- Email: [email protected]
Clinical Aspects of Permeability of the Blood-Aqueous Barrier*
CLINICAL ASPECTS O F PERMEABILITY O F T H E BLOOD-AQUEOUS BARRIER* PAUL WEINSTEIN, M.D.,
AND J. FORGΔCS,
M.D.
Budapest, Hungary
That intravenously administered fluorescein will appear in the aqueous humor has long been known. The method has become significant as a clinical test since the time when Amsler and Huber developed its quan titative possibilities by means of the so-called electric zero-point. The essential character istics of this method are the intravenous in jection of 2.0 ml. of a 10-percent solution of fluorescein-sodium which appears in the aqueous humor within two to five minutes. When the aqueous humor becomes a fluores cent green, the intensity of the lamp is re duced by means of a rheostat inserted be tween the lamp and an amperemeter. Reduc tion is continued until the fluorescein becomes invisible. The same procedure is repeated every two minutes. The ampere value and the time in minutes are recorded on the co ordinates. The investigation is finished after 30 minutes when the fluorescence has passed its peak. Using this method on a large number of normal subjects, Amsler, Huber, and Haefeli worked out a scatter diagram of normal physiologic permeability; values exceeding these are interpreted as indicating a patho logic increase. Studies using this method have been made with varying aims and results. Bernet stated that subconjunctivally administered saline above a two-percent concentration increased permeability. Bottino found permeability in creased by light but uninfluenced by dark ness. Cook and MacDonald found that cortisone reduced permeability; Simonelli and Calamandrei, as well as Pentini, found ACTH had no influence. D'Ermo found antihista* From the Department of Ophthalmology, State Hospital of Szabolcs-Utca.
mines decreased permeability. Franceschetti and his co-workers noted an increased per meability after acetylcholine. Hofstetter, using calcium, successfully de creased permeability and, according to Huber, histamine increases permeability while adrenaline decreases it. Morons, Simonelli, and Stocker investigated the effect of vitamin P. Kalt found permeability increased by iritis with no relationship to hypertension, and Moreau noted increase of permeability in a case of hypotension and iritis. Widmer de termined that, normally, fluorescein disap peared in 10 to 12 hours. PRESENT STUDY
In this study, 150 cases of various eye dis eases were studied according to the method of Amsler and Huber. The diseases included iritis, glaucoma, hypertension, diabetes, chorioretinitis, myxedema, heterochromia, Horner's syndrome, contusion of the eye, retinal hemorrhages, allergies, multiple sclerosis, pernicious anemia, and novocaine block of the ciliary and stellate ganglia. The results showed the permeability of the blood-aqueous barrier to be increased in heterochromia, contusion of the globe, myxedema, hypertensive retinitis, pernicious anemia, allergic conjunctivitis, and iritis. Some cases of myxedema showed normal permeability, however, giving credence to Goldmann's opinion that there may be a "seeming increase" in permeability if, for instance, the osmotic differential of the blood colloids and, with it, that of fluorescein has changed. Some cases of contusion also showed normal values, while other showed patho logically altered ones. Furthermore, permea bility also varied in cases of hypertensive
377
378
PAUL WEINSTEIN AND J. FORGACS
retinitis and glaucoma. Reactions in these two diseases will be described in detail but it is of interest to note here that among the cases of highest increase was one in which simple glaucoma and hypertensive retinitis occurred simultaneously. In this case the fluorescein appeared almost instantly after injection (fig. 1). GLAUCOMA INVESTIGATION
Of the 23 cases of glaucoma studied, six were acute, 11 were chronic inflammatory, and six were chronic simple. The 17 chronic cases showed normal permeability. Two of the six acute cases were investigated during attacks, and permeability proved to be at the upper limits of normal. After the attack, when the eyes softened, the permeability was essentially increased. The same increase was observed in three other cases of acute glau coma, the tests being made after the attacks. In one case of acute glaucoma (the patient had a — 8.0D. myopia), the value was nor mal immediately after an attack. Figure 2 demonstrates permeability dur ing, immediately after, and three weeks after an attack. Our investigations indicate that in creased permeability is present in glaucoma only after an attack of acute glaucoma. This observation seems to bear out Goldmann's statement that, after cyclodialysis or other operations, if ocular tension becomes hypotonic, the increase in permeability is only a
c*
_-2
<Ë
<
MJN
5
10
Þæ
%
3â
30
Fig. 2 (Weinstein). Acute glaucomatous attack, left eye. (1) During attack. (2) Immediately after attack. (3) One week after attack. (4) Three weeks after attack. (Continuous line) Permeability of nonglaucomatous right eye.
"seeming one." Essentially, this is because so-called secretory inhibition is in control, less aqueous humor is being produced, and the concentration of fluorescein is greater (compared to the controls). This increase in permeability after glau comatous attacks may be explained in part by assuming that secretory inhibition also may occur, not invariably, however, as demonstrated by the one case herein de scribed in which permeability was not in creased. In their first report, Amsler and Huber note increased permeability in glaucoma cases; in their later ones they emphasize both possibilities. Guenther found normal values in chronic glaucoma; increased values in acute. However, he does not mention whether the increase in acute glaucoma occurred dur ing or after the attacks. Miller and Swanljung found increased H permeability more frequently in secondary glaucomas; in primary glaucoma they found "*Àߣ%3 no abnormalities in tension, neither increase nor decrease. They also state that permeabil ity may be increased after an attack of acute glaucoma, but that it may also be normal. Leydhecker, investigating the influence of provocative tests, could find no difference 1;0 1*5 10 25 3¼ MINduring the period of increased tension. Our Fig. 1 (Weinstein). Monocular glaucoma sim plex, and hypertensive diabetic retinopathy. (Shaded experience with provocative tests was simi lar. area) Normal permeability.
