Biomicroscopy of conjunctival vessels in hypertension

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HE role played tg- capillaries in the h\-pertension disease process has not been generally emphasized and consequentI\. has received inadequate clinical study and detinition. Perhaps one explanation for the failure to evaluate compIetel>’ the entire vascular tree in h!-pertension lies in the fact that the investiinadequate methods ant1 an all too ii-cSator has been limited by cumbersome, qucnt lack of appreciation of the importance of the capillary in vascular ph\-siology. From the morphologic approach pathologists have generaIl>. failed to As a result, the area of recognize variations from normalit>- in hypertension. vascular pathology associated with h!yertension has been rather sharpl?. limited to the more striking arteriolar involvement. It is our purpose to evaluate capiljar!, as well as arteriolar pathology in clinical assays of h>.pertension. The older methods of nail-bed capillaroscop). have fallen into disuse because they failed to provide adequate definition of the peripheral vascular components. An excellent review of these techniques for capillary loop visualization was presented b,- Roth’ in 1946. The origin of the capillar>- microscope was attributed to Lombard,’ 1912, who first. visualized the nail-fold capillaries in man. With magnifications up to 75 times, capillaries at the bases of 1)oth the finger and tocnails were described as distinct comma-shaped loops. In 1917, QTeiss and Miiller’l first reported the clinical appliration of the method ant1 took photomicrographs of the fields visualized. The\- described the presenw of definite deformities and related them to disease entities. In acute nephritis the authors described a generalized widening and an increased number of capillaries, in Raynaud’s disease marked irregularities were present, and in arteriosclerosis the capillaries \vere found to he longer and more tortuous than normal. From the Birmingham Veterans Administration Hospit.al, DepartmeoW of Pathology sod Investigative Medicine, Van Nuys, Calif., in collaboration with t,hr I-niversit,y of Southern California School of Medicine, Los Angeles, Calif. Published with the permission of the Chief Medical Director. DepartmerIt of Medicirle alld Surger3. Veterans Administrat,ion, who assumes no responsibility for the opinions expressed or conclusions drawn by the authors. Read at the Twenty-first Srie:lltific Hessiom of the .4mericarl Heart Association, (‘hirago. Ill., .Jorlc 19, 194% 0.54

In 1922, Boas,” using the Lombard technique, described the nail-fold wpilFrom a study based on an undisclosed number of cases. laries III hypertension. this author concluded “the most that WC can sa!. is that in diseases in which the vascular s>-stem is affected the capillaries tend to c-hanKe in appearanc-e, and that this change manifests itself chiefly in an illcrease in length ant1 tortuosit!. of the vessels.” WC also pointetl out the difficulties in visunlizinK capillary flop. but described a definite rapid flow in essential hypertension. Brown” (I922 1, [Ising the same method described marked capilk->changes in fift>+ cases oi cardiovascular renal disease. The most constant findings were a contractctl t?~)e marked tliStLll~t~;LllC~ of capi I lary , frequent invisibility of the arterial limb, nlld in flou. In some art’as capillaries appeared elongated and looped. The changes in flo\\- ww dcscril~otl as “halting and jerk).” ant1 at t inics isolated cal)illaries v,wuld disappear from view. There are, according 10 13ro\~n, “essential differences ill the capillaries of chronic nephritis ant1 arteriosclerosis \\ith or without h>yerthe morpholoyic tension.” Hoxvever, “in patients \vith malignant hypertension ;~nd functional changes L\-ere most marked.” In 1924, Grzecho\viak” found changes in the cxpillarics in h) lwrtension characterized b>, a beaded type of blood flow and varieties of shapes of loops during the active illness with a ret urn to normal upon the subsidence of s+xnptoms. Other investigators utilizing the same Lombard technique xvith various slight improvements failed to confirm the presence of consistent morphologic or functional changes in the peripheral capillary bed in h>-pertension. Sotnbl~~ among these studies \vas that reported in 1932 I)!* lLIufson, 7 a-ho could not itlentif!. such irregularities as Grzechowink had described. It is interesting to note that Mufson, \vhile concentrating primarily. on capill;lr\. lxessure changes iI1 h! \“I~tension, described a frequent narrowing, especiall~~ at the arteriole end, and a normal or more rapid flow of blood. (‘onsistent with these findings \~et-~ those oi normal or increased capillar>. pressure in h\-pet-tension. In ~111extensive report, \,Y’right and Dur\w: h in 1933 conipletel~- t’ail(atl t 0 wniirni the previous reports of c~npillar\- changes associate~l \vith h\~lxrtension )‘cr se. ‘l‘he ini~)ortanw of capillaries in the complete vascular network \V;Ls being emphasizetl during this same period. ‘l’he classical investigations 0i (‘annon!’ oil the role of capillar\~ stasis in shock al~pcared in 1918. I MC” tlescril~ctl the “1xkr;iclosical re;rc.tion” oi histamine, \vhich increased the tone oi arterial muscular hut lxwducetl 3 fall in blood pressure on intravenous injection. ‘I’hc oxplanatioll for this paradox \VAS found in the capillaries where paral>.sis, dilatation, anal stasis resulted from histamine stimulation. These studies together \vith the estensivc investigations concernin,y normal capillaries 10. Iiro~li I’ and his students i 1922-1920) served to establish ;I sound base line of essfktial lxinciples ant1 iactr;. 1n 1921 Zeller” reported observations on the conjuncti\-al \~5sels, usin& ;I cornea1 microscope \vith magnifications oi 64 times. He observed normal blood flow and described intravascular as well as capillar>. abnormalities in arteriosclerosis, syphilis, and diabetes. bliliary aneurysms ant1 corkscrew-type tort uositics were descrilwtl. Small hrniorrhages. passive \-enous congest ion, :\ntl \~ilri;ltiOlls in Jlo\v r;ltcas \v(‘re Ilot(‘(l. His scariw (lid not inc~111~l~ otxc.r\.;ltions OII 11\~1~~'1-1~llsi~~ll.

