THE FUNDUS IN ESSENTIAL CARDIOVASCULAR HYPERTENSION 395

'Granit, R., and Harper, P. Comparative studies on the peripheral and central retina II.Synoptic reactions in the eye. Amer, Jour. Physiol., 1930, v. 95, p. 211.

• Hecht, S., Shaler, S., and Verrijp, C. S. The measurement of critical fusion frequencyfor the human eye. Jour. Gen. Physiol., 1933, v. 17, pp. 237,251,269.

• Enroth, E., and Werner, S. Undersokning av ljussinnet medels intermittent ljus : FinskaUk. sallsk. Handl., 1935, v, 78, p, 161.

'0 Gronholm-Therman. Quoted by Granit, R. Die Electrophysiologie der Netzhaut und desSehnerven, Acta Ophth., 1936, v. 14, Supplement 8.

"Phillips, G. Perception of fields in lesions of the visual pathways. Brain, 1933, v. 56,p.464.

,. Riddell, L. A. The use of the flicker phenomenon in the investigation of the field of vision.Brit. Jour. Ophth., 1936, v. 20, p. 386.

.. Niederhoff, P. Das Flimmer-Perirneter, ein Apparat zur genauen Untersuchung des Gesichts-feldes. KHn. M. f. Augenh., 1936,v. 96, May, p. 601.

J4 Creed, R. S., and Ruch, T. C. Regional variations in sensitivity to flicker. Jour. Physiol.,1932, v. 74, p. 407.

ESSENTIAL CARDIOVASCULAR HYPERTENSION AS REVEALED INONE HUNDRED CONSECUTIVE EXAMINATIONS OF THE

FUNDUS OCULI*

FRED T. TOOKE, M.D., AND JOHN V. V. NICHOLLS, M.D.Montreal

In the course of a survey of the resultsof special examinations requisitionedfrom the Department of Ophthalmologyby other services in the Royal VictoriaHospital of Montreal, a wealth of valu­able information has been supplied andplaced on record. Such information hasbeen placed at the disposal not only ofthe ophthalmologist but also of those inthe various branches of medicine whoseek the corroborative evidence or theconstructive information which the find­ings in the fundus oculi so frequently sup­ply in doubtful cases. It was discovered,following a review of a year's work, thatof the cases admitted to the Department ofMedicine, 10 percent were conditions ofhypertension in one form or another,and with such a mass of material at ourdisposal an avenue of investigation wasclearly opened.

It is admitted that the subject has beeninvestigated, and ably so, by many out-

*From the Department of Ophthalmology,Royal Victoria Hospital. Read before theCanadian Medical Association at Ottawa, Ont.,June 24,1937.

standing authorities; but it is felt that un­intentionally the title has been sometimesdisregarded and the results, in conse­quence, beclouded through the fact thatthe authors failed to analyze closely ordefine the precise type of cardiovascularhypertension with which they were deal­ing. We have considered the question un­der discussion, essential cardiovascularhypertension, as separate and distinctfrom such other varieties as those ofnephritic and diabetic origin, as well asthose arising from other potential sources.

Some element of appreciation of theforegoing remarks will best be graspedwhen it is noted that in assembling ourseries of 100 cases of the essential type,450 case reports designated as cardio­vascular hypertension and extending veryslightly over a period of more than twoyears' time had to be systematically in­vestigated and studied. It is to be recordedwith some degree of disappointment thatfrequently the Department of Ophthal­mology had not been requested to submit areport on the fundus oculi, although thecase report in other respects invariably

396 FRED T. TOOKE AND JOHN V. V. NICHOLLS

was perfect in detail. Such a discrepancy,however, very fortunately for the re­viewers, was much more frequently theexception than the rule. Again, the casesof hypertension with an associated ante­cedent diabetes or nephritis, far outnum­bered the type of case which it had beendecided to investigate, and these, with theerrors of omission previously admitted,had to be put aside.

type of ophthalmoscope always was used,and no findings were recorded unless thepupils were satisfactorily dilated withhomatropine.

In the following tables, the results ofour findings are registered in such detailas the data permitted.