379
BLOOD-AQUEOUS BARRIER C O N T U S I O N S OF GLOBE
Pathologically increased permeability was also found in those cases of contusion of the globe in which the intraocular pressure was lowered simultaneously; if the damaged eye were not hypotonic, permeability was unchanged. It was, therefore, assumed that contusion sometimes provokes secretory blockage, which explains the hypotension and the seeming increase in permeability. GLAUCOMA OPERATIONS
In this study, three cases of hypotension following glaucoma operations were studied. In two of them (Elliot trephining opera tion), permeability was seemingly increased (fig. 4) as in Goldmann's cases (secretory blockage). In the third case (cyclodialysis), permeability was found to be normal, show ing that hypotension was due not only to secretory inhibition but also to increased drainage. Gonioscopy revealed a broad cyclo dialysis cleft. GANGLION BLOCK
Karczag and Zilahy found, following sympathectomy in rabbits, that the bloodaqueous barrier was lowered. Bakay, Jr., found the same to be true of the blood-plasm barrier. Steiner assumed a dilatation of the cranial vessels following novocaine block of the stellate ganglion, but his findings were
disputed by Harmel and his co-workers. We undertook to investigate the effect of novocain block on either the ciliary or stel late ganglion and learned that, in some cases, there was increased permeability and, in others, no apparent change. Increased per meability occurred (fig. 3) simultaneously with decreased tension (secretory inhibi tion?). In cases of Horner's triad of several years' duration, after extirpation of the stellate ganglion, permeability was increased only if tension were decreased. These experiments by which drugs in increased amounts were introduced into the cerebral substance or the cerebrospinal fluid by simultaneous blocking of the stellate ganglion, seemed to indicate that permeability increased as the amount of the drug increased and that secretory inhibi tion resulted in a higher concentration of the drug. Amsler and his collaborators investigated the permeability of the blood-aqueous barrier in various systemic diseases. They found an increase to be most frequent in cases of dia betes, hypertensive alterations of the fundus, and Kimmelstiel-Wilson disease. We studied cases in which the fundus showed Grade 3 or Grade 4 hypertension (Wagener and Keith) and discovered what appeared to be a new aspect of the fundus alteration. Litzner (1933) reported anemia and baso-
15 Fig. 3
20 25 30
Fig. 4
10
15
20
25 30
Fig. 5
Figs. 3, 4, and 5 (Weinstein). (Fig. 3) Permeability after novocaine block of stellate ganglion, O.D. Horner's syndrome, O.D. Tension: O.D., 20 mm. Hg (Schijzftz) ; O.S., 26 mm. Hg. (Dotted line) Permeability of right eye. (Fig. 4) Chronic inflammatory glaucoma, O.U. Elliot trephining operation, O.D. Tension: O.D. 8.0 mm. Hg (Schδtz); O.S., 20 mm. Hg. (Dotted line) Permeability of the hypotensive right eye. (Fig. 5) Monocular hypertensive retinitis. RBC, three million; hemoglobin, 60 percent. Blood pressure, 230/120 mm. Hg.
380
PAUL WEINSTEIN AND J. FORGACS
philia in a number of cases of glomerulosclerosis. Hypertensive retinitis was also present in all of his cases. Koyanagi pub lished similar findings in 1937. Gonzales Belmonte (1950) stated that, in Grades 1 and 2 of hypertension, the number of erythrocytes increased to compensate for the anoxia which increased as the disease de veloped. Present knowledge indicates that the alterations of hypertensive retinitis are due to anoxia. As erythropoiesis becomes ex hausted, the number of erythrocytes becomes diminished. Swanljung (1951) stated that anoxia increases blood-aqueous permeability in animals. In some of our cases of hypertensive reti nitis, the erythrocyte count was around three million (fig. 5), the hemoglobin count was decreased, and the permeability of the bloodaqueous barrier was increased. We found that, in pernicious anemia, when severe anoxic alterations of the fundus were present, permeability increased as it did in cases of hypertensive alterations of the fundus. The classical research of Stina Bjφrk demonstrated that hypertensive retinitis en sues only if diastolic tension increases and capillary volume decreases, thus causing anoxia. And anoxia, according to our investi gation, produces not only fundus alterations but anemia and a subsequent increase of per meability as well. In some cases of hypertensive retinitis of recent onset, the erythrocyte count and per meability were still normal. Such cases would seem to indicate that the fundus alterations of hypertensive retinitis are not necessarily concomitant to increased permeability, which is confined to the choroidal walls, the retinal circulation proceeding independently. This
evidence even suggests such therapeutic measures in hypertensive retinitis as oxygen inhalation and the administration of iron. Local administration of pilocarpine, histamine, and adrenaline seemed to have no in fluence on permeability; nor did hyaluronidase when it was injected with fluorescein. SUMMARY
The permeability of the blood aqueous barrier was investigated by the Amsler and Huber zero-point fluorescein method in 150 cases of iritis, glaucoma, hypertension, dia betes, chorioretinitis, myxedema, heterochromia, Horner's syndrome, contusion of the globe, retinal hemorrhage, allergies, mul tiple sclerosis, and novocain block of the ciliary and stellate ganglia*. Normal permeability was found in simple chronic and chronic inflammatory glaucoma. It was not essentially increased during acute attacks but was considerably augmented after the attack subsided. Permeability increased only with contusion of the globe. Permea bility increased only if there was simultane ous decrease in ocular tension in cases of Horner's syndrome and after novocaine block of the ciliary and stellate ganglia. This was considered as due to secretory inhibition ("seeming increase," according to Goldmann). The considerable increase in permeability in hypertensive retinitis was frequently as sociated with anemia. In a case of pernicious anemia, permeability was markedly increased (anoxic phenomenon). Pilocarpine, histamine, and adrenaline locally and hyaluronidase intravenously did not influence permea bility. V. Szemelynφk u. 9/11.
