THIRD EDITION
`
`I-eoon
`
`' Effects on the Eyes and Visual System from
`Chemicals, Drugs, Metals and Minerals,
`Plants, Toxins and Venoms; also,
`Systemic Side Effects from Eye Medications
`
`
`By
`
`W. MORTON GRANT, M.D.
`David Glendmning Cogan Professor qf Ophthalmology, Emeritus
`. Harvard Univem'gy Medical School
`' Home Laboratory of Ophthalmology
`Massachusetts Eye and Ear Irgfirmaiy
`
`
`
`TOXICOLOGY
`OF THE EYE
`
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`CHARLES C THOMAS 0 PUBLISHER
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`Springfield 0
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`Illinois 0 U.S.A.
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`Argentum Pharm. LLC v. Alcon Research, Ltd.
`Case IPR2017-01053
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`ALC ON 2 I 25
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`

`

`Published and Distributed Thmughout the Win-Id by
`CHARLES C. THOMAS . PUBLISHER
`2600 South First Street
`
`Springfield, Illinois 62717
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`This book is protected by copyright. No part of it
`may be reproduced in any manner without written
`permission from the publisher.
`
`0 1986 by CHARLES C THOMAS - PUBLISHER
`ISBN 0-398-05184-4
`
`Library of Congress Catalog Card Number: 85-17366
`
`With THOMAS BOOKS mmfut attention 1': given to at! details of manufacturing and
`design. It is the Publisher’s data: to present Books that are satzkfactmjt as to (Heir physical
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`
`Printed in the United States ofAmm'ca
`SC—R-E}
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`Library of Congrss Cataloging-in-Publicafian Data
`
`Gram, W. Morton (Walter Morton), 1915-
`Toxicology of the eye.
`
`Bibliography: 13.
`.
`Includes index.
`2. Toxicology.
`1. Eye—Diseases and defects.
`I. Title.
`[DNLMz 1. Eye Injuries-chemically induced.
`2. Vision Disorders—chemically induced‘ WW [0067631]
`RE901.T67G73
`1936
`617.7'1
`'
`85—17366
`ISBN 0898051844
`
`

`

`
`
`986
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`’beicology of the Eye
`
`due to accumulation of xylitol, electrolytes and water when D—xylose is added to the
`medium. Addition of an aldose reductase inhibitor prevents these effects of xylose,
`demonstrating the primary role of this enzyme in the cataractogenic process, similar
`to its role in experimental galactose cataracts.
`
`a. Obazawa H, Merola L0, Kimoshita JH: The effects of xylose on the isolated lens.
`INVEST OPHTHALMOL 13:204-209. 1974.
`b. Patterson JW, Bunting KW: Sugar cataracts, polyol levels and lens swelling. DOCUM
`OPHTHALMOL 20:64—72, 1966.
`
`c. Schrader RE: Morphology and pathogenesis of experimental xylose cataract. GRAEFES
`ARCH OPHTHALMOL 163:422—443, 1961. (German)
`d. Van Heyningen R: Xylose cataract; A comparison between the weanling and the older
`rat. EXP E YE RES 8:379-385, 1969.
`
`Xylyl bromides and chlorides (including o-, mm, and p-isomers) are strongly
`lacrimatory.“l
`
`(See also BromOxylene.)
`
`1 aqueous
`:
`Ytterbium chloride tested on rabbit eyes by applying 0.1 ml of l
`solution at pH 3.05 to 3.78, caused “conjunctival irritation“ and ulceration which
`healed in ninety-six hours.”
`
`Yttrium chloride applied to rabbit eyes as a 0.1 M solution (pH 5.4) for ten minutes
`caused no injury. but similar exposure of eyes from which the corneal epithelium
`had been removed to facilitate penetration of the yttrium chloride resulted in
`immediate slight haziness of the cornea, with subsequent increasing opacity in the
`next several days. Finally the corneas became completely opaque and vascularized.