An analysis of the hundred cases ofthe essential hypertensive variety whichwe have made, and a comparison of them

TABLE 1PRIMARY HYPERTENSIVE CASES PRIMARY NEPHRITIC CASES

100 Cases: 52 "Females, 48 Males 17 Cases: 7 Females, 10 Males

Low High Average Low High Average

Age 39 Yrs. 84 Yrs. 58.7 Yrs. 26 Yrs. 58 Yrs. 41.4 Yrs.

Blood pressure160 260+ 195.5 140 260+ 219.480 120 110.6 80 170 131.0

Creatinine 1.01 2.14 1.25 1.03 16.8 3.63mgm. % mgm. % mgm. % mgm. % mgm.% mgm. %

N. P. N. 17.1 75.3 30.4 19.1 284.0 90.8mgm. % mgm. % mgm.% mgm. % mgm. % mgm. %

Urine Sp. Gr. 1004 1036 1017 1006 1030 1013

Urine Albumin 0 ++ 50% showed ++ ++++ 100% showedalbumin albumin

Casts 20% showed 80.2%casts showed casts

Simply to justify our conclusions or toattempt to draw a parallel, a series ofconsecutive cases of cardiovascular hyper­tension associated with nephritis havebeen analyzed, so that a comparison maybe drawn and some deductions arrivedat, which will be referred to later.

Regarding the ophthalmological investi­gation, an attempt at uniformity has beenmade in dealing with the subj ect. In thefirst place, the material supplied has beenobtained without exception from the so­cial class that is found in the public wards.Furthermore, the ophthalmoscopic exam­ination was carried out and the findingsrecorded, with very few exceptions, bythe same member of the department, andthe personal error in interpretation was inconsequence avoided. Again, the same

with those of primary nephritic origin af­ford us the following conclusions (table1) :

As to age, as one would expect, the pa­tients with essential hypertension weredefinitely more advanced in years thanwere those whose condition was of neph­ritic origin, the average of the formerbeing 58.7 years, and of the latter 41.4years. The reason for this is probably thatthe cases of primary nephritis for the mostpart have their origin during childhood,as a result of many intercurrent diseasesat that time, while the hypertensive con­ditions are really the result of an agingprocess. Among women, the onset of themenopause is an apparent factor.

Blood pressure at first glance wouldshow a seeming discrepancy, ranging in

THE FUNDUS IN ESSENTIAL CARDIOVASCULAR HYPERTENSION 397

the hypertensive cases from 160/80 to260/120, with an average of 195.5/110.6.In the nephritic cases the lowest was 140/80 and the highest 260/170, giving anaverage of 219.4/131.0. The pulse pres­sure in the former was 84.9 and in thelatter 88.4, the end results showing a rela­tively slight discrepancy. As would he ex-

mary hypertensive cases in amountsregistered as from 0 to 2 plus while inthe primary nephritic cases it ranged from2 plus to 4 plus in 100 percent of the cases.In the primary hypertensive cases, again,only 20 percent showed casts, while over80 percent manifested these in the latterclass of case.

TABLE 2PRIMARY HYPERTENSIVE CASES-loo CASES

Left Eye Right Eye

Fundus Total ~per Lower Upper Lower Mac- Total Upper Lower Upper Lower Mac-Changes % asal Nasal Temp. Temp. ular % Nasal Nasal Temp. Temp. ular

Normal 29 28

Contractedarteries 63 57

Contractedarterialca pillaries 1 2

Engorgedveins 40 40

Tortuous veins 23 22

Buckled veins 36 8 1 35 6 2

Small petechial1 2 2hemorrhages 16 2 2 3 3 2 11 3

Large hem-morrhages 8 2 2 2 1 6 2 4

Lymph exudate 5 2 1 7 1 4 2

Pigmentchanges 1 1 1

Perineuraledema 5 5

Other findings:1. Old retinal artery thrombosis, 1 in O.S.2. Venous thrombosis, 1 in O.D. (upper temporal).3. Cataracts: 14 bilateral, 1 in O.S., and 1 in O.D.

pected, the blood chemistry values forcreatinine and N. P. N. were definitelypathological in the primary nephriticcases, whereas, in the primary hyperten­sive cases they were essentially normal,although in a relatively few instances highvalues were found.