REFERENCES
Amsler, M., and Huber, A.: Methodik und erste klinische Ergebnisse einer Funktionsprufung der Blut-Kammerwasserschranke. Ophthalmologica, 111:155, 1946. Amsler, M., Verrey, F., and Huber, A.: Zur Physiopathologie einig Gewebsflussigkeit. Schweiz med. Wchnschr., 77.1921, 1947. Amsler, M.: Le liquide lecunaire de l'oeil: L'epreuve clinicque de la permeabilite de lar barriere hemato-oculaire, Bruxelles Med., 33:17, 1947.
BLOOD-AQUEOUS BARRIER
381
Amsler, M., and Huber, A.: Die Blut-Kammerwasserschranke, ein klinischer Begriff. Arch. f. Ophth., 149 :578, 1949. : Technisches und Principielles zu unseren Fluorescein Test. Ophthalmologica, 121:130, 1951. Bakay, L., Jr.: Die Innervation der Pia mater, der Plexus, chorioidei und der Hirngefasse mit Ruksicht auf den Einfluss des sympathischen Nervensystem auf die Liquorsekretien. Arch. f. Psychiat., 113:412, 1941. Belmonte, Gonzales: Erythema in hypertension retinopathy. Arch. Soc. oftal hisp.-am., 10 :453, 1950. Bernet, M.: Die Wirkung von subconj. hypertonischen Kochsalzlosungen auf die Fluoresceinpermeabilitat der Blut-Kammerwasserschranke. Diss. Zurich, 1950. Bottino, C.: Barriera emat-oftalmica e stimoli luminosi. Ann. Ottal., 77 :281, 1951. Cook, C, and MacDonald, R. K.: Effect of cortisone and the permeability of the blood-aqueous barrier to fluorescein. Brit. J. Ophth., 35:730, 1951. Davson, H.: The aqueous humor and the blood-aqueous barrier. Ophth. Lit., 3:254, 1949. d'Ermo, F.: Antistaminici e occhie: Ricerche sperimentali sul passagio degli antistaminici nella camera anteriore e sulla lore azione sulla barriera ematoftalmica. Boll, d'ocul., 29 :375, 1950. Franceschetti, A., Frommel, E., and Johr, P.: De l'influence de l'acetylcholine sur la permeabilite oculaire. Experientia, 7:35, 1951. Giardini, A., and Swanljung, H.: Effects of anoxia on the fluorescein permeability of the blood-aqueous barrier. Brit. J. Ophth., 35:114, 1951. Goldmann, H.: Ueber die Wirkungsweise der Cyclodialyse. Ophthalmologica, 121:94, 1951. Guenther, G.: Beobachtungen όber die Funktionsprufung der Blut-Kammerwasserschranke nach Amsler und Huber. Ber. Versamml. deutsch, ophth. Gesellsch., 56:121, 1950. Haefeli, W.: Die Fluorescein-Permeabilitat der Blut-Kammerwasserschranke des gesunden Auges. Ophthalmologica, 112:326, 1946. Harmel, M. H., Hafkenschiel, J. H., Austin, J. M., Crumpton, C. W., and Kety, S. S.: The effect of bilateral stellate ganglion block on the cerebral circulation in normotensive and hypertensive patients. J. Clin. Investigation, 28:415, 1949. Hofstetter, M.: Die Wirkung von Calcium auf die Fluoresceinpermeabilitat der Blut-Kammerwasser schranke. Schweiz, med. Wchnschr., 78 :402, 1948. Huber, A.: Zur Pharmakologie der Blut-Kammerwasserschranke. Ophthalmologica, 114:217, 1947. Huber, A., and Walch, J.: Untersuchingen όber Gefass-Permeabilitatsstorungen beim Ekzem: Messun gen der Permeabilitδt der Blut-Kammerwasserschrankc. Dermatologica, 99 :242, 1949. Kalt, M.: Les uveites hypertensives: Etudes clinique, pathogenique et therapeutique. Bull. Soc. franc, d'opht, 62 :48, 1949. Karezag, L., and Zilahy, N.: Ueber die Beeinflussung der Zellpermeabilitat durch den Sympathicus. Biochem. Ztschr., 162:18, 1925. Koyanagi, Y.: Verδnderungen an der Netzhaut bei Hochdruck. XV. Internat. Cong. Ophth., 1:262, 1937. Leydhecker, W.: Permeability of the blood-aqueous barrier to fluorescein during the water-drinking test in glaucomatous eyes. Brit. J. Ophth., 34:480, 1950. Litzner, S.: Ueber das Vorkommen basophil getόpfelter roter Blutkφrperchen bei Schrumpfnieren. Med. Klin., 1933, p. 81. Miller, J. H., and Swanljung, H.: Appearance of fluorescein in the aqueous of glaucomatous eyes. Brit. J. Ophth., 35 :356, 1951. Moreau, A.: Notas acerca del diagnostice etiologice de las iridociclitis. Arch. Soc. Oftal. hisp.-am., 9:967, 1949. Morone, G.: Ricerche sull influenza della vitamina P (citrina) sulla permeabilita dellar barriera ematoftalmica. 36th Cong. Soc. Oftal. Ital. Roma, 1947, p. 500. Pentini, G.: Comportamento della barriera ematoftalmica dopo somministrazione di ACTH. Ann. Ottal., 77:181, 1951. Ruegsegger, P.: Die Fluoresceinpermeabilitat der Blut-Kammerwasserschranke bei haemorrhagischen Diathesen. Diss. Zurich, 1947. Simonelli, M.: Ricerche sulla permeabilita della barriera emato-oftalmica: I. Influenza della somminis trazione di acido nicotinico. Gior. ital oftal. 