- Email: [email protected]
Herman Boerhaave and the History of Vessels Carrying Aqueous Humor From the Eye
HERMAN BOERHAAVE AND T H E H I S T O R Y O F VESSELS CARRYING AQUEOUS HUMOR FROM T H E E Y E S. L. KNUTSON, M.D., AND M. L. SEARS, M.D.
New Haven, Connecticut
Early in the 18th century, Herman Boerhaave saw the structures on the episcleral surface of the human eye, which we know now to be aqueous veins, using an ordinary magnifying glass. There was little, if any, information about the flow dynamics of the aqueous humor. Furthermore, enthusiasm for contemporary concepts of pathology, em bodying a rejection of the humoral pathol ogy, led Boerhaave to believe that these ocu lar vessels contained plasma that had been skimmed from larger afferent arterioles. For a long period after Boerhaave's observation, it was felt that the aqueous bearing vessels were actually empty of blood rather than filled with any aqueous. Experimental dem onstrations of a through-and-through circu lation of aqueous humor and proof of the collector nature of the aqueous channels were finally made by Ascher, Goldmann, and others. In 1725, a 17-year-old medical student 1 wrote the following description of one of his professors: . . . [he] still lives as a poor brewer, an un attractive man with cat's eyes, a small nose and a dark face, bristly hair, a plain hat, gray pitiful clothing, rough shoes. Years later, that same student was to reas semble the addresses of that professor and thus make accessible to the modern world the work and observations of Herman Boer haave. Who was this yet obscure professor of medicine? Albrecht von Haller, 1 the stuFrom the Department of Ophthalmology and Visual Science, Yale University School of Medi cine, New Haven, Connecticut. This work was sup ported in part by Public Health Service grants EY-00785 and EY-00237, and Research to Prevent Blindness, Inc. Reprint requests to Marvin L. Sears, M.D., Pro fessor and Chairman, Department of Ophthalmol ogy and Visual Science, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06S10.
dent who made the first publication of Boer haave's lectures, could say of him: In regards to Medicine, Chemistry, Botany, Latin, Theology, Physics, and Mathematics, he was as learned a man as one could wish to see. He also had the largest audience. . . . I don't think that I ever saw a classroom asfilledwith people as Boerhaave's. After Boerhaave's death, several of his pupils adapted their notes of his annual lec ture course for publication. Although the notes are not always complete and faultless, they give one an impression of Boerhaave's teaching and method, and certainly of the es teem in which Boerhaave was held. In more recent times, he has been ap plauded for his early recognition of the axial flow of the solid particles of the blood stream, his discovery of intravascular aggre gation and clotting, and his pioneer work in the field of thrombosis.2 To this list of achievements can be added the acknowledg ment that Boerhaave was the first to observe clear fluid-bearing vessels in the eye, which we now know to be aqueous veins. Boerhaave was not an ophthalmologist, nor was he a specialist in any other medical field. He was a master of the general science of medicine with a passionate belief in care ful and thorough observation. He did, how ever, have a fascination for the vascular workings of the body, and because of the easy visibility of the rich vascular network of the conjunctival coat of the eye, he fo cused much of his attention there. Using only a magnifying glass, Boerhaave3 noticed that " . . . one sees more clear fluid than blood circulating in the capillaries [of the eye]." In Boerhaave's lecture,3 "On the Inflammations of the Skins of the Eye," he said that ". . . normally these capillaries let through only a very pale and separated mois ture which later rejoins the blood in the
648
VOL. 76, NO. 5
HERMAN BOERHAAVE
veins." Knowing that to be the appearance of the well eye, Boerhaave quickly noticed the alteration caused by disease : During inflammation, however, most of them [the previously clear vessels of the eye], and sometimes all of them, are filled with blood. That is to say, the magnifying glass shows capil laries which now contain and conduct blood. Therefore, we conclude from this that the in flammation exists not only in the arteries . . . but also in the capillaries which consist of the ends of the arteries and which were previously so narrow that they could not conduct blood.* Boerhaave escaped the pitfall of other, even later investigators (Coccius,6 for ex ample) who believed that all vessels either carried blood or were empty, depending on whether they were red or clear. He recog nized that there were some vessels in the eye that carried a fluid that was not red. His con clusions, however, were limited by the hematology and ophthalmology of his day. He ex plained his observation in his lecture on eye inflammations : In the most external arteries the blood con sists of two parts which are separable : the white, clear watery fluid and the red portion. The red portion has small particles, each of which is made up of six little corpuscles which compose the clear fluid when they separate from each other. Thus, the red part decomposes into a sub stance which is different from what it was pre viously. The clear white portion flows into the capillaries which are as fine as a hair. The red portion, however, is led back again through the veins. To substantiate his premise that the whole blood had collected in vessels which would normally be so small as to skim off only the thin, clear fluid, Boerhaave3 described an ex periment he had done: When we look at our own eye or the eye of another person by the light of day, either with * Indeed, alterations in the conjunctival vascular bed have often been observed in the years since Boerhaave's time. Observations of sludged blood (a phenomenon perhaps foreshadowed by Boerhaave's description of a "gluing together" of corpuscles in the conjunctival blood flow) have been well docu mented by Knisely and associates.4 Perhaps the most informative use of conjunctival vascular patterns has been made by Paton in sickle cell hemoglobinopathy.5 The diagnostic usefulness of these observa tions has otherwise been limited.