`Exposure to 0.01 M solution after removal of the epithelium resulted in slight to
`mild permanent opacification.
`Treatment by irrigation with neutral 0.01 to 0.1 M sodium edetate (EDTA) solu-
`tions for fifteen minutes immediately after exposure to yttrium chloride solution
`prevented much of the opacification and vasculariiation. Similar treatment with
`sodium chloride solution was without appreciable effect.88 (Compare Rare-earth salts;
`see INDEX.)
`Zinc chloride and zinc sulfate are described together because they have strong
`similarities in their properties,
`though injuries of the cornea have been more
`commonly related to the chloride than to the sulfate, and most animal experiments
`have been carried out with the chloride. Both salts are white, odorless solids, very
`soluble in water (1 g in 0.5 or 0.6 ml of water, forming slightly acid solutions, pH 4 or
`4.5). Zinc chloride is used in high concentration in soldering fluxes, galvanizing
`baths, sometimes in golf balls, and in “chemosurgery” of skin cancer. Dilute solu-
`tions (0.2% to 1%) have long been used as astringent eyedrops without difficulty, but
`concentrated solutions and pastes such as encountered industrially have caused very
`severe injuries of the cornea in numerous cases of accidental splash in the eye.
`The following description is organized to present information on the toxic effects
`in the following order: (a) human eye injuries from concentrated zinc chloride,
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`Encyclopedia of Chemicals, Drugs, Plants, Extras, and Venom:
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`987
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`(b) eye injuries from concentrated zinc sulfate. (c) animal experiments with zinc
`chloride, and (d) clinical experience with dilute zinc salt solutions.
`
`Human eye injuries from concentrated zinc chloride. These have been reported
`several times since 1903. Lewin and Guillery and Wagenmann summarized what
`had been reported to 1913.153'253 Tillot, according to Wagenmann, reported the first
`case of corneal ulceration and iritis, but eventual partial recovery, after accidental
`splash of a concentrated zinc salt in 1903.
`Zur Nedden reported in detail concerning a workman who splashed a zinc
`chloride solution of unstated concentration in one eye. causing at first only some
`redness, and persistent discomfort, but within six days leading to a discrete stromal
`opacity in‘ the lower part of the cornea with irregularity of the overlying epithelium.268
`The opacity was grayish, located in the anterior layers of the stroma. During the
`next month, while some portions cleared, the remainder became dense white, and
`was thought to be a zinc encrustation. A discrete white opacity covered by epithe-
`lium remained, and because it was in the lower part of the cornea did not affect
`vision. Strader also reported a case of partial irreversible corneal opacification from
`zinc chloride burn.“
`
`Van Lint described a workman who had splashed in one eye a liquid composed of
`zinc chloride, ammonium chloride, iron chloride, and hydrochloric acid, producing
`a hum of the cornea, and subsequently white spots in the front of the lens.° At six
`weeks after the injury the cornea still had stromal infiltration. The lens showed a
`great many white spots of varied shape beneath the anterior capsule, smaller than
`initially. From 2.5 to 6 months after injury the vision recovered only from 1/10 to
`1/5, with a correcting spectacle. The impairment of vision was due to abnormality of
`the cornea rather than to the anterior snbcapsular lens changes. The deeper parts of
`the lens remained normal.
`
`Rzehullta described in detail a patient who had an eye accidentally burned by
`instillation of one drop of 50% zinc chloride solution!" There was immediate severe
`pain, which persisted despite immediate irrigation with water. The corneal epithe-
`lium became eroded. Large folds developed in Descemet's membrane, and the
`corneal stroma was turbid. This was accompanied by severe iritis with small hemor-
`rhages in the iris. Deep and superficial vascularization of the cornea followed. The
`eye was treated with mydriatic and cortisone eyedrops and 5% neutral ammonium
`tartrate eye bath. In four months the cornea cleared sufficiently to permit 6/8 vision.
`De Rose described a workman who splashed a reaction mixture of zinc and
`hydrochloric acid in one eye, causing great pain.a After irrigation of the surface, the
`cornea was found to have lost its epithelium but the stroma appeared transparent.