1:317, 1948; II. Influenza della somminstrazione vitamina C. Ibid., 1:426, 1948. III. Modificazioni riscontrale nei soggetti con distacco di retina. Ibid., 1:432, 1948; IV. Influenza della somministrazione di alcuni fattori vitaminici del gruppo B. Ibid., 1:450, 1948; V. Influenza della somministrazione di vitamina Pz. Ibid., 2:185, 1949; VI. Influenza della somministrazione di vitamina K. Ibid., 2:329, 1949. Simonelli, M., and Calamandrei, G.: Comportamento della permeabilita della barriera emato-oftalmica dopo somministrazione di ACTH. Gior. ital. oftal., 4:340, 1951. Steiner, B.: Orvosi Hetilap., 91.1209, 1950. Stina-Bjork: Haemodynamic factors and retinal changes in hypertensive diseases. Acta med. Scandinav. Supplement, 1946. Stocker, F. W.; Experimental studies on the bloodaqueous barrier: I. New electrophotometric method
382
M. A. L. HASSOUNA
of measuring the concentration of fluorescein in the aqueous. Arch. Ophth., 36:612, 1946; II. Electrophotometric measurements of fluorescein content of aqueous after intravenous injection of fluorescein, the eye being under the influence of physostigmin, pilocarpine, neostigmine, or atropine. Ibid., 37:583, 1947. Widmer, A.: Die Elimination von Fluorescein aus der Augenworderkammer. Diss. Zurich, 1950.
TRACHOMA IN BRIEF* M. A. L. HASSOUNA,
M.D.
Cairo, Egypt ETIOLOGY
As early as 1907, von Prowaczek and Halberstaedter 1 discovered the infective agent of trachoma in Java. In scrapings from the upper tarsal conjunctiva of trachomatous patients they found in some of the superficial epithelial cells definite gran ular formations, inclusion bodies, each oc cupying a good part of the cytoplasm of the cell, often capping the nucleus but sometimes filling the cytoplasm to such an extent that eventually the cell bursts. Stained with Giemsa or more quickly with Wright's or PolefF's stain, the inclusion body is seen to consist of very small bodies or granules which differ in size, shape, and staining properties in different inclusions. Some of them are very minute measuring only 0.25 to 0.30 microns in diameter and staining reddish purple—acidophilic—with Giemsa or Wright (the elementary gran ules) ; while others are larger, measuring 0.6 to 1.5 microns and staining blue—basophilic —with these stains (the initial bodies of Lindner). Both forms may occur extracellularly. The inclusion body, which may contain initial bodies alone, or elementary granules alone', or a mixture of both, measures more than ΊΟ μ.. It is now universally recognized that the minute elementary granules and the larger initial bodies are only two phases of one infective unit, a filterable virus, and that the inclusion body as a whole is the intracellular colony of that virus, the infec* From the Memorial Ophthalmic Laboratory, Giza.
tive agent of trachoma (Thygeson). 2 An early small inclusion body consists mainly of basophilic initial bodies, while a large older one consists primarily of acid ophilic elementary granules, but all stages between the two can be seen. Elementary granules, however, are less frequent in Egyption trachoma than initial bodies. It is suggested that an elementary granule penetrates an epithelial cell in which it grows into a large basophilic initial body which multiplies, poorly though, until the minute acidophilic elementary granules are pro duced, appearing first in the center then proceeding outward. In other words, the early inclusions are basophilic and the later ones are acidophilic. The epithelial cell may then burst liberating the small elementary granules in the conjunctival secretion. From conjunctival secretion in acute cases of trachoma, many extra- (and intra-) cel lular reddish granules can be detected sur rounded by a halo of nonstaining material. They can be concentrated by centrifugation (Thygeson 2 ). A suspension of the material is centrifuged at a low speed (1,500 r.p.m.) for five minutes to eliminate tissue material. The supernatant fluid is then removed and centrifuged at a high speed (15,000 r.p.m.) for 30 minutes in an angle high-speed cen trifuge. This carries most of the active virus to the sediment. The sediment shows elementary granules as already mentioned and, upon inoculation in the upper tarsal conjunctiva of a human volunteer after light scarification of the con junctiva with a platinum spatula (the volun-
AND J. FORGΔCS,
M.D.