649
naked vision or through a magnifying glass, everything will appear white. When, however, a neck tourniquet is tightened for a long period of time, so that the jugular vein is pressed to gether, then the tunica adnata will become red. And when this tourniquet is maintained for a long time, inflammation will develop in the tunica adnata because the tightening prevents the blood from returning to the heart and the pressure of the increasing blood broadens the opening of the little capillaries so that the blood is forced into them, although it does not circu late through them. This causes an itch which makes one instinctively blink or rub the eye. This causes the capillaries to contract and force the blood back into the great branch of the artery. When the tourniquet is removed, the in flammation quickly disappears through the action of the capillaries and the motion of the eyelids. In diseased states, a similar reddening is caused by the thickening of blood, which Boerhaave3 believed . . . is caused by the inflamed and compressed blood, in which case it is very red. Anything which increases the pressure on these small par ticles of blood, or anything which increases the force of the blood circulation, thus causing these little corpuscles to become compressed to the extent that they are "glued together," can create such a condition. . . . In order that the red corpuscles become white, they must be freed from compression, or in this case, returned to a broader space. We become aware of this quality of blood if we let blood which has been drawn from an artery stand. It first forms a skin, then [the rest] soon turns to water. To understand why Boerhaave spoke of the clear fluid in the eye as watery fluid sepa rated from the whole blood rather than as a unique fluid, it is important to consider the art of medicine in Boerhaave's time. Boerhaave was born 40 years after 1628, a watershed in the history of medicine in the West, the year of the publication of William Harvey's De Motu Cordts. Harvey's study of the circulation of the blood led to the dis carding of a theory of pathology which had held sway since the time of Hippocrates, the theory of the four humors. These four flu ids, intimately mixed with each other, were said to form blood. Since blood-letting had been the most favored remedy for nearly all deviations from health, as well as a much fa vored stimulant for its preservation, doctors
650
AMERICAN JOURNAL QF OPHTHALMOLOGY
from earliest recorded time had many oppor tunities to study the macroscopic nature of the blood. It was upon these studies, Fahraeus7 pointed out, that the theory of the four humors was built: As the blood dies off through the cooling in fluence of the air outside of the organism, these [four parts] diverge from their intimate union. The black bile collects at the bottom (the darkcolöred lower portion of the blood cake) ; the blood in a limited sense of the word, sanguis, rises toward the surface (the upper portion of the blood cake) ; the phlegm does not secrete itself spontaneously in healthy blood, but is all the same present as the connective substance in the blood cake (fibrin). The Greeks knew that by shaking healthy blood, the last-named fluid could be separated, and thereby the whole be prevented from clotting. In unhealthy blood, however, the phlegm collected in a more or less thick layer on top of the blood cake, which was of course interpreted as being a consequence of this substance having increased. These observations provided the prototype for the humoral pathology. Hippocrates pos tulated that the health of the body was based on a well-proportioned relationship of these four substances: blood, phlegm, yellow bile, and black bile. These four body fluids were analogous to the four elements of which the ancients believed the whole world to be com posed: fire, water, earth, and air. The blood, hot and moist, corresponded to air. The phlegm, cold and moist, corresponded to wa ter. The yellow bile, or choler, hot and dry, corresponded to fire, and the black bile, cold and dry, corresponded to earth. A predomi nance of blood made one sanguine, cheerful ; of phlegm, phlegmatic, testy; of yellow bile, choleric^ hot-tempered ; of black bile, melan choly. More serious imbalances or a sus tained separation of any part from the whole resulted in disease and death. Such separation and imbalance was read ily noticeable7 in the drawn blood : In most cases, the evacuated blood [during a period of disease] had quite a different appear ance to that in health. When coming from a sick person, it secreted a whitish substance of solid consistency which was absolutely lacking in the blood taken from a healthy person, but which, in more severe cases of illness, could perhaps
NOVEMBER, 1973
take up more than half of the liquid volume evacuated. This substance, which could change in quantity, always secreted itself, however, when it made its appearance, in the form of a superficial layer above the rest of the blood cake which was normally conditioned. This layer was the so-called crusta sanguinL· or the buffy coat. . . . The buffy coat was a sign in dicating that the suspension stability of the blood was reduced. Boerhaave knew of the clotting and sepa rating properties of the blood ; he also knew of the buffy coat. In his experience the pres ence of the buffy coat accompanied the signs of inflammation which Boerhaave described as being "glued together," whereas he be lieved that clotting of the red cells and sepa rating out of the clear white serum were phenomena achieved by healthy blood. Boer haave attributed the "gluing together" to in flammation and compression, rather than to an increase in one of the humors. Boerhaave had actually observed two dif ferent vascular phenomena in the eye: the clear flow of the aqueous within the aqueous veins and the agglutinated flow of diseased blood within the bloqd vessels. He believed he was seeing a separated form of whole blood flowing in tiny arterial vessels in the eye—i.e., plasma skirnming. His commit ment to the new humoral pathology, based within the theoretic framework of a circulat ing of blood, led him to consider the clear separated flow and the agglutinated red cells as two parts of the whole blood. He had no idea of the circulation of the intraocular fluid (aqueous) and so could explain his ob servations only in terms of arterial plasma skimming. Since his observations conve niently supported the concepts embodied in the new humoral pathology, Boerhaave, like many others after him, failed to understand the exact nature of the clear vessels he had seen on the surface of the eye. In the 20th century, the outflow of the intraocular fluid, aqueous humor, was charted, proven, and became fully recog nized. As recently as 1934, Sir Stewart Duke-Elder8 stated that the nature and activ-
VOL. 76, NO. S
HERMAN BOERHAAVE
ity of the intraocular fluid continued to be a matter of disagreement. The discussion cen tered around three major theories. One view was that intraocular fluid did riot flow through the vessels of the eye, but that the fluid was renewed by a general met abolic interchange throughout the tissues of the eye. This view, which derived from Ul rich's hypothesis of the physiologic seclusion of the pupil (a condition which would have precluded any flow of fluid through the pu pillary aperture), was stated in its essentials by Hamburger between 1898 and 1924. It was elaborated by Magitot9 in 1917 and re stated by him in 1928: We shall conclude then today, as in 1916, that the aqueous humor . . . is [not] animated by a current in the real sense of the word. It is, in its normal state, a dormant water, like that of a well, which renews itself only extremely slowly if one does not cause any withholding [of the source]. Its production and elimination are two balanced phenomena, resulting from the work of dialysis from the capillaries of the uvea and from the retina. The same membranes, those of the capillaries, produce the liquid, then reabsorb it and reproduce it.