`Two days later most of the cornea was transparent, but for the first time small
`opacities appeared in the anterior cortical layers of the lens. Vision was reduced to
`1/12 and the intraocular pressure was subnormal. At six days the anterior cortical
`lens opacity was more diffuse and the aqueous turbid. At ten days the surface of the
`cornea was almost healed, but the lens opacity and turbidity of the aqueous were
`more accentuated, and much pigment became deposited on the posterior surface of
`the cornea. The intraocular pressure remained low, and treatment with mydriatics
`and local corticosteroid was continued. At twenty days the patient had acute glau-
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`988
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`Toxicology of the Eye
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`coma with pain, corneal edema, and tension of 50 mm Hg, responding to treatment
`with oral acetazolamide during several days, but at about thirty days from the injury
`the glaucoma and pain returned. The cornea was diffusely clouded by edema and
`much pigment on the posterior surface. A scleral staphyloma developed. Vision was
`so low and pain so great that the eye was enucleated. Histologic examination
`confirmed extensive dissemination of pigment on the back surface of the cornea and
`in the trabecular meshwork. Also, iridocorneal synechias were present irregularly.
`The iris was mostly degenerated, with nearly complete loss of pigment. The lens
`had become cataractous. It was believed that these extensive injuries were attribut—
`able to the action of zinc chloride. The glaucoma was believed to have been due to
`infiltration of the trabecular meshwork with pigment.
`Houle and Pavari—Langston have reported on two patients who had severe damage
`to their eyes from concentrated zinc chloride.“k One of these patients had zinc
`chloride solder-flux paste splashed into one eye. The other patient had his eyes
`accidentally drenched by concentrated zinc chloride solution used in galvanizing
`steel. Both patients within the next day or two developed changes in the appearance
`of their eyes that was remarkably similar to the appearance of eyes that have very
`recently undergone severe acute attacks of angle-closme glaucoma. These eyes had
`extensive corneal edema. with wrinkling of the posterior surface, cells in the aque-
`ous humor, and small discrete spots of gray opacity on the front of the lens, exactly
`like Glaukomflecken. Both patients took many months for subsidence of their
`corneal edema and for recovery of useful vision. Glaucoma was not a problem in
`these patients, but acetazolamide was given with the hope of making the intraocular
`pressure lower than normal. Corticosteroids given systemically seemed to help
`relieve discomfort and photophobia that developed after the corneal epithelium
`(and presumably the corneal nerves) regenerated. In these cases, as in those previously
`described in the literature, the spots in the lenses that were evident within the first
`few days after injury not only looked like Glaukomflecken. but also subsequently
`behaved like Glaukomflecken, persisting, but tending to becomesmaller, and caus-
`ing no significant trouble. The corneas were the great problem.
`In treatment of cancer of the eyelid and closely neighboring skin. Mohs has used
`a saturated solution of zinc chloride made into a paste by addition of powdered
`stibnite (antimony trisulfide) and sanguinaria powderfi'h Fortunately, injury to the
`eye has [not occurred. This may be explained by the factthat the paste has been
`applied to the outer surface of the eyelid, and care has been taken not to bring the
`paste into direct contact with the eye.
`
`Human eye infufies from concentrated zinc sulfate solutions. These seem all
`to have been reported in the 1950’s as a complication of use of 20% zinc sulfate
`solution for treatment of dendritic keratitis, recurrent erosion, and ulcus serpens.