Budapest, Hungary
That intravenously administered fluorescein will appear in the aqueous humor has long been known. The method has become significant as a clinical test since the time when Amsler and Huber developed its quan titative possibilities by means of the so-called electric zero-point. The essential character istics of this method are the intravenous in jection of 2.0 ml. of a 10-percent solution of fluorescein-sodium which appears in the aqueous humor within two to five minutes. When the aqueous humor becomes a fluores cent green, the intensity of the lamp is re duced by means of a rheostat inserted be tween the lamp and an amperemeter. Reduc tion is continued until the fluorescein becomes invisible. The same procedure is repeated every two minutes. The ampere value and the time in minutes are recorded on the co ordinates. The investigation is finished after 30 minutes when the fluorescence has passed its peak. Using this method on a large number of normal subjects, Amsler, Huber, and Haefeli worked out a scatter diagram of normal physiologic permeability; values exceeding these are interpreted as indicating a patho logic increase. Studies using this method have been made with varying aims and results. Bernet stated that subconjunctivally administered saline above a two-percent concentration increased permeability. Bottino found permeability in creased by light but uninfluenced by dark ness. Cook and MacDonald found that cortisone reduced permeability; Simonelli and Calamandrei, as well as Pentini, found ACTH had no influence. D'Ermo found antihista* From the Department of Ophthalmology, State Hospital of Szabolcs-Utca.
mines decreased permeability. Franceschetti and his co-workers noted an increased per meability after acetylcholine. Hofstetter, using calcium, successfully de creased permeability and, according to Huber, histamine increases permeability while adrenaline decreases it. Morons, Simonelli, and Stocker investigated the effect of vitamin P. Kalt found permeability increased by iritis with no relationship to hypertension, and Moreau noted increase of permeability in a case of hypotension and iritis. Widmer de termined that, normally, fluorescein disap peared in 10 to 12 hours. PRESENT STUDY
In this study, 150 cases of various eye dis eases were studied according to the method of Amsler and Huber. The diseases included iritis, glaucoma, hypertension, diabetes, chorioretinitis, myxedema, heterochromia, Horner's syndrome, contusion of the eye, retinal hemorrhages, allergies, multiple sclerosis, pernicious anemia, and novocaine block of the ciliary and stellate ganglia. The results showed the permeability of the blood-aqueous barrier to be increased in heterochromia, contusion of the globe, myxedema, hypertensive retinitis, pernicious anemia, allergic conjunctivitis, and iritis. Some cases of myxedema showed normal permeability, however, giving credence to Goldmann's opinion that there may be a "seeming increase" in permeability if, for instance, the osmotic differential of the blood colloids and, with it, that of fluorescein has changed. Some cases of contusion also showed normal values, while other showed patho logically altered ones. Furthermore, permea bility also varied in cases of hypertensive
377
378
PAUL WEINSTEIN AND J. FORGACS
retinitis and glaucoma. Reactions in these two diseases will be described in detail but it is of interest to note here that among the cases of highest increase was one in which simple glaucoma and hypertensive retinitis occurred simultaneously. In this case the fluorescein appeared almost instantly after injection (fig. 1). GLAUCOMA INVESTIGATION
Of the 23 cases of glaucoma studied, six were acute, 11 were chronic inflammatory, and six were chronic simple. The 17 chronic cases showed normal permeability. Two of the six acute cases were investigated during attacks, and permeability proved to be at the upper limits of normal. After the attack, when the eyes softened, the permeability was essentially increased. The same increase was observed in three other cases of acute glau coma, the tests being made after the attacks. In one case of acute glaucoma (the patient had a — 8.0D. myopia), the value was nor mal immediately after an attack. Figure 2 demonstrates permeability dur ing, immediately after, and three weeks after an attack. Our investigations indicate that in creased permeability is present in glaucoma only after an attack of acute glaucoma. This observation seems to bear out Goldmann's statement that, after cyclodialysis or other operations, if ocular tension becomes hypotonic, the increase in permeability is only a
c*
_-2
<Ë
<
MJN
5
10
Þæ
%
3â
30
Fig. 2 (Weinstein). Acute glaucomatous attack, left eye. (1) During attack. (2) Immediately after attack. (3) One week after attack. (4) Three weeks after attack. (Continuous line) Permeability of nonglaucomatous right eye.
"seeming one." Essentially, this is because so-called secretory inhibition is in control, less aqueous humor is being produced, and the concentration of fluorescein is greater (compared to the controls). This increase in permeability after glau comatous attacks may be explained in part by assuming that secretory inhibition also may occur, not invariably, however, as demonstrated by the one case herein de scribed in which permeability was not in creased. In their first report, Amsler and Huber note increased permeability in glaucoma cases; in their later ones they emphasize both possibilities. Guenther found normal values in chronic glaucoma; increased values in acute. However, he does not mention whether the increase in acute glaucoma occurred dur ing or after the attacks. Miller and Swanljung found increased H permeability more frequently in secondary glaucomas; in primary glaucoma they found "*Àߣ%3 no abnormalities in tension, neither increase nor decrease. They also state that permeabil ity may be increased after an attack of acute glaucoma, but that it may also be normal. Leydhecker, investigating the influence of provocative tests, could find no difference 1;0 1*5 10 25 3¼ MINduring the period of increased tension. Our Fig. 1 (Weinstein). Monocular glaucoma sim plex, and hypertensive diabetic retinopathy. (Shaded experience with provocative tests was simi lar. area) Normal permeability.