Seeing no readily visible outflow vessels, Magitot opposed a theory of circulation. Duke-Elder's 8 own view was that there was a metabolic interchange between the intraocular fluid and blood through the capil lary walls throughout all the tissues of the eye, much as Magitot said, but superimposed upon this interchange was a secondary pres sure-derived circulation conditioned by the pulse beat, the respiratory variations, and muscular activity. He noted also an inciden tal thermal circulation which added to the constant internal movement of the aqueous humor. Duke-Elder chose the best of both worlds: no circulatory path and yet a secon dary circulation. Soon, however, it was acknowledged that the aqueous humor did have a definite pri mary circulation. The fluid had its source at the ciliary body, passed through the pupillary aperture into the anterior chamber, and left the eye by the canal of Schlemm. This view
651
was first fully elaborated by Leber10 in 1903, but it had been noted in experiments Lauber performed earlier with dogs. In 1901, Lauber 11 published a comparison of red cell counts of blood taken from the anterior cili ary veins and from the paw of the same dog. The blood from the paw contained 3.61 mil lion red blood cells per cubic millimeter, and that taken from the ciliary veins con tained between 2.90 and 2;68 million red blood cells. Lauber explained this difference between paw and ciliary vein blood counts by assuming a dilution of the blood in the ciliary veins by the outflow of aqueous hu mor into the sclerocorneal vessels that emp tied into the anterior ciliary veins. In 1921, Troncoso 12 was able to document such an outflow of a clear fluid from the eyes of living rabbits. The globe was drawn (proptosed) outside the orbit and held in this position by the return of the eyelids to their normal position. The board on which the ani mal was fastened was then turned so that the apex of the cornea became the lowest point of the eye. The globe was then passed through a hole in a rubber-dam sheet to pre vent collection of liquids from the conjunc tiva or orbit. After the sciera was cleansed of all blood, the globe was immersed in a glass cup filled with olive oil. Minute clear droplets of aqueous collected around the cor nea; five to 10 minutes later new droplets appeared along the limbus. A rate of aque ous flow was calculated by this method. Experiments exploring the possibility of a path of aqueous outflow in animal eyes were numerous in the latter part of the last century and in the early part of this one. Perhaps the most notable of these is that of Seidel.13 He gently forced a solution of 1% in digo-carmine into the emptied anterior chamber of an anesthetized rabbit. Seidel used an infusion with variable pressures and made his observations with a binocular mi croscope. He noticed that the episcleral veins turned blue with the dye and that neither any iris vessels which emptied into the vorticose
652
AMERICAN JOURNAL OF OPHTHALMOLOGY
veins, nor any previously unobserved ves sels, filled with the blue fluid. Thus, he con cluded that the dye was eliminated only by the anterior ciliary veins into which the lim» bal meshwork empties, and that no artificial channels had been formed by the manometer infusion. He further noticed that when India ink was used for the infusion, the dye was apparent first in the axial stream of the larger vessels and the red color was pre served in the periphery of the stream, a phe nomenon which occurs in human aqueous outflow. Seidel concluded from these experi ments, done in 1923, that under physiologic intraocular pressures a continuous outflow of fluid takes place from the anterior cham ber of the living animal into the veins situ ated in the scierai tissue near the chamber angle. He believed that the driving force was the hydrostatic difference between the ante rior chamber and the veins. Ascher14 realized the aqueous-bearing function of the clear, episcleral vessels in hu man eyes. Ascher's review of the subject in cludes the work of Coccius6 and subsequent physiologists, but does not explore the obser vations of Boerhaave. Ascher14 states: The discovery of aqueous veins was delayed because observers were content with the ex planation that in the pericorneal region of the human eye the direction of the blood current is frequently seen to change and that vessels very often "contract" and show a granular stream of corpuscles or frequently even seem to be empty. The presence of "empty" capillaries was mentioned since the early days of slit-lamp microscopy and even long before the slit lamp was invented. Not enough attention was paid to a discrimi nation between lack of visible red cells and ab sence of any content in the vessel. Convinced that the vessels could contain either blood or nothing, the observers believed the absence of red to be proof of complete emptiness. In May, 1941, Ascher16 was examining an Alabama miner, aged 35, in whose eyes he saw what he thought to be a "physiologic connection between the canal of Schlemm or the venous meshwork surrounding it, and the episcleral venous meshwork." He de-
NOVEMBER, 1973
scribed the colorless quality of the vein and the stratified current: The clear stream started just where the color less loop—the aqueous vein—entered its recipient vessel, the lower two thirds of which were filled with blood of normal color. After this discovery, Ascher continued looking for such aqueous humor outflow ves sels in the eyes of all the patients he ob served in the Nutritional Clinic in Hillman Hospital, Birmingham, Alabama. He found aqueous veins in the eyes of 26:78% of am bulatory patients (79 of 295 patients) during routine examinations. From these examinations, Ascher15 set four criteria for identifying aqueous veins: ( 1 ) by their more-or-less characteristic ori gin in or near the corneal limbus or out of an emissarium sclerae; (2) by lack of blood corpuscles as compared to ordinary conjunctival and subconjunctival vessels, and some times, by a typical stratification.; (3) by their characteristic emptying into recipient ves sels ; and (4) by significant phenomena pro duced by compression of their recipient