`Prior to 1955 the application of 20% zinc sulfate solution on a swab directly to such
`ulcers was considered to be fairly safe, and though some cursory mention had been
`made of occasional delicate branching opacities which had developed under the
`anterior lens capsule. such c0mplications were considered to be rareJ-‘xi Pillat presented
`the first detailed description of cases of white flecks induced in the lens after
`cauterization of the cornea with 20% zinc sulfate, having the characteristic appear-
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`Encyclopedia of Chemicals, Drugs, Plants, Toxins, and Venoms
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`989
`
`ance of the “Glaukomflecken” of Vogt, such as typically are associated with acute
`attacks of glaucoma, but Pillat established that in these cases there were no eleva-
`tions of intraocular pressure}
`Filipovic reported that in three cases cauterization of herpetic dendritic keratitis
`with 20% zinc sulfate solution caused Glaukomflecken to appear by the next day.b
`The corneas became gray, but cleared while the flecks in the lenses remained. The
`same author noted that he had used 10% zinc sulfate solution in treating dendritic
`keratitis in three children, and that this had cured the keratitis and had caused no
`
`lens opacities. (All reports of Glaukomflecken had involved use of more concen-
`trated solution in adult patients.)
`
`Am'fizal experiments with zinc chloride solutions. Experiments probably were
`undertaken before 1885, according to Hoffman, who mentioned that application of
`zinc chloride to frogs‘ eyes had been reported to cause purulent keratitis,d but the
`first significant observations from experiments appear to have been made by Zur
`Nedden, who experimented on enucleated pig eyes.268 He found that 'he could
`produce a grayish. but not a white, opacity of the cornea by applying zinc salts, and
`this could be done easier with zinc chloride than zinc sulfate. His experiments led
`him to believe that the opacifications were due to formation of a zinc—mucoid
`precipitate, not due to a zinc-collagen combination, and he concluded that there was
`little or no formation of zinc carbonate.
`
`Cuillery found that when he applied 50% zinc chloride solution repeatedly to one
`eye of an albino rabbit, it caused opacity of the cornea, and that six days later the eye
`had become very hard. with extensive hemorrhage in the anterior segment, and that
`there was much infiltration with inflammatory cells, loss of corneal endothelium,
`and clouding of the anterior portion of the lens.96
`Johnstone and Sullivan investigated whether using sodium edetate (EDTA) in
`first aid treatment of eyes contaminated with zinc chloride might be beneficial.f
`They measured the turgescence properties of pieces of bovine cornea in water and
`obtained evidence that denaturation or fixation occurred when cornea was brought
`into contact with zinc chloride solution. When pieces of cornea were exposed to 50%
`zinc chloride solution and were subsequently placed in water they were found to
`have lost 85% of their normal capacity to swell, and only about 5 per cent of their
`normal swelling capacity could be restored by treatment with edetate. When cornea
`was exposed to only 1.36% (0.1M) zinc chloride solution, the swelling in water was
`similarly inhibited, but by treatment with edetate about half of the swelling capacity
`was restored.
`
`Johnstone and Sullivan exposed the eyes of rabbits to 50% zinc chloride solution in
`a standard manner for one minute. When the eyes were irrigated with 0.05 M
`sodium edetate, starting one minute after termination of exposure to zinc chloride,
`the corneas developed during the next four days a degree of opacification similar to
`that of the corneas irrigated with sodium chloride, but then they showed progressive
`improvement, and by two weeks had relatively slight residual opacity. The edetate—
`treated eyes b‘ecame strikingly better than those irrigated with sodium chloride.
`Unfortunately, if the interval from termination of exposure to beginning of irriga~
`tion with edetate solution was increased to five minutes, the treatment gave no
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`990
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`Toxicology of the Eye
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`evident benefit, and at two weeks the corneas were densely opaque. It was concluded
`from these experiments that irrigation with neutral sodium edetate solution would
`be worthwhile in immediate or first aid treatment of patients who had splashed zinc
`chloride into their eyes, but that it would have to be started very quickly to be of
`benefit.