The question regarding specific gravityof the urine conveys practically no answerto our argument. As to albumin, however,it was present in SO percent of the pri-

To tum for a moment to an analysis ofthe fundus findings (table 2) as recordedindependently in each eye: Of the 100cases, 28 were normal on the right side,while 29 were normal on the left; that isto say, the two eyes were normal in es­sentially the same number of instances.Those showing pathological findings wereinteresting for their various subsections.It will be seen in table 2 that each eyepractically balanced with its fellow as to

398 FRED T. TOOKE AND JOHN V. V. NICHOLLS

TABLE 3MEDICAL DIAGNOSES ASSOCIATED WITH

ESSENTIAL HYPERTENSION

the number of pathological manifesta­tions; also that there was very littlediscrepancy except in the recorded num­ber of small petechial hemorrhages, theleft eye showing relatively more thanthose noted in the right. An explanation

DiagnosisArteriosclerosis with hypertensionMyocarditisEssential hypertensionAuricular fibrillationCoronary thrombosisNephritis (secondary to hypertension)Cerebral hemorrhageCerebral thrombosisSubarachnoid hemorrhagePresenile dementiaSyphilis

Percent8429165627

14116

it would seem most improbable that a de­compression at such a relatively short dis­tance from the disc could be broughtabout. The statements of Foster Moore,"as well as the pathological work of Coats"and of Oatman,' with the various micro­photographs illustrating actual bucklingwould support the stand we take in suchan argument.

When very many manifestations of apathological process have been observed insimilar conditions, such as the occurrenceof buckled veins and smalI petechialhemorrhages, naturalIy the recorded find­ings do not tally with the total percentage,for in many instances it was quite impos­sible to make an absolute record of eachspecific lesion. For the most part, hemor­rhages and exudates were found in the

TABLE 4TOTAL CEREBRAL ACCIDENTS, 21 CASES

posterior part of the retina, relativelyclose to the nerve head, thus confirmingthe findings of Foster Moore."

The medical diagnoses associated withthe condition of essential hypertensionspeak for themselves (table 3). Because

Left Eye

F d Ch Total Per-un us anges cent

4.8

4.8

4.8

4.8

9.6

4.8

61.9

57.1

28.6

33.3

41.6

2

1

6

1

1

Right Eye

12

10

13

Total Per­cent

o

o

4.8

4.8

9.6

33.3

14.3

57.1

61.9

28.6

43.6

Pigment changes 0

Engorged veins 12

Buckled veins 9

Normal 6

Perineural edema 2

Contractedarteries 13

Lymph exudate 1

Contracted arte­rial capillaries

Large hemorrhages 0

Tortuous veins 7

Small petechialhemorrhages 3

is offered which may account for such aresult, in that the left common carotidartery comes off the aorta directly, where­as the right is the branch of the innomi­nate artery. Thus, one would expect agreater arterial hydrostatic thrust in theleft common carotid artery. Regarding thequestion of buckled veins: Fishberg andOppenheimer" would have us believe thatbuckling, as such, does not exist, and thata pressure of the relatively more con­tracted artery exerts little, if any, influ­ence upon the underlying venous wall.They claim that the impression conveyedthrough the ophthalmoscope is due to adisplacement of the vein to a deeper orlower level within a retinal tissue. I f oneis to understand that these two types ofvessels occur normally within a similarstratum it is rather difficult to understandhow the veins can suffer such an altera­tion in tissue displacement. Again, as weso frequently noted in our observations,some of the most manifest instances ofbuckling took place in the vein less than adisc-diameter's distance from the discmargin. And if both the artery and thevein are, so to speak, anchored at one end,

THE FUNDUS IN ESSENTIAL CARDIOVASCULAR HYPERTENSION 399

of the verbal statement of Dr. J. C. Mea­kins, director of the Medical Clinic ofMcGill University, that in his experiencecerebral accidents were for the most partassociated with a normal fundus, we wereled to examine these cases rather closely.Of our 100 cases, 21 might be classedas cerebral accidents; that is, cerebralhemorrhages or cerebral thromboses.From table 4 it will be found that in 28.6

were found in cerebral accidents, and areagain probably the result of the increasedintracranial pressure. It is interesting tonote that in 11 cases of hypertensionLarsson" found increased intracranialpressure in each. Such a condition wouldprobably account for the perineural edemanot associated with a cerebral accident.