ves sels. This last point was of great interest to Ascher, who studied its occurrence in both normal and glaucomatous eyes. Definitive physiologic confirmation of the aqueous content of these vessels was pro vided by Goldmann.16 In 1946, Goldmann performed experiments with both fluorescein and India ink similar to those reported by Seidel, but in human eyes. Goldmann in jected a mixture of equal parts of saline so lution and Guenther-Wagner-Perltusche ink, a brand of India ink with particularly smallsized particles (between 10 and 20 nm ac cording to Seidel), into the anterior cham ber of an eye to be enucleated because of uyeal sarcoma (melanoma). Before this injection, an aqueous vein had been located in the nasal episclera. Under topical cocaine anesthesia, a small amount of aqueous humor was aspi rated from the anterior chamber of the neoplastic eye and partly replaced with inky mixture, without attaining the previous
VOL. 76, NO. S
HERMAN BOERHAAVE
intraocular pressure. While the episcleral vessels maintained their normal red color, the previously located aqueous vein became black. Goldmann17 demonstrated that an aqueous vein could be filled with material in troduced into the anterior chamber without large increases in intraocular pressure. In later fluorescein studies, Goldmann18 demonstrated unequivocally that the color less fluid in the clear vessels stemming from Schlemm's canal really was aqueous humor and not plasma. Goldmann noted that 15 minutes after intravenous injection of 4 ml of 10% sodium fluorescein, the concentra tion in the plasma is about 1,000 times greater than the concentration in the aqueous humor. The concentration in the aqueous hu mor after one hour, compared to that in the plasma, is about 1:100. In normal subjects, the maximum concentration of fluorescein in the anterior chamber is reached 90 minutes after injection. At this later time, aqueous veins may contain fluorescein. Thus, one can understand why in the first half hour after intravenous injection of fluorescein, the blood-conducting vessels fluoresce markedly and the aqueous vessels do not. Vessels which contained pure plasma, were there any such, must fluoresce exactly as do those con taining plasma and blood cells. Clearly the aqueous veins are not blood bearing arteries nor are they primarily blood bearing veins.18 The concept of aqueous humor as a stag nant fluid was rejected promptly when these experiments utilizing dyes proved that there was a through-and-through circulation of the aqueous humor in the eye of man. Subse quent chemical studies of the aqueous hu mor, making use of labeled metabolites, turnover studies of endogenous constituents before and after known suppressants of aqueous humor formation, and other techni ques have established without doubt that the aqueous humor flows from the posterior chamber region of the ciliary body primarily through the pupil into the anterior chamber. The primary exit, after sieving through the
653
meshwork, is via Schlemm's canal, where upon the aqueous is directed into the aqueous veins. The clear aqueous seen within these vessels on the episcleral surface of the eye soon becomes mixed with plasma-containing vessels which were earlier confused with aqueous veins. For the first observation of these aqueousbearing vessels by Boerhaave, we praise him. It lies much further back in time than this 20th century research. Its incubation was in the era of pathology, newly transformed af ter the discovery of the circulation of the blood and the rejection of the humoral theory of pathology. SUMMARY
In the 18th century, Herman Boerhaave saw and described the episcleral vessels of the human eye which we now know to be aqueous veins. He did this using an ordinary magnifying glass. Boerhaave interpreted the nature of these ocular vessels within the con cepts of 18th century pathology. He believed that the aqueous vessels contained plasma skimmed from afferent arterioles. Many years passed before experimental demon strations of a through-and-through circula tion of aqueous humor and proof of the col lector nature of the aqueous channels were finally made. REFERENCES
1. Zeeman, W. P. C. : Boerhaave et l'Oculistique. Janus 23 :207, 1918. 2. De Langen, C. D. : Boerhaave and the periph eral circulation. Proc. Kon. Nederl. Akad. Wet. Biol. Med. 67:1, 1964. 3. Boerhaave, H. : Abhandlung von Augenkrank heiten. Nürnberg, Berlegung Wolfgang Schwarz kopf, 1771, chaps. 7 and 8. 4. Knisely, M. H , Bloch, E. H., and Warner, L. : Microscopic observations of intravascular aggluti nation of red cells and consequent sludging in hu man diseases. Anat. Rec. 82:486, 1942. 5. Paton, D. : The conjunctival sign of sickle-cell disease. Arch. Ophth. 66:118, 1961. 6. Coccius, E. A. : Über die Ernährungsweise der Hornhaut und die serumführenden Gefässe in Men schlichen Körper. Leipzig, I. Müller, 1852, p. 166. 7. Fahraeus, R. : The suspension stability of the blood. Acta Med. Scand. 55 :3, 1921.
654
AMERICAN JOURNAL OF OPHTHALMOLOGY
8. Duke-Elder, S. : Textbook of Ophthalmology, vol. 1. London, Kimpton, 1932, p. 455. 9. Magitot, A. : Sur les sources multiples de l'humeur aqueuse. Ann. Ocul. 165:481, 1928. 10. Leber, T. : Die Zirkulations-und Ernährungs verhältnisse des Auges. Graefe-Saemisch's Hand buch der ges. Augenheilk, vol. 2. Leipzig, W. Engel mann, 1903, p. 63. 11. Lauber, H. : Beitrag zur Anatomie des vor deren Augen-abachnittes der Wirbelthiere. Anat. Hefte 18:430, 1901. 12. Troncoso, M. U. : The physiologic nature of the Schlemm canal. Am. J. Ophth. 4:321, 1921. 13. Seidel, E. : Mikroskopische Beobachtungen über den Mechanismus des Abflusses aus der Vor
NOVEMBER, 1973
derkammer des Lebenden Tieres bie physiologis chem Augendrucke, von Graefe's Arch. Ophth. 111 : 167, 1923. 14. Ascher, K. W. : The Aqueous Veins. Spring field, Charles C Thomas, 1961, p. 4. 15. — : Aqueous veins. Am. J. Ophth. 25 :31, 1942. 16. Goldmann, H. : Weitere Mitteilung über den Abfluss des Kammerwassers beim Menschen. Oph thalmologica 111:146, 1946. 17. : Abfluss des Kammerwassers beim Menschen. Ophthalmologica 112:344, 1946. 18. : Über Fluorescein in der menschlicken Vorderkammer. Ophthalmologica 119:65, 1950.