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Utilizing recent advances contributed by studies of living circulation in animals (Krogh,” Landis,‘” Knisely, 11 Lack15), an adaptation of basic techniques has proved useful and easily applicable to the clinical patient. METHOD

The conjunctival vessels overlying the sclera of the eye were observed by reflecting bright parallel beams of light off the sclera. The images of the conjunctival vascular tree were studied by direct microscopy (Fig. 1). An ophthalmological slit lamp apparatus provided support for the patient’s head and a maneuverable light source. A compound microscope was mounted on a horizontal rack

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compound studies.

microscope

and pinion; 16 and 24 mm. objectives provided safe working distances (Fig. 2,A and B). Wide-field oculars, 3 x to 20 X, gave sufficient definition and magnification for these studies. Most observations were made with a 16 mm. apochromatic objective (for use without coverglass) and 5 or 10 X wide-field oculars. As much of the white of the eye as possible was exposed by the patient’s fixation on a strategically placed small, red light in a darkened examination room. This technique was used for both compound and stereoscope microscopy. A wide-field stereoscopic dissecting microscope (Spencer) mounted on a side arm was used alternately with the rebuilt compound microscope described. The stereoscopic microscope was excellent for survey work and intravascular studies. Complete arteriovenous patterns with capillary networks were clearly visualized.

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2.--A, Photograph of apparatus showing side arm ocular mounting of camera. R. Close-up of apparatus with subject in position. Slit lamp illumination of the sclera was adequate for routine use.

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Kepeated examinations (11 patients made ii pussihlc to study changes in thcx peripheral vessels. Permanentrecords were obtained 1))~ Kodachrome cinematograph>‘, drawings from which are presented. The present apparatus is adapted for cinematograph!. with an Eastman 16 mm. (‘in&Kodak Special C’amer;~, mounted on the microscope by a side arm ocular. This ocular permits sitnutaneous recording and direct observation iol- continuous foc.using.

Normotensive Subsject.s. -Two control series were concurrently studied. One, a hospital group of,sisty-four normotensive patients, and, two, a group of fifty normal adults. Fig. 3 presents the structural plan of a typical normotensive subject (R.J.). The arterioles divide into numerous side capillaries and terminate with an end capillary. The latter, on occasion, functions as a “through and through” channel. The capillaries appear to be of uniform caliber throughout with a smooth, winding course and no evidence of sacculations or abnormal points of constriction. The capillary of the hulhar conjunctiva has indefinite