It is interesting to draw a comparisonbetween the cases which we have just had

TABLE 5PRIMARY NEPHRITIC CASES, 17 CASES

Left Eye Right Eye

Fundus Changes Total % Total %

Normal 2

Contracted arteries 13

Contracted arterial capillaries 0

Engorged veins 7

Tortuous veins 4

Buckled veins 5

11.7

76.5

o41.1

23.5

29.4

3

12

o7

5

5

17.6

70.5

o41.1

29.4

29.4

2 2

Small petechial hemor­rhages

Large hemorrhages

Lymph exudate

Pigment changes

Perineural edema

10 58.8

6 35.4 1 2

9 52.9 1

o 0

8 47.1

3 9 52.9 1

4 23.5 2 2 1

9 52.9 1 2

2 11.7

8 47.1

2

2

percent of these cases there were normalfundi, which compares almost exactly withthe number in the whole group of hyper­tensives. These two groups tally almostexactly except in two characteristicswhich are easily explained. Among thecases of cerebral accident a relatively greatincrease was found in the number of en­gorged, tortuous, and buckled veins, prob­ably as a result of a general backing-upof venous blood caused by the increasedintracranial pressure. In the whole groupof primary hypertensives there were fivecases of perineural edema; two of these

under discussion with a smaller series ofprimary nephritic cases which have beenexamined and recorded with regard tothe same essentials that have already beennoted in the former classification. Thenormal cases numbered 11 percent ascompared with 29 in the left eye. It wouldat first glance seem to be inconsistent thata greater percentage of contracted arteriesshould occur in the nephritic than in thehypertensive cases. A possible explana­tion lies in the fact that in hypertensiveindividuals there is a much thickened ar­terial wall, due to the long and progressive

400 FRED T. TOOKE AND JOHN V. V. NICHOLLS

existence of the disease, whereas, the ne­phritic patient is a younger person withmore contractile arteries. Hence, con­tracted arteries would be more obvious inthe former than in the latter. The fre­quency of engorged and tortuous veins isessentially the same in the two types ofcase. A manifest increase of buckling inthe hypertensive cases is self-explanatoryfor the reason quoted above as well as forthe greater tissue changes occurring in thearterial wall in the first class of case. Thevery evident increase of hemorrhages,both large and small, and particularly oflymph exudates, will be referred to atgreater length in our discussion of thesubject later. The tremendous differencein the occurrence of perineural edema inthe two conditions is simply a manifesta­tion of a generalized edematous processaffecting all organs and all tissues as aresult of nephritic disease. In the lattercondition a meningeal edema results in anincrease of cerebrospinal fluid, and there­fore of increased intracranial pressure,which is transmitted along the optic nervein the subarachnoid space.

DISCUSSION

Regarding the problem as a whole,many theories have been propounded as tothe pathogenesis of the various funduschanges. These have been summarized byFishberg and Oppenheimer' in a recentpaper, under five heads.

1. Renal insufficiency: Early investiga­tors all believed that the retinal changescame as the result of renal dysfunction.Widal, Morax, and Wei1l6 reported 17cases all with nitrogen retention. How­ever, this view is untenable, for greatretinal changes can take place withoutrenal damage.

2. Retinal arteriosclerosis: Von MicheFand other early workers believed albu­minuric retinitis to be due to arterio­sclerosis. This is not necessarily true as

arteriosclerosis does not always exist insuch cases. This was shown anatomicalIyby Schieck."

3. Increased intracranial pressure:Cushing and Bordley" were the first(1908) to describe a case of chronic renaldisease with severe retinal lesions and atremendously increased cerebrospinal­fluid pressure in 11 cases of hypertensiveretinitis. However, we believe that theretinal changes instead of being caused byintracranial pressure are rather a corol­lary.

4. Hypercholesteremia: Chauffard, DeFont-Reaulx and Laroche?" were the firstto bring this theory forward. However,it is not of general validity and we merelymention it to dismiss it.