379
BLOOD-AQUEOUS BARRIER C O N T U S I O N S OF GLOBE
Pathologically increased permeability was also found in those cases of contusion of the globe in which the intraocular pressure was lowered simultaneously; if the damaged eye were not hypotonic, permeability was unchanged. It was, therefore, assumed that contusion sometimes provokes secretory blockage, which explains the hypotension and the seeming increase in permeability. GLAUCOMA OPERATIONS
In this study, three cases of hypotension following glaucoma operations were studied. In two of them (Elliot trephining opera tion), permeability was seemingly increased (fig. 4) as in Goldmann's cases (secretory blockage). In the third case (cyclodialysis), permeability was found to be normal, show ing that hypotension was due not only to secretory inhibition but also to increased drainage. Gonioscopy revealed a broad cyclo dialysis cleft. GANGLION BLOCK
Karczag and Zilahy found, following sympathectomy in rabbits, that the bloodaqueous barrier was lowered. Bakay, Jr., found the same to be true of the blood-plasm barrier. Steiner assumed a dilatation of the cranial vessels following novocaine block of the stellate ganglion, but his findings were
disputed by Harmel and his co-workers. We undertook to investigate the effect of novocain block on either the ciliary or stel late ganglion and learned that, in some cases, there was increased permeability and, in others, no apparent change. Increased per meability occurred (fig. 3) simultaneously with decreased tension (secretory inhibi tion?). In cases of Horner's triad of several years' duration, after extirpation of the stellate ganglion, permeability was increased only if tension were decreased. These experiments by which drugs in increased amounts were introduced into the cerebral substance or the cerebrospinal fluid by simultaneous blocking of the stellate ganglion, seemed to indicate that permeability increased as the amount of the drug increased and that secretory inhibi tion resulted in a higher concentration of the drug. Amsler and his collaborators investigated the permeability of the blood-aqueous barrier in various systemic diseases. They found an increase to be most frequent in cases of dia betes, hypertensive alterations of the fundus, and Kimmelstiel-Wilson disease. We studied cases in which the fundus showed Grade 3 or Grade 4 hypertension (Wagener and Keith) and discovered what appeared to be a new aspect of the fundus alteration. Litzner (1933) reported anemia and baso-
15 Fig. 3
20 25 30
Fig. 4
10
15
20
25 30
Fig. 5
Figs. 3, 4, and 5 (Weinstein). (Fig. 3) Permeability after novocaine block of stellate ganglion, O.D. Horner's syndrome, O.D. Tension: O.D., 20 mm. Hg (Schijzftz) ; O.S., 26 mm. Hg. (Dotted line) Permeability of right eye. (Fig. 4) Chronic inflammatory glaucoma, O.U. Elliot trephining operation, O.D. Tension: O.D. 8.0 mm. Hg (Schδtz); O.S., 20 mm. Hg. (Dotted line) Permeability of the hypotensive right eye. (Fig. 5) Monocular hypertensive retinitis. RBC, three million; hemoglobin, 60 percent. Blood pressure, 230/120 mm. Hg.
380
PAUL WEINSTEIN AND J. FORGACS
philia in a number of cases of glomerulosclerosis. Hypertensive retinitis was also present in all of his cases. Koyanagi pub lished similar findings in 1937. Gonzales Belmonte (1950) stated that, in Grades 1 and 2 of hypertension, the number of erythrocytes increased to compensate for the anoxia which increased as the disease de veloped. Present knowledge indicates that the alterations of hypertensive retinitis are due to anoxia. As erythropoiesis becomes ex hausted, the number of erythrocytes becomes diminished. Swanljung (1951) stated that anoxia increases blood-aqueous permeability in animals. In some of our cases of hypertensive reti nitis, the erythrocyte count was around three million (fig. 5), the hemoglobin count was decreased, and the permeability of the bloodaqueous barrier was increased. We found that, in pernicious anemia, when severe anoxic alterations of the fundus were present, permeability increased as it did in cases of hypertensive alterations of the fundus. The classical research of Stina Bjφrk demonstrated that hypertensive retinitis en sues only if diastolic tension increases and capillary volume decreases, thus causing anoxia. And anoxia, according to our investi gation, produces not only fundus alterations but anemia and a subsequent increase of per meability as well. In some cases of hypertensive retinitis of recent onset, the erythrocyte count and per meability were still normal. Such cases would seem to indicate that the fundus alterations of hypertensive retinitis are not necessarily concomitant to increased permeability, which is confined to the choroidal walls, the retinal circulation proceeding independently. This
evidence even suggests such therapeutic measures in hypertensive retinitis as oxygen inhalation and the administration of iron. Local administration of pilocarpine, histamine, and adrenaline seemed to have no in fluence on permeability; nor did hyaluronidase when it was injected with fluorescein. SUMMARY
The permeability of the blood aqueous barrier was investigated by the Amsler and Huber zero-point fluorescein method in 150 cases of iritis, glaucoma, hypertension, dia betes, chorioretinitis, myxedema, heterochromia, Horner's syndrome, contusion of the globe, retinal hemorrhage, allergies, mul tiple sclerosis, and novocain block of the ciliary and stellate ganglia*. Normal permeability was found in simple chronic and chronic inflammatory glaucoma. It was not essentially increased during acute attacks but was considerably augmented after the attack subsided. Permeability increased only with contusion of the globe. Permea bility increased only if there was simultane ous decrease in ocular tension in cases of Horner's syndrome and after novocaine block of the ciliary and stellate ganglia. This was considered as due to secretory inhibition ("seeming increase," according to Goldmann). The considerable increase in permeability in hypertensive retinitis was frequently as sociated with anemia. In a case of pernicious anemia, permeability was markedly increased (anoxic phenomenon). Pilocarpine, histamine, and adrenaline locally and hyaluronidase intravenously did not influence permea bility. V. Szemelynφk u. 9/11.
