral tissueand of the changes in cerebral oedema. Brain, 62, 426-438.

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