`
`Clinical experience with dilute zinc salt solutions. As already mentioned,
`solutions up to 1% concentration appear almost never to have caused injury, but
`Paul reported a single case in which a patient’s cornea developed an intense white
`precipitate in one small portion of an ulcerated area that had been treated repeatedly
`over a long time with 0.5% to 1% solution of zinc salt, probably zinc sulfate. He
`considered this to beat zinc encrustration rather than a burn)
`
`a. DeRosa C: On a case of severe ocular caustic action ofa zinc salt. RASS ITAL OTTALMOL
`
`28:280—290, 1959. (Italian)
`I]. Filipovic A: On prevention of Vogt's acute subepithelial disseminated cataract after zinc
`hum of the cornea. KLIN MONATSBL AUGENHEILKD 1331263-269, 1958. (German)
`1:. Fleischanderl A: On treatment of recurrent erosionJflJN MONATSBL AUGENHEILKD
`
`125:747-748, 1954. (German)
`d. Hoffman FW: On keratitis and the development of hypopyon. BER OPHTHALMOL
`GESELLSCH HEIDELBER017W67—80 1885. (German)
`e. Houle RE, Grant WM: Zinc chloride keratopathy and cataracts. AM ] OPHTHALMOL
`75:992—996, 1973.
`
`f. Johnstone MA, Sullivan WR, Grant WM: Experimental zinc chloride ocular injury
`and treatment with disodiurn edetate. AM I OPHTHALMOL 76:137—142, 1973.
`g. Mohs FE: Chemosurgiml treatment of cancer of the eyelid. ARCH OPHTHALMOL
`39:43—59, 1948.
`
`h. Mobs FE: Chemosurgery. NE W YORK I MED, Apr 1, 1968, pp. 871~876.
`i. Nemetz U: On the question of acute glaucomatous cataract. KLIN MONATSBL A UGEN
`HEILKD 115:417—421, 1949. (German)
`j. Paul L: 011 corneal ulcerations [tom diplobacilli. KLIN MONAII‘SBL AUGENHEILKD
`43:154484, 1905. (German)
`k. Pawn-Langston D: Personal communication, 1970.
`l. Pillat A: On the development of Vogt‘s acute anterior subepithelial disseminated
`cataract alter zinc hum of the cornea. KLIN MONATSBI. AUGENHEILKD 126:561—568,
`1955. (German)
`m. Rzehullm G: On bums of the eye with zinc chloride. KLIN MONATIS'BL A UGENHEILKD
`130:53SL544, 1957. (German)
`
`n. Stradei-z COLORADO OPHTHALMOL SOC 21, 1908. (Reference from Guillery, 1910.96)
`0. Van Lint M: Vogt’s subepithelial disseminated cataract of traumatic origin. BULL SOC
`BELGE OPHTALMOL 72:62—65, 1936. (French)
`
`Zinc phenosulfonate (zinc sulfocarbolate) has been used as an astringent, and
`insecticide.171 A single instance has been reported in which use of a 3% solution in
`eye compresses resulted in complete necrosis of both corneas of an infant.3 Experi-
`mental application of this solution eight times to the eye of a rabbit caused the
`cornea to become completely opaque in seven days.
`
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`Encyclopedia of Chemicals, Drugs, Plants, 72mins, and Venoms
`
`991
`
`a. Velhagen K: A disastrous iatrogenic eye injury. KLIN MONATSBL AUGENHEILKD
`1261580—585, 1955.
`
`‘Zinc pyrithione (zinc pyridinethione; zinc omadine; zinc-2-pyridinethion—l—oxide‘;
`the zinc chelate of pyrithione) is an antifungal, antibacterial compound that has
`been used as an antidandruff agent in shampoo formulations, such as Head and
`Shoulders Shampoo. When tested on rabbit and monkey eyes by application of 0.5%
`to 2% suspensions as used in shampoos. it was found not to be injurious,"-c although
`1% in dimethyl sulfoxide caused irritation comparable to 70% isopropyl alcohol}-62
`Systemic administration of zinc pyrithione, and also pyrithione itself, has demon-
`strated interesting species differences in toxic effects. When zinc pyrithione has been
`administered systemically to dogs, it has produced blindness, associated with detach-
`ment of the retina. This same effect was produced by pyritlu'one without zinc.