REFERENCES
Amsler, M., and Huber, A.: Methodik und erste klinische Ergebnisse einer Funktionsprufung der Blut-Kammerwasserschranke. Ophthalmologica, 111:155, 1946. Amsler, M., Verrey, F., and Huber, A.: Zur Physiopathologie einig Gewebsflussigkeit. Schweiz med. Wchnschr., 77.1921, 1947. Amsler, M.: Le liquide lecunaire de l'oeil: L'epreuve clinicque de la permeabilite de lar barriere hemato-oculaire, Bruxelles Med., 33:17, 1947.
BLOOD-AQUEOUS BARRIER
381
Amsler, M., and Huber, A.: Die Blut-Kammerwasserschranke, ein klinischer Begriff. Arch. f. Ophth., 149 :578, 1949. : Technisches und Principielles zu unseren Fluorescein Test. Ophthalmologica, 121:130, 1951. Bakay, L., Jr.: Die Innervation der Pia mater, der Plexus, chorioidei und der Hirngefasse mit Ruksicht auf den Einfluss des sympathischen Nervensystem auf die Liquorsekretien. Arch. f. Psychiat., 113:412, 1941. Belmonte, Gonzales: Erythema in hypertension retinopathy. Arch. Soc. oftal hisp.-am., 10 :453, 1950. Bernet, M.: Die Wirkung von subconj. hypertonischen Kochsalzlosungen auf die Fluoresceinpermeabilitat der Blut-Kammerwasserschranke. Diss. Zurich, 1950. Bottino, C.: Barriera emat-oftalmica e stimoli luminosi. Ann. Ottal., 77 :281, 1951. Cook, C, and MacDonald, R. K.: Effect of cortisone and the permeability of the blood-aqueous barrier to fluorescein. Brit. J. Ophth., 35:730, 1951. Davson, H.: The aqueous humor and the blood-aqueous barrier. Ophth. Lit., 3:254, 1949. d'Ermo, F.: Antistaminici e occhie: Ricerche sperimentali sul passagio degli antistaminici nella camera anteriore e sulla lore azione sulla barriera ematoftalmica. Boll, d'ocul., 29 :375, 1950. Franceschetti, A., Frommel, E., and Johr, P.: De l'influence de l'acetylcholine sur la permeabilite oculaire. Experientia, 7:35, 1951. Giardini, A., and Swanljung, H.: Effects of anoxia on the fluorescein permeability of the blood-aqueous barrier. Brit. J. Ophth., 35:114, 1951. Goldmann, H.: Ueber die Wirkungsweise der Cyclodialyse. Ophthalmologica, 121:94, 1951. Guenther, G.: Beobachtungen όber die Funktionsprufung der Blut-Kammerwasserschranke nach Amsler und Huber. Ber. Versamml. deutsch, ophth. Gesellsch., 56:121, 1950. Haefeli, W.: Die Fluorescein-Permeabilitat der Blut-Kammerwasserschranke des gesunden Auges. Ophthalmologica, 112:326, 1946. Harmel, M. H., Hafkenschiel, J. H., Austin, J. M., Crumpton, C. W., and Kety, S. S.: The effect of bilateral stellate ganglion block on the cerebral circulation in normotensive and hypertensive patients. J. Clin. Investigation, 28:415, 1949. Hofstetter, M.: Die Wirkung von Calcium auf die Fluoresceinpermeabilitat der Blut-Kammerwasser schranke. Schweiz, med. Wchnschr., 78 :402, 1948. Huber, A.: Zur Pharmakologie der Blut-Kammerwasserschranke. Ophthalmologica, 114:217, 1947. Huber, A., and Walch, J.: Untersuchingen όber Gefass-Permeabilitatsstorungen beim Ekzem: Messun gen der Permeabilitδt der Blut-Kammerwasserschrankc. Dermatologica, 99 :242, 1949. Kalt, M.: Les uveites hypertensives: Etudes clinique, pathogenique et therapeutique. Bull. Soc. franc, d'opht, 62 :48, 1949. Karezag, L., and Zilahy, N.: Ueber die Beeinflussung der Zellpermeabilitat durch den Sympathicus. Biochem. Ztschr., 162:18, 1925. Koyanagi, Y.: Verδnderungen an der Netzhaut bei Hochdruck. XV. Internat. Cong. Ophth., 1:262, 1937. Leydhecker, W.: Permeability of the blood-aqueous barrier to fluorescein during the water-drinking test in glaucomatous eyes. Brit. J. Ophth., 34:480, 1950. Litzner, S.: Ueber das Vorkommen basophil getόpfelter roter Blutkφrperchen bei Schrumpfnieren. Med. Klin., 1933, p. 81. Miller, J. H., and Swanljung, H.: Appearance of fluorescein in the aqueous of glaucomatous eyes. Brit. J. Ophth., 35 :356, 1951. Moreau, A.: Notas acerca del diagnostice etiologice de las iridociclitis. Arch. Soc. Oftal. hisp.-am., 9:967, 1949. Morone, G.: Ricerche sull influenza della vitamina P (citrina) sulla permeabilita dellar barriera ematoftalmica. 36th Cong. Soc. Oftal. Ital. Roma, 1947, p. 500. Pentini, G.: Comportamento della barriera ematoftalmica dopo somministrazione di ACTH. Ann. Ottal., 77:181, 1951. Ruegsegger, P.: Die Fluoresceinpermeabilitat der Blut-Kammerwasserschranke bei haemorrhagischen Diathesen. Diss. Zurich, 1947. Simonelli, M.: Ricerche sulla permeabilita della barriera emato-oftalmica: I. Influenza della somminis trazione di acido nicotinico. Gior. ital oftal. 