5. Arterial hypertension: The sum totalof all the work on arterial hypertensiontends to show that the tissue changes inthis condition are directly explainable onthe basis of hypertension alone. It waspointed out by Traube" in 1870, thatretinal lesions occur only in those formsof renal disease in which there is hyper­trophy of the left ventricle. Fishberg andOppenheimer, in a recent paper, havestated that not only is it always present,but that it precedes the condition.Gowers.P in 1876, was the first to pointout that in hypertensive states the arteriesof the retina are contracted. A number ofworkers since then have observed spasmsof the retinal arteries in hypertension(Wagenmannl 3 in 1897, Elschnig'" in1898, Labadie-Lagrave and Laubry'" in1906). Recently, Haselhorst and Mylius'"(1928) not only observed but photo­graphed cramplike and rapidly changingcontractions of the retinal arteries in apatient with eclampsia gravidarum. Aftertwo days the contractions became moreconstant and involved longer stretches ofthe arteries. It was at this time that thefirst white degenerative lesions in theretina appeared.

THE FUNDUS IN ESSENTIAL CARDIOVASCULAR HYPERTENSION 401

This brings the whole problem into therealm of the rather revolutionary theoriesput forward by Ricker" some years ago.He believed that the underlying mecha­nism of both inflammatory conditions andhypertension is a neurovascular upset.In inflammatory conditions, bacteria orother stimuli at first set up a vasoconstric­tion of all terminal vascular segments. Butthe capillaries rapidly become fatigued andrelax-a fatigue paresis exactly such asone sees after an overdose of adrenalin.Then a dilatation of capillaries results,with a sustained contraction of the arteri­oles, which must of necessity cause a slow­ing of the blood stream in the capillarybed; a condition which Ricker has called,depending upon its degree, prestasis, peri­stasis, and finally stasis, when no bloodflows. Along with their dilatation thecapillaries become more permeable, an ef­fect possibly due to anoxemia or to theopening-up of stroma between the capil­lary endothelial cells. Krogh'" has con­firmed these latter changes. Thus, depend­ing upon the degree of slowing of theblood stream and, therefore, of the capil­lary dilatation, there will be progressivedegrees of exudate: first, plasma andfibrin only, then white cells, and finallyred cells (three stages of stasis called byRicker, liquor-stasis, leuco-stasis, andrubro-stasis, which correspond to his pre­stasis, peri-stasis and finally stasis).

Ricker believes that the same mecha­nism underlies hypertensive states. Hyper­tension is not caused by contraction oflarge arteries but of the terminal seg­ments, the arterioles and capillaries. Thishas been proved by experiment. Adrena­lin or sympathetic-nerve stimulation pro­duce this effect. Finally, the capillaries be­come fatigued and dilate. Now we havethe self-same condition as is seen in in­flammatory conditions. The patient be­comes decompensated, to use a clinicalterm, edema appears, white cells, and if

severe enough, red blood cells appear out­side the capillary well. It is interesting tonote in this regard the findings of Hasel­

_horst and Mylius'" on eclamptics, men­tioned previously. It is possible that thesechanges would only be seen at their bestin young people whose vessels are essen­tially undamaged or unchanged by thenormal aging processes (such as would beseen in our nephritic group). They wouldnot be seen in old people who have had aslowly progressive hypertension, alongwith normal age-period changes whichwould make the vessels less reactive.

There is that group of cases which hasbeen designated malignant hypertension.This is essentially an hypertension of ex­plosive violence in a comparatively youngperson. Here one sees all the advancedretinal changes that are found in a pri­mary nephritic, the only difference is thatin the latter one knows the cause of thehypertension. Of course, in the malignanthypertensive case the neurovascularchanges are not confined to the eye butinvolve the whole body and cause, amongother lesions, cerebral edema, generalanasarca, and rapid destruction of suchparenchymatous organs as the kidney, asthe result of the perivascular tissuechanges. Hence, in these cases a nephriticfactor is rapidly superimposed and main­tains the hypertension (the primary con­tracted kidney of German nomenclatureas opposed to the secondary contractedkidney resulting from a definite infectiveprocess).