`However, no such effects on the retina were produced in rats, rabbits, or monkeysfi-fid
`In cats, orally administered zinc pyrithione has caused tapetal degeneration and
`atrophy, but not the Severe reaction seen in dogs, which have shown not only
`degeneration of tapetal cells but also tapetal and retinal inflammation with intraretinal
`hemorrhage, and subretinal edema leading to retinal detachment and blindness.a
`It has been of partiCular interest that normal beagle dogs which have a tapetum
`lucidum show this reaction, While another variety of beagle dog which lacks a
`tapetum lucidum does not show injury. This corresponds to lack of reaction in
`monkeys, human beings, rats and rabbits which also do not have this structure.
`It is of interest, as pointed out by Cloyd et al, that the tapetum lucidum is
`rich in zinc, and that certain metal chelating agents (dithizone and diethyldithio—
`carbamate) injure the normal dog's eye in the same manner as pyrithione and
`zinc pyrithione.a However, they also point out that ethambutol and related com—
`pounds that can chelate the zinc of the tapetum lucidum only cause a loss of
`color of the tapetum which is reversible. and do not cause inflammatory and
`degenerative changes. Cloyd et al have suggested that zinc pyrithione (as well
`pyrithione. dithizone, and diethyldithiocarbamate) may not only chelate some of
`the zinc of the tapetum but may also react with sulfhydryl groups that are necessary
`for important metabolic processes in that region. (See INDEX for Pyrithione, DiZhizone,
`and D'ethyldt'thiocarbamate.)
`
`a. Cloyd GG, Wyman M, et al: Ocular toxicity studies with zinc pyridinethione. TDXICOL
`APP]. PHARMACOL 45:771—782, 1978.
`h. Opdylte DL, Burnett CM, Brauer FAN: Antiseborrheic qualities of zinc pyrithione in a
`cream vehicle. II. Safety evaluation. FOOD COSMET TOXICOL 5:321—326, 1967.
`c. Snyder FH. Buehler EV, Winak CL: Safety evaluation of zinc 2—pyridinethiol—1—oxide
`in a shampoo formulation. TOXICOL APPL PHARMACOL 7:425—437. 1965.
`d. Winek CL, Buehler EV: Intravenous toxicity of zinc pyridinethione and several zinc
`salts. TOXICOL APPL PHARMACOL 9:269-273, 1966.
`
`Zinc sulfide, a pigment, has been identified in the tissues of the conjunctivae and
`lids of two children who were accidentally squirted with material from the liquid
`center of golf balls. The zinc sulfide, as well as barium sulfate which was similarly
`encountered, produced only slight mauophage reaction and negligible tissue damage.8
`
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`992
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`Toxicology of the Eye
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`21'. Johnson FB, Zimmerman LE: Barium sulfate and zinc sulfide deposits resulting from
`golf-ball injury to the conjunctiva and eyelid. AM J CLIN PATH 411-533—538, 1965.
`
`Zinc systemic levels, particularly the concentrations measured in the plasma or
`serum, are found to be subnormal in certain diseases and some toxic conditions.
`
`Reviews of the biochemistry and physiology of zinc make clear that zinc has many -
`important natural functions in the eye, but adverse effects on the eyes that may
`result from deficiencies of zinc are much less well deiinediP
`
`The following are some of the clinical correlations that have been made in which
`no toxic substances were involved and ocular effects were believed to be secondary to
`reduction of systemic zinc levels by systemic diseases. In chronic liver disease, such
`as alcoholic cirrhosis, dark adaptation has been impaired,3-iv"‘ and in some patients
`dark adaptation improved when zinc was administered; in these patients treatment
`with vitamin A had failed!" Similarly in a patient who had abnormal dark adapta-
`tion associated with Crohn’s disease and low serum zinc, there was improvement of
`the dark adaptation when zinc was administered.l Another patient with Crohn’s
`disease, and very low serum zinc following parenteral administration of nutrition,
`had paracentral scotomas which disappeared when the zinc deficiency was corrected.h
`In rats, severe diet—induced zinc deficiency has caused accumulation of osmiophilic
`inclusion bodies in the retinal pigment epithelium and degeneration of outer
`segments of photoreceptors.It Patients with dietary zinc deficiency, or failure to
`absorb zinc, as in acrodermatitis enteropathica, may have serious general effects
`without visual symptoms.