OPHTHALMIC MINIATURE
With a vizard over his face, and two tubes projecting from his eyes to defend them from the light, Pepys—looking more a monster than a man —was obliged, that he might further deepen the shade, to resign his ac customed seat in front of the window, and take up his position on the other side of the table. He relates the change with strange satisfaction, and rejoices that now "the fire in winter will not trouble his back." This was cold comfort. If his calamity had permitted it, he might have had a screen at his back, instead of on his face, and been neither troubled by fire nor light. He was reasoning, however, after the event, and was right to console himself the best he could. Spectacle Quart. Rev. 87:1850
New Haven, Connecticut
Early in the 18th century, Herman Boerhaave saw the structures on the episcleral surface of the human eye, which we know now to be aqueous veins, using an ordinary magnifying glass. There was little, if any, information about the flow dynamics of the aqueous humor. Furthermore, enthusiasm for contemporary concepts of pathology, em bodying a rejection of the humoral pathol ogy, led Boerhaave to believe that these ocu lar vessels contained plasma that had been skimmed from larger afferent arterioles. For a long period after Boerhaave's observation, it was felt that the aqueous bearing vessels were actually empty of blood rather than filled with any aqueous. Experimental dem onstrations of a through-and-through circu lation of aqueous humor and proof of the collector nature of the aqueous channels were finally made by Ascher, Goldmann, and others. In 1725, a 17-year-old medical student 1 wrote the following description of one of his professors: . . . [he] still lives as a poor brewer, an un attractive man with cat's eyes, a small nose and a dark face, bristly hair, a plain hat, gray pitiful clothing, rough shoes. Years later, that same student was to reas semble the addresses of that professor and thus make accessible to the modern world the work and observations of Herman Boer haave. Who was this yet obscure professor of medicine? Albrecht von Haller, 1 the stuFrom the Department of Ophthalmology and Visual Science, Yale University School of Medi cine, New Haven, Connecticut. This work was sup ported in part by Public Health Service grants EY-00785 and EY-00237, and Research to Prevent Blindness, Inc. Reprint requests to Marvin L. Sears, M.D., Pro fessor and Chairman, Department of Ophthalmol ogy and Visual Science, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06S10.
dent who made the first publication of Boer haave's lectures, could say of him: In regards to Medicine, Chemistry, Botany, Latin, Theology, Physics, and Mathematics, he was as learned a man as one could wish to see. He also had the largest audience. . . . I don't think that I ever saw a classroom asfilledwith people as Boerhaave's. After Boerhaave's death, several of his pupils adapted their notes of his annual lec ture course for publication. Although the notes are not always complete and faultless, they give one an impression of Boerhaave's teaching and method, and certainly of the es teem in which Boerhaave was held. In more recent times, he has been ap plauded for his early recognition of the axial flow of the solid particles of the blood stream, his discovery of intravascular aggre gation and clotting, and his pioneer work in the field of thrombosis.2 To this list of achievements can be added the acknowledg ment that Boerhaave was the first to observe clear fluid-bearing vessels in the eye, which we now know to be aqueous veins. Boerhaave was not an ophthalmologist, nor was he a specialist in any other medical field. He was a master of the general science of medicine with a passionate belief in care ful and thorough observation. He did, how ever, have a fascination for the vascular workings of the body, and because of the easy visibility of the rich vascular network of the conjunctival coat of the eye, he fo cused much of his attention there. Using only a magnifying glass, Boerhaave3 noticed that " . . . one sees more clear fluid than blood circulating in the capillaries [of the eye]." In Boerhaave's lecture,3 "On the Inflammations of the Skins of the Eye," he said that ". . . normally these capillaries let through only a very pale and separated mois ture which later rejoins the blood in the
648
VOL. 76, NO. 5
HERMAN BOERHAAVE
veins." Knowing that to be the appearance of the well eye, Boerhaave quickly noticed the alteration caused by disease : During inflammation, however, most of them [the previously clear vessels of the eye], and sometimes all of them, are filled with blood. That is to say, the magnifying glass shows capil laries which now contain and conduct blood. Therefore, we conclude from this that the in flammation exists not only in the arteries . . . but also in the capillaries which consist of the ends of the arteries and which were previously so narrow that they could not conduct blood.* Boerhaave escaped the pitfall of other, even later investigators (Coccius,6 for ex ample) who believed that all vessels either carried blood or were empty, depending on whether they were red or clear. He recog nized that there were some vessels in the eye that carried a fluid that was not red. His con clusions, however, were limited by the hematology and ophthalmology of his day. He ex plained his observation in his lecture on eye inflammations : In the most external arteries the blood con sists of two parts which are separable : the white, clear watery fluid and the red portion. The red portion has small particles, each of which is made up of six little corpuscles which compose the clear fluid when they separate from each other. Thus, the red part decomposes into a sub stance which is different from what it was pre viously. The clear white portion flows into the capillaries which are as fine as a hair. The red portion, however, is led back again through the veins. To substantiate his premise that the whole blood had collected in vessels which would normally be so small as to skim off only the thin, clear fluid, Boerhaave3 described an ex periment he had done: When we look at our own eye or the eye of another person by the light of day, either with * Indeed, alterations in the conjunctival vascular bed have often been observed in the years since Boerhaave's time. Observations of sludged blood (a phenomenon perhaps foreshadowed by Boerhaave's description of a "gluing together" of corpuscles in the conjunctival blood flow) have been well docu mented by Knisely and associates.4 Perhaps the most informative use of conjunctival vascular patterns has been made by Paton in sickle cell hemoglobinopathy.5 The diagnostic usefulness of these observa tions has otherwise been limited.