With regard to the causation of hyper­tension in nephritis, there has been a tre­mendous controversy. Some say it is dueto toxemia and others that it is due to a

- reflex neurovascular response. A very sug­gestive factor favoring the latter view isthat in oxalate nephritis hypertensiontakes place if the renal nerves are intact.However, if one has completely dener­vated the kidneys before producing the ex-

402 FRED T. TOOKE AND JOHN V. V. NICHOLLS

perimental nephritis, hypertension doesnot take place. This interpretation is inaccord with the old teleological hypothesisthat hypertension in nephritis is due to theattempt of the body to force more bloodthrough the kidneys.

In conclusion we should like to mentionsome findings in an entirely different fieldwhich might bear some relation to retinalchanges. Menkin.'" in 1934, showed thatthe expected cytological picture of an in­flammatory exudate can be predicted fromthe pH of the tissues, and vice versa. For

example, when the pH is on the alkalineside, polymorphonuclear leucocytes pre­dominate, whereas if the tissue becomesmore acid, mononuclear cells replace themand then finally become predominant. Wewould like to offer as a possible factorin the production of retinal exudate achange in tissue pH. We have shown thatin nephritis, retinal exudates are morecommon than in uncomplicated hyperten­sion. This is also true of diabetes. In boththese conditions acidosis from time to timetakes place.

REFERENCES

1 Fishberg, A. M., and Oppenheimer, B. S. The differentiation and significance of certainophthalmoscopic pictures in hypertensive diseases. Arch. of Int. Med., 1930, v. 46, p. 901.

• Foster Moore. Medical ophthalmology. Ed. 2, London, J. & A. Churchill, 1925, p. 56.• Coats, G. Discussion on retinal vascular disease; pathological aspects. Trans. Ophth. Soc.

U. Kingdom, 1913,v. 33, p. 30.• Oatman, E. L. Diagnosis of fundus oculi. New York, Southworth Co., 1916, p. 62.s Larsson, S. W. Choked disc in nephritis. Acta Ophth., 1923,v. 1, p. 193.• Widal, Morax, and Weill. Retinite albuminurique et azoternie. Ann. d'Ocul., 1910, v. 143-

144, p. 354.'von Michel, J. Ueber Erkrankungen des Gefasssystems der Arteria und Vena centralis

retinae mit besonderer Beriicksichtigung der pathologisch-anatornischen Veranderungen,Zeit. f. Augenh., 1899,v. 2, p. 1.

• Schieck, F. Uber Retinitis albuminurica. Ber, d. Deutschen Ophth, Gesellsch., 1907, v, 34,p.77.

• Cushing and Bordley, Subtemporal decompression in a case of chronic nephritis withuremia; with especial consideration of the neuroretinal lesion. Amer, Jour. Med. Sc., 1908,v. 136,p. 484.

1. Chauffard, De Font-Reaulx, and Laroche, Guy. Nature cholesterinique des plaques blanchesretiniennes dans un cas de retinite albuminurique. Compo rend. Soc. de Bio!., Paris, 1912, v.73, p. 283.

11 Traube. Gesammelte Beitrage, 1870, v. 2, p. 985.1Z Gowers, W. R. The state of the arteries in Bright's disease. Brit. Med. j'our., 1876, v. 2,

p.743."Wagenmann, A. Einiges tiber Augenerkrankungen bci Gicht. Graefe's Arch. f. Ophth., 1897,

V. 43, p. 83.14 Elschnig. Ueber Sehstorungen durch Bleivergiftung. Wien. klin. Woch., 1898, V. 11, p. 400.rs Labadie-Lagrave and Laubry. Accidents aigus du saturnisme et hypertension arterielle,

Tribune med., Paris, 1906,n.s., v. 38, p. 437.,. Haselhorst, G., and Mylius, K. Zur Frage der Gefasskrampfe bei Eklampsie. Zentralbl. f.

Gynakol., 1928,V. 52, p. 1180.11 Ricker, G. Sklerose und Hypertonic der innervierten Arterien, Berlin, Julius Springer, 1927." Krogh. Anatomy and physiology of the capillaries. Yale University Press, 1929.'" Menkin. Studies on inflammation. Amer. Jour. Path., 1934, v, 10.