`When exposure to toxic substances is associated with low zinc levels, it is difficult
`to assess the role of the deficiency of zinc in adverse effects on the eyes. The
`following are circumstances involving tOxic substances and adverse effects on the
`optic nerves with decrease of vision. sometimes optic atrophy, associated with
`subnormal plasma or serum zinc.
`In 1975 Samux and colleaguesn followed up earlier reports of effects of ethambutol
`on zinc in experimental animals (see INDEX for Ethambulol), and reported that a
`single serum zinc measurement in each of 3 patients with retrobulbar neuritis and
`central scotoma from ethambutol (plus ioniazid in 2 of the patients) shawed subnor—
`mal zinc levels averaging 0.75 mg/l compared to normal controls of 1.09 mg/l. Also
`they reported that one patient with optic neuropathy from disulfiram (see INDEX
`for Dz'sulfimm] had 0.95 mg/l. Furthermore, they found that out of 7 patients with
`alcohol-tobacco retrobulbar neuritis, 3 had zinc levels as low as 0.75, while the other
`
`4 were in the range of 0.90 to 1.00.‘‘1 However, subsequent measurements before and
`after varying periods of treatment with ethambutol {for tuberculosis) did not Show a
`reduction of zinc levelsfivdve [t was then suggested that when pre-treatment zinc
`levels were low this increased the risks of retrobulbar neuritis.d-'a This Was supported
`by an observation that of 108 patients with pre-treatment plasma zinc above 0.8 mg/l
`none had any visual disturbance, but that 7 out of 20 with zinc below 0.8 mg/l had
`decreased visual acuity with central scotoma; 3 of these appeared to have macular
`degeneration.e
`'
`_
`The relationshipof alcohol-tobacco amblyopia and systemic zinc. after the report by
`Saraux,“ were studied further by Gerhard in 1982,‘ finding in half the cases serum
`
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`"zinc ranged from 0.45 to 0.85 mg/l, compared to normal values of 1.0 to 1.2 mg/l.
`These patients had evidence of alcoholic cirrhosis which might acc0unt for the
`abnormal zinc levels. In another 52 cases of alcohol-tobacco optic neuropathy,
`Bechetoille and colleagues found significant subnormality of systemic zinc levels,
`slight subnormality of magnesium, normal copper, and lead above normal.a Eight
`patients with central scotomas attributed to alcohol and tobacco were given 400 mg
`of zinc sulfate per day, and nine others were given a placebo. (No vitamins were
`given, but alcohol intake and smoking were reduced during the trial.) After a month
`the visual acuity and color vision were improved in both groups. but not significantly
`more in the treated than in the control group. Only by special examination of the
`central 5°‘of visual field with the Friedmann analyzer was there evidence of some
`superiority in those with the zinc treatment.13
`In another group of 10 patients with alcohol-tobacco retrobulbar neuritis, Grignolo
`found serum zinc significantly lower than in 10 controls. Then, after 60 days of
`medical treatment (not described), 6 of 10 had improvements in visual acuity, visual
`field or chromatic sense, and these patients showed increase in their zinc levelsfi
`Iodoquinol (diiodohydroxyquin) formerly was used in treatment of acrodermatitis
`enteropathica, an inherited disease with failure of zinc absorption. which now is
`more effectively treated by administering zinc. (See INDEX for Iodoquz'nol.) The old
`treatment with iodoquinol may have aided absorption of zinc, but in a small number
`of cases the treatment led to optic atrophy. Acrodermatitis enteropathica is gener—
`ally lethal when untreated, but, since it is not known to cause optic neuropathy,
`some have considered that the optic atrophy associated with iodoquinol treatment to
`be a toxic effect of the drug. Others have proposed that the optic neuropathy might
`be attributable to severe zinc deficiency, and that the iodoquinol merely helped the
`patients to survive long enough to manifest the optic neuropathy from the deficiencyP’P
`If any conclusion is warranted, it seems to be that the relationship of zinc defi—
`ciency to optic neuropathy is in need of further study.