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subdivisions of postarterial, midloop, and prevenule segments. Onl!. rare arteriovenous anastomoses of the short type are seen. There are individual variations in venous patterns with frequent tortuosities, varying with individuals and being klo\v rates in ~~ormal correlated in some degree with the age of the patient. intlividuals are not remarl&k and arc consistent nith Ihc physiology of a xi\-en ;trw. \\‘ith magtiifications of one hundrec! times or more, it is possiblc~ to 1rac‘e the course of an individual red cell through the entire capillar>- loop. ‘I’he morphologic changes in the two control series will be brieH?- summarized. Of the sist>--four nonhypertensive hospital patients, capillar!. changes xvere al,sent in fort).-six (72 per cent) and present in eighteen (38 per cent). The changes tlotetl were otil\, minimal. No patients revealed abnormalities of the h>.pertension I)at tern, but showed, on the other hand, various changes such as abnormal dilatations, minimal narrowing, spiderweb branches, and a rare focal noclulwit\~. In the tiftl- normal adults of the control series the capillaries were normal in appearance in all instances. Capillar?. distensibility, was present throughout and there \v;ts no evidence of thickening of the capillar\. XVAl. IIypevtentive S&jects.---A series of one hundred h>.pertension patients lvith blood pressures of 150,‘100 or more were evaluated b>. biomicroscopy. Definite (-apillar>. irregularities were present in ninet>*-eight of the patients. These have been roughI>. evaluated as being of minimal itlvol\wtent in 5)per cent-, moderate iii 57 per cent, and marked in 34 per cent. These changc~sxvere morl>hologic, consistiti~g of generalized narrowing of that capillar>- lumen, elongation \vith angular torluosities, abnormal loopings, focal const rictiotis, anal occasional sacc~ulatiotis. Definite angularities (that is, fixed lurns of roughl>~ 30 tle~rees or snore), and an incxased length of o\rer-all capillar>. segment nit h al)not-ma1loopings \vcrc’ consistent litidings. Arcompan~:ing such morphologic changes was increased thickness of capillar>~ wall which showed some deg-t-w of thickening- in 83 per cent. In striking cot-relation xvith the morphologic irregulat-it ies UYISthe loss of normal capillar?. tlistensibilitJ- in 80 per cent. 31~lied sparsenessof the capillar~~ bed \vas i0d in casesof long-standing h~pcrtension. The t\.pical capillar!~ findings in h>-Ixrtensiott at-e shown (Fig. 4) in a dr;rn~itig copied irom a 16 ~nm. Kodachrome moving pict lit-e of the pat ietit The elon~atiott of individual capillaries n-it h a tettdenc.\. to loolAng of the midc-apillar!- segment appeared as a striking earl!~ change. ‘l‘he thick-walled cal)illarks sew in hl-pet-tension have a tubular appearance, and ksetl tort uosit ies are striking. ‘1‘1 1c1Ioss of nortnal distetisibilit>, was e;isil>. noted \vhen large itit t-avascular red cell clumps and thrombi could be follcnved through capillar!. chati11~1s.Such findings were sufficientl>- striking and consistent to suggest a h~.pet-tension pat tern of capillar>~ patholog>s as represented diagramtiiatic~tll\- in Fig. 5. The capillar>~ changes of the “hypertension t!.pc” and the height of the diastolic pressures showed a definite correlation. \Vit h increasing diastolic pressures there was a greater incidence of marked capillary change. In the two patients in whom capillary findings were absent the diastolic pressures occurred in the 100 to 110 mm. group; both of these patients had histories of earl!. h>-pertension.

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The age distribution curve reveals a wide sampling with predominance of patients in the middle age groups. There was no correlation between the age of an individual patient and the degree of capillary changes of the hypertension type described. Sex distribution of this hypertension series bears no significant relationship to the degree of capillary pathology observed.

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4:--Capillaries of conjuctiva Note elongated, narrowed Capillary loop shown (W).

in hypertension. Traced from 16 capillaries (R) with marked tortuosities Approximately X 100 (on film).

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Kodachrome sharp. fixed

film of angular

The evaluation of arterioles in the hypertension patients revealed definite irregularities in 80 per cent, with an entirely normal arteriolar structure present in 10 per cent. There was no evaluation made in the remaining 10 per cent. INTRAVASCULAR

AGGLUTINATION

PHENOMENON

OR

“SLUDGED

BLOOD”

The fact that intravascular pathology of considerable severity involving clumped masses of red cells and/or clumped masses of white blood cells may be present in numerous disease states has been reported by several early investigators. In 1908, CroppeP described the intravascular clumping of infected red

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cells in a fatal case of pernicious malaria. He suggested that such formations might form embolisms, thromboses, or infarctions in. various organs. In-ai and ILLleisai,” 1925, reported the formation of agglutinated masses of red cells it1 Raynaud’s disease. .4t their invitation Hayano, using a Zeiss cornea1 microS;cOp?, observed chang-es in the flow of conjunctival vessels. Uroken colunlI1:: of blood flow in capillaries were described after bathing \vi th cold ~\ater ant1 it was felt t-hat these could he due to the formation of small, intravascular l~lood clots.