649
naked vision or through a magnifying glass, everything will appear white. When, however, a neck tourniquet is tightened for a long period of time, so that the jugular vein is pressed to gether, then the tunica adnata will become red. And when this tourniquet is maintained for a long time, inflammation will develop in the tunica adnata because the tightening prevents the blood from returning to the heart and the pressure of the increasing blood broadens the opening of the little capillaries so that the blood is forced into them, although it does not circu late through them. This causes an itch which makes one instinctively blink or rub the eye. This causes the capillaries to contract and force the blood back into the great branch of the artery. When the tourniquet is removed, the in flammation quickly disappears through the action of the capillaries and the motion of the eyelids. In diseased states, a similar reddening is caused by the thickening of blood, which Boerhaave3 believed . . . is caused by the inflamed and compressed blood, in which case it is very red. Anything which increases the pressure on these small par ticles of blood, or anything which increases the force of the blood circulation, thus causing these little corpuscles to become compressed to the extent that they are "glued together," can create such a condition. . . . In order that the red corpuscles become white, they must be freed from compression, or in this case, returned to a broader space. We become aware of this quality of blood if we let blood which has been drawn from an artery stand. It first forms a skin, then [the rest] soon turns to water. To understand why Boerhaave spoke of the clear fluid in the eye as watery fluid sepa rated from the whole blood rather than as a unique fluid, it is important to consider the art of medicine in Boerhaave's time. Boerhaave was born 40 years after 1628, a watershed in the history of medicine in the West, the year of the publication of William Harvey's De Motu Cordts. Harvey's study of the circulation of the blood led to the dis carding of a theory of pathology which had held sway since the time of Hippocrates, the theory of the four humors. These four flu ids, intimately mixed with each other, were said to form blood. Since blood-letting had been the most favored remedy for nearly all deviations from health, as well as a much fa vored stimulant for its preservation, doctors
650
AMERICAN JOURNAL QF OPHTHALMOLOGY
from earliest recorded time had many oppor tunities to study the macroscopic nature of the blood. It was upon these studies, Fahraeus7 pointed out, that the theory of the four humors was built: As the blood dies off through the cooling in fluence of the air outside of the organism, these [four parts] diverge from their intimate union. The black bile collects at the bottom (the darkcolöred lower portion of the blood cake) ; the blood in a limited sense of the word, sanguis, rises toward the surface (the upper portion of the blood cake) ; the phlegm does not secrete itself spontaneously in healthy blood, but is all the same present as the connective substance in the blood cake (fibrin). The Greeks knew that by shaking healthy blood, the last-named fluid could be separated, and thereby the whole be prevented from clotting. In unhealthy blood, however, the phlegm collected in a more or less thick layer on top of the blood cake, which was of course interpreted as being a consequence of this substance having increased. These observations provided the prototype for the humoral pathology. Hippocrates pos tulated that the health of the body was based on a well-proportioned relationship of these four substances: blood, phlegm, yellow bile, and black bile. These four body fluids were analogous to the four elements of which the ancients believed the whole world to be com posed: fire, water, earth, and air. The blood, hot and moist, corresponded to air. The phlegm, cold and moist, corresponded to wa ter. The yellow bile, or choler, hot and dry, corresponded to fire, and the black bile, cold and dry, corresponded to earth. A predomi nance of blood made one sanguine, cheerful ; of phlegm, phlegmatic, testy; of yellow bile, choleric^ hot-tempered ; of black bile, melan choly. More serious imbalances or a sus tained separation of any part from the whole resulted in disease and death. Such separation and imbalance was read ily noticeable7 in the drawn blood : In most cases, the evacuated blood [during a period of disease] had quite a different appear ance to that in health. When coming from a sick person, it secreted a whitish substance of solid consistency which was absolutely lacking in the blood taken from a healthy person, but which, in more severe cases of illness, could perhaps
NOVEMBER, 1973
take up more than half of the liquid volume evacuated. This substance, which could change in quantity, always secreted itself, however, when it made its appearance, in the form of a superficial layer above the rest of the blood cake which was normally conditioned. This layer was the so-called crusta sanguinL· or the buffy coat. . . . The buffy coat was a sign in dicating that the suspension stability of the blood was reduced. Boerhaave knew of the clotting and sepa rating properties of the blood ; he also knew of the buffy coat. In his experience the pres ence of the buffy coat accompanied the signs of inflammation which Boerhaave described as being "glued together," whereas he be lieved that clotting of the red cells and sepa rating out of the clear white serum were phenomena achieved by healthy blood. Boer haave attributed the "gluing together" to in flammation and compression, rather than to an increase in one of the humors. Boerhaave had actually observed two dif ferent vascular phenomena in the eye: the clear flow of the aqueous within the aqueous veins and the agglutinated flow of diseased blood within the bloqd vessels. He believed he was seeing a separated form of whole blood flowing in tiny arterial vessels in the eye—i.e., plasma skirnming. His commit ment to the new humoral pathology, based within the theoretic framework of a circulat ing of blood, led him to consider the clear separated flow and the agglutinated red cells as two parts of the whole blood. He had no idea of the circulation of the intraocular fluid (aqueous) and so could explain his ob servations only in terms of arterial plasma skimming. Since his observations conve niently supported the concepts embodied in the new humoral pathology, Boerhaave, like many others after him, failed to understand the exact nature of the clear vessels he had seen on the surface of the eye. In the 20th century, the outflow of the intraocular fluid, aqueous humor, was charted, proven, and became fully recog nized. As recently as 1934, Sir Stewart Duke-Elder8 stated that the nature and activ-
VOL. 76, NO. S
HERMAN BOERHAAVE
ity of the intraocular fluid continued to be a matter of disagreement. The discussion cen tered around three major theories. One view was that intraocular fluid did riot flow through the vessels of the eye, but that the fluid was renewed by a general met abolic interchange throughout the tissues of the eye. This view, which derived from Ul rich's hypothesis of the physiologic seclusion of the pupil (a condition which would have precluded any flow of fluid through the pu pillary aperture), was stated in its essentials by Hamburger between 1898 and 1924. It was elaborated by Magitot9 in 1917 and re stated by him in 1928: We shall conclude then today, as in 1916, that the aqueous humor . . . is [not] animated by a current in the real sense of the word. It is, in its normal state, a dormant water, like that of a well, which renews itself only extremely slowly if one does not cause any withholding [of the source]. Its production and elimination are two balanced phenomena, resulting from the work of dialysis from the capillaries of the uvea and from the retina. The same membranes, those of the capillaries, produce the liquid, then reabsorb it and reproduce it.