1:317, 1948; II. Influenza della somminstrazione vitamina C. Ibid., 1:426, 1948. III. Modificazioni riscontrale nei soggetti con distacco di retina. Ibid., 1:432, 1948; IV. Influenza della somministrazione di alcuni fattori vitaminici del gruppo B. Ibid., 1:450, 1948; V. Influenza della somministrazione di vitamina Pz. Ibid., 2:185, 1949; VI. Influenza della somministrazione di vitamina K. Ibid., 2:329, 1949. Simonelli, M., and Calamandrei, G.: Comportamento della permeabilita della barriera emato-oftalmica dopo somministrazione di ACTH. Gior. ital. oftal., 4:340, 1951. Steiner, B.: Orvosi Hetilap., 91.1209, 1950. Stina-Bjork: Haemodynamic factors and retinal changes in hypertensive diseases. Acta med. Scandinav. Supplement, 1946. Stocker, F. W.; Experimental studies on the bloodaqueous barrier: I. New electrophotometric method
382
M. A. L. HASSOUNA
of measuring the concentration of fluorescein in the aqueous. Arch. Ophth., 36:612, 1946; II. Electrophotometric measurements of fluorescein content of aqueous after intravenous injection of fluorescein, the eye being under the influence of physostigmin, pilocarpine, neostigmine, or atropine. Ibid., 37:583, 1947. Widmer, A.: Die Elimination von Fluorescein aus der Augenworderkammer. Diss. Zurich, 1950.
TRACHOMA IN BRIEF* M. A. L. HASSOUNA,
M.D.
Cairo, Egypt ETIOLOGY
As early as 1907, von Prowaczek and Halberstaedter 1 discovered the infective agent of trachoma in Java. In scrapings from the upper tarsal conjunctiva of trachomatous patients they found in some of the superficial epithelial cells definite gran ular formations, inclusion bodies, each oc cupying a good part of the cytoplasm of the cell, often capping the nucleus but sometimes filling the cytoplasm to such an extent that eventually the cell bursts. Stained with Giemsa or more quickly with Wright's or PolefF's stain, the inclusion body is seen to consist of very small bodies or granules which differ in size, shape, and staining properties in different inclusions. Some of them are very minute measuring only 0.25 to 0.30 microns in diameter and staining reddish purple—acidophilic—with Giemsa or Wright (the elementary gran ules) ; while others are larger, measuring 0.6 to 1.5 microns and staining blue—basophilic —with these stains (the initial bodies of Lindner). Both forms may occur extracellularly. The inclusion body, which may contain initial bodies alone, or elementary granules alone', or a mixture of both, measures more than ΊΟ μ.. It is now universally recognized that the minute elementary granules and the larger initial bodies are only two phases of one infective unit, a filterable virus, and that the inclusion body as a whole is the intracellular colony of that virus, the infec* From the Memorial Ophthalmic Laboratory, Giza.
tive agent of trachoma (Thygeson). 2 An early small inclusion body consists mainly of basophilic initial bodies, while a large older one consists primarily of acid ophilic elementary granules, but all stages between the two can be seen. Elementary granules, however, are less frequent in Egyption trachoma than initial bodies. It is suggested that an elementary granule penetrates an epithelial cell in which it grows into a large basophilic initial body which multiplies, poorly though, until the minute acidophilic elementary granules are pro duced, appearing first in the center then proceeding outward. In other words, the early inclusions are basophilic and the later ones are acidophilic. The epithelial cell may then burst liberating the small elementary granules in the conjunctival secretion. From conjunctival secretion in acute cases of trachoma, many extra- (and intra-) cel lular reddish granules can be detected sur rounded by a halo of nonstaining material. They can be concentrated by centrifugation (Thygeson 2 ). A suspension of the material is centrifuged at a low speed (1,500 r.p.m.) for five minutes to eliminate tissue material. The supernatant fluid is then removed and centrifuged at a high speed (15,000 r.p.m.) for 30 minutes in an angle high-speed cen trifuge. This carries most of the active virus to the sediment. The sediment shows elementary granules as already mentioned and, upon inoculation in the upper tarsal conjunctiva of a human volunteer after light scarification of the con junctiva with a platinum spatula (the volun-