Fig. 5.-Hyperte~~sio~~ The significant morphologic of IIRCI‘J~S~ material.

pattern of capillary changes charrgrs in c’onjorwt,ival

as st)eu with the biomicroscope (diagrammatic). vess& wew ronfirmed by histopst,hologir stud>

Histologicall\., intravascular agglutinated masses oi red cells iI1 malaria were demonstrated in various tissues at autopqr by Dudgeon and ClarW8 in 1917. Throm hoses were particularly prominent in the adrenals, brain, and kidneys. They pointed out that- this observation of agglutinated erythrocytes in malaria leads not only to the occlusion of capillaries but to obstruction of arterioles as well. This phenomenon consists primarily of intravascular clumpings of red cells forming large, ikgglutinated, firm masses inconsistent with shell layer type oL’ normal vascular flo\v. It appeared to us that such intravascular changes wetxL interesting but clc+inilel~- nonspecitir. Although t hew changw ww of II~-

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doubted importance in vascular pathology, it was not within the province of this paper to embark upon a stud\. of this abnormalit>.. However, we noted that intravascular agglutinations of some severity were present in many of our subjects. These changes \vere graded roughI!- on a basis of size, number, and toughness of clumps (Fig. 6). (~ratle 1 represented fine granularities of several erythrocytes which are rather uniform and not too upsetting to flow rates; Gracle 2 indicated definite clumping which tends to hold together in larger collecting veins; Grade 3 indicated large agglutinations xvhich completely block out normal flow; and Grade 4 represented almost complete clumping of erythrocytes, \vhich suggests the appearance of “sludge.”

Of our series of hypertension patients, intravascular agglutinations of erythrocytes were absent in only four. Subjective estimations revealed 50 per cent with Grade 1 clumping, 45 per cent with Grade 2, 4 per cent with Grade 3, and 1 per cent with Grade 4 clumping-. A sharp line of demarcation occurred in the h),pertension series brt\vecn Grades 2 and 3, with 95 per cent having jnvolvement in Grades 1 and 2 indicative of minimal to moderate severity. There was Transient capillary no relation of degree of clumping to blood pressure levels. and venous thromboses were present in 73 per cent of the hypertension series.

Of the sixty-four nonhypertensivc hospital control patients, intravascular agglutinations were present in forty-three, with fourteen in Grade 1, twentythree in Grade 2, five in Grade 3, and one in Grade 4. Of the fifty normal adult control subjects, only, one showed intravascular pathology (Grade 1). It was of interest to note that the presence of. granularities in this one subject may bc related to the fact that this individual was rec1lperatin.g from an upp~ rrspirator\~ infection.

The original premise for studying patients by direct visualization of the conjunctival vessels was directed toward analJ.ses of intravascular pat holog! similar to the recently described “sludged blood” 1)). Iinisel?. and co-worliersl!’ at the University of Chicago and the ITniversity of Tennessee. The intravascular clumping of red cells is an important physical phenomenon and is definitelyinconsistent with “streamlined” hemodynamics. AAltered cell nutrition as a result of inadequate flow characteristics and the formation of thromboses and infarctions subsequent to such intravascular clumping may all be of considerable significance in the explanation of numerous disease manifestations. However, the nonspecificity of this phenomenon immediately became apparent and its relation to any given disease process required additional clarification and definition of basic factors involved. On the other hand, the adaptability of this technique toward an analJ,sis of the morphologic patholog-!z of the peripheral vascular tree in various disease states, and hypertension in particular, soon became evident. -4n advantage of the methocl presented lies in the fact that the wall of individual capillaries can be discerned with proper illumination and magnification. The clear images obtained contrast sharpI>. with the older methods and make possible more critical analyses of peripheral vascular patholog!-. The consistent changes in capillaries associated with hypertension indicate that the area of peripheral vascular resistance includes capillaries as well as arterioles. On occasion, significant findings in hypertension have been confined to the capillaries. The arterioles of the conjunctiva showed no changes in these cases. If this peripheral area were indicative of general systemic involvement, it would suggest that peripheral resistance could be initiated by capillaries in some cases. Similar capillary patholog)- in h)~pertension was reported in the central nervous system by Scheinker,“L in 1948. He demonstrated at necrops). that vascular alterations in early arterial h\-pertension were confined mostly to capillaries with evidence of proliferative and degenerative changes. Such changes in capillaries may be correlated with a general vascular deterioration, and progressive atresia of individual capillaries mi
.\ND