Seeing no readily visible outflow vessels, Magitot opposed a theory of circulation. Duke-Elder's 8 own view was that there was a metabolic interchange between the intraocular fluid and blood through the capil lary walls throughout all the tissues of the eye, much as Magitot said, but superimposed upon this interchange was a secondary pres sure-derived circulation conditioned by the pulse beat, the respiratory variations, and muscular activity. He noted also an inciden tal thermal circulation which added to the constant internal movement of the aqueous humor. Duke-Elder chose the best of both worlds: no circulatory path and yet a secon dary circulation. Soon, however, it was acknowledged that the aqueous humor did have a definite pri mary circulation. The fluid had its source at the ciliary body, passed through the pupillary aperture into the anterior chamber, and left the eye by the canal of Schlemm. This view
651
was first fully elaborated by Leber10 in 1903, but it had been noted in experiments Lauber performed earlier with dogs. In 1901, Lauber 11 published a comparison of red cell counts of blood taken from the anterior cili ary veins and from the paw of the same dog. The blood from the paw contained 3.61 mil lion red blood cells per cubic millimeter, and that taken from the ciliary veins con tained between 2.90 and 2;68 million red blood cells. Lauber explained this difference between paw and ciliary vein blood counts by assuming a dilution of the blood in the ciliary veins by the outflow of aqueous hu mor into the sclerocorneal vessels that emp tied into the anterior ciliary veins. In 1921, Troncoso 12 was able to document such an outflow of a clear fluid from the eyes of living rabbits. The globe was drawn (proptosed) outside the orbit and held in this position by the return of the eyelids to their normal position. The board on which the ani mal was fastened was then turned so that the apex of the cornea became the lowest point of the eye. The globe was then passed through a hole in a rubber-dam sheet to pre vent collection of liquids from the conjunc tiva or orbit. After the sciera was cleansed of all blood, the globe was immersed in a glass cup filled with olive oil. Minute clear droplets of aqueous collected around the cor nea; five to 10 minutes later new droplets appeared along the limbus. A rate of aque ous flow was calculated by this method. Experiments exploring the possibility of a path of aqueous outflow in animal eyes were numerous in the latter part of the last century and in the early part of this one. Perhaps the most notable of these is that of Seidel.13 He gently forced a solution of 1% in digo-carmine into the emptied anterior chamber of an anesthetized rabbit. Seidel used an infusion with variable pressures and made his observations with a binocular mi croscope. He noticed that the episcleral veins turned blue with the dye and that neither any iris vessels which emptied into the vorticose
652
AMERICAN JOURNAL OF OPHTHALMOLOGY
veins, nor any previously unobserved ves sels, filled with the blue fluid. Thus, he con cluded that the dye was eliminated only by the anterior ciliary veins into which the lim» bal meshwork empties, and that no artificial channels had been formed by the manometer infusion. He further noticed that when India ink was used for the infusion, the dye was apparent first in the axial stream of the larger vessels and the red color was pre served in the periphery of the stream, a phe nomenon which occurs in human aqueous outflow. Seidel concluded from these experi ments, done in 1923, that under physiologic intraocular pressures a continuous outflow of fluid takes place from the anterior cham ber of the living animal into the veins situ ated in the scierai tissue near the chamber angle. He believed that the driving force was the hydrostatic difference between the ante rior chamber and the veins. Ascher14 realized the aqueous-bearing function of the clear, episcleral vessels in hu man eyes. Ascher's review of the subject in cludes the work of Coccius6 and subsequent physiologists, but does not explore the obser vations of Boerhaave. Ascher14 states: The discovery of aqueous veins was delayed because observers were content with the ex planation that in the pericorneal region of the human eye the direction of the blood current is frequently seen to change and that vessels very often "contract" and show a granular stream of corpuscles or frequently even seem to be empty. The presence of "empty" capillaries was mentioned since the early days of slit-lamp microscopy and even long before the slit lamp was invented. Not enough attention was paid to a discrimi nation between lack of visible red cells and ab sence of any content in the vessel. Convinced that the vessels could contain either blood or nothing, the observers believed the absence of red to be proof of complete emptiness. In May, 1941, Ascher16 was examining an Alabama miner, aged 35, in whose eyes he saw what he thought to be a "physiologic connection between the canal of Schlemm or the venous meshwork surrounding it, and the episcleral venous meshwork." He de-
NOVEMBER, 1973
scribed the colorless quality of the vein and the stratified current: The clear stream started just where the color less loop—the aqueous vein—entered its recipient vessel, the lower two thirds of which were filled with blood of normal color. After this discovery, Ascher continued looking for such aqueous humor outflow ves sels in the eyes of all the patients he ob served in the Nutritional Clinic in Hillman Hospital, Birmingham, Alabama. He found aqueous veins in the eyes of 26:78% of am bulatory patients (79 of 295 patients) during routine examinations. From these examinations, Ascher15 set four criteria for identifying aqueous veins: ( 1 ) by their more-or-less characteristic ori gin in or near the corneal limbus or out of an emissarium sclerae; (2) by lack of blood corpuscles as compared to ordinary conjunctival and subconjunctival vessels, and some times, by a typical stratification.; (3) by their characteristic emptying into recipient ves sels ; and (4) by significant phenomena pro duced by compression of their recipient ves sels. This last point was of great interest to Ascher, who studied its occurrence in both normal and glaucomatous eyes. Definitive physiologic confirmation of the aqueous content of these vessels was pro vided by Goldmann.16 In 1946, Goldmann performed experiments with both fluorescein and India ink similar to those reported by Seidel, but in human eyes. Goldmann in jected a mixture of equal parts of saline so lution and Guenther-Wagner-Perltusche ink, a brand of India ink with particularly smallsized particles (between 10 and 20 nm ac cording to Seidel), into the anterior cham ber of an eye to be enucleated because of uyeal sarcoma (melanoma). Before this injection, an aqueous vein had been located in the nasal episclera. Under topical cocaine anesthesia, a small amount of aqueous humor was aspi rated from the anterior chamber of the neoplastic eye and partly replaced with inky mixture, without attaining the previous