`a. Bechetoille A, Allain P, et al: Modifications of blood concentrations of zinc and lead
`
`and the activity of ALAdehydratase in the course of alcohol-tobacco optic neuropathies.
`I FR OPHTALMOL 63:231-435. 1983. (French)
`b. Bechetoille A, Ebran JM, et a1: Therapeutic effect of Zinc sulfate on the central scotoma
`of alcohol-tobacco optic neuropathies. ] FR OPHTALMOL 6:237-242, 1983. (French)
`c. Campbell IA, et al: Ethamhutol and the eye; zinc and copper. LANCET2z'711, 1975.
`cl. Deloux E, Moreau Y, et al: Prevention of ocular toxicity of ethambutol. 1 FR
`OPHTALMOL 1:191—196, 1978. (French)
`e. Fioretli F, Minervino M: Zincemia as a clue to the ocular toxicity of ethambutol. ANN
`OTTALMOL CLIN OCUL 106:543~548, 1980. (Italian)
`f. Gerhard JP: On an advanceconcerning ocular zinc. BULL SOC OPHTALMOL FRANCE
`82:1125—1127, 1982. (French)
`g. Grignolo FM, La Rosa G, et al: Evaluation of plasma zinc in retrobulbar optic
`neuropathies. BOLL OCULIST 59:801—821. 1980. (Italian)
`h. Haas]: Acute zinc deficiency syndrome. AKTUEL NE UROL 9:55—57, 1982. (German)
`
`i. Karcioglu ZA: Zinc in the eye. SURVEY OPHTHALMOL 27:114—122, 1982.
`j. Keeling PWN, O‘Day J, et al: Zinc deficiency and photoreceptor function in chronic
`liver disease. CLIN SCI 62:109-111, 1982.
`
`

`

`Tbxicologj! of the Eye
`
`. Leure—duPree AE, Mc Clain C]: The effect of severe zinc deficiency on the morphology
`of the rat pigment epithelium. [N VEST OPHTHALMOL VIS SCI 23:425—434, 1982.
`. Mc Clain C], Su LC, et al: Zinc-deficiency—induced retinal dysfunction in Crohn’s
`disease. DIG DIS SCI 28:85—87, 1983.
`
`. Morrison SA, Russell RM, et a1: Zinc deficiency: A cause of abnormal dark adaptation
`in cirrhotics. AM ] CLIN NUTR 31:276—281, 1978.
`, Samux H. Bechetoille A, et al: The diminution of the level of serum zinc during some
`toxic optic neuritis cases. ANN OCULIST 208:29—31, 1975. (French)
`. Sturtevant FM: Zinc deficiency, aa‘odermatitis enteropathica, optic atrophy, subacute
`myelo—opticmeuropathy, and 5,7-dihalo-8-quinolinols. PEDIATRICS 65:61M13, 1980.
`. Wong EK Ir, Leopold 1H: Zinc deficiency and visual dysfunction. METAB PEDIAH
`OPHTHALMOL 321—4, 1979.
`
`Zyldon A, a fumigant mixture of 90% methyl cyanocarbonate and 10% methyl
`chlorocarbonate, was inhaled and caused acute poisoning in a man who survived
`collapse and convulsions, but then had reduced visual acuity with macula edema. In
`subsequent weeks the visual acuity returned essentially to normal, but many pig-
`ment flecks developed in the fundi, particularly in the neighborhood of the foveas.
`The patient died with nephrosis 2 months after poisoning.
`
`a.
`
`Illig KM: Retinal injury by cyanide poisoning. KLIN MONATSBL AUGENHEILKD
`120:310—312, 1952. (German)
`
`