CONCLUSIONS

1. A new method of biomicroscopq- ol conjunctival vessels, utilizing high magnification (up to 200 times), is presented. 2. The results from a study of one hundred cases of h!.pertension suggest a “hypertension pattern” of capillary pnthoIog>.. This pattern is characterized

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t,>, extensive narrowing, elongation, and looping of capillaries, which, iu addition, show fixed anguIarities or tortuosities, tubular thickening of walls, and loss of normal distensihilit!,. Ninety-eight per cent of all hypertensive patients showed significant 3. with the +I. could be 5.

capillary changes of this type. ‘The severity of this capillaq~ hypertension pattern correlates directI!rise in diastolic pressure. I\O significant correlations of capillary vascular damage with sex or age determined. Arteriolar pathology is noted in 80 per cent of the hypertension series. 6. Nonhypertensive hospital patients, who composed a control series, showed no capillary involvement in 72 per cent.. iVinimal changes of bizarre t)~~s xvere present in 28 per cent; none showed the “hypertension pattern” d c~apillar\ I)atholog\.. 7. Intrasascular clumping of reel culls was noted in 5)6 l)cr cx~nt of the h)~pcrtension series and in 67 per cent of the control series. that it ma?; be worth while clinicall>. 8. The findings of this study indicate to evaluate the role of the capillary in hypertension by this method and to direct efforts toward a systemic evaluation of the patholog>of the capillqtree as it relates to the hypertension process. REFERENCES 1.

Allen, E. V., Barker, N. W., and Hines, E. A.: Peripheral Vascular Diseases, Chapter \., Nailfold Capillaries in Man, by Roth, Grace M., Philadelphia, 1946, W. B. Saunders

2

Lombard, b. p.I Blood I’ressure in the Arterioles, Capillaries and Slnall Veins, .%n. j. Physiol. 29:335, 1912. Weiss, E., and Mallet-, 0.: Ueber Beobachtung der Hautkapillaren und ihre klinische Bedeutung, Miinchen. med. Wchnschr. 1:609, 1917. Boas, E. P.: The Kale of the Capillaries in Circulatory Disorders, Med. Clin. North America, 5:1007, 1922. Brown, G. E.: Capillary Observations in Cardiovascular Renal Ijisease, Ann. Clin. i%ied.

ColnDanv.

3. 4. 5. 6. 5.

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148.

1:69, 1922. Grzechowiak, F.: Der Kapillardruck, besonders wahrend der Schwangerschaft, Geburtsh u. GvnZk. 87:128. 1924. Mufson, J.: A Stud; of ‘Capillary Pressure in Nephritis and Hypertension, .\m. 18.Tt6.32

Ztschr. f. J. M.

Sr.

19.12

1-L.

I. S., and Duryee, .\. \V.: Human Capillaries in Health and in Disease. Arch. Int. illed. 52:545, 1933. Cannon, W. B.: Blood in Shock and Hemorrhage, j, A M. A. 70:526, 1918. Dale, H. H.: Histamine Shock, J. Physiol. 52:355, 1918. J
15.

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8. 9. 10.

11. 12. 1.3.

\Vright,

19.38

16. 17. 18. 19. 20.

A. 12.: The Occllrrenre ~)f Jntravasclllar Agglutinations in .ivian Malaria, Srience 96:520, 1942. Cropper, J. : Phenomenal Abundance of Parasites in the Peripheral Circulation of a Fatal Case of Pernicious Malaria, J. Trop. Med. 2:91, 1908. Iwai, S., and Meisai, N.: Etiology of Raynaud’s Disease, Japan M. World, 5&S, lY25. Dudgeon, L. S., and Clarke, C.: A Contribution to the Microscopical Histology of Malaria, Lancet, 2:153, 1917. Knisely, hl. H., Rloch; E. H., Eliot, T. S., and Warner, L.: Sludged Blood, Science, 106:43 t , 1917. Scheinker, I. M.: Alterationsof Cerebral Capillaries in the Early Stages of Arterial Hypertension, Am. J, Path. 24:211, 1948.