VOL. 76, NO. S
HERMAN BOERHAAVE
intraocular pressure. While the episcleral vessels maintained their normal red color, the previously located aqueous vein became black. Goldmann17 demonstrated that an aqueous vein could be filled with material in troduced into the anterior chamber without large increases in intraocular pressure. In later fluorescein studies, Goldmann18 demonstrated unequivocally that the color less fluid in the clear vessels stemming from Schlemm's canal really was aqueous humor and not plasma. Goldmann noted that 15 minutes after intravenous injection of 4 ml of 10% sodium fluorescein, the concentra tion in the plasma is about 1,000 times greater than the concentration in the aqueous humor. The concentration in the aqueous hu mor after one hour, compared to that in the plasma, is about 1:100. In normal subjects, the maximum concentration of fluorescein in the anterior chamber is reached 90 minutes after injection. At this later time, aqueous veins may contain fluorescein. Thus, one can understand why in the first half hour after intravenous injection of fluorescein, the blood-conducting vessels fluoresce markedly and the aqueous vessels do not. Vessels which contained pure plasma, were there any such, must fluoresce exactly as do those con taining plasma and blood cells. Clearly the aqueous veins are not blood bearing arteries nor are they primarily blood bearing veins.18 The concept of aqueous humor as a stag nant fluid was rejected promptly when these experiments utilizing dyes proved that there was a through-and-through circulation of the aqueous humor in the eye of man. Subse quent chemical studies of the aqueous hu mor, making use of labeled metabolites, turnover studies of endogenous constituents before and after known suppressants of aqueous humor formation, and other techni ques have established without doubt that the aqueous humor flows from the posterior chamber region of the ciliary body primarily through the pupil into the anterior chamber. The primary exit, after sieving through the
653
meshwork, is via Schlemm's canal, where upon the aqueous is directed into the aqueous veins. The clear aqueous seen within these vessels on the episcleral surface of the eye soon becomes mixed with plasma-containing vessels which were earlier confused with aqueous veins. For the first observation of these aqueousbearing vessels by Boerhaave, we praise him. It lies much further back in time than this 20th century research. Its incubation was in the era of pathology, newly transformed af ter the discovery of the circulation of the blood and the rejection of the humoral theory of pathology. SUMMARY
In the 18th century, Herman Boerhaave saw and described the episcleral vessels of the human eye which we now know to be aqueous veins. He did this using an ordinary magnifying glass. Boerhaave interpreted the nature of these ocular vessels within the con cepts of 18th century pathology. He believed that the aqueous vessels contained plasma skimmed from afferent arterioles. Many years passed before experimental demon strations of a through-and-through circula tion of aqueous humor and proof of the col lector nature of the aqueous channels were finally made. REFERENCES
1. Zeeman, W. P. C. : Boerhaave et l'Oculistique. Janus 23 :207, 1918. 2. De Langen, C. D. : Boerhaave and the periph eral circulation. Proc. Kon. Nederl. Akad. Wet. Biol. Med. 67:1, 1964. 3. Boerhaave, H. : Abhandlung von Augenkrank heiten. Nürnberg, Berlegung Wolfgang Schwarz kopf, 1771, chaps. 7 and 8. 4. Knisely, M. H , Bloch, E. H., and Warner, L. : Microscopic observations of intravascular aggluti nation of red cells and consequent sludging in hu man diseases. Anat. Rec. 82:486, 1942. 5. Paton, D. : The conjunctival sign of sickle-cell disease. Arch. Ophth. 66:118, 1961. 6. Coccius, E. A. : Über die Ernährungsweise der Hornhaut und die serumführenden Gefässe in Men schlichen Körper. Leipzig, I. Müller, 1852, p. 166. 7. Fahraeus, R. : The suspension stability of the blood. Acta Med. Scand. 55 :3, 1921.
654
AMERICAN JOURNAL OF OPHTHALMOLOGY
8. Duke-Elder, S. : Textbook of Ophthalmology, vol. 1. London, Kimpton, 1932, p. 455. 9. Magitot, A. : Sur les sources multiples de l'humeur aqueuse. Ann. Ocul. 165:481, 1928. 10. Leber, T. : Die Zirkulations-und Ernährungs verhältnisse des Auges. Graefe-Saemisch's Hand buch der ges. Augenheilk, vol. 2. Leipzig, W. Engel mann, 1903, p. 63. 11. Lauber, H. : Beitrag zur Anatomie des vor deren Augen-abachnittes der Wirbelthiere. Anat. Hefte 18:430, 1901. 12. Troncoso, M. U. : The physiologic nature of the Schlemm canal. Am. J. Ophth. 4:321, 1921. 13. Seidel, E. : Mikroskopische Beobachtungen über den Mechanismus des Abflusses aus der Vor
NOVEMBER, 1973
derkammer des Lebenden Tieres bie physiologis chem Augendrucke, von Graefe's Arch. Ophth. 111 : 167, 1923. 14. Ascher, K. W. : The Aqueous Veins. Spring field, Charles C Thomas, 1961, p. 4. 15. — : Aqueous veins. Am. J. Ophth. 25 :31, 1942. 16. Goldmann, H. : Weitere Mitteilung über den Abfluss des Kammerwassers beim Menschen. Oph thalmologica 111:146, 1946. 17. : Abfluss des Kammerwassers beim Menschen. Ophthalmologica 112:344, 1946. 18. : Über Fluorescein in der menschlicken Vorderkammer. Ophthalmologica 119:65, 1950.
OPHTHALMIC MINIATURE
With a vizard over his face, and two tubes projecting from his eyes to defend them from the light, Pepys—looking more a monster than a man —was obliged, that he might further deepen the shade, to resign his ac customed seat in front of the window, and take up his position on the other side of the table. He relates the change with strange satisfaction, and rejoices that now "the fire in winter will not trouble his back." This was cold comfort. If his calamity had permitted it, he might have had a screen at his back, instead of on his face, and been neither troubled by fire nor light. He was reasoning, however, after the event, and was right to console himself the best he could. Spectacle Quart. Rev. 87:1850